WO2017164705A1 - Novel pyridine derivative, method for preparing same, and pharmaceutical composition for preventing or treating fgfr-related disease containing same as active component - Google Patents

Abstract

The present invention relates to a novel pyridine derivative, a method for preparing same, and a pharmaceutical composition which contains same as an active component and is for preventing or treating fibroblast growth factor receptor (FGFR)-related disease. A novel pyridine derivative according to the present invention, an optical isomer thereof, and a pharmaceutically acceptable salt of the pyridine derivative can effectively inhibit a fibroblast growth factor receptor (FGFR), and thus FGFR-related disease, preferably has a useful effect on the prevention and treatment of cancer.

Description

Novel pyridine derivatives, preparation methods thereof, and pharmaceutical compositions for the prevention or treatment of FGFR related diseases containing the same as active ingredients

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

Fibroblast growth factor receptor (FGFR) tyrosine kinase consists of about 800 amino acids and contains three immunoglobulin (Ig) -like domains (D1, D2, D3). There are four subtypes FGFR1, FGFR2, FGFR3, and FGFR4 as the type 5 receptor trocine kinases.

Fibroblast growth factor (FGF) and its receptors (FGFR) form part of a unique and diverse signaling system that plays a major role in various physiological processes, including various aspects of embryonic development and adult pathophysiology. FGFs are known to stimulate broad cell functions, including migration, proliferation, differentiation and survival through binding to FGFR.

On the other hand, carcinomas (e.g., bladder, breast, cervix, colorectal, endometrium, stomach, head and neck, kidney, liver, lung, ovary, prostate) from overexpression of FGFR or mutations of FGFR, hematopoietic malignancies (e.g. For example, multiple myeloma, chronic lymphocytic lymphoma, adult T cell leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, myeloproliferative neoplasms and Waldenstrom's Macroglubulinemia, glioblastoma, melanoma and rhabdomyomas This is known to occur, FGFR gene fusion occurs in several types of cancer, and it is known to promote the proliferation of cancer cells by activating FGFR signal transduction, efforts to develop drugs targeting FGFR for the purpose of treating cancer Has been.

In particular, a number of in vitro and in vivo studies have been conducted to identify FGFR-1 to -4 as important cancer targeting agents (Heinzle et al., Expert Opin. Ther. Targets 15 (7)). , 829-846 (2011)), there is no effective drug development at the desired level, and continuous efforts are required.

Accordingly, the present inventors can effectively inhibit FGFR, and while trying to develop drugs for treating diseases such as cancer and tumor therefrom, the compound according to the present invention can effectively inhibit FGFR, After confirming that the growth can be effectively inhibited, the present invention was found to be useful for diseases such as cancer and tumors when used as a pharmaceutical composition containing the same as an active ingredient.

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

Another object of the present invention is to provide a method for preparing the compound.

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

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

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

In order to achieve the above object,

The present invention provides a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Chemical Formula 1,

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

The substituted 6-10-membered aryl and 5-10-membered heteroaryl are independently selected from the group consisting of C _1-3 straight or branched alkyl, C _1-3 straight or branched alkoxy and N, O and S At least one substituent selected from the group consisting of unsubstituted or substituted 5-6 hexacyclic heterocycloalkyl containing 1-3 hetero atoms is substituted, wherein the substituted 5-6 hexacyclic heterocycloalkyl is Substituted with C _1-3 straight or branched alkyl,

R ³ is a 5-6 hexacyclic unsubstituted or substituted heterocycloalkyl including at least one hetero atom selected from the group consisting of N, O and S, wherein the substituted heterocycloalkyl is C _1-3 At least one substituent selected from the group consisting of linear or branched alkyl and oxo groups is substituted, wherein n is an integer of 1-3; And

R ² is hydrogen, —XR ⁴ or —NR ⁵ R ⁶ ,

X is O or S,

R ⁴ is 5- to 6-membered unsubstituted ring containing 1 to 3 heteroatoms selected from the group consisting of C _1-5 straight or branched alkyl unsubstituted or substituted with methoxy or N, O and S; Heterocycloalkyl,

R ⁵ and R ⁶ are each independently -H or substituted or unsubstituted C _1-5 straight or branched alkyl, substituted or unsubstituted C _1-5 straight or branched alkoxy, unsubstituted or substituted 6- Unsubstituted or substituted 5-10 cyclic heteroaryl, unsubstituted or substituted 3-10 cyclic cycloalkyl containing one or more heteroatoms selected from the group consisting of 10 cyclic aryl, N, O and S, Or unsubstituted or substituted 5-6 hexaheterocycloalkyl containing 1-3 hetero atoms selected from the group consisting of N, O and S, or R ⁵ and R ⁶ together are unsubstituted or substituted 4 Form a 10-membered ring or an unsubstituted or substituted 5-10-membered heterocycloalkyl ring containing one or more heteroatoms 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} At least one substituent selected from the group consisting of alkylamino, C _1-3 alkyl or C _1-3 alkoxy is substituted.

In addition, the present invention as shown in Scheme 1,

Preparing a compound represented by Chemical Formula 4 by reacting the compound represented by Chemical Formula 2 with the compound represented by Chemical Formula 3 (step 1); And

Preparing a compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 4 prepared in Step 1 with the compound represented by Chemical Formula 5 (step 2);

It provides a method for producing a compound represented by the formula (1) comprising the step (step 3) of preparing a compound represented by the formula (1) from the compound represented by the formula (6) prepared in step 2.

Scheme 1

In Scheme 1,

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

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating a disease related to Fibroblast growth factor receptor (FGFR) containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. .

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

Furthermore, the present invention provides a health functional food for preventing or improving cancer containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The novel pyridine derivatives, optical isomers thereof and pharmaceutically acceptable salts thereof according to the present invention can effectively inhibit Fibroblast growth factor receptor (FGFR), which is 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 presented to aid in understanding the invention, and the present invention is not limited to the contents of the following description.

The present invention provides a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Chemical Formula 1,

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

The substituted 6-10 cyclic aryl or 5-10 hexacyclic heteroaryl is selected from the group consisting of C _1-3 straight or branched alkyl, C _1-3 straight or branched alkoxy and N, O and S. At least one substituent selected from the group consisting of unsubstituted or substituted 5-6 hexacyclic heterocycloalkyl containing -3 hetero atoms is substituted, wherein the substituted 5-6 hexacyclic heterocycloalkyl is C _{1 Is} substituted with _-3 straight or branched alkyl,

R ³ is a 5-6 hexacyclic unsubstituted or substituted heterocycloalkyl including at least one hetero atom selected from the group consisting of N, O and S, wherein the substituted heterocycloalkyl is C _1-3 At least one substituent selected from the group consisting of linear or branched alkyl and oxo groups is substituted, wherein n is an integer of 1-3; And

R ² is hydrogen, —XR ⁴ or —NR ⁵ R ⁶ ,

X is O or S,

R ⁴ is 5- to 6-membered unsubstituted ring containing 1 to 3 heteroatoms selected from the group consisting of C _1-5 straight or branched alkyl unsubstituted or substituted with methoxy or N, O and S; Heterocycloalkyl,

R ⁵ and R ⁶ are each independently -H or substituted or unsubstituted C _1-5 straight or branched alkyl, substituted or unsubstituted C _1-5 straight or branched alkoxy, unsubstituted or substituted 6- Unsubstituted or substituted 5-10 cyclic heteroaryl, unsubstituted or substituted 3-10 cyclic cycloalkyl containing one or more heteroatoms selected from the group consisting of 10 cyclic aryl, N, O and S, Or unsubstituted or substituted 5-6 hexaheterocycloalkyl containing 1-3 hetero atoms selected from the group consisting of N, O and S, or R ⁵ and R ⁶ together are unsubstituted or substituted 4 Form a 10-membered ring or an unsubstituted or substituted 5-10-membered heterocycloalkyl ring containing one or more heteroatoms 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 substituted heterocycloalkyl ring is halogen, diC _1-3 At least one substituent selected from the group consisting of alkylamino, C _1-3 alkyl or C _1-3 alkoxy is substituted.

Preferably,

R ¹ is hydrogen, unsubstituted or substituted 6-8 cyclic aryl, N, O and S unsubstituted or substituted 5-8 hexacyclic heteroaryl containing one or more heteroatoms selected from the group consisting of, or -(CH ₂ ) _n -R ³ ,

The substituted 6-8 cyclic aryl or 5-8 hexacyclic heteroaryl is selected from the group consisting of C _1-3 straight or branched alkyl, C _1-3 straight or branched alkoxy and N, O and S. At least one substituent selected from the group consisting of unsubstituted or substituted 5-6 hexacyclic heterocycloalkyl containing -3 hetero atoms is substituted, wherein the substituted 5-6 hexacyclic heterocycloalkyl is C _{1 Is} substituted with _-3 straight or branched alkyl,

R ³ is a 5-6 hexacyclic unsubstituted or substituted heterocycloalkyl including at least one hetero atom selected from the group consisting of N, O and S, wherein the substituted heterocycloalkyl is C _1-3 At least one substituent selected from the group consisting of linear or branched alkyl and oxo groups is substituted, wherein n is an integer of 1-3; And

R ² is hydrogen, —XR ⁴ or —NR ⁵ R ⁶ ,

X is O or S,

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

R ⁵ and R ⁶ are each independently -H or substituted or unsubstituted C _1-5 straight or branched alkyl, substituted or unsubstituted C _1-5 straight or branched alkoxy, unsubstituted or substituted 6- Unsubstituted or substituted 5-8 cyclic heteroaryl, unsubstituted or substituted 3-8 cyclic cycloalkyl containing one or more heteroatoms selected from the group consisting of octacyclic aryl, N, O and S, Or unsubstituted or substituted 5-8 cyclic heterocycloalkyl comprising 1-3 hetero atoms selected from the group consisting of N, O and S, or R ⁵ and R ⁶ together are unsubstituted or substituted 4 To form an -8-membered ring or an unsubstituted or substituted 5-8-membered heterocycloalkyl ring containing one or more heteroatoms 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 substituted heterocycloalkyl ring is halogen, dimethylamino, C _{1 At} least one substituent selected from the group consisting of _-3 alkyl or C _1-3 alkoxy is substituted.

More preferably,

R ¹ is -H,

,

,

,

,

, or

ego; And

R ² is -H,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, or

to be.

Preferred examples of the compound represented by Formula 1 according to the present invention include the following compounds.

(1) 7-formyl-N- (4-((2-methoxyethyl) amino) -5-nitropyridin-2-yl) -6- (thiazol-5-yl) -3,4-dihydro -1,8-naphthyridine-1 (2H) -carboxamide;

(2) 7-formyl-N- (4-((2-methoxyethyl) amino) -5-nitropyridin-2-yl) -6- (1-methyl-1H-pyrazol-4-yl)- 3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

(3) N- (4-((2- (dimethylamino) ethyl) amino) -5-nitropyridin-2-yl) -7-formyl-6- (thiazol-5-yl) -3,4- Dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

(4) 7-formyl-N- (4-((2-methoxyethyl) amino) -5-nitropyridin-2-yl) -6- (3-methoxyphenyl) -3,4-dihydro- 1,8-naphthyridine-1 (2H) -carboxamide;

(5) 7-formyl-N- (4-((2-methoxyethyl) amino) -5-nitropyridin-2-yl) -6- (pyridin-3-yl) -3,4-dihydro- 1,8-naphthyridine-1 (2H) -carboxamide;

(6) N- (4- (4- (dimethylamino) piperidin-1-yl) -5-nitropyridin-2-yl) -6- (5-fluoropyridin-3-yl) -7- Formyl-3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

(7) N- (4-((3- (dimethylamino) propyl) amino) -5-nitropyridin-2-yl) -7-formyl-6- (1-methyl-1H-pyrazol-4-yl ) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

(8) 6- (5-fluoropyridin-3-yl) -7-formyl-N- (4-((1-methyl-1H-pyrazol-4-yl) amino) -5-nitropyridine-2 -Yl) -3,4-dihydroi-1,8-naphthyridine-1 (2H) -carboxamide;

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

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

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

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

(13) N- (4- (ethylthio) -5-nitropyridin-2-yl) -7-formyl-6-((4-methyl-2-oxopiperazin-1-yl) methyl) -3 , 4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

(14) 7-formyl-6-((4-methyl-2-oxopiperazin-1-yl) methyl) -N- (4-morpholino-5-nitropyridin-2-yl) -3,4 -Dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

(15) 7- (dimethoxymethyl) -6-((4-methyl-2-oxopiperazin-1-yl) methyl) -N- (5-nitro-4- (piperidin-1-yl) Pyridin-2-yl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

(16) N- (4-((4-fluorophenyl) amino) -5-nitropyridin-2-yl) -7-formyl-6-((4-methyl-2-oxopiperazin-1-yl ) Methyl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

(17) N- (4- (cyclohexylamino) -5-nitropyridin-2-yl) -7-formyl-6-((4-methyl-2-oxopiperazin-1-yl) methyl) -3 , 4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

(18) 7-formyl-N- (4-((2-methoxyethyl) amino) -5-nitropyridin-2-yl) -6-((4-methyl-2-oxopiperazin-1- Yl) methyl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

(19) N- (4- (ethylamino) -5-nitropyridin-2-yl) -7-formyl-6-((4-methyl-2-oxopiperazin-1-yl) methyl) -3, 4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

(20) 7-formyl-N- (4-((4-methoxyphenyl) amino) -5-nitropyridin-2-yl) -6-((4-methyl-2-oxopiperazin-1-yl ) Methyl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

(21) N- (4- (2- (dimethylamino) ethylamino) -5-nitropyridin-2-yl) -7-formyl-6-((4-methyl-2-oxopiperazin-1-yl ) Methyl) -3,4-dihydro-1,8-naphthypyridine-1 (2H) -carboxamide; And

(22) N- (4-((3-chloro-4-fluorophenyl) amino) -5-nitropyridin-2-yl) -7-formyl-6-((4-methyl-2-oxopiperazine -1-yl) methyl) -3,4-dihydro-1,8-naphthypyridine-1 (2H) -carboxamide.

The compound represented by 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 inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, glutaric acid, benzoic acid, citric acid, lactic acid, glulic, unsubstituted or substituted with at least one halogen selected from the group consisting of F, Cl, Br and I Obtained from organic acids such as choline acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, eye Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suve Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chloro Zensulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, 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, a precipitate produced by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and adding an organic or inorganic acid. The solvent may be prepared by filtration and drying, or the solvent and excess acid may be distilled under reduced pressure, dried, and then crystallized under an organic solvent.

Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg silver nitrate).

Furthermore, the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, optical isomers, hydrates, and the like that can be prepared therefrom.

In addition, the present invention as shown in Scheme 1,

Preparing a compound represented by Chemical Formula 4 by reacting the compound represented by Chemical Formula 2 with the compound represented by Chemical Formula 3 (step 1); And

Preparing a compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 4 prepared in Step 1 with the compound represented by Chemical Formula 5 (step 2);

It provides a method for producing a compound represented by the formula (1) comprising the step (step 3) of preparing a compound represented by the formula (1) from the compound represented by the formula (6) prepared in step 2.

Scheme 1

In Scheme 1,

R ¹ and R ² are independently the same as defined in Chemical Formula 1.

Hereinafter, a method for preparing a compound represented by Chemical Formula 1 according to the present invention will be described in detail step by step.

In the method for preparing a compound represented by Chemical Formula 1 according to the present invention, Step 1 is a step of preparing a compound represented by Chemical Formula 4 by reacting the compound represented by Chemical Formula 2 with the compound represented by Chemical Formula 3.

In this case, H 2 O, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile, etc. may be used as the solvent usable in the above step, and preferably H 2 O or tetrahydrofuran (THF) may be used.

In addition, the reaction temperature in the step is preferably carried out between the boiling point of the solvent at 0 ℃, the reaction time is not particularly limited, it is preferable to react for 0.5-20 hours.

In the method for preparing a compound represented by Chemical Formula 1 according to the present invention, Step 2 is a compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 4 prepared in Step 1 with the compound represented by Chemical Formula 5 Manufacturing step.

In this case, as the solvent usable in the step, dimethylformamide (DMF), water, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile and the like can be used, preferably dimethylformamide ( DMF) can be used.

In addition, the reaction temperature in the step is preferably carried out between the boiling point of the solvent at 0 ℃, the reaction time is not particularly limited, it is preferable to react for 0.5-30 hours.

In the method for preparing a compound represented by Formula 1 according to the present invention, Step 3 is a step of preparing a compound represented by Formula 1 from the compound represented by Formula 6 prepared in Step 2.

In this case, as the solvent usable in the step, dimethylformamide (DMF), water, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile and the like can be used, preferably dimethylformamide ( DMF) can be used.

In addition, the reaction temperature in the step is preferably carried out between the boiling point of the solvent at 0 ℃, the reaction time is not particularly limited, it is preferable to react for 0.5-30 hours.

Meanwhile, in the method for preparing a compound represented by Chemical Formula 1, a compound of the present invention may be prepared in a form in which a Suzuki reaction is omitted in the method of Scheme 1, as in Scheme 2 below. Can be prepared.

Scheme 2

In the production method of Scheme 2,

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

In addition, it may be performed similarly to the preparation step of Scheme 1, but the present invention is not limited thereto.

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating a disease related to Fibroblast growth factor receptor (FGFR) containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. .

Herein, the fibroblast growth factor receptor (FGFR) -related disease is not limited to the following, but refers to any disease that can be expressed from a phenomenon other than normal activity such as abnormality, modification, overexpression of FGFR enzyme, and the like. In particular, examples of FGFR-related diseases include cancer, where the compounds of the present invention, the optical isomers thereof and acceptable salts thereof, may be responsible for the activity of FGFR when it results from aberrant activity of FGFR in connection with cell proliferation of cancer cells. It can be effectively suppressed in molar units and can be usefully used for the prevention or treatment of diseases referred to as the above-mentioned FGFR-related diseases.

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

Here, the compound may be characterized by preventing or treating cancer by inhibiting Fibroblast growth factor receptor (FGFR), the cancer may be 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, anal muscle cancer, colon cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureter cancer One or two or more selected from the group consisting of renal cell carcinoma, renal pelvic carcinoma central nervous system tumor and leukemia.

Furthermore, the present invention provides a health functional food for preventing or improving cancer containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Here, the compound may be characterized in that it inhibits Fibroblast growth factor receptor (FGFR) to prevent or improve cancer, the cancer is colon cancer, liver cancer, gastric cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, Uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, anal muscle cancer, colon cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureter cancer One or two or more selected from the group consisting of renal cell carcinoma, renal pelvic carcinoma central nervous system tumor and leukemia.

The compound represented by Formula 1 according to the present invention may be administered in various oral and parenteral formulations during clinical administration, and when formulated, the commonly used fillers, extenders, binders, humectants, disintegrating agents, surfactants, and the like. Prepared using diluents or excipients.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, troches and the like, which solid preparations contain at least one excipient such as starch, calcium carbonate, water, or the like. It is prepared by mixing cross, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, solvents, emulsions or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.

In addition, the effective dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is generally about 0.001-100 mg / kg / day, preferably Preferably 0.01-35 mg / kg / day. Based on an adult patient weighing 70 kg, it is generally 0.07-7000 mg / day, preferably 0.7-2500 mg / day, once a day at regular intervals according to the judgment of the doctor or pharmacist. Multiple doses may be administered.

Experiments have confirmed that the compounds according to the invention, their optical isomers, or pharmaceutically acceptable salts thereof have a useful effect in the treatment of FGFR related diseases in the present invention.

First, as a result of performing the following experiment to evaluate the inhibitory activity of the compound according to the present invention against FGFR 4 enzyme, it was confirmed that the example compound of the present invention has inhibitory activity against FGFR 4, nanomolar units It can be seen that it has a good inhibitory activity of the compounds according to the present invention, as well as FGFR-related diseases, cancers derived therefrom, for example, colon cancer, liver cancer, gastric cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, tofu or Cervical cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, anal muscle cancer, colon cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, urinary tract Cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor, and the distal potential of leukemia or solid tumor can be usefully used for the prevention and treatment of cancer (experimental 1).

In addition, the compound according to the present invention specifically evaluated the effect of inhibiting cancer cell proliferation through the inhibition of extracellular signal-regulated kinase activity, as a result of experiments on the human liver cancer cell line Huh-7 cell line, the embodiment of the present invention Compounds have been shown to effectively inhibit cancer cell proliferation in human cancer cell line Huh7, and not only FGFR related diseases, but also cancers derived therefrom, such as colon cancer, liver cancer, gastric cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or Cervical cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, anal muscle cancer, colon cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, urinary tract It can be usefully used for the prevention and treatment of cancer, renal cell carcinoma, renal pelvic carcinoma central nervous system tumor and cancer that is distal dislocation of leukemia or solid tumor.

Hereinafter, the present invention will be described in detail by production examples, examples and experimental examples.

However, the following Preparation Examples, Examples and Experimental Examples are merely illustrative of the present invention, but the content of the present invention is not limited thereto.

Compounds synthesized in Preparation Examples and Examples of the present invention were purified by the following HPLC conditions or subjected to structural analysis.

Analytical HPLC Conditions:

Gradient condition (7 min at 5-100% B, travel rate = 1.0 ml / min), YMC-Park Pro C18, 150 × 4.6 mm column, solvent A (0.1% TFA in water), solvent B (CH ₃ CN) .

Preparative HPLC Conditions:

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

< Production Example  1> N4- (2- Methoxyethyl ) -5- Nitropyridine -2,4- Diamine  Produce

4-chloro-5-nitropyridin-2-amine (1 g, 5.76 mmol) and diisopropylethylamine (4 ml, 23.05 mmol) were dissolved in dimethylformamide (11 ml), followed by 2-methoxyethylamine (2 ml, 23.05 mmol) was added and stirred at 40 ° C. for 15 h. 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 target compound (868 mg).

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

< Production Example  2> 1-((2- ( Dimethoxymethyl ) -5,6,7,8- Tetrahydro -1,8- Naphthyridine Preparation of -3-yl) methyl) -4-methylpiperazin-2-one

Step 1: ethyl 2-((2- ( tert - Butoxycarbonylamino )ethyl)( Methylamino Manufacture of Acetate

Ethyl bromoacetate in a mixed 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) 2.54 ml, 22.9 mmol) was added at 0 ° C., and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was extracted with dichloromethane and saturated aqueous sodium bicarbonate solution and the organic layers were combined. The combined organic layers were dried over sodium sulfate, and then concentrated under reduced pressure to obtain the target 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

Concentrated hydrochloric acid (20 ml) was added to a mixed solution of tetrahydrofuran (30 ml) and ethanol (150 ml) in which the compound (6.0 g, 22.6 mmol) prepared in Step 1 was dissolved at room temperature, and then stirred at room temperature for 1 hour. Stirred. The reaction solution was concentrated under reduced pressure, and then ethanol (100 ml) was added and stirred at 60 ° C. for 70 minutes. The reaction was cooled to room temperature and then concentrated under reduced pressure to afford 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) , 1.21 (t, 3 H).

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

The compound (12 g, 57.6 mmol) prepared in step 2 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 reaction residue obtained above was extracted with diethyl ether and ice water, and then the combined organic layers were washed with brine, dried over sodium sulfate, concentrated under reduced pressure and purified by MPLC to give the title compound as a yellow solid (11 g, 66%) was obtained.

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, 2H), 1.86 (m, 2H).

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

Methyllithium (1.6 M in ether, 16.3 ml, 26.1 mmol) was slowly added dropwise at -78 ° C to a solution of the compound (7.5 g, 26.1 mmol) prepared in Step 3 in tetrahydrofuran (200 ml). After stirring the reaction mixture for 5 minutes, n-butyllithium (1.6 M in hexane, 18 ml, 28.7 mmol) was slowly added dropwise. After the mixture was stirred for 20 minutes, tetrahydrofuran (50 ml) was added at -78 ° C. N-butyllithium (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 ° C for 10 minutes. Dimethylformamide (1.05 ml, 18.6 mmol) was added and the reaction mixture was stirred at −78 ° C. for 45 minutes, then the temperature was slowly raised to room temperature. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound.

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

step 5: 1 -((2-( Dimethoxymethyl ) -5,6,7,8- Tetrahydro -1,8- Naphthyridine Preparation of -3-yl) methyl) -4-methylpiperazin-2-one

Compound (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) prepared in step 4; mmol) was dissolved in 1,2-dichloroethane (13 ml), and sodium triacetoxyborohydride (1.65 g) was added to the solution, followed by stirring 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. Then sodium triacetoxyborohydride (552 mg) was added and stirred at 4 ° C. for 2.5 days. The reaction mixture was warmed to room temperature and neutralized with saturated aqueous sodium bicarbonate solution. The reaction 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 target compound (1 g, 57%).

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

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

step 1: 4 - Nitrophenyl  6- Bromo -7- ( Dimethoxymethyl ) -3,4- Dehydro -1,8- Naphthyridine Preparation of -1 (2H) -carboxylate

In a mixed solution of dichloromethane (23 ml) in which 4-nitrophenyl carbonochlorate (1.404 g, 6.96 mmol) was dissolved, the compound (2 g, 6.96 mmol) and pyridine prepared in Step 3 of Preparation Example 2 above ( 0.620 ml, 7.66 mmol) was added and the reaction mixture was stirred at rt for 24 h. 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 obtain the target 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 Preparation of 2-Nyl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide

Compound (0.663 g, 3.12 mmol) and sodium hydride (0.375 g, 9.37 mmol) prepared in Preparation Example 1 were added to dimethylformamide (1.3 mL) and stirred for 10 minutes. Thereafter, the compound prepared in Step 1 (2.118 g, 4.68 mmol) was added thereto, 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 title 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 Preparation of 2-yl) -6- (thiazol-5-yl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide

To a mixed solution of dimethoxyethane (1.5 ml) in which the compound (50 mg, 0.095 mmol) prepared in step 2 was dissolved, 5- (4,4,5,5-tetramethyl-1,3,2-dioxa Add boror-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) It was. The reaction mixture was stirred at 120 ° C. for 30 minutes under microwave. The reaction mixture was extracted with dichloromethane and brine to combine the organic layers. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure and purified by MPLC to give the title 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 -2- day) -6- ( Thiazole Preparation of -5-yl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide

To the mixed solution in which the compound (18 mg, 0.034 mmol) prepared in step 3 was dissolved in tetrahydrofuran (1 ml) was added water (0.4 ml) and Conc.HCl (10.33 μl, 0.340 mmol), followed by reaction. The mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified by prep to give the title compound (2.8 mg, 17%) as a yellow solid.

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

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

2-methyl-4 in place of 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) thiazole used in Step 3 of Example 1 above Except for using-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-imidazole, the procedure was performed in the same manner as Example 1 Was prepared.

MS (m / z): 481 [M + 1], ¹ H NMR (400 MHz, CDCl ₃ ) δ 13.94 (s, 1H), 10.24 (s, 1H), 9.14 (s, 1H), 8.45 (s, 1H), 7.80 (s, 1H), 7.69 (s, 2H), 7.65 (s, 1H), 4.12 (s, 2H), 4.01 (s, 3H), 3.70 (m, 2H), 3.59 (s, 2H ), 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 Preparation of 2-yl) -7-formyl-6- (thiazol-5-yl) -3,4-dihydro-1,8-naphthyridine-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 The desired compound was prepared in a similar manner to Example 1, except that pyridine-2,4-diamine was used.

MS (m / z): 497 [m + 1], ¹ H NMR (400 MHz, DMSO) δ 13.61 (s, 1H), 10.04 (s, 1H), 9.28 (s, 1H), 8.98 (s, 1H ), 8.55 (t, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.68 (s, 1H), 4.03 (m, 2H), 3.82-3.78 (m, 2H), 3.41-3.39 ( 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 Preparation of 2-yl) -6- (3-methoxyphenyl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide

2- (3- instead of 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) thiazole used in step 3 of Example 1 above A target compound was prepared in the same manner as in Example 1, except that methoxyphenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used.

MS (m / z): 507 [m + 1], ¹ H NMR (400 MHz, DMSO) δ 13.69 (s, 1H), 9.93 (s, 1H), 8.94 (s, 1H), 8.43 (t, 1H ), 7.90 (s, 1H), 7.71 (s, 1H), 7.41 (t, 1H), 7.09 (s, 1H), 7.08-7.04 (m, 2H), 4.01 (t, 2H), 3.81 (s, 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 Preparation of 2-yl) -6- (pyridin-3-yl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide

3- (4, in place of 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) thiazole, used in Step 3 of Example 1 above The desired compound was prepared in the same manner as in Example 1, except that 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine was used.

MS (m / z): 478 [M + l], ¹ H NMR (400 MHz, CDCl ₃ ) δ 13.68 (s, 1H), 10.12 (s, 1H), 9.10 (s, 1H), 8.91 (m, 1H), 8.82 (m, 1H), 8.60 (m, 1H), 8.26 (d, 1H), 7.84 (m, 1H), 7.74 (s, 1H), 7.61 (s, 1H), 4.22 (m, 2H ), 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> N- (4- (4- (dimethylamino) piperidin-1-yl) -5-nitropyridin-2-yl) -6- (5-fluoropyridin-3-yl) -7-formyl Preparation of -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide

4- (4- (dimethylamino) piperidin-1-yl instead of N ^4- (2-methoxyethyl) -5-nitropyridin-2,4-diamine, used in Step 2 of Example 1 above 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-, which was used in step 3 of Example 1 above, using) -5-nitropyridin-2-amine Except for using 3-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine in place of 2-yl) thiazole In the same manner as in Example 1, to prepare a target compound.

MS (m / z): 549 [m + 1], ¹ H NMR (400 MHz, CDCl ₃ ) δ 13.75 (s, 1H), 10.15 (s, 1H), 8.80 (s, 1H), 8.57 (d, 1H), 8.41 (s, 1H), 7.91 (s, 1H), 7.56 (s, 1H), 7.46-7.42 (m, 1H), 4.17-4.14 (m, 2H), 3.60-3.56 (m, 2H) , 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> N- (4-((3- (dimethylamino) propyl) amino) -5-nitropyridin-2-yl) -7-formyl-6- (1-methyl-1H-pyrazol-4-yl) Preparation of -3,4-dihydro-1,8-naphthyridine-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 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, using pyridine-2,4-diamine and used in Step 3 of Example 1 above Except that 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-imidazole was used in place of thiazole In the same manner as in Example 1, to prepare a target compound.

MS (m / z): 508 [m + 1], ¹ H NMR (400 MHz, DMSO) δ 13.68 (s, 1H), 10.12 (s, 1H), 8.97 (s, 1H), 8.51 (t, 1H ), 8.18 (s, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.69 (s, 1H), 4.01-3.99 (m, 2H), 3.92 (s, 3H), 3.50-3.45 ( m, 2H), 3.19-3.14 (m, 2H), 2.96 (t, 2H), 2.81 (s, 3H), 2.80 (s, 3H), 2.07-2.02 (m, 2H), 2.00-1.96 (m, 2H); HPCL: 4.479 min.

< Example  8> 6- (5-fluoropyridin-3-yl) -7-formyl-N- (4-((1-methyl-1H-pyrazol-4-yl) amino) -5-nitropyridine-2- I) -3,4-Dihydroi-1,8-naphthyridine-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- (4,4,5,5-tetramethyl-1,3,2-dioxaboro, using) -5-nitropyridine-2,4-diamine and used in step 3 of Example 1 above. 3-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine in place of lan-2-yl) thiazole Except for the same procedure as in Example 1, except that the target compound was prepared.

MS (m / z): 518 [m + 1], 1 H NMR (400 MHz, CDCl 3) δ 13.77 (s, 1H), 10.16 (s, 1H), 10.04 (s, 1H), 9.16 (s, 1H) , 8.56 (d, 1H), 8.53 (s, 1H), 8.41 (s, 1H), 7.55 (s, 1H), 7.45-7.42 (m, 1H), 7.41 (d, 1H), 6.30 (d, 1H ), 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- Dehydro -1,8- Naphthyridine Preparation of -1 (2H) -Carboxamide

step 1: 4 - Nitrophenyl  7- ( Dimethoxymethyl ) -3,4- Dihydro -1,8- Naphthyridine Preparation of -1 (2H) -carboxylate

7- (dimethoxymethyl) -1,2,3,4-tetrahydro-1,8-naphthyridine was used in place of the compound prepared in Step 3 of Preparation Example 2, which was used in Step 1 of Example 1. Except for the use, it was carried out in the same manner as in Step 1 of Example 1 to prepare a target compound.

step 2: 7 -( Dimethoxymethyl ) -N- (5- Nitropyridine -2-yl) -3,4- Dehydro -1,8- Naphthyridine Preparation of -1 (2H) -Carboxamide

5-nitropyridin-2-amine and sodium hydride were added to dimethylformamide and stirred for 10 minutes. Thereafter, the compound prepared in Step 1 was added thereto, 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 title compound as a yellow solid.

step 3: 7 - Formyl -N- (5- Nitropyridine Preparation of 2-Nyl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide

Water (0.5 ml) and Conc.HCl (20 μl) were added to a mixed solution of the compound prepared in Step 2 (15 mg, 0.04 mmol) in tetrahydrofuran (1 ml), and then the reaction mixture was cooled to room temperature. Stirred for 3 h. After completion of the reaction, the reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified by prep to give the title compound (3.8 mg, 29%) as a yellow solid.

MS (m / z): 328 [M + l], ¹ H NMR (400 MHz, DMSO) δ 13.86 (s, 1H), 9.94 (s, 1H), 8.27 (m, 2H), 7.93 (d, 1H ), 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 Preparation of 2-yl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide

Except for using N ^4- (2-methoxyethyl) -5-nitropyridine-2,4-diamine in place of 5-nitropyridin-2-amine, which was used in Step 2 of Example 9 above. The preparation of the desired compound was carried out in analogy to Example 9.

MS (m / z): 401 [M + l], ¹ H NMR (400 MHz, CDCl ₃ ) δ 15.49 (s, 1H), 10.03 (s, 1H), 9.19 (s, 1H), 8.85 (s, 1H), 7.80 (d, 2H), 7.66 (d, 2H), 7.41 (s, 1H), 3.75 (t, 4H), 3.46 (s, 3H), 2.99 (t, 2H), 2.08 (s, 2H ); HPLC: 6.245 min.

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

N ⁴ in place of the 5-nitropyridin-2-amine used in Step 2 of Example 9, except for using (4-methoxyphenyl) -5-nitropyridine-2,4-diamine, and the above-described The preparation of the desired compound was carried out in analogy to Example 9.

MS (m / z): 449 [M + l], ¹ H NMR (400 MHz, CDCl ₃ ) δ 14.20 (s, 1H), 10.04 (s, 1H), 9.86 (s, 1H), 9.24 (s, 1H), 7.70 (t, 2H), 7.62 (d, 1H), 7.28 (d, 2H), 7.05 (d, 2H), 4.03 (m, 2H), 3.88 (s, 3H), 2.94 (m, 2H ), 2.02 (m, 2 H); HPLC: 7.537 min.

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

Except for using N ^4- (3-methoxypropyl) -5-nitropyridine-2,4-diamine in place of 5-nitropyridin-2-amine, which was used in Step 2 of Example 9 above The preparation of the desired compound was carried out in analogy to Example 9.

MS (m / z): 415 [M + l], ¹ H NMR (400 MHz, CDCl ₃ ) δ 15.47 (s, 1H), 10.03 (s, 1H), 9.45 (s, 1H), 9.17 (s, 1H), 7.80 (d, 1H), 7.66 (d, 1H), 7.34 (s, 1H), 4.09 (s, 2H), 3.66 (m, 4H), 3.44 (s, 3H), 2.98 (m, 2H ), 2.10 (m, 4 H); HPLC: 6.270 min.

< Example  13> N- (4- ( Ethylthio ) -5- Nitropyridine 2-yl) -7- Formyl -6-((4- methyl Preparation of 2-oxopiperazin-1-yl) methyl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide

Using the compound prepared in Preparation Example 2 in place of 7- (dimethoxymethyl) -1,2,3,4-tetrahydro-1,8-naphthyridine used in Step 1 of Example 9, Example 9 was carried out in the same manner as in Example 9, except that 4- (ethylthio) -5-nitropyridin-2-amine was used instead of 5-nitropyridin-2-amine. To prepare the target compound.

MS (m / z): 514 [M + l], ¹ H NMR (400 MHz, CDCl ₃ ) δ 14.00 (s, 1H), 10.24 (s, 1H), 9.12 (s, 1H), 8.37 (s, 1H), 7.69 (s, 1H), 5.19 (m, 2H), 4.10 (m, 2H), 3.74 (m, 2H), 3.68 (m, 2H), 3.35 (m, 2H), 3.08 (q, 2H ), 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- Morpholino Preparation of -5-nitropyridin-2-yl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide

Example 13 except that 4-morpholino-5-nitropyridin-2-amine was used in place of 4- (ethylthio) -5-nitropyridin-2-amine used in Example 13. Similarly, the desired compound was prepared.

MS (m / z): 539 [m + 1], 1 H NMR (400 MHz, CDCl 3) δ 13.82 (s, 1H), 10.24 (s, 1H), 8.77 (s, 1H), 7.89 (s, 1H) , 7.64 (s, 1H), 5.09 (s, 2H), 4.10-4.07 (m, 2H), 3.88-3.86 (m, 4H), 3.37-3.36 (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  15> 7- (dimethoxymethyl) -6-((4-methyl-2-oxopiperazin-1-yl) methyl) -N- (5-nitro-4- (piperidin-1-yl) pyridine Preparation of 2-yl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide

Except for using 5-nitro-4- (piperidin-1-yl) pyridin-2-amine in place of 4- (ethylthio) -5-nitropyridin-2-amine used in Example 13, In the same manner as in Example 13, to prepare a target compound.

MS (m / z): 537 [m + 1], ¹ H NMR (400 MHz, CDCl ₃ ) δ 13.69 (s, 1H), 10.24 (s, 1H), 8.70 (s, 1H), 7.87 (s, 1H), 7.63 (s, 1H), 5.09 (s, 2H), 4.10-4.07 (m, 2H), 3.37-3.34 (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  16> N- (4-((4-fluorophenyl) amino) -5-nitropyridin-2-yl) -7-formyl-6-((4-methyl-2-oxopiperazin-1-yl) Preparation of Methyl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide

Except for using 5-nitropyridine-2,4-diamine (4-fluorophenyl) - in place of 4- (ethyl-thio) -5-nitropyridin-2-amine used in Example 13 N ⁴ And the target compound was prepared in the same manner as in Example 13.

MS (m / z): 563 [m + 1], ¹ H NMR (400 MHz, CDCl ₃ ) δ 13.78 (s, 1H), 10.24 (s, 1H), 9.72 (s, 1H), 9.10 (s, 1H), 7.85 (s, 1H), 7.62 (s, 1H), 7.35-7.32 (m, 2H), 7.21-7.17 (m, 2H), 5.08 (s, 2H), 4.02-4.00 (m, 2H) , 3.36-3.34 (m, 2H), 3.19 (s, 2H), 2.91-2.88 (m, 2H), 2.67-2.64 (m, 2H), 2.35 (s, 3H), 2.00-1.97 (m, 2H) ; HPLC: 5.485 min.

< Example  17> N- (4- (cyclohexylamino) -5-nitropyridin-2-yl) -7-formyl-6-((4-methyl-2-oxopiperazin-1-yl) methyl) -3, Preparation of 4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide

Example 4 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. Proceed similarly to 13 to prepare the target compound.

MS (m / z): 551 [M + l], ¹ H NMR (400 MHz, CDCl ₃ ) δ 13.84 (s, 1H), 10.20 (s, 1H), 9.11 (s, 1H), 8.46 (m, 2H), 7.77 (s, 1H), 7.71 (s, 1H) 5.13 (m, 2H), 4.07 (m, 2H), 3.83 (m, 2H), 3.72 (m, 4H), 3.44 (m, 2H) , 2.96 (m, 2H), 2.90 (s, 3H), 2.10 (m, 2H), 2.03 (m, 2H), 1.80 (m, 2H), 1.68 (m, 1H) 1.47 (m, 4H); HPLC: 5.609 min.

< Example  18> 7-formyl-N- (4-((2-methoxyethyl) amino) -5-nitropyridin-2-yl) -6-((4-methyl-2-oxopiperazin-1-yl Preparation of Methyl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide

Except for using N ^4- (2-methoxyethyl) -5-nitropyridine-2,4-diamine in place of 4- (ethylthio) -5-nitropyridin-2-amine used in Example 13. And the target compound was prepared in the same manner as in Example 13.

MS (m / z): 526 [m + 1], ¹ H NMR (400 MHz, DMSO) δ 13.65 (s, 1H), 10.09 (s, 1H), 8.94 (s, 1H), 8.44 (t, 1H ), 7.68 (s, 1H), 7.66 (s, 1H), 4.96 (s, 2H), 4.01-3.98 (m, 4H), 3.62 (t, 2H), 3.54-3.50 (m, 5H), 3.32 ( 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 2-yl) -7- Formyl -6-((4- methyl Preparation of 2-oxopiperazin-1-yl) methyl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide

Example 13 above, except that N ⁴ -ethyl-5-nitropyridin-2,4-diamine was used in place of the 4- (ethylthio) -5-nitropyridin-2-amine used in Example 13. Was carried out similarly to prepare the desired compound.

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 ), 7.66 (s, 2H), 4.96 (s, 2H), 4.00 (m, 2H), 3.54 (s, 2H), 3.40 (m, 2H), 3.16 (s, 2H), 2.95 (m, 2H) ; HPLC: 4.705 min.

< Example  20> 7-formyl-N- (4-((4-methoxyphenyl) amino) -5-nitropyridin-2-yl) -6-((4-methyl-2-oxopiperazin-1-yl) Preparation of Methyl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide

In place of 4- (ethyl-thio) -5-nitropyridin-2-amine used in Example 13 N ⁴ - except for using (4-methoxyphenyl) -5-nitropyridine-2,4-diamine And the target compound was prepared in the same manner as in Example 13.

MS (m / z): 575 [M + l], ¹ H NMR (400 MHz, DMSO) δ 13.59 (s, 1H), 10.07 (s, 1H), 9.75 (s, 1H), 8.99 (s, 1H ), 7.63 (d, 2H), 7.30 (d, 2H), 7.06 (d, 2H), 4.94 (s, 2H), 3.98 (m, 2H), 3.87 (m, 2H), 3.82 (s, 3H) , 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  21> N- (4- (2- (dimethylamino) ethylamino) -5-nitropyridin-2-yl) -7-formyl-6-((4-methyl-2-oxopiperazin-1-yl) Preparation of Methyl) -3,4-dihydro-1,8-naphthypyridine-1 (2H) -carboxamide

N ^4- (2- (dimethylamino) ethyl) -5-nitropyridine-2,4-diamine in place of 4- (ethylthio) -5-nitropyridin-2-amine used in Example 13 A target compound was prepared in the same manner as in Example 13 except for the above.

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 , 1H), 7.65 (s, 1H), 7.63 (s, 1H), 5.10 (s, 2H), 4.10-4.07 (m, 2H), 3.46-3.42 (m, 2H), 3.37-3.34 (m, 2H ), 3.20 (s, 2H), 2.94-2.91 (m, 2H), 2.68-2.65 (m, 2H), 2.35 (s, 3H), 2.33 (s, 6H), 2.07-2.03 (m, 2H); HPLC: 3.998 min.

< Example  22> N- (4-((3-chloro-4-fluorophenyl) amino) -5-nitropyridin-2-yl) -7-formyl-6-((4-methyl-2-oxopiperazin- Preparation of 1-yl) methyl) -3,4-dihydro-1,8-naphthypyridine-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 A target compound was prepared in the same manner as in Example 13 except that was used.

MS (m / z): 597 [m + 1], 1 H NMR (400 MHz, DMSO) δ 13.69 (s, 1H), 10.07 (s, 1H), 9.85 (s, 1H), 9.02 (s, 1H) , 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 (m, 2H), 3.88 (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

< Experimental Example  1> FGFR  4 Inhibitory Activity Assessment

In order to evaluate the inhibitory activity against the FGFR 4 enzyme of the compound according to the present invention, the following experiment was performed.

Specifically, FGFR 4 enzymatic activity of the compound according to the present invention was performed by Reaction Biology, and 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

Looking at Table 2, it can be seen that the Example compound according to the present invention inhibits FGFR 4 at a nanomolar unit concentration.

Therefore, as described in Experimental Example 1, the compound according to the present invention, its optical isomers and pharmaceutically acceptable salts thereof can effectively inhibit FGFR, thereby preventing FGFR-related diseases, such as cancer and It can be usefully used for treatment.

Experimental Example 2 Evaluation of Cancer Cell Proliferation Inhibitory Activity

In order to evaluate the inhibitory activity against cancer cell proliferation of the compound according to the present invention, the following experiment was performed.

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, 20 μl / well of the culture medium containing 9 concentrations (0.0015-10 μM) of Example compound and DMSO control, which were serially diluted in multiples of 3, were added in 20 μl / well and the final concentration was 0-10 μM, followed by 37 ° C CO ₂ Incubate for 72 hours in the incubator. After 72 hours, 50 μl of CellTiter-Glo solution is added to each well, orbital shaken for 2 minutes and left in the absence of light for 10 minutes. Thereafter, 100 μl from each well in the dark is transferred to a white plate and luminescence is measured under an integration time of 500 ms with a TECAN microplate reader. GI ₅₀ (Growth inhibition 50%) was 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 based on 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)

Looking at Table 3, it can be seen that the Example compound of the present invention inhibits the proliferation of Huh-7 which is a human liver cancer cell line.

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

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

Claims (10)

1. A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

   [Formula 1]

   

   (In the above formula 1,

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

   The substituted 6-10 cyclic aryl or 5-10 hexacyclic heteroaryl is selected from the group consisting of C _1-3 straight or branched alkyl, C _1-3 straight or branched alkoxy and N, O and S. At least one substituent selected from the group consisting of unsubstituted or substituted 5-6 hexacyclic heterocycloalkyl containing -3 hetero atoms is substituted, wherein the substituted 5-6 hexacyclic heterocycloalkyl is C _{1 Is} substituted with _-3 straight or branched alkyl,

   R ³ is a 5-6 hexacyclic unsubstituted or substituted heterocycloalkyl including at least one hetero atom selected from the group consisting of N, O and S, wherein the substituted heterocycloalkyl is C _1-3 At least one substituent selected from the group consisting of linear or branched alkyl and oxo groups is substituted, wherein n is an integer of 1-3; And

   R ² is hydrogen, —XR ⁴ or —NR ⁵ R ⁶ ,

   X is O or S,

   R ⁴ is 5- to 6-membered unsubstituted ring containing 1 to 3 heteroatoms selected from the group consisting of C _1-5 straight or branched alkyl unsubstituted or substituted with methoxy or N, O and S; Heterocycloalkyl,

   R ⁵ and R ⁶ are each independently -H or substituted or unsubstituted C _1-5 straight or branched alkyl, substituted or unsubstituted C _1-5 straight or branched alkoxy, unsubstituted or substituted 6- Unsubstituted or substituted 5-10 cyclic heteroaryl, unsubstituted or substituted 3-10 cyclic cycloalkyl containing one or more heteroatoms selected from the group consisting of 10 cyclic aryl, N, O and S, Or unsubstituted or substituted 5-6 hexaheterocycloalkyl containing 1-3 hetero atoms selected from the group consisting of N, O and S, or R ⁵ and R ⁶ together are unsubstituted or substituted 4 Form a 10-membered ring or an unsubstituted or substituted 5-10-membered heterocycloalkyl ring containing one or more heteroatoms 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} At least one substituent selected from the group consisting of alkylamino, C _1-3 alkyl or C _1-3 alkoxy).
2. The method of claim 1,

   R ¹ is hydrogen, unsubstituted or substituted 6-8 cyclic aryl, N, O and S unsubstituted or substituted 5-8 hexacyclic heteroaryl containing one or more heteroatoms selected from the group consisting of, or -(CH ₂ ) _n -R ³ ,

   The substituted 6-8 cyclic aryl or 5-8 hexacyclic heteroaryl is selected from the group consisting of C _1-3 straight or branched alkyl, C _1-3 straight or branched alkoxy and N, O and S. At least one substituent selected from the group consisting of unsubstituted or substituted 5-6 hexacyclic heterocycloalkyl containing -3 hetero atoms is substituted, wherein the substituted 5-6 hexacyclic heterocycloalkyl is C _{1 Is} substituted with _-3 straight or branched alkyl,

   R ³ is a 5-6 hexacyclic unsubstituted or substituted heterocycloalkyl including at least one hetero atom selected from the group consisting of N, O and S, wherein the substituted heterocycloalkyl is C _1-3 At least one substituent selected from the group consisting of linear or branched alkyl and oxo groups is substituted, wherein n is an integer of 1-3; And

   R ² is hydrogen, —XR ⁴ or —NR ⁵ R ⁶ ,

   X is O or S,

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

   R ⁵ and R ⁶ are each independently -H or substituted or unsubstituted C _1-5 straight or branched alkyl, substituted or unsubstituted C _1-5 straight or branched alkoxy, unsubstituted or substituted 6- Unsubstituted or substituted 5-8 cyclic heteroaryl, unsubstituted or substituted 3-8 cyclic cycloalkyl containing one or more heteroatoms selected from the group consisting of octacyclic aryl, N, O and S, Or unsubstituted or substituted 5-8 cyclic heterocycloalkyl comprising 1-3 hetero atoms selected from the group consisting of N, O and S, or R ⁵ and R ⁶ together are unsubstituted or substituted 4 To form an -8-membered ring or an unsubstituted or substituted 5-8-membered heterocycloalkyl ring containing one or more heteroatoms 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 substituted heterocycloalkyl ring is halogen, dimethylamino, C _{1 At} least one substituent selected from the group consisting of _-3 alkyl or C _1-3 alkoxy, optical isomers thereof or pharmaceutically acceptable salts thereof.
3. The method of claim 1,

   R ¹ is -H,

   

   ,

   

   ,

   

   ,

   

   ,

   

   , or

   

   ego; And

   R ² is -H,

   

   ,

   

   ,

   

   ,

   

   ,

   

   ,

   

   ,

   

   ,

   

   ,

   

   ,

   

   ,

   

   ,

   

   ,

   

   ,

   

   ,

   

   ,

   

   ,

   

   , or

   

   Compound, optical isomer thereof or pharmaceutically acceptable salt thereof.
4. The method of claim 1,

   The compound represented by Formula 1 is any one selected from the following compound group, optical isomer thereof or pharmaceutically acceptable salt thereof:

   (1) 7-formyl-N- (4-((2-methoxyethyl) amino) -5-nitropyridin-2-yl) -6- (thiazol-5-yl) -3,4-dihydro -1,8-naphthyridine-1 (2H) -carboxamide;

   (2) 7-formyl-N- (4-((2-methoxyethyl) amino) -5-nitropyridin-2-yl) -6- (1-methyl-1H-pyrazol-4-yl)- 3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

   (3) N- (4-((2- (dimethylamino) ethyl) amino) -5-nitropyridin-2-yl) -7-formyl-6- (thiazol-5-yl) -3,4- Dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

   (4) 7-formyl-N- (4-((2-methoxyethyl) amino) -5-nitropyridin-2-yl) -6- (3-methoxyphenyl) -3,4-dihydro- 1,8-naphthyridine-1 (2H) -carboxamide;

   (5) 7-formyl-N- (4-((2-methoxyethyl) amino) -5-nitropyridin-2-yl) -6- (pyridin-3-yl) -3,4-dihydro- 1,8-naphthyridine-1 (2H) -carboxamide;

   (6) N- (4- (4- (dimethylamino) piperidin-1-yl) -5-nitropyridin-2-yl) -6- (5-fluoropyridin-3-yl) -7- Formyl-3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

   (7) N- (4-((3- (dimethylamino) propyl) amino) -5-nitropyridin-2-yl) -7-formyl-6- (1-methyl-1H-pyrazol-4-yl ) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

   (8) 6- (5-fluoropyridin-3-yl) -7-formyl-N- (4-((1-methyl-1H-pyrazol-4-yl) amino) -5-nitropyridine-2 -Yl) -3,4-dihydroi-1,8-naphthyridine-1 (2H) -carboxamide;

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

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

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

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

   (13) N- (4- (ethylthio) -5-nitropyridin-2-yl) -7-formyl-6-((4-methyl-2-oxopiperazin-1-yl) methyl) -3 , 4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

   (14) 7-formyl-6-((4-methyl-2-oxopiperazin-1-yl) methyl) -N- (4-morpholino-5-nitropyridin-2-yl) -3,4 -Dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

   (15) 7- (dimethoxymethyl) -6-((4-methyl-2-oxopiperazin-1-yl) methyl) -N- (5-nitro-4- (piperidin-1-yl) Pyridin-2-yl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

   (16) N- (4-((4-fluorophenyl) amino) -5-nitropyridin-2-yl) -7-formyl-6-((4-methyl-2-oxopiperazin-1-yl ) Methyl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

   (17) N- (4- (cyclohexylamino) -5-nitropyridin-2-yl) -7-formyl-6-((4-methyl-2-oxopiperazin-1-yl) methyl) -3 , 4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

   (18) 7-formyl-N- (4-((2-methoxyethyl) amino) -5-nitropyridin-2-yl) -6-((4-methyl-2-oxopiperazin-1- Yl) methyl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

   (19) N- (4- (ethylamino) -5-nitropyridin-2-yl) -7-formyl-6-((4-methyl-2-oxopiperazin-1-yl) methyl) -3, 4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

   (20) 7-formyl-N- (4-((4-methoxyphenyl) amino) -5-nitropyridin-2-yl) -6-((4-methyl-2-oxopiperazin-1-yl ) Methyl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide;

   (21) N- (4- (2- (dimethylamino) ethylamino) -5-nitropyridin-2-yl) -7-formyl-6-((4-methyl-2-oxopiperazin-1-yl ) Methyl) -3,4-dihydro-1,8-naphthypyridine-1 (2H) -carboxamide; And

   (22) N- (4-((3-chloro-4-fluorophenyl) amino) -5-nitropyridin-2-yl) -7-formyl-6-((4-methyl-2-oxopiperazine -1-yl) methyl) -3,4-dihydro-1,8-naphthypyridine-1 (2H) -carboxamide.
5. As shown in Scheme 1 below,

   Preparing a compound represented by Chemical Formula 4 by reacting the compound represented by Chemical Formula 2 with the compound represented by Chemical Formula 3 (step 1); And

   Preparing a compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 4 prepared in Step 1 with the compound represented by Chemical Formula 5 (step 2);

   A method for preparing a compound represented by Chemical Formula 1 of claim 1 comprising: preparing a compound represented by Chemical Formula 1 from the compound represented by Chemical Formula 6 prepared in Step 2 (Step 3):

   Scheme 1

   

   (In Scheme 1,

   R ¹ and R ² are each as defined in Formula 1 of claim 1).
6. A pharmaceutical composition for the prevention or treatment of a fibroblast growth factor receptor (FGFR) -related disease containing the compound represented by Formula 1 of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
7. A pharmaceutical composition for the prophylaxis or treatment of cancer containing the compound represented by 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

   The compound is a pharmaceutical composition, characterized in that to prevent or treat cancer by inhibiting the fibroblast growth factor receptor (FGFR).
9. The method of claim 7, wherein

   The cancer may be 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, anal muscle cancer, colon cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma Pharmaceutical composition, characterized in that at least one selected from the group consisting of vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma central nervous system tumor and leukemia.
10. A health functional food for preventing or improving cancer containing the compound represented by Formula 1 of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.