Novel 6-6 bicyclic aromatic ring substituted nucleosides as PRMT5 inhibitors

Abstract

The present invention relates to novel 6-6 bicyclic aromatic ring substituted nucleoside analogs as PRMT5 inhibitors, and to novel 6-6 bicyclic aromatic ring substituted nucleoside analogs with chemical formula (I) wherein the variables have the meanings defined in the claims. The compounds according to the present invention are useful as PRMT5 inhibitors. The present invention further relates to pharmaceutical compositions comprising the compounds as active ingredients, together with the use of the compounds as medicaments.

Description

[0001] This application is a divisional application of an invention patent application filed on August 25, 2016, with application number 201680048987.1 and invention name “Novel 6-6 bicyclic aromatic ring substituted nucleoside analogs as PRMT5 inhibitors”. Field of the Invention

[0002] The present invention relates to novel 6-6 bicyclic aromatic ring substituted nucleoside analogs useful as PRMT5 inhibitors. The present invention further relates to pharmaceutical compositions comprising the compounds as active ingredients, as well as the use of the compounds as medicaments. Background of the Invention

[0003] PRMT5, also described as Hsl7, Jbp1, Skb1, Capsuleen, or Dart5, is one of the major methyltransferases responsible for both mono- and symmetric dimethylation of arginine. Post-translational arginine methylation on histones and non-histones appears to be crucial for a wide range of 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, 2015.72(11):p.2041-59][Geoghegan, V. et al., Nature Communications, 2015.6:p.6758]. In multicellular animals, PRMT5 forms a functional complex with methylosome protein 50 (MEP50, also known as Wdr77), androgen receptor coactivator p44, and Valois. Elevated PRMT5-MEP50 protein levels and cytoplasmic accumulation are both associated with cancer tumorigenesis and have only recently been linked to poor clinical outcomes [Shilo, K. et al., Diagnostic Pathology, 2013.8:p.201]. In addition to comprehensive enzymological studies, cell rescue experiments that address both the catalytic and scaffolding effects of the PRMT5-MEP50 complex have confirmed the carcinogenic link between protein levels, distribution, and enzyme function [Gu Z. et al., Biochem J, 2012.446(2):p.235-41][Di Lorenzo A. et al., FEBS Letters, 2011.585(13):p.2024-31][Chan-Penebre E. et al., Nat Chem Biol, 2015.11(6):p.432-7]. This association makes PRMT5 a major small molecule drug target for cancer and other diseases [Stopa, N. et al., Cell Mol Life Sci, 2015, 72(11):p.2041-59].

[0004] PRMT5 is a member of the type II PRMT subfamily, which uses S-adenosylmethionine (SAM) to generate symmetrically dimethylated arginine and S-adenosylhomocysteine ​​(SAH) on histone and non-histone substrates. The crystal structure of human iso-octameric complex (PRMT5)4 (MEP50)4 co-crystallized with SAH and a histone H4 peptide substrate demonstrates the mechanism of methylation and substrate recognition [Antonysamy, S. et al., Proceedings of the National Academy of Sciences of the United States of America (ProcNatl Acad Sci USA), 2012, 109(44): p.17960-5]. Regulation of PRMT5 activity occurs through a large number of different binding couplers, post-translational modification interactions, miRNAs, and subcellular distribution.

[0005] Methylation of histone H2A and H4 at Arg3 and histone H3 at Arg8 specifically inhibits gene transcripts, regulating chromatin organization. This specific inhibition of gene transcripts is associated with differentiation, transformation, cell cycle progression, and tumor suppression [Karkhanis, V. et al., Trends Biochem Sci, 2011, 36(12): p. 633-41]. Furthermore, PRMT5-mediated methylation of histone H4 at Arg3 may recruit the DNA-methyltransferase DNMT3A to couple with histones and methylate DNA, aiming for long-term gene silencing [Zhao, Q. et al., Nature Struct Mol Biol, 2009, 16(3): p. 304-11].

[0006] Non-histone methylation can occur in the cytoplasm or nucleus, depending on the cellular localization of PRMT5. Methylation of Sm proteins D1 and D3 is required for the assembly of the nuclear spliceosome and occurs in the cytoplasm as part of PRMT5 containing a “methyl body” [Friesen et al., Molecular Cell Biology, 2001.21(24):p.8289-300]. Further evidence of PRMT5’s association with splicing has been provided by conditional PRMT5 knockout in mouse neural stem cells. Cells lacking PRMT5 exhibit selective retention of introns and exon skipping (with weak 5' donor sites) [Bezzi et al., Genes Dev, 2013.27(17):p.1903-16].

[0007] In addition to its role in splicing, PRMT5 also affects major pathways related to cell fate and homeostasis by directly methylating major signaling nodes, such as p53 [Jansson, M. et al., Nat Cell Biol, 2008.10(12): p.1431-9], EGFR [Hsu, JM 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, TY et al., Cell Signaling, 2011.4(190): p.ra58], and PI3K / AKT [Wei, TY et al., Cell Signaling, 2011.4(20): p.ra57]. Signal, 2014. 26(12): p. 2940-50], NFκB [Wei, H. et al., Proc Natl Acad Sci USA, 2013. 110(33): p. 13516-21].

[0008] Because PRMT5 is one of the major sym-Arg methyltransferases and is associated with numerous cellular processes, increased protein expression appears to be a significant factor in its tumorigenicity. Interestingly, PRMT5 translation in mantle cell lymphoma (MCL) appears to be regulated by miRNAs. Although MCL cells exhibit less mRNA and a slower PRMT5 transcription rate than normal B lymphocytes, PRMT5 levels and methylation are significantly increased in H3R8 and H4R3 [Pal, S. et al., EMBO J, 2007.26(15):p.3558-69]. Reexpression of miRNAs that bind to the 3'UTR region of PRMT5 reduces PRMT5 protein levels [Wang, L. et al., Molecular Cell Biology, 2008.28(20):p.6262-77]. Surprisingly, the antisense RNA of prmt5 was found in the human prmt5 gene, a finding that supports the hypothesis of specific translation 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 published to date. Just recently, a novel, sub-nanomolar potent PRMT5 inhibitor (EPZ015666) with antitumor activity in multiple MCL xenograft models was described as the first chemical probe suitable for further validation of the life history and role of PRMT5 in cancer [Chan-Penebre, E. et al., Nature Chem Biol, 2015.11(6): 432-7].

[0010] Further research into PRMT5-specific small molecule inhibitors may lead to new chemotherapy therapies for cancer.

[0011] WO 2014100695 A1 discloses compounds for inhibiting PRMT5 activity and describes methods for using these compounds to treat PRMT5-mediated conditions.

[0012] WO 2014100730 A1 discloses PRMT5 inhibitors containing dihydro or tetrahydroisoquinoline and their uses.

[0013] Devkota, K. et al., ACS Med Chem Lett, 2014.5: pp. 293-297, describe the synthesis of a series of analogues of the natural product sinefentanyl and the ability of these analogues to inhibit EHMT1 and EHMT2.

[0014] WO 2003070739 discloses partial and complete agonists of the A1 adenosine receptor, the preparation of these agonists, and their therapeutic uses.

[0015] WO 2012082436 discloses compounds and compositions that act as regulators of histone methyltransferases, as well as compounds and compositions for treating diseases affected by the regulation of histone methyltransferase activity.

[0016] WO 2014100719 disclosed PRMT5 inhibitors and their uses.

[0017] WO 03074083 discloses a combination therapy that selectively kills cells lacking methionine phosphorylase. Analogs of MTA are described herein as antitoxic agents.

[0018] Kung, P.-P. et al., Bioorg Med Chemette, 2005, 15: 2829-2833, describe the design, synthesis and biological evaluation of novel human 5'-deoxy-5'-methionine phosphorylase (MTAP) substrates.

[0019] WO 2012075500 discloses a 7-deoxypurine regulator of histone methyltransferases.

[0020] WO 2014035140 discloses compounds and compositions for regulating histone methyltransferase activity.

[0021] WO 2015200680 describes PRMT5 inhibitors and their uses.

[0022] Therefore, there is a strong demand for novel PRMT5 inhibitors, which open new avenues for the treatment or prevention of cancers, such as mantle cell lymphoma. Therefore, the object of this invention is to provide such compounds.

[0023] Compared with compounds disclosed in the prior art, the compounds of the present invention have different structures and may have improved properties, such as improved potency, or improved pharmacokinetics (PK) and oral bioavailability. SUMMARY OF THE INVENTION

[0024] The compounds of the present invention have been found to be useful as PRMT5 inhibitors. The compounds according to the present invention and compositions thereof can be used to treat or prevent, in particular to treat, diseases such as blood disorders, metabolic disorders, autoimmune diseases, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, sperm motility, transplant rejection, graft rejection, lung injury, and the like.

[0025] This invention relates to novel compounds having the chemical formula (I):

[0026]

[0027] in

[0028] R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0029] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0030] Y represents -O-, -CH2-, or -CF2-;

[0031] Z represents -CH2-, -X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h - or -C≡C-; and when Y represents -CH2- or -CF2-, then Z can also represent -O- or -CR. 5a R 5b -X-;

[0032] 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;

[0033] X represents -O-, -S-, or -NR 11 -;

[0034] R 11 Represents hydrogen, C 1-4 Alkyl, or C substituted by a substituent 1-4 Alkyl group, wherein the substituent is selected from the group consisting of -OH, -OC 1-4 Alkyl, R 12 、-NH2、-NH-C 1-4 Alkyl groups and -N(C) 1-4 alkyl)2; R 12 Represents a 4, 5, 6, or 7-membered heterocycle containing a nitrogen atom and optionally an oxygen atom; the 4, 5, 6, or 7-membered heterocycle is attached to the remainder of the molecule via a cyclic nitrogen atom;

[0035] Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein one or two ring carbon atoms are optionally replaced by nitrogen atoms; the condition being that a carbonyl group is present in the bicyclic aromatic ring system when a nitrogen atom replaces one of the two fused carbon atoms.

[0036] Ar may be optionally substituted by one, two, three, or four substituents independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d -NR 10c R 10dCyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 Alkoxy group, -C(=O)-OC 1-4 Alkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, -NH-C 3-6 Cycloalkyl, -N(C) 3-6 2, C (cycloalkyl) 2-6 alkenyl group, with one C 1-4 alkoxy-substituted C 1-4 Alkyl group, and optionally with a -NR 10a R 10b Replacement C 1-4 alkyl;

[0037] R 10a and R 10b Each independently represents hydrogen or C. 1-4 alkyl;

[0038] R 10c and R 10d Each independently represents C 3-6 Cycloalkyl; R 13 ;R 14 C substituted by one, two or three substituents independently selected from the following group 3-6 Cycloalkyl groups, this group consists of halogens, -OH and -OC. 1-4 Alkyl composition; C14 cells substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups. 1-4 Alkyl groups, this group consists of halogens, -OH and -OC. 1-4 Alkyl composition; or C substituted with one of the following substituents. 1-4 Alkyl groups, this group consists of C 3-6 cycloalkyl, R 13 and R 14 composition;

[0039] R 13 It 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; or it represents a 6- to 11-membered bicyclic fused aromatic ring containing one, two, or three heteroatoms, each independently selected from O, S, S(=O)p, and N.

[0040] The 4- to 7-membered monocyclic aromatic ring or the 6- to 11-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C 1-4 Alkyl composition;

[0041] p represents 1 or 2;

[0042] R 14 Represents a phenyl group that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens;

[0043] Het represents a bicyclic aromatic heterocyclic system selected from the following group, which consists of (a-1), (a-2), (a-3), (a-4), and (a-5):

[0044]

[0045] R 3a 、R 3b 、R 3c 、R 3d and R 3e Each independently represents hydrogen, halogen, and -NR. 7a R 7b 、C 1-4 Alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, -OH, or -OC 1-4 alkyl;

[0046] R 7a Represents hydrogen;

[0047] R 7b Represents hydrogen, C 3-6 cycloalkyl, or C 1-4 alkyl;

[0048] R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f and R 4g Each region independently represents hydrogen, halogen, and -NR. 8a R 8b or C 1-4 alkyl;

[0049] R 8a and R 8b Each independently represents hydrogen or C. 1-4 alkyl;

[0050] Q 1 Represents N or CR 6a ;

[0051] Q 2 Represents N or CR 6b ;

[0052] Q3 Represents N or CR 6c ;

[0053] Q 4 Represents N or CR 6d ;

[0054] Its condition is Q 3 and Q 4 At most one of them represents N;

[0055] Q 8 Represents N or CR 6g ;

[0056] Q 9 Represents N or CR 6h ;

[0057] Q 10 Represents N or CR 6i ;

[0058] Q 11 Represents N or CR 6j ;

[0059] Q 5 Represents CR 3d ;Q 6 Represent N; and Q 7 Represents CR 4f ;or

[0060] Q 5 Represents CR 3d ;Q 6 Represents CR 4e And Q 7 Represents N; or

[0061] Q 5 Representing N; Q 6 Represents CR 4e And Q 7 Represents CR 4f ;or

[0062] Q 5 Representing N; Q 6 Represents CR 4e And Q 7 Represents N; or

[0063] Q 5 Representing N; Q 6 Represent N; and Q 7 Represents CR 4f ;or

[0064] Q 5 Representing N; Q 6 Represent N; and Q7 Represents N;

[0065] R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h 、R 6i and R 6j Each independently represents hydrogen, halogen, and C. 1-4 Alkyl, -NR 9a R 9b Or C atoms replaced by one, two, or three halogen atoms 1-4 alkyl;

[0066] R 9a and R 9b Each independently represents hydrogen or C. 1-4 alkyl;

[0067] and its pharmaceutically acceptable addition salts and solvates;

[0068] The following compounds, and their pharmaceutically acceptable addition salts and solvates, are excluded:

[0069]

[0070] The present invention also relates to methods for preparing the compounds of the present invention and pharmaceutical compositions comprising them.

[0071] It was found that the compounds of the present invention can inhibit PRMT5 themselves, or can undergo metabolism into a form that is (more) active in the body (prodrug), and can therefore be used for the treatment or prevention, in particular for the treatment of the following diseases, such as blood disorders, metabolic disorders, autoimmune diseases, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, sperm motility, transplant rejection, graft rejection, lung injury, etc.

[0072] Based on the pharmacology of the above-mentioned compounds having chemical formula (I) and their pharmaceutically acceptable addition salts and solvates, it is concluded that these compounds are suitable for use as pharmaceutical agents.

[0073] Specifically, compounds having chemical formula (I) and their pharmaceutically acceptable addition salts and solvates may be suitable for the treatment or prevention, especially for the treatment of any disease or condition mentioned in the context, particularly cancer.

[0074] The present invention also relates to the use of compounds having chemical formula (I) and their pharmaceutically acceptable addition salts and solvates for the production of a medicament for the treatment or prevention, particularly for the treatment of any of the diseases or conditions described in the context, especially cancer.

[0075] The invention will now be described further. In the following paragraphs, different aspects of the invention are defined in more detail. Unless expressly stated otherwise, each aspect so defined may be combined with any or more other aspects. Specifically, any feature indicated as preferred or advantageous may be combined with any or more other features indicated as preferred or advantageous. Detailed Description of the Invention

[0076] When describing the compounds of the present invention, unless the context otherwise specifies, the terminology used is intended to be understood in accordance with the following definitions.

[0077] When any variable appears more than once in any component or in any chemical formula (e.g., chemical formula (I)), its definition at each occurrence is independent of its definition at each other occurrence.

[0078] Whenever the term “substitution” is used in this invention, unless otherwise specified or clearly stated in the context, it means that one or more hydrogen atoms (particularly from 1 to 3 hydrogen atoms, preferably 1 or 2 hydrogen atoms, more preferably 1 hydrogen atom) on an atom or group indicated in the use of “substitution” are replaced by an option from the indicated group, provided that the normal valence is not exceeded and that 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 level of purity and robust enough to withstand formulation as a therapeutic agent).

[0079] When two or more substituents are present on a part, unless otherwise specified or clearly stated in the context, these substituents may replace hydrogen atoms on the same atom or may replace hydrogen atoms on different atoms in that part.

[0080] As the prefix "C" is used here x-y "(where x and y are integers)" refers to the number of carbon atoms in a given group. Therefore, C 1-4 Alkyl groups contain 1 to 4 carbon atoms, C 1-3 Alkyl groups contain 1 to 3 carbon atoms, and so on.

[0081] Unless otherwise specified or the context is clear, the term "halogen" as a group or part of a group is generally used for fluorine, chlorine, bromine, and iodine.

[0082] The term "C" as a group or part of a group 1-4"Alkyl" refers to a compound with the chemical formula C n H 2n+1 The hydrocarbon group, where n is a number in the range of 1 to 4. C 1-4 Alkyl groups comprise 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, and more preferably 1 to 2 carbon atoms. C 1-4 Alkyl groups can be linear or branched and can be substituted as indicated herein. When a subscript is used after a carbon atom herein, the subscript indicates the number of carbon atoms that the named group may contain. C 1-4 Alkyl groups include all linear or branched alkyl groups having between 1 and 4 carbon atoms, and therefore include methyl, ethyl, n-propyl, isopropyl, 2-methyl-ethyl, butyl and their isomers (e.g., n-butyl, isobutyl and tert-butyl) and the like.

[0083] Technicians will recognize the term 'C' as a group or part of a group. 1-4 alkoxy' or 'C' 1-4 'alkyloxy' refers to having the formula -OR c The group, wherein R c It is C 1-4 Alkyl group. Suitable C 1-4 Non-limiting examples of alkyloxy groups include methyloxy (also known as methoxy), ethyloxy (also known as ethoxy), propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, and tert-butyloxy.

[0084] As used herein as a group or part of a group, the term "C" 2-4 "Alkenyl" represents a straight-chain or branched hydrocarbon group containing 2 to 4 carbon atoms and a carbon-carbon double bond, such as, but not limited to: vinyl, propenyl, butenyl, 1-propen-2-yl, etc.

[0085] As used herein as a group or part of a group, the term "C" 2-6 "Alkenyl" represents a straight-chain or branched hydrocarbon group containing 2 to 6 carbon atoms and a carbon-carbon double bond, such as, but not limited to: vinyl, propenyl, butenyl, pentenyl, 1-propen-2-yl, hexenyl, etc.

[0086] As used herein, the term 'C' is used as a group or part of a group. 3-6 'Cycloalkyl' represents a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0087] In Z is -X-CR 5a R 5b In the case of -, this means that X is attached to Ar.

[0088] In Z is -CR5c =CR 5d - In the case of R, this means having 5c The carbon atom of the substituent is attached to Ar.

[0089] In Z is -CR 5e R 5g -CR 5f R 5h - In the case of R, this means having 5e and R 5g The carbon atom of the substituent is attached to Ar.

[0090] In Z is -CR 5a R 5b In the case of -X-, this means having R 5a and R 5b The carbon atom of the substituent is attached to Ar.

[0091] Technicians will recognize the 4, 5, 6, or 7-membered heterocycles (see R) attached to the remainder of the molecule via a cyclic nitrogen atom. 12 (by definition), specifically a saturated ring. R 12 Non-limiting examples are 1-piperidinyl, 1-pyrrolidinyl, 1-morpholinyl, 1-azacyclobutyl and the like.

[0092] Those skilled in the art will understand that, unless otherwise specified or clearly stated in the context, 4- to 7-membered monocyclic aromatic rings containing one, two, or three heteroatoms (see R...) 13 The substituents on the alkyl radicals (non-limiting examples are pyrrolyl, pyridyl, furyl, etc.) may replace any hydrogen on a ring carbon atom or, where possible, any hydrogen on a ring nitrogen atom (in which case a hydrogen on a ring nitrogen atom may be replaced by a substituent). The skilled person will be aware that the same applies to 6- to 11-membered bicyclic fused aromatic rings containing one, two or three heteroatoms (see R 13 (Definition of ) (Non-limiting examples are indole, quinolinyl, etc.).

[0093] 4- to 7-membered monocyclic aromatic rings containing one, two, or three heteroatoms (see R 13 The term "a" refers to a group consisting of a 6- to 11-membered bicyclic fused aromatic ring (see R) and a 6- to 11-membered bicyclic fused aromatic ring (see R) which may be attached to the remainder of the molecule of formula (I) via any available ring carbon or nitrogen atom, unless otherwise specified. The skilled person will appreciate that the same applies to 6- to 11-membered bicyclic fused aromatic rings containing one, two or three heteroatoms (see R). 13 (Definition).

[0094] When a nitrogen atom replaces one of the two fused carbon atoms in the Ar group, a carbonyl group exists in the bicyclic aromatic ring system, as illustrated in the following structural diagram:

[0095] It may be optionally replaced according to any embodiment. Obviously, this example is non-limiting.

[0096] Shown below are other non-limiting examples of Ar groups, which are 10-membered bicyclic aromatic ring systems consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are substituted with nitrogen atoms:

[0097]

[0098] Each of these may be optionally substituted according to any embodiment.

[0099] Those skilled in the art will appreciate that the 10-membered Ar group (the 10-membered bicyclic aromatic ring system consists of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are substituted with nitrogen atoms) is 10 carbon atoms, 9 carbon atoms and 1 nitrogen atom, or 8 carbon atoms and 2 nitrogen atoms. Ar is optionally substituted according to any embodiment.

[0100] Whenever a substituent is represented by a chemical structure, "---" represents a bond to the rest of the molecule of Formula (I). A line drawn from a substituent to the ring system indicates that the bond can be attached to any suitable ring atom.

[0101] For example, Covers any of the following ring systems:

[0102]

[0103] yes An alternative representative.

[0104] As used herein, the term "subject" refers to an animal, preferably a mammal (eg, a cat, dog, primate, or human), more preferably a human, that is or has been the object of treatment, observation, or experiment.

[0105] As used herein, the term "therapeutically effective amount" means that amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system (animal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician, including alleviation or reversal of symptoms of the disease or disorder being treated.

[0106] The term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0107] As used herein, the term “treatment” is intended to refer to all processes that may slow, interrupt, halt, or prevent the progression of a disease, but does not necessarily indicate the complete elimination of all symptoms.

[0108] As used herein, the term "compound of the invention" is intended to include compounds having chemical formula (I) and their pharmaceutically acceptable addition salts and solvates.

[0109] Some compounds having chemical formula (I) may also exist in their tautomeric forms. The terms "tautomer" or "tautomeric form" refer to structural isomers with different energies that can interconvert via low-energy barriers. For example, proton tautomers (also called proton-transfer tautomers) include interconversions resulting from proton transfers, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions resulting from the recombination of some bonding electrons. Although not explicitly indicated in the above chemical formula (I), such forms are intended to be included within the scope of this invention where they may exist.

[0110] As used herein, any chemical formula having bonds shown only as solid lines and not as real or virtual wedge bonds, or otherwise represented as having a particular configuration (e.g., R, S) around one or more atoms, is considered for every possible stereoisomer, or a mixture of two or more stereoisomers. In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, all stereoisomers are considered to be compounds of the invention and included in the compounds of the invention, either as a pure stereoisomer or as a mixture of two or more stereoisomers.

[0111] In this context, the term "compound having formula (I)" means including both its stereoisomers and its tautomers. However, as stated in the preceding paragraphs, where the stereochemistry is indicated by bonds shown as solid or virtual wedges, or otherwise represented as bonds with a specific configuration (e.g., R, S), then the stereoisomer is specified and defined. Clearly, this also applies to subgroups having formula (I).

[0112] Therefore, it can be concluded that, where possible, a single compound can exist in stereoisomeric and tautomeric forms.

[0113] In the preceding or following text, the terms “stereoisomer,” “stereoisomeric form,” or “stereochemical isomeric form” are used interchangeably.

[0114] Enantiomers are stereoisomers that are not mirror images of each other. A 1:1 mixture of enantiomer pairs is a racemic mixture or a mixture of racemic components.

[0115] An atropisomer is a stereoisomer with a specific spatial configuration resulting from restricted rotation around a single bond due to steric hindrance. All atropisomers of the compounds of formula (I) are intended to be included within the scope of this invention.

[0116] Diastereomers (or diastereomers) are stereoisomers of diastereomers, i.e., they are not related in mirror image form. If the compound contains a double bond, the substituents can be in E or Z configuration. Substituents on a (partially) saturated group of a divalent ring can have cis-(cis-) or trans-(trans-) configurations; for example, if the compound contains a disubstituted cycloalkyl group, the substituents can be in cis or trans configurations. Therefore, the present invention includes enantiomers, trans-block isomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, as long as chemically possible.

[0117] The meanings of all those terms (i.e., enantiomers, steganous isomers, diastereomers, racemic isomers, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof) are known to a skilled person.

[0118] The absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at the asymmetric atom is specified by R or S. Separated stereoisomers with unknown absolute configurations can be specified by (+) or (-) depending on the direction of their rotational plane-polarized light. For example, separated enantiomers with unknown absolute configurations can be specified by (+) or (-) depending on the direction of their rotational plane-polarized light.

[0119] 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%, particularly less than 2%, and most preferably less than 1%. Therefore, when a compound having chemical formula (I) is specified, for example, as (R), this means that the compound is substantially free of the (S) isomer; when a compound having chemical formula (I) is specified, for example, as E, this means that the compound is substantially free of the Z isomer; and when a compound having chemical formula (I) is specified, for example, as cis, this means that the compound is substantially free of the trans isomer.

[0120] For therapeutic purposes, salts of compounds having chemical formula (I) and their solvates are those in which the balancing ions are pharmaceutically acceptable. However, salts of pharmaceutically unacceptable acids and bases may also be found for 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 this invention.

[0121] Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can be formed by conventional means, for example, by reacting a free acid or a free base form with one or more equivalents of a suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, followed by removal of the solvent or medium using standard techniques (e.g., in a vacuum, by freeze drying or by filtration). Various salts can also be prepared by exchanging a counterion of a compound of the invention in salt form with another counterion, for example, using a suitable ion exchange resin.

[0122] Pharmaceutically acceptable addition salts, as mentioned above or below, are intended to include non-toxic acid and base addition salts with therapeutic activity that can be formed from compounds having chemical formula (I) and their solvates.

[0123] Or organic acid, for example, as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid (i.e. oxalic acid), malonic acid, succinic acid (i.e. succinic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid and similar acid.On the contrary, can be by treating with suitable alkali, described salt form is converted into free alkali form.

[0124] Compounds containing acidic protons and their solvates, as well as their non-toxic metal or amine addition salts, can also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.

[0125] Suitable base salt forms include, for example, ammonium salts, alkali metal and alkaline earth metal salts, such as lithium, sodium, potassium, magnesium, calcium salts and the like; salts of the following organic bases: such as primary, secondary and tertiary aliphatic and aromatic amines, such as methylamine, ethylamine, propylamine, isopropylamine, four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinine ring, pyridine, quinoline and isoquinoline; benzathine penicillin, N-methyl-D-glucosamine, hydrabamine salt; and salts of the following amino acids: such as arginine, lysine, etc. Conversely, this salt form can be converted to a free acid form by acid treatment.

[0126] For the purposes of this invention, prodrugs are also included within the scope of this invention.

[0127] The term "prodrug" for the relevant compounds of this invention includes any compound that, after oral or parenteral administration (especially oral administration), is metabolized in vivo to form an experimentally detectable amount of the compound, and within a predetermined timeframe (e.g., dosing intervals between 6 and 24 hours, i.e., once to four times daily). For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration, specifically intravenous (IV), intramuscular (IM), and subcutaneous (SC) injection.

[0128] Prodrugs can be prepared by modifying functional groups present on the compound in a manner that allows these modifications to be cleaved in vivo when administered to a mammalian subject. Typically, these modifications are accomplished by synthesizing a parent compound having prodrug substituents. Generally, prodrugs comprise compounds of the present invention, wherein hydroxyl, amino, mercapto, carboxyl, or carbonyl groups in the compounds of the present invention are bound to any group that can be cleaved in vivo to regenerate free hydroxyl, amino, mercapto, carboxyl, or carbonyl groups, respectively; specifically, wherein the hydroxyl group of the compounds of the present invention is bound to any group that can be cleaved in vivo (e.g., -C(=O)-C). 1-4 The alkyl group is regenerated to produce a free hydroxyl group. For the purposes of this invention, a specific prodrug is a compound having chemical formula (I) or a subgroup thereof, wherein R... 1 and / or R 2 represents -C(=O)-C 1-4 alkyl.

[0129] Examples of prodrugs include, but are not limited to, esters and carbamates with hydroxyl functional groups, esters with carboxyl functional groups, N-acyl derivatives, and N-Mannich bases. General information about prodrugs can be found, for example, in Bundegaard, H., “Design of Prodrugs,” pp. 1-92, Elesevier, New York-Oxford (1985).

[0130] The term solvate includes hydrates and solvation forms that compounds having the chemical formula (I) can form together with their pharmaceutically acceptable addition salts. Examples of such forms are, for example, hydrates, alcohols, and the like.

[0131] The compounds of the present invention prepared in the methods described below can be synthesized as mixtures of enantiomers, particularly racemic mixtures of enantiomers, which can be separated from each other according to resolution procedures known in the art. One method for separating enantiomers of compounds having chemical formula (I) and their pharmaceutically acceptable addition salts and solvates involves liquid chromatography using a chiral stationary phase. The pure stereochemical isomers can also be derived from corresponding pure stereochemical isomers of suitable starting materials, provided that the reaction proceeds stereospecifically. Preferably, if a particular stereoisomer is desired, the compound is synthesized by a stereotactic method of preparation. These methods will advantageously use enantiomerically pure starting materials.

[0132] The present invention also includes isotopically labeled compounds of the present invention, which are the same as those listed herein, but in fact one or more atoms are replaced by atoms having an atomic mass or mass number different from that found in nature (or the most common one found in nature).

[0133] All isotopes and mixtures of isotopes of any specific atom or element specified herein are considered to be within the scope of this invention, whether naturally occurring or synthetically produced, having natural abundance or being in isotopically enriched form. Exemplary isotopes that may be included in the compounds of this 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, 18F, 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 this invention.

[0134] Certain isotope-labeled compounds of the present invention (e.g., with) 3 H and 14 Those labeled with C are useful in compounds and for substrate tissue distribution determination. Tritium ( 3 H) and carbon-14 ( 14 C) Isotopes are useful because they facilitate preparation and detectability. Furthermore, heavier isotopes (such as deuterium) are also useful. 2 H) substitution can provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement) and is therefore preferred in some settings. Positron-emitting isotopes (such as 15 O、 13 N. 11 C and 18 F) It is useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0135] In all the following examples, the following compounds, as well as their pharmaceutically acceptable addition salts and solvates, were excluded:

[0136]

[0137]

[0138] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0139] R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0140] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0141] Y represents -O-, -CH2-, or -CF2-;

[0142] Z represents -CH2-, -X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h -、or -C≡C-;

[0143] And when Y represents -CH2- or -CF2-, Z can also represent -O- or -CR 5a R 5b -X-;

[0144] 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;

[0145] X represents -O-, -S-, or -NR 11 -;

[0146] R 11 Represents hydrogen or C 1-4 alkyl;

[0147] Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused six-membered rings, wherein optionally one or two ring carbon atoms are substituted 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;

[0148] Ar may be optionally substituted by one, two, three, or four substituents independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d -NR 10c R 10d Cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 Alkoxy group, -C(=O)-OC 1-4 Alkyl, C 3-6 cycloalkyl, -OC3-6 cycloalkyl, -NH-C 3-6 Cycloalkyl, -N(C) 3-6 2, C (cycloalkyl) 2-6 alkenyl group, with one C 1-4 alkoxy-substituted C 1-4 Alkyl group, and optionally with a -NR 10a R 10b Replacement C 1-4 alkyl;

[0149] R 10a and R 10b Each independently represents hydrogen or C. 1-4 alkyl;

[0150] R 10c and R 10d Each independently represents C 3-6 Cycloalkyl; R 14 C substituted by one, two or three substituents independently selected from the following group 3-6 Cycloalkyl groups, this group consists of halogens, -OH and -OC. 1-4 Alkyl composition; C14 cells substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups. 1-4 Alkyl groups, this group consists of halogens, -OH and -OC. 1-4 Alkyl composition; or C substituted with one of the following substituents. 1-4 Alkyl groups, this group consists of C 3-6 cycloalkyl and R 14 composition;

[0151] R 14 Represents a phenyl group that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens;

[0152] Het represents a bicyclic aromatic heterocyclic system selected from the following group, which consists of (a-1), (a-2), (a-3), (a-4), and (a-5):

[0153]

[0154] R 3a 、R 3b 、R 3c 、R 3d and R 3e Each independently represents hydrogen, halogen, and -NR. 7a R 7b 、C 1-4 Alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, -OH, or -OC 1-4 alkyl;

[0155] R 7a Represents hydrogen;

[0156] R 7b Represents hydrogen, C 3-6 cycloalkyl, or C 1-4 alkyl;

[0157] R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f and R 4g Each region independently represents hydrogen, halogen, and -NR. 8a R 8b or C 1-4 alkyl;

[0158] R 8a and R 8b Each independently represents hydrogen or C. 1-4 alkyl;

[0159] Q 1 Represents N or CR 6a ;

[0160] Q 2 Represents N or CR 6b ;

[0161] Q 3 Represents N or CR 6c ;

[0162] Q 4 Represents N or CR 6d ;

[0163] Its condition is Q 3 and Q 4 At most one of them represents N;

[0164] Q 8 Represents N or CR 6g ;

[0165] Q 9 Represents N or CR 6h ;

[0166] Q 10 Represents N or CR 6i ;

[0167] Q 11 Represents N or CR 6j ;

[0168] Q 5 Represents CR 3d;Q 6 Represent N; and Q 7 Represents CR 4f ;or

[0169] Q 5 Represents CR 3d ;Q 6 Represents CR 4e And Q 7 Represents N; or

[0170] Q 5 Representing N; Q 6 Represents CR 4e And Q 7 Represents CR 4f ;or

[0171] Q 5 Representing N; Q 6 Represents CR 4e And Q 7 Represents N; or

[0172] Q 5 Representing N; Q 6 Represent N; and Q 7 Represents CR 4f ;or

[0173] Q 5 Representing N; Q 6 Represent N; and Q 7 Represents N;

[0174] R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h 、R 6i and R 6j Each independently represents hydrogen, halogen, and C. 1-4 Alkyl, -NR 9a R 9b Or C atoms replaced by one, two, or three halogen atoms 1-4 alkyl;

[0175] R 9a and R 9b Each independently represents hydrogen or C. 1-4 alkyl;

[0176] And its pharmaceutically acceptable addition salts and solvates.

[0177] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0178] R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0179] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0180] Y represents -O-, -CH2-, or -CF2-;

[0181] Z represents -CH2-, -X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h -、or -C≡C-;

[0182] And when Y represents -CH2- or -CF2-, Z can also represent -O- or -CR 5a R 5b -X-;

[0183] 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;

[0184] X represents -O-, -S-, or -NR 11 -;

[0185] R 11 Represents hydrogen, C 1-4 Alkyl, or C substituted by a substituent 1-4 Alkyl group, wherein the substituent is selected from the group consisting of -OH, -OC 1-4 Alkyl, R 12 、-NH2、-NH-C 1-4 Alkyl groups and -N(C) 1-4 alkyl)2; R 12 Represents a 4, 5, 6, or 7-membered heterocycle containing a nitrogen atom and optionally an oxygen atom; the 4, 5, 6, or 7-membered heterocycle is attached to the remainder of the molecule via a cyclic nitrogen atom;

[0186] Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein one or two ring carbon atoms are optionally replaced by nitrogen atoms; the condition being that a carbonyl group is present in the bicyclic aromatic ring system when a nitrogen atom replaces one of the two fused carbon atoms.

[0187] Ar may be optionally substituted by one, two, three, or four substituents independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d -NR 10c R 10d Cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 Alkoxy group, -C(=O)-OC 1-4 Alkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, -NH-C 3-6 Cycloalkyl, -N(C) 3-6 2, C (cycloalkyl) 2-6 alkenyl group, with one C 1-4 alkoxy-substituted C 1-4 Alkyl group, and optionally with a -NR 10a R 10b Replacement C 1-4 alkyl;

[0188] R 10a and R 10b Each independently represents hydrogen or C. 1-4 alkyl;

[0189] R 10c and R 10d Each independently represents C 3-6 Cycloalkyl; R 13 ;R 14 C substituted by one, two or three substituents independently selected from the following group 3-6 Cycloalkyl groups, this group consists of halogens, -OH and -OC. 1-4 Alkyl composition; C14 cells substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups. 1-4 Alkyl groups, this group consists of halogens, -OH and -OC. 1-4 Alkyl composition; or C substituted with one of the following substituents. 1-4 Alkyl groups, this group consists of C 3-6 cycloalkyl, R 13 and R 14composition;

[0190] R 13 It 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; or it represents a 6- to 11-membered bicyclic fused aromatic ring containing one, two, or three heteroatoms, each independently selected from O, S, S(=O)p, and N.

[0191] The 4- to 7-membered monocyclic aromatic ring or the 6- to 11-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C 1-4 Alkyl composition;

[0192] p represents 1 or 2;

[0193] R 14 Represents a phenyl group that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens;

[0194] Het represents a bicyclic aromatic heterocyclic system selected from the following group, which consists of (a-1), (a-2), (a-3), (a-4), and (a-5):

[0195]

[0196] R 3a 、R 3b 、R 3c 、R 3d and R 3e Each independently represents hydrogen, halogen, and -NR. 7a R 7b 、C 1-4 Alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, -OH, or -OC 1-4 alkyl;

[0197] R 7a Represents hydrogen;

[0198] R 7b Represents hydrogen, C 3-6 cycloalkyl, or C 1-4 alkyl;

[0199] R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f and R 4g Each region independently represents hydrogen, halogen, and -NR. 8a R8b or C 1-4 alkyl;

[0200] R 8a and R 8b Each independently represents hydrogen or C. 1-4 alkyl;

[0201] Q 1 Represents CR 6a ;

[0202] Q 2 Represents CR 6b ;

[0203] Q 3 Represents N or CR 6c ;

[0204] Q 4 Represents N or CR 6d ;

[0205] Its condition is Q 3 and Q 4 At most one of them represents N;

[0206] Q 8 Represents N or CR 6g ;

[0207] Q 9 Represents N or CR 6h ;

[0208] Q 10 Represents N or CR 6i ;

[0209] Q 11 Represents N or CR 6j ;

[0210] Q 5 Represents CR 3d ;Q 6 Represent N; and Q 7 Represents CR 4f ;or

[0211] Q 5 Represents CR 3d ;Q 6 Represents CR 4e And Q 7 Represents N; or

[0212] Q 5 Representing N; Q 6 Represents CR 4e And Q 7 Represents CR 4f ;or

[0213] Q 5 Representing N; Q 6 Represents CR 4e And Q 7 Represents N; or

[0214] Q 5 Representing N; Q 6 Represent N; and Q 7 Represents CR 4f ;or

[0215] Q 5 Representing N; Q 6 Represent N; and Q 7 Represents N;

[0216] R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h 、R 6i and R 6j Each independently represents hydrogen, halogen, and C. 1-4 Alkyl, -NR 9a R 9b Or C atoms replaced by one, two, or three halogen atoms 1-4 alkyl;

[0217] R 9a and R 9b Each independently represents hydrogen or C. 1-4 alkyl;

[0218] And its pharmaceutically acceptable addition salts and solvates.

[0219] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0220] R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0221] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0222] Y represents -O-, -CH2-, or -CF2-;

[0223] Z represents -CH2-, -X-CR 5a R 5b -、-CR 5c =CR5d -、-CR 5e R 5g -CR 5f R 5h -、or -C≡C-;

[0224] And when Y represents -CH2- or -CF2-, Z can also represent -O- or -CR 5a R 5b -X-;

[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 substituted by a substituent 1-4 Alkyl group, wherein the substituent is selected from the group consisting of -OH, -OC 1-4 Alkyl, R 12 、-NH2、-NH-C 1-4 Alkyl groups and -N(C) 1-4 Alkyl)2 composition; R 12 Represents a 4, 5, 6, or 7-membered heterocycle containing a nitrogen atom and optionally an oxygen atom; the 4, 5, 6, or 7-membered heterocycle is attached to the remainder of the molecule via a cyclic nitrogen atom;

[0228] Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein one or two ring carbon atoms are optionally replaced by nitrogen atoms; the condition being that a carbonyl group is present in the bicyclic aromatic ring system when a nitrogen atom replaces one of the two fused carbon atoms.

[0229] Ar may be optionally substituted by one, two, three, or four substituents independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d -NR 10c R 10d Cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C 1-4Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 Alkoxy group, -C(=O)-OC 1-4 Alkyl, C 3-6 Cycloalkyl, C 2-6 alkenyl group, with one C 1-4 alkoxy-substituted C 1-4 Alkyl group, and optionally with a -NR 10a R 10b Replacement C 1-4 alkyl;

[0230] R 10a and R 10b Each independently represents hydrogen or C. 1-4 alkyl;

[0231] R 10c and R 10d Each independently represents C 3-6 cycloalkyl; C14 substituted with one, two or three substituents independently selected from the group consisting of cycloalkyl groups. 3-6 Cycloalkyl groups, this group consists of halogens, -OH and -OC. 1-4 Alkyl composition; C14 cells substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups. 1-4 Alkyl groups, this group consists of halogens, -OH and -OC. 1-4 Alkyl composition; or C substituted with one of the following substituents. 1-4 Alkyl groups, this group consists of C 3-6 cycloalkyl, R 13 and R 14 composition;

[0232] R 13 It 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; or it represents a 6- to 11-membered bicyclic fused aromatic ring containing one, two, or three heteroatoms, each independently selected from O, S, S(=O)p, and N.

[0233] The 4- to 7-membered monocyclic aromatic ring or the 6- to 11-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C 1-4 Alkyl composition;

[0234] p represents 1 or 2;

[0235] R 14 Represents a phenyl group that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens;

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

[0237]

[0238] R 3a 、R 3b and R 3c Each independently represents hydrogen, halogen, and -NR. 7a R 7b 、C 1-4 Alkyl, or -OC 1-4 Alkyl; R 7a Represents hydrogen;

[0239] R 7b Represents hydrogen or C 1-4 alkyl;

[0240] R 4a 、R 4b and R 4c Each independently represents hydrogen, halogen, and -NR. 8a R 8b or C 1-4 alkyl;

[0241] R 8a 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 3 Represents N or CR 6c ;

[0245] Q 4 Represents N or CR 6d ;

[0246] Its condition is Q 3 and Q 4 At most one of them represents N;

[0247] R 6a 、R 6b 、R 6c 、R 6d 、R 6e and R 6f Each independently represents hydrogen, halogen, and carbon. 1-4 Alkyl, -NR 9a R9b C atoms that are substituted with one, two, or three halogen atoms 1-4 alkyl;

[0248] R 9a and R 9b Each independently represents hydrogen or C. 1-4 alkyl;

[0249] And its pharmaceutically acceptable addition salts and solvates.

[0250] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0251] R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0252] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0253] Y represents -O-, -CH2-, or -CF2-;

[0254] Z represents -CH2-, -X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h -、or -C≡C-;

[0255] And when Y represents -CH2- or -CF2-, Z can also represent -O- or -CR 5a R 5b -X-;

[0256] 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;

[0257] X represents -O-, -S-, or -NR 11 -;

[0258] R 11 Represents hydrogen, C 1-4 Alkyl, or C substituted by a substituent 1-4Alkyl group, wherein the substituent is selected from the group consisting of -OH, -OC 1-4 Alkyl, R 12 、-NH2、-NH-C 1-4 Alkyl groups and -N(C) 1-4 alkyl)2; R 12 Represents a 4, 5, 6, or 7-membered heterocycle containing a nitrogen atom and optionally an oxygen atom; the 4, 5, 6, or 7-membered heterocycle is attached to the remainder of the molecule via a cyclic nitrogen atom;

[0259] Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein one or two ring carbon atoms are optionally replaced by nitrogen atoms; the condition being that a carbonyl group is present in the bicyclic aromatic ring system when a nitrogen atom replaces one of the two fused carbon atoms.

[0260] Ar may be optionally substituted by one, two, three, or four substituents independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 alkoxy group, and optionally a -NR group 10a R 10b Replacement C 1-4 alkyl;

[0261] R 10a and R 10b Each independently represents hydrogen or C. 1-4 alkyl;

[0262] Het represents a bicyclic aromatic heterocyclic system selected from the following group, which consists of (a-1), (a-2), and (a-3):

[0263]

[0264] R 3a 、R 3b and R 3c Each independently represents hydrogen, halogen, and -NR. 7a R 7b 、or -OC 1-4 alkyl;

[0265] R 7a Represents hydrogen;

[0266] R 7b Represents hydrogen or C 1-4 alkyl;

[0267] R 4a 、R 4b and R 4c Each independently represents hydrogen, halogen, and -NR. 8a R 8b or C 1-4 alkyl;

[0268] R 8a and R 8b Each independently represents hydrogen or C. 1-4 alkyl;

[0269] Q 1 Represents N or CR 6a ;

[0270] Q 2 Represents N or CR 6b ;

[0271] Q 3 Represents N or CR 6c ;

[0272] Q 4 Represents N or CR 6d ;

[0273] Its condition is Q 3 and Q 4 At most one of them represents N;

[0274] R 6a 、R 6b 、R 6c 、R 6d 、R 6e and R 6f Each independently represents hydrogen, halogen, and carbon. 1-4 Alkyl, -NR 9a R 9b C atoms that are substituted with one, two, or three halogen atoms 1-4 alkyl;

[0275] R 9a and R 9b Each independently represents hydrogen or C. 1-4 alkyl;

[0276] And its pharmaceutically acceptable addition salts and solvates.

[0277] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0278] R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0279] R2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0280] Y represents -O-, -CH2-, or -CF2-;

[0281] Z represents -CH2-, -X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h -、or -C≡C-;

[0282] And when Y represents -CH2- or -CF2-, Z can also represent -O- or -CR 5a R 5b -X-;

[0283] 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;

[0284] X represents -O-, -S-, or -NR 11 -;

[0285] R 11 Represents hydrogen, C 1-4 Alkyl, or C substituted by a substituent 1-4 Alkyl group, wherein the substituent is selected from the group consisting of -OH, -OC 1-4 Alkyl, R 12 、-NH2、-NH-C 1-4 Alkyl groups and -N(C) 1-4 Composition: alkyl)2;

[0286] R 12 Represents a 4, 5, 6, or 7-membered heterocycle containing a nitrogen atom and optionally an oxygen atom; the 4, 5, 6, or 7-membered heterocycle is attached to the remainder of the molecule via a cyclic nitrogen atom;

[0287] Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

[0288]

[0289] In this ring, at least one carbon atom of ring B is replaced by a nitrogen atom;

[0290] Optionally, one of the other carbon atoms in ring A or ring B is substituted with a nitrogen atom; provided that a carbonyl group is present in the bicyclic aromatic ring system when the nitrogen atom substitutes for one of the two fused carbon atoms; Ar is optionally substituted with one, two, three, or four substituents independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d -NR 10c R 10d Cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 Alkoxy group, -C(=O)-OC 1-4 Alkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, -NH-C 3-6 Cycloalkyl, -N(C) 3-6 2, C (cycloalkyl) 2-6 alkenyl group, with one C 1-4 alkoxy-substituted C 1-4 Alkyl group, and optionally with a -NR 10a R 10b Replacement C 1-4 alkyl;

[0291] R 10a and R 10b Each independently represents hydrogen or C. 1-4 alkyl;

[0292] R 10c and R 10d Each independently represents C 3-6 Cycloalkyl; R 13 ;R 14 C substituted by one, two or three substituents independently selected from the following group 3-6 Cycloalkyl groups, this group consists of halogens, -OH and -OC. 1-4 Alkyl composition; C14 cells substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups. 1-4 Alkyl groups, this group consists of halogens, -OH and -OC. 1-4 Alkyl composition; or C substituted with one of the following substituents. 1-4 Alkyl groups, this group consists of C 3-6 cycloalkyl, R 13 and R 14composition;

[0293] R 13 It 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; or it represents a 6- to 11-membered bicyclic fused aromatic ring containing one, two, or three heteroatoms, each independently selected from O, S, S(=O)p, and N.

[0294] The 4- to 7-membered monocyclic aromatic ring or the 6- to 11-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C 1-4 Alkyl composition;

[0295] p represents 1 or 2;

[0296] R 14 Represents a phenyl group that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens;

[0297] Het represents a bicyclic aromatic heterocyclic system selected from the following group, which consists of (a-1), (a-2), (a-3), (a-4), and (a-5):

[0298]

[0299] R 3a 、R 3b 、R 3c 、R 3d and R 3e Each independently represents hydrogen, halogen, and -NR. 7a R 7b 、C 1-4 Alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, -OH, or -OC 1-4 alkyl;

[0300] R 7a Represents hydrogen;

[0301] R 7b Represents hydrogen, C 3-6 cycloalkyl, or C 1-4 alkyl;

[0302] R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f and R 4g Each region independently represents hydrogen, halogen, and -NR. 8a R8b or C 1-4 alkyl;

[0303] R 8a and R 8b Each independently represents hydrogen or C. 1-4 alkyl;

[0304] Q 1 Represents N or CR 6a ;

[0305] Q 2 Represents N or CR 6b ;

[0306] Q 3 Represents N or CR 6c ;

[0307] Q 4 Represents N or CR 6d ;

[0308] Its condition is Q 3 and Q 4 At most one of them represents N;

[0309] Q 8 Represents N or CR 6g ;

[0310] Q 9 Represents N or CR 6h ;

[0311] Q 10 Represents N or CR 6i ;

[0312] Q 11 Represents N or CR 6j ;

[0313] Q 5 Represents CR 3d ;Q 6 Represent N; and Q 7 Represents CR 4f ;or

[0314] Q 5 Represents CR 3d ;Q 6 Represents CR 4e And Q 7 Represents N; or

[0315] Q 5 Representing N; Q 6 Represents CR 4e And Q 7 Represents CR 4f ;or

[0316] Q 5 Representing N; Q 6 Represents CR 4e And Q 7 Represents N; or

[0317] Q 5 Representing N; Q 6 Represent N; and Q 7 Represents CR 4f ;or

[0318] Q 5 Representing N; Q 6 Represent N; and Q 7 Represents N;

[0319] R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h 、R 6i and R 6j Each independently represents hydrogen, halogen, and C. 1-4 Alkyl, -NR 9a R 9b Or C atoms replaced by one, two, or three halogen atoms 1-4 alkyl;

[0320] R 9a and R 9b Each independently represents hydrogen or C. 1-4 alkyl;

[0321] And its pharmaceutically acceptable addition salts and solvates.

[0322] In one embodiment, the present invention relates to a novel compound having the chemical formula (I), wherein R 1 represents hydrogen;

[0323] R 2 represents hydrogen;

[0324] Y represents -O-, -CH2-, or -CF2-;

[0325] Z represents -CH2-, -X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h-、or -C≡C-;

[0326] And when Y represents -CH2- or -CF2-, Z can also represent -O- or -CR 5a R 5b -X-;

[0327] 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;

[0328] X represents -O-, -S-, or -NR 11 -;

[0329] R 11 Represents hydrogen, C 1-4 Alkyl, or C substituted by a substituent 1-4 Alkyl group, wherein the substituent is selected from the group consisting of -OH, -OC 1-4 Alkyl, R 12 、-NH2、-NH-C 1-4 Alkyl groups and -N(C) 1-4 Composition: alkyl)2;

[0330] R 12 Represents a 4, 5, 6, or 7-membered heterocycle containing a nitrogen atom and optionally an oxygen atom; the 4, 5, 6, or 7-membered heterocycle is attached to the remainder of the molecule via a cyclic nitrogen atom;

[0331] Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein one or two ring carbon atoms are optionally replaced by nitrogen atoms; the condition being that a carbonyl group is present in the bicyclic aromatic ring system when a nitrogen atom replaces one of the two fused carbon atoms.

[0332] Ar may be optionally substituted by one, two, three, or four substituents independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d -NR 10c R 10d Cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4Alkoxy group, -C(=O)-OC 1-4 Alkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, -NH-C 3-6 Cycloalkyl, -N(C) 3-6 2, C (cycloalkyl) 2-6 alkenyl group, with one C 1-4 alkoxy-substituted C 1-4 Alkyl group, and optionally with a -NR 10a R 10b Replacement C 1-4 alkyl;

[0333] R 10a and R 10b Each independently represents hydrogen or C. 1-4 alkyl;

[0334] R 10c and R 10d Each independently represents C 3-6 Cycloalkyl; R 13 ;R 14 C substituted by one, two or three substituents independently selected from the following group 3-6 Cycloalkyl groups, this group consists of halogens, -OH and -OC. 1-4 Alkyl composition; C14 cells substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups. 1-4 Alkyl groups, this group consists of halogens, -OH and -OC. 1-4 Alkyl composition; or C substituted with one of the following substituents. 1-4 Alkyl groups, this group consists of C 3-6 cycloalkyl, R 13 and R 14 composition;

[0335] R 13 It 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; or it represents a 6- to 11-membered bicyclic fused aromatic ring containing one, two, or three heteroatoms, each independently selected from O, S, S(=O)p, and N.

[0336] The 4- to 7-membered monocyclic aromatic ring or the 6- to 11-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C 1-4 Alkyl composition;

[0337] p represents 1 or 2;

[0338] R 14Represents a phenyl group that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens;

[0339] Het represents a bicyclic aromatic heterocyclic system selected from the following group, which consists of (a-1), (a-2), (a-3), (a-4), and (a-5):

[0340]

[0341] R 3a 、R 3b 、R 3c 、R 3d and R 3e Each independently represents hydrogen, halogen, and -NR. 7a R 7b 、C 1-4 Alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, -OH, or -OC 1-4 alkyl;

[0342] R 7a Represents hydrogen;

[0343] R 7b Represents hydrogen, C 3-6 cycloalkyl, or C 1-4 alkyl;

[0344] R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f and R 4g Each region independently represents hydrogen, halogen, and -NR. 8a R 8b or C 1-4 alkyl;

[0345] R 8a and R 8b Each independently represents hydrogen or C. 1-4 alkyl;

[0346] Q 1 Represents N or CR 6a ;

[0347] Q 2 Represents N or CR 6b ;

[0348] Q 3 Represents N or CR 6c ;

[0349] Q 4Represents N or CR 6d ;

[0350] Its condition is Q 3 and Q 4 At most one of them represents N;

[0351] Q 8 Represents N or CR 6g ;

[0352] Q 9 Represents N or CR 6h ;

[0353] Q 10 Represents N or CR 6i ;

[0354] Q 11 Represents N or CR 6j ;

[0355] Q 5 Represents CR 3d ;Q 6 Represent N; and Q 7 Represents CR 4f ;or

[0356] Q 5 Represents CR 3d ;Q 6 Represents CR 4e And Q 7 Represents N; or

[0357] Q 5 Representing N; Q 6 Represents CR 4e And Q 7 Represents CR 4f ;or

[0358] Q 5 Representing N; Q 6 Represents CR 4e And Q 7 Represents N; or

[0359] Q 5 Representing N; Q 6 Represent N; and Q 7 Represents CR 4f ;or

[0360] Q 5 Representing N; Q 6 Represent N; and Q 7 Represents N;

[0361] R 6a 、R 6b 、R6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h 、R 6i and R 6j Each independently represents hydrogen, halogen, and C. 1-4 Alkyl, -NR 9a R 9b Or C atoms replaced by one, two, or three halogen atoms 1-4 alkyl;

[0362] R 9a and R 9b Each independently represents hydrogen or C. 1-4 alkyl;

[0363] And its pharmaceutically acceptable addition salts and solvates.

[0364] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0365] R 1 represents hydrogen;

[0366] R 2 represents hydrogen;

[0367] Y represents -O-, -CH2-, or -CF2-;

[0368] Z represents -CH2-, -X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h -、or -C≡C-;

[0369] And when Y represents -CH2- or -CF2-, Z can also represent -O- or -CR 5a R 5b -X-;

[0370] 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;

[0371] X represents -O-, -S-, or -NR11 -;

[0372] R 11 Represents hydrogen, C 1-4 Alkyl, or C substituted by a substituent 1-4 Alkyl group, wherein the substituent is selected from the group consisting of -OH, -OC 1-4 Alkyl, R 12 、-NH2、-NH-C 1-4 Alkyl groups and -N(C) 1-4 Composition: alkyl)2;

[0373] R 12 Represents a 4, 5, 6, or 7-membered heterocycle containing a nitrogen atom and optionally an oxygen atom; the 4, 5, 6, or 7-membered heterocycle is attached to the remainder of the molecule via a cyclic nitrogen atom;

[0374] Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein one or two ring carbon atoms are optionally replaced by nitrogen atoms; the condition being that a carbonyl group is present in the bicyclic aromatic ring system when a nitrogen atom replaces one of the two fused carbon atoms.

[0375] Ar may be optionally substituted by one, two, three, or four substituents independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 alkoxy group, and optionally a -NR group 10a R 10b Replacement C 1-4 alkyl;

[0376] R 10a and R 10b Each independently represents hydrogen or C. 1-4 alkyl;

[0377] Het represents a bicyclic aromatic heterocyclic system selected from the following group, which consists of (a-1), (a-2) and (a-3);

[0378] R 3a 、R 3b and R 3c Each independently represents hydrogen, halogen, and -NR. 7a R 7b 、or -OC 1-4 alkyl;

[0379] R7a Represents hydrogen;

[0380] R 7b Represents hydrogen or C 1-4 alkyl;

[0381] R 4a 、R 4b and R 4c Each independently represents hydrogen, halogen, and -NR. 8a R 8b or C 1-4 alkyl;

[0382] R 8a and R 8b Each independently represents hydrogen or C. 1-4 alkyl;

[0383] Q 1 Represents N or CR 6a ;

[0384] Q 2 Represents N or CR 6b ;

[0385] Q 3 Represents N or CR 6c ;

[0386] Q 4 Represents N or CR 6d ;

[0387] Its condition is Q 3 and Q 4 At most one of them represents N;

[0388] R 6a 、R 6b 、R 6c 、R 6d 、R 6e and R 6f Each independently represents hydrogen, halogen, and carbon. 1-4 Alkyl, -NR 9a R 9b C atoms that are substituted with one, two, or three halogen atoms 1-4 alkyl;

[0389] R 9a and R 9b Each independently represents hydrogen or C. 1-4 alkyl;

[0390] And its pharmaceutically acceptable addition salts and solvates.

[0391] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0392] R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0393] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0394] Y represents -O-, -CH2-, or -CF2-;

[0395] Z represents -CH2-, -X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h -、or -C≡C-;

[0396] And when Y represents -CH2- or -CF2-, Z can also represent -O- or -CR 5a R 5b -X-;

[0397] 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;

[0398] X represents -O-, -S-, or -NR 11 -;

[0399] R 11 Represents hydrogen, C 1-4 Alkyl, or C substituted by a substituent 1-4 Alkyl group, wherein the substituent is selected from the group consisting of -OH, -OC 1-4 Alkyl, R 12 、-NH2、-NH-C 1-4 Alkyl groups and -N(C) 1-4 Composition: alkyl)2;

[0400] R 12 Represents a 4, 5, 6, or 7-membered heterocycle containing a nitrogen atom and optionally an oxygen atom; the 4, 5, 6, or 7-membered heterocycle is attached to the remainder of the molecule via a cyclic nitrogen atom;

[0401] Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein one or two ring carbon atoms are optionally replaced by nitrogen atoms; the condition being that a carbonyl group is present in the bicyclic aromatic ring system when a nitrogen atom replaces one of the two fused carbon atoms.

[0402] Ar may be optionally substituted by one, two, three, or four substituents independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d -NR 10c R 10d Cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 Alkoxy group, -C(=O)-OC 1-4 Alkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, -NH-C 3-6 Cycloalkyl, -N(C) 3-6 2, C (cycloalkyl) 2-6 alkenyl group, with one C 1-4 alkoxy-substituted C 1-4 Alkyl group, and optionally with a -NR 10a R 10b Replacement C 1-4 alkyl;

[0403] R 10a and R 10b Each independently represents hydrogen or C. 1-4 alkyl;

[0404] R 10c and R 10d Each independently represents C 3-6 Cycloalkyl; R 13 ;R 14 C substituted by one, two or three substituents independently selected from the following group 3-6 Cycloalkyl groups, this group consists of halogens, -OH and -OC. 1-4 Alkyl composition; C14 cells substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups. 1-4 Alkyl groups, this group consists of halogens, -OH and -OC. 1-4 Alkyl composition; or C substituted with one of the following substituents. 1-4 Alkyl groups, this group consists of C 3-6 cycloalkyl, R 13 and R 14composition;

[0405] R 13 This represents a 4- to 7-membered monocyclic aromatic ring containing one, two, or three heteroatoms, each independently selected from O, S, or S (=O). p And N; or representing a fused 6- to 11-membered bicyclic aromatic ring containing one, two, or three heteroatoms, each independently selected from O, S, S (=O). p and N;

[0406] The 4- to 7-membered monocyclic aromatic ring or the 6- to 11-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C 1-4 Alkyl composition;

[0407] p represents 1 or 2;

[0408] R 14 Represents a phenyl group that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens;

[0409] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1);

[0410] R 3a 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;

[0411] R 7a Represents hydrogen;

[0412] R 7b Represents hydrogen, C 3-6 cycloalkyl, or C 1-4 alkyl;

[0413] R 4a Represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0414] R 8a and R 8b Each independently represents hydrogen or C. 1-4 alkyl;

[0415] Q 1 Represents N or CR 6a ;

[0416] Q2 Represents N or CR 6b ;

[0417] Especially Q 1 and Q 2 Represents CH;

[0418] R 6a and R 6b Each of these independently represents hydrogen, halogen, and carbon. 1-4 Alkyl, -NR 9a R 9b , or C 1-4 Alkyl groups are substituted with one, two, or three halogen atoms;

[0419] R 9a and R 9b Each independently represents hydrogen or C. 1-4 alkyl;

[0420] And its pharmaceutically acceptable addition salts and solvates.

[0421] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0422] R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0423] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0424] Y represents -O-, -CH2-, or -CF2-;

[0425] Z represents -CH2-, -X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h -、or -C≡C-;

[0426] And when Y represents -CH2- or -CF2-, Z can also represent -O- or -CR 5a R 5b -X-;

[0427] R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R 5g and R5h Each independently represents hydrogen or C. 1-4 alkyl;

[0428] X represents -O-, -S-, or -NR 11 -;

[0429] R 11 Represents hydrogen, C 1-4 Alkyl, or C substituted by a substituent 1-4 Alkyl group, wherein the substituent is selected from the group consisting of -OH, -OC 1-4 Alkyl, R 12 、-NH2、-NH-C 1-4 Alkyl groups and -N(C) 1-4 Composition: alkyl)2;

[0430] R 12 Represents a 4, 5, 6, or 7-membered heterocycle containing a nitrogen atom and optionally an oxygen atom; the 4, 5, 6, or 7-membered heterocycle is attached to the remainder of the molecule via a cyclic nitrogen atom;

[0431] Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein one or two ring carbon atoms are optionally replaced by nitrogen atoms; the condition being that a carbonyl group is present in the bicyclic aromatic ring system when a nitrogen atom replaces one of the two fused carbon atoms.

[0432] Ar may be optionally substituted by one, two, three, or four substituents independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 alkoxy group, and optionally a -NR group 10a R 10b Replacement C 1-4 alkyl;

[0433] R 10a and R 10b Each independently represents hydrogen or C. 1-4 alkyl;

[0434] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1);

[0435] R 3a Represents hydrogen, halogen, -NR 7a R 7b 、or -OC 1-4 alkyl;

[0436] R 7a Represents hydrogen;

[0437] R 7b Represents hydrogen or C 1-4 alkyl;

[0438] R 4a Represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0439] R 8a and R 8b Each independently represents hydrogen or C. 1-4 alkyl;

[0440] Q 1 Represents N or CR 6a ;

[0441] Q 2 Represents N or CR 6b ;

[0442] Especially Q 1 and Q 2 Represents CH;

[0443] R 6a and R 6b Each independently represents hydrogen, halogen, and carbon. 1-4 Alkyl, -NR 9a R 9b C atoms that are substituted with one, two, or three halogen atoms 1-4 alkyl;

[0444] R 9a and R 9b Each independently represents hydrogen or C. 1-4 alkyl;

[0445] And its pharmaceutically acceptable addition salts and solvates.

[0446] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0447] R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0448] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0449] Y represents -O- or -CH2-;

[0450] Z represents -CH2-, -X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h -、or -C≡C-;

[0451] Furthermore, when Y represents -CH2-, Z can also represent -CR. 5a R 5b -X-;

[0452] 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;

[0453] X represents -O-, -S-, or -NR 11 -;

[0454] R 11 Represents hydrogen or C 1-4 alkyl;

[0455] Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein one or two ring carbon atoms are optionally replaced by nitrogen atoms; the condition being that a carbonyl group is present in the bicyclic aromatic ring system when a nitrogen atom replaces one of the two fused carbon atoms.

[0456] Ar may be optionally substituted by one, two, three, or four substituents independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d Cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C 1-4 Alkyl, C 1-4 Alkoxy group, -C(=O)-OC 1-4 Alkyl, C 3-6 Cycloalkyl, C 2-6 alkenyl group, with one C 1-4 alkoxy-substituted C 1-4 Alkyl group, and optionally with a -NR 10a R 10b Replacement C 1-4 alkyl;

[0457] R 10a and R 10b Representative C 1-4 alkyl;

[0458] R 10d Representative C 3-6 Cycloalkyl; R 14 ; C substituted with one, two or three halogen substituents 1-4 Alkyl, or C substituted by a substituent selected from the group consisting of 1-4 Alkyl, this group consists of: C 3-6 cycloalkyl and R 14 ;

[0459] R 14 Represents a phenyl group that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens;

[0460] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1), (a-2) and (a-4);

[0461] R 3a 、R 3b 、R 3c and R 3d Each independently represents hydrogen, halogen, and -NR. 7a R 7b 、C 2-4 alkenyl, C 3-6 cycloalkyl, -OH, or -OC 1-4 alkyl;

[0462] R 7a Represents hydrogen;

[0463] R 7b Represents hydrogen, C 3-6 Cycloalkyl, or C 1-4 alkyl;

[0464] R 4a 、R 4b 、R 4c 、R 4d 、R 4e and R 4f Each independently represents hydrogen, halogen, and -NR. 8a R 8b or C 1-4 alkyl;

[0465] R 8a and R 8b Each independently represents hydrogen;

[0466] Q 1Represents CR 6a ;

[0467] Q 2 Represents CR 6b ;

[0468] Q 8 Represents CR 6g ;

[0469] Q 9 Represents CR 6h ;

[0470] Q 5 Represents CR 3d ;Q 6 Represent N; and Q 7 Represents CR 4f ;or

[0471] Q 5 Represents CR 3d ;Q 6 Represents CR 4e And Q 7 Represents N; or

[0472] Q 5 Representing N; Q 6 Represents CR 4e And Q 7 Represents CR 4f ;or

[0473] Q 5 Representing N; Q 6 Represents CR 4e And Q 7 Represents N;

[0474] R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g and R 6h Each independently represents hydrogen, halogen, or carbon. 1-4 Alkyl groups; and their pharmaceutically acceptable addition salts and solvates.

[0475] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0476] R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0477] R 2 Represents hydrogen or -C(=O)-C1-4 alkyl;

[0478] Y represents -O-, or -CH2-;

[0479] Z represents -CH2-, -X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h -、or -C≡C-;

[0480] Furthermore, when Y represents -CH2-, Z can also represent -O- or -CR. 5a R 5b -X-;

[0481] 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;

[0482] X represents -O-, -S-, or -NR 11 -;

[0483] R 11 Represents hydrogen or C 1-4 alkyl;

[0484] Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein one or two ring carbon atoms are optionally replaced by nitrogen atoms; the condition being that a carbonyl group is present in the bicyclic aromatic ring system when a nitrogen atom replaces one of the two fused carbon atoms.

[0485] Ar may be optionally substituted by one, two, three, or four substituents independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 alkoxy group, and optionally a -NR group 10a R 10b Replacement C 1-4 alkyl;

[0486] R10a and R 10b Each independently represents hydrogen or C. 1-4 alkyl;

[0487] Het represents a bicyclic aromatic heterocyclic system selected from the following group, which consists of (a-1), (a-2) and (a-3);

[0488] R 3a 、R 3b and R 3c Each independently represents hydrogen, halogen, and -NR. 7a R 7b 、or -OC 1-4 alkyl;

[0489] R 7a Represents hydrogen;

[0490] R 7b Represents hydrogen or C 1-4 alkyl;

[0491] R 4a 、R 4b and R 4c Each independently represents hydrogen, halogen, and -NR. 8a R 8b or C 1-4 alkyl;

[0492] R 8a and R 8b Each independently represents hydrogen or C. 1-4 alkyl;

[0493] Q 1 Represents CR 6a ;

[0494] Q 2 Represents CR 6b ;

[0495] Q 3 Represents CR 6c ;

[0496] Q 4 Represents CR 6d ;

[0497] R 6a 、R 6b 、R 6c 、R 6d 、R 6e and R 6f Each independently represents hydrogen, halogen, and carbon. 1-4 Alkyl, -NR 9a R 9b C atoms that are substituted with one, two, or three halogen atoms1-4 alkyl;

[0498] R 9a and R 9b Each independently represents hydrogen or C. 1-4 alkyl;

[0499] And its pharmaceutically acceptable addition salts and solvates.

[0500] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0501] R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0502] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0503] Y represents -O-, or -CH2-;

[0504] Z represents -CH2-, -X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h -、or -C≡C-;

[0505] Furthermore, when Y represents -CH2-, Z can also represent -O- or -CR. 5a R 5b -X-;

[0506] 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;

[0507] X represents -O-, -S-, or -NR 11 -;

[0508] R 11 Represents hydrogen or C 1-4 alkyl;

[0509] Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein one or two ring carbon atoms are optionally replaced by nitrogen atoms; the condition being that a carbonyl group is present in the bicyclic aromatic ring system when a nitrogen atom replaces one of the two fused carbon atoms.

[0510] Ar may be optionally substituted by a substituent selected from the group consisting of: halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 Alkoxy groups and C 1-4 The alkyl group is optionally substituted with one -NR 10a R 10b ;

[0511] R 10a and R 10b Each independently represents hydrogen or C. 1-4 alkyl;

[0512] Het represents a bicyclic aromatic heterocyclic system selected from the following group, which consists of (a-1), (a-2) and (a-3);

[0513] R 3a 、R 3b and R 3c Representative - NR 7a R 7b ;

[0514] R 7a Represents hydrogen;

[0515] R 7b Represents hydrogen;

[0516] R 4a 、R 4b and R 4c Each independently represents hydrogen, halogen, and -NR. 8a R 8b or C 1-4 alkyl;

[0517] R 8a and R 8b Each independently represents hydrogen or C. 1-4 alkyl;

[0518] Q 1 Represents CR 6a ;

[0519] Q 2 Represents CR6b ;

[0520] Q 3 Represents CR 6c ;

[0521] Q 4 Represents CR 6d ;

[0522] R 6a 、R 6b 、R 6c 、R 6d 、R 6e and R 6f Each independently represents hydrogen and halogen, C 1-4 Alkyl, -NR 9a R 9b or C 1-4 Alkyl groups are substituted with one, two, or three halogen atoms;

[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 novel compound having chemical 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; particularly R 1 and R 2 Represents hydrogen;

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

[0529] Z represents -CH2-, -X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h -、or -C≡C-;

[0530] Furthermore, when Y represents -CH2-, Z can also represent -CR. 5a R 5b -X-;

[0531] 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;

[0532] X represents -O-, -S-, or -NR 11 -;

[0533] R 11 Represents hydrogen or C 1-4 alkyl;

[0534] Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein one or two ring carbon atoms are optionally replaced by nitrogen atoms; the condition being that a carbonyl group is present in the bicyclic aromatic ring system when a nitrogen atom replaces one of the two fused carbon atoms.

[0535] Ar is optionally substituted with one, two or three substituents each independently selected from the group consisting of halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl, C 1-4 Alkoxy groups and C 1-4 alkyl;

[0536] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1) and (a-2);

[0537] R 3a and R 3c Each independently represents halogen, -NR 7a R 7b 、or -OC 1-4 alkyl;

[0538] R 7a Represents hydrogen;

[0539] R 7b Represents hydrogen;

[0540] R 4a and R 4c Each independently represents hydrogen, halogen, or C 1-4 alkyl;

[0541] Q 1 Represents CR 6a ;

[0542] Q 2 Represents CR 6b ;

[0543] R 6a 、R 6b 、R 6e and R 6f Each independently represents hydrogen, halogen, or C 1-4 alkyl;

[0544] And its pharmaceutically acceptable addition salts and solvates.

[0545] In one embodiment, the present invention relates to a novel compound having the chemical formula (I), wherein R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0546] R 2 Represents hydrogen or -C(=O)-C 1-4 Alkyl; particularly R 1 and R 2 Represents hydrogen;

[0547] Y represents -O- or -CH2-;

[0548] Z represents -CH2-, -X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h -、or -C≡C-;

[0549] Furthermore, when Y represents -CH2-, Z can also represent -CR. 5a R 5b -X-;

[0550] 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;

[0551] X represents -O-, -S-, or -NR 11 -;

[0552] R 11 Represents hydrogen or C 1-4 alkyl;

[0553] Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein one or two ring carbon atoms are optionally replaced by nitrogen atoms; the condition being that a carbonyl group is present in the bicyclic aromatic ring system when a nitrogen atom replaces one of the two fused carbon atoms.

[0554] Ar is optionally substituted with one, two or three substituents each independently selected from the group consisting of halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d , cyano, -CF3, -C(=O)-NH-C 1-4 Alkyl, C 1-4 Alkoxy groups and C 1-4 alkyl;

[0555] R 10d Represents C substituted with one, two or three halogen substituents. 1-4 Alkyl; or substituted by a C 3-6 Cycloalkyl C 1-4 alkyl;

[0556] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1) and (a-2);

[0557] R 3a and R 3c Each independently represents hydrogen, halogen, and -NR. 7a R 7b 、or -OC 1-4 alkyl;

[0558] R 7a Represents hydrogen;

[0559] R 7b Represents hydrogen or C 1-4 alkyl;

[0560] R 4a and R 4c Each independently represents hydrogen, halogen, or C 1-4 alkyl;

[0561] Q 1 Represents CR 6a ;

[0562] Q 2 Represents CR 6b ;

[0563] R 6a 、R 6b 、R6e and R 6f Each independently represents hydrogen, halogen, or C 1-4 alkyl;

[0564] And its pharmaceutically acceptable addition salts and solvates.

[0565] Another embodiment of the present invention relates to compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable addition salts and solvates thereof, or any subgroup thereof, wherein one or more of the following limitations apply:

[0566] (i)R 1 and R 2 Represents hydrogen;

[0567] (ii) Y represents -O- or -CH2-; in particular, Y represents -O-;

[0568] (iii) Z represents -CH2-, -X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h - or -C≡C-; and when Y represents -CH2-, then Z can also represent -CR. 5a R 5b -X-;

[0569] (iv)R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R 5g and R 5h Represents hydrogen;

[0570] (v)X represents -O-;

[0571] (vi)R 11 Represents hydrogen or C 1-4 alkyl;

[0572] (vii) Ar may be optionally substituted by one, two, or three, particularly one, substituent selected independently from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl, C 1-4 Alkoxy groups and C1-4 alkyl;

[0573] (viii)Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1) and (a-2);

[0574] (ix)R 3a and R 3c Each independently represents halogen, -NR 7a R 7b 、or -OC 1-4 alkyl;

[0575] (x)R 7a and R 7b Represents hydrogen;

[0576] (xi)R 4a and R 4c Each independently represents hydrogen, halogen, or C 1-4 alkyl;

[0577] (xii)Q 1 Represents CR 6a ;

[0578] (xiii)Q 2 Represents CR 6b ;

[0579] (xiv)R 6a 、R 6b 、R 6e and R 6f Each independently represents hydrogen, halogen, or C 1-4 alkyl.

[0580] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0581] R 1 represents hydrogen;

[0582] R 2 represents hydrogen;

[0583] Y represents -O- or -CH2-;

[0584] Z represents -X-CR 5a R 5b -or-CR 5e R 5g -CR 5f R 5h -;

[0585] Furthermore, when Y represents -CH2-, Z can also represent -CR. 5a R 5b -X-;

[0586] R 5a 、R 5b 、R 5e 、R 5f 、R 5g and R 5h Represents hydrogen;

[0587] X stands for -O-;

[0588] Ar represents

[0589]

[0590] Ar is optionally substituted at the position indicated by α by a substituent selected from the group consisting of: -NH2, -NH-C 1-4 Alkyl groups and -NHR 10d ;and

[0591] Ar is optionally substituted at the position indicated by β by a substituent selected from the group consisting of halogens and CF3;

[0592] However, the condition is that Ar is substituted at at least one position represented by α or β;

[0593] R 10d Representative C 3-6 cycloalkyl; C substituted with one, two or three halogen substituents 1-4 Alkyl; or formed by a C 3-6 C substituted with cycloalkyl substituents 1-4 alkyl;

[0594] Het represents a bicyclic aromatic heterocyclic system selected from the following group, which consists of (a-1) and (a-4);

[0595] R 3a and R 3d Each independently represents hydrogen, halogen, and -NR. 7a R 7b 、C 1-4 Alkyl, or -OC 1-4 alkyl;

[0596] R 7a Represents hydrogen;

[0597] R 7b Represents hydrogen or C 1-4 alkyl;

[0598] R 4a 、R 4d and R 4f Each can independently represent either hydrogen or halogen;

[0599] Q 1 Represents CR 6a ;

[0600] Q 2 Represents CR 6b ;

[0601] Q 8 Represents CR 6g ;

[0602] Q 9 Represents CR 6h ;

[0603] Q 5 Represents CR 3d ;Q 6 Represent N; and Q 7 Represents CR 4f ;

[0604] R 6a 、R 6b 、R 6g and R 6h Represents hydrogen;

[0605] And its pharmaceutically acceptable addition salts and solvates.

[0606] Another embodiment of the present invention relates to compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable addition salts and solvates thereof, or any subgroup thereof, wherein one or more of the following limitations apply:

[0607] (i)R 1 and R 2 Represents hydrogen;

[0608] (ii) Y represents -O- or -CH2-;

[0609] (iii) Z represents -X-CR 5a R 5b -or-CR 5e R 5g -CR 5f R 5h -;

[0610] Furthermore, when Y represents -CH2-, Z can also represent -CR. 5a R 5b -X-;

[0611] (iv)R 5a 、R 5b 、R 5e 、R 5f 、R 5g and R 5hRepresents hydrogen;

[0612] (v)X represents -O-;

[0613] (vi)Ar represents

[0614]

[0615] Ar is optionally substituted at the position indicated by α by a substituent selected from the group consisting of: -NH2, -NH-C 1-4 Alkyl groups and -NHR 10d ;and

[0616] Ar is optionally substituted at the position indicated by β by a substituent selected from the group consisting of halogens and CF3;

[0617] However, the condition is that Ar is substituted at at least one position represented by α or β;

[0618] (vii)R 10d Representative C 3-6 cycloalkyl; C substituted with one, two or three halogen substituents 1-4 Alkyl; or formed by a C 3-6 C substituted with cycloalkyl substituents 1-4 alkyl;

[0619] (viii)Het represents a bicyclic aromatic heterocyclic system selected from the following group, which consists of (a-1) and (a-4);

[0620] (ix)R 3a and R 3d Each independently represents hydrogen, halogen, and -NR. 7a R 7b 、C 1-4 Alkyl, or -OC 1-4 alkyl;

[0621] (x)R 7a Represents hydrogen;

[0622] (xi)R 7b Represents hydrogen or C 1-4 alkyl;

[0623] (xii)R 4a 、R 4d and R 4f Each can independently represent either hydrogen or halogen;

[0624] (xiii)Q 1 Represents CR 6a ;

[0625] (xiv)Q2 Represents CR 6b ;

[0626] (xv)Q 8 Represents CR 6g ;

[0627] (xvi)Q 9 Represents CR 6h ;

[0628] (xvii)Q 5 Represents CR 3d ;Q 6 Represent N; and Q 7 Represents CR 4f ;

[0629] (xviii)R 6a 、R 6b 、R 6g and R 6h It represents hydrogen.

[0630] In one embodiment, the present invention relates to a novel compound having the chemical formula (I), wherein R 1 represents hydrogen;

[0631] R 2 represents hydrogen;

[0632] Y represents -O- or -CH2-;

[0633] Z represents -X-CR 5a R 5b -or-CR 5e R 5g -CR 5f R 5h -;

[0634] Furthermore, when Y represents -CH2-, Z can also represent -CR. 5a R 5b -X-;

[0635] R 5a 、R 5b 、R 5e 、R 5f 、R 5g and R 5h Represents hydrogen;

[0636] X stands for -O-;

[0637] Ar represents

[0638]

[0639] Ar is optionally substituted at the position indicated by α by a substituent selected from the group consisting of: -NH2, -NH-C 1-4 Alkyl groups and -NHR 10d ;and

[0640] Ar is optionally substituted at the position indicated by β by a substituent selected from the group consisting of halogens and CF3;

[0641] However, the condition is that Ar is substituted at at least one position represented by α or β;

[0642] R 10d Representative C 3-6 cycloalkyl; C 1-4 The alkyl group is substituted with one, two, or three halogen substituents; or is substituted with one C. 3-6 C substituted with cycloalkyl substituents 1-4 alkyl;

[0643] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1);

[0644] R 3a Represents hydrogen, halogen, -NR 7a R 7b 、C 1-4 Alkyl, or -OC 1-4 alkyl;

[0645] R 7a Represents hydrogen;

[0646] R 7b Represents hydrogen or C 1-4 alkyl;

[0647] R 4a Represents hydrogen or halogen;

[0648] Q 1 Represents CR 6a ;

[0649] Q 2 Represents CR 6b ;

[0650] R 6a and R 6b Represents hydrogen;

[0651] And its pharmaceutically acceptable addition salts and solvates.

[0652] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0653] R 1 represents hydrogen;

[0654] R 2 represents hydrogen;

[0655] Y represents -O- or -CH2-;

[0656] Z represents -X-CR 5a R 5b -or-CR 5e R 5g -CR 5f R 5h -;

[0657] R 5a 、R 5b 、R 5e 、R 5f 、R 5g and R 5h Represents hydrogen;

[0658] X stands for -O-;

[0659] Ar represents

[0660]

[0661] Ar is optionally substituted at the position indicated by α by a substituent selected from the group consisting of: -NH2, -NH-C 1-4 Alkyl groups and -NHR 10d ;and

[0662] Ar is optionally substituted at the position indicated by β by a substituent selected from the group consisting of halogens and CF3;

[0663] However, the condition is that Ar is substituted at at least one position represented by α or β;

[0664] R 10d Representative C 3-6 cycloalkyl; C 1-4 The alkyl group is substituted with one, two, or three halogen substituents; or is substituted with one C. 3-6 C substituted with cycloalkyl substituents 1-4 alkyl;

[0665] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1);

[0666] R 3a Represents hydrogen, halogen, -NR 7a R 7b 、C 1-4 Alkyl, or -OC 1-4 alkyl;

[0667] R 7a Represents hydrogen;

[0668] R 7b Represents hydrogen or C 1-4 alkyl;

[0669] R 4a Represents hydrogen or halogen;

[0670] Q 1 Represents CR 6a ;

[0671] Q 2 Represents CR 6b ;

[0672] R 6a and R 6b Represents hydrogen;

[0673] And its pharmaceutically acceptable addition salts and solvates.

[0674] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0675] R 1 represents hydrogen;

[0676] R 2 represents hydrogen;

[0677] Y represents -O- or -CH2-;

[0678] Z represents -X-CR 5a R 5b -or-CR 5e R 5g -CR 5f R 5h -;

[0679] Furthermore, when Y represents -CH2-, Z can also represent -CR. 5a R 5b -X-;

[0680] R 5a 、R 5b 、R 5e 、R 5f 、R 5g and R 5h Represents hydrogen;

[0681] X stands for -O-;

[0682] Ar represents

[0683]

[0684] Ar is substituted at the position indicated by α by substituents selected from the following group, which consists of: -NH2, -NH-C. 1-4 Alkyl groups and -NHR 10d ;

[0685] R 10d Representative C 3-6 cycloalkyl; or C substituted with one of the following substituents 1-4 Alkyl groups, this group consists of C 3-6 cycloalkyl and R 14 composition;

[0686] R 14 Represents a phenyl group that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens;

[0687] Het represents a bicyclic aromatic heterocyclic system (a-1);

[0688] R 3a Represents hydrogen, halogen, -NR 7a R 7b or C 1-4 alkyl;

[0689] R 7a Represents hydrogen;

[0690] R 7b Represents hydrogen or C 1-4 alkyl;

[0691] R 4a Represents hydrogen;

[0692] Q 1 Represents CR 6a ;

[0693] Q 2 Represents CR 6b ;

[0694] R 6a and R 6b Represents hydrogen;

[0695] And its pharmaceutically acceptable addition salts and solvates.

[0696] In one embodiment, the present invention relates to a novel compound having the chemical formula (I), wherein R 1 represents hydrogen;

[0697] R 2 represents hydrogen;

[0698] Y represents -O- or -CH2-;

[0699] Z represents -X-CR5a R 5b -or-CR 5e R 5g -CR 5f R 5h -;

[0700] Furthermore, when Y represents -CH2-, Z can also represent -CR. 5a R 5b -X-;

[0701] R 5a 、R 5b 、R 5e 、R 5f 、R 5g and R 5h Represents hydrogen;

[0702] X stands for -O-;

[0703] Ar represents

[0704]

[0705] Ar is optionally replaced by -NH2 at the position represented by α; and

[0706] Ar is substituted at the position represented by β by a substituent selected from the group consisting of halogens and CF3;

[0707] Het represents a bicyclic aromatic heterocyclic system (a-1);

[0708] R 3a Represents hydrogen, halogen, -NR 7a R 7b or 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 Represents hydrogen;

[0715] And its pharmaceutically acceptable addition salts and solvates.

[0716] In one embodiment, the present invention relates to a novel compound having the chemical formula (I), wherein R 1 represents hydrogen;

[0717] R 2 represents hydrogen;

[0718] Y represents -O- or -CH2-;

[0719] Z represents -X-CR 5a R 5b -or-CR 5e R 5g -CR 5f R 5h -;

[0720] Furthermore, when Y represents -CH2-, Z can also represent -CR. 5a R 5b -X-;

[0721] R 5a 、R 5b 、R 5e 、R 5f 、R 5g and R 5h Represents hydrogen;

[0722] X stands for -O-;

[0723] Ar represents

[0724]

[0725] Ar is replaced by -NH2 at the position represented by α; and

[0726] Ar is substituted at the position represented by β by a substituent selected from the group consisting of halogens and CF3;

[0727] Het represents a bicyclic aromatic heterocyclic system (a-1);

[0728] R 3a Represents hydrogen, halogen, -NR 7a R 7b or C 1-4 alkyl;

[0729] R 7a Represents hydrogen;

[0730] R 7b Represents hydrogen or C 1-4 alkyl;

[0731] R4a Represents hydrogen;

[0732] Q 1 Represents CR 6a ;

[0733] Q 2 Represents CR 6b ;

[0734] R 6a and R 6b Represents hydrogen;

[0735] And its pharmaceutically acceptable addition salts and solvates.

[0736] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0737] R 1 represents hydrogen;

[0738] R 2 represents hydrogen;

[0739] Y represents -O- or -CH2-;

[0740] Z represents -X-CR 5a R 5b -or-CR 5e R 5g -CR 5f R 5h -;

[0741] Furthermore, when Y represents -CH2-, Z can also represent -CR. 5a R 5b -X-;

[0742] R 5a 、R 5b 、R 5e 、R 5f 、R 5g and R 5h Represents hydrogen;

[0743] X stands for -O-;

[0744] Ar represents

[0745]

[0746] Het represents a bicyclic aromatic heterocyclic system (a-1);

[0747] R 3a Represents hydrogen, halogen, -NR 7a R 7b or C 1-4 alkyl;

[0748] R 7a Represents hydrogen;

[0749] R 7b Represents hydrogen or C 1-4 alkyl;

[0750] R 4a Represents hydrogen;

[0751] Q 1 Represents CR 6a ;

[0752] Q 2 Represents CR 6b ;

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

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

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

[0756] R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0757] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0758] Especially R 1 and R 2 Represents hydrogen;

[0759] Y represents -CH2- or -O-;

[0760] Z represents -X-CR 5a R 5b -or -CH2CH2-;

[0761] R 5a and R 5b Each independently represents hydrogen or C. 1-4 alkyl;

[0762] X represents -O-, -S-, or -NR 11 -;

[0763] R 11 represents hydrogen;

[0764] Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused six-membered rings, wherein one or two ring carbon atoms are replaced by nitrogen atoms; the condition being that a carbonyl group is present in the bicyclic aromatic ring system when a nitrogen atom replaces one of the two fused carbon atoms.

[0765] Ar is optionally substituted by one or two substituents, each independently selected from the group consisting of halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 alkoxy group, and optionally a -NR group 10a R 10b Replacement C 1-4 Alkyl composition;

[0766] R 10a and R 10b Each independently represents hydrogen or C. 1-4 alkyl;

[0767] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1);

[0768] R 3a Represents hydrogen, halogen, -NR 7a R 7b 、or -OC 1-4 alkyl;

[0769] R 7a Represents hydrogen;

[0770] R 7b Represents hydrogen;

[0771] R 4a Represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0772] R 8a and R 8b Each independently represents hydrogen or C. 1-4 alkyl;

[0773] Q 1 Represents CR 6a ;

[0774] Q 2 Represents CR 6b ;

[0775] R 6a and R6b Each independently represents hydrogen, halogen, and carbon. 1-4 Alkyl, -NR 9a R 9b C atoms that are substituted with one, two, or three halogen atoms 1-4 alkyl;

[0776] R 9a and R 9b Each independently represents hydrogen or C. 1-4 alkyl;

[0777] And its pharmaceutically acceptable addition salts and solvates.

[0778] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0779] R 1 represents hydrogen;

[0780] R 2 represents hydrogen;

[0781] Y represents -CH2-;

[0782] Z represents - CR 5e R 5g -CR 5f R 5h -;

[0783] R 5e 、R 5f 、R 5g and R 5h Represents hydrogen;

[0784] Ar represents any of the following decacyclic bicyclic aromatic ring systems:

[0785]

[0786] Ar may be optionally substituted by one, two, three, or four substituents, each independently selected from the group consisting of: halogen, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d -NR 10c R 10d ; R 10c and R 10d Each independently represents C 3-6 cycloalkyl; C 3-6 The cycloalkyl group is substituted by one, two, or three substituents, each independently selected from the group consisting of: halogens, -OH, and -OC. 1-4 Alkyl; C 1-4The alkyl group is substituted by one, two, or three substituents, each independently selected from the group consisting of: halogens, -OH, and -OC. 1-4 Alkyl; or formed by a C 3-6 C substituted with cycloalkyl substituents 1-4 alkyl;

[0787] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1);

[0788] R 3a Represents hydrogen, -NR 7a R 7b 、or -OC 1-4 alkyl;

[0789] R 7a Represents hydrogen;

[0790] R 7b Represents hydrogen or C 1-4 alkyl;

[0791] R 4a Represents hydrogen;

[0792] Q 1 Represents CR 6a ;

[0793] Q 2 Represents CR 6b ;

[0794] R 6a and R 6b Represents hydrogen;

[0795] And its pharmaceutically acceptable addition salts and solvates.

[0796] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0797] R 1 represents hydrogen;

[0798] R 2 represents hydrogen;

[0799] Y represents -CH2-;

[0800] Z represents - CR 5e R 5g -CR 5f R 5h -;

[0801] R 5e 、R 5f 、R 5g and R 5h Represents hydrogen;

[0802] Ar represents

[0803]

[0804] Ar may be optionally substituted by one, two, three, or four substituents, each independently selected from the group consisting of: halogen, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d ;

[0805] R 10d Represents C substituted with one, two or three halogen substituents. 1-4 Alkyl; or formed by a C 3-6 C substituted with cycloalkyl substituents 1-4 alkyl;

[0806] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1);

[0807] R 3a Represents hydrogen, -NR 7a R 7b 、or -OC 1-4 alkyl;

[0808] R 7a Represents hydrogen;

[0809] R 7b Represents hydrogen or C 1-4 alkyl;

[0810] R 4a Represents hydrogen;

[0811] Q 1 Represents CR 6a ;

[0812] Q 2 Represents CR 6b ;

[0813] R 6a and R 6b Represents hydrogen;

[0814] And its pharmaceutically acceptable addition salts and solvates.

[0815] Another embodiment of the present invention relates to compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable addition salts and solvates thereof, or any subgroup thereof, wherein one or more of the following limitations apply:

[0816] (i)R 1 Represents hydrogen;

[0817] R 2 represents hydrogen;

[0818] (ii) Y represents -CH2-;

[0819] (iii) Z represents -CR 5e R 5g -CR 5f R 5h -;

[0820] (iv)R 5e 、R 5f 、R 5g and R 5h Represents hydrogen;

[0821] (v) Ar represents

[0822]

[0823] Ar may be optionally substituted by one, two, three, or four substituents, each independently selected from the group consisting of: halogen, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d ;

[0824] (vi)R 10d Represents C substituted with one, two or three halogen substituents. 1-4 Alkyl; or formed by a C 3-6 C substituted with cycloalkyl substituents 1-4 alkyl;

[0825] (vii)Het represents a bicyclic aromatic heterocyclic system selected from the following group, which consists of (a-1);

[0826] (viii)R 3a Represents hydrogen, -NR 7a R 7b 、or -OC 1-4 alkyl;

[0827] (ix)R 7a Represents hydrogen;

[0828] R 7b Represents hydrogen or C 1-4 alkyl;

[0829] (x)R 4a Represents hydrogen;

[0830] (xi)Q 1 Represents CR 6a ;

[0831] Q 2 Represents CR 6b ;

[0832] (xii)R 6a and R 6b It represents hydrogen.

[0833] Another embodiment of the present invention relates to compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable addition salts and solvates thereof, or any subgroup thereof, wherein one or more of the following limitations apply:

[0834] (i)R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0835] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0836] Especially R 1 and R 2 Represents hydrogen;

[0837] (ii) Y represents -CH2- or -O-;

[0838] (iii) Z represents -X-CR 5a R 5b -or -CH2CH2-;

[0839] (iv)R 5a and R 5b Each independently represents hydrogen or C. 1-4 alkyl;

[0840] (v)X represents -O-, -S-, or -NR 11 -;

[0841] (vi)R 11 Represents hydrogen;

[0842] (vii) Ar is optionally substituted by one or two substituents, each independently selected from the group consisting of halogens, -OH, -NH2, and -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl group, -C(=O)-C 1-4 Alkyl, C 1-4 alkoxy group, and optionally a -NR group 10a R 10b Replacement C 1-4 Alkyl composition; (viii)R 10aand R 10b Each independently represents hydrogen or C. 1-4 alkyl;

[0843] (ix)Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1);

[0844] (x)R 3a Represents hydrogen, halogen, -NR 7a R 7b 、or -OC 1-4 alkyl;

[0845] (xi)R 7a Represents hydrogen;

[0846] R 7b Represents hydrogen;

[0847] (xii)R 4a Represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0848] (xiii)R 8a and R 8b Each independently represents hydrogen or C. 1-4 alkyl;

[0849] (xiv)Q 1 Represents CR 6a ;

[0850] (xv)Q 2 Represents CR 6b ;

[0851] (xvi)R 6a and R 6b Each independently represents hydrogen, halogen, and carbon. 1-4 Alkyl, -NR 9a R 9b or C 1-4 Alkyl groups are substituted with one, two, or three halogen atoms;

[0852] (xvii)R 9a and R 9b Each independently represents hydrogen or C. 1-4 alkyl.

[0853] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0854] R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0855] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0856] Especially R 1 and R 2 Represents hydrogen;

[0857] Y stands for -O-;

[0858] Z represents -X-CR 5a R 5b -;

[0859] R 5a and R 5b Each independently represents hydrogen or C. 1-4 alkyl;

[0860] X represents -O-, -S-, or -NR 11 -;

[0861] R 11 represents hydrogen;

[0862] Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused six-membered rings, wherein one or two ring carbon atoms are replaced by nitrogen atoms; the condition being that a carbonyl group is present in the bicyclic aromatic ring system when a nitrogen atom replaces one of the two fused carbon atoms.

[0863] Ar is optionally substituted by one or two substituents, each independently selected from the group consisting of halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 alkoxy group, and optionally a -NR group 10a R 10b Replacement C 1-4 Alkyl composition;

[0864] R 10a and R 10b Each independently represents hydrogen or C. 1-4 alkyl;

[0865] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1);

[0866] R 3a Represents hydrogen, halogen, -NR 7a R 7b 、or -OC 1-4 alkyl;

[0867] R 7a Represents hydrogen;

[0868] R 7b Represents hydrogen;

[0869] R 4a Represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0870] R 8a and R 8b Each independently represents hydrogen or C. 1-4 alkyl;

[0871] Q 1 Represents CR 6a ;

[0872] Q 2 Represents CR 6b ;

[0873] R 6a and R 6b Each independently represents hydrogen, halogen, and carbon. 1-4 Alkyl, -NR 9a R 9b C atoms that are substituted with one, two, or three halogen atoms 1-4 alkyl;

[0874] R 9a and R 9b Each independently represents hydrogen or C. 1-4 alkyl;

[0875] And its pharmaceutically acceptable addition salts and solvates.

[0876] Another embodiment of the present invention relates to compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable addition salts and solvates thereof, or any subgroup thereof, wherein one or more of the following limitations apply:

[0877] (i)R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0878] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0879] Especially R 1 and R 2 Represents hydrogen;

[0880] (ii) Y represents -O-;

[0881] (iii) Z represents -X-CR 5a R 5b -;

[0882] (iv)R 5a and R 5b Each independently represents hydrogen or C. 1-4 alkyl;

[0883] (v)X represents -O-, -S-, or -NR 11 -;

[0884] (vi)R 11 Represents hydrogen;

[0885] (vii) Ar is optionally substituted by one or two substituents, each independently selected from the group consisting of halogens, -OH, -NH2, and -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl group, -C(=O)-C 1-4 Alkyl, C 1-4 alkoxy group, and optionally a -NR group 10a R 10b Replacement C 1-4 Alkyl composition; (viii)R 10a and R 10b Each independently represents hydrogen or C. 1-4 alkyl;

[0886] (ix)Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1);

[0887] (x)R 3a Represents hydrogen, halogen, -NR 7a R 7b 、or -OC 1-4 alkyl;

[0888] (xi)R 7a Represents hydrogen;

[0889] R 7b Represents hydrogen;

[0890] (xii)R 4a Represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0891] (xiii)R 8a and R 8b Each independently represents hydrogen or C.1-4 alkyl;

[0892] (xiv)Q 1 Represents CR 6a ;

[0893] (xv)Q 2 Represents CR 6b ;

[0894] (xvi)R 6a and R 6b Each independently represents hydrogen, halogen, and carbon. 1-4 Alkyl, -NR 9a R 9b or C 1-4 Alkyl groups are substituted with one, two, or three halogen atoms;

[0895] (xvii)R 9a and R 9b Each independently represents hydrogen or C. 1-4 alkyl.

[0896] In one embodiment, the present invention relates to a novel compound having the chemical formula (I), wherein R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0897] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0898] Especially R 1 and R 2 Represents hydrogen;

[0899] Y represents -CH2- or -O-;

[0900] Z represents -X-CR 5a R 5b -or-CH2CH2- R 5a and R 5b Each independently represents hydrogen or C. 1-4 alkyl;

[0901] X represents -O-, -S-, or -NR 11 -;

[0902] R 11 represents hydrogen;

[0903] Ar represents Ar specifically represents

[0904] Ar is optionally substituted by one or two substituents, each independently selected from the group consisting of halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 alkoxy group, and optionally a -NR group 10a R 10b Replacement C 1-4 Alkyl composition;

[0905] R 10a and R 10b Each independently represents hydrogen or C. 1-4 alkyl;

[0906] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1);

[0907] R 3a Represents hydrogen, halogen, -NR 7a R 7b 、or -OC 1-4 alkyl;

[0908] R 7a Represents hydrogen;

[0909] R 7b Represents hydrogen;

[0910] R 4a Represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0911] R 8a and R 8b Each independently represents hydrogen or C. 1-4 alkyl;

[0912] Q 1 Represents CR 6a ;

[0913] Q 2 Represents CR 6b ;

[0914] R 6a and R 6b Each independently represents hydrogen, halogen, and carbon. 1-4 Alkyl, -NR 9a R 9b C atoms that are substituted with one, two, or three halogen atoms 1-4 alkyl;

[0915] R 9a and R 9b Each independently represents hydrogen or C. 1-4 alkyl;

[0916] And its pharmaceutically acceptable addition salts and solvates.

[0917] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0918] R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0919] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0920] Especially R 1 and R 2 Represents hydrogen;

[0921] Y stands for -O-;

[0922] Z represents -X-CR 5a R 5b -;

[0923] R 5a and R 5b Each independently represents hydrogen or C. 1-4 alkyl;

[0924] X represents -O-, -S-, or -NR 11 -;

[0925] R 11 represents hydrogen;

[0926] Ar represents Ar specifically represents

[0927] Ar is optionally substituted by one or two substituents, each independently selected from the group consisting of halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 alkoxy group, and optionally a -NR group 10a R 10b Replacement C 1-4 Alkyl composition;

[0928] R10a and R 10b Each independently represents hydrogen or C. 1-4 alkyl;

[0929] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1);

[0930] R 3a Represents hydrogen, halogen, -NR 7a R 7b 、or -OC 1-4 alkyl;

[0931] R 7a Represents hydrogen;

[0932] R 7b Represents hydrogen;

[0933] R 4a Represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0934] R 8a and R 8b Each independently represents hydrogen or C. 1-4 alkyl;

[0935] Q 1 Represents CR 6a ;

[0936] Q 2 Represents CR 6b ;

[0937] R 6a and R 6b Each independently represents hydrogen, halogen, and carbon. 1-4 Alkyl, -NR 9a R 9b C atoms that are substituted with one, two, or three halogen atoms 1-4 alkyl;

[0938] R 9a and R 9b Each independently represents hydrogen or C. 1-4 alkyl;

[0939] And its pharmaceutically acceptable addition salts and solvates.

[0940] Another embodiment of the present invention relates to compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable addition salts and solvates thereof, or any subgroup thereof, wherein one or more of the following limitations apply:

[0941] (i)R1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0942] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0943] Especially R 1 and R 2 Represents hydrogen;

[0944] (ii) Y represents -O-;

[0945] (iii) Z represents -X-CR 5a R 5b -;

[0946] (iv)R 5a and R 5b Each independently represents hydrogen or C. 1-4 alkyl;

[0947] (v)X represents -O-, -S-, or -NR 11 -;

[0948] (vi)R 11 Represents hydrogen;

[0949] (vii) Ar represents Ar specifically represents

[0950] (viii) Ar is optionally substituted by one or two substituents each independently selected from the group consisting of halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl group, -C(=O)-C 1-4 Alkyl, C 1-4 alkoxy group, and optionally a -NR group 10a R 10b Replacement C 1-4 Alkyl composition;

[0951] (ix)R 10a and R 10b Each independently represents hydrogen or C. 1-4 alkyl;

[0952] (x) Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1);

[0953] (xi)R 3a Represents hydrogen, halogen, -NR 7aR 7b 、or -OC 1-4 alkyl;

[0954] (xii)R 7a Represents hydrogen;

[0955] R 7b Represents hydrogen;

[0956] (xiii)R 4a Represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0957] (xiv)R 8a and R 8b Each independently represents hydrogen or C. 1-4 alkyl;

[0958] (xv)Q 1 Represents CR 6a ;

[0959] (xvi)Q 2 Represents CR 6b ;

[0960] (xvii)R 6a and R 6b Each independently represents hydrogen, halogen, and carbon. 1-4 Alkyl, -NR 9a R 9b or C 1-4 Alkyl groups are substituted with one, two, or three halogen atoms;

[0961] (xviii)R 9a and R 9b Each independently represents hydrogen or C. 1-4 alkyl.

[0962] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0963] R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0964] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0965] Especially R 1 and R 2 Represents hydrogen;

[0966] Y represents -O- or -CH2-; Z represents -X-CR 5a R5b -or -CH2CH2-;

[0967] R 5a and R 5b X represents hydrogen; X represents -O-;

[0968] R 11 represents hydrogen;

[0969] Ar represents

[0970] Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, and -CF3 group;

[0971] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1);

[0972] R 3a Representative - NR 7a R 7b ;

[0973] R 7a Represents hydrogen;

[0974] R 7b Represents hydrogen;

[0975] R 4a Represents hydrogen;

[0976] Q 1 Represents CR 6a ;Q 2 Represents CR 6b ;R 6a and R 6b Represents hydrogen;

[0977] And its pharmaceutically acceptable addition salts and solvates.

[0978] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0979] R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0980] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0981] Especially R 1 and R 2 Represents hydrogen;

[0982] Y represents -O- or -CH2-; Z represents -X-CR 5a R 5b -or -CH2CH2-;

[0983] R 5a and R 5b X represents hydrogen; X represents -O-;

[0984] R 11 represents hydrogen;

[0985] Ar represents

[0986] Ar may be optionally substituted by a substituent selected from the group consisting of: halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, and -CF3 group;

[0987] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1);

[0988] R 3a Representative - NR 7a R 7b ;

[0989] R 7a Represents hydrogen;

[0990] R 7b Represents hydrogen;

[0991] R 4a Represents hydrogen;

[0992] Q 1 Represents CR 6a ;Q 2 Represents CR 6b ;R 6a and R 6b Represents hydrogen;

[0993] And its pharmaceutically acceptable addition salts and solvates.

[0994] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[0995] R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0996] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[0997] Especially R1 and R 2 Represents hydrogen;

[0998] Y represents -O-; Z represents -X-CR 5a R 5b -;

[0999] R 5a and R 5b X represents hydrogen; X represents -O-;

[1000] R 11 represents hydrogen;

[1001] Ar represents

[1002] Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, and -CF3 group;

[1003] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1);

[1004] R 3a Representative - NR 7a R 7b ;

[1005] R 7a Represents hydrogen;

[1006] R 7b Represents hydrogen;

[1007] R 4a Represents hydrogen;

[1008] Q 1 Represents CR 6a ;Q 2 Represents CR 6b ;R 6a and R 6b Represents hydrogen;

[1009] And its pharmaceutically acceptable addition salts and solvates.

[1010] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[1011] R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[1012] R 2 Represents hydrogen or -C(=O)-C 1-4alkyl;

[1013] Especially R 1 and R 2 Represents hydrogen;

[1014] Y represents -O-; Z represents -X-CR 5a R 5b -;

[1015] R 5a and R 5b X represents hydrogen; X represents -O-;

[1016] R 11 represents hydrogen;

[1017] Ar represents

[1018] Ar may be optionally substituted by a substituent selected from the group consisting of: halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, and -CF3 group;

[1019] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1);

[1020] R 3a Representative - NR 7a R 7b ;

[1021] R 7a Represents hydrogen;

[1022] R 7b Represents hydrogen;

[1023] R 4a Represents hydrogen;

[1024] Q 1 Represents CR 6a ;Q 2 Represents CR 6b ;R 6a and R 6b Represents hydrogen;

[1025] And its pharmaceutically acceptable addition salts and solvates.

[1026] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[1027] R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[1028] R2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[1029] Especially R 1 and R 2 Represents hydrogen;

[1030] Y represents -O- or -CH2-; Z represents -X-CR 5a R 5b -or -CH2CH2-;

[1031] R 5a and R 5b X represents hydrogen; X represents -O-;

[1032] R 11 represents hydrogen;

[1033] Ar represents

[1034] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1);

[1035] R 3a Representative - NR 7a R 7b ;

[1036] R 7a Represents hydrogen;

[1037] R 7b Represents hydrogen;

[1038] R 4a Represents hydrogen;

[1039] Q 1 Represents CR 6a ;Q 2 Represents CR 6b ;R 6a and R 6b Represents hydrogen;

[1040] And its pharmaceutically acceptable addition salts and solvates.

[1041] In one embodiment, the present invention relates to a novel compound having chemical formula (I), wherein

[1042] R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[1043] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[1044] Especially R1 and R 2 Represents hydrogen;

[1045] Y represents -O-; Z represents -X-CR 5a R 5b -;

[1046] R 5a and R 5b X represents hydrogen; X represents -O-;

[1047] R 11 represents hydrogen;

[1048] Ar represents

[1049] Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1);

[1050] R 3a Representative - NR 7a R 7b ;

[1051] R 7a Represents hydrogen;

[1052] R 7b Represents hydrogen;

[1053] R 4a Represents hydrogen;

[1054] Q 1 Represents CR 6a ;Q 2 Represents CR 6b ;R 6a and R 6b Represents hydrogen;

[1055] And its pharmaceutically acceptable addition salts and solvates.

[1056] Another embodiment of the present invention relates to compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable addition salts and solvates thereof, or any subgroup thereof, wherein one or more of the following limitations apply:

[1057] (i)R 1 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[1058] R 2 Represents hydrogen or -C(=O)-C 1-4 alkyl;

[1059] Especially R 1 and R 2 Represents hydrogen;

[1060] (ii) Y represents -O-;

[1061] (iii) Z represents -X-CR 5a R 5b -;

[1062] (iv)R 5a and R 5b Represents hydrogen;

[1063] (v)X represents -O-;

[1064] (vi)R 11 Represents hydrogen;

[1065] (vii) Ar represents

[1066] Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl group 2, cyano group, and -CF3 group; particularly Ar is optionally substituted with a substituent selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, and -CF3 group;

[1067] More specifically, Ar represents Even more specifically, Ar represents

[1068]

[1069] (ix)Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1);

[1070] (x)R 3a Representative - NR 7a R 7b ;

[1071] (xi)R 7a Represents hydrogen;

[1072] R 7b Represents hydrogen;

[1073] (xii)R 4a Represents hydrogen;

[1074] (xiii)Q 1 Represents CR 6a ;

[1075] (xiv)Q2 Represents CR 6b ;

[1076] (xv)R 6a and R 6b It represents hydrogen.

[1077] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R 1 and R 2 It represents hydrogen.

[1078] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R 1 represents -C(=O)-C 1-4 Alkyl; R 2 represents -C(=O)-C 1-4 alkyl.

[1079] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R 1 and R 2 Represents hydrogen;

[1080] Het represents (a-1);

[1081] Q 1 Represents CH; Q 2 Represents CH; and

[1082] Ar represents

[1083] Optionally, it can be replaced according to any other embodiment.

[1084] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein

[1085] R 1 and R 2 Represents hydrogen;

[1086] Het represents (a-1);

[1087] Q 1 Represents CH; Q 2 Represents CH; and

[1088] Ar represents

[1089]

[1090] Ar is substituted by one, two, three, or four substituents independently selected from the group consisting of: halogen, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d -NR 10c R 10d ; R 10c and R 10d Each independently represents a C substituted with one, two, or three halogen substituents. 1-4 Alkyl; or formed by a C 3-6 C substituted with cycloalkyl substituents 1-4 alkyl.

[1091] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Y represents -O-.

[1092] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Y represents -CH2- or -CF2-; in particular, wherein Y represents -CH2-.

[1093] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Q 1 and Q 2 At most one of them represents N.

[1094] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Q 1 Represents CR 6a And Q 2 Represents CR 6b In particular, Q 1 Represents CH; and Q 2 It represents CH.

[1095] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Het represents (a-1); Q 1 Represents CR 6a And Q2 Represents CR 6b In particular, Q 1 Represents CH; and Q 2 It represents CH.

[1096] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein

[1097] Q 5 Represents CR 3d ;Q 6 Represent N; and Q 7 Represents CR 4f ;or

[1098] Q 5 Represents CR 3d ;Q 6 Represents CR 4e And Q 7 Represents N; or

[1099] Q 5 Representing N; Q 6 Represents CR 4e And Q 7 Represents CR 4f ;or

[1100] Q 5 Representing N; Q 6 Represents CR 4e And Q 7 Represents N.

[1101] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1), (a-2) and (a-4).

[1102] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R 1 and R 2 Y represents hydrogen; and Y represents -O-.

[1103] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1), (a-2) and (a-3).

[1104] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1) and (a-2).

[1105] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1) and (a-4).

[1106] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Het represents a bicyclic aromatic heterocyclic system having chemical formula (a-1).

[1107] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R 1 and R 2 represents hydrogen; Y represents -O-; and Het represents a bicyclic aromatic heterocyclic system with the chemical formula (a-1).

[1108] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Ar represents an optionally substituted 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein one or two ring carbon atoms are substituted by nitrogen atoms; provided that the nitrogen atom does not substitute one of the two fused carbon atoms.

[1109] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Ar is optionally substituted by one or both substituents according to any other embodiment.

[1110] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Ar is optionally substituted with a substituent according to any other embodiment.

[1111] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R 3a 、R 3c 、R 3b Represents hydrogen; and

[1112] R 4a 、R 4c 、R 4b Represents hydrogen, halogen, or C 1-4 Alkyl; particularly R 4a 、R 4c 、R 4b Represents halogen, or C 1-4 alkyl.

[1113] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R 3a 、R 3c 、R 3b 、R 3d and R 3e Represents hydrogen; and

[1114] R 4a 、R 4c 、R 4b 、R 4d 、R 4e 、R 4f and R 4g Represents hydrogen, halogen, or C 1-4 Alkyl; particularly R 4a 、R 4c 、 R 4b 、R 4d 、R 4e 、R 4f and R 4g Represents halogen or C 1-4 alkyl.

[1115] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R 3a 、R 3c 、R 3bRepresents hydrogen, halogen, -NR 7a R 7b 、or -OC 1-4 Alkyl; particularly R 3a 、R 3c 、R 3b Represents halogen, -NR 7a R 7b 、or -OC 1-4 alkyl;

[1116] R 4a 、R 4c 、R 4b It represents hydrogen.

[1117] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R 3a 、R 3c 、R 3b 、R 3d and R 3e Represents hydrogen, halogen, -NR 7a R 7b 、or -OC 1-4 Alkyl; particularly R 3a 、 R 3c 、R 3b 、R 3d and R 3e Represents halogen, -NR 7a R 7b 、or -OC 1-4 alkyl;

[1118] R 4a 、R 4c 、R 4b 、R 4d 、R 4e 、R 4f and R 4g It represents hydrogen.

[1119] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein when R 4a 、R 4c 、R 4b Unlike hydrogen, R 3a 、R 3c 、R 3b It represents hydrogen.

[1120] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein when R 4a 、R 4c 、R 4b 、R 4d 、R 4e 、R 4f 、R 4g Unlike hydrogen, R 3a 、R 3c 、R 3b 、R 3d 、R 3e It represents hydrogen.

[1121] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein when R 3a 、R 3c 、R 3b Unlike hydrogen, R 4a 、R 4c 、R 4b It represents hydrogen.

[1122] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein when R 3a 、R 3c 、R 3b 、R 3d 、R 3e Unlike hydrogen, R 4a 、R 4c 、R 4b 、R 4d 、R 4e 、R 4f 、R 4g It represents hydrogen.

[1123] 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 Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

[1124]

[1125] In this ring, at least one carbon atom of ring B is replaced by a nitrogen atom;

[1126] Optionally, one of the other ring carbon atoms of ring A or ring B is replaced by a nitrogen atom; the condition being that a carbonyl group is present in the bicyclic aromatic ring system when the nitrogen atom replaces one of the two fused carbon atoms; Ar is optionally replaced according to any other embodiment.

[1127] 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 Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

[1128]

[1129] In this ring, at least one carbon atom of ring B is replaced by a nitrogen atom;

[1130] Optionally, one of the other carbon atoms in ring A or ring B is replaced by a nitrogen atom; the condition being that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in the bicyclic aromatic ring system; Ar is optionally replaced by one, two, three, or four substituents independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d -NR 10c R 10d Cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 Alkoxy group, -C(=O)-OC 1-4 Alkyl, C 3-6 Cycloalkyl, C 2-6 alkenyl group, with one C 1-4 alkoxy-substituted C 1-4 Alkyl group, and optionally with a -NR 10a R 10b Replacement C 1-4 alkyl;

[1131] In particular, Ar is optionally substituted by one, two, three or four substituents each independently selected from the group consisting of halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 alkoxy group, and optionally a -NR group10a R 10b Replacement C 1-4 alkyl.

[1132] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings having the following structure:

[1133]

[1134] Optionally, one of the other ring carbon atoms of ring A or ring B is replaced by a nitrogen atom; the condition being that a carbonyl group is present in the bicyclic aromatic ring system when the nitrogen atom replaces one of the two fused carbon atoms; Ar is optionally replaced according to any other embodiment.

[1135] Clearly, Includes any of the following ring systems:

[1136]

[1137] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Ar is selected from the group consisting of the following:

[1138]

[1139] Each Ar may optionally be replaced according to any other embodiment.

[1140] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Ar is selected from the group consisting of the following:

[1141]

[1142] Each Ar may optionally be replaced according to any other embodiment.

[1143] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Ar is selected from the group consisting of the following:

[1144]

[1145] Each Ar may optionally be replaced according to any other embodiment.

[1146] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Ar is selected from the group consisting of the following:

[1147]

[1148] Each Ar may optionally be replaced according to any other embodiment.

[1149] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Ar is selected from the group consisting of the following:

[1150]

[1151] Each Ar may optionally be replaced according to any other embodiment.

[1152] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Ar is

[1153]

[1154] wherein Ar is optionally substituted according to any other embodiment.

[1155] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Ar is not

[1156]

[1157] wherein Ar is optionally substituted according to any other embodiment.

[1158] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Ar represents

[1159]

[1160] Ar is substituted by one, two, three, or four substituents independently selected from the group consisting of: halogen, -NH2, -NH-C.1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d -NR 10c R 10d .

[1161] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Ar represents

[1162]

[1163] wherein Ar is substituted by a substituent selected from the group consisting of: halogen -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d -NR 10c R 10d And optionally substituted with halogen substituents; R 10c and R 10d Each independently represents a C substituted with one, two, or three halogen substituents. 1-4 Alkyl; or formed by a C 3-6 C substituted with cycloalkyl substituents 1-4 alkyl.

[1164] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Ar represents

[1165]

[1166] Ar is substituted at the position indicated by α by substituents selected from the following group, which consists of: -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d -NR 10c R 10d ;and

[1167] wherein Ar is optionally substituted with a halogen substituent at the position indicated by β.

[1168] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Ar represents

[1169]

[1170] Ar is substituted at the position indicated by α by substituents selected from the following group, which consists of: -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d -NR 10c R 10d ;and

[1171] wherein Ar is optionally substituted with a halogen substituent at the position indicated by β;

[1172] R 10c and R 10d Each independently represents a C substituted with one, two, or three halogen substituents. 1-4 Alkyl; or formed by a C 3-6 C substituted with cycloalkyl substituents 1-4 alkyl.

[1173] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Ar represents

[1174]

[1175] wherein Ar is substituted at the position indicated by β by a halogen substituent, particularly chlorine or bromine; more particularly bromine.

[1176] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Het represents (a-1); Q 1 Represents CR 6a ;Q 2 Represents CR 6b ; and Ar represents

[1177]

[1178] wherein Ar is substituted at the position indicated by β by a halogen substituent, particularly chlorine or bromine; more particularly bromine.

[1179] 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 Ar is substituted by a substituent selected from the group consisting of: -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d -NR10c R 10d ; and wherein Ar is optionally substituted by another substituent selected from the list of substituents for Ar in any other embodiment.

[1180] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Ar represents

[1181]

[1182] Optionally, it can be replaced according to any other embodiment.

[1183] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Ar represents

[1184]

[1185] Optionally substituted with one, two, or three substituents independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl, C 1-4 Alkoxy groups and C 1-4 alkyl;

[1186] In particular, it may be optionally substituted with one, two, or three substituents independently selected from the group consisting of: halogen, -NH2, -NH-C. 1-4 Alkyl, cyano, -CF3, C 1-4 Alkoxy groups and C 1-4 alkyl;

[1187] More specifically, it may be optionally substituted with one, two or three substituents selected independently from the group consisting of halogens or -CF3;

[1188] More specifically, it may be optionally substituted with one or two halogen substituents;

[1189] More specifically, it is substituted with one or two halogen substituents;

[1190] Even more specifically, it is substituted by a halogen substituent;

[1191] Most notably, it is substituted with a chlorine substituent.

[1192] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Ar represents

[1193]

[1194] Optionally, it can be replaced according to any other embodiment.

[1195] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Ar represents

[1196]

[1197] Optionally substituted with one, two, or three substituents independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl, C 1-4 Alkoxy groups and C 1-4 alkyl;

[1198] In particular, it may be optionally substituted with one, two, or three substituents independently selected from the group consisting of: halogen, -NH2, -NH-C. 1-4 Alkyl, cyano, -CF3, C 1-4 Alkoxy groups and C 1-4 alkyl;

[1199] More specifically, it may be optionally substituted with one, two or three substituents selected independently from the group consisting of halogens or -CF3;

[1200] More specifically, it may be optionally substituted with one or two halogen substituents;

[1201] More specifically, it is substituted with one or two halogen substituents;

[1202] Even more specifically, it is substituted by a halogen substituent;

[1203] Most notably, it is substituted with a chlorine substituent.

[1204] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Het represents (a-1); and

[1205] Ar represents

[1206]

[1207] Optionally substituted with one, two, or three substituents independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl, C 1-4 Alkoxy groups and C 1-4 alkyl;

[1208] In particular, it may be optionally substituted with one, two, or three substituents independently selected from the group consisting of: halogen, -NH2, -NH-C. 1-4 Alkyl, cyano, -CF3, C 1-4 Alkoxy groups and C 1-4 alkyl;

[1209] More specifically, it may be optionally substituted with one, two or three substituents selected independently from the group consisting of halogens or -CF3;

[1210] More specifically, it may be optionally substituted with one or two halogen substituents;

[1211] More specifically, it is substituted with one or two halogen substituents;

[1212] Even more specifically, it is substituted by a halogen substituent;

[1213] Most notably, it is substituted with a chlorine substituent.

[1214] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Het represents (a-1); and

[1215] Ar represents

[1216] Ar specifically represents

[1217] More specifically, Ar represents

[1218] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein

[1219] Ar represents

[1220] Ar specifically represents

[1221] More specifically, Ar represents

[1222] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R 5b 、R 5g and R 5h It represents hydrogen.

[1223] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Q 1 Represents CR 6a And Q 2 Represents CR 6b .

[1224] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein X represents -O-;

[1225] Q 1 Represents CR 6a And Q 2 Represents CR 6b .

[1226] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein X represents -O-;

[1227] Q 1 Represents CH; and Q 2 Represents CR H .

[1228] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R 5b 、R 5g and R 5h Represents hydrogen;

[1229] Y represents -CH2- or -CF2-; specifically, Y represents -CH2-; and

[1230] Het represents (a-1);

[1231] Q 1 Represents CR 6a And Q 2 Represents CR 6b In particular, Q 1 Represents CH; and Q 2 It represents CH.

[1232] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R 5b 、R 5g and R 5h Y represents hydrogen; Y represents -O-; and

[1233] Het represents (a-1);

[1234] Q 1 Represents CR 6a And Q 2 Represents CR 6b In particular, Q 1 Represents CH; and Q 2 It represents CH.

[1235] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Q 2 Represents CR 6b .

[1236] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Z represents -X-CR 5a R 5b -.

[1237] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Z represents -O-CH2-.

[1238] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Z represents -X-CR 5a R 5b -; X represents -O-; and R 5a and R 5b It represents hydrogen.

[1239] 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 X represents -O- or -NR 11 -; Specifically, X represents -O-.

[1240] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R 7a and R 7b It represents hydrogen.

[1241] 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 Het represents (a-1); R 3a Representative - NR 7a R 7b ; and R 7a and R 7b It represents hydrogen.

[1242] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally one or two ring carbon atoms are substituted by nitrogen atoms; provided that a carbonyl group is present in the bicyclic aromatic ring system when a nitrogen atom substitutes for one of the two fused carbon atoms;

[1243] Ar may be optionally substituted by a substituent selected from the group consisting of: halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 Alkoxy groups and C 1-4 The alkyl group is optionally substituted with one -NR 10a R 10b ;

[1244] R 3a 、R 3b and R 3c Representative - NR 7a R 7b ; and R 7a and R 7b It represents hydrogen.

[1245] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally one or two ring carbon atoms are substituted by nitrogen atoms; provided that a carbonyl group is present in the bicyclic aromatic ring system when a nitrogen atom substitutes for one of the two fused carbon atoms;

[1246] Ar may be optionally substituted by a substituent selected from the group consisting of: halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 Alkoxy groups and C 1-4 The alkyl group is optionally substituted with one -NR 10a R 10b ;

[1247] R 3a 、R 3c 、R 3b 、R 3d and R 3e Representative - NR 7a R 7b ; and R 7a and R 7b It represents hydrogen.

[1248] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R 3a 、R 3b and R 3c This does not represent halogen.

[1249] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R 3a 、R 3c 、R 3b 、R 3d and R 3e This does not represent halogen.

[1250] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R3a 、R 3b and R 3c Representative - NR 7a R 7b

[1251] R 7a Represents hydrogen;

[1252] R 7b It represents hydrogen.

[1253] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R 3a 、R 3b and R 3c Represents -NH2.

[1254] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally one or two ring carbon atoms are substituted by nitrogen atoms; provided that a carbonyl group is present in the bicyclic aromatic ring system when a nitrogen atom substitutes for one of the two fused carbon atoms;

[1255] Ar may be optionally substituted by a substituent selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 Alkoxy groups and C 1-4 The alkyl group is optionally substituted with one -NR 10a R 10b ;

[1256] Het represents (a-1); R 3a Representative - NR 7a R 7b ; and R 7a and R 7b It represents hydrogen.

[1257] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally one or two ring carbon atoms are substituted by nitrogen atoms; provided that a carbonyl group is present in the bicyclic aromatic ring system when a nitrogen atom substitutes for one of the two fused carbon atoms;

[1258] Ar is substituted by substituents selected from the following group, which consists of: halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 alkoxy group, and optionally a -NR group 10a R 10b Replacement C 1-4 alkyl;

[1259] Het represents (a-1); R 3a Representative - NR 7a R 7b ; and R 7a and R 7b It represents hydrogen.

[1260] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Ar represents

[1261]

[1262] Optionally substituted with substituents selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, -CF3 group, -C(=O)-NH-C 1-4 Alkyl, C 1-4 Alkoxy groups and C 1-4 alkyl;

[1263] Specifically, it is optionally substituted with substituents selected from the group consisting of: halogen, -NH2, -NH-C. 1-4 Alkyl, cyano, -CF3, C 1-4 Alkoxy groups and C 1-4 alkyl;

[1264] More particularly optionally substituted with a substituent selected from the group consisting of halogen, and -CF3;

[1265] More particularly optionally substituted with one halogen substituent;

[1266] More specifically, it is substituted by a halogen substituent;

[1267] It is even more specifically substituted by a chlorine substituent.

[1268] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Ar is selected from the group consisting of the following:

[1269]

[1270] wherein each Ar is optionally substituted according to any other embodiment, particularly wherein Ar is optionally substituted with a substituent as defined in any other embodiment.

[1271] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Ar is selected from the group consisting of the following:

[1272]

[1273] wherein each Ar is optionally substituted according to any other embodiment, particularly wherein Ar is optionally substituted with a substituent as defined in any other embodiment.

[1274] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Ar is selected from the group consisting of the following:

[1275]

[1276] wherein each Ar is optionally substituted according to any other embodiment, particularly wherein Ar is optionally substituted with a substituent as defined in any other embodiment.

[1277] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Ar is selected from the group consisting of the following:

[1278]

[1279] Each Ar is optionally substituted at position α by a substituent selected from the group consisting of: -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d , and -NR 10c R 10d ;

[1280] R 10c and R 10d Each independently represents C 3-6 cycloalkyl; C 3-6 The cycloalkyl group is substituted by one, two, or three substituents, each independently selected from the group consisting of: halogens, -OH, and -OC. 1-4 Alkyl group; C substituted with one, two or three substituents independently selected from the group consisting of alkyl groups. 1-4 Alkyl groups, this group consists of the following: halogens, -OH and -OC. 1-4 Alkyl group; or C substituted with a substituent selected from the group consisting of alkyl groups; 1-4 Alkyl, this group consists of: C 3-6 cycloalkyl, R 13 and R 14 ;

[1281] R 13 This represents a 4- to 7-membered monocyclic aromatic ring system containing one, two, or three heteroatoms independently selected from the following group: O, S, S(=O). p And N; or representing a 6- to 11-membered bicyclic fused aromatic ring containing one, two, or three heteroatoms independently selected from the following group, which consists of: O, S, S(=O). p and N;

[1282] The 4- to 7-membered monocyclic aromatic ring or the 6- to 11-membered bicyclic fused aromatic ring is optionally substituted by one or two substituents selected from the group consisting of: C 1-4 alkyl;

[1283] p represents 1 or 2;

[1284] R 14 The phenyl group is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogens.

[1285] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Ar is selected from the group consisting of the following:

[1286]

[1287] Each Ar is optionally substituted at position α by a substituent selected from the group consisting of: -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d , and -NR 10c R 10d And Ar is optionally substituted with a halogen substituent at another site.

[1288] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Ar is selected from the group consisting of the following:

[1289]

[1290] Each Ar is optionally substituted at position α by a substituent selected from the group consisting of: -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d , and -NR 10c R 10d Furthermore, Ar is optionally substituted with a halogen substituent at another position.

[1291] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein one or two ring carbon atoms are substituted by nitrogen atoms; provided that a carbonyl group is present in the bicyclic aromatic ring system when a nitrogen atom substitutes for one of the two fused carbon atoms.

[1292] wherein each Ar is optionally substituted according to any other embodiment, particularly wherein Ar is optionally substituted with a substituent as defined in any other embodiment.

[1293] 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 Ar is optionally substituted with a substituent as defined in any other embodiment.

[1294] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Ar is optionally substituted by one, two, three, or four substituents each independently selected from the group consisting of: halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d -NR 10c R 10d Cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 Alkoxy group, -C(=O)-OC 1-4 Alkyl, C 2-6 alkenyl group, with one C 1-4 alkoxy-substituted C 1-4 Alkyl group, and optionally with a -NR 10a R 10b Replacement C 1-4 alkyl.

[1295] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Ar represents Ar may be optionally substituted by a substituent selected from the group consisting of: halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, and -CF3 group;

[1296] More specifically, Ar represents Even more specifically, Ar represents

[1297] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein

[1298] Ar represents

[1299] The aryl group is substituted by substituents selected from the group consisting of: halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl group, cyano group, and -CF3 group;

[1300] More specifically, Ar represents Even more specifically, Ar represents

[1301]

[1302] Het represents (a-1); R 3a Representative - NR 7a R 7b ; and R 7a and R 7b It represents hydrogen.

[1303] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein the compounds having chemical formula (I) are limited to compounds having chemical formula (I-a1):

[1304]

[1305] As will be apparent below, all variables in the structure of formula (I-a1) may be defined as defined in any other embodiment for the compound of formula (I) or any subgroup thereof.

[1306] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein the compounds having chemical formula (I) are limited to compounds having chemical formula (I-a1):

[1307]

[1308] where R 3a Represents -NH2; R 4a Represents hydrogen; and

[1309] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein the compounds having chemical formula (I) are limited to compounds having chemical formula (I-a1):

[1310]

[1311] where R 3a Represents -NH2; R 4a Represents hydrogen; and

[1312] Ar represents More specifically, Ar represents

[1313] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein the compounds having chemical formula (I) are limited to compounds having chemical formula (I-a1):

[1314]

[1315] in

[1316] R 1 and R 2 Represents hydrogen;

[1317] R 3a Represents hydrogen, -NR 7a R 7b 、or -OC 1-4 alkyl;

[1318] R 4a Represents hydrogen; and

[1319] Ar represents

[1320]

[1321] Ar is substituted at the position indicated by α by substituents selected from the following group, which consists of: -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d -NR 10c R 10d ;and

[1322] wherein Ar is optionally substituted with a halogen substituent at the position indicated by β;

[1323] R 10c and R 10d Each independently represents a C substituted with one, two, or three halogen substituents. 1-4 Alkyl; or formed by a C 3-6 C substituted with cycloalkyl substituents 1-4 alkyl.

[1324] In one embodiment, the present invention relates to novel compounds having the chemical formula (I-a1).

[1325]

[1326] in

[1327] R 1 and R 2 Represents hydrogen;

[1328] R3a Represents hydrogen, -NR 7a R 7b 、or -OC 1-4 alkyl;

[1329] R 7a Represents hydrogen;

[1330] R 7b Represents hydrogen or C 1-4 alkyl;

[1331] Z stands for -CH2CH2-;

[1332] Y represents -O-, -CH2-, or -CF2-; especially -CH2-.

[1333] R 4a Represents hydrogen; and

[1334] Ar represents

[1335]

[1336] Ar is substituted at the position indicated by α by substituents selected from the following group, which consists of: -NH2, -NH-C. 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d -NR 10c R 10d ;and

[1337] wherein Ar is optionally substituted with a halogen substituent at the position indicated by β;

[1338] R 10c and R 10d Each independently represents a C substituted with one, two, or three halogen substituents. 1-4 Alkyl; or formed by a C 3-6 Cycloalkyl-substituted C 1-4 alkyl;

[1339] And its pharmaceutically acceptable addition salts and solvates.

[1340] In one embodiment, the present invention relates to novel compounds having the chemical formula (I-a1).

[1341]

[1342] in

[1343] R 1 and R 2 Represents hydrogen;

[1344] R 3a Represents hydrogen, -NR7a R 7b 、or -OC 1-4 alkyl;

[1345] R 7a Represents hydrogen;

[1346] R 7b Represents hydrogen or C 1-4 alkyl;

[1347] Z represents -X-CR 5a R 5b -or -CH2CH2-;

[1348] R 5a and R 5b X represents hydrogen; X represents -O-;

[1349] Y represents -O-, -CH2-, or -CF2-; especially -CH2-.

[1350] R 4a Represents hydrogen; and

[1351] Ar represents

[1352]

[1353] Ar is optionally substituted at the position indicated by α by a substituent selected from the group consisting of: -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d -NR 10c R 10d ;and

[1354] wherein Ar is optionally substituted with a halogen substituent at the position indicated by β;

[1355] R 10c and R 10d Each independently represents a C substituted with one, two, or three halogen substituents. 1-4 Alkyl; or formed by a C 3-6 Cycloalkyl-substituted C 1-4 alkyl;

[1356] And its pharmaceutically acceptable addition salts and solvates.

[1357] In one embodiment, the present invention relates to novel compounds having the chemical formula (I-a1).

[1358]

[1359] in

[1360] R 1 and R 2 Represents hydrogen;

[1361] R 3a Representative - NR 7a R 7b ;

[1362] R 7a Represents hydrogen;

[1363] R 7b Represents hydrogen;

[1364] Z represents -X-CR 5a R 5b -or -CH2CH2-;

[1365] R 5a and R 5b X represents hydrogen; X represents -O-;

[1366] Y represents -O- or -CH2-;

[1367] R 4a Represents hydrogen; and

[1368] Ar represents

[1369]

[1370] Ar is optionally replaced by -NH2 at the position represented by α; and

[1371] wherein Ar is optionally substituted at the position indicated by β with a halogen substituent, in particular bromine;

[1372] And its pharmaceutically acceptable addition salts and solvates.

[1373] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Z represents -X-CR 5a R 5b -or -CH2CH2-.

[1374] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Z represents -X-CR 5a R 5b -or -CH2CH2-;

[1375] R 5a and R 5b Represents hydrogen;

[1376] X stands for -O-.

[1377] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Z represents -X-CR 5a R 5b -or -CH2CH2-;

[1378] R 5a and R 5b Represents hydrogen;

[1379] X stands for -O-;

[1380] Het represents (a-1).

[1381] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Z represents -X-CR 5a R 5b -or -CH2CH2-;

[1382] R 5a and R 5b Represents hydrogen;

[1383] X stands for -O-;

[1384] Het represents (a-1);

[1385] R 3a Representative - NR 7a R 7b ;

[1386] R 7a Represents hydrogen;

[1387] R 7b It represents hydrogen.

[1388] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein X represents -O-.

[1389] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein Z represents -X-CR 5a R 5b -or -CH2CH2-;

[1390] R 5a and R 5b Represents hydrogen;

[1391] X stands for -O-;

[1392] Ar represents

[1393]

[1394] Ar is optionally substituted at the position indicated by α by a substituent selected from the group consisting of: -NH2, -NH-C 1-4 Alkyl groups and -NHR 10d ;and

[1395] Ar is optionally substituted at the position indicated by β by a substituent selected from the group consisting of halogens and CF3;

[1396] However, the condition is that Ar is substituted at at least one position represented by α or β;

[1397] Het represents (a-1);

[1398] R 3a Representative - NR 7a R 7b ;

[1399] R 7a Represents hydrogen;

[1400] R 7b It represents hydrogen.

[1401] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Het represents (a-1);

[1402] R 3a Representative - NR 7a R 7b ;

[1403] R 7a Represents hydrogen;

[1404] R 7b It represents hydrogen.

[1405] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R 3a 、R 3b 、R 3c 、R 3d and R 3e Representative - NR 7a R 7b ;

[1406] R 7a Represents hydrogen;

[1407] R 7b Represents hydrogen, C 3-6 cycloalkyl, or C 1-4 alkyl.

[1408] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R 3a 、R 3b 、R 3c 、R 3d and R 3e Representative - NR 7a R 7b ;

[1409] R 7a Represents hydrogen;

[1410] R 7b It represents hydrogen.

[1411] In one embodiment, the invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R 11 Represents hydrogen, C 1-4 Alkyl group, or C substituted with a substituent selected from the group consisting of alkyl groups ... 1-4 Alkyl groups, this group consists of the following: -OH, -OC 1-4 Alkyl, R2, -NH2, -NH-C 1-4 Alkyl groups and -N(C) 1-4 Alkyl)2; and

[1412] R 10c and R 10d Each independently represents C 3-6 Cycloalkyl; R 14 ; C 3-6 The cycloalkyl group is substituted by one, two, or three substituents, each independently selected from the group consisting of: halogens, -OH, and -OC. 1-4 Alkyl group; C substituted with one, two or three substituents independently selected from the group consisting of alkyl groups. 1-4 Alkyl groups, this group consists of the following: halogens, -OH and -OC. 1-4 Alkyl; or C substituted with one of the following substituents 1-4 Alkyl groups, this group consists of C 3-6 cycloalkyl and R 14 composition.

[1413] In one embodiment, the present invention relates to those compounds having chemical formula (I) mentioned in any other embodiment, and their pharmaceutically acceptable addition salts and solvates or any subgroup thereof, wherein Y represents -CH2-; and Z represents -CH2CH2-.

[1414] In one embodiment, the present invention relates to a subgroup having chemical formula (I) as defined in a general reaction scheme.

[1415] In one embodiment, the compound having chemical formula (I) is selected from the group consisting of compounds 2 and 58.

[1416] In one embodiment, the compound having chemical formula (I) is selected from the group consisting of compounds 2 and 80.

[1417] In one embodiment, the compound having chemical formula (I) is selected from the group consisting of the following compounds: 74, 75, 76, 77, 78, 79, 80 and 81.

[1418] In one embodiment, the compound having chemical formula (I) is selected from the group consisting of the following compounds: 2, 58, 74, 75, 76, 77, 78, 79, 80, 81, 154, 159, 235, 240 and 247.

[1419] In one embodiment, the compound having chemical formula (I) is selected from the group consisting of compounds 2 and 58.

[1420] And its pharmaceutically acceptable addition salts and solvates.

[1421] In one embodiment, the compound having chemical formula (I) is selected from the group consisting of compounds 2 and 80.

[1422] And its pharmaceutically acceptable addition salts and solvates.

[1423] In one embodiment, the compound having chemical formula (I) is selected from the group consisting of compounds 74, 75, 76, 77, 78, 79, 80, and 81.

[1424] And its pharmaceutically acceptable addition salts and solvates.

[1425] In one embodiment, the compound having chemical formula (I) is selected from the group consisting of the following compounds: 2, 58, 74, 75, 76, 77, 78, 79, 80, 81, 154, 159, 235, 240, and 247.

[1426] And its pharmaceutically acceptable addition salts and solvates.

[1427] In one embodiment, a compound having chemical formula (I) is selected from the group consisting of any exemplary compound,

[1428] It includes its free base, pharmaceutically acceptable addition salt, and solvates.

[1429] All possible combinations of the embodiments indicated above are considered to be included within the scope of this invention.

[1430] Preparation method

[1431] In this section, as in all other sections, unless the context otherwise indicates, references to chemical formula (I) also include all other subgroups and instances thereof as defined herein.

[1432] The general preparation of some typical examples of compounds having chemical formula (I) is described below and in specific examples, and is generally prepared from commercially available starting materials or by standard synthetic processes commonly used by those skilled in the art. The following embodiments are intended to represent examples of the invention only and are in no way intended to limit the invention.

[1433] Alternatively, the compounds of the present invention can also be prepared by combining a similar reaction test scheme as described in the general scheme below with standard synthetic processes commonly used by those skilled in the art of organic chemistry.

[1434] Those skilled in the art will recognize that, in the reactions described in the protocol, it may be necessary to protect desired reactive functional groups, such as hydroxyl, amino, or carboxyl groups, in the final product to prevent them from participating in undesirable reactions. Conventional protecting groups may be used according to standard practice. This will be illustrated in specific examples. Those skilled in the art will recognize that, in the reactions described in the protocol, it may be desirable or necessary to conduct the reaction under an inert atmosphere, such as N2, for example, when NaH is used in the reaction. Those skilled in the art will understand that it may be necessary to cool the reaction mixture prior to reaction treatment (referring to a series of operations necessary for the separation and purification of one or more products of a chemical reaction, such as quenching, column chromatography, extraction).

[1435] Technicians will recognize that heating the reaction mixture with stirring can increase reaction yield. In some reactions, microwave heating can be used instead of conventional heating to shorten the overall reaction time.

[1436] Technicians will recognize that an alternative sequence of chemical reactions shown in the following scheme can also produce the desired compound with chemical formula (I).

[1437] The skilled artisan will recognize that the intermediates and compounds shown in the schemes below can be further functionalized according to methods well known to those skilled in the art.

[1438] The skilled artisan will recognize that further compounds of formula (I) can be prepared by using similar synthetic protocols as described in the schemes below.

[1439] Where one of the starting materials is available as a salt, the skilled person will recognise that it is necessary to first treat the salt with a base such as, for example, N,N-diisopropylethylamine (DIPEA).

[1440] All variables are as defined above unless otherwise indicated or clear from context.

[1441] Those skilled in the art will understand that similar chemical processes described in schemes 1 to 9 can also be used to prepare compounds having chemical formula (I), where Het represents a bicyclic aromatic heterocyclic system (a-4) or (a-5). Some typical examples are shown in the specific examples. Furthermore, 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 chemical formula (I), where Het represents (a-4) or (a-5).

[1442] Generally, compounds of formula (I) can be prepared according to Scheme 1:

[1443] General Solution 1

[1444]

[1445] In Scheme 1, 'LG1' is defined as a suitable leaving group, such as a halogen; 'LG2' is defined as a suitable leaving group, such as a halogen or -SCH3. 'LG3' is defined as a leaving group, such as a halogen and -SCH3. All other variables in Scheme 1 are defined within the scope of the invention.

[1446] In Scheme 1, the following reaction conditions generally apply:

[1447] 1: Depends on R 3a 、R 3b or R 3c The definition has different reaction condition groups:

[1448] 1a: When R 3a 、R 3b or R 3c If the halogen is used, step 1 can be omitted.

[1449] 1b: When R 3a 、R 3bor R 3c NR 7a R 7b At that time, in the presence of the chemical formula HNR 7a R 7b In the presence of a suitable amine and a suitable solvent such as H2O, MeOH or EtOH, at a suitable temperature (e.g., between 100°C and 130°C, typically under microwave conditions or when heated using an autoclave).

[1450] 1c: When R3a, R 3b or R 3c -OC 1-4 When alkyl, at a suitable HO-C 1-4 Alkyl groups, suitable bases such as NaH, potassium tert-butoxide (tBuOK), and suitable solvents such as tetrahydrofuran (THF) are used in the presence of suitable solvents at suitable temperatures. Alternatively, suitable H₂O-C₂ solutions can be used. 1-4 Alkyl groups are used as solvents in the presence of suitable acids such as HCl.

[1451] 1d: When R 3a 、R 3b or R 3c When hydrogen is used, under hydrogenation conditions: H2 atmosphere, in the presence of a catalyst, such as Raney nickel, Pd / C (e.g. 5 wt% to 10 wt%) or Pt / C (e.g. 5 wt%), in a suitable solvent such as methanol (MeOH), ethanol (EtOH) or THF;

[1452] 1e: When R 3a 、R 3b or R 3c C 1-4 When alkyl, in the presence of a suitable boric acid or its ester, such as methylboronic acid, and a suitable catalyst, such as 1,1'-bis(diphenylphosphino)ferrocene, and in a suitable solvent mixture (such as dioxane / H2O, ratio 5:1), in the presence of a suitable base, such as K3PO4, at a suitable temperature, such as 100°C;

[1453] 2: In the presence of a suitable acid, such as 4MHCl in dioxane or 4MHCl in MeOH and a suitable solvent, such as MeOH, at a suitable temperature, such as room temperature; or alternatively, at a suitable temperature in the presence of a suitable acid, such as trifluoroacetic acid (TFA) in dichloromethane (DCM), or at a suitable temperature, such as room temperature, in the presence of acetic acid in THF and water.

[1454] 3: In a suitable environment, having the chemical formula (C 1-4 Alkyl (C=O)₂O anhydrides and suitable solvents, such as pyridine, in the presence of suitable temperatures. When R3a 、R 3b or R 3c When it is NH2, (C 1-4 Alkyl C=O)₂O can react with NH₂ to obtain N(C) 1-4 Alkyl C=O)2 intermediate. This intermediate can be converted to the target product in a suitable solvent, such as in the presence of MeOH, at a suitable temperature, such as 100°C-130°C under microwave conditions or by heating using an autoclave. The reaction can benefit from the presence of an acid, such as HCl or C 1-4 Alkyl CO2H.

[1455] The starting materials in Scheme 1 are commercially available or can be prepared by standard means that are obvious to those skilled in the art or by methods as described in the following general scheme.

[1456] General Solution 2a

[1457] Typically, intermediates with chemical formulas III, V, and VII (where Z represents -O-CHR) 5a -) can be prepared according to scheme 2a. All other variables in scheme 2a are defined within the scope of the invention. Those skilled in the art will recognize that when R 3a 、R 3b or R 3c -NH2 or -NHR 7b At that time, a suitable protective substrate is required;

[1458]

[1459] In scheme 2a, the following reaction conditions apply:

[1460] 1: Three-way reaction: 1a: In the presence of diisopropyl azodicarbonate (DIAD) or diethyl azodicarbonate (DEAD) or bis(1,1-dimethylethyl)-azodicarbonate (DBAD) supported by PPh3-polymer, in a suitable solvent (e.g., anhydrous THF), at a suitable temperature such as room temperature.

[1461] 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.

[1462] 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.

[1463] 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 methods as described in the following general scheme. Those skilled in the art will recognize that when R 5a C 1-4 When alkyl groups are involved, different isomers can be separated from each other using reversed-phase high-performance liquid chromatography (RP-HPLC) or supercritical fluid chromatography (SFC).

[1464] General Solution 2b

[1465] Intermediates having chemical formulas II, IV, and VI (where Z represents -X) a -CHR 5a -) can be prepared according to general scheme 2b. In scheme 2b, 'X a ' is defined as O or S; 'LG' is defined as a leaving group such as, for example, halogen, methanesulfonate (MsO), or tosylate (TosO), preferably TosO. 'LG1' is defined as a leaving group such as, for example, halogen; 'LG2' is defined as a leaving group such as, for example, halogen or -SCH3. 'LG3' is defined as a leaving group such as, for example, halogen or -SCH3. All other variables in Scheme 2b are defined according to the scope of the present invention.

[1466]

[1467] In scheme 2b, the following reaction conditions apply:

[1468] 1: In the presence of bases such as K2CO3, triethylamine (Et3N) or DIPEA, in a suitable solvent such as CH3CN, DCM or N,N-dimethylacetamide (DMA).

[1469] 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 methods as described in the following general scheme. Those skilled in the art will recognize that when R 5a C 1-4 When alkyl groups are involved, different isomers can be separated from each other using reversed-phase high-performance liquid chromatography (RP-HPLC) or supercritical fluid chromatography (SFC).

[1470] General Solution 2c

[1471] Intermediates having chemical formulas III, V, and VII (where 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, for example, halogen, MsO or TosO, preferably TosO. All other variables in Scheme 2c are defined according to the scope of the present invention. The skilled person will recognize that when R 3a 、R 3b or R 3c -NH2 or -NHR 7b At that time, a suitable protective substrate is needed.

[1472]

[1473] In scheme 2c, the following reaction conditions apply:

[1474] 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).

[1475] 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 methods as described in the following general scheme. Those skilled in the art will recognize that when R 5a C 1-4 When alkyl groups are involved, different isomers can be separated from each other using reversed-phase high-performance liquid chromatography (RP-HPLC) or supercritical fluid chromatography (SFC).

[1476] General Solution 3

[1477] Typically, 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, for example, halogen; 'LG2' is defined as a leaving group such as, for example, halogen or -SCH3. 'LG3' is defined as a leaving group such as, for example, halogen or -SCH3. All other variables in Scheme 3 are defined according to the scope of the present invention.

[1478]

[1479] In Scheme 3, the following reaction conditions apply:

[1480] 1: In the presence of a suitable reducing agent such as, for example, sodium triacetoxyborohydride (NaBH(AcO)3) and a suitable solvent such as, for example, DCM, at a suitable temperature such as, for example, room temperature; or alternatively, in the presence of NaBH3CN and a suitable solvent such as, for example, MeOH, at a suitable temperature such as, for example, between room temperature and 50°C.

[1481] 2: In the presence of a suitable base, such as NaH, and a suitable solvent, such as anhydrous THF, N,N-dimethylformamide (DMF), or DMA, at a suitable temperature, such as between room temperature and 50°C.

[1482] The starting materials in Scheme 3 are commercially available or can be prepared by standard means obvious to those skilled in the art or by methods as described in the Specific Experiments section. Those skilled in the art will recognize that when R... 5a C 1-4 When alkyl groups are involved, different isomers can be separated from each other using reversed-phase high-performance liquid chromatography (RP-HPLC) or supercritical fluid chromatography (SFC).

[1483] General Solution 4

[1484] Typically, the intermediate (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; 'LG2' is defined as a leaving group, such as a halogen or -SCH3; 'LG3' is defined as a leaving group, such as a halogen or -SCH3. All other variables in Scheme 4 are defined within the scope of the invention.

[1485]

[1486] In Scheme 4, the following reaction conditions apply:

[1487] 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 under microwave conditions or when heated using an autoclave.

[1488] 2: In the presence of a suitable catalyst, such as bis(triphenylphosphine)palladium(II) chloride and cuprous iodide(I), in a suitable solvent, such as 2-methyltetrahydrofuran and a suitable base, such as triethylamine, at a suitable temperature, such as 80°C.

[1489] 3: In the presence of a suitable salt such as tetraethylammonium chloride (Et4NCl), a suitable solvent such as DMF, a suitable base such as DIPEA, and a palladium catalyst such as Pd(OAc)2 (palladium acetate(II)), at a suitable temperature such as 100°C.

[1490] 4: In an H2 atmosphere, and in the presence of a catalyst such as Pd / C (e.g., 5 wt% or 10 wt%), in a solvent such as MeOH.

[1491] The starting materials in Scheme 4 are either commercially available or can be prepared by standard means apparent to those skilled in the art or as described in the specific experimental section.

[1492] General Solution 5

[1493] Typically, the intermediate (wherein Y represents CH2 or CF2, referred to herein as Y a , and wherein Z represents -CH2O-) can be prepared according to Scheme 5.

[1494] In Scheme 5, 'LG1' is defined as a leaving group, such as a halogen; 'LG2' is defined as a leaving group, such as a halogen or -SCH3; 'LG3' is defined as a leaving group, such as a halogen or -SCH3. All other variables in Scheme 5 are defined within the scope of the invention.

[1495]

[1496] In Scheme 5, the following reaction conditions apply:

[1497] 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).

[1498] General Solution 6

[1499] Typically, the intermediate (where Z represents -CH2-) can be prepared according to the method of Scheme 6. In Scheme 6, 'LG1' is defined as a leaving group, such as a halogen; 'LG2' is defined as a leaving group, such as a halogen or -SCH3; 'LG3' is defined as a leaving group, such as a halogen or -SCH3. All other variables in Scheme 6 are defined within the scope of the invention.

[1500]

[1501] In Scheme 6, the following reaction conditions apply:

[1502] 1: In the presence of toluenesulfonylhydrazide and a suitable solvent such as MeOH, EtOH or DCM, at a suitable temperature such as room temperature.

[1503] 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.

[1504] The starting materials in Scheme 6 are commercially available or can be prepared by standard means that are obvious to those skilled in the art or by methods as described in the Specific Experiments section.

[1505] General Solution 7

[1506] Generally, intermediates (wherein Z represents -CH2-CH2-) can be prepared according to the method of Scheme 7. In Scheme 7, 'LG1' is defined as a leaving group such as, for example, halogen; 'LG2' is defined as a leaving group such as, for example, halogen or -SCH3. 'LG3' is defined as a leaving group such as, for example, halogen or -SCH3. All other variables in Scheme 7 are defined according to the scope of the present invention.

[1507]

[1508] In Scheme 7, the following reaction conditions are generally applicable:

[1509] 1. In the first step, the reaction is carried out in the presence of an alkylene precursor and a 0.5 M solution of 9-boronibirocyclo(3.3.1)nonane (9-BBN) in THF, under a nitrogen atmosphere, at a temperature between room temperature and reflux temperature, for a reaction time between 1 and 3 hours. In the second step, the reaction is carried out in the presence of, for example, a suitable Ar-bromine or Ar-iodide and a suitable catalyst such as 1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichlorodi ...

[1510] 2: Depends on R 3a 、R 3b or R 3c The definition has different reaction condition groups:

[1511] 2a: When R 3a 、R 3b or R 3c If the halogen is used, step 1 can be omitted.

[1512] 2b: When R 3a 、R 3b or R 3c NR 7a R 7b At that time, in the presence of the chemical formula HNR 7a R 7b In the presence of a suitable amine and a suitable solvent such as H2O, MeOH or EtOH, at a suitable temperature (e.g., between 100°C and 130°C, typically under microwave conditions or when heated using an autoclave).

[1513] 2c: When R 3a 、R 3b or R 3c -OC 1-4 When alkyl, at a suitable HO-C 1-4 Alkyl groups, suitable bases such as NaH, potassium tert-butoxide (tBuOK), and suitable solvents such as tetrahydrofuran (THF) are used in the presence of suitable solvents at suitable temperatures. Alternatively, suitable H₂O-C₂ solutions can be used. 1-4 Alkyl groups are used as solvents in the presence of suitable acids such as HCl.

[1514] 2d: When R 3a 、R 3b or R 3c When hydrogen is used, under hydrogenation conditions: H2 atmosphere, in the presence of a catalyst, such as Raney nickel, Pd / C (e.g. 5 wt% to 10 wt%) or Pt / C (e.g. 5 wt%), in a suitable solvent such as methanol (MeOH), ethanol (EtOH) or THF;

[1515] 2e: When R 3a 、R 3b or R 3c C 1-4 When alkyl, in the presence of a suitable boric acid or its 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.

[1516] The starting materials in Scheme 7 are either commercially available or can be prepared by standard means apparent to those skilled in the art or as described in the specific experimental section.

[1517] General Solution 8

[1518] Typically, the intermediate (where Z represents -CH2-CH2-) can be prepared according to the method of Scheme 8. In Scheme 8, 'LG1' is defined as a leaving group, such as a halogen; 'LG2' is defined as a leaving group, such as a halogen or -SCH3; 'LG3' is defined as a leaving group, such as a halogen or -SCH3. All other variables in Scheme 8 are defined within the scope of the invention.

[1519]

[1520] In Scheme 8, the following reaction conditions generally apply:

[1521] 1: Depends on R 3a 、R 3bor R 3c The definition has different reaction condition groups:

[1522] 1a: When R 3a 、R 3b or R 3c If the halogen is used, step 1 can be omitted.

[1523] 1b: When R 3a 、R 3b or R 3c NR 7a R 7b At that time, in the presence of the chemical formula HNR 7a R 7b In the presence of a suitable amine and a suitable solvent such as H2O, MeOH or EtOH, at a suitable temperature (e.g., between 100°C and 130°C, typically under microwave conditions or when heated using an autoclave).

[1524] 1c: When R3a, R 3b or R 3c -OC 1-4 When alkyl, at a suitable HO-C 1-4 Alkyl groups, suitable bases such as NaH, potassium tert-butoxide (tBuOK), and suitable solvents such as tetrahydrofuran (THF) are used in the presence of suitable solvents at suitable temperatures. Alternatively, suitable H₂O-C₂ solutions can be used. 1-4 Alkyl groups are used as solvents in the presence of suitable acids such as HCl.

[1525] 1d: When R 3a 、R 3b or R 3c When hydrogen is used, under hydrogenation conditions: H2 atmosphere, in the presence of a catalyst, such as Raney nickel, Pd / C (e.g. 5 wt% to 10 wt%) or Pt / C (e.g. 5 wt%), in a suitable solvent such as methanol (MeOH), ethanol (EtOH) or THF;

[1526] 1e: When R 3a 、R 3b or R 3c C 1-4 When alkyl, in the presence of a suitable boric acid or its ester, such as methylboronic acid, and a suitable catalyst, such as 1,1'-bis(diphenylphosphino)ferrocene, and in a suitable solvent mixture (such as dioxane / H2O ratio 5:1) in the presence of a suitable base, such as K3PO4, at a suitable temperature, such as 100°C;

[1527] 2: In the first step, in the presence of an alkylene precursor and a 9-BBN solvent 0.5 M in THF, under 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 a suitable (het)aryl bromide or (het)aryl iodide and a suitable catalyst such as, for example, 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a suitable base such as, for example, tripotassium phosphate in a suitable solvent mixture such as, for example, THF and water, at a suitable temperature between 50° C. and reflux temperature, the reaction time is suitable between 1 and 3 hours.

[1528] The starting materials in Scheme 8 are commercially available or can be prepared by standard means that are obvious to those skilled in the art or by methods as described in the Specific Experiments section.

[1529] General Solution 9

[1530] Typically, the intermediate as 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 within the scope of the invention.

[1531]

[1532] 1: In the first step, in the presence of an alkylene precursor and a 9-BBN solvent 0.5M in THF, under 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 (X is Br or I, respectively) and a suitable catalyst such as, for example, 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and in the presence of a suitable base such as, for example, tripotassium phosphate in a suitable solvent mixture such as, for example, THF and water, at a suitable temperature between 50° C. and reflux temperature, the reaction time is suitable between 1 and 3 hours.

[1533] 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.

[1534] 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, and under an inert atmosphere of N2.

[1535] The starting materials in Scheme 9 are commercially available or can be prepared by standard means that are obvious to those skilled in the art or by methods as described in the Specific Experiments section.

[1536] In all these preparations, the reaction products can be separated from the reaction medium and, if necessary, further purified according to methods generally known in the art, such as, for example, extraction, crystallization, grinding, and chromatography.

[1537] The chiral pure form of compounds having chemical formula (I) forms a preferred group of compounds. Therefore, the chiral pure form of the intermediate and their salt forms are particularly useful in the preparation of chiral pure compounds having chemical formula (I). Enantiomeric mixtures of intermediates are also useful in the preparation of compounds having chemical formula (I) with corresponding configurations.

[1538] Pharmacology

[1539] The compounds of this invention have been found to inhibit PRMT5 activity.

[1540] 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.

[1541] Therefore, it is anticipated that the compounds and pharmaceutical compositions thereof of the present invention can be used to treat or prevent diseases, particularly diseases such as metabolic disorders, autoimmune diseases, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, sperm motility, transplant rejection, graft rejection, lung injury, etc.

[1542] Specifically, the compounds and pharmaceutical compositions thereof of the present invention can be used to treat or prevent diseases, especially diseases such as allergic reactions, asthma, hematopoietic system cancers, lung cancer, prostate cancer, melanoma, metabolic disorders, diabetes, obesity, blood disorders, sickle cell anemia, etc.

[1543] The compounds and pharmaceutical compositions thereof of the present invention can be used to treat or prevent diseases, particularly to treat a proliferative condition, such as an autoimmune disease, cancer, benign growth, or inflammatory disease.

[1544] The compounds and pharmaceutical compositions thereof of the present invention can be used to treat or prevent, particularly to treat, diseases such as metabolic disorders including diabetes and obesity; a proliferative disorder including cancer, hematopoietic 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.

[1545] In some embodiments, PRMT5 inhibition by a provided compound may be useful in the treatment or prevention, particularly in the treatment of the following non-limiting list of cancers: breast cancer, lung cancer, esophageal cancer, bladder cancer, hematopoietic system cancers, 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.

[1546] Examples of metabolic disorders that may be treated or prevented, in particular treated, include, but are not limited to, diabetes or obesity.

[1547] Examples of blood disorders that may be treated or prevented, in particular treated, include, but are not limited to, hemoglobinopathies, such as sickle cell disease or beta-thalassemia.

[1548] Examples of cancers that can be treated or prevented, especially those that can be treated, include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma), adnexal cancer, benign monoclonal gammopathy, biliary cancer (e.g., bile duct cancer), bladder cancer, breast cancer (e.g., breast adenocarcinoma, papillary breast carcinoma, breast cancer, medullary breast carcinoma), brain cancer (e.g., meningioma; medulloblastoma), bronchial cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial cancer, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma). sarcoma, multiple idiopathic hemorrhagic sarcomas, endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing sarcoma, ocular cancer (e.g., intraocular melanoma, retinoblastoma), familial eosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumors (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma (OSCC), pharyngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic system cancers (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); lymphomas such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL); Examples include 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, nodular marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, and lymphoplasmacytic lymphoma (i.e., "Woldanstrom macroglobulinemia"). The following are considered leukemias: hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-cell lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-cell lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodular natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); and mixtures of one or more leukemias / lymphomas as described above.And multiple myeloma (MM), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, μ chain disease), angioblastoma, inflammatory myofibroblastoma, immune cell amyloidosis, renal cell carcinoma (e.g., nephroblastoma, also known as Wilms' tumor), hepatocellular carcinoma (e.g., hepatocellular carcinoma (HCC), malignant hepatocellular carcinoma), lung cancer (e.g., bronchial carcinoma, non-small cell lung cancer (NSCLC), squamous cell carcinoma of the lung (SLC), lung adenocarcinoma, Lewis lung cancer (LCC), pulmonary neuroendocrine tumors: typical carcinoid, atypical carcinoid, small cell lung cancer (SCLC), and Large cell neuroendocrine carcinoma), leiomyosarcoma (LMS), mastocytosis (e.g., generalized mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), idiopathic thrombocythemia (ET), idiopathic extramedullary metaplasia (AMM, also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), eosinophilic leukocytosis syndrome (HES)), neuroblastoma, neurofibroma (e.g., type 1 or 2) Multiple neurofibromatosis (NF), Schwann cell carcinoma, neuroendocrine carcinoma (e.g., gastrointestinal pancreatic 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 myxoma (IPMN), islet cell tumor), penile cancer (e.g., Paget's disease of the penis and scrotum). Diseases including pineal gland tumors, primary neuroectodermal tumors (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary duct cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g., adnexal cancer), soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland cancer, sweat gland cancer, synovial tumors, testicular cancer (e.g., seminoma, embryonal testicular carcinoma), thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma), urethral cancer, vaginal cancer, and vulvar cancer (e.g., vulvar Paget's disease).

[1549] Examples of neurodegenerative diseases that can be treated or prevented, especially those that can be treated, include, but are not limited to, motor neuron disease, 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.

[1550] Examples of cardiovascular diseases that can be treated or prevented, especially those that can be treated, include, but are not limited to, cardiac hypertrophy, restenosis, atherosclerosis, and glomerulonephritis.

[1551] Inflammatory diseases that can be treated or prevented, especially those requiring treatment, include, but are not limited to, inflammation associated with: 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 tract diseases, ankylosing spondylitis, amyloidosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, and Chagas disease. Diseases such as chronic obstructive pulmonary disease, diverticulitis, dermatomyositis, diabetes (e.g., type 1 diabetes, type 2 diabetes), skin conditions (e.g., psoriasis, eczema, allergic reactions, burns, dermatitis, pruritus), endometriosis, Gurren Lahm-Barré syndrome, infections, ischemic heart disease, and Kawasaki disease. Diseases including glomerulonephritis, gingivitis, hypersensitivity reactions, headaches (e.g., migraines, tension headaches), 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 ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet's syndrome). Syndrome), undetermined colitis, and inflammatory bowel syndrome (IBS), lupus, scleroderma, myasthenia gravis, myocardial ischemia, multiple sclerosis, nephrotic syndrome, pemphigus vulgaris, pernicious aneaemia, peptic ulcer, polymyositis, primary biliary cirrhosis, and neuroinflammatory diseases associated with encephalopathy (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; spondyloarthritis; Sjogren's syndrome; thyroiditis; transplant rejection; tendinitis; trauma or injury (e.g., frostbite, chemical irritants, toxins, scars, burns, body injuries); vasculitis; vitiligo; and Wegener's granulomatosis.

[1552] Specifically, the inflammatory disease is an acute inflammatory condition (e.g., inflammation caused by infection). Specifically, the inflammatory disease is a chronic inflammatory condition (e.g., symptoms caused by asthma, arthritis, and inflammatory bowel disease). These compounds can also be useful in treating inflammation associated with trauma and non-inflammatory myalgia. These compounds can also be useful in treating inflammation associated with cancer.

[1553] Treatable or preventable, especially treatable, autoimmune diseases include, but are not limited to, arthritis (including rheumatoid arthritis, spondyloarthritis, gouty arthritis, degenerative joint diseases such as osteoarthritis, systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease, hemolytic autoimmune anemia, amyotrophic lateral sclerosis, amyloidosis, multiple sclerosis, acute painful shoulder, psoriatic arthritis, and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendinitis, bursitis, skin conditions (e.g., psoriasis, eczema, allergic reactions, burns, dermatitis, pruritus), enuresis, eosinophilic disorders, and gastrointestinal conditions (e.g., selected from peptic ulcers, regional enteritis, diverticulitis). Gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diverted colitis, Behcet's syndrome, indeterminate colitis), and inflammatory bowel syndrome (IBS)), as well as conditions improved by gastric motility enhancers (e.g., intestinal obstruction, postoperative intestinal obstruction, and intestinal obstruction during sepsis; food intolerance and food allergies, and other functional bowel disorders such as non-ulcerative dyspepsia (NUD) and non-cardiac chest pain (NCCP, including chondritis of the flanks)).

[1554] In one specific embodiment, a provided compound may be useful in somatic cell reprogramming, such as reprogramming somatic cells into stem cells. In one specific embodiment, a provided compound may be useful in germ cell development, and is therefore envisioned to be useful in the fields of reproductive technology and regenerative medicine.

[1555] Other treatable or preventable diseases, especially treatable ones, include, but are not limited to, ischemic injury-related myocardial infarction, immune diseases, stroke, arrhythmias, toxin-induced or alcohol-related liver disease, aspirin-sensitive sinusitis, cystic fibrosis, cancer pain, and blood disorders such as chronic anemia and aplastic anemia.

[1556] The compounds of the present invention can also have therapeutic applications that make tumor cells sensitive to radiotherapy and chemotherapy.

[1557] Therefore, the compounds of the present invention can be used as "radiosensitizers" and / or "chemosensitizers", or can be administered in combination with other "radiosensitizers" and / or "chemosensitizers".

[1558] As used herein, the term "radiosensitizer" refers to a molecule, preferably a low molecular weight molecule, which, when administered to animals in therapeutically effective amounts, can increase the sensitivity of cells to ionizing radiation and / or enhance the efficacy of diseases treatable with ionizing radiation.

[1559] As used herein, the term "chemosensitizer" refers to a molecule, preferably a low molecular weight molecule, which, when administered to animals in a therapeutically effective amount, can increase the sensitivity of cells to chemotherapy and / or enhance the efficacy of treatment for diseases that can be treated with chemotherapeutic agents.

[1560] Several mechanisms of action for radiosensitizers have been proposed in the literature, including: hypoxic cell radiosensitizers (e.g., 2-nitroimidazole compounds and benzotriazine dioxide) mimic oxygen or alternatively act as bioreducing agents under hypoxic conditions; non-hypoxic cell radiosensitizers (e.g., halopyrimidines) can be DNA base analogs and preferably bind to the DNA of cancer cells, thereby enhancing radiation-induced DNA breakage and / or preventing normal DNA repair mechanisms; and various other possible mechanisms of action have been hypothesized as radiosensitizers in disease treatment.

[1561] Many current cancer treatments utilize radiosensitizers that are combined with X-ray radiation. Examples of X-ray-activated radiosensitizers include, but are not limited to, metronidazole, ether metronidazole, desmethyl ether metronidazole, pemonidazole, ethamidazole, nitromethorphan, mitomycin C, RSU1069, SR4233, EO9, RB6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FUdR), alkylurea, cisplatin, and therapeutically effective analogues and derivatives of the above substances.

[1562] Photosensitive therapy (PDT) for cancer uses visible light as a radiation activator, which is a sensitizer. Examples of photosensitive sensitizers include, but are not limited to, hematoporphyrin derivatives, photoporphyrin, benzene-porphyrin derivatives, tin-based porphyrin, pheophorbide-a, bacterial chlorophyll-a, naphtha-iocyanine, cyanine, zinc phthalocyanine, and therapeutically effective analogs and derivatives of the above substances.

[1563] Radiosensitizers may be administered in combination with a therapeutically effective amount of one or more compounds, including but not limited to: compounds that promote the binding of radiosensitizers to 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; chemotherapeutic drugs that act on tumors; or other compounds that are effective in treating cancer or other diseases.

[1564] Chemosensitizers can be administered in combination with one or more therapeutically effective compounds, including but not limited to: compounds that promote the binding of chemosensitizers to target cells; compounds that control the flow of therapeutic agents, nutrients, and / or oxygen to target cells; chemotherapeutic drugs that act on tumors; or other compounds that have therapeutic effects on cancer or other diseases. Calcium channel blockers, such as verapamil, have been found to be used in combination with antitumor drugs to establish chemosensitivity in tumor cells resistant to recognized chemotherapeutic agents and to enhance the efficacy of such compounds in drug-sensitive malignancies.

[1565] The compounds of the present invention may also reduce the risk of cancer recurrence.

[1566] The present invention relates to compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof for use as a medicament.

[1567] This invention relates to compounds having chemical formula (I) for use in inhibiting PRMT5 activity, and their pharmaceutically acceptable addition salts and solvates.

[1568] The compounds of the present invention may be "anticancer agents," and the term also covers "antitumor cell growth agents" and "antitumor agents."

[1569] The present invention relates to compounds having chemical formula (I) for use in the treatment of the aforementioned diseases, and pharmaceutically acceptable addition salts and solvates thereof.

[1570] The present invention relates to compounds having chemical formula (I) for the treatment or prevention (especially the treatment) of said diseases, and pharmaceutically acceptable addition salts and solvates thereof.

[1571] This invention relates to compounds having chemical formula (I) and their pharmaceutically acceptable addition salts and solvates for the treatment or prevention (especially the treatment) of PRMT5-mediated diseases or conditions.

[1572] This invention relates to compounds having chemical formula (I) and their pharmaceutically acceptable addition salts and solvates for the manufacture of a pharmaceutical agent.

[1573] This invention relates to compounds having chemical formula (I) and pharmaceutically acceptable addition salts and solvates thereof for the manufacture of agents for inhibiting PRMT5.

[1574] This invention relates to compounds having chemical formula (I) and their pharmaceutically acceptable addition salts and solvates for the manufacture of medicaments for the treatment or prevention (especially for the treatment) of any of the diseases mentioned above.

[1575] This invention relates to compounds having chemical formula (I) and pharmaceutically acceptable addition salts and solvates thereof for the manufacture of medicaments for the treatment of any of the diseases or conditions mentioned above.

[1576] The present invention relates to compounds having chemical formula (I) and pharmaceutically acceptable addition salts and solvates thereof, which may be administered to mammals, preferably humans, for the treatment or prevention of any of the diseases mentioned above.

[1577] In view of the use of compounds having chemical formula (I) and their pharmaceutically acceptable addition salts and solvates, a method is provided for treating warm-blooded animals (including humans) suffering from any of the diseases mentioned above, or a method for preventing warm-blooded animals (including humans) from suffering from any of the diseases mentioned above.

[1578] The method comprises administering, i.e., systemic or local administration, preferably orally, an effective amount of a compound having chemical formula (I) or a pharmaceutically acceptable addition salt or solvate thereof to a warm-blooded animal (including a human), i.e., systemic or local administration, preferably orally.

[1579] In the treatment of such diseases, a person of ordinary skill can determine the effective daily therapeutic dose from the test results provided below. The effective daily therapeutic dose should be from about 0.005 mg / kg to 50 mg / kg, specifically from 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. Specifically, the effective daily therapeutic dose should be from about 0.01 to 1.00 g (BID) twice daily, more specifically from 0.30 to 0.85 g BID; even more specifically 0.40 g BID. The amount of the compound according to the invention (also referred to herein as the active ingredient) required to achieve therapeutic efficacy can vary depending on the 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.

[1580] Treatment methods may also include administering the active ingredient at a frequency between once and four times daily. In these treatment methods, the compound according to the invention is preferably formulated prior to administration. As described herein, suitable pharmaceutical formulations are prepared using well-known and readily available ingredients through known procedures.

[1581] The compounds of the present invention, suitable for the treatment or prevention of cancer or cancer-related conditions, can be administered alone or in combination with one or more other therapeutic agents. Combination therapies include: administration of a single-dose formulation comprising a compound having chemical formula (I), a pharmaceutically acceptable addition salt or solvation thereof, and one or more other therapeutic agents; or administration of each other therapeutic agent present together with a compound having chemical formula (I), a pharmaceutically acceptable addition salt or solvation thereof, and a separate oral-dose formulation. For example, a patient may be given a compound having chemical formula (I) or a pharmaceutically acceptable addition salt or solvation thereof and a therapeutic agent together in a single oral-dose composition (such as a tablet or capsule), or each agent may be given in separate oral-dose formulations.

[1582] Although the active ingredient may be administered alone, it is preferred to present it as a pharmaceutical composition.

[1583] Therefore, the present invention further provides a pharmaceutical composition, and a therapeutically effective amount of a compound having chemical formula (I) as an active ingredient, a pharmaceutically acceptable addition salt or solvate thereof.

[1584] Therefore, the present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable addition salt or solvate thereof as an active ingredient.

[1585] The carrier or diluent must be "acceptable" in the sense of compatibility with the other components of the composition and harmless to its recipients.

[1586] For ease of administration, these subject compounds can be formulated into various pharmaceutical forms for administration purposes. Compounds according to the invention, particularly those having chemical formula (I) and their pharmaceutically acceptable addition salts and solvates, or any subgroups or combinations thereof, can be formulated into various pharmaceutical forms for administration purposes. All compositions commonly used for systemic administration may be cited as suitable compositions.

[1587] To prepare the pharmaceutical compositions of the present invention, an effective amount of a specific compound as the active ingredient is combined with a pharmaceutically acceptable carrier in a homogeneous blend. This carrier can take various forms depending on the desired formulation for administration. It is desirable that these pharmaceutical compositions be in a unit dosage form particularly suitable for oral, rectal, transdermal, parenteral, or inhalation administration. For example, in preparing compositions in oral dosage forms, any common pharmaceutical medium can be used, such as water, glycols, oils, alcohols, and the like in the case of oral liquid formulations (e.g., suspensions, syrups, elixirs, emulsions, and solutions); or solid carriers such as starch, sugar, kaolin, diluents, lubricants, binders, disintegrants, and the like in the case of powders, pills, capsules, and tablets. Tablets and capsules represent the most advantageous oral unit dosage forms due to their ease of administration, in which case solid pharmaceutical carriers are obviously used. For parenteral compositions, the carrier will typically comprise at least predominantly sterile water, but may also include other components, for example, to aid solubility. Injectable solutions can be prepared, for example, in which the carrier comprises an aqueous solution of physiological saline, a glucose solution, or a mixture of physiological saline and glucose solution. Injectable solutions containing compounds having chemical formula (I), their pharmaceutically acceptable addition salts, or solvates can be formulated in oils to prolong 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. Solid formulations are also included, which are intended to be converted into liquid formulations shortly before use. In compositions suitable for transdermal administration, the carrier may optionally include a penetration enhancer and / or a suitable wetting agent, optionally combined with a small proportion of suitable additives of any nature that do not introduce significant adverse effects on the skin. The additives may facilitate administration to the skin and / or may contribute to the preparation of the desired composition. These compositions can be administered in various ways, such as as transdermal patches, plasters, or ointments. Acid or base addition salts of compounds having chemical formula (I) are more suitable for preparing aqueous compositions because their water solubility increases relative to the corresponding base or acid form.

[1588] For ease of administration and dosage uniformity, it is particularly advantageous to formulate the above-described pharmaceutical compositions into unit dosage forms. As used herein, a unit dosage form refers to a physically discrete unit suitable as a unit dose, each unit containing a predetermined amount of active ingredient, which is calculated to combine with a desired drug carrier to produce the desired therapeutic effect. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions, and similar dosage forms, as well as segregated multiples.

[1589] To enhance the solubility and / or stability of compounds having chemical 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, particularly hydroxyalkyl-substituted cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. Co-solvents (e.g., alcohols) can also improve the solubility and / or stability of compounds according to the invention in pharmaceutical compositions.

[1590] Depending on the route of administration, the pharmaceutical composition will preferably include, by weight, 0.05% to 99%, more preferably 0.1% to 70%, even more preferably 0.1% to 50% of a compound having chemical formula (I), its pharmaceutically acceptable addition salt or solvate, and by weight, 1% to 99.95%, more preferably 30% to 99.9%, even more preferably 50% to 99.9% of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

[1591] As another aspect of the invention, combinations of the compounds of the invention with another anticancer agent are envisioned, particularly for use as a medicine, and more precisely for use in the treatment of cancer or related diseases.

[1592] To treat the above-mentioned symptoms, the compounds of the present invention can be advantageously used in combination with antibody-based immune cell retargeting, such as T-cell / neutrophil retargeting. This objective can be achieved, for example, by using bispecific monoclonal antibodies or artificial T-cell receptors.

[1593] To treat the above-mentioned symptoms, the compounds of the present invention can be advantageously used in combination with one or more other pharmaceutical agents, more specifically with other anticancer agents or adjuvants in cancer therapies. Examples of anticancer agents or adjuvants (supportive agents in therapy) include, but are not limited to:

[1594] - Platinum coordination compounds, such as cisplatin (optionally combined with aifostine), carboplatin, or oxaliplatin;

[1595] -Taxane compounds, such as paclitaxel, paclitaxel protein-bound particles (Abraxane TM ) or Dorsetas;

[1596] - Topoisomerase I inhibitors, such as camptothecin compounds, for example irinotecan, SN-38, topotecan, topotecan hydrochloride;

[1597] - topoisomerase II inhibitors, such as antitumor epipodophyllotoxins or podophyllotoxin derivatives, for example etoposide, etoposide phosphate or teniposide;

[1598] -Antitumor vinca alkaloids, such as vinblastine, vincristine, or vinorelbine;

[1599] - antitumor nucleoside derivatives, such as 5-fluorouracil, leucovorin, gemcitabine, gemcitabine hydrochloride, capecitabine, cladribine, fludarabine, nelarabine;

[1600] - Alkylating agents, such as nitrogen mustard or nitrosourea, for example cyclophosphamide, chlorambucil, carmustine, thiotepa, melphalan, lomustine, hexamethylmelamine, busulfan, dacarbazine, estmustine, ifosfamide (optionally in combination with mesna), pipebromodiphenyl ether, procarbazine, streptozocin, temozolomide, uracil;

[1601] -Antracrine derivatives for tumor treatment, such as doxorubicin, doxorubicin (optionally in combination with dexrazoxane), doxorubicin liposome (doxil), idarubicin, mitoxantrone, epirubicin, epirubicin hydrochloride, pentorubicin;

[1602] - Molecules that target the IGF-1 receptor, such as picropodophyllin;

[1603] -Tetriacalcin derivatives, such as tetriacalcin A;

[1604] - Glucocorticoids, such as prednisone;

[1605] - Antibodies, such as trastuzumab (HER2 antibody), rituximab (CD20 antibody), gemtuzumab, gemtuzumab oxozamicin, cetuximab, pertuzumab, bevacizumab, alemtuzumab, icocurumab, ibritumomab tiuxetan, nofetumab, panitumumab, tosimomab, CNTO328;

[1606] - Estrogen receptor antagonists or selective estrogen receptor modulators or estrogen synthesis inhibitors, such as tamoxifen, fulvestrant, toremifene, droloxifen, faslodex, raloxifene, or letrozole.

[1607] -Aromatase inhibitors, such as exemestane, anastrozole, letrozole, testosterone, and voroxycycline;

[1608] - Differentiators, such as retinoids, vitamin D or retinoic acid, and retinoic acid metabolism blockers (RAMBA), such as isotretinoin;

[1609] -DNA methyltransferase inhibitors, such as azacytidine or decitabine;

[1610] - Anti-folate agents, such as pemetrexed disodium;

[1611] - Antibiotics, such as antimycin D, bleomycin, mitomycin C, actinomycin, erythromycin, daunomycin, levamisole, procainamide, and photomycin;

[1612] -Antimetabolites, such as clofarabine, aminopterin, cytosine arabinoside or methotrexate, azacitidine, cytarabine, fluorouracil, pentostatin, thioguanine;

[1613] - 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 decanoic acid;

[1614] - Microtubule binding agents, such as compressoritine, colchicine, or nocodazole;

[1615] - Kinase inhibitors (e.g., EGFR (epidermal growth factor receptor) inhibitors, MTKI (multi-target kinase inhibitors), mTOR inhibitors), such as furapin, imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, lapatinib dimethylbenzenesulfate, sorafenib, sunitinib, sunitinib maleate, tamsurolimus;

[1616] - Farnesyltransferase inhibitors, such as tepifanil;

[1617] - Histone deacetylase (HDAC) inhibitors, such as sodium butyrate, succinyl aniline isohydroxamic acid (SAHA), pentapeptide (FR 901228), NVP-LAQ824, R306465, JNJ-26481585, nystatin A, and vorinostat;

[1618] -Ubiquitin-proteasome pathway inhibitors, such as PS-341, MLN.41, or bortezomib;

[1619] - Yondelis (trabectedine);

[1620] - Telomerase inhibitors, such as telomerostigmine;

[1621] - Matrix metalloproteinase inhibitors, such as bamastarta, marimastarta, purinstarta, or metastastarta.

[1622] - Recombinant interleukins, such as adefovir, dinifovir diftros, interferon α2a, interferon α2b, pegylated interferon α2b

[1623] -MAPK inhibitors

[1624] - Retinoids, such as retinoic acid, bexarotine, retinoic acid

[1625] Arsenic trioxide

[1626] - Asparaginase

[1627] - Steroids, such as drotaldoprofen propionate, megestrol acetate, nandrolone (decanoate, phenylpropionate), dexamethasone

[1628] - Gonadotropin-releasing hormone agonists or antagonists, such as abaric acid, goserelin acetate, histamine relin acetate, leuprolide acetate

[1629] - Thalidomide, Lenalidomide

[1630] -Mercaptopurine, Mitotan, Pamidronate, Pegastinase, Pegaspargase, Raburicase

[1631] -BH3 emulators, such as ABT-737

[1632] -MEK inhibitors, such as PD98059, AZD6244, CI-1040

[1633] - Colony-stimulating factor analogues, such as filgrastim, glycolated filgrastim, saxagstim; erythropoietin or its analogues (e.g., dabepostatin α); interleukin-11; zoledronic acid; fentanyl; bisphosphonates; parivmin;

[1634] - A steroidal cytochrome P450 17 α-hydroxylase-17,20-lyase inhibitor (CYP17), such as abiraterone or abiraterone acetate.

[1635] Glycolysis inhibitors, such as 2-deoxyglucose

[1636] -mTOR inhibitors, such as rapamycin and rapamycin analogues (rapalog), and mTOR kinase inhibitors

[1637] -PI3K inhibitors and dual mTOR / PI3K inhibitors

[1638] - Autophagy inhibitors, such as chloroquine and hydroxychloroquine

[1639] - Antibodies that reactivate the immune response to tumors, such as nivolumab (anti-PD-1), lambrolizumab (anti-PD-1), ipilimumab (anti-CTLA4), and MPDL3280A (anti-PD-L1).

[1640] The present invention further relates to a product comprising a compound according to the invention as a first active ingredient and one or more anticancer agents as another active ingredient, for use in combination formulation for the simultaneous, separate or continuous treatment of patients suffering from cancer.

[1641] One or more other pharmaceutical agents and the compound according to the present invention can be given simultaneously (for example, in the form of a single or unit composition) or in any order. In the latter case, two or more compounds will be given in a time period and in a certain amount and manner, so as to be sufficient to ensure that a favorable or synergistic effect is achieved. It should be understood that the preferred method and order of each component of the combination and the corresponding dosage and regimen will depend on the specific other pharmaceutical agents and the compound of the present invention, its route of administration, the specific tumor treated, and the specific host treated. The best method and order of administration and dosage and regimen can be easily determined by those skilled in the art using conventional methods and in view of the information stated herein.

[1642] When given in combination, the weight ratio of the compound according to the present invention and one or more other anticancer agents can be determined by those of ordinary skill in the art. The ratio and the exact dosage and frequency of administration depend on the specific compound according to the present invention and other one or more anticancer agents used, the specific disease for treatment, the severity of the disease for treatment, the age, body weight, sex, diet, administration time and general physical condition, administration mode and other drugs that individual can take, as well known to those skilled in the art. In addition, it is obvious that the effective daily dosage can be reduced or improved, and this depends on the response of the experimenter for treatment and / or depends on the assessment of the doctor who gives the compounds of this invention prescription. The specific weight ratio of the compound with chemical formula (I) of the present invention and another anticancer agent can be from 1 / 10 to 10 / 1, more particularly from 1 / 5 to 5 / 1, even more particularly in the scope of 1 / 3 to 3 / 1.

[1643] The platinum coordination compound is advantageously present in an amount of 1 to 500 mg / m2 (mg / m 2 For example, 50 to 400 mg / m² 2 Dosages based on body surface area are given, particularly for cisplatin, at approximately 75 mg / m2 per course of treatment. 2 Carboplatin is given at a dose of approximately 300 mg / m per course.2 give.

[1644] The taxane compound is advantageously administered at a dose of 50 to 400 mg / m2 (mg / m 2 For example, 75 to 250 mg / m² 2 Dosages based on body surface area are given, particularly for paclitaxel, at approximately 175 to 250 mg / m2 per course of treatment. 2 Docetaxel is given at a dose of approximately 75 to 150 mg / m2 per course. 2 give.

[1645] The camptothecin compound is advantageously administered at a dose of 0.1 to 400 mg / m2 (mg / m 2 For example, 1 to 300 mg / m² 2 Dosages based on body surface area are given, particularly for irinotecan, at about 100 to 350 mg / m2 per course of treatment. 2 For topotecan, approximately 1 to 2 mg / m2 per course of treatment is given. 2 give.

[1646] The antitumor podophyllotoxin derivative is advantageously administered at a dose of 30 to 300 mg / m2 (mg / m 2 For example, 50 to 250 mg / m² 2 Doses based on body surface area are given, particularly for etoposide, at approximately 35 to 100 mg / m2 per course of treatment. 2 and, for teniposide, at approximately 50 to 250 mg / m per course of treatment. 2 give.

[1647] The antitumor vinca alkaloids are advantageously administered at a dose of 2 to 30 mg / m2 (mg / m 2 ) body surface area, particularly for vinblastine, at a dose of about 3 to 12 mg / m 2 For vincristine, approximately 1 to 2 mg / m 2 and for vinorelbine, approximately 10 to 30 mg / m2 per course of treatment. 2 The prescribed dosage was administered.

[1648] Antitumor nucleoside derivatives are advantageously available at 200 to 2500 mg / m². 2 For example, 700 to 1500 mg / m³ 2 Doses are given based on body surface area, particularly for 5-FU, at 200 to 500 mg / m 2 For gemcitabine, approximately 800 to 1200 mg / m 2 The dosage is given, and for capecitabine, at approximately 1000 to 2500 mg / m² per cycle.2 give.

[1649] Alkylating agents (such as nitrogen mustard or nitrosourea) are advantageously used at concentrations of 100 to 500 mg / m². 2 For example, 120 to 200 mg / m² 2 Dosage based on body surface area, especially for cyclophosphamide, is administered at approximately 100 to 500 mg / m² per treatment cycle. 2 The dosage is as follows: for chlorambucil, approximately 0.1 to 0.2 mg / kg per cycle; for carmustine, approximately 150 to 200 mg / kg per cycle. 2 The dosage is given, and for lomustine, at approximately 100 to 150 mg / m² per cycle. 2 The prescribed dosage was administered.

[1650] Antitumor anthracycline derivatives are advantageously available at doses of 10 to 75 mg / m². 2 For example, 15 to 60 mg / m³ 2 Administer a dose based on body surface area, especially for doxorubicin, at approximately 40 to 75 mg / m². 2 For daunomycin, the dosage is approximately 25 to 45 mg / m². 2 The dosage is given, and for bilirubin, at approximately 10 to 15 mg / m² per treatment course. 2 The prescribed dosage was administered.

[1651] Anti-estrogens are advantageously administered at doses of approximately 1 to 100 mg daily, depending on the specific drug and the condition being treated. Tamoxifen is advantageously administered orally at doses of 5 to 50 mg, preferably 10 to 20 mg, twice daily, to allow the therapy to continue for an adequate duration to achieve and maintain a therapeutic effect. Toremifene is advantageously administered orally at a dose of approximately 60 mg once daily, to allow the therapy to continue for an adequate duration to achieve and maintain a therapeutic effect. Anastrozole is advantageously administered orally at a dose of approximately 1 mg once daily. Draloxifene is advantageously administered orally at a dose of approximately 20-100 mg once daily. Raloxifene is advantageously administered orally at a dose of approximately 60 mg once daily. Exemestane is advantageously administered orally at a dose of approximately 25 mg once daily.

[1652] Antibodies favorably occur at a concentration of approximately 1 to 5 mg / m². 2 The dose is administered at a rate corresponding to the body surface area, or, if different, as is known in the art. Trastuzumab is advantageously administered at a dose of 1 to 5 mg / m² per cycle. 2 Especially 2 to 4 mg / m 2 Dosage administered based on body surface area.

[1653] These doses may be administered, for example, once, twice or more per course of treatment, and the course of treatment may be repeated, for example, every 7, 14, 21 or 28 days.

[1654] The following examples illustrate the present invention. If no specific stereochemistry is indicated for a stereocenter of a compound, this means that the compound is obtained as a mixture of R and S enantiomers. If more than one stereocenter is present in a structure, each stereocenter for which no specific stereochemistry is indicated is obtained as a mixture of R and S enantiomers.

[1655] The skilled artisan will recognize that typically following column purification, the desired fractions are collected and the solvent evaporated to obtain the desired compound or intermediate.

[1656] Examples

[1657] In the following text, the terms “rt”, “rt”, or “RT” mean room temperature; “Me” means methyl; “MeOH” means methanol; “Et” means ethyl; “EtOH” means ethanol; “NaH” means sodium hydride; “DEAD” means diethyl azodicarboxylate; “HMPT” means hexamethylphosphoric triamide; “Boc2O” means tert-butoxycarbonyl anhydride; “ButONO” means tert-butyl nitrite; “TosOH” means 4-methylbenzenesulfonic acid; “TosCl” means 4-methylbenzenesulfonyl chloride (also known as p-toluenesulfonyl chloride); “CMBP” means cyanomethylenetributylphosphine; “DBAD” means di-tert-butyl azodicarboxylate; and “LAH” means hydrogen. Lithium aluminum hydroxide; "NaBH(AcO)3" or "NaBH(OAc)3" means sodium triacetoxyborohydride; "EtOAc" means ethyl acetate; "TEA" or "Et3N" means triethylamine; "DCM" means dichloromethane; "qs" means sufficient amount; "Int." means intermediate; "MeCN" or "ACN" means acetonitrile; "DMF" means N,N-dimethylformamide; "DMA" means N,N-dimethylacetamide; "DMF-DMA" means N,N-dimethylformamide dimethyl acetal; "Pd(dppf)Cl2" means [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichlorodi ... 34 H 28"FeP2.Cl2Pd" means [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloro(ii); "i-PrOH" or "iPrOH" means 2-propanol; "LC" means liquid chromatography; "LCMS" means liquid chromatography / mass spectrometry; "HPLC" means high performance liquid chromatography; "int." means intermediate; "prep-HPLC" means preparative high performance liquid chromatography; "m-CPBA" means m-chloroperoxybenzoic acid; "TFA" means trifluoroacetic acid; "mp" means melting point; "RP" means reversed phase; "min" means minutes; "h" means hours; "PE" means petroleum ether; "v / v" means volume / volume. "DMSO" means dimethyl sulfoxide; "SFC" means supercritical fluid chromatography; "DIPE" means diisopropyl ether; "Dppf" or "DPPF" means 1,1'-bis(diphenylphosphine)ferrocene; "DIPEA" or "DIEA" means N,N-diisopropylethylamine; "PPh3" means triphenylphosphine; "Et2O" means diethyl ether; "Pd / C" means palladium on carbon; "Pt / C" means platinum on carbon; "Pd(OH)2 / C" means palladium hydroxide on carbon; "CPME" means cyclic... pentyl methyl ether; "Pd2(dba)3" means tris(dibenzylacetone)dipalladium; "DIAD" means diisopropyl azodicarboxylate; "TMSCF3" means trimethyl(trifluoromethyl)silane; "TBAF" means tetrabutylammonium fluoride; "psi" means pounds per square inch; "Et4NCl" means tetraethylammonium chloride; "eq." means equivalent; "Pd(OAc)2" means palladium(II) acetate; "AcOH" means acetic acid; "DMAP" means 4-(dimethylamino)pyridine; "t-BuOK", t"BuOK" or "KOtBu" means potassium tert-butoxide; "Dies Martin periodine" means 1,1,1-triacetoxy-1,1-dihydro-1,2-benzyl-3(1H)-one; "TBDMSCl" means tert-butyldimethylsilyl chloride; "PPh3-polymer" or "PPh3-pol" means polymer-bonded triphenylphosphine; "Ph3PCH3Br" means methyltriphenylphosphine bromide; "Bn" means benzyl "Bz" means benzoyl; "p-TSA" means 4-methylbenzenesulfonic acid; "BF3.Et2O" means boron trifluoride-diethyl ether complex; "9-BBN" means 9-boronbicyclo[3.3.1]nonane; "Pd-118" means dichloro-[1,1'-bis(di-tert-butylphosphino)-ferrocene]palladium(II); and "TLC" means thin-layer chromatography; "prep-TLC" means preparative TLC; "p-Me "C6H4SO3H.H2O" means p-toluenesulfonic acid hydrate; "PMB" means p-methoxybenzyl; "KOAc" means potassium acetate; "PTSA" means p-toluenesulfonic acid; "MTBE" means methyl tert-butyl ether; "Rh(acac)(eth)2" means acetylacetonyl bis(ethylidene) rhodium(I); "(S)-MonoPhos" means (S)-N,N-dimethylbinaphthyl[2,1-D:1',2'- F][1,3,2]dioxophosphoric heterocyclic heptadecene-4-amine; "Tf2O" means trifluoromethanesulfonic anhydride; "MeI" means iodomethane; "Me2NH" means dimethylamine; "Me2NH.HCl" means dimethylamine hydrochloride; "Me4NCl" means tetramethylammonium chloride; "MeONa" means sodium methoxide; "Ts" means toluenesulfonyl; "MsCl" means methanesulfonyl chloride; "DIBAH" means diisobutylaluminum hydrogenate;

[1658] “TBDMS” means tert-butyldimethylsilyl; “Pd(dppf)Cl2.CH2Cl2” means [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II), a complex with dichloromethane; “PPA” means polyphosphoric acid; “NH2Bn” means benzylamine; “Pd(PPh3)2Cl2” means dichlorobis(triphenylphosphine)palladium(II).

[1659] Intermediates containing double bonds and substituents (which may be in the E or Z configuration) are shown as a specific configuration in the experimental section below. However, unless explicitly indicated by (E) or (Z), it is unknown whether these intermediates are obtained in the E or Z configuration or as a mixture of the two configurations. For example, intermediates 24-26, 29-31, 72-76, and 79-88 may be in the E or Z configuration, or may be a mixture thereof.

[1660] For example, intermediates 44, 97-100, 136-138, 150 and compounds 55, 57, 57a and 61 were obtained in the E configuration and were explicitly indicated as (E) as in the experimental section below.

[1661] For intermediates used in the next reaction step as crude products or as partially purified intermediates, the estimated molar amount (in some cases indicated by ≈) is indicated in the reaction protocol below, or alternatively, the theoretical molar amount may be indicated.

[1662] A. Preparation of intermediates

[1663] Example A1

[1664] Preparation of intermediate 1

[1665]

[1666] At 25 °C under a nitrogen atmosphere, 2,2-dimethoxypropane (18.2 g, 175 mmol) and 4-methylbenzenesulfonic acid (TosOH) (1.51 g, 8.75 mmol) were added in a single addition to a mixture of 6-chloro-7-deazonipurine β-d-nucleoside (25.0 g, 87.5 mmol) in acetone (330 mL). The mixture was stirred at 60 °C for 2 hours. The mixture was then cooled to 25 °C. The reaction was quenched by the slow addition of saturated NaHCO3 (100 mL) and then extracted with ethyl acetate (125 mL x 5). The combined organic phases were washed with saturated brine (120 mL), dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (gradient elution: DCM / ethyl acetate from 1:0 to 2:1) to give crude intermediate 1 (38.0 g) as a pale yellow gel.

[1667] Example A2

[1668] Preparation of intermediate 3

[1669]

[1670] HMPT was added dropwise to a solution of 5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-D-ribofuranoside (intermediate 2) (24.3 g, 79.8 mmol) in CCl4 (12.8 mL, 133 mmol) and toluene (200 mL) at -50 °C for 30 minutes. After stirring the mixture at -50 °C for 2 hours, the reaction mixture was rapidly washed with ice-cold brine (30 mL), dried on anhydrous Na2SO4, and immediately added to a well-stirred mixture of powdered KOH (6.5 g, 117 mmol), 2,4-dichloro-7h-pyrrolopyrimidine (10.0 g, 53 mmol), tris(3,6-dioxaneheptyl)amine (8.27 mL, 26.6 mmol), and toluene (200 mL). The mixture was stirred at room temperature for 48 hours. The solvent was then concentrated under vacuum. The residue was treated with 250 ml of NH4Cl solution and extracted with ethyl acetate (300 ml x 2). The organic layers were combined, dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient eluent: petroleum ether / ethyl acetate from 25:1 to 15:1). The product fraction was collected and the solvent was evaporated to obtain the desired intermediate 3 (6.50 g, crude product).

[1671] The intermediates below were prepared using suitable starting materials through a similar reaction scheme as that used to prepare intermediate 3 (Table 1).

[1672] Table 1:

[1673]

[1674]

[1675] Example A3

[1676] Preparation of intermediate 6

[1677]

[1678] Intermediate 3 (7.00 g, 14.8 mmol) was dissolved in a solvent mixture of acetic acid, water and THF mixed in a ratio of 13:7:3 (100 mL). The reaction mixture was stirred at room temperature for 12 hours. Under reduced pressure, at 60 ° C, the solvent was removed to obtain 6.8 g of crude intermediate 6 and by-products. At room temperature, under an N2 atmosphere, 2,2-dimethoxypropane (5 mL, 42 mmol) and 4-methylbenzenesulfonic acid monohydrate (13 mg, 0.07 mmol) were added to a solution of the above crude product in acetone (50 mL). The mixture was stirred at 60 ° C for 2 hours. The solvent was removed under reduced pressure at 30 ° C. The residue was purified by silica gel column chromatography (gradient eluent: EtOAc / petroleum ether from 1 / 10 to 1 / 3) to obtain the desired intermediate 6 (3.02 g, 34% yield).

[1679] Example A4

[1680] Preparation of intermediate 7

[1681]

[1682] At room temperature to the solution of intermediate 4 (9.50g, 20.9mmol) in THF (82mL), drip the solution of 1M TBAF in THF (41.8mL, 41.8mmol).At room temperature, reaction mixture was stirred 3 hours.Mixture evaporated to dryness.Residue is absorbed in water, and extracted with DCM (150ml x2).With organic layer drying (Na2SO4), filter and concentrate filtrate in vacuum.Residue is carried out to purifying to obtain desired intermediate 7 (3.68g, 88% productive rate) by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate from 10 / 1 to 4 / 1).

[1683] The intermediates below were prepared using suitable starting materials through a similar reaction scheme as that used to prepare intermediate 7 (Table 2).

[1684] Table 2:

[1685]

[1686]

[1687] Example A5

[1688] Preparation of intermediate 10

[1689]

[1690] Step a)

[1691]

[1692] At 25°C under a nitrogen atmosphere, Et3N (13.4 g, 132 mmol) was added in a single addition 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 / water (208 mL, 7:1). The mixture was stirred at 90°C for 23 hours. The mixture was cooled to 50°C, and 4M HCl (24 mL, 106 mmol) was slowly added. The residue was then stirred at 50°C for 2 hours. The mixture was cooled to 25°C, and NaHCO3 (14 g, 100 mmol) was slowly added. Ethyl acetate (230 mL) was added, followed by a semi-saturated NaHCO3 solution (appropriate amount). The organic phase 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 under vacuum to obtain intermediate 9 (17.4 g, quantitative yield in both steps) as a yellow solid. The crude product was used directly as is in subsequent steps without further purification.

[1693] Step b)

[1694]

[1695] At 25 °C under a nitrogen atmosphere, 2,2-dimethoxypropane (11.0 g, 105 mmol) and TsOH·H₂O (908 mg, 5.27 mmol) were added in a single addition to a mixture of intermediate 9 (17.4 g, ≈52.7 mmol) in acetone (250 mL). The mixture was stirred at 60 °C for 2 hours. The mixture was cooled to 25 °C and the solution was concentrated under vacuum, slowly quenched with 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 under vacuum. The residue was purified by rapid silica gel chromatography (gradient eluent: DCM / ethyl acetate from 1 / 0 to 2 / 1) to obtain intermediate 10 (15.5 g, 89% yield) as a pale yellow gel.

[1696] Example A6

[1697] Preparation of intermediate 14

[1698]

[1699] Step a)

[1700]

[1701] Under a nitrogen atmosphere, 45.0 g (184 mmol) of 7-bromo-4-(methylthio)pyrrolo[2,1-f][1,2,4]triazine and 1.20 L of dry THF were placed in a dried flask. The yellow solution was cooled to -78 °C to form a yellow suspension. n-BuLi (2.5 M, 79.6 mL) was added dropwise to the reaction mixture over a 25-minute period at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour to form a yellow-brown solution. Under a nitrogen atmosphere, a pre-cooled solution of intermediate 10 (84.0 g, 201 mmol) in 800 mL of dry THF was added to this solution. The resulting reddish-brown solution was stirred at -78 °C for 1.5 hours. Both batches were performed in parallel. The reaction was quenched at -78°C by adding 300 mL of saturated NH4Cl aqueous solution, and the mixture was subsequently heated to 10°C. The mixture was extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was loaded onto silica gel and purified by column chromatography (SiO2, gradient eluent: petroleum ether / ethyl acetate from 10 / 1 to 3:1) to obtain intermediate 11 (149 g, 56% yield) as an orange gel.

[1702] Step b)

[1703]

[1704] BF3·Et2O (90.9 g, 640 mmol) was added dropwise to a stirred solution of intermediate 11 (74.0 g, 127 mmol) and triethylsilane (59.9 g, 515 mmol) in DCM (1.80 L) at -30 °C to -20 °C. Two batches were performed in parallel. The resulting orange solution was stirred between -30 °C and -20 °C for 4.5 h. The reaction mixture was carefully introduced into a saturated aqueous solution of NaHCO3 (2.5 L) with vigorous stirring (gas release). The mixture was stirred for 2 h. The organic layer was separated, and the aqueous phase was extracted with DCM (200 mL x 3). The combined organic layers (500 mL x 2) were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, gradient eluent: petroleum ether: ethyl acetate: from 12:1 to 8:1) to obtain intermediate 12, a pale yellow gel (125.7 g, 83% yield).

[1705] Step c)

[1706]

[1707] Under a nitrogen atmosphere, over a period of 2.5 hours, 1 MBCl3 in CH2Cl2 (860 mL, 860 mmol) was added dropwise at -78 °C to a stirred solution of intermediate 12 (75.0 g, 132 mmol) in DCM (1.20 L). The mixture was stirred at -78 °C for 1 hour. The reaction mixture was then slowly heated to -40 °C. The reaction mixture was poured into MeOH (2.5 L, 20 °C) with stirring. The resulting red solution was stirred for 3 hours. Water (250 mL) was added to the mixture and the mixture was allowed to stand at 20 °C for 16 hours. The solution was carefully poured in portions onto solid NaHCO3 (500 g) with vigorous stirring (gas release, color of the mixture changing from orange-red to yellow). The resulting suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned into iPrOH / CH2Cl2 (1:3, 1 L), filtered (to remove a certain inorganic salt), and the filtrate was concentrated under reduced pressure. The residue was ground with petroleum ether (500 mL x 3) to obtain crude intermediate 13 (40.2 g, crude product), an orange solid, which was used directly as is in the following steps without further purification.

[1708] Step d)

[1709]

[1710] At 25 °C, TsOH·H₂O (5.92 g, 31.10 mmol, 0.23 equivalents) was added to a suspension of intermediate 13 (40.2 g, crude product) and 2,2-dimethoxypropane (34 mL, 277 mmol) in acetone (600 mL) (pH = 2). The resulting mixture was heated at 60 °C for 2 hours. After cooling to 25 °C, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (500 mL) and saturated aqueous NaHCO₃ solution (500 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (100 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, gradient eluent: CH₂Cl₂ / ethyl acetate from 10 / 1 to 6 / 1). The fractions containing the desired intermediate 14 were combined and concentrated under reduced pressure. The residue (28 g, approximately 80% purity) was purified again by column chromatography (silica gel, gradient eluent: petroleum ether / ethyl acetate: from 20 / 1 to 4 / 1). The desired fractions were combined and concentrated under reduced pressure. The residue was diluted with CH2Cl2 (15 mL), and then petroleum ether / ethyl acetate (4:1, 200 mL) was added. The mixture was concentrated to 150 mL and the solid was precipitated. The slurry was diluted with petroleum ether to approximately 400 mL and stirred at 20 °C for 16 hours. The mixture was filtered and the solid was washed with petroleum ether / ethyl acetate (20 / 1, 100 mL). The solid was collected and dried under high vacuum to obtain pure intermediate 14 as a white solid (18.6 g, 42%, yield under both steps).

[1711] Example A7

[1712] Preparation of intermediate 15

[1713]

[1714] Intermediate 1 (10.0 g, ≈28.6 mmol), TEA (12 mL, 85.7 mmol), and DMAP (0.70 g, 5.71 mmol) were dissolved in CH2Cl2 (100 mL). p-Toluenesulfonyl chloride (10.9 g, 57.1 mmol) was added to the solution at 0 °C. The mixture was stirred overnight at room temperature. Water (100 mL) was added to the above solution. The aqueous layer was extracted with DCM (100 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated to dryness. The residue was purified by rapid chromatography (gradient eluent: petroleum ether / EtOAc from 1 / 0 to 3 / 1). The product fraction was collected and the solvent was evaporated to obtain intermediate 15, a yellow oily substance (14.5 g, 97% yield).

[1715] The intermediates below were prepared using suitable starting materials through a similar reaction scheme as that used to prepare intermediate 15 (Table 3).

[1716] Table 3:

[1717]

[1718] Example A8

[1719] Preparation of intermediate 18

[1720]

[1721] Intermediate 1 (100.0 g, theoretically 307 mmol) was dissolved in 400 mL of 1,4-dioxane. Then, 400 mL of ammonia (28%–30%, based on NH3) was added. The mixture was stirred in a sealed tube at 100 °C for 20 hours. The mixture was cooled to room temperature. The reaction mixture was evaporated under vacuum to remove half of the solvent. Water (200 mL) was added and the mixture was extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried, and concentrated to obtain Intermediate 18 as a white solid (93 g, 93% yield).

[1722] The intermediates below were prepared using suitable starting materials through a similar reaction scheme as that used to prepare intermediate 18 (Table 4).

[1723] Table 4:

[1724]

[1725]

[1726] Example A9

[1727] Preparation of intermediate 23

[1728]

[1729] Step a:

[1730]

[1731] Ammonia (28% in water, 65 mL) was added to a solution of intermediate 21 (6.6 g, 9.75 mmol) in THF (130 mL) at room temperature. The reaction mixture was stirred at 100 °C (using an autoclave) for 16 hours. The reaction mixture was cooled to room temperature and evaporated to dryness under reduced pressure. The residue was absorbed into water (100 mL) and DCM (100 mL) and stirred for 1 hour. The layers were separated and the aqueous layer was washed again with DCM (100 mL) to remove impurities. The aqueous layer was filtered and the filtrate was evaporated to dryness. The residue was purified by rapid silica gel column chromatography (gradient eluent: DCM / MeOH 95: 5 to 90:10). The desired fraction was collected and the solvent was evaporated to obtain intermediate 22 (3.4 g, crude product). The crude product was used directly in the following reaction steps without further purification.

[1732] Step b:

[1733]

[1734] At room temperature, 2,2-dimethoxypropane (1.78 mL g, 14.5 mmol) and 4-methylbenzenesulfonic acid (0.61 g, 3.19 mmol) were added in a single addition to a mixture of intermediate 22 (1.0 g, crude product) in acetone (32 mL). The mixture was stirred at 60 °C for 3 hours. The mixture was cooled to room temperature and quenched by the slow addition of saturated NaHCO3 (10 mL) and extracted with ethyl acetate (50 mL x 5). The combined organic layers were washed with saturated brine (120 mL), dried over MgSO4, filtered, and concentrated under vacuum to give intermediate 23 (0.80 g, crude product). The crude product was used directly in subsequent reaction steps without further purification.

[1735] Example A10

[1736] Preparation of intermediate 24

[1737]

[1738] Intermediate 18 (10.0 g, 32.6 mmol) was dissolved in THF (200 mL). Dimethylformamide dimethyl acetal (DMF-DMA) (5.84 g, 49.0 mmol) was then added. The mixture was stirred at 60 °C for 24 hours. The mixture was cooled to room temperature and the solvent was concentrated under vacuum. The residue was milled with EtOAc (200 mL) and water (100 mL). The organic layers were separated, the aqueous layer was extracted with EtOAc (200 mL x 1), the combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the desired intermediate 24 as a yellow solid (10.5 g, 85% yield).

[1739] The following intermediates were prepared by analogous reaction schemes to those used to prepare intermediate 24 using appropriate starting materials (Table 5).

[1740] Table 5:

[1741]

[1742] Example A11:

[1743]

[1744] Step a:

[1745]

[1746] At 0 °C and under a N2 atmosphere, TBDMSCl (52.0 g, 345 mmol) was added in a single batch to a mixture of intermediate 18 (88.0 g, 287 mmol) and imidazole (39.1 g, 575 mmol) in DMF (300.0 mL). The reaction mixture was stirred overnight at room temperature. Subsequently, water (500 mL) was added and the mixture was extracted with EtOAc (800 mL x 3). The organic layer was washed with brine (500 mL). The organic phase was then dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give a crude product. The crude product was purified by silica gel column chromatography (gradient eluent: petroleum ether / ethyl acetate 1:1). The desired fraction was concentrated to give intermediate 27 as an oily substance (120 g, 96% yield).

[1747] Step b:

[1748]

[1749] At room temperature, (Boc)₂O (13.3 g, 61.0 mmol) was added dropwise to a solution of intermediate 27 (12.4 g, ≈24.4 mmol) and DMAP (0.30 g, 2.44 mmol) in THF (50 mL). The reaction mixture was stirred at room temperature for 3 hours. Then, a 1 M TBAF solution in THF (24.4 mL, 24.4 mL) was added dropwise. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into 250 mL of water and extracted with ethyl acetate (250 mL x 2). The organic layer was washed with (water) and brine, dried over Na₂SO₄, and concentrated to dryness. The residue was purified by rapid silica gel chromatography (eluent: ethyl acetate / heptane 50 / 50). The desired fraction was collected and the residue was stirred in heptane. The solid product was filtered off and dried at room temperature and under reduced pressure to give intermediate 28 (10.2 g, 83% yield) as a solid product.

[1750] The intermediates below were prepared using suitable starting materials through a similar reaction scheme as that used to prepare intermediate 28 (Table 23).

[1751] Table 23

[1752]

[1753]

[1754] Example A12

[1755] Preparation of intermediate 29

[1756]

[1757] At room temperature, p-toluenesulfonyl chloride (8.74 g, 45.9 mmol) was added to a reaction mixture containing intermediate 24 (15.0 g, 41.7 mmol), Et3N (11.6 mL, 83.3 mmol), and DMAP (509 mg, 4.17 mmol) in DCM (200 mL). The reaction mixture was stirred at room temperature for 3 hours. Water (100 mL) was added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give crude intermediate 29, a brown solid, which was used directly in subsequent reaction steps without further purification.

[1758] The intermediates below were prepared using suitable starting materials through a similar reaction scheme as that used to prepare intermediate 29 (Table 6).

[1759] Table 6:

[1760]

[1761] Example A12b:

[1762] Preparation of intermediate 32

[1763]

[1764] Intermediate 28 (4.5 g, 8.89 mmol), TEA (2.70 g, 26.6 mmol), DMAP (0.54 g, 4.4 mmol), and DCM (40 mL) were stirred on an ice bath. p-Toluenesulfonyl chloride (3.39 g, 17.8 mmol) was added dropwise. The mixture was stirred at room temperature for 5 hours. The reaction mixture was decanted into water and extracted with DCM. The organic layer was evaporated and purified by rapid silica gel chromatography (elution: DCM 98%, MeOH 2%) to give intermediate 32 (5.6 g, 95% yield).

[1765] Example A13

[1766] Preparation of intermediate 33

[1767]

[1768] At 0°C and under a N2 atmosphere, a single addition of Des Martin periodane (5.24 g, 12.36 mmol) was made to a mixture of intermediate 1 (2.00 g, theoretically 6.18 mmol) in DCM (40 mL). The mixture was stirred at 0°C for 3 hours. A mixture of Na2S2O3 (4 g) in saturated NaHCO3 (20 mL) was added to the mixture, and the mixture was stirred for 10 minutes. The aqueous phase was extracted with DCM (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous MgSO4, filtered, and concentrated under vacuum to obtain intermediate 33 (1.80 g, crude product), a pale yellow gel. The crude product was used directly in subsequent reaction steps without further purification.

[1769] The intermediates below were prepared using suitable starting materials through a similar reaction scheme as that used to prepare intermediate 33 (Table 7).

[1770] Table 7:

[1771]

[1772]

[1773] Example A14

[1774] Preparation of intermediate 37

[1775]

[1776] At -78°C and under a N2 atmosphere, MeMgBr (1M, 18.55mL, 18.55mmol) was added dropwise to a solution of intermediate 33 (6.5g, crude product, ≈15.46mmol) in THF (200mL). The mixture was stirred overnight at room temperature under a N2 atmosphere. The reaction mixture was concentrated under vacuum to give a crude product as a yellow solid. The crude product was purified by column chromatography (gradient eluent: petroleum ether / EtOAc from 40:1 to 10:1). The desired fraction was collected and the solvent was evaporated to obtain intermediate 37, a pale yellow oily substance (700mg crude product; and 3g crude product with more impurities).

[1777] Example A15

[1778] Preparation of intermediate 38

[1779] Method 1

[1780]

[1781] At 0 °C under a N2 atmosphere, 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, was stirred at 0 °C for 0.5 h, and then heated to 25 °C and held at that temperature for 0.5 h. The mixture was cooled to -40 °C. A solution of intermediate 35 (1.46 g, theoretically 4.54 mmol) in THF (130.0 mL) was added dropwise, and the mixture was stirred at -20 °C for 1 h, then heated to 25 °C and held at that temperature for 2 h. Saturated NH4Cl (300 mL) was added to the mixture and 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 under vacuum. The residue was then subjected to silica gel chromatography. 80g Purification was performed by flash column chromatography on silica gel (gradient elution: 0 to 15% ethyl acetate / petroleum ether). The desired fractions were collected and the solvent was evaporated to obtain intermediate 38 as an off-white solid (530 mg, 36% yield).

[1782] The intermediates below were prepared using suitable starting materials through a similar reaction scheme as that used in preparing intermediate 38 (method 1) (Table 8).

[1783] Table 8:

[1784]

[1785]

[1786] Method 2

[1787]

[1788] Under N₂ atmosphere, a solution of intermediate 35 (10.0 g, theoretical 31.1 mmol) in THF (100 mL) was added dropwise over 30 minutes to a solution of bis(iodozincinate)methane in THF (180 mL, 0.31 M, 55.9 mmol, prepared according to the procedure described in Tetrahedron 2002, 58, pp. 8255-8262). Stirring was continued until complete conversion (approximately 2 hours). The reaction mixture was quenched by the slow addition of saturated aqueous NH₄Cl solution, during which salt formation was observed. The salt was dissolved again by the addition of aqueous ammonia solution (25%) before extraction (EtOAc, 2 x 200 mL). 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 (elution buffer: dichloromethane / EtOAc95 / 5) to obtain intermediate 38 as a grayish-white solid (6.9 g, 66%).

[1789] Method 3

[1790] Step 1

[1791] Preparation of intermediate 408

[1792]

[1793] 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]dioxaphosphine-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. (-)-(3AR,6AR)-3A,6A-dihydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-one (25 g, 162.16 mmol) and potassium ethylene trifluoroborate (45.73 g, 324.33 mmol) were then added and the reaction mixture was stirred and refluxed for 4 hours. The reaction mixture (suspension) was cooled to room temperature. The precipitate was filtered through a celite pad and washed with ethanol. Evaporate the solvent from the filtrate. Add 1 L of heptane to the residue. Filter the resulting suspension through a diatomaceous earth mat and wash with heptane to obtain a dark brown solid residue. Wash the filtrate three times with 300 mL of NH4OH, wash with brine, dry with MgSO4, filter, and evaporate the solvent from the filtrate to give intermediate 408 (16.18 g, 51% yield).

[1794] Step 2

[1795] Preparation of intermediate 409

[1796]

[1797] At -78 ℃, under nitrogen atmosphere, the solution of intermediate 408 (16.18g, 82.58mmol) in THF (200mL) is added dropwise to the stirred solution of lithium aluminum hydride solution 1M (24.78mL, 1M, 24.78 mmol) in THF (400mL). Under nitrogen atmosphere, the reaction mixture was stirred at -78 ℃ for 30 minutes. At -78 ℃, the reaction was quenched by dropwise addition of acetone (6.1mL) followed by addition of water 50 mL. After the addition, the reaction mixture was allowed to heat to room temperature, and then 400mL EtOAc was added. The mixture was vibrated vigorously. The organic layer was separated, washed three times with water, washed with salt water, and dried over MgSO4, filtered, and the solvent of the filtrate was evaporated. The residue was dissolved in ethyl acetate and purified by SiO2 column purification using a Grace Reveleris SRC, 80 g, Si40 column on an Armen Spot II final purification system. Ethyl acetate and heptane were used as eluents, with the gradient starting at 100% heptane and ending at 50% heptane and 50% ethyl acetate. Fractions containing the product were combined and the solvent was evaporated to give intermediate 409 (10.77 g, 71% yield).

[1798] Step 3

[1799] Preparation of intermediate 410

[1800]

[1801] At 0 ℃, by Tf in anhydrous DCM (60mL) o (13.31mL, 1.71g / mL, 80.93 mmol) solution dropwise adds in the mixture of intermediate 409 (9.94g, 53.95mmol) and anhydrous pyridine (85mL) in anhydrous DCM (140mL).Reaction mixture is stirred 30 minutes and then 75mL cold water is added.Each layer is separated and organic layer is washed three times with 75mL water, uses MgSO dry, filter and solvent evaporates and with 200mL toluene coevaporation.Residue is dissolved in heptane and ethyl acetate and through SiO column purification, column type is Grace Reveleris SRC, 40g, Si40, on Armen Spot II final purification system, uses ethyl acetate and heptane as eluent, gradient starts from 100% heptane, ends with 50% heptane and 50% ethyl acetate. The fractions containing the product were combined and the solvent was evaporated to obtain intermediate 410 (13.0 g, 67% yield).

[1802] Step 4

[1803] Preparation of intermediate 411

[1804]

[1805] 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 milled with DIPE. The white solid was filtered off and dried under vacuum at 30 °C to give intermediate 411 (112.6 g, 90% yield).

[1806] Step 5

[1807] Preparation of intermediate 38

[1808]

[1809] At 0 °C, a solution of intermediate 410 (13 g, 41.1 mmol) in DMF (50 mL) was added dropwise to a stirred solution of intermediate 411 (7.88 g, 41.1 mmol) in DMF (150 mL). After addition, the reaction mixture was allowed to warm to room temperature and then stirred for 18 hours. An additional amount of intermediate 411 (1.57 g, 8.22 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into a beaker containing ice and water (approximately 0.5 L). The resulting suspension was stirred for 2 hours and then filtered. The residue was washed three times with water and then dried under vacuum at 50 °C to give intermediate 38 as a white solid (8.75 g, 65% yield).

[1810] Example A54

[1811] Preparation of intermediate 433

[1812]

[1813] A solution of intermediate 38 (18.3 g, 57.22 mmol) in a mixture of ammonia (25%, 100 mL) and THF (100 mL) was heated in a sealed metal pressure vessel at 110 °C until complete conversion (approximately 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 under vacuum to give intermediate 433 as a pale yellow solid (17.2 g, 100%), which was used directly in subsequent reaction steps without further purification.

[1814] The intermediates below were prepared using suitable starting materials through a similar reaction scheme as that used to prepare intermediate 433 (Table 24).

[1815] Table 24:

[1816]

[1817]

[1818] Example A16

[1819] Preparation of intermediate 41

[1820]

[1821] To a solution of potassium tert-butoxide (1.28 g; 11.4 mmol) in THF (30 mL) was added a solution of dimethyl (1-diazo-2-oxopropyl) phosphonate (1.72 g; 11.4 mmol) in THF (5 mL) at -78 ° C. The solution was stirred for 5 minutes and a solution of intermediate 33 (1.90 g; theoretically 5.87 mmol) in THF (20 mL) was added. The solution was allowed to warm to room temperature and stirred at room temperature for 15 minutes. Water and EtOAc were added, the organic layer was separated, dried over MgSO , filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 80 g Grace, DCM loading, mobile phase gradient eluent: heptane / 10% MeOH in EtOAc, from 90:10 to 70:30). The desired fraction was collected and the solvent was evaporated to produce intermediate 41, a colorless oily substance (1.08 g, 58% yield).

[1822] Example A17

[1823] Preparation of intermediate 43

[1824]

[1825] To the solution of intermediate 42 (9.2g, 34.114mmol) in acetone (100mL), 2,2-dimethoxypropane (7.1g, 68.118mmol) and p-TSA (1.8g, 10.184mmol) are added. The reaction mixture is stirred at room temperature overnight. The reaction mixture is treated with NaHCO3 aqueous solution (pH is 7-8), then concentrated under reduced pressure. The gained residue is quenched with water (100mL) and extracted with ethyl acetate (100 mL x3). The organic layer is dried, and concentrated under reduced pressure. By silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate, from 8 / 1 to 2 / 1), the crude product is purified. The desired fraction is collected and the evaporating solvent is evaporated to obtain intermediate 43, which is a light yellow solid (9.5g, 90% yield).

[1826] Example A18

[1827] Preparation of intermediate 44

[1828]

[1829] At 0 °C and under a N2 atmosphere, a solution of intermediate 1 (2.00 g, theoretically 6.18 mmol) in DCM (30.00 mL) was added dropwise to a suspension of Desmond-Martin periodoyl alkyl ether (3.14 g, 7.41 mmol) in DCM (30.00 mL). The reaction mixture was allowed to heat to room temperature and stirred (2 h) until the oxidation reaction was complete. Subsequently, MeOH (60 mL) and toluenesulfonyl hydrazide (1.50 g, 8.03 mmol) were added and stirring continued for 3 h. Water and ethyl acetate were added to the reaction mixture to separate the organic phase, which was washed with saturated Na2CO3, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (gradient eluent: dichloromethane / methanol, from 100:0 to 98.5:1.5). The desired fraction was collected and the solvent was evaporated to produce intermediate 44 as a white powder (2.60 g, 70% yield; (E)).

[1830] The intermediates below were prepared using suitable starting materials through a similar reaction scheme as that used to prepare intermediate 44 (Table 25).

[1831] Table 25

[1832]

[1833] Example A55

[1834] Preparation of intermediate 224

[1835]

[1836] Step 1:

[1837] Preparation of intermediate 222

[1838] At room temperature, DIAD (7.6 mL, 38.4 mmol, 2.5 equivalences) was added to a solution of intermediate 2 (5.0 g, 15.3 mmol, 1.0 equivalences), triphenylphosphine (10.0 g, 38.4 mmol, 2.5 equivalences), and acetone cyanohydrin (5.6 mL, 61.4 mmol, 4.0 equivalences) in anhydrous THF (75 mL). The reaction mixture was stirred for 1 hour and then concentrated under vacuum. The crude product was purified by normal-phase rapid chromatography using heptane and DCM as eluents (silica gel column, gradient: 50% to 100% DCM, isocratic 100% DCM) and then by preparative reversed-phase rapid chromatography using acetonitrile and water and 0.2% NH4HCO3 as eluents to obtain intermediate 222 as a white solid product (2.8 g, 8.5 mmol, yield 55%).

[1839] Step 2:

[1840] Preparation of intermediates 223 and 224

[1841] A solution of intermediate 222 (1.54 g, 4.6 mmol, 1 equivalent) in anhydrous DCM was dried overnight using a molecular sieve and filtered. The filtrate was cooled to 0–78 °C and then 1 M DIBAH was added dropwise to a mixture of DCM (4.6 mL, 4.6 mmol, 1 equivalent). The reaction mixture was stirred at -78 °C for 1 h, then an additional 1 M DIBAH was added to DCM (0.46 mL, 0.46 mmol, 0.1 equivalent) and stirred again for 1.5 h. The mixture was then quenched with sodium acetate (4.2 g, 51.2 mmol, 11.1 equivalent) and acetic acid (4.2 mL, 73.4 mL, 16.0 equivalent) in a mixture of water / THF (57 mL / 12 mL). After quenching, the cooling bath was removed and the mixture was stirred until all the ice had melted. The layers were separated, and the aqueous DCM phase (30 mL) was then extracted twice. The organic phases were combined, washed twice with brine, dried over MgSO4, and filtered. MeOH (50 mL) and p-toluenesulfonyl hydrazine (1.1 g, 6.0 mmol, 3 equivalents) were added to the filtrate containing intermediate 223, and the mixture was stirred at room temperature for 40 min. The reaction mixture was washed three times with saturated NaHCO3, twice with brine, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by normal-phase rapid chromatography using heptane and EtOAc as eluents (gradient: 40% to 60% EtOAc) to obtain the crude product. The mixture was further purified by normal-phase rapid chromatography using EtOAc and heptane as eluents (SiO2 column, gradient: 40% to 60% EtOAc) to obtain intermediate 224 (0.5 g, 0.6 mmol, yield: 14%).

[1842] Example A19

[1843] Preparation of intermediate 45

[1844]

[1845] Under N2 atmosphere, intermediate 1 (300mg, theoretically 0.921mmol), 7-quinolinol (160 mg, 1.11mmol) and polymer-bonded triphenylphosphine (approximately 3mmol / g triphenylphosphine is loaded, 0.8g, 2.4mmol) are stirred in anhydrous THF (12mL).Then, at 0 ℃, DIAD (0.465 g, 2.30mmol) is added dropwise.Under N2 atmosphere, the mixture is stirred at room temperature for 12 hours.The reaction mixture is filtered through diatomaceous earth pad.Residue is washed with MeOH.The filtrate is concentrated in a vacuum.Residue is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate from 10 / 1 to 3 / 1).Collect the desired fraction and evaporate the solvent to obtain thick intermediate 45, which is an oily substance (342mg).

[1846] The intermediates below were prepared using suitable starting materials through a similar reaction scheme as that used to prepare intermediate 45 (Table 9).

[1847] Table 9:

[1848]

[1849]

[1850]

[1851] Example A19b:

[1852] Preparation of intermediate 59

[1853]

[1854] At room temperature, diisopropyl azodicarboxylate (0.221 mL, 1.125 mmol) was added dropwise to a stirred suspension of intermediate 1 (0.27 g, 0.80 mmol), 3-bromoquinolin-7-ol (0.18 g, 0.80 mmol) and triphenylphosphine resin (0.375 g, 3 mmol / g, 1.125 mmol) in THF (8 mL). After addition, the reaction mixture was stirred for 18 hours. The reaction mixture was filtered through a liner. The residue was washed with methanol. The solvent in the filtrate was evaporated. The residue was then used in the next step as follows.

[1855] Example A20

[1856] Preparation of intermediate 61

[1857]

[1858] A mixture of intermediate 1 (2.46 g, theoretically 7.54 mmol), 2-methylquinoline-7-ol (1.2 g, 7.54 mmol), and PPh3 (5.93 g, 22.6 mmol) in dry THF (40 mL) was stirred at room temperature under a nitrogen atmosphere. DIAD (4.57 g, 22.6 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. Water (80 mL) was added to the mixture and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (gradient eluent: EtOAc / petroleum ether from 1:20 to 1:1). The desired fraction was collected and the solvent was evaporated to obtain intermediate 61 (3.0 g, crude product). Crude intermediate 61 was used directly in the subsequent reaction steps without further purification.

[1859] The intermediates below were prepared using suitable starting materials through a similar reaction scheme as that used to prepare intermediate 61 (Table 10).

[1860] Table 10:

[1861]

[1862]

[1863] Example A21

[1864] Preparation of intermediate 71

[1865]

[1866] CMBP (1.15 mL, 4.38 mmol) was added to a solution of intermediate 1 (1.00 g, ≈2.92 mmol) and 2-naphthol (463 mg, 3.21 mmol) in toluene (30 mL). The solution was heated at 80 °C for 18 hours and then cooled to room temperature. The reaction mixture was evaporated under vacuum. The residue was purified by preparative LC (irregular SiOH 15–40 μm, 120 g Grace, DCM precipitate, mobile phase gradient: heptane / EtOAc, from 80 / 20 to 70 / 30) to give intermediate 71 as a colorless gel (1.00 g, 76% yield).

[1867] Example A22

[1868] Preparation of intermediate 72

[1869]

[1870] A mixture of PPh3 (9.07 g, 34.6 mmol) and DEAD (4.82 g, 27.7 mmol) in THF (100 mL) was stirred at room temperature for 10 minutes. Then, intermediate 24 (5.0 g, theoretically 13.8 mmol) was added, followed by 2-chloroquinoline-7-ol (2.98 g, 16.6 mmol). The resulting mixture was stirred overnight at room temperature. Subsequently, the mixture was diluted with EtOAc (100 mL) and washed with water and brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (eluent: petroleum ether / EtOAc = 5 / 95). The desired fraction was collected and concentrated to give intermediate 72 (6.0 g, 83% yield) as a solid.

[1871] Example A23

[1872] Preparation of intermediate 73

[1873]

[1874] Triphenylphosphine (624 mg, 2.71 mmol) and DBAD (711 mg, 2.71 mmol) were adde...

Claims

1. A compound having chemical formula (I) in R 1 represents hydrogen or -C(=O)-C 1-4 alkyl; R 2 represents hydrogen or -C(=O)-C 1-4 alkyl; Y stands for -O-; Z represents -CH2-, -X-CR 5a R 5b -、-CR 5c =CR 5d -、-CR 5e R 5g -CR 5f R 5h -, or -C≡C-; 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; X represents -O-, -S- or -NR 11 -; R 11 Represents hydrogen, C 1-4 Alkyl, or C substituted with a substituent 1-4 Alkyl, the substituent is selected from the group consisting of -OH, -OC 1-4 Alkyl, R 12 、-NH2、-NH-C 1-4 Alkyl, and -N(C 1-4 Alkyl)2; R 12 represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom; said 4-, 5-, 6- or 7-membered heterocyclic ring is attached to the remainder of the molecule via the ring nitrogen atom; Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein at least one ring carbon atom of ring B is substituted by a nitrogen atom; wherein any one additional ring carbon atom of ring A or ring B is substituted by a nitrogen atom; 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; Ar is optionally substituted by one, two, three or four substituents each independently selected from the group consisting of: Halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d 、-NR 10c R 10d , cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 Alkoxy, -C(=O)-OC 1-4 Alkyl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, C 2-6 Alkenyl, with a C 1-4 Alkoxy substituted C 1-4 alkyl, and optionally substituted by a -NR 10a R 10b Substituted C 1-4 alkyl; R 10a and R 10b Each independently represents hydrogen or C 1-4 alkyl; R 10c and R 10d Each independently represents 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, a group consisting of halogen, -OH and -OC 1-4 Alkyl; C substituted by one, two or three substituents each independently selected from the following group 1-4 Alkyl, a group consisting of halogen, -OH and -OC 1-4 Alkyl; or C substituted by a substituent selected from the following group 1-4 Alkyl, the group consisting of C 3-6 Cycloalkyl, R 13 and R 14 composition; R 13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms, each of which is independently selected from O, S, S(═O) p and N; or represents a 6- to 11-membered bicyclic fused aromatic ring containing one, two or three heteroatoms, each of which is independently selected from O, S, S(=O) p and N; The 4- to 7-membered monocyclic aromatic ring or the 6- to 11-membered bicyclic fused aromatic ring is optionally substituted by one or two substituents selected from the group consisting of C 1-4 Alkyl composition; p represents 1 or 2; R 14 represents phenyl optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen; Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1), (a-2), (a-3), (a-4) and (a-5): R 3a , R 3b , R 3c , 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; R 7a represents hydrogen; R 7b Represents hydrogen, C 3-6 Cycloalkyl, or C 1-4 alkyl; R 4a , R 4b , R 4c , R 4d , R 4e , R 4f and R 4g Each independently represents hydrogen, halogen, -NR 8a R 8b , or C 1-4 alkyl; R 8a and R 8b Each independently represents hydrogen or C 1-4 alkyl; Q 1 Represents N or CR 6a ; Q 2 Represents N or CR 6b ; Q 3 Represents N or CR 6c ; Q 4 Represents N or CR 6d ; The condition is Q 3 and Q 4 At most one of them represents N; Q 8 Represents N or CR 6g ; Q 9 Represents N or CR 6h ; Q 10 Represents N or CR 6i ; Q 11 Represents N or CR 6j ; Q 5 Represents CR 3d ;Q 6 represents N; and Q 7 Represents CR 4f ;or Q 5 Represents CR 3d ;Q 6 Represents CR 4e ; and Q 7 stands for N; or Q 5 stands for N; Q 6 Represents CR 4e ; and Q 7 Represents CR 4f ;or Q 5 stands for N; Q 6 Represents CR 4e ; and Q 7 stands for N; or Q 5 stands for N; Q 6 represents N; and Q 7 Represents CR 4f ;or Q 5 stands for N; Q 6 represents N; and Q 7 Represents N; R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , 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; R 9a and R 9b Each independently represents hydrogen or C 1-4 alkyl; or a pharmaceutically acceptable addition salt thereof.

2. The compound according to claim 1, wherein Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of: Halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d 、-NR 10c R 10d , cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 Alkoxy, -C(=O)-OC 1-4 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, with a C 1-4 Alkoxy substituted C 1-4 alkyl, and optionally substituted by a -NR 10a R 10b Substituted C 1-4 alkyl; R 10c and R 10d Each independently represents C 3-6 Cycloalkyl; C substituted by one, two or three substituents each independently selected from the group consisting of 3-6 Cycloalkyl, a group consisting of halogen, -OH and -OC 1-4 Alkyl; C substituted by one, two or three substituents each independently selected from the following group 1-4 Alkyl, a group consisting of halogen, -OH and -OC 1-4 Alkyl; or C substituted by a substituent selected from the following group 1-4 Alkyl, the group consisting of C 3-6 Cycloalkyl, R 13 and R 14 composition; Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1), (a-2) and (a-3): R 3a , R 3b and R 3c Each independently represents hydrogen, halogen, -NR 7a R 7b , C 1-4 Alkyl, or -OC 1-4 Alkyl; R 7b Represents hydrogen or C 1-4 alkyl; R 4a , R 4b and R 4c Each independently represents hydrogen, halogen, -NR 8a R 8b , or C 1-4 alkyl; Q 1 Represents N or CR 6a ; Q 2 Represents N or CR 6b ; Q 3 Represents N or CR 6c ; Q 4 Represents N or CR 6d ; The condition is Q 3 and Q 4 At most one of them represents N; R 6a , R 6b , R 6c , R 6d , R 6e and R 6f 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.

3. The compound according to claim 1, wherein Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of: Halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, cyano, -CF3, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 alkoxy, and optionally substituted by a -NR 10a R 10b Substituted C 1-4 alkyl; Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1), (a-2) and (a-3): R 3a , R 3b and R 3c Each independently represents hydrogen, halogen, -NR 7a R 7b , or -OC 1-4 alkyl; R 7b Represents hydrogen or C 1-4 alkyl; R 4a , R 4b and R 4c Each independently represents hydrogen, halogen, -NR 8a R 8b , or C 1-4 alkyl; Q 1 Represents N or CR 6a ; Q 2 Represents N or CR 6b ; Q 3 Represents N or CR 6c ; Q 4 Represents N or CR 6d ; The condition is Q 3 and Q 4 At most one of them represents N; R 6a , R 6b , R 6c , R 6d , R 6e and R 6f 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.

4. The compound according to claim 1, wherein R 1 represents hydrogen or -C(=O)-C 1-4 alkyl; R 2 represents hydrogen or -C(=O)-C 1-4 alkyl; Y stands for -O-; Z stands for -X-CR 5a R 5b -; R 5a and R 5b Each independently represents hydrogen or C 1-4 alkyl; X represents -O-, -S- or -NR 11 -; R 11 represents hydrogen; Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, cyano, -CF3, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 alkoxy, and optionally substituted by a -NR 10a R 10b Substituted C 1-4 Alkyl composition; R 10a and R 10b Each independently represents hydrogen or C 1-4 alkyl; Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1); R 3a Represents hydrogen, halogen, -NR 7a R 7b , or -OC 1-4 alkyl; R 7a represents hydrogen; R 7b represents hydrogen; R 4a Represents hydrogen, halogen, -NR 8a R 8b , or C 1-4 alkyl; R 8a and R 8b Each independently represents hydrogen or C 1-4 alkyl; Q 1 Represents CR 6a ; Q 2 Represents CR 6b ; R 6a and R 6b 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; R 9a and R 9b Each independently represents hydrogen or C 1-4 alkyl.

5. The compound according to claim 1, wherein R 1 represents hydrogen or -C(=O)-C 1-4 alkyl; R 2 represents hydrogen or -C(=O)-C 1-4 alkyl; Z stands for -X-CR 5a R 5b -; R 5a and R 5b Each independently represents hydrogen or C 1-4 alkyl; X represents -O-, -S- or -NR 11 -; R 11 represents hydrogen; Ar stands for Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, cyano, -CF3, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 alkoxy, and optionally substituted by a -NR 10a R 10b Substituted C 1-4 Alkyl composition; R 10a and R 10b Each independently represents hydrogen or C 1-4 alkyl; Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1); R 3a Represents hydrogen, halogen, -NR 7a R 7b , or -OC 1-4 alkyl; R 7a represents hydrogen; R 7b represents hydrogen; R 4a Represents hydrogen, halogen, -NR 8a R 8b , or C 1-4 alkyl; R 8a and R 8b Each independently represents hydrogen or C 1-4 alkyl; Q 1 Represents CR 6a ; Q 2 Represents CR 6b ; R 6a and R 6b 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; R 9a and R 9b Each independently represents hydrogen or C 1-4 alkyl.

6. The compound according to claim 1, wherein R 1 represents hydrogen; R 2 represents hydrogen; Z stands for -X-CR 5a R 5b -or-CR 5e R 5g -CR 5f R 5h -; R 5a , R 5b , R 5e , R 5f , R 5g , and R 5h represents hydrogen; X stands for -O-; Ar stands for wherein Ar is optionally substituted at the position represented by α by a substituent selected from the group consisting of: -NH2, -NH-C 1-4 Alkyl, and -NHR 10d ;and wherein Ar is optionally substituted at the position represented by β with a substituent selected from the group consisting of halogen and CF3; However, there is a proviso that Ar is substituted at least one position represented by α or β; R 10d Represents C 3-6 Cycloalkyl; C substituted with one, two or three halogen substituents 1-4 Alkyl; or a C 3-6 Cycloalkyl substituted C 1-4 alkyl; Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1) and (a-4); R 3a and R 3d Each independently represents hydrogen, halogen, -NR 7a R 7b , C 1-4 Alkyl, or -OC 1-4 alkyl; R 7a represents hydrogen; R 7b Represents hydrogen or C 1-4 alkyl; R 4a , R 4d and R 4f each independently represents hydrogen or halogen; Q 1 Represents CR 6a ; Q 2 Represents CR 6b ; Q 8 Represents CR 6g ; Q 9 Represents CR 6h ; Q 5 Represents CR 3d ;Q 6 represents N; and Q 7 Represents CR 4f ; R 6a , R 6b , R 6g , and R 6h Represents hydrogen.

7. The compound according to claim 1 or 2, wherein R 1 represents hydrogen; R 2 represents hydrogen; Y stands for -O-; Z stands for -X-CR 5a R 5b -or-CR 5e R 5g -CR 5f R 5h -; R 5a , R 5b , R 5e , R 5f , R 5g , and R 5h represents hydrogen; X stands for -O-; Ar stands for wherein Ar is optionally substituted at the position represented by α by a substituent selected from the group consisting of: -NH2, -NH-C 1-4 Alkyl, and -NHR 10d ;and wherein Ar is optionally substituted at the position represented by β with a substituent selected from the group consisting of halogen and CF3; However, there is a proviso that Ar is substituted at least one position represented by α or β; R 10d Represents C 3-6 Cycloalkyl; C substituted with one, two or three halogen substituents 1-4 Alkyl; or a C 3-6 Cycloalkyl substituted C 1-4 alkyl; Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1); R 3a Represents hydrogen, halogen, -NR 7a R 7b , C 1-4 Alkyl, or -OC 1-4 alkyl; R 7a represents hydrogen; R 7b Represents hydrogen or C 1-4 alkyl; R 4a represents hydrogen or halogen; Q 1 Represents CR 6a ; Q 2 Represents CR 6b ; R 6a and R 6b Represents hydrogen.

8. The compound according to claim 1 or 2, wherein Ar is selected from the group consisting of: wherein each Ar is optionally substituted at position α by a substituent selected from the group consisting of: -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHR 10d , and -NR 10c R 10d ; and wherein Ar is optionally substituted with a halogen substituent at another position.

9. The compound according to claim 1, wherein Y stands for -O-; Z stands for -X-CR 5a R 5b - or -CH2CH2-; R 5a and R 5b represents hydrogen; X represents -O-; R 11 represents hydrogen; Ar stands for Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, cyano, and -CF3; Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1); R 3a Representative-NR 7a R 7b ; R 7a represents hydrogen; R 7b represents hydrogen; R 4a represents hydrogen; Q 1 Represents CR 6a ;Q 2 Represents CR 6b ; R 6a and R 6b Represents hydrogen.

10. A compound according to any one of claims 1 to 5, wherein Ar represents 11. A compound according to any one of claims 1 to 5 and claim 9, wherein R 1 and R 2 Represents hydrogen.

12. The compound according to any one of claims 1, 2, 3 or 6, wherein Het represents a bicyclic aromatic heterocyclic ring system of formula (a-1).

13. The compound according to claim 12, wherein R 3a Representative-NR 7a R 7b ; and R 7a and R 7b Represents hydrogen.

14. A compound according to any one of claims 1 to 6 and claim 9, wherein Ar represents wherein Ar is substituted with a halogen substituent at the position indicated by β.

15. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable addition salt thereof.

16. The compound according to claim 1, wherein Y stands for -O-; Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of: Halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, cyano, -CF3, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 alkoxy, and optionally substituted by a -NR 10a R 10b Substituted C 1-4 alkyl; Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1) composition: R 3a Represents hydrogen, halogen, -NR 7a R 7b , or -OC 1-4 alkyl; R 7a represents hydrogen; R 7b Represents hydrogen or C 1-4 alkyl; R 4a Represents hydrogen, halogen, -NR 8a R 8b , or C 1-4 alkyl; R 8a and R 8b Each independently represents hydrogen or C 1-4 alkyl; Q 1 Represents N or CR 6a ; Q 2 Represents N or CR 6b ; R 6a and R 6b 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; R 9a and R 9b Each independently represents hydrogen or C 1-4 alkyl.

17. The compound according to claim 16, wherein Q 1 and Q 2 Represents CH.

18. The compound according to claim 1, wherein R 1 represents hydrogen; R 2 represents hydrogen; Y stands for -O-; Z stands for -X-CR 5a R 5b - or -CH2CH2-; R 5a and R 5b Each independently represents hydrogen or C 1-4 alkyl; X represents -O-, -S- or -NR 11 -; R 11 represents hydrogen; Ar stands for Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, cyano, -CF3, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 alkoxy, and optionally substituted by a -NR 10a R 10b Substituted C 1-4 Alkyl composition; Het represents a bicyclic aromatic heterocyclic system selected from the group consisting of (a-1); R 3a Represents hydrogen, halogen, -NR 7a R 7b , or -OC 1-4 alkyl; R 7a represents hydrogen; R 7b represents hydrogen; R 4a Represents hydrogen, halogen, -NR 8a R 8b , or C 1-4 alkyl; R 8a and R 8b Each independently represents hydrogen or C 1-4 alkyl; Q 1 Represents CR 6a ; Q 2 Represents CR 6b ; R 6a and R 6b 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; R 9a and R 9b Each independently represents hydrogen or C 1-4 alkyl.

19. The compound according to claim 18, wherein Ar represents Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, cyano, -CF3, -C(=O)-NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, C 1-4 alkoxy, and optionally substituted by a -NR 10a R 10b Substituted C 1-4 Alkyl composition.

20. A compound according to any one of claims 1 to 3 and claims 16 to 19, wherein X represents -O- or -NR 11 -.

21. The compound according to claim 20, wherein X represents -NR 11 -.

22. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to any one of claims 1 to 21 as an active ingredient.

23. Use of a compound as defined in any one of claims 1 to 21 in the preparation of a medicament for inhibiting PRMT5.

24. Use of a compound as defined in any one of claims 1 to 21 in the preparation of a medicament for treating or preventing a disease or condition selected from blood disorders, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, sperm motility, transplant rejection, graft rejection, and lung injury.

25. The use according to claim 24, wherein the disease or condition is cancer.

26. The use according to claim 25, wherein the cancer is pancreatic cancer, prostate cancer, colon cancer, rectal cancer, bile duct cancer, head and neck cancer, adrenal cancer, breast cancer, intraocular melanoma, ovarian cancer, myelodysplastic syndrome (MDS) or salivary gland cancer.

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