JP2002020386A - Pyrazolopyridine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pyrazolopyridine derivative which has the PDE4- inhibitory activity and is useful for prophylaxis and/or therapy of inflammatory diseases, diabetic diseases, allergic diseases, autoimmune diseases, osteoporosis, obesity, anti-depressant, Parkinson' disease, ischemic reperfusion trouble, leukemia and the like. SOLUTION: The pyrazolopyridine derivative is represented by formula (I) (wherein R1 is an alkyl substituted with an alkyl, alkylthio or hydroxyl; R2 is H, an alkoxy group; R3 is H, an alkyl; R4 is H, an alkyl, a cycloalkyl, a cycloalkyl-substituted alkyl, a halogen-substituted phenyl, N, O and/or S- including monocyclic, bicyclic or tricyclic heterocycle; R5 is H, an alkyl, a cycloalkyl, a cycloalkyl-substituted alkyl, phenyl which may be substituted) and non-toxic salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to pyrazolopyridine derivatives. More specifically, the present invention relates to (1) a compound represented by the general formula (I):

Embedded image (Wherein all symbols have the same meanings as described below), and a non-toxic salt thereof, (2) a method for producing them, and (3) containing them as an active ingredient. About drugs.

[0002]

BACKGROUND OF THE INVENTION Cyclic adenosine-3 ', 5'-, an intracellular signal messenger (second messenger)
Monophosphate (c-AMP) and cyclic guanosine-
3 ′, 5′-Monophosphate (c-GMP) is decomposed into inactive 5′-AMP and 5′-GMP by a group of hydrolases called phosphodiesterase (PDE). The PDE isozymes that inactivate them do not exist uniformly in the living body but show differences in cell distribution, tissue distribution, and the like, and exist in the living body with localization specific to organs. To date, 11 types of families PDE1 to PDE11 have been confirmed (Current opin
ion in Cell Biology., 12 , 174-179 (2000)).

[0003] Among these PDEs, PDE4 is derived from airway smooth muscle, epithelial cells, inflammatory cells (macrophages, neutrophils,
It is present in various cells including eosinophils) and T-lymphocytes, and regulates intracellular c-AMP levels of these cells to control cell functions. Meanwhile, PDE
5 is present in platelets, myocardium, vascular smooth muscle, and the like, regulates intracellular c-GMP levels, and is involved in controlling the circulatory system. Therefore, PDE4 inhibitors inhibit intracellular c-A by suppressing the degradation of c-AMP by PDE4.
It is known that it has a bronchodilator action, an anti-inflammatory action, a mediator release inhibitory action, an immunosuppressive action, and the like because it causes accumulation of MP. Therefore, a drug that specifically inhibits PDE4 does not show a circulatory effect by PDE5, and various diseases, such as inflammatory diseases (asthma, obstructive pulmonary disease, sepsis, nephritis, hepatitis, etc.), diabetic Diseases, allergic diseases (allergic rhinitis, allergic conjunctivitis, atopic dermatitis, etc.), autoimmune diseases (ulcerative colitis, Crohn's disease, rheumatism, psoriasis, multiple sclerosis, collagen disease, etc.), osteoporosis , Obesity, antidepressant,
Parkinson's disease, ischemia-reperfusion injury, leukemia (Exp. Opi
n. Invest. Drugs., 8 , 1301-1325 (1999)) and the like.

[0004]

2. Description of the Related Art As a pyrazolopyridine derivative, for example, WO 2000/15222 describes a compound represented by the general formula (A):

Embedded image(Where E^2AIs -NH-A^1A-Substituted aryl (group
Medium, A^1AIs a C1-10 alkylene or substituted
Represents lukylen. ) Etc., and X^3AIs -N (R^9A)
(R^10A) (In the group, R^9A, R^10AIs a hydrogen atom, alkyl, etc.
Represents ) Etc., and Y^ARepresents a nitrogen atom, etc.
Z^AIs a nitrogen atom or C (R^7A) (In the group, R ^6AIs hydrogen field
Represents an alkyl, an alkyl or the like. ) And R^3AIs hydrogen field
R, alkyl, cycloalkyl, etc.^4AIs hydrogen
Represents atoms and the like. ) And their drugs
The physiologically acceptable salt is cGMP phosphodiesterase
(PDE5) describes that it has inhibitory activity
(The explanation of the base is excerpted from the necessary parts.)

[0005]

OBJECTS OF THE INVENTION The present inventors have conducted intensive studies to find compounds having PDE4 inhibitory activity. As a result, they have found that the pyrazolopyridine derivative represented by the general formula (I) achieves the object, and Was completed.

[0006]

DISCLOSURE OF THE INVENTION The present invention relates to (1) a compound represented by the general formula (I):

Embedded image

(Wherein R ¹ is 1) —OR ⁶ group, 2) —SR ⁷ group, 3) C2-8 alkynyl group, 4) nitro group, 5) cyano group, 6) hydroxyl group or C1-8 alkoxy. Substituted with a group,
C1~8 alkyl group, 7) a phenyl group, 8) -C (O) R 8 ^{_{group, 9) -SO 2 NR 9 R}} 10 _{^{group, 10) -NR 11 SO 2 R}} 12 group, 11) -NR ¹³ C (O) R ¹⁴ or 12) —CH１２NR ¹⁵ ;

R ⁶ and R ⁷ are i) a hydrogen atom, ii) C1
-8) alkyl group, iii) C1-8 alkyl group substituted with C1-8 alkoxy group, iv) trihalomethyl group, v)
C3-7 cycloalkyl group, vi) C1-8 alkyl group substituted with phenyl group, or vii) 1-4 nitrogen atoms, 1-3 oxygen atoms and / or 1-3 sulfur atoms A 3- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic ring, wherein R ⁸ is a C 1-8 alkyl group, a phenyl group,
-NR ¹⁶ R ¹⁷ group or -NR ¹⁸ NR ¹⁹ R ²⁰ group,
And, R ⁹ and R ¹⁰ and R ¹¹ and R ¹³ represents a hydrogen atom or a C1~8 alkyl group independently, R ¹²
Represents a C1-8 alkyl group, R ¹⁴ is C1-8 alkyl, C1-8 alkoxy or represents -NR ²¹ R ²² group,, R ¹⁵ is hydroxyl, C1-8 alkoxy or -NR ²³ R, represents ^24, R ¹⁶ and R ^17, R ¹⁸ and R ¹⁹ and R ^20, R ²¹ and R ²² and R ²³ and R ²⁴ each independently represents a hydrogen atom or a C1~8 alkyl group,

R ² represents 1) a hydrogen atom or 2) a C1-8 alkoxy group; R ³ represents 1) a hydrogen atom or 2) a C1-8 alkyl group;

R ⁴ represents 1) a hydrogen atom, 2) a C1-8 alkyl group, 3) a C3-7 cycloalkyl group, 4) a C1-8 alkyl group substituted with a C3-7 cycloalkyl group, 5) 1 A phenyl group optionally substituted with up to 3 halogen atoms, or 6) 1 to 4 nitrogen atoms, 1 to 3 oxygen atoms and / or
Or a 3 to 15 membered monocyclic, bicyclic or tricyclic heterocyclic ring containing 1 to 3 sulfur atoms,

R ⁵ represents 1) a hydrogen atom, 2) a C1-8 alkyl group, 3) a C3-7 cycloalkyl group, 4) a C1-8 alkyl group substituted with a C3-7 cycloalkyl group, or 5) Represents a phenyl group which may be substituted with 1 to 3 substituents selected from the following i) to iii): i) a C1-8 alkyl group, ii) a C1-8 alkoxy group, iii) a halogen atom ,

1 to 4 nitrogen atoms, 1 to 3 oxygen atoms and / or 1 to 3 represented by R ⁴ , R ⁶ and R ⁷
The 3- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic ring containing 3 sulfur atoms is selected from the following i) to iii):
I) C1-8 alkyl group, ii) C1-8 alkoxy group, iii) halogen atom, iv) carboxy group, v) C1-8 alkoxycarbonyl group, vi) C2 8 acyl group, vii) -SO ₂ -C1~8 alkyl group, viii) pyrazolo pyridine derivative represented by oxo group),
Or their non-toxic salts,

[0013] The present invention relates to (2) a method for producing them, and (3) a drug containing them as an active ingredient.

In the general formula (I), the C1-8 alkyl group means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof. In the general formula (I), the C2-8 alkynyl group is an ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl group and isomers thereof. In the general formula (I), the C1-8 alkoxy group is a methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy group and isomers thereof.

In the general formula (I), C1-8 alkoxycarbonyl means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl and Isomer. In the general formula (I), C2
8 acyl groups are acetyl, propionyl, butyryl,
Valeryl, hexanoyl, heptanoyl, octanoyl groups and isomers thereof.

In the present invention, the halogen atom is chlorine,
It means bromine, fluorine and iodine atoms. General formula (I)
In the formula, a trihalomethyl group is a methyl group tri-substituted by chlorine, bromine, fluorine and iodine atoms. In the general formula (I), the C3-7 cycloalkyl group is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl group and isomers thereof.

In the general formula (I), 1 to 4 nitrogen atoms, 1
A 3- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic ring containing from 1 to 3 oxygen atoms and / or from 1 to 3 sulfur atoms is defined as 1 to 4 nitrogen atoms, 1 to 3 Oxygen atom and / or
Or a 5 to 18-membered monocyclic, bicyclic or tricyclic heterocyclic aryl having 1 to 3 sulfur atoms or a partially or fully saturated ring thereof.

Examples of the 3- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic aryl having 1 to 4 nitrogen atoms, 1 to 3 oxygen atoms and / or 1 to 3 sulfur atoms include: For example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine,
Pyridazine, azepine, diazepine, furan, pyran,
Oxepin, thiophene, thiazine (thiopyran), thiepin, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, Benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline,
Isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, benzoxepin, benzoxazepine, benzoxadiazepine,
Benzothiepine, benzothiaazepine, benzothiadiazepine, benzoazepine, benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole,
Examples include carbazole, acridine, dibenzofuran, and dibenzothiophene rings.

A 3- to 15-membered monocyclic, bicyclic or tricyclic heterocycle containing from 1 to 4 nitrogen atoms, from 1 to 3 oxygen atoms and / or from 1 to 3 sulfur atoms, partly Or as a completely saturated ring, for example, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, triazoline, triazolidine, tetrazolin, tetrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrohydropyrazine, piperazine, dihydropyrimidine, Tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine,
Dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiaine (dihydrothiopyran), tetrahydro Thiain (tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole, dihydrooxadiazole, tetrahydrooxadiazole, dihydrothiodiazole , Tetrahydrothiodiazole, tetrahydrooxadiazine, Trahydrothiadiazine, tetrahydrooxazepine, tetrahydrooxadiazepine, perhydrooxaazepine, perhydrooxadiazepine, tetrahydrothiaazepine, tetrahydrothiadiazepine, perhydrothiaazepine, perhydrothiadiazepine, morpholine, thiomorpholine , Indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydro Quinoline,
Tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, Dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole,
Perhydrobenzimidazole, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine, tetrahydroacridine, perhydroacridine, dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran,
Examples include tetrahydrodibenzothiophene, perhydrodibenzofuran, perhydrodibenzothiophene, dioxolane, dioxane, dithiolane, dithiane, benzodioxalane, benzodioxane, benzodithiolane, and benzodithiane ring.

In the present invention, all isomers are included unless otherwise indicated. For example, the alkyl group, the alkoxy group and the alkylene group include straight-chain and branched ones. Further, isomers (E, Z, cis, trans) in double bonds, rings and condensed rings, isomers due to the presence of asymmetric carbon (R, S, α, β, enantiomers, diastereomers) , An optically active substance having optical activity (D, L, d, l-form), polar forms (high-polarity forms, low-polarity forms) by chromatographic separation, equilibrium compounds, mixtures of any ratio thereof, and racemic mixtures All are included in the present invention.

In the present invention, unless otherwise specified.
Symbol as obvious to the person skilled in the art

Embedded image Indicates that it is connected to the other side of the paper (ie, α-configuration),

Embedded image Indicates that it is connected to the near side of the paper (that is, β-configuration),

Embedded image Represents α-, β- or a mixture thereof.

The compound represented by formula (I) can be converted into a non-toxic salt by a known method. Non-toxic salts include
Examples include alkali metal salts, alkaline earth metal salts, ammonium salts, amine salts, acid addition salts, and solvates. Non-toxic, water-soluble salts are preferred. Suitable salts include alkali metals (potassium, sodium, etc.)
Salts, salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine,
Methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine,
Monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine, N-methyl-D-glucamine and the like.

The acid addition salts are preferably non-toxic and water-soluble. Suitable acid addition salts include, for example, inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate, benzoate Organic acid salts such as acid, citrate, methanesulphonate, ethanesulphonate, benzenesulphonate, toluenesulphonate, isethionate, glucuronate, gluconate.

Preferably, the solvate is non-toxic and water-soluble. Suitable solvates include, for example, solvates such as water, alcoholic solvents (eg, ethanol, etc.).

In the general formula (I), R ¹ is a —OR ⁶ group or a —SR ⁷ group, preferably a —OR ⁶ group. As the R ⁶ group, a C 1-8 alkyl group or a 3 to 15-membered monocyclic, bicyclic or 3-membered ring containing 1 to 4 nitrogen atoms, 1 to 3 oxygen atoms and / or 1 to 3 sulfur atoms Tricyclic heterocycles are preferred, with methyl, ethyl or pyrrolidine being particularly preferred. In the general formula (I), R ² is preferably a hydrogen atom. In the general formula (I), R ³ is preferably a hydrogen atom. In the general formula (I), R ⁴ is C1 to
An 8 alkyl group or a cycloalkyl group is preferred, and a methyl, ethyl, cyclopropyl, cyclobutyl, or cyclopentyl group is particularly preferred. In the general formula (I), R ⁵
As a C1-8 alkyl group, a C3-7 cycloalkyl group or a phenyl group, a methyl, ethyl, propyl or butyl group is particularly preferable.

Among the compounds represented by the general formula (I), preferred compounds are those represented by the general formula (IA)

Embedded image (In the formula, all symbols have the same meanings as described above.)
Or

General formula (IB)

Embedded image (Wherein all symbols have the same meanings as described above).

As specific compounds of the present invention, Tables 1 to 1
0, the compounds of the examples, non-toxic salts, acid addition salts and solvate salts thereof. In the following tables, Me represents a methyl group, Et represents an ethyl group, i-Pr represents an isopropyl group, and the other symbols have the same meanings as described above.

[0029]

[Table 1]

[0030]

[Table 2]

[0031]

[Table 3]

[0032]

[Table 4]

[0033]

[Table 5]

[0034]

[Table 6]

[0035]

[Table 7]

[0036]

[Table 8]

[0037]

[Table 9]

[0038]

[Table 10]

[0039]

[Method for producing the compound of the present invention] The compound represented by the general formula (I) can be produced by the following method or the method described in Examples. [1] Among the compounds of the present invention represented by the general formula (I), R
^A compound in which ³ represents a hydrogen atom, that is, a compound represented by the general formula (I
A)

Embedded image (Wherein all symbols have the same meanings as described above) can be produced by the following method.

The compound represented by the general formula (IA) is represented by the general formula (II)

Embedded image (Wherein X represents a halogen atom, and R ^1-1 and R ^5-1
Each represents the same meaning as R ¹ and R ^5, R ^1-1
And a hydroxyl group contained in the group represented by R ^5-1 ;
A thiol group, amino group or carboxyl group shall be protected if necessary. Other symbols have the same meaning as described above. And a compound represented by the general formula (III)

[0041]

Embedded image (Wherein all symbols have the same meanings as described above), and then subject to a deprotection reaction of a protecting group, if necessary.

The reaction between the compound represented by the general formula (II) and the compound represented by the general formula (III) is known, and examples thereof include an inert organic solvent (dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride, diethyl ether, Base (triethylamine, pyridine, etc.) in tetrahydrofuran, acetonitrile, dioxane, etc.
The reaction is carried out at 0 to reflux temperature in the presence or absence of

The deprotection reaction of the protecting group can be carried out by the following method. Deprotection reactions of carboxyl, hydroxyl, amino or thiol protecting groups are well known and include, for example, (1) alkaline hydrolysis, (2) deprotection under acidic conditions, and (3) hydrogenolysis. And (4) a deprotection reaction of a silyl group.

These methods will be described in detail. (1) The deprotection reaction by alkali hydrolysis includes, for example,
Alkali metal hydroxides (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) and alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.) in organic solvents (methanol, tetrahydrofuran, dioxane, etc.) ) Or carbonate (sodium carbonate, potassium carbonate, etc.)
Alternatively, using the aqueous solution or a mixture thereof,
The reaction is performed at a temperature of 0 to 40 ° C.

(2) The deprotection reaction under acid conditions is carried out, for example, by using an organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, etc.) in an organic solvent (methylene chloride, chloroform, dioxane, ethyl acetate, anisole, etc.). Or an inorganic acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (hydrogen bromide /
Acetic acid) at a temperature of 0 to 100 ° C.

(3) The deprotection reaction by hydrogenolysis includes, for example, solvent (ether (tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol (methanol, ethanol, etc.), benzene (benzene, toluene, etc.) ), Ketones (acetone, methyl ethyl ketone, etc.), nitriles (acetonitrile, etc.), amides (dimethylformamide, etc.), water, ethyl acetate, acetic acid or a mixture of two or more thereof.
The reaction is performed at a temperature of 0 to 200 ° C. in the presence of a catalyst (palladium-carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel, or the like), in a hydrogen atmosphere at normal pressure or under pressure, or in the presence of ammonium formate.

(4) The deprotection reaction of the silyl group is carried out, for example, by
The reaction is performed at a temperature of 0 to 40 ° C. using tetrabutylammonium fluoride in a water-miscible organic solvent (tetrahydrofuran, acetonitrile, etc.).

The carboxyl protecting group includes
Examples include a methyl group, an ethyl group, a t-butyl group, and a benzyl group. Examples of the hydroxyl-protecting group include a methoxymethyl group, a 2-tetrahydropyranyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, an acetyl group, and a benzyl group. Examples of the amino-protecting group include a benzyloxycarbonyl group, a t-butoxycarbonyl group, a trifluoroacetyl group, and a 9-fluorenylmethoxycarbonyl group. Examples of the thiol protecting group include a benzyl group, a methoxybenzyl group, a methoxymethyl group, a 2-tetrahydropyranyl group, a diphenylmethyl group, and an acetyl group.
The protecting group for the carboxyl group, hydroxyl group, amino group or thiol group is not particularly limited as long as it is a group which can be easily and selectively eliminated in addition to the above. For example, T.
W. Greene, Protective Groups in Organic Synthesis,
The one described in Wiley, New York, 1991 is used. As can be easily understood by those skilled in the art, the target compound of the present invention can be easily produced by properly using these deprotection reactions.

[2] Of the compounds represented by the general formula (I), compounds wherein R ³ represents a C1-8 alkyl group, ie, a compound represented by the general formula (IB)

Embedded image (In the formula, R ^3-1 represents a C1-8 alkyl group, and other symbols have the same meanings as described above.) The compound represented by the following formula can be produced.

The compound represented by the general formula (IB) is obtained by reacting the compound represented by the general formula (II) with the compound represented by the general formula (III) and the compound represented by the general formula (IV)

Embedded image (The symbols in the formula have the same meanings as described above.), And if necessary, the compound is subjected to a deprotection reaction of a protecting group to produce the compound.

The reaction between the compound obtained by reacting the compound represented by the general formula (II) with the compound represented by the general formula (III) and the compound represented by the general formula (IV) is known. For example, in an inert organic solvent (dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride, tetrahydrofuran, acetonitrile, dioxane, toluene, etc.), a base (potassium carbonate, calcium carbonate, sodium carbonate, sodium hydroxide, sodium hydroxide, potassium hydroxide, silver oxide) ) At 0 to reflux temperature. The deprotection reaction of the protecting group can be performed in the same manner as in the above method.

The general formulas (II) and (II) used as starting materials
The compounds represented by I) and (IV) can be produced by a known method or are commercially available compounds. For example, the compound represented by the general formula (II) can be produced by the method represented by the reaction scheme 1.

[0053]

Embedded image In the reaction scheme, Et represents an ethyl group, and other symbols have the same meanings as described above.

In the reaction scheme, the compound represented by the general formula (V) is known or can be easily produced by a known method. In each reaction herein,
The reaction product is obtained by a conventional purification means, for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, or column chromatography or washing, recrystallization, etc. It can be purified. Purification may be performed for each reaction or may be performed after completion of several reactions.

[0055]

[Pharmacological effect] The compound of the present invention represented by the general formula (I)
Having the DE4 inhibitory activity was proved by the following experiment. In vitro enzyme assay [Experimental method] U937 cells (derived from human monocytes) were cultured in RPMI1640 medium containing 10% fetal bovine serum.
U937 cells were collected and 20 mM Tris-HCl (Tris
-HCl) [pH 8.0, PMSF (1 mM), leupeptin (1 µg / ml), pepstatin A (p
epstatin A) (μg / ml)]. After centrifugation (15,000 rpm for 10 minutes), the supernatant was collected and filtered with a 0.45 μm filter. Sample M
onoQ (Pharmacia, strong anion exchange column)
It was loaded on a column and eluted with a concentration gradient of 0 to 0.8 M of NaCl. A fraction depleted of PDE activity by 10 μM rolipram (rolipram: a PDE4 selective inhibitor) was collected, and P
It was used as an enzyme solution for measuring DE4 inhibitory activity.

The enzyme activity was measured by the following method.
80 μl of the diluted enzyme solution (phosphate buffer (pH 7.4) containing 0.1 mg / kg bovine serum albumin), 10 μl of the compound solution of the present invention (10% DMSO) and 10 μl of ³ H
-CAMP (20,000 cpm, 10 μM) [MgSO
₄ (100 mM) and bovine serum albumin (1 mg /
ml) containing imidazole buffer (100 mM, p
H7.5)] and incubated for 30 minutes at room temperature. The reaction was stopped by microwave treatment for 2.5 minutes. After centrifugation (2,000 rpm for 1 minute), 10 μl of snake venom (snake
venom) (1 mg / ml, Sigma, product number V70)
00) was added and incubated at room temperature for 30 minutes. Apply 50 μl of the supernatant to an alumina column (100 μl),
Elution was performed with 0 μl of 0.005N hydrochloric acid, and the radioactivity of the eluate was measured. )

The PDE4 inhibitory activity of the compound of the present invention was calculated by the following equation. PDE4 activity inhibition rate (%) = (1−radioactivity in the presence of the compound of the present invention / radioactivity in the absence of the compound of the present invention) × 10
0

The IC ₅₀ value was calculated for each compound as the concentration of the compound of the present invention that inhibits PDE4 activity by 50%.
Table 11 shows the experimental results.

[0059]

[Table 11]

[0060]

[Toxicity] The toxicity of the compound of the present invention represented by the general formula (I) is extremely low, and it is considered that the compound is sufficiently safe for use as a medicament.

[0061]

[Application to Pharmaceuticals] The compound of the present invention has PDE4 inhibitory activity and can be used for inflammatory diseases (asthma, obstructive pulmonary disease, sepsis, nephritis, hepatitis, etc.), diabetic diseases, allergic diseases (allergic rhinitis, Allergic conjunctivitis, atopic dermatitis, etc.), autoimmune diseases (ulcerative colitis, Crohn's disease, rheumatism, psoriasis, multiple sclerosis, collagen disease, etc.),
It is considered useful for prevention and / or treatment of osteoporosis, obesity, antidepressant, Parkinson's disease, ischemia-reperfusion injury, leukemia and the like.

In order to use the compound represented by the general formula (I), a non-toxic salt thereof, or a solvate thereof for the above-mentioned purpose, usually, systemically or locally, oral or parenteral. It is administered in the form of Dosage should be based on age, weight,
Depending on symptoms, therapeutic effect, administration method, treatment time, etc., it is usually 1 mg to 10 mg per adult.
Orally in the range of 00 mg once to several times a day,
Or 1 mg to 100 per adult
The parenteral administration (preferably, intravenous administration) is performed once to several times a day in the range of mg, or 1 hour to 24 hours a day.
It is continuously administered intravenously for a time range. Of course, as described above, the dose varies depending on various conditions, so that a dose smaller than the above-mentioned dose may be sufficient, or may be required beyond the range.

When administering the compound represented by the general formula (I), solid compositions, liquid compositions and other compositions for oral administration and injections, external preparations and suppositories for parenteral administration are administered. Used as an agent and the like. Solid compositions for oral administration include tablets, pills, capsules, powders, granules and the like. Capsules include hard capsules and soft capsules. In such a solid composition, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminum metasilicate. It is mixed with magnesium acid. The composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, glutamic acid or asparagine. A solubilizing agent such as an acid may be contained. The tablet or pill may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or may be coated with two or more layers, if necessary. . Also included are capsules of absorbable materials such as gelatin.

[0064] Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups, elixirs and the like. In such liquid compositions, one or more active substances are contained in commonly used inert diluents (eg, purified water, ethanol). The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives. Other compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se. The composition may further comprise a buffering agent which provides isotonicity with a stabilizer other than the inert diluent, such as sodium bisulfite,
For example, they may contain isotonic agents such as sodium chloride, sodium citrate or citric acid. Methods for producing sprays are described in detail, for example, in US Pat. Nos. 2,868,691 and 3,095,355.

The injections for parenteral administration according to the present invention include sterile aqueous and / or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.
Examples of the water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (registered trademark). In addition, sterile aqueous and non-aqueous solutions, suspensions, and emulsions may be mixed and used. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid). . These are sterilized by filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used to produce sterile solid compositions, for example, sterilized or dissolved in sterile distilled water for injection or other solvents before use of the lyophilized product. Other compositions for parenteral administration include one or more active substances,
It includes external solutions, ointments, liniments, suppositories for rectal administration, and pessaries for vaginal administration, etc., which are formulated in a conventional manner.

[0066]

Reference Examples and Examples Hereinafter, the present invention will be described in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. Chromatographic separation, TLC
The solvent in parentheses shown in the column indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio. N
The solvent in parentheses shown at the MR indicates the solvent used for the measurement.

Reference Example 1 2-(((1,3-dimethylpyrazol-5-yl) amino) methylene) propane-1,3-dicarboxylic acid diethyl ester

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A mixture of ethoxymethylenemalonic acid / diethyl ester (38.9 g) and 5-amino-1,3-dimethylpyrazole (20.0 g) was stirred at a bath temperature of 120 ° C. for 1 hour. After cooling the reaction mixture to room temperature, hexane (20
0 mL) was added. The resulting crystals were filtered and dried to give the title compound (43.56 g) having the following physical data. TLC: Rf 0.59 (chloroform: methanol = 1
0: 1); NMR (CDCl ₃ ): δ 11.00 (bd, J = 12.3 Hz, 1H),
8.14 (d, J = 12.3 Hz, 1H), 5.86 (s, 1H), 4.32 (q, J
= 7.2 Hz, 2H), 4.24 (q, J = 7.2 Hz, 2H), 3.74 (s,
3H), 2.23 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H), 1.32
(t, J = 7.2 Hz, 3H).

Reference Example 2 1,3-dimethyl-4-chloropyrazolo [5,4-b]
Pyridine-5-carboxylic acid / ethyl ester

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A mixture of the compound prepared in Reference Example 1 (43.56 g) and phosphorus oxychloride (144 mL) was refluxed for 5 hours. After the reaction mixture was cooled to room temperature, it was poured into ice little by little, water was added until the total amount of the mixture became 3 L after the exotherm had stopped, and the crude crystals were filtered. The crude crystals were washed with ethyl acetate (1
L), washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated to give the title compound (28.47 g) having the following physical data. TLC: Rf 0.85 (chloroform: methanol = 1
0: 1); NMR (CDCl ₃ ): δ 8.95 (s, 1H), 4.45 (q, J = 7.
2 Hz, 2H), 4.07 (s, 3H), 2.76 (s, 3H), 1.43 (t, J
= 7.2 Hz, 3H).

Reference Example 3 1,3-dimethyl-4-chloropyrazolo [5,4-b]
Pyridine-5-carboxylic acid

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To a solution of the compound (28.47 g) prepared in Reference Example 2 in dimethoxyethane (225 mL) was added 85% potassium hydroxide (59.15 g), water (180 mL) was added dropwise, and the mixture was stirred at room temperature overnight. did. Under ice-cooling, the reaction mixture was neutralized with 4N-hydrochloric acid (225 mL). The resulting crystals were filtered, washed with water, and dried to give the title compound (25.25 g) having the following physical data. TLC: Rf 0.10 (chloroform: methanol = 1
0: 1); NMR (DMSO-d ₆ ): δ 8.90 (s, 1H), 3.99 (s, 3H),
3.34 (bs, 1H), 2.67 (s, 3H).

Reference Example 4 1,3-dimethyl-4-chloropyrazolo [5,4-b]
Pyridine-5-carboxamide

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A mixture of the compound (15.79 g) produced in Reference Example 3 and thionyl chloride (25.5 mL) was refluxed for 1 hour and concentrated under reduced pressure. A solution of the obtained residue in tetrahydrofuran (140 mL) was added dropwise to a mixed solution of tetrahydrofuran (238 mL) and a 28% ammonium hydroxide aqueous solution (95 mL) under ice cooling, and the mixture was stirred for 30 minutes.
The resulting crystals were filtered, washed with water and dried to give the title compound (14.69 g) having the following physical data. TLC: Rf 0.45 (chloroform: methanol = 1
0: 1); NMR (DMSO-d ₆ ): δ 8.54 (s, 1H), 8.03 (bs, 1
H), 7.79 (bs, 1H), 3.99 (s, 3H), 2.66 (s, 3H).

Example 1 1,3-dimethyl-4- (3-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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Compound prepared in Reference Example 4 (702 mg)
A solution of and 3-methoxyaniline (1.15 g) in dioxane (10 mL) was refluxed for 6 hours and then concentrated under reduced pressure. The obtained residue was dissolved in a mixed solvent of ethyl acetate (70 mL) and tetrahydrofuran (30 mL), washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate.
Concentrated. The crude product was recrystallized from dioxane to give the compound of the present invention (774 mg) having the following physical data. TLC: Rf 0.32 (chloroform: methanol = 1
0: 1); NMR (DMSO-d ₆ ): δ 10.97 (s, 1H), 8.74 (s, 1
H), 8.21 (bs, 1H), 7.56 (bs, 1H), 7.26-7.17 (m, 1
H), 6.75-6.60 (m, 3H), 3.89 (s, 3H), 3.71 (s, 3H),
1.69 (s, 3H).

Examples 1 (1) to 1 (69) The compound prepared in Reference Example 4 or the corresponding halogen derivative, and 3-methoxyaniline or the corresponding amine derivative are subjected to the same operation as in Example 1. As a result, the following compound of the present invention was obtained.

Example 1 (1) 1,3-dimethyl-4- (2-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.32 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.70 (s, 1H), 8.71 (s, 1)
H), 8.18 (bs, 1H), 7.49 (bs, 1H), 7.16-7.08 (m, 2
H), 6.95 (d, J = 7.5 Hz, 1H), 6.88-6.79 (m, 1H),
3.87 (s, 3H), 3.86 (s, 3H), 1.59 (s, 3H).

Example 1 (2) 1,3-dimethyl-4- (4-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.32 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 11.11 (s, 1H), 8.71 (s, 1)
H), 8.16 (bs, 1H), 7.49 (bs, 1H), 7.08 (d, J = 6.9
Hz, 2H), 6.92 (d, J = 6.9 Hz, 2H), 3.85 (s, 3H), 3.
75 (s, 3H), 1.54 (s, 3H).

Example 1 (3) 1,3-dimethyl-4- (2,4-dimethoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.32 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.81 (s, 1H), 8.66 (s, 1)
H), 8.11 (bs, 1H), 7.42 (bs, 1H), 6.92 (d, J = 8.4
Hz, 1H), 6.69 (d, J = 2.7 Hz, 1H), 6.44 (dd, J = 8.
4, 2.7 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.76
(s, 3H), 1.53 (s, 3H).

Example 1 (4) 1,3-dimethyl-4- (2,5-dimethoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.32 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 11.03 (s, 1H), 8.75 (s, 1)
H), 8.29 (bs, 1H), 7.61 (bs, 1H), 7.04 (d, J = 9.0
Hz, 1H), 6.72 (dd, J = 9.0, 3.0 Hz, 1H), 6.59 (d, J
= 3.0 Hz, 1H), 3.91 (s, 3H), 3.78 (s, 3H), 3.59
(s, 3H), 1.66 (s, 3H).

Example 1 (5) 1,3-dimethyl-4- (3,4-dimethoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.32 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 11.12 (s, 1H), 8.70 (s, 1)
H), 8.17 (bs, 1H), 7.49 (bs, 1H), 6.88 (d, J = 8.4
Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 6.61 (dd, J = 8.
4, 2.4 Hz, 1H), 3.86 (s, 3H), 3.73 (s, 3H), 3.69
(s, 3H), 1.59 (s, 3H).

Example 1 (6) 1,3-dimethyl-4- (3,5-dimethoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.32 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.90 (s, 1H), 8.73 (s, 1)
H), 8.20 (bs, 1H), 7.55 (bs, 1H), 6.26 (s, 1H), 6.2
5 (s, 2H), 3.89 (s, 3H), 3.67 (s, 6H), 1.79 (s, 3
H).

Example 1 (7) 1,3-dimethyl-4- (2,3-dimethoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.32 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 11.17 (bs, 1H), 8.78 (s, 1)
H), 8.32 (bs, 1H), 7.65 (bs, 1H), 6.96 (t, J = 8.1
Hz, 1H), 6.86 (dd, J = 8.1, 1.5 Hz, 1H), 6.64 (dd,
J = 8.1, 1.5 Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H),
3.75 (s, 3H), 1.71 (s. 3H).

Example 1 (8) 1- (2,4,6-trichlorophenyl) -3-cyclopropyl-4- (3-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.33 (ethyl acetate: hexane = 1: 1); NMR (DMSO-d ₆ ): δ 10.94 (s, 1H), 8.67 (s, 1)
H), 8.25 (bs, 1H), 7.97 (s, 2H), 7.65 (bs, 1H), 7.2
5 (t, J = 7.8 Hz, 1H), 6.76-6.64 (m, 3H), 3.69 (s,
3H), 1.35-1.20 (m, 1H), 0.72-0.63 (m, 2H), 0.52-
0.43 (m, 2H).

Example 1 (9) 1-methyl-3-cyclopropyl-4- (3-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5
-Carboxamide

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TLC: Rf 0.33 (ethyl acetate); NMR (DMSO-d ₆ ): δ 11.00 (s, 1H), 8.74 (s, 1)
H), 8.22 (bs, 1H), 7.57 (bs, 1H), 7.19 (t, J = 7.8
Hz, 1H), 6.69-6.60 (m, 3H), 3.87 (s, 3H), 3.68 (s,
3H), 1.26-1.14 (m, 1H), 0.70-0.60 (m, 2H), 0.44-
0.34 (m, 2H).

Example 1 (10) 1-methyl-3- (thiophen-2-yl) -4- (3
-Methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.36 (ethyl acetate); NMR (DMSO-d ₆ ): δ 11.12 (1H), 8.84 (s, 1H),
8.29 (bs, 1H), 7.66 (bs, 1H), 7.25 (dd, J = 5.1,
0.9 Hz, 1H), 6.92 (dd, J = 3.6, 0.9 Hz, 1H), 6.81
(t, J = 7.5 Hz, 1H), 6.66 (dd, J = 5.1, 3.6 Hz, 1
H), 6.37-6.24 (m, 3H), 4.04 (s, 3H), 3.55 (s, 3
H).

Example 1 (11) 1-methyl-3- (4-chlorophenyl) -4- (3-
Methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.35 (ethyl acetate); NMR (DMSO-d ₆ ): δ 11.22 (s, 1H), 8.85 (s, 1)
H), 8.30 (bs, 1H), 7.65 (bs, 1H), 7.26 (d, J = 8.4
Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.80-6.70 (m, 1
H), 6.28-6.20 (m, 3H), 4.04 (s, 3H), 3.54 (s, 3
H).

Example 1 (12) 1-phenyl-3-methyl-4- (3-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.43 (chloroform: methanol = 9: 1); NMR (CDCl ₃ ): δ 10.56 (s, 1H), 8.60 (s, 1H),
8.12-8.09 (m, 2H), 7.53-7.48 (m, 2H), 7.26-7.18
(m, 2H), 6.78-6.69 (m, 3H), 5.90-5.70 (brs, 2H),
3.77 (s, 3H), 1.77 (s, 3H).

Example 1 (13) 1-methyl-3-t-butyl-4- (3-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.30 (ethyl acetate); NMR (DMSO-d ₆ ): δ 8.62 (s, 1H), 8.14 (s, 1H),
7.73 (bs, 1H), 7.39 (bs, 1H), 7.03 (t, J = 8.4 H
z, 1H), 6.43-6.35 (m, 1H), 6.27-6.20 (m, 2H), 3.99
(s, 3H), 3.64 (s, 3H), 1.33 (s, 9H).

Example 1 (14) 1-phenyl-3-cyclopropyl-4- (3-methoxyphenylamino) pyrazolo [5,4-b] pyridine-
5-carboxamide

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TLC: Rf 0.44 (chloroform: methanol = 9: 1); NMR (CDCl ₃ ): δ 10.50 (s, 1H), 8.61 (s, 1H),
8.12 (t, J = 7.5 Hz, 2H), 7.49 (t, J = 8.1 Hz, 2
H), 7.31-7.17 (m, 2H), 6.78-6.62 (m, 3H), 6.00-5.6
0 (brs, 2H), 1.37-1.25 (m, 1H), 0.90-0.81 (m, 2
H), 0.53-0.48 (m, 2H).

Example 1 (15) 1-methyl-3-phenyl-4- (3-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.46 (chloroform: methanol = 9: 1); NMR (CDCl ₃ ): δ 10.47 (s, 1H), 8.64 (s, 1H),
7.35-7.31 (m, 2H), 7.11-7.06 (m, 3H), 6.75 (t, J =
8.1 Hz, 1H), 6.37- 6.32 (m, 1H), 6.26-6.19 (m, 2
H), 5.90-5.75 (brs, 2H), 4.14 (s, 3H), 3.59 (s, 3
H).

Example 1 (16) 1,3-dimethyl-4- (3-trifluoromethoxyphenylamino) pyrazolo [5,4-b] pyridine-5-
Carboxamide

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TLC: Rf 0.30 (ethyl acetate); NMR (DMSO-d ₆ ): δ 10.97 (s, 1H), 8.78 (s, 1)
H), 8.26 (bs, 1H), 7.62 (bs, 1H), 7.48-7.37 (m, 1
H), 7.16-7.05 (m, 3H), 3.92 (s, 3H), 1.71 (s, 3
H).

Example 1 (17) 1,3-dimethyl-4- (3-trifluoromethylthiophenylamino) pyrazolo [5,4-b] pyridine-5
-Carboxamide

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TLC: Rf 0.30 (ethyl acetate); NMR (DMSO-d ₆ ): δ 11.04 (s, 1H), 8.79 (s, 1)
H), 8.29 (bs, 1H), 7.63 (bs, 1H), 7.54-7.32 (m, 4
H), 3.92 (s, 3H), 1.66 (s, 3H).

Example 1 (18) 1,3-dimethyl-4- (3-ethoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.36 (chloroform: methanol = 9: 1); NMR (CDCl ₃ ): δ 10.58 (s, 1H), 8.52 (s, 1H),
7.21-7.15 (m, 1H), 6.72-6.65 (m, 3H), 5.85-5.60 (b
rs, 2H), 3.99 (s, 3H), 3.97 (q, J = 6.9 Hz, 2H), 1.
77 (s, 3H), 1.37 (t, J = 6.9 Hz, 3H).

Example 1 (19) 1,3-dimethyl-4- (3-isopropyloxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.41 (chloroform: methanol = 9: 1); NMR (CDCl ₃ ): δ 10.58 (s, 1H), 8.52 (s, 1H),
7.20-7.13 (m, 1H), 6.72-6.65 (m, 3H), 5.85-5.60 (b
rs, 2H), 4.48 (sept, J = 6.0 Hz, 1H), 3.99 (s, 3
H), 1.77 (s, 3H), 1.29 (d, J = 6.0 Hz, 6H).

Example 1 (20) 1,3-dimethyl-4- (3-phenylphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.32 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 11.10 (s, 1H), 8.75 (s, 1)
H), 8.30-8.10 (brs, 1H), 7.60-7.57 (m, 3H), 7.45-7.
34 (m, 6H), 7.13-7.04 (m, 1H), 3.88 (s, 3H), 1.66
(s, 3H).

Example 1 (21) 1,3-dimethyl-4- (3-benzyloxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.28 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 10.94 (s, 1H), 8.72 (s, 1)
H), 8.23-8.10 (brs, 1H), 7.60-7.50 (brs, 1H), 7.40-
7.29 (m, 5H), 7.19 (t, J = 8.7 Hz, 1H), 6.78-6.75
(m, 2H), 6.64 (d, J = 8.7 Hz, 1H), 5.06 (s, 2H),
3.87 (s, 3H), 1.64 (s, 3H).

Example 1 (22) 1,3-dimethyl-4- (3-nitrophenylamino)
Pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.28 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 10.81 (s, 1H), 8.77 (s, 1)
H), 8.24 (brs, 1H), 7.90-7.84 (m, 2H), 7.62 (brs,
1H), 7.58-7.46 (m, 2H), 3.93 (s, 3H), 1.80 (s, 3
H).

Example 1 (23) 1,3-dimethyl-4- (3-acetylphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.30 (ethyl acetate); NMR (DMSO-d ₆ ): δ 11.00 (s, 1H), 8.77 (s, 1)
H), 8.24 (bs, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.63
(s, 1H), 7.59 (bs, 1H), 7.46 (t, J = 7.5 Hz, 1H),
7.35 (d, J = 7.5 Hz, 1H), 3.91 (s, 3H), 2.54 (s, 3
H), 1.65 (s, 3H).

Example 1 (24) 1,3-dimethyl-4- (3-benzoylphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.30 (ethyl acetate); NMR (DMSO-d ₆ ): δ 10.94 (s, 1H), 8.75 (s, 1)
H), 8.22 (bs, 1H), 7.70-7.62 (m, 3H), 7.59 (bs, 1
H), 7.54-7.40 (m, 5H), 7.36-7.31 (m, 1H), 3.93 (s,
3H), 1.76 (s, 3H).

Example 1 (25) 1,3-dimethyl-4- (3-methylthiophenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.30 (ethyl acetate); NMR (DMSO-d ₆ ): δ 10.98 (s, 1H), 8.74 (s, 1)
H), 8.22 (bs, 1H), 7.56 (bs, 1H), 7.23 (t, J = 8.1
Hz, 1H), 7.01 (s, 1H), 7.00 (d, J = 8.1 Hz, 1H),
6.84 (d, J = 8.1 Hz, 1H), 3.89 (s, 3H), 2.42 (s, 3
H), 1.69 (s, 3H).

Example 1 (26) 1,3-dimethyl-4- (3-ethynylphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.22 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 10.91 (s, 1H), 8.75 (s, 1H),
8.25 (s, 1H), 7.60 (brs, 1H), 7.10-7.35 (m, 4H), 4.17
(s, 1H), 3.89 (s, 3H), 1.67 (s, 3H).

Example 1 (27) 1,3-dimethyl-4- (3-hydroxymethylphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.65 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 11.05 (s, 1H), 8.73 (s, 1)
H), 8.20 (br, 1H), 7.54 (br, 1H), 7.26 (dd, J = 8.
0, 8.0 Hz, 1H), 7.08-7.03 (m, 2H), 6.96 (d, J = 8.0
Hz, 1H), 5.16 (t, J = 6.2 Hz, 1H), 4.42 (d, J =
6.2 Hz, 2H), 3.87 (s, 3H), 1.61 (s, 3H).

Example 1 (28) 1,3-dimethyl-4- (3-acetylaminophenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.20 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 10.99 (s, 1H), 9.88 (s, 1)
H), 8.73 (s, 1H), 8.22 (brs, 1H), 7.57 (brs, 1H),
7.35-7.32 (m, 2H), 7.22 (t, J = 8.1 Hz, 1H), 6.78
(d, J = 8.1 Hz, 1H), 3.87 (s, 3H), 1.97 (s, 3H),
1.66 (s, 3H).

Example 1 (29) 1,3-dimethyl-4- (3-butylsulfamoylphenylamino) pyrazolo [5,4-b] pyridine-5-
Carboxamide

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TLC: Rf 0.25 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 11.14 (s, 1H), 8.80 (s, 1)
H), 8.35 (brs, 1H), 7.67 (brs, 1H), 7.57 (brs, 1H),
7.60-7.37 (m, 4H), 3.91 (s, 3H), 2.63 (q, J = 7.2
Hz, 2H), 1.65 (s, 3H), 1.35-1.15 (m, 4H), 0.78 (t,
J = 7.2 Hz, 3H).

Example 1 (30) 1,3-dimethyl-4- (3-propoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.36 (ethyl acetate); NMR (DMSO-d ₆ ): δ 10.96 (s, 1H), 8.74 (s, 1)
H), 8.20 (bs, 1H), 7.55 (bs, 1H), 7.19 (t, J = 8.4
Hz, 1H), 6.74-6.68 (m, 1H), 6.67 (s, 1H), 6.63 (d,
J = 8.4 Hz, 1H), 3.89 (s, 3H), 3.87 (t, J = 6.9 H
z, 2H), 1.69 (s, 3H), 1.68 (sext, J = 6.9 Hz, 2H),
0.94 (t, J = 6.9 Hz, 3H).

Example 1 (31) 1,3-dimethyl-4- (3-cyclopentyloxyphenylamino) pyrazolo [5,4-b] pyridine-5-
Carboxamide

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TLC: Rf 0.35 (ethyl acetate); NMR (DMSO-d ₆ ): δ 10.98 (s, 1H), 8.74 (s, 1)
H), 8.21 (bs, 1H), 7.56 (bs, 1H), 7.19 (t, J = 8.4
Hz, 1H), 6.70-6.60 (m, 3H), 4.80-4.72 (m, 1H), 3.8
9 (s, 3H), 1.90-1.46 (m, 8H), 1.68 (s, 3H).

Example 1 (32) 1,3-dimethyl-4- (3-cyclohexyloxyphenylamino) pyrazolo [5,4-b] pyridine-5-
Carboxamide

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TLC: Rf 0.52 (ethyl acetate); NMR (DMSO-d ₆ ): δ 11.05 (br, 1H), 8.74 (s, 1)
H), 8.23 (br, 1H), 7.58 (br, 1H), 7.18 (dd, J = 8.
1, 8.1 Hz, 1H), 6.73-6.61 (m, 3H), 4.32-4.23 (m, 1
H), 3.88 (s, 3H), 1.90-1.81 (m, 2H), 1.72-1.59 (m,
1H), 1.66 (s, 3H), 1.54-1.43 (m, 1H), 1.43-1.13
(m, 6H).

Example 1 (33) 1,3-dimethyl-4- (3- (2H-3,4,5,6
-Tetrahydropyran-4-yl) oxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.40 (ethyl acetate); NMR (DMSO-d ₆ ): δ 11.11 (br, 1H), 8.75 (s, 1)
H), 8.25 (br, 1H), 7.60 (br, 1H), 7.23-7.17 (m, 1
H), 6.78-6.75 (m, 2H), 6.66 (d, J = 7.8 Hz, 1H),
4.58-4.48 (m, 1H), 3.89 (s, 3H), 3.84-3.76 (m, 2
H), 3.47-3.38 (m, 2H), 1.95-1.85 (m, 2H), 1.65
(s, 3H), 1.58-1.45 (m, 2H).

Example 1 (34) 1,3-dimethyl-4- (3- (oxolan-3-yl) oxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.32 (ethyl acetate); NMR (CDCl ₃ ): δ 10.59 (s, 1H), 8.53 (s, 1H),
7.23-7.15 (m, 1H), 6.77-6.71 (m, 1H), 6.67-6.61
(m, 2H), 5.83 (bs, 2H), 4.90-4.82 (m, 1H), 3.99
(s, 3H), 3.98-3.83 (m, 4H), 2.23-2.04 (m, 2H), 1.7
7 (s, 3H).

Example 1 (35) 1,3-dimethyl-4- (3- (methylsulfonylamino) phenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.30 (methylene chloride: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.96 (s, 1H), 9.72 (s, 1)
H), 8.75 (s, 1H), 8.23 (bs, 1H), 7.59 (bs, 1H), 7.
27 (t, J = 8.1 Hz, 1H), 7.00-6.92 (m, 2H), 6.87-6.
81 (m, 1H), 3.89 (s, 3H), 2.94 (s, 3H), 1.70 (s, 3
H).

Example 1 (36) 1-methyl-3-ethyl-4- (3-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.59 (ethyl acetate); NMR (DMSO-d ₆ ): δ 10.87 (s, 1H), 8.74 (s, 1)
H), 8.21 (br.s, 1H), 7.56 (br.s, 1H), 7.17 (t, J =
8.1 Hz, 1H), 6.70-6.60 (m, 2H), 6.58 (m, 1H), 3.90
(s, 3H), 3.68 (s, 3H), 1.98 (q, J = 7.2 Hz, 2H),
0.93 (t, J = 7.2Hz, 3H).

Example 1 (37) 1,3-dimethyl-4- (3-cyclobutyloxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.50 (toluene: ethyl acetate = 1: 20); NMR (DMSO-d ₆ ): δ 11.08 (br, 1H), 8.74 (s, 1)
H), 8.25 (br, 1H), 7.60 (br, 1H), 7.19 (dd, J = 8.
0, 8.0 Hz, 1H), 6.68-6.56 (m, 3H), 4.61 (quintet,
J = 7.1 Hz, 1H), 3.88 (s, 3H), 2.35-2.23 (m, 2H),
2.03-1.85 (m, 2H), 1.79-1.64 (m, 1H), 1.89 (s, 3
H), 1.64-1.49 (m, 1H).

Example 1 (38) 1,3-Dimethyl-4- (3-((3S) -1-methoxycarbonylpyrrolidin-3-yloxy) phenylamino) pyrazolo [5,4-b] pyridine-5- Carboxamide

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TLC: Rf 0.55 (ethyl acetate: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.93 (br, 1H), 8.73 (s, 1)
H), 8.19 (br, 1H), 7.55 (br, 1H), 7.20 (dd, J = 8.
4, 8.4 Hz, 1H), 6.72-6.63 (m, 3H), 4.99 (m, 1H),
3.87 (s, 3H), 3.57 & 3.56 (s, 3H), 3.53-3.27 (m, 4
H), 2.18-1.95 (m, 2H), 1.68 (s, 3H).

Example 1 (39) 1,3-dimethyl-4- (3-hydroxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.27 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.91 (s, 1H), 9.43 (s, 1)
H), 8.72 (s, 1H), 8.20 (br.s, 1H), 7.54 (br.s, 1
H), 7.09 (t, J = 7.8 Hz, 1H), 6.55-6.45 (m, 3H), 3.
87 (s, 3H), 1.70 (s, 3H).

Example 1 (40) 1- (4-methylphenyl) -3-methyl-4- (3-
Methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.60 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 10.91 (s, 1H), 8.79 (s, 1)
H), 8.26 (brs, 1H), 8.03 (d, J = 8.1 Hz, 2H), 7.66
(brs, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.21 (t, J =
8.4 Hz, 1H), 6.75-6.67 (m, 3H), 3.71 (s, 3H), 2.35
(s, 3H), 1.79 (s, 3H).

Example 1 (41) 1-methyl-4- (3-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.31 (ethyl acetate); NMR (DMSO-d ₆ ): δ 11.49 (s, 1H), 8.72 (s, 1)
H), 8.14 (br.s, 1H), 7.46 (br.s, 1H), 7.38 (t, J =
7.5 Hz, 1H), 7.00-6.85 (m, 3H), 6.67 (s, 1H), 3.89
(s, 3H), 3.75 (s, 3H).

Example 1 (42) 1- (3-methoxyphenyl) -3-methyl-4- (3
-Methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.36 (chloroform: methanol = 9: 1); NMR (DMSO-d6): δ 10.92 (s, 1H), 8.82 (s, 1)
H), 8.35-8.20 (brs, 1H), 7.82-7.79 (m, 2H), 7.73-7.
60 (brs, 1H), 7.42 (t, J = 8.1 Hz, 1H), 7.22 (t, J
= 8.1 Hz, 1H), 6.89- 6.85 (m, 1H), 6.75-6.68 (m, 3
H), 3.82 (s, 3H), 3.71 (s, 3H), 1.80 (s, 3H).

Example 1 (43) 1- (4-methoxyphenyl) -3-methyl-4- (3
-Methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.46 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 10.93 (s, 1H), 8.78 (s, 1)
H), 8.30-8.20 (brs, 1H), 8.00 (d, J = 9.0 Hz, 2H),
7.67-7.58 (brs, 1H), 7.22 (t, J = 8.1 Hz, 1H), 7.0
8 (d, J = 9.0 Hz, 2H), 6.75-6.67 (m, 3H), 3.80 (s,
3H), 3.71 (s, 3H), 1.79 (s, 3H).

Example 1 (44) 1- (3-methylphenyl) -3-methyl-4- (3-
Methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.45 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 10.92 (s, 1H), 8.81 (s, 1)
H), 8.26 (brs, 1H), 8.00-7.95 (m, 2H), 7.67 (brs, 1
H), 7.40 (t, J = 7.8 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1
H), 7.12 (d, J = 7.8Hz, 1H), 6.80-6.65 (m, 3H), 3.71
(s, 3H), 2.39 (s, 3H), 1.80 (s, 3H).

Example 1 (45) 1-methyl-3-cyclopentyl-4- (3-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5
-Carboxamide

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TLC: Rf 0.50 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.82 (s, 1H), 8.74 (s, 1)
H), 8.21 (bs, 1H), 7.56 (bs, 1H), 7.17 (d, J = 8.1
Hz, 1H), 6.70-6.61 (m, 2H), 6.56 (d, J = 8.1Hz, 1
H), 3.91 (s, 3H), 3.69 (s, 3H), 2.25-2.10 (m, 1H),
1.65-1.43 (m, 6H), 1.35-1.15 (m, 2H).

Example 1 (46) 1- (2-chlorophenyl) -3-methyl-4- (3-
Methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.48 (hexane: ethyl acetate = 1: 3); NMR (DMSO-d ₆ ): δ 10.93 (br, 1H), 8.67 (s, 1)
H), 8.23 (br, 1H), 7.70 (dd, J = 7.7, 1.8 Hz, 1H),
7.66-7.49 (m, 4H), 7.25 (dd, J = 7.7, 7.7 Hz, 1H),
6.78-6.67 (m, 3H), 3.72 (s, 3H), 1.78 (s, 3H).

Example 1 (47) 1- (3-chlorophenyl) -3-methyl-4- (3-
Methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.50 (hexane: ethyl acetate = 1: 1); NMR (DMSO-d ₆ ): δ 10.95 (br, 1H), 8.84 (s, 1)
H), 8.39 (dd, J = 2.0, 2.0 Hz, 1H), 8.28 (br, 1H),
8.22-8.18 (m, 1H), 7.70 (br, 1H), 7.55 (dd, J = 8.
1, 8.1 Hz, 1H), 7.38-7.33 (m, 1H), 7.22 (dd, J =
8.0, 8.0 Hz, 1H), 6.79-6.68 (m, 3H), 3.72 (s, 3H),
1.79 (s, 3H).

Example 1 (48) 1- (4-chlorophenyl) -3-methyl-4- (3-
Methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.38 (hexane: ethyl acetate = 1: 1); NMR (DMSO-d ₆ ): δ 10.94 (br, 1H), 8.81 (s, 1)
H), 8.29 (br, 1H), 8.26 (d, J = 9.0 Hz, 2H), 7.69
(br, 1H), 7.58 (d, J = 9.0 Hz, 2H), 7.22 (dd, J =
8.1, 8.1 Hz, 1H), 6.77-6.67 (m, 3H), 3.71 (s, 3H),
1.79 (s, 3H).

Example 1 (49) 1-ethyl-3-methyl-4- (3-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.51 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 10.93 (s, 1H), 8.71 (s, 1)
H), 8.22-8.15 (brs, 1H), 7.60-7.50 (brs, 1H), 7.20
(dd, J = 8.7, 7.8 Hz, 1H), 6.70-6.67 (m, 2H), 6.63
(d, J = 8.7 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 3.7
0 (s, 3H), 1.69 (s, 3H), 1.35 (t, J = 7.2 Hz, 1H).

Example 1 (50) 1- (2-methylphenyl) -3-methyl-4- (3-
Methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.45 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 10.95 (s, 1H), 8.67 (s, 1)
H), 8.21 (brs, 1H), 7.59 (brs, 1H), 7.45-7.30 (m, 4
H), 7.24 (t, J = 8.1 Hz, 1H), 6.80-6.60 (m, 3H), 3.72
(s, 3H), 2.05 (s, 3H), 1.78 (s, 3H).

Example 1 (51) 1-cyclopentyl-3-methyl-4- (3-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5
-Carboxamide

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TLC: Rf 0.35 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.91 (s, 1H), 8.70 (s, 1)
H), 8.18 (br.s, 1H), 7.54 (br.s, 1H), 7.19 (t, J =
8.4 Hz, 1H), 6.75-6.60 (m, 3H), 5.23 (quintet, J
= 7.4 Hz, 1H), 3.70 (s, 3H), 2.10-1.75 (m, 6H), 1.
70 (s, 3H), 1.75-1.60 (m, 2H).

Example 1 (52) 1-butyl-3-methyl-4- (3-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.40 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 10.94 (s, 1H), 8.71 (s, 1)
H), 8.19 (brs, 1H), 7.55 (brs, 1H), 7.23-7.17 (m, 1
H), 6.73-6.60 (m, 3H), 4.28 (t, J = 7.0 Hz, 2H),
3.69 (s, 3H), 1.77 (quint., J = 7.0Hz, 2H), 1.68
(s, 3H), 1.20 (tq, J = 7.0, 7.5 Hz, 2H), 0.8 7 (t,
J = 7.5 Hz, 3H).

Example 1 (53) 1-propyl-3-methyl-4- (3-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.40 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 10.94 (s, 1H), 8.71 (s, 1)
H), 8.18 (brs, 1H), 7.55 (brs, 1H), 7.23-7.17 (m, 1
H), 6.71-6.62 (m, 3H), 4.23 (tq, J = 6.6 Hz, 2H),
3.69 (s, 3H), 1.80 (t, J = 6.6, 7.2 Hz, 2H), 1.69
(a, 3H), 0.81 (t, J = 7.2 Hz, 3H).

Example 1 (54) 1-methyl-3-methyl-4- (3- (methoxycarbonylamino) phenylamino) pyrazolo [5,4-b]
Pyridine-5-carboxamide

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TLC: Rf 0.41 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.99 (s, 1H), 9.62 (s, 1)
H), 8.73 (s, 1H), 8.21 (br, 1H), 7.56 (br, 1H), 7.
23-7.19 (m, 3H), 6.75-6.71 (m, 1H), 3.87 (s, 3H),
3.61 (s, 3H), 1.67 (s, 3H).

Example 1 (55) 1-cyclohexyl-3-methyl-4- (3-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5
-Carboxamide

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TLC: Rf 0.50 (chloroform: methanol = 9: 1); NMR (CDCl ₃ ): δ 10.54 (s, 1H), 8.51 (s, 1H),
7.22-7.15 (m, 1H), 6.73-6.66 (m, 3H), 5.90-5.70 (b
rs, 2H), 4.78-4.68 (m, 1H), 3.76 (s, 3H), 2.05-1.8
5 (m, 6H), 1.80 (s, 3H), 1.75-1.20 (m, 4H).

Example 1 (56) 1- (2-methoxyphenyl) -3-methyl-4- (3
-Methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.52 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 10.87 (s, 1H), 8.63 (s, 1)
H), 8.25-8.15 (brs, 1H), 7.62-7.53 (brs, 1H), 7.52-
7.46 (m, 1H), 7.38-7.34 (m, 1H), 7.27-7.21 (m, 2
H), 7.10-7.05 (m, 1H), 6.74-6.66 (m, 3H), 3.73 (s,
3H), 3.70 (s, 3H), 1.77 (s, 3H).

Example 1 (57) 1,3-dimethyl-4- (3-carbamoylphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.34 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 11.07 (s, 1H), 8.76 (s, 1)
H), 8.23 (br, 1H), 7.94 (s, 1H), 7.63-7.56 (m, 3H),
7.39 (dd, J = 7.8, 7.8 Hz, 1H), 7.35 (s, 1H), 7.2
7-7.23 (m, 1H), 3.88 (s, 3H), 1.59 (s, 3H).

Example 1 (58) 1,3-dimethyl-4- (3- (aminocarbamoyl)
Phenylamino) pyrazolo [5,4-b] pyridine-5
-Carboxamide

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TLC: Rf 0.67 (chloroform: methanol = 5: 1); NMR (DMSO-d ₆ ): δ 11.05 (s, 1H), 9.73 (s, 1)
H), 8.76 (s, 1H), 8.23 (br, 1H), 7.58-7.51 (m, 3
H), 7.39 (dd, J = 7.8, 7.8 Hz, 1H), 7.27-7.23 (m,
1H), 4.75-4.35 (m, 2H), 3.88 (s, 3H), 1.58 (s, 3
H).

Example 1 (59) 1,3-dimethyl-4- (3- (methoxymethoxy) phenylamino) pyrazolo [5,4-b] pyridine-5-
Carboxamide

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TLC: Rf 0.50 (ethyl acetate); NMR (DMSO-d ₆ ): δ 10.97 (s, 1H), 8.73 (s, 1)
H), 8.20 (brs, 1H), 7.55 (brs, 1H), 7.24-7.18 (m, 1
H), 6.80-6.68 (m, 3H), 5.12 (s, 2H), 3.88 (s, 3H),
3.31 (s, 3H), 1.69 (s, 3H).

Example 1 (60) 1,3-dimethyl-4- (3-((hydroxyimino)
Methyl) phenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.47 (chloroform: methanol = 8: 1); NMR (DMSO-d ₆ ): δ 11.23 (s, 1H), 11.00 (s, 1)
H), 8.75 (s, 1H), 8.22 (br, 1H), 8.07 (s, 1H), 7.57
(br, 1H), 7.37-7.28 (m, 3H), 7.14-7.09 (m, 1H), 3.
88 (s, 3H), 1.66 (s, 3H).

Example 1 (61) 1,3-dimethyl-4- (3-((methoxyimino) methyl) phenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.57 (chloroform: methanol = 8: 1); NMR (DMSO-d ₆ ): δ 11.01 (s, 1H), 8.75 (s, 1)
H), 8.21 (br, 1H), 8.17 (s, 1H), 7.57 (br, 1H), 7.3
8-7.31 (m, 3H), 7.16-7.11 (m, 1H), 3.88 (s, 3H),
3.84 (s, 3H), 1.65 (s, 3H).

Example 1 (62) 1,3-dimethyl-4- (3-((aminoimino) methyl) phenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.47 (chloroform: methanol = 8: 1); NMR (DMSO-d ₆ ): δ 10.99 (s, 1H), 8.74 (s, 1)
H), 8.20 (br, 1H), 7.60 (s, 1H), 7.56 (br, 1H), 7.3
0-7.16 (m, 3H), 6.99-6.96 (m, 1H), 6.77 (s, 2H),
3.88 (s, 3H), 1.64 (s, 3H).

Example 1 (63) 1,3-dimethyl-4- (3-cyanophenylamino)
Pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.38 (ethyl acetate); NMR (DMSO-d ₆ ): δ 10.83 (s, 1H), 8.76 (s, 1)
H), 8.23 (br, 1H), 7.60 (br, 1H), 7.56-7.44 (m, 3
H), 7.41-7.36 (m, 1H), 3.91 (s, 3H), 1.72 (s, 3
H).

Example 1 (64) 1,3-Dimethyl-4- (3-((3S) -1-tert-butoxycarbonylpyrrolidin-3-yloxy) phenylamino) pyrazolo [5,4-b] pyridine- 5-carboxamide

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TLC: Rf 0.35 (chloroform: methanol = 9: 1); NMR (CDCl ₃ ): δ 10.59 (s, 1H), 8.54 (s, 1H),
7.20-7.15 (m, 1H), 6.78-6.63 (m, 3H), 6.00-5.70 (b
rs, 2H), 4.85-4.79 (m, 1H), 4.00 (s, 3H), 3.60-3.4
0 (m, 4H), 2.20- 2.00 (m, 2H), 1.78 (s, 3H), 1.46
(s, 9H).

Example 1 (65) 1,3-dimethyl-4- (3-((3S) -1-acetylpyrrolidin-3-yloxy) phenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.26 (chloroform: methanol = 9: 1); NMR (CDCl ₃ ): δ 10.61, 10.58 (s, 1H), 8.56,
8.55 (s, 1H), 7.23- 7.15 (m, 1H), 6.80-6.70 (m, 1
H), 6.65-6.61 (m, 2H), 6.00-5.80 (br, 2H), 4.95-4.
82 (m, 1H), 4.00 (s, 3H), 3.80-3.50 (m, 4H), 2.32-
1.95 (m, 2H), 2.08, 2.04 (s, 3H), 1.79, 1.78 (s, 3
H).

Example 1 (66) 1-pentyl-3-methyl-4- (3-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.46 (hexane: ethyl acetate = 2: 3); NMR (DMSO-d ₆ ): δ 10.92 (s, 1H), 8.70 (s, 1)
H), 8.18 (br, 1H), 7.54 (br, 1H), 7.23-7.17 (m, 1
H), 6.71-6.67 (m, 2H), 6.65-6.61 (m, 1H), 4.26 (t,
J = 7.2 Hz, 2H), 3.69 (s, 3H), 1.84-1.73 (m, 2H),
1.69 (s, 3H), 1.36-1.13 (m, 4H), 0.82 (t, J = 7.1
Hz, 3H).

Example 1 (67) 1-cyclopropylmethyl-3-methyl-4- (3-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.44 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 11.25 (bs, 1H), 8.75 (s, 1)
H), 8.30 (bs, 1H), 7.64 (bs, 1H), 7.25 (t.J = 7.8
Hz, 1H), 6.84-6.66 (m, 3H), 4.20 (d, J = 7.2Hz, 2
H), 3.72 (s, 3H), 1.68 (s, 3H), 1.35-1.20 (m, 1H),
0.56-0.36 (m, 4H).

Example 1 (68) 1-Cyclopropylmethyl-3-ethyl-4- (3-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.45 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.87 (s, 1H), 8.72 (s, 1)
H), 8.20 (bs, 1H), 7.57 (bs, 1H), 7.19 (t, J = 8.1
Hz, 1H), 6.74-6.56 (m, 3H), 4.19 (d, J = 7.2Hz, 2
H), 3.70 (s, 3H), 2.01 (q, J = 7.5 Hz, 2H), 1.35-
1.20 (m, 1H), 0.94 (t, J = 7.5 Hz, 3H), 0.54-0.35
(m, 4H).

Example 1 (69) 1,3-dimethyl-4- (3-((3S) -1-mesylpyrrolidin-3-yloxy) phenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide

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TLC: Rf 0.31 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 10.93 (s, 1H), 8.73 (s, 1)
H), 8.25-8.15 (brs, 1H), 7.60-7.45 (brs, 1H), 7.21
(t, J = 9.0 Hz, 1H), 6.73-6.65 (m, 3H), 5.04-4.99
(m, 1H), 3.87 (s, 3H), 3.52 (dd, J = 11.7, 4.2 Hz,
1H), 3.40-3.25 m, 3H), 2.85 (s, 3H), 2.22-2.00
(m, 2H), 1.68 (s, 3H).

Example 2 1,3-Dimethyl-4- (N-methyl-N- (3-methoxyphenyl) amino) pyrazolo [5,4-b] pyridine-5-carboxamide

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The compound prepared in Example 1 (100 mg)
Anhydrous toluene (10 mL)-anhydrous acetonitrile (5
silver oxide (1 mL) at 0 ° C. under a stream of argon gas.
12 mg) and methyl iodide (568 mg)
Stirred at room temperature for 15 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 50:
The compound of the present invention (98) having the following physical properties was purified by 1).
mg). TLC: Rf 0.36 (chloroform: methanol = 9:
1); NMR (DMSO-d ₆ ): δ 8.64 (s, 1H), 7.62 (brs, 1
H), 7.43 (brs, 1H), 7.03 (t, J = 8.1 Hz, 1H), 6.37
-6.33 (m, 1H), 6.17-6.10 (m, 2H), 3.96 (s, 3H), 3.
64 (s, 3H), 3.27 (s, 3H), 2.02 (s, 3H).

Example 3 1,3-Dimethyl-4- (3-((3S) -pyrrolidin-3-yloxy) phenylamino) pyrazolo [5,4
-B] pyridine-5-carboxamide

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The compound (30) produced in Example 1 (64)
0 mg) of ethyl acetate (10 mL) -methanol (10
10% hydrogen chloride methanol solution (3 mL)
Was added and stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. The residue was adjusted to pH 11 with a saturated aqueous sodium carbonate solution.
, And extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium carbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the compound of the present invention (125 mg) having the following physical data. TLC: Rf 0.36 (chloroform: methanol: acetic acid = 10: 2: 1); NMR (DMSO-d ₆ ): δ 10.93 (s, 1H), 8.73 (s, 1)
H), 8.23-8.12 (brs, 1H), 7.63-7.45 (brs, 1H), 7.21-
7.15 (m, 1H), 6.70-6.60 (m, 3H), 4.80-4.75 (m, 1
H), 3.87 (s, 3H), 3.31 (brs, 1H), 2.98-2.63 (m, 4
H), 1.98-1.82 (m, 1H), 1.70-1.60 (m, 1H), 1.67 (s,
3H).

[0220]

Formulation Example Formulation Example 1 The following components were mixed in a conventional manner and tabletted to give 100 tablets each containing 50 mg of the active ingredient. 1,3-dimethyl-4- (3-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide 5.0 g Calcium carboxymethylcellulose (disintegrant) 0.2 g-Magnesium stearate (lubricant)-0.1 g-Microcrystalline cellulose-4.7 g

Formulation Example 2 After mixing the following components by a conventional method, the solution is sterilized by a conventional method, filled into ampoules in 5 ml portions, freeze-dried by a conventional method, and contains 20 mg of the active ingredient in one ampule. 100 ampoules were obtained. 1,3-dimethyl-4- (3-methoxyphenylamino) pyrazolo [5,4-b] pyridine-5-carboxamide 2.0 g mannitol 20 g distilled water・ ・ 1000ml

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 3/10 A61P 3/10 9/10 9/10 11/00 11/00 11/06 11/06 13 / 12 13/12 17/00 17/00 17/06 17/06 19/10 19/10 25/16 25/16 25/24 25/24 25/28 25/28 27/16 27/16 29/00 29/00 101 101 31/04 31/04 35/02 35/02 37/00 37/00 37/08 37/08 43/00 111 43/00 111 F-term (reference) 4C065 AA01 AA04 BB05 CC02 CC03 CC04 CC05 CC09 DD03 EE02 HH08 JJ06 KK02 KK09 PP06 PP07 PP08 PP09 PP10 PP11 PP12 PP13 4C086 AA03 CB05 NA14 ZA02 ZA33 ZA34 ZA36 ZA59 ZA66 ZA70 ZA75 ZA81 ZA89 ZA97 ZB07 ZB13 ZB15 ZB27 ZB35 ZC

Claims (1)

[Claims] 1. A compound of the general formula (I) (Wherein R ¹ is 1) —OR ⁶ group, 2) —SR ⁷ group, 3) C2-8 alkynyl group, 4) nitro group, 5) cyano group, 6) hydroxyl group or C1-8 alkoxy group. Done,
C1~8 alkyl group, 7) a phenyl group, 8) -C (O) R 8 ^{_{group, 9) -SO 2 NR 9 R}} 10 _{^{group, 10) -NR 11 SO 2 R}} 12 group, 11) -NR ¹³ C (O) a R ¹⁴ group or 12) —CHＣＨNR ¹⁵ group, wherein R ⁶ and R ⁷ are
i) hydrogen atom, ii) C1-8 alkyl group, iii) C1-8
A C1-8 alkyl group substituted with an alkoxy group, iv) a trihalomethyl group, v) a C3-7 cycloalkyl group, vi)
A C1-8 alkyl group substituted with a phenyl group, or vi
i) 1-4 nitrogen atoms, 1-3 oxygen atoms and / or
Or a 3- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic ring containing 1 to 3 sulfur atoms, wherein R ⁸ is a C 1-8 alkyl group, a phenyl group, a —NR ¹⁶ R ¹⁷ group or a —NR ¹⁸ N
R ¹⁹ represents a R ²⁰ group, and R ⁹ and R ¹⁰ and R ¹¹ and R ¹³ each independently represent a hydrogen atom or a C 1-8 alkyl group; R ¹² represents a C 1-8 alkyl group;
R ¹⁴ represents a C1-8 alkyl group, a C1-8 alkoxy group, or a —NR ²¹ R ²² group, and R ¹⁵ represents a hydroxyl group, a C1-8
Represents an alkoxy group, or -NR ²³ R ²⁴ , wherein R ¹⁶ and R
^17, R ¹⁸ and R ¹⁹ and R ^20, R ²¹ and R ²² and R ²³ and R
²⁴ each independently represents a hydrogen atom or a C1-8 alkyl group; R ² represents 1) a hydrogen atom or 2) a C1-8 alkoxy group; R ³ represents 1) a hydrogen atom or 2 ) represents a C1-8 alkyl group, R ⁴ is 1) hydrogen atom, 2) C1-8 alkyl group, 3) C3-7 cycloalkyl group, 4) C3-7 substituted with a cycloalkyl group C1-8 An alkyl group, 5) a phenyl group optionally substituted with 1 to 3 halogen atoms, or 6) 1 to 4 nitrogen atoms, 1 to 3 oxygen atoms and / or
Or a 3 to 15 membered monocyclic, bicyclic or tricyclic heterocyclic ring containing 1 to 3 sulfur atoms, wherein R ⁵ is: 1) a hydrogen atom, 2) a C1-8 alkyl group, 3) a C3 7 cycloalkyl group, 4) C1-8 alkyl group substituted with C3-7 cycloalkyl group, or 5) even if substituted with 1-3 substituents selected from i) to iii) below. A good phenyl group is represented by: i) a C1-8 alkyl group, ii) a C1-8 alkoxy group, iii) a halogen atom, 1 represented by R ⁴ , R ⁶ and R ^7.
A 3- to 15-membered monocyclic, bicyclic or tricyclic heterocycle containing ４4 nitrogen atoms, 1-3 oxygen atoms and / or 1-3 sulfur atoms is represented by the following i) -iii )) May be substituted with 1 to 3 substituents selected from: i) a C1-8 alkyl group, ii) a C1-8 alkoxy group, iii) a halogen atom, iv) a carboxy group, v) C1 8 alkoxycarbonyl group, vi) C2-8 acyl group, vii) -SO ₂ -C1~8 alkyl group, viii) pyrazolo pyridine derivative represented by oxo group),
Or their non-toxic salts.