KR102420263B1 - Novel quinazoline redox derivatives and their use as bet inhibitors - Google Patents

Abstract

The present invention relates to a novel quinazoline derivative compound and uses thereof, and more particularly, to a novel quinazoline derivative compound of Formula 1 having inhibitory activity against Bromodomain Extra-Terminal (BET) protein, and a BET protein comprising the same It relates to a pharmaceutical composition for the prevention or treatment of related diseases.

Description

NOVEL QUINAZOLINE REDOX DERIVATIVES AND THEIR USE AS BET INHIBITORS

The present invention relates to a quinazoline derivative or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing or treating Bromodomain Extra-Terminal (BET) protein-related diseases comprising the same as an active ingredient.

Post-translational modification (PTM) of histones is involved in the regulation of gene expression and chromatin organization in eukaryotic cells. Histone acetylation at specific lysine residues is a PTM regulated by histone acetylases and histone deacetylases. Histone acetylation controls gene expression by recruiting protein complexes by direct binding of well-conserved proteins called bromodomains to acetylated lysines in histones and other proteins. There are more than 60 bromodomain containing proteins in the human genome.

Among bromodomain-containing proteins, the Bromodomain Extra-Terminal (BET) family includes BRD2, BRD3, BRD4, and BRDT, and except for BRDT, which is localized in the testis, the remaining proteins are widely expressed in various tissues. In addition, the BET protein family has been reported to be associated with various diseases including cancer, metabolic diseases and inflammation.

For example, oncogenic fusion of BRD4 or BRD3, and intratesticular nuclear protein (NUT) genes, caused by chromosomal translocations, results in an aggressive cancer termed 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 bromodomain is conserved in these fusion proteins, and a knockdown or selective BET bromodomain inhibitor, JQ1, causes the death of these cancer cells both in vitro and in animal tumor models (Filippakopoulos et al., Nature). , 468 (2010), 1067-73). JQ1 and other selective BET inhibitors are known to bind to the BET bromodomain and prevent acetyl-lysine binding, which prevents the BET protein from interacting with chromatin, thereby regulating transcription.

BRD4 has been identified as a target in acute myeloid leukemia (AML) by an RNAi screen (Zuber et al., Nature, 478 (2011), 524-8). These findings were validated in vitro and in vivo using the BET inhibitors JQ1 and I-BET151 (Dawson et al., Nature, 478 (2011), 529-33). It is also known that BET inhibitors have broad anticancer activity in acute leukemia, multiple myeloma and other hematologic malignancies. Acute downregulation of the oncogenic transcription factor Myc upon BET inhibition was observed in several cancer models (Delmore et al., Cell, 146 (2011), 904-17; Mertz et al., Proc Natl Acad Sci US A, 108 ( 2011), 16669-74). Recent studies suggest broad potential for application of BET inhibitors to other carcinomas such as lung and brain cancer.

Another BET inhibitor, I-BET762, which is closely related to JQ1 in its chemical structure and BET binding mode, has been shown to regulate the expression of key inflammatory genes in mouse models and to protect the human body from endotoxin shock and bacteria-induced sepsis. has been reported (Nicodeme et al., Nature, 468 (2010), 1119-23). In addition, these results have been 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).

Both RVX-208 and I-BET762 were found to upregulate apolipoprotein A-I, which is important for reducing tissue levels of cholesterol. In addition, BET protein is involved in the regulation of proliferation and transcription of several viruses, so it is believed that BET inhibitors may have antiviral activity (Weidner-Glunde, Frontiers in Bioscience 15 (2010), 537-549).

Although several bromodomain inhibitors are known clinically and preclinically, the development of new bromodomain inhibitors capable of solving the problems of disease recurrence and resistance to therapeutic agents and reducing side effects is urgently required.

On the other hand, redox reactions are present in many physiological processes, and oxygen molecules are necessary for life but can produce reactive molecules that lead to disease. Other reactive species, including free radicals, also cause pathological conditions. It has been previously known that aerobic metabolism related to tissue damage is caused by reactive oxygen species (ROS). ROS and recently known reactive nitrogen species (RNS), like hormones, are messengers of cell signal transduction, causing chemical modifications of enzymes, etc., and changes in oxidant levels.

In addition, of the 20 essential amino acids, cysteine, methionine, tyrosine and tryptophan are particularly susceptible to oxidation. Accordingly, these proteinaceous substances metabolized in the human body cause various modifications such as metal binding, disulfide bond formation, methylation, and acetylation.

Until now, studies on the signaling mechanisms of cells have been focused on phosphorylation, but the present invention relates to diseases caused by oxidative and nitrification stress according to the "redox state" by oxidation, nitro It was completed by applying the redox chemistry technique considering the redox regulation mechanism such as S-nitrosylation. That is, the present inventors studied and developed a new bromodomain inhibitor in consideration of the redox state based on the fact that the degree of binding between signal transduction substances according to the redox state is different when the BET inhibitor recognizes the lysine residue of the histone protein. did.

An object of the present invention is to provide a novel quinazoline derivative compound having excellent inhibitory activity against BET protein.

In addition, the present invention is to provide a pharmaceutical composition for preventing or treating BET protein-related diseases comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention provides a quinazoline derivative compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof:

[Formula 1]

In the above formula,

또는

이고, ring A is

or

ego,

X is C, C(=O), N, O, S or absent;

Y is -CR ₅ or -NR ₅ ,

Z is -CR ₆ or -NR ₆ ,

W is C, N, O or S;

---- is an absent or single bond, respectively;

R ₁ , R ₂ , R ₅ and each R ₆ is independently H, halo, 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 may be the same or different one or more selected from the group consisting of H, C ₁ -C ₆ alkyl, -ORa, or -SRa,

R ₄ may be the same or different one or more selected from the group consisting of H, C ₁ -C ₆ alkyl, -ORa, or -SRa,

Ra and Rb are each independently H, alkyl, -alkyl-OH, -alkyl-SH, cycloalkyl, or heterocycloalkyl.

According to another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating BET protein-related diseases, comprising the compound or a pharmaceutically acceptable salt thereof.

The BET protein-related disease is cancer; autoimmune or inflammatory diseases; metabolic diseases; And it may be any one or more selected from the group consisting of viral diseases.

The quinazoline derivative compound represented by Formula 1 provided in the present invention has excellent inhibitory activity against BET protein, and thus can be usefully used as a preventive or therapeutic agent for various diseases related to BET.

1 is a graph showing the binding inhibitory activity of BRD2 (BD1+BD2) protein by Compound 3 (BBC0401) of the present invention.
2 is a graph showing the binding inhibitory activity of the BRD2 (BD2) protein by the compound 5 (BBC0403) of the present invention.
3 is a graph showing the binding inhibitory activity of BRD4 (BD1+BD2) protein by Compound 3 (BBC0401) of the present invention.
4 is a graph showing the binding inhibitory activity of BRD4 (BD2) protein by Compound 3 (BBC0401) of the present invention.
5 is a graph showing the binding inhibitory activity of BRD4 (BD2) protein by Compound 5 (BBC0403) of the present invention.

The present invention relates to a novel quinazoline derivative compound, and more particularly, to a novel quinazoline derivative compound having inhibitory activity against BET protein and a pharmaceutical composition for preventing or treating BET protein-related diseases comprising the same. .

Unless otherwise stated, terms used in the description and claims of the present invention have the meanings set forth below.

"은 잔기 또는 치환기 "R"이 골격 구조에 부착되어 있는 것을 나타내는데 사용된다.In accordance with convention used in the art, in the formulas herein, "

"A" is used to indicate that a moiety or substituent "R" is attached to the backbone structure.

"Alkyl" is a hydrocarbon having primary, secondary, tertiary and/or quaternary carbon atoms and includes saturated aliphatic groups which may be straight-chain, branched or cyclic, or combinations thereof. For example, an alkyl group may have 1 to 20 carbon atoms (ie, C ₁ -C ₂₀ alkyl), 1 to 10 carbon atoms (ie, C ₁ -C ₁₀ alkyl), or 1 to 6 carbon atoms (ie, C 1 -C 10 alkyl). C ₁ -C ₆ alkyl). Unless 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 CH ₂ 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 CH ₃ )), 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 ). may be, but is not limited thereto.

Moreover, the term “alkyl” as used throughout the specification, examples and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which are trifluoromethyl and 2,2,2-trifluoro Refers to an alkyl moiety having a substituent replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including a haloalkyl group such as roethyl, and the like.

The term "C _xy " or "C _x -C _y ", when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy, refers to a group containing x to y carbons in the chain. considered to include C ₀ alkyl represents hydrogen when the group is in a terminal position, or a bond when internal to the group. For example, a (C ₁ -C ₆ )alkyl group contains 1 to 6 carbon atoms in the chain.

“Alkoxy” refers to a group having the formula —O-alkyl, wherein the alkyl group as defined above is attached to the parent compound through an oxygen atom. The alkyl moiety of the alkoxy group may be, for example, 1 to 20 carbon atoms (ie C ₁ -C ₂₀ alkoxy), 1 to 12 carbon atoms (ie C ₁ -C ₁₂ alkoxy), 1 to 10 carbon atoms. (ie, C ₁ -C ₁₀ alkoxy), or 1 to 6 carbon atoms (ie, C ₁ -C ₆ alkoxy). Examples of suitable alkoxy groups include methoxy (-O-CH ₃ or -OMe), ethoxy (-OCH ₂ CH ₃ or -OEt), and t-butoxy (-OC(CH ₃ ) ₃ or -O-tBu ), but is not limited thereto.

"Alkenyl" has primary, secondary, tertiary and/or quaternary carbon atoms, includes straight-chain, branched and cyclic groups, or combinations thereof, and includes one or more regions of unsaturation, i.e., carbon- It is a hydrocarbon with a carbon sp ² double bond. For example, an alkenyl group has 2 to 20 carbon atoms (ie, C ₂ -C ₂₀ alkenyl), 2 to 12 carbon atoms (ie, C ₂ -C ₁₂ alkenyl), 2 to 10 carbon atoms ( ie, C ₂ -C ₁₀ alkenyl), or 2 to 6 carbon atoms (ie, C ₂ -C ₆ alkenyl). Examples of suitable alkenyl groups include vinyl (-CH=CH ₂ ), allyl (-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.

"Alkynyl" has primary, secondary, tertiary and/or quaternary carbon atoms, includes straight-chain, branched and cyclic groups, or combinations thereof, and contains one or more carbon-carbon sp triple bonds. hydrocarbons with For example, an alkynyl group has 2 to 20 carbon atoms (ie, C ₂ -C ₂₀ alkynyl), 2 to 12 carbon atoms (ie, C ₂ -C ₁₂ alkynyl), 2 to 10 carbon atoms ( ie, C ₂ -C ₁₀ alkynyl), or 2 to 6 carbon atoms (ie, C ₂ -C ₆ alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic (-C≡CH) and propargyl (-CH ₂ C≡CH).

As used herein, the term “aryl” includes substituted or unsubstituted monovalent or divalent aromatic hydrocarbon groups wherein each atom of the ring is 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. An aryl group can be a polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein at least one of the rings is aromatic, for example, the other cyclic ring is a cycloalkyl , cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocycloalkyl. Aryl groups include benzene, naphthalene, phenanthrene, anthracene, indene, indane, phenol, aniline, and the like.

The term “carbocyclylalkyl,” or “cycloalkylalkyl,” or “(cycloalkyl)alkyl,” as used herein, refers to an alkyl group substituted with a carbocycle group or a cycloalkyl group.

As used herein, the terms “carbocycle”, “carbocyclyl”, “carbocyclic” or “cycloalkyl” may be monocyclic, bicyclic or polycyclic and each atom of the ring is a carbon non-aromatic. refers to a saturated or unsaturated, monovalent or divalent ring. A cycloalkyl group can have 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. 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 ring systems, spirocyclic ring systems or bridged ring systems. In exemplary cycloalkyl groups, the atoms may be arranged in a bicyclo[4,5], [5,5], [5,6], or [6,6] system. In certain embodiments, cycloalkyl contains 3 to 20 atoms, or 3 to 10 atoms, or more preferably 3 to 7 atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Unless otherwise specified, cycloalkyl may be substituted by one or more substituents described herein.

As used herein, the terms “heterocyclylalkyl” and “heterocycloalkyl” refer to an alkyl group substituted with a heterocycloalkyl group.

The terms "heterocyclyl", "heterocycle", "heterocyclic", and "heterocycloalkyl" mean that the ring structure is at least 1 heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 to 4 heteroatoms. A substituted or unsubstituted, monovalent or divalent, saturated or partially saturated non-aromatic ring structure comprising two heteroatoms, preferably a 3- to 10-membered ring, more preferably a 3- to 7- It refers to a circle ring. The terms "heterocyclyl," "heterocycle," "heterocyclic," and "heterocycloalkyl" also refer to polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings. wherein at least one of the rings is heterocyclic, for example, the other cyclic ring can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl. Bicyclic and polycyclic heterocyclic ring systems may be fused, bridged, or spiro ring systems. Substituted heterocycles include heterocyclic rings substituted with any of the substituents disclosed herein, including, for example, carbonyl groups. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, and the like. Further exemplary heterocyclos include dihydropyridyl, dihydroindolyl, tetrahydropyridyl (piperidyl), tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, indolenyl, piperidinyl, 4- piperidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, pyranyl, chromenyl, xanthenyl, phenoxatinyl, 2H-pyrrolyl, 3H-indolyl, 4H-quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, Acridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl , quinuclidinyl, morpholinyl, and oxazolidinyl, each of which may be substituted or unsubstituted.

"Heteroaryl" refers to a substituted or unsubstituted monovalent or divalent aromatic group, monocyclic, bicyclic or polycyclic, containing one or more heteroatoms in the ring. Non-limiting examples of suitable heteroatoms that may be contained in the aromatic ring include oxygen, sulfur and nitrogen. In polycyclic heteroaryl ring systems, the ring system has at least two cyclic rings in which at least two carbons are common to two adjacent rings, wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl. Heterogroups are, for example, benzofuran, benzothiophene, pyrrole, furan, thiophene, imidazole, indole, isoindole, isoxazole, isothiazole, oxazole, thiazole, quinoline, isoquinoline, pyrazole, pyridine , pyrazine, pyridazine, and pyrimidine, each of which may be substituted or unsubstituted.

As used herein, the terms “halo” and “halogen” mean halogen and include chloro, fluoro, bromo, and iodo.

“Amino” refers to the group —NH ₂ .

"Cyano" refers to the group -CN.

“Nitro” refers to the group —NO ₂ .

"Carboxy" refers to the group -C(O)OH.

"Aldehyde" refers to the group -CHO.

"Alkoxycarbonyl" refers to the group -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein said alkyl and cycloalkyl are as defined above.

"Acyl halide" refers to a compound comprising a -C(O)-halogen group.

The present invention provides a quinazoline derivative compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Formula 1]

In the above formula,

또는

이고, ring A is

or

ego,

X is C, C(=O), N, O, S or absent;

Y is -CR ₅ or -NR ₅ ,

Z is -CR ₆ or -NR ₆ ,

W is C, N, O or S;

---- is an absent or single bond, respectively;

R ₁ , R ₂ , R ₅ and each R ₆ is independently H, halo, 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 may be the same or different one or more selected from the group consisting of H, C ₁ -C ₆ alkyl, -ORa, or -SRa,

R ₄ may be the same or different one or more selected from the group consisting of H, C ₁ -C ₆ alkyl, -ORa, or -SRa,

Ra and Rb are each independently H, alkyl, -alkyl-OH, -alkyl-SH, cycloalkyl, or heterocycloalkyl.

In one embodiment, in the compound of Formula 1 of the present invention, X may be C(=O) or absent, and W may be O.

In one embodiment, in the compound of Formula 1 of the present invention, R ₁ , and R ₂ are each independently H, C ₁ -C ₆ alkyl, or —ORc, wherein Rc is H, C ₁ -C ₆ alkyl, or 3-10 membered heterocycloalkyl containing O heteroatoms.

In one embodiment, R ₃ can be one or more identical or different selected from the group consisting of H, C ₁ -C ₆ alkyl, -ORd, and -SRd,

R ₄ may be the same or different one or more selected from the group consisting of H, C ₁ -C ₆ alkyl, -ORe, and -SRe,

Rd and Re are each independently H, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl-OH, -C ₁ -C ₆ alkyl-SH, or 3-10 membered hetero atom including a heteroatom of O cycloalkyl.

,

,

, 및

로 이루어진 군에서 선택된 동일하거나 상이한 하나 이상이고 R₅ 및 R₆은 각각 독립적으로 H 또는 C₁-C₆ 알킬일 수 있다.In one embodiment, R ₃ is H, C ₁ -C ₆ alkyl,

,

,

, and

At least one identical or different selected from the group consisting of R ₅ and R ₆ may be each independently H or C ₁ -C ₆ alkyl.

Preferred examples of the compound of Formula 1 according to the present invention are as follows, but are not limited thereto.

The compounds according to the invention are capable of forming pharmaceutically acceptable salts. The pharmaceutically acceptable salt is not particularly limited as long as it is an acid that forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion. inorganic acids such as, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid and the like; organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid and the like; and acid addition salts formed with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and the like.

In another aspect, the present invention provides a pharmaceutical composition for preventing or treating BET (Bromodomain Extra-Terminal) protein-related diseases containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. .

The pharmaceutical composition of the present invention is useful for preventing or treating various diseases related to the compound represented by Formula 1 contained therein by inhibiting the BET protein. The BET protein-related disease is cancer; autoimmune or inflammatory diseases; metabolic diseases; or a viral disease.

In one embodiment of the present invention, the cancer is hematologic cancer, multiple myeloma, acute myeloid leukemia, malignant lymphoma, aplastic anemia, thymus cancer, ovarian cancer, cervical cancer, breast cancer, colorectal cancer, liver cancer, stomach cancer, pancreatic cancer, colon cancer, It may be any one or more selected from the group consisting of peritoneal metastasis, skin cancer, bladder cancer, prostate cancer, thyroid cancer, lung cancer, osteosarcoma, fibrous tumor, and brain tumor, but is not limited thereto.

In one embodiment of the present invention, the autoimmune or inflammatory disease is rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes mellitus, hyperthyroidism, myasthenia gravis, Crohn's disease, ankylosing spondylitis, psoriasis, autoimmune pernicious anemia and Sjogren'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 nonalcoholic steatohepatitis It may be any one or more selected from the group consisting of, but is not limited thereto.

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

In one embodiment of the present invention, the viral disease is polio, acute hemorrhagic conjunctivitis, viral meningitis, hand, foot and mouth disease, hepatitis, myositis, myocarditis, pancreatitis, epidemic myalgia, encephalitis, cold, stomatitis herpes, foot-and-mouth disease, asthma, It may be any one or more selected from the group consisting of bronchiolitis, bronchitis, chronic obstructive pulmonary disease, pneumonia, sinusitis, otitis media, herpes simplex, herpes zoster, stomatitis, and chickenpox, but is not limited thereto.

According to another embodiment of the present invention, there is provided a pharmaceutical formulation comprising the pharmaceutical composition.

The pharmaceutical preparation of the present invention may be in various oral dosage forms such as tablets, pills, powders, capsules, syrups or emulsions, or parenteral dosage forms such as intramuscular, intravenous or subcutaneous administration such as injections, preferably oral It may be in dosage form.

In addition, the pharmaceutical preparation may be formulated according to a conventional method by adding one or more selected from the group consisting of carriers, additives, and excipients, for example, as conventional non-toxic pharmaceutically acceptable additives in addition to the active ingredient. have.

Hereinafter, the present invention will be described in detail by way of Examples and Experimental Examples. However, the following examples and experimental examples are only for illustrating the present invention, and the content of the present invention is not limited by the following examples and experimental examples.

[Example]

The structure of the compound was confirmed by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR was measured with a Bruker Avance-400 or Bruker Avance 300 instrument. The solvents for the measurement were deuterium substituted-dimethyl sulfoxide (DMSO-d6), deuterium substituted-chloroform (CDCl ₃ ) and deuterium substituted-methanol (CD ₃ OD), the internal standard was tetramethylsilane (TMS) it was

High performance liquid chromatography (HPLC) was performed by flash chromatography or column chromatography.

Thin layer chromatography (TLC) was performed on silica gel plates. 1000 mesh silica gel was used for thin layer chromatography. In addition, the dimension of the silica gel plate used for TLC was 20-25 μm, and the dimension of the silica gel plate used for product purification was 40 to 45 μm.

Ultraviolet light, iodine, and potassium permanganate were used in water for visualization.

The known starting materials of the present invention may be prepared by conventional synthetic methods in the art, or may be purchased from Alfa Aesar, Aldrich, and the like.

Example 1: Synthesis of Compound 1 (BBC0202)

2-[4-(2-hydroxyethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-1H from 3,5-dimethoxyaniline 1 (1 g, 6.53 mmol, 1 eq ) -quinolin-4-one (BBC0202) (5.78 mg, 15.43 umol, 11.40% yield, 98.6% purity) was obtained.

LCMS: RT=2.505 min, m/z: 370.1 (M+H)+

¹ H NMR (400 MHz, CDOD) δ 7.44 (2H, s), 6.75 (1H, d, J = 2.0 Hz), 6.43 (1H, d, J = 2.4 Hz), 6.34 (1H, s), 3.98- 3.85 (10H, m), 2.40 (6H, s).

Example 2: Synthesis of compound 2 (BBC0203)

2-[4-(2-hydroxyethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-1 from 3,5-dimethoxyaniline 1 (5 g, 32.64 mmol, 1 eq ) -Methyl-quinolin-4-one (4.79 mg, 12.38 umol, 4.77% yield, 99.1% purity) was obtained.

¹ H NMR (400 MHz, CDCl3) δ 7.06 (2H, s), 6.43 (1H, d, J = 2.4 Hz), 6.41 (1H, d, J = 2.4 Hz), 6.18 (1H, s), 4.01- 3.95 (7H, m), 3.93 (3H, s), 3.52 (3H, s), 2.34 (6H, s).

Example 3: Synthesis of compound 3 (BBC0401)

4-Hydroxy-3,5-dimethyl-benzaldehyde 1 (0.4 g, 2.66 mmol, 1 eq) was reacted with 1,2-dibromoethane (5.2 g, 27.68 mmol, 2.09 mL, 10.39 eq) to S- [2-(4-formyl-2,6-dimethyl-phenoxy)ethyl]thioacetate 2 was prepared.

Next, S-[2-(4-formyl-2,6-dimethyl-phenoxy)ethyl]thioacetate 2 (100 mg, 388.92 umol, 1 eq) was mixed with potassium; S-[2-(4-formyl-2,6-dimethyl-phenoxy)ethyl]ethanethioate 3 (70 mg, 277.42 umol, 71.33%) reacted with thioacetate (45 mg, 394.02 umol, 1.01 eq) yield) was prepared.

The intermediate compound 3 (60 mg, 237.79 umol, 1.01 eq) was reacted with 2-amino-4,6-dimethoxy-benzamide 4 (46 mg, 234.45 umol, 1 eq) to S-[2-[4- (5,7-dimethoxy-4-oxo-3H-quinazolin-2-yl-2,6-dimethyl-phenoxylethyl]ethanethioate 5 (82 mg, 191.37 umol, 81.62% yield) was prepared.

Finally, S-[2-[4-(5,7-dimethoxy-4-oxo-3H-quinazolin-2-yl-2,6-dimethyl-phenoxylethyl]ethanethioate 5 (70 mg, 163.36 umol, 1 eq) was reacted with K ₂ CO ₃ (70.00 mg, 506.49 umol, 3.10 eq) to give compound 3 (11 mg, 26.33 umol, 16.12% yield, 92.5% purity).

LCMS: RT=0.796 min, m/z: 387 (M+H)+

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.22 (1H, br s), 7.67 (2H, s), 6.83 (1H, d, J = 2.4 Hz), 6.46 (1H, d, J = 2.2 Hz) ), 3.98 (3H, s), 3.96 (2H, t, J = 6.4 Hz), 3.93 (3H, s), 2.94 (2H, m), 2.39 (6H, s), 1.74 (1H, t, J = ) 8.4 Hz).

Example 4: Synthesis of compound 4 (BBC0402)

2-[4-(2-hydroxyethylsulfanyl)-3,5-dimail from 5-bromo-2-fluoro-1,3-dimethyl-benzene 1 (1 g, 4.92 mmol, 1 eq ) -phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (BBC0402) (43.62 mg, 111.18 umol, 46.76% yield, 98.5% purity) was obtained.

¹ H NMR (400 MHz, d6-DMSO) δ 11.92 (1H, s), 7.96 (2H, s), 6.76 (1H, d, J = 2.4 Hz), 6.54 (1H, d, J = 2.0 Hz), 4.83 (1H, t, J = 5.6 Hz), 3.89 (3H, s), 3.85 (3H, s), 3.47-3.40 (2H, m), 2.78 (2H, t, J = 6.8 Hz), 2.56 (6H) , s).

LCMS: RT = 2.247 min, m/z: 387.1 (M + H) +

Example 5: Synthesis of compound 5 (BBC0403)

4-Hydroxy-3,5-dimethyl-benzaldehyde 1 (50 mg, 332.95 umol, 1 eq) was reacted with oxetan-3-yl 4-methylbenzenesulfonate (106.00 mg, 464.37 umol, 1.39 eq) The intermediate compound 3,5-dimethyl-4-(oxetan-3-yloxy)benzaldehyde 2 was prepared.

Next, 3,5-dimethyl-4-(oxetan-3-yloxy)benzaldehyde 2 (88 mg, 426.69 umol, 1.05 eq) was mixed with 2-amino-4,6-dimethoxy-benzamide 3 (80 mg, 407.74 umol, 1 eq) to give compound 5 (12 mg, 30.39 umol, 7.45% yield, 96.86% purity).

LCMS: RT=0.780 min, m/z: 383.1 (M+H)+

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.66 (2 H, s) 6.82 (1 H, d, J=2.0 Hz) 6.46 (1 H, d, J=2.4 Hz) 4.74 - 5.10 (5 H , m) 3.98 (3 H, s) 3.93 (3 H, s) 2.29 (6 H, s).

Example 6: Synthesis of compound 6 (BBC0404)

2-[4-(2-hydroxyethoxy)-3,5-dimethyl-phenyl]-7- from 1-bromo-3,5-dimethoxy-benzene 1 (20 g, 92.14 mmol, 1 eq) Methoxy-5-(oxetan-3-yloxy)-3H-quinazolin-4-one (BBC0404) (10.11 mg, 23.78 umol, 8.09% yield, 97.0% purity) was obtained.

LCMS: RT=2.393 min, m/z: 413.1 (M+H)+

¹ H NMR (400 MHz, CDCl3): δ (ppm) 9.49 (1H, br s), 7.70 (2H, s), 6.86 (1H, d, J = 2.0 Hz), 5.94 (1H, d, J = 2.4 Hz), 5.30 (1H, q, J = 5.6 Hz), 5.02 (2H, t, J = 8.0 Hz), 4.92 (2H, dd, J = 7.6, 5.6 Hz), 4.04 - 3.95 (4H, m), 3.92 (3H, s), 2.41 (6H, s), 2.19 (1H, br t, J = 6.4 Hz).

Example 7: Synthesis of compound 7 (BBC0405)

2-[4-(2-hydroxyethoxy)-3,5-dimethyl-phenyl from 4-benzyloxy-2-bromo-6-hydroxy-benzaldehyde 1 (1.3 g, 4.2 mmol, 1.0 eq) ]-5-methoxy-7-( oxetan -3-yloxy)-3H-quinazolin-4-one (BBC0405) (10.1 mg, 23.6 umol, 18.7% yield, 96.3% purity) was obtained.

LCMS: RT=2.020 min, m/z: 413.2 (M+H)+

¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.77 (1H, br s) 7.87 (2H, s) 6.51 (1H, d, J = 2.0 Hz) 6.41 (1H, d, J = 2.0 Hz) 5.46 ( 1H, t, J = 5.2 Hz) 5.00 (2H, t, J = 6.8 Hz) 4.91 (1H, t, J = 5.6 Hz) 4.58 (2H, dd, J = 7.6, 4.8 Hz) 3.81-3.87 (5H, m) 3.72 (2H, q, J = 5.2 Hz) 2.30 (6H, s).

Example 8: Synthesis of compound 8 (BBC0406)

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

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

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

Example 9: Synthesis of compound 9 (BBC0407)

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

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

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

Example 10: Synthesis of compound 10 (BBC0206)

2-[4-(5,7-dimethoxy-1H-benzimidazol-2-yl) from 3,5-dimethoxyaniline 1 (2 g, 13.06 mmol, 1 eq ) in Ac ₂ O (10 mL) -2,6-dimethyl-phenoxy]ethanol (BBC0206) (51.16 mg, 148.82 umol, 37.76% yield, 99.6% purity) was obtained.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.98-12.58 (1H, m), 7.79-7.83 (2H, br s), 6.62-6.66 (1H, brs), 6.35-6.39 (1H, br s) , 4.55-4.59 (1H, br s), 3.98 (3H, s), 3.86-3.91 (2H, m) 3.81 (3H, s), 3.75-3.79 (2H, m), 2.34 (6H, s)

LCMS: RT = 1.961 min, m/z: 343.1 (M + H) +

Example 11: Synthesis of compound 11 (BBC0207)

2-[4-(5,7-dimethoxy-1H-indol-2-yl)-2,6 from 2-(3,5-dimethoxyphenyl)acetonitrile 1 (2 g, 11.29 mmol, 1 eq ) -Dimethyl-phenoxy]ethanol (BBC0207) (27.96 mg, 80.26 umol, 14.17% yield, 98.0% purity) was obtained.

LCMS: RT=2.505 min, m/z: 342.2 (M+H)+

¹ H NMR (400 MHz, CDCl3) δ 8.36 (1H, brs), 7.31 (2H, s), 6.65 (1H, d, J = 1.6 Hz), 6.63 (1H, d, J = 2.4 Hz), 6.34 ( 1H, d, J = 2.0 Hz), 4.00-3.91 (7H, m), 3.85 (3H, s), 2.35 (6H, s), 2.23 (1H, brs).

Example 12: Synthesis of compound 12 (BBC0208)

2-[4-(4,6-dimethoxy-1 H -indol-2-yl)-2,6-dimethyl-phenoxy from 3,5-dimethoxyaniline 1 (1.0 g, 6.53 mmol, 1.0 eq) ]Ethanol (BBC0208) (2.51 mg, 7.00 umol, 7.11% yield, 95.2% purity) was obtained.

LCMS: RT = 2.496 min, m/z: 342.1 (M + H) +

¹ H NMR (400 MHz, CDCl3) δ ppm 8.16 (1H, br s) 7.27-7.29 (2H, m) 6.76 (1H, d, J = 1.6 Hz) 6.51 (1H, d, J = 0.8 Hz) 6.24 ( 1H, d, J = 2.0 Hz) 3.96-4.01 (2H, m) 3.94 (5H, s) 3.86 (3H, s) 2.35 (6H, s) 2.16 (1H, t, J = 6.0 Hz).

[Comparative example]

The compounds of Comparative Examples 1 to 3 were prepared by WUXI APPTEC (SHANGHAI) CO. BET inhibitory effects were compared with novel quinazoline compounds of the present invention, purchased from LTD.

The bromodomains of BRD2 (BD1, BD2, BD1+BD2), BRD3 (BD1, BD2, BD1+BD2), BRD4 (BD1, BD2, BD1+BD2), which are one of the BET protein families of the novel compound according to the present invention, and In order to evaluate the ability to inhibit the interaction between tetraacetylated histone H4 peptides, the following experiments were performed.

Test Example 1: Binding inhibitory effect on BRD2 protein

The binding inhibitory effect of the compound of the present invention and the compound of Comparative Example on the BRD2 protein among the BET proteins was tested as follows.

Compounds were diluted 1:5 serial dilutions in assay buffer from a 10 mM stock in DMSO (100 μM starting concentration) in white OptiPlate-384 (PerkinElmer). A mixture of 100 nM GST-BRD2 (BD1, BD2, BD1 + BD2) and 100 nM biotinylated acetyl-histone H4 (Lys5, 8, 12, 16) peptides was treated with assay buffer (50 mM 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 from PerkinElmer each in assay buffer at a concentration of 10 μg/ml. Beads (AlphaScreen Streptavidin Donor Beads) were added, and samples were incubated with shaking at 300 rpm for 30 minutes at room temperature in the dark. Thereafter, signals were measured with a PerkinElmer Envision HTS Multilabel Reader using PerkinElmer's Alpha Screen protocol. Each plate contained a negative control in which biotinylated acetyl-histone H4 peptide and GST-BRD2 (BD1, BD2, BD1 + BD2) were drained and replaced with assay buffer.

When the software GraphPad Prism was used for calculation, a negative control value was entered as a low reference value. A positive control (probe molecule I-BET762 with protein/peptide mixture) was also pipetted. Determination of IC50 values was performed using GraphPad Prism 3.03 software (or an updated version thereof), and the results are shown in Table 1, FIGS. 1 and 2 below.

compound BRD2 (BD1) BRD2 (BD2) BRD2 (BD1+BD2) Comparative Example 1 RVX-208 32,005 1,643 29,360 Comparative Example 2 BBC0201 29,811 2,873 12,549 Comparative Example 3 BBC0204 29,758 5,344 73,431 Example 2 BBC0203 N/D - - Example 3 BBC0401 11,358 - 9,141 Example 4 BBC0402 17,048 1,022 - Example 5 BBC0403 - 1,066 - Example 6 BBC0404 >100,000 - - Example 9 BBC0407 27,591 - - Example 10 BBC0206 65,151 - 20,000 Example 11 BBC0207 >100,000 - - Example 12 BBC0208 35,295 - -

As shown in Table 1, it was confirmed that all of the compounds of the Examples of the present invention had excellent inhibitory activity against the BRD2 protein, as compared to the compounds of Comparative Example 1. In particular, it can be seen that the compound of Example 3 has lower IC50 values of BRD2 (BD1) and BRD2 (BD1+BD2) compared to the compound of Comparative Example 1. Therefore, the compound of the present invention has a better inhibitory effect on BRD2 protein than the conventional BET inhibitor (RVX-208).

Test Example 2: Binding inhibitory effect on BRD3 protein

In the same manner as in Test Example 1, an experiment was performed to confirm the binding inhibitory effect of the compound of the present invention and the compound of Comparative Example on the BRD3 (BD1, BD2, BD1+BD2) protein. The results are shown in Table 2 below.

compound BRD3 (BD1) BRD3 (BD2) BRD3 (BD1+BD2) Comparative Example 1 RVX-208 23,398 2,033 >100,000 Comparative Example 2 BBC0201 >100,000 8,604 >100,000 Comparative Example 3 BBC0204 45,280 745 >100,000 Example 3 BBC0401 9,882 9,264 11,395 Example 4 BBC0402 17,056 - 82,719 Example 5 BBC0403 - 2,512 - Example 8 BBC0406 11,136 - - Example 10 BBC0206 - - 50,000 Example 12 BBC0208 22,315 - -

As shown in Table 2, it was confirmed that all of the compounds of the Examples of the present invention had excellent inhibitory activity against the BRD3 protein as compared to the compounds of Comparative Example 1. In particular, it can be seen that the compound of Example 3 has much lower IC50 values of BRD3 (BD1) and BRD3 (BD1+BD2) compared to the compound of Comparative Example 1. Therefore, the compound of the present invention has a better inhibitory effect on BRD3 protein than the conventional BET inhibitor (RVX-208).

Test Example 3: Binding inhibitory effect on BRD4 protein

In the same manner as in Test Example 1, an experiment was performed to confirm the binding inhibitory effect of the compound of the present invention and the compound of Comparative Example on the BRD4 (BD1, BD2, BD1+BD2) protein. The results are shown in Table 3 and FIGS. 3 to 5 below.

compound BRD4 (BD1) BRD4 (BD1+BD2) Comparative Example 1 RVX-208 23,656 97,219 Comparative Example 2 BBC0201 42,293 >20,000 Comparative Example 3 BBC0204 35,138 97,174 Example 2 BBC0203 - 92,581 Example 3 BBC0401 3,622 7,012 Example 4 BBC0402 27,190 38,109

As shown in Table 3, it was confirmed that all of the compounds of the Examples of the present invention had excellent inhibitory activity against the BRD4 protein as compared to the compounds of Comparative Example 1. In particular, it can be seen that the compound of Example 3 has much lower IC50 values of BRD4 (BD1) and BRD4 (BD1+BD2) compared to the compound of Comparative Example 1. Therefore, the compound of the present invention has a better inhibitory effect on BRD4 protein than the conventional BET inhibitor (RVX-208). As a result, the compound of the present invention has BRD2 (BD1, BD2, BD1+BD2), BRD3 (BD1, BD2, BD1+BD2) and BRD4 (BD1, BD2, BD1+BD2) proteins all have excellent inhibitory effects, so they can be effectively used for treatment and prevention of BET-related diseases.

Claims (12)

A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Formula 1]

In the above formula,
ring A is

ego,
X is absent,
Y is -NR ₅ ,
Z is -NR ₆ ,
---- is an absent or single bond, respectively;
R ₁ , R ₂ , R ₅ and each R ₆ is independently H, C ₁ -C ₆ alkyl, or —ORa;
R ₃ may be the same or different one or more selected from the group consisting of H, C ₁ -C ₆ alkyl, -ORa, or -SRa,
each Ra is independently H, C ₁ -C ₆ alkyl, —C ₁ -C ₆ alkyl-OH, or —C ₁ -C ₆ alkyl-SH.
delete delete delete According to claim 1,
R ₃ is H, C ₁ -C ₆ alkyl,

,

or

A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, characterized in that at least one identical or different selected from the group consisting of
A compound selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof:

,

,

,

and

.
A pharmaceutical composition for preventing or treating BET (Bromodomain Extra-Terminal) protein-related diseases comprising the compound according to any one of claims 1, 5 and 6 or a pharmaceutically acceptable salt thereof,
The BET protein-related disease is cancer; autoimmune or inflammatory diseases; metabolic diseases; And any one or more selected from the group consisting of viral diseases,
The autoimmune or inflammatory disease is rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, hyperthyroidism, myasthenia gravis, Crohn's disease, ankylosing spondylitis, psoriasis, autoimmune pernicious anemia and Sjogren's syndrome, allergy, allergic Any one selected from the group consisting of rhinitis, arthritis, asthma, chronic obstructive pulmonary disease, degenerative joint disease, dermatitis, organ rejection, eczema, hepatitis, inflammatory bowel disease, sepsis, septic syndrome, septic shock and nonalcoholic steatohepatitis more than,
The metabolic disease is characterized in that any one or more selected from the group consisting of hypertriglyceridemia, obesity, hyperlipidemia, hyperinsulinemia, hyperglycemia, arteriosclerosis, hypertension, type 2 diabetes, and insulin resistance disease, a pharmaceutical composition .
delete 8. The method of claim 7, wherein the cancer is hematologic cancer, multiple myeloma, acute myeloid leukemia, malignant lymphoma, aplastic anemia, thymus cancer, ovarian cancer, cervical cancer, breast cancer, colorectal cancer, liver cancer, stomach cancer, pancreatic cancer, colon cancer, peritoneal metastasis Cancer, skin cancer, bladder cancer, prostate cancer, thyroid cancer, lung cancer, osteosarcoma, characterized in that any one or more selected from the group consisting of fibrous tumors and brain tumors, a pharmaceutical composition.
delete delete The method of claim 7, wherein the viral disease is polio, acute hemorrhagic conjunctivitis, viral meningitis, hand, foot and mouth disease, hepatitis, myositis, myocarditis, pancreatitis, myalgia, encephalitis, cold, stomatitis herpes, foot-and-mouth disease, asthma, bronchiolitis , bronchitis, chronic obstructive pulmonary disease, pneumonia, sinusitis, otitis media, herpes simplex, herpes zoster, stomatitis, characterized in that any one or more selected from the group consisting of chickenpox, a pharmaceutical composition.

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