KR102649886B1 - 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 drug composition containing the same. An anticancer composition containing a pyrimidin-4-one compound is very useful as a targeted anticancer treatment agent.

Description

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 containing the same.

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

Cancer is one of the incurable diseases that humanity must solve, and the development of effective treatments for cancer is required.

Treatment of cancer mainly involves surgery or chemotherapy that inhibits cell proliferation (cytotoxic chemotherapy).

Chemotherapy is a treatment that kills cancer cells by using chemicals that kill fast-growing cells (cytotoxic anticancer agents), but since it is not a targeted treatment that acts directly on the target where each cancer originates, repeated chemotherapy treatments may cause cytotoxicity. Despite the initial successful response to the anticancer drugs used during chemotherapy, if the cancer is prolonged or relapses, side effects due to cytotoxicity and drug resistance develop. There was a problem that ultimately caused the treatment to fail.

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

Meanwhile, the production of lactate within 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. It exists in form.

In particular, in the case of LDHA, it was confirmed that its expression was significantly increased in cancer cells, and its expression was known to increase due to the hypoxic reaction that induces malignant cancer.

Therefore, there is a very high possibility that targeting LDHA, which has high cancer specificity, can reduce the side effects of inhibiting the metabolism of normal cells compared to other metabolism-regulating enzymes.

Furthermore, in people with genetically impaired LDHA function, no serious pathological symptoms other than motor muscle disease have been reported (Kanno et al, 173(1), 89-93, 1988, Clin Chim Acta), so it can be used as a target for anticancer treatment. There is a very low possibility of toxic and side effects of concern when using LDHA.

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

Recently, it has been reported that the use of LDHA activity inhibitors together with NAMPT (Nicotinamide phosphoribosyltransferase) inhibitors significantly inhibits cancer growth in mouse models, drawing more attention to the use of LDHA as an anticancer targeting agent.

In addition, studies have reported that extracellular lactate can be used as a growth material for adjacent cancer cells, thereby inducing a deficit in energy supplied to cancer cells within the tumor through lactate growth inhibition (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 novel pyrimidin-4-one compounds, solvates thereof, hydrates thereof, prodrugs thereof, isomers thereof or pharmaceutically acceptable salts thereof.

Additionally, the present invention provides an anticancer composition comprising the novel pyrimidin-4-one compound of the present invention, its solvate, its hydrate, its prodrug, its isomer, or its pharmaceutically acceptable salt.

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

[Formula 1]

(In Formula 1 above,

T is or and;

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

L ₁ to L ₂ are 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 They are independently hydrogen or C1-C20 alkyl;

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

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

R _d and R _e are independently hydrogen or C1-C20alkyl;

A ₁ is C1-C20 alkylene;

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

R ₁₁ and R ₁₂ are independently of each other 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 haloalkyl, alkylcarbonyl and heteroaryl of R ₁ to R ₈ and the 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. Can be substituted;

c is 0 or 1)

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

Additionally, the present invention provides an anticancer kit containing the anticancer composition of the present invention and a chemotherapy 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 to inhibit the growth of cancer cells. It suppresses.

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 the metabolism of normal cells and has significantly low toxicity and side effects.

Therefore, the anticancer drug composition containing the pyrimidin-4-one compound of the present invention, its solvate, its hydrate, its prodrug, its isomer, or its pharmaceutically acceptable salt can be used as an effective cancer-targeted treatment.

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 and scientific terms used, they have meanings commonly understood by those skilled in the art to which this invention pertains, and the following description will not unnecessarily obscure the gist of the present invention. Descriptions of possible notification functions and configurations are omitted.

The following terms used in this specification are defined as follows, but this is merely illustrative and is 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 carbon number is specifically limited). It refers to 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 alkyls include -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-dethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, Includes 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 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 term “haloalkyl” or “haloalkoxy” refers to an alkyl or alkoxy group, respectively, in which one or more hydrogen atoms are replaced with a halogen atom. 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 similar It includes where alkyl and halogen are as defined above.

The term “alkoxy” used in this specification includes -OCH ₃ , -OCH ₂ CH ₃ , -O(CH ₂ ) ₂ CH ₃ , -O(CH ₂ ) ₃ CH ₃ , -O(CH ₂ ) ₄ CH ₃ , means -O-(alkyl), including -O(CH ₂ ) ₅ CH ₃ , and the like, where alkyl is as defined above. As used herein, the term "lower alkoxy" means -O-(lower alkyl), where 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, etc. Including but not limited to this. The carbocyclic aromatic group may be optionally substituted.

As used herein, the term “cycloalkyl” refers to a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and no carbon-carbon multiple bonds. Examples of cycloalkyl groups include, but are not limited to, (C3-C10)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl). Cycloalkyl groups may be optionally substituted. In one embodiment, the cycloalkyl group is a monocyclic or bicyclic ring.

As used herein, the term "heterocycloalkyl" refers to a group consisting of 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. A stable 3- to 18-membered saturated or partially unsaturated group of 1 to 6 heteroatoms, for example 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. Refers to radicals. Exemplary heterocycloalkyls 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, radicals, stable 7-membered saturated or partially unsaturated radicals, stable 6-membered saturated or partially unsaturated radicals, or stable 5-membered saturated or partially unsaturated radicals.

As used herein, the terms “carboxylic acid,” “carboxyl,” and “carboxy” refer to -COOH.

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

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

As used herein, the term “substituted” means that the hydrogen atom of the portion being substituted (e.g., alkyl, aryl, heteroaryl, heterocycle, or cycloalkyl) is replaced with a substituent. In one embodiment, each carbon atom of a substituted group is not substituted with more than two substituents. In other embodiments, each carbon atom of a substituted group is not substituted with more than one substituent. In the case of a keto substituent, two hydrogen atoms are replaced by oxygen, which is attached to the carbon by a double bond. Unless otherwise stated 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 (e.g., sulfoximine), -S(NR _a1 )R _b1 (e.g., sulfilimine), and -SR _a1 may be used, where R _a1 and R _b1 may be the same or different, and may independently be hydrogen, halogen, amino, alkyl, alkoxyalkyl, haloalkyl, aryl, or heterocycle, or R _a1 and R _b1 together with the attached nitrogen atom may be in the form of a heterocycle. You can. Here, R _a1 and R _b1 may be plural depending on the bonded atom, 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- C20alkyl, haloC1-C20alkyl, C3-C10heterocyclocarbonyl, allyl amino, C1-C20alkylsulfonyl, aminosulfonyl, aminoC1-C20alkyl, hydroxyC1-C20alkyl, dihydroxyC1-C20 Alkyl, cyanoC1-C20alkyl, C1-C20alkylamino, diC1-C20alkylamino, C6-C20arylamino, diC6-C20arylamino, C3-C20heteroaryl, haloC6-C20aryl, halo C1- C20alkylC6-C20aryl, C6-C20aryl, C3-C10cycloalkyl, C3-C10cycloalkylcarbonyl, C1-C20alkoxycarbonylC1-C20alkyl and carboxylic acidC1-C20alkyl. There may be more than one selected.

As used herein, “pharmaceutically acceptable salts” include salts of the 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 can be prepared by contacting the neutral form of such compounds with a sufficient amount of the desired base, neat or with 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 the 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, pure or with a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include acetic acid, propionic acid, isobutyric acid, oxalic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, and fumaric acid. ), mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric acid, tartaric acid, methanesulfonic, and analogs thereof. Salts derived from toxic organic acids include hydrogen chloride, hydrogen bromide, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogencarbonic acid, dihydrogenphosphate, sulfuric acid, monohydrosulfuric acid, hydrogen iodide or phosphorous acid. 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 specific compounds of the invention have both basic and acidic functionality, allowing the compounds to be converted to basic or acidic addition salts. Other examples of salts can be found in literature known in the art, such as Remington's Pharmaceutical Sciences, 18th 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” is an animal (e.g., a cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, or guinea pig), preferably Non-primates and mammals such as primates (e.g. monkeys and humans), most preferably humans.

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

“Effective amount” also refers to the 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 preventing the recurrence, spread, or development of cancer in a patient.

As used herein, “treatment” includes killing and inhibiting cancer cells.

As used herein, the term “pyrimidin-4-one compound of the present invention” refers to each compound of Formulas 1 to 10, as well as their clathrates, hydrates, solvates, prodrugs or polymorphs. It means including. In addition, the term "pyrimidin-4-one compound of the present invention" is meant to also include pharmaceutically acceptable salts of the pyrimidin-4-one compound of the present invention when a pharmaceutically acceptable salt thereof is not mentioned. In one embodiment, the pyrimidin-4-one compounds of the invention are stereomerically pure compounds (e.g., substantially free of other stereoisomers (e.g., 85% ee or greater, 90% ee or greater, 95% ee or greater). % ee or greater, 97% ee or greater, or 99% ee or greater). 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 (e.g., 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. If the pyrimidin-4-one compound of the present invention or its salt has an asymmetric carbon in the structure, their optically active compounds and racemic mixtures are also included within the scope of the compound of the present invention. For example, if 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 within the scope of the compounds of the present invention.

Additionally, the pyrimidin-4-one compounds of the present invention may exist in either Keto form or 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 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., thermal or light stability), compressibility and density (important in formulation and product manufacturing), and dissolution rate (which may affect bioavailability). It doesn't work. Differences in stability may be due to changes in chemical reactivity (e.g., differential oxidation, such as faster discoloration in one polymorph than in another polymorph) or in mechanical properties (e.g., kinetics). This results in conversion of tablet fragments stored as the preferred polymorph to the thermodynamically more stable polyform) or both (tablets of one polyform 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, for example, due to its shape or particle size distribution.

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

As used herein, the term “hydrate” refers to the pyrimidin-4-one compound of the present invention containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces, or its pharmaceutical form. 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 (e.g., channels) that confine guest molecules (e.g., solvent or water). means a midin-4-one compound or a salt thereof.

If a compound (prodrug) is isolated in the body to produce the pyrimidin-4-one compound of the present invention or a salt thereof, such compound is also included within the scope of the present invention. As used herein and unless otherwise indicated, the term "prodrug" refers to a substance that is hydrolyzed, oxidized and undergoes other reactions under biological conditions (in vitro or in vivo) to provide an active compound, especially a compound of the invention. It refers to the pyrimidin-4-one compound of the present invention that can be used. Examples of prodrugs are biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, and biohydrolyzable esters. Includes compounds that biohydrolyze to produce the pyrimidin-4-one compounds of the invention, including biohydrolyzable moieties, such as biohydrolyzable ureides, and biohydrolyzable phosphate analogs. However, it is not limited to these specific aspects. Preferably, the prodrug of the pyrimidin-4-one compound having a carboxyl group functional group is a lower alkyl ester of carboxylic acid. Carboxylic esters are usually formed by esterifying a portion of the carboxylic acid present in the 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, it means more than 99.9% pure.

As used herein, the term “hydrido” refers to a single -H atom (H) and can be used interchangeably with the symbol “H” or the term “hydrogen.”

As used herein, the singular forms “a” and “an” include plural forms 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 agency for such use. This means that it is listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

To provide a novel pyrimidin-4-one compound, its solvate, hydrate, prodrug, isomer or pharmaceutically acceptable salt thereof, which has 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 the following formula (1).

[Formula 1]

(In Formula 1 above,

T is or and;

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

L ₁ to L ₂ are 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 They are independently hydrogen or C1-C20 alkyl;

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

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

R _d and R _e are independently hydrogen or C1-C20alkyl;

A ₁ is C1-C20 alkylene;

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

R ₁₁ and R ₁₂ are independently of each other 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 haloalkyl, alkylcarbonyl and heteroaryl of R ₁ to R ₈ and the 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. Can be substituted;

ｏ is 0 or 　１)

The novel pyrimidin-4-one compound of the present invention has very high activity as an LDHA inhibitor, and an anticancer drug composition containing it is very useful as a targeted treatment.

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

Preferably, in Formula 1 according to an embodiment of the present invention, T is or and; Ｚ is O or S; L ₁ to L ₂ are 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 independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C3-C20heteroaryl, or and; 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 are independently of each other 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 haloalkyl and heteroaryl of R ₁ to R ₈ and the alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₁₁ to R ₁₂ are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1 -It may be substituted with one or more selected from C20 alkyl, C1-C20 alkoxy, or C1-C20 alkylcarbonyl; l may be 0 or 1.

More preferably, in Formula 1 according to an embodiment of the present invention, Z is S; L ₁ to L ₂ are 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 independently hydrogen, halogen, amino , aminocarbonyl, haloC1-C20alkyl, C3-C20heteroaryl, or and; 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 are independently of each other 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 haloalkyl and heteroaryl of R ₁ to R ₈ and the 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, and l 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 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 independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C3-C20heteroaryl, or and;

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 are independently of each other 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 haloalkyl and heteroaryl of R ₁ to R ₈ and the 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 alkylcarbonyl may be substituted with one or more selected from;

ｏ is 　0 or 　1.)

More preferably, in Formulas 2 and 3 according to an embodiment of the present invention, Z is S; L ₁ to L ₂ are 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; R ₁ to R ₈ are independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C3-C20heteroaryl, or and; 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 are independently of each other 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 haloalkyl and heteroaryl of R ₁ to R ₈ and the alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₁₁ to R ₁₂ are C1-C20 alkyl, C1-C20 alkoxy or C1-C20 alkylcarbonyl. It may be substituted with one or more selected from ｏ and may be 0 or 1.

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

[Formula 4]

［Chemical formula 5］

[Formula 6]

[Formula 7]

(In the above formulas 4 to 7,

Z is O or S;

R ₁ is hydrogen or and;

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

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 selected from 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 integers from 0 to 10;

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

Preferably, in Chemical Formulas 4 to 7 according to an embodiment of the present invention, Z is S; R ₁ is hydrogen or and; R ₂ to R ₈ are independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C3-C20heteroaryl, or and; 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 selected from 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 integers from 1 to 7; The haloalkyl and heteroaryl of R ₂ to R ₈ and the alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₂₁ to R ₂₃ are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1 -It may be substituted with one or more selected from C20 alkyl, C1-C20 alkoxy or C1-C20 alkylcarbonyl,

More preferably, Z is S; R ₁ is hydrogen or and; R ₂ is hydrogen, C1-C20 alkyl, or and; R ₃ is hydrogen, halogen, C3-C20heteroaryl, or and; R ₄ to R ₈ are 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 selected from 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 integers from 1 to 5; The alkyl of R ₂ , the haloalkyl of R ₃ , the heteroaryl of R ₈ and the alkyl of R ₂₁ to R ₂₃ , alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl 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.

More preferably, in Chemical Formulas 4 to 7 according to an embodiment of the present invention, Z is S; R ₁ is hydrogen or and; R ₂ is hydrogen, C1-C10 alkyl, or and; R ₃ is hydrogen, halogen, C3-C12heteroaryl, or and; R ₄ to R ₈ are 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 selected from 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 integers from 1 to 5; The alkyl of R ₂ , the haloalkyl of R ₃ , the heteroaryl of R ₈ and the alkyl of R ₂₁ to R ₂₃ , 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 better effect as an LDH-A inhibitor, Formula 1 according to an embodiment of the present invention may be preferably represented by Formula 8 or Formula 9 below.

[Formula 8]

［Chemical formula 9］

(In Formulas 8 to 9 above,

L ₁ to L ₂ are 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 They are independently hydrogen or C1-C20 alkyl;

D ₁ and D ₂ are independently N or CR ₁₆ ; Except for the case where D ₁ and D ₂ are simultaneously N;

R ₄ to R ₈ are 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 hydrogen or C1-C20alkyl;

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 -C20heterocycloalkyl or C1-C20alkoxy;

The alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₁₄ to R ₁₈ and R ₂₄ to R ₂₈ are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1-C20alkyl, 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, excluding cases where p and q are 0 at the same time.)

Preferably, in the chemical formula 8 or 9 according to an embodiment of the present invention, L ₁ to L ₂ are 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 independently N or CR ₁₆ ; Except for the case where D ₁ and D ₂ are simultaneously N; R ₄ to R ₈ are 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 -C20heterocycloalkyl or C1-C20alkoxy; The alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₁₄ to R ₁₈ and R ₂₄ to R ₂₈ are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1-C20alkyl, 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 other Independently, it is an integer of 0 or 1, and cases where p and q are 0 at the same time may be excluded,

More preferably, L ₁ to L ₂ are independently a single bond, R _b NCO, OCO or C1-C10 alkylene, and R _b and R _c are independently hydrogen or C1-C5 alkyl; D ₁ and D ₂ are independently N or CR ₁₆ ; Except for the case where D ₁ and D ₂ are simultaneously N; R ₄ to R ₈ are 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 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 alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₁₄ to R ₁₈ and R ₂₄ to R ₂₈ are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1-C20alkyl, C1- It may be substituted with one or more selected from C10 alkoxy, C1-C10 alkylcarbonyl, C3-C10 heterocycloalkyl, C1-C10 heterocycloalkyl, C6-C12 aryl and C3-C12 heteroaryl; p and q are each other Independently, it is an integer of 0 or 1, and may be excluded if p and q are simultaneously 0. More preferably, Chemical Formula 1 according to an embodiment of the present invention may be expressed as Chemical Formula 10 below.

[Formula 10]

(In Formula 10 above,

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

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

R ₁₄ to R ₁₇ are each independently selected from 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 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-C20 heterocycloalkyl, C1-C20 heterocycloalkyl, C6-C20 aryl, and C3-C20 heteroaryl;

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 independently N or CR ₁₆ , excluding the case where D ₁ and D ₂ are both N; R ₄ to R ₈ are independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C10alkyl, C1-C10alkyl, or C1-C10alkylcarbonyl; R ₁₄ to R ₁₇ are each independently selected from 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 alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₁₄ to R ₁₇ 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-C10 heterocycloalkyl, C1-C10 heterocycloalkyl, C6-C12 aryl and C3-C12 heteroaryl; n is 0 or 1; m may be an integer of 1 to 5, and more preferably, the alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₁₄ to R ₁₇ 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.

The method for producing the pyrimidin-4-one compound according to an embodiment of the present invention can be any synthetic method recognized by a person 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 reactant, the type of solvent, and the amount of solvent. For example, the starting material is completely dissolved through TLC, etc. After confirming that it is consumed, the reaction is completed. When the reaction is complete, the solvent can be distilled off under reduced pressure, and then the target product can be separated and purified through a conventional method such as column chromatography.

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

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

Preferably, the novel pyrimidin-4-one compound of the present invention contained in the anticancer drug composition according to an embodiment of the present invention is present in an amount of 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 an amount of 0.1 to 5% by weight.

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

The excipient according to one embodiment of the present invention may be any inert or inactive material used in the manufacture of pharmaceutical products, and may include, but is not limited to, a binder, disintegrant, coating agent, pyroxene, compression/encapsulation agent, cream or lotion, Includes 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, etc.; Coating agents include, for example, cellulose acetate phthalate, ethylcellulose, gellan rubber, maltodextrin, etc.; Compression/encapsulation agents include, for example, calcium carbonate, dextrose, fructose, honey, lactose (anhydrous or monohydrate; optionally in combination with aspartame, cellulose or microcrystalline cellulose), starch, sucrose, etc.; Disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; Creams and lotions contain, for example, maltodextrin, carrageenan, etc.; Lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; Chewable tablets include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; Parenteral agents include, for example, mannitol, povidone, etc.; Plasticizers include, for example, dibutyl sebacate, polyvinylacetate phthalate, etc.; Suspending/gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; Sweeteners include, for example, aspartame, dextrose, fructose, sorbitol, sucrose, etc.; Wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

Of course, the anti-cancer composition according to an embodiment of the present invention can use appropriate excipients in any amount depending on the route of administration.

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

Chemotherapeutic agents according to an embodiment of the present invention may be any agent recognized by a person 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 that have the ability to introduce an alkyl group R-CH ₂ into any compound. When applied to cells, most of them react with N7 of guanine in DNA to form DNA. It modifies the structure and causes chain scission to exhibit anti-cancer and cytotoxic effects. Specific examples include carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, It may be one or more than one selected from dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, aotepa, bendamustine and streptozocin.

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

The antitumor antibiotics (Antibiotics) are those that exhibit anticancer activity among antibiotics produced by bacteria. Examples include bleomycin, doxorubicin, daunorbicin, idarubicin, mitoxantrone, dactinomycin, epirubicin, and plicama. It may be one or more than one selected from isin, pentostatin and valrubicin,

The mitosis inhibitor (vinca alkaloid) is a division-specific drug that stops cell division in metaphase during mitosis, and includes irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, and vinca. may be one or more than one selected from cristine, ixabepilone, vinorelbine, vinblastine, and teniposide;

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

Additionally, the present invention provides an anticancer kit containing a pyrimidin-4-one compound of Formula 1 and a chemotherapy agent according to an embodiment of the present invention.

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

Hereinafter, the novel pyrimidin-4-one compound of the present invention, its solvate, hydrate, prodrug, isomer or pharmaceutically acceptable salt thereof, and anticancer drug composition containing the same will be described with specific examples. 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) over 2 hours and 30 minutes at O ^o C and then at 40 ^{o C.} It was heated at 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

Compound a (1 eq), formamide (47.2 eq), and ammonium formate (6.7 eq) were mixed and stirred at 155 ^o C for 26 hours. The reaction mixture was stored at -18 ^o 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

Compound b (1 eq) and AcOH (3.5 eq) were mixed, stirred at room temperature, Br ₂ (1.77 eq) was slowly added, heated at 80 ^o C, and stirred for 1 hour and 30 minutes. The temperature of the reaction mixture was lowered to room temperature and then adjusted to pH 7 using saturated NaHCO ₃ solution. The solid was filtered and 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. After the reaction mixture was terminated with water, 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.

1-5 Synthesis of compound e

Compound d (1 eq) and TFA (trifluoroacetic acid, 61.8 eq) were mixed and stirred at room temperature for 2 hours. TFA was removed by repeating the addition of DCM to the reaction mixture and 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 , N-Diisopropylethylamine, 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, 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. I ordered 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 below were prepared in the same manner as in Example 2, except that the starting materials were different.

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)

Compound a (1 eq), compound c (1 eq), K ₂ CO ₃ (4 eq), and DMF were mixed and 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.

^1H 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 ^o C for 4 hours. The reaction mixture was diluted with EtOAc, washed with saturated 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

Bromobutanol (0.5 eq) and toluene were mixed and stirred at room temperature, and morpholine (1 eq) was slowly added and stirred at 80 ^o C for 4 hours. After dropping the temperature of the reaction mixture to room temperature, it was washed with toluene, and the filtered 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 ^o C, and after 10 minutes, the starting material dissolved in DCM was added. The reaction mixture was stirred at -78 ^o C for 10 minutes, then 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

Compound b (1 eq), ethyl cyano acetate (1 eq), sulfur (1 eq), Et ₃ N (1.3 eq), and EtOH were mixed, heated at 80 ^o C, and stirred for 20 hours. After dropping the temperature of the reaction mixture to room temperature, it was diluted with EtOAc, washed with saturated 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

Compound c (1 eq), Formamide (53.3 eq), and AcOH (1.2 eq) were mixed and stirred at 150 ^o C for 22 hours. After dropping 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.

5-5 Synthesis of compound e

Compound d (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 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.

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 (2eq), and DMF were mixed and stirred at 100 ^o 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

Compound b (1 eq) and TFA (62 eq) were mixed and stirred at room temperature for 2 hours. TFA was removed by repeating the addition of DCM to the reaction mixture and 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

After mixing 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 at 110 ^o . It was stirred at C for 4 hours. After dropping the temperature of the reaction mixture to room temperature, it was diluted with EtOAc, washed with saturated 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.

^1H 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 different.

compound structure of compounds 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 Manufacturing of CIM 1009 (CNC 2027, c)

8-1 Synthesis of compound b

Compound a (1 eq) and DMF were mixed and stirred 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 below were prepared in a similar manner to Example 8, except that the starting materials used in Example 8 were different.

compound structure of compounds 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 terminating the reaction mixture with water, the pH was adjusted to 7 using saturated NaHCO ₃ solution. 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 a similar manner to Example 9, except that the starting materials used in Example 9 were different.

compound structure of compounds 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)

Compound a (1 eq), Tin(II) chloride dehydrate (4.5 eq), and EtOH were mixed and stirred at 80 ^o C for 20 hours. After dropping the temperature of the reaction mixture to room temperature, the pH was adjusted to 7 by adding saturated NaHCO ₃ solution. 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

After mixing compound a (1 eq) with 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, the mixture was heated to 110 ^o C. It was stirred for 4 hours. After dropping the temperature of the reaction mixture to room temperature, it was diluted with EtOAc, washed with saturated 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

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

11-3 Synthesis of compound d

Compound c (1 eq), aniline (1.25 eq), PyBOP (1.25 eq), DIEA (3 eq), DMAP (0.5 eq), and DMF were mixed and 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 below were prepared in a similar manner to Example 11, except that the starting materials used in Example 11 were different.

compound structure of compounds 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

Propiophenone (1 eq), ethyl 2-cyanoacetate (1.5 eq), morpholine (1.5 eq), AcOH (0.5 eq), and EtOH were mixed and stirred at 55 ^o C for 3 hours. Sulfur (1.5 eq) was added little by little three times in equal amounts and stirred at 55 ^o C for 45 hours. After dropping 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

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

12-3 Synthesis of compound c

Compound b (1 eq), t-Butylbromoacetate (2 eq), C _S2 CO ₃ (1.5 eq), and DMF were mixed and stirred at 100 ^o C for 5 hours. After dropping 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

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

12-5 Synthesis of compound e

Compound d (1 eq), aniline (1.25 eq), PyBOP (1.25 eq), DIEA (3 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, 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 below were prepared in a similar manner to Example 12, except that the starting materials used in Example 12 were different.

compound structure of compounds 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, 3 H) 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

Compound a and formamide (73.5 eq) were mixed and stirred at 200 ^o C for 4 hours. The temperature of the reaction mixture was lowered to room temperature. After filtering and washing with water, compound b was obtained.

13-2 Synthesis of compound c

Compound b (1 eq), benzyl bromide (2 eq), Cs ₂ CO ₃ (1.5 eq), and DMF were mixed and stirred at 100 ^o C for 5 hours. After dropping 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

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

14-2 Synthesis of compound c

Compound b (1 eq), t-Butylbromoacetate (2 eq), Cs ₂ CO ₃ (1.5 eq), and DMF were mixed and stirred at 100 ^o C for 3 hours. After dropping 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

Compound b (1 eq) and TFA (61.8 eq) were mixed and stirred at room temperature for 2 hours. TFA was removed by repeating the addition of DCM to the reaction mixture and 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, 3 H)

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

compound structure of compounds 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 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), 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

4-ethoxyacetophenone (1 eq), ethyl cyanoacetate (1.5 eq), morpholine (1.5 eq), AcOH (1.5 eq), and EtOH were mixed and stirred at 55 ^o C for 3 hours. Sulfur was added little by little three times in the same amount and stirred at 55 ^o C for 12 hours. After dropping 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

Compound a, potassium tert-butoxide (0.01 eq), and ethyl cyanoacetate (2 eq) were mixed and stirred at 120 ^o C for 20 minutes using a microwave. The temperature of the reaction mixture was lowered to room temperature and then adjusted to pH 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) over 2 hours and 30 minutes at O ^o C and then at 40 ^{o C.} It was heated at 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

Compound b (1 eq) was mixed with THF, phenyl chloroformate (1 eq) was added, and 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 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 saturated 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 ^o C for 2 hours. The reaction mixture was diluted with DCM, washed with saturated NaHCO ₃ and brine, dried with 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

Compound d (1 eq), Phenylboronic acid (1.1 eq), 2M K ₂ CO ₃ (4.5 eq), Pd(PPh ₃ ) ₄ (0.1 eq), and THF were mixed and stirred at 85 ^o C for 18 hours. After dropping 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.

17-6 Synthesis of compound f

Compound e (1 eq) was mixed with MeOH, then 1M KOH (0.8 eq) was added and stirred at 50 ^o C for 2 hours. Water was added to the reaction mixture, washed with DCM, and adjusted to pH 2 using 1M HCl. The solid was filtered and 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 Manufacturing 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 saturated NaHCO ₃ and brine, dried with 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

Compound b (1 eq), Phenylboronic acid (1.1 eq), 2M K ₂ CO ₃ (4.5 eq), Pd(PPh ₃ ) ₄ (0.1 eq), and THF were mixed and stirred at 85 ^o C for 18 hours. After dropping 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

Compound c (1 eq), NaOEt (1 eq), and EtOH were mixed and stirred at room temperature for 2 hours. Water was added to the reaction mixture, washed with DCM, and adjusted to pH 2 using 1M HCl. The solid was filtered and washed with water to obtain compound d.

18-4 Synthesis of compound e

Compound d (1 eq) was mixed with THF and EtOH, then 1M NaOH (2.4 eq) was added and stirred at room temperature for 4 hours. 1M HCl was added to the reaction mixture to adjust pH to 2. The solid was filtered and washed with water to obtain compound e.

18-5 Synthesis of compound f

Compound e (1 eq) was mixed with 4-chloro-3-(trifluoromethyl)aniline (1.25 eq), PyBOP (1.25 eq), DMAP (0.5 eq), DIEA (3 eq), and DMF and stirred at room temperature for 18 hours. I ordered 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)

19-1 Synthesis of compound b

Compound a (1 eq) was mixed with THF, phenyl chloroformate (1 eq) was added, and the mixture was 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) with 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 saturated 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 ^o C for 19 hours. The reaction mixture was diluted with DCM, washed with saturated NaHCO ₃ and brine, dried with 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

Compound d (1 eq), Phenylboronic acid (1.5 eq), 2M K ₂ CO ₃ (4.5 eq), Pd(PPh ₃ ) ₄ (0.1 eq), and THF were mixed and stirred at 85 ^o C for 20 hours. After dropping 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.

19-5 Synthesis of compound f

Compound e (1 eq) was mixed with MeOH, then 1M KOH (0.8 eq) was added and stirred at 50 ^o C for 2 hours. Water was added to the reaction mixture, washed with DCM, and adjusted to pH 2 using 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 saturated NaHCO ₃ and brine, dried with 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

Compound b (1 eq), NaOEt (1 eq), and EtOH were mixed and stirred at room temperature for 3 hours. Water was added to the reaction mixture, washed with DCM, and adjusted to pH 2 using 1M HCl. The solid was filtered and washed with water to obtain compound c.

20-3 Synthesis of compound d

Compound c (1 eq), Phenylboronic acid (1.1 eq), 2M K ₂ CO ₃ (4.5 eq), Pd(PPh ₃ ) ₄ (0.1 eq), and THF were mixed and stirred at 85 ^o C for 20 hours. After dropping 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

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

20-5 Synthesis of 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. I ordered 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, t-Butyl 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 (dichloromethane), washed with saturated 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

Compound b (1 eq), Cs ₂ CO ₃ (4 eq), and t-BuOH were mixed and stirred at 80 ^o C for 18 hours. A saturated solution of NH ₄ Cl was added to the reaction mixture, then 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

Compound c (1 eq) and TFA (63 eq) were mixed and stirred at room temperature for 2 hours. TFA was removed by repeating the addition of DCM to the reaction mixture and 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

Compound d (1 eq) was mixed with 4-chloro-3-(trifluoromethyl)aniline (1.25 eq), PyBOP (1.25 eq), DMAP (0.5 eq), DIEA (4 eq), and DMF and stirred at room temperature for 18 hours. I ordered 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

Compound e (1 eq), 4-methoxycarbonylphenylboronic acid (1.2 eq), Pd(dppf)Cl ₂ (0.2 eq), 1M Na ₂ CO ₃ (3 eq) and DME were mixed and stirred at 90 ^o C for 18 hours. . After dropping 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, 1H), 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] Enzyme activity test of the pyrimidin-4-one compound of the present invention in vitro

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

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

The absorbance reduction rate due to 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 activity. The mixing order of the components was that the buffer solution, LDH-A enzyme, pyrimidin-4-one compound of the present invention, and NADH were placed in a 96 well plate in that order. After a reaction time of about 7 to 8 minutes, pyruvate was added and the enzyme was added. The activation reaction started.

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

Enzyme activity test of compounds ( 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 in Table 1, the pyrimidin-4-one compound of the present invention has excellent value as an LDH-A inhibitor 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 targeted 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) are excellent inhibitors and can be usefully used as anticancer agents.

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

Measurement of cell viability by the pyrimidin-4-one compound of the present invention was performed by cell counting.

After replacing the cultured cell medium with 1 mL of RPMI medium containing 10% FBS, 3 uL of 10mM compound of the pyrimidin-4-one compound of the present invention was directly treated in each cultured cell medium so that the final concentration was 30uM, and then 24 After media suction for 48 hours (10% dialyzed FBS) and 48 hours (10% FBS), cells were removed by trypsin treatment. After suspension in RPMI (10% heat-inactivated FBS or 10% heat-inactivated dialyzed FBS), the cells were counted using 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, which was used as a control, and is shown in Table 9 (Cell viability test results 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 the cell viability test results, and it can be seen from this that it has little toxicity to normal cells and has few side effects.

[Example 24] Experiment measuring lactate secretion amount of pyrimidin-one compound of the present invention

After washing the cultured cell medium twice with serum-free media and replacing it with 1mL of medium containing 10% dialyzed FBS, 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, 100ul of the culture medium was collected and stored at -80°C. Lactate measurement was mainly conducted at 6 hours when the difference in viability due to pyrimidin-4-one compounds was small. When analyzing 12-hour and 24-hour results, correction was made based on cell number or protein concentration. Lactate secretion amount was measured using the EnzyChrom™ Lactate Assay Kit (ECLC-100, Bioassay systems).

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

compound Lactate secretion measurement experiment of the 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 secretion amount of lactate was significantly reduced, and from this, it can be seen that the pyrimidin-4-one compound of the present invention is effective as an inhibitor of LDH.

[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 the RIPK1 (Receptor-interating serine/threo nine protein kinase 1) enzyme, the example compounds were subjected to the following experiment, and the results were It is shown in Table 11 below.

That is, RIP1K (h) was incubated with 8mM MOPS pH 7.0, 0.2mM EDTA, 0.33mg/mL myelin basic protein, 10mM Mg acetate, and [γ 33P]-ATP. The reaction was started by addition of MgATP mixture, incubated at room temperature for 40 min and then stopped by adding 3% phosphoric acid solution. A total of 10 μL of reaction was spotted on a P30 filter mat and washed three times for 5 min in 75mM 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, among the pyrimidin-4-one compounds of the present invention, CIM 1288, CIM 1289, and CIM 1310 have excellent RIPK1 inhibitory ability and IC50, and 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 is highly effective, 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 8mM MOPS pH 7.0, 0.2mM EDTA, 0.33mg/mL myelin basic protein, 10mM Mg acetate, and [γ 33P]-ATP. The reaction was started by addition of MgATP mixture, incubated at room temperature for 40 min and then stopped by adding 3% phosphoric acid solution. A total of 10 μL of the reaction was spotted on a P30 filter mat and washed three times for 5 min in 75mM phosphoric acid and 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)

Activity and cell viability tests were performed on pancreatic cancer cell lines of CIM 1310 (CNC 2900), which is a highly effective compound among the pyrimidin-4-one compounds of the present invention.

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 at 0 cells (DMEM or RPMI 1640 medium containing 10% FBS). , were exposed to compound CIM 1310 (CNC 2900) at concentrations of 0.03, 0.1, 0.3, 1, 3, 10, and 30 μM for 48 hours. Afterwards, cell viability was measured through MTT assay.

The obtained activity results are shown in Table 13 below, 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, CIM 1310, a compound of the present invention, has remarkable activity in pancreatic cancer, and cell viability test results show high viability and low toxicity, making it very useful as an excellent anticancer agent.

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

Accordingly, the spirit of the present invention should not be limited to the described embodiments, and the scope of the patent claims described below as well as all modifications that are equivalent or equivalent to the scope of this patent claim shall fall within the scope of the spirit of the present invention. .

Claims (18)

A pyrimidin-4-one compound represented by the following formula (10), a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
[Formula 10]

In Formula 10,
D ₁ and D ₂ are independently N or CR ₁₆ ;
R ₄ to R ₈ are independently hydrogen, halogen, amino, aminocarbonyl, haloC1-C20alkyl, C1-C20alkyl, or C1-C20alkylcarbonyl;
R ₁₄ to R ₁₇ are each independently selected from 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 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-C20 heterocycloalkyl, C6-C20 aryl, and C3-C20 heteroaryl;
n is 1;
m is an integer from 1 to 5. According to clause 1,
In Formula 10,
D ₁ and D ₂ are each independently N or CR ₁₆ , excluding the case where D ₁ and D ₂ are N at the same time, a pyrimidin-4-one compound, a solvate thereof, a hydrate thereof, or a pharmaceutically thereof. Acceptable salts. According to clause 1,
In Formula 10,
R ₄ to R ₈ are each independently hydrogen, halogen, amino, aminocarbonyl, halo C1-C10 alkyl, C1-C10 alkyl or C1-C10 alkylcarbonyl, a pyrimidin-4-one compound, a solvate thereof, A hydrate thereof or a pharmaceutically acceptable salt thereof. According to clause 1,
In Formula 10,
R ₁₄ to R ₁₇ are each independently selected from 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 alkyl, alkoxycarbonyl, haloalkyl, alkoxy and heterocycloalkyl of R ₁₄ to R ₁₇ are halogen, amino, cyano, nitro, hydroxy, carboxyl, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 A pyrimidin-4-one compound, which may be substituted with one or more selected from alkylcarbonyl, C3-C10 heterocycloalkyl, C1-C10 heterocycloalkyl, C6-C12 aryl and C3-C12 heteroaryl, its Solvate, hydrate thereof or pharmaceutically acceptable salt thereof. delete delete delete delete delete delete According to clause 1,
The pyrimidin-4-one compound is a pyrimidin-4-one compound selected from the following compounds, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:













Characterized by containing the pyrimidin-4-one compound according to any one of claims 1 to 4 and 11, its hydrate, its solvate, or its pharmaceutically acceptable salt as an active ingredient. Anticancer composition. According to clause 12,
An anticancer drug composition comprising the pyrimidin-4-one compound, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof in an amount of 0.001 to 10% by weight based on the total weight of the anticancer drug composition. According to clause 12,
The anticancer agent composition is for the prevention and treatment of one or more diseases selected from lung cancer, liver cancer, breast cancer, colon cancer, colorectal cancer, rectal cancer, bladder cancer, cervical cancer, osteosarcoma, leukemia, myeloid leukemia, melanoma and stomach cancer. According to clause 12,
The anticancer drug composition further includes a pharmaceutically acceptable excipient. According to clause 12,
The anticancer drug composition further includes a chemotherapy agent. According to clause 16,
The anticancer agent composition is one or two or more selected from the group consisting of alkylating agents, metabolic antagonists, antitumor antibiotics, mitotic inhibitors, hormones, cisplatin, L-asparaginase, and mTor inhibitors. An anticancer kit comprising the anticancer composition of claim 12 and a chemotherapy agent.