Monocyclic and bicyclic system-substituted carbocyclic nucleoside analogs used as PRMT5 inhibitors

Abstract

The present invention relates to monocyclic and bicyclic system-substituted carbocyclic nucleoside analogs used as PRMT5 inhibitors, in particular monocyclic and bicyclic system-substituted carbocyclic nucleoside analogs of formula (I), #imgabs0# where these variables have the meanings defined in these claims. The compounds according to the invention can be used as PRMT5 inhibitors. The present invention further relates to pharmaceutical compositions containing the compounds as active ingredients and the use of the compounds as medicaments.

Description

[0001] This application is a divisional application of the patent application with the application date of October 2, 2017, the application number of 201780061258.4, and the invention title of "Monocyclic and Bicyclic System-Substituted Carbocyclic Nucleoside Analogs as PRMT5 Inhibitors". Technical Field

[0002] The present invention relates to monocyclic and bicyclic system-substituted carbocyclic nucleoside analogs used as PRMT5 inhibitors. The present invention further relates to a pharmaceutical composition containing the compound as an active ingredient and the use of the compound as a medicament. Background Art

[0003] PRMT5, also described as Hsl7, Jbp1, Skb1, Capsuleen or Dart5, is one of the major methyltransferases responsible for the mono- and symmetric dimethylation of arginine. Post-translational arginine methylation on histones and non-histones appears to be crucial for various biological processes such as genome organization, transcription, differentiation, spliceosome function, signal transduction and regulation of cell cycle progression, stem cell and T cell fate [Stopa, N. et al., Cell Mol Life Sci [Cell and Molecular Life Sciences], 2015.72(11): pp. 2041-59] [Geoghegan, V. et al., Nat Commun [Nature Communications], 2015.6: p. 6758]. Metazoan PRMT5 forms a functional complex with methyltransferase complex protein 50 (MEP50), also known as Wdr77, androgen receptor coactivator p44 and Valois. Both elevated PRMT5-MEP50 protein levels and cytoplasmic accumulation are associated with cancer tumorigenesis and have only recently been associated with poor clinical outcomes [Shilo, K. et al., Diagn Pathol [Diagnostic Pathology], 2013.8: p. 201]. In addition to comprehensive enzymological studies, cell rescue experiments resolving the catalytic and scaffolding functions of the PRMT5-MEP50 complex have confirmed the oncogenic link between protein levels, localization and enzymatic function [Gu, Z. et al., Biochem J [Biochemical Journal], 2012.446(2): pp. 235-41] [Di Lorenzo, A. et al., FEBS Lett [FEBS Letters], 2011.585(13): p. 2024-31] [Chan-Penebre, E. et al., Nat Chem Biol [Nature Chemical Biology], 2015.11(6): pp. 432-7]. This correlation makes PRMT5 an essential small molecule drug target for cancer and other diseases [Stopa, N. et al., CellMol Life Sci [Cell and Molecular Life Sciences], 2015.72(11): pp. 2041-59].

[0004] PRMT5 is a member of the type II PRMT subfamily that uses S-adenosylmethionine (SAM) to generate symmetric dimethylated arginine and S-adenosylhomocysteine (SAH) on histone and non-histone substrates. The crystal structure of the human hetero-octameric complex (PRMT5)4(MEP50)4 co-crystallized with SAH and a histone H4 peptide substrate illustrates the mechanisms of methylation and substrate recognition [Antonysamy, S. et al., Proc Natl Acad Sci U S A, 2012. 109(44): pp. 17960-5]. Regulation of PRMT5 activity occurs through a large number of diverse binding partners, post-translational modification cascades, miRNAs, and subcellular localization.

[0005] Methylation of histone H2A and H4 on Arg3 and histone H3 on Arg8 regulates chromatin organization to specifically repress gene transcripts involved in differentiation, transformation, cell cycle progression, and tumor suppression [Karkhanis, V. et al., Trends Biochem Sci, 2011. 36(12): pp. 633-41]. In addition, methylation of histone H4 on Arg3 mediated by PRMT5 may 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): pp. 304-11].

[0006] Non-histone methylation can occur in the cytoplasm or nucleus, depending on the cellular localization of PRMT5. Methylation of the Sm proteins D1 and D3 required for nuclear spliceosome assembly occurs in the cytoplasm as part of a "methyltransferase complex" containing PRMT5 [Friesen, W.J. et al., Mol Cell Biol, 2001. 21(24): pp. 8289-300]. Further evidence for PRMT5 involvement in splicing was provided by conditional PRMT5 knockout in mouse neural stem cells. Cells lacking PRMT5 showed selective retention of introns and skipping of exons with weak 5' donor sites [Bezzi, M. et al., Genes Dev, 2013. 27(17): pp. 1903-16].

[0007] In addition to its role in splicing, PRMT5 affects key pathways involved in cell fate and homeostasis by directly methylating key signaling nodes such as 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], NFκB [Wei, H. et al., Proc Natl Acad Sci U S A, 2013. 110(33): p. 13516-21].

[0008] Since PRMT5 is one of the major sym-Arg methyltransferases and is involved in multiple cellular processes, increased protein expression appears to be an important factor in its tumorigenicity. Interestingly, the translation of PRMT5 in mantle cell lymphoma (MCL) seems to be regulated by miRNA. Although MCL cells show less mRNA and a slower PRMT5 transcription rate compared to normal B lymphocytes, the levels of PRMT5 as well as the methylation of H3R8 and H4R3 are significantly increased [Pal, S. et al., EMBO J, 2007. 26(15): p. 3558-69]. Re-expression of miRNA that binds to the 3'UTR region of PRMT5 reduces the PRMT5 protein level [Wang, L. et al., Mol Cell Biol, 2008. 28(20): p. 6262-77]. Notably, prmt5 antisense RNA was found in the human prmt5 gene, which supports the hypothesis of specific translational regulation rather than high mRNA expression levels [Stopa, N. et al., Cell Mol Life Sci, 2015. 72(11): p. 2041-59].

[0009] Although PRMT5 is considered a clinically relevant target, very few selective PRMT5 inhibitors have been disclosed to date. Recently, a sub-nanomolar potent PRMT5 inhibitor (EPZ015666) with anti-tumor activity in multiple MCL xenograft models has been described as the first chemical probe suitable for further validating the biology and role of PRMT5 in cancer [Chan-Penebre, E. et al., Nat Chem Biol, 2015.11(6): pp. 432-7].

[0010] Further development of specific small molecule inhibitors of PRMT5 may lead to new cancer chemotherapeutic methods.

[0011] WO 2016135582 and US 20160244475 describe substituted nucleoside derivatives useful as anti-cancer agents.

[0012] WO 2014100695 A1 discloses compounds useful for inhibiting PRMT5 activity; methods of using these compounds for treating PRMT5-mediated disorders are also described.

[0013] WO 2014100730A1 discloses PRMT5 inhibitors containing dihydro- or tetrahydroisoquinoline and their uses.

[0014] Devkota, K. et al., ACS Med Chem Lett, 2014.5: pp. 293-297 describe the synthesis of a series of analogs of the natural product sinefungin and the ability of these analogs to inhibit EHMT1 and EHMT2.

[0015] WO 2003070739 discloses partial and full agonists of the A1 adenosine receptor, their preparation and their therapeutic uses.

[0016] WO 2012082436 discloses compounds and compositions as histone methyltransferase modulators, and compounds and compositions for treating diseases affected by the regulation of histone methyltransferase activity.

[0017] WO 2014100719 discloses PRMT5 inhibitors and their uses.

[0018] WO 03074083 discloses combination therapies for selectively killing methionine adenosylphosphatase-deficient cells. Analogs of MTA are described herein as antidotes.

[0019] Kung, P.-P. et al., Bioorg Med Chem Lett [Bioorganic and Medicinal Chemistry Letters], 2005.15: pp. 2829-2833 describe the design, synthesis, and biological evaluation of substrates for human 5'-deoxy-5'-methylthioadenosine phosphorylase (MTAP).

[0020] WO 2012075500 discloses 7-azapurine modulators of histone methyltransferases.

[0021] WO 2014035140 discloses compounds and compositions for modulating histone methyltransferase activity.

[0022] WO 2015200680 describes PRMT5 inhibitors and their uses.

[0023] WO 9640686 describes heterocyclic-substituted cyclopentane compounds and methods of using these compounds to inhibit adenosine kinase.

[0024] WO 2017032840 relates to 6-6 bicyclic aromatic ring-substituted nucleoside analogs useful as PRMT5 inhibitors.

[0025] Accordingly, there is a strong need for PRMT5 inhibitors, which opens up new avenues for the treatment or prevention of cancers such as mantle cell lymphoma. Accordingly, it is an object of the present invention to provide such compounds.

[0026] Compared to the compounds disclosed in the prior art, the compounds of the present invention are structurally different and may have improved properties such as improved potency, or improved pharmacokinetics (PK) and oral bioavailability. SUMMARY OF THE INVENTION

[0027] It has been found that the compounds of the present invention are useful as PRMT5 inhibitors. The compounds and compositions according to the present invention can be used for treatment or prevention, especially for treating the following diseases such as blood disorders, metabolic disorders, autoimmune disorders, cancers, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney diseases, platelet aggregation, sperm motility, transplant rejection, graft rejection, lung injury, etc.

[0028] The present invention relates to compounds having formula (I):

[0029]

[0030] wherein

[0031] R 1 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0032] R 2 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0033] Y represents -CH2- or -CF2-;

[0034] Z represents -CH2-, -CHR 5i -、-X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h -、-CR 5a R 5b -X-, -C≡C-, -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -or-CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[0035] R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , R 5h and R 5i Each independently represents hydrogen or C 1-4 alkyl;

[0036] X represents -O-, -S- or -NR 11 -;

[0037] R 11 Represents hydrogen, C 1-4 Alkyl or C substituted by a substituent selected from the group consisting of 1-4 Alkyl: -OH, -OC 1-4 Alkyl, -NH2, -NH-C 1-4 Alkyl and -N(C 1-4 Alkyl)2;

[0038] Ar represents a monocyclic aromatic ring or a bicyclic ring system;

[0039] Wherein the monocyclic aromatic ring is selected from the group consisting of: pyridyl, pyrimidinyl, pyrazolyl and imidazolyl;

[0040] Wherein the bicyclic system is

[0041] (i) A 9-membered bicyclic aromatic ring system composed of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, and the 9-membered bicyclic aromatic ring is attached to the rest of the molecule through a ring carbon atom of the 5- or 6-membered ring or a ring nitrogen atom of the 5-membered ring; or

[0042] (ii) A 10-membered bicyclic aromatic ring system composed of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by nitrogen atoms; provided that when a nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in the bicyclic aromatic ring system;

[0043] Provided that when Ar represents a 10-membered bicyclic aromatic ring system, Z only represents -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -; or

[0044] (iii) A fused bicyclic partial aromatic ring system, which is attached to the linking group Z with an aromatic ring, and the fused bicyclic partial aromatic ring system is selected from (b-1), (b-2) and (b-3)

[0045]

[0046] Wherein ring A is a monocyclic aromatic ring selected from the group consisting of: pyridyl, pyrimidinyl, pyrazolyl and imidazolyl;

[0047] Wherein ring B is C 5-6 Cycloalkyl or a 5- to 6-membered saturated heterocyclic group containing one or two heteroatoms each independently selected from O, S and N;

[0048] Ar is optionally substituted on a carbon atom with a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, oxo, -OH, -NH2, -NH-C 1-4 Alkyl, -NHR 10 、cyano, -CF3, C 1-4 Alkoxy, C 3-6Cycloalkyl, -O-C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 1-4 Alkyl and C substituted by one C 1-4 Alkyl substituted by an alkoxy group 1-4 alkyl; and

[0049] Where possible, Ar is optionally substituted at an N-atom by a substituent selected from the group consisting of: C 1-4 alkyl; C 3-6 cycloalkyl; C substituted by one, two or three halogen atoms 1-4 alkyl; and C substituted by one, two or three halogen atoms 3-6 cycloalkyl;

[0050] R 10 represents -(C=O)-C 1-4 alkyl; C 3-6 cycloalkyl; R 13 ; R 14 ; C substituted by one, two or three substituents each independently selected from the group consisting of 3-6 cycloalkyl: halogen, -OH and -O-C 1-4 alkyl; C substituted by one, two or three substituents each independently selected from the group consisting of 1-4 alkyl: halogen, -OH and -O-C 1-4 alkyl; or C substituted by a substituent selected from the group consisting of 1-4 alkyl: C 3-6 cycloalkyl, R 13 and R 14 ;

[0051] R 13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=O) p and N; said 4- to 7-membered monocyclic aromatic ring is optionally substituted by one or two substituents selected from the group consisting of: C 1-4 alkyl;

[0052] p represents 1 or 2;

[0053] R 14 represents a phenyl group optionally substituted by one, two or three substituents each independently selected from the group consisting of: halogen;

[0054] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of: (a-1), (a-2) and (a-3):

[0055]

[0056] R 3a , R 3d and R 3e Each independently represents hydrogen, halogen, -NR 7a R 7b , C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, -OH or -OC 1-4 alkyl;

[0057] R 7a represents hydrogen;

[0058] R 7b Represents hydrogen, C 3-6 Cycloalkyl or C 1-4 alkyl;

[0059] R 4a , R 4d , R 4e , R 4f and R 4g Each independently represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0060] R 8a and R 8b Each independently represents hydrogen or C 1-4 alkyl;

[0061] Q 1 Indicates N or CR 6a ;

[0062] Q 2 Indicates N or CR 6b ;

[0063] Q 8 Indicates N or CR 6g ;

[0064] Q 9 Indicates N or CR 6h ;

[0065] Q 10 Indicates N or CR 6i ;

[0066] Q 11 Indicates N or CR 6j ;

[0067] Q 5 Represents CR 3d ;Q 6 represents N; and Q 7 Represents CR4f ; or

[0068] Q 5 represents CR 3d ; Q 6 represents CR 4e ; and Q 7 represents N; or

[0069] Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents CR 4f ; or

[0070] Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents N; or

[0071] Q 5 represents N; Q 6 represents N; and Q 7 represents CR 4f ; or

[0072] Q 5 represents N; Q 6 represents N; and Q 7 represents N;

[0073] R 6a , R 6b , R 6g , R 6h , R 6i and R 6j each independently represents hydrogen, halogen, C 1-4 alkyl, -NR 9a R 9b or C alkyl substituted by one, two or three halogen atoms; 1-4

[0074] R 9a and R 9b each independently represents hydrogen or C 1-4 alkyl;

[0075] and their pharmaceutically acceptable addition salts and solvates.

[0076] The present invention also relates to methods for preparing the compounds of the present invention and pharmaceutical compositions comprising them.

[0077] ​It has been found that the compounds of the present invention can themselves inhibit PRMT5 or can be metabolized in vivo into (more) active forms (prodrugs), and can thus be used for treatment or prophylaxis, especially for treating the following diseases, such as blood disorders, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney diseases, platelet aggregation, sperm motility, transplant rejection, graft rejection, lung injury, etc.

[0078] In view of the pharmacology of the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates as described above, it has thus been concluded that they can be suitable for use as medicaments.

[0079] Specifically, the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates can be suitable for treatment or prophylaxis, especially for treating any of the diseases or disorders mentioned above or below, especially cancer.

[0080] The present invention also relates to the use of the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for the manufacture of a medicament for inhibiting PRMT5, which medicament is for the treatment or prophylaxis of any of the diseases or disorders mentioned above or below, specifically cancer.

[0081] The present invention will now be further described. In the following paragraphs, different aspects of the present invention are defined in more detail. Unless explicitly indicated to the contrary, each aspect so defined can be combined with any one or more other aspects. Specifically, any feature indicated as being preferred or advantageous can be combined with any one or more other features indicated as being preferred or advantageous. Detailed Description

[0082] When describing the compounds of the present invention, unless the context otherwise dictates, the terms used are intended to be understood in accordance with the following definitions.

[0083] When any variable occurs more than once in any component or in any formula (e.g., formula (I)), its definition at each occurrence is independent of its definition at each other occurrence.

[0084] Whenever the term "substituted" is used in the present invention, unless otherwise indicated or clear from the context, it is intended to indicate that one or more hydrogens (specifically 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen) on the atom or group indicated in the expression in which "substituted" is used are replaced by an option from the indicated group, provided that the normal valency is not exceeded and the substitution results in a chemically stable compound (i.e., a compound that is robust enough to withstand separation from the reaction mixture to a useful degree of purity and formulated into a therapeutic agent).

[0085] When two or more substituents are present on a moiety, unless otherwise indicated or the context is clear, these substituents may replace hydrogens on the same atom, or these substituents may replace hydrogen atoms on different atoms in the moiety.

[0086] As used herein, the prefix "C x-y " (wherein x and y are integers) refers to the number of carbon atoms in a given group. Thus, C 1-4 alkyl groups contain from 1 to 4 carbon atoms, C 1-3 alkyl groups contain from 1 to 3 carbon atoms, and so forth.

[0087] Unless otherwise indicated or the context is clear, the term "halogen" as a group or part of a group is generic to fluorine, chlorine, bromine, and iodine.

[0088] The term "C 1-4 alkyl" as a group or part of a group refers to a hydrocarbyl group having the formula C n H 2n+1 , wherein n is a numerical value in the range of 1 to 4. C 1-4 alkyl groups contain from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms, more preferably from 1 to 2 carbon atoms. C 1-4 alkyl groups may be linear or branched and may be substituted as indicated herein. When a subscript is used following a carbon atom herein, the subscript refers to the number of carbon atoms that the named group may contain.

[0089] C 1-4 alkyl includes all linear or branched alkyl groups having between 1 and 4 carbon atoms and thus includes methyl, ethyl, n-propyl, isopropyl, 2-methyl-ethyl, butyl and its isomers (e.g., n-butyl, isobutyl and tert-butyl), and the like.

[0090] One of ordinary skill in the art will recognize that the term "C 1-4 alkoxy" or "C 1-4 alkyloxy" as a group or part of a group refers to a group having the formula -OR c , wherein R c is C 1-4 alkyl. Non-limiting examples of suitable C 1-4 alkyloxy include methyloxy (also known as methoxy), ethyloxy (also known as ethoxy), propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, and tert-butyloxy.

[0091] The term "C 2-4"Alkenyl" means a straight-chain or branched-chain hydrocarbon group having 2 to 4 carbon atoms and containing a carbon-carbon double bond, such as, but not limited to, vinyl, propenyl, butenyl, 1-propen-2-yl, etc.

[0092] As used herein, the term "C 2-6 alkenyl" means a straight-chain or branched-chain hydrocarbon group having 2 to 6 carbon atoms and containing a carbon-carbon double bond, such as, but not limited to, vinyl, propenyl, butenyl, pentenyl, 1-propen-2-yl, hexenyl, etc.

[0093] As used herein, the term ‘C 3-6 cycloalkyl’ means a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0094] As used herein, the term ‘C 5-6 cycloalkyl’ means a cyclic saturated hydrocarbon group having 5 to 6 carbon atoms, such as cyclopentyl or cyclohexyl.

[0095] The term "oxo" means a double bond group (=O) attached as a substituent.

[0096] When Z is -X-CR 5a R 5b -, this means that X is attached to Ar.

[0097] When Z is -CR 5c =CR 5d -, this means that the carbon atom having the R 5c substituent is attached to Ar.

[0098] When Z is -CR 5e R 5g -CR 5f R 5h -, this means that the carbon atoms having the R 5e and R 5g substituents are attached to Ar.

[0099] When Z is -CR 5a R 5b -X-, this means that the carbon atoms having the R 5a and R 5b substituents are attached to Ar.

[0100] It will be apparent to those skilled in the art that, unless otherwise specified or clear from the context, a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms (see R 13Substituents on the (definition) (non-limiting examples are pyrrolyl, pyridyl, furyl, etc.) can replace any hydrogen atom on the ring carbon atom or, where possible, any hydrogen atom on the ring nitrogen atom (in this case, the hydrogen on the nitrogen atom can be replaced by a substituent).

[0101] A 4- to 7-membered monocyclic aromatic ring containing one, two, or three heteroatoms (see R 13 's definition) can be attached to the remainder of the molecule having the formula (I) through any available ring carbon or nitrogen atom, unless otherwise described.

[0102] Those skilled in the art will recognize that typical 4- to 7-membered monocyclic aromatic rings will be 5- or 6-membered monocyclic aromatic rings, such as pyrrolyl, pyridyl, furyl, etc.

[0103] In the case where Ar represents imidazolyl, it can be attached to the remainder of the molecule through a ring carbon or ring nitrogen atom.

[0104] Non-limiting examples of an Ar group that is a 9-membered bicyclic aromatic ring system composed of a 6-membered ring fused to a 5-membered ring and containing one, two, or three heteroatoms each independently selected from O, S, and N are

[0105]

[0106] The 9-membered bicyclic aromatic ring is attached to the remainder of the molecule through a ring carbon atom of a 5- or 6-membered ring or a ring nitrogen atom of a 5-membered ring;

[0107] Each of them is optionally substituted according to any one of the embodiments.

[0108] In the case where Ar represents a 10-membered bicyclic aromatic ring system composed of two fused 6-membered rings, in which a nitrogen atom replaces one of the two fused carbon atoms in the Ar group, a carbonyl group is present in the bicyclic aromatic ring system of the structural examples shown below:

[0109] It is optionally substituted according to any one of the embodiments. It will be clear that this example is non-limiting.

[0110] Other non-limiting examples are shown below as a 10-membered bicyclic aromatic ring system composed of two fused 6-membered rings, in which optionally 1 or 2 ring carbon atoms are replaced by nitrogen atoms:

[0111]

[0112] Each of them is optionally substituted according to any one of the embodiments.

[0113] Non-limiting examples of an Ar group that is a fused bicyclic partial aromatic ring system attached to the linking group Z with an aromatic ring are shown below:

[0114]

[0115] Each of them is optionally substituted according to any one of the embodiments.

[0116] Whenever a substituent is represented by a chemical structure, "---" represents a bond attached to the remainder of the molecule having formula (I).

[0117] It will be clear that a line drawn from a substituent to the ring system indicates that the bond can be attached to any suitable ring atom, unless otherwise specified or clear from the context.

[0118] As used herein, the term "subject" refers to an animal that is or has been the object of treatment, observation, or experiment, preferably a mammal (such as a cat, dog, primate, or human), more preferably a human.

[0119] As used herein, the term "therapeutically effective amount" means an amount of an active compound or pharmaceutical agent that elicits a biological or pharmaceutical response in a tissue system (animal or human) that is being sought by a researcher, veterinarian, medical doctor, or other clinician, including alleviation or reversal of the symptoms of the disease or disorder being treated.

[0120] The term "composition" is intended to cover a product containing the specified amounts of the specified ingredients, as well as any product directly or indirectly resulting from the combination of the specified amounts of the specified ingredients.

[0121] As used herein, the term "treatment" is intended to refer to all processes in which the progression of a disease may be slowed, interrupted, arrested, or prevented, but not necessarily indicating that all symptoms are completely eliminated.

[0122] As used herein, the term "compounds of the invention" is intended to include compounds having formula (I) and their pharmaceutically acceptable addition salts and solvates.

[0123] Some compounds having formula (I) may also exist in their tautomeric forms. The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert via a low energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversions that occur via proton transfer, such as keto - enol and imine - enamine isomerizations. Valence tautomers include interconversions that result from the reorganization of some of the bonding electrons.

[0124] Although not explicitly indicated in formula (I) above, such forms are intended to be included within the scope of the present invention where they can exist.

[0125] As used herein, any chemical formula having bonds that are shown only as solid lines and not as solid or dashed wedge bonds, or otherwise represented as having a specific configuration (e.g., R, S) around one or more atoms, contemplates each possible stereoisomer, or a mixture of two or more stereoisomers. In these structures shown herein, where the stereochemistry at any particular chiral atom is not specified, then all stereoisomers are considered to be compounds of the invention and are included in the compounds of the invention, either as a pure stereoisomer or as a mixture of two or more stereoisomers.

[0126] In the foregoing and in the following, the term "compound having formula (I)" is intended to include its stereoisomers and its tautomeric forms. However, as mentioned in the preceding paragraph, where the stereochemistry is specified by bonds shown as solid or dashed wedge bonds, or otherwise indicated as having a specific configuration (e.g., R, S), then that stereoisomer is the one specified and defined. It will be clear that this also applies to subgroups having formula (I).

[0127] It follows that, where possible, a single compound can exist in stereoisomeric and tautomeric forms.

[0128] In the foregoing or in the following, the terms "stereoisomer", "stereoisomeric form" or "stereochemical isomeric form" are used interchangeably.

[0129] Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of an enantiomeric pair is a racemate or racemic mixture.

[0130] Atropisomers (or atropoisomers) are stereoisomers having a specific spatial configuration that results from restricted rotation about a single bond due to steric hindrance. All atropisomeric forms of a compound having formula (I) are intended to be included within the scope of the present invention.

[0131] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e., they are not related as mirror images. If the compound contains a double bond, then these substituents can be in the E or Z configuration. Substituents on a divalent cyclic (partially) saturated group can have a cis or trans configuration; for example, if the compound contains a disubstituted cycloalkyl group, then these substituents can be in the cis or trans configuration. Accordingly, the present invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, wherever chemically possible.

[0132] The meanings 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 person skilled in the art.

[0133] The absolute configuration is assigned according to the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is specified by R or S. A resolved stereoisomer of unknown absolute configuration can be designated by (+) or (-) according to the direction in which it rotates plane-polarized light. For example, a resolved enantiomer of unknown absolute configuration can be designated by (+) or (-) according to the direction in which it rotates plane-polarized light.

[0134] When identifying a specific stereoisomer, this means that the stereoisomer is substantially free of other stereoisomers, i.e., associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, especially less than 2% and most preferably less than 1% of other stereoisomers. Thus, when a compound of formula (I) is specified as (R), for example, this means that the compound is substantially free of the (S) isomer; when a compound of formula (I) is specified as E, for example, this means that the compound is substantially free of the Z isomer; when a compound of formula (I) is specified as cis, for example, this means that the compound is substantially free of the trans isomer.

[0135] For therapeutic use, the salts and solvates of the compounds of formula (I) are those in which the counterion is pharmaceutically acceptable. However, salts of pharmaceutically unacceptable acids and bases may also find use, for example, in the preparation or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or unacceptable, are included within the scope of the present invention.

[0136] Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can be formed by conventional means, for example, by reacting the free acid or free base form with one or more equivalents of the appropriate acid or base, optionally in a solvent or in a medium in which the salt is insoluble, followed by removal of the solvent or the medium using standard techniques (e.g., in vacuo, by lyophilization or by filtration). Salts can also be prepared by exchanging the counterion of a compound of the present invention in salt form with another counterion, for example, using a suitable ion exchange resin.

[0137] The pharmaceutically acceptable addition salts mentioned above or below are intended to include the therapeutically active non-toxic acid addition salt and base addition salt forms that the compounds of formula (I) and their solvates are capable of forming.

[0138] Suitable acids include, for example, inorganic acids such as hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid (i.e., ethanedioic acid), malonic acid, succinic acid (i.e., butanedioic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, and the like. Conversely, the salt form can be converted to the free base form by treatment with a suitable base.

[0139] Compounds of formula (I) and their solvates containing an acidic proton can also be converted to their non-toxic metal or amine addition salt forms by treatment with suitable organic and inorganic bases.

[0140] Suitable base salt forms include, for example, ammonium salts, alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium salts, etc., salts with organic bases (e.g., primary, secondary, and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, tetrabutylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline, and isoquinoline); benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids (e.g., arginine, lysine, etc.). Conversely, the salt form can be converted to the free acid form by treatment with an acid.

[0141] For the purposes of the present invention, prodrugs are also included within the scope of the present invention.

[0142] The term "prodrug" of a compound of the present invention includes any compound which, upon oral or parenteral administration (especially oral), is metabolized in vivo to form an experimentally detectable amount of the compound and within a predetermined time (e.g., within a dosing interval between 6 and 24 hours (i.e., one to four times a day)). For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral, specifically intravenous (IV), intramuscular (IM), and subcutaneous (SC) injection.

[0143] Prodrugs can be prepared by modifying the functional groups present in the compound in such a way that these modifications are cleaved in vivo when such prodrugs are administered to a mammalian subject. Typically, these modifications are accomplished by synthesizing the parent compound with a prodrug substituent. Generally, prodrugs include compounds of the present invention in which a hydroxyl, amino, mercapto, carboxyl, or carbonyl group in the compound of the present invention is attached to any group that can be cleaved in vivo to regenerate the free hydroxyl, amino, mercapto, carboxyl, or carbonyl group, respectively; specifically, in which a hydroxyl group in the compound of the present invention is attached to any group that can be cleaved in vivo (e.g., -C(=O)-C1-4 on the (alkyl) group to regenerate the free hydroxyl group. For the purposes of the present invention, specific prodrugs are compounds of formula (I) or subgroups thereof, wherein R 1 and / or R 2 represents -C(=O)-C 1-4 alkyl.

[0144] Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxyl functional groups, ester groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs can be found, for example, in Bundegaard, H. “Design of Prodrugs” pages 1-92, Elesevier, New York-Oxford (1985).

[0145] The term solvate includes hydrates and solvate addition forms that can be formed by compounds of formula (I) and their pharmaceutically acceptable addition salts. Examples of such forms are, for example, hydrates, alcoholates, etc.

[0146] Compounds of the present invention prepared as described in the methods below can be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, and these enantiomers can be separated from each other according to resolution procedures known in the art. One way to separate the enantiomeric forms of compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates involves liquid chromatography using a chiral stationary phase. The pure stereochemical isomeric forms can also be derived from the corresponding pure stereochemical isomeric forms of suitable starting materials, provided that the reaction occurs stereospecifically. Preferably, if a particular stereoisomer is desired, the compound will be synthesized by a stereospecific method of preparation. These methods will advantageously use enantiomerically pure starting materials.

[0147] The present invention also includes isotopically labeled compounds of the present invention, which are identical to those listed herein, but in fact one or more atoms are replaced by atoms having an atomic mass or mass number different from that normally found in nature (or the one most commonly found in nature).

[0148] All isotopes and isotope mixtures of any specific atom or element specified herein are considered to be within the scope of the compounds of the present invention, whether naturally occurring or synthetically produced, whether having natural abundance or in an isotopically enriched form. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C,13 C, 14 C, 13 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 122 I, 123 I, 125 I, 131 I 、75 Br, 76 Br, 77 Br and 82 Br. Preferably, the radioactive isotope is selected from the group consisting of: 2 H, 3 H, 11 C and 18 F. More preferably, the radioactive isotope is 2 H. Specifically, deuterated compounds are intended to be included within the scope of the present invention.

[0149] Certain isotopically labeled compounds of the present invention (e.g., those labeled with 3 H and 14 C) are used for substrate tissue distribution assays. Tritium ([[]] 3 [[]] 3 3 H) and carbon-14 ([[]] 14 [[]] 14 14 C) isotopes are useful because they are easy to prepare and detect. In addition, substitution with heavier isotopes such as deuterium (i.e., 2 H) can provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dose requirements) due to greater metabolic stability and may therefore be preferred in some circumstances. Positron-emitting isotopes such as 15 O, 13 N, 11 C and 18 F) can be used in positron emission tomography (PET) to examine substrate receptor occupancy.

[0150] In one embodiment, the present invention relates to a compound having formula (I), wherein

[0151] R 1 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0152] R 2 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0153] Y represents -CH2- or -CF2-;

[0154] Z represents -CH2-, -CHR 5i -, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[0155] R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R 5g 、R 5h and R 5i each independently represents hydrogen or C 1-4 alkyl;

[0156] X represents -O-;

[0157] R 11 represents hydrogen, C 1-4 alkyl or C alkyl substituted by a substituent selected from the group consisting of: -OH, -O-C 1-4 alkyl, -NH2, -NH-C 1-4 alkyl, and -N(C 1-4 alkyl)2; 1-4 alkyl)2;

[0158] Ar represents a monocyclic aromatic ring or a bicyclic system;

[0159] wherein the monocyclic aromatic ring is selected from the group consisting of: pyridyl, pyrimidinyl, pyrazolyl, and imidazolyl;

[0160] wherein the bicyclic system is

[0161] (i) A 9-membered bicyclic aromatic ring system consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, said 9-membered bicyclic aromatic ring being attached to the remainder of the molecule through a ring carbon atom of a 5- or 6-membered ring or a ring nitrogen atom of a 5-membered ring; or

[0162] (ii) 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 nitrogen atoms; 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;

[0163] Provided that when Ar represents a 10-membered bicyclic aromatic ring system, Z only represents -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -; or

[0164] (iii) A fused bicyclic partial aromatic ring system attached to a linking group Z through an aromatic ring, wherein the fused bicyclic partial aromatic ring system is selected from (b-1), (b-2) and (b-3)

[0165]

[0166] wherein ring A is a monocyclic aromatic ring selected from the group consisting of pyridyl, pyrimidinyl, pyrazolyl and imidazolyl;

[0167] wherein ring B is C 5-6 cycloalkyl or a 5- to 6-membered saturated heterocyclic group containing one or two heteroatoms each independently selected from O, S and N;

[0168] Ar is optionally substituted at a carbon atom by a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, oxo, -OH, -NH2, -NH-C 1-4 alkyl, -NHR 10 , cyano, -CF3, C 1-4 alkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl and C substituted by one C 1-4 alkoxy-substituted C1-4 alkyl; and

[0169] where possible, Ar is optionally substituted on one N-atom with a substituent selected from the group consisting of C 1-4 alkyl; C 3-6 cycloalkyl; C 1-4 alkyl substituted with one, two or three halogen atoms; and C 3-6 cycloalkyl substituted with one, two or three halogen atoms;

[0170] R 10 represents -(C=O)-C 1-4 alkyl; C 3-6 cycloalkyl; R 13 ; R 14 ; C 3-6 cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halogen, -OH and -O-C 1-4 alkyl; C 1-4 alkyl substituted with one, two or three substituents each independently selected from the group consisting of halogen, -OH and -O-C 1-4 alkyl; or C 1-4 alkyl substituted with a substituent selected from the group consisting of C 3-6 cycloalkyl, R 13 and R 14 ;

[0171] R 13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=O) p and N; said 4- to 7-membered monocyclic aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C 1-4 alkyl;

[0172] p represents 1 or 2;

[0173] R 14 represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halogen;

[0174] Het represents a bicyclic aromatic heterocyclic system (a-1);

[0175] R 3a represents halogen, -NR 7a R 7b or -O-C 1-4 alkyl;

[0176] R 7a represents hydrogen;

[0177] R 7b represents hydrogen, C 3-6 cycloalkyl or C 1-4 alkyl;

[0178] R 4a represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0179] R 8a and R 8b each independently represents hydrogen or C 1-4 alkyl;

[0180] Q 1 represents CR 6a ;

[0181] Q 2 represents CR 6b ;

[0182] R 6a and R 6b each independently represents hydrogen, halogen, C 1-4 alkyl, -NR 9a R 9b or C alkyl substituted by one, two or three halogen atoms; 1-4 alkyl;

[0183] R 9a and R 9b each independently represents hydrogen or C 1-4 alkyl;

[0184] and its pharmaceutically acceptable addition salts and solvates.

[0185] In one embodiment, the present invention relates to a compound having the formula (I), wherein

[0186] R 1 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0187] R 2 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0188] Y represents -CH2- or -CF2-;

[0189] Z represents -CH2-, -CHR 5i -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R5h -, -CR 5c R 5d -

[0190] CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[0191] R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , R 5h and R 5i each independently represents hydrogen or C 1-4 alkyl;

[0192] R 11 represents hydrogen, C 1-4 alkyl or C alkyl substituted by a substituent selected from the group consisting of: -OH, -O-C 1-4 alkyl, -NH2, -NH-C 1-4 alkyl and -N(C 1-4 alkyl)2; 1-4 alkyl)2;

[0193] Ar represents a monocyclic aromatic ring or a bicyclic system;

[0194] wherein the monocyclic aromatic ring is selected from the group consisting of: pyridyl, pyrimidinyl, pyrazolyl and imidazolyl;

[0195] wherein the bicyclic system is

[0196] (i) a 9-membered bicyclic aromatic ring system composed of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, said 9-membered bicyclic aromatic ring being attached to the remainder of the molecule through a ring carbon atom of the 5- or 6-membered ring or a ring nitrogen atom of the 5-membered ring; or

[0197] (ii) a 10-membered bicyclic aromatic ring system composed of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by nitrogen atoms; 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;

[0198] Provided that when Ar represents a 10-membered bicyclic aromatic ring system, Z represents only -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -; or

[0199] (iii) a fused bicyclic partial aromatic ring system, which is attached to the aromatic ring via a linking group Z, wherein the fused bicyclic partial aromatic ring system is selected from (b-1), (b-2) and (b-3)

[0200]

[0201] wherein ring A is a monocyclic aromatic ring selected from the group consisting of pyridyl, pyrimidinyl, pyrazolyl and imidazolyl;

[0202] wherein ring B is C 5-6 cycloalkyl or a 5- to 6-membered saturated heterocyclic group containing one or two heteroatoms each independently selected from O, S and N;

[0203] Ar is optionally substituted at a carbon atom with a total of one, two, three or four substituents each independently selected from the group consisting of halogen, oxo, -OH, -NH2, -NH-C 1-4 alkyl, -NHR 10 、cyano, -CF3, C 1-4 alkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl and C substituted with one C 1-4 alkoxy-substituted C 1-4 alkyl; and

[0204] where possible, Ar is optionally substituted at an N-atom with a substituent selected from the group consisting of C 1-4 alkyl; C 3-6 cycloalkyl; C 1-4 alkyl substituted with one, two or three halogen atoms; and C 3-6 cycloalkyl substituted with one, two or three halogen atoms;

[0205] R 10 represents -(C=O)-C1-4 Alkyl; C 3-6 Cycloalkyl; R 13 ; R 14 ; C substituted by one, two or three substituents each independently selected from the group consisting of 3-6 Cycloalkyl: halogen, -OH and -O-C 1-4 Alkyl; C substituted by one, two or three substituents each independently selected from the group consisting of 1-4 Alkyl: halogen, -OH and -O-C 1-4 Alkyl; or C substituted by a substituent selected from the group consisting of 1-4 Alkyl: C 3-6 Cycloalkyl, R 13 and R 14 ;

[0206] R 13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=O) p and N; the 4- to 7-membered monocyclic aromatic ring is optionally substituted by one or two substituents selected from the group consisting of C 1-4 Alkyl;

[0207] p represents 1 or 2;

[0208] R 14 represents a phenyl group optionally substituted by one, two or three substituents each independently selected from the group consisting of: halogen;

[0209] Het represents a bicyclic aromatic heterocyclic system (a-1);

[0210] R 3a represents halogen, -NR 7a R 7b or -O-C 1-4 Alkyl;

[0211] R 7a represents hydrogen;

[0212] R 7b represents hydrogen, C 3-6 Cycloalkyl or C 1-4 Alkyl;

[0213] R 4a represents hydrogen, halogen, -NR 8a R 8b or C 1-4 Alkyl;

[0214] R 8a and R 8b each independently represents hydrogen or C 1-4 Alkyl;

[0215] Q 1 represents CR 6a ;

[0216] Q 2 represents CR 6b ;

[0217] R 6a and R 6b each independently represents hydrogen, halogen, C 1-4 alkyl, -NR 9a R 9b or C 1-4 alkyl substituted by one, two or three halogen atoms;

[0218] R 9a and R 9b each independently represents hydrogen or C 1-4 alkyl;

[0219] and its pharmaceutically acceptable addition salts and solvates.

[0220] In one embodiment, the present invention relates to a compound having the formula (I), wherein

[0221] R 1 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0222] R 2 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0223] Y represents -CH2- or -CF2-;

[0224] Z represents -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, -CR 5a R 5b -X- or -C≡C-;

[0225] R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R 5g and R 5h each independently represents hydrogen or C 1-4 alkyl;

[0226] X represents -O-, -S- or -NR 11 -;

[0227] R 11 represents hydrogen, C 1-4 alkyl or C alkyl substituted by a substituent selected from the group consisting of: 1-4 -OH, -O-C 1-4 alkyl, -NH2, -NH-C 1-4 alkyl and -N(C 1-4 alkyl)2;

[0228] Ar represents a monocyclic aromatic ring selected from pyridyl and imidazolyl; or

[0229] a 9-membered bicyclic aromatic ring system consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, said 9-membered bicyclic aromatic ring being attached to the remainder of the molecule through a ring carbon atom of the 5- or 6-membered ring or a ring nitrogen atom of the 5-membered ring;

[0230] Ar is optionally substituted on a carbon atom by a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 alkyl, -NHR 10 , cyano, -CF3, C 1-4 alkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl and C alkyl substituted by a C 1-4 alkoxy; and 1-4 alkyl; and

[0231] where possible, Ar is optionally substituted on an N-atom by a substituent selected from the group consisting of: C 1-4 alkyl; C 3-6 cycloalkyl; C alkyl substituted by one, two or three halogen atoms; and C 1-4 cycloalkyl substituted by one, two or three halogen atoms; 3-6 ;

[0232] R 10 represents -(C=O)-C 1-4 alkyl; C 3-6 cycloalkyl; R 13 ; R 14 ; C cycloalkyl substituted by one, two or three substituents each independently selected from the group consisting of: 3-6 halogen, -OH and -O-C 1-4Alkyl; C substituted with one, two or three substituents each independently selected from the group consisting of 1-4 alkyl: halogen, -OH and -O-C 1-4 alkyl; or C substituted with a substituent selected from the group consisting of 1-4 alkyl: C 3-6 cycloalkyl, R 13 and R 14 ;

[0233] R 13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=O) p and N; the 4- to 7-membered monocyclic aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C 1-4 alkyl;

[0234] p represents 1 or 2;

[0235] R 14 represents a phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of: halogen;

[0236] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of: (a-1), (a-2) and (a-3):

[0237] R 3a , R 3d and R 3e each independently represents hydrogen, halogen, -NR 7a R 7b , C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, -OH or -O-C 1-4 alkyl;

[0238] R 7a represents hydrogen;

[0239] R 7b represents hydrogen, C 3-6 cycloalkyl or C 1-4 alkyl;

[0240] R 4a , R 4d , R 4e , R 4f and R 4g each independently represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0241] R8a and R 8b each independently represents hydrogen or C 1-4 alkyl;

[0242] Q 1 represents N or CR 6a ;

[0243] Q 2 represents N or CR 6b ;

[0244] Q 8 represents N or CR 6g ;

[0245] Q 9 represents N or CR 6h ;

[0246] Q 10 represents N or CR 6i ;

[0247] Q 11 represents N or CR 6j ;

[0248] Q 5 represents CR 3d ; Q 6 represents N; and Q 7 represents CR 4f ; or

[0249] Q 5 represents CR 3d ; Q 6 represents CR 4e ; and Q 7 represents N; or

[0250] Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents CR 4f ; or

[0251] Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents N; or

[0252] Q 5 represents N; Q 6 represents N; and Q 7 represents CR 4f ; or

[0253] Q 5 represents N; Q 6represents N; and Q 7 represents N;

[0254] R 6a 、R 6b 、R 6g 、R 6h 、R 6i and R 6j each independently represents hydrogen, halogen, C 1-4 alkyl, -NR 9a R 9b or C 1-4 alkyl substituted by one, two or three halogen atoms;

[0255] R 9a and R 9b each independently represents hydrogen or C 1-4 alkyl;

[0256] and its pharmaceutically acceptable addition salts and solvates.

[0257] In one embodiment, the present invention relates to a compound having the formula (I), wherein

[0258] R 1 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0259] R 2 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0260] Y represents -CH2- or -CF2-;

[0261] Z represents -CH2-, -CHR 5i -, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, -CR 5a R 5b -X-, -C≡C-, -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR5f R 5h -;

[0262] R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R 5g 、R 5h and R 5i each independently represents hydrogen or C 1-4 alkyl;

[0263] X represents -O-, -S- or -NR 11 -;

[0264] R 11 represents hydrogen, C 1-4 alkyl or C alkyl substituted with a substituent selected from the group consisting of: -OH, -O-C 1-4 alkyl, -NH2, -NH-C 1-4 alkyl and -N(C 1-4 alkyl)2; 1-4 alkyl)2;

[0265] Ar represents a monocyclic aromatic ring or a bicyclic system;

[0266] wherein the monocyclic aromatic ring is selected from the group consisting of: pyridyl, pyrimidinyl, pyrazolyl and imidazolyl;

[0267] wherein the bicyclic system is

[0268] (i) a 9-membered bicyclic aromatic ring system composed of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, and the 9-membered bicyclic aromatic ring is attached to the remainder of the molecule through a ring carbon atom of the 5- or 6-membered ring or a ring nitrogen atom of the 5-membered ring; or

[0269] (ii) a 10-membered bicyclic aromatic ring system composed of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by nitrogen atoms; provided that when a nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in the bicyclic aromatic ring system;

[0270] provided that when Ar represents a 10-membered bicyclic aromatic ring system, Z represents only -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R5d -CR 5e R 5g -CR 5f R 5h -; or

[0271] (iii) A fused bicyclic partially aromatic ring system, which is attached to the linking group Z by an aromatic ring, wherein the fused bicyclic partially aromatic ring system is selected from (b-1), (b-2) and (b-3)

[0272]

[0273] wherein ring A is a monocyclic aromatic ring selected from the group consisting of: pyridyl, pyrimidinyl, pyrazolyl and imidazolyl;

[0274] wherein ring B is C 5-6 cycloalkyl or a 5- to 6-membered saturated heterocyclic group containing one or two heteroatoms each independently selected from O, S and N;

[0275] Ar is optionally substituted at a carbon atom with a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, oxo, -OH, -NH2, -NH-C 1-4 alkyl, -NHR 10 , cyano, -CF3, C 1-4 alkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl and C substituted with one C 1-4 alkoxy-substituted C 1-4 alkyl; and

[0276] where possible, Ar is optionally substituted at an N-atom with a substituent selected from the group consisting of: C 1-4 alkyl; C 3-6 cycloalkyl; C substituted with one, two or three halogen atoms 1-4 alkyl; and C substituted with one, two or three halogen atoms 3-6 cycloalkyl;

[0277] R 10 represents -(C=O)-C 1-4 alkyl; C 3-6 cycloalkyl; R 14 ; C substituted with one, two or three substituents each independently selected from the group consisting of 3-6 cycloalkyl: halogen, -OH and -O-C 1-4 alkyl; C substituted with one, two or three substituents each independently selected from the group consisting of 1-4Alkyl: halogen, -OH and -O-C 1-4 Alkyl; or C substituted with a substituent selected from the group consisting of 1-4 Alkyl: C 3-6 Cycloalkyl and R 14 ;

[0278] R 14 represents a phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of: halogen;

[0279] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of: (a-1), (a-2) and (a-3):

[0280]

[0281] R 3a , R 3d and R 3e each independently represents hydrogen, halogen, -NR 7a R 7b , C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, -OH or -O-C 1-4 Alkyl;

[0282] R 7a represents hydrogen;

[0283] R 7b represents hydrogen, C 3-6 Cycloalkyl or C 1-4 Alkyl;

[0284] R 4a , R 4d , R 4e , R 4f and R 4g each independently represents hydrogen, halogen, -NR 8a R 8b or C 1-4 Alkyl;

[0285] R 8a and R 8b each independently represents hydrogen or C 1-4 Alkyl;

[0286] Q 1 represents N or CR 6a ;

[0287] Q 2 represents N or CR 6b ;

[0288] Q 8Indicates N or CR 6g ;

[0289] Q 9 Indicates N or CR 6h ;

[0290] Q 10 Indicates N or CR 6i ;

[0291] Q 11 Indicates N or CR 6j ;

[0292] Q 5 Represents CR 3d ;Q 6 represents N; and Q 7 Represents CR 4f ;or

[0293] Q 5 Represents CR 3d ;Q 6 Represents CR 4e ; and Q 7 means N; or

[0294] Q 5 Indicates N; Q 6 Represents CR 4e ; and Q 7 Represents CR 4f ;or

[0295] Q 5 Indicates N; Q 6 Represents CR 4e ; and Q 7 means N; or

[0296] Q 5 Indicates N; Q 6 represents N; and Q 7 Represents CR 4f ;or

[0297] Q 5 Indicates N; Q 6 represents N; and Q 7 Indicates N;

[0298] R 6a , R 6b , R 6g , R 6h , R 6i and R 6j Each independently represents hydrogen, halogen, C 1-4 Alkyl, -NR 9a R 9b or C substituted by one, two or three halogen atoms1-4 alkyl;

[0299] R 9a and R 9b each independently represents hydrogen or C 1-4 alkyl;

[0300] In one embodiment, the present invention relates to a compound having formula (I), wherein

[0301] R 1 represents hydrogen; R 2 represents hydrogen;

[0302] Y represents -CH2-;

[0303] Z represents -CH2-, -CHR 5i -, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -, or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[0304] R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , R 5h and R 5i each independently represents hydrogen or C 1-4 alkyl;

[0305] X represents -O-;

[0306] Ar represents a monocyclic aromatic ring or a bicyclic system;

[0307] wherein the monocyclic aromatic ring is selected from the group consisting of: pyridyl, pyrimidinyl, pyrazolyl, and imidazolyl;

[0308] wherein the bicyclic system is

[0309] (i) A 9-membered bicyclic aromatic ring system consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, said 9-membered bicyclic aromatic ring being attached to the remainder of the molecule through a ring carbon atom of a 5- or 6-membered ring or a ring nitrogen atom of a 5-membered ring; or

[0310] (ii) A 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein 1 or 2 ring carbon atoms are replaced by nitrogen atoms; 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;

[0311] Provided that when Ar represents a 10-membered bicyclic aromatic ring system, Z only represents -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -; or

[0312] (iii) A fused bicyclic partial aromatic ring system, which is attached to a linking group Z through an aromatic ring, wherein the fused bicyclic partial aromatic ring system is selected from (b-1) and (b-3),

[0313] wherein ring A is pyridyl;

[0314] wherein ring B is a 5- to 6-membered saturated heterocyclic group containing one or two heteroatoms each independently selected from O and N;

[0315] Ar is optionally substituted on a carbon atom by a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, oxo, -NH2, -NH-C 1-4 alkyl, -CF3, C 3-6 cycloalkyl and C 1-4 alkyl; and

[0316] where possible, Ar is optionally substituted on an N-atom by a C 1-4 alkyl;

[0317] Het represents a bicyclic aromatic heterocyclic system (a-1);

[0318] R 3a represents halogen, -NR 7a R7b or -O-C 1-4 alkyl;

[0319] R 7a represents hydrogen;

[0320] R 7b represents hydrogen or C 1-4 alkyl;

[0321] R 4a represents hydrogen;

[0322] Q 1 represents CR 6a ;

[0323] Q 2 represents N or CR 6b ;

[0324] R 6a and R 6b each independently represents hydrogen or halogen;

[0325] and its pharmaceutically acceptable addition salts and solvates.

[0326] In one embodiment, the present invention relates to a compound having formula (I), wherein

[0327] R 1 represents hydrogen; R 2 represents hydrogen;

[0328] Y represents -CH2-;

[0329] Z represents -CH2-, -CHR 5i -, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -、-CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[0330] R 5a 、R5b , R 5c , R 5d , R 5e , R 5f , R 5g , R 5h and R 5i each independently represents hydrogen or C 1-4 alkyl;

[0331] X represents -O-;

[0332] Ar represents a monocyclic aromatic ring or a bicyclic system;

[0333] wherein the monocyclic aromatic ring is selected from the group consisting of: pyridyl, pyrimidinyl, pyrazolyl, and imidazolyl;

[0334] wherein the bicyclic system is

[0335] (i) a 9 - membered bicyclic aromatic ring system composed of a 6 - membered ring fused to a 5 - membered ring, containing one, two, or three heteroatoms each independently selected from O, S, and N, and the 9 - membered bicyclic aromatic ring is attached to the rest of the molecule through a ring carbon atom of the 5 - or 6 - membered ring or a ring nitrogen atom of the 5 - membered ring; or

[0336] (ii) a 10 - membered bicyclic aromatic ring system composed of two fused 6 - membered rings, wherein 1 or 2 ring carbon atoms are replaced by nitrogen atoms; provided that when a nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in the bicyclic aromatic ring system;

[0337] provided that when Ar represents a 10 - membered bicyclic aromatic ring system, Z only represents -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -; or

[0338] (iii) a fused bicyclic partial aromatic ring system, which is attached to the linking group Z, and the fused bicyclic partial aromatic ring system is selected from (b - 1) and (b - 3),

[0339] wherein ring A is pyridyl;

[0340] wherein ring B is a 5 - to 6 - membered saturated heterocyclic group containing one or two heteroatoms each independently selected from O and N;

[0341] Ar is optionally substituted on a carbon atom with a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, oxo, -NH2, -NH-C 1-4 alkyl, -CF3, C 3-6 cycloalkyl and C 1-4 alkyl; and

[0342] where possible, Ar is optionally substituted on an N-atom with a C 1-4 alkyl;

[0343] Het represents a bicyclic aromatic heterocyclic system (a-1);

[0344] R 3a represents halogen, -NR 7a R 7b or -O-C 1-4 alkyl;

[0345] R 7a represents hydrogen;

[0346] R 7b represents hydrogen or C 1-4 alkyl;

[0347] R 4a represents hydrogen;

[0348] Q 1 represents CR 6a ;

[0349] Q 2 represents CR 6b ;

[0350] R 6a and R 6b each independently represent hydrogen or halogen;

[0351] and their pharmaceutically acceptable addition salts and solvates.

[0352] In one embodiment, the invention relates to a compound having formula (I), wherein

[0353] R 1 represents hydrogen; R 2 represents hydrogen;

[0354] Y represents -CH2-;

[0355] Z represents -CH2-, -CHR 5i -, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5eR 5g -CR 5f R 5h -、-CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[0356] R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R 5g 、R 5h and R 5i each independently represents hydrogen or C 1-4 alkyl;

[0357] X represents -O-;

[0358] Ar represents a monocyclic aromatic ring or a bicyclic system;

[0359] wherein the monocyclic aromatic ring is selected from the group consisting of: pyridyl, pyrimidinyl, pyrazolyl and imidazolyl;

[0360] wherein the bicyclic system is

[0361] (i) a 9 - membered bicyclic aromatic ring system, consisting of a 6 - membered ring fused to a 5 - membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, and the 9 - membered bicyclic aromatic ring is attached to the rest of the molecule through a ring carbon atom of the 5 - or 6 - membered ring or a ring nitrogen atom of the 5 - membered ring; or

[0362] (ii) a 10 - membered bicyclic aromatic ring system consisting of two fused 6 - membered rings, wherein 1 or 2 ring carbon atoms are replaced by nitrogen atoms; provided that when a nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in the bicyclic aromatic ring system;

[0363] provided that when Ar represents a 10 - membered bicyclic aromatic ring system, Z only represents -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -; or

[0364] (iii) A fused bicyclic partial aromatic ring system, which is attached to the linking group Z through an aromatic ring, wherein the fused bicyclic partial aromatic ring system is selected from (b-1) and (b-3),

[0365] wherein ring A is pyridyl;

[0366] wherein ring B is a 5- to 6-membered saturated heterocyclic group containing one or two heteroatoms each independently selected from O and N;

[0367] Ar is optionally substituted at a carbon atom with a total of one, two, three, or four substituents each independently selected from the group consisting of: halogen, oxo, -NH2, -NH-C 1-4 alkyl, -NHR 10 , -CF3, C 3-6 cycloalkyl, and C 1-4 alkyl; and

[0368] where possible, Ar is optionally substituted at an N-atom with a C 1-4 alkyl;

[0369] R 10 represents -(C=O)-C 1-4 alkyl;

[0370] Het represents the bicyclic aromatic heterocyclic system (a-1);

[0371] R 3a represents halogen, -NR 7a R 7b or -O-C 1-4 alkyl;

[0372] R 7a represents hydrogen;

[0373] R 7b represents hydrogen or C 1-4 alkyl;

[0374] R 4a represents hydrogen;

[0375] Q 1 represents CR 6a ;

[0376] Q 2 represents CR 6b ;

[0377] R 6a and R 6b each independently represents hydrogen or a halogen;

[0378] and pharmaceutically acceptable addition salts and solvates thereof.

[0379] In one embodiment, the present invention relates to a compound having the formula (I), wherein

[0380] R 1 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0381] R 2 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0382] Y represents -CH2- or -CF2-;

[0383] Z represents -CH2-, -CHR 5i -, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -、-CR 5a R 5b -X-、-C≡C-、-CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[0384] R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R 5g 、R 5h and R 5i each independently represents hydrogen or C 1-4 alkyl;

[0385] X represents -O-, -S- or -NR 11-;

[0386] R 11 Represents hydrogen, C 1-4 Alkyl or C substituted by a substituent selected from the group consisting of 1-4 Alkyl: -OH, -OC 1-4 Alkyl, -NH2, -NH-C 1-4 Alkyl and -N(C 1-4 Alkyl)2;

[0387] Ar represents a monocyclic aromatic ring selected from the group consisting of pyridyl, pyrimidinyl, pyrazolyl and imidazolyl;

[0388] Ar is optionally substituted on the carbon atom with a total of one, two, three or four substituents each independently selected from the group consisting of halogen, oxo, -OH, -NH2, -NH-C 1-4 Alkyl, -NHR 10 , cyano, -CF3, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, C 2-6 Alkenyl, C 1-4 Alkyl and a C 1-4 Alkoxy substituted C 1-4 Alkyl; and

[0389] Ar is optionally substituted on one N-atom, where possible, with a substituent selected from the group consisting of: C 1-4 Alkyl; C 3-6 Cycloalkyl; C substituted by one, two or three halogen atoms 1-4 Alkyl; and C substituted by one, two or three halogen atoms 3-6 Cycloalkyl;

[0390] R 10 Represents -(C=O)-C 1-4 Alkyl; C 3-6 Cycloalkyl; R 14 ; C substituted by one, two or three substituents each independently selected from the group consisting of 3-6 Cycloalkyl: halogen, -OH and -OC 1-4 Alkyl; C substituted by one, two or three substituents each independently selected from the group consisting of 1-4 Alkyl: halogen, -OH and -OC 1-4 Alkyl; or C substituted by a substituent selected from the group consisting of 1-4 Alkyl: C 3-6 Cycloalkyl and R 14 ;

[0391] R 14 represents a phenyl group optionally substituted by one, two or three substituents each independently selected from the group consisting of: halogen;

[0392] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of: (a-1), (a-2) and (a-3):

[0393] R 3a 、R 3d and R 3e each independently represent hydrogen, halogen, -NR 7a R 7b 、C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, -OH or -O-C 1-4 alkyl;

[0394] R 7a represents hydrogen;

[0395] R 7b represents hydrogen, C 3-6 cycloalkyl or C 1-4 alkyl;

[0396] R 4a 、R 4d 、R 4e 、R 4f and R 4g each independently represent hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0397] R 8a and R 8b each independently represent hydrogen or C 1-4 alkyl;

[0398] Q 1 represents N or CR 6a ;

[0399] Q 2 represents N or CR 6b ;

[0400] Q 8 represents N or CR 6g ;

[0401] Q 9 represents N or CR 6h ;

[0402] Q 10 represents N or CR 6i ;

[0403] Q 11 represents N or CR 6j ;

[0404] Q 5 represents CR 3d ; Q 6 represents N; and Q 7 represents CR 4f ; or

[0405] Q 5 represents CR 3d ; Q 6 represents CR 4e ; and Q 7 represents N; or

[0406] Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents CR 4f ; or

[0407] Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents N; or

[0408] Q 5 represents N; Q 6 represents N; and Q 7 represents CR 4f ; or

[0409] Q 5 represents N; Q 6 represents N; and Q 7 represents N;

[0410] R 6a , R 6b , R 6g , R 6h , R 6i and R 6j each independently represents hydrogen, halogen, C 1-4 alkyl, -NR 9a R 9b or C alkyl substituted by one, two or three halogen atoms; 1-4

[0411] R 9a and R 9b each independently represents hydrogen or C 1-4 alkyl;

[0412] and its pharmaceutically acceptable addition salts and solvates. ​

[0413] In one embodiment, the present invention relates to compounds having formula (I), wherein

[0414] R 1 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0415] R 2 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0416] Y represents -CH2- or -CF2-;

[0417] Z represents -CH2-, -CHR 5i -、-X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h -、-CR 5a R 5b -X-, -C≡C-, -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -or-CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[0418] R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , R 5h and R 5i Each independently represents hydrogen or C 1-4 alkyl;

[0419] X represents -O-, -S- or -NR 11 -;

[0420] R 11 Represents hydrogen, C 1-4 Alkyl or C substituted by a substituent selected from the group consisting of 1-4 Alkyl: -OH, -OC1-4 alkyl, -NH2, -NH-C 1-4 alkyl and -N(C 1-4 alkyl)2;

[0421] Ar represents a bicyclic system; wherein the bicyclic system is

[0422] (i) a 9-membered bicyclic aromatic ring system composed of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, and the 9-membered bicyclic aromatic ring is attached to the remainder of the molecule through a ring carbon atom of the 5- or 6-membered ring or a ring nitrogen atom of the 5-membered ring; or

[0423] (ii) a 10-membered bicyclic aromatic ring system composed of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by nitrogen atoms; provided that when a nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in the bicyclic aromatic ring system;

[0424] Provided that when Ar represents a 10-membered bicyclic aromatic ring system, Z only represents -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -; or

[0425] (iii) a fused bicyclic partial aromatic ring system, which is attached to the linking group Z through an aromatic ring, and the fused bicyclic partial aromatic ring system is selected from (b-1), (b-2) and (b-3)

[0426]

[0427] wherein ring A is a monocyclic aromatic ring selected from the group consisting of pyridyl, pyrimidinyl, pyrazolyl and imidazolyl;

[0428] wherein ring B is C 5-6 cycloalkyl or a 5- to 6-membered saturated heterocyclic group containing one or two heteroatoms each independently selected from O, S and N;

[0429] Ar is optionally substituted on a carbon atom by a total of one, two, three or four substituents each independently selected from the group consisting of halogen, oxo, -OH, -NH2, -NH-C 1-4 alkyl, -NHR 10, cyano, -CF3, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, C 2-6 Alkenyl, C 1-4 Alkyl and a C 1-4 Alkoxy substituted C 1-4 Alkyl; and

[0430] Ar is optionally substituted on one N-atom, where possible, with a substituent selected from the group consisting of: C 1-4 Alkyl; C 3-6 Cycloalkyl; C substituted by one, two or three halogen atoms 1-4 Alkyl; and C substituted by one, two or three halogen atoms 3-6 Cycloalkyl;

[0431] R 10 Represents -(C=O)-C 1-4 Alkyl; C 3-6 Cycloalkyl; R 14 ; C substituted by one, two or three substituents each independently selected from the group consisting of 3-6 Cycloalkyl: halogen, -OH and -OC 1-4 Alkyl; C substituted by one, two or three substituents each independently selected from the group consisting of 1-4 Alkyl: halogen, -OH and -OC 1-4 Alkyl; or C substituted by a substituent selected from the group consisting of 1-4 Alkyl: C 3-6 Cycloalkyl and R 14 ;

[0432] R 14 represents phenyl optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen;

[0433] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of: (a-1), (a-2) and (a-3):

[0434] R 3a , R 3d and R 3e Each independently represents hydrogen, halogen, -NR 7a R 7b , C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, -OH or -OC 1-4 alkyl;

[0435] R7a represents hydrogen;

[0436] R 7b represents hydrogen, C 3-6 cycloalkyl or C 1-4 alkyl;

[0437] R 4a 、R 4d 、R 4e 、R 4f and R 4g each independently represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0438] R 8a and R 8b each independently represents hydrogen or C 1-4 alkyl;

[0439] Q 1 represents N or CR 6a ;

[0440] Q 2 represents N or CR 6b ;

[0441] Q 8 represents N or CR 6g ;

[0442] Q 9 represents N or CR 6h ;

[0443] Q 10 represents N or CR 6i ;

[0444] Q 11 represents N or CR 6j ;

[0445] Q 5 represents CR 3d ; Q 6 represents N; and Q 7 represents CR 4f ; or

[0446] Q 5 represents CR 3d ; Q 6 represents CR 4e ; and Q 7 represents N; or

[0447] Q 5 represents N; Q 6 represents CR 4e ; and Q7 represents CR 4f ; or

[0448] Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents N; or

[0449] Q 5 represents N; Q 6 represents N; and Q 7 represents CR 4f ; or

[0450] Q 5 represents N; Q 6 represents N; and Q 7 represents N;

[0451] R 6a 、R 6b 、R 6g 、R 6h 、R 6i and R 6j each independently represents hydrogen, halogen, C 1-4 alkyl, -NR 9a R 9b or C alkyl substituted by one, two or three halogen atoms; 1-4

[0452] R 9a and R 9b each independently represents hydrogen or C 1-4 alkyl;

[0453] and their pharmaceutically acceptable addition salts and solvates.

[0454] In one embodiment, the present invention relates to a compound having formula (I), wherein

[0455] R 1 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0456] R 2 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0457] Y represents -CH2- or -CF2-;

[0458] Z represents -CH2-, -CHR 5i -, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR​5e R 5g -CR 5f R 5h -、-CR 5a R 5b -X-, -C≡C-, -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -or-CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[0459] R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , R 5h and R 5i Each independently represents hydrogen or C 1-4 alkyl;

[0460] X represents -O-, -S- or -NR 11 -;

[0461] R 11 Represents hydrogen, C 1-4 Alkyl or C substituted by a substituent selected from the group consisting of 1-4 Alkyl: -OH, -OC 1-4 Alkyl, -NH2, -NH-C 1-4 Alkyl and -N(C 1-4 Alkyl)2;

[0462] Ar represents a fused bicyclic partial aromatic ring system which is attached to the linking group Z with an aromatic ring, wherein the fused bicyclic partial aromatic ring system is selected from (b-1), (b-2) and (b-3)

[0463]

[0464] wherein Ring A is a monocyclic aromatic ring selected from the group consisting of pyridyl, pyrimidinyl, pyrazolyl and imidazolyl;

[0465] Where ring B is C 5-6 Cycloalkyl or a 5- to 6-membered saturated heterocyclic group containing one or two heteroatoms independently selected from O, S and N;

[0466] Ar is optionally substituted on a carbon atom with a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, oxo, -OH, -NH2, -NH-C 1-4 alkyl, -NHR 10 、cyano, -CF3, C 1-4 alkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl and C substituted with one C 1-4 alkoxy-substituted C 1-4 alkyl; and

[0467] where possible, Ar is optionally substituted on an N-atom with a substituent selected from the group consisting of: C 1-4 alkyl; C 3-6 cycloalkyl; C substituted with one, two or three halogen atoms 1-4 alkyl; and C substituted with one, two or three halogen atoms 3-6 cycloalkyl;

[0468] R 10 represents -(C=O)-C 1-4 alkyl; C 3-6 cycloalkyl; R 14 ; C substituted with one, two or three substituents each independently selected from the group consisting of: halogen, -OH and -O-C 3-6 alkyl; C substituted with one, two or three substituents each independently selected from the group consisting of: halogen, -OH and -O-C 1-4 alkyl; or C substituted with a substituent selected from the group consisting of: C 1-4 cycloalkyl and R 1-4 alkyl; or C substituted with a substituent selected from the group consisting of: C 1-4 cycloalkyl and R 3-6 ; 14 ;

[0469] R 14 represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of: halogen;

[0470] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of: (a-1), (a-2) and (a-3):

[0471] R 3a 、R 3d and R 3e each independently represent hydrogen, halogen, -NR 7a R 7b, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, -OH or -O-C 1-4 alkyl;

[0472] R 7a represents hydrogen;

[0473] R 7b represents hydrogen, C 3-6 cycloalkyl or C 1-4 alkyl;

[0474] R 4a , R 4d , R 4e , R 4f and R 4g each independently represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0475] R 8a and R 8b each independently represents hydrogen or C 1-4 alkyl;

[0476] Q 1 represents N or CR 6a ;

[0477] Q 2 represents N or CR 6b ;

[0478] Q 8 represents N or CR 6g ;

[0479] Q 9 represents N or CR 6h ;

[0480] Q 10 represents N or CR 6i ;

[0481] Q 11 represents N or CR 6j ;

[0482] Q 5 represents CR 3d ; Q 6 represents N; and Q 7 represents CR 4f ; or

[0483] Q 5 represents CR 3d ; Q 6 represents CR 4e; and Q 7 represents N; or

[0484] Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents CR 4f ; or

[0485] Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents N; or

[0486] Q 5 represents N; Q 6 represents N; and Q 7 represents CR 4f ; or

[0487] Q 5 represents N; Q 6 represents N; and Q 7 represents N;

[0488] R 6a 、R 6b 、R 6g 、R 6h 、R 6i and R 6j each independently represents hydrogen, halogen, C 1-4 alkyl, -NR 9a R 9b or C 1-4 alkyl substituted with one, two or three halogen atoms;

[0489] R 9a and R 9b each independently represents hydrogen or C 1-4 alkyl;

[0490] and its pharmaceutically acceptable addition salts and solvates.

[0491] In one embodiment, the present invention relates to a compound having formula (I), wherein

[0492] R 1 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0493] R 2 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0494] Y represents -CH2- or -CF2-;

[0495] Z represents -CH2-, -CHR 5i -、-X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h -、-CR 5a R 5b -X-, -C≡C-, -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -or-CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[0496] R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , R 5h and R 5i Each independently represents hydrogen or C 1-4 alkyl;

[0497] X represents -O-, -S- or -NR 11 -;

[0498] R 11 Represents hydrogen, C 1-4 Alkyl or C substituted by a substituent selected from the group consisting of 1-4 Alkyl: -OH, -OC 1-4 Alkyl, -NH2, -NH-C 1-4 Alkyl and -N(C 1-4 Alkyl)2;

[0499] Ar represents a 9-membered bicyclic aromatic ring system consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, said 9-membered bicyclic aromatic ring being attached to the remainder of the molecule via a ring carbon atom of the 5- or 6-membered ring or a ring nitrogen atom of the 5-membered ring;

[0500] Ar is optionally substituted at a carbon atom with a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, oxo, -OH, -NH2, -NH-C 1-4 alkyl, -NHR 10 , cyano, -CF3, C 1-4 alkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl and C substituted with one C 1-4 alkoxy-substituted C 1-4 alkyl; and

[0501] where possible, Ar is optionally substituted at an N-atom with a substituent selected from the group consisting of: C 1-4 alkyl; C 3-6 cycloalkyl; C alkyl substituted with one, two or three halogen atoms; and C 1-4 cycloalkyl substituted with one, two or three halogen atoms; 3-6

[0502] R 10 represents -(C=O)-C 1-4 alkyl; C 3-6 cycloalkyl; R 14 ; C cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of: halogen, -OH and -O-C 3-6 alkyl; C alkyl substituted with one, two or three substituents each independently selected from the group consisting of: halogen, -OH and -O-C 1-4 alkyl; or C alkyl substituted with a substituent selected from the group consisting of: C 1-4 cycloalkyl and R 1-4 ; 1-4 alkyl: C 3-6 cycloalkyl and R 14 ;

[0503] R 14 represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of: halogen;

[0504] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of: (a-1), (a-2) and (a-3):

[0505] R 3a , R 3d and R 3e each independently represent hydrogen, halogen, -NR 7a R 7b alkyl, C 1-4 ​Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, -OH or -O-C 1-4 alkyl;

[0506] R 7a represents hydrogen;

[0507] R 7b represents hydrogen, C 3-6 cycloalkyl or C 1-4 alkyl;

[0508] R 4a , R 4d , R 4e , R 4f and R 4g each independently represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0509] R 8a and R 8b each independently represents hydrogen or C 1-4 alkyl;

[0510] Q 1 represents N or CR 6a ;

[0511] Q 2 represents N or CR 6b ;

[0512] Q 8 represents N or CR 6g ;

[0513] Q 9 represents N or CR 6h ;

[0514] Q 10 represents N or CR 6i ;

[0515] Q 11 represents N or CR 6j ;

[0516] Q 5 represents CR 3d ; Q 6 represents N; and Q 7 represents CR 4f ; or

[0517] Q 5 represents CR 3d ; Q 6 represents CR 4e ; and Q 7represents N; or

[0518] Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents CR 4f ; or

[0519] Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents N; or

[0520] Q 5 represents N; Q 6 represents N; and Q 7 represents CR 4f ; or

[0521] Q 5 represents N; Q 6 represents N; and Q 7 represents N;

[0522] R 6a 、R 6b 、R 6g 、R 6h 、R 6i and R 6j each independently represents hydrogen, halogen, C 1-4 alkyl, -NR 9a R 9b or C alkyl substituted by one, two or three halogen atoms; 1-4

[0523] R 9a and R 9b each independently represents hydrogen or C 1-4 alkyl;

[0524] and its pharmaceutically acceptable addition salts and solvates.

[0525] In one embodiment, the present invention relates to a compound of formula (I), wherein

[0526] R 1 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0527] R 2 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0528] Y represents -CH2- or -CF2-;

[0529] Z represents -CR 5c R​5d -CR 5e R 5g -CR 5f R 5h -or-CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[0530] R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g and R 5h Each independently represents hydrogen or C 1-4 Alkyl;

[0531] X represents -O-, -S- or -NR 11 -;

[0532] R 11 Represents hydrogen, C 1-4 Alkyl or C substituted by a substituent selected from the group consisting of 1-4 Alkyl: -OH, -OC 1-4 Alkyl, -NH2, -NH-C 1-4 Alkyl and -N(C 1-4 Alkyl)2;

[0533] 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 nitrogen atoms; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in the bicyclic aromatic ring system;

[0534] Ar is optionally substituted on the carbon atom with a total of one, two, three or four substituents each independently selected from the group consisting of halogen, oxo, -OH, -NH2, -NH-C 1-4 Alkyl, -NHR 10 , cyano, -CF3, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, C 2-6 Alkenyl, C 1-4 Alkyl and a C 1-4 Alkoxy substituted C 1-4 Alkyl; and

[0535] Where possible, Ar is optionally substituted on an N-atom with a substituent selected from the group consisting of: C 1-4 alkyl; C 3-6 cycloalkyl; C alkyl substituted with one, two or three halogen atoms 1-4 ; and C cycloalkyl substituted with one, two or three halogen atoms 3-6 ;

[0536] R 10 represents -(C=O)-C 1-4 alkyl; C 3-6 cycloalkyl; R 14 ; C cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of: halogen, -OH and -O-C 3-6 alkyl; C alkyl substituted with one, two or three substituents each independently selected from the group consisting of: halogen, -OH and -O-C 1-4 alkyl; or C alkyl substituted with a substituent selected from the group consisting of: C 1-4 cycloalkyl and R 1-4 ; 1-4 alkyl: C 3-6 cycloalkyl and R 14 ;

[0537] R 14 represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of: halogen;

[0538] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of: (a-1), (a-2) and (a-3):

[0539] R 3a 、R 3d and R 3e each independently represent hydrogen, halogen, -NR 7a R 7b 、C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, -OH or -O-C 1-4 alkyl;

[0540] R 7a represents hydrogen;

[0541] R 7b represents hydrogen, C 3-6 cycloalkyl or C 1-4 alkyl;

[0542] R 4a 、R 4d 、R 4e 、R4f and R 4g each independently represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0543] R 8a and R 8b each independently represents hydrogen or C 1-4 alkyl;

[0544] Q 1 represents N or CR 6a ;

[0545] Q 2 represents N or CR 6b ;

[0546] Q 8 represents N or CR 6g ;

[0547] Q 9 represents N or CR 6h ;

[0548] Q 10 represents N or CR 6i ;

[0549] Q 11 represents N or CR 6j ;

[0550] Q 5 represents CR 3d ; Q 6 represents N; and Q 7 represents CR 4f ; or

[0551] Q 5 represents CR 3d ; Q 6 represents CR 4e ; and Q 7 represents N; or

[0552] Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents CR 4f ; or

[0553] Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents N; or

[0554] Q 5Indicates N; Q 6 represents N; and Q 7 Represents CR 4f ;or

[0555] Q 5 Indicates N; Q 6 represents N; and Q 7 Indicates N;

[0556] R 6a , R 6b , R 6g , R 6h , R 6i and R 6j Each independently represents hydrogen, halogen, C 1-4 Alkyl, -NR 9a R 9b or C substituted by one, two or three halogen atoms 1-4 alkyl;

[0557] R 9a and R 9b Each independently represents hydrogen or C 1-4 alkyl;

[0558] and pharmaceutically acceptable addition salts and solvates thereof.

[0559] In one embodiment, the present invention relates to compounds having formula (I), wherein

[0560] R 1 represents hydrogen;

[0561] R 2 represents hydrogen;

[0562] Y represents -CH2-;

[0563] Z represents -CH2-, -CHR 5i -、-X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h -、-CR 5a R 5b -X-, -C≡C-, -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -or-CR 5a R 5b -CR5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[0564] R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R 5g 、R 5h and R 5i each independently represents hydrogen or C 1-4 alkyl;

[0565] X represents -O-, -S- or -NR 11 -;

[0566] R 11 represents hydrogen, C 1-4 alkyl or C 1-4 alkyl substituted with a substituent selected from the group consisting of: -OH, -O-C 1-4 alkyl, -NH2, -NH-C 1-4 alkyl and -N(C 1-4 alkyl)2;

[0567] Ar represents a monocyclic aromatic ring or a bicyclic system;

[0568] wherein the monocyclic aromatic ring is selected from the group consisting of: pyridyl, pyrimidinyl, pyrazolyl and imidazolyl;

[0569] wherein the bicyclic system is

[0570] (i) a 9-membered bicyclic aromatic ring system composed of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, the 9-membered bicyclic aromatic ring being attached to the remainder of the molecule through a ring carbon atom of the 5- or 6-membered ring or a ring nitrogen atom of the 5-membered ring; or

[0571] (ii) a 10-membered bicyclic aromatic ring system composed of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by nitrogen atoms; provided that when a nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in the bicyclic aromatic ring system;

[0572] provided that when Ar represents a 10-membered bicyclic aromatic ring system, Z only represents -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h-or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -; or

[0573] (iii) a fused bicyclic partially aromatic ring system, which is attached to the linking group Z by an aromatic ring, wherein the fused bicyclic partially aromatic ring system is selected from (b-1), (b-2) and (b-3)

[0574]

[0575] wherein ring A is a monocyclic aromatic ring selected from the group consisting of: pyridyl, pyrimidinyl, pyrazolyl and imidazolyl;

[0576] wherein ring B is C 5-6 cycloalkyl or a 5- to 6-membered saturated heterocyclic group containing one or two heteroatoms each independently selected from O, S and N;

[0577] Ar is optionally substituted at a carbon atom with a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, oxo, -OH, -NH2, -NH-C 1-4 alkyl, -NHR 10 , cyano, -CF3, C 1-4 alkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl and C substituted with one C 1-4 alkoxy-substituted C 1-4 alkyl; and

[0578] where possible, Ar is optionally substituted at an N-atom with a substituent selected from the group consisting of: C 1-4 alkyl; C 3-6 cycloalkyl; C substituted with one, two or three halogen atoms 1-4 alkyl; and C substituted with one, two or three halogen atoms 3-6 cycloalkyl;

[0579] R 10 represents -(C=O)-C 1-4 alkyl; C 3-6 cycloalkyl; R 13 ; R 14 ; C substituted with one, two or three substituents each independently selected from the group consisting of 3-6Cycloalkyl: halogen, -OH and -O-C 1-4 Alkyl; C substituted with one, two or three substituents each independently selected from the group consisting of 1-4 Alkyl: halogen, -OH and -O-C 1-4 Alkyl; or C substituted with a substituent selected from the group consisting of 1-4 Alkyl: C 3-6 Cycloalkyl, R 13 and R 14 ;

[0580] R 13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=O) p and N; the 4- to 7-membered monocyclic aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C 1-4 Alkyl;

[0581] p represents 1 or 2;

[0582] R 14 represents a phenyl group optionally substituted with one, two or three substituents each independently selected from the group consisting of: halogen;

[0583] Het represents a bicyclic aromatic heterocyclic system (a-1);

[0584] R 3a represents -NR 7a R 7b ;

[0585] R 7a represents hydrogen; R 7b represents hydrogen;

[0586] R 4a represents hydrogen;

[0587] Q 1 represents CR 6a ; Q 2 represents CR 6b ;

[0588] R 6a and R 6b represent hydrogen;

[0589] and their pharmaceutically acceptable addition salts and solvates.

[0590] In one embodiment, the present invention relates to a compound having formula (I), wherein

[0591] R 1 represents hydrogen or -C(=O)-C 1-4 Alkyl;

[0592] R 2 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0593] Y represents -CH2- or -CF2-;

[0594] Z represents -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, -CR 5a R 5b -X- or -C≡C-;

[0595] R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R 5g and R 5h each independently represents hydrogen or C 1-4 alkyl;

[0596] X represents -O-, -S- or -NR 11 -;

[0597] R 11 represents hydrogen, C 1-4 alkyl or C alkyl substituted by a substituent selected from the group consisting of: -OH, -O-C 1-4 alkyl, -NH2, -NH-C 1-4 alkyl and -N(C 1-4 alkyl)2; 1-4 alkyl)2;

[0598] Ar represents a monocyclic aromatic ring selected from pyridyl and imidazolyl;

[0599] Ar is optionally substituted at a carbon atom by a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 alkyl, -NHR 10 、cyano, -CF3, C 1-4 alkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl and C alkyl substituted by a C 1-4 alkoxy 1-4Alkyl;

[0600] R 10 represents -(C=O)-C 1-4 Alkyl; C 3-6 Cycloalkyl; R 13 ; R 14 ; C substituted by one, two or three substituents each independently selected from the group consisting of 3-6 Cycloalkyl: halogen, -OH and -O-C 1-4 Alkyl; C substituted by one, two or three substituents each independently selected from the group consisting of 1-4 Alkyl: halogen, -OH and -O-C 1-4 Alkyl; or C substituted by a substituent selected from the group consisting of 1-4 Alkyl: C 3-6 Cycloalkyl, R 13 and R 14 ;

[0601] R 13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=O) p and N; the 4- to 7-membered monocyclic aromatic ring is optionally substituted by one or two substituents selected from the group consisting of C 1-4 Alkyl;

[0602] p represents 1 or 2;

[0603] R 14 represents a phenyl optionally substituted by one, two or three substituents each independently selected from the group consisting of: halogen;

[0604] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of: (a-1), (a-2) and (a-3):

[0605] R 3a 、R 3d and R 3e each independently represents hydrogen, halogen, -NR 7a R 7b 、C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, -OH or -O-C 1-4 Alkyl;

[0606] R 7a represents hydrogen;

[0607] R 7b represents hydrogen, C 3-6 Cycloalkyl or C 1-4 Alkyl;

[0608] R 4a 、R 4d 、R 4e 、R 4f and R 4g each independently represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0609] R 8a and R 8b each independently represents hydrogen or C 1-4 alkyl;

[0610] Q 1 represents N or CR 6a ;

[0611] Q 2 represents N or CR 6b ;

[0612] Q 8 represents N or CR 6g ;

[0613] Q 9 represents N or CR 6h ;

[0614] Q 10 represents N or CR 6i ;

[0615] Q 11 represents N or CR 6j ;

[0616] Q 5 represents CR 3d ; Q 6 represents N; and Q 7 represents CR 4f ; or

[0617] Q 5 represents CR 3d ; Q 6 represents CR 4e ; and Q 7 represents N; or

[0618] Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents CR 4f ; or

[0619] Q 5 represents N; Q 6 represents CR4e ; and Q 7 represents N; or

[0620] Q 5 represents N; Q 6 represents N; and Q 7 represents CR 4f ; or

[0621] Q 5 represents N; Q 6 represents N; and Q 7 represents N;

[0622] R 6a 、R 6b 、R 6g 、R 6h 、R 6i and R 6j each independently represents hydrogen, halogen, C 1-4 alkyl, -NR 9a R 9b or C 1-4 alkyl substituted by one, two or three halogen atoms;

[0623] R 9a and R 9b each independently represents hydrogen or C 1-4 alkyl;

[0624] and its pharmaceutically acceptable addition salts and solvates.

[0625] In one embodiment, the present invention relates to a compound having formula (I), wherein

[0626] R 1 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0627] R 2 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0628] Y represents -CH2- or -CF2-;

[0629] Z represents -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, -CR 5a R 5b -X- or -C≡C-;

[0630] R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g and R 5h Each independently represents hydrogen or C 1-4 alkyl;

[0631] X represents -O-, -S- or -NR 11 -;

[0632] R 11 Represents hydrogen, C 1-4 Alkyl or C substituted by a substituent selected from the group consisting of 1-4 Alkyl: -OH, -OC 1-4 Alkyl, -NH2, -NH-C 1-4 Alkyl and -N(C 1-4 Alkyl)2;

[0633] Ar represents a 9-membered bicyclic aromatic ring system consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, said 9-membered bicyclic aromatic ring being attached to the remainder of the molecule via a ring carbon atom of the 5- or 6-membered ring or a ring nitrogen atom of the 5-membered ring;

[0634] Ar is optionally substituted on the carbon atom with a total of one, two, three or four substituents each independently selected from the group consisting of halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -NHR 10 , cyano, -CF3, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, C 2-6 Alkenyl, C 1-4 Alkyl and a C 1-4 Alkoxy substituted C 1-4 Alkyl; and

[0635] Ar is optionally substituted on one N-atom, where possible, with a substituent selected from the group consisting of: C 1-4 Alkyl; C 3-6 Cycloalkyl; C substituted by one, two or three halogen atoms 1-4 Alkyl; and C substituted by one, two or three halogen atoms 3-6 Cycloalkyl;

[0636] R 10 Represents -(C=O)-C 1-4 Alkyl; C3-6 Cycloalkyl; R 13 ; R 14 ; C substituted by one, two or three substituents each independently selected from the group consisting of 3-6 cycloalkyl: halogen, -OH and -O-C 1-4 alkyl; C substituted by one, two or three substituents each independently selected from the group consisting of 1-4 alkyl: halogen, -OH and -O-C 1-4 alkyl; or C substituted by a substituent selected from the group consisting of 1-4 alkyl: C 3-6 cycloalkyl, R 13 and R 14 ;

[0637] R 13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=O) p and N; the 4- to 7-membered monocyclic aromatic ring is optionally substituted by one or two substituents selected from the group consisting of C 1-4 alkyl;

[0638] p represents 1 or 2;

[0639] R 14 represents a phenyl optionally substituted by one, two or three substituents each independently selected from the group consisting of: halogen;

[0640] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of: (a-1), (a-2) and (a-3):

[0641] R 3a , R 3d and R 3e each independently represents hydrogen, halogen, -NR 7a R 7b , C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, -OH or -O-C 1-4 alkyl;

[0642] R 7a represents hydrogen;

[0643] R 7b represents hydrogen, C 3-6 cycloalkyl or C 1-4 alkyl;

[0644] R 4a , R 4d , R 4e , R4f and R 4g each independently represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0645] R 8a and R 8b each independently represents hydrogen or C 1-4 alkyl;

[0646] Q 1 represents N or CR 6a ;

[0647] Q 2 represents N or CR 6b ;

[0648] Q 8 represents N or CR 6g ;

[0649] Q 9 represents N or CR 6h ;

[0650] Q 10 represents N or CR 6i ;

[0651] Q 11 represents N or CR 6j ;

[0652] Q 5 represents CR 3d ; Q 6 represents N; and Q 7 represents CR 4f ; or

[0653] Q 5 represents CR 3d ; Q 6 represents CR 4e ; and Q 7 represents N; or

[0654] Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents CR 4f ; or

[0655] Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents N; or

[0656] Q 5Represents N; Q 6 Represents N; and Q 7 Represents CR 4f ; or

[0657] Q 5 Represents N; Q 6 Represents N; and Q 7 Represents N;

[0658] R 6a 、R 6b 、R 6g 、R 6h 、R 6i and R 6j Each independently represents hydrogen, halogen, C 1-4 alkyl, -NR 9a R 9b or C alkyl substituted by one, two or three halogen atoms; 1-4

[0659] R 9a and R 9b Each independently represents hydrogen or C 1-4 alkyl;

[0660] and its pharmaceutically acceptable addition salts and solvates.

[0661] In one embodiment, the present invention relates to a compound having formula (I), wherein

[0662] R 1 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0663] R 2 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0664] Y represents -CH2- or -CF2-;

[0665] Z represents -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, -CR 5a R 5b -X- or -C≡C-;

[0666] R 5a 、R 5b 、R 5c 、R 5d 、R​5e , R 5f , R 5g and R 5h each independently represents hydrogen or C 1-4 alkyl;

[0667] X represents -O-, -S- or -NR 11 -;

[0668] R 11 represents hydrogen, C 1-4 alkyl or C alkyl substituted with a substituent selected from the group consisting of: -OH, -O-C 1-4 alkyl, -NH2, -NH-C 1-4 alkyl and -N(C 1-4 alkyl)2; 1-4 1-4

[0669] Ar represents a monocyclic aromatic ring selected from pyridyl and imidazolyl; or

[0670] a 9-membered bicyclic aromatic ring system consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, said 9-membered bicyclic aromatic ring being attached to the rest of the molecule through a ring carbon atom of the 5- or 6-membered ring or a ring nitrogen atom of the 5-membered ring;

[0671] Ar is optionally substituted on a carbon atom with a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 alkyl, -NHR 10 , cyano, -CF3, C 1-4 alkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl and C alkyl substituted with a C 1-4 alkoxy; and 1-4 1-4

[0672] where possible, Ar is optionally substituted on an N-atom with a substituent selected from the group consisting of: C 1-4 alkyl; C 3-6 cycloalkyl; C alkyl substituted with one, two or three halogen atoms; and C 1-4 cycloalkyl substituted with one, two or three halogen atoms; 3-6 3-6

[0673] R 10 represents -(C=O)-C 1-4 alkyl; C 3-6Cycloalkyl; C substituted by one, two or three substituents each independently selected from the group consisting of 3-6 Cycloalkyl: halogen, -OH and -O-C 1-4 Alkyl; C substituted by one, two or three substituents each independently selected from the group consisting of 1-4 Alkyl: halogen, -OH and -O-C 1-4 Alkyl; or C substituted by a 3-6 Cycloalkyl-substituted C 1-4 Alkyl;

[0674] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of: (a-1), (a-2) and (a-3):

[0675]

[0676] R 3a 、R 3d and R 3e each independently represents hydrogen, halogen, -NR 7a R 7b 、C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, -OH or -O-C 1-4 Alkyl;

[0677] R 7a represents hydrogen;

[0678] R 7b represents hydrogen, C 3-6 Cycloalkyl or C 1-4 Alkyl;

[0679] R 4a 、R 4d 、R 4e 、R 4f and R 4g each independently represents hydrogen, halogen, -NR 8a R 8b or C 1-4 Alkyl;

[0680] R 8a and R 8b each independently represents hydrogen or C 1-4 Alkyl;

[0681] Q 1 represents CR 6a ;

[0682] Q 2 represents CR 6b ;

[0683] Q8 represents CR 6g ;

[0684] Q 9 represents CR 6h ;

[0685] Q 10 represents CR 6i ;

[0686] Q 11 represents CR 6j ;

[0687] Q 5 represents CR 3d ; Q 6 represents N; and Q 7 represents CR 4f ; or

[0688] Q 5 represents CR 3d ; Q 6 represents CR 4e ; and Q 7 represents N; or

[0689] Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents CR 4f ; or

[0690] Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents N; or

[0691] Q 5 represents N; Q 6 represents N; and Q 7 represents CR 4f ; or

[0692] Q 5 represents N; Q 6 represents N; and Q 7 represents N;

[0693] R 6a , R 6b , R 6g , R 6h , R 6i and R 6j each independently represents hydrogen, halogen, C 1-4 alkyl, -NR 9a R 9bC alkyl optionally substituted by one, two or three halogen atoms; 1-4 alkyl;

[0694] R 9a and R 9b each independently represent hydrogen or C 1-4 alkyl;

[0695] and pharmaceutically acceptable addition salts and solvates thereof.

[0696] In one embodiment, the present invention relates to a compound having formula (I), wherein

[0697] R 1 represents hydrogen;

[0698] R 2 represents hydrogen;

[0699] Y represents -CH2-;

[0700] Z represents -X-CR 5a R 5b -, -CR 5c =CR 5d - or -CR 5e R 5g -CR 5f R 5h -;

[0701] R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R 5g and R 5h represent hydrogen;

[0702] X represents -O-;

[0703] Ar represents a monocyclic aromatic ring selected from pyridyl and imidazolyl; or

[0704] a 9-membered bicyclic aromatic ring system consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, said 9-membered bicyclic aromatic ring being attached to the remainder of the molecule through a ring carbon atom of the 5- or 6-membered ring;

[0705] Ar is optionally substituted on a carbon atom by a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, -NH2, -NH-C 1-4 alkyl, -CF3, C 3-6 cycloalkyl and C 1-4 alkyl; and

[0706] Where possible, Ar is optionally substituted on an N-atom with a substituent selected from the group consisting of C 1-4 alkyl;

[0707] Het represents (a-1);

[0708] R 3a represents halogen, -NR 7a R 7b or -O-C 1-4 alkyl;

[0709] R 7a represents hydrogen;

[0710] R 7b represents hydrogen or C 1-4 alkyl;

[0711] R 4a represents hydrogen;

[0712] Q 1 represents CR 6a ;

[0713] Q 2 represents CR 6b ;

[0714] R 6a and R 6b represent hydrogen or halogen;

[0715] and their pharmaceutically acceptable addition salts and solvates.

[0716] In one embodiment, the present invention relates to a compound having formula (I), wherein

[0717] R 1 represents hydrogen;

[0718] R 2 represents hydrogen;

[0719] Y represents -CH2-;

[0720] Z represents -X-CR 5a R 5b -, -CR 5c =CR 5d - or -CR 5e R 5g -CR 5f R 5h -;

[0721] R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R5f , R 5g and R 5h represent hydrogen;

[0722] X represents -O-;

[0723] Ar represents a monocyclic aromatic ring selected from pyridyl and imidazolyl; or

[0724] a 9 - membered bicyclic aromatic ring system selected from the group consisting of

[0725]

[0726] Ar is optionally substituted on a carbon atom by a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, -NH2, -NH-C 1-4 alkyl, -CF3, C 3-6 cycloalkyl and C 1-4 alkyl; and

[0727] where possible, Ar is optionally substituted on an N - atom by a substituent selected from the group consisting of C 1-4 alkyl;

[0728] Het represents (a - 1);

[0729] R 3a represents halogen, -NR 7a R 7b or -O - C 1-4 alkyl;

[0730] R 7a represents hydrogen;

[0731] R 7b represents hydrogen or C 1-4 alkyl;

[0732] R 4a represents hydrogen;

[0733] Q 1 represents CR 6a ;

[0734] Q 2 represents CR 6b ;

[0735] R 6a and R 6b represent hydrogen or halogen;

[0736] and their pharmaceutically acceptable addition salts and solvates.

[0737] In one embodiment, the present invention relates to a compound having the formula (I), wherein

[0738] R 1 represents hydrogen;

[0739] R 2 represents hydrogen;

[0740] Y represents -CH2-;

[0741] Z represents -CR 5e R 5g -CR 5f R 5h -;

[0742] R 5e 、R 5f 、R 5g and R 5h represent hydrogen;

[0743] Ar represents

[0744]

[0745] Ar is optionally substituted on a carbon atom with a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, -NH2, -NH-C 1-4 alkyl, -CF3, C 3-6 cycloalkyl and C 1-4 alkyl;

[0746] Het represents (a-1);

[0747] R 3a represents -NR 7a R 7b ;

[0748] R 7a represents hydrogen;

[0749] R 7b represents hydrogen;

[0750] R 4a represents hydrogen;

[0751] Q 1 represents CR 6a ;

[0752] Q 2 represents CR 6b ;

[0753] R 6a and R 6b represent hydrogen;

[0754] and its pharmaceutically acceptable addition salts and solvates.

[0755] In one embodiment, the present invention relates to a compound having the formula (I), wherein

[0756] R 1 represents hydrogen;

[0757] R 2 represents hydrogen;

[0758] Y represents -CH2-;

[0759] Z represents -CR 5e R 5g -CR 5f R 5h -;

[0760] R 5e 、R 5f 、R 5g and R 5h represent hydrogen;

[0761] Ar represents

[0762]

[0763] wherein Ar is substituted by C 1-4 alkyl at the position represented by β;

[0764] wherein Ar is optionally substituted by halogen at the position represented by γ;

[0765] Het represents (a-1);

[0766] R 3a represents -NR 7a R 7b ;

[0767] R 7a represents hydrogen;

[0768] R 7b represents hydrogen;

[0769] R 4a represents hydrogen;

[0770] Q 1 represents CR 6a ;

[0771] Q 2 represents CR 6b ;

[0772] R 6a and R 6b represent hydrogen;

[0773] and its pharmaceutically acceptable addition salts and solvates.

[0774] In one embodiment, the present invention relates to a compound having the formula (I), wherein

[0775] R 1 represents hydrogen; R 2 represents hydrogen;

[0776] Y represents -CH2- or -CF2-;

[0777] Z represents -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, -CR 5a R 5b -X- or -C≡C-;

[0778] R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R 5g and R 5h each independently represents hydrogen or C 1-4 alkyl;

[0779] X represents -O-, -S- or -NR 11 -;

[0780] R 11 represents hydrogen, C 1-4 alkyl or C 1-4 alkyl substituted with a substituent selected from the group consisting of: -OH, -O-C 1-4 alkyl, -NH2, -NH-C 1-4 alkyl and -N(C 1-4 alkyl)2;

[0781] Ar represents a monocyclic aromatic ring selected from pyridyl and imidazolyl; or

[0782] a 9-membered bicyclic aromatic ring system composed of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, and the 9-membered bicyclic aromatic ring is attached to the rest of the molecule through a ring carbon atom of the 5- or 6-membered ring or a ring nitrogen atom of the 5-membered ring;

[0783] Ar is optionally substituted on a carbon atom with a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 alkyl, -NHR10 , cyano, -CF3, C 1-4 alkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl and C substituted by one C 1-4 alkoxy-substituted C 1-4 alkyl; and

[0784] When possible, Ar is optionally substituted on an N-atom by a substituent selected from the group consisting of: C 1-4 alkyl; C 3-6 cycloalkyl; C substituted by one, two or three halogen atoms 1-4 alkyl; and C substituted by one, two or three halogen atoms 3-6 cycloalkyl;

[0785] R 10 represents -(C=O)-C 1-4 alkyl; C 3-6 cycloalkyl; R 13 ; R 14 ; C substituted by one, two or three substituents each independently selected from the group consisting of 3-6 cycloalkyl: halogen, -OH and -O-C 1-4 alkyl; C substituted by one, two or three substituents each independently selected from the group consisting of 1-4 alkyl: halogen, -OH and -O-C 1-4 alkyl; or C substituted by a substituent selected from the group consisting of 1-4 alkyl: C 3-6 cycloalkyl, R 13 and R 14 ;

[0786] R 13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=O) p and N; the 4- to 7-membered monocyclic aromatic ring is optionally substituted by one or two substituents selected from the group consisting of: C 1-4 alkyl;

[0787] p represents 1 or 2;

[0788] R 14 represents phenyl optionally substituted by one, two or three substituents each independently selected from the group consisting of: halogen;

[0789] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of: (a-1), (a-2) and (a-3):

[0790] R 3a , R 3d and R 3e Each independently represents hydrogen, halogen, -NR 7a R 7b , C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, -OH or -OC 1-4 alkyl;

[0791] R 7a represents hydrogen;

[0792] R 7b Represents hydrogen, C 3-6 Cycloalkyl or C 1-4 alkyl;

[0793] R 4a , R 4d , R 4e , R 4f and R 4g Each independently represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0794] R 8a and R 8b Each independently represents hydrogen or C 1-4 alkyl;

[0795] Q 1 Indicates N or CR 6a ;

[0796] Q 2 Indicates N or CR 6b ;

[0797] Q 8 Indicates N or CR 6g ;

[0798] Q 9 Indicates N or CR 6h ;

[0799] Q 10 Indicates N or CR 6i ;

[0800] Q 11 Indicates N or CR 6j ;

[0801] Q 5 Represents CR 3d ;Q 6 represents N; and Q 7Represents CR 4f ;or

[0802] Q 5 Represents CR 3d ;Q 6 Represents CR 4e ; and Q 7 means N; or

[0803] Q 5 Indicates N; Q 6 Represents CR 4e ; and Q 7 Represents CR 4f ;or

[0804] Q 5 Indicates N; Q 6 Represents CR 4e ; and Q 7 means N; or

[0805] Q 5 Indicates N; Q 6 represents N; and Q 7 Represents CR 4f ;or

[0806] Q 5 Indicates N; Q 6 represents N; and Q 7 Indicates N;

[0807] R 6a , R 6b , R 6g , R 6h , R 6i and R 6j Each independently represents hydrogen, halogen, C 1-4 Alkyl, -NR 9a R 9b or C substituted by one, two or three halogen atoms 1-4 alkyl;

[0808] R 9a and R 9b Each independently represents hydrogen or C 1-4 alkyl;

[0809] and pharmaceutically acceptable addition salts and solvates thereof.

[0810] In one embodiment, the present invention relates to compounds having formula (I), wherein

[0811] R 1 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0812] R2 represents hydrogen or -C(=O)-C 1-4 alkyl;

[0813] Y represents -CH2- or -CF2-;

[0814] Z represents -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, -CR 5a R 5b -X- or -C≡C-;

[0815] R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R 5g and R 5h each independently represents hydrogen or C 1-4 alkyl;

[0816] X represents -O-, -S- or -NR 11 -;

[0817] R 11 represents hydrogen, C 1-4 alkyl or C alkyl substituted by a substituent selected from the group consisting of: -OH, -O-C 1-4 alkyl, -NH2, -NH-C 1-4 alkyl, and -N(C 1-4 alkyl)2; 1-4 alkyl);

[0818] Ar represents a monocyclic aromatic ring selected from pyridyl and imidazolyl; or

[0819] a 9-membered bicyclic aromatic ring system consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, said 9-membered bicyclic aromatic ring being attached to the rest of the molecule through a ring carbon atom of the 5- or 6-membered ring or a ring nitrogen atom of the 5-membered ring;

[0820] Ar is optionally substituted on a carbon atom by a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 alkyl, -NHR 10 -, cyano, -CF3, C 1-4 alkoxy, C3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl and C substituted by one C 1-4 alkoxy-substituted C 1-4 alkyl; and

[0821] where possible, Ar is optionally substituted on an N-atom by a substituent selected from the group consisting of: C 1-4 alkyl; C 3-6 cycloalkyl; C substituted by one, two or three halogen atoms 1-4 alkyl; and C substituted by one, two or three halogen atoms 3-6 cycloalkyl;

[0822] R 10 represents -(C=O)-C 1-4 alkyl; C 3-6 cycloalkyl; R 13 ; R 14 ; C substituted by one, two or three substituents each independently selected from the group consisting of 3-6 cycloalkyl: halogen, -OH and -O-C 1-4 alkyl; C substituted by one, two or three substituents each independently selected from the group consisting of 1-4 alkyl: halogen, -OH and -O-C 1-4 alkyl; or C substituted by a substituent selected from the group consisting of 1-4 alkyl: C 3-6 cycloalkyl, R 13 and R 14 ;

[0823] R 13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=O) p and N; the 4- to 7-membered monocyclic aromatic ring is optionally substituted by one or two substituents selected from the group consisting of: C 1-4 alkyl;

[0824] p represents 1 or 2;

[0825] R 14 represents a phenyl optionally substituted by one, two or three substituents each independently selected from the group consisting of: halogen;

[0826] Het represents (a-1);

[0827] R 3a represents hydrogen, halogen, -NR 7a R7b , C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, -OH or -O-C 1-4 alkyl;

[0828] R 7a represents hydrogen;

[0829] R 7b represents hydrogen, C 3-6 cycloalkyl or C 1-4 alkyl;

[0830] R 4a represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0831] R 8a and R 8b each independently represents hydrogen or C 1-4 alkyl;

[0832] Q 1 represents N or CR 6a ;

[0833] Q 2 represents N or CR 6b ;

[0834] R 6a and R 6b each independently represents hydrogen, halogen, C 1-4 alkyl, -NR 9a R 9b or C alkyl substituted by one, two or three halogen atoms; 1-4 alkyl;

[0835] R 9a and R 9b each independently represents hydrogen or C 1-4 alkyl;

[0836] and their pharmaceutically acceptable addition salts and solvates.

[0837] Another embodiment of the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein one or more of the following limitations apply:

[0838] (i) R 1 and R 2 represent hydrogen;

[0839] (ii) Y represents -CH2-;

[0840] (iii) Z represents -X-CR 5a R 5b -、-CR 5c =CR 5d -or-CR 5e R 5g -CR 5f R 5h -;

[0841] (iv) R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g and R 5h represents hydrogen;

[0842] (v) X represents -O-;

[0843] (vi) Ar represents a monocyclic aromatic ring selected from pyridyl and imidazolyl; or a 9-membered bicyclic aromatic ring system consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, said 9-membered bicyclic aromatic ring being attached to the rest of the molecule via a ring carbon atom of the 5- or 6-membered ring;

[0844] Ar is optionally substituted on the carbon atom with a total of one, two, three or four substituents each independently selected from the group consisting of halogen, -NH2, -NH-C 1-4 Alkyl, -CF3, C 3-6 Cycloalkyl and C 1-4 Alkyl; and

[0845] Ar is optionally substituted on one N-atom, where possible, with a substituent selected from the group consisting of: C 1-4 alkyl;

[0846] (vii) Het represents (a-1);

[0847] (viii) R 3a Indicates halogen, -NR 7a R 7b or -OC 1-4 alkyl;

[0848] (ix)R 7a Represents hydrogen; R 7b Represents hydrogen or C 1-4 alkyl;

[0849] (x)R 4a represents hydrogen;

[0850] (xi)Q1 represents CR 6a ; Q 2 represents CR 6b ;

[0851] (xii) R 6a and R 6b represent hydrogen or halogen.

[0852] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof as mentioned in any other embodiment, wherein

[0853] R 1 and R 2 represent hydrogen;

[0854] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof as mentioned in any other embodiment, wherein

[0855] R 1 represents -C(=O)-C 1-4 alkyl; R 2 represents -C(=O)-C 1-4 alkyl.

[0856] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof as mentioned in any other embodiment, wherein Y represents -CH2-.

[0857] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof as mentioned in any other embodiment, wherein Q 1 and Q 2 at most one of which represents N.

[0858] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof as mentioned in any other embodiment, wherein Q 1 represents CR 6a ; and Q 2 represents CR 6b ; specifically wherein Q 1 represents CH; and Q 2 represents CH.

[0859] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof as mentioned in any other embodiment, wherein Het represents (a-1).

[0860] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Het represents (a-1); Q 1 represents CR 6a ; and Q 2 represents CR 6b ; specifically wherein Q 1 represents CH; and Q 2 represents CH.

[0861] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[0862] Q 5 represents CR 3d ; Q 6 represents N; and Q 7 represents CR 4f ; or

[0863] Q 5 represents CR 3d ; Q 6 represents CR 4e ; and Q 7 represents N; or

[0864] Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents CR 4f ; or

[0865] Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents N.

[0866] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of: (a-1) and (a-2).

[0867] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Het represents a bicyclic aromatic heterocyclic system of formula (a-1).

[0868] In one embodiment, the present invention relates to those compounds of formula (I), their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any other embodiment, wherein

[0869] Het represents a bicyclic aromatic heterocyclic system of formula (a-1);

[0870] R 1 and R 2 represent hydrogen; and

[0871] R 10 represents -(C=O)-C 1-4 alkyl; C 3-6 cycloalkyl; C 3-6 cycloalkyl substituted by one, two or three substituents each independently selected from the group consisting of: halogen, -OH and -O-C 1-4 alkyl; C 1-4 alkyl substituted by one, two or three substituents each independently selected from the group consisting of: halogen, -OH and -O-C 1-4 alkyl; or C 3-6 alkyl substituted by one C 1-4 cycloalkyl.

[0872] In one embodiment, the present invention relates to those compounds of formula (I), their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any other embodiment, wherein

[0873] R 10 represents -(C=O)-C 1-4 alkyl; C 3-6 cycloalkyl; C 3-6 cycloalkyl substituted by one, two or three substituents each independently selected from the group consisting of: halogen, -OH and -O-C 1-4 alkyl; C 1-4 alkyl substituted by one, two or three substituents each independently selected from the group consisting of: halogen, -OH and -O-C 1-4 alkyl; or C 3-6 alkyl substituted by one C 1-4 cycloalkyl.

[0874] In one embodiment, the present invention relates to those compounds of formula (I), their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any other embodiment, wherein

[0875] R 3a 、R 3d 、R 3e represent hydrogen, halogen, -NR 7a R7b or -O-C 1-4 alkyl; specifically, R 3a , R 3d , R 3e represents halogen, -NR 7a R 7b or -O-C 1-4 alkyl;

[0876] R 4a , R 4d , R 4e , R 4f and R 4g represents hydrogen.

[0877] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Ar represents a monocyclic aromatic ring as defined in any other embodiment, or Ar represents a bicyclic system according to definition (i) or (ii).

[0878] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Ar represents a monocyclic aromatic ring selected from pyridyl and imidazolyl; or a 9-membered bicyclic aromatic ring system selected from the group consisting of

[0879]

[0880] the 9-membered bicyclic aromatic ring is attached to the remainder of the molecule through a ring carbon atom of a 5- or 6-membered ring or a ring nitrogen atom of a 5-membered ring;

[0881] wherein Ar is optionally substituted according to any embodiment.

[0882] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[0883] Ar represents a monocyclic aromatic ring selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 1H-imidazol-4-yl and 1H-imidazol-5-yl; or a 9-membered bicyclic aromatic ring system selected from the group consisting of

[0884]

[0885] wherein Ar is optionally substituted according to any embodiment.

[0886] In one embodiment, the present invention relates to those compounds of formula (I), their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any other embodiment, wherein

[0887] Ar represents a monocyclic aromatic ring selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 1H-imidazol-4-yl and 1H-imidazol-5-yl; or a 9-membered bicyclic aromatic ring system selected from the group consisting of

[0888]

[0889] wherein Ar is substituted at the position indicated by α (if any) with -NH2, -NH-C 1-4 alkyl or -NHR 10 ; and wherein Ar is optionally substituted with substituents selected from the series of substituents on Ar in any other embodiment.

[0890] In one embodiment, the present invention relates to those compounds of formula (I), their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any other embodiment, wherein Ar represents a monocyclic aromatic ring selected from pyridyl and imidazolyl; specifically 2-pyridyl, 3-pyridyl, 4-pyridyl, 1H-imidazol-4-yl or 1H-imidazol-5-yl;

[0891] wherein Ar is optionally substituted according to any embodiment.

[0892] In one embodiment, the present invention relates to those compounds of formula (I), their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any other embodiment, wherein Ar represents a monocyclic aromatic ring selected from the group consisting of pyridyl, pyrimidinyl, pyrazolyl and imidazolyl;

[0893] wherein Ar is optionally substituted according to any embodiment.

[0894] In one embodiment, the present invention relates to those compounds of formula (I), their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any other embodiment, wherein

[0895] Ar represents a bicyclic system;

[0896] wherein Ar is optionally substituted according to any embodiment.

[0897] In one embodiment, the present invention relates to those compounds of formula (I), their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any other embodiment, wherein Ar represents

[0898] A 9-membered bicyclic aromatic ring system, consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, said 9-membered bicyclic aromatic ring being attached to the remainder of the molecule through a ring carbon atom of the 5- or 6-membered ring or a ring nitrogen atom of the 5-membered ring;

[0899] wherein Ar is optionally substituted according to any embodiment.

[0900] In one embodiment, the invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Ar represents

[0901] 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 nitrogen atoms; 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;

[0902] provided that in the case where Ar represents a 10-membered bicyclic aromatic ring system, Z only represents -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[0903] wherein Ar is optionally substituted according to any embodiment.

[0904] In one embodiment, the invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Ar represents

[0905] A 9-membered bicyclic aromatic ring system, consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, said 9-membered bicyclic aromatic ring being attached to the remainder of the molecule through a ring carbon atom of the 5- or 6-membered ring or a ring nitrogen atom of the 5-membered ring; or

[0906] wherein 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 nitrogen atoms; 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;

[0907] Provided that when Ar represents a 10-membered bicyclic aromatic ring system, Z represents only -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[0908] wherein Ar is optionally substituted according to any embodiment.

[0909] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Ar represents

[0910] a fused bicyclic partial aromatic ring system, which is attached to a linking group Z with an aromatic ring, wherein the fused bicyclic partial aromatic ring system is selected from (b-1), (b-2) and (b-3), and wherein ring A is a monocyclic aromatic ring selected from the group consisting of: pyridyl, pyrimidinyl, pyrazolyl and imidazolyl;

[0911] wherein ring B is C 5-6 cycloalkyl or a 5- to 6-membered saturated heterocyclic group containing one or two heteroatoms each independently selected from O, S and N;

[0912] wherein Ar is optionally substituted according to any embodiment.

[0913] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Ar represents a 9-membered bicyclic aromatic ring system selected from the following

[0914]

[0915] wherein Ar is optionally substituted according to any embodiment.

[0916] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Ar represents a 10-membered bicyclic aromatic ring system selected from the following

[0917]

[0918] wherein Ar is optionally substituted according to any embodiment.

[0919] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Ar represents a fused bicyclic partial aromatic ring system selected from the following

[0920]

[0921] wherein Ar is optionally substituted according to any embodiment.

[0922] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Ar represents a monocyclic aromatic ring selected from pyridyl, pyrimidinyl, pyrazolyl and imidazolyl; or a bicyclic system selected from the following

[0923]

[0924] wherein Ar is optionally substituted according to any embodiment.

[0925] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Ar represents a 9-membered bicyclic aromatic ring system selected from the group consisting of the following

[0926]

[0927] The 9-membered bicyclic aromatic ring is attached to the remainder of the molecule through a ring carbon atom of a 5- or 6-membered ring or a ring nitrogen atom of a 5-membered ring;

[0928] wherein Ar is optionally substituted according to any embodiment.

[0929] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Ar represents a 9-membered bicyclic aromatic ring system selected from the group consisting of the following

[0930]

[0931] wherein Ar is optionally substituted according to any embodiment.

[0932] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Ar represents a 9-membered bicyclic aromatic ring system selected from the group consisting of the following

[0933]

[0934] wherein Ar is substituted at the position indicated by α (if any) by -NH2, -NH-C 1-4 alkyl or -NHR 10 ; and wherein Ar is optionally substituted by a substituent selected from the series of substituents on Ar in any other embodiment.

[0935] In one embodiment, the present invention relates to the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Ar represents a bicyclic system selected from the group consisting of

[0936]

[0937] wherein Ar is substituted at the position indicated by α (if any) by -NH2, -NH-C 1-4 alkyl or -NHR 10 ;

[0938] wherein Ar is substituted at the position indicated by β (if any) by oxo;

[0939] wherein Ar is substituted at the position indicated by γ (if any) by C 1-4 alkyl;

[0940] and wherein Ar is optionally substituted by a substituent selected from the series of substituents on Ar in any other embodiment.

[0941] In one embodiment, the present invention relates to the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[0942] Z represents -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[0943] R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R5g , R 5h and R 5i represent hydrogen;

[0944] Ar represents a bicyclic system selected from the group consisting of

[0945]

[0946] wherein Ar is substituted by -NH2 at the position indicated by α (if any).

[0947] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[0948] Z represents -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[0949] R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , R 5h and R 5i represent hydrogen;

[0950] Ar represents a bicyclic system selected from the group consisting of

[0951]

[0952] wherein Ar is substituted by -NH2 at the position indicated by α.

[0953] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Ar is substituted by a substituent selected from the group consisting of: -NH2, -NH-C 1-4 alkyl, -NHR 10; and wherein Ar is optionally substituted by another substituent selected from the series of substituents on Ar in any other embodiment.

[0954] In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein

[0955] Ar represents a monocyclic aromatic ring selected from pyridyl and imidazolyl;

[0956] Ar is optionally substituted on a carbon atom by a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 alkyl, -NHR 10 , cyano, -CF3, C 1-4 alkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl and C substituted by one C 1-4 alkoxy-substituted C 1-4 alkyl.

[0957] In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein

[0958] Ar represents a monocyclic aromatic ring selected from pyridyl and imidazolyl;

[0959] wherein Ar is optionally substituted according to any embodiment.

[0960] In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein

[0961] Ar represents a 9-membered bicyclic aromatic ring system consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, and the 9-membered bicyclic aromatic ring is attached to the remainder of the molecule through a ring carbon atom of the 5- or 6-membered ring or a ring nitrogen atom of the 5-membered ring;

[0962] Ar is optionally substituted on a carbon atom by a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 alkyl, -NHR 10 , cyano, -CF3, C 1-4 alkoxy, C 3-6 cycloalkyl, -O-C3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl and C substituted by one C 1-4 alkoxy-substituted C 1-4 alkyl; and

[0963] where possible, Ar is optionally substituted on an N-atom by a substituent selected from the group consisting of: C 1-4 alkyl; C 3-6 cycloalkyl; C substituted by one, two or three halogen atoms 1-4 alkyl; and C substituted by one, two or three halogen atoms 3-6 cycloalkyl.

[0964] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[0965] Ar represents a 9-membered bicyclic aromatic ring system consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, said 9-membered bicyclic aromatic ring being attached to the remainder of the molecule through a ring carbon atom of the 5- or 6-membered ring or a ring nitrogen atom of the 5-membered ring;

[0966] wherein Ar is optionally substituted according to any embodiment.

[0967] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein R 5b , R 5g and R 5h represent hydrogen.

[0968] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Q 1 represents CR 6a ; and Q 2 represents CR 6b .

[0969] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[0970] R 5b , R 5g and R 5h represent hydrogen;

[0971] Y represents -CH2-;

[0972] Het means (a-1);

[0973] Q 1 Represents CR 6a ; and Q 2 Represents CR 6b Specifically, Q 1 represents CH; and Q 2 Indicates CH.

[0974] In one embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof as mentioned in any other embodiment or any subgroup thereof, wherein Q 2 Represents CR 6b .

[0975] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable addition salts and solvates thereof or any subgroup thereof, wherein Y represents -CH2-.

[0976] In one embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof or any subgroup thereof as mentioned in any other embodiment, wherein

[0977] Z stands for -X-CR 5a R 5b -、-CR 5c =CR 5d -or-CR 5e R 5g -CR 5f R 5h -;

[0978] R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g and R 5h represents hydrogen;

[0979] X represents -O-.

[0980] In one embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof or any subgroup thereof as mentioned in any other embodiment, wherein

[0981] Z stands for -X-CR 5a R 5b -、-CR 5c=CR 5d - or -CR 5e R 5g -CR 5f R 5h -.

[0982] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Z represents -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h - or -C≡C-.

[0983] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Z represents -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, -CR 5a R 5b -X- or -C≡C-.

[0984] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Z represents -X-CR 5a R 5b -.

[0985] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Z represents -O-CH2-.

[0986] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[0987] Z represents -X-CR 5a R 5b -; X represents -O-; and R 5a and R 5b represent hydrogen.

[0988] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[0989] X represents -O- or -NR 11 -; specifically, X represents -O-.

[0990] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[0991] R 7a and R 7b represent hydrogen.

[0992] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Het represents (a-1); R 3a represents -NR 7a R 7b ; and R 7a and R 7b represent hydrogen.

[0993] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein R 3a 、R 3d and R 3e do not represent halogen.

[0994] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[0995] R 3a 、R 3d and R 3e represent -NR 7a R 7b ;

[0996] R 7a represents hydrogen;

[0997] R 7b represents hydrogen.

[0998] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein R 3a, R 3d and R 3e represents -NH2.

[0999] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[1000] Z represents -CH2-, -CHR 5i -, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[1001] R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R 5g 、R 5h and R 5i each independently represents hydrogen or C 1-4 alkyl;

[1002] X represents -O-;

[1003] Het represents the bicyclic aromatic heterocyclic system (a-1);

[1004] R 3a represents halogen, -NR 7a R 7b or -O-C 1-4 alkyl;

[1005] Q 1 represents CR 6a ;

[1006] Q 2 represents CR 6b .

[1007] In one embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof or any subgroup thereof as mentioned in any other embodiment, wherein

[1008] Z stands for -X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h -、-CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -or-CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[1009] R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g and R 5h Each independently represents hydrogen or C 1-4 alkyl;

[1010] X means -O-;

[1011] Het represents a bicyclic aromatic heterocyclic ring system (a-1);

[1012] R 3a Indicates -NR 7a R 7b ;

[1013] R 7a and R 7b represents hydrogen;

[1014] Q 1 Represents CR 6a ;

[1015] Q 2 Represents CR 6b .

[1016] In one embodiment, the present invention relates to those compounds of formula (I), their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any other embodiment, wherein

[1017] Z represents -CH2-, -CHR 5i -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -、-CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[1018] R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R 5g 、R 5h and R 5i each independently represents hydrogen or C 1-4 alkyl;

[1019] Het represents a bicyclic aromatic heterocyclic system (a-1);

[1020] R 3a represents halogen, -NR 7a R 7b or -O-C 1-4 alkyl;

[1021] Q 1 represents CR 6a ;

[1022] Q 2 represents CR 6b .

[1023] In one embodiment, the present invention relates to those compounds of formula (I), their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any other embodiment, wherein

[1024] Z represents -CR5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[1025] R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g and R 5h each independently represents hydrogen or C 1-4 alkyl;

[1026] Het represents a bicyclic aromatic heterocyclic system (a-1);

[1027] R 3a represents -NR 7a R 7b ;

[1028] R 7a and R 7b represent hydrogen;

[1029] Q 1 represents CR 6a ;

[1030] Q 2 represents CR 6b .

[1031] In one embodiment, the present invention relates to those compounds of formula (I), their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, mentioned in any other embodiment, wherein the compounds of formula (I) are limited to compounds of formula (I-a1):

[1032]

[1033] It will be clear that all variables in the structure of formula (I-a1) can be defined as defined for the compounds of formula (I) or any subgroup thereof in any other embodiment.

[1034] In one embodiment, the present invention relates to the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein the compounds of formula (I) are limited to the compounds of formula (I-a1):

[1035]

[1036] wherein R 3a represents -NH2; and R 4a represents hydrogen.

[1037] In one embodiment, the present invention relates to the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[1038] Z represents -X-CR 5a R 5b - or -CH2CH2-.

[1039] In one embodiment, the present invention relates to the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[1040] Z represents -X-CR 5a R 5b - or -CH2CH2-;

[1041] R 5b represents hydrogen.

[1042] In one embodiment, the present invention relates to the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[1043] R 5b represents hydrogen.

[1044] In one embodiment, the present invention relates to the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[1045] Z represents -X-CR 5a R 5b - or -CH2CH2-;

[1046] R 5a and R 5brepresents hydrogen;

[1047] X represents -O-.

[1048] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[1049] Z represents -X-CR 5a R 5b - or -CH2CH2-;

[1050] R 5a and R 5b represent hydrogen;

[1051] X represents -O-;

[1052] Het represents (a-1).

[1053] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[1054] Z represents -X-CR 5a R 5b - or -CH2CH2-;

[1055] R 5a and R 5b represent hydrogen;

[1056] X represents -O-;

[1057] Het represents (a-1);

[1058] R 3a represents -NR 7a R 7b ;

[1059] R 7a represents hydrogen;

[1060] R 7b represents hydrogen.

[1061] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein X represents -O-.

[1062] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[1063] Het represents (a-1);

[1064] R 3a represents -NR 7a R 7b ;

[1065] R 7a represents hydrogen;

[1066] R 7b represents hydrogen.

[1067] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[1068] R 3a , R 3d and R 3e represents -NR 7a R 7b ;

[1069] R 7a represents hydrogen;

[1070] R 7b represents hydrogen, C 3-6 cycloalkyl or C 1-4 alkyl.

[1071] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[1072] R 3a , R 3d and R 3e represents -NR 7a R 7b ;

[1073] R 7a represents hydrogen;

[1074] R 7b represents hydrogen.

[1075] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein Y represents -CH2-; and Z represents -CH2CH2-.

[1076] In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof mentioned in any other embodiment, wherein

[1077] R 1 represents hydrogen; R2 represents hydrogen;

[1078] Y represents -CH2-;

[1079] Z represents -CH2-, -CHR 5i -、-X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h -、-CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -or-CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -;

[1080] R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , R 5h and R 5i Each independently represents hydrogen or C 1-4 alkyl;

[1081] X means -O-;

[1082] Het represents a bicyclic aromatic heterocyclic ring system (a-1);

[1083] R 3a Indicates halogen, -NR 7a R 7b or -OC 1-4 alkyl;

[1084] R 7a represents hydrogen;

[1085] R 7b Represents hydrogen or C 1-4 alkyl;

[1086] R 4a represents hydrogen;

[1087] Q 1 Represents CR6a ;

[1088] Q 2 represents N or CR 6b ;

[1089] R 6a and R 6b each independently represents hydrogen or a halogen.

[1090] In one embodiment, the present invention relates to a subgroup having formula (I) as defined in the general reaction scheme.

[1091] In one embodiment, the compounds having formula (I) are selected from the group consisting of any one of the exemplary compounds,

[1092] and their free bases, pharmaceutically acceptable addition salts, and solvates.

[1093] All possible combinations of the above-indicated embodiments are considered to be included within the scope of the present invention.

[1094] Preparation methods

[1095] In this part, as in all other parts, unless the context otherwise indicates, references to formula (I) also include all other subgroups and their instances as defined herein.

[1096] The general preparation of some typical examples of the compounds having formula (I) is described below and in the specific examples, and is generally prepared from starting materials that are commercially available or prepared by standard synthetic processes commonly used by those of ordinary skill in the art. The following schemes are only intended to illustrate examples of the present invention and are in no way intended to limit the present invention.

[1097] Alternatively, the compounds of the present invention can also be prepared by combining a similar reaction protocol as described in the general protocol below with standard synthetic processes commonly used by those of ordinary skill in the art of organic chemistry.

[1098] Those skilled in the art will recognize that in the reactions described in the schemes, it may be desirable or necessary to protect the reactive functional groups desired in the end product, such as hydroxyl, amino, or carboxyl groups, to avoid their participation in unwanted reactions. Conventional protecting groups can be used according to standard practice. This is illustrated in the specific examples.

[1099] Those skilled in the art will recognize that in the reactions described in the schemes, it may be desirable or necessary to conduct the reactions under an inert atmosphere, such as under a N2 atmosphere, for example when NaH is used in the reaction.

[1100] It will be apparent to those skilled in the art that it may be necessary to cool the reaction mixture prior to the reaction work-up (referring to a series of operations necessary for separating and purifying one or more products of a chemical reaction, such as quenching, column chromatography, extraction).

[1101] Those skilled in the art will recognize that heating the reaction mixture with stirring can increase the reaction yield. In some reactions, microwave heating can be used to replace conventional heating to shorten the overall reaction time.

[1102] Those skilled in the art will recognize that another sequence of chemical reactions shown in the following scheme may also result in the desired compound having the formula (I).

[1103] Those skilled in the art will recognize that the intermediates and compounds shown in the following scheme can be further functionalized according to methods well known to those skilled in the art.

[1104] Those skilled in the art will recognize that more compounds having the formula (I) can be prepared by using a similar synthetic scheme described in the following scheme.

[1105] When one of the starting materials is available in the form of a salt, those skilled in the art will recognize that it is necessary to first treat the salt with a base, such as N,N-diisopropylethylamine (DIPEA).

[1106] All variables are as defined above, unless otherwise specified or clear from the context.

[1107] Those skilled in the art will understand that similar chemical processes described in Schemes 1 to 9 (where Het is shown as (a-1)) can also be used to prepare compounds having the formula (I), where Het represents a bicyclic aromatic heterocyclic system (a-2) or (a-3). In addition, this information can be combined with standard synthetic methods commonly used by those skilled in the art of organic chemistry to obtain more compounds having the formula (I), where Het represents (a-2) or (a-3).

[1108] Generally, compounds having the formula (I) can be prepared according to Scheme 1:

[1109] General Scheme 1

[1110]

[1111] In Scheme 1, "LG1" is defined as a suitable leaving group, such as a halogen. All other variables in Scheme 1 are defined according to the scope of the present invention.

[1112] In Scheme 1, the following reaction conditions typically apply:

[1113] 1: Depending on R 3aThere are different reaction condition groups for the definition of

[1114] 1a: When R 3a is a halogen, step 1 can be omitted.

[1115] 1b: When R 3a is NR 7a R 7b at that time, in the presence of a suitable amine having the formula HNR 7a R 7b and a suitable solvent such as H2O, MeOH or EtOH, at a suitable temperature such as between 100 °C and 130 °C, usually under microwave conditions or using an autoclave for heating.

[1116] 1c: When R 3a is -O-C 1-4 alkyl, in the presence of a suitable HO-C 1-4 alkyl and a suitable base such as NaH, potassium tert-butoxide (tBuOK), in a suitable solvent such as tetrahydrofuran (THF), at a suitable temperature. Alternatively, in the presence of a suitable HO-C 1-4 alkyl as a solvent and a suitable acid such as HCl.

[1117] 1d: When R 3a is hydrogen, under hydrogenation conditions: H2-gas atmosphere, in the presence of a catalyst such as Raney nickel, Pd / C (e.g., 5 wt% or 10 wt%) or Pt / C (e.g., 5 wt%), in a suitable solvent such as methanol (MeOH), ethanol (EtOH) or THF.

[1118] 1e: When R 3a is C 1-4 alkyl, in the presence of a suitable boric acid or ester such as methylboronic acid and a suitable catalyst such as 1,1'-bis(diphenylphosphino)ferrocene, and a suitable base such as K3PO4, in a suitable solvent mixture such as dioxane / H2O, ratio 5:1, at a suitable temperature such as 100 °C.

[1119] 2: In the presence of a suitable acid such as 4M HCl in dioxane or 4M HCl in MeOH, and a suitable solvent such as MeOH, at a suitable temperature such as room temperature; or alternatively, in the presence of a suitable acid such as trifluoroacetic acid (TFA) in dichloromethane (DCM), at a suitable temperature, or in the presence of acetic acid in THF and water, at a suitable temperature such as room temperature.

[1120] 3: In the presence of a suitable acid anhydride having the formula (C 1-4 alkyl C=O)2O and a suitable solvent such as pyridine, at a suitable temperature. When R3a When it is NH2, (C 1-4 alkyl C=O)2O can react with NH2 to obtain an N(C 1-4 alkyl C=O)2 intermediate. This intermediate can be converted into the target product by heating in a suitable solvent such as MeOH, at a suitable temperature such as 100°C - 130°C, under microwave conditions or using an autoclave. The reaction can benefit from the presence of an acid, such as HCl or C 1-4 alkyl CO2H.

[1121] The starting materials in Scheme 1 are commercially available or can be prepared by standard means obvious to those skilled in the art or by the methods described in the following general scheme.

[1122] General Scheme 2a

[1123] Generally, an intermediate of formula III (where Z represents -O-CHR 5a -) can be prepared according to Scheme 2a. All other variables in Scheme 2a are defined according to the scope of the present invention. Those skilled in the art will recognize that when R 3a is -NH2 or -NHR 7b a suitable protecting group is required;

[1124]

[1125] In Scheme 2a, the following reaction conditions apply:

[1126] 1: Mitsunobu reaction:

[1127] 1a: In the presence of diisopropyl azodicarboxylate (DIAD) or diethyl azodicarboxylate (DEAD) or bis(1,1-dimethylethyl)-azodicarboxylate (DBAD) supported on PPh3-polymer, in a suitable solvent such as anhydrous THF, at a suitable temperature such as room temperature.

[1128] 1b: In the presence of triphenylphosphine (PPh3), DIAD or DEAD, in a suitable solvent such as anhydrous THF, at a suitable temperature such as room temperature.

[1129] 1c: In the presence of cyanomethylenetributylphosphine (CMBP) or cyanomethylenetrimethylphosphine (CMMP), in a suitable solvent such as anhydrous toluene, at a suitable temperature such as 80°C.

[1130] The starting materials in Scheme 2a are commercially available or can be prepared by standard means obvious to those skilled in the art or by the methods described in the following general scheme. Those skilled in the art will recognize that when R 5a is C1-4 When R is an alkyl group, the different isomers can be separated from each other by using reverse-phase high performance liquid chromatography (RP-HPLC) or supercritical fluid chromatography (SFC).

[1131] General Scheme 2b

[1132] Generally, an intermediate of formula III, wherein Z represents -CHR 5a -, can be prepared according to Scheme 2a. All other variables in Scheme 2b are defined according to the scope of the present invention. Those skilled in the art will recognize that when R 3a is -NH2 or -NHR 7b , suitable protecting groups are required;

[1133]

[1134] In Scheme 2b, the following reaction conditions apply:

[1135] 1: Mitsunobu reaction:

[1136] 1a: In the presence of diisopropyl azodicarboxylate (DIAD) or diethyl azodicarboxylate (DEAD) or bis(1,1-dimethylethyl)-azodicarboxylate (DBAD) supported on PPh3-polymer, in a suitable solvent such as anhydrous THF, at a suitable temperature such as room temperature.

[1137] 1b: In the presence of triphenylphosphine (PPh3), DIAD or DEAD, in a suitable solvent such as anhydrous THF, at a suitable temperature such as room temperature.

[1138] 1c: In the presence of cyanomethylenetributylphosphine (CMBP) or cyanomethylenetrimethylphosphine (CMMP), in a suitable solvent such as anhydrous toluene, at a suitable temperature such as 80 °C.

[1139] The starting materials in Scheme 2b are commercially available or can be prepared by standard means obvious to those skilled in the art or by the methods described in the following general scheme. Those skilled in the art will recognize that when R 5a is C 1-4 alkyl, the different isomers can be separated from each other by using reverse-phase high performance liquid chromatography (RP-HPLC) or supercritical fluid chromatography (SFC).

[1140] Those skilled in the art will recognize that Scheme 2b can also be used to prepare similar intermediates, wherein Z represents -CR 5e R 5g -CR 5f R 5h -.

[1141] General Scheme 2c

[1142] An intermediate of formula II, wherein Z represents -X a -CHR 5a -), can be prepared according to Scheme 2c. In Scheme 2c, 'X a ' is defined as O or S; 'LG' is defined as a leaving group such as halogen, methanesulfonate (MsO) or tosylate (TosO), preferably TosO. 'LG1' is defined as a leaving group such as halogen. All other variables in Scheme 2c are defined according to the scope of the present invention.

[1143]

[1144] In Scheme 2c, the following reaction conditions apply:

[1145] 1: In the presence of a base such as K2CO3, triethylamine (Et3N) or DIPEA, in a suitable solvent such as CH3CN, DCM or N,N-dimethylacetamide (DMA).

[1146] The starting materials in Scheme 2c are commercially available or can be prepared by standard means obvious to those skilled in the art or by the methods described in the following general scheme. Those skilled in the art will recognize that when R 5a is C 1-4 alkyl, the different isomers can be separated from each other by using reverse-phase high performance liquid chromatography (RP-HPLC) or supercritical fluid chromatography (SFC).

[1147] General Scheme 2d

[1148] An intermediate of formula III, wherein Z represents -X a -CHR 5a -), can be prepared according to Scheme 2d. In Scheme 2d, 'X a ' is defined as O or S. 'LG' is defined as a leaving group such as halogen, MsO or TosO, preferably TosO. All other variables in Scheme 2d are defined according to the scope of the present invention. Those skilled in the art will recognize that when R 3a is -NH2 or -NHR 7b , suitable protecting groups are required.

[1149]

[1150] In Scheme 2d, the following reaction conditions apply:

[1151] 1: In the presence of a base such as K2CO3, Et3N or DIPEA, in a suitable solvent such as CH3CN, DCM or N,N-dimethylacetamide (DMA).

[1152] The starting materials in Scheme 2d are commercially available or can be prepared by standard means that are obvious to those skilled in the art or by the methods described in the following general scheme. Those skilled in the art will recognize that when R 5a is C 1-4 alkyl, the different isomers can be separated from each other by using reverse-phase high performance liquid chromatography (RP-HPLC) or supercritical fluid chromatography (SFC).

[1153] General Scheme 3

[1154] Generally, the intermediate (where Z represents -X-CHR 5a -; and where X represents -NH- or -NR 11 -) can be prepared according to Scheme 3. In Scheme 3, 'LG1' is defined as a leaving group such as a halogen. All other variables in Scheme 3 are defined according to the scope of the present invention.

[1155]

[1156] In Scheme 3, the following reaction conditions apply:

[1157] 1: In the presence of a suitable reducing agent such as sodium triacetoxyborohydride (NaBH(AcO)3) and a suitable solvent such as DCM, at a suitable temperature such as room temperature; or alternatively, in the presence of NaBH3CN and a suitable solvent such as MeOH, at a suitable temperature (such as between room temperature and 50 °C).

[1158] 2: In the presence of a suitable base such as NaH and a suitable solvent such as anhydrous THF, N,N-dimethylformamide (DMF), DMA, at a suitable temperature (such as between room temperature and 50 °C).

[1159] The starting materials in Scheme 3 are commercially available or can be prepared by standard means that are obvious to those skilled in the art or as described in the specific experimental section. Those skilled in the art will recognize that when R 5a is C 1-4 alkyl, the different isomers can be separated from each other by using reverse-phase high performance liquid chromatography (RP-HPLC) or supercritical fluid chromatography (SFC).

[1160] General Scheme 4

[1161] Generally, intermediates (where Z represents -C≡C-, -CH=CH- or -CH2-CH2-) can be prepared according to Scheme 4. In Scheme 4, 'LG1' is defined as a leaving group such as a halogen. All other variables in Scheme 4 are defined according to the scope of the present invention.

[1162]

[1163] In Scheme 4, the following reaction conditions apply:

[1164] 1: In the presence of a suitable amine such as HNR'R” or NaOR' and a suitable solvent such as H2O, MeOH or EtOH, at a suitable temperature such as between 100 °C and 130 °C, heating is carried out under microwave conditions or using an autoclave.

[1165] 2: In the presence of a suitable Ar-bromide or Ar-iodide, a suitable catalyst such as bis(triphenylphosphine)palladium(II) dichloride and copper(I) iodide, in a suitable solvent such as 2-methyltetrahydrofuran and a suitable base such as triethylamine, at a suitable temperature such as 80 °C.

[1166] 3: In the presence of a suitable Ar-bromide or Ar-iodide, a suitable salt such as tetraethylammonium chloride (Et4NCl), in a suitable solvent such as DMF, and a suitable base such as DIPEA and a palladium catalyst such as Pd(OAc)2 (palladium(II) acetate), at a suitable temperature such as 100 °C.

[1167] 4: In an H2-gas atmosphere and in the presence of a catalyst such as Pd / C (e.g., 5 wt% or 10 wt%), in a suitable solvent such as MeOH.

[1168] 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 section.

[1169] General Scheme 5

[1170] Generally, intermediates (where Z represents -CH2O-) can be prepared according to Scheme 5. In Scheme 5, 'LG1' is defined as a leaving group such as a halogen. All other variables in Scheme 5 are defined according to the scope of the present invention.

[1171]

[1172] In Scheme 5, the following reaction conditions apply:

[1173] 1: In the presence of a base such as K2CO3, Et3N or DIPEA, in a suitable solvent such as CH3CN, DCM or N,N-dimethylacetamide (DMA).

[1174] General Scheme 6

[1175] Typically, the intermediate (where Z represents -CH2-) can be prepared according to Scheme 6. In Scheme 6, 'LG1' is defined as a leaving group such as a halogen. All other variables in Scheme 6 are defined according to the scope of the present invention.

[1176]

[1177] In Scheme 6, the following reaction conditions apply:

[1178] 1: In the presence of tosylhydrazide and a suitable solvent such as MeOH, EtOH or DCM, at a suitable temperature such as room temperature.

[1179] 2: In the presence of boric acid and a suitable base such as K2CO3, Na2CO3, Cs2CO3 and a suitable solvent such as 1,4-dioxane, at a suitable temperature such as 90 °C.

[1180] 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 section.

[1181] General Scheme 7

[1182] Typically, the intermediate (where Z represents -CH2-CH2-) can be prepared according to Scheme 7. In Scheme 7, 'LG1' is defined as a leaving group such as a halogen. All other variables in Scheme 7 are defined according to the scope of the present invention.

[1183]

[1184] In Scheme 7, the following reaction conditions typically apply:

[1185] 1: In the first step, in the presence of an alkylene precursor and a 0.5 M solution of 9-borabicyclo[3.3.1]nonane (9-BBN) in THF, under a nitrogen atmosphere, at a temperature between room temperature and reflux temperature, the reaction time is between 1 and 3 hours. In the second step, in the presence of, for example, a suitable Ar-bromide or Ar-iodide and a suitable catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and in the presence of a suitable base such as tripotassium phosphate, in a suitable solvent mixture such as THF and water, at a suitable temperature between 50 °C and reflux temperature, the suitable reaction time is between 1 and 3 hours.

[1186] 2: Depending on the definition of R 3a there are different sets of reaction conditions:

[1187] 2a: When R 3a is a halogen, step 1 can be omitted.

[1188] 2b: When R 3a is NR 7a R 7b at a suitable temperature between, for example, 100 °C - 130 °C, usually under microwave conditions or using an autoclave for heating, in the presence of a suitable amine of the formula HNR 7a R 7b and a suitable solvent such as H2O, MeOH or EtOH.

[1189] 2c: When R 3a is -O-C 1-4 alkyl, in the presence of a suitable HO-C 1-4 alkyl and a suitable base such as NaH, potassium tert-butoxide (tBuOK), in a suitable solvent such as tetrahydrofuran (THF), at a suitable temperature. Alternatively, in the presence of a suitable HO-C 1-4 alkyl as the solvent and a suitable acid such as HCl.

[1190] 2d: When R 3a is hydrogen, under hydrogenation conditions: H2-gas atmosphere, in the presence of a catalyst such as Raney nickel, Pd / C (e.g., 5 wt% or 10 wt%) or Pt / C (e.g., 5 wt%), in a suitable solvent such as methanol (MeOH), ethanol (EtOH) or THF;

[1191] 2e: When R 3a is C 1-4When it is an alkyl group, in the presence of a suitable boric acid or ester such as methylboronic acid and a suitable catalyst such as 1,1'-bis(diphenylphosphino)ferrocene, and a suitable base such as K3PO4, in a suitable solvent mixture such as dioxane / H2O, in a ratio of 5:1, at a suitable temperature such as 100 °C.

[1192] 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 section.

[1193] General Scheme 8

[1194] Generally, the intermediate (where Z represents -CH2-CH2-) can be prepared according to Scheme 8. In Scheme 8, 'LG1' is defined as a leaving group such as a halogen. All other variables in Scheme 8 are defined according to the scope of the present invention.

[1195]

[1196] In Scheme 8, the following reaction conditions typically apply:

[1197] 1: Depending on the definition of R 3a there are different groups of reaction conditions:

[1198] 1a: When R 3a is a halogen, step 1 can be omitted.

[1199] 1b: When R 3a is NR 7a R 7b at that time, in the presence of a suitable amine having the formula HNR 7a R 7b and a suitable solvent such as H2O, MeOH or EtOH, at a suitable temperature between, for example, 100 °C and 130 °C, usually under microwave conditions or using an autoclave for heating.

[1200] 1c: When R 3a is -O-C 1-4 alkyl, in the presence of a suitable HO-C 1-4 alkyl and a suitable base such as NaH, potassium tert-butoxide (tBuOK), in a suitable solvent such as tetrahydrofuran (THF), at a suitable temperature. Alternatively, in the presence of a suitable HO-C 1-4 alkyl as the solvent and a suitable acid such as HCl.

[1201] 1d: When R 3aWhen R is hydrogen, under hydrogenation conditions: H2 - gas atmosphere, in the presence of a catalyst such as Raney nickel, Pd / C (e.g., 5 wt% or 10 wt%) or Pt / C (e.g., 5 wt%), in a suitable solvent such as methanol (MeOH), ethanol (EtOH) or THF.

[1202] 1e: When R 3a is C 1-4 alkyl, in the presence of a suitable boric acid or ester such as methylboronic acid and a suitable catalyst such as 1,1'-bis(diphenylphosphino)ferrocene, and a suitable base such as K3PO4, in a suitable solvent mixture such as dioxane / H2O, ratio 5:1, at a suitable temperature such as 100 °C.

[1203] 2: In the first step, in the presence of an alkylene precursor and a 0.5 M 9 - BBN solution in THF, under a nitrogen atmosphere, at a temperature between room temperature and reflux temperature, the reaction time is 1 to 3 hours. In the second step, in the presence of a suitable Ar - bromide or Ar - iodide and a suitable catalyst such as dichlorobis[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) and in the presence of a suitable base such as tripotassium phosphate, in a suitable solvent mixture such as THF and water, at a suitable temperature between 50 °C and reflux temperature, the suitable reaction time is between 1 and 3 hours.

[1204] 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 section.

[1205] General Scheme 9

[1206] Generally, the intermediate shown in Scheme 9 (where Z represents -CH2-CH2-) can be prepared according to Scheme 9. In Scheme 9, 'LG1' is defined as a leaving group such as a halogen. All other variables in Scheme 9 are defined according to the scope of the present invention.

[1207]

[1208] 1: In the first step, in the presence of an alkylene precursor and a 0.5 M solution of 9-BBN in THF, under a nitrogen atmosphere, at a temperature between room temperature and reflux temperature, the reaction time is 1 to 3 hours. In the 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 such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and in the presence of a suitable base such as tripotassium phosphate, in a suitable solvent mixture such as THF and water, at a suitable temperature between 50 °C and reflux temperature, the suitable reaction time is between 1 and 3 hours.

[1209] 2: In the presence of trifluoromethanesulfonic anhydride and a suitable base such as pyridine, in a suitable solvent such as DCM, at a suitable temperature such as 0 °C, under an inert atmosphere of N2 gas.

[1210] 3: In the presence of a suitable base such as Cs2CO3, in a suitable solvent such as DMF, at a suitable temperature such as room temperature, under an inert atmosphere of N2 gas.

[1211] 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 section.

[1212] In all these preparations, the reaction product can be separated from the reaction medium and, if necessary, further purified according to methods generally known in the art, such as extraction, crystallization, trituration, and chromatography.

[1213] The enantiopure forms of the compounds of formula (I) form a preferred group of compounds. Thus, the enantiopure forms of these intermediates and their salt forms are particularly useful in the preparation of enantiopure compounds of formula (I). The racemic mixtures of these intermediates are also useful in the preparation of compounds of formula (I) having the corresponding configuration.

[1214] Pharmacology

[1215] It has been found that the compounds of the present invention inhibit PRMT5 activity.

[1216] Specifically, the compounds of the present invention bind to the PRMT5 enzyme and compete with the natural substrate SAM (S-adenosyl-L-methionine) to inhibit this enzyme.

[1217] Thus, it is expected that the compounds of the present invention and their pharmaceutical compositions can be used for the treatment or prevention, particularly for the treatment of diseases such as blood disorders, metabolic disorders, autoimmune diseases, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney diseases, platelet aggregation, sperm motility, transplant rejection, graft rejection, lung injury, etc.

[1218] Specifically, the compounds or pharmaceutical compositions thereof according to the present invention can be used for treating or preventing, in particular for treating the following diseases, such as allergy, asthma, hematopoietic system cancer, lung cancer, prostate cancer, melanoma, metabolic disorders, diabetes, obesity, blood disorders, sickle cell anemia, etc.

[1219] The compounds or pharmaceutical compositions thereof according to the present invention can be used for treating or preventing, in particular for treating the following diseases, such as proliferative disorders, such as autoimmune diseases, cancers, benign neoplasms or inflammatory diseases.

[1220] The compounds or pharmaceutical compositions thereof according to the present invention can be used for treating or preventing, in particular for treating the following diseases, such as metabolic disorders, including diabetes, obesity; proliferative disorders, including cancer, hematopoietic system cancer, lung cancer, prostate cancer, melanoma or pancreatic cancer; blood disorders; hemoglobinopathies; sickle cell anemia; β-thalassemia, inflammatory diseases, and autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, diarrhea, gastroesophageal reflux disease, etc.

[1221] In some embodiments, the inhibition of PRMT5 by the provided compounds can be used for treating or preventing, in particular for treating the following non-limiting series of cancers: breast cancer, lung cancer, esophageal cancer, bladder cancer, hematopoietic system cancer, lymphoma, medulloblastoma, rectal adenocarcinoma, colon adenocarcinoma, gastric cancer, pancreatic cancer, liver cancer, adenoid cystic carcinoma, lung adenocarcinoma, head and neck squamous cell carcinoma, brain cancer, hepatocellular carcinoma, renal cell carcinoma, melanoma, oligodendroglioma, ovarian clear cell carcinoma, and ovarian serous cystadenocarcinoma.

[1222] Examples of metabolic disorders that can be treated or prevented, especially treated, include but are not limited to diabetes or obesity.

[1223] Examples of blood disorders that can be treated or prevented, especially treated, include but are not limited to hemoglobinopathies, such as sickle cell disease or β-thalassemia.

[1224] Cancers that can be treated or prevented, especially treated, examples include but are not limited to acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, angiosarcoma), appendiceal cancer, benign monoclonal gammopathy, cholangiocarcinoma (e.g., hepatolithiasis type hepatocellular carcinoma), bladder cancer, breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast cancer, breast medullary carcinoma), brain cancer (e.g., meningioma; glioma, such as astrocytoma, oligodendroglioma; medulloblastoma), bronchial cancer, carcinoid tumor, cervical cancer (e.g., uterine adenocarcinoma), chordoma, choriocarcinoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial cancer, ependymoma, endothelial sarcoma (e.g., Kaposi sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), common eosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC)), laryngeal cancer (e.g., pharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic system cancer (e.g., leukemia such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid 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-cell HL, T-cell 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 (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, 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 macroglobulinemia"), immunoblastic large cell lymphoma, hairy cell leukemia (HCL), precursor B lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma;and T cell NHLs such as precursor T lymphoblastic lymphoma / leukemia, peripheral T cell lymphoma (PTCL) (e.g., cutaneous T cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T cell lymphoma, extranodal natural killer T cell lymphoma, enteropathy-type T cell lymphoma, subcutaneous panniculitis-like T cell lymphoma, anaplastic large cell lymphoma); mixtures of one or more of the leukemias / lymphomas as described above;and multiple myeloma (MM), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immunocyte amyloidosis, kidney cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma), lung cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma), lung cancer (e.g., bronchial carcinoma, non-small cell lung cancer (NSCLC), squamous lung cancer (SLC), lung adenocarcinoma, Lewis lung cancer, lung neuroendocrine tumors: typical carcinoid, atypical carcinoid, small cell lung cancer (SCLC), and large cell neuroendocrine carcinoma), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), agnogenic myeloid metaplasia (AMM) also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis), neuroendocrine carcinoma (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor), penile cancer (e.g., Paget's disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostatic adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small intestine cancer (e.g., appendiceal 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 thyroid carcinoma, papillary thyroid cancer (PTC), medullary thyroid carcinoma), urethral cancer, vaginal cancer, and vulvar cancer (e.g., Paget's disease of the vulva).;

[1225] Examples of neurodegenerative diseases that can be treated or prevented, especially treated, include, but are not limited to, motor neuron diseases, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy, and cerebellar degeneration.

[1226] Examples of cardiovascular diseases that can be treated or prevented, especially treated, include, but are not limited to, cardiac hypertrophy, restenosis, atherosclerosis, and glomerulonephritis.

[1227] Inflammatory diseases that can be treated or prevented, particularly treated, include, but are not limited to, inflammation associated with the following: acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), rhinitis, asthma, arteritis (e.g., polyarteritis, 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 diseases, ankylosing spondylitis, amyloidosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, diverticulitis, dermatomyositis, diabetes (e.g., type I diabetes, type 2 diabetes), skin disorders (e.g., psoriasis, eczema, allergic reactions, burns, dermatitis, pruritus (itching)), endometriosis, Guillain-Barré syndrome, infections, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity reactions, headache (e.g., migraine, tension headache), intestinal obstruction (e.g., postoperative intestinal obstruction and intestinal obstruction during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorders (e.g., selected from peptic ulcer, 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, ischemic colitis, diversion colitis, Behcet’s syndrome, indeterminate colitis), and irritable bowel syndrome (IBS)), lupus, scleroderma, myasthenia gravis, myocardial ischemia, multiple sclerosis, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcer, 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, scleroderma, scierodoma, sarcoidosis, spondyloarthropathy, Sjogren's syndrome, thyroiditis, transplant rejection, tendinitis, trauma or injury (e.g., chilblains, chemical irritants, toxins, scars, burns, physical injury), vasculitis, vitiligo, and Wegener's granulomatosis.

[1228] Specifically, the inflammatory disease is an acute inflammatory disease (e.g., inflammation caused by infection). Specifically, the inflammatory disease is a chronic inflammatory disease (e.g., conditions caused by asthma, arthritis, and inflammatory bowel disease). These compounds may also be useful in treating inflammation associated with trauma and non-inflammatory myalgia. These compounds may also be useful in treating inflammation associated with cancer.

[1229] Autoimmune diseases that can be treated or prevented, particularly treated, include but are not limited to arthritis (including rheumatoid arthritis, spondyloarthropathies, gouty arthritis, degenerative joint diseases such as osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease, hemolytic autoimmune anemia, amyotrophic lateral sclerosis, amyloidosis, multiple sclerosis, acute painful shoulder, psoriatic and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendinitis, bursitis, skin disorders (e.g., psoriasis, eczema, eczema allergic reaction, burns, dermatitis, pruritus (itching)), enuresis, eosinophilic diseases, gastrointestinal disorders (e.g., selected from peptic ulcer, Crohn's disease, 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, ischemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis) and irritable bowel syndrome (IBS)) and disorders improved by gastric motility promoters (e.g., intestinal obstruction, postoperative intestinal obstruction and intestinal obstruction during sepsis; gastroesophageal reflux disease (GORD or its synonym GERD); eosinophilic esophagitis, gastroparesis such as diabetic gastroparesis; food intolerance and food allergy and other functional bowel disorders, such as non-ulcer dyspepsia (NUD) and non-cardiac chest pain (NCCP, including costochondritis)).

[1230] In a specific embodiment, a provided compound can be useful in somatic cell reprogramming, such as reprogramming somatic cells into stem cells. In a specific embodiment, a provided compound can be useful in germ cell development and is thus contemplated to be useful in the fields of reproductive technology and regenerative medicine.

[1231] Other diseases that can be treated or prevented, particularly treated, include but are not limited to ischemic injury-related myocardial infarction, immune diseases, stroke, arrhythmia, toxin-induced or alcohol-related liver disease, aspirin-sensitive sinusitis, cystic fibrosis, cancer pain and blood diseases, such as chronic anemia and aplastic anemia.

[1232] The compounds of the present invention can also have therapeutic applications that sensitize tumor cells to radiotherapy and chemotherapy.

[1233] Therefore, the compounds of the present invention can be used as "radiosensitizers" and / or "chemosensitizers", or can be administered in combination with additional "radiosensitizers" and / or "chemosensitizers".

[1234] As used herein, the term "radiosensitizer" is defined as a molecule, preferably a low molecular weight molecule, which is administered to an animal in a therapeutically effective amount to increase the sensitivity of cells to ionizing radiation and / or to facilitate the treatment of a disease treatable with ionizing radiation.

[1235] As used herein, the term "chemosensitizer" is defined as a molecule, preferably a low molecular weight molecule, which is administered to an animal in a therapeutically effective amount to increase the sensitivity of cells to chemotherapy and / or to facilitate the treatment of a disease treatable with a chemotherapeutic drug.

[1236] Several mechanisms for the mode of action of radiosensitizers have been proposed in the literature, including: hypoxic cell radiosensitizers (e.g., 2-nitroimidazole compounds and benzotriazine dioxide compounds) mimic oxygen under hypoxia or alternatively behave like bioreducing agents; non-hypoxic cell radiosensitizers (e.g., halogenated pyrimidines) can be analogs of DNA bases and are preferentially incorporated into the DNA of cancer cells and thereby promote radiation-induced cleavage of DNA molecules and / or prevent normal DNA repair mechanisms; and a variety of other potential mechanisms of action have been postulated for radiosensitizers in disease treatment.

[1237] Many cancer treatment regimens currently employ radiosensitizers in conjunction with x-ray radiation. Examples of x-ray activated radiosensitizers include, but are not limited to, the following: metronidazole, methoxymethylnitroimidazole ethanol, demethyl ether nitroimidazole, pimonidazole, etanidazole, nitromorph, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iodo[deoxyuridine] riboside (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and therapeutically effective analogs and derivatives thereof.

[1238] Photodynamic therapy (PDT) of cancer uses visible light as a radioactive agent for sensitization. Examples of photodynamic radiosensitizers include, but are not limited to, the following: hematoporphyrin derivatives, photofrin, benzoporphyrin derivatives, tin protoporphyrins, pheophorbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanines, and therapeutically effective analogs and derivatives thereof.

[1239] The radiosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including, but not limited to: compounds that promote the incorporation of the radiosensitizer into target cells; compounds that control the flow of therapeutic agents, nutrients, and / or oxygen to target cells; chemotherapeutic agents that act on tumors with or without additional radiation; or other therapeutically effective compounds for the treatment of cancer or other diseases.

[1240] A chemosensitizer can be administered in combination with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds that facilitate the incorporation of the chemosensitizer into target cells; compounds that control the flow of therapeutic agents, nutrients, and / or oxygen to target cells; chemotherapeutic agents that act on tumors or other therapeutically effective compounds for treating cancer or other diseases. It has been found that calcium antagonists (such as verapamil) can be used in combination with anti-tumor agents to establish chemosensitivity in tumor cells resistant to recognized chemotherapeutic agents and to enhance the efficacy of such compounds in drug-sensitive malignancies.

[1241] The compounds of the present invention can also reduce the risk of cancer recurrence.

[1242] The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for use as medicaments.

[1243] The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for inhibiting PRMT5 activity.

[1244] The compounds of the present invention can be "anticancer agents", a term that also encompasses "antitumor cell growth agents" and "antitumor agents".

[1245] The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for treating the diseases mentioned above.

[1246] The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for treating or preventing, especially treating, the said diseases.

[1247] The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for treating or preventing, especially treating, PRMT5-mediated diseases or disorders.

[1248] The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for manufacturing medicaments.

[1249] The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for manufacturing medicaments for inhibiting PRMT5.

[1250] The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for manufacturing medicaments for treating or preventing, especially treating, any of the disease disorders mentioned above.

[1251] The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates for manufacturing medicaments for treating any of the disease disorders mentioned above.

[1252] The present invention relates to compounds of formula (I), their pharmaceutically acceptable addition salts and solvates, which can be administered to mammals, preferably humans, for the treatment or prevention of any of the diseases mentioned above.

[1253] In view of the use of the compounds of formula (I), their pharmaceutically acceptable addition salts and solvates, there is provided a method of treating warm-blooded animals (including humans) suffering from any of the diseases mentioned above, or a method of preventing warm-blooded animals (including humans) from suffering from any of the diseases mentioned above.

[1254] The method comprises administering, i.e., systemically or topically, preferably orally, to a warm-blooded animal (including a human), an effective amount of a compound of formula (I) or its pharmaceutically acceptable addition salt or solvate.

[1255] In the treatment of such diseases, a person of ordinary skill in the art can determine the effective daily dosage for treatment from the test results provided below. The effective daily dosage for treatment should be from about 0.005 mg / kg to 50 mg / kg, specifically 0.01 mg / kg to 50 mg / kg body weight, more specifically from 0.01 mg / kg to 25 mg / kg body weight, preferably from about 0.01 mg / kg to about 15 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, and most preferably from about 0.05 mg / kg to about 1 mg / kg body weight. The specific effective daily dosage for treatment can be from about 0.01 to 1.00 g, twice a day (BID), more specifically 0.30 to 0.85 g BID; even more specifically 0.40 g BID. The amount of the compound according to the present invention (also referred to herein as the active ingredient) required to achieve a therapeutic effect can of course vary depending on circumstances, such as the specific compound, the route of administration, the age and condition of the recipient, and the specific disorder or disease being treated.

[1256] The treatment method also comprises administering the active ingredient in a regimen of one to four intakes per day. In these treatment methods, the compounds according to the present invention are preferably formulated before administration. As described hereinafter, suitable pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients.

[1257] The compounds of the invention that are suitable for treating or preventing cancer or cancer-related disorders can be administered alone or in combination with one or more additional therapeutic agents. The combination therapy includes administering a single pharmaceutical dosage formulation comprising a compound having formula (I), a pharmaceutically acceptable addition salt or solvate thereof, and one or more additional therapeutic agents, and administering a compound having formula (I), a pharmaceutically acceptable addition salt or solvate thereof, and each additional therapeutic agent in its own separate pharmaceutical dosage formulation. For example, a compound having formula (I), a pharmaceutically acceptable addition salt thereof or a solvate thereof and a therapeutic agent can be administered together to a patient in a single oral dosage composition (such as a tablet or capsule), or each agent can be administered in a separate oral dosage formulation.

[1258] Although the active ingredient can be administered alone, it is preferably administered as a pharmaceutical composition.

[1259] Accordingly, the present invention further provides a pharmaceutical composition and a therapeutically effective amount of a compound having formula (I), a pharmaceutically acceptable addition salt or solvate thereof as the active ingredient.

[1260] Accordingly, the present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound having formula (I), a pharmaceutically acceptable addition salt or solvate thereof as the active ingredient.

[1261] The carrier or diluent must be "acceptable" in the sense of being compatible with the other ingredients of the composition and harmless to its recipient.

[1262] For ease of administration, these subject compounds can be formulated into various pharmaceutical forms for administration purposes. The compounds according to the invention, in particular compounds having formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroup or combination thereof can be formulated into various pharmaceutical forms for administration purposes. As suitable compositions, all compositions commonly used for systemic administration of drugs can be cited.

[1263] For the preparation of the pharmaceutical compositions of the present invention, an effective amount of a specific compound as active ingredient is combined with a pharmaceutically acceptable carrier in a homogeneous blend, which carrier may take a variety of forms depending on the form of the formulation desired for administration. It is desirable that these pharmaceutical compositions be in a unit dosage form particularly suitable for oral, rectal, percutaneous, parenteral injection or inhalation administration. For example, in the preparation of compositions in oral dosage form, any common pharmaceutical vehicle can be used, such as water, glycols, oils, alcohols, etc. in the case of liquid oral preparations (such as suspensions, syrups, elixirs, emulsions and solutions); or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrants, etc. in the case of powders, pills, capsules and tablets. Tablets and capsules represent the most advantageous oral unit dosage forms because of their ease of administration, and in this case solid pharmaceutical carriers are obviously used. For parenteral compositions, the carrier will generally comprise at least predominantly sterile water, but may also include other ingredients for example to aid solubility. Injectable solutions can be prepared, for example, in which the carrier comprises a salt solution, a glucose solution or a mixture of saline and glucose solution. Injectable solutions containing a compound of formula (I), its pharmaceutically acceptable addition salts or solvates can be formulated in oils to prolong the action. Suitable oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerides of long-chain fatty acids and mixtures of these with other oils. Injectable suspensions can also be prepared, in which case suitable liquid carriers, suspending agents, etc. can be used. Also included are solid form preparations which are intended to be converted shortly before use into liquid form preparations. In compositions suitable for percutaneous administration, the carrier may optionally comprise a penetration enhancer and / or a suitable wetting agent, optionally in combination with a small proportion of suitable additives of any nature which do not introduce any significant deleterious effect on the skin. Said additives may facilitate the application to the skin and / or may contribute to the preparation of the desired composition. These compositions can be administered in different ways, for example as transdermal patches, as drops, as ointments. Acid or base addition salts of the compounds of formula (I) are more suitable for the preparation of aqueous compositions because of their increased water solubility relative to the corresponding base or acid forms.

[1264] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate the above pharmaceutical compositions in unit dosage form. As used herein, unit dosage form means a physically discrete unit suitable as a single dosage, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, cachets, suppositories, injectable solutions or suspensions, etc., and their separated multiples.

[1265] To enhance the solubility and / or stability of the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates in pharmaceutical compositions, it is advantageous to employ α-, β- or γ-cyclodextrins or their derivatives, especially hydroxyalkyl-substituted cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. Co-solvents (such as alcohols) can also improve the solubility and / or stability of the compounds according to the invention in pharmaceutical compositions.

[1266] Depending on the mode of administration, the pharmaceutical composition will preferably contain 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), its pharmaceutically acceptable addition salt or solvate, 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.

[1267] As another aspect of the invention, combinations of the compounds of the invention with another anticancer agent are envisaged, especially for use as a medicament, more precisely for the treatment of cancer or related diseases.

[1268] For the treatment of the above-mentioned conditions, the compounds of the invention can advantageously be used in combination with antibody-based immune cell redirection, such as T-cell / neutrophil redirection. This objective can be achieved, for example, by using bispecific monoclonal antibodies or T-cell artificial receptors.

[1269] For the treatment of the above-mentioned conditions, the compounds of the invention can advantageously be used in combination with one or more other medicaments, more specifically with other anticancer agents or adjuvants in cancer therapy. Examples of anticancer agents or adjuvants (supporting agents in therapy) include, but are not limited to:

[1270] - Platinum coordination compounds, such as cisplatin (optionally in combination with amifostine), carboplatin or oxaliplatin;

[1271] - Taxane compounds, such as paclitaxel, albumin-bound paclitaxel particles (Abraxane TM ) or docetaxel;

[1272] - Topoisomerase I inhibitors, such as camptothecin compounds, such as irinotecan, SN-38, topotecan, topotecan hydrochloride;

[1273] - Topoisomerase II inhibitors, such as antitumor epipodophyllotoxins or podophyllotoxin derivatives, such as etoposide, etoposide phosphate or teniposide;

[1274] - Anti-tumor vinca alkaloids, such as vinblastine, vincristine or vinorelbine;

[1275] - Anti-tumor nucleoside derivatives, such as 5-fluorouracil, leucovorin, gemcitabine, gemcitabine hydrochloride, capecitabine, cladribine, fludarabine, nelarabine;

[1276] - Alkylating agents, such as nitrogen mustards or nitrosoureas, e.g., cyclophosphamide, chlorambucil, carmustine, thiotepa, melphalan, lomustine, altretamine, busulfan, dacarbazine, estramustine, ifosfamide (optionally in combination with mesna), pipobroman, procarbazine, streptozocin, temozolomide, uracil;

[1277] - Anti-tumor anthracycline derivatives, such as daunomycin, doxorubicin (optionally in combination with dexrazoxane), doxil, idarubicin, mitoxantrone, epirubicin, epirubicin hydrochloride, valrubicin;

[1278] - Molecules targeting the IGF-1 receptor, such as podophyllotoxin;

[1279] - Triciribine derivatives, such as triciribine A;

[1280] - Glucocorticoids, such as prednisone;

[1281] - Antibodies, such as trastuzumab (HER2 antibody), rituximab (CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab, pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab tiuxetan, ofatumumab, panitumumab, tositumomab, CNTO 328;

[1282] - Estrogen receptor antagonists or selective estrogen receptor modulators or estrogen synthesis inhibitors, such as tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene or letrozole;

[1283] - Aromatase inhibitors, such as exemestane, anastrozole, letrozole, testolactone and vorozole;

[1284] - Differentiating agents, such as retinoids, vitamin D or retinoic acid, and retinoic acid metabolism blockers (RAMBA), such as isotretinoin;

[1285] - DNA methyltransferase inhibitors, such as azacitidine or decitabine;

[1286] - Anti-folates, such as pemetrexed disodium;

[1287] - Antibiotics, such as antimycin D, bleomycin, mitomycin C, actinomycin, carminomycin, daunomycin, levamisole, plicamycin, mithramycin;

[1288] - Antimetabolites, such as clofarabine, aminopterin, cytarabine or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine;

[1289] - Apoptosis inducers and anti-angiogenic agents, such as Bcl-2 inhibitors, such as YC 137, BH 312, ABT737, gossypol, HA 14-1, TW 37 or capric acid;

[1290] - Tubulin-binding agents, such as combretastatin, colchicine or nocodazole;

[1291] - Kinase inhibitors (such as EGFR (epidermal growth factor receptor) inhibitors, MTKI (multi-target kinase inhibitors), mTOR inhibitors), such as flavopiridol, imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, lapatinib ditosylate, sorafenib, sunitinib, sunitinib malate, temsirolimus;

[1292] - Farnesyl transferase inhibitors, such as tipifarnib;

[1293] - Histone deacetylase (HDAC) inhibitors, such as sodium butyrate, suberoylanilide hydroxamic acid (SAHA), depsipeptide (FR 901228), NVP-LAQ824, R306465, JNJ-26481585, trichostatin A, vorinostat;

[1294] - Ubiquitin-proteasome pathway inhibitors, such as PS-341, MLN.41 or bortezomib;

[1295] - Trabectedin (Yondelis);

[1296] - Telomerase inhibitors, such as telomestatin;

[1297] - Matrix metalloproteinase inhibitors, such as batimastat, marimastat, prinomastat or metastat.

[1298] - Recombinant interleukins, such as aldesleukin, denileukin diftitox, interferon α2a, interferon α2b, pegylated interferon α2b

[1299] - MAPK inhibitors

[1300] - Retinoids, such as alitretinoin, bexarotene, tretinoin

[1301] - Arsenic trioxide

[1302] - Asparaginase

[1303] - Steroids, such as Drostanolone Propionate, Megestrol Acetate, Nandrolone (Decanoate, Phenylpropionate), Dexamethasone

[1304] - Gonadotropin-releasing hormone agonists or antagonists, such as Abarelix, Goserelin Acetate, Histrelin Acetate, Leuprolide Acetate

[1305] - Thalidomide, Lenalidomide

[1306] - Mercaptopurine, Mitotane, Pamidronate, Pegademase, Pegaspargase, Rasburicase

[1307] - BH3 mimetics, such as ABT-737

[1308] - MEK inhibitors, such as PD98059, AZD6244, CI-1040

[1309] - Colony-stimulating factor analogs, such as Filgrastim, Pegfilgrastim, Sargramostim; Erythropoietin or its analogs (e.g., darbepoetin alfa); Interleukin 11; Oprelvekin; Zoledronate, Zoledronic acid; Fentanyl; Bisphosphonates; Palifermin

[1310] - Steroid cytochrome P450 17α-hydroxylase-17,20-lyase inhibitors (CYP17), such as Abiraterone, Abiraterone Acetate

[1311] - Glycolysis inhibitors, such as 2-Deoxyglucose

[1312] - mTOR inhibitors such as Rapamycin and Rapamycin analogs (rapalog), and mTOR kinase inhibitors

[1313] - PI3K inhibitors and dual mTOR / PI3K inhibitors

[1314] - Autophagy inhibitors, such as Chloroquine and Hydroxychloroquine

[1315] - Antibodies that reactivate the immune response against tumors, such as Nivolumab (anti-PD-1), Lambrolizumab (anti-PD-1), Ipilimumab (anti-CTLA4) and MPDL3280A (anti-PD-L1).

[1316] The present invention further relates to a product which contains a compound according to the invention as a first active ingredient and one or more anti-cancer agents as another active ingredient, and is used in the form of a combined preparation for simultaneous, separate or sequential use in treating a patient suffering from cancer.

[1317] One or more other medicaments and the compound according to the invention can be administered simultaneously (e.g., in the form of a separate or combined composition) or sequentially in any order. In the latter case, two or more compounds will be administered over a period of time and in amounts and in a manner sufficient to ensure an advantageous or synergistic effect. It should be understood that the preferred method and order of administration of each component of the combination, as well as the corresponding dosage and regimen, will depend on the specific other medicament and the compound of the invention being administered, its route of administration, the specific tumor being treated, and the specific host being treated. The optimal method and order of administration, as well as the dosage and regimen, can be readily determined by those skilled in the art using conventional methods and in view of the information presented herein.

[1318] When administered in combination, the weight ratio of the compound according to the invention to one or more other anti-cancer agents can be determined by a person of ordinary skill in the art. As is well known to those skilled in the art, the ratio, as well as the exact dosage and frequency of administration, depend on the specific compound according to the invention and the other one or more anti-cancer agents used, the specific condition being treated, the severity of the condition being treated, the age, weight, sex, diet, time of administration, and general physical condition of the specific patient, the mode of administration, and other drugs that the individual can take. In addition, it is obvious that the effective daily dosage can be reduced or increased, depending on the response of the subject being treated and / or depending on the assessment of the doctor prescribing the compound of the invention. The specific weight ratio of the compound of formula (I) of the present invention to another anti-cancer agent can be in the range of 1 / 10 to 10 / 1, more particularly 1 / 5 to 5 / 1, and even more particularly 1 / 3 to 3 / 1.

[1319] In each treatment course, the platinum coordination compound is advantageously administered at a dose of 1 to 500 mg per square meter (mg / m 2 ) of body surface area, for example 50 to 400 mg / m 2 , and in particular for cisplatin, at a dose of about 75 mg / m 2 , and for carboplatin, at a dose of about 300 mg / m 2 .

[1320] In each treatment course, the taxane compound is advantageously administered at a dose of 50 to 400 mg per square meter (mg / m 2 ) of body surface area, for example 75 to 250 mg / m 2 , and in particular for paclitaxel, about 175 to 250 mg / m 2administered at a dose of, and for docetaxel, about 75 to 150 mg / m 2 administered.

[1321] For each course of treatment, the camptothecin compound is advantageously administered at a dose of 0.1 to 400 mg per square meter (mg / m 2 ), body surface area, for example 1 to 300 mg / m 2 administered at a dose of, particularly for irinotecan, about 100 to 350 mg / m 2 administered at a dose of, and for topotecan, about 1 to 2 mg / m 2 administered.

[1322] For each course of treatment, the antitumor podophyllotoxin derivative is advantageously administered at a dose of 30 to 300 mg per square meter (mg / m 2 ), body surface area, for example 50 to 250 mg / m 2 administered at a dose of, particularly for etoposide, about 35 to 100 mg / m 2 administered at a dose of, and for teniposide, about 50 to 250 mg / m 2 administered.

[1323] For each course of treatment, the antitumor vinca alkaloid is advantageously administered at a dose of 2 to 30 mg per square meter (mg / m 2 ), body surface area, particularly for vinblastine, at a dose of about 3 to 12 mg / m 2 administered at a dose of, for vincristine, at a dose of about 1 to 2 mg / m 2 administered at a dose of, and for vinorelbine, about 10 to 30 mg / m 2 administered at a dose of.

[1324] For each course of treatment, the antitumor nucleoside derivative is advantageously administered at a dose of 200 to 2500 mg per square meter (mg / m 2 ), body surface area, for example 700 to 1500 mg / m 2 administered at a dose of, particularly for 5-FU, at a dose of 200 to 500 mg / m 2 administered at a dose of, for gemcitabine, at a dose of about 800 to 1200 mg / m 2 administered at a dose of, and for capecitabine, at a dose of about 1000 to 2500 mg / m 2 administered.

[1325] For each course of treatment, the alkylating agent (such as nitrogen mustard or nitrosourea) is advantageously administered at a dose of 100 to 500 mg per square meter (mg / m 2 ), body surface area, for example 120 to 200 mg / m 2 administered at a dose of, particularly for cyclophosphamide, at a dose of about 100 to 500 mg / m 2administered at a dose of, for chlorambucil, administered at a dose of about 0.1 to 0.2 mg / kg, for carmustine, at a dose of about 150 to 200 mg / m 2 administered at a dose of, and for lomustine, at a dose of about 100 to 150 mg / m 2 administered at a dose of.

[1326] For each course of treatment, the anti-tumor anthracycline derivatives are advantageously administered at a dose of 10 to 75 mg per square meter (mg / m 2 ) of body surface area, such as 15 to 60 mg / m 2 administered at a dose of, particularly for doxorubicin, at a dose of about 40 to 75 mg / m 2 administered at a dose of, for daunorubicin, at a dose of about 25 to 45 mg / m 2 administered at a dose of, and for idarubicin, at a dose of about 10 to 15 mg / m 2 administered at a dose of.

[1327] The anti-estrogen agents are advantageously administered at a dose of about 1 to 100 mg per day, depending on the particular agent and the condition being treated. Tamoxifen is advantageously administered orally twice a day at a dose of 5 to 50 mg, preferably 10 to 20 mg, for a sufficient time to achieve and maintain a therapeutic effect. Toremifene is advantageously administered orally once a day at a dose of about 60 mg for a sufficient time to achieve and maintain a therapeutic effect. Anastrozole is advantageously administered orally once a day at a dose of about 1 mg. Droloxifene is advantageously administered orally once a day at a dose of about 20 - 100 mg. Raloxifene is advantageously administered orally once a day at a dose of about 60 mg. Exemestane is advantageously administered orally once a day at a dose of about 25 mg.

[1328] The antibodies are advantageously administered at a dose of about 1 to 5 mg per square meter (mg / m 2 ) of body surface area, or if different, as known in the art. For each course of treatment, trastuzumab is advantageously administered at a dose of 1 to 5 mg per square meter (mg / m 2 ) of body surface area, particularly 2 to 4 mg / m 2 administered at a dose of.

[1329] These doses may be administered, for example, once, twice or more times per course of treatment, and the course of treatment may be repeated, for example, every 7, 14, 21 or 28 days.

[1330] The following examples illustrate the invention. If no specific stereochemistry is indicated for a stereocenter of a compound, this means that a mixture of the R and S enantiomers of the compound is obtained. If more than one stereocenter appears in a structure, each stereocenter for which no specific stereochemistry is indicated is obtained as a mixture of R and S.

[1331] Those skilled in the art will recognize that typically after column purification, the desired fractions are collected and the solvent is evaporated to obtain the desired compound or intermediate.

[1332] Example

[1333] As used hereinafter, the terms "rt", "r.t.", or "RT" mean room temperature; "Me" means methyl; "MeOH" means methanol; "Et" means ethyl; "EtOH" means ethanol; "NaH" means sodium hydride; "Boc" means tert-butoxycarbonyl; "(BOC)2O" means di-tert-butyl dicarbonate; "EtOAc" means ethyl acetate; "Et2O" means diethyl ether; "Et3N" means triethylamine; "DCM" means dichloromethane; "q.s." means a sufficient quantity; "Int." means intermediate; "MeCN" or "ACN" means acetonitrile; "DMF" means N,N-dimethylformamide; "PdCl2(dppf)" means dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II); "THF" means tetrahydrofuran; "IPA" or "iPrOH" means 2-propanol; "LC" means liquid chromatography; "LCMS" means liquid chromatography / mass spectrometry; "HPLC" means high performance liquid chromatography; "TFA" means trifluoroacetic acid; "RP" means reverse phase; "Min" means minute; "h" means hour; "v / v" means volume ratio; “diatomaceous earth” means diatomaceous earth; “DMSO” means dimethyl sulfoxide; “SFC” means supercritical fluid chromatography; “DIPE” means diisopropyl ether; “DIPEA” means N,N - diisopropylethylamine; “PPh3” means triphenylphosphine; “Pd2(dba)3” means tris(dibenzylideneacetone)dipalladium; “DIAD” means diisopropyl azodicarboxylate; “TBAF” means tetrabutylammonium fluoride; “psi” means pounds per square inch; “eq.” means equivalent; “Pd(OAc)2” means palladium(II) acetate; “DMAP” means 4 - (dimethylamino)pyridine; “t - BuOK” or “KOtBu” means potassium tert - butoxide; “Dess - Martin periodinane” means 1,1,1 - triacetoxy - 1,1 - dihydro - 1,2 - benziodoxol - 3(1H) - one; “TBDMSCl” means tert - butyldimethylsilyl chloride; “Bn” means benzyl; “9 - BBN” means 9 - borabicyclo[3.3.1]nonane; “Pd - 118” means dichloro[1,1'-bis(di - tert - butylphosphino)ferrocene]palladium(II); “Tf2O” means trifluoromethanesulfonic anhydride; “TBDMS” means tert - butyldimethylsilyl; “TMSCl” means trimethylsilyl chloride; “BuLi” means n - butyllithium; “aq.” means aqueous; “NaOMe” means sodium methoxide; “tBuOH” means tert - butanol; “n - BuOH” means n - butanol; “NaHMDS” means sodium bis(trimethylsilyl)amide; means N - methyl - N - (p - toluenesulfonyl)nitrosamide; “Ts” or “Tos” means p - toluenesulfonyl.

[1334] Intermediates and compounds with substituents containing double bonds (which can be in the E or Z configuration) are shown in the following experimental section as a specific configuration. However, unless explicitly indicated by E or Z, it is not determined whether these intermediates and compounds are obtained in the E or Z configuration or as a mixture of the two configurations. For example, intermediates 86, 90, 91, and 139 may be in the E or Z configuration, or may be a mixture thereof.

[1335] For example, compounds 30, 34, 35, 36, and 37 are obtained in the E configuration and are explicitly indicated as E as in the following experimental section.

[1336] A. Preparation of Intermediates

[1337] Example A1

[1338] Preparation of Intermediate 1

[1339]

[1340] At 25 °C, under N2, Et3N (13.4 g, 132 mmol) was added in one portion to a mixture of 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (14.0 g, 52.8 mmol) and (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol hydrochloride (10.7 g, 58.1 mmol) in propan-2-ol / H2O (208 mL, 7:1). The mixture was stirred at 90 °C for 23 h. The mixture was cooled to 50 °C and 4 M HCl (24 mL, 106 mmol) was added slowly. Then the residue was stirred at 50 °C for 2 h. The mixture was cooled to 25 °C and NaHCO3 (14 g, 100 mmol) was added slowly. Ethyl acetate (230 mL) was added, followed by semi-saturated NaHCO3 solution (an appropriate amount). The organic layer was separated and the aqueous phase was extracted with ethyl acetate (230 mL x 2). The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated in vacuo to give Intermediate 1 as a yellow solid (17.4 g, quantitative yield, in 2 steps). The crude product was used directly as such without further purification in the next reaction step.

[1341] Example A2

[1342] Preparation of Intermediate 2

[1343]

[1344] At 25 °C, under N2, 2,2-dimethoxypropane (11.0 g, 105 mmol) and TsOH.H2O (908 mg, 5.27 mmol) were added in one portion to a mixture of Intermediate 1 (17.4 g, 52.7 mmol) in acetone (250 mL). The mixture was stirred at 60 °C for 2 h. The mixture was cooled to 25 °C and the solution was partially concentrated in vacuo, quenched by slow addition of saturated NaHCO3 (100 mL) and then extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient elution: from 1 / 0 to 2 / 1 DCM / ethyl acetate) to give Intermediate 2 as a pale yellow gum (15.5 g, 89% yield).

[1345] Example A3

[1346] Preparation of Intermediate 3

[1347]

[1348] Intermediate 3

[1349] At 0 °C, under N2, Dess-Martin periodinane (4.85 g, 11.4 mmol) was added to a mixture of intermediate 2 (2.85 g, 8.8 mmol) in DCM (130 mL). The mixture was stirred at room temperature for 2 h. The mixture was treated with Na2S2O3 (15 g) dissolved in saturated NaHCO3 solution (65 mL) and stirred for an additional 30 min. The layers were separated, and the aqueous phase was extracted with DCM (50 mL x 3). The combined organic phases were washed with saturated NaHCO3 solution (65 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give crude intermediate 3 (2.9 g), which was used directly in the next reaction step without further purification.

[1350] Example A4

[1351] Preparation of Intermediate 4

[1352]

[1353] Method 1

[1354] At 0 °C, under N2, t-BuOK (11.4 mL, 1 M in THF, 1.27 g, 11.35 mmol) was added dropwise to a mixture of methyltriphenylphosphonium bromide (4.87 g, 13.62 mmol) in THF (500 mL). The suspension turned bright yellow and was stirred at 0 °C for 0.5 h, and then warmed to 25 °C and kept for 0.5 h. The mixture was cooled to -40 °C. A solution of intermediate 3 (1.46 g, theoretically 4.54 mmol) in THF (130 mL) was added dropwise, and then the mixture was stirred at -20 °C for 1 h. After that, the mixture was warmed to 25 °C and kept for 2 h. Saturated NH4Cl (300 ml) was added to the mixture and the mixture was stirred for 10 min. The layers were separated and the aqueous phase was extracted with DCM (300 mL x 2). The combined organic phases were washed with saturated brine (500 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography ( 80 g Flash silica gel column, gradient elution: 0% to 15% ethyl acetate / petroleum ether). The desired fractions were collected and the solvent was evaporated. Intermediate 4 (530 mg, 36% yield) was obtained as an off-white solid.

[1355] Method 2

[1356] Under N2, within 30 minutes, a solution of bis(iodo)methane in THF (180 mL, 0.31 M, 55.9 mmol, prepared according to the method described in Tetrahedron 2002, 58, 8255 - 8262) was added dropwise to a solution of intermediate 3 (10.0 g, theoretically 31.1 mmol) in THF (100 mL). Stirring was continued until complete conversion (about 2 hours). The reaction mixture was quenched by the slow addition of saturated aqueous NH4Cl solution, during which the formation of salt could be observed. Before extraction (EtOAc, 2 x 200 mL), the salt was redissolved by the addition of aqueous ammonia solution (25%). The combined organic phases were washed with aqueous sodium bisulfite solution and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: dichloromethane / EtOAc 95 / 5) to afford intermediate 4 as an off-white solid (6.9 g, 66%).

[1357] Method 3

[1358] Step 1

[1359] Preparation of Intermediate 5

[1360]

[1361] Intermediate 5

[1362] Under a nitrogen atmosphere, acetylacetonatobis(ethylene)rhodium(I) (0.837 g, 3.24 mmol) and (R)-N,N-dimethylbinaphtho[2,1-d:1’,2’-f][1,3,2]dioxaphosphepine-4-amine (2.91 g, 8.11 mmol) were dissolved in EtOH (625 mL). The mixture was stirred at room temperature and flushed with nitrogen for 15 minutes. Then (-)-(3aR,6aR)-3a,6a-dihydro-2,2-dimethyl-4H-cyclopenta[1,3]dioxol-4-one (25 g, 162.16 mmol) and potassium vinyltrifluoroborate (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 to room temperature. The precipitate was filtered out through a pad and washed with ethanol. The solvent of the filtrate was evaporated. 1 L of heptane was added to the residue. The resulting suspension was filtered through a pad and washed with heptane to afford a dark brown solid residue. The filtrate was washed three times with 300 mL of NH4OH, washed with brine, dried over MgSO4, filtered and the solvent of the filtrate was evaporated to give intermediate 5 (16.18 g, 51% yield).

[1363] Step 2

[1364] Preparation of Intermediate 6

[1365]

[1366] Intermediate 6

[1367] At -78 °C, under a nitrogen atmosphere, a solution of Intermediate 5 (16.18 g, 82.58 mmol) in THF (200 mL) was added dropwise to a stirred solution of lithium aluminum hydride (24.78 mL, 1 M, 24.78 mmol) in THF (400 mL). The reaction mixture was stirred at -78 °C for 30 minutes under a nitrogen atmosphere. The reaction was quenched by dropwise addition of acetone (6.1 mL) and then 50 mL of water at -78 °C. After addition, the reaction mixture was warmed to room temperature and then 400 mL of EtOAc was added. The mixture was shaken vigorously. The organic layer was separated, washed three times with water, washed with brine, dried over MgSO4, filtered and the solvent of the filtrate was evaporated. The residue was dissolved in ethyl acetate and purified as follows: on an Armen Spot II final purification system through a SiO2 column (column type Grace Reveleris SRC, 80 g, Si 40), using ethyl acetate and heptane as eluents, with a gradient starting from 100% heptane and ending with 50% heptane and 50% ethyl acetate. The fractions containing the product were combined and the solvent was evaporated to obtain Intermediate 6 (10.77 g, 71% yield).

[1368] Step 3

[1369] Preparation of Intermediate 7

[1370]

[1371] Intermediate 7

[1372] At 0 °C, a solution of Tf2O (13.3 mL, 80.9 mmol) in anhydrous DCM (60 mL) was added dropwise to a mixture of intermediate 6 (9.94 g, 53.95 mmol) and anhydrous pyridine (85 mL) in anhydrous DCM (140 mL). The reaction mixture was stirred for 30 minutes and then 75 mL of cold water was added. The layers were separated and the organic layer was washed three times with 75 mL of water, dried over MgSO4, filtered and the solvent was evaporated and co-evaporated with 200 mL of toluene. The residue was dissolved in heptane and ethyl acetate and purified as follows: on an Armen Spot II final purification system through a SiO2 column (column type Grace Reveleris SRC, 40 g, Si 40), using ethyl acetate and heptane as eluents, with a gradient starting from 100% heptane and ending with 50% heptane and 50% ethyl acetate. The fractions containing the product were combined and the solvent was evaporated to give intermediate 7 (13.0 g, 67% yield).

[1373] The following intermediates were prepared using a reaction scheme similar to that used for the preparation of intermediate 7, using appropriate starting materials (Table 1).

[1374] Table 1:

[1375]

[1376] Step 4

[1377] Preparation of Intermediate 8

[1378]

[1379] Intermediate 8

[1380] A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (100 g, 651 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 solvent was evaporated. The residue was triturated in DIPE. The white solid was filtered off and dried in vacuo at 30 °C to give intermediate 8 (112.6 g, 90% yield).

[1381] Step 5

[1382] Preparation of Intermediate 4

[1383]

[1384] At 0 °C, a solution of intermediate 7 (13 g, 41.1 mmol) in DMF (50 mL) was added dropwise to a stirred solution of intermediate 8 (7.88 g, 41.1 mmol) in DMF (150 mL). After the addition, the reaction mixture was warmed to room temperature and then stirred for 18 h. An additional amount of intermediate 8 (1.57 g, 8.22 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into a beaker containing ice and water (ca. 0.5 L). The resulting suspension was stirred for 2 h and then filtered. The filter cake was washed three times with water and then dried in vacuo at 50 °C to give intermediate 4 (8.75 g, 65% yield) as a white solid.

[1385] The following intermediates were prepared using a reaction scheme similar to that used for the preparation of intermediate 4, using appropriate starting materials (Table 2).

[1386] Table 2:

[1387]

[1388] Example A5

[1389] Preparation of intermediate 9

[1390]

[1391] Intermediate 9

[1392] At 110 °C, a solution of intermediate 4 (18.3 g, 57.22 mmol) in a mixture of aqueous ammonia (25%, 100 ml) and THF (100 ml) was heated inside a sealed metal pressure vessel until complete conversion (ca. 16 h). The reaction mixture was allowed to cool to room temperature, after which ethyl acetate and brine were added. The layers were separated and the aqueous layer was extracted once with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give intermediate 9 (17.2 g, 100%) as a pale yellow solid, which was used in the next reaction step without further purification.

[1393] The following intermediates were prepared using a reaction scheme similar to that used for the preparation of intermediate 9, using appropriate starting materials (Table 3).

[1394] Table 3:

[1395]

[1396] Example A31

[1397] Preparation of intermediate 96

[1398] Step 1

[1399]

[1400] Intermediate 95

[1401] A solution of cuprous iodide (43.7 g, 228 mmol) and lithium chloride (9.68 g, 228 mmol) in THF (320 mL) was stirred at room temperature for 5 minutes and then cooled to -78 °C under a nitrogen atmosphere. A solution of 1 M allylmagnesium bromide in Et2O (220 mL, 1 M, 220 mmol) was added dropwise to the solution over 20 minutes. After stirring the reaction for 30 minutes, TMSCl (30 mL, 235 mmol) and hexamethylphosphoramide (42 mL, 241 mmol) were added, and then (-)-(3aR,6aR)-3a,6a-dihydro-2,2-dimethyl-4H-cyclopenta[1,3]dioxol-4-one (12.8 g, 83.0 mmol) in THF (110 mL) was added dropwise. After addition, the reaction mixture was stirred for 2 hours, warmed to 0 °C and quenched with saturated aqueous NH4Cl (100 mL). After adding EtOAc (1 L), the organic layer was separated, washed with water (200 mL) and brine (200 mL), and then dried over MgSO4. The solvent was evaporated under reduced pressure. The residue was purified as follows: on a Grace Reveleris X2 purification system using a Grace Reveleris SRC column (column type, 180 g, Si 40), with heptane and ethyl acetate as eluents, with a gradient starting from 100% heptane up to 70% heptane and 30% ethyl acetate. The fractions containing the product were combined and the solvent was evaporated to give Intermediate 95 (8.00 g, 47% yield).

[1402] The following intermediates were prepared using a reaction scheme similar to that used for the preparation of Intermediate 95, using appropriate starting materials (Table 4).

[1403] Table 4:

[1404]

[1405] Step 2

[1406]

[1407] Intermediate 96

[1408] At 0 °C, under a nitrogen atmosphere, a solution of intermediate 95 (8 g, 39.5 mmol) in THF (40 mL) was added dropwise to a stirred solution of lithium bromide (5.931 mL, 2 M, 11.86 mmol) in THF (40 mL). After the addition, the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding 8 mL of water, then 15 mL of aqueous NaOH solution (1 N), and then 8 mL of water. The resulting solid was filtered off, and the solvent of the filtrate was diluted with ethyl acetate. The organic layer was washed with water, washed with brine, dried over MgSO4, filtered, and the solvent of the filtrate was evaporated to give intermediate 96 (7.41 g, 92% yield).

[1409] The following intermediates were prepared using a reaction scheme similar to that used for the preparation of intermediate 96, using appropriate starting materials (Table 5).

[1410] Table 5:

[1411]

[1412] Example A26

[1413] Preparation of Intermediate 42

[1414] Step 1

[1415] Preparation of Intermediate 39

[1416]

[1417] Intermediate 39

[1418] Intermediate 2 (10 g, 30.5 mmol) was stirred in a mixture of THF (100 ml) and 28% aqueous NH4OH solution (100 ml) in an autoclave at 120 °C for 2 days. The volatiles were evaporated in vacuo. The aqueous layer was extracted several times with DCM / MeOH 90 / 10. The combined organic layers were concentrated under reduced pressure. The crude product was redissolved in the minimum amount of MeOH, and toluene was added thereto. The resulting solution was concentrated again, and this process was repeated twice until intermediate 39 (10.2 g, 100% yield) as a solid product was obtained, which was used as such in the next step.

[1419] Step 2

[1420] Preparation of Intermediate 40

[1421]

[1422] Intermediate 40

[1423] A solution of TBDMSCl (7.6 g, 50.2 mmol, 1.5 equiv) in DMF (50 mL) was added dropwise to a reaction flask containing intermediate 39 (10.2 g, 33.5 mmol), imidazole (4.6 g, 67.0 mmol, 2.0 equiv) and DMF (120 mL). The resulting reaction mixture was stirred overnight at room temperature. Water was added and the mixture was extracted with diethyl ether. The combined organic layers were washed with water, dried over MgSO4, and concentrated under reduced pressure to give intermediate 40 (10.4 g, 74% yield).

[1424] Step 3

[1425] Preparation of Intermediate 41

[1426]

[1427] Intermediate 41

[1428] A solution of (Boc)2O (20.0 g, 86.9 mmol, 3.5 equiv) in THF (40 mL) was added dropwise to a reaction flask containing intermediate 40 (10.4 g, 24.8 mmol), DMAP (607 mg, 5.0 mmol, 0.2 equiv) and THF (85 mL). The resulting reaction mixture was stirred at room temperature for 4 h. Subsequently, TBAF (1 M in THF, 42.2 mL, 42.2 mmol, 1.7 equiv) was added dropwise and stirring was continued until complete conversion was observed. The reaction mixture was poured into water and extracted once with diethyl ether. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography (30% to 0% gradient of heptane in ethyl acetate) to give intermediate 41 (12.1 g, 96% yield).

[1429] The following intermediates were prepared using a reaction scheme similar to that used for the preparation of intermediate 41, using appropriate starting materials (Table 6).

[1430] Table 6:

[1431]

[1432] Step 4

[1433] Preparation of Intermediate 42

[1434]

[1435] Intermediate 42

[1436] At 0 °C, p-toluenesulfonyl chloride (5.1 g, 26.7 mmol) was added portionwise to a solution of Intermediate 41 (9.0 g, 17.8 mmol), Et3N (4.5 g, 44.5 mmol, 2.5 eq), and DMAP (218 mg, 1.8 mmol, 0.1 eq) in CH2Cl2 (50 mL). The reaction mixture was stirred overnight at room temperature. Water was added, the organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (5% EtOH in CH2Cl2) to give Intermediate 42 (10.6 g, 90% yield).

[1437] Example A6

[1438] Preparation of Intermediate 13

[1439] Step 1

[1440] Preparation of Intermediate 10

[1441]

[1442] Intermediate 10

[1443] Under a nitrogen atmosphere, a solution of benzyl alcohol (18.2 g, 168 mmol, 1.0 eq) in DMF (100 mL) was added dropwise to a suspension of NaH (60% dispersion in mineral oil, 6.5 g, 168 mmol, 1.0 eq) in DMF (300 mL). The reaction mixture was stirred for an additional 30 minutes at room temperature. A solution of 2,4-dichloropyridine (24.9 g, 168 mmol, 1.0 eq) in DMF (100 mL) was added dropwise. The reaction mixture was stirred for 2 h, then an additional portion of NaH (60% dispersion in mineral oil, 1.3 g, 33.6 mmol, 0.2 eq) was added. Stirring was continued until complete conversion. After completion, the reaction mixture was quenched by the slow addition of water and extracted with diethyl ether. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The crude product was suspended in heptane, filtered, and dried under high vacuum to give Intermediate 10 (19.3 g, 52% yield).

[1444] Step 2

[1445] Preparation of Intermediate 11

[1446]

[1447] Intermediate 11

[1448] Under a nitrogen atmosphere, LiHMDS (105.4 mL, 1 M THF solution, 105.4 mmol) was added to a solution of Intermediate 10 (19.3 g, 87.9 mmol), Pd2(dba)3 (2.0 g, 2.2 mmol, 0.025 equiv), and 2-dicyclohexylphosphino biphenyl (2.5 g, 5.2 mmol, 0.06 equiv) in anhydrous THF (90 mL). The resulting mixture was stirred at 65 °C for 1 h. Then the reaction was cooled to room temperature and 1 N aqueous HCl was added. After vigorous stirring for 5 min, the reaction mixture was neutralized with saturated Na2CO3 and extracted with CH2Cl2. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The crude product was suspended in isopropyl ether and stirred at reflux temperature for 15 min, then cooled to room temperature overnight. The precipitate was filtered off and dried under high vacuum to give Intermediate 11 (14.7 g, 82% yield).

[1449] Step 3

[1450] Preparation of Intermediate 12

[1451]

[1452] Intermediate 12

[1453] Chloroacetone (1.75 mL, 22.0 mmol, 1.1 equiv) was added dropwise to a solution of Intermediate 11 (4.0 g, 20.0 mmol) in EtOH (20 mL). The reaction mixture was stirred at reflux temperature overnight. The residue obtained after concentrating the reaction mixture under reduced pressure was dissolved in a mixture of ethyl acetate and water. The organic layer was separated, and the aqueous layer was further extracted with CH2Cl2 (+MeOH). The combined organic phases (ethyl acetate and CH2Cl2 (+MeOH)) were concentrated under reduced pressure. The crude product was purified by silica gel chromatography (1% to 6% gradient of MeOH in CH2Cl2) to give Intermediate 12 (1.95 g, 42% yield).

[1454] Step 4

[1455] Preparation of Intermediate 13

[1456]

[1457] Intermediate 13

[1458] A solution of Intermediate 12 (2.2 g, 9.2 mmol) in methanol was hydrogenated at atmospheric pressure for 2 h using Pd (10% carbon, 491 mg, 0.46 mmol, 0.05 equiv) as a catalyst. The reaction mixture was filtered through Filtered and the filtrate concentrated under reduced pressure to give Intermediate 13 as a brown solid (1.4 g, 100% yield).

[1459] The following intermediates were prepared using appropriate starting materials by a reaction scheme similar to that used for the preparation of Intermediate 12 and Intermediate 13 (Table 7).

[1460] Table 7:

[1461]

[1462] Example A7

[1463] Preparation of Intermediate 18

[1464] Step 1

[1465] Preparation of Intermediate 15

[1466]

[1467] Intermediate 15

[1468] A mixture of Intermediate 11 (5.0 g, 25.0 mmol) and (Boc)2O (6.0 g, 27.5 mmol, 1.1 equiv) in tBuOH (55 mL) was stirred at 50 °C for 1 h. The reaction mixture was cooled to room temperature and diluted with ethanol, the precipitate was filtered off and dried under high vacuum to give Intermediate 15 (6.0 g, 80% yield).

[1469] The following intermediates were prepared by a reaction scheme similar to that used for the preparation of Intermediate 15 and using suitable starting materials (Table 8).

[1470] Table 8:

[1471]

[1472]

[1473] Step 2

[1474] Preparation of Intermediate 16

[1475]

[1476] Intermediate 16

[1477] At room temperature, under a nitrogen atmosphere, NaH (1.1 g, a 60% dispersion in mineral oil, 30.0 mmol, 1.4 equiv) was added portionwise to a solution of Intermediate 15 (6.0 g, 20.0 mmol) in anhydrous DMF (80 mL). After the addition, the reaction mixture was stirred for an additional 10 min. Propargyl bromide (3.1 mL, 30.0 mmol, 1.4 equiv) was added and stirring was continued until complete conversion. The reaction was quenched by the addition of water and extracted with diethyl ether. The combined organic phases were washed with water, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0% to 1.5% gradient of MeOH in CH2Cl2) to give Intermediate 16 (4.9 g, 72.5% yield).

[1478] The following intermediates were prepared by a reaction scheme similar to that used for the preparation of Intermediate 16 and using appropriate starting materials (Table 9).

[1479] Table 9:

[1480]

[1481] Step 3

[1482] Preparation of Intermediate 17

[1483]

[1484] Intermediate 17

[1485] KOtBu (1.9 g, 17.0 mmol, 1.2 equiv) was added to a solution of Intermediate 16 (4.8 g, 14.2 mmol) in THF (145 mL). The reaction mixture was stirred at room temperature until complete conversion (usually about 30 min). Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The product was purified by silica gel chromatography (1% to 4% gradient of MeOH in CH2Cl2) to give Intermediate 17 (2.1 g, 62% yield).

[1486] The following intermediates were prepared by a reaction scheme similar to that used for the preparation of Intermediate 17 and using appropriate starting materials (Table 10).

[1487] Table 10:

[1488]

[1489] Step 4

[1490] Preparation of Intermediate 18

[1491]

[1492] Intermediate 18

[1493] A solution of Intermediate 17 (2.1 g, 8.8 mmol) in methanol was hydrogenated at atmospheric pressure for 2 h using Pd (10% carbon, 470 mg, 0.44 mmol, 0.05 eq) as a catalyst. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give Intermediate 18 (1.27 g, 97% yield).

[1494] Example A8

[1495] Preparation of Intermediate 29

[1496] Step 1

[1497] Preparation of Intermediate 28

[1498]

[1499] Intermediate 28

[1500] Under nitrogen, NaHMDS (27.1 mL of 2 M THF solution, 54.2 mmol, 2.5 eq) was added dropwise to a cold mixture of 2-amino-4-bromo-3-chloropyridine (4.5 g, 21.7 mmol) and (Boc)2O (5.9 g, 26.0 mmol, 1.2 eq) in anhydrous THF (165 mL). The resulting suspension was warmed to room temperature and stirred until complete conversion (usually about 1 h). Anhydrous DMF (165 mL) was added, followed by propargyl bromide (3.4 mL, 30.4 mmol, 1.4 eq). The reaction mixture was stirred overnight, quenched with water, and extracted with ether. The combined organic phases were washed with water, dried over MgSO4, and concentrated under reduced pressure to give the crude product. The product was purified by silica gel chromatography (heptane solution of 10% ethyl acetate) to give Intermediate 28 (6.4 g, 85% yield).

[1501] Step 2

[1502] Preparation of Intermediate 29

[1503]

[1504] Intermediate 29

[1505] ​KOtBu (2.6 g, 23.1 mmol, 1.25 equiv) was added to a solution of intermediate 28 (6.4 g, 18.5 mmol) in THF (90 mL). The reaction mixture was stirred at room temperature until complete conversion (usually about 30 min). Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. Intermediate 29 (565 mg, 12.5% yield) was isolated after two successive purifications by silica gel chromatography (first run: 0% to 1.5% gradient of MeOH in CH2Cl2, second run: 50% ethyl acetate in heptane).

[1506] Example A9

[1507] Preparation of Intermediate 32

[1508] Step 1

[1509] Preparation of Intermediate 30

[1510]

[1511] Intermediate 30

[1512] A solution of 2-amino-4-bromopyridine (10.0 g, 57.8 mmol) and 2-bromomalonaldehyde (10.5 g, 69.4 mmol, 1.2 equiv) in EtOH (200 mL) was stirred at reflux temperature overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was suspended in CH2Cl2, the precipitate was filtered off and dried under high vacuum to give intermediate 30 (8.8 g, 67% yield), which was used as such in the next step.

[1513] Step 2

[1514] Preparation of Intermediate 31

[1515]

[1516] Intermediate 31

[1517] A reaction flask containing methyltriphenylphosphonium bromide (30 g, 84.0 mmol, 1.9 eq) and THF (450 mL) was cooled to -78 °C. A solution of KOtBu in THF (1 M, 111 mL, 111 mmol, 2.5 eq) was added thereto, and the resulting suspension was stirred at -78 °C for 30 min. A solution of intermediate 30 (10 g, 44.4 mmol) in THF (50 mL) was added dropwise, and the reaction mixture was stirred at -78 °C for 2 h and then warmed to room temperature and stirred for another 2 h. Quenching was carried out using saturated NH4Cl, and extraction was performed with CH2Cl2. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified by silica gel chromatography (5% to 100% gradient of ethyl acetate in petroleum ether) to give intermediate 31 (6.4 g, 85% yield) as a white solid.

[1518] Step 3

[1519] Preparation of Intermediate 32

[1520]

[1521] Intermediate 32

[1522] Intermediate 31 (1.1 g, 4.5 mmol) was dissolved in a freshly prepared ethereal diazomethane solution (400 mL) from (20 g, 93 mmol, 20.0 eq). The reaction mixture was cooled in an ice bath, and Pd(OAc)2 (100 mg, 0.44 mmol, 0.1 eq) was added. The reaction mixture was stirred at room temperature overnight. Volatiles were removed under reduced pressure, and the desired product was separated by silica gel chromatography (5% to 100% gradient of ethyl acetate in petroleum ether). Final purification was carried out using a preparative reverse-phase HPLC column type: Kromasil 150x 25 mm, 10 μm, conditions: A: water (0.05% ammonium hydroxide v / v); B: MeCN, at the start: A (61%) and B (39%); at the end: A: (61%) and B (39%), gradient time (min) 8; 100% B retention time (min) 2; flow rate (ml / min) 30, to obtain intermediate 32 (160 mg, 15% yield) as a white solid.

[1523] Example A10

[1524] Preparation of Intermediate 34

[1525] Step 1

[1526] Preparation of Intermediate 33

[1527]

[1528] Intermediate 33

[1529] A solution of carbamic acid, N-(7-bromoimidazo[1,2-a]pyridin-2-yl)-, 1,1-dimethylethyl ester (740 mg, 2.37 mmol) in methanol hydrochloride (15 mL of 4 M solution, 60 mmol, 25 eq) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, the resulting residue was basified with ammonia and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to give Intermediate 33 as a white solid (500 mg, 99% yield).

[1530] Step 2

[1531] Preparation of Intermediate 34

[1532]

[1533] Intermediate 34

[1534] At 0 °C, acetyl chloride (201 μL, 2.83 mmol, 1.2 eq) was added to a solution of Intermediate 33 (500 mg, 2.36 mmol) and Et3N (492 μL, 3.54 mmol, 1.5 eq) in CH2Cl2. The resulting reaction mixture was stirred at 0 °C for 30 min. Water was added, the organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give Intermediate 34 (700 mg, 97% yield).

[1535] Example A11

[1536] Preparation of Intermediate 35

[1537]

[1538] At 0 °C, under a N2 atmosphere, 60% NaH in mineral oil (82 mg, 2 mmol) was added portionwise to a solution of 1H-pyrrolo[3,2-b]pyridine, 2-iodo- (500 mg, 2 mmol) in DMF (20 ml). The mixture was stirred for 0.5 h. Then dimethyl sulfate (0.32 g, 2.54 mmol) was added dropwise to the mixture over 30 min. The mixture was then stirred at room temperature for 2 h. The mixture was treated with water and extracted with ethyl acetate. The organic layer was filtered, washed with brine and dried over Na2SO4. The organic phase was concentrated to give Intermediate 35 as a yellow solid (400 g, 57% yield).

[1539] The following intermediates were prepared using suitable starting materials by a reaction scheme similar to that used for the preparation of Intermediate 35 (Table 11).

[1540] Table 11:

[1541]

[1542] Example A12

[1543] Preparation of Intermediate 37

[1544]

[1545] At -78 °C under a N2 atmosphere, 2.5 M BuLi (22 ml, 55 mmol) was added dropwise to a solution of 1H-pyrrolo[3,2-b]pyridine-1-carboxylic acid, 1,1-dimethylethyl ester (10 g, 45.8 mmol) in anhydrous THF (200 ml). The mixture was warmed to -60 °C and stirred for 2 hours. Then a solution of I2 (12.8 g, 50.4 mmol) in THF was slowly added at -72 °C. The reaction mixture was then stirred overnight at room temperature. The reaction mixture was quenched with Na2S2O3 and extracted with ethyl acetate (100 mL x 3). The organic layer was washed with H2O (50 mL x 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate ratio 1 / 0 to 3 / 1). The product fractions were collected and the solvent was evaporated to give Intermediate 37 as a yellow oil (2 mg, 11% yield).

[1546] The following intermediates were prepared using suitable starting materials by a reaction scheme similar to that used for the preparation of Intermediate 37 (Table 12).

[1547] Table 12:

[1548]

[1549] Example A13

[1550] Preparation of Intermediate 45

[1551]

[1552] Intermediate 45

[1553] The reaction flask was charged with intermediate 4 (442 mg, 1.39 mmol), and then a solution of 9-BBN in THF (0.5 M, 5.5 mL, 2.8 mmol, 2.0 eq) was added. The reaction mixture was stirred under nitrogen at room temperature for 2 h. THF (5 mL), K3PO4 (1.5 g, 6.9 mmol, 5 eq) and H2O (1.5 mL) were added and stirring was continued for 10 min. Thereafter, intermediate 27 (407 mg, 1.9 mmol, 1.1 eq) and PdCl2(dppf) (101 mg, 0.14 mmol, 0.1 eq) were added. The resulting reaction mixture was purged with nitrogen for 10 min and stirred at reflux temperature until complete conversion (usually about 2 h). The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (3% methanol in dichloromethane) to give intermediate 45 (110 mg, 16% yield).

[1554] The following intermediates were prepared using a reaction scheme similar to that used for the preparation of intermediate 45, using the appropriate starting materials (Table 13).

[1555] Table 13:

[1556]

[1557] Example A14

[1558] Preparation of intermediate 50

[1559]

[1560] Intermediate 50

[1561] The reaction flask was charged with intermediate 4 (560 mg, 1.75 mmol), and then a solution of 9-BBN in THF (0.5 M, 7.0 mL, 3.5 mmol, 2.0 eq) was added. The reaction mixture was stirred under nitrogen at room temperature for 2 h. THF (5 mL), K3PO4 (1.9 g, 8.8 mmol, 5 eq) and H2O (3 mL) were added and stirring was continued for 10 min. Thereafter, intermediate 21 (407 mg, 1.9 mmol, 1.1 eq) and PdCl2(dppf) (256 mg, 0.35 mmol, 0.2 eq) were added. The resulting reaction mixture was purged with nitrogen for 10 min and stirred at reflux temperature until complete conversion (usually about 3 h). The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0% to 3.5% gradient of methanol in dichloromethane) to give intermediate 50 (300 mg, 38% yield).

[1562] Example A15

[1563] Preparation of Intermediate 49

[1564]

[1565] Intermediate 49

[1566] A mixture of Intermediate 4 (1000 mg, 3.12 mmol) in 0.5 M 9-BBN in THF (31.3 mL, 15.6 mmol) was refluxed for 1 h under N2. The mixture was cooled to room temperature, then K3PO4 (1990 mg, 9.4 mmol) in H2O (10 mL) was added, followed by THF (100 mL), 7-bromo-imidazo[1,2-a]pyridine (924 mg, 4.7 mmol) and Pd-118 (204 mg, 0.31 mmol). The resulting mixture was refluxed for 3 h. The mixture was concentrated. The residue was dissolved in EtOAc (30 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: EtOAc / MeOH ratio 10 / 1). The desired fraction was collected and concentrated to give Intermediate 49 as a solid (486 mg, 35.5% yield).

[1567] The following intermediates were prepared using a reaction scheme similar to that used for the preparation of Intermediate 49, using the appropriate starting materials (Table 14).

[1568] Table 14:

[1569]

[1570] Example A16

[1571] Preparation of Intermediate 54

[1572]

[1573] Intermediate 54

[1574] A metal pressure vessel (75 mL) containing Intermediate 50 (270 mg, 0.60 mmol), THF (30 mL) and 25% aqueous ammonia (30 ml) was heated at 100 °C for one day. The reaction mixture was concentrated under reduced pressure to give crude Intermediate 54, which was used as such in the subsequent step.

[1575] Example A17

[1576] Preparation of Intermediate 55

[1577]

[1578] Intermediate 55

[1579] A metal pressure vessel (75 mL) containing intermediate 45 (110 mg, 0.23 mmol), THF (30 mL) and 25% aqueous ammonia (30 mL) was heated at 100 °C for two days. The reaction mixture was concentrated under reduced pressure to give crude intermediate 55, which was used as such in the subsequent step.

[1580] The following intermediates were prepared using appropriate starting materials by a reaction scheme similar to that used for the preparation of intermediate 54 and intermediate 55 (Table 15).

[1581] Table 15:

[1582]

[1583]

[1584]

[1585] Example A18

[1586] Preparation of intermediate 65

[1587]

[1588] Intermediate 65

[1589] A mixture of intermediate 50 (500 mg, 1.1 mmol) and NaOMe (478 mg, 8.85 mmol) in MeOH (15 mL) was stirred overnight at 60 °C. The mixture was diluted with water (20 mL) and extracted with CH2Cl2 (50 mL x 3). The organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give crude intermediate 65 (510 mg, 64% yield), which was used in the next step without further purification.

[1590] Example A21

[1591] Preparation of intermediate 75

[1592]

[1593] Intermediate 75

[1594] The reaction flask was charged with Intermediate 9 (538 mg, 1.79 mmol), and then a solution of 9-BBN in THF (0.5 M, 12.5 mL, 6.2 mmol, 3.5 eq) was added. The reaction mixture was stirred under nitrogen at room temperature for 2 h. K3PO4 (2.0 g, 8.96 mmol, 5 eq) and H2O (2.5 mL) were added and stirring was continued for 10 min. Then Intermediate 29 (484 mg, 1.97 mmol, 1.1 eq) and PdCl2(dppf) (131 mg, 0.18 mmol, 0.1 eq) were added. The reaction mixture was purged with nitrogen for 10 min and heated at reflux temperature until the conversion was complete. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic phase was washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (4% methanol in dichloromethane) to give Intermediate 75, which was used as such in the next step.

[1595] The following intermediates were prepared by a reaction scheme similar to that used for the preparation of Intermediate 75 and using the appropriate starting materials (Table 16).

[1596] Table 16:

[1597]

[1598] Example A19

[1599] Preparation of Intermediate 66

[1600]

[1601] A mixture of Intermediate 4 (300 mg, 0.94 mmol) in 0.5 M 9-BBN in THF (5.63 mL, 2.81 mmol) was refluxed under N2 for 1.5 h. The mixture was cooled to room temperature, and then K3PO4 (597 mg, 2.81 mmol) in H2O (2 mL) was added, followed by THF (20 mL), Intermediate 35 (290.5 mg, 1.12 mmol) and Pd-118 (795 mg, 0.112 mmol). The resulting mixture was refluxed for 3 h. The residue was dissolved in EtOAc (30 mL) and washed with brine (5 × 50 mL). The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography column (eluent: EtOAc / petroleum ether ratio 2 / 1). The desired fractions were collected and concentrated to give Intermediate 66 as a yellow oil (100 mg, yield 21.2%).

[1602] The following intermediates were prepared by a reaction scheme similar to that used for the preparation of Intermediate 66 and using the appropriate starting materials (Table 17).

[1603] Table 17:

[1604]

[1605]

[1606] Example A20

[1607] Preparation of Intermediate 71

[1608]

[1609] Intermediate 71

[1610] Dissolve Intermediate 66 (100 mg, 0.22 mmol) in 28% NH4OH (20 ml) and dioxane (8 ml). Stir the reaction mixture in a sealed tube at 100 °C for 12 hours. Concentrate the mixture. Dissolve the residue in ethyl acetate, wash with brine and dry over anhydrous Na2SO4. Concentrate the organic phase to obtain Intermediate 71 as an oil (100 mg, 99% yield).

[1611] The following intermediates are prepared using a reaction scheme similar to that used for the preparation of Intermediate 71, using appropriate starting materials (Table 18).

[1612] Table 18:

[1613]

[1614] Example A22

[1615] Preparation of Intermediate 78

[1616]

[1617] Intermediate 78

[1618] To a solution of Intermediate 1 (500 mg, 1.54 mmol, 1.0 eq) and imidazo[1,2-a]pyridin-7-ol (248.6 mg, 1.85 mmol, 1.2 eq) in THF (20 mL) add tributylphosphine (624.9 mg, 3.1 mmol, 2.0 eq) and (NE)-N-(piperidine-1-carbonylimino)piperidine-1-carboxamide (779 mg, 3.1 mmol, 2.0 eq). Stir the mixture at 15 °C for 15 hr. Remove the solvent. Purify the residue by flash column chromatography on silica gel ([ 12 g Purified by silica gel flash column with eluent gradient of 0% to 3% MeOH / DCM at 30 mL / min, and intermediate 78 (240 mg, 33.7% yield) was obtained as a light yellow solid.

[1619] Example A23

[1620] Preparation of Intermediate 79

[1621]

[1622] Intermediate 79

[1623] A solution of intermediate 78 (600 mg, 1.36 mmol, 1.0 equiv) in THF (4 mL), IPA (4 mL) and NH₃·H₂O (8 mL) was stirred in a sealed tube at 85 °C for 48 h. The solvent was removed under reduced pressure. The residue was purified by silica gel flash column ( 40 g Silica gel flash column with eluent of 0% to 10% MeOH(NH₃) / DCM gradient at 40 mL / min), and intermediate 79 (415 mg, 69% yield) was obtained as a light yellow solid.

[1624] Example A24

[1625] Preparation of Intermediate 80

[1626]

[1627] Intermediate 80

[1628] To a solution of intermediate 1 (250 mg, 772 μmol, 1.0 equiv) and 1H - benzimidazol - 5 - ol, 1 - methyl - (149 mg, 1.0 mmol, 1.3 equiv) in THF (10 mL) was added PPh₃ (263 mg, 1.0 mmol, 1.30 equiv) and DIAD (203 mg, 1.0 mmol, 1.3 equiv). The mixture was stirred at 15 °C for 2 h. The solvent was removed. The residue was purified by silica gel flash column: eluent: gradient from 0% to 50% ethyl acetate / petroleum ether and second purification eluent: gradient from 0% to 5% MeOH / DCM, and intermediate 80 (240 mg, 61.6% yield) was obtained as a colorless solid.

[1629] Example A25

[1630] Preparation of Intermediate 81

[1631]

[1632] To a solution of intermediate 80 (500 mg, 1.1 mmol, 1.0 equiv) in THF (3 mL) was added IPA (3 mL) and NH₃·H₂O (6 mL). The mixture was stirred in a sealed tube at 85 °C for 72 h. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel ( 12 g silica gel flash column, eluent gradient from 0% to 7% MeOH / DCM, at 30 mL / min), and intermediate 81 (370 mg, 73.5% yield) as a white solid was obtained.

[1633] Example A27

[1634] Preparation of Intermediate 82

[1635]

[1636] Intermediate 82

[1637] Cs₂CO₃ (1.48 g, 4.55 mmol, 3 equiv) was added to a solution of intermediate 42 (1.0 g, 1.52 mmol) and intermediate 18 (292 mg, 1.97 mmol, 1.3 equiv) in DMF (20 mL). The reaction mixture was stirred at room temperature for 3 days, and then intermediate 82 was precipitated by adding water. The precipitate was separated by centrifugation and washed with water (resuspended in water and then centrifuged). The wet product was used as such for the next step.

[1638] The following intermediates were prepared using a reaction scheme similar to that used for the preparation of intermediate 82, using appropriate starting materials (Table 19).

[1639] Table 19:

[1640]

[1641] Example A33

[1642] Preparation of Intermediate 145

[1643]

[1644] A solution of intermediate 144 (150 mg, 0.29 mmol), 2,4-dimethoxybenzylamine hydrochloride (387 mg, 2.3 mmol), and DIPEA (112 mg, 0.87 mmol) in n-BuOH (0.5 mL) was stirred at 140 °C for one day. The mixture was poured into H₂O (5 mL) and extracted with DCM (3 mL × 3). The organic layer was washed with brine (3 mL) and dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give the crude product as a brown oil.

[1645] The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate ratio 1:0 to petroleum ether / ethyl acetate ratio 1:9). These pure fractions were collected and the solvent was evaporated under vacuum to give Intermediate 145 as a brown oil (135 g, 78% yield).

[1646] Example A34

[1647] Preparation of Intermediate 146

[1648]

[1649] Intermediate 145 (135 mg, 0.23 mmol) and TFA (2 ml) were stirred at 80 °C for 1.5 h. The mixture was evaporated under vacuum to give crude Intermediate 146 as a brown oil (100 mg), which was used as such in the next step.

[1650] Example A28

[1651] Preparation of Intermediate 83

[1652]

[1653] Intermediate 83

[1654] A mixture of Intermediate 9 (0.5 g, 1.66 mmol) in a solution of 9-borabicyclo[3.3.1]nonane (20.0 mL, 0.5 M in THF, 10.0 mmol) was stirred at room temperature under a nitrogen atmosphere for 2 h for complete conversion to the 9-BBN adduct. A solution of nitrogen-flushed tripotassium phosphate (2.83 g, 13.3 mmol) in water (5 mL) was added. The reaction mixture was stirred at room temperature for 10 min and then a solution of nitrogen-flushed 1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium (219 mg, 0.33 mmol) and 2-amino-5-bromopyridine (288 mg, 1.66 mmol) in THF (20 mL) was added. The resulting mixture was purged with nitrogen for 15 min. The reaction mixture was stirred at 70 °C for 30 min under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and washed twice with dilute NH4OH and once with water. The organic layer was separated, dried over MgSO4, filtered and the solvent of the filtrate was evaporated. The residue was dissolved in dichloromethane and purified as follows: on an Armen Spot II final purification system through a SiO2 column (column type Grace Reveleris SRC, 4 g, Si 40), using dichloromethane and methanol as eluents, with a gradient starting from 100% dichloromethane and ending with 10% methanol and 90% dichloromethane. The fractions containing the product were combined and the solvent was evaporated to afford Intermediate 83 (0.18 g, 23% yield).

[1655] The following intermediates are prepared using appropriate starting materials by a reaction scheme similar to that used for preparing Intermediate 83 (Table 20).

[1656] Table 20:

[1657]

[1658]

[1659]

[1660]

[1661]

[1662]

[1663] Example A29

[1664] Preparation of Intermediate 86

[1665]

[1666] Intermediate 86

[1667] A mixture of Intermediate 9 (500 mg, 1.66 mmol), tetraethylammonium chloride (0.30 g, 1.83 mmol), and 2-amino-5-bromopyridine (0.33 g, 1.91 mmol) in DMF (15 mL) was stirred and flushed with nitrogen for 15 minutes. Then DIPEA (1.43 mL, 8.32 mmol) and Pd(OAc)2 (56.0 mg, 0.25 mmol) were added. The reaction vial was sealed, and the reaction mixture was stirred and heated at 100 °C for 3 days. The reaction mixture was poured into water, and the product was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and the solvent of the filtrate was evaporated. The residue was dissolved in dichloromethane and purified as follows: on an Armen Spot II final purification system through a SiO2 column (column type: Grace Reveleris SRC, 4 g, Si 40), using dichloromethane and methanol as eluents, with a gradient starting from 100% dichloromethane and ending with 10% methanol and 90% dichloromethane. The fractions containing the product were combined, and the solvent was evaporated to obtain 0.26 g of Intermediate 86 (0.26 g, 39% yield).

[1668] The following intermediates are prepared using appropriate starting materials by a reaction scheme similar to that used for preparing Intermediate 86 (Table 21).

[1669] Table 21:

[1670]

[1671]

[1672] Example A30

[1673] Preparation of Intermediate 94

[1674]

[1675] Intermediate 94

[1676] A mixture of Intermediate 90 (0.1 g, 0.23 mmol) in THF (30 ml) was hydrogenated at room temperature under a hydrogen atmosphere using 10% Pd / C (30 mg) and 0.4% thiophene in dipe (1 mL) until 1 equivalent of hydrogen was absorbed. The catalyst was removed by filtration through Celite. The combined solvents of the filtrate were evaporated. The residue was dissolved in dichloromethane and purified as follows: on a Grace Reveleris X2 purification system through a SiO2 column (column type: Grace Reveleris SRC, 4 g, Si 40), using dichloromethane and methanol as eluents, with a gradient starting from 100% dichloromethane up to 80% dichloromethane and 20% methanol. The fractions containing the product were combined and the solvent was evaporated to give Intermediate 94 (66.4 g, 44% yield).

[1677] Example A32

[1678] Step 1

[1679] Preparation of Intermediate 139

[1680]

[1681] p-Toluenesulfonyl hydrazide (413 mg, 2.2 mmol) was added to a solution of Intermediate 3 (1.3 g, 2.2 mmol) in MeOH (50 ml). The reaction mixture was stirred at 60 °C for 1 hour.

[1682] The reaction mixture was concentrated to dryness. The residue was purified by flash column chromatography on silica gel (eluent: petroleum ether / ethyl acetate from 100 / 0 to 70 / 30) to give Intermediate 139 as a pale yellow oil.

[1683] Step 2

[1684] Preparation of Intermediate 140

[1685]

[1686] Boric acid, B-(1-methyl-1H-benzimidazol-5-yl)-(389 mg, 1.77 mmol), Intermediate 139 (1.3 g, 2.12 mmol), and cesium carbonate (0.86 g, 2.65 mmol) were stirred in dioxane (30 ml) under N2 at 110 °C for 3 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: petroleum ether / ethyl acetate from 100 / 0 to 0 / 100). The desired fractions were collected and the solvent was evaporated.

[1687] The residue was further purified by preparative HPLC.

[1688] Column type: Gemini 150x 25 mm, 5 μm, Conditions: A: water (10 mM NH4HCO3); B: MeCN, at start: A (51%) and B (49%); at end: A: (36%) and B (64%), gradient time (min) 9.5; 100% B retention time (min) 2.5; flow rate (ml / min) 30

[1689] The pure fractions were collected and the solvent was evaporated in vacuo to give Intermediate 140 (100 mg, 12% yield).

[1690] B. Preparation of the Final Compound

[1691] Example B1

[1692] Preparation of Compound 1

[1693]

[1694] Compound 1

[1695] Intermediate 54 (0.59 mmol) was dissolved in EtOH (5 mL), then 1 M aqueous HCl solution (3 mL, 3.0 mmol) was added. The resulting reaction mixture was stirred at room temperature until complete deprotection (ca. 3 days), then basified by addition of Na2CO3 (253 mg) and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC (stationary phase: XBridge C18, 3.5 μM, 4.6 mm x 100 mm; mobile phase: 0.25% aqueous NH4CO3, MeOH) to give Intermediate 1 (110 mg, 47% yield).

[1696] Example B2

[1697] Preparation of Compound 2

[1698]

[1699] Compound 2

[1700] Intermediate 55 was dissolved in EtOH (2 mL), and then 1 M aqueous HCl (9.86 mL, 9.86 mmol) was added. The resulting reaction mixture was stirred at room temperature until complete deprotection (usually about 2 days), then basified by adding ammonia water and concentrated under reduced pressure. The residue was purified directly by preparative reverse-phase HPLC (stationary phase: XBridge C18, 3.5 μM, 4.6 mm x 100 mm; mobile phase: 0.25% aqueous NH4CO3, MeOH) to give Compound 2 (82 mg, 52% yield).

[1701] The following final compounds were prepared using a reaction scheme similar to that used for preparing Compound 1 and Compound 2, with appropriate starting materials (Table 22).

[1702] Table 22:

[1703]

[1704]

[1705] Example B3

[1706] Preparation of Compound 16

[1707]

[1708] Compound 16

[1709] A solution of Intermediate 71 (100 mg, 0.23 mmol) in 4 M HCl in MeOH (10 ml) was stirred at room temperature for 1 hour. Then NH4OH was added to the mixture until pH > 7. The mixture was concentrated. The residue was purified by preparative HPLC: column type: Waters Xbridge Prep OBD C18: 150 x 30 mm, 5 μm. Conditions: A: water (0.05% ammonium hydroxide v / v); B: MeCN, at the start: A (87%) and B (13%); at the end: A: (57%) and B (43%). Gradient time (min) 10; 100% B retention time (min) 3; flow rate (ml / min) 25, to give 34 mg of Compound 16 as a white solid (34 mg, 37% yield).

[1710] The following final compounds were prepared using a reaction scheme similar to that used for preparing Compound 16, with appropriate starting materials (Table 23).

[1711] Table 23:

[1712]

[1713]

[1714] Example B4

[1715] Preparation of Compound 21

[1716]

[1717] Compound 21

[1718] Dissolve Intermediate 75 (1.79 mmol) in EtOH (2 mL), then add aqueous 1 M HCl (9.86 mL, 9.86 mmol). Stir the resulting reaction mixture at room temperature until complete deprotection (usually about 2 days), then basify it by adding ammonia water and concentrate it under reduced pressure. Purify the residue directly by preparative reverse-phase HPLC (stationary phase: XBridge C18, 3.5 μM, 4.6 mm x 100 mm; mobile phase: 0.25% aqueous NH4CO3, MeOH) to give Compound 21 (82 mg, 52% yield).

[1719] Example B5

[1720] Preparation of Compound 24

[1721]

[1722] Compound 24

[1723] Stir a solution of Intermediate 79 (365 mg, 1.0 equiv) in MeOH (3 mL) and HCl / dioxane (3 mL) at 25 °C for 2 h. Remove the solvent. Adjust the residue to pH = 7 with NH3·H2O and then wash it with H2O (10 mL x 2) and CH3CN (10 mL x 2) to give Compound 24 (235 mg, 67.6% yield).

[1724] Example B6

[1725] Preparation of Compound 25

[1726]

[1727] Compound 25

[1728] To a solution of intermediate 81 (320 mg, 736.5 μmol, 1.0 equiv) in MeOH (2.5 mL) was added HCl / dioxane (2.5 mL). The mixture was stirred at 20 °C for 15 hr. The solvent was removed under reduced pressure. The residue was adjusted to pH > 7 with NH₃·H₂O. The mixture was crystallized from H₂O (10 mL). The precipitate was washed with CH₃CN to give compound 25 (230 mg, 75% yield) as a white solid.

[1729] Example B7

[1730] Preparation of Compound 26

[1731]

[1732] Compound 26

[1733] Intermediate 82 (1.52 mmol) was dissolved in EtOH (20 mL), and then 1 M aqueous HCl (15.2 mL, 15.2 mmol) was added. The reaction mixture was stirred at room temperature until complete deprotection (usually about 3 days), then basified by adding ammonia water and purified directly by preparative reverse-phase HPLC (stationary phase: XBridge C18, 3.5 μM, 4.6 mm x 100 mm; mobile phase: 0.25% aqueous NH₄CO₃, MeOH) to give compound 26 (135 mg, 22.5%).

[1734] The following final compounds were prepared using a reaction scheme similar to that used for preparing compound 26, using the appropriate starting materials (Table 24).

[1735] Table 24:

[1736]

[1737] Example B8

[1738] Preparation of Compound 27

[1739]

[1740] Compound 27

[1741] At room temperature, HCl (3.92 mL, 1 M in H2O, 3.92 mmol) was added dropwise to a stirred solution of intermediate 83 (0.18 g, 0.392 mmol) in iPrOH (5 mL). The reaction mixture was stirred at room temperature for 3 h after the addition. NH3 (28% in H2O) (0.53 mL; 7.85 mmol) was added. The solvent was evaporated. The residue was dissolved in 30 mL of methanol and purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD - 10 μm, 30 x 150 mm, mobile phase: 0.25% NH4HCO3 solution in water, MeOH), to afford compound 27 (102 mg, 73% yield).

[1742] The following compounds were prepared using a reaction scheme similar to that used for the preparation of compound 27, using the appropriate starting materials (Table 25).

[1743] Table 25:

[1744]

[1745]

[1746]

[1747]

[1748]

[1749]

[1750] Example B9

[1751] Preparation of Compound 30

[1752]

[1753] Compound 30

[1754] At room temperature, HCl (6.62 mL, 1 M in H2O, 6.6 mmol) was added dropwise to a stirred solution of intermediate 86 (0.26 g, 0.66 mmol) in MeOH (8 mL). The reaction mixture was stirred at room temperature for 3 h after the addition. NH3 (28% in H2O) (0.90 mL; 13.2 mmol) was added. The solvent was evaporated. The residue was dissolved in 30 mL of methanol and purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD - 10 μm, 30 x 150 mm, mobile phase: 0.25% NH4HCO3 solution in water, MeOH), to afford compound 30 (143 mg, 57% yield).

[1755] The following compounds were prepared using a reaction scheme similar to that used for the preparation of Compound 30, with appropriate starting materials (Table 26).

[1756] Table 26:

[1757]

[1758]

[1759] Preparation of Compound 31 of Example B10

[1760]

[1761] Compound 31

[1762] To a solution of Intermediate 87 (400 mg, 0.69 mmol) in MeOH (10 ml) was added TFA (5 ml). The mixture was stirred at room temperature for 5 hours. The solvent was concentrated in vacuo. The residue was dissolved in water, basified to pH > 7 with NH 3. 4OH and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the crude product as a brown oil. The crude product was purified by preparative high performance liquid chromatography:

[1763] Column: Xtimate C18 150x 25mm, 5μm

[1764] Conditions: A: water (10 mM NH4HCO3) B: ACN

[1765] Start: A (92%) and B (8%), End: A (62%) and B (38%)

[1766] Gradient time (min) 14; 100% B retention time (min) 2.5: Flow rate (ml / min) 25. The pure fractions were collected and the organic solvent was evaporated in vacuo. The aqueous layer was lyophilized to give Compound 31 as a white solid (83 mg, 27% yield).

[1767] Example B11

[1768] Preparation of Compound 75

[1769]

[1770] Compound 75

[1771] Intermediate 146 (100 mg, 0.22 mmol) and K2CO3 (270 mg) were added to MeOH (4 ml) and refluxed for 2 h. The mixture was evaporated under vacuum. The crude product was purified by preparative HPLC. Column: Xtimate C18 150x 25 mm x 5 μm

[1772] Conditions: A: water (0.05% ammonium hydroxide v / v) B: MeCN, at start: A (90%) and B (10%), at end: A (60%) and B (40%). Gradient time (min) 10; 100% B retention time (min) 2.5; flow rate (ml / min) 25.

[1773] These pure fractions were collected and the solvent was evaporated under vacuum.

[1774] The aqueous layer was lyophilized to give compound 75 as a white solid (22.8 mg, 28.6% yield).

[1775] C. Conversion of the final compound

[1776] Example C1

[1777] Preparation of compound 13

[1778]

[1779] Compound 13

[1780] Compound 3 (50 mg, 0.13 mmol) was stirred in DMF (2 mL). N-Chlorosuccinimide (17.6 mg, 0.13 mmol) was added. The reaction mixture was stirred overnight. The reaction mixture was diluted to 10 mL with DMF and used as such for RP purification (XBRidge C18_3.5 μM (100x 4.6 mm), aqueous NH4CO3 and MeOH) to afford compound 13 (27 mg, 49.5% yield).

[1781] The following final compounds were prepared using a reaction scheme similar to that used for preparing compound 13, using the appropriate starting materials (Table 27).

[1782] Table 27:

[1783]

[1784] Analytical section

[1785] NMR

[1786] For many compounds, the 1 H NMR spectra were recorded on a Bruker Avance 400 operating at 400 MHz or on a Varian 400MR spectrometer operating at 400 MHz. Methanol-d4 or DMSO-d6 (deuterated DMSO, dimethyl-d6 sulfoxide) was used as the solvent. Chemical shifts (δ) are reported as parts per million (ppm) relative to tetramethylsilane (TMS) (used as an internal standard).

[1787] Table 28:

[1788]

[1789]

[1790]

[1791]

[1792] LCMS (liquid chromatography / mass spectrometry)

[1793] High-performance liquid chromatography (HPLC) measurements were carried out using an LC pump, a diode array (DAD) or UV detector, and a column as specified in the corresponding method. If necessary, additional detectors were included (see Table 29 below).

[1794] The flow from the column was directed to a mass spectrometer (MS) equipped with an atmospheric pressure ionization source. The tuning parameters (e.g., scan range, dwell time, etc.) were set to obtain ions that allowed the identification of the nominal single isotope molecular weight (MW) of the compound within the knowledge of the person skilled in the art. Data acquisition was carried out using appropriate software.

[1795] The compound was described by its experimental retention time (R t ) and ions. If not otherwise specified in Table 30, the reported molecular ions correspond to [M+H] + (protonated molecule) and / or [M−H] - (deprotonated molecule). In cases where the compound was not directly ionizable, the adduct type was specified (i.e., [M+NH4] + , [M+HCOO] - , etc.). For molecules with multiple isotope patterns (Br, Cl), the reported values are those obtained for the lowest isotope mass. All results obtained have the experimental uncertainties typically associated with the methods used.

[1796] Hereinafter, "SQD" means single quadrupole detector, "MSD" means mass selective detector, "RT" means room temperature, "BEH" means bridged ethylsiloxane / silica hybrid, "DAD" means diode array detector, "HSS" means high strength silica, "Q-Tof" means quadrupole time-of-flight mass spectrometer, "CLND" means chemiluminescent nitrogen detector, "ELSD" means evaporative light scattering detector,

[1797] Table 29: LCMS method codes (flow rate in mL / min; column temperature (T) in °C; run time in minutes).

[1798]

[1799]

[1800] Table 30: Compound number (Co.No.) means compound number; retention time (R t ) in min; n.d. means not determined.

[1801]

[1802]

[1803] In vitro assay experimental procedures (assays 1a and 1b)

[1804] Reagents. The PRMT5-MEP50 enzyme was purchased from Charles River (Argenta). The enzyme complex was produced in insect cells (Sf9) co-infected with two baculoviruses. One virus expressed full-length human PRMT5 with a Flag tag at the N-terminus, and the second virus expressed full-length MEP50 with a His6-TEV cleavage at the N-terminus. The protein was affinity purified using anti-Flag (M2) beads eluted with 3xFLAG peptide, followed by affinity purification using His-Select eluted with 0.5 M imidazole. The eluted protein was then dialyzed against tris-buffered saline (TBS) (pH 8.0) containing 20% glycerol and 3 mM dithiothreitol (DTT).

[1805] Full-length unlabeled human recombinant histone H2A (residues 1 - 130, Genbank accession number NM_021052, MW = 14.1 kDa) expressed in E. coli was purchased from Reaction Biology Corporation (Catalog No. HMT - 11 - 146). Reagents used to buffer or stop reactions were purchased and included Tris base (Sigma, Catalog No. T - 1503), NaCl (Sigma, Catalog No. RGF - 3270), MgCl2 (Sigma, Catalog No. M0250), DTT (Invitrogen, Catalog No. 15508 - 013), and formic acid (Riedel deHaen, Catalog No. 33015)

[1806] High - throughput mass spectrometry determines that PRMT5 catalyzes the sequential methylation of the terminal nitrogen atom on the guanidino group of arginine residues within proteins using the co - substrate S - adenosyl - L - methionine (AdoMet, SAM) to form monomethyl (MMA), symmetric dimethylarginine (sDMA), and S - adenosyl - L - homocysteine (AdoHcy, SAH). Enzyme activity was determined by tracking the formation of the product SAH using high - throughput mass spectrometry (Agilent Rapidfire 300 system coupled to Sciex 4000 series triple quadrupole MS / MS). The reaction buffer was 20 mM Tris - HCl, pH 8.5, 50 mM NaCl, 5 mM MgCl2, and 1 mM DTT. The reaction activity was terminated using 1% formic acid (final concentration).

[1807] Inhibition studies. An 11 - point dosing series prepared with each compound serially diluted 1:2 in dimethyl sulfoxide (DMSO) was used for the IC 50 studies, where point 12 was the DMSO control. Compounds were spotted onto the plate first, and then a 2 μM SAM and 0.6 μM H2A (histone H2A) solution mixture was added. The same volume of enzyme solution was added to initiate the enzymatic reaction. The final concentrations of the reaction were 1 μM SAM, 0.3 μM H2A, and 10 nM enzyme (assay 1a) or 1.25 nM enzyme (assay 1b). The reaction was incubated at 30 °C for 60 minutes (min) when using 10 nM enzyme and for 120 min when using 1.25 nM enzyme. Subsequently, the reaction was quenched by adding formic acid to a final concentration of 1%. The inhibition of SAH formation in the presence of these compounds was calculated as a percentage of the control as a function of inhibitor concentration relative to the uninhibited reaction. Data were fit as follows:

[1808] Y = Bottom + (Top - Bottom) / (1 + 10^((log IC 50 - X) * h))

[1809] where IC 50 is the inhibitor concentration at 50% inhibition (same unit as X) and h is the Hill slope. Y is the percentage of inhibition and X is the logarithm of the compound concentration. Bottom and Top are the plateaus with the same unit as Y.

[1810] Experimental procedure PD assay (assay 2)

[1811] Reagents

[1812] A549 cells (ATCC, catalog number CCL - 185) were cultured in Dulbecco's Modified Eagle Medium (DMEM) (Sigma, catalog number D5796), supplemented with 10% fetal bovine serum (FCS) (HyClone TM , catalog number SV30160.03), 100 mM sodium pyruvate (Sigma, catalog number S8636), 200 mM L - glutamine (Sigma, catalog number G7513), and 50 mg / mL gentamicin (Gibco, catalog number 15750 - 037).

[1813] Reagents for buffering were commercially available: Dulbecco's Phosphate - Buffered Saline (DPBS), without Ca / Mg (Sigma, catalog number D8537), Phosphate - Buffered Saline (PBS) 10X (Roche, catalog number 11 666 789 001), Formalin solution 10% (Sigma, HT50 - 1 - 128 - 4L), Methanol 100% (Sigma, catalog number 32213 - 2.5L), Triton X - 100 (Acros, catalog number 215680010), Bovine Serum Albumin (BSA) (Sigma, catalog number A2153), Alexa fluor 488 goat anti - rabbit antibody (Life Technologies, catalog number A11034), HCS CellMask Deep Red Stain (Life Technologies, catalog number H32721), Hoechst Stain (Life Technologies, catalog number 33258), anti - dimethyl - argin, sym (SYM10) antibody (Millipore, 07 - 412).

[1814] Immunohistochemistry procedure

[1815] Cells were seeded at 400 cells / 40 μL / well in the clear-bottom 384-well black microplates (μ-plates) (Perkin-Elmer) and incubated overnight at 37 °C in 5% CO2. Each compound was studied using a nine-point dosing series method in the range from 10 μM to 1 pM. 80 nL of each dilution of these compounds was added using a Labcyte POD 810 (Labcyte) to achieve a final DMSO concentration of 0.2% in the cell culture medium. After incubation at 37 °C and 5% CO2 for 48 h, the cells were fixed in 10% formalin solution for 15 min and in ice-cold methanol for 20 min at room temperature, and then washed three times in DPBS. Subsequently, the cells were blocked in blocking buffer (PBS + 1% BSA and 0.5% Triton X-100) for 1 h and incubated overnight at 4 °C with SYM10 antibody diluted 1 / 2000 in the blocking buffer. The cells were washed three times with wash buffer (PBS + 0.1% Triton X-100) and incubated for 1 h at room temperature with Alexa Fluor dye 488 goat anti-rabbit antibody diluted 1 / 200 in the blocking buffer. Subsequently, they were washed three times with the wash buffer and incubated for 30 min at room temperature with PBS containing Hoechst stain diluted 1 / 5000 and HCS CellMask Deep Red stain diluted 1 / 5000. After the last wash with PBS, the plates were imaged using a 50 system with a 10xW lens (Perkin Elmer Life Sciences) using the following settings (values in nm): Analysis:

[1816]

[1817] The inhibition of nuclear symmetric arginine dimethylation in the presence of the compound (% effect) was calculated as "median nuclear SYM10 intensity" / "median cytoplasmic SYM10 intensity" and normalized by the following equation:

[1818]

[1819]

[1820] In the above equation, the following variable names were used:

[1821] Standard value Normalized eigenvalue Original value Original eigenvalue Low median value Median of the original values of the low control wells High median value Median of the original values of the high control wells

[1822] For normalization in the above equation, the following controls were used:

[1823] Low control: the lowest level of symmetric dimethylated arginine (cells treated with a reference compound at 10 μM).​

[1824] High control: the highest level of symmetric dimethylarginine (cells treated with DMSO).

[1825] Use appropriate software to calculate IC 50 and pIC 50 (-logIC 50 ) values.

[1826] The pIC 50 values in the following table are the averages (Co.No. means compound number; n.d. means not determined).

[1827]

[1828]

[1829] Composition example

[1830] The "active ingredient" (a.i.) as used in all these examples refers to the compounds having formula (I), and their pharmaceutically acceptable addition salts and solvates; specifically, any one of these exemplary compounds is involved.

[1831] Typical examples of the formulation for the preparation of the pharmaceutical compositions according to the invention are as follows:

[1832] 1. Tablets

[1833]

[1834] 2. Suspensions

[1835] Prepare an aqueous suspension for oral administration such that each milliliter contains 1 to 5 mg of the active ingredient, 50 mg of sodium carboxymethylcellulose, 1 mg of sodium benzoate, 500 mg of sorbitol, and water (to make up to 1 ml).

[1836] 3. Injections

[1837] Prepare a parenteral composition by stirring 1.5% (weight / volume) of the active ingredient in 0.9% NaCl solution or in an aqueous solution of 10% propylene glycol by volume.

[1838] 4. Ointments

[1839]

[1840] In this example, the active ingredient can be replaced by the same amount of any compound according to the invention, especially the same amount of any exemplary compound.

Claims

1. A compound having the formula (I) wherein R 1 represents hydrogen; R 2 represents hydrogen; Y represents -CH2-; Z represents -CH2-, -CHR 5i -, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g - CR 5f R 5h -, -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -; R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R 5g 、R 5h and R 5i each independently represents hydrogen or C 1-4 alkyl; X represents -O-, -S- or -NR 11 -; R 11 represents hydrogen, C 1-4 alkyl or C substituted with a substituent selected from the group consisting of 1-4 alkyl: -OH, -O-C 1-4 alkyl, -NH2, -NH-C 1-4 alkyl and -N(C 1-4 alkyl)2; Ar represents a monocyclic aromatic ring or a bicyclic system; wherein the monocyclic aromatic ring is selected from the group consisting of pyridyl, pyrimidinyl, pyrazolyl, and imidazolyl; wherein the bicyclic system is (i) a 9-membered bicyclic aromatic ring system composed of a 6-membered ring fused to a 5-membered ring, containing one, two, or three heteroatoms each independently selected from O, S, and N, and the 9-membered bicyclic aromatic ring is attached to the remainder of the molecule through a ring carbon atom of the 5- or 6-membered ring or a ring nitrogen atom of the 5-membered ring; or (ii) a 10-membered bicyclic aromatic ring system composed of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by nitrogen atoms; provided that when one of the two fused carbon atoms is replaced by a nitrogen atom, a carbonyl group is present in the bicyclic aromatic ring system; Provided that when Ar represents a 10-membered bicyclic aromatic ring system, Z can only represent -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -; or (iii) a fused bicyclic partial aromatic ring system attached to the linking group Z through an aromatic ring, wherein the fused bicyclic partial aromatic ring system is selected from (b-1), (b-2), and (b-3) wherein ring A is a monocyclic aromatic ring selected from the group consisting of pyridyl, pyrimidinyl, pyrazolyl, and imidazolyl; wherein ring B is C 5-6 a cycloalkyl group or a 5- to 6-membered saturated heterocyclic group containing one or two heteroatoms each independently selected from O, S, and N; Ar is optionally substituted on the carbon atom with a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, oxo, -OH, -NH2, -NH-C 1-4 alkyl, -NHR 10 , cyano, -CF3, C 1-4 alkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl and C 1-4 alkyl substituted with one C 1-4 alkoxy; and Where possible, Ar is optionally substituted on an N-atom with a substituent selected from the group consisting of: C 1-4 alkyl; C 3-6 cycloalkyl; C substituted with one, two or three halogen atoms 1-4 alkyl; and C substituted with one, two or three halogen atoms 3-6 cycloalkyl; R 10 represents -(C=O)-C 1-4 alkyl; C 3-6 cycloalkyl; R 13 ; R 14 ; C substituted by one, two or three substituents each independently selected from the group consisting of 3-6 cycloalkyl: halogen, -OH and -O-C 1-4 alkyl; C substituted by one, two or three substituents each independently selected from the group consisting of 1-4 alkyl: halogen, -OH and -O-C 1-4 alkyl; or C substituted by a substituent selected from the group consisting of 1-4 alkyl: C 3-6 cycloalkyl, R 13 and R 14 ; R 13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=O) p and N; said 4- to 7-membered monocyclic aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C 1-4 alkyl; p represents 1 or 2; R 14 represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of: halogen; Het represents the bicyclic aromatic heterocyclic system (a-1): R 3a represents halogen, -NR 7a R 7b or -O-C 1-4 alkyl; R 7a represents hydrogen; R 7b represents hydrogen or C 1-4 alkyl; R 4a represents hydrogen; Q 1 represents CR 6a ; Q 2 represents CR 6b ; R 6a 、R 6b represent hydrogen, halogen; or a pharmaceutically acceptable addition salt thereof, provided that the compound is not N7-((1'R,4'S)-2',3'-dihydroxy-4'-(3"-picolylthio)-cyclopentyl)-4-chloro-5-iodo-pyrrolopyrimidine.

2. The compound according to claim 1, wherein Z represents -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d - or -CR 5e R 5g -CR 5f R 5h -; R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R 5g and R 5h each independently represents hydrogen or C 1-4 alkyl; Ar represents a monocyclic aromatic ring selected from pyridyl and imidazolyl; or a 9-membered bicyclic aromatic ring system composed of a 6-membered ring fused to a 5-membered ring, containing one, two, or three heteroatoms each independently selected from O, S, and N, and the 9-membered bicyclic aromatic ring is attached to the remainder of the molecule through a ring carbon atom of the 5- or 6-membered ring or a ring nitrogen atom of the 5-membered ring; Ar is optionally substituted on a carbon atom by a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 alkyl, -NHR 10 , cyano, -CF3, C 1-4 alkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl and C 1-4 alkyl substituted by one C 1-4 alkoxy; and Where possible, Ar is optionally substituted on an N-atom by a substituent selected from the group consisting of: C 1-4 alkyl; C 3-6 cycloalkyl; C 1-4 alkyl substituted by one, two or three halogen atoms; and C 3-6 cycloalkyl substituted by one, two or three halogen atoms.

3. The compound according to claim 1, wherein R 1 represents hydrogen; R 2 represents hydrogen; Y represents -CH2-; Z represents -CH2-, -CHR 5i -, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g - CR 5f R 5h -, -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -; R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R 5g 、R 5h and R 5i each independently represents hydrogen or C 1-4 alkyl; X represents -O-; Ar represents a monocyclic aromatic ring or a bicyclic system; wherein the monocyclic aromatic ring is selected from the group consisting of pyridyl, pyrimidinyl, pyrazolyl, and imidazolyl; wherein the bicyclic system is (i) a 9-membered bicyclic aromatic ring system composed of a 6-membered ring fused to a 5-membered ring, containing one, two, or three heteroatoms each independently selected from O, S, and N, and the 9-membered bicyclic aromatic ring is attached to the remainder of the molecule through a ring carbon atom of the 5- or 6-membered ring or a ring nitrogen atom of the 5-membered ring; or (ii) a 10-membered bicyclic aromatic ring system composed of two fused 6-membered rings, wherein 1 or 2 ring carbon atoms are replaced by nitrogen atoms; provided that when one of the two fused carbon atoms is replaced by a nitrogen atom, a carbonyl group is present in the bicyclic aromatic ring system; Provided that when Ar represents a 10-membered bicyclic aromatic ring system, Z can only represent -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -; or (iii) a fused bicyclic partial aromatic ring system attached to the linking group Z through the aromatic ring, wherein the fused bicyclic partial aromatic ring system is selected from (b-1) and (b-3), wherein ring A is pyridyl; wherein ring B is a 5- to 6-membered saturated heterocyclic group containing one or two heteroatoms each independently selected from O and N; The carbon atom is optionally substituted at the carbon atom with a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, oxo, -NH2, -NH-C 1-4 alkyl, -CF3, C 3-6 cycloalkyl and C 1-4 alkyl; and Where possible, Ar is optionally substituted on an N-atom by a C 1-4 alkyl group; Het represents the bicyclic aromatic heterocyclic system (a-1); R 3a represents halogen, -NR 7a R 7b or -O-C 1-4 alkyl; R 7a represents hydrogen; R 7b represents hydrogen or C 1-4 alkyl; R 4a represents hydrogen; Q 1 represents CR 6a ; Q 2 represents CR 6b ; R 6a and R 6b each independently represents hydrogen or a halogen.

4. The compound according to claim 1 or 2, wherein Ar represents a monocyclic aromatic ring selected from pyridyl and imidazolyl; Ar is optionally substituted on the carbon atom by a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 alkyl, -NHR 10 , cyano, -CF3, C 1-4 alkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl and C 1-4 alkyl substituted by one C 1-4 alkoxy.

5. The compound according to claim 1 or 2, wherein Ar represents a 9-membered bicyclic aromatic ring system consisting of a 6-membered ring fused to a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S and N, and the 9-membered bicyclic aromatic ring is attached to the remainder of the molecule through a ring carbon atom of the 5- or 6-membered ring or a ring nitrogen atom of the 5-membered ring; The carbon atom of Ar is optionally substituted by a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 alkyl, -NHR 10 , cyano, -CF3, C 1-4 alkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl and C 1-4 alkyl substituted by one C 1-4 alkoxy; and Where possible, Ar is optionally substituted on an N-atom with a substituent selected from the group consisting of: C 1-4 alkyl; C 3-6 cycloalkyl; C 1-4 alkyl substituted with one, two or three halogen atoms; and C 3-6 cycloalkyl substituted with one, two or three halogen atoms.

6. The compound according to claim 5, wherein Ar represents a monocyclic aromatic ring selected from pyridyl and imidazolyl; or a 9-membered bicyclic aromatic ring system selected from the group consisting of the 9-membered bicyclic aromatic ring is attached to the remainder of the molecule through a ring carbon atom of the 5- or 6-membered ring or a ring nitrogen atom of the 5-membered ring; Ar is optionally substituted on a carbon atom with a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 alkyl, -NHR 10 , cyano, -CF3, C 1-4 alkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl and C 1-4 alkyl substituted with one C 1-4 alkoxy; and Where possible, Ar is optionally substituted on an N-atom with a substituent selected from the group consisting of: C 1-4 alkyl; C 3-6 cycloalkyl; C substituted with one, two or three halogen atoms 1-4 alkyl; and C substituted with one, two or three halogen atoms 3-6 cycloalkyl.

7. The compound according to claim 1, wherein Ar represents a monocyclic aromatic ring selected from the group consisting of pyridyl, pyrimidinyl, pyrazolyl and imidazolyl; Ar is optionally substituted on the carbon atom by a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 alkyl, -NHR 10 , cyano, -CF3, C 1-4 alkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl and C 1-4 alkyl substituted by one C 1-4 alkoxy; and Where possible, Ar is optionally substituted on an N-atom with a substituent selected from the group consisting of: C 1-4 alkyl; C 3-6 cycloalkyl; C 1-4 alkyl substituted with one, two or three halogen atoms; and C 3-6 cycloalkyl substituted with one, two or three halogen atoms.

8. The compound according to claim 1, wherein Ar represents a bicyclic system; Ar is optionally substituted on a carbon atom with a total of one, two, three or four substituents each independently selected from the group consisting of: halogen, oxo, -OH, -NH2, -NH-C 1-4 alkyl, -NHR 10 , cyano, -CF3, C 1-4 alkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl and C 1-4 alkyl substituted with one C 1-4 alkoxy; and Where possible, Ar is optionally substituted on an N-atom by a substituent selected from the group consisting of: C 1-4 alkyl; C 3-6 cycloalkyl; C 1-4 alkyl substituted by one, two or three halogen atoms; and C 3-6 cycloalkyl substituted by one, two or three halogen atoms.

9. The compound according to claim 1, wherein Z represents -CH2-, -CHR 5i -, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g - CR 5f R 5h -, -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h - or -CR 5a R 5b -CR 5c R 5d -CR 5e R 5g -CR 5f R 5h -; R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R 5g 、R 5h and R 5i each independently represents hydrogen or C 1-4 alkyl; X represents -O-; Het represents a bicyclic aromatic heterocyclic system (a-1); R 3a represents halogen, -NR 7a R 7b or -O-C 1-4 alkyl; Q 1 represents CR 6a ; Q 2 represents CR 6b .

10. The compound according to claim 1, wherein R 3a represents -NR 7a R 7b ; and R 7a and R 7b represent hydrogen.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound according to any one of claims 1 to 10 as an active ingredient.

12. Use of the compound according to any one of claims 1 to 10 in the preparation of a medicament for treating or preventing a disease or disorder selected from blood disorders, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, multiple organ failure, kidney diseases, platelet aggregation, sperm motility, graft rejection and lung injury.

13. The use according to claim 12, wherein the disease or disorder is cancer.

14. The use according to claim 12, wherein the disease or disorder is pancreatitis.

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