INHIBITORS OF LEUCINE RICH REPEAT KINASE 2

FIELD OF THE INVENTION The present invention relates to novel compounds that inhibit LRRK2 kinase activity, methods for their preparation, compositions containing them and their use in the treatment of diseases associated with or characterized by LRRK2 kinase activity, for example Parkinson's disease, Alzheimer's disease. and amyotrophic lateral sclerosis (ALS). BACKGROUND OF THE INVENTION

Parkinson's disease (PD) is a neurodegenerative disorder characterized by selective degeneration and cell death of dopaminergic neurons in the substantial nigra region of the brain. Parkinson's disease was generally regarded as sporadic and of unknown etiology, but over the past 15 years there has been a major development in understanding the genetic basis of this disease and associated pathogenic mechanisms. One area of development is the understanding of leucine-rich repeat kinase 2 (LRRK2) protein. A number of mis-sense mutations in the LRRK2 gene have been strongly associated with autosomal dominant Parkinson's disease in familial studies (see WO 2006068492 and WO 2006045392; Trinh and Farrer 2013, Nature Reviews in Neurology 9: 445-454; Paisan-Ruiz et al., 2013, J. Parkinson's Disease 3:85-103). The G2019S mutation in LRRK2 is the most common mis-sense mutation and is associated with a clinical phenotype very similar to sporadic Parkinson's disease. The LRRK2 G2019S mutation is also present in approximately 1.5% of sporadic Parkinson's disease cases (see Gilks et al., 2005, Lancet, 365:415-416). In addition to the known pathogenic coding mutations in LRRK2, additional amino acid-coding variants of LRRK2 have been identified that are also associated with the risk of developing Parkinson's disease (see Ross et al., 2011 Lancet Neurology 10:898-908) . In addition, genome-wide association studies (GWAS) have identified LRRK2 as a susceptibility locus for Parkinson's disease, indicating that LRRK2 may also be relevant to sporadic cases of Parkinson's disease without mutations causing amino acid substitutions in the LRRK2 protein. (See Satake et al., 2009 Nature Genetics 41:1303-1307; Simon-Sanchez et al. 2009 Nature Genetics 41:1308-1312)

LRRK2 is a member of the ROCO protein family and all members of this family share five conserved domains. The most common pathogenic mutation G2019S occurs in the highly conserved kinase domain of LRRK2. This mutation increases LRRK2 kinase activity in in vitro enzyme assays of recombinant LRRK2 proteins (see Jaleel et al., 2007, Biochem J, 405:307-317) and in LRRK2 proteins purified from G2019S PD- patient-derived cells (See Dzamko et al., 2010 Biochem.J. 430:405-413). A less frequent LRRK2 pathogenic mutation causing amino acid substitution at another residue, R1441, has also been shown to increase LRRK2 kinase activity by decreasing the rate of GTP hydrolysis through the GTPase domain of LRRK2 (see Guo et al., 2007 Exp Cell Res.313:3658-3670;West et al., 2007 Hum.Mole Gen.16:223-232). In addition, phosphorylation of Rab protein physiological substrates of LRRK2 has been shown to be increased by a series of Parkinson's disease pathogenic mutations of LRRK2 (see Steger et al., 2016 eLife 5 e12813).

Therefore, evidence indicates that the kinase and GTPase activities of LRRK2 are important for pathogenesis, and that the LRRK2 kinase domain may regulate overall LRRK2 function (see Cookson, 2010 Nat. Rev. Neurosci. 1 1: 791-797 ).

There is evidence that the increased LRRK2 kinase activity is associated with neuronal toxicity in cell culture models (see Smith et al., 2006 Nature Neuroscience 9:1231 - 1233) and kinase inhibitor compounds protect against LRRK2-mediated cell death (see Lee et al., 2010 Nat Med 16: 998-1000). LRRK2 has also been reported to act as a negative regulator of microglia-mediated clearance of alpha-synuclein (see Maekawa et al., 2016 BMC Neuroscience 17:77), suggesting a potential utility of LRRK2 inhibitors in promoting the clearance of neurotoxic forms of alpha. -synuclein in the treatment of Parkinson's disease.

Induced pluripotent stem cells (iPSCs) derived from LRRK2 G2019S patients with Parkinson's disease have been found to exhibit defects in neurite outgrowth and increased sensitivity to rotenone, which can be ameliorated by either genetic correction of the G2019S mutation or treatment of cells with small molecule inhibitors of LRRK2 kinase activity (see Reinhardt et al., 2013 Cell Stem Cell 12:354-367). Mitochondrial DNA damage has been reported as a molecular marker of vulnerable dopamine neurons in substantia nigra from postmortem examination.

Parkinson's disease samples (See Sanders et al 2014 Neurobiol. Dis. 70:214-223).

Elevated levels of such mitochondrial DNA damage associated with LRRK2 G2019S mutation in iSPCs are blocked by genetic correction of the G2019S mutation (see Sanders et al., 2014 Neurobiol. Dis. 62:381-386).

Additional evidence links the function and dysfunction of LRRK2 to autophagy-lysosomal pathways (see Manzoni and Lewis, 2013 Faseb J. 27:3234-3429). LRRK2 proteins cause defects in chaperone-mediated autophagy that negatively impact cells' ability to degrade alpha-synuclein (Orenstein et al., 2013 Nature Neurosci. 16 394-406). In other cell models, selective LRRK2 inhibitors have been shown to stimulate macroautophagy (see Manzoni et al., 2013 BBA Mol. Cell Res. 1833:2900-2910). These data suggest that inhibitors of LRRK2 small molecule kinase activity may be useful in the treatment of diseases characterized by defects in cellular proteostasis resulting from aberrant

autophagy/lysosomal degradation pathways including forms of Parkinson's disease associated with GBA mutations (see Swan and Saunders-Pullman 2013 Curr. Neurol.

Neuroscience Rep. 13:368), other alpha-synucleinopathies, tauopathies, Alzheimer's disease (see Li et al., 2010 Neurodegen. Dis. 7:265-271) and other neurodegenerative diseases (see Nixon 2013 Nat. Med. 19:983 - 997) and Gaucher disease (See Westbroek et al., 2011 Trends. Mol. Med. 17: 485-493). As promoters of autophagy, small molecule inhibitors of LRRK2 kinase may also be useful in the treatment of other diseases, including diabetes, obesity, motor neuron disease, epilepsy and some cancers (see Rubinsztein et al., 2012 Nat.Rev. Drug Discovery 1 1 : 709-730), lung diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (see Araya et al., 2013 Intern. Med. 52: 2295-2303) and autoimmune diseases such as systemic lupus erythematosus (see Martinez et al., 2016 Nature 533: 1 15-1 19). As promoters of autophagy and phagocytic processes, small molecule inhibitors of LRRK2 kinase may also be useful in enhancing host responses in the treatment of a range of intracellular bacterial, parasitic and viral infections, including diseases such as tuberculosis (see Rubinsztein et al. , 2012 Nat Rev Drug Discovery 1 1: 709-730 Araya et al., 2013 Intern Med 52: 2295-2303;

Gutierrez, Biochemical Society Conference; Leucine-rich repeat kinase 2: ten years towards therapeutic intervention, Henley Business School, UK 12 July 2016), HIV, West Nile virus and chikungunya virus (see Shoji-Kawata et al., 2013 Nature 494:201-206) .

LRRK2 inhibitors may be useful in the treatment of such diseases alone, or in combination with drugs that directly target the infectious agent. Furthermore, significantly elevated levels of LRRK2 mRNA have also been observed in fibroblasts from patients with Niemann-Pick Type C (NPC) disease compared to fibroblasts from normal subjects, indicating that aberrant LRRK2 function may play a role in lysosomal disorders (see Reddy et al., 2006 PLOS One 1(1):e19 doi:10.1371/journal.pone.0000019 - supporting information Dataset S1). This observation suggests that LRRK2 inhibitors may be useful for the treatment of NPC. The PD-associated G2019S mutant form of LRRK2 has also been reported to enhance the phosphorylation of tubulin-associated Tau (see Kawakami et al., 2012 PLoS ONE 7:

e30834, doi 10.1371), and disease models have been proposed in which LRRK2 acts upstream of the pathogenic effects of Tau and alpha-synuclein (See Taymans & Cookson, 2010, BioEssays 32:227-235). In support of this, LRRK2 expression has been associated with increased aggregation of insoluble Tau and increased Tau phosphorylation in a transgenic mouse model (see Bailey et al., 2013 Acta Neuropath. 126:809-827). Overexpression of the PD pathogenic mutant protein LRRK2 R1441 G has been reported to cause Parkinson's disease symptoms and hyperphosphorylation of Tau in transgenic mouse models (see Li, Y. et al. 2009, Nature Neuroscience 12:826-828). Therefore, these data suggest that LRRK2 inhibitors of kinase catalytic activity may be useful for the treatment of tauopathy diseases characterized by hyperphosphorylation of Tau, such as argyrophilic grain disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, and hereditary frontotemporal dementia and parkinsonism linked to chromosome. 17 (FTDP-17) (See Goedert, M and Jakes, R (2005) Biochemica et Biophysica Acta 1739, 240-250). In addition, LRRK2 inhibitors may be useful in the treatment of other diseases characterized by decreased dopamine levels, such as withdrawal/relapse associated with drug addiction (see Rothman et al., 2008, Prog. Brain Res, 172:385).

Other studies have also shown that overexpression of the G2019S mutant form of LRRK2 causes defects in subventricular zone (SVZ) and reduces neuroprogenitor cell proliferation and migration in transgenic mouse models (see Winner et al., 2011 Neurobiol. Dis. 41:706-716). the length of neurites and branching cell culture models (see Dachsel et al., 2010

Parkinsonism and Related Disorders 16:650-655). In addition, agents that promote proliferation and migration of SVZ neuroprogenitor cells were also reported to improve neurological outcomes following ischemic injury in rodent models of stroke (see Zhang et al., 2010 J. Neurosci. Res. 88:3275-3281). These findings suggest that compounds that inhibit aberrant activity of LRRK2 may be useful for the treatments designed to stimulate recovery of CNS functions after neuronal injury, such as ischemic stroke, traumatic brain injury, spinal cord injury.

Mutations in LRRK2 have also been identified that are clinically associated with the transition from mild cognitive impairment (MCI) to Alzheimer's disease (see WO 2007149798). These data suggest that inhibitors of LRRK2 kinase activity may be useful for the treatment of diseases such as Alzheimer's disease, other dementias and related neurodegenerative disorders. Aberrant regulation of normal LRRK2 proteins is also observed in some disease tissues and disease models. Normal mechanisms of translational control of LRRK2 by miR-205 are disrupted in some sporadic PD cases, where significant decreases in miR-205 levels in PD brain samples correspond to increased LRRK2 protein levels in those samples (see Cho et al., ( 2013)) Hum.Mol.Gen.22:608-620). Therefore, LRRK2 inhibitors can be used in the treatment of sporadic PD patients with elevated levels of normal LRRK2 proteins. In an experimental model of Parkinson's disease in marmosets, elevation of LRRK2 mRNA is observed in a manner that correlates with the level of L-Dopa-induced dyskinesia (see Hurley, M.J et al., 2007 Eur. J. Neurosci. 26:171-177). This suggests that LRRK2 inhibitors may have a utility in ameliorating such dyskinesias.

Significantly elevated levels of LRRK2 mRNA have been reported in muscle biopsy samples from ALS patients (see Shtilbans et al., 2011 Amyotrophic Lateral Sclerosis 12: 250-256). It is suggested that elevated levels of LRRK2 kinase activity may be a hallmark feature of ALS. . Therefore, this observation indicated that the LRRK2 inhibitor could be useful for the treatment of ALS.

There is also evidence that LRRK2 kinase activity may play a role in mediating microglial proinflammatory responses (see Moehle et al., 2012, J. Neuroscience 32:1602-1611). This observation suggests a potential utility of LRRK2 inhibitors for the treatment of aberrant neuroinflammatory mechanisms contributing to a range of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, multiple sclerosis, HIV-induced dementia, amyotrophic lateral sclerosis, ischemic stroke, traumatic brain injury. and spinal cord injury. There is also evidence that LRRK2 plays a role in regulating neuronal progenitor differentiation in vitro (see Milosevic, J. et al., 2009 Mol. Neurodegen. 4:25). This evidence suggests that inhibitors of LRRK2 may have utility in the production of neuronal progenitor cells in vitro for consistent therapeutic application in cell-based treatment of CNS disorders.

Parkinson's disease patients carrying LRRK2 G2019S mutation have been reported to show an increased frequency of non-skin cancers, including kidney, breast, lung and prostate cancers, as well as acute myeloid leukemia (AML). Since there is evidence showing that the G2019S mutation in LRRK2 increases the catalytic activity of the LRRK2 kinase domain, small molecule inhibitors of LRRK2 may be useful in the treatment of cancer, e.g. kidney cancer, breast cancer, lung cancer, prostate cancer (e.g. solid tumors) and blood cancer (see AML; Saunders-Pullman et al., 2010, Movement Disorders, 25:2536-2541; Inzelberg et al., 2012 Neurology 78:781-786). Amplification and overexpression of LRRK2 has also been reported in papillary renal and thyroid carcinomas, where cooperation between LRRK2 and the MET oncogene may promote tumor cell growth and survival (see Looyenga et al., 2011 PNAS 108:1439-1444.)

Some studies have suggested a genetic association between common LRRK2 variants with susceptibility to ankylosing spondylitis (see Danoy P, et al., 2010. PLoS Genet.; 6(12):e1001 195; and leprosy infection (see Zhang FR, et al 2009, N Engl J Med 361:2609-18 These findings suggest that inhibitors of LRRK2 may be useful in the treatment of ankylosing spondylitis and leprosy infection Meta-analysis of three genome-wide associated scans for the Crohn's disease identified a number of loci associated with the disease, including the locus containing the LRRK2 gene (see Barrett et al., 2008, Nature Genetics, 40:955-962).Evidence has also emerged that LRRK2 is a I FN-γ target gene that may be involved in signaling pathways relevant to Crohn's disease pathogenesis (see Gardet et al., 2010, J. Immunology, 185:5577-5585) These findings suggest that inhibitors of LRRK2 may be useful in the treatment of Crohn's disease.

As an IFN-γ target gene, LRRK2 may also play a role in T cell mechanisms underlying other immune system diseases, such as multiple sclerosis and rheumatoid arthritis. Another potential utility of LRRK2 inhibitors stems from the reported finding that B lymphocytes constitute a large population of LRRK2-expressing cells (see Maekawa et al. 2010, BBRC 392:431-435). This suggests that LRRK2 inhibitors may be effective in the treatment of immune system diseases for which B cell depletion is or may be effective in diseases such as lymphomas, leukemias, multiple sclerosis (see Ray et al., 201 1 J. Immunol. 230: 109), rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, erythrocytic aplasia, idiopathic thrombocytopenic purpura (ITP), Evans syndrome, vasculitis, bullous skin disorders, type 1 diabetes mellitus, Sjögren's syndrome, Devic's disease and inflammatory myopathies (See Engel et al., 2011 Pharmacol. Rev. 63:127-156; Homam et al., 2010 J. Clin. Neuromuscular Disease 12:91-102).

SUMMARY OF THE INVENTION

The present invention provides, in a first aspect, a compound of Formula (I)

Formula (I)

or a pharmaceutically acceptable salt thereof, wherein

X is CH of N; n is 2, 3, 4 of 5;

A is O of NR^A, in which

R^Ais

C3-6 cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl and C1-3 alkoxyl; or

four to seven membered heterocyclyl ring having one or two heteroatom ring members independently selected from O and N, and the heterocyclyl ring is optionally substituted with one to three substituents independently selected from halo and C1-3 alkyl, wherein C1-3 alkyl is optionally substituted with one to three halo substituents;

1 ) H, halo, CN;

2) C 1-4 alkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl and C 1-3 alkoxyl, said C 1-3 alkoxyl optionally substituted with one to three halogen substituents;

3) C 2-6 alkenyl optionally substituted with one to three halo or C 1-3 alkyl, said C 1-3 alkyl optionally substituted with one to three halo substituents;

4) C 2-6 alkynyl optionally substituted with one to three C 1-3 alkyl substituents, wherein C 1-3 alkyl is optionally substituted with one to three halo substituents;

5) C 1-4 alkoxyl optionally substituted with one to three halogen substituents;

6) C3-6 cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl, C1-3 alkoxyl and C1-3 alkyl, wherein C1-3 alkoxyl and C1-3 alkyl are optionally are substituted with one to three halogen substituents;

7) -OC 3-6 cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, C 1-3 alkoxyl and C 1-3 alkyl;

8) four to seven membered heterocyclyl ring having one or two heteroatom ring members independently selected from O and N, and the heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, C 1-3 alkoxyl and C 1-3- alkyl;

9) -O-Heterocyclyl ring having one or two heteroatom ring members independently selected from O and N, wherein the heterocyclyl ring is a four to seven membered ring optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, C1-3- alkoxy and C 1-3 alkyl; or

10) -SC 1-4 -alkyl optionally substituted with one to three halo substituents;

R₂is

H, halo, CN;

C 1-4 alkoxyl optionally substituted with one to three halo substituents;

C3-6cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl and C1-3alkoxyl;

Rs is

1 ) H;

2) -CO-Z, where Z is selected from the group consisting of

four to seven membered heterocyclyl ring having one or two heteroatom ring members independently selected from O and N;

C3-6 cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, C1-3 alkyl and C1-3 alkoxyl; And

C 1-6 alkyl optionally substituted with one to three substituents independently selected from halo and C 1-3 alkoxyl;

3) four to seven membered heterocyclyl ring having one or two heteroatom ring members independently selected from O and N, and the heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of

halo;

cyan;

C 1-3 alkyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl; C 1-3 alkoxyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl; And

four to seven membered heterocyclyl ring having one or two heteroatom ring members independently selected from O and N, and the heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of halo, C1-3 alkyl and C1-3 alkoxyl;

C 1-6 alkyl optionally substituted with one to three substituents independently selected from the group consisting of

CN, hydroxyl, halogeen;

C 1-4 alkoxyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl;

-CO-Q, waarin Q Ci-4alkoxyl, hydroxylor NR is_CRd, where R_Cand R d are each independently H or C 1-4 alkyl;

C3-7 cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of

halogeen, hydroxyl;

C 1-3 alkyl optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl and C 1-3 alkoxyl;

C 1-4 alkoxyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl and C 1-3 alkoxyl; and a four to seven membered heterocyclyl ring having one or two heteroatom ring members independently selected from O and N, wherein the heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, C 1-3 alkyl, and C 1-3 alkoxy ; 6) C-linked 7-9 membered bridged cyclyl ring optionally having one or two heteroatom ring members independently selected from O and N, optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl, C1-3alkyl and C1- 3alkoxyl;

7) C-linked 7-10 membered spirane-cyclyl ring, optionally having one or two heteroatom ring members independently selected from O and N, optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl, C1-3- alkyl and C 1-3 alkoxyl; or

8) C-linked 6-9 membered fused cyclyl ring, optionally having one or two heteroatom ring members independently selected from O and N, optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, C 1-3 alkyl and Ci -3alkoxyl;

R₄and Rs, at each occurrence, each independently selected from the group consisting of

H, halogeen, hydroxyl;

Ci_-4alkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, Ci_-4alkoxyl, OCi_-4haloalkyl, and a four to seven membered heterocyclyl ring having one or two heteroatom ring members independently selected from O and N;

C3-6cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl and Ci_-4alkoxy;

four to seven membered heterocyclyl ring having one or two heteroatom ring members independently selected from O and N, wherein the heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, C 1-3 alkyl and C 1-3 alkoxyl; And

Ci_-4alkoxyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl and C 1-4 alkoxyl.

In a further aspect of the invention, the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

A further aspect of the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis (ALS). DETAILED DESCRIPTION OF THE INVENTION The foregoing and other aspects of the present invention will now be described in greater detail in connection with the description and methodologies provided herein. It is to be understood that the invention may be embodied in various forms and is not to be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

The terminology used in the description of the invention herein is intended only to describe particular embodiments and is not intended to limit the invention. As used in the description of the embodiments of the invention and the appended claims, the singular forms "a", "an" and "the" are intended to include the plural forms unless the context clearly dictates otherwise. Also, as used herein, "and/or" refers to and

includes all possible combinations of one or more of the corresponding listed items. It is further understood that the terms "includes" and/or "comprising", when used in this specification, specify the presence of stated features, integers, steps, operations, elements and/or components, but not the presence exclude or add one or more other attributes, integers, steps, operations, elements, components and/or groups thereof.

In general, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biology described herein are those well known and commonly used in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the event that there are multiple definitions for a term used herein, those in this section will prevail unless otherwise stated.

A. Definitions

As used herein, "alkyl" refers to a monovalent, saturated hydrocarbon chain having a specified number of carbon atoms. For example, C 1-4 alkyl refers to an alkyl group having 1 to 4 carbon atoms. Alkyl groups can be straight or branched. In certain

embodiments, branched alkyl groups can have one to three branches. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl, pentyl, and hexyl. As used herein, "-SC1-4-alkyl" refers to a C1-4 alkyl group attached to the nucleus through a sulfur (S) atom.

As used herein "alkoxyl" refers to the group -O-alkyl. For example, C 1-6 alkoxy groups contain 1 to 6 carbon atoms. C 1-4 alkoxy groups contain 1 to 4 carbon atoms. C 1-3 alkoxy groups contain 1 to 3 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxyl, ethoxyl, propoxyl, butoxyl, pentyloxyl, and hexyloxyl.

As used herein "cycloalkyl" refers to a saturated monocyclic hydrocarbon ring having a specified number of carbon atoms. For example, C3-6 cycloalkyl contains 3 to 6 carbon atoms as member atoms in the ring. -OC3-6 cycloalkyl refers to a C3-6 cycloalkyl group attached to the nucleus through an oxygen atom. Examples of C3-6 cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, and cyclohexyl. As used herein, "alkenyl" refers to a straight or branched hydrocarbon chain of a specified number of carbon atoms, containing at least one double bond. For example, C 2-6 alkenyl refers to an alkenyl group having 2 to 6 carbon atoms. Examples of akenyl groups include, but are not limited to, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, and hexenyl.

As used herein, "alkynyl" refers to a straight or branched hydrocarbon chain of a specified number of carbon atoms, containing at least one triple bond. For example, C2-6 alkynyl refers to an alkynyl group having 2 to 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

As used herein, "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). "Halo" refers to the halogen radicals: fluorine (-F), chlorine (-Cl), bromine (-Br), or iodine (-I).

As used herein, "haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halogen atoms independently selected from F, Cl, Br, or I, on one or all of the carbon atoms of the alkyl group. For example, C 1-4 haloalkyl refers to a C 1-4 alkyl group substituted with one or more halogen atoms. -OCi-4haloalky refers to a C1-4haloalkyl group attached through an oxygen atom. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, chloromethyl, bromoethyl, difluoromethyl, trifluoromethyl, and dichloromethyl.

As used herein, "substituted" in reference to a group indicates that one or more hydrogen atoms attached to a member atom (e.g., carbon atom) within the group are replaced by a substituent selected from the group of defined substituents. It should be understood that the term "substituted" includes the implicit provision that such substitution is in accordance with the permissible valence of the substituted atom and substituent and that the substitution results in a stable compound (i.e., a compound that does not undergo spontaneous transformation such as by rearrangement, cyclization, or elimination and which is robust enough to survive isolation from a reaction mixture). When it is stated that a group may contain one or more substituent(s), one or more (as the case may be) member atom(s) within the group may be substituted. In addition, a single atom within the group may be substituted with more than one substituent as long as such substitution is consistent with the allowed valency of the atom.

As used herein, "optionally substituted" indicates that a particular group, such as alkyl, alkenyl, alkynyl, alkoxyl, heterocyclyl, cycloalkyl, may be unsubstituted, or substituted as further defined.

As used herein, "heterocyclyl" or "heterocyclyl ring" is a monovalent radical derived by removal of a hydrogen atom from a saturated monocyclic ring, which ring consists of ring carbon atoms and 1 or 2 ring heteroatoms independently selected from nitrogen and oxygen. The number of ring atoms can be specified. For example, a "four to seven membered heterocyclyl" or "four to seven membered heterocyclyl ring" is a heterocyclyl or heterocyclyl ring as defined above, consisting of four to seven ring atoms. In addition, other ring heteroatoms (nitrogen or oxygen) may be present. A heterocyclyl ring can be attached to the nucleus through an atom that is not part of the ring. For example, an "O-heterocyclyl" or "O-heterocyclyl ring" is a heterocyclyl or heterocyclyl ring as defined above, attached to the nucleus via an oxygen atom. In one embodiment, the heterocyclyl ring is attached directly to the core. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl (including, for example, tetrahydrofuran-2-yl and

tetrahydrofuran-3-yl), pyrrolidinyl (including, for example, pyrrolidin-1-yl and pyrrolidin-3-yl), tetrahydro-2H-pyranyl or oxanyl (including, for example, tetrahydro-2/-/-pyran-3-yl or oxayn-3 -yl and tetrahydro-2/-/-pyran-4-yl or oxan-4-yl), piperidinyl (including, for example, piperidin-3-yl and piperidin-4-yl) and morpholinyl (including, for example, morpholin-2-yl and morpholin-4-yl).

As used herein, the term "oxygen-containing heterocyclyl" or "oxygen-containing heterocyclyl ring" is a monovalent group derived by removal of a hydrogen atom from a saturated monocyclic ring, which ring consists of ring carbon atoms and 1 oxygen atom. The number of ring atoms can be specified. For example, a "four- to seven-membered oxygen-containing heterocyclyl" or "four- to seven-membered oxygen-containing heterocyclyl ring" is an oxygen-containing heterocyclyl or oxygen-containing heterocyclyl ring as defined above, consisting of four to seven ring atoms. Examples of oxygen-containing heterocyclyl rings include, but are not limited to, oxetanyl, tetrahydrofuranyl (including, for example, tetrahydrofuran-2-yl and tetrahydrofuran-3-yl), tetrahydro-2H-pyranyl, or oxanyl (including, for example, tetrahydro-2/-/-pyran- 3-yl or oxayn-3-yl and tetrahydro-2/-/-pyran-4-yl or oxan-4-yl),

As used herein, the term "nitrogen-containing heterocyclyl" or "nitrogen-containing heterocyclyl ring" is a monovalent group derived by removal of a hydrogen atom from a saturated monocyclic ring, which ring consists of ring carbon atoms and 1 nitrogen atom. The number of ring atoms can be specified. For example, a "four- to seven-membered nitrogen-containing heterocyclyl" or "four- to seven-membered nitrogen-containing heterocyclyl ring" is a nitrogen-containing heterocyclyl or nitrogen-containing heterocyclyl ring as defined above, consisting of four to seven ring atoms. Examples of nitrogen-containing heterocyclyl rings include, but are not limited to, azetidinyl, pyrrolidinyl (including, for example, pyrrolidin-1-yl and pyrrolidin-3-yl), and piperidinyl (including, for example, piperidin-3-yl and piperidinyl-4-yl). As used herein, the term "bridged cyclyl ring" refers to a monovalent group obtained by removal of a hydrogen atom from a bridged ring (a ring in which two non-adjacent ring atoms are linked by a bridge containing at least one atom), which consists of carbon atoms and 0 to 2 heteroatoms independently selected from nitrogen and oxygen. In one embodiment, the bridged cyclil ring is saturated. The number of atoms in the ring and bridge can be specified. For example, the term 7-9 membered bridged cyclyl ring refers to a bridged cyclyl ring having a total of 7 to 9 atoms in the ring plus bridge. The term "C-linked 7-9 membered bridged cyclyl ring" refers to a 7-9 membered bridged cyclyl ring as defined above containing one carbon ring atom through which it is linked to the nucleus. Examples of bridged cyclic rings include, but are not limited to ^ZD³, , I_{t t}^°, KC°, ¾ HS>__In.

As used herein, the term "spirancyclyl ring" refers to a monovalent group obtained by removal of a hydrogen atom from two rings connected by only one atom. The spiranecyclyl ring consists of carbon atoms and 0 to 2 heteroatoms independently selected from nitrogen and oxygen, but the spiro atom must be carbon. In one embodiment, the spiranecyclyl ring is saturated. The number of atoms in the spiranecyclyl ring can be specified. For example, a 7-10 membered spiranecyclyl ring refers to a spiranecyclyl ring that has a total of 7 to 10 atoms in the two rings (including the spiro atom). The term "C-linked 7-10-membered spirane-cyclyl ring" refers to a 7-10-membered spirane-cyclyl ring as defined above containing one carbon ring atom linking it to the nucleus. Examples of spiranecyclyl rings and C-linked spiranecyclyl rings include, but are not limited to, l^~0,

As used herein, the term "fused cyclyl ring" refers to a monovalent radical derived by removal of a hydrogen atom from a bicyclic ring (two rings sharing one bond) consisting of carbon atoms and 0 to 2 heteroatoms selected independently from nitrogen and oxygen. The number of atoms in a fused cyclyl ring can be specified. In one embodiment, the fused cyclyl ring is saturated. For example, the term 6-9 membered fused cyclil ring refers to a fused bicyclic ring having a total of 6 to 9 atoms in the two rings. The term "C-linked 6-9 membered fused cyclyl ring" refers to a 6-9 membered fused bicyclic ring as defined above containing at least one carbon ring atom linking it to the nucleus. In addition, one or two other ring heteroatoms (nitrogen or oxygen) may be present. Examples of fused

-½ R₄R₅¼-'^;N

As used herein, the structure or (CR₄Rs)n refers to , as a skilled artisan would understand.

As used herein, the term "leaving group" means the group having the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group that is movable under substitution reaction conditions. Examples of leaving groups include, but are not limited to, methane sulfonate and 4-methylbenzene sulfonate.

As used herein, the term "protecting group" or "protecting group" means the group having the meaning conventionally associated with it in synthetic chemistry, i.e., a group that selectively blocks one reactive site in a compound having multiple reactive sites such that a chemical reaction can be carried out selectively at another unprotected reactive site. Some methods of this invention rely on the protecting groups to block reactive nitrogen and/or oxygen atoms present in the reactants. Examples of protecting groups include, but are not limited to, tetrahydro-2/-/-pyran, Boc(tert-butyloxycarbonyl) or ((trimethylsilyl)ethoxy)methyl).

As used herein, the term "disease" refers to any change in the condition of the body or some organs that interrupts or disrupts the performance of functions and/or causes symptoms such as discomfort, dysfunction, distress or even death of the patient. the affected person. A disease can also be a distemper, ailment, ailment, ailment, disorder, illness, disease, complaint, interdisposition and/or affectation. As used herein, "treating", "treating" or "treatment" in relation to a disease means: (1) ameliorating the disease or one or more of the biological manifestations of the disease, (2) interfering with (a) one or more points in the biological cascade leading to or responsible for the disease or (b) one or more of the biological manifestations of the disease, (3) one or more of the symptoms or effects associated with the disease to alleviate, (4) to slow the progression of the disease or one or more of the biological manifestations of the disease, and/or (5) to reduce the likelihood of the severity of a disease or biological manifestations of the disease. Symptomatic treatment refers to treatment as referred to in points (1), (3) and (5). Disease-modifying treatment refers to treatment as defined in points (2) and (4). As used herein, "prevent", "avoid" or "avoid" means the prophylactic administration of a drug to reduce the likelihood of the onset of a disease or biological manifestation thereof or to delay its onset.

As used herein, "patient" means a mammalian patient (e.g., dog, cat, horse, cow, sheep, goat, monkey, etc.), and human subjects, including both male and female subjects, and including neonatal, infant, juvenile, adolescent, adult, and geriatric subjects, and further including various races and ethnicities, including, but not limited to, white, black, Asian, American Indian, and Hispanic.

As used herein, "pharmaceutically acceptable salt(s)" refers to salt(s) that retain the desired biological activity of the subject compound and exhibit minimal undesirable toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound separately in its free acid or free base form with a suitable base or acid, respectively. As used herein, "therapeutically effective amount" with respect to a compound of the invention means an amount of the compound sufficient to treat or prevent the patient's disease, but low enough to avoid serious side effects (at a reasonable cost). benefit/risk balance) within the scope of sound medical judgment. A therapeutically effective amount of a compound will vary with the particular compound selected (consider, for example, the compound's potency, efficacy, and half-life); the chosen route of administration; the disease being treated; the severity of the disease being treated; the age, size, weight and physical illness of the patient being treated; the medical history of the patient to be treated; the duration of treatment; the nature of concomitant therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by those skilled in the art. B. Connections

This invention provides, in a first aspect, a compound of Formula (I):

Formula (I)

or a pharmaceutically acceptable salt thereof, wherein

X is CH of N;

n is 2, 3, 4 of 5;

A is O of NR^A, in which

R^Ais

C3-6 cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl and C1-3 alkoxyl; or

1 ) H, halo, CN;

3) C 2-6 alkenyl optionally substituted with one to three halo or C 1-3 alkyl, said C 1-3 alkyl optionally substituted with one to three halo substituents;

4) C 2-6 alkynyl optionally substituted with one to three C 1-3 alkyl substituents, wherein C 1-3 alkyl is optionally substituted with one to three halo substituents;

5) C 1-4 alkoxyl optionally substituted with one to three halogen substituents;

7) -OC 3-6 cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, C 1-3 alkoxyl and C 1-3 alkyl;

10) -SC 1-4 -alkyl optionally substituted with one to three halo substituents;

R₂is

H, halo, CN;

C 1-4 alkoxyl optionally substituted with one to three halo substituents;

C 1-4 alkyl optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl and C 1-3 alkoxyl, wherein C 1-3 alkoxyl is optionally substituted with one to three halo substituents; or C3-6cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl and C1-3alkoxyl;

1 ) H;

2) -CO-Z, where Z is selected from the group consisting of

four to seven membered heterocyclyl ring having one or two heteroatom ring members independently selected from O and N;

C3-6 cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, C1-3 alkyl and C1-3 alkoxyl; And

C 1-6 alkyl optionally substituted with one to three substituents independently selected from halo and C 1-3 alkoxyl;

halo;

cyan;

C 1-3 alkyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl;

C 1-3 alkoxyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl; And

four to seven membered heterocyclyl ring having one or two heteroatom ring members independently selected from O and N, and the heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of halo, C1-3 alkyl and C1-3 alkoxyl;

4) C 1-6 alkyl optionally substituted with one to three substituents independently selected from the group consisting of

CN, hydroxyl, halogeen;

C 1-4 alkoxyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl; -CO-Q, where Q is C 1-4 alkoxyl, hydroxyl or NR_CRd, where R_Cand R d are each independently H or C 1-4 alkyl;

C3-7 cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of

halogeen, hydroxyl;

C 1-3 alkyl optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl and C 1-3 alkoxyl;

) C-linked 7-10 membered spiranecyclyl ring optionally having one or two heteroatom ring members independently selected from O and N, optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, C 1-3 alkyl and C 1- 3alkoxyl; or

) C-linked 6-9-membered fused cyclyl ring optionally having one or two heteroatom ring members independently selected from O and N, optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl, C 1-3 alkyl and C 1-3 alkoxyl ; R₄and R5 at each occurrence are each independently selected from the group consisting of

H, halogeen, hydroxyl;

Ci_-4alkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, Ci_-4alkoxy, OCi_-4haloalkyl, and a four to seven membered heterocyclyl ring having one or two heteroatom ring members independently selected from O and N;

C3-6cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl and Ci_-4alkoxy;

Ci_-4alkoxyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl and C 1-4 alkoxyl.

In certain embodiments, X is CH or N; n is 2, 3, 4 or 5; and A is O or NR^A, Warin R^Ais H of Ci_-4alkyl optionally substituted with C 1-3 alkoxyl. In one embodiment, A is NR^Aan R^Ais H of Ci_-4alkyl, which is Ci_-4alkyl group is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl and C1-3 alkoxyl, wherein C1-3 alkoxyl is optionally substituted with one to three halogen substituents. In one embodiment, A is NR^Aan R^Ais H of Ci_-4alkyl die Ci_-4alkyl group is optionally substituted with one substituent independently selected from the group consisting of halogen, hydroxyl and C 1-3 alkoxyl.

In one embodiment, A is NR^Aan R^Ais H, methyl of ethyl.

In one embodiment, A is NR^Aan R^Ais H. In one embodiment, X is N. In one embodiment, A is NR^A, R^Ais H and X is N. In one embodiment Ri is::

H, halo, CN;

C 1-4 alkyl optionally substituted with one to three halo groups;

C 1-4 alkoxyl optionally substituted with one to three halo groups;

C2-6-alkenyl;

C2-6alkynyl; of

C3-6-cycloalkyl.

In one embodiment, R 1 is H, halogen, CN, C 1-4 alkoxyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-4 alkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl and C 1-3 alkoxyl.

In certain embodiments, R 1 is selected from the group consisting of H, halogen, CN, methyl, isopropyl, tert -butyl, methoxyl, trifluoromethyl, trifluoromethoxyl, ethenyl, prop-1-en-2-yl, ethynyl, and cyclopropyl.

In certain embodiments, R 1 is selected from the group consisting of H, halogen, CN, methyl, methoxy, trifluoromethyl, ethenyl, and ethynyl. In one embodiment, Ri is selected from the group consisting of Br, Cl, and CN.

In one embodiment, Ri is Cl.

In one embodiment, R2 is:

H, halo, CN;

C3-6 cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl and C1-3 alkoxyl.

In one embodiment, R2 is:

H, halo, CN;

C 1-4 alkyl optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl and C 1-3 alkoxyl; or

C3-6 cycloalkyl. In certain embodiments, R 2 is H, halogen, CN, C 1-4 haloalkyl optionally substituted with C 1-3 alkoxyl and C 3-6 cycloalkyl.

In one embodiment, R 2 is selected from the group consisting of H, halogen, CN, methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl, methoxymethyl, and methoxyethyl (e.g., 1-methoxyethyl).

In one embodiment, R 2 is selected from the group consisting of H, halogen, CN, methyl, difluoromethyl, trifluoromethyl, cyclopropyl, and methoxyethyl (e.g., 1-methoxyethyl).

In one embodiment, R 2 is selected from the group consisting of Cl, CN, and methyl.

In one embodiment, R3 is IS

1 ) H;

2) -CO-Z, where Z is selected from the group consisting of

four to seven membered heterocyclyl ring having one or two heteroatom ring members independently selected from O and N;

C3-6 cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, C1-3 alkyl and C1-3 alkoxyl; And

C 1-6 alkyl optionally substituted with one to three substituents independently selected from halo and C 1-3 alkoxyl;

halo;

C 1-3 alkyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl;

C 1-3 alkoxyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl; And

four to seven membered heterocyclyl ring having one or two heteroatom ring members independently selected from O and N, and the heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of halo, C1-3 alkyl and C1-3 alkoxyl;

C 1-6 alkyl optionally substituted with one to three substituents independently selected from the group consisting of

CN, hydroxyl, halogeen;

C 1-4 alkoxyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl;

-CO-Q, waarin Q Ci-4alkoxyl, hydroxyl, NH2 of NR is_CRd, where R_Cand R d are independently H or C 1-4 alkyl;

C3-7 cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of

halogeen, hydroxyl;

C 1-3 alkyl optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl and C 1-3 alkoxyl;

) C-linked 7-9-membered bridged cyclyl ring optionally having one or two heteroatom ring members independently selected from O and N, optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl, C 1-3 alkyl and C 1-3 alkoxyl ; 7) C-linked 7-10 membered spirane-cyclyl ring, optionally having one or two heteroatom ring members independently selected from O and N, optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl, C1-3- alkyl and C 1-3 alkoxyl; or

1 ) H;

2) -CO-Z, where Z is selected from the group consisting of

C3-6 cycloalkyl and four to six membered heterocyclyl ring with O as heteroatom ring member;

3) four to six membered heterocyclyl ring having one to two heteroatom ring members independently selected from O and N, and the heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of

halo;

C 1-3 alkyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl;

C 1-3 alkoxyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl; And

four to six membered heterocyclyl ring having one to two heteroatom ring members independently selected from O and N;

4) C 1-4 alkyl optionally substituted with one to three substituents independently selected from the group consisting of

CN, hydroxyl, halogeen;

Ci-2alkoxy;

-CO-Q, wherein Q is C 1-2 alkoxyl, hydroxyl or Nh; four to six membered heterocyclyl ring having one to two heteroatom ring members independently selected from O and N, wherein the heterocyclyl ring is optionally substituted with one to three halo substituents;

C3-6 cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of

halogeen, hydroxyl;

C 1-3 alkyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl;

C 1-4 alkoxyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl; And

four to six membered heterocyclyl ring having one to two heteroatom ring members independently selected from O and N, wherein the heterocyclyl ring is optionally substituted with one to three halo substituents;

6) C-linked 7-9 membered bridged cyclyl ring optionally having one or two heteroatom ring members independently selected from O and N; or

7) C-linked 7-10-membered spirane-cyclyl ring, optionally with one or two heteroatom ring members independently selected from O and N. One embodiment, F¾ is

1 ) H;

2) -CO-Z, wherein Z is selected from the group consisting of cyclopropyl, oxetanyl and tetrahydro-2/-/-pyranyl;

3) four to six membered heterocyclyl ring selected from the group consisting of oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl and morpholinyl, wherein the heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of hydroxyl , halo;

four to six membered heterocyclyl ring having one to two heteroatom ring members independently selected from O and N; ) C 1-4 alkyl optionally substituted with one to three substituents independently selected from the group consisting of

CN, hydroxyl, halogeen;

Ci-2alkoxy;

-CO-Q, waarin Q Ci-2alkoxyl, hydroxyl of Nh is;

four to six membered heterocyclyl ring selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, pyrrolidinyl, piperidinyl and morpholinyl, wherein the heterocyclyl ring is optionally substituted with one to three halogen substituents;

C4-6cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of

halogeen, hydroxyl;

C 1-3 alkyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl;

C 1-4 alkoxyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl; And

In one embodiment, R3 is H.

In one embodiment, R3 is -CO-Z, where Z is selected from the group consisting of C3-6 cycloalkyl and a four to six membered oxygen-containing heterocyclyl ring.

In one embodiment, R3 is a four to six membered heterocyclyl ring having one to two heteroatom ring members independently selected from O and N, and the heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of:

halo;

cyan;

C 1-3 alkyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl; And

four to six membered heterocyclyl ring having one to two heteroatom ring members independently selected from O and N.

In a particular embodiment, the four to six membered heterocyclyl ring having one to two heteroatom ring members independently selected from O and N is bonded to the pyrazole ring through a carbon atom.

In one embodiment, R3 is a four to six membered heterocyclyl ring with O as the heteroatom ring member.

In one embodiment, R3 is selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, wherein the heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of

hydroxyl, halogeen;

C 1-3 alkyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl;

C 1-3 alkoxyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl; And

four to six membered heterocyclyl ring having one to two heteroatom ring members independently selected from O and N. In one embodiment, R3 is a four to six membered oxygen-containing heterocyclyl ring, which heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of halo; cyano and C1-3 alkyl, which alkyl group is optionally substituted with one to three substituents independently selected from halo, hydroxyl and C1-3 alkoxyl. In a more specific embodiment, R3 is selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydro-2H-pyranyl, wherein the oxetanyl, tetrahydrofuranyl, or tetrahydro-2H-pyranyl ring is optionally substituted with one to three substituents independently selected from the group consisting out of halo; cyano and C1-3 alkyl, which alkyl group is optionally substituted with one to three substituents independently selected from halo, hydroxyl and C1-3 alkoxyl. Even more specifically, R3 is selected from the group consisting of oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-3-yl and tetrahydro-2H-pyran-4-yl, wherein the oxetan-3 - yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-3-yl or tetrahydro-2H-pyran-4-yl ring is optionally substituted with one to three substituents independently selected from the group consisting of halogen and C 1-3 alkyl. Even more specifically, R3 is selected from the group consisting of oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-3-yl and tetrahydro-2H-pyran-4-yl, wherein the oxetan-3 - yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-3-yl or tetrahydro-2H-pyran-4-yl ring is optionally substituted with one to three substituents independently selected from the group consisting of fluorine and methyl.

In one embodiment, R3 is a four to six membered heterocyclyl ring having one heteroatom ring member independently selected from O and N, wherein the heterocyclyl ring is optionally substituted with a four to six membered heterocyclyl ring having one heteroatom ring member independently selected from O and N.

In one embodiment, R3 is a four to six membered heterocyclyl ring with N as the heteroatom ring member.

In one embodiment, R3 is a four to six membered heterocyclyl ring selected from the group consisting of azetidinyl, pyrrolidinyl and piperidinyl, wherein the heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of:

hydroxyl, halogeen;

C1-3 alkyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C1-3 alkoxyl; C 1-3 alkoxyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl; And

four to six membered heterocyclyl ring having one to two heteroatom ring members independently selected from O and N.

In one embodiment, R3 is a four to six membered nitrogen-containing heterocyclyl ring attached to the pyrazole ring by a carbon atom, which nitrogen-containing heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of:

halo;

C 1-3 alkyl, wherein the alkyl group is optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl, and

four to six membered heterocyclyl ring having one to two heteroatom ring members independently selected from O and N.

In one embodiment, R3 is a four to six membered nitrogen-containing heterocyclyl ring, which heterocyclyl ring is:

substituted on the nitrogen ring atom by a substituent selected from the group consisting of a C 1-3 alkyl group, which alkyl group is optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl, and a four to six membered heterocyclyl group ring having one to two ring members with heteroatoms independently selected from O and N; And

optionally further substituted with one or two groups independently selected from halo and C 1-3 alkyl.

In one embodiment, R3 is a four to six membered nitrogen-containing heterocyclyl ring, which heterocyclyl ring is:

substituted on the nitrogen ring atom by a four to six membered heterocyclyl ring having one to two heteroatom ring members independently selected from O and N; And

optionally further substituted with one or two groups independently selected from halo and C 1-3 alkyl. In one embodiment, R3 is a four to six membered nitrogen-containing heterocyclyl ring, which heterocyclyl ring is:

substituted on the nitrogen ring atom with a four- to six-membered oxygen-containing heterocyclyl ring; And

optionally further substituted with one or two groups independently selected from halo and C 1-3 alkyl.

In one embodiment, R3 is an azetidinyl or piperidinyl ring, which is azetidinyl or piperidinyl ring:

substituted on the nitrogen ring atom with a tetrahydro-2H-pyranyl, tetrahydrofuranyl or oxetanyl ring; And

optionally further substituted with one or two groups independently selected from halo and C 1-3 alkyl.

In one embodiment, R3 is an azetidin-3-yl, piperidin-3-yl, or piperidin-4-yl ring, which ring is: substituted on the nitrogen ring atom with a tetrahydro-2H-pyran-4-yl, tetrahydro-2H -pyran-3-yl, tetrahydrofuran-3-yl or oxetan-3-yl ring; And

optionally further substituted with one or two groups independently selected from halo and C 1-3 alkyl.

In one embodiment, R3 is a four to six membered heterocyclyl ring selected from the group consisting of oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, pyrrolidinyl, piperidinyl, and morpholinyl, and the heterocyclyl is optionally substituted with one to three substituents independently. selected from halo, methyl, methoxyethyl and oxetanyl.

In one embodiment, R3 is a four- to six-membered heterocyclyl selected from the group consisting of oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2/-/-pyran-3-yl, tetrahydro-2/-/-pyran-4-yl, azetidin-3-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, and morpholin-4-yl, wherein the heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C1-3 alkyl, methoxyethyl and oxetanyl, or pharmaceutically acceptable salts thereof. In one embodiment, R3 is C1-6 alkyl optionally substituted with one to three substituents independently selected from the group consisting of

CN, hydroxyl, halogeen, Ci-4alkoxyl;

-CO-Q, waarin Q Ci-4alkoxyl, hydroxyl of NR is_CRd, where R_Cand R d are independently H or C 1-4 alkyl;

a 4-7 membered heterocyclyl ring selected from the group consisting of morpholinyl, pyrrolidinyl, tetrahydropyranyl or oxetanyl, which heterocyclyl ring is optionally substituted with one to three halogen substituents.

In one embodiment, R3 is C1-6 alkyl optionally substituted with one CN group. In one embodiment, R3 is 2-cyano-2-propyl.

In one embodiment, R3 is C4-6 cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of

halogeen, hydroxyl;

C 1-3 alkyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl;

C 1-4 alkoxyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl; And

In one embodiment, R3 is C4-6 cycloalkyl substituted with one hydroxyl group. In a particular embodiment, the hydroxyl group is located at a position distal ("para") from the point of attachment of the cycloalkyl group to the pyrazole ring. In a more specific embodiment, R3 is 4-hydroxycyclohexyl. In one embodiment, R3 is C4-6 cycloalkyl substituted with one four to six membered heterocyclyl ring having one to two heteroatom ring members independently selected from O and N, wherein the heterocyclyl ring is optionally substituted with one to three halo substituents. In one embodiment, the heterocyclyl group is bonded to the cycloalkyl group through a ring nitrogen.

In one embodiment, R3 is C4-6 cycloalkyl optionally substituted with one to three substituents

|-N D

independently selected from hydroxyl, morpholinyl or -/. In one embodiment, R3 is C4-6 cycloalkyl substituted with one substituent selected from hydroxyl, morpholinyl or . In certain embodiments where the substituent is morpholinyl, the bond to the cycloalkyl group is through the nitrogen atom.

In diment R3 is cyclohexyl substituted at position 4 by hydroxyl, morpholin-4-yl or

In one statement, R3 is cyclobutyl substituted at position 3 by hydroxyl, morpholine-

4-yl or body, R3 is a bridged or spirocyclic ring selected from the group consisting of

In one embodiment, R3 is IS

1 ) H;

2) four to six membered heterocyclyl ring selected from the group consisting of oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl and morpholinyl, and the heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of halo ;

oxetanyl; and C 1-3 alkyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl;

3) 2-cyano-2-propyl;

4) C4-6cycloalkyl optionally substituted with e substituents independently selected from hydroxyl, morpholinyl and

6) X>

In one embodiment, R3 is IS

1) H;

2) four to six membered oxygen-containing heterocyclyl ring, said heterocyclyl ring optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano and C1-3 alkyl, said alkyl group optionally substituted with one to three substituents independently selected from halogen, hydroxyl and C 1-3 alkoxyl;

3) four- to six-membered nitrogen-containing heterocyclyl ring, which heterocyclyl ring is:

3alkoxy, and a four to six membered heterocyclyl ring having one to two heteroatom ring members independently selected from O and N; and optionally further substituted with one or two groups independently selected from halo and C 1-3 alkyl.

4) C 1-6 alkyl optionally substituted with one CN group; or

5) C4-6 cycloalkyl optionally substituted with one to three substituents independently

|-N / D

selected from hydroxyl, morpholin-4-yl or -/.

In one embodiment, n is 3. In certain embodiments, R is₄and R5 at each occurrence are each independently selected from the group consisting of

H, halogeen, hydroxyl;

Ci_-4alkyl optionally substituted with one to three substituents independently selected from halogen and Ci_-4alkoxy;

C3-6-cycloalkyl; En

Ci_-4alkoxyl optionally substituted with one to three substituents independently selected from halogen and Ci_-4alkoxyl. In one version, R₄and R5 are each independently selected from the group consisting of H, halogen, C1-3 alkyl, methoxyl, ethoxyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxyl, methoxymethyl and cyclopropyl.

In one embodiment, this invention relates to compounds of formula (I) and any of the above applicable embodiments (CR₄R₅)_Nis CHR₄CHR₅CH₂, CR₄R₅CHR₅CH₂, of KHR₄CR₄R5CH2, where R₄and Rs are defined above.

In certain versions, R₄and R5, whenever they occur, are each independently selected from the group consisting of H, F, methyl, ethyl, methoxyl, fluoromethyl, difluoromethyl, trifluoromethyl and methoxymethyl.

In one embodiment, A-(CR₄Rs)n-0 is A-CHR₄CHR₅CH2-0 where either:

R₄is H en R5 is fluor, Ci_-4alkyl of Ci_-4alkoxyl wherein said alkyl or alkoxyl is optionally substituted with one, two or three fluoro groups; or

R₄is cyclopropyl, Ci_-4alkyl of Ci_-4alkoxyl wherein the alkyl or alkoxyl is optionally substituted by one, two or three fluoro or Ci_-4alkoxygroepen en R5 is H; of

R₄is Ci_-4alkyl of Ci_-4alkoxyl wherein the alkyl or alkoxy group is optionally substituted with one, two or three fluoro groups and R 5 is fluoro; or

R₄and R5 are both methyl.

In one embodiment, A-(CR₄Rs)n-0 is A-CHR₄CHR₅CH2-0 where either:

R₄is H en R5 is methyl, methoxyl, ethoxyl, difluormethoxyl of fluor; of

R₄is methyl, ethyl, isopropyl, fluormethyl, difluormethyl, trifluormethyl, methoxy, methoxymethyl of cyclopropyl en R5 is H; of R₄is methyl of fluormethyl en R5 is fluor; of

R₄and R5 are both methyl.

In one embodiment, A-(CR4Rs)n-O is A-CHR4CHR5CH2-O wherein either:

R4 is H en R5 is methoxyl of fluor; of

R4 is methyl, ethyl, fluormethyl, difluormethyl of methoxymethyl en R5 is H; of

R4 is methyl en R5 is fluor; of

R4 and R5 are both methyl.

In certain embodiments, A is NH, X is N, and n is 3.

In certain embodiments, the compound of formula (I) has the structure of formula (IA)

Formula (IA)

in which

R1, R2, R3, R4, R5 are as defined above with respect to Formula (I).

In one embodiment, the compound of formula (I) has the structure of formula (IA) wherein R 1 , R 2 and R 5 are as defined above with respect to formula (I) and wherein either:

R4 is H and R5 is fluorine or C1-4 alkoxyl wherein the alkyl or alkoxyl group is optionally substituted with one, two or three fluorine groups; or

R4 is cyclopropyl, C1-4 alkyl or C1-4 alkoxyl, wherein the alkyl or alkoxyl group is optionally substituted with two or three fluoro or C1-4 alkoxy groups and R5 is H; or

R4 is C1-4 alkyl or C1-4 alkoxy wherein the alkyl or alkoxy group is optionally substituted with one two or three fluoro groups and R5 is fluoro; or

R4 and R5 are both methyl. In one embodiment, the compound of formula (I) has the structure of formula (IA) wherein R 1 , R 2 and R 5 are as defined above with respect to formula (I) and wherein either:

R₄is H en R5 is methyl, methoxyl, ethoxyl, difluormethoxyl of fluor; of

R₄is methyl, ethyl, isopropyl, fluormethyl, difluormethyl, trifluormethyl, methoxy, methoxymethyl of cyclopropyl en R5 is H; of

R₄is methyl of fluormethyl en R5 is fluor; of

R4 is H en R5 is methoxyl of fluor; of

R4 is methyl, ethyl, fluormethyl, difluormethyl of methoxymethyl en R5 is H; of

R4 is methyl en R5 is fluor; of

R4 and R5 are both methyl.

In certain embodiments with respect to Formula (IA):

R 1 is selected from the group consisting of H, halogen, CN, methyl, isopropyl, tert -butyl, methoxy, trifluoromethyl, trifluoromethoxyl, ethenyl, prop-1-en-2-yl, ethynyl, and cyclopropyl; R2 is selected from the group consisting of H, halogen, CN, methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl, methoxymethyl and methoxyethyl; And

Rs is

1 ) H;

2) four- to six-membered oxygen-containing heterocyclyl ring, which heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of halogen; cyano and C1-3 alkyl, which alkyl group is optionally substituted with one to three substituents independently selected from halo, hydroxyl and C1-3 alkoxyl;

3) four- to six-membered nitrogen-containing heterocyclyl ring, which heterocyclyl ring is:

C 1-6 alkyl optionally substituted with one CN group; or

C4-6cycloalkyl optionally substituted with e substituents independently selected from hydroxyl, morpholine

In more specific embodiments relating to formula (IA):

Ri is selected from the group consisting of Br, Cl and CN;

R2 is selected from the group consisting of HCl, CN and methyl; And

Rs is

1 ) H;

four to six membered oxygen-containing heterocyclyl ring, which heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of halogen; cyano and C1-3 alkyl, which alkyl group is optionally substituted with one to three substituents independently selected from halo, hydroxyl and C1-3 alkoxyl;

four- to six-membered nitrogen-containing heterocyclyl ring, which heterocyclyl ring is:

C 1-6 alkyl optionally substituted with one CN group; or

C4-6cycloalkyl optionally substituted with e substituents independently selected from hydroxyl, morpholine

In an even more specific embodiment with respect to Formula (IA): R 1 is selected from the group consisting of Br, Cl and CN;

R2 is selected from the group consisting of HCl, CN and methyl; And

Rs is

1 ) H;

3) four- to six-membered nitrogen-containing heterocyclyl ring, said heterocyclyl ring being substituted on the nitrogen ring atom with one four- to six-membered oxygen-containing heterocyclyl ring, and optionally further substituted with one or two groups independently selected from halogen and C1-3 alkyl; or

4) C4-6cycloalkyl optionally substituted with one to three substituents independently selected from hydroxyl, morpholin-4-yl or

In one embodiment, the compound of formula (I) has the structure of formula (IA) wherein:

R₂is CI, CN of methyl;

Rs is

1) H

2) four to six membered heterocyclyl ring selected from the group consisting of oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl and morpholinyl, wherein the heterocyclyl ring is optionally substituted with one to three substituents independently selected from halo, methyl and oxetanyl ;

3) 2-cyano-2-propyl;

4) C4-6cycloalkyl optionally substituted with e substituents independently selected from hydroxyl, morpholinyl and

R₄H, methyl, ethyl, fluormethyl, difluormethyl, trifluormethyl of methoxymethyl is; En

R5 is H, F, methyl of methoxyl.

In one embodiment, this invention relates to compounds of formula (I) or formula (IA), and any of the above applicable embodiments, wherein R 1 is Br, Cl or CN, R 2 is Cl, CN or methyl, and R 3 IS

1) four to six membered heterocyclyl ring selected from the group consisting of oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl and morpholinyl, wherein the heterocyclyl ring is optionally substituted with one to three substituents independently selected from halo, methyl, methoxyethyl and oxetanyl;

2) 2-cyano-2-propyl;

3) C₄-6-cycloalkyl optionally substituted with e substituents independently selected from hydroxyl, morpholinyl and

5, >C^O;

R₄H, methyl, ethyl, fluormethyl, difluormethyl, trifluormethyl of methoxymethyl is; en R5 is H, F, methyl of methoxyl.

In one embodiment, the invention relates to a compound Formula (IA)

Formula (IA)

in which

Ri is selected from the group consisting of Br, Cl and CN; R2 is selected from the group consisting of HCl, CN and methyl;

Rs is

1 ) H;

4) C4-6cycloalkyl optionally substituted with e substituents independently selected from hydroxyl, morpholin-4-yl; and also

R₄is H en R5 is methoxyl of fluor; of

R4 is methyl, ethyl, fluormethyl, difluormethyl of methoxymethyl en R5 is H; of

R4 is methyl en R5 is fluor; of

R4 and R5 are both methyl;

or a pharmaceutically acceptable salt thereof.

In a particular embodiment, this invention relates to a compound selected from

or a pharmaceutically acceptable salt thereof.

In another embodiment, this invention relates to a compound selected from

In one embodiment, this invention relates to a compound selected from

or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt thereof. or a pharmaceutically acceptable salt thereof.

In one embodiment, this invention relates to

or a pharmaceutically acceptable salt thereof.

In one embodiment, this invention relates to

or a pharmaceutically acceptable salt thereof.

In one embodiment, this invention relates to

or a pharmaceutically acceptable salt thereof. In one embodiment, the invention relates to a crystalline form of (11R)-14-chloro-4,11-dimethyl-5-(oxan-4-yl)-8-oxa-2,5,6,12,16, 17-hexaazatricyclo [1 1 .3.1.0³'⁷]heptadeca-1(16),3,6,13(17),14- pentaene showing characteristic XRPD peaks at 8.7, 10.1, 10.5, 13.9, 15.9, 17.4 , 18.2, 18.7, 19.6, 25.3, and 27.0 (± 0.2°) when measured using a copper anode generating Ka radiation with a wavelength of 1.5406 Å. particular embodiment, the peaks are identified in a PANalytical X'Pert Pro powder diffractometer, model PW3040/60 using an X'Celerator detector with radiation: Cu Ka, generator voltage: 40 kV, generator current: 45 mA, angle of onset: 2.0° 2Θ, end angle: 40.0° 2Θ, step size: 0.0167° 2Θ, time per step: 31.75 seconds.

In a particular embodiment, the invention relates to compounds of formula (I) wherein F¾ is H. In a CE

or pharmaceutically acceptable salt thereof. In one embodiment, this invention relates to or a pharmaceutically acceptable salt thereof. In one embodiment, the invention provides a compound of formula (I) or a salt thereof which is the compound of any of Examples E1-E452, or a salt thereof.

It is to be understood that references herein to a compound of formula (I) or a salt thereof include a compound of formula (I) as a free base or acid, or as a salt thereof, for example as a pharmaceutically acceptable salt thereof. . Thus, in one embodiment, the invention is directed to a compound of formula (I). In another embodiment, the invention is directed to a salt of a compound of formula (I). In another embodiment, the invention is directed to a pharmaceutically acceptable salt of a compound of formula (I). In another embodiment, the invention is directed to a compound of formula (I) or a salt thereof. In another embodiment, the invention is directed to a compound of formula (I) or a

pharmaceutically acceptable salt thereof.

Because of its potential use in medicine, it will be appreciated that a salt of a compound of formula (I) is preferably pharmaceutically acceptable.

As used herein, the term "pharmaceutically acceptable" refers to those compounds

(including salts), materials, compositions and dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation or other problems or complications,

proportionate to a reasonable benefit/risk balance.

Pharmaceutically acceptable salts are within the scope of the present invention.

Pharmaceutically acceptable salts include those described in Berge et al, J. Pharm, Sci., 66, 1-19, 1977, those in PL Gould, International Journal of Pharmaceutics, 33 (1986), 201-217; Bighley et al, Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc., New York 1996, Volume 13, pages 453-497, or those in PH Stahl and CG Wermuth, eds., Handbook of Pharmaceutical Salts; Properties, selection and use, second edition Stahl/Wermuth: Wiley-VCHA HCA, 201 1 (see

http://www.wiley.com/WileyCDA/WileyTitle/productCd-3906390519.html).

Non-pharmaceutically acceptable salts are within the scope of the present invention, for example for use as intermediates in the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Non-pharmaceutically acceptable salts may be used, for example as intermediates in the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compounds of formula (I) contain a basic group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with an appropriate acid. Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzene sulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphor sulfonate (camsylate). ), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecyl sulfate (estolate), edetate (ethylenediamine tetraacetate), estolate (lauryl sulfate), ethane - 1,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate,

hexyl resorcinate, hippurate, hydrabamine (N,N'-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methane sulfonate (mesylate), methyl sulfate, mucate, naphthalene-1,5-disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicyclate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate , phenylethyl barbiturate, phosphate, polygalacturonate, propionate, p-toluene sulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, trithiodide, undecanoate , undecylenate and valerate. In certain embodiments, some of these salts may form solvates. In certain embodiments, some of these salts may be crystalline. Such acid addition salts may be formed by reacting a compound of formula (I) (containing, for example, a basic amine or other basic functional group) with the appropriate acid, optionally in a suitable solvent such as an organic solvent, to form the salt in various ways. can be isolated in several ways, including crystallization and filtration.

It will be appreciated that when a compound of formula (I) contains two or more basic moieties, the stoichiometry of salt formation may include 1, 2 or more equivalents of acid. Such salts would contain 1, 2 or more acidic counterions, for example a dihydrochloride salt.

Stoichiometric and non-stoichiometric forms of a pharmaceutically acceptable salt of a compound of formula (I) are within the scope of the invention, including substoichiometric salts, for example when a counterion contains more than one acidic proton.

Certain compounds of formula (I) contain an acidic group and are therefore capable of forming pharmaceutically acceptable base addition salts by treatment with an appropriate base. Suitable bases include pharmaceutically acceptable inorganic bases and pharmaceutically acceptable organic bases. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, aluminum, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS, tromethamine), arginine, benethamine (N-benzylphenethylamine), benzathine (N-benzylphenethylamine ), Ν'-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole),

cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, procaine, quinine , quinoline, sodium, strontium, t-butylamine and zinc. Such base addition salts may be formed by reacting a compound of formula (I) (e.g. containing an acidic functional group) with the appropriate base, optionally in a suitable solvent such as an organic solvent, to give the salt which may be formed in a variety of ways. isolated ways, including crystallization and filtration. Salts can be prepared in situ during the final isolation and purification of a compound of formula (I). If a basic compound of formula (I) is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known in the art, including treatment of the salt with an inorganic or organic base. Similarly, if a compound of formula (I) containing an acidic functional group is isolated as a salt, the corresponding free acid form of that compound may be prepared by any suitable method known in the art, including treatment of the salt with an inorganic or organic acid. Certain compounds of formula (I) or salts thereof may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms). The individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are within the scope of the present invention. The different isomeric forms can be separated or separated from each other by conventional methods, or any given isomer can be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

Certain compounds of formula (I) may exist in tautomeric forms. For example,

certain compounds exhibit amine-imine tautomerism (such as and may exist in one or more c-forms. In some cases only one of a few tautomeric forms (e.g., hin Formula (I) as drawn. The other alternative

tautomer (e.g. is also part of the invention.

The invention also includes isotopically labeled compounds and salts which are identical to compounds of formula (I) or salts thereof, but because one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic number. mass or mass number that is most common in nature. Examples of isotopes which may be included in compounds of formula (I) or salts thereof isotopes of hydrogen, carbon, nitrogen, fluorine, such as³H,¹¹C,¹⁴C in¹⁸F. Such isotope-labeled compound of formula (I) or salts thereof are useful in drug and/or substrate tissue distribution assays. For example,¹¹C in¹⁸F isotopes are useful in PET (positron emission tomography). PET is useful in brain imaging. Isotopically labeled compounds of formula (I) and salts thereof can generally be prepared by following the procedures described below, by substituting a readily available isotopically labeled reagent with a non-isotopically labeled reagent. In one embodiment, compounds of formula (I) or salts thereof are not isotopically labeled.

Certain compounds of formula (I) or salts thereof may exist in solid or liquid form. In the solid state, certain compounds of formula (I) or salts thereof may exist in crystalline or non-crystalline form, or as a mixture thereof. For compounds of formula (I) or salts thereof which are in crystalline form, those skilled in the art will appreciate that pharmaceutically acceptable solvates can be formed where solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates can contain non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine and ethyl acetate, or they can contain water as the solvent that is incorporated into the crystalline lattice. Solvates in which water is the solvent incorporated into the crystalline lattice are commonly referred to as "hydrates". Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water.

The skilled person will further understand that all compounds of formula (I) or

pharmaceutically acceptable salts thereof that exist in crystalline form, including its various solvates, may exhibit polymorphism (i.e., the ability to exist in different crystalline structures). These different crystalline forms are typically known as "polymorphs".

Polymorphs have the same chemical composition, but differ in packing, geometric arrangement, and other descriptive properties of the crystalline solid state. Polymorphs can therefore have different physical properties such as shape, density, hardness, deformability, stability and dissolving properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which can be used for identification. The skilled artisan will recognize that various polymorphs can be produced, for example, by changing or modifying the reaction conditions or reagents used in making the compound. For example, changes in temperature, pressure or solvent can lead to polymorphs. In addition, one polymorph can spontaneously change into another polymorph under certain conditions.

It is also understood by those skilled in the art that this invention may contain various deuterated forms of compounds of formula (I) or pharmaceutically acceptable salts thereof. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom. One skilled in the art will know how to synthesize deuterated forms of compounds of formula (I) or pharmaceutically acceptable salts thereof. Commercially available deuterated starting materials can be used in the preparation of deuterated forms of compounds of formula (I) or pharmaceutically acceptable salts thereof, or they can be synthesized by conventional techniques using deuterated reagents (e.g., lithium aluminum deuteride).

C. Methods of Use

Compounds of formula (I) or pharmaceutically acceptable salts thereof are inhibitors of LRRK2 kinase activity and thus are believed to be of potential use in the treatment or prevention of the following neurological diseases associated with or characterized by LRRK2 kinase: activity: Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dementia (including Lewy body dementia and vascular dementia, HIV-induced dementia), age-related memory impairment, mild cognitive impairment, argyrophilic cereal disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), drug withdrawal/relapse associated with drug dependence, L-Dopa-induced dyskinesia, ischemic stroke, traumatic brain injury, spinal cord injury, and multiple sclerosis. Other diseases potentially treatable by inhibition of LRRK2 include, but are not limited to, lysosomal disorders (for example, Niemann-Pick type C disease, Gaucher disease), Crohn's disease, inflammatory bowel disease (IBD), cancers (including thyroid, renal, including renal papilla), breast, lung and prostate cancer, leukemias (including acute myeloid leukemia (AML)) and lymphomas), rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, erythrocytic aplasia, idiopathic

thrombocytopenic purpura (ITP), Evans syndrome, vasculitis, bullous skin disorders, type 1 diabetes mellitus, obesity, epilepsy, lung diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, Sjögren's syndrome, Devic's disease, inflammatory myopathies, ankylosing spondylitis, bacterial infections ( including leprosy), viral infections (including tuberculosis, HIV, West Nile virus and chikungunya virus) and parasitic infections. One aspect of the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy. In one embodiment, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of the above conditions (i.e., the neurological diseases and other diseases mentioned above). In one embodiment, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of Parkinson's disease. In one embodiment, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Parkinson's disease. In another embodiment, the invention provides a compound of formula (I) or a

pharmaceutically acceptable salt thereof for use in the treatment or prevention of

Alzheimer's disease. In one embodiment, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Alzheimer's disease. In another embodiment, the invention provides a compound of formula (I) or a

pharmaceutically acceptable salt thereof for use in the treatment of tuberculosis. Another aspect of the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of the above conditions (i.e., the neurological diseases and other diseases listed above). are listed). ). Another aspect of the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a

medicine for the treatment or prevention of Parkinson's disease. Another aspect of the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of Parkinson's disease. In another embodiment, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment, treatment or prevention of Alzheimer's disease. In one embodiment, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of Alzheimer's disease. In another embodiment, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of tuberculosis. A further aspect of the invention provides a method of treating or preventing a disorder enumerated above (i.e., selected from the neurological diseases and other diseases enumerated above), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. A further aspect of the invention provides a method of treating or preventing Parkinson's disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt of them. A further aspect of the invention provides a method of treating Parkinson's disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the subject is a human.

In the context of the present invention, treatment of Parkinson's disease refers to the treatment of sporadic Parkinson's disease and/or familial Parkinson's disease. In one embodiment, the treatment of Parkinson's disease refers to the treatment of familial Parkinson's disease.

In one embodiment, familial patients with Parkinson's disease are those who express at least one of the following LRRK2 kinase mutations: G2019S mutation, N1437H mutation, R1441 G mutation, R1441 C mutation, R1441 H mutation, Y1699C mutation, S1761 R mutation or I2020T mutation. In another embodiment, familial patients with Parkinson's disease express other coding mutations (such as G2385R) or non-coding single nucleotide polymorphisms at the LRRK2 locus associated with Parkinson's disease. In a more specific embodiment, familial Parkinson's disease includes patients expressing at least the G2019S mutation or the R1441 G mutation in LRRK2 kinase. In one embodiment, the treatment of Parkinson's disease refers to the treatment of familial Parkinson's disease, which includes patients expressing LRRK2 kinase who carry at least the G2019S mutation. In another embodiment, familial patients with Parkinson's disease express abnormally high levels of wild-type LRRK2 kinase.

In another embodiment, familial patients with Parkinson's disease are those who express one or more of the following LRRK2 kinase mutations: G2019S mutation, N1437H mutation, R1441 G mutation, R1441 C mutation, R1441 H mutation, Y1699C mutation, S1761 R mutation or I2020T mutation. In another embodiment, familial patients with Parkinson's disease express other coding mutations (such as G2385R) or non-coding single nucleotide polymorphisms at the LRRK2 locus associated with Parkinson's disease. In a more particular embodiment, familial Parkinson's disease includes patients who have the

G2019S mutation or the R1441 G mutation in LRRK2 kinase. In one embodiment, treatment of Parkinson's disease refers to the treatment of familial Parkinson's disease, including patients expressing LRRK2 kinase carrying G2019S mutation. In another embodiment, familial patients with Parkinson's disease express abnormally high levels of normal LRRK2 kinase. Parkinson's disease treatment can be symptomatic or disease-modifying. In one embodiment, treatment of Parkinson's disease refers to symptomatic treatment. In one embodiment, treatment of Parkinson's disease refers to disease-modifying treatment. In one embodiment, treatment of Parkinson's disease refers to both symptomatic treatment and disease-modifying treatment.

Compounds of the present invention may also be useful in treating patients who have been identified as susceptible to progression to severe parkinsonism through one or more subtle features associated with disease progression, such as family history, olfactory disturbances, constipation, cognitive deficits, gait or biological indicators. of disease progression obtained by molecular, biochemical, immunological or imaging technologies. In this context, treatment can be symptomatic or disease-modifying. In another embodiment, the treatment may be symptomatic and disease modifying.

A further aspect of the invention provides a method of treating or preventing Alzheimer's disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt of them. Another aspect of the invention provides a method of treating Alzheimer's disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. A further aspect of the invention provides a method of treating tuberculosis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the subject is a human.

In the context of the present invention, treatment of Alzheimer's disease refers to the treatment of sporadic Alzheimer's disease and/or familial Alzheimer's disease. Treatment of Alzheimer's disease can be symptomatic and/or disease modifying. In one embodiment, the treatment of Alzheimer's disease may be symptomatic or disease modifying. In one embodiment, treatment of Alzheimer's disease refers to symptomatic treatment. A further aspect of the invention provides a method of treating or preventing amyotrophic lateral sclerosis (ALS) disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutical acceptable salt thereof. Another aspect of the invention provides a method of treating amyotrophic lateral sclerosis (ALS) disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt of them. In one embodiment, the subject is a human.

In the context of the present invention, treatment of amyotrophic lateral sclerosis (ALS), dementia (including Lewy body dementia and vascular dementia, HIV-induced dementia), age-related memory dysfunction, mild cognitive impairment, argyrophilic cereal disease, Pick's disease, corticobasal degeneration , progressive supranuclear palsy, hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), multiple sclerosis, lysosomal disorders (e.g., Niemann-Pick type C disease, Gaucher disease), Crohn's disease, inflammatory bowel disease ( IBD) cancers (including thyroid, renal (including renal papillary), breast, lung and prostate cancers, leukemias (including acute myeloid leukemia (AML)) and lymphomas), rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anaemia, erythrocytic aplasia, idiopathic

When a compound of formula (I) or a pharmaceutically acceptable salt thereof is intended for use in the treatment of Parkinson's disease, it may be used in combination with drugs purported to be useful as symptomatic treatments of Parkinson's disease .

Suitable examples of such other therapeutic agents include L-dopa and dopamine agonists (e.g. pramipexole, ropinirole). Accordingly, in one embodiment, the invention provides a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof with an active pharmaceutical ingredient selected from the list consisting of L-dopa and a dopamine agonist (e.g. pramipexole, ropinirole) .

When a compound of formula (I) or a pharmaceutically acceptable salt thereof is intended for use in the treatment of Alzheimer's disease, it may be used in combination with drugs purported to be useful as disease-modifying or symptomatic treatments of the disease from Alzheimer's. Suitable examples of such other therapeutic agents may be symptomatic agents, for example agents known to modify cholinergic transmission, such as M1 muscarinic receptor agonists or allosteric modulators, M2 muscarinic antagonists, acetylcholinesterase inhibitors (such as tetrahydroaminoacridine, donepezil hydrochloride, rivastigmine and galantamine), nicotinic acid. receptor agonists or allosteric modulators (such as α7 agonists or allosteric modulators or α4β2 agonists or allosteric modulators), PPAR agonists (such as PPARγ agonists), partial 5-HT4 receptor agonists, 5-ΗΪ6 receptor antagonists e.g. SB-742457 or 5HT1A receptor antagonists and NMDA receptor antagonists or modulators, or disease modifying agents such as β- or γ-secretase inhibitors, e.g. semagacestat, mitochondrial stabilizers, microtubule stabilizers or modulators of Tau pathology, such as Tau aggregation inhibitors (e.g. REMBER™), NSAIDs, e.g. tarenflurbil, tramiprosil; or antibodies, for example, bapineuzumab or solanezumab; proteoglycans, e.g. tramiprosate. Accordingly, in one embodiment, the invention provides a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof with an active pharmaceutical ingredient selected from the list consisting of: an M1 muscarinic receptor agonist, an M2 muscarinic antagonist, an acetylcholinesterase inhibitor (e.g. tetrahydroaminoacridine, donepezil hydrochloride, rivastigmine and galantamine), a nicotinic receptor agonist (e.g. an α7 agonist or an α4β2 agonist), a PPAR agonist (e.g. a PPARγ agonist), a 5-HT4 partial receptor agonist, a δ-ΗΤε receptor antagonist (e.g., SB-742457), a 5HT1A receptor antagonist, an NMDA receptor antagonist, a β- or γ-secretase inhibitor (e.g., semagacestat), a mitochondrial stabilizer, a microtubule stabilizer, or a Tau aggregation inhibitor (eg, methylene blue and REMBER™), an NSAID (eg, tarenflurbil, tramiprosil), an antibody (eg, bapineuzumab or solanezumab), and a proteoglycan (eg, tramiprosate).

When a compound of formula (I) or a pharmaceutically acceptable salt thereof is intended for use in the treatment of bacterial infections, parasitic infections or viral infections, it may be used in combination with medications purported to be useful as symptomatic treatments that aim directly at the infectious agent.

When a compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with other therapeutic agents, the compound may be administered sequentially or simultaneously by any suitable route.

The invention also provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with one or more further therapeutic agents.

The combinations referred to above may be conveniently presented for use in the form of a pharmaceutical formulation and pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient thus comprise a further aspect of the invention. The individual components of such combinations may be administered sequentially or simultaneously in separate or combined pharmaceutical formulations.

When a compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with a second therapeutic agent active against the same disease state, the dose of each compound may differ from that when the compound is used alone. Suitable dosages will be readily understood by those skilled in the art.

D. Composition

Compounds of formula (I) or pharmaceutically acceptable salts thereof may be formulated into pharmaceutical compositions prior to administration to a patient. In one aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In another aspect, the invention provides a process for the preparation of a pharmaceutical composition comprising mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient.

Pharmaceutical compositions may be presented in unit dose forms containing a

predetermined amount of active ingredient per unit dose. For example, such a unit may contain 0.1 mg, 0.5 mg or 1 mg to 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg, 750 mg or 1 g of a compound of the present invention, depending on the disease being treated, the route of administration and the age, weight and condition of the patient, or

pharmaceutical compositions may be presented in unit dose forms containing a

predetermined amount of active ingredient per unit dose. In other embodiments, the unit dose compositions contain a daily dose or sub-dose as described herein, or an appropriate fraction thereof, of an active ingredient. In addition, such pharmaceutical compositions can be prepared by any of the methods well known to those skilled in the art.

A therapeutically effective amount of a compound of formula (I) will depend on a number of factors including, for example, the age and weight of the intended recipient, the precise condition requiring treatment and its severity, the nature of the formulation and the route of administration, and will ultimately be at the discretion of the supervisor who prescribes the medication. However, a therapeutically effective amount of a compound of formula (I) for the treatment of diseases described in the present invention will generally be in the range of 0.1 to 100 mg/kg body weight of the recipient per day and more usually in the range of 1 to 10 mg/kg body weight per day. Thus, for a 70 kg adult mammal, the actual amount per day would usually be 70 to 700 mg and this amount can be given in a single dose per day or in a number of sub-doses per day, e.g. two, three. , four, five or six doses per day. Or the dosing can be done intermittently, such as once every two days, once a week or once a month. A therapeutically effective amount of a pharmaceutically acceptable salt or solvate, etc. may be defined as a portion of the therapeutically effective amount of the compound of formula (I) per se. It is contemplated that similar dosages would be suitable for the treatment of the other diseases referred to above.

The pharmaceutical compositions of the invention may contain one or more compounds of formula (I). In some embodiments, the pharmaceutical compositions may contain more than one compound of the invention. For example, in some embodiments, the

pharmaceutical compositions may contain two or more compounds of formula (I). In addition, the pharmaceutical compositions may optionally further contain one or more additional pharmaceutically active compounds.

In certain embodiments, the pharmaceutical compositions may contain a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, and a

pharmaceutically acceptable excipient.

In certain embodiments, the present invention is directed to a pharmaceutical composition containing 0.01 to 1000 mg of one or more of a compound of formula (I) or a

pharmaceutically acceptable salt thereof and 0.01 to 5 g of one or more pharmaceutically acceptable excipients.

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle involved in imparting shape or consistency to the pharmaceutical composition. Each excipient may be compatible with the other ingredients of the pharmaceutical composition when mixed in such a way as to avoid interactions that would substantially reduce the efficacy of the compound of the invention when administered to a subject and interactions that would result in pharmaceutical compositions that are not pharmaceutically acceptable. avoided. .

The compounds of the invention and the pharmaceutically acceptable excipient or excipients may be formulated in a dosage form adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1) oral administration (including buccal or sublingual) such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration (including subcutaneous, intramuscular, intravenous or intradermal) such as sterile solutions, suspensions and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) nasal inhalation such as dry powders, aerosols, suspensions and solutions; and (6) topical administration (including buccal, sublingual or transdermal) such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels. Such compositions may be prepared by any method known in pharmacy, for example by bringing into association a compound of formula (I) with the carrier(s) or excipient(s).

Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. Suitable pharmaceutically acceptable excipients may vary depending upon the particular dosage form selected. In addition, appropriate pharmaceutically acceptable excipients may be selected for a particular function they may serve in the composition. For example, certain pharmaceutically acceptable excipients may be selected for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be selected for their ability to facilitate the production of stable dosage forms. Certainly

pharmaceutically acceptable excipients may be selected for their ability to facilitate the carrying or transport of the compound or compounds of the invention once administered to the patient from one organ, or part of the body, to another organ, or part of the body. Certain pharmaceutically acceptable excipients may be selected for their ability to improve patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste-masking agents, coloring agents, anti-caking agents, hemectants , chelating agents, plasticizers, viscosifiers, antioxidants, preservatives, stabilizers, surfactants and buffering agents. The skilled artisan will appreciate that certain pharmaceutically acceptable excipients may have more than one function and serve alternate functions, depending on how much the excipient is present in the formulation and what other ingredients are present in the formulation.

Skilled artisans have the knowledge and skill in the art to enable them to select appropriate pharmaceutically acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources available to those skilled in the art that describe pharmaceutically acceptable excipients and may be helpful in selecting appropriate pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the US

Pharmaceutical Association and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared by techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company). In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a therapeutically effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch and pregelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate and dibasic calcium phosphate. The oral solid dosage form may further contain a binder. Suitable binders include starch (e.g. corn starch, potato starch and pregelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone and cellulose and its derivatives (e.g.

microcrystalline cellulose). The oral solid dosage form may further contain a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid and sodium carboxymethylcellulose. The oral solid dosage form may further contain a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate and talc. In another embodiment, the present invention is directed to a pharmaceutical composition for the treatment of neurodegeneration disease comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In another embodiment, the present invention is directed to a pharmaceutical composition for the treatment of Parkinson's disease, Alzheimer's disease or amyotrophic lateral sclerosis (ALS) comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient .

E. Process for Preparation of Compounds The process to be used in the preparation of compounds of Formula (I) described herein depends on the desired compounds. Factors such as the choice of the specific substituent and various possible locations of the specific substituent all play a role in the route to follow in the preparation of the specific compounds of this invention. Those factors are easily recognized by one skilled in the art.

In general, the compounds of the present invention may be prepared by standard techniques known in the art and by known methods analogous thereto. General methods for preparing compounds of formula (I) are set forth below. All starting materials and reagents described in the general experimental schemes below are commercially available or can be prepared by methods known to those skilled in the art. Those skilled in the art will appreciate that if a substituent described herein is incompatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable under the reaction conditions. The protecting group can be removed at an appropriate point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods of protecting and deprotecting various substituents using such suitable protecting groups are well known to those skilled in the art; examples of this can be found in T. Greene and P. Wuts,

Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999). In some cases, a substituent may be specifically chosen to be reactive under the reaction conditions employed. Under these conditions, the reaction conditions convert the selected substituent to another substituent that is either useful as an intermediate or is a desired substituent in a target compound.

General Schemes 1 and 2 provide exemplary synthetic methods for preparing compounds of the present invention.

General schedule 1

General Scheme 1 provides an example of a synthetic process for preparing compound 11, representing compounds of formula (I). In Scheme 1, R¹, R², R³, R⁴, R⁵, A, X and n are defined in formula I. Hall, Hal2 and Hal3 are halo groups such as CI, Br, I. LG1 and LG2 are leaving groups such as OM's (methane sulfonate) or OT's (4-methylbenzene sulfonate).

Step (i) can be a substitution reaction by reacting compound 1 with compound 2 under basic conditions (e.g. in the presence of a suitable base such as trimethylamine) in a suitable solvent (such as tetrahydrofuran or Tween 20/water solution) at a suitable temperature such as 0°C to 100°C to provide intermediate 3 .

Intermediate 4 can be obtained in step (ii) by reacting intermediate 3 with a suitable reagent such as MsCl (methanesulfonyl chloride) in the presence of a suitable base such as

triethylamine in a suitable solvent such as dichloromethane under a suitable temperature such as -20°C to 40°C.

Step (iii) can be a substitution reaction by reacting compound 5 with compound 6 using a suitable base such as K2CO3 in a suitable solvent such as N,/V-dimethylformamide at a suitable temperature such as 0°C to 100°C to provide intermediary 7.

Intermediate 8 can be obtained in step (iv) by a hydrolysis reaction of intermediate 7 in the presence of a suitable base such as KOH in a suitable solvent such as water at a suitable temperature such as 20°C to 100°C.

Intermediate 9 can be obtained in step (v) by reacting intermediate 4 with intermediate 8 using a suitable base such as K2CO3 in a suitable solvent such as DMF(/V, N-dimethylformamide) at a suitable temperature such as 20°C to 100°C. ° C.

Step (vi) can be a reduction reaction of intermediate 9 in the presence of a suitable metal such as Fe and a suitable reagent such as NH4Cl in a suitable solvent such as EtOH under a suitable temperature such as room temperature to 100°C to reach between 10.

Step (vii) can be an intro-molecular coupling reaction of intermediate 10 using a suitable catalyst such as Pd2(dba)3 in the presence of a suitable base such as K3PO4 and a suitable ligand such as 2-dicyclohexylphosphino-2',4',6 '-triisopropylbiphenyl in a suitable solvent such as dioxane under a suitable temperature such as 90°C to 120°C to provide compound 11 .

Compound 11 can also be obtained directly in step (viii) by reductive cyclization of intermediate 9 in the presence of a suitable metal such as Fe and a suitable reagent such as NH4Cl in a suitable solvent (such as EtOH or EtOH/water) under a suitable temperature such as room temperature up to 100 °C

General schedule 2

General Scheme 2 provides an example of a synthetic process for preparing compound 11, representing compounds of formula (I). In Schedule 2, R¹, R², R³, R⁴, R⁵, R^A, X and n are defined in formula I. Hall , Hal2 and Hal3 are halo groups such as Cl, Br, I, PG1 and PG2 are suitable protecting groups such as THP (tetrahydro-2/-/-pyran), Boc(tert - butyloxycarbonyl) or SEM((trimethylsilyl)ethoxy)methyl).

Step (ix) is a protection reaction wherein compound 4 is reacted with a suitable reagent such as DHP in the presence of a suitable acid such as TsOH in a suitable solvent such as dichloromethane at a suitable temperature such as 20°C to 60°C. °C to provide intermediate 12.

Intermediate 14 can be obtained in step (x) by reacting intermediate 12 with compound 13 in the presence of a suitable base such as NaH in a suitable solvent such as DMF(/V, N-dimethylformamide) at a suitable temperature such as 20 °C to 100°C. Step (x) can also be an Ulmann reaction by reacting intermediate 12 with compound 13 in the presence of a suitable catalyst such as Cul, a suitable base such as K2CO3 and a suitable ligand in a suitable solvent such as toluene under a suitable temperature such as from 90°C to 120°C to provide intermediate 14.

Step (xi) is a deprotection reaction, where intermediate 14 is treated with a suitable acid such as HCl in a suitable solvent such as 1,4-dioxane at a suitable temperature such as 25°C to 40°C to give intermediate 15 Step (xii) can be a substitution reaction by reacting compound 1 with intermediate 15 using a suitable base such as DIPEA in a suitable solvent such as /^'-PrOH at a suitable

temperature such as 20 °C to 100 °C to intermediate 16.

Intermediate 9 can be obtained in step (xiii) by reacting intermediate 16 with compound 6 using a suitable base such as CS2CO3 in a suitable solvent such as DMF at a suitable temperature such as 20°C to 100°C, followed by reductive cyclization to provide connection 11 in step (viii).

Step (xiv) can be a reductive cyclization reaction of intermediate 16 in the presence of a suitable metal such as Fe and a suitable reagent such as NH4CI in a suitable solvent such as EtOH under a suitable temperature such as 20 °C to 100 °C to give compound 17 (which compound 1 is 1 when R3=H).

Compound 11 can also be obtained in step (xv) by reacting intermediate 17 with a suitable acylation reagent such as cyclopropane carbonyl chloride in the presence of a suitable base such as ΕίβΝ in a suitable solvent such as dichloromethane under a suitable temperature such as 0°C to 40°C.

The starting material and reagents described in the above schemes are either commercially available or can be readily prepared from commercially available compounds using procedures known to those of ordinary skill in the art. In one embodiment, the invention may be described by the following numbered paragraphs: Section 1. A compound of formula (I)

Formula (I)

or a pharmaceutically acceptable salt thereof, wherein

X is CH of N;

n is 2, 3, 4 of 5;

A is O of NR^A, in which

R^Ais

H; C 1-4 alkyl optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl and C 1-3 alkoxyl, wherein C 1-3 alkoxyl is optionally substituted with one to three halo substituents;

C3-6 cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl and C1-3 alkoxyl; or

four to seven membered heterocyclyl ring having one or two heteroatom ring members independently selected from O and N, and the heterocyclyl ring is optionally substituted with one to three substituents independently selected from halo and C1-3 alkyl, wherein Chalky is optionally substituted with one to three halo substituents; ) H, halo, CN;

) C 1-4 alkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl and C 1-3 alkoxyl, said C 1-3 alkoxyl optionally substituted with one to three halogen substituents;

) C 2-6 alkenyl optionally substituted with one to three halo or C 1-3 alkyl, said C 1-3 alkyl optionally substituted with one to three halo substituents;

C 2-6 alkynyl optionally substituted with one to three C 1-3 alkyl substituents, wherein C 1-3 alkyl is optionally substituted with one to three halo substituents;

) C 1-4 alkoxyl optionally substituted with one to three halo substituents;

) C3-6 cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, C1-3 alkoxyl and C1-3 alkyl, where C1-3 alkoxyl and C1-3 alkyl are optional substituted with one to three halogen substituents;

) OC 3-6 cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, C 1-3 alkoxyl and C 1-3 alkyl;

) four- to seven-membered heterocyclyl ring having one or two heteroatom ring members independently selected from O and N, and the heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl, C 1-3 alkoxyl, and C 1-3 alkyl ; 9) O-heterocyclyl ring having one or two heteroatom ring members independently selected from O and N, wherein the heterocyclyl ring is a four to seven membered ring optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl, Ci-3 -alkoxy and C1-3-alkyl; or

10) SC 1-4 alkyl optionally substituted with one to three halo substituents;

R₂is

H, halo, CN;

C 1-4 alkoxyl optionally substituted with one to three halo substituents;

C3-6cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl and C1-3alkoxyl;

Rs is

1 ) H;

2) -CO-Z, where Z is selected from the group consisting of

four to seven membered heterocyclyl ring having one or two heteroatom ring members independently selected from O and N;

C3-6cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, C1-3alkl and C1-3alkoxyl; And

C 1-6 alkyl optionally substituted with one to three substituents independently selected from halo and C 1-3 alkoxyl;

halo;

C 1-3 alkyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl;

C 1-3 alkoxyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl; and a four to seven membered heterocyclyl ring having one or two heteroatom ring members independently selected from O and N, and the heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of halo, C1-3alkyl and C1-3alkoxyl;

C 1-6 alkyl optionally substituted with one to three substituents independently selected from the group consisting of

CN, hydroxyl, halogeen;

C 1-4 alkoxyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl;

-CO-Q, waarin Q Ci-4alkoxyl, hydroxyl, NH2 of NR is_CRd, where R_Cand R d are independently H or C 1-4 alkyl;

C3-7 cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of

halogeen, hydroxyl;

C 1-3 alkyl optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl and C 1-3 alkoxyl;

C-linked 7-9 membered bridged cyclyl ring optionally having one or two heteroatom ring members independently selected from O and N, optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, Chalky and C 1-3 alkoxyl; 7) C-linked 7-10 membered spirane-cyclyl ring, optionally having one or two heteroatom ring members independently selected from O and N, optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl, Chalky and Ci- 3alkoxyl; or

R₄and Rs, at each occurrence, each independently selected from the group consisting of

H, halogeen, hydroxyl;

C3-6cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl and Ci_-4alkoxy;

Ci_-4alkoxyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl and C 1-4 alkoxy. Section 2. The compound or a pharmaceutically acceptable salt thereof of Section 1, wherein

X is CH of N;

n is 2, 3, 4 of 5;

A is O of NR^A, Warin R^Ais H of Ci_-4alkyl optionally substituted with C 1-3 alkoxyl;

Ri is H, halo, CN, Ci_-4alkoxyl, C2-6-alkenyl, C2-6-alkynyl of Ci_-4alkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxyl and C1-3 alkoxyl;

R2 is H, halo, CN, Ci_-4halogeenalkyl, Ci_-4alkyl optionally substituted with C 1-3 alkoxyl and C 3-6 cycloalkyl;

R₃is) H;

) -CO-Z, where Z is selected from the group consisting of

C3-6 cycloalkyl and four to six membered heterocyclyl ring with O as heteroatom ring member;

) four to six membered heterocyclyl ring having one to two heteroatom ring members independently selected from O and N, and the heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of

halo;

C 1-3 alkyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl;

C 1-3 alkoxyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl; And

four to six membered heterocyclyl ring having one to two heteroatom ring members independently selected from O and N;

) C 1-4 alkyl optionally substituted with one to three substituents independently selected from the group consisting of

CN, hydroxyl, halogeen;

Ci-2alkoxy;

-CO-Q, waarin Q Ci-2alkoxyl, hydroxyl of Nh is;

C3-6 cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of

halogen, hydroxyl; C 1-3 alkyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl;

C 1-4 alkoxyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl; And

6) C-linked 7-9 membered bridged cyclyl ring optionally having one or two heteroatom ring members independently selected from O and N; or

7) C-linked 7-10 membered spiranecyclyl ring optionally having one or two heteroatom ring members independently selected from O and N;

R₄and Rs, at each occurrence, each independently selected from the group consisting of

H, halogeen, hydroxyl;

Ci_-4alkyl optionally substituted with one to three substituents independently selected from halogen and Ci_-4alkoxy;

C3-6-cycloalkyl; En

Ci_-4alkoxyl optionally substituted with one to three substituents independently selected from halogen and Ci_-4alkoxy.

Section 3. The compound or a pharmaceutically acceptable salt thereof according to any one of sections 1 to 2, wherein R 1 is selected from the group consisting of H, halogen, CN, methyl, methoxy, trifluoromethyl, ethenyl and ethynyl. Section 4. The compound or a pharmaceutically acceptable salt thereof according to any one of sections 1 to 3, wherein R 2 is selected from the group consisting of H, halogen, CN, methyl, difluoromethyl, trifluoromethyl, cyclopropyl and methoxyethyl.

Section 5. The compound or a pharmaceutically acceptable salt thereof according to any of sections 1 to 4, wherein R3 is

1 ) H;

2) -CO-Z, wherein Z is selected from the group consisting of cyclopropyl, oxetanyl and tetrahydro-2/-/-pyranyl; ) four to six membered heterocydyl ring selected from the group consisting of oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl and morpholinyl, wherein the heterocydyl ring is optionally substituted with one to three substituents independently selected from the group consisting of hydroxyl , halo;

C 1-3 alkyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl;

C 1-3 alkoxyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl; And

four to six membered heterocydyl ring having one to two heteroatom ring members independently selected from O and N;

) C 1-4 alkyl optionally substituted with one to three substituents independently selected from the group consisting of

CN, hydroxyl, halogeen;

Ci-2alkoxy;

-CO-Q, waarin Q Ci-2alkoxyl, hydroxyl of Nh is;

four to six membered heterocydyl ring selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, pyrrolidinyl, piperidinyl and morpholinyl, wherein the heterocydyl ring is optionally substituted with one to three halogen substituents;

C4-6cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of

halogeen, hydroxyl;

Ci-3halogeenalkyl;

C 1-3 alkyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl;

C 1-4 alkoxyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl; and a four to six membered heterocyclyl ring having one to two heteroatom ring members independently selected from O and N, wherein the heterocyclyl ring is optionally substituted with one to three halo substituents;

C°.

Section 6. The compound or a pharmaceutically acceptable salt thereof according to any of Sections 1 to 5, where F¾ is

1 ) H;

four to six membered heterocyclyl ring selected from the group consisting of oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl and morpholinyl, and the heterocyclyl ring is optionally substituted with one to three substituents independently selected from the group consisting of halo;

oxetanyl; One

C 1-3 alkyl optionally substituted with one to three substituents independently selected from halo, hydroxyl and C 1-3 alkoxyl;

2-cyano-2-propyl;

C4-6cycloalkyl optionally substituted with e substituents independently selected from hydroxyl, morpholinyl and

6) X>

Section 7. The compound or a pharmaceutically acceptable salt thereof according to any of sections 1 to 6, wherein R₄and Rs, whenever they occur, are each independently selected from the group consisting of H, halogen, C1-3 alkyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, methoxymethyl and cyclopropyl. Section 8. The compound or a pharmaceutically acceptable salt thereof according to any of sections 1 to 7, wherein R₄and Rs are each independently selected from the group consisting of H, F, methyl, ethyl, methoxy, fluoromethyl,

difluormethyl, trifluormethyl en methoxymethyl.

Section 9. The compound or a pharmaceutically acceptable salt thereof according to any one of sections 1 to 8, wherein A is NH, X is N and n is 3.

Section 10. The compound of any of Sections 1 to 9, having the structure of Formula (IA)

Formula (IA)

or a pharmaceutically acceptable salt thereof, wherein

R₂is CI, CN of methyl;

Rs is

1) H

2) four to six membered heterocyclyl ring selected from the group consisting of oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl and morpholinyl, wherein the heterocyclyl ring is optionally substituted with one to three substituents independently selected from halo, methyl, methoxyethyl and oxytanyl;

3) 2-cyano-2-propyl;

4) C_4-6-cycloalkyl optionally substituted with e substituents independently selected from hydroxyl, morpholinyl and a, KX >_:

R₄H, methyl, ethyl, fluormethyl, difluormethyl, trifluormethyl of methoxymethyl is; En

R5 is H, F, methyl of methoxy.

Section 1 1. A connection selected from

or a pharmaceutically acceptable salt thereof.

Section 12. The compound or a pharmaceutically acceptable salt thereof according to any one of sections 1 to 10, wherein F¾ is H.

Par

or a pharmaceutically acceptable salt thereof. Section 14. A compound of formula (I), formula (IA) or a pharmaceutically acceptable salt thereof according to any one of sections 1 to 13 for use in therapy.

Section 15. A compound of formula (I), formula (IA) or a pharmaceutically acceptable salt thereof according to any of sections 1 to 13 for use in the treatment of Parkinson's disease, Alzheimer's disease or amyotrophic lateral sclerosis (ALS ). Section 16. A method of treating Parkinson's disease, Alzheimer's disease or amyotrophic lateral sclerosis (ALS), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) , formula (IA), or a pharmaceutically acceptable salt thereof according to any of paragraphs 1 to 13.

Paragraph 17. The method of paragraph 29, where the subject is a human being.

Section 18. Use of a compound of formula (I), formula (IA) or a pharmaceutically acceptable salt thereof according to any of paragraphs 1 to 13 in the manufacture of a medicament for the treatment of Parkinson's disease, Alzheimer's disease or amyotrophic lateral sclerosis (ALS).

Section 19. A pharmaceutical composition comprising a compound of Formula (I), Formula (IA) or a pharmaceutically acceptable salt thereof according to any of

paragraphs 1 to 13, and one pharmaceutically acceptable excipient.

Section 20. A pharmaceutical composition for use in the treatment of Parkinson's disease, Alzheimer's disease or amyotrophic lateral sclerosis (ALS), where the

composition comprises a compound of formula (I), formula (IA) or a pharmaceutically acceptable salt thereof according to any one of paragraphs 1 to 13, and one pharmaceutically acceptable excipient.

EXAMPLES

General experimental procedures

The following descriptions and examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to those skilled in the art to prepare and use the compounds, compositions and methods of the present invention. While specific embodiments of the present invention are described, those skilled in the art will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.

The chemical names of compounds described in the present application follow the principle of the IUPAC nomenclature.

Heating of reaction mixtures with microwave radiation was performed on a Smith Creator (purchased from Personal Chemistry, Forboro/MA, now owned by Biotage), an Emrys Optimizer (purchased from Personal Chemistry), or an Explorer (supplied by CEM Discover, Matthews/NC) microwave.

Conventional techniques can be used herein to work up reactions and purify the products of the examples.

References in the examples below to drying organic layers or phases may refer to drying the solution over magnesium sulfate or sodium sulfate and filtering off the desiccant in accordance with conventional techniques. Products can generally be obtained by removing the solvent by evaporation under reduced pressure.

Purification of the compounds in the examples can be performed by conventional methods such as chromatography and/or recrystallization using appropriate solvents. Chromatographic methods are known to those skilled in the art and include e.g. column chromatography, flash chromatography, HPLC (high performance liquid chromatography) and MDAP (mass-assisted auto-preparation, also known as mass-assisted LCMS purification). MDAP is described in e.g. W. Goetzinger et al., Int. J. Mass spectro. 2004, 238, 153-162.

Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography (TLC). Both flash and gravity chromatography were performed on E. Merck Kieselgel 60 (230-400 mesh) silica gel. Preparative HPLC was performed using a Gilson Preparative System using a Luna 5u C18(2) 100A reverse phase column eluting with a gradient of 10-80 (0.1% aqueous TFA-acetonitrile) or a gradient of 10-80 80 (water/acetonitrile). The CombiFlash system used for purification in this application was purchased from Isco, Inc. CombiFlash purification was performed using a pre-packed S1O2 column, a detector with a UV wavelength of 254 nm and mixed solvents.

The terms "CombiFlash", "Biotage®", "Biotage 75" and "Biotage SP4®" as used herein refer to commercially available automated purification systems using prepackaged silica gel cartridges.

Title compounds were generally/typically characterized by LCMS and/or NMR.¹H-NMR of¹⁹F NMR spectra were recorded using a Bruker Avance 400 MHz spectrometer. CDCl3 is deuteriochloroform, DMSO-c/6 is hexadeuteriodimethylsulfoxide and CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million (ppm) downfield of the internal standard tetramethylsilane (TMS) or the NMR solvent. Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt= doublet of triplets, td= triplets of doublets, dq= doublet of quartets, br = broad. J denotes the NMR coupling constant, measured in Hertz (Hz).

All temperatures are shown in degrees Celsius (°C). All other abbreviations are as described in the ACS Style Guide (American Chemical Society, Washington, DC, 1986).

Absolute stereochemistry can be determined by methods known to those skilled in the art, e.g. x-ray or vibrational circular dichroism (VCD).

When an enantiomer or a diastereoisomer is described and the absolute stereochemistry of a chiral center is not known, the use of "^*in the chiral center indicates that the absolute stereochemistry of the chiral center is not known, i.e. the compound drawn may be a single R enantiomer or a single S enantiomer. Where the absolute stereochemistry in a chiral center of an enantiomer or a diastereoisomer is known, a bold wedge symbol ( ) or a hashed wedge symbol ( ) is used, without the use of "^*at the chiral center.

LCMS Conditions:

Instruments: HPLC: Agilent 1200 and MS: Agilent 6120

1 ) Acidic conditions:

Kolom: Agilent SB-C18 4,6 x 30 mm - 1,8 micron

Mobile phase: water with 0.05% FA / 0.05% CH₃CN

Detection: MS and Photodiode Array Detector (PDA)

2) Basic conditions: (A)

Kolom: XBridgeTM C18 4,6 x 50 mm - 3,5 micron

Mobile phase: water containing 10 mmol NH4HCO3 / CH3CN

Detection: MS and Photodiode Array Detector (PDA) (B)

Kolom: Welch Ultimate XB-C18 5μηι 4.6^*33mm

Mobile phase: water with 0.02% NH₄OAc / CH₃CN

Detection: MS and Photodiode Array Detector (PDA)

MDAP conditions:

1 ) Acidic conditions:

Instrument: Waters instrument Kolom: Sunfire Prep C18 kolom (5 urn, 19 x 50 mm)

Mobile phase: water with 0.05% TFA / acetonitrile.

2) Basic conditions:

Instrument: Waters-instrument

Kolom: Xbridge Prep C18 kolom (5 urn, 19 x 50 mm)

Mobile phase: water with 0.04% ammonia/acetonitrile.

Prep HPLC conditions

Instrument: Waters-instrument

Kolom: Xbridge Prep C18 kolom OBD (10 urn, 19 x 250 mm)

Mobile phase: water with 0.08% ammonia/acetonitrile.

Chiral HPLC Isolation Instruments:

1 . Gilson Gx-281 Prep LC (Gilson 806 manometrische module, Gilson 81 1 D dynamische mixer, Gilson Gx-281 prep vloeistofhandler, Gilson 306 pomp^*2, Gilson 156-detector),

2. Agilent 1200-serie Prep LC (Agilent G1361A Prep-pomp^*2, Agilent G2260A Prep ALS, Agilent G1315D DAD Detector, Agilent G1364B Prep FC),

3. Thar SFC Prep 80 (TharSFC ABPR1, TharSFC SFC Prep 80 C0₂Pump, TharSFC Co-Solvent Pump, TharSFC Cooling Heat Exchanger and Circulation Bath, TharSFC Mass Flow Meter, TharSFC Static Mixer, TharSFC Injection Module, Gilson UV

detector, TharSFC Fraction Collection-module).

Chiral HPLC Separation Conditions:

1 . Chiral Method A: AD-H, 0.46 cm I.D. *15cm L; mobile phase: heptane: ethanol (0.1% diethylamine) =60:40; flow rate: 0.5 ml/min; wavelength: 254nm; temperature: 25°C.

2. Chiral Method B: AS-H, 0.46 cm I.D. *15cm L; mobile phase: heptane: ethanol (0.1% diethylamine) =80:20; flow rate: 0.5 ml/min; Wavelength: 254nm; Temperature: 25°C.

3. Chiral Method C: OJ-H, 0.46 cm I.D. *15cm L; mobile phase: heptane: ethanol (0.1% diethylamine) =80:20; flow rate: 0.5 ml/min; Wavelength: 254nm; Temperature: 25 Chiral Method D: ID-H, 0.46 cm I.D. x15cmL; mobile phase: heptane: /^'-PrOH (0.1% diethylamine) = 80:20; flow rate: 0.5 ml/min; Wavelength: 254nm; Temperature: 25°C.

Chiral method E: IC-H, 0.46 cm I.D. x15cmL; mobile phase: heptane: ethanol (0.1% diethylamine) =60:40; flow rate: 0.5 ml/min; wavelength: 254nm; temperature: 25°C.

Chiral Method F: OD-H, 0.46 cm I.D. *15cm L; mobile phase: heptane: ethanol (0.1% diethylamine) =60:40; flow rate: 0.5 ml/min; wavelength: 254nm; temperature: 25°C.

Chiral Method G: OZ-H, 0.46 cm I.D. *15cm L; mobile phase: heptane: ethanol (0.1% diethylamine) =60:40; flow rate: 0.5 ml/min; wavelength: 254nm; temperature: 25°C.

Abbreviations and Source Sources

The following abbreviations and sources are used below:

atm - atmosferen

Ac - acetyl

aq. - watery

Boc - dwz f-butyloxycarbonyl

B0C2O - di-ie f-butyldicarbonate

Bn - benzyl

KAS - Cerium Ammonium Nitrate

cone. - concentrated

CyNMe₂- (CN)N(CH3)₂

DAST-Λ/,/V-diethylaminozwaveltrifluoride

DCM - dichloormethaan

DEAD - Diethylazodicarboxylaat

DHP - 3,4-dihydro-2H-pyraan

DIPEA - N, /V-diisopropylethylamine

DIAD - diisopropylazodicarboxylaat

DMAP - 4-Dimethylaminopyridine DMF - N, /V-dimethylformamide

DMSO - dimethylsulfoxide

EA - ethyl acetate

Et - ethyl

EtOAc - ethyl acetate

EtOH - ethanol

Et.3N - triëthylamine

FCC - flash column chromatography

HCI - waterstofchloride

HOAc/AcOH - acetic acid

hour - hour

HATU - 1 -[bis(dimethylamino)methyleen]-1 H-1 ^^-triazolo^S-blpyridiniumS-oxidhexafluorfosfaat

IBX - 2-iodooxybenzoic acid

/^'-PrOH - isopropylalcohol

LDA - lithiumdiisopropylamide

LiHMDS - lithiumbis(trimethylsilyl)amide

LiAIH4 - lithiumaluminiumhydride

mCBPA - meta-chloroperoxybenzoic acid

I - methyl

MeOH - methanol

CH3OH - methanol

Madam - methane sulfonate

MsCl - methanesulfonyl chloride

NMM - 4-methylmorfoline

NMP - 1-methyl-2-pyrrolidon

n-Bu - n-butyl

n-BuLi - n-Butyllithium f-Bu - f-butyl

Pd2(dba)3 - tris(dibenzylideenaceton)dipalladium(0)

Pd(dppf)Cl2 - [1 ,1 '-Bis(difenylfosfino)ferroceen]pa//ad/^'t/m(ll) dichloride

PE - petroleumether

Ph₃P/PPh₃- trifenylfosfine

PMB - paramethoxybenzyl

POC - Fosforylchloride

p-TsOH - p-tolueensulfonzuur

rt - room temperature

RT - retention time

Ru-phos - 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl sat. - saturated

SEM - 2-(trimethylsilyl)ethoxymethyl

SEMCI - 2-(trimethylsilyl)ethoxymethylchloride

SFC - Supercritical Fluid Chromatography

TBAI - tetrabutylammoniumjodide

TBME - tert-butylmethylether

THEE - triëthylamine

TFA - trifluoroacetic acid

TFAA - Trifluoroacetic Anhydride

THF - tetrahydrofuran

THP - tetrahydropyranyl

TLC - dunnelaagchromatographie

TMSCF3- trifluormethyltrimethylsilaan

Tween 20 - polysorbaat 20

Description D1

1 -(Tetrahydro-2H-pyran-4-yl)-1H-pyrazool (D1)

A mixture of 1H-pyrazole (10.5 g, 154.23 mmol), tetrahydro-2/-/-pyran-4-yl methanesulfonate (41.7 g, 231.35 mmol), and Cs₂C0₃(75.4 g, 231.35 mmol) in DMF (600 ml) was stirred at 100°C for 24 hours. The reaction was filtered and the filtrate was diluted with EtOAc (1000 mL). The mixture was washed with brine (6 x 200 mL), dried over anhydrous Na 2 SO₄, filtered and concentrated. The crude product was purified by C18 column chromatography (CH3CN:H2O=30:70) to afford the title compound as an off-white solid (12.6 g, yield 53.7%).¹H NMR (400 MHz, CDCI3): 7,52 (br, 1 H), 7,44 (br, 1 H), 6,27 (br, 1 H), 4,41 -4,33 (m, 1 H), 4,12-4,10 (m, 2H ), 3,58-3,52 (m, 2H), 2,1 1 -2,03 (m, 4H).

Description D2

5-Methyl-1 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazool (D2)

To a solution of D1 (8.5 g, 55.85 mmol) in THF (100 mL) was added n-BuLi (1.6 M in THF, 53 mL, 83.76 mmol) at -78°C under argon for 30 minutes. Dan CH₃I (15.8 g, 1 L 0.70 mmol) was added dropwise. The reaction was stirred at -78°C for 30 min. The mixture was poured into ice water (150 ml) and extracted with EtOAc (2 x 100 ml). The combined organic layers were dried over anhydrous Na 2 SO₄, filtered and concentrated. The crude product was purified by C18 column chromatography (CH3CN:H2O=40:60) to afford the title compound as an off-white solid (5.7 g, yield 61.4%). LC-MS: 167.2 [M+H]⁺.

Description D3

3, 4-Dibroom-5-methyl-1 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazool (D3)

To a solution of D2 (5.7 g, 34.29 mmol) and sodium acetate (5.7 g, 68.58 mmol) in AcOH (50 mL) was added Br2 (17.6 mL, 342.92 mmol). The reaction was stirred at 85°C for 16 hours. Sat. Na2 SC>3 (200 ml) was added and the mixture was stirred at room temperature for 1 hour. Then the mixture was extracted with EtOAc (2 x 150 ml) and the combined organic layers were washed with brine (2 x 100 ml), dried over anhydrous Na 2 SO₄, filtered and concentrated. Then the residue was washed with hexane to give the title compound as a yellow solid (5.407 g, yield 48.7%). LC-MS: 324.9 [M+H]⁺.

Description D4

3-broom-5-methyl-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazool

To a solution of D3 (5.407 g, 16.69 mmol) in 95% H₂S0₄(50 ml) at 0°C was added dropwise 97% HNO3 (50 ml). The reaction was stirred at 0°C for 0.5 hours, then warmed slowly to room temperature and held for 1 hour. The mixture was poured into ice water (300 ml) and extracted with EtOAc (200 ml). The organic layer was washed with H 2 O (2 x 50 mL), dried over anhydrous Na 2 SO₄filtered and concentrated to give the title compound as an off-white solid (1.127 g, yield 23.3%).

Description D5

5-Methyl-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-ol (D5)

To a mixture of D4 (560 mg, 1.93 mmol) in H₂0 (20 ml) KOH (2.24 g) was added. The reaction was stirred at 100°C for 18 hours. The mixture was washed with EtOAc (2 x 10 ml). The aqueous phase was neutralized with 2N HCl to pH = 3 and extracted with DCM (2 x 20 ml). The combined organic layers were dried over anhydrous Na 2 SO₄filtered and concentrated to give the title compound as a yellow solid (380 mg, yield 86.6%).

Description D6

ferf-Butyl-(3-((5-methyl-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)oxy)propyl)carbamaat (D6) Een mengsel van D5 (120 mg, 0,53 mmol), dwz f-butyl (3-broompropyl)carbamaat (187 mg, 0,79 mmol) en Cs₂C0₃(346 mg, 1.06 mmol) in DMF (10 mL) was heated at 80°C for 16 hours. The mixture was poured into water (50 ml) and extracted with EtOAc (2 x 30 ml). The combined organic layer was washed with brine (5 x 30 mL), dried over anhydrous Na 2 SO₄filtered and concentrated to give the title compound, which was used for the next step without further purification. LC-MS: 285 [M+H-100]⁺.

Description D7

3-((5-Methyl-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazool-3-yl)oxy)propaan-1-amine, HCI-zout (D7)

A solution of D6 (204 mg, 0.53 mmol) in 4M HCl/MeOH (15 ml) was warmed to 35°C and stirred for 2 hours. The reaction was concentrated to give the title compound, which was used in the next step without further purification. LC-MS: 285.3 [M+H]⁺.

Description D8

2,5-Dichloor-yV-(3-((5-methyl-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-3-yl)oxy)propyl)pyrimidin- 4-amine (D8)

Et was added to a solution of D7 (151 mg, 0.53 mmol) in DMF (20 mL)₃N (0.4 ml, 2.65 mmol) at room temperature and 2,4,5-trichloropyrimidine (138 mg, 0.75 mmol) was then added dropwise. The reaction was stirred at room temperature for 10 min. The mixture was poured into water (50 ml) and extracted with EtOAc (2 x 30 ml). The combined organic layers were washed with brine (5 x 20 mL), dried over anhydrous Na 2 SO₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EtOAc = 2:1) to afford the title compound as a yellow solid (154 mg, yield 67.6%). LC-MS: 431 .3 [M+H]

Beschrijving D9 W-(3-((4-Amino-5-methyl-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazool-3-yl)oxy)propyl)-2,5- dichloorpyrimidine -4-amine (D9)

To a solution of D8 (154 mg, 0.36 mmol) in EtOH/H₂0 (20ml/5ml) NH was added₄CI (96 mg, 1.79 mmol) and Fe (102 mg, 1.79 mmol). The reaction was stirred at 80°C for 2 hours. The mixture was filtered and the filtrate was concentrated. The residue was diluted with EtOAc (30 ml) and washed with H 2 O (2 x 20 ml). The organic layer was dried over anhydrous Na 2 SO₄filtered and concentrated to give the title compound as a yellow solid (121 mg, yield 84.4%). LC-MS: 401.3 [M+H]⁺.

Description D10

ferf-butylbenzyl(3-(benzyloxy)-2-hydroxypropyl)carbamaat (D10)

Towards a solution of BnNH₂(69.4 g, 0.65 mol) in 2% Tween 20/water (1 L) was added dropwise 2-((benzyloxy)methyl)oxirane (90 g, 0.54 mol) at 5-10°C. The reaction was stirred overnight at room temperature. To this mixture was added BOC20 (164.8 g, 0.756 mol) dropwise at 0-5°C. The reaction was stirred overnight at room temperature. CH2Cl2 was added and the organic layer was washed with brine (500 mL), dried over anhydrous Na2SO₄and concentrated. The crude was purified by flash column chromatography on silica gel (PE:EtOAc = 10:1) to give the title compound as a yellow oil (90 g, yield 45%). LC-MS: 394.3

[I+Na]⁺.

Description D11

ferf-Butylbenzyl (3-(benzyloxy)-2-methoxypropyl)carbamaat (D11)

CH was added to a solution of D10 (5.9 g, 15.9 mmol) in DMF (10 ml)₃I (6.78 g, 47.8 mmol) and NaH (0.69 g, 17.4 mmol, 60%) at 0-5°C. The reaction was stirred at 0-5°C for 3 hours. The mixture was poured into water (100 ml) and extracted with EtOAc (100 ml). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude was purified by column chromatography on silica gel (PE:EtOAc = 3:1) to give the title compound as a yellow oil (3.6 g, yield 59%). LC-MS: 386.3 [M+H]⁺.

Description D12

ferf-Butyl (3-hydroxy-2-methoxypropyl)carbamaat (D12)

A solution of Dll (3.6 g) and Pd/C (1 g) in MeOH (40 ml) was stirred overnight at 50 °C under hydrogen. The mixture was filtered, the filter cake was washed with MeOH (2 x 20 mL) and the combined filtrate was concentrated. The crude was purified by column chromatography on silica gel (PE:EtOAc = 3:1) to give the title compound as an oil (318 mg, yield 16.6%).

Description D13

3-((ferf-Butoxycarbonyl)amino)-2-methoxypropylmethaansulfonaat (D13)

E oc

To a solution of D12 (318 mg, 1.55 mmol) in CH₂CI₂(20 ml) become Et₃N (470 mg, 4.65 mmol) and after stirring for 30 minutes, MsCl (266.5 mg, 2.32 mmol) at 0-5°C was added. The reaction was stirred at 25°C for 3 hours. The mixture was poured into water (50 ml) and extracted with EtOAc (2 x 50 ml). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated to give the title compound as yellow oil (400 mg, yield 91%). LC-MS: 306.2 [M+Na]⁺.

Description D14

ferf-Butyl (2-methoxy-3-((5-methyl-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)oxy)propyl)carbamate (D14 ) To a solution of D13 (350 mg, 1.23 mmol) in DMF (20 ml) was added K₂C0₃(256 mg, 1.85 mmol) and D5 (141 mg, 0.61 mmol). The reaction was stirred overnight at 80°C. The mixture was poured into water (100 ml) and extracted with EtOAc (2 x 80 ml). The organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude was purified by column chromatography on silica gel (PE:EtOAc = 10:1) to give the title compound as a yellow oil (130 mg, yield 50%). LC-MS: 437.3 [M+Na]⁺.

Description D15

2-Methoxy-3-((5-methyl-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)oxy)propaan-1-amine, TFA-zout ( D15)

To a solution of D14 (130 mg) in CH2 Cl2 (20 ml) was added TFA (4 ml). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated to give the title compound as a yellow oil (150 mg, crude). LC-MS: 316.3 [M+H]⁺.

Description D16

2,5-dichloor-W-(2-methoxy-3-((5-methyl-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-3-yl)oxy) propyl)pyrimidine-4-amine (D16)

Et was added to a solution of D15 (97 mg, 0.31 mmol) in 2% Tween/water (2%, 10 mL)₃N (1 mL) and 2,4,5-trichloropyrimidine (57.4 mg, 0.31 mmol). The reaction was stirred at room temperature for 1 hour. The suspension was filtered and the yellow solid was obtained (120 mg, yield 93.7%). LC-MS: 461.1 [M+H]⁺.

Description D17

3-((2,5-dichloropyrimidin-4-yl)amino)butan-1 -ol (D17)

To a solution of 2,4,5-trichloropyrimidine (1.83 g, 10 mmol) in 2% Tween 20/water (50 ml) at 0 °C was added 3-aminobutan-1-ol (880 mg, 10 mmol) added and stirred for 4 hours. The reaction was concentrated and filtered. The solid was washed with CAN to afford the title compound as a white solid (1.5 g, yield 64%). LC-MS: 236.1 [M+H]⁺.

Description D18

3-((2,5-dichloorpyrimidine-4-yl)amino)butylmethaansulfonaat (D18)

To a solution of D17 (1.5 g, 6.4 mmol) in CH₂CI₂(20 ml) become Et₃N (3 mL) and MsCl (2.6 g, 12.7 mmol). The reaction was stirred at room temperature for 3 hours. The mixture was concentrated and the residue was poured into water and extracted with CH2CI2. The organic layer was concentrated to give the title compound as a yellow solid (1.8 g, yield 90%). LC-MS: 314.1 [M+H]⁺.

Description D19

2,5-dichloor-W-(4-((5-methyl-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-3-yl)oxy)butaan-2- yl)pyrimidine-4-amine (D19)

To a solution of D18 (1.0 g, 2.46 mmol) in DMF (40 ml) were added K2 CO3 (340 mg, 2.46 mmol) and D5 (190 mg, 0.82 mmol). The reaction was stirred overnight at 80°C. The mixture was poured into water and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude product was purified by column chromatography on silica gel (PE:EtOAc = 3:1) to afford the title compound as a yellow solid (250 mg, yield 68%). LC-MS: 445.1 [M+H]⁺.

Beschrijving D20 3,4,5-tribroom-1 -(tetrahydro-2H-pyran-3-yl)-1H-pyrazol (D20)

To a solution of 3,4,5-tribromo-1/-/-pyrazole (21 g, 69 mmol) in THF (200 ml) was added tetrahydro-2H-pyran-3-ol (8.5 g, 83 mmol) added. PPh₃(36 g, 138 mmol), DIAD (27 g, 138 mmol) at 0°C. The resulting mixture was stirred at 0°C for 3 hours. The mixture was poured into water (100 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude was purified by column chromatography over silica gel (PE:EtOAc = 10:1) to give the title compound as an oil (10 g, yield 50%).

Description D21 and D22

3,4-dibroom-5-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazool (D21)

3,4-dibroom-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazool (D22)

D21 D22

To a solution of D2O (1.0 g, 2.6 mmol) in THF (10 ml) was added n-BuLi (1.6 M in THF, 1.6 ml, 2.6 mmol) at -70 °C under argon for 30 hours. min, then CH3I (0.8 g, 5.2 mmol) was added dropwise. The reaction was stirred at -70°C for 2 hours. The mixture was poured into ice and the sat. NH₄Cl solution and extracted with EtOAc (2 x 100 ml). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude product was purified by column chromatography on silica gel (PE:EtOAc = 10:1) to give the mixture of the title compounds as a yellow solid (900 mg, yield 60%). D21 : LC-MS: 324.9 [M+F]⁺. D22: LC- MS: 310.9 [M+V]⁺.

Description D23 and D24

3-Broom-5-methyl-4-nitro-1 -(tetrahydro-2H-pyran-3-yl)-1H-pyrazool (D23)

3-Broom-4-nitro-1 -(tetrahydro-2H-pyran-3-yl)-1H-pyrazool (D24)

D23 D24

To a stirred solution of D21 and D22 (900 mg, 2.8 mmol) in 95% H₂S0₄(10 ml) at 0°C was added dropwise 97% HNO3 (9 ml). The mixture was stirred at 0°C for 3 hours. The reaction mixture was poured into ice and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE:EtOAc = 10:1) to give the mixture of the title compounds as a yellow solid (800 mg, yield 90%). D23: LC-MS: 290.1 [M+F]⁺. D24: LC-MS: 276.0 [M+V]⁺.

Description D25 and D26

5-Methyl-4-nitro-1 -(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-ol (D25)

4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-ol (D26)

D25 D26

A mixture of D23, D24 (400 mg, 1.4 mmol) and KOH (1.2 g) in H₂0 (10 ml) was stirred overnight at 120°C. The mixture was washed with EtOAc (2 x 20 mL). The aqueous layer was neutralized with 6N HCl to pH=3 and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated in vacuo to give the mixture of the title compounds as yellow solids (200 mg, yield 56%).

Description D27

W-(3-broompropyl)-2,5-dichloorpyrimidine-4-amine

To a solution of 3-bromopropane-1-amine hydrobromide (5.6 g, 25 mmol) in /^'-PrOH (40 ml) Et was added₃N (7.74 g, 76 mmol) and 2,4,5-trichloropyrimidine (4.69 g, 25 mmol) at 0 °C. The reaction was stirred overnight at room temperature. The mixture was poured into water (100 ml) and extracted with EtOAc (100 ml). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude was purified by column chromatography on silica gel (PE:EtOAc=10:1) to afford the title compound as a white solid (4 g, 55% yield). LC-MS: 286.1 [M+H]⁺.

Description D28 and D29

2,5-Dichloor-yV-(3-((5-methyl-4-nitro-1 -(tetrahydro-2H-pyran-3-yl)-1 H-pyrazol-3-yl)oxy)propyl)pyrimidin- 4-amine (D28)

2,5-Dichloor-yV-(3-((4-nitro-1 -(tetrahydro-2H-pyran-3-yl)-1 H-pyrazol-3-yl)oxy)propyl)pyrimidine-4-amine ( D29)

D28 D29 A solution of D25 and D26 (500 mg, 2.2 mmol), D27 (753 mg, 2.6 mmol) and K₂C0₃(607mg, 4.4mmol) in DMF (5ml) was stirred at 80°C for 16 hours. The mixture was poured into H 2 O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude product was purified by column chromatography on silica gel (PE:EtOAc = 1:1) to give the mixture of title compounds as a yellow solid (500 mg, yield 58%).

Description D30

5-Chloor-3-methyl-4-nitro-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazool (D30)

To a solution of 5-chloro-3-methyl-4-nitro-1H-pyrazole (12.5 g, 77.4 mmol) and Cy2NMe

(21.2 g/23.2 ml, 108.5 mmol) in THF (230 ml) under argon at 0°C, SEMCI (15.5 g/16.5 ml, 93.0 mmol) was added via syringe for 5 minutes. The reaction was stirred under argon at 0°C for 15 minutes and then at room temperature for 1 hour. The mixture was diluted with water (200 ml), followed by the addition of brine (100 ml). The result was extracted with EtOAc (2 x 150 ml). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO₄, filtered and concentrated. The crude product was purified columnwise

chromatography on silica gel (PE:EtOAc = 10:1) to afford the title compound as a pale yellow oil (1.5 g, yield 50%). Description D31

ferf-Butyl (3-((3-methyl-4-nitro-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazool-5-yl)oxy)propyl)carbamaat (D31)

A mixture of D30 (22.9 g, 77.4 mmol) and [V-Boc-propanolamine (27.1 g, 154.7 mmol) was dried under vacuum for 15 minutes. Dry toluene (390 mL) was added under argon, followed by sequential addition of CuI (2.21 g, 11.6 mmol), 1,10-phenanthroline (4.18 g, 23.2 mmol), and CS2 CO3 (40, 4g, 124mmol). The reaction was stirred overnight under argon at 90°C. The cooled mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc (1 L). The combined filtrate was evaporated to dryness and the residual dark oil was purified by chromatography on silica gel (PE:EtOAc = 15:1 to 5:1) to afford the title compound as orange oil (11.8 g, yield 35%) . LC-MS: 453.3 [M+Na]⁺.¹H NMR (400 MHz, CDCI3): 8 5,29 (s, 2H), 5,10 (br, 1H), 4,43 (t, J= 5,8 Hz, 2H), 3,66 (t, J= 8,4 Hz, 2H),

3,39-3,37 (m, 2H), 2,50 (s, 3H), 2,06-2,02 (m, 2H), 1,44 (s, 9H), 0,94 (t, J= 8,4 Hz, 2H), 0,00 (s, 9 uur).

Description D32

3-((5-Methyl-4-nitro-1H-pyrazol-3-yl)oxy)propan-1-amine, HCl salt (D32)

To a solution of D31 (1.1.8 g, 27.4 mmol) in MeOH (20 mL) under argon at room temperature was added HCl/MeOH (5 M, 240 mL). The reaction was stirred overnight under argon at 40°C. The light yellow suspension was evaporated to dryness. The residue was suspended in MeOH (30 ml), stirred for 15 minutes, filtered. The filter cake was collected and dried in vacuo to afford the title compound as a pale yellow solid (5.43 g, 83% yield).¹H-NMR (400 MHz, DMSO-d₆): δ 13,22 (s, 1H), 8,02 (br, 3H), 4,32 (t, J= 6,0 Hz, 2H), 2,95 (br, 2H), 2,50 (s, 3H), 2,09-2,03 (m, 2 uur). Beschrijving D33

2,5-dichloor-W-(3-((5-methyl-4-nitro-1 H^yrazol-3-yl)oxy)propyl)pyrimidine

(D33)

To a suspension of D32 (4.87 g, 20.6 mmol) in /^'-PrOH (150 mL) was added DIPEA (13.6 mL, 82.3 mmol). The reaction was stirred at 0°C under argon for 10 minutes and 2,4,5-trichloropyrimidine (4.15 g, 22.6 mmol) was added via syringe. The mixture was allowed to warm to room temperature and stirred overnight under argon. The mixture was evaporated to dryness. The residue was suspended in water (100 ml), filtered. The filter cake was washed with water (100 ml), dried under an infrared lamp at 50°C for 2 hours and collected to give the title compound as an off-white solid (7.08 g, yield 99%). LC-MS: 347.2 [M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆): δ 12,90 (br, 1 H), 8,14 (s, 1 H), 7,98 (br, 1 H), 4,28 (t, J= 5,6 Hz, 2H), 3,56-3,51 (m, 2H), 2,47 ( s, 3H), 2,05 (t, J = 6,2 Hz, 2H).

Description D34

2,5-Dichloor-yV-(3-((5-methyl-4-nitro-1 -(oxetan-3-yl)-1 H-pyrazol-3-yl)oxy)propyl)pyrimidine-4-amine ( D34)

To a solution of D33 (200 mg, 0.576 mmol) and oxetan-3-yl 4-methylbenzenesulfonate (263 mg, 1.15 mmol) in DMF (3.0 mL) under argon at room temperature was added CS2 CO3 (563 mg, 1. 73mmol). The reaction was stirred overnight under argon at 90°C. The mixture was diluted with water (25 ml), extracted with EtOAc (3 x 25 ml). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO₄, filtered. The filtrate was concentrated and the crude product was purified by prep-TLC (CH 2 Cl 2 :EtOAc = 3:1) to afford the title compound as a white solid (50 mg, yield 21%).¹H-NMR (400 MHz, CDCI₃): δ 8,00 (s, 1 H), 5,98 (s, 1 H), 5,40 (t, J= 7,0 Hz, 1 H), 5,15 (t, J= 6,2 Hz, 2H), 4,94 (t, J= 6,8 Hz, 2H), 4,54 (t, J = 5,4 Hz, 2H), 3,79 (dd, J= 1 1,8, 5,4 Hz, 2H), 2,58 (s, 3H), 2,26-2,20 (m, 2H). Beschrijving D35

3-Chloor-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazool (D35)

A mixture of 5-chloro-4-nitro-1H-pyrazole (12.0 g, 81.34 mmol), tetrahydro-2/-/-pyran-4-yl methanesulfonate (14.660 g, 81.34 mmol), and Cs₂C0₃(53.004 g, 162.68 mmol) in DMF (300 ml) was stirred at 100°C for 16 hours. The mixture was filtered and the filtrate was diluted with EtOAc (300 ml). The mixture was washed with brine, dried over anhydrous Na 2 SO₄and concentrated to give the title compound as a yellow solid (4.5 g, yield 24%).¹H NMR (400 MHz, CDC): 8 9,07 (s, 1H), 4,54-4,46 (m, 1H), 3,98-3,94 (m, 2H), 3,47-3,40 (m, 2H), 2,03-1. 89 (m, 4H).

Description D36

4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-ol (D36)

A mixture of D35 (1.0 g, 4.32 mmol) and KOH (2.0 g) in H₂0 (30 ml) was stirred at 100°C for 2 days. The mixture was washed with EtOAc (2 x 15 mL). The aqueous phase was neutralized with 6N HCl to pH=3 and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na 2 SO₄filtered and concentrated to give the title compound as a yellow solid (730 mg, yield 79%). LC-MS: 214.3 [M+H]⁺.

Description D37

ieri-Butyl (3-((4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)oxy)propyl)carbamaat (D37)

A mixture of D36 (426 mg, 2.00 mmol), ie/f-butyl(3-bromopropyl)carbamate (476 mg, 2.00 mmol) and K2CO3 (553 mg, 4.00 mmol) in DMF (20 mL ) was stirred at 60°C. C for 3 hours. The mixture was poured into ice water (100 ml) and extracted with EtOAc (2 x 60 ml). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude was purified by column chromatography on silica gel (PE:EtOAc = 2:1) to give the title compound as a yellow solid (623 mg, yield 84%).

Description D38

ieri-Butyl (3-((4-amino-1 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)oxy)propyl)carbamaat (D38)

A mixture of D37 (623 mg, 1.68 mmol), Fe (300 mg) and NH₄Cl (300 mg) in EtOH/H₂0 (20ml/5ml) was stirred at 100°C for 2 hours. The mixture was filtered and concentrated. The residue was diluted with EtOAc (60 ml). The mixture was washed with brine, dried and concentrated to give the title compound as a black oil (256 mg, yield 45%).

Description D39

ieri-Butyl A/-{3-[(4-{[(tert-butoxy)carbonyl]amino}-1 -(oxan-4-yl)-1 H-pyrazol-3-yl)oxy] propyl}carbamaat (D39)

To a solution of D38 (256 mg, 0.75 mmol) in THF (18 mL) at 0°C under nitrogen was added LiHMDS (0.9 mL, 0.90 mmol). The reaction was stirred at 0°C for 0.5 hour. Then a solution of BOC20 (197 mg, 0.90 mmol) in THF (2 ml) was added dropwise. The reaction was stirred at 0°C for 0.5 hours and then at room temperature for 16 hours. The mixture was poured into aq.NH₄Cl (60 ml) and extracted with EtOAc (2x50 ml). The combined organic layer was washed with brine, dried and concentrated. The crude was purified by chromatography on silica gel (PE:EtOAc = 1:1) to afford the title compound as a white solid (204 mg, yield 62%). LC-MS: 463.3 [M+Na]⁺.

Description D40

ieri-Butyl W-{3-[(4-{[(tert-butoxy)carbonyl]amino}-5-chloor-1 -(oxan-4-yl)-1 H-pyrazol-3-yl)oxy]propyl }carbamaat(D40)

To a solution of D39 (164 mg, 0.37 mmol) in THF (20 mL) at -50 °C under nitrogen was added LDA (2 M in THF, 1.85 mL, 3.70 mmol). The reaction was stirred at -20°C for 0.5 hour. Then a solution of C2 Cl6 (438 mg, 1.85 mmol) in THF (4 mL) was added dropwise. The reaction was stirred at -20°C for 0.5 hour. The mixture was added to aq. NH4CI (60ml) and extracted with EtOAc (2x50ml). The combined organic layer was washed with brine, dried and concentrated in vacuo. The crude was purified by column chromatography on silica gel (PE:EtOAc = 2:1) to give the title compound as a white solid (83 mg, yield 62%).

Description D41

W-(3-((4-Amino-5-chloor-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-3-yl)oxy)propyl)-2,5- dichloorpyrimidine-4 -amine (D41)

A solution of D40 (83 mg, 0.17 mmol) in 4 M HCl/dioxane (15 ml) was stirred at room temperature for 2 hours. The reaction was concentrated and the residue was diluted with /^'- PrOH (19ml). In₃N (0.5 ml) and 2,4,5-trichloropyrimidine (32 mg, 0.17 mmol) were added and the resulting mixture was stirred at room temperature for 1 hour. The mixture was poured into H 2 O (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine, dried and concentrated. The crude was purified by column chromatography on silica gel (PE:EtOAc = 2:1) to give the title compound as a white solid (60 mg, yield 81%). LC-MS: 421.0 [M+H]⁺.

Description D42

3-((2,5-dichloorpyrimidine-4-yl)amino)-2-fluorpropaan-1-ol (D42)

To a solution of 2,4,5-trichloropyrimidine (887 mg, 4.83 mmol) and 3-amino-2-fluoropropan-1-ol (450 mg, 4.83 mmol) in /^'-PrOH (10 mL) was added to DIPEA (1.013 mL, 5.80 mmol) at 0°C. After stirring at 0°C for 10 minutes, the mixture was quenched with water (10ml), extracted with DCM (3x20ml), dried over anhydrous Na 2 SO₄and concentrated to give the title compound (570 mg, yield 49.1%). LC-MS: 240.0 [M+H]⁺.

Description D43

3-((2,5-dichloorpyrimidine-4-yl)amino)-2-fluorpropylmethaansulfonaat (D43)

To a solution of D42 (270 mg, 1.125 mmol) in DCM (2 ml) was added MsCl (0.105 ml, 1.350 mmol) and DIPEA (0.295 ml, 1.687 mmol) at 25°C. The reaction was stirred at 25°C for 1 hour. The mixture was quenched with water (4 ml), extracted with DCM (2x5 ml), dried over anhydrous Na2 SO₄and concentrated to give the title compound (358 mg, yield 100%). LC-MS: 318.0 [M+H]⁺.

Description D44

2,5-dichloor-W-(2-fluor-3-((5-methyl-4-nitro-1 -(tetrahydro-2H^yran-4-yl)-1H-pyrazol-3-yl)oxy) propyl)pyrimidine-4-amine (D44)

To a solution of D5 (275 mg, 1.210 mmol) in DMF (5 ml) K₂C0₃(152 mg, 1,100 mmol) and D43 (350 mg, 1,100 mmol) at 25°C. The mixture was stirred at 60°C for 2 hours. The mixture was quenched with water (10 ml), extracted with DCM (3x20 ml), dried over anhydrous Na 2 SO₄and concentrated. The crude product was purified columnwise

chromatography on silica gel (PE:EtOAc=5:1 to 1:1) to give the title compound (50 mg, 0.1 L mmol, yield 10.1%). LC-MS: 449.1 [M+H]⁺.

Description D45

3-((2,5-dichloropyrimidin-4-yl)amino)pentan-1-ol (D45) To a solution of 3-aminopentan-1-ol (500 mg, 4.85 mmol) in /^'-PrOH (6 ml) at 0°C, Et 2 N (1.23 g, 12.1 mmol) and 2,4,5-trichloropyrimidine (930 mg, 5.07 mmol) were added dropwise. The reaction was stirred at 0°C for 2 hours. The mixture was filtered and washed with Et 2 O (10 ml). The filtrate was washed with H2 O (2 x 8 ml) and dried over anhydrous Na2 SO₄and concentrated. The crude was purified by flash column chromatography on silica gel (PE:EtOAc = 10:1 to 3:1) to afford the title compound as an off-white solid (900 mg, yield 74%). LC-MS: 250.0 [M+H]⁺.

Description D46

3-((2,5-dichloorpyrimidine-4-yl)amino)pentylmethaansulfonaat (D46)

To a solution of D45 (0.40 g, 1.60 mmol) in CH2 Cl2 (10 mL) was added Et₃N (486 mg, 4.8 mmol) and MsCl (366 mg, 3.2 mmol) at 0 °C. The reaction was stirred at 25°C for 2 hours. The mixture was poured into saturated NH₄Cl aqueous solution (10 ml) and extracted with CH 2 Cl 2 (2x10 ml - ). The organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated. Then purified by flash column chromatography on silica gel (PE:EtOAc = 10:1 to 4:1) to give the title compound as a yellow oil (0.5 g, yield 95%). LC-MS: 328.2 [M+H]⁺.

Description D47

2,5-Dichloor-/V-(1 -((5-methyl-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazool-3-yl)oxy)pentaan-3 -yl)pyrimidine-4-amine (D47)

To a solution of D46 (433 mg, 1.32 mmol) in DMF (4 ml) were added K 2 CO 3 (304 mg, 2.2 mmol) and D5 (200 mg, 0.880 mmol). The reaction was stirred at 80°C for 30 minutes. The cooled mixture was poured into saturated NH₄Cl aqueous solution (15 ml) and extracted with Et.20 (2x10 ml). The organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude was purified by flash column chromatography on silica gel (PE:EtOAc = 8:1 to 3:1) to afford the title compound as an off-white solid (230 mg, yield 56%). LC-MS: 459.3 [M+H]⁺. Description D48

4-(3-broom-5-methyl-4-nitro-1H-pyrazol-1 -yl)tetrahydro-2H-pyran-3-ol (D48)

To a solution of 3-bromo-5-methyl-4-nitro-1H-pyrazole (4 g, 19.42 mmol) in DMF (100 mL) was added K₂CO₃(8.05 g, 58.25 mmol) and 3,7-dioxabicyclo[4.1.0]heptane (5.83 g, 58.26 mmol) at room temperature. The reaction was stirred at 80°C for 10 hours. The mixture was poured into water (200 ml) and extracted with EtOAc (3 x 200 ml). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude was purified by flash column chromatography (PE:EtOAc = 1:1) to give the title compound as a yellow oil (2 g, yield 33%).

Description D49

3-broom-1 -(3-fluortetrahydro-2H-pyran-4-yl)-5-methyl-4-nitro-1H-pyrazool (D49)

To a solution of D48 (2 g, 6.53 mmol) in CH₂CI₂(50 ml) DAST (2.1 1 g) was added. The reaction was stirred at 25°C for 1 hour. The mixture was poured into NaHCC>3 (sat., 100 m and extracted with CH2Cl2 (3x200 ml). The organic layer was concentrated and the crude material was purified by column chromatography over silica gel (PE:EtOAc=1:1) to to give the title compound as yellow oil (1 g, yield 50%).

Description D50

1 -(3-Fluorotetrahydro-2H-pyran-4-yl)-5-methyl-4-nitro-1H-pyrazol-3-ol (D50) Aan een oplossing van D49 (1 g, 3,25 mmol) in H₂0 (30 mL) KOH (910.5 mg, 16.23 mmol) was added. The reaction was stirred at 120°C for 10 hours. The mixture was washed with EtOAc (50 ml) and the aqueous phase was neutralized with 2N HCl to pH = 3-4. The mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were concentrated to afford the title compound as a yellow solid (400mg, yield 50%). LC-MS: 246.3 [M+H]⁺.

Description D51

ferf-Butyl (4-((1 -(3-fluortetrahydro-2H-pyran-4-yl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)butaan-2-yl)carbamaat (D51)

K was added to a solution of D50 (400 mg, 1.63 mmol) in DMF (10 ml)₂C0₃(689 mg, 4.9 mmol) and 3-((i.e., f-butoxycarbonyl)amino)butyl methane sulfonate (654 mg, 2.45 mmol). The reaction was stirred at 80°C for 2 hours. The mixture was poured into water (100 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude was purified by flash column chromatography on silica gel (PE:EtOAc = 1:1) to give the title compound as a yellow solid (400 mg, yield 65%). LC-MS: 439.2 [M+Na]⁺.

Description D52

4-((1 -(3-Fluorotetrahydro-2H-pyran-4-yl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)butaan-2-amine, TFA-zout (D52)

To a solution of D51 (400 mg) in CH2 Cl2 (20 ml) was added TFA (3 ml). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated to give the title compound as a yellow oil (250 mg, yield 83%). LC-MS: 317.3 [M+H]⁺.

Description D53

2,5-Dichloor-/V-(4-((1 -(3-fluortetrahydro-2H-pyran-4-yl)-5-methyl-4-nitro-1 H-pyrazol-3- yl)oxy)butaan -2-yl)pyrimidine-4-amine(D53)

To a solution of D52 (250 mg, 0.79 mmol) in /^'-PrOH (10 ml) Et was added₃N (240 mg, 2.4 mmol) and 2,4,5-trichloropyrimidine (145 mg, 0.79 mmol). The reaction was stirred at 30°C for 1 hour. The mixture was poured into water (50 ml) and extracted with EtOAc (100 ml). The organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated to give the title compound as a yellow solid (330 mg, yield 89%). LC-MS: 463.2 [M+H]⁺.

Description D54

ferf-Butyl (4-((5-methyl-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-3-yl)oxy)butan-2-yl)carbamaat ( D54)

A solution of D5 (600 mg, 2.64 mmol), 3-((i.e. f-butoxycarbonyl)amino)butylmethanesulfonate (847.5 mg, 3.17 mmol) and K₂C0₃(729.7mg, 5.28mmol) in DMF (50ml) was stirred at 100°C for 2 hours. The mixture was poured into ice water and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude product was purified by column chromatography on silica gel (PE:EtOAc = 3:1) to afford the title compound as an off-white solid (820 mg, yield 78%). LC-MS: 421 .3 [M+Na]⁺.

Description D55

4-((5-Methyl-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazool-3-yl)oxy)butaan-2-amine, TFA-zout (D55)

A solution of D54 (820 mg, 2.1 mmol) in CH₂CI₂(20 ml) TFA (5 ml) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to afford the title compound as an off-white solid (800mg, yield 98%). LC-MS: 299.4 [M+H]⁺. Description D56

5-broom-2-chloor-W-(4-((5-methyl-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-3-yl)oxy)butaan- 2-yl)pyrimidine-4-amine (D56)

To a solution of D55 (300 mg, 0.76 mmol), Et₃N (153,8 mg, 1,52 mmol) in/^'To -PrOH (30 mL) was added 5-bromo-2,4-dichloropyrimidine (346.4 mg, 1.52 mmol). The mixture was stirred overnight at room temperature. The mixture was filtered and the filter cake was dried to afford the title compound as an off-white solid (280 mg, yield 75%). LC-MS: 491.1 [M+H]⁺.

Description D57

Ethyl-3-(benzylamino)-2-methylbutanoaat (D57)

To a solution of ethyl 2-methyl-3-oxobutanoate (15.0 g, 104.04 mmol) in MeOH (200 ml) at 0°C was added BnNh (16.7 g, 156.07 mmol). The reaction was stirred at 0°C for 1 hour. Sodium cyanoborohydride (13.1 g, 208.08 mmol) was then added. The reaction was stirred overnight at room temperature. The mixture was concentrated and the crude material was purified by column chromatography on silica gel (PE:EtOAc = 3:1) to afford the title compound as a white solid (16.5 g, yield 67%).

Description D58

3-(Benzylamino)-2-methylbutaan-1-ol (D58)

To a solution of D57 (16.5 g, 70.12 mmol) in THF (200 mL) was added LiAlH₄(5.3 g, 140.23 mmol) at 0°C. The reaction was stirred at room temperature for 2 hours and H 2 O (11 ml) was added dropwise at 0°C. The mixture was dried over anhydrous Na 2 SO₄, filtered and concentrated to give the title compound as a clear oil (10.5 g, yield 77%). Description D59

ferf-Butyl (4-hydroxy-3-methylbutaan-2-yl)carbamaat (D59)

Pd(OH) was added to a solution of D58 (2.0 g, 10.35 mmol) in MeOH (30 mL).₂. The resulting mixture was stirred at 60°C under hydrogen for 16 hours. The reaction was cooled to 0°C, then Et₃N (3.0 mL, 20.70 mmol) and a solution of Boc₂0 (2.2 g, 10.35 mmol) in MeOH (2 ml) was added dropwise. The reaction was stirred at room temperature for 2 hours. The mixture was filtered and the filtrate was concentrated. The crude was purified by column chromatography on silica gel (PE:EtOAc = 2:1) to give the title compound as a white solid (1.5 g, yield 71%).

Description D60

3-((ferf-Butoxycarbonyl)amino)-2-methylbutylmethaansulfonaat (D60)

To a solution of D59 (1.5 g, 7.38 mmol) in CH₂CI₂(20 ml) became It₃N (2.3 g, 22.14 mmol) and MsCl (1.3 g, 1.1.07 mmol) at 0 °C. The reaction was stirred at 0°C for 0.5 hour. The mixture was poured into ice water (20 ml) and extracted with CH₂CI₂(2x20ml). The organic layer was washed with aq. NaHCO3 (2 x 30 mL), dried, filtered and concentrated to give the title compound as a white solid (2.3 g, crude).

Description D61

ferf-Butyl (3-methyl-4-((5-methyl-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-3-yl)oxy)butaan-2-yl )carbamaat (D61 )

A mixture of D60 (1.486 g, 5.28 mmol), D5 (400 mg, 1.76 mmol) and K₂C0₃(730mg, 5.28mmol) in DMF (20ml) was stirred at 80°C for 4 hours. The mixture was poured into ice water (60 ml) and extracted with EtOAc (2 x 30 ml). The combined organic layers were washed with brine (3 x 20 mL), dried and concentrated. The residue was purified by column chromatography over silica gel (PE:EtOAc = 1:1) to give the title compound as a yellow oil (240 mg, yield 33%).

Description D62

3-Methyl-4-((5-methyl-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazool-3-yl)oxy)butaan-2-amine, HCI-zout ( D62)

A mixture of D61 (240mg, 0.58mmol) in HCl/MeOH (3M in MeOH, 6ml) was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo to provide the title compound as a yellow solid (182 mg, crude).

Description D63

2,5-Dichloor-W-(3-methyl-4-((5-methyl-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol- 3-yl)oxy) butaan-2-yl)pyrimidine-4-amine (D63)

To a solution of D62 (182 mg, 0.58 mmol) in /^'-PrOH (15 ml) Et was added₃N (294 mg, 2.90 mmol) and 2,4,5-trichloropyrimidine (213 mg, 1.16 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water (30 ml) and extracted with EtOAc (2 x 30 ml). The organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EtOAc = 1:1) to afford the title compound as a yellow solid (220 mg, yield 82%).

Description D64

3-(Benzylamino)-4-methoxybutaan-1-ol (D64)

To a solution of methyl 3-(benzylamino)-4-methoxybutanoate (which can be prepared from WO2016014463A) (4.0 g, 16.9 mmol) in dry THF (60 ml) under argon at 0 °C was added LiAlhU ( 3.23 g, 85 ml) was added. mmol) portionwise. The reaction was stirred at 25°C for 2 hours. The reaction was quenched by the addition of water (12 ml, diluted with 80 ml of THF). The result was dried, filtered and concentrated. The crude was purified by column chromatography on silica gel (CH 2 Cl 2 :CH 3 OH = 50:1 to 10:1) to give the title compound as a yellow oil (2.0 g, yield 51%). LC-MS: 210.1 [M+H]⁺.

Description D65

3-Amino-4-Methoxybutan-1-ol, TFA Salt (D65)

A mixture of D64 (2.0 g, 9.56 mmol), Pd(OH)₂(1 g) en TFA (2 ml) in CH₃OH (200 ml) was stirred under hydrogen at 50°C for 16 hours. The mixture was filtered and concentrated to give the compound as a yellow oil (1.3 g, crude). LC-MS: 120.1 [M+H]⁺.

Description D66

3-((2,5-dichloorpyrimidine-4-yl)amino)-4-methoxybutaan-1-ol (D66)

To a solution of D65 (977 mg, 8.19 mmol) in /^'-PrOH (20 ml) at 0°C, DIPEA was added

(3.17 g, 24.6 mmol) and 2,4,5-trichloropyrimidine (1.66 g, 9.03 mmol) dropwise. The reaction was stirred at 25°C for 15 hours. The mixture was concentrated and the crude product was purified by flash column chromatography on silica gel (PE:EtOAc = 3:1) to afford the title compound as a white solid (880 mg, yield 40%). LC-MS: 266.0 [M+H]⁺.

Description D67 3-((2,5-dichloropyrimidin-4-yl)amino)-4-methoxybutylmethanesulfonate (D67)

To a solution of D66 (0.88 g, 3.31 mmol) in CH₂CI₂(20 ml) at 0°C Et₃N (1000 mg, 9.93 mmol) and MsCl (455 mg, 3.97 mmol). The reaction was stirred at 25°C for 1 hour. The mixture was poured into water and extracted with ChC. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated to give the title compound as a yellow oil (0.74 g, yield 65%). LC-MS: 344.0 [M+H]⁺.

Description D68

2,5-Dichloor-/V-(1 -methoxy-4-((5-methyl-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-3-yl)oxy )butaan-2-yl)pyrimidine-4-amine (D68)

A mixture of D67 (742 mg, 2.15 mmol), K₂C0₃(894mg, 6.48mmol) and D5 (440mg, 1.95mmol) in DMSO (20ml) was stirred at 75°C for 30 min. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude was purified by flash column chromatography on silica gel (PE:EtOAc = 4:1 to 1:1) to afford the title compound as an off-white solid (247 mg, yield 24%). LC-MS: 475.1 [M+H]⁺.

Description D69

3-Methyl-4-nitro-1 -(tetrahydro-2H-pyran-2-yl)-1H-pyrazool(D69)

To a solution of 3-methyl-4-nitro-1/-/-pyrazole (50 g, 393 mmol) in EtOAc (500 mL) was added DHP (49.6 g, 590 mmol) and pTsOH.H.₂0 (3.66 g, 20 mmol) at room temperature. The reaction was stirred overnight at room temperature. ΕίβΝ (6 ml) was added and the organics were washed with brine (2 x 300 ml). The organic layer was dried over Na 2 SO₄and concentrated in vacuo to give the title compound as a colorless oil, which was used in the next step without further purification (65 g, 78%). LC-MS: 233.9 [M+Na]⁺.

Description D70

5-Chloor-3-methyl-4-nitro-1 -(tetrahydro-2H-pyran-2-yl)-1H-pyrazool (D70)

To a solution of D69 (65 g, 308 mmol) in dry THF (500 ml) was added LiHMDS (370 ml, 1 M in THF) at -70°C under nitrogen. The reaction mixture was stirred at -70°C for 45 minutes and then a solution of C2 Cl6 (218 g, 924 mmol) in THF (400 mL) was added dropwise. The reaction was stirred at room temperature for 30 minutes. NH₄Cl solution (sat.) was added and the mixture was extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with brine (500 mL), dried over Na 2 SO₄and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE:EtOAc = 8:1 to 6:1) to afford the title compound as a yellow solid (69 g, yield 91%). LC-MS: 267.8 [M+Na]⁺.

Description D71

ieri-Butyl (4-((3-methyl-4-nitro-1 -(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)oxy)butaan-2-yl)carbamaat (D71 )

To a solution of e.g. f-butyl(4-hydroxybutan-2-yl)carbamate (1 g, 5.3 mmol) in DMF (20 ml) at 0°C was added NaH (0.53, 13.25 mmol) . After stirring for 1 hour, D70 (1.04 g, 4.2 mmol) was added. The reaction was stirred at 0°C for 6 hours and then diluted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO₄and concentrated. The crude product was purified by column chromatography on silica gel (PE:EtOAc = 20:1 to 10:1) to give the title compound (1.2 g, yield 70%).

Description D72

(4-((3-Methyl-4-nitro-1H-pyrazol-5-yl)oxy)butan-2-amine, HCl salt (D72)

To a solution of D71 (1.19 g) in CH₃OH (20 ml) became con. HCl (1.2 ml) at room temperature. The mixture was stirred at room temperature for 2 hours. The organic solvent was removed in vacuo to give the crude which was used in the next step without further purification (920 mg crude).

Description D73

2,5-dichloor-W-(4-((3-methyl-4-nitro-1 H^yrazol-5-yl)oxy)butaan-2-yl)pyrimidine-4-amine(D73)

To a solution of D72 (1.92 g, crude) in /^'-PrOH (50 ml) was added 2,4,5-trichloropyrimidine (1.97 g, 10.7 mmol) and ΕίβΝ (2.7 ml, 27 mmol) at room temperature. The reaction was stirred overnight at room temperature. The organic solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (PE:EtOAc = 1:1) to give the title compound (1.1 g).

Description D74

Ethyl 2-(3-(3-((2,5-dichloorpyrimidine-4-yl)amino)butoxy)-5-methyl-4-nitro-1 H-pyrazol-1 - yl)-2-methylpropanoaat (D74)

To a solution of ethyl 2-bromo-2-methylpropanoate (975 mg, 5 mmol) in DMF (60 ml) was added D73 (361 mg, 1 mmol) and K 2 CO 3 (690 mg, 5 mmol). Then the reaction was heated to 80°C and stirred overnight. The mixture was diluted with ice water and extracted with

EtOAc (2x100ml). The organic layer was washed with brine, dried and concentrated. The crude was purified by column chromatography on silica gel (PE:EA = 2:1) to give the title compound as a clear oil (980 mg, yield 68%). LC-MS: 475.2 [M+H]⁺. Description D75

3-(3-(3-((2,5-dichloorpyrimidine-4-yl)amino)propoxy)-5-methyl-4-nitro-1 H-pyrazol-1 - yl)cyclobutanon (D75)

To a solution of D33 (1.5 g, 4.32 mmol) in anhydrous DMF (20 mL) was added NaH (207 mg, 5.17 mmol) at 0°C under argon. The reaction was stirred at room temperature for 0.5 hour. 3-Bromocyclobutanone (1.3 g, 8.73 mmol) was added and the reaction mixture was stirred at room temperature for 2.5 hours. Water was added and the result was extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with water (4 x 30 mL) and brine (20 mL), dried over anhydrous Na 2 SO₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel (CH 2 Cl 2 :MeOH = 100:1) to give the title compound as a white solid (690 mg, yield 38%). LC-MS: 415.3 [M+H]⁺.

Description D76

2,5-dichloor-yV-(3-((5-methyl-1 -(3-morfolinocyclobutyl)-4-nitro-1H-pyrazol-3-yl)oxy)propyl)pyrimidine-4-amine (D76)

NaBI- CN added. (32 mg, 0.509 mmol) at 0°C under argon. The reaction was stirred overnight under argon at room temperature. The mixture was filtered and the filtrate was treated with aqueous NaHCC>3. After aqueous work-up and concentration, the residue was purified by prep-TLC to afford the title compound as a white solid (100 mg, yield 85%). LC-MS: 486.2 [M+H]⁺.

Description D77

ferf-Butyl ((2?)-4-((3-methyl-4-nitro-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazol-5-yl) oxy) butaan-2- yl)carbamaat (D77)

To a solution of NaH (96.8 g, 2.42 mol) in DMF (500 ml) was added (R)-ie/f-butyl (4-hydroxybutan-2-yl)carbamate (249.8 g, 1.32 mol)) added at 0 °C . The mixture was stirred at 0°C for 1 hour and D70 (260 g, 1.1 mol) was added and stirred at room temperature for 4 hours. The reaction mixture was poured into ice water and extracted with EtOAc (3x1 L). The combined organic layers were washed with brine, dried over Na 2 SO₄and concentrated. The residue was suspended in PE:EtOAc = 3:1 to give the title compound as a yellow solid (350 g, crude).

Description D78

(?)-4-((3-methyl-4-nitro-1H-pyrazol-5-yl)oxy)butan-2-amine, HCl salt (D78)

A solution of D77 (350 g crude, 0.88 mol) in 4 N HCl (1 L) was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo. The residue was suspended in EtOAc to give the target product as a yellow solid (250 g, 80% yield, two steps). LC-MS: 215.4 [M+H]

Description D79

(?)-2,5-dichloor-W-(4-((3-methyl-4-nitro-1 H-pyrazol-5-yl)oxy)butaan-2-yl)pyrimidine-4-amine (D79)

To a solution of D78 (250 g, 0.88 mol) and Et₃N (178.1 g, 1.76 mol) in MeOH (1 L) 2,4,5-trichloropyrimidine (194.4 g, 1.06 mol) was added. The mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo, poured into saturated NaCl (aq) and extracted with EtOAc (3 x 1 L). The combined organic layer was washed with brine, dried over Na 2 SO₄and concentrated in vacuo. The crude product was suspended in ChC/hexane = 1:1 (1 L) and filtered to give the title compound as a yellow solid (180 g, yield 55%). Description D80

2,5-dichloor-W-((?)-4-((5-methyl-4-nitro-1 -((S)-tetrahydrofuran-3-yl)-1 H^

yl)oxy)butaan-2-yl)pyrimidine-4-amine (D80)

A solution of D79 (200 mg, 0.56 mmol), (R)-tetrahydrofuran-3-yl methanesulfonate (458 mg, 2.78 mmol) and Cs₂C0₃(543mg, 1.7mmol) in DMA (15ml) was heated to 80°C and stirred for 16 hours. The cooled mixture was poured into water (60 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with water, brine, dried over anhydrous Na 2 SO₄and concentrated in vacuo. The crude product was purified columnwise

chromatography on silica gel (PE:EtOAc = 5:1 to 2:1) to give the title compound as a yellow oil (150 mg, yield 62.2%). LC-MS: 431 .2 [M+H]⁺.

Description D81

2,5-dichloor-W-((/?)-4-((5-methyl-4-nit^

yl)oxy)butaan-2-yl)pyrimidine-4-amine (D81 )

A solution of D79 (200 mg, 0.56 mmol), (S)-tetrahydrofuran-3-yl methanesulfonate (276 mg, 1.67 mmol) and Cs₂C0₃(543mg, 1.7mmol) in DMA (10ml) was heated to 80°C and stirred for 16 hours. The cooled mixture was poured into water (60 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with water, brine, dried over anhydrous Na 2 SO₄and concentrated in vacuo. The crude product was purified columnwise

chromatography on silica gel (PE:EtOAc = 5:1 to 2:1) to give the title compound as a yellow oil (130 mg, yield 54%). LC-MS: 431.2 [M+H]⁺.

Description D82

1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate (D82) To a solution of 1,4-dioxaspiro[4.5]decan-8-ol (12 g, 76 mmol), TEA (11.5 g, 114 mmol) in DCM (1.10 ml) at 0-5°C was added dropwise MsCl (1.3 g, 98.7 mmol). Then the solution was stirred at room temperature for 1 hour. Water (50 ml) was added, the combined organic layer was washed with saturated. NaHCC>3, brine, dried over Na2 SO₄and concentrated to give the title compound as a slightly yellow solid (18.5 g, yield 100%).

Description D83

2,5-Dichloor-yV-(3-((5-methyl-4-nitro-1 -(1,4-dioxaspiro[4.5]decaan-8-yl)-1 H-pyrazol-3-yl)oxy) propyl)pyrimidine-4-amine (D83)

A mixture of D33 (1.5 g, 4.32 mmol), D82 (2.05 g, 8.68 mmol) and K₂C0₃(1.79g, 12.95mmol) in DMSO (20ml) was stirred at 100°C for 16 hours. Water (30 ml) was added and the result was extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EtOAc = 10:1 to 3:1) to afford the title compound as a white solid (1.4 g, yield 67%). LC-MS: 487.1 [M+H]⁺.

Description D84

14-Chloro-5-{1,4-dioxaspiro[4.5]decan-8-yl}-4-methyl-8-oxa-2,5,6,12,16,17-hexaaza tricyclo[11.3.1.0³'⁷]heptadeca-1(16),3,6,13(17),14-pentaeen (D84)

A mixture of D83 (1.4 g, 2.87 mmol), Fe (805 mg, 14.4 mmol), and NH₄Cl (1.53g, 28.6mmol) in EtOH (50ml) and H2O (10ml) was stirred at 100°C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was redissolved in CH2Cl2 (100 ml) and then dried over anhydrous Na2SO₄filtered and concentrated to give the title compound as a white solid (500mg, yield 42%). LC-MS: 421.3 [M+H]⁺.

Description D85 4-{14-Chloro-4-methyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca- 1(16),3,6,13(17),14-pentaen-5-yl}cyclohexane-1-one (D85) .

To a solution of D84 (750 mg, 1.78 mmol) in CH₂CI₂(20 mL) TFA (678 mg, 5.95 mmol) was added. The reaction was stirred at 80°C for 5 hours. The mixture was concentrated and the residue redissolved in CH2 Cl2 (100 ml). aq. NaHCC>3 was added to pH = 8 and the mixture was extracted with CH2CI2 (3x50 ml). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO₄and concentrated to give the title compound as a white solid (600 mg, yield 90%). LC-MS: 377.3 [M+H]⁺.

Description D86

Ethyl-4-fluor-3-oxobutanoaat (D86)

To a solution of EtOAc (2.74 g, 31.1 mmol) in dry THF (30 mL) under argon at -78 °C was added LDA (17 mL, 34 mmol) dropwise. The reaction was stirred at -78°C for 1 hour. Ethyl 2-fluoroacetate (3.0 g, 28.3 mmol) was added dropwise at -78°C and the mixture was allowed to warm to room temperature and stirred under argon overnight. The mixture was quenched with aq. HCl (1 M) and extracted with Et.20. The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EtOAc = 10:1-5:1) to afford the title compound as a yellow oil (4.2 g, quantitative).¹H-NMR (400 MHz, CDCI₃): δ 4.91 (d, J = 47.6 Hz, 2H), 4.23 (q, J = 7.2 Hz, 2H), 3.60 (d, J = 3.6 Hz, 2H) , 1.29 (t, J=7.2Hz, 3H).

Description D87

Ethyl 4-fluor-3-((4-methoxybenzyl)amino)butanoaat(D87)

To a solution of D86 (1.0 g, 6.76 mmol) and HOAc (609 mg, 10.14 mmol) in EtOH (10 mL) at 0°C was added (4-methoxyphenyl)methanamine (1.39 g, 10.1 mmol) was added. drop by drop. The mixture was stirred at room temperature for 2.5 hours. After cooling to 0°C, HOAc (1.42 g, 23.65 mmol) and NaBH were added to the mixture.₃CN (1.34g, 20.3mmol). The reaction was stirred at room temperature for an additional 3 hours. The reaction was quenched with Na 2 CO 3 and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over Na 2 SO₄, filtered and concentrated. The crude was purified by chromatography on silica gel (CH 2 Cl 2 :CH 3 OH = 200:1 to 80:1) to give the title compound as a yellow oil (1.4 g, yield 77%).¹H NMR (400 MHz, CDCI's): δ 7,24 (d, J = 8,4 Hz, 2H), 6,86 (d, J = 8,8 Hz, 2H), 4,53-4,48 (m, 1 H), 4,42-4,35 (m, 1H), 4,14 (q, J = 7,1 Hz, 2H), 3,79 (s, 3H), 3,78 (s, 2H), 3,33-3,24 (m, 1H), 2,54-2,52 (m, 2H), 1,26 (t, J = 7,0 Hz, 3H).

Description D88

4-Fluor-3-((4-methoxybenzyl)amino)butaan-1 -ol (D88)

Until a suspension of LiAIH₄(1.18 mg, 3.11 mmol) in dry THF (5 ml) under argon at -60°C was added dropwise a solution of D87 (0.70 g, 2.60 mmol) in dry THF (5 ml) . The reaction was stirred at -60°C for 3 hours. The mixture was slowly quenched with water/THF (0.5ml/5ml) at -60°C. After stirring for 30 minutes, the mixture was filtered through Celite. The filtrate was concentrated to give the title compound as a yellow oil (410 mg, yield 69%).¹H NMR (400 MHz, CDCI's): δ 7,24 (d, J = 8,4 Hz, 2H), 6,87 (d, J = 8,4 Hz, 2H), 4,63-4,49 (m, 1 H), 4,46-4,32 (m, 1H), 3,88-3,73 (m, 7H), 3,13-3,01 (m, 1H), 1,76-1,69 (m, 2H).

Description D89

3-Amino-4-fluorobutaan-1-ol (D89)

To a solution of D88 (2.0 g, 8.80 mmol) and HOAc (1 ml) in MeOH (50 ml) was added Pd(OH) 2 /C (300 mg). The reaction was stirred under hydrogen at 35°C for 48 hours. The mixture was filtered through Celite and the filtrate was concentrated to give the title compound as a yellow oil (1.0 g, crude).

Description D90 3-((2,5-dichloropyrimidin-4-yl)amino)-4-fluorobutan-1-ol (D90)

To a solution of D89 (650 mg, approx. 6.07 mmol) in /^'-PrOH (10 ml) Et was added₃N (1.84 g, 18.2 mmol) and 2,4,5-trichloropyrimidine (1.23 g, 6.68 mmol) at 0 °C. 0°C. The reaction was quenched with aq. NH 4 Cl (18 ml) and extracted with EtOAc (2x18 ml). The organic layer was washed with brine (20 mL), dried over Na 2 SC>4, filtered and concentrated. The crude was purified by chromatography on silica gel (PE:EtOAc=10:1 -3:1) to afford the title compound as a white solid (650 mg, yield 42%). LC-MS: 254.0 [M+H]⁺.

Description D91

2,5-Dichloor-/V-(1 -fluor-4-((5-methyl-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-3-yl)oxy )butaan-2-yl)pyrimidine-4-amine (D91 )

To a solution of D90 (300 mg, 1.18 mmol), D5 (282 mg, 1.24 mmol) and PPh₃(619 mg, 2.36 mmol) in dry THF (12 mL) under argon at 0 °C was added dropwise DEAD (41.1 mg, 2.36 mmol). The reaction was stirred overnight under argon at 26°C. The reaction was diluted with aq. HCl (0.5 M, 30 ml) and extracted with EtOAc (2x20 ml). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO₄, filtered and concentrated. The residue was suspended in methanol (12 ml), stirred at room temperature for 30 min, filtered and the filter cake collected, dried to give the title compound as a white solid (480 mg, yield 87.8%).¹H NMR (400 MHz, CDCI3): δ 8,03 (s, 1 H), 5,85 (d, J = 8,0 Hz, 1 H), 4,76-4,69 (m, 2H), 4,60 (dd, J = 15,6, 3,6 Hz , 1H), 4,46 (t, J = 5,6 Hz, 2H), 4,21 -4,17 (m, 1H), 4,13-4,09 (m, 2H), 3,50 (t, J = 12,0 Hz, 2H), 2,63 ( s, 3H), 2,32-2,18 (m, 4H), 1,75-1 0,70 (m, 2H).

Description D92

2,5-dichloor-W-(4-((5-methyl-4-nitro-1 -(1,4-dioxaspiro[4.5]decaan-8-yl)-1 H-pyrazol-3-yl)oxy) butaan-2-yl)pyrimidine-4-amine (D92)

A solution of D73 (4.5 g, 12.5 mmol), D82 (14.7 g, 62.5 mmol), Nal (1.8 g, 12.0 mmol), and K2CO3 (5.2 g, 37 .5 mmol) in DMA (50 ml - ) was heated to 80 °C and stirred for 16 hours. The mixture was poured into water (200 ml) and extracted with EtOAc (3 x 150 ml). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated in vacuo. The crude was purified by flash column chromatography on silica gel (PE:EtOAc = 5:1 to 2:1) to give the title compound as a little yellow oil (2.5 g, yield 40%). LC-MS: 501.1 [M+H]⁺.

Description D93

14-chloro-5-{1,4-dioxaspiro[4.5]decan-8-yl}-4 1-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen (D93)

A solution of D92 (2.6 g, 5.2 mmol), Fe (2.6 g, 46.4 mmol), and NH₄Cl (5,2 g, 97,2 mmol) in EtOH en H₂0 (50 ml, 3:1) was heated to 90°C for 16 hours. Sat. NaHCO's (5 ml) was added and the mixture was stirred for 10 min, filtered, washed with DCM and concentrated. DCM (25ml) was added and the mixture was stirred for 30min, filtered and concentrated to give the title compound as a yellow solid (2.0g, yield 89%). LC-MS: 435.3 [M+H]⁺.

Description D94

4-{14-chloor-4,11-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1. 0^{3 7}] heptadeca-1(16),3,6,13(17),14-pentaen-5-yl}cyclohexane-1-one (D94) .

To a solution of D93 (2.5 g, 5.76 mmol) in DCM (50 ml) was added TFA (10 ml) and the reaction mixture was stirred at 60°C for 5 hours. The mixture was then cooled to room temperature and water (100 ml) was added. Sat. NaHCO3 was added to pH>7 and the organic layer was washed with brine, dried over Na₂S0₄, filtered and concentrated. The crude was purified by column chromatography on silica gel (PE:EA = 5:1 -1:1) to give the title compound (1.3 g, yield 58%). LC-MS: 391.2 [M+H]⁺.

Description D95

Trans-tert-butyl\ 4-(3-(3-((2,5-dichloorpyrimidine-4-yl)amino)propoxy)-5-methyl-4-nitro-1 H-pyrazol-1 -yl)-3 -fluoropiperidine-1 -carboxylaat(D95)

To a solution of c/s-ie f-butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (858 mg, 2.88 mmol) in DMSO (6.0 mL) was added D33 (500 mg, 1.44 mmol) and K₂C0₃(598mg, 4.33mmol). The reaction was stirred at 85°C for 5 days. The mixture was diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried, filtered and concentrated. The crude was purified by column chromatography over silica gel (PE:EtOAc=1:1, followed by CH₂CI₂: MeOH = 20:1) to give the title compound as a yellow solid (385 mg, yield 48%). LC-MS: 548.3 [M+H]⁺.

Description D96

Trans-ieri-butyl 4-{14-chloor-4-methyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo [11.3.1. 0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen-5-yl}-3-fluorpiperidine-1-carboxylaat (D96)

To a mixture of D95 (385 mg, 0.702 mmol) and Fe (391 mg, 7.00 mmol) in EtOH/H₂0 (10.0ml/2.0ml) NH was added₄CI (374mg, 7.00mmol). The reaction was stirred overnight at 100°C. The mixture was diluted with aq. NaHCO's and filtered. The filtrate was extracted 3 times with EtOAc. The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography over silica gel (CH₂CI₂: MeOH = 10:1) to give the title compound as yellow oil (125 mg, yield 36%). LC-MS: 482.4 [M+H]⁺.

Description D97

rrans-14-chloor-5-(3-fluorpiperidine-4-yl)-4-methyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo [11.3.1.0^{3 7}]heptadeca-1(16),3,6,13(17),14-pentaene, TFA salt (D97)

To a solution of D96 (730 mg, ca. 1.51 mmol) in CH₂CI₂(20 ml) TFA (10 ml) was added. The reaction was stirred at room temperature for 0.5 hour. The mixture was concentrated to give the title compound as a brown oil (1.197 g, crude). LC-MS: 382.3 [M+H]⁺.

Description D98

(/?)-ferf-Butyl 4-(3-(3-((2,5-dichloorpyrimidine-4-yl)amino)butoxy)-5-methyl-4-nitro-1 H-pyrazol-1 -yl) piperidine-1-carboxylaat(D98)

A solution of D79 (1.0 g, 2.78 mmol) i.e. f-butyl 4-bromopiperidine-1-carboxylate (2.2 g, 62.5 mmol) and Cs₂C0₃(2.7 g, 8.33 mmol) in DMA (50 mL) was heated to 80°C and stirred for 8 hours. The reaction mixture was poured into water (250 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layer was washed with brine, dried over anhydrous Na₂S0₄and concentrated in vacuo. The crude product was purified by flash column chromatography (PE:EtOAc = 5:1 to 3:1) to afford the product as a white solid. (700mg yield 46%). LC-MS: 544.3 [M+H]⁺.

Description D99

ferf-Butyl 4-[(11?)-14-chloor-4,11-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo [11. 3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen-5-yl]piperidine-1-carboxylaat (D99)

A solution of D98 (700 mg, 1.29 mmol), Fe (700 mg, 12.5 mmol) and NH₄Cl (1,4 g, 26,1 mmol) in EtOH en H₂0 (30 ml, 3:1) was heated to 90°C for 16 hours. Water (5 ml) and NaHCC>3 (200 mg) were added and the mixture was stirred for 10 min, filtered, washed with DCM and concentrated. The residue was redissolved in DCM (50ml) and the mixture was stirred for 10min, filtered and concentrated to give the title compound as a yellow solid (600mg, yield 97%). LC-MS: 478.3 [M+H]⁺.

Description D100

(11 /?)-14-Chloro-4 1 -dimethyl-5-(pipe^^

[11.3.1.0^{3 7}]heptadeca-1 (16),3,6, 13(17),14-pentaene, HCl salt (D100)

A solution of D99 (600mg, 1.1mmol) in EtOH/HCl (25ml) was stirred at room temperature for 16 hours. The mixture was concentrated to give the title compound as a yellow solid (500mg, yield 94%). LC-MS: 378.3. [M+H]⁺.

Description D102

Methyl-3-(dibenzylamino)-2-fluorbutanoaat (D102)

To a solution of methyl 3-(dibenzylamino)-2-hydroxybutanoate (16.7 g, 53.29 mmol) in THF (220 ml) at room temperature was added dropwise the solution of DAST (12.0 g, 74.60 mmol ) in THF (20 ml) was added. . The reaction was stirred overnight at room temperature. The mixture was poured into saturated NaHCO5 (200 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with water (80 mL), brine (50 mL), dried over Na 2 SO₄and concentrated. The crude was purified by column chromatography on silica gel (PE:EtOAc = 80:1) to give the title compound as a yellow solid (9.9 g, yield 59%).¹H NMR (400 MHz, CDCI's): 8 7,26-7,05 (m, 10H), 4,77 (dd, J = 49,1 , 3,7 Hz, 1 H), 3,83 (d, J = 13,4 Hz, 2H), 3,56 (s, 3H), 3,31 -3,23 (m, 2H), 3,18 (ddd, J = 14,0, 7,0, 3,9 Hz, 1 H), 1,20 (d, J = 7,0 Hz, 3H).

Description D103

3-(Dibenzylamino)-2-fluorbutaan-1-ol (D103)

Until a suspension of LiBH₄(2.1 g, 94.2 mmol) in THF (1.10 ml) at -10°C was added dropwise the solution of D102 (9.9 g, 31.4 mmol) in THF (20 ml). The reaction was warmed to room temperature and stirred overnight. The mixture was poured into saturated NH 4 Cl (200 ml) and extracted with EA (3 x 100 ml). The combined organic layers were washed with water (100 ml), brine (50 ml), dried over Na 2 SO₄, and concentrated. The crude was purified by column chromatography (PE:EtOAc = 10:1) to give the title compound as a colorless oil (8.0 g, yield 89%).¹H NMR (400 MHz, CDCI3): 8 7,41 -7,07 (m, 10H), 4,41 -4,20 (m, 1H), 3,91 (d, J = 13,3 Hz, 2H), 3,82-3,51 (m, 3H), 3,29 (d, J = 13,3 Hz, 2H), 2,93 (dqd, J = 30,3, 7,0, 3,8 Hz, 1 H), 1,17 (d, J = 8,9 Hz, 3H).

Description D104

3-Amino-2-fluorobutan-1-ol (D104).

To a solution of D103 (1.5 g, 5.22 mmol) in MeOH (180 mL) was added Pd/C (10%, 0.3 g). The mixture was stirred overnight at 45°C under 1 atm of hydrogen. The mixture was filtered and the filtrate was concentrated to give the title compound as a colorless oil (0.425 g, yield 76%).¹H NMR (400 MHz, CDCI3): 8 4,44-4,19 (m, 1 H), 4,02-3,65 (m, 2H), 3,35-3,12 (m, 1 H), 2,21 (m, 3H), 1,28-1,14 ( d, J = 6,4 Hz, 3H).

Description D105

3-((2,5-dichloorpyrimidine-4-yl)amino)-2-fluorbutaan-1 -ol(D105)

To a solution of D104 (425 mg, 3.96 mmol) in /^'To -PrOH (10 mL) was added 2,4,5-trichloropyrimidine (728 mg, 3.96 mmol). The mixture was cooled to 0°C and DIPEA (2.3 mL, 14.28 mmol) was added. The reaction was stirred at 0°C for 5 min, then warmed to room temperature and stirred overnight. The mixture was diluted with DCM (30 ml) and washed with water (30 ml). The aqueous layer was further extracted with DCM (2 x 30 ml). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO₄, concentrated. The crude was purified by column chromatography on silica gel (PE:EtOAc=4:1) to give the title compound as a white solid (800 mg, yield 80%).¹H NMR (400 MHz, CDCI's): 8 8,02 (s, 1 H), 5,41 (m, 1 H), 4,66-4,26 (m, 2H), 3,76-3,62 (m, 1 H), 3,47 (m, 1 H), 3,06-3,02 (m, 1 H), 1,36 (d, J = 6,8 Hz, 3H).

Description D106

2,5-dichloor-N-(3-fluor-4-((5-methyl^

yl)oxy)butaan-2-yl)pyrimidine-4-amine(D106)

To a solution of D105 (290 mg, 1.14 mmol) in THF (20 mL), D5 (259 mg, 1.14 mmol) and Ph were added.₃P (598mg, 2.28mol). After cooling to 0°C, DEAD (397 mg, 2.28 mmol) at 0°C was added dropwise. The reaction was stirred at 0°C for 1 hour, then warmed to room temperature and stirred for 2 hours. The mixture was diluted with EA (30 ml) and washed with water (30 ml). The aqueous layer was further extracted with EA (2 x 20 ml). The combined organic layers were washed with water (30 ml), brine (30 ml), dried over Na 2 SO₄, and concentrated. The crude product was purified by column chromatography over silica gel (DCM:

MeOH = 4:1) and then pre-TLC (PE:EtOAc = 1:2) to give the title compound as a white solid (170 mg, yield 32%). LC-MS: 463.1 [M+H]⁺.

Description D107

5-broom-2-chloor-W-(3-((5-methyl-4-nitro-1 H-pyrazol-3-yl)oxy)propyl)pyrimidine-4-amine (D107)

To a solution of D32 (500 mg, 2.11 mmol) in /^'-PrOH (15 mL) DIPEA (1.4 mL, 8.451 mmol) was added. After stirring for 10 minutes under argon at 0°C and 5-bromo-2,4-dichloropyrimidine (0.27 mL, 2.324 mmol) was added via syringe. The reaction was gradually warmed to room temperature and stirred overnight under argon. The mixture was concentrated and the residue was suspended in i-PrOH (1ml) and water (5ml) and stirred at room temperature for 0.5h, filtered, dried and concentrated to afford the title compound as an off-white solid ( 780ml). g, yield 94%). LC-MS: 393.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): δ 12,93 (br, 1 H), 8,22 (s, 1 H), 7,80 (t, J= 5,2 Hz, 1 H), 4,28 (t, J= 6,0 Hz, 2H), 3,53 (q, J= 6,5 Hz, 2H), 2,47 (s, 3H), 2,07-2,01 (m, 2H).

Description D108

5-Broom-2-chloor-yV-(3-((5-methyl-4-nitro-1 -(oxetan-3-yl)-1 H-pyrazol-3-yl)oxy)propyl)pyrimidine-4- amine (D108)

To a solution of 3-bromooxetane (1.245 g, 9.09 mmol) in DMSO (15.0 mL) was added D107 (890 mg, 2.27 mmol) and K2 CO3 (942 mg, 6.82 mmol). The reaction was stirred overnight at 100°C. The cooled mixture was diluted with water (150 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO₄and filtered. The filtrate was concentrated and the crude product was purified columnwise

chromatography on silica gel (PE:EtOAc=4:1) to afford the title compound as a yellow solid (537 mg, yield 52%). LC-MS: 449.1 [M+H]⁺.

Description D109

(?)-2,5-dichloor-yV-(4-((5-methyl-4-nitro-1 -(oxetan-3-yl)-1 H-pyrazol-3-yl)oxy)butaan-2- yl)pyrimidine-4-amine (D109)

A solution of D79 (10.0 g, 27.66 mmol), 3-bromooxetane (13.7 g, 99.67 mmol) and K2 CO3 (1.5 g, 82.98 mmol) in DMSO (100 mL) was heated to 80°C and stirred for 16 hours. The mixture was poured into ice water (300 ml) and extracted with EtOAc (5 x 200 ml). The organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude was purified by chromatography on silica gel (PE:EtOAc = 1:3) to give the title compound (6.5 g, crude). LC-MS: 417.2 [M+H]⁺. Description D110

ferf-Butyl 3-(3-((?)-3-((2,5-dichloorpyrimidine-4-yl)amino)butoxy)-5-methyl-4-nitro-1 ^ pyrazol-1 -yl)piperidine- 1 -carboxylaat (D110)

A solution of D79 (1.0 g, 2.78 mmol), ie f-butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate (2.3 g, 8.33 mmol) and Cs₂C0₃(2.7 g, 8.33 mmol) in DMA (25 mL) was heated to 80°C and stirred for 48 hours. The mixture was poured into water (150 ml) and extracted with EtOAc (3 x 150 ml). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude was purified by flash column

chromatography on silica gel (PE:EtOAc = 5:1 to 3:1) to afford the title compound as a white solid (1.6 g, yield 100%). LC-MS: 544.2 [M+H]⁺.

Description D111

ferf-Butyl 3-[(11?)-14-chloor-4,11-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo-[11. 3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen-5-yl]piperidine-1-carboxylaat (D111)

A solution of D110 (1.6 g, 2.95 mmol), Fe (1.6 mg, 28.5 mmol) and NH₄Cl (3,2 g, 59,8 mmol) in EtOH en H₂0 (50 ml, 3:1) was heated to 90°C for 16 hours. water (5 ml) and saturated NaHCO's (500 mg) were added and the mixture was stirred for 10 min, filtered, washed with DCM and concentrated. The residue was redissolved in DCM (50ml) and the mixture was stirred for 30min, filtered and concentrated to give the title compound as a slightly yellow solid (1.3g, yield 92%). LC-MS: 478.3 [M+H]⁺.

Description D112

(11 ?)-14-chloor-4,11 -dimethyl -5-(piperidine-3-yl)-8-oxa-2,5,6,12,16,17-hexaaza tricyclo[11.3.1.0^{3 7}]heptadeca-1(16),3,6,13(17),14-pentaene, HCl salt (D112)

A solution of D111 (1.3 g, 3.45 mmol) in EtOH/HCl (100 mL) was stirred at room temperature for 5 hours. The mixture was concentrated to give the title compound as a yellow solid (800mg, yield 80%). LC-MS: 378.3 [M+H]⁺.

Description D113

2-chloor-4-((3-((5-methyl-4-nitro^

propyl)amino)pyrimidine-5-carbonitril(D113)

To a solution of D7 (100 mg, 0.35 mmol) in /^'-PrOH (10 ml) Et was added₃N (106.77 mg) and 2,4-dichloropyrimidine-5-carbonitrile (61.2 mg, 0.35 mmol). The reaction was stirred at 30°C for 1 hour. The mixture was poured into water (50ml) and extracted with CH2 Cl2 (3x50ml). The organic layer was dried over anhydrous Na 2 SO₄and concentrated to give the title compound as a colorless oil (100 mg, yield 66%). LC-MS: 422.2 [M+H]⁺.

Description D114

ferf-Butyl (3-((1 -(3-fluortetrahydro-2H-pyran-4-yl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)-2-methoxypropyl)carbamaat ( D114)

K was added to a solution of D50 (350 mg, 1.43 mmol) in DMF (10 ml)₂C0₃(591 mg, 4.28 mmol) and D13 (606 mg, 2.14 mmol). The reaction was stirred at 80°C for 5 hours. The mixture was poured into water (50 ml) and extracted with EtOAc (3 x 50 ml). The organic layers were concentrated and the crude product was purified by column chromatography on silica gel (PE:EtOAc = 1:1) to afford the title compound as a yellow solid (300 mg, yield 50%). LC-MS: 465.3 [M+Na]⁺. Description D115

3-((1 -(3-fluorotetrahydro-2H^yran-4-yl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)-2-methoxypropaan-1-amine, TFA-zout (D115)

To a solution of D114 (300 mg) in CH2 Cl2 (15 ml) was added TFA (5 ml). The reaction was stirred at 25°C for 0.5 hour. The mixture was concentrated to give the title compound as a yellow oil (200 mg, yield 87%). LC-MS: 333.3 [M+H]⁺.

Description D116

2,5-Dichloor-/V-(3-((1 -(3-fluortetrahydro-2H-pyran-4-yl)-5-methyl-4-nitro-1 H-pyrazol-3- yl)oxy)- 2-methoxypropyl)pyrimidine-4-amine (D116)

To a solution of D115 (200 mg, 0.6 mmol) in /^'-PrOH (10 ml) Et was added₃N (182.69 mg) and 2,4,5-trichloropyrimidine (111 mg, 0.6 mmol). The reaction was stirred at 30°C for 1 hour. The reaction was concentrated and the crude product was purified by pre-TLC to afford the title compound as a yellow solid (250mg, yield 86%) LC-MS: 479.2 [M+H]⁺.

Description D117

2,5-Dichloor-/V-(4-((5-methyl-1 -(2-methyltetrahydro-2H-pyran-4-yl)-4-nitro-1 H-pyrazol-3-yl)oxy)butaan -2-yl)pyrimidine-4-amine (D117)

To a solution of 2-methyltetrahydro-2H-pyran-4-ylmethanesulfonate (582 mg, 3 mmol) in DMSO (20 mL) was added K 2 CO 3 (414 mg, 3 mmol) and D73 (361 mg, 1 mmol). The reaction was stirred overnight at 80°C. The mixture was poured into water (100 ml) and extracted with EtOAc (2 x 80 ml). The organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated in vacuo. The product was purified by flash column chromatography on silica gel (PE:EtOAc = 4:1) to afford the title compound as a yellow solid (160 mg, yield 34%). LC-MS: 459.2 [M+H]⁺.

Description D118

3-(3-(3-((2,5-dichloorpyrimidine-4-yl)amino)propoxy)-5-methyl-4-nitro-1 H-pyrazol-1 - yl)dihydro-2H-pyran-4( 3H)-een (D118)

K was added to a solution of D33 (1.0 g, 2.88 mmol) in DMF (10 ml)₂C0₃(636 mg, 4.60 mmol) and 3-bromodihydro-2/-/-pyran-4(3/-/)-one (825 mg, 4.61 mmol). The reaction was stirred at 25°C for 16 hours. The mixture was added to aq. NH₄Cl (40 ml) and extracted with EtOAc (2x40 ml). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated in vacuo. The crude was purified by flash column chromatography on silica gel (PE:EtOAc = 10:1 to 3:1) to afford the title compound as a yellow solid (1.0 g, yield 78%). LC-MS: 445.2 [M+H]⁺.

Description D119

3-(3-(3-((2,5-dichloorpyrimidine-4-yl)amino)propoxy)-5-methyl-4-nitro-1H-pyrazol-1 - yl)tetrahydro-2H-pyran-4- oud (D119)

To a solution of D118 (1.0 g, 2.25 mmol) in MeOH (15 mL) at 0 °C was added NaBH₄(170 mg, 4.49 mmol) slowly at 0°C. The reaction was stirred at 25°C for 2 hours. The mixture was added to aq. HCl (0.5 M, 20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude was purified by column chromatography on silica gel (PE:EtOAc = 10:1 to 2:1) to give the title compound as a yellow oil (700 mg, yield 69.9%). LC-MS: 447.1 [M+H]⁺.

Beschrijving D120 2,5-dichloor-W-(3-((1 -(4-fluortetrahydro-2H^yran-3-yl)-5-methyl-4-nitro-1 H-pyrazol-3-yl)oxy) propyl)pyrimidine-4-amine (D120)

To a solution of D119 (700 mg, 1.565 mmol) in CH₂CI₂(14 mL) at 0°C was slowly added DAST (1.0 g, 6.26 mmol). The reaction was stirred overnight at 25°C. The mixture was added to aq. Na2 CC>3 (15 ml) and extracted with CH2 Cl2 (2x20 ml). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude was purified by column chromatography on silica gel (PE:EtOAc = 10:1 to 4:1) to give the target product as a yellow oil (230 mg, yield 32.7%). LC-MS: 449.1 [M+H]⁺.

Description D121

Ethyl-4,4-difluor-3-oxobutanoaat (D121)

To a suspension of sodium hydride (60%, 1440 mg, 36.0 mmol) in THF (30 mL) was added ethyl acetate (2.94 mL, 30.0 mmol), followed by the addition of ethyl 2,2-difluoroacetate (3.60ml, 36.0mmol). The reaction was stirred overnight at 40°C. The mixture was then cooled to 0°C and quenched with HCl (2N) solution to pH = 6-7. The mixture was stirred at room temperature for 20 min, diluted with EtOAc (40 mL), washed with aqueous NaHCO3 (2 x 40 mL) and brine (2 x 40 mL). The organic layer was dried over anhydrous Na 2 SO₄and concentrated to give the crude oil as a yellow oil, which was used in the next step without further purification.

Description D122

Ethyl 3-(benzylimino)-4,4-difluorbutanoaat (D122)

To a solution of phenylmethanamine (3.45 mL, 31.6 mmol) in EtOH (40 mL) was added

D121 (3,500 g, 21.07 mmol) and acetic acid (1.809 mL, 31.6 mmol). The reaction was stirred at room temperature for 1 hour. The mixture was then diluted with EtOAc (100 ml), washed with aq. NaHCC>3 (2x80 ml) and brine (2x80 ml). The organic layer was dried over anhydrous Na 2 SO₄and concentrated. The crude was purified by column chromatography on silica gel (PE:EtOAc = 1:0 to 5:1) to give the title compound as a yellow oil (2860 mg, yield 53.2%).¹H NMR (600 MHz, CDC): 8 7,32-7,18 (m, 5H), 5,94 (t, J= 53,4 Hz, 1 H), 4,45 (d, J= 6,6 Hz, 2H), 4,13 (d, J= 5,4 Hz, 2H), 4,06 (q, J= 7,2, 2H), 1,19 (t, J= 7,2 Hz, 3H).

Description D123

3-(Benzylamino)-4,4-difluorbutaan-1-ol (D123)

To a mush of LiAIH₄(5.88ml, 11.75mmol, 2M in THF), D122 (1.0g, 3.92mmol) in THF (2ml) was added dropwise at 0°C. The reaction was stirred at room temperature for 3 hours then quenched with brine (2 ml). The mixture was filtered and the filtrate was diluted with EtOAc (50 mL), washed with brine (20 mL). The organic layer was dried over anhydrous Na 2 SO₄, filtered and concentrated. The crude was purified by C18 chromatography (5-95% CH3CN in water) to give the title compound as a colorless oil (370mg, yield 43.9%).¹H NMR (600 MHz, CDCI3): 8 7,38-7,29 (m, 5H), 5,84 (td, J = 56,1 , 3,0 Hz, 1 H), 3,98 (dd, J = 84,7, 12,8 Hz, 2H), 3,83 ( m, 2H), 3,13 (m, 1H), 3,00 (br, 1H), 1,76 (m, 2H).

Description D124

3-Amino-4,4-difluorobutan-1-ol (D124)

To a solution of D123 (508 mg, 2.360 mmol) in methanol (5 ml) was added Pd/C (126 mg, 0.1-18 mmol). The reaction was stirred overnight at room temperature under hydrogen. The mixture was filtered and the filtrate was concentrated to give the title compound as a colorless oil, which was used in the next step without purification.

Description D125

3-((2,5-dichloorpyrimidine-4-yl)amino)-4,4-difluorbutaan-1-ol (D125)

To a solution of D124 (296 mg, 2.366 mmol) in DMF (6 mL) was added 2,4,5-trichloropyrimidine (0.325 mL, 2.84 mmol) and DIPEA (0.618 mL, 3.55 mmol). The reaction was stirred overnight at room temperature. The mixture was diluted with EtOAc (50 mL), washed with water (3 x 30 mL) and brine (30 mL). The organic layer was dried over anhydrous Na 2 SO₄and concentrated. The crude product was purified by column chromatography on silica gel (PE:EtOAc=1:0 to 0:1) to afford the title compound as a white solid (500 mg, yield 73.6%).¹H-NMR (400 MHz, DMSO-d₆): δ 8,27 (s, 1 H), 7,85 (d, J = 8,6 Hz, 1 H), 6,09 (td, J = 55,7, 3,7 Hz, 1 H), 4,68 (m, 1 H), 4,63 (t , J = 4,9 Hz, 1H), 3,46 (m, 2H), 1,87 (m, 2H).

Description D126

3-((2,5-dichloorpyrimidine-4-yl)amino)-4,4-difluorbutylmethaansulfonaat (D126)

To a solution of D125 (500 mg, 1.838 mmol) in THF (4 mL) was added DIPEA (0.480 mL, 2.76 mmol), followed by the addition of methanesulfonyl chloride (0.171 mL, 2.205 mmol). The reaction was stirred at room temperature for 30 minutes. The mixture was then quenched with water (0.2 mL), diluted with EtOAc (40 mL), washed with water (2 x 30 mL) and brine (30 mL). The organic layer was dried over anhydrous Na 2 SO₄and concentrated to give the crude oil as a yellow oil, which was used in the next step without further purification.

Description D127

2,5-Dichloor-/V-(1 ,1 -difluor-4-((5-methyl-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-3-yl )oxy)butaan-2-yl)pyrimidine-4-amine (D127)

To a solution of D126 (280 mg, 0.800 mmol) in DMF (2 ml) was added D5 (182 mg, 0.800 mmol) and CS 2 CO 3 (287 mg, 0.880 mmol). The reaction was heated to 60°C in a sealed system and stirred for 1 hour. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL), washed with water (3 x 20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na 2 SO₄and concentrated. The crude product was purified by column chromatography on silica gel (PE:EtOAc = 1:0 to 0:1) to afford the title compound as a white solid (1.12 mg, yield 18.76%). LC-MS: 481 .1 [M+H]⁺.

Description D128

ferf-Butyl 4-(3-(3-((2,5-dichloorpyrimidine-4-yl)amino)butoxy)-5-methyl-4-nitro-1 H-pyrazol-1 -yl)-3-fluorpiperidine- 1 -carboxylaat (D128)

A solution of D73 (723 mg, 2.0 mmol), ie f-butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (2.97 g, 10.0 mmol) and Cs₂C0₃(1.96 g, 6.0 mmol) in DMSO (30 mL) was stirred overnight at 85°C. The mixture was poured into saturated NaCl (aq) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated in vacuo. The crude product was purified columnwise

chromatography on silica gel (PE:EtOAc = 1:1) to afford the title compound as a yellow solid (280 mg, yield 25%).

Description D129

ferf-butyl-4-{14-chloor-4,11-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.

0^{3 7}]heptadeca-1 (16), 3, 6,13(17), 14-pentaeen-5-yl}-3-fluorpiperidine-1-carboxylaat (D129)

A solution of D129 (571 mg, 1.1 mmol), Fe (285 mg, 5.1 mmol) and NH₄Cl (273 mg, 5.1 mmol) in EtOH/hr O (24 mL, 5:1) was refluxed overnight. The mixture was filtered and the filtrate was concentrated. The crude product was purified by column chromatography on silica gel (PE:EtOAc = 2:1) to afford the title compound as a white solid (175 mg, yield 34.6%). Description D130

14-chloor-5-(3-fluorpiperidine-4-yl)-4 1-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaene, TFA salt (D130)

A solution of D129 (175 mg, 0.35 mmol) and TFA (2.5 ml) in DCM (15 ml) was stirred at room temperature for 5 hours. The mixture was concentrated to give the crude (135 mg) which was used directly for the next step.

Description D131

ferf-Butyl 4-(3-((?)-3-((2,5-dichloorpyrimidine-4-yl)amino)butoxy)-5-methyl-4-nitro-1 H-pyrazol-1 -yl)- 3-fluorpiperidine-1-carboxylaat (D131)

A solution of D79 (1.08 mg, 3.0 mmol), ie f-butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (3.57 g, 12.0 mmol) and K₂C0₃(1.66 g, 12.0 mmol) in DMSO (30 ml) was stirred at 85°C for 3 days. The mixture was poured into water and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over anhydrous Na 2 SO₄and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE:EtOAc = 2:1) to afford the title compound as a yellow solid (1.2 g, yield 71.0%).

Description D132

ferf-Butyl 4-[(11?)-14-chloor-4,11 -dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen-5-yl]-3-fluorpiperidine-1 - carboxylaat (D132)

A solution of D131 (5.3 g, 9.5 mmol), Fe (2.6 g, 47.5 mmol), and NH₄Cl (2.6 g, 47.5 mmol) in EtOH/hO (60 mL, 5:1) was refluxed overnight. The mixture was filtered and the filtrate was concentrated. The crude was purified by column chromatography on silica gel (PE:EtOAc = 2:1) to give the title compound as a white solid (4.0 g, yield 85.1%).

Description D133

(11?)-14-chloor-5-(3-fluorpiperidine-4-yl)-4,11-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}[heptadeca-1(16),3,6,13(17),14-pentaene, TFA salt (D133)

A solution of D132 (4.0 g, 8.1 mmol) and TFA (25 ml) in DCM (50 ml) was stirred at ambient temperature for 3 hours. The solvent was removed in vacuo and the crude desired product (3.1 g, crude) was used directly for the next step.

Description D134

(?)-3-(3-(3-((2,5-dichloorpyrimidine-4-yl)amino)butoxy)-5-methyl-4-nitro-1 H-pyrazol-1 - yl)cyclobutaan-1 - één (D134)

To a solution of D79 (1 g, 2.8 mmol) in DMF (50 ml) at 0°C was added NaH (124 mg, 3.1 mmol). After stirring for 30 minutes, 3-bromocyclobutan-1-one (834.3 mg, 5.6 mmol) was added and the mixture was stirred at room temperature for 4 hours. Then the mixture was poured into ice water and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated in vacuo. The crude was purified by column chromatography on silica gel (PE:EtOAc = 2:1) to afford the title compound as an off-white solid (850 mg, yield 71%). LC-MS: 429.2 [M+H]⁺.

Description D135 3-[(11?)-14-chloro-4,11-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}] heptadeca-1(16),3,6,13(17),14-pentaen-5-yl]cyclobutan-1-one (D135) .

To a solution of D134 (850 mg, 1.98 mmol) in /^'-PrOH (50 ml) Fe (554.4 mg, 9.9 mmol) and a solution of NH 4 Cl (529.3 mg, 9.9 mmol) in H 2 O (5 ml) were added. The reaction was stirred overnight at 95°C. The mixture was filtered and the filter cake was washed with it

ChC/MeOH (10:1, 3 x 100 mL). The combined filtrate was concentrated. The residue was poured into saturated NaHCO5 (aq.) and extracted with CH2 Cl2 (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (EtOAc) to afford the title compound as an off-white solid (320 mg, yield 45%). LC-MS: 363.3 [M+H]⁺.

Description D136

3-(3-broom-5-methyl-4-nitro-1 H-pyrazol-1 -yl)cyclopentanon (D136)

To a stirred suspension of 3-bromo-5-methyl-4-nitro-1/-/-pyrazole (6.0 g, 29.1 mmol) and ScC (441 mg, 2.91 mmol) in CH2C (60 mL ) was added at room temperature cyclopent-2-enone (5.74 g, 69.9 mmol). The reaction was stirred at 25°C for 16 hours. The mixture was poured into brine (50 mL) and extracted with CH2 Cl2 (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude was purified by column chromatography (PE:EtOAc = 10:1 to 4:1) to afford the title compound as a white solid (6.8 g, yield 81%).¹H-NMR (400 MHz, CDCI₃): δ 5,26-5,21 (m, 1 H), 2,86 (dd, J= 18,4, 5,6 Hz, 1 H), 2,73-2,62 (m, 2H), 2,54 (s, 3H), 2,52-2,33 (m, 3H).

Description D137

4-(3-(3-bromo-5-methyl-4-nitro-1H-pyrazol-1-yl)cyclopentyl)morphol To a stirred solution of D136 (500 mg, 1.736 mmol) and AcOH (36 mg, 0.607 mmol ) mmol) in CH 2 Cl 2 (10 mL) at 0 °C, morpholine (163 mg, 1.909 mmol) and NaBH were added₃CN (218mg, 3.471mmol). The reaction was stirred at room temperature for 16 hours. The mixture was washed with aq. NaHCC>3 (10 ml) and brine (10 ml). The organic layer was dried over anhydrous Na 2 SO₄, filtered and concentrated. The crude product was purified columnwise

chromatography (PE:EtOAc=10:1 to 1:1) to afford the title compound as yellow oil (318 mg, yield 51%). LC-MS: 361.2 [M+H]⁺.

Description D138

5-Methyl-1 -(3-morfolinocyclopentyl)-4-nitro-1H-pyrazol-3-ol (D138)

A solution of D137 (2.0 g, 5.57 mmol) and KOH (3.1 g, 55.6 mmol) in DME/water (20 ml/30 ml) in a sealed vessel was heated at 120°C for 16 hours. stirred. Solvents were removed by concentration followed by lyophilization. The solid was suspended in methanol (20 ml), stirred at room temperature for 30 min. The resulting suspension was filtered through Celite. The filtrate was concentrated and the crude product was purified by column chromatography

(CH2CI2: CH₃OH = 40:1 to 10:1) to afford the title compound as a yellow solid (1.2 g, yield 72%).¹H-NMR (400 MHz, DMSO-d₆): 8 7,15 (br, 1H), 4,60-4,57 (m, 1H), 4,76-3,53 (m, 5H), 3,32-2,50 (m, 4H), 2,21 (s, 3H), 2,17-1 . 98 (m, 2H), 1.99-1.60 (m, 4H).

Description D139

ferf-Butyl (3-((5-methyl-1 -(3-morfolinocyclopentyl)-4-nitro-1H-pyrazol-3-yl)oxy)propyl)carbamaat (D139):

One mixture of D138 (300 mg, 1.01 mmol), i/f-butyl (3-bromopropyl)carbamate (482 mg, 2.02 mmol) and Cs₂C0₃(823mg, 2.52mmol) in DMF (6ml) was stirred at 100°C for 2 hours. The reaction was quenched with water (10 ml) and extracted with ether (2 x 10 ml). The organic layer was washed with brine, dried over anhydrous Na 2 SO₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel (CH 2 Cl 2 :CH 3 OH = 300:1 to 30:1) to afford the title compound as a yellow oil (220 mg, yield 48%). LC-MS: 454.3 [M+H]⁺. Description D140

3-((5-Methyl-1 -(3-morfolinocyclopentyl)-4-nitro-1 H-pyrazol-3-yl)oxy)propaan-1 -amine, TFA-zout (D140)

To a solution of D139 (220 mg, 0.485 mmol) in CH₂CI₂(2 ml) at 0°C was added dropwise TFA (0.5 ml). The reaction was stirred at room temperature for 2 hours. The mixture was concentrated to give the title compound, which was used in the next step without further purification.

Description D141

2,5-dichloor-A/-(3-((5-methyl-1 -(3-morfolinocyclopentyl)-4-nitro-1H-pyrazool-3-yl)oxy)propyl)pyrimidine-4-amine (D141 )

To a solution of D140 (170 mg, 0.481 mmol) in /^'-PrOH (2 ml) at 0°C Et was added₃N (487 mg, 4.81 mmol) and 2,4,5-trichloropyrimidine (93 mg, 0.505 mmol) dropwise. The reaction was stirred at room temperature for 2 hours. The mixture was poured into water (6 ml) and extracted with EtOAc (2 x 8 ml). The combined organic layer was dried over anhydrous Na 2 SO₄and concentrated in vacuo. The crude was purified by flash column chromatography (PE:EtOAc = 10:1 to 0:1) to give the title compound as a yellow oil (170 mg, yield 70%). LC-MS: 500.2 [M+H]⁺.

Description D142

8-chloor-3-methyl-2,4,10,11,12,13-hexahydro-5,9-(azeno)pyrazolo[3,4-b][1, 4,6,10]oxatriazacyclotridecine (D142)

To a solution of D33 (150 mg, 0.432 mmol) in EtOH/H₂0 (50ml/5.0ml) in the chamber

temperature, Fe (125 mg, 2.24 mmol) and NH4Cl (140 mg, 2.62 mmol) were added. The reaction was stirred overnight under argon at 100°C. The hot reaction slurry was filtered through a pad of Celite and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (CH 2 Cl 2 :MeOH = 10:1) to afford the title compound as a yellow solid (142 mg). LC-MS: 281.3 [M+H]⁺.

Description D143

3,4,5-tribroom-1 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazool (D143)

To a solution of 3,4,5-tribromo-1H-pyrazole (10,500 g, 34.45 mmol), PPh₃(18.072 g, 68.90 mmol) and tetrahydro-2H-pyran-4-ol (4.222 g, 41.34 mmol) in THF (250 mL) became DIAD (13.6 mL, 68.90 mmol) at 0° C added. The mixture was stirred at 0°C for 0.5 hours and at room temperature for 5 hours. Then the reaction mixture was poured into ice water (200 ml) and extracted with EtOAc (2 x 200 ml). The organic layers were dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EtOAc = 3:1) to give the title compound as a white solid (9.8 g, yield 73%).

Description D144

3,4-Dibroom-1 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazool-5-carbaldehyde (D144)

To a solution of D143 (10.0 g, 25.71 mmol) in THF (200 mL) was added n-BuLi (1.6 M in THF, 24.1 mL, 38.57 mmol) at -78°C under argon for 30 minutes. Then N-formylmorpholine (5.9 g, 51.42 mmol) was added dropwise. The reaction was stirred at -78°C for 1 hour. The reaction mixture was poured into aqueous NH 4 Cl (200 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EtOAc = 10:1) to give the title compound as an off-white solid (5.2 g, yield 60%).¹H-NMR (400 MHz, CDCI₃): 8 9,83 (s, 1H), 5,27-5,21 (m, 1H), 4,13-4,07 (m, 2H), 3,57-3,51 (m, 2H), 2,87-2,18 (m, 2H), 1 . 91 -1,87 (m, 2H).

Description D145

3,4-Dibroom-5-(difluormethyl)-1 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazool (D145)

To a stirred solution of D144 (5.2 g, 15.38 mmol) in CH₂CI₂(100 ml) DAST (4.1 ml, 30.77 mmol) was added at 0°C. The reaction was stirred at room temperature for 2 hours. The reaction was poured into ice. The mixture was extracted with CH2 Cl2 (2x50 ml) and the combined organic layers were washed with aq. NaHCC>3 (2x100ml), dried, filtered and concentrated to give the title compound as a gray solid (5.3g, yield 96%). .¹H NMR (400 MHz, CDCI3): 8 6,87-6,61 (s, 1 H), 4,61 -4,53 (m, 1 H), 4,13-4,09 (m, 2H), 3,54-3,45 (m, 2H), 2,37- 2.37 (m, 2H), 1.88-1.92 (m, 2H).

Description D146

1 -(4,4-Difluorcyclohexyl)-5-methyl-4-nitro-1H-pyrazol-3-ol (D146)

The title compound D146 was prepared using procedures similar to those used to prepare D25 starting from 4,4-difluorocyclohexanol. LC-MS: 262.3 [M+H]⁺.

Description D147

4-Nitro-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-ol (D147) The title compound D147 was prepared using procedures similar to those used to prepare D36 starting from tetrahydrofuran-3 -yl methane sulfonate.

Description D148

4-Nitro-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)-1 -(tetrahydrofuran-3-yl)-1 H-pyrazool (D148)

A mixture of D147 (1.00 g, 5.02 mmol), 2-(3-bromopropoxy)tetrahydro-2H-pyran (1.12 g, 5.02 mmol), and K₂C0₃(1.39 g, 10.04 mmol) in DMF (20 mL) was heated to 80°C for 3 hours. The reaction mixture was poured into ice water (60 ml) and extracted with EtOAc (2 x 30 ml). The organic layer was washed with brine (3 x 40 mL), dried, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EtOAc = 1:1) to afford the title compound as a yellow solid (1.526 g, yield 89%).

Description D149

5-chloor-4-nitro-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)-1 -(tetrahydrofuran-3-yl)-1H-pyrazool (D149)

To a solution of D148 (1.526 g, 4.47 mmol) in THF (20 mL) at -60 °C under nitrogen was added LiHMDS (1.0 M in THF, 5.36 mL, 5.36 mmol). The reaction was stirred at -60°C for 0.5 hour. Then a solution of C2 Cl6 (2.1 x 16 g, 8.94 mmol) in THF (2 mL) was added dropwise. The reaction was stirred at -60°C for 0.5 hour. The reaction mixture was poured into aq.NH₄Cl (50 ml) and extracted with EtOAc (2x30 ml). The combined organic layer was washed with brine (2 x 30 mL), dried and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE:EtOAc = 1:1) to afford the title compound as a white solid (1.149 g, yield 68%).

Description D150

3-((5-Chloor-4-nitro-1 -(tetrahydrofuran-3-yl)-1 H-pyrazol-3-yl)oxy)propaan-1 -ol (D150)

A solution of D149 (1.149 g, 3.06 mmol) in HCl/MeOH (3 M in MeOH, 15 mL) was heated at 50°C for 1 hour. The reaction mixture was poured into ice and aqueous NaHCC>3 (50 ml) and then extracted with EtOAc (2 x 50 ml). The organic layer was dried, filtered and concentrated to give the title compound as a yellow oil (734 mg, yield 82%).

Description D151

3-((5-Chloor-4-nitro-1 -(tetrahydrofuran-3-yl)-1 H-pyrazol-3-yl)oxy)propyl

methane sulfonate (D151)

To a solution of D150 (734 mg, 2.52 mmol) in CH₂CI₂(20 ml) in et₃N (510 mg, 5.04 mmol) MsCl (432 mg, 3.77 mmol) was added at 0°C. The reaction was stirred at 0°C for 0.5 hour. The reaction was poured into ice water and extracted with CH2 Cl2 (2 x 20 mL). The organic layer was washed with aqueous NaHCC>3 (30 ml), dried over anhydrous Na 2 SO₄filtered and concentrated to give the title compound as a white solid (870 mg, crude).

Description D152

2-(3-((4-Nitro-5-chloor-1 -(tetrahydrofuran-3-yl)-1 H-pyrazol-3-yl)oxy)propyl)isoindoline-

1,3-dione (D152) A mixture of D151 (870 mg, 2.35 mmol), potassium 1,3-dioxoisoindolin-2-ide (872 mg, 4.71 mmol), K₂C0₃(325mg, 2.35mmol) and TBAI (89mg, 0.24mmol) in CH3CN/DMF (20ml/10ml) was stirred at 100°C for 4 hours. The reaction mixture was poured into ice water (40 ml) and extracted with EtOAc (2 x 30 ml). The organic layer was washed with brine (3 x 30 mL), dried, filtered and concentrated to give the compound. The crude product was purified by column chromatography on silica gel (PE:EtOAc = 1:1) to afford the title compound as a yellow solid (756 mg, yield 72%). Description D153

2-(3-((4-Amino-5-chloor-1 -(tetrahydrofuran-3-yl)-1 H-pyrazol-3-yl)oxy)propyl)isoindoline-1,3-dion (D153)

To a solution of D152 (756 mg, 1.80 mmol) in concentrated HCl (15 mL) was added SnC (681 mg, 3.59 mmol). The reaction was stirred at 60°C for 20 min. The reaction was poured into ice and aq NaHCC>3 (40 ml). The mixture was extracted with EtOAc (2 x 50 mL). The organic layer was dried, filtered and concentrated to give the title compound as a yellow oil (423 mg, yield 60%).

Description D154

3-(3-Aminopropoxy)-5-chloor-1 -(tetrahydrofuran-3-yl)-1H-pyrazol-4-amine (D154)

To a solution of D153 (430 mg, 1.10 mmol) in EtOH (10 mL) was added hydrazine hydrate (0.5 mL). The reaction was stirred at 50°C for 2 hours. The mixture was poured into ice water (20 ml) and extracted with CH2 Cl2 (2 x 20 ml). The organic layer was dried, filtered and concentrated to give the title compound as a yellow oil (314 mg, crude).

Description D155

yV-(3-((4-Amino-5-chloor-1 -(tetrahydrofuran-3-yl)-1 H-pyrazool-3-yl)oxy)propyl)-2,5- dichloorpyrimidine-4-amine (D155 )

To a solution of D154 (283 mg, 1.09 mmol) in /^'-PrOH (15 mL) in Et₃N (221 mg, 2.18 mmol) was a solution of 2,4,5-trichloropyrimidine (189 mg, 1.03 mmol) in /^'-PrOH (1 ml). The reaction was stirred at room temperature for 0.5 hour. The reaction mixture was poured into ice water (20 ml) and extracted with EtOAc (2 x 20 ml). The organic layer was dried, filtered and concentrated. The residue was purified by column chromatography over silica gel (PE:

EtOAc = 1:2) to give the title compound as a clear oil (280 mg, yield 63%).

Description D156

5-Chloor-4-nitro-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazool (D156 )

The title compound D156 was prepared using procedures similar to those used to prepare D149 starting from D36.

Description D157

5-cyclopropyl-4-nitro-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)-1 -(tetrahydpyran-4-yl)-1H-pyrazool (D157)

A mixture of D156 (832 mg, 2.13 mmol), tricyclohexylphosphine (59 mg, 0.21 mmol), cyclopropylboric acid (367 mg, 4.27 mmol), Pd(dppf)C (154 mg, 0.21 mmol) and K3PO4 (907mg, 4.27mmol) in dioxane (20ml) was stirred at 100°C for 16 hours. The reaction mixture was filtered and purified by column chromatography on silica gel (PE:EtOAc = 2:1) to afford the title compound as a yellow solid (431 mg, yield 51%).

Description for D158

(/?)-ferf-Butyl 3-(3-(3-((2,5-dichloropyrimidin-4-yl)amino)butoxy)-5-methyl-4-nitro-1H-pyrazol-1-yl) azetidine-1-carboxylate (D158) To a solution of D79 (540 mg, 1.50 mmol) and K₂C0₃(622 mg, 4.5 mmol) in DMSO (10 mL) was added tert-butyl 3-iodozetidine-1-carboxylate (637 mg, 2.25 mmol). The reaction was stirred at 75°C for 2 hours. The mixture was cooled to room temperature and extracted with EtOAc and water. The organic layer was dried over anhydrous Na 2 SO₄and concentrated. The crude was purified by pre-TLC (PE:EA = 1:1) to give the title compound as a colorless oil (490 mg, yield 63.4%).¹H-NMR (400 MHz, CDCI₃): 5 7,96 (s, 1 H), 5,67 (d, J= 8,0 Hz, 1 H), 4,97-4,93 (m, 1 H), 4,59-4,55 (m, 1 H), 4,49 (t, 2H) , 4,42-4,38 (m, 1 uur), 4,33-4,25 (m, 3 uur), 4,17-4,09 (m, 2 uur), 3,82-3,78 (m, 1 uur), 2,58 (s, 3 uur), 2,24-2,19 ( m, 1 H), 2,15-2,07 (m, 1 H), 1,62 (s, 2H), 1,46 (s, 9H), 1,44 (s, 3H), 1,38 (d, J= 6,4 Hz, 2 uur).

Description D159

ferf-Butyl 3-[(11?)-14-chloor-4,11 -dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen-5-yl]azetidine-1-carboxylaat (D159)

To a solution of D158 (380 mg, 0.74 mmol) in AcOH/MeOH (11.4 ml/114 ml) was added Zn (482 mg, 7.38 mmol). The mixture was stirred at 75°C under argon for 3 hours. The mixture was evaporated to dryness and the crude material was diluted with PE: EtOAc = 10:1 and the solid was filtered to give the title compound as a red solid (1.4 g, yield 100%, contained some ZnOAc).

Description D160

(1 7 ?)-5-(Azetidine-3-yl)-14-chloor-4,11-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaene, HCl salt (D160)

D159 (1.35 g, 0.7 mmol) was dissolved in HCl/MeOH (3 M, 20 ml) and the reaction mixture was stirred at room temperature for 1.5 h. The mixture was concentrated and the crude product was used directly in the next step without purification. Description D161

2,5-Dichloor-W-(4-((1 -(2,2-diethoxy^

yl)pyrimidine-4-amine(D161 )

K was added to a solution of D73 (1.0 g, 2.7 mmol) in DMSO (50 mL)₂C0₃(1.2 g, 8.3 mmol) and 2-bromo-1,1-diethoxyethane (2.7 g, 13.8 mmol). The reaction was stirred at 90°C for 4 hours. The mixture was poured into ice water and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated to give the title compound as an off-white solid, which was used in the next step without further purification (960mg).

Description D162

14-chloor-5-(2,2-diethoxyethyl)-4,11-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0³'⁷]heptadeca-1 (16),3,6,13(17),14-pentaeen (D162)

To a solution of D161 (960 mg, 2.0 mmol) in EtOH (50 mL) was added Fe (560 mg, 10 mmol) and a solution of NH.₄BI (535 mg, 10 mmol) in H2O (5 mL). The reaction was stirred overnight at 90°C. The mixture was filtered, the filter cake was washed with CH 2 Cl 2 :MeOH (10:1) (3 x 100 mL) and the combined filtrate was concentrated. The residue was poured into saturated NaHCC>3 (aq) and extracted with CH 2 Cl 2 (3 x 100 ml). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude was suspended in MeCN to give the title compound, which was used directly in the next step (770mg).

Description D163

2-{14-chloor-4,11-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0³,⁷]heptadeca-1(16),3,6,13(17),14-pentaen-5-yl}acetaldehyde, TFA salt (D163)

TFA (15 ml) was added to a solution of D162 (770 mg) in DCM (15 ml) at room temperature.

temperature. The reaction was stirred overnight at room temperature. The mixture was concentrated to give the title compound which was used directly in the next step (810mg).

Description D164

4-(3-(3-((2,5-dichloorpyrimidine-4-yl)amino)propoxy)-5-methyl-4-nitro-1H-pyrazol-1 - yl)tetrahydro-2H-pyran-3- oud (D164)

To a solution of D33 (800 mg, 2.30 mmol) in DMSO (12 mL) in a sealable vessel, K2CO3 (1.27 g, 9.19 mmol) and 3,7-dioxabicyclo[4.1.0]heptane ( 1.84 mmol) was added. g, 18.4 mmol). The vessel was sealed and the reaction mixture was stirred overnight at 95°C. The cooled reaction mixture was poured into water (120 ml) and the resultant was extracted with EtOAc (3 x 80 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO₄and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (CH 2 Cl 2 :EtOAc = 5:1 - 2:1) to afford the title compound as an off-white solid (266 mg, yield 25%). LC-MS: 447.2 [M+H]⁺.

Description D165

4-(3-(3-((2,5-dichloorpyrimidine-4-yl)amino)propoxy)-5-methyl-4-nitro-1H-pyrazol-1 - yl)dihydro-2H-pyran-3( 4H)-een (D165)

To a stirred solution of D164 (266 mg, 0.595 mmol) in DMSO (4.0 mL) was added IBX (250 mg, 0.893 mmol) under argon at room temperature. The reaction was stirred overnight at 55°C. The reaction mixture was poured into water (100 ml) and extracted with EtOAc (3-60 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO₄, filtered. The filtrate was concentrated and the crude product was purified by chromatography on silica gel (CH 2 Cl 2 :EtOAc = 5:1 - 3:1) to afford the title compound as an off-white solid (115 mg, yield 43%) . LC-MS: 445.2 [M+H]⁺.

Description D166

2,5-dichloor-N-(3-((1 -(3,3-difluortetrahydro-2H^yran-4-yl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy) propyl)pyrimidine-4-amine (D166)

To a suspension of D165 (1.15 mg, 0.258 mmol) in CH 2 Cl 2 (15 mL) under argon at 0°C was added DAST (208 mg, 1.29 mmol) via syringe. The reaction was allowed to gradually warm to room temperature and stirred for 2 days. The mixture was poured into saturated. NaHCC>3 (30 ml) and extracted with CH2CI2 (3x30 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO₄, filtered. The filtrate was concentrated and the crude product was purified by chromatography on silica gel (CH 2 Cl 2 :EtOAc = 5:1) to afford the title compound as an off-white solid (103 mg, yield 85%). LC-MS: 467.2 [M+H]⁺.

Description D167

5-(3-broom-5-methyl-4-nitro-1H-pyrazol-1 -yl)dihydro-2H-pyran-3(4H)-on (D167)

To a stirred suspension of 5-bromo-3-methyl-4-nitro-1H-pyrazole (1.85 g, 8.98 mmol) in dry CH2 Cl2 (20 mL) under argon at room temperature was added 2/-/-pyran . -3(6/-/)-one (1.77 g, 18.0 mmol) and ScC (123 mg, 0.813 mmol). The reaction was then stirred overnight under argon at 25°C. The reaction mixture was concentrated to a volume of c. 10 ml and the resulting yellow suspension was directly loaded onto a silica gel column (PE:EtOAc = 5:1 -1:1) to give the title compound as an off-white solid (1.98 g, yield 72%). LC-MS: 306.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): δ 4,88-4,81 (m, 1 H), 4,21 -4,10 (m, 3 H), 4,03 (dd, J= 1 1,6, 8,0 Hz, 1 H), 3,24 (dd, J = 16,4, 8,6 Hz, 1 H), 2,95 (dd, J= 16,4, 6,0 Hz, 1 H), 2,71 (s, 3 H) Beschrijving D168

5-(3-broom-5-methyl-4-nitro-1H-pyrazol-1 -yl)tetrahydro-2H-pyran-3-ol (D168)

To a stirred suspension of D167 (1.98 g, 6.51 mmol) in MeOH/THF (30 mL/30 mL) under argon at 0 °C was added NaBH.₄(124 mg, 3.28 mmol) in one serving. The reaction was stirred at 0°C under argon for 1 hour. The reaction was quenched by the addition of saturated aqueous NH 4 Cl (50 mL) at 0°C. The resultant was diluted with water (20 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO₄and filtered. The filtrate was concentrated and the residue was dried in vacuo to afford the crude desired product as a pale yellow solid (2.07 g, crude). LC-MS: 308.2 [M+H]⁺.

Description D169

1 -(5-Hydroxytetrahydro-2H-pyran-3-yl)-5-methyl-4-nitro-1H-pyrazol-3-ol (D169)

To a suspension of D168 (2.07 g, 6.51 mmol) in water (50 mL) was added KOH (5.0 g, 89.1 mmol). The reaction was stirred at 105°C under argon for 3 hours. The cooled mixture was extracted with Et.2 O (2x50 ml). The aqueous layer was acidified with cone. HCl to pH=2. The mixture was extracted with EtOAc (3 x 50 mL) and the combined organics were washed with brine (30 mL), dried over anhydrous Na 2 SO₄, filtered and concentrated. The crude was suspended in CH2 Cl2 (10 ml), stirred for 15 minutes, filtered. The filter cake was dried under an infrared lamp and collected to give the title compound as a yellow solid (1.01 g, yield over 2 steps 63%). LC-MS: 244.3 [M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆): 5 1 1,41 (s, 1 H), 5,1 1 (d, J= 5,2 Hz, 1 H), 4,42-4,36 (m, 1 H), 3,89-3,81 (m, 2H), 3,72-3,66 (m , 1 H), 2,93 (t, J= 10,4 Hz, 1 H), 2,58 (s, 3H), 2,22-2,19 (m, 1 H), 1,85 (q, J= 1 1,6 Hz, 1 H) .

Description D170

ferf-Butyl (3-((1 -(5-hydroxytetrahydro-2H-pyran-3-yl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)propyl)carbamaat (D170)

To a solution of D169 (400 mg, 1.64 mmol) in DMF (5.0 mL) under argon in room

temperature, K 2 CO 3 (680 mg, 4.92 mmol) and ie f-butyl(3-bromopropyl) carbamate (587 mg, 2.47 mmol) were added. The reaction was stirred at 85°C under argon for 3 hours. The cooled reaction mixture was poured into water (60 ml) and the resultant was extracted with EtOAc (3 x 40 ml). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO₄, filtered and concentrated. The crude was purified by chromatography on silica gel (PE:EtOAc = 5:1 -1:1) to give the title compound as a light yellow oil (331 mg, yield 50%). LC-MS: 401 .3 [M+H]⁺.

Description D171

ferf-Butyl (3-((1 -(5-fluortetrahydro-2H-pyran-3-yl)-5-methyl-4-nitro-1H-pyrazool-3-yl)oxy)propyl)carbamaat (D171)

To a solution of D170 (331 mg, 0.827 mmol) in CH 2 Cl 2 (10 mL) under argon at 0°C, DAST (660 mg, 4.09 mmol) was added via syringe. The reaction was stirred overnight under argon at room temperature. The mixture was diluted with CH2 Cl2 (20 ml) and sat. NaHCC>3 (30ml). The result was stirred at room temperature for 1 hour and the organic layer was separated. The aqueous layer was extracted with CH2 Cl2 (2 x 30 mL) and the combined organics were washed with brine (30 mL), dried over anhydrous Na2 SO₄, filtered and concentrated. The crude was purified by chromatography on silica gel (PE:EtOAc = 5:1 - 2:1) to give the title compound as a light yellow oil (338 mg). LC-MS: 425.3 [M+H]⁺.

Description D172

(?)-2,5-Dichloro-γV-(4-((5-methyl-4-nitro-1 -(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-3- yl)oxy)butan-2-yl)pyrimidin-4-amine (D172) A solution of D79 (2.5 g, 6.9 mmol), D82 (8.1 g, 34.3 mmol) and K₂C0₃(2.8 g, 37.5 mmol) in DMA (50 mL) was heated to 80°C and stirred for 16 hours. The mixture was poured into water (300 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude was purified by column chromatography on silica gel (PE:EtOAc = 5:1 - 1:1) to give the title compound as a little yellow oil (1.3 g, yield 37%). LC-MS: 501.1 [M+H]⁺.

Description D173

(/?)-4-(3-(3-((2,5-dichloorpyrimidine-4-^

yl)cyclohexanon (200 mg, 0,44 mmol) (D173)

To a solution of D172 (1.3 g, 2.85 mmol) in DCM (25 ml) was added TFA (5 ml) and the reaction mixture was stirred at 60°C for 5 hours. Water (100 ml) was added to the cooled mixture and sat.

NaHCC>3 to pH>7. The organic layer was washed with sat. NaHCC>3, brine, dried over Na2 SO₄, and concentrated. The product was purified by column chromatography on silica gel (PE:EA = 5:1 -1:1) to give the title compound (800 mg, yield 67%).

Description D174

(?)-2,5-dichloor-yV-(4-((1 -(4,4-difluorcyclohexyl)-5-methyl-4-nitro-1 H-pyrazool-3-yl)oxy)butaan-2- yl)pyrimidine-4-amine (D174)

To a solution of D173 (200 mg, 0.44 mmol) in DCM (20 ml) was added dropwise DAST (21.1 mg, 1.32 mmol) at -60°C under nitrogen. The reaction was stirred at room temperature for 16 hours. The mixture was diluted with MeOH (5 ml), stirred for 10 min and then concentrated. The crude was purified by column chromatography on silica gel (PE: EA = 10:1 -1:1) to give the title compound (60 mg, yield 28%). LC-MS: 479.2 [M+H]⁺.

Beschrijving D175 (?)-4-(3-(3-((2,5-dichloorpyrimidine-4-yl)amino)butoxy)-5-methyl-4-nitro-1 H-pyrazol-1 - yl)cyclohexanol ( D175)

To a solution of D173 (760 mg, 1.66 mmol) in MeOH (20 mL) was added NaBH₄(75 mg, 1.97 mmol) at 5-10°C. The reaction was stirred at room temperature for 4 hours. The mixture was poured into water (100 ml) and extracted with EtOAc (2 x 100 ml). The organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude was purified by column chromatography on silica gel (PE:EA=5:1) to give the title compound (410 mg, yield 53%). LC-MS: 459.2 [M+H]⁺.

Description D176

(?)-2,5-dichloor-W-(4-((1 -(4-(difluormethoxy)cyclohexyl)-5-methyl-4-nitro-1 H-pyrazol- 3-yl)oxy)butaan-2 -yl)pyrimidine-4-amine (D176)

To a solution of D175 (250 mg, 0.54 mmol) in CH₃CN (20 ml) CuI (20.5 mg, 0.108 mmol) was added. After stirring at 50°C for 10 minutes, 2,2-difluoro-2-(fluorosulfonyl)acetic acid (146 mg, 0.82 mmol) in MeCN (0.5 mL) was added dropwise. The reaction was stirred at 50°C for 2 hours. The mixture was concentrated and the crude product was purified columnwise

chromatography on silica gel (PE:EtOAc = 3:1) to give the title compound (1.10 mg, crude). LC-MS: 509.2 [M+H]⁺.

Description D177

(?)-3-(3-(3-((2,5-dichloorpyrimidine-4-yl)amino)butoxy)-5-methyl-4-nitro-1 H-pyrazol-1 - yl)cyclobutanol(D177)

To a solution of D134 (770 mg, 1.8 mmol) in MeOH (20 mL) was added NaBH₄(102 mg, 2.6 mmol) at 5-10°C. The reaction was stirred at room temperature for 4 hours. The mixture was concentrated and the crude product was purified by column chromatography over silica gel (PE:

EtOAc = 2:1) to give the title compound as a white solid (700 mg, yield 95%). LC-MS: 431 .1 [M+H]⁺.

Description D178

3-(3-(3-((2,5-dichloorpyrimidine-4-yl)(methyl)amino)butoxy)-5-methyl-4-nitro-1 H pyrazol-1 -yl)cyclobutanol (D178)

CH was added to a solution of D177 (215 mg, 0.5 mmol) in DMF (20 ml)₃I (85.2 mg, 0.6 mmol) and NaH (0.39 g, 9.9 mmol). The reaction was stirred at room temperature for 5 hours. The mixture was poured into water (50 ml) and extracted with EtOAc (2 x 100 ml). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated in vacuo. The crude was purified by column chromatography on silica gel (PE:EtOAc = 1:1) to give the title compound as a yellow oil (100mg). LC-MS: 445.2 [M+H]⁺. Description D179

tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (D179)

To a solution of tert-butyl 3,6-dihydropyridine-1 (2H)-carboxylate (18.3 g, 1.0 mol) and m-CPBA (34.5 g, 2.0 mol) in CH2Cl2 (200 ml ) was stirred at room temperature overnight. The reaction mixture was filtered and extracted with CH2 Cl2 (300 ml). The combined organic layer was washed with brine, dried over Na 2 SO₄and concentrated in vacuo to give the target product (17.7 g, 89% yield). The crude product was used directly for the next step.

Description D180

Tert-butyl 4-(3-((R)-3-((2,5-dichloorpyrimidine-4-yl)amino)butoxy)-5-methyl-4-nitro-1 H-pyrazol-1 -yl)- 3-hydroxypiperidine-1-carboxylaat (D180) oc

To a solution of D79 (4.8 g, 13.1 mmol), D179 (13 g, 65.5 mmol) and K₂C0₃(5.5g, 39.3mmol) in DMSO (50ml) was stirred overnight at 90°C. The reaction mixture was poured into ice water and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine, dried over Na 2 SO₄and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE:EtOAc=1:1) to give the target product as a light yellow solid (1.42 g, yield 19%).

Description D181

Tert-butyl 4-(3-((R)-3-((2,5-dichloorpyrimidine-4-yl)amino)butoxy)-5-methyl-4-nitro-1 H-pyrazol-1 -yl)- 3-oxopiperidine-1-carboxylaat (D181) oc

A solution of D180 (1.42 g, 2.53 mmol) and Dess-Martin periodinane (2.15 g, 5.06 mmol) in CH2 Cl2 (30 mL) was stirred at room temperature for 2 hours. The reaction mixture was extracted with CH2 Cl2 (3 x 50 ml). The combined organic layer was washed with brine, dried with Na 2 SO₄and concentrated in vacuo to give the target product (1.33 g crude). The crude product was used directly for the next step.

Description D182

Tert-butyl 4-(3-((R)-3-((2,5-dichloorpyrimidine-4-yl)amino)butoxy)-5-methyl-4-nitro-1 H-pyrazol-1 -yl)- 3,3-difluorpiperidine-1-carboxylaat (D182):

To a solution of D181 (1.42 g, 2.53 mmol) in CH₂CI₂(50 ml) DAST (816 mg, 5.06 mmol) was added dropwise at -78°C. The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water and extracted with CH2 Cl2 (3 x 50 ml). The combined organic layer was washed with brine, dried with Na 2 SO₄and concentrated in vacuo to give the target product (1.5 g crude). The crude product was used directly for the next step.

Description D183

3-Methyltetrahydro-2H-pyran-4-ol (D183)

To a solution of 3-methyldihydro-2H-pyran-4(3H)-one (1.0 g, 8.9 mmol) in MeOH (20 ml) was slowly added NaBH₄(410 mg, 10.7 mmol) at 0-5°C. The reaction solution was stirred at the same temperature for 1 hour. Water (3 ml) was added dropwise over 10 minutes. The reaction solution was concentrated in vacuo to give residue. CH2 Cl2 (15 ml) was added and filtered, the filtrate was concentrated to give the title compound (780 mg, 76% yield) as a colorless oil.

Description D184

3,4,5-tribroom-1 -(3-methyltetrahydro-2H-pyran-4-yl)-1H-pyrazool (D184)

To a solution of D183 (0.95 g, 8.3 mmol) in THF (50 mL) was added 3,4,5-tribromo-1H-pyrazole (2.8 g, 9.1 mmol), PPh3 (4, 3 g, 16.6 mmol) and DEAD (3.6 g, 20.7 mmol) at 0-5 °C under N 2 . The reaction solution was stirred at room temperature for 16 hours. The reaction solution was poured into water (50 ml) and extracted with EtOAc (100 ml x 2). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated in vacuo. The crude product was purified by gel-silica column chromatography (PE:EtOAc from 50:1 to 10:1) to afford the title compound as a yellow oil (2.4 g, yield 71.6%). LC-MS 403.0 (M+H)⁺.

Description D185

3,4-dibroom-5-methyl-1 -(3-methyltetrahydro-2H-pyran-4-yl)-1H-pyrazool (D185)

To a solution of D184 (2.4 g, 6.0 mmol) in THF (50 ml) at -50°C under N2 was added n-BuLi (4.1 ml, 6.6 mmol) dropwise. The mixed solution was stirred at -60°C for 1 hour. CH3I (1.8 g, 12.66 mmol) was added dropwise. The reaction solution was stirred for another 2 hours at the same temperature. Water (10 ml) was added and extracted with EtOAc

(100mLx2). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated in vacuo. The crude product was purified by gel-silica column chromatography (PE:EtOAc from 20:1 to 10:1) to afford the title compound as a colorless oil (1.5 g, yield 89%). LC-MS 339.0 (M+H)⁺.

Description D186

3-broom-5-methyl-1 -(3-methyltetrahydro-2H-pyran-4-yl)-4-nitro-1H-pyrazool (D186)

To a solution of H₂S0₄(10 mL) in HN0₃(5 ml) D185 (2.6 g, 7.7 mmol) at 0-10°C was added. The reaction was stirred at 0°C for 1 hour. The reaction solution was poured into ice water (100 ml) and extracted with EtOAc (50 ml <3). The combined organic layer was washed with NaHCO3 aqueous solution, brine, dried over anhydrous Na2SO₄and concentrated in vacuo. The crude product was purified by gel-silica column chromatography (PE:EtOAc from 10:1 to 5:1) to afford the title compound as a little yellow oil (1.0 g, yield 42%). LC-MS 304.1 (M+H)⁺.

Description D187

5-Methyl-1 -(3-methyltetrahydro-2H-pyran-4-yl)-4-nitro-1H-pyrazol-3-ol (D187)

To a solution of D186 (1.0 g, 3.2 mmol) in H₂0 (25 mL) KOH (3.7 g, 65.5 mmol) was added. The reaction was heated to 120°C for 12 hours. The reaction was cooled to room temperature and extracted with EtOAc (15 mL). The aqueous phase was neutralized with 2N HCl to pH = 4-5 and extracted with EtOAc (25 x 4 ml). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to afford the title compound as a yellow oil (450 mg, yield 57%). LC-MS 242.3(M+H)⁺.

Description D188

Tert-butyl (R)-(4-((4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazool-3-yl)oxy)butaan-2-yl)carbamaat (D188 )

To a solution of D36, (R)-3-((tert-butoxycarbonyl)amino)butylmethanesulfonate (2.7 g, 10.1 mmol) and K₂C0₃(2.3 g, 16.8 mmol) in DMF (100 ml) was stirred at 100°C for 2 hours. The reaction mixture was poured into ice water and extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with brine, dried over Na 2 SO₄and concentrated in vacuo. The crude product was purified by column chromatography over silica gel

(PE:EtOAc=3:1) to yield the target product as an off-white solid. (1.4 g, yield 45%).

Beschrijving D189 Tert-butyl (R)-(4-((5-jood-4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-3-yl)ox y)butaan- 2-yl)carbamaat (D189)

To a solution of D188 (1.4 g, 3.6 mmol) in THF (50 ml) was added LiHMDS (10.8 ml, 1 M, 10.8 mmol) at -60°C under N₂. After being stirred at -60°C under N₂for 1 hour, l₂(1.1 g, 4.32 mmol) in THF (5 ml) was added at -60°C. The mixture was stirred at -60°C for 2 hours. The reaction mixture was poured into saturated NH 4 Cl (aq) and extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with brine, dried over Na₂S0₄and concentrated in vacuo. The crude product was purified by column chromatography over silica gel

(PE:EtOAc=5:1) to afford the target product as an off-white solid (1.7 g, yield 85%).

Description D190

Tert-butyl (R)-(4-((4-nitro-1 -(tetrahydro-2H-pyran-4-yl)-5-(trifluormethyl)-1 H-pyrazool-3-yl)oxy)butaan-2 -yl)carbamaat (D190)

To a mixture of D189 (1.7 g, 3.33 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.56 g, 13.32 mmol) and Cul (1.3 g, 6.66 mmol) in DMF (50 ml) was stirred at 80°C under N for 6 hours₂. The reaction mixture was poured into saturated NaCl (aq) and extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with brine, dried over Na₂S0₄and concentrated in vacuo. The crude product was purified by column chromatography on silica gel to afford the target product as an off-white solid. (1g, yield 62.5%).

Description D191

2-(2-Methyl-1,3-dioxolane-2yl)acetohydrazide (D191) To a solution of ethyl 2-(2-methyl-1,3-dioxolane-2yl)acetate (20.0 g, 1 14.8 mmol) in EtOH (100 mL) was added hydrazine (1.5 g, 229.6 mmol) at room temperature. The mixture was stirred overnight at 80°C. The mixture was concentrated in vacuo to give yellow oil (20.5 g).¹H-NMR (400 MHz, CDCI₃): 8 7,68 (s, 1 H), 4,00-3,97 (m, 4 H), 3,48 (s, 1 H), 2,61 (s, 2 H), 1,41 (s, 3 H).

Description D192

N'-(3,3-Dimethyltetrahydro-2H^yran-4-yl)-2-(2-methyl-1,3-dioxolaan-2-yl)acetohydrazide (D192)

To a solution of 3,3-dimethyldihydro-2H-pyran-4(3H)-one (1.0 g, 7.81 mmol) in MeOH (5 ml) at room temperature was added D191 (1.25 g, 7.81 mmol) added. The mixture was stirred at room temperature for 1 hour. NaBI-CN (1.48 g, 23.4 mmol) was added to the mixture and the mixture was stirred at room temperature for 1 hour. The mixture was filtered and washed with NH4Cl solution, dried over Na2SO₄. The organic layer was concentrated in vacuo to give a yellow oil (960 mg, yield 45%).

Description D193

1 -(3,3-Dimethyltetrahydro-2H-pyran-4-yl)-5-methyl-1H-pyrazol-3-ol (D193)

To a solution of D192 (1.80 g, 6.61 mmol) in EtOH (10 mL) at room temperature was added TFA (1.51 g, 13.2 mmol). The mixture was stirred overnight at 90°C. The mixture was concentrated and purified by column chromatography over silica gel (PE:EtOAc from 10:1 to 2:1) to give the target product as a yellow oil (1.18 g, yield 85%).

Beschrijving D194 1 -(3,3-Dimethyltetrahydro-2H-pyran-4-yl)-5-methyl-4-nitro-1H-pyrazol-3-ol

(D194)

To a solution of D193 (500 mg, 2.38 mmol) in H₂S0₄(5 ml) KNO was added₃(720 mg, 7.14 mmol) slowly at 0°C. The mixture was stirred at 0°C for 30 minutes. The reaction mixture was slowly poured into ice water and extracted with EtOAc (2 x 30 ml). The combined organic layer was washed with brine and dried over Na 2 SO₄, concentrated in vacuo to give a yellow solid (450 mg, yield 74%).

Description D195

2-(3-Hydroxypropyl)isoindoline-1,3-dion (D195)

To a solution of isobenzofuran-1,3-dione (50 g, 0.337 mol) in toluan (300 ml) was added 3-aminopropan-1-ol (25.3 g, 0.377 mol). The mixture was stirred overnight at 120°C. The mixture was concentrated and EA was added to the residue. The mixture was poured into NaOH (1 M, 200 ml), stirred for 10 min, extracted with EA, washed with water and brine, dried over Na 2 SO₄and evaporated to give 2-(3-hydroxypropyl)isoindoline-1,3-dione as a white solid. (41 g, yield: 55%).¹H-NMR (400 MHz, CDCI₃) δ 7,78 (dt, J= 7,0, 3,5 Hz, 2H), 7,74-7,61 (m, 2H), 3,86-3,73 (m, 2H), 3,55 (t, J= 5,6 Hz, 2H), 2,41 (s, 1 H), 1 0,82 (dt, J= 12,1 , 6,0 Hz, 2H).

Description D196

Ethyl-2-formyl-3,3-dimethylbutanoaat (D196)

To a solution of ethyl 3,3-dimethylbutanoate (1.3 g, 1.0 mol) in dry THF (50 ml) at -70°C was added LDA (7.5 ml). The mixed solution was stirred at -70°C for 30 minutes. A solution of compound ethyl formate (2.2 g, 30 mmol)m in dry THF (10 mL) was added slowly. The mixed solution was stirred at -70°C for 2 hours and brought to room temperature overnight. The mixture was poured into NH 4 Cl (sat) and extracted with CH 2 Cl 2 (50 ml <3). The combined organic layer was washed with brine, dried over Na 2 SC>4 and concentrated in vacuo. The crude product was used in the next step without purification.

Description D197

5-(tert-butyl)-2-mercaptopyrimidine

To a solution of D196 (1.7 g, crude) in dry H2 O (50 mL) was added thiourea (2.2 g, 30 mmol) at room temperature. The mixed solution was refluxed for 2 hours. The reaction solution was cooled to rt and adjusted to pH = 2 with HCl (6 M). The solid was collected and used in the next step without purification. LC-MS: 185.2 (M+V)⁺.¹HNMR (400 MHz, DMSO-de): δ 12.29 (s, 1 H), 12.15 (s, 1 H), 6.99 (d, J = 5.6 Hz, 1 H), 1, 19 (s, 9H).

Description D198

5-(tert-butyl)pyrimidine-2,4-diol (D198)

To a solution of D197 (1.7 g, 9.24 mmol) in HCl (50 mL, 6 M) was added 2-chloroacetic acid (2.62 g, 27.7 mmol) at room temperature. The mixed solution was refluxed for 48 hours. The reaction solution was cooled to room temperature, filtered and washed with water to give the title compound as a white solid. LC-MS: 169.2 (M+V)⁺.¹HNMR (400 MHz, DMSO-d₆): δ 10.88 (s, 1H), 10.58 (s, 1H), 6.98 (d, J = 5.0 Hz, 1H), 1.18 (s, 9H). Description D199

5-(tert-butyl)-2,4-dichloorpyrimidine (D199)

POCI was added to a solution of D198 (1.1 g, 6.57 mmol) in toluene (50 mL)₃(3.0 g, 19.6 mmol) and DIEA (2.08 g, 16.35 mmol) at room temperature. The mixed solution was refluxed overnight. The reaction solution was poured into ice water and extracted with EtOAc (50 ml <3). The combined organic layer was washed with NaHCC>3 (sat), brine, dried over Na2 SO₄and concentrated in vacuo. The crude product was purified by FCC (PE) to give the product as a colorless oil. LC-MS: 205.2 (M+V)⁺.¹HNMR (400 MHz, CDCI₃): 8 8,58 (s, 1H), 1,49 (s, 9H).

Description D200

3-(Trifluoromethyl)dihydro-2H-pyran-4(3H)-one (D200) To a solution of dihydro-2H-pyran-4(3H)-one (1.0 g, 10.0 mmol) and pyrrolidine ( 0.71 g, 10.0 mmol) in THF (20 mL) was added DMAP (1.46 g, 12.0 mmol) at room temperature. The mixture was stirred at room temperature for 30 minutes. Then 5-(trifluoromethyl)

dibenzothiophenium trifluoromethanesulfonate (4.97 g, 12.0 mmol) was added to the mixture. The mixture was stirred overnight at room temperature. TLC showed that the reaction was complete. The mixture was concentrated in vacuo to give a yellow oil. (500mg, yield 29%)

Description D201

2-(2-Methyl-1,3-dioxolan-2-yl)-N'-(3-(trifluormethyl)tetrahydro-2H-pyran-4-yl)acetohydrazide (D201 )

To a solution of D200 (500 mg, 2.98 mmol) in MeOH (40 mL) at room temperature was added D191 (550 mg, 3.27 mmol). The mixture was stirred overnight at room temperature.

NaBH3CN (938.7 mg, 14.9 mmol) and AcOH (18.0 mg, 0.30 mmol) were added to the mixture and the mixture was stirred at room temperature for 1 hour. The mixture was filtered and washed with a solution of NH4CI and brine, extracted with EA (3x20ml) and dried over Na2SO₄. The solvent was concentrated in vacuo to give a yellow oil. (220 mg, yield 23%)

Beschrijving D202 5-Methyl-1 -(3-(trifluormethyl)tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-3-ol (D202)

To a solution of D2 O1 (220 mg, 0.70 mmol) in EtOH (5 mL) was added TFA (159.6 mg, 1.40 mmol) at room temperature. The mixture was stirred overnight at 90°C. The mixture was concentrated and purified by column chromatography on silica gel (PE:EtOAc from 5:1 to 2:1) to afford the target product as a yellow oil. (130 g, yield 74%).

Description D203

5-Methyl-4-nitro-1 -(3-(trifluormethyl)tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-3-ol (D203)

To a solution of D202 (130 mg, 0.52 mmol) in H₂S0₄(5 ml) KNO was added₃(63 mg, 0.62 mmol) slowly at 0°C. The mixture was stirred at 0°C for 30 minutes. The reaction mixture was slowly poured into ice water and extracted with EtOAc (2 x 20 ml). The combined organic layer was washed with brine and dried over Na2SC>4, concentrated in vacuo to give a yellow solid. (140mg, yield 90%)

Example E1

14-Chloor-4-methyl-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo [11.3.1.0^{3 7}] heptadeca -1 (16),3,6,13(17),14-pentaene (E1)

To a solution of D9 (121 mg, 0.30 mmol) in /^'-PrOH (5 ml) HCl (0.03 ml, 0.3 mmol) was added. The reaction was stirred at 100°C for 16 hours. The reaction mixture was concentrated and the residue was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO3 solution (20 mL). Then the organic layer was concentrated and the residue was purified by prep-HPLC to give the title compound as a white solid (29 mg, yield 26.4%). LC-MS: 367.5[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,81 (s, 1H), 6,26 (s, 1H), 5,55 (s, 1H), 4,40 (br, 2H), 4,12-4,10 (m, 3H), 3,48-3,36 (m, 4H ), 2,29-2,21 (m, 5H), 1,92 (br, 2H), 1,80-1,74 (m, 2H).

Example E2

14-Chloor-10-methoxy-4-methyl-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0^{3 7}]heptadeca-1(16),3,6,13(17),14-pentaeen (E2)

To a solution of D16 (120 mg, 0.26 mmol) in EtOH (20 mL) was added Fe (72 mg). Then a solution of NH 4 Cl (68.9 mg) in H 2 O (2 ml) was added. The reaction was stirred overnight at 100°C. The mixture was filtered and the filter cake was washed with EtOH (2 x 50 mL). The combined filtrate was concentrated to give the title compound as a white solid (40 mg, yield 38.9%). LC-MS: 395.3[M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,85 (s, 1 H), 6,07 (s, 1 H), 5,68 (br, 1 H), 4,50 (d, J= 7,6 Hz, 1 H), 4,34-4,29 (m, 1H), 4,12-4,06 (m, 3H), 3,90 (d, J= 2,0 Hz, 1H), 3,52 (t, J= 1 1,6 Hz, 2H), 3,40 (s, 3H) , 3,36-3,27 (m, 2H), 2,32-2,20 (m, 5H), 1,81 -1,75 (m, 2H).

Examples E3 and E4

Enantiomeer 1 -2: 14-chloor-10-methoxy-4-methyl-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo [11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen (E3-E4)

E3-E4

The title compounds E3 (1.1 mg) and E4 (6 mg) were obtained as white solids from chiral resolution of E2 (27 mg) (chiral method A).

E3: LC-MS: 395,4[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,75 (s, 1 H), 6,57 (s, 1 H), 5,73 (br, 1 H), 4,44-4,21 (m, 2H), 4,05-3,98 (m, 3H), 3,87-3,81 (m , 1 uur), 3,47-3,41 (m, 2 uur), 3,35 (s, 3 uur), 3,29-3,21 (m, 2 uur), 2,25-2,14 (m, 5 uur), 1,75-1 ,68 (m, 2 uur ). Chirale RT= 4,48 min; ee% = 100%.

E4: LC-MS: 395,4[M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,83 (s, 1H), 6,67 (s, 1H), 5,79 (br, 1H), 4,51 -4,28 (m, 2H), 4,12-3,06 (m, 3H ), 3,94-3,88 (m, 1 uur), 3,54-3,48 (m, 2 uur), 3,42 (s, 3 uur), 3,36-3,28 (m, 2 uur), 2,31 -2,19 (m, 5 uur), 1 .82- 1 0,75 (m, 2H). Chirale RT= 5,41 min; ee% = 100%.

Example E5

14-chloor-4,11-dimethyl-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0³,⁷]heptadeca-1 (16),3,6,13(17),14-pentaeen (E5)

To a solution of D19 (250 mg, 0.56 mmol) in EtOH (20 mL) and H₂0 (4 ml) Fe (157 mg, 2.8 mmol) and NH were added₄CI (150mg, 3.8mmol). The reaction was stirred overnight at 100°C. The mixture was poured into water and extracted with EtOAc (3 <50 ml). The organic layer was concentrated. The crude was washed with CH3CN to give the title compound as a white solid (97 mg, yield 46.0%). LC-MS: 379.5[M+H]⁺.¹H NMR (400 MHz, CDCI's): 5 7,79 (s, 1 H), 6,62 (s, 1 H), 5,25-5,23 (m, 1 H), 4,50-4,47 (m, 1 H), 4,37-4,30 ( m, 1 H), 4,12-4,04 (m, 4H), 3,54-3,48 (m, 2H), 2,32-2,18 (m, 5H), 1,99-1,75 (m, 4H), 1,33 (d, J= 6,4 Hz , 3H).

Examples E6 and E7

(11 4-Chloor-4,11 -dimethyl-5-(oxan-4-yl)-8-oxa-2,5,6,12, 16, 17-hexaazatricyclo

[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen (E6)

(11 S)-14-Chloor-4,11 -dimethyl -5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0³'⁷]heptadeca-1 (16),3,6,13(17),14-pentaene (E7)

E6 E7

The title compounds E6 (141 mg) and E7 (148 mg) were obtained as white solids from chiral resolution of E5 (410 mg, chiral method A).

E6: LC-MS: 379,5[M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,82 (s, 1 H), 6,10 (s, 1 H), 5,14- 5,12 (m, 1 H), 4,50-4,47 (m, 1 H), 4,37-4,31 ( m, 1 H), 4.12-4.01 (m, 4H), 3.54-3.48 (m, 2H), 2.33-2.21 (m, 5H), 1.89-1.66 (m, 4H), 1.31 - 1 .25 (m, 3H). Chirale RT=4,84 min; ee= 100%.

E7: LC-MS: 379,5[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,82 (s, 1 H), 6,06 (s, 1 H), 5,13-5,1 1 (m, 1 H), 4,50-4,37 (m, 2H), 4,12-4,00 ( m, 4H), 3,54-3,48 (m, 2H), 2,33-2,20 (m, 5H), 1.89-1.66 (m, 4H), 1.33-1.25 (m, 3H). Chirale RT= 6,02 min; ee= 98,5%.

Examples E8 and E9

14-Chloor-4-methyl-5-(oxan-3-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}] heptadeca-1 (16),3,6, 13(17), 14-pentaeen (E8)

14-Chloor-5-(oxan-3-yl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca- 1 (16),3,6,13(17),14-pentaeen (E9)

To a solution of D28 and D29 (500 mg, 1.1 mmol) in EtOH (10 mL) was added Fe (325 mg, 5.5 mmol) and a solution of NH4Cl (58 mg, 1.1 mmol) in H2O ( 1 ml) added. . The reaction was stirred overnight at 100°C. The mixture was filtered and the filtrate was diluted with H 2 O (50 ml). The mixture was extracted with EtOAc (60 ml). The organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated. The crude was washed with CH3CN and hexane to give the title compounds E8 (50 mg, yield 13.0%) and E9 (41 mg, yield 10.6%) as a white solid.

E8: LC-MS: 365.5[M+H]⁺.¹1H NMR (400 MHz, DMSO-de): 8 8,29 (s, 1H), 7,75 (s, 1H), 7,29(br, 1H), 4,18 (br, 2H), 4,04 (m, 1H) , 3,83 (m, 2H), 3,48-3,30 (m, 2H), 2,14 (s, 3H), 2,02-1 0,93 (m, 3H), 1 0,70 (m, 5H).

E9: LC-MS: 351.2[M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,82 (s, 1H), 7,21 (s, 1H), 6,30 (br, 1H), 5,55 (br, 1H), 4,38 (m, 2H), 4,10 -4,04 (m, 2 uur), 3,88-3,85 (m, 1 uur), 3,68-3,63 (m, 1 uur), 3,54-3,49 (m, 3 uur), 2,18-2,03 (m, 2 uur), 1,95-1,93 ( m, 2H),1.82-1.71 (m, 2H)

Examples E10 and E11

Enantiomeren 1 -2: 14-Chloor-4-methyl-5-(oxan-3-yl)-8-oxa-2,5,6,12,16,17-hexaaza tricyclo-[11.3.1.0^{3 7}] heptadeca-1 (16),3,6,13(17),14-pentaene (E10 en 11)

The title compounds E10 (7.8 mg) and E11 (9.6 mg) were obtained as off-white solids from chiral resolution of E8 (chiral method A).

E10: LC-MS: 365.2[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,80 (s, 1 H), 6,36 (s, 1 H), 5,58- 5,55 (m, 1 H), 4,39-4,37 (m, 2H), 4,07-4,00 (m , 1 uur), 3,96-3,93 (m, 2 uur), 3,71 -3,66 (m, 1 uur), 3,54-3,46 (m, 2 uur), 3,45-3,40 (m 1 uur), 2,25-2,17 (m, 3 uur) , 2.06-2.03 (m, 1H), 1.94-1.90 (m, 2H), 1.89-1.80 (m, 3H). Chirale RT= 2,885 min; ee= 100%.

E11 : LC-MS: 365.2[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1 H), 6,43 (s, 1 H),

5,58-5,55 (m, 1 uur), 4,39-4,37 (m, 2 uur), 4,07-4,01 (m, 1 uur), 3,96-3,93 (m, 2 uur), 3,71 -3,66 (m, 1 uur), 3,53- 3.49 (m, 2H), 3.46-3.40 (m 1 H), 2.25-2.17 (m, 3H), 2.06-2.03 (m, 1 H), 1.91 (m, 2H), 1 .83-1.80 (m, 3H). Chirale RT= 5,694 min; ee= 100%.

Example E12 14-Chloro-4-methyl-5-(oxetan-3-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}] heptadeca-1 (16),3,6,13(17),14-pentaeen (E12)

To a solution of D34 (49 mg, 0.122 mmol) in EtOH/H₂0 (20 ml/2 ml) Fe (35 mg, 0.627 mmol) and NH 4 Cl (52 mg, 0.972 mmol) were added. The reaction was stirred overnight under argon at 100°C. The hot mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was dissolved in EtOAc (20 mL), washed with brine (10 mL), dried over anhydrous Na 2 SO₄, filtered and concentrated. The crude was purified by prep-TLC (CH 2 Cl 2 :MeOH=15:1) to give a yellow solid. The solid was suspended in PE (5 ml) and Et.2 O (a few drops). The result was sonicated, filtered and the filter cake was dried under an infrared lamp, collected to give the title compound as a pale yellow solid (16 mg, yield 39%). LC-MS: 337.1 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,82 (s, 1 H), 6,31 (br, 1 H), 5,59 (t, J= 5,8 Hz, 1 H), 5,32-5,25 (m, 1 H), 5,19 (t, J= 6,4 Hz, 2H), 4,91 (t, J= 6,8 Hz, 2H), 4,47 (t, J= 4,8 Hz, 2H), 3,53 (dd, J= 10,8, 6,0 Hz, 2H), 2,16 (s, 3H), 1,94 (t, J= 4,4 Hz, 2H).

Example E13

4,14-dichloor-5-(oxan-4-yl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}] heptadeca- 1 (16),3,6, 13(17),14-pentaeen (E13)

To a solution of D41 (60 mg, 0.14 mmol) in /^'-PrOH (5 ml) concentrated HCl (0.012 ml, 0.14 mmol) was added. The reaction was stirred at 80°C for 6 hours. The mixture was concentrated and the residue was diluted with EtOAc (20 mL). The mixture was washed with water (20 ml). The combined organic layer was dried over anhydrous Na 2 SO₄and concentrated in vacuo. The crude was washed with CH3CN and hexane to afford the title compound as an off-white solid (23 mg, yield 42%). LC-MS: 385.1 [M+H]⁺. Ή NMR (400 MHz, CDCI₃): δ 7,85 (s, 1 H), 6,25 (s, 1 H), 5,57 (s, 1 H), 4,39-4,30 (m, 3H), 4,12-4,08 (m, 2H), 3,55-3,49 (m , 4H), 2,29-2,19 (m, 2H), 1 .96-1 .94 (m, 2H), 1 .85-1 .82 (m, 2H).

Examples E14 and E15 14-Chloro-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca- 1 (16),3,6,13(17),14-pentaeen-4-carbonitril (E14)

4-Chloor-5-(oxan-4-yl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca- 1 (16),3,6,13(17),14-pentaeen-14-carbonitril (E15)

E14 E15

A mixture of E13 (110 mg, 0.29 mmol), Pd₂(dba)₃(28 mg, 0.03 mmol), Ru-phos (14 mg, 0.03 mmol) and Zn(CN)2 (103 mg, 0.87 mmol) in dioxane (5 ml) was stirred at 100° for 2 hours C in the microwave. The reaction mixture was poured into ice water (30 ml) and extracted with EtOAc (2 x 20 ml). The combined organic layer was dried over anhydrous Na 2 SO₄In

concentrated. The residue was purified by prep HPLC to give the title compound E14 as an off-white solid (2 mg, 2% yield) and E15 as a white solid (4 mg, 3% yield).

E14: LC-MS: 376.1 [M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,89 (s, 1H), 6,71 (br, 1H), 5,64 (br, 1H), 4,38-4,34 (m, 3H), 4,14-4,10 (m, 2H ), 3,56-3,50 (m, 4H), 2,28-2,23 (m, 2H), 1,96- 1,92 (m, 4H).

E15: LC-MS: 376.1 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 8,18 (s, 1 H), 6,69 (br, 1 H), 5,77 (br, 1 H), 4,38-4,34 (m, 3H), 4,13-4,10 (m, 2H ), 3,59-3,50 (m, 4H), 2,26-2,23 (m, 2H), 1,98- 1,97 (m, 2H), 1,86-1,82 (m, 2H).

Example E16

14-chloor-10-fluor-4-methyl-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen (E16)

To a solution of D44 (50 mg, 0.1 - 19 mmol) in /^'To -PrOH (3 ml) was added p-TsOH (22.68 mg, 0.1-19 mmol) at 25°C. The reaction was stirred at 125°C in the microwave for 1.5 hours. The mixture was filtered and the solution was concentrated. The crude was purified by MDAP (basic condition) to afford the title compound as a white solid (40 mg, 88% yield). LC-MS:

383.1 [M+V]⁺.¹H-NMR (400 MHz, DMSO-d₆): δ 8,46 (s, 1 H), 7,84 (s, 1 H), 7,81 (t, J= 6,0 Hz, 1 H), 4,54-4,14 (m, 4H), 4,03-3,87 (m, 2H), 3,82-3,63 (m, 1H), 3,51 -3,39 (m, 2H),

3,30-3,23 (m, 1H), 2,17 (s, 3H), 2,06-1 0,85 (m, 2H), 1 0,79-1 0,64 (m, 2H).

Examples E17 and E18

Enantiomeren 1 -2: 14-chloor-10-fluor-4-methyl-5-(oxan-4-yl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo [11.3.1.0^{3 7}]heptadeca-1 (16),3,6, 13(17),14-pentaeen (E17-E18)

E17-E18

The title compounds E17 (1.1 mg, yield 27.5%) and E18 (1.1 mg, yield 27.5%) were prepared from chiral HPLC resolution of E16 (chiral method B).

E17: LC-MS: 383.2[M+H]⁺.¹H-NMR (600 MHz, DMSO-d₆): δ 8,45 (s, 1 H), 7,84 (s, 1 H), 7,80 (t, J= 6,0 Hz, 1 H), 4,51 -4,30 (m, 3H), 4,26-4,16 (m, 1 H) , 4,02-3,86 (m, 2H), 3,81 -3,68 (m, 1 H), 3,45 (t, J= 12,0 Hz, 2H), 3,37 (dd, J=6,0, 15,2 Hz, 1 H), 2,17 (s , 3H), 2,05-1,88 (m, 2H), 1,80-1,62 (m, 2H). Chirale RT=2.499 min; ee= 100%.

E18: LC-MS: 383.2[M+H]⁺.¹H-NMR (600 MHz, DMSO-d₆): δ 8,45 (s, 1 H), 7,84 (s, 1 H), 7,80 (t, J= 6,0 Hz, 1 H), 4,49-4,31 (m, 3H), 4,28-4,16 (m, 1 H) , 4,00-3,90 (m, 2H), 3,80-3,65 (m, 1 H), 3,45 (t, J= 12,0 Hz, 2H), 3,40-3,35 (m, 1 H), 2,17 (s, 3H), 2,06 -1.88 (m, 2H), 1.80-1.64 (m, 2H). Chirale RT=2,865 min; ee= 99,3%.

Examples E19 and E20

Enantiomeren 1 -2: 14-chloor-11-ethyl-4-methyl-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0³,⁷]heptadeca-1(16),3,6,13(17),14-pentaene (E19-E20)

To a solution of D47 (230 mg, 0.501 mmol) in EtOH (28 ml) were added Fe (224 mg, 4.0 mmol) and a solution of NH₄CI (267 mg, 5.0 mmol) in H2O (3 mL). The reaction was stirred at 110°C for 16 hours. The mixture was filtered and the filter cake was washed with CH3CN. The filtrate was concentrated and the crude product was purified by flash chromatography on silica gel (CH 2 C:MeOH = 60:1 to 30:1) to give the racemic mixture. The solid was further separated by chiral HPLC (chiral method B) to give the title compound E19 (34 mg) as an off-white solid and E20 (33 mg) as a pale yellow solid.

E19: LC-MS: 393.2[M+H]⁺.¹H NMR (400 MHz, DMSO-de): 8 8,29 (s, 1 H), 7,78 (s, 1 H), 6,74 (d, J= 7,6 Hz, 1 H), 4,30-4,1 1 (m, 3H) , 3,96-3,91 (m, 2H), 3,60-3,56 (m, 1 H), 3,43 (t, J= 1 1,8 Hz, 2H), 2,15 (s, 3H), 2,02-1,88 (m, 2H), 1,76 -1,65 (m, 4H), 1,58-1,51 (m, 2H), 0,85 (t, J= 7,2 Hz, 3H). Chirale RT=2,179 min; ee= 100%.

E20: LC-MS: 393,2[M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆): δ 8,29 (s, 1 H), 7,78 (s, 1 H), 6,74 (d, J= 7,6 Hz, 1 H), 4,30-4,1 1 (m, 3H), 3,96-3,91 (m, 2H) , 3,60-3,56 (m, 1 H), 3,43 (t, J= 12,0 Hz, 2H), 2,15 (s, 3H), 2,02-1 0,88 (m, 2H), 1 0,76-1 0,65 (m , 4H), 1,58-1,51 (m, 2H), 0,85 (t, J= 7,2 Hz, 3H). Chirale RT=2,925 min; ee=100%.

Examples E21 -E28

Enantiomeren 1 -8: 14-chloor-5-(3-fluorooxan-4-yl)-4,11-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo [11.3.1.0^{3 7}]heptadeca-1(17),3,6,13,15-pentaeen (E21 -E28)

To a solution of D53 (330 mg, 0.71 mmol) in EtOH (10 ml) were added Fe (300 mg, 5.35 mmol) and a solution of NH₄Cl (1.2 g, 19 mmol) in H2O (2 mL). The reaction was stirred at 100°C for 10 hours. The crude was extracted with DCM (100 ml) and H₂0 (50ml). The organic layer was concentrated to afford a white solid (260 mg, 92% yield) which was further separated by chiral HPLC (chiral method A and C) to afford the title compounds E21-E28 as a white solid.

E21: 12 mg. LC-MS: 397.2[M+H]⁺.¹H NMR (400 MHz, CD3OD): 8 7,73 (s, 1H), 4,79-4,71 (m, 1H), 4,63-4,27 (m, 5H), 4,17 (q, J= 7,6 Hz, 1H), 4,09-4,01 (m, 1 uur), 3,95- 3,91 (m, 1 uur), 2,40-2,26 (m, 2 uur), 2,22 (s, 3 uur), 1,87-1,67 (m, 2 uur), 1 .29 (d, J= 7,2 Hz, 3H).¹⁹F NMR (376 MHz, CD3OD): 8 -195,56 (s, 1 F). Chirale RT=2,92 min (chirale methode A); ee =100%.

E22: 12 mg. LC-MS: 397.2[M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,73 (s, 1 H), 4,82-4,61 (m, 1 H), 4,45-4,25 (m, 3H), 4,17 (dd, J= 5,2, 10,8 Hz, 1 H), 4,06-3,90 ( m, 2H), 3,55 (t, J= 1 1,2 Hz, 1 H), 3,39 (dt, J= 3,6, 10,8 Hz, 1 H), 2,37 (dq, J= 4,8, 12,6 Hz, 1 H), 2,23 (s, 3H), 1,99 (d, J= 13,2 Hz, 1 H), 1,87-1,65 (m, 2H), 1,29 (d, J=7,2 Hz, 3H).¹⁹F-NMR (376 MHz, CD₃OD): 8 -195,56 (s, 1 F). Chirale RT=3,252 min (chirale methode A); ee =99,5%; E23: 13 mg. LC-MS: 397.2[M+H]⁺.¹H-NMR (400 MHz, CD₃OD): 57,73 (s, 1H), 4,79-4,68 (m, 1H), 4,61-4,28 (m, 4H), 4,27-4,13 (m, 2H), 4,05 (q, J= 7,6 Hz, 1H), 3,99 -3,89 (m, 1H), 2,53-2,30 (m, 2H), 2,21 (s, 3H), 1,87-1,66 (m, 2H), 1,29 (d, J= 7,2 Hz, 3H).¹⁹F NMR (376 MHz, CDsOD): 5-232,35 (s, 1F). Chirale RT=3,720 min (chirale methode A); ee =100%; E24: 12 mg. LC-MS: 397.1[M+H]⁺.¹H NMR (400 MHz, CD3OD): 57,73 (s, 1H), 4,81-4,74 (m, 1H), 4,47-4,28 (m, 3H), 4,19 (dd, J= 5,2, 10,8 Hz, 1H), 4,05- 3,87 (m, 2H), 3,54 (t, J= 11,2 Hz, 1H), 3,41 (dt, J= 3,6, 10,8 Hz, 1H), 2,33-2,17 (m, 4H), 1,99-1,65 (m, 3H) , 1,31 (d, J= 6,8 Hz, 3H).¹⁹F-NMR (377 MHz, CD₃OD): 5 -195,18 (s, 1 F). Chirale RT=3,887 min (methode A), 2,195 min (methode C); ee =99,1%;

E25: 11 mg. LC-MS: 397.2[M+H]⁺.¹H-NMR (400 MHz, CD₃OD): 57,73 (s, 1H), 4,79-4,70 (m, 1H), 4,64-4,27 (m, 5H), 4,21-4,12 (m, 1H), 4,09-4,00 (m, 1H), 3,98-3,85 (m, 1H), 2,40-2,27 (m, 2H), 2,22 (s, 3H), 1,86-1,70 (m, 2H), 1,29 (d, J= 6,8 Hz, 3H).¹⁹F-NMR (376 MHz, CD3OD): 5-232,14 (s, 1F). Chirale RT=3,887 min (methode A), 2,606 min (methode C); ee =99,1%;

E26: 16 mg. LC-MS: 397.2[M+H]⁺.¹H NMR (400 MHz, CD3OD): 8 7,74 (s, 1H), 4,82-4,72 (m, 1H), 4,48-4,25 (m, 3H), 4,19 (dd, J= 5,2, 10,8 Hz, 1H), 3,98 (dd, J= 3,2, 7,6 Hz, 2H), 3,54 (t, J= 11,2 Hz, 1H), 3,41 (dt, J= 3,6, 10,8 Hz, 1H), 2,36-2,17 (m, 4H), 1,99- 1,70 (m, 3H), 1,31 (d, J= 6,8 Hz, 3H).¹⁹F NMR (376 MHz, CD3OD): 8 -195,18 (s, 1F). Chirale RT = 4,794 min (chirale methode A); ee% =100%.

E27: 13 mg. LC-MS: 397.2[M+H]⁺.¹H NMR (400 MHz, CD3OD): 8 7,74 (s, 1H), 4,79-4,71 (m, 1H), 4,62-4,28 (m, 4H), 4,27-4,12 (m, 2H), 4,06 (q, J= 7,6 Hz, 1H), 4,00-3,84 (m, 1H), 2,52-2,30 (m, 2H), 2,22 (s, 3H), 1,87-1,67 (m, 2H), 1,30 (d, J= 6,8 Hz, 3H ).¹⁹F NMR (376 MHz, CD3OD): 8 -232,35 (s, 1F). Chirale RT = 5,616 min (chirale methode A); ee% =97,5%.

E28: 11 mg. LC-MS: 397.2[M+H]⁺.¹H NMR (400 MHz, CD3OD): 8 7,73 (s, 1H), 4,81-4,61 (m, 1H), 4,45-4,26 (m, 3H), 4,17 (dd, J= 5,2, 10,8 Hz, 1H) , 4,05-3,87 (m, 2H), 3,55 (t, J= 11,2 Hz, 1H), 3,39 (dt, J= 3,6, 10,8 Hz, 1H), 2,37 (dq, J= 4,8, 12,6 Hz, 1H), 2,23 (s, 3H), 2,05-1,94 (m, 1H), 1,86-1,69 (m, 2H), 1,29 (d, J= 6,8 Hz, 3H).¹⁹F-NMR (376 MHz, CD₃OD): 5-195.56 (s, 1F). Chirale RT= 6.330 min (chirale methode A); ee% =100%.

Examples E29 and E30

Enantiomeren 1-2: 14-broom-4,11-dimethyl-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaaza tricyclo[11.3.1.0³⁷]heptadeca-1(16),3,6,13(17),14-pentaeen (E29-E30)

To a solution of D56 (280 mg, 0.6 mmol) in EtOH (50 ml) were added Fe (168 mg, 3 mmol) and a solution of NH4Cl (160.4 mg, 3 mmol) in H2 O (5 ml) . The reaction was stirred overnight at 100°C. The mixture was filtered and the filter cake was washed with MeOH (3 x 100 mL). The combined filtrate was concentrated and the residue was poured into saturated NaHCO3 . The mixture was then extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO₄and concentrated to give the racemic product (230 mg, yield 95%). The solid was further separated by chiral HPLC (chiral method B) to give the title compounds E29 (70 mg) and E30 (69 mg) as off-white solids. E29: LC-MS: 423.2 [M+H]⁺.¹H NMR (400 MHz, CD3OD): 8 7,82 (s, 1 H), 4,41 -4,33 (m, 1 H), 4,30-4,23 (m, 2H), 4,06-4,02 (m, 2H), 3,94-3,93 ( m, 1H), 3,59-3,53 (m, 2H), 2,22-2,10 (m, 5H), 1,83-1,72 (m, 4H), 1,30-1,28 (d, J= 7,6Hz, 3H) . Chirale RT=2,336 min; ee =100%;

E30: LC-MS: 423.1 [M+H]⁺.¹H NMR (400 MHz, CD3OD): 8 7,82 (s, 1 H), 4,41 -4,38 (m, 1 H), 4,32-4,23 (m, 2H), 4,06-4,03 (m, 2H), 3,95-3,93 ( m, 1 H), 3,59-3,53 (m, 2H), 2,25-2,10 (m, 5H), 1,83-1,74 (m, 4H), 1,30-1,28 (m, 3H). Chirale RT=3,056 min; ee =100%;

Examples E31, E32, E33 and E34

Enantiomeren 1 -4: 14-chloor-4,10,11-trimethyl-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo [11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen (E31 -E34)

A mixture of D63 (220 mg, 0.48 mmol), NH₄CI (220 mg) en Fe (220 mg) in EtOH/H₂0 (20ml/5ml) was stirred at 100°C for 16 hours. Then aqueous NaHCC>3 (5 ml) was added dropwise. The mixture was filtered and the filtrate was concentrated. The residue was diluted with CH2 Cl2 (30 ml), dried over anhydrous Na2 SO₄, filtered and concentrated. The crude product was washed with CH3CN to give the racemic product (180 mg, yield 96%) as an off-white solid, which was resolved chirally (chiral method A) to give the title compounds E31-E34.

E31 : roze vaste stof, 34 mg. LC-MS: 393.2[M+H]⁺.¹1H NMR (400 MHz, CDCI3): 8 7,81 (s, 1H), 6,07 (br, 1H), 4,84 (br, 1H), 4,32-4,26 (m, 3H), 4,12-4,04 (m, 3H ), 3.53-3.47 (m, 2H), 2.33-2.19 (m, 5H), 1.91 (br, 1 H), 1.81 -1.73 (m, 2H), 1.30 (d, J= 7.2 Hz, 3H), 0,82 (d, J= 7,2 Hz, 3H). Chirale RT=1.596 min; ee =100%.

E32: roze vaste stof, 28 mg. LC-MS: 393.2[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,82 (s, 1 H), 6,09 (br, 1 H), 5,15 (br, 1 H), 4,31 -4,25 (m, 2H), 4,23-4,03 (m, 4H), 3,53-3,47 (m , 2H), 2,34-2,20 (m, 5H), 2,08-2,02 (m, 1H), 1,83-1,74 (m, 2H), 1,18 (d, J= 7,2 Hz, 3H), 0,93 (d, J= 7,6 Herz, 3H). Chirale RT=2,159 min; ee =100%.

E33: witte vaste stof, 32 mg. LC-MS: 393.2[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,81 (s, 1 H), 6,07 (br, 1 H), 4,84 (br, 1 H), 4,32-4,26 (m, 3H), 4,12-4,04 (m, 3H), 3,53-3,47 (m , 2H), 2,33-2,19 (m, 5H), 1,91 (s, 1 H), 1,81 -1,73 (m, 2H), 1,30 (d, 3H, J= 7,2 Hz), 0,82 (d, 3H, J= 7,2 Hz). Chirale RT=3,877 min; ee =100%.

E34: witte vaste stof, 30 mg. LC-MS: 393.2[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,83 (s, 1 H), 6,00 (br, 1 H), 5,15 (br, 1 H), 4,29-4,29 (m, 2H), 4,13-4,07 (m, 4H), 3,54-3,47 (m , 2H), 2,28-2,01 (m, 5H), 2,04 (br, 1H), 1,78-1,77 (m, 2H), 1,75 (d, J= 7,6 Hz, 3H), 0,93 (d, J= 8,0 Hz , 3H). Chirale RT=8,91 1 min; ee =100%.

Examples E35 and E36

Enantiomeren 1-2: 14-chloor-11-(methoxymethyl)-4-methyl-5-(oxan-4-yl)-8-oxa-2,5,6, 12, 16,17-hexaazatricyclo-[11.3. 1.0^{3 7}]heptadeca-1 (16),3,6, 13(17),14-pentaeen (E35-E36)

E35-E36 To a solution of D68 (247 mg, 0.520 mmol) in EtOH/H₂0 (80 ml/20 ml) Fe (146 mg, 2.61 mmol) and NH were added₄CI (139mg, 2.60mmol). The reaction was stirred at 105°C for 16 hours. aq. Na2C0₃was added and the mixture was filtered. The filter cake was washed with CH 2 Cl 2 /MeOH = 20:1 and the filtrate was concentrated. The residue was dissolved in DCM and filtered. The filtrate was concentrated to give the racemic product (180 mg, yield 61%). The title compounds E35 (62 mg) and E36 (77 mg) were prepared from chiral resolution (chiral method A) as white solids.

E35: LC-MS: 409.2[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): 5 7,82 (s, 1 H), 6,17 (s, 1 H), 5,68 (d, J= 7,2 Hz, 1 H), 4,50-4,47 (m, 1 H), 4,33 (t, J= 1 1,2 Hz, 1 H), 4,12-4,04 (m, 4H), 3,54-3,45 (m, 4H), 3,41 (s, 3H), 2,31 -2,20 (m, 2H), 2,20 (s, 3H), 2,07-2,01 (m, 1 uur), 1,82-1,75 (m, 3 uur). Chirale RT=3,129 min; ee =100%; E36: LC-MS: 409.2[M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,82 (s, 1 H), 6,14 (s, 1 H), 5,69 (d, J= 7,2 Hz, 1 H), 4,49 (dd, J= 1 1 .2, 3,6 Hz, 1 H), 4,33 (t, J= 1 1,2 Hz, 1 H), 4,12-4,04 (m, 4H), 3,54-3,45 (m, 4H), 3,41 (s, 3H), 2,31 - 2,20 (m, 2H), 2,20 (s, 3H), 2,07-2,01 (m, 1H), 1,83- 1,74 (m, 3H). Chirale RT=12.099 min; ee =100%;

Examples E37 and E38

Enantiomeren 1 -2: Ethyl 2-{14-chloor-4,11-dimethyl-8-oxa-2,5,6,12, 16,17-hexaazatricyclo [11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaen-5-yl}-2-methylpropanoate (E37-E38)

NH was added to a solution of D74 (750 mg) and Fe (750 mg) in 95% EtOH (60 ml)₄CI (1.6g). The reaction was heated to 90°C and stirred overnight. The mixture was filtered and the filtrate was concentrated to give the racemic product (700 mg, crude). The title compounds E37 (8 mg) and E38 (4 mg) were prepared from chiral resolution of racemic compound (52 mg) (chiral method D) as white solids.

E37: LC-MS: 409.3[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,76 (s, 1 H), 7,17 (br, 1 H), 5,39 (d, J= 6,8 Hz, 1 H), 4,47 (dd, J= 2,4, 1 1,6 Hz , 1 H), 4,37-4,28 (m, 1 H), 4,23 (q, J= 6,8 Hz, 2H), 4,14-3,92 (m, 1 H), 2,13 (s, 3H), 1 ,92-1,91 ( m, 2H), 1,76 (s, 3H), 1,75 (s, 3H), 1,35 (d, J= 6,8 Hz, 3H), 1,27 (t, J= 6,8 Hz, 3H). Chirale RT=2,41 min; ee =100%.

E38: LC-MS: 409.3[M+H]⁺.¹H NMR (400 MHz, CDCb): 8 7,75 (s, 1 H), 7,31 (br, 1 H), 5,42 (d, J= 6,4 Hz, 1 H), 4,55-4,41 (m, 1 H), 4,38 -4,28 (m, 1 H), 4,23 (q, J= 6,8 Hz, 2H), 4,09 (m, 1 H), 2,13 (s, 3H), 1,92-1,91 (m, 2H), 1,76 (s, 3H), 1,75 (s, 3H), 1,35 (d, J= 6,8 Hz, 3H), 1,27 (t, J= 6,8 Hz, 3H). Chirale RT=10,99 min; ee =100%.

Examples E39 and E40

Enantiomeren 1 -2: 2-{14-chloor-4,11-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo [11. 3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaen-5-yl}-2-methylpropanoic acid (E39-E40)

To a solution of ethyl 2-{14-chloro-4,1 1-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[1 1 .3.1.0³'⁷]heptadeca-1 (16)_!3_!6_!13(17),14-pentaen-5-yl}-2-methylpropanoate (600mg) in 95% EtOH (50ml) LiOH H was added₂0 (200mg). The reaction was heated to 50°C and stirred for 5 hours. 1M HCl solution (5ml) was added and the solid formed was filtered, dried to give the racemic product (600mg, crude), which was resolved (120mg) chirally (chiral method E) to give the title compound E39 (8 mg) and E40 (8 mg) as white solid.

E39: LC-MS: 381.2[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 10,16 (s, 1 H), 8,01 (s, 1 H), 7,69 (s, 1 H), 6,04 (s, 1 H), 4,47 (m, 1 H), 4,27-4,10 (m, 2H ), 2,17 (s, 3H), 2,00-1,92 (m, 2H), 1,80 (s, 3H), 1,79 (s, 3H) 1,41 (d, J= 7,2 Hz, 3H). Chirale RT=5,59 min; ee =100%.

E40: LC-MS: 381.2[M+H]⁺.¹H NMR (400 MHz, CDC): 8 8,02 (s, 1 H), 7,07 (s, 1 H), 6,06 (s, 1 H), 4,45 (m, 1 H), 4,25-4,09 (m, 2H) , 2,17 (s, 3H), 2,02-1 0,92 (m, 2H), 1,80 (s, 3H) , 1 0,79 (s, 3H), 1,41 (d, J= 6,8 Hz, 3H). Chirale RT=6,65 min; ee =100%.

Examples E41 and E42

Enantiomeren 1 -2: 2-{14-chloor-4,11-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaen-5-yl}-2-methylpropanamide (E41 - E42)

To a solution of 2-{14-chloro-4,1 1-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo [1 1.

3.1 .0³'⁷]heptadeca-1 (16),3,6,13(17),14-pentaen-5-yl}-2-methylpropanoic acid (200 mg, 0.52 mmol) in DMF (20 mL) was added to TBTU (202 mg, 0.62 mmol) and et₃N (127mg, 1.25mmol). After stirring at room temperature for 20 minutes, 7M NH 3 /THF solution (2 ml) was added and the mixture was stirred at room temperature for a further 3 hours. The mixture was then diluted with water (100ml), extracted with EtOAc (2x100ml), dried over Na2SO₄, filtered and concentrated to obtain the racemic product (120 mg, crude). The title compound E41 (3.1 mg and E42 (3.1 mg) were obtained as white solids by chiral resolution of the racemic product (40 mg) (chiral method D).

E41 : LC-MS: 380.3[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,78 (s, 1 H), 7,55-7,37 (m, 1 H), 5,46 (br, 2H), 5,36 (br, 1 H), 4,63-4,26 (m, 2H ), 4.15- 3.91 (m, 1 H), 2.26 (s, 3H), 1.99-1.86 (m, 2H), 1.80 (s, 3H), 1.79 (s, 3H), 1.38 (d, J = 6,8 Hz, 2H). Chirale RT = 5,79 min; ee =100%. E42: LC-MS: 380.3[M+H]⁺.¹H N MR (400 MHz, CDC): 8 8,18 (s, 1 H), 7,75 (br, 1 H), 5,65 (d, J= 6,0 Hz, 1 H), 5,48 (br, 1 H), 5,34 (br , 1 uur), 4,59-4,21 (m, 2 uur), 4,16-3,89 (m, 1 uur), 2,27 (s, 3 uur), 1,97-1 ,85 (m, 2 uur), 1,80 (s, 3 uur) , 1,78 (s, 3H), 1,40 (d, J= 6,8 Hz, 3H). Chirale RT = 8,06 min; ee =100%.

Examples E43 and E44

Enantiomeren 1 -2: 2-{14-chloor-4,11-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen-5-yl}-2-methylpropaannitril (E43-E44)

E43-E44

To a solution of 2-{14-chloro-4,1 1-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo [1 1.3. 1 .0³'⁷]heptadeca-1 (16),3,6,13(17),14-pentaen-5-yl}-2-methylpropanamide (80mg, 0.22mmol) in DCM (20ml) was added Et₃N (106mg, 1.05mmol). After stirring at 0°C for 10 minutes, TFAA (1.10 mg, 0.57 mmol) was added dropwise and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with NaHCC>3 solution (80 ml). The organic layer was dried and concentrated to obtain the racemic product (70 mg, crude). The title compound E43 (18 mg) and E44 (14 mg) were obtained as white solids by chiral resolution of the racemic product (chiral method A).

E43: LC-MS: 362.2[M+H]⁺.¹H NMR (400 MHz, CDCb): 7,79 (s, 1 H), 7,03 (br, 1 H), 5,35 (br, 1 H), 4,52-4,22 (m, 2 H), 4,05 (m, 1 H), 2,48 (s, 3H), 1,99 (s, 3H), 1,90 (s, 3H), 1,88-1,70 (m, 2H), 1,35 (d, J= 6,8 Hz, 3H). Chirale RT = 2,73 min; ee =100%.

E44: LC-MS: 362.2[M+H]⁺.¹1H NMR (400 MHz, CDCb): 8 7,81 (s, 1H), 6,67 (br, 1H), 5,27 (br, 1H), 4,52-4,23 (m, 2H), 4,04 (m, 1H) , 2,47 (s, 3H), 1,99 (s, 3H), 1,90 (s, 3H), 1,88-1,76 (m, 2H), 1,34 (d, J= 6,8 Hz, 3H). Chirale RT = 6,41 min; ee =100%.

Example E45

14-Chloor-4-methyl-5-[3-(morfolin-4-yl)cyclobutyl]-8-oxa-2,5,6,12,16,17-hexaaza tricyclo[11.3.1.0³'⁷]heptadeca-1(16),3,6,13(17),14-pentaeen (E45)

To a solution of D76 (195 mg, 0.401 mmol) and Fe (1.12 mg, 2.01 mmol) in EtOH/H₂0 (20 ml/4 ml) NH 4 Cl (107 mg, 2.00 mmol) was added. The reaction was heated to 100°C and stirred overnight. NaHCC>3 solution was added, the mixture was filtered and the filtrate was concentrated. The residue was suspended in CH2 Cl2 , dried over anhydrous Na2 SO₄filtered and concentrated to give the title compound as a white solid (69.3 mg, yield 41%). LC-MS: 420.2 [M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆): δ 8,30 (s, 1 H), 7,76 (s, 1 H), 7,32 (t, J= 5,8 Hz, 1 H), 4,43-4,32 (m, 1 H), 4,23 (br, 2H), 3,58 (br, 4H), 3,28 (d, J= 4,8 Hz, 2H), 2,45-2,40 (m, 3H), 2,28-2,21 (m, 6H), 2,10 (s, 3H), 1,72 (br, 2H).

Example E46

(11?)-14-chloor-4,11-dimethyl-5-[(3S)-oxolan-3-yl]-8-oxa-2,5,6,12,16,17-hexaazatricyclo [11.3. 1.0³,⁷]heptadeca-1(16),3,6,13(17),14-pentaeen(E46)

A solution of D80 (150 mg, 0.35 mmol), Fe (150 mg, 2.68 mmol) and NH₄BI (300 mg, 5,61 mmol) in EtOH/H₂0 (25 ml, 3:1) was heated to 90°C for 16 hours. Then saturated NaHCO3 (3 ml) was added and the mixture was stirred for 10 minutes. The mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated and the residue redissolved in DCM (50 ml). After stirring for 30 minutes, the mixture was filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EA=3:1 -1:1) to afford the title compound as an off-white solid (47 mg, yield 37%). LC-MS: 365.1 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,78 (s, 1 H), 7,24-7,20 (m, 1 H), 6,18 (m, 1 H), 5,36-5,34 (m, 1 H), 4,74-4,71 ( m, 1 uur), 4,48-4,44 (m, 1 uur), 4,35-4,30 (m, 1 uur), 4,08-4,03 (m, 3 uur), 3,96-3,91 (m, 1 uur), 2,35-2,26 (m , 2H), 2,23 (s, 3H), 1,89-1,81 (m, 2H), 1,31 (d, J= 7,2 Hz, 3H).

Example E47

(11 ?)-14-chloor-4,11 -dimethyl -5-[(3 ?)-oxolan-3-yl]-8-oxa-2,5,6,12, 16,17-hexaaza tricyclo [11.3 .1.0³,⁷]heptadeca-1(16),3,6,13(17),14-pentaeen (E47)

A solution of D81 (130 mg, 0.30 mmol), Fe (130 mg, 2.32 mmol) and NH₄BI (260 mg, 4,86 mmol) in EtOH/H₂0 (25 ml, 3:1) was heated to 90°C for 16 hours. Then saturated NaHCO3 (3 ml) was added and the mixture was stirred for 10 min. The mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated and the residue redissolved in DCM (50 ml). After stirring for 10 minutes, the mixture was filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EA = 5:1 -1:1) to afford the title compound as an off-white solid (41 mg, yield 37%). LC-MS: 365.2[M+H]⁺.¹H NMR (400 MHz, CDCI's): 8 8,20-8,25 (m, 1 H), 7,75 (s, 1 H), 5,59 (d, J= 6,4 Hz 1 H), 4,73-4,71 (m, 1 H), 4,48-4,44 (m, 1 uur), 4,35-4,30 (m, 1 uur), 4,08-4,03 (m, 3 uur), 3,96-3,91 (m, 2 uur), 2,35-2,26 (m, 2 uur), 2,23 (s , 3H),1,89-1 0,81 (m, 2H), 1 0,32 (d, J= 7,2 Hz, 3H).

Examples E48 and E49

Isomeren 1 -2: 14-chloro-4-methyl-5-{4-[(1?,4?)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]cyclohexyl}-8- oxa-2,5,6,12, 16, 17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6, 13 (17),14-pentaeen (E48-E49)

To a mixture of D85 (100 mg, 0.265 mmol), (1 R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (43 mg, 0.317 mmol), 4A molecular sieves (100 mg), AcOH (10 mg) in CH 2 Cl 2 (5 mL) under argon at 0°C, NaBH 3 CN (35 mg, 0.557 mmol) was added. The reaction was stirred at room temperature for 15 hours. The mixture was filtered and aq. NaHCC (20 ml) was added. The result was extracted with CH2 Cl2 (2 x 15 ml). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO₄, filtered and concentrated. The crude was purified by prep-TLC (CH 2 Cl 2 :MeOH = 8:1) to give the mixture as a yellow solid (71 mg, yield 58%). The title compounds E48 (8 mg) and E49 (34 mg) were obtained as white solids from chiral separation of the mixture (chiral method A).

E48: LCMS: 460.3[M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,83 (s, 1 H), 6,13 (s, 1 H), 5,55 (t, J= 6,0 Hz, 1 H), 4,54-4,27 (m, 3H), 4,08 ( d, J= 7,6 Hz, 1 H), 3,98-3,84 (m, 1 H), 3,71 -3,61 (m, 2H), 3,54 (q, J= 6,0 Hz, 2H), 3,09 (d, J= 9,6 Hz , 1H), 2,73 (br, 1H), 2,46-2,25 (m, 3H), 2,22 (s, 3H), 1,94 (m, 5H), 1,77 (d, J= 9,6 Hz, 1H), 1,70-1,48 ( m, 4H). Chirale RT = 4,532 min.

E49: LCMS: 460.4[M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,83 (s, 1H), 6,10 (s, 1H), 5,55 (t, J= 6,0 Hz, 1H), 4,53-4,22 (m, 3H), 4,07 (d, J= 8,0 Hz, 1 H), 3,87 (t, J= 11,6 Hz, 1 H), 3,75 (br, 1H), 3,65 (d, J= 7,6 Hz, 1H), 3,54 (q, J= 6,0 Hz, 2H), 3,13 (d, J= 9,6 Hz, 1H), 2,50 (d, J= 9,6 Hz, 2H), 2,21 (s, 3H), 2,14-1,86 (m, 9H), 1,84-1,75 (m, 1H ), 1.43-1.17 (m, 2H). Chirale RT =6,286 min.

Examples E50 and E51

Isomeren 1-2: 14-chloro-4-methyl-5-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]cyclohexyl}-8-oxa- 2,5,6,12, 16, 17-hexaazatricyclo[11.3.1.0³⁷]heptadeca-1 (16),3,6, 13 (17),14-pentaeen (E50-E51)

To a solution of D85 (100 mg, 0.265 mmol), (1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (43 mg, 0.319 mmol), 4A molecular sieves (100 mg), AcOH ( 10 mg) in CH 2 Cl 2 (5 ml) under argon at 0°C, NaBH 3 CN (35 mg, 0.557 mmol) was added. The reaction was stirred at room temperature for 15 hours. The mixture was filtered and aq. NaHCC (20 ml) was added. The organic layer was concentrated and the crude material was purified by prep-TLC (CH 2 Cl 2 :MeOH = 8:1) to give the mixture as a yellow solid (88 mg, yield 72%). The title compounds E50 (10 mg) and E51 (21 mg) were obtained as white solids from chiral separation of the mixture (chiral method F).

E50: LC-MS: 460,3 [M+H]⁺.¹H NMR (400 MHz, CDCb): 8 7,81 (s, 1H), 6,07 (br, 1H), 5,53 (br, 1H), 4,40 (br, 3H), 4,05 (d, J= 8,0 Hz, 1H ), 3,85 (br, 1H), 3,74 (br, 1H), 3,68-3,46 (m, 3H), 3,11 (d, J= 9,6 Hz, 1H), 2,48 (d, J= 9,2 Hz, 2H), 2,19 (s, 3H), 2,13-1,82 (m, 9H), 1,83- 1,72 (m, 1H), 1,40-1,18 (m, 2H). Chirale RT = 4,549 min.

E51: LC-MS: 460.3 [M+H]⁺.¹H NMR (400 MHz, CDCb): 8 7,81 (br, 1H), 6,07 (br, 1H), 5,53 (br, 1H), 4,40 (br, 3H), 4,06 (d, J= 7,6 Hz, 1H), 3,91 (br, 1H), 3,70-3,58 (m, 2H), 3,52 (d, J= 4,8 Hz, 2H), 3,07 (d, J= 8,4 Hz, 1H), 2,72 (br, 1H), 2,44-2,23 (m, 3H), 2,23-2,14 (m, 4H), 1,93 (br, 5H), 1,68-1,43 (m, 4H). Chirale RT = 5,341 min.

Example E52 (11 ?)-14-chloro-4,11-dimethyl-5-(oxetan-3-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen (E52)

To a solution of D109 (6.5 g, 15.58 mmol) in HOAc/MeOH (6 mL/60 mL) was added Zn (3.1 g, 46.73 mmol). The reaction was stirred at 80°C for 16 hours. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in CH2 Cl2 (150 ml) and washed with saturated NaHCC>3 (2 x 60 ml). The organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography on silica gel (CH 2 Cl 2 :MeOH = 50:1) to give a yellow solid (2.7 g). The solid was washed with CH3CN and EtOH, recrystallized

(CH 3 CN/MeOH then Ch C/hexane) to afford the title compound as a white solid (580 mg, yield 11%). LC-MS: 351.2[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,80 (s, 1 H), 6,61 (br, 1 H), 5,32-5,16 (m, 4H), 4,93-4,88 (m, 2H), 4,54-4,43 (m, 2H), 4,05-4,01 (m, 1H), 2,16 (s, 3H), 1,95-1,82 (m, 2H), 1,34 (d, J= 7,2 Hz, 3H).

Examples E53 and E54

Enantiomeren 1 -2: 14-chloor-11 -(fluormethyl)-4-methyl-5-(oxan-4-yl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen (E53-E54)

To a solution of D91 (480 mg, 1.04 mmol) in EtOH/H₂0 (58 ml/6 ml) Fe (463 mg, 8.29 mmol) and NH 4 Cl (554 mg, 10.4 mmol) were added at room temperature. The reaction was stirred at 110°C under argon for 18 hours. The reaction mixture was cooled to room temperature

temperature and then quenched with aq. Na2CC>3. The mixture was stirred at room temperature for 30 minutes and then filtered. The filtrate was concentrated and the crude product was purified by chromatography on silica gel (CH 2 Cl 2 :MeOH = 100:1 - 40:1) to give a racemic product (300 mg, yield 72%). The solid was then separated by chiral HPLC (chiral method B) to give the title compound E53 (84 mg) and E54 (81 mg) as white solids.

E53: LC-MS: 397,2 [M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆): δ 8,40 (s, 1 H), 7,83 (s, 1 H), 7,06 (d, J= 7,6 Hz, 1 H), 4,72-4,40 (m, 2H), 4,28-4,17 (m, 3H), 4,10-4,03 (m, 1H), 3,95-3,90 (m, 2H), 3,44 (t, J= 12,0 Hz, 2H), 2,16 (s, 3H), 2,07-1,87 (m, 2H), 1,77-1,69 (m, 3H), 1,47-1,41 (m, 1H).¹⁹F-NMR (376 MHz, DMSO-d₆): δ-217.12. Chiral RT= 2.305 min; yes= 100%.

E54: LC-MS: 397,2 [M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆): δ 8,40 (s, 1H), 7,83 (s, 1H), 7,06 (d, J= 8,0 Hz, 1H), 4,72-4,40 (m, 2H), 4,28-4,19 (m, 3H), 4,10-4,05 (m, 1H), 3,95-3,90 (m, 2H), 3,44 (t, J= 12,0 Hz, 2H), 2,15 (s, 3H), 2,07-1,85 (m, 2H), 1,77-1,69 (m, 3H ), 1.47-1.40 (m, 1H).¹⁹F-NMR (376 MHz, DMSO-d₆): δ-217.12. Chiral RT= 2.938 min; yes= 100%.

Examples E55, E56, E57 and E58

Enantiomeren 1-4: 14-chloor-4,11-dimethyl-5-{4-[(1 ?,4?)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]cyclohexyl}- 8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0³⁷]heptadeca- 1 (16),3,6, 13(17),14-pentaeen (E55-E58)

E55-E58

To a solution of D94 (200 mg, 0.51 mmol) and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride in MeOH (25 ml) was slowly added NaBH3CN (97 mg, 1.55 mmol) added. and the reaction was stirred for 16 hours. Then saturated NaHCC>3 (50 ml) was added and the mixture was stirred for 30 minutes. MeOH was evaporated and the mixture was filtered, extracted with DCM (3 x 25 ml). The combined organic layer was washed with saturated NaHCC>3, brine, dried over Na2 SO₄, filtered and concentrated to give the racemic product (200 mg, yield 89.3%). The yellow solid was then further chirally resolved (chiral method A) to afford the title compounds as white solids.

E55: LC-MS: 474.2[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,82 (s, 1H), 6,05 (s, 1H), 5,11(d, J= 4,0 Hz, 1H), 4,48-4,46 (m, 2H), 4,29 (t, J= 8,0 Hz, 1H), 4,08-4,00 (m, 2H), 3,92-3,89 (m, 1H), 3,73-3,71 (m, 1H), 2,68-2,65 (m, 1H), 2,17 (s, 3H), 2,09-1,73 (m, 11H ), 1,75-1,46 (m, 4H), 1,31 (d, J= 7,2 Hz, 3H). Chirale RT= 2.790; ee=100%. E56: LC-MS: 474.2[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,80 (s, 1H), 6,17 (s, 1H), 5,13 (d, J= 8,0 Hz, 1H), 4,52-4,38 (m, 3H), 4,07-3,95 (m , 3H), 3,71-3,69 (m, 2H), 3,20-3,10 (m, 1H), 2,78 (br, 1H), 2,46-2,23 (m, 2H), 2,17 (s, 3H), 1,92-1,72 (m , 9H), 1,50-1,47 (m, 2H), 1,32(d, J= 6,8 Hz, 3H). Chirale RT= 3,021; ee= 99,1%. E57: LC-MS: 474.2[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,81 (s, 1 H), 6,09 (s, 1 H), 5,1 1 (d, J= 8,0 Hz, 1 H), 4,50-4,43 (m, 2H), 4,31 (t, J= 8,0 Hz , 1 H), 4,07-3,99 (m, 2H), 3,87-3,3,84 (m, 2H), 3,66 (d, J= 8,0 Hz, 1 H), 3,19 (br, 1 H), 2,56 (br, 1H), 2,17 (s, 3H), 2,14-2,06 (m, 2H), 2,01 -1 ,73 (m, 9H), 1,46-1 ,37 (m, 2H), 1,31 (d, J= 8,0 Hz , 3H). Chirale RT= 3,293; ee= 100%. E58: LC-MS: 474.2[M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,80 (s, 1 H), 6,18 (s, 1 H), 5,14 (d, J= 8,0 Hz, 1 H), 4,52-4,50 (m, 2 H), 4,43 ( br, 1 H), 4,1 1 -3,93 (m, 3H), 3,66 (d, J= 4,0 Hz, 1 H), 3,14 (br, 1 H), 2,78 (m, 1 H), 2,36-2,24 (m , 3H), 2,17 (s, 3H), 1,92-1,75 (m, 9H), 1,68-1,60 (m, 2H), 1,33 (d, J= 8,0 Hz, 3H). Chirale RT= 3,509; ee=99,7%.

Examples E59 and E60

Enantiomeren 1 -2: irans-14-chloor-5-[3-fluor-1 -(2-methoxyethyl)piperidine-4-yl]-4-methyl-8-oxa-2,5,6,12,16, 17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca 1(16),3,6,13(17),14-pentaene (E59-E60)

E61-E62 To a solution of D97 (crude, 0.259 mmol) in MeCN (10.0 mL) was added 1-bromo-2-methoxyethane (72 mg, 0.518 mmol) and K2 CO3 (359 mg, 2.60 mmol). The reaction was heated to 100°C and stirred overnight. The cooled mixture was diluted with water and extracted 3 times with EtOAc. The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography over silica gel (CH2Cl2:

MeOH = 10:1) (80 mg, yield 70%) and then separated by chiral HPLC (chiral method A) to give the title compound E59 (16 mg) and E60 (16 mg) as white solids.

E59: LCMS: 440.2[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,80 (s, 1 H), 6,24 (s, 1 H), 5,54 (t, J= 6,4 Hz, 1 H), 5,08-4,80 (m, 1 H), 4,36 (t, J= 4,4 Hz, 2H), 3,91 -3,83 (m, 1 H), 3,52 (t, J= 5,4 Hz, 4H), 3,40-3,37 (m, 1 H), 3,37 (s, 3H), 3,04-3,01 (m, 1 uur), 2,70-2,64 (m, 2 uur), 2,47-2,39 (m, 1 uur), 2,23-2,15 (m, 2 uur), 2,20 (s, 3 uur), 1,99-1,74 (m, 3H).¹⁹F NMR (376 MHz, CDC13): 8 - 187,33. Chirale RT= 2,129; ee= 100%.

E60: LCMS: 440.2[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1 H), 6,15 (s, 1 H), 5,53 (d, J= 6,2 Hz, 1 H), 5,12-4,77 (m, 1 H), 4,36 (t, J= 4,6 Hz, 2H), 3,91 -3,84 (m, 1 H), 3,52 (t, J= 5,4 Hz, 4H), 3,40-3,37 (m, 1 H), 3,37 (s, 3H), 3,02 (d, J = 9,6 Hz, 1H), 2,72-2,63 (m, 2H), 2,45- 2,38 (m, 1H), 2,23-2,15 (m, 2H), 2,20 (s, 3H), 1 . 96-1.80 (m, 3H).¹⁹F-NMR (376 MHz, CDCb): δ-187.34. Chiral RT= 3,508; yes=100%. Examples E61 and E62

Enantiomeren 1 -2: irans-14-chloor-5-[3-fluor-1 -(oxetan-3-yl)piperidine-4-yl]-4-methyl-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaene (E61 -E62)

E61-E62

To a solution of D97 (500 mg, 1.3 mmol) in CH₃OH (10.0 ml) at 0°C, NaBH was added₃CN (572 g, 9.1 mmol). After stirring at room temperature for 1 hour, oxetan-3-one (468 mg, 6.5 mmol) at 0°C was added and the reaction mixture was stirred overnight at room temperature. The reaction was quenched with saturated NaHCC>3 and the result was extracted 3 times with EtOAc. The combined organic layers were dried, filtered and concentrated. The crude was purified by column chromatography on silica gel (CH 2 Cl 2 :MeOH = 10:1) (40 mg, 7%) and then separated by chiral HPLC (chiral method A) to yield the title compounds E61 (17 mg) and E62 to deliver. (17 mg) as a white solid.

E61 : LC-MS: 438.3[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1 H), 6,17 (s, 1 H), 5,54 (s, 1 H), 4,94 (d, J= 54,2 Hz, 1 H), 4,68 (t , J= 6,4 Hz, 2H), 4,61 (br, 2H), 4,39 (br, 2H), 3,95-3,90 (m, 1 H), 3,62 (t, J= 6,2 Hz, 1 H), 3,52 (s, 2H), 3,18-3,15 (m, 1 H), 2,82 (d, J= 10,8 Hz, 1 H), 2,44-2,39 (m, 1 H), 2,20 (s, 3H), 2,04-1,91 (m, 5H ).¹⁹F NMR (376 MHz, CDC13): 8 -187,32. Chirale RT= 4,072; ee=100%.

E62: LCMS: 438,3[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1 H), 6,24 (s, 1 H), 5,55 (t, J= 6,0 Hz, 1 H), 5,03-4,80 (m, 1 H), 4,68 (t, J= 6,6 Hz, 2H), 4,61 (t, J= 5,4 Hz, 2H), 4,39 (t, J= 4,6 Hz, 2H), 3,95-3,89 (m, 1 H), 3,62 (t, J = 6,4 Hz, 1 uur), 3,52 (br, 2 uur), 3,18-3,15 (m, 1 uur), 2,82 (d, J= 10,8 Hz, 1 uur), 2,44-2,39 (m, 1 uur), 2,20 ( s, 3H), 2,07-1 ,86 (m, 5H).¹⁹F NMR (376 MHz, CDC13): 8 -187,32. Chirale RT= 6,271 min; ee=100%.

Examples E63 and E64

Enantiomeren 1 -2: 14-chloor-10-fluor-4,11-dimethyl-5-(oxan-4-yl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaene (E63-E64)

E63-E64

To a solution of D106 (180 mg, 0.39 mmol) in MeOH (54 mL), HOAc (5.4 mL) and Zn (254 mg, 3.89 mmol) were added. The mixture was stirred at 75°C under nitrogen for 3 hours. The cooled mixture was filtered and the filtrate was concentrated. The residue was dissolved in DCM (50 ml) and the mixture was filtered. The filtrate was washed with sat. NaHCC>3 (50 ml), water (50 ml) and brine (20 ml), dried over Na2 SO₄, concentrated. The crude was purified by pre-TLC (CH₂CI₂: MeOH = 20:1) (120 mg, yield 78%) and further separated by chiral HPLC (chiral method E) to give the title compounds E63 (15 mg) and E64 (17 mg) as white solids.

E63: LC-MS: 397.2[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,82 (s, 1 H), 6,76 (s, 1 H), 5,23 (m, 1 H), 4,67-4,25 (m, 4H), 4,12-4,05 (m, 3H), 3,51 (t, J = 12,4 Hz, 2H), 2,30-2,13 (m, 5H), 1,78 (t, J= 1 1,2 Hz, 2H), 1 0,42 (d, J= 7,2 Hz, 3H). Chirale RT=2,397 min; ee=100%.

E64: LC-MS: 397.2[M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,80 (s, 1 H), 7,05 (s, 1 H), 5,28 (m, 1 H), 4,68-4,32 (m, 4H), 4,12-4,05 (m, 3H ), 3,51 (t, J= 12,4 Hz, 2H), 2,32-2,16 (m, 5H), 1,78 (t, J= 1 1,2 Hz, 2H), 1,43 (d, J= 7,2 Hz, 3H). Chirale RT=3,507 min; ee=100%.

Example E65

(11 ?)-14-chloor-4,11 -dimethyl -5-[1 -(oxetan-3-yl)piperidine-4-yl]-8-oxa-2,5,6,12,16,17- hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaene (E65)

To a solution of D100 (200 mg, 0.53 mmol) and oxetan-3-one (190 mg, 2.65 mmol) in MeOH (20 ml) was added NaBH3CN (67 mg, 1.55 mmol) and the reaction mixture was stirred for 16 hours. hours at room temperature. Saturated NaHCO3 (5 ml) was added and the reaction mixture was stirred for 10 min. The mixture was concentrated, filtered and extracted with DCM (50 ml). The combined organic layer was washed with saturated NaHCO's, brine, dried over Na 2 SO₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel to afford the title compound as a white solid (120 mg, yield 52%). LC-MS: 434.2[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,82 (s, 1 H), 6,08 (s, 1 H), 5,12 (d, J= 7,2 Hz, 1 H), 4,77- 4,57 (m, 4H), 4,51 - 4,27 (m, 2H), 4,02 (d, J= 3,2 Hz, 1 H), 3,93-3,77 (m, 1 H), 3,52 (t, J= 6,4 Hz, 1 H), 2,87 (d, J= 1 1,2 Hz, 2H), 2,27 (q, J= 12,4 Hz, 2H), 2,19 (s, 3H), 2,04-1,73 (m, 6H), 1,31 (d, J= 7,2 Hz, 3H).

Example E66

14-broom-4-methyl-5-(oxetan-3-yl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}] heptadeca-1 (16),3,6, 13(17),14-pentaeen (E66)

To a solution of D108 (133 mg, 0.297 mmol) and Fe (133 mg, 2.38 mmol) in EtOH/H₂0 (13ml/2ml) NH was added₄CI (266mg, 4.97mmol). The reaction was heated to 100°C and stirred overnight. Saturated NaHCO's (5 ml) was added and the mixture was filtered and concentrated. The residue was suspended in CH2 Cl2 (200 ml) and anhydrous Na2 SO₄had been added. The result was stirred at room temperature for 20 minutes, filtered and the filtrate was removed

concentrated. The residue was suspended in MeCN (10 ml) and the filter cake was dried to give the title compound as a white solid (8 mg, yield 7%). LC-MS: 381.1 [M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆): 5 8,38 (s, 1 H), 7,84 (s, 1 H), 7,18 (t, J = 5,6 Hz, 1 H), 5,44-5,37 (m, 1 H), 4,89 (t, J = 6,2 Hz , 2H), 4,80 (t, J= 7,2 Hz, 2H), 4,28 (t, J= 4,4 Hz, 2H), 3,29-3,28 (m, 2H), 2,09 (s, 3H), 1,73 (br, 2H) .

Examples E67 and E68

Enantiomeren 1 -2: (11 ?)-14-chloor-4,11 -dimethyl-5-[1 -(oxetan-3-yl)piperidine-3-yl]-8-oxa- 2,5,6,12 , 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaene (E67-E68)

E67-E68

To a solution of D112 (300 mg, 0.80 mmol) and oxetan-3-one (268 mg, 4.0 mmol) in MeOH (30 ml) was slowly added NaBH3CN (150 mg, 2.4 mmol) and the reaction mixture was stirred at room temperature. before 4 pm. Saturated NaHCO3 (50 ml) was added and the reaction was stirred for 20 min. Methanol was evaporated and the mixture was filtered, extracted with DCM (3 x 25 ml). The combined organic layers were washed with saturated NaHCC>3, brine, dried over Na2 SO₄, filtered and concentrated to give a yellow oil (240 mg, yield 69%). The racemic was further resolved chirally (chiral method A) to give the title compounds as white solids.

E67: LC-MS: 434.2[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,77 (s, 1 H), 6,97 (br, 1 H), 5,33 (d, J= 6,4 Hz, 1 H), 4,75-4,55 (m, 4H), 4,48 (dd, J= 2,8, 1 1,2 Hz, 1 uur), 4,34-4,22 (m, 1 uur),

4,17-3,95 (m, 2H), 3,56 (t, J= 6,4 Hz, 1 H), 2,84-2,69 (m, 2H), 2,34-2,24 (m, 2H), 2,23 (s, 3H), 2,04-1,95 (m, 2H), 1 0,94-1 0,81 (m, 4H), 1 0,34 (d, J= 7,2 Hz, 3H). Chirale RT=3,566 min; ee=100%.

E68: LC-MS: 434.2[M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,81 (s, 1 H), 6,20 (s, 1 H), 5,12 (d, J= 7,2 Hz, 1 H), 4,73-4,57 (m, 4 H), 4,48 ( dd, J= 2,8, 1 1,2 Hz, 1 H), 4,35-4,23 (m, 1 H),

4,17-3,92 (m, 2H), 3,57 (t, J= 6,4 Hz, 1 H), 2,96-2,68 (m, 2H), 2,37 (t, J= 10,4 Hz, 1 H), 2,20 (s, 3H) , 1,97-1,68 (m, 7H), 1,32 (d, J= 7,2 Hz, 3H). Chirale RT=6,693 min; ee=100%.

Example E69

4-Methyl-5-(oxan-4-yl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca- 1 (16),3,6,13(17),14-pentaeen-14-carbonitril (E69)

To a solution of D113 (100 mg, 0.33 mmol) in EtOH (40 ml) Fe (100 mg) and a solution of NH4 Cl (400 mg) in H were added.₂0 (2ml). The reaction was stirred at 100°C for 10 hours. The mixture was filtered and the filter cake was washed with CH3CN, and purified by prep-HPLC to afford the title compound (6 mg, yield 7.5%) as a white solid. LC-MS: 356.2[M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆): δ 8,19 (s, 1 H), 4,25-4,18 (m, 3H), 3,95-3,91 (m, 2H), 3,47-3,42 (m, 2H), 3,29-3,27 (m, 2H), 2,17 (s , 3H), 2,06-1,91 (m, 2H), 1,73-1,70 (m, 4H).

Examples E70-E77

14-Chloor-5-(3-fluoroxan-4-yl)-10-methoxy-4-methyl-8-oxa-2,5,6,12,16,17-hexaaza tricyclo[11.3.1.0³'⁷]heptadeca-1(16),3,6,13(17),14-pentaeen (E70-E77)

E70-E77 To a solution of D116 (250 mg, 0.52 mmol) in EtOH (10 ml) were added Fe (250 mg) and a solution of NH 4 Cl (1 g) in H.₂0 (2ml). The reaction was stirred at 100°C for 10 hours. The mixture was filtered and the filter was concentrated. The crude was purified by pre-TLC to give a yellow solid (180 mg, yield 83%), which was further separated by chiral HPLC (chiral method A and C) to give the title compounds as off-white solid substances.

E70: 20 mg. LC-MS: 413.2[M+H]⁺.¹H NMR (400 MHz, CD3OD): 8 7,74 (s, 1 H), 4,78-4,70 (m, 1 H), 4,63-4,12 (m, 5 H), 4,10-4,00 (m, 1 H), 3,83-3,73 (m, 1H), 3,42 (s, 3H), 3,27-3,14 (m, 3H), 2,51 -2,30 (m, 2H), 2,22 (s, 3H).¹⁹F-NMR (376 MHz, CD₃OD): 8-232,35 (s, 1F). Chirale RT= 3.844 min (chirale methode A); ja = 100%.

E71: 14 mg. LC-MS: 413.2[M+H]⁺.¹H NMR (400 MHz, CD3OD): 8 7,74 (s, 1 H), 4,79-4,72 (m, 1 H), 4,63-4,24 (m, 5 H), 4,17 (q, J= 7,6 Hz, 1 H), 4,05 (q, J= 7,6 Hz, 1 H), 3,83-3,72 (m, 1 H), 3,42 (s, 3H), 3,27-3,18 (m, 2H), 2,40-2,28 (m, 2H), 2,22 ( s, 3H).¹⁹F NMR (376 MHz, CD3OD): 5 -232,26 (s, 1 F). Chirale RT= 4,09 min (chirale methode A), 3,30 min (chirale methode C); ee = 100%.

E72: 12 mg. LC-MS: 413.2[M+H]⁺.¹H NMR (400 MHz, CD3OD): 8 7,74 (s, 1H), 4,76 (td, J= 4,8, 9,6 Hz, 1H), 4,43-4,24 (m, 3H), 4,19 (dd, J= 5,2, 10,8 Hz, 1 H), 3,98 (d, J= 1 1,6 Hz, 1 H), 3,85-3,74 (m, 1 H), 3,54 (t, J= 1 1,2 Hz, 1 H), 3,45-3,36 (m , 4H), 3,27-3,23 (m, 2H),

2.36-2.25 (m, 1 h), 2.23 (s, 3 h), 1.94-1.91 (m, 1 h).¹⁹F NMR (376 MHz, CD3OD): 8 -195,24 (s, 1 F). Chirale RT= 4,12 min (chirale methode A), 2,63 min (chirale methode C); ee = 100%. E73: 12 mg. LC-MS: 413.2[M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,74 (s, 1 H), 4,79-4,61 (m, 1 H), 4,43-4,23 (m, 3H), 4,17 (dd, J=5,2, 10,8 Hz, 1 H), 4,01 -3,98 ( m, 1 H), 3,83-3,72 (m, 1 H), 3,55 (t, J= 1 1,2 Hz, 1 H), 3,46-3,36 (m, 4H), 3,24 (d, J= 13,2 Hz, 2H), 2,36 (dq, J= 4,8, 12,6 Hz, 1H), 2,23 (s, 3H), 2,00-1,97 (d, 1H).¹⁹F-NMR (376 MHz, CD₃OD): δ -195.57 (s, 1F). Chiral purity: RT = 4.238 min (chiral method A); ee = 100%.

E74: 12 mg. LC-MS: 413.2[M+H]⁺.¹H NMR (400 MHz, CD3OD): 8 7,74 (s, 1 H), 4,79-4,70 (m, 1 H), 4,62-4,14 (m, 5 H), 4,08-4,05 (m, 1 H), 3,80-3,77 (m, 1H), 3,42 (s, 3H), 3,26-3,19 (m, 2H), 2,52-2,28 (m, 2H), 2,22 (s, 3H).¹⁹F-NMR (376 MHz, CD₃OD): 8 -232,35 (s, 1F). Chirale RT= 4,637 min (chirale methode A); ee = 99,4%.

E75: 12 mg. LC-MS: 413.2[M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,74 (s, 1 H), 4,79-4,71 (m, 1 H), 4,63-4,23 (m, 5 H), 4,21 -4,12 (m, 1 H), 4,09-3,99 (m, 1 H) , 3,84-3,73 (m, 1H), 3,42 (s, 3H), 3,26-3,18 (m, 2H), 2,41 -2,27 (m, 2H), 2,22 (s, 3H).¹⁹F-NMR (376 MHz, CD₃OD): 8-232,26 (s, 1F). Chirale RT= 4.805 min (chirale methode A); ja = 96,7%.

E76: 14 mg. LC-MS: 413.2[M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,74 (s, 1 H), 4,77 (dt, J= 5,6, 9,6 Hz, 1 H), 4,42 -4,25 (m, 3H), 4,19 (dd, J= 5,2, 10,8 Hz, 1 H) , 4,04-3,93 (m, 1 H), 3,86-3,75 (m, 1 H), 3,54 (t, J= 1 1,2 Hz, 1 H), 3,46-3,37 (m, 4H), 3,25 (d, J= 14,0 Hz, 2H), 2,35-2,20 (m, 4H), 1,95-1,91 (m, 1H).¹⁹F-NMR (376 MHz, CD₃OD): 8-195,24 (s, 1F). Chirale RT= 5.314 min (chirale methode A); ja = 96,7%.

E77: 14 mg. LC-MS: 413.2[M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,74 (s, 1 H), 4,81 -4,60 (m, 1 H), 4,42-4,10 (m, 4H), 4,04-3,92 (m, 1 H), 3,78 (dd, J= 2,8, 14,4 Hz, 1 H), 3,55 (t, J= 1 1,2 Hz, 1 H), 3,47- 3,34 (m, 4H), 3,26-3,14 (m, 2H), 2,36 (dq, J= 5,2 , 12,6 Hz, 1 H), 2,23 (s, 3H), 2,04-1,89 (m, 1H).¹⁹F-NMR (376 MHz, CD₃OD): 8-195,57 (s, 1F). Chirale RT= 5.658 min (chirale methode A); ja = 99,2%.

Examples E78-E85

Enantiomeren 1 -8: 14-chloor-4,11-dimethyl-5-(2-methyloxan-4-yl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaene (E78-E85)

To a solution of D117 (160 mg) in 95% EtOH (20 ml) were added Fe (160 mg) and NH₄BI (0.32g). The reaction was stirred overnight at 100°C. The reaction mixture was filtered and concentrated. The crude product was resolved chirally (chiral methods A and B) to afford the title compounds as off-white solids.

E78: 3,2 mg, opbrengst 2,3%. LC-MS: 393.3[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,77 (s, 1 H), 7,00 (br, 1 H), 5,34 (d, J= 6,0 Hz, 1 H), 4,48 (dd, J= 3,2, 1 1,2 Hz, 1 H), 4,42- 4,36 (m, 1 H), 4,31 (t, J= 10,4 Hz, 2H), 4,24- 4,15 (m, 1 H), 4,05 (br, 1 H), 3,89-3,74 (m, 1 H), 2,21 ( s, 3H), 2,10-1 0,97 (m, 3H), 1 0,94-1 0,80 (m, 2H), 1,72 (ddd, J= 4,8, 9,2, 13,8 Hz, 1 H), 1,35 (d, J= 6,8 Hz, 3H), 1,21 (d, J= 6,0 Hz, 3H). Chirale RT=3,094 min (chirale methode A); ee=100%.

E79: 2,6 mg, opbrengst 1,8%. LC-MS: 393.3[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,79 (s, 1 H), 6,69 (br, 1 H), 5,27 (d, J= 6,8 Hz, 1 H), 4,52-4,44 (m, 1 H), 4,43-4,27 (m, 3H) , 4,26-4,15 (m, 1 uur), 4,08-3,98 (m, 1 uur), 3,88-3,79 (m, 1 uur), 2,20 (s, 3 uur), 2,03-1,79 (m, 5 uur), 1,71 (ddd, J= 4,8, 9,2, 13,8 Hz, 1H), 1,34 (d, J= 6,8 Hz, 3H), 1,20 (d, J= 6,0 Hz, 3H). Chirale RT=3,780 min (chirale methode A), 2,157 min (chirale methode B); ee=97,5%.

E80: 1 mg, opbrengst 0,7%. LC-MS: 393.3[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): 5 7,67 (s, 1 H), 5,80 (d, J= 6,0 Hz, 1 H), 4,49 (d, J= 10,6 Hz, 1 H), 4,32-4,22 (m, 1 H), 4,12-4,09 (m, 3H), 3,59-3,46 (m, 3H), 2,29 (s, 3H), 2,21 - 2,07 (m, 1 H), 2,01 -1 ,82 (m, 4H), 1 ,73 (d, J = 1 1,6 Hz, 1 H), 1 0,39 (d, J= 6,8 Hz, 3H), 1,27 (d, J= 6,0 Hz, 3H). Chirale RT=3,780 min (chirale methode A), 2,731 min (chirale methode B); ee=97,5%.

E81: 3 mg, opbrengst 2,2%. LC-MS: 393.3[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 10,1 1 (br, 1 H), 7,61 (s, 1 H), 6,08 (d, J= 5,6 Hz, 1 H), 4,55-4,37 (m, 2H), 4,32-4,08 (m, 4H) , 3,88-3,76 (m, 1 uur), 2,30 (s, 3 uur), 2,09-1,84 (m, 5 uur), 1,78-1,68 (m, 1 uur), 1,43 (d, J= 6,8 Hz, 3H), 1,22 (d, J= 6,0 Hz, 3H). Chirale RT=3,780 min (chirale methode A), 3,306 min (chirale methode B); ee=97,5%.

E82: 2,8 mg, opbrengst 2%. LC-MS: 393.3[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,78 (s, 1 H), 6,98 (br, 1 H), 5,34 (d, J= 6,0 Hz, 1 H), 4,48 (dd, J= 2,4, 1 1,2 Hz, 1 H), 4,43- 4,37 (m, 1 uur), 4,36-4,28 (m, 2 uur), 4,25-4,16 (m, 1 uur), 4,09-3,99 (m, 1 uur), 3,89-3,80 (m, 1 uur), 2,21 (s , 3H), 2,07-1 ,80 (m, 5H), 1,71 (ddd, J= 5,2, 9,2, 13,8 Hz, 1 H), 1,35 (d, J= 6,8 Hz, 3H), 1,20 (d, J= 6,8 Herz, 3H). Chirale RT=4,414 min (chirale methode A); ee=100%.

E83: 1,1 mg, opbrengst 0,8%. LC-MS: 393.3[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): 8 7,96 (br, 1H),

7,72 (s, 1 uur), 5,58 (d, J= 5,6 Hz, 1 uur), 4,54-4,44 (m, 1 uur), 4,35-4,24 (m, 1 uur), 4,16-4,00 (m, 3 uur), 3,61 -3,48 (m, 2H), 2,26 (s, 3H), 2,20-2,09 (m, 1H), 2,01 -1,82 (m, 4H), 1,73 (d, J= 13,2 Hz, 1H ), 1,37 (d, J= 6,8 Hz, 3H), 1,27 (d, J= 6,0 Hz, 3H). Chirale RT=4,840 min (chirale methode A); ee=100%.

E84: 1,2 mg, opbrengst 0,8%. LC-MS: 393.3 [M+H]⁺. Ή NMR (400 MHz, CDCI₃): 5 7,82 (br, 1 H),

7,73 (s, 1 H), 5,54 (d, J= 6,0 Hz, 1 H), 4,56-4,44 (m, 1 H), 4,35-4,23 (m, 1 H), 4,09 (t, J= 1 1,6 Hz , 3H), 3,55 (t, J= 1 1,2 Hz, 2H), 2,31 -2,18 (m, 4H), 1,98- 1,71 (m, 5H), 1,36 (d, J= 6,8 Hz, 3H) , 1,25 (d, J= 6,0 Hz, 3H). Chirale RT=5,789 min (chirale methode A); ee=100%.

E85: 2,5 mg, opbrengst 1,8%. LC-MS: 393.3 [M+H]⁺. Ή NMR (400 MHz, CDCI₃): δ 7,97 (s, 1 H), 7,68 (s, 1 H), 5,80 (d, J= 5,6 Hz, 1 H), 4,49 (d, J= 12,4 Hz, 1 H), 4,33-4,24 (m , 1 H), 4,16-4,03 (m, 3H), 3,55 (t, J= 1 1,2 Hz, 2H), 2,28 (s, 3H), 2,22 (dd, J= 4,0, 12,0 Hz, 1 H), 2,03 -1,74 (m, 5H), 1,39 (d, J= 6,8 Hz, 3H), 1,25 (d, J= 6,0 Hz, 3H). Chirale RT=6,285 min (chirale methode A); ee=100%.

Examples E86 and E87

Enantiomeren 1 -2: 14-chloor-5-[4-fluorooxan-3-yl]-4-methyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo [11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen (E86-E87)

E86-E87 To a solution of D120 (230 mg, 0.512 mmol) in EtOH (27 ml) was added Fe (229 mg, 4.10 mmol) and a solution of NH4CI (274 mg, 5.12 mmol) in H2O (3 .0 ml) added. The reaction was stirred at 110°C for 16 hours. The reaction was quenched with aq. Na2CC>3 and the mixture was filtered through Celite. The filtrate was concentrated and the crude material was purified by flash column chromatography on silica gel (CH2CI2:MeOH=50:1 to 25:1) (70 mg, 35.7%) and further separated by chiral HPLC (chiral method A) to yield the title compounds. E86 (7 mg) and E87 (9 mg) as white solids.

E86: LC-MS: 383.2[M+H]⁺.¹H NMR (400 MHz, DMSO-de): 8 8,36 (s, 1 H), 7,76 (s, 1 H), 7,34 (s, 1 H), 5,1 1 -4,97 (m, 1 H), 4,20-4,18 (m, 3H), 3,96-3,94 (m, 2H), 3,56 (t, J= 1 1,2 Hz, 1 H), 3,51 -3,42 (m, 1 H), 3,33-3,28 (m, 2H), 2,16-2,14 (m, 4H), 1,84-1,72 (m, 3H).¹⁹F-NMR (376 MHz, DMSO-de): 5 -177,03. Chirale RT=3,972; ee=100%.

E87: LC-MS: 383.2[M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆): δ 8,36 (s, 1 H), 7,77 (s, 1 H), 7,34 (s, 1 H), 5,1 1 -4,97 (m, 1 H), 4,20-4,18 (m, 3H), 3,96-3,94 (m, 2H), 3,56 (t, J= 10,8 Hz, 1 H), 3,45 (t, J= 1 1 ,8 Hz, 1 H), 3,30-3,27 (m, 2H), 2,18-2,08 (m, 4H), 1.84-1.72 (m, 3H).¹⁹F-NMR (376 MHz, DMSO): 8-177,03. Chirale RT=5.717; ja=100%.

Examples E88 and E89

Enantiomeren 1 -2: 14-chloor-11 -(difluormethyl)-4-methyl-5-(oxan-4-yl)-8-oxa-2,5,6, 12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6, 13(17),14-pentaeen (E88-E89)

To a suspension of D127 (190 mg, 0.395 mmol) in ethanol (18 mL) was added Fe (1.10 mg, 1.974 mmol) followed by the addition of ammonia hydrochloride (106 mg, 1.974 mmol) in water (9 mL) . The reaction was sealed and heated to 90°C overnight. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The crude was purified by C18 chromatography (5-95% CH₃CN in water) (99 mg, yield 60.5%) and then separated by chiral HPLC (chiral method A) to give the title compound E88 (13 mg) and E89 (15 mg) as white solids.

E88: LC-MS: 415.2[M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆): δ 8,57 (s, 1 H), 7,95 (s, 1 H), 7,28 (d, J = 8,4 Hz, 1 H), 6,30 (dt, J = 56,8, 6,0 Hz, 1 H), 4,40-4,16 (m, 4H), 4,02-3,97 (m, 2H), 3,50 (t, J = 1 1,6 Hz, 2H), 2,22 (s, 3H), 2,16-1,92 (m, 3H), 1,85-1,73 (m, 2H), 1.58-1.52 (m, 1H).¹⁹F NMR (376 MHz, DMSO-de): 8 -120,56 (d, J = 280,5 Hz, 1 F), -127,79 (d, J = 280,1 Hz, 1 F). Chirale RT=3,472 min; ee=100%.

E89: LC-MS: 415.2[M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆): δ 8,51 (s, 1 H), 7,89 (s, 1 H), 7,22 (d, J = 8,4 Hz, 1 H), 6,24 (dt, J = 56,8, 6,0 Hz, 1 H), 4,34-4,10 (m, 4H), 3,95-3,91 (m, 2H), 3,43 (t, J = 1 1,8 Hz, 2H), 2,16 (s, 3H), 2,09-1,85 (m, 3H), 1,77-1,66 (m, 2H), 1.52-1.46 (m, 1H).¹⁹F-NMR (376 MHz, DMSO-d₆): δ -120.55 (d, J = 280.1 Hz, 1 F), -127.79 (d, J = 280.1 Hz, 1 F). Chiral RT=10,500 min; one=100%.

Examples E90 and E91

Isomeren 1 -2:4-{14-chloor-4-methyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}] heptadeca-1(16),3,6,13(17),14-pentaen-5-yl}cyclohexane-1-ol (E90-E91) .

E90-E91

To a solution of D85 (200 mg, 0.531 mmol) in MeOH (5 ml) at 0 °C was added NaBH₄(6mg, 0.159mmol). The reaction was stirred at room temperature for 45 minutes. Water (10 ml) was added and the mixture was extracted with CH2 Cl2 (3 x 15 ml). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO₄, filtered and concentrated. The crude was purified by prep-TLC (CH2Cl2:MeOH = 10:1) (120 mg, yield 60%) and then separated by chiral HPLC (chiral method E) to give the title compound E90 (58 mg) and E91 (12 mg). ) deliver. mg) as white solids.

E90: LC-MS: 379,3 [M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,82 (s, 1 H), 6,09 (s, 1 H), 5,53 (t, J= 6,0 Hz, 1 H), 4,42-4,35 (m, 2H), 3,93- 3,83 (m, 1 uur), 3,80-3,69 (m, 1 uur), 3,56-3,47 (m, 2 uur), 2,20 (s, 3 uur), 2,14-2,1 1 (m, 2 uur), 2,09-1,98 ( m, 2H), 1,94-1,91 (m, 4H), 1,49-1,33 (m, 2H). Chirale RT=4.155.

E91 : LCMS: 379,3 [M+H]⁺.¹H NMR (400 MHz, CDCb): 8 7,81 (s, 1 H), 6,06 (s, 1 H), 5,53 (t, J= 6,0 Hz, 1 H), 4,41 -4,38 (m, 2H), 4,08 ( br, 1 uur), 3,92-3,86 (m, 1 uur), 3,54-3,49 (m, 2 uur), 2,36-2,24 (m, 2 uur), 2,22 (s, 3 uur), 2,03-1,89 (m, 4 uur), 1.73-1.65 (m, 4H). Chirale RT=5.923.

Examples E92-E95

Enantiomeren 1 -4: 4-{14-chloor-4,11 -dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0^{3 7}]heptadeca-1(16),3,6,13(17),14-pentaen-5-yl}cyclohexane-1-ol (E92-E95)

E92-E95

To a solution of D94 (250 mg, 0.64 mmol) in MeOH (30 ml) was added NaBH₄(48.4 mg, 1.3 mmol) at 0-5°C. The reaction was stirred at room temperature for 2 hours. The mixture was added to aq. NaHCC>3 (30 ml) and extracted with EtOAc (2x80 ml). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated in vacuo to give the racemic product. The white solid was further chirally resolved by chiral HPLC (chiral method B) to afford the title compounds as white solids.

E92: 1,1 mg opbrengst 0,4%. LC-MS: 393.3[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 9,6 (s, 1 H), 7,63 (s, 1 H), 5,96 (m, 1 H), 4,47 (d, J= 13,6 Hz, 1 H), 4,29 (d, J= 9,2 Hz, 1 H), 4,09 (m, 2H), 2,29 (m, 5H), 1,92 (m, 4H), 1,66 (m, 4H), 1,25 (d, J= 6,8 Hz, 3H). Chirale RT=2,656 min; ee=100%.

E93: 6 mg opbrengst 2,4%. LC-MS: 393.3[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 8,98 (br, 1 H), 7,68 (s, 1 H), 5,81 (d, J= 6,0 Hz, 1 H), 4,53-4,43 (m, 1 H), 4,30-4,17 (m, 1 H ), 4,10 (dd, J= 3,6, 6,4 Hz, 1 H), 3,95-3,67 (m, 2H), 2,27 (s, 3H), 2,15-1 ,81 (m, 8H), 1,51 -1,41 (m, 2H), 1,38 (d, J= 6,8 Hz, 3H). Chirale RT=2,824 min; ee=97,3%.

E94: 1,1 mg opbrengst 0,4%. LC-MS: 393.3[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): 7,67 (s, 1 H), 5,85-5,61 (m, 1 H), 4,48 (d, J= 12,0 Hz, 1 H), 4,29 (d, J= 9,2 Hz, 1 H), 4,09 (br, 2H),

2,36-2,22 (m, 5H), 2,04-1 0,82 (m, 4H), 1,68 (d, J= 12,0 Hz, 4H), 1 0,38 (d, J= 6,8 Hz, 3H). Chirale RT=3.180 min; ee=97,5%.

E95: 6mg opbrengst 2,4%. LC-MS: 393.3[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,85 (br, 1 H), 7,73 (s, 1 H), 5,54 (d, J= 6,0 Hz, 1 H), 4,55-4,41 (m, 1 H), 4,35-4,19 (m, 1 H ), 4,07 (d, J= 3,6 Hz, 1 H), 3,95-3,67 (m, 2H), 2,24 (s, 3H), 2,15-1,84 (m, 8H), 1,51 -1,39 (m, 2H), 1,36 (d, J= 6,8 Hz, 3H). Chirale RT=3,37 min; ee=100%.

Examples E96-E99

Enantiomeren 1 -4: 14-chloor-5-[3-fluor-1 -(oxetan-3-yl)piperidine-4-yl]-4,11 -dimethyl-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6, 13(17),14-pentaeen (E96-E99)

A solution of D130 (151 mg, 0.38 mmol) and oxetan-3-one (124 mg, 1.717 mmol) in MeOH (20 ml) was stirred at room temperature for 1 hour and then NaBH3(CN) (108 mg, 1.717 mmol) was added. The reaction was stirred overnight at room temperature. Sovent was evaporated and the crude product was purified by pre-HPLC followed by chiral resolution (chiral method C) to afford the title compounds as white solids.

E96: LC-MS: 452.2[M+H]⁺.¹H NMR (400 MHz, CDC): 8 8,14 (br, 1H), 7,71 (s, 1H), 5,61 (br, 1H), 5,11-4,85 (m, 1H), 4,74-4,64 (m, 2H), 4,60 (br, 2H), 4,47(d, J= 12,0 Hz, 1H), 4,35-4,25 (m, 1H), 4,09 (br, 1H), 3,92 (d, J= 13,8 Hz, 1H), 3,63 (t, J= 6,4 Hz, 1H), 3,25 -3,09 (m, 1H), 2,82 (d, J= 10,4 Hz, 1H), 2,50-2,32 (m, 1H), 2,25 (s, 3H), 2,11-1,89 (m , 5H),

I.38 (d, J= 6,8 Hz, 3H).¹F NMR (376 MHz, CDCb): 8 -187,108 (s, 1F). Chirale RT=2,748 min; ee= 98,8%.

E97: LC-MS: 452.2[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,73 (s, 1H), 7,59 (br, 1H), 5,48 (d, J= 6,8 Hz, 1H), 5,12-4,83 (m, 1H), 4,72-4,66 (m , 2H), 4,64-4,57 (m, 2H), 4,51-4,43 (m, 1 H), 4,36-4,26 (m, 1 H), 4,07 (d, J= 3,2 Hz, 1 H), 3,97-3,85 ( m, 1H), 3,62 (q, J= 6,4 Hz, 1H), 3,23-3,12 (m, 1H), 2,82 (d, J= 10,0 Hz, 1H), 2,46-2,32 (m, 1H), 2,23 (s, 3H), 2,09-1,86 (m, 5H), 1,36 (d, J= 6,8 Hz, 3H).¹F NMR (376 MHz, CDCI3): 8 -187,043 (s, 1F). Chirale RT=2,812 min; ee= 98,1%.

E98: LC-MS: 452.2[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1 H), 6,47 (br, 1 H), 5,21 (d, J= 6,8 Hz, 1 H), 5,01 -4,79 (m, 1 H), 4,71 -4,65 (m, 2H), 4,63-4,57 (m, 2H), 4,46 (dd, J= 2,4,

II.2 Hz, 1H), 4,39-4,28 (m, 1H), 4,12-3,83 (m, 2H), 3,62 (quin, J= 6,4 Hz, 1H), 3,19-3,12 (m, 1H), 2,83 (d , J= 9,6 Hz, 1H), 2,53-2,38 (m, 1H), 2,21 (s, 3H), 2,08-1,77 (m, 5H), 1,32 (d, J= 6,8 Hz, 3H).¹F NMR (376 MHz, CDCb): 8 -187,647 (s, 1F). Chirale RT=2,955 min; ee= 100%.

E99: LC-MS: 452.2[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 8,14 (br, 1H), 7,71 (s, 1H), 5,61 (br, 1H), 5,10-4,86 (m, 1H), 4,74-4,66 (m, 2H), 4,60 (br, 2H), 4,47 (d, J= 12,0 Hz, 1H), 4,35-4,24 (m, 1H), 4,09 (br, 1H), 3,92 (d, J= 13,6 Hz, 1H), 3,63 (t, J= 6,4 Hz, 1H), 3,22 -3,14 (m, 1H), 2,82 (d, J= 10,4 Hz, 1H), 2,46-2,32 (m, 1H), 2,25 (s, 3H), 2,10-1,85 (m , 5H), 1,38 (d, J= 6,8 Hz, 3H).¹F NMR (376 MHz, CDCb): 8 -187,578 (s, 1F). Chirale RT=3,255 min; ee=98,1%.

Examples E100 and E101 Enantiomers 1 -2: (11 ?)-14-chloro-5-[3-fluoro-1 -(2-methoxyethyl)piperidin-4-yl]-4,11-dimethyl-8-oxa-2 ,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17), 14-pentaene (E100-E101)

E100-E101 A solution of D133 (396 mg, 1.0 mmol), K₂C0₃(692mg, 5.0mmol) and 1-bromo-2-methoxyethane (209mg, 1.5mmol) in CH3CN (15ml) was stirred overnight at 60°C. The mixture was extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated to give the racemic product (1-10 mg, yield 25%). The crude was purified by pre-HPLC and further separated by SFC (chiral method A) to afford the title compounds as white solids.

E100: LC-MS: 454.2[M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,76 (s, 1 H), 6,95 (br, 1 H), 5,32 (d, J= 6,8 Hz, 1 H), 5,1 1 -4,83 (m, 1 H), 4,44 (dd, J= 2,4, 1 1,2 Hz, 1 H), 4,35-4,22 (m, 1 H), 4,05 (br, 1 H), 3,95-3,82 (m, 1 H), 3,64 (d, J= 6,0 Hz, 2H), 3,53 (t, J= 5,2 Hz, 2H), 3,45-3,37 (m, 1 H), 3,37 (s, 3H), 3,03 (d, J= 1 1,2 Hz, 1 H), 2,77 -2,57 (m, 2H), 2,50-2,33 (m, 1H), 2,27-2,12 (m, 4H), 1,98-1,68 (m, 2H), 1,34 (d, J= 7,0 Hz, 3H).¹F-NMR (376 MHz, CDCb): 8-186,91 (s, 1F). Chirale RT=3.734 min; ja= 100%.

E101 : LC-MS: 454.2[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,73 (s, 1 H), 5,52 (d, J= 5,6 Hz, 1 H), 5,05 - 4,69 (m, 1 H), 4,43 (d, J= 12,0 Hz, 1 uur), 4,35-4,23 (m, 1 uur), 4,05 (br, 1 uur), 3,89 (d, J= 9,2 Hz, 1 uur), 3,70-3,48 (m, 4 uur), 3,45-3,37 (m, 1 H), 3,37 (s, 3H), 3,07 (d, J= 1 1,2 Hz, 1 H), 2,72 (d, J= 5,6 Hz, 2H), 2,53-2,37 (m, 1 H), 2,24 (m , 4H), 1 0,97-1,84 (m, 2H), 1,35 (d, J= 6,8 Hz, 3H).¹F NMR (376 MHz, CDCI3): 8 -187,553 (s, 1 F). Chirale RT=5,943 min; ee= 100%.

Examples E102-E105

Enantiomeren 1 -4: 14-chloor-4,11-dimethyl-5-{4-[(1 S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]cyclohexyl}-8 -oxa-2,5,6,12,16,17-hexaazatricyclo-[11.3.1.0^{3 7}]-hepta deca-1(16),3,6,13(17),14-pentaene (E102-105)

E102-E105 To a solution of D94 (200 mg, 0.51 mmol) and (1 S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (346 mg, 2.56 mmol) in MeOH ( 25 ml) NaBH was slowly added₃CN (97 mg, 1.55 mmol) and the reaction was stirred for 16 hours. Sat. NaHCC>3 (50 ml) was added and the mixture was stirred for 30 minutes. MeOH was evaporated and the mixture was filtered and extracted with DCM (3 x 25 ml). The combined organic layer was washed with brine, dried over Na 2 SO₄, filtered and concentrated. The crude product was further chirally resolved (chiral method A) to afford the title compounds as yellow solids.

E102: LC-MS: 474.2[M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,84 (s, 1 H), 6,05 (br, 1 H), 5,1 1 (d, J= 6,8 Hz, 1 H), 4,56-4,25 (m, 3H), 4,05 (d, J= 7,6 Hz , 2H), 3,91 -3,53 (m, 3H), 3,1 1 (d, J= 9,6 Hz, 1 H), 2,47 (d, J= 10,2 Hz, 2H), 2,18 (s, 3H), 2,13-1 . 72 (m, 1 1 H), 1,32 (d, J= 6,8 Hz, 3H). Chirale RT=2,841 min; ee=100%.

E103: LC-MS: 474.2[M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,81 (s, 1 H), 6,06 (br, 1 H), 5,1 1 (d, J= 6,8 Hz, 1 H), 4,58-4,22 (m, 3H), 4,13 -3,81 (m, 3H), 3,72-3,52 (m, 2H), 3,05 (d, J= 9,6 Hz, 1 H), 2,72 (br, 1 H), 2,47-2,20 (m, 3H), 2,20 (s , 3H), 2,04-1,47 (m, 10H), 1,32 (d, J= 6,8 Hz, 3H) Chirale RT=3,031 min; ee=99,7%.

E104: LC-MS: 474.3[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,82 (s, 1 H), 6,05 (br, 1 H), 5,1 1 (d, J= 6,4 Hz, 1 H), 4,58-4,25 (m, 3H), 4,05 (d, J= 8,0 Hz, 2H), 3,90-3,53 (m, 3H), 3,10 (d, J= 9,6 Hz, 1 H), 2,47 (d, J= 9,6 Hz, 2H), 2,18 (s, 3H ), 2,1 1 -1 0,74 (m, 1 1 H), 1,31 (d, J= 6,8 Hz, 3H). Chirale RT=3,296 min; ee= 97,5%

E105: LC-MS: 474.2[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1 H), 6,08 (br, 1 H), 5,1 1 (d, J= 6,8 Hz, 1 H), 4,61 -4,20 (m, 3H), 4,1 1 -3,80 (m, 3H), 3,70-3,56 (m, 2H), 3,09 (d, J= 9,6 Hz, 1 H), 2,73 (br, 1 H), 2,44-2,21 (m, 3H), 2,19 ( s, 3H), 1,99-1,71 (m, 6H), 1,68-1,48 (m, 4H), 1,31 (d, J= 6,8 Hz, 3H). Chirale RT= 3,539 min; ee= 99,3%

Example E106

(11p)-14-chloor-4,11-dimethyl-5-[3-(morfoline-4-yl)cyclobutyl]-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3. 1.0^{3 7}]heptadeca-1 (16),3,6, 13(17),14-pentaeen (E106)

To a solution of D135 (100 mg, 0.3 mmol) in MeOH (20 ml) was added morpholine (130.7 mg, 1.5 mmol) and AcOH (2 ml). After stirring at room temperature for 30 minutes, NaBH3CN (94.26 mg, 1.5 mmol) was added. The reaction was stirred overnight at room temperature. The mixture was poured into saturated NaCl (aq) and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO₄and concentrated in vacuo. The crude was purified by SFC to give the target product as an off-white solid (25 mg, yield 19%). LC-MS: 434.3 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): 5 7,72 (s, 1 uur), 4,50-4,37 (m, 3 uur), 3,97-3,94 (m, 1 uur), 3,75-3,73 (m, 4 uur), 2,73 (br, 1 uur), 2,60- 2.47 (m, 8H), 2.17 (s, 3H), 1.80-1.76 (m, 2H), 1.30-1.23 (m, 3H).

Example E107

(11 ?)-14-chloor-4,11 -dimethyl -5-[1 -(oxetan-3-yl)azetidine-3-yl]-8-oxa-2,5,6,12, 16,17- hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaene (E107)

To a solution of D160 (crude in MeOH (5 ml)) at room temperature was added oxetan-3-one (130 mg, 1.8 mmol), NaBI-CN (189 mg, 3 mmol) and HOAc (1 ml). . The reaction was stirred under argon at 70°C for 1 hour. The cooled mixture was diluted with water and then concentrated. The crude was purified by prep-HPLC to afford the title compound as a white solid (53 mg, yield 22%). LC-MS: 406.1 [M+H]⁺. Ή NMR (400 MHz, CD₃OD): 5 7,95 (s, 1 H), 5,41 -5,35 (m, 1 H), 5,01 -4,93 (m, 2H), 4,78-4,68 (m, 4H), 4,65-4,61 (m, 2H), 4,55 -4,52 (m, 1 uur), 4,49-4,43 (m, 2 uur), 4,08 (br, 1 uur), 2,24 (s, 3 uur), 1,97-1,83 (m, 2 uur), 1,39 (s, 3 uur) .

Examples (E108-E378) shown in Table 1 were generally prepared according to the Examples described above.

table 1

14-chloor-4,5-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0³'⁷]heptadeca-1 (16),3, 6, 13(17), 14-pentaeen (E108)

The compound was prepared using procedures similar to those used to prepare E1 from 1,5-dimethyl-1/-/-pyrazole.

LC-MS: 295,2 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): d 7,82 (s, 1H),

6,12 (s, 1 H), 5,56 (s, 1 H), 4,39 (t, J= 4,4 Hz, 2H), 3,64 (s, 3H), 3,52 (t, J= 4,8 Hz, 2H), 2,19 (s , 3H), 1,93 (s, 2H). 2.43-2.40 (m, 1H), 2.31 -2.22 (m, 4H), 1.93-1.90 (m, 2H). Chirale RT=4,355 min (chirale methode F); ee=100%.

E124: LCMS: 351 .5 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,79 (s, 1 H), 6,57 (s, 1 H), 5,62 (s, 1 H), 4,74-4,70 (m, 1 H), 4,39-4,37 (m, 3 H), 4,17-4,1 1 (m, 2H), 3,99-3,91 (m, 2H), 3,54-3,50 (m, 2H), 2,43- 2,40(m, 1 H), 2,31 -2,22 (m, 4H), 1,93-1,90 (m, 2H). Chirale RT=4,731 min (chirale methode A); ee=98,9%.

4- Methyl-5-(oxan-4-yl)-14-(trifluormethyl)-8-oxa-2,5,6,12,16- pentaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14- pentaeen (E125)

The compound was prepared using procedures similar to those used to prepare E1 starting from 2,4-dichloro-5-(trifluoromethyl)pyridine and D7.

LCMS: 398,5 [M+H]⁺.¹HNMR (400 MHz, CD3OD): 8 7,86 (s, 1 H), 5,63 (s, 1 H), 4,66-4,62 (m, 1 H), 4,32-4,27 (m, 2H), 4,07-4,03 (m, 2H), 3.61 -3.55 (m, 1H), 3.48-3.45 (m, 1H), 2.21 -2.13 (m, 3H), 2.04-1 .90(m, 2H), 1.81 -1 .79 (m , 2H).¹⁹F-NMR (400 MHz, CD₃VAN):

5 - 62,4 (s, 3F).

ΗΝ-Λ 4-Methyl-5-(oxolan-3-yl)-14-(trifluormethyl)-8-oxa-2,5,6,12,16,

17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14- pentaeen (E126)

The compound was prepared using procedures similar to those used before

Prepare E126 / Jo E1, starting from 2,4-dichloro-5-(trifluoromethyl)pyridine and tetrahydrofuran-3-ol.

LCMS: 385,2 [M+H]⁺.¹H NMR (400 MHz, CDC): 8 8,06 (s, 1 H), 6,82 (s, 1 H), 5,58 (s, 1 H), 4,75-4,71 (m, 1 H), 4,40-4,38 (m, 2H), 4,18-4,06 (m, 2H), 3,99-3,92 (m, 2H), 3,54-3,50 (m, 2H), 2,43- 2,37 (m, 2H), 2,30 (s, 3H), 2,06-1 . 91 (m, 2H).

Enantiomeren 1 -2: 4-methyl-5-(oxolan-3-yl)-14-(trifluormethyl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca- 1 (16),3, 6,13(17),14-pentaeen (E127-E128)

Compounds were prepared from chiral resolution of E126.

E127: LCMS: 385,3 [M+H]⁺.¹H NMR (400 MHz, CDCb): 8 8,06 (s,

1 uur), 6,77 (s, 1 uur), 5,58 (s, 1 uur), 4,73-4,71 (m, 1 uur), 4,39-4,38 (m, 2 uur), 4,18-4,06 (m, 2 uur), 3,99- 3,92 (m, 2H), 3,54-3,49 (m, 2H), 2,43-2,37 (m, 2H), 2,3(s, 3H), 1,96-1,82 (m, 2H).¹⁹F NMR (400 MHz, CDCb): 8 -60,9 (s, 3F). Chirale RT= 2,353 min (chirale methode A); ee= 100%.

E128: LCMS: 385,3 [M+H]⁺.¹H NMR (400 MHz, CDCb): 8 8,06 (s, 1 H), 6,82 (s, 1 H), 5,58 (s, 1 H), 4,75-4,71 (m, 1 H), 4,40~4,38 (m, 2H), 4.18-4.06 (m, 2H), 3.99-3.92 (m, 2H), 3.54-3.50 (m, 2H), 2.43-2.37 (m, 2H), 2.3(s, 3H), 1 .97- 1.91 (m, 2H).¹⁹F NMR (400 MHz, CDCb): 8 -60,9 (s, 3F). Chirale RT= 3,581 min (chirale methode A); ee= 100%.

RT = 2.577 min (chiral method A); ee= 100%. for

H),

for H),

8.29

for H), 14-Chloro-4-methyl-5-(3-methyloxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen (E139)

The compound was prepared using procedures similar to those used to prepare E8 starting from 3-methyltetrahydro-2/-/-pyran-4-ol.

LC-MS: 379,2 [M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,8 (s, 1 H), 6,42 (s, 1 H), 5,59 (s, 1 H), 4,39-4,37 (m, 2H), 4,26-4,21 (m, 2H ), 3,92-3,89 (m, 1 uur), 3,64-3,49 (m, 4 uur), 2,49-2,46 (m, 1 uur), 2,21 (s, 3 uur), 2,07-2,05 (m, 1 uur), 1,84- 1,81 (m, 1H), 1,30-1,21 (m, 2H), 0,89-0,84 (m, 3H).

Enantiomeren 1 -2: 14-chloor-4-methyl-5-(3-methyloxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1(16),3,6,13(17),14-pentaene (E140-E141)

Compounds were prepared from chiral resolution of E139.

E140: LC-MS: 379,2 [M+H]⁺.¹1H NMR (400 MHz, CDsODj: 8 7,70

(s, 1 uur), 4,46-4,41 (m, 1 uur), 4,35-4,33 (m, 2 uur), 4,20-4,17 (m, 1 uur), 3,86-3,83 (m, 1 uur), 3,69-3,58 ( m, 2H), 3,42-3,39 (m, 2H), 2,49- 2,44 (m, 1 H), 2,23 (s, 3H), 2,09-2,07 (m, 1 H), 1,88-1,76 (m , 3H), 0,84 (d, J= 8,0 Hz, 3H). Chirale RT= 4,006 min (chirale methode A); ee=98,7%.

E141 : LC-MS: 379,2 [M+H]⁺.¹H NMR (400 MHz, CDsODj: δ 7,71 (s, 1 H), 4,46-4,41 (m, 1 H), 4,35-4,32 (m, 2H), 4,21 -4,16 (m, 1 H), 3,86-3,82 ( m, 1 uur), 3,69-3,58 (m, 2 uur), 3,42-3,40 (m, 2 uur), 2,48- 2,44 (m, 1 uur), 2,23 (s, 3 uur), 2,09-2,07 (m, 1 uur) , 1,88-1,76 (m, 3H), 0,84 (d, J= 8,0 Hz, 3H) Chirale RT= 4,569 min (chirale methode A), ee= 100%.

HN-— v 14-chloor-5-(4,4-difluorcyclohexyl)-4-methyl-8-oxa-2,5,6,12,

16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen (E142)

The compound was prepared using procedures similar to those used before

^E142preparation of E1, starting from D146.

F, LC-MS: 399,2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,92 (s, 1 H), 6,95 (s, 1 H), 5,72 (s, 1 H), 4,43-4,33 (m, 2H), 4,02-3,95 (m, 1 H), 3,61 -3,55 (m, 2H), 2,39-2,31 (m, 7H), 1,99-1,85 (m, 6H).

14-Chloor-4-methyl-5-[(3-methyloxetan-3-yl)methyl]-8-oxa-2,5, 6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1(16),3,6,13(17),14-pentaene (E143)

The compound was prepared using procedures similar to those used to prepare E12, starting from D33 and (3-methyloxetan-3-yl)methyl methane sulfonate.

LC-MS: 365.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1H), 6,17 (br, 1H), 5,55 (br, 1H), 4,77 (d, J= 6,0 Hz, 2H), 4,38 (d, J= 6,0 Hz, 2H), 4,34 (t, J= 4,4 Hz, 2H), 4,05 (s, 2H), 3,51 (dd, J= 10,8, 6,0 Hz, 2H), 2,18 (s, 3H), 1,91 ( br, 2H), 1,26 (s, 3H).

Chirale RT= 5,461 min (chirale methode F); ee= 100%. Enantiomeren 1 -8: 14-chloor-5-[4-(3-fluorpyrrolidin-1 -yl)cyclohexyl]-4,11-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0³-⁷]heptadeca-1(16),3,6,13(17),14-pentaene (E156-E163)

Compounds were prepared using procedures similar to those used to prepare E55 from D94 and 3-fluoropyrrolidine.

E156: LC-MS: 464,3 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,82 (s, 1 H), 6,05 (s, 1 H), 5,30-5,05 (m, 2H), 4,54-4,23 (m, 2H), 4,07-3,74 (m, 2H), 3,10-2,67 ( m, 3H), 2,57-2,43 (m, 1 H), 2,18 (s, 3H), 2,14- 1,75 (m, 1 1 H), 1,48-1,36 (m, 2H), 1,31 ( d, J= 6,8 Hz, 3H). Chiraal

RT= 2,744 min (chiral method A); ee= 100%.

E157: LC-MS: 464.2 [M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,82 (s, 1H), 6,07 (br, 1H), 5,32-5,02 (m, 2H), 4,54-4,24 (m, 2H), 4,08- 3,79 (m, 2H), 3,06-2,88 (m, 2H), 2,87-2,69 (m, 1H), 2,52 (d, J= 6,0 Hz, 1H), 2,26-1,77 (m, 14H), 1,49-1 . 36 (m, 2H), 1,31 (d, J= 6,8 Hz, 3H). Chirale RT= 3,849 min (chirale methode A); ee=100%.

E158: LC-MS: 464.3 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1 H), 6,04 (s, 1 H), 5,32-5,06 (m, 2H), 4,54-4,27 (m, 2H), 4,08- 3,83 (m, 2H), 3.00-2.55 (m, 4H), 2.45-2.22 (m, 3H), 2.19 (s, 3H), 2.15- 1 .98 (m, 3H), 1 .93-1 .78 (m, 2H ), 1,64-1,48 (m, 4H), 1,31 (d, J= 6,4Hz, 3H). Chirale RT= 6,065 min (chirale methode A); ee= 100%.

E159: LC-MS: 464.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1 H), 6,06 (br, 1 H), 5,32-5,01 (m, 2H), 4,57-4,27 (m, 2H), 4,1 1 - 3,86 (m , 2H), 3.07-2.53 (m, 4H), 2.43-2.24 (m, 3H), 2.20 (s, 3H), 2.1 1 -1 .98 (m, 3H), 1 .94-1.85 (m, 2H ), 1,70-1,50 (m, 4H), 1,32 (d, J= 6,0 Hz, 3H). Chirale RT= 6,985 min (chirale methode A), 2,568 min (chirale methode A); ee= 100%.

E160: LC-MS: 464,2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1 H), 6,07 (s, 1 H), 5,35-5,04 (m, 2H), 4,53-4,27 (m, 2H), 4,07-3,85 (m, 2H), 3.07-2.56 (m, 4H), 2.43-2.23 (m, 3H), 2.19 (s, 3H), 2.14- 1 .98 (m, 3H), 1 .94-1 .85 (m, 2H ), 1,70-1,50 (m, 4H), 1,31 (d, J= 7,8 Hz, 3H). Chirale RT= 6,985 min (chirale methode A), 3,107 min (chirale methode A); ee= 100%.

E161 : LC-MS: 464.3 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1 H), 6,05 (s, 1 H), 5,32-5,06 (m, 2H), 4,56-4,27 (m, 2H), 4,07-3,85 (m, 2H), 3,02-2,52 (m, 4H), 2,43-2,21 (m, 3H), 2,19 (s, 3H), 2,15-1 0,96 (m, 3H), 1 0,93-1 0,84 (m, 2H ), 1,70-1,47 (m, 4H), 1,31 (d, J= 6,8 Hz, 3H). Chirale RT= 8,389 min (chirale methode A); ee= 100%.

E162: LC-MS: 464,2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1 H), 6,07 (s, 1 H), 5,31 -5,04 (m, 2H), 4,54-4,23 (m, 2H), 4,08-3,76 (m, 2H), 3,1 1 -2,69 (m, 3H), 2,59-2,38 (m, J= 6,4 Hz, 1 H), 2,18 (s, 3H), 2,15-1 0,72 (m, 1 1 H), 1 . 48-1,37 (m, 2H), 1,31 (d, J= 6,8 Hz, 3H). Chirale RT= 8,759 min (chirale methode A); ee= 100%.

E163: LC-MS: 464.3 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1 H), 6,1 1 (s, 1 H), 5,25-5,1 1 (m, 2H), 4,54-4,21 (m, 2H), 4,10-3,67 ( m, 2H), 3,1 1 -2,69 (m, 3H), 2,57-2,41 (m, 1H), 2,24-1,79 (m, 14H), 1 .48-1 .36 (m, 2H), 1,31 (d , J= 7,2 Hz, 3H). Chirale RT= 9.940 min (chirale methode A); ee= 100%. Enantiomeren 1-4: 2-{14-chloor-4,10,11-trimethyl-8-oxa-2,5,6, 12, 16,17-hexaazatricyclo[11.3.1.0³⁷]heptadeca-1 (16),3,6, 13(17),14-pentaeen-5-yl}-2-methylpropaannitril (E164-E167)

Compounds were prepared using procedures similar to those used to prepare E43.

E164: LC-MS: 376,3 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,82 (s, 1H), 6,29 (s, 1H), 4,87 (d, J= 6,8 Hz, 1H), 4,36-4,11 (m, 3H), 2,46

(s, 3H), 1,96 (s, 3H), 1,92 (s, 3H), 1,90-1,84 (m, 1H), 1,32 (d, J= 7,2 Hz, 3H), 0,82 (d, J= 6,8 Hz, 3H). Chirale RT= 2,942 min (chirale methode A); ee= 100%.

E165: LC-MS: 376,3 [M+H]⁺.¹H NMR (400 MHz, CDC): 57,84 (s, 1H), 6,13 (s, 1H), 5,18 (d, J= 7,6 Hz, 1H), 4,35-4,18 (m, 2H), 4,14 -4,01 (m, 1H), 2,46 (s, 3H), 2,05-1,99 (m, 1H), 1,98 (s, 3H), 1,91 (s, 3H), 1,19 (d, J= 7,6 Hz, 3H), 0,93 (d, J = 7,6 Herz, 3H). Chirale RT= 4,144 min (chirale methode A); ee= 99,5%.

E126: LC-MS: 376.3[M+H]⁺.¹H NMR (400 MHz, CDCb): 8 7,82 (s, 1H), 6,18 (s, 1H), 4,87 (d, J= 6,8 Hz, 1H), 4,32-4,19 (m, 3H), 2,46 (s, 3H ), 1,96 (s, 3H), 1,92 (s, 3H), 1,90-1,84 (m, 1H), 1,32 (d, J= 6,8 Hz, 3H), 0,82 (d, J= 6,8 Hz, 3H). Chirale RT= 4,732 min (chirale methode A); ee= 100%.

E167: LC-MS: 376.3[M+H]⁺.¹H NMR (400 MHz, CDCb): 57,84 (s, 1H), 6,15 (s, 1H), 5,18 (d, J= 7,6 Hz, 1H), 4,34-4,20 (m, 2H), 4,14 -4,04 (m, 1H), 2,46 (s, 3H), 2,06-1,99 (m, 1H), 1,98 (s, 3H), 1,91 (s, 3H), 1,19 (d, J= 7,6 Hz, 3H), 0,93 (d, J = 7,6 Herz, 3H). Chirale RT= 5,656 min (chirale methode A); ee= 100%.

Enantiomeren 1-2: 14-broom-11-(methoxymethyl)-4-methyl-5-(oxan-4-yl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0³⁷] heptadeca-1 (16),3,6,13(17),14-pentaeen (E168-E169)

Compounds were prepared using procedures similar to those used to prepare E35 starting from 5-bromo-2,4-dichloropyrimidine.

E168: LC-MS: 453.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,91 (s,

E168-E169 1H), 6,18 (s, 1H), 5,69 (d, J= 7,2 Hz, 1H), 4,50-4,46 (m, 1H), 4,36- 4,31 (m, 1H), 4,12-4,05 (m, 4H ), 3,54-3,45 (m, 4H), 3,41 (s, 3H), 2,31-2,20 (m, 5H), 2,05-2,01 (m, 1H), 1,82-1,73 (m, 3H). Chirale RT= 2,382 min (chirale methode B); ee= 99,7%.

E169: LC-MS: 453.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,86 (s, 1 H), 5,97 (d, J= 6,8 Hz, 1 H), 4,48 (dd, J= 11,6, 2,8 Hz, 1 H), 4,34- 4,28 ( m, 1H), 4,12-4,05 (m, 4H), 3,54-3,46 (m, 4H), 3,42 (s, 3H), 2,31-2,21 (m, 5H), 2,07-2,03 (m, 1H), 1,81- 1.74 (m, 3H). Chirale RT= 3,057 min (chirale methode B); ee= 99,8%.

HN— (* Enantiomeren 1-8: 14-Chloor-5-(3-methoxycyclohexyl)-4,11-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0³⁷] heptadeca-1 (16),3,6, 13(17),14-pentaeen (E170-E177)

Compounds were prepared using procedures similar to those used

E170-E177' for preparing E79, starting from D73 and 3-methoxycyclohexylmethanesulfonate. E170: LC-MS: 407.3 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,72 (s, 1H), 4,41 (d, J= 6,0, 2,4 Hz, 1H), 4,27 (t, J= 9,6 Hz, 2H), 3,95- 3,93 (m, 1H), 3,74 (br, 1H), 3,35 (s, 3H), 2,19 (s, 3H), 2,09-1,95 (m, 3H), 1,82-1,72 (m, 5H), 1,66-1,41 (m, 2H), 1,29 (d, J= 6,8 Herz, 3H). Chirale RT= 2.920 min (chirale methode F); ee= 100%.

E171 : LC-MS: 407.3 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,72 (s, 1H), 4,42-4,38 (m, 1H), 4,27 (td, J= 8,4 Hz, 2,0 Hz, 2H), 3,95-3,93 (m, 1H), 3,74 (br, 1H) , 3,35 (s, 3H), 2,19 (s, 3H),

2,09-1,95 (m, 3H), 1,82-1,72 (m, 5H), 1,66-1,41 (m, 2H), 1,29 (d, J= 6,8 Hz, 3H). Chirale RT= 3,071 min (chirale methode F); ee= 100%.

E172: LC-MS: 407.3 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,64 (s, 1H), 4,32 (d, J= 12,0 Hz, 1H), 4,19 (t, J= 9,6 Hz, 2H), 3,85-3,80 (m, 1H), 3,64 (br, 1H) , 3,30 (s, 3H), 2,10 (s, 3H), 1,93-1,78 (m, 5H), 1,71-1,57 (m, 4H), 1,34-1,32 (m, 1H), 1,21 (d, J= 6,8 MHz , 3H). Chirale RT= 3,10 min (chirale methode F), 4,10 min (chirale methode A); ee= 100%.

E173: LC-MS: 407.3 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,72 (s, 1H), 4,42-4,39 (m, 1H), 4,29-4,24 (m, 2H), 3,95-3,91 (m, 1H), 3,73 (br, 1H), 3,35 (s, 3H ), 2,19 (s, 3H), 2,02-1,65 (m, 10H), 1,45-1,37 (m, 1H), 1,29 (d, J= 6,8 Hz, 3H). Chirale RT = 3,135 min (chirale methode F); ee=100%.

E174: LC-MS: 407.3 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,72 (s, 1H), 4,41-4,38 (m, 1H), 4,29 (t, J= 12,0 Hz, 1H), 4,08-4,03 (m, 1H), 3,95-3,92 (m, 1H), 3,35 (s, 3H), 3,33-3,30 (m, 1H), 2,28 (d, J= 12,0 Hz, 1H), 2,20 (s, 3H), 2,10 (d, J= 12,0 Hz, 1H), 1,90-1,72 (m, 6H), 1,43-1,40 (m, 1H), 1,30 (d, J= 6,8 Hz, 3H), 1,21-1,14 (m, 1H). Chirale RT= 3,272 min (chirale methode F); ee= 100%.

E175: LC-MS: 407.3 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,62 (s, 1H), 4,30 (dq, J= 12,0, 2,0 Hz, 1H), 4,18 (td, J= 8,8, 2,4 Hz, 1H), 4,00-3,92 (m, 1H), 3,85- 3,82 (m, 1H), 3,27 (s, 3H), 3,24-3,21 (m, 1H), 2,10 (s, 3H), 2,12-2,08 (m, 1H), 2,01 (d, J= 7,6 Hz, 1H) , 1,83-1,61 (m, 6H), 1,34-1,31 (m, 1H), 1,19 (d, J= 7,2 Hz, 3H), 1,08~1,05 (m, 1H). Chirale RT= 3,484 min (chirale methode F); ee= 100%.

E176: LC-MS: 407.3 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,72 (s, 1H), 4,41-4,38 (m, 1H), 4,28 (t, J= 9,6 Hz, 1H), 4,06-4,04 (m, 1H), 3,98-3,90 (m, 1H), 3,38 (s, 3H), 3,33-3,30 (m, 1H), 2,27 (d, J= 12,0 Hz, 1H), 2,20 (s, 3H), 2,12 (d, J= 12,0 H, 1H), 1,91-1,69 (m, 6H), 1,43-1,40 (m, 1H), 1,30 (d, J= 7,2 Hz, 3H), 1,18-1,14 (m, 1H). Chirale RT= 3,571 min (chirale methode F); ee= 99,1%.

E177: LC-MS: 407.4 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,72 (s, 1H), 4,42-4,38 (m, 1H), 4,30-4,25 (m, 1H), 4,07-4,02 (m, 1H), 3,95-3,91 (m, 1H), 3,37 (s , 3H), 3,33-3,30 (m, 1H), 2,20 (s, 3H), 2,20-2,14 (m, 1H), 2,12-2,10 (m, 1H), 1,93-1,69 (m, 6H), 1,44- 1,41 (m, 1H), 1,29 (d, J= 6,8 Hz, 3H), 1,18-1,14 (m, 1H). Chirale RT= 3.830 min (chirale methode F); ee= 100%. Enantiomeren 1-4: 14-Chloor-5-(3-methoxycyclohexyl)-4-methyl-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0³⁷]heptadeca- 1(16),3,6,13(17),14-pentaeen (E178-E181)

Compounds were prepared using procedures similar to those used to prepare E12, starting from D33 and 3-methoxycyclohexyl methane sulfonate.

E178: LC-MS: 393,3 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,81 (s, 1H), 6,12 (s, 1H), 5,53 (t, J= 5,6 Hz, 1H), 4,38 (t, J= 5,2 Hz, 2H), 4,25-4,18 (m, 1H), 3,71 (br, 1H), 3,54-3,45 (m, 2H), 3,33 (s, 3H), 2,19 (s, 3H), 2,12-1,99 (m, 2H), 1,94-1,84 (m, 6H), 1,75- 1.61 (m, 1H), 1.44-1.38 (m, 1H). Chirale RT= 2,363 min (chirale methode G); ee= 100%.

E179: LC-MS: 393,3 [M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,80 (s, 1H), 6,35 (s, 1H), 5,55 (s, 1H), 4,39 (d, J= 4,0 Hz, 2H), 4,25-4,19 (m, 1H ), 3,71 (br, 1H), 3,52 (d, J= 4,8 Hz, 2H), 3,33 (s, 3H), 2,19 (s, 3H), 2,12-2,00 (m, 2H), 1,91-1,86 (m, 6H), 1,78-1,66 (m, 1H), 1,43-1,36 (m, 1H). Chirale RT= 3,676 min (chirale methode G); ee= 100%.

E180: LC-MS: 393,3 [M+H]⁺.¹H NMR (400 MHz, CDCb): δ 7,78 (s, 1H), 6,76 (s, 1H), 5,69 (t, J= 6,4 Hz, 1H), 4,38 (t, J= 4,8 Hz, 2H), 3,89- 3,85 (m, 1H), 3,53 (d, J= 6,0 Hz, 2H), 3,37 (s, 3H), 3,28-3,20 (m, 1H), 2,29-2,25 (m, 1H), 2,21 (s, 3H) , 2,11-2,07 (m, 1H), 1,98-1,80 (m, 6H), 1,36-1,20 (m, 2H). Chirale RT= 3,770 min (chirale methode G); ee= 100%.

E181 : LC-MS: 393,3 [M+H]⁺.¹H NMR (400 MHz, CDCI3): δ 7,81 (s, 1H), 6,13 (s, 1H), 5,54 (s, 1H), 4,39 (t, J= 4,8 Hz, 2H), 3,89-3,85 (m, 1H ), 3,52 (d, J= 4,0 Hz, 2H), 3,37 (s, 3H), 3,28-3,20 (m, 1H), 2,29-2,26 (m, 1H), 2,20 (s, 3H), 2,11-2,08 ( m, 1H), 1,94-1,80 (m, 6H), 1,36-1,20 (m, 2H). Chirale RT= 7,785 min (chirale methode G); ee= 100%.

Enantiomeren 1-4: 14-chloor-4,11-dimethyl-5-[1-(oxan-4-yl)ethyl]-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3. 1.0³⁷]heptadeca- 1 (16),3,6, 13(17),14-pentaeen (E182-E185)

Compounds were prepared using procedures similar to those used to prepare E78 starting from D73 and 1-(tetrahydro-2/-/-pyran-4-yl)ethyl methane sulfonate.

E182: LC-MS: 407.3 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,82 (s, 1H), 6,04 (s, 1H), 5,11 (s, 1H), 4,51-4,34 (m, 1H), 4,30-4,25 (m, 1H), 4,09 -3,93 (m, 3H), 3,78-3,73 (m, 1H), 3,43-3,33 (m, 2H), 2,30 (s, 3H), 2,16-1,99 (m, 1H), 1,93-1,83 (m, 2H) , 1,76-1,73 (m, 2H), 1,59-1,51 (m, 3H), 1,50 (d, J= 4,8 Hz, 3H), 1,47-1,39 (m, 2H). Chirale RT= 2,471 min (chirale methode A); ee= 100%.

E183: LC-MS: 407.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,82 (s, 1 H), 6,11 (s, 1 H), 5,12 (d, J= 6,0 Hz, 1 H), 4,50 (dd, J = 3,2, 3,6 Hz, 1H), 4,29 (t, J= 20,8 Hz, 1H), 4,09-4,01 (m, 2H), 3,98-3,93 (m, 1H), 3,78-3,73 (m, 1H), 3,40 (t, J = 22,0 Hz, 1H), 3,35-3,29 (m, 1H), 2,16 (s, 3H), 2,13 (br, 1H), 1,93-1,83 (m, 2H), 1,76-1,73 (m, 2H), 1,59- 1,51 (m, 3H), 1,49 (d, J= 4,0 Hz, 3H), 1,46-1,38 (m, 2H). Chirale RT= 2,967 min (chirale methode A); ee= 98,5%. E184: LC-MS: 407.3 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,82 (s, 1H), 6,03 (s, 1H), 5,12 (d, J= 6,8 Hz, 1H), 4,49 (dd, J= 3,2, 2,8 Hz, 1H), 4,32 (t, J= 21,2 Hz, 1H), 4,02-3,99 (m, 2H), 3,89-3,86 (m, 1H), 3,74-3,70 (m, 1H), 3,41-3,27 (m, 2H), 2,16 (s, 3H), 2,06- 2,01 (m, 1H), 1,93-1,83 (m, 2H), 1,76-1,73 (m, 2H), 1,59-1,51 (m, 3H), 1,50 (d, J= 4,0Hz, 3H), 1,40-1,38 ( m, 2H). Chirale RT= 4,335 min (chirale methode A); ee= 100%.

E185: LC-MS: 407.3 [M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,82 (s, 1H), 6,04 (s, 1H), 5,12 (d, J= 6,8 Hz, 1H), 4,49 (dd, J= 6,8, 4,8 Hz, 1H), 4,41 (t, J= 15,2 Hz, 1H), 4,32-4,01 (m, 2H), 4,00-3,89 (m, 1H), 3,86-3,68 (m, 1H), 3,41-3,27 (m, 2H), 2,16 ( s, 3H), 2,09-2,01 (m, 1H), 1,92-1,86 (m, 2H), 1,83-1,60 (m, 2H), 1,59-1,51 (m, 3H), 1,48 (d, J= 4,8 Hz, 3H), 1.40-1.38 (m, 2H). Chirale RT= 6,023 min (chirale methode A); ee= 100%.

Enantiomeren 1-2: 14-chloor-4-methyl-5-[1-(oxan-4-yl)ethyl]-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0³⁷]heptadeca-1(16), 3,6, 13(17),14-pentaene (E186-E187)

Compounds were prepared using procedures similar to those used to prepare E12, starting from D33 and 1-(tetrahydro-2/-/-pyran-4-yl)ethyl methane sulfonate.

E186: LC-MS: 393,3 [M+H]⁺.¹H NMR (400 MHz, CDCb): 8 7,83 (s, 1H), 6,11 (s, 1H), 5,55 (t, J= 6,0 Hz, 1H), 4,40 (t, J= 4,8 Hz, 2H), 4,03 ( dd, J= 11,2, 3,6 Hz, 1H), 3,91 (d, J= 12,8 Hz, 1H), 3,78-3,68 (m, 1H), 3,57-3,47 (m, 2H), 3,45-3,25 (m, 2H) , 2,19 (s, 3H), 2,13-2,04 (m, 1H), 1,99-1,84 (m, 2H), 1,78-1,74 (m, 1H), 1,44 (d, J= 6,8 Hz, 3H), 1,42-1,35 (m, 1H), 1,19-1,10 (m, 2H). Chirale RT= 4,333 min (chirale methode E); ee= 100%.

E187: LC-MS: 393,3 [M+H]⁺.¹H NMR (400 MHz, CDCb): 8 7,83 (s, 1H), 6,14 (s, 1H), 5,56 (t, J= 6,0 Hz, 1H), 4,40 (t, J= 4,8 Hz, 2H), 4,03 ( dd, J= 11,2, 3,6 Hz, 1H), 3,90 (d, J= 10,4 Hz, 1H), 3,79-3,69 (m, 1H), 3,57-3,46 (m, 2H), 3,44-3,28 (m, 2H) , 2,19 (s, 3H), 2,13-2,04 (m, 1 H), 1,98-1,86 (m, 2H), 1,78-1,74 (m, 1 H), 1,44 (d, J= 6,4 Hz, 3H), 1,38 -1,32 (m, 1H), 1,22-1,14 (m, 2H). Chirale RT= 5,538 min (chirale methode E); ee= 100%.

2-{14-chloor-4-methyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0³⁷]heptadeca-1 (16),3,6,13(17),14-pentaeen-5-yl}-2-methylpropanoaat (E188)

The compound was prepared using procedures similar to those used to prepare E37 from D33.

LC-MS: 395.1 [M+H]⁺.¹H NMR (400 MHz, CDCb): 8 7,80 (s, 1H), 6,21 (s, 1H), 5,54 (br, 1H), 4,39 (t, J= 4,4 Hz, 2H), 4,23 (q, J= 7,2 Hz, 2H), 3,55-3,51 (m, 2H), 2,10 (s, 3H), 1,91 (br, 2H), 1,76 (s, 6H), 1,27 (t, J= 7,0 Hz, 3H).

2-{14-chloor-4-methyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0³⁷]heptadeca-1 (16),3,6,13(17),14-pentaen-5-yl}-2-

IT Λy,Νi methylpropaanzuur (E189)

E189^H0The compound was prepared using procedures similar to those used to prepare E39 from E188. LC-MS: 367.1 [Μ+Η]⁺.¹Η NMR (400 MHz, DMSO-d₆): δ 13,07 (br, 1Η), 8,33 (s, 1Η), 7,77 (s, 1H), 7,36 (t, J= 5,6 Hz, 1H), 4,20 (br, 2H), 2,07 (s, 3H), 1,71 (br, 2H), 1,62 (s, 6H). (2H overlapt).

2-{14-chloor-4-methyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0³⁷]heptadeca-1 (16),3,6,13(17),14-pentaen-5-yl}-2-methylpropanamide (E190)

The compound was prepared using procedures similar to those used to prepare E41 from E189.

LC-MS: 366.2 [M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆): 8,32 (s, 1H), 7,77 (s, 1H), 7,32 (s, 1H), 7,26 (s, 1H), 7,02 (s, 1H), 4,23 (br, 2H), 2,07 (s, 3H), 1,73 (br, 2H), 1,56 (s, 6H). (2H overlapt).

2-{14-chloor-4-methyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0³⁷]heptadeca-1 (16),3,6,13(17),14-pentaeen-5-yl}-2-methylpropanenitrile (E191)

The compound was prepared using procedures similar to those used before

E191

preparation E43, from E190.

LC-MS: 348.2 [M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆): δ 8,48 (s, 1H), 7,79 (s, 1H), 7,48 (s, 1H), 4,23 (br, 2H), 2,36 (s, 3H), 1,89 (s, 6H), 1,76 (br, 2H ). (2H overlapt).

Enantiomeren 1-2: 14-Chloor-4-methyl-5-(oxan-4-yl)-11-(trifluormethyl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3. 1.0³⁷] heptadeca-1(16),3, 6,13(17),14-pentaeen (E192-E193)

E192-E193

The compound was prepared using procedures similar to those used to prepare E88 starting from 3-amino-4,4,4-trifluorobutan-1-ol.

E192: LC-MS: 433.3 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,91 (s, 1H), 6,54 (s, 1H), 5,42 (d, J= 8,0 Hz, 1H), 4,72-4,66 (m, 1H), 4,51-4,39 (m, 2H), 4,11-4,06 (m, 3H), 3,51 (t, J= 9,6 Hz, 2H), 2,36- 2,23 (m, 3H), 2,23 (s, 3H), 1,85-1,76 (m, 3H).¹⁹F-NMR (376 MHz, CDCI3): 5-75,66. Chirale RT= 2,935 min (chirale methode A); ee= 100%.

E193: LC-MS: 433.3 [M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,91 (s, 1H), 6,46 (s, 1H), 5,37 (d, J= 8,4 Hz, 1H), 4,72-4,66 (m, 1H), 4,51-4,39 (m , 2H), 4,11-4,06 (m, 3H), 3,54-3,49 (m, 2H), 2,36- 2,22 (m, 3H), 2,22 (s, 3H), 1,85-1,76 (m, 3H).¹⁹F-NMR (376 MHz, CDCb): 5-75,68. Chirale RT= 4,593 min (chirale methode A); ee= 100%.

Enantiomeren 1-4: 14-Chloor-5-(2,6-dimethyloxan-4-yl)-4,11-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0³⁷] heptadeca-1 (16),3,6,13(17),14-pentaene (E194-E197)

Compounds were prepared using procedures similar to those used to prepare E79, starting from D73 and 2,6-dimethyltetrahydro-2/-/-pyran-4-yl methanesulfonate.

E194: LC-MS: 407.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,77 (s, 1H), 7,03 (br, 1H), 5,35 (d, J= 8,0 Hz, 1H), 4,49-4,43 (m, 2H), 4,34-4,26 (m , 3H), 4,05-4,03 (m, 1H), 2,20 (s, 3H), 1,92-1,82 (m, 3Η), 1,68-1,60 (m, 3Η), 1,28 (d, J= 8,0 Hz, 3H ), 1,18 (dd, J= 4,0 Hz, 6H). Chirale RT= 3,054 min (chirale methode F); ee= 100%.

E195: LC-MS: 407.2 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,81 (s, 1 H), 6,22 (br, 1 H), 5,15 (d, J= 8,0 Hz, 1 H), 4,49 (dd, J= 8,0 Hz, 1 H), 4,33 (t, J = 8,0 Hz, 1 H), 4,13-4,02 (m, 2H), 3,60-3,58 (m, 2H), 2,20 (s, 3H), 1,88-1,79 (m, 6H), 1,32 (d, J= 8,0 Hz, 3H) ,1 .27 (dd, J= 8,0 Hz, 6H). Chirale RT= 3,425 min (chirale methode F); ee= 99,7%.

E196: LC-MS: 407.2 [M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,76 (s, 1H), 7,15 (br, 1H), 5,37 (d, J= 6,0 Hz, 1H), 4,49-4,42 (m, 2H), 4,44- 4,26 (m, 3H), 4,04 (br, 1H), 2,20 (s, 3H), 1,96-1,82 (m, 4H), 1,72-1,60 (br, 2H), 1 . 35 (d, J= 8,0 Hz, 3H) ,1 .18 (dd, J= 6,0 Hz, 6H). Chirale RT= 4,066 min (chirale methode F); ee= 100%.

E197: LC-MS: 407.2 [M+H]⁺. H NMR (400 MHz, CDCb): 8 7,78 (s, 1 H), 6,66 (br, 1 H), 5,25 (d, J= 8,0 Hz, 1 H), 4,48 (dd, J= 8,0 Hz, 1 H ), 4,32 (t, J= 8,0 Hz, 1 H), 4,13-4,02 (m, 2H), 3,61 -3,57 (m, 2H), 2,21 (s, 3H), 1,93-1 0,79 (m, 6H) , 1,33 (d, J= 8,0 Hz, 3H) ,1,27 (t, J= 6,0 Hz, 6H). Chirale RT= 4,646 min (chirale methode F); ee= 100%.

Isomeren 1 -2: 14-Chloor-5-(2,6-dimethyloxan-4-yl)-10-methoxy-4-methyl-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3 .1.0^{3 7}] heptadeca-1 (16),3,6,13(17),14-pentaeen (E198-E199)

Compounds were prepared by procedures similar to those used to prepare E79 using D13 and 2,6-dimethyltetrahydro-2H-pyran-4-yl methanesulfonate as starting materials.

E198: LC-MS: 423.2[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,84 (s, 1 H), 6,18 (s, 1 H), 5,71 -5,68 (m, 1 H), 4,50 (d, J= 10,0 Hz, 1 H), 4,31 (t, J= 8,0 Hz, 1 H), 4,13-4,07 (m, 1 H), 3,93-3,88 (m, 1 H), 3,61 -3,57 (m, 2H), 3,41 (s, 3H), 3,34- 3,27 (m, 2H), 2,19 (s, 3H), 1,90-1,76 (m, 4H), 1,27(t, J= 6,0 Hz, 6H). Chirale RT= 1.166 min (chirale methode A); ee= 100%.

E199: LC-MS: 423.2[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,83 (s, 1 H), 6,33 (s, 1 H), 5,75-5,73 (m, 1 H), 4,50 (d, J= 8,0 Hz, 1 H), 4,24 (t, J= 6,0 Hz, 1 H), 4,12-4,09 (m, 1 H), 3,94-3,88 (m, 1 H), 3,61 -3,58 (m, 2H), 3,42 (s, 3H), 3,35- 3,28 (m, 2H), 2,20 (s, 3H), 1,90-1,76 (m, 4H), 1,20 (t, J= 6,0 Hz, 6H). Chirale RT= 2,495 min (chirale methode A); ee= 99,8%.

HN—. Enantiomeren 1 -2: 14-Chloor-5-(2,6-dimethyloxan-4-yl)-4-methyl-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca- 1 (16),3,6, 13(17),14-pentaeen (E200-E201)

Compounds were prepared using procedures similar to those used to prepare E12 starting from D33 and 2,6-dimethyltetrahydro-2H-pyran-4-yl methanesulfonate.

Ε200-201 / ° E200: LC-MS: 393,2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,82 (s,

1 H), 6,12 (s, 1 H), 5,54 (t, J= 5,6 Hz, 1 H), 4,42-4,34 (m, 5H), 3,52 (dd, J= 10,6, 5,8 Hz, 2H), 2,18 ( s, 3H), 1,93 (br, 2H), 1,89-1,86 (m, 2H), 1,68-1 0,60 (m, 2H), 1,18 (d, J= 6,4 Hz, 6H). Chirale RT= 5,313 min (chirale methode A); ee= 100%.

E201 : LC-MS: 393,2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,80 (s, 1 H), 6,33 (s, 1 H), 5,54 (t, J= 6,0 Hz, 1 H), 4,40 (t, J= 4,4 Hz, 2H) , 4,13-4,07 (m, 1H), 3,61-3,58 (m, 2H), 3,54-3,49 (m, 2H), 2,20 (s, 3H), 1,91-1,79 (m, 6H), 1,27 (d, J= 6,0 Herz, 6H). Chirale RT= 6,132 min (chirale methode A); ee= 100%.

Enantiomeren 1-2: 14-Chloor-4-methyl-5-(2-methyloxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0³⁷]heptadeca- 1 (16),3,6, 13(17),14-pentaeen (E202-E203)

Compounds were prepared using procedures similar to those used to prepare E12, starting from D33 and 2-methyltetrahydro-2/-/-pyran-4-ylmethanesulfonate.

E202: LC-MS: 379,2 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): d 7,79 (s,

1H), 6,61 (s, 1H), 5,61 (t, J= 5,6 Hz, 1H), 4,39 (t, J= 4,4 Hz, 2H), 4,33-4,30 (m, 1H), 4,24-4,19 (m, 1H ), 3,86-3,82 (m, 1H), 3,53 (dd, J= 10,8, 5,6 Hz, 2H), 2,20 (s, 3H), 2,03-1,94 (m, 5H), 1,75-1,70 (m, 1H), 1,20 (d, J= 6,4 Hz, 3H). Chirale RT= 2,788 min (chirale methode C); ee= 100%.

E203: LC-MS: 379,2 [M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,79 (s, 1H), 6,61 (s, 1H), 5,64 (t, J= 5,6 Hz, 1H), 4,39 (t, J= 4,4 Hz, 2H), 4,33- 4,30 (m, 1H), 4,23-4,19 (m, 1H), 3,85-3,82 (m, 1H), 3,53 (q, J = 5,6 Hz, 2H), 2,20 (s, 3H), 2,03-1,93 (m, 5H), 1,74-1,69 (m, 1H), 1,20 (d, J= 6,4 Hz, 3H). Chirale RT= 2,963 min (chirale methode C); ee= 100%.

HN— O— Enantiomeren 1-4: 14-Chloor-10-methoxy-4-methyl-5-(2-methyl

^"y-oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo [11.3.1.0³⁷] heptadeca-1 (16),3,6, 13(17),14-pentaeen (E204-E207)

Compounds were prepared by procedures similar to those used to prepare E12, using D13 and 2-methyltetrahydro-2/-/-pyran-4-ylmethanesulfonate as starting materials.

E204-207 E204: LC-MS: 409,3 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,84 (s,

1H), 6,12 (s, 1H), 5,68 (br, 1H), 4,49 (d, J= 12,0 Hz, 1H), 4,39 (t, J = 4,0 Hz, 1H), 4,31 (t, J= 12,0 Hz, 1H), 4,20-4,08 (m, 1H), 3,95-3,90 (m,1H), 3,86-3,81 (m, 1H), 3,55-3,51 (m,1H), 3,44 (d, J= 12,0 Hz, 3H) , 3,36-3,27 (m, 2H), 2,18 (t, J= 4,0 Hz, 3H), 2,04-2,01 (m,1H), 1,90-1,86 (m,1H), 1,75-1,68 (m,1H), 1,26 (t, J= 12,0 Hz, 2H), 1,20 (d, J= 6,0 Hz, 3H). Chirale RT= 2,282 min (chirale methode C); ee= 100%.

E205: LC-MS: 409.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,84 (s, 1H), 6,12 (s, 1H), 5,69 (br, 1H), 4,48 (d, J= 12,0 Hz, 1H), 4,40 (t, J = 8,0 Hz, 1H), 4,31 (t, J= 12,0 Hz, 2H), 4,18 (t, J= 8,0 Hz, 1H), 3,91- 3,88 (m, 1H), 3,85-3,82 (m,1H), 3,43 (s , 3H), 3,36-3,26 (m, 2H), 2,18 (d, J=4,0 Hz, 3H), 2,03-1,91 (m, 3H), 1,74-1,67 (m, 1H), 1,19 (d, J= 8,0 Hz, 3H). Chirale RT= 2,390 min (chirale methode C); ee= 95%.

E206: LC-MS: 409.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,84 (s, 1H), 6,18 (s, 1H), 5,69 (br, 1H), 4,49 (d, J= 12,0 Hz, 1H), 4,39 (t, J= 4,0 Hz, 1H), 4,31 (t, J= 8,0 Hz, 1H), 4,20-4,08 (m, 1H), 3,93-3,829 (m, 1 H), 3,85-3,82 (m, 1 H), 3,54 (t, J= 12,0 Hz, 1 H), 3,43 (d, J= 4,0 Hz, 3H), 3,36-3,27 (m, 2H), 2,18 (t, J= 8,0 Hz, 3H), 2,04-1,98 (m, 1 H ), 1,90-1,81 (m, 1 H), 1,75-1,68 (m, 1 H), 1,25 (t, J= 6,0 Hz, 2H),

2F). Chirale RT= 4,356 min (chirale methode A); ee= 100%. Enantiomeren 1 -4: 14-Chloor-5-[2-(3-fluorpyrrolidin-1 -yl)ethyl]- 4,11 -dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo [ 11.3.1.0^{3 7}] heptadeca-1 (16),3,6, 13(17),14-pentaeen (E216-E219)

Compounds were prepared using procedures similar to those used to prepare E208 starting from D163 and 3-fluoropyrrolidine.

E216: LC-MS: 410.1 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,81 (s, 1 H), 6,33 (br, 1 H), 5,23-5,08 (m, 2H), 4,48-4,45 (m, 1 H), 4,33 (t, J=

10.4 Hz, 1 h), 4.1 1 -4.00 (m, 3 h), 3.01 -2.84 (m, 5 h), 2.64 (br, 1 h),

2,23 (s, 3H), 2,18-2,07 (m, 2H), 1,89-1,83 (m, 2H), 1,31 (d, J= 6,8 Hz, 3H).¹⁹F NMR (400 MHz, CDCI3): 8 -168,59 (m, 1 F). Chirale RT= 3,145 min (chirale methode A); ee= 100%.

E217: LC-MS: 410.2 [M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,81 (s, 1 H), 6,46 (br, 1 H), 5,25-5,12 (m, 2 H), 4,48-4,45 (m, 1 H), 4,32 (t, J = 10,4 Hz, 1 uur), 4,16-4,02 (m, 3 uur), 3,06-2,89 (m, 5 uur), 2,74 (br, 1 uur),

2,24 (s, 3H), 2,20-2,09 (m, 2H), 1,93-1,79 (m, 2H), 1,32 (d, J= 6,8 Hz, 3H).¹⁹F NMR (400 MHz, CDCI3): 8 -168,59 (m, 1 F). Chirale RT= 3,495 min (chirale methode A); ee= 100%.

E218: LC-MS: 410.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1 H), 6,32 (br, 1 H), 5,23-5,10 (m, 2 H), 4,47 (dd, J= 10,8, 3,2 Hz, 1 H), 4,33 (t, J= 10,8 Hz, 1 H), 4,10-4,02 (m, 3H), 3,00-2,80 (m, 5H), 2,59 (br, 1 H), 2,22 (s, 3H), 2,20-2,03 ( m, 2H), 1,93-1,79 (m, 2H), 1,32 (d, J= 6,8 Hz, 3H).¹⁹F NMR (400 MHz, CDCI3): 8 -168,59 (m, 1 F). Chirale RT= 6,121 min (chirale methode A), 6,084 min (chirale methode E); ee= 100%.

E219: LC-MS: 410.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1 H), 6,34 (br, 1 H), 5,23-5,09 (m, 2 H), 4,47 (dd, J= 1 1,6, 2,8 Hz, 1 H) , 4,33 (t, J= 10,8 Hz, 1 H), 4,12-4,00 (m, 3H), 3,01 -2,84 (m, 5H), 2,65 (br, 1 H), 2,23 (s, 3H), 2,20-2,05 (m, 2H), 1,89-1,79 (m, 2H), 1,32 (d, J= 6,8 Hz, 3H).¹⁹F NMR (400 MHz, CDCI3): 8 -168,59 (m, 1 F). Chirale RT= 6,121 min (chirale methode A), 7,151 min (chirale methode E); ee=99,6%.

14-chloor-4-methyl-5-[2-(morfoline-4-yl)ethyl]-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14- pentaeen (E220)

The compound was prepared using procedures similar to those used before

E220 to prepare E12, starting from D33 and 4-(2-chloroethyl)morpholine hydrochloride.

LC-MS: 394.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,82 (s, 1 H), 6,18 (s, 1 H), 5,55 (s, 1 H), 4,38 (t, J= 4,4 Hz, 2H), 4,00 (t, J= 6,8 Hz, 2H), 3,69 (t, J= 4,4 Hz, 4H), 3,51 (dd, J= 10,8, 6,0 Hz, 2H), 2,72 (t, J= 6,8 Hz, 2H), 2,48 (t, J= 4,2 Hz, 4H), 2,21 (s, 3H), 1,92 (br, 2H).

14-Chloor-4-methyl-5-{2-[(1 S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]ethyl}-8-oxa-2,5, 6,12,16,17-hexaazatricyclo

[11.3.1.0³-⁷]heptadeca-1 (16),3,6, 13(17),14-pentaeen (E221)

The compound was prepared using procedures similar to those used before

E221 to prepare E12, starting from D33 and (1S,4S)-5-(2-chloroethyl)-2-oxa-5-azabicyclo[2.2.1]heptane. (400 MHz, CDCIs): 5-61.03 (s, 3F). Chiral RT= 3.254 min (chiral method A); ee=97.6%.

E228: LC-MS: 429,2 [M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,97 (s, 1H), 7,21 (br, 1H), 6,39 (br, 1H), 4,46 (d, J= 12,0 Hz, 1H), 4,28 (t, J= 12,0 Hz, 1H), 4,05-3,87 (m, 4H), 3,61 (t, J= 12,0 Hz, 1H), 3,43 (s, 3H), 3,39-3,31 (m, 3H), 2,28 (s, 3H), 2,25 -2,21 (m, 1H), 2,07-2,00 (m, 1H), 1,81-1,77 (m, 2H).¹⁹F NMR (400 MHz, CDCb): 5-61,03 (s, 3 F). Chirale RT= 3,644 min (chirale methode A); ee= 98,9%.

Enantiomeren 1-4: 14-chloor-10-methoxy-4-methyl-5-(oxan-3-yl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0³⁷]heptadeca- 1 (17),3,6, 13,15-pentaeen (E229-E232)

Compounds were prepared by procedures similar to those used to prepare E2, using D25 and D13 as starting materials.

E229: LC-MS: 395,2 [M+H]⁺.¹H NMR (400 MHz, CDCb): 8 7,81 (s, 1H), 7,24 (br, 1H), 5,85 (br, 1H), 4,48 (d, J= 12,0 Hz, 1H), 4,26 (t, J= 8,0 Hz, 1H), 4,06-3,87 (m, 4H), 3,72 (t, J= 8,0 Hz, 1H ), 3,46-3,43 (m, 1H), 3,42 (s, 3H), 3,38-3,31 (m, 2H) , 2,21 (s, 3H), 2,18-2,10 (m, 1H), 1,92-1,92 (m,1 H), 1,82-1,80 (m, 2H). Chirale RT= 4,202 min (chirale methode A); ee= 100%.

E230: LC-MS: 395,2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,80 (s, 1H), 6,95 (br, 1H), 5,90 (br, 1H), 4,47 (d, J= 12,0 Hz, 1H), 4,29 (t, J= 8,0 Hz, 1H), 4,07-3,88 (m, 4H), 3,62 (t, J= 8,0 Hz, 1H ), 3,46-3,45 (m, 1H), 3,42 (s, 3H), 3,36-3,33 (m, 2H) , 2,28-2,25 (m, 1H), 2,22 (s, 3H), 2,07-2,04 (m, 1H), 1,83-1,78 (m, 2H). Chirale RT= 4,381 min (chirale methode A); ee= 99,1%.

E231 : LC-MS: 395,2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 511,41 (s, 1H), 7,68 (s, 1H), 6,60 (br, 1H), 4,47 (d, J= 12,0 Hz, 1H), 4,29 (t, J= 8,0 Hz , 1H), 4,06-4,04 (m, 1H), 3,96-3,88 (m, 3H), 3,60 (t, J= 8,0 Hz, 1H ), 3,48-3,47 (m, 1H), 3,44 (s, 3H), 3,32-3,30 (m, 2H), 2,28 (s, 3H), 2,25-2,21 (m, 1H), 2,06-2,03 (m,1 H), 1,83-1,78 (m, 2H). Chirale RT= 4,958 min (chirale methode A); ee= 99,7%.

E232: LC-MS: 395,2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,79 (s, 1 H), 7,02 (br, 1 H), 5,90 (br, 1 H), 4,48 (d, J= 8,0 Hz, 1 H), 4,26 (t , J = 8,0 Hz, 1H), 4,06-3,88 (m, 4H), 3,72 (t, J= 8,0 Hz, 1H ), 3,46-3,44 (m, 1H), 3,42 (s, 3H), 3,34 (d, J= 12,0 Hz, 2H), 2,22 (s, 3H), 2,16-2,08 (m, 1H), 2,07-2,00 (m,1 H), 1,93-1,80 (m, 2H). Chirale RT= 5,157 min (chirale methode A); ee= 99,6%.

Enantiomeren 1-4: 14-Chloor-5-(3-fluoroxan-4-yl)-4-methyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0³⁷]heptadeca- 1(16),3,6,13 (17),14-pentaeen (E233-E236)

Compounds were prepared using procedures similar to those used to prepare E21, starting from D50 and alpha-butyl(3-bromopropyl)carbamate.

E233: LC-MS: 383.1 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,70 (s, 1H), 4,85-4,71 (m, 1H), 4,37-4,32 (m, 3H), 4,19-4,15 (q, J= 5,6 Hz, 1H), 4,00-3,97 (m, 1H ), 3,54 (t, J= 24 Hz, 1H), 3,43-3,34 (m, 3H), 2,34-2,30 (m, 1H), 2,23 (s, 3H), 1,97-1,78 (m, 3H).¹⁹F NMR (400 MHz, CD3OD): 8 -195,37 (s, F). Chirale RT= 3,299 min (chirale methode A); ee= 100%.

E234: LC-MS: 383.1 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,70 (s, 1 H), 4,75 (t, J= 6,4 Hz, 1 H), 4,60-4,51 (m, 1 H), 4,49-4,39 (m, 2H), 4,38-4,24 (m, 3H), 4,17 (q, J= 8,0 Hz, 1 H), 4,08-4,03 (m, 1 H), 3,41 (t, J= 8,0 Hz, 1 H), 2,40-2,35 (m, 2H), 2,23 ( s, 3H), 1,85-1,82 (m, 2H).¹⁹F NMR (400 MHz, CD3OD): 8 -232,21 (s, F). Chirale RT= 3,597 min (chirale methode A); ee= 98,3%.

E235: LC-MS: 383.1 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,70 (s, 1 H), 4,75 (q, J= 6,4 Hz, 1 H), 4,60-4,45 (m, 2H), 4,40-4,23 (m, 3H), 4,17 (q, J= 7,2 Hz, 1 H), 4,05 (q, J= 7,2 Hz, 1 H), 3,41 (t, J= 8,0 Hz, 1 H), 2,40-2,33 (m, 2H), 2,23 (s, 3H), 1,85- 1.82 (m, 2H).¹⁹F NMR (400 MHz, CD3OD): 8 -232,21 (s, F). Chirale RT= 4,460 min (chirale methode A); ee= 98,1 %.

E236: LC-MS: 383.1 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7.70 (s, 1 H), 4.86-4.68 (m, 1 H), 4.38-4.29 (m, 3H), 4.17 (q, J= 5 ,6 Hz, 1 H), 3,99 (d, J= 8,0 Hz, 1 H), 3,54 (t, J= 24 Hz, 1 H), 3,43-3,37 (m, 3H), 2.36-2.27 (m, 1H), 2.23 (s, 3H), 1 .97- 1.78 (m, 3H).¹⁹F NMR (400 MHz, CD3OD): 8 -195,35 (s, F). Chirale RT=5,352 min (chirale methode A); ee=99,5 %.

Isomeren 1 -2: 14-chloor-5-(4-methoxycyclohexyl)-4-methyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16), 3,6, 13(17),14-pentaeen (E237-E238)

Compounds were prepared using procedures similar to those used to prepare E12, starting from D33 and 4-methoxycyclohexyl methane sulfonate.

E237: LC-MS: 393,2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1 H), 6,15 (s, 1 H), 5,54 (t, J= 5,8 Hz, 1 H), 4,38 (t, J= 4,4 Hz, 2H) , 3,89-3,83 (m, 1 uur), 3,51 (dd, J= 10,8, 6,0 Hz, 2 uur), 3,37 (s, 3 uur), 3,27-3,22 (m, 1 uur), 2,22-2,20 (m, 2 uur) , 2,19 (s, 3H), 2,06-1,90 (m, 6H), 1,39-1,32 (m, 2H). Chirale RT= 3,41 1 min (chirale methode A).

E238: LC-MS: 393,2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1 H), 6,08 (s, 1 H), 5,52 (s, 1 H), 4,40 (t, J= 4,8 Hz, 2H), 3,96-3,81 ( m, 1H), 3,53-3,47 (m, 3H), 3,34 (s, 3H), 2,29-2,17 (m, 2H), 2,19 (s, 3H), 2,1 1 (d, J= 14,4 Hz, 2H) , 1,92-1,88 (m, 2H), 1,68-1,64 (m, 2H), 1,49 (t, J= 13,4 Hz, 2H). Chirale RT= 7,270 min (chirale methode A).

Enantiomeren 1-4: 14-chloor-10-methoxy-5-(4-methoxycyclohexyl)-4-methyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo [11.3.1. 0³'⁷]heptadeca-1 (16),3,6, 13(17),14-pentaeen (E239-E242)

Compounds were prepared using procedures similar to those used to prepare E12, using D13 and 4-methoxycyclohexyl

methane sulfonate as starting materials.

E239: LC-MS: 423,3 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 111 (s, 1 H), 7,27 (br, 1 H), 5,98 (br, 1 H), 4,50 (d, J= 12,0 Hz, 1 H), 4,29 (t , J= 8,0 Hz, 1 H), 3,94-3,88 (m, 2H), 3,47-3,45 (m, 1 H), 3,41 (s, 3H), 3,37-3,36 (m, 2H), 3,33 (s, 3H ), 2,25-2,18 (m, 5H), 2,15-2,10 (m, 2,37 (q, J= 12,0 Hz, 2H), 2,19 (s, 3H), 2,06-2,04 (m, 2H), 1,80 (d, J = 8,0 Hz, 2H), 1,71 -1,68 (m, 2H) Chirale RT= 1,496 min (chirale methode A), ee= 92,0%.

E247: LC-MS: 421.2 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,84 (s, 1 H), 6,13 (s, 1 H), 5,68 (br, 1 H), 4,50-4,47 (m, 3H), 4,29 (t, J = 8 Hz, 2H), 3,89 ( m, 1H), 3,42 (s, 3H), 3,36-3,28 (m, 2H), 2,41 -2,36 (m, 2H), 2,16 (s, 3H), 2,04-1 0,86 (m, 6H). Chirale RT= 1,853 min (chirale methode A); ee=100%.

E248: LC-MS: 421.2 [M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,83 (s, 1H), 6,12 (s, 1H), 5,68 (br, 1H), 4,52-4,46 (m, 3H), 4,30 (t, J= 8,0 Hz, 2H), 3,89 (dd, J= 8,0 Hz, 1H), 3,41 (s, 3H), 3,34-3,26 (m, 2H),

2,38 (q, J= 12,0 Hz, 2H), 2,19 (s, 3H), 2,06-2,04 (m, 2H), 1,80 (d, J= 8,0 Hz, 2H), 1,71 -1,66 (m, 2H). Chirale RT= 2,528 min (chirale methode A); ee= 100%.

Enantiomeren 1 -4: 14-Chloor-4,11 -dimethyl-5-{8- oxabicyclo[3.2.1] octan-3-yl}-8-oxa-2,5,6,12,16,17- hexaazatricyclo [11.3.1.0³-⁷] heptadeca-1 (16),3,6,13(17),14-pentaeen (E249-E252)

Compounds were prepared using procedures similar to those used to prepare E12, starting from D73 and 8-oxabicyclo[3.2.1]octan-3-yl methanesulfonate.

E249: LC-MS: 405.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,74 (s, 1 H), 7,37-7,36 (m, 1 H), 5,43-5,41 (m, 1 H), 4,49-4,46 (m, 3H), 4,31 -4,25 (m, 2H), 4,06-4,03 (m, 1H), 2,42-2,35 (m, 2H), 2,20 (s, 3H), 1 .98-1 .95 (m, 5H), 1 .92-1 0,80 (m, 3H), 1,35-1,34 (d, J= 6,8 Hz, 3H). Chirale RT= 3,794 min (chirale methode A); ee= 100%.

E250: LC-MS: 405.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,74 (s, 1 H), 6,97 (br, 1 H), 5,33-5,32 (m, 1 H), 4,48-4,46 (m, 3H), 4,32- 4,26 (m , 2H), 4.05-4.02 (m, 1H), 2.44-2.33 (m, 2H), 2.18 (s, 3H), 2.00-1.90 (m, 5H), 1.88-1.80 (m, 3H), 1.34~1.28(d, J= 6,8 Hz, 3H). Chirale RT= 6,1 14 min (chirale methode A); ee= 100%.

E251 : LC-MS: 405.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,77 (s, 1 H), 6,81 (br, 1 H), 5,29-5,27 (m, 1 H), 4,52-4,44 (m, 3H), 4,34-4,28 (m , 2H), 4.03-4.01 (m, 1H), 2.40-2.32 (m, 3H), 2.21 (s, 3H), 2.07- 2.04 (m, 2H), 1 .89-1 .80 (m, 4H ), 1,72-1,66 (m, 2H), 1,33-1,32 (d, J=6,8 Hz, 3H). Chirale RT= 7,136 min (chirale methode A); ee= 100%.

E252: LC-MS: 405.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,78 (s, 1 H), 6,68 (br, 1 H), 5,24-5,22 (m, 1 H), 4,52-4,44 (m, 3 H), 4,34- 4,28 (m , 2H), 4,02-4,01 (m, 1H), 2,41 -2,33 (m, 3H), 2,20 (s, 3H), 2,06-2,04 (m, 2H), 1,88-1,78 (m, 4H), 1,73- 1,68 (m, 2H),1,33 ~ 1,32(d, J= 6,8 Hz, 3H). Chirale RT= 8,025 min (chirale methode A); ee=100%.

/ Enantiomeren 1 -4: 14-chloor-10-methoxy-4-methyl-5-(4-methylcyclohexyl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo [11.3.1.0^{3 7}] heptadeca-1 (16),3,6, 13(17),14-pentaeen (E253-E256)

Compounds were prepared using procedures similar to those used to prepare E12, using D13 and 4-methylcyclohexyl

3-E256 methane sulfonate as starting materials. E253: LC-MS: 407.2 [M+H]⁺.¹H NMR (400 MHz, CDC): <57,86 (s, 1 H), 6,09 (s, 1 H), 5,70 (t, J= 11,2 Hz, 1 H), 4,55 (d, J= 1,6 Hz, 1 H ),

4,44- 4,40 (m, 1H), 4,15 (dd, J= 9,2, 2,4 Hz, 1H), 3,87 (br, 1H), 3,44 (s, 3H), 3,42-3,29 (m, 2H), 2,20 (s, 3H), 2,07-1,84 (m, 2H), 1,64- 1,51 (m, 4H), 1,50-1,48 (m, 1H), 1,48-1,43 (m, 2H), 1,31 (d, J= 8,0 Hz, 3H) . Chirale RT= 4,239 min (chirale methode A); ee= 100%.

E254: LC-MS: 407.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,86 (s, 1H), 6,12 (s, 1H), 5,70 (t, J= 12,0 Hz, 1H), 4,54 (d, J= 11,2 Hz, 1H),

4,45- 4,41 (m, 1H), 4,34-3,85 (m, 2H), 3,45 (s, 3H), 3,40-3,29 (m, 2H), 2,20 (s, 3H), 2,16-2,04 (m, 2H), 1,94-1,92 (m, 2H), 1,71- 1,64 (m, 5H), 1,58 (br, 1H), 1,30 (d, J= 8,0 Hz, 3H). Chirale RT= 4,639 min (chirale methode A); ee= 100%.

E255: LC-MS: 407.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): δ 7,86 (s, 1H), 6,11 (s, 1H), 5,70 (t, J= 12,8 Hz, 1H), 4,55 (d, J= 1,2 Hz, 1H), 4,45- 4,40 (m, 1H), 4,16 (dd, J= 2,4, 14,0 Hz, 1H), 3,94-3,79 (m, 1H), 3,44 (s, 3H), 3,39-3,29 (m, 2H), 2,20 (s, 3H), 2,04-2,00 (m, 2H), 1,97-1,84 (m, 4H), 1,51 (br, 1H), 1,49-1,43 (m, 2H), 1,30 (d, J= 8,0 Hz, 3H). Chirale RT= 4.730 min (chirale methode A); ee= 100%.

E256: LC-MS: 407.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,86 (s, 1 H), 6,12 (s, 1 H), 5,70 (t, J= 11,6 Hz, 1 H), 4,54 (d, J= 11,2 Hz, 1 H ), 4,45-4,41 (m, 1H), 4,32-3,86 (m, 2H), 3,44 (s, 3H), 3,40-3,29 (m, 2H), 2,20 (s, 3H), 2,17-2,03 (m, 2H ), 1,94-1,92 (m, 1H), 1,90-1,58 (m, 6H), 1,31 (d, J= 8,0 Hz, 3H). Chirale RT= 4,967 min (chirale methode A); ee= 94,9%.

Isomeren 1-2: 14-Chloor-4-methyl-5-(4-methylcyclohexyl)-8-oxa- 2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0³⁷]heptadeca-1(16),3,6,13 (17),14-pentaeen (E257-E258)

Compounds were prepared using procedures similar to those used to prepare E12 starting from D33 and 4-methylcyclohexyl

E257-E258

methane sulfonate.

E257: LCMS: 377,4 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,80 (s, 1H), 6,11 (s, 1H), 5,52 (s, 1H), 4,39 (t, J= 4,4 Hz, 2H), 3,84-3,78 (m, 1H ), 3,54-3,49 (m, 3H), 2,18 (s, 3H), 1,99-1,82 (m, 8H), 1,12- 1,02 (m, 2H), 0,93 (d, J= 6,4 Hz, 3H). Chirale RT= 2,408 min (chirale methode C); ee=100%.

E258: LCMS: 377,4 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1H), 6,06 (m, 1H), 5,12-5,10 (d, J= 8,0 Hz, 1H), 4,52-4,48 (m, 1H), 4,34-4,29 (m, 1H), 4,03-4,02 (m, 1H), 3,84-3,78 (m, 1H), 2,18 (s, 3H), 2,02-1,95 (m, 4H), 1,90-1,77 (m, 4H), 1,53 -1,47 (m, 2H), 1,32-1,25 (m, 3H), 1,22-1,03 (m, 1H), 1,02-1,00 (m, 3H). Chirale RT= 2,625 min (chirale methode C); ee=99,9%.

Enantiomeren 1-4: 14-Chloor-4,11-dimethyl-5-(4-methylcyclohexyl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0³⁷] heptadeca-1 (16),3,6, 13(17),14-pentaeen (E259-E262)

Compounds were prepared using procedures similar to those used to prepare E37 starting from D73 and 4-methylcyclohexyl

E259-E262 methane sulphonate.

E259: LC-MS: 391.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1H), 6,06 (s, 1H), 5,11 (d, J= 8,0 Hz, 1H), 4,52-4,48 (m, 1H), 4,32 (t, J = 10,4 Hz, 1H), 4,03 (t, J= 3,6 Hz, 1H), 3,84-3,78 (m, 1H), 2,18 (s, 3H), 2,02-1,95 (m, 4H), 1,90-1,77 (m, 4H), 1,53-1,47 (m, 2H), 1,31 (d, J= 3,6 Hz, 3H), 1,25-1,06 (m, 1H), 1,01 (d, J= 8,0 Hz, 3H). Chirale RT= 5,939 min (chirale methode C); ee= 100%.

E260: LC-MS: 391,3 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,81 (s, 1H), 6,05 (s, 1H), 5,11 (d, J= 6,8 Hz, 1H), 4,52-4,48 (m, 1H), 4,34 (t, J= 10,4 Hz, 1H), 4,05-4,02 (m, 1H), 3,85 (t, J= 10,8 Hz, 1H), 2,18 (s, 3H), 2,16-2,00 (m, 4H), 1,93-1,78 (m, 4H), 1,69-1,62 ( m, 2H), 1,30 (d, J= 6,8 Hz, 3H), 1,26-1,07 (m, 1H), 1,04 (d, J= 8,0 Hz, 3H). Chirale RT= 6,203 min (chirale methode C); ee= 98,5%.

E261 : LC-MS: 391.3 [M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,81 (s, 1H), 6,10 (s, 1H), 5,11 (d, J= 6,8 Hz, 1H), 4,52-4,48 (m, 1H), 4,34 (t, J = 10,4 Hz, 1H), 4,06-4,01 (m, 1H), 3,87-3,82 (m, 1H), 2,18 (s, 3H), 2,16-2,00 (m, 4H), 1,93-1,80 (m, 4H), 1,69-1,63 (m, 2H), 1,31 (d, J= 6,8 Hz, 3H), 1,25-1,07 (m, 1H), 1,03 (d, J= 8,0 Hz, 3H). Chirale RT= 6,748 min (chirale methode C); ee= 100%.

E262: LC-MS: 391,3 [M+H]⁺.¹H NMR (400 MHz, CDCb): 8 7,81 (s, 1H), 6,18 (s, 1H), 5,13 (d, J= 6,8 Hz, 1H), 4,52-4,48 (m, 1H), 4,32 (t, J = 10,2 Hz, 1H), 4,04-4,00 (m, 1H), 3,84-3,78 (m, 1H), 2,18 (s, 3H), 2,05-1,95 (m, 4H), 1,90-1,78 (m, 4H), 1,63-1,59 (m, 2H), 1,28 (d, J= 6,8 Hz, 3H), 1,26-1,07 (m, 1H), 1,05 (d, J= 8,0 Hz, 3H). Chirale RT= 9,431 min (chirale methode C); ee= 100%.

1-{14-Chloor-4-methyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0³⁷]heptadeca-1 (16),3,6,13(17),14-pentaen-5-yl}-2-methylpropaan-2-ol (E263)

The compound was prepared using procedures similar to those used to prepare E37, starting from D33 and 2,2-dimethyloxirane.

LC-MS: 353.2 [M+H]⁺.¹H NMR (400 MHz, CDCb): 8 7,82 (s, 1H), 6,17 (s, 1H), 5,56 (s, 1H), 4,63 (s, 1H), 4,37 (t, J= 4,6 Hz, 2H), 3,81 (s, 2H), 3,51 (dd, J= 10,8, 6,0 Hz, 2H), 2,19 (s, 3H), 1,95-1,91 (m, 2H), 1,16 (s, 6H).

Enantiomeren 1-2: 1-{14-chloor-4,11-dimethyl-8-oxa-2,5,6,12,16, 17-hexaazatricyclo[11.3.1.0³⁷]heptadeca-1 (17),3,6,13,15-pentaeen-5-yl}-2-methylpropaan-2-ol (E264-E265)

Compounds were prepared using procedures similar to those used to prepare E37, starting from D73 and 2,2-dimethyloxirane.

E264: LC-MS: 367,2 [M+H]⁺.¹H NMR (400 MHz, CDC13): 8 7,80

(br, 1H), 7,08 (s, 1H), 5,36 (d, J= 6,8 Hz, 1H), 4,58 (br, 1H), 4,47-4,43 (m, 1H), 4,32 (t, J= 3,6 Hz, 1H), 4,02 (t, J= 3,6 Hz, 1H), 3,81 (s, 2H), 2,20 (s, 3H), 1,91-1,81 (m, 2H), 1,35 (d, J= 7,2 Hz, 3H), 1,21 (s, 3H), 1,11 (s, 3H). Chirale RT= 1.620 min (chirale methode C); ee= 100%.

E265: LC-MS: 367,2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,80 (s, 1H), 6,75 (s, 1H), 5,27 (d, J= 6,4 Hz, 1H), 4,61 (br, 1H), 4,46-4,43 (m, 1 H), 4,33 (t, J= 11,2 Hz, 1 H), 4,01 (t, J= 3,2 Hz, 1 H), 3,81 (s, 2H), 2,20 (s, 3H), 1,94-1,79 (m, 2H ), 1,33 (d, J= 7,2 Hz, 3H), 1,21 (s, 3H), 1,12 (s, 3H). Chirale RT= 1,832 min (chirale methode C); ee= 100%. 14-chloor-4-methyl-5-(2,2,2-trifluorethyl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen (E266)

The compound was prepared using procedures similar to those used to prepare E12, starting from D33 and 1,1,1-trifluoro-2-iodoethane.

LC-MS: 363.1 [M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,82 (s, 1H), 6,23 (s, 1H), 5,57 (br, 1H), 4,46 (q, J= 8,4 Hz, 2H), 4,40 (t, J= 4,6 Hz, 2H), 3,52 (dd, J= 10,8, 6,4 Hz, 2H), 2,23 (s, 3H), 1,92 (t, J= 4,4 Hz, 2H).

14-Chloor-10-methoxy-4-methyl-5-(2,2,2-trifluorethyl)-8-oxa- 2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13 (17),14-pentaeen (E267)

Compounds were prepared using procedures similar to those used for E267 to prepare E12, using D13 and 2,2,2-trifluoroethyl-4-methylbenzene sulfonate as starting materials.

LC-MS: 393.1 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,86 (s, 1 H), 6,18 (s, 1 H), 5,73 (s, 1 H), 5,35 (s, 1 H), 4,50-4,44 (m, 2H) , 4,32 (t, J = 9,2 Hz, 1 H), 3,94-3,89 (m, 1 H), 3,42 (s, 3H), 2,23 (s, 3H), 2,02-2,00 (m, 2H).¹⁹F NMR (400 MHz, CDCI3): 8 -70,90 (s, 1 F).

Enantiomeren 1 -2: 14-Chloor-10-methoxy-4-methyl-5-(2,2,2-trifluorethyl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}] heptadeca-1 (16),3,6,13 (17),14-pentaeen (E268-E269)

Compounds were prepared from chiral resolution of E267.

E268-E269 E268: LC-MS: 393,2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,86 (s,

1 h), 6.10 (s, 1 h), 5.71 (br, 1 h), 4.50-4.44 (m, 3 h), 4.32 (t, J = 9.2 Hz , 1 h), 3.94-3.89 (m, 1 h), 3.42 (s, 3H), 3.31 -3.26 (m, 2H), 2.22 (s, 3H).¹⁹F NMR (376 MHz, CDCI3): 8 -70,90 (s, 3F). Chirale RT= 2,999 min (chirale methode A); ee= 100%.

E269: LC-MS: 393,2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,86 (s, 1H), 6,16 (s, 1H), 5,71 (br, 1H), 4,50-4,44 (m, 2H), 4,32 (t, J= 9,2 Hz, 1 uur), 3,94-3,89 (m, 1 uur), 3,42 (s, 3 uur), 3,32-3,27 (m, 2 uur), 2,22 (s, 3 uur).¹⁹F NMR (376 MHz, CDCI3): 8 -70,90 (s, 3F). Chirale RT= 3,314 min (chirale methode A); ee= 100%.

Enantiomeren 1 -2: 14-chloor-10-methoxy-4-methyl-5-(oxetan-3-yl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca- 1 (16),3,6, 13(17),14-pentaeen (E270-E271)

Compounds were prepared using procedures similar to those used E270-E271 to prepare E12, starting with D13 and 3-bromooxetane.

materials.

E270: LC-MS: 367.1 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,87 (s, 1 H), 6,28 (s, 1 H), 5,73-5,71 (m, 1 H), 5,30-5,26 (m, 1 H), 5,25-5,20 ( m, 1 uur), 5,17-5,14 (m, 1 uur), 4,92-4,90 (m, 2 uur), 4,55-4,51 (m, 1 uur), 4,44-4,41 (m, 1 uur), 3,95-3,89 (m , 1H), 3,49 (s, 3H), 3,34-3,28 (m, 3H), 2,15 (s, 3H). Chirale RT= 1.120 min (chirale methode A); ee= 100%. E271 : LC-MS: 367.1 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,85 (s, 1 H), 6,14 (s, 1 H), 5,72-5,70 (m, 1 H), 5,30-5,26 (m, 1 H), 5,25-5,20 (m, 1 H), 5,17 -5,14 (m, 1 uur), 4,92-4,89 (m, 2 uur), 4,55-4,52 (m, 1 uur), 4,43-4,38 (m, 1 uur), 3,95-3,89 (m, 1 uur), 3,43( s, 3H), 3,35~3,27(m, 3H), 2,15(s, 3H). Chirale RT= 1,515 min (chirale methode A); ee= 99,6%.

Enantiomeren 1 -2: 14-chloor-10-methoxy-4-methyl-5-[(3-methyloxetan-3-yl)methyl]-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0³'⁷]heptadeca-1 (16),3,6,13(17),14-pentaeen (E272-E273)

Compounds were prepared by procedures similar to those used to prepare E12, using D13 and (3-methyloxetan-3-yl)methylmethanesulfonate as starting materials.

E272: LC-MS: 395,2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,82 (s, 1 H), 6,65 (s, 1 H), 5,83-5,82 (m, 1 H), 4,79-4,77 (m, 1 H), 4,75-4,73 ( m, 1 H), 4,44-4,41 (m, 1 H), 4,39-4,37 (m, 2H), 4,28-4,23 (m, 1 H), 4,06-4,05 (m, 2H), 3,92-3,86 (m, 1H), 3,42 (s, 3H), 3,33-3,28 (m, 2H), 2,18 (s, 3H),1 .24 (s, 3H). Chirale RT= 3,986 min (chirale methode A); ee= 100%.

E273: LC-MS: 395,2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,82 (s, 1 H), 6,66 (s, 1 H), 5,83-5,81 (m, 1 H), 4,79-4,78 (m, 1 H), 4,75-4,73 ( m, 1 H), 4,44-4,42 (m, 1 H), 4,39-4,37 (m, 2H), 4,28-4,23 (m, 1 H), 4,06-4,05 (m, 2H), 3,92-3,86 (m, 1 uur), 3,42 (s, 3 uur), 3,33-3,28 (m, 2 uur), 2,18 (s, 3 uur), 1,24 (s, 3 uur). Chirale RT= 4,704 min (chirale methode A); ee=96,3%.

Enantiomeren 1 -2: 14-Chloor-10-methoxy-4-methyl-5-(oxan-4-ylmethyl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}] heptadeca-1 (16),3,6, 13(17),14-pentaeen (E274-E275)

Compounds were prepared by procedures similar to those used to prepare E12, using D13 and (bromomethyl)cyclohexane as starting materials.

E274: LC-MS: 409,3 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,84 (s, 1 H), 6,28 (s, 1 H), 5,72-5,69 (m, 1 H), 4,50-4,47 (m, 1 H), 4,31 -4,26 ( m, 1 H), 3,98-3,87 (m, 3H), 3,79-3,73 (m, 2H), 3,41 (s, 3H), 3,36-3,27 (m, 5H), 2,18-2,14 (m, 3H), 1,56 -1.47 (m, 2H), 1.38- 1.31 (m, 2H). Chirale RT= 1,104 min (chirale methode A); ee= 100%.

E275: LC-MS: 409,3 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,84 (s, 1 H), 6,24 (s, 1 H), 5,72-5,69 (m, 1 H), 4,50-4,47 (m, 1 H), 4,31 -4,26 ( m, 1 H), 3,98-3,87 (m, 3H), 3,79-3,73 (m, 2H), 3,41 (s, 3H), 3,36-3,27 (m, 5H), 2,18~2,14 (m, 3H),1 .56-1 .47 (m, 2H), 1 .38- 1 .31 (m, 2H). Chirale RT= 2,1 16 min (chirale methode A); ee= 100%.

HN— Isomeren 1 -2: 14-chloor-4-methyl-5-[4-(trifluormethyl)cyclohexyl]-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]

*H_NA_Nheptadeca-1 (16),3,6, 13(17),14-pentaeen (E276-E277)

Compounds were prepared using procedures similar to those used

E276-E277 - \ for preparing E12, starting with D33 and 4-

CF₃(trifluormethyl)cyclohexylmethaansulfonaat.

E276: LC-MS: 431.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,80 (s, 1 H), 6,28 (s, 1 H), 5,55 (s, 1 H), 4,38 (t, J= 4,6 Hz, 2H), 3,94-3,78 ( m, 1H), 3,51 (dd, J= 10,8, 6,0 Hz, 2H), 2,19 (s, 3H), 2,15-2,09 (m, 3H), 2,01-1,97 (m, 4H), 1,93-1,90 (m, 2H), 1.55-1.43 (m, 2H).¹⁹F NMR (376 MHz, CDC13): 8 -73,57.

E277: LC-MS: 431.2 [M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,79 (s, 1H), 6,81 (s, 1H), 5,70 (s, 1H), 4,37 (br, 2H), 4,13 (br, 1H), 3,53 (d, J = 4,8 Hz, 2H), 2,20 (s, 3H), 2,24-2,13 (m, 5H), 1,93-1,90 (br, 2H), 1,77-1,74 (m, 4H).¹⁹F-NMR (376 MHz, CDCb): 5-71.11.

Enantiomeren 1-2: 14-chloor-10-methoxy-4-methyl-5-[4-(trifluormethyl)cyclohexyl]-8-oxa-2,5,6,12,16,17-hexaazatricyclo [11.3. 1.0³'⁷]heptadeca-1 (16),3,6, 13(17),14-pentaeen (E278-E279)

Compounds were prepared by procedures similar to those used to prepare E12, using D13 and 4-(trifluoromethyl)cyclohexylmethanesulfonate as starting materials.

E278: LC-MS: 461.2[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,84 (s, 1H), 6,18 (s, 1H), 5,70-5,69 (m, 1H), 4,49-4,44 (m, 1H), 4,31-4,26 (m, 1H) , 3,92-3,84 (m, 2H), 3,41 (s, 3H), 3,35-3,26 (m, 2H), 2,18 (s, 3H), 2,11~1,91 (m,7H), 1,53-1,46 (m, 2H) . Chirale RT= 4,417 min (chirale methode G); ee=100%.

E279: LC-MS: 461.2[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,84 (s, 1H), 7,26 (s, 1H), 5,88~5,69 (m, 1H), 4,49-4,46 (m, 1H), 4,30-4,25 (m, 1H) , 3,93-3,84 (m, 2H), 3,42 (s, 3H), 3,34-3,26 (m, 2H), 2,20 (s, 3H), 2,11~1,91 (m, 7H), 1,53~1,46 (m, 2H) . Chirale RT= 5,518 min (chirale methode G); ee=100%.

Enantiomeren 1-4: 4-chloor-4,11-dimethyl-5-[4-(trifluormethyl)cyclohexyl]-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0³⁷] heptadeca-1 (16),3,6, 13(17),14-pentaeen (E280-E283)

Compounds were prepared using procedures similar to those used to prepare E12, starting from D73 and 4-(trifluoromethyl)cyclohexylmethanesulfonate.

E280: LC-MS: 445,2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,82 (s, 1H), 6,08 (s, 1H), 5,12 (d, J= 7,2 Hz, 1H), 4,50-4,46 (m, 1H), 4,31 (t, J = 10,8 Hz, 1H), 4,01 (t, J= 3,4 Hz, 1H), 3,87-3,84 (m, 1H), 2,19 (s, 3H), 2,13-2,04 (m, 4H), 1,96-1,93 (m, 2H), 1.90-1.83 (m, 2H),

1,80-1,78 (m, 1H), 1,50-1,31 (m, 2H), 1,29 (d, J= 8,0 Hz, 3H).¹⁹F NMR (376 MHz, CDCI3): 8 -73,566 (s, 3F). Chirale RT= 1,859 min (chirale methode A); ee= 100%.

E281 : LC-MS: 445.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,82 (s, 1H), 6,11 (s, 1H), 5,12 (d, J= 6,8 Hz, 1H), 4,50-4,46 (m, 1H), 4,30 (t, J = 7,6 Hz, 1H), 4,04-3,99 (m, 1H), 3,89-3,82 (m, 1H), 2,35 (s, 3H), 2,13-2,04 (m, 4H), 1,96-1,93 (m, 2H), 1.91-1.83 (m, 2H),

1,81- 1,78 (m, 1H), 1,51-1,33 (m, 2H), 1,31 (d, J= 8,0 Hz, 3H).¹⁹F NMR (376 MHz, CDCI3): 8 -73,566 (s, 3F). Chirale RT= 2,792 min (chirale methode A); ee= 100%.

E282: LC-MS: 445.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,82 (s, 1H), 6,03 (s, 1H), 5,11 (d, J= 6,8 Hz, 1H), 4,48-4,44 (m, 1H), 4,33 (t, J = 11,2 Hz, 1H), 4,12 (t, J= 4,8 Hz, 1H), 4,01 (t, J= 3,2 Hz, 1H), 2,34-2,25 (m, 2H), 2,18 (s, 3H), 2,15-2,04 (m, 2H), 1,94-1,87 (m, 2H), 1,83-1,72 (m, 5H), 1,28 (d, J= 8,0 Hz, 3H).¹⁹F NMR (376 MHz, CDC): 5 -71,069 (s, 3F). Chirale RT= 3,590 min (chirale methode A); ee= 100%.

E283: LC-MS: 445.2[M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,82 (s, 1 H), 6,12 (s, 1 H), 5,1 1 (d, J= 6,8 Hz, 1 H), 4,48-4,44 (m, 1 H), 4,34 (t, J= 10,8 Hz, 1 H), 4,12 (t, J= 4,8 Hz, 1 H), 4,03-3,98 (m, 2H), 2,34- 2,25 (m, 2H), 2,18 (s, 3H) , 2,15-2,04 (m, 2H), 1,94-1,93 (m, 1H), 1,90-1,62 (m, 5H), 1,29 (d, J= 8,0 Hz, 3H).¹⁹F NMR (376 MHz, CDCb): 8 -71,065 (s, 3F). Chirale RT= 4,124 min (chirale methode A); ee= 100%.

Y Enantiomeren 1 -2: 14-chloor-10-(difluormethoxy)-4-methyl-5-HN-y (oxan-4-yl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo [11.3.1.0^{3 7}] heptadeca-1 (16),3,6, 13(17),14-pentaeen (E284-E285)

^NΛ Ys Compounds were prepared using procedures similar to those used to prepare E5 starting from 3-amino-2-(difluoromethoxy)propan-1-ol.

E284-E285

E284: LC-MS: 431.2 [M+H]⁺.¹H NMR (400 MHz, CDCb): 8 7,87 (s, 1 H), 6,28 (t, J= 72,0 Hz, 1 H), 6,1 1 (s, 1 H), 5,69 (t, J= 6,0 Hz, 1 H), 4.54-4.43 (m, 2H), 4.28-4.25 (m, 1 H), 4.12-4.00 (m, 3H), 3.54-

3,39 (m, 3H), 2,34-2,21 (m, 2H), 2,21 (s, 3H), 1,78 (t, J= 13,2 Hz, 2H).¹⁹F NMR (376 MHz, CDCb): 8 -80,83 (d, J= 159,4 Hz, 1 F), -

82,38 (d, J= 160,6 Hz, 1 F). Chirale RT= 3,957 min (chirale methode A); ee= 100%.

E285: LC-MS: 431.2 [M+H]⁺.¹H NMR (400 MHz, CDCb): 8 7,88 (s, 1 H), 6,28 (t, J= 74,0 Hz, 1 H), 6,09 (s, 1 H), 5,69 (t, J= 6,0 Hz, 1 H ), 4.52-4.43 (m, 2H), 4.27-4.25 (m, 1H), 4.12-4.00 (m, 4H), 3.54-

3,40 (m, 3H), 2,31 -2,21 (m, 2H), 2,21 (s, 3H), 1,78 (t, J= 13,8 Hz, 2H).¹⁹F NMR (376 MHz, CDCb): 8 -80,82 (d, J= 159,4 Hz, 1 F), -

82,39 (d, J= 160,6 Hz, 1F). Chirale RT= 4,974 min (chirale methode A); ee= 100%.

Enantiomeren 1 -2: 14-Chloor-10-ethoxy-4-methyl-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca- 1 (16),3,6, 13(17),14-pentaeen (E286-E287)

Compounds were prepared using procedures similar to those used to prepare E2 starting from D10 and iodoethane.

E286-E287 E286: LC-MS: 409.2 [M+H]⁺.¹H NMR (400 MHz, CDCb): 8 7,84 (s,

1 H), 6,07 (s, 1 H), 5,68 (br, 1 H), 4,47 (d, J= 10,4 Hz, 1 H), 4,34 (t, J= 3,6 Hz, 1 H), 4,12-4,06 ( m, 3H), 3,94-3,89 (m, 1 H), 3,64-3,42 (m, 6H), 3,33-2,28 (m, 1 H), 2,32-2,21 (m, 1 H), 2,17 (s, 3H) , 1,78 (t, J= 13,6 Hz, 2H), 1,21 (t, J= 7,2 Hz, 3H). Chirale RT= 1.740 min (chirale methode E); ee=100%.

E287: LC-MS: 409.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,84 (s, 1 H), 6,10 (s, 1 H), 5,69 (s, 1 H), 4,47 (d, J= 10,4 Hz, 1 H), 4,34 (t , J= 3,6 Hz, 1 uur), 4,12-4,07 (m, 3 uur), 3,94-3,90 (m, 1 uur), 3,62-3,43 (m, 6 uur), 3,41 -2,28 (m, 1 uur), 2,32- 2,21 (m, 1H), 2,17 (s, 3H), 1,78 (t, J= 13,6 Hz, 2H), 1,21 (t, J= 7,2 Hz, 3H). Chirale RT= 2.250 min (chirale methode E); ee= 98,9%. Enantiomeren 1 -2: 14-broom-4-methyl-5-(oxan-3-yl)-8-oxa-2,5,6, 12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6, 13(17), 14-pentaeen (E288-E289)

Compounds were prepared by procedures similar to those used to prepare E29, using D25 and ie f-butyl(3-bromopropyl)carbamate as starting materials.

E288: LC-MS: 41 1,1 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,79 (s, 1 H), 4,32-4,30 (m, 2H), 4,15-4,13 (m, 1 H), 3,93-3,89 (m, 2H), 3,67-3,62 (m, 1 H), 3,45-3,30 (m, 3H), 2,22 (s, 3H), 2,15-2,13 (m, 1H), 2,05-2,03 (m, 1H), 1,83-1,81 (m, 4H). Chirale RT= 3.780 min (chirale methode A); ee= 100%.

E289: LC-MS: 41 1,1 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,79 (s, 1 H), 4,32-4,30 (m, 2H), 4,16-4,1 1 (m, 1 H), 3,93-3,89 (m, 2H), 3,67-3,62 (m, 1 H) , 3.45-3.31 (m, 3H), 2.22 (s, 3H), 2.19-2.12 (m, 1 H), 2.05-2.02 (m, 1 H), 1 .83-1 .81 (m, 4H). Chirale RT= 7,244 min (chirale methode A); ee= 100%.

Enantiomeren 1 -2: 4,11 -Dimethyl-5-(oxan-4-yl)-14- (trifluormethyl) -8-oxa-2,5,6,12,16,17- hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen (E290-E291)

E290-E291 Compounds were prepared using procedures similar to those used to prepare E31, using 3-(((i.e., f-butoxycarbonyl)amino)butylmethanesulfonate and 2,4-dichloro-5-(trifluoromethyl) pyrimidine as starting materials.

E290: LC-MS: 413.2 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 8,01 (s, 1 H), 4,37-4,27 (m, 3H), 4,08-4,04 (m, 3H), 3,60-3,53 (m, 2H), 2,24 -2,1 1 (m, 5H), 1 .83-1.75 (m, 4H), 1.28-1.22 (m, 3H).¹⁹F NMR (400 MHz, CD3OD): 8 -62,61 (s, 3F). Chirale RT= 1.533 min (chirale methode B); ee= 100%.

E291 : LC-MS: 413.2 [M+H]⁺.¹H NMR (400 MHz, CD3OD): 8 8,01 (s, 1 H), 4,38-4,27 (m, 3H), 4,08-4,03 (m, 3H), 3,60-3,54 (m, 2H), 2,24 -2,20 (m , 5H), 1.83-1.74 (m, 4H), 1.30-1.26 (m, 3H).¹⁹F NMR (400 MHz, CD3OD): 8 -62,57 (s, 3F). Chirale RT= 2.260 min (chirale methode B); ee= 100%.

Enantiomeren 1 -2: 14-chloor-11-cyclopropyl-4-methyl-5-(oxan-4-yl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca- 1 (16),3,6, 13(17),14-pentaeen (E292-E293)

Compounds were prepared using procedures similar to those used to prepare E5 starting from 3-amino-3-cyclopropyl-propan-1-ol. E292: LC-MS: 405.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s,

1 H), 6,08 (s, 1 H), 5,42 (d, J= 6,0 Hz, 1 H), 4,56 (dd, J= 1 1,6, 3,6 Hz, 1 H), 4,25 (t, J= 10,8 Hz, 1H), 4,22-4,03 (m, 3H), 3,50 (t, J= 12,0 Hz, 2H), 3,16-3,12 (m, 1H), 2,30-2,22 (m, 2H), 2,19 (s, 3H) , 2,15-2,09 (m, 1 uur), 1,95-1,91 (m, 1 uur), 1,78 (t, J= 13,2 Hz, 2 uur), 1,09-0,97 (m, 1 uur), 0,65-0,52 (m, 2H), 0,37-0,19 (m, 2H). Chirale RT= 2,404 min (chirale methode B); ee= 100%.

E293: LC-MS: 405.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1 H), 6,13 (s, 1 H), 5,43 (d, J= 6,4 Hz, 1 H), 4,56 (dd, J= 1 1,6, 3,6 Hz , 1H), 4,25 (t, J= 10,8 Hz, 1H), 4,22-4,03 (m, 3H), 3,50 (t, J= 12,0 Hz, 2H), 3,16-3,12 (m, 1H), 2,30-2,22 ( m, 2H), 2,19 (s, 3H), 2,15-2,09 (m, 1H), 1,95-1,91 (m, 1H), 1,78 (t, J= 14,4 Hz, 2H), 1,09-0,97 (m, 1H) , 0,65-0,56 (m, 2H), 0,37-0,28 (m, 2H). Chirale RT= 3,172 min (chirale methode B); ee= 99,9%.

(11?)-14-Methoxy-4,11-dimethyl-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0³⁷]heptadeca-1 (16),3,6,13(17),14- pentaeen (E294)

The compound was prepared using procedures similar to those used to prepare E31, using (R)-3-((α-butoxycarbonyl)amino)butyl

methanesulfonate and 2,4-dichloro-5-methoxypyrimidine as starting materials.

LC-MS: 375.3 [M+H]⁺.¹H NMR (400 MHz, CDC): 8 8,02 (s, 1H),

5,64-5,62 (m, 1H), 4,51-4,30 (m, 1H), 4,28-4,25 (m, 1H),

4.11-3.96 (m, 4H), 3.78 (br, 3H), 3.67-3.60 (m, 1H), 3.54-3.48 (m,

2H), 2,26 (s, 3H), 1,89-1,43 (m, 4H), 1,35-1,31 (m, 3H), 1,30-1,28

(m,2H).

(11 ?)-14-Fluor-4,11-dimethyl-5-(oxan-4-yl)-8-oxa- 2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0³⁷]heptadeca- 1 (16),3,6, 13(17),14-pentaeen (E295)

The compound was prepared using procedures similar to those used to prepare E31, using (R)-3-((α-butoxycarbonyl)amino)butyl

methanesulfonate and 2,4-dichloro-5-fluoropyrimidine as starting materials.

LC-MS: 363.3 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,68 (s, 1H), 6,62 (s, 1H), 5,03-5,02 (m, 1H), 4,51-4,89 (m, 1H), 4,35-4,30 (m, 1H) , 4,09-4,04 (m, 4H), 3,53-3,48 (m, 2H), 2,31-2,28 (m, 4H), 2,22 (s, 3H), 1,96-1,75 (m, 2H), 1,34-1,32 (m, 3H).

(11?)-14-Methyl-4,11-dimethyl-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0³⁷]heptadeca- 1 (16),3,6, 13(17),14-pentaeen (E296)

The compound was prepared using procedures similar to those used to prepare E31, using (R)-3-((α-butoxycarbonyl)amino)butyl

methanesulfonate and 2,4-dichloro-5-methylpyrimidine as starting materials.

LC-MS: 359,4 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,65 (s, 1H), 5,97 (s, 1H), 4,51-4,43 (m, 2H), 4,38-4,33 (m, 1H), 4,12-4,03 (m, 4H) , 3,54-3,47 (m, 2H), 3,35-2,23 (m, 2H), 2,22 (s, 3H), 1,92 (s, 3H), 1,88-1,79 (m, 2H), 1,75-1,71 (m, 2H) , 1.30-1.28 (m, 3H).

(11 ?)-14-Chloor-4-methyl-5-(oxan-4-yl)-11-(propaan-2-yl)-8-oxa- 2,5,6,12, 16,17-hexaazatricyclo [11.3.1.0³⁷]heptadeca- 1 (16),3,6, 13(17),14-pentaeen (E297)

The compound was prepared using procedures similar to those used to prepare E5 starting from (R)-3-amino-4-methylpentan-1-ol.

E297

LC-MS: 407.3 [M+H]⁺.¹H NMR (400 MHz, CDCI3): δ 7,81 (s, 1H), 6,28 (s, 1 H), 5,25 (d, J= 7,6 Hz, 1 H), 4,53 (dd, J = 11,6, 3,6 Hz, 1H ), 4,26 (t, J= 10,8 Hz, 1H), 4,12-4,07 (m, 3H), 3,72-3,70 (m, 1H), Enantiomeer 1 -2: 14-Chloor-5-(4,4-difluorooxan- 3-yl)-4-methyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca- 1 (16),3,6, 13(17),14-pentaeen (E302-E303)

Compounds were prepared using procedures similar to those used

to prepare E86, (direct reaction of D118 with DAST before cyclization).

E302: LC-MS: 401.2 [M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆): δ 8,44 (s, 1 H), 7,83 (s, 1 H), 7,40 (t, J= 5,6 Hz, 1 H), 4,70-4,63 (m, 1 H), 4,24-4,04 (m, 5H) , 3,68-3,62 (m, 1 uur), 3,35-3,33 (m, 2 uur),

2.30-2.25 (m, 2H), 2.21 (s, 3H),1.85-1.71 (m, 2H). Chirale RT= 3,353 min (chirale methode C); ee= 100%.

E303: LC-MS: 401.2 [M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆): δ 8,44 (s, 1 H), 7,83 (s, 1 H), 7,41 (t, J= 6,0 Hz, 1 H), 4,70-4,63 (m, 1 H), 4,28 -4,04 (m, 5H) , 3,68-3,62 (m, 1 uur), 3,35-3,28 (m, 2 uur),

2.30-2.25 (m, 2H), 2.21 (s, 3H),1 .85-1 .71 (m, 2H). Chirale RT= 4,089 min (chirale methode C); ee= 100%.

Enantiomeren 1 -2: (11 ?)-14-Chloor-5-(4,4-difluorooxan-3-yl)- 4,11 -dimethyl-8-oxa-2,5,6,12,16,17- hexaazatricyclo[11.3.1.0^{3 7}] heptadeca-1 (16),3,6, 13(17),14-pentaeen (E304-E305)

Compounds were prepared using procedures similar to those used to prepare E302.

E304-E305^F

E304: LC-MS: 415.3 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,72 (s, 1 H), 4,53-4,45 (m, 1 H), 4,40-4,36 (m, 2H), 4,31 (t, J= 24 Hz, 1 H), 4,23-4,18 (m, 3H), 4,04-3,96 (m, 1H), 2,31 -2,17 (m, 5H), 1,80- 1,76 (m, 2H), 1,28 (d, J= 8,0 Hz, 3H). Chirale RT= 5,137 min (chirale methode A); ee= 100%.

E305: LC-MS: 415.3 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,72 (s, 1 H), 4,92-4,82 (m, 1 H), 4,57-4,22 (m, 3 H), 4,14-4,09 (m, 1 H), 4,04 -4,00 (m, 1 H) , 3,93-3,89 (m, 1 uur), 3,74-3,71 (m, 1 uur), 2,25~2,17 (m, 5 uur), 1,77-1,74 (m, 2 uur), 1,28 (d, J= 8,0 Hz,3H). Chirale RT= 6,255 min (chirale methode A); ee= 98,7%.

Enantiomeren 1 -4: 14-Chloor-4,10-dimethyl-5-(oxan-3-yl)-8-oxa- 2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3, 6, 13(17),14-pentaeen (E306-E309)

^HNCompounds were prepared using procedures similar to those used to prepare E2 starting from D25 and 3-((tert-06-E309-'butoxycarbonyl)amino)-2-methylpropyl methanesulfonate.

E306: LC-MS: 379,2 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,70 (s, 1 H), 4,20-4,10 (m, 3H), 3,93-3,91 (m, 2H), 3,70-3,59 (m, 2H), 3,45- 38 (m, 1 H), 3,06 (d, J= 12.0 Hz, 1H), 2.22 (s, 3H), 2.16-2.1 1 (m, 1H), 2.04-1 .99 (m, 1H), 1.81 (br, 3H) , 0,99 (d, J= 8,0 Hz, 3H). Chirale RT= 1.856 min (chirale methode A); ee= 99,1 %.

E307: LC-MS: 379,2 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,70 (s, 1 H), 4,22-4,08 (m, 3H), 3,93-3,86 (m, 2H), 3,66-3,59 (m, 2H), 3,45-3,38 (m, 1 H), 3,03 (d, J= 16,0 Hz, 1 H), 2,22 (s, 3H), 2,18-2,12 (m, 1 H), 2,06-2,03 (m, 1 H), 1,81 (br, 3H), 0,99 ( d, J= 8,0 Hz, 3H). Chirale RT= 1.999 min (chirale methode A); ee= 99,1 %. E308: LC-MS: 379,2 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,70 (s, 1 H), 4,22-4,09 (m, 3H), 3,93-3,86 (m, 2H), 3,66-3,60 (m, 2H), 3,45-3,38 (m, 1 H), 3,04 (d, J= 16,0 Hz, 1 H), 2,22 (s, 3H), 2,18-2,13 (m, 1 H), 2,06-2,01 (m, 1 H), 1,81 (br, 3H), 0,99 ( d, J= 8,0 Hz, 3H). Chirale RT= 2,359 min (chirale methode A); ee= 100%.

E309: LC-MS: 379,2 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,70 (s, 1 uur), 4,20-4,10 (m, 3 uur), 3,93-3,91 (m, 2 uur), 3,70-3,60 (m, 2 uur), 3,45-3,39 (m, 1 uur), 3,05 (d, J= 16,0 Hz, 1 H), 2,22 (s, 3H), 2,16-2,08 (m, 1 H), 2,03-2,01 (m, 1 H), 1,81 (br, 3H), 0,99 ( d, J= 8,0 Hz, 3H). Chirale RT= 3,418 min (chirale methode A); ee= 100%.

14-Chloor-4-methyl-5-{3-[(1?,4?)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-cyclobutyl}-8-oxa-2, 5,6,12,16,17-hexaazatricyclo

[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaene (E310)

The compound was prepared using procedures similar to those used to prepare E45, starting from D75 and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane.

LC-MS: 432.3 [M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆): δ 8,30 (s, 1 H), 7,76 (s, 1 H), 7,32 (t, J= 5,6 Hz, 1 H), 4,34 (br, 2H), 4,23 (d, J = 4,4 Hz, 2H) , 3,77 (d, J= 6,8 Hz, 1 H), 3,49 (d, J= 6,8 Hz, 1 H), 3,43 (br, 1 H), 3,30-3,27 (m, 2H), 3,00-2,97 (m, 1 uur), 2,72 (d, J= 9,6 Hz, 1 uur), 2,45-2,25 (m, 5 uur), 2,09 (s, 3 uur), 1,73-1,70 (m, 3 uur), 1,58-1,55 (m, 1 uur ).

ΗΝ-Λ 14-chloro-4-methyl-5-{3-[(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]

heptan-5-yl]-cyclobutyl}-8-oxa-2,5,6,12,16,17-hexaazatricyclo

HN [11.3.1.0³'⁷]heptadeca-1 (16),3,6, 13(17),14-pentaeen (E311)

The compound was prepared using procedures similar to those used to prepare E45, starting from D75 and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptanes.

LC-MS: 432.3 [M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆): δ 8,29 (s, 1H), 7,76 (s, 1H), 7,31 (s, 1H), 4,35 (br, 2H), 4,23 (br, 2H), 3,77 (d, J= 7,6 Hz, 1 H), 3,49 (d, J= 6,8 Hz, 1 H), 3,43 (br, 1 H), 3,30-3,27 (m, 2H), 3,01 -2,97 (m, 1 H), 2,72 (d, J= 9,2 Hz, 1 H), 2,45-2,25 (m, 5H), 2,09 (s, 3H), 1,73-1,68 (m, 3H), 1,57-1,55 (m, 1 H).

14-Chloor-5-[3-(3,3-difluorpyrrolidine-1 -yl)cyclobutyl]-4-methyl- 8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}] heptadeca-1 (16),3,6,13(17),14-pentaeen (E312)

The compound was prepared using procedures similar to those used to prepare E45 starting from D75 with 3,3-difluoropyrrolidine.

LC-MS: 440.2 [M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆): d 8.31 (s,

1H), 7,76 (s, 1H), 7,33 (s, 1H), 4,37 (br, 1H), 4,23 (br, 2H), 3,28 (br, 2H), 2,85 (t, J= 13,2 Hz , 2H), 2,76 (br, 1H), 2,65 (br, 2H), 2,33-2,39 (m, 6H), 2,10 (s, 3H), 1,72 (br, 2H).¹⁹FNMR (376 MHz, DMSO-d₆): 5 -90,75. Enantiomeren 1 -4: 14-Chloor-5-[3-(3,3-difluorpyrrolidin-1 -yl)cyclobutyl]-4,11 -dimethyl-8-oxa-2,5,6,12,16,17- hexaazatricyclo

[11.3.1.0^{3 7}]-heptadeca-1 (16),3,6, 13(17),14-pentaeen (E313-E316)

Compounds were prepared by procedures similar to those used to prepare E106 using D135 and 3,3-difluoropyrrolidine as starting materials.

E313: LC-MS: 454.2 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,72 (s, 1 H), 4,44-4,33 (m, 2H), 3,97-3,92 (m, 1 H), 2,95-2,90 (m, 3H), 2,77 (t, J= 8,0 Hz, 2H ), 2,73-2,57 (m, 3H), 2,44-2,35 (m, 2H),

2,34- 2,26 (m, 2H), 2,15 (s, 3H), 1,84-1,74 (m, 2H), 1,30 (d, J= 8,0 Hz, 3H).¹⁹F-NMR (400 MHz, CD₃OD): 8-93.72 (s, 2F). Chiral RT= 2.061 min (chiral method E); i= 100%.

E314: LC-MS: 454.2 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,72 (s, 1 H), 4,44-4,33 (m, 2H), 3,97-3,95 (m, 1 H), 2,95-2,90 (m, 3H), 2,77 (t, J= 8,0 Hz, 2H ), 2,73-2,57 (m, 3H), 2,44-2,37 (m, 2H),

2,35- 2,26 (m, 2H), 2,15 (s, 3H), 1,84-1,74 (m, 2H), 1,30 (d, J= 8,0 Hz, 3H).¹⁹F-NMR (400 MHz, CD₃OD): 8-93.72 (s, 2F). Chiral RT= 2.737 min (chiral method E); i= 100%.

E315: LC-MS: 454,2 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,72 (s, 1H), 4,47-4,35 (m, 3H), 3,96 (br, 1H), 2,97-2,85 (m, 3H), 2,76 (t, J = 8,0 Hz, 2H), 2,54-2,49 (m, 4H), 2,33-2,23 (m, 2H), 2,17 (s, 3H), 1,84-1,73 (m, 2H), 1,30 (d, J= 8,0 Hz, 3H).¹⁹F-NMR (400 MHz, CD₃OD): 5-93.90 (s, 2F). Chiral RT= 3.712 min (chiral method E); i= 100%.

E316: LC-MS: 454.2 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,72 (s, 1 H), 4,47-4,34 (m, 3H), 3,96-3,94 (m, 1 H), 2,97-2,85 (m, 3H), 2,76 (t, J= 8,0 Hz, 2H ), 2,54-2,50 (m, 4H), 2,34-2,23 (m, 2H), 2,17 (s, 3H), 1,85-1,74 (m, 2H), 1,30 (d, J= 8,0 Hz, 3H ).¹⁹F-NMR (400 MHz, CD₃OD): 5-93.90 (s, 2F). Chiral RT= 4.949 min (chiral method E); i= 100%.

(11 ?)-14-Chloro-4,11 -dimethyl-5-{3-[(1 ?,4 ?)-2-oxa-5-aza bicycle

[2.2.1]heptaan-5-yl]cyclobutyl}-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0³'⁷]heptadeca-1(16),3,6,13(17),14-pentaeen (E317)

The compound was prepared using procedures similar to those used to prepare E106 by reacting D135 with (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane.

LC-MS: 446.3[M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,72 (s, 1 H), 4,44-4,37 (m, 4H), 3,99-3,94 (m, 2H), 3,63-3,59 (m, 2H), 3,17- 3,13 (m, 1 H), 2,83 -2,80 (m, 1 uur), 2,69-2,67 (m, 1 uur), 2,57-2,46 (m, 4 uur), 2,17 (s, 3 uur), 1,90-1,87 (m, 1 uur), 1,81 -1,72 (m, 3H), 1,30-1,28 (m, 3H).

(11 K)-14-Chloor-4,11 -dimethyl-5-{3-[(1 K,4/?)-2-oxa-5-aza bicyclo[2.2.1]heptan-5-yl]cyclobutyl }-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaene (E318) The compound was prepared according to procedures similar to those used for the preparation of E106, by reacting D135 with (1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane.

LC-MS: 446.3 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,72 (s, 1H), 4,45-4,37 (m, 4H), 3,99-3,94 (m, 2H), 3,62-3,61 (m, 2H), 3,18- 3,12 (m, 1H), 2,84- 2,82 (m, 1H), 2,70-2,67 (m, 1H), 2,60-2,47 (m, 4H), 2,17 (s, 3H), 1,90-1,88 (m, 1H), 1,80-1,73 (m, 3H), 1.30 -1.28 (m, 3H).

Enantiomeren 1-2: 14-Chloor-11-ethyl-4-methyl-5-(oxetan-3-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0³⁷]heptadeca-1(16), 3,6, 13(17),14-pentaeen (E319-E320)

Compounds were prepared using procedures similar to those used to prepare E52 from 3-aminopentan-1-ol.

E319-E320

E319: LC-MS: 365,2 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 8,36 (s, 1H), 7,79 (s, 1H), 6,78 (d, J= 7,6 Hz, 1H), 5,42-5,38 (m, 1H), 4,94 (t, J= 6,4 Hz, 1H), 4,84-4,79 (m, 3H), 4,36-4,25 (m, 2H), 3,62-3,59 (m, 1H), 2,08 (s, 3H), 1,80-1,67 (m, 2H), 1,59-1,53 (m, 2H ), 0,86 (t, J= 7,2 Hz, 3H). Chirale RT= 3.140 min (chirale methode E); ee= 100%.

E320: LC-MS: 365,2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 8,36 (s, 1H), 7,79 (s, 1H), 6,78 (d, J= 7,6 Hz, 1H), 5,42-5,38 (m, 1H), 4,94 (t, J = 6,4 Hz, 1H), 4,84-4,79 (m, 3H), 4,36-4,25 (m, 2H), 3,62-3,59 (m, 1H), 2,08 (s, 3H), 1,80-1,67 (m, 2H), 1,59-1,53 (m, 2H), 0,86 (t, J= 7,2 Hz, 3H). Chirale RT= 6,195 min (chirale methode E); ee= 99,8%.

F Enantiomeren 1-2: 14-chloor-10-fluor-4-methyl-5-(oxetan-3-yl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0³⁷]heptadeca- 1(16),3, 6, 13(17), 14-pentaeen (E321-E322)

Compounds were prepared using procedures similar to those used

E321-E322

for the preparation of E52 starting from 3-amino-2-fluorobutan-1-ol.

E321: LC-MS: 355.1 [M+H]⁺.¹H NMR (400 MHz, CDC): 57,85 (s, 1H), 6,57 (s, 1H), 5,86 (t, J= 5,6 Hz, 1H), 5,33-5,25 (m, 1H), 5,21 (t, J= 6,4 Hz, 1H), 5,15 (d, J= 6,4 Hz, 1H), 4,92 (t, J= 7,2 Hz, 2H), 4,68-4,59 (m, 2H), 4,57-4,48 (m, 1H), 4,11- 3,97 (m, 1H), 3,58-3,45 (m, 1H), 2,16 (s, 3H). Chirale RT= 1,712 min (chirale methode E); ee= 100%.

E322: LC-MS: 355.1 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,85 (s, 1H), 6,76 (s, 1H), 5,91 (t, J= 5,6 Hz, 1H), 5,35-5,25 (m, 1H), 5,21 (t, J = 6,4 Hz, 1H), 5,16 (t, J= 6,4 Hz, 1H), 4,92 (t, J= 7,2 Hz, 2H), 4,68-4,48 (m, 3H), 4,11-3,99 (m, 1H), 3,58 -3,46 (m, 1H), 2,14 (s, 3H). Chirale RT= 2,095 min (chirale methode E); ee= 99,5%.

2-[(11S)-14-Chloor-4-methyl-11 -(propaan-2-yl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0³⁷]heptadeca-1 (16),3,6,13(17), 14-pentaeen-5-yl]-2-methylpropaannitril (E323)

The compound was prepared using procedures similar to those used to prepare E43 starting from (S)-3-amino-4-methylpentan-1-ol.

LC-MS: 390.2 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,84 (s, 1H), 6,67 (br, 1H), 5,32 (d, J= 7,6 Hz, 1H), 4,48 (dd, J= 11,6, 3,2 Hz, 1H ), 4,25 (t, J= 11,2 Hz, 1H), 3,71-3,67 (m, 1H), 2,47 (s, 3H), 2,02 -1,95 (m, 4H), 1,90 (s, 3H), 1,87-1,82 ( m, 2H), 1 0,01 (dd, J= 6,4, 2,8 Hz, 6H).

(11 S)-14-Chloor-4-methyl-5-(oxetan-3-yl)-11 -(propaan-2-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo [11.3.1.0^{3 7}]heptadeca- 1 (16),3,6, 13(17),14-pentaeen (E324)

The compound was prepared using procedures similar to those used before

E324 to prepare E52, starting from (S)-3-amino-4-methylpentan-1-ol.

LC-MS: 379,2 [M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,81 (s, 1H), 6,38 (s, 1H), 5,30-5,17 (m, 4H), 4,91 (t, J= 7,2 Hz, 2H), 4,56 (dd , J= 1 1,6, 3,6 Hz, 1 H), 4,38 (t, J= 1 1,2 Hz, 1 H), 3,70 (d, J= 5,6 Hz, 1 H), 2,15 (s, 3H), 2,03-1,97 (m, 1 H), 1,87-1,80 (m, 1 H), 1,73-1,67 (m, 1 H), 1,01 (d, J= 6,4 Hz, 6H).

Enantiomeren 1 -2: (11 ?)-14-Chloor-5-(4-fluoroxan-3-yl)-4,11 - dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[ 11.3.1.0^{3 7}] heptadeca-1 (16),3,6, 13(17),14-pentaeen (E325-E326)

E325-E326 Compounds were prepared using procedures similar to those used to prepare E86 from D79.

E325: LC-MS: 397,2 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,72 (s, 1 H), 5,18-4,91 (m, 1 H), 4,40-4,30 (m, 2H), 4,23-4,14 (m, 1 H), 4,04-3,90 (m, 3H), 3,79 (t, J= 12,0 Hz, 1 H), 3,50 (t, J= 12,0 Hz, 1 H), 2,23 (s, 3H), 1,95-1,73 (m, 4H), 1,30 (d, J = 8,0 Hz, 3H).¹⁹F NMR (376MHz, CDCb): 8-180.06 (s, 1F). Chiral RT= 2,350 min (chiral method C); yes= 100%.

E326: LC-MS: 397,2 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,72 (s, 1 H), 5,04-4,89 (m, 1 H), 4,40-4,26 (m, 2H), 4,23-4,14 (m, 1 H), 4,06-3,90 (m, 3H), 3,79 (t, J= 12,0 Hz, 1 H), 3,51 (t, J= 12,0 Hz, 1 H), 2,23 (s, 3H), 2,08-1 0,72 (m, 4H), 1,28 (d, J= 8,0 Herz, 3H).¹⁹F NMR (376MHz, CDCb): 8-180.45 (s, 1F). Chiral RT= 2.908 min (chiral method C); yes= 100%.

Enantiomeer 1 -2: 14-Chloor-10-methoxy-4-methyl-5-(oxan-4-yl)-8,12-dioxa-2,5,6,16,17-pentaazatricyclo[11.3.1.0^{3 7}]heptadeca- 1 (16),3,6, 13(17),14-pentaeen (E327-E328)

Compounds were prepared using procedures similar to those used to prepare E5 starting from 2-methoxypropane-1,3-diol.

E327: LC-MS: 396.1 [M+H]⁺.¹H NMR (400 MHz, CDCb): 8 8,08 (s,

1 H), 6,63 (s, 1 H), 4,96 (dd, J= 12,4, 2,4 Hz, 1 H), 4,50 (dd, J=1 1,2, 1,6 Hz, 1 H), 4,41 (dd, J =1 1 .4, 9.0 Hz, 1 H), 4.29 (dd, J = 12.4, 2.4 Hz, 1 H), 4.16-4.08 (m, 3H), 3.56-3.51 (m, 2H), 3.47 (s, 3H), 3,43 (dd, J= 9,2, 2,0 Hz, 1H), 2,44-2,25 (m, 2H), 2,23 (s, 3H),

1.85~1.77(m, 2H). Chirale RT= 4,763 min (chirale methode A); ee= 100%.

E328: LC-MS: 396,2 [M+H]⁺.¹H NMR (400 MHz, CDCb): 8 8,08 (s, 1 H), 6,55 (s, 1 H), 4,96 (dd, J= 12,4, 2,0 Hz, 1 H), 4,50 (dd, J= 1 1,2, 2,0 Hz, 1 uur), 4,41 (dd, J=1 1,2, 9,6 Hz, 1 uur), 4,29 (dd, J= 12,4, 2,0 Hz, 1 uur), 4,16-4,07 (m, 3 uur), 3,56 -3,50 (m, 2H), 3,48 (s, 3H), 3,43 (dd, J=9,2, 2,0 Hz, 1 H), 2,44-2,24 (m, 2H), 2,23 (s, 3H), 1,85-1,77 ( m, 2H). Chirale RT= 5,518 min (chirale methode A); ee= 100%. Enantiomeren 1 -2: 14-Chloor-4,11 -dimethyl-5-(oxan-4-yl)-8,12-dioxa-2,5,6,16,17-pentaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (17), 3,6,13, 15-pentaeen (E329-E330)

Compounds were prepared using procedures similar to those used to prepare E5 starting from 4-((tetrahydro-2/-/-pyran-2-yl)oxy)butan-2-ol followed by THP deprotection .

E329: LC-MS: 380,3 [M+H]⁺.¹H NMR (400 MHz, CDsODj: δ 8,00 (s, 1 H), 5,05-5,01 (m, 1 H), 4,45-4,40 (m, 1 H), 4,37-4,23 (m, 2H), 4,07-4,01 ( m, 2H), 3,55 (t, J= 16,0 Hz, 2H), 2,23 (s, 3H), 2,20-2,03 (m, 2H), 1,90-1,88 (m, 2H), 1,84-1 . 73 (m, 2H), 1,39 (d, J= 8,0 Hz, 3H) Chirale RT= 2,221 min (chirale methode B), ee= 100%.

E330: LC-MS: 380,3 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 8,00 (s, 1 H), 5,05-5,01 (m, 1 H), 4,45-4,40 (m, 1 H), 4,37-4,23 (m, 2H), 4,07-4,01 (m, 2H), 3,55 (t, J= 16,0 Hz, 2H), 2,23 (s, 3H), 2,20-2,06 (m, 2H), 1,90-1,88 (m, 2H), 1,83-1,73 (m, 2H), 1,38 (d, J= 8,0 Hz, 3H). Chirale RT= 3,219 min (chirale methode B); ee= 100%.

{4-[(11?)-14-Chloor-4,11 -dimethyl-8-oxa-2,5,6,12,16,17-hexa azatricyclo[11.3.1.0^{3 7}]heptadeca-1(16),3,6,13(17),14-pentaeen-5-yl]oxan-2-yl}methanol (E331 )

The compound was prepared using procedures similar to those used to prepare E46, starting from ethyl 4-((methylsulfonyl)oxy)tetrahydro-2H-pyran-2-carboxylate and reducing ester group by UAIH4 after cyclization.

LC-MS: 409.3 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,82 (s, 1 H), 6,04 (s, 1 H), 5,13-5,1 1 (m, 1 H), 4,49-4,20 (m, 5H), 4,02-3,99 ( m, 1 uur), 3,88-3,86 (m, 1 uur), 3,66-3,63 (m, 1 uur), 3,58-3,54 (m, 1 uur), 2,18 (s, 3 uur), 2,05-1,79 (m, 7 uur ), 1,34-1,32 (d, J= 6,8 Hz, 3H).

Enantiomeren 1 -2: 14-chloor-10-fluor-4,11-dimethyl-5-(oxetan-3-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]

heptadeca-1 (16),3,6, 13(17),14-pentaeen (E332-E333)

Compounds were prepared using procedures similar to those used to prepare E52 from D104.

E332: 369.2[M+H]⁺.¹H NMR (400 MHz, CDC13): 8 7,79 (s, 1 H), 6,06

E332-E333 (s, 1 h), 5.27-5.14 (m, 1 h), 5.17-5.09 (m, 2 h), 5.02 (d, J = 7.6 Hz ,

1H), 4,84 (t, J= 7,2 Hz, 2H), 4,62-4,39 (m, 3H), 4,39-4,29 (m, 1H), 2,09 (s, 3H), 1,34 (d, J= 7,2 Hz, 3H). Chirale RT= 2,625 min (chirale methode E); ee= 100%.

E333: 369.2[M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,79 (s, 1 H), 6,09 (s, 1 H), 5,29-5,14 (m, 1 H), 5,10 (dt, J= 9,6, 6,4 Hz, 2H), 5,02 (d, J= 7,2 Hz, 1 H), 4,84 (t, J= 7,2 Hz, 2 H), 4,70-4,40 (m, 3 H), 4,40-4,20 (m, 1 H), 2,09 (s, 3 H) , 1,34 (d, J= 7,2 Hz, 3H). Chirale RT= 4,992 min (chirale methode B); ee= 100%. Enantiomeren 1 -4: 14-Chloor-10-fluor-5-(3-fluoroxan-4-yl)-4-methyl-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}] heptadeca-1 (16),3,6, 13(17),14-pentaeen (E334-337)

Compounds were prepared using procedures similar to those used to prepare E46, using 3-amino-2-fluoropropan-1-ol and 3-fluorotetrahydro-2/-/-pyran-4-ylmethanesulfonate as starting materials .

materials.

E334: LC-MS: 401 .3 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,84 (s, 1 H), 6,63 (s, 1 H), 5,86 (s, 1 H), 4,91 (dtd, J= 49,2, 9,6, 5,6 Hz, 1 H), 4,69-4,45 (m, 3H), 4,26 (dd, J= 10,8, 5,2 Hz, 1 H), 4,16-3,98 (m, 3H), 3,64-3,29 (m, 3H), 2,47-2,36 (m, 1 H), 2,22 (s, 3H), 1.97- 1.82 (m, 1H). Chirale RT= 2,688 min (chirale methode A); ee= 100%.

E335: LC-MS: 401.3[M+H]⁺.¹H NMR (400 MHz, CDC): 5 7,87 (s, 1 H), 6,16 (s, 1 H), 5,76 (s, 1 H), 4,92-4,71 (m, 1 H), 4,66-4,42 (m, 3H), 4,24 (dd, J= 1 1,2, 5,2 Hz, 1 H), 4,20-3,91 (m, 3H), 3,58-3,32 (m, 3H), 2,52 (ddd, J= 25,2, 12,4, 4,8 Hz, 1 uur), 2,22 (s, 3 uur), 2,04- 1,91 (m, 1 uur). Chirale RT= 3,478 min (chirale methode A); ee= 100%.

E336: LC-MS: 401.3[M+H]⁺.¹H NMR (400 MHz, CDCb): 5 7,80 (s, 1 H), 6,21 (s, 1 H), 5,70 (t, J= 6,0 Hz, 1 H), 4,89-4,61 (m, 1 H), 4,61 - 4,37 (m, 3H), 4,17 (dd, J = 11,0, 5,2 Hz, 1 H), 4,12 - 3,88 (m, 3H),

3,52- 3,21 (m, 3H), 2,45 (ddd, J=17,2, 12,8, 4,8 Hz, 1 H), 2,15 (s, 3H), 1,99-1,86 (m, 1 H). Chirale RT= 3,692 min (chirale methode A); ee= 100%.

E337: LC-MS: 401.3[M+H]⁺.¹H NMR (400 MHz, CDCb): 5 7,79 (s, 1 H), 6,18 (s, 1 H), 5,69 (d, J= 6,0 Hz, 1 H), 4,98-4,71 (m, 1 H), 4,62 -4,40 (m, 3H), 4,19 (dd, J= 1 1,2, 5,2 Hz, 1 H), 4,14-3,88 (m, 3H),

3,53- 3,22 (m, 3H), 2,36 (ddd, J= 25,2, 12,4, 4,8 Hz, 1 H), 2,14 (s, 3H), 1,95-1,77 (m, 1 H). Chirale RT= 6,041 min (chirale methode A); ee= 100%.

14-Chloor-4-methyl-5-(oxan-4-ylmethyl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen (E338)

E338 (J compound has been prepared with procedures similar to those used for

0 preparation of E12, starting from (tetrahydro-2/-/-pyran-4-yl)methyl

methane sulfonate.

LC-MS: 379,2 [M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆): δ 8,29 (s, 1H), 7,76 (s, 1H), 7,32 (br, 1H), 4,18 (br, 2H), 3,82 (d, J= 9,6 Hz, 2H), 3,72 (d, J= 6,8 Hz, 2H), 3,27-3,17 (m, 4H), 2,12 (s, 3H), 1,99 (br, 1 H), 1,70 (br, 2H), 1,39 (d, J= 12,0 Hz, 2H), 1,27-1,16 (m, 2H).

4,14-dichloor-10-methoxy-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen (E339)

The compound was prepared using procedures similar to those used to prepare E2 using D13 and D36 as starting materials.

LC-MS: 415.1 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 9,90 (br, 1 H), 7,66 (s, 1 H), 6,81 (br, 1 H), 4,42-4,38 (m, 1 H), 4,33-4,27 (m, 1 uur), 4,21 -4,16 (m, 1 uur), 4,05-4,02 (m, 2 uur), 3,90-3,86 (m, 2 uur), 3,45 (t, J = 12,0 Hz, 3 uur), 3,39 (s, 3 uur) , 3,31 -3,29 (m, 1H), 2,19-2,08 (m, 2H), 1,78-1,75 (m, 2H).

Enantiomeren 1 -2: 4,14-dichloor-10-methoxy-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca- 1 (16),3,6, 13(17),14-pentaeen (E340-E341)

Compounds were prepared from chiral resolution of E339.

E340: LC-MS: 415.1 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,88 (s, 1 H), 6,18 (br, 1 H), 5,58 (br, 1 H), 4,51 -4,48 (m, 1 H), 4,27-4,26 (m, 2H), 4,24-4,09 ( m, 2H), 3,55-3,34 (m, 7H), 2,27-2,20 (m, 2H), 1,87-1,81 (m, 2H), 1,95-1,93 (m, 2H), 1,87-1 .80 (m, 2H). Chirale RT= 5,087 min (chirale methode A); ee= 100%.

E341 : LC-MS: 415.1 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,88 (s, 1 H), 6,19 (br, 1 H), 5,69 (br, 1 H), 4,51 -4,48 (m, 1 H), 4,35-4,26 (m, 2H), 4,12-4,09 (s, 2H), 3,87-3,85 (m, 1H), 3,55-3,49 (m, 2H), 3,43-3,34 (m, 5H), 2,27-2,19 (m, 2H), 1 .86-1 .81 (m, 2H). Chirale RT= 5,623 min (chirale methode A); ee= 100%.

14-Chloor-10-methoxy-4-methyl-5-(oxan-4-yl)-8-oxa-2,5,6, 12, 16-pentaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6, 13(17), 14-pentaeen (E342)

The compound was prepared using procedures similar to those used to prepare E5, starting from 2,5-dichloro-4-iodopyridine and 3-amino-2-methoxypropan-1-ol.

LC-MS: 394.2 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,59 (s, 1 H), 5,53 (s, 1 H), 4,44-4,41 (m, 1 H), 4,29-4,28 (m, 1 H), 4,16-4,1 1 (m, 1 H) , 4,07-4,02 (m, 2H), 3,62-3,53 (m, 4H), 3,41 (s, 3H), 3,13-3,10 (m,1 H), 2,26 (s, 3H), 2,23-2,10 (m, 2H ), 1.83-1.75 (m, 2H).

4,14-dichloor-11-methyl-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17- ί—° hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14- pentaeen (E343)

E343^CLThe compound was prepared using procedures similar to those used to prepare E13.

LC-MS: 399.1 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,85 (s, 1 H), 6,29 (br, 1 H), 5,16 (br, 1 H), 4,64-4,50 (m, 1 H), 4,36-4,29 (m, 2H), 4,12-4,02 (m, 3H), 3,55-3,49 (m, 2H), 2,28-2,19 (m, 2H),

1 0,92-1 0,81 (m, 4H), 1,34 (d, J= 7,2 Hz, 3H).

Enantiomeren 1 -2: 14-Chloor-4,11 -dimethyl-5-(oxan-4-yl)-8-oxa- 2,5,6,12, 16-pentaazatricyclo[11.3.1.0^{3 7}]heptadeca-1(16),3,6,13 (17),14-pentaeen (E344-E345)

Compounds were prepared using procedures similar to those used

E344-E345 for preparing E5, starting from 2,5-dichloro-4-iodopyridine.

E344: LC-MS: 378,2 [M+H]⁺.¹H NMR (400 MHz, CD3OD): 8 7,59 (s, 1 H), 5,67 (s, 1 H), 4,56-4,51 (m, 1 H), 4,31 -4,25 (m, 1 H), 4,08-4,01 ( m, 3H), 3,61 -3,53 (m, 3H), 2,26 (s, 3H), 2,24-2,10 (m, 2H), 1 .95-1 .93 (m, 1 H), 1 .83-1 . 74 (m, 2H), 1,68-1,64 (m, 1H), 1,39 (d, J= 7,2Hz, 3H). Chirale RT= 4,047 min (chirale methode A); ee= 100%. Enantiomeren 1-8: 14-chloor-5-(3-fluoroxan-4-yl)-11-(methoxymethyl)-4-methyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo [ 11.3. 1.0³'⁷]heptadeca-1 (16),3,6, 13(17),14-pentaeen (E351 -E358)

Compounds were prepared using procedures similar to those used to prepare E35, starting from D50 and D67.

E351 : LC-MS: 427.3 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): d 7,82 (s,

1H), 6,18 (s, 1H), 5,69 (d, J= 7,2 Hz, 1H), 5,02-4,83 (m, 1H), 4,51- 4,33 (m, 3H), 4,10-4,07 (m, 3H), 3,52 -3,46 (m, 3H), 3,41 (s, 3H), 3,40-3,37 (m, 1H), 2,48-2,36 (m, 1H), 2,21 (s, 3H), 2,07-2,02 (m, 1H), 1,95 -1,81 (m, 1H), 1,74-1,61 (m, 1H).¹⁹F NMR (376 MHz, CDCI3): 8 -192,85 (s, 1F). Chirale RT= 2,439 min (chirale methode A); ee= 100%.

E352: LC-MS: 427,3 [M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,83 (s, 1H), 6,16 (s, 1H), 5,70 (d, J= 7,2 Hz, 1H), 4,67-4,43 (m, 5H), 4,34- 4,22 (m , 2H), 4,10-4,01 (m, 2H), 3,51-3,47 (m, 2H), 3,41 (s, 3H), 2,36-2,31 (m, 2H), 2,21 (s, 3H), 2,06-2,01 (m , 1H), 1.79-1.71 (m, 1H).¹⁹F NMR (376 MHz, CDCb): 8 -231,78 (s, 1F). Chirale RT= 2,831 min (chirale methode A); ee= 100%.

E353: LC-MS: 427.2 [M+H]⁺.¹H NMR (400 MHz, CDCb): 8 7,83 (s, 1 H), 6,10 (s, 1 H), 5,69 (d, J= 7,2 Hz, 1 H), 4,68-4,21 (m, 7H), 4,11-

4,02 (m, 2H), 3,52-3,48 (m, 2H), 3,41 (s, 3H), 2,59-2,49 (m, 1H),

2,38- 2,28 (m, 1H), 2,21 (s, 3H), 2,07-2,01 (m, 1H), 1,73-1,59 (m, 1H).¹⁹F NMR (376 MHz, CDCb): <5 -232,72 (s, 1F). Chirale RT= 4,006 min (chirale methode A); ee= 100%.

E354: LC-MS: 427,2 [M+H]⁺.¹H NMR (400 MHz, CDCb): δ 7,83 (s, 1H), 6,13 (s, 1H), 5,68 (d, J= 7,2 Hz, 1H), 4,91-4,72 (m, 1H), 4,49- 4,21 (m , 3H), 4,08-4,04 (m, 3H), 3,53-3,46 (m, 3H), 3,41 (s, 3H), 3,36-3,31 (m, 1H), 2,56-2,46 (m, 1H), 2,21 (s , 3H), 2,07-1,95 (m, 2H), 1,80-1,59 (m, 1H).¹⁹F NMR (376 MHz, CDCb): 8 -193,39 (s, 1F). Chirale RT= 4,418 min (chirale methode A); ee= 100%.

E355: LC-MS: 427,3 [M+H]⁺.¹H NMR (400 MHz, CDCb): δ 7,82 (s, 1H), 6,37 (s, 1H), 5,68 (d, J= 7,6 Hz, 1H), 4,90-4,72 (m, 1H), 4,49- 4,21 (m , 3H), 4,08-4,05 (m, 3H), 3,53-3,45 (m, 3H), 3,41 (s, 3H), 3,36-3,32 (m, 1H), 2,56-2,45 (m, 1H), 2,21 (s , 3H), 2,07-2,01 (m, 2H), 1,70-1,59 (m, 1H).¹⁹F NMR (376 MHz, CDCb): <5 -193,36 (s, 1F). Chirale RT= 4,447 min (chirale methode A); ee= 100%.

E356: LC-MS: 427.2 [M+H]⁺.¹H NMR (400 MHz, CDCb): 8 7,83 (s, 1H), 6,14 (s, 1H), 5,69 (d, J= 7,2 Hz, 1H), 4,69-4,21 (m, 7H), 4,12-

4,03 (m, 2H), 3,54-3,46 (m, 2H), 3,41 (s, 3H), 2,59-2,51 (m, 1H),

2,39- 2,29 (m, 1H), 2,21 (s, 3H), 2,07-2,01 (m, 1H), 1,73-1,61 (m, 1H).¹⁹F NMR (376 MHz, CDCb): 8 -232,72 (s, 1F). Chirale RT= 6,029 min (chirale methode A); ee= 98,5%.

E357: LC-MS: 427.2 [M+H]⁺.¹H NMR (400 MHz, CDCb): δ 7,82 (s, 1H), 6,33 (s, 1H), 5,69 (d, J= 7,2 Hz, 1H), 5,02-4,83 (m, 1H), 4,50- 4,46 (m , 1H), 4,36-4,24 (m, 2H), 4,14-4,03 (m, 3H), 3,55-3,45 (m, 3H), 3,41 (s, 3H), 3,40-3,35 (m, 1H), 2,46-2,36 (m, 1H), 2,21 (s, 3H), 2,07-2,01 (m, 1H), 1,95-1,89 (m, 1H), 1,81-1,74 (m, 1H).¹⁹F NMR (376 MHz, CDCb): 8 -192,84 (s, 1F). Chirale RT= 7,493 min (chirale methode A); ee= 97,7%. E372: LC-MS: 383,2 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,81 (s, 1H), 6,23 (s, 1H), 5,55 (t, J= 6,0 Hz, 1H), 4,89 (d, J= 46,4 Hz, 1H), 4,50-4,42 (m, 1H), 4,36 (dd, J= 5,6, 3,6 Hz, 2H), 4,12 (t, J= 13,2 Hz, 1H), 4,00-3,97 (m, 1H), 3,70 (t, J= 10,8 Hz, 1H), 3,64-3,49 (m, 3H), 2,59-2,35 (m, 2H), 2,22 (s, 3H), 1,94-1,89 (m, 2H).¹⁹F NMR (376 MHz, CDC13): 8 -185,99. Chirale RT= 7,239 min (chirale methode A); ee= 100%.

(11R)-14-Chloor-5-(4,4-difluorcyclohexyl)-4,11-dimethyl-8-oxa- 2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0³⁷]heptadeca-1(16),3,6,13 (17),14-pentaeen (E373)

The compound was prepared using procedures similar to those used to prepare E5 from D174.

LC-MS: 413.2[M+H]⁺.¹H NMR (400 MHz, CDC): 8 7,81 (s, 1H), 6,15 (s, 1H), 5,12-5,11 (m, 1H), 4,48-4,44 (m, 1H), 4,35-4,29 (m, 1H) , 4,02-3,99 (m, 2H), 2,31-2,21 (m, 4H), 2,19 (s, 3H), 1,97-1,81 (m, 6H), 1,32~1,30(d, J= 6,8 Hz, 3H).

(11 ?)-14-Chloor-5-[4-(difluormethoxy)cyclohexyl]-4,11-dimethyl-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0³⁷]hepta deca-1(16),3,6,13(17),14-pentaene (E374)

The compound was prepared using procedures similar to those used before

E374 prepares E5, starting at D176.

F^F

LC-MS: 443.3 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,80 (s, 1H), 6,54 (br, 1H), 6,45-6,03 (m, 1H), 5,18 (d, J= 7,2 Hz, 1H), 4,47 (dd, J = 3,2, 11,6 Hz, 1 uur), 4,36-4,25 (m, 1 uur), 4,23-4,11 (m, 1 uur), 4,07- 3,97 (m, 1 uur), 3,92-3,76 (m, 1 uur), 2,27- 2,04 (m, 6H), 2,02-1,76 (m, 5H), 1,68-1,48 (m, 2H), 1,32 (d, J= 7,2 Hz, 3H).

3-[(11?)-14-Chloor-4,11-dimethyl-8-oxa-2,5,6,12,16,17- hexaazatricyclo[11.3.1.0³⁷]heptadeca-1(16),3,6,13(17),14-pentaen-5-yl]cyclobutan-1-ol (E375) .

The compound was prepared using procedures similar to those used to prepare E5 from D177.

LC-MS: 365.3 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 6,85 (br, 1H), 5,30 (d, J= 6,8 Hz, 1H), 4,52-4,49 (m, 1H), 4,38 (t, J= 9,6 Hz, 1H),

4,26 (t, J= 10,8 Hz, 1H), 4,17 (t, J= 6,4 Hz, 1H), 4,05-4,03 (m, 1H), 2,92-2,85 (m, 2H), 2,57-2,46 (m, 2H) , 2,17 (s, 3H), 2,11-1,86 (m, 2H), 1,31 (d, J=6,8 Hz, 3H).

3-[(11?)-14-Chloor-4,11,12-trimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0³⁷]heptadeca-1(16),3,6,13(17),14-pentaen-5-yl]cyclobutan-1-ol (E376) .

The compound was prepared using procedures similar to those used to prepare E5 from D178.

LC-MS: 379,3 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1H),

6,69 (s, 1H), 4,75-4,72 (m, 1H), 4,51-4,48 (m, 1H), 4,42 (t, J= 10,8 Hz, 1H), 4,25 (t, J= 7,2 Hz, 1H), 4,17 (t, J= 6,4 Hz, 1H), 3,18 (s, 3H), 2,91-2,84 (m, 2H), 2,58-2,43 (m, 2H), 2,15 (s, 3H), 1,93-1,87 (m, 1 H), 1,73-1,68 (m, 1 H), 1,27 (d, J= 6,8 Hz, 3H). 14-Chloor-10,10-difluor-4-methyl-5-(oxan-4-yl)-8-oxa- 2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1(16),3,6,13(17),14-pentaene (E377)

The compound was prepared using procedures similar to those used to prepare E12 starting from tert -butyl (2,2-difluoro-3-hydroxypropyl)carbamate.

LC-MS: 401.2 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,90 (d, J= 2,4 Hz, 1 H), 6,85 (br, 1 H), 5,68 (br, 1 H), 4,52 (t, J= 10,8 Hz, 2H), 4,13-4,05 (m, 3H), 4,00-3,92 (m, 2H), 3,51 (t, J= 1 1,2 Hz, 2H), 2,31 -2,19 (m, 5H), 1,80-1,77 (m, 2H).

(11 ?)-14-Chloor-5-[3-(difluormethoxy)cyclobutyl]-4,11 -

^C'Y dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]

heptadeca-1(16),3,6,13(17),14-pentaene (E378)

The compound was prepared using procedures similar to those used to prepare E374 from D177.

LC-MS: 415.3 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,79-7,77 (m, 1 H), 6,70 (br, 1 H), 6,21 (t, J= 74 Hz, 1 H), 5,25 (d, J= 6,8 Hz, 1 uur), 4,51 -4,46 (m, 2 uur), 4,40 (d, J= 10,8 Hz, 1 uur), 4,22-4,16 (m, 1 uur), 4,06-4,03 (m, 1 uur), 2,95-2,88 ( m, 2H), 2,88-2,74 (m, 2H), 2,17 (s, 3H), 1,94-1,82 (m, 2H), 1,31 (d, J= 6,8 Hz, 3H).

14-Chloor-4-methyl-5-(oxan-3-yl)-8-oxa-2,5,6,12,16- pentaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaene (E379)

The compound was prepared using procedures similar to those used to prepare E1 starting from 2,5-dichloro-4-iodopyridine and 3-aminopropan-1-ol.

LC-MS: 364.1 [M+H]⁺.¹H NMR (400 MHz, MeOD): δ 7,59 (s, 1 H), 5,62 (s, 1 H), 4,25 (t, J= 4 Hz, 2 H), 4,21 -4,12 (m, 1 H), 3,95-3,88 (m, 2H), 3,65 (t, J= 6 Hz, 1 H), 3,48-3,40 (m, 3H), 2,26 (s, 3H),

2.18-2.1 1 (m, 1 h), 2.07-2.01 (m, 1 h), 1.88-1.78 (m, 4 h).

Isomeren 1 -2: 14-chloor-4-methyl-5-[4-(morfoline-4-yl)cyclohexyl]-8-oxa-2,5,6,12,16,17-hexaazatricyclo

[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaene (E380-E381)

The compound was prepared using procedures similar to those used to prepare E148 from D85.

E380: LC-MS: 448,3 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,81 (s, 1 H), 6,13 (s, 1 H), 5,54 (t, J= 6,0 Hz, 1 H), 4,41 -4,36 (m, 2H), 3,87- 3,79 (m, 1 H), 3,76-3,71 (m, 4H), 3,55-3,49 (m, 2H),

2,62-2,56 (m, 4H), 2,41 -2,32 (m, 1 H), 2,19 (s, 3H), 2,1 1 -2,01 (m, 1 H), 2,00-1,88 (m, 6H), 1 .45- 1 .34 (m, 3H). Chirale RT = 5,805 min (chirale methode F).

E381 : LC-MS: 448.3 [M+H]⁺.¹H NMR (400 MHz, CDCI3): 8 7,82 (s, 1 H), 6,07 (s, 1 H), 5,58-5,51 (m, 1 H), 4,43-4,38 (m, 2H), 4,04-3,95 (m , 1H), 3,79 (t, J= 4,4 Hz, 4H), 3,55-3,50 (m, 2H), 2,52 (br, 4H), 2,27-2,22 (m, 3H), 2,21 (s, 3H), 2,17 -2,09 (m, 2H), 1,96-1,90 (m, 3H), 1,57-1,42 (m, 3H). Chirale RT = 5,881 min (chirale methode F).

preparation of E13, starting from 5-chloro-4-nitro-1H-pyrazole. 4-Methyl-5-(oxan-4-yl)-14-(prop-1-en-2-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14- pentaeen (E429)

The compound was prepared using procedures similar to those used to prepare E428.

LC-MS: 371.2 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,55 (s, 1 H), 5,30 (s, 1 H), 5,10 (s, 1 H), 4,34 (t, J= 4,6 Hz, 2H), 4,30-4,22 (m,1 H), 4,07-4,00 (m, 2H), 3,57 (t, J= 1 1,8 Hz, 2H), 3,43 (t, J= 5,2 Hz, 2H), 2,26 (s, 3H), 2,18-2,10 (m, 2H ), 2.01 (s, 3H), 1.85-1.77 (m, 4H).

(11 R)-14-chloor-4-ethyl-11-methyl-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen (E430)

The compound was prepared using procedures similar to those used before

preparation of E294, starting from 4-nitro-1-(tetrahydro-2H-pyran-2-yl)-E430

1 H-pyrazool.

LC-MS: 393.2 [M+H]⁺.¹H NMR (400 MHz, MeOD): 8 7,73 (s, 1 H), 4,41 -4,26 (m, 2H), 4,00-3,96 (m, 1 H), 2,68-2,54 (m, 2H),

1,81 -1,78 (m, 2H), 1,29 (d, J= 8,0 Hz, 3H), 1,22 (t, J= 16,0 Hz, 3H).

14-chloor-4,10-dimethyl-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaene (E431)

The compound was prepared using procedures similar to those used to prepare E394 starting from 3-amino-2-methylpropanoic acid.

E431

LC-MS: 295.1 [M+H]⁺.¹HNMR (400 MHz, CD₃OD): δ 7,71 (s, 1 H), 4,57 (s, 1 H), 4,19-4,09 (m, 2H), 3,68-3,63 (m, 1 H), 3,06 (d, J= 12,0 Hz, 1 H ), 2,19 (s, 3H), 1,81 (br, 1H), 0,99 (d, J= 7,4 Hz, 3H).

14-broom-4-methyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14- pentaeen (E432)

The compound was prepared using procedures similar to those used to prepare E394 starting from 5-bromo-2,4-dichloropyrimidine.

E432

LC-MS: 326.1 [M+H]⁺.¹HNMR (400 MHz, DMSO-d₆): δ 1 1,39 (s, 1 H), 8,25 (s, 1 H), 7,83 (s, 1 H), 7,13 (t, J= 6,0 Hz, 1 H), 4,18 (t, J= 4,4 Hz, 2H), 3,29-3,26 (m, 2H), 2,09 (s, 3H), 1,70 (s, 2H).

4-Methyl-14-(trifluormethyl)-8-oxa-2,5,6,12,16,17-

HN I NH hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14- pentaeen (E433)

The compound was prepared using procedures similar to those used before

F preparation E394.

E433

LC-MS: 329.0 [M+H]⁺.¹HNMR (400 MHz, CD₃OD): δ 8,03 (s, 1 H), 4,36-4,34 (m, 2H), 3,82-3,78 (m, 1 H), 2,20 (s, 3H), 1,80-1,77 (m, 2H), 1 .23 (d, J= 6,8 Hz, 3H). 14-cyclopropyl-4-methyl-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen (E434)

The E434 compound was prepared using procedures similar to those used to prepare E1 starting from 2,4-dichloro-5-iodopyrimidine.

LC-MS: 371.3 [M+H]⁺.¹H NMR (400 MHz, MeOD): δ 7,46 (s, 1 H), 4,34 (t, J= 12,0 Hz, 2H)., 4,28-4,22 (m, 1 H), 4,05 (dd, J= 16,0 Hz, 2H), 3,56 (t, J= 24,0 Hz, 2H), 3,45 (t, J=12,0 Hz, 2H), 2,23 (s, 1 H), 2,17 (dd, J= 16,0 Hz, 2H), 1,93 -1 0,76 (m, 4H), 1 0,47-1,44 (m, 1 H),0,84 (dd, J= 8,0 Hz, 2H), 0,45 (dd, J= 8,0 Hz, 2H)

(11R)-14-chloor-4-(methoxymethyl)-11-methyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca- 1 (17),3(7),4, 13,15-pentaeen (E435)

The compound was prepared using procedures similar to those used to prepare E424.

LC-MS: 325.3 [M+H]⁺.¹H NMR (400 MHz, MeOD): 8 7,74 (s, 1 H),

4.42-4.40 (m, 3H), 4.31 -4.26 (m, 1 H), 3.98 (s, 1 H), 3.35-3.30 (m, 3H), 1.85-1.82 (m, 2H), 1 .31 -1 .26 (d, J= 20.0 Hz, 3H).

14-chloor-4-methyl-5-(4-methyloxan-4-yl)-8-oxa-2,5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14- pentaeen (E436)

The E436 compound was prepared using procedures similar to those used for the preparation of E420 starting from 2-(2-methyl-1,3-dioxolan-2-yl)acetohydrazide and dihydro-2H-pyran-4 (3H)-one.

LC-MS: 379,2 [M+H]⁺.¹H NMR (400 MHz, MeOD): δ 7,71 (s, 1 H), 4,32 (t, J= 8,0 Hz, 2H), 3,78-3,68 (m, 4H), 3,41 (t, J= 8,0 Hz, 2H) , 2,57-2,53 (m, 2H) 2,31 (s, 3H), 1 0,95-1 0,81 (m, 4H), 1 0,44 (s, 3H).

(11 R)-14-chloor-4,11-dimethyl-5-(4-methyloxan-4-yl)-8-oxa- 2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca- 1 (16),3,6, 13(17),14-pentaeen (E437)

The compound was prepared using procedures similar to those used to prepare E436.

LC-MS: 393.2 [M+H]⁺.¹H NMR (400 MHz, MeOD): 8 7,73 (s, 1 H), 4,35-4,32 (m, 2 H), 3,97-3,93 (m, 1 H), 3,76-3,69 (m, 4 H), 2,55 (dd, J= 16,0 Hz, 2H), 2,23 (s, 3H), 1,95-1,89 (m, 2H), 1,80-1,76 (m, 2H), 1,44 (s, 3H), 1,30 (t, J= 8,0 Hz, 3H).

4-Chloor-5-(3,3-difluorooxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaeen-14-carbonitril (E438)

The compound was prepared using procedures similar to those used to prepare E414, starting from D195 and 4-nitro-1H-pyrazole.

LC-MS: 412.3 [M+H]⁺.¹H NMR (400 MHz, CDC): 8 8,17 (s, 1 H), 7,79 (s, 1 H), 5,97 (s, 1 H), 4,71 -4,52 (m, 1 H), 4,47-4,31 (m, 2H), 4,31 -4,25 (m,1 H), 4,10 (dd, J= 21,2, 9,1 Hz, 1 H), 3,95 (t, J= 5,4 Hz, 2,93-2,86 (m, 3H), 2,25-2,17 ( m, 2H), 1,81 -1,79 (m, 2H), 1,29(d, J= 8,0 Hz, 3H).

Enantiomeren1 -2: (11R)-4,14-dichloor-5-[3,3-difluor-1-(oxetaan-3-yl)piperidine-4-yl]-11-methyl-8-oxa-2, 5,6,12, 16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14- pentaeen (E444-E445)

The compound was prepared using procedures similar to those used to prepare E411.

E444: LC-MS: 490,2 [M+H]⁺.¹H NMR (400 MHz, MeOD): 8 7,76 (s, 1 H), 4,78-4,58 (m, 5H), 4,39-4,37 (m, 2H), 3,95-3,91 (m, 1 H), 3,73 (t, J= 16,0 Hz, 1 uur), 3,09-3,00 (m, 2 uur), 2,67-2,64 (m, 1 uur),

2,53-2,46 (m, 1 H), 2,32 (t, J= 16,0 Hz, 1 H), 2,09-2,06 (m, 1 H), 1,83-1,78 (m, 2 H), 1,30 (d, J= 8,0 Hz, 3H).

E445: LC-MS: 490,2 [M+H]+.¹H NMR (400 MHz, MeOD): 8 7,76 (s, 1 H), 4,72-4,58 (m, 5H), 4,42-4,37 (m, 2H), 4,00-3,96 (m, 1 H), 3,73 (t, J= 16,0 Hz, 1 H), 3,13-3,01 (m, 2H), 2,64-2,45 (m, 2H), 2,32 (t, J= 16,0 Hz, 1 H), 2,02-1,99 (m, 1 H), 1 0,83-1 0,80 (m, 2H), 1 0,30 (d, J= 8,0 Hz, 3H).

4,14-dichloor-5-[3,3-difluor-1-(oxetan-3-yl)piperidine-4-yl]-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3 .1.0^{3 7}]heptadeca- 1 (16),3,6, 13(17),14-pentaeen (E446)

E446 compound was prepared using procedures similar to those used to prepare E411.

LC-MS: 476.3 [M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆): δ 8,61 (s, 1 H), 7,82 (s, 1 H), 7,46 (t, J= 5,6 Hz, 1 H), 4,61 -4,44 (m, 5H), 4,26-4,19 (m, 2H), 3,65 (t, J= 6,2 Hz, 1 H), 3,05-2,98 (m, 1 H), 2,84-2,75 (m, 2 H), 2,21 -2,09 (m, 3 H), 1,84-1,75 (m, 1 H) ,

1.72-1.61 (m, 1 h), 1.35-1.20 (m, 2 h).

(11R)-14-Chloor-4,11-dimethyl-5-[3-(trifluormethyl)oxan-4-yl]-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3. 1.0^{3 7}]heptadeca-1(16),3,6,13(17),14-pentaene (E448)

The compound was prepared using procedures similar to those used to prepare E1 from D2 O3 .

E447 LC-MS: 447.1 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7,82 (d, J= 4,0

Hz, 1 hr), 6.06 (d, J= 20.0 Hz, 1 hr)., 5.1 1 (d, J= 8.0 Hz, 1 hr),

4,67-4,57 (m, 3H), 4,46 (d, J= 8,0 Hz, 1 H), 4,37-4,31 (m, 1 H), 3,96 (d, J= 16,0 Hz, 2H), 3,84 (m, 1 H ), 2,73 (br, 1H), 2,18 (t, J= 4,0 Hz, 5H), 1,87-1,80 (m, 1H), 1,32-1,26 (m, 4H). lsomeren1 -2: (11 R)-14-Chloor-4,11-dimethyl-5-[3- (trifluormethyl)oxan-4-yl]-8-oxa-2,5,6,12,16,17- hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1 (16),3,6,13(17),14-pentaene (E448-E449)

E448-E449

The title compounds E448 and E449 were obtained from chiral resolution of E447 (chiral method E). E448: LC-MS: 447.1 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7.72(s, 1H), 4.51 (t, J = 16.0 Hz, 2H), 4.37 (d, J = 12.0 Hz, 2H), 3.89 ( br, 1H), 3.82-3.74 (m, 1h), 2.89 (br, 1h), 2.16 (s, 3h), 2.04-2.01 (m, 2 h), 1.79 (br, 2 h), 1.63-1.52 (m, 1 h), 1 0.29 (s, 3 h), 0.90-0.88 (m, 1 o'clock). Chiral RT = 0.845 min (chiral method E); ee > 99%.

E449: LC-MS: 447.2 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ 7,71 (s, 1 H), 4,82 (s, 1 H), 4,73-4,49 (m, 1 H), 4,49-4,36 (m, 3H),

3,94-3,93 (m, 1 H), 3,81 (dd, J= 1 1,6 Hz, 3,6 Hz, 1 H), 3,72-3,69 (m, 1 H), 2,84-2,83 (m, 1 H), 2,25 -2,23 (m, 1 H), 2,20 (s, 3H), 2,04-2,00 (m, 1 H), 1,77-1,76 (m, 2H), 1,26 (d, J= 7,2 Hz, 3H). Chirale RT = 1,078 min (chirale methode E); ee > 99%.

4-{14-chloor-4-methyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0^{3 7}]heptadeca-1(17),3,6,13,15-pentaen-5-yl}oxane-4-carbonitrile (E450)

The compound was prepared using procedures similar to those used for E450

preparation of E436, starting from TMSCN.

LC-MS: 390.1 [M+H]⁺.¹HNMR (400 MHz, CDCI₃): δ 7,81 (s, 1 H), 6,63 (s, 1 H), 5,66-5,67 (m, 1 H), 4,35-4,37 (m, 2 H), 4,07-4,10 (t, J= 12,0 Hz, 2 uur), 3,80-3,86 (br, 2 uur), 3,51 -3,55 ( m, 2 uur),

2,46-2,54 (m, 5 H), 2,36-2,39 (t, J= 12,0 Hz, 2 H),1,75~1,91 (t, J= 64,0 Hz, 2 H).

2-{14-Chloor-4-methyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11. 3.1.0³'⁷]heptadeca-1 (16),3,6,13(17),14-pentaen-5-yl}-2-methylpropan-1-ol (E451)

A solution of E188 (100mg, 0.25mmol) in THF (20ml) was added

NaBH₄(28 mg, 0.75 mmol) and LiCl (32 mg, 0.75 mmol) at room temperature. The mixture was stirred overnight at room temperature. The reaction was quenched with water and the mixture was extracted with EtOAc (50ml <3). The combined organic solution was washed with brine (50 mL x 2), dried, filtered and concentrated. The residue was purified by prep-HPLC to give the desired product (4 mg, yield 4%) as a light red solid.

LC-MS: 353.3 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): 5 7,82 (s, 1 uur), 6,05 (s, 1 uur), 5,55 (m, 1 uur), 4,54 (m, 1 uur), 4,33-4,35 (m, 2 uur), 3,84-3,86 (m, 2H), 3.49-3.54 (m, 2H), 2.33 (s, 3H), 1.90-1.93 (m, 2H), 1.50 (s, 6H).

2-[(11R)-14-Chloro-4,11-dimethyl-8-oxa-2,5,6,12,16,17-hexaaze tricyclo[11.3.1.03,7]heptadeca-1(16), 2-4. 3,6,13(17),14-pentaen-5-yl]- 2-methylpropan-1-ol (E452) .

The compound was prepared using procedures similar to those used to prepare E451 from D79.

LC-MS: 367.2 [M+H]⁺.¹H-NMR (400 MHz, CDCI₃): δ 7.81 (s, 1 hr), 6.32 (s, 1 hr), 5.15-5.13 (m, 1 hr), 4.59 (brs, 1 hr), 4.46 -4.24 (m, 2 h), 4.02-4.00 (m, 1 h), 3.90-3.81 (m, 2 h), 2.32 (s, 3 h), 1 .89-1.77 (m, 2 h), 1.52 (s, 3 h), 1.47 (s, 3 h), 1 .33-1.31 (m, 3H). The compounds with descriptions D84, D93, D97, D100, D112, D130, D133, D142, D160 and D162 are also examples of compounds falling within the scope of the invention.

The compound of Example 6 can also be prepared using the following procedure. This procedure was followed to produce a total of 485.8 g of compound in several batches. (single batch of compound produced from multiple batches of intermediates):

Bereiding van 5-chloor-3-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazool

3-Methyl-4-nitro-1H-pyrazole (500 g) and p-toluenesulfonic acid monohydrate (15.0 g) were dissolved in 2-methyltetrahydrofuran (2.5 L) at c. 27°C and stirred for 15 minutes. The solution was then cooled to about -11°C and treated with 3,4-dihydro-2H-pyran (430 mL). The reaction mixture was heated for c. 22 hours at c.-1 1°C before being cooled to c.-63°C and treated with a 1.5 M solution of LiHMDS in THF (2.9 L) over c.60 min. The reaction mixture was heated for 45 stirred at -63°C for min before adding a solution of perchloroethane (1024 g) in 2-methyl THF (2 L) over 80 min. The reaction was stirred for an additional 50 min at c. -63°C, warmed to 18°C and stirred for an additional 15 min before being quenched with a solution of ammonium chloride (930 g) in water (1.57 L). The pH was adjusted to 5-6 by addition of 2M HCl (2.5 L) followed by acetic acid (19 mL) before adding TBME (3 L) and the mixture was stirred at ca. 18°C for 16 minutes. The mixture was filtered through celite (100 g) and washed through with more TBME (1 L). The aqueous layer was separated and back extracted with TBME (1 L). The combined organic phases were then washed twice with 1 L of a 1:1 mixture of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The washed organic phase was concentrated to 2 liters. by vacuum distillation and the temperature was adjusted to c. 42°C before heptane (6.5 L) was added over 25 minutes. The suspension was stirred at about 41°C for 15 minutes, cooled to 2°C over 2 hours and then stirred at 2°C for 1 hour before the product was collected by filtration. The product cake was washed twice with 1 L of a 4:1 mixture of TBME and heptane and dried in vacuo at c. 30°C to deliver the desired product 5-chloro-3-methyl-

4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazool (549 g, 56,8%).

Bereiding van (R)-4-((3-methyl-4-nitro-1H-pyrazol-5-yl)oxy)butaan-2-amine hydrochloride

To a mixture of powdered cesium fluoride (1.85 kg) and tert-butyl (R)-(4-hydroxybutan-2-yl)carbamate (635 g) in Ν,Ν-dimethylacetamide (DMA) (3.75 L) 5-chloro-3-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (750 g) and the suspension was stirred for c. 22 hours. After cooling the reaction mixture to 20°C, water (3.75 L) and TBME (3.75 L) were added, the mixture was stirred for 10 min and the aqueous phase was separated. The organic phase was then washed twice with saturated aqueous ammonium chloride solution (2 x 3.75 L) followed by 15% w/w aqueous NaCl solution (3.75 L). The washed organic phase was concentrated to 2.25 L by vacuum distillation before IPA (3.75 L) was added and the mixture was further concentrated to 3.75 L by vacuum distillation. After clearing the concentrated solution by filtration, using IPA (0.75 L) as a line wash, a 5-6 M solution of HCl in IPA (3.1 L) was added and the reaction heated to 50°C and stirred during c. 1 hour. The resulting suspension was cooled to c. 22°C before adding TBME (6.0 L). The suspension was then aged at c. 22°C for 1 hour before collecting the product by filtration and washing the cake with 2:1 v/v TB ME/I PA (2.25 L) followed by TBME (1.5 L). The moist cake was dried under vacuum at 30°C to give the desired product (R)-4-((3-methyl-4-nitro-1H-pyrazol-5-yl)oxy)butan-2-amine hydrochloride (599 g , 78.3%)

Bereiding van (R)-2,5-dichloor-N-(4-((5-methyl-4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl) oxy)butaan-2-yl)pyrimidine-4-amine

A mixture of (R)-4-((3-methyl-4-nitro-1H-pyrazol-5-yl)oxy)butan-2-amine hydrochloride (700 g) and triethylamine (1.23 L) in 2- methyltetrahydrofuran (7.0 L) was warmed to c. 58°C for about 30 min and then treated with 2,4,5-trichloropyrimidine (320 ml) for 3 hours. The reaction was stirred at 58°C for c. 3 hours before the suspension was cooled to c. 20°C and washed with water (3.5 L), followed by 20% w/w aqueous ammonium chloride solution (3.5 L) and then 15% w/w aqueous NaCl solution (3.5 L). The washed organic layer was concentrated to 2.1 L by vacuum distillation before adding 2-methyl THF (3.5 L) and re-mixing.

concentrated to 2.1 L by vacuum distillation.

DMSO (3.0 L) was added and the solution was concentrated to 4.5 vol by vacuum distillation before adding more DMSO (2.6 L). Tetrahydro-2H-pyran-4-yl methanesulfonate (1.26 kg) and cesium carbonate (1.80 kg) were added and the reaction was heated to c. 80°C for approx. 17 hours. After completion of the reaction, the mixture was cooled to 20°C before water (5.0 L) and isopropyl acetate (5.0 L) were added. The aqueous layer was back extracted with 2:1 v/v isopropyl acetate/heptane (6.0 L). Water (3.0 L) was added to the combined organic layers with vigorous stirring over 10 minutes and the resulting biphasic solution was decanted from the precipitated red interfacial gum. The aqueous phase was discarded and the organic phase was further washed with 10% aqueous NaCl solution. The washed organic phase was evaporated to dryness in vacuo before redissolving in ethanol (3.0 L) at c. 62°C, water (1.0 L) was added and the mixture was cooled to 18°C over c. 4 hours. The resulting suspension was stirred at c. 18°C for an additional approx. 15 hours before the product was collected by filtration and washed twice with 3:1 v/v EtOH/water. The wet cake was dried under vacuum at 40°C to give the desired product (R)-2,5-dichloro-N-(4-((5-methyl-4-nitro-1-(tetrahydro-2H-pyran-4 -yl)-1H-pyrazol-3-yl)oxy)butan-2-yl)pyrimidin-4-amine (572 g, 45.2%)

Preparation of (1 1 R)-14-chloro-4,1 1 -dimethyl-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo [1 1 . 3.1.0³'⁷]heptadeca-1 (16),3,6,13(17),14-pentaeen

A mixture of (R)-2,5-dichloro-N-(4-((5-methyl-4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl )oxy)butan-2-yl)pyrimidin-4-amine (398.7 g), methanol (4 L), 1% Pd/2%V on carbon, 61% wet (160.0 g) and 50% aq phosphinic acid (23.6 g) was hydrogenated under c. 3 bar hydrogen pressure at c. 50°C for about 16 hours until the reaction was complete was observed by HPLC. The reaction mixture was filtered to remove the catalyst, the catalyst cake was washed with methanol (0.8 L) and the filtrate was solvent exchanged with 2-methyltetrahydrofuran. The 2-methyltetrahydrofuran solution (2.4 L) was heated to 57°C and washed with 6% w/w aqueous sodium bicarbonate solution (3.2 L) followed by water (2.8 L). The organic solution was azeotropically dried with 2-methyltetrahydrofuran by vacuum distillation to give a final volume of 2.0 L. 3 hours before heptane (2.0 L) was added over c. 3 hours. The product was then collected by vacuum filtration and washed with a 1:1.4 mixture of 2-methyltetrahydrofuran and heptane (0.8 L) before vacuum drying at 50°C to obtain intermediate grade (11R)-14-chloro - 4,1 1-dimethyl-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[1 1 .3.1.0³'⁷]heptadeca-1 (16),3,6,13(17),14-pentaene (245 g, 72.4%)

Preparation of (11R)-14-Chloro-4,11-dimethyl-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11. 3.1.0³'⁷]heptadeca-1 (16),3,6,13(17),14-pentaene, form 1

Medium Grade (1 1 R)-14-chloro-4,1 1-dimethyl-5-(oxan-4-yl)-8-oxa-2, 5,6, 12, 16,17-hexaazatricyclo [1 1 . 3.1.0³'⁷]heptadeca-1 (16),3,6,13(17),14-pentaene (522.7 g) was stirred in a mixture of 30:70 v/v 1-propanol/heptane (1.57 L) at 20°C. C for approximately 26 hours. The product was collected by vacuum filtration and washed with 30:70 v/v 1-propanol/heptane (1 L) before being dried under vacuum at 50°C to give (1 L)-14-chloro-4,1 1- deliver. dimethyl-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[1 1 .3.1.0³'⁷]heptadeca-1 (16),3,6,13(17),14-pentaene, form 1 (485.8 g, 93%). The compound of Example 6 was subjected to mold testing. In addition to Form 1 (an unsolvated crystalline form), which can be produced as outlined above, a 1,4-dioxane solvate was isolated as a mixture of Form 1 after slow evaporation of a solution of Example 6 in 1,4-dioxane at room temperature for seven days, followed by rapid evaporation of the remaining solutions under reduced pressure for 24 hours.

Form 1 shows a strong endotherm at 223°C and negligible weight loss up to 225°C. XRPD data for Form 1 was obtained using a PANalytical X'Pert Pro powder diffractometer, model PW3040/60 using an X'Celerator detector. The acquisition conditions were: radiation: Cu Ka, generator voltage: 40 kV, generator current: 45 mA, start angle: 2.0° 2Θ, end angle: 40.0° 2Θ, step size: 0.0167° 2Θ, time per step: 31.75 seconds. The sample was prepared by placing a few milligrams of sample on a silicon wafer (zero background plate), resulting in a thin layer of powder. Peak positions were measured using Highscore software.

Form I characteristic XRPD angles produced by the route given above are recorded in Table 2. The margin of error is approximately ± 0.2° 2Θ for each of the peak assignments. Peak intensities may vary from sample to sample due to preferred orientation.

table 2

F. Biological Analysis and Data

As mentioned above, the compounds of the present invention are LRRK2 kinase inhibitors and may be useful in the treatment of diseases mediated by LRRK2. The biological activities and/or properties of the compounds of the present invention may be determined using any suitable assay, including assays to determine the activity of a candidate compound as an LRRK2 kinase inhibitor, as well as tissue and in vivo models. 1. Analytics

A. Full length G2019 human LRRK2 inhibition mass spectrometry assay

This Leucine Rich Repeat Kinase 2 (LRRK2) inhibition assay is based on the direct measurement of the peptide 'LRRKtide' (LRRKtide: RLGRDKYKTLRQIRQ and "^*refers to the site of phosphorylation.) and phosphorylated 'LRRKtide' using a RapidFire high throughput mass spectrometry assay.

Primers used for PCR cloning:

pHTBV-F:SEQ ID Nr: 1

LRRK2 wt-F1 :SEQ ID Nr: 2

LRRK2 wt-R1: SEQ ID Nr: 3

LRRK2 wt-F2: SEQ ID Nr: 4

LRRK2 wt-R2: SEQ ID Nr.: 5

LRRK2 wt-F3:SEQ ID Nr: 6

pHTBV-R: SEQ ID-nr.: 7

pHTBV1-N-Flag-hu LRRK2 was generated by PCR amplification of the full length LRRK2 sequence with N-terminal Flag tag of pcDNA3.1(+)_Human_LRRK2 (NCBI reference sequence: NP_940980.3) with the above described primers, and cloned into pHTBV1 mcs3 vector between Bam HI and Kpn I sites.

The full-length G2019 Flag-LRRK2 coding sequence is SEQ ID NO: 8.

The translated amino acid sequence for human G2019 full length N-terminal flag tagged LRRK2 protein is SEQ ID NO: 9.

Insect cell cultures

Sf9 insect cells (Invitrogen Life Technologies, Carlsbad, CA) were maintained at 27°C in SF 900 II SFM in 500 ml shake flasks (Erienmeyer, Corning). The cells were maintained in an exponential growth phase and subcultured twice a week. For larger volumes, cells were cultured in 2 liter shake flasks (Erienmeyer, Corning) at 120 rpm at 27°C in a shaking incubator, with agitation at 120 rpm. Generation of the BacMam virus

To generate the recombinant BacMam virus, DHI OBac competent cells (10361-012, Invitrogen) were transformed with the genotypically normal human LRRK2 BacMam plasmid to generate the recombinant baculovirus DNA. The Sf9 insect cells were co-transfected with a mixture of recombinant baculovirus DNA and cellfectin (10362-100, Invitrogen). After 4 h of incubation at 27 °C, the transfection medium was replaced with Sf-900 III SFM medium containing 5% HI FBS (10100147, Invitrogen). The cells were further incubated for 4 days. The infected cell culture medium containing the baculovirus (PO virus stock) was collected and amplified by further infecting the 200 ml Sf9 cells with 200-300 µl of the PO virus stock.

Quantification of BacMam Viral Titer by BacPAKRapid Titer

The viral titer, measured as plaque forming unit (pfu)/ml, was determined using BacPAK Rapid Titer Kit (631406, Clontech) according to the manufacturer's protocol. The Sf9 cells seeded in a 96-well plate with 3^H10⁵cells per well were incubated with serial dilution of the viral stocks for 1 h at 27 °C, 50 µl methylcellulose overlay was added to each well, followed by 43–47 h incubation. The cells were then fixed in 4% paraformaldehyde (PFA). After blocking the cells with diluted normal goat serum, mouse anti-gp64 antibody was added to the cells. After 30 minutes of incubation, cells were washed with phosphate buffered saline containing 0.2% Triton-X100 (PBST) and incubated for an additional 30 minutes with goat anti-mouse antibody/HRP conjugate. This was followed by blue peroxidase substrate which detects the single infected cells and foci of infected cells by their dark blue color.

Protein expression and purification

a) Expression of flag Tagged full length G2019 Human LRRK2 HEK293 6E cells were incubated in a 37°C incubator with a humidified atmosphere of 5% CO2 on an orbital shaker rotating at 110 rpm in Freestyle 293 medium (Invitrogen 12338 ) supplemented with o 0.1% Pluronic F68 (Invitrogen 24040-032), 25ug/ml Geneticin (Invitrogen 10131035) and 1 X Glutamax (Gibco 35050). On the day of transduction, cell viability was greater than 98% and cell density was in the range of 1 x10⁶~1.5x10⁶cells/ml.

HEK293 6E cells were centrifuged at 1,000 rpm for 10 minutes and then the cells were resuspended in fresh Freestyle 293 expression medium containing 0.1% Pluronic F-68

(Invitrogen:24040- but without the other additives, at a density of 1 x10⁶cells/ml.

BacMam virus carrying Flag-hu LRRK2 (genotypically normal) was centrifuged at 40,000g for 2 hours and then resuspended in fresh Freestyle 293 expression medium. The resuspended virus was added to the cells at an MOI of 10. The cells were incubated in a 37°C incubator with a humidified atmosphere of 5% CO 2 in air on an orbital shaker rotating at 110 rpm. Cultures were harvested approximately 48 hours after transduction by centrifugation at 4,000 rpm for 20 minutes and pellets were frozen for purification. b) Purification of Flag Tagged Full Length G2019 Human LRRK2 The cell pellet was resuspended in (20 ml/liter cell culture) lysis buffer (50 mM TrisHCl pH 7.5 at 4°C, 500 mM NaCl, 0.5 mM EDTA, 0, 1% TritonX-100, 10% glycerol, add fresh 2 mM DTT), with protease inhibitors (Roche: 04693132001) and benzonase (Merck Millipore:

70746-3CN) in the recommended concentration suggested by suppliers. The suspended cells were lysed by sonication on ice for 30 minutes (2 seconds on/4 seconds off, 20% amplitude), and centrifuged at 10,000 rpm for 30 minutes at 4^°C. The supernatant was incubated with 1 ml per liter of cell culture of anti-Flag magnetic beads (Sigma-Aldrich: M8823) at 4°C for 3 hours, before washing the beads 3 times with 5 ml (5 column volumes) of binding buffer (50 mM Tris pH 7.5 at 4°C, 500 mM NaCl, 0.5 mM EDTA, 0.1% TritonX-100, 10% glycerol, fresh add 2 mM DTT). The Flag-tagged LRRK2 proteins were eluted with elution buffer (50 mM Tris pH 7.5 at 4°C, 500 mM NaCl, 0.5 mM EDTA, 0.1% TritonX-100, 10% glycerol, freshly added 2 mM DTT, 250 µg/ml Flag peptide (Sigma -Aldrich:F3290)) at 4°C for 2 hours. Flag peptide was removed using Zeba Spin Desalting Columns, 7K MWCO (Thermo-Fisher: 89893) and the buffer containing the eluted LRRK2 proteins was exchanged into storage buffer (50 mM Tris pH 7.5 at 4°C, 150 mM NaCl, 0.5 mM EDTA, 0.02% Triton X-100, 2 mM DTT and 50% glycerol) using Amicon Ultra Centrifugal Filter Units (100kD) (Merck:

UFC910096). Fractions containing LRRK2 proteins were pooled, aliquoted and stored at -80°C. Protein concentration was determined by Bradford protein assay and protein purity was analyzed by SDS-PAGE using NuPAGE Novex 4-12% Bis-Tris Protein Gels (Invitrogen: NP0322BOX).

Assay-protocol

1) Compounds were dissolved in 100% DMSO at a concentration of 10 mM, and 1 1-point dose-response curves were generated using a 1 in 4 serial dilution in DMSO. 100 nl_ of this dilution series was then added to a 384-well v-bottom polypropylene plate (Greiner 781280), excluding columns 6 and 18. 100 nl of DMSO was added to column 6 to serve as the high control, while column 18 served as the low control with assay buffer in place of the LRRK2 protein. Assay Dilution gave a highest final assay concentration of test compound of 100 µl 2) 5 µl of 'Enzyme Solution' containing 2x final assay concentration of purified full-length recombinant Flag-LRRK2 in Assay Buffer (50 mM Hepes, pH 7.2, 10 mM MgC, 150 mM NaCl , 5% glycerol, 0.0025% Triton X-100 and 1 mM DTT) were added to all wells using a Multidrop Combi dispenser (ThermoFisher Scientifiec), yielding a final test

concentration of 25 nM LRRK2 enzyme (final concentration may vary depending on the specific activity of different enzyme batches).

3) 5 µl substrate solution containing 50 µl LRRKtide peptide substrate and mM ATP was added to all wells of the plate using a Multidrop Combi dispenser yielding a final assay concentration of 25 µl LRRKtide peptide and 2 mM ATP. Assay plates were then incubated for 1 hour at room temperature. (Incubation may vary depending on the rate and linearity of the reaction with different enzyme batches).

4) 50 µl of laboratory grade 1% formic acid in water was added to all wells to quench the reaction, and the plates were heat sealed prior to centrifugation at 1348xg for 10 minutes. Test plates were then analyzed on an Agilent RapidFire High Throughput Solid Phase Extraction System coupled to AB Sciex API 4000 triple quadropole mass spectrometer with the following setting:

RapidFire Settings:

• Sip height = 2 mm, aspirate = 500 ms, charge time = 3000 ms, elution time = 3000 ms, requilibration = 500 ms.

· Flow rates: pump 1 = 1.5 ml/min, pump 2 1.25 ml/min pump 3 = 0.8 ml/min

Mass spectrometer settings:

• LRRKtide Detection Settings: Q1 Mass 644.8 Da, Q3 Mass 638.8, Declustering Potential 76 Volts, Collision Energy 37 Volts, CXP 34 Volts.

• Phospho-LRRKtide Detection Settings: Ql Mass 671.4 Da, Q3 Mass 638.8, Declustering Potential 76 Volts, Impact Energy 37 Volts, CXP 34 Volts.

• A C4 cartridge was used and running buffers were: A (aqueous) 0.1% formic acid in water B (organic) 0.1% formic acid, 80% acetonitrile, 20% water.

• Collision Gas: 12, Curtain Gas: 25, Ion Source Gas (1): 60, Ion Source Gas (2): 60, Ion Spray Voltage: 5500, Temperature: 600, Interfaec Heater: ON.

· Resolution Q1: low, resolution Q3: low.

5) Data were analyzed using ActivityBase software (I DBS). A percentage conversion from LRRKtide to Phospho-LRRKtide was calculated using the following formula:

%conversion= (peak area of product Phospho-LRRKtide/(peak area of product of Phospho-LRRKtide + peak area of LRRKtide substrate))^*100

A 4-parameter logistic curve fit was applied, using the following formula:

Where x is the concentration of the test sample, y is inhibition (%), a is the minimum, b is the hill slope, c is the I C50 and d is the maximum. The plc50 was derived from this (-log1C50). B. Recombinant Cellular LRRK2 AlphaScreen Assay

To determine the activity of compounds against LRRK2 kinase in cells, the observed LRRK2 kinase-dependent modulation of LRRK2 Ser 935 phosphorylation (Dzamko et al., 2010, Biochem. J. 430:405-413) was used to determine a To develop a quantitative 384-well plate-based immunoassay of LRRK2 Ser935 phosphorylation in the human neuroblastoma cell line SH-SY5Y, designed to overexpress full-length recombinant LRRK2 protein.

Assay-protocol

A full-length BacMam virus expressing recombinant LRRK2 was purchased from Invitrogen and amplified by inoculation of SF-9 cells at MOI 0.3 for 4-5 days in Sf-900 III SFM medium supplemented with 3% fetal bovine serum. Infected cell cultures were then centrifuged at 2000 g for 20 minutes, the titer of the viral supernatant determined by anti-gp64 plaque assay and stored at 4°C.

Affinity-purified anti-phospho LRRK2 Ser935 sheep polyclonal antibody (Dzamko et al., 2010, Biochem. J. 430:405-413) was biotinylated by standard methods (PerkinElmer). Rabbit polyclonal antibody against LRRK2 was purchased from Novus Biologicals. AlphaScreen Protein A IgG Kit (including acceptor and donor beads) was purchased from Perkin Elmer.

SH-SY5Y cells were cultured in DMEM/F12 medium containing 10% dialyzed fetal bovine serum and harvested by treatment with 0.5% trypsin-EDTA for 5 minutes at 37°C followed by centrifugation at 1000 µm for 4 minutes. The cell pellet was resuspended in Opti-MEM-reduced serum medium (Invitrogen) at 200,000 cells/ml and mixed with the BacMam LRRK2 virus at MOI=50. 50 µl of cell solutions were then added to each well of a 384-well plate and incubated at 37 °C, 5% CO₂for 24 hours.

Compounds were prepared at 10X final assay concentration as 1 1 point 1 in 4 serial I dilutions in Opti-MEM reduced serum medium (Invitrogen 31985070) containing 1% DMSO. On the day of the assay, 5.5 μl of the compound solutions were transferred from the compound plate to the cell assay plate to achieve a highest final concentration of the assay of 10 μM. DMSO (0.1% final test concentration) was added to column 6 and 2-(benzyloxy)-5-methyl-4-(1-methyl-1H-pyrazol-4-yl)-N-(pyridin-3-yl) benzamide (2 μΜ final test concentration) was added to column 18 to serve as 0% and 100% inhibition controls, respectively.

Cells were incubated for 60 minutes at 37°C, 5% CO 2 . The medium was then removed and the cells were lysed by adding 20 µl of cell lysis buffer (Cell Signaling Technology) and incubating at 4°C for 20 minutes. 10 μl mixture of antibody/acceptor beads [(1/1000 biotinylated pS935 LRRK2 antibody, 1/1000 total LRRK2 antibody, 1/100 acceptor beads in AlphaScreen Detection Buffer (25 mM Hepes (pH 7.4), 0.5% Triton X-100, 1 mg/ml Dextran 500 and 0.1% BSA)] was then added to each well and the plates were incubated for 2 hours at ambient temperature in the dark. donor beads in AlphaScreen Detection Buffer) was then added to each well After an additional 2 hours incubation at ambient temperature in the dark, the plates were read on an EnVision™ plate reader at emission 520-620 nm with excitation 680 nm. based on a sigmoidal dose-response model Metabolic Stability Test The metabolic stability of compounds of the invention was assessed in hepatocytes of human and preclinical species (e.g., rat) A test compound (0.5 μΜ) was incubated with 0.5 million viable hepatocytes at 37°C in a 95% humidified room. incubator supplied with 5% CO2.7 ethoxycoumarin was used as a positive control and treated in the same manner as the test compound. The incubation samples were mixed gently at 150 rpm. Incubation medium was Williams' Medium E containing 2 mM GlutaMAX ™ and 25 mM HEPES. Samples were run at a specific time interval (t_X): 0, 15, 30, 60, 90, and 120 min. Reactions were terminated by adding an equal volume of ice-cold acetonitrile/methanol/acetic acid (80/20/1, v/v/v) containing an internal standard ( e.g. 100 ng/ml tobutamide as internal standard). The precipitated protein was pelleted by centrifugation and the supernatant was transferred to a new 96-well polypropylene plate for LC/MS/MS analysis. The instrument responses of the test compound and internal standard were measured using a compound-specific LC/MS/MS methodology. The percentage of residual test compound is calculated from the peak area ratio between residual test compound after incubation (t_X) and the peak area of the test compound at the start of the incubation (t_X=0 minutes).

The half-life (ti/2) is calculated using the following equation: where k is the conversion rate constant of regression of In (percent test compound remaining) over t_X.

The metabolic stability of a test compound is expressed as intrinsic clearance (Clint) and is calculated from half-life (ti/2) using the following equation:

Clint (ml/min/g) = (0.693/12) * (ml per incubation/ number of cells per incubation)^H(number of cells/gram of wet tissue weight)

Constants used to represent millions of cells/gram wet tissue weight: 1 17.5 for human tissue and 108 for rat tissue. 2. Biological data

Certain compounds of the invention were tested in the full G2019 human LRRk2 inhibition mass spectrometric assay, the recombinant cellular LRRK2 alphaScreen assay and the metabolic stability assay.

The pl Ceo value or the C value of the assays for each compound tested either reported in at least one experiment or the average of multiple experiments. It is understood that the data described herein may have reasonable variations depending on the specific conditions and procedures used by the person conducting the experiments. In the full G2019 human LRRK2 inhibition mass spectrometry assay, the following compounds of the invention showed pI Cso 5^S5.0: examples E1, E3, E5, E6, E7, E9, E1 1, E12, E13, E19, E20, E26, E28, E29, E30, E31, E32, E33, E34, E35, E36, E43, E45, E46, E47, E48, E49, E51, E52, E53, E54, E56, E57, E58, E60, E61, E62, E63, E64, E65, E66, E67, E68, E70, E84, E88, E89, E90, E104, E105, E106, E107, E109, E1 10, E1 12, E1 14, E1 16, E1 17, E120, E121, E123, E124, E127, E128, E130, E134, E136, E137, E138, E140, E141 3 , E208, E209, E210, E21 1, E212, E213, E214, E215, E217, E218, E221, E222, E228, E236, E243, E244, E245, E246, E250, E251, E258, E259, E260, E2 61 , E262 E263, E264, E265, E266, E270, E271, E272, E273, E274, E275, E278, E279, E280, E286, E287, E290, E291, E292, E293, E294, E295, E296, E298, E 29 9 , E301, E302, E303, E304, E305, E306, E307, E308, E309, E31 1, E315, E316, E317, E318, E319, E320, E323, E351, E352, E353, E354, E355, E356, E 357, E3 58, E360, E363, E364, E365, E366, E367, E369, E370, E375, E376, E377, E378, E379, E382, E385, E386, E387., E399. 432, E433, E444, E445, E446 and E44 7. The following compounds showed pICso≥ 7.0: Examples E1, E3, E5, E6, E11, E12, E13, E20, E28, E30, E31, E32, E35, E36, E45, E47, E48, E49, E51, E52, E54 E57, E58, E60, E61, E62, E64, E65, E66, E67, E68, E70, E84, E88, E90, E104, E105, E106, E107 , E109, E110, E112, E114, E116, E117, E121 E123, E124, E127, E128, E130, E134, E136, E137, E140, E141, E145, E146, E154, E155, E180, E183, E184, E 186, E187, E188, E191, E192, E195, E198, E201 E203, E208, E210, E213, E215, E218, E221, E222, E236, E243, E244, E245, E251, E258, E259, E260, E265, E26 6, E270 , E272, E274, E278, E287, E291, E293 E295, E298, E301, E302, E304, E305, E306, E307, E308, E309, E311, E316, E317, E318, E320, E351, E352, E353, E 354, E355, E357, E358, E364, E365, E366 E367, E369, E375, E376, E377, E378, E379, E382, E385, E386, E387, E388, E389, E390, E391, E394, E395, E396, E39 7, E399 , E401, E403, E404, E405, E406 , E410, E411, E414, E415, E416, E417, E418, E419, E421, E422, E423, E424, E427, E430, E432, E433, E444, E445, E446 en E447 . The following connections are shown plC50 = 4: Example E181, E216 and E312. In the recombinant cellular LRRK2 alphaScreen-assay, the following connections according to the invention plC were shown₅₀≥ 5.0: examples E1 through E188; E190 through E427; E430 through E440; E442 through E452. The following compounds show pIC 50 ≥ 7.0: Examples E1, E2, E3, E5, E6, E8, E10, E11, E12, E13, E14, E15, E16, E17, E18, E20, E24, E25, E27, E28 , E30 , E32, E35, E38, E42, E44, E45, E46, E47, E48, E49, E50, E51, E52, E54, E57, E58, E59, E60, E61, E62, E64, E65, E66, E67 , E68 E69, E70, E71, E72, E73, E80, E81, E82, E84, E86, E87, E88, E90, E91, E94, E95, E96, E98, E100, E101, E104, E105, E106,

E107, E108, E109, E110, E111, E112, E116, E117, E118, E119, E121, E122, E123, E124,

E125, E126, E127, E128, E130, E131, E132, E133, E134, E135, E136, E139, E140, E141,

E142, E143, E144, E145, E146, E150, E151, E152, E153, E154, E158, E161, E162, E163,

E165, E168, E169, E170, E172, E174, E175, E178, E179, E180, E181, E183, E184, E186,

E187, E188, E191, E192, E194, E195, E198, E200, E201, E202, E203, E206, E207, E208,

E210, E213, E215, E218, E219, E220, E221, E222, E223, E227, E228, E229, E230, E233,

E234, E235, E236, E237, E238, E239, E241, E243, E244, E245, E247, E249, E251, E255,

E257, E258, E259, E260, E265, E266, E269, E270, E274, E276, E278, E281, E282, E284,

E287, E288, E289, E291, E293, E300, E301, E302, E303,

E309, E310, E311, E312, E314, E316, E317, E318, E322, E325, E326, E328, E330, E331,

E334, E335, E336, E337, E338, E339, E341, E342, E343, E345, E346, E347, E351, E353,

E354, E357, E358, E359, E362, E363, E364, E365, E366, E367, E369, E371, E372, E373,

E374, E375, E376, E377, E378, E379, E380, E382, E383, E384, E385, E386, E387, E389,

E391, E392, E393, E394, E395, E396, E397, E399, E400, E401, E402, E403, E404, E406,

E408, E410, E411, E412, E413, E415, E416, E417, E421, E422, E423, E427, E430, E431,

E432, E433, E436, E437, E438, E440, E442, E443, E444, E445, E446, E447, E448, E450, E451 and E452. The following compounds showed pC50 < 5.0: Examples E189, E428, E429, E441, racemic 14-chloro-4,1 1-dimethyl-5-{2-oxaspiro[3.3]heptan-6-yl}-8-oxa -2_!5_!6_!12_!16_!17-hexaazatricyclo[1 1.3.1.0³'⁷]heptadeca-1 (17)_!3_!6_!13,15-pentaeen en 3-methyl-8-(prop-1-en-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,4,10,1 1 ,12,13 -hexahydro-5,9-(azeno)pyrazolo[3,4-b][1,4,6,10]oxatriazacyclotridecine.

In the metabolic stability test (in human hepatocytes), the following compounds of the invention showed C (human) < 10.0: Examples E1, E3, E6, E10, E11, E12, E14, E15, E16, E17, E18, E20 E24 , E27, E28, E29, E30, E32, E34, E35, E44, E45, E46, E47, E48, E52, E53, E54, E57, E59, E60, E61, E62, E63, E64, E65, E66 , E67 , E68, E83, E84, E88, E95, E98, E101 , E102, E104, E106, E107, E123, E124, E134, E136, E145, E146, E178, E181 , E183, E184, E187, E191 , E195 E196 , E202, E203, E210, E213, E220, E222, E229, E230, E233, E234, E235, E236, E238, E243, E244, E249, E251, E261, E265, E266, E270, E276, E28 1, E284, E285 , E288, E289, E290, E291 , E292, E293, E297, E298, E301 , E302, E303, E305, E306, E31 1 , E315, E330, E338, E339, E343, E345, E359, E366, E 367, E369 , E371, E380, E393, E395, E400, E406 and E417. The following compounds showed Clint<3.0 (human): Examples E1, E3, E6, E10, E11, E12, E14, E15, E16, E17, E18, E20, E24, E27, E28, E29, E30, E32, E34, E35, E44, E45, E46, E47, E48, E52, E53, E54, E57, E59, E60, E61, E62, E63, E64, E65, E66, E67, E68, E83, E84, E88, E95, E98 E101, E102, E104, E106, E107, E123, E124, E134, E136, E145, E146, E178, E181, E183, E184, E187, E191, E195, E196, E202, E203, E210, E213, E2 2 9, E230 E233, E234, E235, E236, E238, E243, E244, E249, E251, E265, E266, E270, E276, E281, E284, E285, E288, E289, E290, E291, E292, E293, E297, E2 98, E301 , E302, E303, E305, E306, E31 1 , E315, E330, E338, E339, E343, E345, E359, E366, E367, E369, E371, E380, E393, E395, E406 and E417. The compound of example E362 showed Clint>10 (human).

Sequence List

SEQ ID NO: 1 Primers used for PCR cloning of human G2019 LRRK2 plasmid preparation: pHTBV-F

5 -GATCTCGACGGGCGCGGATCCACCATGGATTACAAGGATGACGACGAT-3'

SEQ ID NO: 2 Primers used for PCR cloning of human G2019 LRRK2 plasmid preparation: LRRK2 wt-F1

5 -CATGGATTACAAGGATGACGACGATAAGATGGCTAGTGGCAGCTGTTCAG-3'

SEQ ID NO: 3 Primers used for PCR cloning of human G2019 LRRK2 plasmid preparation: LRRK2 wt-R1

5'-GTTCACGAGATCCACTATTCAGTAAGAGTTCCACCAATTTGGGACTG-3'

SEQ ID NO: 4 Primers used for PCR cloning of human G2019 LRRK2 plasmid preparation: LRRK2 wt-F2

5'- GAATAGTGGATCTCGTGAACAAG -3' SEQ ID NO: 5 Primers used for PCR cloning of human G2019 LRRK2 plasmid preparation: LRRK2 wt-R2

5'- GTCAGACAAACTGCTTGGAACCAGC-3'

SEQ ID NO: 6 Primers used for PCR cloning of human G2019 LRRK2 plasmid preparation: LRRK2 wt-F3

5'-CTGGTTCCAAGCAGTTTGTCTGACCACAGGCCTGTGATAG-3'

SEQ ID NO: 7 Primers used for PCR cloning of human G2019 LRRK2 plasmid preparation: pHTBV-R

5'-GTTCTAGCCAAGCTTGGTACCCTATTACTCAACAGATGTTCGTCTC -3'

SEQ ID NO: 8 G2019 full length Flag-LRRK2 coding sequence

atggattacaaaggatgacgacgataagATGGCTAGTGGCAGCTGTCAGGGGTGCGAAGAGGACGAGGAAAC TCTGAAGAAGTTGATAGTCAGGCTGAACAATGTCCAGGAAGGAAAACAGATAGAAACGCTGGTC CAAATCCTGGAGGATCTGCTGGTGTTCACGTACTCCGAGCACGCCTCCAAGTTATTTCAAGGCAA AAATATCCATGTGCCTCTGTTGATCGTCTTGGACTCCTATATGAGAGTCGC GAGTGTGCAGCAGG TGGGTTGGTCACTTCTGTGCAAATTAATAGAAGTCTGTCCAGGTACAATGCAAAGCTTAATGGGA CCCCAGGATGTTGGAAATGATTGGGAAGTCCTTTGGTGTTCACCAATTGATTCTTAAAATGCTAAC AGTTCATATGCCAGTGTAAACTTGTCAGTGATTGGACTGAAGACCTTAGATCTCCTCCTAACTTC AGGTAAAATCACCTTGCTGATACTGGATGAAGAAAGTGATATTTT CATGTTAATTTTTGATGCCAT GCACTCATTTCCAGCCAATGATGAAGTCCAGAAACTTGGAATGCAAAGCTTTACATGTGCTGTTTG AGAGAGTCTCAGAGGAGCAACTGACTGAATTTGTTGAGAACAAAGATTATATGATATTGTTAAGT GCGTTAACAAATTTTAAAGATGAAGAGGAAATTGTGCTTCATGTGCTGCATTGTTTACATTCCCTA GCGATTCCTTGCAATAATGTGGAAGTCCTCATGA GTGGCAATGTCAGGTGTTATAATATTGTGGT GGAAGCTATGAAAGCATTCCCTATGAGTGAAAGAATTCAAGAAGTGAGTTGCTGTTTGCTCCATA GGCTTACATTAGGTAATTTTTTCAATATCCTGGTATTAAACGAAGTCCATGATGAGTTTGTGGTGAAAG CTGTGCAGCAGTACCCAGAGAATGCAGCATTGCAGATCTCAGCGCTCAGCTGTTTGGCCCTCCT CACTGAGACTATTTTCTTAAATCAAG ATTTAGAGGAAAAGAATGAGAATCAAGAGAATGATGATGA GGGGGAAGAAGATAAATTGTTTTGGCTGGAAGCCTGTTACAAAGCATTAACGTGGCATAGAAAGA ACAAGCACGTGCAGGAGGCCGCATGCTGGGCACTAAATATCTCCTTATGTACCAAAACAGTTTA CATGAGAAGATTGGAGATGAAGATGGCCATTTCCCAGCTCATAGGGAAGTGATGCTCTCCATGC TG ATG CATTCTTC A TCAAAG G AAGTTTTCCAG GCATCTG CG AATG CATTGTC AACTCTCTTAG AAC AAAATGTTAATTTCAGAAAAAATACTGTTATCAAAAGGAATACACCTGAATGTTTTGGAGTTAATGCA GAAGCATATACATTCTCCTGAAGTGGCTGAAAGTGGCTGTAAAATGCTAAATCATCTTTTTGAAGG AAGCAACACTTCCCTGGATATATGGCAGCAGTGGTCCCCAAAATACTAACAGTTATGA AACGTC ATGAGACATCATTACCAGTGCAGCTGGAGGCGCTTCGAGCTATTTTACATTTTATAGTGCCTGGC ATGCCAGAAGAATCCAGGGAGGATACAGAATTTCATCATAAGCTAAATATGGTTAAAAAACAGTG TTTCAAGAATGATATTCACAAACTGGTCCTAGCAGCTTTGAACAGGTTCATTGGAAATCCTGGGAT TCAGAAATGTGGATTAAAAGTAATTTCTTCTATTGTACATTTTCCTGATGCATT AGAGATGTTATCC CTGGAAGGTGCTATGGATTCAGTGCTTCACACACTGCAGATGTATCCAGATGACCAAGAAATTCA GTGTCTGGGTTTAAGTCTTATAGGATACTTGATTACAAAGAAGAATGTGTTCATAGGAACTGGACA TCTGCTGGCAAAAATTCTGGTTTCCAGCTTATACCGATTTAAGGATGTTGCTGAAATACAGACTAA AGGATTTCAGACAATCTTAGCAATCCTCAAATTGTCAGCATC TTTTTCTAAGCTGCTGGTGCATCA TTCATTTGACTTAGTAATATTCCATCAAATGTCTTCCAATATCATGGAACAAAAGGATCAACAGTTT CTAAACCTCTGTTGCAAGTGTTTTGCAAAAGTAGCTATGGATGATTACTTAAAAAATGTGATGCTA GAGAGAGCGTGTGATCAGAATAACAGCATCATGGTTGAATGCTTGCTTCTATTGGGAGCAGATG CCAATCAAGCAAAGGAGGGATCTTCTTTAATT TGTCAGGTATGTGAGAAAGAGAGCAGTCCCAAA TTGGTGGAACTCTTACTGAATAGTGGATCTCGTGAACAAGATGTACGAAAAGCGTTGACGATAAG CATTGGGAAAGGTGACAGCCAGATCATCAGCTTGCTCTTAAGGAGGCTGGCCCTGGATGTGGCC AACAATAGCATTTGCCTTGGAGGATTTTGTATAGGAAAAGTTGAACCTTCTTGGCTTGGTCCTTTA TTTCCAGATAAGACTTCTAATT TAAGGAAACAAACAAATATAGCATCTACACTAGCAAGAATGGTG ATCAGATATCAGATGAAAAGTGCTGTGGAAGAAGGAACAGCCTCAGGCAGCGATGGAAATTTTTC TGAAGATGTGCTGTCTAAATTTGATGAATGGACCTTTATTCCTGACTCTTCTATGGACAGTGTGTT TGCTCAAAGTGATGACCTGGATAGTGAAGGAAGTGAAAGGCTCATTTCTTGTGAAAAAGAAATCTA ATTCAATTAGTGTAGGAGAATTTTACCGAGATGCCGTATTACAGCGTTGCTC ACCAAATTTGCAAA GACATTCCAATTCCTTGGGGCCCATTTTTGATCATGAAGATTTACTGAAGCGAAAAAGAAAAATAT TATCTTCAGATGATTCACTCAGGTCATCAAAACTTCAATCCCATATGAGGCATTCAGACAGCATTT CTTCTCTGGCTTCTGAGAGAGAATATATTACATCACTAGACCTTTCAGCAAATGAACTAAGAGATA TTGATGCCCTAAGCCAGAAATGCTGTATAAGTGTTCATTTG GAGCATCTTGAAAAGCTGGAGCTT CACCAGAATGCACTCACGAGCTTTCCACAACAGCTATGTGAAACTCTGAAGAGTTTGACACATTT GGACTTGCACAGTAATAAATTTACATCATTTCCTTCTTATTTGTTGAAAATGAGTTGTATTGCTAAT CTTGATGTCTCTCGAAATGACATTGGACCCTCAGTGGGTTTTAGATCCTACAGTGAAATGTCCAACT CTGAAACAGTTTAACCTGTCATATAACCAG CTGTCTTTTGTACCTGAGAACCTCACTGATGTGGTA GAGAAACTGGAGCAGCTCATTTTAGAAGGAAATAAAATATCAGGGATATGCTCCCCCTTGAGACT GAAGGAACTGAAGATTTTAAACCTTAGTAAGAACCACATTTCATCCCTATCAGAGAACTTTCTTGA GGCTTGTCCTAAAGTGGAGAGTTTCAGTGCCAGAATGAATTTTCTTGCTGCTATGCCTTTCTTGC CTCCTTCTATGACAATCCTAAA ATTATCTCAGAACAAATTTTCCTGTATTCCAGAAGCAATTTTAAA TCTTCCACACTTGCGGTCTTTAGATATGAGCAGCAATGATATTCAGTACCTACCAGGTCCCGCAC ACTGGAAATCTTTGAACTTAAGGGAACTCTTATTTAGCCATAATCAGATCAGCATCTTGGACTTGA GTGAAAAAGCATATTTATGGTCTAGAGTAGAGAAACTGCATCTTTCTCACAATAAACTGAAAGAGA TTCCTCCTGAG ATTGGCTGTCTTGAAAATCTGACATCTCTGGATGTCAGTTACAACTTGGAACTAA GATCCTTTCCCAATGAAATGGGGGAAATTAAGCAAAATATGGGATCTTCCTTTGGATGAACTGCAT CTTAACTTTGATTTTAAACATATAGGATGTAAAGCCAAAGACATCATAAGGTTTCTTCAACAGCGA TTAAAAAAGGCTGTGCCTTATAACCGAATGAAACTTATGATTGTGGGAAATACTGGGAGTGGTAA AACCA CCTTATTGCAGCAATTAATGAAAACCAAGAAATCAGATCTTGGAATGCAAAGTGCCACAG TTGGCATAGATGTGAAAGACTGGCCTATCCAAATAAGAGACAAAAGAAAGAGAGATCTCGTCCTA AATGTGGGGGATTTTGCAGGTCGTGAGGAATTCTATAGTACTCATCCCCATTTTATGACGCAGCG AGCATTGTACCTTGCTGTCTATGACCTCAGCAAGGGACAGGCTGAAGTTGATGCCATGAAGCC TT GGCTCTTCAATATAAAGGCTCGCGCTTCTTCTTCCCCTGTGATTCTCGTTGGCACACATTTGGAT GTTTCTG ATG AG AAG CAACG CAAAG CCTG CATG AGTAAAATCACC AAG G AACTCCTG AATAAGCG AGGGTTCCCTGCCATACGAGATTACCACTTTGTGAATGCCACCGAGGAATCTGATGCTTTGGCAA AACTTCGGAAAACCATCATAAACGAGAGCCTTAATTTCAAGAT CCGAGATCAGCTTGTTGTTGGA CAGCTGATTCCAGACTGCTATGTAGAACTTGAAAAAATCATTTTATCGGAGCGTAAAAATGTGCCA ATTGAATTTCCCGTAATTGACCGGAAACGATTATTACAACTAGTGAGAGAAAATCAGCTGCAGTTA GATGAAAATGAGCTTCCTCACGCAGTTCACTTTCTAAATGAATCAGGAGTCCTTCTTCATTTTCAA GACCCAGCACTGCAGTTAAGTGACTTGTACTTTGT GGAACCCAAGTGGCTTTGTAAAATCAGGC ACAGATTTTGACAGTGAAAGTGGAAGGTTGTCCAAAACACCCTAAGGGAATTATTTCGCGTAGAG ATGTGGAAAAATTTCTTTCAAAGAAAAGGAAATTTCCAAAGAACTACATGTCACAGTATTTTAAGC TCCTAGAAAAATTCCAGATTGCTTTGCCAATAGGAGAAGAATATTTGCTGGTTCCAAGCAGTTTGT CTGACCACAGGCCTGTGATAGAGCTTCCCCATTGTGAGAACTCTGAAATTATCATCCGACTATAT GAAATGCCTTATTTTCCAATGGGATTTTGGTCAAGATTAATCAATCGATTACTTGAGATTTCACCTT ACATGCTTTCAGGGAGAGAACGAGCACTTCGCCCAAACAGAATGTATTGGCGACAGGCATTTA CTTAAATTGGTCTCCTGAAGCTTATTGTCTGGTAGGATCTGAAGTCTTAGACAATCATCCA GAGA GTTTCTTAAAAATTACAGTTCCTTCTTGTAGAAAAGGCTGTATTCTTTTGGGCCAAGTTGTGGACC ACATTGATTCTCTCATGGAAGAATGGTTTCCTGGGTTGCTGGAGATTGATATTTGTGGTGAAGGA GAAACTCTGTTGAAGAAATGGGCATTATATAGTTTTAATGATGGTGAAGAACATCAAAAAATCTTA CTTGATGACTTGATGAAGAAAGCAGAGGAAGGAGATCTTAGTAAATCCAGAT CAACCAAGGCT CACCATTCCAATATCTCAGATTGCCCCTGACTTGATTTTGGCTGACCTGCCTAGAAATATTATGTT GAATGATGAGTTGGAATTTGAACAAGCTCCAGAGTTTCTCCTAGGTGATGGCAGTTTTGGAT CAGTTTACCGAGCAGCCTATGAAGGAGAAGAAGTGGCTGTGAAGATTTTTAATAAACATACATCA CTCAGGCTGTTAAGACAAGAGCTTGGTGCTTTGCCACCTCC ACCACCCCAGTTTGATATCTTT GCTGGCAGCTGGGATTCGTCCCCGGATGTTGGTGATGGAGTTAGCCTCCAAGGGTTCCTTGGAT CGCCTGCTTCAGCAGGACAAAGCCAGCCTCACTAGAACCCTACAGCACAGGATTGCACTCCACG TAGCTGATGGTTTGAGATACCTCCACTCAGCCATGATTATATACCGAGACCTGAAACCCCACAAT GTGCTGCTTTTCACACTGTATCCCAATGCTGCCAT CATTGCAAAGATTGCTGACTACGGCATTGC TCAGTACTGCTGTAGAATGGGGATAAAAACATCAGAGGGCACACCAGGGTTTCGTGCACCTGAA GTTGCCAGAGGAAATGTCATTTATAACCAACAGGCTGATGTTTATTCATTTGGTTTACTACTCTAT GACATTTTGACAACTGGAGGTAGAATAGTAGAGGGTTTGAAGTTTCCAAATGAGTTTGATGAATTA GAAATACAAGGAAAATTACCTGATCCAGTTAA AGAATATGGTTGTGCCCCATGGCCTATGGTTGA GAAATTAATTAAACAGTGTTTGAAAGAAAATCCTCAAGAAAGGCCTACTTCTGCCCAGGTCTTGA CATTTTGAATTCAGCTGAATTAGTCTGTCTGACGAGACGCATTTTATTACCTAAAAACGTAATTGTT GAATGCATGGTTGCTACACATCACAACAGCAGGAATGCAAGCATTTGGGCTGGGCTGTGGGCACA CCGACAGAGGACAGCTCTCATTTC TTGACTTAAATACTGAAGGATACACTTCTGAGGAAGTTGCT GATAGTAGAATATTGTGCTTAGCCTTGGTGCATCTTCCTGTTGAAAAGGAAAGCTGGATTGTGTC TGGGAACACAGTCTGGTACTCTCCTGGTCATCAATACCGAAGATGGGAAAAAAGAGACATACCCTA GAAAAGATGACTGATTCTGTCACTTGTTTGTATTGCAATTCCTTTTCCAAGCAAAGCAAACAAAAA AATTTTCTTT TG GTTG G AACCGCTG ATGG CAAGTTAG CAATTTTTG AAG ATAAG ACTGTTAAG CTT AAAGGAGCTGCTCCTTTGAAGATACTAAATATAGGAAATGTCAGTACTCCATTGATGTGTTTGAGT GAATCCACAAATTCAACGGAAAAAAAATGTAATGTGGGGAGGATGTGGCACAAAGATTTTCTCCTT TTCTAATGATTTCACCATTCAGAAACTCATTGAGACAAGAACAAGCCAACTGTTTTCTTAT GCAGC TTTCAGTGATTCCAACATCATAACAGTGGTGGTAGACACTGCTCTCTATATTGCTAAGCAAAATAG CCCTGTTGTGGAAGTGTGGGATAAGAAAACTGAAAAACTCTGTGGACTAATAGACTGCGTGCACT TTTTAAGGGAGGTAATGGTAAAAGAAAACAAGGAATCAAAACACAAAATGTCTTATTCTGGGAGA GTG AAAACCCTCTGCTTTC AG AAG AAC ACTGCTCTTTG GAT AG G AACTG GAG G AGG CCATATTTT ACTCCTGGATCTTTCAACTCGTCGACTTATACGTGTAATTTACAACTTTTGTAATTCGGTCAGAGT CATG ATG ACAG CACAG CTAG G AAGCCTTAAAAATGTCATG CTG GTATTG GGCTACAACCGG AAAA ATACTGAAGGTACACAAAAGCAGAAAGAGATACAATCTTGCTTGACCGTTTGGGACATCAATCTT CCACATGAAGTGCAAA ATTTAGAAAAACACATTGAAGTGAGAAAAGAATTAGCTGAAAAAAATGAG ACGAACATCTGTTGAGTAA

SEQ ID NO: 9 Translated protein sequence for full-length human G2019 LRRK2 flag-tagged protein

MDYKDDDDKMASGSCQGCEEDEETLKKLIVRLNNVQEGKQIETLVQILEDLLVFTYSEHASKLFQGKN

IHVPLLIVLDSYMRVASVQQVGWSLLCKLIEVCPGTMQSLMGPQDVGNDWEVLGVHQLILKMLTVHN ASVNLSVIGLKTLDLLLTSGKITLLILDEESDIFMLIFDAMHSFPANDEVQKLGCKALHVLFERVSEEQLT EFVENKDYMILLSALTNFKDEEEIVLHVLHCLHSLAIPCNNVEVLMSGNVRCYNIWEAM KAFPMSERI QEVSCCLLHRLTLGNFFNILVLNEVHEFVVKAVQQYPENAALQISALSCLALLTETIFLNQDLEEKNEN QENDDEGEEDKLFWLEACYKALTWHRKNKHVQEAACWALNNLLMYQNSLHEKIGDEDGHFPAHRE VMLSMLMHSSSKEVFQASANALSTLLEQNVNFRKILLSKGIHLNVLELMQKHIHSPEVAESGCKMLNH L FEGSNTSLDIMAAVVPKILTVMKRHETSLPVQLEALRAILHFIVPGMPEESREDTEFHHKLNMVKKQC FKNDIHKLVLAALNRFIGNPGIQKCGLKVISSIVHFPDALEMLSLEGAMDSVLHTLQMYPDDQEIQCLG LSLIGYLITKKNVFIGTGHLLAKILVSSLYRFKDVAEIQTKGFQTILAILKLSASFSKLLVHHSFD LVIFHQM SSNIMEQKDQQFLNLCCKCFAKVAMDDYLKNVMLERACDQNNSIMVECLLLLGADANQAKEGSSLIC QVCEKESSPKLVELLLNSGSREQDVRKALTISIGKGDSQIISLLLRRLALDVANNSICLGGFCIGKVEPS WLGPLFPDKTSNLRKQTNIASTLARMVIRYQMKSAVEEGTASGSDGNFSEDVLSKFDEWTFIPDSSM DSV FAQSDDLDSEGSEGSFLVKKKSNSISVGEFYRDAVLQRCSPNLQRHSNSLGPIFDHEDLLKRKR KILSSDDSLRSSKLQSHMRHSDSISSLASEREYITSLDLSANELRDIDALSQKCCISVHLEHLEKLELHQ NALTSFPQQLCETLKSLTHLDLHSNKFTSFPSYLLKMSCIANLDVSRNDIGPSVVLDPTVKCPTLKQFN LSYNQ LSFVPENLTDVVEKLEQLILEGNKISGICSPLRLKELKILNLSKNHISSLSENFLEACPKVESFSA RMNFLAAMPFLPPSMTILKLSQNKFSCIPEAILNLPHLRSLDMSSNDIQYLPGPAHWKSLNLRELLFSH NQISILDLSEKAYLWSRVEKLHLSHNKLKEIPPEIGCLENLTSLDVSYNLELRSFPNEMGKLSKIWDLPL DELHLNFDFKHIGCKA KDIIRFLQQRLKKAVPYNRMKLMIVGNTGSGKTTLLQQLMKTKKSDLGMQSA TVGIDVKDWPIQIRDKRKRDLVLNVWDFAGREEFYSTHPHFMTQRALYLAVYDLSKGQAEVDAMKP WLFNIKARASSSPVILVGTHLDVSDEKQRKACMSKITKELLNKRGFPAIRDYHFVNATEESDALAKLRK TIINESLNFKIRDQ LVVGQLIPDCYVELEKIILSERKNVPIEFPVIDRKRLLQLVRENQLQLDENELPHAVH FLNESGVLLHFQDPALQLSDLYFVEPKWLCKIMAQILTVKVEGCPKHPKGIISRRDVEKFLSKKRKFPK NYMSQYFKLLEKFQIALPIGEEYLLVPSSLSDHRPVIELPHCENSEIIIRLYEMPYFPMGFWSRLINRLLE ISPYMLSGRERALRPN RMYWRQGIYLNWSPEAYCLVGSEVLDNHPESFLKITVPSCRKGCILLGQVV DHIDSLMEEWFPGLLEIDICGEGETLLKKWALYSFNDGEEHQKILLDDLMKKAEEGDLLVNPDQPRLTI PISQIAPDLILADLPRNIMLNNDELEFEQAPEFLLGDGSFGSVYRAAYEGEEVAVKIFNKHTSLRLLRQE LVVLCHLHHPSLISLLAAGI RPRMLVMELASKGSLDRLLQQDKASLTRTLQHRIALHVADGLRYLHSAM IIYRDLKPHNVLLFTLYPNAAIIAKIADYGIAQYCCRMGIKTSEGTPGFRAPEVARGNVIYNQQADVYSF GLLLYDILTTGGRIVEGLKFPNEFDELEIQGKLPDPVKEYGCAPWPMVEKLIKQCLKENPQERPTSAQ VFDILNSAELVCLTRRILLPKNVIVECMVA THHNSRNASIWLGCGHTDRGQLSFLDLNTEGYTSEEVAD SRILCLALVHLPVEKESWIVSGTQSGTLLVINTEDGKKRHTLEKMTDSVTCLYCNSFSKQSKQKNFLLV GTADGKLAIFEDKTVKLKGAAPLKILNIGNVSTPLMCLSESTNSTERNVMWGGCGTKIFSFSNDFTIQK LIETRTSQLFSYAAFSDSNIITVVVDTALYIAKQNSP WEVWDKKTEKLCGLIDCVHFLREVMVKENKES KHKMSYSGRVKTLCLQKNTALWIGTGGGHILLLDLSTRRLIRVIYNFCNSVRVMMTAQLGSLKNVMLV LGYNRKNTEGTQKQKEIQSCLTVWDINLPHEVQNLEKHIEVRKELAEKMRRTSVE

SEQ ID NO: 10: 'LRRKtide'-peptide

H-RLGRDKYKTLRQIRQ-OH

INHIBITORS OF LEUCINE RICH REPEAT KINASE 2 - GLAXOSMITHKLINE IP DEV LTD (2023)