KR20200029946A - Novel pyrido-pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating protein kinase related disease containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel pyrido-pyrimidine derivative, a method for producing the same, and a pharmaceutical composition for preventing or treating protein kinase-related diseases, which contains the derivative as an active ingredient. According to the present invention, a compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: has an excellent inhibitory activity against JAK 3 kinase as well as an excellent inhibitory activity against JAK kinase (janus kinase); and has a useful effect of providing pharmaceutical composition or a health functional food composition, which contains the pharmaceutically acceptable salt as an active ingredient, for preventing or treating JAK kinase (janus kinase)-related diseases, in particular, JAK 3 kinase-related diseases such as complex immunodeficiency (SCID), rheumatoid arthritis, myelofibrosis, psoriasis, Crohn′s disease, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, allergic disease, chronic obstructive pulmonary disease, asthma, leukemia, or lymphoma.

Description

Novel pyrido-pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating protein kinase related disease containing the same as an active ingredient}

The present invention relates to a novel pyrido-pyrimidine derivative, a method for preparing the same, and a pharmaceutical composition for the prevention or treatment of a protein kinase-related disease containing it as an active ingredient.

In 2002, Manning et al. Found that 218 of the 518 protein kinase genes in the human kinome are closely related to the development and development of human disease, and drugs obtained to date target enzymes There are 20% of these drugs, especially those targeting protein kinases have special value in clinical applications.

Protein kinases catalyze the phosphorylation of specific proteins, tyrosine protein kinases (JAK, Src, Abl, EGFR, FGFR, PDGFR, etc.), serine / threonine protein kinases (PKC, MAPK, Rho kinase, etc.), bispecific protein kinases (MAPKK ) And phosphatidyl inositol kinase (PI3K) is an intracellular messenger-dependent enzyme that performs a signaling process that mainly comprises. Protein kinase phosphorylation / dephosphorylation processes can regulate multiple biological processes in a variety of cells, such as metabolism, cell differentiation, cell survival, apoptosis, organogenesis, angiogenesis and immune responses.

JAK kinase (Janus kinase, abbreviated JAK, comprising four known members of JAK 3, JAK 1, TYK2 and JAK 2) is a small family of non-receptor tyrosine protein kinase superfamily in the cytoplasm. JAK 3 is distributed in the bone marrow and lymphatic system, while JAK 1, TYK2 and JAK 2 are widely distributed in many tissue cells. When JAK binds to the cytokine receptor on the cell surface, receptor-bound JAK is activated, thereby phosphorylating the receptor to mobilize cytoplasmic signal transduction and transcriptional activators STAT proteins (STAT1-4, STAT5a, STAT5b and STAT6). (recruiting) reaction site, ie, JAK phosphorylation STAT protein After dimerization, JAK phosphorylation STAT protein is delivered to the nucleus to regulate gene expression. This route is called the JAK / STAT signaling route.

The JAK / STAT signaling pathway is a signaling pathway stimulated by multiple cytokines and growth factor receptors. These factors are interleukin (IL-2-7, IL-9, IL-10, IL-15, and IL-21), interferon (IFN-α, IFN-β, and IFN-γ), erythropoietin (EPO), Granulocyte macrophage colony stimulating factor (GM-CSF), growth hormone (GH), prolactin (PRL), thrombopoietin (TPO), etc., which are involved in the proliferation of immune cells and hematopoietic stem cells, and immunomodulatory biological It plays an important role in the process (Ghoreschi K., et al. 2009, Immunol. Rev., 228: 273-287).

Various subtypes of JAK kinase can be activated by various receptors to achieve distinct biological functions.

JAK 1 will bind to the gp130 family of IL-10, IL-19, IL-20, IL-22, IL-26, IL-28, IFN-α, IFN-γ, IL-6 and other γc-containing receptors (Rodig S J., et al. 1998, Cell, 93: 373-383). Knock-off experiments of the JAK 1 gene in a mouse model showed that these enzymes play an important role in the biological effects of many of the aforementioned cytokine receptors (Kisseleva T., et al. 2002, Gene, 285: 1-24). JAK 1 is a novel target for diseases such as immune-related diseases, inflammation and cancer. JAK 1 inhibitors are autoimmune diseases, inflammation and tumors (Hornakova T., et al. 2010, Blood, 115: 3287-3295), such as leukemia, lymphoma, melanoma, arthritis, psoriasis, Crohn's disease, lupus erythematosus, acquired Immune aggregation syndrome, Behcet's disease (Hou S., et al. 2013, Hum. Genet., 132: 1049-1058), etc. can be used for the treatment / prevention of diseases including, but not limited to.

On the other hand, JAK 2 was found to play an important role in the regulation of a number of receptors, including EPO, GH, PRL, IL-3, IFN-γ, etc. (Kisseleva T., et al. 2002, Gene, 285: 1-24; Levy DE, et al. 2002, Nat. Rev. Mol. Cell Biol., 3: 651-662; O'Shea JJ, et al. 2002, Cell, 109 (suppl.): S121-S131) . In a mouse model, JAK 2 gene knock-off can lead to the death of an anemic animal (Schindler C. et al. 2007, J. Biol. Chem., 282: 20059-20063); On the other hand, in humans, the base mutation JAK 2V617F of the JAK 2 gene is of myeloproliferative diseases including polycythemia (PV), essential thrombocytopenia (ET), idiopathic myeloid fibrosis (IMF) and chronic myelogenous leukemia (CML). It is closely related to the onset (Ghoreschi K., et al. 2009, Immunol. Rev., 228: 273-287). Therefore, JAK 2 has been an accurate target for the treatment / prevention of these diseases.

On the other hand, JAK 3 modulates cellular signaling by binding to the gamma common chain (γc) in cytokine-receptor complexes such as IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. do. Mutations in either JAK 3 or γc can cause severe complex immunodeficiency (SCID) (Villa A., et al. 1996, Blood, 88: 817-823). The abnormal activity of JAK 3 appears as a significant decrease in T-cells and NK cells and a loss in B-cells function, which have a significant effect on the normal biological function of the immune system. JAK 3 has been a promising pharmaceutical target for immune system-related diseases depending on its functional properties and specific tissue distribution, and thus its inhibitors are rheumatoid arthritis (RA), Crohn's disease, systemic lupus erythematosus, multiple sclerosis, type I diabetes, It will have great clinical value in the treatment / prevention of psoriasis, allergic disease, asthma, chronic obstructive pulmonary disease, leukemia, lymphoma, organ transplantation and other diseases (Papageorgiou AC, et al. 2004, Trends Pharm. Sci., 2004, 25: 558-562).

TYK2 is the first member of the JAK family and can be activated by multiple receptors, such as interferon (IFN), IL-10, IL-6, IL-12, IL-23 and IL-27. In mice, loss of function of TYK2 can lead to a deficiency in the signaling pathways of many cytokine receptors, which can lead to additional viral infections, decrease antibiotic immune function, and increase the likelihood of lung infection (Kisseleva T., et al. 2002, Gene, 285: 1-24). In addition, a study by Larner A.C. demonstrated that TYK2 helps inhibit breast cancer growth and metastasis (Zhang Q., et al. 2011, J. Interferon Cytokine Res., 31: 671-677); In addition, it has recently been reported that TYK2 can promote the regulation of obesity by differentiation of mouse and human brown adipose tissue (BAT), thereby protecting or reversing organisms from obesity (Derecka M., et al., 2012, Cell Metab., 16: 814-824). This will open up new opportunities for obese patients suffering from cancer.

In November 2012, Pfizer's pan-JAK inhibitor Gelzanz (Tofacitinib) was approved by the FDA for the treatment of rheumatoid arthritis. In October 2013, Phase III clinical data from Gelzanz for the treatment of psoriasis were released by the company. Compared to Enbrel's (Etanelcept) double-blind trial, the drug met the requirements of a non-inferiority trial. However, Gelzanz has some side effects. For example, the amount of red blood cells and white blood cells may decrease and cholesterol levels may increase. This may be related to high JAK 2 inhibitory activity and low selectivity of the drug (Zak M., et al. 2012, J. Med. Chem., 55: 6176-6193).

Therefore, research and discovery of selective JAK inhibitors may be highly demanded, and at present, selective JAK 3 inhibitor VX-509 at various stages of impression used in the treatment of immune system-related diseases such as rheumatoid arthritis, Crohn's disease, psoriasis and myelofibrosis. , Selective JAK 1 inhibitor GLPG0634 (Feist E., et al. 2013, Rheumatology, 52: 1352-1357) has been proposed, and there have been attempts to develop a selective JAK inhibitor, but have yet to undergo sufficient efficacy and verification. The drug has not been presented, and continuous research and development of selective JAK inhibitors is required.

Thus, the present inventors tried to present a new therapeutic agent through a JAK inhibitory mechanism, as well as confirming the JAK inhibitory effect, the compounds of the present invention can be used as a selective JAK inhibitor, specifically confirm the selectivity for JAK 3 Thus, JAK related diseases, in particular JAK 3 related diseases, such as complex immunodeficiency (SCID), rheumatoid arthritis, myelofibrosis, psoriasis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, allergic disease, chronic The present invention has been completed as it has been found to be used for the treatment and / or prevention of immune system-related diseases, including, but not limited to, obstructive pulmonary disease, asthma, leukemia and lymphoma.

Ghoreschi K., et al. 2009, Immunol. Rev., 228: 273-287 Rodig S J., et al. 1998, Cell, 93: 373-383 Kisseleva T., et al. 2002, Gene, 285: 1-24 Hornakova T., et al. 2010, Blood, 115: 3287-3295 Hou S., et al. 2013, Hum. Genet., 132: 1049-1058 Kisseleva T., et al. 2002, Gene, 285: 1-24; Levy D. E., et al. 2002, Nat. Rev. Mol. Cell Biol., 3: 651-662; O'Shea J. J., et al. 2002, Cell, 109 (suppl.): S121-S131 Schindler C. et al. 2007, J. Biol. Chem., 282: 20059-20063 Ghoreschi K., et al. 2009, Immunol. Rev., 228: 273-287 Villa A., et al. 1996, Blood, 88: 817-823 Papageorgiou A. C., et al. 2004, Trends Pharm. Sci., 2004, 25: 558-562 Kisseleva T., et al. 2002, Gene, 285: 1-24 Zhang Q., et al. 2011, J. Interferon Cytokine Res., 31: 671-677 Derecka M., et al., 2012, Cell Metab., 16: 814-824 Zak M., et al. 2012, J. Med. Chem., 55: 6176-6193 Feist E., et al. 2013, Rheumatology, 52: 1352-1357

The object of the present invention is to provide a novel JAK inhibitory compound.

Another object of the present invention is to provide JAK 3 selective inhibitory compounds.

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

Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of JAK kinase (Janus kinase) related diseases.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating JAK 3 kinase related diseases.

Another object of the present invention is to provide a health functional food composition for preventing or improving JAK kinase (janus kinase) related diseases.

Another object of the present invention is to provide a health functional food composition for preventing or improving JAK 3 kinase related diseases.

In order to achieve the above object,

The present invention provides a compound represented by Formula 1 below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

(In the formula 1,

X is halogen, -S-CH ₃ ,-(S = O) -CH ₃ , or -NR ¹ R ² ,

Wherein R ¹ and R ² are each independently H, C ₁ -C ₁₀ alkyl of a straight chain or branched chain unsubstituted or substituted with one or more halogens, C of C ₁ -C ₁₀ alkyl substituted or unsubstituted by one or more halogens, or C _{1 to} C ₁₀ alkoxy, substituted or unsubstituted C _3-10 cycloalkyl, 3 to 10 membered substituted or unsubstituted, including one or more hetero atoms selected from the group consisting of (N, O, and S) Heterocycloalkyl), a substituted or unsubstituted C _6-10 aryl, or a 5-10 membered substituted or unsubstituted hetero containing one or more hetero atoms selected from the group consisting of (N, O, and S) Aryl),

Here again, the substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and substituted heteroaryl, each substituted or unsubstituted C ₁ -C ₁₀ alkyl of a straight or branched chain, substituted or unsubstituted straight chain Or a branched chain C ₁ -C ₁₀ alkoxy, hydroxy, nitro, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted C _3-10 cycloalkyl, (N, O, and S 3 to 10 membered substituted or unsubstituted heterocycloalkyl containing at least one hetero atom selected from the group consisting of), substituted or unsubstituted C _6-10 aryl, and (N, O, and S) Substituted with one or more substituents selected from the group consisting of 5- to 10-membered substituted or unsubstituted heteroaryl) containing at least one hetero atom selected from the group,

Here again, the substituted alkyl, substituted alkoxy, substituted amino, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and substituted heteroaryl, respectively, are straight or branched C ₁ -C ₃ Alkyl, straight or branched C ₁ -C ₃ alkoxy, hydroxy, nitro, cyano, halogen, amino unsubstituted or substituted with one or more methyl, substituted or unsubstituted C _3-6 cycloalkyl, ( 3 to 6 membered substituted or unsubstituted heterocycloalkyl containing at least one hetero atom selected from the group consisting of N, O, and S), substituted or unsubstituted phenyl, and (N, O, and S Is substituted with one or more substituents selected from the group consisting of 5 to 6 membered substituted or unsubstituted heteroaryl) containing at least one hetero atom selected from the group consisting of,

Here again, the substituted cycloalkyl, the substituted heterocycloalkyl, the substituted phenyl, and the substituted heteroaryl are straight or branched C ₁ -C ₃ alkyl, straight or branched C ₁ -C ₃ alkoxy, respectively. , And one or more substituents selected from the group consisting of halogen;

Y is H, substituted or unsubstituted C ₁ -C ₃ alkyl of straight or branched chain, substituted or unsubstituted C _3-10 cycloalkyl, (N, O, and one or more selected from the group consisting of S) 3 to 10 membered substituted or unsubstituted heterocycloalkyl containing a hetero atom), substituted or unsubstituted C _6-10 aryl, (N, O, and one or more hetero atoms selected from the group consisting of S) 5 to 10 membered substituted or unsubstituted heteroaryl), substituted or unsubstituted C _6-10 aryl-C ₁ -C ₃ alkyl, or (N, O, and S) 5 to 10 membered substituted or unsubstituted heteroaryl) -C ₁ -C ₃ alkyl containing one or more hetero atoms,

Here, the substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-alkyl, and substituted heteroaryl-alkyl are hydroxy, nitro, and cyano, respectively. , Halogen, amino, and one or more substituents selected from the group consisting of R ³ ,

Here again, R ³ is nitro, -NR ⁴ R ⁵ , or -NR ^4- (C = O) -R ⁵ ,

Wherein R ⁴ and R ⁵ are each independently H, straight or branched C ₁ -C ₅ alkyl, straight or branched C ₁ -C ₅ alkoxy, straight or branched C ₂ having one or more unsaturated bonds _-10 alkyl,

Here, the unsaturated bond is a double bond or a triple bond; And

Z is H, straight or branched C ₁ -C ₃ alkyl, straight or branched C ₁ -C ₃ alkoxy, halogen, nitro, or cyano).

In addition, the present invention

As shown in Scheme 1 below,

Reacting the compound represented by Formula 5 with the compound represented by Formula 4 to prepare a compound represented by Formula 3 (step 1);

Preparing a compound represented by Formula 2 from the compound represented by Formula 3 prepared in Step 1 (Step 2);

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

[Scheme 1]

(In Scheme 1 above,

X, Y, and Z are as defined in Formula 1 of claim 1;

X 'is X or X substituted with Boc;

V is -S-CH ₃ , or-(S = O) -CH ₃ ;

W is NHBoc or NO ₂ ; And

W 'is NH ₂ ).

Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of JAK kinase (Janus kinase) related diseases containing the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. .

In addition, the present invention provides a health functional food composition for preventing or improving diseases related to JAK kinase (Janus kinase) containing the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. do.

Furthermore, the present invention is a JAK kinase (Janus kinase) comprising the step of administering to a subject in need a pharmaceutical composition or a health functional food composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a method for preventing or treating a related disease.

In addition, the present invention provides the use of a pharmaceutical composition or a health functional food composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient in the prevention or treatment of a protein kinase related disease. do.

 The compound represented by Formula 1 according to the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof not only has excellent inhibitory activity against JAK kinase (Janus kinase), but also particularly excellent inhibitory activity against JAK 3 kinase Bar, JAK kinase (janus kinase) related diseases containing it as an active ingredient, in particular JAK 3 kinase related diseases, such as complex immunodeficiency (SCID), rheumatoid arthritis, myelofibrosis, psoriasis, Crohn's disease, systemic lupus erythematosus , Multiple sclerosis, type 1 diabetes, allergic disease, chronic obstructive pulmonary disease, asthma, leukemia or lymphoma, or a pharmaceutical composition for preventing or treating, or a functional food composition for preventing or improving can be provided.

Hereinafter, the present invention will be described in detail.

The present invention provides a compound represented by Formula 1 below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

(In the formula 1,

X is halogen, -S-CH ₃ ,-(S = O) -CH ₃ , or -NR ¹ R ² ,

Wherein R ¹ and R ² are each independently H, C ₁ -C ₁₀ alkyl of a straight chain or branched chain unsubstituted or substituted with one or more halogens, C of C ₁ -C ₁₀ alkyl substituted or unsubstituted by one or more halogens, or C _{1 to} C ₁₀ alkoxy, substituted or unsubstituted C _3-10 cycloalkyl, 3 to 10 membered substituted or unsubstituted, including one or more hetero atoms selected from the group consisting of (N, O, and S) Heterocycloalkyl), a substituted or unsubstituted C _6-10 aryl, or a 5-10 membered substituted or unsubstituted hetero containing one or more hetero atoms selected from the group consisting of (N, O, and S) Aryl),

Here again, the substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and substituted heteroaryl, each substituted or unsubstituted C ₁ -C ₁₀ alkyl of a straight or branched chain, substituted or unsubstituted straight chain Or a branched chain C ₁ -C ₁₀ alkoxy, hydroxy, nitro, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted C _3-10 cycloalkyl, (N, O, and S 3 to 10 membered substituted or unsubstituted heterocycloalkyl containing at least one hetero atom selected from the group consisting of), substituted or unsubstituted C _6-10 aryl, and (N, O, and S) Substituted with one or more substituents selected from the group consisting of 5- to 10-membered substituted or unsubstituted heteroaryl) containing at least one hetero atom selected from the group,

Here again, the substituted alkyl, substituted alkoxy, substituted amino, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and substituted heteroaryl, respectively, are straight or branched C ₁ -C ₃ Alkyl, straight or branched C ₁ -C ₃ alkoxy, hydroxy, nitro, cyano, halogen, amino unsubstituted or substituted with one or more methyl, substituted or unsubstituted C _3-6 cycloalkyl, ( 3 to 6 membered substituted or unsubstituted heterocycloalkyl containing at least one hetero atom selected from the group consisting of N, O, and S), substituted or unsubstituted phenyl, and (N, O, and S Is substituted with one or more substituents selected from the group consisting of 5 to 6 membered substituted or unsubstituted heteroaryl) containing at least one hetero atom selected from the group consisting of,

Here again, the substituted cycloalkyl, the substituted heterocycloalkyl, the substituted phenyl, and the substituted heteroaryl are straight or branched C ₁ -C ₃ alkyl, straight or branched C ₁ -C ₃ alkoxy, respectively. , And one or more substituents selected from the group consisting of halogen;

Y is H, substituted or unsubstituted C ₁ -C ₃ alkyl of straight or branched chain, substituted or unsubstituted C _3-10 cycloalkyl, (N, O, and one or more selected from the group consisting of S) 3 to 10 membered substituted or unsubstituted heterocycloalkyl containing a hetero atom), substituted or unsubstituted C _6-10 aryl, (N, O, and one or more hetero atoms selected from the group consisting of S) 5 to 10 membered substituted or unsubstituted heteroaryl), substituted or unsubstituted C _6-10 aryl-C ₁ -C ₃ alkyl, or (N, O, and S) 5 to 10 membered substituted or unsubstituted heteroaryl) -C ₁ -C ₃ alkyl containing one or more hetero atoms,

Here, the substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-alkyl, and substituted heteroaryl-alkyl are hydroxy, nitro, and cyano, respectively. , Halogen, amino, and one or more substituents selected from the group consisting of R ³ ,

Here again, R ³ is nitro, -NR ⁴ R ⁵ , or -NR ^4- (C = O) -R ⁵ ,

Wherein R ⁴ and R ⁵ are each independently H, straight or branched C ₁ -C ₅ alkyl, straight or branched C ₁ -C ₅ alkoxy, straight or branched C ₂ having one or more unsaturated bonds _-10 alkyl,

Here, the unsaturated bond is a double bond or a triple bond; And

Z is H, straight or branched C ₁ -C ₃ alkyl, straight or branched C ₁ -C ₃ alkoxy, halogen, nitro, or cyano).

In another aspect of the invention,

In Chemical Formula 1,

X is -S-CH ₃ ,-(S = O) -CH ₃ , or -NR ¹ R ² ,

Wherein R ¹ and R ² are each independently H, C ₁ -C ₁₀ alkyl of a straight chain or branched chain unsubstituted or substituted with one or more halogens, C of C ₁ -C ₁₀ alkyl substituted or unsubstituted by one or more halogens, or C _{1 to} C ₁₀ alkoxy, substituted or unsubstituted C _3-6 cycloalkyl, 3 to 6 membered substituted or unsubstituted including at least one hetero atom selected from the group consisting of (N, O, and S) Heterocycloalkyl), substituted or unsubstituted phenyl, or (5-6 membered substituted or unsubstituted heteroaryl containing at least one hetero atom selected from the group consisting of N, O, and S),

Here again, the substituted cycloalkyl, substituted heterocycloalkyl, substituted phenyl, and substituted heteroaryl are each a substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted straight chain Or a branched chain C ₁ -C ₁₀ alkoxy, hydroxy, nitro, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted C _3-6 cycloalkyl, (N, O, and S 3-6 membered substituted or unsubstituted heterocycloalkyl containing one or more hetero atoms selected from the group consisting of, substituted or unsubstituted phenyl, and 1 selected from the group consisting of (N, O, and S) Substituted with one or more substituents selected from the group consisting of 5- to 6-membered substituted or unsubstituted heteroaryl) containing at least a hetero atom,

Here again, the substituted alkyl, substituted alkoxy, substituted amino, substituted cycloalkyl, substituted heterocycloalkyl, substituted phenyl, and substituted heteroaryl, respectively, are straight or branched C ₁ -C ₃ Alkyl, straight or branched C ₁ -C ₃ alkoxy, hydroxy, nitro, cyano, halogen, amino unsubstituted or substituted with one or more methyl, substituted or unsubstituted C _3-6 cycloalkyl, ( 3 to 6 membered substituted or unsubstituted heterocycloalkyl containing at least one hetero atom selected from the group consisting of N, O, and S), substituted or unsubstituted phenyl, and (N, O, and S Is substituted with one or more substituents selected from the group consisting of 5 to 6 membered substituted or unsubstituted heteroaryl) containing at least one hetero atom selected from the group consisting of,

Here again, the substituted cycloalkyl, the substituted heterocycloalkyl, the substituted phenyl, and the substituted heteroaryl are straight or branched C ₁ -C ₃ alkyl, straight or branched C ₁ -C ₃ alkoxy, respectively. , And one or more substituents selected from the group consisting of halogen.

Furthermore, in another aspect of the invention,

In Chemical Formula 1,

The Y is a substituted or unsubstituted C _3-6 cycloalkyl, a substituted or unsubstituted heterocycloalkyl of 3 to 6 members including one or more hetero atoms selected from the group consisting of (N, O, and S). ), Substituted or unsubstituted phenyl, (5-6 membered substituted or unsubstituted heteroaryl containing at least one hetero atom selected from the group consisting of N, O, and S), substituted or unsubstituted phenyl -C ₁ -C ₃ alkyl, or (5-6 membered substituted or unsubstituted heteroaryl containing one or more hetero atoms selected from the group consisting of N, O, and S) -C ₁ -C ₃ alkyl ego,

Here, the substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted phenyl, substituted heteroaryl, substituted phenyl-alkyl, and substituted heteroaryl-alkyl are each -NR ^4- (C = O) -R ⁵ ,

Wherein R ⁴ is H, or straight or branched C ₁ -C ₅ alkyl,

R ⁵ may be linear or branched C _2-4 alkyl having one or more double bonds.

In addition, in another aspect of the invention,

,

,

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,

,

,

,

,

,

,

,

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,

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,

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, 또는

일 수 있다.X is -S-CH ₃ ,-(S = O) -CH ₃ ,

,

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, or

Can be

Furthermore, in another aspect of the invention,

, 또는

일 수 있다.Y is,

, or

Can be

In one embodiment of the present invention, preferred examples of the compound represented by Chemical Formula 1 include the following compounds:

(1) N- (3-((6-cyano-2-((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2,3 -d] pyrimidin-8- (7H) yl) methyl) phenyl) acrylamide;

(2) N- (3-((6-cyano-2- (1- (3- (dimethylamino) -2-hydroxypropyl) -1H-pyrazol-4ylamino) -7-oxopyrido [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide;

(3) N- (3-((2-((5-chloro-1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) -6-cyano-7-oxopyrido [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide;

(4) N- (3-((6-cyano-7-oxo-2-((1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-yl) amino) pyri Do [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide;

(5) N- (3-((6-cyano-2-((1- (3-methyloxetan-3-yl) methyl) -1H-pyrazol-4-yl) amino) -7-oxo Pyrido [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide;

(6) N- (3-((6-cyano-2-((1- (oxetan-3-yl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2, 3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide;

(7) N- (3-((6-cyano-2-((1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2 , 3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide;

(8) N- (3-((6-cyano-2-((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide;

(9) N- (3-((2-((1- (azetidin-3-yl) -1H-pyrazol-4-yl) amino) -6-cyano-7-oxopyrido [2, 3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide;

(10) N- (3-((6-cyano-7-oxo-2-((1- (piperidin-3-ylmethyl) -1H-pyrazol-4-yl) amino) pyrido [ 2,3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide;

(11) N- (3-((6-cyano-7-oxo-2-((1- (tetrahydrofuran-3-yl) -1H-pyrazol-4-yl) amino) pyrido [2 , 3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide;

(12) N- (3-((6-cyano-2- (1- (morpholin-2-ylmethyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2, 3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide;

(13) N- (3-((6-cyano-2- (1- (2-hydroxypropyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2,3- d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide;

(14) N- (3-((6-cyano-2- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2,3- d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide;

(15) N- (3-((6-cyano-2- (4- (4-methylpiperazin-1-yl) phenylamino) -7-oxopyrido [2,3-d] pyrimidine- 8 (7H) -yl) methyl) phenyl) acrylamide;

(16) N- (3-((6-cyano-2- (2- (2-cyanopropan-2-yl) -4-methylthiazol-5-ylamino) -7-oxopyrido [ 2,3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide;

(17) N- (3-((6-cyano-7-oxo-2-((1- (piperidin-4-yl) -1H-pyrazol-4-yl) amino) pyrido [2 , 3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide;

(18) N- (3-((6-cyano-2-((1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide;

(19) N- (3-((6-cyano-7-oxo-2-((1- (pyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) pyrido [2 , 3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide;

(20) N- (3-((6-cyano-7-oxo-2-((4- (2,2,2-trifluoroethyl) phenyl) amino) pyrido [2,3-d] Pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide;

(21) N- (3-((6-cyano-7-oxo-2-((4- (trifluoromethyl) phenyl) amino) pyrido [2,3-d] pyrimidine-8 (7H ) -Yl) methyl) phenyl) acrylamide;

(22) N- (3-((6-cyano-7-oxo-2-((1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazol-4-yl) amino) pyri Do [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide;

(23) (R) -8- (1-acryloylpyrrolidin-3-yl) -2- (1- (2-methoxyethyl) -1H-pyrazol-4-ylamino) -7-oxo -7,8-dihydropyrido [2,3-d] pyrimidine-6-carbonitrile;

(24) (S) -8- (1-acryloylpyrrolidin-3-yl) -2- (1- (2-methoxyethyl) -1H-pyrazol-4-ylamino) -7-oxo -7,8-dihydropyrido [2,3-d] pyrimidine-6-carbonitrile;

(25) (R) -8- (1-acryloylpyrrolidin-3-yl) -2- (2-methoxy-4- (4-methylpiperazin-1-yl) phenylamino) -7- Oxo-7,8-dihydropyrido [2,3-d] pyrimidine-6-carbonitrile;

(26) N- (3-((2- (4- (4-methylpiperazin-1-yl) phenylamino) -7-oxopyrido [2,3-d] pyrimidine-8 (7H)- 1) methyl) phenyl) acrylamide;

(27) N- (3-((2- (1- (Oxetan-3-yl) -1H-pyrazol-4-ylamino) -7-oxopyrido [2,3-d] pyrimidine- 8 (7H) -yl) methyl) phenyl) acrylamide;

(28) N- (3-((2- (1- (2-methoxyethyl) -1H-pyrazol-4-ylamino) -7-oxopyrido [2,3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide;

(29) N- (3-((2- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-ylamino) -7-oxopyrido [2,3-d] pyrimidine -8 (7H) -yyl) methyl) phenyl) acrylamide;

(30) N- (3-((2- (2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2,3-d] pyrimidine -8 (7H) -yl) methyl) phenyl) acrylamide;

(31) N- (3-((2- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2,3-d] pyrimidine- 8 (7H) -yl) methyl) phenyl) acrylamide;

(32) (R) -8- (1-acryloylpyrrolidin-3-yl) -2-((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one;

(33) (S) -8- (1-acryloylpyrrolidin-3-yl) -2-((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one; And

(34) (R) -8- (1-acryloylpyrrolidin-3-yl) -2-((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyri Figure [2,3-d] pyrimidin-7 (8H) -one.

The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes It is obtained from non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. The types of pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and eye Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Late, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfo Ytte, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a derivative of Formula 1 is dissolved in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and a precipitate formed by adding an organic acid or inorganic acid It can be prepared by filtration and drying, or by distilling a solvent and excess acid under reduced pressure and drying to crystallize under an organic solvent.

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

Furthermore, the compound represented by Formula 1 may be used in the form of solvates, stereoisomers, hydrates, and the like, as well as pharmaceutically acceptable salts thereof.

The compound represented by Formula 1 according to the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof has excellent inhibitory activity against JAK kinase, particularly inhibitory activity against JAK 3 kinase, and inhibition against other JAK families Better than activity, in one example, has selective inhibitory activity against JAK 3, and for one or more selected from the group consisting of other JAK families, such as JAK 1, JAK 2, and TYK2, inhibitory activity It can be understood to be incomplete or absent.

The compound represented by Formula 1 according to the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof has excellent inhibitory activity against JAK kinase, and is useful for preventing, improving, improving, or treating JAK kinase related diseases. It has an effect.

In one embodiment, the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof exhibits a selective inhibitory activity against JAK 3 kinase, thereby preventing or improving JAK 3 kinase-related diseases. It has a useful effect to improve or treat, and at the same time, from the lack or lack of inhibitory activity against other JAK families, side effects problems are solved compared to conventional non-selective JAK inhibitors, and more specific diseases, especially JAK 3 related diseases It is useful because it can show concentrated and improved efficacy. However, in this aspect, the advantages are examples of one aspect of the compounds of the present invention, and the compounds of the present invention are not limited to the above-described description, and may exhibit additional advantages and effects in addition to the above-described advantages.

Here, the JAK kinase-related disease refers to any disease that can be prevented, improved, improved, or treated by inhibiting the activity of JAK kinase or inhibiting expression, but is not limited thereto. Includes all known diseases or syndromes associated with JAK kinase, or diseases reported to be related to JAK kinase.

In one embodiment of the present invention, the JAK kinase related disease may be understood as being a JAK 1, JAK 2, JAK 3, or TYK2 related disease, but is not limited thereto.

JAK 1 related diseases include, for example, IL-10, IL-19, IL-20, IL-22, IL-26, IL-28, IFN-α, IFN-γ, IL-6 and others of the gp130 family diseases associated with γc-containing receptors, immune-related diseases, inflammation and cancer, etc., such as leukemia, lymphoma, melanoma, arthritis, psoriasis, Crohn's disease, lupus erythematosus, AIDS, Behcet's disease, etc.,

JAK 2 related diseases include receptor related diseases including EPO, GH, PRL, IL-3, IFN-γ, polycythemia vera (PV), essential thrombocytopenia (ET), idiopathic myelofibrosis (IMF) and chronic It may be a myeloproliferative disease, including myeloid leukemia (CML),

JAK 3 related diseases can be cytokine-receptor complex related diseases such as IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, and the abnormal activity of JAK 3 is normal in the immune system. It can be an onset or an ongoing disease from having a significant decrease in T-cells and NK cells and a loss in function of B-cells, which have a significant effect on biological function, for example, complex immunodeficiency (SCID), rheumatoid arthritis ( RA), myelofibrosis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, type I diabetes, psoriasis, allergic disease, asthma, chronic obstructive pulmonary disease, leukemia, lymphoma, organ transplantation and other diseases. On the other hand, TYK2-related diseases include interferon (IFN), IL-10, IL-6, IL-12, IL-23 and IL-27-related diseases, such as inflammatory diseases such as lung infection, breast cancer, cancer, etc. It may be a tumor or cancer disease associated with obesity.

In another embodiment of the present invention, the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from an inhibitory activity selective for JAK 3, for example, the amount of red blood cells and white blood cells. Side effects such as decreased and increased cholesterol levels can be avoided, and in particular, the advantage that side effects resulting from JAK 2 inhibitory activity can be avoided can be achieved.

In addition, as identified in another embodiment of the present invention, the compound represented by Formula 1 of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in addition to the JAK family, ABL1 (H396P) -nonphosphorylated, ARK5, BIKE, BTK, BRAF (V600E), BTK, CDK2, CSF1R, CSF1R-autoinhibited, FLT3 (D835V), EPHB6, FLT3, FLT3 (D835H), FLT3 (D835V), FLT3 (D835Y), FLT3 (ITD, D835V) ), FLT3 (ITD, F691L), FLT3 (K663Q), FLT3 (N841I), IRAK1, KIT, KIT (L576P, KIT (V559D), KIT-autoinhibited, MARK3, PDGFRB, PIP5K2C, SNARK, STK16, TRKA, TXK and It also has excellent inhibitory activity against YSK4 kinase.

Thus, the compound represented by Formula 1 of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, ABL1 (H396P) -nonphosphorylated, ARK5, BIKE, BTK, BRAF (V600E), CDK2, CSF1R, CSF1R-autoinhibited, FLT3 (D835V), EPHB6, FLT3, FLT3 (D835H), FLT3 (D835V), FLT3 (D835Y), FLT3 (ITD, D835V), FLT3 (ITD, F691L), FLT3 (K663Q), FLT3 (N841I), IRAK1, KIT, KIT (L576P, KIT (V559D), KIT-autoinhibited, MARK3, PDGFRB, PIP5K2C, SNARK, STK16, TRKA, TXK, or YSK4 kinase-related disease prophylactic or therapeutic pharmaceutical composition provided do.

Here, the Abelson protein (ABL1) related disease, for example, may be cancer, in particular, may be brain cancer, glioblastoma, CNS disease, neurodegenerative disease, such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia , Pick's disease, C-type Niemann-Pick's disease and other degenerative, inflammatory and autoimmune diseases, and may be diseases known as ABL1 related diseases, such as chronic bone marrow leukemia.

Here, the ARK5 (AMPK-related protein kinase 5) related disease may be, for example, cancer, in particular, liver cancer, and other carcinomas such as colorectal cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, and head Or cervical cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, rectal cancer, colon cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, Urinary duct cancer, renal cell carcinoma, renal pelvic carcinoma may be any one selected from the group consisting of central nervous system tumors and leukemia.

Here, the BIKE (BMP-2-inducible protein kinase) -related disease may be cancer, in particular, endometrial cancer, stomach cancer, lung cancer, colon cancer, kidney cancer, bladder cancer, head and neck cancer, glioblastoma, ovarian cancer, and leukemia It may be any one selected from the group consisting of.

Here, the BTK (Bruton Tyrosine Kinase) related diseases include inflammatory pelvic diseases, urethritis, skin sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, degenerative myelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis , Appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, graft rejection, hyperacute rejection of transplated organs, Asthma, allergic rhinitis, chronic obstructive respiratory disease (COPD), autoimmune polylinear disease (also known as autoimmune polylinear syndrome), autoimmune alopecia, malignant anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, sclerosis, vasculitis, Autoimmune hemolytic and low platelet status, Goodpasture's syndrome, axial sclerosis, Addison's disease, Parkinson's disease, Alzha Mercury, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, child arthritis, degenerative arthritis, chronic idiopathic thrombocytopenic purpura, primary macromolecular globulinemia (Waldenstrom macroglobulinemia ), Myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative arthritis, vitiligo, autoimmune pituitary dysfunction, Guillain-Barre syndrome, Behcet's disease, scleroderma, fungal sarcoma, acute inflammatory reactions (e.g. acute respiratory distress syndrome and Ischemia / reperfusion injury), and Graves' disease.

Here, the BRAF (V600E) related diseases include, for example, melanoma, colorectal cancer, papillary thyroid cancer, anaplastic thyroid cancer, ovarian cancer, non-small cell lung cancer, stomach cancer, cholangiocarcinoma, Barrett's esophageal cancer, head and neck cancer, hepatocellular carcinoma , Langerhans cell histiocytosis, gastrointestinal stromal cell tumor, multiple myeloma, pediatric astrocytoma, polymorphic yellow astrocytoma, chronic myelogenous leukemia, acute osteoblastic leukemia, biphenotype B osteoblastic leukemia, acute myeloid leukemia, hair cell leukemia, birthmark, ed Heim-Chester's disease, malignant peripheral nerve sheath tumor, inflammatory and autoimmune disease, tendonic giant cell tumor, pigmented chorionic nodular synoviitis, giant cell tumor of tendon sheath, giant cell tumor of bone, cervical cancer, endometrial cancer, Reproductive cell tumor, prostate cancer, bladder cancer, proximal cell tumor, posterior adenomas, pancreatic neoplasm, neuroendocrine tumor, endocrine tumor, adrenal tumor, adrenal medulla tumor, parotid gland Can be any one selected from cystic carcinoma, glioblastoma polymorphism, cholangiocarcinoma including cholangiocarcinoma, cholangiocarcinoma, B-cell chronic lymphoproliferative disorder, dendritic cell sarcoma, histological sarcoma, and lymphoma.

Here, the CDK2-related diseases include, for example, cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases (eg, rheumatoid arthritis). It may be any one selected from the group consisting of.

Here, the CSF1R-related disease, for example, may be an autoimmune disease, in particular, rheumatoid arthritis, other examples, idiopathic arthritis in children, Castleman's disease, psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis , Multiple sclerosis, systemic lupus erythematosus, and cancer.

Here, the CSF1R-autoinhibited related disease may be, for example, osteoporosis, arthritis, atherosclerosis or chronic glomerulonephritis, or other examples, rheumatoid arthritis, or cancer, and the cancer may include myeloid leukemia, idiopathic myelofibrosis, and breast cancer. , Cervical cancer, ovarian cancer, endometrial cancer, prostate cancer, hepatocellular carcinoma, multiple myeloma, lung cancer, kidney cancer and bone cancer.

Here, the FLT3-related diseases, or FLT3 mutation-related diseases (FLT3 (D835V), FLT3 (D835H), FLT3 (D835V), FLT3 (D835Y), FLT3 (ITD, D835V), FLT3 (ITD, F691L), and FLT3 ( K663Q), FLT3 (N841I)) may be, but is not limited to, a proliferative disorder, such as leukemia, myeloma, myeloproliferative disease, myelodysplastic syndrome, idiopathic hypereosinophilic syndrome (HES), bladder cancer, breast cancer, Cervical cancer, CNS cancer, colon cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, nasopharyngeal cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, salivary gland cancer, small cell lung cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer And, it may be any one selected from the group consisting of hematologic malignancy.

Meanwhile, the leukemia is not limited thereto, for example, Hodgkin's disease, and myeloma, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophil leukemia (CNL), acute undifferentiated leukemia (AUL), malignant giant-cell lymphoma (ALCL), prelymphocytic leukemia (PML), juvenile osteomyeloid leukemia (JMML) ), Adult T-cell ALL, AML with three-line myelodysplastic (AMLITMDS), mixed-line leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD), and multiple myeloma (MM) It can be any one.

Here, the EPHB6-related disease may be, for example, cancer, and the cancer is metastatic carcinoma, breast cancer, invasive breast cancer, triple negative breast cancer (TNBC), lung cancer, melanoma, prostate cancer, ovarian carcinoma, stomach cancer, colon cancer, neuroblastoma , Aggressive neuroblastoma, and the like.

Here, the IRAK1-related diseases include, for example, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, scleroderma, multiple sclerosis, psoriasis, type I diabetes, type II diabetes, Inflammatory bowel disease (Cronh's Disease and ulcerative colitis), hyperimmunoglobulinemia D and periodic fever syndrome, cryopyrin-related periodic syndrome, Schnitzler's syndrome, systemic pediatric idiopathic arthritis, adult-onset Still's disease, gout, False breath, SAPHO syndrome, Castleman's disease, septicemia, stroke, atherosclerosis, celiac disease, DIRA (IL-1 receptor antagonist deficiency), Alzheimer's disease, Parkinson's disease, and cancer. .

Here, the KIT-related diseases, or KIT mutation-related diseases (KIT (L576P, KIT (V559D), KIT-autoinhibited, etc.), for example, systemic mastocytosis, GIST (gastrointestinal stromal tumor), AML (acute myeloid leukemia) ), Melanoma, normal cystoma, intracranial germ cell tumor, mediastinal B-cell lymphoma, Ewing sarcoma, DLBCL (diffuse giant B cell lymphoma), ovarian testicular tumor, MDS (myelodysplastic syndrome), NKTCL (nose NK / T-cell lymphoma), CMML (chronic osteoblastic leukemia), and cancer (eg, brain cancer).

Here, the MARK3-related diseases are not limited thereto, and may be, for example, any one selected from the group consisting of Poitzheimer's syndrome, osteoarthritis, rheumatoid arthritis, intermittent claudication, diabetes, and diabetes mellitus.

Here, the PDGFRB-related diseases, but are not limited to, for example, age-related macular degeneration (AMD), mast-cell related diseases, respiratory diseases, inflammatory disorders, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) ), Autoimmune disorder, metabolic disease, fibrosis disease, dermatological disease, pulmonary arterial hypertension (PAH), primary pulmonary hypertension (PPH), asthma, allergic rhinitis, pulmonary fibrosis, liver fibrosis, heart fibrosis, scleroderma, and diabetes It may be any one selected from.

Other PIP5K2C, SNARK, STK16, TRKA, TXK, or YSK4-related diseases are also included in the present invention without limitation, as long as they are related or reported diseases associated with each kinase, for example, the disease may be cancer , Autoimmune disease, or inflammatory disease.

In addition, the present invention

As shown in Scheme 1 below,

Reacting the compound represented by Formula 5 with the compound represented by Formula 4 to prepare a compound represented by Formula 3 (step 1);

Preparing a compound represented by Formula 2 from the compound represented by Formula 3 prepared in Step 1 (Step 2);

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

[Scheme 1]

(In Scheme 1 above,

X, Y, and Z are as defined in Formula 1 of claim 1;

X 'is X or X substituted with Boc;

V is -S-CH ₃ , or-(S = O) -CH ₃ ;

W is NHBoc or NO ₂ ; And

W 'is NH ₂ ).

Hereinafter, the manufacturing method according to the present invention will be described in detail.

First, the compound represented by Chemical Formula 5 in Step 1 is not limited thereto, but may be prepared by performing the following Preparation Examples 1-4, or it may be prepared by an easily changeable / modifiable manufacturing method therefrom.

Here, the change / modification usually refers to an easy degree of change / modification to a person skilled in the art, and may be, for example, conditions that can be selectively changed in each reaction step to obtain the final target compound. As a more specific example, the easily changeable / modifiable reaction conditions may be a solvent used for each reaction, reaction temperature, reaction time, and the like.

Furthermore, in the production method represented by scheme 1 of the present invention, step 1 is a step of preparing a compound represented by formula 3 by reacting the compound represented by formula 5 with the compound represented by formula 4.

Here, the step 1 may be understood as a step of introducing a substituent represented by X ′ of the formula 4 at the V substitution position of the formula 5, and is not particularly limited, for example, step 1 of the first embodiment, Or it may be performed as in step 1 of Example 10, the present invention includes this.

For example, the compound represented by Formula 4 is a compound of amines, and is a step for introducing it with various substituents, and can be understood as a step of reacting the compound represented by Formula 5 with the compound represented by Formula 4. .

However, here, the substituted part represented by X 'of the compound represented by Formula 4 is a substituent according to the same definition as X in Formula 1, or any part of the substituent represented by X in Formula 1 is a protecting group, eg For example, it may be a substituent substituted with -Boc.

Reaction solvents that can be used include toluene, dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), methylene chloride, dichloroethane, water, ethyl acetate, acetonitrile; Lower alcohols including isopropanol, methanol, ethanol, propanol and butanol; Ether solvents including tetrahydrofuran (THF), dioxane, ethyl ether, 1,2-dimethoxyethane, and the like; And the like, which can be used alone or in combination, and it is preferable to use toluene.

 After the reaction, the reaction mixture can be filtered through a filtration membrane and washed with an organic solvent. Compound 3 obtained after concentration of the filtrate can be purified or used in the next step without further purification.

Meanwhile, the reaction temperature is not particularly limited, but for example, the reaction temperature may be set to about 50 to 150 ° C, or about 80 ° C, or about 100 ° C.

The reaction time is also not particularly limited, and includes more than a time period at which at least a part of the product is obtained.

However, the manufacturing method of the present invention is not limited from the above reaction conditions, and reaction conditions such as solvent, reaction time, reaction temperature, and the like that can be easily changed / modified are all included in the present invention. A technician will understand.

Furthermore, in the production method of the present invention, step 2 is a step of preparing a compound represented by formula 2 from a compound represented by formula 3.

Here, step 2 may be understood as a step of converting a substituent represented by W of Formula 3 into a substituent represented by W 'of Formula 2, for example, if W is NO ₂ or NHBoc, W' is NH ₂ to be.

Here, if the substituent conversion of step 2 is performed, it is understood that the present invention is not particularly limited and may be understood, and may be performed as, for example, step 2 of example 1, or step 10 of example 10 It may be performed as shown in 2.

For example, the compound represented by Chemical Formula 3 may be reacted with TFA, or the compound represented by Chemical Formula 3 may be reacted with tin (II) chloride.

The solvent that can be used is not particularly limited, ethyl acetate, toluene, dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water , Ethyl acetate, acetonitrile; Lower alcohols including isopropanol, methanol, ethanol, propanol and butanol; Ether solvents including tetrahydrofuran (THF), dioxane, ethyl ether, 1,2-dimethoxyethane, and the like; Etc., which can be used alone or in combination.

Again, the reaction conditions in this step, including those described in Step 2 of Example 1 and Step 2 of Example 10, can be easily changed / modified from there, such as solvent, reaction time, reaction temperature, reaction It will be understood by those skilled in the art that the conditions are all included in the present invention.

Furthermore, in the production method of the present invention, step 3 is a step of preparing a compound represented by formula 1 from a compound represented by formula 2.

This step can be understood to be a step of introducing a substituent represented by W ', and a substituent represented by Y, and is not particularly limited as long as the compound represented by Formula 1 is performed in a step in which it is prepared. It may be performed as in Step 6 of Example 1 and Step 5 of Example 7.

For example, it may be performed by adding DIPEA to the compound represented by Chemical Formula 2 and adding acryloyl chloride.

Here, the reaction conditions are not particularly limited, and as the solvent, toluene, dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methylene chloride, dichloroethane, water, ethyl Acetate, acetonitrile; Lower alcohols including isopropanol, methanol, ethanol, propanol and butanol; Ether solvents including tetrahydrofuran (THF), dioxane, ethyl ether, 1,2-dimethoxyethane, and the like; Etc. are possible, and it is preferable to use DMF.

The reaction temperature is not particularly limited, for example, may be performed at -100 to -20 ° C, or about -60 ° C,

The reaction time is not particularly limited, and may be performed for several seconds to 1 hour, or 1 minute to 30 minutes, or about 5 minutes.

Again, the reaction conditions in this step include those described in Step 3 of Example 1 and Step 3 of Example 10, and the solvent, reaction time, reaction temperature, and the like can be easily changed / modified therefrom. It will be understood by those skilled in the art that the conditions are all included in the present invention.

Meanwhile, the step 3 may further include a step of removing a separate protecting group, when X 'of Formula 2 is X substituted with a protecting group. For example, when the protecting group is -Boc, it may optionally further include a step for removing it, wherein the reaction for removing the protecting group and the reaction conditions thereof are generally known in the art, or the following examples It may be performed as in step 4 of 10, or modified / modifiable therefrom.

Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of JAK kinase (Janus kinase) related diseases containing the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. .

Here, the JAK kinase-related disease refers to any disease that can be prevented, improved, improved, or treated by inhibiting the activity of JAK kinase or inhibiting expression, but is not limited thereto. Includes all known diseases or syndromes associated with JAK kinase, or diseases reported to be related to JAK kinase.

In one embodiment of the present invention, the JAK kinase related disease may be understood as being a JAK 1, JAK 2, JAK 3, or TYK2 related disease, but is not limited thereto.

JAK 1 related diseases include, for example, IL-10, IL-19, IL-20, IL-22, IL-26, IL-28, IFN-α, IFN-γ, IL-6 and others of the gp130 family diseases associated with γc-containing receptors, immune-related diseases, inflammation and cancer, etc., such as leukemia, lymphoma, melanoma, arthritis, psoriasis, Crohn's disease, lupus erythematosus, AIDS, Behcet's disease, etc.,

JAK 2 related diseases include receptor related diseases including EPO, GH, PRL, IL-3, IFN-γ, polycythemia vera (PV), essential thrombocytopenia (ET), idiopathic myelofibrosis (IMF) and chronic It may be a myeloproliferative disease, including myeloid leukemia (CML),

JAK 3 related diseases can be cytokine-receptor complex related diseases such as IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, and the abnormal activity of JAK 3 is normal in the immune system. It can be an onset or an ongoing disease from having a significant decrease in T-cells and NK cells and a loss in function of B-cells, which have a significant effect on biological function, for example, complex immunodeficiency (SCID), rheumatoid arthritis ( RA), myelofibrosis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, type I diabetes, psoriasis, allergic disease, asthma, chronic obstructive pulmonary disease, leukemia, lymphoma, organ transplantation and other diseases. On the other hand, TYK2-related diseases include interferon (IFN), IL-10, IL-6, IL-12, IL-23 and IL-27-related diseases, such as inflammatory diseases such as lung infection, breast cancer, cancer, etc. It may be a tumor or cancer disease associated with obesity.

In another embodiment of the invention, the JAK kinase related disease may be, in particular, a JAK 3 kinase related disease. The compound represented by Formula 1 of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof exhibits selective inhibitory activity against JAK 3 kinase, from which prevention, improvement, improvement, or prevention of JAK 3 kinase related diseases It has a useful effect to treat, and at the same time, from the lack or lack of inhibitory activity against other JAK families, side effects problems are solved compared to conventional non-selective JAK inhibitors, and more focused and improved for certain diseases, especially JAK 3 related diseases It is useful because it can exhibit medicinal properties. However, in this aspect, the advantages are examples of one aspect of the compounds of the present invention, and the compounds of the present invention are not limited to the above-described description, and may exhibit additional advantages and effects in addition to the above-described advantages.

In another embodiment of the present invention, the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from an inhibitory activity selective for JAK 3, for example, the amount of red blood cells and white blood cells. Side effects such as decreased and increased cholesterol levels can be avoided, and in particular, the advantage that side effects resulting from JAK 2 inhibitory activity can be avoided can be achieved.

In addition, the present invention provides a health functional food composition for preventing or improving diseases related to JAK kinase (Janus kinase) containing the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. do.

Here, the JAK kinase-related disease refers to any disease that can be prevented, improved, improved, or treated by inhibiting the activity of JAK kinase or inhibiting expression, but is not limited thereto. Includes all known diseases or syndromes associated with JAK kinase, or diseases reported to be related to JAK kinase.

In one embodiment of the present invention, the JAK kinase related disease may be understood as being a JAK 1, JAK 2, JAK 3, or TYK2 related disease, but is not limited thereto.

JAK 1 related diseases include, for example, IL-10, IL-19, IL-20, IL-22, IL-26, IL-28, IFN-α, IFN-γ, IL-6 and others of the gp130 family diseases associated with γc-containing receptors, immune-related diseases, inflammation and cancer, etc., such as leukemia, lymphoma, melanoma, arthritis, psoriasis, Crohn's disease, lupus erythematosus, AIDS, Behcet's disease, etc.,

JAK 2 related diseases include receptor related diseases including EPO, GH, PRL, IL-3, IFN-γ, polycythemia vera (PV), essential thrombocytopenia (ET), idiopathic myelofibrosis (IMF) and chronic It may be a myeloproliferative disease, including myeloid leukemia (CML),

JAK 3 related diseases can be cytokine-receptor complex related diseases such as IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, and the abnormal activity of JAK 3 is normal in the immune system. It can be an onset or an ongoing disease from having a significant decrease in T-cells and NK cells and a loss in function of B-cells, which have a significant effect on biological function, for example, complex immunodeficiency (SCID), rheumatoid arthritis ( RA), myelofibrosis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, type I diabetes, psoriasis, allergic disease, asthma, chronic obstructive pulmonary disease, leukemia, lymphoma, organ transplantation and other diseases. On the other hand, TYK2-related diseases include interferon (IFN), IL-10, IL-6, IL-12, IL-23 and IL-27-related diseases, such as inflammatory diseases such as lung infection, breast cancer, cancer, etc. It may be a tumor or cancer disease associated with obesity.

In another embodiment of the invention, the JAK kinase related disease may be, in particular, a JAK 3 kinase related disease. The compound represented by Formula 1 of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, exhibits selective inhibitory activity against JAK 3 kinase, from which it prevents, ameliorates, improves, or improves JAK 3 kinase-related diseases. It has a useful effect to treat, and at the same time, from the lack or lack of inhibitory activity against other JAK families, side effects problems are solved compared to conventional non-selective JAK inhibitors, and more focused and improved for certain diseases, especially JAK 3 related diseases It is useful because it can exhibit medicinal properties. However, in this aspect, the advantages are examples of one aspect of the compounds of the present invention, and the compounds of the present invention are not limited to the above-described description, and may exhibit additional advantages and effects in addition to the above-described advantages.

In another embodiment of the present invention, the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from an inhibitory activity selective for JAK 3, for example, the amount of red blood cells and white blood cells. Side effects such as decreased and increased cholesterol levels can be avoided, and in particular, the advantage that side effects resulting from JAK 2 inhibitory activity can be avoided can be achieved.

Furthermore, irrespective of the description related to the JAK kinase described above, based on the activity of inhibiting proliferation to cancer cell lines experimentally seen from the compound represented by Chemical Formula 1 in the present specification,

In one aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Here, the cancer is a cancer in the sense that it is a painful work, and is not particularly limited, but the cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, cleft lip cancer, Mycosis, acute myelogenous leukemia, acute lymphocytic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytes Leukemia, retinoblastoma, choroidal melanoma, diffuse giant B cell lymphoma, Barter's swelling cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, non-sinus sinus cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, snow cancer, astrocytoma, small cell lung cancer, Pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, neuroblastoma, renal cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer , Malignant lymphoma, malignant mesothelioma, malignant melanoma, cancer, vulvar cancer, ureteral cancer, urethral cancer, primary site unknown cancer, gastric lymphoma, stomach cancer, gastric carcinoma, gastrointestinal interstitial cancer, Wilms' cancer, breast cancer, sarcoma, penile cancer, pharynx Cancer, gestational villus disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, auditory transadenoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, wave Jet disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, pulmonary squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, larynx cancer, pleural cancer, and thymic cancer.

In the pharmaceutical composition according to the present invention, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various dosage forms, oral and parenteral, during clinical administration. It can be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, and the like.

Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, liquids, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc., and these formulations include diluents (e.g., lactose) , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants (e.g. silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycol). Tablets may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and, if desired, a boron such as starch, agar, alginic acid or its sodium salt, etc. It can contain an releasing or boiling mixture and / or absorbent, colorant, flavoring agent, and sweetening agent.

The pharmaceutical composition of the compound represented by Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally, and parenteral administration may be subcutaneous injection, intravenous injection, intramuscular injection or chest How to inject my injection.

At this time, in order to formulate a formulation for parenteral administration, a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a solution or suspension, and it is administered in ampoules or vials. Can be produced. The composition may be sterile and / or contain preservatives, stabilizers, hydrating or emulsifying accelerators, adjuvants such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances. It can be formulated according to the chemical or coating method.

In addition, the dosage of the compound represented by Formula 1 of the present invention or a pharmaceutical composition containing the pharmaceutically acceptable salt thereof as an active ingredient to the human body is the patient's age, weight, gender, dosage form, health condition and disease Depending on the degree, and based on an adult patient weighing 70 Kg, it is generally 0.1-1000 mg / day, preferably 1-500 mg / day, and is also determined according to the judgment of the doctor or pharmacist. It may be administered in divided doses once to several times a day at time intervals.

The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various dosage forms, oral and parenteral, during clinical administration. In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include at least one excipient in one or more compounds, such as starch, calcium carbonate, sucrose or lactose ( lactose) and gelatin. Also, in addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspending agents, intravenous solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are common diluents, various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, can be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents, suspension solvents may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

On the other hand, in the dietary supplement composition, the compound represented by Formula 1 according to the present invention may be added as it is to a food or used with other foods or food ingredients, and may be suitably used according to a conventional method. The mixing amount of the active ingredient can be appropriately determined according to its purpose of use (for prevention or improvement). In general, the amount of the compound in the health food can be added in 0.1-90 parts by weight of the total food weight. However, in the case of long-term intake for health and hygiene purposes or for health control purposes, the amount may be below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.

In addition, the health functional beverage composition of the present invention has no particular limitation on other components except for containing the compound as an essential component in the indicated proportions, and may contain various flavors or natural carbohydrates, etc., as additional components, such as ordinary beverages. have. Examples of the natural carbohydrates described above include monosaccharides, for example, glucose, fructose, etc .; Disaccharides such as maltose, sucrose, etc .; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatine, stevia extract (for example, rebaudioside A, glycyrrhizine, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of natural carbohydrates is generally about 1-20 g per 100 g of the composition of the present invention, preferably about 5-12 g.

Furthermore, in addition to the above, the compound represented by Chemical Formula 1 according to the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents, and flavoring agents such as natural flavoring agents, coloring agents and neutralizing agents (cheese, chocolate, etc.), pect Acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohol, carbonic acid used in carbonated beverages, and the like. In addition, the compound represented by Chemical Formula 1 of the present invention may contain natural fruit juice and flesh for the production of fruit juice drinks and vegetable drinks.

Furthermore, the present invention is a JAK kinase (Janus kinase) comprising the step of administering to a subject in need a pharmaceutical composition or a health functional food composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a method for preventing or treating a related disease.

Here, the JAK kinase-related diseases include all diseases as described above in detail herein.

The therapeutically effective amount refers to an amount sufficient to improve symptoms or conditions of a subject when administered into the body, depending on the administration method. In addition, the amount may be different depending on the weight, age, sex, condition, family history of the subject to be administered, and in the present invention, the treatment method may determine a different amount of dose according to different conditions for each subject.

The “effective amount” refers to an amount useful for treating a JAK kinase related disease or disorder, or a minimum effective amount for treating cancer. In other embodiments, “effective amount” of a compound refers to a minimum amount that can inhibit the proliferation of cancer.

The compounds and compositions according to the methods of the present invention can be administered using any amount and any route of administration effective for treating a disease. The exact amount required will vary from subject to subject, depending on the subject's species, age, and general condition, severity of infection, specific agent, mode of administration, and the like. The compounds of the present invention are frequently formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein means a physically discrete unit of agent suitable for the subject to be treated. However, it will be understood that the total daily use of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular subject or organism will depend on various factors, including:

The term "subject", as used herein, means an animal, for example a mammal, such as a human.

The pharmaceutical composition of the present invention may be orally, rectally, parenterally, intravaginally, intravaginally, intraperitoneally, topically (powder, ointment, lotion, plaster, or drops) to humans and other animals depending on the severity of the infection to be treated. By), orally, as an oral or nasal spray, and the like. In certain embodiments, the compounds of the invention are from about 0.01 mg / kg to about 50 mg / kg, e.g., from about 1 mg / kg to about 25 mg / kg body weight / day, once per day to achieve the desired therapeutic effect. It can be administered orally or parenterally at a dosage level of more than / 1 day.

In addition, the present invention provides the use of a pharmaceutical composition or a health functional food composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient in the prevention or treatment of a protein kinase related disease. do.

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

However, the following examples and experimental examples are merely illustrative of the present invention, and the contents of the present invention are not limited to the following examples and experimental examples.

In the following Example compound,

Analysis and purification conditions of the prepared compounds are as follows.

<Analysis and purification conditions>

HPLC analysis conditions (A)

Device name: Shimadzu

Column: YMC-pack pro C18, 150x4.6 mm I.D., 5 μm, 40 ° C.

Mobile phase: 5%-> 100% acetonitrile / H ₂ O + 0.1% TFA,

Analysis time: 9 minutes, flow rate: 1 ml / min

UV detector: 254nm

HPLC analysis conditions (B)

Device Name: Thermo Scientific Ultimate 3000RSLC

Column: Kinetex® 2.6 μM Biphenyl 100Å, 100x2.1mm

Mobile phase: 5%-> 100% acetonitrile / H ₂ O + 0.1% TFA,

Analysis time: 4.5 minutes, flow rate: 1.2 ml / min

UV detector: 254nm

LC-MS analysis conditions

Device name: Shimadzu LCMS-2020

Column: ACE Excel2 C18, 75x2.1 mm

Mobile phase: acetonitrile / H ₂ O + 0.1% TFA

Flow rate: 1 mL / min

UV detector: 254nm

MPLC purification conditions

Device name: CombiFlash®Rf +

UV detector: 254nm

Prep-HPLC purification conditions

Device name: Gilson GX-281, 321 pump, UV / VIS-155

Column: Luna® 10 μM C18 (2) 100Å, 250x21.2 mm

Mobile phase: acetonitrile / 0.1% TFA H ₂ O

Flow rate: 15mL / min

UV detector: 254nm

1NH NMR

Device Name: Brucler Avance (400 MHz)

<Production Example 1> tert-butyl (3-((6-cyano-2- (methylsulfinyl) -7-oxopyrido [2,3-d] pyrimidin-8 (7H) -yl) methyl) Preparation of phenyl) carbamate

Step 1: Preparation of 4-amino-2- (methylthio) pyrimidine-5-carbaldehyde

(4-Amino-2- (methylthio) pyrimidin-5-yl) methanol (1.0 eq) was dissolved in chloroform (0.2 M), and then manganese (IV) oxidase (6.0 eq) was added. After the reaction mixture was reacted for 12 hours at room temperature, it was filtered through celite and washed with chloroform. After the obtained filtrate was concentrated, a target compound as a yellow solid was obtained (yield: 82%).

Step 2: Preparation of 2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-6-carbonitrile

After dissolving the compound (1.0 eq) prepared in step 1 in acetic acid (0.6 M), add cyano acetic acid (1.2 eq) and benzylamine (0.1 eq) and react at 120 ° C. for 6 hours using a reflux device. Proceeded. After completion of the reaction, only the solid generated by lowering the temperature to room temperature and adding hexane to the reaction mixture was extracted. The separated solid was washed again with saturated NaHCO ₃ and water, and dried under reduced pressure for about a day to obtain the target compound as a yellow solid (yield: 46%).

Step 3: tert-Butyl (3-((6-cyano-2- (methylthio) -7-oxopyrido [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) carba Mate Production

After dissolving the compound (1.0 eq.) Prepared in Step 2 in DMF (0.1 M), sodium hydride (1.2 eq.) At 0 ° C. was added in 3-4 portions. The reaction mixture was reacted for 30 minutes, and tert-butyl 3- (bromomethyl) phenylcarbamate (1.1 eq.) Was further added, followed by reaction at room temperature for 1 hour. The reaction was terminated by adding water at 0 ° C, and the organics were extracted with EtOAc (x3). After the collected organic layer was washed with brine, the remaining water was removed using Na ₂ SO ₄ . The obtained target compound as a yellow solid was used in the next reaction without further purification (yield: 93%).

Step 4: tert-Butyl 3-((6-cyano-2- (methylsulfinyl) -7-oxopyrido [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) carba Mate Production

After dissolving the compound (1.0 eq) prepared in Step 3 in DCM (0.15 M), m-CPBA (3-chloroperbenzoic acid, 1.5 eq) was added and the reaction was carried out at -10 ° C for 1 hour. The reaction was terminated by adding saturated NaHCO ₃ , and the organic was extracted with DCM (x3). After the collected organic layer was washed with brine, the remaining water was removed using Na ₂ SO ₄ to obtain a target compound as a yellow solid (yield: 96%).

<Production Example 2> Preparation of 2- (methylsulfinyl) -8- (3-nitrobenzyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-6-carbonitrile

Step 1: Preparation of 4-amino-2- (methylthio) pyrimidine-5-carbaldehyde

(4-Amino-2- (methylthio) pyrimidin-5-yl) methanol (1.0 eq) was dissolved in chloroform (0.2 M), and then manganese (IV) oxidase (6.0 eq) was added. After the reaction mixture was reacted for 12 hours at room temperature, it was filtered through celite and washed with chloroform. After the obtained filtrate was concentrated, a target compound as a yellow solid was obtained (yield: 82%).

Step 2: 2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-6-carbonitrile

After dissolving the compound (1.0 eq) prepared in step 1 in acetic acid (0.6 M), cyanoacetic acid (1.2 eq) and benzylamine (0.1 eq) were added and reacted at 120 ° C. for 6 hours using a reflux device. Proceeded. After completion of the reaction, only the solid generated by lowering the temperature to room temperature and adding hexane to the reaction mixture was extracted. The separated solid was washed again with saturated NaHCO ₃ and water, and dried under reduced pressure for about a day to obtain the target compound as a yellow solid (yield: 46%).

Step 3: Preparation of 2- (methylthio) -8- (3-nitrobenzyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-6-carbonitrile

2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-6-carbonitrile (1.0 eq.) Was dissolved in DMF (0.1 M), and then at 0 ° C. Sodium hydride (1.2 eq) was added in portions 3-4. The reaction mixture was reacted for 30 minutes, and 3-nitrobenzyl bromide (1.1 eq.) Was further added, followed by reaction at room temperature for 1 hour. The reaction was terminated by adding water at 0 ° C, and the organics were extracted with EtOAc (x3). After the collected organic layer was washed with brine, the remaining water was removed using Na ₂ SO ₄ . The obtained target compound as a yellow solid was used in the next reaction without further purification (yield: 93%).

Step 4: Preparation of 2- (methylsulfinyl) -8- (3-nitrobenzyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-6-carbonitrile

After dissolving the compound (1.0 eq) prepared in Step 3 in DCM (0.15 M), m-CPBA (3-chloroperbenzoic acid, 1.5 eq) was added and the reaction was carried out at -10 ° C for 1 hour. The reaction was terminated by adding saturated NaHCO ₃ , and the organic was extracted with DCM (x3). The collected organic layer was washed with brine, and the remaining water was removed using Na ₂ SO ₄ to obtain a target compound as a yellow solid (yield: 90%).

<Production Example 3> 2- (methylsulfinyl) -7-oxo-8-((R) -pyrrolidin-3-yl) -7,8-dihydropyrido [2,3-d] pyrimidine Preparation of -6-carbonitrile

In place of tert-butyl 3- (bromomethyl) phenylcarbamate used in Step 3 of Preparation Example 1, except that (R) -tert-butyl 3-bromopyrrolidine-1-carboxylate was used. , Was carried out as in Preparation Example 1 to prepare the target compound.

<Production Example 4> 2- (methylsulfinyl) -7-oxo-8-((S) -pyrrolidin-3-yl) -7,8-dihydropyrido [2,3-d] pyrimidine Preparation of -6-carbonitrile

In place of tert-butyl 3- (bromomethyl) phenylcarbamate used in Step 3 of Preparation Example 1, except that (S) -tert-butyl 3-bromopyrrolidine-1-carboxylate was used. , Was carried out as in Preparation Example 1 to prepare the target compound.

<Production Example 5> Preparation of tert-butyl 3-((2- (methylsulfinyl) -7-oxopyrido [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenylcarbamate

The target compound was prepared in the same manner as in Preparation Example 1, except that acetic acid was used instead of cyanoacetic acid used in Step 2 of Preparation Example 1.

<Production Example 6> Preparation of 2- (methylsulfinyl) -8-((R) -pyrrolidin-3-yl) pyrido [2,3-d] pyrimidin-7 (8H) -one

In place of cyanoacetic acid used in Step 2 of Preparation Example 1, acetic acid was used, and in place of tert-butyl 3- (bromomethyl) phenylcarbamate used in Step 3 of Preparation Example 1, (R ) -tert-Butyl 3-bromopyrrolidine-1-carboxylate was carried out as in Preparation Example 1, except that the target compound was prepared.

<Production Example 7> Preparation of 2- (methylsulfinyl) -8-((S) -pyrrolidin-3-yl) pyrido [2,3-d] pyrimidin-7 (8H) -one

In place of cyanoacetic acid used in Step 2 of Preparation Example 1, acetic acid was used, and in place of tert-butyl 3- (bromomethyl) phenylcarbamate used in Step 3 of Preparation Example 1, (S ) -tert-Butyl 3-bromopyrrolidine-1-carboxylate, except that the same was used as in Preparation Example 1 to prepare the target compound.

Compounds of Examples 9, 10, 12, 17, and 19 were prepared based on the compounds prepared in Preparation Example 2, and Example 1-22 Example compounds were prepared based on the compounds prepared in Preparation Example 1. , Examples 23, 25 compounds were prepared based on the compounds prepared in Preparation Example 3, Example 24 compounds were prepared based on the compounds prepared in Preparation Example 4, Examples 26 to 31 compounds were prepared above Prepared on the basis of the compound prepared in Example 5, Examples 32 and 34 compounds were prepared based on the compound prepared in Preparation Example 6, Example 33 compound was prepared based on the Preparation Example 7 compound.

< Example  1> N- (3-((6-cyano-2-((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2,3- d] Preparation of pyrimidine-8- (7H) yl) methyl) phenyl) acrylamide

Step 1: tert-Butyl 3-((6-cyano-2-((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2,3 -d] Preparation of pyrimidine-8- (7H) -yl) methyl) phenyl) carbamate

The compound (1.0 eq.) Prepared in Preparation Example 1 and 1- (2-methoxyethyl) -1H-pyrazole-4-amine (1.2 eq.) Were added to toluene (0.1 M) and dissolved, followed by 1 hour. Reacted. The reaction was terminated by adding water, and the organic was extracted with EtOAc (x3). After the collected organic layer was washed with brine, the remaining water was removed using Na ₂ SO ₄ . The mixture was purified via prep-HPLC to give the desired compound as a yellow liquid (yield: 52%).

Step 2: 8- (3-aminobenzyl) -2-((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) -7-oxo-7,8-dihydropyrido Preparation of [2,3-d] pyrimidine-6-carbonitrile

After dissolving the compound (1.0 eq) prepared in Step 1 in DCM (0.05 M), TFA (100 eq) was added at room temperature. After 3 hours reaction, the solvent was removed. The desired compound of concentrated light yellow liquid was used in the next reaction without further purification.

Step 3: N- (3-((6-cyano-2-((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2,3 -d] Preparation of pyrimidine-8- (7H) yl) methyl) phenyl) acrylamide

The compound prepared in Step 2 (1.0 eq) was dissolved in DMF (0.05 M) at room temperature, and then DIPEA (1.1 eq) was added. Then, acryloyl chloride (1.0 eq.) Was added to the reaction mixture at -60 ° C, and the reaction was performed for 10 minutes. After 10 minutes, the temperature was changed to room temperature to proceed the reaction for 30 minutes, and water was added to terminate the reaction. The organics were extracted with EtOAc (x3), and the collected organic layer was washed with brine, and the remaining water was removed using Na ₂ SO ₄ . The mixture was purified by prep-HPLC to give the target compound as a yellow liquid (yield: 36%).

Yield: 36%; HPLC (B) r.t .: 2.24 min; Purity: 97%;

¹ H NMR (400 MHz, TFA salt, DMSO- d ₄ ,) δ 10.70 (s, 1H), 10.22 (s, 1H), 8.86 (s, 1H), 8.71 (s, 1H), 7.67 (s, 1H) ), 7.46 (s, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.45-6.38 (m, 1H), 6.23 (d, J = 17.0 Hz , 1H), 5.72 (d, J = 10.0 Hz, 1H), 5.50 (s, 2H), 4.13 (t, J = 5.3 Hz, 1H), 3.54 (t, J = 5.3 Hz, 1H), 3.13 (s , 3H); 471 [M + H] ⁺

<Example 2> N- (3-((6-cyano-2- (1- (3- (dimethylamino) -2-hydroxypropyl) -1H-pyrazol-4ylamino) -7-oxo Preparation of pyrido [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide

1- (4-amino-1H-pyrazol-1-yl) -3- in place of 1- (2-methoxyethyl) -1H-pyrazol-4-amine used in Step 1 of Example 1 above. Except for using (dimethylamino) propan-2-ol, the same procedure as in Example 1 was carried out to prepare the target compound.

Yield: 18%; HPLC (A) r.t .: 5.43 min; Purity: 99%;

¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.77 (s, 1H), 8.49 (s, 1H), 7.76 (s, 1H), 7.64-7.54 (m, 2H), 7.58 (d, J = 8.12 Hz, 1H), 7.45-7.30 (m, 1H), 7.06 (d, J = 7.68 Hz, 1H), 6.48-6.30 (m, 2H), 5.84-5.75 (m, 1H), 5.65 (s , 2H), 4.38-4.21 (m, 1H), 4.19-4.06 (m, 2H), 3.22-3.10 (m, 2H), 2.93 (s, 6H); 514 [M + H] ⁺

<Example 3> N- (3-((2-((5-chloro-1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) -6-cyano-7-oxo Preparation of pyrido [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide

5-chloro-1- (2-methoxyethyl) -1H-pyrazole- in place of 1- (2-methoxyethyl) -1H-pyrazol-4-amine used in step 1 of Example 1 above. A target compound was prepared by performing the same method as in Example 1, except that 4-amine was used.

Yield: 19%; HPLC (A) r.t .: 6.09 min; Purity: 100%;

¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 10.09 (s, 1H), 10.01 (s, 1H), 8.86 (s, 1H), 8.68 (s, 1H), 7.77-7.65 (m, 2H), 7.48 (s, 1H), 7.18 (t, 1H), 6.74 (d, J = 7.68 Hz, 1H), 6.42-6.35 (m, 1H), 6.24 (d, J = 16.88 Hz, 1H), 5.73 (d, J = 10 Hz, 1H), 5.26 (s, 2H), 4.27 (t, 2H), 3.67-3.65 (t, 2H), 3.15 (s, 3H); 505 [M + H] ⁺

<Example 4> N- (3-((6-cyano-7-oxo-2-((1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-yl) amino ) Preparation of pyrido [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide

1- (2,2,2-trifluoroethyl) -1H-pyrazole in place of 1- (2-methoxyethyl) -1H-pyrazol-4-amine used in Step 1 of Example 1 above. Except that -4-amine was used, the same procedure as in Example 1 was carried out to prepare a target compound.

Yield: 29%; HPLC (A) r.t .: 6.19 min; Purity: 99%;

¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 10.74 (s, 1H), 10.07 (s, 1H), 8.87 (s, 1H), 8.72 (s, 1H), 7.82 (s, 1H) , 7.64-7.62 (m, 2H), 7.45 (s, 1H), 7.25 (t, 1H), 7.00 (d, J = 7.76 Hz, 1H), 6.40-6.33 (m, 1H), 6.24-6.18 (m , 1H), 5.73-5.70 (m, 1H), 5.52 (s, 2H), 5.03-4.97 (m, 2H); 495 [M + H] ⁺

<Example 5> N- (3-((6-cyano-2-((1- (3-methyloxetan-3-yl) methyl) -1H-pyrazol-4-yl) amino) -7 -Preparation of oxopyrido [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide

1-((3-methyloxetan-3-yl) methyl) -1H- in place of 1- (2-methoxyethyl) -1H-pyrazol-4-amine used in Step 1 of Example 1 above. Except that the pyrazole-4-amine was used, the same procedure as in Example 1 was carried out to prepare a target compound.

Yield: 7%; HPLC (A) r.t .: 4.60 min; Purity: 92%;

¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.88 (s, 1H), 8.58-8.52 (m, 2H), 8.13 (s, 1H), 7.71 (s, 1H), 7.42 (s, 1H), 7.37 (t, 1H), 7.06 (d, J = 4,52 Hz, 1H), 6.42-6.30 (m, 2H), 5.77-5.74 (m, 1H), 5.66 (s, 2H), 4.52 (d, J = 11 Hz, 2H), 4.27 (d, J = 11.16 Hz, 2H), 3.48 (s, 2H), 1.33 (s, 3H); 497 [M + H] ⁺

<Example 6> N- (3-((6-cyano-2-((1- (oxetan-3-yl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [ Preparation of 2,3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide

1- (oxetan-3-yl) -1H-pyrazol-4-amine in place of 1- (2-methoxyethyl) -1H-pyrazol-4-amine used in step 1 of Example 1 above. Except for using, it was carried out as in Example 1 above to prepare the target compound.

Yield: 4%; HPLC (A) r.t .: 5.59 min; Purity: 99%;

¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 10.73 (s, 1H), 10.12 (s, 1H), 8.86 (s, 1H), 8.71 (s, 1H), 7.76 (s, 1H) , 7.71-7.61 (m, 2H), 7.60 (s, 1H), 7.29 (t, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.42-6.36 (m, 1H), 6.24-6.20 (m , 1H), 5.74-5.71 (m, 1H), 5.51 (s, 2H), 5.44-5.37 (m, 1H), 4.92-4.73 (m, 4H); 469 [M + H] ⁺

<Example 7> N- (3-((6-cyano-2-((1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido Preparation of [2,3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide

1- (2- (dimethylamino) ethyl) -1H-pyrazole-4-instead of 1- (2-methoxyethyl) -1H-pyrazol-4-amine used in step 1 of Example 1 above. Except for using an amine, it was carried out as in Example 1 to prepare a target compound.

Yield: 16%; HPLC (A) r.t .: 4.59 min; Purity: 94%;

¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 10.78 (s, 1H), 10.08 (s, 1H), 8.87 (s, 1H), 8.72 (s, 1H), 7.80 (s, 1H) , 7.65-7.61 (m, 2H), 7.38 (s, 1H), 7.31 (t, 1H), 7.07 (d, J = 6.76 Hz, 1H), 6.40-6.33 (m, 1H), 6.23-6.19 (m , 1H), 5.74-5.71 (m, 1H), 5.23 (s, 2H), 4.43 (t, 2H), 3.58-3.46 (m, 2H), 2.76 (s, 6H); 484 [M + H] ⁺

<Example 8> N- (3-((6-cyano-2-((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [ Preparation of 2,3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide

2-methoxy-4- (4-methylpiperazin-1-yl) benzene in place of 1- (2-methoxyethyl) -1H-pyrazol-4-amine used in Step 1 of Example 1 above. Except for using an amine, it was carried out as in Example 1 to prepare a target compound.

Yield: 11%; HPLC (A) r.t .: 4.88 min; Purity: 98%;

¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 10.11 (s, 1H), 9.43 (s, 1H), 8.81 (s, 1H), 8.64 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.44 (s, 1H), 7.31 (d, J = 8.68 Hz, 1H), 7.20-7.12 (m, 1H), 6.70 (s, 1H), 6.69-6.45 (m, 2H), 6.43-6.37 (m, 1H), 6.25-6.21 (m, 1H), 5.76-5.73 (m, 1H), 5.23 (s, 2H), 4.10-3.92 (m, 2H), 3.74 (s, 3H), 3.38-3.02 (m, 2H), 2.99-2.81 (m, 4H), 2.70 (s, 3H); 551 [M + H] ⁺

<Example 9> N- (3-((2-((1- (azetidin-3-yl) -1H-pyrazol-4-yl) amino) -6-cyano-7-oxopyrido [ Preparation of 2,3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide

In place of tert-butyl3-((4-amino-1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate used in Step 1 of Example 9 below, 1- (azetidine-3 -Day) Except that -1H-pyrazol-4-amine was used, it was carried out as in Example 9 to prepare a target compound.

Yield: 19%; HPLC (A) r.t .: 4.53 min; Purity: 100%;

¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 10.76 (s, 1H), 10.07 (s, 1H), 8.87 (s, 1H), 8.72 (s, 1H), 7.82 (s, 1H) , 7.72 (s, 1H), 7.65 (d, J = 7.88 Hz, 1H), 7.35-7.27 (m, 2H), 7.08 (d, J = 7.56 Hz, 1H), 6.39-6.33 (m, 1H), 6.24-6.19 (m, 1H), 5.74-5.71 (m, 1H), 5.52 (s, 2H), 5.44-5.30 (m, 2H), 4.51-4.24 (m, 4H); 468 [M + H] ⁺

<Example 10> N- (3-((6-cyano-7-oxo-2-((1- (piperidin-3-ylmethyl) -1H-pyrazol-4-yl) amino) pyri Preparation of Figure [2,3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide

Step 1: tert-Butyl 3-((4-((6-cyano-8- (3-nitrobenzyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine- Preparation of 2-yl) amino) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate

The compound (1.0 eq.) Prepared in Preparation Example 2 and tert-butyl3-((4-amino-1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate (1.2 eq.) Toluene ( 0.1 M) and dissolved to react at 100 ° C. for 1 hour. The reaction was terminated by adding water, and the organic was extracted with EtOAc (x3). After the collected organic layer was washed with brine, the remaining water was removed using Na ₂ SO ₄ . The mixture was purified by prep-HPLC to give the desired compound as a yellow liquid (yield: 54%).

Step 2: tert-Butyl 3-((4-((8- (3-aminobenzyl) -6-cyano-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine- Preparation of 2-yl) amino) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate

After dissolving the compound (1.0 eq) prepared in step 1 in ethyl acetate (0.1 M), tin (II) chloride (10.0 eq) was added and the reaction was performed at 60 ° C. for 5 hours. After completion of the reaction, the reaction mixture was adjusted to pH 5 using NH ₄ OH, and then maintained at pH 7 with Na ₂ CO ₃ . The reaction maintained at pH 7 was filtered through celite and washed with EtOAc. After the obtained filtrate was concentrated, the target compound as a concentrated pale yellow solid was used in the next reaction without further purification.

Step 3: tert-Butyl 3-((4-((8- (3-acrylamidobenzyl) -6-cyano-7-oxo-7,8-dihydropyrido [2,3-d] pyri Preparation of midin-2-yl) amino) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate

The compound prepared in Step 2 (1.0 eq) was dissolved in DMF (0.05 M) at room temperature, and then DIPEA (1.1 eq) was added. Then, acryloyl chloride (1.0 eq.) Was added to the reaction mixture at -60 ° C, and the reaction was performed for 10 minutes. After 10 minutes, the temperature was changed to room temperature to proceed the reaction for 30 minutes, and water was added to terminate the reaction. The organics were extracted with EtOAc (x3), and the collected organic layer was washed with brine, and the remaining water was removed using Na ₂ SO ₄ . The obtained yellow solid target compound was used in the next reaction without further purification.

Step 4: N- (3-((6-cyano-7-oxo-2-((1- (piperidin-3-ylmethyl) -1H-pyrazol-4-yl) amino) pyrido [ Preparation of 2,3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide

After dissolving the compound (1.0 eq) prepared in Step 3 in DCM (0.05 M), TFA (100 eq) was added at room temperature. After 3 hours reaction, the solvent was removed. The mixture was purified by prep-HPLC to give the desired compound as a yellow liquid (yield: 36%).

Yield: 36%; HPLC (B) r.t .: 1.81 min; Purity: 99%;

¹ H NMR (400 MHz, TFA salt, MeOH- d ₄ ,) δ 8.72 (s, 1H), 8.44 (s, 1H), 7.55-7.46 (m, 4H), 7.29 (d, J = 7.8 Hz, 1H ), 6.96 (d, J = 7.6 Hz, 1H), 6.29 (s, 2H), 5.72 (d, J = 8.9 Hz, 1H), 5.58 (s, 2H), 4.12-3.97 (m, 1H), 3.91 -3.77 (m, 1H), 3.00-2.97 (m, 1H), 2.86-2.73 (m, 2H), 2.59-2.53 (m, 1H), 2.14-2.07 (m, 1H), 1.80-1.78 (m, 1H), 1.65-1.53 (m, 2H); 510 [M + H] ⁺

<Example 11> N- (3-((6-cyano-7-oxo-2-((1- (tetrahydrofuran-3-yl) -1H-pyrazol-4-yl) amino) pyrido Preparation of [2,3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide

Instead of 1- (2-methoxyethyl) -1H-pyrazol-4-amine used in Step 1 of Example 1 above, 1- (tetrahydrofuran-3-yl) -1H-pyrazole-4- Except for using an amine, it was carried out as in Example 1 to prepare a target compound.

Yield: 18%; HPLC (A) r.t .: 4.59 min; Purity: 99%;

¹ H NMR (400 MHz, TFA salt, MeOH- d ₄ ,) δ 8.70 (s, 1H), 8.44 (s, 1H), 8.40 (s, 1H), 7.93 (s, 1H), 7.50 (s, 1H ), 7.40-7.32 (m, 2H), 7.24-7.19 (m, 3H), 5.58 (s, 2H), 3.95-3.93 (m, 1H), 3.85-3.76 (m, 2H), 3.69-3.61 (m , 2H), 2.16-2.03 (m, 2H); 484 [M + H] ⁺

<Example 12> N- (3-((6-cyano-2- (1- (morpholin-2-ylmethyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [ Preparation of 2,3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide

In place of tert-butyl3-((4-amino-1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate used in step 1 of Example 9 above, 1- (morpholine-2 -Ilmethyl) -1H-pyrazol-4-amine was carried out as in Example 9, except that the target compound was prepared.

Yield: 55%; HPLC (B) r.t .: 1.77 min; Purity: 97%;

¹ H NMR (400 MHz, TFA salt, MeOH- d ₄ ,) δ 8.70 (s, 1H), 8.41 (s, 1H), 7.64 (s, 1H), 7.50 (s, 2H), 7.45 (s, 1H ), 7.26 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.28-6.23 (m, 2H), 5.80 (d, J = 9.1 Hz, 1H), 5.57 (s , 2H), 4.08-4.05 (m, 2H), 3.90-3.86 (m, 2H), 3.62 (t, J = 10.9 Hz, 1H), 3.17 (t, J = 12.4 Hz, 2H), 3.01-2.97 ( m, 1H), 2.72 (t, J = 12.2 Hz, 2H); 512 [M + H] ⁺

<Example 13> N- (3-((6-cyano-2- (1- (2-hydroxypropyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2, Preparation of 3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide

1- (4-amino-1H-pyrazol-1-yl) propane-2 in place of 1- (2-methoxyethyl) -1H-pyrazol-4-amine used in Step 1 of Example 1 above. -Except that the point was used, it was carried out as in Example 1 to prepare a target compound.

Yield: 9%; HPLC (A) r.t .: 5.43 min; Purity: 98%;

¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.76 (s, 1H), 8.42 (s, 1H), 7.73 (s, 1H), 7.68-7.54 (m, 3H), 7.35-7.22 ( m, 1H), 7.07 (d, J = 7.8 Hz, 1H), 6.40-6.31 (m, 2H), 5.85-5.75 (m, 1H), 5.64 (s, 2H), 4.10-3.98 (m, 1H) , 3.97-3.88 (m, 2H), 1.08 (d, J = 6.16 Hz, 3H); 471 [M + H] ⁺

<Example 14> N- (3-((6-cyano-2- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2, Preparation of 3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide

Instead of 1- (2-methoxyethyl) -1H-pyrazol-4-amine used in Step 1 of Example 1 above, 2- (4-amino-1H-pyrazol-1-yl) ethanol was used. Except for the point, it was carried out as in Example 1 to prepare the target compound.

Yield: 10%; HPLC (B) r.t .: 1.86 min; Purity: 93%;

¹ H NMR (400 MHz, TFA salt, MeOH-d ₄ ,) δ 8.77 (s, 1H), 8.49 (s, 1H), 7.76 (s, 1H), 7.60-7.53 (m, 2H), 7.35 (t , J = 7.9 Hz, 2H), 7.10 (d, J = 7.5 Hz, 2H), 5.77 (d, J = 9.4 Hz, 2H), 5.66 (s, 1H), 4.11 (t, J = 5.5 Hz, 2H ), 3.81 (t, J = 5.3 Hz, 2H); 457 [M + H] ⁺

<Example 15> N- (3-((6-cyano-2- (4- (4-methylpiperazin-1-yl) phenylamino) -7-oxopyrido [2,3-d] pyri Preparation of midin-8 (7H) -yl) methyl) phenyl) acrylamide

In place of 1- (2-methoxyethyl) -1H-pyrazol-4-amine used in Step 1 of Example 1 above, 4- (4-methylpiperazin-1-yl) benzeneamine was used. Except, it was carried out as in Example 1 to prepare the target compound.

Yield: 34%; HPLC (B) r.t .: 1.95 min; Purity: 100%;

¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 10.54 (s, 1H), 10.17 (s, 1H), 8.86 (s, 1H), 8.70 (s, 1H), 7.68-7.55 (m, 2H), 7.45 (d, J = 8.92 Hz, 2H), 7.27 (t, 1H), 6.91-6.84 (m, 3H), 6.44-6.38 (m, 1H), 6.27 (d, J = 15.88 Hz, 1H ), 5.78 (d, J = 11.56 Hz, 1H), 5.43 (s, 2H), 3.88-3.71 (m, 2H), 3.54-3.42 (m, 2H), 3.26-3.12 (m, 2H), 3.01- 2.84 (m, 5H); 521 [M + H] ⁺

<Example 16> N- (3-((6-cyano-2- (2- (2-cyanopropan-2-yl) -4-methylthiazol-5-ylamino) -7-oxopyri Preparation of Figure [2,3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide

2- (5-amino-4-methylthiazol-2-yl) -2 in place of 1- (2-methoxyethyl) -1H-pyrazol-4-amine used in Step 1 of Example 1 above. -Except that methylpropanenitrile was used, it was carried out as in Example 1 to prepare a target compound.

Yield: 13%; HPLC (B) r.t .: 2.03 min; Purity: 99%;

¹ H NMR (400 MHz, TFA salt, MeOH- d ₄ ,) δ 8.82 (s, 1H), 8.50 (s, 1H), 8.43 (s, 1H), 7.50 (s, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 8.1 Hz, 2H), 7.14 (s, 1H), 7.06 (d, J = 7.4 Hz, 1H), 5.57 (s, 2H), 2.26 (s, 3H) ), 1.66 (s, 6H); 512 [M + H] ⁺

<Example 17> N- (3-((6-cyano-7-oxo-2-((1- (piperidin-4-yl) -1H-pyrazol-4-yl) amino) pyrido Preparation of [2,3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide

In place of tert-butyl3-((4-amino-1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate used in Step 1 of Example 9 above, 1- (piperidine- 4-yl) -1H-pyrazol-4-amine was carried out as in Example 9, except that the target compound was prepared.

Yield: 37%; HPLC (B) r.t .: 1.77 min; Purity: 100%;

¹ H NMR (400 MHz, TFA salt, MeOH- d ₄ ,) δ 8.68 (s, 1H), 8.39 (s, 1H), 7.70 (s, 1H), 7.51-7.44 (m, 3H), 7.24 (t , J = 7.8 Hz, 1H), 6.94 (d ,, J = 7.7 Hz, 1H), 6.29-6.22 (m, 2H), 5.69 (d, J = 9.0 Hz, 1H), 5.54 (s, 2H), 4.23-4.18 (m, 1H), 3.42 (d, J = 9.7 Hz, 2H), 3.10 (t, J = 12.6 Hz, 2H), 2.19-1.95 (m, 4H); 496 [M + H] ⁺

<Example 18> N- (3-((6-cyano-2-((1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) amino) -7-oxo Preparation of pyrido [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide

1- (4-amino-1H-pyrazol-1-yl) -2- in place of 1- (2-methoxyethyl) -1H-pyrazol-4-amine used in Step 1 of Example 1 above. Except for using methylpropan-2-ol, the same procedure as in Example 1 was carried out to prepare a target compound.

Yield: 21%; HPLC (A) r.t .: 4.53 min; Purity: 99%;

¹ H NMR (400 MHz, TFA salt, MeOH-d ₄ ,) δ 8.69 (s, 1H), 8.43 (s, 1H), 8.41 (s, 1H), 7.76 (s, 1H), 7.52 (s, 1H ), 7.36-7.33 (m, 2H), 7.27 (d, J = 7.5 Hz, 1H), 7.21-7.16 (m, 3H), 5.59 (s, 2H), 3.89 (s, 2H), 1.04 (s, 6H); 486 [M + H] ⁺

<Example 19> N- (3-((6-cyano-7-oxo-2-((1- (pyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) pyrido Preparation of [2,3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide

In place of tert-butyl3-((4-amino-1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate used in step 1 of Example 9 above, 1- (pyrrolidine- 3-yl) -1H-pyrazol-4-amine was carried out as in Example 9, except that the target compound was prepared.

Yield: 40%; HPLC (B) r.t .: 1.77 min; Purity: 98%;

¹ H NMR (400 MHz, TFA salt, MeOH- d ₄ ,) δ 8.72 (s, 1H), 8.43 (s, 1H), 7.69 (s, 1H), 7.52 (s, 2H), 7.47 (d, J = 8.1 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 6.98 (d, J = 7.5 Hz, 1H), 6.35-6.28 (m, 2H), 5.70 (d, J = 9.0 Hz, 1H ), 5.59 (s, 2H), 3.62-3.59 (m, 2H), 3.52-3.32 (m, 3H), 2.39-2.28 (m, 1H), 2.13-2.09 (m, 1H); 482 [M + H] ⁺

<Example 20> N- (3-((6-cyano-7-oxo-2-((4- (2,2,2-trifluoroethyl) phenyl) amino) pyrido [2,3- d] Preparation of pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide

The point of using 4- (2,2,2-trifluoroethyl) benzeneamine in place of 1- (2-methoxyethyl) -1H-pyrazol-4-amine used in Step 1 of Example 1 above. Except, by performing as in Example 1 above to prepare the target compound.

Yield: 21%; HPLC (A) r.t .: 7.18 min; Purity: 100%;

¹ H NMR (400 MHz, TFA salt, DMSO-d ₄ ,) δ 10.67 (NH, 1H), 10.10 (s, 1H), 8.92 (s, 1H), 8.74 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.56 (s, 1H), 7.48 (s, 1H), 7.27 (t, J = 7.7 Hz, 3H), 6.95 (s, 1H), 6.43-6.36 (m, 1H), 6.25 (d, J = 16.9 Hz, 1H), 5.74 (d, J = 10.0 Hz, 1H), 5.45 (s, 2H), 3.59 (q, J = 11.2 Hz, 2H); 505 [M + H] ⁺

<Example 21> N- (3-((6-cyano-7-oxo-2-((4- (trifluoromethyl) phenyl) amino) pyrido [2,3-d] pyrimidine-8 Preparation of (7H) -yl) methyl) phenyl) acrylamide

In place of the 1- (2-methoxyethyl) -1H-pyrazol-4-amine used in Step 1 of Example 1 above, except that 4- (trifluoromethyl) benzeneamine was used, It was carried out as in Example 1 to prepare the target compound.

Yield: 36%; HPLC (A) r.t .: 6.98 min; Purity: 99%;

¹ H NMR (400 MHz, TFA salt, DMSO-d ₄ ,) δ 10.91 (NH, 1H), 10.15 (s, 1H), 8.98 (s, 1H), 8.79 (s, 1H), 7.78 (s, 2H ), 7.63-7.56 (m, 3H), 7.27 (t, J = 7.8 Hz, 1H), 6.95 (s, 1H), 6.44-6.37 (m, 1H), 6.26 (d, J = 16.9 Hz, 1H) , 5.75 (d, J = 10.0 Hz, 1H), 5.49 (s, 2H) ,; 491 [M + H] ⁺

<Example 22> N- (3-((6-cyano-7-oxo-2-((1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazol-4-yl) amino ) Preparation of pyrido [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide

1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazole in place of 1- (2-methoxyethyl) -1H-pyrazol-4-amine used in Step 1 of Example 1 above. Except that -4-amine was used, the same procedure as in Example 1 was carried out to prepare a target compound.

Yield: 26%; HPLC (A) r.t .: 4.64 min; Purity: 99%;

¹ H NMR (400 MHz, TFA salt, MeOH-d ₄ ,) δ 8.70 (s, 1H), 8.45 (s, 1H), 8.40 (s, 1H), 7.89 (s, 1H), 7.70 (s, 1H ), 7.45 (s, 1H), 7.37-7.31 (m, 2H), 7.19 (s, 3H), 5.58 (s, 2H), 4.19-4.13 (m, 1H), 3.91 (d, J = 8.1 Hz, 2H), 3.48 (t, J = 12.5 Hz, 2H), 1.80 (d, J = 10.6 Hz, 2H), 1.66 (q, J = 12.4 Hz, 2H); 498 [M + H] ⁺

<Example 23> (R) -8- (1-acryloylpyrrolidin-3-yl) -2- (1- (2-methoxyethyl) -1H-pyrazol-4-ylamino) -7 -Preparation of oxo-7,8-dihydropyrido [2,3-d] pyrimidine-6-carbonitrile

The target compound was prepared by performing the same method as in Example 1, except that the compound of Preparation Example 3 was used instead of the Preparation Example 1 compound used in Step 1 of Example 1.

Yield: 20%; HPLC (A) r.t .: 5.28 min; Purity: 99%;

¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 10.62 (s, NH), 8.79 (s, 1H), 8.57 (s, 1H), 7.89 (s, 1H), 7.58 (s, 1H) , 6.71-6.65 (m, 1H), 6.20 (d, J = 7.2 Hz, 2H), 5.72-5.69 (m, 1H), 4.04-3.72 (m, 7H), 3.55-3.40 (m, 2H), 3.19 (s, 3H), 2.80-2.54 (m, 2H), 435 [M + H] ⁺

<Example 24> (S) -8- (1-acryloylpyrrolidin-3-yl) -2- (1- (2-methoxyethyl) -1H-pyrazol-4-ylamino) -7 -Preparation of oxo-7,8-dihydropyrido [2,3-d] pyrimidine-6-carbonitrile

The target compound was prepared by performing the same method as in Example 1, except that the compound of Preparation Example 4 was used instead of the Preparation Example 1 compound used in Step 1 of Example 1.

Yield: 46%; HPLC (A) r.t .: 5.29 min; Purity: 98%;

¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.72 (s, 1H), 8.38 (s, 1H), 7.94 (s, 1H), 7.66 (s, 1H), 6.75-6.68 (m, 1H), 6.34-6.28 (m, 2H), 5.82-5.72 (m, 1H), 4.39-4.29 (m, 2H), 4.20-4.02 (m, 1H), 4.02-3.94 (m, 1H), 3.92- 3.74 (m, 1H), 3.75-3.70 (m 2H), 3.68-3.44 (m, 1H), 3.30 (s, 3H), 2.98-2.78 (m, 1H), 2.32-2.18 (m, 1H); 435 [M + H] ⁺

<Example 25> (R) -8- (1-acryloylpyrrolidin-3-yl) -2- (2-methoxy-4- (4-methylpiperazin-1-yl) phenylamino)- Preparation of 7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-6-carbonitrile

In place of the preparation example 1 compound used in step 1 of Example 1, the preparation example 3 compound was used, and 1- (2-methoxyethyl) -1H-pyrazole-4 used in step 1 of example 1 was used. -Instead of amine, except that 2-methoxy-4- (4-methylpiperazin-1-yl) benzeneamine was used, it was carried out as in Example 1 to prepare a target compound.

Yield: 8%; HPLC (A) r.t .: 4.60 min; Purity: 99%;

¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.65 (s, 1H), 8.30 (s, 1H), 6.68-6.33 (m, 3H), 6.2306.18 (m, 1H), 6.00- 5.79 (m, 1H), 5.69 (d, J = 10.3 Hz, 1H), 4.19 (t, J = 9.6 Hz, 1H), 3.89-3.79 (m, 1H), 3.94 (s, 3H), 3.69-3.50 (m, 3H), 3.38-3.10 (m, 5H), 3.08-2.98 (m, 3H), 2.92 (s, 3H), 2.84-2.70 (m, 1H), 515 [M + H] ⁺

<Example 26> N- (3-((2- (4- (4-methylpiperazin-1-yl) phenylamino) -7-oxopyrido [2,3-d] pyrimidine-8 (7H Preparation of) -yl) methyl) phenyl) acrylamide

In place of the compound of Preparation 1 used in Step 1 of Example 1, a compound of Preparation 5 was used, and 1- (2-methoxyethyl) -1H-pyrazole-4 used in Step 1 of Example 1 was used. -Instead of the amine, except for using 4- (4-methylpiperazin-1-yl) benzeneamine, it was carried out as in Example 1 to prepare the target compound.

Yield: 12%; HPLC (A) r.t .: 4.65 min; Purity: 100%;

¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.67 (s, 1H), 7.85 (d, J = 9.32 Hz ,, 1H), 7.68 (s, 1H), 7.58-7.41 (m, 3H ), 7.26 (t, 1H), 7.00-6.82 (m, 3H), 6.52-6.42 (m, 1H), 6.41-6.32 (m, 2H), 5.82-5.78 (m, 1H), 5.57 (s, 2H) ), 3.84-3.72 (m, 2H), 3.70-3.62 (m, 3H), 3.30-3.20 (m, 3H), 2.97 (s, 3H); 496 [M + H] ⁺

<Example 27> N- (3-((2- (1- (oxetan-3-yl) -1H-pyrazol-4-ylamino) -7-oxopyrido [2,3-d] pyri Preparation of midin-8 (7H) -yl) methyl) phenyl) acrylamide

In place of the compound of Preparation 1 used in Step 1 of Example 1, a compound of Preparation 5 was used, and 1- (2-methoxyethyl) -1H-pyrazole-4 used in Step 1 of Example 1 was used. -Instead of the amine, except that the 1- (oxetan-3-yl) -1H-pyrazol-4-amine was used, it was carried out as in Example 1 to prepare a target compound.

Yield: 8%; HPLC (A) r.t .: 5.32 min; Purity: 99%;

¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 10.12 (s, 1H), 10.08 (s, 1H), 8.77 (s, 1H), 7.92 (d, J = 9.28 Hz, 1H), 7.72 (s, 1H), 7.68-7.50 (m, 2H), 7.41 (s, 1H), 7.29 (t, 1H), 6.97 (d, J = 7.4 Hz, 1H), 6.50-6.42 (m, 2H), 6.24-6.19 (m, 1H), 5.73-5.70 (m, 1H), 5.69-5.28 (m, 3H), 4.98-4.82 (m, 3H), 4.80-4.68 (m, 1H); 444 [M + H] ⁺

<Example 28> N- (3-((2- (1- (2-methoxyethyl) -1H-pyrazol-4-ylamino) -7-oxopyrido [2,3-d] pyrimidine Preparation of -8 (7H) -yl) methyl) phenyl) acrylamide

In place of the compound of Preparation 1 used in Step 1 of Example 1, a compound of Preparation 5 was used, and 1- (2-methoxyethyl) -1H-pyrazole-4 used in Step 1 of Example 1 was used. The target compound was prepared by performing the same method as in Example 1, except that 1- (2-methoxyethyl) -1H-pyrazol-4-amine was used instead of -amine.

Yield: 25%; HPLC (A) r.t .: 4.47 min; Purity: 100%;

¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.57 (s, 1H), 8.37 (s, 1H), 7.91 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.65 (s, 1H), 7.49 (s, 1H), 7.42 (s, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.21 (s, 1H), 7.17 (d, J = 8.8 Hz, 1H) , 7.10 (s, 1H), 6.37 (d, J = 9.1 Hz, 1H), 5.55 (s, 2H), 4.19-4.03 (m, 2H), 3.68-3.50 (m, 2H), 3.20 (s, 3H) ), 447 [M + H] ⁺

<Example 29> N- (3-((2- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-ylamino) -7-oxopyrido [2,3-d] Preparation of pyrimidine-8 (7H) -yyl) methyl) phenyl) acrylamide

In place of the compound of Preparation 1 used in Step 1 of Example 1, a compound of Preparation 5 was used, and 1- (2-methoxyethyl) -1H-pyrazole-4 used in Step 1 of Example 1 was used. -Instead of the amine, except for using 1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-amine, it was carried out as in Example 1 to prepare a target compound.

Yield: 30%; HPLC (A) r.t .: 3.91 min; Purity: 100%;

¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.58 (s, 1H), 8.37 (s, 1H), 7.99 (s, 1H), 7.79-7.60 (m, 2H), 7.55 (s, 1H), 7.29 (s, 3H), 7.15 (d, J = 6.9 Hz, 1H), 6.99 (s, 1H), 6.34 (d, J = 7.8 Hz, 1H), 5.55 (s, 2H), 4.50- 4.30 (m, 2H), 3.52 (s, 2H), 2.80 (s, 6H), 460 [M + H] ⁺

<Example 30> N- (3-((2- (2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2,3-d] Preparation of pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide

In place of the compound of Preparation 1 used in Step 1 of Example 1, a compound of Preparation 5 was used, and 1- (2-methoxyethyl) -1H-pyrazole-4 used in Step 1 of Example 1 was used. -Instead of amine, except that 2-methoxy-4- (4-methylpiperazin-1-yl) benzeneamine was used, it was carried out as in Example 1 to prepare a target compound.

Yield: 30%; HPLC (B) r.t .: 4.80 min; Purity: 99%;

¹ H NMR (400 MHz, TFA salt, MeOD-d ₄ ,) δ 8.62 (s, 1H), 7.76 (q, J = 17 Hz, 2H), 7.67 (s, 1H), 7.47 (d, J = 8 Hz, 1H), 6.87 (d, J = 7 Hz, 1H), 6.65 (s, 1H), 6.46 (d, J = 9 Hz, 2H), 6.42-6.35 (m, 2H), 5.77 (d, J = 9.52 Hz, 1H), 5.1 (s, 2H), 3.86 (s, 3H), 3.77 (s, 2H), 3.57 (s, 2H), 3.26 (s, 2H), 3.0 (m 2H), 2.97 ( s, 3H); 526 [M + H] ⁺

<Example 31> N- (3-((2- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2,3-d] pyri Preparation of midin-8 (7H) -yl) methyl) phenyl) acrylamide

In place of the compound of Preparation 1 used in Step 1 of Example 1, a compound of Preparation 5 was used, and 1- (2-methoxyethyl) -1H-pyrazole-4 used in Step 1 of Example 1 was used. -Instead of the amine, except for using 2- (4-amino-1H-pyrazol-1-yl) ethanol, the same procedure as in Example 1 was carried out to prepare the target compound.

Yield: 39%; HPLC (B) r.t .: 4.98 min; Purity: 99%;

¹ H NMR (400 MHz, TFA salt, MeOD-d ₄ ,) δ 88.74 (s, 1H), 7.87 (t, J = 8 Hz, 1H), 7.71 (s, 1H), 7.6.-7-49 ( m, 3H), 7.07 (t, J = 10.52 Hz, 1H), 6.47 (d, J = 8.92 Hz, 1H), 6.42-6.29 (m 2H), 5.73 (d, J = 11.93 Hz, 1H), 5.65 (s, 2H), 4.07 (s, 2H), 3.79 (s, 2H); 432 [M + H] ⁺

<Example 32> (R) -8- (1-acryloylpyrrolidin-3-yl) -2-((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) Preparation of pyrido [2,3-d] pyrimidin-7 (8H) -one

The target compound was prepared by performing the same method as in Example 1, except that the compound of Preparation Example 6 was used instead of the Preparation Example 1 compound used in Step 1 of Example 1.

Yield: 23%; HPLC (B) r.t .: 4.06 min; Purity: 99%;

¹ H NMR (400 MHz, TFA salt, MeOD-d ₄ ,) δ 9.05 (s, 1H), 8.08 (d, J = 9.12 Hz, 2H), 7.07 (d, J = 9.24 Hz, 1H), 6.80 ( d, J = 8.76 Hz, 2H), 6.34 (d, J = 15 Hz, 3H), 5.84-5.81 (m, 2H), 5.48-5.45 (m, 2H), 4.27-4.20 (m, 3H), 3.89 -3.70 (m, 4H); 409 [M] ⁺

<Example 33> (S) -8- (1-acryloylpyrrolidin-3-yl) -2-((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) Preparation of pyrido [2,3-d] pyrimidin-7 (8H) -one

The target compound was prepared by performing the same method as in Example 1, except that the compound of Preparation Example 7 was used instead of the compound of Preparation Example 1 used in Step 1 of Example 1.

Yield: 17%; HPLC (B) r.t .: 4.07 min; Purity: 98%;

¹ H NMR (400 MHz, TFA salt, MeOD-d ₄ ,) δ 8.88 (s, 1H), 8.08 (d, J = 9.08 Hz, 2H), 7.72 (s, 1H), 6.81 (d, J = 8.88 Hz, 2H), 6.35 (d, J = 15.76 Hz, 2H), 5.85-5.83 (m 2H), 5.49-5.45 (m 2H), 4.28-4.22 (m 3H), 3.73-3.69 (m 4H); 409 [M] ⁺

<Example 34> (R) -8- (1-acryloylpyrrolidin-3-yl) -2-((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino ) Preparation of pyrido [2,3-d] pyrimidin-7 (8H) -one

In place of the compound of Preparation 1 used in Step 1 of Example 1, a compound of Preparation 6 was used, and 1- (2-methoxyethyl) -1H-pyrazole-4 used in Step 1 of Example 1 was used. -Instead of the amine, except that 2-methoxy-4- (4-methylpiperazin-1-yl) benzeneamine was used, it was carried out as in Example 1 to prepare a target compound.

Yield: 6%; HPLC (B) r.t .: 4.6 min; Purity: 88.9%;

490 [M + H] ⁺

The chemical structural formulas of the compounds prepared in Examples 1-34 are shown in Table 1 below.

Example Chemical structural formula Example Chemical structural formula One

18

2

19

3

20

4

21

5

22

6

23

7

24

8

25

9

26

10

27

11

28

12

29

13

30

14

31

15

32

16

33

17

34

<Experimental Example 1> JAK 1, JAK 2, JAK 3, TYK2 kinase inhibitory activity evaluation

LanthaScreen Kinase assay experiment was performed to evaluate the inhibitory activity of the compounds according to the present invention for JAK 1, JAK 2, JAK 3, and TYK2 kinase.

In more detail, a final concentration of 533 ng / ml recombinant JAK 1 kinase (Promega PV4774), 7.7 μmol / L ATP (Promega PV3227), and 100 nM GFP-STAT1 (Promega PV5211) were kinase reaction buffer (50 mM HEPES pH7.5) in a 384-well plate. , 0.01% BRIJ-35, 10 mM MgCl ₂ , 1 mM EGTA) and mixed. The final concentration of each compound according to the present invention was added to 10 uM, 3.33 uM, 1.11 uM, 370 nM, 123 nM, 41 nM, 13.7 nM, 4.57 nM, 1.52 nM and 0.5 nM, followed by reaction in a 23 ° C. incubator for 1 hour. After the reaction was completed, the same amount of 4nM LanthaScreen ^TM Tb-anti-pSTAT1 (pTyr701) (Promega PV4844), 20 mm EDTA (Promega P2825) was added to the TR-FRET solution to react for 30 minutes, and the detection solution was added. After adding and reacting for 30 minutes at room temperature, the kinase was measured by measuring the TR-FRET value using TRF / TR-FRET Dual PMT using a microplate ELISA reader (Bio-Tek). IC ₅₀ values were calculated.

For JAK 2, a final concentration of 150 ng / ml recombinant JAK 2 kinase (Promega PV4210), 1 μmol / L ATP (Promega PV3227), and 100 nM GFP-STAT1 (Promega PV5211) in a 384-well plate was kinase reaction buffer (50 mM HEPES pH7. 5, 0.01% BRIJ-35, 10 mM MgCl ₂ , 1mM EGTA) and mixed, and then was performed in the same manner as in JAK 1.

In the case of JAK 3, a final concentration of 180 ng / ml recombinant JAK 3 kinase (Promega PV3855), 1 μmol / L ATP (Promega PV3227), and 100 nM GFP-STAT1 (Promega PV5211) in a 384-well plate was kinase reaction buffer (50 mM HEPES pH7. 5, 0.01% BRIJ-35, 10 mM MgCl ₂ , 1mM EGTA) and mixed, and then was performed in the same manner as in JAK 1.

For TYK2, a final concentration of 300 ng / ml recombinant TYK2 kinase (Promega PV4790), 1 μmol / L ATP (Promega PV3227), 100 nM GFP-STAT1 (Promega PV5211) in a 384-well plate, kinase reaction buffer (50 mM HEPES pH7.5, After mixing by adding to 0.01% BRIJ-35, 10 mM MgCl ₂ , 1 mM EGTA), it was carried out as in the experimental method of JAK 1.

In Tables 2 and 3, the inhibitory activities of the example compounds for JAK 1, JAK 2, JAK 3 and TYK2 are summarized. The measured kinase IC ₅₀ values were classified as A-class when less than 10 nM, and C-class if greater than 100 nM and B when 10-100 nM.

Example JAK 3 (IC50, uM) One B 2 B 3 A 4 B 5 C 6 B 7 B 8 B 9 B 10 B 11 C 12 B 13 B 14 B 15 A 16 C 17 A 18 C 19 B 20 C 21 C 22 C 23 C 24 C 25 C 26 A 27 A 28 C 29 C 30 A 31 B 32 C 33 C 34 C

JAK 1 (IC50, uM) JAK 2 (IC50, uM) JAK 3 (IC50, uM) TYK2 (IC50, uM) One C C B C 4 C C B C 15 C C A C 17 C C A C

Looking at Table 3, the compounds of the present invention, JAK 1, JAK 2, TYK2 compared to JAK 3 more significant inhibitory activity is confirmed, the present invention compounds can be seen that JAK 3 selective inhibitory compound.

In addition, looking at Table 2, it was confirmed that all the compounds according to the present invention exhibit excellent inhibitory activity against JAK 3.

Accordingly, the compound of the present invention may be provided as an active ingredient of a pharmaceutical composition for preventing or treating JAK 1, JAK 2, TYK2, or JAK 3 related diseases, and in particular, It can be provided as an active ingredient.

In addition, it can be seen that the compounds of the present invention are particularly JAK 3 selective inhibitors, which can solve the side effects problems of conventional non-selective inhibitors, problems of low efficacy, and the like, and can be provided as improved therapeutic drugs.

<Experiment 2> Evaluation of kinase inhibitory activity

The following experiment was performed to evaluate the inhibitory activity of the compound according to the present invention for more enzymes.

Specifically, among the example compounds of this nickname, the selected Example 1 was commissioned by DiscoverX to measure enzyme selectivity, and experiments were performed using a scanMAX ^TM Kinase analysis panel.

At this time, the concentration of the drug to be treated with enzyme was 1 uM in DMSO, the control percentage (% control) was determined in the same manner as in Formula 1, and the results are shown in Table 4 below.

[Equation 1]

(Example compound-positive control) / (negative control-positive control) × 100

Here, the positive control refers to a compound showing a control percentage of 0%, and the negative control shows a control percentage of 100% with DMSO. In addition, the enzyme selectivity of the present invention was determined to have activity for the enzyme if the percentage of regulation for each enzyme is <35% (i.e., less than 35%).

Example 1 Example 28 AAK1 100 57 ABL1 (E255K) -phosphorylated 75 60 ABL1 (F317I) -nonphosphorylated 66 100 ABL1 (F317I) -phosphorylated 100 100 ABL1 (F317L) -nonphosphorylated 63 100 ABL1 (F317L) -phosphorylated 95 100 ABL1 (H396P) -nonphosphorylated 20 28 ABL1 (H396P) -phosphorylated 87 65 ABL1 (M351T) -phosphorylated 84 79 ABL1 (Q252H) -nonphosphorylated 35 51 ABL1 (Q252H) -phosphorylated 77 61 ABL1 (T315I) -nonphosphorylated 83 96 ABL1 (T315I) -phosphorylated 70 100 ABL1 (Y253F) -phosphorylated 100 58 ABL1-nonphosphorylated 38 47 ABL1-phosphorylated 66 49 ABL2 80 88 ACVR1 94 100 ACVR1B 100 95 ACVR2A 98 89 ACVR2B 100 100 ACVRL1 100 100 ADCK3 99 100 ADCK4 94 100 AKT1 100 100 AKT2 98 100 AKT3 100 100 ALK 100 100 ALK (C1156Y) 77 97 ALK (L1196M) 100 100 AMPK-alpha1 100 65 AMPK-alpha2 95 73 ANKK1 100 100 ARK5 100 17 ASK1 100 100 ASK2 100 100 AURKA 95 44 AURKB 84 42 AURKC 99 76 AXL 97 100 BIKE 100 31 BLK 8.2 100 BMPR1A 100 90 BMPR1B 70 100 BMPR2 100 78 BMX 50 100 BRAF 51 92 BRAF (V600E) 33 82 BRK 98 100 BRSK1 99 100 BRSK2 95 100 BTK 30 100 BUB1 97 100 CAMK1 94 100 CAMK1B 100 89 CAMK1D 99 88 CAMK1G 100 100 CAMK2A 100 100 CAMK2B 100 100 CAMK2D 100 100 CAMK2G 98 100 CAMK4 100 100 CAMKK1 90 81 CAMKK2 95 86 CASK 100 77 CDC2L1 100 100 CDC2L2 97 100 CDC2L5 100 100 CDK11 93 100 CDK2 100 98 CDK3 78 78 CDK4 99 100 CDK4-cyclinD1 100 100 CDK4-cyclinD3 100 98 CDK5 100 100 CDK7 80 100 CDK8 85 99 CDK9 93 100 CDKL1 75 61 CDKL2 100 27 CDKL3 86 57 CDKL5 100 100 CHEK1 100 100 CHEK2 100 100 CIT 78 100 CLK1 94 98 CLK2 100 100 CLK3 97 100 CLK4 100 100 CSF1R 15 2.7 CSF1R-autoinhibited 0.2 1.6 CSK 96 100 CSNK1A1 100 100 CSNK1A1L 100 100 CSNK1D 100 97 CSNK1E 97 99 CSNK1G1 100 100 CSNK1G2 100 100 CSNK1G3 100 99 CSNK2A1 82 88 CSNK2A2 54 65 CTK 97 100 DAPK1 98 90 DAPK2 100 100 DAPK3 96 95 DCAMKL1 62 40 DCAMKL2 92 100 DCAMKL3 100 6.9 DDR1 93 80 DDR2 100 100 DLK 96 100 DMPK 100 95 DMPK2 100 100 DRAK1 100 96 DRAK2 100 45 DYRK1A 77 100 DYRK1B 95 93 DYRK2 54 100 EGFR 95 91 EGFR (E746-A750del) 88 100 EGFR (G719C) 95 96 EGFR (G719S) 100 87 EGFR (L747-E749del, A750P) 100 100 EGFR (L747-S752del, P753S) 100 98 EGFR (L747-T751del, Sins) 95 100 EGFR (L858R) 100 100 EGFR (L858R, T790M) 100 100 EGFR (L861Q) 89 100 EGFR (S752-I759del) 85 100 EGFR (T790M) 100 100 EIF2AK1 76 100 EPHA1 91 73 EPHA2 98 100 EPHA3 75 97 EPHA4 93 100 EPHA5 100 100 EPHA6 91 100 EPHA7 96 100 EPHA8 95 100 EPHB1 100 87 EPHB2 78 100 EPHB3 93 100 EPHB4 100 100 EPHB6 53 13 ERBB2 100 97 ERBB3 100 100 ERBB4 87 99 ERK1 100 100 ERK2 98 100 ERK3 100 100 ERK4 100 100 ERK5 100 100 ERK8 100 43 ERN1 100 95 FAK 74 92 FER 90 100 FES 86 96 FGFR1 96 97 FGFR2 98 100 FGFR3 100 100 FGFR3 (G697C) 96 100 FGFR4 85 100 FGR 100 100 FLT1 98 64 FLT3 79 9.9 FLT3 (D835H) 100 20 FLT3 (D835V) 2.8 1.1 FLT3 (D835Y) 70 16 FLT3 (ITD) 100 82 FLT3 (ITD, D835V) 100 8.3 FLT3 (ITD, F691L) 94 7.4 FLT3 (K663Q) 71 13 FLT3 (N841I) 66 4.6 FLT3 (R834Q) 92 80 FLT3-autoinhibited 100 99 FLT4 100 83 FRK 86 100 FYN 67 100 GAK 82 75 GCN2 (Kin.Dom.2, S808G) 86 100 GRK1 59 61 GRK2 100 100 GRK3 68 100 GRK4 100 79 GRK7 88 100 GSK3A 100 65 GSK3B 97 100 HASPIN 100 100 HCK 100 100 HIPK1 74 53 HIPK2 100 100 HIPK3 100 100 HIPK4 100 100 HPK1 100 100 HUNK 100 100 ICK 100 92 IGF1R 97 92 IKK-alpha 90 63 IKK-beta 95 71 IKK-epsilon 81 100 INSR 100 100 INSRR 100 94 IRAK1 83 19 IRAK3 100 50 IRAK4 99 61 ITK 98 100 JAK1 (JH1domain-catalytic) 100 100 JAK1 (JH2domain-pseudokinase) 49 47 JAK2 (JH1domain-catalytic) 90 35 JAK3 (JH1domain-catalytic) 0 0 JNK1 62 93 JNK2 60 100 JNK3 74 100 KIT 24 20 KIT (A829P) 100 40 KIT (D816H) 98 96 KIT (D816V) 88 55 KIT (L576P) 40 4.2 KIT (V559D) 23 13 KIT (V559D, T670I) 94 73 KIT (V559D, V654A) 64 100 KIT-autoinhibited 77 6 LATS1 100 100 LATS2 100 100 LCK 77 65 LIMK1 68 100 LIMK2 100 100 LKB1 80 81 LOK 100 100 LRRK2 94 100 LRRK2 (G2019S) 100 100 LTK 100 100 LYN 82 100 LZK 100 100 MAK 100 100 MAP3K1 100 100 MAP3K15 99 88 MAP3K2 80 100 MAP3K3 100 99 MAP3K4 100 100 MAP4K2 100 100 MAP4K3 95 94 MAP4K4 100 95 MAP4K5 100 99 MAPKAPK2 100 100 MAPKAPK5 100 100 MARK1 96 74 MARK2 100 82 MARK3 58 17 MARK4 93 86 MAST1 95 100 MEK1 96 92 MEK2 66 56 MEK3 86 68 MEK4 100 100 MEK5 66 84 MEK6 100 100 MELK 92 92 MERTK 100 100 MET 85 96 MET (M1250T) 100 100 MET (Y1235D) 92 95 MINK 95 62 MKK7 92 100 MKNK1 93 100 MKNK2 96 100 MLCK 77 91 MLK1 100 82 MLK2 100 100 MLK3 91 96 MRCKA 100 100 MRCKB 100 100 MST1 100 100 MST1R 88 100 MST2 100 98 MST3 100 100 MST4 100 100 MTOR 74 100 MUSK 95 78 MYLK 99 100 MYLK2 100 83 MYLK4 100 100 MYO3A 100 100 MYO3B 80 100 NDR1 96 43 NDR2 54 100 NEK1 100 100 NEK10 99 100 NEK11 95 100 NEK2 100 100 NEK3 57 69 NEK4 100 100 NEK5 98 96 NEK6 85 100 NEK7 90 71 NEK9 94 89 NIK 97 100 NIM1 95 100 NLK 82 88 OSR1 100 100 p38-alpha 74 100 p38-beta 100 90 p38-delta 100 100 p38-gamma 89 84 PAK1 81 100 PAK2 97 100 PAK3 100 100 PAK4 97 100 PAK6 100 100 PAK7 95 96 PCTK1 100 97 PCTK2 100 83 PCTK3 99 100 PDGFRA 100 100 PDGFRB 67 8.3 PDPK1 92 57 PFCDPK1 (P.falciparum) 100 97 PFPK5 (P.falciparum) 100 100 PFTAIRE2 92 98 PFTK1 100 100 PHKG1 62 95 PHKG2 100 100 PIK3C2B 90 100 PIK3C2G 100 100 PIK3CA 100 100 PIK3CA (C420R) 100 91 PIK3CA (E542K) 83 97 PIK3CA (E545A) 88 48 PIK3CA (E545K) 72 43 PIK3CA (H1047L) 100 97 PIK3CA (H1047Y) 100 100 PIK3CA (I800L) 63 98 PIK3CA (M1043I) 100 100 PIK3CA (Q546K) 100 100 PIK3CB 100 100 PIK3CD 96 88 PIK3CG 66 72 PIK4CB 100 100 PIKFYVE 83 95 PIM1 100 86 PIM2 76 100 PIM3 100 100 PIP5K1A 100 68 PIP5K1C 100 95 PIP5K2B 100 100 PIP5K2C 24 48 PKAC-alpha 100 100 PKAC-beta 100 100 PKMYT1 82 100 PKN1 98 97 PKN2 100 72 PKNB (M.tuberculosis) 92 81 PLK1 85 100 PLK2 100 100 PLK3 76 71 PLK4 70 100 PRKCD 100 97 PRKCE 74 97 PRKCH 100 100 PRKCI 74 100 PRKCQ 75 100 PRKD1 100 100 PRKD2 100 90 PRKD3 100 100 PRKG1 100 100 PRKG2 100 100 PRKR 100 75 PRKX 100 95 PRP4 100 43 PYK2 100 93 QSK 85 95 RAF1 96 100 RET 100 98 RET (M918T) 100 94 RET (V804L) 100 88 RET (V804M) 93 100 RIOK1 100 57 RIOK2 100 100 RIOK3 100 89 RIPK1 100 100 RIPK2 83 100 RIPK4 100 100 RIPK5 96 100 ROCK1 100 100 ROCK2 100 100 ROS1 93 83 RPS6KA4 (Kin.Dom.1-N-terminal) 100 100 RPS6KA4 (Kin.Dom.2-C-terminal) 100 44 RPS6KA5 (Kin.Dom.1-N-terminal) 93 100 RPS6KA5 (Kin.Dom.2-C-terminal) 100 92 RSK1 (Kin.Dom.1-N-terminal) 100 100 RSK1 (Kin.Dom.2-C-terminal) 94 92 RSK2 (Kin.Dom.1-N-terminal) 81 71 RSK2 (Kin.Dom.2-C-terminal) 100 100 RSK3 (Kin.Dom.1-N-terminal) 91 100 RSK3 (Kin.Dom.2-C-terminal) 96 87 RSK4 (Kin.Dom.1-N-terminal) 100 100 RSK4 (Kin.Dom.2-C-terminal) 86 83 S6K1 95 88 SBK1 100 100 SGK 97 68 SgK110 62 63 SGK2 100 89 SGK3 100 100 SIK 97 100 SIK2 89 80 SLK 92 70 SNARK 100 33 SNRK 85 100 SRC 79 92 SRMS 86 100 SRPK1 100 57 SRPK2 77 100 SRPK3 100 77 STK16 11 3.6 STK33 92 100 STK35 100 100 STK36 86 100 STK39 93 100 SYK 100 100 TAK1 94 100 TAOK1 100 93 TAOK2 67 58 TAOK3 100 89 TBK1 84 40 TEC 46 100 TESK1 100 100 TGFBR1 100 100 TGFBR2 81 91 TIE1 84 79 TIE2 100 88 TLK1 100 90 TLK2 100 100 TNIK 88 85 TNK1 91 100 TNK2 98 100 TNNI3K 91 100 TRKA 75 29 TRKB 98 76 TRKC 99 94 TRPM6 100 100 TSSK1B 100 100 TSSK3 94 100 TTK 100 37 TXK 3.8 95 TYK2 (JH1domain-catalytic) 100 80 TYK2 (JH2domain-pseudokinase) 100 71 TYRO3 95 100 ULK1 85 100 ULK2 89 92 ULK3 80 94 VEGFR2 78 78 VPS34 100 100 VRK2 88 100 WEE1 74 81 WEE2 98 100 WNK1 100 61 WNK2 100 100 WNK3 97 65 WNK4 100 100 YANK1 98 100 YANK2 94 100 YANK3 100 100 YES 99 100 YSK1 94 100 YSK4 92 18 ZAK 87 100 ZAP70 100 100

Looking at Table 4, the compounds according to the present invention are ABL1 (H396P) -nonphosphorylated, ARK5, BIKE, BTK, BRAF (V600E), CDK2, CSF1R, CSF1R-autoinhibited, FLT3 (D835V), EPHB6, FLT3, FLT3 (D835H) , FLT3 (D835V), FLT3 (D835Y), FLT3 (ITD, D835V), FLT3 (ITD, F691L), FLT3 (K663Q), FLT3 (N841I), IRAK1, JAK3 (JH1domain-catalytic), KIT, KIT (L576P, It can be seen that KIT (V559D), KIT-autoinhibited, MARK3, PDGFRB, PIP5K2C, SNARK, STK16, TRKA, TXK and YSK4 kinase have a value smaller than the control percentage of 35%.

Therefore, ABL1 (H396P) -nonphosphorylated, ARK5, BIKE, BTK, BRAF (V600E), CDK2, CSF1R, CSF1R-autoinhibited, FLT3 (D835V), EPHB6, FLT3, FLT3 containing the compound according to the present invention as an active ingredient (D835H), FLT3 (D835V), FLT3 (D835Y), FLT3 (ITD, D835V), FLT3 (ITD, F691L), FLT3 (K663Q), FLT3 (N841I), IRAK1, JAK3 (JH1domain-catalytic), KIT, KIT (L576P, KIT (V559D), KIT-autoinhibited, MARK3, PDGFRB, PIP5K2C, SNARK, STK16, TRKA, TXK or YSK4 kinase-related diseases for preventing or treating pharmaceutical compositions may be provided.

<Experimental Example 3> Ba / F3 cell activity evaluation

CCK analysis was performed in BaF3 (JAK 1, JAK 2, JAK 3, TYK2) cell lines to evaluate the kinase inhibitory effect of the example compounds according to the present invention.

More specifically, BaF3 (JAK 1, JAK 2, JAK 3, TYK2) (abm) is a 96-well plate 1 Х 10 ^4/90 μl / well after planted so that, triplicate serial dilutions of nine concentrations (0.015 -100 μM) of the compound and DMSO control were added to each culture solution at 10 μl / well so that the final concentration was 0-10 μM, followed by incubation in a 37 ° C. CO ₂ incubator for 72 hours. After 72 hours, the plate treated with the compound is taken out, and the Cell Counting Kit-8 (Dojindo Molecular Technologies, Inc) solution is treated with 10 μl / well, and then mixed well. Incubate for 2 hours in a 37 ° C. CO ₂ incubator to measure absorbance at 450 nm with a microplate reader. Data were expressed as a percentage in proportion to vehicle-treated cells, and GI ₅₀ values were calculated using GraphPad Prism 5.0 (GraphPad software Inc., San Diego), and the results are shown in Table 5.

In Table 5, A is 0.5 μM or less, B is more than 0.5 μM to 5 μM, and C shows more than 5 μM to 100 μM or less.

Example Ba / F3-JAK3
(IC ₅₀ , uM) One C 2 C 3 C 4 B 5 C 6 C 7 C 8 C 9 C 10 C 11 C 12 C 13 C 14 C 15 A 16 C 17 C 18 C 19 C 20 B 21 C 22 C 23 C 24 B 25 C 26 A 27 A 28 C 29 C 30 A 31 B

Looking at Table 4, the compounds of the present invention can confirm excellent inhibitory activity even in the Ba / F3 cell line, in particular, more significant inhibitory activity in JAK 3 is confirmed.

Therefore, it can be seen that the compound of the present invention is a JAK 3 selective inhibitor, and can solve the side effect problem, low drug efficacy, etc. of the conventional non-selective inhibitor, and thus can be provided as an improved therapeutic drug.

<Experimental Example 4> Evaluation of HT-2 cell proliferation inhibitory effect

5 μg / ml of human fibronectin was placed in a 96 well plate at 100 μl / well and coated at 37 ° C. for 2 hours. 200U (5 x 10 ⁵ U / ml) interleukin-2 (IL-2) and 1.5 million HT-2 cells (mouse IL-2 dependent lymphocyte T) in 200 μl of RPMI + 10% FBS (Fetal Bovine Serum) medium Cell line), 0.08-10 uM of Janus kinase-3 (Janus kinase 3; JAK 3) target small molecule inhibitor was mixed and dispensed into fibronectin coated wells. This was observed in real time for cell proliferation for 72 hours with an Incucyte incubator (Incucyte S3) to calculate GI ₅₀ values, and the results are shown in Table 6.

In Table 6, A is 0.1 μM or less, B is greater than 0.1 μM to 1 μM or less, and C indicates more than 1 μM to 100 μM or less.

Example HT-2 (GI ₅₀ , uM) 26 A 27 B 28 C 29 C 30 B 31 C

Claims (11)

A compound represented by Formula 1 below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In the formula 1,
X is halogen, -S-CH ₃ ,-(S = O) -CH ₃ , or -NR ¹ R ² ,
Wherein R ¹ and R ² are each independently H, C ₁ -C ₁₀ alkyl of a straight chain or branched chain unsubstituted or substituted with one or more halogens, C of C ₁ -C ₁₀ alkyl substituted or unsubstituted by one or more halogens, or C _{1 to} C ₁₀ alkoxy, substituted or unsubstituted C _3-10 cycloalkyl, 3 to 10 membered substituted or unsubstituted, including one or more hetero atoms selected from the group consisting of (N, O, and S) Heterocycloalkyl), a substituted or unsubstituted C _6-10 aryl, or a 5-10 membered substituted or unsubstituted hetero containing one or more hetero atoms selected from the group consisting of (N, O, and S) Aryl),
Here again, the substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and substituted heteroaryl, each substituted or unsubstituted C ₁ -C ₁₀ alkyl of a straight or branched chain, substituted or unsubstituted straight chain Or a branched chain C ₁ -C ₁₀ alkoxy, hydroxy, nitro, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted C _3-10 cycloalkyl, (N, O, and S 3 to 10 membered substituted or unsubstituted heterocycloalkyl containing at least one hetero atom selected from the group consisting of), substituted or unsubstituted C _6-10 aryl, and (N, O, and S) Substituted with one or more substituents selected from the group consisting of 5- to 10-membered substituted or unsubstituted heteroaryl) containing at least one hetero atom selected from the group,
Here again, the substituted alkyl, substituted alkoxy, substituted amino, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and substituted heteroaryl, respectively, are straight or branched C ₁ -C ₃ Alkyl, straight or branched C ₁ -C ₃ alkoxy, hydroxy, nitro, cyano, halogen, amino unsubstituted or substituted with one or more methyl, substituted or unsubstituted C _3-6 cycloalkyl, ( 3 to 6 membered substituted or unsubstituted heterocycloalkyl containing at least one hetero atom selected from the group consisting of N, O, and S), substituted or unsubstituted phenyl, and (N, O, and S Is substituted with one or more substituents selected from the group consisting of 5 to 6 membered substituted or unsubstituted heteroaryl) containing at least one hetero atom selected from the group consisting of,
Here again, the substituted cycloalkyl, the substituted heterocycloalkyl, the substituted phenyl, and the substituted heteroaryl are straight or branched C ₁ -C ₃ alkyl, straight or branched C ₁ -C ₃ alkoxy, respectively. , And one or more substituents selected from the group consisting of halogen;

Y is H, substituted or unsubstituted C ₁ -C ₃ alkyl of straight or branched chain, substituted or unsubstituted C _3-10 cycloalkyl, (N, O, and one or more selected from the group consisting of S) 3 to 10 membered substituted or unsubstituted heterocycloalkyl containing a hetero atom), substituted or unsubstituted C _6-10 aryl, (N, O, and one or more hetero atoms selected from the group consisting of S) 5 to 10 membered substituted or unsubstituted heteroaryl), substituted or unsubstituted C _6-10 aryl-C ₁ -C ₃ alkyl, or (N, O, and S) 5 to 10 membered substituted or unsubstituted heteroaryl) -C ₁ -C ₃ alkyl containing one or more hetero atoms,
Here, the substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-alkyl, and substituted heteroaryl-alkyl are hydroxy, nitro, and cyano, respectively. , Halogen, amino, and one or more substituents selected from the group consisting of R ³ ,
Here again, R ³ is nitro, -NR ⁴ R ⁵ , or -NR ^4- (C = O) -R ⁵ ,
Wherein R ⁴ and R ⁵ are each independently H, straight or branched C ₁ -C ₅ alkyl, straight or branched C ₁ -C ₅ alkoxy, straight or branched C ₂ having one or more unsaturated bonds _-10 alkyl,
Here, the unsaturated bond is a double bond or a triple bond; And

Z is H, straight or branched C ₁ -C ₃ alkyl, straight or branched C ₁ -C ₃ alkoxy, halogen, nitro, or cyano).
According to claim 1,
X is -S-CH ₃ ,-(S = O) -CH ₃ , or -NR ¹ R ² ,
Wherein R ¹ and R ² are each independently H, C ₁ -C ₁₀ alkyl of a straight chain or branched chain unsubstituted or substituted with one or more halogens, C of C ₁ -C ₁₀ alkyl substituted or unsubstituted by one or more halogens, or C _{1 to} C ₁₀ alkoxy, substituted or unsubstituted C _3-6 cycloalkyl, 3 to 6 membered substituted or unsubstituted including at least one hetero atom selected from the group consisting of (N, O, and S) Heterocycloalkyl), substituted or unsubstituted phenyl, or (5-6 membered substituted or unsubstituted heteroaryl containing at least one hetero atom selected from the group consisting of N, O, and S),
Here again, the substituted cycloalkyl, substituted heterocycloalkyl, substituted phenyl, and substituted heteroaryl are each a substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted straight chain Or a branched chain C ₁ -C ₁₀ alkoxy, hydroxy, nitro, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted C _3-6 cycloalkyl, (N, O, and S 3-6 membered substituted or unsubstituted heterocycloalkyl containing one or more hetero atoms selected from the group consisting of, substituted or unsubstituted phenyl, and 1 selected from the group consisting of (N, O, and S) Substituted with one or more substituents selected from the group consisting of 5- to 6-membered substituted or unsubstituted heteroaryl) containing at least a hetero atom,
Here again, the substituted alkyl, substituted alkoxy, substituted amino, substituted cycloalkyl, substituted heterocycloalkyl, substituted phenyl, and substituted heteroaryl, respectively, are straight or branched C ₁ -C ₃ Alkyl, straight or branched C ₁ -C ₃ alkoxy, hydroxy, nitro, cyano, halogen, amino unsubstituted or substituted with one or more methyl, substituted or unsubstituted C _3-6 cycloalkyl, ( 3 to 6 membered substituted or unsubstituted heterocycloalkyl containing at least one hetero atom selected from the group consisting of N, O, and S), substituted or unsubstituted phenyl, and (N, O, and S Is substituted with one or more substituents selected from the group consisting of 5 to 6 membered substituted or unsubstituted heteroaryl) containing at least one hetero atom selected from the group consisting of,
Here again, the substituted cycloalkyl, the substituted heterocycloalkyl, the substituted phenyl, and the substituted heteroaryl are straight or branched C ₁ -C ₃ alkyl, straight or branched C ₁ -C ₃ alkoxy, respectively. And, characterized in that it is substituted with one or more substituents selected from the group consisting of halogen,
A compound, stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
Y is a substituted or unsubstituted C _3-6 cycloalkyl, (a 3 to 6 membered substituted or unsubstituted heterocycloalkyl containing at least one hetero atom selected from the group consisting of N, O, and S) , Substituted or unsubstituted phenyl, (5-6 membered substituted or unsubstituted heteroaryl containing at least one hetero atom selected from the group consisting of N, O, and S), substituted or unsubstituted phenyl- C ₁ -C ₃ alkyl, or (5-6 membered substituted or unsubstituted heteroaryl containing one or more hetero atoms selected from the group consisting of N, O, and S) -C ₁ -C ₃ alkyl ,
Here, the substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted phenyl, substituted heteroaryl, substituted phenyl-alkyl, and substituted heteroaryl-alkyl are each -NR ^4- (C = O) -R ⁵ ,
Wherein R ⁴ is H, or straight or branched C ₁ -C ₅ alkyl,
R ⁵ is a straight or branched C _2-4 alkyl having one or more double bonds,
A compound, stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
X is -S-CH ₃ ,-(S = O) -CH ₃ ,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, or

ego; And

Y is,

, or

Characterized in that,
A compound, stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
The compound represented by Formula 1 is any one compound selected from the following group of compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:
(1) N- (3-((6-cyano-2-((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2,3 -d] pyrimidin-8- (7H) yl) methyl) phenyl) acrylamide;
(2) N- (3-((6-cyano-2- (1- (3- (dimethylamino) -2-hydroxypropyl) -1H-pyrazol-4ylamino) -7-oxopyrido [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide;
(3) N- (3-((2-((5-chloro-1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) -6-cyano-7-oxopyrido [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide;
(4) N- (3-((6-cyano-7-oxo-2-((1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-yl) amino) pyri Do [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide;
(5) N- (3-((6-cyano-2-((1- (3-methyloxetan-3-yl) methyl) -1H-pyrazol-4-yl) amino) -7-oxo Pyrido [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide;
(6) N- (3-((6-cyano-2-((1- (oxetan-3-yl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2, 3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide;
(7) N- (3-((6-cyano-2-((1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2 , 3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide;
(8) N- (3-((6-cyano-2-((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide;
(9) N- (3-((2-((1- (azetidin-3-yl) -1H-pyrazol-4-yl) amino) -6-cyano-7-oxopyrido [2, 3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide;
(10) N- (3-((6-cyano-7-oxo-2-((1- (piperidin-3-ylmethyl) -1H-pyrazol-4-yl) amino) pyrido [ 2,3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide;
(11) N- (3-((6-cyano-7-oxo-2-((1- (tetrahydrofuran-3-yl) -1H-pyrazol-4-yl) amino) pyrido [2 , 3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide;
(12) N- (3-((6-cyano-2- (1- (morpholin-2-ylmethyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2, 3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide;
(13) N- (3-((6-cyano-2- (1- (2-hydroxypropyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2,3- d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide;
(14) N- (3-((6-cyano-2- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2,3- d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide;
(15) N- (3-((6-cyano-2- (4- (4-methylpiperazin-1-yl) phenylamino) -7-oxopyrido [2,3-d] pyrimidine- 8 (7H) -yl) methyl) phenyl) acrylamide;
(16) N- (3-((6-cyano-2- (2- (2-cyanopropan-2-yl) -4-methylthiazol-5-ylamino) -7-oxopyrido [ 2,3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide;
(17) N- (3-((6-cyano-7-oxo-2-((1- (piperidin-4-yl) -1H-pyrazol-4-yl) amino) pyrido [2 , 3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide;
(18) N- (3-((6-cyano-2-((1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide;
(19) N- (3-((6-cyano-7-oxo-2-((1- (pyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) pyrido [2 , 3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide;
(20) N- (3-((6-cyano-7-oxo-2-((4- (2,2,2-trifluoroethyl) phenyl) amino) pyrido [2,3-d] Pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide;
(21) N- (3-((6-cyano-7-oxo-2-((4- (trifluoromethyl) phenyl) amino) pyrido [2,3-d] pyrimidine-8 (7H ) -Yl) methyl) phenyl) acrylamide;
(22) N- (3-((6-cyano-7-oxo-2-((1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazol-4-yl) amino) pyri Do [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) acrylamide;
(23) (R) -8- (1-acryloylpyrrolidin-3-yl) -2- (1- (2-methoxyethyl) -1H-pyrazol-4-ylamino) -7-oxo -7,8-dihydropyrido [2,3-d] pyrimidine-6-carbonitrile;
(24) (S) -8- (1-acryloylpyrrolidin-3-yl) -2- (1- (2-methoxyethyl) -1H-pyrazol-4-ylamino) -7-oxo -7,8-dihydropyrido [2,3-d] pyrimidine-6-carbonitrile;
(25) (R) -8- (1-acryloylpyrrolidin-3-yl) -2- (2-methoxy-4- (4-methylpiperazin-1-yl) phenylamino) -7- Oxo-7,8-dihydropyrido [2,3-d] pyrimidine-6-carbonitrile;
(26) N- (3-((2- (4- (4-methylpiperazin-1-yl) phenylamino) -7-oxopyrido [2,3-d] pyrimidine-8 (7H)- 1) methyl) phenyl) acrylamide;
(27) N- (3-((2- (1- (Oxetan-3-yl) -1H-pyrazol-4-ylamino) -7-oxopyrido [2,3-d] pyrimidine- 8 (7H) -yl) methyl) phenyl) acrylamide;
(28) N- (3-((2- (1- (2-methoxyethyl) -1H-pyrazol-4-ylamino) -7-oxopyrido [2,3-d] pyrimidine-8 (7H) -yl) methyl) phenyl) acrylamide;
(29) N- (3-((2- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-ylamino) -7-oxopyrido [2,3-d] pyrimidine -8 (7H) -yyl) methyl) phenyl) acrylamide;
(30) N- (3-((2- (2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2,3-d] pyrimidine -8 (7H) -yl) methyl) phenyl) acrylamide;
(31) N- (3-((2- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) -7-oxopyrido [2,3-d] pyrimidine- 8 (7H) -yl) methyl) phenyl) acrylamide;
(32) (R) -8- (1-acryloylpyrrolidin-3-yl) -2-((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one;
(33) (S) -8- (1-acryloylpyrrolidin-3-yl) -2-((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrido [2,3-d] pyrimidin-7 (8H) -one; And
(34) (R) -8- (1-acryloylpyrrolidin-3-yl) -2-((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyri Figure [2,3-d] pyrimidin-7 (8H) -one.
As shown in Scheme 1 below,
Reacting the compound represented by Formula 5 with the compound represented by Formula 4 to prepare a compound represented by Formula 3 (step 1);
Preparing a compound represented by Formula 2 from the compound represented by Formula 3 prepared in Step 1 (Step 2);
Preparing a compound represented by Formula 1 from the compound represented by Formula 2 prepared in Step 2 (Step 3); Method for producing a compound represented by Formula 1 of claim 1 comprising:
[Scheme 1]

(In Scheme 1 above,
X, Y, and Z are as defined in Formula 1 of claim 1;
X 'is X or X substituted with Boc;
V is -S-CH ₃ , or-(S = O) -CH ₃ ;
W is NHBoc or NO ₂ ; And
W 'is NH ₂ ).
ABL1 (H396P) -nonphosphorylated, ARK5, BIKE, BTK, BRAF (V600E), CDK2, CSF1R containing the compound represented by Formula 1 of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient , CSF1R-autoinhibited, FLT3 (D835V), EPHB6, FLT3, FLT3 (D835H), FLT3 (D835V), FLT3 (D835Y), FLT3 (ITD, D835V), FLT3 (ITD, F691L), FLT3 (K663Q), FLT3 (K663Q) N841I), IRAK1, JAK 1, JAK 2, JAK (JH1domain-catalytic) 3, TYK2, KIT, KIT (L576P, KIT (V559D), KIT-autoinhibited, MARK3, PDGFRB, PIP5K2C, SNARK, STK16, TRKA, TXK or YSK4 kinase-related pharmaceutical composition for the prevention or treatment of diseases.
The method of claim 7,
The pharmaceutical composition is a pharmaceutical composition for the prevention or treatment of JAK 3 kinase related diseases.
The method of claim 8,
The JAK 3 kinase related diseases include complex immunodeficiency (SCID), rheumatoid arthritis, myelofibrosis, psoriasis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, allergic disease, chronic obstructive pulmonary disease, asthma, leukemia or A pharmaceutical composition characterized in that it is a lymphoma.
A pharmaceutical composition for the prevention or treatment of cancer, comprising the compound represented by Formula 1 of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
The method of claim 10,
The cancer is pseudoplastic myxoma, intrahepatic biliary cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, cleft lip cancer, mycosis sarcoma, acute myelogenous leukemia, acute lymphocytic leukemia, basal cell cancer , Ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse giant B cell lymphoma, Barter Swelling cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, non sinus cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, snow cancer, astrocytoma, small cell lung cancer, childhood brain cancer, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, Glioma, neuroblastoma, renal cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, Unknown foot cancer, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms' cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, chorionic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, Metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, auditory edema, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, Skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, and characterized in that at least one member selected from the group consisting of thymic cancer, pharmaceutical composition.