KR20150001353A - Pyrimidine derivatives having inhibitory activity on fms kinases - Google Patents

Abstract

A compound selected from a pyrimidine derivative of chemical formula 1, a pharmaceutically acceptable salt of the same, an optical isomer, a hydride, and a solvate has excellent inhibitory activity on FMS kinase. Thus, a pharmaceutical composition including the same has excellent effects for preventing or treating immune diseases, metabolic diseases, inflammatory diseases, and cancer. In the chemical formula 1, A, Y, R1, R2, R3, and R11 are same as defined in the specification.

Description

[0001] PYRIMIDINE DERIVATIVES HAVING INHIBITORY ACTIVITY ON FMS KINASES [0002]

The present invention relates to a novel pyrimidine derivative having FMS kinase inhibitory activity and a pharmaceutical composition for the prophylaxis and treatment of diseases caused by FMS kinase.

Protein kinases play an important role in intracellular signaling through the phosphorylation of the hydroxy group present in the tyrosine, serine or threonine residues of proteins As an enzyme responsible, it is deeply involved in the growth, differentiation and proliferation of cells.

In order for cells to maintain homeostasis, the on and off of intracellular signaling processes must be balanced. However, overexpression or mutation of a specific protein kinase leads to a variety of diseases such as various cancers, inflammatory diseases, metabolic diseases, or brain diseases when the normal intracellular signal transduction process is disrupted (mainly intracellular signal transduction is continued). Protein kinase is presumed to contain 518 species, which accounts for about 1.7% of total human genes, and is largely divided into tyrosine protein kinases (over 90 species) and serine / threonine protein kinases. Tyrosine protein kinases can be divided into 20 subtypes, 58 receptor tyrosine kinases, and 10 subfamilies, 32 cytoplasmic / nonreceptor tyrosine kinases. Receptor tyrosine kinase has a domain capable of accepting a growth factor on the cell surface and an active site capable of phosphorylating a tyrosine residue in the cytoplasm. When the growth factor is bound to the growth factor receptor site on the cell surface, the receptor tyrosine kinase forms a polymer and the cytoplasmic active site tyrosine residue is autophosphorylated. Subsequently, the cytoplasmic protein kinases of the lower lineage are sequentially phosphorylated, and the extracellular signal is transferred into the nucleus to transcribe and synthesize various genes involved in growth, differentiation and proliferation. It is known that when protein kinase is overexpressed or abnormally activated through mutation, various diseases such as cancer are induced.

FMS (c-fms; cellular feline McDonough sarcoma), a protein kinase, is also known as CSF-1R (Colony-Stimulating Factor-1 Receptor), and Susan McDonough, It is a member of the first group of genes isolated from the strain. FMS is a receptor for macrophage-colony-stimulating factor (M-CSF) and is classified as a type III receptor tyrosine kinase (class III RTK) with Kit, Flt-3 and PDGFR, (C-fms proto-oncogene). M-CSF is also referred to as CSF-1 and can be actively expressed in rat endothelial cells (RACE) and is also useful as a biomarker of rat arterial blood vessels.

FMS is a protein that controls the proliferation, survival, differentiation and migration of macrophages and osteoclasts. It regulates the secretion of macrophage cytokines through synergistic action with other proteins and regulates innate immunity and tissue growth And functions. FMS plays an important role in inflammation and bone erosion, in particular, by participating in monocyte-activated macrophage-activated and osteoclast differentiation processes. Specifically, when M-CSF is initially bound to the FMS of mononuclear leukocytes, RANK (a receptor activator of NF-κB) is expressed to become a bipotential precursor and diffuse. The precursor is activated as a macrophage when the RANKL (RANK ligand) is not bound to the expressed RANK and is involved in the inflammatory cytokine secretion such as TNF-α and IL-1β, and the M-CSF is involved and RANKL When combined, they are differentiated into osteoclasts and are involved in bone erosion. In general, FMS is known to be restricted in synovium within the joints.

Such FMS kinases are related to immune diseases, metabolic diseases, inflammatory diseases or cancers and specifically include rheumatoid arthritis, osteoporosis, Crohn's disease, arteriosclerosis, hyperlipidemia, lung cancer, breast cancer , And prostate cancer.

Rheumatoid arthritis is a chronic inflammatory disease characterized by multiple arthritis. Initially, the synovial membrane surrounding the joint is inflamed, but inflammation spreads to surrounding cartilage and bones, causing destruction and deformation of joints. . For example, in the late phase of rheumatoid arthritis, a finger deformity of the thumb, a ulnar deviation of the metacarpophalangeal joint, and a swan-neck deformity of the finger fingers and so on.

Patients with rheumatoid arthritis are estimated to be about 30 million people, or about 1% of the world's population, and more women are among the 20 to 45 year olds. The market for the treatment of rheumatoid arthritis is growing annually. For example, it is known that TNF (tumor necrosis factor) inhibitors, nonsteroidal anti-inflammatory drugs (NSAID), acute inflammatory inducers (COX-2) disease-modifying antirheumatic drugs, and steroids. In particular, the market for TNF inhibitors (anti-TNF) has grown rapidly from $ 13.7 billion in 2007 to $ 18 billion in 2008 and the market for DMARDs is growing from $ 2.5 billion in 2007 to $ 3 billion in 2008.

In the treatment of rheumatoid arthritis, disease-modifying antirheumatic drugs (DMARDs) are prescribed to improve symptoms. The biological agents used in the treatment of rheumatoid arthritis are primarily prescribed TNF inhibitors (anti-TNF), which are currently marketed include Enbrel (TM), Humira (TM), Adalimumab, Remicade (TM) infliximab, and Cimzia ™ (certolizumab), which are prescribed in combination with methotrexate (methotrexate). If such a primary prescription fails, the recommended treatment in the National Institute of Health and Clinical Nutrition (NICE) is that rituximab is secondarily prescribed in combination with MTX. If such secondary regimens fail or are expected to have adverse effects on rituximab, it may be considered to prescribe TNF inhibitors or, in the third, to administer abatacept or tocilizumab in combination with MTX.

However, despite the existence of various DMARD and biological agents as described above, oral preparations have not yet been developed. Therefore, it is necessary to improve the drug efficacy through development of oral preparations.

 D'Aura swanson, C. et al., Tyrosine kinases as targets for treatment of rheumatoid arthritis, Nat. Rev. Rheumatol. 5, pp. 317-324 (2009)  Fiona J. Pixley and E. Richard Stanley, CSF-1 regulation of the wandering macrophage: complexity in action, Trend in Cell Bio. 14 (11) pp.628-638 (2004)

It is an object of the present invention to provide novel pyrimidine derivatives having excellent inhibitory activity against FMS kinase.

It is another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of diseases caused by FMS kinase.

According to this object, the present invention provides a compound selected from pyrimidine derivatives of formula (I), pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof:

Formula 1

A is -CH- or -N-;

Y is H, halogen, _{amino, -NHR, -NH- (CH 2)} m -N (R) 2 or _{-NH- (CH 2) m -C 6} - 12 aryl, wherein R is C _{1 - 10} alkyl, or C _{3 - 10} cycloalkyl, m is an integer from 1 to 6;

R ₁ is H, C _{1 - 10} alkyl or halogen;

R ₂ is H, C _{1 - 10} alkyl, C _{2 - 10} alkenyl, C _{3 - 10} cycloalkyl, or halogen;

R ₃ is H, C _{1 - 10} alkyl, or - a (CH _{2) n} R _4, wherein n is an integer from 0 to 6, R ₄ is C _1-6 alkylamino, di-C _{1 - 6} alkylamino, C _{1 - 6} alkoxy, C _{2 - 5} alkynyl, C _{3 - 10} cycloalkyl, 5-12 membered heterocycloalkyl of, C _{6 - 12} aryl or 5-12 membered heteroaryl of;

R ₁₁ is H, C _{1 - 10} alkyl, C _{3 - 10} cycloalkyl, or - a _{(CH 2) m -N (R} ) 2, wherein R or m are as defined above;

At this time, the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently C _{1 - 6} alkyl, C _{1 - 6} alkylamino, C _{1 - 6} alkoxy, halogen, haloalkyl, nitro, cyano, carbonyl amino , aminocarbonyl, sulfinyl, C _{1 - 6} alkylsulfonyl, C _{1 - 6} alkyl-sulfonylamino, C _1-6 alkyl aminosulfonyl, phenyl, C _{3 - 10} cycloalkyl, and alkyl heterocycloalkyl of 5-6 won Alkyl, < / RTI >< RTI ID = 0.0 >

Wherein said heteroaryl and heterocycloalkyl each independently comprise one or more heteroatoms selected from the group consisting of N, O and S.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising the compound as an active ingredient.

The pyrimidine derivative of formula (I) of the present invention, its pharmaceutically acceptable salt, optical isomer, hydrate or solvate thereof is excellent in inhibitory activity against FMS kinase, and the pharmaceutical composition comprising the pyrimidine derivative of the present invention has immune diseases caused by FMS kinase , A metabolic disease, an inflammatory disease, or cancer.

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

The term " halogen ", as used herein, unless otherwise indicated, means fluorine, chlorine, bromine or iodine.

The term " alkyl ", as used herein, unless otherwise indicated, refers to straight or branched hydrocarbon residues.

The term " cycloalkyl ", as used herein, unless otherwise indicated, refers to cyclic alkyl including cyclopropyl and the like.

The term " aryl ", as used herein, unless otherwise indicated, refers to an aromatic group including phenyl, naphthyl, and the like.

The term " heterocycloalkyl ", as used herein, unless otherwise indicated, refers to a monocyclic or bicyclic cyclic alkyl containing one or more heteroatoms selected from O, N, and S. Examples of monoheterocycloalkyl include, but are not limited to, piperidinyl, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperazinyl, and similar groups no.

The term " heteroaryl ", as used herein, unless otherwise indicated, refers to a monocyclic or bicyclic or higher aromatic group containing a heteroatom selected from O, N and S. Examples of monocyclic heteroaryl include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, But are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and similar groups. Examples of bicyclic heteroaryls include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, Isoquinolinyl, isoquinolinyl, purine, furopyridinyl, and similar groups.

In an example of the compound of formula (I) according to the present invention, A is -N-; Wherein Y is a halogen, amino, -NHR or _{-NH- (CH 2) m -N (} R) 2, wherein R is C _{3 - 8} cycloalkyl, m is an integer from 1 to 6; Wherein R < ₁ > is H; Wherein R ₂ is C _{1 - 8} alkyl or C _{3 - 8} cycloalkyl; Wherein R ₃ is - (CH _{2) n} and R _4, wherein n is an integer from 0 to 6, R ₄ is C _3-8 cycloalkyl, C _{6 - 12} aryl or 5-12 membered heteroaryl of; Wherein R ₁₁ is H, C _{1 - 8} alkyl, C _3-8 cycloalkyl, or - a _{(CH 2) mN (R)} 2, wherein R or m are as defined above; At this time, the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently C _{1 - 4} alkyl, C _{1 - 4} alkylamino, C _{1 - 4} alkoxy, halogen, haloalkyl, nitro, cyano, carbonyl amino , aminocarbonyl, sulfinyl, C _{1 - 4} alkylsulfonyl, C _{1 - 4} alkyl-sulfonylamino, C _{1 - 4} alkyl, aminosulfonyl, phenyl, C _{3 - 8} cycloalkyl, and 5-6 membered heterocycloalkyl Alkyl, wherein said heteroaryl and heterocycloalkyl each independently comprise one or more heteroatoms selected from the group consisting of N, O, and S;

Preferred examples of pyrimidine derivatives according to the present invention are as follows, and pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof are also included in the scope of the present invention:

1) Preparation of 1- (6- (2,4-dimethoxybenzylamino) pyrimidin-4-yl) ) -1H-indazol-4-yl) urea;

2) 1- (6-Aminopyrimidin-4-yl) -1-methyl-3- (3- Yl) urea;

3) 1- (6-Chloropyrimidin-4-yl) -3- (3-cyclopropyl- 1-methylurea;

4) 1- (6-Chloropyrimidin-4-yl) -1-methyl-3- (3- Yl) urea;

5) 1- (6- (2,4-dimethoxybenzylamino) pyrimidin-4-yl) -3- -Indazol-4-yl) -1-methylurea;

6) 1- (6-Aminopyrimidin-4-yl) -3- (l- (6-methoxypyridin- 2- yl) methyl) 1-methylurea;

7) 1- (6- (2,4-dimethoxybenzylamino) pyrimidin-4-yl) -3- -Indazol-4-yl) -1-methylurea;

8) 1- (6-Aminopyrimidin-4-yl) -3- (1- (6-ethoxypyridin- 1-methylurea;

9) 1- (6- (2,4-Dimethoxybenzylamino) pyrimidin-4-yl) -3- -Indazol-4-yl) -1-methylurea;

10) 1- (6-Aminopyrimidin-4-yl) -3- (1- (6-fluoropyridin- 1-methylurea;

11) 1- (6- (2,4-Dimethoxybenzylamino) pyrimidin-4-yl) -1- Yl) methyl) -1H-indazol-4-yl) urea;

12) 1- (6-Aminopyrimidin-4-yl) -1-methyl-3- (3- Indazol-4-yl) urea;

13) 1- (6- (2,4-dimethoxybenzylamino) pyrimidin-4-yl) -3- -Indazol-4-yl) -1-methylurea;

14) 1- (6-Aminopyrimidin-4-yl) -3- (l- (6-isopropylpyridin- 2- yl) methyl) 1-methylurea;

15) 1- (6-Aminopyrimidin-4-yl) -3- (l- (6- cyclopropylpyridin- 1-methylurea;

16) 1- (6-Aminopyrimidin-4-yl) -3- (3-cyclopropyl- 1-methylurea;

17) 1- (6- (2,4-Dimethoxybenzylamino) pyrimidin-4-yl) -3- ) -1-methylurea;

18) 1- (6-Aminopyrimidin-4-yl) -3- (1- (3-methoxybenzyl) -3-methyl-1H-indazol-4-yl) -1-methylurea;

19) 3- (1- (Cyclohexylmethyl) -3-methyl-1H-indazol-4-yl) 1-methylurea;

20) 1- (6-Aminopyrimidin-4-yl) -3- (1- (cyclohexylmethyl) -3-methyl-1H-indazol-4-yl) -1-methylurea;

21) 1- (6- (Cyclopropylamino) pyrimidin-4-yl) -1-methyl-3- 4-yl) urea;

22) 1- (6-Methylpyridin-2-yl) -1- methyl-3- (3- Methyl) -lH-indazol-4-yl) urea;

23) Synthesis of 1- (6- (4- (diethylamino) butylamino) pyrimidin-4-yl) Methyl) -lH-indazol-4-yl) urea;

24) 3- (3-Cyclopropyl-l- (6-methylpyridin-2-yl) methyl) -lH-indazol- ) Pyrimidin-4-yl) -1-methylurea;

25) 1-Cyclopropyl-3- (3-methyl-l- (6-methylpyridin- 2- yl) methyl) 4-yl) urea;

26) 1- (3- (diethylamino) propyl) -3- (3-methyl-1- (6- (methylamino) pyrimidin-4-yl) urea;

27) 1- (6- (2,4-dimethoxybenzylamino) pyrimidin-4-yl) -3- Indazol-4-yl) urea; And

28) 1- (6-Aminopyrimidin-4-yl) -3- (3-methyl-l- (6-methylpyridin-2- yl) methyl) -lH-indazol-4-yl) urea.

The present invention also provides a pharmaceutically acceptable salt of the pyrimidine derivative represented by the above formula (1). Pharmacologically acceptable salts should be low in toxicity to humans and should not adversely affect the biological activity and physicochemical properties of the parent compound. Pharmaceutically acceptable salts include salts of acid addition salts, alkali metal salts (such as sodium salts) and alkaline earth metal salts (such as calcium salts) of pharmaceutically acceptable free acids and base compounds of formula (I), organic bases of carboxylic acids of formula Addition salts, amino acid addition salts, and the like.

Preferred salts of the compounds according to the invention include salts with inorganic or organic acids. The inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, or the like. In addition, the organic acid may be acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, Oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid, and the like. Organic bases that can be used to prepare organic base addition salts include tris (hydroxymethyl) methylamine, dicyclohexylamine, and the like. Amino acids that can be used in the production of amino acid addition bases are natural amino acids such as alanine and glycine.

Such salts may be prepared by conventional methods. For example, the compound of formula (1) can be prepared by dissolving the compound of formula (1) in a solvent which can be mixed with water such as methanol, ethanol, acetone, or 1,4-dioxane, and then adding a free acid or a free base.

On the other hand, the compounds according to the present invention may have asymmetric carbon centers and therefore exist as R or S isomers or racemic compounds, and all these optical isomers and mixtures are included in the scope of the present invention.

In addition, solvates and hydrate forms of the compounds of formula (I) are also included within the scope of the present invention.

The present invention also provides a pharmaceutical composition comprising as an active ingredient a pyrimidine derivative of Formula 1, a pharmaceutically acceptable salt, an optical isomer, a hydrate or a solvate thereof.

Preferably, the pharmaceutical composition is for preventing or treating a disease caused by the activity of FMS kinase.

Examples of the disease caused by the activity of the FMS kinase include an immune disease, a metabolic disease, an inflammatory disease, a cancer and the like.

Specific examples of the immune diseases, metabolic diseases and inflammatory diseases caused by the activity of the FMS kinase include rheumatoid arthritis, osteoporosis, Crohn's disease, arteriosclerosis, hyperlipemia and the like.

Specific examples of the cancer and tumor caused by the activity of the FMS kinase include liver cancer, hepatocellular carcinoma, thyroid cancer, colon cancer, testicular cancer, bone cancer bone cancer, oral cancer, basal cell carcinoma, ovarian cancer, brain tumor, gallbladder carcinoma, biliary tract cancer, head and neck cancer cancer of the esophagus, glioma, glioblastoma, renal cancer, malignant melanoma, renal cancer, malignant melanoma, malignant melanoma, malignant melanoma, Cancer, gastric cancer, breast cancer, sarcoma, pharynx carcinoma, uterine cancer, cervical cancer, prostate cancer, ovarian cancer, Rectal cancer, pancreatic cancer, lung cancer, skin cancer, But it can include other solid tumors, such as, but not limited thereto.

The compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention can enhance the therapeutic effect by co-administration with an inflammatory disease, an autoimmune disease, or another medicament for treating an immunologically mediated disease.

Examples of other medicaments for treating inflammatory diseases, autoimmune diseases or immunologically mediated diseases include steroid drugs (prednisone, prednisolone, methylprednisolone, cortisone, hydroxycortisone, betamethasone and dexamethasone etc.), methotrexate, (Norepinephrine, norepinephrine, norepinephrine, nomade, anti-TNFa agents such as etanercept, infliximab and adalimumab), calcineurin inhibitors (such as tacrolimus and pimecrolimus) and antihistamines (diphenhydramine, hydroxygene, loratadine, But are not limited thereto, and one or more drugs selected therefrom may be included in the pharmaceutical composition of the present invention. Examples of the pharmaceutical composition of the present invention include, but not limited to, corticosteroids, corticosteroids, corticosteroids,

Accordingly, the pharmaceutical composition of the present invention may further comprise these agents as an active ingredient.

The compound of the formula (1) or a pharmaceutically acceptable salt thereof according to the present invention can enhance the therapeutic effect of the anticancer drug by co-administration with other anticancer drugs for treating cancer or tumors.

Examples of other anti-cancer agents for treating cancer or tumors include cell signaling inhibitors (imatinib, gefitinib, bortezomib, allotinib, sorafenib, sunitinib, dasatinib, borinostat, lapatinib, Paclitaxel, paclitaxel, vincristine, and vinblastine), paclitaxel, paclitaxel, paclitaxel, paclitaxel, paclitaxel, paclitaxel, Antimetabolites such as cisplatin, cyclophosphamide, and chromostin, antimetabolites such as methotrexate and 5-FU, and anticancer agents such as actinomycin, anthracycline, bleomycin, and mitomycin Such as topoisomerase inhibitors (irinotecan, topotecan and teniposide), immunotherapeutic agents (interleukin and interferon), and anti-hormonal agents (tamoxifen and raloxifene, etc.) Therefore And one or more agents selected therefrom may be compounded with or combined with the pharmaceutical composition of the present invention.

Accordingly, the pharmaceutical composition of the present invention may further comprise these agents as an active ingredient.

In addition, the pharmaceutical composition of the present invention may be formulated according to a conventional method by adding a conventional non-toxic pharmaceutically acceptable carrier, adjuvant, excipient, etc. in addition to the active ingredient.

The pharmaceutical compositions of the present invention may be prepared in various oral dosage forms such as tablets, pills, powders, capsules, syrups or emulsions or in parenteral dosage forms such as intramuscular, intravenous or subcutaneous administration, Formulations.

The excipient that can be used in the pharmaceutical composition of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, . Examples of suitable additives include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, Sodium alginate, methyl cellulose, sodium carboxylmethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like.

When the pharmaceutical composition of the present invention is formulated into an oral administration form, examples of the carrier to be used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate , Gelatin, talc, a surfactant, a suspending agent, an emulsifier, and a diluent.

When the pharmaceutical composition of the present invention is formulated into an injectable form, the carrier may include water, saline solution, aqueous glucose solution, pseudosugar solution, alcohol, glycol, ether, oil, fatty acid, fatty acid ester, glyceride, surfactant, Emulsifiers and the like.

The dose of the compound according to the present invention to the human body is generally in the range of 1 mg / day to 1,000 mg / day based on adult patients weighing 70 kg. The compounds according to the present invention may be administered once to several times per day. The dosage may vary depending on the patient's health condition, age, weight and sex, dosage form and disease severity, and accordingly, the scope of the present invention is not limited to the above-mentioned dosage.

Hereinafter, the method for preparing the compound of formula (1) of the present invention will be described in detail.

Scheme 1

In the above Reaction Scheme 1, A, Y, R ₁ , R ₂ , R _3, and R ₁₁ are the same as defined in Formula 1.

The compound of formula (a2) can be prepared by reacting the compound of formula (a1) with phosgene, diphosgene, or triphosgene as shown in Reaction Scheme 1 above. At this time, an organic base such as triethylamine or diisopropylamine, or an inorganic base such as sodium hydrogencarbonate or sodium carbonate may be added. The compound of formula (a2) may be used as the reaction solution itself without separation or use from the reaction solution.

Thereafter, the compound of formula (1) may be prepared by reacting the compound of formula (a2) with a compound of formula (b1) in an organic solvent. The organic solvent may be benzene, toluene, methylene chloride, ethane dichloride, dimethylformamide or the like, and the reaction temperature is 0 to 150 ° C, preferably 50 to 100 ° C.

Also, the compound of formula (1) wherein Y is -NH ₂ (formula a3) can be prepared by reacting the compound of formula a3 with TFA as shown in the following reaction scheme 2.

Scheme 2

In the above Reaction Scheme 2, A, Y, R ₁ , R ₂ , R _3, and R ₁₁ are as defined in Formula 1.

Hereinafter, the present invention will be described in more detail with reference to the following Preparation Examples and Examples, but the present invention is not limited thereto.

Example  1: 1- (6- (2,4- Dimethoxybenzylamino ) Pyrimidin-4-yl) -1- methyl -3- (3- methyl -1 - ((6- Till Pyridin-2-yl) methyl ) -1H- Indazole Yl) Urea  Produce

1,2-dichloroethane was added to 3-methyl-1 - ((6-methylpyridin-2-yl) methyl) -1 H- indazol-4-amine (100 mg, 0.396 mmol, 2.0 eq. Xen (59 mg, 0.198 mmol, 1.0 eq.) Was added and stirred at ambient temperature for 1 hour. To the reaction solution was added N4- (2,4-dimethoxybenzyl) -N6-methylpyrimidine-4,6-diamine (54 mg, 0.198 mmol, 1.0 eq.) And diisopropylethylamine (0.207 mL, 1.188 mmol, 6.0 Equivalent) was added and the mixture was stirred at 70 占 폚 for 12 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (DCE / MeOH = 10: 1) to give the title compound (42 mg, 38%).

Example  2: 1- (6- Aminopyrimidine Yl) -1- methyl -3- (3- methyl -1 - ((6- Methyl pyridine -2 days) methyl ) -1H- Indazole Yl) Urea  Produce

Methyl-3- (3-methyl-1 - ((6-methylpyridin-2-yl) methyl) pyrimidin- ) -1H-indazol-4-yl) urea (40 mg, 0.072 mmol) was added trifluoroacetic acid (0.4 mL) and stirred at room temperature for 12 hours. The trifluoroacetic acid was removed under reduced pressure and methylene chloride was added. The organic layer was neutralized by adding saturated aqueous NaHCO ₃ solution and the aqueous layer was extracted twice with methylene chloride. After the collected organic extracts were dried over Na ₂ SO _4, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (DCE / MeOH = 10: 1) to give the title compound (23 mg, 80%).

Example  3: 1- (6- Chloropyrimidine Yl) -3- (3- Cyclopropyl -1 - ((6- Methyl pyridine -2 days) methyl ) -1H- Indazole Yl) -1- Methylurea  Produce

Example 1 was repeated except that 6-chloro-N-methylpyridin-4-amine was used instead of N4- (2,4-dimethoxybenzyl) -N6-methylpyrimidine-4,6- Was repeated to give the title compound.

Example  4: 1- (6- Chloropyrimidine Yl) -1- methyl -3- (3- methyl -1 - ((6- Methyl pyridine -2 days) methyl ) -1H- Indazole Yl) Urea  Produce

Example 1 was repeated except that 6-chloro-N-methylpyridin-4-amine was used instead of N4- (2,4-dimethoxybenzyl) -N6-methylpyrimidine-4,6- Was repeated to give the title compound.

Example  5: 1- (6- (2,4- Dimethoxybenzylamino ) Pyrimidin-4-yl) -3- (1 - ((6- Methoxypyridine -2 days) methyl ) -3- methyl -1H- Indazole Yl) -1- Methylurea  Produce

((6-methoxypyrimidin-2-yl) methyl) -1H-indazol-4-amine in place of 3-methyl- -3-methyl-1H-indazol-4-amine, the procedure of Example 1 was repeated to give the title compound.

Example  6: 1- (6- Aminopyrimidine Yl) -3- (1 - ((6- Methoxypyridine -2 days) methyl ) -3-methyl-1H- Indazole Yl) -1- Methylurea  Produce

(3-methyl-1 - ((6-methylpyridin-2-yl) Yl) -3- (1 - ((6-methoxybenzyl) piperazin-1 -yl) Methyl-1 H-indazol-4-yl) -1-methylurea (Example 5) ≪ / RTI >

Example  7: 1- (6- (2,4- Dimethoxybenzylamino ) Pyrimidin-4-yl) -3- (1 - ((6- Ethoxypyridine -2 days) methyl ) -3- methyl -1H- Indazole Yl) -1- Methylurea  Produce

Except that 1 - ((6-ethoxypyridin-2-yl) methyl) - (3-methylpyrrolidin- The procedure of Example 1 was repeated except that 3-methyl-1H-indazol-4-amine was used to give the title compound.

Example  8: 1- (6- Aminopyrimidine Yl) -3- (1 - ((6- Ethoxypyridine -2 days) methyl ) -3-methyl-1H- Indazole Yl) -1- Methylurea  Produce

(3-methyl-1 - ((6-methylpyridin-2-yl) Yl) -3- (1 - ((6-cyanomethyl) pyridin-4-yl) 2-yl) methyl) -3-methyl-1H-indazol-4-yl) -1-methylurea (Example 7) was used to give the title compound ≪ / RTI >

Example  9: 1- (6- (2,4- Dimethoxybenzylamino ) Pyrimidin-4-yl) -3- (1 - ((6- Fluoropyridine -2 days) methyl ) -3- methyl -1H- Indazole Yl) -1- Methylurea  Produce

Except that 1 - ((6-fluoropyridin-2-yl) methyl) - (3-methylpyridin-2-yl) The procedure of Example 1 was repeated except that 3-methyl-1H-indazol-4-amine was used to give the title compound.

Example  10: 1- (6- Aminopyrimidine Yl) -3- (1 - ((6- Fluoropyridine -2 days) methyl ) -3- methyl -1H- Indazole Yl) -1- Methylurea  Produce

(3-methyl-1 - ((6-methylpyridin-2-yl) Yl) -3- (1 - ((6-fluoro-pyridin-2-ylmethoxy) 2-yl) methyl) -3-methyl-1H-indazol-4-yl) -1-methylurea (Example 9) was used to repeat the procedure of Example 2 to give the title compound ≪ / RTI >

Example  11: 1- (6- (2,4- Dimethoxybenzylamino ) Pyrimidin-4-yl) -1- methyl -3- (3- methyl -1 - ((6- Reflux O-methyl) pyridin-2-yl) methyl ) -1H- Indazole Yl) Urea  Produce

Except that 3-methyl-1 - ((6- (trifluoromethyl) pyridine hydrochloride was used instead of 3-methyl-1- -2-yl) methyl) -1H-indazol-4-amine, the procedure of Example 1 was repeated except that the title compound was obtained.

Example  12: 1- (6- Aminopyrimidine Yl) -1- methyl -3- (3- methyl -1 - ((6- ( Trifluoromethyl ) Pyridin-2-yl) methyl ) -1H- Indazole Yl) Urea  Produce

(3-methyl-1 - ((6-methylpyridin-2-yl) Yl) -1-methyl-3- (3-methylpyridin-2-ylmethyl) Methyl-1H-indazol-4-yl) urea (Example 11) was used as starting material to give the title compound as a white amorphous solid. Lt; / RTI > to yield the title compound.

Example  13: 1- (6- (2,4- Dimethoxybenzylamino ) Pyrimidin-4-yl) -3- (1 - ((6- Isopropylpyridine -2 days) methyl ) -3- methyl -1H- Indazole Yl) -1- Methylurea  Produce

Except that 1 - ((6-isopropylpyridin-2-yl) methyl) - (3-methylpyrrolidin- The procedure of Example 1 was repeated except that 3-methyl-1H-indazol-4-amine was used to give the title compound.

Example  14: 1- (6- Aminopyrimidine Yl) -3- (1 - ((6- Isopropylpyridine -2 days) methyl ) -3- methyl -1H- Indazole Yl) -1- Methylurea  Produce

(3-methyl-1 - ((6-methylpyridin-2-yl) Yl) -3- (1 - ((6-iso) pyridin-4-yl) 2-yl) methyl) -3-methyl-1H-indazol-4-yl) -1-methylurea (Example 13) was used to repeat the procedure of Example 2 to give the title compound ≪ / RTI >

Example  15: 1- (6- Aminopyrimidine Yl) -3- (1 - ((6- Cyclopropylpyridine -2 days) methyl ) -3- methyl -1H- Indazole Yl) -1- Methylurea  Produce

Except that 1 - ((6-cyclopropylpyridin-2-yl) methyl) -1H-indazole was used in place of 3-methyl-1- ) -3-methyl-1H-indazol-4-amine as starting materials, the title compound was obtained.

Example  16: 1- (6- Aminopyrimidine Yl) -3- (3- Cyclopropyl -1 - ((6- Methyl pyridine -2 days) methyl ) -1H- Indazole Yl) -1- Methylurea  Produce

Cyclopropyl-1 - ((6-methylpyridin-2-yl) methyl) -1H-indazol- -Yl) methyl) -1H-indazol-4-amine, the procedure of Examples 1 and 2 was repeated to give the title compound.

Example  17: 1- (6- (2,4- Dimethoxybenzylamino ) Pyrimidin-4-yl) -3- (1- (3-methoxybenzyl) -3- methyl -1H- Indazole Yl) -1- Methylurea  Produce

(3-methoxybenzyl) -3-methyl-1H-indole instead of 3-methyl-1 - ((6- methylpyridin- The procedure of Example 1 was repeated but using the sol-4-amine to give the title compound.

Example  18: 1- (6- Aminopyrimidine Yl) -3- (1- (3-methoxybenzyl) -3- methyl -1H- Indazole Yl) -1- Methylurea  Produce

(3-methyl-1 - ((6-methylpyridin-2-yl) Yl) -3- (1- (3-methoxyphenyl) -1H-indazol- Benzyl) -3-methyl-1H-indazol-4-yl) -1-methylurea (Example 17) was used to give the title compound.

Example  19: 3- (1- ( Cyclohexylmethyl ) -3- methyl -1H- Indazole Yl) -1- (6- (2,4- Dimethoxybenzylamino ) Pyrimidin-4-yl) -1- Methylurea  Produce

(Cyclohexylmethyl) -3-methyl-1H-indazole-1-carboxylic acid in place of 3-methyl-1 - ((6- methylpyridin- The procedure of Example 1 was repeated except that 4-amine was used to give the title compound.

Example  20: 1- (6- Aminopyrimidine Yl) -3- (1- ( Cyclohexylmethyl ) -3- methyl -1H-indazol-4-yl) -1- Methylurea  Produce

(3-methyl-1 - ((6-methylpyridin-2-yl) Indazol-4-yl) -1- (6- (2, 3-dihydro- 4-dimethoxybenzylamino) pyrimidin-4-yl) -1-methylurea (Example 19) was used to obtain the title compound.

Example  21: 1- (6- ( Cyclopropylamino ) Pyrimidin-4-yl) -1- methyl -3- (3- methyl -1 - ((6- Till Pyridin-2-yl) methyl ) -1H- Indazole Yl) Urea  Produce

Except that N4-cyclopropyl-N6-methylpyrimidine-4,6-diamine was used instead of N4- (2,4-dimethoxybenzyl) -N6-methylpyrimidine-4,6-diamine in Example 1 , The procedure of Example 1 was repeated to give the title compound.

Example  22: 1- (6- (3- ( Diethylamino ) Propyl amino ) Pyrimidin-4-yl) -1- methyl -3- (3-methyl-1 - ((6- Methyl pyridine -2 days) methyl ) -1H- Indazole Yl) Urea  Produce

N4- (3- (diethylamino) propyl) -N6-methylpyrimidine-4,6-diol in place of N4- (2,4- dimethoxybenzyl) -N6- methylpyrimidine- -Diamine, the procedure of Example 1 was repeated to give the title compound.

Example  23: 1- (6- (4- ( Diethylamino ) Butylamino ) Pyrimidin-4-yl) -1- methyl -3- (3-methyl-1 - ((6- Methyl pyridine -2 days) methyl ) -1H- Indazole Yl) Urea  Produce

N4- (4- (diethylamino) butyl) -N6-methylpyrimidine-4,6-diol in place of N4- (2,4- dimethoxybenzyl) -N6- methylpyrimidine- -Diamine, the procedure of Example 1 was repeated to give the title compound.

Example  24: 3- (3- Cyclopropyl -1 - ((6- Methyl pyridine -2 days) methyl ) -1H- Indazole Yl) -1- (6- (2,4- Dimethoxybenzylamino ) Pyrimidin-4-yl) -1- Methylurea  Produce

Cyclopropyl-1 - ((6-methylpyridin-2-yl) methyl) -1H-indazol- ) Methyl) -1H-indazol-4-amine was used as the starting material, the title compound was obtained.

Example  25: 1- Cyclopropyl -3- (3- methyl -1 - ((6- Methyl pyridine -2 days) methyl ) -1H- Indazole Yl) -1- (6- ( Methyl amino ) Pyrimidin-4-yl) Urea  Produce

The procedure of Example 21 was repeated to give the title compound.

Example  26: 1- (3- ( Diethylamino ) Propyl) -3- (3- methyl -1 - ((6- Methyl pyridine Yl) methyl) -1H- Indazole Yl) -1- (6- ( Methyl amino ) Pyrimidin-4-yl) Urea  Produce

The procedure of Example 22 was repeated to give the title compound.

Example  27: 1- (6- (2,4- Dimethoxybenzylamino ) Pyrimidin-4-yl) -3- (3- methyl -1 - ((6-methylpyridin-2-yl) methyl ) -1H- Indazole Yl) Urea  Produce

(2,4-diethylbenzyl) pyrimidine-4,6-diamine was used in place of N4- (2,4-dimethoxybenzyl) -N6-methylpyrimidine-4,6- The procedure of Example 1 was repeated except that the title compound was obtained.

Example  28: 1- (6- Aminopyrimidine Yl) -3- (3- methyl -1 - ((6- Methyl pyridine -2 days) methyl ) -1H- Indazole Yl) Urea  Produce

(3-methyl-1 - ((6-methylpyridin-2-yl) Yl) -3- (3-methyl-l- (4-methoxybenzylamino) pyrimidin- (6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea (Example 27) was used to obtain the title compound.

¹ H-NMR data and MS data of the compounds of the above Examples are summarized in Table 1 below.

number Chemical structural formula Data ( ¹ H-NMR, MS) Example 1

MS (ESI +, m / z): 553.3 [M + H] <

¹ H-NMR (300 MHz, CDCl ₃ ):? 13.01 (s, IH), 8.29 (s, IH), 7.65 (d, IH), 7.38 2H), 3.84 (s, 3H), 3.78 (s, 3H), 3.78 (s, ), 3.41 (s, 3H), 2.81 (s, 3H), 2.56 (s, 3H). Example 2

MS (ESI +, m / z): 403.2 [M + H] <

^{1 H-NMR (300MHz, CDCl} 3): δ 12.90 (bs, 1H), 8.50 (s, 1H), 7.65 (d, 1H), 7.42 (t, 1H), 7.32-7.26 (m, 1H), 7.07 2H), 6.44 (s, 3H), 2.84 (s, 3H), 6.04 (s, 2.57 (s, 3 H). Example 3

MS (ESI +, m / z): 448.2 [M + H] <

^{1 H-NMR (300MHz, CDCl} 3): δ 12.30 (bs, 1H), 8.63 (s, 1H), 7.58 (d, 1H), 7.39 (t, 1H), 7.30 (t, 2H), 7.09-7.00 (m, 3H), 6.40 (d, 1H), 5.61 (s, 2H), 3.53 (s, ), 0.92-0.86 (m, 2H). Example 4

MS (ESI +, m / z): 448.2 [M + H] <

^{1 H-NMR (300MHz, CDCl} 3): δ 12.31 (bs, 1H), 8.63 (s, 1H), 7.55 (d, 1H), 7.36-7.21 (m, 2H), 7.05-6.93 (m, 3H) , 6.40 (d, IH), 5.56 (s, 2H), 3.46 (s, 3H), 2.74 (s, 3H), 2.50 (s, 3H). Example 5

MS (ESI +, m / z): [M + H] <

¹ H-NMR (300 MHz, CDCl ₃ ):? 12.99 (s, IH), 8.27 (s, IH), 7.64 3H), 3.76 (s, 3H), 3.76 (s, 3H), 3.86 (s, 3.40 (s, 3H), 2.83 (s, 3H). Example 6

MS (ESI +, m / z): 418.2 [M + H] <

^{1 H-NMR (300MHz, DMSO} -d 6): δ 12.92 (s, 1H), 8.29 (s, 1H), 7.61-7.56 (m, 2H), 7.36-7.26 (m, 2H), 7.09 (bs, 2H), 6.68 (d, 1H), 6.42 (s, 3H), 6.68 (s, ). Example 7

MS (ESI +, m / z): [M + H] <

¹ H-NMR (300 MHz, CDCl ₃ ):? 12.99 (s, IH), 8.27 (s, IH), 7.65 3H), 3.78 (s, 3H), 3.38 (s, 2H), 3.48 (s, (s, 3H), 2.82 (s, 3H), 1.33 (t, 3H). Example 8

MS (ESI +, m / z): 432.2 [M + H] <

^{1 H-NMR (300MHz, DMSO} -d 6): δ 12.92 (s, 1H), 8.29 (s, 1H), 7.60-7.55 (m, 2H), 7.34-7.26 (m, 2H), 7.05 (bs, 2H), 6.64 (d, 1 H), 6.45 (s, 3H), 2.71 (s, ), 1.23 (t, 3H). Example 9

MS (ESI +, m / z): [M + H] <

¹ H-NMR (300 MHz, CDCl ₃ ):? 13.03 (s, IH), 8.30 (s, IH), 7.69-7.60 (d, IH), 6.81-6.79 (m, 2H), 6.50-6.45 (m, 2H), 5.91 (s, IH) ), 3.81 (s, 3H), 3.42 (s, 3H), 2.81 (s, 3H). Example 10

MS (ESI +, m / z): 406.2 [M + H] <

^{1 H-NMR (300MHz, DMSO} -d 6): δ 12.94 (s, 1H), 8.25 (s, 1H), 7.95-7.87 (m, 1H), 7.59 (m, 1H), 7.31-7.27 (m, 2H), 7.08-7.06 (m, 3H), 6.89-6.86 (m, IH), 6.10 (s, IH), 5.61 (s, 2H), 3.31 (s, 3H), 2.69 Example 11

MS (ESI +, m / z): 607.3 [M + H] < Example 12

MS (ESI +, m / z): 457.2 [M + H] <
^{1 H-NMR (300MHz, CDCl} 3): δ 12.91 (s, 1H), 8.36 (s, 1H), 7.65 (m, 2H), 7.53 (d, 1H), 7.63 (d, 1H), 6.86 (m , 2H), 6.03 (s, IH), 5.71 (d, 2H), 3.45 (s, 3H), 2.75 (s, 3H). Example 13

MS (ESI +, m / z): 581.3 [M + H] < Example 14

MS (ESI +, m / z): 431.2 [M + H] < Example 15

MS (ESI +, m / z): 429.2 [M + H] <

^{1 H-NMR (300MHz, DMSO} -d 6): δ 12.89 (s, 1H), 8.28 (s, 1H), 7.57-7.48 (m, 2H), 7.28 (d, 2H), 7.14 (d, 2H) , 7.03 (s, 2H), 6.58 (d, IH), 6.10 (s, IH), 5.51 (s, 2H), 3.31 0.90-0.83 (m, 4H). Example 16

MS (ESI +, m / z): 429.2 [M + H] < Example 17

MS (ESI +, m / z): 568.3 [M + H] <
¹ H-NMR (300 MHz, CDCl ₃ ):? 12.98 (s, IH), 8.31 (s, IH), 7.64 2H), 3.87 (s, 3H), 3.82 (s, 2H), 5.47 (s, 3H), 3.74 (s, 3H), 3.42 (s, 3H), 2.80 (s, 3H). Example 18

MS (ESI +, m / z): 418.2 [M + H] <
^{1 H-NMR (300MHz, CDCl} 3): δ 12.88 (s, 1H), 8.37 (s, 1H), 7.65 (d, 1H), 7.21 (t, 1H), 7.18 (d, 1H), 7.03 (d 2H), 3.75 (s, 3H), 2.82 (s, 3H). Example 19

MS (ESI +, m / z): 544.3 [M + H] <
^{1 H-NMR (300MHz, CDCl} 3): δ 12.94 (s, 1H), 8.26 (s, 1H), 7.59 (d, 1H), 7.27 (t, 2H), 7.18 (d, 1H), 7.04 (d 2H), 3.84 (s, 3H), 3.79 (s, 3H), 3.40 (s, 3H), 2.77 (s, 3H), 1.66 - 1.56 (m, 11H) Example 20

MS (ESI +, m / z): 294.2 [M + H] <
^{1 H-NMR (300MHz, CDCl} 3): δ 12.76 (s, 1H), 8.36 (s, 1H), 7.364 (d, 1H), 7.29 (t, 1H), 7.08 (d, 1H), 6.04 (s 2H), 3.46 (s, 3H), 2.80 (s, 3H), 1.72-7.58 (m, 11H). Example 21

MS (ESI +, m / z): 443.2 [M + H] <
^{1 H-NMR (300MHz, CDCl} 3): δ 13001 (s, 1H), 8.30 (s, 1H), 7.67 (d, 1H), 7.38 (t, 1H), 7.28 (d, 1H), 7.00 (t 2H), 0.67 (m, 2H), 6.45 (d, IH), 6.23 (s, 2H). Example 22

MS (ESI +, m / z): 516.3 [M + H] <
^{1 H-NMR (300MHz, CDCl} 3): δ 13.06 (s, 1H), 8.32 (s, 1H), 7.62 (d, 1H), 7.38 (t, 2H), 7.02 (m, 2H), 6.44 (d 3H), 2.84 (s, 3H), 2.68 (s, 3H), 2.58 (s, 3H), 2.24 2H), 1.11 (m, 6H). Example 23

MS (ESI +, m / z): 530.3 [M + H] <
^{1 H-NMR (300MHz, CDCl} 3): δ 13.02 (s, 1H), 8.33 (s, 1H), 7.68 (d, 1H), 7.38 (t, 2H), 7.01 (d, 2H), 6.43 (d (S, 3H), 2.45 (s, 3H), 2.43 (s, 3H) m, 4H), 1.28 (t, 6H) Example 24

MS (ESI +, m / z): 579.3 [M + H] <
^{1 H-NMR (300MHz, CDCl} 3): δ 12.79 (s, 1H), 8.28 (s, 1H), 7.43 (d, 1H), 7.19 (t, 2H), 7.01 (d, 1H), 6.82 (m 3H), 3.62 (s, 3H), 3.62 (s, 3H), 3.24 (s, 2H) 3H), 2.41 (m, 4H), 0.88 (m, 2H), 0.76 Example 25

MS (ESI +, m / z): 443.2 [M + H] <
^{1 H-NMR (300MHz, CDCl} 3): δ 12.44 (s, 1H), 8.32 (s, 1H), 7.77 (d, 2H), 7.32 (t, 2H), 7.00 (d, 2H), 6.42 (d (S, 3H), 2.58 (s, 3H), 1.25 (m, 2H) 2H), 1.18 (m, 2H). Example 26

MS (ESI +, m / z): 516.3 [M + H] <
^{1 H-NMR (300MHz, CDCl} 3): δ 13.05 (s, 1H), 8.32 (s, 1H), 7.57 (d, 1H), 7.34 (t, 2H), 7.69 (m, 3H), 6.41 (d 2H), 3.99 (m, 2H), 3.05 (m, 4H), 3.02 (d, 3H), 2.78 4H), 1.21 (t, 6H). Example 27

MS (ESI +, m / z): [M + H] <

^{1 H-NMR (300MHz, DMSO} -d 6): δ 12.96 (s, 1H), 9.85 (s, 1H), 8.73 (s, 1H), 8.24 (s, 1H), 7.62-7.54 (m, 3H) (S, 3H), 7.38-7.26 (m, 3H), 7.14-7.09 (m, 2H), 6.48-6.45 (s, 3H), 3.32 (s, 3H), 2.71 (s, 3H), 2.45 (s, 3H). Example 28

MS (ESI +, m / z): 389.2 [M + H] <

^{1 H-NMR (300MHz, DMSO} -d 6): δ 11.18 (bs, 1H), 9.78 (s, 1H), 8.17 (s, 1H), 7.62-7.51 (m, 2H), 7.29-7.24 (m, 2H), 7.11 (d, 1H), 6.84 (s, 3H), 2.43 (s, 3H) ).

Test Example

The compounds prepared in the above examples were evaluated for efficacy as follows.

Test Example  One: FMS Kinase  Evaluation of inhibitory activity

This test example is a test for evaluating the inhibitory effect of FMS kinase on the activity of inhibiting the activity of the FMS kinase, using an assay kit (Z'-Lyte ™ kinase assay-Tyr 1 peptide kit, Cat. Pv3190, Invitrogen) using FRET principle and recombinant human FMS kinase pv3249, Invitrogen) was used.

The test compounds were diluted with 1 μl, 100 nM, 50 nM, 10 nM and 1 nM in 4% DMSO, respectively. The test compounds were then placed in a black bottom 384-well plate (NUNC) and FMS kinase was diluted with Tyr 1 Peptide and kinase buffer were added to each well in a mixture of 10 μl per well and ATP was added at a concentration of 150 μM. The mixture was allowed to react at room temperature for 1 hour in the state of blocking light, and the reaction solution was reacted at room temperature for 1 hour in the state that the developing reagent was added and the light was blocked again. The reaction was terminated by adding a terminating reagent and the fluorescence was measured at 400 nm excitation wavelength and 445 nm emission wavelength in a microplate reader.

In addition, fluorescence was measured by using 4% DMSO instead of the test compound as a 100% low-navy group and reacting in the same manner as above using a kinase reaction solution instead of ATP. In addition, fluorescence was measured by reacting in the same manner as above using 4% DMSO instead of the test compound as a 0% lower navy group. In addition, as a 100% phosphorylation group, 4% DMSO was used instead of the test compound, phospho-peptide solution was used in place of the Tyr 1 peptide mixture, and a kinase reaction solution was used instead of ATP to perform fluorescence Respectively.

Based on the measured fluorescence values, IC ₅₀ concentration values were calculated using Microsoft's Excel ™ program.

Test Example  2: M- NFS -60 cell line evaluation

The M-NFS-60 cell line purchased from the ATCC (American Type Culture Collection, USA) was cultured in RPMI medium (containing 10% FBS, 1% penicillin / streptomycin, and recombinant M-CSF at 20 ng / % CO ₂ at 37 ° C. The cultured M-NFS-60 cell line was cultured in a serum-free medium for 24 hours before being added to the plate. Then, 2.5x10 ⁴ cells per well were prepared as 50 μl and placed in a 96-well plate. Subsequently, 20 ng / mL of recombinant M-CSF was added to the 5% FBS culture, and the test compound was treated by diluting stepwise at a concentration of 1/10 from 10 μM to 0.1 nM.

(CellTiter 96 Assay, Promega Cat. G3581) was used to measure cell viability. MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] Were used. After incubation for 2 hours with 16 μl of dye per well, the absorbance was measured, and the IC ₅₀ value was measured with the analytical software (GraphPad Prism 4.0) at 590 nm wavelength using a microplate reader Respectively.

The results obtained from Test Examples 1 and 2 are shown in Table 2 below.

compound FMS  ( IC ₅₀ ) M- NFS -60 ( IC ₅₀ ) Example 9 65 nM - Example 18 14 nM 201 nM

As shown in Table 2, the compounds of the examples according to the present invention have excellent inhibitory activity against FMS kinase and M-NFS-60 cell lines.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is clearly understood that the same is by way of illustration and example only and is not to be taken by way of limitation, It is to be understood that the invention may be practiced within the scope of the appended claims.

Claims (10)

Claims 1. A compound selected from the group consisting of pyrimidine derivatives of the formula (I), pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof:
Formula 1

A is -CH- or -N-;
Y is H, halogen, _{amino, -NHR, -NH- (CH 2)} m -N (R) 2 or _{-NH- (CH 2) m -C 6} - 12 aryl, wherein R is C _{1 - 10} alkyl, or C _{3 - 10} cycloalkyl, m is an integer from 1 to 6;
R ₁ is H, C _{1 - 10} alkyl or halogen;
R ₂ is H, C _{1 - 10} alkyl, C _{2 - 10} alkenyl, C _{3 - 10} cycloalkyl, or halogen;
R ₃ is H, C _{1 - 10} alkyl, or - a (CH _{2) n} R _4, wherein n is an integer from 0 to 6, R ₄ is C _1-6 alkylamino, di-C _{1 - 6} alkylamino, C _{1 - 6} alkoxy, C _{2 - 5} alkynyl, C _{3 - 10} cycloalkyl, 5-12 membered heterocycloalkyl of, C _{6 - 12} aryl or 5-12 membered heteroaryl of;
R ₁₁ is H, C _{1 - 10} alkyl, C _{3 - 10} cycloalkyl, or - a _{(CH 2) m -N (R} ) 2, wherein R or m are as defined above;
At this time, the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently C _{1 - 6} alkyl, C _{1 - 6} alkylamino, C _{1 - 6} alkoxy, halogen, haloalkyl, nitro, cyano, carbonyl amino , aminocarbonyl, sulfinyl, C _{1 - 6} alkylsulfonyl, C _{1 - 6} alkyl-sulfonylamino, C _1-6 alkyl aminosulfonyl, phenyl, C _{3 - 10} cycloalkyl, and alkyl heterocycloalkyl of 5-6 won Alkyl, < / RTI >< RTI ID = 0.0 >
Wherein said heteroaryl and heterocycloalkyl each independently comprise one or more heteroatoms selected from the group consisting of N, O and S.
The method according to claim 1,
A is -N-;
Wherein Y is a halogen, amino, -NHR or _{-NH- (CH 2) m -N (} R) 2, wherein R is C _{3 - 8} cycloalkyl, m is an integer from 1 to 6;
Wherein R < ₁ > is H; Wherein R ₂ is C _{1 - 8} alkyl or C _{3 - 8} cycloalkyl;
Wherein R ₃ is - (CH _{2) n} and R _4, wherein n is an integer from 0 to 6, R ₄ is C _{3 - 8} cycloalkyl, C _{6 - 12} aryl or 5-12 membered heteroaryl of;
Wherein R ₁₁ is H, C _{1 - 8} alkyl, C _{3 - 8} cycloalkyl, or - a _{(CH 2) mN (R)} 2, wherein R or m are as defined above;
At this time, the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently C _{1 - 4} alkyl, C _{1 - 4} alkylamino, C _{1 - 4} alkoxy, halogen, haloalkyl, nitro, cyano, carbonyl amino , aminocarbonyl, sulfinyl, C _{1 - 4} alkylsulfonyl, C _{1 - 4} alkyl-sulfonylamino, C _1-4 alkyl aminosulfonyl, phenyl, C _{3 - 8} cycloalkyl, and 5-6 membered heterocycloalkyl Alkyl, < / RTI >< RTI ID = 0.0 >
Wherein said heteroaryl and heterocycloalkyl each independently comprise one or more heteroatoms selected from the group consisting of N, O,
The method according to claim 1,
Wherein the pyrimidine derivative of Formula 1 is any one of the following compounds:
1) Preparation of 1- (6- (2,4-dimethoxybenzylamino) pyrimidin-4-yl) ) -1H-indazol-4-yl) urea;
2) 1- (6-Aminopyrimidin-4-yl) -1-methyl-3- (3- Yl) urea;
3) 1- (6-Chloropyrimidin-4-yl) -3- (3-cyclopropyl- 1-methylurea;
4) 1- (6-Chloropyrimidin-4-yl) -1-methyl-3- (3- Yl) urea;
5) 1- (6- (2,4-dimethoxybenzylamino) pyrimidin-4-yl) -3- -Indazol-4-yl) -1-methylurea;
6) 1- (6-Aminopyrimidin-4-yl) -3- (l- (6-methoxypyridin- 2- yl) methyl) 1-methylurea;
7) 1- (6- (2,4-dimethoxybenzylamino) pyrimidin-4-yl) -3- -Indazol-4-yl) -1-methylurea;
8) 1- (6-Aminopyrimidin-4-yl) -3- (1- (6-ethoxypyridin- 1-methylurea;
9) 1- (6- (2,4-Dimethoxybenzylamino) pyrimidin-4-yl) -3- -Indazol-4-yl) -1-methylurea;
10) 1- (6-Aminopyrimidin-4-yl) -3- (1- (6-fluoropyridin- 1-methylurea;
11) 1- (6- (2,4-Dimethoxybenzylamino) pyrimidin-4-yl) -1- Yl) methyl) -1H-indazol-4-yl) urea;
12) 1- (6-Aminopyrimidin-4-yl) -1-methyl-3- (3- Indazol-4-yl) urea;
13) 1- (6- (2,4-dimethoxybenzylamino) pyrimidin-4-yl) -3- -Indazol-4-yl) -1-methylurea;
14) 1- (6-Aminopyrimidin-4-yl) -3- (l- (6-isopropylpyridin- 2- yl) methyl) 1-methylurea;
15) 1- (6-Aminopyrimidin-4-yl) -3- (l- (6- cyclopropylpyridin- 1-methylurea;
16) 1- (6-Aminopyrimidin-4-yl) -3- (3-cyclopropyl- 1-methylurea;
17) 1- (6- (2,4-Dimethoxybenzylamino) pyrimidin-4-yl) -3- ) -1-methylurea;
18) 1- (6-Aminopyrimidin-4-yl) -3- (1- (3-methoxybenzyl) -3-methyl-1H-indazol-4-yl) -1-methylurea;
19) 3- (1- (Cyclohexylmethyl) -3-methyl-1H-indazol-4-yl) 1-methylurea;
20) 1- (6-Aminopyrimidin-4-yl) -3- (1- (cyclohexylmethyl) -3-methyl-1H-indazol-4-yl) -1-methylurea;
21) 1- (6- (Cyclopropylamino) pyrimidin-4-yl) -1-methyl-3- 4-yl) urea;
22) 1- (6-Methylpyridin-2-yl) -1- methyl-3- (3- Methyl) -lH-indazol-4-yl) urea;
23) Synthesis of 1- (6- (4- (diethylamino) butylamino) pyrimidin-4-yl) Methyl) -lH-indazol-4-yl) urea;
24) 3- (3-Cyclopropyl-l- (6-methylpyridin-2-yl) methyl) -lH-indazol- ) Pyrimidin-4-yl) -1-methylurea;
25) 1-Cyclopropyl-3- (3-methyl-l- (6-methylpyridin- 2- yl) methyl) 4-yl) urea;
26) 1- (3- (diethylamino) propyl) -3- (3-methyl-1- (6- (methylamino) pyrimidin-4-yl) urea;
27) 1- (6- (2,4-dimethoxybenzylamino) pyrimidin-4-yl) -3- Indazol-4-yl) urea; And
28) 1- (6-Aminopyrimidin-4-yl) -3- (3-methyl-l- (6-methylpyridin-2- yl) methyl) -lH-indazol-4-yl) urea.
A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 as an active ingredient.
5. The method of claim 4,
Wherein said pharmaceutical composition is for preventing or treating a disease caused by the activity of FMS kinase.
6. The method of claim 5,
Wherein the disease caused by the activity of the FMS kinase is an immune disease, a metabolic disease, an inflammatory disease, a cancer, or a tumor.
The method according to claim 6,
Wherein said immune, metabolic, or inflammatory disease is rheumatoid arthritis, osteoporosis, Crohn's disease, arteriosclerosis, or hyperlipidemia.
The method according to claim 6,
The cancer or the tumor may be a liver cancer, a hepatocellular carcinoma, a thyroid cancer, a colon cancer, a testicular cancer, a bone cancer, an oral cancer, a basal cell Cancer, ovarian cancer, brain tumor, gallbladder carcinoma, biliary tract cancer, head and neck cancer, rectal cancer, bladder cancer, ovarian cancer, esophageal cancer, glioma, glioblastoma, renal cancer, malignant melanoma, gastric cancer, pancreatic cancer, gastric cancer, Breast cancer, sarcoma, pharynx carcinoma, uterine cancer, cervical cancer, prostate cancer, rectal cancer, pancreatic cancer, Lung cancer, skin cancer, or a combination thereof.
6. The method of claim 5,
Wherein said pharmaceutical composition is selected from the group consisting of a steroid agent, mesotrexate, re flunomide, an anti-TNFa agent, a calcineurin inhibitor, an antihistamine agent, a cell signaling inhibitor, a mitotic inhibitor, an alkylating agent, Or a combination thereof with a medicament selected from the group consisting of an antiinflammatory agent, an antiinflammatory agent, an antiinflammatory agent, an antiinflammatory agent, an antiinflammatory agent, an antiinflammatory agent, an antiinflammatory agent, an antiinflammatory agent,
6. The method of claim 5,
Wherein the pharmaceutical composition is an oral preparation in the form of tablets, pills, powders, capsules, syrups or emulsions.