Novel 6-6 bicyclic aromatic ring-substituted nucleoside analogues for use as PRMT5 inhibitors

Abstract

To provide novel 6-6 bicyclic aromatic ring substituted nucleoside analogues useful as PRMT5 inhibitors.SOLUTION: The invention provides compounds represented by formula (I), where Het represents a bicyclic heteroaromatic ring system such as pyrrolopyrimidine and pyrrolotriazine.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to novel 6-6 bicyclic aromatic ring-substituted nucleosides useful as PRMT5 inhibitors. The present invention further relates to pharmaceutical compositions containing the compounds as active ingredients, as well as analogs thereof. The present invention relates to the use of said compounds as medicines. [Background technology]

[0002] P, also known as Hsl7, Jbp1, Skb1, Capsuleen, or Dart5 RMT5 is the main methyltransferase involved in the monomethylation and symmetric dimethylation of arginine. It is one of the transferases that mediate post-translational cleavage of histone and non-histone proteins. Arginine methylation is involved in genome organization, transcription, differentiation, spliceosome function, and signal transduction and various biological processes such as cell cycle progression, stem cell and T cell fate regulation. It seems to be important [Stopa, N. et al., Cell Mol Life e Sci,2015.72(11):p.2041-59][Geoghegan,V .et al., Nat Commun, 2015.6:p.6758]. Metazoa PR MT5 is a methylsome protein 50 (MEP50), also known as Wdr77, and It forms a functional complex with the genotype receptor coactivator p44 and Valois. Both increased PRMT5-MEP50 protein levels and cytoplasmic accumulation are associated with cancer development and has recently been associated with poor clinical outcomes [Shilo, K. et al. l., Diagn Pathol, 2013.8:p.201]. PRMT5-MEP5 Cell rescue experiments addressing the catalytic and scaffolding functions of the O complex are comprehensive enzymatic studies. demonstrated a correlation between protein levels, localization, and enzyme function with tumorigenesis compared with [Gu, Z. et al.,Biochem J,2012.446(2):p.235 -41][Di Lorenzo,A.et.al.,FEBS Lett,2011. 585(13):p.2024-31] [Chan-Penebre, E. et al. ,Nat Chem Biol,2015.11(6):p.432-7]. This correlation This relationship makes PRMT5 an important small molecule drug target for cancer and other diseases [St opa,N.et al.,Cell Mol Life Sci,2015.72(1 1):pp.2041-59].

[0003] PRMT5 utilizes S-adenosylmethionine (SAM) to mediate histone and non-histone Symmetric dimethylation on protein substrates and S-adenosylhomocysteine (SAH) It is a member of the type II PRMT subfamily that produces hydroxylated arginine. Human heterooctameric complex (PRMT5)4(ME) co-crystallized with the tH4 peptide substrate The crystal structure of P504 revealed the mechanism of methylation and substrate recognition [Antonysam y,S.et al.,Proc Natl Acad Sci USA,2012 109(44):pp.17960-5]. Regulation of PRMT5 activity is mediated by a vast number of different Triggered by binding partners, post-translational crosstalk, miRNAs, and subcellular localization This.

[0004] Methylation of histones H2A and H4 on Arg3 and histone H3 on Arg8 specific repression of gene transcripts involved in differentiation, transformation, cell cycle progression and tumor suppression regulates chromatin organization for [Karkhanis, V. et al., Tren ds Biochem Sci, 2011.36(12):p.633-41]. PRMT5-mediated methylation of histone H4 on Arg3 induces long-term gene silencing DNA-methyltransferase binds to histones and DNA methylation for transcription It can recruit the DNMT3A enzyme [Zhao, Q. et al., Nat Struct t Mol Biol,2009.16(3):p.304-11].

[0005] Non-histone methylation occurs in either the cytoplasm or the nucleus, depending on the subcellular localization of PRMT5. Sm proteins, which are required for the assembly of the nuclear spliceosome, Methylation of D1 and D3 occurs via the PRMT5-containing "methylosome" ) occurs in the cytoplasm as part of the Cell Biol, 2001.21(24):p.8289-300]. Splicin Further evidence for PRMT5 involvement in transcription comes from the expression of conditioned mediators in mouse neural stem cells. Cells lacking PRMT5 express weak 5 'Along with the donor site, we showed selective retention of introns and skipping of exons [ Bezzi,M.et al.,Genes Dev,2013.27(17):p.1 903-16].

[0006] In addition to its role in splicing, PRMT5 also mediates the regulation of important signaling pathways such as p53. Direct methylation of transmitter nodes affects key pathways involved in cell fate and homeostasis. [Jansson, M. et al., Nat Cell Biol, 2008.1 0(12):p.1431-9], EGFR[Hsu, JMet al., Nat. Cell Biol,2011.13(2):p.174-81], CRAF[Andr eu-Perez,P.et al.,Sci Signal,2011.4(190) :p.ra58], PI3K / AKT[Wei,TYet al.,Cell Si gnal,2014.26(12):p.2940-50], NFκB[Wei, He t al.,Proc Natl Acad Sci USA,2013.110( 33):pp.13516-21].

[0007] PRMT5 is one of the major sym-Arg methyltransferases and is expressed in many cells. Because it is involved in cellular processes, increased protein expression appears to be an important factor in its oncogenic potential. Interestingly, the translation of PRMT5 in mantle cell lymphoma (MCL) MCL cells have fewer miRNAs than normal B lymphocytes. Although the expression of PRMT5 mRNA and a slower transcription rate of PRMT5 was significantly higher than that of PRMT5, the expression of PRMT5 and H Methylation of 3R8 and H4R3 was significantly increased [Pal, S. et al., EM BO J, 2007.26(15):p.3558-69]. 3'UTR region of PRMT5 Re-expression of miRNAs that bind to this region reduces PRMT5 protein levels [Wan g,L.et al.,Mol Cell Biol,2008.28(20):p.6 262-77]. Surprisingly, prmt5 antisense RNA did not express the human prmt5 gene. Our findings support the hypothesis of specific translational regulation within genes rather than high mRNA expression levels. [Stopa, N. et al., Cell Mol Life Sci, 2015 .72(11):p.2041-59].

[0008] PRMT5 is considered a clinically relevant target, and selective PRMT5 inhibitors However, only a few studies have been published so far. Most recently, studies in multiple MCL xenograft models have shown A novel subnanomolar potent PRMT5 inhibitor (EPZ015666) with antitumor activity ) is the first chemical prototype suitable for further validation of PRMT5 biology and its role in cancer. It has been reported that the β-glucan is a β-glucan [Chan-Penebre, E. et al., Na t Chem Biol,2015.11(6):p.432-7].

[0009] Further development of specific small molecule inhibitors of PRMT5 may be a novel chemotherapeutic approach for cancer. This can result in:

[0010] WO 2014100695A1 pamphlet describes a compound that inhibits PRMT5 activity. Compounds useful for treating PRMT5-mediated disorders are disclosed; The method is also described.

[0011] In the pamphlet of International Publication No. 2014100730A1, dihydro- or tetrahydro- 200901023333 discloses PRMT5 inhibitors containing propylisoquinoline and uses thereof.

[0012] Devkota,K.et al.,ACS Med Chem Lett,2014 .5:pp.293-297 describes the synthesis of a series of analogues of the natural product sinefungin and the E The ability of these analogs to inhibit HMT1 and EHMT2 is described.

[0013] In the pamphlet of International Publication No. 2003070739, the A1 adenosine receptor part and and full agonists, their preparation, and their therapeutic uses are disclosed.

[0014] The pamphlet of International Publication No. 2012082436 describes histone methyltransferase as a regulator of histone methyltransferases and by regulating histone methyltransferase activity Compounds and compositions for treating diseases affected by steroids are disclosed.

[0015] WO 2014100719 pamphlet describes PRMT5 inhibitors and their use. The use is disclosed.

[0016] In the pamphlet of International Publication No. 03074083, methylthioadenosine phosphoryl A combination therapy that selectively kills MTA-deficient cells is disclosed. as described herein.

[0017] Kung,P.-P.et al.,Bioorg Med Chem Lett,2 005.15:p.2829-2833 contains a novel human 5'-deoxy-5'-methyl The design, synthesis, and biological evaluation of thioadenosine phosphorylase (MTAP) substrates are described. It is listed.

[0018] The pamphlet for International Publication No. 2012075500 describes histone methyltransferases. 7-deazapurine modulators of ATPase have been disclosed.

[0019] The pamphlet for International Publication No. 2014035140 describes histone methyltransferases. Compounds and compositions for modulating enzyme activity are disclosed.

[0020] WO 2015200680 pamphlet describes PRMT5 inhibitors and their use. The use is described. Summary of the Invention [Problem to be solved by the invention]

[0021] Therefore, new avenues for the treatment or prevention of cancer, such as mantle cell lymphoma, are possible. There is a strong need for novel PRMT5 inhibitors. The object of the present invention is to provide a compound such as

[0022] The compounds of the present invention are structurally different compared to compounds disclosed in the prior art, For example, improved efficacy, or improved pharmacokinetics (PK) and oral bioavailability It may have improved properties such as ease of use. [Means for solving the problem]

[0023] The compounds of the present invention have been found to be useful as PRMT5 inhibitors. The compounds and compositions thereof are useful for treating hematological disorders, metabolic disorders, autoimmune diseases, cancer, inflammatory diseases, cardiovascular diseases, and the like. Vascular disease, neurodegenerative disease, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, sperm motility, transplant rejection These may be useful in the treatment or prevention, especially the treatment, of diseases such as lung cancer, transplant rejection, and pulmonary disorders.

[0024] The present invention relates to a compound of formula (I): [ka] (In the formula, R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2is hydrogen or -C(=O)-C 1~4 represents alkyl; Y represents -O-, -CH2- or -CF2-; Z is -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, or -C≡C-; When Y represents -CH2- or -CF2-, Z may also represent -O- or -CR2-. 5a R 5b -X- can be represented; R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , and R 5h are respectively , independently, hydrogen or C 1~4 represents alkyl; X is -O-, -S-, or -NR 11 - represents; R 11 But hydrogen, C 1~4 Alkyl, or -OH, -OC 1~4 Alkyl, R 12 , -NH2, -NH-C 1~4 Alkyl, and -N(C 1~4 alkyl)2 C substituted with one substituent selected from 1~4 represents alkyl; R 12 a 4-membered, 5-membered, a 6- or 7-membered heterocyclic ring; said 4-, 5-, 6- or 7-membered heterocyclic ring is attached to the rest of the molecule via; 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 replaced by nitrogen atoms; provided that the nitrogen atoms are not fused to two When a carbonyl group is present in said bicyclic aromatic ring system, it replaces one of the carbon atoms. death; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi Le)2, -NHR 10d , -NR 10c R 10d , cyano, -CF3, -C(=O)-N H2, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, C1 ~4 Alkyloxy, -C(=O)-OC 1~4 Alkyl, C 3~6 cycloalkyl, -OC 3~6 Cycloalkyl, -NH-C 3~6 Cycloalkyl, -N(C 3~6 Shik (C)2, C 2~6 Alkenyl, one C 1~4 C1 substituted with alkyloxy ~4 alkyl, and one -NR 10a R 10b C optionally substituted with 1~4 a one, two, three or four substituents each independently selected from the group consisting of alkyl, alkyl, aryl, aryl, arylalkyl ... optionally replaced by; R 10a and R 10b are each independently hydrogen or C 1~4 represents alkyl; R 10c and R 10d are each independently, C 3~6 Cycloalkyl; R 13 ;R 14;Halo, -OH and -OC 1~4 alkyl, C substituted with one, two or three substituents 3~6 Cycloalkyl; halo, -O H and -OC 1~4 one or two independently selected from the group consisting of alkyl or C substituted with three substituents 1~4 Alkyl; or C 3~6 Cycloalkyl, R 13 and R 14 C substituted with one substituent selected from the group consisting of 1~4 Alkyl represents; R 13 But O, S, S(=O) p and one or two independently selected from N or a 4- to 7-membered monocyclic aromatic ring containing three heteroatoms; or O, S, S(=O) p and N, represents a 6- to 11-membered bicyclic fused aromatic ring; The 4- to 7-membered monocyclic aromatic ring or the 6- to 11-membered bicyclic fused aromatic ring is 1~4 Archi optionally substituted with one or two substituents selected from the group consisting of: p represents 1 or 2; R 14 is one, two, or three substituents independently selected from the group consisting of halo represents phenyl optionally substituted by a substituent; Het consists of (a-1), (a-2), (a-3), (a-4) and (a-5) represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of: [ka] R 3a , R3b , R 3c , R 3d and R 3e are each independently hydrogen, halo, - NR 7a R 7b , C 1~4 Alkyl, C 2~4 Alkenyl, C 3~6 Cycloalkyl, - OH, or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b But hydrogen, C 3~6 Cycloalkyl, or C 1~4 represents alkyl; R 4a , R 4b , R 4c , R 4d , R 4e , R 4f and R 4g are each independently , hydrogen, halo, -NR 8a R 8b , or C 1~4 represents alkyl; R 8a and R 8b are each independently hydrogen or C 1~4 represents alkyl; Q 1 But N or CR 6a represents; Q 2 But N or CR 6b represents; Q 3 But N or CR 6c represents; Q 4 But N or CR 6d represents; However, Q 3 and Q 4 At most one of represents N; Q 8 But N or CR 6g represents; Q 9 But N or CR 6h represents; Q 10 But N or CR 6i represents; Q 11 But N or CR 6j represents; Q 5 is CR 3d represents ;Q 6 represents N;Q 7 is CR 4f represents; or Q 5 is CR 3d represents ;Q 6 is CR 4e represents ;Q 7 represents N; or Q 5 represents N;Q 6 is CR 4e represents ;Q 7 is CR 4f represents; or Q 5 represents N;Q 6 is CR 4e represents ;Q 7 represents N; or Q 5 represents N;Q 6 represents N;Q 7 is CR 4f represents; or Q 5 represents N;Q 6 represents N;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 are each independently hydrogen, halogen, or C 1~4 Alkyl, -NR 9a R 9b ,Ma or C substituted by 1, 2 or 3 halo atoms 1~4 represents alkyl; R 9aand R 9b are each independently hydrogen or C 1~4 (representing alkyl) New compounds; and pharmaceutically acceptable addition salts, and solvates thereof; However, the following compounds and pharmaceutically acceptable addition salts and solvates thereof: [ka] The present invention relates to compounds, and pharmaceutically acceptable addition salts and solvates thereof, excluding do.

[0025] The present invention also relates to methods for the preparation of the compounds of the present invention and pharmaceutical compositions containing them. do.

[0026] The compounds of the present invention have been shown to inhibit PRMT5 by themselves, and have been shown to inhibit PRMT5 in vivo ( can be metabolized to a more active form (prodrug) and therefore can be used to treat hematological disorders, Metabolic disorders, autoimmune diseases, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiple organ failure Treatment of diseases such as kidney disease, platelet aggregation, sperm motility, transplant rejection, graft rejection, and lung disorders These may be useful in the treatment or prophylaxis, especially in the treatment.

[0027] The compounds of formula (I) and their pharmaceutically acceptable addition salts, and solvates thereof, Physical considerations mean that it may be suitable for use as a pharmaceutical.

[0028] In particular, compounds of formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, In the treatment or prevention, in particular, of any one of the diseases or conditions mentioned above or below, It may be particularly suitable for the treatment of cancer.

[0029] The present invention also relates to a method for treating any one of the diseases or conditions described above or below, in particular cancer. a compound of formula (I) for the manufacture of a medicament for the inhibition of PRMT5 for the treatment or prevention of The present invention relates to the use of compounds and their pharmaceutically acceptable addition salts, and solvates.

[0030] The present invention will now be further described. In the following sections, various aspects of the invention will be better understood. Each aspect so defined is defined in more detail unless clearly stated to the contrary. , may be combined with one or more of any other aspects. Any feature indicated as being present may be one or more features indicated as being preferred or advantageous. It may be combined with any other feature. DETAILED DESCRIPTION OF THE INVENTION

[0031] When describing the compounds of the present invention, the terms used may be interpreted differently depending on the context. Except as provided below, the following terms and conditions shall be construed in accordance with the following definitions:

[0032] Any variable may occur more than once in any moiety or in any formula (e.g., formula (I)). In each case, its definition is independent of its definition in all other cases.

[0033] Whenever the term "substituted" is used in the present invention, unless otherwise indicated. Unless otherwise clear from the context, the term "substituted" is used to refer to an atom or group designated by the term "substituted." one or more hydrogen atoms, in particular one to three hydrogen atoms, preferably one or two hydrogen atoms; More preferably, one hydrogen atom is selected from the group shown, provided that the valence is not exceeded. The substitution and the substitution are chemically stable compounds, i.e., the reaction mixture and and chemicals robust enough to withstand isolation from pharmaceutical preparations to therapeutic agents to a useful degree of purity. It is intended to show that the resulting mixture

[0034] When more than one substituent is present on a moiety, they are grouped together unless otherwise indicated or stated. Unless otherwise apparent from the context, hydrogens on the same atom may be substituted or they may be present in the moiety. may replace hydrogen atoms on different atoms in the

[0035] As used herein, "C x~y ” (where x and y are integers) and The prefix C refers to the number of carbon atoms in a given group. 1~4 Alkyl group contains 1 to 4 carbon atoms, C 1~3 The alkyl group contains 1 to 3 carbon atoms. For example,

[0036] The term "halo" as a group or part of a group is intended to mean any group unless otherwise indicated or understood from context. Unless otherwise specified, this is a general term for fluoro, chloro, bromo, and iodo.

[0037] "C" as a group or part of a group 1~4 The term "alkyl" refers to a group of the formula C n H 2n+1 (child where n is a number ranging from 1 to 4. 1~4 Alkyl group has 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. Contains carbon atoms of C 1~4 The alkyl group may be straight or branched. Subscripts used in this specification after carbon atoms may be substituted as indicated in the specification. When used, the subscript refers to the number of carbon atoms the designated group may contain. 1~4a Alkyl includes all straight-chain or branched-chain alkyl groups having 1 to 4 carbon atoms. , therefore, methyl, ethyl, n-propyl, i-propyl, 2-methyl-ethyl, butyl and its isomers (e.g., n-butyl, isobutyl, and tert-butyl), include.

[0038] Those skilled in the art will recognize the "C" as a group or part of a group. 1~4 Alkoxy" or "C 1~4 Archi The term "oxy" refers to a group of the formula -OR c (where R c C 1~4 (which is alkyl) It will be appreciated that the preferred C 1~4 Non-limiting examples of alkyloxy include: Examples include methyloxy (also called methoxy), ethyloxy (also called ethoxy), ), propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec- butyloxy and tert-butyloxy.

[0039] As used herein, "C" as a group or part of a group 2~4 Alkenyl The term refers to a straight-chain or Branched chain hydrocarbon groups, such as, but not limited to, ethenyl, propenyl, butenyl, 1 -propen-2-yl, etc.

[0040] As used herein, "C" as a group or part of a group 2~6 Alkenyl The term refers to a linear or Branched chain hydrocarbon groups, such as, but not limited to, ethenyl, propenyl, butenyl, pentyl, It represents 1-propen-2-yl, hexenyl, etc.

[0041] As used herein, "C" as a group or part of a group 3~6 Cycloalkane The term "cycloalkyl" refers to a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, e.g., cyclopropyl. represents propyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0042] Z is -X-CR 5a R 5b -, it is intended that X is attached to Ar.

[0043] Z is -CR 5c =CR 5d -If R 5c The C atom with the substituent is bonded to Ar. It is intended that

[0044] Z is -CR 5e R 5g -CR 5f R 5h -If R 5e and R 5g Substituent groups It is intended that the corresponding C atom is bonded to Ar.

[0045] Z is -CR 5a R 5b -X-, then R 5a and R 5b C atoms with substituents It is intended to be attached to Ar.

[0046] Those skilled in the art will appreciate that (R 12 (in the definition of) 4 bonded to the rest of the molecule through a ring nitrogen atom It will be appreciated that a 5-, 6- or 7-membered heterocycle is, in particular, a saturated ring. 1 2 Non-limiting examples include 1-piperidinyl, 1-pyrrolidinyl, 1-morpholinyl, 1-amino Zetidinyl, etc.

[0047] Unless otherwise indicated or clear from the context, (R 13 (as in the definition of Substituents on 4- to 7-membered monocyclic aromatic rings containing 1, 2, or 3 heteroatoms (including but not limited to) Typical examples are pyrrolyl, pyridinyl, furanyl, etc.) on a ring carbon atom or possibly on the ring nitrogen atom (in which case the hydrogen on the nitrogen atom may be replaced with a substituent) if It will be apparent to those skilled in the art that the hydrogen atoms of (R 13 Definition of 6- to 11-membered bicyclic fused aromatic rings containing 1, 2, or 3 heteroatoms (as shown in Those skilled in the art will recognize that this is true for aromatic rings (non-limiting examples are indolyl, quinolinyl, etc.). It will be clear to those who

[0048] (R 13 4- to 7-membered alkyl groups containing 1, 2, or 3 heteroatoms (as defined in A membered monocyclic aromatic ring may be bonded to any available ring carbon or The same applies to (R 13 of 6- to 11-membered bicyclic fused rings containing 1, 2, or 3 heteroatoms (as defined) It will be apparent to one skilled in the art that this also applies to synthetic aromatic rings.

[0049] If a nitrogen atom replaces one of the two fused carbon atoms in the Ar group, The structure shown below in which the yl group is optionally substituted according to any of the embodiments: : [ka] In the bicyclic aromatic ring system, as exemplified by: It will be clear that:

[0050] Two fused six-membered rings, optionally with one or two ring carbon atoms replaced by nitrogen atoms Other non-limiting examples of Ar groups that are 10-membered bicyclic aromatic ring systems consisting of: [ka] Each of these is optionally substituted according to any of the embodiments. do.

[0051] Those skilled in the art will recognize the 10-membered Ar group (optionally with one or two ring carbon atoms replaced by nitrogen atoms). The 10 components of the 10-membered bicyclic aromatic ring system (consisting of two fused 6-membered rings) are carbon atoms, 9 carbon atoms and 1 nitrogen atom, or 8 carbon atoms and 2 nitrogen atoms It will be understood that Ar is an element atom. Ar is optionally a group according to any of the embodiments. are selectively replaced.

[0052] Whenever a substituent is represented by a chemical structure, "---" represents the remainder of the molecule of formula (I). Lines drawn from substituents into ring systems indicate that the bond may be to any suitable ring atom. It indicates that it can be connected to either

[0053] for example [ka] is the ring system: [ka] It includes one of the following: [ka] teeth, [ka] is an alternative representation of

[0054] The term "subject" as used herein means an animal, preferably a mammal. animals (e.g., cats, dogs, primates, or humans), more preferably for therapeutic, observational, or experimental purposes. It refers to a human being who is or was a subject.

[0055] The term "therapeutically effective amount" as used herein refers to the amount of a compound or compound that is effective for the disease or condition being treated. The results sought by researchers, veterinarians, physicians or other clinicians, including the reduction or amelioration of symptoms of a disorder, Active compounds or drugs that induce a biological or medical response in tissue systems, animals or humans It means the amount of medicine.

[0056] The term "composition" refers to a product containing predetermined amounts of predetermined ingredients, as well as a product containing predetermined amounts of predetermined ingredients. It is intended to encompass any product obtained directly or indirectly from the combination of the specified ingredients. can be.

[0057] The term "treatment" as used herein means to slow or prevent the progression of a disease, It is intended to refer to any process that can be stopped or halted, but not all symptoms. Does not necessarily indicate complete disappearance.

[0058] The term "compound of the invention" as used herein refers to a compound of formula (I) The term "compound" is intended to include the compound as well as pharmaceutically acceptable addition salts, and solvates thereof.

[0059] Some of the compounds of formula (I) may also exist in their tautomeric forms. These are called "tautomers" or "tautomeric forms." The term refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) ) is a proton-transfer mediated isomerization reaction, such as keto-enol and imine-enamine isomerization. Valence tautomers involve interconversions by reorganization of some of the bonding electrons. Such forms, to the extent that they may exist, are not explicitly indicated in formula (I) above but are included within the scope of the present invention. It is intended to be included within

[0060] As used herein, lines are shown only as solid lines and may be solid wedges or dashed wedges. or a specific bond centered on one or more atoms. Any chemical formula shown as having a configuration (e.g., R, S) may be A stereoisomer or a mixture of two or more stereoisomers is contemplated. Where the stereochemistry of an atom is not specified in a structure shown herein, all stereoisomers are The compounds are envisaged as pure stereoisomers or as mixtures of two or more stereoisomers. Included as compounds of the invention.

[0061] Above and below, the term "compounds of formula (I)" refers to stereoisomers and their analogs. However, it is intended that the stereochemistry be as described in the previous paragraph. As such, they are identified by bonds shown as solid or dashed wedge bonds, or When depicted as having a particular configuration (e.g., R, S), the stereoisomer is This obviously also applies to subgroups of formula (I). cormorant.

[0062] A single compound may, where possible, exist in both stereoisomeric and tautomeric forms. This means that...

[0063] The above or below "stereoisomers" and "stereoisomers" The terms "stereoisomeric form" or "stereochemical isomer" refer to the same It is used in a proper way.

[0064] Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of enantiomers of is a racemate or racemic mixture.

[0065] Atropisomers (or atropoisomers) are isomers that are oriented around a single bond due to large steric hindrance. A compound of formula (I) is a stereoisomer having a specific spatial configuration resulting from restricted rotation. All atropisomers of are intended to be included within the scope of the present invention.

[0066] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers. i.e., they are not related as mirror images. If the compound contains a double bond, In this case, the substituents may be in the E or Z configuration. For example, the compound may have either a disubstituted cycloalkane or a trans configuration; When the alkyl group contains an alkyl group, the substituents may be in the cis or trans configuration. Therefore, the present invention provides for the preparation of enantiomers, atropisomers, diastereoisomers, and the like whenever chemically possible. mer, racemic, E isomer, Z isomer, cis isomer, trans isomer and mixtures thereof Includes things.

[0067] All of these terms, i.e., enantiomers, atropisomers, diastereomers, Meaning of semi-isomer, E isomer, Z isomer, cis isomer, trans isomer and mixtures thereof is known to those skilled in the art.

[0068] The absolute configuration is described according to the Cahn-Ingold-Prelog rules. The configuration in the molecule is described by either R or S. The separated stereoisomers are either (+) or (-) depending on the direction they rotate plane polarized light. For example, resolved enantiomers of unknown absolute configuration may be represented as It can be designated as (+) or (-) depending on the direction it rotates the light.

[0069] When a particular stereoisomer is identified, this means that said stereoisomer may be present in other stereoisomers. Qualitatively free, i.e., less than 50%, preferably less than 20%, more preferably 1 less than 0%, even more preferably less than 5%, especially less than 2%, most preferably less than 1%. It is therefore intended that compounds of formula (I) may be, for example, When described as (R), this means that the compound is substantially free of the (S) isomer. However, when a compound of formula (I) is described as, for example, E, this means that the compound may also be a Z isomer. When a compound of formula (I) is described as, for example, cis, this means that it is means that the compound is substantially free of the trans isomer.

[0070] For therapeutic use, salts of compounds of formula (I) and solvates thereof may be used where the counterion is pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable are also acceptable, e.g. For example, it may be used in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether or not they are hydroxypropyl or methyl, are included within the scope of the present invention.

[0071] Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts are conventionally by means of, for example, free radicals, optionally in a solvent or medium in which the salt is insoluble. Reaction of the acid or free base form with one or more equivalents of an appropriate acid or base, followed by standard the solvent or precursor using techniques such as under reduced pressure, by freeze-drying or filtration. Salts can also be formed by removal of the solvent, for example, using a suitable ion exchange resin. , prepared by exchanging the counter ion of a compound of the present invention in the form of a salt with another counter ion. It is possible.

[0072] The pharmaceutically acceptable addition salts described above or below are compounds of formula (I) and their derivatives. The compounds may include therapeutically active non-toxic acid and base addition salt forms, of which solvates may occur. It is intended.

[0073] Suitable acids are inorganic acids, for example hydrohalic acids, such as hydrochloric acid or hydrobromic acid, sulfuric acid, acids such as nitric acid, phosphoric acid; or organic acids such as acetic acid, propanoic acid, hydroxyacetic acid , lactic acid, pyruvic acid, oxalic acid (i.e., ethanedioic acid), malonic acid, succinic acid (i.e., butanedioic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonyl sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid , salicylic acid, p-aminosalicylic acid, pamoic acid, etc. Conversely, the salt forms include: It can be converted to the free base form by treatment with an appropriate base.

[0074] The compounds of formula (I) and solvates thereof containing an acidic proton may also be reacted with a suitable organic base. and converted to their non-toxic metal or amine addition salt forms by treatment with inorganic bases. It can be made into

[0075] Suitable base salt forms include, for example, ammonium salts, alkali metal salts, and alkaline earth metal salts. metal salts, such as lithium salts, sodium salts, potassium salts, magnesium salts, and calcium salts salts with organic bases, e.g., primary, secondary and tertiary aliphatic and aromatic amines, , for example, methylamine, ethylamine, propylamine, isopropylamine, four kinds Butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine Aminopropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, Fluorine, trimethylamine, triethylamine, tripropylamine, quinuclidine, Pyridine, quinoline and isoquinoline; benzathine, N-methyl-D-glucamine, hydroxybenzoates These include drabamine salts and salts with amino acids such as arginine, lysine, etc. The salt form can be converted into the free acid form by treatment with acid.

[0076] For purposes of this invention, prodrugs are also included within the scope of the present invention.

[0077] The term "prodrug" of the related compounds of the present invention refers to prodrugs that are administered orally or parenterally, particularly After oral administration, it is metabolized in vivo to produce compounds in experimentally detectable amounts and within a given time ( For example, within a 6- to 24-hour dosing interval (i.e., 1 to 4 times daily), For the avoidance of doubt, the term "parenteral" administration includes any compound that forms a compound with , all forms of administration other than oral administration, particularly intravenous (IV), intramuscular (IM), and subcutaneous (SC) injections.

[0078] Prodrugs are compounds that, when administered in vivo to a mammalian subject, can be prepared by modifying functional groups present on the compound such that the modification is cleaved The modifications are typically obtained by synthesizing the parent compound with a prodrug substituent. Generally, prodrugs are compounds that replace hydroxyl, amino, sulfhydryl, Carboxy or carbonyl groups are free hydroxyl, amino, sulfhydryl, respectively. The hydroxyl group may be bonded to any group that can be cleaved in vivo to produce an alkyl, carboxyl or carbonyl group. In particular, the hydroxyl groups in the compounds of the present invention are free hydroxyl groups. Any group (e.g., —C(═O)—C) that can be cleaved in vivo to form a 1~4 Al Within the context of this invention, prodrugs include compounds of the invention linked to In particular, R 1 and / or R 2 is -C(=O)-C 1~4 Compounds of formula (I) representing alkyl It is an object or a subgroup thereof.

[0079] Examples of prodrugs include, but are not limited to, esters and carboxylates of hydroxy functional groups. Carbamates, ester groups of carboxyl functional groups, N-acyl derivatives and N-Mannich derivatives General information about prodrugs can be found, for example, in Bundegaa rd, H. “Design of Prodrugs” pl-92, Elesevie r, New York-Oxford (1985).

[0080] The term solvates refers to the hydrates and solvent addition forms, if any, that the compounds of formula (I) may occur in. and pharmaceutically acceptable addition salts thereof. Examples of such forms include, for example, hydrates, aldehydes, acetaldehyde, acetone, methyl methyl acrylate, ... Korat, etc.

[0081] The compounds of the invention prepared by the methods described below may be prepared by art-known resolution procedures. In the form of a mixture of enantiomers, which are therefore separable from one another, in particular a racemic mixture of enantiomers. The compounds of formula (I) and their pharmaceutically acceptable addition salts and solvents can be synthesized by the method of The method for separating the enantiomers of a solvate is liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms also include those obtained by reacting the appropriate starting compounds, provided that the reaction occurs stereospecifically. It can be derived from the corresponding pure stereochemical isomers of the material. If desired, said compounds may be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

[0082] The present invention relates to a method for treating an atom or atoms having an atomic mass or mass number (or mass number) that is commonly found in nature. or most common in nature) with an atom having a different atomic mass or mass number. Isotopically labeled compounds of the invention identical to those described herein, except that The term also includes compounds.

[0083] Naturally or synthetically produced in natural abundance or isotopically enriched form Also, all isotopes and isotopic compositions of any particular atom or element identified herein. Mixtures of compounds are considered to be within the scope of the present invention. Exemplary isotopes that can be obtained include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and and isotopes of iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 O. 1 7 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 122 I, 123 I, 12 5 I, 131 I, 75 Br, 76 Br, 77 Br and 82 Br is preferred. is a radioactive isotope 2 H, 3 H, 11 C and 18 More preferably, For example, radioactive isotopes 2 H. In particular, deuterated compounds are included within the scope of the present invention. It is intended that

[0084] Some isotopically labeled compounds of the present invention (e.g., 3 H and 14 Labeled with C Tritium ( 3 H) and and carbon-l4(14 C) Isotopes are useful because of their ease of preparation and detectability. Furthermore, deuterium (i.e., 2 Substitution with heavier isotopes such as H results in higher metabolic Several therapeutic advantages derive from chemical stability (e.g., increased in vivo half-life or This may be preferable in some circumstances as it can provide a reduced dose. 15 O. 13 N, 11 C and 18 Positron-emitting isotopes such as F are used to measure substrate receptor occupancy. (substrate receptor occupancy) It is useful for photon emission tomography (PET) studies.

[0085] In all of the following embodiments, the following compounds, as well as pharmaceutically acceptable adducts thereof, are included: Salts and solvates are excluded: [ka]

[0086] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; Y represents -O-, -CH2- or -CF2-; Z is -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, or -C≡C-; When Y represents -CH2- or -CF2-, Z may also represent -O- or -CR2-. 5a R 5b -X- can be represented; R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , and R 5h are respectively , independently, hydrogen or C 1~4 represents alkyl; X is -O-, -S-, or -NR 11 - represents; R 11 is hydrogen or C 1~4 represents alkyl; 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 replaced by nitrogen atoms; provided that the nitrogen atoms are not fused to two When a carbonyl group is present in said bicyclic aromatic ring system, it replaces one of the carbon atoms. death; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi Le)2, -NHR 10d , -NR 10c R 10d , cyano, -CF3, -C(=O)-N H2, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, C1 ~4 Alkyloxy, -C(=O)-OC 1~4 Alkyl, C 3~6 cycloalkyl, -OC 3~6 Cycloalkyl, -NH-C 3~6 Cycloalkyl, -N(C 3~6 Shik (C)2, C 2~6 Alkenyl, one C1~4 C1 substituted with alkyloxy ~4 alkyl, and one -NR 10a R 10b C optionally substituted with 1~4 a one, two, three or four substituents each independently selected from the group consisting of alkyl, alkyl, aryl, aryl, arylalkyl ... optionally replaced by; R 10a and R 10b are each independently hydrogen or C 1~4 represents alkyl; R 10c and R 10d are each independently, C 3~6 Cycloalkyl; R 14 ;Ha -OH and -OC 1~4 1 independently selected from the group consisting of alkyl C substituted with one, two or three substituents 3~6 Cycloalkyl; halo, -OH and -OC 1~4 one, two, or three independently selected from the group consisting of alkyl C substituted with two substituents 1~4 Alkyl; or C 3~6 cycloalkyl, and R 1 4 C substituted with one substituent selected from the group consisting of 1~4 represents alkyl; R 14 is one, two, or three substituents independently selected from the group consisting of halo represents phenyl optionally substituted by a substituent; Het consists of (a-1), (a-2), (a-3), (a-4) and (a-5) represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of: [ka] R 3a, R 3b , R 3c , R 3d and R 3e are each independently hydrogen, halo, - NR 7a R 7b , C 1~4 Alkyl, C 2~4 Alkenyl, C 3~6 Cycloalkyl, - OH, or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b But hydrogen, C 3~6 Cycloalkyl, or C 1~4 represents alkyl; R 4a , R 4b , R 4c , R 4d , R 4e , R 4f and R 4g are each independently , hydrogen, halo, -NR 8a R 8b , or C 1~4 represents alkyl; R 8a and R 8b are each independently hydrogen or C 1~4 represents alkyl; Q 1 But N or CR 6a represents; Q 2 But N or CR 6b represents; Q 3 But N or CR 6c represents; Q 4 But N or CR 6d represents; However, Q 3 and Q 4 At most one of represents N; Q 8 But N or CR 6g represents; Q 9 But N or CR 6hrepresents; Q 10 But N or CR 6i represents; Q 11 But N or CR 6j represents; Q 5 is CR 3d represents ;Q 6 represents N;Q 7 is CR 4f represents; or Q 5 is CR 3d represents ;Q 6 is CR 4e represents ;Q 7 represents N; or Q 5 represents N;Q 6 is CR 4e represents ;Q 7 is CR 4f represents; or Q 5 represents N;Q 6 is CR 4e represents ;Q 7 represents N; or Q 5 represents N;Q 6 represents N;Q 7 is CR 4f represents; or Q 5 represents N;Q 6 represents N;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 are each independently hydrogen, halogen, C 1~4 Alkyl, -NR 9a R 9b ,Ma or C substituted by 1, 2 or 3 halo atoms 1~4 represents alkyl; R9a and R 9b are each independently hydrogen or C 1~4 (representing alkyl) New compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0087] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; Y represents -O-, -CH2- or -CF2-; Z is -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, or -C≡C-; When Y represents -CH2- or -CF2-, Z may also represent -O- or -CR2-. 5a R 5b -X- can be represented; R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , and R 5h are respectively , independently, hydrogen or C 1~4 represents alkyl; X is -O-, -S-, or -NR 11 - represents; R 11 But hydrogen, C 1~4 Alkyl, or -OH, -OC 1~4 Alkyl, R 12 , -NH2, -NH-C 1~4Alkyl, and -N(C 1~4 alkyl)2 C substituted with one substituent selected from 1~4 represents alkyl; R 12 a 4-membered, 5-membered, a 6- or 7-membered heterocyclic ring; said 4-, 5-, 6- or 7-membered heterocyclic ring is attached to the rest of the molecule via; 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 replaced by nitrogen atoms; provided that the nitrogen atoms are not fused to two When a carbonyl group is present in said bicyclic aromatic ring system, it replaces one of the carbon atoms. death; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi Le)2, -NHR 10d , -NR 10c R 10d , cyano, -CF3, -C(=O)-N H2, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, C1 ~4 Alkyloxy, -C(=O)-OC 1~4 Alkyl, C 3~6 cycloalkyl, -OC 3~6 Cycloalkyl, -NH-C 3~6 Cycloalkyl, -N(C 3~6 Shik (C)2, C 2~6 Alkenyl, one C 1~4 C1 substituted with alkyloxy ~4 alkyl, and one -NR 10a R 10b C optionally substituted with 1~4 a one, two, three or four substituents each independently selected from the group consisting of alkyl, alkyl, aryl, aryl, arylalkyl ... optionally replaced by; R 10a and R 10b are each independently hydrogen or C 1~4 represents alkyl; R 10c and R 10d are each independently, C 3~6 Cycloalkyl; R 13 ;R 14 ;Halo, -OH and -OC 1~4 each independently selected from the group consisting of alkyl C substituted with one, two or three substituents 3~6 Cycloalkyl; halo, -O H and -OC 1~4 one or two independently selected from the group consisting of alkyl or C substituted with three substituents 1~4 Alkyl; or C 3~6 Cycloalkyl, R 13 and R 14 C substituted with one substituent selected from the group consisting of 1~4 Alkyl represents; R 13 But O, S, S(=O) p and one or two independently selected from N or a 4- to 7-membered monocyclic aromatic ring containing three heteroatoms; or O, S, S(=O) p and N, represents a 6- to 11-membered bicyclic fused aromatic ring; The 4- to 7-membered monocyclic aromatic ring or the 6- to 11-membered bicyclic fused aromatic ring is 1~4 Archi optionally substituted with one or two substituents selected from the group consisting of: p represents 1 or 2; R 14is one, two, or three substituents independently selected from the group consisting of halo represents phenyl optionally substituted by a substituent; Het consists of (a-1), (a-2), (a-3), (a-4) and (a-5) represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of: [ka] R 3a , R 3b , R 3c , R 3d and R 3e are each independently hydrogen, halo, - NR 7a R 7b , C 1~4 Alkyl, C 2~4 Alkenyl, C 3~6 Cycloalkyl, - OH, or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b But hydrogen, C 3~6 Cycloalkyl, or C 1~4 represents alkyl; R 4a , R 4b , R 4c , R 4d , R 4e , R 4f and R 4g are each independently , hydrogen, halo, -NR 8a R 8b , or C 1~4 represents alkyl; R 8a and R 8b are each independently hydrogen or C 1~4 represents alkyl; Q 1 is CR 6a represents; Q 2 is CR 6b represents; Q3 But N or CR 6c represents; Q 4 But N or CR 6d represents; However, Q 3 and Q 4 At most one of represents N; Q 8 But N or CR 6g represents; Q 9 But N or CR 6h represents; Q 10 But N or CR 6i represents; Q 11 But N or CR 6j represents; Q 5 is CR 3d represents ;Q 6 represents N;Q 7 is CR 4f represents; or Q 5 is CR 3d represents ;Q 6 is CR 4e represents ;Q 7 represents N; or Q 5 represents N;Q 6 is CR 4e represents ;Q 7 is CR 4f represents; or Q 5 represents N;Q 6 is CR 4e represents ;Q 7 represents N; or Q 5 represents N;Q 6 represents N;Q 7 is CR 4f represents; or Q 5 represents N;Q 6 represents N;Q 7 represents N; R 6a , R 6b , R 6c , R 6d , R6e , R 6f , R 6g , R 6h , R 6i and R 6j are each independently hydrogen, halogen, C 1~4 Alkyl, -NR 9a R 9b ,Ma or C substituted by 1, 2 or 3 halo atoms 1~4 represents alkyl; R 9a and R 9b are each independently hydrogen or C 1~4 (representing alkyl) New compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0088] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; Y represents -O-, -CH2- or -CF2-; Z is -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, or -C≡C-; When Y represents -CH2- or -CF2-, Z may also represent -O- or -CR2-. 5a R 5b -X- can be represented; R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , and R5h are respectively , independently, hydrogen or C 1~4 represents alkyl; X is -O-, -S-, or -NR 11 - represents; R 11 But hydrogen, C 1~4 Alkyl, or -OH, -OC 1~4 Alkyl, R 12 , -NH2, -NH-C 1~4 Alkyl, and -N(C 1~4 alkyl)2 C substituted with one substituent selected from 1~4 represents alkyl; R 12 a 4-membered, 5-membered, a 6- or 7-membered heterocyclic ring; said 4-, 5-, 6- or 7-membered heterocyclic ring is attached to the rest of the molecule via; 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 replaced by nitrogen atoms; provided that the nitrogen atoms are not fused to two When a carbonyl group is present in said bicyclic aromatic ring system, it replaces one of the carbon atoms. death; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi Le)2, -NHR 10d , -NR 10c R 10d , cyano, -CF3, -C(=O)-N H2, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, C1 ~4 Alkyloxy, -C(=O)-OC 1~4 Alkyl, C 3~6 cycloalkyl, C 2~6 Alkenyl, one C1~4 C substituted with alkyloxy 1~4 Alkyl, and one -NR 10a R 10b C optionally substituted with 1~4 alkyl and optionally substituted with 1, 2, 3, or 4 substituents each independently selected from Converted; R 10a and R 10b are each independently hydrogen or C 1~4 represents alkyl; R 10c and R 10d are each independently, C 3~6 Cycloalkyl; halo, -O H and -OC 1~4 one or two independently selected from the group consisting of alkyl or C substituted with three substituents 3~6 Cycloalkyl; halo, -OH and -OC 1~4 one, two, or three substituted alkyl groups each independently selected from the group consisting of C substituted with a group 1~4 Alkyl; or C 3~6 Cycloalkyl, R 13 and R 14 C substituted with one substituent selected from the group consisting of 1~4 represents alkyl; R 13 But O, S, S(=O) p and one or two independently selected from N or a 4- to 7-membered monocyclic aromatic ring containing three heteroatoms; or O, S, S(=O) p and N, represents a 6- to 11-membered bicyclic fused aromatic ring; The 4- to 7-membered monocyclic aromatic ring or the 6- to 11-membered bicyclic fused aromatic ring is 1~4 Archi optionally substituted with one or two substituents selected from the group consisting of: p represents 1 or 2; R 14 is one, two, or three substituents independently selected from the group consisting of halo represents phenyl optionally substituted by a substituent; Het is a bicyclic ring selected from the group consisting of (a-1), (a-2) and (a-3). Aromatic heterocyclic ring systems: [ka] R 3a , R 3b and R 3c are each independently hydrogen, halo, or -NR 7a R 7b , C 1~4 Alkyl, or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b is hydrogen or C 1~4 represents alkyl; R 4a , R 4b and R 4c are each independently hydrogen, halo, or -NR 8a R 8b , or C 1~4 represents alkyl; R 8a and R 8b are each independently hydrogen or C 1~4 represents alkyl; Q 1 But N or CR 6a represents; Q 2 But N or CR 6b represents; Q 3 But N or CR 6c represents; Q 4 But N or CR 6drepresents; However, Q 3 and Q 4 At most one of represents N; R 6a , R 6b , R 6c , R 6d , R 6e and R 6f are each independently hydrogen, Halogen, C 1~4 Alkyl, -NR 9a R 9b , or 1, 2 or 3 halo atoms C replaced by child 1~4 represents alkyl; R 9a and R 9b are each independently hydrogen or C 1~4 (representing alkyl) New compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0089] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; Y represents -O-, -CH2- or -CF2-; Z is -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, or -C≡C-; When Y represents -CH2- or -CF2-, Z may also represent -O- or -CR2-. 5a R 5b -X- can be represented; R 5a , R5b , R 5c , R 5d , R 5e , R 5f , R 5g , and R 5h are respectively , independently, hydrogen or C 1~4 represents alkyl; X is -O-, -S-, or -NR 11 - represents; R 11 But hydrogen, C 1~4 Alkyl, or -OH, -OC 1~4 Alkyl, R 12 , -NH2, -NH-C 1~4 Alkyl, and -N(C 1~4 alkyl)2 C substituted with one substituent selected from 1~4 represents alkyl; R 12 a 4-membered, 5-membered, a 6- or 7-membered heterocyclic ring; said 4-, 5-, 6- or 7-membered heterocyclic ring is attached to the rest of the molecule via; 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 replaced by nitrogen atoms; provided that the nitrogen atoms are not fused to two When a carbonyl group is present in said bicyclic aromatic ring system, it replaces one of the carbon atoms. death; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi C(=O)-NH-C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, C 1~4 alkyloxy, and one -NR 10a R 10b Select arbitrarily Selectively substituted C1~4 alkyl, optionally substituted with one, three or four substituents; R 10a and R 10b are each independently hydrogen or C 1~4 represents alkyl; Het is a bicyclic ring selected from the group consisting of (a-1), (a-2) and (a-3). Aromatic heterocyclic ring systems: [ka] R 3a , R 3b and R 3c are each independently hydrogen, halo, or -NR 7a R 7b , or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b is hydrogen or C 1~4 represents alkyl; R 4a , R 4b and R 4c are each independently hydrogen, halo, or -NR 8a R 8b , or C 1~4 represents alkyl; R 8a and R 8b are each independently hydrogen or C 1~4 represents alkyl; Q 1 But N or CR 6a represents; Q 2 But N or CR 6b represents; Q 3 But N or CR 6c represents; Q 4 But N or CR 6d represents; However, Q3 and Q 4 At most one of represents N; R 6a , R 6b , R 6c , R 6d , R 6e and R 6f are each independently hydrogen, Halogen, C 1~4 Alkyl, -NR 9a R 9b , or 1, 2 or 3 halo atoms C replaced by child 1~4 represents alkyl; R 9a and R 9b are each independently hydrogen or C 1~4 (representing alkyl) New compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0090] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; Y represents -O-, -CH2- or -CF2-; Z is -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, or -C≡C-; When Y represents -CH2- or -CF2-, Z may also represent -O- or -CR2-. 5a R 5b -X- can be represented; R 5a , R 5b , R 5c , R5d , R 5e , R 5f , R 5g , and R 5h are respectively , independently, hydrogen or C 1~4 represents alkyl; X is -O-, -S-, or -NR 11 - represents; R 11 But hydrogen, C 1~4 Alkyl, or -OH, -OC 1~4 Alkyl, R 12 , -NH2, -NH-C 1~4 Alkyl, and -N(C 1~4 alkyl)2 C substituted with one substituent selected from 1~4 represents alkyl; R 12 a 4-membered, 5-membered, a 6- or 7-membered heterocyclic ring; said 4-, 5-, 6- or 7-membered heterocyclic ring is attached to the rest of the molecule via; Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings; [ka] wherein at least one ring carbon atom of ring B is replaced with a nitrogen atom; wherein optionally one further ring carbon atom of ring A or ring B is replaced with a nitrogen atom provided that if a nitrogen atom replaces one of the two fused carbon atoms, a aryl group is present in said bicyclic aromatic ring system; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi Le)2, -NHR 10d , -NR 10c R 10d , cyano, -CF3, -C(=O)-N H2, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, C1 ~4 Alkyloxy, -C(=O)-OC 1~4 Alkyl, C 3~6 cycloalkyl, -OC 3~6 Cycloalkyl, -NH-C 3~6 Cycloalkyl, -N(C 3~6 Shik (C)2, C 2~6 Alkenyl, one C 1~4 C1 substituted with alkyloxy ~4 alkyl, and one -NR 10a R 10b C optionally substituted with 1~4 a one, two, three or four substituents each independently selected from the group consisting of alkyl, alkyl, aryl, aryl, arylalkyl ... optionally replaced by; R 10a and R 10b are each independently hydrogen or C 1~4 represents alkyl; R 10c and R 10d are each independently, C 3~6 Cycloalkyl; R 13 ;R 14 ;Halo, -OH and -OC 1~4 each independently selected from the group consisting of alkyl C substituted with one, two or three substituents 3~6 Cycloalkyl; halo, -O H and -OC 1~4 one or two independently selected from the group consisting of alkyl or C substituted with three substituents 1~4 Alkyl; or C 3~6 Cycloalkyl, R 13 and R 14 C substituted with one substituent selected from the group consisting of 1~4Alkyl represents; R 13 But O, S, S(=O) p and one or two independently selected from N or a 4- to 7-membered monocyclic aromatic ring containing three heteroatoms; or O, S, S(=O) p and N, represents a 6- to 11-membered bicyclic fused aromatic ring; The 4- to 7-membered monocyclic aromatic ring or the 6- to 11-membered bicyclic fused aromatic ring is 1~4 Archi optionally substituted with one or two substituents selected from the group consisting of: p represents 1 or 2; R 14 is one, two, or three substituents independently selected from the group consisting of halo represents phenyl optionally substituted by a substituent; Het consists of (a-1), (a-2), (a-3), (a-4) and (a-5) represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of: [ka] R 3a , R 3b , R 3c , R 3d and R 3e are each independently hydrogen, halo, - NR 7a R 7b , C 1~4 Alkyl, C 2~4 Alkenyl, C 3~6 Cycloalkyl, - OH, or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b But hydrogen, C 3~6 Cycloalkyl, or C 1~4represents alkyl; R 4a , R 4b , R 4c , R 4d , R 4e , R 4f and R 4g are each independently , hydrogen, halo, -NR 8a R 8b , or C 1~4 represents alkyl; R 8a and R 8b are each independently hydrogen or C 1~4 represents alkyl; Q 1 But N or CR 6a represents; Q 2 But N or CR 6b represents; Q 3 But N or CR 6c represents; Q 4 But N or CR 6d represents; However, Q 3 and Q 4 At most one of represents N; Q 8 But N or CR 6g represents; Q 9 But N or CR 6h represents; Q 10 But N or CR 6i represents; Q 11 But N or CR 6j represents; Q 5 is CR 3d represents ;Q 6 represents N;Q 7 is CR 4f represents; or Q 5 is CR 3d represents ;Q 6 is CR 4e represents ;Q 7 represents N; or Q5 represents N;Q 6 is CR 4e represents ;Q 7 is CR 4f represents; or Q 5 represents N;Q 6 is CR 4e represents ;Q 7 represents N; or Q 5 represents N;Q 6 represents N;Q 7 is CR 4f represents; or Q 5 represents N;Q 6 represents N;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 are each independently hydrogen, halogen, or C 1~4 Alkyl, -NR 9a R 9b ,Ma or C substituted by 1, 2 or 3 halo atoms 1~4 represents alkyl; R 9a and R 9b are each independently hydrogen or C 1~4 (representing alkyl) New compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0091] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 represents hydrogen; R 2 represents hydrogen; Y represents -O-, -CH2- or -CF2-; Z is -CH2-, -X-CR 5a R5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, or -C≡C-; When Y represents -CH2- or -CF2-, Z may also represent -O- or -CR2-. 5a R 5b -X- can be represented; R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , and R 5h are respectively , independently, hydrogen or C 1~4 represents alkyl; X is -O-, -S-, or -NR 11 - represents; R 11 But hydrogen, C 1~4 Alkyl, or -OH, -OC 1~4 Alkyl, R 12 , -NH2, -NH-C 1~4 Alkyl, and -N(C 1~4 alkyl)2 C substituted with one substituent selected from 1~4 represents alkyl; R 12 a 4-membered, 5-membered, a 6- or 7-membered heterocyclic ring; said 4-, 5-, 6- or 7-membered heterocyclic ring is attached to the rest of the molecule via; 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 replaced by nitrogen atoms; provided that the nitrogen atoms are not fused to two When a carbonyl group is present in said bicyclic aromatic ring system, it replaces one of the carbon atoms. death; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi Le)2, -NHR 10d , -NR 10c R 10d , cyano, -CF3, -C(=O)-N H2, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, C1 ~4 Alkyloxy, -C(=O)-OC 1~4 Alkyl, C 3~6 cycloalkyl, -OC 3~6 Cycloalkyl, -NH-C 3~6 Cycloalkyl, -N(C 3~6 Shik (C)2, C 2~6 Alkenyl, one C 1~4 C1 substituted with alkyloxy ~4 alkyl, and one -NR 10a R 10b C optionally substituted with 1~4 a one, two, three or four substituents each independently selected from the group consisting of alkyl, alkyl, aryl, aryl, arylalkyl ... optionally replaced by; R 10a and R 10b are each independently hydrogen or C 1~4 represents alkyl; R 10c and R 10d are each independently, C 3~6 Cycloalkyl; R 13 ;R 14 ;Halo, -OH and -OC 1~4 each independently selected from the group consisting of alkyl C substituted with one, two or three substituents 3~6 Cycloalkyl; halo, -O H and -OC 1~4one or two independently selected from the group consisting of alkyl or C substituted with three substituents 1~4 Alkyl; or C 3~6 Cycloalkyl, R 13 and R 14 C substituted with one substituent selected from the group consisting of 1~4 Alkyl represents; R 13 But O, S, S(=O) p and one or two independently selected from N or a 4- to 7-membered monocyclic aromatic ring containing three heteroatoms; or O, S, S(=O) p and N, represents a 6- to 11-membered bicyclic fused aromatic ring; The 4- to 7-membered monocyclic aromatic ring or the 6- to 11-membered bicyclic fused aromatic ring is 1~4 Archi optionally substituted with one or two substituents selected from the group consisting of: p represents 1 or 2; R 14 is one, two, or three substituents independently selected from the group consisting of halo represents phenyl optionally substituted by a substituent; Het consists of (a-1), (a-2), (a-3), (a-4) and (a-5) represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of: [ka] R 3a , R 3b , R 3c , R 3d and R 3e are each independently hydrogen, halo, - NR 7a R 7b , C 1~4 Alkyl, C 2~4Alkenyl, C 3~6 Cycloalkyl, - OH, or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b But hydrogen, C 3~6 Cycloalkyl, or C 1~4 represents alkyl; R 4a , R 4b , R 4c , R 4d , R 4e , R 4f and R 4g are each independently , hydrogen, halo, -NR 8a R 8b , or C 1~4 represents alkyl; R 8a and R 8b are each independently hydrogen or C 1~4 represents alkyl; Q 1 But N or CR 6a represents; Q 2 But N or CR 6b represents; Q 3 But N or CR 6c represents; Q 4 But N or CR 6d represents; However, Q 3 and Q 4 At most one of represents N; Q 8 But N or CR 6g represents; Q 9 But N or CR 6h represents; Q 10 But N or CR 6i represents; Q 11 But N or CR 6j represents; Q 5 is CR 3d represents ;Q6 represents N;Q 7 is CR 4f represents; or Q 5 is CR 3d represents ;Q 6 is CR 4e represents ;Q 7 represents N; or Q 5 represents N;Q 6 is CR 4e represents ;Q 7 is CR 4f represents; or Q 5 represents N;Q 6 is CR 4e represents ;Q 7 represents N; or Q 5 represents N;Q 6 represents N;Q 7 is CR 4f represents; or Q 5 represents N;Q 6 represents N;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 are each independently hydrogen, halogen, or C 1~4 Alkyl, -NR 9a R 9b ,Ma or C substituted by 1, 2 or 3 halo atoms 1~4 represents alkyl; R 9a and R 9b are each independently hydrogen or C 1~4 (representing alkyl) New compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0092] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 represents hydrogen; R 2 represents hydrogen; Y represents -O-, -CH2- or -CF2-; Z is -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, or -C≡C-; When Y represents -CH2- or -CF2-, Z may also represent -O- or -CR2-. 5a R 5b -X- can be represented; R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , and R 5h are respectively , independently, hydrogen or C 1~4 represents alkyl; X is -O-, -S-, or -NR 11 - represents; R 11 But hydrogen, C 1~4 Alkyl, or -OH, -OC 1~4 Alkyl, R 12 , -NH2, -NH-C 1~4 Alkyl, and -N(C 1~4 alkyl)2 C substituted with one substituent selected from 1~4 represents alkyl; R 12 a 4-membered, 5-membered, a 6- or 7-membered heterocyclic ring; said 4-, 5-, 6- or 7-membered heterocyclic ring is attached to the rest of the molecule via; 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 replaced by nitrogen atoms; provided that the nitrogen atoms are not fused to two When a carbonyl group is present in said bicyclic aromatic ring system, it replaces one of the carbon atoms. death; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi C(=O)-NH-C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, C 1~4 alkyloxy, and one -NR 10a R 10b Select arbitrarily Selectively substituted C 1~4 alkyl, optionally substituted with one, three or four substituents; R 10a and R 10b are each independently hydrogen or C 1~4 represents alkyl; Het is a bicyclic ring selected from the group consisting of (a-1), (a-2) and (a-3). represents an aromatic heterocyclic ring system; R 3a , R 3b and R 3c are each independently hydrogen, halo, or -NR 7a R 7b , or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b is hydrogen or C 1~4 represents alkyl; R 4a , R 4b and R 4c are each independently hydrogen, halo, or -NR8a R 8b , or C 1~4 represents alkyl; R 8a and R 8b are each independently hydrogen or C 1~4 represents alkyl; Q 1 But N or CR 6a represents; Q 2 But N or CR 6b represents; Q 3 But N or CR 6c represents; Q 4 But N or CR 6d represents; However, Q 3 and Q 4 At most one of represents N; R 6a , R 6b , R 6c , R 6d , R 6e and R 6f are each independently hydrogen, Halogen, C 1~4 Alkyl, -NR 9a R 9b , or 1, 2 or 3 halo atoms C replaced by child 1~4 represents alkyl; R 9a and R 9b are each independently hydrogen or C 1~4 (representing alkyl) New compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0093] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; Y represents -O-, -CH2- or -CF2-; Z is -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, or -C≡C-; When Y represents -CH2- or -CF2-, Z may also represent -O- or -CR2-. 5a R 5b -X- can be represented; R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , and R 5h are respectively , independently, hydrogen or C 1~4 represents alkyl; X is -O-, -S-, or -NR 11 - represents; R 11 But hydrogen, C 1~4 Alkyl, or -OH, -OC 1~4 Alkyl, R 12 , -NH2, -NH-C 1~4 Alkyl, and -N(C 1~4 alkyl)2 C substituted with one substituent selected from 1~4 represents alkyl; R 12 a 4-membered, 5-membered, a 6- or 7-membered heterocyclic ring; said 4-, 5-, 6- or 7-membered heterocyclic ring is attached to the rest of the molecule via; 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 replaced by nitrogen atoms; provided that the nitrogen atoms are not fused to two When a carbonyl group is present in said bicyclic aromatic ring system, it replaces one of the carbon atoms. death; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi Le)2, -NHR 10d , -NR 10c R 10d , cyano, -CF3, -C(=O)-N H2, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, C1 ~4 Alkyloxy, -C(=O)-OC 1~4 Alkyl, C 3~6 cycloalkyl, -OC 3~6 Cycloalkyl, -NH-C 3~6 Cycloalkyl, -N(C 3~6 Shik (C)2, C 2~6 Alkenyl, one C 1~4 C1 substituted with alkyloxy ~4 alkyl, and one -NR 10a R 10b C optionally substituted with 1~4 a one, two, three or four substituents each independently selected from the group consisting of alkyl, alkyl, aryl, aryl, arylalkyl ... optionally replaced by; R 10a and R 10b are each independently hydrogen or C 1~4 represents alkyl; R 10c and R 10d are each independently, C 3~6 Cycloalkyl; R 13 ;R 14 ;Halo, -OH and -OC 1~4 each independently selected from the group consisting of alkyl C substituted with one, two or three substituents 3~6 Cycloalkyl; halo, -O H and -OC 1~4 one or two independently selected from the group consisting of alkyl or C substituted with three substituents 1~4 Alkyl; or C 3~6 Cycloalkyl, R 13 and R 14 C substituted with one substituent selected from the group consisting of 1~4 Alkyl represents; R 13 But O, S, S(=O) p and one or two independently selected from N or a 4- to 7-membered monocyclic aromatic ring containing three heteroatoms; or O, S, S(=O) p and N, represents a 6- to 11-membered bicyclic fused aromatic ring; The 4- to 7-membered monocyclic aromatic ring or the 6- to 11-membered bicyclic fused aromatic ring is 1~4 Archi optionally substituted with one or two substituents selected from the group consisting of: p represents 1 or 2; R 14 is one, two, or three substituents independently selected from the group consisting of halo represents phenyl optionally substituted by a substituent; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R 3a But hydrogen, halo, -NR 7a R 7b , C 1~4 Alkyl, C 2~4 alkenyl, C 3~6 Cycloalkyl, -OH, or -OC 1~4 represents alkyl; R7a represents hydrogen; R 7b But hydrogen, C 3~6 Cycloalkyl, or C 1~4 represents alkyl; R 4a But hydrogen, halo, -NR 8a R 8b , or C 1~4 represents alkyl; R 8a and R 8b are each independently hydrogen or C 1~4 represents alkyl; Q 1 But N or CR 6a represents; Q 2 But N or CR 6b represents; In particular, Q 1 and Q 2 represents CH; R 6a and R 6b are each independently hydrogen, halogen, or C 1~4 Alkyl, -N R 9a R 9b or C substituted with 1, 2 or 3 halo atoms 1~4 Alkyl Represents; R 9a and R 9b are each independently hydrogen or C 1~4 (representing alkyl) New compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0094] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; Y represents -O-, -CH2- or -CF2-; Z is -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, or -C≡C-; When Y represents -CH2- or -CF2-, Z may also represent -O- or -CR2-. 5a R 5b -X- can be represented; R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , and R 5h are respectively , independently, hydrogen or C 1~4 represents alkyl; X is -O-, -S-, or -NR 11 - represents; R 11 But hydrogen, C 1~4 Alkyl, or -OH, -OC 1~4 Alkyl, R 12 , -NH2, -NH-C 1~4 Alkyl, and -N(C 1~4 alkyl)2 C substituted with one substituent selected from 1~4 represents alkyl; R 12 a 4-membered, 5-membered, a 6- or 7-membered heterocyclic ring; said 4-, 5-, 6- or 7-membered heterocyclic ring is attached to the rest of the molecule via; 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 replaced by nitrogen atoms; provided that the nitrogen atoms are not fused to two When a carbonyl group is present in said bicyclic aromatic ring system, it replaces one of the carbon atoms. death; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi C(=O)-NH-C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, C 1~4 alkyloxy, and one -NR 10a R 10b Select arbitrarily Selectively substituted C 1~4 alkyl, optionally substituted with one, three or four substituents; R 10a and R 10b are each independently hydrogen or C 1~4 represents alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R 3a But hydrogen, halo, -NR 7a R 7b , or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b is hydrogen or C 1~4 represents alkyl; R 4a But hydrogen, halo, -NR 8a R 8b , or C 1~4 represents alkyl; R 8a and R 8b are each independently hydrogen or C 1~4 represents alkyl; Q 1 But N or CR 6a represents; Q 2 But N or CR 6b represents; In particular, Q1 and Q 2 represents CH; R 6a and R 6b are each independently hydrogen, halogen, C 1~4 Alkyl, -N R 9a R 9b or C substituted with 1, 2 or 3 halo atoms 1~4 Alkyl Represents; R 9a and R 9b are each independently hydrogen or C 1~4 (representing alkyl) New compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0095] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; Y represents -O- or -CH2-; Z is -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, or -C≡C-; When Y represents -CH2-, Z also represents -CR 5a R 5b -X- can be represented; R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , and R 5h are respectively , independently, hydrogen or C1~4 represents alkyl; X is -O-, -S-, or -NR 11 - represents; R 11 is hydrogen or C 1~4 represents alkyl; 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 replaced by nitrogen atoms; provided that the nitrogen atoms are not fused to two When a carbonyl group is present in said bicyclic aromatic ring system, it replaces one of the carbon atoms. death; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi Le)2, -NHR 10d , cyano, -CF3, -C(=O)-NH2, -C(=O)-N HC 1~4 Alkyl, C 1~4 Alkyloxy, -C(=O)-OC 1~4 Alkyl , C 3~6 Cycloalkyl, C 2~6 Alkenyl, one C 1~4 Substituted with alkyloxy C 1~4 alkyl, and one -NR 10a R 10b is optionally replaced by C 1~4 one, two, three or four independently selected from the group consisting of alkyl optionally substituted with one or more substituents; R 10a and R 10b But C 1~4 represents alkyl; R 10d But C 3~6 Cycloalkyl; R 14 with one, two or three halo substituents Replaced C 1~4 Alkyl; or C 3~6 cycloalkyl, and R 14A group consisting of C substituted with one substituent selected from 1~4 represents alkyl; R 14 is one, two, or three substituents independently selected from the group consisting of halo represents phenyl optionally substituted by a substituent; Het is a bicyclic ring selected from the group consisting of (a-1), (a-2) and (a-4). represents an aromatic heterocyclic ring system; R 3a , R 3b , R 3c and R 3d are each independently hydrogen, halo, or -NR 7a R 7b , C 2~4 Alkenyl, C 3~6 Cycloalkyl, -OH, or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b But hydrogen, C 3~6 Cycloalkyl, or C 1~4 represents alkyl; R 4a , R 4b , R 4c , R 4d , R 4e and R 4f are each independently hydrogen, Halo, -NR 8a R 8b , or C 1~4 represents alkyl; R 8a and R 8b each independently represents hydrogen; Q 1 is CR 6a represents; Q 2 is CR 6b represents; Q 8 is CR 6g represents; Q 9 is CR 6hrepresents; Q 5 is CR 3d represents ;Q 6 represents N;Q 7 is CR 4f represents; or Q 5 is CR 3d represents ;Q 6 is CR 4e represents ;Q 7 represents N; or Q 5 represents N;Q 6 is CR 4e represents ;Q 7 is CR 4f represents; or Q 5 represents N;Q 6 is CR 4e represents ;Q 7 represents N; R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g and R 6h are respectively, independently hydrogen, halogen, or C 1~4 novel compounds of the formula (representing alkyl); and pharmaceutically acceptable addition salts, and solvates thereof.

[0096] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; Y represents -O- or -CH2-; Z is -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g-CR 5f R 5h -, or -C≡C-; When Y represents -CH2-, Z may also represent -O- or -CR 5a R 5b -X- and can; R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , and R 5h are respectively , independently, hydrogen or C 1~4 represents alkyl; X is -O-, -S-, or -NR 11 - represents; R 11 is hydrogen or C 1~4 represents alkyl; 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 replaced by nitrogen atoms; provided that the nitrogen atoms are not fused to two When a carbonyl group is present in said bicyclic aromatic ring system, it replaces one of the carbon atoms. death; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi C(=O)-NH-C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, C 1~4 alkyloxy, and one -NR 10a R 10b Select arbitrarily Selectively substituted C 1~4 alkyl, optionally substituted with one, three or four substituents; R 10a and R 10b are each independently hydrogen or C 1~4represents alkyl; Het is a bicyclic ring selected from the group consisting of (a-1), (a-2) and (a-3). represents an aromatic heterocyclic ring system; R 3a , R 3b and R 3c are each independently hydrogen, halo, or -NR 7a R 7b , or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b is hydrogen or C 1~4 represents alkyl; R 4a , R 4b and R 4c are each independently hydrogen, halo, or -NR 8a R 8b , or C 1~4 represents alkyl; R 8a and R 8b are each independently hydrogen or C 1~4 represents alkyl; Q 1 is CR 6a represents; Q 2 is CR 6b represents; Q 3 is CR 6c represents; Q 4 is CR 6d represents; R 6a , R 6b , R 6c , R 6d , R 6e and R 6f are each independently hydrogen, Halogen, C 1~4 Alkyl, -NR 9a R 9b , or 1, 2 or 3 halo atoms C replaced by child 1~4 represents alkyl; R9a and R 9b are each independently hydrogen or C 1~4 (representing alkyl) New compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0097] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; Y represents -O- or -CH2-; Z is -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, or -C≡C-; When Y represents -CH2-, Z may also represent -O- or -CR 5a R 5b -X- and can; R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , and R 5h are respectively , independently, hydrogen or C 1~4 represents alkyl; X is -O-, -S-, or -NR 11 - represents; R 11 is hydrogen or C 1~4 represents alkyl; 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 replaced by nitrogen atoms; provided that the nitrogen atoms are not fused to two When a carbonyl group is present in said bicyclic aromatic ring system, it replaces one of the carbon atoms. death; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi C(=O)-NH-C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, C 1~4 alkyloxy, and one -NR 10a R 10b Select arbitrarily Selectively substituted C 1~4 and optionally one substituent selected from the group consisting of alkyl is replaced by; R 10a and R 10b are each independently hydrogen or C 1~4 represents alkyl; Het is a bicyclic ring selected from the group consisting of (a-1), (a-2) and (a-3). represents an aromatic heterocyclic ring system; R 3a , R 3b and R 3c Ga-NR 7a R 7b represents; R 7a represents hydrogen; R 7b represents hydrogen; R 4a , R 4b and R 4c are each independently hydrogen, halo, or -NR 8a R 8b , or C 1~4 represents alkyl; R 8a and R 8b are each independently hydrogen or C 1~4 represents alkyl; Q 1 is CR6a represents; Q 2 is CR 6b represents; Q 3 is CR 6c represents; Q 4 is CR 6d represents; R 6a , R 6b , R 6c , R 6d , R 6e and R 6f are each independently hydrogen, Halogen, C 1~4 Alkyl, -NR 9a R 9b , or 1, 2 or 3 halo atoms C replaced by child 1~4 represents alkyl; R 9a and R 9b are each independently hydrogen or C 1~4 (representing alkyl) New compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0098] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 Represents alkyl; in particular, R 1 and R 2 but represents hydrogen; Y represents -O- or -CH2-; Z is -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, or -C≡C-; When Y represents -CH2-, Z also represents -CR 5a R 5b -X- can be represented; R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , and R 5h are respectively , independently, hydrogen or C 1~4 represents alkyl; X is -O-, -S-, or -NR 11 - represents; R 11 is hydrogen or C 1~4 represents alkyl; 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 replaced by nitrogen atoms; provided that the nitrogen atoms are not fused to two When a carbonyl group is present in said bicyclic aromatic ring system, it replaces one of the carbon atoms. death; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi C(=O)-NH-C 1~4 Alkyl, C 1~4 Alkyl Oxy, and C 1~4 one or two independently selected from the group consisting of alkyl or optionally substituted with three substituents; Het is a bicyclic aromatic heterocycle selected from the group consisting of (a-1) and (a-2) Represents the system; R 3a and R 3c are each independently halo, -NR 7a R 7b , or -OC 1~4 represents alkyl; R 7arepresents hydrogen; R 7b represents hydrogen; R 4a , and R 4c are each independently hydrogen, halo, or C 1~4 Alkyl Represents; Q 1 is CR 6a represents; Q 2 is CR 6b represents; R 6a , R 6b , R 6e and R 6f are each independently hydrogen, halogen, or C 1~4 novel compounds of the formula (representing alkyl); and pharmaceutically acceptable addition salts, and solvates thereof.

[0099] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 Represents alkyl; in particular, R 1 and R 2 but represents hydrogen; Y represents -O- or -CH2-; Z is -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -, -CR 5e R 5g -CR 5f R 5h -, or -C≡C-; When Y represents -CH2-, Z also represents -CR 5a R 5b -X- can be represented; R 5a , R 5b , R 5c , R5d , R 5e , R 5f , R 5g , and R 5h are respectively , independently, hydrogen or C 1~4 represents alkyl; X is -O-, -S-, or -NR 11 - represents; R 11 is hydrogen or C 1~4 represents alkyl; 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 replaced by nitrogen atoms; provided that the nitrogen atoms are not fused to two When a carbonyl group is present in said bicyclic aromatic ring system, it replaces one of the carbon atoms. death; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi Le)2, -NHR 10d , cyano, -CF3, -C(=O)-NH-C 1~4 Alkyl, C 1~4 Alkyloxy, and C 1~4 each independently selected from the group consisting of alkyl optionally substituted with one, two or three substituents selected from the group consisting of: R 10d is substituted with one, two or three halo substituents 1~4 alkyl; also is one C 3~6 Cycloalkyl-substituted C 1~4 represents alkyl; Het is a bicyclic aromatic heterocycle selected from the group consisting of (a-1) and (a-2) Represents the system; R 3a and R 3c are each independently hydrogen, halo, or -NR 7a R 7b ,or- OC 1~4represents alkyl; R 7a represents hydrogen; R 7b is hydrogen or C 1~4 represents alkyl; R 4a , and R 4c are each independently hydrogen, halo, or C 1~4 Alkyl Represents; Q 1 is CR 6a represents; Q 2 is CR 6b represents; R 6a , R 6b , R 6e and R 6f are each independently hydrogen, halogen, or C 1~4 novel compounds of the formula (representing alkyl); and pharmaceutically acceptable addition salts, and solvates thereof.

[0100] Another embodiment of the present invention is a compound of formula (I) wherein one or more of the following conditions apply: and pharmaceutically acceptable addition salts, and solvates, or other embodiments thereof. With respect to any subgroup thereof described in any of the above states: (i)R 1 and R 2 represents hydrogen; (ii) Y represents -O- or -CH2-; in particular, Y represents -O-; (iii) Z is -CH2-, -X-CR 5a R 5b -, -CR 5c =CR 5d -,- CR 5e R 5g -CR 5f R 5h -, or -C≡C-; When Y represents -CH2-, Z also represents -CR 5a R 5b -X- can be represented; (iv)R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , and R 5h but represents hydrogen; (v) X represents -O-; (vi)R 11 is hydrogen or C 1~4 represents alkyl; (vii) Ar is halo, -OH, -NH, -NH-C 1~4 Alkyl, -N(C1 ~4 alkyl), cyano, -CF, -C(=O)-NH-C 1~4 Alkyl, C 1~ 4 alkyloxy, and C 1~4 alkyl optionally substituted with 1, 2 or 3 substituents, in particular 1 substituent; (viii) Het is a bicyclic ring selected from the group consisting of (a-1) and (a-2) represents an aromatic heterocyclic ring system; (ix)R 3a and R 3c are each independently halo, -NR 7a R 7b ,or -OC 1~4 represents alkyl; (x)R 7a and R 7b represents hydrogen; (xi)R 4a , and R 4c are each independently hydrogen, halo, or C 1~4 a Represents Lukir; (xii)Q 1 is CR 6a represents; (xiii)Q 2 is CR 6b represents; (xiv)R6a , R 6b , R 6e and R 6f are independently hydrogen, halogen, N or C 1~4 Represents alkyl.

[0101] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 represents hydrogen; R 2 represents hydrogen; Y represents -O- or -CH2-; Z is -X-CR 5a R 5b -or-CR 5e R 5g -CR 5f R 5h - represents; When Y represents -CH2-, Z also represents -CR 5a R 5b -X- can be represented; R 5a , R 5b , R 5e , R 5f , R 5g , and R 5h represents hydrogen; X represents -O-; Ar, [ka] where Ar is -NH, -NH-C at the position indicated by α. 1~4 Al Kill, and -NHR 10d optionally substituted with a substituent selected from the group consisting of: wherein Ar is selected from the group consisting of halo and CF3 at the position indicated by β. optionally substituted with a substituent selected from the group consisting of aryl, aryl, aryl- ... provided that Ar is placed in at least one of the positions indicated by α or β. Converted; R 10d But C3~6 cycloalkyl; substituted with one, two or three halo substituents RuC 1~4 alkyl; or one C 3~6 C substituted with cycloalkyl substituents 1~4 represents alkyl; Het is a bicyclic aromatic heterocycle selected from the group consisting of (a-1) and (a-4). Represents the system; R 3a and R 3d are each independently hydrogen, halo, or -NR 7a R 7b , C 1~4 Alkyl, or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b is hydrogen or C 1~4 represents alkyl; R 4a , R 4d and R 4f each independently represents hydrogen or halo; Q 1 is CR 6a represents; Q 2 is CR 6b represents; Q 8 is CR 6g represents; Q 9 is CR 6h represents; Q 5 is CR 3d represents ;Q 6 represents N;Q 7 is CR 4f represents; R 6a , R 6b , R 6g , and R 6h represents hydrogen); and pharmaceutically acceptable addition salts, and solvates thereof.

[0102] Another embodiment of the present invention is a compound of formula (I) wherein one or more of the following conditions apply: and pharmaceutically acceptable addition salts, and solvates, or other embodiments thereof. With respect to any subgroup thereof described in any of the above states: (i)R 1 and R 2 represents hydrogen; (ii) Y represents -O- or -CH2-; (iii) Z is -X-CR 5a R 5b -or-CR 5e R 5g -CR 5f R 5h - represents; When Y represents -CH2-, Z also represents -CR 5a R 5b -X- can be represented; (iv)R 5a , R 5b , R 5e , R 5f , R 5g , and R 5h represents hydrogen; (v) X represents -O-; (vi) Ar is [ka] where Ar is -NH, -NH-C at the position indicated by α. 1~4 Al Kill, and -NHR 10d optionally substituted with a substituent selected from the group consisting of: wherein Ar is selected from the group consisting of halo and CF3 at the position indicated by β. optionally substituted with a substituent selected from the group consisting of aryl, aryl, aryl- ... provided that Ar is placed in at least one of the positions indicated by α or β. Converted; (vii)R 10d But C 3~6cycloalkyl; one, two or three halo substituents C replaced by 1~4 alkyl; or one C 3~6 substituted with cycloalkyl substituents RuC 1~4 represents alkyl; (viii) Het is a bicyclic ring selected from the group consisting of (a-1) and (a-4). represents an aromatic heterocyclic ring system; (ix)R 3a and R 3d are each independently hydrogen, halo, or -NR 7a R 7b , C 1~4 Alkyl, or -OC 1~4 represents alkyl; (x)R 7a represents hydrogen; (xi)R 7b is hydrogen or C 1~4 represents alkyl; (xii)R 4a , R 4d and R 4f each independently represents hydrogen or halo; ; (xiii)Q 1 is CR 6a represents; (xiv)Q 2 is CR 6b represents; (xv)Q 8 is CR 6g represents; (xvi)Q 9 is CR 6h represents; (xvii)Q 5 is CR 3d represents ;Q 6 represents N;Q 7 is CR 4f represents; (xviii)R 6a , R 6b , R 6g , and R 6h represents hydrogen.

[0103] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 represents hydrogen; R 2 represents hydrogen; Y represents -O- or -CH2-; Z is -X-CR 5a R 5b -or-CR 5e R 5g -CR 5f R 5h - represents; When Y represents -CH2-, Z also represents -CR 5a R 5b -X- can be represented; R 5a , R 5b , R 5e , R 5f , R 5g , and R 5h represents hydrogen; X represents -O-; Ar, [ka] where Ar is -NH, -NH-C at the position indicated by α. 1~4 Al Kill, and -NHR 10d optionally substituted with a substituent selected from the group consisting of: wherein Ar is selected from the group consisting of halo and CF3 at the position indicated by β. optionally substituted with a substituent selected from the group consisting of aryl, aryl, aryl- ... provided that Ar is placed in at least one of the positions indicated by α or β. Converted; R 10d But C 3~6 cycloalkyl; substituted with one, two or three halo substituents RuC 1~4 alkyl; or one C 3~6 C substituted with cycloalkyl substituents 1~4 represents alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R 3a But hydrogen, halo, -NR 7a R 7b , C 1~4 Alkyl, or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b is hydrogen or C 1~4 represents alkyl; R 4a represents hydrogen or halo; Q 1 is CR 6a represents; Q 2 is CR 6b represents; R 6a and R 6b represents hydrogen); and pharmaceutically acceptable addition salts, and solvates thereof.

[0104] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 represents hydrogen; R 2 represents hydrogen; Y represents -O- or -CH2-; Z is -X-CR 5a R 5b -or-CR 5e R 5g -CR 5f R 5h - represents; R 5a , R 5b , R 5e , R 5f , R 5g , and R 5h represents hydrogen; X represents -O-; Ar, [ka] where Ar is -NH, -NH-C at the position indicated by α. 1~4 Al Kill, and -NHR 10d optionally substituted with a substituent selected from the group consisting of: wherein Ar is selected from the group consisting of halo and CF3 at the position indicated by β. optionally substituted with a substituent selected from the group consisting of aryl, aryl, aryl- ... provided that Ar is placed in at least one of the positions indicated by α or β. Converted; R 10d But C 3~6 cycloalkyl; substituted with one, two or three halo substituents RuC 1~4 alkyl; or one C 3~6 C substituted with cycloalkyl substituents 1~4 represents alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R 3a But hydrogen, halo, -NR 7a R 7b , C 1~4 Alkyl, or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b is hydrogen or C 1~4 represents alkyl; R 4a represents hydrogen or halo; Q 1 is CR 6a represents; Q 2 is CR 6b represents; R 6a and R 6b represents hydrogen); and pharmaceutically acceptable addition salts, and solvates thereof.

[0105] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 represents hydrogen; R 2 represents hydrogen; Y represents -O- or -CH2-; Z is -X-CR 5a R 5b -or-CR 5e R 5g -CR 5f R 5h - represents; When Y represents -CH2-, Z also represents -CR 5a R 5b -X- can be represented; R 5a , R 5b , R 5e , R 5f , R 5g , and R 5h represents hydrogen; X represents -O-; Ar, [ka] where Ar is -NH, -NH-C at the position indicated by α. 1~4 Al Kill, and -NHR 10d substituted with a substituent selected from the group consisting of: R 10d But C 3~6 cycloalkyl; or C 3~6 cycloalkyl, and R 14 C substituted with one substituent selected from the group consisting of 1~4 represents alkyl; R 14 is one, two, or three substituents independently selected from the group consisting of halo represents phenyl optionally substituted by a substituent; Het represents a bicyclic aromatic heterocyclic ring system (a-1); R 3a But hydrogen, halo, -NR 7a R 7b, or C 1~4 represents alkyl; R 7a represents hydrogen; R 7b is hydrogen or C 1~4 represents alkyl; R 4a represents hydrogen; Q 1 is CR 6a represents; Q 2 is CR 6b represents; R 6a and R 6b represents hydrogen); and pharmaceutically acceptable addition salts, and solvates thereof.

[0106] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 represents hydrogen; R 2 represents hydrogen; Y represents -O- or -CH2-; Z is -X-CR 5a R 5b -or-CR 5e R 5g -CR 5f R 5h - represents; When Y represents -CH2-, Z also represents -CR 5a R 5b -X- can be represented; R 5a , R 5b , R 5e , R 5f , R 5g , and R 5h represents hydrogen; X represents -O-; Ar, [ka] wherein Ar is optionally substituted with -NH2 at the position indicated by α. ; wherein Ar is selected from the group consisting of halo and CF3 at the position indicated by β. substituted with the substituents Het represents a bicyclic aromatic heterocyclic ring system (a-1); R 3a But hydrogen, halo, -NR 7a R 7b , or C 1~4 represents alkyl; R 7a represents hydrogen; R 7b is hydrogen or C 1~4 represents alkyl; R 4a represents hydrogen; Q 1 is CR 6a represents; Q 2 is CR 6b represents; R 6a and R 6b represents hydrogen); and pharmaceutically acceptable addition salts, and solvates thereof.

[0107] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 represents hydrogen; R 2 represents hydrogen; Y represents -O- or -CH2-; Z is -X-CR 5a R 5b -or-CR 5e R 5g -CR 5f R 5h - represents; When Y represents -CH2-, Z also represents -CR 5a R 5b -X- can be represented; R 5a , R 5b , R 5e , R 5f , R 5g , and R 5h represents hydrogen; X represents -O-; Ar, [ka] wherein Ar is substituted with -NH2 at the position indicated by α; wherein Ar is selected from the group consisting of halo and CF3 at the position indicated by β. substituted with the substituents Het represents a bicyclic aromatic heterocyclic ring system (a-1); R 3a But hydrogen, halo, -NR 7a R 7b , or C 1~4 represents alkyl; R 7a represents hydrogen; R 7b is hydrogen or C 1~4 represents alkyl; R 4a represents hydrogen; Q 1 is CR 6a represents; Q 2 is CR 6b represents; R 6a and R 6b represents hydrogen); and pharmaceutically acceptable addition salts, and solvates thereof.

[0108] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 represents hydrogen; R 2 represents hydrogen; Y represents -O- or -CH2-; Z is -X-CR 5a R 5b -or-CR 5e R 5g -CR 5f R 5h - represents; When Y represents -CH2-, Z also represents -CR 5a R 5b-X- can be represented; R 5a , R 5b , R 5e , R 5f , R 5g , and R 5h represents hydrogen; X represents -O-; Ar, [ka] represents Het represents a bicyclic aromatic heterocyclic ring system (a-1); R 3a But hydrogen, halo, -NR 7a R 7b , or C 1~4 represents alkyl; R 7a represents hydrogen; R 7b is hydrogen or C 1~4 represents alkyl; R 4a represents hydrogen; Q 1 is CR 6a represents; Q 2 is CR 6b represents; R 6a and R 6b represents hydrogen); and pharmaceutically acceptable addition salts, and solvates thereof.

[0109] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; In particular, R 1 and R 2 represents hydrogen; Y represents -CH2- or -O-; Z is -X-CR5a R 5b - or -CH2CH2-; R 5a and R 5b are each independently hydrogen or C 1~4 represents alkyl; X is -O-, -S-, or -NR 11 - represents; R 11 represents hydrogen; Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein one or two ring carbon atoms are replaced by nitrogen atoms; provided that the nitrogen atoms are not adjacent to two fused carbon atoms; If one of them is substituted, a carbonyl group is present in said bicyclic aromatic ring system; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi C(=O)-NH-C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, C 1~4 alkyloxy, and one -NR 10a R 10b Select arbitrarily Selectively substituted C 1~4 one or more independently selected from the group consisting of alkyl is optionally substituted with two substituents; R 10a and R 10b are each independently hydrogen or C 1~4 represents alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R 3a But hydrogen, halo, -NR 7a R 7b , or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b represents hydrogen; R 4aBut hydrogen, halo, -NR 8a R 8b , or C 1~4 represents alkyl; R 8a and R 8b are each independently hydrogen or C 1~4 represents alkyl; Q 1 is CR 6a represents; Q 2 is CR 6b represents; R 6a and R 6b are each independently hydrogen, halogen, C 1~4 Alkyl, -N R 9a R 9b or C substituted with 1, 2 or 3 halo atoms 1~4 Alkyl Represents; R 9a and R 9b are each independently hydrogen or C 1~4 (representing alkyl) New compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0110] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 represents hydrogen; R 2 represents hydrogen; Y represents -CH2-; Z is -CR 5e R 5g -CR 5f R 5h - represents; R 5e , R 5f , R 5g , and R 5h represents hydrogen; Ar represents any one of the following 10-membered bicyclic aromatic ring systems: [ka] Ar, halo, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 alkyl)2, -NHR 10d , -NR 10c R 10d each independently selected from the group consisting of , optionally substituted with 2, 3, or 4 substituents; R 10c and R 10d are each independently, C 3~6 Cycloalkyl; halo, -O H and -OC 1~4 one or two independently selected from the group consisting of alkyl or C substituted with three substituents 3~6 Cycloalkyl; halo, -OH and -OC 1~4 one, two, or three substituted alkyl groups each independently selected from the group consisting of: C substituted with a group 1~4 alkyl; or one C 3~6 Substituted with cycloalkyl substituents C 1~4 represents alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R 3a is hydrogen, -NR 7a R 7b , or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b is hydrogen or C 1~4 represents alkyl; R 4a represents hydrogen; Q 1 is CR 6a represents; Q 2 is CR 6b represents; R 6a and R 6b represents hydrogen); and pharmaceutically acceptable addition salts, and solvates thereof.

[0111] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 represents hydrogen; R 2 represents hydrogen; Y represents -CH2-; Z is -CR 5e R 5g -CR 5f R 5h - represents; R 5e , R 5f , R 5g , and R 5h represents hydrogen; Ar, [ka] represents Ar, halo, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 alkyl)2, -NHR 10d one, two, three, or four independently selected from the group consisting of optionally substituted with a substituent of R 10d is substituted with one, two or three halo substituents 1~4 alkyl; also is one C 3~6 C substituted with cycloalkyl substituents 1~4 represents alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R 3a is hydrogen, -NR 7a R 7b , or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b is hydrogen or C 1~4 represents alkyl; R 4a represents hydrogen; Q 1 is CR 6a represents; Q 2 is CR 6b represents; R 6a and R 6b represents hydrogen); and pharmaceutically acceptable addition salts, and solvates thereof.

[0112] Another embodiment of the present invention is a compound of formula (I) wherein one or more of the following conditions apply: and pharmaceutically acceptable addition salts, and solvates, or other embodiments thereof. With respect to any subgroup thereof described in any of the above states: (i)R 1 represents hydrogen; R 2 represents hydrogen; (ii) Y represents -CH2-; (iii) Z is -CR 5e R 5g -CR 5f R 5h - represents; (iv)R 5e , R 5f , R 5g , and R 5h represents hydrogen; (v) Ar is [ka] represents Ar, halo, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 alkyl)2, -NHR 10d one, two, three, or four independently selected from the group consisting of optionally substituted with a substituent of (vi)R 10d is substituted with one, two or three halo substituents1~4 Archi or one C 3~6 C substituted with cycloalkyl substituents 1~4 represents alkyl; (vii) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) death; (viii)R 3a is hydrogen, -NR 7a R 7b , or -OC 1~4 Represents alkyl death; (ix)R 7a represents hydrogen; R 7b is hydrogen or C 1~4 represents alkyl; (x)R 4a represents hydrogen; (xi)Q 1 is CR 6a represents; Q 2 is CR 6b represents; (xii)R 6a and R 6b represents hydrogen.

[0113] Another embodiment of the present invention is a compound of formula (I) wherein one or more of the following conditions apply: and pharmaceutically acceptable addition salts, and solvates, or other embodiments thereof. With respect to any subgroup thereof described in any of the above states: (i)R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; In particular, R 1 and R 2 represents hydrogen; (ii) Y represents -CH2- or -O-; (iii) Z is -X-CR 5a R 5b- or -CH2CH2-; (iv)R 5a and R 5b are each independently hydrogen or C 1~4 Represents alkyl death; (v) X is -O-, -S-, or -NR 11 - represents; (vi)R 11 represents hydrogen; (vii) Ar is halo, -OH, -NH, -NH-C 1~4 Alkyl, -N(C1 ~4 alkyl), cyano, -CF, -C(=O)-NH-C 1~4 Alkyl, -C( =O)-C 1~4 Alkyl, C 1~4 alkyloxy, and one -NR 10a R 10 b C optionally substituted with 1~4 alkyl, optionally substituted with one or two substituents selected from the group consisting of: (viii)R 10a and R 10b are each independently hydrogen or C 1~4 Al represents a kill; (ix) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1): ; (x)R 3a But hydrogen, halo, -NR 7a R 7b , or -OC 1~4 Represents alkyl death; (xi)R 7a represents hydrogen; R 7b represents hydrogen; (xii)R 4a But hydrogen, halo, -NR 8a R 8b , or C 1~4 Represents alkyl ; (xiii)R 8a and R 8b are each independently hydrogen or C 1~4 Alkyl represents; (xiv)Q 1 is CR 6a represents; (xv)Q 2 is CR 6b represents; (xvi)R 6a and R 6b are each independently hydrogen, halogen, C 1~4 Al Kill, -NR 9a R 9b or C substituted with 1, 2 or 3 halo atoms 1~4 represents alkyl; (xvii)R 9a and R 9b are each independently hydrogen or C 1~4 Alkyl represent.

[0114] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; In particular, R 1 and R 2 represents hydrogen; Y represents -O-; Z is -X-CR 5a R 5b - represents; R 5a and R 5b are each independently hydrogen or C 1~4 represents alkyl; X is -O-, -S-, or -NR 11 - represents; R 11 represents hydrogen; Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein one or two ring carbon atoms are replaced by nitrogen atoms; provided that the nitrogen atoms are not adjacent to two fused carbon atoms; If one of them is substituted, a carbonyl group is present in said bicyclic aromatic ring system; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi C(=O)-NH-C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, C 1~4 alkyloxy, and one -NR 10a R 10b Select arbitrarily Selectively substituted C 1~4 one or more independently selected from the group consisting of alkyl is optionally substituted with two substituents; R 10a and R 10b are each independently hydrogen or C 1~4 represents alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R 3a But hydrogen, halo, -NR 7a R 7b , or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b represents hydrogen; R 4a But hydrogen, halo, -NR 8a R 8b , or C 1~4 represents alkyl; R 8a and R 8b are each independently hydrogen or C 1~4 represents alkyl; Q 1 is CR 6a represents; Q2 is CR 6b represents; R 6a and R 6b are each independently hydrogen, halogen, C 1~4 Alkyl, -N R 9a R 9b or C substituted with 1, 2 or 3 halo atoms 1~4 Alkyl Represents; R 9a and R 9b are each independently hydrogen or C 1~4 (representing alkyl) New compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0115] Another embodiment of the present invention is a compound of formula (I) wherein one or more of the following conditions apply: and pharmaceutically acceptable addition salts, and solvates, or other embodiments thereof. With respect to any subgroup thereof described in any of the above states: (i)R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; In particular, R 1 and R 2 represents hydrogen; (ii) Y represents -O-; (iii) Z is -X-CR 5a R 5b - represents; (iv)R 5a and R 5b are each independently hydrogen or C 1~4 Represents alkyl death; (v) X is -O-, -S-, or -NR 11 - represents; (vi)R 11 represents hydrogen; (vii) Ar is halo, -OH, -NH, -NH-C 1~4 Alkyl, -N(C1 ~4 alkyl), cyano, -CF, -C(=O)-NH-C 1~4 Alkyl, -C( =O)-C 1~4 Alkyl, C 1~4 alkyloxy, and one -NR 10a R 10 b C optionally substituted with 1~4 alkyl, optionally substituted with one or two substituents selected from the group consisting of: (viii)R 10a and R 10b are each independently hydrogen or C 1~4 Al represents a kill; (ix) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1): ; (x)R 3a But hydrogen, halo, -NR 7a R 7b , or -OC 1~4 Represents alkyl death; (xi)R 7a represents hydrogen; R 7b represents hydrogen; (xii)R 4a But hydrogen, halo, -NR 8a R 8b , or C 1~4 Represents alkyl ; (xiii)R 8a and R 8b are each independently hydrogen or C 1~4 Alkyl represents; (xiv)Q 1 is CR 6a represents; (xv)Q 2 is CR 6b represents; (xvi)R 6a and R 6b are each independently hydrogen, halogen, C 1~4 Al Kill, -NR 9a R 9b or C substituted with 1, 2 or 3 halo atoms 1~4 represents alkyl; (xvii)R 9a and R 9b are each independently hydrogen or C 1~4 Alkyl Represents.

[0116] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; In particular, R 1 and R 2 represents hydrogen; Y represents -CH2- or -O-; Z is -X-CR 5a R 5b - or -CH2CH2-, R 5a and R 5b are each independently hydrogen or C 1~4 represents alkyl; X is -O-, -S-, or -NR 11 - represents; R 11 represents hydrogen; Ar, [ka] In particular, Ar represents [ka] represents; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi C(=O)-NH-C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, C 1~4 alkyloxy, and one -NR 10a R 10b Select arbitrarily Selectively substituted C 1~4 one or more independently selected from the group consisting of alkyl is optionally substituted with two substituents; R 10a and R 10b are each independently hydrogen or C 1~4 represents alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R 3a But hydrogen, halo, -NR 7a R 7b , or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b represents hydrogen; R 4a But hydrogen, halo, -NR 8a R 8b , or C 1~4 represents alkyl; R 8a and R 8b are each independently hydrogen or C 1~4 represents alkyl; Q 1 is CR 6a represents; Q 2 is CR 6b represents; R 6a and R 6b are each independently hydrogen, halogen, C 1~4 Alkyl, -N R 9a R 9bor C substituted with 1, 2 or 3 halo atoms 1~4 Alkyl Represents; R 9a and R 9b are each independently hydrogen or C 1~4 (representing alkyl) New compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0117] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; In particular, R 1 and R 2 represents hydrogen; Y represents -O-; Z is -X-CR 5a R 5b - represents; R 5a and R 5b are each independently hydrogen or C 1~4 represents alkyl; X is -O-, -S-, or -NR 11 - represents; R 11 represents hydrogen; Ar, [ka] In particular, Ar represents [ka] represents; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi C(=O)-NH-C 1~4Alkyl, -C(=O)-C 1~4 Alkyl, C 1~4 alkyloxy, and one -NR 10a R 10b Select arbitrarily Selectively substituted C 1~4 one or more independently selected from the group consisting of alkyl is optionally substituted with two substituents; R 10a and R 10b are each independently hydrogen or C 1~4 represents alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R 3a But hydrogen, halo, -NR 7a R 7b , or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b represents hydrogen; R 4a But hydrogen, halo, -NR 8a R 8b , or C 1~4 represents alkyl; R 8a and R 8b are each independently hydrogen or C 1~4 represents alkyl; Q 1 is CR 6a represents; Q 2 is CR 6b represents; R 6a and R 6b are each independently hydrogen, halogen, C 1~4 Alkyl, -N R 9a R 9b or C substituted with 1, 2 or 3 halo atoms 1~4 Alkyl Represents; R 9a and R 9bare each independently hydrogen or C 1~4 (representing alkyl) New compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0118] Another embodiment of the present invention is a compound of formula (I) wherein one or more of the following conditions apply: and pharmaceutically acceptable addition salts, and solvates, or other embodiments thereof. With respect to any subgroup thereof described in any of the above states: (i)R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; In particular, R 1 and R 2 represents hydrogen; (ii) Y represents -O-; (iii) Z is -X-CR 5a R 5b - represents; (iv)R 5a and R 5b are each independently hydrogen or C 1~4 Represents alkyl death; (v) X is -O-, -S-, or -NR 11 - represents; (vi)R 11 represents hydrogen; (vii) Ar is [ka] In particular, Ar represents [ka] represents; (viii) Ar is halo, -OH, -NH, -NH-C 1~4 Alkyl, -N(C 1~4 alkyl), cyano, -CF, -C(=O)-NH-C 1~4 Alkyl, -C (=O)-C 1~4 Alkyl, C 1~4 alkyloxy, and one -NR 10a R 1 0b C optionally substituted with 1~4 alkyl, optionally substituted with one or two substituents selected from the group consisting of: (ix)R 10a and R 10b are each independently hydrogen or C 1~4 Alkyl represents; (x) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); (xi)R 3a But hydrogen, halo, -NR 7a R 7b , or -OC 1~4 Alkyl Represents; (xii)R 7a represents hydrogen; R 7b represents hydrogen; (xiii)R 4a But hydrogen, halo, -NR 8a R 8b , or C 1~4 Represents alkyl death; (xiv)R 8a and R 8b are each independently hydrogen or C 1~4 Alkyl Represents; (xv)Q 1 is CR 6a represents; (xvi)Q 2 is CR 6b represents; (xvii)R 6a and R 6b are each independently hydrogen, halogen, C 1~4 a Lukil, -NR 9a R 9b or C substituted with 1, 2 or 3 halo atoms 1~ 4 represents alkyl; (xviii)R 9a and R 9b are each independently hydrogen or C 1~4 Archi Represents a rule.

[0119] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; In particular, R 1 and R 2 represents hydrogen; Y represents -O- or -CH2-; Z represents -X-CR 5a R 5b - or -CH2 represents CH2-; R 5a and R 5b represents hydrogen; X represents -O-; R 11 represents hydrogen; Ar, [ka] represents; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi one or more independently selected from the group consisting of -CF3, -CF4, -CF6, -CF7, -CF8, -CF9 ... optionally substituted with two substituents; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R 3a Ga-NR 7a R7b represents; R 7a represents hydrogen; R 7b represents hydrogen; R 4a represents hydrogen; Q 1 is CR 6a represents ;Q 2 is CR 6b represents;R 6a and R 6b represents hydrogen) Novel compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0120] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; In particular, R 1 and R 2 represents hydrogen; Y represents -O- or -CH2-; Z represents -X-CR 5a R 5b - or -CH2 represents CH2-; R 5a and R 5b represents hydrogen; X represents -O-; R 11 represents hydrogen; Ar, [ka] represents; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi optionally with one substituent selected from the group consisting of -C1, -C2, -C3, -C4, -C6, -C7, -C8, -C9, -C10, -C11, -C12, -C13, -C14, -C15, -C16, -C17, -C18, -C19 ...20, -C21, -C22, -C23, -C24, Replaced; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R 3a Ga-NR 7a R 7b represents; R 7a represents hydrogen; R 7b represents hydrogen; R 4a represents hydrogen; Q 1 is CR 6a represents ;Q 2 is CR 6b represents;R 6a and R 6b represents hydrogen) Novel compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0121] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; In particular, R 1 and R 2 represents hydrogen; Y represents -O-; Z represents -X-CR 5a R 5b - represents; R 5a and R 5b represents hydrogen; X represents -O-; R 11 represents hydrogen; Ar, [ka] represents; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi one or more independently selected from the group consisting of -CF3, -CF4, -CF6, -CF7, -CF8, -CF9 ... optionally substituted with two substituents; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R 3a Ga-NR 7a R 7b represents; R 7a represents hydrogen; R 7b represents hydrogen; R 4a represents hydrogen; Q 1 is CR 6a represents ;Q 2 is CR 6b represents;R 6a and R 6b represents hydrogen) Novel compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0122] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; In particular, R 1 and R 2 represents hydrogen; Y represents -O-; Z represents -X-CR 5a R 5b - represents; R 5a and R 5b represents hydrogen; X represents -O-; R 11 represents hydrogen; Ar, [ka] represents; Ar is halo, -OH, -NH2, -NH-C1~4 Alkyl, -N(C 1~4 Archi optionally with one substituent selected from the group consisting of -C1, -C2, -C3, -C4, -C6, -C7, -C8, -C9, -C10, -C11, -C12, -C13, -C14, -C15, -C16, -C17, -C18, -C19 ...20, -C21, -C22, -C23, -C24, Replaced; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R 3a Ga-NR 7a R 7b represents; R 7a represents hydrogen; R 7b represents hydrogen; R 4a represents hydrogen; Q 1 is CR 6a represents ;Q 2 is CR 6b represents;R 6a and R 6b represents hydrogen) Novel compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0123] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; In particular, R 1 and R 2 represents hydrogen; Y represents -O- or -CH2-; Z represents -X-CR 5a R 5b - or -CH2 represents CH2-; R 5a and R 5b represents hydrogen; X represents -O-; R 11 represents hydrogen; Ar, [ka] represents; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R 3a Ga-NR 7a R 7b represents; R 7a represents hydrogen; R 7b represents hydrogen; R 4a represents hydrogen; Q 1 is CR 6a represents ;Q 2 is CR 6b represents;R 6a and R 6b represents hydrogen) Novel compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0124] In one embodiment, the present invention provides a compound of formula (I), wherein: R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; In particular, R 1 and R 2 represents hydrogen; Y represents -O-; Z represents -X-CR 5a R 5b - represents; R 5a and R 5b represents hydrogen; X represents -O-; R 11 represents hydrogen; Ar, [ka] represents; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R3a Ga-NR 7a R 7b represents; R 7a represents hydrogen; R 7b represents hydrogen; R 4a represents hydrogen; Q 1 is CR 6a represents ;Q 2 is CR 6b represents;R 6a and R 6b represents hydrogen) Novel compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0125] Another embodiment of the present invention is a compound of formula (I) wherein one or more of the following conditions apply: and pharmaceutically acceptable addition salts, and solvates, or other embodiments thereof. With respect to any subgroup thereof described in any of the above states: (i)R 1 is hydrogen or -C(=O)-C 1~4 represents alkyl; R 2 is hydrogen or -C(=O)-C 1~4 represents alkyl; In particular, R 1 and R 2 represents hydrogen; (ii) Y represents -O-; (iii) Z is -X-CR 5a R 5b - represents; (iv)R 5a and R 5b represents hydrogen; (v) X represents -O-; (vi)R 11 represents hydrogen; (vii) Ar is [ka] represents; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi one or more independently selected from the group consisting of -CF3, -CF4, -CF6, -CF7, -CF8, -CF9 ... Optionally substituted with two substituents; in particular, Ar is halo, -OH, -NH, -NH -C 1~4 Alkyl, -N(C 1~4 The group consisting of alkyl), cyano, and -CF optionally substituted with one substituent selected from More particularly, Ar is [ka] and even more particularly, Ar represents [ka] represents; (ix) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1): ; (x)R 3a Ga-NR 7a R 7b represents; (xi)R 7a represents hydrogen; R 7b represents hydrogen; (xii)R 4a represents hydrogen; (xiii)Q 1 is CR 6a represents; (xiv)Q 2 is CR 6b represents; (xv)R 6a and R 6b represents hydrogen.

[0126] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 1 and R 2 represents hydrogen, for compounds of formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any of the other embodiments. It relates to any subgroup thereof described.

[0127] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 1 is -C(=O)-C 1~4 R represents alkyl; 2 is -C(=O)-C 1~4 The compounds of formula (I) and their pharmaceutically acceptable salts thereof, and the like. Concerning subgroups.

[0128] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: R 1 and R 2 represents hydrogen; Het represents (a-1); Q 1 represents CH;Q 2 represents CH; Ar is optionally substituted according to any of the other embodiments [ka] and pharmaceutically acceptable addition salts, solvates, or the like, of formula (I) which represent or any subgroup thereof as described in any of the other embodiments.

[0129] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: R 1 and R 2 represents hydrogen; Het represents (a-1); Q 1 represents CH;Q 2 represents CH; Ar, [ka] where Ar is halo, -NH, -NH-C 1~4 Alkyl, -N(C 1~4 alkyl)2, -NHR 10d , -NR 10c R 10d Independently from the group consisting of substituted with one, two, three or four selected substituents; R 10c and R 10d are each independently one, two or three halo substituents; Replaced C 1~4 alkyl; or one C 3~6 substituted with cycloalkyl substituents C 1~4

[0023] Compounds of formula (I) and pharmaceutically acceptable addition salts thereof, wherein R represents an alkyl group; and solvates, or any subgroup thereof as described in any of the other embodiments.

[0130] In one embodiment, the present invention provides compounds of formula (I) wherein Y represents -O-, as well as pharmaceutical compositions thereof. and physiologically acceptable addition salts, and solvates thereof, or any of the other embodiments. It relates to any subgroup of it.

[0131] In one embodiment, the present invention provides compounds wherein Y represents -CH2- or -CF2-; in particular, Y represents -CH2- and pharmaceutically acceptable addition salts thereof, and solvates, or any subgroup thereof as described in any of the other embodiments.

[0132] In one embodiment, the present invention provides a method for treating a cancer 1 and Q 2 At most one of these represents N, I) and pharmaceutically acceptable addition salts, solvates, or other embodiments thereof. The present invention relates to any subgroup thereof as described in any of the aspects.

[0133] In one embodiment, the present invention provides a method for treating a cancer 1 is CR 6a represents ;Q 2 is CR 6b Represents; especially , Q 1 represents CH;Q 2 represents CH as well as pharmaceutically acceptable salts thereof. and the addition salts, and solvates thereof, or any portion thereof as described in any of the other embodiments. Concerning subgroups.

[0134] In one embodiment, the present invention provides a compound according to the present invention, wherein Het represents (a-1); Q 1 is CR 6a represents; Q 2 is CR 6b In particular, Q 1 represents CH;Q 2 represents CH and pharmaceutically acceptable addition salts, and solvates thereof, or any of the other embodiments. It relates to any subgroup thereof described above.

[0135] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: Q 5 is CR 3d represents ;Q 6 represents N;Q 7 is CR 4f represents; or Q 5 is CR 3d represents ;Q 6 is CR 4e represents ;Q 7 represents N; or Q 5 represents N;Q 6 is CR 4e represents ;Q 7 is CR 4f represents; or Q 5 represents N;Q 6 is CR 4e represents ;Q 7represents N, and pharmaceutically acceptable addition salts, and solvates thereof, or as described in any of the other embodiments. for any subgroup of it that is

[0136] In one embodiment, the present invention provides a compound in which Het is selected from the group consisting of (a-1), (a-2) and (a-4). and compounds of formula (I) and its Pharmaceutically acceptable addition salts, and solvates, or any of the compounds described in any of the other embodiments. any subgroup of it.

[0137] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 1 and R 2 represents hydrogen; Y represents -O-, Compounds of formula (I) and pharmaceutically acceptable addition salts, solvates, or other compounds thereof Any subgroup thereof as described in any of the embodiments.

[0138] In one embodiment, the present invention provides a compound in which Het is selected from the group consisting of (a-1), (a-2) and (a-3). and compounds of formula (I) and its Pharmaceutically acceptable addition salts, and solvates, or any of the compounds described in any of the other embodiments. any subgroup of it.

[0139] In one embodiment, the present invention provides a compound wherein Het is selected from the group consisting of (a-1) and (a-2): Compounds of formula (I) and their pharmaceutically acceptable salts, and the like. Concerning subgroups.

[0140] In one embodiment, the present invention provides a compound wherein Het is selected from the group consisting of (a-1) and (a-4). Compounds of formula (I) and their pharmaceutically acceptable salts, and the like. Concerning subgroups.

[0141] In one embodiment, the present invention provides a compound in which Het represents a bicyclic heteroaromatic ring system of formula (a-1): a compound of formula (I) and its pharmaceutically acceptable addition salts and solvates, or Any subgroup thereof as described in any of the other embodiments.

[0142] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 1 and R 2 represents hydrogen; Y represents -O-; H Compounds of formula (I) and their medicaments, wherein et represents a bicyclic aromatic heterocyclic ring system of formula (a-1): and physiologically acceptable addition salts, and solvates thereof, or any of the other embodiments. It relates to any subgroup of it.

[0143] In one embodiment, the present invention provides an optionally substituted aryl group wherein Ar is a fused 6-membered ring. and wherein one or two ring carbon atoms are bonded to a nitrogen atom. with the proviso that the nitrogen atom does not replace one of the two fused carbon atoms; I) and pharmaceutically acceptable addition salts, solvates, or other embodiments thereof. The present invention relates to any subgroup thereof as described in any of the aspects.

[0144] In one embodiment, the present invention provides a method for treating a cancer, comprising administering to a patient a cancer treatment comprising administering to said ... Compounds of formula (I) and their pharmaceutically acceptable salts, optionally substituted with one or two substituents, and any of the acceptable addition salts, and solvates thereof, as described in any of the other embodiments. is related to a subgroup of

[0145] In one embodiment, the present invention relates to a method for treating a cancer, comprising administering to a subject ... Compounds of formula (I) and pharmaceutically acceptable salts thereof, optionally substituted with substituents. salts, and solvates, or any subgroup thereof as described in any of the other embodiments. Regarding.

[0146] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: R 3a , R 3c , R 3b represents hydrogen; R 4a , R 4c , R 4b is hydrogen, halo, or C 1~4 Represents alkyl; in particular, R 4 a , R 4c , R 4b But halo, or C 1~4 Compounds of formula (I) and and pharmaceutically acceptable addition salts, and solvates thereof, or any of the other embodiments. Any subgroup of the

[0147] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: R 3a , R 3c , R 3b , R 3d and R 3e represents hydrogen; R 4a , R 4c , R 4b , R 4d , R 4e , R 4f and R 4g But hydrogen, halo, and is C 1~4 Represents alkyl; in particular, R 4a , R 4c , R 4b , R 4d, R 4e , R 4f oh Yobi R 4g But halo, or C 1~4 The compound of formula (I) and its medicament and physiologically acceptable addition salts, and solvates thereof, or any of the other embodiments. It relates to any subgroup of it.

[0148] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: R 3a , R 3c , R 3b But hydrogen, halo, -NR 7a R 7b , or -OC 1~4 a Represents rukil; especially R 3a , R 3c , R 3b But, halo, -NR 7a R 7b , or -O -C 1~4 represents alkyl; R 4a , R 4c , R 4b represents hydrogen as well as pharmaceutically acceptable salts thereof. and the addition salts, and solvates thereof, or any portion thereof as described in any of the other embodiments. Concerning subgroups.

[0149] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: R 3a , R 3c , R 3b , R 3d and R 3e But hydrogen, halo, -NR 7a R 7b ,Ma TAHA-OC 1~4 Represents alkyl; in particular, R 3a , R 3c , R 3b , R 3d and R 3 e But, halo, -NR7a R 7b , or -OC 1~4 represents alkyl; R 4a , R 4c , R 4b , R 4d , R 4e , R 4f and R 4g represents hydrogen, and pharmaceutically acceptable addition salts, and solvates, or other embodiments thereof. The present invention relates to any subgroup thereof described in any of the above aspects.

[0150] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 4a , R 4c , R 4b If is different from hydrogen, R 3a , R 3c , R 3b represents hydrogen, as well as pharmaceutically acceptable adducts thereof. With respect to salts, and solvates, or any subgroup thereof as described in any of the other embodiments. do.

[0151] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 4a , R 4c , R 4b , R 4d , R 4e , R 4f , R 4g If is different from hydrogen, R 3a , R 3c , R 3b , R 3d , R 3e represents hydrogen, Compounds of formula (I) and pharmaceutically acceptable addition salts, solvates, or other compounds thereof Any subgroup thereof as described in any of the embodiments.

[0152] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 3a , R 3c , R 3bIf is different from hydrogen, R 4a , R 4c , R 4b represents hydrogen, as well as pharmaceutically acceptable adducts thereof. With respect to salts, and solvates, or any subgroup thereof as described in any of the other embodiments. do.

[0153] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 3a , R 3c , R 3b , R 3d , R 3e is different from hydrogen If so, R 4a , R 4c , R 4b , R 4d , R 4e , R 4f , R 4g represents hydrogen, Compounds of formula (I) and pharmaceutically acceptable addition salts, solvates, or other compounds thereof Any subgroup thereof as described in any of the embodiments.

[0154] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings; [ka] wherein at least one ring carbon atom of ring B is replaced with a nitrogen atom; wherein optionally one further ring carbon atom of ring A or ring B is replaced with a nitrogen atom provided that if a nitrogen atom replaces one of the two fused carbon atoms, a aryl group is present in said bicyclic aromatic ring system; A compound of formula (I) in which Ar is optionally substituted according to any of the other embodiments. and pharmaceutically acceptable addition salts, and solvates thereof, or any of the other embodiments. This also relates to any subgroup thereof described anywhere in the specification.

[0155] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings; [ka] wherein at least one ring carbon atom of ring B is replaced with a nitrogen atom; wherein optionally one further ring carbon atom of ring A or ring B is replaced with a nitrogen atom provided that if a nitrogen atom replaces one of the two fused carbon atoms, a aryl group is present in said bicyclic aromatic ring system; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi Le)2, -NHR 10d , -NR 10c R 10d , cyano, -CF3, -C(=O)-N H2, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, C1 ~4 Alkyloxy, -C(=O)-OC 1~4 Alkyl, C 3~6 cycloalkyl, C 2~6 Alkenyl, one C 1~4 C substituted with alkyloxy 1~4 Alkyl, and one -NR 10a R 10b C optionally substituted with 1~4 alkyl and optionally substituted with 1, 2, 3, or 4 substituents each independently selected from Converted; In particular, Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 alkyl), cyano, -CF, -C(=O)-NH-C 1~4 Alkyl, -C(=O )-C 1~4 Alkyl, C 1~4 alkyloxy, and one -NR 10a R 10b in Optionally substituted C 1~4 1 independently selected from the group consisting of alkyl Compounds of formula (I) optionally substituted with one, two, three or four substituents; and pharmaceutically acceptable addition salts, and solvates thereof, or any of the other embodiments. Any subgroup of the

[0156] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings having the structure: [ka] wherein optionally one further ring carbon atom of ring A or ring B is replaced with a nitrogen atom provided that if a nitrogen atom replaces one of the two fused carbon atoms, a aryl group is present in said bicyclic aromatic ring system; A compound of formula (I) in which Ar is optionally substituted according to any of the other embodiments. and pharmaceutically acceptable addition salts, and solvates thereof, or any of the other embodiments. This also relates to any subgroup thereof described anywhere in the specification.

[0157] [ka] but the following ring system: [ka] It will be clear that the present invention encompasses any one of the following:

[0158] In one embodiment, the present invention provides a compound wherein Ar is [ka] wherein each Ar is optionally selected from the group consisting of optionally substituted compounds of formula (I) and pharmaceutically acceptable addition salts thereof, and solvates, or any subgroup thereof as described in any of the other embodiments.

[0159] In one embodiment, the present invention provides a compound wherein Ar is [ka] wherein each Ar is optionally selected from the group consisting of optionally substituted compounds of formula (I) and pharmaceutically acceptable addition salts thereof, and solvates, or any subgroup thereof as described in any of the other embodiments.

[0160] In one embodiment, the present invention provides a compound wherein Ar is [ka] wherein each Ar is optionally selected from the group consisting of optionally substituted compounds of formula (I) and pharmaceutically acceptable addition salts thereof, and solvates, or any subgroup thereof as described in any of the other embodiments.

[0161] In one embodiment, the present invention provides a compound wherein Ar is [ka] wherein each Ar is optionally selected from the group consisting of optionally substituted compounds of formula (I) and pharmaceutically acceptable addition salts thereof, and solvates, or any subgroup thereof as described in any of the other embodiments.

[0162] In one embodiment, the present invention provides a compound wherein Ar is [ka] wherein each Ar is optionally selected from the group consisting of optionally substituted compounds of formula (I) and pharmaceutically acceptable addition salts thereof, and solvates, or any subgroup thereof as described in any of the other embodiments.

[0163] In one embodiment, the present invention provides a compound wherein Ar is [ka] where Ar is optionally substituted according to any of the other embodiments. , compounds of formula (I) and pharmaceutically acceptable addition salts, solvates, or other any subgroup thereof as described in any of the embodiments.

[0164] In one embodiment, the present invention provides a compound wherein Ar is [ka] where Ar is optionally substituted according to any of the other embodiments. Compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof, relates to any subgroup thereof as described in any of the other embodiments.

[0165] In one embodiment, the present invention provides a compound wherein Ar is [ka] where Ar is halo, -NH, -NH-C 1~4 Alkyl, -N(C 1~4 alkyl)2, -NHR 10d , -NR 10c R 10d Independently from the group consisting of Compounds of formula (I) substituted with one, two, three or four selected substituents; and pharmaceutically acceptable addition salts, and solvates thereof, or any of the other embodiments. Any subgroup of the

[0166] In one embodiment, the present invention provides a compound wherein Ar is [ka] where Ar is -NH, -NH-C 1~4 Alkyl, -N(C 1~4 Archi Le)2, -NHR 10d , -NR 10c R 10d one substituent selected from the group consisting of substituted with; optionally substituted with halo substituents; R 10c and R 10d are each independently one, two or three halo substituents; Replaced C 1~4 alkyl; or one C 3~6 substituted with cycloalkyl substituents C 1~4

[0023] Compounds of formula (I) and pharmaceutically acceptable addition salts thereof, wherein R represents an alkyl group; and solvates, or any subgroup thereof as described in any of the other embodiments.

[0167] In one embodiment, the present invention provides a compound wherein Ar is [ka] where Ar is -NH, -NH-C at the position indicated by α. 1~4 Al Kill, -N(C 1~4 alkyl)2, -NHR 10d , -NR 10c R 10d A group consisting of substituted with a substituent selected from: wherein Ar is optionally substituted with a halo substituent at the position indicated by β; Compounds of formula (I) and their pharmaceutically acceptable addition salts, solvates, or other Any subgroup thereof as described in any of the embodiments.

[0168] In one embodiment, the present invention provides a compound wherein Ar is [ka] where Ar is -NH, -NH-C at the position indicated by α. 1~4 Al Kill, -N(C 1~4 alkyl)2, -NHR 10d , -NR 10c R 10d A group consisting of substituted with a substituent selected from: wherein Ar is optionally substituted with a halo substituent at the position indicated by β; R 10c and R 10d are each independently one, two or three halo substituents; Replaced C 1~4 alkyl; or one C 3~6 substituted with cycloalkyl substituents C 1~4

[0023] Compounds of formula (I) and pharmaceutically acceptable addition salts thereof, wherein R represents an alkyl group; and solvates, or any subgroup thereof as described in any of the other embodiments.

[0169] In one embodiment, the present invention provides a compound wherein Ar is [ka] where Ar, at the position indicated by β, is a halo substituent; in particular chloro or Bromo; more particularly, compounds of formula (I) and pharmaceutically acceptable salts thereof that are substituted with bromo; and the addition salts, and solvates thereof, or any portion thereof as described in any of the other embodiments. Concerning subgroups.

[0170] In one embodiment, the present invention provides a compound according to the present invention, wherein Het represents (a-1); Q 1 is CR 6a represents; Q 2 is CR 6b Ar represents [ka] where Ar, at the position indicated by β, is a halo substituent; in particular chloro or Bromo; more particularly, compounds of formula (I) and pharmaceutically acceptable salts thereof that are substituted with bromo; and the addition salts, and solvates thereof, or any portion thereof as described in any of the other embodiments. Concerning subgroups.

[0171] In one embodiment, the present invention provides a method for treating a cancer cell comprising administering to a patient a cancer treatment, comprising administering to a patient a cancer treatment, 1~4 Alkyl, -N (C 1~4 alkyl)2, -NHR 10d , -NR 10c R 10d Selected from the group consisting of wherein Ar is substituted with one substituent as defined above; Compounds of formula (I) optionally substituted with another substituent selected from the list of groups and pharmaceutically acceptable addition salts, and solvates thereof, or any of the other embodiments. It relates to any subgroup thereof described.

[0172] In one embodiment, the present invention provides a method for treating a cancer, wherein Ar is optionally according to any of the other embodiments. Selectively replaced [ka] and pharmaceutically acceptable addition salts, solvates, or the like, of formula (I) which represent or any subgroup thereof as described in any of the other embodiments.

[0173] In one embodiment, the present invention provides a method for producing a polymerizable composition comprising the steps of: 1~4 Alkyl, -N(C 1~4 alkyl), cyano, -CF, -C(=O)-NH-C ~4 Alkyl, C 1~4 Alkyloxy, and C 1~4 Each of the groups consisting of alkyl optionally substituted with 1, 2, or 3 independently selected substituents; In particular, halo, -NH2, -NH-C 1~4 Alkyl, Cyano, -CF3, C 1~4 Al Kiloxi, and C 1~4 each independently selected from the group consisting of alkyl, optionally substituted with two or three substituents; More particularly, one, two, or more independently selected from the group consisting of halo, or -CF3. optionally substituted with one or three substituents; More particularly, optionally substituted with one or two halo substituents; More particularly, substituted with one or two halo substituents; Even more particularly, substituted with one halo substituent; Most particularly, substituted with one chloro substituent [ka] and pharmaceutically acceptable addition salts, solvates, or the like, of formula (I) which represent or any subgroup thereof as described in any of the other embodiments.

[0174] In one embodiment, the present invention provides a method for treating a cancer, wherein Ar is optionally according to any of the other embodiments. Selectively replaced [ka] and pharmaceutically acceptable addition salts, solvates, or the like, of formula (I) which represent or any subgroup thereof as described in any of the other embodiments.

[0175] In one embodiment, the present invention provides a method for producing a polymerizable composition comprising the steps of: 1~4 Alkyl, -N(C 1~4 alkyl), cyano, -CF, -C(=O)-NH-C ~4 Alkyl, C 1~4 Alkyloxy, and C 1~4 Each of the groups consisting of alkyl optionally substituted with 1, 2, or 3 independently selected substituents; In particular, halo, -NH2, -NH-C 1~4 Alkyl, Cyano, -CF3, C 1~4 Al Kiloxi, and C 1~4 each independently selected from the group consisting of alkyl, optionally substituted with two or three substituents; More particularly, one, two, or more independently selected from the group consisting of halo, or -CF3. optionally substituted with one or three substituents; More particularly, optionally substituted with one or two halo substituents; More particularly, substituted with one or two halo substituents; Even more particularly, substituted with one halo substituent; Most particularly, substituted with one chloro substituent [ka] and pharmaceutically acceptable addition salts, solvates, or the like, of formula (I) which represent or any subgroup thereof as described in any of the other embodiments.

[0176] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: Het represents (a-1); Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi C(=O)-NH-C 1~4 Alkyl, C 1~4 Alkyl Oxy, and C 1~4 one or two independently selected from the group consisting of alkyl or optionally substituted with three substituents; In particular, halo, -NH2, -NH-C 1~4 Alkyl, Cyano, -CF3, C 1~4 Al Kiloxi, and C 1~4 each independently selected from the group consisting of alkyl, optionally substituted with two or three substituents; More particularly, one, two, or more independently selected from the group consisting of halo, or -CF3. optionally substituted with one or three substituents; More particularly, optionally substituted with one or two halo substituents; More particularly, substituted with one or two halo substituents; Even more particularly, substituted with one halo substituent; Most particularly, substituted with one chloro substituent [ka] and pharmaceutically acceptable addition salts, solvates, or the like, of formula (I) which represent or any subgroup thereof as described in any of the other embodiments.

[0177] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: Het represents (a-1); Ar, [ka] represents; In particular, Ar [ka] represents; More particularly, Ar is [ka] and pharmaceutically acceptable addition salts, solvates, or the like, of formula (I) which represent or any subgroup thereof as described in any of the other embodiments.

[0178] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: Ar, [ka] represents; In particular, Ar [ka] represents; More particularly, Ar is [ka] and pharmaceutically acceptable addition salts, solvates, or the like, of formula (I) which represent or any subgroup thereof as described in any of the other embodiments.

[0179] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 5b , R 5g and R 5h represents hydrogen, and pharmaceutically acceptable addition salts, and solvates thereof, or other embodiments thereof. It relates to any subgroup thereof described in any of the above.

[0180] In one embodiment, the present invention provides a method for treating a cancer 1 is CR 6a represents ;Q 2 is CR 6b Representing the expression ( I) and pharmaceutically acceptable addition salts, solvates, or other embodiments thereof. The present invention relates to any subgroup thereof as described in any of the aspects.

[0181] In one embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X represents -O-; Q 1 is CR 6a represents ;Q 2 is CR 6b and pharmaceutical compositions thereof. and the like. The compounds of formula (I) and (II) are also compounds of formula (I) and (II) and ... For any subgroup.

[0182] In one embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X represents -O-; Q 1 represents CH;Q 2 is CR H and pharmaceutically acceptable salts thereof, and the like. Concerning subgroups.

[0183] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: R 5b , R 5g and R 5h represents hydrogen; Y represents -CH2- or -CF2-; in particular, Y represents -CH2-; Het represents (a-1); Q 1 is CR 6a represents ;Q 2 is CR 6b In particular, Q 1 represents CH;Q 2 is CH and pharmaceutically acceptable addition salts, solvates, or the like, of formula (I) which represent or any subgroup thereof as described in any of the other embodiments.

[0184] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: R 5b , R 5g and R 5h represents hydrogen; Y represents -O-; Het represents (a-1); Q 1 is CR 6a represents ;Q 2 is CR 6b In particular, Q 1 represents CH;Q 2 is CH and pharmaceutically acceptable addition salts, solvates, or the like, of formula (I) which represent or any subgroup thereof as described in any of the other embodiments.

[0185] In one embodiment, the present invention provides a method for treating a cancer2 is CR 6b Compounds of formula (I) and the compounds thereof pharmaceutically acceptable addition salts, and solvates of any of the compounds described in any of the other embodiments. any subgroup of it that

[0186] In one embodiment, the present invention provides a compound wherein Z is -X-CR 5a R 5b - a compound of formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any of the other embodiments. It relates to any subgroup thereof described in any of the preceding paragraphs.

[0187] In one embodiment, the present invention provides compounds of formula (I) and and pharmaceutically acceptable addition salts, and solvates thereof, or any of the other embodiments. Any subgroup of the

[0188] In one embodiment, the present invention provides a compound wherein Z is -X-CR 5a R 5b -; X represents -O- s;R 5a and R 5b represents hydrogen as well as pharmaceutically acceptable salts thereof. and addition salts, and solvates thereof, or any moiety thereof as described in any of the other embodiments. Pertaining to a group.

[0189] In one embodiment, the present invention provides a method for treating cancer, wherein X is —O— or —NR 11 In particular, X represents Compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof, wherein or any subgroup thereof as described in any of the other embodiments.

[0190] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 7a and R 7brepresents hydrogen and pharmaceutically acceptable addition salts, and solvates thereof, or any of the other embodiments. It relates to any subgroup thereof described above.

[0191] In one embodiment, the present invention provides a compound in which Het represents (a-1); R 3a Ga-NR 7a R 7 b represents;R 7a and R 7b represents hydrogen, and the compounds of formula (I) and their pharmaceutically acceptable salts and any of the acceptable addition salts, and solvates thereof, as described in any of the other embodiments. is related to a subgroup of

[0192] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 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 replaced by nitrogen atoms; provided that the nitrogen atoms are not fused to two When a carbonyl group is present in said bicyclic aromatic ring system, it replaces one of the carbon atoms. death; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi C(=O)-NH-C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, C 1~4 alkyloxy, and one -NR 10a R 10b Select arbitrarily Selectively substituted C 1~4 and optionally one substituent selected from the group consisting of alkyl is replaced by; R 3a , R 3b and R 3c But, -NR 7a R 7brepresents;R 7a and R 7b is hydrogen and pharmaceutically acceptable addition salts, solvates, or the like, of formula (I) which represent or any subgroup thereof as described in any of the other embodiments.

[0193] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 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 replaced by nitrogen atoms; provided that the nitrogen atoms are not fused to two When a carbonyl group is present in said bicyclic aromatic ring system, it replaces one of the carbon atoms. death; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi C(=O)-NH-C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, C 1~4 alkyloxy, and one -NR 10a R 10b Select arbitrarily Selectively substituted C 1~4 and optionally one substituent selected from the group consisting of alkyl is replaced by; R 3a , R 3c , R 3b , R 3d and R 3e Ga-NR 7a R 7b represents;R 7a Oh BiR 7b represents hydrogen as well as pharmaceutically acceptable addition salts thereof, and and solvates, or any subgroup thereof as described in any of the other embodiments.

[0194] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 3a , R3b and R 3c represents a non-halo Compounds of formula (I) and pharmaceutically acceptable addition salts, solvates, or other compounds thereof Any subgroup thereof as described in any of the embodiments.

[0195] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 3a , R 3c , R 3b , R 3d and R 3e But, Compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof, or any subgroup thereof as described in any of the other embodiments.

[0196] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: R 3a , R 3b and R 3c Ga-NR 7a R 7b represents; R 7a represents hydrogen; R 7b represents hydrogen as well as pharmaceutically acceptable addition salts thereof, and and solvates, or any subgroup thereof as described in any of the other embodiments.

[0197] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 3a , R 3b and R 3c represents -NH2, the formula ( I) and pharmaceutically acceptable addition salts, solvates, or other embodiments thereof. The present invention relates to any subgroup thereof as described in any of the aspects.

[0198] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 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 replaced by nitrogen atoms; provided that the nitrogen atoms are not fused to two When a carbonyl group is present in said bicyclic aromatic ring system, it replaces one of the carbon atoms. death; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi C(=O)-NH-C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, C 1~4 alkyloxy, and one -NR 10a R 10b Select arbitrarily Selectively substituted C 1~4 and optionally one substituent selected from the group consisting of alkyl is replaced by; Het represents (a-1); R 3a Ga-NR 7a R 7b represents;R 7a and R 7b but and pharmaceutically acceptable addition salts, and solvates thereof, of formula (I), wherein or any subgroup thereof as described in any of the other embodiments.

[0199] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 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 replaced by nitrogen atoms; provided that the nitrogen atoms are not fused to two When a carbonyl group is present in said bicyclic aromatic ring system, it replaces one of the carbon atoms. death; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi C(=O)-NH-C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, C 1~4 alkyloxy, and one -NR 10a R 10b Select arbitrarily Selectively substituted C 1~4 substituted with one substituent selected from the group consisting of alkyl; Het represents (a-1); R 3a Ga-NR 7a R 7b represents;R 7a and R 7b but and pharmaceutically acceptable addition salts, and solvates thereof, of formula (I), wherein or any subgroup thereof as described in any of the other embodiments.

[0200] In one embodiment, the present invention provides a method for producing a polymerizable composition comprising the steps of: 1~4 Alkyl, -N(C 1~4 alkyl), cyano, -CF, -C(=O)-NH-C ~4 Alkyl, C 1~4 Alkyloxy, and C 1~4 alkyl is optionally substituted with one substituent selected from the group consisting of methyl, ... In particular, halo, -NH2, -NH-C 1~4 Alkyl, Cyano, -CF3, C 1~4 Archi Ruoxy, and C 1~4 and optionally one substituent selected from the group consisting of alkyl is replaced by; More particularly, optionally with one substituent selected from the group consisting of halo, and -CF3 be replaced; More particularly, optionally substituted with one halo substituent; More particularly, substituted with one halo substituent; Even more particularly, substituted with one chloro substituent [ka] and pharmaceutically acceptable addition salts, solvates, or the like, of formula (I) which represent or any subgroup thereof as described in any of the other embodiments.

[0201] In one embodiment, the present invention provides a compound wherein Ar is [ka] wherein each Ar is optionally selected from the group consisting of optionally substituted; in particular, Ar is one substituent as defined in any of the other embodiments; Optionally substituted compounds of formula (I) and pharmaceutically acceptable addition salts thereof, and and solvates, or any subgroup thereof as described in any of the other embodiments.

[0202] In one embodiment, the present invention provides a compound wherein Ar is [ka] wherein each Ar is optionally selected from the group consisting of optionally substituted; in particular, Ar is one substituent as defined in any of the other embodiments; Optionally substituted compounds of formula (I) and pharmaceutically acceptable addition salts thereof, and and solvates, or any subgroup thereof as described in any of the other embodiments.

[0203] In one embodiment, the present invention provides a compound wherein Ar is [ka] wherein each Ar is optionally selected from the group consisting of optionally substituted; in particular, Ar is one substituent as defined in any of the other embodiments; Optionally substituted compounds of formula (I) and pharmaceutically acceptable addition salts thereof, and and solvates, or any subgroup thereof as described in any of the other embodiments.

[0204] In one embodiment, the present invention provides a compound wherein Ar is [ka] wherein each Ar is selected from the group consisting of -NH, -NH-C at position α. 1~4 a Rukill, -N(C 1~4 alkyl)2, -NHR 10d , and -NR 10c R 10d mosquito optionally substituted with a substituent selected from the group consisting of: R 10c and R 10d are each independently, C 3~6 Cycloalkyl; halo, -O H and -OC 1~4 one or two independently selected from the group consisting of alkyl or C substituted with three substituents 3~6 Cycloalkyl; halo, -OH and -OC 1~4 one, two, or three substituted alkyl groups each independently selected from the group consisting of: C substituted with a group 1~4 Alkyl; or C 3~6 Cycloalkyl, R 13 and R 14 C substituted with one substituent selected from the group consisting of 1~4 represents alkyl; R 13 But O, S, S(=O) p and one or two independently selected from N or a 4- to 7-membered monocyclic aromatic ring containing three heteroatoms; or O, S, S(=O) p and N, represents a 6- to 11-membered bicyclic fused aromatic ring; The 4- to 7-membered monocyclic aromatic ring or the 6- to 11-membered bicyclic fused aromatic ring is 1~4 Archi optionally substituted with one or two substituents selected from the group consisting of: p represents 1 or 2; R 14 is one, two, or three substituents independently selected from the group consisting of halo The compounds of formula (I) and their pharmaceutically acceptable salts are Acceptable addition salts, and solvates thereof, or any of the compounds described in any of the other embodiments. It relates to a subgroup of interest.

[0205] In one embodiment, the present invention provides a compound wherein Ar is [ka] wherein each Ar is selected from the group consisting of -NH, -NH-C at position α. 1~4 a Rukill, -N(C 1~4 alkyl)2, -NHR 10d , and -NR 10c R 10d mosquito optionally substituted with a substituent selected from the group consisting of: Compounds of formula (I) wherein Ar is optionally substituted at another position with a halo substituent. and pharmaceutically acceptable addition salts, and solvates thereof, or any of the other embodiments. It relates to any subgroup thereof described in any of the preceding paragraphs.

[0206] In one embodiment, the present invention provides a compound wherein Ar is [ka] wherein each Ar is selected from the group consisting of -NH, -NH-C at position α. 1~4 a Rukill, -N(C 1~4 alkyl)2, -NHR 10d , and -NR 10c R 10d mosquito substituted with a substituent selected from the group consisting of: Compounds of formula (I) wherein Ar is optionally substituted at another position with a halo substituent. and pharmaceutically acceptable addition salts, and solvates thereof, or any of the other embodiments. It relates to any subgroup thereof described in any of the preceding paragraphs.

[0207] In one embodiment, the present invention provides a compound in which Ar is a 10-membered bicyclic aromatic ring consisting of two fused 6-membered rings. represents a ring system in which one or two ring carbon atoms are replaced by a nitrogen atom; provided that nitrogen When a nitrogen atom replaces one of the two fused carbon atoms, the carbonyl group forms the bicyclic ring. Formula present in an aromatic ring system; wherein each Ar is optionally substituted according to any of the other embodiments; in particular Ar is optionally substituted with one substituent as defined in any of the other embodiments. Compounds of formula (I) and their pharmaceutically acceptable addition salts, solvates, or other Any subgroup thereof as described in any of the embodiments.

[0208] In one embodiment, the present invention provides a method for treating a rhodium salt of rhodium, wherein Ar is one of the rhodium salts defined in any of the other embodiments. Compounds of formula (I) and pharmaceutically acceptable salts thereof, optionally substituted with substituents. salts, and solvates, or any subgroup thereof as described in any of the other embodiments. Regarding.

[0209] In one embodiment, the present invention provides a method for producing a polymerizable composition comprising the steps of: 1~4 Alkyl, -N(C 1~4 alkyl)2, -NHR 10d , -NR 10c R 10d , Shea -CF3, -C(=O)-NH2, -C(=O)-NH-C 1~4 Alkyl, -C( =O)-C 1~4 Alkyl, C 1~4 Alkyloxy, -C(=O)-OC 1~4 Al Kill, C 2~6 Alkenyl, one C 1~4 C substituted with alkyloxy 1~4 Archi Le, and one -NR 10a R 10b C optionally substituted with 1~4 From alkyl optionally 1, 2, 3, or 4 substituents each independently selected from the group consisting of substituted compounds of formula (I) and pharmaceutically acceptable addition salts thereof, and solvents or any subgroup thereof as described in any of the other embodiments.

[0210] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: Ar, [ka] represents; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi optionally with one substituent selected from the group consisting of -C1, -C2, -C3, -C4, -C6, -C7, -C8, -C9, -C10, -C11, -C12, -C13, -C14, -C15, -C16, -C17, -C18, -C19 ...20, -C21, -C22, -C23, -C24, Replaced; More particularly, Ar is [ka] and even more particularly, Ar represents [ka] and pharmaceutically acceptable addition salts, solvates, or the like, of formula (I) which represent or any subgroup thereof as described in any of the other embodiments.

[0211] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: Ar, [ka] represents; Ar is halo, -OH, -NH2, -NH-C 1~4 Alkyl, -N(C 1~4 Archi substituted with one substituent selected from the group consisting of -CH, cyano, and -CF; More particularly, Ar is [ka] and even more particularly, Ar represents [ka] represents; Het represents (a-1); R 3a Ga-NR 7a R 7b represents;R 7a and R 7b but and pharmaceutically acceptable addition salts, and solvates thereof, of formula (I), wherein or any subgroup thereof as described in any of the other embodiments.

[0212] In one embodiment, the present invention relates to a compound of formula (I) having the formula (I-a1): [ka] Compounds of formula (I) and pharmaceutically acceptable addition salts thereof, and and solvates, or any subgroup thereof as described in any of the other embodiments.

[0213] All variables in the structure of formula (I-a1) may be any of the compounds of formula (I) or any of the other embodiments. It is clear that the definition of any of the subgroups described in It would be.

[0214] In one embodiment, the present invention relates to a compound of formula (I) having the formula (I-a1): [ka] where R 3a represents -NH2; R 4a represents hydrogen, and pharmaceutically acceptable addition salts, and solvates thereof, or other embodiments thereof. It relates to any subgroup thereof described in any of the above.

[0215] In one embodiment, the present invention relates to a compound of formula (I) having the formula (I-a1): [ka] where R 3a represents -NH2; R 4a represents hydrogen; Ar, [ka] more particularly, Ar represents [ka] and pharmaceutically acceptable addition salts, solvates, or the like, of formula (I) which represent or any subgroup thereof as described in any of the other embodiments.

[0216] In one embodiment, the present invention relates to a compound of formula (I) having the formula (I-a1): [ka] is limited to compounds of the formula: R 1 and R 2 represents hydrogen; R 3a is hydrogen, -NR 7a R 7b , or -OC 1~4 represents alkyl; R 4a represents hydrogen; Ar, [ka] where Ar is -NH, -NH-C at the position indicated by α. 1~4 Al Kill, -N(C 1~4 alkyl)2, -NHR 10d , -NR 10c R 10d A group consisting of substituted with a substituent selected from: wherein Ar is optionally substituted with a halo substituent at the position indicated by β; R 10c and R 10d are each independently one, two or three halo substituents; Replaced C 1~4 alkyl; or one C 3~6 substituted with cycloalkyl substituents C 1~4

[0023] Compounds of formula (I) and pharmaceutically acceptable addition salts thereof, wherein R represents an alkyl group; and solvates, or any subgroup thereof as described in any of the other embodiments.

[0217] In one embodiment, the present invention provides a compound of formula (I-a1) [ka] (In the formula, R 1 and R 2 represents hydrogen; R 3a is hydrogen, -NR 7a R 7b , or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b is hydrogen or C 1~4 represents alkyl; Z represents -CH2CH2-; Y represents -O-, -CH2- or -CF2-; in particular -CH2-; R 4a represents hydrogen; Ar, [ka] where Ar is -NH, -NH-C at the position indicated by α. 1~4 Al Kill, -N(C 1~4 alkyl)2, -NHR 10d , -NR 10c R 10d A group consisting of substituted with a substituent selected from: wherein Ar is optionally substituted with a halo substituent at the position indicated by β; R 10c and R 10d are each independently one, two or three halo substituents; Replaced C 1~4 alkyl; or one C 3~6 substituted with cycloalkyl substituents C 1~4 novel compounds of the formula (representing alkyl); and pharmaceutically acceptable addition salts, and solvates thereof.

[0218] In one embodiment, the present invention provides a compound of formula (I-a1) [ka] (In the formula, R 1 and R 2 represents hydrogen; R 3a is hydrogen, -NR 7a R 7b , or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b is hydrogen or C 1~4 represents alkyl; Z is -X-CR 5a R 5b - or -CH2CH2-; R 5a and R 5b represents hydrogen; X represents -O-; Y represents -O-, -CH2- or -CF2-; in particular -CH2-; R 4a represents hydrogen; Ar, [ka] where Ar is -NH, -NH-C at the position indicated by α. 1~4 Al Kill, -N(C 1~4 alkyl)2, -NHR 10d , -NR 10c R 10d A group consisting of optionally substituted with a substituent selected from wherein Ar is optionally substituted with a halo substituent at the position indicated by β; R10c and R 10d are each independently one, two or three halo substituents; Replaced C 1~4 alkyl; or one C 3~6 substituted with cycloalkyl substituents C 1~4 novel compounds of the formula (representing alkyl); and pharmaceutically acceptable addition salts, and solvates thereof.

[0219] In one embodiment, the present invention provides a compound of formula (I-a1) [ka] (In the formula, R 1 and R 2 represents hydrogen; R 3a Ga-NR 7a R 7b represents; R 7a represents hydrogen; R 7b represents hydrogen; Z is -X-CR 5a R 5b - or -CH2CH2-; R 5a and R 5b represents hydrogen; X represents -O-; Y represents -O- or -CH2-; R 4a represents hydrogen; Ar, [ka] wherein Ar is optionally substituted with -NH2 at the position indicated by α. ; wherein Ar is substituted with a halo substituent, particularly Br, at the position indicated by β. novel compounds; and pharmaceutically acceptable addition salts, and solvates thereof.

[0220] In one embodiment, the present invention provides a method for treating a cancer cell comprising administering to a patient a cancer treatment agent comprising: 5a R 5b -or-CH2CH2 and pharmaceutically acceptable addition salts, and solvates thereof, of formula (I), or any subgroup thereof as described in any of the other embodiments.

[0221] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: Z is -X-CR 5a R 5b - or -CH2CH2-; R 5a and R 5b represents hydrogen; Compounds of formula (I) and pharmaceutically acceptable addition salts thereof, wherein X represents -O-, and solvates, or any subgroup thereof as described in any of the other embodiments.

[0222] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: Z is -X-CR 5a R 5b - or -CH2CH2-; R 5a and R 5b represents hydrogen; X represents -O-; Compounds of formula (I) wherein Het represents (a-1) as well as pharmaceutically acceptable addition salts thereof and solvates, or any subgroup thereof as described in any of the other embodiments. do.

[0223] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: Z is -X-CR 5a R 5b - or -CH2CH2-; R 5a and R 5b represents hydrogen; X represents -O-; Het represents (a-1); R 3a Ga-NR 7a R 7b represents; R 7a represents hydrogen; R 7b represents hydrogen as well as pharmaceutically acceptable addition salts thereof, and and solvates, or any subgroup thereof as described in any of the other embodiments.

[0224] In one embodiment, the present invention provides compounds of formula (I) wherein X represents -O-, as well as pharmaceutical compositions thereof. and physiologically acceptable addition salts, and solvates thereof, or any of the other embodiments. It relates to any subgroup of it.

[0225] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: Z is -X-CR 5a R 5b - or -CH2CH2-; R 5a and R 5b represents hydrogen; X represents -O-; Ar, [ka] where Ar is -NH, -NH-C at the position indicated by α. 1~4 Al Kill, and -NHR 10d optionally substituted with a substituent selected from the group consisting of: wherein Ar is selected from the group consisting of halo and CF3 at the position indicated by β. optionally substituted with a substituent selected from the group consisting of aryl, aryl, aryl- ... provided that Ar is placed in at least one of the positions indicated by α or β. Converted; Het represents (a-1); R 3a Ga-NR 7a R 7b represents; R 7a represents hydrogen; R 7b represents hydrogen as well as pharmaceutically acceptable addition salts thereof, and and solvates, or any subgroup thereof as described in any of the other embodiments.

[0226] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: Het represents (a-1); R 3a Ga-NR 7a R 7b represents; R 7a represents hydrogen; R 7b represents hydrogen as well as pharmaceutically acceptable addition salts thereof, and and solvates, or any subgroup thereof as described in any of the other embodiments.

[0227] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: R 3a , R 3b , R 3c , R 3d and R 3e Ga-NR 7a R 7b represents; R 7a represents hydrogen; R 7b But hydrogen, C 3~6 Cycloalkyl, or C 1~4 Representing alkyl, formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or other embodiments thereof. It relates to any subgroup thereof described in any of the above.

[0228] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: R 3a , R 3b , R 3c , R 3d and R 3e Ga-NR 7a R 7b represents; R 7a represents hydrogen; R 7b represents hydrogen as well as pharmaceutically acceptable addition salts thereof, and and solvates, or any subgroup thereof as described in any of the other embodiments.

[0229] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: R 11 But hydrogen, C 1~4 Alkyl, or -OH, -OC 1~4 Alkyl, -NH 2. -NH-C 1~4 Alkyl, and -N(C 1~4 Selected from the group consisting of alkyl)2 C substituted with one substituent 1~4 represents alkyl; R 10c and R 10d are each independently, C 3~6 Cycloalkyl; R 14 ;Ha -OH and -OC 1~4 1 independently selected from the group consisting of alkyl C substituted with one, two or three substituents 3~6 Cycloalkyl; halo, -OH and -OC 1~4 one, two, or three independently selected from the group consisting of alkyl C substituted with two substituents 1~4 Alkyl; or C 3~6 cycloalkyl, and R 1 4 C substituted with one substituent selected from the group consisting of 1~4 Representing alkyl, and pharmaceutically acceptable addition salts, and solvates, or other embodiments thereof. The present invention relates to any subgroup thereof described in any of the above aspects.

[0230] In one embodiment, the present invention provides a method for producing a compound according to the present invention, wherein Y represents -CH2-; Z represents -CH2CH2-; , compounds of formula (I) and pharmaceutically acceptable addition salts, solvates, or other any subgroup thereof as described in any of the embodiments.

[0231] In one embodiment, the present invention provides a method for producing a compound of formula (I) as defined in the general reaction scheme: Regarding.

[0232] In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 2 and 58. can be.

[0233] In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 2 and 80. can be.

[0234] In one embodiment, the compound of formula (I) is compound 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 9, 80 and 81.

[0235] In one embodiment, the compound of formula (I) is compound 2, 58, 74, 75, 76, 77 , 78, 79, 80, 81, 154, 159, 235, 240 and 247 are selected.

[0236] In one embodiment, the compound of formula (I) is selected from compounds 2 and 58, and pharmaceutically acceptable addition salts, and solvates thereof.

[0237] In one embodiment, the compound of formula (I) is selected from compounds 2 and 80, and pharmaceutically acceptable addition salts, and solvates thereof.

[0238] In one embodiment, the compound of formula (I) is compound 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 9, 80 and 81, and pharmaceutically acceptable addition salts, and solvates thereof.

[0239] In one embodiment, the compound of formula (I) is compound 2, 58, 74, 75, 76, 77 , 78, 79, 80, 81, 154, 159, 235, 240 and 247 and pharmaceutically acceptable addition salts, and solvates thereof.

[0240] In one embodiment, the compounds of formula (I) are the exemplified compounds and their free bases. , a pharmaceutically acceptable addition salt, and a solvate thereof.

[0241] All possible combinations of the above embodiments are considered to fall within the scope of the present invention. do.

[0242] Methods for preparation In this section, as in all other sections, unless the context indicates otherwise, reference to formula (I) Reference also includes all other subgroups and examples thereof defined herein.

[0243] The general preparation of some representative examples of compounds of formula (I) is described below and in the specific examples. Standard synthetic procedures are described, commercially available, or commonly used by those skilled in the art. The following schemes are examples of the present invention. are intended to be illustrative only and are not intended to be a limitation of the invention in any way.

[0244] Alternatively, the compounds of the present invention may also be prepared by standard methods commonly used by those skilled in the art of organic chemistry. In combination with the conventional synthetic process, the same reaction process as described in the general scheme below can be used. It can be prepared by Tocol.

[0245] Those skilled in the art will appreciate that in the reactions depicted in the schemes, reactive functional groups will react in the final product. Reactive functional groups, e.g., hydroxyl groups, may be added to the hydroxyl groups if it is desired to avoid their undesired participation in the reaction. It will be recognized that it may be necessary to protect hydroxy, amino, or carboxy groups. Conventional protecting groups may be used in accordance with the practice of the invention. .

[0246] Those skilled in the art will recognize that in the reactions depicted in the schemes, for example, when NaH is used in the reaction, It may be desirable to carry out the reaction under an inert atmosphere, for example under N2 gas, or You will realize that this may be necessary.

[0247] Reaction work-up (e.g., quenching, column chromatography, extraction) refers to the series of operations required to isolate and purify the products of a chemical reaction, such as It will be apparent to one skilled in the art that it may be necessary to cool the reaction mixture.

[0248] Those skilled in the art will appreciate that the outcome of the reaction may be improved by heating the reaction mixture while stirring. For several reasons, microwaves may be used to shorten the overall reaction time. Heating may be used in place of conventional heating.

[0249] Those skilled in the art will recognize that alternative sequences of chemical reactions shown in the following schemes may also be used to produce the desired compounds of formula (I). will recognize that this can result in

[0250] Those skilled in the art will appreciate that the intermediates and compounds shown in the following schemes can be prepared by methods well known to those skilled in the art. It will be appreciated that it may be further functionalized accordingly.

[0251] Those skilled in the art will appreciate that additional compounds of formula (I) can be prepared by similar syntheses as described in the following schemes. It will be appreciated that the present invention can be prepared using protocols.

[0252] If one of the starting materials is available as a salt form, one skilled in the art can first convert it into, for example, an N,N-diamine. It may be necessary to treat the salt with a base such as isopropylethylamine (DIPEA). You will realize that.

[0253] Unless otherwise indicated or apparent from context, all variables are as defined above. is defined as follows.

[0254] Those skilled in the art will appreciate that chemical reactions similar to those described in Schemes 1-9 can be carried out using the compounds of formula (I) t represents a bicyclic aromatic heterocyclic ring system (a-4) or (a-5) It will be understood that the present invention can also be applied to the following cases. Some typical examples are shown in the examples. Furthermore, this information is provided by formula (I) (wherein Het represents (a-4) or (a-5) To obtain further compounds of the formula (i.e., This can be combined with conventional synthetic processes.

[0255] Generally, compounds of formula (I) can be prepared according to Scheme 1: General Scheme 1 [ka] In Scheme 1, "LG1" is defined as a suitable leaving group, such as, for example, a halogen. "LG2" is defined as a suitable leaving group, such as, for example, a halogen or -SCH3; "LG3" is defined as a leaving group such as halogen and -SCH3. Scheme 1 All other variables therein are defined in accordance with the scope of the present invention.

[0256] In Scheme 1, the following reaction conditions typically apply: 1:R 3a , R 3b or R 3c Different combinations of reaction conditions depend on the definition of: 1a:R 3a , R 3b or R 3c When is a halogen, step 1 may be omitted.

[0257] 1b:R 3a , R 3b or R 3c NR 7a R 7b Typically, microwave under suitable conditions, for example, at 100 to 130°C, using an autoclave container for heating. with a suitable solvent such as, for example, HO, MeOH, or EtOH, at a temperature NR 7a R 7b in the presence of a suitable amine.

[0258] 1c:R 3a , R 3b or R 3c Ga-OC 1~4 If the alkyl group is in a suitable solvent such as tetrahydrofuran (THF), e.g., NaH, potassium A suitable HO-C with a suitable base such as tert-butoxide (tBuOK) 1~4 Alternatively, in the presence of a suitable acid, such as HCl, Suitable HO-C 1~4 In the presence of alkyl.

[0259] 1d:R 3a , R 3b or R 3c When is hydrogen, for example, methanol (MeOH), In a suitable solvent such as ethanol (EtOH) or THF, e.g., Raney Ni, Pd / of catalysts such as C (e.g., 5 wt. % or 10 wt. %) or Pt / C (e.g., 5 wt. %) In the presence of hydrogenation conditions: under H2 gas atmosphere; 1e:R 3a , R 3b or R 3c C 1~4 If it is an alkyl, for example, 100°C in a suitable solvent mixture, such as dioxane / H2O in a ratio of 5:1, e.g. Suitable catalysts, such as 1,1'-bis(diphenylphosphino)ferrocene, and a suitable boronic acid, such as methylboronic acid, or In the presence of esters; 2: At a suitable temperature, e.g., room temperature, with a suitable solvent, e.g., MeOH, e.g., In the presence of a suitable acid such as 4M HCl in dioxane or 4M HCl in MeOH; or for example trifluoroacetic acid (TFA) in dichloromethane (DCM) at a suitable temperature; or in the presence of a suitable acid, such as acetic acid, in THF and water at a suitable temperature, such as room temperature , 3: At a suitable temperature, a compound of formula (C) 1~4 Alkyl (C=O) In the presence of a suitable acid anhydride of R 3a , R 3b or R 3c If is NH2, ( C 1~4 Alkyl C=O)O reacts with NH to form N(C 1~4 Alkyl C=O)2 Such intermediates can be obtained under microwave conditions or by heating. Using an autoclave vessel, at a suitable temperature, for example, 100 to 130°C, The reaction can be carried out in a suitable solvent such as HCl or C 1~4 a The enzyme may benefit from the presence of an acid such as alkyl CO2H.

[0260] The starting materials in Scheme 1 are either commercially available or can be prepared by standard procedures apparent to one skilled in the art. or as described in the following general scheme.

[0261] General Scheme 2a Generally, compounds of formula III, V and VII, where Z is -O-CHR 5a -representing an intermediate can be prepared according to Scheme 2a. All other variables in Scheme 2a are the same as those of the present invention. Those skilled in the art will understand that R 3a , R 3b or R 3c But -NH2 or -NHR 7b It will be appreciated that suitable protecting groups may be required if [ka] In Scheme 2a, the following reaction conditions apply: 1: Mitsunobu reaction: 1a: PPh in a suitable solvent, such as anhydrous THF, at a suitable temperature, such as room temperature 3 Polymer-supported, diisopropyl azodicarboxylate (DIAD) or azodicarboxylic acid Diethyl (DEAD) or bis(1,1-dimethylethyl) azodicarboxylate (DBA D) in the presence of

[0262] 1b: Trifluoromethanesulfonyl ether (III) is reacted with 1,2-dichloromethane (III) in a suitable solvent, such as anhydrous THF, at a suitable temperature, such as room temperature. In the presence of phenylphosphine (PPh3), DIAD or DEAD.

[0263] 1c: At a suitable temperature, for example 80° C., in a suitable solvent, for example anhydrous toluene, Anomethylenetributylphosphorane (CMBP) or cyanomethylenetrimethylphosphorane In the presence of orchid (CMMP).

[0264] The starting materials in Scheme 2a are either commercially available or prepared by standard procedures apparent to one skilled in the art. These compounds can be prepared in stages or as described in the following general schemes. , R 5a C 1~4 When the alkyl group is alkyl, different isomers can be identified by reversed-phase high-performance liquid chromatography. and each other using RP-HPLC or supercritical fluid chromatography (SFC). It will be appreciated that the present invention may be separated.

[0265] General Scheme 2b Formulas II, IV and VI, wherein Z is -X a -CHR 5a The intermediate (representing -) is In Scheme 2b, "X" can be prepared according to Scheme 2b. a " is O or S "LG" is defined as, for example, halogen, mesylate (MsO) and tosylate ( TosO), preferably TosO. "LG2" is defined as a leaving group such as a halogen or -SCH 3. "LG3" is defined as a leaving group such as halogen or -SCH3. All other variables in Scheme 2b are defined as leaving groups within the scope of the present invention. It is defined as follows. [ka]

[0266] In Scheme 2b, the following reaction conditions apply: 1: A suitable solvent such as CH3CN, DCM or N,N-dimethylacetamide (DMA) In a solvent, a base such as K2CO3, triethylamine (Et3N) or DIPEA In the presence of.

[0267] The starting materials in Scheme 2b are either commercially available or prepared by standard procedures apparent to one skilled in the art. These compounds can be prepared in stages or as described in the following general schemes. , R 5a C 1~4 When the alkyl group is alkyl, different isomers can be identified by reversed-phase high-performance liquid chromatography. and each other using RP-HPLC or supercritical fluid chromatography (SFC). It will be appreciated that the present invention may be separated.

[0268] General Scheme 2c Intermediates III, V and VII (wherein Z is -X a -CHR 5a -) represents skiing In Scheme 2c, "X a " is O or S "LG" is, for example, halogen, MsO or TosO, preferably To All other variables in Scheme 2c are within the scope of the present invention. Those skilled in the art will recognize that R 3a , R 3b or R 3c But -NH2 or - NHR 7b It will be appreciated that where this is the case, suitable protecting groups will be required. [ka]

[0269] In Scheme 2c, the following reaction conditions apply: 1: A suitable solvent such as CH3CN, DCM or N,N-dimethylacetamide (DMA) in a solvent in the presence of a base such as K2CO3, Et3N or DIPEA.

[0270] The starting materials in Scheme 2c are either commercially available or prepared by standard procedures apparent to one skilled in the art. These compounds can be prepared in stages or as described in the following general schemes. , R 5a C 1~4 When the alkyl group is alkyl, different isomers can be identified by reversed-phase high-performance liquid chromatography. and each other using RP-HPLC or supercritical fluid chromatography (SFC). It will be appreciated that the present invention may be separated.

[0271] General Scheme 3 Generally, an intermediate (wherein Z is -X-CHR 5a -; X represents -NH- or -NR 11 -) can be prepared according to Scheme 3. In Scheme 3, "LG "LG1" is defined as a leaving group, e.g., a halogen; "LG2" is defined as a leaving group, e.g., a halogen or or -SCH3. "LG3" is defined as a leaving group such as a halogen or - All other variables in Scheme 3 are within the scope of the present invention. It is defined according to the [ka]

[0272] In Scheme 3, the following reaction conditions apply: 1: At a suitable temperature, for example room temperature, with a suitable solvent, for example DCM, of a suitable reducing reagent such as sodium triacetoxyborohydride (NaBH(AcO)3) or in the presence of a suitable solvent such as MeOH at a suitable temperature, for example, from room temperature to 50°C. In the presence of NaBH3CN together with a suitable solvent.

[0273] 2: A suitable temperature, for example, from room temperature to 50° C., is prepared by adding, for example, anhydrous THF, N,N-dimethylformamide, a suitable salt, e.g., NaH, together with a suitable solvent, e.g., dichloromethane (DMF), DMA, In the presence of groups.

[0274] The starting materials in Scheme 3 are either commercially available or can be synthesized by standard procedures apparent to one skilled in the art. or as described in the specific experimental section. 5a but C 1~4 When the alkyl group is present, different isomers can be identified by reversed-phase high-performance liquid chromatography (RPLC). can be separated from each other using HPLC or supercritical fluid chromatography (SFC). You will realize that.

[0275] General Scheme 4 Generally, the intermediate (wherein Z is -C≡C-, -CH=CH-, or -CH2-CH2 -) can be prepared according to Scheme 4. In Scheme 4, "LG1" is defined as a leaving group, e.g., a halogen; "LG2" is defined as a leaving group, e.g., a halogen or "LG3" is defined as a leaving group such as a halogen or -SC All other variables in Scheme 4 are within the scope of the present invention. Therefore it is defined. [ka]

[0276] In Scheme 4, the following reaction conditions apply: 1: Under microwave conditions or using an autoclave container for heating, e.g., 100-1 in a suitable solvent such as H2O, MeOH, or EtOH at a suitable temperature such as 30°C in the presence of a suitable amine such as HNR'R'' or NaOR'.

[0277] 2: with a suitable base, e.g., triethylamine, at a suitable temperature, e.g., 80°C. in a suitable solvent such as 2-methyltetrahydrofuran, ) in the presence of a suitable catalyst such as palladium(II) dichloride and copper(I) iodide.

[0278] 3: At a suitable temperature, for example 100°C, a suitable base, for example DIPEA, and with a palladium catalyst such as Pd(OAc)2 (palladium(II) acetate), e.g. In a suitable solvent such as DMF, for example, tetraethylammonium chloride (EtNCl) In the presence of any suitable salt.

[0279] 4: In a suitable solvent, such as MeOH, an atmosphere of H2 gas and, for example, Pd / C (e.g. In the presence of a catalyst, such as 5% or 10% by weight.

[0280] The starting materials for Scheme 4 are either commercially available or can be prepared by standard procedures apparent to one skilled in the art. or can be prepared as described in the specific experimental section.

[0281] General Scheme 5 Generally, intermediates (wherein Y represents CH or CF, as used herein, a Call where Z represents -CH2O-) can be prepared according to Scheme 5.

[0282] In Scheme 5, "LG1" is defined as a leaving group, such as, for example, a halogen; "LG2" is defined as a leaving group, such as a halogen or -SCH3. " is defined as a leaving group such as halogen or -SCH3. All of the Other variables are defined according to the scope of the present invention. [ka]

[0283] In Scheme 5, the following reaction conditions apply: 1: A suitable solvent such as CH3CN, DCM or N,N-dimethylacetamide (DMA) in a solvent in the presence of a base such as K2CO3, Et3N or DIPEA.

[0284] General Scheme 6 Generally, intermediates (wherein Z represents -CH2-) are prepared according to 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. G3" is defined as a leaving group such as, for example, a halogen or -SCH3. Scheme 6 All other variables therein are defined in accordance with the scope of the present invention. [ka]

[0285] In Scheme 6, the following reaction conditions apply: 1: At a suitable temperature, such as room temperature, in a suitable solvent, such as MeOH, EtOH, or DCM In the presence of tosylhydrazide, together with a solvent.

[0286] 2: At a suitable temperature such as 90° C. with a suitable solvent such as 1,4-dioxane In the presence of a boronic acid together with a suitable base such as K2CO3, Na2CO3, or Cs2CO3 Below.

[0287] The starting materials for Scheme 6 are either commercially available or can be prepared by standard procedures apparent to one skilled in the art. or can be prepared as described in the specific experimental section.

[0288] General Scheme 7 Generally, the intermediate (wherein Z represents -CH2-CH2-) can be prepared according to Scheme 7 In Scheme 7, "LG1" can be prepared by adding a leaving group such as a halogen atom to the alkane-containing compound. "LG2" is defined as a leaving group, e.g., halogen or -SCH3. "LG3" is defined as a leaving group, e.g., halogen or -SCH3. All other variables in Scheme 7 are defined in accordance with the scope of the present invention. [ka]

[0289] In Scheme 7, the following reaction conditions typically apply: 1: At room temperature to reflux and for 1 to 3 hours, the alkene precursor is reacted under a nitrogen atmosphere. 9-Borabicyclo(3.3.1)nonane (9-BBN) solution in water and 0.5M in THF In the first step, the reaction mixture is heated at a temperature of 50° C. to reflux for 1 to 3 hours. for a suitable reaction time in a suitable solvent mixture, such as, for example, THF and water, for example, in a suitable Ar chloride or Ar iodide, and, for example, 1,1'-bis(diphenylphosphino)ferro in the presence of a suitable catalyst such as palladium(II) dichloroselenium(II) and, for example, phosphoric acid In the second step, in the presence of a suitable base such as tripotassium.

[0290] 2:R 3a , R 3b or R 3c Different combinations of reaction conditions depend on the definition of: 2a:R 3a , R 3b or R 3c When is a halogen, step 1 may be omitted.

[0291] 2b:R 3a , R 3b or R 3c NR 7a R 7b If under suitable conditions, for example, at 100 to 130°C, using an autoclave container for heating. with a suitable solvent such as, for example, HO, MeOH, or EtOH, at a temperature NR 7a R 7b in the presence of a suitable amine.

[0292] 2c:R 3a , R 3b or R 3c Ga-OC 1~4 If the alkyl group is in a suitable solvent such as tetrahydrofuran (THF), e.g., NaH, potassium A suitable HO-C with a suitable base such as tert-butoxide (tBuOK) 1~4 Alternatively, in the presence of a suitable acid, such as HCl, Suitable HO-C 1~4 In the presence of alkyl.

[0293] 2d:R 3a , R 3b or R 3c When is hydrogen, for example, methanol (MeOH), In a suitable solvent such as ethanol (EtOH) or THF, e.g., Raney Ni, Pd / of catalysts such as C (e.g., 5 wt. % or 10 wt. %) or Pt / C (e.g., 5 wt. %) In the presence of hydrogenation conditions: under H2 gas atmosphere; 2e:R 3a , R 3b or R 3c C 1~4 If it is an alkyl, for example, 100°C in a suitable solvent mixture, such as dioxane / H2O in a ratio of 5:1, e.g. Suitable catalysts, such as 1,1'-bis(diphenylphosphino)ferrocene, and a suitable boronic acid, such as methylboronic acid, or In the presence of esters.

[0294] The starting materials for Scheme 7 are either commercially available or can be prepared by standard procedures apparent to one skilled in the art. or can be prepared as described in the specific experimental section.

[0295] General Scheme 8 Generally, the intermediate (wherein Z represents -CH2-CH2-) can be prepared according to Scheme 8 In Scheme 8, "LG1" can be prepared by adding a leaving group such as a halogen atom to the alkane-containing compound. "LG2" is defined as a leaving group, e.g., halogen or -SCH3. "LG3" is defined as a leaving group, e.g., halogen or -SCH3. All other variables in Scheme 8 are defined in accordance with the scope of the present invention. [ka]

[0296] In Scheme 8, the following reaction conditions typically apply: 1:R 3a , R 3b or R 3c Different combinations of reaction conditions depend on the definition of: 1a:R 3a , R 3b or R 3c When is a halogen, step 1 may be omitted.

[0297] 1b:R 3a , R 3b or R 3c NR 7a R 7b If under suitable conditions, for example, at 100 to 130°C, using an autoclave container for heating. with a suitable solvent such as, for example, HO, MeOH, or EtOH, at a temperature NR 7a R 7b in the presence of a suitable amine.

[0298] 1c:R 3a , R 3b or R 3c Ga-OC 1~4 If the alkyl group is in a suitable solvent such as tetrahydrofuran (THF), e.g., NaH, potassium A suitable HO-C with a suitable base such as tert-butoxide (tBuOK) 1~4 Alternatively, in the presence of a suitable acid, such as HCl, Suitable HO-C 1~4 In the presence of alkyl.

[0299] 1d:R 3a , R 3b or R 3c When is hydrogen, for example, methanol (MeOH), In a suitable solvent such as ethanol (EtOH) or THF, e.g., Raney Ni, Pd / of catalysts such as C (e.g., 5 wt. % or 10 wt. %) or Pt / C (e.g., 5 wt. %) In the presence of hydrogenation conditions: under H2 gas atmosphere; 1e:R 3a , R 3b or R 3c C 1~4 If it is an alkyl, for example, 100°C in a suitable solvent mixture, such as dioxane / H2O in a ratio of 5:1, e.g. Suitable catalysts, such as 1,1'-bis(diphenylphosphino)ferrocene, and a suitable boronic acid, such as methylboronic acid, or In the presence of esters; 2: At room temperature to reflux and for 1 to 3 hours, under a nitrogen atmosphere, the alkene precursor In the first step, in the presence of the compound and a 0.5 M solution of 9-BBN in THF, The reaction is carried out at a suitable temperature of from 1 to 3 hours, for example, in THF and water. In a suitable solvent mixture, a suitable hetaryl bromide or hetaryl iodide is and for example, 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium In the presence of a suitable catalyst, such as potassium hydroxide (II), and in the presence of a suitable catalyst, such as potassium phosphate tripotassium phosphate In the second step, in the presence of a base.

[0300] The starting materials for Scheme 8 are either commercially available or can be prepared by standard procedures apparent to one skilled in the art. or can be prepared as described in the specific experimental section.

[0301] General Scheme 9 In general, the intermediates shown in Scheme 9 (wherein Z represents -CH2-CH2-) can be prepared by the synthesis of In Scheme 9, "LG1" can be prepared according to, for example, a halogen atom. All other variables in Scheme 9 are within the scope of the present invention. It is defined as follows: [ka]

[0302] 1: At room temperature to reflux and for 1 to 3 hours, the alkene precursor is reacted under a nitrogen atmosphere. In the first step, in the presence of the compound and a 0.5 M solution of 9-BBN in THF, The reaction is carried out at a suitable temperature of from 1 to 3 hours, for example, in THF and water. In a suitable solvent mixture, for example, a suitable Ar bromide or Ar iodide (where X is B r or I) and for example 1,1'-bis(diphenylphosphino)ferrocene] In the presence of a suitable catalyst such as dichloropalladium(II) and, for example, tripotassium phosphate In the second step, in the presence of a suitable base such as ammonium.

[0303] 2: Under an inert atmosphere of N2 gas, at a suitable temperature, e.g., 0°C, trifluoromethanesulfonic anhydride and a suitable solvent such as pyridine in the presence of a suitable base.

[0304] 3. Under an inert atmosphere of N2 gas, at a suitable temperature, e.g., room temperature, in a suitable solvent such as, for example, Cs2CO3 in the presence of a suitable base.

[0305] The starting materials for Scheme 9 are either commercially available or can be prepared by standard procedures apparent to one skilled in the art. or can be prepared as described in the specific experimental section.

[0306] In all these preparations, the reaction product may be isolated from the reaction medium, if necessary. Accordingly, techniques known in the art, such as extraction, crystallization, trituration and chromatography, may be used. It may be further purified according to commonly known methods.

[0307] Chirally pure forms of the compounds of formula (I) form a preferred group of compounds. Thus, chirally pure forms of the intermediates and their salt forms are chirally pure compounds of formula (I) It is particularly useful for the preparation of enantiomeric mixtures of intermediates with corresponding configurations. These compounds are useful in the preparation of compounds of formula (I)

[0308] Pharmacology Compounds of the present invention have been found to inhibit PRMT5 activity.

[0309] In particular, the compounds of the present invention bind to the PRMT5 enzyme and inhibit the natural substrate SAM (S-adenosyl -L-methionine) to inhibit such enzymes.

[0310] Therefore, the compound according to the present invention or a pharmaceutical composition thereof can be used to treat blood diseases, metabolic disorders, autoimmune diseases, and the like. Immune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney diseases, blood Treatment or prevention of diseases such as platelet aggregation, sperm motility, transplant rejection, graft rejection, and lung disorders; It is anticipated that they may be particularly useful in therapy.

[0311] In particular, the compound according to the present invention or a pharmaceutical composition thereof is useful for treating allergies, asthma, hematopoietic disorders (hematopoietic disorders), and the like. matopoietic cancer, lung cancer, prostate cancer, melanoma, metabolic disorders, diabetes, obesity, blood The compounds may be useful in the treatment or prevention, particularly the treatment of diseases such as sickle cell anemia.

[0312] The compounds of the present invention or pharmaceutical compositions thereof can be used to treat proliferative diseases, such as autoimmune diseases, cancer, They may be useful in the treatment or prevention, especially the treatment, of diseases such as benign tumors or inflammatory diseases.

[0313] The compound according to the present invention or a pharmaceutical composition thereof is useful for treating diabetes, obesity; cancer, hematopoietic cancer, lung cancer, and pre-existing conditions. Proliferative disorders, including prostate cancer, melanoma, or pancreatic cancer; blood disorders; hemoglobinopathy; sickle cell anemia anemia; beta-thalassemia, inflammatory diseases, and autoimmune diseases, such as rheumatoid arthritis, systemic Treatment or prevention of diseases such as lupus erythematosus, Sjogren's syndrome, diarrhea, and gastroesophageal reflux disease They may be useful in the prevention and especially in the treatment.

[0314] In certain embodiments, inhibition of PRMT5 by provided compounds is useful in treating cancers including, but not limited to: Qualitative list: breast cancer, lung cancer, esophageal cancer, bladder cancer, hematopoietic cancer, lymphoma, medulloblastoma, rectal adenocarcinoma, Colon adenocarcinoma, stomach cancer, pancreatic cancer, liver cancer, adenoid cystic carcinoma, lung adenocarcinoma, head and neck squamous cell carcinoma, brain tumor , hepatocellular carcinoma, renal cell carcinoma, melanoma, oligodendroglioma, ovarian clear cell carcinoma, and ovarian serous cystoid carcinoma These compounds may be useful in treating or preventing, especially treating, tumors.

[0315] Examples of metabolic disorders that may be treated or prevented, particularly treated, include, but are not limited to, diabetes Or obesity may be raised.

[0316] Examples of blood disorders that can be treated or prevented, particularly treated, include, but are not limited to, abnormal blood Pigmentopathies, such as sickle cell disease or β-thalassemia.

[0317] Examples of cancers that can be treated or prevented, particularly treated, include, but are not limited to, acoustic neuroma, adenocarcinoma, and thyroid cancer. Carcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, hemangiosarcoma) , appendix cancer, benign monoclonal gammopathy, bile duct cancer r) (e.g. cholangiocarcinoma), bladder cancer, breast cancer (e.g. breast adenocarcinoma, papillary breast carcinoma, breast cancer, medullary breast carcinoma), brain tumors (e.g., meningioma; glioma) , e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchial carcinoma, carcinoid tumor, cervical cancer ( cervical adenocarcinoma), chordoma, choriocarcinoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer) carcinoma, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic esophageal carcinoma, hematogenous sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett's adenocarcinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familial Hypereosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck Head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma (OSCC) ), throat cancer (e.g., pharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic organ cancer (e.g., acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia Myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) ( B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g. leukemias such as B-cell CLL, T-cell CLL); Hodgkin's lymphoma (HL) (e.g., B lymphoma (e.g., diffuse large cell HL, T-cell HL) and non-Hodgkin's lymphoma (NHL) (e.g., diffuse large cell HL, diffuse large cell HL, T-cell HL) Diffuse large B-cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL) B-cell NHL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CL) L / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosal Associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma ( i.e., "Waldenström's macroglobulinemia"), immunoblastic large cell lymphoma leukemia, hairy cell leukemia (HCL), precursor B lymphoblastic lymphoma and primary central nervous system (CNS) CNS) lymphoma; and precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezari) - syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, Enteropathic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, etc. Lymphoma, such as T-cell NHL; mixed leukemia / lymphoma, including one or more of the above; and multiple myeloma (MM)), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, μ chain disease), hemangioblastoma, inflammation Myofibroblastic tumors, immunocytic amyloidosis, kidney cancer (e.g., nephroblastoma, also known as virulence myofibroblastic tumors), Lums tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatocellular carcinoma), lung cancer (e.g., bronchogenic carcinoma, non-small cell lung cancer (NSCLC), squamous cell lung cancer (SLC), Cancer, Lewis lung carcinoma, pulmonary neuroendocrine tumors: typical carcinoid, atypical carcinoid, small cell lung cancer (SCLC), and large cell neuroendocrine carcinoma), leiomyosarcoma (LMS), mastocytosis (e.g. For example, systemic mastocytosis, myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (M PD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myeloid leukemia Myelofibrosis (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, and chronic myeloid leukemia (CML) ML), chronic neutrophilic leukemia (CNL), idiopathic hypereosinophilic syndrome (HES), neuroblastoma Neurofibromas, neurofibromas (e.g., neurofibromatosis (NF) type I or II, schwannoma neuroendocrine cancers (e.g., gastrointestinal pancreatic neuroendocrine tumors (GEP-NETs), carcinomas) id tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma , pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor), negative Stem cancer (e.g., extramammary Paget's disease), pinealoma, primitive neuroectodermal tumor (PNT), Prostate cancer (e.g., prostatic adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., tonsils) squamous cell carcinoma (SCC), keratoacanthocytoma (KA), melanoma, basal cell carcinoma (BCC)), small Intestinal cancer (e.g., appendix cancer), soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), adipose tissue malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma Adenocarcinoma, synovial tumor, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., thyroid papillary thyroid carcinoma (PTC), medullary thyroid carcinoma), urethral cancer, vaginal cancer, and vulvar cancer (e.g. Examples include Paget's disease of the vulva.

[0318] Examples of neurodegenerative diseases that can be treated or prevented, particularly treated, include, but are not limited to, pulmonary 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 Muscle atrophy, and cerebellar degeneration.

[0319] Examples of cardiovascular diseases that can be treated or prevented, particularly treated, include, but are not limited to, cardiac These include hypertrophy, restenosis, atherosclerosis, and glomerulonephritis.

[0320] Examples of inflammatory diseases that can be treated or prevented, particularly treated, include, but are not limited to, inflammation associated with rhinitis, anemia (e.g., aplastic anemia, autoimmune hemolytic 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) arthritis, rheumatoid arthritis and reactive arthritis), upper respiratory tract diseases, ankylosing spondylitis, hay fever, amyotrophic lateral sclerosis Lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis , bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, diverticulum inflammation, dermatomyositis, diabetes (e.g., type 1 diabetes, type 2 diabetes), skin diseases (e.g., psoriasis, Eczema, eczema hypersensitivity reaction, burns, dermatitis, pruritus (itching), endometriosis, Guillain-Barré syndrome Barre syndrome, infections, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headache (e.g. migraine, tension headache), intestinal obstruction (e.g., postoperative intestinal obstruction and intestinal obstruction during sepsis) , idiopathic thrombocytopenic purpura, interstitial cystitis (bladder pain syndrome), gastrointestinal disorders (e.g., digestive ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis) , eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GO RD, or its alternative name GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcers) genital colitis, collagen fibrous colitis, lymphocytic colitis, ischemic colitis, empty space colitis (dive rsion colitis, Behcet's syndrome, indeterminate colitis, and inflammatory bowel disease IBS syndrome), lupus erythematosus, localized scleroderma, myasthenia gravis, myocardial ischemia , multiple sclerosis, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcer, polymyositis , primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g., Parkinson's disease, Huntington's disease) Chronic inflammation associated with head injury due to radiation, prostatitis, and Alzheimer's disease pelvic inflammatory disease, reperfusion injury, regional enterocolitis, rheumatic fever, systemic lupus erythematosus Scleroderma, systemic sclerosis (scierodoma), sarcoidosis, spondyloarthropathy, Sjögren's syndrome, thyroiditis, transplant rejection, tendonitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scars, burns, physical injuries), vasculitis, vitiligo and Wegener's granulomatosis Examples include:

[0321] In particular, the inflammatory disease is an acute inflammatory disease (eg, inflammation caused by an infection). In particular, inflammatory diseases include chronic inflammatory diseases (e.g., those resulting from asthma, arthritis, and inflammatory bowel disease). The compounds also treat inflammatory and non-inflammatory muscle pain associated with trauma. The compounds may also be useful in treating inflammation associated with cancer.

[0322] Examples of autoimmune diseases that can be treated or prevented, particularly treated, include, but are not limited to, Degenerative joint diseases such as arthritis (rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, etc.), Systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Beche disease Ott's disease, autoimmune hemolytic anemia, amyotrophic lateral sclerosis, hay fever, multiple sclerosis, acute shoulder pain , psoriasis, and juvenile arthritis), asthma, atherosclerosis, osteoporosis, tracheal ulcerative colitis, tendonitis, bursitis, skin conditions (e.g., psoriasis, eczema, eczema hypersensitivity reactions, burns, dermatitis) , pruritus (itchiness), enuresis, eosinophilic disorders, gastrointestinal disorders (e.g., peptic ulcer, Regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, also GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, Collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet's syndrome , indeterminate colitis) and inflammatory bowel syndrome (IBS), and gastrointestinal motility Disorders that can be improved by ameliorating drugs (e.g., ileus, postoperative ileus, and ileus during sepsis) Gastroesophageal reflux disease (GORD, also known as GERD); eosinophilic esophagitis, diabetic gastropathy gastroparesis, including total paralysis; food intolerance and food allergies and non-ulcer dyspepsia ( Other functional bowel disorders, such as noncardiac chest pain (NCCP, including costochondritis), are listed. It can be obtained.

[0323] In certain embodiments, provided compounds are capable of reprogramming somatic cells into stem cells. In certain embodiments, the provided The compounds may be useful in the development of germ cells, and thus in the fields of reproductive technology and regenerative medicine. It is considered to be useful.

[0324] Other conditions that may be treated or prevented, particularly treated, include, but are not limited to, ischemic injury. Associated myocardial infarction, immune disorders, stroke, cardiac arrhythmias, toxic or alcoholic liver disease , aspirin-sensitive rhinosinusitis, cystic fibrosis, cancer pain, and blood diseases, e.g., chronic These include anemia and aplastic anemia.

[0325] The compounds of the present invention may also have therapeutic effects in sensitizing tumor cells to radiation and chemotherapy. It may have therapeutic applications.

[0326] Thus, the compounds of the present invention may be referred to as "radiosensitizers" and / or "chemosensitizers." may be used alone or in combination with other "radiosensitizers" and / or "chemosensitizers" may be given together.

[0327] The term "radiosensitizer" as used herein refers to a drug that, when administered in a therapeutically effective amount to an animal, administered to sensitize cells to ionizing radiation and / or treat them with ionizing radiation It is defined as a molecule, preferably a small molecular weight molecule, that facilitates the treatment of a potential disease.

[0328] The term "chemosensitizer" as used herein refers to a compound administered to an animal in a therapeutically effective amount. to sensitize cells to chemotherapy and / or make them treatable with chemotherapy. It is defined as a molecule, preferably a small molecular weight molecule, that facilitates the treatment of a disease.

[0329] Several mechanisms for the action of radiosensitizers have been proposed in the literature, including: Suggested: mimic oxygen or act as a bioreductant under hypoxia Hypoxic cell radiosensitizers (e.g., 2-nitroimidazole compounds, and benzotriazoles) non-hypoxic cell radiosensitizers (e.g., halogenated pyrimidines) can be analogs of DNA bases and are preferentially incorporated into the DNA of cancer cells, This may enhance radiation-induced damage to DNA molecules and / or disrupt normal DNA repair mechanisms. and various other potential mechanisms of action hypotheses for radiosensitizers in the treatment of disease. has been erected.

[0330] Many cancer treatment protocols now use radiosensitizers in combination with x-ray irradiation. Examples of activated radiosensitizers include, but are not limited to: Metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, ethoxylated Nidazole, Nimorazole, Mitomycin C, RSU 1069, SR 4233, E O9, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5 -Iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine Lysine (FudR), hydroxyurea, cisplatin, and their therapeutic effects Analogues and derivatives.

[0331] Photodynamic therapy (PDT) of cancer uses visible light as a radioactivator for sensitizing agents. Examples of photodynamic radiosensitizers include, but are not limited to: Hematoporphyrin derivatives, Photofrin, benzoporphyrin derivatives, tin etiopol Phyllin, pheophorbide-a, bacteriochlorophyll-a, naphthalocyanine, phthalocyanine cyanines, zinc phthalocyanines, and their therapeutically active analogs and derivatives.

[0332] Radiosensitizers are compounds that promote the incorporation of radiosensitizers into target cells; compounds that regulate the flow of therapeutic agents, nutrients, and / or oxygen; along with further radiation chemotherapeutic agents that act on tumors with or without the use of chemotherapeutic agents; or to treat cancer or other diseases a therapeutically effective amount of one or more other therapeutically effective compounds for may be administered in conjunction with multiple other compounds.

[0333] Chemosensitizers are compounds that enhance the uptake of chemosensitizers into target cells; compounds that control the flow of therapeutic drugs, nutrients, and / or oxygen; chemotherapeutic agents that act on tumors or other therapeutically effective compounds for treating cancer or other diseases. It may be administered in conjunction with an unspecified therapeutically effective amount of one or more other compounds. Antagonists, such as verapamil, are effective against tumor cells that are resistant to commonly accepted chemotherapeutic agents. establish chemotherapy sensitivity in cells and demonstrate the efficacy of such compounds in drug-sensitive malignancies. It has been found to be useful in combination with anti-tumor agents to enhance efficacy.

[0334] The compounds of the invention may also reduce the risk of cancer recurrence.

[0335] The present invention provides compounds of formula (I) as well as pharmaceutically acceptable salts thereof for use as pharmaceuticals. The present invention relates to the addition salts and solvates thereof.

[0336] The present invention relates to compounds of formula (I) and their therapeutic uses for the inhibition of PRMT5 activity. The present invention relates to physiologically acceptable addition salts, and solvates.

[0337] The compounds of the present invention may be "anti-cancer agents," a term that is also used to describe "anti-tumor cell proliferation agents." and "antineoplastic agents."

[0338] The present invention relates to compounds of formula (I) and their pharmaceutical compositions for use in the treatment of the above-mentioned diseases. and the like. The present invention relates to the addition salts and solvates thereof which are acceptable for the compound of the present invention.

[0339] The present invention relates to compounds of formula (I) and It relates to pharmaceutically acceptable addition salts, and solvates thereof.

[0340] The present invention relates to a method for treating or preventing a PRMT5-mediated disease or condition, in particular for treating The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates:

[0341] The present invention relates to the use of a compound of formula (I) and its pharmaceutically acceptable salts for the manufacture of a medicament. It relates to salts and solvates.

[0342] The present invention relates to a compound of formula (I) and a compound of formula (I) for the manufacture of a medicament for the inhibition of PRMT5. It relates to pharmaceutically acceptable addition salts, and solvates thereof.

[0343] The present invention relates to the manufacture of a medicament for the treatment or prevention, in particular the treatment, of any one of the above pathologies. The compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates are Regarding.

[0344] The present invention relates to a compound of formula (I) for the manufacture of a medicament for the treatment of any one of the above conditions. The present invention relates to compounds and their pharmaceutically acceptable addition salts, and solvates.

[0345] The present invention provides a method for treating or preventing any one of the above diseases in a mammal, preferably The present invention relates to compounds of formula (I) and their pharmaceutically acceptable addition salts, which may be administered to humans. and solvates.

[0346] The compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates are useful Considering this, it is important to understand how to treat warm-blooded animals, including humans, suffering from any of the above diseases. or a method for preventing warm-blooded animals, including humans, from contracting any one of the above diseases. is provided.

[0347] The method comprises administering to a warm-blooded animal, including a human, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Administration of an acceptable addition salt or solvate, i.e., systemic or local administration, preferably includes oral administration.

[0348] Those skilled in the art of treating such diseases will be able to determine effective daily therapeutic amounts from the test results presented below. An effective therapeutic daily dose may be determined to be approximately 0.005 mg / kg to 50 mg / kg, particularly 0.01mg / kg to 50mg / kg body weight, more particularly 0.01mg / kg g to 25 mg / kg body weight, preferably about 0.01 mg / kg to about 15 mg / kg, more preferably Preferably, about 0.01 mg / kg to about 10 mg / kg, even more preferably about 0. 0.01 mg / kg to about 1 mg / kg, most preferably about 0.05 mg / kg to about 1 mg / kg A specific effective therapeutic daily dose would be approximately 0.01 to 1.00 g 2 times a day. once per day (BID), more particularly, 0.30 to 0.85 g BID; even more particularly, 0.40 g BID. The active ingredient herein may be any ingredient necessary to achieve a therapeutic effect. The amount of the compound of the invention referred to will of course vary individually, e.g., depending on the particular compound, dosage, by route, the age and condition of the recipient, and the specific disorder or disease being treated. It will change.

[0349] The method of treatment also includes administering the active ingredient in a dosage regimen of 1 to 4 intakes per day. In these methods of treatment, the compounds of the present invention are preferably formulated prior to administration. As discussed herein below, suitable pharmaceutical formulations are available from well-known and readily available It can be prepared by known procedures using suitable ingredients.

[0350] The compounds of the present invention that may be suitable for treating or preventing cancer or cancer-related conditions include, but are not limited to, It may be administered alone or in combination with one or more additional therapeutic agents. , a compound of formula (I), a pharmaceutically acceptable addition salt, or solvate thereof, and one or more administration of a single pharmaceutical formulation containing multiple additional therapeutic agents, as well as a compound of formula (I), its pharmaceutically acceptable addition salts, or solvates, and in separate pharmaceutical formulations thereof The administration of each additional therapeutic agent, for example, a compound of formula (I), its pharmaceutically acceptable salts, The therapeutic agent may be administered in a single oral administration such as a tablet or capsule. The drugs may be administered to the patient together in an oral composition, or each drug may be administered in a separate oral dosage form. may be given.

[0351] While it is possible to administer the active ingredient alone, it is also possible to provide it as a pharmaceutical composition. is preferred.

[0352] Therefore, the present invention further provides a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of a compound of formula ( I), a pharmaceutically acceptable addition salt, or solvate thereof.

[0353] Thus, the present invention further provides a compound comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutic agent. A medicament comprising an effective amount of a compound of formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof. A composition is provided.

[0354] The carrier or diluent must be compatible with the other ingredients of the composition and not deleterious to the recipient thereof. It must be "acceptable" in the sense that

[0355] For ease of administration, the compounds may be formulated into various dosage forms for administration purposes. The compounds according to the invention, in particular the compounds of formula (I) and their pharmaceutically acceptable addition salts, The compounds and solvates, or any subgroups or combinations thereof, may be formulated into various dosage forms for administration. Suitable compositions include all compositions commonly used for systemically administered drugs. It is possible.

[0356] To prepare the pharmaceutical compositions of the present invention, an effective amount of the specified compound as the active ingredient is added to the pharmaceutical composition. The compound is combined in intimate admixture with a pharmaceutical acceptable carrier, which carrier is soluble in water depending on the dosage form desired for administration. These pharmaceutical compositions can be administered in a variety of forms, in particular for oral administration, rectal administration, and the like. Preferably in a unit dosage form suitable for administration transdermally, by parenteral injection or by inhalation. For example, when preparing a composition for oral administration, suspensions, syrups, elixirs, milk For oral liquid preparations such as tablets and liquids, e.g., water, glycol, oil, alcohol, etc. or in the case of powders, pills, capsules and tablets, starch, sugar, kaolin, diluents, Any of the usual pharmaceutical media may be used, such as solid carriers, such as lubricants, binders, disintegrants and the like. Because of their ease of administration, tablets and capsules are the most advantageous oral dosage unit forms, and In parenteral compositions, the carrier will usually be at least Both will mostly comprise sterile water, though other ingredients, for example, to aid solubility, may be included. For example, the carrier may be a saline solution, a glucose solution, or a mixture of saline and glucose solutions. Injectable solutions containing the compound of formula (I), its pharmaceutically acceptable adducts, Injectable solutions containing salts or solvates may be formulated in oil for prolonged action. Suitable oils for this purpose include, for example, peanut oil, sesame oil, cottonseed oil, corn oil, corn oil, and corn starch. Soybean oil, synthetic glycerol esters of long chain fatty acids, and mixtures of these with other oils. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In compositions suitable for transdermal administration, the carrier may contain a small number of suitable additives of any nature. Optionally, a penetration enhancer and / or a suitable wetting agent, optionally in combination in the ratio These additives do not cause any significant adverse effects on the skin. and / or are useful in preparing a desired composition. These compositions can be administered in various ways, for example, as a transdermal patch, as a spot-on, or as an active ingredient in a pharmaceutical composition. The acid or base addition salts of the compounds of formula (I) can be administered as the corresponding It is more soluble in water than either the base or acid form and is therefore more suitable for the preparation of aqueous compositions .

[0357] For ease of administration and uniformity of dosage, the above pharmaceutical compositions are formulated in unit dosage form. As used herein, unit dosage form refers to a unit dose. "A" refers to physically discrete units suitable for administration, each unit being combined with the required pharmaceutical carrier to provide the desired therapeutic effect. An example of such a unit dosage form is , tablets (including scored or coated tablets), capsules, pills, powder packets, wafers These include sachets, suppositories, injection solutions or suspensions, and their separate combinations.

[0358] The compounds of formula (I) and their pharmaceutically acceptable addition salts, and To enhance the solubility and / or stability of the solvate, α-, β-, or γ-cyclodextrin may be used. cyclodextrins or their derivatives, in particular hydroxyalkyl-substituted cyclodextrins, e.g. For example, 2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. It may be advantageous to use dextrin. Cosolvents such as alcohol may also be used in pharmaceutical compositions. The solubility and / or stability of the compounds according to the present invention may be improved.

[0359] Depending on the method of administration, the pharmaceutical composition preferably contains 0.05 to 99% by weight, more preferably or 0.1 to 70% by weight, even more preferably 0.1 to 50% by weight of the compound of formula (I) 1 to 99.95% by weight of the compound, a pharmaceutically acceptable addition salt, or a solvate thereof, Preferably, 30 to 99.9% by weight, even more preferably 50 to 99.9% by weight of pharmaceutical and a commercially acceptable carrier, and all percentages are based on the total weight of the composition. do.

[0360] In another aspect of the present invention, there is provided a method for treating cancer or related conditions, in particular for use as a medicament, more particularly for treating cancer or related conditions. Combinations of the compounds of the present invention with other anti-cancer agents are envisaged for use in treating disease.

[0361] For the treatment of the above conditions, the compounds of the present invention are useful in the treatment of immune cell redirection (r and T cell / neutrophil redirection), for example. This can be achieved, for example, by using bispecific monoclonal antibodies or artificial T cell receptors. This can be achieved by:

[0362] For the treatment of the above conditions, the compounds of the invention may be used in combination with one or more other drugs, more particularly In addition, it can be advantageously used in combination with other anti-cancer agents or adjuvants in cancer treatment. Examples of adjuvants (supporting agents in treatment) include, but are not limited to: Available: - optionally in combination with amifostine, carboplatin or oxaliplatin platinum coordination compounds, such as cisplatin; - Taxane compounds, e.g., paclitaxel, paclitaxel protein-bound particles (Ab raxane™) or docetaxel; - topoisomerase I inhibitors such as camptothecin compounds, e.g., irinotecan, SN -38, topotecan, topotecan hcl; - topoisomers such as antitumor epipodophyllotoxins or podophyllotoxin derivatives Enzyme II inhibitors, such as etoposide, etoposide phosphate, or teniposide; - antitumor vinca alkaloids, e.g., vinblastine, vincristine or vinorelbine Rubin; -Antineoplastic nucleoside derivatives, such as 5-fluorouracil, leucovorin, gemcitabine Tabine, gemcitabine hcl, capecitabine, cladribine, fludarabine, nelarabine ; - alkylating agents such as nitrogen mustard or nitrosoureas, e.g., cyclophosphite Sufamide, chlorambucil, carmustine, thiotepa, mephalan (melphalan), Lomustine, altretamine, busulfan, dacarbazine, estramustine, mesna Ifosfamide, pipobroman, procarbazine, streptobromide, or thiazolinone, optionally in combination with putozocin, temozolomide, uracil; - antitumor anthracycline derivatives, such as daunorubicin, dexrazoxane, and Optional combination of doxorubicin, doxil, idarubicin, and mitoxantrone , epirubicin, epirubicin hcl, valrubicin; - Molecules that target the IGF-1 receptor, such as picropodophyllin; - Tetrocarcin derivatives, such as tetrocarcin A; - Glucocorticoids, e.g. prednisone; -Antibodies, such as trastuzumab (HER2 antibody), rituximab (CD20 antibody), Mutuzumab, gemtuzumab-ozogamicin, cetuximab, pertuzumab, bevacizumab alemtuzumab, eculizumab, ibritumomab tiuxetan, nofetumomab, panitumumab, tositumomab, CNTO 328; -Estrogen receptor antagonists or selective estrogen receptor modulators or inhibitors of estrogen synthesis, such as tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene or letrozole; - Exemestane, Anastrozole, Letrazole, Testolactone and Borozole Aromatase inhibitors, such as le; - Differentiation agents and retinoic acid metabolic blockers such as retinoids, vitamin D or retinoic acid Abstinence medications (RAMBA), such as Accutane; DNA methyltransferase inhibitors, such as azacitidine or decitabine; -Antifolates, e.g., pemetrexed disodium; -Antibiotics, such as antinomycin D, bleomycin, mitomycin C, dactylic acid onomycin, carminomycin, daunomycin, levamisole, plicamycin, mitomycin Ramycin; - antimetabolites, e.g., clofarabine, aminopterin, cytosine arabinoside or Methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, Oguanine; - apoptosis inducers such as Bcl-2 inhibitors and anti-angiogenic agents, e.g., YC 13 7, BH 312, ABT 737, Gossypol, HA 14-1, TW 37 or De citric acid; -tubulin-binding agents, such as combrestatin, colchicine or nocodazole; -Kinase inhibitors (e.g., EGFR (epidermal growth factor receptor) inhibitors, MTKI (multi Targeted kinase inhibitors), mTOR inhibitors), e.g., flaboperidol, mesylate Imatinib, erlotinib, gefitinib, dasatinib, lapatinib, lapatinib-zitosine RATT, sorafenib, sunitinib, sunitinib maleate, temsirolimus; - Farnesyltransferase inhibitors, e.g. tipifarnib; histone deacetylase (HDAC) inhibitors, e.g., sodium butyrate, hydroxamic acid Suberoylanilide Phosphate (SAHA), Depsipeptide (FR 901228), NV P-LAQ824, R306465, JNJ-26481585, trichostatin A, Rinostat; - inhibitors of the ubiquitin-proteasome pathway, such as PS-341, MLN.41 or is bortezomib; - Yondelis; - telomerase inhibitors, e.g. telomestatin; - Matrix metalloproteinase inhibitors, e.g. batimastat, marimastat , Purinostat or Metastat. Recombinant interleukins, such as aldesleukin and denileukin diftitox, Interferon alpha 2a, interferon alpha 2b, pegylated interferon Alpha 2b -MAPK inhibitors - Retinoids, e.g. alitretinoin, bexarotene, tretinoin -Arsenic trioxide -Asparaginase -Steroids, such as dromostanolone propionate, megestrol acetate, and nandro ron (decanoate, fenpropionate), dexamethasone - gonadotropin-releasing hormone agonists or antagonists, e.g., abarelix, gosse acetate Relin, histrelin acetate, leuprolide acetate -thalidomide, lenalidomide -mercaptopurine, mitotane, pamidronate, pegademase, pegaspargase, Rasburicase -BH3 mimetics, e.g. ABT-737 -MEK inhibitors, e.g., PD98059, AZD6244, CI-1040 Colony-stimulating factor analogues, e.g., filgrastim, pegfilgrastim, sargu Lamostim; erythropoietin or its analogues (e.g., darbepoetin alfa); Interleukin-11; Oprelvekin; Zoledronate, zoledronic acid; Fentanyl; Bisphosphonates; Palifermin -Steroidal cytochrome P450 17alpha-hydroxylase-17,20- Lyase inhibitors (CYP17), e.g., abiraterone, abiraterone acetate Glycolysis inhibitors such as 2-oxyglucose -mTOR inhibitors such as rapamycin and rapalogs, and mTOR kinase inhibitors Agent -PI3K inhibitors and dual mTOR / PI3K inhibitors -Autophagy inhibitors such as chloroquine and hydroxychloroquine -Antibodies that reactivate the immune response against tumors, such as nivolumab (anti-PD-1), Brolizumab (anti-PD-1), ipilimumab (anti-CTLA4), and MPDL3280 A (anti-PD-L1).

[0363] The present invention further provides a method for treating a patient suffering from cancer, comprising administering to said patient, simultaneously, separately or sequentially, a compound according to the present invention as a first active ingredient in a combined preparation for therapeutic use; and one or more anti-cancer agents as further active ingredients.

[0364] The one or more other drugs and the compound of the present invention may be administered simultaneously (e.g., in separate compositions). The compounds may be administered in separate doses (as a single unit or unit composition) or sequentially in any order. In the latter case, two or more compounds may be present in sufficient amounts to ensure a beneficial or synergistic effect. The preferred administration methods and administration sequences, and The dosage and administration schedule of each component of the combination may vary depending on the specific other drugs and and the compounds of the present invention, their routes of administration, the particular tumors to be treated, and the particular host It will be understood that the optimum method and sequence of administration, as well as the dosage, will depend primarily on and dosage regimens can be determined by those skilled in the art using conventional methods and in view of the information provided herein. can be easily determined by

[0365] A compound of the present invention and one or more other anti-cancer agents when administered as a combination The weight ratio of the agents can be determined by one skilled in the art. The frequency will depend on the particular compound of the present invention and other anti-cancer agents used, as will be well known to those skilled in the art. the cancer drug, the specific condition being treated, the severity of the condition being treated, the age, weight, and sex of the specific patient , diet, administration time and general physical condition, administration method, and the individual's intake Furthermore, the effective daily amount will depend on the response of the treated subject. and / or depending on the evaluation of the physician prescribing the compounds of the present invention. It is apparent that the specific weight ratio of the compound of formula (I) and another anticancer agent can be is 1 / 10 to 10 / 1, more particularly 1 / 5 to 5 / 1, even more particularly 1 / 3 to 3 / 1 The range may be:

[0366] Platinum coordination compounds are administered in doses of 1 to 500 mg per square meter of body surface area per treatment course. mg / m 2 ), e.g., 50-400 mg / m 2 At a dose of 100 mg / kg, cisplatin in particular is about 7 mg / kg. 5 mg / m 2 and carboplatin at a dose of approximately 300 mg / m 2 and is advantageously administered .

[0367] Taxane compounds are administered at a dose of 50 to 400 mg per square meter of body surface area per treatment course. (mg / m 2 ), e.g., 75-250 mg / m 2 At this dose, paclitaxel in particular Approximately 175~250mg / m 2 and docetaxel at a dose of approximately 75-150 mg / m 2 in , is advantageously administered.

[0368] Camptothecin compounds are administered at doses of 0.1 to 4 per square meter of body surface area per course of treatment. 00mg(mg / m 2 ), e.g., 1 to 300 mg / m 2 In particular, irinotecan Approximately 100 to 350 mg / m 2 The dose of topotecan is approximately 1-2 mg / m2 So, yes It is administered to the benefit.

[0369] The antitumor podophyllotoxin derivatives are administered at a dose of 100 mg / m² of body surface area per treatment course. 30 to 300 mg (mg / m 2 ), e.g., 50-250 mg / m 2 In particular, at a dosage of Etoposide: approximately 35 to 100 mg / m 2 At a dose of 100mg / kg, teniposide is effective at approximately 50-250mg / kg. g / m 2 and is advantageously administered.

[0370] Antitumor vinca alkaloids are administered at doses of 2 to 100 mg / m² of body surface area per course of treatment. 30 mg (mg / m 2 ) dosage, especially for vinblastine, about 3-12 mg / m 2 of The dosage for vincristine is approximately 1-2 mg / m 2 At a dose of 10 mg / kg, vinorelbine ~30mg / m 2 It is advantageously administered in a dosage of

[0371] Antitumor nucleoside derivatives are administered at a dose of 20 mg / m² of body surface area per treatment course. 0 to 2500 mg (mg / m 2 ), e.g., 700-1500 mg / m 2 Especially at doses of , 200-500mg / m for 5-FU 2 At a dose of 120mg / kg, gemcitabine is about 800mg / kg. 00mg / m 2 and for capecitabine, the dose is approximately 1000-2500 mg / m 2 And advantageous is administered.

[0372] Alkylating agents such as nitrogen mustards or nitrosoureas should be administered at each course of treatment. , 100 to 500 mg per square meter of body surface area (mg / m2 ), for example, 120~2 00mg / m 2 In particular, cyclophosphamide is administered at a dose of approximately 100-500 mg / m 2 chlorambucil at a dose of about 0.1-0.2 mg / kg, and carmustine at a dose of about 0.1-0.2 mg / kg. Approximately 150-200 mg / m 2 The dose of lomustine is about 100-150 mg / m 2 It is advantageously administered in a dosage of

[0373] Antitumor anthracycline derivatives are administered at a dose of 100 mg / m² of body surface area per treatment course. 10 to 75 mg (mg / m 2 ), e.g., 15-60 mg / m 2 At this dosage, especially Sorubicin: approximately 40 to 75 mg / m 2 At a dose of 25-45mg / kg, daunorubicin g / m 2 and idarubicin at a dose of approximately 10-15 mg / m 2 Advantageously administered at a dose of will be done.

[0374] Antiestrogens are taken approximately 1-100 mg daily, depending on the specific drug and the condition being treated. Tamoxifen is advantageously administered in a dose of 5 to 50 mg, preferably 10 It is advantageously administered orally at a dose of ~20 mg twice daily to achieve and maintain a therapeutic effect. Continue treatment for a sufficient period of time. Toremifene is administered at a dose of approximately 60 mg once daily. and is advantageously administered orally and for a period of time sufficient to achieve and maintain a therapeutic effect. Anastrozole is advantageously administered orally in a dosage of about 1 mg once daily. Droloxifene is advantageously administered orally in a dose of about 20 to 100 mg once daily. Raloxifene is advantageously administered orally in a dosage of about 60 mg once a day. Semestane is advantageously administered orally in a dosage of about 25mg once a day.

[0375] Antibodies are released at a rate of approximately 1-5 mg per square meter of body surface area (mg / m 2 ) dosage, and If different, they are advantageously administered as known in the art. Mab is administered at a dose of 1 to 5 mg per square meter of body surface area (mg / m) per treatment course. 2 ), special 2-4 mg / m 2 It is advantageously administered in a dosage of

[0376] These dosages may be administered, for example, once, twice or more per course of treatment. This may be repeated, for example, every 7, 14, 21 or 28 days. Good too.

[0377] The following examples illustrate the invention. If no reference is given to R, this indicates that a mixture of R and S enantiomers was obtained. When two or more stereocenters are present in a structure, the specific stereochemistry is not shown. Each stereocenter was obtained as a mixture of R and S configurations.

[0378] Those skilled in the art typically collect the desired fractions after column purification and evaporate the solvent to obtain the desired product. It will be appreciated that by this method a compound or intermediate of formula (I) is obtained. [Example]

[0379] Hereinafter, the terms "rt", "rt" or "RT" mean room temperature; "Me" means "MeOH" means methanol; "Et" means ethyl; "E "tOH" means ethanol; "NaH" means sodium hydride; "DEAD" means diethyl azodicarboxylate; "HMPT" means hexamethylphosphorous triamide "BocO" means tert-butoxycarbonyl anhydride; "Bu t O "NO" means tert-butyl nitrite; "TosOH" means 4-methylbenzenesulfonate "TosCl" means 4-methylbenzenesulfonyl chloride (p-toluenesulfonic acid); "CMBP" means cyanomethylenetributyl ether (also known as sulfonyl chloride); "DBAD" means di-tert-butyl azodicarboxylate; "LAH" means lithium aluminum hydride; "NaBH(AcO)3" or " "NaBH(OAc)3" means sodium triacetoxyborohydride; "EtOA "c" means ethyl acetate; "TEA" or "Et3N" means triethylamine "DCM" means dichloromethane; "qs" means quantitative; "Int." means "MeCN" or "ACN" means acetonitrile; "DMF" means means N,N-dimethylformamide; "DMA" means N,N-dimethylacetamide "DMF-DMA" means N,N-dimethylformamide dimethyl acetal "Pd(dppf)Cl2" is [1,1'-bis(diphenylphosphino)ferro "THF" means tetrahydrofuran; ; "C 34 H 28 FeP2.Cl2Pd" is [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II); "i-PrOH" or "iPrO "H" means 2-propanol; "LC" means liquid chromatography; "LC "MS" means liquid chromatography / mass spectrometry; "HPLC" means high performance liquid chromatography "int." means intermediate; "prep-HPLC" means preparative "m-CPBA" means meta-chloroperbenzoic acid "TFA" means trifluoroacetic acid; "mp" means melting point; "RP" means melting point. means reverse phase; "min" means minute; "h" means hour; "PE" means petroleum ether "v / v" means volume / volume; "Celite®" means diatom "DMSO" means dimethyl sulfoxide; "SFC" means supercritical fluid chloride "DIPE" means diisopropyl ether; "dpp "f" or "DPPF" means 1,1'-bis(diphenylphosphino)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; "d(OH)2 / C" means palladium hydroxide / carbon; "CPME" means cyclopentyl methyl ether; Pd2(dba)3 is tris(dibenzylideneacetone)di "DIAD" means diisopropyl azodicarboxylate; "TM" means palladium; "SCF3" means trimethyl(trifluoromethyl)silane; "TBAF" means fluorinated "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 B "uOK" or "KOtBu" means potassium tert-butoxide; "Desmer "Thiphene periodinane" is 1,1,1-triacetoxy-1,1-dihydro-1,2-benzyl "TBDMSCl" means tert-butylbenzoyl-3(1H)-one; "PPh3-polymer" or "PPh3-pol " means polymer-bound triphenylphosphine; "Ph3PCH3Br" means methyltriphenylphosphine; "Bn" means benzyl; "Bz" means benzyl "p-TSA" means 4-methylbenzenesulfonic acid; "BF3 ".Et2O" means boron trifluoride-ethyl ether complex; "9-BBN" means 9-boron trifluoride. "Pd-118" means dichloro[1,1'-bicyclo[3.3.1]nonane; "T" means [(di-tert-butylphosphino)ferrocene]palladium(II); "LC" means thin layer chromatography; "prep-TLC" means preparative TLC "p-MeC6H4SO3H.H2O" means paratoluenesulfonic acid hydrate; "PMB" means paramethoxybenzyl; "KOAc" means potassium acetate; "P "TSA" means paratoluenesulfonic acid; "MTBE" means methyl tert-butyl ether Rh(acac)(eth)2 means acetylacetonatobis(ethylene ) rhodium(I); "(S)-MonoPhos" means (S)-N,N-dimethyl Dinaphtho[2,1-D:1',2'-F][1,3,2]dioxaphosphepin-4-a "Tf2O" means trifluoromethanesulfonic anhydride; "MeI " means methyl iodide; "Me2NH" means dimethylamine; "Me2NH. "HCl" means dimethylamine hydrochloride; "Me4NCl" means tetramethylammonium chloride "MeONa" means sodium methoxide; "Ts" means tosyl "MsCl" means mesyl chloride; "DIBAH" means diisobutylaluminum hydride "TBDMS" means tertbutyldimethylsilyl; "Pd(d ppf)Cl2.CH2Cl2 is [1,1'-bis(diphenylphosphino)ferrocene "PPA" stands for polyphosphorus dichloropalladium(II) dichloromethane complex; "NH2Bn" means benzylamine; "Pd(PPh3)2Cl2" means means dichlorobis(triphenylphosphine)palladium(II).

[0380] Intermediates containing double bonds with substituents that can be in the E or Z configuration are shown in the experimental section below. However, if explicitly indicated as (E) or (Z), Unless otherwise specified, these intermediates were obtained in either the E or Z configuration or as a mixture of both configurations. For example, intermediates 24-26, 29-31, 72-76, and Intermediates 79-88 may be in the E or Z configuration, or may be a mixture thereof. Intermediates 44, 97-100, 136-138, 150 and compounds 55, 57, 57 a and 61 were obtained in the E configuration and are explicitly designated as (E) as such in the experimental section below. will be done.

[0381] Intermediates used in the next reaction step either crude or as partially purified intermediates In the reaction protocol described below, the estimated molar amount (sometimes indicated by ≒) is Alternatively, the theoretical molar amount is shown.

[0382] A. Preparation of Intermediates Example A1 Preparation of Intermediate 1 [ka] 6-Chloro-7-deazapurine β-d-riboside (25. 2,2-dimethoxypropane (18.2 g, 17.0 mmol) was added to a mixture of 2,2-dimethoxypropane (18.2 g, 17.0 mmol). 5 mmol) and 4-methylbenzenesulfonic acid (TosOH) (1.51 g, 8.7 5 mmol) was added in one portion under N2 at 25° C. The mixture was stirred at 60° C. for 2 h. The mixture was cooled to 25° C. The reaction was cooled by the slow addition of saturated NaHCO3 (100 mL). The mixture was quenched by addition of 125 mL of ethyl acetate, followed by extraction with ethyl acetate (125 mL x 5). The combined organic phase was washed with saturated brine (120 mL), dried over anhydrous MgSO4, filtered, and The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (gradient elution: 1:0 to 2:1 DCM / ethyl acetate) to give crude Intermediate 1 (38.0 g) Obtained as colored gum.

[0383] Example A2 Preparation of intermediate 3 [ka] 5-O in CCl4 (12.8 mL, 133 mmol) and toluene (200 mL) -tert-Butyldimethylsilyl-2,3-o-isopropylidene-D-ribofuran A solution of 24.3 g (79.8 mmol) of acetone (Intermediate 2) was added to a solution of 24.3 g (79.8 mmol) of acetone (Intermediate 2) at -50°C for 30 min. After stirring the mixture at -50°C for 2 hours, the reaction mixture was cooled to -50°C and cooled to -50°C. It was quickly washed with cold brine (30 mL), dried over anhydrous Na2SO4, and added powdered KOH (6 .5g, 117mmol), 2,4-dichloro-7h-pyrrolopyrimidine (10.0g, 53 mmol), tris(3,6-dioxaheptyl)amine (8.27 mL, 26.6 The mixture was immediately added to a vigorously stirred mixture of 100 mmol of toluene (200 ml). The mixture was stirred at room temperature for 48 hours. The solvent was then concentrated under reduced pressure. The residue was dissolved in 250 ml of N The mixture was treated with HCl solution and extracted with ethyl acetate (300 ml x 2). The organic layers were combined. The mixture was evaporated, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel. Column chromatography (gradient elution: 25:1 to 15:1 petroleum ether) The product fractions were collected and the solvent was evaporated to give the desired Intermediate 3 (6.50 g, crude) was obtained.

[0384] Using the appropriate starting materials (Table 1), a reaction protocol similar to that used to prepare intermediate 3 was used. The following intermediates were prepared by

[0385] [Table 1]

[0386] Example A3 Preparation of Intermediate 6 [ka] Intermediate 3 (7.00 g, 14.8 mmol) was dissolved in a solvent mixture of acetic acid, water, and THF. The reaction mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure at 60° C. to give 6.8 g of crude intermediate 6, together with by-products. To a solution of the above crude product in acetone (50 mL) was added 2, 2-Dimethoxypropane (5 mL, 42 mmol) and 4-methylbenzenesulfonic acid monohydrate (13 mg, 0.07 mmol) was added, and the mixture was stirred at 60° C. for 2 hours. The solvent was removed under reduced pressure below 30° C. The residue was purified by column chromatography on silica gel. The column was purified by chromatography (gradient elution: 1 / 10 to 1 / 3 EtOAc / petroleum ether). and purification to give the desired intermediate 6 (3.02 g, 34% yield).

[0387] Example A4 Preparation of Intermediate 7 [ka] To a solution of intermediate 4 (9.50 g, 20.9 mmol) in THF (82 mL) at room temperature A 1 M solution of TBAF in THF (41.8 mL, 41.8 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 3 hours. The mixture was evaporated to dryness. The residue was taken up in water and diluted with DCM (15 The organic layer was dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient elution: 1 Purification by 0 / 1 to 4 / 1 petroleum ether / ethyl acetate gave the desired intermediate 7 (3 0.68g, 88% yield).

[0388] Using the appropriate starting materials (Table 2), a reaction protocol similar to that used to prepare intermediate 7 was used. The following intermediates were prepared by

[0389] [Table 2]

[0390] Example A5 Preparation of Intermediate 10 [ka] Process a) [ka] 4,6-Dichloro-5-propan-2-ol / H2O (208 mL, 7:1) (2,2-diethoxyethyl)pyrimidine (14.0 g, 52.8 mmol) and (1R ,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2 To a mixture of 10.7 g of 1,000 methyl-2 ... g, 132 mmol) was added in one portion at 25° C. under N2. The mixture was heated at 90° C. for 23 h. The mixture was cooled to 50°C and 4 M HCl (24 mL, 106 mmol) was added slowly. The residue was then stirred at 50°C for 2 hours. The reaction mixture was cooled to 25°C and N aHCO3 (14 g, 100 mmol) was added slowly. Ethyl acetate (230 mL) After adding acetic acid, a half-saturated NaHCO3 solution (appropriate amount) was added. The organic phase was isolated, and the aqueous phase was The combined organic phase was dried over anhydrous MgSO4 and extracted with ethyl acetate (230 mL x 2). , filtered, and concentrated under reduced pressure to give Intermediate 9 as a yellow solid (17.4 g, quantitative yield in two steps). The crude product was used directly in the next reaction step without further purification.

[0391] Step b) [ka] To a mixture of intermediate 9 (17.4 g, ≈52.7 mmol) in acetone (250 mL) , 2,2-dimethoxypropane (11.0 g, 105 mmol) and TsOH.HO (908 mg, 5.27 mmol) was added in one portion under N2 at 25 °C. The mixture was stirred for 60 The mixture was stirred at 25°C for 2 hours. The mixture was cooled to 25°C, and the solution was concentrated under reduced pressure and saturated NaHCO Quench slowly with 3 (100 mL), then ethyl acetate (100 mL x 3) The combined organic phase was washed with saturated brine (100 mL) and extracted with anhydrous MgSO4 The mixture was dried at 77°C, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel. Purification by chromatography (gradient elution: 1 / 0 to 2 / 1 DCM / ethyl acetate) This gave Intermediate 10 as a pale yellow gum (15.5 g, 89% yield).

[0392] Example A6 Preparation of intermediate 14 [ka] Process a) [ka] In an oven-dried flask, 7-bromo-4-(methylthio)pyrrolo[2 ,1-f][1,2,4]triazine (45.0 g, 184 mmol) and dry THF (1.20 L). The yellow solution was cooled to -78°C, forming a yellow suspension. n-BuLi (2.5 M, 79.6 mL) was added and the mixture was reacted at -78°C for 25 minutes. The reaction mixture was stirred at -78°C for 1 hour, forming a yellow-brown solution. In a separate flask (-78 °C), intermediate 10 (8 mL) in dry THF (800 mL) was added. A pre-cooled solution of 4.0 g (201 mmol) was added to the solution under N2. The reddish-brown solution was stirred at -78°C for 1.5 hours. Two batches were run in parallel. The reaction was Quench the reaction at 78°C by adding saturated aqueous NH4Cl (300 mL), then mix. The mixture was warmed to 10°C. The mixture was extracted with ethyl acetate (500 mL x 3). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Packed on silica gel and then subjected to column chromatography (SiO2, gradient elution 1:10 / 1 to 3:1 petroleum ether / ethyl acetate) to give Intermediate 11 (1 49 g, 56% yield) was obtained as an orange gum.

[0393] Step b) [ka] Intermediate 11 (74.0 g, 127 mmol) and triethylenediamine in DCM (1.80 L) A stirred solution of ruthenium (59.9 g, 515 mmol) was added to BF3.E at -30 to -20 °C. t2O (90.9 g, 640 mmol) was added dropwise. Two batches were run in parallel. The resulting orange solution was stirred at -30 to -20°C for 4.5 hours. The mixture was carefully poured into saturated aqueous NaHCO3 (2.5 L) with vigorous stirring (gas evolution). The mixture was stirred for 2 hours. The organic layer was separated and the aqueous layer was extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (500 mL × 2) and dried over MgSO4. The residue was purified by column chromatography (silica gel, gradient Purification by elution with petroleum ether:ethyl acetate:12:1 to 8:1 12 was obtained as a pale yellow gum (125.7 g, 83% yield).

[0394] Process c) [ka] 1 M BCl in CH2Cl2 (860 mL, 860 mmol) was dissolved in DCM (1.20 dropwise to a stirred solution of Intermediate 12 (75.0 g, 132 mmol) in 1 mL of HCl at −78° C. The mixture was added dropwise under N2 over a period of 2.5 hours. The mixture was stirred at -78 °C for 1 hour. The reaction mixture was slowly warmed to -40°C. The reaction mixture was stirred and added with MeOH ( The resulting red solution was stirred for 3 hours. The mixture was then heated to 20°C for 16 hours. The mixture was carefully poured in portions onto solid NaHCO3 (500 g) (gas evolution occurred, the color of the mixture The resulting suspension was filtered and the filtrate was concentrated under reduced pressure. Partitioned in iPrOH / CH2Cl2 (1:3, 1 L) and filtered (to remove some inorganic salts) The filtrate was concentrated under reduced pressure, and the residue was triturated with petroleum ether (500 mL × 3). This gave crude intermediate 13 (40.2 g, crude) as an orange solid, which was further purified by It was used in the next reaction step without purification.

[0395] Step d) [ka] Intermediate 13 (40.2 g, crude) and 2,2-dimethacrylate in acetone (600 mL) A suspension of 2,4-dimethylpropane (34 mL, 277 mmol) was added to 100 mL of TsOH at 25 °C (pH = 2). HO (5.92 g, 31.10 mmol, 0.23 equiv.) was added. The resulting mixture The mixture was heated at 60° C. for 2 hours. After cooling to 25° C., the reaction mixture was concentrated under reduced pressure. The mixture was partitioned between ethyl acetate (500 mL) and saturated aqueous NaHCO3 (500 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (200 mL x 3). Washed with water (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting mixture was purified by column chromatography (silica gel, gradient elution: 10 / 1 to 6 / 1 The fractions containing the desired intermediate 14 were combined. The combined solution was concentrated under reduced pressure. The residue (28 g, approximately 80% pure) was purified by column chromatography. Fee (silica gel, gradient elution: petroleum ether / ethyl acetate: 20 / 1 to 4 / The desired fractions were combined and concentrated under reduced pressure. The residue was purified again by CH Diluted with 200 mL of petroleum ether / ethyl acetate (4:1, The mixture was concentrated to about 150 mL and the solid was allowed to settle. The mixture was diluted with petroleum ether to approximately 400 mL and stirred at 20° C. for 16 hours. Filter and rinse the solid with petroleum ether / ethyl acetate (20 / 1, 100 mL). The pure intermediate 14 was collected and dried under high vacuum to give a white solid (18.6 g, 2 steps). The compound was obtained as a 42% yield.

[0396] Example A7 Preparation of Intermediate 15 [ka] Intermediate 1 (10.0g, ≒28.6mmol), TEA (12mL, 85.7mmol ) and DMAP (0.70 g, 5.71 mmol) in CHCl (100 mL). p-Toluenesulfonyl chloride (10.9 g, 57.1 mmol) was dissolved at 0°C. The mixture was stirred at room temperature overnight. Water (100 mL) was added to the above solution. The aqueous layer The mixture was extracted with DCM (100 mL x 3). The combined organic layers were dried over Na2SO4. The residue was purified by flash column elution (gradient elution: 1 / 0 to 3 / 1). The product fractions were collected and the solvent was evaporated. This gave Intermediate 15 as a yellow oil (14.5 g, 97% yield).

[0397] Using the appropriate starting materials (Table 3), a reaction protocol similar to that used to prepare intermediate 15 was used. The following intermediates were prepared by Coll.

[0398] [Table 3]

[0399] Example A8 Preparation of intermediate 18 [ka] Intermediate 1 (100.0 g, theoretically 307 mmol) was dissolved in 400 mL of 1,4-dioxa- Next, 400 mL of aqueous ammonia (28-30% 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 reduced pressure to remove half of the solvent. Water (200 mL) was added and Et The combined organic layer was extracted with brine (200 ml × 2). The mixture was washed with HCl, dried and concentrated to give intermediate 18 as a white solid (93 g, 93% yield). I got it.

[0400] Using the appropriate starting materials (Table 4), a similar reaction protocol to that used to prepare intermediate 18 was used. The following intermediates were prepared by Coll.

[0401] [Table 4]

[0402] Example A9 Preparation of intermediate 23 [ka] Step a: [ka] To a solution of intermediate 21 (6.6 g, 9.75 mmol) in THF (130 mL) was added 10 mL of HCl at room temperature. Ammonia (28% in H2O, 65 mL) was added at rt. The reaction mixture was stirred for 16 h. The reaction mixture was cooled to room temperature and stirred at 100°C (using an autoclave). The residue was taken up in water (100 mL) and DCM (100 mL) and 1 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 flash chromatography on silica. by chromatography (gradient elution: 95:5 to 90:10 DCM / MeOH). The desired fractions were collected and the solvent was evaporated to give intermediate 22 (3.4 g, crude). The crude product was used directly in the next reaction step without further purification.

[0403] Step b: [ka] To a mixture of Intermediate 22 (1.0 g, crude) in acetone (32 mL) was added 2,2-dimethyl Iodoxypropane (1.78 mL, 14.5 mmol) and 4-methylbenzenesulfonyl To the mixture was added carboxylic acid (0.61 g, 3.19 mmol) at room temperature in one portion. The mixture was heated at 60°C for 3 hours. The mixture was cooled to room temperature and saturated NaHCO3 (10 mL) was added slowly. The mixture was quenched by addition of 10 mL of ethyl acetate and then extracted with ethyl acetate (50 mL x 5). The combined organic phase was washed with saturated brine (120 mL), dried over MgSO4, filtered, and evaporated under reduced pressure. The crude product was carried on to the next step without further purification. was used directly in the reaction step.

[0404] Example A10 Preparation of intermediate 24 [ka] Intermediate 18 (10.0 g, 32.6 mmol) was dissolved in THF (200 ml). Next, dimethylformamide dimethyl acetal (DMF-DMA) (5.84 g, 49 0.0 mmol) was added. The mixture was stirred at 60°C for 24 hours. The mixture was cooled to room temperature and The solvent was concentrated under reduced pressure. The residue was triturated with EtOAc (200 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (200 mL × 1). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. This gave the desired intermediate 24 as a yellow solid (10.5 g, 85% yield).

[0405] Using the appropriate starting materials (Table 5), a similar reaction protocol to that used to prepare intermediate 24 was used. The following intermediates were prepared by Coll.

[0406] [Table 5]

[0407] Example A11 [ka] Step a: [ka] Intermediate 18 (88.0 g, 287 mmol) and iminomethyl ... To a mixture of 1,2-dimethyl-2,4-triazol-2-one (39.1 g, 575 mmol), TBDMSCl (52.0 g, 345 mmol) was added in one portion under N2 at 0°C. The reaction mixture was stirred at room temperature overnight. Then, water (500 ml) was added, and the mixture was extracted with EtOAc (800 mL × 3). The organic layer was washed with brine (500 mL). The organic layer was then dried over anhydrous Na2SO4. The crude product was purified by column chromatography on silica gel. Column chromatography (gradient elution: petroleum ether / ethyl acetate 1:1) The desired fractions were concentrated to give Intermediate 27 as an oil (120 g, 96% yield). I got it.

[0408] Step b: [ka] Intermediate 27 (12.4 g, ≈24.4 mmol) and DMA in THF (50 mL) A solution of P (0.30 g, 2.44 mmol) was added to (Boc)O (13.3 g, 6 The reaction mixture was stirred at room temperature for 3 hours. Then, THF A 1 M solution of TBAF in (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 ethyl acetate (250 mL The organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (elution: ethyl acetate / heptane). The desired fractions were collected and the residue was stirred in heptane. The solid product was filtered off and dried under reduced pressure at room temperature to give Intermediate 28 (10.2 g). , 83% yield) was obtained as a solid product.

[0409] Using the appropriate starting materials (Table 23), a reaction protocol similar to that used to prepare intermediate 28 was used. The following intermediates were prepared by protocol:

[0410] [Table 6]

[0411] Example A12 Preparation of intermediate 29 [ka] Intermediate 24 (15.0 g, 41.7 mmol) and Et3 N (11.6 mL, 83.3 mmol) and DMAP (509 mg, 4.17 mmol) To the reaction mixture was added p-toluenesulfonyl chloride (8.74 g, 45.9 mmol) was added at room temperature. 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 layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. Condensation gave crude intermediate 29 as a brown solid, which was carried to the next reaction step without further purification. Used.

[0412] Using the appropriate starting materials (Table 6), a reaction protocol similar to that used to prepare intermediate 29 was used. The following intermediates were prepared by Coll.

[0413] [Table 7]

[0414] Example A12b Preparation of intermediate 32 [ka] Intermediate 28 (4.5g, 8.89mmol), TEA (2.70g, 26.6mmol ), DMAP (0.54 g, 4.4 mmol) and DCM (40 ml) were stirred in an ice bath. p-Toluenesulfonyl chloride (3.39 g, 17.8 mmol) was added dropwise. The mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water and extracted with DCM. The layer was evaporated and purified by flash chromatography on silica (eluent: DCM 98% M Purification by eOH 2%) gave intermediate 32 (5.6 g, 95% yield).

[0415] Example A13 Preparation of intermediate 33 [ka] A mixture of intermediate 1 (2.00 g, theoretically 6.18 mmol) in DCM (40 mL) Dess-Martin periodinane (5.24 g, 12.36 mmol) was added to the , was added in one portion at 0°C. The mixture was stirred at 0°C for 3 hours. The mixture was added with saturated NaHCO3 ( NaSO (4 g) in 20 mL of DCM was added and stirred for 10 min. The combined organic phase was washed with saturated brine (20 mL × 2) and Drying with MgSO4, filtering and concentrating under reduced pressure gave Intermediate 33 (1.80 g, crude ) was obtained as a pale yellow gum. The crude product was used directly in the next reaction step without further purification. .

[0416] Using the appropriate starting materials (Table 7), a reaction protocol similar to that used to prepare intermediate 33 was used. The following intermediates were prepared by Coll.

[0417] [Table 8]

[0418] Example A14 Preparation of intermediate 37 [ka] of intermediate 33 (6.5 g, crude, ≈15.46 mmol) in THF (200 mL) The solution was treated with MeMgBr (1M, 18.55 ml, 18.55 mmol) at -78 °C under N2. l) was added dropwise. The mixture was stirred overnight at room temperature under N2. The reaction mixture was then cooled under reduced pressure. The crude product was purified by column chromatography to give the crude product as a yellow solid. Purified by (gradient elution: 40:1 to 10:1 petroleum ether / EtOAc) The desired fractions were collected and the solvent was evaporated to give intermediate 37 as a pale yellow oil (700 mg crude; and 3 g of crude containing further impurities).

[0419] Example A15 Preparation of intermediate 38 Method 1 [ka] Methyltriphenylphosphonium bromide (4.87 g, 1 To a mixture of t-BuOK (11.4 mL, THF 3.62 mmol) was added t-BuOK (11.4 mL, THF 3.62 mmol) at 0 °C under N A solution of 1M HCl (1.27 g, 11.35 mmol) was added dropwise. The suspension turned bright yellow. It was stirred at 0° C. for 0.5 h and then warmed to 25° C. over 0.5 h. The mixture was cooled to -40°C. Intermediate 35 (1.46 g, theoretical) in THF (130.0 mL) A solution of 4.54 mmol) was added dropwise, followed by stirring at -20°C for 1 hour. The mixture was warmed to 25° C. over 2 hours. The mixture was added saturated NH4Cl (300 ml ) was added and stirred for 10 minutes. The layers were separated and the aqueous phase was extracted with DCM (300 mL x 2). The combined organic phase was washed with saturated brine (500 mL) and dried over anhydrous MgSO4. The residue was purified by silica gel chromatography (ISCO). 80 g SepaFlash® silica flash column, gradient The desired fractions were collected. The mixture was collected and the solvent was evaporated. Intermediate 38 was obtained as an off-white solid (530 mg, 36% yield). The results were obtained as the rate.

[0420] Using the appropriate starting materials (Table 8), a similar reaction protocol to that used to prepare intermediate 38 was used. The following intermediates were prepared by Coll (Method 1):

[0421] [Table 9]

[0422] Method 2 [ka] Dissolution of intermediate 35 (10.0 g, theoretically 31.1 mmol) in THF (100 mL) The solution was stirred under N2 for a period of 30 minutes in a solution of bis(iodozincio)methane in THF. Liquid (180mL, 0.31M, 55.9mmol, Tetrahedron 2002, 58, 8255-8262) and Stirring was continued until complete conversion (approximately 2 hours). The reaction mixture was slowly diluted with saturated aqueous NH4Cl. The mixture was quenched by the rapid addition of HCl, during which salt formation was observed. The salts were redissolved by the addition of aqueous ammonia (25%). The combined organic phase was washed with aqueous sodium bisulfite and brine, and then with anhydrous MgS The residue was purified by silica gel chromatography ( Purification by dichloromethane / EtOAc 95 / 5 gave intermediate 38. Obtained as a white solid (6.9 g, 66%).

[0423] Method 3 Process 1 Preparation of Intermediate 408 [ka] Acetylacetonatobis(ethylene)rhodium(I) (0.837 g, 3.24 mmol) l) and (R)-N,N-dimethyldinaphtho[2,1-D:1',2'-F][1,3 ,2]Dioxaphosphepin-4-amine (2.91 g, 8.11 mmol) was added to a nitrogen atmosphere. The mixture was stirred at room temperature and stirred for 15 minutes. The mixture was then flushed with nitrogen gas. 2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-one (25 g, 162.16 mmol) and potassium vinyltrifluoroborate (45.73 g , 324.33 mmol) was added, and then the reaction mixture was stirred and refluxed for 4 hours. The mixture (suspension) was cooled to room temperature. The precipitate was removed by filtration on a pad of Celite. The filtrate was evaporated and 1 L of heptane was added to the residue. The resulting suspension was filtered over a pad of Celite and washed with heptane to give a dark brown A solid residue was obtained. The filtrate was washed with 300 mL of NH4OH three times, washed with brine, and Drying over O4, filtration and evaporation of the filtrate's solvent gave intermediate 408 (16.18 g, 51 % yield).

[0424] Process 2 Preparation of Intermediate 409 [ka] A solution of intermediate 408 (16.18 g, 82.58 mmol) in THF (200 mL) was dissolved in THF (24.78 mL, 1 Add dropwise to a stirred solution of 1M lithium aluminum hydride in 1M HCl (24.78 mmol). The reaction mixture was stirred at −78° C. under a nitrogen atmosphere for 30 minutes. The mixture was then cooled to -78°C by dropwise addition of acetone (6.1 mL) followed by 50 mL of water. After the addition, the reaction mixture was warmed to room temperature and then quenched with 400 mL of EtOAc. The mixture was shaken vigorously. The organic layer was separated and washed three times with water, then with brine, It was dried over MgSO4, filtered, and the filtrate was evaporated. The residue was dissolved in ethyl acetate. , starting with 100% heptane and ending with 50% heptane and 50% ethyl acetate Armen Spot was run using ethyl acetate and heptane as eluents with a gradient of II Ultimate Purification System, SiO2 column, type Grace R The product was purified on a Benzene sieve, 80 g, Si 40. The fractions containing the product were Combined and evaporated the solvent to give intermediate 409 (10.77 g, 71% yield) .

[0425] Process 3 Preparation of Intermediate 410 [ka] TfO (13.31 mL, 1.71 g / mL, 80.9 mL) in anhydrous DCM (60 mL) A solution of Intermediate 409 (9.94 g, 3 mmol) in anhydrous DCM (140 mL) was added at 0° C. The reaction mixture was added dropwise to a mixture of 1,2-dimethyl-3-pyridine (53.95 mmol) and anhydrous pyridine (85 mL). The mixture was stirred for 30 minutes, then 75 mL of cold water was added. The layers were separated and the organic layer was extracted with 75 mL of Wash with 3 L of water, dry with MgSO4, filter, evaporate the solvent, and add 200 mL of The residue was dissolved in heptane and ethyl acetate and diluted with 100% heptane. The eluent was a gradient starting from hexane and ending with 50% heptane and 50% ethyl acetate. Armen Spot II Ultima with ethyl acetate and heptane as In the te purification system, SiO2 column, type Grace Reveleris SRC, 40 g, purified on Si 40. The product-containing fractions were combined and Evaporation gave intermediate 410 (13.0 g, 67% yield).

[0426] Process 4 Preparation of Intermediate 411 [ka] 4-Chloro-7H-pyrrolo[2,3-D]pyrimidine (100g) in THF (1L) A mixture of KOtBu (73.07 g, 651 mmol) and KOtBu (73.07 g, 651 mmol) was The mixture was stirred at room temperature for 45 minutes until a clear solution was obtained. The solvent was evaporated. The residue was dissolved in DIPE. The white solid was filtered off and dried under vacuum at 30° C. to give Intermediate 4 11 (112.6 g, 90% yield) was obtained.

[0427] Process 5 Preparation of intermediate 38 [ka] A solution of intermediate 410 (13 g, 41.1 mmol) in DMF (50 mL) was added at 0 °C. To a stirred solution of intermediate 411 (7.88 g, 41.1 mmol) in DMF (150 mL) After the addition, the reaction mixture was allowed to warm to room temperature and then stirred for 18 hours. A quantity of Intermediate 411 (1.57 g, 8.22 mmol) was added. The reaction mixture was stirred at room temperature for 2 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 heated at 50°C. Drying under reduced pressure gave intermediate 38 as a white solid (8.75 g, 65% yield) .

[0428] Example A54 Preparation of intermediate 433 [ka] Intermediate 3 in a mixture of aqueous ammonia (25%, 100 ml) and THF (100 ml) A solution of 8 (18.3 g, 57.22 mmol) was stirred in a sealed vessel until complete conversion (approximately 16 h). The reaction mixture was heated to 110°C in a metal pressure vessel. The reaction mixture was cooled to room temperature and then Ethyl acetate and brine were added. The layers were separated and the aqueous layer was extracted once with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. to give intermediate 433 as a pale yellow solid (17.2 g, 100%), which was further purified by It was used in the next reaction step without purification.

[0429] Using the appropriate starting materials (Table 24), a reaction protocol similar to that used to prepare intermediate 433 was used. The following intermediates were prepared by protocol:

[0430] [Table 10]

[0431] Example A16 Preparation of intermediate 41 [ka] Potassium tert-butoxide (1.28 g; 11 To a solution of 1.4 mmol) of dimethyl (1-diazo-2-oxopropanol) in THF (5 mL) A solution of 1.72 g (11.4 mmol) of methyl phosphonate was added. The solution was stirred for 5 minutes. Stir, then add intermediate 33 (1.90 g; theoretical 5.87 mmol) in THF (20 mL). l) solution was added. The solution was warmed to room temperature and stirred at room temperature for 15 minutes. Water and EtOAc was added and the organic layer was separated, dried over MgSO4, filtered and evaporated under reduced pressure. The column was then subjected to preparative LC (amorphous SiOH 15-40 μm, 80 g of Grace, packed in DCM, and transferred to a Phase gradient elution: 90:10 to 70:30 heptane in EtOAc: 10% The desired fractions were collected and the solvent was evaporated to give intermediate 41. Obtained as a colored oil (1.08 g, 58% yield).

[0432] Example A17 Preparation of intermediate 43 [ka] To a solution of intermediate 42 (9.2 g, 34.114 mmol) in acetone (100 mL) , 2,2-dimethoxypropane (7.1 g, 68.118 mmol) and p-TSA ( The reaction mixture was stirred at room temperature overnight. The mixture was treated with aqueous NaHCO3 (to pH 7-8) and then concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The layers were dried and concentrated under reduced pressure. The crude product was purified by silica gel chromatography ( Purification was carried out by elution with petroleum ether / ethyl acetate (8 / 1 to 2 / 1). The fractions were collected and the solvent was evaporated to give intermediate 43 as a pale yellow solid (9.5 g, 90% yield) ) was obtained.

[0433] Example A18 Preparation of intermediate 44 [ka] of intermediate 1 (2.00 g, theoretical 6.18 mmol) in DCM (30.00 mL) The solution was diluted with Dess-Martin periodinane in DCM (30.00 mL) at 0 °C under N2. The mixture was added dropwise to a suspension of ethanol (3.14 g, 7.41 mmol). The reaction mixture was allowed to warm to room temperature for 2 h. Then, MeOH (60 mL) and tosylhydrazine were added. Diazide (1.50 g, 8.03 mmol) was added and stirring was continued for 3 hours. The organic phase was separated, washed with saturated Na2CO3 and anhydrous MgSO4. The crude product was purified by silica gel column chromatography after drying, filtering and concentrating under reduced pressure. - (Gradient elution: 100:0 to 98.5:1.5 dichloromethane / methanol The desired fractions were collected and the solvent was evaporated to give intermediate 44 as a white powder. (2.60 g, 70% yield; (E)).

[0434] Using the appropriate starting materials (Table 25), a reaction protocol similar to that used to prepare Intermediate 44 was used. The following intermediates were prepared by Coll.

[0435] [Table 11]

[0436] Example A55 Preparation of Intermediate 224 [ka] Step 1: Preparation of Intermediate 222 DIAD (7.6 mL, 38.4 mmol, 2.5 equiv.) was dissolved in anhydrous THF (75 Intermediate 2 (5.0 g, 15.3 mmol, 1.0 equiv.) in 1 mL of 10 ... Acetone cyanohydrin (5.0 g, 38.4 mmol, 2.5 equiv.) and acetone cyanohydrin (5.0 g, 38.4 mmol, 2.5 equiv.) were added. The reaction mixture was stirred for 1 hour. The crude product was purified by sequential elution with heptane and DCM as eluents. Phase flash chromatography (SiO column, gradient: 50% to 100% DCM , isocratic 100% DCM), followed by 0.2% NH4HCO3 as eluent. Purified by preparative reversed-phase flash chromatography using acetonitrile and water Intermediate 222 was obtained as a white solid product (2.8 g, 8.5 mmol, 55% yield). I got it.

[0437] Step 2: Preparation of Intermediate 223 and Intermediate 224 A solution of intermediate 222 (1.54 g, 4.6 mmol, 1 equiv.) in anhydrous DCM was added to the The mixture was dried on a sieve overnight and filtered. The filtrate was cooled to -78°C and then diluted with DCM (4.6 mL, 1 M DIBAH in HCl (4.6 mmol, 1 equiv.) was added dropwise. The reaction mixture was cooled to -78°C. The mixture was stirred at rt for 1 h, then added to DCM (0.46 mL, 0.46 mmol, 0.1 equiv). Additional 1M DIBAH was added and stirred for an additional 1.5 hours, then the mixture was diluted with water / THF (5 Sodium acetate (4.2 g, 51.2 mmol, 11.1 equiv.) in 1 mL of HCl (7 mL / 12 mL). and acetic acid (4.2 mL, 73.4 mL, 16.0 equiv.). 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 phase The extract was extracted twice with DCM (30 mL). The organic phases were combined, washed twice with brine, and The resulting filtrate containing intermediate 223 was added to MeOH (5 0 mL), p-toluenesulfonyl hydrazide (1.1 g, 6.0 mmol, 3 equiv.) The reaction mixture was added and then stirred at room temperature for 40 minutes. The reaction mixture was washed with saturated NaHCO3 three times and brine three times. The crude product was washed twice, dried over MgSO4, filtered and concentrated under reduced pressure. Normal phase flash chromatography (gradient: 4 Purification with 0% to 60% EtOAc gave the crude product. Normal phase flash chromatography (SiO2 column) using EtOAc and heptane Further purification by hexane distillation (eluent, gradient: 40% to 60% EtOAc) gave intermediate 224 ( 0.5g, 0.6mmol, yield: 14%) was obtained.

[0438] Example A19 Preparation of intermediate 45 [ka] Intermediate 1 (300 mg, theoretical 0.921 mmol), 7-quinolinol (160 mg), g, 1.11 mmol) and polymer-bound triphenylphosphine (approximately 3 mmol / g triphenylphosphine charge (0.8 g, 2.4 mmol) was dissolved in anhydrous THF under N2. (12 mL). Then, DIAD (0.465 g, 2.30 mmol) was added to The mixture was stirred at room temperature under N2 for 12 hours. The residue was filtered over a pad of diatomaceous earth, washed with MeOH, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: petroleum eluent 10 / 1 to 3 / 1). The desired fractions were collected and the solvent was evaporated to give the crude product. Intermediate 45 was obtained as an oil (342 mg).

[0439] Using the appropriate starting materials (Table 9), a reaction protocol similar to that used to prepare intermediate 45 was used. The following intermediates were prepared by Coll.

[0440] [Table 12]

[0441] [Table 13]

[0442] [Table 14]

[0443] [Table 15]

[0444] Example A19b Preparation of intermediate 59 [ka] Diisopropyl azodicarboxylate (0.221 mL, 1.125 mmol) was added at room temperature Intermediate 1 (0.27 g, 0.80 mmol), 3-bromoquinoline in THF (8 ml) -7-ol (0.18 g, 0.80 mmol) and triphenylphosphine resin (0 The solution was added dropwise to a stirred suspension of 1.375 g, 3 mmol / g, 1.125 mmol. After the addition, the reaction mixture was stirred for 18 hours. The residue was washed with methanol. The filtrate was evaporated. The residue was Used as is in the next step.

[0445] Example A20 Preparation of Intermediate 61 [ka] Intermediate 1 (2.46 g, theoretically 7.54 mmol) in dry THF (40 ml) , 2-methylquinolin-7-ol (1.2 g, 7.54 mmol) and PPh3 (5. A mixture of 4.93 g, 22.6 mmol) was stirred at room temperature under N2. 57 g, 22.6 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. 80 mL) was added to the mixture and extracted with EtOAc (100 mL x 3). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (gradient elution: 1:20 to 1: The desired fractions were collected and the solvent was evaporated. Intermediate 61 (3.0 g, crude) was obtained. The crude Intermediate 61 was used in the next reaction without further purification. It was used in the reaction process.

[0446] Using the appropriate starting materials (Table 10), a reaction protocol similar to that used to prepare Intermediate 61 was used. The following intermediates were prepared by protocol:

[0447] [Table 16]

[0448] [Table 17]

[0449] Example A21 Preparation of intermediate 71 [ka] Intermediate 1 (1.00 g, ≈2.92 mmol) and 2-naphthalene-2-ol in toluene (30 mL) A solution of acetone (463 mg, 3.21 mmol) was added to CMBP (1.15 mL, 4.3 8 mmol) was added. The solution was heated at 80°C for 18 hours and then cooled to room temperature. The mixture was evaporated under reduced pressure. The residue was purified by preparative LC (amorphous SiOH 15-40 μm, 120 Grace, DCM sediment, mobile phase gradient: 80 / 20 to 70 / 30 heptane / E tOAc) to give intermediate 71 as a colorless gum (1.00 g, 76% yield). And got it.

[0450] Example A22 Preparation of intermediate 72 [ka] PPh3 (9.07 g, 34.6 mmol) in THF (100 mL) and DEAD (4.82 g, 27.7 mmol) was stirred at room temperature for 10 minutes. 24 (5.0 g, theoretically 13.8 mmol) was added, followed by 2-chloroquinolin-7-ol. The resulting mixture was stirred at room temperature overnight. The mixture was then diluted with EtOAc (100 mL) and washed with water and brine. The phase was dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (elution The desired fractions were collected and concentrated. This gave Intermediate 72 as a solid (6.0 g, 83% yield).

[0451] Example A23 Preparation of intermediate 73 [ka] Intermediate 24 (700 mg, theoretical 1.94 mmol) in THF (20 mL) and A solution of 4-methylquinolin-7-ol (370 mg, 2.32 mmol) was added to triphenyl Triphenylphosine (624mg, 2.71mmol) ) and DBAD (711 mg, 2.71 mmol) were added. The mixture was stirred at room temperature overnight. The crude product was purified by preparative LC (amorphous SiOH, 15-40 μm , 50 g, Merck, dry packed (Celite®) Mobile phase gradient: heptane 8 0%, 18% EtOAc, 2% MeOH to 10% heptane, 81% EtOAc, MeO Purification by HCl (9%) gave intermediate 73 as an off-white foam (697 mg, 67%). The yield was 100%.

[0452] Using the appropriate starting material...

Claims

1. The following: 【Chemistry 1-1】 【Chemistry 1-2】 1. A compound selected from the group consisting of: or a pharmaceutically acceptable addition salt or solvate thereof.

2. The compound is: 【Chemistry 2】 2. The compound of claim 1, which is a compound of formula (I): or a pharmaceutically acceptable addition salt or solvate thereof.

3. The following: 【Chemistry 3】 3. The compound of claim 2, wherein

4. The compound is: 【Chemistry 4】 2. The compound of claim 1, which is a compound of formula (I): or a pharmaceutically acceptable addition salt or solvate thereof.

5. The following: 【Chemistry 5】 5. The compound of claim 4, wherein 6. The compound of claim 1, wherein: 【Chemistry 6】 2. The compound of claim 1, which is a compound of formula (I): or a pharmaceutically acceptable addition salt or solvate thereof.

7. The following: 【Chemistry 7】 7. The compound of claim 6, wherein 8. The compound of claim 7, wherein: 【Chemistry 8】 2. The compound of claim 1, which is a compound of formula (I): or a pharmaceutically acceptable addition salt or solvate thereof.

9. The following: 【Chemistry 9】 9. The compound of claim 8, wherein 10. The compound of claim 1, wherein: 【Chemistry 10】 2. The compound of claim 1, which is a compound of formula (I): or a pharmaceutically acceptable addition salt or solvate thereof.

11. The following: 【Chemistry 11】 11. The compound of claim 10, 12. The compound of claim 1, wherein: 【Chemistry 12】 2. The compound of claim 1, which is a compound of formula (I): or a pharmaceutically acceptable addition salt or solvate thereof.

13. The following: 【Chemistry 13】 13. The compound of claim 12, wherein 14. The compound of claim 1, wherein: 【Chemistry 14】 2. The compound of claim 1, which is a compound of formula (I): or a pharmaceutically acceptable addition salt or solvate thereof.

15. The following: 【Chemistry 15】 15. The compound of claim 14, 16. The compound of claim 1, wherein: 【Chemistry 16】 2. The compound of claim 1, which is a compound of formula (I): or a pharmaceutically acceptable addition salt or solvate thereof.

17. The following: 【Chemistry 17】 17. The compound of claim 16, 18. The compound of claim 17, wherein: 【Chemistry 18】 2. The compound of claim 1, which is a compound of formula (I): or a pharmaceutically acceptable addition salt or solvate thereof.

19. The following: 【Chemistry 19】 19. The compound of claim 18,

20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound according to any one of claims 1 to 19.

21. A compound according to any one of claims 1 to 19 or a pharmaceutical composition according to claim 20 for use as a medicament.

22. 21. A compound according to any one of claims 1 to 19, or a pharmaceutical composition according to claim 20, for use in the treatment or prevention of a disease or condition selected from a blood disorder, a metabolic disorder, an autoimmune disease, cancer, an inflammatory disease, a cardiovascular disease, a neurodegenerative disease, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, sperm motility, transplant rejection, graft rejection, and lung disorder.

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