KR20140019055A - Pyrazolopyridine or indazole derivatives as protein kinase inhibitors - Google Patents

Abstract

The present invention relates to novel pyrazolopyridine or indazole derivatives or pharmaceutically acceptable salts thereof having inhibitory activity against protein kinases. Compounds of the present invention are protein kinases such as ABL, ACK1, ALK, Aurora A, Aurora B, Aurora C, BLK, BMX / ETK, BRSK1, BTK, c-Src, CAMKK, CDK1, CDK2, CDK5, CLK, DDR , DYRK1B, EPHA, EPHB, FAK / PTK2, FER, FES / FPS, FGFR, 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, YES / YES1, etc. It is useful as a drug for treatment and prevention.

Description

New pyrazolopyridine or indazole derivatives as protein kinase inhibitors

The present invention relates to novel pyrazolopyridine derivatives or indazole derivatives or pharmaceutically acceptable salts thereof having inhibitory activity against protein kinases. Since the compounds of the present invention have inhibitory activity against protein kinases, It is useful as a drug for treatment and prevention.

Protein kinases are enzymes that catalyze the phosphorylation of hydroxy groups located at tyrosine, serine and threonine residues of proteins and play an important role in the growth factor signal transduction that causes cell growth, differentiation and proliferation.

In order to maintain the homeostasis of the living body, the signaling system in vivo should be smoothly turned on and off. However, mutation or overexpression of certain protein kinases disrupts normal cellular signaling systems (mainly in vivo), leading to a variety of diseases, including cancer, inflammation, metabolic diseases, and brain diseases.

Human protein kinases are estimated to be present in 518 species, corresponding to about 1.7% of the total human gene, and are largely divided into tyrosine protein kinases (more than 90 species) and serine / threonine protein kinases. Tyrosine protein kinases can be divided into 58 receptor tyrosine kinases divided into 20 subfamily and 32 cytoplasmic / non-receptors separated into 10 subfamily. Receptor tyrosine kinases have a domain that can accommodate growth factors on the cell surface and an active site that can phosphorylate tyrosine residues on 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 tyrosine residues of the cytoplasm are autophosphorylated. Signal transduction proceeds into the nucleus through sequential phosphorylation of the lower family proteins, resulting in overexpression of cancer-causing transcription factors.

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

Biological function of VEGF is mediated through type III RTK, VEGFR-1 (Flt-1), VEGFR-2 (KDR / Flk-1), VEGFR-3 (Flt-4). EGFR is closely related to Fms, Kit and PDGFR, and VEGF binds to specific receptors, respectively, while VEGF-A binds to VEGFR-1, -2 and receptor heteropolymers, while VEGF-C binds to VEGF-2, Bind to -3. Also, PIGF and VEGF-B are exclusive to VEGFR-1, and VEGF-E only interacts with VEGFR-2. The VEGF-F variant interacts with VEGFR-1 or -2. VEGF-A, -B, and PIGF are primarily required for blood vessel formation, while VEGF-C, -D are essential for lymphatic vessel formation. New blood vessels supply nutrients and oxygen to tumors and provide a pathway for cancer cell metastasis, essential for their proliferation and metastasis. Angiogenesis is normally balanced by the mutual regulation of angiogenic stimulators and angiogenic suppressors in vivo, but the greatest impact on vascular endothelial growth when such balances are broken, such as in cancer cells. The receptor, VEGFR, is activated by the Vascular Endothelial Growth Factor (VEGF). Among various mechanisms of action, various inhibitors that inhibit the tyrosine kinase, a receptor of VEGF, using a low molecular weight compound have been researched and developed. Most of them have the potential to be commonly used in solid tumors and neovascularization activated only in cancer cells. Because it suppresses the relatively low side effects have the advantage that you can expect effective efficacy.

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 nucleophosmin (NPM), is an oncogene and a trigger for anaplastic large cell lymphoma (ALCL) disease. In addition, ALK and EML4 (echinoderm microtubule-associated proteins

Like 4) fused EML4-ALK is also a tumor gene, NSCLC (non-small cell lung cancer) disease causing factor. Crizotinib (PF-02341066) has been approved as a non-small cell lung cancer (NSCLC) treatment as an inhibitor of ALK receptor tyrosine kinase. Crizotinib (PF-02341066) is under clinical trial for the treatment of anaplastic large cell lymphoma (ALCL) disease.

Tie2 is a type of receptor tyrosine kinase that is highly associated with angiogenesis and vasculature. The domain structure of Tie2 is very highly conserved in all vertebrates. Ligands of Tie2 are angiopoietins (Ang). Ang2 does not induce autophosphorylation of Tie2, but interferes with the activation of Tie2 induced by Ang1. Activation of Tie2 by Ang2 in endothelial cells leads to the activation of PI3K-Akt. In the mitogen-activated protein kinase (MAPK) signaling pathway, Tie2's main signaling system, the adapter protein GRB2 and protein tyrosine phosphatase SHP2 are involved in the dimerization process through autophosphorylation of Tie2 receptor tyrosine kinase. Plays an important role. Ang / Tie2 and vascular endothelial growth factor (VEGF) signaling pathways play an important role in the neovascularization of cancer cells. Tie2 is expressed in vascular endothelial cells, especially in the place where cancer cells invade. Overexpression of Tie2 has been identified in breast cancer (Peters et al., 1998), and at the same time in uterine cancer, liver cancer and brain cancer.

To date, several compounds having a parent structure of pyrazolopyridine or indazole have been synthesized. However, in the C3 position of the parent nucleus, an amide group of -C (O) NH- or -NHC (O)- No compound was introduced at the same time that the sulfide (SR ¹ ), sulfinyl (SOR ¹ ), or sulfonyl (SO ₂ R ¹ ) group was introduced at the C5 position of the parent nucleus, and also the protein kinase for these compounds. It has not been published in any literature to confirm its inhibitory activity and can be used as a tumor treatment and prevention agent.

It is an object of the present invention to provide novel pyrazolopyridine derivatives, indazole derivatives or pharmaceutically acceptable salts thereof.

Another object of the present invention 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 problems, the present invention is characterized by a compound represented by the following formula (1), pharmaceutically acceptable salts, hydrates or solvates thereof that inhibit the activity of protein kinases:

[Formula 1]

In Formula 1,

X is CH; Or N,

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

L ¹ is -SR ¹ ; -S (O) R ¹ ; Or -S (O) ₂ R ¹ ,

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

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

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

R ² is a hydrogen atom; C ₁ -C ₁₀ alkyl group; C ₃ -C ₁₀ cycloalkyl group; Or a phenyl group unsubstituted or substituted with a substituent selected from halo, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, and C ₁ -C ₁₀ haloalkyl substituted with 1 to 10 halogen,

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

R ⁴ and R ⁵ are the same as or different from each other and an amino group; Mono (C ₁ -C ₁₀ alkyl) amino group; Or a di (C ₁ -C ₁₀ alkyl) amino group,

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

R ⁷ is Halogen atom; C ₁ -C ₁₀ alkyl group; C ₁ -C ₁₀ alkoxy group; Haloalkyl group substituted with 1 to 10 halogens; A 5 to 7 hexagonal heterocycloalkyl group which may be unsubstituted or substituted with a C _{1 to} C ₁₀ alkyl group and contains 1 to 3 heteroatoms selected from an oxygen atom and a nitrogen atom; An amino group; Mono (C ₁ -C ₁₀ alkyl) amino group; Or a di (C ₁ -C ₁₀ alkyl) amino group,

R ⁸ is a C ₁ -C ₁₀ alkyl group; Or a 5 to 7 hexagonal heterocycloalkyl group including 1 to 3 heteroatoms selected from an oxygen atom and a nitrogen atom.

The novel compounds of the present invention are ABL, ACK1, ALK, Aurora A, Aurora B, Aurora C, BLK, BMX / ETK, BRSK1, BTK, c-Src, CAMKK, CDK1, CDK2, CDK5, CLK, DDR, DYRK1B, EPHA , EPHB, FAK / PTK2, FER, FES / FPS, FGFR, 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, YES / YES1, etc. It 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 are gastric cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, scleroderma, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer , Thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, blood cancer (including leukemia, multiple myeloma, myelodysplastic syndrome), lymphoma (including Hochkin's disease, non-Hodgkin's lymphoma), psoriasis, or fibroadenoma Etc. may be included.

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 to prepare amino acid addition bases are natural amino acids such as alanine, glycine and the like.

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.

In the present invention, the term "halogen atom" 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.

In the present invention, the "haloalkyl group" means an alkyl group in which a hydrogen atom is substituted by one or more halogen atoms, such as 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.

In the present invention, the "aryl group" means a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group having 6 to 15 carbon atoms, including phenyl, naphthyl, anthranilyl, phenanthryl, and the like. do.

In the present invention, the "heteroaryl group" refers to pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadia Zolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, indolyl, isoindolyl, benzofuranyl, benzofurazanyl, dibenzofuranyl, isobenzo Furanyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, dibenzothiophenyl, naphthyridyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxyl It means a 5- to 7-membered monocyclic, bicyclic, or tricyclic aromatic heterohydrocarbon group containing one or more heteroatoms, including salinyl, phthalazinyl, chinolinyl, quinazolinyl, and the like.

In the present invention, the term "heterocycloalkyl group" includes a morpholinyl, piperidine group, piperazinyl, N -protected piperazinyl, and the like, and a 5- to 7-membered aliphatic hetero-containing group containing one or more heteroatoms. It means a hydrocarbon ring group. The N -protecting group of piperazinyl may typically contain an alkyl group.

In the compound represented by the formula (1) according to the present invention, Preferably it is as follows.

X is CH; Or N, wherein P is a hydrogen atom; C ₁ -C ₆ alkyl group; Benzyl group; Trityl group; A phenyl group; Or a 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, G is absent; Or -NHC (O)-; Or -C (O) NH-, L ² is an amino group; Cyclohexylamino group; Phenylamino group; C ₁ -C ₆ alkoxyphenylamino group; Phenylamino group substituted with a substituent selected from halo and haloalkyl; A hydroxyl group; C ₁ -C ₆ alkoxy group; C ₁ -C ₆ alkyl group; Dimethylamino C _{1 to} C ₆ alkyl group; Cyclohexyl group; Dimethylaminocyclohexyl group; A morpholino group; Piperidinyl group; Piperazinyl groups; 4- (C ₁ -C ₆ alkyl) piperazinyl group; A phenyl group; Chlorophenyl group; Fluorophenyl group; 4-chloro-3-trifluoromethylphenyl group; C ₁ -C ₆ alkylphenyl group; C ₁ -C ₆ alkoxyphenyl group; Trifluoromethylphenyl group; Morpholinophenyl group; (4-methylpiperazinyl) phenyl group; (4-ethylpiperazinyl) phenyl group; Aminophenyl group; Dimethylaminophenyl group; Thiophenyl group; Pyridinyl group; (C ₁ -C ₆ alkyl) pyridinyl group; Or a compound showing a morpholino pyridinyl group.

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

5-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -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- 1-yl) benzamide (Compound No. 2);

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

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

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

4-Fluoro- N- (5-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -pyrazolo [3,4- b ] pyridin-3-yl) -benzamide (compound Number 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 Amides (Compound No. 8);

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

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

4- (dimethylamino) - N - (5 - ((3- fluorophenyl) sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-yl) -pentanoic amide (Compound number 13);

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

tert -butyl- (5-((3-fluorophenyl) sulfonyl) -1-trityl- 1H -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-trityl-1 H -pyrazolo [3,4- b ] pyridin-3-yl) -piperidine-1-carboxamide (Compound number 17);

1- (5-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -pyrazolo [3,4- b ] pyridin-3-yl) -3-phenylurea (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);

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

1-cyclohexyl-3- (5-((3-fluorophenyl) 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) benz 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-((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) -3- (trifluoromethyl) 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-fluorophenyl) sulfonyl) -1 H -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) pivalamide (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);

1- (5-((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) -3- (2-methoxyphenyl) urea (Compound No. 39 );

1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (5-((3-fluorophenyl) sulfonyl) -1 H -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 Voxamide (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 -3-carboxamide (Compound No. 43);

N- (4- (4-ethylpiperazin-1-yl) phenyl) -5-((3-fluorophenyl) sulfonyl) -1- (tetrohydro- 2H -pyran-2-yl)- 1 H -indazol-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- (4-chloro-3- (trifluoromethyl) phenyl))-5-((3-fluorophenyl) sulfonyl) -1- (tetrohydro- 2H -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-ethylpiperazin-1-yl) phenyl) -5-((3-fluorophenyl) sulfonyl) -1 H -indazol-3-carboxamide (Compound No. 49);

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

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

On the other hand, the present invention is characterized by a method for producing a compound represented by the formula (1). Hereinafter, the manufacturing method according to the present invention will be described in detail.

Manufacturing Method 1

As represented by Scheme 1, the compound represented by the following Chemical Formula 3, which is a core intermediate, may be subjected to a coupling reaction (eg, Buchwald coupling reaction) using an organometallic compound from the compound represented by the following Chemical Formula 2. Can be prepared.

[Reaction Scheme 1]

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

In the Buchwald coupling reaction performed in the preparation method according to Scheme 1, Pd ₂ (dba) ₃ , Pd (OAc) ₂ , PdCl ₂ (PPh ₃ ) ₂ , Pd (PPh ₃ ) _4, etc. may be used as the metal compound. Can be. As ligand, Xantphos (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 can be used. Examples of the base include organic bases of amines, tamate salts of alkali metals or alkaline earth metals, sulfates, phosphates, alkoxides and the like. As the reaction solvent, a conventional organic solvent containing tetrahydrofuran, dioxane, N, N -dimethylformamide, N, N -dimethylsulfoxide, 2-butanol, 2-pentanol and the like can be used. The reaction temperature is in the range of 50 ° C to 200 ° C, and preferably in the range of 80 ° C to 150 ° C.

Manufacturing Method 2

As represented by Scheme 2 below, the 3-amino-5-substituted 1 H -pyrazolo [3,4- b ] pyridine compound represented by Chemical Formula 6 may be prepared by performing the following three steps. have.

(Step 2-1) preparing a compound represented by the following Chemical Formula 4 by reacting the compound represented by the following Chemical Formula 3 with phosphorus pentoxide (PCl ₅ ) and phosphoryl chloride (POCl ₃ );

(Step 2-2) The compound represented by the following formula (4) is oxidized to convert the sulfide (-S-) group into a sulfinyl (-SO-) or sulfonyl (-SO _2- ) group, represented by the following formula (5). Preparing a compound;

(Step 2-3) preparing a compound represented by the following Chemical Formula 6 by reacting a hydrazine monohydrate with a compound represented by the following Chemical Formula 5;

It can be prepared via.

[Reaction Scheme 2]

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

(In Scheme 2, L ¹ is as defined in the formula (1).)

Manufacturing Method 3

As represented by Scheme 3 below, the 3-amino-5-substituted 1 H -pyrazolo [3,4- b ] pyridine compound represented by Formula 6 may be prepared by performing the following two steps. have.

(Step 3-1) reacting a compound represented by Chemical Formula 3 with phosphorus pentoxide (PCl ₅ ) and phosphoryl chloride (POCl ₃ ) to prepare a compound represented by Chemical Formula 4; And

(Step 2-3) preparing a compound represented by the following formula (6) by reacting the hydrazine monohydrate to the compound represented by the formula (4);

It can be prepared via.

Scheme 3

(In Reaction Scheme 3, L ¹ is as defined in Formula 1).

Manufacturing Method 4

As shown in Scheme 4 below, 1,3,5-trisubstituted 1 H -pyrazolo [3] represented by the following formula (9) in which a P group and a -NHC (O)-group are introduced at a C1 position , 4- b ] pyridine compound can be prepared by performing the following two steps.

(Step 4-1) preparing a compound represented by the following Chemical Formula 8 by reacting the compound represented by the following Chemical Formula 6 with trifluoroacetic anhydride;

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

It can be prepared via.

[Reaction Scheme 4]

(In Scheme 4, L ¹ and P are as defined in Formula 1, X represents a halogen atom or tert -butyl carbonate.)

Manufacturing Method 5

As shown in Scheme 5 below, the compound represented by Formula 1 according to the present invention having various L ² groups introduced at the C3 position may be prepared from the compound represented by Formula 9 by performing the following three steps. Can be.

(Step 5-1) preparing a compound represented by the following Chemical Formula 10 by performing a deprotection reaction using an organic base to the compound represented by the following Chemical Formula 9;

(Step 5-2) preparing a compound represented by the following Chemical Formula 11 by performing a coupling reaction between the compound represented by the following Chemical Formula 10 and the compound represented by L ² -X ¹ ; And

(Step 5-3) preparing a compound represented by the following Chemical Formula 1 by performing a deprotection reaction using an acid with the compound represented by the following Chemical Formula 11;

It can be prepared via.

[Reaction Scheme 5]

(In Scheme 5, L ¹ , L ² , and P are as defined in Chemical Formula 1, and X ¹ represents acyl chloride (C (O) Cl), isocyanate (NCO).)

Manufacturing Method 6

As shown in Scheme 6, the ethyl 5-bromo-1 H -indazole-3-carboxylate compound represented by the following Formula 15 may be prepared by performing the following two steps.

(Step 6-1) preparing a 5-bromo-1 H -indazole-3-carboxylic acid compound represented by the following Chemical Formula 13 from the compound represented by the following Chemical Formula 12;

(Step 6-2) esterifying a 5-bromo- 1H -indazole-3-carboxylic acid compound represented by the following Chemical Formula 13 to prepare an ester compound represented by the following Chemical Formula 14;

(Step 6-3) preparing a compound represented by the following Chemical Formula 15 by reacting an ester compound represented by the following Chemical Formula 14 with a tetrahydropyran compound;

It can be prepared via.

[Reaction Scheme 6]

(In Scheme 6, PTSA represents p- toluenesulfonyl acid and THP represents tetrahydropyran.)

Manufacturing Method 7

As shown in Scheme 7 below, the compound represented by the following Formula 17 having various L ¹ groups introduced at the C5 position may be prepared by performing the following two steps.

(Step 7-1) preparing a compound represented by the following Chemical Formula 16 by performing a Buchwald coupling reaction with the compound represented by the following Chemical Formula 15; And

(Step 7-2) The compound represented by the following formula (16) is oxidized to convert the sulfide (-S-) group into a sulfinyl (-SO-) or sulfonyl (-SO _2- ) group, represented by the following formula (17). Preparing a compound;

≪ / RTI >

[Reaction Scheme 7]

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

Manufacturing Method 8

As represented by the following Scheme 8, the compound represented by the formula (20) in which the -C (O) NH- group is introduced at the C3 position is prepared by performing the following two-step process from the ester compound represented by the formula (17) can do.

(Step 8-1) 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) preparing a compound represented by the following Chemical Formula 19 by carrying out an amide bond reaction with various amine compounds of the carboxylic acid compound represented by the following Chemical Formula 18;

(Step 8-3) preparing a compound represented by the following Chemical Formula 20 by performing a deprotection reaction on the compound represented by the following Chemical Formula 19;

≪ / RTI >

[Reaction Scheme 8]

(In Scheme 8, L ¹ and R ² are as defined in Formula 1, 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 Chemical Formula 1 exhibits excellent inhibitory activity on protein kinases, it may be used as an agent for preventing or treating a disease caused by abnormal cell growth.

The protein kinase is for example ABL, ACK1, ALK, Aurora A, Aurora B, Aurora C, BLK, BMX / ETK, BRSK1, BTK, c-Src, CAMKK, CDK1, CDK2, CDK5, CLK, DDR, DYRK1B, EPHA, EPHB, FAK / PTK2, FER, FES / FPS, FGFR, 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, YES / YES1 and the like.

Diseases caused by abnormal cell growth in the present invention are, for example, stomach cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerotic adenocarcinoma, uterine cancer, cervical cancer, head and neck cancer, Various cancers, such as esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, leukemia, multiple myeloma, myelodysplastic syndrome, lymphomas such as Hochkin's disease and non-Hodgkin's lymphoma, or fibroadenoma 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.

Excipients that may be used in the pharmaceutical compositions of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances and the like. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth rubber, arginine acid, sodium Alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, 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 based on the following Examples, Preparation Examples, and Experimental Examples. The following Preparation Examples, Examples, Preparation Examples, and Experimental Examples are merely illustrative of the present invention. The scope of the invention is not limited by these.

[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

Compound of Example 1 represented by the above structural formula can be prepared through the 11-step synthesis process as follows.

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

To 2-chloronicotinonitrile (7.25 g, 0.052 mol) was added acetic acid (45 mL). Stir at 130 ° C for 24 h and cool to 0 ° C. The mixture was filtered, washed with acetic acid and water and dried at room temperature to obtain the target 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

To 2-oxo-1,2-dihydropyridine-3-carbonitrile (6.28 g, 0.052 mol) was added acetic acid (34 mL) and warmed to 130 ° C. When the solid was dissolved bromine (12.5 g, 0.078 mol) was slowly added and stirred at the same temperature for 3 hours. After cooling the reaction solution to room temperature, dichloromethane and water were added. The organic layer was separated and the aqueous layer was washed with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the target 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-carbonitrile

In a closed container, 5-bromo-2-oxo-1,2-dihydropyridine-3-carbonitrile (800 mg, 4.00 mmol), Xantphos (116 mg, 0.2 mmol), Pd ₂ (dba) ₃ (92 mg , 0.1 mmol) and 1,4-dioxane (8.4 mL) were added. The gas in the mixed solution was removed using ultrasonic waves and nitrogen gas. Diisopropylethylamine (1.4 mL, 8.00 mmol) and 3-fluorothiophenol (0.34 mL, 4.00 mmol) were added, sealed, and 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. Water was added to the organic layer and extracted. The organic layer was separated and the water 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 afford 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 + l]

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

5-((3-fluorophenyl) thio) -2-oxo-1,2-dihydropyridine-3-carbonitrile (2.283 g, 9.27 mmol) and phosphorus pentachloride (5.43 g, 26.00 mmol) were added to the reaction vessel. And nitrogen gas was blown. Phosphoryl chloride (11.2 mL, 120.50 mmol) was added to the mixture, followed by stirring under reflux for 5 hours. The reaction 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 combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the target 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

To the reaction vessel was added 2-chloro-5-((3-fluorophenyl) thio) nicotinonitrile (2.165 g, 8.179 mmol) and 40 mL of dichloromethane. 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, cooled to 0 ° C., and 30 mL of 10% aqueous sodium sulfite solution was added thereto, followed by stirring. The aqueous layer was removed and the organic layer was collected and washed sequentially with 40 mL of 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 target 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-3-amine

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 stirred at 80 ° C for 30 minutes. The reaction solution was cooled to room temperature and concentrated to give the target 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) and tetrahydrofuran (24 mL) were added. Added and stirred. The mixture was cooled to 0 ° C. and trifluoroacetic anhydride (0.83 mL, 6.00 mmol) was added. The reaction solution was stirred at room temperature for 1 hour, concentrated and methanol (5 mL) was added to the residue to give the target compound (700 mg, 90% yield) as a yellow solid. The target 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 Acylamide

2,2,2-trifluoro-to the reaction vessel - N - (5 - (( 3- fluorophenyl) sulfonyl) -1 H - pyrazolo [3,4- b] pyridin-3-yl) acetamide (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 ° C., triphenylmethyl chloride (502 mg, 1.80 mmol) was added, and stirred at room temperature for 18 hours. Dichloromethane (5 mL) and saturated sodium carbonate solution (10 mL) were added to the reaction mixture, followed by stirring. The aqueous layer was washed twice with dichloromethane (10 mL). The combined organic layers were 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 target compound (766 mg, 67% yield) as a yellow solid. It was.

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 + 1]

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

2,2,2-trifluoro- N- (5-((3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4- b ] pyridine-3 in the reaction vessel -Yl) acetamide (231 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 mixed solution, which was warmed to 100 ° C 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 target compound (100 mg, 50% yield) as a yellow solid. .

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 + l].

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., oxalylchloride (0.36 mL, 4.0 mmol) was added and stirred at room temperature. The reaction solution was concentrated and the target compound (76 mg, 80% yield) was used for the next reaction without purification.

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

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

5-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -pyrazolo [3,4- b ] pyridin-3-amine (53 mg, 0.1 mmol), dimethylaminopyridine (5 mg, 0.04 mmol) and pyridine (3.2 mL) were added and stirred at 0 ° C. 4- (4-methylpiperazin-1-yl) benzoyl chloride (33 mg, 0.14 mmol) was added and 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 combined organic layers were 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 target compound (25 mg, 39% yield) as a 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, 1H), 7.86 (m, 1H), 7.66 (m, 2H), 7.56 (m, 2H), 7.10 (m, 15H), 6.99 (s, 2H), 2.88 (m, 4H), 2.44 (m, 4H ), 2.22 (s, 3 H), MS m / z: 737.27 [M + l].

Examples 2-16

As shown in the following chemical scheme, 5-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -pyrazolo [3,4- synthesized in step 9 of the compound preparation process of Example 1 b ] The desired compounds of Examples 2 to 16 can be synthesized through the coupling reaction between pyridin-3-amine and various acyl chloride compounds. The preparation method of the coupling reaction is the same as in step 11 of the compound preparation process of Example 1.

Example 2 N- (5-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -pyrazolo [3,4- b ] pyridin-3-yl) -3- (trifluoro Rhomethyl) benzamide

MS m / z: 707.17 [M + 1]

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

MS m / z: 669.19 [M + 1]

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

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

Example 5: 4-Fluoro- N- (5-((3-fluorophenyl) sulfonyl) -1-trityl-1 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) -benz 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 Sun) -benzamide

MS m / z: 695.24 [M + 1]

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

MS m / z: 724.23 [M + l]

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) -cyclohexanecarboxamide

MS m / z: 645.23 [M + 1]

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

MS m / z: 619.21 [M + l]

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

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

MS m / z: 634.21 [M + 1]

Example 15 N- (5-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -pyrazolo [3,4- b ] pyridin-3-yl) -thiophen-2- Carboxamide

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

Example 16 N- (5-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -pyrazolo [3,4- b ] pyridin-3-yl) -piperidine-1 Carboxamide

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

Example 17 1- (5-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -pyrazolo [3,4- b ] pyridin-3-yl) -3-phenylurea

THF of 5-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -pyrazolo [3,4- b ] pyridin-3-amine (53 mg, 0.1 mmol) in a reaction vessel (1 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]

As shown in the following chemical scheme, 5-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -pyrazolo [3,4- synthesized in step 9 of the compound preparation process of Example 1 b ] The desired compounds of Examples 18 to 20 can be synthesized through the coupling reaction between pyridin-3-amine and various isocyanate compounds. The preparation method of this coupling reaction is the same as the preparation of the compound of Example 17.

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-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -pyrazolo [ 3,4- b ] pyridin-3-yl) urea

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

Example 20 1-cyclohexyl-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-((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) -4- (4-methylpiperazin-1 Benzamide

N- (5-((3-fluorophenyl) sulfonyl) -1-trityl- 1H -pyrazolo [3,4- b ] pyridin-3-yl) -4- (4-methyl in the reaction vessel Piperazin-1-yl) benzamide (22 mg, 0.03 mmol) and dichloromethane (1 mL) were added and stirred at 0 ° C. Trifluoroacetic acid (0.06 mL) was added to the mixture, and stirred for 18 hours at room temperature. The reaction solution was concentrated and the residue was purified by column chromatography (silica gel, dichloromethane: methanol = 20: 1 to 10: 1) to obtain the target compound (10 mg, 67% yield) as a 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, 1H), 7.56 (m, 1H), 7.02 (d, J = 9.08 Hz, 2H), 2.49 (m, 4H), 2.44 (m, 4H), 2.23 (s, 3H), MS m / z: 495.16 [M + 1].

As shown in the following chemical reaction scheme, the compounds of Examples 1 to 20 may be subjected to a deprotection reaction to synthesize target compounds of Examples 22 to 40. The preparation method of this coupling reaction is the same as the preparation of the compound of Example 21.

Example 22 N- (5-((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) -4- (4-methylpiperazin-1 -Yl) -4-methoxybenzamide

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 + l].

Example 24 N- (5-((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) benzamide

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

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 + l].

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

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

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 + l].

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

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

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 + l].

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

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

Example 31 N- (5-((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) pivalamide

MS m / z: 377.10 [M + 1].

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

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

Example 33 ethyl- (5-((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) carbamate

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

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 + l].

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-phenylurea

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

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 + l].

Example 39 1- (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 + l].

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

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

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

Compound of Example 41 represented by the above structural formula can be prepared through a nine-step synthesis process as follows.

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

6-bromoissatin (10.0 g, 22 mmol) and 1 N aqueous NaOH solution (48 mL) were added to the reaction vessel, which was then heated to 50 ° C. and stirred for 1 hour. The reaction solution was cooled to 0 ° C. and a mixture of sodium nitrite (3.0 g, 22 mmol) and water (11 mL) was slowly added. Water (90 mL) and sulfuric acid (4.6 mL) were slowly added to the mixture at the same temperature and stirred. A mixture of tin chloride dihydrate (24.0 g, 53 mmol) and hydrochloric acid (40 mL) was added to the reaction solution at 0 ° C., and 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: ethyl 6-bromo-1 H -indazol-3-carboxylate

6-Bromo- 1H -indazole-3-carboxylic acid (5.0 g, 21 mmol) and ethanol (100 mL) were added to the reaction vessel, followed by stirring. Sulfuric acid (5 mL) was added to the mixture, followed by stirring under reflux. The reaction solution was cooled to room temperature and concentrated. Ethyl acetate and saturated sodium bicarbonate solution were added to the residue, followed by stirring. 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 give the target 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: ethyl 5-bromo-1- (tetrahydro-2 H -pyran-2-yl) -1 H -indazol-3-carboxylate

Ethyl 6-bromo-1 H -indazole-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. P - toluenesulfonic acid (0.31 g, 1.8 mmol) was added to the mixture, and the mixture was stirred at room temperature. The reaction solution 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 a 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, 2H), 3.88 (m, 1H), 3.79 (m, 1H), 2.33 (m, 1H), 2.00 (m, 2H), 1.75 (m, 1H), 1.60 (m, 2H), 1.37 (t, 3H) ).

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

In an airtight container, 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), 1,4-dioxane (2 mL) was added. The gas in the mixed solution was removed 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 sealed and 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. Water was added to the organic layer and extracted. The organic layer was separated and the water 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 target 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, 1H), 3.79 (m, 1H), 2.36 (m, 1H), 2.03 (m, 2H), 1.76 (m, 1H) ), 1.60 (m, 2 H), 1.32 (t, 3 H).

Step 5: Ethyl 5-((3-fluorophenyl) sulfonyl) -1- (tetrahydro- 2H -pyran-2-yl) -1 H -indazol-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) , Dichloromethane (2 mL) was 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 mixture, and the mixture was cooled to 0 ° C., followed by addition of 10% aqueous sodium sulfite solution (3 mL), followed by stirring. The aqueous layer was removed, the organic layers were collected and washed sequentially with saturated aqueous sodium carbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the target 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), 4.45 (m, 2H), 3.87 (m, 1H), 3.78 (m, 1H), 2.34 (m, 1H), 2.02 (m, 2H), 1.74 (m, 1H), 1.60 (m, 2H), 1.40 (t, 3H).

Step 6: 5-((3-fluorophenyl) sulfonyl) -1- (tetrahydro- 2H -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), methanol (1 mL) was added. Lithium hydroxide hydrate (28 mg, 0.66 mmol) was added to the mixture, and the mixture was stirred at 55 ° C. for 16 hours. The reaction solution was cooled to room temperature and concentrated. 1 N hydrochloric acid solution was slowly added to the residue to make pH 5. Ethyl acetate and brine were added and stirred. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to give the target compound (120 mg, 98% yield) as a white solid. The target compound was used for the next reaction without purification.

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

Step 7: 4- (4-nitrophenyl) morpholine

1-fluoro-4-nitrobenzene (1 g, 7.09 mmol) and dimethylformamide (10 mL) were added to the reaction vessel. Morpholine (0.62 g, 7.09 mmol) and potassium carbonate (1.96 g, 14.17 mmol) were added to the mixture, and the mixture was warmed and stirred 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. Drying with anhydrous magnesium sulfate and concentration gave 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 + l].

Step 8: 4-morpholinoaniline

4- (4-nitrophenyl) morpholine (1 g, 4.80 mmol) and methanol (30 mL) were added to the reaction vessel. 10% Pd / C (100 mg) was added to the mixture, 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 desired compound (728 mg, 85% yield) was used in the next reaction without purification.

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

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

5-((3-fluorophenyl) sulfonyl) -1- (tetrahydro- 2H -pyran-2-yl) -1 H -indazole-3-carboxylic acid (40 mg, 0.1 mmol) in the reaction vessel, 4-morpholinoaniline (29 mg, 0.16 mmol), diisopropylethylamine (0.035 mL, 0.2 mmol), 1-hydroxybenzotriazole monohydrate (19 mg, 0.12 mmol) and dichloromethane (2 mL) Put and stir. 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI ?? HCl, 23 mg, 0.12 mmol) was added and stirred at room temperature. The reaction was diluted with dichloromethane (10 mL), water (10 mL) was added and 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 target 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, 1H), 7.22 (m, 1H), 6.97 (m, 2H), 5.81 (m, 1H), 4.15 (m, 1H), 3.90 (m, 4H), 3.81 (m, 1H), 3.20 (m, 4H ), 2.58 (m, 1H), 2.17 (m, 2H), 1.81 (m, 3H), MS m / z: 565.19 [M + 1].

5-((3-fluorophenyl) sulfonyl) -1- (tetrahydro- 2H -pyran-2-yl) -1 H -indazole- synthesized in step 6 of the compound preparation of Example 41 above The desired compounds of Examples 42 to 45 can be synthesized through the coupling reaction between 3-carboxylic acid and various aniline compounds. The preparation method of this coupling reaction is the same as the preparation of the compound of Example 40.

Example 42: 5 - ((3-fluorophenyl) sulfonyl) - N - (6- Reno Dimorpholino-3-yl) -1- (tetrahydro -2 H in Tet-pyran-2-yl) -1 H -indazol-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, 1H), 7.49 (m, 1H), 7.22 (m, 1H), 6.73 (m, 1H), 5.82 (m, 1H), 4.15 (m, 1H), 3.90 (m , 4H), 3.81 (m, 1H), 3.20 (m, 4H), 2.58 (m, 1H), 2.18 (m, 2H), 1.80 (m, 3H), MS m / z: 566.18 [M + 1] .

Example 43 N- (4- (4-ethylpiperazin-1-yl) phenyl) -5-((3-fluorophenyl) sulfonyl) -1- (tetrohydro- 2H -pyran-2 -Yl) -1 H -indazole-3-carboxamide

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

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- (trifluoromethyl) phenyl))-5-((3-fluorophenyl) sulfonyl) -1- (tetrohydro- 2H -pyran- 2-yl) -1 H -indazol-3-carboxamide

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

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), p- toluenesulfonic acid monohydrate (233 mg, 1.23 mmol) and ethanol (4.8 mL) were added thereto and stirred. Acetic acid (2.2 mL) was added to the mixed solution, which was then heated to 80 ° 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 target 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 (m, 2H), 3.75 (m, 4H), 3.09 (m, 4H), MS m / z: 481.13 [M + 1 ].

The compounds of Examples 42 to 46 can synthesize the target compounds of Examples 47 to 50 through a deprotection reaction. The preparation method of this coupling reaction is the same as the preparation of the compound of Example 46.

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), 7.86 (m, 3H), 7.69 (m, 1H), 7.56 (m, 1H), 6.88 (m, 1H), 3.72 (m, 4H), 3.42 (m, 4H), MS m / z: 482.13 [M +1].

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

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

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

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

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 Tablets (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 Powders and Capsules

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

As a representative compound according to the present invention, N- (5-((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) -4- (4-methylpipepe The inhibitory activity (% inhibition) of various protein kinases was measured for razin-1-yl) benzamide (Compound No. 22, Example 21) and is shown in Table 1 below.

Kinase % Low resolution (1 uM) Kinase % Low resolution (1 uM) ABL1 96 FLT3 97 ABL2 / ARG 96 FLT4 / VEGFR3 71 ACK1 100 FMS 96 ALK 92 FRK / PTK5 91 Aurora A 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 Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof:
[Chemical Formula 1]

In Formula 1,
X is CH; Or N,
P is a hydrogen atom; A C ₁ -C ₁₀ alkyl group; C ₁ -C ₁₀ alkyl group substituted with 1 to 3 phenyl; A phenyl group; Or a 5 to 7 heterocyclic alkyl group containing an oxygen atom,
L ¹ is -SR ¹ ; -S (O) R ¹ ; Or -S (O) ₂ R ¹ ,
G is absent; Or -NHC (O)-; Or -C (O) NH-,
L ² is -NHR ² ; -OR ³ ; C ₁ -C ₁₀ alkyl group unsubstituted or substituted with R ⁴ ; C ₃ -C ₁₀ cycloalkyl group unsubstituted or substituted with R ⁵ ; A 5 to 7 hexagonal heterocycloalkyl group which may be unsubstituted or substituted with R ⁶ , and contains 1 to 2 nitrogen atoms; C ₆ -C ₁₅ aryl group unsubstituted or substituted with R ⁷ ; Or it may be substituted or unsubstituted with R ⁸ and represents a 5 to 7 heteroaryl group containing 1 to 3 heteroatoms selected from a sulfur atom and a nitrogen atom,
R ¹ is a hydrogen atom; Or a C ₆ to C ₁₅ aryl group unsubstituted or substituted with 1 to 3 halogen atoms,
R ² is a hydrogen atom; C ₁ -C ₁₀ alkyl group; C ₃ -C ₁₀ cycloalkyl group; Or a phenyl group unsubstituted or substituted with a substituent selected from halo, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, and C ₁ -C ₁₀ haloalkyl substituted with 1 to 10 halogen,
R ³ is a hydrogen atom; Or a C _{1 to} C ₁₀ alkyl group,
R ⁴ and R ⁵ are the same as or different from each other and an amino group; Mono (C ₁ -C ₁₀ alkyl) amino group; Or a di (C ₁ -C ₁₀ alkyl) amino group,
R ⁶ is a hydrogen atom; Or a C _{1 to} C ₆ alkyl group,
R ⁷ is Halogen atom; C ₁ -C ₁₀ alkyl group; C ₁ -C ₁₀ alkoxy group; Haloalkyl group substituted with 1 to 10 halogens; A 5 to 7 hexagonal heterocycloalkyl group which may be unsubstituted or substituted with a C _{1 to} C ₁₀ alkyl group and contains 1 to 3 heteroatoms selected from an oxygen atom and a nitrogen atom; An amino group; Mono (C ₁ -C ₁₀ alkyl) amino group; Or a di (C ₁ -C ₁₀ alkyl) amino group,
R ⁸ is a C ₁ -C ₁₀ alkyl group; Or a 5 to 7 hexagonal heterocycloalkyl group including 1 to 3 heteroatoms selected from an oxygen atom and a nitrogen atom.
The method according to claim 1,
X is CH; Or N,
P is a hydrogen atom; C ₁ -C ₆ alkyl group; Benzyl group; Trityl group; A phenyl group; Or a 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,
G is absent; Or -NHC (O)-; Or -C (O) NH-,
L ² is an amino group; Cyclohexylamino group; Phenylamino group; C ₁ -C ₆ alkoxyphenylamino group; Phenylamino group substituted with a substituent selected from halo and haloalkyl; A hydroxyl group; C ₁ -C ₆ alkoxy group; C ₁ -C ₆ alkyl group; Dimethylamino C _{1 to} C ₆ alkyl group; Cyclohexyl group; Dimethylaminocyclohexyl group; A morpholino group; Piperidinyl group; Piperazinyl groups; 4- (C ₁ -C ₆ alkyl) piperazinyl group; A phenyl group; Chlorophenyl group; Fluorophenyl group; 4-chloro-3-trifluoromethylphenyl group; C ₁ -C ₆ alkylphenyl group; C ₁ -C ₆ alkoxyphenyl group; Trifluoromethylphenyl group; Morpholinophenyl group; (4-methylpiperazinyl) phenyl group; (4-ethylpiperazinyl) phenyl group; Aminophenyl group; Dimethylaminophenyl group; Thiophenyl group; Pyridinyl group; (C ₁ -C ₆ alkyl) pyridinyl group; Or a morpholino pyridinyl group.
The method according to claim 1,
5-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -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- 1-yl) benzamide (Compound No. 2);
N- (5-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -pyrazolo [3,4- b ] pyridin-3-yl) -3- (trifluoromethyl) benz Amides (Compound No. 3);
N- (5-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -pyrazolo [3,4- b ] pyridin-3-yl) -4-methoxybenzamide (Compound No. 4);
N- (5-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -pyrazolo [3,4- b ] pyridin-3-yl) -benzamide (Compound No. 5);
4-Fluoro- N- (5-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -pyrazolo [3,4- b ] pyridin-3-yl) -benzamide (compound Number 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 Amides (Compound No. 8);
N- (5-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -pyrazolo [3,4- b ] pyridin-3-yl) -4-morpholinobenzamide (Compound No. 9);
4- (dimethylamino) - N - (5 - ((3- fluorophenyl) sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-yl) -benzamide (Compound number 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) Amides (Compound No. 12);
4- (dimethylamino) - N - (5 - ((3- fluorophenyl) sulfonyl) -1-trityl -1 H-pyrazolo [3,4- b] pyridin-3-yl) -pentanoic amide (Compound number 13);
Ethyl- (5-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -pyrazolo [3,4- b ] pyridin-3-yl) -carbamate (Compound No. 14);
tert -butyl- (5-((3-fluorophenyl) sulfonyl) -1-trityl- 1H -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-trityl-1 H -pyrazolo [3,4- b ] pyridin-3-yl) -piperidine-1-carboxamide (Compound number 17);
1- (5-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -pyrazolo [3,4- b ] pyridin-3-yl) -3-phenylurea (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);
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (5-((3-fluorophenyl) sulfonyl) -1-trityl-1 H -pyrazolo [3,4- b ] pyridin-3-yl) urea (Compound No. 20);
1-cyclohexyl-3- (5-((3-fluorophenyl) 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) benz 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-((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) -3- (trifluoromethyl) 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-fluorophenyl) sulfonyl) -1 H -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) pivalamide (Compound No. 32);
N- (5-((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) pentanamide (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);
1- (5-((3-fluorophenyl) sulfonyl) -1 H -pyrazolo [3,4- b ] pyridin-3-yl) -3- (2-methoxyphenyl) urea (Compound No. 39 );
1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (5-((3-fluorophenyl) sulfonyl) -1 H -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 Voxamide (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 -3-carboxamide (Compound No. 43);
N- (4- (4-ethylpiperazin-1-yl) phenyl) -5-((3-fluorophenyl) sulfonyl) -1- (tetrohydro- 2H -pyran-2-yl)- 1 H -indazol-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- (4-chloro-3- (trifluoromethyl) phenyl))-5-((3-fluorophenyl) sulfonyl) -1- (tetrohydro- 2H -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-ethylpiperazin-1-yl) phenyl) -5-((3-fluorophenyl) sulfonyl) -1 H -indazol-3-carboxamide (Compound No. 49);
5 - ((3-fluorophenyl) sulfonyl) - N - (6- methylpyridin-3-yl) -1 H-indazole-3-carboxamide (Compound No. 50); And
N- (4-chloro-3- (trifluoromethyl) phenyl) -5-((3-fluorophenyl) sulfonyl) -1 H -indazole-3-carboxamide (Compound No. 51);
Compounds characterized in that selected from.
A pharmaceutical composition for preventing and treating cancer diseases containing the compound of any one of claims 1 to 3 as an active ingredient.
The method of claim 4,
A pharmaceutical composition for preventing and treating cancer diseases having inhibitory activity against protein kinases.
The method of claim 4,
The cancer diseases include stomach cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosis, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, Pharmaceutical composition for the prevention and treatment of cancer diseases, characterized in that selected from prostate cancer, urethral cancer, bladder cancer, hematologic cancer, lymphoma, psoriasis, or fibroadenoma.