Novel quercetin redox derivatives and their use as BET inhibitors

Abstract

The present invention relates to novel quercetin derivative compounds and uses thereof, and more particularly, to novel quercetin derivative compounds having inhibitory activity on BET (Bromodomain Extra-Terminal) proteins and pharmaceutical compositions containing the same for preventing or treating BET protein-related diseases.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition for preventing or treating BET (Bromodomain Extra-Terminal) protein-related diseases, comprising a quercetin derivative or a pharmaceutically acceptable salt thereof and comprising the same as an effective ingredient. Background Art

[0002] Post-translational modification (PTM) of histones is associated with the systematic regulation of gene expression and chromatin in eukaryotic cells. Histone acetylation at specific lysine residues is a post-translational modification (PTM) regulated by histone acetylases and histone deacetylases. Histone acetylation is a well-conserved group of proteins called bromodomains that directly bind to acetylated lysines in histones and other proteins to mobilize protein complexes to control gene expression. There are more than 60 bromodomain-containing proteins in the human genome.

[0003] Among bromodomain-containing proteins, the BET family includes BRD2, BRD3, BRD4, and BRDT. Except for BRDT, which is localized in the testis, the other proteins are widely expressed in various tissues. In addition, it has been reported that the BET protein family is associated with a variety of diseases including cancer, metabolic diseases, and inflammation.

[0004] For example, tumor-derived fusions of BRD4 or BRD3 and the nuclear protein of testis (NUT) gene induced by chromosomal translocations cause an invasive cancer named NUT midline carcinoma (French et al., J Clin Oncol, 22 (2004), 4135-9; French et al., J Clin Pathol, 63 (2008), 492-6). The BRD3 / 4 bromodomains are preserved in their fusion proteins, and JQ1, a knockdown or selective BET bromodomain inhibitor, induces apoptosis of cancer cells both in the laboratory and in animal tumor models (Filippakopoulos et al., Nature, 468 (2010), 1067-73). JQ1 and other selective BET inhibitors bind to the BET bromodomains to prevent acetyl-lysine binding, which is known to prevent the interaction of BET proteins with chromatin and thus regulate transcription in this way.

[0005] BRD4 was identified as a target in acute myeloid leukemia (AML) by RNAi screening (Zuber et al., Nature, 478 (2011), 524-8). This finding was confirmed in the laboratory and in vivo by using BET inhibitors JQ1 and I-BET151 (Dawson et al., Nature, 478 (2011), 529-33). In addition, BET inhibitors are known to have a wide range of anticancer activity in acute leukemia, multiple myeloma and other hematological malignancies. In a variety of tumor models, acute downregulation of the tumor-derived transcription factor Myc was observed upon BET inhibition (Delmore et al., Cell, 146 (2011), 904-17; Mertz et al., Proc Natl Acad Sci USA, 108 (2011), 16669-74). Recent studies suggest that BET inhibitors have expanded potential to work in other tumors, such as lung and brain cancers.

[0006] It is reported that another BET inhibitor, I-BET762, whose chemical structure and BET binding mode are closely related to JQ1, modulates the expression of major inflammatory genes in mouse models and protects humans from endotoxin shock and bacterial sepsis (Nicodeme et al., Nature, 468 (2010), 1119-23). ​​Moreover, these results are used to support the clinical evaluation of the BET inhibitor RVX-208 in clinical trials in patients with atherosclerosis, coronary artery disease, dyslipidemia, diabetes and other cardiovascular diseases (McNeill, Curr Opin Investig Drugs, 3 (2010), 357-64 and www.clinicaltrials.gov).

[0007] It was found that both RVX-208 and I-BET762 up-regulate apolipoprotein AI, which plays an important role in reducing tissue cholesterol levels. In addition, BET proteins are involved in the proliferation and transcriptional regulation of various viruses, which may indicate that BET inhibitors may have antiviral activity (Weidner-Glunde, Frontiers in Bioscience 15 (2010), 537-549).

[0008] Although several bromodomain inhibitors are known in the clinic and preclinical settings, there is an urgent need to develop novel bromodomain inhibitors that can address the problems of disease recurrence and resistance to therapeutic agents and reduce side effects.

[0009] On the other hand, redox reactions are present in many physiological processes, and although oxygen molecules are essential for life, they can generate reactive molecules that cause disease. Other reactive chemical species, including free radicals, also cause pathological conditions. It has been known in the past that aerobic metabolism associated with tissue damage is caused by reactive oxygen species (ROS). ROS and the more recently known reactive nitrogen species (RNS) act as messengers for cell signaling, like hormones, causing chemical denaturation of enzymes and changes in oxidant levels.

[0010] Furthermore, among the 20 essential amino acids, cysteine, methionine, tyrosine, and tryptophan are particularly susceptible to oxidation, which causes various protein substances that play a metabolic role in the human body to undergo various deformations such as metal binding, disulfide bond formation, methylation, and acetylation.

[0011] Although the research on the signal regulation mechanism of cells has been focused on phosphorylation, the present invention is completed by considering the redox chemistry technology of the redox regulation mechanism such as oxidation and S-nitrosylation based on the "redox state" for diseases caused by oxidative and nitrosative stress. That is, based on the fact that BET inhibitors make the degree of binding between signal transduction substances different depending on the redox state when recognizing lysine residues of histones, the present inventors studied and developed a new bromodomain inhibitor taking into account the above redox state. Summary of the invention

[0012] Technical issues

[0013] The present invention provides a novel quercetin derivative compound having excellent BET protein inhibitory activity.

[0014] Furthermore, the present invention provides a pharmaceutical composition for preventing or treating a BET protein-related disease, comprising the above-mentioned compound or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0015] Technical Solution

[0016] According to one aspect of the present invention, a quercetin derivative compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof is provided.

[0017] Chemical formula 1

[0018]

[0019] In the above chemical formula 1, ring X is or a substituted or unsubstituted aryl group, wherein A, B, C and D are independently C, C(=O), N, O, S or none, Y is C, C(=O), N, O or S, and Z is CR 5 or NR 5 , ---- respectively no or single bond, R 1 , R 2 and R 5 are independently H, halogen, cyano, alkyl, alkenyl, alkynyl, -C(=O)Ra, -C(=O)N(Ra)(Rb), -C(=O)ORa, -N(Ra)(Rb), -N(Ra)C(=O)Rb, -N(Ra)S(=O)Rb, -N(Ra)S(=O) 2 Rb, -NO 2 , -ORa, -OC(=O)Ra, -SRa, -S(=O)Ra, -S(=O)N(Ra)(Rb), -S(=O) 2 Ra, -S(=O) 2 N(Ra)(Rb), cycloalkyl, heterocycloalkyl, aryl or heteroaryl, R 3 R may be the same or different from one or more selected from the group consisting of H, alkyl and -ORa. 4 They may be the same or different from one or more selected from the group consisting of H, alkyl, alkenyl and alkynyl, and Ra and Rb are each independently H, halogen, cyano, alkyl, cycloalkyl or heterocycloalkyl.

[0020] According to another aspect of the present invention, a pharmaceutical composition for preventing or treating a BET protein-related disease is provided, comprising the above-mentioned compound or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0021] The BET protein-related disease is one or more selected from the group consisting of cancer, autoimmune disease or inflammatory disease, metabolic disease and viral disease.

[0022] Effects of the Invention

[0023] The quercetin derivative compound represented by Chemical Formula 1 provided in the present invention has excellent inhibitory activity against BET proteins and can be usefully used as a preventive or therapeutic agent for the above-mentioned various diseases associated with BET. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 It is a graph showing the BRD2 (BD1+BD2) protein binding inhibitory activity by the compound 1 (BBC0109) of the present invention.

[0025] Figure 2It is a graph showing the BRD2 (BD1+BD2) protein binding inhibitory activity by the compound of Comparative Example 1 (RVX-208).

[0026] Figure 3 It is a graph showing the BRD4 (BD1+BD2) protein binding inhibitory activity by the compound 1 (BBC0109) of the present invention.

[0027] Figure 4 It is a graph showing the BRD4 (BD1+BD2) protein binding inhibitory activity by the compound of Comparative Example 1 (RVX-208). DETAILED DESCRIPTION

[0028] The present invention relates to novel quercetin derivative compounds, and more particularly, to novel quercetin derivative compounds having inhibitory activity on BET proteins and pharmaceutical compositions containing the same for preventing or treating BET protein-related diseases.

[0029] Unless otherwise specified, the terms used in the description and claims of the present invention have the following meanings.

[0030] According to the common practice in the technical field to which the present invention belongs, in the chemical formula of the present application, "R" is used in the sense of a residue or substituent attached to the backbone structure.

[0031] "Alkyl" refers to a hydrocarbon having primary, secondary, tertiary and / or quaternary carbon atoms, including a straight chain, branched chain or cyclic type, or a saturated aliphatic group that can be a combination thereof. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C 1 -C 20 alkyl), 1 to 10 carbon atoms (i.e., C 1 -C 10 alkyl) or 1 to 6 carbon atoms (i.e., C 1 -C 6 If not otherwise defined, in a preferred embodiment, alkyl refers to C 1 -C 6 Alkyl. Examples of suitable alkyl groups include methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH (CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH (CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl(t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 )、1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 )、3-hexyl(-CH(CH 2 CH 3 )(CH 2 CH 2 CH3 ))、2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 )、2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 )、3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ) and octyl (-(CH 2 ) 7 CH 3 ), but is not limited thereto.

[0032] Furthermore, the term "alkyl" as used throughout the specification, examples and claims includes all unsubstituted and substituted alkyl groups, wherein the latter refers to alkyl residues having substituents replacing hydrogen on one or more carbons of the hydrocarbon backbone, including halogen alkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl.

[0033] The term "C x-y ” or “C x -C y "" when used with a chemical residue such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy, is considered to include a group containing from x to y carbon atoms in the chain. 0 Alkyl represents hydrogen when located at the terminal, and represents a bond when located internally. 1 -C 6 )Alkyl groups contain 1 to 6 carbon atoms in the chain.

[0034] "Alkoxy" refers to a group having the formula -O-alkyl in which an alkyl group as defined above is attached to the parent compound through an oxygen atom. For example, the alkyl residue of an alkoxy group can have from 1 to 20 carbon atoms (i.e., C 1 -C 20 alkoxy), 1 to 12 carbon atoms (i.e., C 1 -C 12 alkoxy), 1 to 10 carbon atoms (i.e., C 1 -C 10 alkoxy) or 1 to 6 carbon atoms (i.e., C 1 -C 6 Suitable alkoxy groups include methoxy (-O-CH 3 or -OMe), ethoxy (-OCH 2 CH 3 or -OEt) and t-butyloxy (-OC(CH 3 ) 3 or -O-tBu), but is not limited thereto.

[0035] "Alkenyl" refers to a linear, branched, or cyclic group or a combination thereof having primary, secondary, tertiary, and / or quaternary carbon atoms and having one or more unsaturated regions, i.e., a carbon-carbon sp 2 For example, an alkenyl group can have 2 to 20 carbon atoms (i.e., C 2 -C 20 alkylene), 2 to 12 carbon atoms (i.e., C 2 -C 12 alkenyl), 2 to 10 carbon atoms (i.e., C 2 -C 10 alkenyl) or 2 to 6 carbon atoms (i.e., C 2 -C 6 Suitable alkenyl groups include vinyl (-CH=CH 2 ), propenyl (-CH 2 CH=CH 2 ), cyclopentenyl (-C 5 H 7 ) and 5-hexenyl (-CH 2 CH 2 CH 2 CH 2 CH=CH 2 ), but is not limited thereto.

[0036] "Alkynyl" refers to hydrocarbons having primary, secondary, tertiary and / or quaternary carbon atoms, including straight chain, branched and cyclic groups or combinations thereof, and having one or more carbon-carbon sp triple bonds. For example, an alkynyl group can have 2 to 20 carbon atoms (i.e., C2 -C 20 alkynyl), 2 to 12 carbon atoms (i.e., C 2 -C 12 alkynyl), 2 to 10 carbon atoms (i.e., C 2 -C 10 Alkynyl) or 2 to 6 carbon atoms (i.e., C 2 -C 6 Examples of suitable alkynyl groups include ethynyl (-C≡CH) and propynyl (-CH 2 C≡CH), but is not limited to this.

[0037] The term "aryl" used in this application includes substituted or unsubstituted monovalent or divalent aromatic hydrocarbon groups whose ring atoms are carbon, monocyclic, bicyclic or polycyclic. Preferably, the aryl ring is a 6- to 20-membered ring, a 6- to 14-membered ring, a 6- to 10-membered ring, or, more preferably, a 6-membered ring. The aryl group can be a polycyclic group with more than 2 carbons and more than 2 rings on 2 adjacent rings, wherein more than one of these rings is aromatic, for example, the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocycloalkyl. The aryl group can be benzene, naphthalene, phenanthrene, anthracene, indene, indane, phenol, aniline.

[0038] The term "carbocycloalkyl", "cycloalkylalkyl" or "(cycloalkyl)alkyl" as used herein refers to an alkyl group substituted with a carbocyclyl or cycloalkyl group.

[0039] The terms "carbocycle", "carbocyclyl" or "cycloalkyl" as used in this application may be monocyclic, bicyclic or polycyclic and refer to non-aromatic saturated or unsaturated, monovalent or divalent rings whose atoms are carbon, respectively. Cycloalkyls may have 3 to 7 carbon atoms in a monocyclic ring, 7 to 12 carbon atoms in a bicyclic ring, or about 20 or less carbon atoms in a polycyclic ring. Monocyclic cycloalkyls have 3 to 7 ring atoms, more typically 5 or 6 ring atoms. Bicyclic cycloalkyls may have 7 to 12 ring atoms and may be fused rings, spiro rings or bridged rings. In exemplary cycloalkyls, the atoms may be arranged according to a bicyclic [4,5], [5,5], [5,6] or [6,6] system. In particular embodiments, the cycloalkyl contains 3 to 20 atoms or 3 to 10 atoms, or, more preferably, 3 to 7 atoms. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. Unless otherwise specified, the cycloalkyl group may be substituted with one or more substituents described in the present application.

[0040] As used herein, "heterocycloalkyl" refers to an alkyl group substituted by a heterocycloalkyl group.

[0041] The terms "heterocycle", "heterocyclic group" and "heterocycloalkyl" refer to a substituted or unsubstituted monovalent or divalent saturated or partially saturated non-aromatic ring structure containing one or more heteroatoms in the ring structure, preferably containing 1 to 4 heteroatoms, more preferably containing 1 to 2 heteroatoms, preferably a 3- to 10-membered ring, more preferably a 3- to 7-membered ring. Furthermore, the terms "heterocycle", "heterocyclyl" and "heterocycloalkyl" also include polycyclic rings in which two or more carbon atoms have two or more common rings in two adjacent rings, wherein one or more of the rings is a heterocycle, for example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocycle. Bicyclic and polycyclic heterocyclyls may be fused rings, bridged rings or spiro rings. Substituted heterocycles include heterocycles substituted with any substituent described in the present application, including, for example, carbonyl. Heterocyclyls include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, and the like. Additional exemplary heterocycles may be dihydropyridyl, dihydroindole, tetrahydropyridyl (piperidyl), tetrahydrothiophenyl, thioxotetrahydrothiophenyl, indolyl, piperidinyl, 4-piperidinyl, pyrrolidinyl, 2-pyrrolidine keto, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, 6H-1,2,thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, pyranyl, chromenyl, xanthenyl, phenoxazinyl, 2H-pyrrolyl, 3H-indolyl, 4H-quinolinyl, thiazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnamyl, pteridine The invention also includes pyridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazolidyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, quinuclyl, morpholinyl and oxazolidinyl (each of which may be substituted or unsubstituted), but is not limited to these.

[0042] "Heteroaryl" refers to a monocyclic, bicyclic or polycyclic substituted or unsubstituted monovalent or divalent aromatic group containing one or more heteroatoms in the ring. Non-limiting examples of heteroatoms that may be contained in an aromatic ring may be oxygen, sulfur and nitrogen. In polycyclic heteroaryl rings, the ring has more than two rings in two adjacent rings with more than two carbon atoms, wherein one or more of the rings is heteroaromatic, for example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic. Heteroaryl includes, for example, benzofuran, benzothiophene, pyrrole, furan, thiophene, imidazole, indole, isoindole, isoxazole, isothiazole, oxazole, thiazole, quinoline, isoquinoline, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine (which may be substituted or unsubstituted, respectively).

[0043] The terms "heterocycle", "heterocyclic group" and "heterocycloalkyl" refer to a substituted or unsubstituted monovalent or divalent saturated or partially saturated non-aromatic ring structure containing one or more heteroatoms in the ring structure, preferably containing 1 to 4 heteroatoms, more preferably containing 1 to 2 heteroatoms, preferably a 3- to 10-membered ring, more preferably a 3- to 7-membered ring. Furthermore, the terms "heterocycle", "heterocyclyl" and "heterocycloalkyl" also include polycyclic rings in which two or more carbon atoms have two or more common rings in two adjacent rings, wherein one or more of the rings is a heterocycle, for example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocycle. Bicyclic and polycyclic heterocyclyls may be fused rings, bridged rings or spiro rings. Substituted heterocycles include heterocycles substituted with any substituent described in the present application, including, for example, carbonyl. Heterocyclyls include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, and the like. Additional exemplary heterocycles may be dihydropyridyl, dihydroindole, tetrahydropyridyl (piperidyl), tetrahydrothiophenyl, thioxotetrahydrothiophenyl, indolyl, piperidinyl, 4-piperidinyl, pyrrolidinyl, 2-pyrrolidine keto, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, 6H-1,2,thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, pyranyl, chromenyl, xanthenyl, phenoxazinyl, 2H-pyrrolyl, 3H-indolyl, 4H-quinolinyl, thiazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnamyl, pteridine The invention also includes pyridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazolidyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, quinuclyl, morpholinyl and oxazolidinyl (each of which may be substituted or unsubstituted), but is not limited to these.

[0044] The terms "halo" and "halogen" as used herein refer to halogens including chlorine, fluorine, bromine and iodine.

[0045] "Amino" means -NH 2 Group.

[0046] "Cyano" means a -CN group.

[0047] "Nitro" means -NO 2 Group.

[0048] "Carboxy" means a -C(O)OH group.

[0049] "Aldehyde" means a -CHO group.

[0050] "Alkoxycarbonyl" refers to a -C(O)O(alkyl) or -C(O)O(cycloalkyl) group, wherein the alkyl and cycloalkyl groups are as defined above.

[0051] "Acyl halide" means a compound containing a -C(O)-halogen group.

[0052] The present invention relates to a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0053] Chemical formula 1

[0054]

[0055] In the above chemical formula 1, ring X is or a substituted or unsubstituted aryl group, wherein A, B, C and D are independently C, C(=O), N, O, S or none, Y is C, C(=O), N, O or S, and Z is CR 5 or NR 5 , ---- respectively no or single bond, R 1 , R 2 and R 5 are independently H, halogen, cyano, alkyl, alkenyl, alkynyl, -C(=O)Ra, -C(=O)N(Ra)(Rb), -C(=O)ORa, -N(Ra)(Rb), -N(Ra)C(=O)Rb, -N(Ra)S(=O)Rb, -N(Ra)S(=O) 2 Rb, -NO 2 , -ORa, -OC(=O)Ra, -SRa, -S(=O)Ra, -S(=O)N(Ra)(Rb), -S(=O) 2 Ra, -S(=O) 2 N(Ra)(Rb), cycloalkyl, heterocycloalkyl, aryl or heteroaryl, R 3 R may be the same or different from one or more selected from the group consisting of H, alkyl and -ORa. 4 They may be the same or different from one or more selected from the group consisting of H, alkyl, alkenyl and alkynyl, and Ra and Rb are each independently H, halogen, cyano, alkyl, cycloalkyl or heterocycloalkyl.

[0056] In one embodiment, in the compound of the above chemical formula 1, the above ring X can be R 3 Can be selected from H, C 1 -C 6 The same or different one or more of the group consisting of alkyl and -ORa, Ra can be H, C 1 -C 6 alkyl, cycloalkyl or a three-membered to ten-membered heterocycloalkyl containing a heteroatom selected from N, O or S, R 6 and R7 can be independently H or C 1 -C 6 alkyl.

[0057] In one embodiment, in the compound of the above chemical formula 1, Y may be N or O, and Z may be CR 5 or NR 5 , R 1 , R 2 and R 5 can be H, C 1 -C 6 Alkyl, OH, or -OC 1 -C 6 alkyl.

[0058] In one embodiment, in the compound of the above chemical formula 1, the above ring X can be R 8 Can be H or C 1 -C 6 Alkyl, R 9 , R 10 or R 11 can be H, C 1 -C 6 Alkyl or -ORa, wherein Ra can be H, C 1 -C 6 Alkyl or a heteroatom-containing three-membered to ten-membered heterocycloalkyl group.

[0059] Preferred examples of the present invention are as follows, but are not limited thereto.

[0060]

[0061]

[0062]

[0063]

[0064] The compounds of the present invention can form pharmaceutically acceptable salts. The above-mentioned pharmaceutically acceptable salts are not particularly limited as long as they are acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions. For example, they can be acid addition salts formed by inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid, tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, and maleic acid, and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid.

[0065] In another aspect, the present invention provides a pharmaceutical composition for preventing or treating a BET protein-related disease, comprising the compound represented by the above Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0066] The pharmaceutical composition of the present invention is useful for preventing or treating various diseases related to BET proteins by inhibiting BET proteins through the compound represented by Chemical Formula 1. The BET protein-related diseases may be cancer, autoimmune or inflammatory diseases, metabolic diseases or viral diseases.

[0067] In one example of the present invention, the above-mentioned cancer can be one or more selected from the group consisting of blood cancer, multiple myeloma, acute myeloid leukemia, malignant lymphoma, aplastic anemia, thymic cancer, ovarian cancer, cervical cancer, breast cancer, colorectal cancer, liver cancer, gastric cancer, pancreatic cancer, colon cancer, peritoneal metastasis, skin cancer, bladder cancer, prostate cancer, thyroid cancer, lung cancer, osteosarcoma, fibroma and brain tumor, but is not limited to this.

[0068] In one embodiment of the present invention, the above-mentioned autoimmune disease or inflammatory disease can be one or more selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, hyperthyroidism, myasthenia gravis, Crohn's disease, ankylosing spondylitis, psoriasis, autoimmune pernicious anemia, Sjögren's syndrome, allergy, allergic rhinitis, arthritis, asthma, chronic obstructive pulmonary disease, degenerative joint disease, dermatitis, organ rejection, eczema, hepatitis, inflammatory bowel disease, sepsis, sepsis syndrome, septic shock and non-alcoholic steatohepatitis, but is not limited thereto.

[0069] In one embodiment of the present invention, the metabolic disease may be one or more selected from the group consisting of hypertriglyceridemia, obesity, hyperlipidemia, hyperinsulinemia, hyperglycemia, arteriosclerosis, hypertension, type 2 diabetes and insulin resistance, but is not limited thereto.

[0070] In one example of the present invention, the above-mentioned viral disease can be one or more selected from the group consisting of poliomyelitis, acute hemorrhagic conjunctivitis, viral meningitis, hand, foot and mouth disease, hepatitis, myositis, myocarditis, pancreatitis, epidemic myalgia, encephalitis, colds, herpetic stomatitis, foot and mouth disease, asthma, bronchiolitis, bronchitis, chronic obstructive pulmonary disease, pneumonia, sinusitis, otitis media, herpes simplex, herpes zoster, stomatitis and chickenpox, but is not limited to this.

[0071] According to yet another embodiment of the present invention, a pharmaceutical preparation comprising the above pharmaceutical composition is provided.

[0072] The pharmaceutical preparation of the present invention may be in various oral administration forms such as tablets, pills, powders, capsules, syrups or emulsions, or in parenteral administration forms such as injections for intramuscular, intravenous or subcutaneous administration.

[0073] Furthermore, in addition to the active ingredients, the above-mentioned pharmaceutical preparations may also be added with common non-toxic pharmaceutically acceptable additives, for example, one or more selected from the group consisting of carriers, additives and excipients, and prepared in a common manner.

[0074] Hereinafter, the present invention will be described in detail by the following examples and test examples. However, the following examples and test examples are only for illustrating the present invention, and the content of the present invention is not limited to the following examples and test examples.

[0075] Example

[0076] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and mass spectrometry (MS). Bruker Avance-400 or Bruker Avance 300 instruments were used to detect the NMR. The solvents used for detection were deuterated dimethyl sulfoxide (DMSO-d6), deuterated trichloromethane (CDCl 3 ) and deuterium-substituted methanol (CD 3 OD), and the internal standard was tetramethylsilane (TMS).

[0077] High performance liquid chromatography (HPLC) is performed by flash chromatography or column chromatography.

[0078] Thin layer chromatography (TLC) was performed on a silica gel plate. 1000 mesh silica gel was used in the thin layer chromatography. Also, the size of the silica gel plate used in the thin layer chromatography was 20 μm to 25 μm, and the size of the silica gel plate used for purifying the product was 40 μm to 45 μm.

[0079] For visualization, ultraviolet light, iodine, potassium permanganate in water were used.

[0080] The known starting materials of the present invention can be prepared by a common synthesis method in the technical field to which the present invention belongs, or can be purchased from Alfa Aesar, Aldrich and the like.

[0081] Example 1: Synthesis of Compound 1 (BBC0109)

[0082] Reactive

[0083]

[0084] Step 1. Preparation of 3-(1H-benzenediimidazol-5-yl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one

[0085]

[0086] 1-(2-Hydroxy-4,6-dimethoxy)phenyl ketone (500 mg, 2.55 mmol, 1 eq) was dissolved in N,N-dimethylformamide (DMF) (15 mL), and sodium hydroxide (254.84 mg, 6.37 mmol, 60% purity, 2.5 eq) and 1H-benzimidazole-5-carboxaldehyde (409.69 mg, 2.80 mmol, 1.1 eq) were added at 0°C, and the mixture was stirred at 25°C for 12 hours. After the reaction, distilled water and ethyl acetate were used for extraction. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain intermediate 3 (300 mg, 924.98 umol, yield 36.30%).

[0087] LCMS: RT=0.821min, m / z: 325.2(M+H)+

[0088] Step 2. Synthesis of 2-(1H-benzimidazol-5-yl)-3-hydroxy-5,7-dimethoxy-4H-benzopyran-4-one

[0089]

[0090] 3-(1H-benzimidazol-5-yl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one (270 mg, 832.49 umol, 1 eq) was dissolved in methanol (60 mg) / water (30 mL), and sodium hydroxide (170.09 mg, 4.25 mmol, 5.11 eq) and hydrogen peroxide (288.00 mg, 2.54 mmol, 244.07 uL, 30% purity, 3.05 eq) were added at 0°C, and the mixture was stirred at 25°C for 12 hours. After the reaction was completed, the pH was adjusted to 5 by dilution with distilled water, and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain intermediate 4 (120 mg).

[0091] LCMS: RT=0.650min, m / z: 339.0(M+H)+

[0092] Step 3. Preparation of 2-(1H-benzimidazol-5-yl)-3,5,7-trihydroxy-4H-benzopyran-4-one (BBC0109)

[0093]

[0094] 2-(1H-benzimidazol-5-yl)-3-hydroxy-5,7-dimethoxy-4H-benzopyran-4-one (50 mg, 147.79 umol, 1 equivalent) was dissolved in dichloroethane (3 mL), and then boron tribromide (370.25 mg, 1.48 mmol, 142.40 uL, 10 eq) was added thereto, and then stirred at 60° C. for 12 hours. After the reaction was completed, methanol was added and concentrated, and then purified by preparative high performance liquid chromatography (prep-HPLC) to obtain compound 1 (3.23 mg, 9.67 umol, yield 3.27%, 92.9% purity).

[0095] 1 H NMR (400MHz, METHANOL-d4) δppm 8.60 (1H, s), 8.33 (1H, s), 8.15-8.22 (1H, m), 7.77 (1H, d, J = 8.4Hz), 6.49 (1H, d, J = 2.0Hz), 6.24 (1H, d, J = 2.0Hz)

[0096] LCMS: RT=2.049min, m / z: 311.0(M+H)+

[0097] Example 2: Synthesis of Compound 2 (BBC0110)

[0098] Reactive

[0099]

[0100] 5-(3,5,7-trihydroxy-4-oxo-chromen-2-yl)-1,3-dihydrobenzimidazol-2-one (BBC0110) (2.64 mg, 7.3 umol, yield 3.6%, 90.5% purity) was obtained from 2-oxo-1,3-dihydrobenzimidazole-5-carboxylic acid 1 (196.0 mg, 1.1 mmol, 2.0 eq) through the above reaction formula.

[0101] LCMS: RT=2.270min, m / z: 327.0(M+H)+

[0102] 1 H NMR (400MHz, DMSO-d6) δppm 10.71-10.88 (1H, m) 7.78-7.87 (2H, m) 7.08 (1H, d, J = 8.4Hz) 6.39 (1H, d, J = 1.6Hz) 6.15 (1H, d, J = 2.0Hz).

[0103] Example 3: Synthesis of Compound 3 (BBC0111)

[0104] Reaction 1

[0105]

[0106] Reaction 2

[0107]

[0108] Reaction 3

[0109]

[0110] The compound of BBC0111 is prepared by any one of the above reaction formulas 1 to 3.

[0111] Example 4: Synthesis of Compound 4 (BBC0113)

[0112] Reactive

[0113]

[0114] 6-(3,5,7-Trihydroxy-4-oxo-benzopyran-2-yl)-3H-1,3-benzoxazol-2-one (BBC0113) (4.6 mg, 12.8 umol, 18.2% yield, 91% purity) was obtained from 2-amino-5-bromo-phenol 1 (1.0 g, 5.32 mmol, 1.0 eq).

[0115] LCMS: RT=2.447min, m / z: 328.0(M+H)+

[0116] 1 H NMR (400MHz, MeOD) δppm 8.11 (2H, s), 7.22 (1H, br d, J = 8.0Hz), 6.44 (1H, s), 6.20 (1H, s)

[0117] Example 5: Synthesis of Compound 5 (BBC0114)

[0118] Reactive

[0119]

[0120] 3,5,7-Trihydroxy-2-(1H-indol-5-yl)benzopyran-4-one (BBC0114) (2.38 mg, 7.16 umol, 4.6% yield, 93% purity) was obtained from 1H-indole-5-carboxylic acid 1 (92.2 mg, 572.0 umol, 2.0 eq).

[0121] LCMS: RT=2.666min, m / z: 310.0(M+H)+

[0122] 1 H NMR (400MHz, MeOD) δppm 8.50 (1H, d, J = 1.2Hz) 7.99 (1H, dd, J = 8.8, 1.6Hz) 7.50 (1H, d, J = 8.8Hz) 7.32 (1H, d , J=3.2Hz) 6.58 (1H, dd, J=3.2, 0.8Hz) 6.45 (1H, d, J=2.0Hz) 6.20 (1H, d, J=2.0Hz)

[0123] Example 6: Synthesis of Compound 6 (BBC0115)

[0124] Reactive

[0125]

[0126] 3,5,7-Trihydroxy-2-(1H-indol-6-yl)benzopyran-4-one (BBC0115) (4.73 mg, 13.8 umol, 8.0% yield, 90.4% purity) was obtained from 1H-indole-6-carboxylic acid 1 (106.4 mg, 660.1 umol, 2.0 eq).

[0127] LCMS: RT=2.711min, m / z: 310.0(M+H)+

[0128] 1 H NMR (400MHz, DMSO-d6) δppm 12.52(1H,s)11.45(1H,brs)10.81(1H,s)9.48(1H,s)8.39(1H,s)7.82(1H,dd,J=8.4,1 .6Hz) 7.69 (1H, d, J = 8.4Hz) 7.54 (1H, t, J = 2.8Hz) 6.45-6.54 (2H, m) 6.21 (1H, d, J = 2.0Hz)

[0129] Example 7: Synthesis of Compound 7 (BBC0116)

[0130] Reaction 1

[0131]

[0132] Reaction 2

[0133]

[0134] Reaction 3

[0135]

[0136] Reaction 4

[0137]

[0138] Compound 7 (BBC0116) was prepared by any one of the methods in Reaction Schemes 1 to 4 above.

[0139] Example 8: Synthesis of Compound 8 (BBC0309)

[0140] Reactive

[0141]

[0142] 2-Benzopyran-6-yl-3,5,7-trihydroxy-benzopyran-4-one (10.85 mg, 32.55 umol, 13.87% yield, 97.893% purity) was obtained from benzopyran-6-carboxylic acid 1 (55 mg, 308.67 umol, 2 eq).

[0143] LCMS: RT=2.857min, m / z: 327.0(M+H)+

[0144] 1 H NMR (400MHz, DMSO): δ (ppm) 12.44 (1H, s), 7.95-7.84 (2H, m), 6.88 (1H, d, J = 8.40Hz), 6.43 (1H, d, J=2.00Hz), 6.18 (1H, d, J=2.00Hz), 4.32-4.12 (2H, m), 2.82 (2H, t, J=6.00Hz), 2.04-1.83 (2H, m)

[0145] Example 9: Synthesis of Compound 9 (BBC0310)

[0146] Reactive

[0147]

[0148] 2-(Benzofuran-5-yl)-3,5,7-trihydroxy-benzopyran-4-one (BBC0310) (19.45 mg, 61.51 umol, yield 14.88%, 98.112% purity) was obtained from benzofuran-5-carboxylic acid (143 mg, 881.94 umol, 2 eq) and 2-benzyloxy-1-(2,4-dibenzyloxy-6-hydroxyphenyl)ethanone (200 mg, 440.0 umol, 1 eq).

[0149] LCMS: RT=2.834min, m / z: 311.0(M+H)+

[0150] 1 H NMR (400 MHz, dimethyl sulfoxide (DMSO)): δ (ppm) 8.52 (1H, s), 8.16 (1H, d, J=8.8 Hz), 8.10 (1H, d, J=2.40 Hz), 7.77 (1H, d, J=8.80 Hz), 7.12 (1H, d, J=1.2 Hz), 6.48 (1H, d, J=2.0 Hz), 6.20 (1H, d, J=2.00 Hz).

[0151] Example 10: Synthesis of Compound 10 (BBC0311)

[0152] Reactive

[0153]

[0154] 2-(2,3-Dihydroxybenzofuran-5-yl)-3,5,7-trihydroxy-benzopyran-4-one (BBC0311) (41.24 mg, 126.61 umol, yield 36.88%, 95.867% purity) was obtained from 2-benzyloxy-1-(2,4-dibenzyloxy-6-hydroxy-phenyl)ethanone (200 mg, 440.03 umol, 1 eq) and 2,3-dihydroxybenzofuran-5-carboxylic acid (148.00 mg, 901.57 umol, 2.05 eq).

[0155] LCMS: RT=2.436min, m / z: 313.0(M+H)+

[0156] 1 H NMR (400MHz, MeOD): δ (ppm) 8.09 (1H, s), 8.01 (1H, dd, J=8.8, 1.6Hz), 6.85 (1H, d, J=8. 8Hz), 6.40 (1H, d, J=2.0Hz), 6.18 (1H, d, J=2.4Hz), 4.63 (2H, t, J=8.8Hz), 3.27 (2H, s).

[0157] Example 11: Synthesis of Compound 11 (BBC0312)

[0158] Reactive

[0159]

[0160] 2-(2,3-Dihydroxybenzofuran-6-yl)-3,5,7-trihydroxy-benzopyran-4-one (BBC0312) (29.12 mg, 88.7 umol, 36.9% yield, 95.1% purity) was obtained from benzofuran-6-carboxylic acid (300.0 mg, 1.85 mmol, 1.0 eq).

[0161] LCMS: RT=2.762min, m / z: 313.1(M+H)+

[0162] 1 H NMR (400MHz, DMSO-d6) δppm 12.36 (1H, s) 10.85 (1H, br s) 9.61 (1H, br s) 7.67 (1H, dd, J = 8.0, 1.2Hz) 7.53 (1H, d, J = 1.2Hz) 7.39 (1H, d, J = 8.0Hz) 6.46 (1 H, d, J = 2.0 Hz) 6.20 (1H, d, J = 2.0 Hz) 4.58 (2H, t, J = 8.8 Hz) 3.24 (2H, t, J = 8.8 Hz).

[0163] Example 12: Synthesis of Compound 12 (BBC0313)

[0164] Reactive

[0165]

[0166] 2-(Benzofuran-6-yl)-3,5,7-trihydroxy-benzopyran-4-one (BBC0313) (13 mg, 40.7 umol, 26.3% yield, 97.1% purity) was obtained from 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-benzopyran-4-one (15.0 g, 49.6 mmol, 1.0 eq).

[0167] LCMS: RT=2.836min, m / z: 97.1(M+H)+

[0168] 1 H NMR (400MHz, DMSO-d6) δppm 12.39 (1H, s) 8.43 (1H, s) 8.16 (1H, d, J = 2.0Hz) 8.11 (1H, dd, J = 8.4, 1.6Hz) 7.82 (1H, d, J=8.4Hz) 7.07 (1H, dd, J=2.0, 0.8Hz) 6.52 (1H, d, J=2.0Hz) 6.22 (1H, d, J=2.0Hz).

[0169] Example 13: Synthesis of Compound 13 (BBC0406)

[0170] Reactive

[0171]

[0172] 5,7-Dimethoxy-2-(7-methyl-2,3-dihydrobenzofuran-5-yl)-3H-quinazolin-4-one (BBC0406) (13 mg, 38.11 umol, 4.15% yield, 99.2% purity) was obtained from 2,3-dihydrobenzofuran-5-carbaldehyde 1 (500 mg, 3.37 mmol, 1 eq).

[0173] LCMS: RT=2.200min, m / z: 339.1(M+H)+

[0174] 1 H NMR (400MHz, CHLOROFORM-d) δppm 8.98 (1H, br s), 7.71 (1H, s), 7.60 (1H, s), 6.80 (1H, d, J = 2.4Hz) 6.44 (1H, d, J = 2.4Hz), 4.68 (2H, t, J = 8.8Hz), 3.98 (3H, s), 3.92 (3H, s), 3.30 (2H, t, J = 8.8Hz), 2.28 (3H, s).

[0175] Example 14: Synthesis of Compound 14 (BBC0407)

[0176] Reactive

[0177]

[0178] 5,7-Dimethoxy-2-(7-methylbenzofuran-5-yl)-3H-quinazolin-4-one (BBC0407) (6.77 mg, 19.14 umol, 43.17% yield, 95.070% purity) was obtained from 2,3-dihydroxybenzofuran-5-carbaldehyde (1 g, 6.75 mmol, 1 eq).

[0179] LCMS: RT=2.264min, m / z: 337.1(M+H)+

[0180] 1 H NMR (400MHz, MeOD): δ (ppm) 8.15 (1H, s), 7.91 (1H, d, J = 2.0Hz), 7.85 (1H, s), 7.00 (1H , d, J=2.0Hz), 6.86 (1H, d, J=2.0Hz), 6.61 (1H, d, J=2.0Hz), 3.96 (6H, m), 2.64 (3H, s).

[0181] Example 15: Synthesis of Compound 15 (BBC0301)

[0182] Reactive

[0183]

[0184] 3,5,7-Trihydroxy-2-[3-hydroxy-4-(oxabutan-3-yloxy)phenyl]benzopyran-4-one (BBC0301) (5.57 mg, 15.3 umol, 19% yield, 98.3% purity) was obtained from 3,4-dihydroxybenzaldehyde (1.0 g, 7.24 mmol, 1.0 eq).

[0185] LCMS: RT=2.465min, m / z: 359.0(M+H)+

[0186] 1 H NMR (400MHz, DMSO-d6) δppm 12.43 (1H, s) 10.82 (1H, s) 9.47-9.54 (2H, m) 7.72 (1H, d, J = 2.4Hz) 7.58 (1H, dd, J = 8.8, 2.4Hz) 6.74 (1H, d, J = 8.8Hz) 6.42 (1H, d, J = 2.0Hz) 6.20 (1H, d, J = 2.0Hz) 5.32 (1H, t, J = 5.6Hz) 4.94 (2H, t, J = 6.8Hz) 4.61 (2H, dd, J = 7.6, 5.2Hz).

[0187] Example 16: Synthesis of Compound 16 (BBC0302)

[0188] Reactive

[0189]

[0190] 3,5,7-Trihydroxy-2-[4-(oxabutan-3-yloxy)phenyl]benzopyran-4-one (1.69 mg, 4.49 umol, 46.95% yield, 91% purity) was obtained from 4-hydroxybenzaldehyde 1 (65 mg, 532.26 umol, 1.21 eq).

[0191] LCMS: RT=2.792min, m / z: 343.1(M+H)+

[0192] 1H NMR (400MHz, CD3OD) δ8.19 (2H, d, J = 8.8Hz), 6.91 (2H, d, J = 8.8Hz), 6.41 (1H, d, J = 2.0 Hz), 6.19 (1H, d, J=2.0Hz), 5.41-5.35 (1H, m), 5.08-5.04 (2H, m), 6.74-4.69 (2H, m).

[0193] Example 17: Synthesis of Compound 17 (BBC0303)

[0194] Reactive

[0195]

[0196] 3,5,7-Trihydroxy-2-[4-hydroxy-3-(oxabutan-3-yloxy)phenyl]benzopyran-4-one (BBC0303) (5.11 mg, 13.41 umol, 9.6% yield, 94% purity) was obtained from 3,4-dihydroxybenzaldehyde (200.0 mg, 1.45 mmol, 1.0 eq).

[0197] LCMS: RT=2.471min, m / z: 359.0(M+H)+

[0198] 1 H NMR (400MHz, DMSO-d6) δppm 10.79 (1H, s) 9.93 (1H, s) 9.46 (1H, s) 7.70 (1H, dd, J = 8.4, 2.0Hz) 7.45 (1H, d, J = 2.0Hz) 6.99 (1H, d, J = 8.4Hz) 6.4 8 (1H, d, J = 2.0Hz) 6.19 (1H, d, J = 2.0Hz) 5.29 (1H, t, J = 5.6Hz) 4.91 (2H, t, J = 6.8Hz) 4.66 (2H, dd, J = 7.6, 5.6Hz).

[0199] Example 18: Synthesis of Compound 18 (BBC0305)

[0200] Reactive

[0201]

[0202] 3,5,7-Trihydroxy-2-[3-hydroxy-5-methyl-4-(oxetan-3-yloxy)phenyl]benzopyran-4-one (BBC0305) (6 mg, 15.79 umol, 98% purity) was obtained from 3-bromo-4-hydroxy-5-methoxy-benzaldehyde 1 (2.0 g, 8.66 mmol, 1.7 mL, 1.0 eq).

[0203] LCMS: RT=2.607min, m / z: 373.1(M+H)+

[0204] 1 H NMR (400MHz, DMSO-d6) δppm 12.31-12.49 (1H, m) 9.65-9.90 (1H, m) 7.59 (1H, d, J = 2.0Hz) 7.45 (1H, d, J = 1.6Hz) 6.39 (1H, d, J = 2 .0Hz) 6.18 (1H, d, J = 2.0Hz) 5.14 (1H, t, J = 5.6Hz) 4.73-4.81 (2H, m) 4.64-4.71 (2H, m) 2.24 (3H, s).

[0205] Example 19: Synthesis of Compound 19 (BBC0306)

[0206] Reactive

[0207]

[0208] 2-[3,5-dimethyl-4-(oxadiazole-3-yloxy)phenyl]-3,5,7-trihydroxy-benzopyran-4-one (BBC0306) (23.28 mg, 61.68 umol, yield 15.81%, 98.128% purity) was obtained from 4-hydroxy-3,5-dimethyl-benzaldehyde 1 (1 g, 6.66 mmol, 1 eq)

[0209] LCMS: RT=2.876min, m / z: 371.0(M+H)+

[0210] 1 H NMR (400MHz, DMSO): δ (ppm) 7.85 (2H, s), 6.44 (1H, d, J = 2.00Hz), 6.18 (1H, d, J = 2.00 Hz), 4.94 (1H, q, J=6.20Hz), 4.83 (2H, t, J=6.40Hz), 4.80-4.76 (2H, m), 2.23 (6H, s).

[0211] Example 20: Synthesis of Compound 20 (BBC0307)

[0212] Reactive

[0213]

[0214] 3,5,7-Trimethoxy-2-[4-hydroxy-3-methyl-5-(oxadiazole-3-yloxy)phenyl]benzopyran-4-one (BBC0307) (5.99 mg, 15.0 umol, yield 6.9%, 93.5% purity) was obtained from 3-bromo-4-hydroxy-5-methoxy-benzaldehyde 1 (2.0 g, 8.66 mmol, 1.7 mL, 1.0 eq).

[0215] LCMS: RT=2.654min, m / z: 373.1(M+H)+

[0216] 1 H NMR (400MHz, DMSO-d6) δppm 12.44 (1H, br d, J = 1.6Hz) 7.62 (1H, s) 7.31 (1H, s) 6.47 (1H, d, J = 2.0Hz) 6.17 (1H, d, J = 2.0Hz) 5.30 (1H, br t, J=5.6Hz) 4.91 (2H, t, J=6.8Hz) 4.65-4.72 (2H, m) 2.22 (3H, s).

[0217] Example 21: Synthesis of Compound 21 (BBC0104)

[0218] Reactive

[0219]

[0220] 2-(3,4-dihydroxyphenyl)-3,5-dihydroxy-benzopyran-4-one (BBC0104) (19 mg, 64.89 umol, 52.48% yield, 97.75% purity) was obtained from 1-(2,6-dihydroxyphenyl)ethanone 1 (1.0 g, 6.57 mmol, 1.0 eq).

[0221] LCMS: RT=0.735min, m / z: 287(M+H)+

[0222] 1 H NMR (400 MHz, dimethyl sulfoxide (DMSO)-d6) δ ppm 12.41 (1H, s), 9.60 (2H, br s), 9.35 (1H, br s), 7.74 (1H, d, J=2.0 Hz), 7.58-7.65 (2H, m), 7.12 (1H, d, J=8.0 Hz), 6.91 (1H, d, J=8.0 Hz), 6.76 (1H, d, J=8.0 Hz).

[0223] Example 22: Synthesis of Compound 22 (BBC0105)

[0224]

[0225] 2-(3,4-dihydroxyphenyl)-3,7-dihydroxy-benzopyran-4-one (BBC0105) (12.0 mg, 39.95 umol, 40.4% yield, 95.3% purity) was obtained from 1-(2,4-dihydroxyphenyl)ethanone 1 (1.0 g, 6.57 mmol, 847.5 uL, 1.0 eq).

[0226] LCMS: RT=3.420min, m / z: 287.0(M+H)+

[0227] 1 H NMR (400MHz, METHANOL-d4) δppm 7.99 (1H, d, J = 9.2Hz) 7.77 (1H, d, J = 2.0Hz) 7.67 (1H, dd, J = 8.4, 2.00Hz) 6.88-6.95 (3H, m).

[0228] Comparative Example

[0229] The compounds of Comparative Examples 1 to 3 were purchased from WuXi Apptec (Shanghai) Co., Ltd. to compare the BET inhibition effect with the novel quercetin compound of the present invention.

[0230]

[0231] Test example

[0232] In order to evaluate the ability of the novel compounds of the present invention to inhibit the interaction between the bromodomains of BRD2 (BD1, BD2, BD1+BD2), BRD3 (BD1, BD2, BD1+BD2), and BRD4 (BD1, BD2, BD1+BD2), one of the BET protein family, and tetraacetylated histone H4 peptide, the following experiment was performed.

[0233] Test Example 1: Inhibitory effect on binding to BRD2 protein

[0234] The following experiment was used to evaluate the inhibitory effect of the compounds of the present invention and the comparative example compounds on the binding of BRD2 protein among BET proteins.

[0235] Compounds were sub-diluted 1:5 in dimethyl sulfoxide (DMSO) (100 μM starting concentration) starting at 10 mM assay buffer. A mixture of 100 nM GST-BRD2 (BD1, BD2, BD1+BD2) and 100 nM biotinylated acetylated histone H4 (Lys5, 8, 12, 16) peptide was prepared in assay buffer (50 mM 4-hydroxyethylpiperazineethanesulfonic acid (HEPES), pH 7.4; 25 mM NaCl; 0.05% Tween 20; 0.1% bovine serum albumin (BSA); 10 mM dithiothreitol (DTT)). After adding 6 μl of the mixture to the above dilution, 6 μl of premixed AlphaLISA Glutathione Acceptor Beads and AlphaScreen Streptavidin Donor Beads purchased from PerkinElmer in an assay buffer at a concentration of 10 μg / ml were added, and each sample was cultured at room temperature in the dark with shaking at 300 rpm. Then, the signal was measured by PerkinElmer Envision HTS Multilabel Reader using the AlphaScreen instruction manual of PerkinElmer. Each culture plate contained a negative control group that did not contain biotinylated acetylated histone H4 peptide and GST-BRD2 (BD1, BD2, BD1+BD2) but was replaced by assay buffer.

[0236] When the software GraphPad Prism is used for calculation, the value of the negative control group is input as the low reference value. In addition, the positive control group (probe molecule I-BET762 with protein / peptide mixture) is pipetted. IC50 values ​​are determined using GraphPadPrism 3.03 software (or higher version), and the results are shown in the following Table 1, Figure 1 and Figure 2 shown.

[0237] Table 1

[0238] Compound BRD2(BD1) BRD2(BD2) BRD2(BD1+BD2) Comparative Example 1 RVX-208 32005 1643 29360 Comparative Example 2 BBC0206 65151 >50000 >20000 Comparative Example 3 BBC0204 29758 5344 73431 Example 1 BBC0109 8626 - 9702 Example 2 BBC0110 9060 - - Example 4 BBC0113 12248 5115 - Example 5 BBC0114 4136 - - Example 6 BBC0115 5238 - - Example 8 BBC0309 7035 - - Example 9 BBC0310 10080 - - Example 10 BBC0311 5850 3792 - Embodiment 11 BBC0312 3686 - - Example 12 BBC0313 4627 499 - Embodiment 15 BBC0301 16946 - - Example 16 BBC0302 2399 - - Embodiment 17 BBC0303 8348 - - Embodiment 18 BBC0305 6547 - - Embodiment 19 BBC0306 2706 - - Embodiment 20 BBC0307 18481 - - Embodiment 21 BBC0104 8518 - - Embodiment 22 BBC0105 8885 - -

[0239] As shown in Table 1 above, it is confirmed that the Example compounds of the present invention have excellent inhibitory activity on BRD2 protein compared with the compound of Comparative Example 1. In particular, it is known that the IC50 values ​​of BRD2 (BD1) and BRD2 (BD1 + BD2) of the compound of Example 1 are about 30% of the level compared with the compound of Comparative Example 1. In particular, it is known that the IC50 values ​​of BRD2 (BD1) of the compounds of Examples 11 and 19 are less than 10% compared with the compound of Comparative Example 1. Therefore, the compounds of the present invention have a better BRD2 protein inhibitory effect than the existing BET inhibitor (RVX-208).

[0240] Experimental Example 2: Inhibitory effect on binding of BRD3 protein

[0241] An experiment to confirm the inhibitory effect of the compounds of the present invention and the comparative example compounds on the binding of BRD3 (BD1, BD2, BD1+BD2) protein was conducted in the same manner as in the above-mentioned Test Example 1. The results are shown in Table 2 below.

[0242] Table 2

[0243] Compound BRD3(BD1) BRD3(BD2) BRD3(BD1+BD2) Comparative Example 1 RVX-208 23398 2033 >100000 Comparative Example 2 BBC0206 >50000 >150000 >50000 Comparative Example 3 BBC0204 45280 - >100000 Example 1 BBC0109 - - 20776 Example 2 BBC0110 - - 20097 Example 4 BBC0113 17075 - - Example 5 BBC0114 7983 - 51347 Example 6 BBC0115 7180 - 86037 Example 8 BBC0309 1461 - - Example 9 BBC0310 3261 - - Example 10 BBC0311 7200 - - Embodiment 11 BBC0312 2640 - - Example 12 BBC0313 1897 - - Embodiment 13 BBC0406 11136 - - Embodiment 15 BBC0301 - - 29362 Embodiment 17 BBC0303 3181 - 95569 Embodiment 18 BBC0305 3002 - - Embodiment 19 BBC0306 1412 1344 - Embodiment 20 BBC0307 9291 - -

[0244] As shown in Table 2 above, it is confirmed that the Example compounds of the present invention have excellent inhibitory activity on BRD3 protein compared with the compound of Comparative Example 1. In particular, it is known that the IC50 value of BRD3 (BD1 + BD2) of the compound of Example 1 is significantly lower than that of the compound of Comparative Example 1. In particular, it is known that the IC50 value of BRD3 (BD1) of the compounds of Examples 12 and 19 is less than 10% compared with that of the compound of Comparative Example 1. Therefore, the compounds of the present invention have a more excellent BRD3 protein inhibitory effect than the existing BET inhibitor (RVX-208).

[0245] Experimental Example 3: Inhibitory effect on binding of BRD4 protein

[0246] The same method as in the above-mentioned Test Example 1 was used to confirm the binding inhibitory effect of the compounds of the present invention and the comparative example compounds on the BRD4 (BD1, BD2, BD1+BD2) protein. The results are shown in the following Table 3, Figure 3 and Figure 4 shown.

[0247] Table 3

[0248] Compound BRD4(BD1) BRD4(BD1+BD2) Comparative Example 1 RVX-208 23656 97219 Comparative Example 2 BBC0206 >50000 >20000 Comparative Example 3 BBC0204 35138 97174 Example 1 BBC0109 - 15579 Example 2 BBC0110 15519 38634 Embodiment 15 BBC0301 - 30270 Embodiment 20 BBC0307 - 87294

[0249] As shown in Table 3 above, it is confirmed that the Example compounds of the present invention have excellent inhibitory activity on BRD4 protein compared with the compound of Comparative Example 1. In particular, it is known that the IC50 value of BRD4 (BD1+BD2) of the compound of Example 1 is significantly lower than that of the compound of Comparative Example 1. Therefore, the compound of the present invention has a better BRD4 protein inhibitory effect than the existing BET inhibitor (RVX-208).

[0250] In summary, the compounds of the present invention have excellent inhibitory effects on BRD2 (BD1, BD2, BD1+BD2), BRD3 (BD1, BD2, BD1+BD2), and BRD4 (BD1, BD2, BD1+BD2) proteins, and can be effectively used to treat and prevent BET-related diseases.

Claims

1. A compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof, characterized in that: Chemical formula 1: In the above chemical formula 1, Ring X is Y is O, Z is CR5, R1 and R2 are -ORa, R5 is -ORa, Ra is H or C1-C6 alkyl.

2. A compound or a pharmaceutically acceptable salt thereof, characterized in that: Selected from the group consisting of the following compounds: as well as

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