Benzamide derivatives, their preparation methods and uses

Abstract

The present invention relates to 3-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-phenylbenzamide derivatives, a method for preparing the same, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient. The derivative can significantly inhibit the proliferation of cancer cells by inhibiting kinases, especially Bcr-Abl kinase or Bcr-Abl (T315I) kinase. Therefore, the derivative can be effectively used as a pharmaceutical composition for preventing or treating cancer.

Description

Background Art Field of the Invention

[0001] The present invention relates to 3-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-phenylbenzamide derivatives, a method for preparing the same, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.

[0002] Description of Related Art

[0003] Protein tyrosine kinases (PTKs) are important target molecules in the drug development for treating various diseases, especially for treating proliferative diseases. The dysregulation of tyrosine kinase activity is considered to be the main mechanism by which cancer cells avoid normal physiological limitations in growth, proliferation, and survival.

[0004] Tyrosine kinases (TKs) are enzymes that catalyze the transfer of phosphate from ATP to tyrosine residues in polypeptides. The human genome contains approximately 90 TK and 43 TK-like genes, and the products of these genes control a variety of cellular functions, including cell proliferation, survival, differentiation, function, and migration.

[0005] The dysregulation of TK activity caused by mutations, overexpression, or dysfunction of self-regulatory mechanisms is associated with many diseases, including cancer. A common mechanism of TK activation in blood cancers is the fusion of receptor or non-receptor TKs with partner proteins, usually as a result of balanced chromosomal translocations. A fundamental example of this mechanism is Bcr-Abl, a non-receptor fusion TK in chronic myelogenous leukemia (CML). At this time, the tetramerization domain in Bcr overcomes the autoinhibition of Abl catalytic activity through oligomerization and autophosphorylation. For some receptor TKs, the absence of a juxtamembrane inhibitory domain in the fusion protein contributes to activation.

[0006] The second important mechanism of TK dysregulation is mutations that disrupt kinase self-regulation. Mutations in the Fms-like tyrosine kinase 3 (FLT3) receptor in acute myeloid leukemia (AML) render the TK active in the absence of ligand. The third mechanism of TK dysregulation is increased or abnormal expression of the receptor TK, its ligand, or both. Finally, the increase in TK activity may be due to a decrease in factors that limit TK activity, such as impaired tyrosine phosphatase activity or reduced expression of TK inhibitor proteins. Abnormal TK activation can increase the survival, proliferation, and cytotoxic drug resistance of malignant cells, and can increase angiogenesis, permeability, and metastatic potential in tumors.

[0007] The TK family of enzymes has emerged as an important target class for therapeutic intervention, and TK can be pharmacologically inhibited by multiple mechanisms. One of the important focuses in the screening of anti-TK drugs is the design and development of small molecules that can directly inhibit the catalytic activity of kinases by interfering with the binding of ATP or substrates. An important advantage of TK-related therapies is the ability to conduct pharmacodynamic studies that correlate the inhibition of targeted TK in cancer cells with the clinical response to the drug (Korean Patent Publication No. 10-2014-0016889).

[0008] In particular, Bcr-Abl is a key cause in the pathogenesis of 95% of chronic myeloid leukemia (CML) and 10% of acute lymphoblastic leukemia (AML). Therefore, Bcr-Abl kinase inhibitors can be effectively used as targeted therapeutic agents for chronic myeloid leukemia, and based on many studies, targeted anticancer drugs have been released, and a representative example is Gleevec.

[0009] Gleevec is effective by blocking the Bcr-Abl activity that prevents blood cell proliferation, but recently it has been reported that Gleevec has developed resistance due to Bcr-Abl mutations. Some patients in the acute critical stage of CML are caused by Bcr-Abl kinase mutations, and to date, more than 22 mutations have been reported. Among them, T315I (a gating residue mutation) is becoming the biggest problem.

[0010] Tasigna and Sprycell are second-generation drugs that have been developed to improve Gleevec, but so far they cannot effectively act on mutant Abl such as T315I, and no drugs available for this mutation have been reported. Therefore, there is an urgent need to develop drugs that can simultaneously inhibit wild-type Abl kinase and mutant Abl kinases such as T315I (Korean Patent Publication No. 10-2013-0084083). SUMMARY OF THE INVENTION

[0011] An object of the present invention is to provide 3-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-phenylbenzamide derivatives, their solvates or their pharmaceutically acceptable salts.

[0012] Another object of the present invention is to provide a method for preparing 3-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-phenylbenzamide derivatives.

[0013] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating kinase-related diseases, which contains 3-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-phenylbenzamide derivatives, their solvates or their pharmaceutically acceptable salts as active ingredients.

[0014] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, which contains 3-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-phenylbenzamide derivatives, their solvates or their pharmaceutically acceptable salts as active ingredients.

[0015] Another object of the present invention is to provide a health functional food composition for preventing or improving kinase-related diseases, which contains 3-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-phenylbenzamide derivatives, their solvates or their pharmaceutically acceptable salts as active ingredients.

[0016] Another object of the present invention is to provide a health functional food composition for preventing or improving cancer, which contains 3-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-phenylbenzamide derivatives, their solvates or their pharmaceutically acceptable salts as active ingredients.

[0017] Another object of the present invention is to provide a method for treating kinase-related diseases or cancer, which includes the step of administering 3-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-phenylbenzamide derivatives, their solvates or their pharmaceutically acceptable salts to an individual or subject in need.

[0018] Another object of the present invention is to provide the use of 3-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-phenylbenzamide derivatives, their solvates or their pharmaceutically acceptable salts in the preparation of a drug for treating kinase-related diseases or cancer.

[0019] To achieve the above object, in one aspect of the present invention, the present invention provides a compound represented by Formula 1, its solvate or its pharmaceutically acceptable salt:

[0020] [Formula 1]

[0021]

[0022] In the above Formula 1,

[0023] R 1 is hydrogen or C 1-10 alkyl;

[0024] X is halogen;

[0025] R 2 is

[0026] wherein, R 2a , R 2b and R 2c are independently hydrogen, halogen, cyano or C 1-10 alkyl;

[0027] L 1 is a single bond, -O- or C 1-10 alkylene;

[0028] R 3 is a 5- to 8-membered unsubstituted or substituted heteroaryl containing one or more heteroatoms selected from N, O and S, a 4- to 8-membered unsubstituted or substituted heterocycloalkyl containing one or more heteroatoms selected from N, O and S, an unsubstituted or substituted C 1-10 alkyl or NR 3a R 3b , wherein, R 3a and R 3b are independently hydrogen or unsubstituted or substituted C 1-10 alkyl,

[0029] wherein, the substituted heteroaryl, substituted heterocycloalkyl and substituted alkyl are substituted by one or more substituents selected from: an unsubstituted or halogen-substituted C 1-10 alkyl, C 1-10 alkyl alcohol, C 1-10 alkylsulfonyl, C 1-10 alkoxy, oxo, NR 3c R 3d and a heterocycloalkyl substituted by a 5- to 8-membered C 1-10 alkyl containing one or more heteroatoms selected from N, O and S, wherein, R 3c and R 3d are independently hydrogen or C 1-10 alkyl.

[0030] In another aspect of the present invention, the present invention provides a method for preparing a compound represented by Formula 1, comprising the step of preparing a compound represented by Formula 1 by reacting a compound represented by Formula 2 with a compound represented by Formula 3, as shown in the following Reaction Scheme 1:

[0031] [Reaction Scheme 1]

[0032]

[0033] In the above Reaction Scheme 1, L 1 , R 1 , R 2 , R 3 and X are as defined in Scheme 1.

[0034] In another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating a disease associated with one or more protein kinases, which comprises a compound represented by Formula 1, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, and the protein kinases are selected from ABL1(E255K)-phosphorylated, ABL1(F317I)-non-phosphorylated, ABL1(F317I)-phosphorylated, ABL1(F317L)-non-phosphorylated, ABL1(F317L)-phosphorylated, ABL1(H396P)-non-phosphorylated, ABL1(H396P)-phosphorylated, ABL1(M351T)-phosphorylated, ABL1(Q252H)-non-phosphorylated, ABL1(Q252H)-phosphorylated, ABL1(T315I)-non-phosphorylated, ABL1(T315I)-phosphorylated, ABL1(Y253F)-phosphorylated, ABL1-non-phosphorylated, ABL1-phosphorylated, ABL2, AURKB, AURKC, AXL, BLK, BMX, BRAF, BRAF(V600E), BRK, BTK, CDC2L1, CDC2L2, CDC2L5, CDK11, CDK7, CDKL2, CIT, CSF1R, CSK, DDR1, DDR2, DLK, EGFR, EGFR(E746-A750del), EGFR(G719C), EGFR(G719S), EGFR(L747-E749del,A750P), EGFR(L747-S752del,P753S), EGFR(L747-T751del,Sins), EGFR(L858R), EGFR(L861Q), EGFR(S752-I759del), EPHA1, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB6, ERBB2, ERBB4, ERK8, FER, FES, FGFR1, FGFR2, FGFR3, FGFR3(G697C), FGFR4, FGR, FLT1, FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT4, FRK, FYN, GAK, GCN2(Kin.Dom.2, S808G), HCK, HPK1, IKK-alpha, IKK-beta, IRAK1, IRAK4, JNK2, KIT, KIT(A829P), KIT(D816H), KIT(D816V), KIT(L576P), KIT(V559D), KIT(V559D,T670I), KIT(V559D,V654A), LCK, LIMK1, LOK, LRRK2, LTK, LYN, MAP3K2, MAP3K3, MAP4K2, MAP4K3, MAP4K4, MAP4K5, MEK5, MERTK, MET(Y1235D), MINK, MKNK1, MKNK2, MLK1, MLK3, MST3, MUSK, NEK1, NEK4, NLK, p38-alpha, p38-beta, p38-delta, p38-gamma, PAK3, PCTK2, PDGFRA, PDGFRB, PFCDPK1 (Plasmodium falciparum), PFTAIRE2, PFTK1, RET, RET(M918T), RET(V804L), RET(V804M), RIOK3, RIPK1, RIPK2, SIK, SLK, SRC, SRMS, STK33, STK35, STK36, TAK1, TAOK1, TAOK2, TAOK3, TEC, TESK1, TIE1, TIE2, TNIK, TNK1, TNK2, TNNI3K, TRKA, TRKB, TRKC, TXK, TYK2 (JH1 domain - catalytic), VEGFR2, YES, YSK4, and ZAK.

[0035] In another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating cancer, which contains a compound represented by Formula 1, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0036] In another aspect of the present invention, the present invention provides a health functional food composition for preventing or improving kinase-related diseases, which contains a compound represented by Formula 1, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0037] In another aspect of the present invention, the present invention provides a health functional food composition for preventing or improving cancer, which contains a compound represented by Formula 1, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0038] In another aspect of the present invention, the present invention provides a method for treating kinase-related diseases or cancers, comprising the step of administering to an individual or subject in need thereof the compound, its solvate or its pharmaceutically acceptable salt.

[0039] Furthermore, the present invention provides the use of the compound, its solvate or its pharmaceutically acceptable salt in the preparation of a medicament for treating kinase-related diseases or cancers.

[0040] Beneficial effects

[0041] The 3-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-phenylbenzamide derivative of the present invention can significantly inhibit the proliferation of cancer cells by inhibiting kinases, especially Bcr-Abl kinase or Bcr-Abl(T315I) kinase. Therefore, the derivative can be effectively used as a pharmaceutical composition for preventing or treating cancers. Description of the drawings

[0042] Figure 1 is an optical image showing each of the 5 groups in the leukemia animal model according to the carrier or drug treatment process.

[0043] Figure 2 is a luminescence signal map showing the emission of leukemia cells in each of the 5 groups in the leukemia model according to the carrier or drug treatment process.

[0044] Figure 3 is a schematic diagram showing the survival rate of mice in each of the 5 groups in the leukemia model according to the carrier or drug treatment process.

[0045] Figure 4 is a graph showing the change in body weight of mice in each of the 5 groups in the leukemia model according to the carrier or drug treatment process. Detailed description of the invention

[0046] The present invention will be described in detail below.

[0047] The present invention provides a compound represented by formula 1, its solvate or its pharmaceutically acceptable salt:

[0048] [Formula 1]

[0049]

[0050] In the above formula 1,

[0051] R 1 is hydrogen or C 1-10 alkyl;

[0052] X is a halogen;

[0053] R2 is

[0054] wherein, R 2a 、R 2b and R 2c are independently hydrogen, halogen, cyano or C 1-10 alkyl;

[0055] L 1 is a single bond, -O- or C 1-10 alkylene;

[0056] R 3 is a 5- to 8-membered unsubstituted or substituted heteroaryl containing one or more heteroatoms selected from N, O and S, a 4- to 8-membered unsubstituted or substituted heterocycloalkyl containing one or more heteroatoms selected from N, O and S, an unsubstituted or substituted C 1-10 alkyl or NR 3a R 3b wherein, R 3a and R 3b are independently hydrogen or unsubstituted or substituted C 1-10 alkyl,

[0057] wherein, the substituted heteroaryl, substituted heterocycloalkyl and substituted alkyl are substituted by one or more substituents selected from: C 1-10 alkyl which is unsubstituted or substituted by one or more halogens, C 1-10 alkyl alcohol, C 1-10 alkylsulfonyl, C 1-10 alkoxy, oxo, NR 3c R 3d and a heterocycloalkyl substituted by a 5- to 8-membered C 1-10 alkyl containing one or more heteroatoms selected from N, O and S, wherein, R 3c and R 3d are independently hydrogen or C 1-10 alkyl.

[0058] In the above formula 1,

[0059] R 1 is hydrogen or C 1-6 alkyl;

[0060] X is halogen;

[0061] R 2 is

[0062] wherein, R 2a 、R 2b and R 2c are independently hydrogen, halogen, cyano or C 1-6 alkyl;

[0063] L 1 is a single bond, -O-, or C 1-6 alkylene;

[0064] R 3 is a 5- or 6-membered unsubstituted or substituted heteroaryl containing one or more heteroatoms selected from N and O, a 4- to 7-membered unsubstituted or substituted heterocycloalkyl containing one or more heteroatoms selected from N and O, an unsubstituted or substituted C 1-6 alkyl, or NR 3a R 3b , where R 3a and R 3b are independently hydrogen or unsubstituted or substituted C 1-6 alkyl,

[0065] wherein the substituted heteroaryl, substituted heterocycloalkyl, and substituted alkyl are substituted by one or more substituents selected from: C 1-6 alkyl which is unsubstituted or substituted by one or more halogens, C 1-6 alkyl alcohol, C 1-6 alkylsulfonyl, C 1-6 alkoxy, oxo, NR 3c R 3d and a heterocycloalkyl substituted by a 5- or 6-membered C 1-6 alkyl containing one or more heteroatoms selected from N and O, where R 3c and R 3d are independently hydrogen or C 1-6 alkyl.

[0066] In the above formula 1,

[0067] R 1 is hydrogen or methyl;

[0068] X is fluorine or chlorine;

[0069] R 2 is

[0070] wherein, R 2a 、R 2b and R 2c are independently fluorine, cyano, or methyl;

[0071] L 1 is a single bond, -O-, or methylene;

[0072] R 3is an unsubstituted or substituted imidazolyl, pyridyl, pyrimidinyl, substituted piperazinyl, substituted pyrazolyl, substituted diazepanyl, substituted piperidinyl, morpholinyl, substituted pyrrolidinyl, substituted azetidinyl, triazolyl, substituted ethyl, substituted propyl or NR 3a R 3b , wherein R 3a and R 3b are independently methyl, substituted ethyl or substituted propyl,

[0073] wherein the substituted imidazolyl, substituted piperazinyl, substituted pyrazolyl, substituted diazepanyl, substituted piperidinyl, substituted pyrrolidinyl, substituted azetidinyl, substituted ethyl and substituted propyl are substituted by one or more substituents selected from: methyl, CF3, CH2CF3, isopropyl, methylsulfonyl, isopropoxy, ethanol, methyl-substituted piperazine, methyl-substituted piperidine, oxo and NR 3c R 3d , wherein R 3c and R 3d may be methyl.

[0074] The compound represented by Formula 1 may be the compound represented by the following Formula 2.

[0075] [Formula 2]

[0076]

[0077] In the above Formula 1,

[0078] R 1 is hydrogen or methyl;

[0079] X is fluorine or chlorine;

[0080] R 2 is L 1 -R 3 is

[0081]

[0082] Examples of the compound represented by Formula 1 according to the present invention include the following compounds:

[0083] <1>N-(3-(2-cyanopropan-2-yl)-5-(4-methyl-1H-imidazol-1-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0084] <2>3-Fluoro-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0085] <3>N-(3-(2-Cyanopropan-2-yl)-5-(4-methyl-1H-imidazol-1-yl)phenyl)-2-fluoro-4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0086] <4>2-Fluoro-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0087] <5>3-Fluoro-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0088] <6>2-Fluoro-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0089] <7>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(pyridin-4-yloxy)-5-(trifluoromethyl)phenyl)benzamide;

[0090] <8>3-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(pyridin-4-yloxy)-5-(trifluoromethyl)phenyl)benzamide;

[0091] <9>2-Fluoro-4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(pyridin-4-yloxy)-5-(trifluoromethyl)phenyl)benzamide;

[0092] N-(3-(2-cyanopropan-2-yl)-5-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0093] N-(3-(2-cyanopropan-2-yl)-5-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)-3-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0094] N-(3-(2-cyanopropan-2-yl)-5-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0095] 2-chloro-N-(3-(2-cyanopropan-2-yl)-5-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0096] 2-chloro-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0097] 2-chloro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(pyridin-4-yloxy)-5-(trifluoromethyl)phenyl)benzamide;

[0098] 2-chloro-N-(3-(2-cyanopropan-2-yl)-5-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0099] <17>N-(3-(2-Cyanopropan-2-yl)-5-(pyridin-4-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0100] <18>N-(3-(2-Cyanopropan-2-yl)-5-(pyridin-3-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0101] <19>N-(3-(2-Cyanopropan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0102] <20>N-(3-(2-Cyanopropan-2-yl)-5-(4-methylpiperazin-1-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0103] <21>N-(3-(2-Cyanopropan-2-yl)-5-(4-methyl-1,4-diazepan-1-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0104] <22>N-(3-(2-Cyanopropan-2-yl)-5-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0105] <23>N-(3-(2-Cyanopropan-2-yl)-5-((3-(dimethylamino)propyl)(methyl)amino)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0106] <24>N-(3-(2-Cyanopropan-2-yl)-5-(4-methyl-3-oxopiperazin-1-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0107] <25>N-(3-(2-Cyanopropan-2-yl)-5-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0108] <26>N-(3-(2-Cyanopropan-2-yl)-5-(pyridin-4-yloxy)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0109] <27>N-(3-(2-Cyanopropan-2-yl)-5-((4-methylpiperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0110] <28>N-(3-(2-Cyanopropan-2-yl)-5-(morpholinomethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0111] <29>N-(3-(2-Cyanopropan-2-yl)-5-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0112] <30>N-(3-(2-Cyanopropan-2-yl)-5-((4-methyl-1,4-diazepan-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0113] <31>N-(3-(2-Cyanopropan-2-yl)-5-((4-(trifluoromethyl)piperidin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0114] <32>N-(3-(2-Cyanopropan-2-yl)-5-((4-(2,2,2-trifluoroethyl)piperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0115] <33>N-(3-(2-Cyanopropan-2-yl)-5-((4-isopropylpiperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0116] <34>N-(3-(2-Cyanopropan-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0117] <35>N-(3-(2-Cyanopropan-2-yl)-5-((4-methyl-3-oxopiperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0118] <36>N-(3-(2-Cyanopropan-2-yl)-5-((3-isopropoxyazetidin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0119] <37>N-(3-((1H-Imidazol-1-yl)methyl)-5-(2-cyanopropan-2-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0120] <38>N-(3-((1H-1,2,4-triazol-1-yl)methyl)-5-(2-cyanopropan-2-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0121] <39>N-(3-(2-cyanopropan-2-yl)-4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0122] <40>N-(3-(2-cyanopropan-2-yl)-4-(morpholinomethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0123] <41>N-(3-(2-cyanopropan-2-yl)-4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0124] <42>N-(3-(2-cyanopropan-2-yl)-4-((4-methyl-1,4-diazepan-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0125] <43>N-(3-(2-cyanopropan-2-yl)-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0126] <44>N-(3-(2-cyanopropan-2-yl)-4-((4-methyl-3-oxopiperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0127] <45>N-(3-(2-cyanopropan-2-yl)-4-((4-(methylsulfonyl)piperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0128] <46>N-(4-((1H-imidazol-1-yl)methyl)-3-(2-cyanopropan-2-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0129] <47>2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;

[0130] <48>N-(3-((2-(dimethylamino)ethyl)(methyl)amino)-5-(trifluoromethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0131] <49>2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(4-methyl-3-oxopiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;

[0132] <50>N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0133] <51>N-(3-(3-(dimethylamino)propoxy)-5-(trifluoromethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0134] <52>2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)benzamide;

[0135] <53>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)benzamide;

[0136] <54>2-Fluoro-4-methyl-N-(3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0137] <55>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0138] <56>2-Fluoro-N-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0139] <57>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(4-(morpholinomethyl)-3-(trifluoromethyl)phenyl)benzamide;

[0140] <58>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(4-((4-methyl-3-oxopiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0141] <59>N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0142] <60>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(4-((4-(methylsulfonyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0143] <61>2-Fluoro-4-methyl-N-(4-((4-methyl-1,4-diazepan-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0144] <62>2-Fluoro-N-(4-((3-isopropoxyazetidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0145] <63>N-(4-((1H-imidazol-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0146] <64>N-(4-((1H-1,2,4-triazol-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0147] <65>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(4-(pyridin-4-yloxy)-3-(trifluoromethyl)phenyl)benzamide;

[0148] <66>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(morpholinomethyl)-5-(trifluoromethyl)phenyl)benzamide;

[0149] <67>2-Fluoro-4-methyl-N-(3-((4-methyl-1,4-diazepan-1-yl)methyl)-5-(trifluoromethyl)phenyl)-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0150] <68>N-(3-((3-(Dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0151] <69>2-Fluoro-N-(3-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0152] <70>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-((4-(methylsulfonyl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide;

[0153] <71>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-((4-methyl-3-oxopiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide;

[0154] <72>2-Fluoro-N-(3-((3-isopropoxyazetidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0155] <73>N-(3-((1H-Imidazol-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0156] <74>N-(3-((1H-1,2,4-Triazol-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide;

[0157] (8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-(4-methyl-1H-imidazol-1-yl)phenyl)-2-fluoro-4-methylbenzamide;

[0158] (76)5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-chloro-N-(3-(2-cyanopropan-2-yl)-5-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methylbenzamide;

[0159] (77)5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-fluoro-4-methylbenzamide;

[0160] (78)5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-(pyridin-4-yl)phenyl)-2-fluoro-4-methylbenzamide;

[0161] (79)5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-(pyridin-3-yl)phenyl)-2-fluoro-4-methylbenzamide;

[0162] (80)5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-(4-methylpiperazin-1-yl)phenyl)-2-fluoro-4-methylbenzamide;

[0163] (81)5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-2-fluoro-4-methylbenzamide;

[0164] (82)5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-(4-methyl-3-oxopiperazin-1-yl)phenyl)-2-fluoro-4-methylbenzamide;

[0165] <83>(8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-(pyridin-4-yloxy)phenyl)-2-fluoro-4-methylbenzamide;

[0166] <84>(8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-((4-methylpiperazin-1-yl)methyl)phenyl)-2-fluoro-4-methylbenzamide;

[0167] <85>((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-2-fluoro-4-methylbenzamide;

[0168] <86>5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)-2-fluoro-4-methylbenzamide;

[0169] <87>5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)phenyl)-2-fluoro-4-methylbenzamide;

[0170] <88>(8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-((4-methyl-3-oxopiperazin-1-yl)methyl)phenyl)-2-fluoro-4-methylbenzamide;

[0171] <89>N-(3-((1H-1,2,4-triazol-1-yl)methyl)-5-(2-cyanopropan-2-yl)phenyl)-5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methylbenzamide;

[0172] <90>(8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-fluoro-4-methylbenzamide;

[0173] <91>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-2-fluoro-4-methylbenzamide;

[0174] <92>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)-2-fluoro-4-methylbenzamide;

[0175] <93>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-4-((4-methyl-3-oxopiperazin-1-yl)methyl)phenyl)-2-fluoro-4-methylbenzamide;

[0176] <9s>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-4-((4-(methylsulfonyl)piperazin-1-yl)methyl)phenyl)-2-fluoro-4-methylbenzamide;

[0177] <95>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide;

[0178] <96>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)benzamide;

[0179] <97>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)benzamide;

[0180] <98>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(3-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)benzamide;

[0181] <99>5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;

[0182] <100>5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(3-(4-methyl-3-oxopiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;

[0183] <101>5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(3-(pyridin-4-yloxy)-5-(trifluoromethyl)phenyl)benzamide;

[0184] <102>5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-fluoro-4-methylbenzamide;

[0185] <103>(<8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(3-(dimethylamino)propoxy)-5-(trifluoromethyl)phenyl)-2-fluoro-4-methylbenzamide;

[0186] <104>5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide;

[0187] <105>5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-fluoro-4-methylbenzamide;

[0188] <106>(8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-N-(3-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;

[0189] (8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(3-((4-methyl-3-oxopiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide;

[0190] (8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(3-((1H-1,2,4-triazol-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide;

[0191] (8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0192] (8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-fluoro-4-methylbenzamide;

[0193] (8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-N-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide;

[0194] (8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(4-((4-methyl-3-oxopiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0195] (8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(4-((4-(methylsulfonyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0196] (8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(4-((1H-1,2,4-triazol-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide.

[0197] The compounds of formula 1 according to the present invention can be used in the form of pharmaceutically acceptable salts, wherein the salts are preferably acid addition salts formed from pharmaceutically acceptable free acids. The acid addition salts described herein can be obtained from: inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid and phosphorous acid; non-toxic organic acids such as aliphatic mono / dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids and aliphatic / aromatic sulfonic acids; or organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid and fumaric acid. Examples of pharmaceutically non-toxic salts are as follows: sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, caprylate, octanoate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, octanedioate, cabacate, fumarate, malate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and mandelate.

[0198] The acid addition salts of the present invention can be prepared by conventional methods known to those skilled in the art. For example, the derivative of formula 1 is dissolved in an organic solvent such as methanol, ethanol, acetone, dichloromethane and acetonitrile, and an organic acid or an inorganic acid is added thereto to induce precipitation. Then, the precipitate is filtered and dried to obtain the salt. Alternatively, the solvent and the excess acid are distilled under reduced pressure and dried. Then, the precipitate is crystallized in an organic solvent to obtain the salt.

[0199] Pharmaceutically acceptable metal salts can be prepared using bases. Alkali metal or alkaline earth metal salts are obtained by the following method: the compound is dissolved in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution; the insoluble complex salt is filtered; the remaining solution is evaporated and dried. At this time, it is preferred to prepare the metal salt in the form of a pharmaceutically suitable sodium salt, potassium salt or calcium salt. And the corresponding salt is prepared by reacting the alkali metal or alkaline earth metal salt with an appropriate silver salt (such as silver nitrate).

[0200] In addition, the present invention includes not only the compounds represented by formula 1, but also their pharmaceutically acceptable salts, as well as solvates, isomers and hydrates that may be generated therefrom.

[0201] The term "solvate" refers to a compound of the invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Accordingly, preferred solvents include volatile, non-toxic, and / or solvents suitable for administration to humans. In such cases, when the solvent is water, it is referred to as a "hydrate".

[0202] The term "isomer" refers to a compound of the invention or a salt thereof that has the same chemical formula or molecular formula but is different in structure or space. These isomers include structural isomers such as tautomers, R or S isomers having an asymmetric carbon center, stereoisomers such as geometric isomers (trans, cis), and optical isomers (enantiomers). All such isomers and mixtures thereof are also included within the scope of the present invention.

[0203] In another aspect of the present invention, there is provided a method for preparing a compound represented by Formula 1, comprising the step of preparing a compound represented by Formula 1 by reacting a compound represented by Formula 2 with a compound represented by Formula 3, as shown in Reaction Scheme 1 below:

[0204] [Reaction Scheme 1]

[0205]

[0206] In the above Reaction Scheme 1, L 1 , R 1 , R 2 , R 3 and X are as defined in Formula 1.

[0207] Hereinafter, the preparation method shown in Reaction Scheme 1 above will be described in more detail.

[0208] In the method for preparing a compound represented by Formula 1 of the present invention, the step of Reaction Scheme 1 is a step of preparing a compound represented by Formula 1 by reacting a compound represented by Formula 2 with a compound represented by Formula 3. Specifically, it is a step of reacting the carboxyl group of the compound represented by Formula 2 with the amino group of the compound represented by Formula 3 to form the compound represented by Formula 1.

[0209] At this time, as long as it is a method for preparing a 3-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-phenylbenzamide derivative represented by Formula 1, there is no particular limitation, and it is all included within the scope of the present invention. The compound represented by Formula 2 can be understood as a compound containing a carboxyl group capable of reacting with an amine to form an amide, and the compound represented by Formula 3 can be understood as an amine capable of undergoing an amide formation reaction. However, this is only an example and is not limited thereto. The 3-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-phenylbenzamide derivative of the present invention is the final compound and is prepared by an amide formation reaction between a carboxyl group and an amino group.

[0210] More specifically, it can be understood by referring to the preparation methods of the example compounds of the present invention below. Various reaction conditions (reaction conditions conceivable by those skilled in the art of organic synthesis, such as reaction temperature, time, atmospheric conditions, pressure conditions, etc.) can be changed, and it can be understood that the present invention is not limited thereto. In addition, it can be understood that the compounds and their derivatives used in each step include derivatives other than those disclosed herein, which can be modified by simple modification, change, or removal of substituents, and the modified derivatives are included in the present invention.

[0211] Preferred embodiments of the preparation method include the preparation methods disclosed in Examples 1 to 114 below, but the present invention is not limited thereto.

[0212] In another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating a disease associated with one or more protein kinases, which comprises a compound represented by Formula 1, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient, and the protein kinases are selected from ABL1(E255K)-phosphorylated, ABL1(F317I)-non-phosphorylated, ABL1(F317I)-phosphorylated, ABL1(F317L)-non-phosphorylated, ABL1(F317L)-phosphorylated, ABL1(H396P)-non-phosphorylated, ABL1(H396P)-phosphorylated, ABL1(M351T)-phosphorylated, ABL1(Q252H)-non-phosphorylated, ABL1(Q252H)-phosphorylated, ABL1(T315I)-non-phosphorylated, ABL1(T315I)-phosphorylated, ABL1(Y253F)-phosphorylated, ABL1-non-phosphorylated, ABL1-phosphorylated, ABL2, AURKB, AURKC, AXL, BLK, BMX, BRAF, BRAF(V600E), BRK, BTK, CDC2L1, CDC2L2, CDC2L5, CDK11, CDK7, CDKL2, CIT, CSF1R, CSK, DDR1, DDR2, DLK, EGFR, EGFR(E746-A750del), EGFR(G719C), EGFR(G719S), EGFR(L747-E749del, A750P), EGFR(L747-S752del, P753S), EGFR(L747-T751del, Sins), EGFR(L858R), EGFR(L861Q), EGFR(S752-I759del), EPHA1, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB6, ERBB2, ERBB4, ERK8, FER, FES, FGFR1, FGFR2, FGFR3, FGFR3(G697C), FGFR4, FGR, FLT1, FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD, F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT4, FRK, FYN, GAK, GCN2(Kin.Dom.2, S808G), HCK, HPK1, IKK-alpha, IKK-beta, IRAK1, IRAK4, JNK2, KIT, KIT(A829P), KIT(D816H), KIT(D816V), KIT(L576P), KIT(V559D), KIT(V559D, T670I), KIT(V559D, V654A), LCK, LIMK1, LOK, LRRK2, LTK, LYN, MAP3K2, MAP3K3, MAP4K2, MAP4K3, MAP4K4, MAP4K5, MEK5, MERTK, MET(Y1235D), MINK, MKNK1, MKNK2, MLK1, MLK3, MST3, MUSK, NEK1, NEK4, NLK, p38-alpha, p38-beta, p38-delta, p38-gamma, PAK3, PCTK2, PDGFRA, PDGFRB, PFCDPK1 (Plasmodium falciparum), PFTAIRE2, PFTK1, RET, RET(M918T), RET(V804L), RET(V804M), RIOK3, RIPK1, RIPK2, SIK, SLK, SRC, SRMS, STK33, STK35, STK36, TAK1, TAOK1, TAOK2, TAOK3, TEC, TESK1, TIE1, TIE2, TNIK, TNK1, TNK2, TNNI3K, TRKA, TRKB, TRKC, TXK, TYK2 (JH1 domain - catalytic), VEGFR2, YES, YSK4, and ZAK.

[0213] In another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating cancer, which contains the compound represented by Formula 1, its solvate, or its pharmaceutically acceptable salt as an active ingredient.

[0214] At this time, the compound can prevent or treat cancer by showing inhibitory activity against Bcr-Abl kinase or Bcr-Abl(T315I) kinase.

[0215] The cancer is not limited as long as it is a known cancer. For example, it can be selected from pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelocytic leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampullary cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal cavity cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, childhood brain cancer, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer (gastriccancer), gastric carcinoma, gastrointestinal stromal cancer, nephroblastoma, breast cancer, triple-negative breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational choriopathy, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer (rectal cancer), rectal carcinoma, vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, pulmonary tuberculosis squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer.

[0216] The compound of formula 1 of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally and can be used in the general form of a pharmaceutical preparation. That is, the compound or a pharmaceutically acceptable salt thereof can be prepared for oral or parenteral administration by mixing with common diluents or excipients such as fillers, fillers, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration are tablets, pills, powders, granules, and capsules. These solid preparations are prepared by mixing one or more compounds with one or more suitable excipients such as starch, calcium carbonate, sucrose or lactose, gelatin, etc.

[0217] In addition to simple excipients, lubricants such as magnesium stearate, talc, etc. can be used. Liquid preparations for oral administration are suspensions, solutions, emulsions, and syrups, and the above preparations can contain various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives in addition to commonly used simple diluents such as water and liquid paraffin.

[0218] Parenteral administration is carried out by subcutaneous injection, intravenous injection, intramuscular injection or intrapleural injection. The preparations for parenteral administration are sterile aqueous solutions, water-insoluble excipients, suspensions and emulsions. In addition to the active compound, the water-insoluble excipients and suspensions may also contain propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc.

[0219] In another aspect of the present invention, the present invention provides a health functional food composition for preventing or improving a disease associated with one or more protein kinases, which contains a compound represented by Formula 1, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient, and the protein kinases are selected from ABL1(E255K)-phosphorylated, ABL1(F317I)-non-phosphorylated, ABL1(F317I)-phosphorylated, ABL1(F317L)-non-phosphorylated, ABL1(F317L)-phosphorylated, ABL1(H396P)-non-phosphorylated, ABL1(H396P)-phosphorylated, ABL1(M351T)-phosphorylated, ABL1(Q252H)-non-phosphorylated, ABL1(Q252H)-phosphorylated, ABL1(T315I)-non-phosphorylated, ABL1(T315I)-phosphorylated, ABL1(Y253F)-phosphorylated, ABL1-non-phosphorylated, ABL1-phosphorylated, ABL2, AURKB, AURKC, AXL, BLK, BMX, BRAF, BRAF(V600E), BRK, BTK, CDC2L1, CDC2L2, CDC2L5, CDK11, CDK7, CDKL2, CIT, CSF1R, CSK, DDR1, DDR2, DLK, EGFR, EGFR(E746-A750del), EGFR(G719C), EGFR(G719S), EGFR(L747-E749del,A750P), EGFR(L747-S752del,P753S), EGFR(L747-T751del,Sins), EGFR(L858R), EGFR(L861Q), EGFR(S752-I759del), EPHA1, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB6, ERBB2, ERBB4, ERK8, FER, FES, FGFR1, FGFR2, FGFR3, FGFR3(G697C), FGFR4, FGR, FLT1, FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT4, FRK, FYN, GAK, GCN2(Kin.Dom.2, S808G), HCK, HPK1, IKK-alpha, IKK-beta, IRAK1, IRAK4, JNK2, KIT, KIT(A829P), KIT(D816H), KIT(D816V), KIT(L576P), KIT(V559D), KIT(V559D,T670I), KIT(V559D,V654A), LCK, LIMK1, LOK, LRRK2, LTK, LYN, MAP3K2, MAP3K3, MAP4K2, MAP4K3, MAP4K4, MAP4K5, MEK5, MERTK, MET(Y1235D), MINK, MKNK1, MKNK2, MLK1, MLK3, MST3, MUSK, NEK1, NEK4, NLK, p38-alpha, p38-beta, p38-delta, p38-gamma, PAK3, PCTK2, PDGFRA, PDGFRB, PFCDPK1 (Plasmodium falciparum), PFTAIRE2, FTK1, RET, RET(M918T), RET(V804L), RET(V804M), RIOK3, RIPK1, RIPK2, SIK, SLK, SRC, SRMS, STK33, STK35, STK36, TAK1, TAOK1, TAOK2, TAOK3, TEC, TESK1, TIE1, TIE2, TNIK, TNK1, TNK2, TNNI3K, TRKA, TRKB, TRKC, TXK, TYK2 (JH1 domain - catalytic), VEGFR2, YES, YSK4 and ZAK.

[0220] In another aspect of the present invention, the present invention provides a health functional food composition for preventing or improving cancer, which contains a compound represented by Formula 1, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

[0221] At this time, the compound can prevent or improve cancer by showing inhibitory activity against Bcr-Abl kinase or Bcr-Abl(T315I) kinase.

[0222] The cancer is not limited as long as it is a known cancer. For example, it can be selected from pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampullary cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal cavity cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, childhood brain cancer, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms tumor, breast cancer, triple-negative breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational choriopathy, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, pulmonary tuberculosis squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer.

[0223] At this time, the health functional food may contain the compound represented by Formula 1 of the present invention, its solvate, or its pharmaceutically acceptable salt as an active ingredient, and may be prepared and used as a general health functional food. In addition, the health functional food is included within the scope of the present invention as long as it is a preparation, food form, or administration form known to those skilled in the art, and if it falls within the scope that can be considered a health functional food, then it is included in the health functional food of the present invention.

[0224] Hereinafter, the present invention will be described in detail through the following preparation examples, examples, and experimental examples.

[0225] However, the following preparation examples, examples, and experimental examples are only for illustrating the present invention, and the content of the present invention is not limited thereto.

[0226] <Analysis and purification conditions>

[0227] In the embodiments of the present invention, the synthesized compounds are purified or structurally analyzed by the following methods.

[0228] 1. LC-MS analysis conditions

[0229] Equipment name: Shimadzu LCMS-2020

[0230] Column: ACE Excel2 C18, 75×2.1 mm

[0231] Mobile phase: acetonitrile / H2O + 0.1% TFA

[0232] Flow rate: 0.5 mL / min

[0233] UV detector: 254 nm

[0234] 2. MPLC purification conditions (A)

[0235] Equipment name:

[0236] UV detector: 254 nm

[0237] 1. Preparation of HPLC purification conditions (B)

[0238] Equipment name: Gilson GX-281, 321 pump, UV / VIS-155

[0239] Column:

[0240] Mobile phase: acetonitrile / 0.1% TFA H2O

[0241] Flow rate: 18 mL / min

[0242] UV detector: 254 nm

[0243] 4. 1 1H NMR

[0244] Equipment name: Bruker Avance (400 MHz)

[0245] Scheme-1

[0246]

[0247] <Example 1> Preparation of N-(3-(2-cyanopropan-2-yl)-5-(4-methyl-1H-imidazol-1-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide

[0248]

[0249] Step 1: Preparation of methyl 5-((8-chloroimidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methylbenzoate Preparation

[0250]

[0251] Methyl 2-fluoro-5-iodo-4-methylbenzoate (12.1 g, 35.0 mmol) was dissolved in DMF (80 mL). To this was added 8-chloro-3-ethynylimidazo[1,2-a]pyridine (6.18 g, 35.0 mmol), Pd(PPh3)4 (2.02 g, 1.75 mmol), CuI (0.666 g, 3.50 mmol), and DIPEA (9.14 mL, 52.5 mmol) at room temperature. The reaction mixture was degassed using a nitrogen balloon and then stirred at room temperature for 30 minutes. Then, the reaction mixture was heated to 80 °C and stirred for 1 hour under heating. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and then concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the target compound as a yellow solid (8.0 g, 67%).

[0252] 1 1H NMR (400 MHz, CDCl3) δ 8.28 (dd, J = 6.8, 0.9 Hz, 1H), 8.13 (d, J = 7.3 Hz, 1H), 7.97 (s, 1H), 7.38 (dd, J = 7.4, 0.9 Hz, 1H), 7.08 (d, J = 11.2 Hz, 1H), 6.94 (t, J = 7.1 Hz, 1H), 3.95 (s, 3H), 2.58 (s, 3H); LC-MS (ESI) m / z: 343 [M+H] +

[0253] Step 2: Preparation of methyl 2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzoate Preparation

[0254]

[0255] Dissolve methyl 5-((8-chloroimidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methylbenzoate (2.00 g, 5.84 mmol) prepared in Step 1 in toluene (10 mL), and add 1-methyl-1H-pyrazol-4-amine (0.623 g, 6.42 mmol) and Cs2CO3 (3.80 g, 11.7 mmol) thereto at room temperature. Gradually heat the mixture and degas it at 70 °C for 5 minutes, then add Pd2(dba)3 (0.267 g, 0.292 mmol) and Xantphos (0.338 g, 0.584 mmol). Gradually heat the reaction mixture and stir it under reflux for 24 hours. After completion of the reaction, filter the mixture through diatomaceous earth, and then concentrate it under reduced pressure. Purify the obtained residue by silica gel chromatography, and then wash it with acetonitrile to obtain the target compound as a yellow solid (1.3 g, 55%).

[0256] 1 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 7.3 Hz, 1H), 7.80 (s, 1H), 7.79 (dd, J = 6.7, 0.9 Hz, 1H), 7.53 (s, 1H), 7.43 (s, 1H), 7.07 (d, J = 11.3 Hz, 1H), 6.81 (t, J = 7.1 Hz, 1H), 6.59 (s, 1H), 6.48 (dd, J = 7.5, 0.8 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 2.59 (s, 3H); LC-MS (ESI) m / z: 404 [M+H] +

[0257] Step 3: Preparation of 2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzoic acid Preparation

[0258]

[0259] Methyl 2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzoate (1.30 g, 3.22 mmol) obtained in Step 2 was dissolved in THF / MeOH / H2O (4 / 2 / 2 mL each), and then LiOH·H2O (0.193 g, 8.06 mmol) was added thereto at room temperature, followed by stirring for 20 minutes. Then, the reaction mixture was gradually heated and stirred at 60 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and then 1N aqueous hydrochloric acid was slowly added dropwise to adjust the pH to 3. The resulting solid was filtered and dried in vacuo to obtain methyl 2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzoate as a pale yellow solid (1.2 g, 96%).

[0260] 1 1H NMR (400 MHz, DMSO-d6) δ 13.35 (s, 1H), 8.27 (s, 1H), 8.08 (d, J = 7.5 Hz, 1H), 8.03 (s, 1H), 7.99 (d, J = 6.3 Hz, 1H), 7.83 (s, 1H), 7.52 (s, 1H), 7.39 (d, J = 11.7 Hz, 1H), 7.03 - 6.94 (m, 1H), 6.63 (d, J = 7.5 Hz, 1H), 3.83 (s, 3H), 2.57 (s, 3H).; LC-MS (ESI) m / z: 390 [M+H] +

[0261] Step 4: Preparation of N-(3-(2-cyanopropan-2-yl)-5-(4-methyl-1H-imidazol-1-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide benzamide Preparation

[0262]

[0263] Dissolve 2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzoic acid (25 mg, 0.064 mmol) obtained in Step 3 in DMF (1 mL), and add EDCI (19.9 mg, 0.128 mmol), DMAP (15.7 mg, 0.128 mmol), and 2-(3-amino-5-(4-methyl-1H-imidazol-1-yl)phenyl)-2-methylpropanenitrile (16.2 mg, 0.067 mmol) thereto at room temperature. Gradually heat the reaction mixture and stir at 60 °C for 16 hours. After the reaction is completed, cool the mixture to room temperature, wash with brine, and extract with dichloromethane. Dry the extracted organic layer over anhydrous sodium sulfate, filter, and then concentrate under reduced pressure. The obtained residue is purified by silica gel chromatography to obtain the compound of Example 1 as an off-white solid (12.3 mg, 31%).

[0264] 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 2.2 Hz, 1H), 8.57 (d, J = 2.2 Hz, 1H), 8.27 (d, J = 3.0 Hz, 1H), 8.17 (d, J = 6.5 Hz, 1H), 7.76 (s, 1H), 7.54 (s, 1H), 7.47 - 7.43 (m, 1H), 7.28 (td, J = 7.9, 2.6 Hz, 1H), 7.21 (s, 1H), 7.02 (dd, J = 7.7, 3.9 Hz, 1H), 6.77 (s, 1H), 3.92 (s, 3H), 3.77 (t, J = 7.1 Hz, 2H), 3.40 (t, J = 7.0 Hz, 2H), 3.05 (s, 3H), 2.99 (s, 6H), 2.87 (s, 3H), 1.74 (s, 6H); LC-MS (ESI) m / z: 615 [M + H] +

[0265] The compounds of Examples 2 - 74 are prepared by a method similar to the method described in Example 1, and the structures and analytical results of the compounds are summarized in Table 1 below.

[0266] [Table 1]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300] Scheme-2

[0301]

[0302] <Example 75>Preparation of 5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-(4-methyl-1H-imidazol-1-yl)phenyl)-2-fluoro-4-methylbenzamide

[0303]

[0304] Step 1: Preparation of N-(3-(2-cyanopropan-2-yl)-5-(4-methyl-1H-imidazol-1-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide ethynyl)benzamide Preparation

[0305]

[0306] Dissolve 2-fluoro-4-methyl-5-((8-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzoic acid (50 mg, 0.109 mmol) in DMF (1 mL), and add HATU (62.1 mg, 0.163 mmol), DIPEA (0.038 mL, 0.218 mmol), and 2-(3-amino-5-(4-methyl-1H-imidazol-1-yl)phenyl)-2-methylpropanenitrile (28.8 mg, 0.120 mmol) thereto. Heat the reaction mixture at 60 °C and stir for 16 h. After completion of the reaction, cool the mixture to room temperature, dilute with ethyl acetate, and wash with distilled water and brine. Dry the organic layer over Na2SO4, filter, and concentrate. Purify the obtained residue by silica gel chromatography to obtain the target compound as a yellow solid (40 mg, 54%).

[0307] LC-MS (ESI) m / z: 682 [M+H] +

[0308] Step 2: Preparation of 5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3- (2-cyanopropan-2-yl)-5-(4-methyl-1H-imidazol-1-yl)phenyl)-2-fluoro-4-methylbenzamide

[0309]

[0310] Dissolve N-(3-(2-cyanopropan-2-yl)-5-(4-methyl-1H-imidazol-1-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide (40 mg, 0.059 mmol) prepared in Step 1 in CH2Cl2 (1 mL), add TFA (0.5 mL, 6.53 mmol) thereto, and then stir at room temperature for 2 hours. After completion of the reaction, concentrate the mixture under reduced pressure, and purify the obtained residue by preparative HPLC (aqueous solution of 0.1% TFA in water / acetonitrile). The obtained target compound in the form of TFA salt is neutralized with an aqueous solution of saturated NaHCO3, extracted with ethyl acetate, and washed with distilled water. The extracted organic layer is dried over Na2SO4, filtered, and then concentrated under reduced pressure to obtain the target compound as a yellow solid (33.3 mg, 80%).

[0311] 1 H NMR (400 MHz, DMSO-d6) δ 12.7 (br s, 1H), 10.8 (br s, 1H), 8.18 (s, 1H), 8.16 (s, 1H), 8.15 - 8.12 (m, 1H), 8.04 - 7.93 (m, 4H), 7.86 (s, 1H), 7.84 - 7.53 (br s, 2H), 7.48 - 7.41 (m, 3H), 6.95 (t, J = 7.1 Hz, 1H), 6.58 (d, J = 7.4 Hz, 1H), 2.60 (s, 3H), 2.18 (s, 3H), 1.75 (s, 6H); LC-MS (ESI) m / z: 598 [M + H] +

[0312] The compounds of Examples 76 to 114 were prepared by a method similar to that described in Example 75, and the structures and analytical results of the compounds are summarized in Table 2 below.

[0313] [Table 2]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332] <Comparative Example 1> Pr Separation of 4-Methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide

[0333] AAA

[0334] The target compound was prepared in the same manner as described in Example 12 of Korean Patent No. 10-1931435.

[0335] <Comparative Example 2> Preparation of N-(3-(2-cyanopropan-2-yl)-5-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide

[0336]

[0337] The target compound was prepared in the same manner as described in Example 27 of Korean Patent No. 10-1920456.

[0338] <Comparative Example 3> Preparation of N-(3-(2-cyanopropan-2-yl)-5-(4-methylpiperazin-1-yl)phenyl)-4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide

[0339]

[0340] The target compound was prepared in the same manner as described in Example 21 of Korean Patent No. 10-1920456.

[0341] <Comparative Example 4> Preparation of N-(3-(2-cyanopropan-2-yl)-5-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide

[0342]

[0343] 4-Methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzoic acid (15 mg, 0.039 mmol) was dissolved in dimethylformamide (1 mL), and EDCI (12 mg, 0.077 mmol), DMAP (9.4 mg, 0.077 mmol), and 2-(3-amino-5-(4-methyl-1H-imidazol-1-yl)phenyl)-2-methylpropanenitrile (9.36 mg, 0.039 mmol) were added thereto at room temperature. The reaction mixture was gradually heated and stirred at 60 °C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, washed with brine, and extracted with dichloromethane. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (aqueous solution of 0.1% TFA / acetonitrile solution) to obtain the compound of Comparative Example 4 (17.9 mg, yield 54.4%).

[0344] 11H NMR (400 MHz, TFA salt, MeOD-d4) δ 9.40 (d, J = 1.48 Hz, 1H), 8.36 (s, 1H), 8.25 (d, J = 1.56 Hz, 1H), 8.09 - 8.07 (m, 2H), 8.00 (s, 1H), 7.96 (dd, J = 8.12, 1.76 Hz, 1H), 7.85 (s, 1H), 7.76 (s, 1H), 7.59 (s, 1H), 7.54 - 7.53 (m, 2H), 7.16 (t, J = 7.64 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 3.93 (s, 3H), 2.67 (s, 3H), 2.46 (s, 3H), 1.83 (s, 6H); LC-MS (ESI) m / z: 594 [M+H] +

[0345] <Comparative Example 5> Preparation of N-(3-(2-cyanopropan-2-yl)-5-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide

[0346]

[0347] Dissolve 4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzoic acid (15 mg, 0.039 mmol) in dimethylformamide (1 mL). Add EDCI (12 mg, 0.077 mmol), DMAP (9.4 mg, 0.077 mmol) and 2-(3-amino-5-((4-methylpiperazin-1-yl)methyl)phenyl)-2-methylpropanenitrile (9.36 mg, 0.039 mmol) thereto at room temperature. Gradually heat the reaction mixture and stir at 60 °C for 16 hours. After completion of the reaction, cool the mixture to room temperature, wash with brine, and extract with dichloromethane. Dry the extracted organic layer over anhydrous sodium sulfate, filter, and then concentrate under reduced pressure. The obtained residue was purified by preparative HPLC (aqueous / acetonitrile solution of 0.1% TFA) to give the compound of Comparative Example 5 (17.9 mg, yield 54.4%).

[0348] 11H NMR (400 MHz, TFA salt, MeOD-d4) δ 8.23 (d, J = 1.72 Hz, 1H), 8.20 (s, 1H), 8.16 (d, J = 6.36 Hz, 1H), 7.95 (dd, J = 8.06, 1.76 Hz, 1H), 7.87 (s, 1H), 7.77 (s, 1H), 7.75 (s, 1H), 7.55 - 7.52 (m, 2H), 7.35 (s, 1H), 7.26 (dd, J = 7.8, 6.68 Hz, 1H), 6.99 (d, J = 7.76 Hz, 1H), 3.93 (s, 3H), 3.75 (s, 2H), 2.89 (s, 3H), 2.67 (s, 3H), 1.75 (s, 6H); LC-MS (ESI) m / z: 626 [M+H] +

[0349] <Experimental Example 1> Evaluation of the inhibitory activity of the compounds of the present invention against enzymes

[0350] In order to evaluate the inhibitory activity of the compounds of the present invention against enzymes, the following experiments were conducted.

[0351] Specifically, Request Biology was used to evaluate the effects of the compound of Example 1 according to the present invention on the enzyme activities of ABL1, ABL1 (E255K), ABL1 (E255V), ABL1 (F317I), ABL1 (F317L), ABL1 (G250E), ABL1 (H396P), ABL1 (M351T), ABL1 (Q252H), ABL1 (T315I), ABL1 (V299L), ABL1 (Y253F), and ABL1 (Y253H). The results are shown in Table 3 below.

[0352] [Table 3]

[0353]

[0354]

[0355] <Experimental Example 2> Evaluation of the inhibitory activity of the compounds of the present invention against various kinases

[0356] In order to evaluate the inhibitory activity of the compounds of the present invention against multiple enzymes, the following experiments were conducted, and the results are shown in Table 4.

[0357] Among the compounds of the examples of the present invention, the enzyme (kinase) selectivity of the selected compounds in Examples 1 and 4 was determined by Request Discoverx. At this time, ScanMAX was used TM Kinase profiling screening (a panel for scanMAX TMExperiments were conducted with (Kinase). The concentration of the enzyme-treated drug in DMSO was 1 μM, and the percentage control (% control) was determined by the method shown in Equation 1 below. The results are shown in Table 4.

[0358] [Equation 1]

[0359] (Example compound - Positive control) / (Negative control - Positive control) × 100

[0360] Here, the positive control refers to a compound showing a control percentage of 0%, and the negative control refers to DMSO showing a control percentage of 100%. Additionally, if the enzyme selectivity of the compound of the present invention is lower than 35% (< 35%) of the control percentage of each enzyme, it is judged to be active against the enzyme.

[0361] [Table 4]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369] As shown in Table 4, it was confirmed that the compounds of Example 1 or Example 4 had a control percentage of less than 35% against one or more protein kinases selected from the following: ABL1 (E255K)-phosphorylated, ABL1 (F317I)-non-phosphorylated, ABL1 (F317I)-phosphorylated, ABL1 (F317L)-non-phosphorylated, ABL1 (F317L)-phosphorylated, ABL1 (H396P)-non-phosphorylated, ABL1 (H396P)-phosphorylated, ABL1 (M351T)-phosphorylated, ABL1 (Q252H)-non-phosphorylated, ABL1 (Q252H)-phosphorylated, ABL1 (T315I)-non-phosphorylated, ABL1 (T315I)-phosphorylated, ABL1 (Y253F)-phosphorylated, ABL1-non-phosphorylated, ABL1-phosphorylated, ABL2, AURKB, AURKC, AXL, BLK, BMX, BRAF, BRAF (V600E), BRK, BTK, CDC2L1, CDC2L2, CDC2L5, CDK11, CDK7, CDKL2, CIT, CSF1R, CSK, DDR1, DDR2, DLK, EGFR, EGFR (E746-A750del), EGFR (G719C), EGFR (G719S), EGFR (L747-E749del, A750P), EGFR (L747-S752del, P753S), EGFR (L747-T751del, Sins), EGFR (L858R), EGFR (L861Q), EGFR (S752-I759del), EPHA1, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB6, ERBB2, ERBB4, ERK8, FER, FES, FGFR1, FGFR2, FGFR3, FGFR3 (G697C), FGFR4, FGR, FLT1, FLT3, FLT3 (D835H), FLT3 (D835V), FLT3 (D835Y), FLT3 (ITD), FLT3 (ITD, F691L), FLT3 (K663Q), FLT3 (N841I), FLT3 (R834Q), FLT4, FRK, FYN, GAK, GCN2 (Kin.Dom.2, S808G), HCK, HPK1, IKK-alpha, IKK-beta, IRAK1, IRAK4, JNK2, KIT, KIT(A829P), KIT(D816H), KIT(D816V), KIT(L576P), KIT(V559D), KIT(V559D, T670I), KIT(V559D, V654A), LCK, LIMK1, LOK, LRRK2, LTK, LYN, MAP3K2, MAP3K3, MAP4K2, MAP4K3, MAP4K4, MAP4K5, MEK5, MERTK, MET(Y1235D), MINK, MKNK1, MKNK2, MLK1, MLK3, MST3, MUSK, NEK1, NEK4, NLK, p38-alpha, p38-beta, p38-delta, p38-gamma, PAK3, PCTK2, PDGFRA, PDGFRB, PFCDPK1 (Plasmodium falciparum), PFTAIRE2, PFTK1, RET, RET(M918T), RET(V804L), RET(V804M), RIOK3, RIPK1, RIPK2, SIK, SLK, SRC, SRMS, STK33, STK35, STK36, TAK1, TAOK1, TAOK2, TAOK3, TEC, TESK1, TIE1, TIE2, TNIK, TNK1, TNK2, TNNI3K, TRKA, TRKB, TRKC, TXK, TYK2 (JH1 domain - catalytic), VEGFR2, YES, YSK4 and ZAK, so the compound has enzyme inhibitory activity.

[0370] <Experimental Example 3> Evaluation of the inhibitory effect on Ba / F3 cell proliferation

[0371] Rat lymphocytes, parental (Ba / F3) and T315I - Bcr - Abl (Ba / F3) were seeded into 96 - well plates at a density of 1×10 4 / 90 μL / well. Culture media containing each compound of the examples at 9 concentrations (0.015 to 100 μM) (serially diluted 3 - fold or with DMSO (control)) were added to the plates (10 μL / well) to a final concentration of 0 - 10 μM. The plates were incubated in a 37°C CO2 incubator for 72 hours.

[0372] After 72 hours of incubation, the plates treated with the compound were treated with a Cell Counting Kit-8 (Dojindo Molecular Technologies, Inc) solution at a concentration of 10 μL / well, and then thoroughly mixed. Then, the plates were incubated in a CO2 incubator at 37 °C for 2 hours, and the absorbance at 450 nm was measured using a microplate reader. The data are expressed as a percentage compared to the vehicle-treated cells, and the GI 50 value was calculated using GraphPad Prism 5.0 (GraphPad Software, San Diego). The results are shown in Table 5 below.

[0373] In the following table, the inhibitory effect on cancer cell proliferation was evaluated using the following names.

[0374] GI50: A < 0.05 μM; 0.05 μM < B < 0.5 μM; 0.5 μM < C < 5 μM; 5 μM < D

[0375] [Table 5]

[0376]

[0377]

[0378]

[0379] [Experimental Example 4] Evaluation of the inhibitory effect on the proliferation of human chronic myeloid leukemia (CML) cells

[0380] To evaluate the therapeutic effect of the compound of the present invention on chronic myeloid leukemia (CML), the following experiment was conducted, and the results are shown in Table 6 below. The inhibitory activity against Bcr-Abl kinase was evaluated by experiments using TCCS and KOPM28 cells, and the inhibitory activity against T315I-Bcr-Abl kinase was evaluated by experiments using T315I-TCCS and T315I-KOPM28 cells.

[0381] The human chronic myeloid leukemia (CML) cells used in the experiment were TCCS, T315I-TCCS, KOPM28, and T315I-KOPM28, and these four types of cells were provided by the University of Yamanashi.

[0382] The four types of human CML cells were seeded at 1 × 10 4Inoculate at a density of 90 μL / well in a 96-well plate. Add culture medium (serially diluted 5-fold or with DMSO (control)) containing the compound of each example at 9 concentrations (0.000256 to 100 μM) to the plate (10 μL / well), with a final concentration of 0 to 10 μM. Incubate the plate in a 37 °C CO₂ incubator for 72 hours.

[0383] After 72 hours of incubation, treat the plate treated with the compound with a solution of Cell Counting Kit-8 (Dojindo Molecular Technologies, Inc) at a density of 10 μL / well, and then mix well. Then, incubate the plate in a CO₂ incubator at 37 °C for 2 hours, and measure the absorbance at 450 nm using a microplate reader. The data is expressed as a percentage compared to the cells treated with the vehicle, and the GI 50 value is calculated using GraphPad Prism 8.0 (GraphPad Software, San Diego). The results are shown in Table 6 below.

[0384] In the following table, the inhibitory activity against human CML cells is evaluated using the following names.

[0385] GI50: A < 10 nM; 10 nM < B < 100 nM; 100 nM < C;

[0386] [Table 6]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392] <Experimental Example 5> Evaluation of Platelet Aggregation Inhibitory Effect

[0393] To prepare platelet-rich plasma, collect human venous blood from healthy volunteers who have not received drug treatment and have no cardiovascular diseases, allergies, or lipid metabolism disorders using sodium citrate (0.32%, final concentration: 10.9 mM). Centrifuge the blood at 1000 × g for 10 minutes to separate PRP (platelet-rich plasma). Then, obtain PPP (platelet-poor plasma) by centrifuging at 1200 × g for 10 minutes.

[0394] Platelet aggregation studies were carried out according to the previously reported methods (Arch Pharm Res, 38 (2015) 893 - 903, BMB Rep, 44 (2011) 140 - 145). More specifically, after treating 300 μl of PRP with a compound (in DMSO) at a concentration of 1 μM for 5 minutes, platelet aggregation was induced by treating with collagen (2 μg / ml) or thrombin (0.1 U / ml). The degree of platelet aggregation was monitored using an aggregometer (Chronoolog, Havertown, PA, USA), and the change in light transmittance was measured at 37 °C. The degree of platelet aggregation (%) is shown in Table 7 below.

[0395] In the following table, the following names were used to evaluate the degree of inhibition of platelet aggregation.

[0396] A < 30%; 30% ≤ B < 50%; 50% ≤ C < 70%; 70% ≤ D;

[0397] [Table 7]

[0398]

[0399]

[0400] [Experimental Example 6] In Vivo PK (Oral Administration)

[0401] To evaluate the in vivo pharmacokinetic properties, oral pharmacokinetic tests were performed on the compounds of Comparative Examples 1 and 4 and Examples 1 and 4 using mice and rats, and the PK parameters are shown in Table 10 below.

[0402] 6-1. Oral Pharmacokinetics Test

[0403] ICR mice (6 - 7 weeks old) and SD rats (6 - 7 weeks old) were used for the tests. The fasting group was fasted for about 16 hours before oral administration, and the fed group was fasted for about 4 hours before oral administration. The test drug for oral administration was dissolved in a vehicle at a concentration of 1 mg / mL and used. Blood samples were collected from the heart (mice, 500 μL / time point) or jugular vein (rats, 120 μL / time point) (time points: 0.25, 0.5, 1, 2, 4, 8, 12, 24, 32, n = 3). The blood was centrifuged at 12,000 G for 2 minutes at 4 °C to separate the plasma, and stored at -80 °C until analysis.

[0404] Vehicle A (NMP:PEG400 = 5:95)

[0405] Vehicle B (0.5% methylcellulose)

[0406] 6-2. Sampling and Pretreatment

[0407] To 20 μl of plasma, 180 μl of acetonitrile (including internal standard) was added. The mixture was stirred and centrifuged at 15,000 rpm for 5 minutes at 4 °C. The supernatant obtained after centrifugation was analyzed by LC-MS / MS.

[0408] [Table 8]

[0409] HPLC conditions

[0410]

[0411] [Table 9]

[0412] Mass spectrometry conditions

[0413]

[0414] 6-3. PK Analysis

[0415] The PK parameters were calculated using the non-compartmental analysis model with the Phoenix WinNonlin version 6.4 (Pharsight, USA) program.

[0416] [Table 10]

[0417]

[0418]

[0419] <Experimental Example 7> Evaluation of in vivo pharmacological activity

[0420] In the above Experimental Examples 1 and 2, it was confirmed that the compounds of the present invention have excellent inhibitory effects on Bcr-Abl and T315I-Bcr-Abl enzymes related to blood cancer. To evaluate the efficacy of the compounds of the present invention against actual diseases, in vivo experiments were performed using a mouse model induced by the following diseases.

[0421] A total of 50 five-week-old male nude mice (14 - 17 g) were obtained from Orient Bio Inc. (322, Galmachi-ro, Jungwon-gu, Seongnam-si, Gyongggi-do, Korea). After the mice were acclimated to the animal facility for 1 week, the Luc_Ba / F3T315I-Bcr-Abl cell line that emits luciferase was transplanted into the tail vein at a density of 5 × 10 6 / animal. Group separation was performed 3 days after the cell line transplantation. On the day of group separation, 10 mice were randomly assigned to each of the 5 groups so that the luminescence values were equal after luminescence measurement using an IVIS Spectrum-CT optical imaging device.

[0422] 5 groups: Control (vehicle, 0.5% methylcellulose solution), Ponatinib (25 mg / kg), Example 1 (50 mg / kg), Example 1 (100 mg / kg).

[0423] After group separation, the compounds of Example 1, Ponatinib and the vehicle were orally administered at an interval of once a day for 10 days to evaluate the therapeutic efficacy of the drugs. The drug efficacy was confirmed by optical imaging, which was confirmed before dosing (day 0) and on days 4, 11, 18 and 21 after dosing. In addition, the body weight and survival rate of each experimental group were monitored.

[0424] Statistical analysis was performed using GraphPad Prism 8, and the unpaired t-test and log-rank (Mantel-Cox) test were used to confirm the statistical significance of the survival rate.

[0425] As Figure 1 shown, in the optical images taken on days 0, 4, 11 and 18 after applying the luminescence signal emitted by the blood cancer cells, strong luminescence signals were confirmed in all subjects in the vehicle group. However, on day 21 after dosing, since all subjects had died, luminescence images could no longer be obtained. In all groups treated with Ponatinib and the compounds of Example 1, weak luminescence values were confirmed compared with the vehicle group.

[0426] As Figure 2 shown, on day 18 after dosing, strong luminescence signals emitted by blood cancer cells were confirmed in all subjects in the vehicle group, and weak luminescence signals were observed in the experimental groups treated with the compounds of Example 1 of the present invention compared with the vehicle group. In addition, it was confirmed that the luminescence signal decreased in a dose-dependent manner.

[0427] As Figure 3 shown, as a result of the survival rate analysis, all subjects in the vehicle group died on day 21 after dosing, and all subjects in the group treated with Ponatinib (25 mg / kg) died on day 35 after dosing. In the group treated with 25 mg / kg of the compound of Example 1, all patients died on day 31 after dosing, in the group treated with 50 mg / kg of the compound of Example 1, all patients died on day 32 after dosing, and in the group treated with 100 mg / kg of the compound of Example 1, all patients died on day 35 after dosing. Therefore, it was confirmed that the survival rate was improved in all groups administered the drugs compared with the vehicle group.

[0428] As Figure 4As shown, after the 18th day from the start of the experiment, a sharp decrease in body weight was observed in the vehicle group. On the other hand, during the experiment, no significant change in body weight was observed in all groups using 25 mg / kg ponatinib, 25 mg / kg of the compound of Example 1, 50 mg / kg of the compound of Example 1, or 100 mg / kg of the compound of Example 1.

[0429] Therefore, the compounds of the present invention can significantly inhibit the proliferation of cancer cells in a hematological cancer model and have a significant effect of killing cancer cells. Therefore, a pharmaceutical composition containing the compounds of the present invention as an active ingredient can be effectively used for preventing or treating cancer.

Claims

1. A compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof: Formula 1 In the above Formula 1, R 1 is hydrogen or C 1-10 alkyl; X is F or Cl; R 2 is Among them, R 2a 、R 2b and R 2c are each independently halogen, cyano or C 1-10 alkyl; L 1 is a single bond, -O- or C 1-10 alkylene; R 3 is a 5- to 8-membered unsubstituted or substituted heteroaryl containing one or more heteroatoms selected from N, O, and S, a 4- to 8-membered unsubstituted or substituted heterocycloalkyl containing one or more heteroatoms selected from N, O, and S, an unsubstituted or substituted C 1-10 alkyl group or NR 3a R 3b , wherein R 3a and R 3b are independently hydrogen or an unsubstituted or substituted C 1-10 alkyl group. Among them, the substituents of the substituted heteroaryl, substituted heterocycloalkyl and substituted C 1-10 alkyl are independently selected from one or more of the following: unsubstituted or C substituted by one or more halogens 1-10 alkyl, C 1-10 alkylsulfonyl, C 1-10 alkoxy, oxo, NR 3c R 3d and a 5-8 membered C 1-10 alkyl-substituted heterocycloalkyl containing one or more heteroatoms selected from N, O and S, wherein R 3c and R 3d are independently hydrogen or C 1-10 alkyl, or L 1 -R 3 is 2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 1 is hydrogen or C 1-6 alkyl; R 2 Yes Wherein, R 2a , R 2b and R 2c are independently halogen, cyano or C 1-6 alkyl; L 1 is a single bond, -O- or C 1-6 alkylene; R 3 is a 5- or 6-membered unsubstituted or substituted heteroaryl containing one or more heteroatoms selected from N and O, a 4- to 7-membered unsubstituted or substituted heterocycloalkyl containing one or more heteroatoms selected from N and O, an unsubstituted or substituted C 1-6 alkyl or NR 3a R 3b , wherein R 3a and R 3b are independently hydrogen or an unsubstituted or substituted C 1-6 alkyl. Wherein, the substituents of the substituted heteroaryl, substituted heterocycloalkyl and substituted C 1-6 alkyl are independently selected from one or more of the following: C 1-6 alkyl which is unsubstituted or substituted by one or more halogens, C 1-6 alkylsulfonyl, C 1-6 alkoxy, oxo, NR 3c R 3d and heterocycloalkyl substituted by a 5-6 membered C 1-6 alkyl containing one or more heteroatoms selected from N and O, wherein R 3c and R 3d are independently hydrogen or C 1-6 alkyl. or L 1 -R 3 yes 3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 1 is hydrogen or methyl; R 2 is wherein, R 2a , R 2b and R 2c are independently fluorine, cyano or methyl; L 1 is a single bond, -O- or methylene; R 3 is an unsubstituted or substituted imidazolyl, pyridyl, pyrimidinyl, substituted piperazinyl, substituted pyrazolyl, substituted diazepanyl, substituted piperidinyl, morpholinyl, substituted pyrrolidinyl, substituted azetidinyl, triazolyl, substituted ethyl, substituted propyl or NR 3a R 3b , wherein R 3a and R 3b are independently methyl, substituted ethyl or substituted propyl, Wherein the substituents of the substituted imidazolyl, substituted piperazinyl, substituted pyrazolyl, substituted diazepanyl, substituted piperidinyl, substituted pyrrolidinyl, substituted azetidinyl, substituted ethyl, and substituted propyl are independently selected from one or more of the following: methyl, CF3, CH2CF3, isopropyl, methylsulfonyl, isopropoxy, methyl-substituted piperazine, methyl-substituted piperidine, oxo, and NR 3c R 3d , where R 3c and R 3d is methyl, or L 1 -R 3 Yes 4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by Formula 1 is a compound represented by the following Formula 2: Formula 2 In Formula 2, R 1 、R 2 、R 3 、L 1 and X are as defined in claim 1.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein the compound represented by the above Formula 1 is a compound represented by the following Formula 2: Formula 2 In Formula 2, R 1 、R 2 、R 3 、L 1 and X are as defined in claim 2.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein the compound represented by the above Formula 1 is a compound represented by the following Formula 2: Formula 2 In Formula 2, R 1 、R 2 、R 3 、L 1 and X are as defined in claim 3.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 1 is hydrogen or methyl; R 2 is L 1 -R 3 Yes 8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by Formula 1 is selected from the following compounds: <1> N-(3-(2-cyanopropan-2-yl)-5-(4-methyl-1H-imidazol-1-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <2> 3-fluoro-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <3> N-(3-(2-cyanopropan-2-yl)-5-(4-methyl-1H-imidazol-1-yl)phenyl)-2-fluoro-4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <4> 2-fluoro-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <5> 3-fluoro-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <6> 2-fluoro-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <7>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(pyridin-4-yloxy)-5-(trifluoromethyl)phenyl)benzamide; <8>3-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(pyridin-4-yloxy)-5-(trifluoromethyl)phenyl)benzamide; <9>2-Fluoro-4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(pyridin-4-yloxy)-5-(trifluoromethyl)phenyl)benzamide; <10>N-(3-(2-cyanopropan-2-yl)-5-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <11>N-(3-(2-cyanopropan-2-yl)-5-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)-3-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <12>N-(3-(2-cyanopropan-2-yl)-5-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <13>2-Chloro-N-(3-(2-cyanopropan-2-yl)-5-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <14>2-Chloro-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <15>2-Chloro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(pyridin-4-yloxy)-5-(trifluoromethyl)phenyl)benzamide; <16>2-Chloro-N-(3-(2-cyanopropan-2-yl)-5-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <17>N-(3-(2-cyanopropan-2-yl)-5-(pyridin-4-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <18>N-(3-(2-cyanopropan-2-yl)-5-(pyridin-3-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <19>N-(3-(2-cyanopropan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <20>N-(3-(2-cyanopropan-2-yl)-5-(4-methylpiperazin-1-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <21>N-(3-(2-cyanopropan-2-yl)-5-(4-methyl-1,4-diazepan-1-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <22>N-(3-(2-cyanopropan-2-yl)-5-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <23>N-(3-(2-cyanopropan-2-yl)-5-((3-(dimethylamino)propyl)(methyl)amino)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <24>N-(3-(2-cyanopropan-2-yl)-5-(4-methyl-3-oxopiperazin-1-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <25>N-(3-(2-Cyanopropan-2-yl)-5-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <26>N-(3-(2-Cyanopropan-2-yl)-5-(pyridin-4-yloxy)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <27>N-(3-(2-Cyanopropan-2-yl)-5-((4-methylpiperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <28>N-(3-(2-Cyanopropan-2-yl)-5-(morpholinomethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <29>N-(3-(2-Cyanopropan-2-yl)-5-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <30>N-(3-(2-Cyanopropan-2-yl)-5-((4-methyl-1,4-diazepan-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <31>N-(3-(2-Cyanopropan-2-yl)-5-((4-(trifluoromethyl)piperidin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <32>N-(3-(2-Cyanopropan-2-yl)-5-((4-(2,2,2-trifluoroethyl)piperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <33>N-(3-(2-Cyanopropan-2-yl)-5-((4-isopropylpiperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <34>N-(3-(2-Cyanopropan-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <35>N-(3-(2-Cyanopropan-2-yl)-5-((4-methyl-3-oxopiperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <36>N-(3-(2-Cyanopropan-2-yl)-5-((3-isopropoxyazetidin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <37>N-(3-((1H-Imidazol-1-yl)methyl)-5-(2-cyanopropan-2-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <38>N-(3-((1H-1,2,4-Triazol-1-yl)methyl)-5-(2-cyanopropan-2-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <39>N-(3-(2-Cyanopropan-2-yl)-4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <40>N-(3-(2-Cyanopropan-2-yl)-4-(morpholinomethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <41>N-(3-(2-Cyanopropan-2-yl)-4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <42>N-(3-(2-Cyanopropan-2-yl)-4-((4-methyl-1,4-diazepan-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethyl)benzamide; <43>N-(3-(2-Cyanopropan-2-yl)-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <44>N-(3-(2-Cyanopropan-2-yl)-4-((4-methyl-3-oxopiperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <45>N-(3-(2-Cyanopropan-2-yl)-4-((4-(methylsulfonyl)piperazin-1-yl)methyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <46>N-(4-((1H-Imidazol-1-yl)methyl)-3-(2-cyanopropan-2-yl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <47>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide; <48>N-(3-((2-(Dimethylamino)ethyl)(methyl)amino)-5-(trifluoromethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <49>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(4-methyl-3-oxopiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide; <50>N-(3-(2-(Dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <51>N-(3-(3-(Dimethylamino)propoxy)-5-(trifluoromethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <52>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)benzamide; <53>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)benzamide; <54>2-Fluoro-4-methyl-N-(3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <55>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; <56>2-Fluoro-N-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <57>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(4-(morpholinomethyl)-3-(trifluoromethyl)phenyl)benzamide; <58>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(4-((4-methyl-3-oxopiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; <59>N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <60>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(4-((4-(methylsulfonyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; <61>2-Fluoro-4-methyl-N-(4-((4-methyl-1,4-diazepan-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <62>2-Fluoro-N-(4-((3-isopropoxyazetidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <63>N-(4-((1H-imidazol-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <64>N-(4-((1H-1,2,4-triazol-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <65>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(4-(pyridin-4-yloxy)-3-(trifluoromethyl)phenyl)benzamide; <66>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(morpholinomethyl)-5-(trifluoromethyl)phenyl)benzamide; <67>2-Fluoro-4-methyl-N-(3-((4-methyl-1,4-diazepan-1-yl)methyl)-5-(trifluoromethyl)phenyl)-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <68>N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <69>2-Fluoro-N-(3-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <70>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-((4-(methylsulfonyl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide; <71>2-Fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-((4-methyl-3-oxopiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide; <72>2-Fluoro-N-(3-((3-isopropoxyazetidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <73>N-(3-((1H-Imidazol-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <74>N-(3-((1H-1,2,4-Triazol-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-fluoro-4-methyl-5-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)benzamide; <75>(8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-(4-methyl-1H-imidazol-1-yl)phenyl)-2-fluoro-4-methylbenzamide; <76>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-chloro-N-(3-(2-cyanopropan-2-yl)-5-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methylbenzamide; <77>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-fluoro-4-methylbenzamide; <78>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-(pyridin-4-yl)phenyl)-2-fluoro-4-methylbenzamide; <79>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-(pyridin-3-yl)phenyl)-2-fluoro-4-methylbenzamide; <80>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-(4-methylpiperazin-1-yl)phenyl)-2-fluoro-4-methylbenzamide; <81>5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-2-fluoro-4-methylbenzamide; <82>5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-(4-methyl-3-oxopiperazin-1-yl)phenyl)-2-fluoro-4-methylbenzamide; <83>(8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-(pyridin-4-yloxy)phenyl)-2-fluoro-4-methylbenzamide; <84>(8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-((4-methylpiperazin-1-yl)methyl)phenyl)-2-fluoro-4-methylbenzamide; <85>[5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-2-fluoro-4-methylbenzamide; <86>5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)-2-fluoro-4-methylbenzamide; <87>5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)phenyl)-2-fluoro-4-methylbenzamide; <88>(8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-5-((4-methyl-3-oxopiperazin-1-yl)methyl)phenyl)-2-fluoro-4-methylbenzamide; <89>N-(3-((1H-1,2,4-triazol-1-yl)methyl)-5-(2-cyanopropan-2-yl)phenyl)-5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methylbenzamide; <90>(8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-fluoro-4-methylbenzamide; <91>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-2-fluoro-4-methylbenzamide; <92>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)-2-fluoro-4-methylbenzamide; <93>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-4-((4-methyl-3-oxopiperazin-1-yl)methyl)phenyl)-2-fluoro-4-methylbenzamide; <94>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-cyanopropan-2-yl)-4-((4-(methylsulfonyl)piperazin-1-yl)methyl)phenyl)-2-fluoro-4-methylbenzamide; <95>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide; <96>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)benzamide; <97>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)benzamide; <98>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(3-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)benzamide; <99>5-((8-((1H-Pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide; <100>5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethyl)-2-fluoro-4-methyl-N-(3-(4-methyl-3-oxopiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide; <101>5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(3-(pyridin-4-yloxy)-5-(trifluoromethyl)phenyl)benzamide; <102>5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-fluoro-4-methylbenzamide; <103>(<8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-(3-(dimethylamino)propoxy)-5-(trifluoromethyl)phenyl)-2-fluoro-4-methylbenzamide; <104>5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide; <105>5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-fluoro-4-methylbenzamide; <106>(8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-N-(3-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide; <107>(8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(3-((4-methyl-3-oxopiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide; <108>N-(3-((1H-1,2,4-triazol-1-yl)methyl)-5-(trifluoromethyl)phenyl)-5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methylbenzamide; <109>5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; <110>[5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-fluoro-4-methylbenzamide; <111>5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-N-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide; <112>(8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(4-((4-methyl-3-oxopiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; <113>5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methyl-N-(4-((4-(methylsulfonyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; <114>N-(4-((1H-1,2,4-triazol-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((8-((1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)-2-fluoro-4-methylbenzamide.

9. A method for preparing the compound represented by formula 1 as claimed in claim 1, comprising the step of preparing the compound represented by formula 1 by reacting the compound represented by formula 2 with the compound represented by formula 3, as shown in the following reaction scheme 1: Reaction Scheme 1 In the above Reaction Scheme 1, L 1 , R 1 , R 2 , R 3 and X are as defined in Formula 1 of Claim 1.

10. Use of the compound represented by formula 1 according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient in the preparation of a medicament for preventing or treating a disease associated with one or more protein kinases selected from the following: ABL1 - non - phosphorylated, ABL1 - phosphorylated, ABL2, AURKB, AURKC, AXL, BLK, BMX, BRAF, BRK, BTK, CDC2L1, CDC2L2, CDC2L5, CDK11, CDK7, CDKL2, CIT, CSF1R, CSK, DDR1, DDR2, DLK, EGFR, EPHA1, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB6, ERBB2, ERBB4, ERK8, FER, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1, FLT3, FLT4, FRK, FYN, GAK, GCN2, HCK, HPK1, IKK - alpha, IKK - beta, IRAK1, IRAK4, JNK2, KIT, LCK, LIMK1, LOK, LRRK2, LTK, LYN, MAP3K2, MAP3K3, MAP4K2, MAP4K3, MAP4K4, MAP4K5, MEK5, MERTK, MET, MINK, MKNK1, MKNK2, MLK1, MLK3, MST3, MUSK, NEK1, NEK4, NLK, p38 - alpha, p38 - beta, p38 - delta, p38 - gamma, PAK3, PCTK2, PDGFRA, PDGFRB, PFCDPK1 from Plasmodium falciparum, PFTAIRE2, PFTK1, RET, RIOK3, RIPK1, RIPK2, SIK, SLK, SRC, SRMS, STK33, STK35, STK36, TAK1, TAOK1, TAOK2, TAOK3, TEC, TESK1, TIE1, TIE2, TNIK, TNK1, TNK2, TNNI3K, TRKA, TRKB, TRKC, TXK, TYK2, VEGFR2, YES, YSK4 and ZAK.

11. Use according to claim 10, wherein, The protein kinases are selected from: ABL1-E255K-phosphorylated, ABL1-F317I-non-phosphorylated, ABL1-F317I-phosphorylated, ABL1-F317L-non-phosphorylated, ABL1-F317L-phosphorylated, ABL1-H396P-non-phosphorylated, ABL1-H396P-phosphorylated, ABL1-M351T-phosphorylated, ABL1-Q252H-non-phosphorylated, ABL1-Q252H-phosphorylated, ABL1-T315I-non-phosphorylated, ABL1-T315I-phosphorylated, ABL1-Y253F-phosphorylated, BRAF-V600E, EGFR-E746-A750del, EGFR-G719C, EGFR-G719S, EGFR-L747-E749del, EGFR-A750P, EGFR-L747-S752del, EGFR-P753S, EGFR-L747-T751del, EGFR-Sins, EGFR-L858R, EGFR-L861Q, EGFR-S752-I759del, FGFR3-G697C, FLT3-D835H, FLT3-D835V, FLT3-D835Y, FLT3-ITD, FLT3-ITD-F691L, FLT3-K663Q, FLT3-N841I, FLT3-R834Q, GCN2-Kin.Dom.2, GCN2-S808G, KIT-A829P, KIT-D816H, KIT-D816V, KIT-L576P, KIT-V559D, KIT-V559D, T670I, KIT-V559D, V654A, MET-Y1235D, RET-M918T, RET-V804L, RET-V804M.

12. Use of the compound represented by Formula 1 according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient in the preparation of a medicament for treating cancer.

13. The use according to claim 12, wherein the compound prevents or treats cancer by showing inhibitory activity against Bcr-Abl kinase or Bcr-Abl(T315I) kinase, and the substance described in parentheses shows a mutant form.

14. The use according to claim 12, wherein the cancer is selected from pseudomyxoma, liver cancer, thyroid cancer, testicular cancer, glioblastoma, lip cancer, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal cavity cancer, tongue cancer, astrocytoma, small intestine cancer, meningioma, esophageal cancer, glioma, kidney cancer, heart cancer, duodenal cancer, vulvar cancer, urethral cancer, gastric cancer, breast cancer, penile cancer, pharyngeal cancer, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, mediastinal cancer, vaginal cancer, spinal cancer, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, tonsil cancer, lung cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer and thymic cancer.

15. The use according to claim 12, wherein the cancer is selected from intrahepatic cholangiocarcinoma, hepatoblastoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, pulmonary tuberculosis squamous cell carcinoma, renal pelvic cancer, nephroblastoma, male breast cancer, triple negative breast cancer, colon cancer, rectal cancer, childhood brain cancer, childhood lymphoma, gastric lymphoma.

16. The use according to claim 12, wherein the cancer is selected from at least one of oral cancer, blood cancer, brain cancer, eye cancer and skin cancer.

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