New Macrocyclic LRRK2 Kinase Inhibitors

Abstract

Compound of formula (I): #imgabs0# wherein R, X1, X2, X3, Z1, Z2, Z3, A and Ra are as defined in the present specification. A medicament.

Description

Field of the Invention

[0001] The present invention relates to novel macrocyclic compounds and compositions containing said compounds, which are used as kinase inhibitors, in particular as inhibitors of LRRK2 (leucine-rich repeat kinase 2). In addition, the present invention provides methods for preparing the disclosed compounds, pharmaceutical compositions containing them, and methods of using them, such as for use as a medicament or diagnostic agent, in particular for the treatment and / or diagnosis of diseases affected or regulated by LRRK2 kinase activity, such as neurological disorders, including Parkinson's disease and Alzheimer's disease, and heart diseases or inflammatory disorders, such as Crohn's disease. Background of the Invention

[0003] 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 over 65 years of age and is characterized by four typical core motor complications: resting tremor, bradykinesia, postural instability, and muscle rigidity. Patients with Parkinson's disease are also affected by many non-motor symptoms, such as constipation, hyposmia, orthostatic hypotension, sleep disturbances (including REM sleep behavior disorder), dementia, visual disturbances, depression, anxiety, hallucinations, and mood swings.

[0004] The standard of care for Parkinson's disease is the use of dopamine replacement therapies such as the dopamine precursor L-dopa, dopamine agonists, or compounds that affect the dopamine half-life such as MAO-B inhibitors to relieve the symptoms of motor complications. So far, there is no approved therapy to prevent, cure, or delay the progression of Parkinson's disease.

[0005] The pathological hallmark of Parkinson's disease is the loss of dopaminergic neurons in the substantia nigra pars compacta and the postmortem evidence of proteinaceous inclusions (also known as Lewy bodies and Lewy neurites). Lewy bodies and neurites are observed throughout the central nervous system in postmortem tissues from patients with Parkinson's disease and also in peripheral tissues. The major component of the inclusions is aggregated misfolded α-synuclein protein, which is phosphorylated at serine at position 129 (Nature 388, 839–840, 1997; Nat Cell Biol 4, 160–64, 2002). Lewy bodies and neurites also contain proteins implicated in other neurodegenerative diseases, such as hyperphosphorylated tau protein, 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 of Parkinson's disease is not limited to the loss of dopaminergic neurons in the basal ganglia system. Different neuronal populations in other brain regions such as the neocortex, sleep nuclei (or raphe nuclei of the pons) in patients with Parkinson's disease and also in peripheral organs and tissues such as the heart and gastrointestinal system are also affected by the degenerative process.

[0006] Leucine-rich repeat kinase 2 (LRRK2) is a 2,527-amino acid protein with a molecular weight of 286 kDa encoded by the LRRK2 gene. It consists of the following functional and structural protein domains: armadillo (ARM), ankyrin (ANK), leucine-rich repeats (LRR), Ras of complex domain (ROC), C-terminal of Roc (COR), map kinase (MAPK), and tryptophan-aspartic acid repeat domain (WD40). LRRK2 mainly exists in the form of a dimerized protein associated with the membrane structure or cytoplasmic localization. The ARM, ANK, LRR, and WD40 protein-protein interaction domains enable LRRK2 to interact with many different protein partners and affect the subcellular localization of its partner proteins. The central enzymatic core of the LRRK2 protein containing the Roc-COR and MAPK domains has different GTPase and ATPase enzymatic activities, which enable LRRK2 to phosphorylate and control the functions of intracellular substrates. LRRK2 affects various subcellular processes and biological mechanisms important for the transport of intracellular vesicle structures and organelles such as lysosomes, endosomes, autophagosomes, Golgi apparatus, and mitochondria through its enzymatic activity and substrate interactions. Structural work and modeling have highlighted how naturally occurring missense variants in the functional and structural domains of LRRK2 affect enzymatic activity (bioRxiv 2020.01.06.895367). In the inactive (open) LRRK2 conformation, there is a major interaction between the GTPase (ROC-COR) and ATPase (MAPK) domains of the enzyme. In addition, the final C-terminus of the WD40 domain binds along the entire kinase (MAPK) domain. In the active (closed) LRRK2 conformation, the LRR domain positions the autophosphorylation site Ser1292 near the kinase active site. Phosphorylation of LRRK2 at a serine cluster immediately before the LRR domain enables the LRR domain of LRRK2 to bind 14-3-3 proteins. These phosphorylation sites include serine (Ser) at the following amino acid positions: Ser910, Ser935, Ser955, and Ser973. Pathogenic LRRK2 mutations originating from the GTPase domain have reduced phosphorylation at these sites, thus reducing 14-3-3 binding, which leads to increased microtubule network recruitment. All ATP-competitive LRRK2 inhibitors induce dephosphorylation at the Ser910, Ser935, Ser955, and Ser973 sites, which enables these sites to be used as alternative target engagement markers (Biochem J 430(3), 405-13, 2010; JNeurochem 120(1), 37-45, 2012). True LRRK2 substrates consist of a subset of small Rab GTPases including Rab10 and Rab29.The Golgi-resident protein Rab29, also known as RAB7L1, is a Parkinson's disease susceptibility gene located at the PARK16 locus (Nat Genet 41(12), 1308-12, 2009).

[0007] Rare protein-coding variants in the LRRK2 gene cause Parkinson's disease. The most common pathogenic variant causing autosomal-dominant familial Parkinson's disease is the p.G2019S substitution, which changes glycine to serine in the activation loop of the LRRK2 kinase domain, making the p.G2019S variant more active than the wild-type LRRK2 protein (Lancet 365(9457),412-5,2005). This results in increased autophosphorylation of serine at amino acid position 1292 (Sci Transl Med,4(164),164ra161,2012). The estimated global prevalence of the p.G2019S mutation in Parkinson's disease patients is 1-2%; however, in the Ashkenazi Jewish and North African Arab populations, the prevalence of p.G2019S in Parkinson's disease patients is as high as 30% and 40% respectively (Lancet Neurol 7,583–90,2008; N Engl J Med 354(4),424-5,2006; Lancet Neurol 7,591–4,2008). The clinical manifestations of Parkinson's disease in patients carrying the p.G2019S mutation are indistinguishable from those of patients with the sporadic form of Parkinson's disease (Ann Neurol 57(5),762-5,2005). In addition to p.G2019S, seven other rare LRRK2 exon variants with non-synonymous amino acid substitutions in the central enzyme core (p.N1437H; p.R1441C / G / H; p.Y1699C; p.S1761R; p.I2020T) also cause autosomal-dominant Parkinson's disease (Parkinsonism RelatDisord 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 Neurol57(6),918-21,2005; Mov Disord 27(1),146-51,2012). Like p.G2019S, the clinical manifestations are indistinguishable from those of idiopathic Parkinson's disease (Neurology 70,1456–60,2008).LRRK2 missense variants exhibit increased Ser1292 phosphorylation, increased trans-Golgi recruitment of Rab29, and increased phosphorylation of Rab10 at amino acid position 73 (Rab10-Thr73), which can be reversed by LRRK2 inhibition (Sci Transl Med 4(164),164ra161,2012; EMBO J37(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 the 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 have increased kinase activity (bioRxiv 447946,2018) (Proc Natl Acad Sci USA 116(5),1579-1584,2019), while the p.N551K variant is associated with a reduced risk of Parkinson's disease (Lancet Neurol 10(10),898-908,2011) and has reduced kinase activity (bioRxiv 447946,2018). Evidence that LRRK2 also plays a role in sporadic Parkinson's disease comes from genetic studies and autopsy analyses of Parkinson's disease brains. Single nucleotide polymorphisms (SNPs) at the LRRK2 locus are genome-wide associated with the risk of Parkinson's disease (Nat Genet 46(9),989-93,2014). This particular SNP variant is associated with increased LRRK2 expression (Sci Transl Med 9(421),2017), which is consistent with increased LRRK2 kinase activity observed in surviving dopaminergic neurons in autopsy brains from patients with sporadic Parkinson's disease (Sci Transl Med 10(451),2018).

[0008] Thus, inhibitors of LRRK2 kinase activity can be used to treat patients with sporadic Parkinson's disease and patients with Parkinson's disease with LRRK2 mutations or Rab29 / Rab7L1 polymorphisms.

[0009] 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, have been identified through genome-wide association studies (GWAS) and linkage studies. LRRK2 also plays a key role in the endosomal-lysosomal system and in processes related to endosomal function, such as autophagy and mitophagy. LRRK2 interacts with the vacuolar H+-ATPase α subunit to regulate lysosomal pH, and LRRK2 inhibition can alleviate rotenone-induced endosomal-lysosomal dysfunction (Neurobiol Dis 134,104626,2020), a toxin known to be associated with an increased risk of Parkinson's disease. Disease-causing LRRK2 mutations induce lysosomal stress by enlarging lysosomes (Hum Mol Genet 24(21),6013-28,2015). Similarly, a missense mutation of aspartic acid to asparagine at amino acid position 620 in the retromer complex protein VPS35 (VPS35-D620N) causes late-onset autosomal dominant familial Parkinson's disease. In the disease state, the VPS35-D620N missense mutation disrupts the trafficking of cathepsin D, a protease responsible for α-synuclein degradation (Traffic 15(2),230-44,2014) and activates LRRK2, which leads to increased autophosphorylation at the LRRK2-Ser1292 site and increased phosphorylation of Rab10-Thr73 (Biochem J 475(11),1861-1883,2018). In lysosomes, LRRK2 interacts with GBA, which has a causal relationship with the risk genes of lysosomal storage disorder Gaucher disease and Parkinson's disease. The reduction of LRRK2 missense mutations can counteract GBA activity (Nat Commun 10(1),5570,2019). Conversely, GBA disease-related defects in lysosomal biology in astrocytes can also be alleviated by LRRK2 inhibition (Mov Disord February 8, 2020, doi:10.1002 / mds.27994). Missense mutations in the mitochondrial kinases PINK1 and the E3 ligase PARKIN both cause autosomal recessive early-onset Parkinson's disease associated with mitochondrial dysfunction (Science 304(5674),1158-60,2004; Nature 392(6676),605-8,1998).LRRK2-dependent phosphorylation of Rab8a at threonine at amino acid position 72 is regulated by PINK1 phosphorylation of serine at amino acid position 111 on Rab8a (Biochem J. Mar 30, 2020, doi: 10.1042 / BCJ20190664). In addition, this LRRK2 activity impairs mitophagy, which is regulated by the PINK1 / PARKIN pathway under normal conditions. This can be reversed by LRRK2 inhibition (Hum Mol Genet 28(10), 1645-1660, 2019). LRRK2 missense mutations cause mitochondrial DNA damage, which can be corrected genetically (Neurobiol Dis 62, 381-6, 2014) and reversed with LRRK2 inhibitors (Hum Mol Genet. 26(22), 4340-4351, 2017).

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

[0011] Autopsy analyses of brains from Parkinson's disease patients carrying LRRK2 mutations revealed the presence of β-synucleinopathy (JAMA Neurol. 72(1), 100-5, 2015). In preclinical Parkinson's disease (PD) models, p.G2019S exacerbated PD-related pathologies that could be reversed by LRRK2 inhibition. LRRK2 has been identified in Lewy bodies in the substantia nigra and brainstem regions (Neuropathol Appl Neurobiol 34(3), 272-83, 2008), and has also been shown to phosphorylate α-synuclein at Ser129 (Biochem Biophys Res Commun 387(1), 149-52, 2009). LRRK2 exon variants are associated with the risk of multiple system atrophy (Neurology 83(24), 2256-61, 2014), and LRRK2 missense mutations have also been reported in patients with multiple system atrophy (J Parkinsons Dis; 8(1), 93-100, 2018). Single nucleotide polymorphisms in the MAPT (tau) locus are associated with an increased risk of Parkinson's disease and multiple system atrophy (Hum Genet 124(6), 593-605, 2009; Parkinsonism Relat Disord 30, 40-5, 2016). Tau pathology is also a prominent feature observed in Parkinson's disease patients with LRRK2 missense mutations (Acta Neuropathol Commun 7(1), 183, 2019). Overexpression of pathogenic LRRK2 in animal models increases Tau pathology (Neurobiol Dis 40(3), 503-17, 2010). LRRK2 missense mutations have been reported in patients with tauopathies such as progressive supranuclear palsy and corticobasal degeneration (Mov Disord. 32(1), 115-123, 2017). Common variants at the LRRK2 locus are associated with survival in the primary tauopathy progressive supranuclear palsy (bioRxiv 2020.02.04.932335), and GWAS studies have identified the risk of frontotemporal dementia at the LRRK2 locus (PLoS Med 15(1), e1002487, 2018).

[0012] This suggests that LRRK2 inhibitors could be used to treat synucleinopathies and tauopathies, including frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, and Alzheimer's disease.

[0013] LRRK2 mRNA and protein are widely expressed, but are particularly abundant in the brain tissue and in peripheral organs, more specifically the kidney, lung, intestine, and spleen. In addition, LRRK2 expression is highly enriched in immune cells of the brain and in neutrophils, B cells, macrophages, and monocytes in the periphery. LRRK2 mRNA and protein expression are induced after pro-inflammatory stimuli or pathogens, thereby increasing LRRK2 kinase activity. In human peripheral blood monocytes, the LRRK2 substrates Rab10 and Rab12 are phosphorylated after stimulation with reagents mimicking viral infection (Sci Rep 7(1),10300,2017). Consistent with LRRK2 biology playing a role in the response to inflammatory stimuli, LRRK2 missense mutations are associated with the risk of inflammatory bowel disease Crohn's disease, and GWAS studies have identified single nucleotide polymorphisms in the LRRK2 locus that are genome-wide significantly associated with Crohn's disease (Inflamm Bowel Dis 17(12),2407-15,2011). In the Ashkenazi Jewish population, the prevalence of Crohn's disease is increased 2- to 4-fold, and in the same population, LRRK2 variants are associated with an increased risk of Crohn's disease (PLoS Genet 14(5),e1007329,2018). LRRK2 exon variants such as p.N2081D and p.M2397T increase the risk of Crohn's disease, and, as observed for Parkinson's disease, the protective haplotype variant p.N551K / p.R1348H reduces the risk of Crohn's disease. In cell-based studies, the p.N2081D variant has increased kinase activity, which results in enhanced Rab10 phosphorylation (bioRxiv 447946,2018; Sci Transl Med 10(423),2018). The biological link between Parkinson's disease and autoimmune disorders is further supported by studies that have found common genetic pathways, including LRRK2, shared between Parkinson's disease and autoimmune disorders such as rheumatoid arthritis, ulcerative colitis, and Crohn's disease (JAMA Neurol 74(7),780-92,2017). Consistent with this, LRRK2 is also associated with the risk of lupus (JAMA Neurol 74(7),780-92,2017) and leprosy (N Engl J Med 361(27),2609-18,2009; PLoS One 8(8),e73103,2013; PLoS Negl Trop Dis 10(2),e0004412,2016).

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

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

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

[0017] Extended prior art is known in the field of LRRK2 inhibitors. The most recent patent applications filed in this field cover oligomerization derivatives, such as the compounds disclosed in WO20 / 006267, non - macrocyclic or polycyclic structures such as the compounds disclosed in WO2019 / 222173, WO2019 / 112269, WO2019 / 074809, WO2018 / 217946, WO2018 / 163066, WO2018 / 155916, WO2018 / 137618, WO2018 / 06931, and macrocyclic derivatives such as the compounds disclosed in WO2019 / 012093, WO2016 / 042089. Despite the large number of structures described in the past few years, there is still a need to design new scaffold structures with better potency and selectivity to meet unmet medical needs. DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention will be described below. In the following paragraphs, different aspects of the present invention are defined in more detail. Unless explicitly stated to the contrary, each of the defined aspects can be combined with any other one or more aspects. In particular, any feature specified as being preferred or advantageous can be combined with any other one or more features specified as being preferred or advantageous.

[0020] In a first aspect, the present invention provides a compound of formula (I)

[0021]

[0022] wherein:

[0023] ◆ R represents a hydrogen atom, a halogen atom or an alkyl group,

[0024] ◆ Z1, Z2, Z3 each independently represent a carbon atom or a nitrogen atom, it being understood that the 6-membered ring containing Z1, Z2 and Z3 can have 0, 1 or 2 nitrogen atoms,

[0025] ◆ -X1- is absent or represents -O-, -S- or -N(R’a)-, where R’a represents a hydrogen atom or an alkyl group,

[0026] ◆ -X2- represents an alkanediyl group optionally substituted by one or more identical or different substituents selected from a halogen atom, a polyhaloalkyl group, an alkoxy group, a hydroxyl group, an amino group, an alkylamino group, a dialkylamino group and a cyano group,

[0027] It is understood that the carbon atom at the α-position of -N(Ra) and the carbon atom at the α-position of -X1- when -X1- represents -O-, -S- or -N(R’a)- cannot be substituted by an oxygen or nitrogen heteroatom,

[0028] ◆ -X3- represents an alkanediyl group optionally substituted by one or more identical or different substituents selected from a halogen atom, a polyhaloalkyl group, an alkoxy group, a hydroxyl group, an amino group, an alkylamino group, a dialkylamino group, a cyano group, a cycloalkyl group and a heterocycloalkyl group,

[0029] It is understood that the carbon atom at the α-position of -O- and the carbon atom at the α-position of A1 when A1 represents a nitrogen atom cannot be substituted by an oxygen or nitrogen heteroatom,

[0030] ◆ Ra represents a hydrogen atom or an alkyl group,

[0031] It is understood that when Ra represents an alkyl group, one carbon atom of Ra can be linked to the carbon atom of -X2-

[0032] or to the carbon atom of -X3- to form a cyclic moiety containing 5 or 6 ring members,

[0033] ◆ A represents

[0034] - An aromatic or partially hydrogenated cyclic group of formula (a):

[0035]

[0036] wherein

[0037] √ A1 and A4 each independently represent a carbon atom or a nitrogen atom,

[0038] √ A2, A3 and A5 each independently represent a carbon atom, an oxygen atom, a sulfur atom or a nitrogen atom,

[0039] It should be understood that A1, A2, A3, A4 and A5 cannot simultaneously represent heteroatoms,

[0040] - Or an aromatic or partially hydrogenated cyclic group of formula (b):

[0041]

[0042] wherein A'1, A'2, A'3 and A'4 each independently represent a carbon atom or a nitrogen atom,

[0043] It should be understood that * means that the bond is connected to X3,

[0044] The aromatic or partially hydrogenated cyclic group A as defined is optionally substituted by one or more identical or different substituents selected from halogen atoms, alkyl groups, alkoxy groups, hydroxy groups, oxo groups, alkoxyalkyl groups, alkoxyalkoxy groups, polyhaloalkyl groups, polyhaloalkoxy groups, heterocycloalkyl groups, heterocycloalkylalkyl groups, (alkoxyalkyl)(alkyl)amino groups, amino groups, alkylamino groups, dialkylamino groups, cycloalkyl groups, (heterocycloalkyl)(alkyl)amino groups, dialkylaminoalkyl groups, heterocycloalkylalkoxy groups, cyano groups and cyanoalkyl groups,

[0045] wherein the heterocycloalkyl groups and cycloalkyl groups as defined may optionally be substituted by one or more substituents selected from alkyl groups, halogen atoms, polyhaloalkyl groups, polyhaloalkoxy groups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, cyano groups and oxo groups,

[0046] Their enantiomers, diastereoisomers, tautomers, racemates, hydrates, solvates, N - oxides, isotopes, deuterated derivatives and addition salts thereof with pharmaceutically acceptable acids or bases.

[0047] When describing the compounds of the present invention, unless otherwise specified in the context, the terms used shall be interpreted according to the following definitions:

[0048] The term "alkyl", by itself or as part of another substituent, refers to a fully saturated monovalent hydrocarbon radical, including the corresponding deuterated derivatives. The alkyl groups of the present invention contain 1-6 carbon atoms. The alkyl groups can be straight-chain or branched-chain, can include spiro ring structures, and can be optionally substituted as described herein. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, butyl and its isomers (e.g., n-butyl, isobutyl and tert-butyl), pentyl and its isomers, hexyl and its isomers.

[0049] 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 a "-(alkyl)-" group, where the alkyl is as defined above. The alkanediyl groups of the present invention contain 1-6 carbon atoms, can be straight-chain or branched-chain, can include spiro ring structures, and can be substituted as described herein. Non-limiting examples of alkanediyl groups include: -CH2-, -CH2-CH2-, -CD2-, -CD2-CD2-, -CH(CH3)-, -CH(CH2-CH3)-, -CH(i-Pr)-, -C(CH3)(CH3)-, -CH2-C(CH3)(CH3)-, -CH2-CH2-C(CH3)(CH3)-, -CH2-CH(i-Pr)-, -CH(i-Pr)-CH2-, -CH2-CH(i-Bu)-, -CH(i-Bu)-CH2-, -CH(CH3)-CH2-, -CH2-CH(CH3)-, -CH2-CH2-CH2-, -CD2-CD2-CD2-, -CH(CH3)-CH2-CH2-, -CH2-CH2-CH(CH3)-, -CH2-CH(CH3)-CH2-, -CH(CH3)-CH2-CH(CH3)-, -CH2-CH2-CH(CH2-CH3)-, -CH(CH2-CH3)-CH2-CH2-, -CH(CH2-CH3)-CH2-CH(CH3)-, -CH(CH3)-CH2-CH(CH2-CH3)-, and when so indicated, these groups may be further substituted. For example, alkanediyl groups substituted with an alkoxy group will include, but not be limited to, -CH(OCH3)-, -CH(OCH3)-CH(CH3)-, -CH2-CH2-CH(OCH3)-, -CH(OCH3)-CH2-CH2-, -CH2-CH2-CH(CH2-OCH3)-, -CH(CH2-OCH3)-CH2-CH2-, -CH(O-CH2-CH3)-CH2-, -CH2-CH(O-CH2-CH3)-. As other non-limiting examples, alkanediyl groups substituted with a cycloalkyl group include -CH2-CH(Cy-Pr)-, -CH(Cy-Pr)-CH2-, where Cy-Pr means cyclopropyl. Alkanediyl groups substituted with one or more halogen atoms include, for example, but are not limited to, -CHF-, -CHF-CH2-, -CF2-, -CF2-CH2-, -CH2-CF2-. Alkanediyl groups substituted with a heterocycloalkyl group include, for example, but are not limited to, -CH2-CH(tetrahydropyranyl)-, -CH(tetrahydropyranyl)-CH2-, -CH2-CH(oxolanyl)-, -CH(oxolanyl)-CH2-.

[0050] The term "cycloalkyl", by itself or as part of another substituent, is a monovalent, saturated or unsaturated hydrocarbon group having one or two ring structures. Cycloalkyl includes fully saturated, partially saturated or aromatic hydrocarbon groups having one or two ring structures. Cycloalkyl contains 3 or more carbon atoms and typically contains 3 - 10 carbon atoms according to the present invention.

[0051] Examples of cycloalkyl having one ring structure include, but are not limited to, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0052] When having a bicyclic structure, the two rings may be:

[0053] -Fused, meaning they share a common bond; exemplary cycloalkyl bicyclic fused systems include, but are not limited to, naphthyl, bicyclo[1.1.0]butyl, octahydro-s-indacenyl, decahydronaphthyl, octahydro-1H-indenyl;

[0054] -Two cyclic structures are connected by a bond; exemplary cycloalkyl bicyclic linking systems include, but are not limited to, biphenyl, bi-cyclopropanyl, bi-cyclopentenyl, bi-cyclohexanyl, cyclopropylcyclohexyl, cyclopropylcyclopentyl;

[0055] -Bridged, meaning two rings share three or more atoms, and the two bridgehead atoms are separated by a bridge containing at least one atom; exemplary cycloalkyl bicyclic bridged systems include, but are not limited to, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl;

[0056] -Or represents a spiro bicyclic system, where the two rings are connected by a single atom; exemplary cycloalkyl spiro bicyclic systems include, but are not limited to, spiro[2.2]pentyl, spiro[2.4]heptyl, spiro[4.4]nonyl, spiro[5.5]undecyl.

[0057] The defined "cycloalkyl" may optionally be substituted with 1 - 3 substituents selected from alkyl, halogen atom, polyhaloalkyl, polyhaloalkoxy, alkoxy, alkoxyalkyl, hydroxy, cyano, and oxo groups. When cycloalkyl is substituted with 2 or 3 substituents, the substituents may be located on the same atom or different atoms, provided that the valence of each atom is compliant.

[0058] The term "alkoxy" by itself or as part of another substituent refers to the "(alkyl)-O-" group, where "alkyl" is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy (and its isomers), pentyloxy (and its isomers), hexyloxy (and its isomers).

[0059] The term "alkoxyalkyl" refers to the "(alkyl)-O-(alkyl)-" group, where "alkyl" is as defined above. Non-limiting examples include CH3-O-CH2-, CH3-O-CH2-CH2-.

[0060] The term "alkoxyalkoxy" refers to the "(alkyl)-O-(alkyl)-O-" group, where "alkyl" is as defined above. Non-limiting examples include CH3-O-CH2-O-, CH3-O-CH2-CH2-O-.

[0061] The term "alkylamino" refers to the "-NH-(alkyl)" group, where "alkyl" is as defined above. Non-limiting examples include -NH-CH3, -NH-CH2-CH3, -NH-CH(CH3)(CH3).

[0062] The term "dialkylamino" refers to the "-N(alkyl)(alkyl)" group, where "alkyl" is as defined above. Non-limiting examples include -N(CH3)2, -N(CH3)(CH2-CH3).

[0063] The term "polyhaloalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms carried by the same or different carbon atoms are replaced by one or more halogen atoms. Non-limiting examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl.

[0064] The term "polyhaloalkoxy" refers to the "(polyhaloalkyl)-O-" group, where "polyhaloalkyl" is as defined above. Non-limiting examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-chloroethoxy.

[0065] The term "heterocyclyl" means a monovalent monocyclic or bicyclic aromatic or non-aromatic carbocyclic group containing 3 - 10 ring members and containing 1 - 3 heteroatoms selected from oxygen, sulfur and nitrogen atoms. When possible, the heterocyclyl may be attached through a carbon or nitrogen atom. The defined heterocyclyl may be a monocyclic ring system or a bicyclic ring system. Monocyclic ring systems of heterocyclyl include, but are not limited to, pyridyl, piperazinyl, piperidinyl, tetrahydropyridyl, tetrahydropyranyl, pyrrolidinyl, dihydropyrrolyl, oxolanyl, dihydrofuryl, morpholinyl, pyrazolyl, azetidinyl, oxetanyl. When it is a bicyclic ring system, the two rings may be:

[0066] - fused, meaning they share a common bond; exemplary bicyclic fused systems of heterocyclyl include, but are not limited to, indolyl, dihydroindolyl, benzopyranyl, benzofuryl, naphthyridinyl, quinolinyl, pyridopyrazinyl, pyridopyridazinyl, pyridopyrimidinyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl;

[0067] - the two ring structures are linked by a bond; exemplary bicyclic linked systems of heterocyclyl include, but are not limited to, phenylpyridyl, bipyridyl, oxetanyl pyridyl, oxetanyl piperidinyl, oxetanyl tetrahydropyridyl, pyrrolidinyl piperidinyl, morpholinyl piperidinyl, pyrrolidinyl tetrahydropyridyl, pyrrolidinyl pyridyl, oxetanyl piperazinyl, pyrrolidinyl piperazinyl;

[0068] - Bridged, meaning that two rings share three or more atoms and the two bridgehead atoms are separated by a bridge containing at least one atom; exemplary heterocycloalkyl bicyclic bridged systems include, but are not limited to, azabicyclo[2.2.1]heptyl, oxaazabicyclo[2.2.1]heptyl;

[0069] - Or represents a spirobicyclic ring system, in which two rings are connected by a single atom; exemplary heterocycloalkyl spirobicyclic ring systems include, but are not limited to, oxaspirooctane, azaspirooctane, diazaspirooctane, oxaazaspirooctane, oxaspirononane, azaspirononane, diazaspirononane, oxaazaspirononane.

[0070] The defined "heterocycloalkyl" can optionally be substituted by 1 - 3 substituents selected from alkyl, halogen atom, polyhaloalkyl, polyhaloalkoxy, alkoxy, alkoxyalkyl, hydroxy, cyano, and oxo groups. When the heterocycloalkyl is substituted by 2 or 3 substituents, the substituents can be located on the same atom or different atoms, provided that the valence of each atom is compliant.

[0071] The term "heterocycloalkylalkyl" refers to a "(heterocycloalkyl)-(alkyl)-" group, where heterocycloalkyl and alkyl are as defined above. Non - limiting examples include morpholinomethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl.

[0072] The term "halogen atom" refers to a fluorine, chlorine, bromine, or iodine atom.

[0073] Among pharmaceutically acceptable acids, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphoric acid, etc. can be non - restrictively mentioned.

[0074] Among pharmaceutically acceptable bases, sodium hydroxide, potassium hydroxide, triethylamine, tert - butylamine, etc. can be non - restrictively mentioned.

[0075] Specific embodiments of the compound of formula (I) of the present invention are described below. The features of these specific embodiments can exist alone or in combination to produce new specific embodiments.

[0076] In a specific embodiment, the present invention more preferably relates to a compound of formula (I), wherein R represents a hydrogen atom.

[0077] In another embodiment, R preferably represents a halogen atom, most preferably a fluorine or chlorine atom.

[0078] When R is alkyl, it is preferably methyl.

[0079] When Z2 represents a carbon atom, R is preferably attached to Z2.

[0080] In another particularly preferred embodiment of the present invention, Z1, Z2 and Z3 simultaneously represent carbon atoms.

[0081] In an advantageous alternative embodiment, one of Z1, Z2 and Z3 is a nitrogen atom and the other two represent carbon atoms. More particularly, when one of Z1, Z2 and Z3 represents a nitrogen atom, it is preferably Z1 or Z2.

[0082] Another specific embodiment of the present invention relates to a compound of formula (I), wherein

[0083] -X1- represents -O- or -NH-. More preferably, -X1- represents -O-.

[0084] In another specific embodiment of the present invention, -X2- represents a straight-chain or branched alkanediyl having 2, 3, 4 or 5 carbon atoms, more preferably 3, 4 or 5 carbon atoms. -X2- is preferably unsubstituted. When -X2- is substituted, it is preferably fluorine or methoxy.

[0085] Advantageously, -X2- represents -(CH2)2-, -(CH2)3-, -CH(CH3)-(CH2)2-, -(CH2)2-CH(CH3)-, -CH2-CH(CH3)-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-CF2-CH2- or -CH2-CHF-CH2-.

[0086] A preferred value of Ra in the compound of formula (I) is a hydrogen atom.

[0087] In another specific embodiment of the present invention, -X3- represents a straight-chain or branched alkanediyl having 1, 2, 3, 4 or 5 carbon atoms, more preferably 1 or 2 carbon atoms. -X3- is preferably unsubstituted. Advantageously, -X3- represents -CH2-, -CH(CH3)-, -(CH2)2-, -(CH2)3-, -CH(CH2-CH3)-, -CH(CH3)-CH2-, -CH2-CH(CH3)-, -CH2-CH(i-Pr)-, -CH(i-Pr)-CH2-, -CH2-CH(Cy-Pr)-, -CH(Cy-Pr)-CH2-. Even more preferably, -X3- represents -(CH2)2-, -CH2- or -CH(CH3)-.

[0088] Another specific embodiment of the present invention is a compound of formula (I), wherein A represents a group of formula (b):

[0089]

[0090] The preferred values of (A’1, A’2, A’3, A’4) are:

[0091] - 4 carbon atoms, or

[0092] - 3 carbon atoms and 1 nitrogen atom, more preferably the nitrogen atom is at A’4,

[0093] - or 2 carbon atoms and 2 nitrogen atoms.

[0094] A’3 is advantageously a carbon atom.

[0095] As a specific embodiment of the present invention, A represents the following preferred skeleton, given herein in an unsubstituted manner:

[0096]

[0097] The most preferred embodiment of A of formula (b) is phenyl or pyridyl. An advantageous alternative of A is pyrazinyl.

[0098] An advantageous alternative of A is as shown by the group of formula (a):

[0099]

[0100] The most preferred skeleton of formula (a) contains 1, 2 or 3 heteroatoms, one of which is a nitrogen atom. Representative preferred skeletons of formula (a) are as follows, given herein in an unsubstituted manner:

[0101]

[0102] The most preferred embodiments of A of formula (a) are triazolyl or pyrazolyl.

[0103] Preferably, the group A of the compound of formula (I) is unsubstituted.

[0104] When the group A of the compound of formula (I) is substituted, the substitution can occur on any carbon or nitrogen atom of the A skeleton having at least one free valence. The most preferred substituents include halogen atoms, cyano group, cyanoalkyl group, oxo group, alkoxy group, alkyl group, cycloalkyl group and heterocycloalkyl group. In particular, the preferred substituents include fluorine, bromine or chlorine atom, methyl group, ethyl group, cyclopropyl group, methoxy group, isopropoxy group, cyano group, cyanomethyl group and oxo group.

[0105] The most preferred heterocycloalkyl groups include pyrrolidinyl, piperazinyl, morpholinyl, azetidinyl, piperidinyl, tetrahydropyridyl, tetrahydrofuryl, dihydrofuryl, oxetanyl, pyrazolidinyl.

[0106] The most preferred substituents of group A are fluorine or bromine atom, methoxy group, methyl group, ethyl group, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted piperazinyl.

[0107] Another specific embodiment of the present invention is shown by the compound of formula (I-a):

[0108]

[0109] wherein X1, X2, X3, Ra and A are as defined for formula (I).

[0110] In another preferred embodiment, the present invention relates to the compound of formula (I-b):

[0111]

[0112] wherein X2, X3, Ra and A are as defined for formula (I). The most preferred compounds of formula (I-b) are those in which -X2- represents -(CH2)3-, -CH(CH3)-(CH2)2-, -CH2-CHF-CH2-, -CH2-CF2-CH2- or -(CH2)2-CH(CH3)-. Another most preferred compound of formula (I-b) is those in which -X3- represents -CH2- or –(CH)(CH3)-.

[0113] Another specific embodiment of the present invention relates to a compound of formula (I), wherein the -X1-X2-N(Ra)-C(O)O-X3-chain preferably represents -O-(CH2)3-NH-C(O)O-CH2-, -O-CH(CH3)-(CH2)2-NH-C(O)O-CH2-, -O-CH2-CHF-CH2-NHC(O)O-CH2-, -O-CH2-CF2-CH2-NHC(O)O-CH2-, -O-CH(CH3)-(CH2)2-NHC(O)O-(CH2)2- or -O-CH(CH3)-(CH2)2-NH-C(O)O-CH(CH3)-.

[0114] Preferably, the compounds of the present invention are compounds of formula (I-c) or (I-c'):

[0115]

[0116] wherein X1, X2, X3, Ra, A'1, A'2 and A'4 are as defined for formula (I).

[0117] Another specific embodiment relates to a compound of formula (I-d) or (I-d'):

[0118]

[0119] wherein X2, X3, Ra, A'1, A'2 and A'4 are as defined for formula (I). The most preferred compounds of formula (I-d) or (I-d') are those in which -X2- represents -(CH2)3-, -CH(CH3)-(CH2)2-, -CH2-CHF-CH2-, -CH2-CF2-CH2- or -(CH2)2-CH(CH3)-. Another most preferred compounds of formula (I-d) or (I-d') are those in which -X3- represents -CH2- or -(CH2)2-.

[0120] Another preferred compound of the present invention is a compound of formula (I-e):

[0121]

[0122] wherein X1, X2, X3, Ra, A1, A2 and A5 are as defined for formula (I).

[0123] Another preferred compound of the present invention is a compound of formula (I-f):

[0124]

[0125] wherein X2, X3, Ra, A1, A2 and A5 are as defined for formula (I). The most preferred compounds of formula (I-f) are those in which -X2- represents -(CH2)3-, -CH(CH3)-(CH2)2-, -CH2-CHF-CH2-, -CH2-CF2-CH2- or -(CH2)2-CH(CH3)-. Another most preferred compound of formula (I-f) are those in which -X3- represents -CH2- or -(CH2)2-.

[0126] In another specific embodiment, preferred compounds of the present invention are:

[0127] -8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0128] -10-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0129] -4-fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0130] -8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0131] -8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0132] -10-(propan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0133] -8,14-Dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0134] -4-Methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0135] -4-Bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0136] -5-Fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0137] -5-Methyl-8,14-dioxa-1,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0138] -4-(Pyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0139] -4-[4-(Propan-2-yl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2 ,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0140] -4-{2-Oxa-6-azaspiro[3.4]octan-6-yl}-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0141] -4-[4-(Oxetan-3-yl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0142] -4-(Morpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0143] -4-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0144] -4-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0145] -5-Methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0146] -4-(4,4-Difluoropiperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0147] -4-(3,3-Difluoropyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2, 6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0148] -7-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0149] -4-[4-(2-Methoxyethyl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0150] -9,14-Dioxa-11,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-10-one;

[0151] -4-[(3R)-3-Hydroxypyrrolidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2 ,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0152] -4-[(2-Methoxyethyl)(methyl)amino]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0153] -4-Chloro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0154] -4-Fluoro-5-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0155] -4,5-Difluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0156] -5-Bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0157] -4-(4-Methylpiperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0158] -4-(3-Methoxyazetidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0159] -1-{9-Oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-4-yl}piperidine-4-carbonitrile;

[0160] -4-[4-(Pyrrolidin-1-yl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0161] -4-(Azetidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0162] -4-(Piperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0163] -4-(2,5-Dihydrofuran-3-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0164] -4-[4-(Morpholin-4-yl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2 ,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0165] -4-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0166] -4-[(2S,5S)-2,5-Dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0167] -4-[(Morpholin-4-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0168] -4-[(Pyrrolidin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0169] -4-[(Piperidin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0170] -4-[(4-Methylpiperazin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2 ,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0171] -5-(Morpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0172] -4-[4-(2-Methoxyethyl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0173] -4-(Diethylamino)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0174] -4-Cyclopropyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0175] -5-(4-Methylpiperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0176] -13-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0177] -8,14-Dioxa-4,5,10,19,20-pentazatetracyclo[13.5.2.1 2,5 .0 18,21 Tricos-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one;

[0178] -4-[Methyl(oxetan-3-yl)amino]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0179] -4-[(Dimethylamino)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0180] -4,10-Dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0181] -4-(Propan-2-yloxy)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,211(20),2,4,6(23),15,17,21 - Heptadecen - 9 - one;

[0182] -4 - fluoro - 7 - methyl - 8,14 - dioxo - 10,19,20 - triazatetracyclo[13.5.2.1 2,6 .0 18,21 1(20),2,4,6(23),15,17,21 - Heptadecen - 9 - one;

[0183] -4 - [1 - (oxetan - 3 - yl) - 1,2,3,6 - tetrahydropyridin - 4 - yl] - 8,14 - dioxo - 10,19,20 - triazatetracyclo[13.5.2.1 2,6 .0 18,21 1(20),2,4,6(23),15,17,21 - Heptadecen - 9 - one;

[0184] -4 - (3 - methylpiperidin - 1 - yl) - 8,14 - dioxo - 10,19,20 - triazatetracyclo[13.5.2.1 2,6 .0 18,21 1(20),2,4,6(23),15,17,21 - Heptadecen - 9 - one;

[0185] -4 - [(3S) - 3 - hydroxypyrrolidin - 1 - yl] - 8,14 - dioxo - 10,19,20 - triazatetracyclo[13.5.2.1 2 ,6 .0 18,21 1(20),2,4,6(23),15,17,21 - Heptadecen - 9 - one;

[0186] -4 - fluoro - 8,14 - dioxo - 10,19,20 - triazapentacyclo[13.5.2.1 2,6 .1 7,10 .0 18,21 1(20),2(24),3,5,15(22),16,18(21) - Octadecen - 9 - one;

[0187] -4 - (oxolan - 3 - yl) - 8,14 - dioxo - 10,19,20 - triazatetracyclo[13.5.2.1 2,6 .0 18,21 1(20),2,4,6(23),15,17,21 - Heptadecen - 9 - one;

[0188] -(13S) - 13 - methyl - 8,14 - dioxo - 10,19,20 - triazatetracyclo[13.5.2.12,6 .0 18,21 1(20),2(23),3,5,15(22),16,18(21)-Heptadecen-9-one;

[0189] -(13R)-13-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 1(20),2(23),3,5,15(22),16,18(21)-Heptadecen-9-one;

[0190] -4-(1-Methyl-1H-pyrazol-3-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2, 6 .0 18,21 1(20),2(23),3,5,15(22),16,18(21)-Heptadecen-9-one;

[0191] -(7S)-7-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 1(20),2(23),3,5,15(22),16,18(21)-Heptadecen-9-one;

[0192] -4-[2-(Morpholin-4-yl)ethoxy]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2, 6 .0 18,21 1(20),2(23),3,5,15(22),16,18(21)-Heptadecen-9-one;

[0193] -4-(2-Methoxyethyl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 1(20),2(23),3,5,15(22),16,18(21)-Heptadecen-9-one;

[0194] -(7R)-7-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 1(20),2(23),3,5,15(22),16,18(21)-Heptadecen-9-one;

[0195] -5-Cyclopropyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0196] -4-(2-Methoxyethoxy)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0197] -4-Fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0198] -11-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0199] -4-(3-Oxomorpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0200] -4-(2-Oxopyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0201] -5-(2-Oxopyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0202] -4-(2-methylpyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0203] -2-{9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-4-yl}acetonitrile;

[0204] -(11R)-11-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0205] -(11S)-11-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0206] -4-ethynyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0207] -4-(piperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0208] -4-(1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2 ,6 .0 18,21Tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0209] -11-(methoxymethyl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0210] -8,14-dioxa-5,10,19,20,23-pentazatetracyclo[13.5.2.1 2,5 .0 18,21 Tricos-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one;

[0211] -11-methyl-8,14-dioxa-4,5,10,19,20-pentazatetracyclo[13.5.2.1 2,5 .0 18,21 Tricos-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one;

[0212] -12-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0213] -11-ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0214] -4-fluoro-5,7-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0215] -4-fluoro-5-methoxy-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 1(20),2(23),3,5,15(22),16,18(21)-Heptadecaene-9-one;

[0216] -5-Fluoro-4,7-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 1(20),2(23),3,5,15(22),16,18(21)-Heptadecaene-9-one;

[0217] -8,14-Dioxa-10,19,20-triazapentacyclo[13.5.2.1 2,6 .1 7,10 .0 18,21 1(20),2(24),3,5,15(22),16,18(21)-Octadecaene-9-one;

[0218] -13-Methyl-8,14-dioxa-10,19,20,23-tetrazatetracyclo[13.5.2.1 2,6 .0 18,21 1(20),2(23),3,5,15(22),16,18(21)-Heptadecaene-9-one;

[0219] -12-Methyl-8,14-dioxa-4,5,10,19,20-pentazatetracyclo[13.5.2.1 2,5 .0 18,21 1(20),2(23),3,15(22),16,18(21)-Hexadecaene-9-one;

[0220] -7-Methyl-8,14-dioxa-4,5,10,19,20-pentazatetracyclo[13.5.2.1 2,5 .0 18,21 1(20),2(23),3,15(22),16,18(21)-Hexadecaene-9-one;

[0221] -5-Fluoro-4-methoxy-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 1(20),2(23),3,5,15(22),16,18(21)-Heptadecaene-9-one;

[0222] -(7R,13R)-7,13-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0223] -(13R)-13-methyl-8,14-dioxa-4,5,10,19,20-pentazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15,17,21-hexaen-9-one;

[0224] -8,15-dioxa-4,10,20,21-tetrazapentacyclo[14.5.2.1 2,6 .1 10,13 .0 19,22 pentacos-1(21),2(25),3,5,16(23),17,19(22)-heptaen-9-one;

[0225] -8,14-dioxa-5,10,19,20-tetrazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one;

[0226] -(13S)-4-fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0227] -(13R)-4-fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0228] -(13R)-13-methyl-8,14-dioxa-4,10,19,20-tetrazatetracyclo[13.5.2.1 2,6 .0 18,21Tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0229] -6-cyclopropyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 Tricos-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one;

[0230] -7-ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0231] -(13R)-13-methyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0232] -(7R,13R)-4-fluoro-7,13-dimethyl-8,14-dioxa-..... 2 ,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0233] -7-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; }

[0234] -(7R)-4-fluoro-7-methyl-8,14-dioxa-10,19,2....... 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0235] -(7S)-4-fluoro-7-methyl-8,14-dioxa-10,19,20-tria...... 2,6 .0 18,21Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0236] -6-methyl-8,14-dioxa-4,5,10,19,20-pentazatricyclo[13.5.2.1 2,5 .0 18,21 Tricos-1(20),2(23),3,15,17,21-hexaen-9-one;

[0237] -7-methyl-8,14-dioxa-10,19,20,23-tetrazatricyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0238] -6-(propan-2-yl)-8,14-dioxa-4,5,10,19,20-pentazatricyclo[13.5.2.1 2,5 .0 18,21 Tricos-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one;

[0239] -(13R)-7,13-dimethyl-8,14-dioxa-4,5,10,19,20-pentazatricyclo[13.5.2.1 2,5 .0 18 ,21 Tricos-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one;

[0240] -(13R)-13-methyl-8,14-dioxa-10,19,20,23-tetrazatricyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0241] -(7R)-7-ethyl-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0242] -(7S)-7-ethyl-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0243] -(13R)-13-methyl-8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0244] -6-(oxan-4-yl)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2, 5 .0 18,21 Tricos-1(20),2(23),3,15,17,21-hexaen-9-one;

[0245] -4-ethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 Tricos-1(20),2(23),15,17,21-pentaen-9-one;

[0246] -(13R)-23-fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0247] -9,14-dioxa-4,5,11,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 Tricos-1(20),2(23),3,15,17,21-hexaen-10-one;

[0248] -4-ethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 Tricos-1(20),2(23),3,15,17,21-hexaen-9-one;

[0249] -3,9,15-trioxa-4,11,20,21-tetraazatetracyclo[14.5.2.1 2,5 .0 19,22 Tetracos-1(21),2(24),4,16,18,22-hexaen-10-one;

[0250] -(13R)-16-Fluoro-13-methyl-8,14-dioxa-4,10,19,20-tetraazatricyclo[13.5.2.1 2,6 .0 18 ,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0251] -(13R)-4-Chloro-13-methyl-8,14-dioxa-10,19,20,23-tetraazatricyclo[13.5.2.1 2,6 .0 18 ,21 tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0252] -8,14-Dioxa-2,4,10,19,20-pentaazatricyclo[13.5.2.1 2,5 .0 18,21 tricosa-1(20),3,5(23),15(22),16,18(21)-hexaen-9-one;

[0253] -(13R)-4-Methoxy-13-methyl-8,14-dioxa-10,19,20,23-tetraazatricyclo[13.5.2.1 2 ,6 .0 18,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0254] -(13R)-13-Methyl-9-oxo-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18 ,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-5-carbonitrile;

[0255] -(13R)-13-Methyl-4-(pyrrolidin-1-yl)-8,14-dioxa-5,10,19,20,23-pentaazatricyclo[13.5.2.1 2,6 .0 18,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0256] -(7S,13R)-7,13-dimethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2 ,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0257] -(7R,13R)-7,13-dimethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2 ,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0258] -(13R)-16-fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0259] -(13R)-13-methyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .\(0\) 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0260] -8,14-dioxa-4-thia-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2,5(23),15,17,21-hexaen-9-one;

[0261] -8,14-dioxa-3-thia-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),4,15,17,21-hexaen-9-one;

[0262] -(7R,13R)-7,13-dimethyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2, 6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0263] -(13R)-4-[(3R)-3-methoxypyrrolidin-1-yl]-13-methyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0264] -(13R)-16-chloro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0265] -(13R)-13,16-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0266] -(13R)-13-methyl-8,14-dioxa-3,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one;

[0267] -8-oxa-10,14,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one hydrochloride;

[0268] -8-oxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0269] -(13R)-5-methoxy-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2, 6 .0 18,211(20),2,4,6(23),15,17,21 - Heptadecen - 9 - one;

[0270] -(13R)-13 - methyl - 8,14 - dioxo - 4,10,19,20 - tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 1(20),2,6(23),15,17,21 - Hexadecen - 5,9 - dione;

[0271] -4 - methyl - 8,14 - dioxo - 3,4,10,19,20 - pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 1(20),2,5(23),15(22),16,18(21)-Hexadecen - 9 - one;

[0272] -(13R)-16 - fluoro - 13 - methyl - 8,14 - dioxo - 10,19,20,23 - tetraazatetracyclo[13.5.2.1 2, 6 .0 18,21 1(20),2,4,6(23),15,17,21 - Heptadecen - 9 - one;

[0273] -7,13 - dioxo - 4 - thia - 9,18,19,22 - tetraazatetracyclo[12.5.2.1 2,5 .0 17,20 1(19),2,5(22),14(21),15,17(20)-Hexadecen - 8 - one;

[0274] -(13R)-4,13 - dimethyl - 8,14 - dioxo - 5,10,19,20,23 - pentaazatetracyclo[13.5.2.1 2, 6 .0 18,21 1(20),2(23),3,5,15(22),16,18(21)-Heptadecen - 9 - one;

[0275] -8,14 - dioxo - 23 - thia - 4,10,19,20 - tetraazatetracyclo[13.5.2.1 2,5 .0 18,21 1(20),2,4,15(22),16,18(21)-Hexadecen - 9 - one;

[0276] -(7S,13R)-7,13 - dimethyl - 8,14 - dioxo - 10,19,20,23 - tetraazatetracyclo[13.5.2.12, 6 .0 18,21 9 - oxo - 1(20),2(23),3,5,15(22),16,18(21) - heptadecatetraene;

[0277] - (13R) - 13 - methyl - 8,14 - dioxo - 5,10,19,20 - tetraaza - tetracyclo[13.5.2.1 2, 5 .0 18,21 4 - carbonitrile - 1(20),2(23),3,15(22),16,18(21) - hexadecatriene;

[0278] - 12,12 - difluoro - 8,14 - dioxo - 10,19,20 - triaza - tetracyclo[13.5.2.1 2,6 .0 18,21 9 - oxo - 1(20),2(23),3,5,15(22),16,18(21) - heptadecatetraene;

[0279] - (13R) - 17 - fluoro - 13 - methyl - 8,14 - dioxo - 10,19,20 - triaza - tetracyclo[13.5.2.1 2,6 .0 18,21 9 - oxo - 1(20),2(23),3,5,15(22),16,18(21) - heptadecatetraene;

[0280] - (7S,13R) - 7,13 - dimethyl - 8,14 - dioxo - 4,10,19,20,23 - pentaaza - tetracyclo[13.5.2.1 2 ,6 .0 18,21 9 - oxo - 1(20),2(23),3,5,15(22),16,18(21) - heptadecatetraene;

[0281] - (7R,13R) - 7,13 - dimethyl - 8,14 - dioxo - 4,10,19,20,23 - pentaaza - tetracyclo[13.5.2.1 2 ,6 .0 18,21 9 - oxo - 1(20),2(23),3,5,15(22),16,18(21) - heptadecatetraene;

[0282] - (13S) - 13 - methyl - 8,14 - dioxo - 4,10,19,20,23 - pentaaza - tetracyclo[13.5.2.1 2,6 .0 18,211(20),2(23),3,5,15(22),16,18(21)-Heptadecen-9-one;

[0283] -(13R)-13-Methyl-8,14-dioxa-10,19,20,22-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 1(20),2(23),3,5,15,17,21-Heptadecen-9-one;

[0284] -(12R)-4,12-Dimethyl-7,13-dioxa-4,9,18,19,22-pentaazatetracyclo[12.5.2.1 2,5 .0 17 ,20 1(19),2,5(22),14(21),15,17(20)-Hexadecen-8-one;

[0285] -(13R)-13-Methyl-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1 2,5 .0 18 ,21 1(20),-1(20),2(23),3,15,17,21-Hexadecen-9-one;

[0286] -(13R)-13-Methyl-8,14-dioxa-23-thia-4,10,19,20-tetraazatetracyclo[13.5.2.1 2, 5 .0 18,21 1(20),2,4,15,17,21-Hexadecen-9-one;

[0287] -(13R)-4,13-Dimethyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2, 5 .0 18,21 1(20),2,5(23),15(22),16,18(21)-Hexadecen-9-one;

[0288] -(13R)-13-Methyl-8,14-dioxa-10,16,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 1(20),2(23),3,5,15(22),16,18(21)-Heptadecen-9-one;

[0289] -14-Methyl-8-oxa-10,14,19,20-tetraazatricyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15,17,21-heptaen-9-one;

[0290] -(13R)-13-Methyl-8,14-dioxa-4,10,19,20,22-pentaazatricyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15,17,21-heptaen-9-one;

[0291] -(13R)-13-Methyl-8,14-dioxa-10,17,19,20-tetraazatricyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0292] -8,14-Dioxa-4,5,10,19,20,23-hexaazatricyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one;

[0293] -12,12-Difluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatricyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one);

[0294] -(12R)-12-Fluoro-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0295] -(12S)-12-Fluoro-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0296] -12,12-Difluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

[0297] -(12S)-12-Fluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15,17,21-heptaen-9-one;

[0298] -(12R)-12-Fluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15,17,21-heptaen-9-one;

[0299] -(12S)-12-Fluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15,17,21-hexaen-9-one;

[0300] -(12R)-12-Fluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15,17,21-hexaen-9-one;

[0301] -8',14'-Dioxa-10',19',20'-triazaspiro[cyclopropane-1,13'-tetracyclo[13.5.2.1 2,6 .0 18 ,21 tricosane]-1'(20'),2'(23'),3',5',15'(22'),16',18'(21')-heptaen-9'-one.

[0302] The present invention also relates to a general method for preparing the compound of formula (I), which is characterized by using the compound of formula (I-1) as a raw material:

[0303]

[0304] wherein R, X1, Z1, Z2 and Z3 are as defined for formula (I),

[0305] On which the compound PG1-LG1 is first condensed, and then the compound PG2-LG2 is condensed, or the compound PG2-LG2 is first condensed and then the compound PG1-LG1 is condensed, wherein PG1 is a protecting group or PG1 represents a halogen when -X1- is a bond, and PG2 is a protecting group, and LG1 and LG2 are leaving groups, to obtain a compound of formula (I-2):

[0306]

[0307] wherein R, X1, Z1, Z2, Z3, PG1 and PG2 are as defined above,

[0308] The compound of formula (I-2):

[0309] - A leaving group LG3 is condensed thereon to obtain a compound of formula (I-3):

[0310]

[0311] wherein R, X1, Z1, Z2, Z3, PG1, PG2 and LG3 are as defined above,

[0312] The compound of formula (I-3):

[0313] · After deprotection of X1, the compound LG4-X²-NPG3 is condensed thereon, wherein LG4 is a leaving group, PG3 is a protecting group, and X² is as defined for formula (I), to obtain a compound of formula (I-4):

[0314]

[0315] wherein R, X1, X², Z1, Z2, Z3, PG2, PG3 and LG3 are as defined above,

[0316] The compound of formula (I-4), on which the compound of formula (I-5) is condensed:

[0317]

[0318] wherein A and X³ are as defined in the compound of formula (I), or an organometallic derivative such as a borate of the compound of formula (I-5), to obtain a compound of formula (I-6):

[0319]

[0320] wherein R, X1, X², X³, A, Z1, Z2, Z3, PG2 and PG3 are as defined above,

[0321] The compound of formula (I-6) is subjected to -X2-NPG3 deprotection and then cyclized to obtain the compound of formula (I-7):

[0322]

[0323] wherein R, X1, X2, X3, A, Z1, Z2, Z3 and PG2 are as defined above,

[0324] The compound of formula (I-7) is optionally alkylated on the carbamate functional group and / or optionally substituted on the A ring, and then -N(PG2)- is deprotected to obtain the compound of formula (I),

[0325] · Alternatively, the compound of formula (I-3) is condensed with the compound of formula (I-8) thereon:

[0326]

[0327] wherein Ra, X2, X3 and A are as defined above and LG4 is a leaving group, or an organometallic derivative such as a boronate of the compound of formula (I-8), to obtain the compound of formula (I-9):

[0328]

[0329] wherein R, Ra, X1, X2, X3, A, Z1, Z2, Z3, PG1, PG2 and LG4 are as defined above,

[0330] After deprotection of X1, the compound of formula (I-9) is cyclized to obtain the compound of formula (I-7) as defined above, and after deprotection of -N(PG2)- and / or optional substitution on the A ring thereof, the compound of formula (I) is obtained,

[0331] · Alternatively, after deprotection of X1, the compound of formula (I-3) is condensed with the compound LG5-X2-NRaCOOBn thereon, wherein X2 and Ra are as defined in formula (I) and LG5 is a leaving group, to obtain the compound of formula (I-10):

[0332]

[0333] wherein R, Ra, X1, X2, Z1, Z2, Z3, PG2 and LG3 are as defined above,

[0334] The compound of formula (I-10) is condensed with the compound of formula (I-5) thereon:

[0335]

[0336] wherein X3 and A are as defined above, or an organometallic derivative of a compound of formula (I-5) such as a borate ester, to obtain a compound of formula (I-11):

[0337]

[0338] wherein R, Ra, X1, X2, X3, Z1, Z2, Z3, A and PG2 are as defined above,

[0339] Cyclizing the compound of formula (I-11) to obtain a compound of formula (I-7) as defined above, and after deprotecting its -N(PG2)- and / or optionally substituting on the A ring, obtaining a compound of formula (I),

[0340] - Or a compound of formula (I-2), after deprotecting X1, condensing a compound of formula (I-12) thereon:

[0341]

[0342] wherein A, X3 and X2 are as defined above, and LG6 and LG7 are leaving groups, to obtain a compound of formula (I-13):

[0343]

[0344] wherein R, X1, X2, X3, A, Z1, Z2, Z3, PG2 and LG6 are as defined above,

[0345] Cyclizing the compound of formula (I-13) to obtain a compound of formula (I-7), optionally alkylating it on the carbamate functional group, and then performing -N(PG2) deprotection and / or optional substitution on the A ring to obtain a compound of formula (I),

[0346] - Or a compound of formula (I-2), converting it to a boronic acid derivative of formula (I-14):

[0347]

[0348] wherein R, X1, Z1, Z2, Z3, PG1 and PG2 are as defined above, and R' represents a hydrogen atom or an alkyl group, it should be understood that two R' alkyl groups can be joined to form a cyclic structure,

[0349] · A compound of formula (I-14), condensing a compound of formula (I-15) thereon:

[0350]

[0351] wherein A is as defined above, X4 is a carboxylic acid or ester or carbonyl derivative of X3, and LG8 is a leaving group, to obtain a compound of formula (I-16):

[0352]

[0353] wherein R, X1, Z1, Z2, Z3, X4, PG1 and PG2 are as defined above,

[0354] For the compound of formula (I-16), after deprotection of X1, the compound LG5-X2-NRaCOOBn as defined above is condensed thereon to obtain the compound of formula (I-17):

[0355]

[0356] wherein R, Ra, X1, X2, Z1, Z2, Z3, X4 and PG2 are as defined above,

[0357] Subject it to reduction to obtain the compound of formula (I-11), and convert it into the compound of formula (I) as described above,

[0358] · Or for the compound of formula (I-14), condense the compound of formula (I-18) thereon:

[0359]

[0360] wherein A, X2, X3 and Ra are as defined above and LG9 is a leaving group, to obtain the compound of formula (I-19):

[0361]

[0362] wherein R, Ra, A, X1, X2, X3, Z1, Z2, Z3, PG1 and PG2 are as defined above,

[0363] For the compound of formula (I-19), introduce a leaving group thereon to obtain the compound of formula (I-9) as defined above, and convert it into the compound of formula (I) as described above,

[0364] - Or for the compound of formula (I-2), after deprotection of X1, condense the compound LG5-X2-NRaCOOBn as defined above thereon to obtain the compound of formula (I-20):

[0365]

[0366] wherein R, Ra, X1, X2, Z1, Z2, Z3 and PG2 are as defined above,

[0367] For the compound of formula (I-20), convert it into the boronic acid derivative of formula (I-21):

[0368]

[0369] wherein R, Ra, X1, X2, Z1, Z2, Z3, PG2 and R' are as defined above,

[0370] · a compound of formula (I-21) onto which is condensed a compound of formula (I-22):

[0371]

[0372] wherein X3 and A are as defined above and LG10 is a leaving group, to give a compound of formula (I-11), which is converted into a compound of formula (I) as described above,

[0373] · or a compound of formula (I-21) onto which is condensed a compound of formula (I-15) as defined above, to give a compound of formula (I-17), which is converted into a compound of formula (I) as described above,

[0374] The compound of formula (I) can then be purified according to conventional separation techniques and, if desired, converted into its addition salts with pharmaceutically acceptable acids or bases and optionally separated into its isomers according to conventional separation techniques,

[0375] It should be understood that at any moment deemed appropriate during the above process, some groups of the starting reagents or synthetic intermediates can be protected according to the needs of the synthesis, followed by deprotection and functionalization.

[0376] The compounds of formula (I-5), (I-8), (I-12), (I-15), (I-18) and (I-22) are commercially available or can be obtained by those skilled in the art using conventional chemical reactions described in the literature.

[0377] Pharmacological studies of the compounds of the invention of formula (I) have shown inhibitory activity against LRRK2 kinase (including LRRK2 mutant kinases, such as the mutant p.G2019S). Kinase activity can be measured using kinase assays, which typically employ a kinase substrate and a phosphate group donor such as ATP (or its derivatives). Exemplary kinase assays are described in the pharmacological studies.

[0378] The compounds of formula (I) of the invention or their pharmaceutically acceptable salts are inhibitors of LRRK2 kinase activity and are therefore considered to have potential use in the treatment or prevention of diseases associated with or characterized by LRRK2 kinase activity, such as neurological diseases, endosomal-lysosomal disorders, inflammatory diseases, bacterial, viral and parasitic infections, cardiovascular diseases, autoimmune diseases and cancer.

[0379] In particular, the compounds of the present invention can be used for treating neurological diseases, including but not limited to Parkinson's disease (including patients with sporadic Parkinson's disease and patients with LRRK2 mutations such as p.G2019S or Rab29 / Rab7L1 polymorphisms), Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dementia (including Lewy body dementia and vascular dementia, HIV-induced dementia), diabetic neuropathy, age-related memory impairment, mild cognitive impairment, argyrophilic grain disease, Pick's disease, epilepsy, tauopathies such as progressive supranuclear palsy and corticobasal degeneration, other synucleinopathies such as multiple system atrophy, frontotemporal dementia, chromosome 17-related hereditary frontotemporal dementia and parkinsonism (FTDP-17), withdrawal symptoms / relapse related to drug addiction, L-dopa-induced dyskinesia, ischemic stroke, traumatic brain injury, spinal cord injury and multiple sclerosis.

[0380] Other diseases that can potentially be treated by inhibiting LRRK2 activity are endosomal-lysosomal diseases, including but not limited to Niemann-Pick disease types A, B or C, Gaucher's disease, Krabbe disease, Fabry disease and conditions with mitochondrial defects; inflammatory diseases, including but not limited to vasculitis, lung diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, inflammatory myopathies, ankylosing spondylitis; autoimmune diseases, including but not limited to Crohn's disease, inflammatory bowel disease, rheumatoid arthritis, ulcerative colitis, lupus, autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura, type I diabetes, obesity, Evans syndrome, bullous skin disorders, Sjögren's syndrome, Devic's disease and leprosy. The compounds of the present invention also have anti-cancer effects and may be used for treating cancer, including but not limited to thyroid cancer, renal cancer (including papillary renal cancer), breast cancer, hormone-related cancers, adenocarcinoma- and squamous cell lung cancer, non-small cell lung cancer, colon cancer, prostate cancer, skin cancer, leukemia (including acute myeloid leukemia) and lymphoma.

[0381] The compounds of the present invention can also be used for treating cardiovascular diseases, including but not limited to stroke.

[0382] Other diseases that can be treated with the compounds of the present invention are bacterial infections, such as but not limited to leprosy and tuberculosis; viral infections, such as but not limited to coronaviruses such as SARS-CoV, MERS-CoV and SARS-CoV-2, HIV, West Nile virus and chikungunya virus.

[0383] Another aspect of the present invention relates to pharmaceutical compositions comprising at least one compound of formula (I) and one or more pharmaceutically acceptable excipients. In particular, these pharmaceutical compositions are useful for treating or preventing 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 specific embodiment, the pharmaceutical compositions of the present invention can be used to treat or prevent Parkinson's disease (including patients with sporadic Parkinson's disease and those with LRRK2 mutations or Rab29 / Rab7L1 polymorphisms), Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dementia (including Lewy body dementia and vascular dementia, HIV-induced dementia), diabetic neuropathy, age-related memory impairment, mild cognitive impairment, argentophilic grain disease, sphingomyelin storage disease, epilepsy, tauopathies such as progressive supranuclear palsy and corticobasal degeneration, other synucleinopathies such as multiple system atrophy, frontotemporal dementia, chromosome 17-related hereditary frontotemporal dementia and parkinsonism (FTDP-17). Withdrawal symptoms and / or relapse associated with drug addiction, L-dopa-induced dyskinesia, ischemic stroke, traumatic brain injury, spinal cord injury, multiple sclerosis, type A, B or C Niemann-Pick disease, Gaucher's disease, Krabbe's disease, Fabry's disease, disorders with mitochondrial defects, regional enteritis, inflammatory bowel disease, rheumatoid arthritis, ulcerative colitis, lupus, autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura, type I diabetes, obesity, Evans syndrome, bullous skin diseases, Sjogren's syndrome, Devic's disease, leprosy, thyroid cancer, renal cancer (including papillary renal cancer), breast cancer, hormone-related cancers, adenocarcinoma- and squamous cell lung cancer, non-small cell lung cancer, colon cancer, prostate cancer, skin cancer, leukemia (including acute myeloid leukemia), lymphoma, stroke, leprosy, tuberculosis and SARS-CoV, MERS-CoV, SARS-CoV-2, HIV, West Nile virus and chikungunya virus infections.

[0384] Among the pharmaceutical compositions of the present invention, particular mention may be made of those suitable for oral, parenteral, nasal, percutaneous or transdermal, rectal, sublingual, ocular or respiratory administration, in particular tablets or dragées, sublingual tablets, sachets, paquets, capsules, sublingual or rectal glossettes, lozenges, suppositories, creams, ointments, skin gels and drinkable or injectable ampoules.

[0385] The pharmaceutical composition of the present invention comprises one or more excipients or carriers selected from diluents, lubricants, binders, disintegrants, stabilizers, preservatives, absorbents, colorants, sweeteners, flavoring agents, etc. As a non-limiting example, it can be mentioned that: as follows:

[0386] ◆ As diluents: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerol,

[0387] ◆ As lubricants: silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol,

[0388] ◆ As binders: magnesium aluminum silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone,

[0389] ◆ As disintegrants: agar, alginic acid and its sodium salts, effervescent mixtures.

[0390] The dosage varies according to the patient's gender, age and weight, route of administration, nature of the therapeutic indication or any relevant treatment, and the dosage ranges from 0.01 mg to 1 g per 24 hours, administered once or in multiple doses.

[0391] The following preparation examples and examples are used to illustrate the present invention, but do not limit the present invention in any way. The compounds of the present invention can be prepared by any of several standard synthetic methods commonly used by those skilled in the art of organic chemistry. The compounds are generally prepared from starting materials that are commercially available or prepared by standard methods that are obvious to those skilled in the art.

[0392] General solution

[0393] As shown above, the present invention provides compounds of formula (I):

[0394]

[0395] wherein R, Z1, Z2, Z3, X1, X2, X3, Ra and A are as defined for formula (I).

[0396] Regarding the general reaction schemes suitable for preparing the compounds, these compounds can be represented by formula (I), and the general reaction schemes can be found below. In the following general scheme, R, Z1, Z2, Z3, X1, X2, X3, Ra and A have the same meanings as those defined for formula (I).

[0397] Hereinafter, the fused pyrazolo bicyclic structure containing Z1, Z2, Z3 and R is referred to as the fused pyrazolo structure.

[0398] In the following general scheme, Lg1 and Lg2 each independently represent a suitable leaving group. Pg1 and Pg3 each independently represent a suitable protecting group that can be used to protect X1 and / or X2. Pg2 represents a protecting group suitable for protecting the NH of the fused pyrazolo structure.

[0399] Rb in the following scheme can be H, alkyl or cycloalkyl.

[0400] For those compounds for which a transcarbamoylation reaction is used, the CbzX2Lg2 moiety can be prepared by reacting the corresponding bromoalkylamine with Cbz chloride or by reacting a hydroxyalkylamine with Cbz chloride followed by mesylation or tosylation.

[0401] In all of the following general schemes, before deprotecting the NH of the fused pyrazolo structure, the carbamate can optionally be substituted by an alkylation reaction to give a compound of formula (XIIIa), and then the NH of the fused pyrazolo structure can be deprotected to give the final compound of formula (I).

[0402] Alternatively, in all of the following general schemes, before deprotecting the NH of the fused pyrazolo structure, an optional cross-coupling reaction such as Buchwald, Suzuki, Sonogashira reaction or O-alkylation or nucleophilic aromatic substitution can be carried out on the (hetero-)aromatic ring bearing a leaving group such as halogen to form a compound of formula (XIIIa). After the cross-coupling reaction such as Buchwald, Suzuki, Sonogashira reaction or O-alkylation or nucleophilic aromatic substitution, the NH of the fused pyrazolo structure can be deprotected to give the final compound of formula (I).

[0403] The compounds of formula (I) can be prepared as shown in the following general Scheme A, in which a compound of formula (II) is converted into a protected compound of formula (III). The compound of formula (III) can be converted into a compound of formula (IV) having 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 to give a compound of formula (IX). The compound of formula (VIII) can be prepared from a compound of formula (VII) by nucleophilic substitution. The compound of formula (IX) can be coupled with a (hetero-)aryl of formula (X) or (Xa) via an organometallic cross-coupling such as Suzuki or Ullmann coupling to form a compound of formula (XI). The compound of formula (XI) can then be selectively deprotected to a compound of formula (XII), which is then cyclized to form a compound of formula (XIII). After optional alkylation of the carbamate moiety and / or substitution of the A ring, the nitrogen of the fused pyrazolo structure is finally deprotected to give a compound of formula (I).

[0404] Solution A

[0405]

[0406] In the above reaction Scheme A, the reaction between the compound of formula (VI) and the compound of formula (VIII) can be carried out in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate.

[0407] In the reaction between the above compound of formula (IX) and the compound of formula (X), the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such halogen displacement reactions can be carried out under cross-coupling conditions such as Suzuki conditions using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), with or without the combined use of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos), in the presence of tripotassium phosphate, in a solvent mixture such as 1,4-dioxane / water, at an elevated temperature such as 90 °C, with or without microwave irradiation.

[0408] Alternatively, the halogen displacement reaction can be carried out under Ullmann conditions using copper iodide in the presence of potassium carbonate and 8-hydroxyquinoline, in a solvent such as dimethyl sulfoxide, at an elevated temperature such as 70 °C.

[0409] Suitable compounds of formula (X) or formula (Xa) are commercially available or can be obtained by different selective protection and deprotection steps known to those skilled in the art. For the synthesis of compounds of formula (Xa), a borylation step may be required.

[0410] Deprotection of Pg3 yields the compound of formula (XII).

[0411] Cyclization of the compound of formula (XII) to form the compound of formula (XIII) can be carried out by methods known to those skilled in the art as carbamylation reactions, for example, by treatment with 1,1′-carbonyldiimidazole and N,N-diisopropylethylamine or sodium hydride in a solvent such as N,N-dimethylacetamide at, for example, 90 °C. After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the NH of the fused pyrazolo structure is finally deprotected under acidic conditions to give the final compound of formula (I).

[0412] Alternatively, the compound of formula (I) can be prepared as shown in the following general Scheme B, in which the fused pyrazolo structure of formula (II) is converted into the protected compound of formula (III). The NH of the fused pyrazolo structure can be protected as the compound of formula (XIV). The compound of formula (XIV) can be converted into the boronic acid (or boronic ester) of formula (XV). The compound of formula (XV) can be coupled with the (hetero-)aryl of formula (XVI) by an organometallic cross-coupling reaction such as Suzuki coupling to form the compound of formula (XVII). The compound of formula (XVII) can be alkylated with an intermediate of formula (XIX) containing a carbamate such as benzyl carbamate to give the compound of formula (XX). The compound of formula (XIX) is commercially available or can be prepared from the compound of formula (XVIII) by reaction with CbzCl or by introducing the leaving group Lg2 on the compound of formula (XVIIIa). The X4 moiety of the compound (XX) can generally be converted into X3-OH by reduction of a carboxylic acid or carboxylic ester or (cyclo)alkyl-carbonyl or heterocycloalkyl-carbonyl. Then the compound of formula (XXI) can be cyclized by a transcarbamylation reaction to form the compound of formula (XIII). After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected to give the compound of formula (I).

[0413] Solution B

[0414]

[0415] In the above Reaction Scheme B, the borylation of the fused pyrazolo structure of the compound of formula (XV) to form the compound of formula (XVI) can be carried out using an iridium catalyst and bis(pinacolato)diboron in a solvent such as TBME.

[0416] In the reaction between the compound of formula (XV) and the compound of formula (XVI), the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such halogen substitution reactions can be carried out under cross-coupling conditions such as Suzuki conditions using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), with or without the combination of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos), in the presence of tripotassium phosphate, in a solvent mixture such as 1,4-dioxane / water, at an elevated temperature such as 110 °C, with or without microwave conditions.

[0417] In the above reaction scheme, the alkylation between the compound of formula (XVII) and the compound of formula (XIX) can be carried out in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as caesium carbonate or potassium carbonate at an elevated temperature such as 120 °C. Suitable compounds of formula (XIX) are commercially available or can be obtained by the reaction of a compound of formula (XVIII) with CbzCl and sodium hydroxide in water as the solvent. Alternatively, the compound of formula (XIX) can be prepared by introducing Lg2 onto the compound of formula (XVIIIa).

[0418] X4 in the compound of formula (XX) can be (cyclo)alkyl-carbonyl, heterocycloalkyl-carbonyl or a carboxylic acid derivative (carboxylic acid or ester), which can be reduced to the corresponding alcohol using sodium borohydride or lithium aluminium hydride in a solvent such as THF at an elevated temperature such as 120 °C.

[0419] The transcarbamylation of the compound of formula (XXI) to the macrocycle of formula (XIII) can be carried out using potassium carbonate or caesium carbonate or potassium hydroxide in a solvent such as acetonitrile at a temperature ranging from room temperature to the reflux temperature of the solvent, or using sodium hydride in a dry solvent such as toluene at a temperature ranging from 0 °C to the reflux temperature of the solvent, with or without microwave conditions.

[0420] After the carbamate alkylation and / or A-ring substitution is carried out or not carried out, the nitrogen of the fused pyrazolo structure is finally deprotected under acidic conditions to obtain the final compound of formula (I).

[0421] Alternatively, the compound of formula (I) can be prepared as shown in the following general Scheme C, in which the fused pyrazolo structure of formula (II) is converted into the protected compound of formula (III). The compound of formula (III) can be converted into the compound of formula (IV) containing a leaving group on the fused pyrazolo structure, and then into the nitrogen-protected compound of formula (V). The compound of formula (V) can be converted into the selectively protected fused pyrazolo structure of formula (VI), and then alkylated with the intermediate of formula (XIX) containing a leaving group to obtain the compound of formula (XXII). The compound of formula (XIX) can be commercially available or prepared from the compound of formula (XVIII) by reaction with CbzCl or by introducing the leaving group Lg2 on the compound of formula (XVIIIa). The compound of formula (XXII) can be coupled with the (hetero)-aryl of formula (X) by an organometallic cross-coupling reaction such as Suzuki coupling to form the compound of formula (XXI). Then the compound of formula (XXI) can be cyclized by a transcarbamoylation reaction to form the compound of formula (XIII). After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected to obtain the compound of formula (I).

[0422] Solution C

[0423]

[0424] In the above Reaction Scheme C, the alkylation between the compound of formula (VI) and the compound of formula (XIX) can be carried out in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 120 °C.

[0425] Suitable compounds of formula (XIX) can be commercially available or obtained by the reaction of the compound of formula (XVIII) with CbzCl and sodium hydroxide in water as a solvent. Alternatively, the compound of formula (XIX) can be prepared by introducing Lg2 on the compound of formula (XVIIIa).

[0426] In the reaction between the above compound of formula (XXII) and the compound of formula (X), the leaving group Lg1 is preferably a halogen atom such as chlorine, bromine or iodine. Such halogen substitution reactions can be carried out under organometallic cross-coupling conditions such as Suzuki conditions using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), with or without 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) in combination, in the presence of tripotassium phosphate, in a solvent mixture such as 1,4-dioxane / water, at an elevated temperature such as 110 °C, with or without microwave conditions.

[0427] Suitable compounds of formula (X) can be obtained commercially or by various selective protection and deprotection steps known to those skilled in the art. A borylation step may be required to obtain the compounds of formula (X).

[0428] The transcarbamoylation of the compound of formula (XXI) to the macrocycle of formula (XIII) can be carried out using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at a temperature from room temperature to the reflux temperature of the solvent, or using sodium hydride in a dry solvent such as toluene at a temperature from 0 °C to the reflux temperature of the solvent, with or without microwave conditions.

[0429] After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected under acidic conditions to give the final compound of formula (I).

[0430] Alternatively, the compound of formula (I) can be prepared as shown in General Scheme D below, in which the fused pyrazolo structure of formula (II) is converted to the protected compound of formula (III), and then to the nitrogen-protected compound of formula (XIV). The compound of formula (XIV) can be converted to the selectively protected fused pyrazolo structure of formula (XXIII), which is then alkylated with the compound of intermediate (XIX) containing a Cbz group to give the compound of formula (XXIV). The compound of formula (XIX) can be prepared from the compound of formula (XVIII) by reaction with CbzCl or by introducing a leaving group Lg2 on the compound of formula (XVIIIa). The compound of formula (XXIV) can be boronic esterified to the compound of formula (XXV). The boronic esterified compound of formula (XXV) can be reacted with the (hetero)-aryl of formula (XXVI) in a cross-coupling reaction such as Suzuki coupling to form the compound of formula (XXI). Then the compound of formula (XXI) can be cyclized by a transcarbamoylation reaction to form the compound of formula (XIII). After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected to give the compound of formula (I).

[0431] Solution D

[0432]

[0433] In the above Reaction Scheme D, the reaction between the compound of formula (XXIII) and the compound of formula (XIX) is carried out in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate.

[0434] Suitable compounds of formula (XIX) are commercially available or can be obtained by the reaction of compounds of formula (XVIII) with CbzCl and sodium hydroxide in water as the solvent. Alternatively, compounds of formula (XIX) can be prepared by introducing Lg2 onto compounds of formula (XVIIIa).

[0435] In the above reaction scheme, the boronylation of the fused pyrazolo structure of the compound of formula (XXIV) to the compound of formula (XXV) can be carried out using an iridium catalyst and bis(pinacolato)diboron in a solvent such as TBME.

[0436] In the reaction between the compound of formula (XXV) and the compound of formula (XXVI) above, the leaving group Lg1 is advantageously a halogen atom, such as chlorine, bromine or iodine. Such halogen substitution reactions can be achieved under organometallic cross-coupling conditions such as Suzuki conditions using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), with or without the combination of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos), in the presence of tripotassium phosphate, in a solvent mixture such as 1,4-dioxane / water, at an elevated temperature such as 90 °C, with or without microwave conditions.

[0437] Suitable compounds of formula (XXVI) are commercially available or can be obtained by various reactions known to those skilled in the art, including selective protection and deprotection steps.

[0438] The transcarbamoylation of the compound of formula (XXI) to the macrocycle of formula (XIII) can be carried out using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at a temperature ranging from room temperature to the reflux temperature of the solvent, or using sodium hydride in a dry solvent such as toluene at a temperature ranging from 0 °C to the reflux temperature of the solvent, with or without microwave conditions.

[0439] After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected under acidic conditions to give the final compound of formula (I).

[0440] Alternatively, the compounds of formula (I) can be prepared as shown in the following general Scheme E, in which the fused pyrazolo structure of formula (II) is converted into a protected compound of formula (III). The compound of formula (III) can be converted into 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 with a (hetero)-aryl of formula (XXVII) in a cross-coupling reaction such as Suzuki coupling to form a compound of formula (XXVIII). The X4 moiety in the compound of formula (XXVII) contains a carbonyl precursor such as (cyclo)alkyl-carbonyl, heterocycloalkyl-carbonyl, carboxylic acid or ester, which can be reduced to a compound of formula (XXIX). Then the compound of formula (XXIX) is alkylated with an intermediate of formula (XIX) containing a leaving group to obtain a compound of formula (XXI). The compound of formula (XIX) can be commercially available or obtained from a compound of formula (XVIII) by reaction with CbzCl or by introducing a leaving group Lg2 on the compound of formula (XVIIIa). Then the compound of formula (XXI) can be cyclized by a transcarbamoylation reaction to form a compound of formula (XIII). After no or carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected to obtain the final compound of formula (I).

[0441] Solution E

[0442]

[0443] In the reaction between the compounds of formula (VI) in Scheme E above, the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such halogen displacement reactions can be carried out under organometallic cross-coupling conditions such as Suzuki conditions using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), with or without the combined use of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos), in the presence of tripotassium phosphate, in a solvent mixture such as 1,4-dioxane / water, at an elevated temperature such as 110 °C, with or without microwave conditions.

[0444] Suitable compounds of formula (XXVII) contain a precursor moiety of an alcohol such as an ester or a carboxylic acid. The compounds of formula (XXVII) can be commercially available or obtained by various reactions known to those skilled in the art including selective protection and deprotection steps. For the compounds of formula (XXVII), a borylation step may be required.

[0445] The X4 carbonyl in the compound of formula (XXVIII) is reduced to obtain a compound of formula (XXIX).

[0446] In the above reaction scheme, the alkylation between the compound of formula (XXIX) and the compound of formula (XIX) can be carried out in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 120 °C.

[0447] Suitable compounds of formula (XIX) are commercially available or can be obtained by the reaction of a compound of formula (XVIII) with CbzCl and sodium hydroxide in water as the solvent. Alternatively, the compound of formula (XIX) can be prepared by introducing Lg2 onto the compound of formula (XVIIIa).

[0448] The transcarbamoylation of the compound of formula (XXI) to the macrocycle of formula (XIII) can be carried out using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at a temperature ranging from room temperature to the reflux temperature of the solvent, or using sodium hydride in a dry solvent such as toluene at a temperature ranging from 0 °C to the reflux temperature of the solvent, with or without microwave conditions.

[0449] After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected under acidic conditions to give the final compound of formula (I).

[0450] Alternatively, the compound of formula (I) can be prepared as shown in the following general scheme F, in which the fused pyrazolo structure of formula (II) is converted into the protected compound of formula (III). This compound of formula (III) can be converted into the compound of formula (IV) containing a leaving group on the fused pyrazolo structure, and then into the nitrogen-protected compound of formula (V). The compound of formula (V) can be converted into the selectively protected fused pyrazolo structure of formula (VI), which is then alkylated with the intermediate of formula (XIX) containing a leaving group to give the compound of formula (XXII). The compound of formula (XIX) is commercially available or can be prepared from the compound of formula (XVIII) by reaction with CbzCl or by introducing the leaving group Lg2 onto the compound of formula (XVIIIa). The compound of formula (XXII) can be coupled with a (hetero-)aryl of formula by an organometallic cross-coupling reaction such as Suzuki coupling to form the 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 to the compound of formula (XXI). Then the compound of formula (XXI) can be cyclized by a transcarbamoylation reaction to form the compound of formula (XIII). After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected to give the compound of formula (I).

[0451] Solution F

[0452]

[0453] In the above reaction scheme F, the alkylation between the compound of formula (VI) and the compound of formula (XIX) can be carried out in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 120 °C.

[0454] Suitable compounds of formula (XIX) can be obtained commercially or by reacting a compound of formula (XVIII) with CbzCl and sodium hydroxide in water as a solvent. Alternatively, the compound of formula (XIX) can be prepared by introducing Lg2 onto the compound of formula (XVIIIa).

[0455] In the reaction between the above compound of formula (XXII) and the compound of formula (XXVII), the leaving group Lg1 is preferably a halogen atom such as chlorine, bromine or iodine. Such halogen substitution reactions can be carried out under cross-coupling conditions such as Suzuki conditions using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), with or without 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos), in the presence of tripotassium phosphate, in a solvent mixture such as 1,4-dioxane / water, at an elevated temperature such as 110 °C, with or without microwave conditions.

[0456] Suitable compounds of formula (XXVII) can be obtained commercially or by various reactions known to those skilled in the art including selective protection and deprotection steps. For compounds of formula (XXVII), a borylation step may be required.

[0457] Reducing the X4 carbonyl group in the compound of formula (XX) gives the compound of formula (XXI).

[0458] The transcarbamoylation of the compound of formula (XXI) to the macrocycle of formula (XIII) can be carried out using sodium hydride in dry toluene at an elevated temperature such as from 130 °C to 150 °C. Alternatively, the transcarbamoylation can be carried out using potassium carbonate or KOH in a solvent such as acetonitrile at an elevated temperature such as 140 °C. After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected under acidic conditions to give the final compound of formula (I).

[0459] Alternatively, the compounds of formula (I) can be prepared as shown in the following general scheme G, in which the fused pyrazolo structure of formula (II) is converted into a protected compound of formula (III), and then into a compound of formula (XIV) in which the nitrogen is protected. 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 give a compound of formula (XXIV). The compound of formula (XIX) can be prepared from a compound of formula (XVIII) by reaction with CbzCl or by introducing a leaving group Lg2 onto a compound of formula (XVIIIa). The compound of formula (XXIV) can be boronic esterified into a compound of formula (XXV). The boronic esterified compound of formula (XXV) can be reacted with an (hetero-)aryl of formula (XVI) in a cross-coupling such as a Suzuki coupling 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 to a compound of formula (XXI). Then the compound of formula (XXI) can be cyclized by a transcarbamoylation reaction to form a compound of formula (XIII). After carbamate alkylation and / or A-ring substitution is carried out or not carried out, the nitrogen of the fused pyrazolo structure is finally deprotected to give a compound of formula (I).

[0460] Solution G

[0461]

[0462] In the above reaction scheme G, the reaction between the compound of formula (XXIII) and the compound of formula (XIX) can be carried out in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate.

[0463] Suitable compounds of formula (XIX) are commercially available or can be obtained by reaction of a compound of formula (XVIII) with CbzCl and sodium hydroxide in water as a solvent. Alternatively, the compound of formula (XIX) can be prepared by introducing Lg2 onto a compound of formula (XVIIIa).

[0464] In the above reaction scheme, the boronation of the fused pyrazolo structure of the compound of formula (XXIV) into a compound of formula (XXV) can be carried out using an iridium catalyst and bis(pinacolato)diboron in a solvent such as TBME.

[0465] In the reaction between a compound of formula (XXV) and a compound of formula (XVI), the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such halogen substitution reactions can be carried out under cross-coupling conditions such as Suzuki conditions, for example using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), with or without 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos), in the presence of tripotassium phosphate, in a solvent mixture such as 1,4-dioxane / water, at an elevated temperature such as 90 °C, with or without microwave conditions.

[0466] Suitable compounds of formula (XVI) are commercially available or can be obtained by various reactions known to those skilled in the art, including selective protection and deprotection steps.

[0467] The X4 carbonyl moiety in the compound of formula (XX) can be reduced to the corresponding alcohol using, for example, sodium borohydride or lithium aluminium hydride in a solvent such as THF at an elevated temperature such as 120 °C.

[0468] The transcarbamoylation of the compound of formula (XXI) to the macrocycle of formula (XIII) can be carried out using potassium carbonate or caesium carbonate or potassium hydroxide in a solvent such as acetonitrile at a temperature ranging from room temperature to the reflux temperature of the solvent, or using sodium hydride in a dry solvent such as toluene at a temperature ranging from 0 °C to the reflux temperature of the solvent, with or without microwave conditions.

[0469] After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected under acidic conditions to give the final compound of formula (I). [[ID=~13]]

[0470] Alternatively, the compound of formula (I) can be prepared as shown in General Scheme H below, in which the fused pyrazolo structure of formula (II) is converted to a protected compound of formula (III), and then to a nitrogen-protected compound of formula (XIV). The compound of formula (XIV) can be converted to a selectively protected fused pyrazolo structure of formula (XXIII), which is then alkylated with a compound of an intermediate (XXX) containing a (hetero-)aromatic group to give a compound of formula (XXXI). The compound of formula (XXX) can be prepared using different reaction steps known to those skilled in the art and is described in detail for exemplary compounds. The compound of formula (XXXI) can be macrocyclized by a CH-activation reaction. After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected to give the compound of formula (I).

[0471] Solution H

[0472]

[0473] In the above reaction scheme H, the alkylation between the compound of formula (XXIII) and the compound of formula (XXX) can be carried out in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 80 °C.

[0474] Suitable compounds of formula (XXX) are commercially available or can be obtained by synthetic routes available in the literature. In the reaction between the above compound of formula (XXX) and the compound of formula (XXIII), the leaving group Lg2 is advantageously a mesylate group.

[0475] The CH activation of the compound of formula (XXXI) to the macrocycle of formula (XIII) can be carried out using CataCXium, palladium acetate and potassium acetate in dry toluene under microwave conditions at an elevated temperature such as 140 °C. The leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected under acidic conditions to give the compound of formula (I).

[0476] Alternatively, the compound of formula (I), particularly in the case of the compound of formula (I) in which X1 is NR’a, can be prepared as shown in the following general scheme I, in which the fused pyrazolo structure of formula (XXXII) in which X5 is, for example, nitro is converted into the protected compound of formula (XXXIII), and then into the nitrogen-protected compound of formula (XXXIV). The compound of formula (XXXIV) can be converted into the selectively protected fused pyrazolo structure of formula (VI), which is then alkylated with the compound of formula (VIII) containing the protecting group Pg3. After alkylation, X2 is deprotected to give the compound of formula (XXXVI), which is then coupled with the compound of formula (X) in a cross-coupling such as a Suzuki reaction. The resulting compound of formula (XII) can be macrocyclized to give the compound of formula (XIII). After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected to give the compound of formula (I).

[0477] Solution I

[0478]

[0479] In the above reaction scheme I, X5 is nitro and X1 is particularly NR’a in this scheme. The halogenation of the fused pyrazolo structure can be carried out using, for example, iodine and potassium oxide in a solvent such as N,N-dimethylformamide at an elevated temperature such as 60 °C.

[0480] The reduction of the nitro group can be obtained using iron in the presence of ammonium chloride in a solvent mixture such as EtOH, THF and water at an elevated temperature such as 80 °C, to give the compound of formula (VI).

[0481] The alkylation between the compound of formula (VI) and the compound of formula (VIII) can be carried out in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 80 or 90 °C. The compound of formula (VIII) contains a protecting group Pg3, which can be a phthalimide group.

[0482] The deprotection of X2-NPg3 in the compound of formula (IX) can be carried out using a reagent such as hydrazine in a solvent such as EtOH at an elevated temperature such as 60 °C.

[0483] The organometallic cross-coupling of the compound of formula (XXXVI) with the compound of formula (X), such as Suzuki coupling, can be carried out using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), with or without 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos), in the presence of tripotassium phosphate, in a solvent mixture such as 1,4-dioxane / water, at an elevated temperature such as 120 °C, with or without microwave conditions.

[0484] The cyclization of the compound of formula (XII) to give the compound of formula (XIII) can be carried out by methods known to those skilled in the art, such as carbamylation reaction, for example by treating with 1,1′-carbonyldiimidazole and N,N-diisopropylethylamine in a solvent such as N,N-dimethylacetamide at, for example, 90 °C. After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected under acidic conditions to give the final compound of formula (I).

[0485] Alternatively, the compound of formula (I) can be prepared as shown in the following general Scheme J, in which the fused pyrazolo structure of formula (II) is converted into the protected compound of formula (III). The compound of formula (III) can be converted into the compound of formula (IV) having a leaving group on the fused pyrazolo structure, and then into the nitrogen-protected compound of formula (V). The compound of formula (V) can be converted into the selectively protected fused pyrazolo structure of formula (VI), in which X1 is then protected into the compound of formula (XXXVII). The compound of formula (XXXVII) can be coupled with the (hetero)-aryl of formula (XXXVIII) by organometallic cross-coupling such as Suzuki coupling to form the compound of formula (XXXIX). The (hetero)-aromatic ring is alkylated to give the compound of formula (XL). Deprotection of X1 and then alkylation with the compound of formula (XIX) gives the compound of formula (XLII). The compound of formula (XIX) can be commercially available or prepared from the compound of formula (XVIII) by reaction with CbzCl or by introducing the leaving group Lg2 on the compound of formula (XVIIIa). Deprotection of X3 gives the compound of formula (XXI). Then the compound of formula (XXI) is cyclized by a transcarbamoylation reaction to the compound of formula (XIII). After no or carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected to give the compound of formula (I).

[0486] Solution J

[0487]

[0488] In the above Scheme J, the protection of X1 of the compound of formula (VI) can be carried out using benzyl chloride in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at room temperature or at an elevated temperature.

[0489] In the reaction between the compound of formula (XXXVII) and the compound of formula (XXXVIII) above, the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such halogen displacement reactions can be achieved under organometallic cross-coupling conditions such as Suzuki conditions using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), with or without 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) in combination, in the presence of tripotassium phosphate, in a solvent mixture such as 1,4-dioxane / water, at an elevated temperature such as 110 °C, with or without microwave conditions.

[0490] Suitable compounds of formula (XXXVIII) are commercially available or can be obtained by various reactions known to those skilled in the art, including selective protection and deprotection steps. For compounds of formula (XXXVIII), a borylation step may be required.

[0491] In the above reaction scheme, alkylation of the compound of formula (XXXIX) can be achieved using (2-bromoethoxy)(tert-butyl)dimethylsilane in a solvent such as N,N-dimethylformamide and a base such as sodium hydride at 0 °C or at room temperature.

[0492] Deprotection of X1 in the compound of formula (XL) can be achieved using hydrogen in the presence of Pd / C in a solvent such as EtOH at room temperature.

[0493] Alkylation between the compound of formula (XLI) and the compound of formula (XIX) can be achieved in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 120 °C.

[0494] Suitable compounds of formula (XIX) are commercially available or can be obtained by reacting a compound of formula (XVIII) with CbzCl and sodium hydroxide in water as a solvent. Alternatively, a compound of formula (XIX) can be prepared by introducing Lg2 onto a compound of formula (XVIIIa).

[0495] Deprotection of X3-OPg4 in the compound of formula (XLII) can be carried out using TBAF in a solvent such as THF at room temperature.

[0496] Transcarbamoylation of the compound of formula (XXI) to the macrocycle of formula (XIII) can be carried out using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at a temperature ranging from room temperature to the reflux temperature of the solvent, or using sodium hydride in a dry solvent such as toluene at a temperature ranging from 0 °C to the reflux temperature of the solvent, with or without microwave conditions.

[0497] After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected under acidic conditions to give the final compound of formula (I).

[0498] Alternatively, the compound of formula (I) can be prepared as shown in the following general Scheme K, in which the fused pyrazolo structure of formula (II) is converted into a protected compound of formula (III). The NH of the fused pyrazolo structure can be protected as a compound of formula (XIV). This compound of formula (XIV) can be converted into a boric acid (or boronic ester) of formula (XV). The compound of formula (XV) can be coupled with a (hetero-)aryl of formula (XLIII) or formula (XXVI) by organometallic cross-coupling such as Suzuki coupling to form a compound of formula (XLIV) or a compound of formula (XLIVa). Deprotection of X1 gives a compound of formula (XLV) or a compound of formula (XLVa). The compound of formula (XLV) or the compound of formula (XLVa) can be alkylated with an intermediate of formula (XIX) containing a carbamate to give a compound of formula (XLVI) or a compound of formula (XXI). Deprotection of X3-OPg4 in the compound of formula (XLVI) gives a compound of formula (XXI). The compound of formula (XXI) can then be cyclized to a compound of formula (XIII) by a transcarbamoylation reaction. After carbamate alkylation and / or A-ring substitution is carried out or not carried out, the nitrogen of the fused pyrazolo structure is finally deprotected to give a compound of formula (I).

[0499] Solution K

[0500]

[0501] In the above Scheme K, the boronylation of the fused pyrazolo structure of the compound of formula (XIV) to the compound of formula (XV) can be achieved using an iridium catalyst and bis(pinacolato)diboron in a solvent such as TBME.

[0502] In the reaction between the above compound of formula (XV) and the compound of formula (XLIII) or the compound of formula (XXVI), the leaving group Lg1 is preferably a halogen atom such as chlorine, bromine or iodine. Such a halogen substitution reaction can be carried out under cross-coupling conditions such as Suzuki conditions using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), in combination with 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos), in the presence of tripotassium phosphate, in a solvent mixture such as 1,4-dioxane / water, at an elevated temperature such as 90 °C, with or without microwave conditions.

[0503] Deprotection of X1 in the compound of formula (XLIV) or the compound of formula (XLVa) can be achieved using, for example, TBAF in a solvent such as THF at room temperature.

[0504] In the above reaction scheme, the alkylation between the compound of formula (XLV) or the compound of formula (XLVa) and the compound of formula (XIX) can be achieved in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 50 °C. Suitable compounds of formula (XIX) are commercially available or can be obtained by reacting a compound of formula (XVIII) with CbzCl and sodium hydroxide in water as a solvent. Alternatively, the compound of formula (XIX) can be prepared by introducing Lg2 onto the compound of formula (XVIIIa).

[0505] The deprotection of X3-OPg4 in the compound of formula (XLVI) can be achieved using conditions such as potassium carbonate in a solvent such as MeOH at room temperature.

[0506] The transcarbamoylation of the compound of formula (XXI) to the macrocycle of formula (XIII) can be carried out using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at a temperature ranging from room temperature to the reflux temperature of the solvent, or using sodium hydride in a dry solvent such as toluene at a temperature ranging from 0 °C to the reflux temperature of the solvent, with or without microwave conditions.

[0507] After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected under acidic conditions to give the final compound of formula (I).

[0508] Alternatively, the compound of formula (I) can be prepared as shown in the following general scheme L, in which the fused pyrazolo structure of formula (II) is converted to the protected compound of formula (III). The NH of the fused pyrazolo structure can be protected as the compound of formula (XIV). This compound of formula (XIV) can be converted to the boric acid (or borate ester) of formula (XV). The compound of formula (XV) can be coupled with the (hetero-)aryl of formula (XLVIII) in a cross-coupling reaction such as Suzuki coupling to form the compound of formula (XLIX). A leaving group is introduced at X2 to give the compound of formula (L). The deprotection of X1 gives the compound of formula (LI). Then the compound of formula (LI) can be cyclized by nucleophilic substitution to the compound of formula (XIII). After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected to give the compound of formula (I).

[0509] Solution L

[0510]

[0511] In the above reaction scheme L, the boronylation of the fused pyrazolo structure of the compound of formula (XIV) to the compound of formula (XV) can be achieved using an iridium catalyst and bis(pinacolato)diboron in a solvent such as TBME.

[0512] In the reaction between the compound of formula (XV) and the compound of formula (XLVIII) above, the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such halogen substitution reactions can be carried out under cross-coupling conditions such as Suzuki conditions using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), with or without 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) in combination, in the presence of tripotassium phosphate, in a solvent mixture such as 1,4-dioxane / water, at an elevated temperature such as 90 °C, with or without microwave conditions.

[0513] The compound of formula (XLVIII) can be prepared by reacting an alcohol of formula (XXVI), a chloroformate such as nitrobenzyl chloroformate and an amine of formula (XLVII).

[0514] The introduction of the leaving group X2 such as mesylate on the compound of formula (XLIX) can be carried out using methanesulfonyl chloride in the presence of a base such as trimethylamine in a solvent such as DCM at room temperature to give the compound of formula (L).

[0515] The deprotection of X1 to the compound of formula (LI) can be achieved using a reagent such as TBAF in a solvent such as THF at room temperature.

[0516] The macrocyclization of the compound of formula (LI) by nucleophilic substitution can be carried out using cesium carbonate in a solvent such as N,N-dimethylformamide at an elevated temperature such as 80 °C to give the compound of formula (XIII).

[0517] After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected under acidic conditions to give the final compound of formula (I).

[0518] Alternatively, the compounds of formula (I) can be prepared as shown in the following general Scheme M, in which the fused pyrazolo structure of formula (II) is converted into the protected compound of formula (III). The compound of formula (III) can be converted into the compound of formula (IV) having a leaving group on the fused pyrazolo structure, and then into the nitrogen-protected compound of formula (V). The compound of formula (V) can be converted into the selectively protected fused pyrazolo structure of formula (VI), which is then alkylated with the intermediate of formula (XIX) containing a leaving group to give the compound of formula (XXII). The compound of formula (XIX) can be commercially available or prepared from the compound of formula (XVIII) by reaction with CbzCl or by introducing the leaving group Lg2 on the compound of formula (XVIIIa). The compound of formula (XXII) can be coupled into the compound of formula (LIII) in a copper-mediated coupling with the protected alkyne (LII).

[0519] Deprotection of the alkyne gives the compound of formula (LIV). An (hetero-)aromatic ring can be formed from the alkyne to give the compound of formula (XLII). Deprotection of X3-OPg4 gives the compound of formula (XXI). The compound of formula (XXI) can then be cyclized to the compound of formula (XIII) by a transcarbamoylation reaction. After optional carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected to give the compound of formula (I).

[0520] Solution M

[0521]

[0522] In the above Scheme M, A is a 5-membered aromatic cyclic group as defined in formula (a), wherein A4 is a carbon atom and A5 represents an optionally substituted carbon atom.

[0523] In the above reaction scheme, the alkylation between the compound of formula (VI) and the compound of formula (XIX) can be achieved in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 120 °C.

[0524] Suitable compounds of formula (XIX) can be commercially available or obtained by reaction of the compound of formula (XVIII) with CbzCl and sodium hydroxide in water as a solvent. Alternatively, the compound of formula (XIX) can be prepared by introducing Lg2 on the compound of formula (XVIIIa).

[0525] In the reaction between the compound of formula (XXII) and the compound of formula (LII), the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such halogen displacement reactions can be achieved under conditions such as using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), with or without the combined use of CuI, in the presence of triethylamine, in a solvent such as THF, at an elevated temperature such as 80 °C.

[0526] The deprotection of the alkyne can be achieved using TBAF in a solvent such as THF at room temperature to give the compound of formula (LIV).

[0527] The formation of the heteroaromatic ring to give the compound of formula (XLII) can be achieved by reaction with a reagent such as tert-butyl-(3-nitropropoxy)-diphenyl-silane in the presence of PhNCO and trimethylamine in a solvent such as THF at an elevated temperature such as 80 °C.

[0528] The deprotection of X3-OPg4 on the compound (XLII) can be carried out using TBAF in a solvent such as THF at room temperature to give the compound of formula (XXI).

[0529] The transcarbamoylation of the compound of formula (XXI) to the macrocycle of formula (XIII) can be carried out using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at a temperature from room temperature to the reflux temperature of the solvent, or using sodium hydride in a dry solvent such as toluene at a temperature from 0 °C to the reflux temperature of the solvent, with or without microwave conditions.

[0530] After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected under acidic conditions to give the final compound of formula (I).

[0531] Alternatively, the compounds of formula (I) can be prepared as shown in the following general Scheme N, in which the fused pyrazolo structure of formula (II) is converted into a protected compound of formula (III). The compound of formula (III) can be converted into a compound of formula (IV) having 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 (VIIIa) to form a compound of formula (LV). Deprotection of X2-N(Ra)Pg3 gives a compound of formula (LVI). The compound of formula (LVI) can be coupled to an (hetero-)aromatic compound of formula (LVII) by reaction with CDI. Then, the compound of formula (LVIII) can be cyclized by CH activation reaction to form a compound of formula (XIII). After carbamate alkylation and / or A-ring substitution is carried out or not carried out, the nitrogen of the fused pyrazolo structure is finally deprotected to give the compound of formula (I).

[0532] Solution N

[0533]

[0534] In the above Reaction Scheme N, the alkylation between the compound of formula (VI) and the compound of formula (VIIIa) can be achieved in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at room temperature or at an elevated temperature. Suitable compounds of formula (VIIIa) are commercially available or can be obtained by various selective protection and deprotection steps known to those skilled in the art.

[0535] Deprotection of the compound of formula (LV) can be achieved using palladium on carbon and hydrogen at room temperature in a solvent such as MeOH.

[0536] Coupling of the (hetero-)aromatic moiety on formula (LVI) can be achieved at room temperature using 1,1′-carbonyldiimidazole and a base such as cesium carbonate in a solvent such as N,N-dimethylacetamide.

[0537] The ring closure of the CH activation of the compound of formula (LVIII) to the macrocycle of formula (XIII) can be carried out using cataCXium, palladium acetate and potassium acetate in dry toluene under microwave conditions at an elevated temperature such as 150 °C.

[0538] After carbamate alkylation and / or A-ring substitution is carried out or not carried out, the nitrogen of the fused pyrazolo structure is finally deprotected under acidic conditions to give the final compound of formula (I).

[0539] Alternatively, the compounds of formula (I) can be prepared as shown in the following general Scheme O, in which the fused pyrazolo structure of formula (II) is converted into a protected compound of formula (III). The NH of the fused pyrazolo structure can be protected as a compound of formula (XIV). This compound of formula (XIV) can be converted into a boric acid (or boronic ester) of formula (XV). The compound of formula (XV) can be coupled with a (hetero-)aryl of formula (XLIII) or formula (XXVI) by organometallic cross-coupling such as Suzuki coupling to form a compound of formula (XLIV) or a compound of formula (XLIVa), which is then alkylated with a compound of formula (XIX) and cyclized by a transcarbamoylation reaction in a one-pot reaction to form a compound of formula (XIII). Alternatively, the compound of formula (XLIVa) can first be deprotected to a compound of formula (XLIVb), followed by one-pot alkylation and cyclization. After no or with carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected to give the compound of formula (I).

[0540] Solution O

[0541]

[0542] In the above Scheme O, the borylation of the fused pyrazolo structure of the compound of formula (XIV) to the compound of formula (XV) can be achieved using an iridium catalyst and bis(pinacolato)diboron in a solvent such as TBME.

[0543] In the reaction between the above compound of formula (XV) and the compound of formula (XLIII) or the compound of formula (XXVI), the leaving group Lg1 is preferably a halogen atom such as chlorine, bromine or iodine. Such halogen substitution reactions can be carried out under cross-coupling conditions such as Suzuki conditions using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), in combination with 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos), in the presence of tripotassium phosphate, in a solvent mixture such as 1,4-dioxane / water, at an elevated temperature such as 90 °C, with or without microwave conditions.

[0544] The possible deprotection of X1 can be carried out using TBAF in a solvent such as THF at a temperature such as room temperature.

[0545] The possible one-pot alkylation and transcarbamoylation to the macrocycle of formula (XIII) with the compound of formula (XIX) can be carried out using cesium carbonate in a solvent such as acetonitrile at a temperature ranging from room temperature to 80 °C.

[0546] After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected under acidic conditions to give the compound of formula (I).

[0547] Alternatively, the compound of formula (I) can be prepared as shown in the following general scheme P, in which the fused pyrazolo structure of formula (II) is converted into the protected compound of formula (III). The NH of the fused pyrazolo structure can be protected as the compound of formula (XIV). This compound of formula (XIV) can be converted into the boric acid (or borate ester) of formula (XV). The compound of formula (XV) can be coupled with the (hetero-)aryl of formula (XXVI) by organometallic cross-coupling such as Suzuki coupling to form the compound of formula (XLIVa), which is then alkylated with the compound of formula (XLVI) and cyclized by a carbamylation reaction to form the compound of formula (XLVIII). After carrying out or not carrying out carbamate alkylation and / or A-ring substitution, the nitrogen of the fused pyrazolo structure is finally deprotected to give the compound of formula (I).

[0548] Solution P

[0549]

[0550] In the above reaction scheme P, the borylation of the fused pyrazolo structure of the compound of formula (XIV) into the compound of formula (XV) can be carried out using an iridium catalyst and bis(pinacolato)diboron in a solvent such as TBME.

[0551] In the reaction between the above compound of formula (XV) and the compound of formula (XXVI), the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such halogen displacement reactions can be achieved under cross-coupling conditions such as Suzuki coupling conditions using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), in combination with 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos), in the presence of tripotassium phosphate, in a solvent mixture such as 1,4-dioxane / water, at an elevated temperature such as 90 °C, with or without microwave conditions.

[0552] The alkylation of the compound of formula (XLV) with the compound of formula (XLVI) can be carried out using cesium carbonate in a solvent such as acetonitrile at a temperature from room temperature to 80 °C.

[0553] The carbamylation of the compound of formula (XLVIII) can be achieved using reagents such as CDI, COCl2, CO2 or CO.

[0554] After the carbamate alkylation and / or A-ring substitution is carried out or not, the nitrogen of the fused pyrazolo structure is finally deprotected under acidic conditions to obtain the final compound of formula (I). Example

[0555] The IUPAC names of the compounds of the present invention were generated using the following software:

[0556] Product version: MarvinSketch 18.3.0

[0557] Build date: 2018-01-26

[0558] Internal build id: 18.3.0-7913

[0559] Operating system: amd64 Windows 10.10.0

[0560] Character encoding: windows-1252

[0561] Java: Jeroen Frijters Java 1.8.0

[0562] Memory: Total 43.8M, 10.0M available

[0563] Environment: Application

[0564] .NET version: v2.0.50727

[0565] IKVM version: 8.10.1.2

[0566] JChem.NET API component version: 18.3.07913

[0567] JChem.NET API file version: 18.3.0.7913

[0568] Marvin.NET version: 18.3.0.137

[0569] Process type: x64

[0570] http: / / www.chemaxon.com

[0571] If there is a difference between the drawn chemical structure and the corresponding chemical name, the drawn chemical structure shall prevail.

[0572] To prepare the compounds described in the examples, the following experimental protocol was followed, unless otherwise stated.

[0573] Unless otherwise stated, the reaction mixture was magnetically stirred at room temperature.

[0574] When organic solutions are "dried", they are usually dried with desiccants such as sodium sulfate or magnesium sulfate. When mixtures, solutions and extracts are "concentrated", they are typically concentrated under reduced pressure on a rotary evaporator.

[0575] All intermediate and final exemplified compounds are analyzed by high performance liquid chromatography (HPLC) according to one of the following methods.

[0576] LCMS Method A

[0577] Analysis is performed using a Thermo Scientific Accucore C18 (50 mm long x 2.1 mm I.D., 2.6 μm) at 35 °C with a flow rate of 1.50 mL / min. Gradient elution is carried out: from 95% (water + 0.1% formic acid) / 5% acetonitrile to 5% (water + 0.1% formic acid) / 95% acetonitrile in 1.30 minutes; the resulting composition is 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 is 1 μL. The MS acquisition range and UV detector are set to 100 - 1000 m / z and 190 - 400 nm, respectively.

[0578] LCMS Method B

[0579] Analysis is performed using a Phenomenex Kinetex 00B - 4475 - AN C18 column (50 mm long x 2.1 mm I.D.; 1.7 μm particles) at 60 °C with a flow rate of 1.5 mL / min. Gradient elution is carried out: from 90% (water + 0.1% formic acid) / 10% acetonitrile to 10% (water + 0.1% formic acid) / 90% acetonitrile in 1.50 minutes; the resulting composition is 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 is 2 μL using an Agilent autosampler injector, or 5 μL using a Gerstel MPS injector. The MS acquisition range and DAD detector are set to 100 - 800 m / z and 190 - 400 nm, respectively.

[0580] LCMS Method C

[0581] Analysis was performed using a YMC Packed ODS-AQ C18 column (50 mm length x 4.6 mm I.D.; 3 μm particle size) at 35 °C with a flow rate of 2.6 mL / min. Gradient elution was carried out: from 95% (water + 0.1% formic acid) / 5% acetonitrile to 5% (water + 0.1% formic acid) / 95% acetonitrile over 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 over 0.2 min. The standard injection volume was 2 μL. The acquisition range was 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.

[0582] LCMS Method D

[0583] Analysis was performed using a Phenomenex Kinetex C18 column (50 mm length x 2.1 mm I.D.; 2.6 μm particle size) at 35 °C with a flow rate of 0.7 mL / min. Gradient elution was carried out: from 95% (water + 50 mM ammonium acetate) / 5% acetonitrile to 5% (water + 50 mM ammonium acetate) / 95% acetonitrile over 4.8 min; the resulting composition was held for 1.0 min; from 5% (water + 50 mM ammonium acetate) / 95% acetonitrile to 95% (water + 50 mM ammonium acetate) / 5% acetonitrile over 0.2 min. The standard injection volume was 2 μL. The acquisition range was 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.

[0584] LCMS Method E

[0585] [[ID=,12]]Analysis was performed using a YMC Packed ODS-AQ C18 column (50 mm length x 4.6 mm I.D.; 3 μm particle size) at 35 °C with a flow rate of 2.6 mL / min. Gradient elution was carried out: from 95% (water + 0.1% formic acid) / 5% acetonitrile - 5% (water + 0.1% formic acid) / 95% acetonitrile over 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 over 0.2 min. The standard injection volume was 2 μL. The acquisition range was set to 190 - 400 nm for the UV-PDA detector and 100 - 1400 m / z for the MS detector.

[0586] LCMS Method F

[0587] Analytical HPLC was performed using an X-Select CSH C18 XP column (2.5 μm 30 x 4.6 mm id), eluted with 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B), using the following elution gradient: 0 - 3 minutes: 5% - 100% B, 3 - 4 minutes 100% B, flow rate of 1.8 mL / minute, 40 °C. A Waters ZQ mass spectrometer (scanning 200 - 900 uma) was used with electrospray positive ionization [ES+ to obtain [M+H] + molecular ion] or electrospray negative ionization [ES- to obtain [M-H] - molecular ion] mode to record the mass spectrum (MS) at a cone voltage of 20 V.

[0588] LCMS method G

[0589] Analytical HPLC was performed using an X-Select CSH C18 XP column (2.5 μm 30 x 4.6 mm id), eluted with 2 g / L aqueous (NH4)2CO3 (solvent A) and acetonitrile (solvent B), using the following elution gradient: 0 - 3 minutes: 5% - 100% B, 3 - 4 minutes 100% B, flow rate of 1.8 mL / minute, 40 °C. A Waters ZQ mass spectrometer (scanning 200 - 900 uma) was used with electrospray positive ionization [ES+ to obtain [M+H] + molecular ion] or electrospray negative ionization [ES- to obtain [M-H] - molecular ion] mode to record the mass spectrum (MS) at a cone voltage of 20 V.

[0590] LCMS method H

[0591] Analytical HPLC was performed using an X-Select CSH C18 XP column (2.5 μm 30 x 4.6 mm id), eluted 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: 5% - 100% B, flow rate of 1.8 mL / minute, 40 °C. A Waters ZQ mass spectrometer (scanning 200 - 900 uma) was used with electrospray positive ionization [ES+ to obtain [M+H] + molecular ion] or electrospray negative ionization [ES- to obtain [M-H] - molecular ion] mode to record the mass spectrum (MS) at a cone voltage of 20 V.

[0592] LCMS method I

[0593] Analytical HPLC was performed using an X-Select CSH C18 XP column (2.5 μm 30x4.6 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% - 100% B, 4 - 5 min: 100% B, flow rate of 1.8 mL / minute, 40 °C. A Waters ZQ mass spectrometer (scanning 200 - 900 uma) was used with electrospray positive ionization [ES+, to obtain [M+H] + molecular ion] or electrospray negative ionization [ES-, to obtain [M-H] - molecular ion] mode to record the mass spectrum (MS) at a cone voltage of 20 V.

[0594] LCMS method J

[0595] Analytical HPLC was performed using an X-Select CSH C18 XP column (2.5 μm 30x4.6 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 - 6 minutes: 5% - 100% B, 6 - 7 min: 100% B, flow rate of 1.8 mL / minute, 40 °C. A Waters ZQ mass spectrometer (scanning 200 - 900 uma) was used with electrospray positive ionization [ES+, to obtain [M+H] + molecular ion] or electrospray negative ionization [ES-, to obtain [M-H] - molecular ion] mode to record the mass spectrum (MS) at a cone voltage of 20 V.

[0596] Chiral analytical SFC was performed using a Whelk O1 (R,R) column (1.8 μm 100x4.6 mmid), eluting with CO2 / methanol (70 / 30), flow rate of 2.5 mL / minute, 35 °C.

[0597] All final exemplary compounds were analyzed by proton NMR.

[0598] 11H NMR spectra were recorded on a Bruker Avance 400 MHz in CDCl3, d6-DMSO or CD3OD, or on a Bruker Ultrashield AV 300 MHz spectrometer, using a 5 mm BBI 1H / D-BB Z-GRD probe, a BACS-60 sample changer, and were registered with Bruker Topspin 2.1 software. Chemical shifts are reported in parts per million (ppm) relative to the residual protonated solvent (7.26 ppm for CDCl3, 2.50 ppm for d6-DMSO, 3.31 ppm for CD3OD). For 1 1H NMR spectra, multiplicities, coupling constants in Hz, and number of protons are given in parentheses. Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br s = broad singlet.

[0599] Alternatively, 1H-NMR measurements were performed using a Bruker Avance III 500 MHz spectrometer, 1 using DMSO-d6 (deuterated dimethyl sulfoxide) or CDCl3 (deuterated chloroform) as solvents. 1 1H-NMR data are in the form of δ values, given in parts per million (ppm), using the residual peak of the solvent (2.50 ppm for DMSO-d6, 7.26 ppm for CDCl3) as the internal standard. Splitting patterns are designated as: s (singlet), 2s (2x singlet), d (doublet), 2d (2x doublet), t (triplet), 2t (2x triplet), q (quartet), 2q (2x quartet), quint (quintet), sept (septet), m (multiplet), 2m (2x multiplet), brs (broad singlet), brd (broad doublet), brt (broad triplet), brq (broad quartet), brm (broad multiplet), vbrs (very broad singlet), dd (doublet of doublets), td (triplet of doublets), dt (doublet of triplets), dq (doublet of quartets), ddd (doublet of double doublets), dm (doublet of multiplets), tm (triplet of multiplets), qm (quartet of multiplets).

[0600] Abbreviation:

[0601] The following abbreviations are used in this article:

[0602] Ph = phenyl

[0603] Ac = acetate

[0604] Bn = benzyl

[0605] t-Bu = tert-butyl

[0606] n-Bu = n-butyl

[0607] Me = methyl

[0608] Et = ethyl

[0609] Pr = propyl

[0610] iPr = isopropyl

[0611] Bu = butyl

[0612] TMS = trimethylsilyl

[0613] TBS = tert-butyldimethylsilyl

[0614] TFA = trifluoroacetic acid

[0615] i-Pr2Net or DIPEA = N,N-diisopropylethylamine

[0616] TEA = triethylamine

[0617] DMAP = 4-dimethylaminopyridine

[0618] Pd / C = palladium on carbon

[0619] KOH = potassium hydroxide

[0620] NaOH = sodium hydroxide

[0621] LiOH = lithium hydroxide

[0622] Ar = argon

[0623] N2 = nitrogen

[0624] H2 = hydrogen

[0625] LAH = lithium aluminum hydride

[0626] Boc = tert-butoxycarbonyl

[0627] Cbz = carbobenzoxy

[0628] LDA = lithium diisopropylamide

[0629] NBS = N-bromosuccinimide

[0630] NIS = N-iodosuccinimide

[0631] ACN = acetonitrile

[0632] PTSA = p-toluenesulfonic acid

[0633] THF = tetrahydrofuran

[0634] DCM = Dichloromethane

[0635] DMF = N,N - Dimethylformamide

[0636] AA = Acetic acid

[0637] TBME = Methyl tert - butyl ether

[0638] Hept = Heptane

[0639] EtOAc = Ethyl acetate

[0640] DHP = 3,4 - Dihydro - 2H - pyran

[0641] THP = Tetrahydrofuran

[0642] TBAF = Tetrabutylammonium fluoride

[0643] cataCXium = Bis(1 - adamantyl)-n - butylphosphine

[0644] XPhos = 2 - Dicyclohexylphosphino - 2′,4′,6′ - triisopropylbiphenyl

[0645] dppf = 1,1′ - Bis(diphenylphosphino)ferrocene

[0646] wt% = Weight %

[0647] e.e. = Enantiomeric excess

[0648] min = Minute

[0649] h or hr = Hour

[0650] L = Liter

[0651] mL = Milliliter

[0652] μL = Microliter

[0653] g = Gram

[0654] mg = Milligram

[0655] mol = Mole

[0656] mmol = Millimole

[0657] RT = Room temperature

[0658] t R = Retention time

[0659] sat = Saturated

[0660] aq. = Aqueous

[0661] TLC = Thin - layer chromatography

[0662] HPLC = High Performance Liquid Chromatography

[0663] LC / MS = Liquid Chromatography / Mass Spectrometry

[0664] MS or Mass Spec = Mass Spectrometry

[0665] NMR = Nuclear Magnetic Resonance

[0666] ppm = parts per million

[0667] Example 1 : 8,14 - dioxo - 4,10,19,20 - tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos - 1(20),2,4,6(23),15,17,21 - heptaen - 9 - one

[0668]

[0669] Example 1 was prepared according to the synthetic route described in General Scheme A.

[0670] Preparation of Intermediate 1 : 5 - ((tert - butyldimethylsilyl)oxy) - 1H - indazole

[0671]

[0672] 1H - 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 - butyldimethylchlorosilane (23.485 g, 155.807 mmol) were added, and the mixture was stirred at RT for 16 h. Saturated NaHCO3 solution was added, and the reaction mixture was extracted with DCM (2x). The combined organic layers were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by silica gel flash chromatography using Hept / EtOAc (100:0 - 70:30). The required fractions were combined and concentrated under reduced pressure to give 5 - ((tert - butyldimethylsilyl)oxy) - 1H - indazole 1 as a salmon solid.

[0673] LCMS Method A: [M + H] + = 249.0, t R = 0.997 min

[0674] Preparation of Intermediate 2 : 5 - ((tert - butyldimethylsilyl)oxy) - 3 - iodo - 1H - indazole

[0675]

[0676] Dissolve 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1H-indazole 1 (20 g, 80.515 mmol) in 240 mL of DCM, add N-iodosuccinimide (19.021 g, 84.541 mmol), and stir the mixture at RT for 16 h. Dilute the reaction mixture with DCM and add saturated NaHCO3 solution. Separate the two layers and extract the aqueous layer with DCM (2x). Dry the combined organic layers over MgSO4, filter, and remove the solvent under reduced pressure to obtain the crude product. Purify the crude product by silica gel flash chromatography using Hept / EtOAc (100:0 - 80:20) as the eluent. Combine the desired fractions and remove the solvent under reduced pressure to obtain 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1H-indazole 2 as a light brown solid.

[0677] LCMS method A: [M + H] + = 374.9, t R = 1.156 min

[0678] Preparation of Intermediate 3 : 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0679]

[0680] To a solution of 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1H-indazole 2 (27.960 g, 74.699 mmol) in 224 mL of DCM, add 4-methylbenzenesulfonic acid monohydrate (1.421 g, 7.470 mmol) and 3,4-dihydro-2H-pyran (20.490 mL, 224.097 mmol). Stir the reaction mixture at RT for 16 h. Dilute the mixture with DCM and add saturated NaHCO3 solution. Separate the two layers and extract the aqueous layer with DCM (2x). Dry the combined organic layers over MgSO4, filter, and remove the solvent under reduced pressure. Purify the concentrate by flash chromatography (silica gel; heptane / EtOAc 100:0 - 95:5). Combine the desired fractions and remove the solvent under reduced pressure to obtain 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 3 as a light orange oil.

[0681] LCMS method A: [M + H] + = 458.9, t R = 1.377 min

[0682] Preparation of Intermediate 4 : 3-iodo-1-(tetrahydro-pyran-2-yl)-1H-indazol-5-ol

[0683]

[0684] 5-((tert-Butyldimethylsilyl)oxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (10.000 g, 21.814 mmol) was dissolved in 62 mL of THF. A solution of TBAF [1 M] in THF (32.8 mL, 32.800 mmol) was added at 0 °C. The reaction was stirred at RT for 16 h. Saturated NaHCO3 solution was added and the two layers were separated. The aqueous layer was extracted with DCM (2x). The combined organic layers were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (silica gel; heptane / EtOAc 100:0 - 60:40). The fractions containing the desired product were combined and the solvent was evaporated under reduced pressure to give 3-iodo-1-(tetrahydro-pyran-2-yl)-1H-indazol-5-ol 4 as a cream-like solid.

[0685] LCMS method B: [M+H] + = 345.0, t R = 0.767 min

[0686] Preparation of Intermediate 5 : 3-(Dibenzylamino)propan-1-ol

[0687]

[0688] Potassium carbonate (18.861 g, 136.466 mmol) and benzyl bromide (17.395 mL, 146.452 mmol) were carefully added to a solution of 3-aminopropan-1-ol (5 g, 66.569 mmol) in 200 mL of EtOH. The resulting mixture was stirred at reflux at 70 °C for 4 h. The mixture was filtered and the filtrate was washed with water. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel flash chromatography using Hept / EtOAc (100:0 - 80:20) as the eluent. The desired fractions were combined and the solvent was removed under reduced pressure to give 3-(dibenzylamino)propan-1-ol 5 as a slightly yellow oil.

[0689] LCMS method B: m / z not detected, t R = 0.248 min

[0690] Preparation of Intermediate 6 : 3-(Dibenzylamino)propyl methanesulfonate

[0691]

[0692] Dissolve 3-(dibenzylamino)propan-1-ol 5 (5.000 g, 19.580 mmol) in 60 mL of DCM, and add triethylamine (8.187 mL, 58.740 mmol). Cool the mixture to 0 °C, and add methanesulfonyl chloride (1.970 mL, 25.454 mmol). Stir the mixture at RT for 16 h. Add DCM and saturated NaHCO3 solution. Separate the two layers, and extract the mixture with DCM (x2). Dry the combined organic layers over MgSO4, filter, and remove the solvent under reduced pressure to obtain 3-(dibenzylamino)propyl methanesulfonate 6 as a yellow oil, which is used in the next step without further purification.

[0693] LCMS method B: m / z, t not detected R = 0.380 min

[0694] Preparation of Intermediate 7 : N,N-Dibenzyl-3-((3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)oxy)propan-1-amine

[0695]

[0696] Dissolve 3-(dibenzylamino)propyl methanesulfonate 6 (crude, 6.298 g, 18.888 mmol) in 10 mL of N,N-dimethylformamide, and add to a stirred mixture of 3-iodo-1-(tetrahydro-pyran-2-yl)-1H-indazol-5-ol 4 (5.000 g, 14.529 mmol) and cesium carbonate (7.101 g, 21.794 mmol) in 40 mL of N,N-dimethylformamide. Stir the reaction at RT for 30 min, then heat at 85 °C for 2 h. Dilute the mixture with EtOAc, and add water. Separate the two layers, and extract the aqueous layer with DCM (x2). Dry the combined organic layers over MgSO4, filter, and concentrate under reduced pressure. Purify the crude product by silica gel flash chromatography using (100:0 - 80:20). Combine the fractions containing the desired compound, and remove the solvent under reduced pressure to obtain N,N-dibenzyl-3-((3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)oxy)propan-1-amine 7 as a slightly yellow oil.

[0697] LCMS method B: [M+H] + = 582.2, t R = 0.890 min

[0698] Preparation of Intermediate 8 : (5-(Hydroxymethyl)pyridin-3-yl)boronic acid

[0699]

[0700] Dissolve (5-bromopyridin-3-yl)methanol (3.000 g, 15.956 mmol), bis(pinacolato)diboron (4.862 g, 19.147 mmol) and potassium acetate (4.698 g, 47.868 mmol) in 50 mL of 1,4-dioxane. After degassing with N2 for 5 minutes, add Pd(dppf)Cl2·DCM (1.303 g, 1.596 mmol), and stir the reaction mixture at 110 °C for 4 hours. Dilute the mixture with EtOAc and filter through a celite pad. Evaporate the solvent under reduced pressure to obtain (5-(hydroxymethyl)pyridin-3-yl)boronic acid 8 as a dark brown solid. Use the crude product in the next step without purification.

[0701] LCMS method B: [M+H] + = 154.1, t R = 0.107 min

[0702] Preparation of Intermediate 9 :{5-[5-(3-dibenzylamino-propoxy)-1-(tetrahydro-pyran-2-yl)-1H-indazol-3-yl]-pyridin-3-yl}-methanol

[0703]

[0704] Add a solution of tetrakis(triphenylphosphine)palladium(0) (1.411 g, 1.221 mmol) and XPhos (0.291 g, 0.611 mmol) to a mixture of N,N-dibenzyl-3-((3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)oxy)propan-1-amine 7 (7.100 g, 12.210 mmol), (5-(hydroxymethyl)pyridin-3-yl)boronic acid 8 (crude, 8.84 g, 15.873 mmol) and tripotassium phosphate (7.77 g, 36.63 mmol) in 122.00 mL of 1,4-dioxane / H2O (3:1). Degas the mixture with N2 for 5 min and stir at 90 °C for 16 hours. Dilute the mixture with EtOAc and add water. Separate the two layers and extract the aqueous layer with DCM (x2). Dry the combined organic layers over MgSO4, filter, and concentrate under reduced pressure. Purify the crude product by silica gel flash chromatography using DCM:MeOH (100:0 - 98:2). Combine the desired fractions and remove the solvent under reduced pressure to obtain {5-[5-(3-dibenzylamino-propoxy)-1-(tetrahydro-pyran-2-yl)-1H-indazol-3-yl]-pyridin-3-yl}-methanol 9 as a yellow oil.

[0705] LCMS method B: [M+H] + = 563.3, t R= 0.749 min

[0706] Preparation of Intermediate 10 :{5-[5-(3-Amino-propoxy)-1-(tetrahydro-pyran-2-yl)-1H-indazol-3-yl]-pyridin-3-yl}-methanol

[0707]

[0708] Dissolve {5-[5-(3-Dibenzylamino-propoxy)-1-(tetrahydro-pyran-2-yl)-1H-indazol-3-yl]-pyridin-3-yl}-methanol 9 (6.000 g, 10.662 mmol) in 106 mL EtOAc and degas with N2. Add Pd / C 10% w / w (6.000 g) and stir the reaction mixture with a balloon in a H2 atmosphere at RT for 66 h. Filter the reaction mixture through a celite pad and wash with a mixture of DCM:MeOH:DMA (9:1:1). Concentrate the filtrate under reduced pressure to obtain the crude product, which is purified by flash chromatography (silica gel, DCM / MeOH / MeOH(NH3) (100:0:0 - 90:9:1)). Combine the desired fractions and remove the solvent under reduced pressure to obtain {5-[5-(3-Amino-propoxy)-1-(tetrahydro-pyran-2-yl)-1H-indazol-3-yl]-pyridin-3-yl}-methanol 10 as a cream-like solid.

[0709] LCMS method B: [M+H] + = 383.3, t R = 0.316 min

[0710] Preparation of Intermediate 11 :19-(Oxan-2-yl)-8,14-dioxa-4,10,19,20-tetraazacyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0711]

[0712] CDI (0.103 g, 0.633 mmol) was added to a solution of (5-(5-(3-aminopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridin-3-yl)methanol 10 (0.220 g, 0.575 mmol) in 133 mL of DMA. The mixture was stirred at RT for 2 h and then at 90 °C for 72 h. The reaction was diluted with EtOAc, cooled to 0 °C, and saturated NaHCO3 solution was added. The two layers were separated and the aqueous layer was extracted with EtOAc (x2). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The product was purified by flash chromatography (silica gel, DCM:MeOH 100:0 - 97.5:2.5). The desired fractions were combined and the solvent was removed under reduced pressure to give 19-(oxan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one 11, as a colorless foam.

[0713] LCMS method B: [M+H] + = 409.1, t R = 0.753 min

[0714] Preparation of Example 1 :8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0715]

[0716] At RT, 19-(oxan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21A mixture of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one (0.135 g, 0.331 mmol) in 1,4-dioxane solution of HCl [4N] (33 mL) was stirred for 2 h. The mixture was cooled to 0 °C, diluted with DCM, and carefully quenched with saturated NaHCO3 solution. The two layers were separated, and the aqueous layer was extracted with DCM (x2). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel flash chromatography (DCM:MeOH, 100:0 - 94:6). The required fractions were combined, and the solvent was removed under reduced pressure to give 8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2, 6 .0 18,21 Tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one, Example 1, was a white solid.

[0717] LCMS method C: [M+H] + = 325.05, t R = 2.020 min

[0718] LCMS method D: [M+H] + = 325.1, t R = 3.945 min

[0719] 1 1H NMR (300 MHz, DMSO) δ: 13.32 (s, 1H), 9.03 (s, 1H), 8.53 (s, 1H), 8.15 (s, 1H), 7.99 (t, J = 5.9 Hz, 1H), 7.54 (d, J = 9.0 Hz, 1H), 7.21 (s, 1H), 7.01 (d, J = 8.9 Hz, 1H), 5.28 (brs, 2H), 4.29 (t, J = 8.3 Hz, 2H), 3.17 (d, J = 4.6 Hz, 2H), 1.97 (brs, 2H) ppm.

[0720] Example 2 : 10-Methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0721]

[0722] Example 2 was prepared according to the synthetic route described in General Scheme A.

[0723] Preparation of Intermediate 12 : 10-Methyl-19-(oxan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 eicosacosa-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0724]

[0725] Under a nitrogen atmosphere at 0 °C, sodium hydride 60% (0.007 g, 0.15 mmol) in mineral oil was added to a solution of intermediate 11 (0.05 g, 0.12 mmol) in 5 mL of dry N,N-dimethylformamide. 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 carefully quenched with water. The two layers were separated and the aqueous 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 silica gel flash chromatography (DCM:MeOH 100:0 - 97.5:2.5). The required fractions were combined and the solvent was removed under reduced pressure to give 10-methyl-19-(oxan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 eicosacosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 12, as a yellow oil.

[0726] LCMS method B: [M+H] + = 423.1, t R = 0.897 min

[0727] Preparation of Example 2 : 10-Methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2, 6 .0 18,21 eicosacosa-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0728]

[0729] At RT, 10-methyl-19-(oxan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21A mixture of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 12 (0.042 g, 0.099 mmol) in 1,4-dioxane solution of HCl [4N] (5.0 mL) was stirred for 2 h. The mixture was cooled to 0 °C, diluted with DCM, and carefully quenched with saturated NaHCO3 solution. The two layers were separated, and the aqueous layer was extracted with DCM (x2). The combined organic layers were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The product was purified by silica gel flash chromatography (DCM:MeOH, 100:0 - 94:6). The desired fractions were combined, and the solvent was removed under reduced pressure to give 10-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one, Example 2, was a white solid.

[0730] LCMS method E: [M+H] + = 339.1, t R = 2.298 min

[0731] LCMS method D: [M+H] + = 339.1, t R = 3.425 min

[0732] 1 1H NMR (300 MHz, 100 °C, d6-DMSO) δ 13.00 (s, 1H), 9.03 (s, 1H), 8.55 (s, 1H), 8.28 (s, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.20 (s, 1H), 7.02 (dd, J = 9.0, 2.3 Hz, 1H), 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.

[0733] Example 3 : 4-Fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0734]

[0735] Example 3 was prepared according to the synthetic route described in General Scheme A.

[0736] Preparation of Intermediate 13 : 2-[3-(3-Iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]isoindoline-1,3-dione

[0737]

[0738] A suspension of 3-iodo-1-tetrahydropyran-2-yl-indazol-5-ol 4 (4 g, 11.63 mmol), cesium carbonate (7.560 g, 23.26 mmol), and N-(3-bromopropyl)phthalimide (4.679 g, 17.45 mmol) in N,N-dimethylformamide (48 mL) was heated at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The resulting white solid was triturated with ethyl acetate and recovered. The recovered filtrate was washed with water. The aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with water and then with brine, dried over sodium sulfate, filtered, and evaporated in vacuo to give a cream-like solid. The white and cream-like solids were collected to give 2-[3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]isoindoline-1,3-dione 13 as a cream-like solid.

[0739] LCMS method F: [M+H] + = 532, t R = 3.12 min

[0740] Preparation of Intermediate 14 : 3-(3-Iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropan-1-amine

[0741]

[0742] A mixture of 2-[3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]isoindoline-1,3-dione 13 (6.176 g, 11.63 mmol) and hydrazine monohydrate (2.04 mL, 58.15 mmol) in EtOH (40 mL) was heated to 50 °C for 16 h. The reaction mixture was evaporated under reduced pressure, and EtOH was added to the white solid. The solid was filtered, washed with EtOH (3x), and the filtrate was evaporated under reduced pressure to give 3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropan-1-amine 14 as a light brown oil.

[0743] LCMS method F: [M+H] + = 402, t R = 1.65 min

[0744] Preparation of Intermediate 15:[3-[5-(3-aminopropoxy)-1-tetrahydropyran-2-yl-indazol-3-yl]-5-fluoro-phenyl]methanol

[0745]

[0746] To a degassed solution of 3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropan-1-amine 14 (200 mg, 0.500 mmol), 3-fluoro-5-(hydroxymethyl)phenylboronic acid (127 mg, 0.750 mmol), tripotassium phosphate (318 mg, 1.500 mmol) and xPhos (24 mg, 0.050 mmol) in 1,4-dioxane (3.2 mL) and water (1.4 mL) was added tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol). The reaction mixture was irradiated under μ-wave (Biotage Initiator +), absorption level: high, at 120 °C for 1 h. The reaction mixture was filtered through a celite bed and 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 and then with brine, dried over sodium sulfate and concentrated under reduced pressure to give [3-[5-(3-aminopropoxy)-1-tetrahydropyran-2-yl-indazol-3-yl]-5-fluoro-phenyl]methanol 15 as a pale yellow oil.

[0747] LCMS method F: [M+H] + = 400, t R = 1.76 min

[0748] Preparation of Intermediate 16 : 4-fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaene-9-one

[0749]

[0750] To a solution of [3-[5-(3-aminopropoxy)-1-tetrahydropyran-2-yl-indazol-3-yl]-5-fluoro-phenyl]methanol 15 (199 mg, 0.499 mmol) in DMA (150 mL) was added 1,1′-carbonyldiimidazole (89 mg, 0.549 mmol). The reaction mixture was stirred at RT for 2 h and then heated to 90 °C for 48 h. The reaction was concentrated in vacuo and then ethyl acetate and saturated aqueous NaHCO3 were added. The mixture was extracted with ethyl acetate (2x). The combined organic layers were washed with water and then with brine, dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography, eluting with cyclohexane / EtOAc / EtOH (3-1) 100 / 0 - 70 / 30 to afford 4-fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one 16, as a white solid.

[0751] LCMS method F: [M+H] + = 426, t R = 2.84 min

[0752] Preparation of Example 3 : 4-fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0753]

[0754] To a solution of 4-fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2 ,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one 16 (92 mg, 0.217 mmol) in 1,4-dioxane (2.6 mL) was added a 1,4-dioxane solution of 4M HCl (0.54 mL, 2.17 mmol). The reaction was stirred at RT for 1 h 30 min. The reaction mixture was heated to 50 °C for 60 h. The solvent was removed under reduced pressure and the gummy solid was recrystallized from acetonitrile to afford 4-fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .018,21 Example 3 of tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one is a white solid.

[0755] LCMS method F: [M+H] + = 342, t R = 2.16 min

[0756] LCMS method G: [M+H] + = 342, t R = 2.24 min

[0757] 1 H NMR (400 MHz, d6-DMSO) δ 13.06 (1H, s), 7.74 (2H, m), 7.62 - 7.58 (1H, m), 7.52 - 7.49 (1H, m), 7.35 (1H, m), 7.14 - 7.11 (1H, m), 7.00 (1H, m), 5.29 (2H, s), 4.33 (2H, t), 3.22 - 3.18 (2H, m), 2.06 - 2.05 (2H, m) ppm.

[0758] Example 4 : 8,14-dioxa-10,19,20,23-tetraazatricyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0759]

[0760] Example 4 was prepared according to the synthetic route described in General Scheme B.

[0761] Preparation of Intermediate 17 : tert-butyl-dimethyl-(1-tetrahydropyran-2-ylindazol-5-yl)oxy-silane

[0762]

[0763] To a solution of tert-butyl-(1H-indazol-5-yloxy)-dimethyl-silane 1 (15.95 g, 64.28 mmol) in DCM (200 mL) and THF (100 mL) at RT was added methanesulfonic acid (0.834 mL, 12.86 mmol) and DHP (17.59 mL, 192.84 mmol). The resulting mixture was stirred overnight at RT. The residue was diluted with saturated sodium bicarbonate solution and extracted twice with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (120 g silica Biotage) (cyclohexane-ethyl acetate, 1:0 - 90 / 10). The required fractions were combined and the solvent was evaporated under pressure to give tert-butyl-dimethyl-(1-tetrahydropyran-2-ylindazol-5-yl)oxy-silane 17 as white crystals.

[0764] LCMS method F: [M+H] + = 333.2, t R = 3.53 min

[0765] Preparation of Intermediate 18 : [5-[tert-butyl(dimethyl)silyl]oxy-1-tetrahydropyran-2-yl-indazol-3-yl]boronic acid and 5-[(tert-butyldimethylsilyl)oxy]-1-(oxan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

[0766]

[0767] Add tert-butyl-dimethyl-(1-tetrahydropyran-2-yl-indazol-5-yl)oxy-silane 17 (3 g; 9.03 mmol), TBME (15 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.3 g; 9.03 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (145 mg; 0.54 mmol) and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (119 mg; 0.18 mmol) to a sealed test tube. Degas the reaction with argon for 10 min and then react at 80 °C overnight. Remove the solvent under reduced pressure, and then dissolve the oily substance with ethyl acetate and water. Separate the layers and extract the aqueous layer with ethyl acetate twice. Combine the organic layers and remove the solvent under reduced pressure to obtain a mixture of [5-[tert-butyl(dimethyl)silyl]oxy-1-tetrahydropyran-2-yl-indazol-3-yl]boronic acid and 5-[(tert-butyldimethylsilyl)oxy]-1-(oxan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 18 as a brown oil. Use the product for the next step without further purification.

[0768] LCMS method F: [M+H] + = 459, t R = 3.80 min

[0769] LCMS method G: [M+H] + = 377.2, t R = 3.15 min

[0770] Preparation of Intermediate 19 : 2-(5-Hydroxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyridine-4-carboxylate

[0771]

[0772] To a solution of RT-[5-(tert-butyl(dimethyl)silyloxy)-1-tetrahydropyran-2-yl]indazole-3-ylboronic acid and 5-[(tert-butyldimethylsilyl)oxy]-1-(oxan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 18 (1.5 g, 3.99 mmol) in N,N-dimethylformamide (5 mL) was added methyl 6-bromopyridine-2-carboxylate (1.030 g, 4.78 mmol), cesium carbonate (3.8 g, 11.96 mmol), and PdCl2dppf.DCM (163 mg, 0.2 mmol). The resulting reaction mixture was stirred at 110 °C overnight. The solvent was removed under reduced pressure, and the oil was dissolved in EtOAc and water. The two layers were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (30 g silica BIOTAGE) (cyclohexane-ethyl acetate, 100 / 0 - 50 / 50) to give methyl 2-(5-hydroxy-1-tetrahydropyran-2-yl)indazole-3-ylpyridine-4-carboxylate 19 as a yellow powder.

[0773] LCMS method F: [M+H] + = 354.1, t R = 2.59 min

[0774] Preparation of Intermediate 20 : Benzyl N-(3-bromopropyl)carbamate

[0775]

[0776] To a solution of 3-bromopropylamine hydrochloride (6 g, 27 mmol) in 10% aqueous NaOH (40 mL) at 0 °C was slowly added CbzCl (4.3 mL, 30 mmol) and 10% NaOH (40 mL). After 12 h, the reaction mixture was diluted with DCM. The aqueous layer was extracted twice with DCM (100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica flash column chromatography (Macherey Nagel, 80 g) with gradient elution: cyclohexane / EtOAc 0 - 20% to give benzyl N-(3-bromopropyl)carbamate 20 as a clear oil.

[0777] LCMS method F: [M+H] + = 274, t R = 2.41 min

[0778] Preparation of Intermediate 21: Methyl 6-[5-(3-{[(benzyloxy)carbonyl]amino}propoxy)-1-(oxan-2-yl)-1H-indazol-3-yl]pyridine-2-carboxylate

[0779]

[0780] To a solution of methyl 6-[5-hydroxy-1-(oxan-2-yl)-1H-indazol-3-yl]pyridine-2-carboxylate 19 (1 g, 2.82 mmol) in N,N-dimethylformamide (100 mL) was added cesium carbonate (1.83 g, 5.6 mmol) and benzyl N-(3-bromopropyl)carbamate 20 (0.765 g, 2.82 mmol). The reaction was stirred at 120 °C for 16 h. The mixture was concentrated under reduced pressure. Water (200 mL) was added and the resulting mixture was extracted with EtOAc (4 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL). The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give a brown / orange oil. The residue was purified by silica gel flash chromatography (Macherey Nagel, 120 g), eluting with a gradient of cyclohexane / EtOAc 0 - 70% to give methyl 6-[5-(3-{[(benzyloxy)carbonyl]amino}propoxy)-1-(oxan-2-yl)-1H-indazol-3-yl]pyridine-2-carboxylate 21 as a white solid.

[0781] LCMS method F: [M+H] + = 545.2, t R = 3.21 min

[0782] Preparation of Intermediate 22 : Benzyl N-[3-({3-[6-(hydroxymethyl)pyridin-2-yl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamate[[ID=!8]]

[0783]

[0784] At 0 °C, a 1 M solution of lithium aluminum hydride (4.4 mL, 4.2 mmol) was added to methyl 6-[5-(3-{[(benzyloxy)carbonyl]amino}propoxy)-1-(oxan-2-yl)-1H-indazole-3-yl]pyridine-2-carboxylate 21 (1.2 g, 2.2 mmol) in THF (50 mL). The reaction mixture was stirred at 0 °C for 1 h. At 0 °C, EtOAc (10 mL) was added to the reaction mixture, which was then poured into 10% Rochelle's salt solution (100 mL) and EtOAc (100 mL). The mixture was stirred at RT for 2 h. After separation, the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give a brown / orange oil. The residue was purified by silica gel flash chromatography (Macherey Nagel, 120 g) with gradient elution: cyclohexane / EtOAc 0 - 100% to afford benzyl N-[3-({3-[6-(hydroxymethyl)pyridin-2-yl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamate 22 as a yellow oil.

[0785] LCMS method F: [M+H] + = 517.3, t R = 2.76 min

[0786] Preparation of Intermediate 23 : 19-(oxan-2-yl)-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0787]

[0788] A solution of benzyl N-[3-({3-[6-(hydroxymethyl)pyridin-2-yl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamate 22 (0.4 g; 0.775 mmol) in 100 mL of toluene was added over 30 min to a solution of sodium hydride (60% suspension in paraffin oil) (310 mg, 7.75 mmol) in 100 mL of toluene at room temperature. The reaction mixture was stirred at RT for 5 min and then at 130 °C for 1 h. The reaction was cooled and then 10 mL of EtOH was carefully added. 100 mL of water was added. After separation, the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give an orange oil. Purification by column chromatography (DCM / MeOH 0 - 10%) gave pure 19-(oxan-2-yl)-8,14-dioxa-10,19,20,23-tetraazatricyclo[13.5.2.1 2, 6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one 23, as a slightly off-white solid.

[0789] LCMS method F: [M + H] + = 409.2, t R = 2.53 min

[0790] Preparation of Example 4 : 8,14-dioxa-10,19,20,23-tetraazatricyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0791]

[0792] At room temperature, to 19-(oxan-2-yl)-8,14-dioxa-10,19,20,23-tetraazatricyclo[13.5.2.1 2,6 .0 18,21A solution of tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one (0.2 g; 0.489 mmol) in DCM (20 mL) was added with trifluoroacetic acid (0.38 mL, 4.89 mmol). The mixture was stirred at 50 °C for 24 hours. The reaction mixture was cooled. 50 mL of toluene was added to the solution, and the reaction mixture was concentrated under reduced pressure to obtain an orange oil. 25 mL of water, 25 mL of DCM and 25 wt% aqueous ammonia solution (1.5 mL) were added. After separation, the aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain an orange oil. Purification by column chromatography (DCM / MeOH 0 - 5%) gave pure 8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2, 6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one, Example 4, is a slightly white solid.

[0793] LCMS method F: [M+H] + = 325.2, t R = 1.93 min

[0794] LCMS method G: [M+H] + = 325.2, t R = 1.94 min

[0795] 1 H NMR (400 MHz, d6-DMSO) δ 13.2 (1H, m), 8.08 (1H, d, J = 9.7 Hz), 7.90 (1H, d, J = 3.5 Hz), 7.83 (1H, t, J = 8.3 Hz), 7.75 (1H, t, J = 5.9 Hz), 7.47 (1H, d, J = 8.3 Hz), 7.26 (1H, d, J = 8.3 Hz), 6.97 (1H, dd, J = 2.5, 9.1 Hz), 5.31 (2H, m), 4.31 (2H, dd, J = 7.7, 8.6 Hz), 3.11 - 3.09 (2H, m), 1.97 - 2.03 (2H, m) ppm.

[0796] Example 5 : 8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.]] 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0797]

[0798] Example 5 was prepared according to the synthetic route described in General Scheme A.

[0799] Preparation of Intermediate 24 :[3-[5-(3-aminopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl]phenyl]methanol

[0800]

[0801] To a degassed solution of 3-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)oxypropan-1-amine 14 (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 at 120 °C for 1 h under microwave conditions (Biotage initiator +). The reaction mixture was filtered through celite and the celite was washed with ethyl acetate. The filtrate was then diluted with water and extracted with ethyl acetate (3x). The organic layer was washed with water and then with brine, dried over sodium sulfate and concentrated under reduced pressure to give [3-[5-(3-aminopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl]phenyl]methanol 24 as a pale yellow oil.

[0802] LCMS method F: [M+H] + = 382, t R = 1.64 min

[0803] Preparation of Intermediate 25 :19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0804]

[0805] To a solution of 24 ([3-[5-(3-aminopropoxy)-1-tetrahydropyran-2-yl]indazol-3-yl]phenyl)methanol (380 mg, 0.998 mmol) in DMA (300 mL) was added 1,1′-carbonyldiimidazole (178 mg, 1.100 mmol). The reaction mixture was stirred at RT for 2 h and then at 90 °C for 64 h. The reaction was concentrated in vacuo, then ethyl acetate and saturated aqueous NaHCO3 were added. The mixture was extracted with ethyl acetate (2x). The combined organic layers were washed with water and then with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography, eluting with cyclohexane / ethyl acetate-EtOH (3-1):100 / 0-70 / 30 to give a white solid. The solid was recrystallized from acetonitrile to give 19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one 25, as a white solid.

[0806] LCMS method F: [M+H] + = 408, t R = 2.76 min

[0807] Preparation of Example 5 : 8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0808]

[0809] To a solution of 19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one 25 (81 mg, 0.199 mmol) in dioxane (2.4 mL) was added a solution of 4 M HCl in dioxane (0.75 mL, 2.985 mmol), and the reaction was heated to 50 °C for 24 h. The reaction mixture was cooled to RT, the solid was filtered, and then washed with diisopropyl ether (3x) to give 8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21Example 5 of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one is a white solid.

[0810] LCMS method F: [M+H] + = 324, t R = 2.02 min

[0811] LCMS method G: [M+H] + = 324, t R = 2.10 min

[0812] 1 H NMR (400 MHz, d6-DMSO) δ 7.93 - 7.87 (2H, m), 7.69 - 7.66 (1H, m), 7.50 - 7.44 (2H, m), 7.36 (1H, d, J = 2.3 Hz), 7.28 - 7.25 (1H, m), 6.98 (1H, dd, J = 2.3, 8.9 Hz), 5.33 - 5.29 (3H, m), 4.32 (2H, m), 3.18 (2H, m), 2.04 (2H, m) ppm.

[0813] Example 6 : 10-(propan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2, 6 .0 18,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0814]

[0815] Prepare Example 6 according to the synthetic route described in General Scheme A.

[0816] Prepare Example 6 using conditions similar to those of Example 2. 2-Iodopropane was used in the alkylation step of the carbamate to obtain 10-(propan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .01 8,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 6.

[0817] LCMS method E: [M+H] + = 367.2, t R = 2.829 min

[0818] LCMS method D: [M+H] += 367.2, t R = 3.832 min

[0819] 1 1H NMR (300 MHz, 100 °C, d6-DMSO) δ 12.96 (s, 1H), 9.01 (s, 1H), 8.54 (s, 1H), 8.39 (t, J = 2.1 Hz, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.23 (s, 1H), 6.99 (dd, J = 9.0, 2.3 Hz, 1H), 5.36 (brs, 2H), 4.28 (t, J = 8.6 Hz, 2H), 4.20–4.04 (m, 1H), 3.32 (brt, J = 7.3 Hz, 2H), 2.19 (brs, 2H), 1.18 (s, 3H), 1.15 (s, 3H) ppm.

[0820] Example 7 : 8,14-Dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0821]

[0822] Example 7 was prepared according to the synthetic route described in General Scheme B.

[0823] Example 7 was prepared using conditions similar to those of Example 4. Methyl 4-bromopyridine-2-carboxylate was used in the Suzuki reaction to obtain 8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 7.

[0824] LCMS method F: [M + H] + = 325.1, t R = 1.58 min

[0825] LCMS method G: [M + H] + = 325.2, t R = 1.83 min

[0826] 11H NMR (400 MHz, d6-DMSO) δ 13.28 (1H, s), 8.59 - 8.57 (1H, m), 7.86 (2H, m), 7.83 (1H, dd, J = 2.1, 5.5 Hz), 7.55 (1H, d, J = 9.0 Hz), 7.44 (1H, d, J = 2.1 Hz), 7.03 (1H, dd, J = 2.1, 9.0 Hz), 5.32 - 5.31 (2H, m), 4.37 (2H, dd, J = 8.3, 8.6 Hz), 3.19 - 3.18 (2H, m), 2.10 - 2.05 (2H, m) ppm.

[0827] Example 8 : 4-Methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0828]

[0829] Example 8 was prepared according to the synthetic route described in General Scheme C.

[0830] Preparation of Intermediate 26 : Benzyl N-[3-(3-iodo-1-(tetrahydropyran-2-yl)-1H-indazol-5-yl)oxypropyl]carbamate

[0831]

[0832] A suspension of 3-iodo-1-(tetrahydropyran-2-yl)-1H-indazol-5-ol 4 (17.012 g, 49.453 mmol), cesium carbonate (32.144 g, 98.906 mmol) and benzyl N-(3-bromopropyl)carbamate 20 (10.6 mL, 54.398 mmol) in N,N-dimethylformamide (250 mL) was heated at 60 °C for 20 h. The reaction mixture was filtered and rinsed with acetonitrile. The filtrate was crystallized, filtered to give a white solid, which was rinsed with water (3x). The filtrate was recovered, evaporated under reduced pressure to give a pink solid, which was dissolved in DCM and water was added. Extraction was carried out with DCM (2x), and then the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a light pink solid. The solid was recrystallized from acetonitrile to give benzyl N-[3-(3-iodo-1-(tetrahydropyran-2-yl)-1H-indazol-5-yl)oxypropyl]carbamate 26 as a white solid.

[0833] LCMS method F: [M+H] + = 536.0, t R = 3.11 min

[0834] Preparation of Intermediate 27 : Benzyl N-[3-[3-[3-(hydroxymethyl)-5-methoxyphenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl]oxypropyl]carbamate

[0835]

[0836] To a degassed solution of benzyl N-[3-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)oxypropyl]carbamate 26 (600 mg, 1.12 mmol), [3-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (444 mg, 1.68 mmol), tripotassium phosphate (713 mg, 3.36 mmol), and xPhos (53 mg, 0.112 mmol) in 1,4-dioxane (7 mL) and water (4.8 mL) was added tetrakis(triphenylphosphine)palladium(0) (65 mg, 0.056 mmol). The reaction mixture was irradiated under μ-wave (Biotage Initiator +), absorption level: high, at 120 °C for 1 h. The reaction mixture was filtered through celite and 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 and then with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography, eluting with DCM / ethyl acetate, 100 / 0 - 70 / 30, to give benzyl N-[3-[3-[3-(hydroxymethyl)-5-methoxyphenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl]oxypropyl]carbamate 27 as a colorless oil.

[0837] LCMS method F: [M+H] + = 546, t R = 2.89 min

[0838] Preparation of Intermediate 28 : 4-Methoxy-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0839]

[0840] To a suspension of potassium carbonate (80 mg, 0.582 mmol) in acetonitrile (12 mL) at RT was added dropwise a solution of N-[3-[3-[3-(hydroxymethyl)-5-methoxyphenyl]-1-(tetrahydropyran-2-yl)-1H-indazol-5-yl]oxypropyl]carbamic acid benzyl ester 27 (53 mg, 0.097 mmol) in acetonitrile (7 mL). The reaction mixture was heated at 140 °C for 6 h under microwave conditions. The reaction mixture was filtered and purified directly by column chromatography, eluting with DCM / ethyl acetate 100 / 0 - 80 / 20 to give 4-methoxy-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one 28, as a colorless oil.

[0841] LCMS method F: [M+H] + =438, t R =2.76 min

[0842] Preparation of Example 8 : 4-methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0843]

[0844] To a solution of 4-methoxy-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one 28 (23 mg, 0.053 mmol) in DCM (4 mL) at RT was added trifluoroacetic acid (80 μL, 1.06 mmol). The reaction mixture was irradiated under μ-wave (Biotage initiator +), absorption level: high, at 80 °C for 1 hour 30 minutes.

[0845] The crude reaction mixture was purified by flash column chromatography, eluting with DCM / ethyl acetate: 100 / 0 - 80 / 20 to give 4-methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21Example 8 of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one is a white solid.

[0846] LCMS method F: [M+H] + = 354, t R = 2.07 min

[0847] LCMS method G: [M+H] + = 354, t R = 2.09 min

[0848] 1 1H NMR (400 MHz, d6-DMSO) δ 12.89 (1H, s), 7.67 (1H, m), 7.52 - 7.47 (2H, m), 7.42 - 7.34 (2H, m), 6.99 - 6.96 (1H, m), 6.88 (1H, m), 5.25 (2H, m), 4.31 (2H, t), 3.86 (3H, s), 3.17 (2H, m), 2.03 (2H, m) ppm.

[0849] Example 9 : 4-bromo-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0850]

[0851] Example 9 can be prepared according to the synthetic routes described in General Schemes A, C, and D.

[0852] Preparation of Intermediate 29 : 1-tetrahydropyran-2-ylindazol-5-ol

[0853]

[0854] To a solution of tert-butyl-dimethyl-(1-tetrahydropyran-2-yl-indazol-5-yl)oxy-silane 17 (12.58 g, 37.8 mmol) in tetrahydrofuran (100 mL) was added portionwise a 1.0 M solution of tetra-n-butylammonium fluoride in THF (47.58 mL, 47.58 mmol). The reaction mixture was stirred at RT for 1 h. The reaction mixture was poured into ice water (300 mL) and stirred for 1 h. The aqueous phase was extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by silica column (RS SiOH 80 g) using cyclohexane / ethyl acetate 90 / 10 - 80 / 20 as eluent gave 1-tetrahydropyran-2-yl-indazol-5-ol 29 as a colorless oil.

[0855] LCMS method F: [M+H] + = 219, t R = 1.81 min

[0856] Preparation of Intermediate 30 : Benzyl N-[3-(1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]carbamate

[0857]

[0858] To a solution of 1-tetrahydropyran-2-yl-indazol-5-ol 29 (7.06 g, 32.3 mmol) in N,N-dimethylformamide (110 mL) at RT was added cesium carbonate (21.0 g, 64.6 mmol) and benzyl N-(3-bromopropyl)carbamate 20 (10.14 g, 37.3 mmol). The mixture was stirred at 80 °C overnight. The reaction mixture was concentrated under reduced pressure. Water (100 mL) and ethyl acetate (200 mL) were added to the residue. After separation, the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure.

[0859] Purification by silica column (RS SiOH 200 g) using cyclohexane / ethyl acetate 80 / 20 - 60 / 40 as eluent gave benzyl N-[3-(1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]carbamate 30 as an off-white solid.

[0860] LCMS method F: [M+H] + = 410.2, t R = 2.77 min (current 20 V)

[0861] Preparation of Intermediate 31: Benzyl N-[3-[1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl]oxypropyl]carbamate

[0862]

[0863] To a solution of benzyl N-[3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)oxypropyl]carbamate 30 (11.42 g, 27.9 mmol) in TBME / THF (500 / 100 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (7.79 g, 30.69 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (450 mg, 1.67 mmol). The reaction mixture was degassed by bubbling nitrogen through it for 15 min, and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (370 mg, 0.56 mmol) was added. The reaction mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The solvent was removed under reduced pressure, and the oil was then dissolved in ethyl acetate and water. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined and the solvent was removed under reduced pressure to give benzyl N-[3-[1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl]oxypropyl]carbamate 31 as a brown oil. The product was used in the next step without further purification.

[0864] LCMS method F: [M+H] + = 536.2, t R = 3.18 min (current 20 V)

[0865] Preparation of Intermediate 32 : (3-Bromo-5-iodo-phenyl)methanol

[0866]

[0867] To a solution of 3-bromo-5-iodobenzoic acid (10.0 g, 30.6 mmol) in THF (450 mL) at 0 °C was slowly added solid sodium borohydride (3.47 g, 91.8 mmol). At the end of gas evolution (i.e., 5 min), boron trifluoride etherate (11.3 mL, 91.8 mmol) was added dropwise at 0 °C. The reaction mixture was warmed to RT and stirred overnight at RT. The reaction mixture was cooled to 0 °C and 1 M aqueous sodium hydroxide solution (100 mL) was slowly added. The reaction mixture was filtered through a celite pad and eluted with ethyl acetate. The solution was washed with water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered off, and dried under reduced pressure to give the clean (3-bromo-5-iodophenyl)methanol 32 as a beige solid.

[0868] LCMS method F: [M+H] + = not detected, t R = 2.54 min (current 20 V)

[0869] Preparation of Intermediate 33 : Benzyl N-[3-[3-[3-bromo-5-(hydroxymethyl)phenyl]-1-(tetrahydropyran-2-yl)-1H-indazol-5-yl]oxypropyl]carbamate

[0870]

[0871] To a solution of benzyl N-[3-[1-(tetrahydropyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl]oxypropyl]carbamate 32 (1.870 g, 3.50 mmol) in N,N-dimethylformamide (15 mL) at RT was added (3-bromo-5-iodophenyl)methanol 31 (1.314 g, 4.20 mmol) and Cs2CO3 (3.421 g, 10.50 mmol). The reaction mixture was degassed by bubbling nitrogen through it for 15 min, and PdCl2dppf (0.128 g, 0.18 mmol) was added. The resulting mixture was stirred under microwave irradiation at 110 °C for 50 min. The reaction mixture was filtered through a 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) (cyclohexane-ethyl acetate, 100 / 0 - 50 / 50) gave benzyl N-[3-[3-[3-bromo-5-(hydroxymethyl)phenyl]-1-(tetrahydropyran-2-yl)-1H-indazol-5-yl]oxypropyl]carbamate 33 as an orange oil.

[0872] LCMS method F: [M+H] + = 596.1, t R = 3.07 min (current 20V)

[0873] Preparation of Intermediate 34 : 4-bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0874]

[0875] To a solution of N-[3-[3-[3-bromo-5-(hydroxymethyl)phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamic acid benzyl ester 33 (288 mg, 0.48 mmol) in dry toluene (300 mL) was added sodium hydride 60% in oil (480 mg, 12 mmol). The reaction mixture was stirred at 130 °C for 1 h. Then the reaction was stirred at RT overnight, and sodium hydride 60% in oil (192 mg, 4.8 mmol) was added. The reaction mixture was stirred at 130 °C for 3 h. Sodium hydride 60% in oil (192 mg, 4.8 mmol) was added again, and the reaction mixture was stirred at 140 °C overnight. Sodium hydride 60% in oil (192 mg, 4.8 mmol) was added again, and the reaction mixture was stirred at 140 °C for 5 h. Sodium hydride 60% in oil (192 mg, 4.8 mmol) was added again, and the reaction mixture was stirred at 140 °C for 1 h until the reaction was complete. The reaction mixture was allowed to reach RT and cooled with an ice bath. EtOH (50 mL) was added slowly. The reaction mixture was diluted with ethyl acetate (200 mL) and water (200 mL) was added. After separation, the aqueous layer was extracted with ethyl acetate (x3 50 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered, and dried under reduced pressure to give an orange oil.

[0876] Purification was carried out using a silica column (RS SiOH 80 g), using cyclohexane / ethyl acetate 100 / 0 - 0 / 100 and DCM / MeOH 90 / 10 as eluents to give 60 mg of the desired product. The impure fractions were collected and the solvent was removed under reduced pressure. The residue was purified using a silica column (RS SiOH 40 g), using cyclohexane / ethyl acetate 100 / 0 - 50 / 50 as eluent to give 4-bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one 34 is a white solid.

[0877] LCMS method F: [M+H] + = 487.7, t R = 3.05 min

[0878] Preparation of Example 9 : 4-Bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0879]

[0880] To a solution of 4-bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2 ,6 .0 18,21 Tricos-1(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 μL, 1.24 mmol). The reaction mixture was stirred at 80 °C under microwave irradiation for 2 h. The reaction mixture was diluted with DCM (20 mL). Water (50 mL) and 25% aqueous ammonium hydroxide solution (3 mL) were added. After separation, the aqueous layer was extracted with DCM (x3 10 mL). The organic layer was washed with saturated aqueous sodium carbonate solution (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate, filtered, and dried under reduced pressure to obtain an off-white solid. DCM was added to the solid. The precipitate was filtered and the filtrate was purified by preparative TLC using cyclohexane / ethyl acetate; 50 / 50 as the eluent. The resulting product was purified by preparative TLC one more time using cyclohexane / ethyl acetate; 50 / 50 as the eluent to obtain 4-bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 9 is an off-white solid.

[0881] LCMS method F: [M+H] + = 403, t R = 2.40 min

[0882] LCMS method G: [M+H] += 403, t R = 2.38 min

[0883] 1 H NMR (400 MHz, d6-DMSO) δ 13.07 (1H, s), 8.02 (1H, s), 7.87 (1H, s), 7.74 (1H, s), 7.51 (2H, q, J = 2.8 Hz), 7.32 (1H, d, J = 2.7 Hz), 7.00 (1H, dd, J = 2.3, 8.9 Hz), 5.29 (2H, m), 4.32 (2H, m), 3.18 (2H, m, J = 8.1 Hz), 2.03 (2H, m) ppm.

[0884] Example 10 : 5-Fluoro-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0885]

[0886] Example 10 was prepared according to the synthetic route described in General Scheme E.

[0887] Preparation of Intermediate 35 : 2-Fluoro-5-[5-hydroxy-1-(oxan-2-yl)-1H-indazol-3-yl]benzoic acid

[0888]

[0889] To a solution of 3-iodo-1-(oxan-2-yl)-1H-indazol-5-ol 4 (1 g, 2.90 mmol) and 2-fluoro-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.925 g, 2.52 mmol) in dioxane / water; 70 / 30 (12 mL) was added tripotassium phosphate (1.84 g, 8.7 mmol). The mixture was degassed for 15 minutes by bubbling with nitrogen. Xphos (0.138 g, 0.29 mmol) and tetrakis(triphenylphosphine)palladium (0.167 g, 0.145 mmol) were added. The mixture was heated at 120 °C under microwave irradiation (BIOTAGE) for 2 hours. The reaction mixture was filtered through celite and eluted with ethyl acetate. The solution was washed with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to give a brown oil, which was purified by Biotage silica column using cyclohexane / ethyl acetate 100 / 0 - 20 / 80 as eluent to give 2-fluoro-5-[5-hydroxy-1-(oxan-2-yl)-1H-indazol-3-yl]benzoic acid 35 as a white powder.

[0890] LCMS method F: [M + H] + = 357.1, t R = 2.34 min

[0891] Preparation of Intermediate 36 : 3-[4-fluoro-3-(hydroxymethyl)phenyl]-1-(oxan-2-yl)-1H-indazol-5-ol

[0892]

[0893] To a solution of RT 2-fluoro-5-[5-hydroxy-1-(oxan-2-yl)-1H-indazol-3-yl]benzoic acid 35 (0.2 g, 0.56 mmol) in THF (25 mL) was added solid sodium borohydride (0.062 g, 1.68 mmol). At the end of gas evolution (i.e., 5 min), the reaction mixture was cooled to 0 °C and neat boron trifluoride diethyl etherate (0.163 mL, 1.68 mmol) was added dropwise over 1 h. The reaction mixture was warmed to RT and stirred at 65 °C for 2 h. The reaction mixture was cooled to 0 °C and 1 M aqueous sodium hydroxide solution (50 mL) was added. The mixture was stirred at RT for 2 h. The reaction mixture was filtered through celite and eluted with ethyl acetate. The solution was washed with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to give a brown oil. Purification using a silica column (Biotage) with cyclohexane / ethyl acetate 100 / 00 - 50 / 50 as the eluent gave 3-[4-fluoro-3-(hydroxymethyl)phenyl]-1-(oxan-2-yl)-1H-indazol-5-ol 36 as a white powder.

[0894] LCMS method F: [M + H] + = 343.1, t R = 2.27 min

[0895] Preparation of Intermediate 37 : Benzyl N-[3-({3-[4-fluoro-3-(hydroxymethyl)phenyl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamate

[0896]

[0897] To a solution of 3-[4-fluoro-3-(hydroxymethyl)phenyl]-1-(oxan-2-yl)-1H-indazol-5-ol 36 (0.18 g, 0.52 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (0.338 g, 1.04 mmol) and tert-butyl 3-[(formyloxy)methyl]pyrrolidine-1-carboxylate 20 (0.169 g, 0.624 mmol). The reaction was stirred at 80 °C for 16 h. The mixture was concentrated under reduced pressure. Water (50 mL) was added and the resulting mixture was extracted with EtOAc (4 x 100 mL). The 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 give a brown / orange oil. The residue was purified by flash chromatography on silica gel (Macherey Nagel, 12 g), eluting with a gradient of cyclohexane / EtOAc 0 - 70% to give benzyl N-[3-({3-[4-fluoro-3-(hydroxymethyl)phenyl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamate 37 as a white solid.

[0898] LCMS method F: [M+H] + = 534.2, t R = 2.90 min

[0899] Preparation of Intermediate 38 : 5-fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0900]

[0901] At room temperature, sodium hydride (a 60% suspension in paraffin oil) (114 mg, 2.8 mmol) in 50 mL of toluene was added to a solution of N-[3-({3-[4-fluoro-3-(hydroxymethyl)phenyl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamic acid benzyl ester 37 (0.153 g; 0.28 mmol) in 50 mL of toluene. The reaction mixture was stirred at RT for 5 min and then at 130 °C for 1 h. The reaction was cooled to room temperature, and then 10 mL of EtOH was carefully added. 100 mL of water was added. After separation, the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to give an orange oil. Purification by column chromatography (DCM / MeOH 0 - 10%) gave pure 5-fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one 38, as a slightly white solid.

[0902] LCMS method F: [M + H] + = 426.2, t R = 2.78 min

[0903] Preparation of Example 10 : 5-fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0904]

[0905] To 5-fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2 ,6 .0 18,21A solution of tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one 38 (35 mg, 0.082 mmol) in DCM (5 mL) was added with trifluoroacetic acid (63 μL, 0.82 mmol). The reaction mixture was stirred at RT for 6 h and at 30 °C overnight. Trifluoroacetic acid (32 μL, 0.41 mmol) was added again, and the reaction mixture was stirred at 50 °C for 5 h. Another portion of trifluoroacetic acid (32 μL, 0.41 mmol) was added again, 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 25% aqueous ammonium hydroxide solution (3 mL) were added. After separation, the aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layers were washed with saturated sodium carbonate solution (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give a beige solid.

[0906] The residue was triturated once in acetonitrile, five times in DCM, and twice in EtOH to give 5-fluoro-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 10, was a white powder.

[0907] LCMS method F: [M+H] + = 342.1, t R = 2.18 min

[0908] LCMS method G: [M+H] + = 342.1, t R = 2.36 min

[0909] 1 1H NMR (400 MHz, d6-DMSO) δ 12.95 (1H, s), 7.93 (2H, m), 7.81 (1H, s), 7.89 (1H, d, J = 9.0 Hz), 7.33 (2H, m), 6.99 (1H, dd, J = 9.1 Hz), 5.35 (2H, s), 4.33 (2H, m), 3.19 (2H, m), 2.03 (2H, m) ppm.

[0910] Example 11 : 5-methyl-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,211(20),2,4,6(23),15,17,21 - Heptadecen - 9 - one

[0911]

[0912] Example 11 was prepared according to the synthetic route described in General Scheme F.

[0913] Preparation of Intermediate 39 Methyl 5 - [5 - [3 - (benzyloxycarbonylamino)propoxy] - 1 - tetrahydropyran - 2 - yl - indazol - 3 - yl] - 2 - methylbenzoate

[0914]

[0915] A solution of N - [3 - (3 - iodo - 1 - tetrahydropyran - 2 - yl - indazol - 5 - yl)oxypropyl]carbamic acid benzyl ester 26 (1.2 g, presumed 2.2 mmol), (3 - methoxycarbonyl - 4 - methyl - phenyl)boronic acid (467 mg, 2.42 mmol), tripotassium phosphate (1.4 g, 6.6 mmol) and triethylamine (1.4 mL, 9.9 mmol) in THF / H2O (6.5 / 3.2 mL) was degassed for 15 minutes. Pd(dppf)Cl2.DCM (179 mg, 0.22 mmol) was added and the reaction mixture was stirred at 100 °C for 17 hours under a nitrogen atmosphere. The reaction mixture was filtered through celite and washed with EtOAc. The filtrate was diluted with water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by column (Macherey Nagel, 40 g) chromatography using eluent cyclohexane / EtOAc (100 / 0 - 80 / 20). The desired fractions were collected and the solvent was removed under reduced pressure to give methyl 5 - [5 - [3 - (benzyloxycarbonylamino)propoxy] - 1 - tetrahydropyran - 2 - yl - indazol - 3 - yl] - 2 - methylbenzoate 39 (1.04 g, 1.87 mmol) as a white solid.

[0916] LCMS method F: [M + H] + = 558, t R = 3.33 min

[0917] Preparation of Intermediate 40 N - [3 - [3 - [3 - (hydroxymethyl) - 4 - methyl - phenyl] - 1 - tetrahydropyran - 2 - yl - indazol - 5 - yl]oxypropyl]carbamic acid benzyl ester

[0918]

[0919] At 0 °C under a N2 atmosphere, a 1 M solution of LAH in THF (2.2 mL, 2.2 mmol) was added to a solution of methyl 5-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-methyl-benzoate 39 (1 g, 1.8 mmol) in THF (6 mL). The reaction was stirred at 0 °C for 2 hours and 30 minutes. The mixture was quenched with water (1 mL), 10% NaOH (0.2 mL), and water (0.5 mL). The mixture was filtered and washed with EtOAc. The filtrate was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by passing through a silica pad, using cyclohexane / EtOAc (60 / 40) as the eluent, to give N-[3-[3-[3-(hydroxymethyl)-4-methyl-phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamic acid benzyl ester 40 as a white oil.

[0920] LCMS method F: [M+H] + = 530, t R = 2.90 min

[0921] Preparation of Intermediate 41 : 5-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0922]

[0923] Potassium carbonate (190 mg, 1.38 mmol) was added to a solution of N-[3-[3-[3-(hydroxymethyl)-4-methyl-phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamic acid benzyl ester 40 (120 mg, 0.23 mmol) in acetonitrile (40 mL). The mixture was divided into two vials and then heated in a microwave at 140 °C for 4 hours and 30 minutes. The two vials were heated in the microwave at 140 °C for an additional 4 hours. The mixture was filtered to remove potassium carbonate and the solvent was evaporated under reduced pressure to give 5-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one 41 as a white powder. The crude product was used in the next step without further purification.

[0924] LCMS method F: [M+H] + = 422, t R = 2.87 min

[0925] Preparation of Example 11 : 5-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0926]

[0927] To a solution of 5-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one 41 (84 mg, 0.2 mmol) in DCM (15 mL) was added trifluoroacetic acid (306 μL, 4 mmol). The mixture was heated in a microwave at 80 °C for 1 h. The solvent was removed under reduced pressure to give an oily residue, which was dissolved in DCM (20 mL). A precipitate formed and was filtered. The solid was dissolved in DCM / MeOH (15 mL), and then saturated NaHCO3 (15 mL) was added. After separation, the aqueous layer was removed with DCM (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give 5-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 11, as a white solid.

[0928] LCMS method F: [M+H] + = 338, t R = 2.32 min

[0929] LCMS method G: [M+H] + = 338, t R = 2.35 min

[0930] 11H NMR (400 MHz, d6-DMSO) δ 12.86 - 12.79 (1H, m), 7.84 (1H, m), 7.82 (1H, m), 7.74 (1H, s), 7.46 (1H, d, J = 8.9 Hz), 7.42 (1H, m), 7.28 (1H, dd, J = 0.6, 8.3 Hz), 6.98 (1H, dd, J = 2.4, 9.0 Hz), 5.28 (2H, s), 4.34 (2H, dd, J = 8.2, 8.5 Hz), 3.2 (2H, m), 2.32 (3H, s), 2.04 - 1.99 (2H, m) ppm.

[0931] Example 12 : 4-(Pyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2, 6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0932]

[0933] Example 12 was prepared according to the synthetic route described in General Scheme C. Pyrrolidine was used for the Buchwald reaction with bromide intermediate 34.

[0934] Preparation of Intermediate 42 : 19-(Oxan-2-yl)-4-(pyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0935]

[0936] In a solution of 4-bromo-10-methyl-19-(oxan-2-yl)-7-oxa-10,13,19,20-tetraazatetracyclo[13.5.2.12,6.018,21]tricosa-1(20),2,4,6(23),15(22),16,18(21)-heptaen-14-one Example 9 (100 mg, 0.206 mmol), pyrrolidine (19 μl, 0.227 mmol), tBuONa (40 mg, 0.412 mmol) and SPhos (3 mg, 0.008 mmol) in dioxane (2.5 mL) was added Pd2dba3 (4 mg, 0.004 mmol). The reaction mixture was stirred at 60 °C for 45 min under microwave irradiation. Pyrrolidine (2 μl; 0.021 mmol) was added again and the reaction was stirred at 60 °C for 20 min under microwave irradiation. After cooling to RT, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column (5 g SiO2) chromatography (cyclohexane / ethyl acetate, 1:0 - 50 / 50) to give 19-(oxan-2-yl)-4-(pyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 42, as a white powder.

[0937] LCMS method F: [M+H] + = 477.2, t R = 3.00 min

[0938] Preparation of Example 12 : 4-(pyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0939]

[0940] To 19-(oxan-2-yl)-4-(pyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21A mixture of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 42 (60 mg; 0.126 mmol) in DCM (2.5 mL) was added to TFA (48 μl; 0.630 mmol). The reaction mixture was stirred at 80 °C for 30 min under microwave irradiation. The solvent was removed under reduced pressure, and the mixture was dissolved in EtOAc and washed with 1 N NaOH (pH = 7) and then with water. The organic layer was concentrated under reduced pressure, and the product was purified by chromatography using a 4 g SiO2 column, eluting with DCM / MeOH 100 / 0 - 90 / 10. The desired fractions were combined to give 4-(pyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21 Tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one, Example 12, was a yellow powder.

[0941] LCMS method F: [M+H] + = 393.1, t R = 2.39 min (current 20 V)

[0942] LCMS method G: [M+H] + = 393.1, t R = 2.47 min (pH 10 current 20 V)

[0943] 1 1H NMR (400 MHz, d6-DMSO) δ 7.61 (1H, m), 7.47 - 7.44 (1H, m), 7.36 (1H, d, J = 2.7 Hz), 7.20 (1H, s), 7.04 (1H, t, J = 1.9 Hz), 6.95 (1H, dd, J = 2.4, 9.0 Hz), 6.50 (1H, s), 5.22 - 5.20 (2H, m), 4.30 (2H, d, J = 16.9 Hz), 3.32 (4H, m), 3.17 - 3.15 (2H, m), 2.03 - 1.99 (6H, m), 1.07 (1H, d, J = 6.1 Hz) ppm.

[0944] Example 13 : 4-[4-(propan-2-yl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21 Tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0945]

[0946] Example 13 was prepared according to a synthetic route similar to that described in General Procedure C and the method used to obtain Example 12. 1-(Propan-2-yl)piperazine was used for the Buchwald reaction with bromide intermediate 34 to obtain 4-[4-(propan-2-yl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 13.

[0947] LCMS method F: [M+H] + = 450.2, t R = 1.54 min

[0948] LCMS method G: [M+H] + = 450.2, t R = 2.26 min

[0949] 1 H NMR (400 MHz, d6-DMSO, 80 °C) δ 12.80 (1H, s), 7.68 - 7.57 (1H, m), 7.46 (1H, d, J = 9.3 Hz), 7.37 - 7.34 (3H, m), 6.96 (1H, dd, J = 2.4, 8.8 Hz), 6.87 (1H, s), 5.23 (2H, s), 4.28 (2H, s), 3.25 - 3.22 (4H, m), 3.17 (2H, s), 2.76 - 2.67 (1H, m), 2.66 - 2.61 (4H, m), 2.02 (2H, s), 1.05 (6H, d, J = 6.5 Hz) ppm.

[0950] Example 14 : 4-{2-oxa-6-azaspiro[3.4]octan-6-yl}-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0951]

[0952] Example 14 was prepared according to the synthetic route described in General Scheme C and a method similar to the method for obtaining Example 12. 2-Oxa-6-azaspiro[3.4]octane was used for the Buchwald reaction with bromide intermediate 34 to obtain 4-{2-oxa-6-azaspiro[3.4]octan-6-yl}-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 14.

[0953] LCMS method F: [M+H] + = 435, t R = 2.16 min

[0954] LCMS method G: [M+H] + = 435, t R = 2.20 min

[0955] 1 H NMR (400 MHz, d6-DMSO, 80 °C) δ 12.77 (1H, s), 7.61 (1H, m), 7.46 (1H, d, J = 9.2 Hz), 7.36 (1H, m), 7.22 (1H, m), 7.04 (1H, m), 6.96 (1H, m), 6.51 (1H, m), 5.22 (2H, m), 4.64–4.56 (4H, m), 4.30 (2H, m), 3.60 (2H, s), 3.35 (2H, t), 3.16 (2H, m), 2.31 (2H, m), 2.02 (2H, m) ppm.

[0956] Example 15 : 4-[4-(oxetan-3-yl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0957]

[0958] Example 15 was prepared according to the synthetic route described in General Scheme C and a method similar to the method for obtaining Example 12. 1-(Oxetan-3-yl)piperazine was used for the Buchwald reaction with bromide intermediate 34 to obtain 4-[4-(oxetan-3-yl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12,6 .0 18,21 Example 15 of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one.

[0959] LCMS method F: [M+H] + = 464.2, t R = 1.47 min

[0960] LCMS method G: [M+H] + = 464.2, t R = 2.00 min

[0961] 1 H NMR (400 MHz, d6-DMSO, 80 °C) δ 12.81 (1H, s), 7.64 (1H, s), 7.48 - 7.45 (1H, d, J = 9.0 Hz), 7.39 - 7.34 (3H, m), 6.96 (1H, dd, J = 2.2, 8.8 Hz), 6.89 (1H, m), 5.23 (2H, s), 4.62–4.57 (2H, t, J = 6.5 Hz), 4.55 - 4.51 (2H, m), 4.33–4.27 (2H, t, J = 8.6 Hz), 3.58 - 3.51 (1H, q, J = 6.2 Hz), 3.30 - 3.26 (4H, m), 3.17 - 3.11 (2H, m), 2.10 - 1.99 (2H, m) ppm. Four protons are under the DMSO peak and are not reported here.

[0962] Example 16 : 4-(morpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0963]

[0964] Example 16 was prepared according to the synthetic route described in General Scheme C and a method similar to that used to obtain Example 12. Morpholine was used for the Buchwald reaction with bromide intermediate 34 to give 4-(morpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 16.

[0965] LCMS method F: [M+H] + =409.2,t R =2.13min

[0966] LCMS method G: [M+H] + =409.2,t R =2.15min

[0967] 1 H NMR (400MHz, d6-DMSO, 80℃) δ12.82(1H,s),7.63(1H,m),7.48-7.45(1H,d,J=9.0Hz),7.40(2H,m),7.34(1H,m),6.97(1H,dd,J=2.3,8.9Hz), 6.89(1H,s),5.23(2H,s),4.33-4.28(2H,t,J=8.32),3.82–3.76(4H,t,J=4.8Hz),3.23-3.20(4H,t,J=4.9Hz),3.17(2H,s),2.02(2H,s)ppm.

[0968] Example 17 :4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]Triticocarbon-1(20),2,4,6(23),15,17,21-heptene-9-one

[0969]

[0970] Example 17 was prepared according to the synthetic route described in General Scheme C and in a manner analogous to that used to obtain Example 12. cis-2,6-Dimethylmorpholine was used in a Buchwald reaction with bromide intermediate 34 to give 4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]Twenty-three carbon-1(20),2,4,6(23),15,17,21-heptene-9-one Example 17.

[0971] LCMS method F: [M+H] + =437.1,t R =2.30min

[0972] LCMS method G: [M+H] + =437.2,t R= 2.36 min

[0973] 1 1H NMR (400 MHz, d6-DMSO, 80 °C) δ 12.81 (1H, s), 7.63 (1H, s), 7.48 - 7.45 (1H, m), 7.39 - 7.34 (3H, m), 6.98 - 6.90 (2H, m), 5.23 (2H, s), 4.30 (2H, m), 3.80 - 3.73 (2H, m), 3.64 (2H, dd, J = 1.5, 12.1 Hz), 3.17 (2H, s), 2.41 - 2.35 (2H, m), 2.06 - 2.05 (2H, m), 1.21 (6H, d, J = 6.3 Hz) ppm.

[0974] Example 18 : 4-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0975]

[0976] Example 18 was prepared according to a synthetic route similar to that described in General Scheme F and the method used to obtain Example 11. (3-Methoxycarbonyl-5-methyl-phenyl)boronic acid was used for Suzuki coupling with Intermediate 26 to obtain 4-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 18.

[0977] LCMS method F: [M+H] + = 338, t R = 2.25 min

[0978] LCMS method G: [M+H] + = 338, t R = 2.30 min

[0979] 11H NMR (400 MHz, d6-DMSO) δ 7.73 - 7.65 (3H, m), 7.49 - 7.45 (1H, m), 7.34 (1H, d, J = 2.1 Hz), 7.10 - 7.07 (1H, m), 6.97 (1H, dd, J = 2.2, 9.0 Hz), 5.26 - 5.25 (2H, m), 4.34 - 4.28 (2H, m), 3.17 (2H, m), 2.41 (3H, s), 2.04 - 2.01 (2H, m) ppm. The indazole NH proton is not visible in this solvent.

[0980] Example 19 : 5-Methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0981]

[0982] Example 19 was prepared according to a synthetic route similar to that described in General Scheme F and the method used to obtain Example 11. (4-Methoxy-3-methoxycarbonyl-phenyl)boronic acid was used for Suzuki coupling with Intermediate 26 to obtain 5-methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 19.

[0983] LCMS method F: [M+H] + = 354, t R = 2.19 min

[0984] LCMS method G: [M+H] + = 354, t R = 2.17 min

[0985] 1H NMR(400MHz,d6-DMSO)δ12.75(1H,s),7.91(1H,dd,J=2.2,8.6Hz),7.83(1H,m),7.72(1H,m),7.45(1H,d,J=8.9Hz),7.37(1H,d,J =2.2Hz),7.15(1H,d,J=8.5Hz),6.97(1H,dd,J=2.4,9.0Hz),5.26(2H,s),4.33(2H,m),3.90(3H,s),3.18(2H,m),2.02(2H,m)ppm.

[0986] Example 20 :4-(4,4-difluoropiperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclic [13.5.2.1 2,6 .0 18,21 ]Triticocarbon-1(20),2,4,6(23),15,17,21-heptene-9-one

[0987]

[0988] Example 20 was prepared according to the synthetic route described in General Scheme C and in a manner analogous to that used to obtain Example 12. 4,4-Difluoropiperidine was used to react with bromide intermediate 34 in a Buchwald reaction to afford 4-(4,4-difluoropiperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]Twenty-three carbon-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 20.

[0989] LCMS method F: [M+H] + =443.1,t R =2.46min

[0990] LCMS method G: [M+H] + =443.1,t R =2.49min

[0991] 1 H NMR (400MHz, d6-DMSO, 80℃) δ12.83(1H,s),7.64(1H,s),7.49–7.43(2H,m),7.39(1H,s),7.36–7. 33(1H,m),5.24(2H,s),4.36–4.27(2H,m),3.46–3.42(4H,m),3.17(4H,s),2.17–1.98(6H,m)ppm.

[0992] Example 21 : 4-(3,3-difluoropyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0993]

[0994] Example 21 was prepared according to the synthetic route described in General Scheme C and a method similar to the method for obtaining Example 12. 3,3-Difluoropyrrolidine was used for the Buchwald reaction with bromide intermediate 34 to obtain 4-(3,3-difluoropyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 21.

[0995] LCMS method F: [M+H] + = 429.1, t R = 2.46 min

[0996] LCMS method G: [M+H] + = 429.1, t R = 2.48 min

[0997] 1 1H NMR (400 MHz, d6-DMSO, 80 °C) δ 12.82 (1H, s), 7.63 (1H, s,), 7.47 (1H, d, J = 8.9 Hz), 7.36 - 7.31 (2H, m), 7.10 - 7.08 (1H, m), 6.96 (1H, dd, J = 2.4, 9.0 Hz), 6.59 - 6.58 (1H, m), 5.23 (2H, s), 4.33 - 4.27 (2H, m), 3.37 (2H, t, J = 13.7 Hz), 3.58 (2H, t, J = 7.2 Hz), 3.16 (2H, s), 2.63 – 2.53 (2H, m) 2.02 (2H, m) ppm.

[0998] Example 22 : 7-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[0999]

[1000] Example 22 was prepared according to the synthetic route described in General Scheme C and a method similar to that used to obtain Example 8. (3-(1-Hydroxyethyl)phenyl)boronic acid was used for the Suzuki coupling to give 7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 22.

[1001] LCMS method F: [M+H] + = 338, t R = 2.22 min

[1002] LCMS method G: [M+H] + = 338, t R = 2.25 min

[1003] 1 1H NMR (400 MHz, d6-DMSO) δ 13.12 (1H, s), 7.95–7.92 (1H, m), 7.86 - 7.83 (2H, m), 7.50–7.46 (2H, m), 7.35 (1H, m), 7.31 - 7.29 (1H, m), 7.00 - 6.97 (1H, m), 5.95 - 5.90 (1H, m), 4.37 - 4.25 (2H, m), 3.56 - 3.49 (1H, m), 2.77 - 2.68 (1H, m), 2.24–2.15 (1H, m), 1.77–1.69 (1H, m), 1.59 (3H, d, J = 6.7 Hz) ppm.

[1004] Example 23 : 4-[4-(2-Methoxyethyl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1005]

[1006] Example 23 was prepared according to a synthetic route described in General Procedure C and a method similar to that used to obtain Example 12. 4-(2-Methoxyethyl)piperidine was used for the Buchwald reaction with bromide intermediate 34 to give 4-[4-(2-methoxyethyl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 23.

[1007] LCMS Method F: [M+H] + = 465.2, t R = 1.81 min

[1008] LCMS Method G: [M+H] + = 465.2, t R = 2.53 min

[1009] 1 H NMR (400 MHz, d6-DMSO, 80 °C) δ 12.79 (1H, br.s), 7.63 - 7.59 (1H, m), 7.46 (1H, d, J = 9.2 Hz), 7.37 (1H, d, J = 2.0 Hz), 7.34 (1H, d, J = 2.0 Hz), 7.32 (1H, s), 6.96 (1H, dd, J = 2.3, 8.9 Hz), 6.86 (1H, s), 5.22 - 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.

[1010] Example 24 :9,14-dioxa-11,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-10-one

[1011]

[1012] Example 24 was prepared according to the synthetic route described in General Scheme C and a method similar to the method for obtaining Example 8. 2-[3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethan-1-ol was used in the Suzuki coupling to obtain 9,14-dioxa-11,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-10-one Example 24.

[1013] LCMS method F: [M+H] + = 324.1, t R = 2.14 min

[1014] LCMS method G: [M+H] + = 324.1, t R = 2.19 min

[1015] 1 H NMR (400 MHz, d6-DMSO) δ 13.05 - 13.03 (1H, m), 7.99 (1H, t, J = 5.9 Hz), 7.82 (1H, s), 7.68 (1H, d, J = 7.6 Hz), 7.58 (1H, d, J = 1.9 Hz), 7.46 - 7.41 (2H, m), 7.28 - 7.25 (1H, m), 7.04 (1H, dd, J = 2.2, 9.0 Hz), 4.33 - 4.21 (4H, m), 3.40 - 3.3 (2H, m), 3.01 (2H, t, J = 5.0 Hz) ppm.

[1016] Example 25 : 4-[(3R)-3-Hydroxypyrrolidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1017]

[1018] Example 25 was prepared according to the synthetic route described in General Scheme C and a method similar to the method for obtaining Example 12. (3R)-Pyrrolidin-3-ol was used in the Buchwald reaction with bromide intermediate 34 to obtain 4-[(3R)-3-hydroxypyrrolidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .018,21 Example 25 of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1019] LCMS method F: [M+H] + = 409.1, t R = 1.96 min

[1020] LCMS method G: [M+H] + = 409.2, t R = 2.04 min

[1021] 1 H NMR (400 MHz, d6-DMSO) δ 7.65 - 7.56 (1H, m), 7.48 - 7.45 (1H, m), 7.36 (1H, d, J = 2.5 Hz), 7.19 (1H, s), 7.01 (1H, s), 6.93 (1H, dd, J = 2.3, 9.1 Hz), 6.46 (1H, s), 5.22 (2H, s), 4.48 - 4.43 (1H, m), 4.32 - 4.27 (2H, m), 3.53 - 3.32 (3H, m), 3.18 - 3.13 (2H, m), 3.11 - 2.99 (2H, m), 2.15 - 2.07 (1H, m), 2.07 - 1.97 (2H, m), 1.97 - 1.92 (1H, m) ppm. The indazole NH proton is not visible in this solvent.

[1022] Example 26 : 4-[(2-Methoxyethyl)(methyl)amino]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1023]

[1024] Example 26 was prepared according to a synthetic route similar to that described in General Scheme C and the method used to obtain Example 12. 2-Methoxy-N-methyl-ethylamine was used for the Buchwald reaction with bromide intermediate 34 to obtain 4-[(2-Methoxyethyl)(methyl)amino]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 26.

[1025] LCMS method F: [M+H] + = 411.2, t R = 2.07 min

[1026] LCMS method G: [M+H] + = 411.2, t R = 2.32 min

[1027] 1 H NMR (400 MHz, d6-DMSO) δ 12.74 (1H, s), 7.48 - 7.45 (1H, m), 7.36 (1H, d, J = 2.3 Hz), 7.23 - 7.19 (2H, m), 6.96 (1H, dd, J = 2.4, 9.0 Hz), 6.67 (1H, dd, J = 1.3, 2.5 Hz), 5.22 (1H, t, J = 9.7 Hz), 4.30 (2H, d, J = 16.7 Hz), 3.31 - 3.31 (3H, m), 3.11–3.04 (8H, s), 3.01 (3H, s), 2.01 - 2.02 (2H, m) ppm.

[1028] [[ID=M8]]Example 27 : 4-chloro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1029]

[1030] Example 27 was prepared according to a synthetic route similar to that described in General Scheme F and the method used to obtain Example 11. (3-Chloro-5-methoxycarbonyl-phenyl)boronic acid was used for Suzuki coupling with Intermediate 26 to obtain 4-chloro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 27.

[1031] LCMS method F: [M+H] + = 358.0, t R = 2.38 min

[1032] LCMS method G: [M+H] + = 358.1, t R = 2.52 min

[1033] 11H NMR (400 MHz, d6-DMSO, 80 °C) δ 13.08 (1H, s), 7.85 (2H, d, J = 15.0 Hz), 7.77 - 7.75 (1H, m), 7.50 (1H, d, J = 8.0 Hz), 7.36 (1H, s), 7.32 (1H, d, J = 2.4 Hz), 7.00 (1H, dd, J = 2.3, 8.9 Hz), 5.29 - 5.25 (2H, m), 4.35 - 4.30 (2H, m), 3.23 - 3.12 (2H, m), 2.06 - 2.00 (2H, m) ppm.

[1034] Example 28 : 4-Fluoro-5-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1035]

[1036] Example 28 was prepared according to the synthetic route described in General Scheme G.

[1037] Preparation of Intermediate 43 : Methyl 5-[5-(3-{[(benzyloxy)carbonyl]amino}propoxy)-1-(oxan-2-yl)-1H-indazol-3-yl]-3-fluoro-2-methylbenzoate

[1038]

[1039] To a solution of RT N-(3-{[1-(oxan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl]oxy}propyl)carbamic acid benzyl ester 31 (0.6 g, 1.12 mmol) in N,N-dimethylformamide (15 mL) was added methyl 5-bromo-3-fluoro-2-methylbenzoate (0.332 g, 1.35 mmol), Cs2CO3 (1.096 g, 3.36 mmol) and PdCl2(dppf)·DCM (0.041 g, 0.06 mmol). The resulting mixture was degassed by bubbling with nitrogen for 10 minutes and stirred under microwave irradiation at 110 °C 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 (25 g silica BIOTAGE) chromatography (cyclohexane-ethyl acetate, 100 / 0 - 50 / 50) to give methyl 5-[5-(3-{[(benzyloxy)carbonyl]amino}propoxy)-1-(oxan-2-yl)-1H-indazol-3-yl]-3-fluoro-2-methylbenzoate 43 as a yellow powder.

[1040] LCMS method F: [M+H] + = 576.2, t R = 3.48 min

[1041] Preparation of Intermediate 44 : N-[3-({3-[3-fluoro-5-(hydroxymethyl)-4-methylphenyl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamic acid benzyl ester

[1042]

[1043] At 0 °C, a 1 M solution of lithium aluminum hydride (0.78 mL, 0.78 mmol) was added to methyl 5-[5-(3-{[(benzyloxy)carbonyl]amino}propoxy)-1-(oxan-2-yl)-1H-indazole-3-yl]-3-fluoro-2-methylbenzoate 43 (0.225 g, 0.39 mmol) in THF (50 mL). The mixture was stirred at 0 °C for 1 h. At 0 °C, EtOAc (10 mL) was added to the reaction mixture, which was then poured into 10% Rochelle's salt solution (100 mL) and EtOAc (100 mL). The mixture was stirred at RT for 2 h. After separation, the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to give a brown / orange oil. The residue was purified by silica gel flash chromatography (Macherey Nagel, 25 g), gradient elution: cyclohexane / EtOAc 0 - 100%, to give N-[3-({3-[3-fluoro-5-(hydroxymethyl)-4-methylphenyl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamic acid benzyl ester 44 as a yellow oil.

[1044] LCMS method F: [M+H] + = 548.2, t R = 3.10 min

[1045] Preparation of Intermediate 45 : 4-fluoro-5-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1046]

[1047] At RT, cesium carbonate (0.447 g, 1.37 mmol) was added to a solution of N-[3-({3-[3-fluoro-5-(hydroxymethyl)-4-methylphenyl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamic acid benzyl ester 44 (0.125 g, 0.23 mmol) in anhydrous acetonitrile (33 mL). The resulting reaction mixture was stirred at 90 °C for 1 h 30 min. The reaction mixture was filtered, the solvent was removed under reduced pressure, and the residue was purified by flash column (15 g silica gel Macherey Nagel) chromatography (DCM–ethyl acetate, 1:0 - 8:2) to give 4-fluoro-5-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one 45 is a white foam.

[1048] LCMS method F: [M+H] + = 440.2, t R = 3.03 min

[1049] Preparation of Example 28 : 4-Fluoro-5-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2 ,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1050]

[1051] To a solution of tricos-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 TFA (0.143 mL, 1.92 mmol). The resulting reaction mixture was stirred at 80 °C for 1 hour 30 minutes under microwave irradiation. The reaction mixture was concentrated under reduced pressure, diluted with saturated sodium bicarbonate solution, and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by flash column (5 g silica gel Macherey Nagel) chromatography (DCM–ethyl acetate, 1:0 - 4:6) to give a solid, which was triturated in acetonitrile, filtered, to give 4-fluoro-5-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 28, a white solid. 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1052] LCMS method F: [M+H] + = 356.2, t R = 2.36 min

[1053] LCMS method G: [M+H] + = 356.2, t R = 2.39 min

[1054] 1 1H NMR (400 MHz, d6-DMSO) δ 7.80 (1H, s), 7.67 (1H, s), 7.63 (1H, d, J = 11.2 Hz), 7.48 (1H, dd, J = 0.6, 9.1 Hz), 7.40 (1H, d, J = 2.4 Hz), 6.96 (1H, dd, J = 2.3, 8.9 Hz), 5.29 (2H, s), 4.35 (2H, t, J = 8.1 Hz), 3.24–3.17 (2H, m), 2.22 (3H, d, J = 1.7 Hz), 2.06 - 2.05 (2H, m) ppm. The indazole NH proton is not visible in this solvent.

[1055] Example 29 : 4,5-Difluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1056]

[1057] Example 29 was prepared according to the synthetic route described in General Scheme F and a method similar to that used to obtain Example 11. Methyl 2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate was used for Suzuki coupling with Intermediate 26 to obtain 4,5-difluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 29.

[1058] LCMS method F: [M+H] + = 360, t R = 2.47 min

[1059] LCMS method G: [M+H] + = 360, t R = 2.52 min

[1060] 11H NMR (400 MHz, d6-DMSO, 80 °C) δ 13.06 (1H, s), 7.84 - 7.78 (2H, m), 7.71 - 7.69 (1H, m), 7.51 (1H, d, J = 9.1 Hz), 7.31 (1H, d, J = 2.1 Hz), 7.01 (1H, dd, J = 2.4, 9.0 Hz), 5.38 (2H, m), 4.34 (2H, dd, J = 8.1, 8.8 Hz), 3.18 (2H, m), 2.03 (2H, m) ppm.

[1061] Example 30 : 5-Bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1062]

[1063] Example 30 was prepared according to the synthetic route described in General Procedure C and a method similar to the method for obtaining Example 8.

[1064] Preparation of Intermediate 46 : [3-Bromo-5-(hydroxymethyl)phenyl]boronic acid

[1065]

[1066] At 0 °C, borane tetrahydrofuran complex (1.0 M solution in THF, 8.2 mL, 8.2 mmol) was slowly added to a solution of 3-dihydroxyboranyl-6-bromobenzoic acid (500 mg, 2.05 mmol) in THF (30 mL). The reaction mixture was brought to room temperature and stirred for 16 hours. At 0 °C, MeOH (25 mL) was added to quench the reaction until no gas was evolved. The solvent was evaporated and the residue was partitioned between ethyl acetate (50 mL) and water (50 mL). After separation, the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate magnesium, filtered, and concentrated under reduced pressure to give [3-bromo-5-(hydroxymethyl)phenyl]boronic acid 46 as a white solid.

[1067] LCMS method F: m / z not detected, t R = 1.58 min

[1068] Preparation of Intermediate 47 : Benzyl N-[3-[3-[4-bromo-3-(hydroxymethyl)phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate

[1069]

[1070] To a solution of N-[3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]carbamic acid benzyl ester 26 (692 mg, 1.29 mmol), [4-bromo-3-(hydroxymethyl)phenyl]boronic acid 46 (357 mg, 1.55 mmol), and 1 M Na2CO3 solution (3.9 mL, 3.87 mmol) in DME (13 mL) was added tetrakis(triphenylphosphine)palladium (75 mg, 0.065 mmol, 5 mol%). The reaction mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted twice with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid. The crude product was purified by flash chromatography using 24 g Redisep (CyH / EtOAc 0-100% EtOAc) to give N-[3-[3-[4-bromo-3-(hydroxymethyl)phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamic acid benzyl ester 47 as a white solid.

[1071] LCMS method F: [M+H] + = 594, t R = 3.12 min

[1072] Preparation of Intermediate 48 : 5-bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1073]

[1074] A suspension of N-[3-[3-[4-bromo-5-(hydroxymethyl)phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamic acid benzyl ester 47 (590 mg, 0.99 mmol) and cesium carbonate (1.94 g, 5.96 mmol) in acetonitrile (200 mL) was heated to 90 °C for 2 h. The reaction mixture was cooled to RT, then filtered and concentrated under reduced pressure. The resulting solid was triturated with acetonitrile to give 5-bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one 48 is a white solid.

[1075] LCMS method F: [M+H] + = 486 / 488, t R = 3.25 min

[1076] Preparation of Example 30 : 5-Bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1077]

[1078] To a solution of 5-bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2 ,6 .0 18,21 A solution of tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one 48 (50 mg, 0.10 mmol) in DCM (3 mL) was added trifluoroacetic acid (157 μL, 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 25% by weight aqueous ammonium hydroxide solution (3 mL) were added. A white precipitate appeared in the organic layer and was insoluble in DCM. The solid was filtered and dried under reduced pressure to obtain 5-bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 30 is a white solid.

[1079] LCMS method F: [M+H] + = 403, t R = 2.58 min

[1080] LCMS method G: [M+H] + = 403, t R = 2.48 min

[1081] 11H NMR (400 MHz, d6-DMSO) δ 13.05 (1H, s), 7.91 - 7.87 (3H, m), 7.73 - 7.69 (1H, m), 7.52 - 7.49 (1H, m), 7.37 (1H, d, J = 1.7 Hz), 7.01 (1H, dd, J = 2.3, 8.9 Hz), 5.27 (2H, s), 4.37 - 4.33 (2H, m), 3.19 (2H, m), 2.02 - 1.99 (2H, m) ppm.

[1082] Example 31 : 4-(4-Methylpiperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1083]

[1084] Example 31 was prepared according to a synthetic route similar to that described in General Procedure C and the method used to obtain Example 12. 1-Methylpiperazine was used to carry out a Buchwald reaction with bromide intermediate 34 to obtain 4-(4-methylpiperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 31.

[1085] LCMS method F: [M+H] + = 422, t R = 1.44 min

[1086] LCMS method G: [M+H] + = 422, t R = 2.02 min

[1087] 1 1H NMR (400 MHz, d6-DMSO) δ 12.80 (1H, s), 7.62 (1H, m), 7.46 (1H, d, J = 9.2 Hz), 7.38 (1H, m), 7.35 (2H, m), 6.98–6.95 (1H, m), 6.88 (1H, m), 5.23 (2H, m), 4.32–4.28 (2H, m), 3.25 (4H, m), 3.16 (2H, m), 2.53 (4H, m), 2.28 (3H, s), 2.04 (2H, m) ppm.

[1088] Example 32 : 4-(3-methoxyazetidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1089]

[1090] Example 32 was prepared according to the synthetic route described in General Scheme C and a method similar to that used to obtain Example 12. 3-Methoxyazetidine hydrochloride was used to carry out a Buchwald reaction with bromide intermediate 34 to obtain 4-(3-methoxyazetidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 32.

[1091] LCMS method F: [M+H] + = 409.2, t R = 2.15 min

[1092] LCMS method G: [M+H] + = 409.1, t R = 2.13 min

[1093] 1 H NMR (400 MHz, d6-DMSO, 80 °C) δ 12.85 (1H, br s), 7.61 (1H, br s), 7.48 - 7.45 (1H, m), 7.36 - 7.34 (1H, m), 7.27 (1H, s), 6.95 (1H, dd, J = 2.4, 9.2 Hz), 6.90 (1H, t, J = 2.0 Hz), 6.37 (1H, dd, J = 1.5, 2.1 Hz), 5.20 (2H, s), 4.40 - 4.27 (3H, m), 4.15 - 4.11 (2H, m), 3.69 (2H, dd, J = 4.3, 8.6 Hz), 3.30 (3H, s), 3.22 – 3.12 (2H, m), 2.09 – 1.96 (2H, m) ppm.

[1094] Example 33 : 1-{9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,211-{9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1

[1095]

[1096] Example 33 was prepared according to the synthetic route described in General Procedure C and a method similar to that used to obtain Example 12. Piperidine-4-carbonitrile was used for the Buchwald reaction with bromide intermediate 34 to give 1-{9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-4-yl}piperidine-4-carbonitrile Example 33.

[1097] LCMS method F: [M+H] + = 432, t R = 2.15 min

[1098] LCMS method G: [M+H] + = 432, t R = 2.21 min

[1099] 1 1H NMR (400 MHz, d6-DMSO) δ 12.82 (1H, s), 7.63 (1H, m), 7.48–7.46 (1H, m), 7.40–7.35 (3H, m), 7.98–7.95 (1H, m), 7.90 (1H, m), 5.23 (2H, m), 4.30 (2H, m), 3.50–3.44 (2H, m), 3.22–3.15 (4H, m), 2.08–2.00 (4H, m), 1.92–1.84 (2H, m), 1.07 (1H, d, J = 5.9 Hz) ppm.

[1100] Example 34 : 4-[4-(pyrrolidin-1-yl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1101]

[1102] Example 34 was prepared according to a synthetic route similar to that described in General Procedure C and the method used to obtain Example 12. 4-Pyrrolidin-1-ylpiperidine was used for the Buchwald reaction with bromide intermediate 34 to give 4-[4-(pyrrolidin-1-yl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 34.

[1103] LCMS method F: [M+H] + = 476, t R = 1.59 min

[1104] LCMS method G: [M+H] + = 476, t R = 1.51 min

[1105] 1 H NMR (400 MHz, DMSO) δ 12.85 (1H, m), 7.47 (1H, d, J = 8.7 Hz), 7.37 (3H, t, J = 13.0 Hz), 6.98 - 6.92 (2H, m), 5.28 (2H, m), 4.30 (2H, s), 3.85 (2H, m), 3.42 (1H, q, J = 7.0 Hz), 3.18 (3H, s), 2.88 - 2.82 (2H, m), 2.14 (2H, s), 2.04 (10H, m) ppm. Two protons are under the DMSO peak and are not reported herein.

[1106] Example 35 : 4-(azetidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1107]

[1108] Example 35 was prepared according to a synthetic route similar to that described in General Procedure C and the method used to obtain Example 12. Azetidine was used for the Buchwald reaction with bromide intermediate 34 to give 4-(azetidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21Example 35 of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1109] LCMS method F: [M+H] + = 379, t R = 2.08 min

[1110] LCMS method G: [M+H] + = 379, t R = 2.23 min

[1111] 1 H NMR (400 MHz, d6-DMSO) δ 12.78 (1H, m), 7.59 (1H, m), 7.48 - 7.44 (1H, m), 7.35 (1H, s), 7.25 (1H, s), 6.98 - 6.94 (1H, m), 6.88 - 6.87 (1H, m), 6.34 (1H, s), 5.20 (2H, s), 4.32 - 4.27 (2H, m), 3.90 (3H, t, J = 7.2 Hz), 3.15 (3H, m), 2.39 - 2.32 (2H, m), 2.06 (2H, s) ppm.

[1112] Example 36 : 4-(piperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1113]

[1114] Example 36 was prepared according to the synthetic route described in General Scheme A. Piperidine was used for the Buchwald reaction with bromide intermediate 34 to obtain 4-(piperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2, 6 .0 18,21 Example 36 of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1115] LCMS method F: [M+H] + = 407.2, t R = 1.65 min

[1116] LCMS method G: [M+H] + = 407.2, tR = 2.48 min

[1117] 1 1H NMR (400 MHz, d6-DMSO, 80 °C) δ 12.79 (1H, s), 7.64 - 7.62 (1H, m), 7.48 - 7.44 (1H, d, J = 8.4 Hz), 7.38 - 7.32 (3H, m), 6.96 (1H, dd, J = 2.3, 9.1 Hz), 6.87 - 6.86 (1H, m), 5.22 (2H, s), 4.30 (2H, dd, J = 7.6, 10.0 Hz), 3.27 - 3.21 (4H, m), 3.20 - 3.11 (2H, m), 2.06–1.97 (2H, m), 1.71 - 1.64 (4H, m), 1.63 - 1.58 (2H, m) ppm.

[1118] Example 37 : 4-(2,5-Dihydrofuran-3-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1119]

[1120] Example 37 was prepared according to the synthetic route described in General Scheme A and a method similar to that used to obtain Example 12. 2-(2,5-Dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used for the Suzuki reaction with bromide intermediate 34 to give 4-(2,5-dihydrofuran-3-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 37.

[1121] LCMS method F: [M+H] + = 392.2, t R = 2.19 min

[1122] LCMS method G: [M+H] + = 392.2, t R = 2.19 min

[1123] 11H NMR (400 MHz, d6-DMSO, 80 °C) δ 12.94 (1H, s), 7.85 (2H, d, J = 6.3 Hz), 7.69 (1H, s), 7.50 (1H, d, J = 9.6 Hz), 7.37 (1H, s), 7.33 (1H, d, J = 2.0 Hz), 6.99 (1H, dd, J = 2.3, 8.9 Hz), 6.55 - 6.52 (1H, m), 5.33 - 5.30 (2H, m), 5.00 - 4.96 (2H, m), 4.80 - 4.77 (2H, m), 4.35 - 4.29 (2H, m), 3.19 - 3.17 (2H, m), 1.99 (2H, s) ppm.

[1124] Example 38 : 4-[4-(Morpholin-4-yl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1125]

[1126] Example 38 was prepared according to a synthetic route similar to that described in General Scheme A and the method used to obtain Example 12. 4-(4-Piperidyl)morpholine was used to carry out a Buchwald reaction with bromide intermediate 34 to give 4-[4-(morpholin-4-yl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 38.

[1127] LCMS method F: [M+H] + = 492.2, t R = 1.48 min

[1128] LCMS method G: [M+H] + = 492.2, t R = 2.07 min

[1129] 1H NMR(400MHz,d6-DMSO)δ12.79(1H,s),7.61(1H,s),7.47(1H,d,J=5.8Hz),7.39-7.29(3H,m),6.97(1H,dd,J=2.2,9.1Hz),6.89(1H,s),5.22(2H ,s),4.36-4.26(2H,m),3.87–3.75(2H,m),3.64-3.54(4H,m),3.23-3.1 2(2H,m),2.88-2.76(2H,m),2.57-2.52(4H,m),2.41-2.29(1H,m),2.09 -1.88(4H,m),1.63-1.5(2H,m)ppm.

[1130] Example 39 :4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclic [13.5.2.1 2,6 .0 18,21 ]Triticocarbon-1(20),2,4,6(23),15,17,21-heptene-9-one

[1131]

[1132] Example 39 was prepared according to the synthetic route described in General Scheme A. 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine was used in a Suzuki reaction with bromide intermediate 34 to give 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]Twenty-three carbon-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 39.

[1133] LCMS method F: [M+H] + =419.2,t R =1.49min

[1134] LCMS method G: [M+H] + =419.2,t R =2.16min

[1135] 11H NMR (400 MHz, d6-DMSO, 80 °C) δ 12.95 (1H, s), 7.97 (1H, s), 7.87 (1H, s), 7.71 - 7.69 (1H, m), 7.50 (1H, d, J = 8.0 Hz), 7.40 (1H, s), 7.34 (1H, d, J = 1.5 Hz), 7.00 (1H, dd, J = 2.3, 8.9 Hz), 6.28 - 6.25 (1H, m), 5.35 - 5.32 (2H, m), 4.32 (2H, dd, J = 8.1, 9.0 Hz), 3.94 - 3.91 (2H, m), 3.55–3.41 (2H, m), 3.25–3.17 (2H, m), 2.92 (3H, s), 2.90 - 2.84 (2H, m), 2.10–1.99 (2H, m) ppm.

[1136] Example 40 : 4-[(2S,5S)-2,5-Dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1137]

[1138] Example 40 was prepared according to the synthetic route described in General Scheme C and a method similar to that used to obtain Example 12. (1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptane hydrochloride was used for the Suzuki reaction with 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 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 40.

[1139] LCMS method F: [M+H] + = 421.1, t R = 2.06 min

[1140] LCMS method G: [M+H] + = 421.2, t R = 2.06 min

[1141] 11H NMR (400 MHz, d6-DMSO) δ 12.78 (1H, s), 7.62 (1H, m), 7.46 (1H, d, J = 9.1 Hz), 7.36 (1H, s), 7.23 (1H, s), 7.06 (1H, s), 6.97–6.95 (1H, m), 6.58 (1H, s), 5.21 (2H, m), 4.63 (2H, d, J = 17.5 Hz), 4.32 - 4.28 (2H, m), 3.82 (1H, m), 3.76 (1H, m), 3.58–3.56 (1H, m), 3.16 (2H, m), 3.10 (1H, m), 2.03 (2H, m), 1.98–1.95 (1H, m), 1.90–1.88 (1H, m) ppm.

[1142] Example 41 : 4-[(morpholin-4-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1143]

[1144] Example 41 was prepared according to the synthetic route described in General Scheme C.

[1145] Preparation of Intermediate 49 : 4-[(morpholin-4-yl)methyl]-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1146]

[1147] In a sealed test tube, at RT, to a solution of 4-bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.12,6.018,21]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one Example 12 (100 mg, 0.21 mmol) in THF / H2O 9 / 1 (4 mL) was added potassium 1-trifluoroboratomethylmorpholine (87 mg, 0.42 mmol) and cesium carbonate (205 mg, 0.63 mmol). The reaction mixture was degassed by bubbling nitrogen through the solution for 15 min, then palladium acetate (2 mg, 0.01 mmol) and Xphos (10 mg, 0.02 mmol) were added, and the reaction mixture was stirred at 100 °C for 18 h. The reaction mixture was cooled to RT, and the solvent was removed under reduced pressure. EtOAc (50 mL) was added to the residue, and the suspension was filtered through celite. The filtrate was extracted with EtOAc (2 x 20 mL), washed with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to give a yellow oil. The oil was triturated with acetonitrile and diethyl ether to give 4-[(morpholin-4-yl)methyl]-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 49, as a beige powder.

[1148] LCMS method F: [M+H] + = 507, t R = 1.74 min

[1149] Preparation of Example 41 : 4-[(morpholin-4-yl)methyl]-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1150]

[1151] At RT, to 4-[(morpholin-4-yl)methyl]-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one 49 (60 mg, 0.13 mmol) was stirred in DCM (2 mL) for 6 hours. The reaction mixture was evaporated under reduced pressure to give a brown oil. DCM (20 mL) and saturated bicarbonate solution (10 mL) were added to the residue. After separation, the organic layer was extracted with DCM (2 x 10 mL), washed with brine, dried over sodium sulfate, and evaporated under reduced pressure to give a yellow oil. Some acetonitrile and ether were added to the oil, and the formed precipitate was filtered to obtain 4-[(morpholin-4-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one, Example 41, was an off-white solid.

[1152] LCMS method F: [M+H] + = 423, t R = 1.42 min

[1153] LCMS method G: [M+H] + = 423, t R = 2.03 min

[1154] 1 H NMR (400 MHz, DMSO) δ 12.89 (1H, s), 7.81 (2H, d, J = 11.8 Hz), 7.66 (1H, s), 7.50 - 7.47 (1H, m), 7.35 (1H, d, J = 1.9 Hz), 7.22 (1H, s), 6.98 (1H, dd, J = 2.4, 9.0 Hz), 5.29 - 5.26 (2H, m), 4.34 - 4.28 (2H, m), 3.63 (4H, m), 3.56 (2H, s), 3.18 (2H, s), 2.46 (4H, m), 2.06 - 2.03 (2H, m) ppm.

[1155] Example 42 : 4-[(pyrrolidin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1156]

[1157] Example 42 was prepared according to the synthetic route described in General Procedure C and a method similar to the method used to obtain Example 41. Potassium trifluoro[(pyrrolidin-1-yl)methyl]borate was used for Suzuki coupling with bromide intermediate 34 to give 4-[(pyrrolidin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 42.

[1158] LCMS method F: [M+H] + = 407, t R = 1.44 min

[1159] LCMS method G: [M+H] + = 407, t R = 2.12 min

[1160] 1 H NMR (400 MHz, d6-DMSO) δ 12.88 (1H, s), 7.84 (1H, s), 7.79 (1H, s), 7.66 (1H, m), 7.48 (1H, d, J = 8.8 Hz), 7.35 (1H, d, J = 1.7 Hz), 7.22 (1H, s), 6.98 (1H, dd, J = 2.3, 8.9 Hz), 5.28 (2H, s), 4.32 (2H, dd, J = 8.1, 8.6 Hz), 3.69 (2H, s), 3.17 (2H, m), 2.54 (4H, m), 2.03 (2H, m), 1.75 (4H, m) ppm.

[1161] Example 43 : 4-[(piperidin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1162]

[1163] Example 43 was prepared according to the synthetic route described in General Procedure C and a method similar to the method used to obtain Example 41. Potassium trifluoro[(piperidin-1-yl)methyl]borate was used for Suzuki coupling with bromide intermediate 34 to give 4-[(piperidin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .018,21 Example 43 of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1164] LCMS method F: [M+H] + = 421, t R = 1.49 min

[1165] LCMS method G: [M+H] + = 421, t R = 2.33 min

[1166] 1 H NMR (400 MHz, d6-DMSO, 80 °C) δ 12.86 (1H, s), 7.86 (2H, m), 7.59 (1H, m), 7.48 (1H, d, J = 8.4 Hz), 7.37 (1H, d, J = 2.1 Hz), 7.25 (1H, m), 6.99 (1H, dd, J = 2.3, 8.9 Hz), 5.30 (2H, s), 4.32 (2H, m), 3.19 (2H, m), 2.05 (2H, m), 1.62 (4H, m), 1.48 (2H, m) ppm. Some protons are not visible due to different conformations. The structure was confirmed by COSY.

[1167] Example 44 : 4-[(4-Methylpiperazin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1168]

[1169] Example 44 was prepared according to the synthetic route described in General Scheme C and a method similar to that used to obtain Example 41. Potassium trifluoro[(4-methylpiperazin-1-yl)methyl]borate was used for Suzuki coupling with the bromide intermediate 34 to give 4-[(4-methylpiperazin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 44.

[1170] LCMS method F: [M+H] + = 436, t R= 1.36 min (current 20 V)

[1171] LCMS method G: [M+H] + = 436, t R = 1.95 min (pH 10, current 20 V)

[1172] 1 H NMR (400 MHz, d6-DMSO, 80 °C) δ 12.89 (1H, s), 7.81 (1H, s), 7.79 (1H, s), 7.66 (1H, m), 7.48 (1H, d, J = 8.8 Hz), 7.35 (1H, m), 7.20 (1H, m), 6.98 (1H, dd, J = 2.3, 9.1 Hz), 5.28 (2H, s), 4.31 (2H, m), 3.55 (2H, s), 3.17 (2H, m), 2.46–2.37 (8H, m), 2.20 (3H, s), 2.04 (2H, m) ppm.

[1173] Example 45 : 5-(morpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1174]

[1175] Example 45 was prepared according to the synthetic route described in General Procedure C. Morpholine was used for Buchwald coupling with bromide intermediate 48 to give 5-(morpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2, 6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 45.

[1176] LCMS method F: [M+H] + = 409, t R = 2.17 min

[1177] LCMS method G: [M+H] + = 409, t R = 2.16 min

[1178] 11H NMR (400 MHz, d6-DMSO) δ 12.80 (1H, s), 7.89 - 7.86 (2H, m), 7.68 (1H, s), 7.49 - 7.45 (1H, m), 7.35 (1H, d, J = 1.3 Hz), 7.29 - 7.25 (1H, m), 6.97 (1H, dd, J = 2.3, 8.9 Hz), 5.37 (2H, s), 4.31 (2H, dd, J = 8.3, 8.6 Hz), 3.78 (4H, m), 3.17 (2H, s), 2.91 (4H, m), 2.05 (2H, s) ppm.

[1179] Example 46 : 4-[4-(2-Methoxyethyl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1180]

[1181] Example 46 was prepared according to the synthetic route described in General Scheme A. 1-(2-Methoxyethyl)piperazine was used for the Buchwald reaction with bromide intermediate 34 to obtain 4-[4-(2-Methoxyethyl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 46.

[1182] LCMS method F: [M + H] + = 466.2, t R = 1.48 min

[1183] LCMS method G: [M + H] + = 466.2, t R = 2.06 min

[1184] 11H NMR (400 MHz, d6-DMSO, 80 °C) δ 12.83 (1H, s), 7.64 (1H, s), 7.49 - 7.46 (1H, m), 7.40 (2H, s), 7.34 (1H, s), 6.99 - 6.91 (2H, m), 5.24 (2H, s), 4.33 - 4.27 (2H, m), 3.67 - 3.63 (2H, m), 3.17 - 3.08 (15H, m), 2.10 - 1.99 (2H, m) ppm.

[1185] Example 47 : 4-(Diethylamino)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2, 6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1186]

[1187] Example 47 was prepared according to the synthetic route described in General Scheme A. Diethylamine was used to perform a Buchwald reaction with bromide intermediate 34 to give 4-(diethylamino)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2 ,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 47.

[1188] LCMS method F: [M+H] + = 395.2, t R = 1.57 min

[1189] LCMS method G: [M+H] + = 395.2, t R = 2.48 min

[1190] 11H NMR (400 MHz, d6-DMSO, 80 °C) δ 12.73 (1H, br s), 7.59 (1H, br s), 7.46 (1H, d, J = 9.3 Hz), 7.36 (1H, d, J = 2.1 Hz), 7.18 - 7.16 (2H, m), 6.95 (1H, dd, J = 2.4, 8.8 Hz), 6.63 (1H, s), 5.21 - 5.20 (2H, m), 4.32 - 4.27 (2H, m), 3.42 (4H, q, J = 7.0 Hz), 3.21 - 3.10 (2H, m), 2.08 – 1.96 (2H, m), 1.17 (6H, t, J = 6.9 Hz) ppm.

[1191] Example 48 : 4-Cyclopropyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1192]

[1193] Example 48 was prepared according to the synthetic route described in General Scheme C. Potassium trifluoro[cyclopropyl]borate was used for Suzuki coupling with bromide intermediate 34 to obtain 4-cyclopropyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 48.

[1194] LCMS method F: [M+H] + = 364, t R = 2.40 min

[1195] LCMS method G: [M+H] + = 364, t R = 2.39 min

[1196] 11H NMR (400 MHz, d6-DMSO, 80 °C) δ 12.87 (1H, s), 7.68 (1H, s), 7.64 (1H, m), 7.60 (1H, s), 7.47 (1H, d, J = 9.1 Hz), 7.33 (1H, d, J = 2.1 Hz), 6.99 (1H, s), 6.97 (1H, dd, J = 9.0, 2.3 Hz), 5.24 (2H, m), 4.30 (2H, m), 3.17 (2H, m), 2.03 (3H, m), 1.00 (2H, m), 0.74 (2H, m) ppm.

[1197] Example 49 : 5-(4-Methylpiperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1198]

[1199] Example 49 was prepared according to the synthetic route described in General Scheme C. 4-Methylpiperazine was used for Buchwald coupling with bromide intermediate 48 to give 5-(4-methylpiperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 49.

[1200] LCMS method F: [M+H] + = 422, t R = 1.44 min

[1201] LCMS method G: [M+H] + = 422, t R = 2.13 min

[1202] 11H NMR (400 MHz, CD3OD) δ 8.01 - 7.99 (1H, m), 7.92 (1H, dd, J = 2.1, 8.4 Hz), 7.79 (1H, t, J = 6.1 Hz), 7.49 - 7.34 (4H, m), 7.04 (1H, dd, J = 2.3, 9.1 Hz), 5.51 - 5.47 (2H, m), 4.36 (2H, m), 3.74 - 3.63 (2H, m), 3.42 (4H, m), 3.21 (4H, m), 3.03 (3H, s), 2.12 (2H, m) ppm.

[1203] Example 50 : 13 - Methyl - 8,14 - dioxo - 10,19,20 - triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos - 1(20),2,4,6(23),15,17,21 - heptaen - 9 - one

[1204]

[1205] Example 50 was prepared according to the synthetic route described in General Scheme C and by a method similar to that used to obtain Example 8.

[1206] At RT, trifluoroacetic acid (1.19 mL, 15.65 mmol) was added to a solution of 13 - methyl - 19 - (oxan - 2 - yl) - 8,14 - dioxo - 10,19,20 - triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos - 1(20),2(23),3,5,1(22),16,18(21) - heptaen - 9 - one (330 mg, 0.78 mmol) in dichloromethane (12 mL). The solution was then irradiated under microwave (Biotage initiator +) for 2 h. The reaction mixture was concentrated in vacuo, and the residue was dissolved in EtOAc. The organic phase was washed with saturated aqueous sodium bicarbonate, brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting solid was triturated in diisopropyl ether and dried to give the desired compound 13 - methyl - 8,14 - dioxo - 10,19,20 - triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos - 1(20),2,4,6(23),15,17,21 - heptaen - 9 - one Example 50, as a pale yellow solid.

[1207] LCMS method F: [M + H] + = 338, t R = 2.25 min

[1208] LCMS method G: [M+H] + = 338, t R = 2.24 min

[1209] 1 H NMR (400 MHz, d6-DMSO) δ 13.12 (1H, s), 7.93 - 7.84 (3H, m), 7.47 (2H, dd, J = 8.5, 15.8 Hz), 7.27 (2H, d, J = 7.0 Hz), 6.97 (1H, dd, J = 2.1, 8.9 Hz), 5.75 (1H, d, J = 12.1 Hz), 4.81 (1H, d, J = 12.5 Hz), 4.57 (1H, dd, J = 6.0, 9.2 Hz), 3.59 - 3.54 (1H, m), 2.93 - 2.86 (1H, m), 2.47 - 2.33 (1H, m), 1.41 - 1.38 (4H, m) ppm.

[1210] Example 51 : 8,14-Dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one

[1211]

[1212] Example 51 was prepared according to the synthetic route described in General Scheme C.

[1213] Preparation of Intermediate 50 : Benzyl N-[3-({3-[1-(2-hydroxyethyl)-1H-pyrazol-​4-yl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamate

[1214]

[1215] To a solution of N-(3-{[3-iodo-1-(oxan-2-yl)-1H-indazol-5-yl]oxy}propyl)carbamic acid benzyl ester 26 (0.535 g, 1.0 mmol) in dioxane (3 mL) and water (1 mL) was added 1-(2-hydroxyethyl)-1H-pyrazole-4-boronic acid pinacol ester (0.286 g, 1.2 mmol), K3PO4 (0.637 g, 3.0 mmol), XPhos (0.048 g, 0.1 mmol) and Pd(PPh3)4 (0.058 g, 0.05 mmol). The resulting reaction mixture was stirred at 120 °C for 1 h under microwave irradiation. The residue was diluted with saturated sodium chloride solution and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash column (25 g silica gel Macherey Nagel) chromatography (cyclohexane-ethyl acetate 3 / EtOH 1, 1:0 - 1:1) to give N-[3-({3-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamic acid benzyl ester 50 as a yellow oil.

[1216] LCMS method F: [M+H] + = 520.2, t R = 2.56 min

[1217] Preparation of Intermediate 51 :

[1218]

[1219] To a solution of N-[3-({3-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamic acid benzyl ester 50 (0.380 g, 0.73 mmol) in anhydrous acetonitrile (146 mL) was added cesium carbonate (1.430 g, 4.39 mmol). The resulting reaction mixture was stirred at 90 °C for 36 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column (15 g silica gel Macherey Nagel) chromatography (cyclohexane-ethyl acetate 3 / EtOH 1, 1:0 - 3:7) to give 19-(oxan-2-yl)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15(22),16,18(21)-hexaene-9-one 51 as a white solid.

[1220] LCMS method F: [M+H] + = 412.2, t R = 2.20 min

[1221] Preparation of Example 51 : 8,14 - dioxo - 4,5,10,19,20 - pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos - 1(20),2(23),3,15(22),16,18(21) - hexaen - 9 - one

[1222]

[1223] To a solution of 19 - (oxan - 2 - yl) - 8,14 - dioxo - 4,5,10,19,20 - pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos - 1(20),2(23),3,15(22),16,18(21) - hexaen - 9 - one 51 (0.155 g, 0.38 mmol) in DCM (3 mL) was added TFA (0.561 mL, 7.53 mmol). The resulting reaction mixture was stirred under microwave irradiation at 80 °C for 1 hour 30 minutes. The reaction mixture was concentrated under reduced pressure, diluted with saturated sodium bicarbonate solution, and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column (15 g silica gel Macherey Nagel) chromatography (cyclohexane - ethyl acetate 3 / EtOH 1, 9:1 - 0:1) to give a solid (70 mg), which was triturated in diisopropyl ether, filtered, to give 8,14 - dioxo - 4,5,10,19,20 - pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos - 1(20),2(23),3,15(22),16,18(21) - hexaen - 9 - one Example 51, as a white solid.

[1224] LCMS method F: [M+H] + = 328.1, t R = 1.68 min

[1225] LCMS method G: [M+H] + = 328.1, t R = 1.68 min

[1226] 11H NMR (400 MHz, d6-DMSO) δ 12.82 (1H, s), 8.09 (1H, s), 7.86 (1H, t, J = 6.1 Hz), 7.77 (1H, d, J = 0.6 Hz), 7.44 - 7.41 (1H, m), 7.07 (1H, d, J = 2.3 Hz), 6.94 (1H, dd, J = 2.3, 8.9 Hz), 4.53 - 4.49 (2H, m), 4.38 - 4.28 (4H, m), 3.14 - 3.09 (2H, m), 1.86 (2H, q, J = 8.7 Hz) ppm.

[1227] Example 52 : 4-[Methyl(oxetan-3-yl)amino]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1228]

[1229] Example 52 was prepared according to the synthetic route described in General Scheme C. N-Methyloxetan-3-amine was used for the Buchwald reaction with bromide intermediate 34 to give 4-[methyl(oxetan-3-yl)amino]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 52.

[1230] LCMS method F: [M+H] + = 409, t R = 2.04 min

[1231] LCMS method G: [M+H] + = 409, t R = 2.06 min

[1232] 11H NMR (400 MHz, d6-DMSO) δ 12.81 (1H, s), 7.62 (1H, s), 7.46 (1H, d), 7.34 (2H, s), 7.13 (1H, s), 6.98–6.95 (1H, m), 6.64 (1H, s), 5.22 (2H, m), 4.84–4.81 (2H, m), 4.77 - 4.74 (1H, m), 4.65–4.64 (2H, m), 4.32–4.28 (2H, m), 3.16 (2H, m), 2.96 (3H, s), 2.03 (2H, m) ppm.

[1233] Example 53 : 4-[(Dimethylamino)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1234]

[1235] Example 53 was prepared according to the synthetic route described in General Scheme C. Potassium (dimethylamino)methyltrifluoroborate was used for Suzuki coupling with bromide intermediate 34 to give 4-[(dimethylamino)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 53.

[1236] LCMS method F: [M + H] + = 381, t R = 1.39 min

[1237] LCMS method G: [M + H] + = 381, t R = 2.03 min

[1238] 11H NMR (400 MHz, d6-DMSO) δ 12.93 (1H, s), 7.87 (2H, m), 7.70 - 7.66 (1H, m), 7.51 - 7.47 (1H, m), 7.36 (1H, d, J = 2.1 Hz), 7.25 (1H, s), 6.99 (1H, dd, J = 2.3, 9.1 Hz), 5.30 - 5.26 (2H, m), 4.34 - 4.30 (2H, m), 3.73 (2H, m), 3.17 (2H, s), 2.40 - 2.33 (6H, m), 2.06 (2H, s) ppm.

[1239] Example 54 : 4,10 - Dimethyl - 8,14 - dioxo - 10,19,20 - triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos - 1(20),2,4,6(23),15,17,21 - heptaen - 9 - one

[1240]

[1241] Example 54 was prepared according to the synthetic route described in General Scheme F.

[1242] Preparation of Intermediate 52: 4,10 - Dimethyl - 19 - (oxan - 2 - yl) - 8,14 - dioxo - 10,19,20 - triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos - 1(20),2,4,6(23),15,17,21 - heptaen - 9 - one

[1243]

[1244] At 0 °C, to 4 - methyl - 19 - (oxan - 2 - yl) - 8,14 - dioxo - 10,19,20 - triazatetracyclo[13.5.2.1 2,6 .0 18,21A mixture of tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one (115 mg, 0.273 mmol) in THF (2.5 mL) was added with a 60% oil dispersion of NaH (8 mg, 0.328 mmol) and MeI (20 μL, 0.328 mmol). The reaction mixture was stirred overnight at RT. Another 60% oil dispersion of NaH (8 mg, 0.328 mmol) and MeI (20 μL, 0.328 mmol) were added. The reaction mixture was stirred overnight at RT. The solvent was removed under reduced pressure, and EtOAc and water were added. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, and the solvent was removed under reduced pressure to obtain 4,10-dimethyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one 52 was a colorless oil.

[1245] LCMS method F: [M+H] + = 436.2, t R = 3.15 min

[1246] Preparation of Example 54 : 4,10-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2 ,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1247]

[1248] To 4,10-dimethyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21A mixture of tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one 52 (150 mg; 0.345 mmol) in DCM (2.5 mL) was added to TFA (132 μl, 1.723 mmol). The reaction mixture was stirred at 80 °C for 60 min under microwave conditions. The solvent was removed under reduced pressure, and the mixture was dissolved in EtOAc and washed with saturated 1N NaHCO3 solution (pH = 7) and then with water. The organic layer was concentrated under reduced pressure, and the oil was purified by chromatography using a 10 g SiO2 column, eluting with DCM / MeOH 100 / 0 - 95 / 5. The required fractions were combined, but the product was not pure enough and was further purified by chromatography using a 10 g SiO2 column, eluting with cyclohexane / ethyl acetate 70 / 30 - 50 / 50. The required fractions were combined, the solvent was removed under reduced pressure, and the oil was triturated with pentane. The solid was filtered, boiled in hot water, filtered, and dried under high vacuum to give 4,10-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 Tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 54, was a white powder.

[1249] LCMS method F: [M+H] + = 352.2, t R = 2.49 min

[1250] LCMS method G: [M+H] + = 352.2, t R = 2.49 min

[1251] 1 1H NMR analysis showed the presence of rotamers.

[1252] 11H NMR (400 MHz, d6-DMSO) δ 13.11 - 13.05 (1H, m), 7.68 (2H, d, J = 13.7 Hz), 7.51 - 7.47 (1H, m), 7.20 - 7.12 (2H, m), 6.99 (1H, dd, J = 2.2, 9.0 Hz), 5.82 (0.75H, d, J = 13.3 Hz), 5.15 (0.25H, s), 4.78 (0.75H, d, J = 13.5 Hz), 4.43 - 4.35 (0.75H, m), 4.28 - 4.12 (1.25H, m), 3.94 - 3.84 (0.75H, m), 3.47 - 3.39 (0.25H, m), 3.04 - 3.03 (3H, m), 2.91 - 2.82 (1.25H, m), 2.41 - 2.39 (4H, m), 2.27 - 2.16 (0.25H, m), 1.77 - 1.70 (0.75H, m) ppm.

[1253] Example 55 : 4-(propan-2-yloxy)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2 ,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1254]

[1255] Example 54 was prepared according to the synthetic route described in General Scheme F.

[1256] Preparation of Intermediate 53 : Methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-5-hydroxy-benzoate

[1257]

[1258] To a solution of degassed N-[3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]carbamic acid benzyl ester 26 (2.876 g, 5.372 mmol), methyl 3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.988 g, 10.473 mmol), XPhos (256 mg, 0.537 mmol) and K3PO4 (3.421 g, 16.116 mmol) in dioxane (40.0 mL) and water (10.0 mL) was added Pd(PPh3)4 (311 mg, 0.269 mmol). The resulting turbid brown solution was degassed with nitrogen for 5 minutes, aliquoted in three portions, sealed and each portion was heated to 120 °C for 1 h under microwave irradiation. The mixture was poured into water (50 mL), EtOAc (100 mL) was added and the phases were separated. The aqueous layer was extracted with EtOAc (3 x 100 mL), the combined organic extracts were washed with saturated aqueous NaCl solution (1 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material obtained (brown oil, 4.1 g) was purified by column chromatography (220 g Macherey Nagel SiO2, 100 mL / min, CyH / EtOAc 100:0 - 60:40) to give methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-5-hydroxybenzoate 53 as a brown oil.

[1259] LCMS method F: [M+H] + = 560.1, t R = 2.97 min

[1260] Preparation of Intermediate 54 : Methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-5-isopropoxybenzoate

[1261]

[1262] To a solution of methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-5-hydroxybenzoate 53 (2.800 g, 5.004 mmol) and K2CO3 (1.729 g, 12.510 mmol) in N,N-dimethylformamide (25.0 mL) was added 2-bromopropane (940 μL, 1.231 mg, 10.008 mmol). The resulting turbid brown solution was heated to 70 °C for 2 h. The reaction was quenched with water (20 mL), EtOAc (50 mL) was added, and the phases were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL), the combined organic extracts were washed with saturated NaCl aqueous solution (1 x 20 mL), dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure. The crude material obtained (brown solid, 3.5 g) was purified by column chromatography (120 g Macherey Nagel SiO2, CyH / EtOAc 100; 0 - 70; 30) to give methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-5-isopropoxybenzoate 54 as a brown solid.

[1263] LCMS method F: [M + H] + = 602.3, t R = 3.48 min

[1264] Preparation of Intermediate 55 : Benzyl N-[3-[3-[3-(hydroxymethyl)-5-isopropoxyphenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate

[1265]

[1266] At 0 °C, a solution of methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydropyran-2-yl]indazole-3-carboxylate 54 (3.000 g, 4.986 mmol) in THF (50.0 mL) was added dropwise with LiAlH4 (1.0 M in THF, 9.97 mL, 9.972 mmol). The resulting brown solution was stirred at 0 °C for 15 minutes and then at room temperature for 1 h. The reaction was carefully quenched with saturated Rochelle salt solution (20 mL), EtOAc (50 mL) was added, and the phases were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL), the combined organic extracts were washed with saturated NaCl aqueous solution (1 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product N-[3-[3-[3-(hydroxymethyl)-5-isopropoxyphenyl]-1-tetrahydropyran-2-yl]indazol-5-yl]oxypropyl]carbamic acid benzyl ester 55 as a brown oil, which was used in the next step without further purification.

[1267] LCMS method F: [M+H] + = 574.2, t R = 3.06 min

[1268] Preparation of Intermediate 56 : 19-(oxan-2-yl)-4-(propan-2-yloxy)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1269]

[1270] To a solution of N-[3-[3-[3-(hydroxymethyl)-5-isopropoxyphenyl]-1-tetrahydropyran-2-yl]indazol-5-yl]oxypropyl]carbamic acid benzyl ester 55 (100 mg, 0.174 mmol) in MeCN (18.0 mL) was added Cs2CO3 (341 mg, 1.046 mmol). The resulting turbid yellow mixture was heated to reflux for 5 h. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting crude material (yellow oil, 100 mg) was purified by column chromatography (4 g Macherey Nagel SiO2, 15 mL / min, CH2Cl2 / MeOH 100:0 - 98:2) to give 19-(oxan-2-yl)-4-(propan-2-yloxy)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .018,21 56, 1(20),2,4,6(23),15,17,21 - heptadecaene - 9 - one is a transparent oily substance.

[1271] LCMS method F: [M + H] + = 466.2, t R = 3.03 min

[1272] Preparation of Example 55 : 4 - (propan - 2 - yloxy) - 8,14 - dioxo - 10,19,20 - triazatricyclo[13.5.2.1 2,6 .0 18,21 1(20),2,4,6(23),15,17,21 - heptadecaene - 9 - one

[1273]

[1274] To a solution of 56 (54 mg, 0.116 mmol) of 19 - (oxan - 2 - yl) - 4 - (propan - 2 - yloxy) - 8,14 - dioxo - 10,19,20 - triazatricyclo[13.5.2.1 2,6 .0 18,21 1(20),2,4,6(23),15,17,21 - heptadecaene - 9 - one in CH2Cl2 (5.0 mL) was added TFA (300 μL, 447 mg, 3.920 mmol). The vial containing the resulting clear yellow solution was sealed and heated to 50 °C for 3 h under microwave irradiation. Saturated aqueous NaHCO3 (1 mL) was added and the phases were separated. The aqueous layer was extracted with CH2Cl2 (3 x 5 mL), the combined organic extracts were washed with water (1 x 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material (pale yellow oil, 49 mg) was triturated with iPr2O to give 4 - (propan - 2 - yloxy) - 8,14 - dioxo - 10,19,20 - triazatricyclo[13.5.2.1 2,6 .0 18,21 1(20),2,4,6(23),15,17,21 - heptadecaene - 9 - one, Example 55, as a white amorphous solid.

[1275] LCMS method F: [M + H] + = 382.1, t R = 2.41 min

[1276] LCMS method G: [M + H] + = 382.2, t R = 2.40 min

[1277] 1 H NMR (400 MHz, d6-DMSO, 80 °C) δ 7.66 (brs, 1H), 7.49 - 7.46 (m, 2H), 7.39 - 7.34 (m, 2H), 6.98 (dd, J = 2.4, 9.0 Hz, 1H), 6.85 (brs, 1H), 5.24 (brs, 1H), 4.72 - 4.63 (sept, J = 5.9 Hz, 1H), 4.33 - 4.29 (m, 2H), 3.19 - 3.15 (m, 2H), 2.04 - 2.02 (m, 2H), 1.35 - 1.33 (m, 6H) ppm. Two labile protons are not visible in this solvent.

[1278] Example 56 : 4-Fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1279]

[1280] Example 56 was prepared according to the synthetic route described in General Scheme A.

[1281] Preparation of Intermediate 57 : 1-(3-Bromo-5-fluorophenyl)ethanol

[1282]

[1283] To a cooled solution of 3-bromo-5-fluorobenzaldehyde (1.5 g, 7.389 mmol) in dry tetrahydrofuran (19 mL) at 0 °C was added dropwise a 3 M ethereal solution of methylmagnesium bromide (4.93 mL, 14.778 mmol). The reaction mixture was stirred at 0 °C for 20 min and then at RT for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl and then extracted with ethyl acetate (2x). The combined organic layers were washed with water and then with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography, eluting with cyclohexane / ethyl acetate-EtOH (3 - 1): 100 / 0 - 80 / 20 to give 1-(3-bromo-5-fluorophenyl)ethanol 57 as a colorless oil.

[1284] LCMS method F: [M + H] + = Mass not detected, t R = 2.32 min

[1285] Preparation of Intermediate 58: 1-[3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol

[1286]

[1287] To a solution of degassed 1-(3-bromo-5-fluorophenyl)ethanol 57 (1.196 g, 5.461 mmol), bis(pinacolato)diboron (2.080 g, 8.192 mmol), and potassium acetate (2.144 g, 21.844 mmol) in dioxane (17 mL) in a sealed tube was added PdCl2(dppf)·CH2Cl2 (0.446 g, 0.546 mmol). The reaction mixture was heated at 90 °C for 24 h. The reaction mixture was filtered through celite on Whatman filter paper and rinsed with ethyl acetate. The reaction mixture was diluted with water and extracted with ethyl acetate (3x). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol 58 as a black oil.

[1288] LCMS method F: m / z, t not detected R = 2.65 min.

[1289] Preparation of Intermediate 59 : N-[3-[3-[3-Fluoro-5-(1-hydroxyethyl)phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamic acid benzyl ester

[1290]

[1291] To a solution of degassed N-[3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]carbamic acid benzyl ester 26 (1.462 g, 2.734 mmol), 1-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol 58 (1.453 g, 5.466 mmol), tripotassium phosphate (1.742 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 in a microwave (Biotage initiator+) at 120 °C for 1 h. The reaction mixture was filtered through celite and the celite was rinsed 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.

[1292] The crude product was purified by column chromatography, eluting with DCM / ethyl acetate, 100 / 0 - 80 / 20, to afford N-[3-[3-[3-fluoro-5-(1-hydroxyethyl)phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamic acid benzyl ester 59 as a cream-like solid.

[1293] Yield: 780 mg of intermediate 59 (50%)

[1294] LCMS method F: [M+H] + = 548, t R = 3.07 min

[1295] Preparation of Intermediate 60 : 1-[3-[5-(3-aminopropoxy)-1-tetrahydropyran-2-yl-indazol-3-yl]-5-fluoro-phenyl]ethanol and 4-fluoro-7-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaene-9-one

[1296]

[1297] A suspension of N-[3-[3-[3-fluoro-5-(1-hydroxyethyl)phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamic acid benzyl ester 59 (0.780 g, 1.426 mmol) and cesium carbonate (2.781 g, 8.556 mmol) in acetonitrile (300 mL) was heated to 90 °C for 16 h. LCMS analysis showed formation of the desired product, but starting material was still present, and 1-[3-[5-(3-aminopropoxy)-1-tetrahydropyran-2-yl-indazol-3-yl]-5-fluoro-phenyl]ethanol was observed to form. The reaction mixture was heated to 90 °C for 16 h. The reaction mixture was cooled to RT, then filtered and concentrated under reduced pressure to afford 1-[3-[5-(3-aminopropoxy)-1-tetrahydropyran-2-yl-indazol-3-yl]-5-fluoro-phenyl]ethanol (66%) and 4-fluoro-7-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21A mixture of tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one (26%) (0.667 g, 1.426 mmol (presumed)), an orange oil. The crude product was not purified and was used in the next step without further purification.

[1298] Preparation of Intermediate 61 : 4-Fluoro-7-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1299]

[1300] To a solution of 1-[3-[5-(3-aminopropoxy)-1-(tetrahydropyran-2-yl)-1H-indazol-3-yl]-5-fluorophenyl]ethanol and 4-fluoro-7-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2, 6 .0 18,21 of tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one 60 (0.567 g, 1.373 mmol) in DMA (350 mL) was added 1,1'-carbonyldiimidazole (0.245 g, 1.510 mmol). The reaction mixture was stirred at RT for 2 h and then at 90 °C for 22 h. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and saturated aqueous NaHCO3 were added. The mixture was extracted with ethyl acetate (2x). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.

[1301] The crude product was purified by column chromatography, eluting with cyclohexane / ethyl acetate–EtOH (3-1):100 / 0-70 / 30 to give a cream-like solid. The solid was triturated with diisopropyl ether to give 4-fluoro-7-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 61, a white solid.

[1302] Yield: 100 mg of Intermediate 61 (14%)

[1303] LCMS method F: [M+H]+ = 440, t R = 2.96 min

[1304] Preparation of Example 56 : 4-Fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2 ,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1305]

[1306] At RT, trifluoroacetic acid (350 μL, 4.560 mmol) was added to a solution of 4-fluoro-7-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one 61 (100 mg, 0.228 mmol) in DCM (16 mL). The reaction mixture was irradiated under microwave conditions (Biotage initiator). The solid was triturated with diisopropyl ether to give 4-fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 56, a cream-like solid.

[1307] LCMS method F: [M + H] + = 356, t R = 2.33 min

[1308] LCMS method G: [M + H] + = 356, t R = 2.32 min

[1309] 11H NMR (400 MHz, d6-DMSO) δ 13.26 (1H, s), 8.01–7.98 (1H, m), 7.69 (1H, s), 7.59–7.56 (1H, m), 7.53 - 7.50 (1H, m), 7.33 (1H, m), 7.22 - 7.18 (1H, m), 7.02–6.99 (1H, m), 5.91–5.86 (1H, m), 4.35–4.28 (2H, m), 3.56–3.49 (1H, m), 2.79–2.72 (1H, m), 2.21–2.16 (1H, m), 1.77–1.71 (1H, m), 1.61–1.58 (3H, d) ppm. Example 57 : 4-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1310]

[1311] Example 57 was prepared according to the synthetic route described in General Scheme C.

[1312] Preparation of Intermediate 62 : 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-3,6-dihydro-2H-pyridine

[1313]

[1314] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,2,3,6-tetrahydropyridine (370 mg, 1.77 mmol) in DCM (9 mL) was added triethylamine (245 μL, 1.77 mmol) and 3-bromooxetane (750 mg, 5.5 mmol). The resulting mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated under reduced pressure to give 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-3,6-dihydro-2H-pyridine 62 (500 mg, 1.77 presumed), as an orange oil. The compound was used in the next step without further purification.

[1315] Preparation of Intermediate 63:19-(oxan-2-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1316]

[1317] To a solution of 4-bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2 ,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one intermediate 34 (260 mg, 0.53 mmol) in dioxane / water (15 / 1.5 mL) was added 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-3,6-dihydro-2H-pyridine 62 (300 mg, 1.06 mmol estimated) and K3PO4 (337 mg, 1.59 mmol). The mixture was degassed for 10 minutes and then Pd(dppf)Cl2.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 and then 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-3,6-dihydro-2H-pyridine (200 mg, 0.71 mmol estimated) and K3PO4 (168 mg, 0.79 mmol) were added again. The mixture was degassed for 10 minutes and Pd(dppf)Cl2.DCM (8 mg, 0.0098 mmol) was added again. The mixture was heated at 90 °C for 1 day. The reaction mixture was filtered through celite and diluted with EtOAc (50 mL) and water (50 mL). After separation, the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (Macherey Nagel, 25 g) using DCM / (MeOH / NH3) (100 / 0 - 90 / 10). The desired fractions were collected, combined, evaporated to give 19-(oxan-2-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12,6 .0 18,21 1(20),2,4,6(23),15,17,21 - Heptadecen - 9 - one 63, an orange solid.

[1318] LCMS method F: [M + H] + = 489, t R = 1.81 min

[1319] Preparation of Intermediate 64 : 19 - (oxan - 2 - yl) - 4 - [1 - (oxetan - 3 - yl) - 1,2,3,6 - tetrahydropyridin - 4 - yl] - 8,14 - dioxo - 10,19,20 - triazatetracyclo[13.5.2.1 2,6 .0 18,21 1(20),2,4,6(23),15,17,21 - Heptadecen - 9 - one

[1320]

[1321] To a solution of 19 - (oxan - 2 - yl) - 4 - (1,2,3,6 - tetrahydropyridin - 4 - yl) - 8,14 - dioxo - 10,19,20 - triazatetracyclo[13.5.2.1 2,6 .0 18,21 1(20),2,4,6(23),15,17,21 - Heptadecen - 9 - one 63 (289 mg, 0.59 mmol) in dry THF (15 mL) was added oxetan - 3 - one (212 mg, 2.95 mmol). The mixture was cooled to 0 °C and then sodium tri(acetoxy)borohydride (248 mg, 1.18 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with 1 M Na2CO3 (~7 mL, pH = 8) and then the mixture was diluted with EtOAc (50 mL). After separation, the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Macherey Nagel, 15 g) using DCM / MeoH (100 / 0 - 97 / 3) as the eluent to give 19 - (oxan - 2 - yl) - 4 - [1 - (oxetan - 3 - yl) - 1,2,3,6 - tetrahydropyridin - 4 - yl] - 8,14 - dioxo - 10,19,20 - triazatetracyclo[13.5.2.1 2,6 .0 18,21 1(20),2,4,6(23),15,17,21 - Heptadecen - 9 - one 64, a white crystal.

[1322] LCMS method F: [M+H] + = 545, t R = 1.84 min

[1323] Preparation of Example 57 : 4-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1324]

[1325] To a solution of 19-(oxan-2-yl)-4-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one 64 (82 mg, 0.15 mmol) in DCM (4 mL) was added trifluoroacetic acid (107 μL, 1.4 mmol). The mixture was stirred at room temperature for 24 h. Then the reaction mixture was heated at 40 °C for 4 h. Trifluoroacetic acid (26 μL, 0.35 mmol) was added again and the reaction mixture was heated at 40 °C for 3 h and stirred at room temperature overnight. The reaction mixture was diluted with DCM (25 mL) and saturated NaHCO3 solution (25 mL). After separation, the aqueous layer was extracted with DCM (3 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 product was triturated in acetonitrile, filtered, and the solid was washed several times with acetonitrile to give 4-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 57, as a cream-like powder.

[1326] LCMS method F: [M+H] + = 461, t R = 1.49 min

[1327] LCMS method G: [M+H] + = 461, t R= 2.19 min

[1328] 1 H NMR (400 MHz, d6-DMSO, 80 °C) δ 12.89 (1H, m), 7.90 (1H, s), 7.80 (1H, s), 7.67 (1H, m), 7.48 (1H, d, J = 9.5 Hz), 7.35 (2H, m), 6.98 (1H, dd, J = 1.5, 8.9 Hz), 6.23 (1H, m), 5.29 (2H, m), 4.61 (2H, t, J = 6.5 Hz), 4.55 (2H, t, J = 5.9 Hz), 4.31 (2H, t, J = 9.3 Hz), 3.65 (1H, t, J = 6.1 Hz), 3.18 (2H, m), 3.09 (2H, m), 2.61 (2H, m), 2.57 (2H, m), 2.04 (2H, m) ppm.

[1329] Example 58 : 4-(3-Methylpiperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1330]

[1331] Example 58 was prepared according to the synthetic route described in General Procedure C. 3-Methylpiperidine was used for the Buchwald reaction with bromide intermediate 34 to give 4-(3-methylpiperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 58.

[1332] LCMS Method F: [M+H] + = 421.2, t R = 1.88 min

[1333] LCMS Method G: [M+H] + = 421.2, t R = 2.66 min

[1334] 11H NMR (400 MHz, d6-DMSO) δ 7.69 - 7.56 (1H, m), 7.48 - 7.45 (1H, m), 7.38 - 7.31 (3H, m), 6.95 (1H, dd, J = 2.4, 9.0 Hz), 6.87 - 6.86 (1H, m), 5.24 - 5.20 (2H, m), 4.30 (2H, dd, J = 8.0, 9.1 Hz), 3.22 - 3.1 (2H, m), 3.07 (6H, s), 2.79 - 2.68 (1H, m), 2.07 - 1.98 (2H, m) 1.83 - 1.74 (3H, m), 1.7 - 1.55 (1H, m), 1.19 - 1.05 (1H, m) ppm. The indazole NH proton is not visible in this solvent.

[1335] Example 59 : 4-[(3S)-3-Hydroxypyrrolidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one

[1336]

[1337] Example 59 was prepared according to the synthetic route described in General Scheme C. (3S)-Pyrrolidin-3-ol was used for the Buchwald reaction with bromide intermediate 34 to obtain 4-[(3S)-hydroxypyrrolidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 59.

[1338] LCMS method F: [M+H] + = 409.2, t R = 1.98 min

[1339] LCMS method G: [M+H] + = 409.2, t R = 1.96 min

[1340] 11H NMR (400 MHz, d6-DMSO) δ 12.84 (1H, m), 7.61 - 7.60 (1H, m), 7.48 - 7.45 (1H, m), 7.36 (1H, d, J = 2.1 Hz), 7.21 - 6.93 (3H, m), 6.47 (1H, s), 5.25 - 5.21 (2H, m), 4.88 - 4.66 (1H, m) 4.48 - 4.45 (1H, m), 4.32 - 4.27 (2H, m), 3.53 - 3.32 (3H, m), 3.20 - 3.16 (3H, m), 2.16 - 2.07 (1H, m), 2.02 - 1.94 (3H, m) ppm.

[1341] Example 60 : 4-Fluoro-8,14-dioxa-10,19,20-triazapentacyclo[13.5.2.1 2,6 .1 7,10 .0 18,21 tetracosa-1(20),2(24),3,5,15(22),16,18(21)-heptaen-9-one

[1342]

[1343] Example 60 was prepared according to the synthetic route described below.

[1344] Preparation of Intermediate 65 : 1-(3-Bromo-5-fluorophenyl)-2-nitroethan-1-ol

[1345]

[1346] To a stirred solution of 3-bromo-5-fluorobenzaldehyde (2 g, 10 mmol) in THF (20 mL) at 0 °C was added dropwise nitromethane (0.536 mL, 10 mmol), and then 1N sodium hydroxide solution (10 mL, 10 mmol). The solution was stirred at 0 °C for 15 min. The solution was quenched with acetic acid solution (12 mL). Water (25 mL) was added to the resulting mixture. The aqueous layer was extracted with EtOAc (4 x 50 mL). The combined organic layers were washed with saturated brine (2 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure to give a brown / orange oil. The residue was purified by silica gel flash chromatography (Macherey Nagel, 120 g), gradient elution: cyclohexane / EtOAc 0 - 30%, to give 1-(3-bromo-5-fluorophenyl)-2-nitroethan-1-ol 65 as a white solid.

[1347] LCMS method F: [M - H] - = 262.2, t R= 2.28 min

[1348] Preparation of Intermediate 66 : 2 - Amino - 1 - (3 - bromo - 5 - fluorophenyl)ethan - 1 - ol

[1349]

[1350] To a solution of 1 - (3 - bromo - 5 - fluorophenyl)-2 - nitroethan - 1 - ol 65 (6.2 g, 15.2 mmol) in EtOH (100 mL) was added - Nickel (2 g) and 0.5 mL of acetic acid. Hydrogen was bubbled through the mixture for 5 min. The reaction mixture was stirred under a hydrogen atmosphere for 16 h. The reaction mixture was filtered through celite, and the solvent of the filtrate was removed under reduced pressure to give 2 - amino - 1 - (3 - bromo - 5 - fluorophenyl)ethan - 1 - ol 66, which was used directly in the next step without purification.

[1351] LCMS method F: [M + H] + = 236, t R = 1.12 min

[1352] Preparation of Intermediate 67 : 5 - (3 - bromo - 5 - fluorophenyl)-1,3 - oxazolidin - 2 - one

[1353]

[1354] To a solution of 2 - amino - 1 - (3 - bromo - 5 - fluorophenyl)ethan - 1 - ol 66 (1.75 g, 1.75 mmol) in THF (100 mL) was added 1,1′ - carbonyldiimidazole (1.34 g, 8.25 mmol) and imidazole (0.561 g, 8.25 mmol). The reaction mixture was stirred at RT for 16 h. A saturated aqueous solution of NH4Cl (100 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Biotage column chromatography, eluting with cyclohexane / ethyl acetate (3 - 1):100 / 0 - 70 / 30 to give a white solid, 5 - (3 - bromo - 5 - fluorophenyl)-1,3 - oxazolidin - 2 - one 67.

[1355] LCMS method F: [M + H] + = 262.0, t R = 2.07 min

[1356] Preparation of Intermediate 68 : 5 - (3 - bromo - 5 - fluorophenyl)-3 - {3 - [(tert - butyldimethylsilyl)oxy]propyl}-1,3 - oxazolidin - 2 - one

[1357]

[1358] At 0 °C, sodium hydride (0.366 g, 9.1 mmol) was added to a stirred solution of 5-(3-bromo-5-fluorophenyl)-1,3-oxazolidin-2-one 67 (1.6 g, 6.1 mmol) in THF (10 mL). The solution was stirred at 0 °C for 10 min. Then a solution of (3-bromopropoxy)(tert-butyl)dimethylsilane (1.5 g, 6.1 mmol) in THF (10 mL) was added to the mixture. The mixture was stirred at room temperature for 16 h. The solution was quenched with saturated ammonium chloride solution (25 mL). The resulting mixture was extracted with EtOAc (4 x 100 mL). The combined organic layers were washed with saturated brine (2 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure to give a brown / orange oil. The residue was purified by silica gel flash chromatography (Macherey Nagel, 24 g), gradient elution: cyclohexane / EtOAc 0 - 50%, to give 5-(3-bromo-5-fluorophenyl)-3-{3-[(tert-butyldimethylsilyl)oxy]propyl}-1,3-oxazolidin-2-one 68 as a yellow oil.

[1359] LCMS method F: [M+H] + = 434.0, t R = 3.42 min

[1360] Preparation of Intermediate 69 : 5-(3-bromo-5-fluorophenyl)-3-(3-hydroxypropyl)-1,3-oxazolidin-2-one

[1361]

[1362] To a solution of 5-(3-bromo-5-fluorophenyl)-3-{3-[(tert-butyldimethylsilyl)oxy]propyl}-1,3-oxazolidin-2-one 68 (0.8 g, 1.85 mmol estimated) in tetrahydrofuran (50 mL) at RT was added dropwise a 1.0 M solution of tetrabutylammonium fluoride in THF (1.85 mL, 1.85 mmol). 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 (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column (24 g silica BIOTAGE) chromatography (cyclohexane - ethyl acetate, 100 / 0 - 50 / 50) to give 5-(3-bromo-5-fluorophenyl)-3-(3-hydroxypropyl)-1,3-oxazolidin-2-one 69 as an off-white powder.

[1363] LCMS method F: [M+H] + = 320.0, t R = 2.02 min

[1364] Preparation of Intermediate 70 : 3-[5-(3-Bromo-5-fluorophenyl)-2-oxo-1,3-oxazolidin-3-yl]propyl methanesulfonate

[1365] ...

Claims

1. A compound of formula (I): Wherein: R represents a hydrogen atom, a halogen atom or an alkyl group, Z1, Z2, Z3 each independently represent a carbon atom or a nitrogen atom, wherein the 6-membered ring containing Z1, Z2 and Z3 may have 0, 1 or 2 nitrogen atoms, -X1- is absent or represents -O-, -S- or -N(R’a)-, wherein R’a represents a hydrogen atom or an alkyl group, -X2- represents an alkanediyl optionally substituted by one or more identical or different substituents selected from a halogen atom, a polyhaloalkyl group, an alkoxy group, a hydroxyl group, an amino group, an alkylamino group, a dialkylamino group and a cyano group, wherein the carbon atom at the α-position of -N-Ra and the carbon atom at the α-position of -X1- when -X1- represents -O-, -S- or -N(R’a)- cannot be substituted by an oxygen or nitrogen heteroatom, -X3- represents an alkanediyl optionally substituted by one or more identical or different substituents selected from a halogen atom, a polyhaloalkyl group, an alkoxy group, a hydroxyl group, an amino group, an alkylamino group, a dialkylamino group, a cyano group, a C3-C 10 cycloalkyl group, a heterocycloalkyl group, wherein the carbon atom at the α-position of -O- and the carbon atom at the α-position of A1 when A1 represents a nitrogen atom cannot be substituted by an oxygen or nitrogen heteroatom, Ra represents a hydrogen atom or an alkyl group, wherein when Ra represents an alkyl group, one carbon atom of Ra can be connected to the carbon atom of -X2- or to the 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 formula (a): Wherein A1, A4 each independently represent a carbon atom or a nitrogen atom, A2, A3, A5 each independently represent a carbon atom, an oxygen atom, a sulfur atom or a nitrogen atom, provided that A1, A2, A3, A4 and A5 cannot all represent heteroatoms simultaneously, or an aromatic or partially hydrogenated cyclic group of formula (b): Wherein A’1, A’2, A’3, A’4 each independently represent a carbon atom or a nitrogen atom, wherein * means that the bond is connected to X3, The defined aromatic or partially hydrogenated cyclic group A is optionally substituted by one or more identical or different substituents selected from halogen atoms, alkyl groups, alkoxy groups, hydroxy groups, oxo groups, alkoxyalkyl groups, alkoxyalkoxy groups, polyhaloalkyl groups, polyhaloalkoxy groups, heterocycloalkyl groups, heterocycloalkylalkyl groups, (alkoxyalkyl)(alkyl)amino groups, amino groups, alkylamino groups, dialkylamino groups, C3-C 10 cycloalkyl groups, (heterocycloalkyl)(alkyl)amino groups, dialkylaminoalkyl groups, heterocycloalkylalkoxy groups, cyano groups, and cyanoalkyl groups, wherein "heterocycloalkyl" means a monovalent monocyclic or bicyclic aromatic or non-aromatic carbocyclic group containing 3-10 ring members and containing 1-3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, wherein the heterocycloalkyl and cycloalkyl as defined may optionally be substituted by one or more substituents selected from an alkyl group, a halogen atom, a polyhaloalkyl group, a polyhaloalkoxy group, an alkoxy group, an alkoxyalkyl group, a hydroxyl group, a cyano group and an oxo group, wherein the alkyl and alkanediyl contain 1-6 carbon atoms, are straight-chain or branched, or include a spiro structure, and wherein the alkoxy contains 1-6 carbon atoms and is straight-chain or branched, their enantiomers, diastereomers, racemates, and addition salts thereof with pharmaceutically acceptable acids or bases.

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

3. The compound according to claim 1, wherein R represents a halogen atom.

4. The compound according to any one of claims 1 to 3, wherein Z1, Z2 and Z3 all represent carbon atoms.

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

6. The compound according to any one of claims 1 to 3, wherein -X1- represents -O-.

7. A compound according to any one of claims 1 to 3, wherein -X2- represents a straight-chain or branched alkanediyl having 2, 3, 4 or 5 carbon atoms.

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

9. The compound according to any one of claims 1 to 3, wherein Ra is a hydrogen atom.

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

11. The compound according to claim 10, wherein -X3- represents -(CH2)2-, -CH2- or -CH(CH3)-.

12. The compound according to any one of claims 1 to 3, wherein A represents a group of formula (b): wherein A’1, A’2, A’3, A’4 and * are as defined in claim 1.

13. The compound according to claim 12, wherein A represents The defined A group is unsubstituted or optionally substituted.

14. The compound according to claim 12, wherein A represents phenyl.

15. The compound according to claim 12, wherein A represents pyridyl.

16. The compound according to claim 12, wherein A represents pyrazinyl.

17. The compound according to any one of claims 1 to 3, wherein A represents a group of formula (a): wherein A1, A2, A3, A4, A5 and * are as defined in claim 1.

18. The compound according to claim 17, wherein A represents The defined A group is unsubstituted or optionally substituted.

19. The compound according to claim 17, wherein A represents triazolyl.

20. The compound according to claim 17, wherein A represents pyrazolyl.

21. The compound according to any one of claims 1 to 3, wherein A is unsubstituted.

22. The compound according to any one of claims 1 to 3, wherein A is substituted by one or more groups selected from halogen atoms, cyano groups, cyanoalkyl groups, oxo groups, alkoxy groups, alkyl groups, cycloalkyl groups and heterocycloalkyl groups.

23. The compound according to claim 1, which is a compound of formula (I-a): wherein X1, X2, X3, Ra and A are as defined in claim 1.

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

25. The compound according to claim 23, which is a compound of formula (I-c) or (I-c’): wherein X1, X2, X3, Ra, A’1, A’2 and A’4 are as defined in claim 1.

26. The compound according to claim 23 or 25, which is a compound of formula (I-d) or (I-d’): wherein X2, X3, Ra, A’1, A’2 and A’4 are as defined for formula (I).

27. The compound according to claim 23, which is a compound of formula (I-e): wherein X1, X2, X3, Ra, A1, A2 and A5 are as defined for formula (I).

28. The compound according to claim 23 or 27, which is a compound of formula (I-f): wherein X2, X3, Ra, A1, A2 and A5 are as defined for formula (I).

29. The compound according to claim 23, 25 or 27, wherein the -X1-X2-N(Ra)-C(O)O-X3- chain 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. A compound, which is: 8,14-Dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 10-Methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 8,14-Dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 8,14-Dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 10-(propan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 8,14-Dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 5-Fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 5-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(Pyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[4-(Propan-2-yl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-{2-Oxa-6-azaspiro[3.4]octan-6-yl}-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[4-(oxetan-3-yl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(Morpholin-4-yl)-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2 ,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 5-Methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(4,4-Difluoropiperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(3,3-Difluoropyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 7-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[4-(2-Methoxyethyl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2, 6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 9,14-Dioxa-11,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-10-one; 4-[(3R)-3-Hydroxypyrrolidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(2-Methoxyethyl)(methyl)amino]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2, 6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Chloro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Fluoro-5-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4,5-Difluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 5-Bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(4-Methylpiperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(3-Methoxyazetidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2, 6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 1-{9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-4-yl}piperidine-4-carbonitrile; 4-[4-(Pyrrolidin-1-yl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2, 6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(azetidin-1-yl)-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(Piperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(2,5-Dihydrofuran-3-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[4-(Morpholin-4-yl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(2S,5S)-2,5-Dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2 ,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(morpholin-4-yl)methyl]-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(Pyrrolidin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(Piperidin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(4-Methylpiperazin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 5-(Morpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[4-(2-Methoxyethyl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2, 6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(Diethylamino)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Cyclopropyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 5-(4-Methylpiperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 13-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 8,14-Dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15(22),16,18(21)-hexaene-9-one; 4-[Methyl(oxetan-3-yl)amino]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2, 6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(Dimethylamino)methyl]-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4,10-Dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(Propan-2-yloxy)-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[1-(Oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(3-Methylpiperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(3S)-3-Hydroxypyrrolidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Fluoro-8,14-dioxa-10,19,20-triazapentacyclo[13.5.2.1 2,6 .1 7,10 .0 18,21 tetracosa-1(20),2(24),3,5,15(22),16,18(21)-heptaen-9-one; 4-(oxolan-3-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13S)-13-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaene-9-one; (13R)-13-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-(1-Methyl-1H-pyrazol-3-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaene-9-one; (7S)-7-Methyl-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaene-9-one; 4-[2-(Morpholin-4-yl)ethoxy]-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaene-9-one; 4-(2-Methoxyethyl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (7R)-7-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 5-Cyclopropyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(2-Methoxyethoxy)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 11-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(3-oxomorpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaene-9-one; 4-(2-oxopyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 5-(2-oxopyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-(2-Methylpyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 2-{9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-4-yl}acetonitrile; (11R)-11-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (11S)-11-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-Ethynyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-(Piperazin-1-yl)-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaene-9-one; 4-(1,2,3,6-Tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaene-9-one; 11-(Methoxymethyl)-8,14-dioxa-10,19,20-triazatricyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 8,14-Dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15(22),16,18(21)-hexaene-9-one; 11-Methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15(22),16,18(21)-hexaene-9-one; 12-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaene-9-one; 11-Ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-Fluoro-5,7-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-Fluoro-5-methoxy-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 5-Fluoro-4,7-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaene-9-one; 8,14 - Dioxo - 10,19,20 - triazapentacyclo[13.5.2.1 2,6 .1 7,10 .0 18,21 tetracosa - 1(20),2(24),3,5,15(22),16,18(21) - heptaen - 9 - one; 13-Methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 12-Methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15(22),16,18(21)-hexaene-9-one; 7-Methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; 5-Fluoro-4-methoxy-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (7R,13R)-7,13-Dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-13-Methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15,17,21-hexaen-9-one; 8,15-Dioxa-4,10,20,21-tetraazapentacyclo[14.5.2.1 2,6 .1 10,13 .0 19,22 pentacosa-1(21),2(25),3,5,16(23),17,19(22)-heptaen-9-one; 8,14-Dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; (13S)-4-Fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-4-Fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 6-Cyclopropyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15(22),16,18(21)-hexaene-9-one; 7-Ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13-Methyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7R,13R)-4-Fluoro-7,13-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 7-Methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7R)-4-Fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7S)-4-Fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 6-Methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15,17,21-hexaen-9-one; 7-Methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 6-(propan-2-yl)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15(22),16,18(21)-hexaene-9-one; (13R)-7,13-dimethyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; (13R)-13-Methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7R)-7-Ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7S)-7-Ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13-Methyl-8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 6-(oxan-4-yl)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15,17,21-hexaen-9-one; 4-Ethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),15,17,21-pentaene-9-one; (13R)-23-Fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 9,14-Dioxo-4,5,11,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15,17,21-hexaene-10-one; 4-Ethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15,17,21-hexaen-9-one; 3,9,15-Trioxa-4,11,20,21-tetraazatetracyclo[14.5.2.1 2,5 .0 19,22 tetracosa-1(21),2(24),4,16,18,22-hexaen-10-one; (13R)-16-Fluoro-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-4-chloro-13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 8,14-Dioxa-2,4,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),3,5(23),15(22),16,18(21)-hexaen-9-one; (13R)-4-Methoxy-13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13-Methyl-9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-5-carbonitrile; (13R)-13-Methyl-4-(pyrrolidin-1-yl)-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7S,13R)-7,13-Dimethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7R,13R)-7,13-dimethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-16-Fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13-Methyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 8,14-Dioxa-4-thia-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2,5(23),15,17,21-hexaen-9-one; 8,14-Dioxa-3-thia-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),4,15,17,21-hexaen-9-one; (7R,13R)-7,13-Dimethyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-4-[(3R)-3-methoxypyrrolidin-1-yl]-13-methyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-16-chloro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13,16-Dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13-Methyl-8,14-dioxa-3,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 8-Oxa-10,14,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaene-9-one hydrochloride; 8-Oxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-5-Methoxy-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13-Methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,6(23),15,17,21-hexaene-5,9-dione; 4-Methyl-8,14-dioxa-3,4,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2,5(23),15(22),16,18(21)-hexaen-9-one; (13R)-16-Fluoro-13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2,4,6(23),15,17,21-heptaen-9-one; 7,13-dioxa-4-thia-9,18,19,22-tetraazatetracyclo[12.5.2.1 2,5 .0 17,20 docosa-1(19),2,5(22),14(21),15,17(20)-hexaen-8-one; (13R)-4,13-Dimethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 8,14-Dioxa-23-thia-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2,4,15(22),16,18(21)-hexaen-9-one; (7S,13R)-7,13-dimethyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaene-9-one; (13R)-13-Methyl-9-oxo-8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15(22),16,18(21)-hexaene-4-carbonitrile; 12,12-Difluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 [[ID= (13R)-17-Fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (7S,13R)-7,13-Dimethyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (7R,13R)-7,13-Dimethyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18 ,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaene-9-one; (13S)-13-Methyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-13-Methyl-8,14-dioxa-10,19,20,22-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15,17,21-heptaen-9-one; (12R)-4,12-Dimethyl-7,13-dioxa-4,9,18,19,22-pentaazatetracyclo[12.5.2.1 2,5 .0 17,20 docosa-1(19),2,5(22),14(21),15,17(20)-hexaen-8-one; (13R)-13-Methyl-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15,17,21-hexaen-9-one; (13R)-13-Methyl-8,14-dioxa-23-thia-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2,4,15,17,21-hexaen-9-one; (13R)-4,13-dimethyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2,5(23),15(22),16,18(21)-hexaen-9-one; (13R)-13-Methyl-8,14-dioxa-10,16,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 14-Methyl-8-oxa-10,14,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15,17,21-heptaen-9-one; (13R)-13-Methyl-8,14-dioxa-4,10,19,20,22-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15,17,21-heptaen-9-one; (13R)-13-Methyl-8,14-dioxa-10,17,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 8,14-Dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15(22),16,18(21)-hexaene-9-one; 12,12-Difluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricosa-1(20),2(23),3,15(22),16,18(21)-hexaene-9-one); (12R)-12-Fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (12S)-12-Fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 12,12-Difluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (12S)-12-Fluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15,17,21-heptaen-9-one; (12R)-12-Fluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 tricos-1(20),2(23),3,5,15,17,21-heptaen-9-one; (12S)-12-Fluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15,17,21-hexaen-9-one; (12R)-12-Fluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1 2,5 .0 18,21 tricos-1(20),2(23),3,15,17,21-hexaen-9-one; 8',14'-Dioxa-10',19',20'-triazaspiro[cyclopropane-1,13'-tetracyclo[13.5.2.1 2,6 .0 18,21 tricosan]-1'(20'),2'(23'),3',5',15'(22'),16',18'(21')-heptaene-9'-one.

31. A pharmaceutical composition comprising the compound according to any one of claims 1 to 30 or an addition salt thereof with a pharmaceutically acceptable acid or base and one or more pharmaceutically acceptable excipients.

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

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

34. The pharmaceutical composition according to claim 33, wherein the neurological disease is selected from Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), diabetic neuropathy, argyrophilic grain disease, sphingomyelin storage disease, epilepsy, tauopathy, progressive supranuclear palsy, corticobasal degeneration, Lewy body dementia, multiple system atrophy, frontotemporal dementia, hereditary frontotemporal dementia and parkinsonism associated with chromosome 17 (FTDP-17), L-dopa-induced dyskinesia, ischemic stroke, traumatic brain injury, spinal cord injury and multiple sclerosis.

35. The pharmaceutical composition according to claim 33, wherein the neurological disease is dementia.

36. The pharmaceutical composition according to claim 33, wherein the neurological disease is age-related memory impairment.

37. The pharmaceutical composition according to claim 33, wherein the neurological disease is mild cognitive impairment.

38. The pharmaceutical composition according to claim 34, for the treatment of Parkinson's disease or Alzheimer's disease.

39. The pharmaceutical composition according to claim 33, wherein the endosomal-lysosomal disorder is selected from type A, B or C Niemann-Pick disease, Gaucher's disease, Krabbe disease, Fabry disease, disorders with mitochondrial defects.

40. The pharmaceutical composition according to claim 33, wherein the inflammatory disease is selected from vasculitis, lung disease, inflammatory myopathy, ankylosing spondylitis.

41. The pharmaceutical composition according to claim 33, wherein the inflammatory disease is idiopathic pulmonary fibrosis.

42. The pharmaceutical composition according to claim 40, wherein the lung disease is chronic obstructive pulmonary disease.

43. The pharmaceutical composition according to claim 33, wherein the autoimmune disease is selected from inflammatory bowel disease, rheumatoid arthritis, lupus, autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura, type I diabetes, obesity, Evans syndrome, bullous skin disease, Sjögren's syndrome, Devic's disease, and leprosy.

44. The pharmaceutical composition according to claim 33, wherein the autoimmune disease is selected from Crohn's disease, ulcerative colitis.

45. The pharmaceutical composition according to claim 33, wherein the cancer is selected from thyroid cancer, renal cancer, breast cancer, adenocarcinoma- and squamous cell lung cancer, non-small cell lung cancer, colon cancer, prostate cancer, skin cancer, leukemia, and lymphoma.

46. The pharmaceutical composition according to claim 33, wherein the cardiovascular disease is stroke.

47. The pharmaceutical composition according to claim 33, wherein the bacterial or viral infection is selected from leprosy, tuberculosis, SARS-CoV, MERS-CoV, and SARS-CoV-2, HIV, West Nile virus, and chikungunya virus.

48. Use of the compound according to any one of claims 1 to 30 or an addition salt thereof with a pharmaceutically acceptable acid or base in the manufacture of a medicament for use as an inhibitor of LRRK2 kinase activity for the treatment of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), diabetic neuropathy, argyrophilic grain disease, sphingomyelin storage disease, epilepsy, tauopathy, progressive supranuclear palsy, corticobasal degeneration, Lewy body dementia, frontotemporal dementia, chromosome 17-related hereditary frontotemporal dementia and parkinsonism (FTDP-17), L-dopa-induced dyskinesia, ischemic stroke, traumatic brain injury, spinal cord injury, multiple sclerosis, type A, B or C Niemann-Pick disease, Gaucher's disease, Krabbe's disease, Fabry's disease, disorders with mitochondrial defects, inflammatory bowel disease, rheumatoid arthritis, lupus, autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura, type I diabetes, obesity, Evans syndrome, bullous skin disease, Sjögren's syndrome, Devic's disease, leprosy, thyroid cancer, renal cancer, papillary renal cancer, breast cancer, adenocarcinoma- and squamous cell lung cancer, non-small cell lung cancer, colon cancer, prostate cancer, skin cancer, leukemia, lymphoma, stroke, tuberculosis, and SARS-CoV, MERS-CoV, SARS-CoV-2, HIV, West Nile virus, and chikungunya virus infections.

50. Use of a compound according to any one of claims 1 to 30 or an addition salt thereof with a pharmaceutically acceptable acid or base in the preparation of a medicament for use as an inhibitor of LRRK2 kinase activity for Crohn's disease and ulcerative colitis.

51. Use of a compound according to any one of claims 1 to 30 or an addition salt thereof with a pharmaceutically acceptable acid or base in the preparation of a medicament for use as an inhibitor of LRRK2 kinase activity for the treatment of dementia.

52. Use of a compound according to any one of claims 1 to 30 or an addition salt thereof with a pharmaceutically acceptable acid or base in the preparation of a medicament for use as an inhibitor of LRRK2 kinase activity for the treatment of age-related memory impairment.

53. Use of a compound according to any one of claims 1 to 30 or an addition salt thereof with a pharmaceutically acceptable acid or base in the preparation of a medicament for use as an inhibitor of LRRK2 kinase activity for the treatment of mild cognitive impairment.

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