KR20100097939A - Novel ck2 inhibitor and method of preparing the same - Google Patents

Abstract

PURPOSE: A CK2 inhibitor compound and a composition containing the same for suppressing CK2 are provided to treat CK2 inhibition-associated diseases. CONSTITUTION: A compound with activity of suppressing CK2 is denoted by chemical formula I. The compound of chemical formula I is prepared by reacting a compound of chemical formula II with a compound of chemical formula III and acid under the presence of an organic solvent. The acid is X-Y-Z, wherein X is halogen, Y is alkenyl, and Z is carboxyl. A composition for suppressing CK2 contains the compound of chemical formula I, pharmaceutically acceptable salt or solvate thereof as active ingredients. The composition is used for treating cancer or viral infection.

Description

Novel CK2 inhibitor and method for preparing the same {Novel CK2 inhibitor and method of preparing the same}

The present invention relates to novel CK2 inhibitors and methods for their preparation.

Protein kinase CK2 is a serine / threonine specific protein kinase present everywhere in eukaryotic cells that is involved in pathways involved in the control of cell proliferation and survival. CK2 is known to play an important role during the process of neoplasia and malignant metastasis (Tawfic S., Yu S., Wang H., et al. (2001) Protein kinase CK2 signal in neoplasia. Histol. Histopathol. 16: 573-582), and further several major viral proteins for disease development of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) have been reported as CK2 substrates (Meggio F., Marin O., et al. (2001). Mol Cell Biochem 227: 145-151; Franck N., Le Seyec J., et al. (2005) Hepatitis C virus NS2 protein is phosphorylated by the protein kinase CK2 and targeted for degradation to the proteasome.J Virol. 79: 2700-2008). It has also been reported that CK2 is present in a range of 3 to 7 times higher than normal tissue in other solid tumors derived from epithelial tissue (Tawfic S., Yu S., et al. (2001) Protein kinase CK2 signal Histol Histopatol. 16: 573-582; Faust RA, Gapany M., et al (1996) Elevated protein kinase CK2 activity in chromatin of head and neck tumors: association with malignant transformation. Cancer Letters 101: 31-35) In addition, the phosphorylation activity of the CK2 enzyme has been shown to be very important in malignant transformation of cells, which constitute a potent marker for tumor progression (Seldin DC, Leder P. (1995) Casein Kinase IIa transgene-induced murine lymphoma). : relation to theileroiosis in cattle.Science 267: 894-897). Overexpression of CK2 has been shown to induce breast cell tumor formation by upregulation in the Wnt / beta-catenin cascade (Landesman-Bollag E., Romien-Mourez R., et al (2001) Protein Kinase). CK2 in mammary gland tumorigenesis.Oncogene 20: 3247-3257). Recent findings also indicate that CK2 is a chromatin remodeling (Barz T., Ackenmann K., et al. (2003) Genome-wide expression screens indicate a global role for protein kinase CK2 in chromatin remodeling. J Cell Sci. 116: 1563- 1577) and control of cell survival (Unger GM, Davis AT, Slaton JW, Ahmed K. (2004) Protein kinase CK2 as regulator of cell survival: implications for cancer therapy.Curr Cancer Drug Targets, 4: 77-84). It is suggested that it play an essential role in some other processes. In addition, there were findings demonstrating that CK2-mediated phosphorylation is a very potent signal for cell survival and therefore this enzyme is considered as a mediator of anti-apoptosis for cell physiology (Ahmed K., Gerber DA, Cochet). C. (2002) Joining the cell survival squad: an emerging role for protein kinase CK2.Trends Cell Biol, 12: 226-229; Torres J., Rodriguez J., et al (2003) Phosphorylation-regulated cleavage of the tumour suppressor PTEN by caspase-3: implications for the control of protein stability and PTEN-protein interactions.J Biol Chem, 278: 30652-60).

Based on these findings, the CK2-mediated phosphorylation reaction has begun to be recognized as a powerful target for the treatment of diseases such as cancer, and there is an increasing interest in the development of selective inhibitors for CK2, which can be a leading compound for drug development. It is getting higher.

To date, the development of CK2 inhibitors has been attempted through two experimental approaches: a) direct inhibition of the CK2 enzyme, or b) blocking the phosphorylation reaction site near the acidic region described in common for all CK2 substrates.

A representative example of a CK2 inhibitor using direct inhibition of the CK2 enzyme is 4,5,6,7-tetrabromobenzotriazole (TBB), which induces strong cell death and caspase dependent degradation of HS1 (Ruzzene M. , Penzo D., Pinna L. (2002) Protein kinase CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) induces apoptosis and caspase-dependent degradation of haematopoietic lineage cell-specific protein 1 (HS1) in Jurkat cells.Biochem J., 364: 41-47). In addition, by inhibiting the expression of CK2 enzyme by using anti-sense oligonucleotides, the effect of laboratory cell death and anti-tumor activity in experimental cancer models in mice has been confirmed. (Guo C., Yu S., et al. (2001) A potential role of nuclear matrix-associated protein kinase CK2 in protection against drug-induced apoptosis in cancer cells.J Biol Chem, 276: 5992-5999; Slaton JW, et al. (2004) Induction of apoptosis by antisense CK2 in human prostate cancer xenograft model.Mol Cancer Res. 2: 712-721).

Other compounds such as anthraquinone derivatives, flavonoids, and halogenated azobenzylimimidazoles have been described as CK2 ATP binding site inhibitors (Sarno S., et al. (2002) Toward the rational design of protein kinase casein kinase-). Pharmacol Therapeutics 93: 159-168), and 5-oxo-5,6-dihydroindolo (1,2-a) quinazolin-7-yl acetate (IQA) have also been reported as selective CK2 inhibitors. (Vangrevelinghe E., et al. (2003) Biochemical and three-dimensional-structural study of the specific inhibition of protein kinase CK2 by [5-oxo-5,6-dihydroindolo- (1,2-a) quinazolin-7 -yl] acetic acid (IQA) J. Med. Chem. 46: 2556-2662).

Another approach to inhibiting CK2 activity is to interfere with the phosphorylation reaction site on the substrate, see patent applications WO03 / 054002 and Cancer Res. Perea SE et al. (2004) "Antitumor effect of a novel proapoptotic peptide impairing the phosphorylation by the protein kinase CK2." Described in 64: 7127-7129, which demonstrates the cytotoxic and antitumor effects of tumor cells in cancer clinical models. , The use of cyclic peptides to block CK2 mediated phosphorylation on substrate sites is proposed. However, the peptides described have the limitation that they cannot penetrate into cells themselves and therefore require membrane permeable peptides to be melted on them.

It is an object of the present invention to provide a novel CK2 inhibitor and a method for producing the same that can effectively prevent or treat a disease associated with CK2 by effectively inhibiting CK2.

In order to solve the above problems, the present invention provides a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, a preparation method thereof and a composition for inhibiting CK2 comprising the same as an active ingredient.

The compound of formula (I) according to the present invention shows excellent CK2 inhibitory activity compared to the conventionally known CK2 inhibitors, and thus can be usefully used for the treatment of diseases associated with CK2 inhibition such as cancer and viral infection.

The present invention provides a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof.

Where

R ₁ and R ₂ are each independently substituted or unsubstituted 6 to 12 membered aryl; Or substituted or unsubstituted 5 to 10 membered heteroaryl,

R ₃ and R ₄ are each independently hydrogen; halogen; Hydroxy; Substituted or unsubstituted C _1-12 alkyl; Or substituted or unsubstituted C _1-12 alkoxy.

In one embodiment of the invention,

R ₁ and R ₂ are each independently phenyl, biphenyl or naphthalene, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C _1-6 alkyl and C _1-6 alkoxy. ; Or a halogen, hydroxy, substituted or unsubstituted with at least one substituent selected from the group consisting of alkyl and alkoxy of C _1-6 of C _1-6, furanyl, pyridyl, benzimidazolyl, benzothiazolyl, benzo Thienyl, benzoxazolyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyrimidinyl, pyrrolyl, quinolinyl, thiazolyl or thienyl.

In another embodiment, R ₁ and R ₂ are each independently phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C _1-6 alkyl and C _1-6 alkoxy; Or a halogen, hydroxy, may be the, or furanyl dilil flutes substituted or unsubstituted with at least one substituent selected from the group consisting of alkyl and alkoxy of C _1-6 of C _1-6.

In another embodiment, R ₁ and R ₂ are each independently 4-methoxyphenyl, 4-chlorophenyl, 3-furanyl, 3-pyridyl, 2-furanyl, 4-hydroxy-3-meth Methoxyphenyl, 4-hydroxy-3-methoxyphenyl, 4-hydroxy-3-bromo-5-methoxyphenyl, 4-hydroxy-2-bromo-5-methoxyphenyl, 4-hydroxy 3-chloro-5-methoxyphenyl.

In another embodiment, R ₃ and R ₄ are each independently substituted or unsubstituted C _1-4 alkyl; Or substituted or unsubstituted C _1-4 alkoxy.

In still other embodiments, R ₃ can be ethyl or methyl and R ₄ can be ethoxy or methoxy.

In a preferred embodiment of the invention, the compound of formula (I) is

Ethyl 2- (5-bromo-2,4-dimethoxy-benzylidene) -5- (4-methoxyphenyl) -7-methyl-3-oxo-2,3-dihydro -5 H-thiazolo [ 3,2- a ] pyrimidine-6-carboxylate (Compound 5, DCP-48),

Ethyl 2- (5-bromo-2,4-dimethoxybenzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3-dihydro-5 H -thiazolo [3 , 2- a ] pyrimidine-6-carboxylate (Compound 6, DCP-49),

Ethyl 2- (5-bromo-2,4-dimethoxy-benzylidene) -5- (furan-3-yl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazolo [ 3,2- a ] pyrimidine-6-carboxylate (Compound 7, DCP-50),

Ethyl 2- (5-bromo-2,4-dimethoxy-benzylidene) -5- (pyridin-3-yl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazolo [ 3,2- a ] pyrimidine-6-carboxylate (Compound 8, DCP-54),

Ethyl 2- (4-hydroxy-3-methoxy-benzylidene) -5- (furan-2-yl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazolo [3, 2- a ] pyrimidine-6-carboxylate (Compound 16, DCP-63),

Ethyl 2- (4-methoxy-benzylidene) -5- (4-hydroxy-3-methoxyphenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazolo [3, 2- a ] pyrimidine-6-carboxylate (Compound 17, DCP-61),

Ethyl 2- (4-hydroxy-3-bromo-5-methoxy-benzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazole Zolo [3,2- a ] pyrimidine-6-carboxylate (Compound 18, DCP-62),

Ethyl 2- (4-hydroxy-2-bromo-5-methoxy-benzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazole Solo [3,2- a ] pyrimidine-6-carboxylate (compound 19, 773), or

Ethyl 2- (4-hydroxy-3-chloro-5-methoxy-benzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazolo [3,2- a ] pyrimidine-6-carboxylate (Compound 20, DCP-60)

Can be.

In the present invention, the term "aryl" refers to a monocyclic or bicyclic aromatic ring system containing 6 to 12 carbons in the ring. Alkyl substituents may optionally be present on the ring. Examples thereof include phenyl, biphenyl and naphthalene.

The term “heteroaryl” refers to a 5 to 7 membered mono- or 8 to 10 membered bicyclic aromatic ring system, each ring having 1 to 4 heteros selected from N, O or S in which nitrogen and sulfur atoms may be present in an acceptable oxidation state It may consist of atoms. Examples thereof include furanyl, pyridyl, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, Pyrimidinyl, pyrrolyl, quinolinyl, thiazolyl and thienyl.

The term "alkyl" refers to straight and branched radicals having up to 12, preferably up to 6 carbon atoms, unless otherwise specified, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert -Butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl.

The term "alkoxy" refers to an -OR radical, where R represents alkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy and cyclohexyloxy and the like.

Pharmaceutically acceptable salts of compounds of formula I include conventional non-toxic or quaternary ammonium salts formed with inorganic or organic acids or bases. Examples of such acid addition salts include acetates, adipates, benzoates, benzenesulfonates, citrates, camphorates, dodecylsulfates, hydrochlorides, hydrobromide, lactates, maleates, methanesulfonates, nitrates, oxalates, Pivalate, propionate, succinate, sulfate and tartrate. Basic salts include alkali metal salts such as ammonium salts, sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts with organic bases such as dicyclohexylamino salts, and salts with amino acids such as arginine. have. The basic nitrogen containing group can also be quaternized with, for example, an alkyl halide.

In addition, the compounds of the present invention may have one or more polymorphic or amorphous crystalline forms, and are themselves within the scope of the present invention. In addition, the compounds may form solvates with, for example, water (ie, hydrates) or general purpose organic solvents. As used herein, the term “solvate” means a physical bond of a compound of the invention with one or more solvent molecules. Such physical bonds include hydrogen bonds, including varying degrees of ionic and covalent bonds. In some cases, solvates may be separated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The term "solvate" is intended to include liquid and separable solvates. Non-limiting examples of suitable solvates include ethanolate, methanolate, and the like.

The invention also

Reacting a compound of formula (II) with a compound of formula (III) and an acid in the presence of an organic solvent

Provided are processes for the preparation of compounds of formula (I).

[Formula I]

[Formula II]

[Formula III]

Where

R ₁ and R ₂ are each independently substituted or unsubstituted 6 to 12 membered aryl; Or substituted or unsubstituted 5 to 10 membered heteroaryl,

R ₃ and R ₄ are each independently hydrogen; halogen; Hydroxy; Substituted or unsubstituted C _1-12 alkyl; Or substituted or unsubstituted C _1-12 alkoxy.

The reaction of the compound of formula (II) with formula (III) is carried out in the presence of a suitable organic solvent and acid.

The organic solvent and acid may be used as long as it can induce a reaction between the compound of formula (II) and the compound of formula (III).

For example, the organic solvent and acid may be a solvent of an aliphatic acid including acetic acid capable of inducing a reaction between a compound of formula (II) and a compound of formula (III), and bromo- or iodoacetic acid including chloroacetic acid. Can be used as an acid. Acetic anhydride may be added when synthesizing a compound in which the hydroxyl group is protected by an acetyl group, and in the case of synthesizing with another aliphatic ester group, the anhydrous fatty acid may be used.

In one embodiment, the acid is X—Y—Z, wherein X is halogen, Y is alkenyl, and Z is carboxyl. For example, chloroacetic acid can be used as the acid.

The compound of Formula (II) used as a precursor in Scheme 1 may be produced by reacting a compound of Formula (IV), a compound of Formula (V), and thiourea.

[Formula IV]

[Formula V]

Where

Each R ₁ is independently, substituted or unsubstituted 6 to 12 membered aryl; Or substituted or unsubstituted 5 to 10 membered heteroaryl,

R ₃ and R ₄ are each independently hydrogen; halogen; Hydroxy; Substituted or unsubstituted C _1-12 alkyl; Or substituted or unsubstituted C _1-12 alkoxy.

The invention also

Reacting a compound of formula (II) with a compound of formula (III) and an acid in the presence of an organic solvent to prepare a compound of formula (I ′); And

Hydrolyzing a compound of formula (I ') to produce a compound of formula (I)

Provided are processes for the preparation of compounds of formula (I).

[Formula I]

[Formula I ']

[Formula II]

[Formula III]

Where

R ₁ and R ₂ are each independently substituted or unsubstituted 6 to 12 membered aryl; Or substituted or unsubstituted 5 to 10 membered heteroaryl,

At least one of R ₁ and R ₂ is 6-12 membered aryl in which one or more substituents are substituted by hydroxy or 5-10 membered heteroaryl in which one or more substituents are substituted by hydroxy,

R ₁ 'and R ₂ 'is at least one of one or more substituent is -OC (O) R _x a substituted aryl of 6 to 12 or more than one substituent is won -OC (O) R _x a 5 to 10 membered heteroaryl optionally substituted with _Wherein R _x is a C _1-12 aliphatic hydrocarbon group,

R ₃ and R ₄ are each independently hydrogen; halogen; Hydroxy; Substituted or unsubstituted C _1-12 alkyl; Or substituted or unsubstituted C _1-12 alkoxy.

At this time, a base may be used for hydrolysis of the compound of formula (I ′). Preferably weak bases such as pyrrolidine can be used.

The present invention also provides a compound of formula (I ').

[Formula I ']

Where

R ₁ 'and R ₂ 'is at least one of one or more substituent is -OC (O) R _x a substituted aryl of 6 to 12 or more than one substituent is won -OC (O) R _x a 5 to 10 membered heteroaryl optionally substituted with _Wherein R _x is a C _1-12 aliphatic hydrocarbon group,

R ₃ and R ₄ are each independently hydrogen; halogen; Hydroxy; Substituted or unsubstituted C _1-12 alkyl; Or substituted or unsubstituted C _1-12 alkoxy.

In one embodiment,

Compound of formula (I ')

Ethyl 2- (4-acetoxy-3-methoxy-benzylidene) -5- (furan-2-yl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazolo [3, 2- a ] pyrimidine-6-carboxylate (intermediate compound 10, DCP-52), ethyl 2- (4-methoxybenzylidene) -5- (4-acetoxy-3-methoxyphenyl) -7- 3-oxo-2,3-dihydro -5 H - thiazolo [3,2- a] pyrimidin-6-carboxylate (intermediate compound 11, DCP-55),

Ethyl 2- (4-acetoxy-3-bromo-5-methoxy-benzylidene) -5- (4-methoxyphenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - Thiazolo [3,2- a ] pyrimidine-6-carboxylate (intermediate compound 12, DCP-56)

Ethyl 2- (4-acetoxy-3-bromo-5-methoxy-benzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazole Solo [3,2- a ] pyrimidine-6-carboxylate (Intermediate Compound 13, DCP-57)

Ethyl 2- (4-acetoxy-2-bromo-5-methoxy-benzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazole Solo [3,2- a ] pyrimidine-6-carboxylate (intermediate compound 14, DCP-58) or

Ethyl 2- (4-Acetoxy-3-chloro-5-methoxy-benzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazolo [3,2- a ] pyrimidine-6-carboxylate (intermediate compound 15, DCP-59).

The compound of formula (I) according to the present invention has excellent CK2 inhibitory activity, as can be seen in the following examples. Accordingly, the present invention also provides a composition for inhibiting CK2 comprising the compound of formula (I), a pharmaceutically acceptable salt or solvate thereof as an active ingredient. The invention also provides the use of a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a compound of formula (I), for the preparation of a CK2 inhibitory drug, pharmaceutically acceptable Provided are methods of inhibiting CK2 comprising administering a salt or solvate to the subject.

In one embodiment, the composition can be used for the treatment of diseases associated with CK2 inhibition, eg cancer or viral infections.

The pharmaceutical composition of the present invention may also include additional active ingredients known as CK2 inhibitors. Known CK2 inhibitors are well known to those skilled in the art, for example, 4,5,6,7-tetrabromobenzotriazole (TBB), 2-dimethylamino-4,5,6,7-tetrabromo- 1 H -benzimidazole (DMAT), 5-oxo-5,6-dihydroindolo (1,2-a) quinazolin-7-yl acetic acid (IQA), and the like.

The pharmaceutical composition of the present invention may be prepared using a pharmaceutically suitable and physiologically acceptable adjuvant in addition to the active ingredient, and the adjuvant may include excipients, disintegrants, sweeteners, binders, coating agents, swelling agents, lubricants, lubricants. Or solubilizers such as flavoring agents can be used.

The pharmaceutical composition of the present invention can be preferably formulated into a pharmaceutical composition by containing one or more pharmaceutically acceptable carriers in addition to the active ingredient for administration.

Acceptable pharmaceutical carriers in compositions formulated in liquid solutions are sterile and physiologically compatible, including saline, sterile water, Ringer's solution, buffered saline, albumin injectable solutions, dextrose solution, maltodextrin solution, glycerol, ethanol and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers and bacteriostatic agents may be added as necessary. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into injectable solutions, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Furthermore, the method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA can be formulated according to each disease or component according to the appropriate method in the art.

Pharmaceutical formulation forms of the pharmaceutical compositions of the present invention may be granules, powders, coated tablets, tablets, capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and sustained release formulations of the active compounds, and the like. Can be.

The pharmaceutical compositions of the present invention may be administered in a conventional manner via intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, sternum, transdermal, nasal, inhalation, topical, rectal, oral, intraocular or intradermal routes. Can be administered.

An effective amount of the active ingredient of the pharmaceutical composition of the present invention means an amount required to prevent or treat a disease or to achieve a bone growth inducing effect. Thus, the type of disease, the severity of the disease, the type and amount of active and other ingredients contained in the composition, the type of formulation and the age, weight, general health, sex and diet, time and route of administration, composition and composition of the patient. It can be adjusted according to various factors including the rate of secretion, the duration of treatment, the drug used concurrently. For example, in the case of an adult, the compound of the present invention may be administered at a dose of 0.1 ng / kg to 10 mg / kg once or several times a day.

In the present invention, the 'object' includes, but is not limited to, humans, orangutans, chimpanzees, mice, rats, dogs, cattle, chickens, pigs, goats, sheep, and the like.

Advantages and features of the present invention and methods for achieving them will be apparent with reference to the embodiments described below in detail. However, the present invention is not limited to the embodiments disclosed below, but may be implemented in various forms. It is provided to fully convey the scope of the invention to those skilled in the art, and the present invention is defined only by the scope of the claims.

Example Synthesis of Benzylidenethiazolopyrimidine Derivatives

The solvents and reagents used in the experiments were the highest commercially available, and the solvents were used immediately without purification unless otherwise stated. TLC plates were Kieselgel 60 F ₂₅₄ (Art A715, Merck) and column silica gel Silica gel 60 (0.040-0.063 mm ASTM, Merck). ¹ H and ¹³ C NMR data were measured using a Varian NMR AS 400 MHz instrument, and chemical shifts (δ) were expressed in parts per million (ppm) using tetramethyl silane as the internal standard. Coupling constants are expressed in Hertz ( J values). Mass data was measured using a GC: 7890A MS: 5975C MSD (Agilent, USA) machine equipped with an electron ionization (EI) device. Melting points were taken using a Barnstead International MEL-TEMP 1202D machine and the values were not corrected separately.

Example 1 Synthesis of Compounds 5-8

General synthetic methods of compounds 5 to 8 are as follows.

Thiopyrimidone (1 eq.), 2,4-dimethoxy-5-bromobenzaldehyde (1 eq.), Chloroacetic acid (1.025 eq.) And NaOAc (1 eq.) Were added to acetic anhydride (acetic anhydride) and acetic acid. Put it in 6 or It was refluxed and stirred for 16 hours. The reaction mixture was cooled to room temperature and poured into ice water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with saturated NaHCO ₃ again, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography or solvent. Specific synthesis methods are as follows.

Example 1-1: ethyl 2- (5-bromo-2,4-dimethoxybenzylidene) -5- (4-methoxyphenyl) -7-methyl-3-oxo-2,3-dihydro- 5 H -Thiazolo [3,2- a ] Pyrimidine-6-carboxylate (Compound 5, DCP-48)

Ethyl 4- (4-methoxyphenyl) -6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylate (0.62 g, 2 mmol), 2,4- Dimethoxy-5-bromobenzaldehyde ( 1 ) (0.49g, 2 mmol), chloroacetic acid (0.19g, 2.05 mmol) and NaOAc (0.16g, 2 mmol) were diluted with acetic anhydride (3 mL) and acetic acid (4 mL) It was added to reflux for 10 hours, and stirred. The reaction mixture was cooled to room temperature and poured into ice water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with saturated NaHCO ₃ again, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The remaining residue was purified by SGC (developing solvent, ethyl acetate: CH ₂ Cl ₂ = 2: 3) to give 0.90 g (78.3%) of a brown solid; R _f 0.33 (ethyl acetate: n -hexane = 1: 1); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.19 (t, J = 7.2 Hz, 3H), 2.51 (s, 3H), 3.76 (s, 3H), 3.88 (s, 3H), 3.95 (s, 3H ), 4.10 (dq, J = 2.8, 7.2 Hz, 2H), 6.14 (s, 1H), 6.44 (s, 1H), 6.81 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.8 Hz , 1H), 7.56 (s, 1 H), 7.93 (s, 1 H); ¹³ C-NMR (CDCl ₃ , 100 MHz) δ 14.3, 23.0, 55.0, 55.4, 56.0, 56.6, 60.6, 96.1, 103.0, 109.1, 114.1, 116.6, 118.9, 127.8, 129.6, 132.8, 133.7, 152.6, 156.7, 159.0, 159.5, 159.8, 165.7, 165.9 ppm.

Example 1-2 ethyl 2- (5-bromo-2,4-dimethoxybenzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3-dihydro-5 H -Thiazolo [3,2- a ] Pyrimidine-6-carboxylate (Compound 6, DCP-49)

Ethyl 4- (4-chlorophenyl) -6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylate ( 2 ) (0.59 g, 2 mmol), 2, 4-dimethoxy-5-bromobenzaldehyde (0.49g, 2 mmol), chloroacetic acid (0.19g, 2.05 mmol) and NaOAc (0.16g, 2 mmol) were added to acetic anhydride (3 mL) and acetic acid (4 mL). The mixture was refluxed for 16 hours and stirred. The reaction mixture was cooled to room temperature and poured into ice water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with saturated NaHCO ₃ again, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The remaining residue was treated with ethyl acetate / CH ₂ Cl ₂ and triturated to give 0.60 g (52.0%) brown solid; R _f 0.56 (ethyl acetate: n -hexane = 1: 1); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.19 (t, J = 7.2 Hz, 3H), 2.51 (s, 3H), 3.89 (s, 3H), 3.95 (s, 3H), 4.10 (dq, J = 2.0, 7.2 Hz, 2H), 6.15 (s, 1H), 6.44 (s, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.56 (s , 1H), 7.93 (s, 1 H); ¹³ C-NMR (CDCl ₃ , 100 MHz) δ 14.3, 23.1, 54.9, 56.0, 56.6, 60.8, 96.1, 103.0, 108.5, 116.4, 118.4, 128.3, 129.0, 129.7, 133.8, 134.7, 138.9, 153.2, 156.8, 159.2, 159.6, 165.5, 165.6 ppm.

Example 1-3: ethyl 2- (5-bromo-2,4-dimethoxybenzylidene) -5- (furan-3-yl) -7-methyl-3-oxo-2,3-dihydro- 5 H -Thiazolo [3,2- a ] Pyrimidine-6-carboxylate (Compound 7, DCP-50)

Ethyl 4- (furan-3-yl) -6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylate ( 3 ) (0.27 g, 1 mmol), 2 , 4-Dimethoxy-5-bromobenzaldehyde (0.25 g, 1 mmol), chloroacetic acid (0.10 g, 1.03 mmol) and NaOAc (0.08 g, 1 mmol) were diluted with acetic anhydride (1.5 mL) and acetic acid (2.0 mL) It was added to reflux for 6 hours, and stirred. The reaction mixture was cooled to room temperature and poured into ice water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with saturated NaHCO ₃ again, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The remaining residue was treated with ethyl acetate / n -hexane and tritized to yield 0.38 g (71.2%) brown solid; R _f 0.43 (ethyl acetate: n -hexane = 1: 1); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.25 (t, J = 7.2 Hz, 3H), 2.49 (s, 3H), 3.92 (s, 3H), 3.96 (s, 3H), 4.18 (dq, J = 4.0, 7.2 Hz, 2H), 6.24 (s, 1H), 6.36 (s, 1H), 6.46 (s, 1H), 7.30 (s, 1H), 7.44 (s, 1H), 7.59 (s, 1H) , 8.00 (s, 1 H); ¹³ C-NMR (CDCl ₃ , 100 MHz) δ 14.4, 23.0, 47.0, 56.0, 56.7, 60.7, 96.1, 103.1, 107.8, 109.6, 116.5, 118.9, 133.8, 141.3, 143.6, 153.5, 156.8, 159.1, 159.6, 165.7, 165.8 ppm. Two peaks were not identified.

Example 1-4: ethyl 2- (5-bromo-2,4-dimethoxybenzylidene) -5- (pyridin-3-yl) -7-methyl-3-oxo-2,3-dihydro- 5 H -Thiazolo [3,2- a ] Pyrimidine-6-carboxylate (Compound 8, DCP-54)

Ethyl 4- (pyridin-3-yl) -6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylate ( 4 ) (0.50 g, 1.8 mmol), 2 , 4-dimethoxy-5-bromobenzaldehyde ( 1 ) (0.44 g, 1.8 mmol), chloroacetic acid (0.17 g, 1.85 mmol) and NaOAc (0.15 g, 1.8 mmol) were added to acetic anhydride (3 mL) and acetic acid ( 4 mL) and refluxed and stirred for 9 hours. The reaction mixture was cooled to room temperature and poured into ice water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with saturated NaHCO ₃ again, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The remaining residue was purified by SGC (developing solvent, ethyl acetate: n -hexane = 1: 5 δ 1: 3) to obtain 0.05 g (5.1%) orange solid; ¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.19 (t, J = 7.2 Hz, 3H), 2.51 (s, 3H), 3.90 (s, 3H), 3.95 (s, 3H), 4.11 (dq, J = 1.2, 7.2 Hz, 2H), 6.20 (s, 1H), 6.45 (s, 1H), 7.25 (dd, J = 8.0, 5.6 Hz, 1H), 7.57 (s, 1H), 7.71 (ddd, J = 2.0, 2.0, 8.0 Hz, 1H), 7.94 (s, 1H), 8.52 (dd, J = 1.6, 5.6 Hz, 1H), 8.69 (d, J = 2.0 Hz, 1H); ¹³ C-NMR (CDCl ₃ , 100 MHz) δ 14.3., 23.2, 53.5, 56.0, 56.7, 60.9, 96.1, 103.1, 107.8, 116.3, 118.3, 123.8, 128.6, 133.9, 135.8, 136.1, 149.8, 150.0, 153.9 , 157.0, 159.3, 159.6, 165.4, 165.5 ppm.

Example 2: Synthesis of Compounds 16-20

In synthesizing compounds of formula (I), intermediate compounds 10 to 15 wherein the hydroxyl groups on R ₁ or R ₂ are acetylated when R ₂ is aryl or heteroaryl substituted with hydroxy Is generated. Intermediate compounds 10-15 are hydrolyzed again to synthesize compounds 16-20 which are the final benzylidenethiazolopyrimidine derivatives. In Example 2-1, the synthesis of the intermediate compounds 10 to 15 is described. In Example 2-2, the synthesis of the compounds 16 to 20 is described in detail.

Example 2-1: Synthesis of Intermediate Compounds 10-15

General synthetic methods of intermediate compounds 10 to 15 are as follows.

Thiopyrimidone (1 equiv.), The corresponding aldehyde (1 equiv.), Chloroacetic acid (1.025 equiv.), And NaOAc (1 equiv.) Were added to acetic anhydride and acetic acid and refluxed and stirred for 6-16 hours. The reaction mixture was cooled to room temperature and poured into ice water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with saturated NaHCO ₃ again, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The remaining residue was purified by silica gel chromatography or solvent.

Example 2-1-1: Ethyl 2- (4-acetoxy -3-methoxybenzylidene) -5- (furan-2-yl) -7-methyl-3-oxo-2,3-dihydro -5 H -thiazolo [3,2- a ] pyrimidine-6-carboxylate (Intermediate Compound 10, DCP-52)

Ethyl 4- (furan-2-yl) -6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylate ( 26 ) (0,27 g, 1.0 mmol) , 4-hydroxy-3-methoxybenzaldehyde (0.15 g, 1.0 mmol), chloroacetic acid (0.10 g, 1.03 mmol), and NaOAc (0.08 g, 1.0 mmol) with acetic anhydride (3 mL) and acetic acid (4 mL ) Was refluxed and stirred for 12 hours. The reaction mixture was cooled to room temperature and poured into ice water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with saturated NaHCO ₃ again, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The remaining residue was purified by silica gel chromatography (ethyl acetate: n -hexane = 1: 2 δ 1: 1) to give 0.33 g (75.0%) of an orange solid; R _f 0.59 (ethyl acetate: n -hexane = 1: 1); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.25 (t, J = 7.2 Hz, 3H), 2.33 (s, 3H), 2.51 (s, 3H), 3.88 (s, 3H), 4.11-4.23 (m , 2H), 6.29 (brs, 1H), 6.35 (d, J = 3.6 Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H), 7.08 (s, 1H), 7.10 (d, J = 8.4 Hz , 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.31 (dd, J = 0.8, 1.6 Hz, 1H), 7.77 (s, 1H); ¹³ C-NMR (CDCl ₃ , 100 MHz) δ 14.4, 20.9, 23.0, 48.7, 56.1, 60.8, 106.4, 109.2, 110.7, 113.4, 120.6, 123.5, 123.9, 132.3, 133.1, 141.7, 143.1, 151.5, 151.9, 154.0, 156.0, 165.2, 165.5, 168.8 ppm.

Example 2-1-2: Ethyl 2- (4-methoxybenzylidene) -5- (4-acetoxy -3-methoxyphenyl) -7-methyl-3-oxo-2,3-dihydro -5 H -thiazolo [3,2- a ] pyrimidine-6-carboxylate (Intermediate Compound 11, DCP-55)

Ethyl 4- (4-hydroxy-3-methoxyphenyl) -6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylate ( 9 ) (0,32 g, 1.0 mmol), 4-methoxybenzaldehyde (0.14 g, 1.0 mmol), chloroacetic acid (0.10 g, 1.03 mmol), and NaOAc (0.08 g, 1.0 mmol) with acetic anhydride (2 mL) and acetic acid (3 mL ) Was refluxed and stirred for 11 hours. The reaction mixture was cooled to room temperature and poured into ice water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with saturated NaHCO ₃ again, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The remaining residue was purified by silica gel chromatography (ethyl acetate: n -hexane = 1: 3) to give 0.37 g (70.8%) of an orange solid; R _f 0.51 (ethyl acetate: n -hexane = 1: 1); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.20 (t, J = 7.2 Hz, 3H), 2.29 (s, 3H), 2.52 (s, 3H), 3.81 (s, 3H), 3.86 (s, 3H ), 4.13 (dq, J = 4.0, 7.2 Hz, 1H), 6.20 (s, 1H), 6.95 (d, J = 1.2 HZ, 2H), 6.98 (d, J = 8.8 Hz, 2H), 7.06 (s , 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.73 (S, 1H); ¹³ C-NMR (CDCl ₃ , 100 MHz) 14.3, 20.9, 55.1, 55.7, 56.1, 60.8, 108.7, 112.8, 115.0, 117.4, 120.3, 123.1, 126.0, 132.3, 139.0, 140.0, 151.2, 153.1, 156.9, 161.7 , 165.6, 165.7, 169.0 ppm. One peak was not identified.

Example 2-1-3: Ethyl 2- (4-acetoxy- 3-bromo-5-methoxybenzylidene) -5- (4-methoxyphenyl) -7-methyl-3-oxo-2 , 3-dihydro-5 H -thiazolo [3,2- a ] pyrimidine-6-carboxylate (Intermediate Compound 12, DCP-56)

Ethyl 4- (4-methoxyphenyl) -6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine- 5-carboxylate ( 1 ) (0,31 g, 1.0 mmol) Acetic anhydride (3 mL), 3-bromo-4-hydroxy-5-methoxybenzaldehyde (0.23 g, 1.0 mmol), chloroacetic acid (0.10 g, 1.03 mmol), and NaOAc (0.08 g, 1.0 mmol) It was added to acetic acid (4 mL) and refluxed and stirred for 7 hours. The reaction mixture was cooled to room temperature and poured into ice water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with saturated NaHCO ₃ again, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The remaining residue was purified by silica gel chromatography (ethyl acetate: n -hexane = 1: 3 δ 1: 2) to give 0.19 g (31.6%) of an orange solid; R _f 0.19 (ethyl acetate: n -hexane = 1: 3); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.19 (t, J = 7.2 Hz, 3H), 2.37 (s, 3H), 2.52 (s, 3H), 3.78 (s, 3H), 3.86 (s, 3H ), 4.11 (dq, J = 2.8, 7.2 Hz, 2H), 6.16 (s, 1H), 6.83 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 2.0 Hz, 1H), 7.28 (d , J = 2.0 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 7.60 (s, 1H); ¹³ C-NMR (CDCl ₃ , 100 MHz) 14.3, 20.6, 22.9, 55.3, 56.5, 60.8, 109.8, 111.9, 114.2, 118.4, 122.3, 126.6, 129.6, 131.2, 132.3, 133.0, 139.5, 152.0, 153.0, 155.4 , 160.0, 165.0, 165.7, 167.8 ppm.

Example 2-1-4: ethyl 2- (4-acetoxy- 3-bromo-5-methoxybenzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2, 3-dihydro-5 H -thiazolo [3,2- a ] pyrimidine-6-carboxylate (Intermediate Compound 13, DCP-57)

Ethyl 4- (4-chlorophenyl) -6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylate ( 2 ) (0,17 g, 0.56 mmol), 3-bromo-4-hydroxy-5-methoxybenzaldehyde (0.12 g, 0.56 mmol), chloroacetic acid (0.05 g, 0.57 mmol), and NaOAc (0.05 g, 0.56 mmol) with acetic anhydride (2 mL) It was added to acetic acid (3 mL) and refluxed and stirred for 16 hours. The reaction mixture was cooled to room temperature and poured into ice water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with saturated NaHCO ₃ again, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The remaining residue was purified by silica gel chromatography (ethyl acetate: n -hexane = 1: 4) to give 0.20 g (59.4%) of a dark orange solid; R _f 0.28 (ethyl acetate: n -hexane = 1: 3); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.20 (t, J = 7.2 Hz, 3H), 2.37 (s, 3H), 2.52 (s, 3H), 3.86 (s, 3H), 4.12 (dq, J = 1.6, 7.2 Hz, 2H), 6.17 (s, 1H), 6.96 (d, J = 1.6 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 1.6 Hz, 1H ), 7.35 (d, J = 8.4 Hz, 2H), 7.61 (s, 1H); ¹³ C-NMR (CDCl ₃ , 100 MHz) 14.3, 20.7, 23.0, 55.2, 56.5, 60.9, 109.1, 111.9, 118.5, 121.9, 126.6, 129.1, 129.7, 131.6, 132.9, 134.9, 138.4, 139.6, 152.7, 153.1 , 155.5, 164.9, 165.4, 167.8 ppm.

Example 2-1-5: ethyl 2- (4-acetoxy-2 -bromo-5-methoxybenzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2, 3-dihydro -5 H - thiazolo [3,2- a] pyrimidin-6-carboxylate (intermediate compound 14, DCP-58)

Ethyl 4- (4-chlorophenyl) -6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylate ( 2 ) (0,62 g, 2.12 mmol), 2-bromo-4-hydroxy-5-methoxybenzaldehyde (0.49 g, 2.12 mmol), chloroacetic acid (0.21 g, 2.18 mmol), and NaOAc (0.17 g, 2.12 mmol) with acetic anhydride (6 mL) It was added to acetic acid (9 mL) and refluxed and stirred for 16 hours. The reaction mixture was cooled to room temperature and poured into ice water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with saturated NaHCO ₃ again, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The remaining residue was tritulated with ethyl acetate / n -hexane to give 0.69 g (53.3%) of an orange solid; ¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.20 (t, J = 7.2 Hz, 3H), 2.32 (s, 3H), 2.52 (s, 3H), 3.85 (s, 3H), 4.11 (dq, J = 2.4, 7.2 Hz, 2H), 6.17 (s, 1H), 7.10 (s, 1H), 7.29 (d, J = 8 Hz, 2H), 7.35 (s, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.97 (s, 1 H); ¹³ C-NMR (CDCl ₃ , 100 MHz) 14.3, 20.7, 23.0, 52.2, 56.4, 60.9, 109.2, 112.0, 116.9, 123.1, 128.2, 129.1, 129.8, 131.7, 132.0, 135.0, 138.3, 141.6, 151.2, 152.6 , 155.5, 164.6, 165.4, 168.4 ppm.

Example 2-1-5: Ethyl 2- (4-acetoxy -3-chloro-5-methoxybenzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3 -dihydro -5 H-thiazolo [3,2- a] pyrimidin-6-carboxylate (intermediate compound 15, DCP-59)

Ethyl 4- (4-chlorophenyl) -6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylate ( 2 ) (0,10 g, 0.34 mmol), 3-chloro-4-hydroxy-5-methoxybenzaldehyde (0.06 g, 0.34 mmol), chloroacetic acid (0.03 g, 0.35 mmol), and NaOAc (0.03 g, 0.34 mmol) were added with acetic anhydride (2 mL) and acetic acid. (3 mL) and refluxed and stirred for 16 h. The reaction mixture was cooled to room temperature and poured into ice water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with saturated NaHCO ₃ again, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The remaining residue was purified by silica gel chromatography (ethyl acetate: n -hexane = 1: 3) to obtain 0.09 g (44.6%) of an orange solid; R _f 0.32 (ethyl acetate: n -hexane = 1: 3); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.21 (t, J = 7.2 Hz, 3H), 2.38 (s, 3H), 2.53 (s, 3H), 3.87 (s, 3H), 4.12 (d, J = 7.2 Hz, 2H), 6.18 (s, 1H), 6.94 (d, J = 1.6 Hz, 1H), 7.15 (d, J = 1.6 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.82 (s, 1H); ¹³ C-NMR (CDCl ₃ , 100 MHz) 14.3, 20.5, 24.7, 55.2, 56.6, 60.9, 109.2, 111.4, 118.3, 122.0, 123.7, 129.1, 129.4, 129.7, 131.8, 132.3, 134.9, 138.4, 152.7, 153.2 , 155.5, 164.9, 165.4, 167.8 ppm.

Example 2-2: Synthesis of Compounds 16-20

General synthesis of the compounds 16 to 20 is as follows.

The acetoxy compound of intermediate compounds 10 to 15 prepared in Example 2-1 was dissolved in pyrrolidine and stirred at room temperature for 10-20 minutes. The reaction mixture was diluted with ethyl acetate and the organic layer was washed sequentially with 1M-H ₂ SO ₄ , saturated-NH ₄ Cl, and saturated-NaCl, followed by removal of water with anhydrous Na ₂ SO ₄ . The solid compound obtained after concentration under reduced pressure was treated with ethyl acetate / n -hexane solution and tritized to obtain the desired compound.

Example 2-2-1: ethyl 2- (4-hydroxy-3-methoxybenzylidene) -5- (furan-2-yl) -7-methyl-3-oxo-2,3-dihydro- 5 H -Thiazolo [3,2- a ] Pyrimidine-6-carboxylate (Compound 16, DCP-63)

Ethyl 2- (4-acetoxy-3-methoxy-benzylidene) -5- (furan-2-yl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazolo [3, 2- a ] pyrimidine-6-carboxylate ( 10 ) (53.3 mg, 0.10 mmol) The compound was dissolved in pyrrolidine (0.5 mL) and stirred at room temperature for 10 minutes. The reaction mixture was diluted with ethyl acetate and the organic layer was washed sequentially with 1M-H ₂ SO ₄ , saturated-NH ₄ Cl, and saturated-NaCl, followed by removal of water with anhydrous Na ₂ SO ₄ . Concentration under reduced pressure gave 50.5 mg (quantitative) orange solid compound; R _f 0.53 (ethyl acetate: n -hexane = 1: 1); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.25 (t, J = 7.2 Hz, 3H), 2.51 (s, 3H), 3.93 (s, 3H), 4.10-4.25 (m, 2H), 6.28 (dd , J = 1.6, 3.6 Hz, 1H), 6.34 (d, J = 3.6 Hz, 1H), 6.35 (s, 1H), 6.99 (d, J = 1.6 Hz, 1H), 7.00 (d, J = 8.4 Hz , 1H), 7.07 (dd, J = 1.6, 8.4 Hz, 1H), 7.30 (dd, J = 0.8, 0.8 Hz, 1H), 7.75 (s, 1H); ¹³ C-NMR (CDCl ₃ , 100 MHz) δ 14.4, 23.0, 48.6, 56.1, 60.8, 106.0, 109.0, 110.7, 111.9, 115.6, 117.2, 125.7, 125.9, 134.3, 142.9, 147.2, 148.5, 151.8, 154.2, 156.6, 165.5, 165.6 ppm.

Example 2-2-2: ethyl 2- (4-methoxybenzylidene) -5- (4-hydroxy-3-methoxyphenyl) -7-methyl-3-oxo-2,3-dihydro- 5 H -Thiazolo [3,2- a ] Pyrimidine-6-carboxylate (Compound 17, DCP-61)

Ethyl 2- (4-methoxy-benzylidene) -5- (4-acetoxy-3-methoxyphenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazolo [3, 2- a ] pyrimidine-6-carboxylate ( 11 ) (21 mg, 0.04 mmol) The compound was dissolved in pyrrolidine (0.5 mL) and stirred at room temperature for 10 minutes. The reaction mixture was diluted with ethyl acetate and the organic layer was washed sequentially with 1M-H ₂ SO ₄ , saturated-NH ₄ Cl, and saturated-NaCl, followed by removal of water with anhydrous Na ₂ SO ₄ . Concentration under reduced pressure gave 18.0 mg (93.3%) orange solid compound; R _f 0.12 (ethyl acetate: n -hexane = 1: 3); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.23 (t, J = 7.2 Hz, 3H), 2.53 (s, 3H), 3.87 (s, 3H), 3.88 (s, 3H), 4.13 (dq, J = 2.0, 7.2 Hz, 2H), 5.62 (s, 1H), 6.15 (s, 3H), 6.83 (d, J = 8.4 Hz, 1H), 6.90 (dd, J = 2.0, 8.4 Hz, 1H), 6.95 (d, J = 2.0 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.72 (s, 1H); ¹³ C-NMR (CDCl ₃ , 100 MHz) δ 14.4, 23.0, 55.4, 55.7, 56.2, 60.7, 109.2, 111.1, 114.6, 115.0, 117.5, 121.2, 126.1, 132.3, 132.4, 133.6, 146.1, 146.5, 152.5, 156.6, 161.7, 165.8, 165.9 ppm.

Example 2-2-3: ethyl 2- (4-hydroxy-3-bromo-5-methoxybenzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3 -Dehydro-5 H -Thiazolo [3,2- a ] Pyrimidine-6-carboxylate (Compound 18, DCP-62)

Ethyl 2- (4-acetoxy-3-bromo-5-methoxy-benzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazole Solo [3,2- a ] pyrimidine-6-carboxylate ( 13 ) (36 mg, 0.06 mmol) The compound was dissolved in pyrrolidine (0.5 mL) and stirred at room temperature for 10 minutes. The reaction mixture was diluted with ethyl acetate and the organic layer was washed sequentially with 1M-H ₂ SO ₄ , saturated-NH ₄ Cl, and saturated-NaCl, followed by removal of water with anhydrous Na ₂ SO ₄ . Concentrated under reduced pressure, the remaining residue was treated with ethyl acetate / n -hexane and triturated to give 28.0 mg (83.6%) orange solid compound; R _f 0.57 (ethyl acetate: n -hexane = 1: 1); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.21 (t, J = 7.2 Hz, 3H), 2.52 (s, 3H), 3.95 (s, 3H), 4.12 (dq, J = 1.2, 7.2 Hz, 2H ), 6.17 (s, 1H), 6.91 (d, J = 1.6 Hz, 1H), 7.27 (d, J = 1.6 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.60 (s, 1H); ¹³ C-NMR (CDCl ₃ , 100 MHz) δ 14.3, 23.0, 55.1, 56.6, 60.9, 108.9, 109.3, 110.7, 118.9, 126.6, 128.2, 129.1, 129.7, 132.6, 134.8, 138.6, 145.6, 147.6, 152.9, 156.1, 165.2, 165.5 ppm.

Example 2-2-4: ethyl 2- (4-hydroxy-2-bromo-5-methoxybenzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3 -Dehydro-5 H -Thiazolo [3,2- a ] Pyrimidine-6-carboxylate (Compound 19, 773)

Ethyl 2- (4-acetoxy-2-bromo-5-methoxy-benzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazole Solo [3,2- a ] pyrimidine-6-carboxylate ( 14 ) (0.63 g, 1.04 mmol) The compound was dissolved in pyrrolidine (5 mL) and stirred at room temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate and the organic layer was washed sequentially with 1M-H ₂ SO ₄ , saturated-NH ₄ Cl, and saturated-NaCl, followed by removal of water with anhydrous Na ₂ SO ₄ . Concentration under reduced pressure tritulation of the remaining residue with CH ₂ Cl ₂ / n -hexane to give 0.54 g (92.0%) orange solid compound; mp: 234-235 ° C .; R _f 0.53 (ethyl acetate: n -hexane = 1: 1); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.11 (t, J = 7.2 Hz, 3H), 2.38 (s, 3H), 3.85 (s, 3H), 4.03 (dq, J = 3.2, 7.2 Hz, 2H ), 6.01 (s, 1H), 7.01 (s, 1H), 7.13 (s, 1H), 7.32 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 7.77 (s , 1H); ¹³ C-NMR (CDCl ₃ , 100 MHz) 13.9, 22.5, 54.5, 55.8, 60.3, 108.2, 111.3, 117.9, 119.0, 119.9, 122.5, 128.8, 129.6, 131.2, 133.2, 139.1, 147.8, 150.6, 151.6, 155.5 , 164.1, 164.7 ppm.

Example 2-2-5: ethyl 2- (4-hydroxy-3-chloro-5-methoxybenzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3- Dehydro-5 H -Thiazolo [3,2- a ] Pyrimidine-6-carboxylate (Compound 20, DCP-60)

Ethyl 2- (4-acetoxy-3-chloro-5-methoxy-benzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazolo [3,2- a ] pyrimidine-6-carboxylate ( 15 ) (19.7 mg, 0.04 mmol) The compound was dissolved in pyrrolidine (0.5 mL) and stirred at room temperature for 10 minutes. The reaction mixture was diluted with ethyl acetate and the organic layer was washed sequentially with 1M-H ₂ SO ₄ , saturated-NH ₄ Cl, and saturated-NaCl, followed by removal of water with anhydrous Na ₂ SO ₄ . The residue remaining after concentration under reduced pressure was treated with CH ₂ Cl ₂ / n -hexane and triturated to give 16.5 mg (90.5%) orange solid compound; R _f 0.61 (ethyl acetate: n -hexane = 1: 1); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.18 (t, J = 7.2 Hz, 3H), 2.50 (s, 3H), 3.93 (s, 3H), 4.11 (q, J = 7.2 Hz, 2H), 6.14 (s, 1H), 6.86 (s, 1H), 7.10 (s, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.57 (s, 1H ); ¹³ C-NMR (CDCl ₃ , 100 MHz) 14.3, 23.1, 55.1, 56.7, 60.9, 108.9, 110.2, 118.9, 120.8, 125.3, 125.9, 129.1, 129.7, 132.8, 134.8, 138.6, 144.5, 147.9, 152.9, 156.0 , 165.2, 165.5 ppm.

Experimental Example: Analysis of Inhibition of CK2 Activity of Benzylidenethiazolopyrimidine Derivatives of the Present Invention

In order to confirm the effect of the benzylidene thiazolopyrimidone derivatives of the present invention on the inhibition of CK2 enzyme activity, the activity inhibition activity was measured using an in vitro CK2 activity assay. Specifically, compound 19 (773) among the compounds prepared through the examples and 2-dimethylamino-4,5,6,7-tetrabromo-1 H -benzimidazole (well known as a CK2 inhibitor) ( DMAT) 3 mg of CK2 substrate peptide (GST-CS: GST- LVPR RRRDDDSDDD) fused with glutathione S-transferase (GST) purified by expression in E. coli in the presence of 50 ng activity purified by E.coli A final volume of 20 ml of kinase reaction buffer containing 4 ml of 5x kinase buffer (20 mM MOPS, pH 7.2, 25 mM b-glycerol phosphate, 5 mM EGTA, 1 mM sodium orthovanadate, 1 mM dithiothreitol) ), 4 ml of magnesium / ATP cocktail solution (90 ml of 75 mM MgCl ₂ / 500mM ATP plus 10 ml (100 mCi) of [g- ³² P] -ATP (3000 Ci / mmole)] After the reaction was performed for 10 minutes, 5 ml of 5x SDS gel loading buffer solution was added and the reaction was terminated by boiling at 100 ° C. for 5 minutes. DS polyacrylamide gel was electrophoresed and stained with Coomassie Brilliant Blue stain (450 ml of distilled water, 450 ml of distilled water, 100 ml of acetic acid, 2.5 g of coomassie brilliant blue R250) and dried in a gel dryer and subjected to autoradiography. Is an electrophoresis result showing the reaction of CK2 substrate peptide (GST-CS) fused with GST in the presence of a known CK2 inhibitor, DMAT, Compound 19 (773) prepared in the Examples above.

Cut each GST-CS band obtained by electrophoresis into scintillation vial, add 5 ml of scintillation cocktail solution, and obtain cpm value of GST-CS using b-counter to show relative inhibitory effect of CK2 activity. 2 is shown. As can be seen in Figure 2, Compound 19 (773) prepared in the Examples of the present invention had a better effect of inhibiting the activity of CK2 than DMAT, a known CK2 inhibitor.

IC ₅₀ of Compound 19 (773) was calculated using the in vitro CK2 activity assay described above. In order to compare the CK2 inhibitory activity of Compound 19 (773), 4,5,6,7-tetrabromobenzotriazole (TBB), a well-known CK2 inhibitor, was used as a control. The concentration of the compound was 0, 1, 2, 4, 5, 10, 20 mM, and the other experimental conditions were carried out in the same manner as described above, and the results are shown in FIG. 3, and the respective GST-CS bands were cut out b. The cpm value of GST-CS was obtained using -counter to show the relative inhibitory effect of CK2 activity in FIG. 4. A graph obtained as a result of calculating the IC ₅₀ value of Compound 19 (773) using the values shown in FIG. 4 is shown in FIG. 5. As can be seen in FIG. 5, Compound 19 (773) has an IC ₅₀ value compared to TBB, which is previously known to be a selective, specific and potent inhibitor of the CK2 enzyme. Very low.

1 is an electrophoresis result showing the reaction of CK2 substrate peptide (GST-CS) fused with GST in the presence of a known CK2 inhibitor DMAT, compound 19 (773) prepared in the above example.

FIG. 2 is a graph showing the relative inhibitory effect of CK2 activity obtained from the electrophoresis result of FIG. 1.

Figure 3 is an electrophoresis result showing the reaction of CK2 substrate peptide (GST-CS) fused with GST in the presence of a known CK2 inhibitor TBB, compound 19 (773) prepared in the above example.

4 is a graph showing the relative inhibitory effect of CK2 activity obtained from the electrophoresis result of FIG. 3.

FIG. 5 is a graph obtained by calculating IC ₅₀ values of Compound 19 (773) using the values shown in FIG. 4.

Claims (15)

A compound of formula (I): a pharmaceutically acceptable salt or solvate thereof: [Formula I]

Where R ₁ and R ₂ are each independently substituted or unsubstituted 6 to 12 membered aryl; Or substituted or unsubstituted 5 to 10 membered heteroaryl, R ₃ and R ₄ are each independently hydrogen; halogen; Hydroxy; Substituted or unsubstituted C _1-12 alkyl; Or substituted or unsubstituted C _1-12 alkoxy. The method of claim 1, R ₁ and R ₂ are each independently phenyl, biphenyl or naphthalene, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C _1-6 alkyl and C _1-6 alkoxy ; Or a halogen, hydroxy, substituted or unsubstituted with at least one substituent selected from the group consisting of alkyl and alkoxy of C _1-6 of C _1-6, furanyl, pyridyl, benzimidazolyl, benzothiazolyl, benzo Thienyl, benzoxazolyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyrimidinyl, pyrrolyl, quinolinyl, thiazolyl or thienyl. The method of claim 1, R ₁ and R ₂ are each independently phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C _1-6 alkyl and C _1-6 alkoxy; Or with at least one substituent selected from halogen, hydroxy, an alkoxy group consisting of alkyl and C _1-6 of C _1-6 substituted or unsubstituted, furanyl or pyridyl compound. The method of claim 1, R ₁ and R ₂ are each independently 4-methoxyphenyl, 4-chlorophenyl, 3-furanyl, 3-pyridyl, 2-furanyl, 4-hydroxy-3-methoxyphenyl, 4-hydroxy Hydroxy-3-methoxyphenyl, 4-hydroxy-3-bromo-5-methoxyphenyl, 4-hydroxy-2-bromo-5-methoxyphenyl, 4-hydroxy-3-chloro- 5-methoxyphenyl. The method of claim 1, R ₃ and R ₄ are each independently substituted or unsubstituted C _1-4 alkyl; Or substituted or unsubstituted C _1-4 alkoxy. The method of claim 1, R ₃ is ethyl or methyl, R ₄ is ethoxy or methoxy. The method of claim 1, The compound of formula (I) Ethyl 2- (5-bromo-2,4-dimethoxy-benzylidene) -5- (4-methoxyphenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazolo [ 3,2- a ] pyrimidine-6-carboxylate (Compound 5, DCP-48), Ethyl 2- (5-bromo-2,4-dimethoxybenzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3-dihydro-5 H -thiazolo [3 , 2- a ] pyrimidine-6-carboxylate (Compound 6, DCP-49), Ethyl 2- (5-bromo-2,4-dimethoxy-benzylidene) -5- (furan-3-yl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazolo [ 3,2- a ] pyrimidine-6-carboxylate (Compound 7, DCP-50), Ethyl 2- (5-bromo-2,4-dimethoxy-benzylidene) -5- (pyridin-3-yl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazolo [ 3,2- a ] pyrimidine-6-carboxylate (Compound 8, DCP-54), Ethyl 2- (4-hydroxy-3-methoxy-benzylidene) -5- (furan-2-yl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazolo [3, 2- a ] pyrimidine-6-carboxylate (Compound 16, DCP-63), Ethyl 2- (4-methoxy-benzylidene) -5- (4-hydroxy-3-methoxyphenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazolo [3, 2- a ] pyrimidine-6-carboxylate (Compound 17, DCP-61), Ethyl 2- (4-hydroxy-3-bromo-5-methoxy-benzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazole Zolo [3,2- a ] pyrimidine-6-carboxylate (Compound 18, DCP-62), Ethyl 2- (4-hydroxy-2-bromo-5-methoxy-benzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazole Solo [3,2- a ] pyrimidine-6-carboxylate (compound 19, 773), or Ethyl 2- (4-hydroxy-3-chloro-5-methoxy-benzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazolo [3,2- a ] pyrimidine-6-carboxylate (Compound 20, DCP-60) Phosphorus compounds. Reacting a compound of formula (II) with a compound of formula (III) and an acid in the presence of an organic solvent Process for the preparation of the compound of formula (I): [Formula I]

[Formula II]

[Formula III]

Where R ₁ and R ₂ are each independently substituted or unsubstituted 6 to 12 membered aryl; Or substituted or unsubstituted 5 to 10 membered heteroaryl, R ₃ and R ₄ are each independently hydrogen; halogen; Hydroxy; Substituted or unsubstituted C _1-12 alkyl; Or substituted or unsubstituted C _1-12 alkoxy. The method of claim 8, The acid is X-Y-Z, Wherein X is halogen, Y is alkenyl, and Z is carboxyl Process for the preparation of compounds of formula (I). The method of claim 8,  The compound of formula (II) is produced by reacting a compound of formula (IV), a compound of formula (V) and thiourea Process for the preparation of the compound of formula (I): [Formula IV]

[Formula V]

Where Each R ₁ is independently, substituted or unsubstituted 6 to 12 membered aryl; Or substituted or unsubstituted 5 to 10 membered heteroaryl, R ₃ and R ₄ are each independently hydrogen; halogen; Hydroxy; Substituted or unsubstituted C _1-12 alkyl; Or substituted or unsubstituted C _1-12 alkoxy. Reacting a compound of formula (II) with a compound of formula (III) and an acid in the presence of an organic solvent to prepare a compound of formula (I ′); And Hydrolyzing the compound of formula (I ') to produce a compound of formula (I) Process for the preparation of the compound of formula (I): [Formula I]

[Formula I ']

[Formula II]

[Formula III]

Where R ₁ and R ₂ are each independently substituted or unsubstituted 6 to 12 membered aryl; Or substituted or unsubstituted 5 to 10 membered heteroaryl, At least one of R ₁ and R ₂ is 6-12 membered aryl in which one or more substituents are substituted by hydroxy or 5-10 membered heteroaryl in which one or more substituents are substituted by hydroxy, R ₁ 'and R ₂ 'is at least one of one or more substituent is -OC (O) R _x a substituted aryl of 6 to 12 or more than one substituent is won -OC (O) R _x a 5 to 10 membered heteroaryl optionally substituted with _Wherein R _x is a C _1-12 aliphatic hydrocarbon group, R ₃ and R ₄ are each independently hydrogen; halogen; Hydroxy; Substituted or unsubstituted C _1-12 alkyl; Or substituted or unsubstituted C _1-12 alkoxy. A compound of formula (I ') [Formula I ']

Where R ₁ 'and R ₂ 'is at least one of one or more substituent is -OC (O) R _x a substituted aryl of 6 to 12 or more than one substituent is won -OC (O) R _x a 5 to 10 membered heteroaryl optionally substituted with _Wherein R _x is a C _1-12 aliphatic hydrocarbon group, R ₃ and R ₄ are each independently hydrogen; halogen; Hydroxy; Substituted or unsubstituted C _1-12 alkyl; Or substituted or unsubstituted C _1-12 alkoxy. The method of claim 12, The compound of formula (I ') Ethyl 2- (4-acetoxy-3-methoxy-benzylidene) -5- (furan-2-yl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazolo [3, 2- a ] pyrimidine-6-carboxylate (intermediate compound 10, DCP-52), ethyl 2- (4-methoxybenzylidene) -5- (4-acetoxy-3-methoxyphenyl) -7- 3-oxo-2,3-dihydro -5 H - thiazolo [3,2- a] pyrimidin-6-carboxylate (intermediate compound 11, DCP-55), Ethyl 2- (4-acetoxy-3-bromo-5-methoxy-benzylidene) -5- (4-methoxyphenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - Thiazolo [3,2- a ] pyrimidine-6-carboxylate (intermediate compound 12, DCP-56) Ethyl 2- (4-acetoxy-3-bromo-5-methoxy-benzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazole Solo [3,2- a ] pyrimidine-6-carboxylate (Intermediate Compound 13, DCP-57) Ethyl 2- (4-acetoxy-2-bromo-5-methoxy-benzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazole Solo [3,2- a ] pyrimidine-6-carboxylate (intermediate compound 14, DCP-58) or Ethyl 2- (4-acetoxy-3-chloro-5-methoxy-benzylidene) -5- (4-chlorophenyl) -7-methyl-3-oxo-2,3-dihydro -5 H - thiazolo Is [3,2- a ] pyrimidine-6-carboxylate (intermediate compound 15, DCP-59) compound. A composition for inhibiting CK2 comprising the compound of formula (I), a pharmaceutically acceptable salt or solvate thereof as an active ingredient: [Formula I]

Where R ₁ and R ₂ are each independently substituted or unsubstituted 6 to 12 membered aryl; Or substituted or unsubstituted 5 to 10 membered heteroaryl, R ₃ and R ₄ are each independently hydrogen; halogen; Hydroxy; Substituted or unsubstituted C _1-12 alkyl; Or substituted or unsubstituted C _1-12 alkoxy. The method of claim 14, The composition is a composition for inhibiting CK2, characterized in that used for the treatment of cancer or virus infection.

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