KR20100057433A - Novel pyrazolo[4,3-b]pyridine derivatives or pharmaceutically acceptable salt thereof, preparation method thereof and pharmaceutical composition containing the same as an active ingredient - Google Patents

Abstract

PURPOSE: A pharmaceutical composition for preventing or treating melanoma containing a novel pyrazolo[4,3-b]pyridine derivative is provided to ensure suppression activity to tyrosine kinase. CONSTITUTION: A pyrazolo[4,3-b]pyridine derivative is denoted by chemical formula 1. A method for manufacturing the pyrazolo[4,3-b]pyridine derivative comprises: a step of reacting Boc-protected hydrazine to a compound of chemical formula 2 to obtain a compound of chemical formula 3; a step of adding acid to the compound of chemical formula 3 to obtain a compound of chemical formula 4; and a step of reacting benzylhalide or arylmethylene halide under the presence of inorganic base to obtain a compound of chemical formula 5.

Description

Novel pyrazolo [4,3-ｂ] pyridine derivatives or pharmaceutically acceptable salts thereof, preparation methods thereof and pharmaceutical compositions containing the same as active ingredients Novel pyrazolo [4,3-b] pyridine derivatives or pharmaceutically acceptable salts definitely, preparation method according to the formula and the pharmaceutical composition

The present invention relates to a novel pyrazolo [4,3-b] pyridine derivative or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient.

Ligands of hepatocyte growth factor receptor (c-Met or HGFR) tyrosine kinase (RTK) may be HGF or scatter factor [L. Naldini, K.M. Weidner, E. Vigna, G. Gaudino, A. Bardelli, C. Ponzetto, G.K. Michalopoulos, Eur. Mol. Biol. Org. J. 10 (1991) 2867-2878; D.P. Bottaro, J.S. Rubin, D.L. Faletto, A.M. Chan, T.E. Kmiecik, G.F. Vande Woude, S.A. Aaronson, Science 251 (1991) 802-804], a disulfide-linked heterodimeric protein produced mainly by mesenchymal cells. Hepatocyte growth factor (HGF), a ligand, binds to receptor c-Met and is automatically phosphorylated to specific tyrosine kinases in the cell. When activated, cell growth, survival, angiogenesis, wound healing, tissue regeneration, dispersion, and cell motility Regulating various cellular functions, including invasion and morphogenesis. c-MET and HGF are expressed in many tissues, but their expression normally occurs in tissues consisting primarily of epithelial and mesenchymal cells and is required for normal mammalian development, cell migration, cell proliferation and survival, differentiation, and tissue arrangement Turned out to be important. HGF / SF is also an angiogenesis factor, and c-Met signaling in epithelial cells can induce many things, such as cell proliferation, motility, and invasiveness necessary for angiogenesis.

c-Met receptors have been shown to be expressed in many human cancers. In addition, c-Met gene amplification, mutations and rearrangements have been observed in various human cancers. c-Met and its ligand, HGF, have also been reported to overexpress various human cancers, such as brain tumors, lung cancers, gastric cancers, pancreatic cancers, colon cancers, ovarian cancers, renal cell cancers, prostate cancers, etc. [Oncology Reports, 1998, 5, 1013]. Classes with mutations that activate c-Met kinase are susceptible to multiple kidney tumors and tumors of other tissues. In addition, overexpression of c-Met or HGF has been found to correlate with poor prognosis and disease outcome in many major human cancers, including lung, liver, stomach, breast, and the like, and c-Met has also been described in pancreatic cancer [R. M. Thomas, K Toney, C Fenoglio-Preiser, M. P. Revelo-Penafiel, S. R. Hingorani, D. A. Tuveson, S. E. Waltz, A. M. Lowy, Cancer Res 2007, 67, 6075; E. R. Camp, A. Yang, M. J. Gray, F. Fan, S. R. Hamilton, D. B. Evans, A. T. Hooper, D. S. Pereira, D. J. Hicklin, L. M. Ellis, CANCER, 2007, 109, 1031], glioma [B. Wullich, H.P. Sattler, U. Fischer, E. Meese, T, Anticancer Res. 1994, 14, 577-579] is directly related to difficult cancer. In particular, gastric cancer has been reported to overexpress c-Met or raise HGF levels in serum [Int. J. Cancer, 1993, 55, 72].

Therefore, inhibition of hepatocyte growth factor receptor (c-MET or HGFR) tyrosine kinase (RTK), which is involved in the growth and cell migration, cell proliferation and survival, differentiation, and tissue alignment of various cancers, allows the arrest and regression of tumorigenesis. can do.

Conventionally, compounds that inhibit the signaling system of HGF have been developed in clinical and preclinical studies. Currently, phase 2 clinical trials are progressed for pancreatic cancer and multi-target inhibitor XL-880 for renal cancer such as ARQ-197, a c-Met selective inhibitor. Pfizer's PF-2341066 and MP-470 are under development in Phase I clinical trials. In addition, MGCD265, SGX-523, and unstructured compounds are known to be undergoing preclinical or clinical studies at Merck, Amgen and Johnson & Johnson.

Meanwhile, although compounds having a pyrazolopyridine skeleton as a kinase inhibitor are known from International Patent Publications WO07 / 023110 and WO2002022604, a compound in which a benzyl or aryl group is substituted at the N-1 position of pyrazolopyridine is not disclosed. In terms of efficacy, Roche has only been reported as a kinase inhibitor targeting P38 MAP kinase (WO07 / 023110) and Vertex Corp. targeting GSK-3, CDK-2 and Aurora.

None of the documents reported to date disclose a pyrazolopyridine derivative according to the invention having a substituent at the C-7 position of pyrazolopyridine and a benzyl or aryl group substituted at the N-1 position.

Accordingly, the present inventors have studied to develop a compound having a new structure that inhibits the signaling system of c-Met tyrosine kinase, and thus synthesizes a novel pyrazolo [4,3-b] pyridine derivative, and the derivative is c-Met. It has been confirmed that there is an excellent inhibitory activity against tyrosine kinase, and the derivatives are useful for preventing and treating diseases related to abnormal cellularity involving c-Met tyrosine kinase, such as tumors, psoriasis, rheumatism and diabetic retinopathy. It has been found that it can be used and the present invention has been completed.

It is an object of the present invention to provide novel pyrazolo [4,3-b] pyridine derivatives or pharmaceutically acceptable salts thereof having excellent inhibitory activity against c-Met tyrosine kinases.

Another object of the present invention is to provide a method for preparing the pyrazolo [4,3-b] pyridine derivative.

Still another object of the present invention is to provide a c-Met tyrosine kinase such as tumor, psoriasis, rheumatism, diabetic retina, etc. containing the pyrazolo [4,3-b] pyridine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a pharmaceutical composition for the prevention or treatment of diseases related to abnormal cell growth involved.

In order to achieve the above object, the present invention provides a novel pyrazolo [4,3-b] pyridine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for preparing the pyrazolo [4,3-b] pyridine derivative.

Furthermore, the present invention is for the prevention or treatment of diseases related to abnormal cell growth involving c-Met tyrosine kinase containing the pyrazolo [4,3-b] pyridine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a pharmaceutical composition.

[Formula 1]

(R ¹ in Formula ¹ , R ² and R ³ are as defined herein)

Since the pyrazolo [4,3-b] pyridine derivatives according to the present invention exhibit inhibitory activity against tyrosine kinases, diseases caused by abnormal tyrosine kinase activity, for example, tumors, psoriasis, rheumatism, diabetic retinopathy, etc. It can be usefully used for the prevention or treatment of.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

The present invention provides a pyrazolo [4,3-b] pyridine derivative represented by Formula 1 below or a pharmaceutically acceptable salt thereof.

In Chemical Formula 1,

R ¹ is C ₅ unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, straight or branched chain alkyl of C ₁ to C ₄ , and straight or branched chain alkyl of C ₁ to C ₄ substituted with halogen. ˜C ₁₂ aryl C ₁ ˜C ₄ alkyl,

R ² is hydrogen or —NRR ′ wherein R is unsubstituted or is selected from the group consisting of C ₁ to C ₄ straight or branched chain alkyl, benzyl and -C (═O) R ⁴ , wherein R ⁴ is any one selected from the group consisting of straight or branched alkyl, phenyl and benzyl of C ₁ ~ C ₄ a C ₁ ~ C ₄ linear or branched alkyl, substituted by halogen, the said R 'is hydrogen or C ₁ Straight or branched alkyl of ˜C ₄ ,

R ³ is unsubstituted or pyrazole substituted with a substituent selected from the group consisting of C ₁ -C ₄ straight or branched chain alkyl and piperidine; Or phenyl substituted with a substituent selected from the group consisting of -CONR ⁵ R ⁶ and -NR ⁵ R ⁶ , wherein R ⁵ and R ⁶ are independently of one another or optionally hydrogen or C ₁ -C ₄ linear or branched alkyl Or; Or R ⁵ and R ⁶ may include one or more N or O to form a ring such that the NR ⁵ R ⁶ moieties of the above-CONR ⁵ R ⁶ and -NR ⁵ R ⁶ are a morpholine group or a piperazine group.

Preferably

R ¹ is benzyl or naphthalenylmethyl unsubstituted or substituted with one or more substituents selected from the group consisting of chloro, fluoro, methyl, ethyl, propyl, isopropyl, and trifluoromethyl,

R ² is hydrogen or —NRR ′ wherein R is unsubstituted or is selected from the group consisting of methyl, ethyl, benzyl and —C (═O) R ⁴ , wherein R ⁴ is methyl, ethyl , Trifluoromethyl, phenyl and benzyl, any one selected from the group consisting of hydrogen, methyl, ethyl,

R ³ is pyrazole wherein nitrogen is substituted with a substituent selected from the group consisting of methyl, ethyl and piperidine; Or phenyl substituted with an amide compound substituted with a piperazine group.

More preferably,

R ¹ is benzyl, dichlorobenzyl, 2-chloro-6-fluorobenzyl, isopropylbenzyl, trifluoromethylbenzyl, 2,6-dichloro-3-fluorobenzyl, naphthalen-1-ylmethyl and 2- Methylnaphthalen-1-ylmethyl is any one selected from the group consisting of,

R ² is hydrogen or —NRR ′ wherein R is any one selected from the group consisting of hydrogen, methyl, benzyl, methylcarbonyl, trifluoromethylcarbonyl, phenylcarbonyl and benzylcarbonyl, wherein R 'Is hydrogen or methyl,

R ³ is 1-methyl-1H-pyrazol-4-yl, 1-piperidin-4-yl-1H-pyrazol-4-yl and 4- (4-methyl-piperidin-1-ylcar Or any one selected from the group consisting of carbonyl) phenyl.

Preferred compounds among the pyrazolo [4,3-b] pyridine derivatives according to the present invention are specifically as follows.

(1) 1- (2,6-dichlorobenzyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-ylamine;

(2) 1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine- 3-ylamine;

(3) 1-benzyl-6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-ylamine;

(4) 1-benzyl-6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-ylamine;

(5) 1- (2-chloro-6-fluorobenzyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-yl Amines;

(6) 1- (2-chloro-6-fluorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b ] Pyridin-3-ylamine;

(7) 1- (4-isopropylbenzyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-ylamine;

(8) 6- (1-methyl-1H-pyrazol-4-yl) -1- (3-trifluoromethylbenzyl) -1H-pyrazolo [4,3-b] pyridin-3-ylamine ;

(9) 1- (2,6-dichloro-3-fluorobenzyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine-3 -Ylamine;

(10) 1- (2,6-dichloro-3-fluorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3 -b] pyridin-3-ylamine;

(11) 6- (1-methyl-1H-pyrazol-4-yl) -1-naphthalen-1-ylmethyl-1H-pyrazolo [4,3-b] pyridin-3-ylamine;

(12) 1-naphthalen-1-ylmethyl-6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine-3- Monoamine;

(13) 1- (2-methyl-naphthalen-1-ylmethyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine-3- Monoamine;

(14) 1- (2-methyl-naphthalen-1-ylmethyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3- b] pyridin-3-ylamine;

(15) 6- (1-methyl-1H-pyrazol-4-yl) -1-naphthalen-2-ylmethyl-1H-pyrazolo [4,3-b] pyridin-3-ylamine;

(16) benzyl- [1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b ] Pyridin-3-yl] -amine;

(17) [1- (2,6-dichlorobenzene) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine -3-yl] -methylamine;

(18) N- [1- (2,6-dichloro-3-fluorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [ 4,3-b] pyridin-3-yl] -2,2,2-trifluoro-acetamide;

(19) N- [1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b ] Pyridin-3-yl] -benzamide;

(20) N- [1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b ] Pyridine-3-]-2-phenyl-acetamide;

(21) N- [1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b ] Pyridin-3-yl] -acetamide;

(22) N- [1- (2,6-dichlorobenzyl-3-fluorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrazolo [4 , 3-b] pyridin-3-yl] -2,2,2-trifluoro-N-methyl-acetamide;

(23) {4- [3-amino-1- (2,6-dichlorobenzyl) -1H-pyrazolo [4,3-b] pyridin-6-yl] -phenyl}-(4-methyl-piperazine -1-yl) -methanone; And

(24) 1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine.

The following table summarizes the structure of the derivative of Formula 1 according to the present invention.

compound rescue compound rescue One

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

The present invention includes not only pyrazolo [4,3-b] pyridine derivatives represented by Formula 1 or pharmaceutically acceptable salts thereof, but also all possible solvates or hydrates that can be prepared therefrom.

The derivative of formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonates, naphthalene-2-sulfonates or mandelate.

The acid addition salts according to the invention are dissolved in conventional methods, for example, by dissolving a derivative of formula 1 in an excess of aqueous acid solution and using the water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation. It may also be prepared by evaporating the solvent or excess acid from the mixture and then drying or by suction filtration of the precipitated salt.

In addition, bases can be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg, silver nitrate).

The present invention also provides a method for preparing a novel pyrazolo [4,3-b] pyridine derivative of Chemical Formula 1.

As the present invention is shown in Scheme 1,

Preparing a compound of Formula 3 by reacting Boc-protected hydrazine with a compound of Formula 2 which is a starting material in an organic solvent (step 1);

Preparing an compound of formula 4 by adding an acid to the compound of formula 3 prepared in step 1 (step 2);

Preparing a compound of Chemical Formula 5 by reacting benzyl halide or arylmethylene halide represented by R ¹ X at the N-1 position of the compound of Chemical Formula 4 prepared in step 2 under inorganic base conditions (step 3); And

Comprising the compound of formula (5) prepared in step 3 in the presence of palladium and the Suzuki bond reaction with pyrazolboronic acid or phenylboronic acid represented by R ³ B (OH) ₂ (step 4) Provided is a method for preparing a derivative of Formula 1 ( Preparation 1 ).

(In Scheme 1, R ¹ and R ³ are as defined in Formula 1, Formula 1a is a kind of derivative represented by Formula 1.)

In addition, the present invention as shown in Scheme 2,

By acylation or acylation of the compound of Formula 1a prepared in Step 4 of Preparation Method 1, an alkylation reaction and an acyl group removal reaction are performed to introduce R and R 'groups into the amine group at the C-3 position. It provides a method for producing a derivative represented by Formula 1 further comprising the step of preparing a compound of Formula 1b (Step 5) ( Preparation 2 ).

(In Scheme 2, R ¹ , R ³ and -NRR 'are as defined in Formula 1, Formula 1a and 1b is a kind of derivative represented by Formula 1.)

Furthermore, the present invention, as shown in Scheme 3 below,

Preparing a compound of formula 8 by reacting a compound of formula 2 as a starting material in an organic solvent with methanol in the presence of an acid (step a);

Preparing an aldehyde compound of Formula 9 by performing a reduction reaction to obtain an alcohol derivative by reducing the compound of Formula 8 prepared in step a (step b);

Preparing a compound of formula 10 by reacting hydrazine with the compound of formula 9 prepared in step b (step c);

Preparing a compound of Chemical Formula 11 by reacting benzyl halide or arylmethylene halide represented by R ¹ X at the N-1 position of the compound of Chemical Formula 10 prepared in step c under inorganic base conditions (step d); And

Comprising the compound of formula 11 prepared in step d in the presence of palladium and the Suzuki bond reaction with pyrazolboronic acid or phenylboronic acid represented by R ³ B (OH) ₂ (step e) Provided is a method for preparing a derivative of Formula 1 ( Preparation 3 ).

(In Scheme 3, R ¹ and R ³ are as defined in Formula 1, Formula 1c is a kind of derivative of Formula 1).

Hereinafter, the above production method 1-3 according to the present invention will be described in more detail.

Preparation 1:

First, Step 1 according to the present invention is a step of preparing a compound of Formula 3 by reacting a hydrazine-protected hydrazine with a compound of Formula 2, which is a starting material, under an organic solvent.

The compound of Formula 2 may be purchased commercially or described in Organic Lett. 2005, 7, 577, but is not limited thereto.

The compound of Formula 2 obtained by the above method is added to an organic solvent, hydrazine protected with Boc, and then heated and stirred at 50 to 110 ° C. to prepare the compound of Formula 3.

In this case, ethanol, benzene, toluene, tetrahydrofuran, dioxane, dimethylformaldehyde, dimethyl sulfoxide, dimethylacetamide, etc. may be used as the organic solvent.

Next, step 2 is a step of preparing a compound of formula 4 by adding an acid to the compound of formula 3 prepared in step 1.

In the preparation method according to the present invention, the acid may be 4M HCl / dioxane or trifluoroacetic acid, but is not limited thereto, and the compound of Chemical Formula 4 may be obtained by acid treatment at 20 to 150 ° C.

The method was developed by the applicant and many similar reactions have been reported for the synthesis of indazole from 2-fluorobenzonitrile, but the literature used for the synthesis of pyrazolepyridine is a new method that has not been reported. Through this method, a derivative represented by Chemical Formula 4, which is a medically useful intermediate, can be easily synthesized.

Next, step 3 is a step of preparing a compound of formula 5 by reacting benzyl halide or aryl methylene halide represented by R ¹ X at the N-1 position of the compound of formula 4 prepared in step 2 under inorganic base conditions to be.

Specifically, R ¹ X is substituted benzyl bromide or benzyl chloride or arylmethylene bromide or arylmethyl chloride, and the inorganic base may be sodium carbonate, potassium carbonate cesium carbonate, etc., and acetone, methyl ethyl ketone as a reaction solvent. , Tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and the like can be used, and the reaction temperature is preferably 10 to 100 ° C.

Next, step 4 is a step of preparing a compound of formula 1a by suzuki bond reaction of the compound of formula 5 prepared in step 3 with pyrazolboronic acid or phenylboronic acid represented by R ³ B (OH) ₂ in the presence of palladium to be.

Step 4 may be performed using a coupling reaction commonly used in the art, but it is preferable to use a Suzuki coupling reaction.

Recipe 2:

In the preparation method 2 according to the present invention, after performing the preparation method 1, various substitution reactions may be further performed to introduce R and R ′ to the amine group at the C-3 position of the prepared compound of Formula 1a. Specifically, the compound of formula 1b in which the amine group in the C-3 position is substituted with an amide group can be obtained through an acylation reaction, and the C- can be obtained through the alkylation reaction of the amide compound obtained by the acylation reaction and the removal of the acyl group. Another compound of formula (Ib) may be obtained in which the amine group at the 3-position is substituted with alkylamine.

Recipe 3:

Furthermore, Preparation 3 according to the present invention is a method of preparing a compound in which R ² of the derivative represented by Formula 1 is substituted with hydrogen. Specifically, as in step a of Scheme 3, the compound of Formula 2 is reacted with methanol in the presence of an acid to obtain a compound of Formula 8; As in step b, after the reduction reaction using a reducing agent such as NaBH ₄ , LiAlH ₄ , DIBAL-H and the like, the obtained alcohol derivative is oxidized using an oxidizing agent such as PCC, ClCOCOCl / DMSO (Swern oxidation), IBX and the like. An aldehyde compound of formula 9 can be obtained.

Thereafter, as in step c, hydrazine is added to the compound of formula 9 obtained in step b and stirred at 50 to 150 ° C. to obtain a pyrazolopyridine compound of formula 10.

Compounds of formula (10) can be obtained by the same method as in steps 3 and 4 of Preparation 1 to obtain compounds of formula (1c) in which R ² in formula (1) is replaced with hydrogen. d and step e).

However, the pyrazolo [4,3-b] pyridine derivatives according to the present invention are not limited to the above synthesis methods, and in addition to the known methods, the pyrazolo [4,3-b] pyridine derivatives may be used. If the method can be synthesized can be used without limitation.

The reaction intermediate compound or the novel pyrazolo [4,3-b] pyridine derivative represented by Formula 1 may be separated and purified by conventional methods such as chromatography and recrystallization. The molecular structure can be confirmed by nuclear magnetic resonance.

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating melanoma, which comprises a pyrazolo [4,3-b] pyridine derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The novel pyrazolo [4,3-b] pyridine derivatives or their pharmaceutically acceptable salts of formula (I) of the present invention exhibited an IC ₅₀ of 2.3-8.8 μM in the inhibitory activity of tyrosine kinases, thus providing an excellent effect on c-Met. It can be seen that it shows inhibitory activity (see Table 2).

Therefore, the compounds of the present invention exhibit inhibitory activity against tyrosine kinases, and thus can be usefully used for the prevention or treatment of diseases caused by abnormal tyrosine kinase activity, such as tumors, psoriasis, rheumatism, diabetic retinopathy, and the like. have.

When the composition of the present invention is used as a medicine, a pharmaceutical composition containing a pyrazolo [4,3-b] pyridine derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be used during clinical administration. It may be formulated and administered in various oral or parenteral dosage forms, but is not limited thereto.

Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and the like. Rose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt. Disintegrant or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.

The pharmaceutical composition comprising the derivative represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be by injecting subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

In this case, to prepare a formulation for parenteral administration, the pyrazolo [4,3-b] pyridine derivative of Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a buffer to prepare a solution or suspension. It may be prepared in ampule or vial unit dosage forms. The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.

In addition, the dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally based on an adult patient having a weight of 70 kg. It is 0.01-400 mg / day, and may be dividedly administered once to several times a day at regular intervals according to the judgment of a doctor or a pharmacist.

Hereinafter, the present invention will be described in detail through examples. However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited by the following examples.

Example 1 1- (2,6-dichlorobenzyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-ylamine Manufacture

Step 1: Preparation of N '-(5-bromo-2-cyanopyridin-3-yl) hydrazinecarboxylic acid t-butylest

5-bromo-3-fluoropicolinonitrile (0.82 g, 4.08 mmol) and hydrazinecarboxylic acid t-butylest (BocNHNH ₂ ; 1.08 g 8.16 mmol) were dissolved in DMSO (10 mL), followed by Et ₃ N ( 1.9 mL) was slowly added thereto and the mixture was heated and stirred at 95 ° C. After the reaction was completed, ethyl acetate (10 mL) was added, washed several times with brine, and dried over sodium sulfate (Na ₂ SO ₄ ). Then, the residue was purified by column chromatography (hexane: ethyl acetate = 3: 1) to obtain 2- (5-bromo-2-cyanopyridin-3-yl) hydrazinecarboxylic acid t-butyl ester as a target compound (0.72). g, yield 56%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.20 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 6.51 (s, 2H), 1.48 (s, 9H).

Step 2: Preparation of 6-Bromo-1H-pyrazolo [4,3-b] pyridin-3-amine

N '-(5-bromo-2-cyanopyridin-3-yl) hydrazinecarboxylic acid t-butyl est (0.43 g, 1.37 mmol) prepared in step 1 was dissolved in dioxane (4 mL) (10 mL). ) Was heated to reflux for 6 hours. Thereafter, the volatile gas was removed, dissolved by adding water (10 mL), and neutralized by adding 1N NaOH aqueous solution. The resulting solid was filtered and dried to give the title compound 6-bromo-1H-pyrazolo [4,3-b] pyridin-3-amine (142 mg, yield 49%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 11.80 (s, 1 H), 8.32 (d, J = 1.9 Hz, 1 H), 7.99 (d, J = 1.9 Hz, 1 H), 5.50 (s, 2H).

Step 3: Preparation of 6-Bromo-1- (2,6-dichlorophenyl) -1H-pyrazolo [4,3-b] pyridin-3-amine

6-Bromo-1H-pyrazolo [4,3-b] pyridin-3-amine (0.1 g, 0.47 mmol) and potassium carbonate (0.08 g, 0.56 mmol) prepared in step 2 were added with DMF (10 mL). After addition to the mixture was stirred for about 30 minutes at room temperature. Thereafter, 2- (bromomethyl) -1,3-dichlorobenzene (0.11 g, 0.47 mmol) was added to the reaction solution, followed by stirring at 50 ° C. for 2 hours. After the reaction was completed, ethyl acetate (20 mL) was added thereto, diluted, washed with water and brine, dried over sodium sulfate (Na ₂ SO ₄ ), and concentrated. The obtained solid was recrystallized with ethyl ether to give 6-bromo-1- (2,6-dichlorobenzyl) -1H-pyrazolo [4,3-b] pyridin-3-amine (57 mg, Yield 33%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.37 (d, J = 1.8 Hz, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.39 (s, 1H), 7.36 (s, 1H), 7.28-7.26 (m, 1 H), 5.51 (s, 2 H), 4.36 (brs, 2 H).

Step 4: Preparation of 1- (2,6-dichlorobenzyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-ylamine

6-bromo-1- (2,6-dichlorobenzyl) -1H-pyrazolo [4,3-b] pyridin-3-amine (0.1 g 0.27 mmol) prepared in step 3 above, and Cs ₂ CO ₃ (0.27 g, 0.84 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (20 mg 0.03 mmol) and t-butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-di Oxaborole-2-yl) -1H-pyrazolo-1-yl) piperidine-1-carboxylate (0.16 g, 0.42 mmol) was dissolved in dimethoxyethylene glycol (8 mL) and water (2 mL). It was put into the mixed solution and heated and stirred at 85 ° C. After the reaction was completed, water and ethyl acetate were added to separate the organic layer, washed with NaHCO ₃ aqueous solution and brine, dried over Na ₂ SO ₄ , and concentrated. Next, the product was purified by column chromatography (hexane: ethyl acetate = 1: 1) to obtain 1- (2,6-dichlorobenzyl) -6- (1-methyl-1H-pyrazol-4-yl)-as a target compound. 1H-pyrazolo [4,3-b] pyridin-3-ylamine was obtained (55 mg, yield 55%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.50 (d, J = 1.7 Hz, 1H), 7.78 (s, 1H), 7.69 (s, 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.39 (s, 1 H), 7.37 (s, 1 H), 7.27-7.22 (m, 1 H), 5.56 (s, 2 H), 4.35 (brs, 2H), 3.99 (s, 3H); MS-ESI 374 (M ⁺ , 47), 213 (29), 135 (100).

Example 2 1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] Preparation of Pyridin-3-ylamine

Steps 1-3: Preparation of 6-bromo-1- (2,6-dichlorophenyl) -1H-pyrazolo [4,3-b] pyridin-3-amine

The target compound was obtained in the same manner as the steps 1 to 3 of Example 1.

Step 4: 1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine- Preparation of 3-ylamine

6-Bromo-1- (2,6-dichlorobenzyl) -1H-pyrazole [4,3-b] pyridin-3-amine (70 mg, 0.19 mmol) prepared in step 3 above, and Pd (PPh ₃ ) ₂ Cl ₂ (13 mg, 0.019 mmol), Cs ₂ CO ₃ (0.18 g, 0.57 mmol) and 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxa Borolein-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid t-butylest (0.16 g, 0.29 mmol) was added to DEM: H ₂ O (4: 1, 7.5 mL). ) Was dissolved in and heated to 85 ° C and stirred. After the reaction was completed, ethyl acetate (10 mL) was added, washed several times with brine, dried over Na ₂ SO ₄ , and concentrated. After purification by column chromatography (hexane: ethyl acetate = 2: 1), 4- (4- (3-amino-1- (2,6-dichlorobenzyl) -1H-pyrazolo [4,3-b] Pyridin-6-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid t-butylest was obtained (25 mg, yield 24%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.50 (d, J = 1.5 Hz, 1H), 7.81 (s, 1H), 7.75 (s, 1H), 7.56 (d, J = 1.5 Hz, 1H), 7.39 (s, 1H), 7.36 (s, 1 H), 7.27-7.22 (m, 1H), 5.56 (s, 2H), 4.39 (brs, 2H), 4.37-4.28 (m, 2H), 2.96 (m , 2H), 2.21 (m, 2H), 2.04-1.96 (m, 2H).

4- (4- (1- (2,6-dichlorobenzyl) -1H-pyrazole [4,3-b] pyridin-6-yl) -1H-pyrazol-1-yl) piperidine-1 -Carboxylic acid t-butyl ester (50 mg, 0.094 mmol) was dissolved in dichloromethane (4 mL), then 4M HCl (4 mL in dioxane solution) was added and stirred. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the desired compound 1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [ 4,3-b] pyridin-3-ylamine was obtained (53 mg, yield 100%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.21 (brs, 1H), 9.04 (brs, 1H), 8.81 (d, J = 1.5 Hz, 1H), 8.53 (s, 1H), 8.52 (d , J = 1.5 Hz, 1H), 8.19 (s, 1H), 7.55 (m, 2H), 7.44-7.39 (m, 1H), 5.63 (s, 2H), 4.60-4.52 (m, 1H), 3.43- 3.34 (m, 2H), 3.13-3.09 (m, 2H), 2.30-2.19 (m, 4H).

Example 3 Preparation of 1-benzyl-6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-ylamine

Steps 1-2: Preparation of 6-bromo-1H-pyrazolo [4,3-b] pyridin-3-amine

It carried out in the same manner as in steps 1 to 2 of Example 1.

Step 3: Preparation of 1-benzyl-6-bromo-1H-pyrazolo [4,3, -b] pyridin-3-ylamine

Except for using benzyl bromide instead of 2- (bromomethyl) -1,3-dichlorobenzene was carried out in the same manner as in Step 3 of Example 1 to obtain the target compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.36 (d, J = 1.8 Hz, 1H), 7.75 (d, J = 1.8 Hz, 1H), 7.20 to 7.07 (m, 1H), 5.52 (s, 2H ), 4.35 (s, 2 H).

Step 4: Preparation of 1-benzyl-6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-ylamine

The target compound was obtained by performing the method of Example 4 of Example 1 using the compound prepared in Step 3 as a starting material (yield: 43%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.51 (d, J = 1.8 Hz, 1H), 7.77 (s, 1H), 7.68 (s, 1H), 7.46 (d, J = 1.8 Hz, 1H), 7.16 (m, 5H), 5.55 (s, 2H), 4.36 (s, 2H), 3.97 (s, 3H).).

Example 4 of 1-benzyl-6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-ylamine Produce

Steps 1-3: Preparation of 1-benzyl-6-bromo-1H-pyrazolo [4,3, -b] pyridin-3-ylamine

It was carried out in the same manner as in steps 1 to 3 of Example 3.

Step 4: 1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine- Preparation of 3-ylamine

The desired compound was obtained by performing the method of Step 4 of Example 2 using the compound prepared in Step 3 as a starting material.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.20 (brs, 1H), 9.02 (brs, 1H), 8.80 (d, J = 1.5 Hz, 1H), 8.52 (s, 1H), 8.52 (d, J = 1.5 Hz, 1H), 8.20 (s, 1H ), 7.16 (m, 5H), 5.57 (s, 2H), 4.60-4.52 (m, 1H), 3.43 (m, 2H), 3.08 (m, 2H), 2.27 (m, 4H).

Example 5 1- (2-Chloro-6-fluorobenzyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine-3 Preparation of Ilamine

Steps 1-2: Preparation of 6-bromo-1H-pyrazolo [4,3-b] pyridin-3-amine

It carried out in the same manner as in steps 1 to 2 of Example 1.

Step 3: Preparation of 6-Bromo-1- (2-chloro-6-fluorobenzyl) -1H-pyrazolo [4,3-b] pyridin-3-amine

A target compound was obtained by the same method as Step 3 of Example 1, except that 2-chloro-6-fluorobenzylbromide was used instead of 2- (bromomethyl) -1,3-dichlorobenzene ( Yield: 65%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.37 (d, J = 1.8 μs, 1H), 7.84 (d, J = 1.8 μs, 1H), 7.28 ~ 7.24 (m, 2H), 7.05 (m, 1H ), 5.41 (s, 2H), 4.37 (s, 2H).

Step 4: 1- (2-Chloro-6-fluorobenzyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-yl Preparation of Amine

The target compound was obtained by performing the method of Example 4 of Example 1 using the compound prepared in Step 3 as a starting material (yield: 58%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.50 (d, J = 1.7 Hz, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7.28 ~ 7.22 (m , 2H), 7.07-7.03 (m, 1H), 5.47 (s, 2H), 4.36 (brs, 2H), 3.99 (s, 3H); MS-ESI 356 (M ⁺ , 47), 213 (28), 185 (100).

Example 6 1- (2-Chloro-6-fluorobenzyl) -6- (1-piperidin-4-yl-1 H-pyrazol-4-yl) -1 H-pyrazolo [4,3 -b] preparation of pyridin-3-ylamine

Steps 1-3: Preparation of 6-bromo-1- (2-chloro-6-fluorobenzyl) -1H-pyrazolo [4,3-b] pyridin-3-amine

The target compound was obtained in the same manner as the steps 1 to 3 of Example 5.

Step 4: 1- (2-Chloro-6-fluorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b ] Preparation of Pyridin-3-ylamine

The target compound was obtained by performing the method of Example 4 of Example 2 using the compound prepared in Step 3 as a starting material (yield 45%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.21 (brs, 1H), 9.01 (brs, 1H), 8.82 (s, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 8.19 (s, 1H), 7.56 (m, 2H), 7.40 (m, 1H), 5.60 (s, 2H), 4.57 (m, 1H), 3.37 (m, 2H), 3.12 (m, 2H), 2.24 (m, 4H).

Example 7 of 1- (4-isopropylbenzyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-ylamine Produce

Steps 1-2: Preparation of 6-bromo-1H-pyrazolo [4,3-b] pyridin-3-amine

The target compound was obtained in the same manner as in the steps 1 to 2 of Example 1.

Step 3: Preparation of 6-bromo-1- (4-isopropylbenzyl) -1H-pyrazolo [4,3-b] pyridin-3-amine

Except for using 4-isopropylbenzyl bromide instead of 2- (bromomethyl) -1,3-dichlorobenzene in the same manner as in Step 3 of Example 1 to obtain the target compound (yield: 49% ).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.37 (d, J = 1.6 μs, 1H), 7.62 (d, J = 1.8 μs, 1H), 7.19 to 7.09 (m, 4H), 5.26 (s, 2H ) 4.40 (s, 2H), 2.85 (m, 1H), 1.23 (d, J = 6.9 Hz, 6H).

Step 4: Preparation of 1- (4-isopropylbenzyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-ylamine

The desired compound was obtained by performing the method of Example 4 of Example 1 using the compound prepared in Step 3 as a starting material (yield: 64%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.50 (d, J = 1.7 Hz, 1H), 7.77 (s, 1H), 7.70 (s, 1H), 7.42 (d, J = 1.7 Hz, 1H), 7.17 (d, J = 8.3 Hz, 2H), 7.13 (m, J = 8.3 Hz, 2H), 5.31 (s, 2H), 4.39 (brs, 2H), 3.97 (s, 3H), 2.89 (m, 1H), 1.19 (d, J = 6.9 Hz, 3H ); MS-ESI 346 (M ⁺ , 35), 133 (100), 105 (20).

Example 8 6- (1-Methyl-1H-pyrazol-4-yl) -1- (3-trifluoromethylbenzyl) -1H-pyrazolo [4,3-b] pyridin-3-yl Preparation of Amine

Steps 1-2: Preparation of 6-bromo-1H-pyrazolo [4,3-b] pyridin-3-amine

It carried out in the same manner as in steps 1 to 2 of Example 1.

Step 3: Preparation of 6-Bromo-1- (3-trifluoromethylbenzyl) -1H-pyrazolo [4,3-b] pyridin-3-amine

Except for using 3-trifluoromethylbenzyl bromide instead of 2- (bromomethyl) -1,3-dichlorobenzene in the same manner as in Step 3 of Example 1 to obtain the target compound (yield: 39%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.37 (d, J = 1.7 μs, 1H), 7.84 (d, J = 1.7 μs, 1H), 7.28 to 7.21 (m, 2H), 7.08 to 7.01 (m , 1H), 5.41 (d, J = 1.7 Hz, 2H), 4.37 (s, 2H).

Step 4: Preparation of 6- (1-methyl-1H-pyrazol-4-yl) -1-naphthalen-2-ylmethyl-1H-pyrazolo [4,3-b] pyridin-3-ylamine

The desired compound was obtained by performing the method of Example 4 of Example 1 using the compound prepared in Step 3 as a starting material (yield: 28%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.54 (d, J = 1.7 Hz, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.55-7.40 (m, 4H), 7.33 (d, J = 1.7 Hz, 1H), 5.39 (s , 2H), 4.43 (brs, 2H), 3.97 (s, 3H); MS-ESI 371 (M ⁺ , 53), 213 (42), 185 (100).

Example 9 1- (2,6-dichloro-3-fluorobenzyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine Preparation of 3-ylamine

Steps 1-2: Preparation of 6-bromo-1H-pyrazolo [4,3-b] pyridin-3-amine

It carried out in the same manner as in steps 1 to 2 of Example 1.

Step 3: Preparation of 6-Bromo-1- (2,6-dichloro-3-fluorobenzyl) -1H-pyrazolo [4,3-b] pyridin-3-amine

A target compound was prepared by the same method as Step 3 of Example 1, except that 2,6-dichloro-3-fluorobenzyl bromide was used instead of 2- (bromomethyl) -1,3-dichlorobenzene. Obtained (yield: 55%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.40 (d, J = 1.8 Hz, 1H), 7.81 (d, J = 1.8 Hz, 1H), 7.39 ~ 7.34 (m, 1H), 7.18 (t, J = 8.7 Hz, 1H), 5.56 (s, 2H), 4.38 (s, 2H).

Step 4: 1- (2,6-dichloro-3-fluorobenzyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine-3 Preparation of Ilamine

The desired compound was obtained by performing the method of Example 4 of Example 1 using the compound prepared in Step 3 as a starting material (yield: 61%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.52 (d, J = 1.5 Hz, 1H), 7.85 (s, 1H), 7.78 (s, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.37 (m, 1H), 7.17 (m, 1H), 5.55 (s, 2H), 4.37-4.31 (m, 5H), 2.97-2.89 (m, 2H), 3.96 (s, 3H).

Example 10 1- (2,6-dichloro-3-fluorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4 , 3-b] preparation of pyridin-3-ylamine

Steps 1-3: Preparation of 6-bromo-1- (2,6-dichloro-3-fluorobenzyl) -1H-pyrazolo [4,3-b] pyridin-3-amine

The target compound was obtained in the same manner as in the steps 1 to 3 of Example 9.

Step 4: 1- (2,6-Dichloro-3-fluorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3 -b] preparation of pyridin-3-ylamine

As a starting material, the method of Example 2 was carried out using the compound prepared in Step 3, to obtain 4- (4- (3-amino-1- (2,6-dichloro-3-fluorobenzyl)- 1H-pyrazolo [4,3-b] pyridin-6-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid t-butylest was obtained. 4- (4- (1- (2,6-dichloro-3-fluorobenzyl) -1H-pyrazol [4,3-b] pyridin-6-yl) -1H-pyrazol-1-yl) Piperidine-1-carboxylic acid t-butylest (50 mg, 0.094 mmol) was dissolved in dichloromethane (4 mL), then 4M HCl (4 mL in dioxane solution) was added and stirred. After the reaction was completed, the resultant was concentrated under reduced pressure to obtain a target compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.15 (brs, 1H), 8.99 (brs, 1H), 8.78 (d, J = 1.5 Hz, 1H), 8.51 (s, 1H), 8.46 (d , J = 1.5 Hz, 1H), 8.18 (s, 1H), 7.55 (m, 2H), 7.42 (m, 1H), 5.62 (s, 2H), 4.55 (m, 1H), 3.42 (m, 2H) , 3.13 (m, 2 H), 2,26 (m, 4 H).

Example 11 Preparation of 6- (1-methyl-1H-pyrazol-4-yl) -1-naphthalen-1-ylmethyl-1H-pyrazolo [4,3-b] pyridin-3-ylamine

Steps 1-2: Preparation of 6-bromo-1H-pyrazolo [4,3-b] pyridin-3-amine

The target compound was obtained in the same manner as in the steps 1 to 2 of Example 1.

Step 3: Preparation of 6-bromo-1- (naphthalen-1-ylmethyl) -1H-pyrazolo [4,3-b] pyridin-3-amine

A target compound was obtained by the same method as Step 3 of Example 1, except that 1-bromomethylnaphthalene was used instead of 2- (bromomethyl) -1,3-dichlorobenzene (yield: 57% ).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.35 (d, J = 1.8 μs, 1H), 8.07 (m, 1H), 7.91 to 7.83 (m, 2H), 7.55 to 7.52 (m, 3H) 7.41 ( t, J = 6.9 Hz, 1H), 7.13 (d, J = 6.9 Hz, 1H), 5.78 (s, 2H), 4.44 (s, 2H).

Step 4: Preparation of 6- (1-methyl-1H-pyrazol-4-yl) -1-naphthalen-1-ylmethyl-1H-pyrazolo [4,3-b] pyridin-3-ylamine

The target compound was obtained by performing the method of Example 4 of Example 1 using the compound prepared in Step 3 as a starting material (yield: 48%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.50 (d, J = 1.7 Hz, 1H), 8.12-8.09 (m, 1H), 7.90-7.87 (m, H), 7.84 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 7.57 to 7.49 (m, 2H), 7.42 (t, J = 8.4 Hz, 1H), 7.32 (d, J = 1.7 Hz, 1H), 7.12 (m, 1H), 5.84 (s , 2H), 4.43 (brs, 2H), 3.93 (s, 3H); MS-ESI 354 (M ⁺ , 44), 141 (100), 115 (17).

Example 12 1-naphthalen-1-ylmethyl-6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine- Preparation of 3-ylamine

Steps 1-3: Preparation of 6-bromo-1- (naphthalen-1-ylmethyl) -1H-pyrazolo [4,3-b] pyridin-3-amine

It carried out in the same manner as in steps 1 to 3 of Example 11.

Step 4: 1-naphthalen-1-ylmethyl-6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine-3- Preparation of Ilamine

The target compound was obtained by performing the method of step 4 of Example 2 using the compound prepared in step 3 as a starting material (yield 52%).

¹ H-NMR (300 MHz, CDCl ₃ + MeOH-d ₄ ) δ 8.85 (s, 1H), 8.40 (s, 1H), 8.12 (m, 2H), 7.91 (m, 2H), 7.81 (s, 1H), 7.55 (m, 2H), 7.45 (m, 1H), 7.29 (m, 1H), 6.00 (s, 2H), 4.60 (m, 1H), 3.54 (m, 2H), 3.20 (m, 2H), 2.38 (m, 4H).

Example 13 1- (2-Methyl-naphthalen-1-ylmethyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine- Preparation of 3-ylamine

Steps 1-2: Preparation of 6-bromo-1H-pyrazolo [4,3-b] pyridin-3-amine

The target compound was obtained in the same manner as in the steps 1 to 2 of Example 1.

Step 3: Preparation of 6-Bromo-1- (2-methyl-naphthalen-1-ylmethyl) -1H-pyrazole [4,3-b] pyridin-3-ylamine

A target compound was obtained by the same method as Step 3 of Example 1, except that 1-bromomethyl-2-methylnaphthalene was used instead of 2- (bromomethyl) -1,3-dichlorobenzene. Yield: 43%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.26 (d, J = 1.8 ㎐, 1H), 8.01 (d, J = 1.8 ㎐, 1H), 7.84 (d, J = 5.4 ㎐, 2H), 7.48 ~ 7.42 (m, 3H), 7.02 (m, 1H), 5.74 (s, 2H), 4.38 (s, 2H), 2.62 (s, 3H).

Step 4: 1- (2-Methyl-naphthalen-1-ylmethyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine-3- Preparation of Ilamine

The target compound was obtained by performing the method of Example 4 of Example 1 using the compound prepared in Step 3 as a starting material (yield: 41%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.37 (d, J = 1.7 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.87-7.83 (m, 2H), 7.49-7.38 (m, 5H), 6.71 (d, J = 1.7 Hz , 1H), 5.80 (s, 2H), 4.37 (brs, 2H), 3.90 (s, 3H), 2.62 (s, 3H); MS-ESI 368 (M ⁺ , 12), 214 (58), 155 (100).

Example 14 1- (2-Methyl-naphthalen-1-ylmethyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4, 3-b] preparation of pyridin-3-ylamine

Steps 1-3: Preparation of 6-bromo-1- (2-methyl-naphthalen-1-ylmethyl) -1H-pyrazole [4,3-b] pyridin-3-ylamine

The target compound was obtained in the same manner as in the steps 1 to 3 of Example 13.

Step 4: 1- (2-Methyl-naphthalen-1-ylmethyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3- b] preparation of pyridin-3-ylamine

The target compound was obtained by performing the method of Example 4 of Example 2 using the compound prepared in Step 3 as a starting material (yield 41%).

¹ H-NMR (300 MHz, CDCl ₃ + MeOH-d ₄ ) δ 8.79 (s, 1H), 8.27 (m, 1H), 7.98 (m, 1H), 7.93 (m, 2H), 7.51-7.39 (m, 5H), 5.97 (s, 2H), 4.48 (s, 1H) , 3.66 (m, 2H), 3.21 (m, 2H), 2.39 (m, 4H); MS-ESI 437 (M ⁺ , 13), 283 (18), 155 (100).

Example 15 Preparation of 6- (1-methyl-1H-pyrazol-4-yl) -1-naphthalen-2-ylmethyl-1H-pyrazolo [4,3-b] pyridin-3-ylamine

Steps 1-2: Preparation of 6-bromo-1H-pyrazolo [4,3-b] pyridin-3-amine

The target compound was obtained in the same manner as in the steps 1 to 2 of Example 1.

Step 3: Preparation of 6-Bromo-1- (naphthalen-2-ylmethyl) -1H-pyrazolo [4,3-b] pyridin-3-amine

A target compound was obtained by the same method as Step 3 of Example 1, except that 2- (bromomethyl) -naphthalene was used instead of 2- (bromomethyl) -1,3-dichlorobenzene (yield) : 32%).

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.36 (d, J = 1.8 Hz, 1H), 7.88-7.78 (m, 5H), 7.57 (dd, J = 1.8, 8.4 Hz, 1H), 7.47- 7.44 (m, 2 H), 4.79 (s, 2 H); MS-ESI 354 (M ⁺ , 3), 227 (30), 141 (100).

Step 4: Preparation of 6- (1-methyl-1H-pyrazol-4-yl) -1-naphthalen-2-ylmethyl-1H-pyrazolo [4,3-b] pyridin-3-ylamine

The target compound was obtained by performing the method of Example 4 of Example 1 using the compound prepared in Step 3 as a starting material (yield: 76%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.53 (d, J = 1.7 Hz, 1H), 7.90 (s, 1H), 7.82-7.78 (m, 5H), 7.68 (s, 1H), 7.61 (s , 1H), 7.55 (m, 1H), 7.46 (m, 2H), 4.84 (s, 2H), 3.98 (s, 3H).

Example 16 Benzyl- [1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3 -b] preparation of pyridin-3-yl] -amine

Steps 1-3: Preparation of 6-bromo-1- (2,6-dichlorophenyl) -1H-pyrazolo [4,3-b] pyridin-3-amine

The target compound was obtained in the same manner as in the steps 1 to 3 of Example 1.

Step 4: 1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine- Preparation of 3-ylamine

6-Bromo-1- (2,6-dichlorobenzyl) -1H-pyrazolo [4,3-b] pyridin-3-amine (0.07 g, 0.19 mmol) prepared in step 3 was diluted with dichloromethane (8 mL), triethylamine (0.053 mL, 0.38 mmol) and (CF ₃ CO) ₂ O (0.03 mL, 0.21 mmol) were slowly added and stirred at 0 ° C. After the reaction was completed, water was added and the organic layer was separated and saturated sodium bicarbonate was added. Aqueous solution and brine, and then dried over Na ₂ SO ₄ to N- (6-bromo-1- (2,6-ditlobenzyl) -1H-pyrazole [4,3-b] pyridine-3- Il) -2,2,2-trifluoroacetamide was obtained (100 mg, yield 100%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.87 (brs, 1H), 8.58 (d, J = 1.8 Hz, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.43-7.40 (m, 2H) , 7.33-7.28 (m, 1 H), 5.77 (s, 2 H).

N- (6-bromo-1- (2,6-ditlobenzyl) -1H-pyrazole [4,3-b] pyridin-3-yl) -2,2,2-trifluoroacet Amide (0.1 g, 0.21 mmol), K ₂ CO ₃ (60 mg, 0.42 mmol), catalytic amount of potassium iodide (KI; 5 mg) and benzylbromide (27 μL, 0.23 mmol) were added to acetone (20 mL) It was then heated to reflux at 70 ℃. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate (20 mL), washed with water and brine, and dried over Na ₂ SO ₄ . Then purified by column chromatography (hexane: ethyl acetate = 4: 1) N-benzyl-N- (6-bromo-1- (2,6-dichlorobenzyl) -1H-pyrazolo [4,3-b ] Pyridin-3-yl) -2,2,2-trifluoroacetamide was obtained (80 mg, yield 68%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.58 (d, J = 1.8 Hz, 1H), 7.86 (d, J = 1.8 Hz, 1H), 7.39-7.36 (m, 2H), 7.31-7.28 (m , 1H), 7.16 (m, 5H), 5.67 (s, 2H), 5.13 (s, 2H).

Thereafter, the same procedure as in Example 2 was carried out to remove 4- (4- (3- (benzylamino) -1- (2,6-dichlorobenzyl) -1H-pyrazolo [4,3) from which the trifluoroacetyl group was removed. -b] pyridin-6-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid t-butylest.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.42 (d, J = 1.8 Hz, 1H), 7.77 (s, 1H), 7.72 (s, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.42 ~ 7.37 (m, 3H), 7.31 ~ 7.27 (m, 5H), 5.58 (s, 2H), 4.80 (m, 1H), 4.60 (d, J = 5.7 Hz, 2H), 4.32 ~ 4.28 (m , 3H), 2.92-2.87 (m, 2H), 2.20-2.16 (m, 2H), 2.03-1.95 (m, 2H), 1.59 (s, 9H).

4- (4- (3- (benzylamino) -1- (2,6-dichlorobenzyl) -1H-pyrazolo [4,3-b] pyridin-6-yl) -1H-pyrazol-1- (1) Piperidine-1-carboxylic acid t-butyl ester was dissolved in dichloromethane, 4M HCl was added, followed by stirring to remove the Boc protecting group to obtain the target compound (yield 98%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.92 (brs, 1 H), 8.73 (brs, 1 H), 8.61 (d, J = 1.5 Hz, 1H), 8.42 (s, 1H), 8.18 (d, J = 1.5 Hz, 1H), 8.09 (s, 1H), 7.53-7.51 (m, 2H), 7.43-7.38 (m, 1H), 7.29 (m, 2H), 7.14 (m, 3H), 5.51 (s, 2H), 4.53-4.48 (m, 1H), 4.43 (s, 2H), 3.69-3.64 (m, 2H), 3.15-3.07 (m, 2H), 2,22-2.06 (m, 4H).

Example 17 [1- (2,6-Dichlorobenzene) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b ] Pyridin-3-yl] -Methylamine Preparation

The target compound was obtained using the method of Example 16 (yield 99%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.90 (brs, 1H), 8.71 (brs, 1H), 8.58 (s, 1H), 8.40 (s, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 7.52 (m, 2H), 7.42 (m, 1H), 5.51 (s, 2H), 4.53 (m, 1H), 3.39 (m. 2H), 3.14 (m. 2H), 2.70 ( s, 3H), 2.22-1.96 (m, 4H).

Example 18 N- [1- (2,6-Dichloro-3-fluorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyra Preparation of zolo [4,3-b] pyridin-3-yl] -2,2,2-trifluoro-acetamide

4- (4- (3-amino-1- (2,6-dichloro-3-fluorobenzyl) -1H-pyrazolo [4,3-b] pyridine- prepared in Step 4 of Example 10 above 6-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid t-butylest (40 mg 0.07 mmol) was dissolved in dichloromethane (4 mL) and then triethylamine (0.02 mL, 0.14 mmol) and (CF ₃ CO) ₂ O (0.11 mL) were slowly added and stirred at 0 ° C. After the reaction was completed, water was added, and then the organic layer was washed with NaHCO ₃ aqueous solution and brine, dried over Na ₂ SO _4, and concentrated under reduced pressure to obtain 4- (4- (1- (2,6-dichloro-3-fluorobenzyl). ) -3- (2,2,2-trifluoroacetamido) -1H-pyrazolo [4,3-b] pyridin-6-yl) -1H-pyrazol-1-yl) piperidine- 1-carboxylic acid t-butyl est was obtained (30 mg, yield 65%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.69 (d, J = 1.7 Hz, 1H), 7.82 (s, 1H), 7.78 (s, 1H), 7.74 (d, J = 1.7 Hz, 1H), 7.37 (m, 1H), 7.21 (m, 1H), 5.79 (s, 2H), 4.34-4.43 (m, 3H), 2.93 (m, 2H), 2.21 (m, 2H), 1.98 (m, 2H) , 1.48 (s, 9 H).

4- (4- (1- (2,6-dichloro-3-fluorobenzyl) -3- (2,2,2-trifluoroacetamido) -1H-pyrazolo [4,3-b ] Pyridin-6-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid t-butyleste was dissolved in dichloromethane, 4M HCl was added, followed by stirring to remove the Boc protecting group. Was obtained (yield 84%).

¹ H-NMR (300 MHz, MeOH-d ₄ ) δ 9.00 (m, 2H), 8.59 (s, 1H), 8.16 (s, 1H), 7.41 (s, 1H), 7.27 (s, 1H), 5.96 (s, 2H), 4.76 (m, 1H), 3.64-3.53 (m, 2H), 3.25-3.22 (m, 2H), 2.33 (m, 4H).

Example 19 N- [1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3 -b] preparation of pyridin-3-yl] -benzamide

4- (4- (3-amino-1- (2,6-dichlorobenzyl) -1H-pyrazolo [4,3-b] pyridin-6-yl) -1H-pyrazole prepared in Example 2 above -1-yl) piperidine-1-carboxylic acid t-butylest and benzoyl chloride were reacted in the same manner as in Example 18 to obtain an amide, and a Boc protecting group removal reaction was carried out to carry out the target compound N- [1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-yl] benz Amide was obtained (yield 89%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (brs, 1H), 9.16 (brs, 1H), 8.89 (s, 1H), 8.69 (s, 1H), 8.55 (s, 1H), 8.22 (s, 1H), 7.65-7.42 (m, 8H), 5.85 (s, 2H), 4.57 (m, 1H), 3.51 (m. 2H), 3.10 (m. 2H), 2.27 (m, 4H).

Example 20 N- [1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3 -b] preparation of pyridine-3-]-2-phenyl-acetamide

4- (4- (3-amino-1- (2,6-dichlorobenzyl) -1H-pyrazolo [4,3-b] pyridin-6-yl) -1H-pyrazole prepared in Example 2 above -1-yl) piperidine-1-carboxylic acid t-butyl ester and 2-phenylacetyl chloride were reacted in the same manner as in Example 18 to obtain an amide, and a Boc protecting group removal reaction was carried out to carry out N- as the target compound. [1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine-3- Il] -2-phenyl-acetamide was obtained (yield 92%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 10.35 (brs, 1H), 8.85 (brs, 1H), 8.83 (s, 1H), 8.51 (s, 1H), 8.49 (s, 1H), 8.17 (s, 1H), 7.55 (m, 2H), 7.44 (m, 1H), 7.33-7.25 (m, 5H), 5.89 (s, 2H), 4.57 (m, 1H), 3.52 (m. 2H), 3.11 (m. 2 H), 2.27 (m, 4 H).

Example 21 N- [1- (2,6-Dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3 -b] preparation of pyridin-3-yl] -acetamide

4- (4- (3-amino-1- (2,6-dichlorobenzyl) -1H-pyrazolo [4,3-b] pyridin-6-yl) -1H-pyrazole prepared in Example 2 above -1-yl) piperidine-1-carboxylic acid t-butyl est and Ac ₂ O were reacted in the same manner as in Example 18 to obtain an amide, and a Boc protecting group removal reaction was carried out to carry out the target compound N- [1. -(2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-yl] Acetamide was obtained (yield 96%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 10.35 (brs, 1H), 8.85 (brs, 1H), 8.83 (s, 1H), 8.51 (s, 1H), 8.49 (s, 1H), 8.17 (s, 1H), 7.55 (m, 2H), 7.44 (m, 1H), 7.33-7.25 (m, 5H), 5.89 (s, 2H), 4.57 (m, 1H), 3.52 (m. 2H), 3.11 (m. 2 H), 2.27 (m, 4 H).

Example 22 N- [1- (2,6-Dichlorobenzyl-3-fluorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrazolo Preparation of [4,3-b] pyridin-3-yl] -2,2,2-trifluoro-N-methyl-acetamide

4- (4- (1- (2,6-dichloro-3-fluorobenzyl) -3- (2,2,2-trifluoroacetamido) -1H-pyrazolo prepared in Example 18 above [4,3-b] pyridin-6-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid t-butylest (20 mg, 0.03 mmol) in acetone (4 mL) After dissolving, K ₂ CO ₃ (10 mg) and MeI (20 μL) were added thereto, followed by heating and stirring at 60 ° C. After the reaction was completed, the volatile gas was removed, and then dissolved by adding ethyl acetate, washed with brine, dried over Na ₂ SO ₄ and concentrated to 4- (4- (1- (2,6-dichloro-3-fluorobenzyl). ) -3- (2,2,2-trifluoro-N-methylacetamido) -1H-pyrazole [4,3-b] pyridin-6-yl) -1H-pyrazol-1-yl) Piperidine-1-carboxylic acid t-butylest was obtained (13 mg, yield 65%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.75 (d, J = 1.8 Hz, 1H), 7.86 (s, 1H), 7.82 (s, 1H), 7.82 (d, J = 1.8 Hz, 1H), 7.38 (m, 1H), 7.20 (m, 1H), 5.77 (s, 2H), 4.39-4.30 (m, 3H), 3.51 (s, 3H), 2.97-2.89 (m, 2H), 2.22-2.17 ( m, 2H), 1.93 (m, 2H), 1.55 (s, 9H).

4- (4- (1- (2,6-dichloro-3-fluorobenzyl) -3- (2,2,2-trifluoro-N-methylacetamido) -1 H-pyrazole [4]; , 3-b] pyridin-6-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid t-butyleste was dissolved in dichloromethane, 4M HCl was added and stirred to boc protecting groups. By removing, the target compound was obtained (yield 82%).

¹ H-NMR (300 MHz, MeOH-d ₄ ) δ 8.88 (s, 1H), 8.80 (s, 1H), 8.47 (s, 1H), 8.11 (s, 1H), 7.42 (m, 1H), 7.28 (m, 1H), 5.75 (s, 2H), 4.62 (m, 1H), 3.62 (m, 2H), 3.23 (m, 2H), 2.31 (m, 4H).

Example 23 {4- [3-Amino-1- (2,6-dichlorobenzyl) -1H-pyrazolo [4,3-b] pyridin-6-yl] -phenyl}-(4-methyl- Preparation of Piperazin-1-yl) -Methanone

Steps 1-3: Preparation of 6-bromo-1- (2,6-dichlorophenyl) -1H-pyrazolo [4,3-b] pyridin-3-amine

The target compound was obtained in the same manner as in the steps 1 to 3 of Example 1.

Step 4: {4- [3-Amino-1- (2,6-dichlorobenzyl) -1H-pyrazolo [4,3-b] pyridin-6-yl] -phenyl}-(4-methyl-piperazine -1-yl) -Methanone Preparation

6-bromo-1- (2,6-dichlorobenzyl) -1H-pyrazolo [4,3-b] pyridin-3-amine (0.4 g, 1.07 mmol) prepared in step 3 above, 4- ( Methoxycarbonyl) phenylboronic acid (0.21 g, 1.18 mmol), Na ₂ CO ₃ (0.79 g, 7.5 mmol) and Pd (PPh ₃ ) ₄ (0.13 g, 0.11 mmol) were mixed with a DME / H ₂ O mixed solvent ( 1: 1, 14 mL) and then heated to reflux for 3 hours. After the reaction was completed, the temperature was lowered to room temperature and concentrated under reduced pressure to remove volatile gas. Dichloromethane was added to the residue, diluted, washed with 1N aqueous HCl solution, saturated aqueous NaHCO ₃ solution and brine, and dried over Na ₂ SO ₄ . Thereafter, the residue was purified by column chromatography (hexane: ethyl acetate = 2: 1) to prepare 4- (3-amino-1- (2,6-dichlorobenzyl) -1H-pyrazolo [4,3-b] pyridine-. 6-yl) benzoate methyl ester was obtained (0.24 g, yield 52%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.62 (d, J = 1.5 Hz, 1H), 8.18 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 1.5 Hz, 1H), 7.69 ( d, J = 8.4 Hz, 2H), 7.40 (s, 1H), 7.37 (s, 1H), 7.28-7.22 (m, 1H). 5.62 (s, 2H), 4.42 (brs, 2H), 3.96 (s, 3H).

The 4- (3-amino-1- (2,6-dichlorobenzyl) -1H-pyrazolo [4,3-b] pyridin-6-yl) benzoic acid methyl ester (0.24 g, 0.56 mmol) was added MeOH / THF. / H ₂ O mixed solvent (1: 1: 1, 60 mL) was dissolved, LiOHH ₂ O (0.12 g, 2.81 mmol) was added, followed by stirring at room temperature for 3 hours. Thereafter, the volatile gas was removed and then adjusted to pH 4 with 1N HCl aqueous solution. Next, ethyl acetate was added for extraction, the organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated to 4- (3-amino-1- (2,6-dichlorobenzyl) -1H-pyrazolo [4,3 -b] pyridin-6-yl) benzoic acid was obtained (0.18 g, yield 78%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.65 (d, J = 1.5 Hz, 1H), 8.35 (d, J = 1.5 Hz, 1H), 8.08 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.1 Hz, 2H), 7.51 (s, 1H), 7.49 (s, 1H), 7.41-7.35 (m, 1H), 5.60 (s, 4H).

4- (3-amino-1- (2,6-dichlorobenzyl) -1H-pyrazolo [4,3-b] pyridin-6-yl) benzoic acid (49 mg, 0.12 mmol) and 1- (3 -Dimethylaminopropyl) -3-ethylcarbodiimide hydrogen chloride (EDCI; 25 mg, 0.13 mmol), 1-hydroxy- 1H -benzotriazole (HOBT; 18 mg, 0.13 mmol) and 1-methylpiperazine (13 μL, 0.12 mmol) was dissolved in dimethylformamide (DMF; 5 mL) and stirred at room temperature for 12 hours. Ethyl acetate was added to the reaction mixture, the mixture was diluted, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. After purification by column chromatography (5% MeOH / CH ₂ Cl ₂ ), the desired compound {4- [3-amino-1- (2,6-dichlorobenzyl) -1H-pyrazolo [4,3-b ] Pyridin-6-yl] -phenyl}-(4-methyl-piperazin-1-yl) -methanone was obtained (12 mg, yield 20%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.59 (d, J = 1.5 Hz, 1H), 7.67 (d, J = 1.5 Hz, 1H), 7.63 (d, J = 8.3 Hz, 2H), 7.55 ( d, J = 8.3 Hz, 2H), 7.38 (m, 2H), 7.25 (m, 1H), 5.62 (s, 2H), 4.41 (brs, 2H), 3.81 (m, 2H), 3.54 (m, 2H ), 2.41 (m, 4H), 2.34 (s, 3H); MS-ESI 496 (M ⁺ , 2), 411 (13), 179 (46), 70 (100).

Example 24 1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] Preparation of Pyridine

Step a

5-Bromo-3-fluoropyridine-2-carbonitrile (3.9 g, 19.4 mmol) was added to methanol: saturated HCl (1: 1, 200 mL), followed by heating and stirring at 100 ° C. After the reaction was completed, the mixture was cooled to 0 ° C., neutralized by slowly adding a saturated aqueous NaHCO ₃ solution, and then methanol was removed by concentration under reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO ₄ , concentrated and purified by column chromatography (10% ethyl acetate / hexane) to give 5-bromo-3-fluoropyridine-2-carboxylic acid methyl ester. Obtained (2.7 g, 62% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.61 (dd, J = 1.0, 1.7 Hz, 1H), 7.77 (dd, J = 1.7, 9.3 Hz, 1H), 4.02 (s, 3H).

Step b

To methanol (50 mL) was added NaBH ₄ (1.91 g, 50.4 mmol) at 0 ° C., followed by 5-bromo-3-fluoropyridine-2-carboxylic acid methyl ester (2.36 g, 10.1 mmol) in THF (50 mL) was slowly added dropwise for 20 minutes using a syringe pump, followed by stirring at room temperature for 18 hours. Saturated aqueous NaHCO ₃ solution was added followed by extraction with dichloromethane. The mixture was washed with brine and concentrated to give (5-bromo-3-fluoropyridin-2-yl) -methanol (1.7 g, yield 83%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.49 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 4.79 (s, 2H), 3.57 (s, 1H).

The (5-bromo-3-fluoropyridin-2-yl) -methanol (1.7 g, 8.3 mmol) was dissolved in DMSO (20 mL), and then IBX (4.66 g, 16.7 mmol) was added thereto for 10 hours at room temperature. Stirred. Ethyl acetate (50 mL) and water (50 mL) were added, and then the solid material was filtered through celite and the organic layer was separated. Thereafter, the mixture was washed several times with water and brine, dried over MgSO ₄ , and concentrated to obtain 5-bromo-3-fluoropyridine-2-carboxaldehyde (1.67 g, 100% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 10.17 (s, 1H), 8.69 (dd, J = 1.0, 1.7 Hz, 1H), 7.80 (dd, J = 1.7, 9.7 Hz, 1H).

Step c

5-Bromo-3-fluoropyridine-2-carboxaldehyde (0.55 g, 2.71 mmol) prepared in step b was added to NH ₂ NH ₂ H ₂ O (7 mL) at 0 ° C. for 5 minutes. Stir and then stir at room temperature for 12 hours. The reaction mixture was heated and stirred at 130 ° C. for 5 hours, cooled to room temperature, added with water, and extracted with ethyl acetate. The organic layer was sufficiently washed with water and brine, dried over Na ₂ SO ₄ , concentrated, and purified by column chromatography (40% ethyl acetate / hexane) to give 6-bromo-1H-pyrazolo [4,3-b]. Pyridine was obtained (0.27 g, 50% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.59 (d, J = 1.8 Hz, 1H), 8.21 (d, J = 1.0 Hz, 1H), 7.98 (dd, J = 1.0, 1.8 Hz, 1H), 7.40 (m, 1 H), 7.28 (m, 1 H), 5.77 (s, 2 H).

Step d ~ e

The 6-bromo-1H-pyrazolo [4,3-b] pyridine prepared in step c was subjected to N-dichlorobenzyl substitution reaction, Suzuki substitution reaction and Boc deprotection group reaction using the method of Example 2. Phosphorus 1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine was obtained ( Yield 87%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.78 (brs, 1H), 8.77 (s, 1H), 8.60 (brs, 1H), 8.42 (s, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 8.05 (s, 1H), 7.42 (m, 2H), 7.32 (m 1H), 5.70 (s, 2H), 4.44 (m, 1H), 3.42 (m, 2H), 3.13 (m , 2H), 2,26 (m, 4H).

Experimental Example Measurement of c-Met Kinase Inhibitory Activity

In order to determine the proliferation inhibitory activity of the abnormal cells of the pyrazolo [4,3-b] pyridine derivative or a pharmaceutically acceptable salt thereof according to the present invention, the following experiment was performed.

Specifically, dissociation enhanced Lanthanide Fluoro Immuno Assay (DELFIA; Perkin Elmer), which is a kind of time-resolved fluorescence (TRF) for c-Met kinase The analysis was carried out.

10 mL of PF-02341066 (Piza), which was used as a test compound or a comparative group as a c-Met inhibitor, was added to a Greyner 96-well V-type bottom plate, and the c-Met enzyme was mixed. After tyrosine kinase buffer (20 mL) was added, the enzyme and test compound were mixed and incubated for 15 minutes. ATP solution (10 mL) was added thereto, followed by kinase reaction at room temperature for 30 minutes, and then 50 mM ethylenediaminetetraacetic acid solution (EDTA, 40 mL) was added to stop the reaction. The reactions were transferred to streptavidin-coated plates, incubated under shaking and washed three times with PBS-T buffer (PBS 0.05% Tween20) after 2 hours.

Europium-containing anti-phosphotyrosine antibody was diluted 1: 2,500, added 100 mL per well, incubated under shaking, and washed 1 time with PBS-T buffer (PBS 0.05% Tween20).

Then, an enhancement solution (100 mL) was added and shaken for 5 minutes, and then read in the wavelength range of 615/665 nm with a Wallac Envision 2103 instrument.

The percentage inhibition was expressed at IC ₅₀ or 1 μM concentrations of the compound which reduced c-Met kinase enzyme activity by 50%. The IC ₅₀ of the test compound which carried out the experiment was determined by two data sets and was obtained using Prism (version 5.01, GraphPad) software.

The measurement results are shown in Table 2.

division IC ₅₀ (μM) or% inhibition rate of c-Met division IC ₅₀ (μM) on c-Met
Or% inhibition Example 1 14% Example 2 4.1 μM Example 3 22% Example 4 5.9 μM Example 5 37% Example 6 3.8 μM Example 7 32% Example 8 10% Example 9 42% Example 10 4.1 μM Example 11 32% Example 12 43% Example 13 39% Example 14 3.2 μM Example 15 33% Example 16 4.3 μM Example 17 2.6 μM Example 18 2.3 μM Example 19 20% Example 20 5% Example 21 22% Example 22 3.6 μM Example 23 45% Example 24 8.8 μM Comparison 0.05 μM - -

As shown in Table 2 above, the compounds according to the invention, in particular the compounds of Examples 2, 4, 6, 10, 14, 16, 17, 18, 20 and 24, exhibit an IC ₅₀ of 2.3-8.8 μM and thus c It can be seen that the inhibitory activity against -Met. Therefore, the compounds according to the present invention can be usefully used for the prevention or treatment of diseases caused by abnormal activity of tyrosine kinases, such as diseases such as tumors, psoriasis, rheumatism, diabetic retinopathy.

On the other hand, the compound of Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

Preparation Example 1 Preparation of Tablet (Direct Pressing)

Active ingredient 5.0 mg

Lactose 14.1 mg

Crospovidone USNF 0.8 mg

Magnesium Stearate 0.1mg

According to a conventional method for preparing tablets, the tablets were prepared by adding the above ingredients in the contents indicated, mixing them uniformly and pressing.

Preparation Example 2 Preparation of Tablet (Wet Granulation)

Active ingredient 5.0 mg

Lactose 16.0 mg

Starch 4.0 mg

Presorbate 80 0.3 mg

Silicon dioxide 2.7 mg

Magnesium Stearate 2.0mg

After sifting the active ingredient, lactose and starch were mixed. Thereafter, the polysorbate was dissolved in pure water, and then an appropriate amount was added to the active ingredient, lactose and starch mixture, followed by atomization. After drying, the granules were granulated and then mixed with colloidal silicon dioxide and magnesium stearate. Tablets were prepared by pressing the granules.

Preparation Example 3 Preparation of Capsule

Active ingredient 5.0 mg

Lactose 14.8 mg

Polyvinylpyrrolidone 10.0 mg

Magnesium Stearate 0.2mg

According to a conventional method for preparing a capsule, the desired components were prepared by adding the above components in the amounts shown in the present invention, mixing them uniformly, and filling the gelatine capsules with an appropriate size.

Preparation Example 4 Preparation of Injection

Active ingredient 100 mg

Mannitol 180 mg

Na ₂ HPO _{4 12} H ₂ O 26 mg

Distilled water 2974 mg

According to a conventional method of preparing an injection, an injection was prepared by containing the above components in the contents shown.

Claims (9)

A pyrazolo [4,3-b] pyridine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1]

(In the formula 1, R ¹ is substituted C the substituent is unsubstituted or substituted, or halogen, at least one selected from the group consisting of straight or branched alkyl of C ₁ ~ C ₄ a C ₁ - C ₄ straight-chain or a branched chain alkyl and halogen substituted in the ₅ and C ₁₂ aryl C ₁ -C ₄ alkyl, R ² is hydrogen or —NRR ′ wherein R is unsubstituted or is selected from the group consisting of C ₁ to C ₄ straight or branched chain alkyl, benzyl and -C (═O) R ⁴ , wherein R ⁴ is any one selected from the group consisting of straight or branched alkyl, phenyl and benzyl of C ₁ ~ C ₄ a C ₁ ~ C ₄ linear or branched alkyl, substituted by halogen, the said R 'is hydrogen or C ₁ Straight or branched alkyl of ˜C ₄ , R ³ is unsubstituted or pyrazole substituted with a substituent selected from the group consisting of C ₁ -C ₄ straight or branched chain alkyl and piperidine; Or phenyl substituted with a substituent selected from the group consisting of -CONR ⁵ R ⁶ and -NR ⁵ R ⁶ , wherein R ⁵ and R ⁶ are independently of one another or optionally hydrogen or C ₁ -C ₄ linear or branched alkyl Or; Or R ⁵ and R ⁶ may comprise at least one N or O to form a ring such that the NR ⁵ R ⁶ moieties of —CONR ⁵ R ⁶ and —NR ⁵ R ⁶ are a morpholin group or piperazine group). The benzyl or naphthalenyl of claim 1, wherein R ¹ is unsubstituted or substituted with one or more substituents selected from the group consisting of chloro, fluoro, methyl, ethyl, propyl, isopropyl and trifluoromethyl. Methyl, R ² is hydrogen or —NRR ′ wherein R is unsubstituted or is selected from the group consisting of methyl, ethyl, benzyl and —C (═O) R ⁴ , wherein R ⁴ is methyl, ethyl , Trifluoromethyl, phenyl and benzyl, any one selected from the group consisting of hydrogen, methyl, ethyl, R ³ is pyrazole wherein nitrogen is substituted with a substituent selected from the group consisting of methyl, ethyl and piperidine; Or a pyrazolo [4,3-b] pyridine derivative represented by Formula 1 of claim 1, wherein the amide compound substituted with the piperazine group is substituted phenyl. The compound of claim 1, wherein R ¹ is benzyl, dichlorobenzyl, 2-chloro-6-fluorobenzyl, isopropylbenzyl, trifluoromethylbenzyl, 2,6-dichloro-3-fluorobenzyl, naphthalene-1 Any one selected from the group consisting of -ylmethyl and 2-methylnaphthalen-1-ylmethyl, R ² is hydrogen or —NRR ′ wherein R is any one selected from the group consisting of hydrogen, methyl, benzyl, methylcarbonyl, trifluoromethylcarbonyl, phenylcarbonyl and benzylcarbonyl, wherein R 'Is hydrogen or methyl, R ³ is 1-methyl-1H-pyrazol-4-yl, 1-piperidin-4-yl-1H-pyrazol-4-yl and 4- (4-methyl-piperidin-1-ylcar A pyrazolo [4,3-b] pyridine derivative represented by formula (1) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is any one selected from the group consisting of carbonyl) phenyl. The method of claim 1, wherein the pyrazolo [4,3-b] pyridine derivative is: (1) 1- (2,6-dichlorobenzyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-ylamine; (2) 1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine- 3-ylamine; (3) 1-benzyl-6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-ylamine; (4) 1-benzyl-6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-ylamine; (5) 1- (2-chloro-6-fluorobenzyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-yl Amines; (6) 1- (2-chloro-6-fluorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b ] Pyridin-3-ylamine; (7) 1- (4-isopropylbenzyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-ylamine; (8) 6- (1-methyl-1H-pyrazol-4-yl) -1- (3-trifluoromethylbenzyl) -1H-pyrazolo [4,3-b] pyridin-3-ylamine; (9) 1- (2,6-dichloro-3-fluorobenzyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine-3 -Ylamine; (10) 1- (2,6-dichloro-3-fluorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3 -b] pyridin-3-ylamine; (11) 6- (1-methyl-1H-pyrazol-4-yl) -1-naphthalen-1-ylmethyl-1H-pyrazolo [4,3-b] pyridin-3-ylamine; (12) 1-naphthalen-1-ylmethyl-6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine-3- Monoamine; (13) 1- (2-methyl-naphthalen-1-ylmethyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine-3- Monoamine; (14) 1- (2-methyl-naphthalen-1-ylmethyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3- b] pyridin-3-ylamine; (15) 6- (1-methyl-1H-pyrazol-4-yl) -1-naphthalen-2-ylmethyl-1H-pyrazolo [4,3-b] pyridin-3-ylamine; (16) benzyl- [1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b ] Pyridin-3-yl] -amine; (17) [1- (2,6-dichlorobenzene) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine -3-yl] -methylamine; (18) N- [1- (2,6-dichloro-3-fluorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [ 4,3-b] pyridin-3-yl] -2,2,2-trifluoro-acetamide; (19) N- [1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b ] Pyridin-3-yl] -benzamide; (20) N- [1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b ] Pyridine-3-]-2-phenyl-acetamide; (21) N- [1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b ] Pyridin-3-yl] -acetamide; (22) N- [1- (2,6-dichlorobenzyl-3-fluorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrazolo [4 , 3-b] pyridin-3-yl] -2,2,2-trifluoro-N-methyl-acetamide; (23) {4- [3-amino-1- (2,6-dichlorobenzyl) -1H-pyrazolo [4,3-b] pyridin-6-yl] -phenyl}-(4-methyl-piperazine -1-yl) -methanone; And (24) 1- (2,6-dichlorobenzyl) -6- (1-piperidin-4-yl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine A pyrazolo [4,3-b] pyridine derivative represented by Formula 1 of claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: As shown in Scheme 1 below, Preparing a compound of Formula 3 by reacting Boc-protected hydrazine with a compound of Formula 2 which is a starting material in an organic solvent (step 1); Preparing an compound of formula 4 by adding an acid to the compound of formula 3 prepared in step 1 (step 2); Preparing a compound of Chemical Formula 5 by reacting benzyl halide or arylmethylene halide represented by R ¹ X at the N-1 position of the compound of Chemical Formula 4 prepared in step 2 under inorganic base conditions (step 3); And Comprising the compound of formula (5) prepared in step 3 in the presence of palladium and the Suzuki bond reaction with pyrazolboronic acid or phenylboronic acid represented by R ³ B (OH) ₂ (step 4) Method for preparing a pyrazolo [4,3-b] pyridine derivative represented by Formula 1 of claim 1: Scheme 1

(In Scheme 1, R ¹ and R ³ are as defined in Formula 1, Formula 1a is a kind of derivative represented by Formula 1). The C-3 position according to claim 5, wherein as shown in Scheme 2, the compound of Formula 1a prepared in Step 4 is subjected to an acylation reaction, or the compound obtained after the acylation reaction is subjected to alkylation reaction and acyl group removal reaction. Preparation of the pyrazolo [4,3-b] pyridine derivative represented by Formula 1 according to claim 1, further comprising the step (step 5) of preparing a compound of Formula 1b by introducing R and R 'groups into an amine group of Way: Scheme 2

(In Scheme 2, R ¹ , R ³ and -NRR 'are as defined in Formula 1, Formula 1a and 1b is a kind of derivative represented by Formula 1.). As shown in Scheme 3 below, Preparing a compound of formula 8 by reacting a compound of formula 2 as a starting material in an organic solvent with methanol in the presence of an acid (step a); Preparing an aldehyde compound of Formula 9 by performing a reduction reaction to obtain an alcohol derivative by reducing the compound of Formula 8 prepared in step a (step b); Preparing a compound of formula 10 by reacting hydrazine with the compound of formula 9 prepared in step b (step c); Preparing a compound of Chemical Formula 11 by reacting benzyl halide or arylmethylene halide represented by R ¹ X at the N-1 position of the compound of Chemical Formula 10 prepared in step c under inorganic base conditions (step d); And Comprising the compound of formula 11 prepared in step d in the presence of palladium and the Suzuki bond reaction with pyrazolboronic acid or phenylboronic acid represented by R ³ B (OH) ₂ (step e) Method for preparing a pyrazolo [4,3-b] pyridine derivative represented by Formula 1 of claim 1: Scheme 3

(In Scheme 3, R ¹ and R ³ are as defined in formula 1 of claim 1, wherein formula 1c is a kind of derivative of formula 1). A pharmaceutical composition for the prevention or treatment of diseases caused by the activity of abnormal tyrosine kinases containing the pyrazolo [4,3-b] pyridine derivative represented by Formula 1 of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. . The pharmaceutical composition according to claim 8, wherein the disease caused by abnormal activity of tyrosine kinase is tumor, psoriasis, rheumatism or diabetic retinopathy.