KR20140002476A - Fused pyrimidine derivatives having inhibitory activity on fms kinases - Google Patents

Abstract

A pyrimidine combination ring derivative denoted by chemical formula 1, pharmaceutically acceptable salt thereof, and a compound selected from an optical isomer, a hydrate, and a solvented product have excellent inhibitory activity on FMS kinase, and a pharmaceutical composition containing thereof has excellent prevention and treatment effects on immune diseases, metabolic diseases, inflammatory diseases, and cancer result from the FMS kinase. In the chemical formula 1, A, X, Y, R1, R2, and R3 are defined in the present specification.

Description

Pyrimidine conjugated derivative having FMS kinase inhibitory activity {FUSED PYRIMIDINE DERIVATIVES HAVING INHIBITORY ACTIVITY ON FMS KINASES}

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

Protein kinase plays an important role in intracellular signaling through the phosphorylation reaction of hydroxy groups in the tyrosine, serine or threonine residues of proteins. As an enzyme in charge, it is deeply involved in cell growth, differentiation and proliferation.

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 58 receptor tyrosine kinases divided into 20 subtypes and 32 cytoplasmic / non-receptor tyrosine kinases divided into 10 subfamily. Receptor tyrosine kinases have a domain capable of accepting growth factors on the cell surface and an active site capable of phosphorylating tyrosine residues in the cytoplasm. When growth factors bind to growth factor receptor sites on the cell surface, receptor tyrosine kinases form polymers and active site tyrosine residues in the cytoplasm are autophosphorylated. Subsequently, as the cytoplasmic protein kinases of the lower family are sequentially phosphorylated, extracellular signals are transferred into the nucleus, whereby various genes involved in growth, differentiation and proliferation are transcribed and synthesized. At this time, when the protein kinase is abnormally overexpressed or abnormally activated through mutation, it is known that various diseases such as cancer are caused.

Cellular feline McDonough sarcoma (FMS), a type of protein kinase, is also known as colony-stimulating factor-1 receptor (CSF-1R), and is Susan McDonough of the feline sarcoma virus. It is part of a family of genes first isolated from strains. FMS, a receptor for macrophage-colony-stimulating factor (M-CSF), is classified as a type III receptor tyrosine kinase (class III RTK) along with Kit, Flt-3 and PDGFR, and is an FMS primary cancer It is encoded by the gene (c-fms proto-oncogene). M-CSF is also referred to as CSF-1 and can be actively expressed in RACE (RA) endothelial cells 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 FMS of mononuclear leukocytes, RANK (receptor activator factor of NF-κB) is expressed to become a bipotential precursor state 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-a and IL-1b, and the M-CSF participates in the RANKL When combined, they are differentiated into osteoclasts and are involved in bone erosion. In general, FMS is known to be limited in expression in the synoviium in 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.

Among these, rheumatoid arthritis is an unexplained chronic inflammatory disease characterized by multiple arthritis, which initially causes inflammation of the synovial lining of the joint, but gradually spreads to the surrounding cartilage and bones to destroy and deform the joint. Will result. For example, in the late stages of rheumatoid arthritis, the so-called boutonniere deformity of thumb of the thumb, the ulnar deviation of metacarpophalangeal joint, and the swan-neck deformity of the finger fingers) and the like.

The number of patients with rheumatoid arthritis is currently about 30 million, or about 1% of the world's population, and there are more women among 20-45 year olds. The rheumatoid arthritis market is growing every year, including, for example, tumor necrosis factor (TNF) inhibitors, NSAIDs, acute inflammatory factor (COX-2) inhibitors, and antirheumatic agents (DMARD). disease-modifying antirheumatic drugs, and steroidal drugs. In particular, the market for TNF inhibitors (anti-TNF) grew rapidly from $ 13.7 billion in 2007 to $ 18 billion in 2008, and the DMARD formulation market is growing from $ 2.5 billion in 2007 to $ 3 billion in 2008.

Treatment of rheumatoid arthritis is basically prescribed disease-modifying antirheumatic drugs (DMARDs) that improve symptoms. As a biological agent used in the treatment of rheumatoid arthritis, a TNF inhibitor (anti-TNF) is primarily prescribed, and currently commercially available Enbrel ^™ (etanercept), Humira ^™ (adalimumab), Remicade ^™ ; infliximab), and Cimzia ^™ (certolizumab) and these are prescribed in combination with method (methotrexate; mesotrexate). If this first prescription fails, Rituximab is prescribed in combination with MTX, according to a treatment recommended by the National Institutes of Health and Clinical Research (NICE). If such a second regimen fails or a side effect to rituximab is expected, represcription of the TNF inhibitor or a third regimen of avatacept or tocilizumab in combination with MTX is considered.

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

 D'Aura swanson, C. et al., Tyrosine kinases as targets for the 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)

An object of the present invention is to provide a novel pyrimidine conjugated derivative having excellent inhibitory activity against FMS kinase.

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

In accordance with the above object, the present invention provides a compound selected from pyrimidine conjugated derivatives of formula (1), pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof:

Formula 1

A is -CH- or -N-;

X is -S-, -NH-, or -N (C _1-10 alkyl)-;

Y is H, halogen, amino, -NHR, -NHOR, -NH- (CH ₂ ) mN (R) ₂ , -OR, -SR, -S (O) R, or -S (O) ₂ R, 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 — (CH ₂ ) nR ₄ , where n is an integer from 0 to 6;

R ₄ is C _1-6 alkylamino, diC _1-6 alkylamino, C _1-6 alkoxy, C _2-5 alkynyl, C _3-10 cycloalkyl, 5-12 membered heterocycloalkyl, C _{6- 12} aryl, or 5-12 membered heteroaryl;

Wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkoxy, halogen, nitro, cyano, carbonylamino, aminocarbon carbonyl, sulfinyl, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonyl amino, C _1-6 alkyl aminosulfonyl, selected from the group consisting of phenyl and 5-6 membered heterocycloalkyl of 1-3 won May be substituted with a substituent,

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

According to this other object, the present invention provides a pharmaceutical composition containing the compound as an active ingredient.

The pyrimidine conjugated ring derivatives of the present invention, pharmaceutically acceptable salts, optical isomers, hydrates, or solvates thereof have excellent inhibitory activity against FMS kinases, and pharmaceutical compositions comprising them are derived from FMS kinases. It is effective as an agent for preventing or treating an immune disease, metabolic disease, 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.

As used herein, the term 'alkyl' refers to a straight or branched hydrocarbon moiety unless stated otherwise.

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

As used herein, the term 'aryl' refers to an aromatic group including phenyl, naphthyl, and the like, unless stated otherwise.

The term 'heterocycloalkyl' as used herein refers to monocyclic or bicyclic or higher cyclic alkyl containing at least one hetero atom selected from O, N and S, unless stated otherwise. 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 one example of the compound of formula (1) according to the present invention,

A is -CH- or -N-;

X is -S-, -NH-, or -N (Ci_ ₆ alkyl)-;

Y is halogen, amino, -NHR, -NHOR, -NH- (CH ₂ ) mN (R) ₂ , -SR, -S (O) R, or -S (O) ₂ R, wherein R is C _1-6 alkyl or C _3-6 cycloalkyl, m is an integer from 1 to 3;

R ₁ is H, C _1-6 alkyl, or halogen;

R ₂ is H, C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, or halogen;

R ₃ is H, C _1-10 alkyl, or — (CH ₂ ) nR ₄ , where n is an integer from 1 to 3;

R ₄ is C _1-6 alkoxy, C _2-4 alkynyl, C _3-6 cycloalkyl, 5-6 membered heterocycloalkyl, C _6-8 aryl, or 5-6 membered heteroaryl,

Wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently C _1-6 alkyl, C _1-6 alkoxy, halogen, cyano, C _1-6 alkylsulfonylamino, phenyl and 5-6 member It may be substituted with 1 to 3 substituents selected from the group consisting of heterocycloalkyl.

In another example of the compound of formula (1) according to the present invention,

A is -CH- or -N-;

X is -S-;

Y is halogen, amino, C _1-6 alkylamino, C _1-6 alkoxyamino, C _3-6 cycloalkylamino, diC _1-3 alkylamino-C _1-3 alkylene-amino or C _1-6 Alkylthio;

R ₁ is H, C _1-3 alkyl, or halogen;

R ₂ is H, C _1-3 alkyl, C _2-3 alkenyl, C _3-6 cycloalkyl, or halogen;

R ₃ is H, C _1-6 alkyl, or — (CH ₂ ) n R ₄ , where n is an integer from 1 to 3;

R ₄ is C _1-6 alkoxy, C _2-3 alkynyl, C _3-6 cycloalkyl, 5-6 membered heterocycloalkyl, C _6-8 aryl, or 5-6 membered heteroaryl,

At this time, the aryl and heteroaryl are each independently composed of C _1-3 alkyl, C _1-3 alkoxy, halogen, cyano, C _1-6 alkylsulfonylamino, phenyl and 5-6 membered heterocycloalkyl It may be substituted with 1 to 3 substituents selected from the group.

In another example of the compound of formula (1) according to the present invention,

A is -CH- or -N-;

X is -S-;

Y is halogen, amino, C _1-6 alkoxyamino, C _3-6 cycloalkylamino, dimethylamino-C _1-3 alkylene-amino or C _1-3 alkylthio;

R ₁ is H, C _1-3 alkyl, or halogen;

R ₂ is H, C _1-3 alkyl, C _2-3 alkenyl, C _3-6 cycloalkyl, or halogen;

R ₃ is H, C _1-6 alkyl, or — (CH ₂ ) n R ₄ , where n is an integer from 1 to 3;

R ₄ is C _1-3 alkoxy, C _2-3 alkynyl, C _3-6 cycloalkyl, 5-6 membered heterocycloalkyl, C _6-8 aryl, or 5-6 membered heteroaryl,

In this case, the aryl and heteroaryl may be each independently substituted with 1 to 3 substituents selected from the group consisting of C _1-3 alkyl, C _1-3 alkoxy, halogen, phenyl and 5-6 membered heterocycloalkyl. have.

Preferred examples of pyrimidine conjugated ring 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) 4-amino-N- (3-cyclopropyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine -7-carboxamide;

2) 4-amino-N- (1H-indol-5-yl) thieno [3,2-d] pyrimidine-7-carboxamide;

3) 4-amino-N- (3-methyl-1H-indazol-6-yl) thieno [3,2-d] pyrimidine-7-carboxamide;

4) 4-amino-N- (1-((6-methylpyridin-2-yl) methyl) -1H-indazol-5-yl) thieno [3,2-d] pyrimidine-7-carbox Amides;

5) 4-amino-N- (3-methyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine- 7-carboxamide;

6) 4-amino-N- (1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine-7-carbox Amides;

7) 4-amino-thieno [3,2-d] pyrimidine-7-carboxylic acid (1-benzyl-3-cyclopropyl-1H-indazol-4-yl) -amide;

8) 4-amino-N- (3-bromo-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine -7-carboxamide;

9) 4-amino-N- (1-benzyl-3-bromo-1H-indazol-4-yl) thieno [3,2-d] pyrimidine-7-carboxamide;

10) 4-amino-N- (3-bromo-1-((pyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidin-7- Carboxamide;

11) N- (1- (4-methoxybenzyl) -3-bromo-1H-indazol-4-yl) -4-amino-thieno [3,2-d] pyrimidine-7-carbox Amides;

12) 4-amino-N- (3-bromo-1- (cyclohexylmethyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine-7-carboxamide;

13) 4-amino-N- (3-bromo-1- (2-propynyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine-7-carboxamide;

14) 4-amino-N- (3-bromo-1-((6-bromopyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyri Midine-7-carboxamide;

15) 4-amino-N- (3-bromo-1-((tetrahydrofuran-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine- 7-carboxamide;

16) 4-amino-N- (3-bromo-1-((6-fluoropyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyri Midine-7-carboxamide;

17) 4-amino-N- (3-bromo-1-phenethyl-1H-indazol-4-yl) thieno [3,2-d] pyrimidine-7-carboxamide;

18) 4-amino-N- (3-bromo-1-((6-phenylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine -7-carboxamide;

19) 4-amino-thieno [3,2-d] pyrimidine-7-carboxylic acid (3-bromo-1-pyridin-3-ylmethyl-1H-indazol-4-yl) -amide;

20) 4-amino-thieno [3,2-d] pyrimidine-7-carboxylic acid (3-bromo-1-pyridin-4-ylmethyl-1H-indazol-4-yl) -amide;

21) 4-amino-N- (3-bromo-1-((thiophen-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidin-7 Carboxamide;

22) 4-amino-N- (3-bromo-1-((furan-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidin-7- Carboxamide;

23) 4-amino-N- (3-bromo-1-propyl-1H-indazol-4-yl) thieno [3,2-d] pyrimidine-7-carboxamide;

24) 4-amino-N- (3-bromo-1- (2-methoxyethyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine-7-carboxamide ;

25) 4-amino-N- (3-bromo-1-((1-ethyl-5-isopropyl-1H-pyrazol-3-yl) methyl) -1H-indazol-4-yl) -thier No [3,2-d] pyrimidine-7-carboxamide;

26) N- (1- (4-morpholinobenzyl) -3-bromo-1H-indazol-4-yl) -4-amino-thieno [3,2-d] pyrimidine-7-car Voxamides;

27) 4-amino-N- (3-ethyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine- 7-carboxamide;

28) 4-amino-N- (1-((6-methylpyridin-2-yl) methyl) -3-vinyl-1H-indazol-4-yl) thieno [3,2-d] pyrimidine- 7-carboxamide;

29) 4-amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-5-methyl-1- (6-methyl-pyridin-2-ylmethyl) -1H-indazole -4-yl] -amide;

30) 4-amino-N- (5-methyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine- 7-carboxamide;

31) 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-1- (6-methoxy-pyridin-2-ylmethyl) -1H-indazol-4- General] -amide;

32) 4-amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-5-chloro-1- (6-methoxy-pyridin-2-ylmethyl) -1H- Zol-4-yl] -amide;

33) N- (3-cyclopropyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) -4- (methylthio) thieno [3,2-d ] Pyrimidine-7-carboxamide;

34) N- (3-cyclopropyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) -4- (cyclopropylamino) thieno [3,2- d] pyrimidine-7-carboxamide;

35) 4-methoxyamino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-cyclopropyl-1- (6-methyl-pyridin-2-ylmethyl) -1H-indazole-4 -Yl] -amide;

36) 4-amino-N- (3-bromo-1-((6-methylpyridin-2-yl) methyl) -1H-indol-4-yl) thieno [3,2-d] pyrimidine- 7-carboxamide;

37) 4-chloro-thieno [3,2-d] pyrimidin-7-carboxylic acid [3-cyclopropyl-1- (6-methyl-pyridin-2-ylmethyl) -1H-indazol-4-yl ] -Amide;

38) 4-methylamino-thieno [3,2-d] pyrimidin-7-carboxylic acid [3-cyclopropyl-1- (6-methylpyridin-2-ylmethyl) -1H-indazol-4-yl ) -Amide;

39) 4- (2-dimethylamino-ethylamino) -thieno [3,2-d] pyrimidine-7-carboxylic acid [3-cyclopropyl-1- (6-methylpyridin-2-ylmethyl)- 1H-indazol-4-yl) -amide;

40) 4-chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-1- (1-ethyl-1H-pyrazol-3-ylmethyl) -1H-indazole- 4-yl] -amide;

41) 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-1- (1-ethyl-1 H-pyrazol-3-ylmethyl) -1 H-indazole- 4-yl] -amide;

42) 4-Chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-cyclopropyl-1- (6-methoxy-pyridin-2-ylmethyl) -1 H-indazol-4- General] -amide;

43) 4-amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-cyclopropyl-1- (6-methoxy-pyridin-2-ylmethyl) -1H-indazol-4- General] -amide;

44) 4-Chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid (3-bromo-1- (pyrimidin-4-ylmethyl) -1H-indazol-4-yl) -amide ;

45) 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid (3-bromo-1- (pyrimidin-4-ylmethyl) -1H-indazol-4-yl) -amide ;

46) 4-Chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-1- (4-methyl-thiazol-2-ylmethyl) -1 H-indazol-4- General] -amide;

47) 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-1- (4-methyl-thiazol-2-ylmethyl) -1 H-indazol-4- General] -amide;

48) 4-amino-thieno [3,2-d] pyrimidine-7-carboxylic acid (3-bromo-1- (pyrazin-2-ylmethyl) -1H-indazol-4-yl) -amide;

49) 4-Chloro-thieno [3,2-d] pyrimidin-7-carboxylic acid [1- (6-methoxy-pyridin-2-ylmethyl) -3-methyl-1H-indazol-4-yl ] -Amide; And

50) 4-amino-thieno [3,2-d] pyrimidin-7-carboxylic acid [1- (6-methoxy-pyridin-2-ylmethyl) -3-methyl-1H-indazol-4-yl ] -Amide.

The present invention also provides a pharmaceutically acceptable salt of the pyrimidine conjugated ring derivative represented by the 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 pharmaceutically usable free acids and acid addition salts of base compounds of formula (1), alkali metal salts (such as sodium salts) and alkaline earth metal salts (such as calcium salts), organic bases and organic bases of carboxylic acids of formula (1). Addition salts, amino acid addition salts and the like are possible.

Preferred salt forms of the compounds according to the invention include salts with inorganic or organic acids. At this time, the inorganic acid may be used hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid and 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 for the preparation of organic base addition salts are 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 can be prepared by conventional methods. For example, the compound of Formula 1 may be prepared by dissolving in a solvent which may be mixed with water such as methanol, ethanol, acetone, 1,4-dioxane, and then crystallizing after adding a free acid or 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, solvate and hydrate forms of the compound of formula 1 are also included within the scope of the present invention.

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

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

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

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, colorectal cancer, testicular cancer, bone cancer, oral cancer, basal cell carcinoma, ovarian cancer, brain tumor, gallbladder carcinoma, biliary tract cancer, head and neck cancer cancer, colorectal cancer, colorectal cancer, vesical carcinoma, tongue cancer, esophageal cancer, glioma, glioblastoma, renal cancer, Malignant melanoma, gastric cancer, breast cancer, sarcoma, pharynx carcinoma, uterine cancer, cervical cancer, prostate cancer, Rectal cancer, pancreatic cancer, lung cancer, skin cancer (skin cancer) ncer, or other solid rock, but are not limited thereto.

The compound of formula 1 or a pharmaceutically acceptable salt thereof according to the present invention can enhance the therapeutic effect by co-administration with other agents for treating inflammatory disease, autoimmune disease or 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 formula 1 or a pharmaceutically acceptable salt thereof according to the present invention can enhance the therapeutic effect of an anticancer agent by co-administration with other anticancer agents for treating cancer or a tumor.

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, Antioxidants such as methotrexate and 5-FU), intercalating anticancer agents (such as actinomycin, anthracycline, bleomycin and mitomycin), antimetabolites (such as cisplatin, cyclophosphamide, chlorambucil and camestine) (Eg, tamoxifen, raloxifene, etc.), topoisomerase inhibitors (eg, iridotecan, topotecan, and tenofoside), immunotherapies (interleukins and interferons), and anti- 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, preferably oral It is preferably formulated in a dosage form.

Examples of excipients which can be used in the pharmaceutical composition of the present invention include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonizing agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers and perfumes. 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 dosage of the compound according to the present invention for 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, a method for preparing the compound of formula 1 of the present invention will be described in detail.

Scheme 1A

Scheme 1B

Scheme 1C

In Schemes 1A to 1C, A, X, R ₁ , R ₂ , and R ₃ are the same as defined in Chemical Formula 1.

As in Scheme 1A, the compound of formula a1 and the compound of formula b are converted to 2- (1H-7-abenzobenzotriazol-1-yl) -1,1,3,3-tetramethyl uronium hexafluoro The compound of Formula 1 'may be prepared by a method comprising the step of reacting with phosphate methaneaminium (HATU).

Alternatively, as in Scheme 1B, the compound of formula a2 and the compound of formula b are 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyl uroni The compound of Formula 1 ′ may be prepared by a method comprising reacting with Um hexafluorophosphate methaneaminidium (HATU) followed by reaction with TFA.

Alternatively, as in Scheme 1C, the compound of formula a3 and the compound of formula b may be selected from 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyl The compound of Formula 1 ′ may be prepared by a method comprising the step of reacting with Rhonium hexafluorophosphate methanemininium (HATU) followed by reaction with m-CPBA and an amine compound.

A method for preparing the compound of formula (a1) is disclosed in Korean Patent Laid-Open Publication No. 2011-88960.

[Reaction Scheme 2]

As in Scheme 2, by reacting the compound of formula c1 in ether or THF in the presence of n-BuLi at a temperature of -78 ℃ and reacted with DMF, CO ₂ or (MeO) ₂ CO A compound of formula a2, a compound of formula a2 ', or a compound of formula a2''may be prepared.

Scheme 3

In addition, as in Scheme 3, the compound of formula a3 by reacting the compound of formula c2 in ether or THF in the presence of n-BuLi at a temperature of -78 ℃ and reacted with DMF or CO ₂ Or a compound of formula a3 '.

[Reaction Scheme 4]

As in Scheme 4, the compound of formula d1 may be prepared by a method comprising the step of reacting the compound of formula d with an amine compound in DMF at a temperature of 50 ° C. for about 1 hour, or the compound of formula d Compound of formula c2 may be prepared by a method comprising reacting with NaSMe for about 12 hours in THF.

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

Preparation Example: Preparation of Thieno [3,2-d] pyrimidine Compound

Preparation Example 1 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid

Step 1) 3H-thieno [3,2-d] pyrimidin-4-one

Acetic anhydride (185 mL, 1.96 mol) and formic acid (85 mL, 2.22 mmol) were added and stirred. Methyl-3-aminothiophene-2-carboxylate (50 g, 0.16 mol) was added to the reaction solution, followed by stirring at room temperature for about 3 hours. The reaction solvent was removed under reduced pressure. Ammonium formate (90 g, 1.43 mol) and formamide (150 mL, 3.76 mol) were added thereto, followed by stirring for about 30 minutes. The above-synthesized material was added to the reaction solution, and the mixture was stirred at 150 占 폚 for 8 hours. The temperature was lowered to room temperature and stirred for about 12 hours. The resulting solid was filtered and washed with water to give the desired compound (39 g, 81%).

¹ H-NMR (300 MHz, DMSO-d6): δ 12.48 (br, 1H), 8.18 (d, 1H), 8.14 (s, 1H), 7.40 (d, 1H)

Step 2) 7-Bromothieno [3,2-d] pyrimidin-4 (3H) -one

Thieno [3,2-d] pyrimidin-4 (3H) -one (38.0 g, 0.25 mol) was dissolved in acetic acid (143 mL, 2.5 mol) and bromine (40.4 mL, 0.78 mol) was diluted with acetic acid (122 mL, 2.1 diluted in mol) and added slowly. The reaction mixture was stirred in a sealed reactor at 120 DEG C for 18 hours. The reaction mixture was cooled to room temperature and then acetic acid was removed by distillation under reduced pressure. The mixture was poured into ice water, and the resulting solid compound was filtered and dried. The desired compound (37.5 g, 65%) was obtained without purification.

¹ H-NMR (300 MHz, DMSO-d6): δ 12.75 (brs, 1 H), 8.36 (s, 1 H), 8.24 (s, 1 H)

Step 3) 7-bromo-4-chlorothieno [3,2-d] pyrimidine

Dimethylformamide (25.8 mL, 0.33 mol) and dichloromethane (150 mL) were added to the reaction vessel. Oxalyl chloride (46.4 mL, 0.53 mol) was diluted in dichloromethane (150 mL) at room temperature and added for about 30 minutes. 7-bromothieno [3,2-d] pyrimidin-4 (3H) -one (35 g, 0.15 mol) was added thereto, followed by heating to reflux for 3 hours. The temperature was lowered and water was added carefully. The organic layer was separated and the water layer was extracted with dichloromethane. The extracted organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure and distilled under reduced pressure, and then dried over nitrogen gas to obtain a target compound (30.5 g, 85%).

¹ H-NMR (300 MHz, DMSO-d 6): δ 9.16 (s, 1H), 8.79 (s, 1H).

Step 4) 7-Bromothieno [3,2-d] pyrimidin-4-amine

7-Bromo-4-chlorothieno [3,2-d] pyrimidine (84.0 g) and 2.0 M ammonia (672 mL) obtained in step (3) were sealed and stirred under a 2-propanol solvent. The external temperature was raised to 95-100 ° C. and stirred for 7 hours. The reaction solution was cooled to room temperature and the solvent was distilled off under reduced pressure. 400 mL of distilled water was added to the concentrate, followed by stirring for 30 minutes. The solid mixture was filtered and washed twice with distilled water (168 mL). Drying in an oven at 50 ° C. gave the desired compound (75 g, 97%).

¹ H-NMR (300 MHz, DMSO-d 6): δ 7.71 (s, 2H), 8.33 (s, 1H), 8.47 (s, 1H).

Step 5) 7-Vinylthieno [3,2-d] pyrimidin-4-amine

7-bromothieno [3,2-d] pyrimidin-4-amine (53.0 g, 0.23 mol) and tetrakispalladium triphenylphosphine (15.8 g, 0.014 mol) obtained in step (4), and Copper iodide (5.3 g, 0.028 mol) was stirred under 1,4-dioxane (530 mL) solvent. Tributylvinyltin (83.2 mL, 0.276 mol) was slowly added to the mixed solution, and the mixture was refluxed for at least 7 hours. The reaction solution was cooled to room temperature, an aqueous potassium fluoride solution (795 mL) and ethyl acetate (795 mL) were added thereto, followed by vigorous stirring for at least 3 hours. The reaction solution was filtered under a celite pad under reduced pressure, washed with ethyl acetate (105 mL), and the organic layer of the filtrate was separated and dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure and distilled under reduced pressure, ethyl acetate (106 mL) / hexane (106 mL) was added to the concentrate, and the mixture was stirred for 1 hour. The reaction solution was filtered under reduced pressure and washed with ethyl acetate / hexane (27 mL / 27 mL). The filtered solid was dried in a hot air oven (50 ° C.) for at least 3 hours to obtain the target compound (34.2 g, 83.8%).

¹ H-NMR (300 MHz, DMSO-d6): δ 8.40 (s, 1H), 8.13 (s, 1H), 7.44 (s, 2H), 6.94 (dd, 1H), 6.34 (dd, 1H), 5.37 ( dd, 1 H).

Step 6) 4-Amino-thieno [3,2-d] pyrimidine-7-carboaldehyde

The 7-vinylthieno [3,2-d] pyrimidin-4-amine (40.0 g, 0.226 mol) obtained in the step (5) was stirred under a solvent of chloroform (280 mL) and methanol (280 mL). The reaction solution was cooled to -78 DEG C while being filled with nitrogen gas, and then ozone gas was supplied for 3 hours or more. After removing the ozone gas apparatus and filling with nitrogen gas, the temperature of the reactant was raised to room temperature, followed by addition of dimethyl sulfide (60 mL) and stirring at room temperature for 3 hours or more. The reaction solution was concentrated under reduced pressure, ethyl acetate (80 mL) was added to the concentrate, and the mixture was stirred for 1 hour. The reaction solution was filtered under reduced pressure and the filtered solid was washed with ethyl acetate (10 mL). The filtered solid was dried in a hot air oven (50 ° C.) for at least 3 hours to obtain the target compound (36 g, 89%).

¹ H-NMR (300 MHz, CDCl ₃ ): δ 10.25 (s, 1H), 8.99 (s, 1H), 8.50 (s, 1H), 7.82 (s, 2H).

Step 7) 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid

Sodium hydrogen phosphate dihydrate (48.2 g, 0.402 mol) was dissolved in distilled water (180 mL), and the temperature of the reaction solution was cooled to 0 deg. 4-amino-thieno [3,2-d] pyrimidine-7-carboaldehyde (36.0 g, 0.201 mol) obtained in step (6) was dissolved in acetone (244 mL) / dimethyl sulfoxide (176 mL). Then, it was slowly added to the reaction solution of 3 ° C or lower. Sodium chlorite (30.3 g, 0.268 mol) was dissolved in distilled water (180 mL) and slowly added to the reaction solution at 3 ° C or lower. The reaction solution was warmed to room temperature and stirred for 3 hours or more. Distilled water (1,280 mL) was added to the reaction solution, and the mixture was stirred for 5 hours or more. The reaction solution was filtered under reduced pressure and the filtered solid was washed with diethyl ether (72 mL). Ethanol (180 mL) was added to the filtered solid, followed by distillation under reduced pressure, and the concentrated solid was dried in a heating oven (50 ° C.) for at least 3 hours to obtain a target compound (36 g, 91.8%).

¹ H-NMR (300 MHz, DMSO-d 6): δ 8.92 (s, 1H), 8.50 (s, 1H), 7.94 (s, 2H).

Preparation Example 2 7-Bromo-4- (methylthio) thieno [3,2-d] pyrimidine

7-Bromo-4-chlorothieno [3,2-d] pyrimidine (13.6 g, 54.5 mmol) obtained in step 3 of Preparation Example 1 was dissolved in THF (150 mL), followed by sodium methanethiolate (9.6 g). , 136.3 mmol) was added at 0 ° C. After stirring for 12 hours at room temperature, ice water was added. The resulting solid compound was filtered and dried at 50 ° C. to obtain the desired compound (10.1 g, 71%).

¹ H-NMR (300 MHz, DMSO-d 6) δ 9.09 (s, 1H), 8.57 (s, 1H), 2.76 (s, 3H).

Preparation Example 3 7-Bromo-N- (2,4-dimethoxybenzyl) thieno [3,2-d] pyrimidin-4-amine

7-Bromo-4-chlorothieno [3,2-d] pyrimidine (1.0 g, 4.0 mmol) obtained in step 3 of Preparation Example 1 was dissolved in DMF (10 mL), followed by dimethoxybenzylamine (0.63 mL, 4.21 mmol) and diisopropylethylamine (1.05 mL, 6.01 mmol) were added. After stirring for 12 hours at room temperature, ice water was added. The resulting solid compound was filtered and dried at 50 ° C. to obtain the desired compound (1.36 g, 89%).

¹ H-NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.43 (dd, 1H), 8.30 (s, 1H), 7.05 (d, 1H), 6.56 (d, 1H), 6.42 ( d, 1H), 4.60 (d, 2H), 3.80 (s, 3H), 3.72 (s, 3H).

Preparation Example 4 4- (methylthio) thieno [3,2-d] pyrimidine-7-carboxylic acid

The 7-bromo-4- (methylthio) thieno [3,2-d] pyrimidine (10.0 g, 38.3 mmol) obtained in Preparation Example 2 was dissolved in diethyl ether (200 mL) and the temperature was raised to -78 ° C. Got off. n-BuLi solution (1.6 M hexane solution, 52.6 mL, 57.5 mmol) was slowly added dropwise and stirred at the same temperature for 30 minutes. Dry ice (100 g) was added and stirred at the same temperature for 1 hour and the temperature was slowly raised to room temperature and stirred for 1 hour. Distilled water (200 mL) was added to the reaction solution, and the resulting solid compound was filtered. Drying in an oven at 50 ° C. gave a solid (7.0 g, 81%). The obtained solid was added to ethyl acetate (200 mL), stirred at 40 ° C. for 1 hour, and filtered to obtain the target compound (5.8 g, 83%).

¹ H-NMR (300 MHz, DMSO-d 6) δ 8.98 (s, 1H), 8.49 (s, 1H), 2.72 (s, 1H).

Preparation Example 5 4- (methylthio) thieno [3,2-d] pyrimidine-7-carbaldehyde

7-Bromo-4- (methylthio) thieno [3,2-d] pyrimidine (100 mg, 0.38 mmol) obtained in Preparation Example 2 was dissolved in diethyl ether (4 mL), and the temperature was decreased to -78 ° C. . n-BuLi solution (1.6 M hexane solution, 0.53 mL, 0.57 mmol) was slowly added dropwise and stirred at the same temperature for 30 minutes. DMF (0.032 mL, 0.42 mmol) was added and stirred at the same temperature for 1 hour and the temperature was slowly raised to room temperature and stirred for 1 hour. Dichloromethane (10 mL) was added to the reaction solution, and the mixture was washed twice with distilled water (5 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the target compound (66 mg, 83%).

¹ H-NMR (300 MHz, DMSO-d 6) δ 10.30 (s, 1H), 9.20 (s, 1H), 9.12 (s, 1H), 2.76 (s, 3H).

Preparation Example 6: 4-((2,4-dimethoxybenzyl) amino) thieno [3,2-d] pyrimidine-7-carboxylic acid

7-Bromo-N- (2,4-dimethoxybenzyl) thieno [3,2-d] pyrimidin-4-amine (3.0 g, 7.89 mmol) obtained in Preparation Example 3 was diluted with ethyl (70 mL). Melted at) and then the temperature was lowered to -78 ° C. n-BuLi solution (1.6 M hexane solution, 7.4 mL, 11.8 mmol) was slowly added dropwise and stirred at the same temperature for 30 minutes. Dry ice (5 g) was added and stirred at the same temperature for 1 hour, and the temperature was slowly raised to room temperature and stirred for 1 hour. Distilled water (50 mL) was added to the reaction solution, and 2N HCl solution was added until the pH of the solution was 2-3. Extracted with dichloromethane (200 mL), dried over magnesium sulfate, and the solvent was removed under reduced pressure. The resulting solid was added to ethyl acetate (30 mL), stirred and filtered to afford the desired compound (1.75 g, 64%).

¹ H-NMR (300 MHz, DMSO-d6) δ8.91 (s, 1H), 8.73 (dd, 1H), 8.54 (s, 1H), 7.04 (d, 1H), 6.56 (d, 1H), 6.43 ( d, 1H), 4.63 (d, 2H), 3.80 (s, 3H), 3.72 (s, 3H).

Preparation Example 7 4-((2,4-dimethoxybenzyl) amino) thieno [3,2-d] pyrimidine-7-carboaldehyde

7-bromo-N- (2,4-dimethoxybenzyl) thieno [3,2-d] pyrimidin-4-amine (100 mg, 0.263 mmol) obtained in Preparation Example 3 was diluted with ethyl (4 mL). After melting in, the temperature was lowered to -78 ℃. n-BuLi solution (1.6 M hexane solution, 0.24 mL, 0.394 mmol) was slowly added dropwise and stirred at the same temperature for 30 minutes. DMF (0.022 mL, 0.289 mmol) was added and stirred at the same temperature for 1 hour and the temperature was slowly raised to room temperature and stirred for 1 hour. Dichloromethane (10 mL) was added to the reaction solution, and the mixture was washed twice with distilled water (5 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the target compound (68 mg, 79%).

¹ H-NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.95 (s, 1H), 8.51 (s, 1H), 7.08 (d, 1H), 6.55 (d, 1H), 6.43 ( d, 1H), 4.59 (d, 2H), 3.81 (s, 3H), 3.72 (s, 3H).

Preparation Example 8 2- (Chloromethyl) -6-methylpyridine

Thionyl chloride (30.0 mL) was added to (6-methylpyridin-2-yl) methanol (13.0 g) at 0 ° C. for 30 minutes, followed by stirring for 1 hour. The solution was distilled under reduced pressure to give 18.0 g of the target compound. [See WO 2011/079076 A1]

Examples: Preparation of compounds of formula (I)

Example 1: 4-amino-N- (3-cyclopropyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] Pyrimidine-7-carboxamide

Step 1) 3-Bromo-4-nitro-1H-indazole

4-nitro-1H-indazole (5.0 g) and sodium acetate (2.6 g) were added to an acetic acid / chromoform (1/1, 10.0 mL) mixed solvent. Bromine (liquid, 2.6 g) was diluted with acetic acid (1 mL) for 10 minutes while maintaining the reaction temperature at 20 占 폚 or lower, followed by stirring for 2 hours. Water (20 mL) was added to the reaction solution and stirred for 30 minutes. The resulting solid was filtered under reduced pressure and dried to obtain the desired compound (7.0 g).

Step 2) 3-Bromo-1-((6-methylpyridin-2-yl) methyl) -4-nitro-1H-indazole

3-bromo-4-nitro-lH-indazole (1.0 g) and 2- (chloromethyl) -6-methylpyridine (0.8 g) obtained in Preparation Example 8 were added N, N-dimethylformamide (10 mL). Was added. Potassium carbonate (1.14 g) was added to the mixed solution, and the mixture was stirred at 25 ° C for 24 hours. Ethyl acetate (20 mL, repeated 3 times) and water (20 mL) were added to the reaction solution, and the organic layer was separated. The combined organic layers were dried over anhydrous magnesium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (1.36 g).

Step 3) 3-cyclopropyl-1-((6-methylpyridin-2-yl) methyl) -4-nitro-1H-indazole

In a closed flask under argon gas, 3-bromo-1-((6-methylpyridin-2-yl) methyl) -4-nitro-1H-indazole (600 mg), cyclopropylboronic acid (193 mg), potassium phosphate ( 1.1 g), palladium acetate (19 mg) and tricyclohexyl phosphine (48 mg) were added to toluene / water (15/1, 9 mL), and the temperature was raised to 100 ° C. in a sealed flask and stirred for 24 hours. The solution was cooled to room temperature, filtered under reduced pressure using celite, the filtrate was concentrated, and the residue was purified by column chromatography to obtain the target compound (450 mg).

Step 4) 3-cyclopropyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-amine

3-cyclopropyl-1-((6-methylpyridin-2-yl) methyl) -4-nitro-1H-indazole (113 mg) and palladium (12 mg) under hydrogen gas were added with tetrahydrofuran / methanol (1/1). , 5mL) and stirred for 12 hours. The solution was filtered under reduced pressure using celite and the filtrate was distilled to obtain the target compound (103 mg).

Step 5) 4-Amino-N- (3-cyclopropyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyridine Midine-7-carboxamide

3-cyclopropyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-amine (40 mg), 4-amino-thieno [3,2-d obtained in Preparation Example 1 ] Pyrimidine-7-carboxylic acid (28 mg), and 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyl uronium hexafluorophosphite methane 160 mg) was added to N, N-dimethylformamide (3 mL) and stirred at room temperature. Diisopropylethylamine (122 µl) was added to the solution, which was stirred for 24 hours at room temperature. Ethyl acetate (10 mL, repeated three times) and 10 mL of water were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was purified by column chromatography to obtain the target compound (18 mg).

Example 2: 4-amino-N- (1H-indol-5-yl) thieno [3,2-d] pyrimidine-7-carboxamide

Proceed in the same procedure as in Example 1, but in step 5) 1H-indol-5- instead of 3-cyclopropyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-amine Prepared using monoamine.

Example 3: 4-amino-N- (3-methyl-1H-indazol-6-yl) thieno [3,2-d] pyrimidine-7-carboxamide

Proceed as in Example 1, but with 3-methyl-1H- in place of 3-cyclopropyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-amine Prepared using indazole-6-ylamine.

Example 4: 4-amino-N- (1-((6-methylpyridin-2-yl) methyl) -1H-indazol-5-yl) thieno [3,2-d] pyrimidin-7- Carboxamide

Proceed in the same procedure as in Example 1, but without performing steps 1) and 3), using 5-nitro-1H-indazole instead of 3-bromo-4-nitro-1H-indazole in step 2) Prepared.

Example 5: 4-amino-N- (3-methyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyri Midine-7-carboxamide

Proceed in the same procedure as in Example 1, was prepared using methyl boronic acid instead of cyclopropyl boronic acid in step 3).

Example 6: 4-amino-N- (1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidin-7- Carboxamide

Proceed in the same procedure as in Example 1, but prepared in step 2) using 4-nitro-1H-indazole compound instead of 3-bromo-4-nitro-1H-indazole.

Example 7: 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid (1-benzyl-3-cyclopropyl-1 H-indazol-4-yl) -amide

Proceed in the same procedure as in Example 1, but was prepared using benzyl bromide instead of 2- (chloromethyl) -6-methylpyridine in step 2).

Example 8: 4-amino-N- (3-bromo-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] Pyrimidine-7-carboxamide

Proceed in the same procedure as in Example 1, but was prepared without performing step 3).

Example 9: 4-amino-N- (1-benzyl-3-bromo-1H-indazol-4-yl) thieno [3,2-d] pyrimidine-7-carboxamide

Proceed in the same procedure as in Example 8, but was prepared in step 2) using benzyl chloride instead of 2- (chloromethyl) -6-methylpyridine.

Example 10: 4-amino-N- (3-bromo-1-((pyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine- 7-carboxamide

Proceed in the same procedure as in Example 8, but prepared in step 2) using 2-chloromethyl-pyridine instead of 2- (chloromethyl) -6-methylpyridine.

Example 11: N- (1- (4-methoxybenzyl) -3-bromo-1H-indazol-4-yl) -4-amino-thieno [3,2-d] pyrimidine-7- Carboxamide

Proceed in the same procedure as in Example 8, but was prepared in step 2) using 4-methoxybenzylchloride instead of 2- (chloromethyl) -6-methylpyridine.

Example 12 4-amino-N- (3-bromo-1- (cyclohexylmethyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine-7-carboxamide

Proceed in the same procedure as in Example 8, but prepared in step 2) using chloromethylcyclohexane instead of 2- (chloromethyl) -6-methylpyridine.

Example 13: 4-amino-N- (3-bromo-1- (2-propynyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine-7-carbox Amide

Proceed in the same procedure as in Example 8, but prepared in step 2) using 3-bromo-propine instead of 2- (chloromethyl) -6-methylpyridine.

Example 14 4-amino-N- (3-bromo-1-((6-bromopyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d ] Pyrimidine-7-carboxamide

Proceed in the same procedure as in Example 8, but prepared in step 2) using 2-bromo-6-chloromethyl-pyridine instead of 2- (chloromethyl) -6-methylpyridine.

Example 15 4-amino-N- (3-bromo-1-((tetrahydrofuran-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyri Midine-7-carboxamide

Proceed in the same procedure as in Example 8, but prepared in step 2) using 2-chloromethyl-tetrahydrofuran instead of 2- (chloromethyl) -6-methylpyridine.

Example 16: 4-amino-N- (3-bromo-1-((6-fluoropyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d ] Pyrimidine-7-carboxamide

Proceed in the same procedure as in Example 8, but was prepared in step 2) using 2-fluoro-6-chloromethyl-pyridine instead of 2- (chloromethyl) -6-methylpyridine.

Example 17 4-amino-N- (3-bromo-1-phenethyl-1H-indazol-4-yl) thieno [3,2-d] pyrimidine-7-carboxamide

Proceed in the same procedure as in Example 8, but prepared in step 2) using (2-bromo-ethyl) -benzene instead of 2- (chloromethyl) -6-methylpyridine.

Example 18: 4-amino-N- (3-bromo-1-((6-phenylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] Pyrimidine-7-carboxamide

Proceed in the same procedure as in Example 8, but was prepared in step 2) using 2-chloromethyl-6-phenyl-pyridine instead of 2- (chloromethyl) -6-methylpyridine.

Example 19 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid (3-bromo-1-pyridin-3-ylmethyl-1H-indazol-4-yl) -amide

Proceed in the same procedure as in Example 8, but prepared in step 2) using 3-chloromethyl-pyridine instead of 2- (chloromethyl) -6-methylpyridine.

Example 20 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid (3-bromo-1-pyridin-4-ylmethyl-1 H-indazol-4-yl) -amide

Proceed in the same procedure as in Example 8, but was prepared in step 2) using 4-chloromethyl-pyridine instead of 2- (chloromethyl) -6-methylpyridine.

Example 21 4-amino-N- (3-bromo-1-((thiophen-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine -7-carboxamide

Proceed in the same procedure as in Example 8, but was prepared in step 2) using 2-chloromethyl-thiophene instead of 2- (chloromethyl) -6-methylpyridine.

Example 22: 4-amino-N- (3-bromo-1-((furan-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine- 7-carboxamide

Proceed in the same procedure as in Example 8, but prepared in step 2) using 2-chloromethyl-furan instead of 2- (chloromethyl) -6-methylpyridine.

Example 23 4-amino-N- (3-bromo-1-propyl-1H-indazol-4-yl) thieno [3,2-d] pyrimidine-7-carboxamide

Proceed in the same procedure as in Example 8, but was prepared in step 2) using bromopropane instead of 2- (chloromethyl) -6-methylpyridine.

Example 24 4-amino-N- (3-bromo-1- (2-methoxyethyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine-7-car Voxamide

Proceed in the same procedure as in Example 8, but prepared in step 2) using 1-chloro-2-methoxy-ethane instead of 2- (chloromethyl) -6-methylpyridine.

Example 25 4-amino-N- (3-bromo-1-((1-ethyl-5-isopropyl-1H-pyrazol-3-yl) methyl) -1H-indazol-4-yl) -Thieno [3,2-d] pyrimidine-7-carboxamides

Proceed in the same procedure as in Example 8, but prepared in step 2) using 3-chloromethyl-1-ethyl-5-isopropyl-1H-pyrazole instead of 2- (chloromethyl) -6-methylpyridine.

Example 26 N- (1- (4-morpholinobenzyl) -3-bromo-1H-indazol-4-yl) -4-amino-thieno [3,2-d] pyrimidine-7 Carboxamide

Proceed as in Example 8, but prepared in step 2) using 4- (4-chloromethyl-phenyl) -morpholine instead of 2- (chloromethyl) -6-methylpyridine.

Example 27 4-amino-N- (3-ethyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyri Midine-7-carboxamide

Step 1) 1-((6-methylpyridin-2-yl) methyl) -4-nitro-3-vinyl-1H-indazole

In a closed flask under argon gas, 3-bromo-1-((6-methylpyridin-2-yl) methyl) -4-nitro-1H-indazole (500 mg) and potassium trifluoro (vinyl) borate (580 mg) , Triethylamine (0.6 mL), bis (diphenylphosphino) ferrocine palladium (II) dichloride dichloromethane (12 mg) were added to isopropanol / tetrahydrofuran (4/1, 15 mL) and in a sealed flask The temperature was raised to 100 ° C. and stirred for 24 hours. The solution was cooled to room temperature, filtered under reduced pressure using celite, distilled, and the residue was purified by column chromatography to obtain the target compound (310 mg).

Step 2) 3-ethyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-amine

Under hydrogen gas, 1-((6-methylpyridin-2-yl) methyl) -4-nitro-3-vinyl-1H-indazole (310 mg) and palladium hydroxide (30 mg) were added to methanol (10 mL). Stirred for time. The solution was filtered under reduced pressure using celite and distilled to give the title compound (300 mg).

Step 3) 4-Amino-N- (3-ethyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine -7-carboxamide

3-ethyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-amine (26 mg) with 4-amino-thieno [3,2-d] pyrimidine-7- Carboxylic acid (19 mg), 2- (1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphite methanealuminum (114 mg) Stir in dimethylformamide (3 mL). Diisopropylethylamine (87 µl) was added to the solution, which was stirred for 24 hours at room temperature. Ethyl acetate (10 mL, repeated three times) and water (10 mL) were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was purified by column chromatography to obtain the target compound (15 mg).

Example 28: 4-amino-N- (1-((6-methylpyridin-2-yl) methyl) -3-vinyl-1H-indazol-4-yl) thieno [3,2-d] pyri Midine-7-carboxamide

Proceed as in Example 27, but prepared without performing step 2).

Example 29 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-5-methyl-1- (6-methyl-pyridin-2-ylmethyl) -1H- Indazol-4-yl] -amide

Step 1) Preparation of 2,4-dimethyl-3-nitro-phenylamine

Concentrated sulfuric acid (80 mL) was slowly added dropwise to 2,4-dimethyl-phenylamine (12.4 mL, 100 mmol) with stirring at 0 ° C. Nitric acid (5 mL) was slowly added dropwise at 4 ° C, stirred for 20 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture is added to ice water (600 mL) and the acidity is adjusted to 10 with 5 N aqueous sodium hydroxide solution. After filtering under reduced pressure and washing with water, the obtained solid was dried in an oven at 50 ° C. for 24 hours to obtain a target compound (14.8 g, 89.5%).

Step 2) Preparation of 5-methyl-4-nitro-1H-indazole

After dissolving the compound (500 mg, 3.01 mmol) prepared in step 1) in acetic acid (15 mL), t-butyl nitrite was slowly added dropwise at 15 ° C. The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure to obtain the title compound (479 mg, 90%).

Step 3) Preparation of 3-bromo-5-methyl-4-nitro-1H-indazole

The compound prepared in step 2) (363 mg, 2.05 mmol) and sodium acetate (177 mg, 2.15 mmol) were dissolved in acetic acid / chloroform (1: 1, 8 mL) and stirred at room temperature. Bromine (0.06 mL, 2.15 mmol) was diluted with acetic acid (1 mL), and then slowly added dropwise to the reaction solution while maintaining the temperature at 21 degrees or less. The reaction mixture was stirred at room temperature for 8 hours. Water (5 mL) was added to the reaction mixture, and the mixture was concentrated by distillation under reduced pressure and stirred at room temperature for 1 hour. The resulting solid was filtered off and washed with water. The obtained compound was dried at 40 ° C. for 16 hours to give the target compound (446 mg, 85%).

Step 4) Preparation of 3-bromo-5-methyl-1- (6-methyl-pyridin-2-ylmethyl) -4-nitro-1H-indazole

Compound (100 mg, 0.39 mmol), 2-chloromethyl-6-methyl-pyridine (77 mg, 0.43 mmol) and potassium carbonate (216 mg, 1.56 mmol) prepared in step 3) were dissolved in dimethylformamide (1.5 mL). After the reaction, the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by distillation under reduced pressure was separated by column chromatography (ethyl acetate: hexane = 1: 4) to obtain the target compound (130 mg, 92%).

Step 5) Preparation of 3-bromo-5-methyl-1- (6-methyl-pyridin-2-ylmethyl) -1H-indazol-4-ylamine

Iron (101 mg, 1.80 mmol) and hydrochloric acid (0.02 mL, 0.15 mmol) were dissolved in 50% ethanol aqueous solution (1.5 mL), and then the reaction mixture was stirred at 80 ° C. for 1.5 hours, the compound prepared in step 4 (130 mg) , 0.36 mmol) was added dropwise to the above solution, and the reaction mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution, filtered and washed with dichloromethane: methanol mixed solution. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the residue obtained by distillation under reduced pressure was separated by column chromatography (ethyl acetate: hexane = 1: 1) to obtain the target compound (40 mg, 34%).

Step 6) 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-5-methyl-1- (6-methyl-pyridin-2-ylmethyl) -1H- Preparation of Zol-4-yl] -amide

4-amino-thieno [3,2-d] pyrimidin-7-carboxylic acid (21 mg, 0.11 mmol) and 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3 Tetramethyl uronium hexafluorophosphate methaneaminidium (HATU, 125 mg, 0.33 mmol), diisopropylethylamine (0.1 mL, 0.55 mmol) was dissolved in dimethylformamide (1.5 mL) And stirred at room temperature for 10 minutes. To the above solution was added dropwise the compound prepared in step 5) (40 mg, 0.12 mmol). The reaction mixture was stirred at 40 ° C. for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (dichloromethane: methanol = 25: 1) to obtain a target compound (1.6 mg, 3%).

Example 30 4-Amino-N- (5-methyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyri Midine-7-carboxamide

Proceed as in Example 29, but prepared without performing step 3).

Example 31 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-1- (6-methoxy-pyridin-2-ylmethyl) -1 H-indazole- 4-day] -amide

Step 1) Preparation of 6-methoxy-pyridine-2-carboxylic acid methyl ester

6-hydroxypyridine-2-carboxylic acid (1 g, 7.19 mmol) and silver carbonate (2.2 g, 7.90 mmol) are placed in a flask and dissolved in chloroform (20 mL). To the above solution is added dropwise methyl iodide (1 mL, 15.81 mmol). The reaction mixture was stirred at 60 ° C. for 26 hours, the reaction mixture was filtered, extracted with chloroform, filtered under reduced pressure and distilled under reduced pressure, and the obtained residue was separated by column chromatography (ethyl acetate: hexane = 1: 5) to obtain the title compound. (1.25 g, 100%) was obtained.

Step 2) Preparation of (6-methoxy-pyridin-2-yl) -methanol

After dissolving the compound (730 mg, 4.37 mmol) prepared in step 1) in diethyl ether, lithium aluminum hydride (175 mg, 4.37 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours. Celite (1.5 g) and sodium sulfate decahydrate (0.8 g) were added dropwise to the reaction mixture, followed by stirring at room temperature for 10 minutes. The reaction mixture was filtered and extracted with diethyl ether. The combined organic layer was filtered under reduced pressure and distilled under reduced pressure, and the residue was separated by column chromatography (ethyl acetate: hexane = 1: 3) to obtain the title compound (55 mg, 10%).

Step 3) Preparation of 2-Chloromethyl-6-methoxy-pyridine

The compound (55 mg, 0.40 mmol) prepared in step 2) was dissolved in thionyl chloride (1 mL), and then stirred at room temperature for 2 hours. The residue obtained by filtration under reduced pressure and distillation under reduced pressure was used without purification in the next step.

Step 4) Preparation of 3-bromo-1- (6-methoxy-pyridin-2-ylmethyl) -4-nitro-1H-indazole

Compound (60 mg, 0.38 mmol) prepared in step 3), 3-bromo-4-nitro-1H-indazole (85 mg, 0.35 mmol), potassium carbonate (195 mg, 1.40 mmol), and dimethylformamide (1.5) were prepared. mL), and stirred for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (ethyl acetate: hexane = 1: 5) to obtain the title compound (117 mg, 92%).

Step 5) Preparation of 3-bromo-1- (6-methoxy-pyridin-2-ylmethyl) -1H-indazol-4-ylamine

After dissolving iron (150 mg, 1.01 mmol) and hydrochloric acid (0.02 mL, 0.08 mmol) in 50% ethanol aqueous solution (1.5 mL), the reaction mixture was stirred at 80 ° C. for 1.5 hours, compound prepared in step 4 (73 mg) , 0.20 mmol) was added dropwise to the above solution, and the reaction mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution, filtered and washed with dichloromethane: methanol mixed solution. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (ethyl acetate: hexane = 1: 5) to obtain the title compound (32 mg, 48%).

Step 6) 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-1- (6-methoxy-pyridin-2-ylmethyl) -1 H-indazol-4 Preparation of amide

4-amino-thieno [3,2-d] pyrimidin-7-carboxylic acid (19 mg, 0.10 mmol) and 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3 Tetramethyl uronium hexafluorophosphate methaneaminidium (HATU, 114 mg, 0.30 mmol) and diisopropylethylamine (0.1 mL, 0.50 mmol) were dissolved in dimethylformamide (1.5 mL). And stirred at room temperature for 10 minutes. To the above solution was added dropwise the compound prepared in step 5) (32 mg, 0.10 mmol). The reaction mixture was stirred at 40 ° C. for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (dichloromethane: methanol = 100: 1) to obtain a target compound (10 mg, 20%).

Example 32: 4-amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-5-chloro-1- (6-methoxy-pyridin-2-ylmethyl) -1H -Indazol-4-yl] -amide

Step 1) Preparation of 3-bromo-1- (6-methyl-pyridin-2-ylmethyl) -1H-indazol-4-ylamine

Iron (210 mg, 3.73 mmol) and hydrochloric acid (0.03 mL, 0.30 mmol) were dissolved in 50% aqueous ethanol solution (4 mL), and the reaction mixture was stirred at 80 ° C. for 1.5 hours. 3-bromo-1- (6-methyl-pyridin-2-ylmethyl) -4-nitro-1H-indazole (200 mg, 0.75 mmol) was added dropwise to the above solution, and the reaction mixture was then heated at 80 ° C. Stir for 2 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution, filtered and extracted with dichloromethane / methanol solution. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (ethyl acetate, 100%) to obtain the title compound (191 mg, 80%).

Step 2) Preparation of 3-bromo-5-chloro-1- (6-methyl-pyridin-2-ylmethyl) -1H-indazol-4-ylamine

After dissolving the compound (50 mg, 0.15 mmol) and N-chlorosuccinimide (24 mg, 0.18 mmol) prepared in step 1) in acetonitrile (1 mL), the reaction mixture was stirred at 60 ° C. for 4 hours, Stirred at room temperature for 16 hours. The residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (ethyl acetate: hexane = 1: 10) to obtain the title compound (55 mg, 100%).

Step 3) 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-5-chloro-1- (6-methoxy-pyridin-2-ylmethyl) -1H- Preparation of Indazol-4-yl] -amide

4-Amino-thieno [3,2-d] pyrimidin-7-carboxylic acid (25 mg, 0.13 mmol) and 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3 Tetramethyl uronium hexafluorophosphate methaneaminidium (HATU, 146 mg, 0.38 mmol) and diisopropylethylamine (0.1 mL, 0.65 mmol) were dissolved in dimethylformamide (1.5 mL). And stirred at room temperature for 10 minutes.

To the above solution was added dropwise the compound prepared in step 2) (50 mg, 0.13 mmol). The reaction mixture was stirred at 40 ° C. for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (dichloromethane: methanol = 50: 1) to obtain a target compound (3.4 mg, 5%).

Example 33 N- (3-cyclopropyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) -4- (methylthio) thieno [3,2 -d] pyrimidine-7-carboxamide

4- (methylthio) thieno [3,2-d] pyrimidine-7-carboxylic acid (1.67 g) obtained in Preparation Example 4 was added to dichloromethane (30 mL) and cooled to 0 ° C. Oxalyl chloride (2.15 mL) was added to the reaction solution for 10 minutes, and a catalytic amount of N, N-dimethylformamide was added, followed by stirring for 1 hour. The reaction solution was distilled under reduced pressure to obtain 4- (methylthio) thieno [3,2-d] pyrimidine-7-carbonyl chloride, followed by 3-cyclopropyl-1-((6-methylpyridine-2). -Yl) methyl) -1H-indazol-4-amine (1.37g) and N, N-dimethylformamide (30mL) were added, followed by triethylamine (3.43mL), followed by stirring for 1 hour. Water (30 mL) was added and extracted three times with ethyl acetate (30 mL). The organic layer was dried over anhydrous magnesium sulfate, distilled under reduced pressure, and the residue was purified by column chromatography to obtain the target compound (1.63 g).

Example 34 N- (3-cyclopropyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) -4- (cyclopropylamino) thieno [3, 2-d] pyrimidine-7-carboxamide

N- (3-cyclopropyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) -4- (methylthio) thieno [3, obtained in Example 33. 2-d] pyrimidine-7-carboxamide (296 mg) was added to dichloromethane (10 mL) and cooled to 0 ° C. To this solution, 3-chloroperoxybenzoic acid (125 mg) was diluted in dichloromethane (5 mL), added for 10 minutes, and stirred for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted twice with dichloromethane (20 mL). The organic layer was dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to obtain N- (3-cyclopropyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) -4- (methyl Sulfinyl) thieno [3,2-d] pyrimidine-7-carboxamide was obtained. Isopropyl alcohol (4 mL) and cyclopropylamine (0.5 mL) were added together to the sealed reaction container, and the temperature was raised to 100 ° C. and stirred for 24 hours. The reaction solution was cooled, distilled under reduced pressure, and purified using column chromatography to obtain the target compound (20 mg).

Example 35 4-methoxyamino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-cyclopropyl-1- (6-methyl-pyridin-2-ylmethyl) -1H-indazole -4-yl] -amide

Proceed as in Example 34, but prepared using methoxyamine instead of cyclopropylamine.

Example 36 4-amino-N- (3-bromo-1-((6-methylpyridin-2-yl) methyl) -1H-indol-4-yl) thieno [3,2-d] pyri Midine-7-carboxamide

Step 1) 3-Bromo-4-nitro-1H-indole

To N, N-dimethylformamide (30 mL) 4-nitro-1H-indole (2.0 g) was added to the reaction vessel. Bromine (318 μl) was added to N, N-dimethylformamide (10 mL) while maintaining the reaction temperature at 0 ° C. or lower for 10 minutes, followed by stirring at room temperature for 18 hours. The reaction solution was extracted three times with water (100 mL) and ethyl acetate (100 mL). The organic layer was dried over anhydrous magnesium sulfate, distilled under reduced pressure and dried to obtain the target compound (2.5 g).

Step 2) 3-Bromo-1-((6-methylpyridin-2-yl) methyl) -4-nitro-1H-indole

3-bromo-4-nitro-1H-indole (1.0 g) and 2- (chloromethyl) -6-methylpyridine (0.74 g) were added to N, N-dimethylformamide (10 mL). Potassium carbonate (1.15 g) was added to this solution and stirred at 25 ° C for 24 hours. Ethyl acetate (20 mL, repeated 3 times) and water (20 mL) were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.75 g).

Step 3) 3-bromo-1-((6-methylpyridin-2-yl) methyl) -1H-indol-4-amine

Iron (81 mg) and concentrated hydrochloric acid (2 drops) were added to an ethanol / water (1: 1) mixed solution (5 mL), and the reaction temperature was raised to 80 ° C. and stirred for 1 hour. 3-bromo-1-((6-methylpyridin-2-yl) methyl) -4-nitro-1H-indole (100 mg) was added to the reaction solution, stirred for 1 hour, and the temperature of the solution was reduced to 30 ° C. It was then filtered using Celite. The filtered liquid was extracted three times with an aqueous sodium hydrogen carbonate solution (10 mL) and dichloromethane (10 mL), and the organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure. The obtained residue was purified by column chromatography to obtain the target compound (10 mg).

Step 4) 4-Amino-N- (3-bromo-1-((6-methylpyridin-2-yl) methyl) -1H-indol-4-yl) thieno [3,2-d] pyrimidine -7-carboxamide

3-bromo-1-((6-methylpyridin-2-yl) methyl) -1H-indol-4-amine (9 mg), 4-amino-thieno [3,2-d] pyrimidine-7- Carboxylic acid (6 mg), and HATU (33 mg) were stirred in N, N-dimethylformamide (3 mL). Diisopropylethylamine (26 µl) was added to the solution, which was stirred for 24 hours at room temperature. Ethyl acetate (10 mL, repeated 3 times) and water (10 mL) were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was purified using column chromatography to give the title compound (7 mg).

Example 37 4-chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-cyclopropyl-1- (6-methyl-pyridin-2-ylmethyl) -1H-indazol-4 -Work] -amide

Step 1) 4-Chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid

4-Chlorothieno [3,2-d] pyrimidine-7-carboxylic acid (20 mg, 0.093 mmol; see WO 2011/093672) was dissolved in thionyl chloride (5 mL) and N, N-dimethylformamide (1 Drops) were added. The mixture was stirred at room temperature for 2 hours and the solvent was removed under reduced pressure. The solvent was removed by azeotropic distillation twice with toluene and used in the next reaction without purification.

Step 2) 4-Chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-cyclopropyl- 1- (6- Yl] -amide

3-cyclopropyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-amine (26 mg, 0.093 mmol) was dissolved in dichloromethane and triethylamine (18.8 mg, 0.186 mmol) was added. 4-chlorothieno [3,2-d] pyrimidine-7-carbonylchloride was slowly added at room temperature and stirred at 35 ° C. for 4 hours. After the reaction was completed, water was added and the organic layer was separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (DCM: MeOH = 20: 1) to obtain the desired compound (20 mg).

Example 38 4-Methylamino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-cyclopropyl-1- (6-methylpyridin-2-ylmethyl) -1 H-indazol-4 -Work)-amide

Step 1) 4-Chloro-thieno [3,2-d] pyrimidine-7-carbonylchloride

4-hydroxy-thieno [3,2-d] pyrimidine-7-carboxylic acid (500 mg) and catalytic amount of N, N-dimethylformamide were added to thionyl chloride (10 mL), and the temperature was 100 ° C. Raised to and stirred for 2 hours. The solution was cooled to room temperature, filtered under reduced pressure, and azeotropically distilled with toluene. It was dried and used for the next reaction without purification.

Step 2) 4-Chloro-thieno [3,2-d] pyrimidin-7-carboxylic acid [3-cyclopropyl-1- (6-methylpyridin-2-ylmethyl) -1 H-indazol-4-yl ) -Amide

3-cyclopropyl-1- (6-methyl-pyridin-2-ylmethyl) -1H-indazol-4-ylamine (200 mg) and diisopropylethylamine (1.2 mL) in dichloromethane (6 ml) Was added. To this mixed solution, the compound prepared in step 1 above was dissolved in dichloromethane and slowly added. The solution was stirred at 25 ° C. for 2 hours. Ethyl acetate (20 mL, repeated 3 times) and water (20 mL) were added to the reaction solution, and the organic layer was separated. The combined organic layer was dried over anhydrous magnesium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was purified using column chromatography to give the target compound (200 mg).

Step 3) 4-Methylamino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-cyclopropyl-1- (6-methylpyridin-2-ylmethyl) -1 H-indazol-4- Sun)-amide

The compound prepared in step 2 (50 mg), methylamine (0.3 mL) and isopropanol solution (1 mL) were placed in a closed flask, and the temperature was raised to 100 ° C. and stirred for 16 hours. The solution was cooled to room temperature, filtered under reduced pressure, the filtrate was concentrated, and the residue was purified by column chromatography to obtain the target compound (40 mg).

Example 39: 4- (2-dimethylamino-ethylamino) -thieno [3,2-d] pyrimidine-7-carboxylic acid [3-cyclopropyl-1- (6-methylpyridin-2-ylmethyl ) -1H-indazol-4-yl) -amide

The same procedure as in Example 38 was repeated, but using N, N-dimethylethylenediamine instead of methylamine in step 3, the desired compound was obtained.

Example 40 4-chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-1- (1-ethyl-1H-pyrazol-3-ylmethyl) -1H- Zol-4-yl] -amide

Step 1) (1-ethyl-1H-pyrazol-3-yl) methanol

1-ethylpyrazole-3-carbaaldehyde (275 mg) was added to methanol (5 mL) followed by sodium borohydride (126 mg). The solution was stirred at 25 ° C. for 2.5 hours. Ethyl acetate (20 mL, repeated 3 times) and ammonium chloride aqueous solution (20 mL) were added to the reaction solution, and the organic layer was separated. The combined organic layers were dried over anhydrous magnesium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was purified using column chromatography to give the target compound (98 mg).

Step 2) 3-Chloromethyl-1-ethyl-1 H-pyrazole

Compound (98 mg) and thionyl chloride (0.1 mL) prepared in step 1 above were added to tetrahydrofuran (1.5 ml). The solution was stirred at 50 ° C. for 2.5 hours. The solution was cooled to room temperature, filtered under reduced pressure, and azeotropically distilled with toluene. It was dried and used for the next reaction without purification.

Step 3) 3-Bromo-1- (1-ethyl-1H-pyrazol-3-ylmethyl) -4-nitro-1H-indazole

The compound prepared in step 2 (230 mg) and potassium carbonate (530 mg) were added to N, N-dimethylformamide (4 mL). The solution was stirred at 25 ° C. for 2.5 hours. Ethyl acetate (20 mL, repeated 3 times) and aqueous ammonium chloride solution (20 mL) were added to the reaction solution, and the organic layer was separated. The combined organic layer was dried over anhydrous magnesium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was purified using column chromatography to give the target compound (170 mg).

Step 4) 3-Bromo-1- (1-ethyl-1H-pyrazol-3-ylmethyl) -1H-indazol-4-ylamine

Iron (250 mg) and hydrochloric acid (0.05 mL) were added to a 50% aqueous ethanol solution (1.5 mL), and then the reaction solution was stirred at 80 ° C for 1.5 hours. To this solution was added dropwise the compound (110 mg) prepared in step 3, which was stirred at 80 ° C. for 2 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution, then filtered and washed with dichloromethane / methanol mixed solution. The organic layer was washed with water and then dried over anhydrous sodium sulfate. This was filtered under reduced pressure and distilled under reduced pressure, and the obtained residue was separated by column chromatography to obtain the title compound (73.5 mg).

Step 5) 4-Chloro-thieno [3,2-d] pyrimidine-7-carbonylchloride

4-hydroxy-thieno [3,2-d] pyrimidine-7-carboxylic acid (100 mg) and catalytic amount of N, N-dimethylformamide were added to thionyl chloride (2 mL), and the temperature was 100 ° C. Raised to and stirred for 2 hours. The solution was cooled to room temperature, filtered under reduced pressure, and azeotropically distilled with toluene. After drying, the reaction was used without purification.

Step 6) 4-Chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-1- (1-ethyl-1 H-pyrazol-3-ylmethyl) -1 H-indazole -4-yl] -amide

3-bromo-1- (1-ethyl-1H-pyrazol-3-ylmethyl) -1H-indazol-4-ylamine (49 mg) and diisopropylethylamine (0.3 mL) were diluted with dichloromethane ( 2.5 mL). To this mixture, the compound (119 mg) prepared in step 5 above was dissolved in dichloromethane and slowly added dropwise. The solution was stirred at 25 ° C. for 2 hours. Ethyl acetate (20 mL, repeated 3 times) and water (20 mL) were added to the reaction solution, and the organic layer was separated. The combined organic layer was dried over anhydrous magnesium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was purified using column chromatography to give the title compound (55 mg).

Example 41: 4-amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-1- (1-ethyl-1H-pyrazol-3-ylmethyl) -1H- Zol-4-yl] -amide

4-Chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-1- (1-ethyl-1 H-pyrazol-3-ylmethyl) -prepared in Example 40 above- 1 H-indazol-4-yl] -amide (50 mg) and 2.0 M isopropanol ammonia solution were placed in a closed flask, and the temperature was raised to 100 ° C. and stirred for 16 hours. The solution was cooled to room temperature, filtered under reduced pressure, the filtrate was concentrated, and the residue was purified by column chromatography to obtain the target compound (24 mg).

Example 42: 4-Chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-cyclopropyl-1- (6-methoxy-pyridin-2-ylmethyl) -1 H-indazole- 4-day] -amide

Step 1) 6-methoxy-pyridine-2-carboxylic acid methyl ester

6-hydroxypyridine-2-carboxylic acid (10 g), methyl iodide (9.8 mL) and silver carbonate (22 g) were added to chloroform (200 mL). This solution was stirred for 28 hours at 60 ° C. under dark reaction conditions. The reaction solution was filtered, washed with chloroform, and the combined organic layers were filtered under reduced pressure and distilled under reduced pressure. The obtained residue was purified by column chromatography to give the target compound (11.2 g).

Step 2) (6-methoxy-pyridin-2-yl) methanol

Compound (11 g) prepared in step 1 above was added to diethyl ether (200 mL). To this solution, tetrahydrofuran solution (67 mL) to which 1.0 M lithium aluminum hydride was added was added. The solution was stirred at 25 ° C. for 4 hours. Celite (1 g) and sodium sulfate decahydrate (0.5 g) were added to the reaction solution, followed by stirring for 10 minutes. The reaction solution was filtered, washed with diethyl ether, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was used for the next reaction without purification.

Step 3) 2-Chloromethyl-6-methoxypyridine

The target compound was prepared by repeating the same procedure as in Step 2 of Example 40, using (6-methoxy-pyridin-2-yl) methanol instead of (1-ethyl-1H-pyrazol-3-yl) methanol. It was.

Step 4) 3-Bromo-1- (6-methoxy-pyridin-2-ylmethyl) -4-nitro-1H-indazole

The target compound was prepared by repeating the same procedure as in Step 3 of Example 40, using 2-chloromethyl-6-methoxypyridine instead of 3-chloromethyl-1-ethyl-1H-pyrazole.

Step 5) 3-cyclopropyl-1- (6-methoxy-pyridin-2-ylmethyl) -4-nitro-1H-indazole

Compound (360mg), cyclopropylboronic acid (111mg), potassium phosphate tribasic (630mg), palladium acetate (22mg) and tricyclohexylphosphine (56mg) prepared in step 4 were mixed with toluene / water (2.5mg). mL). The solution was stirred at 100 ° C. for 16 hours. The reaction solution was filtered, dichloromethane (20 mL, repeated three times) and water (20 mL) were added, and then the organic layer was separated. The combined organic layer was dried over anhydrous magnesium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was purified using column chromatography to give the target compound (188 mg).

Step 6) 3-cyclopropyl-1- (6-methoxy-pyridin-2-ylmethyl) -4-indazol-4-ylamine

The compound (188 mg) prepared in step 5 above was added to methanol / tetrahydrofuran mixed solution (4 mL) under hydrogen gas. After adding a palladium catalyst (40 mg) to this solution, it stirred at 25 degreeC for 16 hours. The reaction solution was filtered under reduced pressure using celite, and the filtrate was filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography to give the title compound (153 mg).

Step 7) 4-Chloro-thieno [3,2-d] pyrimidine-7-carbonyl chloride

4-hydroxy-thieno [3,2-d] pyrimidine-7-carboxylic acid (1.36 g) and catalytic amount of N, N-dimethylformamide were added to thionyl chloride (25 mL) and the temperature was 100 ° C. Raised to and stirred for 2 hours. The solution was cooled to room temperature, filtered under reduced pressure, and azeotropically distilled with toluene. It was dried and used for the next reaction without purification.

Step 8) 4-Chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-cyclopropyl-1- (6-methoxy-pyridin-2-ylmethyl) -1 H-indazol-4 -Work] -amide

3-cyclopropyl-1- (6-methoxy-pyridin-2-ylmethyl) -4-indazol-4-ylamine (32 mg) and diisopropylethylamine (0.15 mL) were diluted with dichloromethane (1.2 mL Dropwise). To this solution, the compound (30 mg) prepared in step 7 above was dissolved in dichloromethane and slowly added dropwise. The solution was stirred at 25 ° C. for 2 hours. Dichloromethane (20 mL, repeated 3 times) and water (20 mL) were added to the reaction solution, and the organic layer was separated. The combined organic layers were dried over anhydrous magnesium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was purified using column chromatography to give the target compound (37 mg).

Example 43: 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-cyclopropyl-1- (6-methoxy-pyridin-2-ylmethyl) -1 H-indazole- 4-day] -amide

4-Chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-cyclopropyl-1- (6-methoxy-pyridin-2-ylmethyl) -1H- prepared in Example 42 above. Indazol-4-yl] -amide (27 mg) and 2.0 M isopropanol ammonia solution (1.5 mL) were placed in a closed flask, and the temperature was raised to 100 ° C. and stirred for 16 hours. The solution was cooled to room temperature, filtered under reduced pressure, and the filtrate was concentrated. The obtained residue was purified by column chromatography to obtain the target compound (20 mg).

Example 44 4-chloro-thieno [3,2-d] pyrimidin-7-carboxylic acid (3-bromo-1- (pyrimidin-4-ylmethyl) -1H-indazol-4-yl) Amide

Step 1) 4-Bromomethyl-pyrimidine

4-methylpyrimidine (1.0 g), N-bromosuccinimide (2.2 g) and azobisisobutronitrile (174 mg) were added to benzene (25 mL). The solution was raised to 100 ° C. and stirred for 20 hours. The solution was cooled to room temperature, filtered under reduced pressure, and the filtrate was concentrated. The obtained residue was purified by column chromatography to obtain the target compound (68 mg).

Step 2) 4-Chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid (3-bromo-1- (pyrimidin-4-ylmethyl) -1 H-indazol-4-yl)- Amide

The same procedure as in Step 3 of Example 40 was repeated, but 4-bromomethyl-pyrimidine was used instead of 3-chloromethyl-1-ethyl-1H-pyrazole to obtain the target compound (24 mg).

Example 45 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid (3-bromo-1- (pyrimidin-4-ylmethyl) -1H-indazol-4-yl) Amide

4-Chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid (3-bromo-1- (pyrimidin-4-ylmethyl) -1H-indazol-4 prepared in Example 44 above -Yl) -amide (20 mg) and 2.0 M isopropanol ammonia solution (1.5 mL) were placed in a closed flask, the temperature was raised to 100 ° C and stirred for 16 hours. The solution was cooled to room temperature, filtered under reduced pressure, and the filtrate was concentrated. The obtained residue was purified using column chromatography to give the target compound (5 mg).

Example 46: 4-Chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-1- (4-methyl-thiazol-2-ylmethyl) -1 H-indazole- 4-day] -amide

Step 1) (4-Methyl-thiazol-2-yl) -methanol

4-methyl-2-thiazolecarboxaldehyde (350 mg) was added to methanol (10 mL), followed by dropwise addition of sodium borohydride (135 mg). This solution was stirred at 0 ° C. for 3 hours. Dichloromethane (20 mL, repeated 3 times) and ammonium chloride aqueous solution (20 mL) were added to the reaction solution, and the organic layer was separated. The combined organic layers were dried over anhydrous magnesium sulfate, filtered under reduced pressure and distilled under reduced pressure to obtain the target compound (261 mg).

Step 2) 2-Chloromethyl-4-methyl-thiazole

Compound (142 mg) and thionylchloride (1 mL) prepared in step 1 above were added to dichloromethane (3 mL). This solution was stirred at 0 ° C. for 2 hours. The solution was cooled to room temperature, filtered under reduced pressure, and azeotropically distilled with toluene. It was dried and used for the next reaction without purification.

Step 3) 4-Chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-1- (4-methyl-thiazol-2-ylmethyl) -1 H-indazol-4 -Work] -amide

The same procedure as in Step 3 of Example 40 was repeated, but using 2-chloromethyl-4-methyl-thiazole instead of 3-chloromethyl-1-ethyl-1H-pyrazole to obtain the target compound (43 mg).

Example 47 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-1- (4-methyl-thiazol-2-ylmethyl) -1 H-indazole- 4-day] -amide

4-Amino-thieno [3,2-d] pyrimidin-7-carboxylic acid (3-bromo-1-pyrimidin-4-ylmethyl-1H-indazol-4-yl prepared in Example 46 above ) -Amide (43 mg) and 2.0 M isopropanol ammonia solution (2 mL) were placed in a closed flask, and the temperature was raised to 100 ° C. and stirred for 16 hours. The solution was cooled to room temperature, filtered under reduced pressure, and the filtrate was concentrated. The obtained residue was purified by column chromatography to give the title compound (10 mg).

Example 48 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid (3-bromo-1- (pyrazin-2-ylmethyl) -1H-indazol-4-yl)- Amide

Step 1) 2-Chloromethyl-pyrazine

2-methylpyrazine (700 mg), N-chlorosuccinimide (1.3 g) and azobisisobutyronitrile (134 mg) were added to carbon tetrachloride (20 mL). The solution was raised to 90 ° C. and stirred for 16 hours. The solution was cooled to room temperature, filtered under reduced pressure, and the filtrate was concentrated. The obtained residue was purified by column chromatography to obtain the target compound (68 mg).

Step 2) 4-Chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid (3-bromo-1-pyrazin-2-ylmethyl-1H-indazol-4-yl) -amide

The same procedure as in Step 3 of Example 40 was repeated, but using 2-chloromethyl-pyrazine instead of 3-chloromethyl-1-ethyl-1H-pyrazole to obtain the title compound (12 mg).

Step 3) 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid (3-bromo-1- (pyrazin-2-ylmethyl) -1 H-indazol-4-yl) -amide

The compound prepared in step 2 (12 mg) and 2.0 M isopropanol ammonia solution (1 mL) were placed in a closed flask, and the temperature was raised to 100 ° C. and stirred for 16 hours. The solution was cooled to room temperature, filtered under reduced pressure, and the filtrate was concentrated. The obtained residue was purified by column chromatography to obtain the target compound (1.2 mg).

Example 49: 4-Chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid [1- (6-methoxy-pyridin-2-ylmethyl) -3-methyl-1H-indazole-4 -Work] -amide

The same procedure as in Step 5 of Example 42 was repeated, but methyl boronic acid was used instead of cyclopropylboronic acid to obtain the target compound (58 mg).

Example 50: 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [1- (6-methoxy-pyridin-2-ylmethyl) -3-methyl-1H-indazole-4 -Work] -amide

4-Chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid [1- (6-methoxy-pyridin-2-ylmethyl) -3-methyl-1H- is prepared as in Example 49 above. Zol-4-yl] -amide (58 mg) and 2.0 M isopropanol ammonia solution (3 mL) were placed in a closed flask, and the temperature was raised to 100 ° C. and stirred for 16 hours. The solution was cooled to room temperature, filtered under reduced pressure, and the filtrate was concentrated. The obtained residue was purified using column chromatography to give the target compound (36 mg).

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

Test Example

The results of evaluating the efficacy of the compounds prepared in the above examples were as follows.

Test Example 1 Evaluation of FMS Kinase Inhibitory Activity

This test example is a test for evaluating the inhibitory effect of FMS kinase. The assay kit using the FRET principle (Z'-Lyte ™ kinase assay-Tyr 1 peptide kit, Cat.pv3190, Invitrogen) and recombinant human FMS kinase (Cat pv3249, Invitrogen) was used.

The test compound was diluted with 1 μl, 100 nM, 50 nM, 10 nM, and 1 nM in 4% DMSO, then placed in a black bottom 384-well plate (NUNC, shank), followed by Tyr 1 at a concentration of 0.3 μg / mL of FMS kinase. The peptide and the kinase reaction solution (kinase buffer) were added in a mixture of 10 μl per well and ATP was added at a concentration of 150 μM. The reaction was carried out at room temperature for 1 hour while blocking the light, and after the addition of the developing reagent, the reaction was performed at room temperature for 1 hour while blocking the light again. Termination reagent was added to terminate the reaction, and the fluorescence was measured at an excitation wavelength of 400 nm and an emission wavelength of 445 nm in a microplate reader.

In addition, fluorescence was measured by reacting in the same manner as above using 4% DMSO instead of the test compound and kinase reaction solution instead of ATP as a 100% inhibitory group. In addition, fluorescence was measured by the same reaction as above using 4% DMSO instead of the test compound as the 0% inhibitory group. In addition, as a 100% phosphorylated group, 4% DMSO was used instead of the test compound, a phospho-peptide solution was used instead of the Tyr 1 peptide mixture, and a kinase reaction solution was used instead of ATP to react the same as above. Measured.

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

Test Example 2: M-NFS-60 Cell Line evaluation

M-NFS-60 cell lines purchased from the American Type Culture Collection, USA (ATCC) were prepared using RPMI culture [containing 10% FBS, 1% penicillin / streptomycin, and 20ng / mL of recombinant M-CSF]. Incubated at 37 ° C. in the presence of% CO ₂ . The cultured M-NFS-60 cell line was incubated in serum-free medium for 24 hours before being plated, and then 50 × l of 2.5 × 10 ⁴ cells per well were prepared in 96-well plates. Thereafter, 20ng / mL of recombinant M-CSF was added to 5% FBS culture, and the test compound was treated by stepwise dilution at a concentration of 1/10 ratio from 10 μM to 0.1 nM, respectively.

(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 Calculated.

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 14 12 nM 243 nM Example 16 13 nM 233 nM

As shown in Table 2, the compound of the embodiment according to the present invention can be seen that the inhibitory activity against the FMS kinase and M-NFS-60 cell line.

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 (12)

A compound selected from pyrimidine conjugated derivatives of Formula 1, pharmaceutically acceptable salts thereof, optical isomers, hydrates and solvates thereof:
Formula 1

In this formula,
A is -CH- or -N-;
X is -S-, -NH-, or -N (C _1-10 alkyl)-;
Y is H, halogen, amino, -NHR, -NHOR, -NH- (CH ₂ ) mN (R) ₂ , -OR, -SR, -S (O) R, or -S (O) ₂ R, 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 — (CH ₂ ) nR ₄ , where n is an integer from 0 to 6;
R ₄ is C _1-6 alkylamino, diC _1-6 alkylamino, C _1-6 alkoxy, C _2-5 alkynyl, C _3-10 cycloalkyl, 5-12 membered heterocycloalkyl, C _{6- 12} aryl, or 5-12 membered heteroaryl,
Wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkoxy, halogen, nitro, cyano, carbonylamino, aminocarbon carbonyl, sulfinyl, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonyl amino, C _1-6 alkyl aminosulfonyl, selected from the group consisting of phenyl and 5-6 membered heterocycloalkyl of 1-3 won May be substituted with a substituent,
Wherein said heteroaryl and heterocycloalkyl each independently comprise one or more heteroatoms selected from the group consisting of N, O and S.
The method of claim 1,
A is -CH- or -N-;
X is -S-, -NH-, or -N (Ci_ ₆ alkyl)-;
Y is halogen, amino, -NHR, -NHOR, -NH- (CH ₂ ) mN (R) ₂ , -SR, -S (O) R, or -S (O) ₂ R, wherein R is C _1-6 alkyl or C _3-6 cycloalkyl, m is an integer from 1 to 3;
R ₁ is H, C _1-6 alkyl, or halogen;
R ₂ is H, C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, or halogen;
R ₃ is H, C _1-10 alkyl, or — (CH ₂ ) nR ₄ , where n is an integer from 1 to 3;
R ₄ is C _1-6 alkoxy, C _2-4 alkynyl, C _3-6 cycloalkyl, 5-6 membered heterocycloalkyl, C _6-8 aryl, or 5-6 membered heteroaryl,
Wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently C _1-6 alkyl, C _1-6 alkoxy, halogen, cyano, C _1-6 alkylsulfonylamino, phenyl and 5-6 member It may be substituted with 1 to 3 substituents selected from the group consisting of heterocycloalkyl of
Wherein said heteroaryl and heterocycloalkyl each independently comprise one or more hetero atoms selected from the group consisting of N, O and S.
The method of claim 1,
A is -CH- or -N-;
X is -S-;
Y is halogen, amino, C _1-6 alkylamino, C _1-6 alkoxyamino, C _3-6 cycloalkylamino, diC _1-3 alkylamino-C _1-3 alkylene-amino or C _1-6 Alkylthio;
R ₁ is H, C _1-3 alkyl, or halogen;
R ₂ is H, C _1-3 alkyl, C _2-3 alkenyl, C _3-6 cycloalkyl, or halogen;
R ₃ is H, C _1-6 alkyl, or — (CH ₂ ) n R ₄ , where n is an integer from 1 to 3;
R ₄ is C _1-6 alkoxy, C _2-3 alkynyl, C _3-6 cycloalkyl, 5-6 membered heterocycloalkyl, C _6-8 aryl, or 5-6 membered heteroaryl,
At this time, the aryl and heteroaryl are each independently composed of C _1-3 alkyl, C _1-3 alkoxy, halogen, cyano, C _1-6 alkylsulfonylamino, phenyl and 5-6 membered heterocycloalkyl May be substituted with 1 to 3 substituents selected from the group,
Wherein said heteroaryl and heterocycloalkyl each independently comprise one or more hetero atoms selected from the group consisting of N, O and S.
The method of claim 1,
A is -CH- or -N-;
X is -S-;
Y is halogen, amino, C _1-6 alkoxyamino, C _3-6 cycloalkylamino, dimethylamino-C _1-3 alkylene-amino or C _1-3 alkylthio;
R ₁ is H, C _1-3 alkyl, or halogen;
R ₂ is H, C _1-3 alkyl, C _2-3 alkenyl, C _3-6 cycloalkyl, or halogen;
R ₃ is H, C _1-6 alkyl, or — (CH ₂ ) n R ₄ , where n is an integer from 1 to 3;
R ₄ is C _1-3 alkoxy, C _2-3 alkynyl, C _3-6 cycloalkyl, 5-6 membered heterocycloalkyl, C _6-8 aryl, or 5-6 membered heteroaryl,
In this case, the aryl and heteroaryl may be each independently substituted with 1 to 3 substituents selected from the group consisting of C _1-3 alkyl, C _1-3 alkoxy, halogen, phenyl and 5-6 membered heterocycloalkyl. There is,
And said heteroaryl and heterocycloalkyl each independently comprise one or more hetero atoms of N and O.
The method of claim 1,
Compound wherein the pyrimidine conjugate ring derivative of Formula 1 is any one of the following compounds:
1) 4-amino-N- (3-cyclopropyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine -7-carboxamide;
2) 4-amino-N- (1H-indol-5-yl) thieno [3,2-d] pyrimidine-7-carboxamide;
3) 4-amino-N- (3-methyl-1H-indazol-6-yl) thieno [3,2-d] pyrimidine-7-carboxamide;
4) 4-amino-N- (1-((6-methylpyridin-2-yl) methyl) -1H-indazol-5-yl) thieno [3,2-d] pyrimidine-7-carbox Amides;
5) 4-amino-N- (3-methyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine- 7-carboxamide;
6) 4-amino-N- (1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine-7-carbox Amides;
7) 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid (1-benzyl-3-cyclopropyl-1 H-indazol-4-yl) -amide
8) 4-amino-N- (3-bromo-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine -7-carboxamide;
9) 4-amino-N- (1-benzyl-3-bromo-1H-indazol-4-yl) thieno [3,2-d] pyrimidine-7-carboxamide;
10) 4-amino-N- (3-bromo-1-((pyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidin-7- Carboxamide;
11) N- (1- (4-methoxybenzyl) -3-bromo-1H-indazol-4-yl) -4-amino-thieno [3,2-d] pyrimidine-7-carbox Amides;
12) 4-amino-N- (3-bromo-1- (cyclohexylmethyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine-7-carboxamide;
13) 4-amino-N- (3-bromo-1- (2-propynyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine-7-carboxamide;
14) 4-amino-N- (3-bromo-1-((6-bromopyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyri Midine-7-carboxamide;
15) 4-amino-N- (3-bromo-1-((tetrahydrofuran-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine- 7-carboxamide;
16) 4-amino-N- (3-bromo-1-((6-fluoropyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyri Midine-7-carboxamide;
17) 4-amino-N- (3-bromo-1-phenethyl-1H-indazol-4-yl) thieno [3,2-d] pyrimidine-7-carboxamide;
18) 4-amino-N- (3-bromo-1-((6-phenylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine -7-carboxamide;
19) 4-amino-thieno [3,2-d] pyrimidine-7-carboxylic acid (3-bromo-1-pyridin-3-ylmethyl-1H-indazol-4-yl) -amide;
20) 4-amino-thieno [3,2-d] pyrimidine-7-carboxylic acid (3-bromo-1-pyridin-4-ylmethyl-1H-indazol-4-yl) -amide;
21) 4-amino-N- (3-bromo-1-((thiophen-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidin-7 Carboxamide;
22) 4-amino-N- (3-bromo-1-((furan-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidin-7- Carboxamide;
23) 4-amino-N- (3-bromo-1-propyl-1H-indazol-4-yl) thieno [3,2-d] pyrimidine-7-carboxamide;
24) 4-amino-N- (3-bromo-1- (2-methoxyethyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine-7-carboxamide ;
25) 4-amino-N- (3-bromo-1-((1-ethyl-5-isopropyl-1H-pyrazol-3-yl) methyl) -1H-indazol-4-yl) -thier No [3,2-d] pyrimidine-7-carboxamide;
26) N- (1- (4-morpholinobenzyl) -3-bromo-1H-indazol-4-yl) -4-amino-thieno [3,2-d] pyrimidine-7-car Voxamides;
27) 4-amino-N- (3-ethyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine- 7-carboxamide;
28) 4-amino-N- (1-((6-methylpyridin-2-yl) methyl) -3-vinyl-1H-indazol-4-yl) thieno [3,2-d] pyrimidine- 7-carboxamide;
29) 4-amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-5-methyl-1- (6-methyl-pyridin-2-ylmethyl) -1H-indazole -4-yl] -amide;
30) 4-amino-N- (5-methyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) thieno [3,2-d] pyrimidine- 7-carboxamide;
31) 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-1- (6-methoxy-pyridin-2-ylmethyl) -1H-indazol-4- General] -amide;
32) 4-amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-5-chloro-1- (6-methoxy-pyridin-2-ylmethyl) -1H- Zol-4-yl] -amide;
33) N- (3-cyclopropyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) -4- (methylthio) thieno [3,2-d ] Pyrimidine-7-carboxamide;
34) N- (3-cyclopropyl-1-((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) -4- (cyclopropylamino) thieno [3,2- d] pyrimidine-7-carboxamide;
35) 4-methoxyamino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-cyclopropyl-1- (6-methyl-pyridin-2-ylmethyl) -1H-indazole-4 -Yl] -amide;
36) 4-amino-N- (3-bromo-1-((6-methylpyridin-2-yl) methyl) -1H-indol-4-yl) thieno [3,2-d] pyrimidine- 7-carboxamide;
37) 4-chloro-thieno [3,2-d] pyrimidin-7-carboxylic acid [3-cyclopropyl-1- (6-methyl-pyridin-2-ylmethyl) -1H-indazol-4-yl ] -Amide;
38) 4-methylamino-thieno [3,2-d] pyrimidin-7-carboxylic acid [3-cyclopropyl-1- (6-methylpyridin-2-ylmethyl) -1H-indazol-4-yl ) -Amide;
39) 4- (2-dimethylamino-ethylamino) -thieno [3,2-d] pyrimidine-7-carboxylic acid [3-cyclopropyl-1- (6-methylpyridin-2-ylmethyl)- 1H-indazol-4-yl) -amide;
40) 4-chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-1- (1-ethyl-1H-pyrazol-3-ylmethyl) -1H-indazole- 4-yl] -amide;
41) 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-1- (1-ethyl-1 H-pyrazol-3-ylmethyl) -1 H-indazole- 4-yl] -amide;
42) 4-Chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-cyclopropyl-1- (6-methoxy-pyridin-2-ylmethyl) -1 H-indazol-4- General] -amide;
43) 4-amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-cyclopropyl-1- (6-methoxy-pyridin-2-ylmethyl) -1H-indazol-4- General] -amide;
44) 4-Chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid (3-bromo-1- (pyrimidin-4-ylmethyl) -1H-indazol-4-yl) -amide ;
45) 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid (3-bromo-1- (pyrimidin-4-ylmethyl) -1H-indazol-4-yl) -amide ;
46) 4-Chloro-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-1- (4-methyl-thiazol-2-ylmethyl) -1 H-indazol-4- General] -amide;
47) 4-Amino-thieno [3,2-d] pyrimidine-7-carboxylic acid [3-bromo-1- (4-methyl-thiazol-2-ylmethyl) -1 H-indazol-4- General] -amide;
48) 4-amino-thieno [3,2-d] pyrimidine-7-carboxylic acid (3-bromo-1- (pyrazin-2-ylmethyl) -1H-indazol-4-yl) -amide;
49) 4-Chloro-thieno [3,2-d] pyrimidin-7-carboxylic acid [1- (6-methoxy-pyridin-2-ylmethyl) -3-methyl-1H-indazol-4-yl ] -Amide; And
50) 4-amino-thieno [3,2-d] pyrimidin-7-carboxylic acid [1- (6-methoxy-pyridin-2-ylmethyl) -3-methyl-1H-indazol-4-yl ] -Amide.
A pharmaceutical composition comprising as an active ingredient a compound according to any one of claims 1 to 5.
The method according to claim 6,
Wherein said pharmaceutical composition is for preventing or treating a disease caused by the activity of FMS kinase.
The method of claim 7, wherein
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 of claim 8,
Wherein said immune, metabolic, or inflammatory disease is rheumatoid arthritis, osteoporosis, Crohn's disease, arteriosclerosis, or hyperlipidemia.
The method of claim 8,
The cancer or tumor may be a liver cancer, a hepatocellular carcinoma, a thyroid cancer, a colorectal 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, colorectal cancer, ovarian cancer, Cancer of the esophagus, glioma, glioblastoma, renal cancer, malignant melanoma, gastric cancer, gastric cancer, Breast cancer, sarcoma, pharynx carcinoma, uterine cancer, cervical cancer, prostate cancer, rectal cancer, pancreatic cancer, , Lung cancer, or skin cancer.
The method according to claim 6,
The pharmaceutical composition is a steroid drug, methotrexate, leflunoamide, anti-TNFα drug, calcineurin inhibitor, antihistamine drug, cell signaling inhibitor, mitosis inhibitor, alkylating agent, anti-metabolic agent, intercalating anticancer agent, topoisomerase A pharmaceutical composition, characterized in that it is formulated or combined with a medicament selected from the group consisting of inhibitors, immunotherapeutics, anti-hormones and mixtures thereof.
The method according to claim 6,
Pharmaceutical composition, characterized in that the oral preparation in the form of tablets, pills, powders, capsules, syrups or emulsions.