KR20230014505A - Novel pyrimidine-4-one compound and anticancer composition comprising the same - Google Patents

Abstract

The present invention provides a novel pyrimidin-4-one compound, a solvate thereof, a hydrate thereof, a predrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof, and an anticancer agent composition comprising the same. The anticancer composition containing the pyrimidin-4-one compound is very useful as a targeted anticancer therapeutic agent.

Description

Novel pyrimidine-4-one compound and anticancer composition comprising the same {Novel pyrimidine-4-one compound and anticancer composition comprising the same}

The present invention relates to a novel pyrimidin-4-one compound and an anticancer drug composition comprising the same.

While normal cells are capable of regular and controlled proliferation and suppression according to the needs of the individual, cancer cells proliferate indefinitely ignoring the necessary conditions within the tissue. That is, cancer is a cell mass composed of undifferentiated cells and is also referred to as a tumor. Cancer cells that proliferate without limit continue to infiltrate surrounding tissues and metastasize to other organs in the body, causing severe pain and ultimately leading to death.

Cancer is one of the incurable diseases that mankind must solve, and it is required to develop a therapeutic agent for effective cancer treatment.

For the treatment of cancer, surgery or chemotherapy that inhibits cell proliferation (cytotoxic chemotherapy) has been used.

Chemotherapy is a therapy that kills cancer cells by using chemicals (cytotoxic anticancer drugs) that kill fast-growing cells, but it is not a targeted therapy that acts directly on the target of each cancer. Despite the initial successful response by anticancer drugs used in chemotherapy, side effects caused by cytotoxicity and resistance to drugs in the case of prolonged cancer treatment or recurrence In the end, there was a problem that the treatment failed.

Therefore, various studies on targeted anticancer drugs with less toxicity and side effects are being conducted.

On the other hand, the production of lactate in cells is regulated by LDH (lactate dehydrogenase), and LDH is composed of five isoforms composed of tetramers according to different combinations of two types of monomeric subunits, LDHA and LDHB. exist in the form

In particular, in the case of LDHA, it was confirmed that its expression was remarkably increased in cancer cells, and its expression was known to be increased by the hypoxic response that induces malignant cancer.

Therefore, when targeting LDHA, which has high cancer specificity, it is very likely that side effects that inhibit metabolism of normal cells can be reduced compared to other metabolic regulating enzymes.

Furthermore, in the case of people with genetically impaired LDHA function, no serious pathological symptoms have been reported except for motor muscle disease (Kanno et al, 173(1), 89-93, 1988, Clin Chim Acta), making it an anti-cancer treatment target. The potential for toxicity and side effects of concern when using LDHA is very low.

The possibility of LDHA as an anti-cancer target was found to inhibit the growth of cancer cell lines when LDHA expression was inhibited through shRNA in metastatic breast cancer cell lines (Fantin et al, 9(6), 425-434, 2006, Cancer Cell).

Recently, it has been reported that the growth of cancer is significantly inhibited in a mouse model by using an LDHA activity inhibitor together with a NAMPT (Nicotinamide phosphoribosyltransferase) inhibitor, and more attention has been focused on the use of LDHA as an anticancer target.

In addition, it has been reported that lactate released extracellularly is used as a growth material for adjacent cancer cells, so that energy deficits supplied to cancer cells in tumors can be induced through inhibition of lactate growth (Sonveaux et al, 118(12), 3930-3942, 2008, J Clin Invest).

However, more research on anticancer targeting agents through inhibition of LDH is still needed.

Kanno et al, 173(1), 89-93, 1988, Clin Chim Acta. Fantin et al, 9(6), 425-434, 2006, Cancer Cell Sonveaux et al, 118(12), 3930-3942, 2008, J Clin Invest

The present invention provides a novel pyrimidin-4-one compound, a solvate thereof, a hydrate thereof, a prodrug thereof, an isomer thereof or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides an anticancer agent composition comprising the novel pyrimidin-4-one compound of the present invention, a solvate thereof, a hydrate thereof, a prodrug thereof, an isomer thereof or a pharmaceutically acceptable salt thereof.

The present invention is to provide anticancer agents, in particular, novel pyrimidin-4-one compounds, solvates thereof, hydrates thereof, prodrugs thereof, isomers thereof, or pharmaceutically acceptable salts thereof, which exhibit anticancer effects by inhibiting LDHA secretion. , The novel pyrimidin-4-one compound of the present invention is represented by the following formula (1):

[Formula 1]

(In Formula 1 above,

또는

이며;T is

or

is;

Z is O, S or NR _a ; R _a is hydrogen or C1-C20 alkyl;

L ₁ to L ₂ are each independently a single bond, R _b NCO, CONR _c , SO ₂ , OCO, CO, O, S, C1-C20 alkylene, or C6-C20 arylene, and R _b and R _c are independently of each other hydrogen or C1-C20 alkyl;

또는

이며; R ₁ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C1-C20alkylcarbonyl, C3-C20heteroaryl,

or

is;

Z ₁ is a single bond, CO, CONR _d , R _e NCO or O;

R _d and R _e are independently of each other hydrogen or C1-C20 alkyl;

A ₁ is C1-C20 alkylene;

A ₂ is a single bond or C1-C20 alkylene;

R ₁₁ and R ₁₂ independently of each other are hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C20 alkoxycarbonyl, C1-C20 alkyl, haloC1-C20 alkyl, C3-C20 heterocycloalkyl or C1-C20 alkoxy;

Haloalkyl, alkylcarbonyl and heteroaryl of R ₁ to R ₈ and alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₁₁ to R ₁₂ are halogen, amino, cyano, nitro, hydroxy, At least one selected from carboxyl, C1-C20 alkyl, C1-C20 alkoxy, C1-C20 alkylcarbonyl, C3-C20 heterocycloalkyl, C1-C20 heterocycloalkyl, C6-C20 aryl and C3-C20 heteroaryl may be substituted;

o is 0 or 1)

In addition, the present invention provides an anticancer agent composition comprising the pyrimidin-4-one compound of the present invention, a hydrate thereof, a solvate thereof, an isomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. do.

In addition, the present invention provides an anti-cancer kit comprising the anti-cancer composition of the present invention and a chemotherapeutic agent.

The pyrimidin-4-one compound of the present invention, its solvate, its hydrate, its prodrug, its isomer, or its pharmaceutically acceptable salt acts very effectively as an LDH-A inhibitor with high cancer specificity and inhibits the growth of cancer cells. suppress

Furthermore, the pyrimidin-4-one compound of the present invention, its solvate, its hydrate, its prodrug, its isomer, or its pharmaceutically acceptable salt does not inhibit normal cell metabolism and thus has remarkably low toxicity and side effects.

Therefore, the anticancer composition comprising the pyrimidin-4-one compound, a solvate thereof, a hydrate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof of the present invention can be used as an effective cancer-targeting therapeutic agent.

Hereinafter, the novel pyrimidin-4-one compound of the present invention, its solvate, its hydrate, its prodrug, its isomer or its pharmaceutically acceptable salt will be described in detail. At this time, if there is no other definition in the technical terms and scientific terms used, they have meanings commonly understood by those of ordinary skill in the art to which this invention belongs, and will unnecessarily obscure the gist of the present invention in the following description. Descriptions of possible known functions and configurations are omitted.

The following terms used herein are defined as follows, but these are only illustrative and are not intended to limit the present invention, application or use.

In this specification, the terms “substituent”, “radical”, “group”, “moiety”, and “fragment” are used interchangeably.

As used herein, the term "alkyl" refers to a saturated alkyl having 1 to 20 carbon atoms, preferably 1 to 15 carbon atoms, more preferably 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms (unless the number of carbon atoms is specifically limited). It means a straight-chain or branched non-cyclic hydrocarbon. "Lower alkyl" means straight chain or branched alkyl having 1 to 4 carbon atoms or 1 to 6 carbon atoms. Representative saturated straight-chain alkyls are -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n- decyl, while saturated branched alkyl is -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, isopentyl, 2-methylhexyl, 3-methylbutyl, 2-methylpentyl, 3- Methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5- Methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethyl Pentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-decylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and 3,3-diethylhexyl.

In this specification, when described as "C1-C20", it means that the number of carbon atoms is 1 to 10. For example, C1-C20 alkyl means an alkyl having 1 to 10 carbon atoms.

As used herein, the terms "halogen" and "halo" mean fluorine, chlorine, bromine or iodine.

As used herein, the terms "haloalkyl" or "haloalkoxy" refer to an alkyl or alkoxy group in which one or more hydrogen atoms are replaced by halogen atoms, respectively. For example, haloalkyl is -CF ₃ , -CHF ₂ , -CH ₂ F, -CBr ₃ , -CHBr ₂ , -CH ₂ Br, -CC1 ₃ , -CHC1 ₂ , -CH ₂ CI, -CI ₃ , -CHI ₂ , -CH ₂ I, -CH ₂ -CF ₃ , -CH ₂ -CHF ₂ , -CH ₂ -CH ₂ F, -CH ₂ -CBr ₃ , -CH ₂ -CHBr ₂ , -CH ₂ -CH ₂ Br, -CH ₂ -CC1 ₃ , -CH ₂ -CHC1 ₂ , -CH ₂ -CH ₂ CI, -CH ₂ -CI ₃ , -CH ₂ -CHI ₂ , -CH ₂ -CH ₂ I, and the like include that wherein alkyl and halogen are as defined above.

As used herein, the term "alkoxy" means -OCH ₃ , -OCH ₂ CH ₃ , -O(CH ₂ ) ₂ CH ₃ , -O(CH ₂ ) ₃ CH ₃ , -O(CH ₂ ) ₄ CH ₃ , -O-(alkyl), including -O(CH ₂ ) ₅ CH ₃ , and the like, wherein alkyl is as defined above. As used herein, the term "lower alkoxy" means -O-(lower alkyl), wherein lower alkyl is as defined above.

As used herein, the term “aryl” refers to a carbocyclic aromatic group containing 5 to 10 ring atoms. Representative examples include phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. Including, but not limited to. Carbocyclic aromatic groups may be optionally substituted.

As used herein, the term "cycloalkyl" means a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and not having carbon-carbon multiple bonds. Examples of cycloalkyl groups include, but are not limited to, (C3-C10)cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl). Cycloalkyl groups may be optionally substituted. In one embodiment, a cycloalkyl group is a monocyclic or bicyclic ring (ring).

As used herein, the term "heterocycloalkyl" means 3 to 20, preferably 3 to 15, preferably 3 to 10, preferably 3 to 6 carbon atoms and selected from the group consisting of nitrogen, oxygen and sulfur. stable 3- to 18-membered saturated or partially unsaturated consisting of 1 to 6 heteroatoms, such as 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms refers to radicals. Exemplary heterocyclealkyls include, but are not limited to, stable 3-15 membered saturated or partially unsaturated radicals, stable 3-12 membered saturated or partially unsaturated radicals, stable 3-9 membered saturated or partially unsaturated radicals, stable 8-membered saturated or partially unsaturated radicals, stable 8-membered saturated or partially unsaturated radicals. radical, a stable 7-membered saturated or partially unsaturated radical, a stable 6-membered saturated or partially unsaturated radical, or a stable 5-membered saturated or partially unsaturated radical.

As used herein, the terms "carboxylic acid" "carboxyl" and "carboxy" mean -COOH.

As used herein, the term "alkylcarbonyl" means -CO-(alkyl), wherein alkyl is as defined above.

As used herein, "heteroaryl" has at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur, and contains from 5 to 10 carbon atoms containing at least one carbon atom, including mono- and bicyclic ring systems. It is an aromatic heterocycle ring of a member. Representative heteroaryls are triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl ( benzoxazolyl), imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, tria Zinyl, cinnolinyl, phthalazinyl, quinazolinyl, pyrimidyl, oxetanil, azepinil, piperazinyl, morpholinyl, dioxanil, thietanyl and oxazolyl. Heteroaryl groups can be monocyclic or bicyclic. Heteroaryl may be used interchangeably with the terms heteroaryl ring, heteroaryl group, or heteroaromatic, all of which may include optionally substituted rings.

As used herein, the term “substituted” means that a hydrogen atom of the moiety being substituted (eg, an alkyl, aryl, heteroaryl, heterocycle or cycloalkyl) is replaced with a substituent. In one embodiment, each carbon atom of a group being substituted is substituted by no more than two substituents. In another embodiment, each carbon atom of a group being substituted is unsubstituted by more than one substituent. In the case of a keto substituent, two hydrogen atoms are replaced with oxygen attached to the carbon by a double bond. Unless otherwise specified with respect to substituents, optionally substituted substituents of the present invention include halogen, hydroxyl, (lower) alkyl, haloalkyl, mono- or di-alkylamino, aryl, heterocycle, -NO ₂ , -NR _a1 R _b1 , -NR _a1 C(=O) R _b1 , -NR _a1 C(=O)NR _a1 R _b1 , -NR _a1 C(=O)OR _b1 , -NR _a1 SO ₂ R _b1 , - OR _a1 , -CN, -C(=O)R _a1 , -C(=O)OR _a1 , -C(=O)NR _a1 R _b1 , -OC(=O)R _a1 , -OC(=O) OR _a1 , -OC(=O)NR _a1 R _b1 , -NR _a1 SO ₂ R _b1 , -PO ₃ R _a1 , -PO(OR _a1 )(OR _b1 ), -SO ₂ R _a1 , -S(O) R _a1 , -SO(NR _a1 )R _b1 (eg sulfoximine), -S(NR _a1 )R _b1 (eg sulfilimine) and -SR _a1 may be used, where R _a1 and R _b1 can be the same or different, and independently of each other hydrogen, halogen, amino, alkyl, alkoxyalkyl, haloalkyl, aryl or heterocycle, or as a nitrogen atom to which they are attached, R _a1 and R _b1 can be in the form of a heterocycle. can Here, R _a1 and R _b1 may be plural depending on the bonded atoms, the alkyl may be C1-C20 alkyl, the aryl may be C6-C20, and the heterocycle may be C3-C20.

Preferably, the substituted substituents of the present invention are halogen, amino, nitro, hydroxy, carboxyl, -B(OH) ₂ , C1-C20 alkylcarbonyl, C1-C10 alkoxycarbonyl, C2-C10 alkenyl, C1- C20 Alkyl, HaloC1-C20 Alkyl, C3-C10 Heterocyclocarbonyl, Allylamino, C1-C20 Alkylsulfonyl, Aminosulfonyl, AminoC1-C20 Alkyl, HydroxyC1-C20 Alkyl, DihydroxyC1-C20 Alkyl, CyanoC1-C20 Alkyl, C1-C20 Alkylamino, DiC1-C20 Alkylamino, C6-C20 Arylamino, DiC6-C20 Arylamino, C3-C20 Heteroaryl, HaloC6-C20 Aryl, Halo C1- C20 alkylC6-C20 aryl, C6-C20 aryl, C3-C10 cycloalkyl, C3-C10 cycloalkylcarbonyl, C1-C20 alkoxycarbonylC1-C20 alkyl and carboxylic acid from C1-C20 alkyl There may be one or more selected.

In the present invention, "pharmaceutically acceptable salts" include salts of active compounds prepared with relatively non-toxic acids and bases depending on the specific substituents found in the compounds mentioned herein. When the pyrimidin-4-one compounds of the present invention contain relatively acidic functionality, base addition salts are prepared by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent. You can get it. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functionality, acidic addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts are acetic acid, propionic acid, isobutyric acid, oxalic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid. ), mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric acid, tartaric acid, methanesulfonic, and their analogues. Hydrogen chloride, hydrogen bromide, nitric acid, carbonic acid, monohydrogencarbonic, phosphoric, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrosulfuric acid, hydrogen iodide or phosphorous acid, as well as salts derived from toxic organic acids. acid) and its analogues. Also included are salts of amino acids, such as alginate and their analogs, and analogs of organic acids, such as glucuronic or galactunoric acids and their analogs (e.g., Berge et al. (1977 ) J. Pharm. Sci. 66: 1-19). Some particular compounds of the present invention have both basic and acidic functionality which allows them to be converted into basic or acidic addition salts. Other examples of salts may be found in literature known in the art, for example Remington's Pharmaceutical Sciences, l8th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th ^eds . , Mack Publishing, Easton PA (1995).

As used herein, the term "patient" refers to an animal (eg, cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig), preferably mammals such as non-primates and primates (eg monkeys and humans), most preferably humans.

As used herein, "effective amount" refers to an amount of a compound of the present invention sufficient to provide a therapeutic benefit in the treatment or management of a cancer infection.

"Effective amount" also refers to an amount of the compound of the present invention sufficient to cause death or inhibition of development of cancer cells. "Effective amount" also refers to an amount sufficient for the treatment and prevention of cancer, either in vitro or in vivo.

As used herein, "prevention" includes prevention of recurrence, expansion or development of cancer in a patient.

"Treatment" as used herein includes the killing and suppression of cancer cells.

As used herein, the term “pyrimidin-4-one compound of the present invention” refers to compounds of Formulas 1 to 10, as well as clathrates, hydrates, solvates, prodrugs or polymorphs thereof. means including In addition, the term "pyrimidin-4-one compound of the present invention" is meant to include pharmaceutically acceptable salts of the pyrimidin-4-one compound of the present invention, when pharmaceutically acceptable salts thereof are not mentioned. In one embodiment, the pyrimidin-4-one compounds of the present invention are stereomerically pure compounds (e.g., substantially free of other stereoisomers (e.g., greater than 85% ee, greater than 90% ee, 95% ee). % ee or more, 97% ee or more, or 99% ee or more)). That is, the pyrimidin-4-one compounds of Formulas 1 to 10 or salts thereof according to the present invention are tautomeric isomers and/or stereoisomers (eg, geometrical isomers and conformational isomers) )), each of their isolated isomers and mixtures are also included within the scope of the pyrimidin-4-one compounds of the present invention. When the pyrimidin-4-one compounds or salts thereof of the present invention have an asymmetric carbon in the structure, their optically active compounds and racemic mixtures are also included in the scope of the compounds of the present invention. For example, when the pyrimidin-4-one compounds of the present invention have a sulfoxide (SOR) structure, they may have chirality. The pyrimidin-4-one compounds of the present invention include the R and S forms of these isomers, and mixtures of the R and S forms are also included in the scope of the compounds of the present invention.

In addition, the pyrimidin-4-one compounds of the present invention may exist in either the Keto form or the Enol form, and both of these forms are included in the scope of the pyrimidin-4-one compounds of the present invention.

As used herein, the term “polymorph” refers to a solid crystal form of a pyrimidin-4-one compound of the present invention or a complex thereof. Different polymorphs of the same pyrimidin-4-one compound exhibit different physical, chemical and/or spectral properties. Differences in terms of physical properties include, but are not limited to, stability (e.g. heat or light stability), compressibility and density (important for formulation and product manufacturing), and dissolution rate (which may affect bioavailability). It doesn't. Differences in stability may be due to chemical reactivity changes (e.g. differential oxidation such as faster discoloration when composed of one polymorph than when composed of another polymorph) or mechanical properties (e.g. kinetically Tablet fragments stored as the preferred polymorph may result in conversion of the thermodynamically more stable polymorph) or both (tablets of one polymorph are more susceptible to degradation at high humidity). Other physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form solvates, or may be more difficult to filter or wash, than another polymorph, eg, due to its shape or particle size distribution.

As used herein, the term “solvent compound” refers to a pyrimidin-4-one compound of the present invention or a pharmaceutically acceptable compound thereof comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. means salt. Preferred solvents are volatile, non-toxic, and can be administered in very small amounts to humans.

As used herein, the term "hydrate" refers to a pyrimidin-4-one compound of the present invention or a pharmaceutically acceptable form thereof containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. means an acceptable salt.

As used herein, the term "clathrate" refers to a flute of the present invention in the form of a crystal lattice containing spaces (eg, channels) in which guest molecules (eg, solvent or water) are confined. means a midin-4-one compound or a salt thereof.

If any compound (prodrug) is isolated in the body to produce the pyrimidin-4-one compound or salt thereof of the present invention, such compound is also included in the scope of the present invention. As used herein and unless otherwise indicated, the term "prodrug" refers to hydrolysis, oxidation and other reactions under biological conditions (ex vivo or in vivo) to provide an active compound, particularly a compound of the present invention. means a pyrimidin-4-one compound of the present invention capable of Examples of prodrugs are biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides that can be biohydrolyzed to produce pyrimidin-4-one compounds of the present invention, including biohydrolyzable moieties such as ureides that can be biohydrolyzed, and phosphate analogues that can be biohydrolyzed. However, it is not limited to these specific aspects. Preferably, the prodrug of the pyrimidin-4-one compound having a carboxyl functional group is a lower alkyl ester of a carboxylic acid. Carboxylic esters are commonly formed by esterifying a portion of a carboxylic acid present in a molecule. Prodrugs are described in Burger's Medicinal Chemistry and Drug Discovery 6thed. (Donald J. Abrahamed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).

As used herein, the term "purified" means that, when isolated, the isolate is at least 90% pure, in one embodiment at least 95% pure, in another embodiment at least 99% pure, and In other embodiments, at least 99.9% pure.

As used herein, the term "hydrido" refers to a single -H atom (H) and is used interchangeably with the symbol "H" or the term "hydrogen".

As used herein, the singular "a" and "an" may include the plural form unless the context clearly dictates otherwise.

As used herein, the term "pharmaceutically acceptable" means suitable for use as a pharmaceutical preparation, generally considered safe for such use, and officially approved by a national regulatory authority for such use. or listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

To provide a novel pyrimidin-4-one compound, a solvate thereof, a hydrate thereof, a prodrug thereof, an isomer thereof or a pharmaceutically acceptable salt thereof having excellent effects as an anticancer agent of the present invention, the novel pyrimidin-4-one compound of the present invention The midin-4-one compound is represented by Formula 1 below.

[Formula 1]

(In Formula 1 above,

또는

이며;T is

or

is;

Z is O, S or NR _a ; R _a is hydrogen or C1-C20 alkyl;

L ₁ to L ₂ are each independently a single bond, R _b NCO, CONR _c , SO ₂ , OCO, CO, O, S, C1-C20 alkylene, or C6-C20 arylene, and R _b and R _c are independently of each other hydrogen or C1-C20 alkyl;

또는

이며; R ₁ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C1-C20alkylcarbonyl, C3-C20heteroaryl,

or

is;

Z ₁ is a single bond, CO, CONR _d , R _e NCO or O;

R _d and R _e are independently of each other hydrogen or C1-C20 alkyl;

A ₁ is C1-C20 alkylene;

A ₂ is a single bond or C1-C20 alkylene;

R ₁₁ and R ₁₂ independently of each other are hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C20 alkoxycarbonyl, C1-C20 alkyl, haloC1-C20 alkyl, C3-C20 heterocycloalkyl or C1-C20 alkoxy;

Haloalkyl, alkylcarbonyl and heteroaryl of R ₁ to R ₈ and alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₁₁ to R ₁₂ are halogen, amino, cyano, nitro, hydroxy, At least one selected from carboxyl, C1-C20 alkyl, C1-C20 alkoxy, C1-C20 alkylcarbonyl, C3-C20 heterocycloalkyl, C1-C20 heterocycloalkyl, C6-C20 aryl and C3-C20 heteroaryl may be substituted;

ｏ is 0 or 　１)

Since the novel pyrimidin-4-one compound of the present invention has very high activity as an LDHA inhibitor, an anticancer drug composition containing the same is very useful as a target therapeutic agent.

Furthermore, since the novel pyrimidin-4-one compound of the present invention does not inhibit normal cell metabolism, toxicity and side effects can be remarkably improved.

또는

이며; Ｚ는　O 또는 S이며; Ｌ_１　내지　Ｌ_２는　서로　독립적으로　단일결합， R_bNCO, CONR_c, OCO, Ｏ，Ｓ 또는　C1-C20알킬렌이며， Ｒ_ｂ　및　Ｒ_ｃ는　서로　독립적으로　수소　또는　C1-C20알킬이며；R₁ 내지 R_８은 서로 독립적으로 수소，　할로겐，　아미노, 아미노카보닐，　할로C1-C20알킬， C3-C20헤테로아릴,

또는

이며; Z₁은 단일결합, CO, CONR_d 또는 O이며; R_d 는 수소　또는　C1-C20알킬이며; A₁은 C1-C20알킬렌이며; A₂는 단일결합 또는 C1-C20알킬렌이며; R₁₁ 및 R₁₂는 서로 독립적으로 수소, 하이드록시, 아미노, 니트로, 시아노, 카르복실산기, C1-C20알콕시카보닐, C1-C20알킬, 할로C1-C20알킬, C3-C20헤테로시클로알킬 또는 C1-C20알콕시이며; 상기 R₁ 내지 R_８의 할로알킬 및 헤테로아릴과 R₁₁ 내지 R₁₂의 알킬，　알콕시카보닐, 할로알킬, 알콕시　및　헤테로시클로알킬은 할로겐，　아미노，　시아노，　니트로，　하이드록시，　카르복실, C1-C20알킬， C1-C20알콕시 또는 C1-C20알킬카보닐에서　선택되는　하나이상으로　치환될　수　있으며；ｏ는　０또는　１일 수 있다.Preferably, in Formula 1 according to an embodiment of the present invention, T is

or

is; Z is O or S; L ₁ to L ₂ are each independently a single bond, R _b NCO, CONR _c , OCO, O, S or C1-C20 alkylene, and R _b and R _c are independently hydrogen or C1-C20 alkyl; R ₁ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C3-C20heteroaryl,

or

is; Z ₁ is a single bond, CO, CONR _d or O; R _d is hydrogen or C1-C20 alkyl; A ₁ is C1-C20 alkylene; A ₂ is a single bond or C1-C20 alkylene; R ₁₁ and R ₁₂ independently of each other are hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C20 alkoxycarbonyl, C1-C20 alkyl, haloC1-C20 alkyl, C3-C20 heterocycloalkyl or C1-C20 alkoxy; Haloalkyl and heteroaryl of R ₁ to R ₈ and alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₁₁ to R ₁₂ are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1 -C20 It may be substituted with one or more selected from alkyl, C1-C20 alkoxy or C1-C20 alkylcarbonyl; o may be 0 or 1.

또는

이며; Z₁은 단일결합, CO 또는 CONR_d이며; R_d 는 수소　또는　C1-C10알킬이며; A₁은 C1-C10알킬렌이며; A₂는 단일결합 또는 C1-C10알킬렌이며; R₁₁ 및 R₁₂는 서로 독립적으로 수소, 하이드록시, 아미노, 니트로, 시아노, 카르복실산기, C1-C10알콕시카보닐, C1-C10알킬, 할로C1-C10알킬, C3-C10헤테로시클로알킬 또는 C1-C10알콕시이며; 상기 R₁ 내지 R_８의 할로알킬 및 헤테로아릴과 R₁₁ 내지 R₁₂의 알킬, 알콕시카보닐, 할로알킬, 알콕시　및　헤테로시클로알킬은 할로겐, C1-C10알킬， C1-C10알콕시 또는 C1-C10알킬카보닐에서　선택되는　하나이상으로　치환될　수　있으며；ｏ는　０또는　１일 수 있다.More preferably, in Formula 1 according to an embodiment of the present invention, Z is S; L ₁ to L ₂ are each independently a single bond, R _b NCO, OCO or C1-C10 alkylene, R _b is hydrogen or C1-C10 alkyl; R ₁ to R ₈ are each independently hydrogen, halogen, amino , aminocarbonyl, haloC1-C20alkyl, C3-C20heteroaryl,

or

is; Z ₁ is a single bond, CO or CONR _d ; R _d is hydrogen or C1-C10 alkyl; A ₁ is C1-C10 alkylene; A ₂ is a single bond or C1-C10 alkylene; R ₁₁ and R ₁₂ independently of each other are hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C10 alkoxycarbonyl, C1-C10 alkyl, haloC1-C10 alkyl, C3-C10 heterocycloalkyl or C1-C10 alkoxy; Haloalkyl and heteroaryl of R ₁ to R ₈ and alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₁₁ to R ₁₂ are halogen, C1-C10 alkyl, C1-C10 alkoxy or C1-C10 alkyl It may be substituted with one or more selected from carbonyl; o may be 0 or 1.

Preferably, Chemical Formula 1 according to an embodiment of the present invention may be represented by Chemical Formula 2 or 3 below.

[Formula 2]

[Formula 3]

(In Formula 2 or 3,

Z is O or S;

L ₁ to L ₂ are each independently a single bond, R _b NCO, CONR _c , OCO, O, S or C1-C20 alkylene, and R _b and R _c are independently hydrogen or C1-C20 alkyl;

또는

이며; R ₁ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C3-C20heteroaryl,

or

is;

Z ₁ is a single bond, CO, CONR _d or O;

R _d is hydrogen or C1-C20 alkyl;

A ₁ is C1-C20 alkylene;

A ₂ is a single bond or C1-C20 alkylene;

R ₁₁ and R ₁₂ independently of each other are hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C20 alkoxycarbonyl, C1-C20 alkyl, haloC1-C20 alkyl, C3-C20 heterocycloalkyl or C1-C20 alkoxy;

Haloalkyl and heteroaryl of R ₁ to R ₈ and alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₁₁ to R ₁₂ are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1 -C20 Alkyl, C1-C20 Alkoxy or C1-C20 It may be substituted with one or more selected from alkyl carbonyl;

ｏ is 　0 or 　１.)

또는

이며; Z₁은 단일결합, CO 또는 CONR_d이며; R_d 는 수소　또는　C1-C10알킬이며; A₁은 C1-C10알킬렌이며; A₂는 단일결합 또는 C1-C10알킬렌이며; R₁₁ 및 R₁₂는 서로 독립적으로 수소, 하이드록시, 아미노, 니트로, 시아노, 카르복실산기, C1-C10알콕시카보닐, C1-C10알킬, 할로C1-C10알킬, C3-C10헤테로시클로알킬 또는 C1-C10알콕시이며; 상기 R₁ 내지 R_８의 할로알킬 및 헤테로아릴과 R₁₁ 내지 R₁₂의 알킬，　알콕시카보닐, 할로알킬, 알콕시　및　헤테로시클로알킬은 C1-C20알킬， C1-C20알콕시 또는 C1-C20알킬카보닐에서　선택되는　하나이상으로　치환될　수　있으며；ｏ는　0 또는　１일 수 있다.More preferably, in Chemical Formulas 2 and 3 according to an embodiment of the present invention, Z is S; L ₁ to L ₂ are each independently a single bond, R _b NCO, CONR _c , OCO or C1-C20 alkylene, R _b and R _c are independently hydrogen or C1-C10 alkyl; R ₁ to R ₈ are independently of each other hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C3-C20heteroaryl,

or

is; Z ₁ is a single bond, CO or CONR _d ; R _d is hydrogen or C1-C10 alkyl; A ₁ is C1-C10 alkylene; A ₂ is a single bond or C1-C10 alkylene; R ₁₁ and R ₁₂ independently of each other are hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C10 alkoxycarbonyl, C1-C10 alkyl, haloC1-C10 alkyl, C3-C10 heterocycloalkyl or C1-C10 alkoxy; Haloalkyl and heteroaryl of R ₁ to R ₈ and alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₁₁ to R ₁₂ are C1-C20alkyl, C1-C20alkoxy or C1-C20alkylcarbonyl It may be substituted with one or more selected from; O may be 0 or 1.

Preferably, the pyrimidin-4-one compound of Chemical Formula 1 according to an embodiment of the present invention may be represented by Chemical Formula 4 or 7 below.

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

(In Formula 4 to 7,

Z is O or S;

이며;R ₁ is hydrogen or

is;

또는

이며; R ₂ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C3-C20heteroaryl,

or

is;

Z ₁₁ is a single bond, CO, CONR _d or O;

R _d is hydrogen or C1-C20 alkyl;

A ₁₁ to A ₁₃ are C1-C20 alkylene;

R ₂₁ to R ₂₃ are each independently hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C20 alkoxycarbonyl, C1-C20 alkyl, haloC1-C20 alkyl, C3-C20 heterocycloalkyl or C1-C20 alkoxy;

n and m are independently of each other an integer from 0 to 10;

The R ₂ to R ₈ haloalkyl and heteroaryl and R ₂₁ to R ₂₃ alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1 -C20 Alkyl, C1-C20 Alkoxy or C1-C20 It may be substituted with one or more selected from alkylcarbonyl.)

이며; R₂ 내지 R_８은 서로 독립적으로 수소，　할로겐，　아미노, 아미노카보닐，　할로C1-C20알킬， C3-C20헤테로아릴,

또는

이며; Z₁₁은 단일결합, CO 또는 CONR_d 이며; R_d 는 수소　또는　C1-C20알킬이며; A₁₁ 내지 A₁₃은 C1-C20알킬렌이며; R₂₁ 내지 R₂₃은 서로 독립적으로 수소, 하이드록시, 아미노, 니트로, 시아노, 카르복실산기, C1-C20알콕시카보닐, C1-C20알킬, 할로C1-C20알킬, C3-C20헤테로시클로알킬 또는 C1-C20알콕시이며; n 및 m은 서로 독립적으로 1 내지 7의 정수이며; 상기 R₂ 내지 R_８의 할로알킬 및 헤테로아릴과 R₂₁ 내지 R₂₃의 알킬，　알콕시카보닐, 할로알킬, 알콕시　및　헤테로시클로알킬은 할로겐，　아미노，　시아노，　니트로，　하이드록시，　카르복실, C1-C20알킬， C1-C20알콕시 또는 C1-C20알킬카보닐에서　선택되는　하나이상으로　치환될　수 있는 수 있으며, Preferably, in Chemical Formulas 4 to 7 according to an embodiment of the present invention, Z is S; R ₁ is hydrogen or

is; R ₂ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C3-C20heteroaryl,

or

is; Z ₁₁ is a single bond, CO or CONR _d ; R _d is hydrogen or C1-C20 alkyl; A ₁₁ to A ₁₃ are C1-C20 alkylene; R ₂₁ to R ₂₃ are each independently hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C20 alkoxycarbonyl, C1-C20 alkyl, haloC1-C20 alkyl, C3-C20 heterocycloalkyl or C1-C20 alkoxy; n and m are independently of each other an integer from 1 to 7; The R ₂ to R ₈ haloalkyl and heteroaryl and R ₂₁ to R ₂₃ alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1 It may be substituted with one or more selected from -C20alkyl, C1-C20alkoxy or C1-C20alkylcarbonyl,

이며; R₂는 수소，C1-C20알킬 또는

이며; R₃은 수소，　할로겐， C3-C20헤테로아릴,

또는

이며; R₄ 내지 R_８은 서로 독립적으로 수소，　할로겐，아미노, 아미노카보닐 또는할로C1-C20알킬이며; Z₁₁은 단일결합, CO 또는 CONR_d 이며; R_d 는 수소　또는　C1-C20알킬이며; A₁₁ 내지 A₁₃은 C1-C20알킬렌이며; R₂₁ 내지 R₂₃은 서로 독립적으로 수소, 하이드록시, 아미노, 니트로, 시아노, 카르복실산기, C1-C20알콕시카보닐, C1-C20알킬, 할로C1-C20알킬, C3-C20헤테로시클로알킬 또는 C1-C20알콕시이며; n 및 m은 서로 독립적으로 1 내지 5의 정수이며; 상기 R₂의 알킬, R₃의 할로알킬, R_８의 헤테로아릴과 R₂₁ 내지 R₂₃의 알킬，　알콕시카보닐, 할로알킬, 알콕시　및　헤테로시클로알킬은 할로겐，　아미노，　시아노，　니트로，　하이드록시，　카르복실, C1-C20알킬， C1-C20알콕시 또는 C1-C20알킬카보닐에서　선택되는　하나이상으로　치환될　수 있다.More preferably Z is S; R ₁ is hydrogen or

is; R ₂ is hydrogen, C1-C20 alkyl or

is; R ₃ is hydrogen, halogen, C3-C20 heteroaryl,

or

is; R ₄ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl or haloC1-C20alkyl; Z ₁₁ is a single bond, CO or CONR _d ; R _d is hydrogen or C1-C20 alkyl; A ₁₁ to A ₁₃ are C1-C20 alkylene; R ₂₁ to R ₂₃ are each independently hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C20 alkoxycarbonyl, C1-C20 alkyl, haloC1-C20 alkyl, C3-C20 heterocycloalkyl or C1-C20 alkoxy; n and m are independently of each other an integer from 1 to 5; Alkyl of R ₂ , haloalkyl of R ₃ , heteroaryl of R ₈ and alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₂₁ to R ₂₃ are halogen, amino, cyano, nitro, hydroxy It may be substituted with one or more selected from carboxyl, C1-C20 alkyl, C1-C20 alkoxy or C1-C20 alkylcarbonyl.

이며; R₂는 수소，C1-C10알킬 또는

이며; R₃은 수소，　할로겐， C3-C12헤테로아릴,

또는

이며; R₄ 내지 R_８은 서로 독립적으로 수소，　할로겐，아미노, 아미노카보닐 또는할로C1-C10알킬이며; Z₁₁은 단일결합, CO 또는 CONR_d 이며; R_d 는 수소　또는　C1-C10알킬이며; A₁₁ 내지 A₁₃은 C1-C10알킬렌이며; R₂₁ 내지 R₂₃은 서로 독립적으로 수소, 하이드록시, 아미노, 니트로, 시아노, 카르복실산기, C1-C10알콕시카보닐, C1-C10알킬, 할로C1-C10알킬, C3-C10헤테로시클로알킬 또는 C1-C10알콕시이며; n 및 m은 서로 독립적으로 1 내지 5의 정수이며; 상기 R₂의 알킬, R₃의 할로알킬, R_８의 헤테로아릴과 R₂₁ 내지 R₂₃의 알킬，　알콕시카보닐, 할로알킬, 알콕시　및　헤테로시클로알킬은 할로겐 C1-C10알킬， C1-C10알콕시 또는 C1-C10알킬카보닐에서　선택되는　하나이상으로　치환될　수 있다.More preferably, in Chemical Formulas 4 to 7 according to an embodiment of the present invention, Z is S; R ₁ is hydrogen or

is; R ₂ is hydrogen, C1-C10 alkyl or

is; R ₃ is hydrogen, halogen, C3-C12 heteroaryl,

or

is; R ₄ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl or haloC1-C10alkyl; Z ₁₁ is a single bond, CO or CONR _d ; R _d is hydrogen or C1-C10 alkyl; A ₁₁ to A ₁₃ are C1-C10 alkylene; R ₂₁ to R ₂₃ are each independently hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C10 alkoxycarbonyl, C1-C10 alkyl, haloC1-C10 alkyl, C3-C10 heterocycloalkyl or C1-C10 alkoxy; n and m are independently of each other an integer from 1 to 5; The R ₂ Alkyl, R ₃ Haloalkyl, R ₈ Heteroaryl and R ₂₁ to R ₂₃ Alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl are halogen C1-C10 Alkyl, C1-C10 Alkoxy or It may be substituted with one or more selected from C1-C10 alkylcarbonyl.

In terms of having a more excellent effect as an LDH-A inhibitor, Formula 1 according to an embodiment of the present invention may be represented by Formula 8 or 9 below.

[Formula 8]

[Formula 9]

(In Formula 8 to 9

L ₁ to L ₂ are each independently a single bond, R _b NCO, CONR _c , SO ₂ , OCO, CO, O, S, C1-C20 alkylene, or C6-C20 arylene, and R _b and R _c are independently of each other hydrogen or C1-C20 alkyl;

D ₁ and D ₂ are each independently N or CR ₁₆ ; except when D ₁ and D ₂ are simultaneously N;

R ₄ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C1-C20alkyl or C1-C20alkylcarbonyl;

Z ₁ is a single bond, CO, CONR _d , R _e NCO or O;

R _d and R _e are independently of each other hydrogen or C1-C20 alkyl;

A ₁ is C1-C20 alkylene;

A ₂ is a single bond or C1-C20 alkylene;

R ₁₄ to R ₁₈ and R ₂₄ to R ₂₈ are each independently hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C20 alkoxycarbonyl, C1-C20 alkyl, haloC1-C20 alkyl, C3 -C20 heterocycloalkyl or C1-C20 alkoxy;

The R ₁₄ to R ₁₈ and R ₂₄ to R ₂₈ alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1-C20 alkyl, C1- It may be substituted with one or more selected from C20 alkoxy, C1-C20 alkylcarbonyl, C3-C20 heterocycloalkyl, C1-C20 heterocycloalkyl, C6-C20 aryl and C3-C20 heteroaryl;

p and q are independently integers of 0 or 1, except when p and q are 0 at the same time.)

Preferably, in Chemical Formula 8 or 9 according to an embodiment of the present invention, L ₁ to L ₂ are each independently a single bond, R _b NCO, CONR _c , OCO or C1-C20 alkylene, and R _b and R _c are independently hydrogen or C1-C10 alkyl; D ₁ and D ₂ are each independently N or CR ₁₆ ; except when D ₁ and D ₂ are simultaneously N; R ₄ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C1-C20alkyl or C1-C20alkylcarbonyl; Z ₁ is a single bond, CO or CONR _d ; R _d is hydrogen or C1-C10 alkyl; A ₁ is C1-C10 alkylene; A ₂ is a single bond or C1-C10 alkylene; R ₁₄ to R ₁₈ and R ₂₄ to R ₂₈ are each independently hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C20 alkoxycarbonyl, C1-C20 alkyl, haloC1-C20 alkyl, C3 -C20 heterocycloalkyl or C1-C20 alkoxy; The R ₁₄ to R ₁₈ and R ₂₄ to R ₂₈ alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1-C20 alkyl, C1- C20 Alkoxy, C1-C20 Alkylcarbonyl, C3-C20 Heterocycloalkyl, C1-C20 Heterocycloalkyl, C6-C20 Aryl and C3-C20 It may be substituted with one or more selected from heteroaryl; p and q are mutually Independently an integer of 0 or 1, and may be excluded when p and q are 0 at the same time,

More preferably, L ₁ to L ₂ are each independently a single bond, R _b NCO, OCO or C1-C10 alkylene, R _b and R _c are independently hydrogen or C1-C5 alkyl; D ₁ and D ₂ are independently of each other N or CR ₁₆ ; except when D ₁ and D ₂ are simultaneously N; R ₄ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C10alkyl, C1-C10alkyl or C1-C20alkylcarbonyl; Z ₁ is a single bond, CO or CONR _d ; R _d is hydrogen or C1-C5 alkyl; A ₁ is C1-C10 alkylene; A ₂ is a single bond or C1-C10 alkylene; R ₁₄ to R ₁₈ and R ₂₄ to R ₂₈ are each independently hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C10 alkoxycarbonyl, C1-C10 alkyl, haloC1-C10 alkyl, C3 -C10 heterocycloalkyl or C1-C10 alkoxy; The R ₁₄ to R ₁₈ and R ₂₄ to R ₂₈ alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1-C20 alkyl, C1- C10 alkoxy, C1-C10 alkylcarbonyl, C3-C10 heterocycloalkyl, C1-C10 heterocycloalkyl, C6-C12 aryl and C3-C12 heteroaryl may be substituted with one or more selected from; p and q are mutually It is independently an integer of 0 or 1, and may be excluded when p and q are both 0. More preferably, Chemical Formula 1 according to an embodiment of the present invention may be represented by Chemical Formula 10 below.

[Formula 10]

(In Chemical Formula 10,

D ₁ and D ₂ are each independently N or CR ₁₆ ;

R ₄ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C1-C20alkyl or C1-C20alkylcarbonyl;

R ₁₄ to R ₁₇ are each independently hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C20 alkoxycarbonyl, C1-C20 alkyl, haloC1-C20 alkyl, C3-C20 heterocycloalkyl or C1-C20 alkoxy;

Alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₁₄ to R ₁₇ are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1-C20 Alkyl, C1-C20 Alkoxy, C1-C20 It may be substituted with one or more selected from alkylcarbonyl, C3-C20heterocycloalkyl, C1-C20heterocycloalkyl, C6-C20aryl and C3-C20heteroaryl;

n is 0 or 1;

m is an integer from 1 to 5.)

Preferably, in Formula 10 according to an embodiment of the present invention, D ₁ and D ₂ are each independently N or CR ₁₆ , except when D ₁ and D ₂ are N at the same time; R ₄ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C10alkyl, C1-C10alkyl or C1-C10alkylcarbonyl; R ₁₄ to R ₁₇ are each independently hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C10 alkoxycarbonyl, C1-C10 alkyl, haloC1-C10 alkyl, C3-C10 heterocycloalkyl or C1-C10 alkoxy; The R ₁₄ to R ₁₇ alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 It may be substituted with one or more selected from alkylcarbonyl, C3-C10heterocycloalkyl, C1-C10heterocycloalkyl, C6-C12aryl and C3-C12heteroaryl; n is 0 or 1; m may be an integer of 1 to 5, more preferably R ₁₄ to R ₁₇ Alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl are halogen, C1-C10 Alkyl, C1-C10 Alkoxy and C1- It may be substituted with one or more selected from C10 alkylcarbonyl.

Specifically, the pyrimidin-4-one compound according to an embodiment of the present invention may be selected from the following compounds, but is not limited thereto.

Any method for preparing a pyrimidin-4-one compound according to an embodiment of the present invention can be any synthetic method recognized by those skilled in the art.

In addition, the reaction time in the method for producing a pyrimidin-4-one compound according to an embodiment of the present invention may vary depending on the type and amount of the reactant, solvent, and the starting material is completely After confirming consumption, the reaction is completed. When the reaction is complete, the solvent may be distilled off under reduced pressure, and then the target product may be separated and purified through a conventional method such as column chromatography.

In addition, the present invention provides an anticancer agent composition comprising the pyrimidin-4-one compound of the present invention, a hydrate thereof, a solvate thereof, an isomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. do.

The anticancer composition according to one embodiment of the present invention essentially includes, as an active ingredient, the pyrimidin-4-one compound of the present invention, a hydrate thereof, a solvate thereof, an isomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof It has a high anti-cancer effect.

Preferably, the novel pyrimidin-4-one compound of the present invention included in the anticancer drug composition according to an embodiment of the present invention is 0.001 to 10% by weight, preferably 0.01 to 5% by weight, more preferably 0.01 to 5% by weight, based on the total weight of the anticancer drug composition It may be included in 0.1 to 5% by weight.

The anticancer agent composition according to an embodiment of the present invention is any one or two or more selected from lung cancer, liver cancer, breast cancer, colon cancer, colorectal cancer, rectal cancer, colon cancer, bladder cancer, cervical cancer, osteosarcoma, leukemia, myelogenous leukemia, melanoma, and gastric cancer. It can be used for the prevention and treatment of diseases, and may further include a pharmaceutically acceptable excipient.

Excipients according to an embodiment of the present invention can be any inactive or non-active substances used in the manufacture of pharmaceutical products, without limitation, binders, disintegrants, coating agents, pyroxenes, compression / encapsulation agents, creams or lotions, including any substance used as a lubricant, parenteral agent, sweetening or flavoring agent, suspending/gelling agent or wet granulating agent.

binders include, for example, carbopol, povidone, xanthan gum, and the like; coating agents include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin and the like; compression/encapsulating agents include, for example, calcium carbonate, dextrose, fructose, honey, lactose (anhydrous or monohydrate; optionally in combination with aspartame, cellulose or microcrystalline cellulose), starch, sucrose, and the like; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate and the like; creams and lotions containing, for example, maltodextrin, carrageenan, and the like; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, and the like; Chewable tablets include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), and the like; Parenteral agents include, for example, mannitol, povidone, and the like; plasticizers include, for example, dibutyl sebacate, polyvinylacetate phthalate, and the like; suspending/gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, and the like; Sweeteners include, for example, aspartame, dextrose, fructose, sorbitol, sucrose, and the like; Wet granulation agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, and the like.

Of course, the anti-cancer composition according to an embodiment of the present invention may be used in any amount of an appropriate excipient depending on the route of administration.

The anticancer agent composition according to an embodiment of the present invention may further include a chemotherapeutic agent.

Any chemotherapeutic agent according to an embodiment of the present invention is possible as long as it is recognized by those skilled in the art, but examples include alkylating agents, metabolic antagonists, antitumor antibiotics, mitotic inhibitors, hormones, cisplatin, L-asparaginase and mTor inhibitors. There may be one or more than one selected.

Alkylating agents according to an embodiment of the present invention are highly reactive substances having the ability to introduce an alkyl group R-CH ₂ into a compound, and when acted on cells, most of them react with N7 of guanine of DNA to form DNA It transforms the structure and causes chain scission to exhibit anticancer and cytotoxic effects. Specific examples include carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, It may be one or two or more selected from dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, aotepa, bendamustine, and streptozocin.

Metabolites according to an embodiment of the present invention have an action of inhibiting metabolic processes necessary for the proliferation of cancer cells, for example, in fluorouracil, gemcitabine hydrochloride, methotrexate, cytarabine and fludarabine. It may be one or more than one selected,

The anti-tumor antibiotics (Antibiotics) are among antibiotics produced by bacteria that exhibit anticancer activity, for example, bleomycin, doxorubicin, daunorvicin, idarubicin, mitoxantrone, dactinomycin, epirubicin, plicama It may be one or two or more selected from isin, pentostatin and valrubicin;

The mitotic inhibitor (vinca alkaloid) is a mitotic phase-specific drug that stops cell division in metaphase during mitotic phase, and includes irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, and bin. It may be one or two or more selected from Christine, Ixabepilone, Vinorelbine, Vinblastine and Teniposide,

The mTor inhibitor (mammalian target of rapamycin) may be one or more selected from limus, siroliumus, and temsirolimus.

In addition, the present invention provides a kit for anti-cancer including the pyrimidin-4-one compound of formula 1 and a chemotherapeutic agent according to an embodiment of the present invention.

The anti-cancer kit according to one embodiment of the present invention includes the pyrimidin-4-one compound represented by Formula 1 of the present invention and the above-mentioned chemotherapeutic agent, so that combined administration is easier and the anti-cancer effect can be increased. there is.

The novel pyrimidin-4-one compounds of the present invention, solvates thereof, hydrates thereof, prodrugs thereof, isomers thereof or pharmaceutically acceptable salts thereof, and anticancer compositions containing the same will be described with specific examples, but these The present invention is not limited to specific examples.

[Example 1] Preparation of compound CIM 1021 (CNC 2031, f)

1-1 Synthesis of compound a

After mixing 2,5-dihydroxy-1,4-dithiane (1 eq), methyl cyanoacetate (1.5 eq) and MeOH, slowly inject Et ₃ N (3 eq) at 0 ^o C for 2 hours and 30 minutes, then 40 ^o C and stirred for 1 hour and 30 minutes. The reaction mixture was diluted with DCM (dichloromethane), washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound a.

1-2 Synthesis of compound b

After mixing compound a (1 eq), formamide (47.2 eq) and ammonium formate (6.7 eq), the mixture was stirred at 155 ^o C for 26 hours. The reaction mixture was stored at -18 ^° C for one day, and the resulting solid was filtered, washed with water, and dried to obtain compound b.

1-3 Synthesis of compound c

After mixing compound b (1 eq) and AcOH (3.5 eq) and stirring at room temperature, Br ₂ (1.77 eq) was slowly added, heated at 80 ^° C, and stirred for 1 hour and 30 minutes. After the temperature of the reaction mixture was lowered to room temperature, the pH was adjusted to 7 using a saturated solution of NaHCO ₃ . After filtering the solid, it was washed with water to obtain compound c.

1-4 Synthesis of Compound d

Compound c (1 eq), t-Butyl bromoacetate (2 eq), cesium carbonate (1.5 eq) and DMF were mixed and stirred at 100 ^o C for 2 hours. The reaction mixture was quenched with water, diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound d.

1-5 Synthesis of compound e

After mixing compound d (1 eq) and TFA (trifluoroacetic acid, 61.8 eq), the mixture was stirred at room temperature for 2 hours. TFA was removed by repeating the addition of DCM to the reaction mixture followed by evaporation. Ether was added to the concentrated reaction mixture, and the resulting solid was filtered, washed with ether, and dried to obtain compound e.

1-6 Synthesis of compound f

Compound e(1 eq), 4-chloro-3-(trifluoromethyl)aniline (1.25 eq), PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, 1.25 eq), DMAP (4-Dimethylaminopyridine, 0.5 eq), DIEA (N After mixing N-Diisopropylethylamine, 5 eq) and DMF, the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound f.

¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm 10.96 (br. s., 1 H), 8.45 (s, 1 H), 8.17 (s, 1 H), 7.80 (d, J =9.22 Hz, 1 H), 7.70 (d, J =8.66 Hz, 1 H), 7.60 (s, 1 H), 4.90 (s, 2 H)

[Example 2] Preparation of compound CIM 1288 (CNC 2088, g)

Compound f (1 eq), 2-hydroxyphenylboronic acid (1.1 eq), 2M K ₂ CO ₃ (4.5 eq), Pd(PPh ₃ ) ₄ (0.05 eq), and THF were mixed and stirred at 85 ^o C for 20 hours. made it The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound g.

¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm 10.93 (s, 1H), 10.59 (s, 1H), 8.40 (s, 1H), 8.19 (s, 1H), 7.77 (m, 4H), 7.21 (d, J =1.58 Hz, 1H), 6.96 (m, 2H), 4.92 (s, 2H)

The compounds shown in Table 1 were prepared in the same manner as in Example 2, except that the starting materials were changed in Example 2.

compound compound structure ¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm CIM 1289 (CNC 2089)

10.92 (s, 1H), 9.85 (s, 1H), 8.39 (s, 1H), 8.19 (s, 1H), 7.82 (d, J =8.38 Hz, 1H), 7.70 (d, J =8.57 Hz, 1H) ), 7.60 (m, 3H), 6.84 (d, J =8.57 Hz, 2H), 4.91 (s, 2H) CIM 1284 (CNC 2084)

10.93 (s, 1H), 8.44 (s, 1H), 8.18 (s, 1H), 7.88 (s, 1H), 7.82 (d, J =9.69 Hz, 1H), 7.70 (d, J =8.94 Hz, 1H) ), 7.36 (m, 3H), 6.97 (d, J =7.82 Hz, 1H), 4.93 (s, 2H), 3.84 (s, 3H) CIM 1283 (CNC 2083)

10.93 (s, 1H), 8.41 (s, 1H), 8.19 (s, 1H), 7.72 (m, 5H), 7.03 (s, 2H), 4.92 (s, 2H), 3.81 (s, 3H) CIM 1285 (CNC 2085)

10.94 (br. s., 1 H), 8.47 (s, 1 H), 8.17 (m, 3 H), 7.95 (s, 2 H), 7.79 (s, 1 H), 7.67 (m, 2 H) , 4.91 (br. s., 2 H), 3.91 (br. s., 3 H) CIM 1286 (CNC 2086)

10.95 (s, 1H), 8.48 (s, 1H), 8.19 (s, 1H), 7.98 (m, 5H), 7.82 (d, J =8.90 Hz, 1H), 7.70 (d, J =8.94 Hz, 1H) ), 4.93 (s, 2H), 3.88 (s, 3H) CIM 1307 (CNC 2097)

10.95 (br. s, 1H), 8.42 (s, 1H), 8.19 (d, J =1.96 Hz, 1H), 7.82 (d, J =8.75 Hz, 1H), 7.70 (d, J =8.85 Hz, 1H) ), 7.46 (s, 1H), 7.23 (d, J =7.54 Hz, 1H), 7.11 (t, J =7.64 Hz, 1H), 6.83 (d, J =8.29 Hz, 1H), 6.66 (t, J =7.45 Hz, 1H), 5.28 (s, 2H), 4.92 (s, 2H) CIM 1308 (CNC 2098)

10.94 (br. s, 1H), 8.42 (s, 1H), 8.19 (s, 1H), 7.82 (d, J =8.10 Hz, 1H), 7.70 (d, J =8.10 Hz, 1H), 7.60 (s , 1H), 7.10 (br. s, 1H), 6.92 (br. s, 2H), 6.60 (br. s, 1H), 5.29 (s, 2H), 4.91 (s, 2H) CIM 1306 (CNC 2096)

10.95 (s, 1 H), 8.51 (s, 1 H), 8.28 (d, J =8.38 Hz, 2 H), 8.13 (m, 4 H), 7.82 (d, J =8.94 Hz, 1 H), 7.70 (d, J =9.41 Hz, 1 H), 4.94 (s, 2 H) CIM 1301 (CNC 2091)

10.95 (s, 1H), 8.50 (s, H), 8.19 (d, J =2.42 Hz, 1H), 7.92 (d, J =7.45 Hz, 1H), 7.80 (t, J =7.12 Hz, 2H), 7.72 (m, 3H), 7.39 (s, 1H), 4.93 (s, 2H) CIM 1302 (CNC 2092)

10.94 (s, 1H), 8.48 (s, 1H), 8.18 (m, 2H), 8.10 (m, 2H), 7.81 (m, 1H), 7.71 (m, 3H), 4.93 (s, 2H) CIM 1303 (CNC 2093)

10.94 (s, 1H), 8.49 (s, 1H), 8.19 (s, 1H), 8.03 (m, 3H), 7.81 (d, J =8.47 Hz, 3H), 7.71 (d, J =8.75 Hz, 1H) ), 4.93 (s, 2H) CIM 1311 (CNC 2901)

10.95 (s, 1H), 8.48 (s, 1H), 8.37 (s, 1H), 8.19 (d, J =2.24 Hz, 1H), 8.11 (d, J =7.82 Hz, 1H), 8.06 (s, 1H) ), 7.83 (t, J =7.59 Hz, 2H), 7.68 (m, 2H), 4.93 (s, 2H) CIM 1300 (CNC 2090)

10.98 (s, 1H), 8.46 (s, 1H), 8.21 (d, J =2.14 Hz, 1H), 7.81 (m, 1H), 7.70 (d, J =8.94 Hz, 1H), 7.27 (m, 1H) ), 7.19 (m, 3H), 4.92 (s, 2H), 2.16 (s, 6H) CIM 1281 (CNC 2081)

10.94 (s, 1H), 9.03 (s, 1H), 8.58 (s, 1H), 8.48 (s, 1H), 8.19 (s, 2H), 8.00 (s, 1H), 7.80 (s, 1H), 7.72 (s, 1H), 7.49 (s, 1H), 4.93 (s, 2H) CIM 1280 (CNC 2080)

10.94 (s, 1H), 8.62 (s, 2H), 8.50 (s, 1H), 8.18 (s, 2H), 7.80 (s, 3H), 7.70 (d, J =8.47 Hz, 1H), 4.93 (s , 2H) CIM 1282 (CNC 2082)

10.93 (s, 1H), 8.61 (s, 1H), 8.44 (s, 1H), 8.15 (m, 2H), 7.82 (s, 2H), 7.70 (d, J =7.92 Hz, 1H), 6.93 (d , J =7.36 Hz, 1H), 4.92 (s, 2H), 3.90 (s, 3H) CIM 1309 (CNC 2099)

13.16 (br. s, 1 H), 10.92 (br. s, 1H), 8.37 (s, 1H), 8.18 (m, 3H), 7.81 (m, 1H), 7.70 (d, J =8.85 Hz, 1H ), 7.53 (s, 1H), 4.91 (s, 2H)

[Example 3] Preparation of compound CIM 1022 (CNC 2032, c)

After mixing compound a (1 eq), compound c (1 eq), K ₂ CO ₃ (4 eq) and DMF, the mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with EtOAc, washed with cold water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound c.

¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm 9.74 (br. s, 1H), 8.45 (s, 1H), 7.62 (s, 1H), 7.20 (s, 1H), 7.10 (d, J = 7.36 Hz, 1H), 6.92 (d, J =6.43 Hz, 1H), 4.90 (s, 2H), 2.23 (s, 3H), 2.18 (s, 3H)

[Example 4] Preparation of compound CIM 1023 (CNC 2033, b)

After mixing compound a (1 eq) with 3-(Morpholino)phenylboronic Acid Pinacol Ester (1.2 eq), K ₂ CO ₃ (2.2 eq), Pd(PPh ₃ ) ₄ (0.053 eq) and dioxane/H ₂ O It was stirred at 110 ^° C for 4 hours. The reaction mixture was diluted with EtOAc, washed with a saturated solution of NH ₄ Cl, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound b.

¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm 9.75 (s, 1H), 8.43 (s, 1H), 7.90 (s, 1H), 7.31 (m, 2H), 7.21 (s, 1H), 7.13 (m, 2H), 6.95 (m, 2H), 4.92 (s, 2H), 3.76 (t, J =4.75 Hz, 4H), 3.21 (t, J =4.90 Hz, 4H), 2.24 (s, 3H) , 2.19 (s, 3H)

[Example 5] Preparation of compound CIM 1078 (CNC 2036, e)

5-1 Synthesis of compound a

After mixing bromobutanol (0.5 eq) and toluene and stirring at room temperature, morpholine (1 eq) was slowly injected and stirred at 80 ^° C for 4 hours. After lowering the temperature of the reaction mixture to room temperature, washing with toluene and filtering the mixture was concentrated and dried to obtain compound a.

5-2 Synthesis of compound b

After mixing compound a (1 eq), oxalyl chloride (1.1 eq) and DCM, DMSO (2.4 eq) dissolved in DCM was added at -78 ^° C. After 10 minutes, the starting material dissolved in DCM was added. After the reaction mixture was stirred at -78 ^o C for 10 minutes, Et ₃ N (5 eq) was added and stirred for 24 hours. The reaction mixture was diluted with DCM, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, DCM/MeOH) to obtain compound b.

5-3 Synthesis of compound c

After mixing compound b (1 eq), ethyl cyano acetate (1 eq), sulfur (1 eq), Et ₃ N (1.3 eq) and EtOH, the mixture was heated at 80 ^° C and stirred for 20 hours. After reducing the temperature of the reaction mixture to room temperature, it was diluted with EtOAc, washed with a saturated solution of NaHCO ₃ , dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound c.

5-4 Synthesis of Compound d

After mixing compound c (1 eq), Formamide (53.3 eq) and AcOH (1.2 eq), the mixture was stirred at 150 ^° C for 22 hours. After reducing the temperature of the reaction mixture to room temperature, it was diluted with EtOAc, washed with water, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, DCM/MeOH) to obtain compound d.

Synthesis of 5-5 compound e

After mixing compound d (1 eq), benzyl bromide (1 eq), K ₂ CO ₃ (4 eq) and DMF, the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc, washed with cold water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound e.

¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm 8.56 (s, 1H), 7.31 (m, 5H), 7.18 (s, 1H), 5.19 (s, 2H), 3.59 (t, J =4.30 Hz , 4H), 3.01 (t, J =6.61 Hz, 2H), 2.56 (t, J =6.80 Hz, 2H), 2.43 (t, J =4.30 Hz, 4H)

Compound CIM 1079 (CNC 2037) was prepared in the same manner as in Example 5, except that 2-chlorobenzyl bromide was used instead of benzyl bromide in Example 5.

¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm 8.47 (s, 1H), 7.51 (dd, J =7.50, 1.50 Hz, 1H), 7.32 (m, 2H), 7.19 (s, 1H), 6.99 (d, J =7.17 Hz, 1H), 5.26 (s, 2H), 3.60 (t, J =4.50 Hz, 4H), 3.02 (t, J =6.75 Hz, 2H), 2.57 (t, J =6.71 Hz) , 2H), 2.45 (t, J =4.00 Hz, 4H)

[Example 6] Preparation of compound CIM 1088 (CNC 2038, d)

6-1 Synthesis of compound b

Compound a (1 eq), t-Butylbromoacetate (2 eq), Cs ₂ CO ₃ (2 eq) and DMF were mixed and stirred at 100 ^° C for 2 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound b.

6-2 Synthesis of compound c

After mixing compound b (1 eq) and TFA (62 eq), the mixture was stirred at room temperature for 2 hours. TFA was removed by repeating the addition of DCM to the reaction mixture followed by evaporation. The reaction mixture was dried to obtain compound c.

6-3 Synthesis of Compound d

Compound c (1 eq), 5-amino-2chloro benzotrifluride (1.25 eq), PyBOP (1.25 eq), DIEA (6 eq), DMAP (0.5 eq) and DMF were mixed and stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, DCM/MeOH) to obtain compound d.

¹ H NMR (300 MHz, Acetone) d ppm 10.06 (br. s., 1 H), 8.27 (s, 1 H), 8.22 (d, J =2.23 Hz, 1 H), 7.88 (dd, J =8.52 , 2.28 Hz, 1 H), 7.61 (d, J =8.57 Hz, 1 H), 7.17 (s, 1 H), 4.99 (s, 2 H), 3.67 (t, J =4.47 Hz, 4 H), 3.10 (t, J =5.91 Hz, 2 H), 2.69 (br. s., 2 H), 2.54 (s., 4 H)

[Example 7] Preparation of compound CIM 922 (CNC 2019, c)

7-1 Synthesis of compound b

Compound a (1 eq), Benzyl bromide (1 eq), K ₂ CO ₃ (4 eq) and DMF were mixed and stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc, washed with cold water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound b.

7-2 Synthesis of compound c

Compound b (1 eq), phenyl boronic acid (1.2 eq), K ₂ CO ₃ (2.2 eq), Pd(PPh ₃ ) ₄ (0.053 eq) and H ₂ O/1,4-dioxane were mixed and heated to 110 ^o C was stirred for 4 hours. After reducing the temperature of the reaction mixture to room temperature, it was diluted with EtOAc, washed with a saturated solution of NaHCO ₃ , dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound c.

¹ H NMR (300 MHz, DMSO-d ₆ ) d 8.66 (s, 1H), 7.82 (s, 1H), 7.78 (m, 2H), 7.39 (m, 8H), 5.24 (s, 2H)

The compounds shown in Table 2 below were prepared in the same manner as in Example 7, except that the starting materials used in Example 7 were changed.

compound structure of a compound ¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm CIM 1007 (CNC2024)

8.64 (s, 1H), 7.86 (s, 1H), 7.33 (m, 7H), 7.14 (d, J =6.43 Hz, 1H), 6.96 (s, 1H), 5.24 (s, 2H), 3.75 (m , 4H), 3.20 (m, 4H) CIM 1006 (CNC2023)

8.60 (s, 1H), 7.62 (m, 3H), 7.33 (m, 5H), 7.00 (d, J =8.57 Hz, 2H), 5.22 (s, 2H), 3.74 (t, J =4.70 Hz, 4H) ), 3.18 (t, J =4.70 Hz, 4H) CIM 980 (CNC 2020)

8.66 (m, 1H), 7.79 (s, 1H), 7.67 (m, 2H), 7.37 (m, 7H), 5.29 (t, J =5.96 Hz, 1H), 5.23 (s, 2H), 4.56 (d , J =5.87 Hz, 2H) CIM 1326 (CNC 2902)

8.57 (s, 1H), 7.81 (m, 3H), 7.52 (m, 1H), 7.37 (m, 5H), 7.06 (d, J =5.87 Hz, 1H), 5.30 (s, 2H)

[Example 8] Compound Manufacture of CIM 1009 (CNC 2027, c)

8-1 Synthesis of compound b

After mixing compound a (1 eq) and DMF while stirring at room temperature, PBr ₃ (1.5 eq) was slowly added and stirred at room temperature for 1 hour. The reaction mixture was washed with water to obtain compound b.

8-2 Synthesis of compound c

Compound b (1 eq), 1-acetylpiperazine (1.5 eq), K ₂ CO ₃ (4 eq) and DMF were mixed and stirred at room temperature for 20 hours. The reaction mixture was diluted with DCM, washed with cold water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound c.

¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm 8.66 (s, 1H), 7.81 (s, 1H), 7.68 (m, 2H), 7.37 (m, 7H), 5.24 (s, 2H), 3.56 (s, 2H), 3.44 (m, 4H), 2.40 (t, J =5.40 Hz, 2H), 2.33 (t, J =5.03 Hz, 2H), 1.97 (s, 3H)

The compounds shown in Table 3 were prepared in the same manner as in Example 8, except that the starting materials used in Example 8 were different.

compound structure of a compound ¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm CIM 1010 (CNC 2028)

8.66 (s, 1 H), 7.79 (s, 1 H), 7.65 (m, 2 H), 7.36 (m, 7 H), 5.23 (s, 2 H), 3.62 (s, 2 H), 2.44 ( m, 4 H), 1.70 (m, 4 H) CIM 981 (CNC 2021)

8.66 (s, 1H), 7.81 (s, 1H), 7.67 (m, 2H), 7.38 (m, 7H), 5.23 (s, 2H), 3.58 (t, J =4.28 Hz, 4H), 3.52 (s , 2H), 2.38 (s, 4H) CIM 982 (CNC 2022)

8.66 (s, 1H), 7.79 (s, 1H), 7.65 (m, 2H), 7.35 (m, 7H), 5.23 (s, 2H), 3.48 (s, 2H), 2.34 (t, J =5.5x2 Hz, 4H), 1.51 (m, 4H), 1.39 (m, 2H) CIM 1008 (CNC 2026)

8.67 (s, 1H), 7.82 (s, 1H), 7.67 (m, 2H), 7.44 (t, J =7.64 Hz, 1H), 7.34 (m, 5H), 7.23 (d, J =6.98 Hz, 1H) ), 5.24 (s, 2H), 4.43 (s, 2H), 3.27 (t, J =6.94 Hz, 2H), 2.31 (t, J =8.10 Hz, 2H), 1.93 (m, 2H)

[Example 9] Preparation of compound CIM 1287 (CNC 2087, b)

After mixing compound a (1 eq) and DCM, 1M BBr ₃ in DCM was slowly added at 0 ^o C and stirred at room temperature for 16 hours. After quenching the reaction mixture with water, the pH was adjusted to 7 using a saturated solution of NaHCO ₃ . It was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound b.

¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm 10.94 (s, 1H), 9.73 (s, 1H), 8.44 (s, 1H), 8.19 (d, J =2.33 Hz, 1H), 7.82 (dd , J =8.30, 1.96 Hz, 1H), 7.70 (t, J =4.50 Hz, 2H), 7.25 (m, 2H), 7.11 (s, 1H), 6.80 (d, J =7.08 Hz, 1H), 4.92 (s, 2H)

The compounds shown in Table 4 below were prepared in the same manner as in Example 9, except that the starting materials used in Example 9 were different.

compound structure of a compound ¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm CIM 1304 (CNC 2094)

11.17 (br. s, 1H), 8.44 (s, 1H), 8.21 (d, J =2.42 Hz, 1H), 8.14 (s, 1H), 7.85 (d, J =8.29 Hz, 2H), 7.72 (m , 3H), 7.35 (t, J =7.70 Hz, 1H), 4.94 (s, 2H) CIM 1305 (CNC 2095)

11.03 (s, 1H), 8.47 (s, 1H), 8.19 (s, 1H), 7.98 (m, 3H), 7.86 (m, 3H), 7.70 (d, J =8.94 Hz, 1H), 4.94 (s , 2H)

[Example 10] Preparation of compound CIM 1310 (CNC 2900, b)

After mixing compound a (1 eq) with Tin(II) chloride dehydrate (4.5 eq) and EtOH, the mixture was stirred at 80 ^o C for 20 hours. After the temperature of the reaction mixture was lowered to room temperature, a saturated solution of NaHCO ₃ was used to adjust the pH to 7. It was diluted with EtOAc, washed with water, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound b.

¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm 10.93 (br. s, 1H), 8.35 (s, 1H), 8.18 (d, J =2.14 Hz, 1H), 7.81 (m, 1H), 7.70 (d, J =8.60 Hz, 1H), 7.43 (m, 3H), 6.61 (d, J =8.57 Hz, 2H), 5.52 (s, 2H), 4.89 (s, 2H)

[Example 11] Preparation of compound CIM 1213 (CNC 2061, d)

11-1 Synthesis of compound b

Compound a (1 eq), phenylboronic acid (1.2 eq), K ₂ CO ₃ (2.2 eq), Pd(PPh ₃ ) ₄ (0.05 eq), H ₂ O and 1,4-Dioxane were mixed and heated to 110 ^o C. was stirred for 4 hours. After reducing the temperature of the reaction mixture to room temperature, it was diluted with EtOAc, washed with a saturated solution of NaH ₄ Cl, water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound b.

11-2 Synthesis of compound c

After mixing compound b (1 eq) and TFA (62 eq), the mixture was stirred at room temperature for 2 hours. TFA was removed by repeating the addition of DCM to the reaction mixture followed by evaporation. The crude product was purified by column chromatography (silicagel column, DCM/MeOH) to obtain compound c.

11-3 Synthesis of Compound d

After mixing compound c (1 eq) with aniline (1.25 eq), PyBOP (1.25 eq), DIEA (3 eq), DMAP (0.5 eq) and DMF, the mixture was stirred at room temperature for 20 hours. The reaction mixture was washed with water, and the crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound d.

¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm 10.47 (s, 1H), 8.44 (s, 1H), 7.81 (m, 3H), 7.59 (d, J =7.45 Hz, 2H), 7.47 (t , J =7.70 Hz, 2H), 7.41 (d, J =6.71 Hz, 1H), 7.33 (t, J =7.73 Hz, 2H), 7.08 (t, J =7.31 Hz, 1H), 4.90 (s, 2H) )

The compounds shown in Table 5 were prepared in the same manner as in Example 11, except that the starting materials used in Example 11 were different.

compound structure of a compound ¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm CIM 1218 (CNC 2065)

9.75 (s, 1 H), 8.44 (s, 1 H), 7.85 (s, 1 H), 7.80 (d, J =7.08 Hz, 2 H), 7.47 (m, 2 H), 7.41 (d, J =7.08 Hz, 1 H), 7.21 (s, 1 H), 7.10 (d, J =7.36 Hz, 1 H), 6.92 (d, J =6.80 Hz, 1 H), 4.92 (s, 2 H), 2.24 (s, 3 H), 2.19 (s, 3 H) CIM 1215 (CNC 2062)

10.70 (s, 1 H), 8.44 (s, 1 H), 7.84 (s, 1 H), 7.80 (d, J =7.08 Hz, 2 H), 7.56 (m, 1 H), 7.47 (t, J =7.30 Hz, 2 H), 7.39 (t, J =7.17 Hz, 2 H), 7.32 (t, J =7.60 Hz, 1 H), 6.92 (t, J =8.60 Hz, 1 H), 4.91 (s , 2H) CIM 1216 (CNC 2063)

10.10 (s, 1H), 8.45 (s, 1H), 7.85 (s, 1H), 7.80 (d, J =7.26 Hz, 2H), 7.73 (d, J =8.29 Hz, 1H), 7.53 (d, J =8.10 Hz, 1H), 7.47 (m, 2H), 7.41 (d, J =7.17 Hz, 1H), 7.34 (t, J =7.68 Hz, 1H), 7.21 (t, J =7.30 Hz, 1H), 5.00 (s, 2H) CIM 1217 (CNC 2064)

9.64 (s, 1H), 8.44 (s, 1H), 7.85 (s, 1H), 7.80 (d, J =7.54 Hz, 2H), 7.47 (m, 2H), 7.39 (m, 1H), 7.13 (d , J =7.82 Hz, 1H), 6.93 (t, J =7.45 Hz, 1H), 6.72 (d, J =7.08 Hz, 1H), 6.54 (t, J =7.36 Hz, 1H), 4.93 (s, 2H) ), 4.90 (s, 2H) CIM 1011 (CNC 2025)

10.96 (br. s., 1 H), 8.44 (s, 1 H), 8.19 (s, 1 H), 7.81 (m, 4 H), 7.70 (m, 1 H), 7.47 (m, 2 H) , 7.41 (d, J =6.98 Hz, 1 H), 4.92 (s, 2 H)

[Example 12] Preparation of compound CIM 1206 (CNC 2058, e)

12-1 Synthesis of compound a

After mixing propiophenone (1 eq), ethyl 2-cyanoacetate (1.5 eq), morpholine (1.5 eq), AcOH (0.5 eq) and EtOH, the mixture was stirred at 55 ^° C for 3 hours. Sulfur (1.5 eq) was added 3 times little by little in the same amount and stirred at 55 ^o C for 45 hours. After reducing the temperature of the reaction mixture to room temperature, it was diluted with DCM, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound a.

12-2 Synthesis of compound b

After mixing compound a (1 eq) and formamide (73.5 eq), it was stirred at 200 ^o C for 4 hours. The temperature of the reaction mixture was lowered to room temperature, filtered, and then washed with water to obtain compound b.

12-3 Synthesis of compound c

After mixing compound b (1 eq) with t-Butylbromoacetate (2 eq), C _S2 CO ₃ (1.5 eq) and DMF, the mixture was stirred at 100 ^° C for 5 hours. After reducing the temperature of the reaction mixture to room temperature, it was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound c.

12-4 Synthesis of Compound d

After mixing compound c (1 eq) and TFA (62 eq), the mixture was stirred at room temperature for 2 hours. TFA was removed by repeating the addition of DCM to the reaction mixture followed by evaporation. The crude product was purified by column chromatography (silicagel column, EtOAc/MeOH) to obtain compound d.

12-5 Synthesis of compound e

After mixing compound d (1 eq) with aniline (1.25 eq), PyBOP (1.25 eq), DIEA (3 eq), DMAP (0.5 eq) and DMF, the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound e.

¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm 10.60 (s, 1 H), 8.37 (s, 1 H), 7.52 (m, 1 H), 7.35 (m, 1 H), 7.26 (m, 1 H), 7.17 (d, J =8.66 Hz, 2 H), 6.90 (m, 3 H), 4.78 (s, 2 H), 4.05 (m, 2 H), 2.33 (s, 3 H), 1.34 (t, J = 6.94 Hz, 3 H)

The compounds shown in Table 6 were prepared in the same manner as in Example 12, except that the starting materials used in Example 12 were different.

compound structure of a compound ¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm CIM 1121 (CNC 2042)

9.62 (s, 1 H), 8.37 (s, 1 H), 7.19 (d, J =8.29 Hz, 3 H), 7.07 (d, J =7.54 Hz, 1 H), 6.90 (m, 3 H), 4.81 (s, 2 H), 4.06 (q, J =7.23 Hz, 2 H), 2.32 (s, 3 H), 2.21 (s, 3 H), 2.14 (s, 3 H), 1.35 (t, J =6.75 Hz, 3H) CIM 1205 (CNC 2057)

10.84 (s, 1 H), 8.37 (s, 1 H), 8.15 (d, J =2.14 Hz, 1 H), 7.76 (dd, J =8.60, 2.20 Hz, 1 H), 7.67 (d, J = 8.50 Hz, 1 H), 7.17 (d, J =8.57 Hz, 2 H), 6.90 (d, J =8.57 Hz, 2 H), 4.79 (s, 2 H), 4.04 (q, J =7.08 Hz, 2 H), 2.33 (s, 3 H), 1.33 (t, J =6.94 Hz, 3 H) CIM 1204 (CNC 2056)

10.36 (s, 1H), 8.37 (s, 1H), 7.54 (d, J =7.82 Hz, 2H), 7.30 (t, J =7.78 Hz, 2H), 7.17 (d, J =8.48 Hz, 2H), 7.05 (t, J =7.40, Hz 1H), 6.90 (d, J =8.47 Hz, 2H), 4.77 (s, 2H), 4.04 (q, J =7.02 Hz, 2H), 2.32 (s, 3H), 1.33 (t, J =6.94 Hz, 3H) CIM 883 (CNC 2005)

10.02 (s, 1H), 8.46 (s, 1H), 7.72 (dd, J =8.01,1.68 Hz, 1H), 7.50 (dd, J =7.87,1.44 Hz, 1H), 7.47 (s, 1H), 7.43 (m, 2H), 7.31 (m, 1H), 7.19 (m, 1H), 6.92 (m, 2H), 4.94 (s, 2H), 4.05 (q, J =6.89 Hz, 2H), 1.34 (t, J = 6.98 Hz, 3H) CIM 1211 (CNC 2059)

9.98 (s, 1H), 8.38 (s, 1H), 7.71 (d, J =7.92 Hz, 1H), 7.50 (d, J =7.64 Hz, 1H), 7.30 (t, J =7.68 Hz, 1H), 7.18 (d, J =8.20 Hz, 3H), 6.92 (d, J =8.38 Hz, 2H), 4.88 (s, 2H), 4.05 (q, J =7.14 Hz, 2H), 2.32 (s, 3H), 1.35 (t, J =6.94 Hz, 3H) CIM 884 (CNC 2006)

9.57 (s, 1H), 8.45 (s, 1H), 7.47 (s, 1H), 7.43 (m, 2H), 7.11 (dd, J =7.82, 1.49 Hz, 1H), 6.92 (m, 3H), 6.71 (dd, J =8.01,1.40 Hz, 1H), 6.51 (td, J =7.54,1.49 Hz, 1H), 4.90 (s, 2H), 4.84 (s, 2H), 4.06 (q, J =6.92 Hz, 2H), 1.35 (t, J =6.98 Hz, 3H) CIM 1212 (CNC 2060)

9.53 (s, 1H), 8.37 (s, 1H), 7.19 (d, J =8.38 Hz, 2H), 7.10 (d, J =7.64 Hz, 1H), 6.91 (m, 3H), 6.70 (d, J =8.10 Hz, 1H), 6.50 (t, J =7.31 Hz, 1H), 4.88 (s, 2H), 4.78 (s, 2H), 4.06 (q, J =7.17 Hz, 2H), 2.33 (s, 3H) ), 1.35 (t, J =6.85 Hz, 3H) CIM 902 (CNC 2011)

12.13 (s, 1H), 8.49 (s, 1H), 8.39 (d, J =8.57 Hz, 1H), 8.29 (br. s, 1H), 7.81 (dd, J =7.96, 1.35 Hz, 1H), 7.76 (br. s, 1H), 7.49 (m, 2H), 7.42 (m, 2H), 7.14 (t, J =7.17 Hz, 1H), 6.91 (m, 2H), 4.83 (s, 2H), 4.04 ( q, J =7.02 Hz, 2H), 1.33 (t, J =6.98 Hz, 3H) CIM 882 (CNC 2004)

10.64 (s, 1H), 8.45 (s, 1H), 7.54 (m, 1H), 7.48 (s, 1H), 7.41 (m, 2H), 7.30 (m, 2H), 6.90 (m, 3H), 4.84 (s, 2H), 4.04 (m, 2H), 1.33 (t, J =7.08 Hz, 3H) CIM 862 (CNC 2003)

9.68 (s, 1H), 8.45 (s, 1H), 7.47 (s, 1H), 7.44 (d, J =8.75 Hz, 2H), 7.21 (s, 1H), 7.08 (d, J =7.45 Hz, 1H) ), 6.91 (m, 3H), 4.87 (s, 2H), 4.06 (q, J =6.92 Hz, 2H), 2.21 (s, 3H), 2.16 (s, 3H), 1.34 (t, J =6.98 Hz) , 3H) CIM 901 (CNC 2010)

10.89 (br. s, 1H), 8.45 (s, 1H), 8.16 (d, J =2.24 Hz, 1H), 7.78 (dd, J =9.03, 2.14 Hz, 1H), 7.68 (d, J =9.03 Hz) , 1H), 7.48 (s, 1H), 7.42 (d, J =8.75 Hz, 2H), 6.90 (d, J =8.75 Hz, 2H), 4.86 (s, 2H), 4.04 (q, J =6.86 Hz) , 2H), 1.33 (t, J =6.98 Hz, 3H)

[Example 13] Preparation of compound CIM 903 (CNC 2012, c)

13-1 Synthesis of compound b

After mixing compound a and formamide (73.5 eq), it was stirred at 200 ^o C for 4 hours. The temperature of the reaction mixture was lowered to room temperature. After filtering, the mixture was washed with water to obtain compound b.

13-2 Synthesis of compound c

After mixing compound b (1 eq) with benzyl bromide (2 eq), Cs ₂ CO ₃ (1.5 eq) and DMF, the mixture was stirred at 100 ^o C for 5 hours. After reducing the temperature of the reaction mixture to room temperature, it was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound c.

¹ H NMR (300 MHz, DMSO-d ₆ ) d 8.67 (s, 1H), 7.45 (s, 1H), 7.41 (d, J =8.57 Hz, 2H), 7.31 (m, 5H), 6.91 (d, J =8.57 Hz, 2H), 5.18 (s, 2H), 4.05 (q, J =7.23 Hz, 2H), 1.34 (t, J =6.89 Hz, 3H)

[Example 14] Preparation of compound CIM 1019 (CNC 2029, e)

14-1 Synthesis of compound b

After mixing compound a (1 eq) with formamide (53.3 eq) and AcOH (1.2 eq), the mixture was stirred at 150 ^o C for 20 hours. After dropping the temperature of the reaction mixture to 70 ^° C, water was added. After dropping the temperature of the suspension to room temperature, the resulting solid was filtered and washed with water to obtain compound b.

14-2 Synthesis of compound c

After mixing compound b (1 eq) with t-Butylbromoacetate (2 eq), Cs ₂ CO ₃ (1.5 eq) and DMF, the mixture was stirred at 100 ^° C for 3 hours. After lowering the temperature of the reaction mixture to room temperature, it was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound c.

14-3 Synthesis of Compound d

After mixing compound b (1 eq) and TFA (61.8 eq), the mixture was stirred at room temperature for 2 hours. TFA was removed by repeating the addition of DCM to the reaction mixture followed by evaporation. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound d.

14-4 Synthesis of Compound e

Compound d (1 eq), aniline (1.25 eq), PyBOP (1.5 eq), DIEA (8 eq), DMAP (0.5 eq) and DMF were mixed and stirred at room temperature for 18 hours. It was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound e.

¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm 10.95 (br. s., 1 H), 8.54 (s, 1 H), 8.19 (s 1 H), 7.81 (d, J =9.31 Hz, 1 H), 7.70 (d, J =8.85 Hz, 1 H), 4.89 (s, 2 H), 4.32 (q, J =7.20 Hz, 2 H), 2.82 (s, 3 H), 1.32 (t, J =7.08 Hz, 3H)

The compounds shown in Table 7 below were prepared in the same manner as in Example 14, except that the starting materials used in Example 14 were different.

compound structure of a compound ¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm CIM 1198 (CNC2052)

10.47 (s, 1H), 8.53 (s, 1H), 7.58 (d, J =7.73 Hz, 2H), 7.33 (t, J =7.73 Hz, 2H), 7.08 (t, J =7.60 Hz, 1H), 4.86 (s, 2H), 4.32 (q, J =7.02 Hz, 2H), 2.83 (s, 3H), 1.32 (t, J =7.08 Hz, 3H) CIM 1199 (CNC 2053)

10.10 (s, 1H), 8.55 (s, 1H), 7.74 (dd, J =7.82, 1.30 Hz, 1H), 7.53 (dd, J =7.90, 1.30 Hz, 1H), 7.34 (t, J =8.15 Hz) , 1H), 7.21 (t, J =7.40 Hz, 1H), 4.97 (s, 2H), 4.32 (q, J =7.14 Hz, 2H), 2.84 (s, 3H), 1.32 (t, J =7.12 Hz) , 3H) CIM 1200 (CNC 2054)

10.70 (br. s., 1 H), 8.53 (s, 1 H), 7.55 (d, J =11.64 Hz, 1 H), 7.34 (m, 2 H), 6.92 (t, J =8.15 Hz, 1 H), 4.87 (br. s., 2 H), 4.32 (q, J =7.10 Hz, 2 H), 2.83 (s, 3 H), 1.32 (t, J =7.12 Hz, 3 H) CIM 1201 (CNC 2055)

9.61 (br. s, 1H), 8.53 (s, 1H), 7.14 (d, J =8.29 Hz, 1H), 6.93 (t, J =7.20 Hz, 1H), 6.72 (d, J =8.20 Hz, 1H) ), 6.53 (t, J =7.50 Hz, 1H), 4.92 (s, 2H), 4.87 (s, 2H), 4.32 (q, J =7.30 Hz, 2H), 2.84 (s, 3H), 1.31 (t , J =7.22 Hz, 3H) CIM 1062 (CNC 2035)

9.74 (s, 1H), 8.54 (s, 1H), 7.23 (s, 1H), 7.10 (d, J =7.82 Hz, 1H), 6.91 (d, J =8.29 Hz, 1H), 4.89 (s, 2H) ), 4.32 (q, J =7.26 Hz, 2H), 2.84 (s, 3H), 2.23 (s, 3H), 2.19 (s, 3H), 1.32 (t, J =7.03 Hz, 3H)

[Example 15] Preparation of compound CIM1061 (CNC 2034, b)

Compound a (1 eq), 4-Aminotetrahydropyran hydrochloride (1.25 eq), PyBOP (1.25 eq), DMAP (0.5 eq), DIEA (4.25 eq) and DMF were mixed and stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to prepare the compound CIM 1061 (CNC 2034).

¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm 10.94 (s, 1 H), 8.46 (s, 1 H), 8.20 (m, 2 H), 7.81 (dd, J =8.48, 2.61 Hz, 1 H), 7.71 (d, J =8.66 Hz, 1 H), 4.88 (s, 2 H), 3.97 (d, J =7.64 Hz, 1 H), 3.85 (m, 2 H), 3.40 (m, 2 H) H), 2.66 (s, 3 H), 1.77 (m, 2 H), 1.59 (m, 2 H)

[Example 16] Preparation of compound CIM 1020 (CNC 2030, b)

16-1 Synthesis of compound a

After mixing 4-ethoxyacetophenone (1 eq), ethyl cyanoacetate (1.5 eq), morpholine (1.5 eq), AcOH (1.5 eq) and EtOH, the mixture was stirred at 55 ^o C for 3 hours. Sulfur was added 3 times little by little in the same amount and stirred at 55 ^o C for 12 hours. After reducing the temperature of the reaction mixture to room temperature, it was diluted with DCM, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound a.

16-2 Synthesis of compound b

After mixing compound a with potassium tert-butoxide (0.01 eq) and ethyl cyanoacetate (2 eq), the mixture was stirred at 120 ^o C for 20 minutes using a microwave. After the temperature of the reaction mixture was lowered to room temperature, the pH was adjusted to 7 using HCl. The mixture was filtered and recrystallized with EtOAc, and the crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound b.

¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm 11.17 (br. s, 1H), 7.20 (d, J =8.57 Hz, 2H), 6.91 (t, J =7.60 Hz, 3H), 4.26 (s , 2H), 4.07 (m, 4H), 1.33 (t, J =6.89 Hz, 3H), 0.98 (t, J =7.08 Hz, 3H)

[Example 17] Preparation of compound CIM 1328 (CNC 2904, f)

17-1 Synthesis of compound a

After mixing 2,5-dihydroxy-1,4-dithiane (1 eq), methyl cyanoacetate (1.5 eq) and MeOH, slowly inject Et ₃ N (0.4 eq) at 0 ^o C for 2 hours and 30 minutes and then 40 ^o C and stirred for 1 hour and 30 minutes. The reaction mixture was diluted with DCM (dichloromethane), washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound a.

17-2 Synthesis of compound b

After mixing compound b (1 eq) with THF, phenyl chloroformate (1 eq) was added and stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound b.

17-3 Synthesis of compound c

After mixing compound b (1 eq), AcOH (26.2 eq), and DCM, NBS (1.2 eq) was added at 0 ^o C and stirred at room temperature for 1 hour. After adding water to the reaction mixture, it was diluted with EtOAc, washed with a saturated solution of NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound c.

17-4 Synthesis of Compound d

Compound c (1 eq), 2-Chlorobenzylamine (1.3 eq), Et ₃ N (3 eq) and CHCl ₃ were mixed and stirred at 60 ^° C for 2 hours. The reaction mixture was diluted with DCM, washed with a saturated solution of NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound d.

17-5 Synthesis of compound e

After mixing compound d (1 eq) with Phenylboronic acid (1.1 eq), 2M K ₂ CO ₃ (4.5 eq), Pd(PPh ₃ ) ₄ (0.1 eq) and THF, the mixture was stirred at 85 ^o C for 18 hours. After lowering the temperature of the reaction mixture to room temperature, it was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound e.

Synthesis of 17-6 compound f

After mixing compound e (1 eq) with MeOH, 1M KOH (0.8 eq) was added and stirred at 50 ^° C for 2 hours. Water was added to the reaction mixture, washed with DCM, and adjusted to pH 2 with 1M HCl. After filtering the solid, it was washed with water and DCM to prepare compound f.

¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm 12.55 (s, 1H), 7.67 (m, 3H), 7.47 (m, 3H), 7.29 (m, 3H), 7.03 (dd, J =6.98, 2.61 Hz, 1H), 5.09 (s, 2H)

[Example 18] Compound Manufacture of CIM 1329 (CNC 2910, f)

18-1 Synthesis of compound b

Compound a (1 eq), ethyl 2-aminoacetate hydrochloride (1.3 eq), Et ₃ N (3 eq) and CHCl ₃ were mixed and stirred at 60 ^o C for 2 hours. The reaction mixture was diluted with DCM, washed with a saturated solution of NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound b.

18-2 Synthesis of compound c

After mixing compound b (1 eq) with Phenylboronic acid (1.1 eq), 2M K ₂ CO ₃ (4.5 eq), Pd(PPh ₃ ) ₄ (0.1 eq) and THF, the mixture was stirred at 85 ^o C for 18 hours. After lowering the temperature of the reaction mixture to room temperature, it was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound c.

18-3 Synthesis of Compound d

After mixing compound c (1 eq) with NaOEt (1 eq) and EtOH, the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, washed with DCM, and adjusted to pH 2 with 1M HCl. After filtering the solid, it was washed with water to obtain compound d.

18-4 Synthesis of compound e

After mixing compound d (1 eq) with THF and EtOH, 1M NaOH (2.4 eq) was added and stirred at room temperature for 4 hours. The reaction mixture was adjusted to pH 2 by adding 1M HCl. After filtering the solid, it was washed with water to obtain compound e.

Synthesis of 18-5 compound f

After mixing compound e (1 eq) with 4-chloro-3-(trifluoromethyl)aniline (1.25 eq), PyBOP (1.25 eq), DMAP (0.5 eq), DIEA (3 eq) and DMF, stir at room temperature for 18 hours. made it It was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound f.

¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm 12.53 (br. s, 1H), 10.73 (s, 1H), 8.17 (d, J =1.86 Hz, 1H), 7.80 (m, 1H), 7.68 (m, 3H), 7.63 (s, 1H), 7.43 (t, J =7.30 Hz, 2H), 7.34 (t, J =7.30 Hz, 1H), 4.70 (s, 2H)

[Example 19] Preparation of compound CIM 1327 (CNC 2908, f)

Synthesis of 19-1 compound b

After mixing compound a (1 eq) with THF, phenyl chloroformate (1 eq) was added and stirred at room temperature for 20 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound b.

19-2 Synthesis of compound c

After mixing compound b (1 eq) and AcOH, Br ₂ (3.05 eq) was slowly added at 0 ^o C and stirred at 70 ^o C for 18 hours. The reaction mixture was diluted with EtOAc, washed with a saturated solution of NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound c.

19-3 Synthesis of Compound d

Compound c (1 eq), 2-Chlorobenzylamine (1.3 eq), Et ₃ N (3 eq) and CHCl ₃ were mixed and stirred at 60 ^° C for 19 hours. The reaction mixture was diluted with DCM, washed with a saturated solution of NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound d.

19-4 Synthesis of compound e

After mixing compound d (1 eq) with Phenylboronic acid (1.5 eq), 2M K ₂ CO ₃ (4.5 eq), Pd(PPh ₃ ) ₄ (0.1 eq) and THF, the mixture was stirred at 85 ^o C for 20 hours. After lowering the temperature of the reaction mixture to room temperature, it was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound e.

Synthesis of 19-5 compound f

After mixing compound e (1 eq) with MeOH, 1M KOH (0.8 eq) was added and stirred at 50 ^° C for 2 hours. Water was added to the reaction mixture, washed with DCM, and adjusted to pH 2 with 1M HCl. After filtering the solid, it was washed with water and DCM to obtain compound f.

¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm 12.17 (s, 1H), 7.80 (d, J =8.10 Hz, 2H), 7.51 (m, 4H), 7.29 (m, 3H), 7.02 (d , J =6.89 Hz, 1H), 5.11 (s, 2H)

[Example 20] Preparation of compound CIM 1330 (CNC 2909, f)

20-1 Synthesis of compound b

Compound a (1 eq), ethyl 2-aminoacetate hydrochloride (1.3 eq), Et ₃ N (3 eq) and CHCl ₃ were mixed and stirred at 60 ^o C for 24 hours. The reaction mixture was diluted with DCM, washed with a saturated solution of NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound b.

20-2 Synthesis of compound c

After mixing compound b (1 eq) with NaOEt (1 eq) and EtOH, the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, washed with DCM, and adjusted to pH 2 with 1M HCl. After filtering the solid, it was washed with water to obtain compound c.

20-3 Synthesis of Compound d

After mixing compound c (1 eq) with Phenylboronic acid (1.1 eq), 2M K ₂ CO ₃ (4.5 eq), Pd(PPh ₃ ) ₄ (0.1 eq) and THF, the mixture was stirred at 85 ^o C for 20 hours. After lowering the temperature of the reaction mixture to room temperature, it was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound d.

20-4 Synthesis of Compound e

After mixing compound d (1 eq) with THF and EtOH, 1M NaOH (2.4 eq) was added and stirred at room temperature for 4 hours. The reaction mixture was adjusted to pH 2 by adding 1M HCl, diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The solid was filtered to obtain compound e.

Synthesis of 20-5 compound f

Compound e (1 eq), 4-chloro-3-(trifluoromethyl)aniline (1.25 eq), PyBOP (1.25 eq), DMAP (0.5 eq), DIEA (3 eq) and DMF were mixed and stirred at room temperature for 18 hours. made it It was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound f.

¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm 10.73 (s, 1H), 8.18 (d, J =2.33 Hz, 1H), 7.80 (d, J =7.64 Hz, 3H), 7.68 (d, J =8.38 Hz, 1H), 7.50 (m, 4H), 7.28 (s, 1H), 4.70 (s, 2H)

[Example 21] Preparation of compound CIM 1352 (CNC 2912, f)

21-1 Synthesis of compound b

Compound a was mixed with t-Butyl aminoacetate hydrochloride (1.3 eq), Et ₃ N (3 eq) and CHCl ₃ and stirred at 60 ^o C for 24 hours. The reaction mixture was diluted with DCM (dichloromethane), washed with a saturated solution of NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound b.

21-2 Synthesis of compound c

After mixing compound b (1 eq), Cs ₂ CO ₃ (4 eq), and t-BuOH, the mixture was stirred at 80 ^o C for 18 hours. A saturated solution of NH ₄ Cl was added to the reaction mixture, diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound c.

21-3 Synthesis of Compound d

After mixing compound c (1 eq) and TFA (63 eq), the mixture was stirred at room temperature for 2 hours. TFA was removed by repeating addition of DCM to the reaction mixture followed by evaporation. Ether was added to the concentrated reaction mixture, and the resulting solid was filtered, washed with ether, and dried to obtain compound d.

21-4 Synthesis of compound e

After mixing compound d (1 eq) with 4-chloro-3-(trifluoromethyl)aniline (1.25 eq), PyBOP (1.25 eq), DMAP (0.5 eq), DIEA (4 eq) and DMF, stir at room temperature for 18 hours. made it It was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound e.

21-5 Synthesis of compound f

After mixing compound e (1 eq) with 4-methoxycarbonylphenylboronic acid (1.2 eq), Pd(dppf)Cl ₂ (0.2 eq), 1M Na ₂ CO ₃ (3 eq) and DME, the mixture was stirred at 90 ^o C for 18 hours. . After lowering the temperature of the reaction mixture to room temperature, it was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silicagel column, Hexane/EtOAc) to obtain compound f.

¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm 12.70 (br. s, 1 H), 10.74 (s, 1 H), 8.18 (s, 1 H), 8.01 (m, 4 H), 7.81 (d , J =9.78 Hz, 1 H), 7.68 (d, J =9.78 Hz, 1 H), 7.42 (s, 1 H), 4.71 (s, 2 H), 3.89 (s, 3 H)

[Example 22] In vitro enzyme activity test of the pyrimidin-4-one compound of the present invention

Lactate dehydrogenase A (LDH-A) was purchased in the form of a human recombinant protein from Abcam, and Sodium Pyruvate was purchased from Sigma and prepared as a 100 mM stock, diluted to 5 mM and used to have a final concentration of 1 mM when measuring activity. .

NADH was purchased from Sigma, prepared as a 10 mM stock, diluted to 0.5 mM when measuring activity, and used to have a final concentration of 100 μM.

The absorbance reduction rate by NADH oxidation was measured at 340 nm using a 96 well microplate reader.

Enzyme specific activity was calculated using the change in absorbance for about 1 minute at the beginning of the activity. The mixing order of the components was put into a 96 well plate in the order of buffer solution, LDH-A enzyme, pyrimidin-4-one compound of the present invention, and NADH, and after giving a reaction time of about 7 to 8 minutes, pyruvate was added to the enzyme An active reaction was initiated.

The relative inhibitory ability was verified based on the value measured by adding the same volume (2 μL) of DMSO instead of the pyrimidin-4-one compound of the present invention, and the results (enzymatic activity test results of the compound) are shown in Table 1 was

Enzymatic activity test of compound ( in vitro ) compound Concentration (μM) inhibitory ability
(% inhibition) IC ₅₀ (μM) CIM 1021 (CNC 2031) 10 44 - CIM 1288 (CNC 2088) 10 86 - CIM 1289 (CNC 2089) 10 77 - CIM 1284 (CNC 2084) 10 97 - CIM 1283 (CNC 2083) 10 90 1.53 CIM 1285 (CNC 2085) 10 89 - CIM 1286 (CNC 2086) 10 90 0.84 CIM 1307 (CNC 2097) 10 74 - CIM 1308 (CNC 2098) 10 97 1.80 CIM 1306 (CNC 2096) 10 97 1.06 CIM 1301 (CNC 2091) 10 92 - CIM 1302 (CNC 2092) 10 97 - CIM 1303 (CNC 2093) 10 100 1.29 CIM 1311 (CNC 2901) 10 95 - CIM 1300 (CNC 2090) 10 94 - CIM 1281 (CNC 2081) 10 99 1.94 CIM 1280 (CNC 2080) 10 97 - CIM 1282 (CNC 2082) 10 93 1.49 CIM 1309 (CNC 2099) 10 100 - CIM 1023 (CNC 2033) 10 73 7.45 CIM 922 (CNC 2019) 10 97 7.60 CIM 1006 (CNC 2023) 10 55 - CIM 980 (CNC 2020) 10 21 - CIM 1326 (CNC 2902) 10 37 - CIM 1008 (CNC 2026) 10 34 - CIM 1287 (CNC 2087) 10 72 - CIM 1304 (CNC 2094) 10 45 - CIM 1305 (CNC 2095) 10 88 - CIM 1310 (CNC 2900) 10 93 - CIM 1213 (CNC 2061) 10 91 - CIM 1218 (CNC 2065) 10 95 4.84 CIM 1215 (CNC 2062) 10 100 1.81 CIM 1216 (CNC 2063) 10 93 - CIM 1217 (CNC 2064) 10 97 6.94 CIM 1011 (CNC 2025) 10 100 8.00 CIM 1206 (CNC 2058) 10 48 - CIM 1121 (CNC 2042) 10 91 5.90 CIM 1205 (CNC 2057) 10 89 - CIM 1204 (CNC 2056) 10 32 - CIM 1211 (CNC 2059) 10 8 - CIM 1212 (CNC 2060) 10 13 - CIM 862 (CNC 2003) 10 90 - CIM 901 (CNC 2010) 10 90 - CIM 903 (CNC 2012) 10 20 - CIM 1019 (CNC 2029) 10 99 6.78 CIM 1198 (CNC 2052) 10 28 - CIM 1199 (CNC 2053) 10 76 - CIM 1200 (CNC 2054) 10 95 - 10 95 - CIM 1061 (CNC 2034) 10 30 17.6 CIM 1328 (CNC 2904) 10 100 - CIM 1329 (CNC 2910) 10 96 - CIM 1327 (CNC 2908) 10 99 - CIM 1330 (CNC 2909) 3 93 0.43

-: not measured As can be seen from Table 1, the pyrimidin-4-one compounds of the present invention have excellent values as LDH-A inhibitors and can effectively inhibit the growth of cancer cells.

Therefore, it can be seen that the pyrimidin-4-one compound of the present invention can be usefully used as a target anticancer agent.

In particular the compounds of the present invention CIM 1283 (CNC 2083), CIM 1286 (CNC 2086), CIM 1289 (CNC 2089), CIM 1303 (CNC 2093), CIM 1306 (CNC 2096), CIM 1310 (CNC 2900), CIM 1282 ( CNC 2082), 0.84, CIM 1330 (CNC 2909) is very excellent as an inhibitor and can be usefully used as an anticancer agent.

[Example 23] Cell viability test after treatment with the pyrimidin-4-one compound of the present invention

Cell viability was measured by the pyrimidin-4-one compound of the present invention by cell counting.

After replacing the cultured cell medium with 1mL of RPMI medium containing 10% FBS, the pyrimidin-4-one compound of the present invention was directly treated with 3 uL of 10mM compound in each cultured cell medium so that the final concentration was 30uM, and then 24 After media suction at time (10% dialyzed FBS) and 48 hours (10% FBS), cells were detached by trypsin treatment. After suspension in RPMI (10% heat-inactivated FBS or 10% heat-inactivated dialyzed FBS), the cells were counted using a Countess II FL Automated Cell Counter and the number of cells was recorded. Cell viability by compound was measured by normalizing based on the number of cells treated with DMSO used as a control, and is shown in Table 9 (Results of cell viability test after compound treatment).

compound Concentration (μM) Viability (%) CIM 1288 (CNC 2088) 30 80 CIM 1289 (CNC 2089) 30 90 CIM 1284 (CNC 2084) 30 80 CIM 1283 (CNC 2083) 30 95 CIM 1285 (CNC 2085) 30 80 CIM 1286 (CNC 2086) 30 85 CIM 1280 (CNC 2080) 30 65 CIM 1282 (CNC 2082) 30 85 CIM 1287 (CNC 2087) 30 85 CIM 1011 (CNC 2025) 30 80 CIM 1121 (CNC 2042) 30 80 CIM 902 (CNC 2011) 30 70 CIM 862 (CNC 2003) 30 60 CIM 901 (CNC 2010) 30 95

As shown in Table 9, the pyrimidin-4-one compound of the present invention showed high viability in cell viability test results, and from this, it can be seen that there is little side effect due to little toxicity to normal cells.

[Example 24] Lactate secretion measurement experiment of the pyrimidin-one compound of the present invention

After washing the cultured cell medium twice with serum-free media, 10mM of the pyrimidin-4-one compound of the present invention was added to each cultured cell medium so that the final concentration was 30uM. Directly treated with 3 uL of compound After 6, 12, and 24 hours, 100 ul of the culture medium was recovered and stored at -80 ° C. Lactate measurement was performed at 6 hours, where there was little difference in viability caused by pyrimidin-4-one compounds. When analyzing the results at 12 hours and 24 hours, it was corrected by cell number or protein concentration. The amount of lactate secretion was measured using the EnzyChrom™ Lactate Assay Kit (ECLC-100, Bioassay systems).

The collected culture medium was diluted 1 to 50 times with serum free RPMI according to the expected concentration. After putting 20ul of the diluted sample in a 96-well plate first, 80ul of Reagent mix (assay buffer 60ul, NAD 10ul, MTT 14ul, Enzyme A, B 1ul) was added and measured immediately at RT and 565nm (0min). After incubation at room temperature for 20 minutes, measurement was performed at 565 nm again (20 min). All measurements were performed in duplicate for each pyrimidin-4-one compound. The value obtained by subtracting the value measured at 20 min from the value measured at 0 min was measured for the amount of lactate secretion compared to the standard value, and is shown in Table 10 (Results of experiment for measuring the amount of lactate secretion of compounds).

compound Lactate secretion measurement test of compound (%) CIM 1284 (CNC 2084) 50 CIM 1283 (CNC 2083) 40 CIM 1286 (CNC 2086) 20 CIM 1280 (CNC 2080) 30 CIM 1282 (CNC 2082) 65 CIM 1011 (CNC 2025) 20 CIM 1121 (CNC 2042) 20 CIM 862 (CNC 2003) 50 CIM 901 (CNC 2010) 50

As shown in Table 10, it can be seen that the amount of lactate secretion was significantly reduced, and from this, it can be seen that the pyrimidin-4-one compound of the present invention is effective as an LDH inhibitor.

[Example 25] Evaluation of RIPK1 (Receptor-interating serine/threo nine protein kinase 1) enzyme inhibitory activity of the pyridin-4-one compound of the present invention

In order to evaluate the inhibitory activity of the compounds of the present invention, CIM 1288, CIM 1289 and CIM 1310 on RIPK1 (Receptor-interating serine / threo nine protein kinase 1) enzyme, the following experiments were performed on the example compounds, and the results were It is shown in Table 11 below.

That is, RIP1K (h) was cultured with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.33 mg/mL myelin basic protein, 10 mM Mg acetate and [γ 33 P]-ATP. The reaction was initiated by the addition of the MgATP mixture, and after incubation at room temperature for 40 minutes, the reaction was stopped by the addition of 3% phosphoric acid solution. A total of 10 μL of the reaction was spotted onto a P30 filter mat and used by washing three times for 5 min in 75 mM phosphoric acid and once in methanol before drying and scintillation counting.

compound RIPK1 inhibitory ability
(% inhibition) IC ₅₀
(nM)
CIM 1289

88 1354 CIM 1310

74 1128 CIM 1288

- 2700

As shown in Table 9, it can be seen that among the pyrimidin-4-one compounds of the present invention, CIM 1288, CIM 1289 and CIM 1310 have excellent RIPK1 inhibitory activity and IC50, and thus can be very effective as anticancer agents.

[Example 26] In vitro activity test of compound CIM 1310 (CNC 2900)

Among the pyrimidin-4-one compounds of the present invention, CIM 1310 (CNC 2900), which has excellent effects, was evaluated for its inhibitory effect on cKit, Flt3 (FMS-like tyrosine kinase 3) and RIP1K.

Specifically, cKit(h) and Flt3(h) were incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.33 mg/mL myelin basic protein, 10 mM Mg acetate and [γ 33 P]-ATP. The reaction was initiated by the addition of the MgATP mixture, and after incubation at room temperature for 40 minutes, the reaction was stopped by the addition of 3% phosphoric acid solution. A total of 10 μL of the reaction was spotted onto a P30 filter mat and used three times for 5 min in 75 mM phosphoric acid, washed once in methanol before drying and scintillation counting.

The results are shown in Table 12 below.

IC ₅₀ ((μM) cKit(h) 5 uM Flt3(h) 8 uM RIP1K 1 uM

[Example 27] Activity and cell viability test of compound CIM 1310 (CNC 2900)

The activity and cell viability of CIM 1310 (CNC 2900), a compound with excellent effects among the pyrimidin-4-one compounds of the present invention, were performed on pancreatic cancer cell lines.

Pancreatic cancer cell lines MlAPaCa-2 cells, PANC-1 cells, AsPC-1 cells and BxPC-3 cells (3*10^3 cells/96-well) were cultured in DMEM or RPMI 1640 medium containing 10% FBS. , 0.03, 0.1, 0.3, 1, 3, 10, 30 μM of the compound CIM 1310 (CNC 2900) was exposed for 48 hours. Subsequently, cell viability was measured by MTT assay.

The obtained activity results are shown in Table 13, and the cell viability results are shown in Table 14 below.

MIAPaCa2 PANC1 AsPC1 BxPC3 IC ₅₀ (μM) 4.44 27.90 7.16 1.13

Concentration (μM) MIAPaCa2 PANC1 AsPC1 BxPC3 0 1.00 1.00 1.00 1.OO 0.03 1.10 0.99 0.96 1.16 0.1 1.17 0.96 1.00 1.16 0.3 1.19 0.99 0.97 1.01 One 1.02 0.84 0.73 0.57 3 0.62 0.83 0.65 0.43 10 0.42 0.55 0.41 0.26 30 0.13 0.13 0.08 -0.01

As shown in Tables 13 and 14, the compound of the present invention, CIM 1310, has a surprising activity in pancreatic cancer, and as a result of cell viability experiments, it shows high viability and low toxicity, so it can be seen that it is very useful as an excellent anticancer agent.

As described above, the present invention has been described by specific details and limited embodiments and drawings, but this is only provided to help a more general understanding of the present invention, the present invention is not limited to the above embodiments, and the present invention Those skilled in the art can make various modifications and variations from these descriptions.

Therefore, the spirit of the present invention should not be limited to the described embodiments, and it will be said that not only the claims to be described later, but also all modifications equivalent or equivalent to these claims belong to the scope of the present invention. .

Claims (18)

A pyrimidin-4-one compound represented by Formula 1 below, a solvate thereof, a hydrate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
T is

or

is;
Z is O, S or NR _a ; R _a is hydrogen or C1-C20 alkyl;
L ₁ to L ₂ are each independently a single bond, R _b NCO, CONR _c , SO ₂ , OCO, CO, O, S, C1-C20 alkylene, or C6-C20 arylene, and R _b and R _c are independently of each other hydrogen or C1-C20 alkyl;
R ₁ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, C1-C20alkyl, haloC1-C20alkyl, C1-C20alkylcarbonyl, C1-C20alkoxycarbonyl, C3-C20heteroaryl,

or

is;
Z ₁ is a single bond, CO, CONR _d , R _e NCO or O;
R _d and R _e are independently of each other hydrogen or C1-C20 alkyl;
A ₁ is a single bond, C1-C20 alkylene;
A ₂ is a single bond or C1-C20 alkylene;
R ₁₁ and R ₁₂ independently of each other are hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C20 alkoxycarbonyl, C1-C20 alkyl, haloC1-C20 alkyl, C3-C20 heterocycloalkyl or C1-C20 alkoxy;
Haloalkyl, alkylcarbonyl and heteroaryl of R ₁ to R ₈ and alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₁₁ to R ₁₂ are halogen, amino, cyano, nitro, hydroxy, At least one selected from carboxyl, C1-C20 alkyl, C1-C20 alkoxy, C1-C20 alkylcarbonyl, C3-C20 heterocycloalkyl, C1-C20 heterocycloalkyl, C6-C20 aryl and C3-C20 heteroaryl may be substituted;
o is 0 or 1. According to claim 1,
In Formula 1,
T is

or

is;
Z is O or S;
L ₁ to L ₂ are each independently a single bond, R _b NCO, CONR _c , OCO, O, S or C1-C20 alkylene, and R _b and R _c are independently hydrogen or C1-C20 alkyl;
R ₁ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C3-C20heteroaryl,

or

is;
Z ₁ is a single bond, CO, CONR _d or O;
R _d is hydrogen or C1-C20 alkyl;
A ₁ is C1-C20 alkylene;
A ₂ is a single bond or C1-C20 alkylene;
R ₁₁ and R ₁₂ independently of each other are hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C20 alkoxycarbonyl, C1-C20 alkyl, haloC1-C20 alkyl, C3-C20 heterocycloalkyl or C1-C20 alkoxy;
Haloalkyl and heteroaryl of R ₁ to R ₈ and alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₁₁ to R ₁₂ are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1 -C20 Alkyl, C1-C20 Alkoxy or C1-C20 It may be substituted with one or more selected from alkyl carbonyl;
o is 0 or 1, a pyrimidin-4-one compound, a solvate thereof, a hydrate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof. According to claim 1,
Formula 1 is a pyrimidin-4-one compound represented by Formula 2 or 3, a solvate thereof, a hydrate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 2]

[Formula 3]

In Formula 2 or 3,
Z is O or S;
L ₁ to L ₂ are each independently a single bond, R _b NCO, CONR _c , OCO, O, S or C1-C20 alkylene, and R _b and R _c are independently hydrogen or C1-C20 alkyl;
R ₁ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C3-C20heteroaryl,

or

is;
Z ₁ is a single bond, CO, CONR _d or O;
R _d is hydrogen or C1-C20 alkyl;
A ₁ is C1-C20 alkylene;
A ₂ is a single bond or C1-C20 alkylene;
R ₁₁ and R ₁₂ independently of each other are hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C20 alkoxycarbonyl, C1-C20 alkyl, haloC1-C20 alkyl, C3-C20 heterocycloalkyl or C1-C20 alkoxy;
Haloalkyl and heteroaryl of R ₁ to R ₈ and alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₁₁ to R ₁₂ are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1 -C20 Alkyl, C1-C20 Alkoxy or C1-C20 It may be substituted with one or more selected from alkyl carbonyl;
o is 0 or 1. According to claim 3,
In Formulas 2 and 3,
Z is S;
L ₁ to L ₂ are each independently a single bond, R _b NCO, CONR _c , OCO or C1-C20 alkylene, R _b and R _c are independently hydrogen or C1-C10 alkyl;
R ₁ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C3-C20heteroaryl,

or

is;
Z ₁ is a single bond, CO or CONR _d ;
R _d is hydrogen or C1-C10 alkyl;
A ₁ is C1-C10 alkylene;
A ₂ is a single bond or C1-C10 alkylene;
R ₁₁ and R ₁₂ independently of each other are hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C10 alkoxycarbonyl, C1-C10 alkyl, haloC1-C10 alkyl, C3-C10 heterocycloalkyl or C1-C10 alkoxy;
Haloalkyl and heteroaryl of R ₁ to R ₈ and alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₁₁ to R ₁₂ are C1-C20alkyl, C1-C20alkoxy or C1-C20alkylcarbonyl It may be substituted with one or more selected from;
o is 0 or 1, a pyrimidin-4-one compound, a solvate thereof, a hydrate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof. According to claim 1,
Formula 1 is a pyrimidin-4-one compound represented by Formulas 4 to 7, a solvate thereof, a hydrate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

In Formulas 4 to 7,
Z is O or S;
R ₁ is hydrogen or

is;
R ₂ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C3-C20heteroaryl,

or

is;
Z ₁₁ is a single bond, CO, CONR _d or O;
R _d is hydrogen or C1-C20 alkyl;
A ₁₁ to A ₁₃ are each independently C1-C20 alkylene;
R ₂₁ to R ₂₃ are each independently hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C20 alkoxycarbonyl, C1-C20 alkyl, haloC1-C20 alkyl, C3-C20 heterocycloalkyl or C1-C20 alkoxy;
n and m are independently of each other an integer from 0 to 10;
The R ₂ to R ₈ haloalkyl and heteroaryl and R ₂₁ to R ₂₃ alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1 -C20 Alkyl, C1-C20 Alkoxy or C1-C20 It may be substituted with one or more selected from alkyl carbonyl. According to claim 5,
In Formulas 4 to 7,
Z is S;
R ₁ is hydrogen or

is;
R ₂ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C3-C20heteroaryl,

or

is;
Z ₁₁ is a single bond, CO or CONR _d ;
R _d is hydrogen or C1-C20 alkyl;
A ₁₁ to A ₁₃ are each independently C1-C20 alkylene;
R ₂₁ to R ₂₃ are each independently hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C20 alkoxycarbonyl, C1-C20 alkyl, haloC1-C20 alkyl, C3-C20 heterocycloalkyl or C1-C20 alkoxy;
n and m are independently of each other an integer from 1 to 7;
The R ₂ to R ₈ haloalkyl and heteroaryl and R ₂₁ to R ₂₃ alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1 -C20 Alkyl, C1-C20 Alkoxy or C1-C20 A pyrimidin-4-one compound, which may be substituted with one or more selected from alkoxy or C1-C20 alkylcarbonyl, a solvate thereof, a hydrate thereof, a prodrug thereof, an isomer thereof or a pharmaceutical thereof an acceptable salt. According to claim 5,
In Formulas 4 to 7,
Z is S;
R ₁ is hydrogen or

is;
R ₂ is hydrogen, C1-C20 alkyl or

is;
R ₃ is hydrogen, halogen, C3-C20 heteroaryl,

or

is;
R ₄ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl or haloC1-C20alkyl;
Z ₁₁ is a single bond, CO or CONR _d ;
R _d is hydrogen or C1-C20 alkyl;
A ₁₁ to A ₁₃ are each independently C1-C20 alkylene;
R ₂₁ to R ₂₃ are each independently hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C20 alkoxycarbonyl, C1-C20 alkyl, haloC1-C20 alkyl, C3-C20 heterocycloalkyl or C1-C20 alkoxy;
n and m are independently of each other an integer from 1 to 7;
Alkyl of R ₂ , haloalkyl of R ₃ , heteroaryl of R ₈ and alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₂₁ to R ₂₃ are halogen, amino, cyano, nitro, hydroxy A pyrimidin-4-one compound, a solvate thereof, a hydrate thereof, a prodrug thereof, which may be substituted with one or more selected from carboxyl, C1-C20 alkyl, C1-C20 alkoxy or C1-C20 alkylcarbonyl, Isomers thereof or pharmaceutically acceptable salts thereof. According to claim 1,
Formula 1 is a pyrimidin-4-one compound represented by Formula 8 or Formula 9 below, a solvate thereof, a hydrate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof.
[Formula 8]

[Formula 9]

In Chemical Formulas 8 and 9
L ₁ to L ₂ are each independently a single bond, R _b NCO, CONR _c , SO ₂ , OCO, CO, O, S, C1-C20 alkylene, or C6-C20 arylene, and R _b and R _c are independently of each other hydrogen or C1-C20 alkyl;
D ₁ and D ₂ are each independently N or CR ₁₆ ; except when D ₁ and D ₂ are simultaneously N;
R ₄ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C1-C20alkyl or C1-C20alkylcarbonyl;
R ₁₄ to R ₁₈ and R ₂₄ to R ₂₈ are each independently hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C20 alkoxycarbonyl, C1-C20 alkyl, haloC1-C20 alkyl, C3 -C20 heterocycloalkyl or C1-C20 alkoxy;
The R ₁₄ to R ₁₈ and R ₂₄ to R ₂₈ alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1-C20 alkyl, C1- It may be substituted with one or more selected from C20 alkoxy, C1-C20 alkylcarbonyl, C3-C20 heterocycloalkyl, C3-C20 heterocycloalkyl, C6-C20 aryl and C3-C20 heteroaryl;
p and q are independently integers of 0 or 1, except when p and q are 0 at the same time. According to claim 8,
In Formulas 8 to 9,
L ₁ to L ₂ are each independently a single bond, R _b NCO, CONR _c , OCO or C1-C20 alkylene, R _b and R _c are independently hydrogen or C1-C10 alkyl;
D ₁ and D ₂ are each independently N or CR ₁₆ ; except when D ₁ and D ₂ are simultaneously N;
R ₄ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C1-C20alkyl or C1-C20alkylcarbonyl;
R ₁₄ to R ₁₈ and R ₂₄ to R ₂₈ are each independently hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C20 alkoxycarbonyl, C1-C20 alkyl, haloC1-C20 alkyl, C3 -C20 heterocycloalkyl or C1-C20 alkoxy;
The R ₁₄ to R ₁₈ and R ₂₄ to R ₂₈ alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1-C20 alkyl, C1- It may be substituted with one or more selected from C20 alkoxy, C1-C20 alkylcarbonyl, C3-C20 heterocycloalkyl, C1-C20 heterocycloalkyl, C6-C20 aryl and C3-C20 heteroaryl;
p and q are each independently an integer of 0 or 1, and a pyrimidin-4-one compound, a solvate thereof, a hydrate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutical product thereof, except when p and q are 0 at the same time acceptable salts. According to claim 1,
Formula 1 is a pyrimidin-4-one compound represented by Formula 10, a solvate thereof, a hydrate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof.
[Formula 10]

In Formula 10,
D ₁ and D ₂ are each independently N or CR ₁₆ ;
R ₄ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C1-C20alkyl or C1-C20alkylcarbonyl;
R ₁₄ to R ₁₇ are each independently hydrogen, hydroxy, amino, nitro, cyano, carboxylic acid group, C1-C20 alkoxycarbonyl, C1-C20 alkyl, haloC1-C20 alkyl, C3-C20 heterocycloalkyl or C1-C20 alkoxy;
The R ₁₄ to R ₁₇ Alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1-C20 Alkyl, C1-C20 Alkoxy, C1-C20 It may be substituted with one or more selected from alkylcarbonyl, C3-C20heterocycloalkyl, C1-C20heterocycloalkyl, C6-C20aryl and C3-C20heteroaryl;
n is 0 or 1;
m is an integer from 1 to 5; According to claim 1,
The pyrimidin-4-one compound is a pyrimidin-4-one compound selected from the following compounds, a hydrate thereof, a solvate thereof, an isomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof:

. A pyrimidin-4-one compound according to any one of claims 1 to 11, a hydrate thereof, a solvate thereof, an isomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, containing as an active ingredient Anticancer agent composition, characterized in that. According to claim 12,
The pyrimidin-4-one compound, a hydrate thereof, a solvate thereof, an isomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof is contained in an amount of 0.001 to 10% by weight based on the total weight of the anticancer composition. According to claim 12,
The anticancer composition is an anticancer agent for preventing and treating any one or two or more diseases selected from lung cancer, liver cancer, breast cancer, colon cancer, colorectal cancer, rectal cancer, colon cancer, bladder cancer, cervical cancer, osteosarcoma, leukemia, myelogenous leukemia, melanoma, and gastric cancer composition. According to claim 12,
The anticancer composition further comprises a pharmaceutically acceptable excipient. According to claim 11,
The anti-cancer composition is a therapeutic composition further comprising a chemotherapeutic agent. According to claim 16,
Wherein the chemotherapeutic agent is one or two or more selected from alkylating agents, metabolic antagonists, antitumor antibiotics, mitotic inhibitors, hormones, cisplatin, L-asparaginase and mTor inhibitors. An anti-cancer kit comprising the anti-cancer composition of claim 12 and a chemotherapeutic agent.