KR20110062351A - Method for preparing heterobiarylpyridine derivative compound and heterobiarylpyridine derivative compound prepared by such method - Google Patents

Abstract

PURPOSE: A method for preparing hetero-biaryl pyridine derivative compounds is provided to easily produce the compounds and to suppress tumor cell proliferation. CONSTITUTION: A method for preparing hetero-biaryl pyridine derivative compound of chemical formula 1 comprises a step of reacting a compound of chemical formula 2 with a compound of chemical formula 3 in a polar protic solvent under the presence of acid catalyst. The polar protic solvent is methanol, ethanol, dichloroethane, dimethyl formamide, or mixture thereof. The acid catalyst is AlCl_3, AcOH, formic acid, trifluoroacetic acid(TFA), or HCl.

Description

Method for preparing heterobiarylpyridine derivative compound and heterobiarylpyridine derivative compound produced by such method

The present invention relates to a method for preparing a novel heterobiarylpyridine derivative compound and a heterobiarylpyridine derivative compound prepared by such a method.

Biaryls and hetero-biaryls compounds are of great interest due to their various biological activities. In particular, heterobiaryl is frequently identified in many small molecules with bioactivity, and heterobiaryl compounds fused with heterocycles are used as important pharmacophores.

The major heterobiaryl compounds known so far are, for example, Viagra (Viagra ^R , sildenafil citrate, compound (a)), WYE-354 (compound (b)), a potent anticancer agent, and soluble guanylate. BAY 41-2272, a sGC activator (compound (c)), 6-aryl pyrazolo [3,4-b] pyridine, a potent inhibitor of glycogen synthase kinase-3 (GSK-3) Compound (d)) and the like.

In general, biaryl or heterobiaryl compounds are synthesized in cross-coupling reactions in the presence of transition metal catalysts. While cross-linking reactions offer a variety of advantages, there are problems such as low reaction efficiency to bulky substrates, toxicity / safety / high cost of transition metals, and heavy screening to find suitable catalysts. Furthermore, it requires a multi-step synthesis process.

In order to solve the above problems, the present inventors introduced an aldehyde group to the C-3 position of indole to make a dielectrophilic indole derivative, and then an acid catalyst in a polar protic solvent. Reaction with an aminopyrazole derivative which is a dinucleophile in the presence of a compound yields a high yield of hetero-biaryl pyrazolo [3,4-b] pyridine compound through the opening of an indole ring. The present invention was completed by confirming that these compounds selectively inhibit the proliferation of tumor cells.

Accordingly, it is an object of the present invention to provide a method for preparing a heterobiarylpyridine derivative compound having biologically useful activity and a heterobiarylpyridine derivative compound prepared by such a method.

According to the above object, the present invention comprises the step of reacting the compound of formula 2 with the compound of formula 3 in the presence of an acid catalyst in a polar protic solvent Provide the manufacturing method:

<Formula 1>

<Formula 2>

<Formula 3>

Where

X is a nitrogen (N), oxygen (O) or sulfur (S) atom;

Y, Q and M are each independently carbon (C), nitrogen (N), oxygen (O) or sulfur (S) atoms (provided that if Y is a carbon atom, at least one of Q and M is nitrogen, oxygen or sulfur) And if Q is a carbon atom, then at least one of Y and M is a nitrogen, oxygen or sulfur atom, and if M is a carbon atom, then at least one of Y and Q is a nitrogen, oxygen or sulfur atom.);

R ¹ is absent, hydrogen, hydroxy, aryl unsubstituted or substituted with C1-C6 alkoxy or halogen, C1-C6 alkyl, aryl unsubstituted or substituted with C1-C6 alkoxy, halogen or C1-C6 alkyl Or heteroaryl unsubstituted or substituted with C1-C6 alkoxy, halogen or C1-C6 alkyl;

R ² is hydrogen, halogen, amine unsubstituted or substituted with C1-C6 alkyl, nitro, C1-C6 alkylester, C1-C6 alkoxy unsubstituted or substituted with C1-C6 alkyl, unsubstituted or C1-C6 alkyl, Aryl substituted with C1-C6 haloalkyl, C1-C6 alkoxy or halogen, or heteroaryl unsubstituted or substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or halogen;

R ³ is absent if X is O or S, and if X is N, then C 1 -C 6 alkyl, unsubstituted or substituted with C 1 -C 6 alkyl or halogen is hydrogen, unsubstituted or substituted with C 1 -C 6 alkyl or halogen; C1-C6 alkoxy, unsubstituted or substituted with C1-C6 alkyl or halogen, C1-C6 alkoxycarbonyl, sulfonyl, COR ⁶ , CONR ⁶ R ⁷ or CSNR ⁶ R ⁷ , wherein R ⁶ and R ⁷ is each independently hydrogen, C 3 -C 6 alkyl unsubstituted or substituted with halogen, C 1 -C 6 alkoxy or C 1 -C 6 alkyl, C 3 -C 6 cyclo unsubstituted or substituted with halogen, C 1 -C 6 alkoxy or C 1 -C 6 alkyl Alkyl, aryl unsubstituted or substituted with halogen, C1-C6 alkoxy or C1-C6 alkyl, or benzyl unsubstituted or substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or halogen;

R ⁴ and R ⁵ are each independently absent, hydrogen, C 1 -C 6 alkyl or aryl unsubstituted or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen.

The present invention also provides heterobiarylpyridine derivative compounds of formula

<Formula 1>

Where

X, Y, M, Q, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above.

Heterobiarylpyridine derivative compounds of the formula (1) of the present invention can be easily prepared in a high yield regioselectively through one-step ring opening and cyclization Furthermore, it can be used as an anticancer pharmaceutical composition as it has excellent proliferation inhibitory activity against tumor cells.

In the method for preparing a heterobiarylpyridine derivative compound of formula 1 of the present invention, the compound of formula 3 may be used in an amount of preferably 1.0 to 1.5 equivalents, more preferably 1.0 equivalent to the compound of formula 2.

The polar protic solvent may preferably be methanol, ethanol, dichloroethane, dimethylformamide, mixtures thereof, and the like, and the acid catalyst may be AlCl ₃ , AcOH, formic acid, trifluoroacetic acid (TFA). , HCl and the like can be used, with AlCl ₃ being preferred. The amount of the acid catalyst used may be 5 to 30 mol%, preferably 10 mol% based on the total moles of the polar protic solvent containing the acid catalyst.

The reaction conditions are not particularly limited, but for example, the reaction may be performed for 2 to 5 hours at a temperature range of 40 to 70 ° C. under reflux conditions.

Aminopyrazoles have generally been reported to act as N / N-1 dinucleophiles to produce pyrazolo [1,5-a] pyrimidines (Quiroga, J .: Portilla, J .; Abonia, R .; Insuasty, B .; Nogueras, M .; Cobo, J. Tetrahedron Lett . 2008, 49, 6254-6256; Ghotekar, BK; Jachak, MN; Toche, RB J. Heterocyclic Chem . 2009, 46, 708-719). In contrast, in the present invention, the compound of Formula 3 may act as an N / C-4 nucleophile to selectively attack the compound of Formula 2 to prepare a hetero-biarylpyridine derivative compound having excellent regioselectivity. have.

Furthermore, unlike the cross-linking method for the preparation of the heterobiaryl compound, it does not use a transition metal catalyst or additive that causes toxicity, and by the conventional cross-linking method due to steric hindrance It is possible to effectively prepare even bulky 2,6-disubstituted biarylpyridine compounds which are difficult to obtain.

The compound of Formula 2 may be an indole-3-carboxyaldehyde derivative compound represented by the following Formula 2a.

Wherein R ² and R ³ are as defined above.

The compound of Formula 3 may be, but is not limited to, a dinucleophiles selected from the group consisting of compounds of the following structures:

Wherein R ¹ , R ⁴ and R ⁵ are as defined above.

The compound of formula 3 may in particular be an aminopyrazole derivative compound of formula 3a:

Wherein R ¹ and R ⁴ are as defined above.

Compounds of formula (2) and (3) used as starting materials may be obtained by purchasing a commercially available product or by synthesis by methods generally known in the art ( Bioorg . Med . Chem . Lett . 15: 5039-5044 (2005)) . Can be used.

In particular, the indole-3-carboxyaldehyde derivative compounds of the following Chemical Formulas 2b, 2c and 2d are synthesized according to the methods described in Preparation Examples 8, 10, 11, 15, etc. of the applicant.

Where

R ³ is hydrogen, unsubstituted or substituted by C1-C6 alkyl or halogen, C1-C6 alkyl, unsubstituted or substituted by C1-C6 alkyl or halogen, C1-C6 aralkyl, unsubstituted or C1-C6 alkyl Or C1-C6 alkoxycarbonyl, sulfonyl, COR ⁶ , CONR ⁶ R ⁷ or CSNR ⁶ R ⁷ substituted with halogen, wherein R ⁶ and R ⁷ are each independently hydrogen, unsubstituted or halogen, C1-C6 alkoxy or C1-C6 alkyl substituted with C1-C6 alkyl, C3-C6 cycloalkyl unsubstituted or substituted with halogen, C1-C6 alkoxy or C1-C6 alkyl, unsubstituted or halogen, C1-C6 alkoxy or C1-C6 alkyl Substituted aryl, or benzyl unsubstituted or substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or halogen;

R ⁸ and R ⁹ are each independently hydrogen, a halogen atom, C 1 -C 6 alkyl, or C 1 -C 6 alkyl or alkoxyalkyl substituted with halogen;

Except that R ³ , R ⁸ and R ⁹ are hydrogen at the same time.

Where

R ³ is hydrogen, unsubstituted or substituted with C1-C6 alkyl or halogen, C1-C6 alkyl, unsubstituted or substituted with C1-C6 alkyl or halogen, C1-C6 aralkyl, unsubstituted or C1-C6 alkyl Or C1-C6 alkoxycarbonyl, sulfonyl, COR ⁶ , CONR ⁶ R ⁷ or CSNR ⁶ R ⁷ substituted with halogen, wherein R ⁶ and R ⁷ are each independently hydrogen, unsubstituted or halogen, C1-C6 alkoxy or C1-C6 alkyl substituted with C1-C6 alkyl, C3-C6 cycloalkyl unsubstituted or substituted with halogen, C1-C6 alkoxy or C1-C6 alkyl, unsubstituted or halogen, C1-C6 alkoxy or C1-C6 alkyl Substituted aryl, or benzyl unsubstituted or substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or halogen.

Where

R ¹⁰ is hydrogen, C 1 -C 6 alkyl unsubstituted or substituted with halogen or C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl unsubstituted or substituted with halogen or C 1 -C 6 alkoxy, unsubstituted or halogen, C 1 -C 6 alkyl or Aryl substituted with C1-C6 alkoxy, or benzyl unsubstituted or substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or halogen.

Representative compounds of formula (I) obtained by the preparation method as described above are heterobiaryl pyrazolo [3,4-b] pyridine derivative compounds of formula (I):

<Formula 1a>

Where

R ¹ , R ² , R ³ and R ⁴ are as defined above.

The process for preparing the compound of Formula 1a is schematically shown in Scheme 1:

Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above.

As shown in Scheme 1, the compound of Formula 2a is reacted with the compound of Formula 3a in the presence of an acid catalyst in a polar protic solvent to form a heterobiaryl pyrazolo [3, 4-b] pyridine derivatives can be prepared.

Specific examples of the compound of Formula 1,

2- (3-phenyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

2- ( 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

2- (3-methyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

5- (2-amino-phenyl) - 1H - pyrazolo [3,4-b] pyridin-3-ol;

2- (3- (4-methoxyphenyl) - 1H - pyrazolo [3,4-b] pyridin-5-yl) benzene amine;

2- (3- (4-fluorophenyl) - 1H - pyrazolo [3,4-b] pyridin-5-yl) benzene amine;

2- (3- (furan-2-yl) - 1H - pyrazolo [3,4-b] pyridin-5-yl) benzene amine;

2- (3- (thiophen-2-yl) - 1H - pyrazolo [3,4-b] pyridin-5-yl) benzene amine;

3-nitro-2- (3-phenyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

4 '-(chloromethyl) -2- (3-phenyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) biphenyl-3-amine;

tert-butyl3-amino-2- (3-phenyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) phenylcarbamate;

Methyl 3-amino-2- (3-phenyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzoate;

2- (3-phenyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) -3- (pyridin-4-yl) benzeneamine;

2 ', 6'-dimethyl-2- (3-phenyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) biphenyl-3-amine;

4-nitro-2- (3-phenyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

2- (3-phenyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) -4- (thiophen-2-yl) benzeneamine;

4-methoxy-2- (3-phenyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

4-chloro-2- (3-phenyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

4-bromo-2- (3-phenyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

5-chloro-2- (3-phenyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

2-fluoro-6- (3-phenyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

2-chloro-6- (3-phenyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

N-methyl-2- (3-phenyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

N-benzyl-2- (3-phenyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

1-benzyl-3- (2- (3-phenyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) phenyl) urea;

2- (3-methyl-1-phenyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

2- (3- (4-methoxyphenyl) - 1H - pyrazolo [3,4-b] pyridin-5-yl) -3-nitrobenzene-amine;

5-fluoro-2- (3- (4-methoxyphenyl) - 1H - pyrazolo [3,4-b] pyridin-5-yl) benzene amine;

2-fluoro-6- (3-methyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

5-fluoro-2- (3-methyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

3-nitro-2- (3-methyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

Methyl 3-amino-2- (3-methyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzoate;

4-bromo-2- (3-methyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

4-chloro-2- (3-methyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

5-chloro-2- (3-methyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

N-methyl-2- (3-methyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine;

N-benzyl-2- (3-methyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) benzeneamine; And

1-benzyl-3- (2- (3-methyl- 1H -pyrazolo [3,4-b] pyridin-5-yl) phenyl) urea

.

As used herein, “aryl” refers to a mono- or polycyclic aromatic ring having 5 to 6 carbon atoms, for example phenyl. Aryl may be unsubstituted or have one or more substituent groups.

“Heteroaryl” means a 5-6 membered aromatic ring containing at least one, preferably one or two, heteroatoms O, N or S, for example pyrrole, pyra Sol, furan, thiophene, pyridine, pyrimidine, pyrazine, pyridazine, oxazole, oxadiazole, tetrazole, thiazole, thiadiazole, imidazole, benzimidazole, benzothiaphene. Benzopyrrole, benzofuran and the like.

Hereinafter, one-step mechanisms expected for ring-opening of indole derivatives and cyclization of aminopyrazole derivatives will be briefly described with reference to Scheme 2 below.

As shown in Scheme 2, first, an imine is formed, followed by a pericyclic rearrangement of intermediate ( I ) or C-4 of pyrazole in iminium electrophiles ( II ). The nucleophilic addition induces intramolecular cyclization to give tetracyclic compound ( IV ). Finally, the rearomatization of the cyclic intermediate ( IV ) opens the indole ring, resulting in the desired hetero-biaryl pyrazolo [3,4-b] pyridine derivative compound ( 1b ).

On the other hand, Applicant, to demonstrate the positional specificity of the compound of formula 1 of the present invention, as shown in Scheme 3, indole 3-carboxyaldehyde ( a ) 5-amino-3-methyl-1-phenyl-pyra As a result of reaction with sol ( b ) or 4- (4-fluorophenyl) -1H-pyrazole-5-amine ( c ), the modification at the N-1 position of pyrazole (corresponding to compound b ) is C- 4 The desired product was obtained by nucleophilic addition, but the modification at the C-4 position of pyrazole (corresponding to compound c ) confirmed that the desired product was not obtained under the same conditions. This shows that C-4 of aminopyrazole acts as a nucleophile to perform one-step cyclization in a specific position.

The heterobiarylpyridine derivative compound of formula 1 of the present invention was shown to selectively inhibit the proliferation of tumor cells compared to normal cells in the cytotoxicity test (see Test Example 1). Therefore, the heterobiarylpyridine derivative compound of Formula 1 prepared in the present invention may be used as an active ingredient of a pharmaceutical composition for preventing or treating cancer.

Hereinafter, the present invention will be described in detail with reference to production examples and examples, but the present invention is not limited only to these examples.

Manufacturing example  1: 4-nitro-lH-indole-3- Carboxyaldehyde

To a stirred solution by adding 4-nitro-1H-indole (80 mg) in anhydrous DMF under a dry argon atmosphere, phosphorus chloride oxide (138 μl) was added at 0 ° C., and the resulting mixed solution was allowed to come to room temperature. Stirred for 1 h. Thereafter, the reaction solution was poured into cold saturated aqueous sodium hydrogen carbonate (NaHCO ₃ ) and stirred for 30 minutes.

The resulting solution was extracted several times with ethyl acetate (EtOAc), and the combined organic layers were dried over anhydrous Na ₂ SO _{4 and} filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography on silica gel to give the title compound (86 mg, yield: 92%) of the following structural formula.

¹ H NMR (500 MHz, Acetone- d ₆ ) δ 11.84 (s, 1H) 10.29 (s, 1H) 8.43 (s, 1H) 8.00 (d, J = 8.07 Hz, 1H) 7.96 (d, J = 7.83 Hz , 1H) 7.47 (t, J = 8.07 Hz, 1H); ^{13 C NMR (125 MHz, Acetone-} d 6) δ 186.4, 140.4, 137.7, 123.4, 119.5, 118.5, 117.6; LRMS (MALDI) m / z calcd for C ₉ H ₇ N ₂ 0 ₃ [M + H] ⁺ : 191.04; Found: 191.39.

Manufacturing example  2: methyl  3- Formyl -1H-indole-4- Carboxylate

The title compound (160 mg, Yield: 79%) of the following structural formula in the same manner as in Preparation Example 1, except that indole-4-carboxylic acid methyl ester (175 mg) and phosphorus chloride oxide (280 μl) were used as starting materials. Obtained.

¹ H NMR (500 MHz, Acetone- d ₆ ) δ 11.49 (s, 1H) 10.43 (s, 1H) 8.28 (s, 1H) 7.80 (dd, J = 8.19, 1.10 Hz, 1H) 7.73 (dd, J = 7.46, 1.10 Hz, 1 H) 7.34 (t, 1 H) 3.94 (s, 3 H); ^{13 C NMR (125 MHz, Acetone-} d 6) δ 187.6, 187.6, 169.5, 139.0, 135.8, 125.6, 124.7, 123.1, 123.1, 120.0, 117.2, 52.2, 52.2; LRMS (MALDI) m / z calcd for C ₁₁ H ₉ NO ₃ [M + H] &lt; + &gt;:204.06; Found: 204.40.

Manufacturing example  3: 5-nitro-1H-indole-3- Carboxyaldehyde

The title compound (46 mg, yield: 76%) of the following structural formula in the same manner as in Preparation Example 1, except that 5-nitro-1H-indole (50 mg) and phosphorus chloride oxide (86 μl) were used as starting materials. Obtained.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.70 (br.s., 1H) 10.03 (s, 1H) 8.94 (d, J = 2.21 Hz, 1H) 8.58 (s, 1H) 8.16 (dd, J = 8.98, 2.35 Hz, 1H) 7.72 (d, J = 9.12 Hz, 1H); ¹³ C NMR (125 MHz, DMSO- d ₆ ) δ 185.99, 185.96, 143.31, 141.92, 140.60, 123.97, 119.50, 119.23, 117.50, 113.68; LRMS (MALDI) m / z calcd for C ₉ H ₆ N ₂ O ₃ [M + H] &lt; + &gt;:191.04; Found: 191.40.

Manufacturing example  4: 5- Chloro -1H-indole-3- Carboxyaldehyde

The title compound (74 mg, yield: 93%) of the following structural formula in the same manner as in Preparation Example 1, except that 5-chloro-1H-indole (70 mg) and phosphorus chloride oxide (130 μl) were used as starting materials. Obtained.

¹ H NMR (500 MHz, Acetone- d ₆ ) δ 11.33 (s, 1H) 10.03 (s, 1H) 8.29 (s, 1H) 8.23 (d, J = 1.96 Hz, 1H) 7.58 (d, J = 8.56 Hz , 1H) 7.28 (dd, J = 8.68, 2.08 Hz, 1H); ^{13 C NMR (125 MHz, Acetone-} d 6) δ 185.4, 139.1, 136.7, 128.5, 126.6, 124.7, 121.5, 119.5, 114.5; LRMS (MALDI) m / z calcd for C ₉ H ₆ ClNO [M + H] &lt; + &gt;:180.01; Found: 180.40.

Manufacturing example  5: 6- Chloro -1H-indole-3- Carboxyaldehyde

The title compound (64 mg, Yield: 77%) of the following structural formula in the same manner as in Preparation Example 1, except that 6-chloro-1H-indole (70 mg) and phosphorus chloride oxide (130 μl) were used as starting materials. Obtained.

¹ H NMR (500 MHz, Acetone- d ₆ ) δ 11.27 (s, 1 H) 10.04 (s, 1 H) 8.26 (s, 1H) 8.20 (d, J = 8.56 Hz, 1H) 7.60 (d, J = 1.71 Hz, 1 H) 7.26 (dd, J = 8.44, 1.83 Hz, 1 H); ^{13 C NMR (125 MHz, Acetone-} d 6) δ 185.4, 138.8, 138.7, 129.7, 124.1, 123.4, 123.3, 119.9, 113.0; LRMS (MALDI) m / z calcd for C ₉ H ₆ ClNO [M + H] &lt; + &gt;:180.01; Found: 180.40.

Manufacturing example  6: 7- Fluoro -1H-indole-3- Carboxyaldehyde

The title compound of the following structural formula (59 mg, yield: 83%) in the same manner as in Preparation Example 1, except that 7-fluoro-1H-indole (60 mg) and phosphorus chloride oxide (124 μl) were used as starting materials. ) Was obtained.

¹ H NMR (500 MHz, Acetone- d ₆ ) δ 11.62 (br. S., 1 H) 10.08 (s, 1 H) 8.29 (s, 1H) 8.03 (d, J = 7.83 Hz, 1H) 7.18-7.31 (m, 1H) 7.08 (dd, J = 11.25, 7.83 Hz, 1H); ^{13 C NMR (125 MHz, Acetone-} d 6) δ 185.6, 151.3, 149.4, 138.5, 129.1, 129.1, 123.8, 123.8, 120.7, 118.3, 118.3, 109.5, 109.4; LRMS (MALDI) m / z calcd for C ₉ H ₆ FNO [M + H] &lt; + &gt;:164.04; Found: 164.42.

Manufacturing example  7: 7- Chloro -1H-indole-3- Carboxyaldehyde

The title compound (66 mg, yield: 79%) of the following structural formula in the same manner as in Preparation Example 1, except that 7-chloro-1H-indole (70 mg) and phosphorus chloride oxide (130 μl) were used as starting materials. Obtained.

¹ H NMR (500 MHz, Acetone- d ₆ ) δ 11.49 (br. S., 1 H) 10.08 (s, 1 H) 8.30 (s, 1 H) 8.20 (dd, J = 7.83, 0.98 Hz, 1 H ) 7.34-7.36 (m, 1H) 7.26 (t, J = 7.70 Hz, 1H); ^{13 C NMR (125 MHz, Acetone-} d 6) δ 185.6, 138.5, 135.1, 127.2, 124.1, 124.0, 121.1, 120.7, 117.7; LRMS (MALDI) m / z calcd for C ₉ H ₆ ClNO [M + H] &lt; + &gt;:180.01; Found: 180.43.

Manufacturing example  8: 4- (4- ( Chloromethyl ) Phenyl ) -1H-indole-3- Carboxyaldehyde

(8-1) 4- (4- Hydroxymethylphenyl ) Indole  Produce

4- (hydroxymethyl) phenylboronic acid (1.5 equiv., In a solution obtained by dissolving 4-bromoindole (1 equiv, 125 μl) in a mixed solvent of water, toluene and ethanol (volume ratio 1: 1: 1: 3) 228 mg), Pd (OAc) ₂ (10 mol%, 22 mg) and Na ₂ SO ₄ (3 equiv, 318 mg) were added and the resulting mixed solution was stirred at 80 ° C. for 8 hours.

After the reaction was completed, the reaction solution was diluted with ethyl acetate, and then the organic layer was separated and filtered through celite. The filtrate was concentrated under reduced pressure and then purified by flash column chromatography on silica gel to give a yellow solid (143 mg, yield: 64%) of the following structural formula.

¹ H NMR (500 MHz, acetone) δ ppm 10.39 (br. S., 1 H) 7.67 (d, J = 7.34 Hz, 2 H) 7.49 (d, J = 7.58 Hz, 2 H) 7.43 (d, J = 8.07 Hz, 1 H) 7.35-7.41 (m, 1 H) 7.20 (t, J = 7.58 Hz, 1 H) 7.12 (d, J = 7.34 Hz, 1 H) 6.60-6.68 (m, 1 H) 4.71 (d, J = 5.38 Hz, 2H) 4.25 (t, J = 5.50 Hz, 1H); ¹³ C NMR (125 MHz, acetone) δ ppm 141.92 141.12 137.76 134,60 129.13 127.89 127.67 127.09 126.00 125.95 122.48 122.45 119.69 119.67 111.36 101.69 101.68; LRMS (MALDI) m / z calcd for C ₁₅ H ₁₃ NO [M + H] &lt; + &gt;:224.10; Found: 224.44

(8-2) 4- (4- ( Chloromethyl ) Phenyl ) -1H-indole-3- Carboxyaldehyde  Produce

4- (hydroxymethylphenyl) indole (1 equivalent, 55 mg) obtained in the above (8-1) was added to anhydrous DMF under a dry argon atmosphere and stirred, and then, phosphorus chloride oxide (3 equivalents, 69 µl) was added at 0 ° C. ) Was added and the resulting mixed solution was stirred at room temperature for 1 hour. Thereafter, the reaction solution was poured into cold saturated aqueous sodium hydrogen carbonate (NaHCO ₃ ) and stirred for 30 minutes.

The obtained solution was extracted several times with ethyl acetate, and the combined organic layers were dried over anhydrous Na ₂ SO _{4 and} filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography on silica gel to give the title compound (32 mg, yield: 52%) of the following structural formula.

¹ H NMR (500 MHz, Acetone- d ₆ ) δ 11.41 (s, 1H) 9.54 (s, 1H) 8.16 (d, J = 3.18 Hz, 1H) 7.60 (dd, J = 8.31, 0.98 Hz, 1H) 7.52 -7.58 (m, 4H) 7.33 (dd, J = 8.31, 7.34 Hz, 4H) 7.13 (dd, J = 7.34, 0.98 Hz, 1H) 4.81 (s, 2H); ^{13 C NMR (125 MHz, Acetone-} d 6) δ 185.2, 185.2, 143.5, 138.6, 138.1, 135.6, 133.2, 133.0, 130.2, 124.7, 124.2, 123.8, 119.8, 112.8, 112.7, 46.7; LRMS (MALDI) m / z calcd for C ₁₆ H ₁₂ ClNO [M + H] ⁺ : 270.06; Found: 270.41

Manufacturing example  9: 4- (pyridin-4-yl) -1H-indole-3- Carboxyaldehyde

(9-1) 4- (4- Pyridinyl ) Indole  Produce

4-bromoindole (1 equiv, 62 μl), 4-pyridinyl boronic acid (2 equiv, 205 mg), Pd (PPh ₃ ) ₄ (20 mol%, 115 mg), K ₂ CO ₃ (4 equiv, 276 mg) was dissolved in a mixed solvent of water, toluene and ethanol (volume ratio 1: 1: 1) and then the reaction mixture was stirred at 80 ° C. overnight.

After the reaction was completed, the reaction solution was diluted with ethyl acetate and then the organic layer was separated and filtered using celite. The filtrate was concentrated under reduced pressure and purified by flash column chromatography on silica gel to give a white solid (85 mg, yield: 88%) of the following structural formula.

¹ H NMR (500 MHz, acetone) δ ppm 10.59 (br. S., 1 H) 8.68 (d, J = 4.40 Hz, 2 H) 7.69 (d, J = 4.40 Hz, 2 H) 7.56 (d, J = 5.87 Hz, 1H) 7.45-7.50 (m, 1H) 7.20-7.30 (m, 2H) 6.71-6.74 (m, 1H); ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ ppm 149.94, 148.21, 136.48, 129.86, 126.62, 125.23, 122.96, 121.36, 118.91, 112.38, 99.77; LRMS (MALDI) m / z calcd for C ₁₃ H ₁₀ N ₂ [M + H] &lt; + &gt;:195.08; Found: 195.44.

(9-2) 4- (pyridin-4-yl) -1H-indole-3- Carboxyaldehyde  Produce

Phosphorous chloride oxide (3 equivalents, 122 µl) was added to the stirred solution by adding 4- (4-pyridinyl) indole (85 mg) obtained in the above (9-1) in anhydrous DMF under a dry argon atmosphere. After the addition, the resulting mixed solution was stirred at room temperature for 1 hour. Thereafter, the reaction solution was poured into cold saturated aqueous sodium hydrogen carbonate (NaHCO ₃ ) and stirred for 30 minutes.

The obtained solution was extracted several times with ethyl acetate, and the combined organic layers were dried over anhydrous Na ₂ SO _{4 and} filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography on silica gel to give the title compound (46 mg, yield: 47%) of the following structural formula.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.49 (s, 1H) 8.53-8.62 (m, 2H) 8.24 (s, 1H) 7.57 (d, J = 8.07 Hz, 1H) 7.37-7.45 (m, 2H) 7.24 (t, J = 7.70 Hz, 1 H) 7.04 (d, J = 7.09 Hz, 1 H); ^{13 C NMR (125 MHz, DMSO-} d 6) δ 181.8, 150.1, 149.0, 142.2, 141.2, 131.6, 124.1, 124.0, 123.2, 122.4, 121.8, 117.8, 114.6; LRMS (MALDI) m / z calcd for C ₁₄ H ₁₀ N ₂ O [M + H] &lt; + &gt;:223.08; Found: 223.41.

Manufacturing example  10: 4- (2,6- Dimethylphenyl ) -1H-indole-3- Carboxyaldehyde

(10-1) 4- (2,6- Dimethylphenyl ) Indole  Produce

4-bromoindole (1 equiv, 124 μl), 2,6-dimethylphenyl boronic acid (2 equiv, 300 mg), Pd (PPh ₃ ) ₄ (10 mol%, 115 mg), K ₂ CO ₃ (4 Equivalent: 553 mg) was dissolved in a mixed solvent of water, toluene and ethanol (volume ratio 1: 2: 2) and then the reaction mixture was stirred at 70 ° C. overnight.

After the reaction was completed, the reaction solution was diluted with ethyl acetate, the organic layer was separated and filtered through Celite. The filtrate was concentrated under reduced pressure and purified by silica gel flash column chromatography to give a white solid (97 mg, yield: 44%) of the following structural formula.

¹ H NMR (500 MHz, acetone) δ ppm 10.31 (br.s., 1 H) 7.44 (d, J = 8.07 Hz, 1 H) 7.28-7.30 (m, 1 H) 7.11-7.21 (m, 4 H ) 6.78 (dd, J = 7.21, 0.86 Hz, 1H) 5.94-5.97 (m, 1H) 1.96 (s, 6H); ¹³ C NMR (125 MHz, acetone) δ ppm 141.5, 137.4, 137.1, 133.9, 128.0, 128.0, 127.7, 125.7, 122.3, 120.1, 111.0, 101.5, 101.5, 20.6, 20.6; LRMS (MALDI) m / z calcd for C ₁₆ H ₁₅ N [M + H] &lt; + &gt;:222.12; Found: 222.47.

(10-2) 4- (2,6- Dimethylphenyl ) -1H-indole-3- Carboxyaldehyde  Produce

Phosphorous chloride oxide (3 equivalents, 84 µl) was added to the stirred solution by adding 4- (2,6-dimethylphenyl) indole (66 mg) obtained in the above (10-1) in anhydrous DMF under a dry argon atmosphere. ) Was added and the resulting mixed solution was stirred at room temperature for 1 hour. Thereafter, the reaction solution was poured into cold saturated aqueous sodium hydrogen carbonate (NaHCO ₃ ) and stirred for 30 minutes.

The obtained solution was extracted several times with ethyl acetate, and the combined organic layers were dried over anhydrous Na ₂ SO _{4 and} filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography on silica gel to give the title compound (64 mg, yield: 85%) of the following structural formula.

¹ H NMR (500 MHz, Acetone- d ₆ ) δ 11.39 (s, 1H) 8.92 (s, 1H) 8.11 (s, 1H) 7.60 (dd, J = 8.31, 0.98 Hz, 1H) 7.36 (dd, J = 8.19, 7.21 Hz, 1H) 7.19-7.26 (m, 1H) 7.13-7.20 (m, 2H) 6.99 (dd, J = 7.34, 0.98 Hz, 1H) 1.97 (s, 6H); ¹³ C NMR (125 MHz, Acetone- d ₆ ) δ 185.45, 185.44, 141.89, 138.21, 136.8, 133.85, 131.52, 128.4, 128.39, 128.29, 125.26, 123.96, 123.41, 120.01, 112.21, 20.36; LRMS (MALDI) m / z calcd for C ₁₇ H ₁₅ NO [M + H] &lt; + &gt;:250.12; Found: 250.42.

Manufacturing example  11: tert -Butyl 4-amino-3- Formyl -1H-indole-1- Carboxylate

Crude reaction mixture obtained according to the procedure of Preparation Example 1 using 4-nitro-1H-indole (81 mg) and phosphorus chloride oxide (140 μl), without any further purification of acetonitrile (ACN) (5 mL). )). To this was added DMAP (0.2 equiv, 12 mg) and Boc ₂ O (1.5 equiv, 164 mg) and stirred overnight at room temperature.

After completion of the reaction, the reaction solution was evaporated to remove volatiles and purified by flash column chromatography on silica gel to give N-Boc-4-nitroindole-3-carboxyaldehyde (140 mg, yield: 95%) as a yellow solid. ) Was obtained.

¹ H NMR (500 MHz, acetone) δ ppm 10.17 (s, 1H) 8.61-8.64 (m, 2H) 7.98 (d, J = 7.83 Hz, 1H) 7.65 (t, J = 8.19 Hz, 1H) 1.75 (s, 9 H); ¹³ C NMR (125 MHz, acetone) δ ppm 149.79, 141.35, 137.91, 131.31, 125.59, 124.70, 122.43, 120.25, 120.22, 106.83, 86.03, 28.26; LRMS not detected.

N-Boc-4-nitroindole-3-carboxyaldehyde (122 mg) was treated with DMF containing SnCl ₂ · H ₂ O (10 equiv, 948 mg) at room temperature for 30 minutes, and then the reaction solution was treated with NaHCO _{3 ( aq )} was added to a saturated solution and extracted several times with ethyl acetate.

The combined organic layers were dried over anhydrous Na ₂ SO _{4 and} filtered. The filtrate was concentrated under reduced pressure to give the title compound (45 mg, yield: 41%) as a yellow solid.

¹ H NMR (500 MHz, acetone) δ ppm 9.82 (s, 1 H) 8.44 (s, 1 H) 7.39 (d, J = 8.31 Hz, 1 H) 7.11 (t, J = 7.95 Hz, 1 H) 6.54 (d, J = 7.83 Hz, 1H) 6.15 (br. s., 2H) 1.69 (s, 9H); ¹³ C NMR (75 MHz, acetone) δ ppm 187.6, 149.6, 144.6, 140.2, 139.4, 128.5, 124.4, 113.4, 109.3, 103.6, 86.1, 28.2; LRMS (ESI +) m / z calcd for C ₁₄ H ₁₆ N ₂ O ₃ [M + Na] +: 283.11; Found: 283.10

Manufacturing example  12: 5- (thiophen-2-yl) -1H-indole-3- Carboxyaldehyde

In a 20 ml vial, 5-bromo-1H-indole-3-carboxyaldehyde (224 mg), Pd (OAc) ₂ (2 mol%, 4.5 mg), thiophen-2-ylboronic acid (1.5 Equivalent, 192 mg), 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (SPhos, 4 mole%, 16 mg) as an phosphine ligand and anhydrous Na ₂ CO ₃ (3 equivalents, 318 mg ) Was filled with a rubber diaphragm. The air was then removed and refilled with argon.

A syringe was used to add n-butanol through the diaphragm and then the diaphragm was replaced with a Teflon Screwcap. The reaction mixture was heated to 100 ° C. overnight, then cooled and concentrated in high vacuum to remove solvent.

The crude mixture was diluted with ethyl acetate, filtered through celite and recrystallized with acetone and methanol to give the title compound (137 mg, yield: 60%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 12.24 (s, 1 H) 9.96 (s, 1 H) 8.36 (s, 1 H) 8.32 (s, 1 H) 7.53-7.65 (m, 2 H ) 7.48 (d, J = 4.89 Hz, 1 H) 7.44 (d, J = 3.42 Hz, 1 H) 7.12 (t, J = 4.16 Hz, 1 H); ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ ppm 185.2, 185.1, 144.5, 139.3, 136.6, 128.5, 128.5, 128.3, 124.8, 124.8, 124.8, 122.9, 122.8, 121.8, 118.3, 117.6, 117.5, 113.1; LRMS (MALDI) m / z calcd for C ₁₃ H ₉ NOS [M + H] &lt; + &gt;:228.04; Found: 228.39.

Manufacturing example  13: 1- methyl -1H-indole-3- Carboxyaldehyde

Indole-3-carboxyaldehyde (58 mg) was treated with anhydrous DMF solution containing NaH (1.2 equivalents, 12 mg, 60% dispersion in mineral oil) at 0 ° C. for 10 minutes, followed by methyl iodide (1.2 equivalents, 30 μl). ) Was added and stirred at room temperature for 1 hour.

The reaction solution was cooled using H ₂ O and then further stirred for 30 minutes, and filtered through ethyl acetate in the presence of Na ₂ S ₂ O ₄ to cool methyl iodide.

The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and purified by flash column chromatography on silica gel to give the title compound (46 mg, yield: 73%).

¹ H NMR (500 MHz, acetone) δ ppm 9.96 (s, 1 H) 8.23 (d, J = 7.83 Hz, 1 H) 8.03 (s, 1 H) 7.50 (d, J = 8.07 Hz, 1 H) 7.32 (t, J = 6.97 Hz, 1 H) 7.27 (t, J = 6.97 Hz, 1 H) 3.92 (s, 3H); ¹³ C NMR (125 MHz, acetone) δ ppm 184.7, 141.5, 139.2, 126.2, 124.5, 123.3, 122.4, 118.9, 111.4, 33.9; LRMS (MALDI) m / z calcd for C ₁₀ H ₉ NO [M + H] &lt; + &gt;:160.07; Found: 160.45.

Manufacturing example  14: 1-benzyl-1H-indole-3- Carboxyaldehyde

The title compound (216 mg, yield: 92) was obtained in the same manner as in Example 13, except that indole-3-carboxyaldehyde (145 mg) was used as the starting material and benzyl bromide (171 mg) was used instead of methyl iodide. %) Was obtained.

¹ H NMR (500 MHz, acetone) δ ppm 10.02 (s, 1 H) 8.25 (d, J = 6.36 Hz, 1 H) 8.24 (s, 1 H) 7.50-7.53 (m, 1 H) 7.23-7.37 ( m, 7 H) 5.56 (s, 2H); ¹³ C NMR (125 MHz, acetone) δ ppm 185.0, 140.9, 138.5, 137.7, 129.7, 128.8, 128.2, 126.4, 124.6, 123.4, 122.6, 119.3, 111.9, 51.2; LRMS (MALDI) m / z calcd for C ₁₆ H ₁₃ NO [M + H] &lt; + &gt;:236.10; Found: 236.43.

Manufacturing example  15: N-benzyl-3- Formyl -1H-indole-1- Carboxyxamide

To a DCM solution containing indole-3-carboxyaldehyde and DIPEA (1.0 equiv, 591 μl), isocyanatobenzene (BnNCO, 1.5 equiv., 417 μl) was added and stirred at room temperature for 3 hours.

After the reaction was complete, the reaction solution was diluted with dichloromethane (DCM) and washed with saturated citric acid (aq). The combined organic layers were dried over anhydrous Na ₂ SO _{4 and} filtered. The filtrate was concentrated under reduced pressure and recrystallized from DCM and hexanes to give the title compound (739 mg, yield: 78%) as a white solid.

¹ H NMR (500 MHz, CHLOROFORM-d) δ ppm 10.06 (s, 1 H) 8.31 (d, J = 7.34 Hz, 1 H) 8.17 (s, 1 H) 7.92 (d, J = 7.58 Hz, 1 H ) 7.33-7.45 (m, 7H) 6.14 (br.s., 1H) 4.71 (d, J = 5.62 Hz, 2H); ¹³ C NMR (125 MHz, acetone) δ ppm 185.9, 151.2, 137.2, 135.8, 135.4, 129.1, 128.2, 128.1, 126.0, 124.6, 122.3, 121.0, 113.9, 45.4, 45.3; LRMS (MALDI) m / z calcd for C ₁₇ H ₁₄ N ₂ O ₂ [M + H] &lt; + &gt;:279.11; Found: 279.41.

Example  1: 2- (3- Phenyl -1H- Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

To a solution of MeOH (0.05M) containing indole-3-carboxyaldehyde (29 mg) and 3-amino-5-phenylpyrazole (1.0 equiv, 32 mg), aluminum trichloride (0.10 equiv, 2.7 mg) was added. The reaction mixture was then heated in a 20 ml volume vial set at 70 ° C. for 4 hours under reflux conditions.

After the reaction was completed, the reaction solution was cooled to room temperature and the solid obtained was slowly filtered and washed with cold methanol and diethyl ether. The filtrate was purified by flash column chromatography on silica gel (eluent: 1% TEA with ethyl acetate / hexanes / methanol) to afford the desired title compound (34 mg, yield: 58%).

¹ H NMR (500 MHz, acetone) δ ppm 12.90 (br.s., 1 H) 8.60 (d, J = 1.96 Hz, 1 H) 8.53 (d, J = 1.96 Hz, 1 H) 8.12 (dd, J = 8.56, 1.22 Hz, 2H) 7.54 (t, J = 7.70 Hz, 2H) 7.41-7.45 (m, 1H) 7.13-7.17 (m, 2H) 6.89 (dd, J = 8.44, 1.10 Hz, 1 H) 6.76 (td, J = 7.46, 1.22 Hz, 1 H) 4.58-4.64 (m, 2H); ¹³ C NMR (125 MHz, acetone) δ ppm 151.1, 146.8, 134.8, 131.9, 130.9, 130.5, 129.9, 129.8, 129.1, 127.9, 124.8, 118.5, 116.6, 116.5, 113.5; HRMS (EI +) m / z calcd for C ₁₈ H ₁₄ N ₄ [M] &lt; + &gt;:286.1218; Found: 286.1216

Example  2: 2- (1H- Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

The same procedure as in Example 1 was used except that indole-3-carboxyaldehyde (15 mg) was used as starting material and 3-aminopyrazole (8.3 mg) instead of 3-amino-5-phenylpyrazole. The desired compound was obtained (15 mg, yield 71%).

¹ H NMR (500 MHz, acetone) δ ppm 12.76 (br.s., 1 H) 8.55 (d, J = 1.96 Hz, 1 H) 8.23 (d, J = 1.96 Hz, 1 H) 8.13 (s, 1 H) 7.13 (td, J = 7.64, 1.59 Hz, 1 H) 7.10 (dd, J = 7.58, 1.47 Hz, 1 H) 6.87 (dd, J = 8.07, 0.98 Hz, 1 H) 6.74 (td, J = 7.46, 1.22 Hz, 1 H) 4.56 (br. S., 2H); ¹³ C NMR (125 MHz, acetone) δ ppm 150.9, 146.7, 134.5, 132.0, 131.8, 130.4, 130.0, 129.7, 118.5, 116.5, 115.8; HRMS (EI +) m / z calcd for C ₁₂ H ₁₀ N ₄ [M] &lt; + &gt;:210.0905; Found: 210.0908.

Example  3: 2- (3- methyl -1H- Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

Except for using 3-amino-5-methylpyrazole (19 mg) instead of 3-amino-5-phenylpyrazole as starting material, the same procedure as in Example 1 was carried out to give the desired title compound (35 mg, Yield: 79%).

¹ H NMR (500 MHz, acetone) δ ppm 12.34 (br. S., 1 H) 8.51 (d, J = 2.20 Hz, 1 H) 8.15 (d, J = 1.96 Hz, 1 H) 7.11-7.15 (m , 1 H) 7.09 (dd, J = 7.46, 1.59 Hz, 1 H) 6.87 (dd, J = 8.07, 0.98 Hz, 1 H) 6.74 (td, J = 7.40, 1.10 Hz, 1 H) 4.56 (br. s., 2H) 2.55 (s, 3H); ¹³ C NMR (125 MHz, acetone) δ ppm 150.6, 146.7, 131.8, 129.8, 129.6, 129.1, 124.9, 118.4, 116.4, 115.3, 12.6; HRMS (EI +) m / z calcd for C ₁₃ H ₁₂ N ₄ [M + H] &lt; + &gt;:224.1062; Found: 224.1061.

Example  4: 5- (2- Aminophenyl ) - 1H - Pyrazolo [3,4-b] pyridine -3-ol

The same procedure as in Example 1 was carried out except that 3-amino-5-hydroxypyrazole (20 mg) was used instead of 3-amino-5-phenylpyrazole as the starting material (28 mg). , Yield: 62%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 12.23 (br. S., 1 H) 10.06 (s, 1 H) 9.66 (s, 1 H) 8.08 (s, 1 H) 8.05 (dd, J = 6.24, 2.81 Hz, 1H) 7.54 (dd, J = 5.38, 3.67 Hz, 1H) 7.33-7.28 (m, 2H) 5.72 (s, 2H); ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ ppm 164.9, 152.7, 136.1, 136.1, 133.1, 133.1, 128.3, 122.9, 121.4, 118.3, 114.4, 112.7, 111.2; HRMS (EI +) m / z calcd for C ₁₂ H ₁₀ N ₄ O [M] &lt; + &gt;:226.0854; Found: 226.0855.

Example  5: 2- (3- (4- Methoxyphenyl ) - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

The same procedure as in Example 1 was carried out except that 3-amino-5- (4-methoxyphenyl) pyrazole (38 mg) was used instead of 3-amino-5-phenylpyrazole as a starting material. The title compound (50 mg, yield: 78%) was obtained.

¹ H NMR (500 MHz, acetone) δ ppm 12.77 (br.s., 1 H) 8.57 (d, J = 1.47 Hz, 1 H) 8.49 (d, J = 1.71 Hz, 1 H) 8.05 (d, J = 8.80 Hz, 2H) 7.13-7.17 (m, 2H) 7.10 (d, J = 9.05 Hz, 2H) 6.89 (d, J = 8.31 Hz, 1H) 6.76 (t, J = 7.46 Hz, 1 H) 4.58-4.65 (m, 2H) 3.87 (s, 3H); ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ ppm 159.2, 149.5, 145.8, 130.8, 129.6, 128.7, 128.5, 127.9, 125.7, 122.9, 116.7, 115.2, 114.3, 114.3, 111.8, 55.1, 55.1; HRMS (EI +) m / z calcd for C ₁₉ H ₁₆ N ₄ O [M] &lt; + &gt;:316.1324; Found: 316.1323.

Example  6: 2- (3- (4- Fluorophenyl ) - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

The same procedure as in Example 1 was carried out except that 5-amino-3- (4-fluorophenyl) pyrazole (35 mg) was used instead of 3-amino-5-phenylpyrazole as a starting material. The title compound (42 mg, yield: 69%) was obtained.

¹ H NMR (500 MHz, acetone) δ ppm 12.93 (br.s., 1 H) 8.60 (d, J = 1.96 Hz, 1 H) 8.51 (d, J = 1.96 Hz, 1 H) 8.15-8.19 (m , 2H) 7.28-7.34 (m, 2H) 7.13-7.17 (m, 2H) 6.89 (dd, J = 8.44, 1.10 Hz, 1H) 6.76 (td, J = 7.46, 1.22 Hz, 1H) 4.59-4.66 (m, 2H); ¹³ C NMR (125 MHz, acetone) δ ppm 164.7, 162.7, 151.1, 146.8,1 31.9, 131.2, 130.7, 130.6, 129.8, 129.8, 129.8, 124.6, 118.4, 116.7, 116.6, 116.5, 113.3; HRMS (EI +) m / z calcd for C ₁₈ H ₁₃ FN ₄ [M] &lt; + &gt;:304.1124; Found: 304.1123.

Example  7: 2- (3- (furan-2-yl)- 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

Except using indole-3-carboxyaldehyde (15 mg) as starting material and 3-amino-5- (2-furyl) pyrazole (15 mg) instead of 3-amino-5-phenylpyrazole Was subjected to the same procedure as in Example 1 to obtain the desired title compound (20 mg, yield: 72%).

¹ H NMR (500 MHz, acetone) δ ppm 12.93 (br. S., 1 H) 8.60 (d, J = 2.20 Hz, 1 H) 8.52 (d, J = 1.96 Hz, 1 H) 7.76 (dd, J = 1.71, 0.73 Hz, 1 H) 7.13-7.18 (m, 2 H) 7.05 (dd, J = 3.18, 0.73 Hz, 1 H) 6.89 (d, J = 7.83 Hz, 1 H) 6.77 (td, J = 7.46, 1.22 Hz, 1 H) 6.65 (dd, J = 3.42, 1.96 Hz, 1 H) 4.63 (br. S., 2 H); ¹³ C NMR (125 MHz, acetone) δ ppm 152.0, 151.5, 150.1, 146.8, 143.7, 131.8, 130.9, 130.7, 129.8, 124.5, 118.4, 116.5, 112.9, 112.4, 107.8; HRMS (EI +) m / z calcd for C ₁₆ H ₁₂ N ₄ O [M] &lt; + &gt;:276.1011; Found: 276.1014.

Example  8: 2- (3- (thiophen-2-yl)- 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

Except using indole-3-carboxyaldehyde (15 mg) as starting material and 5-amino-3- (2-thienyl) pyrazole (17 mg) instead of 3-amino-5-phenylpyrazole And the same procedure as in Example 1 to give the title compound (19 mg, yield: 65%).

¹ H NMR (500 MHz, acetone) δ ppm 12.87 (br. S., 1 H) 8.60 (d, J = 1.96 Hz, 1 H) 8.52 (d, J = 1.96 Hz, 1 H) 7.85 (d, J = 3.67 Hz, 1 H) 7.53 (dd, J = 5.01, 1.10 Hz, 1 H) 7.21 (dd, J = 5.01, 3.55 Hz, 1 H) 7.13-7.18 (m, 2H) 6.89 (d, J = 8.31 Hz, 1 H) 6.77 (t, J = 7.34 Hz, 1 H) 4.65 (br. S., 2 H); ¹³ C NMR (125 MHz, acetone) δ ppm 151.3, 146.7, 137.0, 131.8, 130.6, 130.3, 129.7, 128.7, 126.2, 125.9, 124.4, 118.3, 118.3, 116.4, 116.4, 112.8; HRMS (EI +) m / z calcd for C ₁₆ H ₁₂ N ₄ S [M] &lt; + &gt;:292.0782; Found: 292.0785

Example  9: 3-nitro-2- (3- Phenyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

3-amino-5-phenylparasol (16 mg) was used as a starting material, and 4-nitro- 1H -indole-3-carboxyaldehyde (19 mg) obtained in Preparation Example 1 was used instead of indole-3-carboxyaldehyde. The same procedure as in Example 1 was carried out except that the title compound (25 mg, yield: 75%) was obtained.

¹ H NMR (500 MHz, acetone) δ ppm 13.00 (br. S., 1 H) 8.47 (d, J = 1.96 Hz, 1 H) 8.43 (d, J = 1.96 Hz, 1 H) 8.11 (dd, J = 8.44, 1.34 Hz, 2H) 7.53 (t, J = 7.70 Hz, 2H) 7.40-7.45 (m, 1H) 7.37 (t, J = 8.19 Hz, 1H) 7.21 (dd, J = 7.95, 1.10 Hz, 1 H) 7.18 (dd, J = 8.19, 1.10 Hz, 1 H) 5.02-5.13 (m, 2H); ¹³ C NMR (125 MHz, acetone) δ ppm 152.6, 150.9, 149.8, 149.8, 134.5, 132.0, 130.3, 129.9, 129.2, 127.8, 124.7, 119.6, 119.5, 117.0, 113.7, 112.3; HRMS (EI +) m / z calcd for C ₁₈ H ₁₃ N ₅ O ₂ [M] &lt; + &gt;:331.1069; Found: 331.1068

Example  10: 4 '-( Chloromethyl ) -2- (3- Phenyl - 1H - Pyrazolo [3,4-b] pyridine -5-yl) biphenyl-3-amine

4- (4- (chloromethyl) phenyl) -1H-indole-3 prepared in Preparation Example 8 using 3-amino-5-phenylparasol (19 mg) as a starting material and replacing indole-3-carboxyaldehyde. The same procedure as in Example 1 was carried out except for using carboxyaldehyde (30 mg) to give the desired title compound (28 mg, yield: 61%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 13.69 (s, 1 H) 8.27 (d, J = 1.96 Hz, 1 H) 8.05 (d, J = 1.96 Hz, 1 H) 7.92 (d, J = 7.09 Hz, 2H) 7.50 (t, J = 7.58 Hz, 2H) 7.40 (t, J = 7.34 Hz, 1H) 7.14-7.21 (m, 3H) 7.07 (d, J = 8.07 Hz, 2 H) 6.84 (dd, J = 8.07, 1.22 Hz, 1 H) 6.62 (dd, J = 7.46, 1.10 Hz, 1 H) 4.84 (br. S., 2 H) 4.60 (s, 2 H); ¹³ C NMR (125 MHz, acetone) δ ppm 151.6, 151.1, 142.7, 141.8, 135.3, 133.1, 1312.0, 129.8, 128.9, 128.4, 128.2, 128.0, 126.6, 121.5, 118.3, 114.4, 111.9, 45.8; HRMS (EI +) m / z calcd for C ₂₅ H ₁₉ ClN ₄ [M] &lt; + &gt;:410.1298; Found: 410.1297

Example  11: tert -Butyl 3-amino-2- (3- Phenyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Phenyl Carbamate

Tert -Butyl 4-amino-3-formyl- 1H -indole- 1 -prepared in Preparation Example 11 using 3-amino-5-phenylparasol (16 mg) as starting material and replacing indole-3-carboxyaldehyde. The same procedure as in Example 1 was carried out except for using carboxylate (26 mg) to afford the title compound (17 mg, yield: 43%).

¹ H NMR (500 MHz, acetone) δ ppm 12.96 (br. S., 1 H) 8.41 (s, 1 H) 8.39 (s, 1 H) 8.11 (d, J = 7.58 Hz, 2 H) 7.53 (t , J = 7.70 Hz, 2 H) 7.42 (t, J = 8.07 Hz, 1 H) 7.21 (d, J = 8.07 Hz, 1 H) 7.12 (t, J = 8.19 Hz, 1 H) 7.07 (br. S ., 1 H) 6.67 (d, J = 8.07 Hz, 1 H) 4.39 (br. S., 2 H) 1.26 (s, 9 H); ¹³ C NMR (125 MHz, acetone) δ ppm 154.0, 152.2, 148.0, 144.6, 138.6, 134.6, 133.4, 129.8, 129.7, 129.1, 127.8, 125.7, 117.4, 114.0, 112.6, 112.0, 79.6, 28.4; HRMS (EI +) m / z calcd for C ₂₃ H ₂₃ N ₅ O ₂ [M] &lt; + &gt;:401.1851; Found: 401.1851

Example  12: methyl  3-amino-2- (3- Phenyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzoate

The same procedure as in Example 1 was conducted except that methyl 3-formyl- 1H -indole-4-carboxylate (41 mg) obtained in Preparation Example 2 was used instead of indole-3-carboxyaldehyde as a starting material. The title compound (52 mg, yield: 76%) was obtained.

¹ H NMR (500 MHz, acetone) δ ppm 12.90 (br.s., 1 H) 8.35 (s, 2 H) 8.10 (dd, J = 8.31, 1.22 Hz, 2 H) 7.53 (t, J = 7.70 Hz , 2H) 7.39-7.44 (m, 1H) 7.26 (t, J = 7.83 Hz, 1H) 7.19-7.23 (m, 1H) 7.08 (dd, J = 7.95, 1.34 Hz, 1H) 4.62- 4.67 (m, 2H); ¹³ C NMR (125 MHz, acetone) δ ppm 168.8, 151.4, 148.4, 148.4, 134.8, 133.5, 131.4, 129.9, 129.5, 129.1, 128.5, 127.8, 124.1, 119.2, 119.2, 119.1, 113.5, 52.0; HRMS (EI +) m / z calcd for C ₂₀ H ₁₆ N ₄ O ₂ [M] +: 344.1273; Found: 344.1275

Example  13: 2- (3- Phenyl - 1H - Pyrazolo [3,4-b] pyridine -5-yl) -3- (pyridin-4-yl) Benzeneamine

The use of 3-amino-5-phenyl-para-sol (16 mg) as a starting material and produced in Production Example 9 in place of indole-3-carboxy aldehyde 4- (pyridin-4-yl) - 1H - indole-3-carboxylic The same procedure as in Example 1 was carried out except for the use of aldehyde (22 mg) to give the desired title compound (26 mg, yield: 71%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 13.73 (s, 1 H) 8.31 (d, J = 1.47 Hz, 1 H) 8.29 (d, J = 5.87 Hz, 2H) 8.08 (d, J = 1.96 Hz, 1 H) 7.95 (d, J = 7.34 Hz, 2 H) 7.50 (t, J = 7.83 Hz, 2 H) 7.41 (t, J = 7.58 Hz, 1 H) 7.22 (t, J = 7.83 Hz, 1H) 7.07 (d, J = 5.62 Hz, 2H) 6.89 (d, J = 8.07 Hz, 1H) 6.64 (d, J = 7.09 Hz, 1H) 4.93 (s, 2H); HRMS (EI +) m / z calcd for C ₂₃ H ₁₇ N ₅ [M + H] &lt; + &gt;:363.1484; Found: 363.1489

Example  14: 2 ', 6'-dimethyl-2- (3- Phenyl - 1H - Pyrazolo [3,4-b] pyridine -5-yl) biphenyl-3-amine

The use of 3-amino-5-phenyl-para-sol (13 mg) as a starting material and produced in Production Example 10 in place of indole-3-carboxy-4-aldehyde (2,6-dimethylphenyl) - 1H - indol-3 The same procedure as in Example 1 was carried out except for using carboxyaldehyde (20 mg) to give the desired title compound (19 mg, yield: 61%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 13.66 (br. S., 1 H) 8.23 (d, J = 1.96 Hz, 1 H) 7.96 (d, J = 2.20 Hz, 1 H) 7.75 ( dd, J = 8.44, 1.34 Hz, 2H) 7.52 (t, J = 7.70 Hz, 2H) 7.39-7.44 (m, 1H) 7.18 (dd, J = 8.07, 7.58 Hz, 1H) 6.81-6.95 (m, 4H) 6.39 (dd, J = 7.46, 1.10 Hz, 1H) 4.84 (s, 2H) 2.03 (br. s., 3H) 1.92 (br. s., 3H); ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ ppm 151.65, 149.97, 146.82, 141.05, 140.6, 133.06, 130.44, 128.98, 128.73, 128.11, 126.61, 126.36, 121.43, 117.39, 114.18, 111.64, 20.42; HRMS (EI +) m / z calcd for C ₂₆ H ₂₂ N ₄ [M] &lt; + &gt;:390.1844; Found: 390.1845

Example  15: 4-nitro-2- (3- Phenyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

Using 3-amino-5-phenylparazol (16 mg) as starting material and 5-nitro- 1H -indole-3-carboxyaldehyde (19 mg) prepared in Preparation Example 3 instead of indole-3-carboxyaldehyde. Except for using the same procedure as in Example 1 to give the desired title compound (26 mg, yield: 80%).

¹ H NMR (500 MHz, acetone) δ ppm 12.99 (br. S., 1 H) 8.64 (d, 1 H) 8.62 (d, 1 H) 8.14 (dd, J = 8.31, 0.98 Hz, 2 H) 8.07 -8.11 (m, 2H) 7.54 (t, J = 7.58 Hz, 2H) 7.41-7.46 (m, 1H) 6.99 (d, J = 9.29 Hz, 1H) 6.04 (br.s., 2H ); ¹³ C NMR (125 MHz, acetone) δ ppm 153.9, 150.8, 138.9, 134.6, 131.7, 129.9, 129.2, 128.4, 128.1, 127.9, 126.4, 115.0, 113.6; HRMS (EI +) m / z calcd for C ₁₈ H ₁₃ N ₅ O ₂ [M] &lt; + &gt;:331.1069; Found: 331.1073

Example  16: 2- (3- Phenyl - 1H - Pyrazolo [3,4-b] pyridine -5-yl) -4- (thiophen-2-yl) Benzeneamine

As the starting material 5- (thiophen-2-yl) produced in Production Example 12 in place of indole-3-carboxy aldehyde - 1H - and are carried out but using indole-3-carboxy-aldehyde (45 mg) Example 1 The same procedure was followed to obtain the title compound (60 mg, yield: 82%).

¹ H NMR (500 MHz, acetone) δ ppm 12.96 (br. S., 1 H) 8.66 (d, J = 1.71 Hz, 1 H) 8.60 (d, J = 0.98 Hz, 1 H) 8.15 (dd, J = 8.44, 1.10 Hz, 2H) 7.54 (t, J = 7.83 Hz, 2H) 7.45-7.49 (m, 2H) 7.40-7.45 (m, 1H) 7.27-7.32 (m, 2H) 7.03- 7.07 (m, 1H) 6.94 (d, J = 7.83 Hz, 1H) 4.82-4.91 (m, 2H); ¹³ C NMR (125 MHz, acetone) δ ppm 151.05, 146.74, 145.82, 134.73, 131.15, 129.98, 129.86, 129.40, 129.11, 128.92, 127.88, 127.46, 125.09, 123.84, 122.14, 116.84, 113.55; HRMS (EI +) m / z calcd for C ₂₂ H ₁₆ N ₄ S [M] &lt; + &gt;:368.1096; Found: 368.1101

Example  17: 4- Methoxy -2- (3- Phenyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

The same procedure as in Example 1 was carried out except that 5-methoxy-1H-indole-3-carboxyaldehyde (35 mg) was used instead of indole-3-carboxyaldehyde as starting material to obtain the desired title compound (36 mg). , Yield: 56%) was obtained.

¹ H NMR (500 MHz, acetone) δ ppm 12.96 (br.s., 1 H) 8.64 (d, J = 1.96 Hz, 1 H) 8.56 (d, J = 1.96 Hz, 1 H) 8.12 (d, J = 7.09 Hz, 2H) 7.53 (t, J = 7.70 Hz, 2H) 7.42 (t, J = 7.46 Hz, 1H) 6.78-6.87 (m, 3H) 4.25 (br.s., 2H) 3.75 (s, 3H); ¹³ C NMR (125 MHz, acetone) δ ppm 153.4, 151.0, 140.3, 134.7, 130.9, 130.5, 129.8, 129.1, 127.8, 125.7, 117.8, 117.0, 115.8, 113.4, 56.0; HRMS (EI +) m / z calcd for C ₁₉ H ₁₆ N ₄ O [M] &lt; + &gt;:316.1324; Found: 316.1326

Example  18: 4- Chloro -2- (3- Phenyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

3-amino-5-phenylparazol (16 mg) was used as starting material and 5-chloro-1H-indole-3-carboxyaldehyde (18 mg) prepared in Preparation Example 4 was used instead of indole-3-carboxyaldehyde. Except for using the same procedure as in Example 1 to give the desired title compound (22 mg, yield: 68%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 13.88 (br. S., 1 H) 8.56 (d, J = 1.71 Hz, 1 H) 8.50 (d, J = 1.71 Hz, 1 H) 8.06 (d , J = 7.09 Hz, 2H) 7.52 (t, J = 7.58 Hz, 2H) 7.42 (t, J = 7.34 Hz, 1H) 7.15 (d, J = 2.45 Hz, 1H) 7.11-7.14 (m , 1 H) 6.78-6.82 (m, 1 H) 5.15 (br. S., 2 H); ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ ppm152.2, 150.2, 145.9, 143.6, 133.9, 130.8, 130.7, 129.7, 128.8, 128.5, 127.4, 125.1, 120.4, 117.3, 112.8; HRMS (EI +) m / z calcd for C ₁₈ H ₁₃ ClN ₄ [M] &lt; + &gt;:320.0829; Found: 320.0827

Example  19: 4- Bromo -2- (3- Phenyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

Except for using 5-bromo-1H-indole-3-carboxyaldehyde (45 mg) instead of indole-3-carboxyaldehyde as starting material, the same procedure as in Example 1 was carried out to give the desired title compound (51 mg). , Yield: 70%) was obtained.

¹ H NMR (500 MHz, acetone) δ ppm 12.94 (br. S., 1 H) 8.60 (d, J = 1.96 Hz, 1 H) 8.56 (d, J = 1.96 Hz, 1 H) 8.13 (dd, J = 8.31, 1.22 Hz, 2H) 7.54 (t, J = 7.58 Hz, 2H) 7.43 (t, J = 7.46 Hz, 1H) 7.31 (d, J = 2.45 Hz, 1H) 7.28 (dd, J = 8.56, 2.45 Hz, 1 H) 6.86 (d, J = 8.56 Hz, 1 H) 4.80-4.87 (m, 2H); ¹³ C NMR (125 MHz, acetone) δ ppm 150.8, 146.4, 134.6, 134.0, 132.3, 131.2, 129.9, 129.2, 127.9, 126.8, 118.1, 118.1, 113.5, 109.1; HRMS (EI +) m / z calcd for C ₁₈ H ₁₃ BrN ₄ [M] &lt; + &gt;:364.0323; Found: 364.0326

Example  20: 5- Chloro -2- (3- Phenyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

Use 3-amino-5-phenylparasol (16 mg) as starting material and 6-chloro-1H-indole-3-carboxyaldehyde (18 mg) obtained in Preparation Example 5 instead of indole-3-carboxyaldehyde. The same procedure as in Example 1 was carried out except that the title compound (20 mg, yield: 61%) was obtained.

¹ H NMR (500 MHz, acetone) δ ppm 12.95 (br.s., 1 H) 8.57 (d, J = 1.96 Hz, 1 H) 8.53 (d, J = 1.96 Hz, 1 H) 8.11 (dd, J = 8.31, 1.22 Hz, 2H) 7.54 (t, J = 7.70 Hz, 2H) 7.41-7.45 (m, 1H) 7.15 (d, J = 8.07 Hz, 1H) 6.94 (d, J = 2.20 Hz , 1 H) 6.75 (dd, J = 8.07, 2.20 Hz, 1 H) 4.92-4.98 (m, 2H); ¹³ C NMR (125 MHz, acetone) δ ppm 150.9, 148.4, 134.8, 134.7, 133.3, 131.1, 129.8, 129.3, 129.1, 127.8, 127.8, 123.4, 117.8, 115.6, 113.5; HRMS (EI +) m / z calcd for C ₁₈ H ₁₃ ClN ₄ [M] &lt; + &gt;:320.0829; Found: 320.0827

Example  21: 2- Fluoro -6- (3- Phenyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

7-fluoro-1H-indole-3-carboxyaldehyde (16 mg) prepared in Preparation Example 6 using 3-amino-5-phenylparazol (16 mg) as starting material and replacing indole-3-carboxyaldehyde. The same procedure as in Example 1 was carried out except that the title compound (22 mg, yield: 72%) was obtained.

¹ H NMR (500 MHz, acetone) δ ppm 12.98 (br. S., 1 H) 8.61 (d, J = 1.96 Hz, 1 H) 8.57 (d, J = 1.96 Hz, 1 H) 8.12 (dd, J = 8.31, 1.22 Hz, 2H) 7.53 (t, J = 7.58 Hz, 2H) 7.41-7.45 (m, 1H) 7.07 (ddd, J = 11.25, 8.19, 1.35 Hz, 1H) 7.03 (dd, J = 7.70, 0.86 Hz, 1 H) 6.75 (td, J = 7.89, 5.26 Hz, 1 H) 4.66 (br. S., 2 H); ¹³ C NMR (125 MHz, acetone) δ ppm 153.7, 153.6, 151.7, 150.7, 135.2, 134.6, 131.0, 129.8, 129.2, 129.1, 127.8, 127.4, 127.4, 127.2, 117.8, 117.8, 115.3, 115.1, 113.5; HRMS (EI +) m / z calcd for C ₁₈ H ₁₃ FN ₄ [M] &lt; + &gt;:304.1124; Found: 304.1123

Example  22: 2- Chloro -6- (3- Phenyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

3-amino-5-phenylparazol (16 mg) was used as starting material and 7-chloro-1H-indole-3-carboxyaldehyde (18 mg) prepared in Preparation Example 7 was used instead of indole-3-carboxyaldehyde. Except for using the same procedure as in Example 1 to give the desired title compound (23 mg, yield: 71%).

¹ H NMR (500 MHz, acetone) δ ppm 12.95 (br. S., 1 H) 8.58 (d, J = 1.96 Hz, 1 H) 8.56 (d, J = 1.96 Hz, 1 H) 8.13 (dd, J = 8.07, 0.98 Hz, 2 H) 7.54 (t, J = 7.83 Hz, 2 H) 7.43 (t, J = 7.34 Hz, 1 H) 7.33 (dd, J = 8.07, 1.47 Hz, 1 H) 7.15 (dd , J = 7.46, 1.10 Hz, 1 H) 6.79 (t, J = 7.83 Hz, 1 H) 4.82-4.91 (m, 2H) ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ ppm 149.5, 142.0, 133.0, 130.1, 129.9, 128.9, 128.7, 128.1, 126.6, 125.0, 118.2, 117.2, 112.0; HRMS (EI +) m / z calcd for C ₁₈ H ₁₃ ClN ₄ [M] &lt; + &gt;:320.0829; Found: 320.0829

Example  23: N- methyl -2- (3- Phenyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

The same procedure as in Example 1 was carried out except that 1-methyl- 1H -indole-3-carboxyaldehyde (32 mg) obtained in Preparation Example 13 was used instead of indole-3-carboxyaldehyde as the starting material. Compound (41 mg, yield: 68%) was obtained.

¹ H NMR (500 MHz, acetone) δ ppm 12.92 (br.s., 1 H) 8.51 (d, J = 1.96 Hz, 1 H) 8.46 (d, J = 1.96 Hz, 1 H) 8.11 (dd, J = 8.31, 1.22 Hz, 2H) 7.53 (t, J = 7.58 Hz, 2H) 7.40-7.45 (m, 1H) 7.28 (td, J = 7.83, 1.71 Hz, 1H) 7.12 (dd, J = 7.34, 1.71 Hz, 1H) 6.71-6.77 (m, 2H) 4.74 (d, J = 4.65 Hz, 1H) 2.79 (d, J = 5.14 Hz, 3H); ¹³ C NMR (75 MHz, acetone) δ ppm 153.7, 150.3, 147.4, 143.6, 133.7, 130.7, 129.2, 129.2, 128.9, 128.1, 126.8, 124.3, 116.3, 112.5, 109.7, 29.8; HRMS (EI +) m / z calcd for C ₁₉ H ₁₆ N ₄ [M] &lt; + &gt;:300.1375; Found: 300.1376

Example  24: N-benzyl-2- (3- Phenyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

The same procedure as in Example 1 was carried out except that 1-benzyl- 1H -indole-3-carboxyaldehyde (47 mg) obtained in Preparation Example 14 was used instead of indole-3-carboxyaldehyde as the starting material. Compound (63 mg, yield: 83%) was obtained.

¹ H NMR (500 MHz, acetone) δ ppm 12.93 (br. S., 1 H) 8.61 (d, J = 1.96 Hz, 1 H) 8.56 (d, J = 1.96 Hz, 1 H) 8.13 (dd, J = 8.31, 1.22 Hz, 2H) 7.55 (t, J = 7.70 Hz, 2H) 7.44 (tt, J = 7.37, 1.31 Hz, 1H) 7.40 (d, J = 7.09 Hz, 2H) 7.26-7.31 (m, 2H) 7.14-7.22 (m, 3H) 6.74 (td, J = 7.40, 1.10 Hz, 1H) 6.69 (d, J = 8.07 Hz, 1H) 5.31 (t, J = 5.75 Hz, 1 H) 4.39-4. 42 (m, 2H); ¹³ C NMR (125 MHz, acetone) δ ppm 151.3, 146.2, 140.5, 133.9, 131.1, 130.6, 129.4, 129.2, 129.1, 128.6, 128.4, 127.3, 127.1, 126.9, 124.8, 117.0, 117.0, 112.8, 111.3, 47.3 , 47.3; HRMS (EI +) m / z calcd for C ₂₅ H ₂₀ N ₄ [M] &lt; + &gt;:376.1688; Found: 376.1691

Example  25: 1-benzyl-3- (2- (3- Phenyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Phenyl ) Urea

N-benzyl-3-formyl- 1H -indole-1-carboxamide (28) obtained in Preparation Example 15 using 3-amino-5-phenylparasol (16 mg) as a starting material and replacing indole-3-carboxyaldehyde (28) Except for using mg), the same procedure as in Example 1 was carried out to obtain the title compound (19 mg, yield: 51%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 13.93 (br.s., 1 H) 8.50 (d, J = 1.71 Hz, 1 H) 8.48 (d, J = 1.71 Hz, 1 H) 8.05 ( d, J = 7.09 Hz, 2H) 7.95 (d, J = 8.07 Hz, 1H) 7.65 (s, 1H) 7.51 (t, J = 7.58 Hz, 2H) 7.42 (t, J = 7.34 Hz, 1 H) 7.32-7.38 (m, 2H) 7.11-7.22 (m, 6H) 6.84 (t, J = 5.75 Hz, 1H) 4.20 (d, J = 5.62 Hz, 2H); ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ ppm 155.5, 152.3, 149.8, 140.0, 137.4, 133.2, 131.0, 130.4, 129.9, 129.0, 128.2, 127.0, 126.6, 122.9, 122.3, 112.1, 42.8, 42.8; HRMS (EI +) m / z calcd for C ₂₆ H ₂₁ N ₅ O [M] &lt; + &gt;:419.1746; Found: 419.1744.

Example  26: 2- (3- methyl -One- Phenyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

Except using indole-3-carboxyaldehyde (17 mg) as starting material and 5-amino-3-methyl-1-phenyl pyrazole (15 mg) instead of 3-amino-5-phenylpyrazole Was subjected to the same procedure as in Example 1 to obtain the desired title compound (16 mg, yield: 54%).

¹ H NMR (500 MHz, Acetone- d6 ) δ 8.66 (d, J = 1.96 Hz, 1 H) 8.45 (d, J = 8.56 Hz, 2H) 8.28 (d, J = 1.96 Hz, 1H) 7.55 (t, J = 7.58 Hz, 2H) 7.29 (td, J = 7.46, 0.98 Hz, 1H) 7.11-7.18 (m, 2H) 6.89 (d, J = 7.83 Hz, 1H) 6.76 (t, J = 7.46 Hz, 1H) 4.62 (br. S., 2 H) 2.66 (s, 3 H); ¹³ C NMR (125 MHz, Acetone- d6 ) δ 175.18, 150.20, 145.99, 143.16, 140.28, 130.99, 130.01, 129.72, 129.12, 129.10, 125.23, 123.56, 119.99, 117.72, 117.37, 115.78, 12.55; LRMS (MALDI) m / z calcd for C 19 H 17 N 4 [M + H] +: 301.14; Found: 301.45.

Example  27: 2- (3- (4- Methoxyphenyl ) - 1H - Pyrazolo [3,4-b] pyridine -5-day) -3- Nitrobenzeneamine

As a starting material, 4-nitro-1H-indole-3-carboxyaldehyde (19 mg) prepared in Preparation Example 1 was used instead of indole-3-carboxyaldehyde and 3-amino instead of 3-amino-5-phenylpyrazole. Except for using -5- (4-methoxyphenyl) pyrazole (19 mg), the same procedure as in Example 1 was carried out to obtain the title compound (27 mg, yield: 74%).

¹ H NMR (500 MHz, DMSO- d 6) δ 13.81 (br. S., 1H) 8.35 (d, J = 1.96 Hz, 1H) 8.33 (d, J = 1.96 Hz, 1H) 7.93-7.98 (m, 2H) 7.31 (t, J = 8.19 Hz, 1H) 7.14 (d, J = 8.07 Hz, 1H) 7.07 (dd, J = 8.68, 2.57 Hz, 3H) 5.37 (s, 2H) 3.78-3.82 (m, 3H ); 13 C NMR (125 MHz, DMSO- d 6) δ 159.42, 152.47, 151.18, 149.62, 148.99, 142.84, 131.06, 129.33, 128.05, 125.71, 123.12, 118.69,115.31, 114.55, 112.23, 110.64, 55.31, 55.28 LRMS (MALDI) m / z calcd for C 19 H 16 N 5 O 3 [M + H] +: 362.35; Found: 362.34

Example  28: 5- Fluoro -2- (3- (4- Methoxyphenyl ) - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

Use 6-fluoroindole-3-carboxyaldehyde (16 mg) instead of indole-3-carboxyaldehyde as starting material and 3-amino-5- (4-methoxy instead of 3-amino-5-phenylpyrazole The same procedure as in Example 1 was carried out except for using phenyl) pyrazole (19 mg) to give the desired title compound (25 mg, yield: 74%).

¹ H NMR (500 MHz, Acetone- d6 ) δ 12.78 (br. S., 1H) 8.53 (d, J = 1.71 Hz, 1H) 8.46 (d, J = 1.71 Hz, 1H) 8.02-8.07 (m, 2H ) 7.15 (dd, J = 8.31, 6.60 Hz, 1H) 7.07-7.12 (m, 2H) 6.65 (dd, J = 11.37, 2.57 Hz, 1H) 6.49 (td, J = 8.50, 2.57 Hz, 1H) 4.90- 4.99 (m, 2 H) 3.87 (s, 3 H); 13 C NMR (125 MHz, DMSO- d 6) δ 163.88, 161.96, 159.34, 152.11, 149.75, 148.21, 148.11,142.81, 132.54, 132.47, 130.07, 128.06, 127.94, 125.9, 119.46, 114.51, 112.05, 103.01, 102.01, 102.01 , 100.94, 55.29, 55.25; LRMS (MALDI) m / z calcd for C19H16FN4O [M + H] +: 335.35; Found: 335.52

Example  29: 2- Fluoro -6- (3- methyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

Use 7-fluoro- 1H -indole-3-carboxyaldehyde (16 mg) prepared in Preparation Example 6 instead of indole-3-carboxyaldehyde as starting material and 3-in place of 3-amino-5-phenylpyrazole Except for using amino-5-methylpyrazole (10 mg), the same procedure as in Example 1 was carried out to obtain the title compound (13 mg, yield: 55%).

¹ H NMR (500 MHz, Acetone- d6 ) δ 12.39 (br. S., 1H) 8.52 (d, J = 1.96 Hz, 1H) 8.19 (d, J = 1.96 Hz, 1H) 7.05 (ddd, J = 11.19 , 8.13, 1.22 Hz, 1H) 6.97 (d, J = 7.58 Hz, 1H) 6.74 (td, J = 7.95, 5.38 Hz, 1H) 4.58 (br. S., 2H) 2.56 (s, 3H); 13C NMR (125 MHz, Acetone- d6 ) δ 153.59, 151.7, 150.36, 135.09,134.99, 130, 127.83, 127.81, 127.48, 127.45, 127.36, 127.34, 117.84, 117.82, 117.78, 117.75, 115.24, 115.14, 12. ; LRMS (MALDI) m / z calcd for C 13 H 12 FN 4 [M + H] +: 243.25; Found: 243.47.

Example  30: 5- Fluoro -2- (3- methyl -1H- Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

The same procedure as in Example 1 was carried out using 3-amino-5-methylparasol (39 mg) and 6-fluoro-1H-indole-3-carboxyaldehyde (65 mg) as starting materials, but the chromatography was carried out. Recrystallization without purification gave the desired title compound (18 mg, yield: 19%).

¹ H NMR (500 MHz, acetone) d ppm 2.55 (s, 3 H) 4.89 (br. S., 2 H) 6.47 (tt, J = 8.47, 2.05 Hz, 1 H) 6.63 (dt, J = 11.31, 2.05 Hz, 1H) 7.10 (td, J = 7.46, 1.47 Hz, 1H) 8.14 (d, J = 1.96 Hz, 1H) 8.47 (d, J = 1.96 Hz, 1H) 12.36 (br. S. , 1 H); LRMS (MALDI) m / z calcd for C ₁₃ H ₁₂ FN ₄ [M + H] &lt; + &gt;:243.10; Found: 243.40

Example  31: 3-nitro-2- (3- methyl -1H- Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

The same procedure as in Example 1 was carried out using 3-amino-5-methylparasol (24 mg) and 4-nitro- 1H -indole-3-carboxyaldehyde (48 mg) as starting materials, but by chromatography. Recrystallization without purification gave the desired title compound (6 mg, yield: 9%).

¹ H NMR (500 MHz, DMSO-d6) d ppm 2.51 (s, 3 H) 5.34 (br. S., 2 H) 7.06 (t, J = 6.85 Hz, 1 H) 7.12 (t, J = 6.85 Hz , 1 H) 7.27-7.34 (m, 1 H) 8.08 (d, J = 5.82 Hz, 1 H) 8.25 (d, J = 5.38 Hz, 1 H) 13.33 (br. S., 1 H); ^{13 C NMR (125 MHz, DMSO-} d 6) d ppm 12.67 110.85 114.67 115.74 118.84 122.14 129.59 130.63 141.65 149.30 149.66 151.67 152.37; LRMS (MALDI) m / z calcd for C ₁₃ H ₁₂ N ₅ 0 ₂ [M + H] &lt; + &gt;:270.09; Found: 270.37

Example  32: methyl  3-amino-2- (3- methyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzoate

The same procedure as in Example 1 was carried out using 3-amino-5-methylparasol (29 mg) and methyl 3-formyl- 1H -indole-4-carboxylate (61 mg) as starting materials, but the chromatography was carried out. Recrystallization without purification gave the desired title compound (39 mg, yield: 46%).

¹ H NMR (500 MHz, DMSO-d6) d ppm 2.50 (s, 3 H) 3.45 (s, 3 H) 4.88 (s, 2 H) 6.97 (d, J = 8.07 Hz, 1 H) 7.04 (d, J = 7.83 Hz, 1 H) 7.20 (t, J = 7.83 Hz, 1 H) 7.96 (s, 1 H) 8.16 (s, 1 H) 13.20 (s, 1 H); ^{13 C NMR (125 MHz, DMSO-} d 6) d ppm 114.43 117.48 118.29 122.80 125.77 127.61 128.75 129.96 132.53 141.36 147.91 150.01 152.10 168.34; LRMS (MALDI) m / z calcd for C ₁₅ H ₁₅ N ₄ O ₂ [M + H] +: 283.11; Found: 283.36

Example  33: 4- Bromo -2- (3- methyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

The same procedure as in Example 1 was carried out using 3-amino-5-methylparasol (29 mg) and 5-bromo-1H-indole-3-carboxyaldehyde (67 mg) as starting materials, but chromatography was performed. Recrystallization without the purification was used to give the desired title compound (47 mg, yield: 52%).

¹ H NMR (500 MHz, DMSO-d6) d ppm 2.50 (s, 3 H) 5.12 (br. S., 2 H) 6.73 (d, J = 8.56 Hz, 1 H) 7.07-7.31 (m, 2 H ) 8.18 (s, 1 H) 8.45 (s, 1 H) 13.24 (br. S., 1 H); ¹³ C NMR (125 MHz, DMSO- d 6) d ppm 12.68 69.86 107.46 114.45 117.49 125.72 126.68 129.82 131.31 133.08 145.93 149.53; LRMS (MALDI) m / z calcd for C ₁₃ H ₁₂ BrN ₄ [M + H] &lt; + &gt;:303.02; Found: 303.29

Example  34: 4- Chloro -2- (3- methyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

Using the same procedure as in Example 1 using 3-amino-5-methylparazol (15 mg) and 5-chloro-1H-indole-3-carboxyaldehyde (27 mg) as starting materials, Recrystallization without purification gave the desired title compound (10 mg, yield: 26%).

¹ H NMR (500 MHz, DMSO-d6) d ppm 2.50 (br. S., 3 H) 5.08 (br. S., 2 H) 6.78 (d, J = 8.31 Hz, 1 H) 6.95-7.25 (m , 2H) 8.18 (s, 1H) 8.45 (s, 1H) 13.24 (br.s., 1H); ¹³ C NMR (125 MHz, DMSO- d 6) d ppm 12.24 114.00 116.57 119.68 124.69 126.32 128.04 129.91 141.25 145.11 149.09 151.67

Example  35: 5- Chloro -2- (3- methyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

The same procedure as in Example 1 was carried out using 3-amino-5-methylparasol (10 mg) and 6-chloro-1H-indole-3-carboxyaldehyde (18 mg) as starting materials, but using chromatography. Recrystallization without purification gave the desired title compound (5 mg, yield: 20%).

¹ H NMR (500 MHz, DMSO-d6) d ppm 2.50 (s, 3 H) 5.23 (br. S., 2 H) 6.64 (d, J = 8.07 Hz, 1 H) 6.82 (s, 1 H) 7.02 (dd, J = 7.95, 1.83 Hz, 1 H) 8.14 (s, 1 H) 8.42 (s, 1 H) 13.24 (br. s., 1 H); ^{13 C NMR (125 MHz, DMSO-} d 6) d ppm 12.66 103.26 114.39 114.50 116.37 122.40 126.85 129.65 132.70 133.23 148.01 149.62; LRMS (MALDI) m / z calcd for C ₁₃ H ₁₂ ClN ₄ [M + H] +: 259.07; Found: 259.43

Example  36: N- methyl -2- (3- methyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

Using the same procedure as in Example 1 using 3-amino-5-methylpyrazole (15 mg) and 1-methyl- 1H -indole-3-carboxyaldehyde (24 mg) as starting materials, Recrystallization without purification gave the desired title compound (16 mg, yield: 46%).

¹ H NMR (500 MHz, DMSO-d6) d ppm 2.50 (s, 3H) 2.64 (d, J = 3.42 Hz, 3H) 4.96 (d, J = 3.91 Hz, 1H) 6.62 (d, J = 8.07 Hz, 1 H) 6.68 (t, J = 7.34 Hz, 1 H) 7.01 (d, J = 7.34 Hz, 1 H) 7.22 (t, J = 7.70 Hz, 1 H) 8.12 (s, 1 H) 8.39 (s, 1 H) 13.22 (br. s., 1 H); ^{13 C NMR (125 MHz, DMSO-} d 6) d ppm 12.66 30.71 110.00 114.44 116.31 124.48 127.68 129.33 129.95 131.04 147.54 149.98 152.12; LRMS (MALDI) m / z calcd for C ₁₄ H ₁₅ N ₄ [M + H] &lt; + &gt;:238.12; Found: 239.47

Example  37: N-benzyl-2- (3- methyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Benzeneamine

The same procedure as in Example 1 was carried out except that 3-amino-5-methylpyrazole (15 mg) and 1-benzyl- 1H -indole-3-carboxyaldehyde (35 mg) were used as starting materials, Recrystallization without purification using chromatography gave the desired title compound (13 mg, yield: 27%).

¹ H NMR (500 MHz, DMSO-d6) d ppm 2.51 (s, 3 H) 4.26 (d, J = 3.91 Hz, 2 H) 5.58 (br. S., 1 H) 6.49 (d, J = 8.07 Hz , 1 H) 6.63 (t, J = 7.34 Hz, 1 H) 7.02 (d, J = 7.34 Hz, 1 H) 7.06 (t, J = 7.70 Hz, 1 H) 7.18 (t, J = 6.60 Hz, 1 H) 7.25-7.36 (m, 4H) 8.17 (s, 1H) 8.47 (s, 1H) 13.24 (br.s., 1H); ^{13 C NMR (125 MHz, DMSO-} d 6) d ppm 12.92 47.11 111.42 114.82 116.86 125.02 127.18 127.49 128.01 128.97 129.34 130.29 131.54 141.01 146.30 150.24 152.40; LRMS (MALDI) m / z calcd for C 20 H 19 N 4 [M + H] +: 315.15; Found: 315.43

Example  38: 1-benzyl-3- (2- (3- methyl - 1H - Pyrazolo [3,4-b] pyridine -5 days) Phenyl ) Urea

The same procedure as in Example 1 was carried out using 3-amino-5-methylparazol (15 mg) and N-benzyl-3-formyl- 1H -indole- 1 -carboxamide (42 mg) as starting materials, Recrystallization without purification using chromatography gave the desired title compound (15 mg, yield: 28%).

¹ H NMR (500 MHz, DMSO-d6) d ppm 2.50 (s, 3H) 4.21 (d, J = 5.62 Hz, 2H) 6.89 (t, J = 5.75 Hz, 1H) 7.10 (t, J = 6.97 Hz, 1 H) 7.15-7.29 (m, 6 H) 7.32 (t, J = 7.70 Hz, 1 H) 7.56 (s, 1 H) 7.97 (d, J = 8.31 Hz, 1 H) 8.15 (s, 1 H) 8.40 (s, 1 H) 13.29 (s, 1 H); ^{13 C NMR (125 MHz, DMSO-} d 6) d ppm 12.77 13.00 43.40 114.71 122.61 127.23 127.38 127.58 127.91 128.77 128.92 129.12 130.40 138.09 140.79 141.89 149.89 150.09 152.42 156.08; LRMS (MALDI) m / z calcd for C 21 H 20 N 5O [M + H] +: 358.16; Found: 358.38

Test Example  1: cytotoxicity test cytotoxicity test )

In order to investigate the anticancer activity of the compounds of the present invention, a cell counting kit (CCK) -8 assay was performed.

1) Cell Culture

Human lung melanoma cells (A549), human cervical carcinoma cells (HeLa), human kidney cells (293T) and myogenic cells (C2C12) are identified as ATCCs (ATCCs). American Typ Culture Collection, USA.

For HeLa cells and A549 cells, RPMI supplemented with heat-inactivated 10% (v / v) fetal bovine serum (Gibco, Invitrogen) and 1% (v / v) antibiotic-antimicrobial solution (Gibco, Invitrogen) Cultured in 1640 medium (Gibco, Invitrogen), and for 293T cells and C2C12 cells, heat-inactivated 10% (v / v) fetal calf serum (Gibco, Invitrogen) and 1% (v / v) antibiotics- The cells were cultured in DMEM (Gibco, Invitrogen) supplemented with antimicrobial solution (Gibco, Invitrogen).

The cells thus cultured were maintained at 37 ° C. under a humidified atmosphere consisting of 5% CO ₂ and 95% air and then cultured in a T75 flask (Nalge Nunc International, USA).

2) Cancer cell proliferation inhibitory activity test

Cell viability was tested according to the CCK (cell counting kit) -8 assay (Dojindo, Japan). Specifically, the obtained cells were inoculated in each well of a 96-well plate at a density of 2 × 10 ³ cells and incubated for 24 hours, and then the cells of the present invention obtained in Examples 3, 28, 29, 30, 35, and 36 Compounds (1, 5, 10 uM) were treated. Cells not treated with any compound were used as controls. After 72 hours, CCK-8 solution (10 μl, 2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2,4-disulfophenyl) -2H-tetra Jolyum, monosodium salt) was added to each well and then further incubated at 37 ° C. for 1 hour. The absorbance of each well was measured at 450 nm (based on 630 nm) using a Bio-Tek model ELx800TM microplate reader (Bio-Tek Instruments, Inc., USA). The test was performed twice for each cell line. Cell survival rate (%) and proliferation inhibition rate (%) were calculated according to the following formula:

% Cell viability = (average absorbance in test sample) / (average absorbance in control sample) x 100

% Growth inhibition = (1-average absorbance in test sample / average absorbance in control sample) x 100

The results are shown in Tables 1, 1, 2 and 3 below.

Sample (10 uM) Cell proliferation inhibition rate (%) HeLa / A549 cell inhibition
(IC ₅₀ , uM) HeLa A549 293T C2C12 Example 3 80 89 12 7 4.5 / 5.5 Example 28 84 84 44 22 3.2 / 4.2 Example 29 81 90 One 12 5.1 / 3.9 Example 30 85 89 5 - 2.4 / 2.7 Example 35 86 91 9 - 0.31 / 0.38 Example 36 85 90 17 - 3.5 / 3.5

As shown in Table 1, Figure 1, Figure 2 and Figure 3 , it can be seen that the compound of the present invention exhibits a particularly excellent inhibitory activity against cancer cells.

1, 2 and 3 show human lung melanoma cell lines (A549), human cervical cancer cell lines (HeLa) and human embryonic kidney cell lines 293T treated with compounds of the invention (1, 5 and 10 uM), respectively. It is a graph showing the results of cytotoxicity test ( C01 : Example 3, E02 : Example 28, C03 : Example 29, C02 : Example 30, C08 : Example 35, C09 : Example 36).

Figure 4 is a graph showing the results of cytotoxicity test for the muscle cell line (C2C12) treated with the compound (1, 5 and 10 uM) of the present invention ( 1 : Example 3, 2 : Example 28, 3 : Example 29).

Claims (7)

A method for preparing a heterobiarylpyridine derivative compound of Formula 1, comprising reacting a compound of Formula 2 with a compound of Formula 3 in the presence of an acid catalyst in a polar protic solvent: <Formula 1>

<Formula 2>

<Formula 3>

Where X is a nitrogen (N), oxygen (O) or sulfur (S) atom; Y, Q and M are each independently carbon (C), nitrogen (N), oxygen (O) or sulfur (S) atoms (provided that if Y is a carbon atom, at least one of Q and M is nitrogen, oxygen or sulfur) And if Q is a carbon atom, then at least one of Y and M is a nitrogen, oxygen or sulfur atom, and if M is a carbon atom, then at least one of Y and Q is a nitrogen, oxygen or sulfur atom.); R ¹ is absent, hydrogen, hydroxy, aryl unsubstituted or substituted with C1-C6 alkoxy or halogen, C1-C6 alkyl, aryl unsubstituted or substituted with C1-C6 alkoxy, halogen or C1-C6 alkyl Or heteroaryl unsubstituted or substituted with C1-C6 alkoxy, halogen or C1-C6 alkyl; R ² is hydrogen, halogen, amine unsubstituted or substituted with C1-C6 alkyl, nitro, C1-C6 alkylester, C1-C6 alkoxy unsubstituted or substituted with C1-C6 alkyl, unsubstituted or C1-C6 alkyl, Aryl substituted with C1-C6 haloalkyl, C1-C6 alkoxy or halogen, or heteroaryl unsubstituted or substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or halogen; R ³ is absent if X is O or S, and if X is N, then C 1 -C 6 alkyl, unsubstituted or substituted with C 1 -C 6 alkyl or halogen is hydrogen, unsubstituted or substituted with C 1 -C 6 alkyl or halogen; C1-C6 alkoxycarbonyl, sulfonyl, COR ⁶ , CONR ⁶ R ⁷ or CSNR ⁶ R ⁷ , wherein R ⁶ and R are unsubstituted or substituted with C 1 -C 6 alkyl or halogen ⁷ is each independently hydrogen, C 3 -C 6 alkyl unsubstituted or substituted with halogen, C 1 -C 6 alkoxy or C 1 -C 6 alkyl, C 3 -C 6 cyclo unsubstituted or substituted with halogen, C 1 -C 6 alkoxy or C 1 -C 6 alkyl Alkyl, aryl unsubstituted or substituted with halogen, C1-C6 alkoxy or C1-C6 alkyl, or benzyl unsubstituted or substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or halogen; R ⁴ and R ⁵ are each independently absent, hydrogen, C 1 -C 6 alkyl or aryl unsubstituted or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen. The method of claim 1, The polar protic solvent is selected from the group consisting of methanol, ethanol, dichloroethane, dimethylformamide and mixtures thereof. The method of claim 1, Wherein said acid catalyst is selected from the group consisting of AlCl ₃ , AcOH, formic acid, trifluoroacetic acid (TFA) and HCl. A heterobiarylpyridine derivative compound of formula <Formula 1>

Where X, Y, Q, M, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 1. Indole-3-carboxyaldehyde derivatives of Formula 2b: <Formula 2b>

Where R ³ is hydrogen, unsubstituted or substituted by C1-C6 alkyl or halogen, C1-C6 alkyl, unsubstituted or substituted by C1-C6 alkyl or halogen, C1-C6 aralkyl, unsubstituted or C1-C6 alkyl Or C1-C6 alkoxycarbonyl, sulfonyl, COR ⁶ , CONR ⁶ R ⁷ or CSNR ⁶ R ⁷ substituted with halogen, wherein R ⁶ and R ⁷ are each independently hydrogen, unsubstituted or halogen, C1-C6 alkoxy or C1-C6 alkyl substituted with C1-C6 alkyl, C3-C6 cycloalkyl unsubstituted or substituted with halogen, C1-C6 alkoxy or C1-C6 alkyl, unsubstituted or halogen, C1-C6 alkoxy or C1-C6 alkyl Substituted aryl, or benzyl unsubstituted or substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or halogen; R ⁸ and R ⁹ are each independently hydrogen, a halogen atom, C 1 -C 6 alkyl, or C 1 -C 6 alkyl or alkoxyalkyl substituted with halogen; Except that R ³ , R ⁸ and R ⁹ are hydrogen at the same time. Indole-3-carboxyaldehyde derivatives of formula <Formula 2c>

Where R ³ is hydrogen, unsubstituted or substituted with C1-C6 alkyl or halogen, C1-C6 alkyl, unsubstituted or substituted with C1-C6 alkyl or halogen, C1-C6 aralkyl, unsubstituted or C1-C6 alkyl Or C1-C6 alkoxycarbonyl, sulfonyl, COR ⁶ , CONR ⁶ R ⁷ or CSNR ⁶ R ⁷ substituted with halogen, wherein R ⁶ and R ⁷ are each independently hydrogen, unsubstituted or halogen, C1-C6 alkoxy or C1-C6 alkyl substituted with C1-C6 alkyl, C3-C6 cycloalkyl unsubstituted or substituted with halogen, C1-C6 alkoxy or C1-C6 alkyl, unsubstituted or halogen, C1-C6 alkoxy or C1-C6 alkyl Substituted aryl, or benzyl unsubstituted or substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or halogen. Indole-3-carboxyaldehyde derivatives of formula <Formula 2d>

Where R ¹⁰ is hydrogen, C 1 -C 6 alkyl unsubstituted or substituted with halogen or C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl unsubstituted or substituted with halogen or C 1 -C 6 alkoxy, unsubstituted or halogen, C 1 -C 6 alkyl or Aryl substituted with C1-C6 alkoxy, or benzyl unsubstituted or substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or halogen.

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