KR20120038033A - 1h-indazole compounds having gsk-3 inhibitory activity - Google Patents

Abstract

PURPOSE: A 1H-indazole compound with GSK3 inhibition and pharmaceutically acceptable salt thereof are provided to be used as a therapeutic agent for treating diseases caused by GSK-3 activation. CONSTITUTION: A 1H-indazole compounds is denoted by chemical formula 1. A method for preparing the compound comprises: a step of performing amidation of 3-amino-1H-indazole compounds of chemical formula 2 and a substituted carboxylic acid compound of chemical formula 3 under the presence of pyridine base and 1-ethyl-3-(3'-dimethyl aminopropyl)carbodiimide hydrochloride(EDCI).

Description

1H-Indazole compounds having GSK-3 inhibitory activity

The present invention relates to a 1 H -indazole compound exhibiting inhibitory activity against GSK-3, a pharmaceutically acceptable salt thereof, a method for preparing these compounds, and a pharmaceutical composition containing these compounds as an active ingredient.

Protein kinases are enzymes that mediate intracellular signal transduction by delivering and phosphorylating phosphoryl groups derived from nucleoside triphosphate (NTP) to specific proteins. Numerous types of protein kinases have been reported according to signaling pathways, and the activation of signaling pathways has been known to produce proliferation factors or cytokines to regulate cell proliferation, differentiation and death. Schlessinger et al., Neuron, 9, 383, 1992]

Abnormal cellular responses triggered by protein kinase-mediated phenomena are directly related to disease induction. These diseases include autoimmune diseases, inflammatory diseases, metabolic diseases, neurological diseases, neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, Alzheimer's disease, hormone-related diseases and the like. Therefore, considerable efforts have been made in the medical and chemical fields to develop protein kinase inhibitors.

Glycogen synthase kinase-3 (GSK-3), which represents a protein kinase, has been identified as two types of isoforms, type α and β, encoded by genes that are distinguished as serine / threonine protein kinases, respectively. Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kim and Kimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)] Abnormal behavior of certain cellular signaling pathways in which GSK-3 plays a role can be attributed to diabetes, Alzheimer's disease, CNS disorders (eg, mood swings, neurodegenerative disorders). It is known to be associated with diseases such as cardiomyocyte hypertrophy. International Publication Nos. WO 99/65897, WO 00/38675; Kaytor and Orr, Curr. Opin. Neurobiol., 12, 275-8 (2000); Haq et al., J. Cell Biol., 151, 117-30 (2000); Eldar-Finkelman, Trends Mol. Med., 8, 126-32 (2002)]

More detailed description of the disease associated with GSK-3 is as follows.

GSK-3 inhibitors are effective for improving glucose tolerance, type 1 diabetes, type 2 diabetes or complications thereof. Type 1 diabetes is caused by the autoimmune destruction of β cells, which are insulin-producing cells of the pancreas, resulting in a deficiency of insulin. Therefore, type 1 diabetes patients need to routinely administer insulin to maintain life. Type 2 diabetes is a multifactorial disease, and hyperglycemia occurs due to insulin resistance in the liver, skeletal muscle and adipose tissue and the lack of insulin secretion from the pancreas. GSK-3 phosphorylates glycogen synthase to inhibit glycogen accumulation on peripheral tissues, thereby lowering insulin reactivity and increasing blood glucose.

Recently, GSK-3 has been expressed in skeletal muscle of type 2 diabetic patients, and it has been reported that reverse correlation between skeletal muscle GSK-3α activity and insulin action is recognized. [Diabetes, United States, 2000, 49, p.263] Overexpression of GSK-3β and active GSK-3β variants (S9A, S9E) in HEK-293 cells inhibits glycogen synthase activity. Proc. Natl. Acad. Sci., USA, 1996, Volume 93, p.10228] Overexpression of GSK-3β in CHO cells expressing the insulin receptor and insulin receptor substrate 1 (IRS-1) results in a decrease in insulin action. Proc. Natl. Acad. Sci., USA, 1997, Vol. 94, p.9660] Recent studies using C57BL / 6J mice showing a tendency to obesity diabetes have shown a clear association between GSK-3 hyperactivity and progression of insulin resistance / type 2 diabetes. Done [Diabetes, USA, 1999, Vol. 48, p.1662] In addition, lithium salt as a drug that inhibits GSK-3 activity lowers blood glucose levels in both type 1 and type 2 diabetic patients to improve the condition. Is reported. Proc. Natl. Acad. Sci., USA, 1996, Vol. 93, p. 8455; Biol. Trace Elements Res., 1997, Vol. 60, p. 131]

According to the data reported above, GSK-3 inhibitors are effective in improving glucose tolerance, type 1 diabetes, type 2 diabetes or complications thereof.

GSK-3 is also effective for treating diseases associated with myocardial infarction. See, Jonassen et al., Circ Res, 89: 1191, 2001 (reduction of myocardial infarction by insulin administration in reperfusion is mediated through Akt dependent signaling pathways); Matsui et al., Circulation, 104: 330, 2001 (Akt activation preserves cardiac function and prevents cardiomyocyte damage after transient cardiac ischemia in vivo); Miao et al., J. Mol. CellCardiol, 32: 2397, 2000 (intracoronary, adenovirus-mediated Akt gene delivery in the heart reduced overall infarct size after ischemic-reperfusion injury in vivo); And Fujio et al., Circulation et al., 101: 660, 2000 (Akt signaling inhibits cardiomyocyte apoptosis in vitro and defends ischemic-reperfusion injury in mouse heart).

GSK-3 is also involved in the progression of Alzheimer's disease. Alzheimer's disease is characterized by the formation of senile plaques by deposition of amyloid beta peptides (Aβ) in the brain, followed by the formation of neuronal fiber changes. These changes lead to the massive death of neurons leading to dementia symptoms. GSK-3 is involved in aberrant phosphorylation of tau protein following neuronal fiber changes during the development of this condition. [Acta Neuropathol., 2002, Vol. 103, p.91] It has also been reported that inhibitors of GSK-3 prevent neuronal cell death. [J. Neurochem., 2001, Vol. 77, p. 94] From these facts, GSK-3 inhibitors are effective in improving Alzheimer's dementia.

GSK-3 inhibitors are effective in diseases involving neuronal cell death. GSK-3 inhibitors have been reported to inhibit neuronal cell death, particularly neuronal cell death caused by overexcitation through glutamic acid. Proc. Natl. Acad. Sci., USA, 1998, Vol. 95, p.2642; J. Neurochem., 2001, Vol. 77, p.94]. This suggests that GSK-3 inhibitors are effective in the treatment of bipolar mood disorder (manic-depressive disease), epilepsy or the majority of degenerative brain diseases and neurological diseases. . Examples of neurodegenerative diseases include AIDS encephalopathy, Huntington's disease, Parkinson's disease, Amyotrophic lateral sclerosis, multiple sclerosis, Pick's disease, advanced nucleus palsy, and the like, in addition to Alzheimer's disease described above. In addition, glutamic acid is considered to be a disorder of the brain in stroke (cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage), traumatic brain and spinal cord injury, bacterial and viral infections, and GSK-3 inhibitors may be useful for these diseases. It is expected to be. These are all diseases that involve the death of nerve cells. At present, no drug effectively inhibits neuronal cell death. In view of the above, the GSK-3 inhibitor is considered to be an effective drug for improving various neurodegenerative diseases, bipolar emotional disorders (manic-depressive diseases), epilepsy, stroke, and traumatic brain and spinal cord injury.

GSK-3 inhibitors are also effective for the treatment of inflammatory diseases. Studies on fibroblasts derived from GSK-3β knockout mice suggest that GSK-3β positively regulates the activity of the transcription factor NFκB. [Nature, 2000, 406, p. 86] NFκB is responsible for cellular response to numerous inflammatory stimuli. In view of the above, GSK-3 inhibitors negatively regulate NFκB activity, thereby inducing inflammatory diseases such as deformable arthrosis, rheumatism, atopic dermatitis, psoriasis, ulcerative colitis, clonal disease, sepsis, and systemic inflammatory response syndrome. It is thought to be effective medicine for the treatment of.

In addition, GSK-3, which is involved in mitosis, is known to be overexpressed in cancer cells such as breast, colon, pancreas and ovarian, and oncoprotein. Suspected. Carvajal RD et al., Clin. Cancer Res., 12 (23), 6869-75, 2006] Recently, Aurora kinase inhibitors developed by Vertex, USA, have been reported to inhibit tumors in nude mice. Elizabeth A Harrington et al., Nature Medicine, 10, 262-267, 2004

To date, GSK-3 inhibitors include hymenialdisine derivatives [Chmistry & Biology, 2000, Vol. 7, p.51 and International Publication No. 01/41768], maleimide derivatives [Chmistry & Biology , 2000, Vol. 7, p.793], Paulone Derivatives [Eur. J. Biochem., 2000, 267, p.5983 and International Patent Publication No. WO01 / 60374], Purine derivatives [International Patent Publication No. WO98 / 16528], Pyrimidine and pyridine derivatives [International Patent Publication WO99 / 65897] , Hydroxyflavone derivatives [WO00 / 17184], pyrimidone derivatives [WO00 / 18758, WO01 / 70683, WO01 / 70729, WO01 / 70728, WO01 / 70727, WO01 / 70726] No. WO01 / 70725], pyrrole-2,5-dione derivatives [WO 00/21927 and WO01 / 74771], diamino-1,2,4-triazole-carboxylic acid derivatives [International Patent Publication WO01 / 09106], Pyrazine Derivatives [International Patent Publication WO01 / 44206], Binary Inhibitor [International Patent Publication WO01 / 44246], Indirubine Derivative [International Patent Publication WO01 / 37819], Carboxamide derivatives [WO 01/42224], Peptide inhibitors [WO 01/49709], 2,4-Diaminothiazole derivatives [WO 01/56567], Thiadiazole Dinda ion derivatives have been reported including [International Patent Publication WO01 / 85685 No.], aromatic amide derivatives International Patent Publication WO01 / 81345 Ho.

The present invention aims to provide a 1 H -indazole compound of novel structure and a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preparing the 1 H -indazole compound by amidation reaction between a 3-amino-1 H -indazole compound and a substituted carboxylic acid compound.

In addition, the present invention is another object to provide a pharmaceutical composition containing the 1 H -indazole compound and a pharmaceutically acceptable salt thereof as an active ingredient.

It is another object of the present invention to provide a GSK-3 inhibitor containing the 1 H -indazole compound and a pharmaceutically acceptable salt thereof as an active ingredient.

In order to realize the above object, the present invention is characterized by a 1 H -indazole compound represented by the following formula (1) having a GSK-3 inhibitory activity, a method for preparing the compound, and a pharmaceutical composition comprising the compound.

In Chemical Formula 1,

R ¹ represents a formamido group, a C ₁ -C ₆ alkylamido group, or a furanyl group; R ² and R ³ are the same or different and represents hydrogen atom, or _{- (CH 2) m -C (} O) -X- (CH 2) _n -R ⁴ represents, but R ² and R ³ are hydrogen atoms at the same time Except if; R ⁴ represents a hydrogen atom, a C ₁ -C ₆ alkylamino group, a di (C ₁ -C ₆ alkyl) amino group, or a heterocyclic group consisting of 5 to 10 atoms including one or two heteroatoms selected from oxygen and nitrogen, wherein Heterocyclic groups may be unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halo, C ₁ -C ₆ alkyl, phenyl, and phenyl substituted with halo or C ₁ -C ₆ alkyl; X is a single bond or represents an oxazolenyl group or an isooxazolenyl group; m and n are the same as or different from each other and represent an integer of 0 to 6.

The 1 H -indazole compound represented by Formula 1 according to the present invention has an inhibitory activity against GSK-3.

Therefore, the compound of the present invention is a disease caused by the activity of GSK-3, for example abnormal glucose tolerance, type 1 diabetes, type 2 diabetes, diabetic complications (retinopathy, nephropathy, neuropathy, macrovascular disorders, etc.) ), Alzheimer's disease, neurodegenerative diseases (AIDS encephalopathy, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis pick disease, progressive nucleolar palsy), bipolar emotional disorder (manic-depressive disease), traumatic brain and spinal cord injury, epilepsy, obesity , Atherosclerosis, hypertension, polycystic ovary syndrome, syndrome X, alopecia, inflammatory diseases (deformative arthrosis, rheumatism, atopic dermatitis, psoriasis, ulcerative colitis, clonal disease, sepsis, systemic inflammatory response syndrome, etc.), cancer (breast cancer , Colorectal cancer, pancreatic cancer, ovarian cancer, etc.) and immunodeficiency.

The 1 H -indazole compound represented by Chemical Formula 1 according to the present invention may form a pharmaceutically acceptable salt by a conventional method in the art. For example, non-toxic inorganic acids such as hydrochloric acid, bromic acid, sulfonic acid, sulfuric acid, phosphoric acid, nitric acid, or acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, paratoluenesulfonic acid, methanesulfonic acid It is also possible to form salts with non-toxic organic acids added with their pharmaceutically acceptable acids.

Hereinafter, the substituents used to define the 1 H -indazole compound represented by Formula 1 according to the present invention will be described in more detail.

'Alkyl group' includes all linear, pulverized and cyclic carbon chains having 1 to 6 carbon atoms, and preferred alkyl groups are methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, tert- butyl group, cyclopentyl group, cyclohexyl group, and the like. 'Heterocyclic group' is a ring group composed of 1 to 2 heteroatoms of a nitrogen atom (N) or an oxygen atom (O) and a carbon atom, and may include pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, and the like. have. The heterocyclic group may be substituted by other substituents, which may be substituted with a halogen atom such as chloro or fluoro, C ₁ -C ₆ alkyl, phenyl, or halo or C ₁ -C ₆ alkyl as defined above. Phenyl, and these substituents may be substituted with one to three.

In the 1 H -indazole compound represented by Chemical Formula 1, preferably, R ¹ represents a formamido group, an acetamido group, a furan-2-yl group, or a furan-3-yl group; R ² represents a hydrogen atom,-(CH ₂ ) _m -C (O)-(CH ₂ ) _n -R ⁴ , or -C (O) -X- (CH ₂ ) _n -R ⁴ ; R ³ represents a hydrogen atom or-(CH ₂ ) _m -C (O)-(CH ₂ ) _n -R ⁴ ; Except that when R ² and R ³ are hydrogen atoms at the same time; R ⁴ is a hydrogen atom, methylamino group, dimethylamino group, diethylamino group, pyrrolidinyl group, morpholino group, piperidinyl group, 1-methylpiperidinyl group, piperazinyl group, 4-methylpiperazinyl group , 4-ethylpiperazinyl group, 4- (2-chlorophenyl) piperazinyl group, 4- (3-chlorophenyl) piperazinyl group, 4- (2-fluorophenyl) piperazinyl group, 4 -(3-fluorophenyl) piperazinyl group, 4- (4-fluorophenyl) piperazinyl group, or 4- (2,3-dimethylphenyl) piperazinyl group; X represents a single bond or represents an oxazolenyl group or an isooxazolenyl group; M represents an integer of 0, 1, 2, or 3; N is the case of the compound which shows the integer of 0, 1, 2, or 3.

Particularly preferred 1 H -indazole compound represented by Formula 1 is as follows:

N- (6- (furan-2-yl) -1 H -indazol-3-yl) -4- (4-methylpiperazin-1-yl) butanamide (Compound No. 1);

N- (6- (furan-3-yl) -1 H -indazol-3-yl) -4- (4-methylpiperazin-1-yl) butanamide (Compound No. 2);

N- (6- (furan-2-yl) -1 H -indazol-3-yl) -4-morpholinobutaneamide (Compound No. 3);

N- (6- (furan-3-yl) -1 H -indazol-3-yl) -4-morpholinobutaneamide (Compound No. 4);

N- (6- (furan-3-yl) -1 H -indazol-3-yl-4- (pyrrolidin-1-yl) butanamide (Compound No. 5);

4- (4-ethyl-piperazin-1-yl) - N - (6- (furan-2-yl) -1 H - indazol-3-yl) butane amide (Compound No. 6);

4- (4-ethyl-piperazin-1-yl) - N - (6- (furan-3-yl) -1 H - indazol-3-yl) butane amide (Compound No. 7);

N- (6- (furan-2-yl) -1 H -indazol-3-yl) pentanamide (Compound No. 8);

N- (6- (furan-3-yl) -1 H -indazol-3-yl) pentanamide (Compound No. 9);

N- (6- (furan-2-yl) -1 H -indazol-3-yl) -1-methylpiperidine-4-carboxamide (Compound No. 10);

N- (6- (furan-3-yl) -1 H -indazol-3-yl) -1-methylpiperidine-4-carboxamide (Compound No. 11);

4- (dimethylamino) - N - (6- (furan-3-yl) -1 H - indazol-3-yl) butane amide (Compound No. 12);

1- (3-amino-6- (furan-2-yl) -1 H -indazol-1-yl) -4- (dimethylamino) butan-1-one hydrochloride (Compound No. 13);

1- (3-amino-6- (furan-2-yl) -1 H -indazol-1-yl) -4- (4-methylpiperazin-1-yl) butan-1-one hydrochloride (compound Number 14);

1- (3-amino-6- (furan-2-yl) -1 H -indazol-1-yl) -4-morpholinobutan-1-one hydrochloride (Compound No. 15);

1- (3-amino-6- (furan-2-yl) -1 H -indazol-1-yl) -4- (4-ethylpiperazin-1-yl) butan-1-one hydrochloride (compound Number 16);

1- (3-amino-6- (furan-3-yl) -1 H -indazol-1-yl) -4- (4-ethylpiperazin-1-yl) butan-1-one hydrochloride (compound Number 17);

1- (3-amino-6- (furan-3-yl) -1 H -indazol-1-yl) -5- (4-ethylpiperazin-1-yl) pentan-1-one hydrochloride (compound Number 18);

(3-amino-6- (furan-2-yl) -1 H -indazol-1-yl)-(1-methylpiperazin-4-yl) methanone hydrochloride (Compound No. 19);

(3-amino-6- (furan-3-yl) -1 H -indazol-1-yl) (1-methylpiperazin-4-yl) methanone hydrochloride (Compound No. 20);

N- (6-acetamido-1 H -indazol-3-yl) -5-((4- (3-fluorophenyl) piperazin-1-yl) methyl) isoxazole-3-carbox Amide (Compound No. 21);

5 - ((4- (3-phenyl), fluoro-1-yl) methyl) - N - (6- form omicron] -1 H-indazol-3-yl) isoxazole-3-carboxamide Amide (Compound No. 22);

5 - ((4- (3-fluorophenyl) piperazin-1-yl) methyl) - N - (6- (furan-2-yl) -1 H-indazol-3-yl) isoxazole-- 3-carboxamide (Compound No. 23);

5 - ((4- (3-fluorophenyl) piperazin-1-yl) methyl) - N - (6- (furan-3-yl) -1 H-indazol-3-yl) isoxazole-- 3-carboxamide (Compound No. 24);

N- (6-acetamido-1 H -indazol-3-yl) -1-methylpiperidine-4-carboxamide (Compound No. 25);

N- (6-acetamido-1 H -indazol-3-yl) pentaneamide (Compound No. 26);

N- (6-acetamido-1 H -indazol-3-yl) -4- (dimethylamino) butanamide (Compound No. 27);

N- (6-formamido-1 H -indazol-3-yl) -1-methylpiperidine-4-carboxamide (Compound No. 28);

4- (dimethylamino) - N - (6- form omicron] -1 H - indazol-3-yl) butane amide (Compound No. 29);

N- (6-acetamido-1 H -indazol-3-yl) -5- (3- (4-phenylpiperazin-1-yl) propyl) isoxazole-3-carboxamide (Compound No. 30);

N- (6-acetamido-1 H -indazol-3-yl) -5- (3- (4- (4-fluorophenyl) piperazin-1-yl) propyl) isoxazole-3- Carboxamide (Compound No. 31);

N- (6-acetamido-1 H -indazol-3-yl) -5- (3- (4- (3-fluorophenyl) piperazin-1-yl) propyl) isoxazole-3- Carboxamide (Compound No. 32);

N- (6-acetamido-1 H -indazol-3-yl) -5- (3- (4- (3-chlorophenyl) piperazin-1-yl) propyl) isoxazole-3-car Radiamide (Compound No. 33);

N- (6-acetamido-1 H -indazol-3-yl) -5- (3- (4- (2-chlorophenyl) piperazin-1-yl) propyl) isoxazole-3-car Radiamide (Compound No. 34);

N- (6-acetamido-1 H -indazol-3-yl) -5-((4- (2-fluorophenyl) piperazin-1-yl) methyl) isoxazole-3-carbox Amide (Compound No. 35);

N- (6-acetamido-1 H -indazol-3-yl) -5-((4- (2-chlorophenyl) piperazin-1-yl) methyl) isoxazole-3-carboxamide (Compound No. 36);

N- (3- (2- (4- (2,3-dimethylphenyl) piperazin-1-yl) -2-oxoethylamino) -1 H -indazol-6-yl) acetamide (Compound No. 37 );

N- (6-acetamido-1 H -indazol-3-yl) -5-((4- (3-chlorophenyl) piperazin-1-yl) methyl) isoxazole-3-carboxamide (Compound number 38);

N- (6-acetamido-1 H -indazol-3-yl) -5-((4-phenylpiperazin-1-yl) methyl) isoxazole-3-carboxamide (Compound No. 39) .

On the other hand, the present invention includes a method for producing a 1 H -indazole compound represented by the formula (1).

Scheme 1 below is a representative example of synthesizing a compound wherein R ² is —C (O) —X— (CH ₂ ) _n —R ⁴ in Chemical Formula 1, and is 3-amino-1 H − represented by Chemical Formula 2 It can be prepared by an amidation reaction between the sol compound and the substituted carboxylic acid compound represented by the following formula (3).

Scheme 1

In Scheme 1, X, R ¹ , R ⁴ , and n are as defined above, respectively.

The amidation reaction according to Scheme 1 can be carried out in the presence of a suitable base and binder. As the base, an amine base can be mainly used. Specifically, triethylamine, N-methylmorpholine (NMM), pyridine, or the like can be used. As the binder, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) can be used. The reaction solvent may be used as a solvent by using an excess of the base used above, and if necessary, dichloromethane, tetrahydrofuran (THF), dimethylformamide (DMF), and dimethylacetamide (DMAc). ), Dioxane and the like can be used. The reaction temperature may maintain a temperature around room temperature of 20 ℃ to 30 ℃.

In addition, Reaction Scheme 2 below is a representative example of synthesizing a compound wherein R ³ is -C (O) -X- (CH ₂ ) _n -R ⁴ in Chemical Formula 1, and 3-amino-1 H represented by the following Chemical Formula 2 It can be prepared by an amidation reaction between an indazole compound and a substituted carboxylic acid compound represented by the following formula (3).

Scheme 2

In Scheme 2, X, R ¹ , R ⁴ , and n are each as defined above.

The amidation reaction according to Scheme 2 can be carried out in the presence of a suitable N -methylmorpholine (NMM) and a binder. As the binder, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and hydroxy-1 H -benzotriazole (HOBT) can be used. As the reaction solvent, conventional inert solvents including dichloromethane, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMAc), dioxane, and the like can be used. The temperature around the room temperature of 30 ℃ can be maintained.

In addition, the 3-amino-1 H -indazole compound represented by Formula 2 used as starting materials in Schemes 1 and 2 can be easily prepared and used by the synthesis method shown in Scheme 3 below.

Scheme 3

In Scheme 3, R ¹ is as defined above.

According to Scheme 3, a 2-fluorobenzonitrile compound is first prepared by furan-2-yl-boronic acid and a palladium catalyst (eg, Pd (PPh ₃ ) ₄ ) and a base (eg, an alkali metal carbonate). Or hydrogen carbonate) to prepare an R ¹ substituted 2-fluorobenzonitrile compound represented by Chemical Formula 5. Thereafter, the compound represented by Chemical Formula 5 is reacted with hydrazine and an alcohol solvent to prepare a 3-amino-1 H -indazole compound represented by Chemical Formula 2.

In addition, the substituted carboxylic acid compound represented by Formula 3 used as starting materials in Schemes 1 and 2 can be easily prepared and used by the synthesis method shown in Scheme 4.

Scheme 4

In Scheme 4, X, R ⁴ , and n are as defined above, respectively.

First, ethyl 4-bromo alkanoate is reacted with a compound represented by R ² -H in a base such as sodium hydrogen carbonate and an alcohol solvent to obtain an R ² substituted alkanoate compound represented by Chemical Formula 6 above. Then, the compound represented by Chemical Formula 6 is sequentially treated with an aqueous sodium hydroxide solution and an aqueous hydrochloric acid solution to prepare a substituted carboxylic acid compound represented by Chemical Formula 3.

Compounds synthesized in each of the above-described preparation reactions may be diluted and washed with a general separation and purification process, for example, with an organic solvent, and the organic layer may be concentrated under reduced pressure, and, if necessary, purified by column chromatography.

In addition, the present invention includes a pharmaceutically acceptable salt of the compound represented by the formula (1) as a right range, the method for preparing a pharmaceutically acceptable salt can be easily prepared by conventional synthetic methods according to known literature It can be separated purely without any purification process. Next, a method for preparing a pharmaceutically acceptable salt of a compound represented by Chemical Formula 1 will be described based on the preparation of hydrochloride. That is, the extractant is dried and evaporated, and then the residue is dissolved in a small amount of ether, and about 1 to 10 equivalents of an ether solution of hydrogen chloride is added to form a hydrochloride of a desired target compound in the form of a white solid. The organic solvent that can be used to prepare the hydrogen chloride solution may be used chloroform, methylene chloride, ether, methanol, ethyl acetate or a mixed solvent thereof, preferably ether is useful. At this time, the product obtained in the form of a white solid can be separated using a centrifuge or a solvent removal device using a simple cotton. The solid is washed with ether two to three times and then dried well to obtain high purity hydrochloride in the solid state.

On the other hand, the present invention includes a pharmaceutical composition comprising a 1 H -indazole compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as a therapeutically effective ingredient.

The pharmaceutical composition of the present invention is suitable for oral or parenteral administration by formulating in a conventional formulation method including the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof and other conventional carriers, adjuvants or diluents and the like. It may be prepared in the form. In the case of oral administration, it may be prepared in the form of tablets, capsules, solutions, syrups, suspensions, etc., and in the case of parenteral administration, it may be prepared in the form of injections for intraperitoneal, subcutaneous, muscle, and transdermal.

The pharmaceutical composition of the present invention is an anticancer drug, and the effective daily dose is 0.01 to 1000 mg / day based on an adult, but the dosage may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient. Depending on the judgment of the doctor or pharmacist, it may be administered once a day or divided into several times at regular intervals.

Accordingly, the present invention provides a pharmaceutical use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same for the purpose of treating cancer.

The present invention as described above will be described in more detail through the following Examples and Experimental Examples, but the present invention is not limited to these Examples and Experimental Examples.

[Manufacture reference example]

Reference Example 1.

1) Preparation of 2-fluoro-4- (furan-2-yl) benzonitrile (Formula 5)

4-bromo-2-fluorobenzonitrile (1.5 g, 7.48 mmol), furan-2-yl boronic acid (1.0 g, 8.93 mmol) and Pd (PPh ₃ ) ₄ (0.6 g, 0.52 mmol) And filled with nitrogen. Na ₂ CO ₃ (0.95 g, 8.93 mol) dissolved in anhydrous DMF (75 mL) and water (0.2 mL) was added sequentially. The reaction solution was heated to 150 ° C. for 4 hours, cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. Column chromatography (eluate: ethyl acetate / hexane, 1/2) separated and obtained the target compound (1.1 g, 5.82 mmol, 78%) of a reddish yellow solid.

R _f 0.7 (ethyl acetate / hexane 2/3); C ₁₁ H ₆ FNO; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64-7.58 (t, 1H), 7.56 (dd, J = 0.492 Hz, 1.72 Hz, 1H), 7.53 (dd, J = 3.26 Hz, 1.53 Hz, 1H), 7.49-7.46 (dd, J = 1.43 Hz, 10.12 Hz, 1H), 6.86-6.85 (dd, J = 0.59 Hz, 3.50 Hz, 1H), 6.55 (q, J = 1.79 Hz, 1H)

2) Preparation of 6- (furan-2-yl) -1 H -indazol-3-amine (Formula 2)

Dissolve 2-fluoro-4- (furan-2-yl) benzonitrile (0.42 g, 2.22 mmol) in normal butanol (11 mL), slowly add hydrazine monohydrate (1.6 mL), and then add the reaction solution to 120 ° C. After heating for 10 hours, the temperature was lowered to room temperature. The reaction solution was poured into ice, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. Drying was concentrated under pressure. Solidified in dichloromethane and filtered to give the title compound (0.4 g, 2.0 mmol, 90%) as a white solid.

R _f 0.5 (CH ₂ Cl ₂ / MeOH 10/1); C ₁₁ H ₉ N ₃ O; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.44 (s, 1H), 7.73 (m, 1H), 7.69 (d, J = 8.39 Hz, 1H), 7.47 (s, 1H), 7.26 (d, J = 8.40 Hz, 1H), 6.94 (d, J = 3.34 Hz, 1H), 6.58 (m, 1H), 5.35 (s, 2H); ¹³ C NMR (400 MHz, DMSO- d ₆ ) δ 154.17, 149.73, 143.21, 142.10, 128.70, 121.32, 114.55, 113.63, 112.54, 106.40, 103.96

Reference Example 2.

1) Preparation of ethyl 4- (4-methylpiperazin-1-yl) butanoate (Formula 6)

To ethanol (50 mL) was added 1-methylpiperazine (1 mL, 8 mmol), NaHCO ₃ (1.34 g, 16 mmol) and ethyl 4-bromobutanoate (1.56 g, 8 mmol). Heated for hours. After the temperature was lowered to room temperature, 2/3 of the solution was concentrated, and dichloromethane and water were extracted. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the target compound (1.8 g, 8.45 mmol, 100%).

R _f 0.3 (CHCl ₃ : (CHCl ₃ / methanol / trimethylamine, 80/10/1) 2: 1); ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.13 (t, J = 7.14 Hz, 2H), 2.49-2.29 (m, 12H), 2.27 (s, 3H), 1.80 (quint, J = 7.32 Hz, 2H) , 1.24 (t, J = 7.12 Hz, 3H)

2) Preparation of 4- (4-methylpiperazin-1-yl) butanoic acid (Formula 7)

Ethyl-4- (4-methylpiperazin-1-yl) butanoate (1.81 g, 8.45 mmol) and 1N aqueous NaOH solution (1 mL) were added to ethanol (50 mL), followed by heating to 50 ° C. and stirring for 3 hours. It was. After the temperature was lowered to room temperature, the reaction solution was adjusted to pH 2 using 1N HCl aqueous solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the target compound (0.6 g, 1.9 mmol, 89%).

¹ H NMR (300 MHz, MeOD) δ 2.61-2.45 (m, 12H), 2.35 (s, 3H), 1.94 (quint, J = 7.32 Hz, 2H)

3) Preparation of N- (6- (furan-2-yl) -1 H -indazol-3-yl) -4- (4-methylpiperazin-1-yl) butanamide (Formula 1e)

6- (furan-2-yl) -1 H -indazol-3-amine (0.08 g, 0.4 mmol), 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCI; 0.14 g, 7.23 mmol) was added to anhydrous pyridine (5 mL) and stirred. After 30 minutes, 4- (4-methylpiperazin-1-yl) butanoic acid (0.067 g, 0.36 mmol) was added, followed by stirring at room temperature for 1 hour. After extracting with supersaturated NaHCO ₃ aqueous solution and dichloromethane, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography (eluent: CHCl ₃ / methanol / trimethylamine, 80/10/1) gave the title compound (0.0325 g, 0.401 mmol, 22%).

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.69 (s, 1H), 10.38 (s, 1H), 7.82-7.78 (s, 1H), 7.65 (s, 1H), 7.42 (d, J = 8.64 Hz, 1H), 7.03 (d, J = 3.27 Hz, 1H), 6.62 (dd, J = 3.29 Hz, 1.76 Hz, 1H), 2.42-2.29 (m, 12H), 2.16 (s, 3H), 1.81- 1.74 (m, J = 7.06 Hz, 2H)

4) 1- (3-amino-6- (furan-2-yl) -1 H -indazol-1-yl) -4- (4-methylpiperazin-1-yl) butan-1-one hydrochloride Preparation of (Compound 1d)

6- (furan-2-yl) -1 H -indazol-3-amine (0.08 g, 0.4 mmol), 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCI; 0.14 g, 7.23 mmol), hydroxybenzotriazole (HOBT; 0.97 g, 7.23 mmol) and N -methylmorpholine (NMM; 0.8 mL, 7.23 mmol) were added to anhydrous dichloromethane and stirred at room temperature. After 30 minutes, 4- (4-methylpiperazin-1-yl) butanoic acid (0.067 g, 0.36 mmol) was added, followed by stirring at room temperature for 1 hour. After extracting with supersaturated NaHCO ₃ aqueous solution and dichloromethane, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography (eluent: CHCl ₃ / methanol / trimethylamine, 80/10/1) afforded the title compound (0.096 g, 0.2.4 mmol, 60%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.90 (s, HCl), 8.53 (s, 1H), 7.94 (d, J = 8.32 Hz, ¹ H), 7.82 (d, J = 1.44 Hz, 1H ), 7.70 (d, J = 8.24 Hz, 1H), 7.08 (s, 1H), 6.4-6.63 (dd, J = 3.28 Hz, 1.74 Hz, 1H), 6.51 (s, 2H), 2.98-2.90 (m , 7H), 2.72-2.67 (m, 3H), 2.49-2.43 (m, 4H), 1.98 (m, 3H)

Reference Example 3.

1) Preparation of ethyl-5- (hydroxymethoxyl) isoxazole-3-carboxylate (Formula 8)

In a round reactor filled with nitrogen, (Z) -ethyl 2-chloro-2- (hydroxyimino) acetate (3 g, 0.0198 mol) was diluted in dichloromethane (46 mL) and stirred at room temperature. Propy-2-in-1-ol (1.762 mL, 0.03 mol) diluted in dichloromethane (4.7 mL) was added slowly. After 30 minutes triethylamine (TEA; 4.13 mL, 0.03 mol) diluted in dichloromethane (9 mL) was slowly added and the reaction stirred at room temperature for 5 hours. After the reaction was completed, the mixture was extracted with water and dichloromethane and the organic layer was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated by column chromatography (eluent: ethyl acetate / hexane, 1/1) to obtain a yellow target compound (1.91 g, 0.011 mol, 56%).

¹ H (400 MHz, CDCl ₃ ) δ 6.69 (s, 1H), 4.81 (s, 2H), 4.47-4.42 (q, J = 7.12 Hz, 2H), 3.15 (br, 1H), 1.39-1.35 (t , J = 7.12 Hz, 3H)

2) Preparation of Ethyl 5-formylisoxazole-3-carboxylate (Formula 9)

In a round reactor filled with nitrogen, ethyl 5- (hydroxymethyl) isoxazole-3-carboxylate (1.91 g, 0.011 mol) and silica gel (4 g) dissolved in dichloromethane (60 mL) were added. Stirred. After the addition of PCC, the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the filtrate was concentrated by filtration using diatomaceous earth. After separation by column chromatography (ethyl acetate / hexane, 1/1), an oily target compound (1.32 g, 7.8 mmol, 70%) was obtained.

¹ H (400 MHz, CDCl ₃ ) δ 10.01 (s, 1H), 7.26 (s, 1H), 4.50-4.45 (t, J = 7.2 Hz, 2H), 1.38-1.37 (t, J = 7.2 Hz, 3H)

3) Preparation of ethyl 5-((4- (3-fluorophenyl) piperazin-1-yl) methyl) isoxazole-3-carboxylate (Formula 10)

Ethyl 5-formylisoxazole-3-carboxylate (0.4 g, 2.36 mmol), dried molecular sieve and anhydrous dichloromethane (25 mL) were placed in a round reactor. 1- (3-fluorophenyl) piperazine (0.55 g, 3.08 mmol) was added to the reaction. After two hours, NaBH (OAc) ₃ (1.5 g, 7.1 mmol) and anhydrous dichloromethane (25 mL) were added sequentially. The reaction was vigorously stirred for 6 hours at room temperature, and then the organic layer was separated with water and dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography (eluate: ethyl acetate / hexane, 1/1) to give the title compound (0.74 g, 2.23 mmol, 94%).

¹ H (400 MHz, CDCl ₃ ) δ 7.21-7.15 (q, J = 8.23 Hz, 1H), 6.64 (s, 1H), 6.59-6.51 (m, 2H), 4.48-4.42 (q, J = 7.15 Hz, 2H), 3.80 (s, 2H ), 3.23-3.21 (m, 4H), 2.69-2.67 (m, 4H), 1.42-1.39 (t, J = 7.12 Hz, 3H)

4) Preparation of 5-((4- (3-fluorophenyl) piperazin-1-yl) methyl) isoxazole-3-carboxylic acid (Formula 11)

Dissolve ethyl 5-((4- (3-fluorophenyl) piperazin-1-yl) methyl) isoxazole-3-carboxylate (0.74 g, 2.23 mmol) in ethyl alcohol (3.4 mL), A 2N NaOH aqueous solution was added to the reaction solution, followed by heating to 50 ° C. for 1 hour. After the reaction was cooled to room temperature, the reaction solution was adjusted to pH 2 using 1N HCl aqueous solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a target compound (0.6 g, 1.9 mmol, 89%) as a colorless solid.

¹ H (400 MHz, DMSO- d ₆ ) δ 7.21-7.15 (q, J = 8.04 Hz, 1H), 6.75 (s, 1H), 6.74-6.68 (m, 2H), 6.54-6.50 (td, J = 2.14 Hz, 8.40 Hz, 1H), 3.81 ( s, 2H), 3.17-3.15 (m, 4H), 2.56-2.54 (m, 4H)

5) 5 - ((4- (3-Pro-phenyl) piperazin-1-yl) methyl) - N - (6- (furan-2-yl) -1 H-indazol-3-yl) child sook Preparation of Sazol-3-carboxamide (Compound 1f)

6- (furan-2-yl) -1 H -indazol-3-amine (30 mg, 0.15 mmol), 5-((4- (3-fluorophenyl) piperazin-1-yl) in the reaction vessel Methyl) isoxazole-3-carboxylic acid (47 mg, 0.15 mmol) and anhydrous pyridine (1 mL) were added together and stirred at room temperature. After 10 minutes, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCI; 58 mg, 0.3 mmol) was added to the reaction solution, followed by stirring for 3 hours. The reaction solution was extracted with water and dichloromethane, and the organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Then, the mixture was solidified in ethyl acetate / hexane (1/1) to obtain a target compound (54 mg, 0.11 mmol, 74%) as a white solid.

Melting point 213.9 ° C .; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.95 (s, 1H), 11.01 (s, 1H), 7.79-7.73 (m, 3H), 7.47 (dd, J = 1.26 Hz, 8.58 Hz, 1H) , 7.24-7.16 (m, 1H), 7.06 (d, J = 3.29 Hz, 1H), 6.95 (s, 1H), 6.76-6.71 (m, 2H), 6.63-6.62 (m, 1H), 6.56-6.50 (td, J = 2.22 Hz, 8.4 Hz, 1H), 3.87 (s, 1H), 3.20 (s, 4H), 2.61 (s, 4H); ¹³ C NMR (400 MHz, DMSO- d ₆ ) δ 171.57, 164.92, 158.93, 158.24, 153.60, 153.11, 143.65, 141.79, 139.38, 130.73, 129.10, 122.62, 117.21, 116.42, 112.71, 111.37, 107. 105.09. , 104.60, 103.97, 102.43, 102.17, 52.44, 48.10

Reference Example 4.

1) Preparation of 6-nitro-1 H -indazol-3-amine (Formula 13)

2-Fluoro-4-nitrobenzonitrile (0.1 g, 0.6 mol) was diluted in n -butanol (5 mL), then hydrazine (0.44 mL) was added and heated at 120 ° C. for 4 hours. After the reaction was completed, the reaction solution was poured into ice after cooling to room temperature, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain a target compound (0.071 g, 0.39 mol, 66%) as a red solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.12 (s, NH), 8.12 (d, J = 1.77 Hz, 1H), 7.92 (d, J = 8.79 Hz, 1H), 7.73 (dd, J = 1.92 Hz, 8.79 Hz, 1H), 5.73 (s, 2H)

2) 5 - ((4- (3-fluorophenyl) piperazin-1-yl) methyl) - N - (6- nitro -1 H-indazol-3-yl) isoxazole-3-carboxamide Preparation of Amide (Formula 14)

6-nitro-1 H -indazol-3-amine (0.071 g, 0.39 mol) and anhydrous pyridine (5 mL) were mixed and then nitrogen gas was injected. The reaction solution was stirred at room temperature for 20 minutes, followed by 5-((4- (3-fluorophenyl) piperazin-1-yl) methyl) isoxazole-3-carboxylic acid (0.14 g, 0.47 mol). 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCI; 1.52 g, 7.9 mol) was added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction, the mixture was extracted with water and dichloromethane, and then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Solidified with methyl alcohol and filtered to give the yellow target compound (0.14 g, 0.31 mol, 80%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.67 (s, NH), 11.37 (s, NH), 8.41 (d, J = 1.54 Hz, 1H), 7.98-7.89 (dd, J = 8.99 Hz, 1.83 Hz, 2H), 7.21-7.15 (q, J = 8.62 Hz, 1H), 6.95 (s, 1H), 6.74-6.70 (m, 2H), 6.53-6.49 (td, J = 8.19 Hz, 1.80 Hz, 1H), 3.86 (s, 2H), 3.22 (br, 4H), 2.67 (br, 4H)

3) N- (6-amino-1 H -indazol-3-yl) -5-((4- (3-fluorophenyl) piperazin-1-yl) methyl) isoxazole-3-carbox Preparation of amide (Formula 15)

5 - ((4- (3-fluorophenyl) piperazin-1-yl) methyl) - N - (6- nitro -1 H-indazol-3-yl) isoxazole-3-carboxamide ( 0.14 g, 0.31 mmol) and 10% Pd / C (5 mg) were added to methyl alcohol (20 mL), and hydrogen gas was introduced into the reaction vessel. After the reaction was completed, the resultant was filtered using diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a yellow target compound (0.11 g, 0.26 mmol, 83%).

¹ H NMR (300 MHz, DMSO- d ₆ ), 12.10 (s, 1H), 10.85 (br, 1H), 7.21 (d, J = 7.68 Hz, 1H), 6.91 (s, 1H), 6.76-6.71 ( m, 3H), 6.54-6.42 (m, 3H), 5.35 (s, 2H), 3.85 (s, 2H), 3.35-3.15 (m, 4H), 2.60-2.55 (m, 4H)

4) N- (6-acetamido-1 H -indazol-3-yl) -5-((4- (3-fluorophenyl) piperazin-1-yl) methylisoxazole-3-car Preparation of Radimide (Formula 1g)

N- (6-amino-1 H -indazol-3-yl) -5-((4- (3-fluorophenyl) piperazin-1-yl) methyl) isoxazole-3-carboxamide ( 0.11 g, 0.31 mmol) was dissolved in anhydrous pyridine (2 mL), and at 0 ° C., DMAP (7.5 mg, 0.06 mmol) and acetyl chloride (26 uL, 0.37 mmol) were added. After 1 hour, the mixture was extracted with water and dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluate: CH ₂ Cl ₂ / CH ₃ OH, 1/1) to obtain the target compound. .

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.66 (s, 1H), 10.99 (s, 1H), 10.08 (s, 1H), 8.11 (s, 1H), 7.64 (d, J = 8.58, 1H ), 7.24-7.16 (q, J = 8.08 Hz, 1H), 7.11 (d, J = 8.88 Hz, 1H), 6.92 (s, 1H), 6.76-6.70 (m, 2H), 6.54 (m, 1H) , 3.86 (s, 2H), 3.20 (s, 4H), 2.610 (s, 4H), 2.08 (s, 3H) ¹³ C NMR (300 MHz, DMSO- d ₆ ) δ 171.53, 169.13, 165.33, 162.15, 158.97 , 158.14, 153.09, 142.09, 139.11, 138.40, 130.83, 122.12, 114.17, 113.36, 111.38, 105.33, 103.89, 102.45, 99.12, 52.42, 48.11, 24.59; FABMS (m / z): [M ⁺ + H] calcd for 478.1924, Found 478.2003

Reference Example 5.

1) Preparation of 1- (4- (2,3-dimethylphenyl) piperazin-1-yl) propan-1-one (Formula 18)

Triethylamine (5.90 mmol, 0.83 mL) was added to a mixture of 2,3-dimethylphenyl piperazine (4.95 mmol, 0.95 g) and anhydrous dichloromethane (20 mL), followed by stirring at room temperature for 30 minutes. After lowering to 0 ⁰ C, bromo acetyl bromide (4.95 mmol, 0.43 mL) was added, stirred at low temperature for 30 minutes, and after completion of reaction, the reaction mixture was separated with dichloromethane and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. After column chromatography (eluent; ethyl acetate: hexane 1: 2) was obtained (0.91 g, 2.94 mmol, 60%) to obtain a compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ7.13 (d, J = 7.69 Hz, 1H), 6.97 (d, J = 7.31 Hz, 1H), 6.91 (d, J = 7.96 Hz, 1H), 3.92 ( s, 2H), 3.68 (t, 2H), 2.96 (t, J = 4.83 Hz, 2H), 2.88 (t, J = 4.87 Hz, 2H), 2.29 (s, 3H), 2.26 (s, 3H)

2) Preparation of 2- (6-nitro-1 H -indazol-3-ylamino) -1- (4- (2,3-dimethylphenyl) piperazin-1-yl) ethanone (Formula 19)

Method for preparing 1- (4- (2,3-dimethylphenyl) piperazin-1-yl) -2- (6-nitro-1H-indazol-3-ylamino) ethanone (Formula 19)

2-bromo-1- (4- (2,3-dimethylphenyl) piperazin-1-yl) ethanone (0.21 mmol), 6-nitro-1H-indazol-3-amine (0.17 mmol) and After mixing dimethylformamide (DMF, 2 mL), tetrabutyl ammonium iodide (TBAI) was added and heated at 80 ⁰ C for 2 hours. When the reaction is completed, the reaction material is cooled down and then concentrated under reduced pressure. Purified by column chromatography (eluent; ethyl acetate: hexane 1: 4) to give a compound (0.058 mmol, 33%).

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.19 (s, 1 H), 8.15 (d, J = 1.98, 1 H), 8.08 (d, J = 8.82 Hz, 1H), 7.72 (dd, J = 1.95 Hz, 8.82 Hz, 1H), 7.04 (m, 1H), 6.90-6.67 (m, 3H), 6.56 (s, br, 1H), 4.20 (s, 2H), 3.67 (br, 4H), 2.83 ( s, 2H), 2.75 (s, 2H), 2.03 (s, 3H), 1.98 (s, 3H)

3) Preparation of 2- (6-amino-1 H -indazol-3-ylamino) -1- (4- (2,3-dimethylphenyl) piperazin-1-yl) ethanone (Formula 20)

2- (6-nitro-1 H -indazol-3-ylamino) -1- (4- (2,3-dimethylphenyl) piperazin-1-yl) ethanone (0.058 mmol) with 10% Pd / C (3 mg) was added to methyl alcohol (20 mL) and hydrogen gas was injected into the reaction vessel. After stirring at room temperature for 10 hours to confirm the reaction was completed, filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to obtain the target compound 17mg (yield 80%).

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.17 (s, 1H), 8.05 (s, 1H), 7.52 (d, 1H), 6.72 (m, 1H), 6.59 ~ 6.56 (m, 1H) , 6.65 ~ 6.43 (m, 5H), 6.43 (s, br, 1H), 4.20 (s, 2H), 3.67 (br, 4H), 2.83 (s, 2H), 2.75 (s, 2H), 2.03 (s , 3H), 1.98 (s, 3H)

4) N- (3- (2- (4- (2,3-dimethylphenyl) piperazin-1-yl) -2-oxoethylamino) -1 H -indazol-6-yl) acetamide 1h) manufacturing

2- (6-amino-1 H -indazol-3-ylamino) -1- (4- (2,3-dimethylphenyl) piperazin-1-yl) ethanone (72mg, 0.19mmol) with anhydrous pyridine After dissolving in (2 mL), at 0 ° C., DMAP (30 mg, 0.22 mmol) and acetyl chloride (16 uL, 0.22 mmol) were added. After 1 hour, the mixture was extracted with water and dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and separated and purified by column chromatography (eluent: CH ₂ Cl ₂ / CH ₃ OH, 1/1) to give 26 mg of the target compound. (Yield 33%) was obtained.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.25 (s, 1H), 8.54 (s, 1H), 7.90 (d, J = 8.70 Hz, 1H), 7.60 (d, J = 8.58 Hz, 1H) , 7.17 (s, 1 H), 7.05 (t, J = 7.89 Hz, 1 H), 6.88 (t, J = 7.38 Hz, 2H). 4.23 (d, 2H), 3.68 (s, 4H), 2.84-2.76 (s, 4H), 2.21 (s, 3H), 2.19 (s, 3H), 2.07 (s, 3H)

[Example]

Compounds of the present invention were synthesized according to the representative synthesis examples described as the above reference examples. The structural confirmation data of each synthesized compound is as follows.

N- (6- (furan-2-yl) -1 H -indazol-3-yl) -4- (4-methylpiperazin-1-yl) butanamide (Compound No. 1)

Yield 22%; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.69 (s, 1H), 10.38 (s, 1H), 7.82-7.78 (s, 1H), 7.65 (s, 1H), 7.42 (d, J = 8.64 Hz, 1H), 7.03 (d, J = 3.27 Hz, 1H), 6.62 (dd, J = 3.29 Hz, 1.76 Hz, 1H), 2.42-2.29 (m, 12H), 2.16 (s, 3H), 1.81- 1.74 (m, J = 7.06 Hz, 2H)

N- (6- (furan-3-yl) -1 H -indazol-3-yl) -4- (4-methylpiperazin-1-yl) butanamide (Compound No. 2)

Yield 19%; Melting point 200.7 ° C .; IR 3237, 1656 (C = 0), 2820 (-CH _2- ), 1283, 1163, 1011 cm ^-1 (piperazine); ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.62 (s, 1H), 10.34 (s, 1H), 8.26 (s, 1H), 7.76-7.74 (m, 2H), 7.56 (s, 1H), 7.32 (d, J = 8.54 Hz, 1H), 7.04 (s, 1H), 2.41-2.29 (m, 12H), 2.15 (s, 3H), 1.76 (t, J = 6.94 Hz, 2H); ¹³ C NMR (400 MHz, DMSO- d ₆ ) δ 171.65, 144.79, 142.08, 140.94, 140.20, 130.63, 126.52, 123.37, 118.51, 115.66, 109.41, 106.44, 57.75, 55.22, 53.14, 46.24, 33.78, 22.84

N- (6- (furan-2-yl) -1 H -indazol-3-yl) -4-morpholinobutaneamide (Compound No. 3)

Yield 29%; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.62 (s, 1H), 10.34 (s, 1H), 8.26 (s, 1H), 7.76 (m, 2H), 7.56 (s, 1H), 7.32 ( d, J = 8.77 Hz, 1H), 7.04 (s, 1H), 2.42-2.23 (m, 14H), 1.76 (m, J = 6.81 Hz, 2H), 0.96 (t, J = 7.13 Hz, 3H)

N- (6- (furan-3-yl) -1 H -indazol-3-yl) -4-morpholinobutaneamide (Compound No. 4)

Yield 31%; Melting point 190 ° C; IR 3165, 1670 (C═O), 1261, 1161, 1049 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.63 (s, 1H), 10.36 (s, 1H), 8.26 (s, 1H), 7.78-7.75 (m, 2H), 7.57 (s, 1H), 7.32 (d, J = 8.55 Hz, 1H), 7.04 (s, 1H), 3.57 (s, 4H), 2.44-2.39 (m, 8H), 1.79 (t, J = 6.93, 2H); ^{13 C NMR (300 MHz, DMSO-} d 6) δ 170.79, 144.80, 142.04, 140.63, 140.21, 130.60, 126.55, 123.28, 118.56, 115.58, 109.38, 106.56, 64.38, 56.52, 51.98, 32.96, 20.20

N- (6- (furan-3-yl) -1 H -indazol-3-yl-4- (pyrrolidin-1-yl) butanamide (Compound No. 5)

Yield 21%; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.59 (s, 1H), 10.37 (s, 1H), 8.26 (s, 1H), 7.77-7.74 (m, 2H), 7.56 (s, 1H), 7.33 (d, J = 8.67 Hz, 1H), 7.04 (s, 1H), 3.33-3.26 (m, J = 7.26 Hz, 4H), 1.79 (m, 2H), 1.67 (m, 4H), 1.67 (m , 4H), 1.17 (m, J = 7.19 Hz, 4H)

4- (4-ethyl-piperazin-1-yl) - N - (6- (furan-2-yl) -1 H - indazol-3-yl) butane amide (Compound No. 6)

Yield 27%; Melting point 192.3 ° C .; IR 3258, 1664 (C = 0), 2811 (-CH _2- ), 1348, 1154, 1012 cm ^-1 ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.68 (s, 1H), 10.38 (s, 1H), 7.82 (s, 1H), 7.78 (m, 1H), 7.65 (s, 1H), 7.41 ( d, J = 8.44 Hz, 1H), 7.03 (d, J = 3.30 Hz, 1H), 6.62 (dd, J = 1.79 Hz, 3.27 Hz, 1H), 2.49-2.24 (m, 14H), 1.77 (m, J = 7.11 Hz, 2H), 0.96 (t, J = 7.14 Hz, 3H); ¹³ C NMR (400 MHz, DMSO- d ₆ ) δ 171.67, 153.73, 143.52, 141.82, 141.07, 128.88, 123.68, 116.45, 115.76, 112.64, 106.97, 104.35, 57.80, 53.25, 52.86, 52.10, 33.81, 22.84, 12.47, 12.47

4- (4-ethyl-piperazin-1-yl) - N - (6- (furan-3-yl) -1 H - indazol-3-yl) butane amide (Compound No. 7)

Yield 35%; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.62 (s, 1H), 10.34 (s, 1H), 8.26 (s, 1H), 7.76-7.74 (m, 2H), 7.56 (s, 1H), 7.32 (d, J = 8.54 Hz, 1H), 7.04 (s, 1H), 2.41-2.29 (m, 12H), 2.15 (s, 3H), 1.76 (t, J = 6.94 Hz, 2H)

N- (6- (furan-2-yl) -1 H -indazol-3-yl) pentanamide (Compound No. 8)

Yield 30%; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.69 (s, 1H), 10.35 (s, 1H), 7.80 (s, 1H), 7.78 (s, 1H), 7.65 (s, 1H), 7.42 ( d, J = 8.58 Hz, 1H), 7.03 (d, J = 3.33 Hz, 1H), 6.61 (m, 1H), 2.39 (t, J = 7.35 Hz, 2H), 1.61 (m, J = 7.44 Hz, 2H), 1.37 (m, J = 7.56 Hz, 2H), 0.92 (t, J = 7.26 Hz, 3H)

N- (6- (furan-3-yl) -1 H -indazol-3-yl) pentanamide (Compound No. 9)

Yield 27%; Melting point 182 ° C .; IR 3288, 1659 (C = 0), 2954, 2871 (-CH _2- ), 1534, 1449 cm ^-1 ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.62 (s, 1H), 10.30 (s, 1H), 8.25 (s, 1H), 7.76-7.73 (m, 2H), 7.57 (s, 1H), 7.33 (d, J = 8.61 Hz, 1H), 7.04 (s, 1H), 2.38 (t, J = 7.23 Hz, 1.61 (quintet, J = 6.99 Hz, 2H), 1.40 (m, J = 7.35 Hz, 2H ), 0.92 (t, J = 7.27 Hz, 3H); ¹³ C NMR (300 MHz, DMSO- d ₆ ) δ 171.76, 144.79, 142.10, 140.95, 140.22, 130.64, 126.57, 123.31, 118.55, 115.72, 109.41, 106.49

N- (6- (furan-2-yl) -1 H -indazol-3-yl) -1-methylpiperidine-4-carboxamide (Compound No. 10)

Yield 35%; IR 3292, 1689 (C = 0), 2942 (CH3), 1353, 1266, 1153 cm ^-1 ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.71 (s, 1H), 10.33 (s, 1H), 7.78-7.76 (m, 2H), 7.65 (s, 1H), 7.42 (d, J = 8.64 Hz, 1H), 7.03 (d, J = 3.30 Hz, 1H), 6.62-6.61 (m, 1H), 2.83 (m, 2H), 2.36 (m, 1H), 2.16 (s, 3H), 1.91-1.66 (m, 6H)

N- (6- (furan-3-yl) -1 H -indazol-3-yl) -1-methylpiperidine-4-carboxamide (Compound No. 11)

Yield 25.5%; IR 3286, 1682 (C═O), 2942 (CH 3), 1352, 1158 cm ⁻¹ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.66 (s, 1H), 8.40 (s, 1H), 8.29 (s, 1H), 7.93 (d, J = 8.24 Hz, 1H), 7.79 (t, J = 1.68 Hz, 1H), 7.63 (m, J = 1.33 Hz), 6.98 (s, 1H), 6.56 (s, 2H), 3.78 (s, 1H), 3.43 (m, 2H), 3.06-3.00 ( m, 2H), 2.73 (s, 3H), 2.14-2.04 (m, 4H)

4- (dimethylamino) - N - (6- (furan-3-yl) -1 H - indazol-3-yl) butane amide (compound No. 12)

Yield 26%; IR 3250, 1686 (C = 0), 3068 (-CH _2- ), 2950, 2828 (N (CH ₃ ) ₂ ), 1601, 1551, 1454 cm ^-1 ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.64 (s, NH), 10.36 (s, NH), 8.26 (s, 1H), 7.76 (d, 2H), 7.57 (s, 1H), 7.72 ( d, J = 8.51 Hz, 1H), 7.04 (s, 1H), 2.40 (t, J = 7.31 Hz, 2H), 2.25 (t, J = 6.92 Hz, 2H), 2.13 (s, 6H), 1.75 ( quint, J = 7.01 Hz, 2H)

1- (3-amino-6- (furan-2-yl) -1 H -indazol-1-yl) -4- (dimethylamino) butan-1-one hydrochloride (Compound No. 13)

Yield 42%; Melting point 220.8 ° C .; IR 3318, 1682 (C = 0), 2935 (-CH _2- ), 2935,2561, 2464, 1641, 1434 cm ^-1 (amine salt); ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.11 (s, HCl), 8.53 (s, 1H), 7.94 (d, J = 8.31 Hz, 1H), 7.83 (d, J = 1.17 Hz, 1H) , 7.73-7.69 (dd, J = 8.34 Hz, 1.14 Hz, 1H), 7.08 (m, 1H), 6.65 (t, J = 1.74 Hz, 1H), 6.53 (s, 2H), 3.17-3.04 (m, 4H), 2.77 (s, 6H), 2.10-1.99 (m, 2H); ¹³ C NMR (400 MHz, DMSO- d ₆ ) δ 170.83, 153.15, 144.15, 140.23, 131.95, 122.02, 120.15, 119.42, 112.84, 109.51, 107.94, 56.35, 49.036, 42.43, 31.86, 19.35

1- (3-amino-6- (furan-2-yl) -1 H -indazol-1-yl) -4- (4-methylpiperazin-1-yl) butan-1-one hydrochloride (compound Number 14)

Yield 67%; Melting point 193.7 ° C .; IR 3328, 1693 (C═O), 2965, 2687, 1635, 1421 cm ⁻¹ (amine salt); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.90 (s, HCl), 8.53 (s, 1H), 7.94 (d, J = 8.32 Hz, 1H), 7.82 (d, J = 1.44 Hz, 1H) , 7.70 (d, J = 8.24 Hz, 1H), 7.08 (s, 1H), 6.4-6.63 (dd, J = 3.28 Hz, 1.74 Hz, 1H), 6.51 (s, 2H), 2.98-2.90 (m, 7H), 2.72-2.67 (m, 3H), 2.49-2.43 (m, 4H), 1.98 (m, 3H)

1- (3-amino-6- (furan-2-yl) -1 H -indazol-1-yl) -4-morpholinobutan-1-one hydrochloride (Compound No. 15)

Yield 85%; Melting point 239.2 ° C .; IR 3313, 1691 (C═O), 2930, 2868 (CH ₂ ), 2555, 1630, 1424 cm ⁻¹ (amine salt); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.90 (s, HCl), 8.53 (s, 1H), 7.93 (d, J = 8.28 Hz, 1H), 7.83 (d, J = 1.56 Hz, 1H) , 7.72 (d, J = 8.32 Hz, 1H), 7.08 (s, 1H), 6.4-6.63 (dd, J = 3.32 Hz, 1.81 Hz, 1H), 6.53 (s, 2H), 3.93-3.80 (m, 4H), 3.42 (m, 2H), 3.26-3.16 (m, 2H), 2.99-2.97 (m, 4H), 0.99 (m, 2H); ¹³ C NMR (300 MHz, DMSO- d ₆ ) δ 170.83, 153.16, 144.14, 140.26, 131.97, 121.96, 120.16, 119.43, 112.83, 109.57, 107.91, 63.70, 55.93, 51.53, 31.99, 18.57

1- (3-amino-6- (furan-2-yl) -1 H -indazol-1-yl) -4- (4-ethylpiperazin-1-yl) butan-1-one hydrochloride (compound Number 16)

Yield 80%; Melting point 223.3 ° C .; IR 3316, 1698 (C═O), 2940 (CH ₂ ), 2615, 1625, 1422 cm ⁻¹ (amine salt); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.52 (s, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 1.61,1H), 7.66 (td, J = 1.52 Hz, 8.3 Hz, 1H), 7.05 (d, 1H), 6.63 (m, 1H), 6.44 (s, 2H), 2.94 (q, J = 7.12 Hz, 2H), 2.34-2.18 (m, 12H), 1.83 (dd, J = 6.99 Hz, 2H), 0.90 (t, J = 7.12 Hz, 3H); ^{13 C NMR (300 MHz, DMSO-} d 6) δ 172.33, 153.18, 152.98, 144.14, 140.22, 131.89, 121.99, 120.01, 119.32, 112.84, 109.53, 107.92, 63.81, 52.84, 50.917, 49.48, 32.58, 21.65, 10.12

1- (3-amino-6- (furan-3-yl) -1 H -indazol-1-yl) -4- (4-ethylpiperazin-1-yl) butan-1-one hydrochloride (compound Number 17)

Yield 51%; Melting point 210.6 ° C .; IR 3314, 1698 (C═O), 2938 (CH ₂ ), 2617, 1625, 1428 cm ⁻¹ (amine salt); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.83 (s, HCl), 8.53 (s, 1H), 7.93 (d, J = 8.32 Hz, 1H), 7.82 (s, 1H), 7.69 (d, J = 8.28 Hz, 1H), 7.08 (d, J = 3.20 Hz, 1H), 6.64 (dd, J = 3.2 Hz, 1.6 Hz, 1H), 6.51 (s, 2H), 3.82 (m, 2H), 2.99 -2.66 (m, 10H), 1.85 (m, 2H), 0.98 (m, 3H); ^{13 C NMR (400 MHz, DMSO-} d 6) δ 171.72, 153.00, 145.12, 140.66, 140.42, 133.95, 126.26, 122.11, 121.87, 119.31, 111.73, 109.29, 63.82, 52.8351, 50.94, 50.38, 49.61, 42.91, 32.57

1- (3-amino-6- (furan-3-yl) -1 H -indazol-1-yl) -5- (4-ethylpiperazin-1-yl) pentan-1-one hydrochloride (compound Number 18)

Yield 80%; Melting point 219.9 ° C .; IR 3328, 1695 (C═O), 2933, 2872 (CH ₂ ), 2675, 1633, 1447 cm ⁻¹ (amine salt); ¹ H NMR (400 MHz, DMSO- d ₆ 6) δ 10.88-10.77 (s, HCl), 8.53 (s, 1H), 8.39 (s, 1H), 7.95 (d, J = 8.88 Hz, 1H), 7.79 (s, 1H), 7.61 (d, J = 8.2 Hz, 1H), 6.97 (s, 1H), 6.50 (s, 2H), 3.04-2.87 (m, 14H), 1.69 (m, 2H), 1.16 ( t, J = 7.08 Hz, 3H); ¹³ C NMR (300 MHz, DMSO- d ₆ ) δ 171.76, 153.03, 145.11, 140.65, 140.41, 133.94, 126.27, 122.13, 121.82, 119.33, 111.76, 109.30, 63.75, 52.78, 51.00, 49.90, 42.82, 34.40, 22.20

(3-amino-6- (furan-2-yl) -1 H -indazol-1-yl)-(1-methylpiperazin-4-yl) methanone hydrochloride (Compound No. 19)

Yield 35%; Melting point 271 ° C .; IR 3393, 1667 (C═O), 2954 (CH ₂ ), 2665, 1639, 1426 cm ⁻¹ (amine salt); ¹ H (400 MHz, DMSO- d ₆ ) δ 10.32 (s, HCl), 8.54 (s, 1H), 7.93 (d, J = 8.28 Hz, 1H), 7.83 (s, 1H), 7.73 (dd, J = 8.28 Hz, 1H), 7.09 (s, 1H), 6.65 (m, 1H), 6.58 (s, 1H), 3.62 (m, 1H), 3.49 (m, 2H), 3.03 (m, 2H), 2.75 (s, 3H), 2.16 (m, 2H), 1.99 (m, 2H); ¹³ C NMR (400 MHz, DMSO- d ₆ ) δ 172.28, 153.47, 153.10, 144.20, 140.30, 132.10, 121.99, 120.35, 119.51, 112.86, 109.76, 108.01, 52.74, 42.95, 37.75, 25.67

(3-amino-6- (furan-3-yl) -1 H -indazol-1-yl) (1-methylpiperidin-4-yl) methanone hydrochloride (Compound No. 20)

Yield 80%; Melting point 248.7 ° C .; IR 3356, 1669 (C═O), 2958 (CH ₂ ), 3219, 2628, 1650, 1434 cm ⁻¹ (amine salt); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.35 (s, HCl), 8.54 (s, 1H), 8.03 (d, J = 8.42 Hz, 1H), 7.85 (s, 1H), 7.98 (dd, J = 8.50 Hz, 1H), 7.39 (m, 1H), 6.65 (m, 1H), 6.58 (s, 1H), 3.62 (m, 1H), 3.49 (m, 2H), 3.03 (m, 2H), 2.75 (s, 3 H), 2.16 (m, 2 H), 1.99 (m, 2 H); ¹³ C NMR (300 MHz, DMSO- d ₆ ) δ 172.20, 153.48, 145.13, 140.71, 140.50, 134.19, 126.22, 122.45, 121.82, 119.47, 111.98, 109.26, 52.64, 42.89, 37.48, 25.52

N- (6-acetamido-1 H -indazol-3-yl) -5-((4- (3-fluorophenyl) piperazin-1-yl) methyl) isoxazole-3-carbox Amide (Compound No. 21)

Yield 98%; Melting point 220 ° C; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.66 (s, 1H), 10.99 (s, 1H), 10.08 (s, 1H), 8.11 (s, 1H), 7.64 (d, J = 8.58,1H ), 7.24-7.16 (q, J = 8.08 Hz, 1H), 7.118 (d, J = 8.88 Hz, 1H), 6.92 (s, 1H), 6.76-6.70 (m, 2H), 6.54 (m, 1H) , 3.86 (s, 2H), 3.20 (s, 4H), 2.610 (s, 4H), 2.08 (s, 3H) ¹³ C NMR (300 MHz, DMSO- d ₆ ) δ 171.53, 169.13, 165.33, 162.15, 158.97 , 158.14, 153.09, 142.09, 139.11, 138.40, 130.83, 122.12, 114.17, 113.36, 111.38, 105.33, 103.89, 102.45, 99.12, 52.42, 48.11, 24.59; FABMS (m / z): [M ⁺ + H] calcd for 478.1924, Found 478.2003

5 - ((4- (3-phenyl), fluoro-1-yl) methyl) - N - (6- form omicron] -1 H-indazol-3-yl) isoxazole-3-carboxamide Amide (Compound No. 22)

Yield 70%; IR 3328, 1684 (C═O), 2831 cm ⁻¹ (CHO); ¹ H (300 MHz, DMSO- d ₆ ) δ 12.75 (s, 1H), 11.06 (s, 1H), 10.40 (s, 1H), 8.34 (d, J = 1.44 Hz, 1H), 8.14 (s, 1H ), 8.10 (s, 1H), 7.70-7.66 (d, J = 8.55 Hz, 1H), 7.24-7.15 (q, J = 8.37 Hz, 1H), 7.06-7.02 (dd, J = 8.85 Hz, 1.41 Hz 1H), 6.93 (s, 1H), 6.75-6.70 (m, 2H), 6.56-6.50 (td, J = 8.04 Hz, 1.77 Hz, 1H) 3.86 (s, 2H), 3.19 (s, 4H), 2.53 (s, 4H)

5 - ((4- (3-fluorophenyl) piperazin-1-yl) methyl) - N - (6- (furan-2-yl) -1 H-indazol-3-yl) isoxazole-- 3-carboxamide (Compound No. 23)

Yield 63%; Melting point 213.9 ° C .; IR 3366, 1690 (C═O), 1582, 1546, 1452 (Aromatic), 1337, 1177, 1010 cm ⁻¹ (piperazine); ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.95 (s, 1H), 11.01 (s, 1H), 7.79-7.73 (m, 3H), 7.47 (dd, J = 1.26 Hz, 8.58 Hz, 1H) , 7.24-7.16 (m, 1H), 7.06 (d, J = 3.29 Hz, 1H), 6.95 (s, 1H), 6.76-6.71 (m, 2H), 6.63-6.62 (m, 1H), 6.56-6.50 (td, J = 2.22 Hz, 8.4 Hz, 1H), 3.87 (s, 1H), 3.20 (s, 4H), 2.61 (s, 4H); ¹³ C NMR (400 MHz, DMSO- d ₆ ) δ 171.57, 164.92, 158.93, 158.24, 153.60, 153.11, 143.65, 141.79, 139.38, 130.73, 129.10, 122.62, 117.21, 116.42, 112.71, 111.37, 107. 105.09. , 104.60, 103.97, 102.43, 102.17, 52.44, 48.10

5 - ((4- (3-fluorophenyl) piperazin-1-yl) methyl) - N - (6- (furan-3-yl) -1 H-indazol-3-yl) isoxazole-- 3-carboxamide (Compound No. 24)

Yield 55%; Melting point 205.2 ° C .; IR 3302, 1702 (C═O), 1583, 1495, 1452 (Aromatic), 1353, 1164, 1000 cm ⁻¹ (piperazine); ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.91 (s, 1H), 11.09 (s, 1H), 8.29 (s, 1H), 7.77 (t, J = 1.66 Hz, 1H), 7.74 (m, 1H), 7.65 (s, 1H), 7.40 (dd, J = 1.15 Hz, 8.51 Hz, 1H), 7.21-7.16 (m, 1H), 7.0 (s, 1H), 6.95 (s, 1H), 6.76- 6.71 (m, 2 H), 6.54-6.51 (td, J = 1.83 Hz, 8.22 Hz, 1H); ¹³ C NMR (300 MHz, DMSO- d ₆ ) δ 171.57, 165.33, 162.14, 158.97, 158.21, 153.23 (d, J = 54.8 Hz), 144.84, 142.08, 140.34, 139.28, 130.89, 130.83 (d, J = 53.6 Hz), 126.49, 122.34, 119.26, 116.30, 111.39, 109.41, 106.75, 105.32 (d, J = 112.4 Hz), 103.94, 102.46 (d, J = 133.6 Hz), 52.51, 52.43, 48.11

N- (6-acetamido-1 H -indazol-3-yl) -1-methylpiperidine-4-carboxamide (Compound No. 25)

Yield 42%; IR 3211, 1658 (C = 0); ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.4 (s, 1H), 10.24 (s, 1H), 10.06 (s, 1H), 8.05 (s, 1H), 7.64 (d, J = 8.79 Hz, 1H), 6.95 (d, J = 8.82, 1H), 2.86 (m, 2H), 2.21 (s, 3H), 2.06 (s, 3H), 1.93 (m, 2H), 1.78 (m, 4H)

N- (6-acetamido-1 H -indazol-3-yl) pentaneamide (Compound No. 26)

yield 40%; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.4 (s, 1H), 10.2 (s, 1H), 10.1 (s, 1H), 8.05 (s, 1H), 7.65 (d, J = 8.73 Hz, 1H), 6.95 (d, J = 7.77 Hz, 1H), 2.36 (q, J = 7.38 Hz, 2H), 2.06 (s, 3H), 1.36 (m, 4H), 0.91 (t, J = 7.29 Hz, 3H)

N- (6-acetamido- 1H -indazol-3-yl) -4- (dimethylamino) butanamide (Compound No. 27)

Yield 43%; Melting point 245.1 ° C .; IR 3260, 1698 (C═O), 2948, 2829 (CH ₂ ) cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 10.32 (s, 1H), 10.07 (s, 1H), 8.05 (s, 1H), 7.68 (d, J = 8.76 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 2.41 (m, 4H), 2.25 (s, 6H), 2.06 (s, 3H), 1.80 (m, 2H)

N- (6-formamido- 1H -indazol-3-yl) -1-methylpiperidine-4-carboxamide (Compound No. 28)

yield 44%; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.47 (s, 1H), 10.33 (s, 1H), 10.28 (s, 1H), 8.31 (s, 1H), 8.02 (s, 1H), 7.7 ( d, J = 8.82 Hz, 1H), 6.97 (d, J = 8.82 Hz, 1H), 3.16 (s, 3H), 2.94 (m, 2H), 1.75 (m, 6H)

4- (dimethylamino) - N - (6- form omicron] -1 H - indazol-3-yl) butane amide (Compound No. 29)

yield 42%; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.45 (s, 1H), 10.33 (s, 1H), 10.31 (s, 1H), 8.31 (s, 1H), 8.02 (s, 1H), 7.70 ( d, J = 8.74 Hz, 1H), 6.75 (d, J = 8.04 Hz, 1H), 2.38 (t, J = 7.41 Hz, 2H), 2.24 (t, J = 6.8 Hz, 2H), 2.13 (s, 6H), 1.75 (m, 2H)

N- (6-acetamido-1 H -indazol-3-yl) -5- (3- (4-phenylpiperazin-1-yl) propyl) isoxazole-3-carboxamide (Compound No. 30)

Yield 43%; IR 3298, 1691 (C═O), 2950, 2833 (CH ₂ ), 1594, 1497, 1440 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.68 (s, 1H), 10.93 (s, 1H), 10.12 (s, 1H), 8.12 (s, 1H), 7.61 (d, J = 8.80 Hz, 1H), 7.20 (t, J = 7.4 Hz, 2H), 7.04 (dd, J = 8.95 Hz, 1.61 Hz, 1H), 6.92 (d, J = 8.03 Hz, 2H), 6.79-6.73 (m, 2H) , 3.18-3.10 (m, 4H), 2.90 (t, J = 7.4 Hz, 2H), 2.56-2.51 (m 4H), 2.41 (t, J = 7.01 Hz, 2H), 2.09 (s, 3H), 1.97 -1.87 (m, 2 H); ¹³ C NMR (75 MHz, DMSO- d ₆ ) δ 175.55, 169.13,159.01, 158.34, 151.49, 142.07, 139.10, 138.39, 129.36, 122.06, 119.22, 115.79, 114.15, 113.39, 101.44, 99.09, 72.74, 57.09, 57.09 , 48.64, 24.61, 24.38

N- (6-acetamido-1 H -indazol-3-yl) -5- (3- (4- (4-fluorophenyl) piperazin-1-yl) propyl) isoxazole-3- Carboxamide (Compound No. 31)

yield 51%; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.69 (s, 1H), 10.94 (s, 1H), 10.14 (s, 1H), 8.12 (s, 1H), 7.62 (d, J = 8.80 Hz, 1H), 7.03 (t, J = 8.91 Hz, 3H), 6.95-6.88 (m, 2H), 6.78 (s, 1H), 3.06 (s, 4H), 2.90 (t, J = 7.3 Hz, 2H), 2.52 (s, 4H), 2.39 (t, J = 6.81 Hz, 2H), 2.09 (s, 3H), 1.94-1.84 (m, 2H.

N- (6-acetamido-1 H -indazol-3-yl) -5- (3- (4- (3-fluorophenyl) piperazin-1-yl) propyl) isoxazole-3- Carboxamide (Compound No. 32)

Yield 39%; Melting point 210.9 ° C .; IR 3358, 1683 (C═O), 2953, 2826 (CH ₂ ), 1596, 1495, 1467, 1137 (CF) cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.69 (s, 1H), 10.93 (s, 1H), 10.14 (s, 1H), 8.12 (s, 1H), 7.60 (d, J = 8.78 Hz, 1H), 7.22-7.15 (m, 1H), 7.04 (d, J = 8.91 Hz, 1H), 6.78 (s, 1H), 6.75-6.68 (m, 2H), 6.52 (t, J = 8.21 Hz, 1H ), 3.16 (s, 4H), 2.90 (t, J = 7.3 Hz, 2H), 2.52 (s, 4H), 2.39 (t, J = 7.3 Hz, 2H), 2.09 (s, 3H0, 1.94-1.85 ( m, 2H); ¹³ C NMR (75 MHz, DMSO- d ₆ ) δ 175.80, 169.41, 165.57, 160.78 (d, J = 286.4 Hz), 159.24, 158.57, 153.51 (d, J = 10.1 Hz), 142.29, 139.32, 138.63, 130.97 (d, J = 10.5 Hz), 122.28, 114.38, 113.62, 111.45, 105.25 (d, J = 21.5 Hz), 102.51, 102.19, 101.69, 99.31, 72.98, 60.94, 57.31, 53.16, 48.36, 24.85

N- (6-acetamido-1 H -indazol-3-yl) -5- (3- (4- (3-chlorophenyl) piperazin-1-yl) propyl) isoxazole-3-car Copyamide (Compound No. 33)

Yield 30%; Melting point 197.4 ° C .; IR 3354, 1683 (C═O), 2826 (CH ₂ ), 1595, 1468, 1405, 746 (C—Cl) cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.69 (s, 1H), 10.94 (s, 1H), 10.12 (s, 1H), 8.12 (s, 1H), 7.61 (d, J = 8.80 Hz, 1H), 7.19 (t, J = 8.1 Hz, 2H), 7.05 (dd, J = 8.95 Hz, 1.61 Hz, 1H), 6.94-6.85 (m, 2H), 6.79-6.74 (m, 2H), 3.20- 3.10 (m, 4H), 2.90 (t, J = 7.3 Hz, 2H), 2.57-2.51 (m 4H), 2.41 (t, J = 6.8 Hz, 2H), 2.09 (s, 3H), 1.94-1.86 ( m, 2H); ¹³ C NMR (75 MHz, DMSO- d ₆ ) δ 175.76, 169.38, 159.25, 158.57, 152.93, 142.61, 139.34, 138.63, 134.51, 131.09, 122.32, 118.68, 115.17, 114.38, 114.28, 113.62, 72.98, 60. , 53.12, 48.29, 24.85, 24.60

N- (6-acetamido-1 H -indazol-3-yl) -5- (3- (4- (2-chlorophenyl) piperazin-1-yl) propyl) isoxazole-3-car Radiamide (Compound No. 34)

Yield 33%; Melting point 217.6 ° C .; IR 3307, 1686 (C = O), 2935, 2814 (CH ₂ ), 1594, 1464, 1434, 741 (C-Cl) cm ^-1 ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.68 (s, 1H), 10.93 (s, 1H), 10.10 (s, 1H), 8.12 (s, 1H), 7.61 (d, J = 8.80 Hz, 1H), 7.39 (dd, J = 7.9 Hz, 1.1 Hz, 1H), 7.31-7.25 (m, 1H), 7.15 (dd, J = 8.0 Hz, 1.16 Hz, 1H), 7.05-6.99 (m, 2H) , 6.78 (s, 1H), 2.98 (s, 4H), 2.90 (t, J = 7.4 Hz, 2H), 2.56 (s, 4H), 2.44 (t, J = 6.6 Hz, 2H), 2.09 (s, 3H), 1.94-1.86 (m, 2H); ¹³ C NMR (75 MHz, DMSO- d ₆ ) δ 175.82, 169.38, 159.25, 158.58, 149.73, 142.30, 139.35, 138.62, 131.02, 128.77, 128.31, 124.54, 122.33, 121.53, 114.37, 113.63, 101.68, 99.31, , 60.96, 57.32, 53.49, 51.54, 24.85

N- (6-acetamido-1 H -indazol-3-yl) -5-((4- (2-fluorophenyl) piperazin-1-yl) methyl) isoxazole-3-carbox Amide (Compound No. 35)

Yield 42%; Melting point 212.1 ° C .; IR 3249, 1689 (C = 0), 2837 (CH ₃ ) cm ^-1 ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.67 (s, 1H), 11.00 (s, 1H), 10.10 (s, 1H), 8.11 (s, 1H), 7.63 (d, J = 8.73 Hz, 1H), 7.15-6.92 (m, 6H), 3.87 (s, 2H), 3.04 (s, 4H), 2.61 (s, 4H), 2.08 (s, 3H)

N- (6-acetamido-1 H -indazol-3-yl) -5-((4- (2-chlorophenyl) piperazin-1-yl) methyl) isoxazole-3-carboxamide (Compound No. 36)

yield 26%; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.67 (s, 1H), 11.01 (s, 1H), 10.10 (s, 1H), 8.11 (s, 1H), 7.63 (d, J = 8.79 Hz, 1H), 7.41-7.38 (dd, J = 7.87 Hz, 0.82 Hz, 1H), 7.31-7.26 (t, J = 8.08 Hz, 1H), 7.16 (d, J = 7.92 Hz, 1H), 7.06-7.01 ( m, 2H), 6.92 (s, 1H), 3.89 (s, 2H), 3.00 (s, 4H), 2.66 (s, 4H), 2.08 (s, 3H)

N- (3- (2- (4- (2,3-dimethylphenyl) piperazin-1-yl) -2-oxoethylamino) -1 H -indazol-6-yl) acetamide (Compound No. 37 )

yield 32%; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.25 (s, 1H), 8.54 (s, 1H), 7.90 (d, J = 8.70 Hz, 1H), 7.60 (d, J = 8.58 Hz, 1H) , 7.17 (s, 1 H), 7.05 (t, J = 7.89 Hz, 1 H), 6.88 (t, J = 7.38 Hz, 2H). 4.23 (d, 2H), 3.68 (s, 4H), 2.84-2.76 (s, 4H), 2.21 (s, 3H), 2.19 (s, 3H), 2.07 (s, 3H)

N- (6-acetamido-1 H -indazol-3-yl) -5-((4- (3-chlorophenyl) piperazin-1-yl) methyl) isoxazole-3-carboxamide (Compound No. 38)

yield 30%; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.67 (s, 1H), 11.00 (s, 1H), 10.09 (s, 1H), 8.11 (s, 1H), 7.63 (d, J = 8.85 Hz, 1H), 7.22-7.17 (td, J = 8.29 Hz, 1.20 Hz, 1H) 7.04-7.01 (d, J = 8.85 Hz, 1H), 6.93-6.79 (m, 2H), 6.76 (d, J = 7.83 Hz , 1H), 3.86 (s, 2H), 3.17 (s, 4H), 2.61 (s, 4H), 2.08 (s, 3H)

N- (6-acetamido-1 H -indazol-3-yl) -5-((4-phenylpiperazin-1-yl) methyl) isoxazole-3-carboxamide (Compound No. 39)

Yield 44%; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.66 (s, 1H), 11.00 (s, 1H), 10.09 (s, 1H), 8.11 (s, 1H), 7.62 (d, J = 9.36 Hz, 1H), 7.23-7.17 (t, J = 8.52 Hz, 3H), 7.04-7.01 (dd, J = 8.85 Hz, 1.62 Hz, 1H), 6.94-6.91 (m, 4H), 6.77 (m, 1H), 3.86 (s, 1H), 3.16 (s, 4H), 2.08 (s, 3H)

[Example]

On the other hand, the novel compound represented by Formula 1 according to the present invention can be formulated in 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 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 2 . Tablets (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 fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.

Formulation 3 . Powder and Capsule

5.0 mg of the active ingredient was sieved, followed by mixing with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. Filled in 5 gelatin capsules.

Formulation 4 . Injection

Injectables were prepared by containing 100 mg as the active ingredient, as well as 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ -12H ₂ O and 2974 mg of distilled water.

Experimental Example

1. Inhibitory activity test for GSK-3β

GSK-3β (h) 5-10 mU was added to 8 mM MOPS pH 7.0, 0.2 mM EDTA, 20 u MYRRAAVPPSPSLSRHSSPHQS (p) EDEEE (Phspho GS2) with a final reaction volume of 25 uL using the assay protocol presented by Milipore. peptide), 10 mM magnesium acetate buffer solution [γ33P-ATP] (specific activity approx. 500 cpu / pmol). The reaction was initiated by adding a mixed solution of MgATP, and then incubated at room temperature for 40 minutes. 5 uL of 3% phosphate solution was added to the reaction solution to stop the solution. A 10 uL solution was taken and the solution was mucused on a P30 filter paper and washed three times with 50 mM phosphate solution for 5 minutes. After washing with methanol solution, and dried to calculate the dosage is shown in Table 1 below.

Test compound  GSK-3β remaining (%) (at 20) Aurora A GSK-3β Compound number 1 97 21 Compound number 2 97 24 Compound number 3 96 13 Compound number 4 94 17 Compound number 5 101 27 Compound number 6 95 32 Compound number 7 99 32 Compound number 8 96 9 Compound number 9 117 10 Compound number 10 101 14 Compound number 11 100 19 Compound number 12 113 39 Compound number 13 130 103 Compound number 14 126 105 Compound number 15 124 100 Compound number 16 106 94 Compound number 17 111 112 Compound no.18 108 107 Compound number 19 104 94 Compound number 20 112 99 Compound number 21 70 48 Compound number 22 69 32 Compound number 23 84 10 Compound number 24 103 15 AR-A014418 71 AR-A014418: (N- (4-methoxybenzyl) -N '-(5-nitrothiazol-2-yl)) urea
AR-A014418 is measured at 1.

2. Anticancer Drug Search Test

In order to determine the anticancer activity for the compound of the present invention was carried out as follows.

In this experiment, DU145 (Human prostate cancer cell line) and HT-29 (Human colon adenocarcinoma cell line) and HCT-116 (Human colorectal carcinoma cell line) were used as prostate cancer cell lines. These cancer cells were all human tumor cells and were cultured by the Korean Cell Line Bank. The culture medium was RPMI-1640 medium containing 10% fetal calf serum, and cultured in a constant temperature and humidity incubator (37 ℃, 5% CO ₂ ). Cell passage was performed once every 3 days using 0.25% trypsin-1 mM EDTA.

This study used the SRB assay (Sulforhodamine B assay method) developed in 1989 to measure the in vitro anticancer activity of the drug at the National Cancer Institute of the United States. Cells were separated from the implant using trypsin-CDTA solution for the passage of passaged cells for experiments, and the cells in culture were dispensed in 96-well microplates with 5 × 10 ³ cells per well in a CO ₂ incubator. Time incubation. The medium was removed and 100 uL of the test compound solution diluted to 4-fold concentration was added and incubated for 48 hours. 100 uL of formalin solution was added to fix the cells, and then washed five times with distilled water and dried at room temperature. 100% of 0.4% SRB solution was added thereto, and the mixture was left at room temperature for 30 minutes, washed five times with 1% acetic acid, and dried at room temperature. 200 mM of 10 mM Tisma base pH 10.3 was added to each well to completely dissolve the absorbance at 520 nm.

In order to calculate the efficacy of the test compound on cancer cells, GI ₅₀ was calculated according to the following formula (1) or (2).

In Equation 1, T ₀ is the number of cells before adding the test compound, and T ₂ is the number of cells after incubation for 48 hours after adding the test compound.

In Equation 2, T ₀ is the number of cells before adding the test compound, T ₂ is the number of cells after incubation for 48 hours after adding the test compound, and C is 48 hours incubating the control group without adding the test compound. The number of cells after one.

In addition, from the values calculated by Equation 1, the degree of inhibition (% inhibition) of each test compound by inhibiting the growth of cancer cells was determined by using data regression by the Lotus program. To Table 2 and Table 3, respectively. In addition, IC ₅₀ values were calculated from the% inhibition concentrations and are shown in Table 4 below.

 Test compound DU145  HT29 100 (μM) 25 (μM) 6.25 (μM) 100 (μM) 25 (μM) 6.25 (μM) Compound number 1 61.53 16.73 4.86 80.60 29.71 -0.68 Compound number 2 60.11 42.18 11.48 69.13 60.66 10.91 Compound number 3 37.31 15.71 4.73 72.49 22.75 9.44 Compound number 4 49.86 12.02 2.75 63.20 26.50 6.10 Compound number 5 65.53 53.38 13.78 84.37 63.90 29.55 Compound number 6 59.71 13.18 1.85 82.83 25.26 11.58 Compound number 7 57.05 30.41 7.21 67.99 52.05 11.65 Compound number 8 57.06 13.73 5.54 81.64 52.41 22.66 Compound number 9 49.78 30.30 8.42 70.72 54.75 23.42 Compound number 10 51.47 16.94 -3.91 78.62 48.16 19.40 Compound number 11 55.02 36.79 21.22 80.01 55.33 50.13 Compound number 12 45.39 32.74 3.18 61.58 56.54 14.14 Compound number 13 46.62 14.99 -1.40 89.90 46.42 9.87 Compound number 14 46.73 29.86 8.49 85.04 52.26 13.14 Compound number 15 51.38 34.04 16.31 77.34 39.67 13.08 Compound number 16 54.23 42.06 8.81 89.85 62.69 26.04 Compound number 17 47.95 29.96 6.84 83.26 43.47 19.83 Compound no.18 63.31 30.41 8.72 91.42 71.10 18.02 Compound number 19 82.75 19.06 6.12 93.10 69.31 24.89 Compound number 20 69.83 19.07 1.24 91.71 59.04 20.47 Compound number 21 44.77 34.35 32.62 64.12 62.07 62.34 Compound number 22 59.98 49.49 nd 62.26 56.10 nd Compound number 23 47.71 20.43 10.15 25.32 1.67 1.50 Compound number 24 28.57 27.49 18.67 12.10 -1.04 -2.29

 Test compound DU145  HT29 HCT-116 100 (μM) 10 (μM) 100 (μM) 10 (μM) 100 (μM) 10 (μM) Compound number 30 36.23 17.86 42.88  -3.56 81.31 14.00 Compound number 31 50.74 13.12 73.46 23.09 82.93 17.86 Compound number 32 47.63 15.87 45.79 20.92 71.88 13.12 Compound number 33 78.79 17.59 87.68 17.32 92.34 15.87 Compound number 34 92.84 51.23 92.30 26.39 92.69 17.59 Compound number 35 48.54 8.47 68.99 52.19 66.97 51.23 Compound number 36 36.74 14.00 55.05 14.78 64.46 8.47

 Test compound IC ₅₀ (μM) for cancer cell lines DU145 HT29 Compound number 5 45.58 ± 36.7 16.75 ± 0.64 Compound number 8 > 100 86.2 ± 19.52 Compound number 9 73.38 ± 37.6 35.70 ± 1.25 Compound number 11 55.98 ± 29.0 6.03 ± 0.13 Compound number 16 64.96 ± 39.8 27.15 ± 1.34 Compound number 17 72.09 ± 39.5 60.2 ± 0.00 Compound no.18 64.62 ± 17.8 35.45 ± 5.30 Compound number 19 45.86 ± 1.1 26.6 ± 2.83 Compound number 20 58.43 ± 13.8 39.1 ± 8.91 Compound number 21 61.99 ± 43.8 0.449 ± 0.61 Compound number 22 > 100 1.22 ± 0.78 Doxorubicin 0.66 ± 0.10 2.62 ± 0.69

As confirmed in Tables 2 to 4, the 1 H -indazole compound represented by Chemical Formula 1 according to the present invention exhibits cytotoxicity against various cancer cells.

Since the 1 H -indazole compound represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention has inhibitory activity against GSK-3, a disease caused by the activity of GSK-3, for example, glucose tolerance (이상 能) abnormalities, type 1 diabetes, type 2 diabetes, diabetic complications (retinopathy, nephropathy, neuropathy, macrovascular disorders, etc.), Alzheimer's disease, neurodegenerative diseases (AIDS encephalopathy, Huntington's disease, Parkinson's disease, muscular dystrophy, Multiple sclerosis peek disease, advanced nucleus paralysis, etc.), bipolar emotional disorders (depressive disorder), traumatic brain and spinal cord injury, epilepsy, obesity, atherosclerosis, hypertension, polycystic ovary syndrome, syndrome X, alopecia, inflammatory diseases (deformed arthrosis) , Rheumatoid, atopic dermatitis, psoriasis, ulcerative colitis, clonal disease, sepsis, systemic inflammatory response syndrome, etc.), cancer (breast cancer, colon cancer, pancreatic cancer, ovarian cancer, etc.), and immunodeficiency.

Claims (6)

Compounds characterized in that selected from the 1 H -indazole compound represented by the formula (1) and a pharmaceutically acceptable salt:
[Formula 1]

In Chemical Formula 1,
R ¹ represents a formamido group, a C ₁ -C ₆ alkylamido group, or a furanyl group;
R ² and R ³ are the same or different and represents hydrogen atom, or _{- (CH 2) m -C (} O) -X- (CH 2) _n -R ⁴ represents, but R ² and R ³ are hydrogen atoms at the same time Except if;
R ⁴ represents a hydrogen atom, a C ₁ -C ₆ alkylamino group, a di (C ₁ -C ₆ alkyl) amino group, or a heterocyclic group consisting of 5 to 10 atoms including one or two heteroatoms selected from oxygen and nitrogen, wherein Heterocyclic groups may be unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halo, C ₁ -C ₆ alkyl, phenyl, and phenyl substituted with halo or C ₁ -C ₆ alkyl;
X is a single bond or represents an oxazolenyl group or an isooxazolenyl group;
m and n are the same as or different from each other and represent an integer of 0 to 6.
The method according to claim 1,
X is a single bond or represents an isoxazolyl group;
R ¹ represents a formamido group, an acetamido group, a furan-2-yl group, or a furan-3-yl group;
R ² represents a hydrogen atom,-(CH ₂ ) _m -C (O)-(CH ₂ ) _n -R ⁴ , or -C (O) -X- (CH ₂ ) _n -R ⁴ ;
R ³ represents a hydrogen atom or-(CH ₂ ) _m -C (O)-(CH ₂ ) _n -R ⁴ ; Except that when R ² and R ³ are hydrogen atoms at the same time;
R ⁴ is a hydrogen atom, methylamino group, dimethylamino group, diethylamino group, pyrrolidinyl group, morpholino group, piperidinyl group, 1-methylpiperidinyl group, piperazinyl group, 4-methylpiperazinyl group , 4-ethylpiperazinyl group, 4- (2-chlorophenyl) piperazinyl group, 4- (3-chlorophenyl) piperazinyl group, 4- (2-fluorophenyl) piperazinyl group, 4 -(3-fluorophenyl) piperazinyl group, 4- (4-fluorophenyl) piperazinyl group, or 4- (2,3-dimethylphenyl) piperazinyl group;
X represents a single bond or represents an oxazolenyl group or an isooxazolenyl group;
M represents an integer of 0, 1, 2, or 3;
N is an integer of 0, 1, 2, or 3, characterized in that the compound.
N- (6- (furan-2-yl) -1 H -indazol-3-yl) -4- (4-methylpiperazin-1-yl) butanamide (Compound No. 1);
N- (6- (furan-3-yl) -1 H -indazol-3-yl) -4- (4-methylpiperazin-1-yl) butanamide (Compound No. 2);
N- (6- (furan-2-yl) -1 H -indazol-3-yl) -4-morpholinobutaneamide (Compound No. 3);
N- (6- (furan-3-yl) -1 H -indazol-3-yl) -4-morpholinobutaneamide (Compound No. 4);
N- (6- (furan-3-yl) -1 H -indazol-3-yl-4- (pyrrolidin-1-yl) butanamide (Compound No. 5);
4- (4-ethyl-piperazin-1-yl) - N - (6- (furan-2-yl) -1 H - indazol-3-yl) butane amide (Compound No. 6);
4- (4-ethyl-piperazin-1-yl) - N - (6- (furan-3-yl) -1 H - indazol-3-yl) butane amide (Compound No. 7);
N- (6- (furan-2-yl) -1 H -indazol-3-yl) pentanamide (Compound No. 8);
N- (6- (furan-3-yl) -1 H -indazol-3-yl) pentanamide (Compound No. 9);
N- (6- (furan-2-yl) -1 H -indazol-3-yl) -1-methylpiperidine-4-carboxamide (Compound No. 10);
N- (6- (furan-3-yl) -1 H -indazol-3-yl) -1-methylpiperidine-4-carboxamide (Compound No. 11);
4- (dimethylamino) - N - (6- (furan-3-yl) -1 H - indazol-3-yl) butane amide (Compound No. 12);
1- (3-amino-6- (furan-2-yl) -1 H -indazol-1-yl) -4- (dimethylamino) butan-1-one hydrochloride (Compound No. 13);
1- (3-amino-6- (furan-2-yl) -1 H -indazol-1-yl) -4- (4-methylpiperazin-1-yl) butan-1-one hydrochloride (compound Number 14);
1- (3-amino-6- (furan-2-yl) -1 H -indazol-1-yl) -4-morpholinobutan-1-one hydrochloride (Compound No. 15);
1- (3-amino-6- (furan-2-yl) -1 H -indazol-1-yl) -4- (4-ethylpiperazin-1-yl) butan-1-one hydrochloride (compound Number 16);
1- (3-amino-6- (furan-3-yl) -1 H -indazol-1-yl) -4- (4-ethylpiperazin-1-yl) butan-1-one hydrochloride (compound Number 17);
1- (3-amino-6- (furan-3-yl) -1 H -indazol-1-yl) -5- (4-ethylpiperazin-1-yl) pentan-1-one hydrochloride (compound Number 18);
(3-amino-6- (furan-2-yl) -1 H -indazol-1-yl)-(1-methylpiperazin-4-yl) methanone hydrochloride (Compound No. 19);
(3-amino-6- (furan-3-yl) -1 H -indazol-1-yl) (1-methylpiperazin-4-yl) methanone hydrochloride (Compound No. 20);
N- (6-acetamido-1 H -indazol-3-yl) -5-((4- (3-fluorophenyl) piperazin-1-yl) methyl) isoxazole-3-carbox Amide (Compound No. 21);
5 - ((4- (3-phenyl), fluoro-1-yl) methyl) - N - (6- form omicron] -1 H-indazol-3-yl) isoxazole-3-carboxamide Amide (Compound No. 22);
5 - ((4- (3-fluorophenyl) piperazin-1-yl) methyl) - N - (6- (furan-2-yl) -1 H-indazol-3-yl) isoxazole-- 3-carboxamide (Compound No. 23);
5 - ((4- (3-fluorophenyl) piperazin-1-yl) methyl) - N - (6- (furan-3-yl) -1 H-indazol-3-yl) isoxazole-- 3-carboxamide (Compound No. 24);
N- (6-acetamido-1 H -indazol-3-yl) -1-methylpiperidine-4-carboxamide (Compound No. 25);
N- (6-acetamido-1 H -indazol-3-yl) pentaneamide (Compound No. 26);
N- (6-acetamido-1 H -indazol-3-yl) -4- (dimethylamino) butanamide (Compound No. 27);
N- (6-formamido-1 H -indazol-3-yl) -1-methylpiperidine-4-carboxamide (Compound No. 28);
4- (dimethylamino) - N - (6- form omicron] -1 H - indazol-3-yl) butane amide (Compound No. 29);
N- (6-acetamido-1 H -indazol-3-yl) -5- (3- (4-phenylpiperazin-1-yl) propyl) isoxazole-3-carboxamide (Compound No. 30);
N- (6-acetamido-1 H -indazol-3-yl) -5- (3- (4- (4-fluorophenyl) piperazin-1-yl) propyl) isoxazole-3- Carboxamide (Compound No. 31);
N- (6-acetamido-1 H -indazol-3-yl) -5- (3- (4- (3-fluorophenyl) piperazin-1-yl) propyl) isoxazole-3- Carboxamide (Compound No. 32);
N- (6-acetamido-1 H -indazol-3-yl) -5- (3- (4- (3-chlorophenyl) piperazin-1-yl) propyl) isoxazole-3-car Radiamide (Compound No. 33);
N- (6-acetamido-1 H -indazol-3-yl) -5- (3- (4- (2-chlorophenyl) piperazin-1-yl) propyl) isoxazole-3-car Radiamide (Compound No. 34);
N- (6-acetamido-1 H -indazol-3-yl) -5-((4- (2-fluorophenyl) piperazin-1-yl) methyl) isoxazole-3-carbox Amide (Compound No. 35);
N- (6-acetamido-1 H -indazol-3-yl) -5-((4- (2-chlorophenyl) piperazin-1-yl) methyl) isoxazole-3-carboxamide (Compound No. 36);
N- (3- (2- (4- (2,3-dimethylphenyl) piperazin-1-yl) -2-oxoethylamino) -1 H -indazol-6-yl) acetamide (Compound No. 37 );
N- (6-acetamido-1 H -indazol-3-yl) -5-((4- (3-chlorophenyl) piperazin-1-yl) methyl) isoxazole-3-carboxamide (Compound number 38);
N- (6-acetamido-1 H -indazol-3-yl) -5-((4-phenylpiperazin-1-yl) methyl) isoxazole-3-carboxamide (Compound No. 39) ; And
A compound characterized in that it is selected from pharmaceutically acceptable salts thereof.
The 3-amino-1 H -indazole compound represented by the following formula (2) and the substituted carboxylic acid compound represented by the following formula (3) include pyridine base and 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydro hydrochloride (EDCI) by amide-forming reaction in the presence, to H 1 of the formula 1a - process for producing a compound indazol - 1 H, characterized in that for preparing indazole compounds:
(2)

(3)

[Formula 1a]

In Formula 1a, 2, or 3, X, R ¹ , R ⁴ , and n are the same as defined in Claim 1, respectively.
To 3-amino-1 H -indazole compound represented by the following Chemical Formula 2 and the substituted carboxylic acid compound represented by the following Chemical Formula 3, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCI ), Hydroxy- 1H -benzotriazole (HOBT) and amidation reaction in the presence of N -methylmorpholine (NMM) to prepare 3-amino- 1H -indazole compound represented by the following general formula (1b). Method for producing a 1 H -indazole compound characterized by:
(2)

(3)

[Chemical Formula 1b]

In Formula 1b, 2, or 3, X, R ¹ , R ⁴ , and n are the same as defined in Claim 1, respectively.
Glucose tolerance (耐 糖 能) abnormalities containing any one of the compounds selected from claims 1 to 3, type 1 diabetes, type 2 diabetes, diabetes complications, Alzheimer's disease, neurodegenerative disorders, bipolar emotional disorders, traumatic brain and spinal cord A pharmaceutical composition for treating a disease selected from the group consisting of injury, epilepsy, obesity, atherosclerosis, hypertension, polycystic ovary syndrome, syndrome X, alopecia, inflammatory disease, cancer, and immunodeficiency.