KR102328435B1 - 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 preparing the same, and a pharmaceutical composition for preventing or treating a protein kinase-related disease containing the same as an active ingredient, the compound represented by Formula 1 according to the present invention, a three-dimensional thereof Isomers, or pharmaceutically acceptable salts thereof, have excellent inhibitory activity against JAK kinase (Janus kinase), and in particular, excellent inhibitory activity against JAK 3 kinase, JAK kinase (Janus kinase) containing it as an active ingredient ) related diseases, in particular JAK 3 kinase related diseases such as combined immunodeficiency (SCID), rheumatoid arthritis, myelofibrosis, psoriasis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, allergic disease, chronic obstructive There is a useful effect that a pharmaceutical composition for the prevention or treatment of lung disease, asthma, leukemia or lymphoma, or a functional health food composition for prevention or improvement can be provided.

Description

Novel pyrido-pyrimidine derivatives, a method for preparing the same, and a pharmaceutical composition for preventing or treating protein kinase-related diseases containing the same as an active ingredient TECHNICAL FIELD [0002] 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 preventing or treating protein kinase-related diseases containing the same as an active ingredient.

In 2002, Manning et al. revealed that 218 of 518 protein kinase genes in the human kinome are closely related to the development and development of human diseases, and drugs obtained to date include enzymes targeting There are 20% of pharmaceuticals that do this, and in particular, drugs that target protein kinases are of special value in clinical use.

Protein kinases catalyze the phosphorylation of specific proteins and include 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). The phosphorylation/dephosphorylation process of protein kinases can regulate several biological processes in various cells such as metabolism, cell differentiation, cell survival, apoptosis, organogenesis, angiogenesis and immune response.

JAK kinases (Janus kinases abbreviated as JAK, comprising four known members of JAK 3, JAK 1, TYK2 and JAK 2) are a small family of intracytoplasmic non-receptor tyrosine protein kinase superfamily. JAK 3 is distributed in the bone marrow and lymphatic system, whereas JAK 1, TYK2 and JAK 2 are widely distributed in many tissue cells. When JAK binds to cytokine receptors on the cell surface, receptor-bound JAK is activated, which results in receptor phosphorylation and recruitment to STAT proteins (STAT1-4, STAT5a, STAT5b and STAT6), which are cytoplasmic signal transducers and transcriptional activators. (recruiting) Provides a reaction site, that is, a JAK phosphorylated STAT protein. After dimerization, the JAK phosphorylated STAT protein is delivered to the nucleus to regulate gene expression. This pathway is called the JAK/STAT signaling pathway.

The JAK/STAT signaling pathway is a signaling pathway stimulated by multiple cytokine and growth factor receptors. These factors include interleukins (IL-2-7, IL-9, IL-10, IL-15, and IL-21), interferons (IFN-α, IFN-β, and IFN-γ), erythropoietin (EPO), Includes 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).

Different subtypes of JAK kinases can be activated by different receptors to achieve distinct biological functions.

JAK 1 can bind to IL-10, IL-19, IL-20, IL-22, IL-26, IL-28, IFN-α, IFN-γ, IL-6 and other γc-containing receptors of the gp130 family. (Rodig S J., et al. 1998, Cell, 93: 373-383). Knock-off experiments of the JAK 1 gene in a mouse model showed that this enzyme plays 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 include 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 It can be used for the treatment/prevention of diseases including, but not limited to, immunoassociation syndrome, Behcet's disease (Hou S., et al. 2013, Hum. Genet., 132:1049-1058).

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; . In a mouse model, JAK 2 gene knock-off can result in death of anemic animals (Schindler C. et al. 2007, J. Biol. Chem., 282: 20059-20063); On the other hand, in humans, the nucleotide mutation JAK 2V617F of the JAK 2 gene is associated with myeloproliferative diseases including polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF) and chronic myelogenous leukemia (CML). It is closely associated with pathogenesis (Ghoreschi K., et al. 2009, Immunol. Rev., 228: 273-287). Therefore, JAK 2 has been a precise target for the treatment/prevention of these diseases.

On the other hand, JAK 3 regulates cell signaling by binding to the gamma consensus 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 lead to severe combined immunodeficiency (SCID) (Villa A., et al. 1996, Blood, 88:817-823). Abnormal activity of JAK 3 appears as a significant decrease in T-cells and NK cells and loss of function of B-cells, which greatly affect the normal biological function of the immune system and the like. JAK 3 has been a promising pharmaceutical target for immune system-related diseases, depending on its functional properties and specific tissue distribution, and therefore 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 diseases, 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 a 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 result in a deficiency in signaling pathways of many cytokine receptors, which can lead to further viral infections and lower antibiotic immune function, increasing the likelihood of lung infections (Kisseleva). T., et al. 2002, Gene, 285: 1-24). In addition, a study by Larner A.C. demonstrated that TYK2 helps to inhibit the growth and metastasis of breast cancer (Zhang Q., et al. 2011, J. Interferon Cytokine Res., 31:671-677); In addition, it was recently reported that TYK2 can protect or reverse the organism from obesity by promoting the regulation of obesity by differentiation of brown adipose tissue (BAT) in mice and humans (Derecka M., et al., 2012, Cell). Metab., 16:814-824). This will provide new opportunities for obese patients suffering from cancer.

In November 2012, Pfizer's pan-JAK inhibitor Xeljanz (tofacitinib) was approved by the FDA for the treatment of rheumatoid arthritis. In October 2013, data from a phase 3 clinical trial of Xeljanz for the treatment of psoriasis were published by the company. Compared with the double-blind trial of Enbrel (etanelcept), this drug met the requirements of a non-inferiority trial. However, Xeljanz has several side effects. For example, the amount of red 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, the study and discovery of selective JAK inhibitors may be highly demanded, and currently selective JAK 3 inhibitor VX-509 is used in the treatment of immune system-related diseases such as rheumatoid arthritis, Crohn's disease, psoriasis and myelofibrosis in several impression steps. , a selective JAK 1 inhibitor GLPG0634 (Feist E., et al. 2013, Rheumatology, 52:1352-1357), etc., have been suggested. In addition, attempts have been made to develop a selective JAK inhibitor. Since no drug has been proposed, continuous research and development of selective JAK inhibitors is required.

Accordingly, the present inventors not only confirmed the JAK inhibitory effect while trying to present a novel therapeutic agent through the JAK inhibitory mechanism, but also confirmed that the compound of the present invention can be used as a selective JAK inhibitor, and in particular, the selectivity for JAK 3 Thus, JAK related diseases, particularly JAK 3 related diseases such as combined immunodeficiency (SCID), rheumatoid arthritis, myelofibrosis, psoriasis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes mellitus, allergic diseases, chronic The present invention has been completed by finding that it can 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

It is an object of the present invention to provide novel JAK inhibitory compounds.

Another object of the present invention is to provide in particular 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 preventing or treating JAK kinase (Janus kinase) related diseases.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating, in particular, a JAK 3 kinase-related disease.

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

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

In order to achieve the above object,

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

[Formula 1]

(In Formula 1,

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

Here, R ¹ and R ² are each independently H, straight-chain or branched C ₁ -C ₁₀ alkyl unsubstituted or substituted with one or more halogen, straight-chain or branched C 1 -C 10 alkyl substituted or unsubstituted with one or more halogen ₁ -C ₁₀ alkoxy, substituted or unsubstituted C _3-10 cycloalkyl, (N, O, and S 3 to 10 membered substituted or unsubstituted containing one or more heteroatoms selected from the group consisting of heterocycloalkyl), substituted or unsubstituted C _6-10 aryl, or (N, O, and S 5 to 10 membered substituted or unsubstituted hetero atom containing at least one hetero atom selected from the group consisting of aryl),

Again, wherein said substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and substituted heteroaryl are, respectively, substituted or unsubstituted straight or branched C ₁ -C ₁₀ alkyl, substituted or unsubstituted straight chain or branched C ₁ -C ₁₀ alkoxy, hydroxy, nitro, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted C _3-10 cycloalkyl, (with N, O, and S the consisting of 3 to 10 members comprising one or more heteroatoms selected from the group a substituted or unsubstituted heterocycloalkyl), optionally substituted aryl, or unsubstituted C _6-10, and (consisting of 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 one or more heteroatoms selected from the group,

Again wherein said substituted alkyl, substituted alkoxy, substituted amino, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and substituted heteroaryl are each straight or branched C ₁ -C ₃ Alkyl, straight-chain or branched C ₁ -C ₃ alkoxy, hydroxy, nitro, cyano, halogen, amino substituted or unsubstituted with one or more methyl, substituted or unsubstituted C _3-6 cycloalkyl, ( 3 to 6 membered substituted or unsubstituted heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S), substituted or unsubstituted phenyl, and (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 one or more heteroatoms selected from the group consisting of

Again, wherein said substituted cycloalkyl, substituted heterocycloalkyl, substituted phenyl, and substituted heteroaryl are, respectively, straight or branched C ₁ -C ₃ alkyl, straight or branched C ₁ -C ₃ alkoxy , and substituted with one or more substituents selected from the group consisting of halogen;

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

wherein said substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-alkyl, and substituted heteroaryl-alkyl are each hydroxy, nitro, cyano , halogen, amino, and R ³ is substituted with one or more substituents selected from the group consisting of,

Again, wherein R ³ is nitro, —NR ⁴ R ⁵ , or —NR ⁴ —(C=O)—R ⁵ ,

Here, 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} is an alkyl,

wherein 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).

Also, the present invention

As shown in Scheme 1 below,

reacting a compound represented by Formula 5 with a 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 preparing the compound represented by the formula (1) of claim 1, comprising a step (step 3) of preparing a compound represented by the formula (1) from the compound represented by the formula (2) prepared in step 2 above.

[Scheme 1]

(In Scheme 1,

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 preventing or treating 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 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 do.

Furthermore, the present invention provides a JAK kinase (Janus kinase) comprising 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 A method for preventing or treating a related disease is provided.

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 protein kinase-related diseases do.

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 (Janus kinase) and, in particular, excellent inhibitory activity against JAK 3 kinase. Bar, JAK kinase (Janus kinase)-related diseases containing the same as an active ingredient, in particular JAK 3 kinase-related diseases, such as combined immunodeficiency (SCID), rheumatoid arthritis, myelofibrosis, psoriasis, Crohn's disease, systemic lupus erythematosus , multiple sclerosis, type 1 diabetes, allergic disease, chronic obstructive pulmonary disease, asthma, a pharmaceutical composition for the prevention or treatment of leukemia or lymphoma, or a functional health food composition for prevention or improvement, there is a useful effect.

Hereinafter, the present invention will be described in detail.

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

[Formula 1]

(In Formula 1,

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

Here, R ¹ and R ² are each independently H, straight-chain or branched C ₁ -C ₁₀ alkyl unsubstituted or substituted with one or more halogen, straight-chain or branched C 1 -C 10 alkyl substituted or unsubstituted with one or more halogen ₁ -C ₁₀ alkoxy, substituted or unsubstituted C _3-10 cycloalkyl, (N, O, and S 3 to 10 membered substituted or unsubstituted containing one or more heteroatoms selected from the group consisting of heterocycloalkyl), substituted or unsubstituted C _6-10 aryl, or (N, O, and S 5 to 10 membered substituted or unsubstituted hetero atom containing at least one hetero atom selected from the group consisting of aryl),

Again, wherein said substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and substituted heteroaryl are, respectively, substituted or unsubstituted straight or branched C ₁ -C ₁₀ alkyl, substituted or unsubstituted straight chain or branched C ₁ -C ₁₀ alkoxy, hydroxy, nitro, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted C _3-10 cycloalkyl, (with N, O, and S the consisting of 3 to 10 members comprising one or more heteroatoms selected from the group a substituted or unsubstituted heterocycloalkyl), optionally substituted aryl, or unsubstituted C _6-10, and (consisting of 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 one or more heteroatoms selected from the group,

Again wherein said substituted alkyl, substituted alkoxy, substituted amino, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and substituted heteroaryl are each straight or branched C ₁ -C ₃ Alkyl, straight-chain or branched C ₁ -C ₃ alkoxy, hydroxy, nitro, cyano, halogen, amino substituted or unsubstituted with one or more methyl, substituted or unsubstituted C _3-6 cycloalkyl, ( 3 to 6 membered substituted or unsubstituted heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S), substituted or unsubstituted phenyl, and (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 one or more heteroatoms selected from the group consisting of

Again, wherein said substituted cycloalkyl, substituted heterocycloalkyl, substituted phenyl, and substituted heteroaryl are, respectively, straight or branched C ₁ -C ₃ alkyl, straight or branched C ₁ -C ₃ alkoxy , and substituted with one or more substituents selected from the group consisting of halogen;

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

wherein said substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-alkyl, and substituted heteroaryl-alkyl are each hydroxy, nitro, cyano , halogen, amino, and R ³ is substituted with one or more substituents selected from the group consisting of,

Again, wherein R ³ is nitro, —NR ⁴ R ⁵ , or —NR ⁴ —(C=O)—R ⁵ ,

Here, 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} is an alkyl,

wherein 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,

of Formula 1,

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

Here, R ¹ and R ² are each independently H, straight-chain or branched C ₁ -C ₁₀ alkyl unsubstituted or substituted with one or more halogen, straight-chain or branched C 1 -C 10 alkyl substituted or unsubstituted with one or more halogen ₁ -C ₁₀ alkoxy, substituted or unsubstituted C _3-6 cycloalkyl, (N, O, and S 3 to 6 membered substituted or unsubstituted containing one or more heteroatoms selected from the group consisting of heterocycloalkyl), substituted or unsubstituted phenyl, or (5-6 membered substituted or unsubstituted heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S);

Again, wherein said substituted cycloalkyl, substituted heterocycloalkyl, substituted phenyl, and substituted heteroaryl are, respectively, substituted or unsubstituted straight or branched C ₁ -C ₁₀ alkyl, substituted or unsubstituted straight chain or branched C ₁ -C ₁₀ alkoxy, hydroxy, nitro, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted C _3-6 cycloalkyl, (with N, O, and S 3 to 6 membered substituted or unsubstituted heterocycloalkyl containing at least one hetero atom selected from the group consisting of 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 heteroatom,

Again wherein said substituted alkyl, substituted alkoxy, substituted amino, substituted cycloalkyl, substituted heterocycloalkyl, substituted phenyl, and substituted heteroaryl are each straight or branched C ₁ -C ₃ Alkyl, straight-chain or branched C ₁ -C ₃ alkoxy, hydroxy, nitro, cyano, halogen, amino substituted or unsubstituted with one or more methyl, substituted or unsubstituted C _3-6 cycloalkyl, ( 3 to 6 membered substituted or unsubstituted heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S), substituted or unsubstituted phenyl, and (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 one or more heteroatoms selected from the group consisting of

Again, wherein said substituted cycloalkyl, substituted heterocycloalkyl, substituted phenyl, and substituted heteroaryl are, respectively, straight or branched C ₁ -C ₃ alkyl, straight or branched C ₁ -C ₃ alkoxy , and may be substituted with one or more substituents selected from the group consisting of halogen.

Furthermore, in another aspect of the present invention,

of Formula 1,

Y is a substituted or unsubstituted C _3-6 cycloalkyl, (N, O, and S is a 3-6 membered substituted or unsubstituted heterocycloalkyl containing one or more heteroatoms selected from the group consisting of ), substituted or unsubstituted phenyl, (5 to 6 membered substituted or unsubstituted heteroaryl containing one or more heteroatoms 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 heteroatoms selected from the group consisting of N, O, and S)-C ₁ -C ₃ alkyl ego,

wherein said substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted phenyl, substituted heteroaryl, substituted phenyl-alkyl, and substituted heteroaryl-alkyl are each -NR ⁴ -(C= substituted with O)-R ^{5 ,}

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

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

Also, in another aspect of the present invention,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, 또는

일 수 있다.The X is, -S-CH ₃ , -(S=O)-CH ₃ ,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, or

can be

Furthermore, in another aspect of the present invention,

, 또는

일 수 있다.The Y is,

, or

can be

In one embodiment of the present invention, preferred examples of the compound represented by 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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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] pyrimidin-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)- yl)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 do[2,3-d]pyrimidin-7(8H)-one.

The compound represented by Formula 1 of the present invention may 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 dioates, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, and organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, and the like. Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and 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, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

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

In addition, a pharmaceutically acceptable metal salt may be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. The corresponding salt is also 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, etc. that may be prepared therefrom, 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, and in particular, inhibitory activity against JAK 3 kinase, inhibition of other JAK families It is superior to the activity, and in one example, has selective inhibitory activity against JAK 3, and has inhibitory activity against one or more selected from the group consisting of other JAK families, for example, JAK 1, JAK 2, and TYK2. It can be understood as insignificant 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, ameliorating, or treating JAK kinase-related diseases. have an effect

In one embodiment, the compound represented by Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof exhibits selective inhibitory activity against JAK 3 kinase, thereby preventing, improving, and improving JAK 3 kinase-related diseases, It has a useful effect that can improve or treat, and at the same time, since it has insufficient or no inhibitory activity against other JAK families, the problem of side effects compared to conventional non-selective JAK inhibitors is solved, and more specific diseases, especially JAK 3 related diseases It is useful because it can exhibit concentrated and improved medicinal effect. However, in this aspect, the advantage is an example of one aspect of the compound of the present invention, and the compound of the present invention is not limited to the above 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, ameliorated, ameliorated, or treated by inhibiting the activity or expression of JAK kinase, but is not limited thereto, for example, currently It includes all known diseases or syndromes related to 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 to be a disease related to JAK 1, JAK 2, JAK 3, or TYK2, but is not limited thereto,

JAK 1-associated 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, such as leukemia, lymphoma, melanoma, arthritis, psoriasis, Crohn's disease, lupus erythematosus, acquired immunoassociation syndrome, Behcet's disease, etc.;

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

The JAK 3-related disease may be a cytokine-receptor complex-related disease 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 may be a disease that develops or progresses from causing a significant decrease in T-cells and NK cells and loss of function of B-cells that have a significant impact on biological functions, for example, combined 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 transplant 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, cancer such as breast cancer, and cholangiolipoma. etc., may be a tumor or cancer disease associated with obesity.

In another embodiment of the present invention, the compound represented by Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof has a selective inhibitory activity against JAK 3, for example, the amount of red blood cells and white blood cells The advantage of being able to avoid side effects such as decreased and increased cholesterol levels, in particular side effects resulting from JAK 2 inhibitory activity, can be achieved.

In addition, as confirmed 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 (VITD) ), 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.

Accordingly, 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(K663) (N841I), IRAK1, KIT, KIT (L576P, KIT (V559D), KIT-autoinhibited, MARK3, PDGFRB, PIP5K2C, SNARK, STK16, TRKA, TXK, or a pharmaceutical composition for preventing or treating a YSK4 kinase-related disease is 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, type C Niemann-Pick's disease and other degenerative, inflammatory and autoimmune diseases, chronic myelogenous leukemia, etc., may be known diseases related to ABL1 in the prior art.

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

Here, the BIKE (BMP-2-inducible protein kinase)-related disease may be cancer, and in particular, endometrial cancer, stomach cancer, lung cancer, colorectal 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's tyrosine kinase) related disease is inflammatory pelvic disease, 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 organ, Asthma, allergic rhinitis, chronic obstructive respiratory disease (COPD), autoimmune polyclonal disease (also known as autoimmune polyclonal syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, Autoimmune hemolytic and thrombocytopenic conditions, Goodpasture's syndrome, axial atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, Psoriatic arthritis, juvenile arthritis, degenerative arthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo It may be any one selected from immune hypopituitarism, Guillain-Barré syndrome, Behçet's disease, scleroderma, mycosis fungoides, acute inflammatory reactions (eg acute respiratory distress syndrome and ischemia/reperfusion injury), and Graves' disease.

Here, the BRAF (V600E)-related disease is, for example, melanoma, colorectal cancer, papillary thyroid cancer, anaplastic thyroid cancer, ovarian cancer, non-small cell lung cancer, gastric cancer, cholangiocarcinoma, Barrett's esophageal cancer, head and neck cancer, hepatocellular carcinoma , Langerhans cell histiocytosis, gastrointestinal stromal cell tumor, multiple myeloma, juvenile astrocytoma, xanthoblastoma multiforme, chronic myelogenous leukemia, acute myelomonocytic leukemia, biphenotypic B myelomonocytic leukemia, acute myelogenous leukemia, hairy cell leukemia, nevus, ed Heim-Chester disease, malignant peripheral nerve sheath tumor, inflammatory and autoimmune diseases, tendon synovial giant cell tumor, villonodular synovitis pigmentosa, giant cell tumor of tendon sheath, giant cell tumor of bone, cervical cancer, endometrial cancer, Germ cell tumor, prostate cancer, bladder cancer, myopericytoma, epirenal adenoma, pancreatic neoplasm, neuroendocrine tumor, endocrine tumor, adrenal tumor, adrenal medullary tumor, cystic adenocarcinoma of parotid gland, glioblastoma polymorphism, biliary duct cancer including cholangiocarcinoma , cholangiocarcinoma, B-cell chronic lymphoproliferative disorder, dendritic cell sarcoma, histiocytic sarcoma, and lymphoma.

Here, the CDK2-related disease is, 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 may be, for example, an autoimmune disease, in particular, rheumatoid arthritis, and in other examples, juvenile idiopathic arthritis, Castleman's disease, psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis , multiple sclerosis, systemic lupus erythematosus, and cancer may be any one selected from the group consisting of.

Herein, the CSF1R-autoinhibited related disease may be, for example, osteoporosis, arthritis, atherosclerosis or chronic glomerulonephritis, or, as another example, rheumatoid arthritis, or cancer, and the cancer is myelocytic leukemia, idiopathic myelofibrosis, breast cancer. , cervical cancer, ovarian cancer, endometrial cancer, prostate cancer, hepatocellular carcinoma, multiple myeloma, lung cancer, may be any one selected from the group consisting of kidney cancer and bone cancer.

Here, the FLT3-related disease, or FLT3 mutation-related disease (FLT3 (D835V), FLT3 (D835H), FLT3 (D835V), FLT3 (D835Y), FLT3 (ITD, D835V), FLT3 (ITD, F691L), and FLT3 ( K663Q), FLT3(N841I)) may be, but are not limited to, a proliferative disorder, for example, 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 may be any one selected from the group consisting of hematologic malignancies.

On the other hand, the leukemia is, but not limited to, for example, Hodgkin's disease, and myeloma, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), malignant giant-cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML) ), adult T-cell ALL, AML with trilineage myelodysplasia (AMLITMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD), and multiple myeloma (MM). may be any one of

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, colorectal cancer, neuroblastoma. , aggressive neuroblastoma, and the like.

Here, the IRAK1-related disease is, for example, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, scleroderma, multiple sclerosis, psoriasis, type I diabetes mellitus, type II diabetes mellitus, Inflammatory Bowel Disease (Cronh's Disease and Ulcerative Colitis), Hyperimmunoglobulinemia D and Cyclic Fever Syndrome, Cryopyrin-Related Periodic Syndrome, Schnitzler's Syndrome, Systemic Juvenile Idiopathic Arthritis, Adult Onset Still's Disease, Gout, It may be any one selected from the group consisting of pseudogout, SAPHO syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (IL-1 receptor antagonist deficiency), Alzheimer's disease, Parkinson's disease, and cancer. .

Here, the KIT-related disease, or KIT mutation-related disease (KIT (L576P, KIT (V559D), KIT-autoinhibited, etc.) is, for example, systemic mastocytosis, GIST (gastrointestinal stromal tumor), AML (acute myeloid leukemia) ), melanoma, seminoma, intracranial germ cell tumor, mediastinal B-cell lymphoma, Ewing's sarcoma, DLBCL (diffuse large B-cell lymphoma), ovarian testis, MDS (myelodysplastic syndrome), NKTCL (nose NK) /T-cell lymphoma), CMML (chronic myelomonocytic leukemia), and cancer (eg, brain cancer).

Here, the MARK3-related disease, but is not limited thereto, may be, for example, any one selected from the group consisting of Peutzjeers syndrome, osteoarthritis, rheumatoid arthritis, intermittent claudication, diabetes, and diabetes mellitus.

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

Other PIP5K2C, SNARK, STK16, TRKA, TXK, or YSK4 related diseases are also included without limitation in the present invention, as long as they are related to each kinase or have been reported, for example, the disease may be cancer, , an autoimmune disease, or an inflammatory disease.

Also, the present invention

As shown in Scheme 1 below,

reacting a compound represented by Formula 5 with a 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 preparing the compound represented by the formula (1) of claim 1, comprising a step (step 3) of preparing a compound represented by the formula (1) from the compound represented by the formula (2) prepared in step 2 above.

[Scheme 1]

(In Scheme 1,

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 of Step 1, but is not limited thereto, may be prepared by performing Preparation Examples 1-4 below, or may be prepared by a manufacturing method that can be easily changed/modified therefrom.

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

Furthermore, in the preparation method represented by Scheme 1 of the present invention, Step 1 is a step of preparing a compound represented by Formula 3 by reacting a compound represented by Formula 5 with a compound represented by Formula 4 .

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

For example, the compound represented by Formula 4 is an amine compound, which has various substituents and is a step for introducing it, 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 moiety 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 one of the substituents represented by X in Formula 1 is a protecting group, e.g. For example, it may be a substituent substituted with -Boc.

Usable reaction solvents 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, and it can be used alone or in combination, and it is preferable to use toluene.

After the reaction, the reaction mixture may be filtered through a filtration membrane and washed with an organic solvent. After concentrating the filtrate, the obtained compound 3 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 a time longer than the extent to which even a small portion of the product can be obtained.

However, from the above reaction conditions, the production method of the present invention is not limited, and reaction conditions such as solvent, reaction time, reaction temperature, etc. to a degree that can be easily changed/modified therefrom are all included in the present invention. Technicians will understand.

Furthermore, in the preparation method of the present invention, step 2 is a step of preparing a compound represented by the formula 2 from the compound represented by the 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, when W is NO ₂ or NHBoc, W' is NH ₂ am.

Here, if it is to perform the substituent conversion of step 2, it can be understood that it is not particularly limited and is encompassed by the present invention, for example, it can be carried out as in step 2 of Example 1, or the step of Example 10 2 may be performed.

For example, it may be a step of reacting the compound represented by Formula 3 with TFA, or it may be a step of reacting the compound represented by Formula 3 with tin(II) chloride.

The usable solvent is not particularly limited, and ethyl acetate, toluene, dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (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; and the like, and these may be used alone or in combination.

Again, the reaction conditions in this step include those described in Step 2 of Example 1 and Step 2 of Example 10, and the reaction of the solvent, reaction time, reaction temperature, etc. to a degree that can be easily changed/modified therefrom. It will be understood by those skilled in the art that all conditions are encompassed by the present invention.

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

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

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

Here, the reaction conditions are not particularly limited, and solvents include toluene, dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), methylene chloride, dichloroethane, water, and 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 and, for example, may be carried out at -100 to -20 °C, or about -60 °C,

The reaction time is not particularly limited, and may be carried out 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, etc. to a degree that can be easily changed/modified therefrom. It will be understood by those skilled in the art that all conditions are encompassed by the present invention.

Meanwhile, step 3 may further include a separate protecting group removal step 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 its reaction conditions are commonly known in the art, or the following Examples It may be performed as in step 4 of 10, or may be modified/changeable therefrom.

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating 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, ameliorated, ameliorated, or treated by inhibiting the activity or expression of JAK kinase, but is not limited thereto, for example, currently It includes all known diseases or syndromes related to 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 to be a disease related to JAK 1, JAK 2, JAK 3, or TYK2, but is not limited thereto,

JAK 1-associated 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, such as leukemia, lymphoma, melanoma, arthritis, psoriasis, Crohn's disease, lupus erythematosus, acquired immunoassociation syndrome, Behcet's disease, etc.;

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

The JAK 3-related disease may be a cytokine-receptor complex-related disease 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 may be a disease that develops or progresses from causing a significant decrease in T-cells and NK cells and loss of function of B-cells that have a significant impact on biological functions, for example, combined 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 transplant 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, cancer such as breast cancer, and cholangiolipoma. etc., may be a tumor or cancer disease associated with obesity.

In another embodiment of the present 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, thereby preventing, improving, improving, or It has a useful effect to treat, and at the same time, since it has insufficient or no inhibitory activity against other JAK families, the problem of side effects compared to conventional non-selective JAK inhibitors is solved, and specific diseases, particularly JAK 3 related diseases, are more focused and improved. It is useful because it can show medicinal effect. However, in this aspect, the advantage is an example of one aspect of the compound of the present invention, and the compound of the present invention is not limited to the above 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 Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof has a selective inhibitory activity against JAK 3, for example, the amount of red blood cells and white blood cells The advantage of being able to avoid side effects such as decreased and increased cholesterol levels, in particular side effects resulting from JAK 2 inhibitory activity, can be achieved.

In addition, the present invention provides a health functional food composition for preventing or improving 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 do.

Here, the JAK kinase-related disease refers to any disease that can be prevented, ameliorated, ameliorated, or treated by inhibiting the activity or expression of JAK kinase, but is not limited thereto, for example, currently It includes all known diseases or syndromes related to 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 to be a disease related to JAK 1, JAK 2, JAK 3, or TYK2, but is not limited thereto,

JAK 1-associated 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, such as leukemia, lymphoma, melanoma, arthritis, psoriasis, Crohn's disease, lupus erythematosus, acquired immunoassociation syndrome, Behcet's disease, etc.;

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

The JAK 3-related disease may be a cytokine-receptor complex-related disease 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 may be a disease that develops or progresses from causing a significant decrease in T-cells and NK cells and loss of function of B-cells that have a significant impact on biological functions, for example, combined 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 transplant 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, cancer such as breast cancer, and cholangiolipoma. etc., may be a tumor or cancer disease associated with obesity.

In another embodiment of the present 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, thereby preventing, improving, improving, or It has a useful effect to treat, and at the same time, since it has insufficient or no inhibitory activity against other JAK families, the problem of side effects compared to conventional non-selective JAK inhibitors is solved, and specific diseases, particularly JAK 3 related diseases, are more focused and improved. It is useful because it can show medicinal effect. However, in this aspect, the advantage is an example of one aspect of the compound of the present invention, and the compound of the present invention is not limited to the above 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 Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof has a selective inhibitory activity against JAK 3, for example, the amount of red blood cells and white blood cells The advantage of being able to avoid side effects such as decreased and increased cholesterol levels, in particular side effects resulting from JAK 2 inhibitory activity, can be achieved.

Furthermore, regardless of the description related to the JAK kinase, based on the antiproliferative activity against cancer cell lines experimentally shown from the compound represented by 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 of familial production, and is not particularly limited, but the cancer includes pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, oral cancer, Mycosis fungoides, acute myeloid 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 tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocyte Leukemia, retinoblastoma, choroidal melanoma, diffuse giant B-cell lymphoma, ampulla Barter cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, tongue cancer, astrocytoma, small cell lung cancer, Pediatric brain cancer, juvenile lymphoma, juvenile leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, neuroblastoma, kidney cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, mesothelioma malignant, malignant melanoma , eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal interstitial cancer, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational villous disease, cervical cancer, uterus Endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acoustic schwannoma, 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 may be at least one selected from the group consisting of thymus 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 oral and parenteral formulations during clinical administration. It can be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and the like.

Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine and the like, and optionally boron such as starch, agar, alginic acid or its sodium salt. It may contain releasing or boiling mixtures and/or absorbents, colorants, flavoring agents, and sweetening agents.

The pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient can be administered parenterally, and parenteral administration is subcutaneous injection, intravenous injection, intramuscular injection, or thoracic administration. Depends on how I inject my injection.

At this time, in order to formulate a formulation for parenteral administration, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or buffer to prepare a solution or suspension, and this is an ampoule or vial unit dosage form. can be manufactured with The composition may be sterilized and/or contain adjuvants such as preservatives, stabilizing agents, wetting or emulsifying agents, salts and/or buffers for regulating osmotic pressure, and other therapeutically useful substances, and mixing, granulation, in a conventional manner. It can be formulated according to the method of formulation or coating.

In addition, the dose to the human body of the pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient of the present invention is the patient's age, weight, sex, dosage form, health condition and disease. It may vary 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 it is also constant according to the judgment of a doctor or pharmacist. It may be administered in divided doses from once a day to several times a day at intervals of time.

The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral formulations during clinical administration. In the case of formulation, it is prepared using diluents or excipients, such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in one or more compounds, for example, starch, calcium carbonate, sucrose or lactose ( lactose), gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, internal solutions, emulsions, syrups, etc. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, and emulsions. Non-aqueous solvents and suspensions 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 health functional food composition, the compound represented by Formula 1 according to the present invention may be added to food as it is or used together with other food or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient may be suitably determined according to the purpose of its use (for prevention or improvement). In general, the amount of the compound in the health food can be added in an amount of 0.1-90 parts by weight of the total food weight. However, in the case of long-term ingestion for health and hygiene purposes or for health control, the above amount may be less than 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 is not particularly limited in other ingredients except for containing the compound as an essential ingredient in the indicated ratio, and may contain various flavoring agents or natural carbohydrates as additional ingredients like a conventional beverage. have. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and 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, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrate is generally about 1-20 g, preferably about 5-12 g per 100 g of the composition of the present invention.

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

Furthermore, the present invention provides a JAK kinase (Janus kinase) comprising 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 A method for preventing or treating a related disease is provided.

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

The therapeutically effective amount refers to an amount capable of improving 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, and family history of the subject to be administered, and in the present invention, the treatment method may determine a different amount of dosage according to different conditions for each subject.

The "effective amount" means an amount useful for treating a JAK kinase-related disease or disorder, or more than the minimum effective amount for treating cancer. In another embodiment, an "effective amount" of a compound refers to at least the minimum amount capable of inhibiting the growth of cancer.

The compounds and compositions according to the methods of the present invention may be administered in any amount and by any route of administration effective to treat a disease. The exact amount required will vary from subject to subject, depending on the subject's species, age, and general condition, the severity of the infection, the particular agent, its 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 physically discrete units of an agent suitable for the subject to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The particular effective dosage level for any particular subject or organism will depend on a variety of factors, including:

The term “subject”, as used herein, refers to an animal, such as a mammal, such as a human.

The pharmaceutical composition of the present invention may be administered orally, rectally, parenterally, intracystically, intravaginally, intraperitoneally, topically (powder, ointment, lotion, salve, 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 present invention are from about 0.01 mg/kg to about 50 mg/kg, for example from about 1 mg/kg to about 25 mg/kg of subject's body weight/once per day, to obtain the desired therapeutic effect. It may be administered orally or parenterally at dosage levels of more than one/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 protein kinase-related diseases do.

Hereinafter, the present invention will be described in detail by way of Examples and Experimental Examples.

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

In the following example compound,

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

<Analysis and purification conditions>

HPLC analysis conditions (A)

Device name: Shimadzu

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

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

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

UV detector: 254nm

HPLC analysis conditions (B)

Instrument Name: Thermo Scientific Ultimate 3000RSLC

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

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

Analysis time: 4.5 minutes, flow rate: 1.2ml/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: 1mL/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) 100 Å, 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)

<Preparation 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 equiv.) was dissolved in chloroform (0.2 M), and then manganese(IV) oxidase (6.0 equiv.) was added. The reaction mixture was reacted at room temperature for 12 hours, filtered through celite, and washed with chloroform. After the resulting filtrate was concentrated, the 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

The compound (1.0 equiv.) prepared in step 1 was dissolved in acetic acid (0.6 M), cyanoacetic acid (1.2 equiv.) and benzylamine (0.1 equiv.) were added thereto, and reacted at 120° C. for 6 hours using a reflux device. proceeded. After completion of the reaction, the temperature was lowered to room temperature and only the solid generated by 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 one 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 manufacture of mates

The compound prepared in step 2 (1.0 equiv.) was dissolved in DMF (0.1 M), and sodium hydride (1.2 equiv.) was added at 0° C. in 3 - 4 portions. The reaction mixture was reacted for 30 minutes, tert-butyl 3-(bromomethyl)phenylcarbamate (1.1 equivalents) was further added, and then reacted at room temperature for 1 hour. The reaction was terminated by adding water at 0 °C, and the organic material was extracted with EtOAc (x3). The collected organic layers were 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 (yield: 93%).

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

The compound (1.0 equiv.) prepared in step 3 was dissolved in DCM (0.15 M), m-CPBA (3-chloroperbenzoic acid, 1.5 equiv) was added, and the reaction was carried out at -10 °C for 1 hour. The reaction was _{terminated by the addition of saturated NaHCO 3} , and the organic material was extracted with DCM (x3). The collected organic layers were washed with brine, and then the _{remaining water was removed using Na 2} SO ₄ to obtain the target compound as a yellow solid (yield: 96%).

<Preparation 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 equiv.) was dissolved in chloroform (0.2 M), and then manganese(IV) oxidase (6.0 equiv.) was added. The reaction mixture was reacted at room temperature for 12 hours, filtered through celite, and washed with chloroform. After the obtained filtrate was concentrated, the 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

The compound prepared in step 1 (1.0 equiv.) was dissolved in acetic acid (0.6 M), cyanoacetic acid (1.2 equiv.) and benzylamine (0.1 equiv.) were added, and reacted at 120° C. for 6 hours using a reflux device. proceeded. After completion of the reaction, the temperature was lowered to room temperature and only the solid generated by 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 one 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 3 - 4 portions. The reaction mixture was reacted for 30 minutes, and 3-nitrobenzyl bromide (1.1 equivalents) was further added, followed by reaction at room temperature for 1 hour. The reaction was terminated by adding water at 0 °C, and the organic material was extracted with EtOAc (x3). The collected organic layers were 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 (yield: 93%).

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

The compound (1.0 equiv.) prepared in step 3 was dissolved in DCM (0.15 M), m-CPBA (3-chloroperbenzoic acid, 1.5 equiv) was added, and the reaction was carried out at -10 °C for 1 hour. The reaction was _{terminated by the addition of saturated NaHCO 3} , and the organic material was extracted with DCM (x3). The collected organic layers were washed with brine, and then the _{remaining water was removed using Na 2} SO ₄ to obtain the target compound as a yellow solid (yield: 90%).

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

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

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

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

<Preparation 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, which was used in step 2 of Preparation Example 1.

<Preparation 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 is used, and instead of tert-butyl 3-(bromomethyl)phenylcarbamate used in Step 3 of Preparation Example 1, (R )-tert-Butyl 3-bromopyrrolidine-1-carboxylate was carried out in the same manner as in Preparation Example 1, except that the target compound was prepared.

<Preparation 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 is used, and instead of tert-butyl 3-(bromomethyl)phenylcarbamate used in Step 3 of Preparation Example 1, (S )-tert-Butyl 3-bromopyrrolidine-1-carboxylate was carried out in the same manner as in Preparation Example 1, except that the target compound was prepared.

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

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

The compound prepared in Preparation Example 1 (1.0 equiv.) and 1-(2-methoxyethyl)-1H-pyrazol-4-amine (1.2 equiv.) were added to and dissolved in toluene (0.1 M) for 1 hour. reacted. The reaction was terminated by adding water to the reaction product, and the organic material was extracted with EtOAc (x3). The collected organic layers were washed with brine, and the remaining water was removed using _{Na 2} SO _{4 .} The mixture was purified through prep-HPLC to obtain the title 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

The compound prepared in step 1 (1.0 equiv.) was dissolved in DCM (0.05 M), and then TFA (100 equiv) was added at room temperature. After 3 hours of reaction, the solvent was removed. The target compound as a concentrated pale 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 Preparation of -d]pyrimidin-8-(7H)yl)methyl)phenyl)acrylamide

The compound prepared in step 2 (1.0 equiv.) was dissolved in DMF (0.05 M) at room temperature, and then DIPEA (1.1 equiv.) was added. Then, acryloyl chloride (1.0 equivalent) was added to the reaction mixture at -60°C, and the reaction was allowed to proceed for 10 minutes. After 10 minutes, the temperature was changed to room temperature and the reaction was carried out for 30 minutes, and the reaction was terminated by adding water. The organic material was 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 through prep-HPLC to obtain the title 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

Instead of 1-(2-methoxyethyl)-1H-pyrazol-4-amine used in step 1 of Example 1, 1-(4-amino-1H-pyrazol-1-yl)-3- The target compound was prepared in the same manner as in Example 1, except that (dimethylamino)propan-2-ol was used.

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

Instead of 1-(2-methoxyethyl)-1H-pyrazol-4-amine used in step 1 of Example 1, 5-chloro-1-(2-methoxyethyl)-1H-pyrazole- A target compound was prepared in the same manner 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

Instead of 1-(2-methoxyethyl)-1H-pyrazol-4-amine used in step 1 of Example 1, 1-(2,2,2-trifluoroethyl)-1H-pyrazole A target compound was prepared in the same manner as in Example 1, except that -4-amine was used.

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 -Oxopyrido [2,3-d] pyrimidin-8 (7H) -yl) methyl) phenyl) preparation of acrylamide

Instead of 1-(2-methoxyethyl)-1H-pyrazol-4-amine used in step 1 of Example 1, 1-((3-methyloxetan-3-yl)methyl)-1H- A target compound was prepared in the same manner as in Example 1, except that pyrazol-4-amine was used.

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]pyrimidin-8(7H)-yl)methyl)phenyl)acrylamide

Instead of 1-(2-methoxyethyl)-1H-pyrazol-4-amine used in step 1 of Example 1, 1-(oxetan-3-yl)-1H-pyrazol-4-amine A target compound was prepared in the same manner as in Example 1, except that .

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]pyrimidin-8(7H)-yl)methyl)phenyl)acrylamide

Instead of 1-(2-methoxyethyl)-1H-pyrazol-4-amine used in step 1 of Example 1, 1-(2-(dimethylamino)ethyl)-1H-pyrazole-4- A target compound was prepared in the same manner as in Example 1, except that an amine was used.

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]pyrimidin-8(7H)-yl)methyl)phenyl)acrylamide

Instead of 1-(2-methoxyethyl)-1H-pyrazol-4-amine used in step 1 of Example 1, 2-methoxy-4-(4-methylpiperazin-1-yl)benzene A target compound was prepared in the same manner as in Example 1, except that an amine was used.

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]pyrimidin-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 -yl)-1H-pyrazol-4-amine was used, and the target compound was prepared in the same manner as in Example 9 below.

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 do[2,3-d]pyrimidin-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 prepared in Preparation Example 2 (1.0 equivalent) and tert-butyl 3-((4-amino-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (1.2 equivalents) were mixed with toluene ( 0.1 M) was added and dissolved, followed by reaction at 100 °C for 1 hour. The reaction was terminated by adding water to the reaction product, and the organic material was extracted with EtOAc (x3). The collected organic layers were washed with brine, and the remaining water was removed using _{Na 2} SO _{4 .} The mixture was purified through prep-HPLC to obtain the title 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

The compound prepared in step 1 (1.0 equiv.) was dissolved in ethyl acetate (0.1 M), tin(II) chloride (10.0 equiv.) was added thereto, and the reaction was carried out at 60° C. for 5 hours. After completion of the reaction, the reaction mixture was adjusted to pH 5 using _{NH 4} OH, and maintained at pH 7 with _{Na 2} CO _{3 .} The reaction product maintained at pH 7 was filtered through celite and washed with EtOAc. After concentrating the obtained filtrate, 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]pyrido) Preparation of midin-2-yl)amino)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

The compound prepared in step 2 (1.0 equiv.) was dissolved in DMF (0.05 M) at room temperature, and then DIPEA (1.1 equiv.) was added. Then, acryloyl chloride (1.0 equivalent) was added to the reaction mixture at -60°C, and the reaction was allowed to proceed for 10 minutes. After 10 minutes, the temperature was changed to room temperature and the reaction was carried out for 30 minutes, and the reaction was terminated by adding water. The organic material was 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]pyrimidin-8(7H)-yl)methyl)phenyl)acrylamide

The compound prepared in step 3 (1.0 equiv.) was dissolved in DCM (0.05 M), and then TFA (100 equiv.) was added at room temperature. After 3 hours reaction, the solvent was removed. The mixture was purified through prep-HPLC to obtain the title 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]pyrimidin-8(7H)-yl)methyl)phenyl)acrylamide

Instead of 1-(2-methoxyethyl)-1H-pyrazol-4-amine used in step 1 of Example 1, 1-(tetrahydrofuran-3-yl)-1H-pyrazole-4- A target compound was prepared in the same manner as in Example 1, except that an amine was used.

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]pyrimidin-8(7H)-yl)methyl)phenyl)acrylamide

Instead of tert-butyl3-((4-amino-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate used in step 1 of Example 9, 1-(morpholine-2) The target compound was prepared in the same manner as in Example 9, except that -ylmethyl)-1H-pyrazol-4-amine was used.

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

Instead of 1-(2-methoxyethyl)-1H-pyrazol-4-amine used in step 1 of Example 1, 1-(4-amino-1H-pyrazol-1-yl)propane-2 The target compound was prepared in the same manner as in Example 1, except that -ol was used.

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, 2-(4-amino-1H-pyrazol-1-yl)ethanol was used. Except for the point, the target compound was prepared in the same manner as in Example 1.

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

It was noted that 4-(4-methylpiperazin-1-yl)benzeneamine was used instead of 1-(2-methoxyethyl)-1H-pyrazol-4-amine used in step 1 of Example 1 Except, the target compound was prepared in the same manner as in Example 1.

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 do[2,3-d]pyrimidin-8(7H)-yl)methyl)phenyl)acrylamide

In place of 1-(2-methoxyethyl)-1H-pyrazol-4-amine used in step 1 of Example 1, 2-(5-amino-4-methylthiazol-2-yl)-2 - The target compound was prepared in the same manner as in Example 1, except that methylpropanenitrile was used.

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]pyrimidin-8(7H)-yl)methyl)phenyl)acrylamide

Instead of tert-butyl3-((4-amino-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate used in step 1 of Example 9, 1-(piperidine- The target compound was prepared in the same manner as in Example 9, except that 4-yl)-1H-pyrazol-4-amine was used.

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

Instead of 1-(2-methoxyethyl)-1H-pyrazol-4-amine used in step 1 of Example 1, 1-(4-amino-1H-pyrazol-1-yl)-2- A target compound was prepared in the same manner as in Example 1, except that methylpropan-2-ol was used.

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]pyrimidin-8(7H)-yl)methyl)phenyl)acrylamide

Instead of tert-butyl3-((4-amino-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate used in step 1 of Example 9, 1-(pyrrolidine- 3-yl)-1H-pyrazol-4-amine was used, and the same procedure as in Example 9 was carried out to prepare the target compound.

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 pyrimidin-8(7H)-yl)methyl)phenyl)acrylamide

Instead of 1-(2-methoxyethyl)-1H-pyrazol-4-amine used in step 1 of Example 1, 4-(2,2,2-trifluoroethyl)benzeneamine was used Except for, the target compound was prepared in the same manner as in Example 1.

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

The above implementation except that 4-(trifluoromethyl)benzeneamine was used instead of 1-(2-methoxyethyl)-1H-pyrazol-4-amine used in step 1 of Example 1 In the same manner as in Example 1, the target compound was prepared.

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

Instead of 1-(2-methoxyethyl)-1H-pyrazol-4-amine used in step 1 of Example 1, 1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole A target compound was prepared in the same manner as in Example 1, except that -4-amine was used.

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

A target compound was prepared in the same manner as in Example 1, except that the compound of Preparation Example 3 was used instead of the compound of Preparation Example 1 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

A target compound was prepared in the same manner as in Example 1, except that the compound of Preparation Example 4 was used instead of the compound of Preparation Example 1 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

Instead of the compound of Preparation Example 1 used in Step 1 of Example 1, the compound of Preparation Example 3 was used, and 1-(2-methoxyethyl)-1H-pyrazole-4 used in Step 1 of Example 1 - A target compound was prepared in the same manner as in Example 1, except that 2-methoxy-4-(4-methylpiperazin-1-yl)benzeneamine was used instead of -amine.

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

Instead of the compound of Preparation Example 1 used in Step 1 of Example 1, the compound of Preparation Example 5 was used, and 1-(2-methoxyethyl)-1H-pyrazole-4 used in Step 1 of Example 1 - A target compound was prepared in the same manner as in Example 1, except that 4-(4-methylpiperazin-1-yl)benzeneamine was used instead of -amine.

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

Instead of the compound of Preparation Example 1 used in Step 1 of Example 1, the compound of Preparation Example 5 was used, and 1-(2-methoxyethyl)-1H-pyrazole-4 used in Step 1 of Example 1 - A target compound was prepared in the same manner as in Example 1, except that 1-(oxetan-3-yl)-1H-pyrazol-4-amine was used instead of -amine.

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

Instead of the compound of Preparation Example 1 used in Step 1 of Example 1, the compound of Preparation Example 5 was used, and 1-(2-methoxyethyl)-1H-pyrazole-4 used in Step 1 of Example 1 - A target compound was prepared in the same manner 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 pyrimidin-8(7H)-yyl)methyl)phenyl)acrylamide

Instead of the compound of Preparation Example 1 used in Step 1 of Example 1, the compound of Preparation Example 5 was used, and 1-(2-methoxyethyl)-1H-pyrazole-4 used in Step 1 of Example 1 - A target compound was prepared in the same manner as in Example 1, except that 1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-amine was used instead of -amine.

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 pyrimidin-8(7H)-yl)methyl)phenyl)acrylamide

Instead of the compound of Preparation Example 1 used in Step 1 of Example 1, the compound of Preparation Example 5 was used, and 1-(2-methoxyethyl)-1H-pyrazole-4 used in Step 1 of Example 1 - A target compound was prepared in the same manner as in Example 1, except that 2-methoxy-4-(4-methylpiperazin-1-yl)benzeneamine was used instead of -amine.

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

Instead of the compound of Preparation Example 1 used in Step 1 of Example 1, the compound of Preparation Example 5 was used, and 1-(2-methoxyethyl)-1H-pyrazole-4 used in Step 1 of Example 1 - The target compound was prepared in the same manner as in Example 1, except that 2-(4-amino-1H-pyrazol-1-yl)ethanol was used instead of -amine.

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

A target compound was prepared in the same manner as in Example 1, except that the compound of Preparation Example 6 was used instead of the compound of Preparation Example 1 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

A target compound was prepared in the same manner 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

Instead of the compound of Preparation Example 1 used in Step 1 of Example 1, the compound of Preparation Example 6 was used, and 1-(2-methoxyethyl)-1H-pyrazole-4 used in Step 1 of Example 1 - A target compound was prepared in the same manner as in Example 1, except that 2-methoxy-4-(4-methylpiperazin-1-yl)benzeneamine was used instead of -amine.

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

490 [M+H] ⁺

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

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

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

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

In the case of TYK2, a final concentration of 300ng/ml recombinant TYK2 kinase (Promega PV4790), 1μmol/L ATP (Promega PV3227), 100nM GFP-STAT1 (Promega PV5211) was added to a 384-well plate in a kinase reaction buffer (50mM HEPES pH7.5, 0.01% BRIJ-35, 10 mM MgCl ₂ , 1 mM EGTA) was added and mixed, followed by the same method as JAK 1.

In Table 2 and Table 3 below, the inhibitory activity against JAK 1, JAK 2, JAK 3 and TYK2 of the example compounds are summarized and shown. _{When the IC 50} value of the measured kinase is less than 10 nM, it is class A, when it is 10 - 100 nM, it is class B, and when it exceeds 100 nM, it is classified as class C.

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

Referring to Table 3, the compounds of the present invention have more significant inhibitory activity on JAK 3 compared to JAK 1, JAK 2, TYK2, and it can be seen that the compound of the present invention is a JAK 3 selective inhibitory compound.

In addition, looking at Table 2, it was confirmed that all of 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, the pharmaceutical composition for preventing or treating JAK 3 related diseases. It may be provided as an active ingredient.

In addition, it can be seen that the compound of the present invention can be provided as an improved therapeutic drug, particularly as a JAK 3 selective inhibitor, because it can solve the side effects and low efficacy of conventional non-selective inhibitors.

<Experimental Example 2> Kinase inhibitory activity evaluation

In order to evaluate the inhibitory activity of the compound according to the present invention to more enzymes, the following experiment was performed.

Specifically, among the example compounds of this alias, the selected Example 1 was commissioned by DiscoverX to measure enzyme (kinase) selectivity, and the experiment was conducted using a ^{scanMAX TM Kinase analysis panel.}

At this time, the concentration of the drug treated with the enzyme was 1 uM in DMSO, and the control percentage (% control) was determined in the same way as in Equation 1 below, 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 percentage control of 0%, and the negative control indicates a percentage control of 100% with DMSO. In addition, the enzyme selectivity of the present invention was determined to have activity for each enzyme if the control percentage was <35% (ie, less than 35%) for each enzyme.

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 JH1 domain-catalytic (JAK1) 100 100 JH2domain-pseudokinase (JAK1) 49 47 JH1 domain-catalytic (JAK2) 90 35 JH1 domain-catalytic (JAK3) 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 (JH1 domain-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

Referring to 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 kinases have a value of less than 35% of the control percentage.

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 a pharmaceutical composition for the prevention or treatment of a YSK4 kinase-related disease may be provided.

<Experimental Example 3> Ba/F3 cell activity evaluation

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

More specifically, BaF3 (JAK 1, JAK 2, JAK 3, TYK2)(abm) was ^{planted in a 96-well plate at 1 Х 10 4} /90 μl/well, and then serially diluted threefold to 9 concentrations (0.015). - 100 μM) of a culture solution containing a compound and DMSO control was added at a rate of 10 μl/well so that the final concentration was 0 - 10 μM, and then _{incubated in a 37° C. CO 2} incubator for 72 hours. After 72 hours, the plate treated with the compound is taken out, and after treatment with 10 μl/well of Cell Counting Kit-8 (Dojindo Molecular Technologies, Inc) solution, mix well. Incubate for 2 hours in a 37° C. CO ₂ incubator, and measure the absorbance at 450 nm with a microplate reader. The data were expressed as a percentage in proportion to the treated cells based on the vehicle standard, 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 represents 0.5 μM or less, B represents more than 0.5 μM to 5 μM or less, and C represents 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

Referring to Table 4, the compounds of the present invention can confirm excellent inhibitory activity even in the Ba/F3 cell line, and in particular, more pronounced inhibitory activity is confirmed for JAK3.

Accordingly, it can be seen that the compound of the present invention can be provided as an improved therapeutic drug, particularly as a JAK 3 selective inhibitor, because it can solve the side effects and low efficacy of conventional non-selective inhibitors.

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

Human fibronectin (fibronectin) 5 ㎍ / ㎖ into a 96-well (well) plate 100 ㎕ / well, and then coated at 37 ℃ for 2 hours. ^{200U (5 x 10 5} U/ml) interleukin-2 (IL-2) and 15,000 HT-2 cells (mouse IL-2 dependent lymphoid T cells) in 200 μl of RPMI+10% FBS (Fetal Bovine Serum) medium cell line), 0.08-10 uM of Janus kinase-3 (JAK 3) targeting small molecule inhibitor was mixed and dispensed into fibronectin-coated wells. Cell proliferation was observed in real time for 72 hours in an Incucyte incubator (Incucyte S3), and GI ₅₀ values were calculated, and the results are shown in Table 6.

In Table 6, A represents 0.1 μM or less, B represents more than 0.1 μM to 1 μM or less, and C represents 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)

Any one selected from the group of compounds, a stereoisomer thereof, or a pharmaceutically acceptable salt 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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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] pyrimidin-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)- yl)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 do[2,3-d]pyrimidin-7(8H)-one.
delete delete delete delete delete The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof containing as an active ingredient, combined immunodeficiency (SCID), rheumatoid arthritis, myelofibrosis, psoriasis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, A pharmaceutical composition for preventing or treating type 1 diabetes, allergic disease, chronic obstructive pulmonary disease, asthma, leukemia or lymphoma.
8. The method of claim 7,
The pharmaceutical composition is, 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, JAK 1, JAK 2, JAK(JH1domain-catalytic) 3, TYK2, KIT, Inhibiting KIT (L576P, KIT (V559D), KIT-autoinhibited, MARK3, PDGFRB, PIP5K2C, SNARK, STK16, TRKA, TXK or YSK4 kinase, a pharmaceutical composition.
delete A pharmaceutical composition for preventing or treating cancer, comprising the compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
11. The method of claim 10,
The cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma , ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse giant B-cell lymphoma, Barter Ample cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, tongue cancer, astrocytoma, small cell lung cancer, juvenile brain cancer, juvenile lymphoma, juvenile leukemia, small intestine cancer, meningioma, esophageal cancer, Glioma, neuroblastoma, renal pelvis cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, lymphoma malignant, mesothelioma malignant melanoma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site , gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational villous disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinum Cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acoustic schwannoma, 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 thymus cancer, characterized in that at least one selected from the group consisting of, a pharmaceutical composition.