KR20170114254A - Novel pyridine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating FGFR relating diseases containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel pyridine derivative, a process for producing the same, and a pharmaceutical composition for the prevention or treatment of FGFR (Fibroblast growth factor receptor) -related diseases containing the same as an active ingredient. The present invention relates to a novel pyridine derivative, The isomer and its pharmaceutically acceptable salt can effectively inhibit FGFR (Fibroblast growth factor receptor) and thus have an effect useful for the prevention or treatment of FGFR-related diseases, preferably cancer.

Description

TECHNICAL FIELD The present invention relates to a novel pyridine derivative, a process for producing the same, and a pharmaceutical composition for preventing or treating FGFR-related diseases containing the same as an active ingredient. as an active ingredient}

The present invention relates to a novel pyridine derivative, a process for producing the same, and a pharmaceutical composition for preventing or treating FGFR (Fibroblast growth factor receptor) -related disease containing the same as an active ingredient.

Fibroblast growth factor receptor (FGFR) tyrosine kinase is composed of about 800 amino acids and contains three immunoglobulin (Ig) -like domains (D1, D2, D3) FGFR2, FGFR3, and FGFR4 are four types of subtype receptor tyrosine kinases having the subtype FGFR1, FGFR2, FGFR3, and FGFR4.

Fibroblast growth factor (FGF) and its receptor (FGFR) are part of a unique and diverse signaling system that plays a major role in various physiological processes, including embryogenesis and various aspects of adult pathophysiology. FGF is known to stimulate broad cell function including migration, proliferation, differentiation and survival through binding with FGFR.

On the other hand, it has been reported that the overexpression of FGFR or the mutation of FGFR can be used to treat cancer (for example, bladder, breast, cervix, colon rectum, endometrium, stomach, head and neck, kidney, liver, lung, ovary, prostate) For example, in the case of multiple myeloma, chronic lymphocytic lymphoma, adult T cell leukemia, acute myelogenous leukemia, non-Hodgkin's lymphoma, myeloproliferative neoplasm and Waldenstrom's Macroglubulinemia), glioblastoma, melanoma, It is known that FGFR gene fusion occurs in various types of cancer and promotes the proliferation of cancer cells by activating FGFR signal transduction. Therefore, efforts to develop FGFR-targeting drugs for the treatment of cancer I have been.

In particular, efforts have been made to carry out a number of in vitro and in vivo studies to identify FGFR-1 to -4 as important cancer targeting agents (Non-Patent Document 1), but the development of a desired level of effective drug development It is not achieved, and continuous efforts are required.

Accordingly, the inventors of the present invention have been able to effectively inhibit FGFR and, in an effort to develop a drug for treating diseases such as cancer and tumor, the compound according to the present invention can effectively inhibit FGFR, It can be effectively used for diseases such as cancer and tumor when it is used as a pharmaceutical composition containing it as an active ingredient. Thus, the present invention has been completed.

Heinzle et al., Expert Opin. Ther. Targets 15 (7), 829-846 (2011)

It is an object of the present invention to provide a compound useful as an active ingredient of a pharmaceutical composition for the prevention or treatment of FGFR (Fibroblast growth factor receptor) -related diseases.

Another object of the present invention is to provide a process for producing the above compound.

Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating FGFR (Fibroblast growth factor receptor) -related diseases containing the above-mentioned compound as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer containing the above-mentioned compound as an active ingredient.

Another object of the present invention is to provide a health functional food for preventing or ameliorating FGFR (Fibroblast growth factor receptor) -related diseases containing the above-mentioned compound as an active ingredient.

In order to achieve the above object,

The present invention provides a compound represented by the following general formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

R ¹ is hydrogen, aryl of unsubstituted or substituted 6-10 ring, heteroaryl of unsubstituted or substituted 5-10 ring containing one or more heteroatoms selected from the group consisting of N, O and S, or - (CH ₂ ) _n -R ³ ,

Aryl and heteroaryl of the 5-10 heterocyclic ring are independently selected from the group consisting of C _1-3 straight or branched chain alkyl, C _1-3 straight or branched chain alkoxy and N, O and S Heterocycloalkyl of unsubstituted or substituted 5-6-membered rings containing 1 to 3 heteroatoms, wherein heterocycloalkyl of said substituted 5-6-membered ring is substituted with one or more substituents selected from the group consisting of C _1-3 linear or branched alkyl,

Wherein R ³ is unsubstituted or substituted heterocycloalkyl of 5-6-membered ring containing at least one heteroatom selected from the group consisting of N, O and S, said substituted heterocycloalkyl being C _1-3 Linear or branched alkyl and oxo groups, and n is an integer of 1 to 3; And

R ² is hydrogen, -XR ⁴ or -NR ⁵ R ⁶ ,

Wherein X is O or S,

R < ⁴ > is straight or branched alkyl of C < _1-5 > substituted or unsubstituted with methoxy or unsubstituted 5-6 rings containing 1-3 heteroatoms selected from the group consisting of N, Lt; RTI ID = 0.0 >

R ⁵ and R ⁶ are each independently -H or a substituted or unsubstituted C _1-5 linear or branched alkyl, a substituted or unsubstituted C _1-5 straight or branched alkoxy, an unsubstituted or substituted 6- Aryl of 10-membered rings, heteroaryl of unsubstituted or substituted 5-10-membered rings containing at least one heteroatom selected from the group consisting of N, O and S, cycloalkyl of unsubstituted or substituted 3-10 heterocyclic ring, Or heterocycloalkyl of unsubstituted or substituted 5-6-membered heterocycles comprising 1-3 heteroatoms selected from the group consisting of N, O and S, or R ⁵ and R ⁶ together are an unsubstituted or substituted 4 -10-membered ring, or a heterocycloalkyl ring of an unsubstituted or substituted 5- to 10-membered ring containing at least one hetero atom selected from the group consisting of N, O and S,

Wherein, the substituted alkyl, alkoxy, substituted aryl, substituted heteroaryl, substituted cycloalkyl, heterocycloalkyl, substituted ring or a substituted heterocycloalkyl ring substituted for the halogen, di-C _{1-substituted-3} Alkylamino, C _1-3 alkyl or C _1-3 alkoxy is substituted.

The present invention also relates to a process for producing a compound represented by the formula (1)

Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1); And

Reacting the compound represented by the formula (4) and the compound represented by the formula (5) prepared in the step 1 to prepare a compound represented by the formula (6) (step 2);

And a step of preparing a compound represented by the formula (1) from the compound represented by the formula (6) prepared in the step (2).

[Reaction Scheme 1]

In the above Reaction Scheme 1,

R ¹ and R ² are the same as defined in Formula 1, respectively.

Further, the present invention provides a pharmaceutical composition for preventing or treating FGFR (Fibroblast growth factor receptor) -related disease comprising the compound represented by the above-mentioned formula (1), its optical isomer or a pharmaceutically acceptable salt thereof as an active ingredient .

The present invention also provides a pharmaceutical composition for preventing or treating cancer comprising the compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Further, the present invention provides a health functional food for preventing or ameliorating cancer comprising the compound represented by the above-mentioned formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The novel pyridine derivatives, their optical isomers and pharmaceutically acceptable salts thereof according to the present invention can effectively inhibit FGFR (Fibroblast growth factor receptor), and thus have an effect useful for the prevention or treatment of FGFR-related diseases, preferably cancer have.

Hereinafter, the present invention will be described in detail.

The following description is provided to assist the understanding of the invention, and the present invention is not limited to the following description.

The present invention provides a compound represented by the following general formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

R ¹ is hydrogen, aryl of unsubstituted or substituted 6-10 ring, heteroaryl of unsubstituted or substituted 5-10 ring containing one or more heteroatoms selected from the group consisting of N, O and S, or - (CH ₂ ) _n -R ³ ,

Wherein said heteroaryl of said substituted 6-10-membered ring or heteroaryl of 5-10-membered ring is selected from the group consisting of C _1-3 straight or branched chain alkyl, C _1-3 straight or branched chain alkoxy and N, O and S Or heterocycloalkyl of an unsubstituted or substituted 5-6-membered ring containing 3 heteroatoms, wherein said heterocycloalkyl of said substituted 5-6-membered ring is substituted with one or more substituents selected from the group consisting of C _{1 -3} < / RTI > linear or branched alkyl,

Wherein R ³ is unsubstituted or substituted heterocycloalkyl of 5-6-membered ring containing at least one heteroatom selected from the group consisting of N, O and S, said substituted heterocycloalkyl being C _1-3 Linear or branched alkyl and oxo groups, and n is an integer of 1 to 3; And

R ² is hydrogen, -XR ⁴ or -NR ⁵ R ⁶ ,

Wherein X is O or S,

R < ⁴ > is straight or branched alkyl of C < _1-5 > substituted or unsubstituted with methoxy or unsubstituted 5-6 rings containing 1-3 heteroatoms selected from the group consisting of N, Lt; RTI ID = 0.0 >

R ⁵ and R ⁶ are each independently -H or a substituted or unsubstituted C _1-5 linear or branched alkyl, a substituted or unsubstituted C _1-5 straight or branched alkoxy, an unsubstituted or substituted 6- Aryl of 10-membered rings, heteroaryl of unsubstituted or substituted 5-10-membered rings containing at least one heteroatom selected from the group consisting of N, O and S, cycloalkyl of unsubstituted or substituted 3-10 heterocyclic ring, Or heterocycloalkyl of unsubstituted or substituted 5-6-membered heterocycles comprising 1-3 heteroatoms selected from the group consisting of N, O and S, or R ⁵ and R ⁶ together are an unsubstituted or substituted 4 -10-membered ring, or a heterocycloalkyl ring of an unsubstituted or substituted 5- to 10-membered ring containing at least one hetero atom selected from the group consisting of N, O and S,

Wherein, the substituted alkyl, alkoxy, substituted aryl, substituted heteroaryl, substituted cycloalkyl, heterocycloalkyl, substituted ring or a substituted heterocycloalkyl ring substituted for the halogen, di-C _{1-substituted-3} Alkylamino, C _1-3 alkyl or C _1-3 alkoxy is substituted.

Preferably,

R ¹ is hydrogen, heteroaryl of unsubstituted or substituted 5-8-membered rings containing at least one heteroatom selected from the group consisting of aryl, unsubstituted or substituted 6-8-membered ring, N, O and S, or - (CH ₂ ) _n -R ³ ,

Wherein said heteroaryl of said substituted 6-8-membered ring or heteroaryl of 5-8-membered ring is selected from the group consisting of C _1-3 straight or branched chain alkyl, C _1-3 straight or branched chain alkoxy and N, O and S Or heterocycloalkyl of an unsubstituted or substituted 5-6-membered ring containing 3 heteroatoms, wherein said heterocycloalkyl of said substituted 5-6-membered ring is substituted with one or more substituents selected from the group consisting of C _{1 -3} < / RTI > linear or branched alkyl,

Wherein R ³ is unsubstituted or substituted heterocycloalkyl of 5-6-membered ring containing at least one heteroatom selected from the group consisting of N, O and S, said substituted heterocycloalkyl being C _1-3 Linear or branched alkyl and oxo groups, and n is an integer of 1 to 3; And

R ² is hydrogen, -XR ⁴ or -NR ⁵ R ⁶ ,

Wherein X is O or S,

R < ⁴ > is straight or branched alkyl of C < _1-5 > substituted or unsubstituted with methoxy,

R ⁵ and R ⁶ are each independently -H or a substituted or unsubstituted C _1-5 linear or branched alkyl, a substituted or unsubstituted C _1-5 straight or branched alkoxy, an unsubstituted or substituted 6- Cycloalkyl of unsubstituted or substituted 3 to 8-membered rings, heteroaryl of unsubstituted or substituted 5- to 8-membered rings containing at least one heteroatom selected from the group consisting of N, O and S, Or an unsubstituted or substituted 5-8-membered heterocycloalkyl comprising 1-3 heteroatoms selected from the group consisting of N, O and S, or R ⁵ and R ⁶ together are an unsubstituted or substituted 4 -8 form a ring of each ring or form a heterocycloalkyl ring of an unsubstituted or substituted 5- to 8-membered ring containing at least one heteroatom selected from the group consisting of N, O and S,

Wherein, the substituted alkyl, substituted alkoxy, substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted heterocycloalkyl, substituted ring or a substituted heterocycloalkyl rings include halogen, dimethylamino, C _{1 -3} alkyl or C _1-3 alkoxy is substituted.

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Preferable examples of the compound represented by the formula (1) according to the present invention include the following compounds.

(1) Synthesis of 7-formyl-N- (4 - ((2-methoxyethyl) amino) -5-nitropyridin-2-yl) -6- (thiazol- -1,8-naphthyridin-1 (2H) -carboxamide;

(2) Synthesis of 7-formyl-N- (4 - ((2-methoxyethyl) amino) -5-nitropyridin- 3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;

(3) Synthesis of N- (4 - ((2- (dimethylamino) ethyl) amino) -5-nitropyridin- Dihydro-1,8-naphthyridin-1 (2H) -carboxamide;

(4) Synthesis of 7-formyl-N- (4 - ((2-methoxyethyl) amino) -5-nitropyridin- 1, 8-naphthyridin-1 (2H) -carboxamide;

(5) Synthesis of 7-formyl-N- (4 - ((2-methoxyethyl) amino) -5-nitropyridin- 1, 8-naphthyridin-1 (2H) -carboxamide;

(6) Synthesis of N- (4- (4- (dimethylamino) piperidin-1-yl) -5-nitropyridin- Formyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;

(7) Synthesis of N- (4 - ((3- (dimethylamino) propyl) amino) -5-nitropyridin- ) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;

(8) 6- (5-Fluoropyridin-3-yl) -7-formyl-N- (4- -Yl) -3,4-dihydro-i-1,8-naphthyridin-1 (2H) -carboxamide;

(9) 7-Formyl-N- (5-nitropyridin-2-yl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;

(10) Synthesis of 7-formyl-N- (4 - ((2-methoxyethyl) amino) -5-nitropyridin-2-yl) -3,4-dihydro-1,8-naphthyridin- ) -Carboxamide;

(11) Synthesis of 7-formyl-N- (4 - ((4-methoxyphenyl) amino) -5-nitropyridin-2-yl) -3,4-dihydro-1,8-naphthyridin- ) -Carboxamide;

(12) Synthesis of 7-formyl-N- (4 - ((3-methoxyphenyl) amino) -5-nitropyridin-2-yl) -3,4-dihydro-1,8-naphthyridin- ) -Carboxamide;

(13) Synthesis of N- (4- (ethylthio) -5-nitropyridin-2-yl) -7-formyl- , 4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;

(14) 7- Formyl-6 - ((4-methyl-2-oxopiperazin-1-yl) methyl) - dihydro-1,8-naphthyridin-1 (2H) -carboxamide;

(15) 7- (Dimethoxymethyl) -6- (4-methyl-2-oxopiperazin-1 -yl) Pyridin-2-yl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;

(16) Synthesis of N- (4 - ((4-fluorophenyl) amino) -5-nitropyridin-2-yl) ) Methyl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;

(17) Synthesis of N- (4- (cyclohexylamino) -5-nitropyridin-2-yl) -7- , 4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;

(18) Synthesis of 7-formyl-N- (4 - ((2-methoxyethyl) amino) -5-nitropyridin- Yl) methyl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;

(19) Synthesis of N- (4- (ethylamino) -5-nitropyridin-2-yl) -7- 4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;

(20) Synthesis of 7-formyl-N- (4 - ((4-methoxyphenyl) amino) -5-nitropyridin- ) Methyl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;

(21) Synthesis of N- (4- (2- (dimethylamino) ethylamino) -5-nitropyridin-2-yl) ) Methyl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide; And

(22) Synthesis of N- (4 - ((3-chloro-4-fluorophenyl) amino) -5-nitropyridin- -1-yl) methyl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide.

The compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, glutaric acid, and the like, in which at least one halogen selected from the group consisting of F, Cl, Br and I is substituted or unsubstituted, Citric acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chloro Such as benzenesulfonate, benzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving a derivative of the formula (1) in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, Followed by filtration and drying, or by distillation of the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

Furthermore, the present invention encompasses the compounds represented by the formula (1) and pharmaceutically acceptable salts thereof as well as solvates, optical isomers and hydrates thereof which can be prepared therefrom.

The present invention also relates to a process for producing a compound represented by the formula (1)

Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1); And

Reacting the compound represented by the formula (4) and the compound represented by the formula (5) prepared in the step 1 to prepare a compound represented by the formula (6) (step 2);

And a step of preparing a compound represented by the formula (1) from the compound represented by the formula (6) prepared in the step (2).

[Reaction Scheme 1]

In the above Reaction Scheme 1,

Wherein R ¹ and R ² are independently as defined in the above formula (1).

Hereinafter, the process for preparing the compound represented by the formula (1) according to the present invention will be described in detail.

In step (1), the compound represented by formula (2) is reacted with the compound represented by formula (3) to produce a compound represented by formula (4).

At this time, H2O, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile and the like can be used as the solvent which can be used in the above step, and H2O or tetrahydrofuran (THF) can be preferably used.

In the above step, the reaction is preferably carried out at a temperature ranging from 0 ° C to the boiling point of the solvent. The reaction time is not particularly limited, but it is preferably 0.5-20 hours.

In the process for preparing a compound represented by the general formula (1) according to the present invention, the step (2) may be carried out by reacting the compound represented by the general formula (4) and the compound represented by the general formula (5) .

The solvent used in the above step may include dimethylformamide (DMF), water, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile and the like, preferably dimethylformamide DMF) can be used.

In the above step, the reaction is preferably carried out at a temperature ranging from 0 ° C to the boiling point of the solvent. The reaction time is not particularly limited, but is preferably 0.5 to 30 hours.

In the process for preparing a compound represented by the formula (1) according to the present invention, the above step (3) is a step for preparing a compound represented by the formula (1) from the compound represented by the formula (6)

The solvent used in the above step may include dimethylformamide (DMF), water, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile and the like, preferably dimethylformamide DMF) can be used.

In the above step, the reaction is preferably carried out at a temperature ranging from 0 ° C to the boiling point of the solvent. The reaction time is not particularly limited, but is preferably 0.5 to 30 hours.

In another method of preparing the compound of Formula 1, the compound of the present invention may be prepared in a manner in which the Suzuki reaction is omitted in the process of Reaction Scheme 1, . ≪ / RTI >

[Reaction Scheme 2]

In the production method of the above Reaction Scheme 2,

R ¹ and R ² are the same as defined in the above formula (1).

In addition, the present invention can be carried out similarly to the preparation step of Scheme 1, but the present invention is not limited thereto.

Further, the present invention provides a pharmaceutical composition for preventing or treating FGFR (Fibroblast growth factor receptor) -related disease comprising the compound represented by the above-mentioned formula (1), its optical isomer or a pharmaceutically acceptable salt thereof as an active ingredient .

Herein, the FGFR (Fibroblast growth factor receptor) -related disease is not limited to the following, but refers to any disease that can be expressed from a non-normal activity such as abnormality, alteration, overexpression, etc. of the FGFR enzyme. Particularly, examples of FGFR-related diseases include cancer. When the compound of the present invention, an optical isomer thereof, and an acceptable salt thereof are derived from abnormal activity of FGFR associated with cell proliferation of cancer cells, Moles, and can be effectively used for prevention or treatment of diseases referred to as FGFR-related diseases.

The present invention also provides a pharmaceutical composition for preventing or treating cancer comprising the compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Herein, the compound may be characterized by inhibiting FGFR (Fibroblast growth factor receptor) to prevent or treat cancer. The cancer may be cancer, colon cancer, liver cancer, Cancer of the uterus, cancer of the endometrium, cancer of the cervix, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, renal cancer, ureteral cancer, endometrial carcinoma, endometrial carcinoma, Renal cell carcinoma, kidney pelvic carcinoma, central nervous system tumor, and leukemia.

Further, the present invention provides a health functional food for preventing or ameliorating cancer comprising the compound represented by the above-mentioned formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Herein, the compound may be characterized by inhibiting FGFR (Fibroblast growth factor receptor) to prevent or ameliorate cancer, wherein the cancer is selected from the group consisting of colon cancer, liver cancer, stomach cancer, breast cancer, colon cancer, pancreatic cancer, Cancer of the uterus, cancer of the endometrium, cancer of the cervix, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, renal cancer, ureteral cancer, endometrial carcinoma, endometrial carcinoma, Renal cell carcinoma, kidney pelvic carcinoma, central nervous system tumor, and leukemia.

The compound of formula (I) according to the present invention may be administered orally or parenterally in a variety of formulations at the time of clinical administration. In the case of formulation, the compound of the present invention may be used as a filler, an extender, a binder, a wetting agent, a disintegrant, Diluents or excipients.

Solid formulations for oral administration include tablets, pills, powders, granules, capsules, troches, and the like, which may contain one or more excipients such as starch, calcium carbonate, Sucrose, lactose, gelatin or the like. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are included in addition to commonly used simple diluents such as water and liquid paraffin. .

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol, gelatin and the like can be used.

The effective dose of the compound of the present invention on the human body may vary depending on the age, weight, sex, dosage form, health condition and disease severity of the patient, and is generally about 0.001-100 mg / kg / 0.0 > mg / kg / day. ≪ / RTI > It is generally from 0.07 to 7000 mg / day, preferably from 0.7 to 2500 mg / day, based on adult patients weighing 70 kg, and may be administered once a day It may be divided into several doses.

The compounds, their optical isomers, or pharmaceutically acceptable salts thereof according to the present invention have been confirmed through experimentation that they are useful for the treatment of FGFR-related diseases in the present invention.

First, in order to evaluate the inhibitory activity of the compound of the present invention against FGFR 4 enzyme, the following experiment was conducted. As a result, it was confirmed that the compound of Example of the present invention had an inhibitory activity against FGFR 4, The compounds according to the present invention can be used not only for FGFR-related diseases but also for the treatment of cancers induced therefrom such as colon cancer, liver cancer, gastric cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, Endometrial carcinoma, cervical cancer, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, urinary tract cancer, uterine cancer, ovarian cancer, rectum cancer, esophageal cancer, small intestine cancer, Cancer, kidney cell carcinoma, renal pelvic carcinoma, central nervous system tumor, and leukemia or solid tumor, 1).

In addition, the compounds according to the present invention were evaluated for inhibiting the proliferation of cancer cells through inhibition of extracellular signal-regulated kinase activity. Experiments were carried out on Huh-7 cell line, which is a human liver cancer cell line, It is possible to confirm that the compound effectively inhibits cancer cell proliferation in the human hypotensive cancer cell line Huh7 and thus can be used not only for FGFR related diseases but also for cancer derived therefrom such as colon cancer, liver cancer, gastric cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, Endometrial carcinoma, cervical cancer, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, urinary tract cancer, uterine cancer, ovarian cancer, rectum cancer, esophageal cancer, small intestine cancer, Cancer, kidney cell carcinoma, renal pelvic carcinoma, central nervous system tumor, and leukemia or solid tumors.

Hereinafter, the present invention will be described in detail with reference to Production Examples, Examples and Experimental Examples.

However, the following Production Examples, Examples and Experimental Examples are illustrative of the present invention, and the contents of the present invention are not limited thereto.

The compounds synthesized in the preparation examples and examples of the present invention were purified or subjected to structural analysis under the following HPLC conditions.

Analytical HPLC conditions:

YMC-Park Pro C18, 150 x 4.6 mm column, Solvent A (0.1% TFA in water), Solvent B (CH ₃ CN), and a solvent gradient (5-100% B for 7 min, .

Preparative HPLC conditions:

Gradient condition (Solvent A (0.1% TFA in water), Solvent B (CH ₃ CN)), Luna 10u C18, 250 x 21.2 mm column.

PREPARATION EXAMPLE 1 Preparation of N4- (2-methoxyethyl) -5-nitropyridine-2,4-diamine

After dissolving 4-chloro-5-nitropyridin-2-amine (1 g, 5.76 mmol) and diisopropylethylamine (4 ml, 23.05 mmol) in dimethylformamide (11 ml), 2-methoxyethylamine ml, 23.05 mmol), and the mixture was stirred at 40 ° C for 15 hours. The reaction mixture was cooled to room temperature, extracted with ethyl acetate and water, and the organic layers were combined. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the desired compound (868 mg).

MS (m / z): 213 [M + H].

< Manufacturing example  2 > 1 - ((2- ( Dimethoxymethyl ) -5,6,7,8- Tetrahydro -1,8- Naphthyridine Yl) methyl) -4-methylpiperazin-2-one &lt; EMI ID =

Step 1: Ethyl 2 - ((2- ( tert - Butoxycarbonylamino )ethyl)( Methyl amino ) &Lt; / RTI &gt; acetate

To a solution of tert-butyl (2- (methylamino) ethyl) carbamate (4.0 g, 23.0 mmol) and triethylamine (9.62 ml, 69.0 mmol) in tetrahydrofuran (48 ml) was added ethyl bromoacetate 2.54 ml, 22.9 mmol) at 0 ° C, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was extracted with an aqueous solution of dichloromethane and saturated sodium bicarbonate, and the organic layers were combined. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the desired compound (6.0 g, 100%) as a liquid.

^{1 H NMR (400 MHz, CDCl} 3) δ 5.18 (br s, 1H), 4.17 (q, 2H), 3.25 (s, 2H), 3.19 (m, 2H), 2.60 (t, 2H), 2.36 (s , 3H), 1.43 (s, 9H), 1.27 (t, 3H).

Step 2: Preparation of ethyl 2 - ((2-aminoethyl) (methyl) amino) acetate

To the mixed solution obtained by dissolving 6.0 g (22.6 mmol) of the compound prepared in Step 1 in tetrahydrofuran (30 ml) and ethanol (150 ml), concentrated hydrochloric acid (20 ml) was added at room temperature, Lt; / RTI &gt; After concentrating the reaction solution under reduced pressure, ethanol (100 ml) was added and the mixture was stirred at 60 ° C for 70 minutes. The reaction product was cooled to room temperature, and then concentrated under reduced pressure to obtain the desired compound.

^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.58 (br s 3H), 4.19 (q, 2H), 4.26-4.15 (m, 2H), 3.44 (br s, 2H), 2.88 (s, 3H) , &Lt; / RTI &gt; 1.21 (t, 3H).

step 3: 6 - Bromo -7- ( Dimethoxymethyl ) -1,2,3,4- Tetrahydro -1,8- Naphthyridine  Produce

The compound prepared in Step 2 (12 g, 57.6 mmol) was dissolved in acetonitrile (192 ml), and N-bromosuccinimide (NBS) (10.77 g, 60.5 mmol) was slowly added at room temperature. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The resulting reaction residue was extracted with diethyl ether and ice water. The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and purified by MPLC to obtain the desired compound (11 g, 66%).

MS (m / z): 288 [M + H]. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.25 (s, 1H), 5.54 (s, 1H), 5.17 (br s, 1H), 3.44 (s, 6H), 3.37 (br t, 2H), 2.69 ( t, 2 H), 1.86 (m, 2 H).

step 4: 2 - ( Dimethoxymethyl ) -5,6,7,8- Tetrahydro -1,8- Naphthyridine -3- Of carbaldehyde  Produce

Methyl lithium (1.6 M in ether, 16.3 ml, 26.1 mmol) was slowly added dropwise to a solution of the compound (7.5 g, 26.1 mmol) prepared in step 3 in tetrahydrofuran (200 ml) at -78 ° C. The reaction mixture was stirred for 5 minutes and then n-butyl lithium (1.6 M in hexane, 18 ml, 28.7 mmol) was slowly added dropwise. The mixture was stirred for 20 min before tetrahydrofuran (50 ml) was added at -78 &lt; 0 &gt; C. N-butyl lithium (1.6 M in hexane, 24.5 ml, 39.0 mmol) was added sequentially and the reaction mixture was stirred for 20 minutes. Then n-butyllithium (1.6 M in hexane, 3.3 ml, 5.2 mmol) was added and the reaction mixture was stirred at -78 <0> C for 10 min. Dimethylformamide (1.05 ml, 18.6 mmol) was added and the reaction mixture was stirred at -78 &lt; 0 &gt; C for 45 min and then slowly ramped to room temperature. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the desired compound.

MS (m / z): 237 [M + H].

step 5: 1 -((2-( Dimethoxymethyl ) -5,6,7,8- Tetrahydro -1,8- Naphthyridine Yl) methyl) -4-methylpiperazin-2-one &lt; EMI ID =

(1.23 g, 5.21 mmol), ethyl 2- ((2-aminoethyl) (methyl) amino) acetate dihydrochloride (1.82 g, 7.81 mmol) and triethylamine (3.63 ml, 26.0 mmol) was dissolved in 1,2-dichloroethane (13 ml), sodium triacetoxyborohydride (1.65 g) was added to the solution, and the mixture was stirred at room temperature for 21 hours. Sodium triacetoxyborohydride (1.1 g) was added to the reaction mixture and stirred at room temperature for 4 hours. Sodium triacetoxyborohydride (552 mg) was then added and stirred at 4 [deg.] C for 2.5 days. The reaction mixture was warmed to room temperature and neutralized with saturated sodium bicarbonate solution. The reaction mixture was extracted with dichloromethane, and the combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified by MPLC to obtain the desired compound (1 g, 57%).

MS (m / z): 335 [M + H].

< Example  1> 7- Formyl -N- (4 - ((2- Methoxyethyl ) Amino) -5- Nitropyridine Yl) -6- (thiazol-5-yl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

step 1: 4 - Nitrophenyl  6- Bromo -7- ( Dimethoxymethyl ) -3,4- Dihydro -1,8- Naphthyridine -1 (2H) -carboxylate &lt; / RTI &gt;

(2 g, 6.96 mmol) and pyridine (1.60 g, 6.96 mmol) were added to a mixed solution of dichloromethane (23 ml) in which 4-nitrophenylcarbonochloridate (1.404 g, 6.96 mmol) 0.620 ml, 7.66 mmol), and the reaction mixture was stirred at room temperature for 24 hours. Thereafter, the reaction mixture was extracted with dichloromethane and brine, and the organic layers were combined. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the desired compound (3.15 g, 100%) as a liquid.

MS (m / z): 452 [M + H].

step 2: 6 - Bromo -7- ( Dimethoxymethyl ) -N- (4 - ((2- Methoxyethyl ) Amino) -5- Nitropyridine 2-yl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

The compound (0.663 g, 3.12 mmol) prepared in Preparation Example 1 and sodium hydride (0.375 g, 9.37 mmol) were added to dimethylformamide (1.3 mL) and stirred for 10 minutes. Then, the compound (2.118 g, 4.68 mmol) prepared in the above Step 1 was added, and the reaction mixture was stirred at 40 ° C for 24 hours. The reaction mixture was extracted with ethyl acetate and brine, and the organic layers were combined. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure and purified by MPLC to give the desired compound (0.610 g, 37%) as a yellow solid.

MS (m / z): 525 [M + H].

step 3: 7 - ( Dimethoxymethyl ) -N- (4- (2- Methoxyethylamino ) -5- Nitropyridine Yl) -6- (thiazol-5-yl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

To a mixed solution of the compound prepared in Step 2 (50 mg, 0.095 mmol) and dimethoxyethane (1.5 ml) was added 5- (4,4,5,5-tetramethyl-1,3,2-dioxa 2-yl) thiazole (40 mg, 0.190 mmol), Pd (dppf) Cl ₂ (12 mg, 9.52 μmol) and 1M Na ₂ CO ₃ (0.286 ml, 0.286 mmol in H ₂ O) Respectively. The reaction mixture was stirred at 120 ° C for 30 minutes under microwave. The reaction mixture was extracted with dichloromethane and brine, and the organic layers were combined. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure and purified by MPLC to give the desired compound (18.1 mg, 34%) as a yellow solid.

MS (m / z): 529 [M + H].

step 4: 7 - Formyl -N- (4 - ((2- Methoxyethyl ) Amino) -5- Nitropyridine Yl) -6- ( Thiazole -5-yl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

Water (0.4 ml) and Con HC1 (10.33 [mu] l, 0.340 mmol) were added to a mixed solution of the compound (18 mg, 0.034 mmol) prepared in Step 3 dissolved in tetrahydrofuran (1 ml) The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified by prep to give the object compound as a yellow solid (2.8 mg, 17%).

MS (m / z): 483 [M + H]; HPLC: 5.782 min

< Example  2> 7- Formyl -N- (4 - ((2- Methoxyethyl ) Amino) -5- Nitropyridine Yl) -6- (1 -methyl-1 H-pyrazol-4-yl) -3,4-dihydro-1,8-naphthyridin- 1 (2H) -carboxamide

Instead of 5- (4,4,5,5-tetramethyl-1,3,2-dioxabororan-2-yl) thiazole used in step 3 of Example 1, 2- - (4,4,5,5-tetramethyl-1,3,2-dioxabororane-2-yl) -2H-imidazole was used in place of the target compound .

¹ H NMR (400 MHz, CDCl ₃ )? 13.94 (s, IH), 10.24 (s, IH), 9.14 (s, IH), 8.45 (s, 3H), 3.70 (m, 2H), 3.59 (s, 2H), 7.65 (s, ), 3.44 (s, 3H), 2.97 (m, 2H), 2.08 (m, 2H); HPLC: 5.502 min.

< Example  3> N- (4 - ((2- (dimethylamino) ethyl) amino) -5- Nitropyridine -2-yl) -7-formyl-6- (thiazol-5-yl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

Used in step 2 of Example 1, N ⁴ - (2- methoxy-ethyl) -5-nitropyridin-2,4-diamine in place of N ⁴ - (2- (dimethylamino) ethyl) -5-nitro Pyridine-2,4-diamine, the target compound was prepared.

¹ H NMR (400 MHz, DMSO) [delta] 13.61 (s, IH), 10.04 (s, IH), 9.28 ), 8.55 (t, IH), 8.16 (s, IH), 8.01 (s, IH), 7.68 (s, IH), 4.03 (m, 2H), 3.82-3.78 m, 2H), 2.99 (t, 2H), 2.89 (s, 3H), 2.88 (s, 3H), 2.01 - 1.96 (m, 2H); HPLC: 4.543 min.

< Example  4> 7- Formyl -N- (4 - ((2- Methoxyethyl ) Amino) -5- Nitropyridine -2-yl) -6- (3-methoxyphenyl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

2- (3-tert-butoxycarbonylamino) thiazole was used in place of 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- Methoxyphenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used in place of the compound obtained in Example 1, to thereby produce the desired compound.

¹ H NMR (400 MHz, DMSO) 隆 13.69 (s, 1H), 9.93 (s, 1H), 8.94 (s, 1H), 8.43 1H), 7.90 (s, 1H), 7.41 (t, 1H), 7.09 (s, 1H), 7.08-7.04 3H), 3.63 (t, 2H), 3.54-3.50 (m, 2H), 3.33 (s, 3H), 2.97 (t, 2H), 1.97 (m, 2H); HPLC: 6.520 min.

< Example  5> 7- Formyl -N- (4 - ((2- Methoxyethyl ) Amino) -5- Nitropyridine Yl) -6- (pyridin-3-yl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) thiazole used in step 3 of Example 1 was replaced by 3- 4,5,5-tetramethyl-1,3,2-dioxabororane-2-yl) pyridine was used instead of 2-pyridylmethoxycarbonylamino-4-methylpyridine.

¹ H NMR (400 MHz, CDCl ₃ )? 13.68 (s, IH), 10.12 (s, IH), 9.10 (s, IH), 8.91 (m, 1H), 8.62 (m, 1H), 8.60 (m, IH), 8.26 (d, IH), 7.84 ), 3.72 (m, 2H), 3.62 (m, 2H), 3.45 (s, 3H), 3.03 (m, 2H), 2.13 (m, 2H); HPLC: 5.008 min.

< Example  6 - (5-fluoropyridin-3-yl) -7-formyl-5-nitropyridin-2-yl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

Used in step 2 of Example 1, N ⁴ - (2- methoxy-ethyl) -5-nitropyridin-2,4-diamine in place of 4- (4- (dimethylamino) piperidin-1-yl ) -5-nitropyridin-2-amine was used in place of 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- Except that 3-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxabororan-2-yl) pyridine was used in place of 2- , The procedure of Example 1 was repeated to produce the target compound.

¹ H NMR (400 MHz, CDCl ₃ )? 13.75 (s, IH), 10.15 (s, IH), 8.80 (s, IH), 8.57 (d, 2H), 3.60-3.56 (m, 2 H), 7.41-7.42 (m, 1H), 8.41 (s, , 3.03-3.00 (m, 4H), 2.68-2.40 (m, 7H), 2.14-2.09 (m, 2H), 2.05-2.02 (m, 2H), 1.81-1.78 (m, 2H); HPLC: 4.977 min.

< Example  7-Formyl-6- (1-methyl-1H-pyrazol-4-yl) -7- -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

Used in step 2 of Example 1, N ⁴ - (2- methoxy-ethyl) -5-nitropyridin--2,4- N ⁴ in place of the diamine (3- (dimethylamino) propyl) -5-nitro (4,4,5,5-tetramethyl-1,3,2-dioxabororane-2-yl) pyridine-2,4-diamine, used in Step 3 of Example 1, ) Thiazole was replaced with 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxabororane-2-yl) -2H-imidazole , The procedure of Example 1 was repeated to produce the target compound.

¹ H NMR (400 MHz, DMSO)? 13.68 (s, IH), 10.12 (s, IH), 8.97 (s, IH), 8.51 2H), 3.92 (s, 3H), 3.50-3.45 (m, 2H), 8.18 (s, 2H), 2.00 (s, 3H), 2.80 (s, 3H), 2.07-2.02 (m, 2H), 2.00-1.96 2H); HPCL: 4.479 min.

< Example  2-methyl-1H-pyrazol-4-yl) amino] -5-nitropyridin-2- Yl) -3,4-dihydro-i-1,8-naphthyridin-1 (2H) -carboxamide

Used in step 2 of Example 1, N ⁴ - N ⁴ in place of 5-nitropyridine-2,4-diamine (2-methoxyethyl) - (1-methyl -1H- pyrazol-4-yl ) -5-nitropyridine-2,4-diamine was used in place of 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborol Fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxabororan-2-yl) pyridine was used in place of thiazole , The target compound was prepared.

1 H NMR (400 MHz, CDCl 3)? 13.77 (s, IH), 10.16 (s, IH), 10.04 , 8.56 (d, IH), 8.53 (s, IH), 8.41 (s, IH), 7.55 (s, IH), 7.45-7.42 ), 4.17-4.14 (m, 2H), 3.93 (s, 3H), 3.02-2.99 (m, 2H), 2.12-2.06 (m, 2H); HPLC: 6.687 min.

< Example  9> 7- Formyl -N- (5- Nitropyridine -2-yl) -3,4- Dihydro -1,8- Naphthyridine -1 (2H) -carboxamide &lt; / RTI &gt;

step 1: 4 - Nitrophenyl  7- ( Dimethoxymethyl ) -3,4- Dihydro -1,8- Naphthyridine -1 (2H) -carboxylate &lt; / RTI &gt;

(Dimethoxymethyl) -1,2,3,4-tetrahydro-1,8-naphthyridine was used instead of the compound prepared in Step 3 of Preparation Example 2, which was used in Step 1 of Example 1, The procedure of Step 1 of Example 1 was repeated to prepare the target compound.

step 2: 7 - ( Dimethoxymethyl ) -N- (5- Nitropyridine -2-yl) -3,4- Dihydro -1,8- Naphthyridine -1 (2H) -carboxamide &lt; / RTI &gt;

5-Nitropyridin-2-amine and sodium hydride were added to dimethylformamide and stirred for 10 minutes. Then, the compound prepared in the above step 1 was added, and the reaction mixture was stirred at 40 ° C for 24 hours. The reaction mixture was extracted with ethyl acetate and brine, and the organic layers were combined. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure and purified by MPLC to give the desired compound as a yellow solid.

step 3: 7 - Formyl -N- (5- Nitropyridine 2-yl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

Water (0.5 ml) and ConcoHCl (20 [mu] l) were added to a mixed solution of the compound (15 mg, 0.04 mmol) prepared in Step 2 above in tetrahydrofuran (1 ml) Lt; / RTI &gt; for 3 h. After the reaction was completed, the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified by prep to give the desired compound (3.8 mg, 29%) as a yellow solid.

¹ H NMR (400 MHz, DMSO)? 13.86 (s, IH), 9.94 (s, IH), 8.27 (m, 2H), 7.93 ), 7.67 (d, 1H), 3.98 (m, 2H), 2.98 (m, 2H), 1.97 (m, 2H).

< Example  10> 7- Formyl -N- (4 - ((2- Methoxyethyl ) Amino) -5- Nitropyridine -2-yl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

Except that N ⁴ - (2-methoxyethyl) -5-nitropyridine-2,4-diamine was used instead of 5-nitropyridin-2-amine used in step 2 of Example 9. The target compound was prepared in a similar manner to Example 9.

MS (m / z): 401 [M + 1], 1 H NMR (400 MHz, CDCl 3) δ 15.49 (s, 1H), 10.03 (s, 1H), 9.19 (s, 1H), 8.85 (s, 3H), 2.99 (t, 2H), 2.08 (s, 2H), 7.80 (d, ); HPLC: 6.245 min.

< Example  11> 7- Formyl -N- (4 - ((4- Methoxyphenyl ) Amino) -5- Nitropyridine -2-yl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

Except that N ⁴ - (4-methoxyphenyl) -5-nitropyridine-2,4-diamine was used in place of 5-nitropyridin-2-amine used in Step 2 of Example 9, The target compound was prepared in a similar manner to Example 9.

¹ H NMR (400 MHz, CDCl ₃ )? 14.20 (s, IH), 10.04 (s, IH), 9.86 (s, IH), 9.24 2H), 3.88 (s, 3H), 2.94 (m, 2H), 7.70 (d, ), 2.02 (m, 2H); HPLC: 7.537 min.

< Example  12> 7- Formyl -N- (4 - ((3- Methoxyphenyl ) Amino) -5- Nitropyridine -2-yl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

Except that N ⁴ - (3-methoxypropyl) -5-nitropyridine-2,4-diamine was used instead of 5-nitropyridin-2-amine used in Step 2 of Example 9. The target compound was prepared in a similar manner to Example 9.

¹ H NMR (400 MHz, CDCl ₃ )? 15.47 (s, IH), 10.03 (s, IH), 9.45 (s, IH), 9.17 (s, 2H), 3.66 (m, 4H), 3.44 (s, 3H), 2.98 (d, ), 2.10 (m, 4H); HPLC: 6.270 min.

< Example  13 > N- (4- ( Ethyl thio ) -5- Nitropyridine Yl) -7- Formyl -6 - ((4- methyl Yl) methyl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

The compound prepared in Preparative Example 2 was used instead of 7- (dimethoxymethyl) -1,2,3,4-tetrahydro-1,8-naphthyridine used in Step 1 of Example 9, The procedure of Example 9 was repeated except that 4- (ethylthio) -5-nitropyridin-2-amine was used instead of 5-nitropyridin-2-amine used in Step 2 of Example 9 To give the desired compound.

¹ H NMR (400 MHz, CDCl ₃ )? 14.00 (s, IH), 10.24 (s, IH), 9.12 (s, IH), 8.37 (s, 2H), 3.68 (m, 2H), 3.65 (m, 2H), 3.69 (m, ), 2.97 (m, 2H), 2.84 (s, 3H), 2.03 (m, 2H), 1.48 (t, 3H); HPLC: 5.612 min.

< Example  14> 7- Formyl -6 - ((4- methyl -2- Oxopiperazine -1 day) methyl ) -N- (4- Morpolino -5-nitropyridin-2-yl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

The procedure of Example 13 was repeated except for using 4-morpholino-5-nitropyridin-2-amine instead of 4- (ethylthio) -5-nitropyridin- The target compound was prepared.

1 H NMR (400 MHz, CDCl 3)? 13.82 (s, IH), 10.24 (s, IH), 8.77 (s, IH), 7.89 2H), 3.74-3. 36 (m, 2H), 3.27-3.25 (m, 4H) , 3.20 (s, 2H), 2.95-2.92 (m, 2H), 2.67-2.65 (m, 2H), 2.35 (s, 3H), 2.06-2.03 (m, 2H); HPLC: 4.803 min.

< Example  (5-nitro-4- (piperidin-1-yl) pyridin-2-ylmethyl) -2-yl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

Except that 5-nitro-4- (piperidin-1-yl) pyridin-2-amine was used in place of 4- (ethylthio) -5-nitropyridin- , The procedure of Example 13 was repeated to produce the target compound.

¹ H NMR (400 MHz, CDCl ₃ )? 13.69 (s, IH), 10.24 (s, IH), 8.70 (s, IH), 7.87 2H), 3.63-3.34 (m, 2H), 3.24-3.21 (m, 4H), 3.20 (s, 2H) , 2.94-2.91 (m, 2H), 2.67-2.64 (m, 2H), 2.35 (s, 3H), 2.07-2.01 (m, 2H), 1.74-1.67 (m, 4H); HPLC: 5.051 min.

< Example  (4-methyl-2-oxopiperazin-1-yl) -7-formyl-6 - ((4- Methyl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

Except that N ⁴ - (4-fluorophenyl) -5-nitropyridine-2,4-diamine was used in place of 4- (ethylthio) -5-nitropyridin- , And the procedure of Example 13 was repeated to produce the desired compound.

¹ H NMR (400 MHz, CDCl ₃ )? 13.78 (s, IH), 10.24 (s, IH), 9.72 2H), 5.08 (s, 2H), 4.02-4.00 (m, 2H), 7.85 (s, 2H), 2.35 (s, 3H), 2.00-1.97 (m, 2H), 2.35-2. ; HPLC: 5.485 min.

< Example  (4-methyl-2-oxopiperazin-1-yl) methyl) -3, 7-formyl- Preparation of 4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

Except that N ⁴ -cyclohexyl-5-nitropyridine-2,4-diamine was used in place of 4- (ethylthio) -5-nitropyridin-2-amine used in Example 13, 13, the target compound was prepared.

¹ H NMR (400 MHz, CDCl ₃ )? 13.84 (s, IH), 10.20 (s, IH), 9.11 (s, IH), 8.46 (m, 2H), 3.72 (m, 2H), 3.72 (m, 2H), 3.70 (m, , 2.96 (m, 2H), 2.90 (s, 3H), 2.10 (m, 2H), 2.03 (m, 2H), 1.80 (m, 2H), 1.68 (m, HPLC: 5.609 min.

< Example  Yl) -6 - ((4-methyl-2-oxopiperazin-1-ylmethyl) ) Methyl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

Except that N ⁴ - (2-methoxyethyl) -5-nitropyridine-2,4-diamine was used in place of 4- (ethylthio) -5-nitropyridin- , And the procedure of Example 13 was repeated to produce the desired compound.

¹ H NMR (400 MHz, DMSO) [delta] 13.65 (s, IH), 10.09 (s, IH), 8.94 (s, IH), 8.44 ), 7.68 (s, 1H), 7.66 (s, 1H), 4.96 (s, 2H), 4.01-3.98 (m, 4H), 3.62 s, 3H), 3.16 (s, 1H), 2.95-2.93 (m, 2H), 2.92 (s, 3H), 1.97-1.94 (m, 2H); HPLC: 4.732 min.

< Example  19> N- (4- ( Ethylamino ) -5- Nitropyridine Yl) -7- Formyl -6 - ((4- methyl Yl) methyl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

Except that N ⁴ -ethyl-5-nitropyridine-2,4-diamine was used in place of 4- (ethylthio) -5-nitropyridin-2-amine used in Example 13, The target compound was prepared.

_{MS (m / z): 497} [M + 1], 1 H NMR (400 MHz, DMSO) δ 13.63 (s, 1H), 10.09 (s, 1H), 8.94 (s, 1H), 8.45 (t, 1H 2H), 4.96 (s, 2H), 4.00 (m, 2H), 3.54 (s, 2H) ; HPLC: 4.705 min.

< Example  (4-methyl-2-oxopiperazin-1-yl) -6- (4-methyl-2-oxopiperazin- Methyl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

Except that N ⁴ - (4-methoxyphenyl) -5-nitropyridine-2,4-diamine was used in place of 4- (ethylthio) -5-nitropyridin- , And the procedure of Example 13 was repeated to produce the desired compound.

¹ H NMR (400 MHz, DMSO) [delta] 13.59 (s, IH), 10.07 (s, IH), 9.75 2H), 3.82 (s, 3H), 3.70 (d, 2H) , 3.16 (s, 2H), 2.91 (m, 2H), 2.90 (s, 3H), 2.50 (m, 2H), 1.89 (m, 2H); HPLC: 5.441 min.

< Example  (4-methyl-2-oxopiperazin-1-yl) -7-formyl-6 - ((4- Methyl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

Example 4 (ethyl thio) used by the 13-5-nitropyridin-2-amine in place of N ⁴ - (2- (dimethylamino) ethyl) -5-nitropyridin-2,4-diamine with , The target compound was prepared in a similar manner to Example 13.

MS (m / z): 540 [m + 1], 1 H NMR (400 MHz, CDCl 3) δ 13.71 (s, 1H), 10.25 (s, 1H), 9.02 (s, 1H), 8.56 (br s 2H), 3.46-3.42 (m, 2H), 3.37-3.34 (m, 2H), 7.65 (s, ), 3.20 (s, 2H), 2.94-2.91 (m, 2H), 2.68-2.65 (m, 2H), 2.35 (s, 3H), 2.33 (s, 6H), 2.07-2. HPLC: 3.998 min.

< Example  2-yl) -7-formyl-6 - ((4-methyl-2-oxopiperazine- Yl) methyl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide

Example 13 4- (ethyl-thio) used in the 5-nitropyridin-2-amine in place of N ⁴ - (3-chloro-4-fluorophenyl) -5-nitropyridine-2,4-diamine The target compound was prepared in a similar manner to Example 13.

1 H NMR (400 MHz, DMSO)? 13.69 (s, IH), 10.07 (s, IH), 9.85 , 7.73 (s, 1H), 7.69 (t, 2H), 7.57 (t, 1H), 7.46-7.42 (m, 1H), 4.97-4.91 (m, 2H), 3.99-3.96 (t, 2H), 3.57 (br s, 2H), 2.92-2.91 (m, 2H), 2.88 (s, 3H), 1.90-1.86 (m, 2H); HPLC: 5.779 min.

The chemical structures of the compounds prepared in Examples 1-22 are shown in Table 1 below.

Example constitutional formula Example constitutional formula One

12

2

13

3

14

4

15

5

16

6

17

7

18

8

19

9

20

10

21

11

22

&Lt; Experimental Example 1 > Evaluation of FGFR4 Inhibitory Activity

In order to evaluate the inhibitory activity of the compound of the present invention on the FGFR 4 enzyme, the following experiment was conducted.

Specifically, the FGFR 4 enzyme activity of the compound of Example according to the present invention was performed by Reaction Biology, Inc. The results are shown in Table 2 below.

Example FGFR4 (uM) One 66.9 nM 10 3.39 nM 11 2.24 nM 12 1.13 nM 18 6.84 nM

As shown in Table 2, it can be seen that the compound of Example according to the present invention inhibits FGFR 4 at a unit concentration of nano moles.

Thus, as shown in Experimental Example 1, the compounds according to the present invention, their optical isomers and pharmaceutically acceptable salts thereof can effectively inhibit FGFR, thereby preventing and treating FGFR-related diseases such as cancer, And can be useful for treatment.

<Experimental Example 2> Evaluation of cancer cell proliferation inhibitory activity

In order to evaluate the inhibitory activity of the compound of the present invention on cancer cell proliferation, the following experiment was conducted.

The Huh-7 cells, plant to be ³ × 10 3/80 μl / well in 96-well plates are attached for a day. The next day, triplicate serial dilutions of nine different concentrations (0.0015 - 10 μM) Example compound and DMSO is included culture solution 20 μl / welssik control of the addition, and a final concentration of 0 - then to be 10 μM, 37 ℃ CO ₂ Incubate for 72 hours in an incubator. After 72 hours, add 50 μl of CellTiter-Glo solution to each well, orbital shake for 2 minutes, and allow to stand for 10 minutes without light. Then, transfer 100 μl from each well to a white plate in the dark and measure luminescence at integration time 500 ms with a TECAN microplate reader. GI ₅₀ (Growth inhibition 50%) is calculated using GraphPad Prism 6 software. In order to derive the GI _50, measures the light emitting time of the wells separately planted in the addition of the compound to the cell culture in the same manner as above ^{(3 × 10 3/100 μl} / well). The emission value was set to 0% when T ₀ (Time zero). The results of the experiment are shown in Table 3 below.

Example Huh7 (uM) One C 3 C 4 C 5 C 10 C 11 C 12 C 13 B 14 B 15 B 16 B 17 B 18 C 19 A 20 B 21 C 22 B

(In Table 3, respectively, _{A: GI 50 <1μM, B} : 1μM≤GI 50 ≤10μM, C: GI 50> is 10 μM)

As shown in Table 3, it can be confirmed that the compound of Example of the present invention excellently inhibits the proliferation of Huh-7, a human liver cancer cell line.

Therefore, the compound according to the present invention can inhibit the proliferation of cancer cells in units of uM or less as shown in Experimental Example 2, and is useful as a pharmaceutical composition for prevention and treatment of cancer diseases such as liver cancer Can be used.

Claims (10)

Claims 1. A compound represented by the following formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

(In the formula 1,
R ¹ is hydrogen, aryl of unsubstituted or substituted 6-10 ring, heteroaryl of unsubstituted or substituted 5-10 ring containing one or more heteroatoms selected from the group consisting of N, O and S, or - (CH ₂ ) _n -R ³ ,
Wherein said heteroaryl of said substituted 6-10-membered ring or heteroaryl of 5-10-membered ring is selected from the group consisting of C _1-3 straight or branched chain alkyl, C _1-3 straight or branched chain alkoxy and N, O and S Or heterocycloalkyl of an unsubstituted or substituted 5-6-membered ring containing 3 heteroatoms, wherein said heterocycloalkyl of said substituted 5-6-membered ring is substituted with one or more substituents selected from the group consisting of C _{1 -3} &lt; / RTI &gt; linear or branched alkyl,
Wherein R ³ is unsubstituted or substituted heterocycloalkyl of 5-6-membered ring containing at least one heteroatom selected from the group consisting of N, O and S, said substituted heterocycloalkyl being C _1-3 Linear or branched alkyl and oxo groups, and n is an integer of 1 to 3; And

R ² is hydrogen, -XR ⁴ or -NR ⁵ R ⁶ ,
Wherein X is O or S,
R &lt; ⁴ &gt; is straight or branched alkyl of C &lt; _1-5 &gt; substituted or unsubstituted with methoxy or unsubstituted 5-6 rings containing 1-3 heteroatoms selected from the group consisting of N, Lt; RTI ID = 0.0 &gt;
R ⁵ and R ⁶ are each independently -H or a substituted or unsubstituted C _1-5 linear or branched alkyl, a substituted or unsubstituted C _1-5 straight or branched alkoxy, an unsubstituted or substituted 6- Aryl of 10-membered rings, heteroaryl of unsubstituted or substituted 5-10-membered rings containing at least one heteroatom selected from the group consisting of N, O and S, cycloalkyl of unsubstituted or substituted 3-10 heterocyclic ring, Or heterocycloalkyl of unsubstituted or substituted 5-6-membered heterocycles comprising 1-3 heteroatoms selected from the group consisting of N, O and S, or R ⁵ and R ⁶ together are an unsubstituted or substituted 4 -10-membered ring, or a heterocycloalkyl ring of an unsubstituted or substituted 5- to 10-membered ring containing at least one hetero atom selected from the group consisting of N, O and S,
Wherein, the substituted alkyl, alkoxy, substituted aryl, substituted heteroaryl, substituted cycloalkyl, heterocycloalkyl, substituted ring or a substituted heterocycloalkyl ring substituted for the halogen, di-C _{1-substituted-3} Alkylamino, C _1-3 alkyl, or C _1-3 alkoxy).
The method according to claim 1,
R ¹ is hydrogen, heteroaryl of unsubstituted or substituted 5-8-membered rings containing at least one heteroatom selected from the group consisting of aryl, unsubstituted or substituted 6-8-membered ring, N, O and S, or - (CH ₂ ) _n -R ³ ,
Wherein said heteroaryl of said substituted 6-8-membered ring or heteroaryl of 5-8-membered ring is selected from the group consisting of C _1-3 straight or branched chain alkyl, C _1-3 straight or branched chain alkoxy and N, O and S Or heterocycloalkyl of an unsubstituted or substituted 5-6-membered ring containing 3 heteroatoms, wherein said heterocycloalkyl of said substituted 5-6-membered ring is substituted with one or more substituents selected from the group consisting of C _{1 -3} &lt; / RTI &gt; linear or branched alkyl,
Wherein R ³ is unsubstituted or substituted heterocycloalkyl of 5-6-membered ring containing at least one heteroatom selected from the group consisting of N, O and S, said substituted heterocycloalkyl being C _1-3 Linear or branched alkyl and oxo groups, and n is an integer of 1 to 3; And

R ² is hydrogen, -XR ⁴ or -NR ⁵ R ⁶ ,
Wherein X is O or S,
R &lt; ⁴ &gt; is straight or branched alkyl of C &lt; _1-5 &gt; substituted or unsubstituted with methoxy,
R ⁵ and R ⁶ are each independently -H or a substituted or unsubstituted C _1-5 linear or branched alkyl, a substituted or unsubstituted C _1-5 straight or branched alkoxy, an unsubstituted or substituted 6- Cycloalkyl of unsubstituted or substituted 3 to 8-membered rings, heteroaryl of unsubstituted or substituted 5- to 8-membered rings containing at least one heteroatom selected from the group consisting of N, O and S, Or an unsubstituted or substituted 5-8-membered heterocycloalkyl comprising 1-3 heteroatoms selected from the group consisting of N, O and S, or R ⁵ and R ⁶ together are an unsubstituted or substituted 4 -8 form a ring of each ring or form a heterocycloalkyl ring of an unsubstituted or substituted 5- to 8-membered ring containing at least one heteroatom selected from the group consisting of N, O and S,
Wherein, the substituted alkyl, substituted alkoxy, substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted heterocycloalkyl, substituted ring or a substituted heterocycloalkyl rings include halogen, dimethylamino, C _{1 -3} alkyl or C _1-3 alkoxy is substituted, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
R &lt; ^{1 &gt;} is -H,

,

,

,

,

, or

ego; And
R ² is -H,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, or

&Lt; / RTI &gt; or an &lt; RTI ID = 0.0 &gt; pharmaceutically &lt; / RTI &gt; acceptable salt thereof.
The method according to claim 1,
The compound represented by the formula (1) is any one selected from the group consisting of the following compounds, an optical isomer thereof or a pharmaceutically acceptable salt thereof:
(1) Synthesis of 7-formyl-N- (4 - ((2-methoxyethyl) amino) -5-nitropyridin-2-yl) -6- (thiazol- -1,8-naphthyridin-1 (2H) -carboxamide;
(2) Synthesis of 7-formyl-N- (4 - ((2-methoxyethyl) amino) -5-nitropyridin- 3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;
(3) Synthesis of N- (4 - ((2- (dimethylamino) ethyl) amino) -5-nitropyridin- Dihydro-1,8-naphthyridin-1 (2H) -carboxamide;
(4) Synthesis of 7-formyl-N- (4 - ((2-methoxyethyl) amino) -5-nitropyridin- 1, 8-naphthyridin-1 (2H) -carboxamide;
(5) Synthesis of 7-formyl-N- (4 - ((2-methoxyethyl) amino) -5-nitropyridin- 1, 8-naphthyridin-1 (2H) -carboxamide;
(6) Synthesis of N- (4- (4- (dimethylamino) piperidin-1-yl) -5-nitropyridin- Formyl-3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;
(7) Synthesis of N- (4 - ((3- (dimethylamino) propyl) amino) -5-nitropyridin- ) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;
(8) 6- (5-Fluoropyridin-3-yl) -7-formyl-N- (4- -Yl) -3,4-dihydro-i-1,8-naphthyridin-1 (2H) -carboxamide;
(9) 7-Formyl-N- (5-nitropyridin-2-yl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;
(10) Synthesis of 7-formyl-N- (4 - ((2-methoxyethyl) amino) -5-nitropyridin-2-yl) -3,4-dihydro-1,8-naphthyridin- ) -Carboxamide;
(11) Synthesis of 7-formyl-N- (4 - ((4-methoxyphenyl) amino) -5-nitropyridin-2-yl) -3,4-dihydro-1,8-naphthyridin- ) -Carboxamide;
(12) Synthesis of 7-formyl-N- (4 - ((3-methoxyphenyl) amino) -5-nitropyridin-2-yl) -3,4-dihydro-1,8-naphthyridin- ) -Carboxamide;
(13) Synthesis of N- (4- (ethylthio) -5-nitropyridin-2-yl) -7-formyl- , 4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;
(14) 7- Formyl-6 - ((4-methyl-2-oxopiperazin-1-yl) methyl) - dihydro-1,8-naphthyridin-1 (2H) -carboxamide;
(15) 7- (Dimethoxymethyl) -6- (4-methyl-2-oxopiperazin-1 -yl) Pyridin-2-yl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;
(16) Synthesis of N- (4 - ((4-fluorophenyl) amino) -5-nitropyridin-2-yl) ) Methyl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;
(17) Synthesis of N- (4- (cyclohexylamino) -5-nitropyridin-2-yl) -7- , 4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;
(18) Synthesis of 7-formyl-N- (4 - ((2-methoxyethyl) amino) -5-nitropyridin- Yl) methyl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;
(19) Synthesis of N- (4- (ethylamino) -5-nitropyridin-2-yl) -7- 4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;
(20) Synthesis of 7-formyl-N- (4 - ((4-methoxyphenyl) amino) -5-nitropyridin- ) Methyl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide;
(21) Synthesis of N- (4- (2- (dimethylamino) ethylamino) -5-nitropyridin-2-yl) ) Methyl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide; And
(22) Synthesis of N- (4 - ((3-chloro-4-fluorophenyl) amino) -5-nitropyridin- -1-yl) methyl) -3,4-dihydro-1,8-naphthyridin-1 (2H) -carboxamide.
As shown in Scheme 1 below,
Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1); And
Reacting the compound represented by the formula (4) and the compound represented by the formula (5) prepared in the step 1 to prepare a compound represented by the formula (6) (step 2);
A process for producing a compound represented by the general formula (1) as set forth in claim 1, comprising the step of preparing a compound represented by the general formula (1) from the compound represented by the general formula (6)
[Reaction Scheme 1]

(In the above Reaction Scheme 1,
R ¹ and R ² are the same as defined respectively in claim 1 I).
A pharmaceutical composition for preventing or treating FGFR (Fibroblast growth factor receptor) -related disease, which comprises the compound represented by the formula (1) of claim 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
A pharmaceutical composition for preventing or treating cancer comprising the compound represented by the general formula (1) of claim 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
8. The method of claim 7,
Wherein said compound inhibits FGFR (Fibroblast growth factor receptor) to prevent or treat cancer.
8. The method of claim 7,
Wherein the cancer is selected from the group consisting of colon cancer, liver cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, Wherein the composition is at least one selected from the group consisting of vaginal cancer, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, renal cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma central nervous system tumor and leukemia.
A health functional food for preventing or ameliorating cancer comprising the compound represented by the general formula (1) of claim 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.