NOVEL 6-6 BICYCLIC AROMATIC RING SUBSTITUTED NUCLEOSIDE ANALOGUES FOR USE AS PRMT5 INHIBITORS

Abstract

The present invention relates novel 6-6 bicyclic aromatic ring substituted nucleoside analogues of Formula (I) wherein the variables have the meaning defined in the claims. The compounds according to the present invention are useful as PRMT5 inhibitors. The invention further relates to pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

Description

NOVEL 6-6 BICYCLIC AROMATIC RING SUBSTITUTED NUCLEOSIDE ANALOGUES FOR USE AS PRMT5 INHIBITORSField of the InventionThe present invention relates to novel 6-6 bicyclic aromatic ring substituted nucleoside analogues useful as PRMT5 inhibitors. The invention further relates to pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.Background of the inventionPRMT5, also described as Hsl7, Jbpl, Skbl, Capsuleen or Dart5, is one of the major methyltransferases responsible for mono- and symmetric dimethylation of arginines. Post-translational arginine methylation on histones and non-histone proteins seems to be crucial for a variety of biological processes, like genome organisation, transcription, differentiation, spliceosome function, signal transduction and regulation of cell-cycle progression, stem cells and T-cell fate [Stopa, N. et al, Cell Mol Life Sci, 2015. 72(11): p. 2041-59] [Geoghegan, V. et al, Nat Commun, 2015. 6: p. 6758]. Metazoan PRMT5 forms a functional complex with the methylosome protein 50 (MEP50) also named as Wdr77, androgen receptor coactivator p44 and Valois. Both, elevated PRMT5-MEP50 protein level and cytoplasmic accumulation are implicated in cancer tumorigenesis and have recently been correlated with poor clinical outcome [Shilo, K. et al, Diagn Pathol, 2013. 8: p. 201]. Cellular rescue experiments that addressed both the catalytic and scaffold function of the PRMT5-MEP50 complex, beside comprehensive enzymo logical studies have substantiate the oncogenic link between protein level, localisation and enzymatic function [Gu, Z. et al, Biochem J, 2012. 446(2): p. 235-41] [Di Lorenzo, A. et. al, FEBS Lett, 2011. 585(13): p. 2024-31] [Chan-Penebre, E. et al, Nat Chem Biol, 2015. 11(6): p. 432-7]. This correlation turns PRMT5 into an essential small molecule drug target against cancer and other diseases [Stopa, N. et al, Cell Mol Life Sci, 2015. 72(11): p. 2041-59].PRMT5 is a member of the type II PRMT subfamily that utilises S-adenosylmethionine (SAM) to generate symmetric dimethylated arginine on histones and non-histone protein substrates and S-adenosylhomocysteine (SAH). The crystal structure of the human hetereo-octameric complex (PRMT5)4(MEP50)4 co-crystalised with SAH and a histone H4 peptide substrate illustrated the mechanism of methylation and substrate recognition [Antonysamy, S. et al, Proc Natl Acad Sci U S A, 2012. 109(44): p. 17960-5]. The regulation of PRMT5 activity occurs through a vast number of different binding partners, post-translational modification cross talk, miRNAs and subcellular localisation.Methylation of histones H2A and H4 on Arg3 and histone H3 on Arg8 regulate chromatin organisation for specific repression of gene transcripts that are involved in differentiation, transformation, cell-cycle progression and tumour suppression [Karkhanis, V. et al, Trends Biochem Sci, 2011. 36(12): p. 633-41]. Furthermore, PRMT5 -mediated methylation of histone H4 on Arg3 might recruit the DNA- methyltransferase DNMT3A to couple histone and DNA methylation for long-term gene silencing [Zhao, Q. et al, Nat Struct Mol Biol, 2009. 16(3): p. 304-11].Non-histone methylation can occur either in the cytoplasm or nucleus dependent on the cellular localisation of PRMT5. The methylation of the Sm proteins Dl and D3, which are required for the assembly of the nuclear splicesome, takes place in the cytoplasm as part of the PRMT5 containing "methylosome" [Friesen, W.J. et al., Mol Cell Biol, 2001. 21(24): p. 8289-300]. Further evidence for PRMT5 involved in splicing has been provided by the conditional PRMT5 knockout in mouse neural stem cells. Cells that lack PRMT5 showed a selective retention of introns and skipping of exons with weak 5' donor sites [Bezzi, M. et al, Genes Dev, 2013. 27(17): p. 1903-16].In addition to a role in splicing, PRMT5 influences key pathways involved in cell fate and homeostasis by direct methylation of key signalling nodules like p53 [Jansson, M. et al, Nat Cell Biol, 2008. 10(12): p. 1431-9], EGFR [Hsu, J.M. et al, Nat Cell Biol, 2011. 13(2): p. 174-81], CRAF [Andreu-Perez, P. et al, Sci Signal, 2011. 4(190): p. ra58], PI3K / AKT [Wei, T.Y. et al, Cell Signal, 2014. 26(12): p. 2940-50], NFKB [Wei, H. et al., Proc Natl Acad Sci U S A, 2013. 110(33): p. 13516-21].Since PRMT5 is one of the major sym-Arg methyltransferases and involved in a multitude of cellular processes, an increased protein expression appears to be an important factor in its tumourigenicity. Interestingly, the translation of PRMT5 in mantle cell lymphoma (MCL) seems to be regulated by miRNAs. Although MCL cells show less mRNA and a slower transcription rate of PRMT5 than normal B lymphocytes, the PRMT5 level and the methylation of H3R8 and H4R3 are significantly increased [Pal, S. et al, EMBO J, 2007. 26(15): p. 3558-69]. Re- expression of miRNAs that binds the 3'UTR region of PRMT5 decreases PRMT5 protein level [Wang, L. et al, Mol Cell Biol, 2008. 28(20): p. 6262-77]. Strikingly, a prmt5 antisense RNA has been found within the human prmt5 gene that supports the hypothesis of a specific translational regulation rather than high mRNA expression level [Stopa, N. et al, Cell Mol Life Sci, 2015. 72(11): p. 2041-59]. Although PRMT5 is considered as a clinical relevant target, very few selective PRMT5 inhibitors have been published, yet. Very recently, a novel sub-nanomolar potent PRMT5 inhibitor (EPZO 15666) with anti-tumour activity in multiple MCL xenograft models has been described to be the first chemical probe suitable for further validation of PRMT5 's biology and role in cancer [Chan-Penebre, E. et al, Nat Chem Biol, 2015. 11(6): p. 432-7].Further development of specific small molecule inhibitors of PRMT5 may lead to novel chemotherapeutic approaches for cancer.WO2014100695 A 1 discloses compounds useful for inhibiting PRMT5 activity;Methods of using the compounds for treating PRJV1T5 -mediated disorders are also described.WO2014100730A 1 discloses PRMT5 inhibitors containing a dihydro- ort etrah yd ro i soq u i no i i ne and uses thereof.Dcvkota, K. et al., ACS Med Chem Lett, 2014. 5: p. 293-297, describes the synthesis of a series of analogues of the natural product sinefungin and the ability of these analogues to inhibit EHMT1 and EHMT2.WO2003070739 discloses partial and full agonists of A 1 adenosine receptors, their preparation, and their therapeutic use.WO2012082436 discloses compounds and compositions as modulators of histone methyltransferases, and for treating diseases influenced by modulation of histone methyltransferase activity.WO2014 10071 9 discloses PR MT5 inhibitors and uses thereof.WO03074083 discloses combination therapies that selectively kill methylthioadenosine phosphorylase deficient cells. Analogs of MTA are described herein as anti-toxicity agents.Kung, P.-P. et al, Bioorg Med Chem Lett, 2005. 15: p. 2829-2833, describes the design, synthesis, and biological ev aluation of nov el human 5 '-deoxy-5 '- methylthioadenosine phosphorylase (MTAP) substrates.WO2012075500 discloses 7-deazapurine modulators of histone methyltransferase. WO2014035 140 discloses compounds and compositions for modulating histone methyltransferase activity.WQ201 5200680 describes PRMT5 inhibitors and uses thereof.There is thus a strong need for novel PRMT5 inhibitors thereby opening new avenues for the treatment or prevent ion of cancer, such as e.g. mantle cell lymphoma. It is accordingly an object of the present invention to provide such compounds. The compounds of the present invention are structurally different and may have improved properties such as for example improved potency, or improvedpharmacokinetics (PK) and oral bioavailability, compared with compounds disclosed in the prior art.Summary of the inventionIt has been found that the compounds of the present invention are useful as PRMT5 inhibitors. The compounds according to the invention and compositions thereof, may be useful for the treatment or prevention, in particular for the treatment, of diseases such as a blood disorder, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatit is, mult iorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection, lung injuries, and the like.The present invention concerns novel compounds of Formula (I):whereinR1 represents hydrogen or -C(=0)-Ci_4alkyl;R2 represents hydrogen or -C(=0)-Ci_4alkyl;Y represents -0-, -CH2- or -CF2-;Z represents -CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C≡C-;and when Y represents -CH2- or -CF2-, then Z can also represent -O- or -CR5aR5b-X-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5h each independently represent hydrogen or Ci_ 4alkyl;X represents -0-, -S-, or -NR11-;R11 represents hydrogen, Ci_4alkyl, or Ci_4alkyl substituted with one substituent selected from the group consisting of -OH, -0-Ci_4alkyl, R12, -NH2, -NH-Ci_4alkyl, and -N(C1_4alkyl)2;R12 represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom; said 4-, 5-, 6- or 7-membered heterocyclic ring being attached to the remainder of the molecule via a ring nitrogen atom; Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, -NHR10d, -NR10cR10d, cyano, -CF3, -C(=0)-NH2, -C(=0)- H-C alkyl,Ci_4alkyloxy, -C(=0)-0-Ci_4alkyl, C3_6cycloalkyl, -0-C3_6cycloalkyl, -NH-C3_6cycloalkyl, -N(C3_6cycloalkyl)2, C2_6alkenyl, Ci_4alkyl substituted with one Ci_ 4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b;R10a and R10b each independently represent hydrogen or Ci_4alkyl;R10c and R10d each independently represent C3_6cycloalkyl; R13; R14; C3_6Cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -0-Ci_4alkyl; Ci_4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -0-Ci_4alkyl; or Ci_4alkyl substituted with one substituent selected from the group consisting of C3_6Cycloalkyl, R13 and R14;R13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=0)p and N; or a 6- to 1 1- membered bicyclic fused aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=0)p and N;said 4- to 7-membered monocyclic aromatic ring or 6- to 1 1 -membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of Ci_4alkyl;p represents 1 or 2;R14 represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4) and (a-5):(a-2) (a-4)R3a, R3b, R3c, R3d and R3e each independently represent hydrogen, halo, -NR7aR7b, Ci_4alkyl, C2_4alkenyl, C3-6cycloalkyl, -OH, or -0-Ci_4alkyl;R7a represents hydrogen;R represents hydrogen, C3-6cycloalkyl, or Ci_4alkyl;R4a, R4b, R4c, R4d, R4e, R4f and R4g each independently represent hydrogen, halo, -NR8aR8b, or Ci_4alkyl;R8a and R8b each independently represent hydrogen or Ci_4alkyl;Q1 represents N or CR6a;Q2 represents N or CR6b;Q3 represents N or CR6c;Q4 represents N or CR6d;provided that maximum one of Q3 and Q4 represents N;Q8 represents N or CR6g;Q9 represents N or CR6h;Q10 represents N or CR6i;Q11 represents N or CR6j;Q5 represents CR3d; Q6 represents N; and Q7 represents CR4f; orQ5 represents CR3d; Q6 represents CR4e; and Q7 represents N; orQ5 represents N; Q6 represents CR4e; and Q7 represents CR4f; orQ5 represents N; Q6 represents CR4e; and Q7 represents N; orQ5 represents N; Q6 represents N; and Q7 represents CR4f; orQ5 represents N; Q6 represents N; and Q7 represents N;R6a, R6b, R6c, R6d, R6e, R6f, R6g, R6h, R6i and R6j each independently represent hydrogen, halogen, Ci_4alkyl, -NR9aR9b, or Ci_4alkyl substituted with one, two or three halo atoms;R9a and R9b each independently represent hydrogen or Ci_4alkyl; and pharmaceutically acceptable addition salts, and solvates thereof;prov ided that the following compounds, and pharmaceutically acceptable addition salts, and solvates thereof are excluded:The present invention also concerns methods for the preparation of compounds of the present invent ion and pharmaceutical compositions comprising them.The compounds of the present invention were found to inhibit PRMT5 per se or can undergo metabolism to a ( more) active form in vivo (prodrugs), and therefore may be useful in the treatment or prevention, in particular in the treatment, of diseases such as a blood disorder, metabol ic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerat i ve diseases, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection, lung injuries, and the like.In view of the aforement ioned pharmacology of the compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, it follows that they may be suitable for use as a medicament.In particular the compounds of Formula ( I ) and pharmaceutical ly acceptable addition salts, and solvates thereof, may be suitable in the treatment or prevention, in particular in the treatment, of any one of the diseases or conditions mentioned hereinbefore or hereinafter, in particular cancer.The present invent ion also concerns the use of compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for the manufacture of a medicament for the inhibition of PRMT5, for the treatment or prevention of any one of the diseases or conditions mentioned hereinbefore or hereinafter, in particular cancer.The present invention will now be further described. In the following passages, di fferent aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined w ith any other feature or features indicated as being preferred oradvantageous.Detailed descript ionWhen describing the compounds of the invention, the terms used are to be construed in accordance with the follow ing definitions, unless a context dictates otherw ise.When any variable occurs more than one time in any constituent or in any formula ( e.g. Formula (I)), its definition in each occurence is independent of its definition at every other occurrence.Whenever the term "substituted" is used in the present invention, it is meant, unless otherwise is indicated or is clear from the context, to indicate that one or more hydrogens, in particular from 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using"substituted" are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the subst itution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.When two or more substituents are present on a moiety they may, unless otherwise is indicated or is clear from the context, replace hydrogens on the same atom or they may replace hydrogen atoms on different atoms in the moiety.The prefix "Cx_y" (where x and y are integers) as used herein refers to the number of carbon atoms in a given group. Thus, a Chalky I group contains from 1 to 4 carbon atoms, a Chal ky! group contains from 1 to 3 carbon atoms and so on.The term "halo" as a group or part of a group is generic for fluoro, chloro, bromo, iodo unless otherwise is indicated or is clear from the context.The term "C ialkyl" as a group or part of a group refers to a hydrocarbyl radical of Formula CnH.->„. i wherein n is a number ranging from 1 to 4. Ci_4alkyi groups comprise from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. Chalky! groups may be linear or branched and may be substituted as indicated herein. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. Ci_4alkyl includes al l linear, or branched alkyl groups with between 1 and 4 carbon atoms, and thus includes methyl, ethyl, «-propyl, / -propyl, 2-methyl-ethyl, butyl and its isomers (e.g. n-butyl, / .wbutyl and / v / Y-butyl ), and the like.The skilled person will realize that the term 'Ci_4alkoxy' or 'Ci_4alkyloxy' as a group or part of a group refers to a radical having the Formula -ORc wherein Rc is Ci_4alkyl. Non-limiting examples of suitable Ci_4alkyloxy include methyloxy (also methoxy), ethyloxy (also ethoxy), propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy and / er / -butyloxy.The term "C2-4alkenyl" as used herein as a group or part of a group represents a straight or branched chain hydrocarbon group containing from 2 to 4 carbon atoms and containing a carbon carbon double bond such as, but not limited to, ethenyl, propenyl, butenyl, l-propen-2-yl, and the like.The term "C2-6alkenyl" as used herein as a group or part of a group represents a straight or branched chain hydrocarbon group containing from 2 to 6 carbon atoms and containing a carbon carbon double bond such as, but not limited to, ethenyl, propenyl, butenyl, pentenyl, l-propen-2-yl, hexenyl and the like.The term 'C^.cycloalkyl ' as used herein as a group or part of a group represents cyclic saturated hydrocarbon radicals hav ing from 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.In case Z is -X-CR5aR5b-, it is intended that X is attached to Ar.In case Z is -CR5c=CR5d-, it is intended that the C-atom with the R5c substituent is attached to Ar.In case Z is -CR5eR5g-CR5fR5h-, it is intended that the C-atom with the R5e and R5g substituents is attached to Ar.In case Z is -CR5aR5b-X-, it is intended that the C-atom with the R5a and R5bsubstituents is attached to Ar.The skilled person will realize that the 4-, 5-, 6- or 7-membered heterocyclic ring being attached to the remainder of the molecule via a ring nitrogen atom (in the definition of R 1 ) particularly is a saturated ring. Non-limiting examples of R 1 are l -piperidinyl, 1 - pyrrolidinyl, 1 -morpholinyl, 1 -azetidinyl, and the like.It will be clear for the skilled person that, unless otherwise is indicated or is clear from the context, a substituent on a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms (as in the definition of R13) (non-limiting examples are pyrrolyl, pyridinyl, furanyl, and the like), may replace any hydrogen atom on a ring carbon atom or where possible on a ring nitrogen atom (in which case a hydrogen on a nitrogen atom may be replaced by a substituent). It will be clear for the skilled person that the same is applicable to the 6- to 11-membered bicyclic fused aromatic ring containing one, two or three heteroatoms (as in the definition of R13) (non- limiting examples are indolyl, quinolinyl, and the like).A 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms (as in the definition of R13), may be attached to the remainder of the molecule of Formula ( I ) through any available ring carbon or nitrogen atom as appropriate, if not otherwise specified. It will be clear for the skilled person that the same is applicable to the 6- to 11-membered bicyclic fused aromatic ring containing one, two or three heteroatoms (as in the definition of R13).In case a nitrogen atom replaces one of the two fused carbon atoms in the Ar group, a carbonyl group is present in said bicyclic aromatic ring system as exemplified by the structure shown below:which is optionally substituted according to any of the embodiments. It will be clear this example is non-limiting.Other, non- limiting, examples of the Ar group being a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom, are shown below:each of which are optionally substituted according to any of the embodiments. The skilled person will understand that the 10 members of the 10-membered Ar group (the 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom), are 10 carbon atoms, 9 carbon atoms and 1 nitrogen atom, or 8 carbon atoms and 2 nitrogen atoms. Ar is optionally substituted according to any of the embodiments.Whenever substituents are represented by chemical structure, "— " represents the bond of attachment to the remainder of the molecule of Formula (I). Lines drawn from substituents into ring systems indicate that the bond may be attached to any of the suitable ring atoms.For exam le covers any one of the following ring systems:is an alternative representation forThe term "subject" as used herein, refers to an animal, preferably a mammal (e.g. cat, dog, primate or human), more preferably a human, who is or has been the object of treatment, observation or experiment.The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medicinal doctor or other clinician, which includes alleviation or reversal of the symptoms of the disease or disorder being treated.The term "composit ion" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the speci ied amounts. The term "treatment", as used herein, is intended to refer to all processes wherein there may be a slowing, interrupting, arresting or stopping of the progression of a disease, but does not necessarily indicate a total elimination of all symptoms.The term "compounds of the (present ) invent ion" as used herein, is meant to include the compounds of Formula ( I ) and pharmaceutically acceptable addit ion salts, and solvates thereof.Some of the compounds of Formula ( I ) may also exist in their tautomeric form. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerisations. Valence tautomers include interconversions by reorganisation of some of the bonding electrons.Such forms in so far as they may exist, although not explicitly indicated in the above Formula ( I ), are intended to be included within the scope of the present invention. As used herein, any chemical formula with bonds shown only as solid lines and not as solid wedged or hashed wedged bonds, or otherwise indicated as having a particular configuration (e.g. R, S) around one or more atoms, contemplates each possible stereoisomer, or mixture of two or more stereoisomers. Where the stereochemistry of any particular chiral atom is not specified in the structures shown herein, then all stereoisomers are contemplated and included as the compounds of the invention, either as a pure stereoisomer or as a mixture of two or more stereoisomers.Hereinbefore and hereinafter, the term "compound of Formula (I)" is meant to include the stereoisomers thereof and the tautomeric forms thereof. Howev er wherestereochemistry, as mentioned in the previous paragraph, is specified by bonds which are shown as solid wedged or hashed wedged bonds, or are otherw ise indicated as hav ing a particular configuration (e.g. R, S), then that stereoisomer is so specified and defined. It will be clear this also applies to subgroups of Formula (I).It follows that a single compound may, where possible, exist in both stereoisomeric and tautomeric form.The terms "stereoisomers", "stereoisomeric forms" or "stereochemically isomeric forms" hereinbefore or hereinafter are used interchangeably.Enantiomers are stereoisomers that are non-su peri m posab 1 e mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a racematc or racemic mixture.Atropisomers (or atropoisomers) are stereoisomers which hav e a particular spatial configuration, resulting from a restricted rotation about a single bond, due to large steric hindrance. All atropisomeric forms of the compounds of Formula ( I ) are intended to be included within the scope of the present invention.Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configurat ion. Substituents on bivalent cyclic (partially ) saturated radicals may have either the cis- or trans-configuration; for example if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration. Therefore, the invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.The meaning of all those terms, i.e. enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof are known to the skilled person.The absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is specified by either R or S. Resolved stereoisomers whose absolute configuration is not known can be designated by (+) or (-) depending on the di ection in which they rotate plane polarized light. For instance, resolved enantiomers whose absolute configuration is not known can be designated by (+) or (-) depending on the di ect ion in which they rotate plane polarized light.When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other stereoisomers. Thus, when a compound of Formula (I) is for instance specified as (R), this means that the compound is substantially free of the (S) isomer; when a compound of Formula (I) is for instance specified as E, this means that the compound is substantially free of the Z isomer; when a compound of Formula ( I ) is for instance specified as cis, this means that the compound is substantially free of the trans isomer.For therapeutic use, salts of the compounds of Formula ( I ) and solvates thereof, are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutical ly acceptable may also f nd use, fo example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention. Pharmaceutically-acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.The pharmaceutically acceptable addition salts as mentioned hereinabove or hereinafter are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of Formula (I) and solvates thereof, are able to form.Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic ( i.e. ethanedioic ), ma Ionic, succinic ( i.e. butanedioic acid ), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p- toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.The compounds of Formula ( I ) and solv ates thereof containing an acidic proton may also be conv erted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamide, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinol ine; the benzathine, -methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conv ersely the salt form can be converted by treatment with acid into the free acid form.For the purposes of this inv ention prodrugs are also included within the scope of the invent ion.The term "prodrug" of a relevant compound of the inv ention includes any compound that, following oral or parenteral administration, in particular oral administration, is metabolised in vivo to a form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four t imes daily)). For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration, in particular intravenous ( IV ), intramuscular (IM), and subcutaneous (SC) injection.Prodrugs may be prepared by modifying funct ional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typical ly are achieved by synthesising the parent compound w ith a prodrug substituent. In general, prodrugs include compounds of the invention wherein a hydroxyl, amino, sulfliydryl, carboxy or carbonyl group in a compound of the invention is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfliydryl, carboxy or carbonyl group, respectively; in particular w herein a hydroxyl group in a compound of the invent ion is bonded to any group (e.g. - C( =0 )-C i _ja Iky 1 ) that may be cleaved in vivo to regenerate the free hydroxyl. Within the context of this invent ion, prodrugs in particular are compounds of Formula ( I ) or subgroups thereof wherein R1 and or R representExamples of prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxy! functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs" p. 1-92, Elesev ier, New York-Oxford (1985).The term solvate comprises the hydrates and solvent addition forms which the compounds of Formula ( I ) are able to form, as wel l as pharmaceutically acceptable addition salts thereof. Examples of such forms are e.g. hydrates, alcoholates and the like.The compounds of the invent ion as prepared in the processes described below may be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enant iomers, that can be separated from one another following art-known resolution procedures. A manner of separating the enantiomeric forms of the compounds of Formula (I), and pharmaceut ical ly acceptable addit ion salts, and solvates thereof, involves liquid chromatography using a chiral stationary phase. Said purestereochemicaliy isomeric forms may also be derived from the corresponding pure stereochemicaliy isomeric forms of the appropriate starting materials, prov ided that the reaction occurs stereospecifical ly. Preferably if a specific stereoisomer is desired, said compound would be synthesized by stereospecific methods of preparation. These methods will advantageously employ enant iomerically pure starting materials. The present invention also embraces isotopically- labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature).All isotopes and isotopic mixtures of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. Exemplary isotopes that can be incorporated into compounds of the invent ion include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2H, 3H, "C, 'Τ, 14C , 13N, i50, 170, 180, 32P, 33P, 35S, 18F, 36Ci, mI, 123I, 1251, 1311, 75 Br, 76Br, 77Br and 82Br. Preferably, the radioactive isotope is selected from the group of 2H, 3H, 1 1 C and 18F. More preferably, the radioactive isotope is H. In particular, deuterated compounds are intended to be included within the scope of the present inv ention.Certain i so top i call y- 1 abel ed compounds of the present invention (e.g., those labeled with 3H and 14C) are useful in compound and for substrate tissue distribution assays. Tritiated (3H) and carbon-14 (14C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half- life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as 150, 13N, nC and 18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.In all embodiments below, the following compounds, and pharmaceutically acceptable addition salts, and solv ates thereof are excluded:In an embodiment, the present invention concerns novel compounds of Formula ( I ), whereinR1 represents hydrogen orR2 represents hydrogen orY represents -0-, -CH2- or -CF2-;Z represents -CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C≡C-;and when Y represents -CH2- or -CF2-, then Z can also represent -O- or -CR5aR5b-X-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5h each independently represent hydrogen or Ci_ 4alkyl;X represents -0-, -S-, or -NR1 1-;R1 1 represents hydrogen or Ci_4alkyl;Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, -NHR10d, -NR10cR10d, cyano, -CF3, -C(=0)-NH2, -C(=0)- H-C alkyl,Ci_4alkyloxy, -C(=0)-0-Ci_4alkyl, C3_6cycloalkyl, -0-C3_6cycloalkyl, -NH-C3_6cycloalkyl, -N(C3_6cycloalkyl)2, C2_6alkenyl, Ci_4alkyl substituted with one Ci_ 4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b;R10a and R10b each independently represent hydrogen or Ci_4alkyl;R10c and R10d each independently represent C3_6cycloalkyl; R14; C3_6Cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -0-Ci_4alkyl; Ci_4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -0-Ci_4alkyl; or Ci_4alkyl substituted with one substituent selected from the group consisting of C3_6Cycloalkyl, and R14;R14 represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4) and (a-5):(a-2) (a-4)R3a, R3b, R3c, R3d and R3e each independently represent hydrogen, halo, -NR7aR7b, Ci_4alkyl, C2_4alkenyl, C3-6cycloalkyl, -OH, or -0-Ci_4alkyl;R7a represents hydrogen;R represents hydrogen, C3-6cycloalkyl, or Ci_4alkyl;R4a, R4b, R4c, R4d, R4e, R4f and R4g each independently represent hydrogen, halo, -NR8aR8b, or Ci_4alkyl;R8a and R8b each independently represent hydrogen or Ci_4alkyl;Q1 represents N or CR6a;Q2 represents N or CR6b;Q3 represents N or CR6c;Q4 represents N or CR6d;provided that maximum one of Q3 and Q4 represents N;Q8 represents N or CR6g;Q9 represents N or CR6h;Q10 represents N or CR6i;Q11 represents N or CR6j;Q5 represents CR3d; Q6 represents N; and Q7 represents CR4f; orQ5 represents CR3d; Q6 represents CR4e; and Q7 represents N; orQ5 represents N; Q6 represents CR4e; and Q7 represents CR4f; orQ5 represents N; Q6 represents CR4e; and Q7 represents N; orQ5 represents N; Q6 represents N; and Q7 represents CR4f; orQ5 represents N; Q6 represents N; and Q7 represents N;R6a, R6b, R6c, R6d, R6e, R6f, R6g, R6h, R6i and R6j each independently represent hydrogen, halogen, Ci_4alkyl, -NR9aR9b, or Ci_4alkyl substituted with one, two or three halo atoms;R9a and R9b each independently represent hydrogen or Ci_4alkyl; and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula ( I ), whereinR1 represents hydrogen orR2 represents hydrogen orY represents -0-, -CH2- or -CF2-;Z represents -CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C≡C-;and when Y represents -CH2- or -CF2-, then Z can also represent -O- or -CR5aR5b-X-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5h each independently represent hydrogen or Ci_ 4alkyl;X represents -0-, -S-, or -NR11-;R11 represents hydrogen, Ci_4alkyl, or Ci_4alkyl substituted with one substituent selected from the group consisting of -OH, -0-Ci_4alkyl, R12, -NH2, -NH-Ci_4alkyl, and -N(Ci_4alkyl)2;R12 represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom; said 4-, 5-, 6- or 7-membered heterocyclic ring being attached to the remainder of the molecule via a ring nitrogen atom;Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, -NHR10d, -NR10cR10d, cyano, -CF3, -C(=0)-NH2, -C(=0)-NH-Ci_4alkyl,-C(=0)-Ci_4alkyl, Ci_4alkyloxy, -C(=0)-0-Ci_4alkyl, C3_6cycloalkyl, -0-C3_6cycloalkyl, -NH-C3_6cycloalkyl, -N(C3_6cycloalkyl)2, C2_6alkenyl, Ci_4alkyl substituted with one Ci_ 4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b;R10a and R10b each independently represent hydrogen or Ci_4alkyl;R10c and R10d each independently represent C3_6cycloalkyl; R13; R14; C3_6Cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -0-Ci_4alkyl; Ci_4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -0-Ci_4alkyl; or Ci_4alkyl substituted with one substituent selected from the group consisting of C3_6Cycloalkyl, R13 and R14; R13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=0)p and N; or a 6- to 11- membered bicyclic fused aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=0)p and N;said 4- to 7-membered monocyclic aromatic ring or 6- to 11-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of Ci_4alkyl;p represents 1 or 2;R14 represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4) and (a-5):(a-2) (a-4)R3a, R3b, R3c, R3d and R3e each independently represent hydrogen, halo, -NR7aR7b, Ci_4alkyl, C2_4alkenyl, C3-6cycloalkyl, -OH, or -0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen, C3-6cycloalkyl, or Ci_4alkyl;R4a, R4b, R4c, R4d, R4e, R4f and R4g each independently represent hydrogen, halo,-NR8aR8b, or Ci_4alkyl;R8a and R8b each independently represent hydrogen or Ci_4alkyl;Q1 represents CR6a;Q2 represents CR6b;Q3 represents N or CR6c;Q4 represents N or CR6d;provided that maximum one of Q3 and Q4 represents N;Q8 represents N or CR6g;Q9 represents N or CR6h; Q10 represents N or CR6i;Q11 represents N or CR6j;Q5 represents CR3d; Q6 represents N; and Q7 represents CR4f; orQ5 represents CR3d; Q6 represents CR4e; and Q7 represents N; orQ5 represents N; Q6 represents CR4e; and Q7 represents CR4f; orQ5 represents N; Q6 represents CR4e; and Q7 represents N; orQ5 represents N; Q6 represents N; and Q7 represents CR4f; orQ5 represents N; Q6 represents N; and Q7 represents N;R6a, R6b, R6c, R6d, R6e, R6f, R6g, R6h, R6i and R6j each independently represent hydrogen, halogen, Ci_4alkyl, -NR9aR9b, or Ci_4alkyl substituted with one, two or three halo atoms;R9a and R9b each independently represent hydrogen or Ci_4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof. In an embodiment, the present invention concerns novel compounds of Formula ( I ). whereinR1 represents hydrogen or -C(=0)-Ci_4alkyl;R2 represents hydrogen or -C(=0)-Ci_4alkyl;Y represents -0-, -CH2- or -CF2-;Z represents -CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C≡C-;and when Y represents -CH2- or -CF2-, then Z can also represent -O- or -CR5aR5b-X-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5h each independently represent hydrogen or Ci_ 4alkyl;X represents -0-, -S-, or -NR11-;R11 represents hydrogen, Ci_4alkyl, or Ci_4alkyl substituted with one substituent selected from the group consisting of -OH, -0-Ci_4alkyl, R12, -NH2, -NH-Ci_4alkyl, and -N(C1_4alkyl)2;R12 represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom; said 4-, 5-, 6- or 7-membered heterocyclic ring being attached to the remainder of the molecule via a ring nitrogen atom;Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, -NHR10d, -NR10cR10d, cyano, -CF3, -C(=0)-NH2, -C(=0)- H-C alkyl, -C(=0)-Ci_ 4alkyl, Ci_4alkyloxy, C3_6Cycloalkyl, C2_6alkenyl, Ci_4alkyl substituted with one Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b.R10a and R10b each independently represent hydrogen or Ci_4alkyl;R10c and R10d each independently represent C3_6cycloalkyl; C3_6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -0-Ci_4alkyl; Ci_4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and - 0-Ci_4alkyl; or Ci_4alkyl substituted with one substituent selected from the group consisting of C3_6Cycloalkyl, R13 and R14;R13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=0)p and N; or a 6- to 1 1- membered bicyclic fused aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=0)p and N;said 4- to 7-membered monocyclic aromatic ring or 6- to 1 1-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of Ci_4alkyl;p represents 1 or 2;R14 represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3):R3a, R3b and R3c each independently represent hydrogen, halo, -NR7aR7b, Ci_4alkyl, or -0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen or Ci_4alkyl; R4a, R4b and R4c each independently represent hydrogen, halo, -NR8aR8b, or Ci_4alkyl; R8a and R8b each independently represent hydrogen or Ci_4alkyl;Q1 represents N or CR6a;Q2 represents N or CR6b;Q3 represents N or CR6c;Q4 represents N or CR6d;provided that maximum one of Q3 and Q4 represents N;R6a, R6b, R6c, R6d, R6e and R6f each independently represent hydrogen, halogen, Ci_4alkyl, -NR9aR9b, or Ci_4alkyl substituted with one, two or three halo atoms;R9a and R9b each independently represent hydrogen or Ci_4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula ( I ). whereinR1 represents hydrogen or -C(=0)-Ci_4alkyl;R2 represents hydrogen or -C(=0)-Ci_4alkyl;Y represents -0-, -CH2- or -CF2-;Z represents -CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C≡C-;and when Y represents -CH2- or -CF2-, then Z can also represent -O- or -CR5aR5b-X-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5h each independently represent hydrogen or Ci_ 4alkyl;X represents -0-, -S-, or -NR11-;R11 represents hydrogen, Ci_4alkyl, or Ci_4alkyl substituted with one substituent selected from the group consisting of -OH, -0-Ci_4alkyl, R12, -NH2, -NH-Ci_4alkyl, and -N(Ci_4alkyl)2;R12 represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom; said 4-, 5-, 6- or 7-membered heterocyclic ring being attached to the remainder of the molecule via a ring nitrogen atom;Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, cyano, -CF3, -C(=0)-NH-Ci_4alkyl, -C(=0)-Ci_4alkyl, Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b;R10a and R10b each independently represent hydrogen or Ci_4alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3):R3a, R3b and R3c each independently represent hydrogen, halo, -NR7aR7b, or-0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen or Ci_4alkyl;R4a, R4b and R4c each independently represent hydrogen, halo, -NR8aR8b, or Ci_4alkyl; R8a and R8b each independently represent hydrogen or Ci_4alkyl;Q1 represents N or CR6a;Q2 represents N or CR6b;Q3 represents N or CR6c;Q4 represents N or CR6d;provided that maximum one of Q3 and Q4 represents N;R6a, R6b, R6c, R6d, R6e and R6f each independently represent hydrogen, halogen, Ci_ 4alkyl, -NR9aR9b, or Ci_4alkyl substituted with one, two or three halo atoms;R9a and R9b each independently represent hydrogen or Ci_4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof. In an embodiment, the present invention concerns novel compounds of Formula (I), whereinR1 represents hydrogen or -C(=0)-Ci_4alkyl;R2 represents hydrogen or -C(=0)-Ci_4alkyl;Y represents -0-, -CH2- or -CF2-;Z represents -CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C≡C-;and when Y represents -CH2- or -CF2-, then Z can also represent -O- or -CR5aR5b-X-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5h each independently represent hydrogen or Ci_ 4alkyl;X represents -0-, -S-, or -NR11-; R1 1 represents hydrogen, Ci_4alkyl, or Ci_4alkyl substituted with one substituent selected from the group consisting of -OH, -0-Ci_4alkyl, R12, -NH2, -NH-Ci_4alkyl, and -N(C1_4alkyl)2;R12 represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom; said 4-, 5-, 6- or 7-membered heterocyclic ring being attached to the remainder of the molecule via a ring nitrogen atom;Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,wherein at least 1 ring carbon atom of ring B is replaced by a nitrogen atom;wherein optionally 1 additional ring carbon atom of ring A or ring B is replaced by a nitrogen atom; provided that when a nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, -NHR10d, -NR10cR10d, cyano, -CF3, -C(=0)-NH2, -C(=0)-NH-Ci_4alkyl,-C(=0)-Ci_4alkyl, Ci_4alkyloxy, -C(=0)-0-Ci_4alkyl, C3_6cycloalkyl, -0-C3_6cycloalkyl, -NH-C3_6cycloalkyl, -N(C3_6cycloalkyl)2, C2_6alkenyl, Ci_4alkyl substituted with one Ci_ 4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b;R10a and R10b each independently represent hydrogen or Ci_4alkyl;R10c and R10d each independently represent C3_6cycloalkyl; R13; R14; C3_6Cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -0-Ci_4alkyl; Ci_4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -0-Ci_4alkyl; or Ci_4alkyl substituted with one substituent selected from the group consisting of C3_6Cycloalkyl, R13 and R14;R13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=0)p and N; or a 6- to 1 1- membered bicyclic fused aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=0)p and N;said 4- to 7-membered monocyclic aromatic ring or 6- to 1 1-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of Ci_4alkyl;p represents 1 or 2; R14 represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4) and (a-5):(a-2) (a-4)R3a, R3b, R3c, R3d and R3e each independently represent hydrogen, halo, -NR7aR7b, Ci_4alkyl, C2_4alkenyl, C3-6cycloalkyl, -OH, or -0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen, C3-6cycloalkyl, or Ci_4alkyl;R4a, R4b, R4c, R4d, R4e, R4f and R4g each independently represent hydrogen, halo, -NR8aR8b, or Ci_4alkyl;R8a and R8b each independently represent hydrogen or Ci_4alkyl;Q1 represents N or CR6a;Q2 represents N or CR6b;Q3 represents N or CR6c;Q4 represents N or CR6d;provided that maximum one of Q3 and Q4 represents N;Q8 represents N or CR6g;Q9 represents N or CR6h;Q10 represents N or CR6i;Q11 represents N or CR6j;Q5 represents CR3d; Q6 represents N; and Q7 represents CR4f; orQ5 represents CR3d; Q6 represents CR4e; and Q7 represents N; orQ5 represents N; Q6 represents CR4e; and Q7 represents CR4f; orQ5 represents N; Q6 represents CR4e; and Q7 represents N; orQ5 represents N; Q6 represents N; and Q7 represents CR4f; orQ5 represents N; Q6 represents N; and Q7 represents N; R6a, R6b, R6c, R6d, R6e, R6f, R6g, R6h, R6i and R6j each independently represent hydrogen, halogen, Ci_4alkyl, -NR9aR9b, or Ci_4alkyl substituted with one, two or three halo atoms;R9a and R9b each independently represent hydrogen or Ci_4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula ( I ). whereinR1 represents hydrogen;R2 represents hydrogen;Y represents -0-, -CH2- or -CF2-;Z represents -CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C≡C-;and when Y represents -CH2- or -CF2-, then Z can also represent -O- or -CR5aR5b-X-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5h each independently represent hydrogen or Ci_ 4alkyl;X represents -0-, -S-, or -NR11-;R11 represents hydrogen, Ci_4alkyl, or Ci_4alkyl substituted with one substituent selected from the group consisting of -OH, -0-Ci_4alkyl, R12, -NH2, -NH-Ci_4alkyl, and -N(d_4alkyl)2;R12 represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom; said 4-, 5-, 6- or 7-membered heterocyclic ring being attached to the remainder of the molecule via a ring nitrogen atom;Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, -NHR10d, -NR10cR10d, cyano, -CF3, -C(=0)-NH2, -C(=0)-NH-Ci_4alkyl,-C(=0)-Ci_4alkyl, Ci_4alkyloxy, -C(=0)-0-Ci_4alkyl, C3_6cycloalkyl, -0-C3_6cycloalkyl, -NH-C3_6cycloalkyl, -N(C3_6cycloalkyl)2, C2_6alkenyl, Ci_4alkyl substituted with one Ci_ 4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b;R10a and R10b each independently represent hydrogen or Ci_4alkyl;R10c and R10d each independently represent C3_6cycloalkyl; R13; R14; C3_6Cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -0-Ci_4alkyl; Ci_4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -0-Ci_4alkyl; or Ci_4alkyl substituted with one substituent selected from the group consisting of C3_6cycloalkyl, R13 and R14;R13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=0)p and N; or a 6- to 1 1- membered bicyclic fused aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=0)p and N;said 4- to 7-membered monocyclic aromatic ring or 6- to 1 1 -membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of Ci_4alkyl;p represents 1 or 2;R14 represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4) and (a-5):(a-2) (a-4)R3a, R3b, R3c, R3d and R3e each independently represent hydrogen, halo, -NR7aR7b, Ci_4alkyl, C2_4alkenyl, C3-6cycloalkyl, -OH, or -0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen, C3-6cycloalkyl, or Ci_4alkyl;R4a, R4b, R4c, R4d, R4e, R4f and R4g each independently represent hydrogen, halo, -NR8aR8b, or Ci_4alkyl;R8a and R8b each independently represent hydrogen or Ci_4alkyl;Q1 represents N or CR6a;Q2 represents N or CR6b;Q3 represents N or CR6c;Q4 represents N or CR6d;provided that maximum one of Q3 and Q4 represents N; Q8 represents N or CR6g;Q9 represents N or CR6h;Q10 represents N or CR6i;Q11 represents N or CR6j;Q5 represents CR3d; Q6 represents N; and Q7 represents CR4f; orQ5 represents CR3d; Q6 represents CR4e; and Q7 represents N; orQ5 represents N; Q6 represents CR4e; and Q7 represents CR4f; orQ5 represents N; Q6 represents CR4e; and Q7 represents N; orQ5 represents N; Q6 represents N; and Q7 represents CR4f; orQ5 represents N; Q6 represents N; and Q7 represents N;R6a, R6b, R6c, R6d, R6e, R6f, R6g, R6h, R6i and R6j each independently represent hydrogen, halogen, Ci_4alkyl, -NR9aR9b, or Ci_4alkyl substituted with one, two or three halo atoms;R9a and R9b each independently represent hydrogen or Ci_4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula ( I ). whereinR1 represents hydrogen;R2 represents hydrogen;Y represents -0-, -CH2- or -CF2-;Z represents -CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C≡C-;and when Y represents -CH2- or -CF2-, then Z can also represent -O- or -CR5aR5b-X-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5h each independently represent hydrogen or Ci_ 4alkyl;X represents -0-, -S-, or -NR11-;R11 represents hydrogen, Ci_4alkyl, or Ci_4alkyl substituted with one substituent selected from the group consisting of -OH, -0-Ci_4alkyl, R12, -NH2, -NH-Ci_4alkyl, and -N(d_4alkyl)2;R12 represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom; said 4-, 5-, 6- or 7-membered heterocyclic ring being attached to the remainder of the molecule via a ring nitrogen atom;Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system; Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=0)-NH-Ci_4alkyl, -C(=0)-Ci_4alkyl, Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b;R10a and R10b each independently represent hydrogen or Ci_4alkyl;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3);R3a, R3b and R3c each independently represent hydrogen, halo, -NR7aR7b, or-0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen or Ci_4alkyl;R4a, R4b and R4c each independently represent hydrogen, halo, -NR8aR8b, or Ci_4alkyl; R8a and R8b each independently represent hydrogen or Ci_4alkyl;Q1 represents N or CR6a;Q2 represents N or CR6b;Q3 represents N or CR6c;Q4 represents N or CR6d;provided that maximum one of Q3 and Q4 represents N;R6a, R6b, R6c, R6d, R6e and R6f each independently represent hydrogen, halogen, Ci_ 4alkyl, -NR9aR9b, or Ci_4alkyl substituted with one, two or three halo atoms;R9a and R9b each independently represent hydrogen or Ci_4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula ( I ). whereinR1 represents hydrogen or -C(=0)-Ci_4alkyl;R2 represents hydrogen or -C(=0)-Ci_4alkyl;Y represents -0-, -CH2- or -CF2-;Z represents -CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C≡C-;and when Y represents -CH2- or -CF2-, then Z can also represent -O- or -CR5aR5b-X-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5h each independently represent hydrogen or Ci_ 4alkyl;X represents -0-, -S-, or -NR11-;R11 represents hydrogen, Ci_4alkyl, or Ci_4alkyl substituted with one substituent selected from the group consisting of -OH, -0-Ci_4alkyl, R12, -NH2, -NH-Ci_4alkyl, and -N(d_4alkyl)2; R12 represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom; said 4-, 5-, 6- or 7-membered heterocyclic ring being attached to the remainder of the molecule via a ring nitrogen atom;Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, -NHR10d, -NR10cR10d, cyano, -CF3, -C(=0)-NH2, -C(=0)- H-C alkyl,Ci_4alkyloxy, -C(=0)-0-Ci_4alkyl, C3_6cycloalkyl, -0-C3_6cycloalkyl, -NH-C3_6cycloalkyl, -N(C3_6cycloalkyl)2, C2_6alkenyl, Ci_4alkyl substituted with one Ci_ 4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b;R10a and R10b each independently represent hydrogen or Ci_4alkyl;R10c and R10d each independently represent C3_6cycloalkyl; R13; R14; C3_6Cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -0-Ci_4alkyl; Ci_4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -0-Ci_4alkyl; or Ci_4alkyl substituted with one substituent selected from the group consisting of C3_6Cycloalkyl, R13 and R14;R13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=0)p and N; or a 6- to 1 1- membered bicyclic fused aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=0)p and N;said 4- to 7-membered monocyclic aromatic ring or 6- to 1 1-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of Ci_4alkyl;p represents 1 or 2;R14 represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);R3a represents hydrogen, halo, -NR7aR7b, Ci_4alkyl, C2_4alkenyl, C3_6cycloalkyl, -OH, or -0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen, C3_6cycloalkyl, or Ci_4alkyl; R4a represents hydrogen, halo, -NR8aR8b, or Ci_4alkyl;R8a and R8b each independently represent hydrogen or Ci_4alkyl;Q1 represents N or CR6a;Q2 represents N or CR6b;in particular Q1 and Q2 represent CH;R6a and R6b, each independently represent hydrogen, halogen, Ci_4alkyl, -NR9aR9b, orCi_4alkyl substituted with one, two or three halo atoms;R9a and R9b each independently represent hydrogen or Ci_4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula (I), whereinR1 represents hydrogen or -C(=0)-Ci_4alkyl;R2 represents hydrogen or -C(=0)-Ci_4alkyl;Y represents -0-, -CH2- or -CF2-;Z represents -CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C≡C-;and when Y represents -CH2- or -CF2-, then Z can also represent -O- or -CR5aR5b-X-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5h each independently represent hydrogen or Ci_ 4alkyl;X represents -0-, -S-, or -NR11-;R11 represents hydrogen, Ci_4alkyl, or Ci_4alkyl substituted with one substituent selected from the group consisting of -OH, -0-Ci_4alkyl, R12, -NH2, -NH-Ci_4alkyl, and -N(d_4alkyl)2;R12 represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom; said 4-, 5-, 6- or 7-membered heterocyclic ring being attached to the remainder of the molecule via a ring nitrogen atom;Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, cyano, -CF3, -C(=0)-NH-Ci_4alkyl, -C(=0)-Ci_4alkyl, Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b;R10a and R10b each independently represent hydrogen or Ci_4alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);R3a represents hydrogen, halo, -NR7aR7b, or -0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen or Ci_4alkyl;R4a represents hydrogen, halo, -NR8aR8b, or Ci_4alkyl;R8a and R8b each independently represent hydrogen or Ci_4alkyl;Q1 represents N or CR6a;Q2 represents N or CR6b;in particular Q1 and Q2 represent CH;R6a and R6b each independently represent hydrogen, halogen, Ci_4alkyl, -NR9aR9b, orCi_4alkyl substituted with one, two or three halo atoms;R9a and R9b each independently represent hydrogen or Ci_4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula ( I ). whereinR1 represents hydrogen or -C(=0)-Ci_4alkyl;R2 represents hydrogen or -C(=0)-Ci_4alkyl;Y represents -O- or -CH2-;Z represents -CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C≡C-;and when Y represents -CH2-, then Z can also represent -CR5aR5b-X-;R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5h each independently represent hydrogen or Ci_ 4alkyl;X represents -0-, -S-, or -NR11-;R11 represents hydrogen or Ci_4alkyl;Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, -NHR10d, cyano, -CF3, -C(=0)-NH2, -C(=0)-NH-Ci_4alkyl, Ci_4alkyloxy, -C(=0)-0-Ci_ 4alkyl, C3_6cycloalkyl, C2_6alkenyl, Ci_4alkyl substituted with one Ci_4alkyloxy, and Ci_ 4alkyl optionally substituted with one -NR10aR10b;R10a and R10b represent Ci_4alkyl; R10d represents C3_6cycloalkyl; R14; Ci_4alkyl substituted with one, two or three halo substituents; or Ci_4alkyl substituted with one substituent selected from the group consisting of C3_6cycloalkyl, and R14;R14 represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-4);R3a, R3b, R3c and R3d each independently represent hydrogen, halo, -NR7aR7b, C2-4alkenyl, C3-6cycloalkyl, -OH, or -0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen, C3-6cycloalkyl, or Ci_4alkyl;R4a, R4b, R4c, R4d, R4e and R4f each independently represent hydrogen, halo,-NR8aR8b, or Ci_4alkyl;R8a and R8b each independently represent hydrogen;Q1 represents CR6a;Q2 represents CR6b;Q8 represents CR6g;Q9 represents CR6h;Q5 represents CR3d; Q6 represents N; and Q7 represents CR4f; orQ5 represents CR3d; Q6 represents CR4e; and Q7 represents N; orQ5 represents N; Q6 represents CR4e; and Q7 represents CR4f; orQ5 represents N; Q6 represents CR4e; and Q7 represents N;R6a, R6b, R6c, R6d, R6e, R6f, R6g and R6h each independently represent hydrogen, halogen, or Ci_4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula (I), whereinR1 represents hydrogen or -C(=0)-Ci_4alkyl;R2 represents hydrogen or -C(=0)-Ci_4alkyl;Y represents -0-, or -CH2-;Z represents -CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C≡C-; and when Y represents -CH2-, then Z can also represent -O- or -CR5aR5b-X-;R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5h each independently represent hydrogen or Ci_4alkyl;X represents -0-, -S-, or -NR11-;R11 represents hydrogen or Ci_4alkyl; Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=0)-NH-Ci_4alkyl, -C(=0)-Ci_4alkyl, Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b;R10a and R10b each independently represent hydrogen or Ci_4alkyl;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3);R3a, R3b and R3c each independently represent hydrogen, halo, -NR7aR7b, or-0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen or Ci_4alkyl;R4a, R4b and R4c each independently represent hydrogen, halo, -NR8aR8b, or Ci_4alkyl;R8a and R8b each independently represent hydrogen or Ci_4alkyl;Q1 represents CR6a;Q2 represents CR6b;Q3 represents CR6c;Q4 represents CR6d;R6a, R6b, R6c, R6d, R6e and R6f each independently represent hydrogen, halogen, Ci_ 4alkyl, -NR9aR9b, or Ci_4alkyl substituted with one, two or three halo atoms;R9a and R9b each independently represent hydrogen or Ci_4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula ( I ). whereinR1 represents hydrogen or -C(=0)-Ci_4alkyl;R2 represents hydrogen or -C(=0)-Ci_4alkyl;Y represents -0-, or -CH2-;Z represents -CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C≡C-;and when Y represents -CH2-, then Z can also represent -O- or -CR5aR5b-X-;R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5h each independently represent hydrogen or Ci_4alkyl;X represents -0-, -S-, or -NR11-;R11 represents hydrogen or Ci_4alkyl; Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system; Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C alkyl)2, cyano, -CF3, -C(=0)- H-C alkyl, - Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b.R10a and R10b each independently represent hydrogen or Ci_4alkyl;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3);R3a, R3b and R3c represent -NR7aR7b;R7a represents hydrogen;R7b represents hydrogen;R4a, R4b and R4c each independently represent hydrogen, halo, -NR8aR8b, or Ci_4alkyl;R8a and R8b each independently represent hydrogen or Ci_4alkyl;Q1 represents CR6a;Q2 represents CR6b;Q3 represents CR6c;Q4 represents CR6d;R6a, R6b, R6c, R6d, R6e and R6f each independently represent hydrogen, halogen,Ci_4alkyl, -NR9aR9b, or Ci_4alkyl substituted with one, two or three halo atoms;R9a and R9b each independently represent hydrogen or Ci_4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula (I ). whereinR1 represents hydrogen or -C(=0)-Ci_4alkyl;R2 represents hydrogen or -C(=0)-Ci_4alkyl; in particular R1 and R2 represent hydrogen;Y represents -O- or -CH2-;Z represents -CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C≡C-;and when Y represents -CH2-, then Z can also represent -CR5aR5b-X-;R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5h each independently represent hydrogen or Ci_4alkyl;X represents -0-, -S-, or -NR11-;R11 represents hydrogen or Ci_4alkyl; Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system; Ar is optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, cyano, -CF3, Ci_4alkyloxy, and Ci_4alkyl;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2);R3a and R3c each independently represent halo, -NR7aR7b, or -0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen;R4a, and R4c each independently represent hydrogen, halo, or Ci_4alkyl;Q1 represents CR6a;Q2 represents CR6b;R6a, R6b, R6e and R6f each independently represent hydrogen, halogen, or Ci_4alkyl; and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula ( I ). whereinR1 represents hydrogen orR2 represents hydrogen or in particular R1 and R2 represent hydrogen;Y represents -O- or -CH2-;Z represents -CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C≡C-;and when Y represents -CH2-, then Z can also represent -CR5aR5b-X-;R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5h each independently represent hydrogen or Ci_4alkyl;X represents -0-, -S-, or -NR1 1-;R1 1 represents hydrogen or Ci_4alkyl;Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system; Ar is optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, -NHR10d, cyano, -CF3, -C(=0)- H-C alkyl, Ci_4alkyloxy, and Ci_4alkyl;R10d represents Ci_4alkyl substituted with one, two or three halo substituents; or Ci_4alkyl substituted with one C3_6cycloalkyl;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2);R3a and R3c each independently represent hydrogen, halo, -NR7aR7b, or -0-Ci_4alkyl; R7a represents hydrogen;R7b represents hydrogen or Ci_4alkyl;R4a, and R4c each independently represent hydrogen, halo, or Ci_4alkyl;Q1 represents CR6a;Q2 represents CR6b;R6a, R6b, R6e and R6f each independently represent hydrogen, halogen, or Ci_4alkyl; and pharmaceutically acceptable addition salts, and solvates thereof.Another embodiment of the present invention relates to those compounds of Formula ( I ), and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein one or more of the following restrictions apply:(i) R1 and R2 represent hydrogen;(ii) Y represents -O- or -CH2-; in particular Y represents -0-;(iii) Z represents -CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C≡C-; and when Y represents -CH2-, then Z can also represent -CR5aR5b-X-;(iv) R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5h represent hydrogen;(v) X represents -0-;(vi) R11 represents hydrogen or Ci_4alkyl;(vii) Ar is optionally substituted with one, two or three substituents, in particular one substituent, each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, cyano, -CF3, -C(=0)-NH-Ci_4alkyl, Ci_4alkyloxy, and Ci_ 4alkyl;(viii) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2);(ix) R3a and R3c each independently represent halo, -NR7aR7b, or -0-Ci_4alkyl;(x) R7a and R7b represent hydrogen;(xi) R4a, and R4c each independently represent hydrogen, halo, or Ci_4alkyl; (xii) Q1 represents CR6a;(xiii) Q2 represents CR6b;(xiv) R6a, R6b, R6e and R6f each independently represent hydrogen, halogen, or Ci_4alkyl.In an embodiment, the present invention concerns novel compounds of Formula ( I ). whereinR1 represents hydrogen;R2 represents hydrogen;Y represents -O- or -CH2-;Z represents -X-CR5aR5b- or -CR5eR5g-CR5fR5h-;and when Y represents -CH2-, then Z can also represent -CR5aR5b-X-;R5a, R5b, R5e, R5f, R5g, and R5h represent hydrogen;X represents -0-;Ar representswherein Ar is optionally substituted in the position indicated by a with a substituent selected from the group consisting of -NH2, -NH-Ci_4alkyl, and -NHR10d; and wherein Ar is optionally substituted in the position indicated by β with a substituent selected from the group consisting of halo and CF3;provided however that Ar is substituted in at least one of the positions indicated by a β;R10d represents C3_6cycloalkyl; Ci_4alkyl substituted with one, two or three halo substituents; or Ci_4alkyl substituted with one C3_6cycloalkyl substituent;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-4);R3a and R3d each independently represent hydrogen, halo, -NR7aR7b, Ci_4alkyl, or-0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen or Ci_4alkyl;R4a, R4d and R4f each independently represent hydrogen or halo;Q1 represents CR6a;Q2 represents CR6b;Q8 represents CR6g;Q9 represents CR6h; Q5 represents CR3d; Q6 represents N; and Q7 represents CR4f;R6a, R6b, R6g, and R6h represent hydrogen;and pharmaceutically acceptable addition salts, and solvates thereof. Another embodiment of the present invention relates to those compounds of Formula ( I ), and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein one or more of the following restrictions apply:(i) R1 and R2 represent hydrogen;(ii) Y represents -O- or -CH2-;(iii) Z represents -X-CR5aR5b- or -CR5eR5g-CR5fR5h-;and when Y represents -CH2-, then Z can also represent -CR5aR5b-X-;(iv) R5a, R5b, R5e, R5f, R5g, and R5h represent hydrogen;(v) X represents -0-;(vi) Ar representswherein Ar is optionally substituted in the position indicated by a with a substituent selected from the group consisting of -NH2, -NH-Ci_4alkyl, and -NHR10d; and wherein Ar is optionally substituted in the position indicated by β with a substituent selected from the group consisting of halo and CF3;provided however that Ar is substituted in at least one of the positions indicated by a β;(vii) R10d represents C3_6cycloalkyl; Ci_4alkyl substituted with one, two or three halo substituents; or Ci_4alkyl substituted with one C3_6cycloalkyl substituent;(viii) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-4);(ix) R3a and R3d each independently represent hydrogen, halo, -NR7aR7b, Ci_4alkyl, or -0-Ci_4alkyl;(x) R7a represents hydrogen;(xi) R7b represents hydrogen or Ci_4alkyl;(xii) R4a, R4d and R4f each independently represent hydrogen or halo;(xiii) Q1 represents CR6a;(xiv) Q2 represents CR6b;(xv) Q8 represents CR6g;(xvi) Q9 represents CR6h; (xvii) Q5 represents CR3d; Q6 represents N; and Q7 represents CR4f;(xviii) R6a, R6b, R6g, and R6h represent hydrogen.In an embodiment, the present invention concerns novel compounds of Formula ( I ). whereinR represents hydrogen;R2 represents hydrogen;Y represents -O- or -CH2-;Z represents -X-CR5aR5b- or -CR5eR5g-CR5fR5h-;and when Y represents -CH2-, then Z can also represent -CR5aR"R5a, R5b, R5e, R5f, R5g, and R5h represent hydrogen;X represents -0-;Ar representswherein Ar is optionally substituted in the position indicated by a with a substituent selected from the group consisting of -NH2, -NH-Ci_4alkyl, and -NHR10d; and wherein Ar is optionally substituted in the position indicated by β with a substituent selected from the group consisting of halo and CF3;provided however that Ar is substituted in at least one of the positions indicated by a β;R10d represents C3_6cycloalkyl; Ci_4alkyl substituted with one, two or three halo substituents; or Ci_4alkyl substituted with one C3_6cycloalkyl substituent;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);R3a represents hydrogen, halo, -NR7aR7b, Ci_4alkyl, or -0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen or Ci_4alkyl;R4a represents hydrogen or halo;Q1 represents CR6a;Q2 represents CR6b;R6a and R6b represent hydrogen;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula (I), wherein R represents hydrogen;R2 represents hydrogen;Y represents -O- or -CH2-;Z represents -X-CR5aR5b- or -CR5eR5g-CR5fR5h-;R5a, R5b, R5e, R5f, R5g, and R5h represent hydrogen;X represents -0-;Ar representswherein Ar is optionally substituted in the position indicated by a with a substituent selected from the group consisting of -NH2, -NH-Ci_4alkyl, and -NHR10d; and wherein Ar is optionally substituted in the position indicated by β with a substituent selected from the group consisting of halo and CF3;provided however that Ar is substituted in at least one of the positions indicated by a β;R10d represents C3_6cycloalkyl; Ci_4alkyl substituted with one, two or three halo substituents; or Ci_4alkyl substituted with one C3_6cycloalkyl substituent;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);R3a represents hydrogen, halo, -NR7aR7b, Ci_4alkyl, or -0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen or Ci_4alkyl;R4a represents hydrogen or halo;Q1 represents CR6a;Q2 represents CR6b;R6a and R6b represent hydrogen;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula ( I ), whereinR1 represents hydrogen;R2 represents hydrogen;Y represents -O- or -CH2-;Z represents -X-CR5aR5b- or -CR5eR5g-CR5fR5h-;and when Y represents -CH2-, then Z can also represent -CR5aR"R5a, R5b, R5e, R5f, R5g, and R5h represent hydrogen; X represents -0-;Ar representswherein Ar is substituted in the position indicated by a with a substituent selected from the group consisting of -NH2, -NH-Ci_4alkyl, and -NHR10d;R10d represents C3-6cycloalkyl; or Ci_4alkyl substituted with one substituent selected from the group consisting of C3_6Cycloalkyl, and R14;R14 represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;Het represents the bicyclic aromatic heterocyclic ring system (a-1);R3a represents hydrogen, halo, -NR7aR7b, or Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen or Ci_4alkyl;R4a represents hydrogen;Q1 represents CR6a;Q2 represents CR6b;R6a and R6b represent hydrogen;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula (I), whereinR1 represents hydrogen;R2 represents hydrogen;Y represents -O- or -CH2-;Z represents -X-CR5aR5b- or -CR5eR5g-CR5fR5h-;and when Y represents -CH2-, then Z can also represent -CR5aR5b-X-;R5a, R5b, R5e, R5f, R5g, and R5h represent hydrogen;X represents -0-;Ar representswherein Ar is optionally substituted in the position indicated by a with -NH2; and wherein Ar is substituted in the position indicated by β with a substituent selected from the group consisting of halo and CF3; Het represents the bicyclic aromatic heterocyclic ring system (a-1);R3a represents hydrogen, halo, -NR7aR7b, or Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen or Ci_4alkyl;R4a represents hydrogen;Q1 represents CR6a;Q2 represents CR6b;R6a and R6b represent hydrogen;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula (I), whereinR represents hydrogen;R2 represents hydrogen;Y represents -O- or -CH2-;Z represents -X-CR5aR5b- or -CR5eR5g-CR5fR5h-;and when Y represents -CH2-, then Z can also represent -CR5aR5b-X-;R5a, R5b, R5e, R5f, R5g, and R5h represent hydrogen;X represents -0-;Ar representswherein Ar is substituted in the position indicated by a with -NH2; andwherein Ar is substituted in the position indicated by β with a substituent selected from the group consisting of halo and CF3;Het represents the bicyclic aromatic heterocyclic ring system (a-1);R3a represents hydrogen, halo, -NR7aR7b, or Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen or Ci_4alkyl;R4a represents hydrogen;Q1 represents CR6a;Q2 represents CR6b;R6a and R6b represent hydrogen;and pharmaceutically acceptable addition salts, and solvates thereof. In an embodiment, the present invention concerns novel compounds of Formula ( I ), whereinR represents hydrogen;R2 represents hydrogen;Y represents -O- or -CH2-;Z represents -X-CR5aR5b- or -CR5eR5g-CR5fR5h-;and when Y represents -CH2-, then Z can also represent -CR5aR5b-X-;R5a, R5b, R5e, R5f, R5g, and R5h represent hydrogen;X represents -0-;Ar representsHet represents the bicyclic aromatic heterocyclic ring system (a-1);R3a represents hydrogen, halo, -NR7aR7b, or Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen or Ci_4alkyl;R4a represents hydrogen;Q1 represents CR6a;Q2 represents CR6b;R6a and R6b represent hydrogen;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula (I), whereinR1 represents hydrogen orR2 represents hydrogen orin particular R1 and R2 represent hydrogen;Y represents -CH2- or -0-;Z represents -X-CR5aR5b- or -CH2CH2-;R5a and R5b each independently represent hydrogen or Ci_4alkyl;X represents -0-, -S-, or -NR11-;R11 represents hydrogen;Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system; Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=0)-NH-Ci_4alkyl, -C(=0)-Ci_4alkyl, Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b;R10a and R10b each independently represent hydrogen or Ci_4alkyl;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);R3a represents hydrogen, halo, -NR7aR7b, or-0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen;R4a represents hydrogen, halo, -NR8aR8b, or Ci_4alkyl;R8a and R8b each independently represent hydrogen or Ci_4alkyl;Q1 represents CR6a;Q2 represents CR6b;R6a and R6b each independently represent hydrogen, halogen, Ci_4alkyl, -NR9aR9b, or Ci_4alkyl substituted with one, two or three halo atoms;R9a and R9b each independently represent hydrogen or Ci_4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula ( I ). whereinR1 represents hydrogen;R2 represents hydrogen;Y represents -CH2-;Z represents -CR5eR5g-CR5fR5h-;R5e, R5f, R5g, and R5h represent hydrogen;Ar represents any one of the following 10-membered bicyclic aromatic ring systems:Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, -NHR10d, -NR10cR10d;R10c and R10d each independently represent C3_6cycloalkyl; C3_6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -0-Ci_4alkyl; Ci_4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -0-Ci_4alkyl; or Ci_4alkyl substituted with one C3-6cycloalkyl substituent;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a- 1);R3a represents hydrogen, -NR7aR7b, or -0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen or Ci_4alkyl;R4a represents hydrogen;Q1 represents CR6a;Q2 represents CR6b;R6a and R6b represent hydrogen;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula (I), whereinR1 represents hydrogen;R2 represents hydrogen;Y represents -CH2-;Z represents -CR5eR5g-CR5fR5h-;R5e, R5f, R5g, and R5h represent hydrogen;Ar represents f y)""Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, -NHR10d;R10d represents Ci_4alkyl substituted with one, two or three halo substituents; or Ci_4alkyl substituted with one C3-6cycloalkyl substituent;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a- 1);R3a represents hydrogen, -NR7aR7b, or -0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen or Ci_4alkyl;R4a represents hydrogen;Q1 represents CR6a; Q2 represents CR6b;R6a and R6b represent hydrogen;and pharmaceutically acceptable addition salts, and solvates thereof.Another embodiment of the present invention relates to those compounds of Formula (I), and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein one or more of the following restrictions apply:(i) R1 represents hydrogen;R2 represents hydrogen;(ii) Y represents -CH2-;(iii) Z represents -CR5eR5g-CR5fR5h-;(iv) R5e, R5f, R5g, and R5h represent hydrogen;(v) Ar representsAr is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, -NHR10d;(vi) R10d represents Ci_4alkyl substituted with one, two or three halo substituents; or Ci_4alkyl substituted with one C3-6cycloalkyl substituent;(vii) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);(viii) R3a represents hydrogen, -NR7aR7b, or -0-Ci_4alkyl;(ix) R7a represents hydrogen;R7b represents hydrogen or Ci_4alkyl;(x) R4a represents hydrogen;(xi) Q1 represents CR6a;Q2 represents CR6b;(xii) R6a and R6b represent hydrogen.Another embodiment of the present inv ention relates to those compounds of Formula (I), and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein one or more of the following restrictions apply: (i) R1 represents hydrogenR2 represents hydrogen orin particular R1 and R2 represent hydrogen;(ii) Y represents -CH2- or -0-;(iii) Z represents -X-CR5aR5b- or -CH2CH2-;(iv) R5a and R5b each independently represent hydrogen or Ci_4alkyl;(v) X represents -0-, -S-, or -NR11-;(vi) R11 represents hydrogen;(vii) Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=0)-Ci_4alkyl, Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b;(viii) R10a and R10b each independently represent hydrogen or Ci_4alkyl;(ix) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a- 1);(x) R3a represents hydrogen, halo, -NR7aR7b, or -0-Ci_4alkyl;(xi) R7a represents hydrogen;R7b represents hydrogen;(xii) R4a represents hydrogen, halo, -NR8aR8b, or Ci_4alkyl;(xiii) R8a and R8b each independently represent hydrogen or Ci_4alkyl;(xiv) Q1 represents CR6a;(xv) Q2 represents CR6b;(xvi) R6a and R6b each independently represent hydrogen, halogen, Ci_4alkyl, -NR9aR9b, or Ci_4alkyl substituted with one, two or three halo atoms;(xvii) R9a and R9b each independently represent hydrogen or Ci_4alkyl.In an embodiment, the present invention concerns novel compounds of Formula (I), whereinR1 represents hydrogen or -C(=0)-Ci_4alkyl;R2 represents hydrogen or -C(=0)-Ci_4alkyl;in particular R1 and R2 represent hydrogen;Y represents -0-;Z represents -X-CR5aR5b-;R5a and R5b each independently represent hydrogen or Ci_4alkyl;X represents -0-, -S-, or -NR11-;R11 represents hydrogen; Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=0)-NH-Ci_4alkyl, -C(=0)-Ci_4alkyl, Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b;R10a and R10b each independently represent hydrogen or Ci_4alkyl;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);R3a represents hydrogen, halo, -NR7aR7b, or-0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen;R4a represents hydrogen, halo, -NR8aR8b, or Ci_4alkyl;R8a and R8b each independently represent hydrogen or Ci_4alkyl;Q1 represents CR6a;Q2 represents CR6b;R6a and R6b each independently represent hydrogen, halogen, Ci_4alkyl, -NR9aR9b, or Ci_4alkyl substituted with one, two or three halo atoms;R9a and R9b each independently represent hydrogen or Ci_4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.Another embodiment of the present invention relates to those compounds of Formula(I), and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein one or more of the following restrictions apply:(i) R1 represents hydrogen or -C(=0)-Ci_4alkyl;R2 represents hydrogen or -C(=0)-Ci_4alkyl;in particular R1 and R2 represent hydrogen;(ii) Y represents -0-;(iii) Z represents -X-CR5aR5b-;(iv) R5a and R5b each independently represent hydrogen or Ci_4alkyl;(v) X represents -0-, -S-, or -NR11-;(vi) R11 represents hydrogen;(vii) Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, cyano, -CF3, -C(=0)-NH-Ci_4alkyl, -C(=0)-Ci_4alkyl, Ci_4alkyloxy, and Cioptionally substituted with one -NR10aR10b;(viii) R10a and R10b each independently represent hydrogen or Ci_4alkyl;(ix) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a- 1);(x) R3a represents hydrogen, halo, -NR7aR7b, or -0-Ci_4alkyl;(xi) R7a represents hydrogen;R7b represents hydrogen;(xii) R4a represents hydrogen, halo, -NR8aR8b, or Ci_4alkyl;(xiii) R8a and R8b each independently represent hydrogen or Ci_4alkyl;(xiv) Q1 represents CR6a;(xv) Q2 represents CR6b;(xvi) R6a and R6b each independently represent hydrogen, halogen, Ci_4alkyl, -NR9aR9b, or Ci_4alkyl substituted with one, two or three halo atoms;(xvii) R9a and R9b each independently represent hydrogen or Ci_4alkyl.In an embodiment, the present invention concerns novel compounds of Formula (I), whereinR1 represents hydrogen or -C(=0)-Ci_4alkyl;R2 represents hydrogen or -C(=0)-Ci_4alkyl;in particular R1 and R2 represent hydrogen;Y represents -CH2- or -0-;Z represents -X-CR5aR5b- or -CH2CH2-R5a and R5b each independently represent hydrogen or Ci_4alkyl;X represents -0-, -S-, or -NR11-;R11 represents hydrogen;Ar represents particular Ar representsAr is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, cyano, - CF3, -C(=0)-NH-Ci_4alkyl, -C(=0)-Ci_4alkyl, Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b;R10a and R10b each independently represent hydrogen or Ci_4alkyl;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R3a represents hydrogen, halo, -NR7aR7b, or-0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen;R4a represents hydrogen, halo, -NR8aR8b, or Ci_4alkyl;R8a and R8b each independently represent hydrogen or Ci_4alkyl;Q1 represents CR6a;Q2 represents CR6b;R6a and R6b each independently represent hydrogen, halogen, Ci_4alkyl, -NR9aR9b, or Ci_4alkyl substituted with one, two or three halo atoms;R9a and R9b each independently represent hydrogen or Ci_4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula ( I ). whereinR1 represents hydrogen or -C(=0)-Ci_4alkyl;R2 represents hydrogen or -C(=0)-Ci_4alkyl;in particular R1 and R2 represent hydrogen;Y represents -0-;Z represents -X-CR5aR5b-;R5a and R5b each independently represent hydrogen or Ci_4alkyl;X represents -0-, -S-, or -NR11-;R11 represents hydrogen;Ar represents particular Ar representsAr is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, cyano, - CF3, -C(=0)-NH-Ci_4alkyl, -C(=0)-Ci_4alkyl, Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b;R10a and R10b each independently represent hydrogen or Ci_4alkyl;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a- 1);R3a represents hydrogen, halo, -NR7aR7b, or-0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen;R4a represents hydrogen, halo, -NR8aR8b, or Ci_4alkyl; R8a and R8b each independently represent hydrogen or Ci_4alkyl;Q1 represents CR6a;Q2 represents CR6b;R6a and R6b each independently represent hydrogen, halogen, Ci_4alkyl, -NR9aR9b, or Ci_4alkyl substituted with one, two or three halo atoms;R9a and R9b each independently represent hydrogen or Ci_4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.Another embodiment of the present invention relates to those compounds of Formula(I), and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein one or more of the following restrictions apply:(i) R1 represents hydrogen or -C(=0)-Ci_4alkyl;R2 represents hydrogen or -C(=0)-Ci_4alkyl;in particular R1 and R2 represent hydrogen;(ii) Y represents -0-;(iii) Z represents -X-CR5aR5b-;(iv) R5a and R5b each independently represent hydrogen or Ci_4alkyl;(v) X represents -0-, -S-, or -NR11-;(vi) R11 represents hydrogen;(vii) Ar represents ; in particular Ar represents ;(viii) Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=0)-NH-Ci_4alkyl, -C(=0)-Ci_4alkyl, Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b;(ix) R10a and R10b each independently represent hydrogen or Ci_4alkyl;(x) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);(xi) R3a represents hydrogen, halo, -NR7aR7b, or-0-Ci_4alkyl;(xii) R7a represents hydrogen;R7b represents hydrogen;(xiii) R4a represents hydrogen, halo, -NR8aR8b, or Ci_4alkyl;(xiv) R8a and R8b each independently represent hydrogen or Ci_4alkyl;(xv) Q1 represents CR6a;(xvi) Q2 represents CR6b; (xvii) R a and R each independently represent hydrogen, halogen, Ci_4alkyl, - NR9aR9b, or Ci_4alkyl substituted with one, two or three halo atoms;(xviii) R9a and R9b each independently represent hydrogen or Ci_4alkyl. In an embodiment, the present invention concerns novel compounds of Formula ( I ). whereinR1 represents hydrogen or -C(=0)-Ci_4alkyl;R2 represents hydrogen or -C(=0)-Ci_4alkyl;in particular R1 and R2 represent hydrogen;Y represents -O- or -CH2-; Z represents -X-CR5aR5b- or -CH2CH2-;R5a and R5b represent hydrogen; X represents -0-;R11 represents hydrogen;Ar representsAr is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, cyano, and -CF3;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);R3a represents -NR7aR7b;R7a represents hydrogen;R7b represents hydrogen;R4a represents hydrogen;Q1 represents CR6a; Q2 represents CR6b; R6a and R6b represent hydrogen;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula (I), whereinR1 represents hydrogen or -C(=0)-Ci_4alkyl;R2 represents hydrogen or -C(=0)-Ci_4alkyl;in particular R1 and R2 represent hydrogen;Y represents -O- or -CH2-; Z represents -X-CR5aR5b- or -CH2CH2-;R5a and R5b represent hydrogen; X represents -0-;R11 represents hydrogen;Ar represents ;Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, cyano, and -CF3;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a- 1);R3a represents -NR7aR7b;R7a represents hydrogen;R7b represents hydrogen;R4a represents hydrogen;Q1 represents CR6a; Q2 represents CR6b; R6a and R6b represent hydrogen;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula ( I ), whereinR1 represents hydrogen or -C(=0)-Ci_4alkyl;R2 represents hydrogen or -C(=0)-Ci_4alkyl;in particular R1 and R2 represent hydrogen;Y represents -0-; Z represents -X-CR5aR5b-;R5a and R5b represent hydrogen; X represents -0-;R11 represents hydrogen;Ar representsAr is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, cyano, and -CF3;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);R3a represents -NR7aR7b;R7a represents hydrogen;R7b represents hydrogen;R4a represents hydrogen;Q1 represents CR6a; Q2 represents CR6b; R6a and R6b represent hydrogen;and pharmaceutically acceptable addition salts, and solvates thereof. In an embodiment, the present invention concerns novel compounds of Formula ( I ), whereinR represents hydrogen or -C(=0)-Ci_4alkyl;R2 represents hydrogen or -C(=0)-Ci_4alkyl;in particular R1 and R2 represent hydrogen;Y represents -0-; Z represents -X-CR5aR5b-;represent hydrogen; X representsR11 represents hydrogen;Ar represents ;Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, cyano, and -CF3;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);R3a represents -NR7aR7b;R7a represents hydrogen;R7b represents hydrogen;R4a represents hydrogen;Q1 represents CR6a; Q2 represents CR6b; R6a and R6b represent hydrogen;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula (I), whereinR1 represents hydrogen or -C(=0)-Ci_4alkyl;R2 represents hydrogen or -C(=0)-Ci_4alkyl;in particular R1 and R2 represent hydrogen;Y represents -O- or -CH2-; Z represents -X-CR5aR5b- or -CH2CH2-;R5a and R5b represent hydrogen; X represents -0-;R11 represents hydrogen;Ar represents ;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);R3a represents -NR7aR7b;R7a represents hydrogen; R represents hydrogen;R4a represents hydrogen;Q1 represents CR6a; Q2 represents CR6b; R6a and R6b represent hydrogen;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula ( I ). whereinR1 represents hydrogen orR2 represents hydrogen orin particular R1 and R2 represent hydrogen;Y represents -0-; Z represents -X-CR5aR5b-;R5a and R5b represent hydrogen; X represents -0-;R11 represents hydrogen;Ar represents ;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);R3a represents -NR7aR7b;R7a represents hydrogen;R7b represents hydrogen;R4a represents hydrogen;Q1 represents CR6a; Q2 represents CR6b; R6a and R6b represent hydrogen;and pharmaceutically acceptable addition salts, and solvates thereof.Another embodiment of the present invent ion relates to those compounds of Formula (I), and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein one or more of the following restrictions apply:(i) R1 represents hydrogenR2 represents hydrogen orin particular R1 and R2 represent hydrogen;(ii) Y represents -0-;(iii) Z represents -X-CR5aR5b-;(iv) R5a and R5b represent hydrogen; (v) X represents -0-;(vi) R11 represents hydrogen;(vii) Ar representsAr is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, cyano, and -CF3; in particular Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, cyano, and - CF3;more in particular Ar represents ; even more in particular Ar(ix) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);(x) R3a represents -NR7aR7b;(xi) R7a represents hydrogen;R7b represents hydrogen;(xii) R4a represents hydrogen;(xiii) Q1 represents CR6a;(xiv) Q2 represents CR6b;(xv) R6a and R6b represent hydrogen.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinR1 and R2 represent hydrogen.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinR1 represents-C(=0)-Ci_4alkyl; R2 represents-C(=0)-Ci_4alkyl. In an embodiment, the present invention relates to those compounds of Formula ( I ) pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, whereinR1 and R2 represent hydrogen;Het represents (a-1);Q1 represents CH; Q2 represents CH; andAr represents optionally substituted according to any of the other embodiments. In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinR1 and R2 represent hydrogen;Het represents (a-1);Q1 represents CH; Q2 represents CH; andAr representswherein Ar is substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2,-NHR10d, -NR10cR10d;R10c and R10d each independently represent Ci_4alkyl substituted with one, two or three halo substituents; or Ci_4alkyl substituted with one C3-6cycloalkyl substituent.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein Y represents -0-.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solv ates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein Y represents -CH2- or -CF2-; in particular wherein Y represents -CH2-.In an embodiment, the present inv ention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein maximum one of Q and Q represents N.In an embodiment, the present invent ion relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Q1 represents CR6a; and Q2 represents CR6b; in particular wherein Q1 represents CH; and Q represents CH.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents (a-1); Q1 represents CR6a; and Q2 represents CR6b; in particular wherein Q1 represents CH; and Q represents CH. In an embodiment, the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, whereinQ5 represents CR3d; Q6 represents N; and Q7 represents CR4f; orQ5 represents CR3d; Q6 represents CR4e; and Q7 represents N; orQ5 represents N; Q6 represents CR4e; and Q7 represents CR4f; orQ5 represents N; Q6 represents CR4e; and Q7 represents N.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-4).In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinR1 and R2 represent hydrogen; and Y represents -0-.In an embodiment, the present invent ion relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a- 1 ), (a-2) and (a-3 ). In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2).In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addit ion salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a- 1 ) and (a-4).In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a bicyclic aromatic heterocyclic ring system of Formula (a- 1 ).In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addit ion salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, whereinR1 and R2 represent hydrogen; Y represents -0-; and Het represents a bicyclic aromatic heterocyclic ring system of Formula ( a- 1 ).In an embodiment, the present invent ion relates to those compounds of Formula (I) and pharmaceutically acceptable addit ion salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar represents an optionally substituted 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that the nitrogen atom does not replace one of the two fused carbon atoms.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is optionally substituted with one or two substituents according to any of the other embodiments. In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is optionally substituted with one substituent according to any of the other embodiments.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinR3a, R3c, R3b represent hydrogen; andR4a, R4c, R4b represent hydrogen, halo, or Ci_4alkyl; in particular R4a, R4c, R4b represent halo, or Ci_4alkyl.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinR3a, R3c, R3b, R3d and R3e represent hydrogen; andR4a, R4c, R4b, R4d, R4e, R4f and R4g represent hydrogen, halo, or C alkyl; in particular R4a, R4c, R4b, R4d, R4e, R4f and R4g represent halo, or C alkyl. In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinR3a, R3c, R3b represent hydrogen, halo, -NR7aR7b, or -0-Ci_4alkyl; in particular R3a, R3c, R3b represent halo, -NR7aR7b, or -0-C alkyl;R4a, R4c, R4b represent hydrogen.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinR3a, R3c, R3b, R3d and R3e represent hydrogen, halo, -NR7aR7b, or -0-Ci_4alkyl; in particular R3a, R3c, R3b, R3d and R3e represent halo, -NR7aR7b, or -0-C alkyl;R4a, R4c, R4b, R4d, R4e, R4f and R4g represent hydrogen.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinR3a, R3c, R3b represent hydrogen, when R4a, R4c, R4b are different from hydrogen. In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, whereinR3a, R3c, R3b, R3d, R3e represent hydrogen, when R4a, R4c, R4b, R4d, R4e, R4f, R4g are different from hydrogen.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, whereinR4a, R4c, R4b represent hydrogen, when R3a, R3c, R3b are different from hydrogen.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinR4a, R4c, R4b, R4d, R4e, R4f, R4g represent hydrogen, when R3a, R3c, R3b, R3d, R3e are different from hydrogen.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinAr represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,wherein at least 1 ring carbon atom of ring B is replaced by a nitrogen atom;wherein optionally 1 additional ring carbon atom of ring A or ring B is replaced by a nitrogen atom; provided that when a nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted according to any of the other embodiments.In an embodiment, the present invent ion relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinAr represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,wherein at least 1 ring carbon atom of ring B is replaced by a nitrogen atom;wherein optionally 1 additional ring carbon atom of ring A or ring B is replaced by a nitrogen atom; provided that when a nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, -NHR10d, -NR10cR10d, cyano, -CF3, -C(=0)-NH2, -C(=0)- H-C alkyl, -C(=0)-Ci_ 4alkyl, Ci_4alkyloxy, C3_6Cycloalkyl, C2_6alkenyl, Ci_4alkyl substituted with one Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one_NR10aR10b.in particular Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, - N(Ci_4alkyl)2, cyano, -CF3, -C(=0)-NH-Ci_4alkyl, -C(=0)-Ci_4alkyl, Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, whereinAr represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings with the following structure,wherein optionally 1 additional ring carbon atom of ring A or ring B is replaced by nitrogen atom; provided that when a nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted according to any of the other embodiments.covers any one of the following ring systems:In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein Ar is selected from the group consisting of:wherein each Ar is optionally substituted according to any of the other embodiments. In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein Ar is selected from the group consisting of:wherein each Ar is optionally substituted according to any of the other embodiments.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein Ar is selected from the group consisting of:wherein each Ar is optionally substituted according to any of the other embodiments.In an embodiment, the present invent ion relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein Ar is selected from the group consisting of:wherein each Ar is optionally substituted according to any of the other embodiments.In an embodiment, the present inv ention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is selected from the group consisting of:wherein each Ar is optionally substituted according to any of the other embodiments.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein Ar iswherein Ar is optionally substituted according to any of the other embodiments.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is other thanwherein Ar is optionally substituted according to any of the other embodiments.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein Ar representswherein Ar is substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2,-NHR10d, -NR^R1In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein Ar representswherein Ar is substituted with one substituent selected from the group consisting of -NH2, -NH-Ci_4alkyl, -N(C alkyl)2, -NHR10d, -NR10cR10d; and optionally substituted with a halo substituent;R10c and R10d each independently represent Ci_4alkyl substituted with one, two or three halo substituents; or Ci_4alkyl substituted with one C3-6cycloalkyl substituent.In an embodiment, the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar representswherein Ar is substituted in the position indicated by a with a substituent selected from the group consisting of -NH2, -NH-Ci_4alkyl, -N(C alkyl)2, -NHR10d, -NR10cR10d; and wherein Ar is optionally substituted in the position indicated by β with a halo substituent.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar representswherein Ar is substituted in the position indicated by a with a substituent selected from the group consisting of -NH2, -NH-Ci_4alkyl, -N(C alkyl)2, -NHR10d, -NR10cR10d; and wherein Ar is optionally substituted in the position indicated by β with a halo substituent;R10c and R10d each independently represent Ci_4alkyl substituted with one, two or three halo substituents; or Ci_4alkyl substituted with one C3-6cycloalkyl substituent. In an embodiment, the present invention relates to those compounds of Formula ( I ) pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein Ar representswherein Ar is substituted in the position indicated by β with a halo substituent; in particular chloro or bromo; more in particular bromo.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represent (a-1); Q1 a; Q2 represents CR6b; and Ar representswherein Ar is substituted in the position indicated by β with a halo substituent; in particular chloro or bromo; more in particular bromo.In an embodiment, the present invent ion relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein Ar is substituted with one substituent selected from the group consisting of -NH2, -NH-Ci_4alkyl,-N(Ci_4alkyl)2, -NHR10d, -NR10cR10d; and wherein Ar is optionally substituted with another substituent selected from the list of substituents on Ar in any of the other embodiments.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addit ion salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein Ar representsoptionally substituted according to any of the other embodiments.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein Ar representsoptionally substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, cyano, - CF3, -C(=0)-NH-Ci_4alkyl, Ci_4alkyloxy, and C alkyl;in particular optionally substituted with one, two or three substituents eachindependently selected from the group consisting of halo, -NH2, -NH-Ci_4alkyl, cyano, -CF3, Ci_4alkyloxy, and Ci_4alkyl;more in particular optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, or -CF3;more in particular optionally substituted with one or two halo substituents;more in particular substituted with one or two halo substituents;even more in particular substituted with one halo substituent;most in particular substituted with one chloro substituent.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar representsoptionally substituted according to any of the other embodiments.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar representsoptionally substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=0)-NH-Ci_4alkyl, Ci_4alkyloxy, and C alkyl;in particular optionally substituted with one, two or three substituents eachindependently selected from the group consisting of halo, -NH2, -NH-Ci_4alkyl, cyano, -CF3, Ci_4alkyloxy, and Ci_4alkyl;more in particular optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, or -CF3;more in particular optionally substituted with one or two halo substituents;more in particular substituted with one or two halo substituents;even more in particular substituted with one halo substituent;most in particular substituted with one chloro substituent.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinHet represents (a-1); andAr representsoptionally substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=0)-NH-Ci_4alkyl, Ci_4alkyloxy, and Ci_4alkyl;in particular optionally substituted with one, two or three substituents eachindependently selected from the group consisting of halo, -NH2, -NH-Ci_4alkyl, cyano, -CF3, Ci_4alkyloxy, and Ci_4alkyl;more in particular optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, or -CF3;more in particular optionally substituted with one or two halo substituents;more in particular substituted with one or two halo substituents;even more in particular substituted with one halo substituent;most in particular substituted with one chloro substituent.In an embodiment, the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinHet represents (a- 1 ); and Ar representsparticular Ar representsmore in particular Ar representsIn an embodiment, the present invention relates to those compounds of Formula ( I ) pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioAr representsparticular Ar representsmore in particular Ar representsIn an embodiment, the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R51'. R5g and R5tl represent hydrogen.In an embodiment, the present inv ention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addit ion salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein Q1 represents CR6a; and Q2 represents CR6b. In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein X represents -0-;Q1 represents CR6a; and Q2 represents CR6b.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein X represents -0-;Q 1 represents CH; and Q 2 represents CR H .In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, whereinR5b, R5 and R5h represent hydrogen;Y represents -CH2- or -CF2-; in particular Y represents -CH2-; andHet represents (a-1);Q1 represents CR6a; and Q2 represents CR6b; in particular wherein Q1 represents CH; and Q represents CH. In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, whereinR5b, R5g and R5h represent hydrogen; Y represents -0-; andHet represents (a- 1 );Q1 represents CR6a; and Q2 represents CR6b; in particular wherein Q1 represents CH; and Q2 represents CH.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Q represents CR6b.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinZ represents -X-CR5aR5b-. In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, whereinZ represents -O-CH2-.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solv ates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, whereinZ represents -X-CR5aR5b-; X represents -0-; and R5a and R5b represent hydrogen.In an embodiment, the present inv ention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, whereinX represents -O- or -NR1 1-; in particular X represents -0-.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinR7a and R7b represent hydrogen.In an embodiment, the present inv ention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents (a-1); R3a represents -NR7aR'b; and R7a and R7b represent hydrogen.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutical ly acceptable addition salts, and solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinAr represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C alkyl)2, cyano, -CF3, -C(=0)-NH-Ci_4alkyl, - Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b.R3a, R3b and R3c represent -NR7aR7b; and R7a and R7b represent hydrogen. In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, whereinAr represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C alkyl)2, cyano, -CF3, -C(=0)-NH-Ci_4alkyl, - Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b.R3a, R3c, R3b, R3d and R3e represent -NR7aR7b; and R7a and R7b represent hydrogen. In an embodiment, the present invent ion relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3a, R3b and R3c represent other than halo.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addit ion salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3a, R3c, R3b, R3d and R3e represent other than halo.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, whereinR3a, R3b and R3c represent -NR7aR7b;R7a represents hydrogen;R7b represents hydrogen. In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3a, R3b and R3c represent IK In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinAr represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C alkyl)2, cyano, -CF3, - Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one -Het represents (a-1); R a represents -NR7aR7b; and R7a and R7h represent hydrogen.In an embodiment, the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinAr represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is substituted with one substituent selected from the group consisting of halo, -OH, - NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, cyano, -CF3, -C(=0)-NH-Ci_4alkyl, -C(=0)-Ci_ 4alkyl, Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b;Het represents (a- 1 ); R3a represents -NR7aR7b; and R7a and R7b represent hydrogen.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar representsoptionally substituted with one substituent selected from the group consisting of halo, OH, -NH2, -NH-Ci_4alkyl, -N(C alkyl)2, cyano, -CF3, -C(=0)-NH-Ci_4alkyl, Ci_ 4alkyloxy, and Ci_4alkyl;in particular optionally substituted with one substituent selected from the group consisting of halo, -NH2, -NH-Ci_4alkyl, cyano, -CF3, Ci_4alkyloxy, and Ci_4alkyl; more in particular optionally substituted with one substituent selected from the group consisting of halo, and -CF3;more in particular optionally substituted with one halo substituent;more in particular substituted with one halo substituent;even more in particular substituted with one chloro substituent.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein Ar is selected from the group consisting of:wherein each Ar is optionally substituted according to any of the other embodiments; in particular wherein Ar is optionally substituted with one substituent as defined in any of the other embodiments.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is selected from the group consisting of:wherein each Ar is optionally substituted according to any of the other embodiments; in particular wherein Ar is optionally substituted with one substituent as defined in any of the other embodiments.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceut ically acceptable addition salts, and solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is selected from the group consistingwherein each Ar is optionally substituted according to any of the other embodiments; in particular wherein Ar is optionally substituted with one substituent as defined in any of the other embodiments.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein Ar is selected from the group consistingwherein each Ar is optionally substituted in position a with a substituent selected from the group consisting of -NH2, -NH-Ci_4alkyl, -N(C alkyl)2, -NHR10d, and -NR10cR10d; R10c and R10d each independently represent C3-6cycloalkyl; C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -0-Ci_4alkyl; Ci_4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and - 0-Ci_4alkyl; or Ci_4alkyl substituted with one substituent selected from the group consisting of C3_6cycloalkyl, R13 and R14;R13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=0)p and N; or a 6- to 11- membered bicyclic fused aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=0)p and N;said 4- to 7-membered monocyclic aromatic ring or 6- to 11-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of Ci_4alkyl;p represents 1 or 2;R14 represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is selected from the group consistingwherein each Ar is optionally substituted in position a with a substituent selected from the group consisting of -NH2, -NH-Ci_4alkyl, -N(C alkyl)2, -NHR10d, and -NR10cR10d; and wherein Ar is optionally substituted in another position with a halo substituent.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutical ly acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is selected from the group consistingwherein each Ar is substituted in position a with a substituent selected from the group consisting of -NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, -NHR10d, and -NR10cR10d;and wherein Ar is optionally substituted in another position with a halo substituent.In an embodiment, the present inv ention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar represents a 10- membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;wherein each Ar is optionally substituted according to any of the other embodiments; in particular wherein Ar is optionally substituted with one substituent as defined in any of the other embodiments.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is optionally substituted with one substituent as defined in any of the other embodiments. In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2,-NHR10d, -NR10cR10d, cyano, -CF3, -C(=0)-NH2,Ci_4alkyloxy, -C(=0)-0-Ci_4alkyl, C2_6alkenyl, Ci_4alkyl substituted with one Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinAr representr is option tsA ally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, and -CF3;more in particular Ar represents ; even more in particular ArrepreIn an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinAr represen tts ;Ar is substituted with one substituent selected from the group consisting of halo, -OH, NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, cyano, and -CF3;more in particular Ar represents ; even more in particular Arrepre ;Het represents (a-1); R a represents -NR7aR7b; and R7a and R7b represent hydrogen.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutical ly acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula ( I ) are restricted to compounds of Formula (I-al):It wil l be clear that all v ariables in the structure of Formula ( l-a l ), may be defined as defined for the compounds of Formula ( I ) or any subgroup thereof as mentioned in any of the other embodiments.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutical ly acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula ( I ) are restricted to compounds of Formula (I-al):wherein R3a represents -NH2; and R4a represents hydrogen.In an embodiment, the present inv ention relates to those compounds of Formula ( I ) pharmaceutically acceptable addition salts, and solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula ( I ) are restricted to compounds of Formula ( l-a l ):wherein R3a re 4a represents hydrogen; and; more in particular Ar representsIn an embodiment, the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula ( I ) are restricted to compounds of Formula ( l-a l ):whereinR1 and R2 represent hydrogen;R3a represents hydrogen, -NR7aR7b, or -OCi_4alkyl;R4a represents hydrogen; andAr represents wherein Ar is substituted in the position indicated by a with a substituent selected from the group consisting of -NH2, -NH-Ci_4alkyl, -N(C alkyl)2, -NHR10d, -NR10cR10d; and wherein Ar is optionally substituted in the position indicated by β with a halo substituent;R10c and R10d each independently represent Ci_4alkyl substituted with one, two or three halo substituents; or Ci_4alkyl substituted with one C3-6cycloalkyl substituent.In an embodiment, the present invention concerns novel compounds of Formula ( I-a l )whereinR1 and R2 represent hydrogen;R3a represents hydrogen, -NR7aR7b, or -OCi_4alkyl;R7a represents hydrogen;R7b represents hydrogen or Ci_4alkyl;Z represents -CH2CH2-;Y represents -0-, -CH2- or -CF2-; in particular -CH2-;R4a represents hydrogen; andAr representswherein Ar is substituted in the position indicated by a with a substituent selected from the group consisting of -NH2, -NH-Ci_4alkyl, -N(C alkyl)2, -NHR10d, -NR10cR10d; and wherein Ar is optionally substituted in the position indicated by β with a halo substituent;R10c and R10d each independently represent Ci_4alkyl substituted with one, two or three halo substituents; or Ci_4alkyl substituted with one C3-6cycloalkyl substituent;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula (I-al)whereinR1 and R2 represent hydrogen;R3a represents hydrogen, -NR7aR7b, or -OCi_4alkyl;R7a represents hydrogen;R7b represents hydrogen or Ci_4alkyl;Z represents -X-CR5aR5b- or -CH2CH2-;R5a and R5b represent hydrogen; X represents -0-;Y represents -0-, -CH2- or -CF2-; in particular -CH2-;R4a represents hydrogen; andAr representswherein Ar is optionally substituted in the position indicated by a with a substituent selected from the group consisting of -NH2, -NH-Ci_4alkyl, -N(Ci_4alkyl)2, -NHR10d, - NR10cR10d; andwherein Ar is optionally substituted in the position indicated by β with a halo substituent;R10c and R10d each independently represent Ci_4alkyl substituted with one, two or three halo substituents; or Ci_4alkyl substituted with one C3-6cycloalkyl substituent;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention concerns novel compounds of Formula ( I-a l )wherein R1 and R2 represent hydrogen;RR77aa rreepprreesseennttss hhyyddrrooggeenn;;RR77bb rreepprreesseennttss hhyyddrrooggeenn;;ZZ rreepprreesseennttss --XX--CCRR55aaRR55bb-- oorr --CCHH22CCHH22--;;RR55aa aanndd RR55bb rreepprreesseenntt hhyyddrrooggeenn;; XX rreepprreesseennttss -0-;YY rreepprreesseennttss --OO-- oorr --CCHH22--;;RR44aa rreepprreesseennttss hhyyddrrooggeenn;; aannddAArr rreepprreesseennttsswherein Ar is optionally substituted in the position indicated by a with -NH2; and wherein Ar is substituted in the position indicated by β with a halo substituent, in particular Br;and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinZ represents -X-CR5aR5b- or -CH2CH2-.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinZ represents -X-CR5aR5b- or -CH2CH2-;R5a and R5b represent hydrogen;X represents -0-.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinZ represents -X-CR5aR5b- or -CH2CH2-;R5a and R5b represent hydrogen;X represents -0-;Met represents (a-1). In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinZ represents -X-CR5aR5b- or -CH2CH2-;R5a and R5b represent hydrogen;X represents -0-;Met represents (a-1);R3a represents-NR7aR7b;R7a represents hydrogen;R7b represents hydrogen.In an embodiment, the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein X represents -0-.In an embodiment, the present inv ention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinZ represents -X-CR5aR5b- or -CH2CH2-;R5a and R5b represent hydrogen;X represents -0-;Ar representswherein Ar is optionally substituted in the position indicated by a with a substituent selected from the group consisting of -NH2, -NH-Ci_4alkyl, and -NHR10d; and wherein Ar is optionally substituted in the position indicated by β with a substituent selected from the group consisting of halo and CF3;provided however that Ar is substituted in at least one of the positions indicated by a β;Het represents (a-1);R3a represents-NR7aR7b;R7a represents hydrogen;R7b represents hydrogen. In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, whereinHet represents (a-1);R3a represents-NR7aR7b;R7a represents hydrogen;R7b represents hydrogen.In an embodiment, the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, whereinR3a, R3b, R3c, R3d and R3e represent -NR7aR7b;R7a represents hydrogen;R7b represents hydrogen, C3-6cycloalkyl, or Ci_4alkyl.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinR3a, R3b, R3c, R3d and R3e represent -NR7aR7b;R7a represents hydrogen;R7b represents hydrogen.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, whereinR1 1 represents hydrogen, Ci_4alkyl, or Ci_4alkyl substituted with one substituent selected from the group consisting of -OH, -0-Ci_4alkyl, -NH2, -NH-Ci_4alkyl, and -N(Ci_4alkyl)2; andR10c and R10d each independently represent C3-6cycloalkyl; R14; C3_6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -0-Ci_4alkyl; Ci_4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -0-Ci_4alkyl; or Ci_4alkyl substituted with one substituent selected from the group consisting of C3_6cycloalkyl, and R14.In an embodiment, the present invention relates to those compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y represents -CH2-; and Z represents -CH2CH2-.In an embodiment, the present invention relates to a subgroup of Formula (I) as defined in the general reaction schemes.In an embodiment the compound of Formula ( I ) is selected from the group consisting of compounds 2 and 58.In an embodiment the compound of Formula ( I ) is selected from the group consisting of compounds 2 and 80.In an embodiment the compound of Formula ( I ) is selected from the group consisting of compounds 74, 75, 76, 77, 78, 79, 80 and 81.In an embodiment the compound of Formula ( I ) is selected from the group consisting of compounds 2, 58, 74, 75, 76, 77, 78, 79, 80, 81, 154, 159, 235, 240 and 247.In an embodiment the compound of Formula ( I ) is selected from the group consisting of compounds 2 and 58,and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment the compound of Formula ( I ) is selected from the group consist ing of compounds 2 and 80,and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment the compound of Formula ( I ) is selected from the group consisting of compounds 74, 75, 76, 77, 78, 79, 80 and 81,and pharmaceutically acceptable addition salts, and solvates thereof.In an embodiment the compound of Formula ( I ) is selected from the group consisting of compounds 2, 58, 74, 75, 76, 77, 78, 79, 80, 81, 1 54, 159, 235, 240 and 247 and pharmaceutically acceptable addit ion salts, and solvates thereof.In an embodiment the compound of Formula ( I ) is selected from the group consisting of any of the exemplified compounds,and the free bases, the pharmaceutically acceptable addition salts, and the solvates thereof.All possible combinations of the above-indicated embodiments are considered to be embraced within the scope of this invention. Methods for the PreparationIn this section, as in all other sections unless the context indicates otherwise, references to Formula (I) also include all other sub-groups and examples thereof as defined herein.The general preparation of some typical examples of the compounds of Formula (I) is described hereunder and in the specific examples, and are generally prepared from starting materials which are either commercially available or prepared by standard synthetic processes commonly used by those skilled in the art. The following schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention.Alternatively, compounds of the present invention may also be prepared by analogous reaction protocols as described in the general schemes below, combined with standard synthetic processes commonly used by those skilled in the art of organic chemistry.The skilled person will realize that in the reactions described in the Schemes, it may be necessary to protect reactive functional groups, for example hydroxy, amino, or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups can be used inaccordance with standard practice. This is illustrated in the specific examples.The skilled person will realize that in the reactions described in the Schemes, it may be advisable or necessary to perform the reaction under an inert atmosphere, such as for example under N2-gas atmosphere, for example when NaH is used in the reaction. It will be apparent for the skilled person that it may be necessary to cool the reaction mixture before reaction work-up (refers to the series of manipulations required to isolate and purify the product(s) of a chemical reaction such as for example quenching, column chromatography, extraction).The skilled person will realize that heating the reaction mixture under stirring may enhance the reaction outcome. In some reactions microwave heating may be used instead of conventional heating to shorten the overall reaction time.The skilled person will realize that another sequence of the chemical reactions shown in the Schemes below, may also result in the desired compound of Formula ( I ).The skilled person will realize that intermediates and compounds shown in the schemes below may be further functional ized according to methods well-known by the person skilled in the art.The skilled person will realize that more Compounds of Formula ( I ) can be prepared by using similar synthetic protocols as described in the Schemes below. In case one of the starting materials is available as a salt form, the skilled person will realize that it may be necessary to first treat the salt with a base, such as for example Ν,Ν-diisopropylethylamine (DIPE A) .All variables are defined as mentioned hereabove unless otherwise is indicated or is clear from the context.The skilled person will understand that analogous chemistry as described in Schemes 1 to 9, may also be applied to make compounds of Formula (I) wherein Het represents a bicyclic aromatic heterocyclic rings system (a-4) or (a-5). Some typical examples are illustrated in the specific examples. In addition, this information may be combined with standard synthetic processes commonly used by those skilled in the art of organic chemistry to obtain more compounds of Formula (I) wherein Het represents (a-4) or (a- 5).In general, compounds of Formula (I) can be prepared according to Scheme 1 :eneral scheme 1Int. VI In scheme 1, 'LGi ' is defined as a suitable leaving group such as for example halogen; 'LG2' is defined as a suitable leaving group such as for example halogen or -SCH3. 'LG3' is defined as a leaving group such as halogen and -SCH3. All other variables in Scheme 1 are defined according to the scope of the present invention.In scheme 1, the following reaction conditions typically apply:1: Different sets of reaction conditions dependent on the definition of R3a, R3b or R3c: la: When R3a, R3b or R3c is halogen, step 1 can be skipped.lb: When R3a, R3b or R3c is NR7aR7b, in the presence of a suitable amine of formula HNR7aR7b, with a suitable solvent such as for example, H20, MeOH, or EtOH, at a suitable temperature such as for example between 100-130 °C typicall under microwave conditions or using an autoclave vessel for heating.lc: When R3a, R3b or R3c is -0-Ci- alkyl, in the presence of a suitable HO-Ci_4alkyl, with a suitable base such as for example NaH, potassium tert-butoxide (tBuOK) in a suitable solvent such as for example tetrahydrofuran. (THF) at a suitable temperature. Alternatively in the presence of the suitable HO-Ci_4alkyl as solvent with a suitable acid such as for example HC1. Id: When R3a, R3b or R3c is hydrogen, under hydrogenation conditions: H2-gas atmosphere in the presence of a catalyst such as for example Raney Ni, Pd / C (for example 5 wt % or 10 wt %) or Pt / C (for example 5 wt %) in a suitable solvent such as for example methanol (MeOH), ethanol (EtOH ) or THF;le: When R a, R3b or R3c is C Y-ialkyl, in the presence of a suitable boron ic acid or ester such as for example methylboronic acid with a suitable catalyst such as for example 1 , l'-bis(diphenylphosphino)ferrocene and with with a suitable base such as for example K3PO4 in a in a suitable solvent mixture such as for example dioxane H20 ratio 5 to 1 at a suitable temperature such as for example 100°C;2: in the presence of a suitable acid, such as for example 4M HCl in dioxane or 4M HCl in MeOH, with a suitable solvent such as for example MeOH at a suitable temperature such as for example room temperature; or alternatively in the presence of a suitable acid such as for example trifluoroacetic acid (TFA) in dichloromethane (DCM) at a suitable temperature, or acetic acid in THF and water at a suitable temperature such as for example room temperature.3: in the presence of suitable acid anhydride of formula (Ci_4alkylC=0)20 with a suitable solvent such as pyridine at a suitable temperature. When R3a, R3b or R3c is NH2, (Ci_4alkylC=0)20 can react with the NH2 to obtain the N(Ci_4alkylC=0)2 intermediate. Such an intermediate can be converted to the targeted product in a suitable solvent such as for example MeOH at a suitable temperature such as for example 100-130 °C under microwave conditions or using an autoclave vessel for heating. The reaction may benefit from the presence of an acid, such as HCl or C alkylC02H.The starting materials in scheme 1 are commercially available or can be prepared by standard means obvious to those skilled in the art or as described in following general schemes.General scheme 2aIn general, intermediates of Formula I II, V and VII wherein Z represents -O-CH Recall be prepared according to Scheme 2a. All other variables in Scheme 2a are defined according to the scope of the present invention. The skilled person will realize a suitable protection group is needed when R3a, R3b or R3c is -NH2 or -NHR7b;In scheme 2a, the following reaction conditions apply:1 : The Mitsunobu reaction:la: In the presence of PPfi3-Polymer supported, diisopropyl azodicarboxylate(DIAD) or diethyl azodicarboxylate (DEAD) or Bis(l , l-dimethylethyl)- azodicarboxylate (DBAD) in a suitable solvent such as for example anhydrous THF at a suitable temperature such as for example room temperature.lb: In the presence of triphenylphosphine (PPh3), DIAD or DEAD in a suitable solvent such as for example anhydrous THF at a suitable temperature such as for example room temperature.lc: In the presence of cyanomethylenetributylphosphorane (CMBP) orcyanomethylenetrimethylphosphorane (CMMP), in a suitable solvent such as for example anhydrous toluene at a suitable temperature such as for example 80 °C.The starting materials in scheme 2a are commercially available or can be prepared by standard means obvious to those skilled in the art or as described in following general schemes. The skilled person will realize that when R5a is Ci_4alkyl, the different isomers can be separated from each other by using Reversed-Phase High-Performance Liquid Chromatography (RP-HPLC) or Supercritical Fluid Chromatography (SFC).General scheme 2bIntermediates of Formula II, IV and VI wherein Z represents -Xa-CHR5a- can be prepared according to Scheme 2b. In scheme 2b, 'Xa' is defined as O or S; 'LG' is defined as a leaving group such as for example halogen, mesylate (MsO) and tosylate (TosO), preferably TosO. "LGT is defined as leaving group such as for example halogen; ' LG:' is defined as a leaving group such as for example halogen or -SCH3. "LG;' is defined as a leaving group such as for example halogen or - SO L,. All other variables in Scheme 2b are defined according to the scope of the present invention.Int. VIIn scheme 2b, the following reaction conditions apply:1 : in the presence of a base such as for example K2CO3, trietylamine (Et3N) or DIPEA, in a suitable solvent such as CH3CN, DCM or Ν,Ν-dimethylacetamide (DMA).The starting materials in scheme 2b are commercially available or can be prepared by standard means obvious to those skilled in the art or as described in following general schemes. The skilled person will realize that when R5a is Ci_4alkyl, the different isomers can be separated from each other by using Reversed-Phase High-Performance Liquid Chromatography (RP-HPLC) or Supercritical Fluid Chromatography (SFC).General scheme 2cIntermediates III, V and VII wherein Z represents -Xa-CHR5a- can be prepared according to Scheme 2c. In scheme 2c, 'Xa' is defined as O or S. 'LG' is defined as a leaving group such as for example halogen, MsO or TosO, preferably TosO. All other variables in Scheme 2c are defined according to the scope of the present invention. The skilled person will realize that a suitable protection group is needed when R3a, R3b or R3c is -NH2 or -NHR7b.In scheme 2c, the following reaction conditions apply:1 : in the presence of a base such as for example K2C03, Et3N or DIPEA, in a suitable solvent such as CH3CN, DCM or Ν,Ν-dimethylacetamide (DMA).The starting materials in scheme 2c are commercially available or can be prepared by standard means obvious to those skilled in the art or as described in following general schemes. The skilled person will realize that when R5a is Ci_4alkyl, the different isomers can be separated from each other by using Reversed-Phase High-Performance Liquid Chromatography (RP-HPLC) or Supercritical Fluid Chromatography (SFC). General scheme 3In general, intermediates wherein Z represents -X-CHR5a- ; and wherein X represents -NH or -NR."- can be prepared according to Scheme 3. In scheme 3, 'LGi ' is defined as a leaving group such as for example halogen; 'LG2' is defined as a leaving group such as for example halogen or -SCH3. 'LG3' is defined as a leaving group such as for example halogen or -SCH3. All other variables in Scheme 3 are defined according to the scope of the present invention.In scheme 3, the following reaction conditions apply:1 : in the presence of a suitable reduction reagent such as for example sodium triacetoxyborohydride (NaBH(AcO) together with a suitable solvent such as for example DCM at a suitable temperature such as for example room temperature; or alternatively NaBH3CN together with a suitable solvent such as for example MeOH at a suitable temperature such as for example between room temperature and 50 °C.2: in the presence of a suitable base such as for example NaH together with a suitable solvent such as for example anhydrous THF, N, N-d i m ethyl fo m amide (DMF), DMA at a suitable temperature such as for example between room temperature and 50 C. The starting materials in scheme 3 are commercially available or can be prepared by standard means obvious to those skilled in the art or as described in the specific experimental part. The skilled person will realize that when R5a is the different isomers can be separated from each other by using Reversed-Phase High- Performance Liquid Chromatography (RP-HPLC) or Supercritical FluidChromatography (SFC).General scheme 4In general, intermediates wherein Z represents - C≡C-, -CH=CH-, or -CH2-CH2- can be prepared according to Scheme 4. In scheme 4, 'LGi ' is defined as a leaving group such as for example halogen; 'LG2' is defined as a leaving group such as for example halogen or -SCH3. 'LG3' is defined as leaving group such as for example halogen or - SCH3. All other variables in Scheme 4 are defined according to the scope of the present invention.In scheme 4, the following reaction conditions apply:1 : In the presence of suitable amine, such as H R'R" or NaOR', with a suitable solvent such as for example H20, MeOH, or EtOH at a suitable temperature such as for example between 100-130 °C under microwave condition or using an autoclave vessel for heating.2: In the presence of suitable catalyst, such as bis(triphenylphosphine)palladium(II) dichloride and copper(I) iodide in a suitable solvent, such as 2-methyltetrahydrofuran with a suitable base, such as for example triethylamine at a suitable temperature, such as for example 80 °C.3: in the presence of a suitable salt, such as for example tctracthylammonium chloride (Et4NCl), in a suitable solvent, such as for example DMF, with a suitable base such as for example DIPEA and a palladium catalyst, such as for example Pd(OAc)2 (palladium(II) acetate) at suitable temperature such as for example 100 °C.4: in the presence of a H2-gas atmosphere and a catalyst such as for example Pd / C (for example 5 wt % or 10 wt %) in a suitable solvent such as for example MeOH.The starting materials in scheme 4 are commercially available or can be prepared by standard means obvious to those skilled in the art or as described in the specific experimental part.General scheme 5In general, intermediates wherein Y represents CH2 or CF2, hereby named Ya, and wherein Z represents -CH20- can be prepared according to Scheme 5.In scheme 5, 'LGi ' is defined as a leaving group such as for example halogen; 'LG2' is defined as a leaving group such as for example halogen or -SCH3. 'LG3' is defined as leaving group such as halogen or -SCH3. All other variables in Scheme 5 are defined according to the scope of the present invention.In scheme 5, the following reaction conditions apply:1: in the presence of a base such as for example K2CO3, Et3N or DIPEA, in a suitable solvent such as CH3CN, DCM or Ν,Ν-dimethylacetamide (DMA).General scheme 6In general, intermediates wherein Z represents -CH2- can be prepared according to Scheme 6. In scheme 6, 'LGi ' is defined as a leaving group such as for example halogen; 'LG2' is defined as a leaving group such for example halogen or -SCH3.'LG3' is defined as a leaving group such as for example halogen or -SCH3. All other variables in Scheme 6 are defined according to the scope of the present invention.In scheme 6, the following reaction conditions apply:1: In the presence of tosylhydrazide, with a suitable solvent such as for example, MeOH, EtOH, or DCM at a suitable temperature such as room temperature.2: In the presence of Boronic acids, with suitable base such as K2CO3, Na2C03,CS2CO3, with a suitable solvent such as for example, 1,4-dioxane at a suitable temperature such 90 °C.The starting materials in scheme 6 are commercially available or can be prepared by standard means obvious to those skilled in the art or as described in the specific experimental part.General scheme 7In general, intermediates wherein Z represents -CH2-CH2- can be prepared according to Scheme 7. In scheme 7, 'LGi ' is defined as a leaving group such as for example halogen; 'LG2' is defined as a leaving group such as for example halogen or -SCH3. 'LG3 ' is defined as leaving group such as for example halogen or -SCH3. All other variables in Scheme 7 are defined according to the scope of the present invention.In scheme 7, the following reaction conditions typically apply:1 : In a first step in the presence of an alkene precursor and a 9- Borabicyclo(3.3.1)nonane (9-BBN) solution 0.5 M in THF under nitrogen atmosphere at a temperature between room temperature and reflux and a reaction time between 1 to 3 hours. In a second step in the presence of, for example, a suitable Ar-bromide or Ar- iodide and a suitable catalyst as for example Ι,Γ- bis(diphenylphosphino)ferrocene]dichloropalladium(II) and in the presence of a suitable base as for example potassium phosphate tribasic in a suitable solvent mixture as for example THF and water at a suitable temperature between 50 C and reflux and a suitable reaction time between 1 and 3 hours.2: Different sets of reaction conditions dependent on the definition of R3a, R3b or R3c: 2a: When R3a, R3b or R3c is halogen, step 1 can be skipped.2b: When R3a, R3b or R3c is NR7aR7b, in the presence of a suitable amine of formula HNR7aR7b, with a suitable solvent such as for example, H20, MeOH, or EtOH, at a suitable temperature such as for example between 100-130 °C typicall under microwave conditions or using an autoclave vessel for heating.2c: When R3a, R3b or R3c is -0-Ci_4alkyl, in the presence of a suitable HO-Ci_4alkyl, with a suitable base such as for example NaH, potassium tert-butoxide (tBuOK) in a suitable solvent such as for example tetrahydrofuran (THF) at a suitable temperature. Alternatively in the presence of the suitable HO-Ci-ialkyl as solvent with a suitable acid such as for example HC1. 2d: When R3a, R3b or R3c is hydrogen, under hydrogenation conditions: H2-gas atmosphere in the presence of a catalyst such as for example Raney Ni, Pd / C (for example 5 wt % or 10 wt %) or Pt / C (for example 5 wt %) in a suitable solvent such as for example methanol (MeOH), ethanol (EtOH) or THF;2e: When R3a, R3b or R3c is C' l^alkyl, in the presence of a suitable boron ic acid or ester such as for example methylboronic acid with a suitable catalyst such as for example 1.1 '-bis(diphenylphosphino)feiToeenc and with w ith a suitable base such as for example K3PO4 in a in a suitable solvent mixture such as for example dioxane / H20 ratio 5 to 1 at a suitable temperature such as for example 100°C.The starting materials in scheme 7 are commercially available or can be prepared by standard means obvious to those skilled in the art or as described in the specific experimental part.General scheme 8In general, intermediates wherein Z represents -CH2-CH2- can be prepared according to Scheme 8. In scheme 8, 'LGi ' is defined as a leaving group such as for example halogen; 'LG2' is defined as a leaving group such as for example halogen or -SCH3. 'LG3 ' is defined as leaving group such as for example halogen or -SCH3. All other variables in Scheme 8 are defined according to the scope of the present invention.In scheme 8, the following reaction conditions typically apply: 1: Different sets of reaction conditions dependent on the definition of R3a, R3b or R3c: la: When R3a, R3b or R3c is halogen, step 1 can be skipped.lb: When R3a, R3b or R3c is NR7aR7b, in the presence of a suitable amine of formula HNR7aR7b, with a suitable solvent such as for example, H20, MeOH, or EtOH, at a suitable temperature such as for example between 100-130 °C typicall under microwave conditions or using an autoclave vessel for heating.lc: When R3a, R3b or R3c is -0-Ci_4alkyl, in the presence of a suitable HO-Ci_4alkyl, with a suitable base such as for example NaH, potassium tert-butoxide (tBuOK) in a suitable solvent such as for example tetrahydrofuran (THF) at a suitable temperature. Alternatively in the presence of the suitable HO-C ialkyl as solvent with a suitable acid such as for example HC1.Id: When R3a, R3b or R3c is hydrogen, under hydrogenation condit ions: H2-gas atmosphere in the presence of a catalyst such as for example Raney Ni, Pd / C (for example 5 wt % or 10 wt %) or Pt / C (for example 5 wt %) in a suitable solv ent such as for example methanol (MeOH), ethanol (EtOH) or THF;le: When R3a, R3b or R3c is CV^alkyl, in the presence of a suitable boron ic acid or ester such as for example methylboronic acid with a suitable catalyst such as for example 1 , l'-bis(diphenylphosphino)ferrocene and with with a suitable base such as for example K3PO4 in a in a suitable solvent mixture such as for example dioxane / H20 ratio 5 to 1 at a suitable temperature such as for example 100°C;2: In a first step in the presence of an alkene precursor and a 9-BBN solution 0.5 M in THF under nitrogen atmosphere at a temperature between room temperature and reflux and a reaction time between 1 to 3 hours. In a second step in the presence of suitable (het)arylbromide or (het)aryliodide and a suitable catalyst as for example Ι,Γ- bis(diphenylphosphino)ferrocene]dichloropalladium(II) and in the presence of a suitable base as for example potassium phosphate tribasic in a suitable solvent mixture as for example THF and water at a suitable temperature between 50°C and reflux and a suitable reaction time between 1 and 3 hours.The starting materials in scheme 8 are commercially available or can be prepared by standard means obvious to those skilled in the art or as described in the specific experimental part.General scheme 9In general, intermediates as shown in Scheme 9 wherein Z represents -CH2-CH2- can be prepared according to Scheme 9. In scheme 9, 'LGi ' is defined as a leaving group such as for example halogen. All other variables in Scheme 9 are defined according to the scope of the present invention1: In a first step in the presence of an alkene precursor and a 9-BBN solution 0.5 M in THF under nitrogen atmosphere at a temperature between room temperature and reflux and a reaction time between 1 to 3 hours. In a second step in the presence of, for example, a suitable Ar-bromide or Ar-iodide (X being Br or I respectively) and a suitable catalyst as for example Ι,Γ- bis(diphenylphosphino)ferrocene]dichloropalladium(II) and in the presence of a suitable base as for example potassium phosphate tribasic in a suitable solvent mixture as for example THF and water at a suitable temperature between 50°C and reflux and a suitable reaction time between 1 and 3 hours.2: In the presence of trifiic anhydride and a suitable base as for example pyridine in a suitable solvent as for example DCM at a suitable temperature as for example 0°C under an inert atmosphere of N2 gas.3: In the presence of a suitable base as for example Cs2C03 in a suitable solvent as for example DMF at a suitable temperature as for example room temperature under an inert atmosphere of N2 gas.The starting materials in scheme 9 are commercially available or can be prepared by standard means obvious to those skilled in the art or as described in the specific experimental part.In all these preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration andchromatography. The chi rally pure forms of the compounds of Formula ( I ) form a preferred group of compounds. It is therefore that the chi rally pure forms of the intermediates and their salt forms are particularly useful in the preparation of chirally pure compounds of Formula ( I ). Also enant iomeric mixtures of the intermediates are useful in the preparation of compounds of Formula ( I ) with the corresponding configuration.PharmacologyIt has been found that the compounds of the present invention inhibit PRMT5 activity.In particular compounds of the present inv ention bind to the PRMT5 enzyme, and compet itively with natural substrate SAM ( S-adenosyl-L-methionine), to inhibit such enzyme.It is therefore anticipated that the compounds according to the present invention or pharmaceutical compositions thereof may be useful for treating or preventing, in particular treating, of diseases such as a blood disorder, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerat i v e diseases, pancreat itis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft reject ion, lung injuries and the l ike.In particular the compounds according to the present inv ention or pharmaceutical compositions thereof may be useful for treating or preventing, in particular treating, of diseases such as allergy, asthma, hematopoietic cancer, lung cancer, prostate cancer, melanoma, metabolic disorder, diabetes, obesity, blood disorder, sickle cell anemia, and the like.The compounds according to the present invention or pharmaceutical compositions thereof may be useful for treating or prev enting, in particular treating, of diseases such as a prol iferative disorder, such as an autoimmune disease, cancer, a benign neoplasm, or an inflammatory disease.The compounds according to the present invention or pharmaceutical compositions thereof may be useful for treating or preventing, in particular treating, of diseases such as a metabolic disorder comprising diabetes, obesity; a proliferative disorder comprising cancer, hematopoietic cancer, lung cancer, prostate cancer, melanoma, or pancreatic cancer; blood disorder; hemoglobinopathy; sickle cell anemia; β - thalassemia, an inflammatory disease, and autoimmune disease e.g. rheumatoid arthrit is, systemic lupus erythematosus, Sjogren's syndrome, diarrhea, gastroesoph agea 1 reflu disease, and the like. In some embodiments, the inhibition of PRMT5 by a provided compound may be useful in treating or preventing, in particular treating, the following non-limiting list of cancers: breast cancer, lung cancer, esophageal cancer, bladder cancer, hematopoietic cancer, lymphoma, medulloblastoma, rectum adenocarcinoma, colon adenocarcinoma, gastric cancer, pancreatic cancer, liver cancer, adenoid cystic carcinoma, lung adenocarcinoma, head and neck squamous cell carcinoma, brain tumors, hepatocellular carcinoma, renal cell carcinoma, melanoma, oligodendroglioma, ovarian clear cell carcinoma, and ovarian serous cystadenoma.Examples of metabolic disorders which may be treated or prevented, in particular treated, include, but are not limited to, diabetes or obesity.Examples of blood disorders which may be treated or prevented, in particular treated, include, but are not limited to, hemoglobinopathy, such as sickle cell disease or β- thalassemia.Examples of cancers which may be treated or prevented, in particular treated, include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangio sarcoma, lymphangioendothelio sarcoma, hemangio sarcoma), appendix cancer, benign monoclonal gammopathy, bil iary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast ), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma: m ed u 11 o b 1 asto ma), bronchus cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), chordoma, choriocarcinoma, c ra n i o ph a ry n gi o m a , colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma ), epithelial carcinoma, ependymoma, endothelio sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma ), endometrial cancer (e.g. , uterine cancer, uterine sarcoma ), esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett' s adenocarinoma), Ewing sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), famil iar hypereosinophilia, gall bladder cancer, gastric cancer (e.g., stomach adenocarcinoma), gastrointestinal stromal tumor (G IST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cel l carcinoma (OSCC ), throat cancer (e.g., pharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoiet ic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell AL L), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell A M L ), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL ) (e.g., B-cell CLL, T- cell CLL); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-ccll HL, T- cel l HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CL L SL L), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa- associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma ), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., "Waldenstrom's macro globulinemia" ), immunoblast ic large cell lymphoma, hairy cell leukemia (HCL), precursor B -lymphoblast ic lymphoma and primary central nervous system (CNS) lymphoma: and T-cell NH L such as precursor T-lymphoblastic lymphoma leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell lymphoma, e tranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and mult iple myeloma (MM)), heavy chain disease (e.g. , alpha chain disease, gamma chain disease, mu chain disease), h e m a n g i o b 1 a s t o ma , inflammatory myo fibroblastic tumors, immunocyt ic amyloidosis, kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cel l carcinoma ), liver cancer (e.g., hepatocel lular cancer (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, non-small cell lung cancer (NSCLC), squamous lung cancer (SLC), adenocarcinoma of the lung. Lewis lung carcinoma, lung neuroendocrine tumors: typical carcinoid, atypical carcinoid, small cell lung cancer (SCLC), and large cell neuroendocrine carcinoma ), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplasia syndromes (MDS), mesothelioma, myelopro 1 i ferat i ve disorder (MPD) (e.g., polycythemia Vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a.myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophil ic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g.. n eu rofibro matos i s (NF) type 1 or type 2, schwannomatosis ), neuroendocrine cancer (e.g., gastroenteropancreaticneuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors), penile cancer (e.g., Paget' s disease of the penis and scrotum ), pinealoma, primit ive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer. rhabdo myosarco ma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma ( SCO, keratoacanthoma ( A ), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g., appendi cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST),chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma ( PTC), medullary thyroid cancer), urethral cancer, vaginal cancer, and vulvar cancer (e.g. , Paget' s disease of the vulva ). Examples of neurodegenerative diseases which may be treated or prevented, in particular treated, include, but are not limited to, motor neurone disease, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotropic lateral sclerosis, retinitis pigmentosa, spinal muscular atropy, and cerebellar degeneration. Examples of cardiovascular diseases which may be treated or prevented, in particular treated, include, but are not limited to, cardiac hypertrophy, restenosis, atherosclerosis, and glomerulonephritis.Examples of inflammatory diseases which may be treated or prevented, in particular treated, include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, haemo lytic autoimmune anaemia ), rhinitis, asthma, arteritis (e.g., polyarterit is, temporal arteritis, periarteritis nodosa, Takayasu's arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter's arthritis), upper respiratory tract disease, ankylosing spondylit is, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis. Chagas disease, chronic obstructive pulmonary disease, diverticulitis, cermatomyositis, diabetes (e.g., type I diabetes mellitus, type 2 diabetes mellitus ), a skin condition (e.g., psoriasis, eczema, eczema hypersensitivity reactions, burns, dermatitis, pruritus (itch)), endometriosis, Guillain-Barre syndrome, infection, ischaemic heart disease, Kawasaki di.sea.se, glomerulonephritis, gingivitis, hypersensitiv ity, headaches (e.g., migraine headaches, tension headaches), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, interstit ial cystitis (painful bladder syndrome), gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, morphea, myeasthenia gravis, myocardial ischemia, multiple sclerosis, nephrotic syndrome, pemphigus vulgaris, pernicious aneaemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g. , Parkinson's disease, Huntington's disease, and Alzheimer's disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, schleroderma, scierodoma, sarcoidosis, spondyloarthopathies, Sjogren's syndrome, thyroiditis, transplantation rejection, tendonitis, trauma or injury (e.g. , frostbite, chemical irritants, toxins, scarring, burns, physical injury), vasculitis, vitiligo and Wegener's granulomatosis. In particular the inflammatory disease is an acute inflammatory disease (e.g., for example, inflammation resulting from infection). In particular the inflammatory disease is a chronic inflammatory disease (e.g., conditions resulting from asthma, arthritis and inflammatory bowel disease). The compounds may also be useful in treating inflammation associated with trauma and non-inflammatory myalgia. The compounds may also be useful in treating inflammation associated with cancer.Examples of autoimmune diseases which may be treated or prevented, in particular treated, include, but are not limited to, arthritis (including rheumatoid arthritis, spondyloarthopathies, gouty arthritis, degenerative joint diseases such as osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis,undifferentiated spondylitis, Behcet's disease, haemo lytic autoimmune anaemias, amyotrophic lateral sclerosis, amylosis, multiple sclerosis, acute painful shoulder, psoriatic, and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, eczema hypersensitivity reactions, burns, dermatitis, pruritus (itch)), enuresis, eosinophilic disease,gastrointestinal disorder (e.g. , selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), and disorders ameliorated by a gastroprokinetic agent (e.g. , ileus, postoperative ileus and ileus during sepsis; gastroesophageal reflux disease (GORD, or its synonym GERD); eosinophilic esophagitis, gastroparesis such as diabetic gastroparesis; food intolerances and food al lergies and other functional bowel disorders, such as non-ulcerative dyspepsia (NUD) and non-cardiac chest pain (NCCP, including costo-chondritis)).In a particular embodiment, a provided compound may be useful in somatic cell reprogramming, such as reprogramming somatic cells into stem cells. In a particular embodiment, a provided compound may be useful in germ cell development, and are thus env isioned useful in the areas of reproductive technology and regenerative medicine.Other diseases which may be treated or prevented, in particular treated, include, but are not limited to, ischemic injury associated myocardial infarctions, immunological diseases, stroke, arrhythmia, toxin-induced or alcohol related liver diseases, aspirin- sensitive rhinosinusitis, cystic fibrosis, cancer pain, and haematological diseases, for example chronic anemia and aplastic anemia.The compounds of the present invention may also have therapeutic applications in sensitising tumour cells for radiotherapy and chemotherapy.Hence the compounds of the present invention may be used as "radiosensit izer" and / or "chemosensitizer" or can be given in combination with another "radiosensit izer" and / or "chemosensitizer".The term "radiosensitizer", as used herein, is defined as a molecule, preferably a low molecular weight molecule, administered to animals in therapeutically effective amounts to increase the sensitivity of the cel ls to ionizing radiation and / or to promote the treatment of diseases which are treatable with ionizing radiation.The term "chemosensitizer", as used herein, is defined as a molecule, preferably a low molecular weight molecule, administered to animals in therapeutically effective amounts to increase the sensitiv ity of cells to chemotherapy and / or promote the t reatment of diseases w hich are treatable with chemotherapeutics.Several mechanisms for the mode of action of radiosensitizers have been suggested in the literature including: hypoxic cell radiosensitizers ( e.g., 2- nitroimidazole compounds, and benzotriazine dioxide compounds) mimicking oxygen or alternatively behave like bioreductive agents under hypoxia; non-hypo ic cell radiosensitizers (e.g., halogenated pyrimidines) can be analogoues of DNA bases and preferentially incorporate into the DNA of cancer cells and thereby promote the radiation-induced breaking of DNA molecules and / or prevent the normal DNA repair mechanisms; and various other potential mechanisms of act ion have been hypothesized forradiosensitizers in the treatment of disease.Many cancer treatment protocols currently employ radiosensitizers in conjunction with radiation of x-rays. Examples of x-ray activated radiosensitizers include, but are not limited to, the following: metronidazole, misonidazole, d e s m e t h y I m i s o n i d a zo I e , pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, E09, RB 6145, nicotinamide, 5 - b ro mo d eo y u r i d i n e ( BUdR ), 5- iododeoxyuridine (lUdR), bro modeoxycyt id i ne, fluorodeoxyuridine ( FudR), hydroxyurea, cisplat in, and therapeutically effective analogs and derivatives of the same.Photodynamic therapy (PDT) of cancers employs visible light as the radiation act ivator of the sensit izing agent. Examples of photodynamic radiosensit izers include the follow ing, but are not limited to: hematoporphyrin derivat ives, Photofrin,benzoporphyrin derivatives, tin et ioporphyrin, pheoborbide-a, bacterioch lorophy 11-a, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs and derivatives of the same.Radiosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds which promote the incorporation of radiosensitizers to the target cells; compounds which control the flow of therapeutics, nutrients, and / or oxygen to the target cel ls; chemotherapeutic agents which act on the tumour with or w ithout additional radiation; or other therapeutically effective compounds for treating cancer or other diseases.Chemosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds which promote the incorporation of chemosensit izers to the target cells; compounds which control the flow of therapeutics, nutrients, and / or oxygen to the target cells; chemotherapeutic agents which act on the tumour or other therapeutically effective compounds for treating cancer or other disease. Calcium antagonists, for example verapamil, are found useful in combination with antineoplastic agents to establish chemosensit ivity in tumor cells resistant to accepted chemotherapeutic agents and to potentiate the efficacy of such compounds in drug-sensitive malignancies.The compounds of the present invention might also reduce the risk of cancer recurrence.The invention relates to compounds of Formula ( 1 ) and pharmaceutically acceptable addition salts, and solvates thereof, for use as a medicament. The invention relates to compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for use in the inhibition of PRMT5 activity.The compounds of the present invention can be "anti-cancer agents", which term also encompasses "anti-tumor cell growth agents" and "anti-neoplastic agents".The invention relates to compounds of Formula ( I ) and pharmaceutical ly acceptable addit ion salts, and solvates thereof, for use in the treatment of diseases mentioned above.The invent ion relates to compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for the treatment or prevention, in particular for the treatment, of said diseases.The invention relates to compounds of Formula (I) and pharmaceut ically acceptable addit ion salts, and solvates thereof, for the treatment or prevention, in particular in the treatment, of PRMT5 mediated diseases or conditions.The invention relates to compounds of Formula ( I ) and pharmaceutically acceptable addit ion salts, and solvates thereof, for the manufacture of a medicament.The invention relates to compounds of Formula ( I ) and pharmaceutically acceptable addit ion salts, and solvates thereof, for the manufacture of a medicament for the inhibit ion of PRMT5.The invention relates to compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for the manufacture of a medicament for the treatment or prevent ion, in particular for the treatment, of any one of the disease conditions mentioned hereinbefore.The invention relates to compounds of Formula ( I ) and pharmaceutically acceptable addition salts, and solvates thereof, for the manufacture of a medicament for the treatment of any one of the disease conditions mentioned hereinbefore.The invention relates to compounds of Formula ( I ) and pharmaceutically acceptable addit ion salts, and solvates thereof, can be administered to mammals, preferably humans, for the treatment or prevention of any one of the diseases mentioned hereinbefore.In view of the utility of the compounds of Formula ( I ) and pharmaceut ically acceptable addition salts, and solvates thereof, there is prov ided a method of treating warmblooded animals, including humans, suffering from or a method of preventing warmblooded animals, including humans, to suffer from any one of the diseases mentioned hereinbefore. Said methods comprise the administration, i.e. the systemic or topical administration, preferably oral administration, of an effective amount of a compound of Formula (I) or a pharmaceutically acceptable addition salt, or a solv ate thereof, to warm-blooded animals, including humans.Those of skill in the treatment of such diseases could determine the effective therapeutic daily amount from the test results presented hereinafter. An effective therapeutic daily amount would be from about 0.005 mg / kg to 50 mg / kg. in particular 0.01 mg / kg to 50 mg / kg body weight, more in particular from 0.01 mg / kg to 25 mg / kg body weight, preferably from about 0.01 mg / kg to about 1 5 mg / kg, more preferably from about 0.01 mg / kg to about 10 mg / kg, even more preferably from about 0.01 mg / kg to about 1 mg / kg, most preferably from about 0.05 mg / kg to about 1 mg / kg body weight. A particular effectiv e therapeutic daily amount might be from about 0.01 to 1 .00 g twice a day ( BI D ), more in particular 0.30 to 0.85 g BI D; even more in particular 0.40 g BI D. The amount of a compound according to the present inv ent ion, also referred to here as the active ingredient, which is required to achieve a therapeutically effect will of course, vary on case-by-case basis, for example with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.A method of treatment may also include administering the activ e ingredient on a regimen of between one and four intakes per day. In these methods of treatment the compounds according to the invention are preferably formulated prior toadministration. As described herein below, suitable pharmaceutical formulations are prepared by known procedures using well known and readily av ailable ingredients.The compounds of the present inv ention, that can be suitable to treat or prev ent cancer or cancer-related conditions, may be administered alone or in combination with one or more additional therapeutic agents. Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of Formula (I), a pharmaceutically acceptable addit ion salt, or a solvate thereof, and one or more additional therapeutic agents, as well as administration of the compound of Formula (I), a pharmaceutically acceptable addition salt, or a solv ate thereof, and each additional therapeutic agents in its own separate pharmaceutical dosage formulation. For example, a compound of Formula ( I ), a pharmaceutically acceptable addition salt, or a solv ate thereof, and a therapeutic agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulat ions. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition.Accordingly, the present invention further prov ides a pharmaceutical composition and. as active ingredient, a therapeutically effective amount of a compound of Formula ( I ), a pharmaceutical ly acceptable addition salt, or a solvate thereof.Accordingly, the present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof.The carrier or diluent must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.For ease of administration, the subject compounds may be formulated into various pharmaceutical forms for administration purposes. The compounds according to the invention, in particular the compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for system ically administering drugs.To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, in particular, for administration orally, rectal ly, percutaneously, by parenteral injection or by inhalation. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obv iously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises sal ine solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing a compound of Formula ( I ), a pharmaceutically acceptable addition salt, or a solvate thereof, may be formulated in an oil for prolonged action. Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wetting agent, opt ionally combined with suitable addit ives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and / or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. Acid or base addition salts of compounds of Formula ( I ) due to their increased water solubility over thecorresponding base or acid form, are more suitable in the preparation of aqueous compositions.It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physical ly discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the requiredpharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated mult iples thereof.In order to enhance the solubility and / or the stabil ity of the compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, in pharmaceutical compositions, it can be advantageous to employ α-, β- or γ-cyclodextrins or their derivatives, in particular hydroxyaikyl substituted cyclodextrins, e.g. 2-hydroxypropyl- β-cyclodextrin or sulfobutyl-P-cyclodextrin. Also co-solvents such as alcohols may improve the solubility and / or the stability of the compounds according to the invention in pharmaceutical compositions.Depending on the mode of administration, the pharmaceutical composition w ill preferably comprise from 0.05 to 99 % by weight, more preferably from 0. 1 to 70 % by weight, even more preferably from 0.1 to 50 % by weight of the compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, and from 1 to 99.95 % by weight, more preferably from 30 to 99.9 % by weight, even more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.As another aspect of the present invention, a combination of a compound of the present invent ion with another anticancer agent is envisaged, especially for use as a medicine, more specifically for use in the treatment of cancer or related diseases.For the treatment of the above conditions, the compounds of the invention may be advantageously employed in combination with ant ibody based immune cell redirection, for example T-cel 1 / neutrophil redirection. This can be achieved for example by the use of bi specific monoclonal antibodies or artificial T-cel 1 receptors.For the treatment of the above conditions, the compounds of the invention may be advantageously employed in combination w ith one or more other medicinal agents, more particularly, with other anti-cancer agents or adjuvants in cancer therapy.Examples of anti-cancer agents or adjuvants (supporting agents in the therapy) include but are not limited to :platinum coordination compounds for example ci splat in optionally combined with amifostine, carboplat in or oxaliplatin;taxane compounds for example paclitaxel, paclitaxel protein bound particles ( Abraxane™) or docetaxel;- topoi.somerase I inhibitors such as camptothecin compounds for exampleirinotecan, SN-38, topotecan, topotecan hcl;topoi.somerase 11 inhibitors such as anti-tumour epipodophyllotoxins or podophyllotoxin derivatives for example etoposide, etoposide phosphate or teniposide:- ant i-tumour vinca alkaloids for example vinblastine, vincristine or vinorelbine;- anti-tumour nucleoside derivatives for example 5-fluorouraciI, leucovorin, gemcitabine, gemcitabine hcl, capecitabine, cladribine, fludarabine, nelarabine; alkylating agents such as nitrogen mustard or nitrosourea for example cyclophosphamide, chlorambucil, carmustine, thiotepa, mephalan (melphalan ), lomustine, altretamine, busulfan, dacarbazine, estramustine, ifosfamide optional ly in combination with mesna. pipobroman, procarbazine, streptozocin, temozolomide, uracil;anti-tumour anthracycline derivatives for example daunorubicin, doxorubicin optionally in combination with dexrazoxane, doxil, idarubicin, mitoxantrone, epirubicin, epirubicin hcl. valrubicin;molecules that target the IGF-1 receptor for example picropodophilin; tetracarcin derivatives for example tctrocarcin A;- glucocorticoids for example prednisone;antibodies for example trastuzumab ( HER 2 antibody), rituximab (CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab. pertuzumab, bevacizumab, alemtiizumab. eculizumab, ibritumomab tiuxetan, nofetiimomab, panitumumab, tositumomab, CNTO 328;estrogen receptor antagonists or selective estrogen receptor modulators or inhibitors of estrogen synthesis for example tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene or letrozole;- aromatase inhibitors such as exemestane, anastrozole, letrazole. testolactone and vorozole;differentiat ing agents such as retinoids, vitamin D or retinoic acid and retinoic acid metabolism blocking agents (RAMBA) for example accutane;DNA methyl transferase inhibitors for example azacyt idine or decitabine;- antifolates for example premetrexed disodium;ant ibiotics for example antinomycin D, bleomycin, mitomycin C, dactinomycin. carminomycin, daunomycin, levamisole, plicamycin, mithramyein;antimetabolites for example clofarabine, aminopterin. cytosine arabinoside or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine; - apoptosis inducing agents and antiangiogenic agents such as Bcl-2 inhibitors for example YC 137, BH 3 1 2, ABT 737, gossypol, HA 14- 1 , TW 37 or decanoic acid;tubuline-binding agents for example combrestatin, colchicines or nocodazole; kinase inhibitors (e.g. EGFR (epithelial growth factor receptor) inhibitors,TK.I (mu It i target kinase inhibitors), mTOR inhibitors) for example flavoperidoi, imatinib mesylate, erlotinib, gefit inib, dasatinib, lapat inib, lapatinib ditosylate, sorafenib, sunitinib, sunitinib maleate, temsirolimus;farnesyltransferase inhibitors for example t ipifarnib;hi stone deacetylase (HDAC) inhibitors for example sodium butyrate, suberoylanilide hydroxamic acid (SAHA ), depsipeptide ( FR 901228), NVP-LAQ824, R306465, J J-26481585, trichostatin A, vorinostat;Inhibitors of the ubiquitin-proteasome pathway for example PS-341 , MLN .41 or bortezomib;- Yondelis;- Telomerase inhibitors for example telomestatin;Matrix metalloproteinase inhibitors for example batimastat, marimastat, prinostat or metastat. Recombinant interleukins for example aldesleukin, dcnilcukin diftitox, interferon a I fa 2a, interferon a! fa 2b, peginterferon alfa 2b- MAP inhibitorsRetinoids for example alitretinoin, bexarotene, tretinoin- Arsenic trioxideAsparaginaseSteroids for example dromostanolone propionate, megestrol acetate, nandrolone (decanoate, phenpropionate), dexamethasoneGonadotropin releasing hormone agonists or antagonists for example abarelix, goserelin acetate, histrelin acetate, leuprolide acetateThalidomide, lenalidomideercaptopurine, mitotane, pamidronate, pegademase, pegaspargase, rasburicase BH3 mi met ics for example ABT-737- ME inhibitors for example PD98059, AZD6244. CI- 1040- colony-stimulating factor analogs for example filgrastim, pegfilgrastim,sargramostim; erythropoietin or analogues thereof (e.g. darbepoetin alfa );interleukin 1 1 ; oprelvekin; zoledronate, zoledronic acid; fentanyl;bisphosphonate; pa li term ina steroidal cytochrome P450 17alpha- hydroxylase- 17,20-lyase inhibitor ( CYP 1 7), e.g. abiraterone, abiraterone acetateGlycolysis inhibitors, such as 2-deoxyglucosemTOR inhibitors such as rapamycins and rapalogs, and mTOR kinase inhibitors- PI3 inhibitors and dual mTOR / PB inhibitorsautophagy inhibitors, such as chloroquine and hydroxy-ch loroq u i ne- antibodies that re-activate the immune response to tumors, for examplenivolumab (anti-PD- 1 ), lambrol izumab (anti-PD- 1 ), ipilimumab (anti-CTLA4), and MPDL3280A (ant i-PD-L l ).The present invention further relates to a product containing as first active ingredient a compound according to the inv ention and as further active ingredient one or more anticancer agents, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.The one or more other medicinal agents and the compound according to the present inv ention may be administered simultaneously (e.g. in separate or unitarycomposit ions ) or sequentially in either order. In the latter case, the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. It will be appreciated that the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and compound of the present invent ion being administered, their route of administration, the particular tumour being treated and the particular host being treated. The optimum method and order of administration and the dosage amounts and regime can be readily determined by those skilled in the art using conventional methods and in view of the informat ion set out herein.The weight ratio of the compound according to the present invention and the one or more other anticancer agent(s ) when given as a combinat ion may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency ofadministration depends on the particular compound according to the invention and the other anticancer agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as well as other medicat ion the individual may be taking, as is w el l known to those skilled in the art. Furthermore, it is ev ident that the effective daily amount may be lowered or increased depending on the response of the treated subject and / or depending on the evaluation of the physician prescribing the compounds of the instant invention. A particular weight ratio for the present compound of Formula ( I ) and another anticancer agent may range from 1 / 10 to 10 / 1 , more in particular from 1 / 5 to 5 / 1 , even more in particular from 1 / 3 to 3 / 1 .The plat inum coordination compound is advantageously administered in a dosage of 1 to 500mg per square meter (mg / m2) of body surface area, for example 50 to 400 mg / m2, particularly for cisplatin in a dosage of about 75 mg / m2 and for carboplatin in about 300mg / m2 per course of treatment.The taxane compound is advantageously administered in a dosage of 50 to 400 mg per square meter (mg / m ) of body surface area, for example 75 to 250 mg / m2, particularly for paclitaxel in a dosage of about 1 75 to 250 mg / m2 and for docetaxel in about 75 to 1 50 mg / m2 per course of treatment.The camptothecin compound is advantageously administered in a dosage of 0. 1 to 400 mg per square meter (mg / m2) of body surface area, for example 1 to 300 mg / m2, particularly for irinotecan in a dosage of about 100 to 350 mg / m2 and for topotecan in about 1 to 2 mg / m ' per course of treatment. The anti-tumour podophyllotoxin derivative is advantageously administered in a dosage of 30 to 300 mg per square meter (mg / m ) of body surface area, for example 50 to 250mg / m2, particularly for etoposide in a dosage of about 35 to 1 00 mg / m2 and for teniposide in about 50 to 250 mg / m2 per course of treatment.The anti-tumour v inca alkaloid is advantageously administered in a dosage of 2 to 30 mg per square meter (mg / m2) of body surface area, particularly for vinblastine in a dosage of about 3 to 12 mg / m2, for vincristine in a dosage of about 1 to 2 mg / m2, and for vinorelbine in dosage of about 10 to 30 mg / m2 per course of treatment.The anti-tumour nucleoside derivat ive is advantageously administered in a dosage of 200 to 2500 mg per square meter (mg / m2) of body surface area, for example 700 to 1 500 mg / m2, part icularly for 5-FU in a dosage of 200 to 500mg / m2, for gemcitabine in a dosage of about 800 to 1 200 mg / m2 and for capecitabine in about 1000 to2500 mg / m2 per course of treatment.The alkylat ing agents such as nitrogen mustard or nitrosourea is advantageously administered in a dosage of 100 to 500 mg per square meter (mg / m ) of body surface area, for example 1 20 to 200 mg / m2, particularly for cyclophosphamide in a dosage of about 100 to 500 mg / m2, for chlorambucil in a dosage of about 0. 1 to 0.2 mg kg, for carmustine in a dosage of about 1 50 to 200 mg / m2 , and for lomustine in a dosage of about 100 to 1 50 mg / m2 per course of treatment. The anti-tumour anthracycline derivat ive is advantageously administered in a dosage of 10 to 75 mg per square meter (mg / m2) of body surface area, for example 1 5 to60 mg / m2, particularly for doxorubicin in a dosage of about 40 to 75 mg / m2, for daunorubicin in a dosage of about 25 to 45 mg / m2, and for idarubicin in a dosage of about 10 to 1 5 mg / m2 per course of treatment.The antiestrogen agent is advantageously administered in a dosage of about 1 to 100 mg daily depending on the particular agent and the condition being treated. Tamoxifen is advantageously administered orally in a dosage of 5 to 50 mg, preferably 10 to 20 mg twice a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect. Toremifene is advantageously administered orally in a dosage of about 60 mg once a day. continuing the therapy for sufficient time to achieve and maintain a therapeutic effect. Anastrozole is advantageously administered orally in a dosage of about 1 mg once a day. Droloxifene is advantageously administered orally in a dosage of about 20- 100 mg once a day. Raloxifene is advantageously administered orally in a dosage of about 60 mg once a day. Exemestane is advantageously administered orally in a dosage of about 25 mg once a day.Antibodies are advantageously administered in a dosage of about 1 to 5 mg per square meter (mg / m2) of body surface area, or as known in the art, if different. Trastuzumab is advantageously administered in a dosage of 1 to 5 mg per square meter (mg / m2) of body surface area, particularly 2 to 4 mg / m 2 per course of treatment.These dosages may be administered for example once, twice or more per course of treatment, which may be repeated for example every 7, 14, 2 1 or 28 days.The following examples illustrate the present invention. In case no specificstereochemistry is indicated for a stereocenter of a compound, this means that a mixture of the R and the S enantiomers was obtained. In case more than 1 stereocenter is present in a structure, each stereocenter for which no specific stereochemistry is indicated was obtained as a mixture of R and S.The skilled person will realize that typically after a column purification, the desired fractions were collected and the solvent was evaporated to obtain the desired compound or intermediate.ExamplesHereinafter, the term "rt", "r.t." or "RT" means room temperature; "Me" means methyl;"MeOH" means methanol; "Et" means ethyl; "EtOH" means ethanol; "NaH" means sodium hydride; "DEAD" means diethyl azodicarboxylate; "HMPT" meanshexamethylphosphorous triamide; "Boc20" means t rt-h u tox yea rbo n y 1 anhydride;"Bu ONO" means tert-butyl nitrite; "TosOH" means 4-methy lbenzenesu 1 fo n ic acid;"TosCl" means 4-methy lbenzenesulfonyl chloride (also p-toluenesulfonyl. chloride);"CM BP" means cyanomethylenetributylphosphorane; "DBAD" means di-tert -butyl. azodicarboxylate; "LAH" means lithium aluminum hydride; " aBH(AcO);" or "NaBH(OAc );" means sodium triacetoxyborohydride; "EtOAc" means ethyl acetate;"TEA" or "Et;N" means triethylamine; "DCM" means dichloromethane; "q.s." means quantum sufficit; "Int." Means intermediate; "MeCN" or "ACN" means acetonitrile;"DMF" means iY-di methyl formamide; "DMA" means Λ ', Λ - d i m e t h y 1 a c e t a m i d e ;"DMF-DMA" means N , N - D i m e t h y 1 fo rm amide dimethyl acetal; "Pd(dppf)G.'" means [ 1 . 1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium( I I ); "THF" means tetrahydrofuran; "C H >S FeP;> .C 1 Pd" means [ 1 , 1 '-bis(diphenylphosphino )ferrocene] dichloropalladium( ii ); "i-PrOH" or "iPrOH" means 2-propanol; "LC" means liquid chromatography; "LCMS" means Liquid Chromatography / Mass spectrometry;"HPLC" means high-performance l iquid chromatography; "int." means intermediate; "prep-HPLC" means preparative high-performance liquid chromatography; "m-CPBA" means meta-Chloroperoxybenzoic acid; "TFA" means trifluoroacetic acid; "m.p." means melting point; "RP" means reversed phase; "min" means minute(s); "h" means hour(s ); "PE" means petroleum ether; "v / v" means volume per volume; "Celite®" means diatomaceous earth; "DM SO" means dimethyl sulfoxide; "SFC" meansSupercritical Fluid Chromatography; "DIPE" means diisopropyl ether; "dppf ' or "DPPF" means 1 , 1 '-Bis(diphenylphosphino)ferrocene; "DIPEA" or "DIE A" means N,N-diisopropylethylamine; "PPh3" means triphenylphosphine; "Et20" means diethyl ether; "Pd / C" means pal ladium on carbon; "Pt / C" means platina on carbon;"Pd(OH)2 / C" means palladium hydroxide on carbon; "CPME" means cyclopentyl methyl ether; "Pd2(dba)3 means Tris(dibenzylideneacetone)dipalladium; "DIAD" means diisopropyl azodicarboxylate; "TMSCF3" meanstrimethy 1( tri fluoromethyl )si lane; "TBAF" means tetrabu ty 1 am mo n i u m fluoride; "psi" means pound-force per square inch; "EtjNG" means tetraethylammonium chloride; "eq." means equivalent(s); "Pd(OAc)2" means palladium(II) acetate; "AcOH" means acetic acid; "DMAP" means 4-(dimethylamino)pyridine; "t-BuO ", "'BuO " or " OtBu"means potassium tert-butoxide; "Dess-Martin period inane" means 1 , 1 , 1 - Triacetoxy-l ,l-dihydro-l ,2-benziodoxol-3(lH)-one; "TBDMSC1" means tert- Butyldimethylsilyl chloride; "PPh3-polymer" or "PPh3-pol" means triphenylphosphine polymer bound; "Ph ,PCH ,Br" means methyltriphenylphosphonium bromide; "Bn" means benzyl; "Bz" means benzoyl; "p-TSA" means 4-methy lbenzenesu 1 fo n ic acid; "BF3.Et20" means Boron Tri fluoride-Ethyl Ether Complex; "9-BBN" means 9- Borabicyclo[3.3. 1 Jnonane; "Pd- 1 1 8" means Dichlorof 1 , 1 '-bis(di-tert- butylphosphino)ferrocene]pal ladium( 11 ); and "TLC" means thin layer chromatography; "prep-TLC" means preparative TLC;"p - M eC(, H 4 S O 3 H . H Ό " means para toluenesulfonic acid hydrate; "PMB" means para methoxybenzyl; "KOAc" means potassium acetate; "PTSA" para toluenesulfonic acid; "MTBE" means methyl tert. butyl ether; Rh(acac)(eth)2" meansAcetylacetonatobis(ethylene)rhodium( I ); "(S)-MonoPhos" means (S )-N,N- dimethyldinaphtho[2, 1 -D: 1 '.2'-F][ 1 ,3,2]dioxaphosphepin-4-amine; "Tf20" means tri flic anhydride; "Mel" means methyliodide; "Me2NH" means dimethylamine;"Me2NH.HCl" means dimethylamine hydrochloric acid; "Me4 Cl" meanst et ra m et h y 1 a m mo n i u m chloride; "MeONa" means sodium methoxide; "Ts" means tosyl; "MsCl" means mesylchloride; "DIBAH" means D i i sob utylal u mini u m hydride; "TBDMS" means tertButyl dimcthylsilyk "Pd(dppf)Cl2.CH2Cl2" means [ 1 , 1 '- Bis(diphenylphosphino )feiTocene]dichloropalladium( I I ), comple withdichloromethane,; "PPA" means polyphosphoric acid;"NH2Bn" means benzylaminc;"Pd(PPh3)2Cl2" means Dichlorobis(triphenylphosphine)palladium(II).Intermediates containing a double bond with substituents which may be in the E or the Z configuration are show in one particular configuration in the experimental part below. However, unless explicitly indicated by (E) or (Z ), it is unkown if these intermediates were obtained in the E or Z configuration or as a mixture of both configurations. For example intermediates 24-26, 29-31 , 72-76, and intermediates 79- 88 might be in the E or Z configuration or might be mixtures thereof.For example Intermediates 44, 97- 100, 136- 138, 150 and compounds 55, 57, 57a and 61 were obtained in the E configuration and are explicitly indicated as such (E) in the experimental part below.For intermediates that were used in a next reaction step as a crude or as a partially purified intermediate, estimated mol amounts ( in some cases indicated by ~) are indicated in the reaction protocols described below, or alternatively theoretical mol amounts are indicated.A. Preparation of intermediatesExample AlPreparation of intermediate Iintermediate 1To a mixture of 6-chloro-7-deazapurinebeta-d-riboside (25.0 g, 87.5 mmol ) in acetone (330 mL) was added 2.2-dimethoxypropane (18.2 g, 1 75 mmol ) and 4- methylbenzenesulfonic acid (TosOH) (1.51 g, 8.75 mmol) in one portion at 25°C under N2.The mixture was stirred at 60 °C for 2 hours. The mixture was cooled to 25°C. The reaction was quenched by adding saturated NaHCOs (100 mL) slowly and then extracted with ethyl acetate (125 mL x 5).The combined organic phase was washed with saturated brine (120 mL), dried with anhydrous MgS04, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (gradient elution: DCM / Ethyl acetate from 1 :0 to 2: 1 ) to afford crude intermediate 1 (38.0 g) as light yellow gum.Example A2Preparation of intermediate 3intermediate 2 Tris(3,6-dioxaheptyl)amine, KOH , toluene intermediate sTo a solution of 5-0-tert-Butyldimethylsilyl-2,3-o-isopropylidene-D-ribofuranose (intermediate 2) ( 24.3 g, 79.8 mmol) in CC14 (12.8 mL, 133 mmol ) and toluene (200 ml ) was added dropwise HMPT at -50 °C over 30 minutes. After the mixture was stirred at -50°C for 2 hours, the reaction mixture was quickly washed with ice cold brine (30 mL), dried over anhydrous Na2S04 and added immediately to a heavily stirred mixture of powdered KOH (6.5 g, 117 mmol), 2,4-dichloro-7h- pyrrolopyrimidine (10.0 g, 53 mmol), tris(3,6-dioxaheptyl)amine (8.27 mL, 26.6 mmol) and toluene (200 ml). The mixture was stirred at room temperature for 48 hours. Then the solvent was concentrated in vacuum. The residue was treated with 250 ml NH4CI solution and extracted with ethyl acetate (300 ml x 2). The organic layers were combined and dried with Na2S04, filtered and the filtrate was concentrated in vacuum. The residue was purified by column chromatography over silica gel (gradient elution: petroleum ether / ethyl acetate from 25 : 1 to 15: 1). The product fractions were collected and the solvent was evaporated to give the desired intermediate 3 (6.50 g, crude)Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 3 using the appropriate starting materials (Table 1). Table 1:Example A3Preparation of intermediate 6Intermediate 3 (7.00 g, 14.8 mmol ) was dissolved into the solvent mixture of acetic acid, water and THF with ratio as 13:7:3 ( 100 mL). The reaction mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure at 60 °C, afforded 6.8 g of crude intermediate 6 together with by-product. To the solution of the above crude product in acetone (50 mL) was added 2,2-dimethoxyprapane (5 mL, 42 mmol ) and 4-methy lbenzenesu 1 fo n ic acid mono hydrate ( 13 mg, 0.07 mmol) at room temperature under N2. The mixture was stirred at 60 C for 2 hours. The solvent was removed under reduced pressure below 30 °C. The residue was purified by column chromatography (gradient elution: EtOAc petroleum ether from 1 / 10 to 1 / 3) on silica gel to afford the desired intermediate 6 (3.02 g, 34% yield).Example A4Preparation of intermediate 7intermediate 4 intermediate 7To a solution of intermediate 4 (9.50 g, 20.9 mmol) in THF (82 mL) was added 1 M TBAF solution in THF (41.8 mL, 41.8 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The mixture was evaporated to dryness. The residue was taken up into water and extracted with DCM (150 ml x 2). The organic layers were dried (Na2S04), filtered and the filtrate was concentrated in vacuum. The residue was purified by column chromatography over silica gel (gradient elution: petroleum ether / ethyl acetate from 10 / 1 to 4 / 1) to give the desired intermediate 7 (3.68 g, 88% yield) Below intermediate was prepared by an analogous reaction protocol as was used preparation of intermediate 7 using the appropriate starting materials (Table 2). Table 2:Example A 5Preparation of intermediate 10intermediate 10Step a) intermediate 9To a mixture of 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine ( 14.0 g, 52.8 mmol ) and ( 1 R,2S ,3 R,5 R)-3 -amino-5 -(hydroxymethyl)cyclopentane- 1 ,2-diol hydrochloride ( 10.7 g, 58.1 mmol) in propan-2-ol / H20 (208 ml.., 7: 1), was added EhN (13.4 g, 132 mmol) in one portion at 25 C under N2. The mixture was stirred at 90 C for 23 hours. The mixture was cooled to 50 C and 4M HCI (24 mL, 106 mmol ) was added slowly. The residue was then stirred at 50 C for 2 hours. The reaction mixture was cooled to 25 C and aHCO; ( 14 g, 100 mmol ) was added slowly. Ethyl acetate (230 niL) was added, followed by the addition of a half-saturated aHCO; solution (q.s.). The organic phase was isolated and the aqueous phase was extracted with ethyl acetate (230 mL x 2). The combined organic phase was dried with anhydrous MgSO.4, filtered and concentrated in vacuum to afford intermediate 9 as yellow solid ( 17.4 g, quantitative yield in 2 steps). The crude product was di ectly used as such in the next reaction step without further purification.Step b)To a mixture of intermediate 9 (17.4 g, -52.7 mmol ) in acetone (250 mL) was added 2,2-dimethoxypropane (11.0 g, 105 mmol) and TsOH.H20 (908 mg, 5.27 mmol) in one portion at 25 C under N2.The mixture was stirred at 60 C for 2 hours. The mixture was cooled to 25 C and the solution was concentrated in vacuum, quenched by saturated NaHC03 (100 mL) slowly and then extracted with ethyl acetate (100 mL x 3).The combined organic phase was washed with saturated brine (100 mL), dried with anhydrous MgSC^, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (gradient elution: DCM / Ethyl acetate from 1 / 0 to 2 / 1) to afford intermediate 10 as light yellow gum ( 15.5 g, 89 % yield). Example A 6Preparation of intermediate 14intermediate 14Step a)intermediate 11An oven-dried flask was charged with 7-bromo-4-(methylthio)pyrrolo[2,l- f][ l ,2,4]triazine (45.0 g, 184 mmol) and dry THF ( 1 .20 L) under N2. The yellow solution was cooled to -78 °C, and a yellow suspension was formed. n-BuLi (2.5 M, 79.6 mL) was added dropwise to the reaction mixture over period of 25 minutes at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour and a yellow-brown solution formed. A pre-cooled solution of intermediate 10 (84.0 g, 201 mmol ) in dry THF (800 mL) in another flask (-78 °C) was added to the solution under N2. The resulting red- brown solution was stirred at -78 °C for 1.5 h. 2 batches were carried out in parallel. The reaction was quenched by addition of a saturated NH4C1 aqueous solution (300 mL) at -78 °C, and subsequently the mixture was warmed to 10 °C. The mixture was extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The residue was load on silica gel then purified by column chromatography (Si02, gradient elution: Petroleum ether / Ethyl acetate from 10 / 1 to 3 : 1 ) to afford intermediate 11 ( 149 g, 56 % yield) as an orange gum. Step b)intermediate 11 intermediate 12To a stirred solution of intermediate 11 (74.0 g, 127 mmol) and triethylsilane (59.9 g, 5 15 mmol ) in DCM (1.80 L) was added BF3.Et20 (90.9 g, 640 mmol ) dropwi.se at - 30— 20 C. 2 batches were carried out in parallel. The resulting orange solution was stirred between -30 and -20 °C for 4.5 hours. The reaction mixture was carefully poured into a saturated aHCO, aqueous solution (2.5 L) with vigorous stirring (gas evolution). The mixture was stirred for 2 hours. The organic layer was separated and the aqueous phase was extracted with DCM (200 mL x 3 ). The combined organic layers were washed with brine (500 ml, x 2), dried over MgSOi, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, gradient elution: petroleum ether : ethyl acetate: from 12: 1 to 8: 1), affording intermediate 12 as a light yellow gum ( 125.7 g, 83% yield, ) Step c)intermediate 12 intermediate 131M BCh in CH2Cl2 (860 mL, 860 mmol) was added dropwise at -78 °C to a stirred solution of intermediate 12 (75.0 g, 132 mmol) in DCM ( 1 .20 L) dropwise over period of 2.5 hour under N2. The mixture was stirred at -78 °C for 1 hour. The reaction mixture was slowly warmed to -40 °C. The reaction mixture was poured into MeOH (2.5 L,20 °C) with stirring. The resulting red solution was stirred for 3 hours. Water (250 mL) was added into the mixture and left at 20 °C for 16 h. The solution was portion wise poured onto solid NaHC03 (500 g) carefully with vigorous stirring (gas evolution, the color of mixture was turned from orange-red to yellow). The resulting suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was dispensed in iPrOH / CH2Cl2 (1 :3, 1 L) then filtered (to remove some inorganic salt) and the filtrate was concentrated under reduced pressure. The residue was triturated with petroleum ether (500 mL x 3 ) to afford crude intermediate 13 (40.2 g, crude) as an orange solid, which used in the next reaction step without further purification.Step d)intermediate 14To a suspension of intermediate 13 (40.2 g, crude) and 2,2-dimethoxypropane (34 mL, 277 mmol) in acetone (600 mL) was added TsOH.H20 (5.92 g, 31.10 mmol, 0.23 eq) at 25 °C (pH = 2). The resulting mixture was heated at 60 °C for 2 hours. After being cooled to 25 °C, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (500 mL) and saturated aqueous NaHC03 solution (500 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (200 mL x 3 ). The combined organic layers were washed with brine ( 100 mL), dried over MgS04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, gradient elution: CH2C12 / Ethyl acetate from 10 / 1 to 6 / 1). The fractions containing desired intermediate 14 were combined and concentrated under reduced pressure. The residue (28 g, about 80% purity) was purified again by column chromatography (silica gel, gradient elution: Petroleum ether / Ethyl acetate: from 20 / 1 to 4 / 1). The desired fractions were combined and concentrated under reduced pressure. The residue was diluted with CH2C12 ( 15 mL) then petroleum ether / ethyl acetate (4: 1 , 200 mL) was added. The mi ture was concentrated to about 150 mL and solids were precipitated. The slurry was diluted with petroleum ether to about 400 mL and stirred for 16 hours at 20 °C. The mixture was filtered and the solid was rinsed with petroleum ether / ethyl acetate (20 / 1, 100 mL). The solids were collected and dried under high vacuum to afford pure intermediate 14 as white solid (18.6 g, 42 % yield for 2 steps).Example A 7Preparation of intermediate 15intermediate 1intermediate 15The intermediate 1 ( 10.0 g, -28.6 mmol ), TEA ( 12 mL, 85.7 mmol ) and DMAP (0.70 g, 5.71 mmol) were dissolved in CH2CI2 ( 100 m L ). p-toluenesulfonyl chloride ( 10.9 g, 57. 1 mmol) was added at 0°C. The mixture was stirred at room temperature overnight. Water ( 100 mL) was added to the above solution. The aqueous layer was extracted with DCM ( 1 00 mL x 3). The combined organic layer was dried over and concentrated to dryness. The residue was purified by flash column (gradient edition: petroleum ether EtOAc from 1 Ό to 3 / 1). The product fractions were collected and the solvent was evaporated to give intermediate 15 as yellow oil ( 14.5 g, 97 % yield ).Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 15 using the appropriate starting materials (Table 3).Table 3 :Example APreparation of intermediate 18Intermediate 1 Intermediate 18Intermediate 1 ( 1 00.0 g, theoretically 307 mmol ) was dissolved in 400 mL of l , 4- dioxane. Then 400 mL of Ammonia water (28- 30% N3¾ basis) was added. The mixture was stirred in a sealed tube at 1 00°C for 20 hours. The mixture was cooled to room temperature. The reaction mixture was evaporated in vacuum to remove half of the solvent. Water (200 mL) was added and extracted with EtOAc (500 mL x 3 ). The combined organic layers were washed with brine (200 ml x 2), dried and concentrated to give Intermediate 18 as white solid ( 93 g, 93% yield ).Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 18 using the appropriate starting materials (Table 4).Table 4:Example A9Preparation of intermediate 23intermediate 23Step a:intermediate 21 intermediate 22To a solution of intermediate 21 (6.6 g, 9.75 mmol ) in THF ( 130 niL) was added ammonia (28% in H20, 65 mL ) at room temperature. The reaction mixture was stirred at 100 C (using an autoclave) for 1 6 hours. The reaction mi ture cooled to room temperature and evaporated to dryness under reduced pressure. The residue was taken up into water ( 100 mL) and DCM ( 100 ml. ) and stirred for 1 hour. The layers were separated and the water layer was washed again with DCM ( 100 ml. ) to remove impurities. The water layer was filtered and the filtrate was evaporated to dryness. The residue was purified on flash chromatgraphy on silica (gradient eluention: DCM / MeOH from 95 :5 to 90: 10 ). The desired fractions were collected and the solvent was evaporated, yielding intermediate 22 (3.4 g, crude). The crude product was directly used for the next reaction step w ithout further purification.Step b:intermediate 22 intermediate 23To a mixture of intermediate 22 ( 1 .0 g, crude) in acetone (32 mL) was added 2,2- dimethoxy propane (1.78 mL g. 14.5 mmol ) and 4-methy lbenzenesu 1 fo n ic acid (0.61 g, 3. 19 mmol) in one portion at room temperature. The mixture was stirred at 60 °C for 3 hours. The mixture was cooled to room temperature and quenched by adding saturated aHCO; ( 10 niL) slowly and then extracted with ethyl acetate (50 mL x 5 ). The combined organic phase was washed with saturated brine (120 mL ), dried with MgS04, filtered and concentrated in vacuum, offered intermediate 23 (0.80 g, crude). The crude product was directly used for the next reaction step w ithout further purification.Example A 10Preparation of intermediate 24intermediate 18 intermediate 24Intermediate 18 ( 10.0 g, 32.6 mmol ) was dissolved in THF (200 ml ). ThenDimethyl fo rm amide Dimethylacetal (DMF-DMA) (5.84 g, 49.0 mmol) was added. The mixture was stirred at 60 C for 24 hours. The mixture was cooled to room temperature and the solvent was concentrated in vacuum. The residue was triturated with EtOAc ( 200 mL ) and water ( 100 mL ). The organic layer was separated, the aqueous was extracted with EtOAc (200 mL x 1), the combined organic layer was washed by brine ( 50 mL ), dried over anhydrous filtration and concentration to afford the desired intermediate 24 as a yellow solid ( 10.5 g, 85% yield )Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 24 using the appropriate starting materials (Table 5).Table 5 :Intermediates structure Starting materialHO 125 Intermediate 19X C|Example A 1 1intermediate 28Step a:Intermediate 18 Intermediate 27To the mixture of intermediate 18 (88.0 g, 287 mmol) and imidazole (39.1 g, 575 mmol) in DMF ( 300.0 niL) was added TBDMSC1 (52.0 g, 345 mmol) in one portion at 0 °C under N2. The reaction mixture was stirred overnight at room temperature.Subsequently, water (500 ml ) was added and the mi ture was extracted with EtOAc (800 ml_ x 3 ). The organic layer was washed with brine (500mL). Then the organic phase was dried w ith anhydrous a2S04, filtered, and the organic phase was concentrated under vacuum to give the crude product. The crude product was purified by column chromatography over silica gel (gradiente edition : petroleum ether / ethyl acetate 1 : 1). The desired fraction was concentrated to give the intermediate 27 as oil (120 g, 96 % yield). tep b:Intermediate 27 Intermediate 28To the solution of intermediate 27 (12.4 g, -24.4 mmol) and DMAP (0.30 g, 2.44 mmol) in THF (50 mL) was added (Boc)20 ( 13.3 g, 61 .0 mmol) dropwise at room temperature. The reaction mi ture was stirred at room temperature for 3 hours. Then 1 M TBAF solution in THF (24.4 mL, 24.4 mL) was added dropwise. The reaction mixture was stirred at rt for 18 hours. The reaction mixture was poured into 250 ml of water and extracted with ethylacetate (250 mL x 2). The organ ice layer was washed (water) and brine, dried w ith Na2S04, and concentrated to be dry. The residue was purified by flash chromatography (edition: ethylacetate / heptane = 50 / 50). The desired fraction was col lected and the residue was stirred in heptane. The solid product is filtered off and dried at rt under reduced pressure, yielding intermediate 28 ( 10.2 g, 83% yield ) as solid product.Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 28 using the appropriate starting materials (Table 23).Table 23Example A 12 Preparation of intermediate 29To a reaction mixture of intermediate 24 ( 1 5.0 g, 41 .7 mmol). Et3N ( 1 1 .6 mL, 83.3 mmol) and DMAP (509 mg, 4. 1 7 mmol ) in DCM ( 200 ml . ) was added p- Toluenesulfonyl chloride ( 8.74 g, 45.9 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hou s. Water ( 100 mL ) was added into the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with EtOAc ( 100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous filtered and concentrated to yield the crude intermediate 29 as a brown solid, which was used in the next reaction step without further purification.Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 29 using the appropriate starting materials (Table 6)Table 6:Example A 12bPreparation of intermediate 32interm ediate 28 intevm ediate 32Intermediate 28 (4.5 g, 8.89 mmol), TEA (2.70 g, 26.6 mmol), DMAP (0.54 g, 4.4 mmol) and DCM (40 ml) were stirred on an ice bath. p-Toluenesulfonyl chloride (3.39 g, 17.8 mmol) was added dropwise. The mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water and was extracted with DCM. The organic layer was evaporated and purified with flash chromatography on silica (eluent: DCM 98% MeOH 2%) to give intermediate 32 (5.6 g, 95% yield).Example A 1 3Preparation of intermediate 33intermediate 1 intermediate 33To a mixture of intermediate 1 (2.00 g, theoretically 6.18 mmol) in DCM (40 mL) was added Dess-Martin period inane ( 5.24 g, 12.36 mmol ) in one portion at 0 C under N2.The mixture was stirred at 0 C for 3 hours. To the mixture was added Na2S203 (4 g) in saturated NaHCC (20 mL) and stirred for 10 min. The aqueous phase was extracted with DCM (20 ml, x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried with anhydrous MgSOi, filtered and concentrated in vacuum to afford intermediate 33 (1.80 g, crude) as light yellow gum. The crude product was directly used for the next reaction step without further purification.Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 33 using the appropriate starting materials (Table 7).Table7:Int. structure Starting material512 intermediate 28Example A 14Preparation of intermediate 37intermediate 33 intermediate 37To a solution of intermediate 33 (6.5 g, crude, -15.46 mmol) in THF (200 mL ) was added dropwise MeMgBr (1M, 18.55 ml, 18.55 mmol) at -78°C under N2. The mixture was stirred overnight at room temperature under N2. The reaction mixture was concentrated under vacuum to give crude product as a yellow solid. The crude product was purified by column chromatography (gradient elution: petroleum ether EtOAc from 40: 1 to 1 0: 1 ). The desired fractions were collected and the solv ent was evaporated to giv e Intermediate 37 as light yellow oil (700 mg crude: and 3 g crude with more impurit ies).Example A 1 5Preparation of intermediate 38Method 1Intermediate 35 Intermediate 38 To a mixture of methyltriphenylphosphonium bromide (4.87 g, 13.62 mmol) in THF (500 niL) was added t-BuOK. ( 1 1 .4 ml, 1 M in THF, 1.27g, 1 1 .35 mmol. ) dropwise at O' C under N2. The suspension was turned to bright yellow and stirred at 0 °C for 0.5 h and then w armed to 25°C for 0.5 h. The mi ture was cooled to -40°C. The solution of Intermediate 35 ( 1 .46 g, theoretically 4.54 mmol) in THF ( 130.0 ml. ) was added drop- wise and then stirred at -20°C for 1 h, after this, the mixture was w armed to 25 °C for 2h. To the mixture was added saturated NH4C1 (300ml ) and stirred for 1 0 min. Layers were separated and the aqueous phase was extracted with DCM (300 mL x 2). The combined organic phase was washed with saturated brine (500 mL), dried with anhydrous MgS04, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Gradient eluention: From 0 to 15% of Ethyl acetate / Petroleum ether). The desired fractions were collected and the solvent was evaporated. Intermediate 38 was obtained as off- white solid (530 mg, 36% yield).Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 38 (Method 1) using the appropriate starting materials (Table 8).Table 8:Int. structure Startingmaterial39 Intermediate 3340 °x° Intermediate 36513 Intermediate 512 Method 2Intermediate 35 intermediate 38 A solution of Intermediate 35 ( 10.0 g, theoretically 31.1 mmol ) in THF ( 100 mL) was added drop-wise under N2 over a period of 30 minutes to a bis(iodozincio)methane solution in THF (180 mL, 0.3 1 M, 55.9 mmol, prepared according to the procedure described in Tetrahedron 2002, 58, 8255-8262), stirring was continued until complete conversion (approximately 2 hours). The reaction mixture was quenched by the slow addition of a saturated aqueous NH4C1 solution, during which salt formation was observ ed. Prior to extraction ( EtOAc, 2 x 200 mL), the salts were dissolv ed again by the addition of an aqueous ammonia solution (25%). The combined organic phases were washed w ith an aqueous sodium bisulfite solution and brine, dried with anhydrous MgSO t, filtered and concentrated in v acuum. The residue was purified by silica gel chromatography (eluent: dichloromethane EtOAc 95 / 5 ) to prov ide Intermediate 38 as an off-white solid (6.9 g, 66%).Method 3 Step 1Preparation of intermediate 408Intermediate 408Acetylacetonatobis(ethylene)rhodium(I) (0.837 g, 3.24 mmol) and (R)-N,N- dimethyldinaphtho[2, 1 -Γ3: l '.2'-F][ l ,3,2]dioxaphosphepin-4-amine ( 2.91 g, 8.1 1 mmol ) were dissolved in EtOH (625 mL ) under nitrogen atmosphere. The mixture was stirred at room temperature and flushed through with nitrogen gas for 1 5 minutes. Then (-)- (3AR,6AR)-3 A,6A-dihydro-2,2-dimethyl-4H-cyclopenta- 1 ,3-dioxol-4-one (25 g, 162.16 mmol) and potassium v inyltrifluoroborate (45.73 g, 324.33 mmol) were added and then the reaction mixture was stirred and refluxed for 4 hours. The reaction mixture (suspension ) was cooled down to room temperature. The precipitate was filtered off over a pad of Celite and washed with ethanol. The solvents of the filtrate were evaporated. 1 L heptane was added to the residue. The result ing suspension was filtered off over a pad of Celite and washed w ith heptanes resulting in a dark brown solid residue. The filtrate was washed three times with 300 mL NH4OH, washed with brine, dried with MgSO i, filtered and the solvents of the filtrate evaporated yieldingintermediate 408 (16.18 g, 51% yield ).Step 2Preparation of intermediate 409Intermediate 408 Intermediate 409A solution of intermediate 408 (16.18 g, 82.58 mmol ) in THF (200 mL) was added dropwise to a stirred solution of lithium aluminum hydride 1 M in THF (24.78 mL, 1 M, 24.78 mmol ) in THF (400 mL) at -78°C under nitrogen atmosphere. The reaction mixture was stirred at -78°C under nitrogen atmosphere for 30 minutes. The reaction was quenched by the dropwise addit ion of acetone (6. 1 mL) followed by 50 mL water at -78°C. After addition the reaction mixture was allowed to warm up to room temperature and then 400 mL EtOAc was added. The mixture was shaken vigorously. The organic layer was seprated, washed three times with water, washed with brine, dried with MgSO t, filtered and the solvents of the filtrate evaporated. The residue was dissolved in ethylacetate and purified over a Si02 column, type Grace Reveleris SRC, 80 g. Si 40. on an Armen Spot 11 Ultimate purification system using ethyl acetate and heptane as eluent in a gradient starting from 100% heptanes and ending with 50% heptane and 50% ethyl acetate. The fractions containing product were combined and the solvents were evaporated yielding intermediate 409 (10.77 g, 71 > yield).Step 3 Preparation of intermediate 410Intermediate 410 A solution of Tf20 (13.31 mL, 1 .71 g / mL, 80.93 mmol) in DCM, anhydrous (60 ml ) was added dropwise to a mixture of intermediate 409 (9.94 g, 53.95 mmol) and pyridine, anhydrous (85 mL) in DCM, anhydrous ( 140 mL) at 0 C. The reaction mixture was stirred for 30 minutes and then 75 m L cold water was added. The layers were separated and the organic layer was washed three times with 75 mL water, dried w ith MgSC"4, filtered and the solvents evaporated and co-evaporated with 200 mL toluene. The residue was dissolved in heptane and ethyl acetate and purified over a Si( column, type Grace Reveleris SRC, 40 g. Si 40, on an Armen Spot 11 Ultimate purificat ion system using ethyl acetate and heptane as eluent in a gradient starting from 100% heptane and ending with 50% heptane and 50% ethyl acetate. The fractions containing product were combined and the solvents were evaporated yieldingintermediate 410 (13.0 g, 67% yield ).Step 4Preparation of intermediate 411Intermediate 411A mixture of 4-chloro-7H-pyrrolo[2,3-D]pyrimidine ( 100 g, 65 1 mmol ) and KOtBu (73.07 g, 651 mmol) in THF ( 1 L) was stirred at room temperature for 45 minutes until a clear solution was obtained. The solvents were evaporated. The residue was triturated in DI PE. The white solids were filtered off and dried in vacuo at 30 C yielding intermediate 411 (1 12.6 g, 90% yield). Step 5Preparation of Intermediate 38Intermediate 410 Intermediate 38A solution of intermediate 410 ( 13 g, 4 1 . 1 mmol ) in DMF (50 ml. ) was added dropwise to a stirred solution of intermediate 411 (7.88 g, 4 1 . 1 mmol) in DMF ( 1 50 niL) at 0 C. After addition the reaction mixture was allowed to warm up to room temperature and was then stirred for 18 hours. Another amount of intermediate 411 (1.57 g, 8.22 mmol ) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured out into a beaker with ice and water (-0.5L). The resulting suspension was stirred for 2 hours and then filtered off. The residue was washed three times with water and then dried in vacuo at 50 C yielding intermediate 38 as a white solid (8.75 g, 65% yield ).Example A 54Preparation of intermediate 433Intermediate 38 Intermediate 433A solution of intermediate 38 ( 1 .3 g, 57.22 mmol ) in a mixture of aqueous ammonia (25%, 100 ml ) and THF ( 100 ml ) was heated in a sealed metal pressure vessel at 1 1 0 °C unt il complete conversion (- 1 6 h).The reaction mixture was allowed to cool to room temperature, after which ethyl acetate and brine were added. Both layers were separated, the water layer was extracted once with ethyl acetate. The combined organic phases were washed with brine, dried with anhydrous MgSO t, filtered and concentrated in vacuum to give Intermediate 433 as a light yellow solid ( 1 7.2 g, 100%), which was used in the next reaction step without further puri fication.Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 433 using the appropriate starting materials (Table 24Table 24:Example A 16 Preparation of intermediate 41intermediate 33intermediate 41To a solution of potassium tert-butoxide (1.28 g; 1 1 .4 mmol) in THF (30 mL ) at -78°C was added a solut ion of dimethyl ( 1 -diazo-2-oxopropyl )phosphonate ( 1 .72 g; 1 1 .4 mmol) in THF (5 mL). The solution was stirred for 5 min and then the solution of intermediate 33 ( 1 .90 g; theoretically 5.87 mmol ) in THF (20 mL ) was added. The solution was allowed to warm to room temperature and stirred at room temperature for 1 5 minutes. Water and EtOAc were added, the organic layer was separated, dried over MgS04, filtered and evaporated in vacuo. The residues were purified by preparative LC ( Irregular SiOH 1 5-40 μηι, 80 g Grace, DCM loading, mobile phase gradient elution: heptane : 10% MeOI l in EtOAc from 90: 10, to 70:30). The desired fractions were col lected and the solvent was evaporated to yield intermediate 41 as a colorless oil (1.08 g, 58% yield).Example A 1 7Preparation of intermediate 43intermediate 42intermediate 43To a solution of intermediate 42 (9.2 g, 34. 1 14 mmol) in acetone ( 100 mL) was added 2.2-dimethoxypropane (7. 1 g, 68.1 18 mmol ) and p-TSA (1.8 g, 10.184 mmol). The reaction mixture was stirred overnight at room temperature.The reaction mixture was treated with aqueous NaHCQ? (PH to 7-8), then concentrated under reduced pressure. The resulting residue was diluted w ith water ( 100 mL) and extracted w ith ethyl acetate ( 1 00 mL x 3 ). The organic layer was dried and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (gradient elution:petroleum ether / ethyl acetate from 8 / 1 to 2 / 1). The desired fractions were collected and the solvent was evaporated to afford the intermediate 43 as a pale yellow solid (9.5 g, 90% yield).Example A 1Preparation of intermediate 44intermediate 1 intermediate 44(70% over two steps)A solution of intermediate 1 (2.00 g, theoretically 6.18 mmol) in DCM (30.00 mL) was added dropwise to a suspension of Dess-Martin periodinane (3.14 g, 7.41 mmol) in DCM (30.00 mL) at 0°C under N2. The reaction mixture was allowed to warm to room temperature and stirred until oxidation was finished (2 hours). Subsequently, MeOH (60 mL) and tosylhydrazide (1.50 g, 8.03 mmol) were added and stirring was continued for 3 hours. Water and ethyl acetate were added to the reaction mixture, the organic phase was separated and washed with saturated Na2C03, dried with anhydrous MgS04, filtered and concentrated in vacuum. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol from 100:0 to 98.5: 1.5). The desired fractions were collected and the solvent was evaporated to yield intermediate 44 as a white powder (2.60 g, 70% yield: (E)).Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 44 using the appropriate starting materials (Table 25Table 25Int. Structure Starting materialsExample A 55 Preparation of intermediate 224intermediate 222intermediate 2intermediate 223Step 1 :Preparation of intermediate 222DIAD (7.6 mL, 38.4 mmol, 2.5 eq) was added to a solution of intermediate 2 (5.0 g, 15.3 mmol, 1 .0 eq ), triphenylphosphine ( 10.0 g, 38.4 mmol, 2.5 eq ) and acetone cyanohydrin (5.6 mL, 61 .4 mmol, 4.0 eq ) in anhydrous THF (75 mL) at r.t.. The reaction mixture was stirred for 1 hour and then concentrated in vacuo. The crude product was purified by normal phase flash chromatography using heptane and DCM as eluent (Si02 column, gradient: 50% to 100% DCM , isocratic 100% DCM ) and then followed by a preparative reversed phase flash chromatography using acetonitrile and water with 0.2% NH4HCO3 as eluent to afford intermediate 222 as white solid product (2.8 g, 8.5 mmol, yield 55%)Step 2:Preparation of intermediate 223 and intermediate 224A solution of intermediate 222 ( 1 .54 g, 4.6 mmol, 1 eq) in anhydrous DCM was dried overnight over molecular sieves and filtered. The filtrate was cooled to -78 °C and then 1M DIBAH in DCM (4.6 niL, 4.6 mmol, 1 eq ) was added dropwise. The reaction mixture was stirred for 1 hour at -78°C, then extra 1 M DI BAH in DCM (0.46 ml., 0.46 mmol. 0. 1 eq ) was added and stirred for another 1 .5 hours, then quenched with sodium acetate (4.2 g, 5 1 .2 mmol, 1 1 . 1 eq ) and acetic acid (4.2 mL, 73.4 mL, 16.0 eq ) in a mixture of water / THF (57 mL / 12mL). After the quench, the cooling bath was removed and the mixture was stirred until all ice was melted. The layers were separated and then the aqueous phase was extracted twice with DCM (30 mL ). The organic phases were combined, washed twice with brine, dried over MgS04 and filtered. To the obtained filtrate containing intermediate 223 was added MeOH (50 ml.. ). / oluenesulfonyl. hydrazide (1.1 g, 6.0 mmol, 3 eq ) and then stirred at r.t. for 40 minutes The reaction mixture was washed three times with sat. NaHCO;, twice with brine, dried overMgSO t, filtered and concentrated in vacuo. The crude product was purified by normal phase flash chromatography using heptane and EtOAc as eluent (gradient: 40% to 60% EtOAc to afford the crude product. The mixture was further purified by normal phase flash chromatography using EtOAc and heptane as eluent (Si02 column, gradient: 40% to 60% EtOAc ) to afford intermediate 224 (0.5 g, 0.6 mmol, yield: 14%).Example A 19Preparation of intermediate 45Intermediate 1Intermediate 45 Intermediate 1 (300 mg, theoretically 0.921 mmol), 7-Quinolinol ( 160 mg, 1 . 1 1 mmol) and po 1 y m er-bo u n d ed Triphenylphosphine (~3 mmol / g triphenylphosphine loading, 0.8 g, 2.4 mmol) were stirred in anhydrous THF (12 ml.) under N2. Subsequently, DIAD (0.465 g, 2.30 mmol) was added dropwise at 0 °C. The mi ture was stirred at room temperature for 12 hours under N2. The reaction mixture was filtered over a pad of diatomaceous earth. The residue was washed with MeOH. The filtrate was concentrated in vacuum. The residue was purified by column chromatography over silica gel (eluent: petroleum ether / ethyl acetate from 10 / 1 to 3 / 1). The desired fractions were collected and the solvent was evaporated to giv e the crude intermediate 45 as oil (342 mg).Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 45 using the appropriate starting materials (Table 9).Int. Structure Starting materials233 a) Intermediate 190b) 3-bromoquinolin-7- olExample A 19bPreparation of intermediate 59Diisopropyl azodicarboxylate (0.221 mL, 1.125 mmol) was added dropwise to a stirred suspension of intermediate 1 (0.27 g, 0.80 mmol), 3-bromoquinolin-7-ol (0.18 g, 0.80 mmol) and triphenylphosphine resin (0.375 g, 3 mmol / g, 1.125 mmol) in THF (8 ml ) at room temperature. After addition the reaction mixture was stirred for 18 hours. The reaction mixture was filtered over a pad of Dicalite®. The residue was washed with methanol. The solvents of the filtrate were evaporated. The residue was used as such in the next step.Example A20Preparation of intermediate 61intermediate 61intermediate 1The mixture of intermediate 1 (2.46 g, theoretically 7.54 mmol), 2-methylquinolin-7-ol (1.2 g, 7.54 mmol) and PPh3 (5.93 g, 22.6 mmol) in dry THF (40 ml) was stirred at room temperature under N2. DIAD (4.57 g, 22.6 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. Water (80 mL) was added to the mixture, extracted with EtO Ac (100 mL x 3). The combined organic layers were washed by brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated under vacuum. The residue was purified by column chromatography (gradient elution: EtO A c / Petro leu m ether from 1 :20 to 1 : 1). The desired fractions were collected and the solvent was evaporated to yield intermediate 61 (3.0 g, crude). The crude intermediate 61 was used for the next reaction step without further purification.Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 61 using the appropriate starting materials (Table 10).Table 10:Example A21Preparation of intermediate 71intermediate 1 intermediate 71To a solution of intermediate 1 ( 1 .00 g, -2.92 mmol ) and 2-naphthol (463 mg, 3.21 mmol) in toluene (30 ml_) was added C BP ( 1 .15 mL, 4.38 mmol). The solution was heated at 80 °C for 18 hours and was then cooled down to room temepature. The reaction mixture was evaporated in vacuo. The residues were purified by preparative LC ( Irregular SiOH 15-40 iim, 120 g Grace, DCM deposit, mobile phase gradient: heptane / EtOAc from 80 / 20 to 70 / 30) to giv e intermediate 71 as a colourless gum (1.00 g, 76% yield). Example A22Preparation of intermediate 72intermediate 24 intermediate 72A mixture of PPh3 (9.07 g, 34.6 mmol) and DEAD (4.82g, 27.7 mmol) in THF ( 100 mL) was stirred at room temperature for 10 min. Then Intermediate 24 (5.0 g, theoretically 13.8 mmol) was added, followed by 2-chloroquinolin-7-ol (2.98g, 16.6 mmol). The resulting mixture was stirred at room temperature overnight. Subsequently, the mixture was diluted with EtOAc (100 mL), washed with water and brine. The organic phase was dried over Na2S04, filtered and concentrated. The residue was purified bychromatography (elution: Petroleum ether / EtOAc = 5 / 95). The desired fractions were collected and concentrated to give Intermediate 72 as solid (6.0 g, 83 % yield).Example A23Preparation of intermediate 73intermediate 24intermediate 73To a solution of intermediate 24 (700 mg, theoretically 1 .94 mmol) and 4- mcthylquinolin-7-ol (370 mg, 2.32 mmol ) in THF (20 mL) were added triphenylphosine (624 mg, 2.71 mmol) and DBAD ( 71 1 mg. 2.71 mmol). The mixture was stirred overnight at room temperature and was then evaporated in vacuo. The crude was purified by preparative LC ( irregular SiOH, 15-40 μπι, 50 g, Merck, dry loading (Celite®) mobile phase gradient: from Heptane 80%, EtOAc 18%, MeOH 2% to Heptane 10%, EtOAc 81%, MeOH 9%) to give intermediate 73 as an off-white foam (697 mg, 67% yield).Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 73 using the appropriate starting materials (Table 12).Int. Structure Starting materials504 a) Intermediate 503N O b) 3-chioroquinolin-7- ol517 a) Intermediate 24 b) 2-Quinolinecarboxylic acid, 7-hydroxy-, methyl esterExample A24 Preparation of intermediate 77intermediate 17intermediate 77Cesium Carbonate (2.18 g, 6.70 mmol) was added to a solution of intermediate 17 (1.15 g, -2.23 mmol ) and 3 -b ro mo q u i no 1 i n - 7-o 1 ( 0.5 g, 2.23 mmol ) in DMF ( 25 mL ). The mixture was stirred overnight at room temperature. The reaction mixture was treated with H20 ( 100 ml ) and filtrated. The resulting residue was washed with H20 ( 30 mL ) and dried under reduced pressure to obtain desired crude intermediate 77 as a pale yellow solid (1.1 g).Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 77 using the appropriate starting materials (Table 13).Table 13 :Int. Structure Starting materials Int. Structure Starting materials463 a) Intermediate 17 b) Intermediate 274466 a) Intermediate 17 b) 2-Quinolinamine, 7- h y d ro x y- V- m ethyl-469 a) Intermediate 17 b) Intermediate 468478 a) Intermediate 15 b) Intermediate 477484 a) Intermediate 17 b) IntermediateExample A25 Preparation of intermediate 79intermediate 29 intermediate 79To a solution of intermediate 29 (500 mg, crude, -0.67 mmol ) in DMF (20 niL) were added 3-methoxyquino 1 in-7-o 1 (187 mg. 0.80 mmol) and CS2O3 (652 mg, 2.0 mmol ). The react ion mixture was stirred at room temperature for 1 2 hours. The mixture was quenched with water (80 ml ) and extracted with DCM (50 ml x 3). The organic layers were dried (NaiSO i), filtered and the solvent was concentrated in vacuum to give the crude intermediate 79 as a yellow oil ( 650 mg).Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 79 using the appropriate starting materials (Table 14).Table 14:Int. structure Starting materials199 a) Intermediate 29b) 7-Quinolinol, 6-chloroExample A26Preparation of intermediate 89Intermediate 89Intermediate 32 (48.3 g, -67.99 mmol) was dissolved in 400 ml of DMF. 7-Br- quinolin-7-ol (16.03 g, -67.98 mmol) and Cs2C03 (44.33 g, 135.97 mmol) were added into the reaction mixture and the mixture was stirred at room temperature 16 hours. The reaction mixture was poured into 1000 ml of cold water and extracted by EtOAc (2x600 mL). The organic layer was washed with water (300 mL x 2), dried with anhydrous Na2S04, filtered and the solvent was concentrated in vacuum to give the crudeintermediate 89 (52 g) as an oil which was used in the next step without further purification.Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 89 using the appropriate starting materials (Table 26Table 26Int. structure Starting materials206 a) Intermediate 32 bjlntermediate 205211 a) Intermediate 32 bjlntermediate 210213 a) Intermediate 32 bjlntermediate 212215 a) Intermediate 32 b) 7-Quinolino!, 4- (trifluoromethyl)-217 a) Intermediate 32 b) lntermediate 216 Int. structure Starting materials219 a) Intermediate 32o bjlntermediate 218221 a) Intermediate 32bjlntermediate 220a227 a) Intermediate 32b) 7-Quinolinol, 4-methoxy-o228 a) Intermediate 32 b) 3-Q.uinolinecarboxy!ic acid, 7- hydroxy-, methyl ester230 a) Intermediate 32bjlntermediate 229Example A27Preparation of intermediate 90intermediate 90A mixture of intermediate 15 (893 mg, -1.68 mmol), 7-quinolinethiol ( 1 .6 g, 3.374 mmol, crude) and CS2CO3 (1.21 g, 3.72 mmol) in DMF (20 mL) was stirred overnight at room temperature. The reaction was quenched with water (100 mL). The aqueous phase was extracted with ethyl acetate (200mL x 2). The combined organic layer was washed with brine (100 ml), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by flash column (gradient elution: Petroleum ether / ethyl acetate from 100 / 0 to 1 / 1) to give desired compound intermediate 90 ( 1 70 mg, 20% yield) as off-white solid.Example A28Preparation of intermediate 91intermediate 33 intermediate 917-aminoquinoline (Ar-NH2 in scheme above) (700 mg, 4.85 mmol) was added to a solution of intermediate 33 (2.20 g, theoretically 6.80 mmol) in DCM (45 niL) and acetic acid (278 μί, 4.85 mmol). The solution was stirred for 10 min then sodium triacetoxyborohydride (2.98 g; 14.1 mmol) was added and the mixture was stirred at room temperature for 18 hours. A saturated aqueous solution of NaHC03 was added and the mixture was stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgS04, filtered off and evaporated in vacuo. The residues were purified by preparative LC (Irregular SiOH 15-40 μιη, 80 g Grace, mobile phase gradient: from DCM 100% to DCM 95%, MeOH 5%>) to give intermediate 91 as a yellow oil which crystallized on standing (1.22 g, 56 % yield).Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 91 using the appropriate starting materials (Table 15).Table 15:Example A29Preparation of intermediate 96intermediate 93 intermediate 96To a stirred solution of intermediate 93 ( 1 .0 g, 1.88 mmol ) in DMF (20 niL ) was added NaH (60% dispersion in mineral oil) (0.151 g, 3.77 mmol) at 0°C under nitrogen atmosphere. Subsequently, the reaction mixture was stirred at room temperature for 30 minutes. Then CH3I (0.141 mL, 2.261 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched by pouring it out into a beaker with ice and water under nitrogen atmosphere. The precipitate was filtered off yielding the precipitated int. 96. The remaining product was extracted from the water layer with ethylacetate. The separated organic layer was combined with the precipitated int. 96 and then dried with MgS04, filtered and the solvents of the filtrate evaporated. The residue was dissolved in ethylacetate and purified over a Si02 column, type Grace Reveleris SRC, 40 g, Si 40, on a Grace Reveleris X2 purification system using heptanes and ethylacetate as eluens in a gradient starting from 100% heptanes to 100% ethylacetate. The fractions containing product were combined and the solvents were evaporated yielding intermediate 96 (0.51 g, crude). This intermediate was used for next step reaction without further purification. Below intermediates were also formed with the same reaction protocol as was used for the preparation of intermediate 96 (Table 27).Table 27:Example A30Preparation of intermediate 97intermediate 38 intermediate 97A mixture of intermediate 38 (520 mg, 1.60 mmol ), 7-bromoquinoline (390 mg, 1.87 mmol) and Et4NCl (261mg, 1.79 mmol,) in DMF (15.00 mL) was degassed under vacuum and purged with N2 for three times. DIEA (1.05 g, 8.15 mmol) and Pd(OAc)2 (54.9 mg, 244 μιηοΐ,) were added to the reaction mixture. The mixture was stirred at 100°C for 16 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried with anhydrous MgS04, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, gradient elutionL from 100% of DCM to 25% Ethyl acetate in DCM), yielded Intermediate 97 as off- white solid. (670 mg, 91% yield; (E)). The intermediates in Table 16 (all in the E configuration) were prepared by an analogous reaction protocol as was used for the preparation of intermediate 97 the appropriate starting materials (Table 16).Example A31Preparation of intermediate 101intermediate 41 intermediate 101In a sealed tube, bis(triphenylphosphine)palladium(II) dichloride (79.0 mg; 113 μιηοΐ) and copper(I) iodide (21.4 mg; 1 13 μιηοΐ) were added to a solution of 7- bromoquninoline (468 mg; 2.25 mmol) in 2-methyltetrahydrofuran (8 mL) previously degassed with N2. The reaction mixture was degassed with N2 and Et3N (1.25 mL; 9.01 mmol) was added, followed by adding intermediate 41 (1.08 g; 3.38 mmol) in (4 mL). The reaction mixture was degassed with N2 then refluxed (80°C) for 18h. After cooling down to room temperature, the crude was partitioned between EtOAc and H20. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried over MgS04, filtered off and evaporated in vacuo. The residues were purified by preparative LC (Irregular SiOH 15-40 μιη, 50 g Merck, DCM loading, mobile phase gradient: from heptane 80%, EtOAc 20% to heptane 50%, EtOAc 50%) to give intermediate 101 as a pale yellow oil (304 mg, yield: 27%>). Example A32Preparation of intermediate 102intermediate 43 intermediate 102To a solution of intermediate 43 ( 100 mg, 0.323 mmol) and 7-(bromomethyl)quinoline ( 1 1 7 mg, 0.387 mmol ) in DMF ( 3 mL) was added NaH ( 1 17 mg, 80% purity in mineral oil, 1.615 mmol). The mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with saturated aqueous NH4C1 (10 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with H20 (25 mL x 3), dried with anhydrous Na2S04 and concentrated under reduced pressure to give the crude product. The crude product was purified with Preparative-TLC (petroleum ether / ethyl acetate = 3 / 2) to give intermediate 102 as a colourless oil (50 mg, 91 % purity, 35% yield).Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 102 using the appropriate starting materials (Table 17).Table 17:Int. Structure Starting materials102a a) Intermediate 43b) 6-(Bromomethyl)quinoline 102b a) Intermediate 43 b) 6-(Bromomethyl)isoquinoline333 a) Intermediate 43 bjintermediate 332Example A33Preparation of intermediate 103intermediate 44Potassium carbonate (507 mg, 3.67 mmol) was added in one portion to a solution of intermediate 44 (600 mg, 1.23 mmol ) and quinolin-7-yl bo o n i c acid (254 mg, 1 .47 mmol) in dioxane (15 mL). The reaction mixture was stirred at 90 °C under N2 for 2 hours, after which the mixture was allowed to cool to room temperature. Subsequently, ethyl acetate was added, the organic phase was washed with saturated Na2C03 and brine, dried with anhydrous MgS04, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient eluention: heptane / ethyl acetate from 100 / 0 to 40 / 60) to give intermediate 103 ( 1 00 mg, 19 % yield ).Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 103 using the appropriate starting materials (Table 28).Table 28: Int. structure Starting material197 Intermediate 207 and 2- naphthaleneboronicX acid208 Intermediate 207 and isoquinoline-7- boronic acid225 N . Intermediate 224 and isoquinoline-7- boronic acidExample A34 Preparation of intermediate 104Intermediate 45 Intermediate 104Intermediate 45 (350 mg, crude, -0.626 mmol ) was dissolved in 5 mL of dio ane. Then 5 mL of NH3.H2O was added. The mixture was heated in a sealed tube (autoclave) at 90°C for 12 hours. The mixture was cooled to room temperature. The solvent was concentrated in vacuum to give the crude intermediate 104 (300 mg, ) as yellow oil. Example A35Preparation of intermediate 105intermediate 59 intermediate 105The crude Intermediate 59 (q.s., theoretically 0.83 mmol) was dissolved in 7M NH3 in MeOH (20 mL, 7 M, 140 mmol). The resulting solution was stirred and heated at 130°C using microwave irradiation for 2 hour. The solvents were evaporated. The residue was dissolved in dichloromethane and purified over a Si02 column, type Grace Reveleris SRC, 12 g, Si 40, on a Grace Reveleris X2 purification system using dichloromethane and methanol as eluens in a gradient starting from 100% DCM for 20 column volumes to 20% MeOH and 80% DCM over 20 column volumes. The fractions containing the product were combined and the solvents were evaporated yielding crude Intermediate 105 ( 1 75 mg) used as such in the next reaction step.The intermediates in Table 18 were prepared by an analogous reaction protocol as described in A34 or A35 using the appropriate starting materials (Table 18).Intermediates 136, 137 and 138 were obtained in the E-configuration.Int. structure Ref Starting material188 A34 Intermediate 187192 A34 Intermediate 191194 A34 Intermediate 102b198 A35 Intermediate 197209 A34 Intermediate 208x226 N— A34 Intermediate 225234 A35 Intermediate 233 Int. structure Ref Starting material265 A34 Intermediate 264334 A34 Intermediate 333462 A34 Intermediate 461464 A34 Intermediate 463485 A34 Intermediate 484Λ Int. structure Ref Starting material516 A34 Intermediate 515518 A34 Intermediate 517520 A34 Intermediate 519522 A34 Intermediate 521H O O H524 A34 Intermediate 523Example A36Intermediate 144a A solution of Intermediate 56 (35.7 mg, -0.0662 mmol) in 7M NH3 in MeOH (1 mL, 7 mmol) was stirred and heated at 130 °C using microwave irradiation for 1 hour. The solvents were evaporated. The residues were purified with Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 μιη, 30 x 150 mm, Mobile phase: 0.25% NH4HC03 solution in water, CH3CN). The solvents of the purified fractions were evaporated and co-evaporated with MeOH yielding Intermediate 144 ( 12.9 mg, 37%> yield) and Intermediate 144a (26.5 mg , 73%>).Example A37Preparation of intermediate 145 and 145aIntermediate 145aA solution of crude Intermediate 57 (theoretically 2.36 mmol) in 7M N¾ in MeOH (20 mL, 7 mmol) was stirred and heated at 130 °C using microwave irradiation for 2 hours. The solvents were evaporated. The residue was dissolved in DCM with MeOH and purified over a Si02 column, type Grace Reveleris SRC, 40 g, Si 40, on a Armen Spot II Ultimate purification system (gradient elution: DCM:MeOH from 100:0 to 20:80). The fractions containing product were combined and the solvents were removed, yielding crude Intermediate 145 (0.64 g) and crude Intermediate 145a (0.13 g). Both crude intermediates were used for the next reaction step reaction without further purification.Example A38Preparation of intermediate 146intermediate 137 intermediate 146To a mixture of Intermediate 137 (340 mg, theoretically 795 μηιοΐ) in MeOH ( 10.0 mL) was added Pd / C (100 mg, 10%) at 25 °C. The suspension was degassed under vacuum and purged with H2 (several times). The mixture was stirred under H2 (15psi) at 25 °C for 5 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by preperative-HPLC (Column: Diamonsil 150*20ιηιη,5μιη, Mobile phase: from 15% MeCN in water (0.225% formic acid) to 45% MeCN in water (0.225% formic acid)Flow Rate (ml / min): 25 ml / min), The fractions containing the desired product were combined and lyophilized. The residues were further purified by Chiral SFC (Column: OD (250ιηιη*30ιηιη,10μιη), Mobile phase: Supercritical C02 / EtOH + NH3.H20 (0.1%) = 50 / 50 Flow rate: 80 ml / min). Intermediate 146 (130 mg, 38 % yield) was obtained as a white solid.Below intermediates were prepared by an analogous reaction protocol as described for preparing intermediate 146 using the appropriate starting materials (Table 19).Table 19:Example A39Preparation of intermediate 149To a solution of Intermediate 70 (360 mg, -542 μηιοΐ) in THF (3.00 mL) was added iPrOH (3.00 mL) and ammonia (28 % in water, 6.00 mL). The mixture was stirred at 85 °C for 72 hours in an autoclave. The solvent was removed and the residue was purified by flash column on silica gel (gradient elution: MeOH / DCM from 0 / 100 to 4 / 96), yielded Intermediate 149 as a white solid. (230 mg, 65 % yield). The intermediate in Table 20 was prepared by an analogous reaction protocol as was used for the preparation of intermediate 149 using the appropriate starting materials (Table 20). Intermediate 150 was obtained in the E-configuration.TabiExample A40Preparation of intermediate 151intermediate 150 intermediate 151A suspension of intermediate 150 (150 mg, 349 μηιοΐ) and Pd / C (80 mg, 10%) was stirred under an atmosphere of ¾ (15 Psi) for 7 hours at 15 °C. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to afford intermediate 151 as a yellow solid ( 135 mg, 90 % yield).Example A41Preparation of intermediate 152To the solution of Intermediate 119 (550 mg, theoretically 1.18 mmol) in DMA ( 20 mL) were added Zinc cyanide ( 410 mg, 3.49 mmol), Zinc (55 mg,0.86 mmol), Tris(dibenzylideneacetone)dipalladium (46 mg, 0.051 mmol), Ι,Γ-Bis(diphenylphosphino)ferrocene (92 mg, 0.17 mmol). The mixture was stirred at 100 °C for 12 hours under N2. The catalyst was filtered and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (gradient eluent: EtOAc / Petroleum ether from 1 / 20 to 1 / 0). The solvent was evaporated to give the intermediate 152 as oil (450 mg, 70% yield).Example A56Preparation of intermediate 214A mixture of intermediate 105 (5 12. mg, 1 mmol), CuCN ( 358.2 mg, 4 mmol ), Pd.!dba;,(92 mg. 0.1 mmol ) and DPPF ( 221 .7 mg, 0.4 mmol) in dioxane(6 ml ) were stirred at 100°C for 16h. The reaction mixture was cooled, poured into water and extracted three times with ethylacetate. The organic layer was washed two times with water. The organic layer was dried and evaporated to dryness. The residue was purified by Prep HPLC (Stationary phase: RP XBridge Prep C I OBD- 1 Oiim.SOx 150 mm. Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) yielding intermediate 214 (363 mg, 79% yield).Example A42Preparation of intermediate 153intermediate 23 Intermediate 153The mixture of intermediate 23 (50 mg, theoretically 0.13 mmol), 7-hy droxy q u i no 1 i ne (22 mg, 0.156 mmol) and PPh3 (53 mg, 0.26 mmol) in dry THF (20 ml) was stirred at room temperature under N2. DIAD (6.47 g, 32.037 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrate to dryness, yielding crude intermediate 153.Example A43Preparation of intermediate 154 and intermediate 154aintermediate 154aTo a solution of intermediate 72 ( l .0 g, 1 .91 mmol ) in 1 ,4-dioxane (10 mL) was added 2M NaOH (10 mL, 20 mmol). The reaction mixture was stirred at 150 °C for 1 hour under microwave condition. The mixture was diluted with water (15 mL), extracted with EtOAc (10 mL x 3). The organic phase was washed with brine (15 mL), dried over Na2S04, filtered and concentrated. The residue was purified by chromatography column (elution: EtOAc / MeOH 85 / 15). The desired fractions were collected and concentrated to give intermediate 154 (359 mg of a white solid, 41% yield) and intermediate 154a (300 mg, 32 % yield). Example A44Preparation of intermediate 155intermediate 155Sodium (440 mg, 19.1 mmol) was stirred in MeOH (25 mL) at room temperature until sodium was dissolved compeletly. Then intermediate 72 (1.0 g, 1 .91 mmol) was added into the reaction mixture and the reaction mixture was refiuxed for 72 hours. The mixture was diluted with DCM (100 mL), washed with water (10 mL), brine (10 mL).The organic phase was dried over Na2S04, filtered and concentrated to give crude intermediate 155 which was used as such fo the next reation step without further purification.Example A45Preparation of intermediate 157intermediate 1577- bromo-2-chloro-quinoline (10.0 g, 41.2 mmol) and cyclopropylmethylamine (18 mL) in EtOH (80 mL) was stirred in a sealed tube at 120°C overnight. The mixture was evaporated under vacuo to give intermediate 157 (15 g; crude) as a brown solid which used as such in the next reaction step without further purification.Preparation of intermediate 159Intermediate 38 (3.8 g, 1 1.9 mmol) in 9-BBN (0.5 M in THF, 95.1 mL, 47.5mmol) was refluxed for lh under N2. The mixture was cooled to room temperature, then K3PO4 (7.56 g, 35.6 mmol) in H20 (20 mL) was added, followed by THF (150 mL),intermediate 157 (4.4 g, ~13mmol) and Pd-1 18 (155 mg, 0.24 mmol). The resulting mixture was refluxed overnight. The mixture was diluted with H20 (100 mL), extracted with ethyl acetate (150 mL), the organic phase was dried by Na2S04, then filtered and concentrated in vacuo to give the crude product. The crude product was purified by chromatography (ethyl acetate / petroleum ether 0 / 1 to 1 / 3) to give intermediate 159 (3.1 g, yield: 42.8%) as a yellow oil.Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 159 using the appropriate starting materials (Table 29).Table 29:Int. Structure Starting materials242 a ) Intermediate 38 b) 3-methyl- 7-bromoquinoline245 a) Intermediate 38 b) Intermediate 244r YV Int. Structure Starting materials248 a) Intermediate 38 b) 7-bromo-N-methyl-2- quinolinamine249 a) Intermediate 39 b) 7-bromo-3-ethyl-quinoline251 a) Intermediate 39 b) 7-bromo-3-methyl-quinoline254 a) Intermediate 38 b) Intermediate 253256 a) Intermediate 38 b) 7-bromo-3-ethyl-q inoline259 a) Intermediate 39 b) 7 -bromo-N-methyl-2- quinolinamine Int. Structure Starting materials291 a) Intermediate 38 b) Intermediate 290294 a) Intermediate 38 b) Intermediate 293297 a) Intermediate 38 b) Intermediate 296300 a) Intermediate 38 b) Intermediate 299303 a) Intermediate 38 b) Intermediate 302 Int. Structure Starting materials306 a) Intermediate 38 b) Intermediate 305309 a) Intermediate 38 b) Intermediate 308312 a) Intermediate 38 b) Intermediate 311315 a) Intermediate 38 b) Intermediate 314318 a) Intermediate 38 b) Intermediate 317T^Nv ci Int. Structure Starting materials321 a) Intermediate 38 b) Intermediate 320324 a) Intermediate 38 b) Intermediate 323327 CI a) Intermediate 39 b) Intermediate 326330 a) Intermediate 38 b) Intermediate 329336 a) Intermediate 38 b) Intermediate 335V Int. Structure Starting materials473 a) Intermediate 39 b) Intermediate 329Preparation of intermediate 160intermediate 159intermediate 160Reaction performed in a sealed tube. Intermediate 159 (3.1 g,—5.1 mmol) was added to NH3.H2O (30 mL) and dioxane (30 mL) and was stirred at 120°C overnight. The mixture was concentrated in vacuo to give crude intermediate 160. This residue was purified by silica gel chromatography (ethylacetate 100% to ethyl acetate / MeOH 90 / 10) to give intermediate 160 (3.95 g, yield: 77%).Example A46Preparation of intermediate 161intermediate 1617- Bromo-2- chloro-quinoline (1.5 g, 6.18 mmol) and 2,2-difluoroethylamine (0.552 g, 6.804 mmol) in EtOH (30 mL) were heated in a sealed tube at 120°C overnight. The mixture was evaporated under vacuo to give intermediate 161 (1.8g, yield: 88.1%) as a brown solid which used for next step without further purification. Preparation of intermediate 162Intermediate 38 (500 mg, 1.56 mmol) in 9-BBN (0.5M in THF, 15.6 mL, 7.8 mmol) was refluxed for lh under N2. The mixture was cooled to room temperature, then K3PO4 (995.6 mg, 4.7 mmol) in H20 (2 mL) was added, followed by THF (20 mL), intermediate 161 (538.7 mg,—1.88 mmol) and Pd-1 18 (20.4 mg, 0.031 mmol). The resulting mixture was refluxed overnight. The mixture was diluted with H20 (60 mL), extracted with ethyl acetate (100 mL x2), the combined organic phases were dried by Na2S04, then filtered and concentrated in vacuo to give the crude product. The crude product was purified by chromatography (ethyl acetate : petroleum ether ratio 1 : 10 to 1 :5) to give intermediate 162 (650 mg, yield: 68.1%) as yellow oil.Preparation of intermediate 163Reaction performed in a sealed tube. Intermediate 162 (650 mg, -1.06 mmol) was added to NH3.H2O (15 mL) and dioxane (10 mL) and was stirred at 120°C overnight. The mixture was concentrated in vacuo to give intermediate 163 (680 mg, yield: 97.9%).Example A47Preparation of intermediate 164intermediate 164 A mixture of 7- bromo-2-chloroquinoline (10 g, 41.24 mmol) and 4- methoxybenzylamine (11.3 g, 82.5 mmol) in ethanol (40 ml) was heated in a sealed tube at 120 °C for 72 h. The mixture was evaporated under reduced pressure and purified by chromatography column (gradient eluent: CH2Cl2 / petroleum ether from 1 / 10 to 1 / 0) to afford the desired product intermediate 164 (13 g, 82% yield) as a white solid.Preparation of intermediate 165intermediate 164 intermediate 165A mixture of intermediate 38 (2 g, 5.0 mmol ) in 9-BBN (50.0 ml, 25.0 mmol, 0.5M in THF) was re fluxed for 1 h under N2. The mixture was cooled to room temperature, then K3PO4 (3.18 mg, 15.0 mmol ) in H20 (10 mL) was added, followed by THF (20 ml), intermediate 164 (2.58 mg, -7.50 mmol) and [Ι , Γ- bis(diphenylphosphino)ferrocene]dichloropalladium(II)( 163.0 mg, 0.25 mmol). The resulting mixture was refluxed for 3h. The mixture was concentrated. The residue was dissolved in ethyl acetate (40 ml), washed with water(6 ml), brine(6 ml).The organic phase was dried over Na2S04, filtered and concentrated to obtain the crude product. This was purified by chromatography column (gradient eluent: ethyl acetate / petroleum ether from 1 / 10 to 1 / 1). The desired fractions were collected and concentrated to give product intermediate 165 as a solid (2 g, 52.4% yield).Below intermediates were prepared by an analogous reaction protocol as was used for the preparation of intermediate 165 using the appropriate starting materials (Table 30).Table 30:Int. Structure Starting materials237 a) Intermediate 38 b) 2-amino- 7-bromoquinoline Int. Structure Starting materials238 a) Intermediate 39b) 3-bromo- 7-iodoquinoline260 a) Intermediate 38b) 3-bromo- 7-iodoquinoline°x°482 a) Intermediate 39bjintermediate 175488 a) Intermediate 487bjintermediate 175491 a) Intermediate 490bjintermediate 175 Int. Structure Starting materials514 a) Intermediate 513 b intermediate 314Preparation of intermediate 166intermediate 165 intermediate 166A mixture of intermediate 165 (500 mg, -0.655 mmol) and NH3.H2O(10 ml) in dioxane(10 ml) was heated in a sealed tube at 120°C for 14h. This reaction was evaporated under vacuo to obtain intermediate 166 (400 mg, 93.5% yield) as anPreparation of intermediate 167intermediate 166 intermediate 167 The mixture of intermediate 166 (340 mg, -0.52 mmol) in CF3COOH(5 ml) was stirred at 60°C for lh. The mixture was evaporated under vacuo to obtain intermediate 167 as a crude product(300 mg, 85.9 % yield).Example A48Preparation of intermediate 168intermediate 165 intermediate 168Intermediate 165 (300 mg, -0.39 mmol)was dissolved in EtOH(20 ml) and ethyl acetate (4 ml) and hydrogenated under 1 atm of H2 over Pd(OH)2 / C (30 mg) for 7 hours. The mixture was filtered and evaporated under vacuo to obtain intermediate 168 as a crude product(200 mg, 70.6 % yield).Preparation of intermediate 169intermediate 168 intermediate 169The mixture of intermediate 168 (200 mg, -0.278 mmol) in CF3COOH (5 ml) was stirred at 60°C for lh. The mixture was evaporated under vacuo to obtain intermediate 169 as a crude product(120 mg, 89.0%yield).Example A49Preparation of intermediate 170intermediate 165 intermediate 170 A mixture of intermediate 165 (310 mg, -0.406 mmol) and CH3NH2 / H2O (5 ml) in dioxane (5 ml) was stirred in a sealed tube at 120°C for 14h. This mixture was evaporated under vacuo to obtain intermediate 170 (200 mg, 80.1 % yield) as a crude product.Preparation of intermediate 171intermediate 170 intermediate 171The mixture of intermediate 170 (200 mg, -0.325 mmol) in CF3COOH (5 ml) was stirred at 50°C for lh. The mixture was evaporated under vacuo to obtain intermediate 777(160 mg, 84.0 % yield) as a crude product.Example A50Preparation of intermediate 172intermediate 165 intermediate 172A mixture of intermediate 165 (300 mg, 0.393 mmol) and sodium methoxide (63.7 mg, 1.18 mmol) in methanol (10 ml) was refluxed at 60°C for 12h. The mixture was evaporated under vacuo to give a crude product. Water (10 ml) was added, the mixture was extracted with ethyl acetate(10 ml x 2), the organic layers were combined and evaporated under vacuo to obtain intermediate 172 (200 mg, 71.8 % yield) as a crude product. Preparation of intermediate 173intermediate 172 intermediate 173 The mixture of intermediate 172 (200 mg, -0.282 mmol) in TFA (5 ml) was stirred at 60°C for lh.. The mixture was evaporated under vacuo to obtain intermediate 173 (250 mg, 85.3 % yield,) as the crude product. Example A51Preparation of intermediate 174intermediate 1743-Bromo-7-iodo-quinoline (5.99 g, 17.7 mmol) was dissolved in dichloromethane (60 mL), then m-CPBA (4.57 g, 26.5 mmol) was added in portions. The mixture was stirred at room temperature for 4 days. The mixture was quenched by a saturated Na2S203 aqueous solution (40 mL) and a saturated NaHC03 aqueous solution (PH to 6-7), then extracted by dichloromethane (50 mL x3). The organic phase was washed with H20 (50 mL), dried with anhydrous Na2S04 and evaporated under reduced pressure. The residue was purified by silica gel column (eluent: petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to afford the desired product intermediate 174 (1.9 g, 14.1% yield) as a yellow solid.Preparation of intermediate 175intermediate 174 intermediate 175To a solution of intermediate 174 (2.9 g, 8.29 mmol) in chloroform (60 mL) was added phosphoryl trichloride (8.3 g, 54.1 mmol). The mixture was stirred at 80°C for 12 h. The mixture was evaporated under reduced pressure to obtain crude product. The crude product was purified by chromatography column (eluent: petroleum ether / ethyl acetate = 10 / 1 to 1 / 1). The desired fractions were collected and concentrated to give product intermediate 175 (1.3 g, 41.5% yield) as a white solid.Preparation of intermediate 176intermediate 175 intermediate 1764-methoxybenzylamine(1.34 g, 9.78 mmol) was added into the mixture of intermediate 175 (0.8 g, -1.95 mmol) in ethanol (10 ml). The mixture was heated in a sealed tube at 100°C for 12h. The mixture was evaporated under vacuo to obtain the crude product. This was purified by chromatography column (gradient eluent: ethyl acetate / petroleum ether from 0 / 1 to 1 / 10). The desired fractions were collected and concentrated to give product intermediate 176 (600 mg, 51.6 % yield) as an oil.Preparation of intermediate 177intermediate 176 intermediate 177A mixture of intermediate 38 (44 mg, 0.138 mmol) in 9-BBN (1.3 ml, 0.69 mmol, 0.5M in THF) was refluxed for lh under N2. The mixture was cooled to room temperature, then K3PO4 (87 mg, 0.413 mmol) in H20 (lmL) was added, followed by THF (5 ml), intermediate 176 (122.727 mg, -0.206 mmol) and [Ι,Γ- bis(diphenylphosphino)ferrocene]dichloropalladium(II) ( 4.48 mg, 0.007 mmol). The reaction mixture was refluxed for 3 hours. The mixture was concentrated. The residue was dissolved in ethyl acetate (40 ml), washed with water (6 ml), brine (6 ml).The organic phase was dried over Na2S04, filtered and concentrated to give crude intermediate 177 fraction 1 (120 mg, 71.5% yield).A mixture of intermediate 38 (233 mg, 0.73 mmol) in 9-BBN (7.31 ml, 3.65 mmol, 0.5M in THF) was refluxed for lh under N2. The mixture was cooled to room temperature, then K3PO4 (87 mg, 0.413 mmol) in H20(lmL) was added, followed by THF (5 ml), intermediate 176 (478 mg, -0.80 mmol) and [1,1*- bis(diphenylphosphino)ferrocene]dichloropalladium(II)( 23.8 mg, 0.037 mmol). The reaction mixture was refluxed for 3 hours. The mixture was concentrated. The residue was dissolved in ethyl acetate (40 ml), washed with water (6 ml), brin...

Claims

Claims1. A compound of Formula ( I )whereinR represents hydrogen orR2 represents hydrogen orY represents -0-, -CH2- or -CF2-;Z represents -CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C≡C-;and when Y represents -CH2- or -CF2-, then Z can also represent -O- or -CR5aR5b-X-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5h each independently represent hydrogen or Ci_ 4alkyl;X represents -0-, -S-, or -NR11-;R11 represents hydrogen, Ci_4alkyl, or Ci_4alkyl substituted with one substituent selected from the group consisting of -OH, -0-Ci_4alkyl, R12, -NH2, -NH-Ci_4alkyl, and -N(C1_4alkyl)2;R12 represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom; said 4-, 5-, 6- or 7-membered heterocyclic ring being attached to the remainder of the molecule via a ring nitrogen atom;Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, -NHR10d, -NR10cR10d, cyano, -CF3, -C(=0)-NH2, -C(=0)- H-C alkyl,-C(=0)-Ci_4alkyl, Ci_4alkyloxy, -C(=0)-0-Ci_4alkyl, C3_6cycloalkyl, -0-C3_6cycloalkyl, -NH-C3_6cycloalkyl, -N(C3_6cycloalkyl)2, C2_6alkenyl, Ci_4alkyl substituted with one Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b;R10a and R10b each independently represent hydrogen or Ci_4alkyl; R10c and R10d each independently represent C3-6cycloalkyl; R13; R14; C3_6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -0-Ci_4alkyl; Ci_4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH and -0-Ci_4alkyl; or Ci_4alkyl substituted with one substituent selected from the group consisting of C3_6cycloalkyl, R13 and R14;R13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=0)p and N; or a 6- to 1 1- membered bicyclic fused aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=0)p and N;said 4- to 7-membered monocyclic aromatic ring or 6- to 1 1-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of Ci_4alkyl;p represents 1 or 2;R14 represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4) and (a-5):(a-2) (a-4)R3a, R3b, R3c, R3d and R3e each independently represent hydrogen, halo, -NR7aR7b, Ci_4alkyl, C2_4alkenyl, C3-6cycloalkyl, -OH, or -0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen, C3-6cycloalkyl, or Ci_4alkyl;R4a, R4b, R4c, R4d, R4e, R4f and R4g each independently represent hydrogen, halo, -NR8aR8b, or Ci_4alkyl;R8a and R8b each independently represent hydrogen or Ci_4alkyl; Q1 represents N or CR6a;Q2 represents N or CR6b;Q3 represents N or CR6c;Q4 represents N or CR6d;provided that maximum one of Q3 and Q4 represents N;Q8 represents N or CR6g;Q9 represents N or CR6h;Q10 represents N or CR6i;Q11 represents N or CR6j;Q5 represents CR3d; Q6 represents N; and Q7 represents CR4f; orQ5 represents CR3d; Q6 represents CR4e; and Q7 represents N; orQ5 represents N; Q6 represents CR4e; and Q7 represents CR4f; orQ5 represents N; Q6 represents CR4e; and Q7 represents N; orQ5 represents N; Q6 represents N; and Q7 represents CR4f; orQ5 represents N; Q6 represents N; and Q7 represents N;R6a, R6b, R6c, R6d, R6e, R6f, R6g, R6h, R6i and R6j each independently represent hydrogen, halogen, Ci_4alkyl, -NR9aR9b, or Ci_4alkyl substituted with one, two or three halo atoms;R9a and R9b each independently represent hydrogen or Ci_4alkyl;or a pharmaceutically acceptable addition salt or a solvate thereof;provided that the following compounds, and pharmaceutically acceptable addition salts, and solvates thereof are excluded:

2. The compound according to claim 1 , whereinAr represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=0)-NH-Ci_4alkyl, -C(=0)-Ci_4alkyl, Ci_4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3):R3a, R3b and R3c each independently represent hydrogen, halo, -NR7aR7b, or-0-Ci_4alkyl;R7b represents hydrogen or Ci_4alkyl;R4a, R4b and R4c each independently represent hydrogen, halo, -NR8aR8b, or Ci_4alkyl; Q1 represents N or CR6a;Q2 represents N or CR6b;Q3 represents N or CR6c;Q4 represents N or CR6d;provided that maximum one of Q3 and Q4 represents N; R , R , R , R , R and R each independently represent hydrogen, halogen, Ci_ 4alkyl, -NR9aR9b, or Ci_4alkyl substituted with one, two or three halo atoms.

3. The compound according to claim 1, whereinAr represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,wherein at least 1 ring carbon atom of ring B is replaced by a nitrogen atom;wherein optionally 1 additional ring carbon atom of ring A or ring B is replaced by a nitrogen atom; provided that when a nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci_4alkyl, -N(C1-4alkyl)2, -NHR10d, -NR10cR10d, cyano, -CF3, -C(=0)-NH2, -C(=0)- H-C alkyl,-C(=0)-Ci_4alkyl, Ci_4alkyloxy, -C(=0)-0-Ci_4alkyl, C3_6cycloalkyl, -0-C3_6cycloalkyl, -NH-C3_6cycloalkyl, -N(C3_6cycloalkyl)2, C2_6alkenyl, Ci_4alkyl substituted with one Ci_ 4alkyloxy, and Ci_4alkyl optionally substituted with one -NR10aR10b.

4. The compound according to claim 1 , whereinR 1 represents hydrogen or -C(=0)-Ci_4alkyl;R represents hydrogen orY represents -0-; Z represents -X-CR5aR5b-;R and R5b each independently represent hydrogen or Ci_4alkyl;X represents -0- -S-, or -NR11-; R" represents hydrogen;Ar representsAr is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-Ci-4alkyl, -N(Ci_4alkyi)2, cyano, - CF3, Ci_4alkyioxy, and Ci_4alkyl optionally substituted with one -NR10aR10b;R10a and R10b each independently represent hydrogen or Ci_4alkyi;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R3a represents hydrogen, halo, -NR7aR7b, or-0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen;R4a represents hydrogen, halo, -NR8aR8b, or Ci_4alkyl;R8a and R8b each independently represent hydrogen or Ci_4alkyl;Q1 represents CR6a;Q represents CR6b;R6a and R6b each independently represent hydrogen, halogen, Ci_4alkyl, -NR9aR9b, or Ci_4alkyl substituted with one, two or three halo atoms;R9a and R9b each independently represent hydrogen or Ci_4alkyl.

5. The compound according to claim 1 , whereinR1 represents hydrogen;R2 represents hydrogen;Y represents -O- or -CH2-;Z represents -X-CR5aR5b- or -CR5eR5g-CR5fR5h-;and when Y represents -CH2-, then Z can also represent -CR5aR5b-X-;R5a, R5b, R5e, R5f, R5g, and R5h represent hydrogen;X represents -0-;Ar representsawherein Ar is optionally substituted in the position indicated by a with a substituent selected from the group consisting of -NH2, -NH-Ci_4alkyl, and -NHR10d; and wherein Ar is optionally substituted in the position indicated by β with a substituent selected from the group consisting of halo and CF3;provided however that Ar is substituted in at least one of the positions indicated by a β;R10d represents C3-6cycloalkyl; Ci_4alkyl substituted with one, two or three halo substituents; or Ci_4alkyl substituted with one C3_6cycloalkyl substituent;Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-4);R3a and R3d each independently represent hydrogen, halo, -NR7aR7b, Ci_4alkyl, or -0-Ci_4alkyl;R7a represents hydrogen;R7b represents hydrogen or Ci_4alkyl; R a, R and R each independently represent hydrogen or halo;Q1 represents CR6a;Q2 represents CR6b;Q8 represents CR6g;Q9 represents CR6h;Q5 represents CR3d; Q6 represents N; and Q7 represents CR4f;R6a, R6b, R6g, and R6h represent hydrogen;6. The compound according to any one of claims 1 to 4, wherein R1 and R represent hydrogen.

7. The compound according to any one of claims 1 to 3 and claims 5 to 6, wherein Y represents -0-.

8. The compound according any one of claims 1 to 3 and claims 5 to 7, wherein Het represents a bicyclic aromatic heterocycl ic ring system of Formula (a-1).

9. The compound according to claim 8, whereinR3a represents -NR7aR7b; and R7a and R7b represent hydrogen.

10. The compound according to any one of claims 1 to 9, whereinAr representswherein Ar is substituted in the position indicated by β with a halo substituent.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effect ive amount of a compound according to any one of claims 1 to 10.A compound as defined in any one of claims 1 to 10 for use as a medicament.

13. A compound as defined in any one of claims 1 to 10 for use in the treatment or prevention of a disease or condit ion selected from a blood disorder, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft reject ion, and lung injuries.

14. The compound according to claim 13 wherein the disease or condition is an autoimmune disorder, cancer, inflammatory disease, or a neurodegenerative disease.

15. The compound according to claim 14 wherein the disease or condition is cancer.