WO2018004258A1 - Novel heterocyclic derivative compound and use thereof - Google Patents

Abstract

The present invention relates to a novel heterocyclic derivative compound and a use thereof and, more particularly, to a novel heterocyclic derivative compound having selective inhibitory activity against a fibroblast growth factor receptor (FGFR), and a pharmaceutical composition comprising the same for preventing or treating various diseases associated with the FGFR.

Description

Novel heterocyclic derivative compounds and uses thereof

The present invention relates to novel heterocyclic derivative compounds and uses thereof, and more particularly to novel heterocyclic derivative compounds having selective inhibitory activity against Fibroblast growth factor receptor (FGFR) and It relates to a pharmaceutical composition for preventing or treating various diseases associated with the FGFR comprising the same.

The fibroblast growth factor (FGF) family of signaling polypeptides regulates a diverse series of physiological functions, such as cell mitogenesis, wound healing, cell differentiation, angiogenesis and development. . FGFs include a family of 22 structurally related polypeptides with a variety of biological activities. Most of these signaling molecules function by binding to and activating their cognate receptors (FGFR; called FGFR1-4), a family of receptor tyrosine kinases (Eswarakumar et al., 2005; Ornitz and Itoh, 2001). ).

Different ligand-receptor pairs in 22 FGFs and 4 FGFRs regulate cell growth in a positive or negative manner, depending on cell type and developmental stage (Dailey et al., Cytokine Growth Factor Rev. 16, 233- 247; Eswarakumar et al. Cytokine Growth Factor Rev., 16, 139-149). Upon ligand binding, the receptors dimerize specific cytoplasmic tyrosine residues and autophosphorize or trans phosphorylate to deliver intracellular signals that ultimately reach the nuclear transcription factor activator. Mitogenic signaling by these FGFRs is subsequently mediated through a number of pathways including ras / raf / MAP kinase cascade (Ozawa et al., Teratog. Carcinog. Mutagen. , 2001, 21, 27-44).

These FGFR-FGF signaling systems play an important role in development and tissue repair by regulating cell functions / processes such as growth, differentiation, migration, morphogenesis and angiogenesis. Thus, unregulated FGFR signaling networks have been implicated in many types of human pathological conditions, and in more detail alterations in FGFR (ie, overexpression, mutations, translocations and truncations) may cause myeloma, breast, stomach, colon, bladder , Pancreas and hepatocellular carcinoma, are known to be associated with numerous human cancers (Bange et al., 2002; Cappellen et al., 1999; Chesi et al., 2001; Chesi et al., 1997; Gowardhan et. al., 2005; Jaakkola et al., 1993; Jang et al., 2001; Jang et al., 2000; Jeffers et al., 2002; Xiao et al., 1998].

On the other hand, fibroblast growth factor receptor 4 (FGF receptor 4 or FGFR4) preferentially binds fibroblast growth factor 19 (FGF19) preferentially and is known to regulate cell proliferation and anti-cell death. FGFR4 or FGF19 described above is expressed or overexpressed in many cancers (See, e.g., Dieci et al. 2013, Cancer Discovery, OF1-OF16). To date, many studies have predicted that expression of FGFR4 or FGF19 is a phenotype that significantly accelerates disease progression in cancer patients. And when FGFR4 or FGF19 expression was reduced or knocked down, cell proliferation decreased and cell death increased (See, e.g., Wesche et al. 2011, Biochem J, 437; 199-213).

In addition, FGFR4, in the transcription of FGFR4 gene from breast carcinoma cell line, G-to-A transition causes substitution of glycine by arginine at position 388 in the intermembrane domain of the receptor, and the clinical data of 84 breast cancer patients examined arg388. It has been shown that homozygous or heterozygous carriers of alleles have a significantly reduced disease-free survival (P = 0.01) within a 62 month follow-up mean period. In addition, the FGFR4 arg388 allele was also associated with early metastasis and advanced tumor node metastasis stages in 82 colon cancer patients.

Expression or overexpression of FGF19, a selective ligand of FGFR4, is associated with aggressiveness in many cancers, including liver cancer, skin cancers such as melanoma, rectal cancer, and thyroid cancer. For example, FGF19 is overexpressed in 30-50% of liver cancer patients. When comparing progression-free survival (PFS) and overall survival (OS) between groups overexpressed and not in liver cancer, the risk index of the overexpressed group was higher than that of the non-overexpressed group. It was 2.3-3.6 times higher (S. Miura et al., 2012, BMC Cancer, 12, 1471-2407).

These results supported the conclusion that FGFR4 represents oncogenic genes or determinants that significantly accelerate the progression of cancer in cancer patients (Bange et al., 2002, Cancer Res., 62, 840-847).

One object of the present invention is to provide a novel heterocyclic derivative compound having excellent selective inhibitory activity against fibroblast growth factor receptor.

Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the compound.

According to one embodiment of the present invention, there is provided a compound selected from a heterocyclic derivative compound of Formula 1, a pharmaceutically acceptable salt thereof, an optical isomer, a hydrate, and a solvate thereof:

[Formula 1]

In Chemical Formula 1,

R ^1, R ^2, R ³ and R ⁴ is selected from each independently H, halogen, C _{1- 4} group consisting of alkyl and C _{1- 4} alkoxy;

E is CH or N;

D is NH or a bond;

Q is hydrogen or

Is;

W is hydrogen, halogen or-(CH ₂ ) _p NR'R ";

R 'and R "is selected from the group consisting of H or C _{1- 6} alkyl, each independently, wherein R' and R" are bonded to each other may form a _3- C ₆ alkylene bridge, the alkylene At least one methylene in the bridge is unsubstituted or substituted with one or more selected from the group consisting of -O-, -S (O)-, -S (O) _2-, and -N (R ')-;

Ring A is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocyclyl, wherein the heteroaryl represents a 5-7 membered aromatic ring containing 1 to 3 heteroatoms selected from O, N and S Heterocyclyl means a 5 to 7 membered cyclic moiety containing 1 to 3 heteroatoms or functional groups selected from N, O, S, SO and SO ₂ ;

R ⁵ is halogen, C _{1- 6} alkyl, C _{2- 6} alkenyl, C _{2- 6 alkynyl, -CN, - (CH 2)} p NR'R ", -N (R ') (CH 2) p _{^{OR 6, - (CH 2)}} p OR 6, aryl, heteroaryl, C _{3- 7} cycloalkyl, _{heterocyclyl, - (CH 2) p C} (= O) NR'R ", - (CH 2) p C (= 0) R ⁶ ,-(CH ₂ ) _p SR ⁶ and-(CH ₂ ) _p SO ₂ R ⁶ , wherein the heterocyclyl is N, O, S, SO and SO ₂ It means a 3 to 7 membered cyclic moiety containing 1 to 3 hetero atoms or functional groups selected from among;

When the R ⁵ a plurality individuals they may be the same or different and form a _3- C ₆ alkylene bridge adjacent R ⁵ are bonded to each other to each other, at least one methylene in the alkylene bridge is -O-, - Or unsubstituted or substituted with one or more selected from the group consisting of S (O)-, -S (O) _2-, and -N (R ')-;

R ⁶ is hydrogen, halogen, hydroxy, C _{1- 6} alkyl, - (CH _{2) q} NR'R ", - ₍₂ CH) _q OR ^7, C _{3- 7} cycloalkyl, heterocyclyl, - (CH ₂ ) _q C (═O) R ⁷ , — (CH ₂ ) _q SR ⁷ and — (CH ₂ ) _q SO ₂ R ⁷ ;

R ⁷ is hydrogen, halogen, C _{1- 6} alkyl, C _{3- 7} cycloalkyl, heterocyclyl, and -C (= O) is selected from the group consisting of R ^6;

Wherein the C _{1- 6} alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, hydroxy, -CN, straight chained or branched C _{1- 6} alkyl, halogenated C _{1 - 6} alkyl, C _May be unsubstituted or substituted with one or more substituents selected from the group consisting of _3-7 cycloalkyl and heterocyclyl;

Wherein R ⁵ to R ¹⁰ on the cycloalkyl and heterocyclyl, and wherein R ⁵ of the aryl and heteroaryl are each independently halogen, hydroxy, -CN, straight or branched C _{1- 6} alkyl, halogenated C _{1 -6-alkyl,} -NR'R ", C _{1- 6 alkoxy, - (CH 2) q OR} ', -C (= O) C 3- 7 cycloalkyl, C _{3- 7} cycloalkyl and heterocyclyl group consisting of reels further substituted by one substituent at least one selected from or may be unsubstituted, in which, R 'and R "is selected from the group consisting of independently, is H or C _{1- 6} alkyl;

p and q are each independently integers of 0 to 6;

n is an integer of 0-4.

According to another embodiment of the present invention, there is provided a pharmaceutical composition and a pharmaceutical formulation for the prophylaxis or treatment of various diseases related to the FGFR comprising the above compound in a therapeutically effective amount.

The heterocyclic derivative compound represented by the formula (1) provided in the present invention may be selectively used as a prophylactic or therapeutic agent for various diseases related to the FGFR because of its excellent inhibitory activity against FGFR.

The definitions listed below are definitions of various terms used to describe the present invention. These definitions apply throughout this specification, either individually or as part of a term including them, unless otherwise limited.

As used herein, the term 'halogen' means fluorine, chlorine, bromine or iodine unless otherwise noted.

The term 'hydroxy' as used herein refers to an -OH group unless otherwise indicated.

As used herein, the term 'alkyl', unless stated otherwise, refers to a saturated, straight-chain or branched hydrocarbon radical represented by CnH _{2n +1} , specifically between 1 and 6, each between 1 and 6 It refers to a saturated, straight or branched hydrocarbon radical comprising between, between 1 and 10, or between 1 and 20 carbon atoms. Examples of these radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl, n-hexyl, heptyl, octyl radicals. For example, the term "C _{1- 6} alkyl, as used herein, unless otherwise noted, refers to a hydrocarbon moiety having from 1 to 6 straight-chain or branched. Examples thereof include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

As used herein, the term 'alkenyl', unless stated otherwise, refers to monovalent groups derived from unsaturated, straight chain or branched hydrocarbon moieties having at least one carbon-carbon double bond, in particular each It refers to an unsaturated, straight or branched monovalent group comprising between 2 and 6, between 2 and 8, between 2 and 10, or between 2 and 20 carbon atoms. Examples thereof include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl radicals.

As used herein, the term 'alkynyl', unless stated otherwise, refers to a monovalent group derived from an unsaturated, straight or branched hydrocarbon moiety having at least one carbon-carbon triple bond.

The term alkoxy, as used herein, unless otherwise indicated, is between 1 and 6, between 1 and 8, between 1 and 10, or between 1 and 20, each represented by OC _n H _{2n +1} . It refers to an oxygen radical having a monovalent group derived from a saturated, straight or branched hydrocarbon moiety containing carbon atoms. For example, "C _{1- 6} alkoxy" are unless otherwise noted, means an oxygen radical having a hydrocarbon residue having 1 to 6 straight-chain or branched. Examples thereof include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, pentoxy, hexoxy and the like.

The term 'cycloalkyl', as used herein, unless otherwise indicated, refers to monovalent groups derived from monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring compounds. For example, the term used herein "C _{3- 7} cycloalkyl" is unless otherwise noted, refers to a hydrocarbon moiety having 3 to 7 ring-shaped. Examples thereof include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

As used herein, the term 'heterocyclyl', unless stated otherwise, means a 3-7 membered cyclic moiety containing 1 to 3 heteroatoms or functional groups selected from N, O, S, SO and SO ₂ . do. Examples thereof include oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2 H -pyran-4-yl, tetrahydro-2 H -pyran-3-yl, oxepan-4-yl, ox Cefpan-3-yl, piperidin-1-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4- 1,1,1-dioxide thiomorpholin-4-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, azetidin-1-yl, azetidin-3-yl, aziridine-1 -Yl, azepan-1-yl, azepan-3-yl, azepan-4yl, and the like, but are not limited thereto.

The term 'aryl', as used herein, unless otherwise indicated, refers to a mono- or polycyclic carbocyclic ring system having 6 to 14 carbon atoms having one or more aromatic rings fused or non-fused, aryl Examples of include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indenyl, andracenyl, and the like.

As used herein, the term 'heteroaryl', unless stated otherwise, refers to five to five, containing one or more, for example one to four, preferably one to three heteroatoms selected from O, N and S. 12-membered, preferably 5-7 membered monocyclic or bicyclic or higher aromatic group. Examples of monocyclic heteroaryl include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazoleyl, tetrazoyl, oxadiazoleyl, pyridine 1, pyridazinyl, pyrimidinyl, pyrazinyl and the like, but are not limited to these. Examples of bicyclic heteroaryl include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, iso Quinolinyl, purinyl, puropyridinyl, and the like, but are not limited to these.

The term 'alkylene bridge' as used in the present invention connects two different carbons of the same ring structure, may consist of carbon and hydrogen, contains no unsaturation, preferably has 3 to 6 carbon atoms Straight or branched chain divalent hydrocarbon bridges such as propylene, n -butylene and the like. The alkylene bridge may connect any two carbons in the ring structure. In addition, at least one methylene in the alkylene bridge is one or more selected from the group consisting of -O-, -S-, -S (O)-, -S (O) _2-, and -N (R ')-. to be substituted and, where, R 'is hydrogen, C _{1- 6} alkyl, C _{3- 7} cycloalkyl or aryl.

Alkyl used in the present invention, cycloalkyl, heterocyclyl, aryl, heteroaryl are each independently selected from halogen, hydroxy, -CN, straight chained or branched C _{1- 6} alkyl, halogenated C _{1 -6} alkyl, - NR'R ", C _{1- 6 alkoxy, - (CH 2) q OR} ', -C (= O) C 3- 7 cycloalkyl, C _{3- 7} at least one selected from the group consisting of cycloalkyl and heterocyclyl Lilo further substituted with a substituent or may be unsubstituted, in which, R 'and R "is selected from the group consisting of H or C _{1- 6} alkyl, each independently, q is an integer from 0 to 6.

Hereinafter, the present invention will be described in more detail.

The present invention relates to a novel heterocyclic derivative compound of Formula 1 and its use, and more particularly to novel novel Formula 1 having selective inhibitory activity against Fibroblast growth factor receptor (FGFR). Heterocyclic derivative compounds of the present invention and pharmaceutical compositions for preventing or treating a variety of diseases associated with the FGFR comprising the same.

Specifically, according to one embodiment of the present invention, a compound selected from a heterocyclic derivative compound of Formula 1, a pharmaceutically acceptable salt thereof, an optical isomer, a hydrate, and a solvate thereof is provided.

[Formula 1]

In Chemical Formula 1,

R ^1, R ^2, R ³ and R ⁴ is selected from each independently H, halogen, C _{1- 4} group consisting of alkyl and C _{1- 4} alkoxy;

E is CH or N;

D is NH or a bond;

Q is hydrogen or

Is;

W is hydrogen, halogen or-(CH ₂ ) _p NR'R ";

R 'and R "is selected from the group consisting of H or C _{1- 6} alkyl, each independently, wherein R' and R" are bonded to each other may form a _3- C ₆ alkylene bridge, the alkylene At least one methylene in the bridge is unsubstituted or substituted with one or more selected from the group consisting of -O-, -S (O)-, -S (O) _2-, and -N (R ')-;

Ring A is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocyclyl, wherein the heteroaryl represents a 5-7 membered aromatic ring containing 1 to 3 heteroatoms selected from O, N and S Heterocyclyl means a 5 to 7 membered cyclic moiety containing 1 to 3 heteroatoms or functional groups selected from N, O, S, SO and SO ₂ ;

R ⁵ is halogen, C _{1- 6} alkyl, C _{2- 6} alkenyl, C _{2- 6 alkynyl, -CN, - (CH 2)} p NR'R ", -N (R ') (CH 2) p _{^{OR 6, - (CH 2)}} p OR 6, aryl, heteroaryl, C _{3- 7} cycloalkyl, _{heterocyclyl, - (CH 2) p C} (= O) NR'R ", - (CH 2) p C (= 0) R ⁶ ,-(CH ₂ ) _p SR ⁶ and-(CH ₂ ) _p SO ₂ R ⁶ , wherein the heterocyclyl is N, O, S, SO and SO ₂ It means a 3 to 7 membered cyclic moiety containing 1 to 3 hetero atoms or functional groups selected from among;

When the R ⁵ a plurality individuals they may be the same or different and form a _3- C ₆ alkylene bridge adjacent R ⁵ are bonded to each other to each other, at least one methylene in the alkylene bridge is -O-, - Or unsubstituted or substituted with one or more selected from the group consisting of S (O)-, -S (O) _2-, and -N (R ')-;

R ⁶ is hydrogen, halogen, hydroxy, C _{1- 6 alkyl, - (CH 2) q NR'R} ", - (CH 2) q OR 7, C 3- 7 cycloalkyl, heterocyclyl, - (CH ₂ ) _q C (═O) R ⁷ , — (CH ₂ ) _q SR ⁷ and — (CH ₂ ) _q SO ₂ R ⁷ ;

R ⁷ is hydrogen, halogen, C _{1- 6} alkyl, C _{3- 7} cycloalkyl, heterocyclyl, and -C (= O) is selected from the group consisting of R ^6;

Wherein the C _{1- 6} alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, hydroxy, -CN, straight chained or branched C _{1- 6} alkyl, halogenated C _{1 - 6} alkyl, C _May be unsubstituted or substituted with one or more substituents selected from the group consisting of _3-7 cycloalkyl and heterocyclyl;

Wherein R ⁵ to R ¹⁰ on the cycloalkyl and heterocyclyl, and wherein R ⁵ of the aryl and heteroaryl are each independently halogen, hydroxy, -CN, straight or branched C _{1- 6} alkyl, halogenated C _{1 -6-alkyl,} -NR'R ", C _{1- 6 alkoxy, - (CH 2) q OR} ', -C (= O) C 3- 7 cycloalkyl, C _{3- 7} cycloalkyl and heterocyclyl group consisting of reels further substituted by one substituent at least one selected from or may be unsubstituted, in which, R 'and R "is selected from the group consisting of independently, is H or C _{1- 6} alkyl;

p and q are each independently integers of 0 to 6;

n is an integer of 0-4.

According to another embodiment of the present invention, in the compound represented by Chemical Formula 1, E is N.

According to another embodiment of the present invention, the compound represented by Chemical Formula 1 may be represented by the following Chemical Formula 2 to Chemical Formula 5:

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

In Chemical Formulas 2 to 5,

X is selected from the group consisting of O, S, NH, and CH ₂ ;

m is an integer from 0 to 2;

At least one of Z ¹ to Z ⁴ is N and the others are each independently N or C (R ⁵ );

Y is selected from the group consisting of O, S and N (R ⁵ );

R ¹ to R ⁵ , D, E, W, and n are as defined in the formula (1).

According to another embodiment of the present invention, in the compound represented by Chemical Formula 3, any one of Z ¹ to Z ⁴ is N and the other compound is C (R ⁵ ).

According to another embodiment of the present invention, in the compound represented by Formula 4, Y is N (R ⁵ ), and any one of Z ¹ and Z ² provides a compound.

Preferred examples of the compound of Formula 1 according to the present invention include, but are not limited to:

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) cyclopentyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) cyclohexyl) acrylamide;

N- (4-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) tetrahydrofuran-3-yl) acrylamide;

N-((3S, 4S) -3-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3- d] pyrimidin-2-yl) amino) tetrahydro-2H-pyran-4-yl) acrylamide;

N-((3S, 4S) -3-((6- (2,6-difluoro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2, 3-d] pyrimidin-2-yl) amino) tetrahydro-2H-pyran-4-yl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) phenyl) acrylamide;

N- (3-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) phenyl) acrylamide;

N- (2-((6- (3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-2-yl) amino)- 3-methylphenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imido [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -3-methylphenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -3-fluorophenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -3-methoxyphenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -4-fluorophenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -4- (4-ethylpiperazin-1-yl) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-fluorophenyl) acrylamide;

N- (5-chloro-2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] Pyrimidin-2-yl) amino) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-ethynylphenyl) acrylamide;

N- (5-cyano-2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d ] Pyrimidin-2-yl) amino) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (methylsulfonyl) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-methylphenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-ethylphenyl) acrylamide;

N- (5-cyclopropyl-2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d ] Pyrimidin-2-yl) amino) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-isopropylphenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (1-methylpiperidin-4-yl) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (dimethylamino) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-((2-methoxyethyl) (methyl) amino) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-methoxyphenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-ethoxyphenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-isopropoxyphenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (2-methoxyethoxy) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (2- (dimethylamino) ethoxy) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-morpholinophenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (pyrrolidin-1-yl) phenyl) acrylamide;

(E) -N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] Pyrimidin-2-yl) amino) -5-morpholinophenyl) -4- (dimethylamino) but-2-enamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (4- (methylsulfonyl) piperazin-1-yl) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (1,1-dioxidothiomorpholino) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (3-methoxyazetidin-1-yl) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-((2S, 6R) -2,6-dimethylmorpholino) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (piperazin-1-yl) phenyl) acrylamide trifluoroacetic acid salt;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (4-methoxypiperidin-1-yl) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (3-methoxypyrrolidin-1-yl) phenyl) acrylamide;

N- (5- (4- (cyclopropanecarbonyl) piperazin-1-yl) -2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2 ': 1,6] pyrido [2,3-d] pyrimidin-2-yl) amino) phenyl) acrylamide;

N- (5- (4- (cyclopropylmethyl) piperazin-1-yl) -2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2' : 1,6] pyrido [2,3-d] pyrimidin-2-yl) amino) phenyl) acrylamide;

(S) -N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] Pyrimidin-2-yl) amino) -5- (3-methoxypyrrolidin-1-yl) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (3-hydroxyazetidin-1-yl) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) acrylamide;

(Z) -3-chloro-N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2, 3-d] pyrimidin-2-yl) amino) -5-morpholinophenyl) acrylamide;

(S) -N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] Pyrimidin-2-yl) amino) -5- (3- (dimethylamino) pyrrolidin-1-yl) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (2-methylmorpholino) phenyl) acrylamide;

(S) -N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] Pyrimidin-2-yl) amino) -5- (2- (methoxymethyl) pyrrolidin-1-yl) phenyl) acrylamide;

N- (5- (4-cyclopropylpiperazin-1-yl) -2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1, 6] pyrido [2,3-d] pyrimidin-2-yl) amino) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (4-methylpiperazin-1-yl) phenyl) acrylamide;

(R) -N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] Pyrimidin-2-yl) amino) -5-((tetrahydrofuran-3-yl) oxy) phenyl) acrylamide;

N- (5- (cyclopentyloxy) -2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2, 3-d] pyrimidin-2-yl) amino) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-((1- (2,2,2-trifluoroethyl) piperidin-4-yl) oxy) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-((1-ethylpiperidin-4-yl) oxy) phenyl) acrylamide;

N- (6-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -2,3-dihydro-1H-inden-5-yl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -3,5-dimethylphenyl) acrylamide;

(R) -N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] Pyrimidin-2-yl) amino) -4-fluoro-5-((tetrahydrofuran-3-yl) oxy) phenyl) acrylamide;

(R) -N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] Pyrimidin-2-yl) amino) -4-methyl-5-((tetrahydrofuran-3-yl) oxy) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -4-methyl-5-morpholinophenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -4-fluoro-5-((1-methylpiperidin-4-yl) oxy) phenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -3-methyl-5-morpholinophenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-fluoro-3-methylphenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -3-methoxy-5-morpholinophenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (4-ethylpiperazin-1-yl) -3-fluorophenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -3-fluoro-5-morpholinophenyl) acrylamide;

N- (3-chloro-2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] Pyrimidin-2-yl) amino) -5-morpholinophenyl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) pyridin-3-yl) acrylamide;

N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-morpholinopyridin-3-yl) acrylamide;

N- (3-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -1-methyl-1H-pyrazol-4-yl) acrylamide;

N- (2-((6- (2,6-difluoro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine -2-yl) amino) -3-fluorophenyl) acrylamide;

N- (2-((6- (2,6-difluoro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine -2-yl) amino) -5-morpholinophenyl) acrylamide;

N- (3-((6- (2,6-difluoro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine -2-yl) amino) phenyl) acrylamide;

N- (2-((6- (2,6-difluoro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine -2-yl) amino) phenyl) acrylamide;

N- (2-((6- (2,6-difluoro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine -2-yl) amino) -3,5-difluorophenyl) acrylamide;

N- (2-((6- (2,6-difluoro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine -2-yl) amino) -4,5-difluorophenyl) acrylamide;

N- (2-((6- (2,6-difluoro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine -2-yl) amino) -3,4-difluorophenyl) acrylamide;

-(3-chloro-2-((6- (2,6-difluro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d ] Pyrimidin-2-yl) amino) phenyl) acrylamide;

4- (3- (6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2- Yl) phenyl) morpholine;

4- (5- (6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2- Yl) pyridin-3-yl) morpholine;

N- (3- (6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2- One) -5-morpholinophenyl) acrylamide;

N- (2-((4- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1,2-a] [1,6] naphthyridin-8-yl) amino) -5- Morpholinophenyl) acrylamide;

N- (2-((4- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1,2-a] [1,6] naphthyridin-8-yl) amino) -5- ((2S, 6R) -2,6-dimethylmorpholino) phenyl) acrylamide;

N- (2-((4- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1,2-a] [1,6] naphthyridin-8-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) acrylamide;

N- (2-((4- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1,2-a] [1,6] naphthyridin-8-yl) amino) -5- Morpholinopyridin-3-yl) acrylamide; And

N- (3-((4- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1,2-a] [1,6] naphthyridin-8-yl) amino) -1- Methyl-1H-pyrazol-4-yl) acrylamide.

In the present invention, a method for preparing the compound represented by Chemical Formula 1 is not particularly limited, but may be synthesized by, for example, a method of preparing the following Reaction Schemes 1, 2, 3, 4 or 5:

Scheme 1

In Formula 1, R ¹ , R ² , R ³ and R ⁴ are each as defined in Formula 1.

Condensation reaction of the compound of Formula 4 with 2-phenylacetonitrile having the substituent at the 3,5 position in the presence of a base such as NaH in the scheme 1 to synthesize a compound represented by the formula (5) , And reacted with 1,2-dichloroethyl ethyl ether or chloroacetaldehyde to synthesize an imidazole ring to synthesize a compound represented by the formula (6) consisting of three rings. By reacting a compound represented by the formula (6) with a material such as SO ₂ Cl ₂ which can act as a halogen donor to introduce a substituent of R ¹ and R ⁴ to synthesize a compound represented by the formula (7), The sulfide of the compound was oxidized using mCPBA or oxone to synthesize a compound represented by Chemical Formula 8.

Scheme 2

In Scheme 2, a compound represented by Chemical Formula 5 'is synthesized by conducting a compound of Chemical Formula 4 and 2-phenylacetonitrile having four substituents at 2,3,4,5 positions in the presence of a base such as NaH. , And reacted with 1,2-dichloroethyl ethyl ether or chloroacetaldehyde to synthesize the imidazole ring to synthesize a compound represented by the formula (7) consisting of three rings. The compound represented by Chemical Formula 8 was synthesized by oxidizing sulfide of the compound represented by Chemical Formula 7 using mCPBA or oxone.

Scheme 3

Starting from the compound represented by Chemical Formula 8 in Scheme 3, a sulfonyl group was substituted with an OH group to synthesize a compound represented by Chemical Formula 9, and the compound of Chemical Formula 9 was reacted with a material such as POCl ₃ to be replaced with a chloro group to give a compound of Chemical Formula 10 Was synthesized and used for the next reaction.

Scheme 4

4, respectively in the above reaction scheme R ^1, R ^2, R ³ and R ⁴ are as defined in formula (I).

Condensation reaction of the compound of Formula 11 and 2-phenylacetonitrile having a substituent at the 3,5 position in the scheme 4 in the presence of a base such as NaH to synthesize a compound represented by Formula 12 , And reacted with 1,2-dichloroethyl ethyl ether or chloroacetaldehyde to synthesize the imidazole ring to synthesize a compound represented by the formula (13) consisting of three rings. The compound represented by Chemical Formula 14 was synthesized by reacting the compound represented by Chemical Formula 13 with a material such as SO ₂ Cl ₂ which may act as a halogen donor to introduce substituents of R ¹ and R ⁴ .

Scheme 5

E1 in Scheme 5 is hydrogen, NO ₂ , N ₃ , NH-Boc;

D, E, Q, R ¹ , R ² , R ³ and R ⁴ are each as defined in Chemical Formula 1.

The compound represented by the formula (8), (9) and (14) in the scheme 5 is reacted with an amine or aniline in which the amine group is protected under a base or palladium catalyst to synthesize the compound represented by the formula (15), represented by the formula (15) The compound represented by the formula (16) was synthesized by deprotecting the amine protecting group from the compound under reduced or acid catalyst, and the compound represented by the formula (1) was synthesized by introducing an acrylic group into the compound represented by the formula (16).

The compounds according to the invention can also form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts are not particularly limited as long as they form acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions. For example, inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc .; Organic carbon acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, and the like; And acid addition salts formed by sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like.

On the other hand, the compounds according to the invention may have an asymmetric carbon center and therefore may exist as R or S isomers, racemic compounds, diastereomeric mixtures, or individual diastereomers, all of these isomers and mixtures being within the scope of the invention. Included.

In addition, solvate and hydrate forms of the indole compound of Formula 1 are also included within the scope of the present invention.

According to another embodiment of the present invention, there is provided a pharmaceutical composition containing a therapeutically effective amount of a compound selected from the compound of Formula 1 and a pharmaceutically acceptable salt thereof.

The pharmaceutical composition of the present invention is useful for preventing or treating various diseases related thereto by inhibiting the activity of the fibroblast growth factor receptor (FGFR) compound represented by Formula 1 included therein.

According to another embodiment of the invention, the pharmaceutical composition is a pharmaceutical composition for preventing or treating cancer or a tumor, specifically, the cancer is liver cancer, liver cell carcinoma, hepatocellular carcinoma, thyroid cancer , Colorectal cancer, testicular cancer, testicular cancer, bone cancer, oral cancer, basal cell carcinoma, ovarian cancer, brain tumor, gallbladder carcinoma, biliary tract cancer, head and neck cancer, colorectal cancer, bladder cancer, vesical carcinoma, tongue cancer, esophageal cancer, glioma , Glioblastoma, renal cancer, malignant melanoma, gastric cancer, breast cancer, sarcoma, pharynx carcinoma, uterine cancer ), Cervical cancer, prostate cancer, rectal cancer cancer, pancreatic cancer, lung cancer, skin cancer and other solid cancers, but are not limited to these.

According to another embodiment of the present invention, there is provided a pharmaceutical formulation comprising the pharmaceutical composition described above.

The pharmaceutical preparations of the invention may be in various oral dosage forms, such as tablets, pills, powders, capsules, syrups or emulsions, or parenteral dosage forms such as intramuscular, intravenous or subcutaneous administration, such as injections, preferably oral Dosage forms.

In addition, the pharmaceutical preparation is a conventional non-toxic pharmaceutically acceptable additive in addition to the active ingredient, and may be formulated according to a conventional method by adding one or more selected from the group consisting of, for example, a carrier, an adjuvant, and an excipient. have.

Excipients that may be used in the pharmaceutical formulations of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, and the like. However, the present invention is not limited thereto. For example, as excipients, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, magnesium aluminum silicate, starch, gelatin, tragacanth gum, alginate, sodium alginate, methylcellulose, sodium carboxymethyl Cellulose, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like can be used.

When the pharmaceutical preparation of the present invention is in an oral dosage form, examples of the carrier used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin , Talc, and the like, but are not limited thereto.

When the pharmaceutical formulation of the present invention is in the form of an injection, the carrier may include water, saline solution, aqueous glucose solution, pseudoglucose solution, alcohol, glycol, ether, oil, fatty acid, fatty acid ester, glyceride, and the like. Does not.

For the use of the compounds according to the invention as medicaments, the latter are prepared in the form of pharmaceutical preparations, which are suitable for use in addition to the active ingredient for oral or parenteral administration, for example, pharmaceutically organic or inorganic inert carrier materials such as water, gelatin, Gum arabic, lactose, starch, vegetable oil, polyalkylene glycol and the like. Pharmaceutical formulations may be in solid form, eg, tablets, dragees, suppositories or capsules, or in liquid form, eg, solutions, suspensions or emulsions. In addition, they may optionally contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers; It contains an osmotic pressure modifying salt or buffer.

For parenteral administration, injectable solutions or suspensions are particularly preferred.

As carrier systems, it is also possible to use surfactant aids such as bile salts or animal or plant phospholipids, also mixtures thereof, and liposomes or components thereof.

For oral administration, tablets, dragees or capsules containing talc and / or hydrocarbon vehicles or binders, for example lactose, corn or potato starch, are particularly suitable. It may also be administered in liquid form, such as juice with added sweeteners.

In addition, the dose of the compound of Formula 1 according to the present invention to the human body is generally in the range of 0.1 mg / day to 2,000 mg / day based on an adult patient weighing 70 kg. The compounds according to the invention can be administered once daily to divided doses. However, the dosage may vary depending on the patient's state of health, age, weight and sex, dosage form and degree of disease, and thus the scope of the present invention is not limited to the above-described dosage.

Hereinafter, the present invention will be described in more detail based on the following Preparation Examples and Examples, which are illustrative only of the present invention, but the scope of the present invention is not limited thereto.

Real  Yes

Synthesis Example 1 N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d ] Pyrimidin-2-yl) amino) cyclopentyl) acrylamide [Compound 1]

Step 1. Preparation of 6- (3,5-dimethoxyphenyl) -2- (methylthio) pyrido [2,3- d ] pyrimidin-7-amine

After dissolving 3, 5-dimethoxyphenylacetonitrile (2.89 g, 16.3 mmol) in tetrahydrofuran, 60% NaH (720 mg, 17.9 mmol) was added thereto. After stirring for 1 hour at room temperature, 4-amino-2- (methylsulfanyl) -5-pyrimidinecaraldehyde (2.5 g, 14.8 mmol) was added thereto. After 6 hours of reaction at room temperature, tetrahydrofuran was removed under reduced pressure. The obtained solid was dissolved in dichloromethane and washed with saturated ammonium chloride. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain the title compound (3.6 g) (J. Med. Chem. 2005, 48, 4628-4653).

Step 2. Preparation of 6- (3,5-dimethoxyphenyl) -2- (methylthio) imidazo [1 ', 2': 1,6] pyrido [2,3- d ] pyrimidine

6- (3,5-dimethoxyphenyl) -2- (methylthio) pyrido [2,3- d ] pyrimidin-7-amine (2.59 g, 7.9 mmol) synthesized in the above [Step 1] After adding to acetonitrile / water (1/1) mixed solution, triethylamine (6.6 ml, 47.6 mmol) was added thereto. To this, 1,2-dichloroethyl ethyl ether (4ml, 32mmol) was added for 30 minutes, stirred overnight, and then heated to reflux for 4 hours to complete the reaction. After cooling to room temperature, water was added, and the resulting crystals were filtered under reduced pressure to obtain the title compound (1.67 g).

Step 3. 6- (2,6-Dichloro-3,5-dimethoxyphenyl) -2- (methylthio) imidazo [1 ', 2': 1,6] pyrido [2,3- d ] pyridine Preparation of midines

6- (3,5-dimethoxyphenyl) -2- (methylthio) imidazo [1 ', 2': 1,6] pyrido [2,3- d ] pyridine synthesized in the above [Step 2] The weak compound (1.5 g, 4.25 mmol) was dissolved in dichloromethane and cooled to -20. Sulfuryl chloride (SO ₂ Cl ₂ , 1.14 g, 8.5 mmol) was added thereto and reacted for 30 minutes. After the reaction was completed, a small amount of methanol was added thereto, followed by distillation under reduced pressure to remove the solvent. Ethyl acetate was added to the resulting solid, followed by stirring for 30 minutes, followed by filtration to obtain the title compound (1.3 g).

Step 4. 6- (2,6-Dichloro-3,5-dimethoxyphenyl) -2- (methylsulfonyl) imidazo [1 ', 2': 1,6] pyrido [2,3- d ] Preparation of pyrimidine

6- (2,6-dichloro-3,5-dimethoxyphenyl) -2- (methylsulfonyl) imidazo [1 ', 2': 1,6] pyrido synthesized in the above [Step 3] [ 2,3- d ] pyrimidine (1.2 g, 2.85 mmol) was added to dichloromethane, and m -chloroperbenzoic acid (1.14 g, 8.5 mmol) was added thereto and reacted for 6 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure. Ethyl acetate was added to the resulting solid, followed by stirring for 30 minutes, followed by filtration to obtain the title compound (1.0 g).

Step 5. t -Butyl (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3- d ] Preparation of pyrimidin-2-yl) amino) cyclopentyl) carbamate

6- (2,6-dichloro-3,5-dimethoxyphenyl) -2- (methylsulfonyl) imidazo [1 ', 2': 1,6] pyrido synthesized in the above [Step 4] [ 2,3- d ] pyrimidine (200 mg, 0.44 mmol) and (±) cis- t -butyl (2-aminocyclopentyl) carbamate (17 mg, 0.85 mmol) were added to N, N -dimethylformamide. It stirred for 30 minutes after heating up at 100 degreeC. After cooling to room temperature, water is slowly added to form a solid. The solid was filtered to give the title compound (100 mg). Proceed to the next reaction without purification.

Step 6. N ^1- (6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3- d ] pyrimidine-2 Preparation of -yl) cyclopentane-1,2-diamine

T -butyl (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [ 2,3- d ] pyrimidin-2-yl) amino) cyclopentyl) carbamate (100 mg, 0.17 mmol) was added to dichloromethane (2 ml). Trifluoroacetic acid (trifluoroacetic acid, 1 ml) was added thereto, followed by stirring at room temperature for 2 hours. The organic solvent was removed under reduced pressure and the reaction proceeded to the next reaction without purification.

Step 7. N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3- d ] pyridine Preparation of midin-2-yl) amino) cyclopentyl) acrylamide

N ^1- (6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3- synthesized in the above [Step 6] d] Pyrimidin-2-yl) cyclopentane-1,2-diamine (40 mg, 0.16 mmol) and sodium bicarbonate (42 mg, 0.5 mmol) were added tetrahydrofuran / water (4/1) and cooled to 0 ° C. . Acryl chloride (22 mg, 0.24 mmol) was added thereto and stirred for 1 hour. The reaction solution concentrated under reduced pressure was extracted using a chloroform / isopropyl alcohol (4/1) mixed solvent. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by distillation under reduced pressure was column separated to obtain the title compound (30 mg).

[Correction under Article 91 of the Rule 01.09.2017]

Synthesis Example 4 N -((3S, 4S) -3-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3- d ] pyrimidin-2-yl) amino) tetrahydro- 2H -pyran-4-yl) acrylamide [Compound 4]

Step 1. N -((3S, 4S) -4-azidotetrahydro-2 H -pyran-3-yl) -6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 Preparation of ', 2': 1,6] pyrido [2,3- d ] pyrimidin-2-amine

6- (2,6-dichloro-3,5-dimethoxyphenyl) -2- (methylsulfonyl) imidazo [1 ', 2': 1,6 synthesized in [Step 4] of [Synthesis Example 1] ] Pyrido [2,3- d ] pyrimidine (170mg, 0.375mmol), (3S, 4S) -4-azidotetrahydro- 2H -pyran-3-amine hydrochloride (87mg, 0.487mmol) and sodium bicarbonate (95 mg, 1.125 mmol) was added to N-methylpyrrolidine. After warming to 100 ° C. and stirring for 4 hours, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by distillation under reduced pressure was column separated to obtain the title compound (60 mg).

Step 2. (3S, 4S) -N ^3- (6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3- d ] pyrimidin-2-yl) tetrahydro- 2H -pyran-3,4-diamine

N -((3S, 4S) -4-azidotetrahydro- 2H -pyran-3-yl) -6- (2,6-dichloro-3,5-dimethoxy synthesized in the above [Step 1] Phenyl) imidazo [1 ', 2': 1,6] pyrido [2,3- d ] pyrimidin-2-amine (60 mg, 0.11 mmol) was added to tetrahydrofuran / methanol (1/1). An excess of Raney Ni was added thereto, followed by stirring for 2 hours under hydrogen balloon conditions. After filtration using Celite, the residue obtained by distillation under reduced pressure was separated by column to obtain the title compound (25 mg).

Step 3. N -((3S, 4S) -3-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2 Preparation of, 3- d ] pyrimidin-2-yl) amino) tetrahydro-2H-pyran-4-yl) acrylamide

(3S, 4S) -N ^3- (6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyridine synthesized in the above [Step 2] [2,3- d ] pyrimidin-2-yl) tetrahydro- 2H -pyran-3,4-diamine (120 mg, 0.245 mmol) was synthesized by the synthesis method of [Step 7] of [Synthesis Example 1]. The title compound (69 mg) was obtained.

[Correction under Article 91 of the Rule 01.09.2017]

Synthesis Example 6 N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d ] Pyrimidin-2-yl) amino) phenyl) acrylamide [Compound 6]

[Correction under Article 91 of the Rule 01.09.2017]

Step 1. 6- (2,6-Dichloro-3,5-dimethoxyphenyl) -N- (2-nitrophenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d ] Preparation of Pyrimidin-2-amine

6- (2,6-dichloro-3,5-dimethoxyphenyl) -2- (methylsulfonyl) imidazo [1 ', 2': 1,6 synthesized in [Step 4] of [Synthesis Example 1] ] Pyrido [2,3- d ] pyrimidine (150 mg, 0.33 mmol) and 2-nitroaniline (68 mg, 0.66 mmol) were added to N, N -dimethylformamide. Potassium t -butoxide (110 mg, 0.99 mmol) was added thereto, followed by stirring for 30 minutes. After cooling to room temperature, water was added, and the resulting solid was filtered to yield the title compound (120 mg, 70%).

Step 2. N1- (6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2- (1) Preparation of benzene-1,2-diamine

6- (2,6-dichloro-3,5-dimethoxyphenyl) -N- (2-methoxy-6-nitro-4- (pyrrolidin-1-yl) synthesized in the above [Step 1] Phenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-2-amine (120 g, 0.23 mmol) of [Step 6] of [Synthesis Example 1] Synthesis gave the title compound (84 mg).

Step 3. N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrid Preparation of midin-2-yl) amino) phenyl) acrylamide

N1- (6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d synthesized in the above [Step 2] ] The title compound (13 mg) was obtained by the synthesis method of [Step 7] of [Synthesis Example 1] using [pyrimidin-2-yl) benzene-1,2-diamine (84 mg, 0.18 mmol).

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[Correction under Article 91 of the Rule 01.09.2017]

Synthesis Example 72 N- (2-((6- (2,6-difluoro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3 -d] pyrimidin-2-yl) amino) -3-fluorophenyl) acrylamide [Compound 72]

[Correction under Article 91 of the Rule 01.09.2017]

Step 1. Preparation of 6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [2,3-d] pyrimidin-7-amine

[Correction under Article 91 of the Rule 01.09.2017]

2- (2,6-difluoro-3,5-dimethoxyphenyl) acetonitrile (5.26 g, 24.6 mmol) was dissolved in N, N-dimethylformamide, followed by 60% NaH (1.5 mg, 33.69). mmol) was added. After stirring for 1 hour at room temperature, 4-amino-2- (methylsulfanyl) -5-pyrimidinecaraldehyde (3.8 g, 22.4 mmol) was added thereto. After stirring at room temperature overnight, water was added to form a solid and filtered to obtain the title compound (6.4 g).

Step 2. 6- (2,6-Difluoro-3,5-dimethoxyphenyl) -2- (methylthio) imidazo [1 ', 2': 1,6] pyrido [2,3-d ] Preparation of Pyrimidine

6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [2,3-d] pyrimidin-7-amine synthesized in the above [Step 1] Using (6.4g), the title compound (4.5g) was obtained by the synthesis method of [Step 2] of [Synthesis Example 1].

Step 3. 6- (2,6-Difluoro-3,5-dimethoxyphenyl) -2- (methylsulfonyl) imidazo [1 ', 2': 1,6] pyrido [2,3- d] preparation of pyrimidine

6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [2,3-d] pyrimidin-7-amine synthesized in the above [Step 2] The title compound (0.74 g) was obtained by the synthesis method of [Step 4] of [Synthesis Example 1] using (1.0 g, 2.57).

Step 5. N1- (6- (2,6-Difluoro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine- Preparation of 2-yl) -6-fluorobenzene-1,2-diamine

6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylsulfonyl) imidazo [1 ', 2': 1,6] pyridine synthesized in the above [Step 3] [2,3-d] pyrimidine (100 mg, 0.023 mmol) and 2-fluoro-6-nitrophenylaniline (56 mg, 0.035 mmol) were synthesized according to the synthesis method of [Step 1] of [Synthesis Example 5]. -(2,6-difluoro-3,5-dimethoxyphenyl) -N- (2-fluoro-6-nitrophenyl) imidazo [1 ', 2': 1,6] pyrido [2, 3-d] pyrimidin-2-amine was obtained. Using this compound, the title compound (80 mg) was obtained by the synthesis method of [Step 6] of [Synthesis Example 1].

Step 6. N- (2-((6- (2,6-difluoro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d ] Production of pyrimidin-2-yl) amino) -3-fluorophenyl) acrylamide

N1- (6- (2,6-difluoro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3 synthesized in step 5] above -d] Pyrimidin-2-yl) -6-fluorobenzene-1,2-diamine (80 mg, 0.17 mmol) was synthesized by the synthesis method of [Step 7] of [Synthesis Example 1] to obtain the title compound (40 mg). Obtained.

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[Correction under Article 91 of the Rule 01.09.2017]

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[Correction under Article 91 of the Rule 01.09.2017]

Synthesis Example 80 4- (3- (6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] Pyrimidin-2-yl) phenyl) morpholine [Compound 80]

[Correction under Article 91 of the Rule 01.09.2017]

Step 1. Preparation of 2-chloro-6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine

[Correction under Article 91 of the Rule 01.09.2017]

6- (2,6-dichloro-3,5-dimethoxyphenyl) -2- (methylsulfonyl) imidazo [1 ', 2': 1,6 synthesized in [Step 4] of [Synthesis Example 1] ] Pyrido [2,3-d] pyrimidine (2 g, 4.31 mmol) was added to tetrahydrofuran / water (30 ml: 30 ml). Potassium hydroxide (726 mg, 12.9 mmol) was added and stirred at room temperature for 3 hours. 6N hydrochloric acid was added to adjust pH = 2, and the solid formed was filtered to give 6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [ 2,3-d] pyrimidin-2-ol was obtained. Acetonitrile (50 ml) was added thereto, POCl ₃ (5.7 ml, 61.3 mmol) was added thereto, and the mixture was stirred under reflux for 3 hours. After cooling to room temperature, methanol / water (10 ml / 20 ml) was added, and the formed solid was filtered under reduced pressure and recrystallized from acetone to obtain the title compound (1.2 g).

Step 2. 4- (3- (6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine Preparation of -2-yl) phenyl) morpholine

2-chloro-6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3- synthesized in the above [Step 1] d] pyrimidine (100 mg, 0.244 mmol) and 4- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) morpholine (141 mg , 0.488 mmol), Pd (dppf) Cl ₂ (10 mg, 0.012 mmol) and sodium carbonate (78 mg, 0.732 mmol) were added to t-butanol / water (3 ml / 3 ml). After heating up to 90 ° C. and stirring for 3 hours, sat. The organic layer separated by extraction with aqueous NH ₄ Cl solution and dichloromethane was dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. The residue obtained was purified by column to give the title compound (67 mg).

[Correction under Article 91 of the Rule 01.09.2017]

[Correction under Article 91 of the Rule 01.09.2017]

Synthesis Example 83 N- (2-((4- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1,2-a] [1,6] naphthyridin-8-yl) Amino) -5-morpholinophenyl) acrylamide [Compound 83]

Step 1. Preparation of 7-chloro-3- (3,5-dimethoxyphenyl) -1,6-naphthyridin-2-amine

3, 5-dimethoxyphenylacetonitrile (1.24 g, 7.03 mmol, ARK Pharm) was dissolved in tetrahydrofuran (25 ml), and then 60% NaH (0.38 g, 7.7 mmol) was added thereto. After stirring for 1 hour at room temperature, 4-amino-6-chloronicotinaldehyde (1.0 g, 6.4 mmol, ARK Phram) was added thereto. After 6 hours of reaction at room temperature, tetrahydrofuran was removed under reduced pressure. The obtained solid is dissolved in dichloromethane and washed with saturated ammonium chloride. The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), and distilled under reduced pressure to obtain the title compound (1.56 g).

Step 2. Preparation of 2-chloro-6- (3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine

7-chloro-3- (3,5-dimethoxyphenyl) -1,6-naphthyridin-2-amine (1.56 g, 4.9 mmol) synthesized in the above [Step 1] was diluted to acetonitrile / water (50 ml / 5 ml) was added to the mixture, and triethylamine (4.13 ml, 29.6 mmol) was added thereto. To this, 1,2-dichloroethyl ethyl ether (2.4ml, 19.8mmol) was added for 30 minutes, then stirred overnight, then warmed to reflux overnight to complete the reaction. After cooling to room temperature, water (45 ml) was added and the resulting crystals were filtered under reduced pressure to give the title compound (0.92 g).

Step 3. Preparation of 8-chloro-4- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1,2-a] [1,6] naphthyridine

2-chloro-6- (3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine (930mg) synthesized in the above [Step 2] , 2.7 mmol) was dissolved in dichloromethane (30 ml) and cooled to -20. Sulfuryl chloride (SO ₂ Cl ₂ , 730 mg, 5.4 mmol) was added thereto and reacted for 3 minutes. After the reaction was completed, a small amount of methanol was added thereto, followed by distillation under reduced pressure to remove the solvent. Ethyl acetate (30 ml) was added to the resulting solid, followed by stirring for 30 minutes, followed by filtration to obtain the title compound (900 mg).

Step 4. N1- (4- (2,6-Dichloro-3,5-dimethoxyphenyl) imidazo [1,2-a] [1,6] naphthyridin-8-yl) -4-morpholinobenzene Preparation of -1,2-diamine

8-chloro-4- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1,2-a] [1,6] naphthyridine (100 mg, 0.24) synthesized in the above [Step 3] mmol) and 4-morpholino-2-nitroaniline (55 mg, 0.24 mmol) were added to 1,4-dioxane (4 ml). To this was added Pa (OAc) ₂ (5.4 mg, 0.024 mmol), Xantphos (23 mg, 0.048 mmol) and Cs ₂ CO ₃ (156 mmol, 0.48 mmol). Substituted in argon atmosphere and stirred at 100 for 3 hours. After cooling to room temperature, the reaction solution was filtered through Celite and ethyl acetate was added. After washing with water and brine, dried over anhydrous magnesium sulfate, and the filtrate was concentrated after filtration. The resulting residue was purified by column to give 4- (2,6-dichloro-3,5-dimethoxyphenyl) -N- (4-morpholino-2-nitrophenyl) imidazo [1,2-a] [1, 6] naphthyridin-8-amine (120 mg) was obtained. Using this compound, the title compound (60 mg) was obtained by the synthesis method of [Step 6] of [Synthesis Example 1].

Step 5. N- (2-((4- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1,2-a] [1,6] naphthyridin-8-yl) amino) Preparation of -5-morpholinophenyl) acrylamide

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[Correction under Article 91 of the Rule 01.09.2017]

[Correction under Article 91 of the Rule 01.09.2017]

Experimental Example 1: FGFR1 , 4 Kinase  Activity inhibition test

Inhibitory activity against FGFR1, 2, 3, 4 kinases was measured for the synthetic compounds. Activity measurements were conducted by the Commission Invitrogen Corporation SelectScreen ^® Biochemical Kinase Profiling Service. Z'-LYTE ^® biochemical assays were used and ATP concentrations were set based on Km values. The results are shown in Table 1 in percent inhibition of kinase activity of the control group.

Experimental Example 2: Using Cell Lines FGFR  Determination of Inhibitory Effect of Inhibitors

The experiment was conducted to confirm the proliferation inhibitory effect of the compounds of the present invention on HUH7 cells. After counting HUH7 cell lines, 96 well plates were inoculated with 5.0 X 10 ³ cells per well. After inoculation, the cells were incubated for 24 hours in 37, 5% carbon dioxide (CO ₂ ) incubator. The next day, the synthetic compounds were prepared by diluting each. Diluted compounds were added to the cell lines inoculated the day before by concentration, and reacted in 37, 5% carbon dioxide (CO ₂ ) incubator for 72 hours. However, in the positive control without compound, 0.1% DMSO (DMSO, dimethyl sulfoxide) diluted with medium was added. Negative control plate was fixed at 4 and put trichloroacetic acid (TCA, Trichloroacetic acid) solution. After the reaction for 72 hours, the medium containing the compound was removed, then the TS solution was added, and the cells were fixed at 4 to 30 to 60 minutes. The TS solution was discarded and the plate was washed with distilled water and then dried in air. 0.4% ESB (SRB, Sulforhodamin B) solution was added to the plate and stained at room temperature for 10 minutes. The plates were washed with tap water containing 1% acetic acid solution and then dried in air. 10 mM Trisma base solution was added to dissolve the solid SALB. Absorbance (OD value) was measured at 540 nm with a Microplate Reader. GI ₅₀ values of each compound were calculated using GraphPad Prism V6.0 Software. The results are shown in Table 1 below.

(A: <50 nM; B:> 50 nM, <500 nM; C:> 500 nM;-: not measured)

Synthesis Example Number	IC 50
	FGFR4	FGFR1	HUH7 cell line
One	-	-	B
2	-	-	B
3	-	-	B
4	A	B	B
5	-	-	B
6	A	A	A
7	-	-	A
8	-	-	C
9	A	C	B
10	A	B	A
11	A	B	B
12	-	-	B
13	-	-	A
14	-	-	B
15	-	-	B
16	-	-	B
17	-	-	B
18	A	A	B
19	A	B	A
20	-	-	B
21	-	-	B
22	-	-	B
23	-	-	A
24	A	A	A
25	A	A	A
26	A	B	A
27	-	-	A
28	-	-	A
29	A	A	A
30	-	-	A
31	A	A	A
32	A	A	A
33	-	-	B
34	-	-	B
35	A	A	A
36	A	A	A
37	A	A	A
38	A	A	A
39	A	A	A
40	-	-	A
41	-	-	A
42	-	-	A
43	-	-	A
44	-	-	A
45	-	-	A
46	-	-	A
47	-	-	A
48	A	A	A
49	-	-	A
50	-	-	A
51	-	-	B
52	A	A	A
53	A	A	A
54	B	C	B
55	-	-	B
56	-	-	A
57	-	-	B
58	B	C	B
59	-	-	A
60	-	-	B
61	A	A	A
62	-	-	A
63	A	B	B
64	-	-	C
65	-	-	B
66	-	-	C
67	-	-	B
68	-	-	C
69	-	-	B
70	-	-	B
71	-	-	B
72	A	C	A
73	A	A	A
74	-	-	A
75	-	-	A
76	-	-	B
77	-	-	B
78	-	-	B
79	-	-	B
80	-	-	C
81	-	-	C
82	-	-	C
83	A	A	A
84	-	-	A
85	A	A	A
86	-	-	A
87	-	-	A

As shown in Table 1, it can be seen that the compounds of Synthesis Examples 1 to 87 according to the present invention have excellent specific inhibitory activity, particularly against FGFR4, among fibroblast growth factor receptors.

In the above, the present invention has been described with reference to the above embodiment, which is merely an example, and the present invention includes various modifications and other equivalent embodiments that are obvious to those skilled in the art. It should be understood that it can be carried out within the scope of the appended claims.

Claims (13)

1. A compound selected from a heterocyclic derivative compound of Formula 1, a pharmaceutically acceptable salt thereof, an optical isomer, a hydrate and a solvate thereof:

   [Formula 1]

   

   In Chemical Formula 1,

   R ^1, R ^2, R ³ and R ⁴ is selected from each independently H, halogen, C _{1- 4} group consisting of alkyl and C _{1- 4} alkoxy;

   E is CH or N;

   D is NH or a bond;

   Q is hydrogen or

   

   Is;

   W is hydrogen, halogen or-(CH ₂ ) _p NR'R ";

   R 'and R "is selected from the group consisting of H or C _{1- 6} alkyl, each independently, wherein R' and R" are bonded to each other may form a _3- C ₆ alkylene bridge, the alkylene At least one methylene in the bridge is unsubstituted or substituted with one or more selected from the group consisting of -O-, -S (O)-, -S (O) _2-, and -N (R ')-;

   Ring A is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocyclyl, wherein the heteroaryl represents a 5-7 membered aromatic ring containing 1 to 3 heteroatoms selected from O, N and S Heterocyclyl means a 5 to 7 membered cyclic moiety containing 1 to 3 heteroatoms or functional groups selected from N, O, S, SO and SO ₂ ;

   R ⁵ is halogen, C _{1- 6} alkyl, C _{2- 6} alkenyl, C _{2- 6 alkynyl, -CN, - (CH 2)} p NR'R ", -N (R ') (CH 2) p _{^{OR 6, - (CH 2)}} p OR 6, aryl, heteroaryl, C _{3- 7} cycloalkyl, _{heterocyclyl, - (CH 2) p C} (= O) NR'R ", - (CH 2) p C (= 0) R ⁶ ,-(CH ₂ ) _p SR ⁶ and-(CH ₂ ) _p SO ₂ R ⁶ , wherein the heterocyclyl is N, O, S, SO and SO ₂ It means a 3 to 7 membered cyclic moiety containing 1 to 3 hetero atoms or functional groups selected from among;

   When the R ⁵ a plurality individuals they may be the same or different and form a _3- C ₆ alkylene bridge adjacent R ⁵ are bonded to each other to each other, at least one methylene in the alkylene bridge is -O-, - Or unsubstituted or substituted with one or more selected from the group consisting of S (O)-, -S (O) _2-, and -N (R ')-;

   R ⁶ is hydrogen, halogen, hydroxy, C _{1- 6} alkyl, - (CH _{2) q} NR'R ", - ₍₂ CH) _q OR ^7, C _{3- 7} cycloalkyl, heterocyclyl, - (CH ₂ ) _q C (═O) R ⁷ , — (CH ₂ ) _q SR ⁷ and — (CH ₂ ) _q SO ₂ R ⁷ ;

   R ⁷ is hydrogen, halogen, C _{1- 6} alkyl, C _{3- 7} cycloalkyl, heterocyclyl, and -C (= O) is selected from the group consisting of R ^6;

   Wherein the C _{1- 6} alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, hydroxy, -CN, straight chained or branched C _{1- 6} alkyl, halogenated C _{1 - 6} alkyl, C _May be unsubstituted or substituted with one or more substituents selected from the group consisting of _3-7 cycloalkyl and heterocyclyl;

   Wherein R ⁵ to R ¹⁰ on the cycloalkyl and heterocyclyl, and wherein R ⁵ of the aryl and heteroaryl are each independently halogen, hydroxy, -CN, straight or branched C _{1- 6} alkyl, halogenated C _{1 -6-alkyl,} -NR'R ", C _{1- 6 alkoxy, - (CH 2) q OR} ', -C (= O) C 3- 7 cycloalkyl, C _{3- 7} cycloalkyl and heterocyclyl group consisting of reels further substituted by one substituent at least one selected from or may be unsubstituted, in which, R 'and R "is selected from the group consisting of independently, is H or C _{1- 6} alkyl;

   p and q are each independently integers of 0 to 6;

   n is an integer of 0-4.
2. The method of claim 1,

   E is N;
3. The method of claim 1,

   The compound represented by Chemical Formula 1 is a compound represented by the following Chemical Formula 2 to Formula 5:

   [Formula 2]

   

   [Formula 3]

   

   [Formula 4]

   

   [Formula 5]

   

   In Chemical Formulas 2 to 5,

   X is selected from the group consisting of O, S, NH, and CH ₂ ;

   m is an integer from 0 to 2;

   At least one of Z ¹ to Z ⁴ is N and the others are each independently N or C (R ⁵ );

   Y is selected from the group consisting of O, S and N (R ⁵ );

   R ¹ to R ⁵ , D, E, W, and n are as defined in the formula (1).
4. The compound of claim 3, wherein in the compound represented by Chemical Formula 3, any one of Z ¹ to Z ⁴ is N and the others are C (R ⁵ ).
5. 4. The compound of claim 3, wherein in the compound represented by Formula 4, Y is N (R ⁵ ), and only one of Z ¹ and Z ² is N. ⁵ .
6. The method of claim 1,

   Compound of Formula 1 is characterized in that the compound selected from the group consisting of:

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) cyclopentyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) cyclohexyl) acrylamide;

   N- (4-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) tetrahydrofuran-3-yl) acrylamide;

   N-((3S, 4S) -3-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3- d] pyrimidin-2-yl) amino) tetrahydro-2H-pyran-4-yl) acrylamide;

   N-((3S, 4S) -3-((6- (2,6-difluoro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2, 3-d] pyrimidin-2-yl) amino) tetrahydro-2H-pyran-4-yl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) phenyl) acrylamide;

   N- (3-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) phenyl) acrylamide;

   N- (2-((6- (3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-2-yl) amino)- 3-methylphenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imido [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -3-methylphenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -3-fluorophenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -3-methoxyphenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -4-fluorophenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -4- (4-ethylpiperazin-1-yl) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-fluorophenyl) acrylamide;

   N- (5-chloro-2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] Pyrimidin-2-yl) amino) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-ethynylphenyl) acrylamide;

   N- (5-cyano-2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d ] Pyrimidin-2-yl) amino) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (methylsulfonyl) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-methylphenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-ethylphenyl) acrylamide;

   N- (5-cyclopropyl-2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d ] Pyrimidin-2-yl) amino) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-isopropylphenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (1-methylpiperidin-4-yl) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (dimethylamino) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-((2-methoxyethyl) (methyl) amino) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-methoxyphenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-ethoxyphenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-isopropoxyphenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (2-methoxyethoxy) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (2- (dimethylamino) ethoxy) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-morpholinophenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (pyrrolidin-1-yl) phenyl) acrylamide;

   (E) -N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] Pyrimidin-2-yl) amino) -5-morpholinophenyl) -4- (dimethylamino) but-2-enamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (4- (methylsulfonyl) piperazin-1-yl) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (1,1-dioxidothiomorpholino) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (3-methoxyazetidin-1-yl) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-((2S, 6R) -2,6-dimethylmorpholino) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (piperazin-1-yl) phenyl) acrylamide trifluoroacetic acid salt;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (4-methoxypiperidin-1-yl) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (3-methoxypyrrolidin-1-yl) phenyl) acrylamide;

   N- (5- (4- (cyclopropanecarbonyl) piperazin-1-yl) -2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2 ': 1,6] pyrido [2,3-d] pyrimidin-2-yl) amino) phenyl) acrylamide;

   N- (5- (4- (cyclopropylmethyl) piperazin-1-yl) -2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2' : 1,6] pyrido [2,3-d] pyrimidin-2-yl) amino) phenyl) acrylamide;

   (S) -N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] Pyrimidin-2-yl) amino) -5- (3-methoxypyrrolidin-1-yl) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (3-hydroxyazetidin-1-yl) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) acrylamide;

   (Z) -3-chloro-N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2, 3-d] pyrimidin-2-yl) amino) -5-morpholinophenyl) acrylamide;

   (S) -N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] Pyrimidin-2-yl) amino) -5- (3- (dimethylamino) pyrrolidin-1-yl) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (2-methylmorpholino) phenyl) acrylamide;

   (S) -N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] Pyrimidin-2-yl) amino) -5- (2- (methoxymethyl) pyrrolidin-1-yl) phenyl) acrylamide;

   N- (5- (4-cyclopropylpiperazin-1-yl) -2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1, 6] pyrido [2,3-d] pyrimidin-2-yl) amino) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (4-methylpiperazin-1-yl) phenyl) acrylamide;

   (R) -N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] Pyrimidin-2-yl) amino) -5-((tetrahydrofuran-3-yl) oxy) phenyl) acrylamide;

   N- (5- (cyclopentyloxy) -2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2, 3-d] pyrimidin-2-yl) amino) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-((1- (2,2,2-trifluoroethyl) piperidin-4-yl) oxy) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-((1-ethylpiperidin-4-yl) oxy) phenyl) acrylamide;

   N- (6-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -2,3-dihydro-1H-inden-5-yl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -3,5-dimethylphenyl) acrylamide;

   (R) -N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] Pyrimidin-2-yl) amino) -4-fluoro-5-((tetrahydrofuran-3-yl) oxy) phenyl) acrylamide;

   (R) -N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] Pyrimidin-2-yl) amino) -4-methyl-5-((tetrahydrofuran-3-yl) oxy) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -4-methyl-5-morpholinophenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -4-fluoro-5-((1-methylpiperidin-4-yl) oxy) phenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -3-methyl-5-morpholinophenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-fluoro-3-methylphenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -3-methoxy-5-morpholinophenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5- (4-ethylpiperazin-1-yl) -3-fluorophenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -3-fluoro-5-morpholinophenyl) acrylamide;

   N- (3-chloro-2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] Pyrimidin-2-yl) amino) -5-morpholinophenyl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) pyridin-3-yl) acrylamide;

   N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -5-morpholinopyridin-3-yl) acrylamide;

   N- (3-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2 -Yl) amino) -1-methyl-1H-pyrazol-4-yl) acrylamide;

   N- (2-((6- (2,6-difluoro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine -2-yl) amino) -3-fluorophenyl) acrylamide;

   N- (2-((6- (2,6-difluoro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine -2-yl) amino) -5-morpholinophenyl) acrylamide;

   N- (3-((6- (2,6-difluoro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine -2-yl) amino) phenyl) acrylamide;

   N- (2-((6- (2,6-difluoro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine -2-yl) amino) phenyl) acrylamide;

   N- (2-((6- (2,6-difluoro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine -2-yl) amino) -3,5-difluorophenyl) acrylamide;

   N- (2-((6- (2,6-difluoro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine -2-yl) amino) -4,5-difluorophenyl) acrylamide;

   N- (2-((6- (2,6-difluoro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine -2-yl) amino) -3,4-difluorophenyl) acrylamide;

   -(3-chloro-2-((6- (2,6-difluro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d ] Pyrimidin-2-yl) amino) phenyl) acrylamide;

   4- (3- (6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2- Yl) phenyl) morpholine;

   4- (5- (6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2- Yl) pyridin-3-yl) morpholine;

   N- (3- (6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine-2- One) -5-morpholinophenyl) acrylamide;

   N- (2-((4- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1,2-a] [1,6] naphthyridin-8-yl) amino) -5- Morpholinophenyl) acrylamide;

   N- (2-((4- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1,2-a] [1,6] naphthyridin-8-yl) amino) -5- ((2S, 6R) -2,6-dimethylmorpholino) phenyl) acrylamide;

   N- (2-((4- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1,2-a] [1,6] naphthyridin-8-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) acrylamide;

   N- (2-((4- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1,2-a] [1,6] naphthyridin-8-yl) amino) -5- Morpholinopyridin-3-yl) acrylamide; And

   N- (3-((4- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1,2-a] [1,6] naphthyridin-8-yl) amino) -1- Methyl-1H-pyrazol-4-yl) acrylamide.
7. A pharmaceutical composition comprising a compound of claim 1 in a therapeutically effective amount.
8. The method of claim 7, wherein

   Pharmaceutical composition, characterized in that the pharmaceutical composition inhibits the activity of fibroblast growth factor receptor (FGFR).
9. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is for preventing or treating cancer or a tumor.
10. The method of claim 9, wherein the cancer is liver cancer, hepatocellular carcinoma, thyroid cancer, colorectal cancer, testicular cancer, bone cancer, oral cancer. ), Basal cell carcinoma, ovarian cancer, brain tumor, gallbladder carcinoma, biliary tract cancer, head and neck cancer, and colorectal cancer colorectal cancer, vesical carcinoma, tongue cancer, esophageal cancer, glioma, glioblastoma, renal cancer, malignant melanoma, gastric cancer gastric cancer, breast cancer, sarcoma, sarcoma, pharynx carcinoma, uterine cancer, cervical cancer, prostate cancer, rectal cancer, pancreatic cancer from the group consisting of pancreatic cancer, lung cancer, skin cancer and other solid cancers A pharmaceutical composition characterized in that the selection.
11. A pharmaceutical formulation comprising the pharmaceutical composition of claim 7.
12. The method of claim 11,

    Pharmaceutical formulation, characterized in that the pharmaceutical formulation is in the form of tablets, pills, powders, capsules, syrups or emulsions.
13. The method of claim 11,

    The pharmaceutical preparations further comprise one or more selected from the group consisting of pharmaceutically acceptable carriers, adjuvant and excipients.