KR20120092768A - Aminopyridine derivatives and extracellular signal-regulated kinase inhibitor containing the same - Google Patents

Abstract

PURPOSE: A novel aminopyridine derivative is provided to effectively suppress extracellular signal-regulated kinase 1 and/or 2 activity and to treat cancer. CONSTITUTION: A novel aminopyrdine derivative having an extracellular signal-regulated kinase activity is denoted by chemical formula 1. A composition for suppressing extracellular signal-regulated kinase activity contains the compound of chemical formula 1 or pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof as an active ingredient. A composition for preventing or treating cancer contains the compound, salt, hydrate, solvate, or isomer as an active ingredient.

Description

Aminopyridine derivatives and extracellular signal-regulated kinase inhibitor containing the same}

The present invention relates to a novel aminopyridine derivative having an inhibitory activity against extracellular signal-regulated kinase, the novel aminopyridine derivative, the aminopyridine derivative and / or a pharmaceutically acceptable salt thereof. It relates to an extracellular signal-regulated kinase inhibitor containing as an active ingredient, and a composition for the prevention and / or treatment of cancer containing the aminopyridine derivative and / or pharmaceutically acceptable salt thereof as an active ingredient.

Cells recognize and respond to extracellular stimuli by specific intracellular programs, such as signaling cascades. This signaling system activates mitogen-activated protein kinase (MAPK). All eukaryotic cells have a MAPK signaling system that cooperates with each other in gene expression, mitosis, and metabolism to motility, survival, and apoptosis. And regulates a variety of cellular activities throughout the entire spectrum up to differentiation. MAPKs so far known in mammals include extracellular signal-regulated kinases (ERKs) 1 and 2 (ERK1 / 2)); c-Jun amino-terminal kinases (JNKs) 1,2, and 3; p38 isoforms a, b, g, and d; ERKs 3 and 4; There are five types of ERK5, among which ERK1 / 2, JNKs, and p38 kinase have been intensively studied.

MAPK is activated by a variety of stimuli, but typically ERK1 / 2 is activated by growth factors and phorbol esters, whereas JNK and p38 kinases are osmotic shock and ionizing radiation. It is known to respond to a variety of stress stimuli ranging from radiation to mechanical wear cytokine stimulation.

The ERK1 / 2 signaling system, known as the p42 / p44 MAPK pathway, includes mitogen-activated protein kinase kinase (MAPKKK), A-Raf, B-Raf, and Raf-1; Consists of mitogen-activated protein kinase kinase (MAPKK) and extracellular signal-regulated kinase (ERK) kinase (MEK2) and MAPK, ERK1 and ERK2, which are important determinants of cell growth, differentiation and survival.

This signaling system, which operates downstream of Ras, is frequently upregulated in human carcinomas, making it an attractive target for anticancer drug development. ERK1 and ERK2 have 83% amino acid similarity and are expressed over a wide range in all tissues (ChemMed Chem 2007, 2, 1116-1140).

Ras / Raf / MEK / ERK signaling pathways link many of the proteins involved in apoptosis, as well as linking transcription factors that regulate gene expression from cell surface receptors. Regulate the activity of. This signaling system is used for chromosomal translocations such as BCR-ABL, mutations in cytokine receptors such as Flt-3, Kit, and Fms, overexpression of receptors such as EGFR (epidermal growth factor receptor), or cancer caused by mutant receptors. Active on Raf / MEK / ERK signaling pathways also include post-translational phosphorylation of Bad, Bim, Mcl-1, caspase-9, and, arguably, apoptotic regulatory molecules, including Bcl-2. -translational phosphorylation) has an important effect on the regulation of cell death.

This signaling system has a variety of effects that regulate cell cycle progression, apoptosis or differentiation. This signaling system is abnormally activated in cancer, possibly due to mutations in upstream membrane receptors, Ras and B-Raf, or mutations in other pathway genes such as PI3K, PTEN, and Akt that regulate Raf activity. .

In addition, the ectopic activiation of Raf in the Raf / MEK / ERK pathway is known to induce resistance to doxorubicin and paclitaxel in breast cancer, thus affecting chemotherapeutic drug resistance.

For this reason, the Raf / MEK / ERK pathway is an important signaling system as a target for therapeutic intervention and Raf and MEK inhibitors have been developed and are currently in clinical practice.

Raf inhibitors are known such as L-779,450, ZM 336372, Bay 43-9006 that competitively inhibits the ATP-binding site of Raf protein. Some Raf inhibitors inhibit only one of the Raf isoforms (e.g., Raf-1), while pan Raf inhibitors inhibit all three Raf proteins (Raf-1, A-Raf and B-Raf). Knowing whether a particular Raf gene has been mutated or overexpressed in a particular carcinoma could result in a more sensitive inhibition of the corresponding Raf gene by a therapeutic agent targeting that Raf protein. Inhibition of certain Raf genes may be useful. On the other hand, under certain circumstances, inhibition of other Raf genes may be disadvantageous. Thus, development of characteristic or extensive Raf inhibitors may be useful for treating cancer. Raf activity is modulated by dimerization and thus is affected by protein: protein inhibitors such as geldanamycin. Raf isoforms dimerize themselves to activate other Raf isoforms. Coumermycin inhibits Raf dimerization and geldanmycin inhibits Raf binding to Hsp90. Another approach to targeting Raf is to inhibit Raf by targeting kinases (e.g., Src, PKC, PKA, PAK or Akt) and phosphorylating agents (e.g., PP2A) included in Raf activation. This may activate or inactivate other proteins or affect cell physiology.

MEK1 rarely detects mutations in cancer, but abnormal expression of MEK1 is found in many cancers, including upstream kinase (eg BCR-ABL) and growth factor receptors (eg, EGFR) is known to be due to activation of the Raf / MEK / ERK signaling system. Several MEK inhibitors (PD98059, U0126, PD184352 (a.k.a., CI1040), PD-0325901, Array MEK inhibitors [ARRY-142886, etc.)) have been developed. The advantage of targeting the Raf / MEK / ERK signaling system is that it is possible without information on abnormally activated gene mutations. This is important because the nature of important mutations that induce malignant growth of at least 50% of AML and other cancers is not yet known. The advantage of targeting MEK is that Raf / MEK / ERK signaling can prevent numerous upstream signaling from MEK inhibition. (Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 2007, 1773, 1263-1284)

ERK inhibitors have not yet been developed to the clinical stage, but ERK is the final stage of the Raf / MEK / ERK signaling system and can phosphorylate many targets (at least 150 such as Rsk, c-Myc, Elk, etc.). ERK inhibitors can be very useful for the prevention or treatment of various forms of cancer (Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 2007, 1773, 1263-1284). Since the final stage of the Raf / MEK / ERK signaling system directly inhibits the activity of abnormally activated ERK in cancer cells, it is possible to prevent the Raf / MEK / ERK signaling system without information on abnormally activated upper gene mutations. It can be usefully used for prevention and treatment.

Accordingly, the present invention has completed the present invention by developing a novel aminopyridine derivative that inhibits the activity of extracellular signal-regulated kinase (ERK).

Accordingly, one object of the present invention is to provide a novel aminopyridine derivative.

Another example is to provide an extracellular signal-regulated kinase inhibitor containing the aminopyridine derivative and / or a pharmaceutically acceptable salt thereof as an active ingredient.

Another example is to provide a composition for the prevention and / or treatment of cancer containing the aminopyridine derivative and / or pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object, one example of the present invention relates to an aminopyridine derivative of formula (1) below, pharmaceutically acceptable salts, solvates, hydrates, and isomers thereof.

Another example relates to an extracellular signal-regulated kinase inhibitor containing an aminopyridine derivative of Formula 1, a pharmaceutically acceptable salt, solvate, hydrate, and isomer thereof as an active ingredient.

Another example relates to a composition for the prophylaxis and / or treatment of cancer containing an aminopyridine derivative of Formula 1, a pharmaceutically acceptable salt, solvate, hydrate, and isomer thereof as an active ingredient.

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

The present invention relates to an aminopyrimidine derivative represented by Formula 1 below:

[Formula 1]

In the above formula,

R1 is H, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted, cycloalkyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms substituted, heterocycloalkyl of 3 to 6 carbon atoms, carbon atoms substituted Heterocycloalkyl of 3 to 6, aryl of 3 to 6 carbon atoms, aryl of 3 to 6 carbon atoms substituted, hetero aryl of 3 to 6 carbon atoms, or hetero aryl of 3 to 6 carbon atoms,

R 2 is H or halogen (eg Cl).

The substituted alkyl, substituted cycloalkyl, substituted hetero cycloalkyl, substituted aryl, and substituted heteroaryl may have one or more hydrogen atoms, straight or branched alkyl of 1 to 6 carbon atoms, straight or branched alkyl of 1 to 6 carbon atoms. Oxy, halogen, hydroxy, nitro, aryl having 3 to 6 carbon atoms, aryloxy having 3 to 6 carbon atoms, benzimidazolyl methyl, hydroxymethyl, heteroaryl, fluorophenoxymethyl, difluorophenoxymethyl, Chlorophenoxymethyl, chlorophenyl, carboxyphenyl, aminoethyloxy, cyanomethyl, benzyl, amine, piperidine, benzyloxy, chlorobenzyloxy, phenoxymethyl, phenylethyl, naphthoxymethyl, benzodioxoylme Methoxy (eg 3-benzo [1,3] dioxo-4-ylmethoxy), indolyl, benzoylamino, fluorobenzoyl amino, acetylamino, cyclopropanecarbonylamino, imidazolylcarbon Group consisting of amino, pyridinecarbonylamino, benzyloxy, thiazolylmethoxy, phenylcarbamoyl, pyridinecarbamoyl, methylphenyl, naphthyl, phenylamino methyl and cyclopropylureido (eg, 3-cyclopropyl-ureido) Substituted with one or more selected from, or connected to each other to form a ring.

In addition, the heterocycloalkyl and heteroaryl means that at least one of the carbon atoms constituting the ring is substituted with N.

For example, R1 may be selected from the following compounds (a) to (w):

In the above formula,

R3 is H,

R 4 is H, straight or branched alkoxy having 1 to 5 carbon atoms (eg isopropyloxy, etc.), phenyl, benzyl, or halogen substituted benzyl (eg Cl-benzyl, etc.),

R 5 is H, phenyl, halogen substituted phenyl (eg F-phenyl, di-F-phenyl, ortho-Cl-phenyl, etc.), or naphthyl,

R6 is halogen (e.g. Cl, etc.), straight or branched alkyl of 1 to 4 carbon atoms (e.g. methyl, etc.), or alkoxy (e.g. methoxy etc.) of 1 to 5 carbon atoms, preferably ortho or para (Eg, ortho-Cl, ortho-methyl, ortho-methoxy, etc.),

R7 comprises alkyl having 1 to 4 carbon atoms (eg methyl), cycloalkyl having 3 to 6 carbon atoms (eg cyclopropyl), phenyl, halogen substituted phenyl (eg F-phenyl etc.), or N; 5- or 6-membered cyclic compounds (eg, pyrimidyl (ortho-pyrimidyl), imidazole, etc.),

R8 is H, CH ₂ OH, CO ₂ H, O (CH ₂ ) NH ₂ , or CH ₂ CN,

R 9 is NO ₂ , phenyl, toluyl (eg m-toluyl, etc.), or naphthyl,

A may be CH or N.

In an embodiment of the present invention, the compound represented by Formula 1 may preferably be a compound described in Table 1 below.

rescue Compound Name Compound Name

5-Chloro-2- (pyridine-4-amino) -pyrimidine-4-carboxylic acid cyclohexyl amide 5-Chloro-2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid cyclohexylamide

5-Chloro-2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid phenylamide 5-Chloro-2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid phenylamide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (4-methoxyphenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (4-methoxy-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-methoxyphenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-methoxy-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (2-methoxyphenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (2-methoxy-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (4-chlorophenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (4-chloro-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-chlorophenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-chloro-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid ((S) -2-hydroxy-1-phenylethyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid ((S) -2-hydroxy-1-phenyl-ethyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-hydroxymethylphenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-hydroxymethyl-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-hydroxyphenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-hydroxy-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-phenoxyphenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-phenoxy-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzyloxyphenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzyloxy-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-isobutoxyphenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-isobutoxy-phenyl) -amide

2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid piperidin-4-ylamide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid piperidin-4-ylamide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (piperidin-4-ylmethyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (piperidin-4-ylmethyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2-chlorobenzyloxy) -phenyl] -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2-chloro-benzyloxy) -phenyl] -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3-chlorobenzyloxy) -phenyl] -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3-chloro-benzyloxy) -phenyl] -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (4-chlorobenzyloxy) -phenyl] -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (4-chloro-benzyloxy) -phenyl] -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-phenoxymethylphenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-phenoxymethyl-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (1-phenethylpyrrolidin-3-yl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (1-phenethyl-pyrrolidin-3-yl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (naphthalen-1-yloxymethyl) -phenyl] -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (naphthalen-1-yloxymethyl) -phenyl] -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (benzo [1,3] dioxo-4-ylmethoxy) -phenyl] -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (benzo [1,3] dioxol-4-ylmethoxy) -phenyl] -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzoimidazol-1-ylmethyl-phenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzoimidazol-1-ylmethyl-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-indol-1-ylmethylphenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-indol-1-ylmethyl-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3H-benzoimidazol-4-ylmethoxy) -phenyl] -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3H-benzoimidazol-4-ylmethoxy) -phenyl] -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid ((1S, 2S, 4S) -1,7,7-trimethyl-bicyclo [2.2.1] hept-2-yl)- Amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid ((1S, 2S, 4S) -1,7,7-trimethyl-bicyclo [2.2.1] hept-2-yl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzoylamino-phenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzoylamino-phenyl) -amide

2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid phenylamide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid phenylamide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-nitrophenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-nitro-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid {3- [benzyl- (2-dimethylaminoacetyl) -amino] -phenyl} -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid {3- [benzyl- (2-dimethylamino-acetyl) -amino] -phenyl} -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-{[(2-dimethylamino-acetyl) -phenyl-amino] -methyl} -phenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-{[(2-dimethylamino-acetyl) -phenyl-amino] -methyl} -phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (thiazol-4-ylmethoxy) -phenyl] -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (thiazol-4-ylmethoxy) -phenyl] -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (5-benzyloxy-2-methylphenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (5-benzyloxy-2-methyl-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (5-benzyloxy-2-chlorophenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (5-benzyloxy-2-chloro-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzyloxy-4-methoxyphenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzyloxy-4-methoxy-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-phenylcarbamoylphenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-phenylcarbamoyl-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid {3-[(pyridine-2-carbonyl) -amino] -phenyl} -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid {3-[(pyridine-2-carbonyl) -amino] -phenyl} -amide

2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid biphenyl-3-ylamide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid biphenyl-3-ylamide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3'-methyl-biphenyl-3-yl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-
carboxylic acid (3'-methyl-biphenyl
-3-yl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-naphthalen-2-yl-phenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-naphthalen-2-yl-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2-fluorobenzoylamino) -phenyl] -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2-fluoro-benzoylamino) -phenyl] -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-acetylaminophenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-acetylamino-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (cyclopropanecarbonylamino) -phenyl] -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (cyclopropanecarbonyl-amino) -phenyl] -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid {3-[(1H-imidazol-2-carbonyl) -amino] -phenyl} -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid {3-[(1H-imidazole-2-carbonyl) -amino] -phenyl} -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid {3-[(1H-imidazole-4-carbonyl) -amino] -phenyl} -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid {3-[(1H-imidazole-4-carbonyl) -amino] -phenyl} -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (pyridin-2-ylcarbamoyl) -phenyl] -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (pyridin-2-ylcarbamoyl) -phenyl] -amide

5-Chloro-2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzyloxy-phenyl) -amide 5-Chloro-2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzyloxy-phenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3-fluoro-benzoylamino) -phenyl] -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3-fluoro-benzoylamino) -phenyl] -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-phenylaminomethyl-phenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-phenylaminomethyl-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3-cyclopropyl-ureido) -phenyl] -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3-cyclopropyl-ureido) -phenyl] -amide

2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid benzylamide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid benzylamide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid 4-chloro-benzylamide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid 4-chloro-benzylamide

2-{[2- (pyridin-4-ylamino) -pyrimidine-4-carbonyl] -amino} -benzoic acid 2-{[2- (Pyridin-4-ylamino) -pyrimidine-4-carbonyl] -amino} -benzoic acid

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (2-hydroxymethyl-phenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (2-hydroxymethyl-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [2- (2-amino-ethoxy) -phenyl] -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [2- (2-amino-ethoxy) -phenyl] -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (2-cyanomethyl-phenyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (2-cyanomethyl-phenyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (1-cyano-2-phenyl-ethyl) -phenyl] -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (1-cyano-2-phenyl-ethyl) -phenyl] -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (1-aminomethyl-2-phenyl-ethyl) -phenyl] -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (1-aminomethyl-2-phenyl-ethyl) -phenyl] -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2-fluoro-phenoxymethyl) -phenyl] -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2-fluoro-phenoxymethyl) -phenyl] -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2,3-difluoro-phenoxymethyl) -phenyl] -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-
carboxylic acid [3- (2,3-difluoro-ph
enoxymethyl) -phenyl] -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3,4-difluoro-phenoxymethyl) -phenyl] -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3,4-difluoro-phenoxymethyl) -phenyl] -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2-chloro-phenoxymethyl) -phenyl] -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2-chloro-phenoxymethyl) -phenyl] -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (pyridin-4-ylmethyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (pyridin-4-ylmethyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid ((1S, 2S) -2-amino-cyclohexyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid ((1S, 2S) -2-amino-cyclohexyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-amino-cyclohexyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-amino-cyclohexyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (4-amino-cyclohexyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (4-amino-cyclohexyl) -amide

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzoylamino-cyclohexyl) -amide 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzoylamino-cyclohexyl) -amide

In a preferred embodiment, R 1 is cyclohexyl, benzyloxyphenyl (eg 3-benzyloxyphenyl), chlorobenzyloxyphenyl (eg 3- (2-chlorobenzyloxy) -phenyl), phenoxymethylphenyl (eg 3-phenoxymethylphenyl), benzoylaminophenyl (eg, 3-benzoylamino-phenyl), phenylcarbamoylphenyl (eg, 3-phenylcarbamoylphenyl), fluorobenzoylaminophenyl (eg, 3- (2-fluoro) Robenzoylamino) -phenyl, 3- (3-fluorobenzoylamino) -phenyl), phenylaminomethylphenyl (eg 3-phenylaminomethyl-phenyl), cyanophenylethylphenyl (eg 3- (1-sia) No-2-phenyl-ethyl) -phenyl), aminomethylphenylethylphenyl (eg 3- (1-aminomethyl-2-phenyl-ethyl) -phenyl), fluorophenoxymethylphenyl (eg 3- (2- Fluoro-phenoxymethyl) -phenyl), difluorophenoxymethylphenyl (eg 3- (2,3-difluoro-phenoxymethyl) -phenyl), chlorophenoxymethylphenyl ( For example, 3- (2-chloro-phenoxymethyl) -phenyl), phenyl, methoxyphenyl (eg 3-methoxyphenyl, 4-methoxyphenyl), chlorophenyl (eg 3-chlorophenyl), hydroxy Hydroxyphenylethyl (eg 2-hydroxy-1-phenylethyl), hydroxymethylphenyl (eg 3-hydroxymethylphenyl), hydroxyphenyl (eg 3-hydroxyphenyl), phenoxyphenyl (eg 3 -Phenoxyphenyl), isobutoxyphenyl (eg 3-isobutoxyphenyl), chlorobenzyloxyphenyl (eg 3- (3-chlorobenzyloxy) -phenyl), phenethylpyrrolidinyl (eg 1 Phenethylpyrrolidin-3-yl), benzodioxoylmethoxymethoxyphenyl (eg 3- (benzo [1,3] dioxo-4-ylmethoxy) -phenyl), benzoimidazolylmethylphenyl (eg 3-benzoimidazol-1-ylmethyl-phenyl), indolylmethylphenyl (eg 3-indol-1-ylmethylphenyl), benzoimidazolylmethoxyphenyl (eg 3- (3H-benzoimidazol-4- Monomethoxy) -phenyl), Dimethylbicycloheptyl (eg (1S, 2S, 4S) -1,7,7-trimethyl-bicyclo [2.2.1] hept-2-yl), nitrophenyl (eg 3-nitrophenyl) Thiazolylmethoxyphenyl (eg 3- (thiazol-4-ylmethoxy) -phenyl), benzyloxychlorophenyl (eg 5-benzyloxy-2-chlorophenyl), pyridinecarbonylaminophenyl (eg 3-[(pyridine-2-carbonyl) -amino] -phenyl), biphenyl (eg biphenyl-3-yl), pyridinylcarbamoylphenyl (eg 3- (pyridin-2-ylcarbamoyl) -Phenyl), benzyl, chlorobenzyl (eg 4-chloro-benzyl), hydroxymethylphenyl (eg 2-hydroxymethyl-phenyl), and aminocyclohexyl (eg 3-amino-cyclohexyl, 4-amino It may be selected from the group consisting of (cyclohexyl).

In a more preferred embodiment, R 1 is cyclohexyl, benzyloxyphenyl (eg 3-benzyloxyphenyl), chlorobenzyloxyphenyl (eg 3- (2-chlorobenzyloxy) -phenyl), phenoxymethylphenyl (eg , 3-phenoxymethylphenyl), benzoylaminophenyl (eg 3-benzoylamino-phenyl), phenylcarbamoylphenyl (eg 3-phenylcarbamoylphenyl), fluorobenzoylaminophenyl (eg 3- (2- Fluorobenzoylamino) -phenyl, 3- (3-fluorobenzoylamino) -phenyl), phenylaminomethylphenyl (eg 3-phenylaminomethyl-phenyl), cyanophenylethylphenyl (eg 3- (1- Cyano-2-phenyl-ethyl) -phenyl), aminomethylphenylethylphenyl (eg 3- (1-aminomethyl-2-phenyl-ethyl) -phenyl), fluorophenoxymethylphenyl (eg 3- (2) -Fluoro-phenoxymethyl) -phenyl), difluorophenoxymethylphenyl (eg, 3- (2,3-difluoro-phenoxymethyl) -phenyl), and chlorophenoxyme Butylphenyl (eg, 3- (2-chloro-phenoxymethyl) -phenyl).

The compound of formula 1 of the present invention has ERK inhibition by having a 4-pyridine substituent on the aminopyrimidine-4-carboxylic acid amide nucleus (patent application 10-2006-0132973, PCT / KR2006 / 005661), which is known as the nucleus of kinase inhibitors It is characterized by showing the effect. As can be seen from the comparative examples described below, compounds having a diatom similar to the chemical formula of the present invention and having a phenyl substituent or a 3-pyridine substituent in the aminopyrimidine-4-carboxylic acid nucleus but not a 4-pyridine substituent are relatively ERK inhibitory activity (IC50) was not shown even at high doses (50 μM).

The compounds according to the invention may be provided in the form of their pharmaceutically acceptable salts, hydrates, solvates, or isomers.

The 'pharmaceutically acceptable salts' may be all kinds of pharmaceutically acceptable salts derived from inorganic or organic acids, or bases. For example, 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 or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide , Fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate, Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, methoxy Benzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonate, naphthalene-2-sulfonate or mandelate.

The 'solvate' means herein that the compound molecule of Formula 1 and a pharmaceutically acceptable solvent, such as a lower alcohol molecule having 1 to 4 carbon atoms, form a complex, wherein the 'hydrate' is a compound molecule of Formula 1 Means that it forms a complex with the water molecule.

In addition, the scope of the compound of the present invention can be extended to the form of introducing a generally known protecting group or deprotecting group, and if there is an optical isomer in the compound, each of the enantiomers, diastereomers (diastereomer) And racemic mixtures.

Compounds of formula (I) of the present invention may be prepared by any method of compound synthesis commonly known in the art.

For example, in the present invention, the compound of Formula 1 and the intermediate may be prepared by the preparation process of Scheme 1 or Scheme 2.

[Reaction Scheme 1]

According to Scheme 1, an amide such as PyBop, EDCI, TBTU, etc. from a commercially available 2-methylsulfanyl-pyrimidine-4-carboxylic acid derivative (Compound 1-1) Compound 1-2 is produced by reaction with an amine (R1-NH2) in the presence of a coupling agent, and sulfide of compound 1-2 is used to synthesize sulfone (compound 1-3) by reaction with an oxidizing agent such as oxone. Can be. 1-3 may synthesize the compound of Formula 1 by substitution with 4-aminopyridine in the presence of a base.

Scheme 2

According to Scheme 2, the compound of Formula 1 may be synthesized by Scheme 2 from 2-amino-4-methylpyrimidine (2-1). 2-amino-4-methylpyrimidine is converted to compound 2-2 by Buchwald coupling with 4-bromopyridine in the presence of a palladium catalyst, and converted to carboxylic acid (compound 2-3) by oxidizing agents such as SeO2 and KMnO4. do. Compound 2-3 may be reacted with various amines in the presence of an amide coupling agent such as PyBop, EDCI, TBTU, etc. to synthesize the compound of Formula 1.

R 1 in Chemical Formula 1 may be converted into a different kind of R 1 and R 2 by chemical reaction from a compound of Chemical Formula 1 or an intermediate of the reaction process by a known method or a method well known to those skilled in the art.

As a result of measuring the inhibitory activity of the derivative of Formula 1 according to the present invention into ERK1 and ERK2, the inhibitory activity (IC50) against ERK2 was determined in Examples 1, 12, 16, 19, 27, 36, 41, 47, 48, 1 μM or less for compounds 49, 57, 58, 59, 60, and 62, Examples 2, 3, 4, 7, 8, 9, 10, 11, 13, 17, 20, 22, 23, 24, 25 For compounds of, 26, 28, 29, 32, 34, 37, 38, 46, 51, 52, 54, 65, and 66, about 1-10 μM. In addition, to confirm the effect of inhibiting cancer cell proliferation through the inhibition of ERK activity, the results of experiments in human colon cell lines COLO-205 and HCT116 cells, EC50 20 μM for the compounds of Examples 12, 16, 19, 41, and 49 It showed the following cancer cell proliferation inhibitory effect.

Meanwhile, the compound of Formula 2 or Formula 3, which has a structure similar to that of Formula 1 of the present invention, but has a phenyl substituent or a 3-pyridine substituent which is not a 4-pyridine substituent in the aminopyrimidine-4-carboxylic acid parent, has an ERK even at 50 μM. Inhibitory activity (IC50) was not shown (see Comparative Example and Table 6).

R1 and R2 are the same as defined above.

On the other hand, Examples 7, 12 and 28, which are the corresponding compounds having the structure of Formula 1, show an ERK inhibitory effect of 10 μM or less.

Therefore, the derivative of formula 1 according to the present invention is a compound having a specific structure in which 4-pyridine substituent is bound to a known aminopyrimidine structure, and thus exhibits an effective inhibitory activity against extracellular signal-regulated kinase by the structural properties of the compound. In addition to being useful as an inhibitor of extracellular signal kinase, it can be effectively used for the prevention or treatment of cancer caused by extracellular signal kinase activity.

Accordingly, another embodiment of the present invention relates to the use of the compound of formula 1, a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof for inhibiting extracellular signal-regulated kinase activity.

Specifically, there is provided a composition for inhibiting extracellular signal-regulated kinase activity containing the compound of Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof as an active ingredient. In another aspect, preparing a biological sample separated from the living body; And applying a compound of Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof to the biological sample. The biological sample is a cell, tissue, blood, saliva, other body fluids, etc. derived from a mammal, preferably a human, and means a sample separated from a living body.

Another example of the invention relates to the use of the prophylaxis and / or treatment of cancer caused by the extracellular signal-regulated kinase activity of a compound of formula 1, a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof.

Specifically, there is provided a composition for the prevention and / or treatment of cancer containing the compound of Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof as an active ingredient. In another aspect, preventing and / or administering a compound of Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof to a patient in need thereof, and / or treating the cancer Or a method of treatment is provided. By patient is meant a mammal, preferably a human, an individual in need of and / or prevention of cancer caused by extracellular signal-regulated kinase activity.

The cancer may be any cancer caused by extracellular signal-regulated kinase activity, such as lung cancer, pancreatic cancer, colon cancer (eg colorectal cancer), myeloid leukemia (eg acute lymphocytic leukemia (AML), chronic) Myeloid Leukemia (CML) and Chronic Bone Cell Leukemia (CMML), Thyroid Cancer, Myelodysplastic Syndrome (MDS), Bladder Carcinoma, Epidermal Carcinoma, Melanoma, Breast Cancer, Prostate Cancer, Head and Neck Cancer (e.g. Cancer), ovarian cancer, brain cancer (eg glioma, eg glioblastoma multiforme), cancer of mesenchymal origin (eg fibrosarcoma and rhabdomyosarcoma), sarcoma, teratcarcinomas, neuroblastoma , Renal carcinoma, liver cancer, non-Hodgkin's lymphoma, multiple myeloma, or thyroid undifferentiated cancer, and the like.

The content of the compound of formula 1, a pharmaceutically acceptable salt, solvate, hydrate, and / or isomer thereof as an active ingredient in the composition for inhibiting extracellular signal-regulated kinase activity and the composition for preventing or treating cancer may be It can be appropriately adjusted according to the degree, condition, patient condition to be applied, and the like, for example, 0.001 to 99.9% by weight, for example, 0.01 to 90% by weight, 0.1 to 70% by weight, preferably 1 to 50% by weight, based on the total composition weight. Although it is preferable that it is%, it is not limited to this.

When the composition is used in the form of a pharmaceutical composition, it may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions, powders, granules, tablets, capsules, It may be used in the form of oral dosage forms such as suspensions, emulsions, syrups, aerosols, external preparations, suppositories, or sterile injectable solutions.

When the composition is formulated, it is prepared using a diluent such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, or an excipient usually used. Solid preparations for oral administration include tablets, pills, powders, powders, granules, capsules, and the like, and such solid preparations may include at least one excipient and / or lubricant. Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups, and various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. have. Preparations for parenteral administration include injections, sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.

Preferred dosages of the composition may be appropriately determined according to the condition, the symptoms, the weight of the patient, the form of the drug, the route and duration of administration, and the like. For a more preferable effect, the dosage of the composition of the present invention is preferably 0.1 mg / kg to 1000 mg / kg per day by weight of the active ingredient, preferably 1 to 500 mg / kg, but is not limited thereto. no. Administration may be administered once a day or may be divided several times. The compositions of the present invention can be administered by a variety of routes to mammals or birds, including animals, preferably humans. All modes of administration can be envisaged, for example, by oral, intravenous, intramuscular, subcutaneous injection or the like. The pharmaceutical dosage form of the composition of the present invention may be used in the form of a pharmaceutically acceptable salt of the active ingredient, and may be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection.

The invention is further understood with reference to the following examples, for which pure illustration is intended. The present invention is not limited by the illustrated embodiments and any method that is functionally equivalent is within the scope of the present invention.

The aminopyrimidine derivatives according to the present invention effectively inhibit the activity of extracellular signal-regulated kinase 1 and / or extracellular signal-regulated kinase 2 and thus are very useful for the treatment of cancer caused by their activity.

Hereinafter, the present invention will be described in detail by way of examples.

However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.

To prepare the compounds of Examples 1 to 67 as shown in Table 2 by the following Preparation Example:

Example rescue Compound name R1 R2 One

5-Chloro-2- (pyridine-4-amino) -pyrimidine-4-carboxylic acid cyclohexyl amide Cyclohexyl Cl 2

5-Chloro-2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid phenylamide Phenyl Cl 3

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (4-methoxyphenyl) -amide 4-methoxyphenyl H 4

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-methoxyphenyl) -amide 3-methoxyphenyl H 5

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (2-methoxyphenyl) -amide 2-methoxyphenyl H 6

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (4-chlorophenyl) -amide 4-chlorophenyl H 7

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-chlorophenyl) -amide 3-chlorophenyl H 8

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid ((S) -2-hydroxy-1-phenylethyl) -amide (S) -2-hydroxy-1-phenylethyl H 9

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-hydroxymethylphenyl) -amide 3-hydroxymethylphenyl H 10

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-hydroxyphenyl) -amide 3-hydroxyphenyl H 11

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-phenoxyphenyl) -amide 3-phenoxyphenyl H 12

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzyloxyphenyl) -amide 3-benzyloxyphenyl H 13

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-isobutoxyphenyl) -amide 3-isobutoxyphenyl H 14

2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid piperidin-4-ylamide Piperidin-4-yl H 15

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (piperidin-4-ylmethyl) -amide Piperidin-4-ylmethyl H 16

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2-chlorobenzyloxy) -phenyl] -amide 3- (2-chlorobenzyloxy) -phenyl H 17

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3-chlorobenzyloxy) -phenyl] -amide 3- (3-chlorobenzyloxy) -phenyl H 18

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (4-chlorobenzyloxy) -phenyl] -amide 3- (4-chlorobenzyloxy) -phenyl H 19

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-phenoxymethylphenyl) -amide 3-phenoxymethylphenyl H 20

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (1-phenethylpyrrolidin-3-yl) -amide 1-phenethylpyrrolidin-3-yl H 21

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (naphthalen-1-yloxymethyl) -phenyl] -amide 3- (naphthalen-1-yloxymethyl) -phenyl H 22

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (benzo [1,3] dioxo-4-ylmethoxy) -phenyl] -amide 3- (benzo [1,3] dioxo-4-ylmethoxy) -phenyl H 23

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzoimidazol-1-ylmethyl-phenyl) -amide 3-benzoimidazol-1-ylmethyl-phenyl H 24

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-indol-1-ylmethylphenyl) -amide 3-indol-1-ylmethylphenyl H 25

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3H-benzoimidazol-4-ylmethoxy) -phenyl] -amide 3- (3H-benzoimidazol-4-ylmethoxy) -phenyl H 26

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid ((1S, 2S, 4S) -1,7,7-trimethyl-bicyclo [2.2.1] hept-2-yl)- Amide (1S, 2S, 4S) -1,7,7-trimethyl-bicyclo [2.2.1] hept-2-yl H 27

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzoylamino-phenyl) -amide 3-benzoylamino-phenyl H 28

2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid phenylamide Phenyl H 29

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-nitrophenyl) -amide 3-nitrophenyl H 30

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid {3- [benzyl- (2-dimethylaminoacetyl) -amino] -phenyl} -amide 3- [benzyl- (2-dimethylaminoacetyl) -amino] -phenyl H 31

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-{[(2-dimethylamino-acetyl) -phenyl-amino] -methyl} -phenyl) -amide 3-{[(2-dimethylamino-acetyl) -phenyl-amino] -methyl} -phenyl H 32

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (thiazol-4-ylmethoxy) -phenyl] -amide 3- (thiazol-4-ylmethoxy) -phenyl H 33

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (5-benzyloxy-2-methylphenyl) -amide 5-benzyloxy-2-methylphenyl H 34

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (5-benzyloxy-2-chlorophenyl) -amide 5-benzyloxy-2-chlorophenyl H 35

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzyloxy-4-methoxyphenyl) -amide 3-benzyloxy-4-methoxyphenyl H 36

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-phenylcarbamoylphenyl) -amide 3-phenylcarbamoylphenyl H 37

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid {3-[(pyridine-2-carbonyl) -amino] -phenyl} -amide 3-[(pyridine-2-carbonyl) -amino] -phenyl H 38

2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid biphenyl-3-ylamide Biphenyl-3-yl H 39

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3'-methyl-biphenyl-3-yl) -amide 3'-methyl-biphenyl-3-yl H 40

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-naphthalen-2-yl-phenyl) -amide 3-naphthalen-2-yl-phenyl H 41

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2-fluorobenzoylamino) -phenyl] -amide 3- (2-fluorobenzoylamino) -phenyl H 42

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-acetylaminophenyl) -amide 3-acetylaminophenyl H 43

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (cyclopropanecarbonylamino) -phenyl] -amide 3- (cyclopropanecarbonylamino) -phenyl H 44

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid {3-[(1H-imidazol-2-carbonyl) -amino] -phenyl} -amide 3-[(1H-imidazole-2-carbonyl) -amino] -phenyl H 45

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid {3-[(1H-imidazole-4-carbonyl) -amino] -phenyl} -amide 3-[(1H-imidazole-4-carbonyl) -amino] -phenyl H 46

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (pyridin-2-ylcarbamoyl) -phenyl] -amide 3- (pyridin-2-ylcarbamoyl) -phenyl H 47

5-Chloro-2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzyloxy-phenyl) -amide 3-benzyloxy-phenyl Cl 48

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3-fluoro-benzoylamino) -phenyl] -amide 3- (3-Fluoro-benzoylamino) -phenyl H 49

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-phenylaminomethyl-phenyl) -amide 3-phenylaminomethyl-phenyl H 50

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3-cyclopropyl-ureido) -phenyl] -amide 3- (3-cyclopropyl-ureido) -phenyl H 51

2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid benzylamide benzyl H 52

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid 4-chloro-benzylamide 4-chloro-benzyl H 53

2-{[2- (pyridin-4-ylamino) -pyrimidine-4-carbonyl] -amino} -benzoic acid 2-carboxyphenyl H 54

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (2-hydroxymethyl-phenyl) -amide 2-hydroxymethyl-phenyl H 55

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [2- (2-amino-ethoxy) -phenyl] -amide 2- (2-amino-ethoxy) -phenyl H 56

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (2-cyanomethyl-phenyl) -amide 2-cyanomethyl-phenyl H 57

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (1-cyano-2-phenyl-ethyl) -phenyl] -amide 3- (1-cyano-2-phenyl-ethyl) -phenyl H 58

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (1-aminomethyl-2-phenyl-ethyl) -phenyl] -amide 3- (1-Aminomethyl-2-phenyl-ethyl) -phenyl H 59

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2-fluoro-phenoxymethyl) -phenyl] -amide 3- (2-Fluoro-phenoxymethyl) -phenyl H 60

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2,3-difluoro-phenoxymethyl) -phenyl] -amide 3- (2,3-Difluoro-phenoxymethyl) -phenyl H 61

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3,4-difluoro-phenoxymethyl) -phenyl] -amide 3- (3,4-Difluoro-phenoxymethyl) -phenyl H 62

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2-chloro-phenoxymethyl) -phenyl] -amide 3- (2-Chloro-phenoxymethyl) -phenyl H 63

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (pyridin-4-ylmethyl) -amide Pyridin-4-ylmethyl H 64

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid ((1S, 2S) -2-amino-cyclohexyl) -amide (1S, 2S) -2-Amino-cyclohexyl H 65

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-amino-cyclohexyl) -amide 3-amino-cyclohexyl H 66

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (4-amino-cyclohexyl) -amide 4-amino-cyclohexyl H 67

2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzoylamino-cyclohexyl) -amide 3-benzoylamino-cyclohexyl H 68
(Comparative Example)

2-phenylamino-pyrimidine-4-carboxylic acid phenylamine Phenyl H 69
(Comparative Example)

2-phenylamino-pyrimidine-4-carboxylic acid (3-chlorophenyl) -amide 3-chlorophenyl H 70
(Comparative Example)

2- (Pyridin-3-ylamino) -pyrimidine-4-carboxylic acid (3-benzyloxyphenyl) -amide 3-benzyloxyphenyl H

Hereinafter, the preparation process of the compounds of Examples 1 to 67 will be illustrated by the preparation examples below.

Manufacturing example  1: 2- Methylsulfanyl  Pyrimidine-4- Carboxylic acid from  Synthesis of Compound of Formula 1

Scheme 3

(1-1) Synthesis of Compound 2

Compound 1 (1 equiv), Pybop (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, 1.5 equiv), and DMAP (4-Dimethylaminopyridine, 1.5 equiv) were dissolved in DMF (Dimethylformaldehyde) in a solution of amine (R1-NH ₂ , R1 = In the case of phenyl, aniline, 1.2 equivalents) was added thereto, followed by stirring at room temperature for 3 hours. The reaction product was distilled under reduced pressure to remove the solvent, which was dissolved in EA (ethyl acetate) and washed with water and brine. The organic layer was dried over MgSO ₄ , concentrated and purified by silica gel column chromatography (Hexane: Ethyl acetate = 2: 1 (v / v)) to give compound 2 (5-chloro- 2 -methylsulfanyl-pyrimidine-4). -Carboxylic acid phenylamine) was obtained in a yield of 96%.

5-Chloro-2-methylsulfanyl-pyrimidine-4-carboxylic acid phenylamine (R1 = phenyl)

1 H NMR (300 MHz, DMSO-d 6, δ); 10.79 (s, 1H), 8.93 (s, 1H), 7.66-7.69 (m, 2H), 7.35-7.40 (m, 2H), 7.15 (t, J = 7.5 Hz, 1H), 2.56 (s, 3H) , LCMS (M + 1: 280.1)

(1-2) Synthesis of Compound 3

The obtained compound 2 (5-chloro- 2 -methylsulfanyl-pyrimidine-4-carboxylic acid phenylamine) was dissolved in EtOH / H ₂ O (4/1 (v / v)) and Oxone (2.1 equiv) was added at room temperature. Was added. The reaction was stirred at room temperature for 3 hours, concentrated by distillation under reduced pressure, dissolved in EA, washed with water and brine, dried over MgSO ₄ , and distilled under reduced pressure to remove the solvent. The residue was washed with MeOH and dried to afford compound 3 (5-chloro-2-methylsulfonyl-pyrimidine-4-carboxylic acid phenylamine) in 70% yield.

5-Chloro-2-methylsulfonyl-pyrimidine-4-carboxylic acid phenylamine (R1 = phenyl)

1 H NMR (300 MHz, DMSO-d 6, δ); 10.80 (s, 1H), 9.41 (s, 1H), 7.64-7.69 (m, 2H), 7.34-7.40 (m, 2H), 7.16 (t, J = 7.5 Hz, 1H), 3.40 (s, 3H)

(1-3) Synthesis of Compound 4

To a solution of 4-aminopyridine hydrochloride (1 equiv) and sodium hydride (2 equiv) in anhydrous DMF was added dropwise a DMF solution of compound 3 (1 equiv) prepared slowly at 0 ° C. under nitrogen. The reaction was stirred at room temperature for 3 hours, concentrated under reduced pressure, dissolved in EA, and the organic layer was washed with water and brine and dried over MgSO ₄ . Concentrated and distilled under reduced pressure, and purified by prep HPLC (C18, 0.1% aq. HCO ₂ H: CH ₃ CN) to give the compound 4 in 84% yield (R1 = phenyl, Example 2).

Examples 1 and 47 were also synthesized in the same manner as in Example 2.

Example Compound structure 1H NMR LC Mass yield One

(300 MHz, DMSO-d6, δ):
10.51 (s, 1H), 8.74 (s, 1H), 8.63 (d, J = 4.5 Hz, 1H), 8.37 (m, 2H), 7.69 (d, J = 5.7 Hz, 2H), 3.72-3.75 (m , 1H), 1.58-1.8 (m, 4H), 1.16-1.30 (m, 6H) 332.2
(M + 1) 87% 2

(300 MHz, DMSO-d6, δ):
10.81 (s, 1H), 10.57 (s, 1H), 8.84 (s, 1H), 8.38 (s, 2H), 7.67-7.70 (m, 4H), 7.35-7.41 (m, 2H), 7.17 (t, 1H) 326.2
(M + 1) 84% 47

(300 MHz, DMSO-d6, δ):
10.79 (s, 1H), 9.98 (s, 1H), 8.65 (s, 1H), 7.80 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.36-7.41 (m, 2H), 7.21 -7.31 (m, 3H), 7.07 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.93 (t, J = 7.2 Hz, 1H) 6.84 (d, J = 8.7 Hz, 1H), 5.01 (s, 2H) 432
(M + 1) 65%

Manufacturing example  2: 2-amino-4- From methylpyrimidine  Synthesis of Compound of Formula 1

Scheme 4

(2-1) Synthesis of Compound 6

Compound 5 (1 equiv), 4-bromopyridine (1.05 equiv), Pd ₂ (dba) ₃ (0.02 equiv), Xantphos (0.04 equiv), and K ₃ PO ₄ (1.5 equiv) were placed in a reaction flask under nitrogen Toluene was added followed by ^t BuOK (1M solution in THF, 1 equiv) with stirring. The reaction was stirred at 100 ° C. for 8 hours, distilled under reduced pressure to remove toluene, and extracted with EA. The organic layer was washed with brine, dried over MgSO ₄ , filtered through silica gel, and concentrated by distillation under reduced pressure to obtain Compound 6 in 84% yield.

1 H NMR (300 MHz, DMSO-d 6, δ); 9.71 (s, 1H), 8.89 (d, J = 4.8 Hz, 1H), 8.45 (d, J = 6.9 Hz, 2H), 8.32 (d, J = 6.9 Hz, 2H), 6.79 (d, J = 4.8 Hz, 1H), 2.36 (s, 3H), LCMS (M + 1: 187.2)

(2-2) Synthesis of Compound 7

A mixture of compound 6 (1 equiv), SeO ₂ (2 equiv) and pyridine (10 equiv) was heated to reflux at 120 ° C. for 12 hours, and then distilled under reduced pressure to remove pyridine, followed by CH ₂ Cl ₂ / MeOH (8/1 , (v / v)), and then acidified with 2N HCl to pH = 3. At this point all the yellow solids are dissolved and only black precipitates remain. The solution was filtered through a pad of celite and the pad of celite was washed with CH ₂ Cl ₂ / MeOH (8/1, (v / v)). The filtered solution was collected, concentrated by distillation under reduced pressure, and crystallized by adding MeOH, followed by filtration and drying to obtain Compound 7 as a beige solid in a yield of 55%.

1 H NMR (300 MHz, DMSO-d 6, δ); 11.68 (s, 1H), 8.98 (d, J = 4.8 Hz, 1H), 8.63 (d, J = 6.9 Hz, 2H), 8.29 (d, J = 6.9 Hz, 2H), 7.69 (d, J = 4.8 Hz, 1H), LCMS (M + 1: 217.0)

(2-3) Synthesis of Compound 8

Compound 7 (1 equiv), R1-NH ₂ (1 equivalent, R1 corresponds to the compound shown in Table 4 below) and TBTU (1.5 equivalents) were dissolved in DMF, Et ₃ N was added, followed by stirring at room temperature for 3 hours. The reaction product was concentrated under reduced pressure, dissolved in EA, washed with water and brine, dried over MgSO ₄ , concentrated, and purified by prep HPLC (C18, 0.1% aq.HCO ₂ H: CH ₃ CN). Compound 8 was obtained in 75-84% yield.

Compounds corresponding to compound 8 which may be prepared by the above method are as described in Table 4 below:

Example Compound structure 1H NMR LC Mass yield 3

(300 MHz, DMSO-d6, δ):
10.43 (s, 1H), 10.32 (s, 1H), 8.86 (d, J = 5.1 Hz, 1H), 8.41 (br s, 2H), 7.81-7.83 (m, 2H), 7.48-7.51 (m, 2H ), 7.27-7.37 (m, 2H), 6.74 (d, J = 8.1 Hz, 1H), 3.76 (s, 3H) 322 (M + 1) 82% 4

(300 MHz, DMSO-d6, δ):
10.89 (s, 1H), 10.26 (s, 1H), 8.91 (d, J = 4.8 Hz, 1H), 8.49 (br s, 2H), 8.00 (d, J = 5.1 Hz, 2H), 7.71 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 5.1 Hz, 1H), 6.96 (d, J = 9.3 Hz, 2H), 3.75 (s, 3H) 322 (M + 1) 80% 5

(300 MHz, CD3OD, δ):
8.83 (d, J = 4.8 Hz, 1H), 8.46 (d, J = 8.1 Hz, 1H), 8.40 (d, J = 6.6 Hz, 2H), 7.84 (d, J = 6.3 Hz, 2H), 7.66 ( d, J = 4.8 Hz, 1H), 7.08-7.19 (m, 2H), 7.00 (t, J = 8.1 Hz, 1H), 3.98 (s, 3H) 322 (M + 1) 84% 6

(300 MHz, CD3OD, δ):
8.84 (d, J = 4.8 Hz, 1H), 8.36 (br s, 2H), 7.85 (d, J = 5.4 Hz, 2H), 7.79 (d, J = 6.9 Hz, 2H), 7.61 (d, J = 4.8 Hz, 1H), 7.38 (d, J = 6.6 Hz, 2H) 326.2 (M + 1) 80% 7

(300 MHz, CD3OD, δ): 8.84 (d, J = 5.1 Hz, 1H), 8.37 (d, J = 4.8 Hz, 2H), 7.96-7.97 (m, 1H), 7.84 (d, J = 6.6 Hz , 2H), 7.62-7.65 (m, 2H), 7.38 (t, J = 8.1 Hz, 1H), 7.17-7.20 (m, 1H) 326.2 (M + 1) 85% 8

(300 MHz, CD3OD, δ):
8.78 (d, J = 4.8 Hz, 1H), 8.33 (br s, 2H), 7.81 (d, J = 6.0 Hz, 2H), 7.51 (d, J = 4.8 Hz, 1H), 7.28-7.44 (m, 5H), 5.16 (t, J = 5.1 Hz, 1H), 3.92 (t, J = 5.1 Hz, 2H) 336.3 (M + 1) 72% 9

(300 MHz, CD3OD, δ):
8.80 (d, J = 5.1 Hz, 1H), 8.35 (br s, 2H), 7.83 (d, J = 6.0 Hz, 2H), 7.75 (s, 1H), 7.65 (d, J = 8.1 Hz, 1H) , 7.60 (d, J = 5.1 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 4.63 (s, 2H) 322.3 (M + 1) 78% 10

(300 MHz, DMSO-d6, δ):
10.88 (s, 1H), 10.21 (s, 1H), 9.54 (s, 1H), 8.91 (d, J = 5.1 Hz, 1H), 8.49 (br s, 2H), 7.98 (d, J = 4.8 Hz, 2H), 7.58 (d, J = 4.8 Hz, 1H), 7.35 (s, 1H), 7.15 (m, 2H), 6.57 (m, 1H) 308 (M + 1) 78% 11

(300 MHz, CD3OD, δ):
8.98 (d, J = 5.1 Hz, 1H), 8.49 (d, J = 5.4 Hz, 2H), 8.33 (d, J = 5.4 Hz, 2H), 7.83 (d, J = 4.8 Hz, 1H), 7.57 ( s, 1H), 7.44-7.46 (m, 2H), 7.25-7.38 (m, 5H), 6.82-6.86 (m, 1H), 384 (M + 1) 86% 12

(300 MHz, CD3OD, δ):
8.97 (d, J = 5.1 Hz, 1H), 8.50 (d, J = 5.4 Hz, 2H), 8.32 (d, J = 5.4 Hz, 2H), 7.83 (d, J = 4.8 Hz, 1H), 7.57 ( s, 1H), 7.44-7.46 (m, 2H), 7.28-7.40 (m, 5H), 6.82-6.86 (m, 1H), 5.11 (s, 2H) 398.2 (M + 1) 82% 13

(300 MHz, DMSO-d6, δ):
10.88 (s, 1H), 10.21 (s, 1H), 9.54 (s, 1H), 8.91 (d, J = 5.1 Hz, 1H), 8.49 (br s, 2H), 7.98 (d, J = 4.8 Hz, 2H), 7.58 (d, J = 4.8 Hz, 1H), 7.35 (s, 1H), 7.15 (m, 2H), 6.57 (m, 1H), 5.10 (s, 2H), 4.30 (m, 1H), 1.00 (d, 6H) 364.2 (M + 1) 84% 14

(300 MHz, CD3OD, δ):
8.78 (d, J = 4.8 Hz, 1H), 8.34 (d, J = 6.3 Hz, 2H), 7.81 (d, J = 6.3 Hz, 2H), 3.67-3.70 (m, 1H), 1.79-2.10 (m) , 4H), 1.69-1.85 (m, 4H) 200 (M + 1) 59% 15

(300 MHz, CD3OD, δ):
8.93 (d, J = 4.8 Hz, 1H), 8.87 (s, 1H), 8.51 (d, J = 7.2 Hz, 2H), 8.32 (d, J = 6.3 Hz, 2H), 7.75 (d, J = 4.8 Hz, 1H), 3.41-3.44 (m, 2H), 3.15 (d, J = 6.0 Hz, 2H), 1.93-2.02 (m, 4H) 313.1 (M + 1) 56% 16

(300 MHz, CD3OD, δ):
8.88 (d, J = 5.4 Hz, 1H), 8.42 (br s, 2H), 8.00 (m, 2H), 7.69 (d, J = 5.1 Hz, 1H), 7.58-7.61 (m, 2H), 7.44- 7.47 (m, 1H), 7.33-7.34 (m, 4H), 6.85-6.88 (m, 1H), 5.22 (s, 2H) 432.4 (M + 1) 84% 17

(300 MHz, CDCl3, δ):
9.56 (s, 1H), 8.80 (d, J = 4.8 Hz, 1H), 8.52 (br s, 1H), 7.65-7.77 (m, 4H), 7.46 (s, 1H), 7.16-7.32 (m, 6H ), 6.80 (d, J = 7.8 Hz, 1H), 5.09 (s, 2H) 432.4 (M + 1) 80% 18

(300 MHz, CD3OD, δ):
8.85 (d, J = 4.8 Hz, 1H), 8.39 (br s, 2H), 7.92 (br s, 2H), 7.65 (d, J = 5.1 Hz, 1H), 7.59 (s, 1H), 7.23-7.45 (m, 6H), 6.82 (d, J = 7.8 Hz, 1H), 5.10 (s, 2H) 432.5 (M + 1) 81% 19

(300 MHz, CD3OD, δ):
8.87 (d, J = 4.5 Hz, 1H), 8.42 (br s, 2H), 8.01 (br s, 2H), 7.86 (s, 1H), 7.69-7.76 (m, 2H), 7.41 (t, J = 7.5 Hz, 1H), 7.24-7.39 (m, 3H), 6.91-7.01 (m, 3H), 5.11 (s, 2H) 398.5 (M + 1) 85% 20

(300 MHz, CD3OD, δ):
8.78 (d, J = 5.4 Hz, 1H), 8.35 (br s, 2H), 7.81 (br s, 2H), 7.51 (d, J = 4.8 Hz, 1H), 7.15-7.29 (m, 5H), 4.59 -4.62 (m, 1H), 3.02-3.08 (m, 1H), 2.78-2.87 (m, 6H), 2.52-2.60 (m, 1H), 2.40-2.45 (m, 1H), 1.82-1.88 (m, 1H) 389 (M + 1) 72% 21

(300 MHz, CD3OD, δ):
8.83 (d, J = 5.1 Hz, 1H), 8.29-8.32 (m, 1H), 7.96 (m, 3H), 7.71-7.78 (m, 3H), 7.67 (d, J = 4.5 Hz, 1H), 7.30 -7.47 (m, 6H), 6.92 (d, J = 7.2 Hz, 1H), 5.27 (s, 2H) 448.3 (M + 1) 80% 22

(300 MHz, CD3OD, δ):
8.85 (d, J = 4.8 Hz, 1H), 8.39 (br s, 2H), 7.92 (br s, 2H), 7.65 (d, J = 5.1 Hz, 1H), 7.59 (m, 3H), 7.23-7.45 (m, 3H), 6.82 (d, J = 7.8 Hz, 1H), 6.05 (s, 2H), 5.10 (s, 2H) 442.1 (M + 1) 80% 23

(300 MHz, DMSO-d6, δ):
10.33 (m, 2H), 8.83 (d, J = 4.8 Hz, 1H), 8.40 (br s, 3H), 7.64-7.77 (m, 5H), 7.44-7.47 (m, 2H), 7.37 (t, J = 7.8 Hz, 1H), 7.11-7.20 (m, 3H), 5.53 (s, 2H) 422.2 (M + 1) 74% 24

(300 MHz, DMSO-d6, δ):
10.28-10.33 (m, 2H), 8.82 (d, J = 4.8 Hz, 1H), 8.39 (br s, 2H), 7.73 (s, 2H), 7.65-7.70 (m, 2H), 7.40-7.56 (m , 4H), 7.33 (t, J = 7.8 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.98-7.02 (m, 2H), 6.49 (d, 1H), 5.44 (s, 2H) 421.2 (M + 1) 70% 25

(300 MHz, CD3OD, δ):
8.84 (d, J = 4.8 Hz, 1H), 8.36 (br s, 2H), 8.20 (br s, 2H), 7.84 (d, J = 5.7 Hz, 2H), 7.62-7.64 (m, 3H), 7.26 -7.41 (m, 4H), 6.91-6.94 (m, 1H), 5.50 (s, 2H) 438.2 (M + 1) 72% 26

(300 MHz, DMSO-d6, δ):
10.31 (s, 1H), 8.79 (d, J = 4.8 Hz, 1H), 8.37 (br s, 2H), 8.13-8.16 (m, 1H), 7.74 (br s, 2H), 7.38 (d, J = 4.8 Hz, 1H), 4.26 (m, 1H), 2.26 (sm, 1H), 1.68-1.74 (m, 4H), 1.28-1.43 (m, 2H), .95 (s, 3H), 0.87 (s, 3H), 0.77 (s, 3H) 352.2 (M + 1) 76% 27

(300 MHz, DMSO-d6, δ):
11.06 (s, 1H), 10.35 (d, J = 7.5 Hz, 2H), 8.94 (d, J = 4.8 Hz, 1H), 8.37 (s, 1H), 8.12 (s, 1H), 7.96 (d, J = 7.5 Hz, 2H), 7.50-7.65 (m, 6H), 7.37 (t, J = 8.1 Hz, 1H) 411.3 (M + 1) 70% 28

(300 MHz, DMSO-d6, δ):
10.33 (s, 1H), 10.21 (s, 1H), 8.74 (d, J = 5.1 Hz, 1H), 7.76-7.78 (m, 4H), 7.48-7.51 (m, 2H), 7.27-7.37 (m, 2H), 7.15 (t, J = 7.5 Hz, 1H), 7.00 (t, J = 7.2 Hz, 1H) 292 (M + 1) 86% 29

(300 MHz, CD3OD, δ):
8.86 (d, J = 5.1 Hz, 1H), 8.77 (s, 1H), 8.40 (br s, 2H), 8.12 (d, J = 8.1 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H) , 7.95 (br s, 2H), 7.70 (d, J = 5.1 Hz, 1H), 7.61 (t, J = 8.1 Hz, 1H) 337.2 (M + 1) 83% 30

(300 MHz, CDCL3, δ):
9.63 (s, 1H), 8.81 (d, J = 4.8 Hz, 1H), 8.54-8.55 (m, 2H), 7.81 (s, 1H), 7.61-7.73 (m, 4H), 7.53 (s, 1H) , 7.34 (t, J = 7.8 Hz, 1H), 7.17-7.26 (m, 5H), 4.92 (s, 2H), 2.95 (s, 2H), 2.28 (s, 6H) 482 (M + 1) 56% 31

(300 MHz, CDCL3, δ):
9.63 (s, 1H), 8.81 (d, J = 4.8 Hz, 1H), 8.54-8.55 (m, 2H), 7.81 (s, 1H), 7.72 (d, J = 4.8 Hz, 1H), 7.61-7.70 (m, 4H), 7.53 (s, 1H), 7.17-7.36 (m, 5H), 6.78 (br s, 1H), 4.92 (s, 2H), 2.95 (s, 2H), 2.28 (s, 6H) 482 (M + 1) 61% 32

(300 MHz, CD3OD, δ):
9.04 (s, 1H), 8.87 (d, J = 4.8 Hz, 1H), 8.42 (s, 1H), 8.09 (s, 2H), 7.67-7.70 (m, 2H), 7.58 (s, 1H), 7.28 -7.29 (m, 2H), 6.83-6.87 (m, 1H), 5.25 (s, 2H) 405.3 (M + 1) 82% 33

(300 MHz, DMSO-d6, δ):
10.39 (s, 1H), 9.84 (s, 1H), 8.87 (d, J = 4.5 Hz, 1H), 8.39 (br s, 2H), 7.76-7.81 (m, 2H), 7.56 (d, J = 5.1 Hz, 1H), 7.31-7.46 (m, 4H), 7.19 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H) 5.08 (s, 2H), 2.31 (s, 3H) 412.3 (M + 1) 80% 34

(300 MHz, DMSO-d6, δ):
10.44 (s, 1H), 10.22 (s, 1H), 8.88-8.91 (m, 1H), 8.40 (br s, 1H), 8.13-8.20 (m, 2H), 7.76 (s, 2H), 7.57-7.61 (m, 1H), 7.32-7.53 (m, 5H), 6.90 (d, J = 8.4 Hz, 1H), 5.12 (s, 2H) 432 (M + 1) 81% 35

(300 MHz, DMSO-d6, δ):
11.16 (s, 1H), 10.27 (s, 1H), 8.95 (d, J = 4.8 Hz, 1H), 8.57 (br s, 2H), 8.12 (s, 2H), 7.60-7.65 (m, 2H), 7.31-7.47 (m, 6H), 7.01 (d, J = 8.7 Hz, 1H), 5.07 (s, 2H), 3.77 (s, 1H) 428.3 (M + 1) 78% 36

(300 MHz, DMSO-d6, δ):
10.54 (s, 1H), 10.40 (s, 1H), 10.30 (s, 1H), 8.87 (d, J = 4.8 Hz, 1H), 8.40 (m, 2H), 8.31 (s, 1H), 8.15 (s , 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.73-7.82 (m, 5H), 7.51-7.59 (m, 2H), 7.35 (d, J = 7.5 Hz, 2H), 7.10 (t, J = 7.5 Hz, 1H) 411.2 (M + `) 76% 37

(300 MHz, DMSO-d6, δ):
10.68 (s, 1H), 10.44 (s, 1H), 10.29 (s, 1H), 8.86 (d, J = 4.8 Hz, 1H), 8.75 (s, 1H), 8.44 (s, 1H), 8.17 (m , 1H), 8.08 (t, J = 7.8 Hz, 1H), 7.88 (br s, 1H), 7.57-7.70 (m, 3H), 7.51 (d, J = 4.8 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H) 412.3 (M + 1) 61% 41

(300 MHz, DMSO-d6, δ):
11.09 (s, 1H), 10.53 (s, 1H), 10.36 (s, 1H), 8.95 (d, J = 5.1 Hz, 1H), 8.60) s, 1H), 8.31 (s, 1H), 8.12 (s , 2H), 7.57-7.68 (m, 4H), 7.33-7.45 (m, 5H) 429 (M + 1) 78% 42

(300 MHz, DMSO-d6, δ):
11.03 (s, 1H), 10.27 (s, 1H), 10.01 (s, 1H), 8.93 (d, J = 4.8 Hz, 1H), 8.14 (s, 3H), 7.61 (d, J = 4.8 Hz, 1H ), 7.47 (s, 1H), 7.31 (s, 2H), 2.04 (s, 3H) 349.2 (M + 1) 81% 43

(300 MHz, DMSO-d6, δ):
10.75 (s, 1H), 10.23-10.27 (m, 2H), 8.89 (d, J = 4.8 Hz, 1H), 8.41 (br s, 2H), 8.15 (m, 4H), 7.56 (d, J = 4.8 Hz, 1H), 7.46-7.48 (m, 1H), 7.26-7.32 (m, 3H), 1.79 (m, 1H), 0.79 (d, 4H) 375 (M + 1) 78% 44

(300 MHz, DMSO-d6, δ):
13.20 (s, 1H), 10.39-10.43 (m, 2H), 10.25 (s, 1H), 8.86 (d, J = 4.8 Hz, 1H), 8.33-8.43 (m, 3H), 7.82 (s, 2H) , 7.51-7.62 (m, 3H), 7.33-7.38 (m, 2H), 7.15 (s, 1H) 401.3 (M + 1) 69% 45

(300 MHz, DMSO-d6, δ):
12.64 (s, 1H), 10.44 (s, 1H), 10.22 (s, 1H), 9.84 (sm 1H), 8.85 (d, J = 4.8 Hz, 1H), 8.40-8.41 (m, 2H), 8.29 ( s, 1H), 7.78-7.80 (m, 4H), 7.56-7.58 (m, 1H), 7.47-7.51 (m, 2H), 7.32 (t, J = 7.8 Hz, 1H) 401.1 (M + 1) 58% 46

(300 MHz, DMSO-d6, δ):
10.78 (s, 1H), 10.51 (s, 1H), 10.39 (s, 1H), 8.87 (d, J = 4.5 Hz, 1H), 8.37 (m, 4H), 8.17 (d, J = 8.4 Hz, 1H ), 8.03 (d, J = 8.1 Hz, 1H), 7.81-7.87 (m, 4H), 7.51-7.55 (m, 2H), 7.16 (t, J = 6.3 Hz, 1H) 412.2 (M + 1) 61% 48

(300 MHz, DMSO-d6, δ):
10.42 (m, 2H), 10.30 (s, 1H), 8.86 (d, J = 5.1 Hz, 1H), 8.35-8.40 (m, 2H), 8.12 (s, 1H), 7.76-7.83 (m, 4H) , 7.35-7.62 (m, 6H) 429.0 (M + 1) 78% 49

(300 MHz, DMSO-d6, δ):
10.94 (s, 1H), 10.34 (s, 1H), 8.92 (d, 1H), 8.13 (s, 2H), 7.79 (s, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.59-7.60 (m, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.16-7.18 (m, 1H), 7.01-7.05 (m, 2H), 6.48-6.57 (m, 4H), 6.28 (s, 1H ), 4.28 (s, 2 H) 397.2 (M + 1) 75% 50

(300 MHz, DMSO-d6, δ):
10.63 (s, 1H), 10.16 (s, 1H), 8.87 (d, J = 5.1 Hz, 1H), 8.41 (s, 1H), 8.12 (s, 1H), 7.90 (m, 3H), 7.53 (d , J = 5.4 Hz, 1H), 7.38 (m, 1H), 7.16-7.26 (m, 2H), 6.36 (s, 1H), 0.62 (m, 2H), 0.39 (m, 2H) 390.1 (M + 1) 83% 51

(300 MHz, DMSO-d6, δ):
10.37-10.43 (m, 2H), 8.87 (d, J = 4.8 Hz, 1H), 8.41 (br s, 2H), 8.10-8.14 (m, 2H), 7.34-7.57 (m, 5H), 7.19 (d , J = 7.8 Hz, 1H), 4.8 (s, 2H) 306.0 (M + 1) 82% 52

(300 MHz, DMSO-d6, δ):
10.36-10.42 (m, 2H), 8.87 (d, J = 4.8 Hz, 1H), 8.41 (br s, 2H), 8.10-8.14 (m, 2H), 7.36 (m, 2H), 7.59 (m, 2H) ), 7.20 (d, J = 7.8 Hz, 1H), 4.72 (s, 2H) 340.0 (M + 1) 85% 53

(300 MHz, DMSO-d6, δ):
13.21 (s, 1H), 10.50 (s, 1H), 8.87 (d, J = 4.5 Hz, 1H), 8.77 (d, J = 8.1 Hz, 1H), 8.43 (m, 2H), 8.07-8.13 (m , 2H), 7.97 (m, 2H), 7.63-7.64 (m, 2H), 7.23 (t, J = 6.9 Hz, 1H) 336.0 (M + 1) 69% 54

(300 MHz, CD3OD, δ):
8.94 (d, 1H), 8.45 (br s, 2H), 8.29-8.32 (m, 1H), 8.17 (m, 2H), 7.82 (m, 1H), 7.33-7.38 (m, 2H), 7.17 (t , J = 6.9 Hz, 1H), 4.79 (s, 2H) 322.1 (M + 1) 76% 55

(300 MHz, CD3OD, δ):
8.87 (d, J = 5.1 Hz, 1H), 8.47 (m, 2H), 8.20 (d, J = 7.8 Hz, 1H), 8.04 (m, 2H), 7.71 (d, J = 5.1 Hz, 1H), 7.15-7.22 (m, 2H), 7.07 (t, J = 7.8 Hz, 1H), 4.42 (m, 2H), 3.40 (m, 2H) 351.1 (M + 1) 57% 56

(300 MHz, DMSO-d6, δ):
10.35 (s, 1H), 10.16 (s, 1H), 8.86 (d, J = 5.1 Hz, 1H), 8.39 (m, 2H), 7.82-7.83 (m, 2H), 7.64-7.66 (m, 1H) , 7.50-7.53 (m, 2H), 7.43 (t, J = 7.8 Hz, 1H), 7.35-7.37 (m, 1H), 4.10 (s, 2H) 331.1 (M + 1) 78% 57

(300 MHz, DMSO-d6, δ):
10.39-10.42 (m, 2H), 8.86 (d, J = 4.8 Hz, 1H), 8.46 (br s, 1H), 8.12 (br s, 1H), 7.76-7.92 (m, 4H), 7.50 (d, J = 4.8 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.17-7.29 (m, 6H), 4.59 (t, J = 8.1 Hz, 1H) 3.16-3.18 (m, 2H) 421.1 (M + 1) 63% 58

(300 MHz, CDCl3, δ):
8.71 (s, 1H), 8.40 (br s, 1H), 7.83 (br s, 1H), 7.70-7.72 (s, 1H), 7.58 (s, 1H), 7.39-7.45 (m, 1H), 7.08- 7.22 (m, 5H), 6.86-6.98 (m, 4H) 3.06-3.08 (m, 2H), 2.87 (m, 2H), 2.50 (s, 1H) 425.1 (M + 1) 56% 59

(300 MHz, DMSO-d6, δ):
10.38-10.40 (m, 2H), 8.85 (d, J = 4.5 Hz, 1H), 7.92 (br s, 2H), 7.77 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 4.5 Hz, 1H), 7.43 (t, J = 8.1 Hz, 1H), 7.19-7.26 (m, 3H), 7.11 (t, J = 8.1 Hz, 1H), 6.93-6.98 (m, 1H), 5.20 (s, 2H ) 416.1 (M + 1) 77% 60

(300 MHz, DMSO-d6, δ):
10.37-10.41 (m, 2H), 8.85 (d, J = 5.1 Hz, 1H), 8.40 (br s, 1H), 8.13 (br s, 1H), 7.75-7.93 (m, 4H), 7.49 (d, J = 5.1 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.08-7.17 (m, 2H), 6.95-7.04 (m, 1H), 5.25 (s, 2H) 434.1 (M + 1) 82% 61

(300 MHz, DMSO-d6, δ):
10.39-10.42 (m, 2H), 8.86 (d, J = 5.1 Hz, 1H), 8.12 (br s, 1H), 7.91 (m, 3H), 7.73-7.75 (m, 1H), 7.50 (d, J = 5.1 Hz, 1H), 7.30-7.45 (m, 3H), 7.13-7.25 (m, 2H), 6.84-6.87 (m, 1H), 5.12 (s, 2H) 434.1 (M + 1) 78% 62

(300 MHz, DMSO-d6, δ):
8.89 (d, J = 4.8 Hz, 1H), 8.45 (br s, 1H), 8.12 (s, 1H), 7.94 (m, 3H), 7.75 (d, J = 6.9 Hz, 1H), 7.54 (d, J = 4.8 Hz, 1H), 7.41-7.46 (m, 2H), 7.21-7.32 (m, 3H), 6.96 (t, J = 7.8 Hz, 1H), 5.23 (s, 2H) 432.1 (M + 1) 79% 63

(300 MHz, CD3OD, δ):
8.79 (d, J = 4.8 Hz, 1H), 8.48 (d, J = 5.7 Hz, 2H), 8.33 (br s, 2H), 7.80 (d, J = 6.0 Hz, 2H), 7.54 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 6.0 Hz, 2H), 4.69 (s, 2H) 307.0 (M + 1) 70% 64

(300 MHz, CD3OD, δ):
8.78 (d, J = 4.8 Hz, 1H), 8.34 (d, J = 6.3 Hz, 2H), 7.81 (d, J = 6.3 Hz, 2H), 3.65-3.72 (m, 1H), 3.19-3.22 (m , 1H), 1.99-2.15 (m, 4H), 1.79-1.93 (m, 4H) 313.2 (M + 1) 61% 65

(300 MHz, CD3OD, δ):
8.77 (d, J = 4.8 Hz, 1H), 8.33 (d, J = 4.8 Hz, 2H), 7.79 (d, J = 5.1 Hz, 2H), 7.50 (d, J = 4.8 Hz, 1H), 4.86 ( m, 1H), 2.78 (m, 1H), 1.82-2.00 (m, 6H), 1.24-1.46 (m, 2H) 313.2 (M + 1) 57% 66

(300 MHz, CD3OD, δ):
8.77-8.80 (m, 1H), 8.35 (br s, 2H), 7.81-7.83 (m, 2H), 7.52 (d, J = 4.8 Hz, 1H), 4.05 (m, 1H), 2.90 (m, 1H ), 1.75-1.89 (m, 4H), 1.47-1.57 (m, 4H) 313.2 (M + 1) 60% 67

(300 MHz, CD3OD, δ):
8.84 (d, J = 4.8 Hz, 1H), 8.32 (d, J = 7.2 Hz, 1H), 8.10 (br s, 1H), 7.80 (d, J = 6.9 Hz, 2H), 7.60 (d, J = 4.8 Hz, 1H), 7.41-7.54 (m, 4H), 4.02-4.06 (m, 2H), 1.92-2.02 (m, 2H), 1.31-1.59 (m, 6H) 417.1 (M + 1) 75%

Manufacturing example  3: Biaryl  ( R1 Having Formula 1  synthesis

Scheme 5

(3-1) Synthesis of Compound 9

A mixture of compound 7 (1 equiv), 3-bromoaniline (1.1 equiv), TBTU (1.5 equiv), Et ₃ N (2 equiv) and DMF was stirred at room temperature for 2 hours and then distilled under reduced pressure to remove DMF and EA After dissolving in, washed with water, brine and dried over MgSO ₄ . Concentrated under reduced pressure distillation and purified by silica gel column chromatography (Hexane: Ethyl acetate = 1: 1, v / v) to give the compound 9 in 85% yield.

(300 MHz, DMSO-d6, δ) 8.84 (d, J = 5.1 Hz, 1H), 8.37 (d, J = 4.8 Hz, 1H), 7.96-7.97 (m, 1H), 7.84 (d, J = 6.6 Hz, 2H), 7.62-7.65 (m, 2H), 7.38 (t, J = 8.1 Hz, 1H), 7.17-7.20 (m, 1H), LCMS (M + 1; 371.1)

(3-2) Synthesis of Compound 10

Compound 9 (1 equiv), Pd (dppf) Cl ₂ (0.1 equiv), dppf (0.1 equiv), and K ₃ PO ₄ (3 equiv) was added to the reaction flask and DME (dimethoxyethane) was added under nitrogen, followed by addition of boronic acid derivative (2 equiv) with stirring at room temperature. The reaction was stirred at 100 ° C for 8 hours, concentrated by distillation under reduced pressure and extracted with EA. The organic layer was washed with brine, dried over MgSO ₄ , and the solvent was removed by distillation under reduced pressure to obtain Compound 10 .

Identification data and yield of the obtained Compound 10 are shown in Table 5 below:

Example Compound structure R 1H NMR LC Mass yield 38

Phenyl (300 MHz, CDCl3, δ):
8.81-8.83 (m, 1H), 8.04 (br s, 2H), 7.91 (br s, 2H), 7.63-7.75 (m, 4H), 7.36-7.49 (m. 6H) 368 (M + 1) 86% 39

3-methylphenyl (300 MHz, DMSO-d6, δ):
10.37-10.43 (m, 2H), 8.87 (d, J = 4.8 Hz, 1H), 8.41 (br s, 2H), 8.10-8.14 (m, 2H), 7.81 (s, 2H), 7.34-7.57 (m , 5H), 7.19 (d, J = 7.8 Hz, 1H), 2.38 (s, 3H) 382.2 (M + 1) 81% 40

2-naphthyl (300 MHz, DMSO-d6, δ):
10.47 (s, 1H), 10.40 (s, 1H), 8.88 (d, J = 4.8 Hz, 1H), 8.35-8.42 (m, 2H), 8.21-8.26 (m, 2H), 8.12 (s, 1H) , 7.93-8.05 (m, 3H), 7.83-7.90 (m, 3H), 7.48-7.63 (m, 5H) 418 (M + 1) 80%

Experimental Example  One: Extracellular  Signal control Kinase  ( ERK -One/ ERK -2) inhibition activity measurement

Extracellular signal-regulated kinade inhibitory activity of the prepared compounds was determined by Koresawa, M. and Okaba, T. (2004) High-throughput screening with quantitation of ATP concentration: A universal non-radioactove, homogenous assay for protien kinases. Assay Drug Dev . Technol . It measured according to the description in 2, 153-60 '.

Each compound of Examples 1 to 67 obtained in Preparation Examples 1 and 2 was dissolved in dimethylsulfoxide (DMSO) at a concentration of 12.5 mM to prepare a sample compound. The enzymatic reaction was performed with 20 mM HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid, pH 7.4), 5 mM MgCl 2, 0.5 mM ethylene glycol tetraacetic acid (EGTA), 200 mM KCl, 0.05% TritonX-100 and 1 mM It was performed in buffer containing DTT (dithiothreitol). After adding 0.33 mg / ml MBP (Maltose Binding Protein) (Upstate) and 1 μM of ATP to the buffer, ERK-1 activity was evaluated by 20 nM of recombinant ERK-1 enzyme (M84490) and ERK-2 activity. 50 nM of recombinant ERK-2 enzyme (M84489) was added thereto and reacted at 30 ° C. for 1 hour. By adding 25 µl of Kinase glo (promega) to 25 µl of the reaction solution, a reaction by Luciferase, which is the second reaction, was carried out to react with ERK-1 or ERK-2, and the amount of ATP remaining was changed to Fusion a-FP (Packard). It measured using. The enzyme inhibitory ability was evaluated by adding a solution prepared by dissolving the sample compound in dimethyl sulfoxide (DMSO) to within 5% of the total reaction solution. In addition, the enzyme inhibitory ability expressed the measured value in the presence of a sample compound with respect to the measured value in the absence of a test compound as a percentage, and the concentration of the compound which inhibits the enzymatic activity of 50% was determined as the IC50 (μM) value.

As a result of measuring the inhibitory activity of the derivative of Formula 1 according to the present invention into ERK1 and ERK2, the inhibitory activity (IC50) against ERK2 was determined in Examples 1, 12, 16, 19, 27, 36, 41, 47, 48, 1 μM or less for compounds 49, 57, 58, 59, 60, and 62, Examples 2, 3, 4, 7, 8, 9, 10, 11, 13, 17, 20, 22, 23, 24, 25 For compounds of, 26, 28, 29, 32, 34, 37, 38, 46, 51, 52, 54, 65, and 66, about 1-10 μM.

More detailed results are shown in Table 6 below.

Example Compound name IC50 (μM) ERK1 ERK2 One 5-Chloro-2- (pyridine-4-amino) -pyrimidine-4-carboxylic acid cyclohexyl amide 1.4 0.8 2 5-Chloro-2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid phenylamide 1.6 1.2 3 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (4-methoxyphenyl) -amide 8.5 7.5 4 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-methoxyphenyl) -amide 7.5 6 7 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-chlorophenyl) -amide 5.7 4 8 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid ((S) -2-hydroxy-1-phenylethyl) -amide 5.5 5 9 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-hydroxymethylphenyl) -amide 5.6 4.5 10 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-hydroxyphenyl) -amide 3.7 2.8 11 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-phenoxyphenyl) -amide 3.4 4.1 12 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzyloxyphenyl) -amide 0.47 0.66 13 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-isobutoxyphenyl) -amide 7 9.5 16 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2-chlorobenzyloxy) -phenyl] -amide 0.6 0.5 17 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3-chlorobenzyloxy) -phenyl] -amide 4.8 5 18 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (4-chlorobenzyloxy) -phenyl] -amide > 10 10 19 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-phenoxymethylphenyl) -amide 0.33 0.27 20 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (1-phenethylpyrrolidin-3-yl) -amide 7.6 5.5 22 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (benzo [1,3] dioxo-4-ylmethoxy) -phenyl] -amide 1.8 1.4 23 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzoimidazol-1-ylmethyl-phenyl) -amide 3.5 2.3 24 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-indol-1-ylmethylphenyl) -amide 2.2 1.3 25 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3H-benzoimidazol-4-ylmethoxy) -phenyl] -amide 1.4 1.1 26 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid ((1S, 2S, 4S) -1,7,7-trimethyl-bicyclo [2.2.1] hept-2-yl)- Amide 3 1.9 27 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzoylamino-phenyl) -amide 0.42 0.24 28 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid phenylamide 3.6 3.7 29 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-nitrophenyl) -amide 2.3 1.1 32 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (thiazol-4-ylmethoxy) -phenyl] -amide 3 2.1 34 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (5-benzyloxy-2-chlorophenyl) -amide 2.8 1.6 36 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-phenylcarbamoylphenyl) -amide 0.44 0.46 37 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid {3-[(pyridine-2-carbonyl) -amino] -phenyl} -amide 9.3 7 38 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid biphenyl-3-ylamide 10.3 7.8 41 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2-fluorobenzoylamino) -phenyl] -amide 0.72 0.74 46 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (pyridin-2-ylcarbamoyl) -phenyl] -amide 2.9 2 47 5-Chloro-2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzyloxy-phenyl) -amide 0.71 0.4 48 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3-fluoro-benzoylamino) -phenyl] -amide One 0.85 49 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-phenylaminomethyl-phenyl) -amide 0.9 0.65 50 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3-cyclopropyl-ureido) -phenyl] -amide 7 11.5 51 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid benzylamide 4.5 7.25 52 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid 4-chloro-benzylamide 3.3 3.95 54 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (2-hydroxymethyl-phenyl) -amide 3.35 4.05 57 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (1-cyano-2-phenyl-ethyl) -phenyl] -amide 0.275 0.235 58 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (1-aminomethyl-2-phenyl-ethyl) -phenyl] -amide 0.505 0.41 59 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2-fluoro-phenoxymethyl) -phenyl] -amide 0.315 0.22 60 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2,3-difluoro-phenoxymethyl) -phenyl] -amide 1.2 0.98 62 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2-chloro-phenoxymethyl) -phenyl] -amide 0.855 0.8 65 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-amino-cyclohexyl) -amide 2.7 3.2 66 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (4-amino-cyclohexyl) -amide 3.3 3.5

Comparative example

Formula 1 is similar to the formula (1) of the present invention, but the IC50 value of the compound of formula (2) or formula (3) having a phenyl substituent or a 3-pyridine substituent in the aminopyrimidine-4-carboxylic acid nucleus but not a 4-pyridine substituent is obtained. It was compared with the compound of.

 [Formula 2]

(3)

Compounds 2-1, 2-2 and 2-3 were synthesized in the same manner as in Preparation Example 2, instead of 4-bromopyridine, using bromobenzene for compounds 68 and 69 and 3-bromopyridine for compound 70. .

compound Compound name 1H NMR LC Mass yield 68 2-phenylamino-pyrimidine-4-carboxylic acid phenylamine (300 MHz, DMSO-d6, δ):
10.23 (s, 1H), 9.88 (s, 1H), 8.74 (d, J = 5.1 Hz, 1H), 7.76-7.78 (m, 4H), 7.30-7.42 (m, 5H), 7.15 (t, J = 7.5 Hz, 1H), 7.00 (t, J = 7.2 Hz, 1H) 291 (M + 1) 86% 69 2-phenylamino-pyrimidine-4-carboxylic acid (3-chlorophenyl) -amide (300 MHz, DMSO-d6, δ):
10.45 (s, 1H), 9.86 (s, 1H), 8.74 (d, J = 4.5 Hz, 1H), 7.98 (s, 1H), 7.76-7.78 (m, 2H), 7.67 (d, J = 8.1 Hz , 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.30-7.35 (m, 3H), 7.21 (d, J = 7.2 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H) 326.1 (M + 2) 82% 70 2- (Pyridin-3-ylamino) -pyrimidine-4-carboxylic acid (3-benzyloxyphenyl) -amide (300 MHz, DMSO-d6, δ):
10.27 (s, 1H), 10.09 (s, 1H), 8.92 (s, 1H), 8.77 (d, J = 4.8 Hz, 1H), 8.22-8.26 (m, 2H), 7.57 (s, 1H), 7.26 -7.47 (m, 9H), 6.80-6.83 (m, 1H), 5.10 (s, 2H) 398.1 (M + 1) 74%

Specifically, IC50 values were measured in the same manner as in Experimental Example 1, using the compounds 68, 69, and 70 shown in Table 6 below, and the results correspond to the compounds of the compounds Nos. 68, 69, and 70. It is shown in Table 6 below with the results obtained in the compounds of Examples 7, 12 and 28 of the present invention having a structure to.

Comparison of ERK Inhibitory Activity According to Compound Structure Comparative example rescue IC50 (μM) Example rescue IC50 (μM) ERK1 ERK2 ERK1 ERK2 68

> 50 > 50 28

3.6 3.7 69

> 50 > 50 7

5.7 4 70

> 50 > 50 12

0.47 0.66

As identified in Table 6 above, compounds 68, 69 and 70, although having similar diatoms as the formula of the present invention, are phenyl substituents or 3 that are not 4-pyridine substituents on the aminopyrimidine-4-carboxylic acid parent Compounds having a pyridine substituent did not show ERK inhibitory activity (IC 50) even at 50 μM. On the other hand, Examples 7, 12, and 28, which are the corresponding compounds having the structure of Formula 1 of the present invention, show an ERK inhibitory effect of 10 μM or less. These results indicate that the 4-pyridine substituent located at the aminopyrimidine-4-carboxylic acid nucleus in the general formula (1) of the present invention plays an important role in the inhibition of kinase activity. It can be seen that the aminopyridine derivatives of similar structure are novel as well as have significant kinase inhibitory activity.

Experimental Example  2: MTS  Essay

In order to confirm that the compounds prepared in Preparation Examples 1 and 2 had cancer cell proliferation inhibitory effects through inhibition of extracellular signal-regulated kinase activity, MTS assays were performed on the compounds of Examples 12, 16, 19, 41, and 49. (Barltrop, JA et al (1991) 5- (3-carboxymethoxyphenyl) -2- (4,5-dimethylthiazoly) -3- (4-sulfophenyl) tetrazolium, inner salt (MTS) and related analog of 3- ( 4,5-dimethylthiazolyl) -2,5, -diphenyltetrazolium bromide (MTT) reducing to purple water soluble formazans as cell-viability indicators Bioorg Med Chem Lett 1, 611-4;..... Cory, AH et al (1991 ) Use of an aqueous soluble tertrazolium / formazan assay for cell growth assays in culture. Cancer Comm . 3 , 207-12.)

Human colon cell lines COLO-205 (ATCC, http://www.atcc.org/) and HCT116 cells (ATCC, http://www.atcc.org/) were analyzed as follows.

COLO-205 cells contained 96 well plates containing RPMI1640 medium (GIBCO, invitrogen) containing 5% FBS, while HCT116 cells contained Dulbecco's Modified Eagle Medium (DMEM) medium containing 5% FBS (GIBCO, invitrogen). In 96-well plate, each was dispensed at a concentration of 5000 cells / well, and then incubated for 24 hours at 5% CO ₂ and 37 ℃. Each well was then treated with compounds of the above examples at concentrations of 0.2, 1, 5, 25 and 100 μM, respectively, and treated with dimethyl sulfoxide (DMSO) at 0.08% by weight, the same as the percent used for compound treatment. . Each cell was then incubated for 48 hours.

AQ_ueous Non-Radioactive Cell Proliferation Assay Kit(Promega)에서 제공되는 MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt)와 PMS (phenazine methosulfate) 혼합액 20 ul를 첨가하여 37℃조건에서 1시간 동안 더 배양하였다. 그 후 490 ㎚에서 흡광도를 측정하였다. 화합물을 처리하지 않은 대조군 세포의 흡광도를 기준으로 각 화합물들의 처리 농도에 따른 세포증식 저해정도를 산출하였으며, 이때 암세포의 증식을 50% 억제하는 각 화합물의 농도를 EC50(μM) 값으로 산출하였다. In order to confirm the viability of the cells, CellTiter 96 was added to each cultured cell medium.

MTS (3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium provided by AQ _ueous Non-Radioactive Cell Proliferation Assay Kit (Promega) , inner salt) and 20 ul of PMS (phenazine methosulfate) mixture were added and incubated for 1 hour at 37 ° C. The absorbance was then measured at 490 nm. The degree of inhibition of cell proliferation according to the treatment concentration of each compound was calculated based on the absorbance of the control cells not treated with the compound, and the concentration of each compound that inhibits the proliferation of cancer cells by 50% was calculated as an EC 50 (μM) value.

The results thus obtained are shown in Table 9 below.

Example Compound name EC50 (μM) Colo-205 HCT-116 12 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzyloxyphenyl) -amide 24 23 16 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2-chlorobenzyloxy) -phenyl] -amide 9 14 19 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-phenoxymethylphenyl) -amide 17 14 27 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzoylamino-phenyl) -amide 40 18 41 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2-fluorobenzoylamino) -phenyl] -amide 12 16 49 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-phenylaminomethyl-phenyl) -amide 13 11 Control group Sorafenib (Bayer) 19 6

As a result of the cancer cell proliferation inhibition test of the compound of the present invention, the EC50 value of all the test compounds was 40 μM or less, and the compounds of Examples 12, 16, 19, 41, and 49 had a very good cancer cell proliferation inhibitory effect of 20 μM or less of the EC50. Showed. On the other hand, none of the compounds of Comparative Examples showed a proliferation inhibitory effect on cancer cells.

Claims (9)

A compound of formula 1, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof.
[Formula 1]

R1 is H, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted, cycloalkyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms substituted, heterocycloalkyl of 3 to 6 carbon atoms, carbon atoms substituted Heterocycloalkyl of 3 to 6, aryl of 3 to 6 carbon atoms, aryl of 3 to 6 carbon atoms substituted, hetero aryl of 3 to 6 carbon atoms, or heteroaryl of 3 to 6 carbon atoms,
R 2 is H or halogen,
The substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and substituted heteroaryl may have one or more hydrogen atoms, straight or branched alkyl of 1 to 6 carbon atoms, straight or branched alkyl of 1 to 6 carbon atoms. Oxy, halogen, hydroxy, nitro, aryl having 3 to 6 carbon atoms, aryloxy having 3 to 6 carbon atoms, benzimidazolyl methyl, hydroxymethyl, heteroaryl, fluorophenoxymethyl, difluorophenoxymethyl, Chlorophenoxymethyl, chlorophenyl, carboxyphenyl, aminoethyloxy, cyanomethyl, benzyl, amine, piperidine, benzyloxy, chlorobenzyloxy, phenoxymethyl, phenylethyl, naphthoxymethyl, benzodioxoylme Methoxy, indolyl, benzoylamino, fluorobenzoyl amino, acetylamino, cyclopropanecarbonylamino, imidazolylcarbonylamino, pyridinecarbonylamino, benzyljade , Thiazol-ylmethoxy, phenylcarbamoyl, pyridine, carbamoyl, phenyl, naphthyl, phenyl-amino-methyl and propyl urea cycle would cost Ido substituted with one or more selected from the group consisting of,
Wherein said hetero cycloalkyl and hetero aryl are those wherein at least one of the carbon atoms constituting the ring is substituted with N. The method of claim 1, wherein
R 1 is selected from the group consisting of the following compounds (a) to (w), a compound of Formula 1, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof:

Wherein,
R3 is H,
R4 is H, straight or branched alkoxy, phenyl, benzyl, or halogen substituted benzyl of 1 to 5 carbon atoms,
R 5 is H, phenyl, halogen substituted phenyl, or naphthyl,
R6 is halogen, straight or branched alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 5 carbon atoms,
R7 is a 5- or 6-membered cyclic compound comprising alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, halogen substituted phenyl, or N,
R8 is H, CH ₂ OH, CO ₂ H, O (CH ₂ ) NH ₂ , or CH ₂ CN,
R 9 is NO ₂ , phenyl, toluyl, or naphthyl,
A is CH or N. The method of claim 2,
R 3 is H or benzyl,
R 4 is H, isopropyloxy, phenyl, benzyl, or Cl-benzyl,
R 5 is H, phenyl, F-phenyl, di-F-phenyl, ortho-Cl-phenyl, or naphthyl,
R 6 is Cl, methyl, or methoxy,
R7 is methyl, cyclopropyl, phenyl, F-phenyl, pyrimidyl, or imidazole,
R8 is H, CH ₂ OH, CO ₂ H, O (CH ₂ ) NH ₂ , or CH ₂ CN,
R 9 is NO ₂ , phenyl, m-toluyl, or naphthyl,
A is CH or N,
A compound of formula 1, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof. The method of claim 1, wherein
A compound of formula 1, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof, selected from the group consisting of:
5-Chloro-2- (pyridine-4-amino) -pyrimidine-4-carboxylic acid cyclohexyl amide, 5-chloro-2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid phenyl Amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (4-methoxyphenyl) -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-methoxyphenyl) -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (2-methoxyphenyl) -amide, 2- (pyridin-4-ylamino)- Pyrimidine-4-carboxylic acid (4-chlorophenyl) -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-chlorophenyl) -amide, 2- (pyridine- 4-ylamino) -pyrimidine-4-carboxylic acid ((S) -2-hydroxy-1-phenylethyl) -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxyl Acid (3-hydroxymethylphenyl) -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-hydroxyphenyl) -amide, 2- (pyridin-4-yl Amino) -pyrimidine-4-carboxylic acid (3-phenoxyphenyl) -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzyloxyphenyl) -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-isobutoxyphenyl) -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid Ferridin-4-ylamide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (piperidin-4-ylmethyl) -amide, 2- (pyridin-4-ylamino) -Pyrimidine-4-carboxylic acid [3- (2-chlorobenzyloxy) -phenyl] -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3- Chlorobenzyloxy) -phenyl] -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (4-chlorobenzyloxy) -phenyl] -amide, 2- (pyridine- 4-ylamino) -pyrimidine-4-carboxylic acid (3-phenoxymethylphenyl) -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (1-phenethylpyrroli Din-3-yl) -a Amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (naphthalen-1-yloxymethyl) -phenyl] -amide, 2- (pyridin-4-ylamino)- Pyrimidine-4-carboxylic acid [3- (benzo [1,3] dioxo-4-ylmethoxy) -phenyl] -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxyl Acid (3-benzoimidazol-1-ylmethyl-phenyl) -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-indol-1-ylmethylphenyl) -amide, 2- (Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3H-benzoimidazol-4-ylmethoxy) -phenyl] -amide, 2- (pyridin-4-ylamino) -Pyrimidin-4-carboxylic acid ((1S, 2S, 4S) -1,7,7-trimethyl-bicyclo [2.2.1] hept-2-yl) -amide, 2- (pyridin-4-yl Amino) -pyrimidine-4-carboxylic acid (3-benzoylamino-phenyl) -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid phenylamide, 2- (pyridine-4 -Ylamino) -pyrimidine-4-carboxylic acid (3-knight Phenyl) -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid {3- [benzyl- (2-dimethylaminoacetyl) -amino] -phenyl} -amide, 2- ( Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-{[(2-dimethylamino-acetyl) -phenyl-amino] -methyl} -phenyl) -amide, 2- (pyridine-4 -Ylamino) -pyrimidine-4-carboxylic acid [3- (thiazol-4-ylmethoxy) -phenyl] -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (5-benzyloxy-2-methylphenyl) -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (5-benzyloxy-2-chlorophenyl) -amide, 2- (pyridine 4-ylamino) -pyrimidine-4-carboxylic acid (3-benzyloxy-4-methoxyphenyl) -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid ( 3-phenylcarbamoylphenyl) -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid {3-[(pyridine-2-carbonyl) -amino] -phenyl} -amide, 2- (pyridin-4-yl) No) -pyrimidine-4-carboxylic acid biphenyl-3-ylamide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3'-methyl-biphenyl-3-yl ) -Amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-naphthalen-2-yl-phenyl) -amide, 2- (pyridin-4-ylamino) -pyrimidine 4-carboxylic acid [3- (2-fluorobenzoylamino) -phenyl] -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-acetylaminophenyl)- Amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (cyclopropanecarbonylamino) -phenyl] -amide, 2- (pyridin-4-ylamino) -pyrimidine 4-carboxylic acid {3-[(1H-imidazol-2-carbonyl) -amino] -phenyl} -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid { 3-[(1H-Imidazole-4-carbonyl) -amino] -phenyl} -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (pyridine-2- Ylcarbamoyl) -phenyl]-flax De, 5-chloro-2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzyloxy-phenyl) -amide, 2- (pyridin-4-ylamino) -pyrimidine- 4-carboxylic acid [3- (3-fluoro-benzoylamino) -phenyl] -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-phenylaminomethyl-phenyl ) -Amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3-cyclopropyl-ureido) -phenyl] -amide, 2- (pyridin-4-ylamino ) -Pyrimidine-4-carboxylic acid benzylamide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid 4-chloro-benzylamide, 2-{[2- (pyridine-4- Monoamino) -pyrimidine-4-carbonyl] -amino} -benzoic acid, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (2-hydroxymethyl-phenyl) -amide, 2 -(Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [2- (2-amino-ethoxy) -phenyl] -amide, 2- (pyridin-4-ylamino) -pyrimidine-4 -Carboxylic acid (2- Cyanomethyl-phenyl) -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (1-cyano-2-phenyl-ethyl) -phenyl] -amide, 2 -(Pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (1-aminomethyl-2-phenyl-ethyl) -phenyl] -amide, 2- (pyridin-4-ylamino)- Pyrimidine-4-carboxylic acid [3- (2-fluoro-phenoxymethyl) -phenyl] -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- ( 2,3-Difluoro-phenoxymethyl) -phenyl] -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (3,4-difluoro-phenoxy Dimethyl) -phenyl] -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid [3- (2-chloro-phenoxymethyl) -phenyl] -amide, 2- (pyridine 4-ylamino) -pyrimidine-4-carboxylic acid (pyridin-4-ylmethyl) -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid ((1S, 2S ) -2-amino-cyclohexyl) -amide, 2- (pyridin-4-ylamino) -Pyrimidine-4-carboxylic acid (3-amino-cyclohexyl) -amide, 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (4-amino-cyclohexyl) -amide, And 2- (pyridin-4-ylamino) -pyrimidine-4-carboxylic acid (3-benzoylamino-cyclohexyl) -amide. The method of claim 1, wherein
R1 is cyclohexyl, benzyloxyphenyl, chlorobenzyloxyphenyl, phenoxymethylphenyl, benzoylaminophenyl, phenylcarbamoylphenyl, fluorobenzoylaminophenyl, phenylaminomethylphenyl, cyanophenylethylphenyl, aminomethylphenylethylphenyl, fluoro Rophenoxymethylphenyl, difluorophenoxymethylphenyl, chlorophenoxymethylphenyl, phenyl, methoxyphenyl, chlorophenyl, hydroxyphenylethyl, hydroxymethylphenyl, hydroxyphenyl, phenoxyphenyl, isobutoxyphenyl, chlorobenzyl Oxyphenyl, phenethylpyrrolidinyl, benzodioxoylmethoxyphenyl, benzoimidazolylmethylphenyl, indolylmethylphenyl, benzoimidazolylmethoxyphenyl, trimethylbicycloheptyl, nitrophenyl, thiazolylmethoxyphenyl, benzyloxy Chlorophenyl, pyridinecarbonylaminophenyl, biphenyl, pyridinylcarbamoylphenyl, benzyl, chlorobenzyl, hydroxymeth Ylphenyl, and aminocyclohexyl selected from the group consisting of
A compound of formula 1, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof. The method of claim 5, wherein
R1 is cyclohexyl, benzyloxyphenyl, chlorobenzyloxyphenyl, phenoxymethylphenyl, benzoylaminophenyl, phenylcarbamoylphenyl, fluorobenzoylaminophenyl, phenylaminomethylphenyl, cyanophenylethylphenyl, aminomethylphenylethylphenyl, fluoro Rophenoxymethylphenyl, difluorophenoxymethylphenyl, and chlorophenoxymethylphenyl,
A compound of formula 1, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof. A composition for inhibiting extracellular signal-regulated kinase activity containing the compound of formula 1 according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof as an active ingredient. A composition for the prophylaxis or treatment of cancer comprising the compound of formula 1 according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof as an active ingredient. The method of claim 8, wherein the cancer is lung cancer, pancreatic cancer, colon cancer, myeloid leukemia, thyroid cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, brain cancer, A composition for preventing or treating cancer, which is cancer, sarcoma, tetracarcinomas, neuroblastomas, renal carcinomas, liver cancers, non-Hodgkin's lymphomas, multiple myeloma, or thyroid undifferentiated cancers of mesenchymal origin.