KR101936851B1 - Pyrazolopyridine or indazole derivatives as protein kinase inhibitors - Google Patents

Abstract

The present invention relates to a novel pyrazolopyridine or indazole derivative having inhibitory activity against protein kinase or a pharmaceutically acceptable salt thereof. The compounds of the present invention may also be used in combination with protein kinases such as ABL, ACK1, ALK, Aurora A, Aurora B, Aurora C, BLK, BMX / ETK, BRSKl, BTK, c-Src, CAMKK, CDKl, CDK2, CDK5, IGF1R, IR, IRAK1, IRR / INSRR, ITK, FGF, FGF, FGF, FGF, FGR, FLT3, FLT4 / VEGFR3, FMS, FRK / PTK5, FYN, GSK3b, , JAK2, KHS / MAP4K5, LCK, LYN, PHKg, PLK4 / SAK, PYK2, RET, ROS / ROS1, TIE2 / TEK, TRK, TXK, TYK and YES / YES1. It is useful as a drug for treatment and prevention.

Description

[0002] Pyrazolopyridine or indazole derivatives as protein kinase inhibitors, which are protein kinase inhibitors,

The present invention relates to a novel pyrazolopyridine derivative or indazole derivative or a pharmaceutically acceptable salt thereof having an inhibitory activity against a protein kinase, and the compound of the present invention has an inhibitory activity against a protein kinase, It is useful as a drug for treatment and prevention.

Protein kinases are enzymes that catalyze the phosphorylation of hydroxyl groups located in the tyrosine, serine and threonine residues of proteins and play an important role in the signaling of growth factors leading to cell growth, differentiation and proliferation.

In order to maintain the homeostasis of the living body, the in vivo signal transmission system should be smoothly balanced between on and off. However, mutations or overexpression of certain protein kinases disrupt the normal intracellular signaling pathway (predominantly in vivo signal transduction) leading to a variety of diseases, including cancer, inflammation, metabolic disease, and brain disease.

It is estimated that 518 species of human protein kinase, which accounts for about 1.7% of total human genes, are largely divided into tyrosine protein kinases (over 90 species) and serine / threonine protein kinases. Tyrosine protein kinases can be divided into 20 subtypes of 58 receptor tyrosine kinases and 10 subpopulations of 32 cytoplasmic / nonreceptor subtypes. The receptor tyrosine kinase has a domain capable of accepting a growth factor on the cell surface and an active site capable of phosphorylating a tyrosine residue in the cytoplasm. When the growth factor is bound to the growth factor receptor site on the receptor tyrosine kinase cell surface, the receptor tyrosine kinase forms a polymer and the cytoplasmic tyrosine residue is autophosphorylated. Sequential phosphorylation of the subgenomic proteins leads to signal transduction into the nucleus, ultimately overexpressing cancer-causing transcription factors.

Vascular Endothelial Growth Factor Receptors (VEGFRs) are receptor tyrosine kinases (RTKs) and are important regulators of angiogenesis. It is involved in the development of blood vessels and lymphatic vessels and maintenance of homeostasis, and it has an important effect on nerve cells. VEGF is mainly produced in vascular endothelial cells, hematopoietic cells, and stromal cells by hypoxia and stimulation of cell growth factors such as TGF, interleukin, and PDGF. VEGF binds to the VEGF receptors (VEGFR) -1, -2, -3, and each VEGF isoform binds to a specific receptor to induce homozygous or heterozygous formation of the receptor and then activates its respective signaling pathway. The signal specificity of VEGFR is more finely regulated by coreceptors such as neurophilin, heparan sulfate, integrin, cadherin, and the like.

The biological function of VEGF is mediated through type III RTK, VEGFR-1 (Flt-1), VEGFR-2 (KDR / Flk-1), and VEGFR-3 (Flt-4). EGFR is closely related to Fms, Kit, PDGFR, and VEGF binds to specific receptors, while VEGF-A binds to VEGFR-1, -2 and receptor-type polymers, while VEGF- -3. ≪ / RTI > In addition, PIGF and VEGF-B interact exclusively with VEGFR-1 and VEGF-E interact only with VEGFR-2. VEGF-F variant interacts with VEGFR-1 or -2. VEGF-A, -B, and PIGF are preferentially required for angiogenesis, whereas VEGF-C, -D is essential for lymphangiogenesis. New blood vessels supply nutrients and oxygen to tumors and provide a pathway for cancer cell metastasis, which is essential for their proliferation and metastasis. Angiogenesis is normally balanced by the interaction of angiogenic stimulators and angiogenic suppressors in vivo. However, when such a balance is broken as in cancer cells, the greatest effect is on vascular endothelial growth VEGFR is activated by the growth factor VEGF (Vascular Endothelial Growth Factor). Inhibitors that inhibit tyrosine kinase, which is a receptor for VEGF, using various low molecular weight compounds during various mechanisms of action, have been extensively studied. Most of them have the possibility of being commonly used for solid tumors, It has an advantage that an effective drug effect can be expected with relatively few side effects.

ALK (ANAPLASTIC LYMPHOMA KINASE) is a type of receptor tyrosine kinase. The ALK consisting of 1620 amino acids is about 180 kDa. ALK-NPM, a fusion of ALK and NPM (nucleophosmin), is a tumor gene and is an inducer of ALCL (anaplastic large cell lymphoma) disease. In addition, ALK and EML4 (echinoderm microtubule-associated protein

like 4) is also a tumor gene, which is a non-small cell lung cancer (NSCLC) -induced factor. Crizotinib (PF-02341066) is an inhibitor of ALK receptor tyrosine kinase and has been approved for the treatment of NSCLC (non-small cell lung cancer) disease. Crizotinib (PF-02341066) is in clinical trials for the treatment of AAPL (anaplastic large cell lymphoma) disease.

Tie2 is a type of receptor tyrosine kinase that is associated with neovascularization and vasculature. The domain structure of Tie2 is highly conserved in all vertebrates. The ligand of Tie2 is angiopoietins (Ang). Ang2 does not induce autophosphorylation of Tie2, but interferes with the activation of Ang1-induced Tie2. Activation of Tie2 by Ang2 in endothelial cells induces activation of PI3K-Akt. In the mitogen-activated protein kinase (MAPK) signaling pathway, the main signaling pathway of Tie2, the adapter protein GRB2 and the protein tyrosine phosphatase SHP2 are involved in the dimerization process through autophosphorylation of the Tie2 receptor tyrosine kinase It plays an important role. Ang / Tie2 and vascular endothelial growth factor (VEGF) signaling pathways play important roles in the neovascularization of cancer cells. Tie2 is expressed in vascular endothelial cells, particularly in the site where cancer cells infiltrate. Overexpression of Tie2 has been identified in breast cancer (Peters et al., 1998), as well as in uterine cancer, liver cancer, and brain cancer.

Various compounds having a pyrazolopyridine or indazole structure as a parent have been synthesized to date. However, as in the present invention, an amide group of -C (O) NH- or -NHC (O) (SR ¹ ), sulfanyl (SOR ¹ ), or sulfonyl (SO ₂ R ¹ ) groups were simultaneously introduced into the C5 position of the mother nucleus. In addition, a protein kinase And the use thereof as a tumor treatment and prophylactic agent has not been disclosed in any literature to date.

It is an object of the present invention to provide a novel pyrazolopyridine derivative, an indazole derivative or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a pharmaceutical composition for the prevention and treatment of cancer diseases containing the novel compound or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to solve the above-mentioned problems, the present invention is characterized by a compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, which inhibits the activity of a protein kinase:

[Chemical Formula 1]

In Formula 1,

X is CH; Or N,

P is a hydrogen atom; A C ₁ -C ₁₀ alkyl group; 1 to 3 is phenyl substituted with C ₁ ~C ₁₀ alkyl group; A phenyl group; Or a 5- to 7-membered heterocycloalkyl group containing an oxygen atom,

L ¹ is -SR ¹ ; -S (O) R &^lt; ^{1 &} gt ;; Or -S (O) ₂ R ¹ ,

G is absent; Or -NHC (O) -; Or -C (O) NH-,

L ² is -NHR ² ; -OR ³ ; A C ₁ to C ₁₀ alkyl group substituted or unsubstituted with R ⁴ ; A C ₃ -C ₁₀ cycloalkyl group substituted or unsubstituted with R ⁵ ; A 5 to 7-membered heterocycloalkyl group which may be substituted or unsubstituted with R ⁶ and contains 1 to 2 nitrogen atoms; A C ₆ -C ₁₅ aryl group substituted or unsubstituted with R ⁷ ; Or a 5 to 7-membered heteroaryl group which may be substituted or unsubstituted with R ⁸ and contains 1 to 3 hetero atoms selected from a sulfur atom and a nitrogen atom,

R ¹ is a hydrogen atom; Or a C ₆ -C ₁₅ aryl group substituted or unsubstituted with 1 to 3 halogen atoms,

R ² is a hydrogen atom; A C _{1 to} C ₁₀ alkyl group; A C ₃ -C ₁₀ cycloalkyl group; Or halo, C ₁ ~C ₁₀ alkyl, C ₁ ~C ₁₀ alkoxy, and 1 to 10 halogens represents a substituted or unsubstituted phenyl group with substituents selected from substituted C ₁ ~C ₁₀ haloalkyl,

R ³ is a hydrogen atom; Or a C _{1 to} C ₁₀ alkyl group,

R ⁴ and R ⁵ are the same or different and are an amino group; Mono (C ₁ ~C ₁₀ alkyl) amino group; Or di (C ₁ ~C ₁₀ alkyl) represents an amino group,

R ⁶ is a hydrogen atom; Or a C _{1 to} C ₆ alkyl group,

R ⁷ is A halogen atom; A C _{1 to} C ₁₀ alkyl group; A C _{1 to} C ₁₀ alkoxy group; 1 to 10 halogen-substituted haloalkyl groups; A 5- to 7-membered heterocycloalkyl group which may be substituted or unsubstituted with a C _{1 to} C ₁₀ alkyl group and contains 1 to 3 hetero atoms selected from an oxygen atom and a nitrogen atom; An amino group; Mono (C ₁ ~C ₁₀ alkyl) amino group; Or di (C ₁ ~C ₁₀ alkyl) represents an amino group,

R ⁸ is a C ₁ to C ₁₀ alkyl group; Or a 5- to 7-membered heterocycloalkyl group containing 1 to 3 hetero atoms selected from an oxygen atom and a nitrogen atom.

The novel compounds of the present invention are useful for the treatment and / or prophylaxis of a variety of diseases and disorders, including, but not limited to, ABL, ACK1, ALK, Aurora A, Aurora B, Aurora C, BLK, BMX / ETK, BRSKl, BTK, c-Src, CAMKK, CDK1, CDK2, CDK5, CLK, , FKP, FGF, FGF, FGF, FGR, FLT3, FLT4 / VEGFR3, FMS, FRK / PTK5, FYN, GSK3b, HCK, IGF1R, IR, IRAK1, IRR / INSRR, ITK, JAK2, KHS / MAP4K5, LCK, LYN, PHKg, PLK4 / SAK, PYK2, RET, ROS / ROS1, TIE2 / TEK, TRK, TXK, TYK and YES / YES1. Can be used as an active ingredient of a pharmaceutical composition for prevention and treatment.

Cancer diseases that can be prevented and treated from the compounds according to the present invention include gastric cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, cervical cancer, uterine cancer, cervical cancer, head and neck cancer, (Including leukemia, multiple myeloma, myelodysplastic syndrome), lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma), psoriasis, or fibrosarcoma, including, but not limited to, thyroid cancer, pituitary cancer, kidney cancer, sarcoma, prostate cancer, And the like.

The pharmaceutically acceptable salts of the compound represented by the formula (1) according to the present invention can be prepared by a conventional method in the art. 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 acceptable free acids, acid addition salts of base compounds of formula (I), and alkali metal salts (such as sodium salts) and alkaline earth metal salts (such as calcium salts) Organic base addition salts of acids, and amino acid addition salts. Free acids that can be used in the preparation of pharmaceutically acceptable salts can be divided into inorganic and organic acids. As the inorganic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid and the like can be used. The organic acid may be selected from the group consisting of 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, tartaric acid, Benzoic acid, embonic acid, aspartic acid, glutamic acid and the like can be used. Organic bases that can be used to prepare organic base addition salts include tris (hydroxymethyl) methylamine, dicyclohexylamine, and the like. Amino acids that can be used in the production of amino acid addition bases are natural amino acids such as alanine and glycine.

The compound represented by the formula (1) according to the present invention includes all the hydrates and solvates as well as the pharmaceutically acceptable salts described above. The above-mentioned pharmaceutically acceptable salts can be prepared by the conventional methods described below. The base compound of Formula 1 may be dissolved in a solvent such as methanol, ethanol, acetone, or 1,4-dioxane and then crystallized or recrystallized after addition of a free acid or a free base.

In addition, the compound represented by Formula 1 according to the present invention may have one or more asymmetric centers, and in the case of such a compound, an enantiomer or diastereomer may exist. Accordingly, the present invention includes each isomer or a mixture of these isomers. The different isomers may be separated or cleaved by conventional methods, or any desired isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric synthesis.

The present invention also includes a radioactive derivative of the compound represented by Formula 1 according to the present invention, and these radioactive compounds are useful in the field of biomedical research.

The substituents used to define the compounds according to the invention are described in more detail below.

The term "halogen atom" in the present invention means chloro, fluoro, bromo, iodo.

La 'alkyl group' in the present invention means the methyl, ethyl, n - propyl, i - propyl, n - butyl, i - butyl, t - butyl, n - pentyl, i - pentyl, neopentyl, t - pentyl, n Means an aliphatic saturated hydrocarbon group having from 1 to 10 carbon atoms including hexyl, i -hexyl, heptyl, octyl, and the like.

The term "cycloalkyl group" in the present invention means an aliphatic cyclic hydrocarbon group having 1 to 10 carbon atoms including cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, and the like.

The term "haloalkyl group" in the present invention means an alkyl group substituted by a hydrogen atom by one or more halogen atoms such as a trifluoromethyl group.

La "alkoxy group" in the present invention means the methoxy, ethoxy, n - propoxy, i - propoxy, n - butoxy, i - butoxycarbonyl, t - containing butoxy, C ₁ -C ₁₀ Means a hydroxy group substituted with a hydrogen atom by a substituent selected from an alkyl group.

The term "aryl group" used in the present invention means an aromatic hydrocarbon group having 6 to 15 carbon atoms, including a phenyl group, a naphthyl group, an anthranilyl group, a phenanthridinyl group, etc., having a single ring, do.

The term "heteroaryl group" used in the present invention refers to pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazole Wherein the heteroaryl group is selected from the group consisting of benzoyl, benzyl, furyl, benzyl, furyl, benzyl, furyl, benzyl, furyl, Benzyloxycarbonyl, furanyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, dibenzothiophenyl, naphthyridyl, benzisothiazolyl, quinolinyl, isoquinolinyl, Means a 5- to 7-membered monocyclic, bicyclic or tricyclic aromatic heterocyclic group containing at least one hetero atom, including, for example, monovalent heterocyclic ring, salinyl, phthalazinyl, chinolinyl, quinazolinyl and the like.

The term "heterocycloalkyl group" in the present invention means a 5- to 7-membered aliphatic hetero ring containing one or more hetero atoms, including morpholinyl, piperidine, piperazinyl, N -protected piperazinyl, Means a hydrocarbon ring group. The N -protecting group of the piperazinyl may ordinarily include an alkyl group.

In the compound represented by the general formula (1) according to the present invention, the following are preferable.

X is CH; Or N, wherein P represents a hydrogen atom; A C _{1 to} C ₆ alkyl group; Benzyl group; Trityl; A phenyl group; Or tetrahydropyranyl group, L ¹ is -S (O) R ¹ ; Or -S (O) ₂ R ¹ , wherein R ¹ is a hydrogen atom; A phenyl group; Or a phenyl group substituted with 1 to 3 halogen atoms, and G is absent; Or -NHC (O) -; Or -C (O) NH-; L ² represents an amino group; Cyclohexylamino group; A phenylamino group; A C _{1 to} C ₆ alkoxyphenylamino group; A phenylamino group substituted with a substituent selected from halo and haloalkyl; A hydroxyl group; A C _{1 to} C ₆ alkoxy group; A C _{1 to} C ₆ alkyl group; A dimethylamino C ₁ -C ₆ alkyl group; Cyclohexyl group; Dimethylaminocyclohexyl group; A morpholino group; Piperidinyl group; A piperazinyl group; A 4- (C ₁ -C ₆ alkyl) piperazinyl group; A phenyl group; Chlorophenyl group; A fluorophenyl group; 4-chloro-3-trifluoromethylphenyl group; A C ₁ -C ₆ alkylphenyl group; A C _{1 to} C ₆ alkoxyphenyl group; A trifluoromethylphenyl group; A morpholinophenyl group; (4-methylpiperazinyl) phenyl group; (4-ethylpiperazinyl) phenyl group; An aminophenyl group; Dimethylaminophenyl group; A thiophenyl group; A pyridinyl group; (C ₁ -C ₆ alkyl) pyridinyl group; Or a morpholinopyridinyl group.

The compound represented by the formula (1) according to the present invention is specifically exemplified as follows:

5 - ((3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4- b ] pyridin-3-amine (Compound No. 1);

N - (5 - ((3-fluorophenyl) sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-yl) -4- (4-methylpiperazin-l- Yl) benzamide (Compound No. 2);

N - (5 - ((3- fluorophenyl) sulfonyl) -1-trityl -1 H - pyrazolo [3,4- b] pyridin-3-yl) -3- (trifluoromethyl) benzamide Amide (Compound No. 3);

N - (5 - ((3- fluorophenyl) sulfonyl) -1-trityl -1 H - pyrazolo [3,4- b] pyridin-3-yl) -4-methoxy-benzamide (Compound No. 4);

N - (5 - ((3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4- b ] pyridin-3-yl) -benzamide (Compound No. 5);

Fluoro- N - (5 - ((3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4- b ] pyridin- No. 6);

4-Chloro-N - (5 - ((3- fluorophenyl) sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-yl) benzamide (Compound No. 7);

4- (tert-butyl) - N - (5 - ( (3- fluorophenyl) sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-yl) benzamide Amide (Compound No. 8);

N - (5 - ((3- fluorophenyl) sulfonyl) -1-trityl -1 H - pyrazolo [3,4- b] pyridin-3-yl) -4-Dimorpholino Reno benzamide (Compound No. 9);

4- (dimethylamino) - N - (5 - ((3- fluorophenyl) sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-yl) -benzamide (Compound No. 10);

4- (dimethylamino) - N - (5 - ((3- fluorophenyl) sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-yl) cyclo-hexane Carboxamide (Compound No. 11);

4- (dimethylamino) - to Sangapi - N - (5 - ((3- fluorophenyl) sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-yl) Amide (Compound No. 12);

4- (dimethylamino) - N - (5 - ((3- fluorophenyl) sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-yl) -pentanoic amide (Compound No. 13);

Ethyl- (5 - ((3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4- b ] pyridin-3-yl) -carbamate (Compound No. 14);

tert-butyl- (5 - ((3-fluorophenyl) sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-yl) carbamate (Compound No. 15) ;

N - (5 - ((3- fluorophenyl) sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-yl) thiophene-2-carboxamide ( Compound No. 16);

N - (5 - ((3- fluorophenyl) sulfonyl) -1 H -1-trityl-pyrazolo [3,4- b] pyridin-3 yl) -piperidin-1-carboxamide (Compound No. 17);

1 - (5 - ((3-phenyl) sulfonyl) -1-trityl-fluoro -1 H -pyrazolo [3,4- b] pyridin-3-yl) -3-phenyl urea (compound No. 18) ;

1 - (5 - ((3-fluorophenyl) sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-yl) -3- (2-methoxyphenyl) Urea (Compound No. 19);

3- (5 - ((3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4- b ] pyridin-3-yl) urea (Compound No. 20);

1-cyclo-hexyl-3- (5 - ((phenyl) 3-fluoro-sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-yl) urea (Compound No. 21 );

N - (5 - ((3- fluorophenyl) sulfonyl) -1 H - pyrazolo [3,4- b] pyridin-3-yl) -4- (4-methylpiperazin-1-yl) benzamide Amide (Compound No. 22);

N - (5 - ((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) -4-methoxybenzamide (Compound No. 23);

N - (5 - ((phenyl) 3-fluoro-sulfonyl) -1 H - pyrazolo [3,4- b] pyridin-3-yl) (trifluoromethyl) -3-benzamide (Compound No. 24 );

N - (5 - ((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) benzamide (Compound No. 25);

4-Fluoro- N - (5 - ((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) benzamide (Compound No. 26);

4-Chloro-N - (5 - ((3- phenyl) sulfonyl) -1 H-fluoro-pyrazolo [3,4- b] pyridin-3-yl) benzamide (Compound No. 27);

4- (tert-butyl) - N - (5 - ((3- phenyl) sulfonyl) -1 H-fluoro-pyrazolo [3,4- b] pyridin-3-yl) benzamide (Compound No. 28) ;

N - (5 - ((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) -4-morpholinobenzamide (Compound No. 29);

4- (dimethylamino) - N - (5 - ( ( 3-fluorophenyl) sulfonyl) -1 H - pyrazolo [3,4- b] pyridin-3-yl) benzamide (Compound No. 30);

N - (5 - ((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) cyclohexanecarboxamide (Compound No. 31);

N - (5 - ((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) pvbaramide (Compound No. 32);

N - (5 - ((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) hexanamide (Compound No. 33);

Ethyl- (5 - ((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) carbamate (Compound No. 34);

tert -Butyl- (5 - ((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) carbamate (Compound No. 35);

N - (5 - ((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) thiophene-2-carboxamide (Compound No. 36);

N - (5 - ((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) piperidine-1-carboxamide (Compound No. 37);

1- (5 - ((3-Fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) -3-phenylurea (Compound No. 38);

3- (2-methoxyphenyl) urea (Compound No. 39) was obtained in the same manner as in 1- (5 - ((3- fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin- );

1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (5 - ((3- -1 H -fluorophenyl) sulfonyl) pyrazolo [3,4- b] pyridine -3 Yl) urea (Compound No. 40);

1 -cyclohexyl-3- (5 - ((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) urea (Compound No. 41);

5 - ((3-fluorophenyl) sulfonyl) - N - (4- Dimorpholino Reno phenyl) -1- (tetrahydro -2 H in Tet-pyran-2-yl) -1 H-indazol-3-car Lt; / RTI > (Compound No. 42);

5 - ((3-fluorophenyl) sulfonyl) - N - (6- Reno Dimorpholino-3-yl) -1- (tetrahydro -2 H in Tet-pyran-2-yl) -1 H-indazole Carboxamide (Compound No. 43);

N - (4- (4- ethyl-piperazin-1-yl) phenyl) -5 - ((3-fluorophenyl) sulfonyl) -1- (tetrahydro in Tet -2 H-pyran-2-yl) - 1 H -indazole-3-carboxamide (Compound No. 44);

5 - ((3-fluorophenyl) sulfonyl) - N - (6- methylpyridin-3-yl) -1- (tetrahydro -2 H in Tet-pyran-2-yl) -1 H-indazol- 3-carboxamide (Compound No. 45);

N - (3-chloro-4- (methylsulfonyl) phenyl Tryp Rd)) - 5 - ((3-fluorophenyl) sulfonyl) -1- (tetrahydro in Tet -2 H-pyran-2-yl) -1 H - indazole-3-carboxamide (compound No. 46);

5 - ((3-fluorophenyl) sulfonyl) - N - (4- Dimorpholino Reno phenyl) -1 H-indazole-3-carboxamide (Compound No. 47);

5 - ((3-fluorophenyl) sulfonyl) - N - (4- Reno Dimorpholino-3-yl) -1 H-indazole-3-carboxamide (Compound No. 48);

N - (4- (4- ethyl-piperazin-1-yl) phenyl) -5 - ((3-fluorophenyl) sulfonyl) -1 H-indazole-3-carboxamide (Compound No. 49);

5 - ((3-fluorophenyl) sulfonyl) - N - (6- methylpyridin-3-yl) -1 H-indazole-3-carboxamide (Compound No. 50); or

Contain the indazole-3-carboxamide (Compound No. 51) - N - (4- chloro-3- (trifluoromethyl) phenyl) -5 - ((3-fluorophenyl) sulfonyl) -1 H .

The present invention also provides a process for producing the compound represented by the above formula (1). The production method according to the present invention will be described in detail as follows.

Production Method 1

As shown in the following Reaction Scheme 1, the key intermediates represented by the following formula (3) can be prepared by a coupling reaction (e.g., Buchwald coupling reaction) using an organometallic compound from a compound represented by the following formula . ≪ / RTI >

[Reaction Scheme 1]

(In the above Reaction Scheme 1, L ¹ is as defined in Formula 1.)

Performed in the production process according to the scheme 1 to be Buk Wald coupling reaction, as a metal compound _{Pd 2 (dba) 3, Pd} (OAc) 2, PdCl 2 (PPh 3) 2, Pd (PPh 3) the like ₄ . Xalphos (CAS number: 161265-03-8), Davephos (CAS number: 213697-53-1), Johnphos (CAS number: 224311-51-7), X-phos (CAS number: 564483-18-7) ), tert- Butyl Xphos (CAS nuber: 564483-19-8), and the like. As the base, organic bases of amines, alkali metal or alkaline earth metal phosphates, sulfates, phosphates, alkoxides and the like can be used. As the reaction solvent, a conventional organic solvent including tetrahydrofuran, dioxane, N, N -dimethylformamide, N, N -dimethylsulfoxide, 2-butanol and 2-pentanol can be used. The reaction temperature is in the range of 50 ° C to 200 ° C, preferably in the range of 80 ° C to 150 ° C.

Production Method 2

As shown in the following Reaction Scheme 2, a 3-amino-5-substituted 1 H -pyrazolo [3,4- b ] pyridine compound represented by the following Formula 6 can be prepared by the following three- have.

(Step 2-1) A compound represented by the following formula (3) is reacted with phosphorus pentoxide (PCl ₅ ) and phosphoryl chloride (POCl ₃ ) to prepare a compound represented by the following formula (4).

(Step 2-2) A compound represented by the following Chemical Formula 4 is oxidized to convert a sulfide (-S-) group into a sulfanyl (-SO-) or sulfonyl (-SO ₂ - ≪ / RTI >

(Step 2-3) reacting a compound represented by the following formula (5) with hydrazine monohydrate to prepare a compound represented by the following formula (6);

≪ / RTI >

[Reaction Scheme 2]

(상기 반응식 2에서, L¹은 상기 화학식 1에서 정의한 바와 같다.)

(In the above scheme 2, L ¹ is as defined in formula (I).)

Production Method 3

As shown in Scheme 3 below, the 3-amino-5-substituted 1 H -pyrazolo [3,4- b ] pyridine compound represented by the following formula 6 can be prepared by the following two- have.

(Step 3-1) A compound represented by the following formula (3) is reacted with phosphorus pentoxide (PCl ₅ ) and phosphoryl chloride (POCl ₃ ) to prepare a compound represented by the following formula (4). And

(Step 2-3) reacting hydrazine monohydrate with a compound represented by Formula 4 to prepare a compound represented by Formula 6 below;

≪ / RTI >

[Reaction Scheme 3]

(In the above scheme 3, L ¹ is as defined in formula (I).)

Production method 4

As shown in the following Reaction Scheme 4, 1,3,5-trisubstituted 1 H -pyrazolo [3 (3) -bis , & Lt ; / RTI > 4- b ] pyridine compound can be prepared by performing the following two-step preparation process.

(Step 4-1) reacting a compound represented by the following formula (6) with trifluoroacetic anhydride to prepare a compound represented by the following formula (8);

(Step 4-2) reacting the compound represented by Formula 8 with a compound represented by P-X to prepare a compound represented by Formula 9;

≪ / RTI >

[Reaction Scheme 4]

(In the above Scheme 4, L ¹ and P are the same as defined in the above formula (1), and X represents a halogen atom or tert -butylcarbonate.)

Production method 5

As shown in the following Reaction Scheme 5, the compound represented by Formula 1 according to the present invention having various L ² groups introduced at the C3 position can be prepared from the compound represented by Formula 9 by performing the following 3-step preparation process .

(Step 5-1) a step of preparing a compound represented by the following formula (10) by performing deprotection reaction of a compound represented by the following formula (9) using an organic base;

(Step 5-2) Binding reaction of a compound represented by Formula 10 and a compound represented by L ² -X ¹ to prepare a compound represented by Formula 11 below; And

(Step 5-3) a step of preparing a compound represented by the following formula (1) by performing deprotection reaction using a compound represented by the following formula (11) using an acid;

≪ / RTI >

[Reaction Scheme 5]

(In the above Reaction Scheme 5, L ¹ , L ² , and P are the same as defined in the above formula (1), and X ¹ represents an acyl chloride (C (O) Cl) or an isocyanate (NCO).

Production Method 6

As shown in the following Reaction Scheme 6, the ethyl 5-bromo-1 H -indazole-3-carboxylate compound represented by the following general formula (15) can be prepared by the following two-

(Step 6-1) A 5-bromo-1 H -indazole-3-carboxylic acid compound represented by the following formula (13) is prepared from a compound represented by the following formula (12).

(Step 6-2) Esterification reaction of the 5-bromo-1 H -indazole-3-carboxylic acid compound represented by the following formula (13) to prepare an ester compound represented by the following formula (14)

(Step 6-3) reacting an ester compound represented by the following formula (14) with a tetrahydropyran compound to prepare a compound represented by the following formula (15);

≪ / RTI >

[Reaction Scheme 6]

(In the above Scheme 6, PTSA represents p- toluenesulfonic acid and THP represents tetrahydropyran).

Production Method 7

As shown in the following Reaction Scheme 7, compounds represented by the following general formula (17) wherein various L ¹ groups are introduced at the C5 position can be prepared by the following two-step preparation process.

(Step 7-1) A step of preparing a compound represented by the following formula (16) by carrying out a Bukwald coupling reaction of a compound represented by the following formula (15); And

(Step 7-2) A compound represented by the following Chemical Formula 16 is oxidized to convert the sulfide (-S-) group into a sulfanyl (-SO-) or sulfonyl (-SO ₂ -) group, ≪ / RTI >

≪ / RTI >

[Reaction Scheme 7]

(In the above Reaction Scheme 7, L ¹ is as defined in the above formula (1), and THP represents tetrahydropyran.)

Production Method 8

As shown in the following Reaction Scheme 8, a compound represented by the following general formula (20) in which a -C (O) NH- group is introduced at the C3 position can be prepared by the following two-step preparation process from the ester compound represented by the general formula can do.

(Step 8-1) a step of hydrolyzing an ester compound represented by the following formula (17) to prepare a carboxylic acid compound represented by the following formula (18);

(Step 8-2) Carboxylic acid compound represented by the following formula (18) is subjected to an amide bond reaction with various amine compounds to prepare a compound represented by the following formula (19);

(Step 8-3) a step of deprotecting the compound represented by the following formula (19) to prepare a compound represented by the following formula (20);

≪ / RTI >

[Reaction Scheme 8]

(In the above Reaction Scheme 8, L ¹ and R ² are as defined in the above formula (1), and THP represents tetrahydropyran.)

Meanwhile, the scope of the present invention includes a pharmaceutical composition containing the compound represented by the formula (1), a pharmaceutically acceptable salt thereof, a solvate thereof, and a hydrate thereof as an active ingredient.

Since the compound represented by Formula 1 exhibits an excellent inhibitory activity against protein kinase, it can be used as a prophylactic or therapeutic agent for diseases caused by abnormal cell growth.

The protein kinase may be selected from the group consisting of ABL, ACK1, ALK, Aurora A, Aurora B, Aurora C, BLK, BMX / ETK, BRSKl, BTK, c-Src, CAMKK, CDK1, CDK2, CDK5, CLK, DDR, DYRK1B, FGF, FGF, FGF, FGR, FLT3, FLT4 / VEGFR3, FMS, FRK / PTK5, FYN, GSK3b, HCK, IGF1R, IR, IRAK1, IRR / INSRR, ITK, JAK2, EPHB, FAK / PTK2, FER, And may include KHS / MAP4K5, LCK, LYN, PHKg, PLK4 / SAK, PYK2, RET, ROS / ROS1, TIE2 / TEK, TRK, TXK, TYK, YES /

The diseases caused by abnormal cell growth in the present invention include, for example, gastric cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, cystic adenoma, uterine cancer, cervical cancer, Various cancers such as cancer of the esophagus, thyroid cancer, pituitary cancer, kidney cancer, sarcoma, prostate cancer, urethra cancer, bladder cancer, leukemia, multiple myeloma, hematologic cancer such as Hodgkin's lymphoma and non-Hodgkin's lymphoma, Diseases may be included.

The pharmaceutical composition of the present invention comprises a compound represented by the general formula (1), a pharmaceutically acceptable salt thereof, a solvate thereof, and a hydrate thereof as an active ingredient, wherein a usual non-toxic pharmaceutically acceptable carrier, adjuvant and excipient And the like can be formulated into preparations for oral administration such as tablets, capsules, troches, liquids and suspensions, or parenteral administration preparations which are customary in the pharmaceutical field.

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 fragrances. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, Water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, and the like.

The dose of the compound according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and disease severity of the patient, and is generally 0.01 To 1,000 mg / day. Depending on the judgment of a doctor or a pharmacist, it may be administered once to several times a day at a predetermined interval.

The present invention as described above will be described in more detail with reference to the following examples, preparation examples and experimental examples. However, the following production examples, examples, preparation examples and experimental examples are only illustrative of the present invention. The scope of the invention is not limited thereto.

[Example]

Example 1: N - (5 - ( ( 3-fluorophenyl) sulfonyl) -1-trityl -1 H - pyrazolo [3,4- b] pyridin-3-yl) -4- (4 Methylpiperazin-1-yl) benzamide

The compound of Example 1 represented by the above structural formula can be prepared through the synthesis of 11 steps as described below.

Step 1: 2-Oxo-l, 2-dihydropyridine-3-carbonitrile

Acetic acid (45 mL) was added to 2-chloronicotinonitrile (7.25 g, 0.052 mol). Stir at 130 < 0 > C for 24 h and cool to 0 < 0 > C. The mixture was filtered, washed with acetic acid and water, and dried at room temperature to give the desired compound (6.28 g) as a white solid.

¹ H NMR (400 _{MHz, DMSO -d 6) δ 8.14} (m, 1H), 7.78 (m, 1H), 6.34 (m, 1H), MS m / z: 121.04 [M + 1]

Step 2: 5-Bromo-2-oxo-1,2-dihydropyridine-3-carbonitrile

Acetic acid (34 mL) was added to 2-oxo-1,2-dihydropyridine-3-carbonitrile (6.28 g, 0.052 mol) and the mixture was heated to 130 占 폚. When the solid was dissolved, bromine (12.5 g, 0.078 mol) was added slowly and stirred at the same temperature for 3 hours. After the reaction solution was cooled to room temperature, dichloromethane and water were added. The organic layer was separated and the aqueous layer was washed with dichloromethane. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate and concentrated to give the desired compound (9.11 g, 88% yield) as a yellow solid.

¹ H NMR (400 _{MHz, DMSO -d 6) δ 8.91} (d, J = 2.48 Hz, 1H), 8.89 (d, J = 2.46 Hz, 1H), MS m / z: 199.00 [M + 1]

Step 3: 5 - ((3-Fluorophenyl) thio) -2-oxo-1,2-dihydropyridine-3-

(800 mg, 4.00 mmol), Xantphos (116 mg, 0.2 mmol) and Pd ₂ (dba) ₃ (92 mg, 0.2 mmol) were added to a sealed vessel. , 0.1 mmol) and 1,4-dioxane (8.4 mL). The gas in the mixed solution was removed by using ultrasonic waves and nitrogen gas. Diisopropylethylamine (1.4 mL, 8.00 mmol) and 3-fluorothiophenol (0.34 mL, 4.00 mmol) were added and the mixture was stirred at 110 ° C for 36 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth pad and washed several times with ethyl acetate. The organic layer was extracted with water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by chromatography (silica gel, dichloromethane: methanol = 97: 3) to obtain the desired compound (424 mg, 43% yield) as a yellow solid.

¹ H NMR (400 _{MHz, DMSO -d 6) δ 8.31} (d, J = 2.60 Hz, 1H), 8.12 (d, J = 2.66 Hz, 1H), 7.35 (m, 1H), 7.33 (m, 1H), 7.24 (m, 2H), MS m / z: 247.03 [M + 1]

Step 4: 2-Chloro-5 - ((3-fluorophenyl) thio) nicotinonitrile

The reaction vessel was charged with 5 - ((3-fluorophenyl) thio) -2-oxo-1,2-dihydropyridine-3-carbonitrile (2.283 g, 9.27 mmol) And nitrogen gas was blown. To the mixture was added phosphoryl chloride (11.2 mL, 120.50 mmol) and the mixture was refluxed with stirring for 5 hours. The reaction solution was cooled to room temperature and slowly added to ice water (150 mL). Dichloromethane (200 mL) was added to the mixture and extracted twice. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate and concentrated to give the desired compound (2.165 g, 88% yield) as a brown oil.

¹ H NMR (400 _{MHz, DMSO -d 6) δ 8.65} (d, J = 2.41 Hz, 1H), 8.55 (d, J = 2.42 Hz, 1H), 7.47 (m, 1H), 7.33 (m, 1H), 7.24 (m, 2H), MS m / z: 265.00 [M + 1]

Step 5: 2-Chloro-5 - ((3-fluorophenyl) sulfonyl) nicotinonitrile

2-Chloro-5 - ((3-fluorophenyl) thio) nicotinonitrile (2.165 g, 8.179 mmol) and 40 mL of dichloromethane were added to the reaction vessel. M -Chloroperbenzoic acid (mCPBA (72%), 6.86 g, 28.626 mmol) was added at room temperature and stirred for 3 hours. 30 mL of dichloromethane was added to the reaction solution, the mixture was cooled to 0 占 폚, 30 mL of a 10% aqueous sodium sulfite solution was added, and the mixture was stirred. The aqueous layer was removed and the organic layer was collected and washed with 40 mL of a saturated aqueous sodium carbonate solution and 40 mL of brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate: n-hexane = 4: 1) to obtain the desired compound (1.99 g, 82% yield) as a white solid.

¹ H NMR (400 _{MHz, CDCl 3) δ 9.06 (} d, J = 2.48 Hz, 1H), 8.45 (d, J = 2.44 Hz, 1H), 7.77 (m, 1H), 7.61 (m, 1H), 7.40 (m, 1H) , MS m / z: 296.70 [M + 1] <

Step 6: 5 - ((3-Fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-

2-Chloro-5 - ((3-fluorophenyl) sulfonyl) nicotinonitrile (860 mg, 2.900 mmol) and ethanol (2.5 mL) were added to the reaction vessel and stirred. Hydrazine monohydrate (362 mg, 7.255 mmol) was added at room temperature, and the mixture was stirred at 80 占 폚 for 30 minutes. The reaction solution was cooled to room temperature and concentrated to obtain the desired compound (762 mg, 90% yield) as a yellow solid.

¹ H NMR (400 _{MHz, DMSO -d 6) δ 12.68} (s, 1H), 8.87 (s, 2H), 7.82 (m, 2H), 7.69 (m, 1H), 7.56 (m, 1H), 6.04 (s, 2H), MS m / z: 293.05 [M + 1] <

Step 7: 2,2,2-trifluoro - N - (5 - ((3-fluorophenyl) sulfonyl) -1 H - pyrazolo [3,4- b] pyridin-3-yl) acetamide

To the reaction vessel 5 - ((3-fluorophenyl) sulfonyl) -1 H-pyrazolo [3,4- b] pyridin-3-amine (585 mg, 2.00 mmol), tetrahydrofuran (24 mL) to And the mixture was stirred. The mixture was cooled to 0 C and anhydrous trifluoroacetic acid (0.83 mL, 6.00 mmol) was added. The reaction solution was stirred at room temperature for 1 hour and concentrated. Methanol (5 mL) was added to the residue and the mixture was concentrated to obtain the desired compound (700 mg, 90% yield) as a yellow solid. The desired compound was used in the next reaction without purification.

MS m / z: 389.03 [M + 1] <

Step 8: 2,2,2-trifluoro - N - (5 - ((3-fluorophenyl) sulfonyl) -1-trityl -1 H - pyrazolo [3,4- b] pyridine -3 Yl) acetamide

The reaction vessel was charged with 2,2,2-trifluoro- N - (5 - ((3-fluorophenyl) sulfonyl) -1 H- pyrazolo [3,4- b ] pyridin- (700 mg, 1.80 mmol) and dichloromethane (3 mL) were added and stirred. Triethylamine (0.502 mL, 3.61 mmol) was added to the mixture. The reaction solution was cooled to 0 deg. C, triphenylmethyl chloride (502 mg, 1.80 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Dichloromethane (5 mL) and saturated sodium carbonate solution (10 mL) were added to the reaction solution and stirred. The aqueous layer was washed twice with dichloromethane (10 mL). The organic layer was collected and dried over anhydrous sodium sulfate and the residue was purified by column chromatography (silica gel, ethyl acetate: n-hexane = 1: 4 → 1: 1) to obtain the desired compound (766 mg, 67% Respectively.

¹ H NMR (400 _{MHz, DMSO -d 6) δ 12.64} (s, 1H), 8.99 (d, J = 2.24 Hz, 1H), 8.87 (d, J = 2.2 Hz, 1H), 7.89 (m, 2H), 7.68 (m, 2H), 7.24 (m, 15H), MS m / z: 631.14 [M +

Step 9: 5 - ((3-fluorophenyl) sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-amine

The reaction vessel was charged with 2,2,2-trifluoro- N- (5 - ((3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4- b ] (239 mg, 0.366 mmol), isopropyl alcohol (IPA, 2.96 mL) and tetrahydrofuran (THF, 0.74 mL) were added and stirred. Triethylamine (0.45 mL, 3.22 mmol) was added to the mixture, the mixture was heated to 100 占 폚 and stirred for 18 hours. The reaction solution was concentrated to room temperature and the residue was purified by column chromatography (silica gel, ethyl acetate: n-hexane = 1: 4 -> 1: 2) to obtain the desired compound (100 mg, 50% .

¹ H NMR (400 _{MHz, DMSO -d 6) δ 8.82} (d, J = 2.24 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 7.80 (m, 2H), 7.60 (m, 2H), 7.24 (m, 15H), 6.26 (s, 2H), MS m / z: 535.16 [M + 1].

Step 10: 4- (4-Methylpiperazin-1-yl) benzoyl chloride

To the reaction vessel was added 4- (4-methylpiperazin-1-yl) benzoic acid (88 mg, 0.4 mmol), dichloromethane (5 mg) and dimethylformamide (0.023 mL). The mixture was cooled to 0 ° C, oxalyl chloride (0.36 mL, 4.0 mmol) was added, and the mixture was stirred at room temperature. The reaction mixture was concentrated and the desired compound (76 mg, 80% yield) was used in the next reaction without purification.

MS m / z: 240.08 [M + 1].

Step 11: N - (5 - ((3-Fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4- b ] pyridin- Piperazin-1-yl) benzamide

The reaction vessel was charged with 5 - ((3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4- b ] pyridin- (5 mg, 0.04 mmol) and pyridine (3.2 mL) were added thereto, followed by stirring at 0 ° C. 4- (4-methylpiperazin-1-yl) benzoyl chloride (33 mg, 0.14 mmol) was added and the mixture was stirred at room temperature for 18 hours. Ethyl acetate (10 mL) was added and saturated sodium carbonate solution (5 mL) was added and stirred. The organic layer was collected, washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate: n-hexane = 2: 1 → dichloromethane: methanol = 10: 1) to obtain the desired compound (25 mg, 39% yield) as yellow solid.

¹ H NMR (400 _{MHz, DMSO -d 6) δ 11.06} (s, 1H), 8.94 (d, J = 2.24 Hz, 1H), 8.82 (d, J = 2.2 Hz, 1H), 7.98 (m, 2H), 7.91 (m, 2H), 7.86 (m, 2H), 7.86 (m, 2H), 7.86 ), 2.22 (s, 3H), MS m / z: 737.27 [M + 1].

Examples 2 to 16

(3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4-b] pyridine synthesized in the step 9 of the preparation of the compound of Example 1, b ] pyridin-3-amine with various acyl chloride compounds. The method for preparing this coupling reaction is the same as that in Step 11 of the compound preparation process of Example 1 above.

Example 2: Synthesis of N - (5 - ((3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4- b ] pyridin- ≪ / RTI >

MS m / z: 707.17 [M + 1] <

Example 3: Synthesis of N - (5 - ((3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4- b ] pyridin- amides

MS m / z: 669.19 [M + 1] <

Example 4: Synthesis of N - (5 - ((3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4- b ] pyridin-

MS m / z: 639.18 [M + 1].

Example 5: 4-fluoro - N - (5 - (( 3- -1- -1-trityl-fluorophenyl) sulfonyl) H-pyrazolo [3,4- b] pyridin-3-yl) Benzamide

MS m / z: 657.17 [M + 1] <

Example 6: 4-chloro - N - (5 - (( 3- fluorophenyl) sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-yl) benzamide amides

MS m / z: 673.14 [M + 1] <

Example 7: 4- (tert - butyl) - N - (5 - ( ( 3-fluorophenyl) sulfonyl) -1-trityl -1 H - pyrazolo [3,4- b] pyridin-3 Yl) -benzamide

MS m / z: 695.24 [M + 1] <

Example 8: Synthesis of N - (5 - ((3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4- b ] pyridin- amides

MS m / z: 724.23 [M + 1] <

Example 9: 4- (dimethylamino) - N - (5 - ( ( 3-fluorophenyl) sulfonyl) -1-trityl -1 H - pyrazolo [3,4- b] pyridin-3-yl ) -Benzamide

MS m / z: 682.22 [M + 1] <

Example 10: N - (5 - ( (3- fluorophenyl) sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-yl) cyclo-hexane-carboxamide

MS m / z: 645.23 [M + 1] <

Example 11: Synthesis of N - (5 - ((3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4- b ] pyridin-

MS m / z: 619.21 [M + 1] <

Example 12: N - (5 - ( (3- fluorophenyl) sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-yl) -pentanoic amide

MS m / z: 633.23 [M + 1] <

Example 13: ethyl (5 - ((3-fluorophenyl) sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-yl) carbamate

MS m / z: 607.18 [M + 1] <

Example 14: tert-butyl - (- 1-trityl -1 H ((3- fluorophenyl) sulfonyl) -5-pyrazolo [3,4- b] pyridin-3-yl) carbamate

MS m / z: 634.21 [M + 1] <

Example 15: Synthesis of N - (5 - ((3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4- b ] pyridin- Carboxamide

MS m / z: 645.14 [M + 1].

Example 16: Synthesis of N - (5 - ((3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4- b ] pyridin- - carboxamide

MS m / z: 646.22 [M + 1].

Example 17: Synthesis of 1- (5 - ((3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4- b ] pyridin-

To a reaction vessel was added a solution of 5 - ((3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4- b ] pyridin- mL) was added phenyl isocyanate (11.8 mg, 0.1 mmol) at room temperature. The mixture was stirred at room temperature for 12 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by chromatography (silica gel, ethyl acetate: n-hexane = 1: 1 → dichloromethane: methanol = 20: 1) to obtain the target compound.

MS m / z: 654.19 [M + 1] <

(3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4-b] pyridine synthesized in the step 9 of the preparation of the compound of Example 1, b ] pyridin-3-amine with various isocyanate compounds. The method of preparing this coupling reaction is the same as the preparation of the compound of Example 17 above.

Example 18: 1 - (5 - ((3-fluorophenyl) sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-yl) -3- (2 Methoxyphenyl) urea

MS m / z: 684.20 [M + 1].

Example 19: 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (5- (sulfonyl) -1-trityl -1 H (3-fluorophenyl) -pyrazolo [ 3,4- b ] pyridin-3-yl) urea

MS m / z: 756.14 [M + 1].

Example 20: 1-cyclo-hexyl-3- (5 - ((3-fluorophenyl) sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-yl) urea

MS m / z: 660.24 [M + 1] <

Example 21: N - (5 - ( ( phenyl) 3-fluoro-sulfonyl) -1 H - pyrazolo [3,4- b] pyridin-3-yl) -4- (4-methyl-piperazin -1 Yl) benzamide

The reaction vessel was charged with N - (5 - ((3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4- b ] pyridin- Piperazin-1-yl) benzamide (22 mg, 0.03 mmol) and dichloromethane (1 mL) were added and the mixture was stirred at 0 ° C. Trifluoroacetic acid (0.06 mL) was added to the mixture, and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated and the residue was purified by column chromatography (silica gel, dichloromethane: methanol = 20: 1 - > 10: 1) to obtain the desired compound (10 mg, 67% yield) as yellow solid.

¹ H NMR (400 _{MHz, DMSO -d 6) δ 11.06} (s, 1H), 9.10 (d, J = 2.24 Hz, 1H), 9.04 (d, J = 2.2 Hz, 1H), 8.00 (m, 2H), 7.91 (m, 2H), 7.68 (m, 1 H), 7.56 (m, 1 H), 7.02 (d, J = 9.08 Hz, MS m / z: 495.16 [M + 1].

As shown in the following chemical reaction formula, the compounds of Examples 1 to 20 can synthesize the objective compounds of Examples 22 to 40 through the deprotection reaction. This coupling reaction was prepared in the same manner as in the preparation of the compound of Example 21 above.

Example 22: Synthesis of N - (5 - ((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin- -Yl) -4-methoxybenzamide < / RTI >

¹ H NMR (400 _{MHz, DMSO -d 6) δ 11.23} (s, 1H), 9.11 (d, J = 2.24 Hz, 1H), 9.07 (d, J = 2.2 Hz, 1H), 8.11 (m, 2H), 7.92 (m, 2H), 7.69 (m, 1H), 7.56 (m, 1H), 7.09 (d, J = 8.92 Hz, 2H), 2.86 (s, 3H), MS m / z: 427.08 [M + 1].

Example 23: N - (5 - ( (3- fluorophenyl) sulfonyl) -1 H - pyrazolo [3,4- b] pyridin-3-yl) -3- (trifluoromethyl) benzamide

MS m / z: 465.06 [M + 1].

Example 24: Synthesis of N - (5 - ((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-

MS m / z: 397.07 [M + 1].

Example 25: 4-fluoro - N - (5 - ((3-fluorophenyl) sulfonyl) -1 H - pyrazolo [3,4- b] pyridin-3-yl) benzamide

MS m / z: 415.06 [M + 1].

Example 26: Preparation of 4-chloro- N - (5 - ((3-fluorophenyl) sulfonyl) -1 H- pyrazolo [3,4- b ] pyridin-

MS m / z: 432.03 [M + 1].

Example 27: 4- (tert - butyl) - N - (5 - ( ( 3-fluorophenyl) sulfonyl) -1 H - pyrazolo [3,4- b] pyridin-3-yl) benzamide

MS m / z: 453.14 [M + 1].

Example 28: N - (5 - ( (3- fluorophenyl) sulfonyl) -1 H - pyrazolo [3,4- b] pyridin-3-yl) -4-Dimorpholino Reno benzamide

MS m / z: 482.13 [M + 1].

Example 29: 4- (dimethylamino) - N - (5 - ( (3- fluorophenyl) sulfonyl) -1 H - pyrazolo [3,4- b] pyridin-3-yl) benzamide

MS m / z: 440.11 [M + 1].

Example 30: N - (- sulfonyl) -1 H ((3-fluorophenyl) -5-pyrazolo [3,4- b] pyridin-3-yl) cyclo-hexane-carboxamide

MS m / z: 403.12 [M + 1].

Example 31: N - (5 - ((3-Fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-

MS m / z: 377.10 [M + l].

Example 32: N - (5 - ( (3- fluorophenyl) sulfonyl) -1 H - pyrazolo [3,4- b] pyridin-3-yl) hexanoic amide

MS m / z: 391.12 [M + 1].

Example 33: Preparation of ethyl- (5 - ((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-

MS m / z: 365.07 [M + 1].

Example 34: tert-butyl- (5 - ((3-fluorophenyl) sulfonyl) -1 H-pyrazolo [3,4- b] pyridin-3-yl) carbamate

MS m / z: 393.10 [M + 1].

Example 35: N - (5 - ( ( 3-fluorophenyl) sulfonyl) -1 H - pyrazolo [3,4- b] pyridin-3-yl) thiophene-2-carboxamide

MS m / z: 403.03 [M + 1].

Example 36: N - (5 - ( ( 3-fluorophenyl) sulfonyl) -1 H - pyrazolo [3,4- b] pyridin-3-yl) piperidine-1-carboxamide

MS m / z: 404.11 [M + 1].

Example 37: 1- (5 - ((3-fluorophenyl) sulfonyl) -1 H-pyrazolo [3,4- b] pyridin-3-yl) -3-phenyl urea

MS m / z: 412.08 [M + 1].

Example 38: 1 - (5 - ((3-fluorophenyl) sulfonyl) -1 H-pyrazolo [3,4- b] pyridin-3-yl) -3- (2-methoxyphenyl) urea

MS m / z: 442.09 [M + 1].

Example 39: l- (4-Chloro-3- (trifluoromethyl) phenyl) -3- (5 - ((3-fluorophenyl) sulfonyl) -1 H- pyrazolo [3,4- b ] Pyridin-3-yl) urea

MS m / z: 515.03 [M + 1].

Example 40: 1-cyclo-hexyl-3- (5 - ((3-fluorophenyl) sulfonyl) -1 H-pyrazolo [3,4- b] pyridin-3-yl) urea

MS m / z: 418.13 [M + 1].

Example 41: 5 - ((3-fluorophenyl) sulfonyl) - N - (4- Dimorpholino Reno phenyl) -1- (tetrahydro -2 H in Tet-pyran-2-yl) -1 H-indazole -3-carboxamide

The compound of Example 41 represented by the above structural formula can be prepared through the following 9-step synthesis procedure.

Step 1: 6-Bromo -1 H - indazole-3-carboxylic acid

6-Bromoisatin (10.0 g, 22 mmol) and 1 N NaOH aqueous solution (48 mL) were added to the reaction vessel, and the mixture was heated to 50 deg. C and stirred for 1 hour. The reaction solution was cooled to 0 deg. C, and a mixture of sodium nitrite (3.0 g, 22 mmol) and water (11 mL) was added slowly. Water (90 mL) and sulfuric acid (4.6 mL) were slowly added to the mixture at the same temperature and stirred. To the reaction mixture was added a mixture of tin chloride dihydrate (24.0 g, 53 mmol) and hydrochloric acid (40 mL) at 0 ° C, and the mixture was stirred at room temperature. The resulting solid was filtered, washed with water and dried to give the desired compound (8.53 g, 80% yield) as a yellow solid.

¹ H NMR (400 _{MHz, DMSO -d 6) δ 13.99} (s, 1H), 13.00 (bs, 1H), 8.21 (s, 1H), 7.65 (d, J = 8 Hz, 1H), 7.57 (d, J = 8 Hz, 1H).

Step 2: Preparation of ethyl 6-bromo -1 H - indazole-3-carboxylate

6-Bromo-1 H -indazole-3-carboxylic acid (5.0 g, 21 mmol) and ethanol (100 mL) were added to the reaction vessel and stirred. Sulfuric acid (5 mL) was added to the mixture and the mixture was stirred under reflux. The reaction solution was cooled to room temperature and concentrated. To the residue were added ethyl acetate and a saturated sodium hydrogencarbonate solution and stirred. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane: methanol = 9: 1) to obtain the desired compound (2.8 g) as a yellow solid.

¹ H NMR (400 _{MHz, CDCl 3) δ 14.04 (} bs, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 1.2 Hz, 1H), 7.45 (dd, J = 1.5, 8.7 Hz, 1H) , 4.39 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H).

Step 3: Preparation of ethyl 5-bromo-1- (tetrahydro -2 H - pyran-2-yl) -1 H - indazole-3-carboxylate

Ethyl 6-bromo -1 H in a reaction vessel-indazol-3-carboxylate (4.84 g, 18 mmol), 3,4- dihydro -2 H-pyran (3.03 g, 36 mmol) and acetonitrile ( 50 mL) was added and stirred. To the mixture was added p- toluenesulfonic acid (0.31 g, 1.8 mmol) and the mixture was stirred at room temperature. The reaction mixture was concentrated and the residue was purified by column chromatography (silica gel, ethyl acetate: n-hexane = 3: 1) to obtain the target compound (3.8 g, 60% yield) as yellow solid.

¹ H NMR (400 _{MHz, DMSO -d 6) δ 8.21} (d, J = 8.6 Hz, 1H), 7.89 (d, J = 8.95 Hz, 1H), 7.66 (m, 1H), 6.01 (m, 1H), 4.42 (m, (M, 2H), 3.88 (m, 1H), 3.79 (m, 1H), 2.33 ).

Step 4: ethyl 5 - ((3-fluorophenyl) thio) -1- (tetrahydro -2 H-pyran-2-yl) -1 H-indazole-3-carboxylate

In a sealed vessel with ethyl 5-bromo-1- (tetrahydro -2 H - pyran-2-yl) -1 H - indazole-3-carboxylate (176 mg, 0.5 mmol) and Xantphos (29 mg, 0.05 mmol ), Pd ₂ (dba) ₃ (23 mg, 0.025 mmol) and 1,4-dioxane (2 mL). The gas in the mixed solution was removed by using ultrasonic waves and nitrogen gas. Diisopropylethylamine (0.18 mL, 1.0 mmol) and 3-fluorothiophenol (0.042 mL, 0.5 mmol) were added and the mixture was stirred at 110 ° C for 36 hours. The reaction solution was cooled to room temperature, filtered through a pad of diatomaceous earth and washed several times with ethyl acetate. The organic layer was extracted with water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate: n-hexane = 6: 1 - > 4: 1) to obtain the desired compound (131 mg, 65% yield) as a yellow solid.

¹ H NMR (400 _{MHz, DMSO -d 6) δ 8.15} (d, J = 1.50 Hz, 1H), 7.97 (d, J = 8.83 Hz, 1H), 7.57 (m, 1H), 7.39 (m, 1H), 7.11 (m, 1H), 7.04 (m, 2H), 4.38 (m, 2H), 3.91 (m, ), 1.60 (m, 2H), 1.32 (t, 3H).

Step 5: ethyl 5 - ((3-fluorophenyl) sulfonyl) -1- (tetrahydro -2 H-pyran-2-yl) -1 H-indazole-3-carboxylate

To the reaction vessel of ethyl 5 - ((3-phenylpropyl) thio-fluorophenyl) -1- (tetrahydro -2 H-pyran-2-yl) -1 H-indazole-3-carboxylate (125 mg, 0.32 mmol) , And dichloromethane (2 mL) were added. M -Chloroperbenzoic acid (mCPBA (72%), 244 mg, 1.09 mmol) was added at room temperature and stirred for 3 hours. Dichloromethane (3 mL) was added to the reaction solution, and the mixture was cooled to 0 deg. C and 10% sodium sulfite aqueous solution (3 mL) was added and stirred. The aqueous layer was removed, and the organic layer was collected and washed with saturated aqueous sodium carbonate solution and brine in turn. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the desired compound (130 mg, 93% yield) as a white solid.

¹ H NMR (400 _{MHz, DMSO -d 6) δ 8.72} (s, 1H), 8.08 (m, 2H), 7.87 (m, 2H), 7.69 (m, 1H), 7.58 (m, 1H), 6.08 (m, 1H), 2H), 1.74 (m, 2H), 3.87 (m, 1H), 3.78 (m, (t, 3 H).

Step 6: 5 - ((3-fluorophenyl) sulfonyl) -1- (tetrahydro -2 H-pyran-2-yl) -1 H-indazole-3-carboxylic acid

5 to a reaction vessel ethyl - ((3-fluorophenyl) sulfonyl) -1- (tetrahydro -2 H-pyran-2-yl) -1 H-indazole-3-carboxylate (130 mg, 0.3 mmol ), Tetrahydrofuran (10 mL), water (6 mL) and methanol (1 mL). Lithium hydroxide hydrate (28 mg, 0.66 mmol) was added to the mixture, and the mixture was stirred at 55 占 폚 for 16 hours. The reaction solution was cooled to room temperature and concentrated. The pH of the residue was adjusted to pH 5 by slowly adding 1 N hydrochloric acid solution. Ethyl acetate and brine were added and stirred. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated to give the desired compound (120 mg, 98% yield) as a white solid. The desired compound was used directly in the next reaction without purification.

MS m / z: 405.09 [M + 1].

Step 7: 4- (4-Nitrophenyl) morpholine

To the reaction vessel was added 1-fluoro-4-nitrobenzene (1 g, 7.09 mmol) and dimethylformamide (10 mL). To the mixture was added morpholine (0.62 g, 7.09 mmol) and potassium carbonate (1.96 g, 14.17 mmol), followed by stirring at 80 ° C. The reaction solution was cooled to room temperature, ethyl acetate and water were added and stirred. The aqueous layer was washed with ethyl acetate. The organic layer was collected and washed with brine. Dried over anhydrous magnesium sulfate and concentrated to give the desired compound (1.18 g, 80% yield) as a yellow solid. The compound was used directly in the next reaction without purification.

MS m / z: 209.09 [M + 1].

Step 8: 4-Morpholinoaniline

4- (4-Nitrophenyl) morpholine (1 g, 4.80 mmol) and methanol (30 mL) were placed in a reaction vessel. 10% Pd / C (100 mg) was added to the mixed solution, and the mixture was stirred at room temperature under a balloon pressure filled with hydrogen gas. The reaction solution was filtered through a pad of diatomaceous earth and concentrated. The target compound (728 mg, 85% yield) was used in the next reaction without purification.

MS m / z: 179.11 [M + 1].

Step 9: 5 - ((3-fluorophenyl) sulfonyl) - N - (4- pyridin-Dimorpholino Reno) -1- (tetrahydro -2 H in Tet-pyran-2-yl) -1 H-indazol- 3-carboxamide

To the reaction vessel 5 - ((phenyl) 3-fluoro-sulfonyl) -1- (tetrahydro -2 H-pyran-2-yl) -1 H-indazole-3-carboxylic acid (40 mg, 0.1 mmol), 4-morpholinoaniline (29 mg, 0.16 mmol), diisopropylethylamine (0.035 mL, 0.2 mmol), 1-hydroxybenzotriazole monohydrate (19 mg, 0.12 mmol) and dichloromethane And stirred. 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI ?? HCl, 23 mg, 0.12 mmol) was added and stirred at room temperature. The reaction mixture was diluted with dichloromethane (10 mL), water (10 mL) was added, and the mixture was stirred. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane: methanol = 30: 1) to obtain the desired compound (50 mg, 90% yield).

¹ H NMR (400 _{MHz, CDCl 3) δ 9.17 (} d, J = 1.6 Hz, 1H), 8.67 (s, 1H), 8.02 (m, 1H), 7.79 (m, 2H), 7.69 (m, 4H), 7.49 (m, 4H), 3.81 (m, IH), 3.20 (m, 4H), 4.20 (m, IH) ), 2.58 (m, 1 H), 2.17 (m, 2H), 1.81 (m, 3H), MS m / z: 565.19 [M + 1].

Example 41 Compound synthesized in Step 6 of the manufacturing process of 5 - ((3-fluorophenyl) sulfonyl) -1- (tetrahydro -2 H-pyran-2-yl) -1 H-indazol- The objective compounds of Examples 42 to 45 can be synthesized through a coupling reaction between 3-carboxylic acid and various aniline compounds. The method for preparing this coupling reaction is the same as the preparation of the compound of Example 40 above.

Example 42: 5 - N - - ( (3- phenyl) sulfonyl-fluorophenoxy) (6-Reno Dimorpholino-3-yl) -1- (tetrahydro -2 H in Tet-pyran-2-yl) -1 H -indazole-3-carboxamide

¹ H NMR (400 _{MHz, CDCl 3) δ 9.14 (} s, 1H), 8.62 (s, 1H), 8.02 (m, 1H), 8.35 (m, 1H), 8.17 (m, 1H), 8.01 (m, 1H), 7.79 ( (m, 2H), 7.69 (m, IH), 7.49 (m, IH), 7.22 2H), 1.80 (m, 3H), MS m / z: 566.18 [M + 1] < .

Example 43: N - (4- (4- ethyl-piperazin-1-yl) phenyl) -5 - ((3-fluorophenyl) sulfonyl) -1- (tetrahydro in Tet -2 H-pyran -2 -yl) -1 H-indazole-3-carboxamide

MS m / z: 592.23 [M + 1].

Example 44: 5 - ((3-fluorophenyl) sulfonyl) - N - (6- methylpyridin-3-yl) -1- (Tet as dihydro -2 H-pyran-2-yl) -1 H - indazole-3-carboxamide

MS m / z: 495.15 [M + 1].

Example 45: N - (4- chloro-3- (Tryp Luo methyl) phenyl)) - 5-sulfonyl) -2 H -1- (tetrahydro in Tet ((3-fluorophenyl) - pyran - 2-1) -1 H - indazole-3-carboxamide

MS m / z: 583.08 [M + 1].

Example 46: 5 - ((3-fluorophenyl) sulfonyl) - N - (4- Dimorpholino Reno phenyl) -1 H-indazole-3-carboxamide

To the reaction vessel 5 - ((3-fluorophenyl) sulfonyl) - N - (4- Dimorpholino Reno phenyl) -1- (tetrahydro -2 H in Tet-pyran-2-yl) -1 H-indazol- 3-carboxamide (46.5 mg, 0.082 mmol) and p- toluenesulfonic acid monohydrate (233 mg, 1.23 mmol) and ethanol (4.8 mL) were added and stirred. Acetic acid (2.2 mL) was added to the mixed solution, which was then heated to 80 DEG C and stirred. The reaction solution was cooled to room temperature and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane: methanol = 50: 1 - > 30: 1) to obtain the desired compound (19 mg) as a white solid.

¹ H NMR (400 _{MHz, DMSO -d 6) δ 14.25} (bs, 1H), 10.37 (s, 1H), 8.88 (d, J = 0.8 Hz, 1H), 7.98 (m, 1H), 7.85 (m, 3H), 7.76 ( (m, 2H), 7.68 (m, 1H), 7.56 (m, 1H), 6.95 ].

The compounds of Examples 42 to 46 can be synthesized by subjecting the compounds of Examples 47 to 50 to deprotection. The method for preparing this coupling reaction is the same as the preparation of the compound of Example 46 above.

Example 47: 5 - ((3-fluorophenyl) sulfonyl) - N - (4- Reno Dimorpholino-3-yl) -1 H-indazole-3-carboxamide

¹ H NMR (400 _{MHz, DMSO -d 6) δ 14.28} (bs, 1H), 10.50 (s, 1H), 8.88 (s, 1H), 8.61 (m, 1H), 8.06 (m, 1H), 7.98 (m, 1H), 4H), 3.42 (m, 4H), MS m / z: 482.13 [M (IH) +1].

Example 48: N - (4- (4- ethyl-piperazin-1-yl) phenyl) -5 - ((3-fluorophenyl) sulfonyl) -1 H-indazole-3-carboxamide

MS m / z: 508.18 [M + 1].

Example 49: 5 - ((3-fluorophenyl) sulfonyl) - N - (6- methylpyridin-3-yl) -1 H-indazole-3-carboxamide

MS m / z: 411.09 [M + 1].

Example 50: N - (4- chloro-3- (trifluoromethyl) phenyl) -5 - ((3-fluorophenyl) sulfonyl) -1 H-indazole-3-carboxamide

MS m / z: 499.02 [M + 1] <

Meanwhile, the novel compounds represented by Formula 1 according to the present invention can be formulated into various forms according to the purpose. The following is a description of some formulations containing the compound of Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

[Formulation Example]

Formulation Example 1 Tablet (Direct Pressurization)

After 5.0 mg of the active ingredient was sieved, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressurized to make tablets.

Formulation Example 2. Tablet (wet assembly)

After 5.0 mg of the active ingredient was sieved, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressurized to make tablets.

Formulation Example 3. Powder and Capsule

5.0 mg of the active ingredient was sieved and mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. 5 gelatin capsules.

Formulation Example 4. Injection

100 mg as an active ingredient, 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water were added to prepare an injection.

[Experimental Example]

Experimental Example 1. Measurement of kinase inhibitory activity

N as representative of the compounds according to the invention - (5-sulfonic ((3-fluorophenyl) sulfonyl) -1 H-pyrazolo [3,4- b] pyridin-3-yl) -4- (4-methylpiperazin- (% Inhibition) of various protein kinases was measured for each of the compounds shown in Table 1 below.

Kinase % Inhibition (1 uM) Kinase % Inhibition (1 uM) ABL1 96 FLT3 97 ABL2 / ARG 96 FLT4 / VEGFR3 71 ACK1 100 FMS 96 ALK 92 FRK / PTK5 91 Aurorae 96 FYN 95 Aurora B 96 GSK3b 79 Aurora C 82 HCK 94 BLK 78 HPK1 / MAP4K1 89 BMX / ETK 98 IGF1R 95 BTK 94 IR 83 c-Src 99 IRAK1 82 CAMKK1 75 IRR / INSRR 99 CAMKK2 87 ITK 81 CDK1 / cyclin A 86 JAK2 78 CDK2 / cyclin A 88 KDR / VEGFR2 56 CDK5 / p25 90 KHS / MAP4K5 97 CDK5 / p35 89 LCK 93 CLK1 76 LYN 93 CLK2 89 LYN B 90 DDR1 97 PHKg1 74 DDR2 79 PHKg2 86 DYRK1B 74 PLK4 / SAK 96 EPHA1 94 PYK2 85 EPHA2 94 RET 83 EPHB1 95 ROS / ROS1 99 EPHB2 84 TIE2 / TEK 91 EPHB4 92 TRKA 99 FAK / PTK2 95 TRKB 99 FER 96 TRKC 99 FES / FPS 90 TXK 86 FGFR1 92 TYK1 / LTK 101 FGFR2 96 TYK2 77 FGFR3 87 YES / YES1 92 FGR 96

Claims (6)

A compound selected from a compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof:
[Chemical Formula 1]

In Formula 1,
X represents N,
P represents a hydrogen atom,
L ¹ represents an -S (O) ₂ R ^1, wherein R ¹ represents a 1 to 3 halogen-substituted phenyl group,
G represents -NHC (O) -,
L ² represents a (4-methylpiperazinyl) phenyl group.
delete The method according to claim 1,
N - (5 - ((3- fluorophenyl) sulfonyl) -1 H - pyrazolo [3,4- b] pyridin-3-yl) -4- (4-methylpiperazin-1-yl) benzamide Amide (Compound No. 22).
A pharmaceutical composition for the prevention and treatment of cancer diseases containing the compound of claim 1 or 3 as an active ingredient.
The method of claim 4,
A pharmaceutical composition for the prevention and treatment of cancer diseases having inhibitory activity against protein kinase.
The method of claim 4,
The cancer diseases include cancer, lung cancer, liver cancer, colon cancer, small bowel cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, Prostate cancer, urethra cancer, bladder cancer, blood cancer, lymphoma, psoriasis, or fibrosarcoma.