WO2001081345A1 - Aromatic amide compounds - Google Patents

Abstract

Aromatic amide compounds of the general formula (I), pharmaceutically acceptable salts of the same, or hydrates of both, (wherein Z1 and Z2 are each CH or N; R is hydrogen or alkyl; and Ar is optionally substituted phenyl, pyridyl, or the like). The invention provides compounds which exhibit a potent inhibitory effect on glycogen synthase kinase 3ß (GSK-3ß) and are useful as preventive or therapeutic drugs for diabetes, complications of diabetes, Alzheimer dementia, neurodegenerative diseases (such as AIDS encephalopathy, Huntington disease, Parkinson disease, and cerebral ischemia), manic-depressive psychosis, or the like, or as immunopotentiators.

Description

 Specification

 Aromatic amide compound

 Technical field

 TECHNICAL FIELD The present invention relates to a novel pharmaceutical compound having glycogencin inhibitory activity (GSK-3?) Inhibitory activity.

 Background art

 Glycogen synthase kinase (GSK-3?), A protein kinase, has been reported to be involved in the causes of various diseases as follows.

 Type 2 diabetes is a disease in which the insulin responsiveness of Teng / 5 cells is decreased, and the darcos in the blood is increased. As a result, it induces complications such as diabetic nephropathy, retinopathy, and heart disease. GSK-3 works by phosphorylating glycogen synthase to inhibit glycogen accumulation in peripheral tissues, decrease insulin responsiveness, and increase blood glucose. In fact, lithium, which has GSK-3 作用 inhibitory action, lowers blood glucose by GSK-3 ^ inhibitory action (Proceding of National Academy of Sciences “Ob. Science. United 'Steve of America' (Pro Nat. Acad. Sci.) Vol. 93, p. 8455 (1996)). Therefore, drugs with GSK-3? Inhibitory activity are considered to be effective drugs for improving type 2 diabetes and its complications.

Although the mechanism of Alzheimer's disease dementia has not yet been elucidated, amyloid aggregation and neurofibrillary tangles are thought to be closely related to the cause. GSK-3? Is involved in both amyloid aggregation and neurofibrillary tangles as follows. (1) Binds to mutant presenilin to increase insoluble amyloid production (Procedures of National, Academy of Sciences, Science, Science, Science, The United Sciences, Science 'America (Proc. Nat. Acad. Sci.), Vol. 95, No. 9637 (1998)). (2) Causes of neurofibrillary tangles It induces the phosphorylation of protein, which weakens the skeleton of nerve cells and induces neuronal cell death (Neurosci. Lett.), Vol. 128, pp.195 (19 9 1 year)). In addition, GSK-35 also (3) inactivates pyruvate dehydrogenase by phosphorylation and reduces the amount of acetylcholine produced to maintain cell activity. Proc. Nat. Acad. Sci., Proc. Nat. Acad. Sci., Vol. 93, pp. 2719 (1996) )) Has also been reported to be directly involved in neuronal cell death. In addition, as a neurodegenerative disease other than Alzheimer's disease, its efficacy for AIDS encephalopathy has been suggested. Tat, a protein produced by the HIV virus that causes AIDS, increases GSK-3β activity in neurons and causes neuronal death (J. Neurochem.), Vol. 73, p. 578 (1999)). Based on the above, GSK-3y5 inhibitors are considered to be effective drugs for improving neurodegenerative diseases such as Alzheimer's type 1 dementia.

 Lithium and valproic acid, which have an anti-manic depressant effect, have a GSK-3 ^ inhibitory effect (J. Neurochem., Vol. 72, p. 1327 (1989)). ). The relationship between anti-manic depression and GSK-3? Inhibitory effect is not clear, but the inhibitory effect on glutamate toxicity (Proceeding of the National Academy of Sciences of Ob-The United States) Of America (Pro Nat. Acad. Sci.), Vol. 95, No. 2642

(1992)) is thought to be involved in part in maintaining the activity of neurons. Based on the above, GSK-3? Inhibitors are considered to be effective drugs for improving manic depression.

NF-AT, a transcription factor, is dephosphorylated by calcineurin and enhances the immune response (Science, Vol. 275, pp. 930 (1997)). GSK-3 ^ acts to suppress immune function by phosphorylating NF-AT. Based on the above, GSK-35 inhibitors can be used for immunostimulation. It is thought to be an effective drug.

 WO 95/28387 describes penzamide compounds useful as preventive and therapeutic agents for cardiovascular diseases such as therapeutic agents for smooth muscle relaxation, therapeutic agents for hypertension, and therapeutic agents for angina pectoris. There is no suggestion for an effect on? Or on the central nervous system.

 An object of the present invention is to provide a novel compound having a selective and strong inhibitory action on glycogen synthase kinase-3 (yet) (GSK-3β), and further provide a medicament containing these compounds. It is to be.

 Disclosure of the invention

 The present inventors have conducted intensive studies to achieve the above object, and found that the novel aromatic amide compound has a selective and potent inhibitory activity on GSK-3 / 3. The present invention has been completed. That is, the present invention provides an aromatic amide compound represented by the following general formula (I), which has GSK-3 / 5 inhibitory activity and can be used as a medicament, a pharmaceutically acceptable salt thereof, or a hydration thereof. And a drug containing the compound as an active ingredient.

 (1) General formula (I)

[Wherein τ _γ Ζ ₂ is the same or different and represents CH or Ν, respectively. I also represents hydrogen or alkyl.

Ar is selected from naphthyl which may have a substituent, or a group represented by the following formulas (11), (II 1), (IV), (V), (VI) and (VI I) Represents a group.

(IV) (V) P-R ²

 (VI) (VII)

(Wherein, X represents C—R ¹ or N. Y represents CH ₂ , N—R ⁷ , 0 or S. RR ² , R ³ , RR ⁵ , and R ⁶ may be the same or different. , Each hydrogen, alkyl, alkoxy, phenoxy, phenylalkoxy, hydroxy, mercapto, alkylthio, amino, acylamino, alkylamino, carboxy, no, logen, haloalkyl, phenylalkyl, cyano, phenyl, nitro, cycloalkoxy, amino Represents an alkoxy, alkylaminoalkoxy, alkoxycarbonyl or azide, R ⁷ represents hydrogen, alkyl or phenylalkyl, and R ⁸ and R ⁹ may be the same or different and represent hydrogen, alkyl or oxo, respectively. Represents 1 or 2 carbon atoms.)]

Or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 (2) The aromatic amide compound according to the above (1), wherein in the general formula (I) is CH and R is hydrogen, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

(3) In the general formula (I), Ar is a group represented by the formula (II), (111), (IV), (V) or (VI), An amide compound, a pharmaceutically acceptable salt thereof, or a hydrate thereof. (4) In the general formula (I), Ar is naphthyl which may have a substituent or a group represented by the formula (VI I), wherein the aromatic amide compound according to the above (1), Pharmaceutically acceptable salts or hydrates thereof.

(5) In the formula (II) of Ar, R ²ヽ R ³ , R ⁴ , R ⁵ , R ⁶ are the same or different and are each hydrogen, alkyl, alkoxy, alkylthio, halogen, haloalkyl or nitro The aromatic amide compound according to the above (1), a pharmaceutically acceptable salt thereof or a hydrate thereof.

(6) In the formula (VI) for Ar, Υ is 0 or S, and X is C—R ¹ (R ¹ has the same meaning as in the above (1)) or Ν. Group amide compounds, pharmaceutically acceptable salts thereof and hydrates thereof.

(7) In the formula (VI I) of Ar, X is CH, Y is CH ₂ or N—R ⁷ (R ⁷ is as defined in (1) above), and n is 1 or 2 The aromatic amide compound according to the above (1), a pharmaceutically acceptable salt thereof or a hydrate thereof.

 (8) (4) 2—Fluoro N— (1H—Pyrazo mouth [3,4-b] pyridine 1-4—yl) benzamide,

 (5) 2-N-N- (1H-Pyrazo [3,4-b] pyridin-4-yl) benzamide,

 (7) 2-Methoxy-N- (1H-Bilazolo [3,4-b] pyridine-14-yl) benzamide,

 (8) 2-ethoxy-N- (1H-birazolo [3,4-b] pyridine-1-4-yl) benzamide,

 (9) 2-propyloxy-N- (1H-pyrazo-mouth [3,4-b] pyridine-41-yl) penzamide,

 (10) 2-Isopropyl hydrogen—N— (1H—pyrazo [3,4-b] pyridin-4-yl) benzamide,

(16) 2-trifluoromethyl-N— (1H-pyrazo [3,4-b] pyridine 1—4) benzamide,

 (17) 2-two-row N— (1 H-pyrazo-mouth [3,4-b] pyridine-41-yl) benzamide,

 (20) 2-Methylthio-N- (1H-pyrazo-mouth [3,4-b] pyridine-14-yl) penzamide,

 (32) 4-chloromethyl-N- (1H-pyrazo-mouth [3,4-b] pyridin-4-yl) benzamide,

 (33) 4—Promomethyl-N— (1H—Pyrazo mouth [3,4-b] pyridin-4-yl) penzamide,

 (34) 4-Trifluoromethyl-1-N— (1H—birazolo [3,4-b] pyridine—4-yl) benzamide,

 (46) 2,6-Difluoro-N— (1H-Bilazolo [3,4-b] pyridine-4-yl) benzamide,

 (49) N- (1H-birazolo [3,4-b] pyridine-14-yl) -13-pyridincarboxamide,

 (50) 2-Methylthio_N— (1H-Bilazolo [3,4-b] pyridine-14-yl) -1-3-pyridinecarboxamide,

 (54) 2-Methyl-1-N— (1H—Pyrazo-mouth [3,4-b] pyridin-4-yl) —3-furancarboxamide,

 (58) 5-Methyl-N— (1H—Pyrazo [3,4-b] pyridin-4-yl) —4-isoxazolecarboxamide,

 (68) 3,4-Dihydro-14-methyl-16-methylthio-1N— (1H—pyrazo-mouth [3,4-b] pyridine-14-yl) 1-2H—1,4-benzoxazine-18 — Carboxamide, <

(75) 2-chloro-N- (1H-pyro- [2,3-b] pyridine-41-yl) benzamide,

(79) 2-Nitro-N- (1H-pyro-mouth [2,3-b] pyridine-14-yl) Nzamide,

 (80) 2,6-difluoro-N— (1H—pyro [2,3—To] pyridin-4-yl) benzamide,

 (82) 3-Chloro-2,6-difluoro-N— (1H—pyro [2,3-b] pyridin-4-yl) penzamide,

 (83) 2,6-difluoro-1-methyl-1-N— (1H-pyrro [2,3-b] pyridin-1-41) benzamide,

 (85) 2,5-Dichloro-1-N— (1H—pyro [2,3-b] pyridin-4-yl) benzamide,

 (86) 5-Promo 2-N- (1H-Pyro [2,3-b] pyridin-4-yl) penzamide,

 (87) 2-chloro-1-5-nitro-N- (1H-pyro [2,3-b] pyridine-4-yl) penzamide, and

 (90) N— (1 H—Pyrazo mouth [3,4-b] pyridine-14-yl) 1-2-thiophenecarboxamide

The aromatic amide compound according to the above (1), a pharmaceutically acceptable salt thereof or a hydrate thereof (the numbers indicate the example numbers) selected from the group consisting of:

 (9) A medicament comprising the aromatic amide compound according to any one of the above (1) to (8), a pharmaceutically acceptable salt thereof or a hydrate thereof.

 (10) The aromatic amide compound according to any one of the above (1) to (8), a pharmaceutically acceptable salt thereof or a hydrate thereof, and a pharmaceutically acceptable additive. Composition.

 (11) A GSK-33 inhibitor comprising the aromatic amide compound according to any one of (1) to (8) above, a pharmaceutically acceptable salt thereof or a hydrate thereof.

(12) A therapeutic agent for diabetes, comprising the aromatic amide compound according to any one of the above (1) to (8), a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. (13) A treatment for complications of diabetes comprising the aromatic amide compound according to any one of the above (1) to (8), a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. medicine.

 (14) A treatment for Alzheimer's dementia comprising the aromatic amide compound according to any one of the above (1) to (8), a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. medicine.

 (15) A therapeutic agent for a neurodegenerative disease, comprising, as an active ingredient, the aromatic amide compound according to any one of the above (1) to (8), a pharmaceutically acceptable salt thereof or a hydrate thereof.

 (16) A prophylactic / therapeutic agent for manic depression, comprising the aromatic amide compound according to any one of the above (1) to (8), a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

 (17) An immunostimulant comprising the aromatic amide compound according to any one of the above (1) to (8), a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, The compound represented by I) (hereinafter, also referred to as compound (I) of the present invention) will be described in detail below.

 In the definition of the general formula in this specification, unless otherwise specified, “alkyl” is a straight-chain or branched alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, butyl, pentyl ( Amyl), hexyl, or their structural isomers such as isopropyl, isobutyl, secondary butyl, tertiary butyl, 1,1-dimethylethyl, isopentyl, neopentyl, tertiary pentyl, and the like. Or alkyl having 1 to 4 carbon atoms.

“Alkoxy” is a straight-chain or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, pentyloxy (amyloxy), hexyloxy, or a structural isomer thereof. Isobutoxy, isobutoxy, secondary butoxy, tertiary butoxy, isopentyloxy, neopentyloxy, tertiary pentyloxy, etc., preferably having 1 to 4 carbon atoms. Alkoxy.

 “Phenylalkoxy” has the same meaning as the above-mentioned alkoxy, and examples thereof include benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy and 1-methyl- 1-phenylethoxy, 1-methyl-2-phenylethoxy, 1-phenylpropoxy, 2-phenylpropoxy, 1-methyl-1-phenylpropoxy, 1-methyl-2-phenylpropoxy, 1-methyl-3-phenyl And an alkoxy moiety having 1 to 4 carbon atoms.

 “Alkylthio” refers to straight-chain or branched alkylthio having 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, butylthio, pentylthio (amylthio), hexylthio, or structural isomers thereof. Certain isopropylthio, isopropylthio, secondary butylthio, tertiary butylthio, isopentylthio, neopentylthio, tertiary pentylthio and the like are preferable, and alkylthio having 1 to 3 carbon atoms is preferable.

 "Alkylamino" is a secondary or tertiary amino in which the alkyl part has the same meaning as the above-mentioned alkyl and the alkyl part is substituted by one or two. Examples thereof include methylamino, dimethylamino, ethylamino, acetylamino, propylamino, Examples thereof include propylamino, butylamino, dibutylamino and the like, and the preferred alkyl moiety has 1 to 4 carbon atoms.

 "Acylamino" includes, for example, alkenylcarbonylamino having 2 to 6 carbon atoms, such as acetylamino, propionylamino, butyrylamino, valerylamino, and vivaloylamino; arylcarbonylamino such as benzoylamino; phenylacetylamino, phenyl. And aralkylcarbonylamino (alkyl has 1 to 4 carbon atoms) such as propionylamino and phenylbutyrylamino.

 “Halogen” is fluorine, chlorine, bromine, or iodine.

“Haloalkyl” is the above-mentioned alkyl substituted with 1 to 5 halogens, for example, trifluoromethyl, 2,2,2-trifluoroethyl, 2, 2 3, 3, 3 — Penn fluoropentyl and the like.

 “Phenylalkyl” has the same meaning as the above-mentioned alkyl in the alkyl part. Examples thereof include methylphenyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1-phenylethyl, 1-methyl-2-phenylethyl, Examples include 1-phenylpropyl, 2-phenylpropyl, 1-methyl-1-phenylpropyl, 1-methyl-2-phenylpropyl, 1-methyl-3-phenylpropyl, and the like. There are four.

 "Cycloalkoxy" refers to cycloalkoxy having 3 to 8 carbon atoms, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, etc. And preferably a cycloalkoxy having 5 to 6 carbon atoms.

 The term "aminoalkoxy" has the same meaning as the above-mentioned alkoxy, and examples thereof include aminomethoxy, aminoethoxy, aminopropyloxy, aminopropyloxy, and aminobutyloxy. One to four.

 “Alkylaminoalkoxy” means that the alkoxy part has the same meaning as the above-mentioned alkoxy, and the alkyl part has the same meaning as the above-mentioned alkyl, and the alkyl part has been substituted by one or two aminos. Toxic acid, dimethylaminomethoxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 4-dimethylaminobutoxy and the like are preferred. The preferred number of carbon atoms in the alkoxy moiety is 1 to 4, and the preferred carbon number in the alkyl moiety is The number is one to four.

 “Alkoxycarbonyl” has the same meaning as the above-mentioned alkoxy, and includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxypropyl, isopropoxycarbonyl, butoxycarbonyl, secondary butoxycarbonyl, and tertiary butoxycarbonyl. Butoxycarbonyl, etc., preferably alkoxycarbonyl having 2 to 5 carbon atoms.

In addition, as a substituent of "naphthyl which may have a substituent", halogen, Alkyl, alkoxy, hydroxy, alkylthio, amino, carboxy, nitro, cyano, trifluoromethyl, etc., and the number of substituents thereof is 1 to 7.c Also, phenyl, phenoxy, and phenyl Enylalkoxy "and

The phenyl moiety in “phenylalkyl” may have a substituent such as halogen, alkyl, alkoxy, hydroxy, alkylthio, amino, carboxy, nitro, cyano, trifluoromethyl, etc., and the number of substituents is 1 to 5 Individual.

The compound (I) of the present invention can be used as an addition salt with a pharmaceutically acceptable acid, and such an acid addition salt is also included in the scope of the present invention. Examples of such acid addition salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, Salts with organic acids such as succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and glutamic acid. Further, the compound (I) of the present invention can form a solvate with hydrate, ethanol and the like, and a polymorph, and these are all included in the scope of the present invention. When an asymmetric carbon is present, an optically active substance, a racemic form thereof, and the like may be present, all of which are included in the scope of the present invention. Incidentally, sigma ₂ is: ^ a, where R is hydrogen, although there are tautomers as shown below, are encompassed this tautomers Te to base this onset light range.

The compound (I) of the present invention has the following structural formula

 (In the formula, the definition of each symbol is as defined above.)

In particular, the following compounds are preferable.

 -A compound of the formula (I), wherein is CH and R is hydrogen.

 'A compound in which, in the general formula (I), Ar is a group represented by the formula (II), (111), (IV :), (V) or (VI).

 'A compound in which, in the general formula (I), Ar is an optionally substituted naphthyl or a group represented by the formula (VI I).

• In the formula (I) of Ar, compounds wherein R ² , R ³ and RRR ⁶ are the same or different and are each hydrogen, alkyl, alkoxy, alkylthio, halogen, haloalkyl or nitro.

• In the formula (VI) for Ar, compounds wherein Y is 0 or S, and X is C—R ¹ (R ¹ is as defined in the above (1)) or N.

• In the formula (VII) for Ar, compounds wherein X is CH, Y is CH ₂ or N—R ⁷ (R ⁷ is as defined in the above (1)), and n is 1 or 2. Specifically, the following compounds are suitable (the numbers represent the example numbers).

 (4) 2-Fluoro N— (1H—Bilazolo [3,4-b] pyridine-4-yl) benzamide

 (5) 2-N- (1-H-pyrazo [3,4-b] pyridine-4-yl) penzamide

 (7) 2-Methoxy-N- (1H-Pyrazo-mouth [3,4-b] pyridine-14-yl) Penzamide

(8) 2-ethoxy-N- (1H-pyrazo-mouth [3,4-b] pyridine-14-yl) benzamide (9) 2-Propoxy-N- (1H-Pyrazo-mouth [3,4-b] pyridine-1-yl) Benzamide

 (10) 2— ^ f Sopropyloxy-N- (1H—Bilazolo [3,4-b] pyridine—41-yl) Penzamide

 (16) 2-Trifluoromethyl-N— (1 H—pyrazo [3,4-b] pyridine—4-yl) benzamide

 (17) 2-nitro-N- (1H-pyrazo [3,4-b] pyridine-4-41) benzamide

 (20) 2-Methylthio-1-N— (1H—pyrazo-mouth [3,4-b] pyridine-14-yl) benzamide

 (32) 4-Chloromethyl-1-N— (1H—Pyrazo-mouth [3,4-b] pyridin-4-yl) Benzamide

 (33) 4-Bromomethyl-1-N- (1H-pyrazo-mouth [3,4-b] pyridin-4-yl) penzamide

 (34) 4-Trifluoromethyl-N— (1 H—pyrazo [3,4-b] pyridine—4-yl) benzamide

 (46) 2, 6-difluoro-1-N- (1H-pyrazo-mouth [3,4-b] pyridine-1-'4-yl) benzamide,

(49) N— (1 H—pyrazo mouth [3, 4-b] pyridine-14-yl) 13-pyridincarboxamide

 (50) 2-Methylthio-N- (1H-Pyrazo-mouth [3,4-b] pyridine-14-yl) — 3-Pyridinecarboxamide

 (54) 2-Methyl-N- (1H-Pyrazo-mouth [3,4-b] pyridine-14-yl) -13-Furancarboxamide

 (58) 5-Methyl-1-N— (1H—Pyrazo-mouth [3,4-b] pyridine-14-yl) -14-Isoxazole carboxamide

(68) 3,4-Dihydro 4-methyl-6-methylthio-N- (1H-pyrazo [3,4-b] pyridine-14-yl) 1-2H-1, 4-benzoxazine-18-carboxamide

 (75) 2-Chloro-N- (1H-pyro [2,3-b] pyridin-4-yl) benzamide

 (79) 2-Nitro-N- (1H-pyro [2,3-b] pyridin-41-yl) benzamide

 (80) 2,6-Difluoro-N- (1H-pyrro [2,3-b] pyridin-4-yl) benzamide

 (82) 3-chloro-1,6-difluoro-N— (1H-pyro [2,3-b] pyridin-1-41) benzamide

 (83) 2,6-Difluoro-3-methyl-1-N- (1H-pyro [2,3-b] pyridine_4-yl) benzamide

 (85) 2,5-Dichloro-1-N- (1H-pyrro [2,3-b] pyridine-14-yl) benzamide

 (86) 5-Bromo-2-chloro-N- (1H-Pyro- [2,3-b] pyridin-4-yl) benzamide

 (87) 2-Chloro-5-nitro-N- (1H-pyro [2,3-b] pyridin-4-yl) benzamide

 (90) N— (1 H—pyrazo [3,4-b] pyridine-14-yl) -1-2-thiophenecarboxamide

The compound (I) of the present invention can be produced by the following method.

(Wherein, Zi, Z ₂ , R and Ar are as defined above.)

 The compound (I) of the present invention is produced by reacting an aromatic amine represented by the general formula (VI II) with an aromatic carboxylic acid represented by the general formula (IX) in the presence of a condensing agent. it can. Suitable condensing agents include, for example, dicyclohexylcarpoimide (DCC), diisopropylcarpoimide (DIPC), N-ethyl-N, 13-dimethylaminopropylcarpoimide (WSCI) and the like. Hydrochloride, benzotriazo-1-yl 1-yllute tris (dimethylamino) phosphoniumhexafluorophosphoride (B0P), diphenylphosphorylazide (DPPA), carbonyldiimidazole (CDI), getylphosphonyl cyanide (DPC), etc. Are listed. The reaction is carried out in the presence of a solvent inert to the reaction, but usually, hydroxyl groups such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethane, dimethylformamide, and dimethylimidazolidinone are used. Solvent not used is used. The reaction is carried out at any temperature, for example -10 to 200 ° C; preferably 0 to 100 ° C.

Manufacturing method 2

(Wherein τ, Z ₂ , R, and Ar have the same meanings as above. A represents a halogen.) The compound (I) of the present invention comprises an aromatic amine represented by the general formula (VI II)

The aromatic carboxylic acid halide represented by (X) can be produced by reacting in the presence of a base. Suitable bases include, for example, triethylamine, diisopropylethylamine and the like. The reaction is performed in the presence of a solvent inert to this reaction, but usually does not contain hydroxyl groups such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethane, dimethylformamide, and dimethylimidazolidinone. A solvent is used. The reaction is carried out at any temperature, for example -10 to 200 ° C, preferably 0 to;

(Wherein, τ, Z ₂ , R, and Ar have the same meanings as described above. B is an active ester. 4-12-Trophenyl ester (ONp), N-hydroxysuccinimide ester (ONSu), pen The compound (I) of the present invention comprises an aromatic amine represented by the general formula (VI II) and an aromatic amine represented by the general formula (VI II). It can be produced by reacting an aromatic carboxylic acid active ester represented by (XI). The reaction is carried out in the presence of a solvent inert to this reaction, but usually, hydroxyl groups such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethan, dimethylformamide, and dimethylimidazolidinone are used. A solvent containing no is used. The reaction is carried out at any temperature, for example -10 to 200 ° C, preferably 0 to 10 ° C.

Manufacturing method 4

(In the formula, τ, Z ₂ , R, and Ar have the same meanings as described above. D represents an active acyl, such as isobutyloxycarbonyl, getylacetyl, and trimethylacetyl.)

 The compound (I) of the present invention can be produced by reacting an aromatic amine represented by the general formula (VIII) with an aromatic carboxylic acid mixed anhydride represented by the general formula (XII). The reaction is carried out in the presence of a solvent inert to this reaction, but usually, hydroxyl groups such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethan, dimethylformamide, and dimethylimidazolidinone are used. A solvent containing no is used. The reaction is carried out at any temperature, for example -10 to 200 ° C, preferably 0 to 10 ° C.

 The aromatic carboxylic acid represented by the general formula (IX), which is a raw material, is described in the journal "Op" Organic "Chemistry" (J. Org. Chem.), Vol. 46, p. 783 (1981). Can be synthesized.

In addition, the aromatic amine of the general formula (VI II), which is a raw material, is described in Journal Op- J. Med. Chem., Vol. 32, p. 945 (1989), Vol. 25, p. 128, (1982), Journal Op. J. Heterocycl. Chem., Vol. 1, p. 42 (1964), and the journal 'Hyua' Practice 'Chem., J. Prakt. It can be synthesized by the method described in Vol. 324, p.

 The compound (I) of the present invention thus produced is isolated or purified as it is or as a salt thereof. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography. When the purified product obtained is a racemic form, it is separated into a desired optically active substance, for example, by fractional recrystallization with an optically active acid or by passing through a column packed with an optically active carrier. can do. The present invention also includes an optically active substance.

 The compound (I) of the present invention is a compound showing a selective and potent inhibitory effect on glycogen synthase kinase-3 (GSK-3j3), and is useful for diabetes, complications of diabetes, and Alzheimer's disease. It is useful as a prophylactic / therapeutic agent for type dementia, neurodegenerative diseases (AIDS encephalopathy, Huntington's disease, Parkinson's disease, cerebral ischemia), manic depression, etc., or a drug such as an immunostimulant.

Formulations containing the compound (I) of the present invention, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient are prepared using carriers, excipients and other additives usually used in the formulation. Is done. The carrier or excipient for the preparation may be solid or liquid, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter , Ethylene glycol and the like and other commonly used ones. Administration can be in the form of tablets, pills, capsules, granules, powders, liquids, etc., oral administration, injections such as intravenous injections, intramuscular injections, suppositories, transdermals, etc. You may. The dose is appropriately determined depending on the individual case in consideration of the symptoms, age, sex, etc. of the administration subject. Usually, the dose is 1 to L / 00 Omg, preferably 50 to 100 mg / day for each adult. ~ 20 Omg Is orally administered once or several times daily in the range of 1 to 5 mg / day, or once to several times daily in adults in the range of 1 to 50 mg / day Or, it is administered intravenously continuously for 1 hour to 24 hours a day.

 Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention. In such a solid composition, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, pudose, hydroxypropylcellulose, microcrystalline cellulose, starch, It is mixed with polyvinylpyrrolidone, metasilicic acid and magnesium aluminate. The composition may be prepared in a conventional manner using additives other than inert diluents, for example, lubricating agents such as magnesium stearate, disintegrating agents such as calcium cellulose glucose, and stabilizing agents such as lactose. It may contain a solubilizing agent such as glutamate / aspartic acid. The tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, or hydroxypropyl cellulose, if necessary. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as , Including purified water and ethanol. The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, flavoring agents, and preservatives. Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 and the like. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing, and solubilizing agents. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. In addition, these can be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile injection solvent before use.

 Example

Hereinafter, the present invention will be described more specifically based on Examples, Formulation Formulation Examples, and Experimental Examples. However, the present invention is not limited to these.

N- (1 H_ Villa, Noro "3.4-bl pyridine-1-41") Benzami · 1 /

To a solution of 4-aminovirazolo [3,4-b] pyridine (1.0 g) and triethylamine (1.1 g) in THF (3 OmL) was added benzoylcopenlide (1.0 g) under water cooling. It was dropped. After stirring at 5 ° C for 2 hours, the precipitate was separated by filtration and the filtrate was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give the title compound (159 mg) as colorless crystals. Melting point 242—245 ° C

Elemental analysis: C ₁₃ H _{1 ()} N ₄ 0 · 1/10 H ₂ O

 C (%) H (%) N (%)

Calculated value 6 5. 0 5 4. 2 8 23.34.

Actual value 65.0 0 14.3 1 22.9 3.

MS (EI): 238 (M +). ¹ H-NMR (40 OMHz, DMSO-d ₆ ) δ (ppm): 7.56 (3 H, m), 7.70 (1 Η, d, J = 4.9 Hz) 7.98 (2 H, m), 8.40 (1 H, d, J = 4.9 Hz), 10.82 (1 H, s), 13. 5 2 (1 H ₃ s). IR (KB r): 3032, 16 64, 16 1 8, 1 5 9 3, 1 504, 1 325, 1 2 90 cm " ¹ .

Example 2

 2-Methyl-1-N— (1T—Vilazolo “3.4-bl pyridine-1-41”) benzamide,

To a solution of 2-methylbenzoic acid (1.1 g) in toluene (5 mL) was added thionyl chloride (1.5 mL), and the mixture was heated and stirred at 40 ° C for 1 hour. The solvent was distilled off under reduced pressure to obtain a residue. To a solution of 4-aminovirazolo [3,4-b] pyridine (1.0 g) in THF (3 OmL), add triethylamine (1.1 mL), and add ice-cooled residue in THF (1 OmL). Was added dropwise and stirred for 1 hour. The salt formed is filtered and the solvent Was distilled off under reduced pressure to obtain a residue. Methanol (30 mL) was added to the residue, and the mixture was heated under reflux for 1 hour. After cooling to room temperature, the generated crystals were filtered to give the title compound (0.8 g) as colorless crystals. Melting point 23 1-233 ° C

Elemental analysis: as C ₁₄ H ₁₂ N ₄₀

 C (%) H (%) N (%)

Calculated value: 6 6. 5 9 4. 93 2 1. 8 5

Measured value: 6 6. 6 5 4. 79 22.2 1

MS (EI): 2 52 (M +). ¹ H-NMR (400 MHz, DMS 0-d ₆ ) δ (ppm): 2.41 (3H, s), 7.32-7.36 (2 H, m), 7.44 (1 H, dd, J = 7.4 and 7.8 Hz), 7.54 (1 H, d, J-7.4 Hz), 7.83 (1 H, d, J = 5.3 Hz), 8.40 (1 H, d J = 5.3 Hz), 8.41 (1 H, s), 10.0.96 (1 H, br. s), 1 3.57 (1 H, br.s) .IR (KB r): 3306, 1674, 1591: 1525, 1020, 937, 833, 666 cm- ¹ .

Example a

 2—Fenr Nu N_ (1 H—Pyrazo Mouth “3.4-bl pyridine 1-41 yl) Benzamide

 Production was carried out in the same manner as in Example 2 except that 2-phenylbenzoic acid was used instead of 2-methylbenzoic acid. Melting point 2 6 5— 2 6 9 ° C

Elemental analysis: as C ₁₉ H ₁₄ N ₄₀

 C (%) H (%) N (%)

Calculated value: 72. 60 4. 49 1 7. 82.

Measured value: 72.36 4.47 1 7. 1.

MS (FAB): 3 15 (M + 1). ¹ H-NMR (40 OMH z ₃ DMSO-d ₆ ) δ (ppm): 7.25 (1 H, d, J = 7.3 H z ), 7. 32 (1 H, d, J = 7. 8 H z), 7. 34 (1 H 3 d, J = 7. 3H z), 7. 44 (2 H d, J = 7. 3 H z), 7.5 1 (1 H, d, J = 7.8 H z), 7.54 (1 H 3H z), 7.68 (1H, d, J = 7.8 Hz), 7.6 1 -7.67 (2H, m), 8.08 (1H, s) , 8.32 (1H, d, J = 4.9Hz), 10.0.79 (1H, br.s), 13.45 (1H, br.s) .IR (KBr ): 32 5 6, 1 689 , 1 6 1 6, 1 5 8 9, 1 502, 1 323, 1 2 9 2, 1 27 5 cm '1.

Kushie example 4

 2-Fluoro N— (1H—Pyrazo mouth “3.4-bl pyridine-14-yl pentazamide”

 Production was carried out in the same manner as in Example 2 except that 2-fluorobenzoic acid was used instead of 2-monobenzoic acid. Melting point 2 16 ° C

Elemental analysis: as C ₁₃ H ₉ FN ₄₀

 C (%) H (%) N (%)

Calculated value: 60.94 3.54 2 1.87

Measured value: 60.68 3.94 2 1.99 9

MS (EI): 256 (M ⁺ ). ¹ H-NMR (40 OMH z, DMS 0-d ₆ ) δ (ppm): 7.27-7.32 (lH, m), 7.35 -7.39 (1H, m), 7.61-7.66 (lH, m), 7.72-7.76 (1H, m), 786 (1H, d, J = 5.4Hz), 8.38 (1H, s), 8.42 (1H, d, J = 5.4Hz), 11.06 (1H, br.s), 13.57 (1 H, br. S) .IR (KB r): 308 1, 1669, 1615, 1597, 1531, 15008, 148 1, 1453, 1433, 1331 cm— ¹ .

N—M T—Pyrazo mouth “3. 4-bl pyridine-1 41-yl) benzamide,

 The production was carried out in the same manner as in Example 2 except that 2-methylbenzoic acid was used instead of 2-methylbenzoic acid. Melting point> 270 ° C

Elementary analysis: as C ₁₃ H ₉ C 1N ₄ 0 C (%) H (%) N (%)

Calculated 57.2 6 3.33 20.5.5

Actual 57.54 3.67 20.49

MS (EI): 272 (M ⁺ ). ¹ H-NMR (40 OMHz, DMS 0-d ₆ ) δ (ppm): 7.48-7.49 (lH, m), 7.50-7 52 (1 H, m), 7.60-7.62 (1 H, m), 7.69 (1 H, d, J = 5.3 Hz), 7.84 (1 H, d , J = 5. 3 H z) , 8. 39 (1 H 5 s), 8. 4 2 (1 H, d, J = 5. 3 H z), 1 1. 1 7 (1 E, br. .. s), 1 3. 58 (1 H 5 b r s) IR (KB r): 3037, 1 69 8, 1 624, 1 5 9 0, 1 5 6 9, 1 538, 1 5 1 3, 1475, 1436, 14 1 3 cm ' ^1. Summary 6

 2—Promote N— (1H—Pyrazo Mouth “3.4-bl pyridine-14-yl) Benzamide,

 Production was carried out in the same manner as in Example 2 except that 2-bromobenzoic acid was used instead of 2-methylbenzoic acid. 272-274 ° C

Elemental analysis: as C ₁₃ H ₉ B rN ₄₀

 C (%) H (%) N (%)

Calculated value: 49.23 2.8 6 17.67

Measured value: 48.82 3.22 1 7.54

MS (EI):. 3 1 8 (M + + 1) 1 H-NMR (40 OMH z, DMS Od 6) δ (ppm):. 7. 47 (1 H 5 ddd, J = l 4, 7. 3 nd 7. 8 Hz), 7. 54 (1 H, dd 3 J = 6. 3 and 7. 3 H z), 7. 6 5 (1 H 3 dd, J = l. 5 and 7. 3 H z ) ₃ 7.76 (l H, d ₅ J = 9.3 H z), 7.84 (1 H, d, J = 5.3 H z), 8.39 (1 H, s) 8. 43 (1H, d, J = 5.3Hz), 11.16 (1H, br.s), 1357 (1H, br.s) .IR (KBr): 32 52, 1693, 1589, 1325, 1298, 1282, 948 cm— ¹ . rnmm i

 2-Methoxy N- (1 H-Pyrazo, mouth “3,4-bl pyridine-14-yl) Benzamide

 Production was carried out in the same manner as in Example 2 except that 2-methoxybenzoic acid was used instead of 2-methylbenzoic acid. 234-236 ° C

Elementary analysis: as C ₁₄ H ₁₂ N ₄ 0 ₂

 C (%) H (%) N (%)

Calculated value: 62. 68 4. 5 1 20. 88

Measured value: 62. 1 5 4. 60 20. 3 5

MS (EI): 268 (M +). ¹ H-NMR (40 OMH z, DMS 0-d ₆ ) δ (p pm): 3.94 (3 H, s), 7.1 1 (1 H, dd, J = 7.3 and 7.4 Hz), 7.24 (1 H, d, J = 8.3 Hz), 7.57 (1 Hdd, J = 7. 9 and 8 8 Hz), 7.70 (1 H, d, J = 7.9 Hz), 7.89 (1 H, d, J = 5.3 Hz), 8.35 (1 H, s ), 8. 4 0 (1 H , d, J = 5. 3 H z), 10. 7 5 (1 H, br. s), 1 3. 57 (1 H 5 b r. s). IR ( KB r): 332 1, 1 680, 1597, 1020, 752 cm- ¹ .

卖 Example 8

 2-ethoxy-N- (1H-pyrazo-mouth "3.4-bl pyridine-14-yl" benzamide

 The production was carried out in the same manner as in Example 2 except that 2-ethoxybenzoic acid was used instead of 2-methylbenzoic acid. Melting point 229-23 1 ° C

Elementary analysis: as C ₁₅ H ₁₄ N ₄ 0 ₂

 C (%) H (%) N (%)

Calculated value: 63.82 5.00 1 9.85

Measured value: 63. 6 5 4. 9 1 1 9. 79

MS (FAB): 283 (M + + 1) · 1 H-NMR C40 OMH z, DMS 0- _{d 6) δ (ppm):} 1. 3 6 (3 H, t, J = 6. 8 H z), 4. 2 1 (2 H 5 q, J = 6. 8Hz), 7. 10 (1 H , dd, J = 6.9 and 7.3 Hz), 7.22 (1H, d, J = 8.3Hz), 7.53 (1H, dd, J = 7.9 and 8.8 Hz, 7.7 1 (1 H, d, J = l. 5 and 7.3 Hz): 7.92 (1 H, d, J = 5.4 Hz), 8.38 (1H, s), 8.40 (1H, d, J = 4.8Hz), 10.6.8 (1H, br.s), 13.58 (1H: br IR (KB r): 3354, 1684, 1593, 1487, 1288 cm- ¹ .

Example 9

 2-propyloxy N-M H-pillar “3. 4-bl pyridine 14-yl) benzamide

 To a DMF (12 OmL) solution of methyl salicylate (10 g) were added potassium t-butoxide (11.0 g) and propyl iodide (16.8 g) under ice-cooling, and the mixture was stirred for 3 hours. did. The solvent was distilled off under reduced pressure, and an aqueous solution (4 OmL) of sodium hydroxide ′ (7.8 g) was added to a solution of the obtained residue in ethanol (100 ml), and the mixture was heated under reflux for 1 hour. The solution was acidified with concentrated hydrochloric acid, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure to obtain 2-propyloxybenzoic acid (8.5 g) as colorless crystals. To a solution of 2-propyloxybenzoic acid (8.5 g) in toluene (10 mL) was added thionyl chloride (10 mL), and the mixture was heated and stirred at 40 ° C for 1 hour. The solvent was distilled off under reduced pressure to obtain a residue. To a solution of 4-aminovirazolo [3,4-b] pyridine (5.8 g) in THF (15 OmL) was added triethylamine (4.8 g), and the residue THF (5 OmL) under ice-cooling. The solution was added dropwise and stirred for 1 hour. The generated salt was filtered, and the solvent was distilled off under reduced pressure to obtain a residue. Methanol (10 OmL) was added to the residue, and the mixture was heated under reflux for 1 hour. After cooling to room temperature, the generated crystals were filtered to give the title compound (2.7 g) as colorless crystals. 235 ° C

Elementary analysis: as C ₁₆ H ₁₆ N ₄ 0 ₂

C (%) H (%) N (%) Calculated value: 64.85 5.44 18.91

Measured value: 64.73 5.50 18.80

MS (EI): 296 (M ⁺ ). ¹ H-NMR (400 MHz, DMSO_d ₆ ) d

(ppm): 0.89 (3H, t, J = 7.3 Hz), 1.72-1.75 (2 H, m), 4.09 (2 H, t, J = 7.3 Hz) , 7.09 (1 H, t, J = 8.3 Hz), 7.2 1 (1 H, d, J = 8.3 Hz), 7.53 (1 H ₃ t, J = 8.3 Hz) 7.68 (1 H, dd, J = 1.5 and 8.3 Hz), 7.91 (1 H, d, J = 5.4 Hz), 8.38 (1 H, s), 8.40 (1 H, d, J = 5.4 Hz),

. 10. 70 (. 1 H, br s), 13. 57 (. 1 H 3 br s) IR (KB r): 3336, 1678, 16 14, 1592, 1525, 1508, I 486, 1 326, 1303 cm- ¹ .

Dragon example 1 Q

 2-Isopropyloxy N- (1H-villa, Noro “3.4-bl pyridine-14-yl”) benzamide

 Produced in the same manner as in Example 9 except that 2-bromopropane was used instead of propyl iodide. Melting point 199 ° C

Elementary analysis: as C ₁₆ H ₁₆ N ₄ 0 ₂

 C (%) H () N (%)

Calculated value: 64.85 5.44 18.91

Measured value: 64.53 5.66 18.62

MS (EI):. 296 ( M +) 1 H-NMR (40 OMH z, DMSO-d 6) d (ppm): 1. 30 (6 H, d, J = 7. 3 Hz), 4. 74 -7.82 (1 H ₅ m), 7.08 (1 H ₃ t, J = 8.3 Hz), 7.2 1 (1 H, d, J = 8.3 Hz), 7.52 ( 1 H, t, J = 8.3 Hz), 7.70 (1 H, dd, J = 1.5 and 8.3 Hz), 7.90 (1 H, d, J = 5.4 Hz), _{8. 36 (1 H 3 s)} , 8. 40 (1 H, d, J = 5. 4 Hz), 10. 64 (1 H, br. s), 13 58 (1 H 3 br. s). IR (KB r): 3 160, 1684, 16 1 5, 15 89, 1505, 1454, 1321, 1300 cm- Example 11

 2-Hexyloxy N- (1H-Pyrazo Mouth “3.4-bl Pyridine 1-4-yl) Benzamide

 Production was carried out in the same manner as in Example 9 except that hexylpromide was used instead of propyl iodide. Melting point 185 ° C

Elementary analysis: as C ₁₉ H ₂₂ N ₄ 0 ₂

 C (%) H (%) Ν (%)

Calculated: 67.44 6.55 16.56

Found: 67. 14 6. 54 16. 51

MS (EI): 338 (Μ +). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (p pm): 0.62 (3H, t, J = 7.3 Hz), 0.96-1. 02 (2Η, m), 1.06-1.14 (2H, m), 1.28-1.32 (2H, m), 1.67-1.71 (2H ₃ m), 4.11 _{(2 H 5 t, J =} 7. 3 H z), 7. 08 (lH, t, J = 8. 3Hz), 7. 20 (1 H 5 d, J = 8. 3Hz), 7. 53 ( 1H, t, J = 8.3Hz), 7.66 (1H, dd, J = 1.5 and 8.3Hz), 7.91 (1H, d, J = 5.3Hz) ₃ 838 (1H, . s), 8. 40 (1 H 3 d, J = 5. 4Hz), 10. 68 (1 H br s), 13. 54 (1H, br s) IR (KBr):.. 2929, 16 80 , 1590, 1509, 1324, 1299 cm " ¹ .

Example 1 2

 2-cyclohexylmethyloxy-N- (1H-pyrazo-mouth "3.4-bl pyridin-4-yl" benzamide

 Production was carried out in the same manner as in Example 9 except that cyclohexylmethyl bromide was used instead of propyl iodide. Melting point 223 ° C

Elementary analysis: as C _2Q H ₂₂ N ₄ 0 ₂

C (%) H () N (%) 6 8.5 5 6.33 1 5. 9 9

Measured value: 6 8. 1 8 6.44 1 5.68

MS (EI): 350 (M ⁺ ). ¹ H-NMR (40 OMH z ₅ DMSO—d ₆ ) δ (ppm): 0.98-1.02 (5 H, m), 1.45-1. 49 (3H, m), 1.70-1.73 (3H, m), 3.93 (2H, t, J = 7.3Hz), 7.08 (1H, t, J = 8.3 Hz), 7.19 (1 H, d, J = 8.3 Hz), 7.51 (1 H, t, J = 8.3 Hz), 7.64 (1 H , dd, J = 1. 5 and 8. 3 H z), 7. 9 1 (1 H 5 d, J = 5. 3 H z), 8 38 (1 H, s), 8. 40 (1 H , d, J = 5.4 Hz, 10.7 1 (1 Hbr.s), 13.53 (1H, br.s) .IR (KBr): 3343, 2928 , 1665, 1618, 1559, 1529, 1513, 1451, 1327 cm " ¹ .

卖 Example 1 3

 2—Phenylo di-N— (1H—villa, black “3.4—b, pi I) gin—4-yl) benzamide

To a solution of 2-chlorobenzoic acid (10 g) in toluene (15 mL) was added phenol (12 g), and the mixture was heated to 90 ° C. An aqueous solution (10 mL) of potassium hydroxide (8.5 g) was added, and the solution was adjusted to 150 ° C while distilling off toluene. Cuprous chloride (0.1 g) was added, and the mixture was heated and stirred at 200 ° C for 1 hour. After allowing to cool, the solution was acidified with concentrated hydrochloric acid under ice cooling, and extracted with ethyl acetate. After evaporating the solvent under reduced pressure, the residue was isolated by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give 2-phenyloxybenzoic acid (11.8 g) as colorless crystals. Was. To a solution of 2-phenyloxybenzoic acid (5.0 g) in toluene (5 mL) was added thionyl chloride (5 mL), and the mixture was heated and stirred at 40 ° C for 1 hour. The solvent was distilled off under reduced pressure to obtain a residue. To a solution of 4-aminovirazolo [3,4-b] pyridine (29 g) in THF (100 mL) was added triethylamine (2.4 g), and the residue was dissolved in THF (2 OmL) under ice-cooling. The mixture was added dropwise and stirred for 1 hour. And the resulting salt After filtration, the solvent was distilled off under reduced pressure to obtain a residue. Methanol (100 mL) was added to the residue, and the mixture was heated under reflux for 1 hour. After cooling to room temperature, the resulting crystals were filtered to give the title compound (1.1 lg) as colorless crystals. Mp 248 ° C Elemental analysis: as C ₁₉ H ₁₄ N ₄ 0 ₂

 C (%) H (%) N ()

Calculated value: 69. 08 4. 27 1 6. 9 6

Measured value: 6 9. 1 9 4. 33 1 6. 9 6

MS (EI): 330 (M +). ¹ H-NMR (400 MHz, DMSO-d ₆ ) d (ppm): 6.96 (1 H, d, J = 8.3 Hz), 7.09 -7.15 (3 H ₅ m), 7.30 (1 H, t, J = 8.3 Hz), 7.38 (2 H, t, J = 8.3 Hz), 7.54 (1 H, t, J = 8.3 Hz), 7.74 (1 H, dd, J = l. 5 and 8.3 Hz), 7.80 (1 H, d, J = 5.4 Hz), 8. 28 (1 H, s) , 8. 38 (1 H, d, J = 5. 4 Hz), 1 0. 9 6 (1 H, br. s), 13 57 (1 H 5 br. s ). IR (KB r): 3364, 1 684, 15 93, 15 3 7, 15 13, 14 9 0, 14 76, 13 33, 13 03, 12 17 cm ^-1 mm 1 4

 2-benzyloxy-N- (1H-villa, b "3.4-bl pyridine-14-yl" benzamide

 Examples except that pentylbuide amide was used instead of propyl iodide

Manufactured in the same manner as 9. Melting point 2 5 9 ° C

Elemental analysis: as C ₂₀ H ₁₆ N ₄ O ₂

 C (%) H (%) N (%)

Calculated value: 6 9.76 4.68 1 6.27

Measured value: 6 9.84 4.87 1 5.88

MS (EI): 344 (M ⁺ ). ¹ H-NMR (40 OMH z ₅ DMSO- d ₆ ) 5 (ppm): 5.26 (2 H, s), 7.14 (1 H, t, J = 8. 3 Hz), 7. 24 - 7. 28 (3 H, m), 7. 3 5 (2 H 3 d, J = 7. 8 Hz), 7. 50 (1 H, d, J = 7.8 Hz), 7.56-7.59 (lH, m), 7.74 (1 H, d J = 7.8 Hz), 7.87 (1H, d, J = 5.4Hz), 7.93 (1H, s), 8.36 (1H, d, J = 5.4Hz), 10.75 (1H, br.s), 13.50 ( 1 H, br. S). IR (KBr): 3343, 1677, 1597, 152 7, 1509, 1329, 1297 cm " ¹ .

rn m 1 5

 2— (2-phenylethyloxy) -N- (1-pyrazolo “3. 4-bl pyridin-1-yl”) Penzamide

 Production was carried out in the same manner as in Example 9 except that 2-phenylethylpromide was used instead of propyl iodide. Melting point 228 ° C

Elementary analysis: as C _{2 8} N ₄ 0 ₂

 C (%) H (%) N (%)

Calculated value: 70. 38 5. 06 15. 63

Measured value: 70.07 5.22 15.39

MS (EI): 358 (M ⁺ ). ¹ H-NMR (400 MHz, DMSO-d ₆ ) (5 (ppm): 3.02 (2 H, t, J = 7.3 Hz), 4.33 (2 H ₅ t, J = 73 Hz), 7.06-7.10 (4H, m), 7.1 -7. 16 (2H, m), 7.23 (1H, d, J = 8.3 Hz) , 7.52 (1 H, t, J = 8.3 Hz), 7.64 (1H, d, J = 8.3 Hz), 7.87 (1 H ₃ d, J = 5.4 Hz), 8. 39 (1H, s), 8. 42 (1H, d, J = 5. 4Hz), 10. 70 (1H, br. s), 13. 56 (1 H 3 br. s). IR (KBr ): 3348, 1676, 1597, 1510, 1330 cm- ¹ .

荬 Example 1 6

 2-Trifluoromethyl-N— (1H-birazolo “3.4-bl pyridine-14-yl”)

Production was carried out in the same manner as in Example 2, except that 2-trifluoromethylbenzoic acid was used instead of 2-methylbenzoic acid. Melting point 247 ° C Elemental analysis: as C ₁₄ H ₉ F ₃ N ₄₀

 C (%) H (%) N (%)

Calculated value: 54. 9 1 2. 9 6 1 8. 29

Measured value: 54. 87 3. 3 1 1 8. 1 0

MS (EI): 306 (M ⁺ ). ¹ H-NMR (40 OMHz, DMS 0-d ₆ ) δ (ppm): 7.74-7.82 (4H, m), 7.89 (1 H, d, J = 53 Hz), 8.35 (1 H, s), 8.43 (1 H, d, J = 5.3 Hz), 11.24 (1 H, br. S), . 1 3. 5 9 (. 1 H, br s) IR (KB r): 3038, 1 684, 1 6 1 5, 1 5 92, 1 52 5, 1449, 143 1 cm "1.

Kushie example 1 7

 2—Nitro N— (1H—Villa, Noro “3. 4-bl pyridine-14-yl”) Benz amide

 It was produced in the same manner as in Example 2 except that 2-nitrobenzoic acid was used instead of 2-methylbenzoic acid. Melting point> 270 ° C

Elementary analysis: as C ₁₃ H ₉ N ₅ 0 ₃

 C (%) H (%) N (%)

Calculated value: 5 5. 12 3. 20 24. 72

Measured value: 54. 7 1 3. 47 24. 6 5

MS (EI): 284 (M ⁺ ). ¹ H-NMR (400 MHz, DMS 0-d ₆ ) δ (ppm): 7.80-7.87 (4H, m), 8.24 (1 H , d, J = 78 Hz), 8.31 (1H, s), 8.44 (1H, d, J = 5.0Hz), 11.27 (1H, br.s), 1 3.60 (1 H, br .s) .IR (KB r): 3 1 60, 1 683, 1 600, 1443 cm- contract I 1 H

2-Amino N— (1H—Pillar, black “3.4-bl pyridine-14-ylbenzamide · 1Z5f k The 2-nitro-N- (1H-pyrazo [3,4-b] pyridin-4-yl) obtained in Example 17 was added to a solution of benzamide (1.85 g) in DMF (4 OmL). To the mixture was added 0% palladium carbon (280 mg), and the mixture was stirred at room temperature and 20 atm under a hydrogen atmosphere for 8 hours. After confirming the completion of the reaction, the mixture was filtered through celite, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from methanol-ethyl acetate to give the title compound (1.25 g) as pale-yellow crystals. Melting point> 2 70 ° C

Elementary analysis: as C HuNs O '1/5 H ₂ 0

 C (%) H (%) N (%)

Calculated value: 60. 78 4. 47 27. 2 7

Measured value: 6 1. 05 4. 49 27. 1 3

MS (EI): 253 (M ⁺ ). ¹ H-NMR (40 OMHz, DMSO-d ₆ ) δ (p pm): 6.35-6.38 (2 H, br), 6.63 ( lH, t, J = 73 Hz), 6.79 (1H, d, J = 7.3 Hz), 7.25 (lH, t, J = 73 Hz), 7 .5 9 (1H, d, J = 5.4Hz), 7.69 (1H, d, J = 73Hz), 8.35 (1H, S), 8.36 ( 1 H, d, J = 5.4 Hz), 10.5.3 (1 H, br. S), 13.47 (1 H, br. S). IR (KBr): 1 678, 1 6 14, 1 584, 15 55, 1 507, 1485, 1455, 1406, 1 377, 1 327 cm- ¹ .

Kushie example 1 9

 2-Acetylamino-N- (1H-Pyrazo-mouth [3,4-b] pyridin-4-yl) Benzami 1/5

Example 18 To a solution of 2-amino-1-N- (1H-pyrazo [3,4-b] pyridin-141-yl) benzamide (0.96 g) obtained in Example 8 in THF (5 OmL) was added. , Triethylamine (1.15 g) and acetyl chloride (0.9 g) were added, and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction, the mixture was filtered and the solvent was distilled off under reduced pressure to obtain a residue. After addition of methanol (10 OmL), the mixture was heated under reflux for 1 hour. After evaporating the solvent under reduced pressure, isolate by silica gel column chromatography (ethyl acetate: hexane = 1: 1) Then, the title compound (66 Omg) was obtained as pale yellow crystals by recrystallization from methanol-diisopropyl ether. Melting point 2 53 ° C

Elemental analysis: C ₁₅ H ₁₃ N ₅ 0 ₂ '1/5 H ₂ 0

 C (%) H (%) N (%)

Calculated value: 60. 27 4. 5 2 2 3. 43

Measured value: 60.63 4.70 23.05

MS (EI): 295 (M +). ¹ H-NMR (400 MHz, DMS 0-d ₆ ) δ (ppm): 1.99 (3H, s), 7.27 (lH, t, J = 7.3 Hz), 7.55 (1H, t, J = 7.3Hz), 7.71-7.74 (2H, m), 7.82 (1H, d , J = 7.3 Hz), 8.39 (1 H, s), 8.40 (1 H, d, J = 5.4 Hz), 10.09 (1 H, b r.s) , 10.09 1 (1H, br.s), 13.50 (1H, br.s) .IR (KBr): 3225, 1657, 1623, 1585, 1435, 136 2 cm- ¹ .

 m 20

 2—Nutylthio-1-N— (1H—Birazolo “3-4-bl pyridine-1—4-pyridyl” · 1/10 yk

 Produced in the same manner as in Example 2 except that 2-methylthiobenzoic acid was used instead of 2-methylbenzoic acid. 239-242 ° C

Elemental analysis: as C ₁₄ H ₁₂ N ₄ SO · 1/10 H ₂ O

 C (%) H (%) N (%)

Calculated value: 58.77 4.30 1 9.60

Measured value: 58. 2 5 4. 5 6 20. 09

MS (EI): 284 (M +). ¹ H-NMR (400 MHz, DMS 0-d ₆ ) δ (ppm): 2.46 (3 H, s), 7.31 (1 H, t, J = 7. 3H z): 7. 47 (1 H, d, J = 7. 8 Hz), 7. 53 (1 H 3 dd, J = 6. 8 and 7. 3 H z) 5 7. 5 9 _{(1 H 3 d, J =} 7. 3 H z), 7. 78 (1 H, d, J = 5. 3 H z), 8. 40 (1 H, d, J = 5. 3 Hz), 8. 4 1 (1H, s), 11.00 (1H, br.s) ₃ 13.54 (1H, br.s). IR (KBr): 3015, 1685, 1624, 1589, 1537, 1504, 1325, 1296 cm- ¹ .

荬 Example 21

 2—Hydroxy N— (1H—Pyrazo Mouth “3.4—hi Pyridine-14-yl Benzamide

 Thionyl chloride (1 OmL) was added to a dichloromethane (1 OmL) solution of acetylsalicylic acid (5.0 g), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain a residue. To a solution of 4-aminovirazolo [3,4-b] pyridine (3.7 g) in THF (10 OmL) was added triethylamine (9.9 g).

(3 OmL) The solution was added dropwise and stirred for 1 hour. The formed salt was filtered and the solvent was distilled off under reduced pressure to obtain a residue. Methanol (5 OmL) was added to the residue, and the mixture was heated under reflux for 1 hour. After cooling to room temperature, the resulting crystals are filtered to give the title compound.

(4.5 g) was obtained as colorless crystals. 235 ° C

Elementary analysis: as C ₁₃ H ₁₀ N ₄ O ₂

 C (%) H (%) N ()

Calculated value: 61. 41 3. 96 22. 04

Found: 61. 50 4. 29 21. 72

MS (EI): 296 (M +). ¹ H-NMR (40 OMHz, DMS 0-d ₆ ) δ (p pm): 7.00 (lH, t, 7.4 Hz), 7.06 (1H, d, J = 83 Hz), 7.44-7.48 (lH, m), 7.86 (1H, d, J = 5.4 Hz), 7.92 (lH, dd, J = 1. 5 and 7.3 Hz), 8.21 (1H, s), 8.42 (1H, d, J = 5.4 Hz), 11.05 (1H, br.s), 11.60 (1H, br.s), 13.64 (1H, br.s) .IR (KBr): 3049, 1698, 1626, 1597, 1551, 1516 1453, 1335, 1305 cm- ¹ .

Kushie example 22 2-“N— (1H—villa, b” 3.4-bl pyridine-1-yl)

 A suspension of 4-aminobiazolo [3,4-b] pyridine (1.0 g) and fluoric anhydride in toluene was heated to reflux for 9 hours. The precipitate was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give the title compound (13.7 mg) as colorless crystals. As obtained. Melting point> 270 ° C

Elemental analysis value: as _{CHT ^ C ^ '1/5 H 2} 0

 C (%) H (%) N (%)

Calculated value: 5 8.09 3.76 1 9.36

Measured value: 5 8.63 3.93 1 9.88

MS (EI): 282 (M ⁺ ). 1 H-NMR (400 MHz, DMSO-d ₆ ) (5 (ppm): 7.6 1 (1 H, d, J = 7.4 Hz), 7.63 (1H, d, J = 7.8Hz), 7.69 (1H, d, J = 7.3Hz), 7.80 (1H, dJ = 5.3Hz), 7 9 5 (2 H, d, J = 7.8 Hz), 8.37 (1 H, s), 8.39 (1 H, d, J = 4.9 Hz), 11.0 3 (1 H, br. S) 1 3.49 (1 H, br. S). IR (KB r): 3 11 5, 2806, 170 3, 16 26, 1 595, 15 16, 1 332, 1 26 1 cm- ¹ .

Example 2 3

 2-(2-Dimethylamino ethoxy) -N- (1 H-pyrazo opening "3,4-bl pyridin-1-yl" benzamide

To a solution of 2-bromoethylamine hydrobromide (1.0 g) in DMF (10 mL) was added triethylamine (2.5 g). Under ice cooling, carbopenzoxycyclolide (0. 9 g) was added dropwise, and the mixture was stirred overnight. The resulting salt was filtered, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to N-benzyloxycarbonyl-2-ethyl chromatography by silica gel column chromatography (eluent: ethyl acetate: hexane = 3: 7). Promoethylamine (0.8 g) was obtained as a colorless oil. ^{1 H-NMR (400MHz, CDC} 1 3) δ (ppm): 3. 47 (. 2 H, t, J = 3 Hz), 3. 5 5 (1 H, t, J = 7. 3 H z) , 3.6 1 (2 H, q, J = 7.3 H z), 5.12 (2 H, s), 7.36-7.40 (5 H, m)

 To a solution of methyl salicylate (0.43 g) in DMF (1 OmL) under ice-cooling, add potassium t-butoxide (0.34 g) and N-pentyloxycarbonyl-2-bromoethyl obtained above. (0.8 g) was added, and the mixture was heated and stirred at 100 ° C for 6 hours. The formed salt was filtered, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution). Liquid: ethyl acetate: hexane = 1: 4) to give methyl 2- (N-benzyloxycarbonyl-2-aminoethoxy) benzoate (0.6 g) as a colorless oil.

^{1 H-NMR (400 MH z} , CD C 1 3) δ (ppm): 3. 6 5 (2 H, q 3 J = 7. 3 Hz), 3. 88 (3 H, s), 4. 1 5 (2 H, t, J = 7.3 Hz), 5.13 (2 H ₃ s), 5.98 (1 H, br.s), 6.96 (1 H, d, J = 8. 3 H z), 7. 0 2 (1 H, t, J = 8. 3 H z), 7. 2 6-7 34 (5 H, m), 7. 46 (1 H 3 1 3 J = 8.3 Hz), 7.82 (lH, dd, J = 1.5 and 8.3 Hz).

NaOH (1.4 g) was added to a mixture of the obtained 2- (N-benzyloxycarbonyl-2-aminoethoxy) methyl benzoate (3.7 g) in ethanol / water (4 OmL-2 OmL). Was added and heated under reflux for 1 hour. The solution was acidified with concentrated hydrochloric acid, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure to give 2- (N-benzyloxycarbonyl_2-aminoethoxy) benzoic acid (3.5 g). Obtained as colorless crystals. To a solution of the obtained crystals (3.5 g) in toluene (10 mL) was added thionyl chloride (15 mL), and the mixture was stirred for 3 hours. The solvent was distilled off under reduced pressure to obtain a residue (3.5 g) as a yellow oil. Triethylamine (1.6 g) and the residue (3.5 g) were added to a solution of 4-aminovirazolo [3,4-b] pyridine (0.7 g) in THF (3 OmL), and the mixture was stirred for 2 hours. . The salt formed is filtered and the solvent Was distilled off under reduced pressure to obtain a diamide compound (1.1 g) as yellow crystals. To a solution of the diamide in DMF (3 OnL) was added palladium carbon (1.0 g), and the mixture was stirred at 20 atm for 1 hour. After celite filtration, the solvent was distilled off under reduced pressure to obtain a deprotected compound (0.6 g) as yellow crystals. Sodium hydride (0.5 g) and methyl iodide (2.5 g) were added to a solution of the amide in DMF (3 OmL) under ice cooling, and the mixture was stirred for 3 hours. The solvent was distilled off under reduced pressure, methanol (3 OmL) was added to the obtained residue, and the mixture was heated under reflux for 1 hour. After cooling to room temperature, the generated crystals were filtered to give the title compound (0.4 g) as colorless crystals. 260 ° C

Elementary analysis: as C ₁₇ H ₁₉ N ₅ 0 ₂

 C (%) H (%) N (%)

Calculated value: 62. 75 5. 89 21. 52

Measured value: 62. 65 5. 68 21. 31

MS (EI):. 325 ( M +) 1 H-NMR (400MHz, DMS 0- d 6) δ (ppm): 2. 66 (6 H, s), 3. 68 (2H, t, J = 7 .3 Hz)

4.12 (2H, t, J = 7.3Hz), 7.10 (1H, t, J = 8.3Hz), 7.22 (1H, d, J = 8.3Hz), 7. 56 (1 H, t, J = 8.3 Hz), 7.70 (1H, dd ₅ J = l. 5 and 8.3 Hz), 7.9

5 (1H, d, J = 5.3 Hz), 8.39 (1H, s), 8.1 (1H, d J = 5.4 Hz), 10.68 (1H, br.s), 13.58 (1H, br.s) .IR (KBr): 3303, 2695, 1656, 1602, 1583,

1511, 1495, 1298 cm-

3—Chill-1 N— (1 T—Villa, Noro “3. 4-bl Pyridine-1 41-yl”) Benz amide

 The production was carried out in the same manner as in Example 2 except that 3-methylbenzoic acid was used instead of 2-methylbenzoic acid. 226-228 ° C

Elemental analysis: as C ₁₄ H _{1¾N 40} C (%) H (%) N (%)

Calculated value: 66. 6 5 4. 79 22.2 1

Measured value: 6 6.70 4.88 2 1.97

MS (EI): 25 2 (M +). ¹ H-NMR (40 OMH z, DMS O— d ₆ ) δ (ppm): 2.32 (3 H, s), 7.45 (2 H, d , J = 4.4Hz), 769 (1H, s), 7.77-7.80 (2H, s), 8.40 (1H, s), 8.41 (1H , d, J = 4.4 Hz), 10.78 (1 H, b r.s), 13.52 (1 H, b r.s). IR (KB r): 1701, 1 622 , 1597, 1 504, 1 273, 1 184, 875, 727 cm- ¹ .

 Example 2 5

 3—Methoxy N— (1H—Pyrazo Mouth “3.4-bl Pyridine 1-4-yl) Benzamide

 Production was carried out in the same manner as in Example 2 except that 3-methoxybenzoic acid was used instead of 2-methylbenzoic acid. Melting point 1 90 ° C

Elementary analysis: as C ₁₄ H ₁₂ N ₄ 0 ₂

 C (%) H (%) N (%)

Calculated value: 62. 68 4. 5 1 20. 88

Measured value: 62. 7 1 4.5 1 20. 73

MS (EI): 268 (M ⁺ ). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 3.85 (3 H, s), 7.22 (1 H, d , J = 5. 3 H z) , 7 46-7. 5 1 (2 H, m), 7. 57 (1 H, d 3 J = 5. 3 H z), 7. 68 (1 H, d , J = 5. 3 H z) , 8. 40-8. 42 (2 H, m), 10. 78 (1 H 3 br. s), 1 3. 5 2 (1 H, br. s). IR (KB r): 34 1 8, 16 90 1 672, 16 18, 1 594, 1 508, 1487, 1434, 1 379, 1 329 cm- ¹ .

卖 Example 2 6

3—Nitro N——Pyrazo, mouth “3,4-bl pyridine-1-4-yl) benz Amid

 Production was carried out in the same manner as in Example 2, except that 3-nitrobenzoic acid was used instead of 2-methylbenzoic acid. 274-276

Elementary analysis: as C ₁₃ H ₉ N ₅ 0 ₃

 C () H (%) N (%)

Calculated value: 55. 13 3. 20 24. 73

Measured value: 54. 94 3. 49 24. 31

MS (EI): 283 (M +). ¹ H-NMR (400 MHz, DMS 0-d ₆ ) ό "(ppm): 7.67 (1 H, d, J = 5.3 Hz), 7.63 (1 H, dd, J = 7.8 and 8.3 H z) ₃ 8.38 (1 H, s), 8.43-8.46 (2H ₅ m), 8.49 (1 H ₅ d, J = 7.8 Hz), 8.80 (1H, s), 1 11 (1H, br.s), 13.58 (1H, br.s). IR (KBr): 326 9, 1666, 1616 , 1595, 1520, 1350 cm- 27

 4-Methyl-N- 门 H-Pyrazo mouth “3. 4-bl pyridine-1-yl) Benzamide 1 Z 27k

 It was produced in the same manner as in Example 2 except that 4-methylbenzoic acid was used instead of 2-methylbenzoic acid. Melting point 215—217 ° C

Elemental analysis: as C ₁₄ H ₁₂ N ₄₀ · 1 / 2H ₂₀

 C (%) H (%) N (%)

Calculated value: 65. 72 4. 88 21. 90

Measured value: 65. 95 4. 79 22. 21

MS (EI): 252 (M ⁺ ). ¹ H-NMR (40 OMHz, DMS 0-d ₆ ) δ (m): 2.41 (3 H, s), 7.38 (2 H, d, J = 8.3 Hz)

7.68 (1H, d, J = 4.9z), 7.91 (2H, d, J = 7.8Hz)

8. 39 (1H, s), 8. 41 (1H, d, J = 4. 9Hz), 10. 72 (1 H, br. S), 13. 51 (1 H 5 br. S). IR ( KBr): 3107, 1 699, 1595, 1494, 1329 cm- ¹ .

Example 28

 4 1-ethyl 1 N_ (1 T—villa, noro “3. 4-bl pyridine 1 4-yl) benzamide,

 Produced in the same manner as in Example 2 except that 4-methylbenzoic acid was used instead of 2-methylbenzoic acid. Melting point 215—217 ° C

Elemental analysis: as C ₁₅ H ₁₄ N ₄₀

 C (%) H (%) N (%)

Calculated value: 67. 65 5. 30 21. 04

Obtained: 67.49 5.17 20.79

MS (EI): 266 (M ⁺ ). ¹ H-NMR (40 OMH z, DMS 0-d ₆ ) δ (p pm): 1.22 (3H, t, J = 7.3 Hz), 2.71 (2H, q, J = 7.3Hz), 7.41 (2H, d, J = 8.3Hz), 7.69 (1H, d, J = 5.4Hz), 7.91 (2H, d, J = 8.3Hz), 8.39 (1Hs), 8.40 (1H, d, J = 5.4Hz), 10.72 (1H, br.s), 13.51 ( 1 H ₃ br .s) .IR (KBr): 3300, 1660, 1614, 1591, 1523, 1489, 1429, 1242 cm ' ¹ .

Example 29

 4-Methoxy N— (1. H—Pyrazo mouth “3. 4-bl pyridine-14-yl” penzamide

 Produced in the same manner as in Example 2, except that 4-methoxybenzoic acid was used instead of 2-methylbenzoic acid. Melting point 253-255 ° C

Elementary analysis: as C ₁₄ H ₁₂ N ₄ 0 ₂

 C (%) H (%) N (%)

Calculated value: 62. 68 4. 51 20. 88

Measured value: 62. 42 4. 61 20. 34

MS (EI): 268 (M ⁺ ). ¹ H-NMR (40 OMHz, DMSO- d ₆ ) δ · (p pm): 3.85 (3H, s), 7.10 (2H, d, J = 8.8 Hz), 766 (1H, d, J = 4.9 Hz) ), 8. 00 (2 H, d, J = 8. 8H z), 8. 38 (1 H, s), 8. 38 (1 H, d, J = 4. 9 H z) 5 1 0. . 64 (. 1 H, br s), 1 3. 4 9 (. 1 H 5 br s) IR (KB r): 33 50, 1 6 7 2 1 6 08, 1 5 9 1, 1 5 1 6 , 1502, 1 2 53 cm- ¹ .

荬 Example 30

 4— (1.1—Dimethylethyl) -N— (1H—Pyrazo mouth “3. 4-hl pyridin-1-yl” benzamide

The production was carried out in the same manner as in Example 2 except that 4- (1,1-dimethylethyl) benzoic acid was used instead of 2-methylbenzoic acid. Melting point 2 63-2 64 ° C Elemental analysis: C ₁₇ H ₁₈ N ₄₀

 C (%) H () N (%)

Calculated value: 6 9.37 6.17 1 9.93

Measured value: 6 9.27 6.20 1 9.83

MS (EI): 294 (M ⁺ ). ¹ H-NMR (40 OMHz, DMS 0-d ₆ ) δ (p pm): 1.33 (9 H, s), 7.59 (2 H, d , J = 8. 8 H z) , 7 7 1 (1 H, d 3 J = 5. 4H z), 7. 9 1 (2 H 5 d, J = 8. 3H z), 8. 40 (1 _{H 5 d, J = 5. 4H} z), 8. 4 1 (1 H 5 s), 1 0. 74 (1 H, br. s), 1 3. 5 2 (1 H, br. s). IR (KB r): 2962, 1689 91, 20, 1587, 1527, 1242 cm ' ¹ .

rn m 31

 4-Fluoro-N— (1H-birazolo “3.4-bl pyridine-14-yl” benzamide

 The production was carried out in the same manner as in Example 2 except that 4-fluorobenzoic acid was used instead of 2-methylbenzoic acid. Melting point 26 2— 26 5 ° C

Elemental analysis: as C ₁₃ H ₉ FN ₄₀

C (%) H (%) N () 60.94 3.54 21.87

Measured value: 60.77 3.91 21.32

MS (EI): 256 (M ⁺ ). ¹ H-NMR (400 MHz, DMS d d ₆ ) δ (pm): 7.41 (2H, dd, J = 8.8 and 8.8 Hz) ₃ 7. 67 (1 H, d, J = 5. 3Hz), 8. 07 (2 H 5 d, J = 5. 4 and 8. 8Hz), 8. 38 (1H, s), 8. 41 (1 H 5 ... d, J = 5. 3Hz), 1 0. 82 (1 H, br s), 13. 53 (1 H 3 br s) IR (KB r): 3 302, 1666, 1614, 1595, 1514 , 1494 cm- ¹ .

 mrn a 2

 4-Chloromethyl-N— (1 TT—Villa, Noro “3.4-bl pyridine-14-ylbenzamide”

 The production was carried out in the same manner as in Example 2 except that 4-monochloromethylbenzoic acid was used instead of 2-methylbenzoic acid. Melting point> 270 ° C

Elemental analysis: as C Hu C 1N ₄₀

 C () H (%) N (%)

Calculated value: 58.65 3.87 19.54

Measured value: 58.32 4.12 19.31

MS (EI): 286 (M +). ¹ H-NMR (40 OMH z, DMS 0-d ₆ ) 0 "(pm): 4.86 (2 H, s), 7.58 (1 H, d, J = 8. 3Hz), 7 63 (1H, d, J = 7. 8Hz), 7. 71 (1 H, d, J = 4. 9Hz), 7. 99 (2 H 3 d, J = 7. 8Hz), 8. 41 (1 H , d, J = 5. 3Hz), 8. 43 (1H, s), 10. 83 (1 H 3 br. s), 13. 57 (1 H, br. s ) .IR (KBr): 3261, 1664, 1612, 1597, 1516, 133 1, 1305 cm- ¹ .

Example 33

1-Bromomethyl-1-N- (1H-pyrazo 'mouth "3.4-hi pyridine-1-41") Benzamide 1/2 Production was carried out in the same manner as in Example 2 except that 4-bromomethylbenzoic acid was used instead of 2-methylbenzoic acid. Melting point> 270 ° C

Elemental analysis: (^ Α ΗΗ Β Γ ΝΑ Ο Ο ■ As 1/2 H ₂₀

 C (%) H () N (%)

Calculated value: 49.43 3.5 6 1 6.47

Measured value: 49. 5 9 3.5 5 1 6. 1 1

MS (EI): 33 1 (M +). ¹ H-NMR (40 OMH z DMSO-d ₆ ) δ (p pm): 4.80 (2 H, s), 7.64 (2 H, d, J = 9.8 Hz), 7.71 (1 H, d, J = 5.3 Hz), 7.96 (2 H, d, J = 9.8 Hz), 8.40 ( 1 H, s), 8.41 (1 H ₅ d, J = 5.3 Hz), 10.82 (1 Hbr.s), 13.53 (1H, br.s). IR (KB r): 32 63, 1662, 1614, 1591, 1523 cm " ¹ .

Kushie 34

 4—Trifluoromethyl-1-N— (1.H—Pyrazo mouth “3.4-bl pyridine-1-4-yl”) benzamide

 Produced in the same manner as in Example 2, except that 4-trifluoromethylbenzoic acid was used instead of 2-methylbenzoic acid. Melting point 277 ° C

Elemental analysis: as C ₁₄ H ₉ F ₃ N ₄₀

 C (%) H (%) N (%)

Calculated value: 54. 9 1 3. 2 5 1 8. 29

Measured value: 54. 8 1 3. 23 18. 27

MS (FAB): 307 (M +). ¹ H-NMR (40 OMHz, DMS Od ₆ ) δ (ppm): 7.72 (1 H ₃ d, J = 5.4 Hz), 7.95 (2 H, d, J = 8.3 Hz), 8.17 (2H, d, J = 7.8Hz), 8.39 (1H, s) 8.43 (1H, d , J = 5.4 Hz), 11.02 (1 H, br.s), 13.57 (1 H, br.s). IR (KB r): 332 1, 1 678, 16 14, 1 5 9 1, 15 29, 1 325 cm- ¹ . Example 5

 4-Nitro-N- (1H-Pyrazo-mouth "3. 4-bl pyridine-1-yl") Benzamide / 1 07k

 Production was carried out in the same manner as in Example 2 except that 4-nitrobenzoic acid was used instead of 2-methylbenzoic acid. Melting point 2 82-284 ° C

Elementary analysis: as _{C 13 H 9 N 5 0 3} '1/1 0Η 2 Ο

 C (%) H (%) N (%)

Calculated value: 54. 73 3. 2 5 24. 57

Measured value: 5 5.1 0 3.5 3 24. 1 2

¹ H-NM (400 MHz, DMS 0-d ₆ ) δ (ppm): 7.7 1 (1 H, d, J = 5.4 Hz), 8.2 1 (2 H, d, J = 8. 7 Hz), .8. 40 (2 H ₅ d, J = 8.7 H z), 8.41 (1 H, s), 8.45 (1 H, d, J = 4.9 Hz), . 1 1. 1 2 (. 1 H 3 br s), 13. 59 (. 1 H, br s) IR (KB r): 3404, 1 6 97, 1 6 1 8, 1 589, 1 5 1 8 , 1344, 1325, 1294cm- ¹ .

赛 Example 36

 4Amino N— (1H—Pyrazo mouth “3.4—bl pyridine-1-yl”) Benzamide '1 / 57k

 Instead of 2-nitro-N- (1H-pyrazo [3,4-b] pyridine-14-yl) benzamide, 4-nitro-N- (1H-birazolo) obtained in Example 35 was used. [3, 4-b] Pyridine-1-yl) The production was carried out in the same manner as in Example 18 except that benzamide was used. Melting point> 280V

Elemental analysis: CuHnNg O ■ 1/5 H ₂₀

 C (%) H (%) N (%)

Calculated value: 60. 78 4. 47 27. 2 6

Measured value: 6 1.00 4.50 2 6.98

MS (EI): 253 (M ⁺ ). ¹ H-NMR (40 OMH z ₃ DMSO—d ₆ ) δ (ppm): 5.90 (2H, s), 6.63 (2H, d, J = 8.8H), 762 (1H, d, J = 4.9Hz), 7.75 ( 2 H ₅ d, J = 8.8 Hz), 8.34 (1 H, d, J = 5.3 Hz), 8.37 (1 H, s), 10.28 (1 H, br.s), 13. 43 (1 H, br. S). IR (KB r): 3391, 3298 3207, 1655, 1601, 1496 cm " ¹ .

 施 .in I 7

 2. 3-Dimethoxy-N- (1H-Pyrazo-mouth "3.4-bl pyridine-14-yl" benzamide

 The production was carried out in the same manner as in Example 2 except that 2,3-dimethoxybenzoic acid was used instead of 2-methylbenzoic acid. Melting point 229 ° C

Elementary analysis: as C ₁₅ H ₁₄ N ₄ 0 ₃

 C (%) H (%) N (%)

Calculated value: 60.40 4.73 18.78

Measured value: 60.33 4.98 18.96

MS (EI):. 298 ( M +) 1 H-NMR (40 OMH z, DMSO- d 6) δ (ppm): 3. 83 (3H, s), 3. 87 (3H, s), 7. 17-7. 26 (3H, m), 7.87 (1H, d, J = 5.3Hz), 8.36 (1H, s), 8.40 (1H, d, J = 5.3Hz) , 10.92 (1H, br.s) .13.57 (lH, br.s) .IR (KBr): 3029, 1688, 161 8, 1596, 1514, 1476, 1463, 1432, 1374, 1329 cm ".

Ma 施. 你 I 3 R

 3-Methyl-2_Nitro-N- (1H-Villary 'Mouth' 3.4-bl pyridine-1 ') Benzamide

 Production was carried out in the same manner as in Example 2 except that 3-methyl-2-nitrobenzoic acid was used instead of 2-methylbenzoic acid. Melting point> 270 ° C

Elemental analysis: C as HuNsOs C (%) H (%) N (%)

Calculated value: 5 6. 5 6 3. 73 23.5 6

Measured value: 5 6.50 3.94 23. 1 7

MS (EI): 297 (M ⁺ ). NMR (400 MHz, DMS 0-d ₆ ) δ (ppm): 2.40 (3H, s), 7.68-7.74 (3 H, m), 7.79-7.81 (1H, m), 8.35 (1H, s), 8.42 (1H, d, J = 5.3Hz), 11.33 (1H , br.s), 13.60 (1H, br.s) .IR (KBr): 2987, 1695, 1624, 1590, 1509, 1462, 142, 0, 1382, 1333 cm ^-1 .

2.4-Dimethoxy N- (1H-villa, Noro “3.4-bl pyridine-14-yl”) benzamide 1/10

 Production was carried out in the same manner as in Example 2 except that 2,4-dimethoxybenzoic acid was used instead of 2-methylbenzoic acid. Melting point 2 64-2 66 ° C

Elemental analysis: C ₁₅ H ₁₄ N ₄ 0 ₃ '1/1 0 Η ₂ Ο

 C (%) H (%) N (%)

Calculated value: 60.08 4.77 1 8.67

Measured value: 60. 1 7 4. 5 9 1 8. 43

MS (FAB): 299 (M ⁺⁺ 1). NMR (400 MHz, DMS 0-d ₆ ) δ (ppm): 3.86 (3 H, s), 4.03 (3 H, s) ), 6.71 (1 H, dd, J = l. 9 and 8.8 Hz), 6.77 (1 H ₃ d, J = 25 Hz), 7.82 (1 H, d , J = 8.3 Hz), 7.90 (1 H, d, J = 49 Hz), 8.29 (1 H, s), 8.39 (1 H, d, J = IR (KB r): 333 1, 1 6 78, 1 5 97 (4.9 Hz), 10.55 (1 H, br.s), 13.58 (1 H, br.s) , 1 539, 1 5 14, 1 25 5 cm ' ^1. ^^ 14 Q

2. 4-difluoro-N— (1H—pyrazo-opening “3.4-bl pyridine 1-4 Le) Benzamide · 1 / 27k

 The production was carried out in the same manner as in Example 2 except that 2,4-difluorobenzoic acid was used instead of 2-monobenzoic acid. Melting point 239 _ 24 1 ° C

Elemental analysis: C ₁₃ H ₈ F ₂ Ν ₄₀ · 1/2 H ₂₀

 C (%) H (%) N (%)

Calculated value: 5 5.1 3 3.20 1 9.78

Measured value: 5 5.36 3.39 1 9.68

MS (FAB):. 27 5 (M + + 1) 1 H-NMR (400 MH z, DMS 0- d 6) δ (ppm): 7. 28 (1 H, dd, J = 8. 3 and 8 7 H z) 7.48 (1 H, dd ₅ J = 8.2 and 9.3 H z), 7.79 (1 H ₅ d, J = 5.4 H z), 7.84 (1 H , dd, J = 6. 9 and 8. 3 H z), 8. 36 (1 H, s), 8. 42 (1 H 5 d, J = 5 4H z), 1 1. 04 (1 H, s), 13.59 (1H, br.s). IR (KBr): 3433, 1695, 1674, 1595, 1510 cm— ¹ .

Dazai. Ex. 4 1

 2-nitro-41-trifluoromethyl-N-pyrazo mouth “3.4-bl pyridin—4-yl) benzamide · 3/10

Production was carried out in the same manner as in Example 2, except that 2-nitro-4-trifluoromethylbenzoic acid was used instead of 2-methylbenzoic acid. Melting point 270 ° C Elemental analysis: as C ₁₄ H ₈ F ₃ N ₅ 0 ₃ '3/10 H ₂ O

 C (%) H (%) N (%)

Calculated value: 47.14 2.43 19.5 3

Measured value: 47.36 2.83 19.1 5

MS (EI): 352 (M ⁺ ). ¹ H-NMR (40 OMH z DMS 0-d ₆ ) δ (ppm): 7.80 (1 H, d, J = 5.3 Hz), 8 14 (1H, d, J = 5.3Hz), 8.28 (1H, s), 8.36 (1H, d, J = 5.3Hz), 8.46 (1H, d, J = 5.3 Hz), 8.59 (1 H, s), 1 1. 34 (1H, br.s), 13.65 (1H, br.s) .I (KBr): 3049, 1674, 1618, 1544, 1511, 1432, 1407, 1358, 1323, 1265, 1249 cm- ¹ .

 WM42

 2. 4-bis (trifluoromethyl) -N- (1-birazolo “3.4-bl pyridin-1-yl”) benzamide

The production was carried out in the same manner as in Example 2 except that 2,4-bis (trifluoromethyl) benzoic acid was used instead of 2-methylbenzoic acid. Melting point> 270 ° C Elemental analysis: C ₁₅ H ₈ F ₆ N ₄ 〇

 C () H (%) N (%)

Calculated value: 48. 14 2. 1 5 14. 97

Measured value: 48. 2 1 2. 53 14. 89

MS (FAB): 374 (M + + 1). ¹ H-NMR (40 ΟΜΗζ, DMS 0- d ₆ ) δ (ppm): 7.8 1 (1 H, d, J = 5.3 Hz), 8.10 (1 H, d, J = 7.8 Hz), 8.10 (1 H, d, J = 7.8 Hz), 8.26-8.3 1 (2 H, m), 8.45 (1H, d, J = 5.3Hz), 11.32 (1Hbr.s), 13.64 (1H, br.s) .I (KBr ): 332 5, 1 684, 1 62 0, 1 5 9 3, 1 5 1 2, 1 327, 1 1 32 cm- ¹ .

Kushie, ex. 43

 2-Methoxy-1-N-methylthio-1N- (1H-Pyrazo-mouth 3.4-bl pyridine

—4-bill) Benzamide 1 z 5 f t n

The production was carried out in the same manner as in Example 2 except that 2-methoxy-4-methylthiobenzoic acid was used instead of 2-methylbenzoic acid. Melting point 2 60— 2 62 ° C Elemental analysis: C ₁₅ H ₁₄ N ₄ 0 ₂ S · 1/5 H ₂ 0

 C (%) H (%) N (%)

Calculated value: 5 6.60 4.5 6 1 7.62

Measured value: 57.12 4.64 16.9 9 9 MS (EI): 31 (M ⁺ ). ¹ H-NMR (40 OMHz, DMS 0-d ₆ ) δ (ppm): 2.56 (3H, s), 4.01 (3 H, s ), 6.99 (1 Hd, J = 8.3Hz), 7.06 (1H, s), 7.72 (1H, d, J = 7.8Hz), 7.89 (1H , d, J = 5. 4Hz) , 8. 31 (1 H 5 s), 8. 39 (1 H, d, J = 5. 4Hz) 3 10. 62 (1 H, br. s), 13. Five

8 (1 H, b r.s) .IR (KBr): 3335, 1670, 1620, 15

93, 1331, 1294, 1277 cm " ¹ .

5-Methyl-1-nitro_N— (1H—Pyrazo mouth “3.4—bl Pyridine-1-yl” benzamide

 The production was carried out in the same manner as in Example 2 except that 5-methyl-2-nittobenzoic acid was used instead of 2-methylbenzoic acid. Melting point> 270 ° C

Elemental analysis: C H NS OS

 C () H (%) N (%)

Calculated value: 56. 56 3. 73 23. 56

Measured value: 56. 68 4. 06 23. 55

MS (EI): 297 (M +). ¹ H-NMR (40 OMHz, DMS Od ₆ ) δ (ppm): 2.49 (3H, s), 7.6 1 (1H, d, J = 5) .3 Hz) 7.67 (1 H, s), 7.80 (1 H, d, J = 5.3 Hz), 8.14 (1 H, d, J = 5.3 Hz), 8 32 (1H, s), 8.44 (1H, d, J = 53Hz), 11.23 (1H, br.s), 13.59 (1H, br.s). IR (KB r): 2982, 169 1, 1590, 1523, 1463, 1436 1265 cm- ¹ .

Example 45

 N-M H-Pyrazo mouth “3.4-bl Pyridine 1-41) Penzamide

5-methyl-2-benzobenzoic acid was used instead of 2-methylbenzoic acid. Except for, the production was carried out in the same manner as in Example 2. Melting point> 270 ° C

Elementary analysis: as _{C 13 H 8 C 1N 5 0} 3

 C (%) H (%) N (%)

Calculated value: 49. 1 5 2. 54 22. 04

Measured value: 48. 92 2. 88 2 1. 7 1

MS (EI): 3 18 (M ⁺ ). ¹ H-NMR (40 OMHz: DMSO-d ₆ ) δ (ppm): 7.78 (1 H, d, J = 5.3 Hz), 7 89 -7. 91 (lH, m), 8.07 (1H, d, J = 5.3Hz), 826 (1H, s)

8.29 (1H, d, J = 5.3Hz), 8.44 (1H, d, J = 5.3Hz) 11.29 (1H, br.s), 1 3.62 (1 H, br. S). IR (KB r): 3059, 1709, 1692, 1626, 1607, 1589, 1569, 1527, 15 1 0, 146 9, 14 1 8, 1 390, 1345 cm ' ¹ .

 9.--Difluoro-N- (1H-villa, black "3.4-bl pi 1) jin 4- 4-yl) benzamide 1 / 107k

 Production was carried out in the same manner as in Example 2 except that 2,6-difluorobenzoic acid was used instead of 2-methylbenzoic acid. 275—276 ° C

Elementary analysis: as _{C i3 H 8 F 2 N 4} 0 · 1/1 0H 2 O

 C (%) H (%) N (%)

Calculated value: 5 6.57 2. 9 9 20. 30

Measured value: 5 6.37 3.22 1 9.93

MS (FAB): 275 (M ⁺ + 1). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.28-7.32 (2 H, m), 7.65 (1 H, d, J = 5.4 Hz), 7.86 (1 H ₃ d, J = 4.9 Hz), 8.35 (1 H, s), 8.45 (1 H, d , J = 5.4Hz), 1 1.42 (1H, br.s) 13.65 (1H, br.s) .IR (KBr): 3296, 1701, 162 6, 1 54, 1 336, 130 5 cm— ¹ . Example 47 '

 N— (1 H—billa, noro “3- 4-bl pyridine-1-4-yl) 1 1 1-naphthylene power Lupoxami · 1 / B7k n i

 Produced in the same manner as in Example 2, except that 1-naphthylene carboxylic acid was used instead of 2-methylbenzoic acid. 266- 269 ° C

Elemental analysis: C ₁₇ H ₁₂ N ₄₀ · 1 / 5H ₂ 〇

 C (%) H (%) N (%)

Calculated value: 69.94 4.28 19.19

Measured value: 70.27 4.36 19.67

MS (EI): 288 (M ⁺ ). ¹ H-NMR (40 OMHz, DMS 0-d ₆ ) 6 (ppm): 7.59-7.67 (3H, m), 7.86 (1H , D, J = 63 Hz), 7.91 (1 H, d, J = 5.3 Hz), 8.04-8.19 (3H _: m), 8.42 (1 5 Hz), 8.44 (1 H, d, J = 4.8 Hz), 11.2 1 (1 H, br.s), 13.56 (1 H ₃ br. s) .IR (K Br): 3 1 15, 1660, 1622, 159 1, 15 16, 1329 cm- ¹ , Example 48

 N— (ITT—Pyrazo mouth “3. 4-bl pyridine-14-yl”) 1—2-pyridinecarboxamide

 Production was carried out in the same manner as in Example 2 except that 2-pyridinecarboxylic acid was used instead of 2-methylbenzoic acid. 245-246 ° C

Elementary analysis: as C ₁₂ H ₉ N ₅ 0

 C (%) H (%) N (%)

Calculated value: 60. 25 3. 79 29. 27

Measured value: 60. 30 3. 74 29. 27

MS (EI): 239 (M ⁺ ). ^ -NMR (40 OMHz, DMS 0-d ₆ ) δ (ppm): 7.76-7.78 (2H, m), 8.12 (1H, dd) , J = 7.3 and 7.3 Hz) ₅ 8.22 (1 H ₃ d, J = 7.3 Hz), 8. 38 (1 H, s), 8.44 (1 H, d, J = 5.4 Hz), 8.8 1 (1 H, d, J = 5.4 Hz), 1 1.09 ( IR (KBr): 305 1, 17 11, 1 6 1 7, 1 5 94, 1 5 09, 1467, 1 H, br. S), 1 3.60 (1 H, br. S). 1438, 1327, 1 2 94 cm- ¹ .

Example 49

 N- (1 H—villa, b “3.4-bl pyridine-14-yl”) 1-3-pyridinecarboxamide '

 Produced in the same manner as in Example 2, except that 3-pyridinecarboxylic acid was used instead of 2-methylbenzoic acid. 273- 276 ° C

Elementary analysis: as C ₁₂ H ₉ N ₅ 0

 C (%) H () N ()

Calculated value: 6 0.2 5 3. 79 2 9. 27

Measured value: 60. 1 8 3.5 5 2 9. 1 7

. MS (EI): 2 39 (M +) 1 H-NMR (40 OMH z, DMSO- d 6) δ (ppm): 7. 5 9 - 7. 6 2 (l H, m), 7. 72 ( 1 H, d, J = 5, 3 Hz), 8.33 (1 H, d, J = l. 8 Hz), 8.40 (1 H, s), 8, 42 (1 H, d , J = 5.4 Hz), 8.8 1 (1 H, dd, J = l. 0 and 4.4 Hz), 9.14 (1 H, d, J = 2.5 Hz) ₅ 1 1.01 (1H _: br.s), 13.56 (1H, br.s) .IR (KBr): 1699, 1624, 1593, 154, 148 1, 1 329 cm ' ¹ .

Case B 0

 2-Methylthio-1-N— (1H—villa, noro “3.4-bl pyridine-14-yl”)-

3-pyridinecarboxamide

Production was carried out in the same manner as in Example 2 except that 2-methylthio-3-pyridinecarboxylic acid was used instead of 2-methylbenzoic acid. Melting point 236— 23 9 ° C Elemental analysis: C ₁₃ H _{1 ()} N ₅ OS · 1/2 H ₂₀

C () H (%) N (%) Calculated value: 53. 05 4. 1 1 23. 79

Obtained value: 53. 32 4.2 1 23. 50

MS (EI): 285 (M ⁺ ). ¹ H-NMR (400 MHz, DMSO-d ₆ ) (5 (pm): 2.48 (3H ₃ s), 7.30 (1H, dd ₃ J = 4. 8 and 7.8Hz), 7.76 (1H, d, J = 5.4Hz), 7.99 (1Hd, J = l.4Hz), 8.36 (1H, s) , 8.43 (1H, d, J = 4.9 Hz), 8.63 (IE, d, J = 4.9Hz), 11.07 (1H, br.s), 13.57 (1 H, br .s) .IR (KB r): 3036, 1689,

1591, 1388, 1325, 1298, 1282 cm- ¹ .

Case 5 1

 2. 6-Dimethoxy N- (1H-Pyrazo Mouth "3. 4-bl Pyridine 1-4-yl) 1-3-Biridinecarboxamide 1/5

Produced in the same manner as in Example 2 except that 2,6-dimethoxy-13-pyridinecarboxylic acid was used instead of 2-methylbenzoic acid. Melting point> 260 ° C Elemental analysis: C ₁₄ H ₁₃ N ₅ 0 ₃ '1/5 H ₂ 0

 C (%) H (%) N (%)

Calculated value: 55. 52 4. 46 23. 12

Found: 55. 73 4. 39 23. 07

MS (EI): 299 (M +). ¹ H-NMR (40 OMHz, DMS〇_d ₆ ) 6 (ppm): 3.97 (3 H, s), 4.12 (3 H, s), 6.58 (1 Hd, J = 8.2 Hz), 7.88 (1 H, d, J = 4.9 Hz), 8.16 (1 H, d, J = 8.3 Hz), 8.30 (1H, s), 8.40 (1H, d, J = 5.3Hz), 10.50 (1H, br.s), 13.61 (1H, br.s) .IR ( KB r): 3109, 169 1, 1595, 1 535, 1485, 132 9, 1298 cm- ¹ .

卖 Example 52

N— (1 H—Pyrazo Mouth “3. 4-bl pyridine-14-yl”) 1-4-pyridinecal Boxamido '

 Produced in the same manner as in Example 2 except that 4-pyridinecarboxylic acid was used instead of 2-methylbenzoic acid. Melting point> 280 ° C

Elementary analysis: as C ₁₂ H ₉ N ₅ 0

 C (%) H (%) N (%)

Calculated value: 60. 25 3. 79 29. 27

Measured value: 60.25 3.56 29.39

MS (EI): 239 (M ⁺ ). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.72 (1 H, d, J = 5.4 Hz), 7.89 (2 H, d, J = 5. 4Hz), 8. 39 (1 H 3 s), 8. 44 (1H, d, J = 5. 4H z), 8. 83 (2 H, d, J = 5. 4Hz) 11. 05 (1 H, br. s), 13. 60 (1 H 5 br. s). IR (KB r) 3134, 1701, 1593 1438, 1325, 1274cm-荬施example 53

 N- (1H-pyrazo-mouth "3,4-bl pyridine-14-yl" -1-3-furancarboxamide

 Produced in the same manner as in Example 2, except that 3-furancarboxylic acid was used instead of 2-methylbenzoic acid. Melting point 242 ° C

Elemental analysis value:

As

 C (%) H (%) N (%)

Calculated value: 57. 89 3.53 24. 55

Found: 57. 91 3. 73 24. 52

MS (EI): 228 (M +). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.05 (1H, s), 7.61 (1H, d, J = 5.4 H z) 7.85 (1H, s), 8.37 (1H, s), 8.40 (1H, d, J = 5.4Hz), 8.54 (1H, s), 10.43- 10.44 (1H, br.s) 13.52-13.54 (1H, br.s) .IR (KBr): 3068, 16 94, 1625, 1602, 1573, 1512, 1416, 1377 cm- ¹ .

 2-Methyl-N- (1H-pyrazo-mouth 3.4-bl pyridine-41-yl) -3 -furancarboxamide

 Produced in the same manner as in Example 2 except that 2-methyl-3-furancarboxylic acid was used instead of 2-methylbenzoic acid. Melting point 2 26-22 8 ° C

Elemental analysis: C ₁₂ H _{1 ()} N ₄ 0 ₂ '1/2 H ₂ 0

 C (%) H (%) N (%)

Calculated value: 58. 4 1 4. 2 9 2 2. 70

Measured value: 5 8.70 4.43 2 2.50

MS (EI): 242 (M +). ¹ H-NMR (400 MHz, DMSO-d ₆ ) ό (ρ pm): 2.52 (3 Η, s), 7.12 (1 Η, d, J = 2.0 Hz) 7.60 (1 H, d, J = 5.4 Hz), 7.66 (1 H, d, J = 1.9 Hz), 7.34 (1 H, d, J = 1.5 Hz), 7.37 (1H, d, J = 5.3 Hz), 10.25 (1H, br.s), 13.51 (1H, br s). IR (KB r): 3121, 1648, 1625, 1600, 1536, 1514, 1328, 1303 cm— ¹ .

Skewer case 5 5

 2,5-Dimethyl-N- († H-Pyrazo Mouth “3. 4-bl Pyridine 1-4-yl) _ 3-furancarpoxamide

Production was carried out in the same manner as in Example 2 except that 2,5-dimethyl-3-furancarboxylic acid was used instead of 2-methylbenzoic acid. Melting point 1 82— 186 ° C Elemental analysis: C ₁₃ H ₁₂ N ₄ 0 ₂ '1Z2 H ₂ 0

 C (%) H (%) N (%)

Calculated value: 58.86 4.94 2 1.12

Measured value: 58.40 5.06 2 1.07

MS (EI): 256 (M ⁺ ). ¹ H-NMR (40 OMHz, DMSO-d ₆ ) δ (pm): 2.26 (3 H, s), 2.56 (3 H, s), 6.71 (1 H: s), 7.60 (1 H, d, J = 5.4 Hz) , 8.34 (1H, s), 8.36 (1H, d, J = 5.4Hz), 10.14 (1H, br.s), 13.40 (1H, br.s) .) IR (KB r): 3487, 3265, 1693, 167 2, 1 575, 1508, 1327 cm "1.

Example 56

 N- (1 H—Pyrazo Mouth “3. 4-hl Pyridine 1-4 4-yl) 1 3-Thophene Force Lupoxamide”

 Produced in the same manner as in Example 2, except that 3-thiophenecarboxylic acid was used instead of 2-methylbenzoic acid. 235 ° C

Elemental analysis: C HBNAO S

 C (%) H (%) N (%)

Calculated value: 54.09 3.30 22.94

Found: 53. 99 3.49 22. 62

MS (EI): 244 (M ⁺ ). ¹ H-NMR (40 OMH z, DMS 0-d ₆ ) δ (ppm): 7.63-7.7 1 (3H, m), 8.39-8 41 (2 H, m), 8.50 (1 H, s), 10.57 (1 H, br.s), 13.53 (1 H, br.s) .IR (KB r): 3054 , 2974, 169 1, 1622, 1598, 1536, 1506, 1410, 1379, 1328 cm- ¹ .

 Example 7

 2-Bromo-5-methyl-1-N— (1 TT—villa, noro “3.4-bl pyridine_4-yl”) — 3-thiophenecarboxamide

Production was carried out in the same manner as in Example 2 except that 2-bromo-5-methyl-3-thiophenecarboxylic acid was used instead of 2-methylbenzoic acid. Melting point> 280 ° C MS (EI): 336 (M ⁺ ). ¹ H-NMR (40 OMH z, DMS 0-d ₆ ) δ (ppm): 2.46 (3 H, s), 7.13 ( 1 H, s), 7.73 (1 H d, J = 5.4 Hz), 8.39 (1 H, s), 8.40 (1 H, d, J = 5.4 Hz), 10.82 (1H, br.s), 13.55 (1H, br.s) .IR (KBr): 3373, 1693, 1595, 1533, 1 5 14, 1 33 1 cm- ¹ .

卖 Example 58

 5-Methyl-N- (1H-pyrazo-mouth "3. 4-hl-pyridine-4-yl-4-isoxazole-carboxami"

 Production was carried out in the same manner as in Example 2 except that 5-methyl-14-isoxazolecarboxylic acid was used instead of 2-methylbenzoic acid. Melting point 22 1-225 ° C Elemental analysis: Cu HgNsOa

 C (%) H (%) N (%)

Calculated value: 54. 32 3. '73 28. 79

Measured value: 54. 1 5 3. 97 28. 60

MS (EI): 243 (M ⁺ ). ¹ H-NMR (40 OMH z ₅ DMSO— d ₆ ) δ (ppm): 2.71 (3 H, s), 7.63 (1 H, d, J = 4.8 Hz) 8.35 (1 H, s), 8.4 1 (1 H, d, J = 4, 9 Hz), 9.15 (1 H, s), 1 0.55 (1H, br.s), 13.57 (1H, br.s) .IR (KBr): 3 11 7, 16 9 9, 16 24, 15 9 1 , 1 5 10, 13 27 1 242 cm " ¹ .

荬 Example 5 9

 2,3-Dihydro N-MH-Pyrazo Mouth "3.4-bl pyridine-14-yl) 1-benzo" bl Furan-7-carboxamide

 Production was carried out in the same manner as in Example 2 except that 2,3-dihydrobenzo [b] furan-17-force rubonic acid was used instead of 2-methylbenzoic acid. Melting point> 270 ° C

Elementary analysis: as C ₁₅ H ₁₂ N ₄ 0 ₂

 C () H (%) N (%)

Calculated value: 64.28 4.32 1 9.99 Measured value: 64.02 4.44 1 9.79

MS (EI):. 2 80 (M +) 1 H-NMR (40 OMH z, DMS 0-d 6) δ (ppm): 3. 33 (2 H, t 3 J = 8. 8 H z), 4. 8 6 (2 H, t , J = 8. 8Hz), 7. 03 (l H, t, J = 7. 3 H z), 7. 5 1 (1 H, d 5 J = 7. 3H z), 7.67 (1H, d, J = 7.3Hz), 7.89 (1H, d, J = 5.4Hz), 8.21 (lH, s), 84 1 (1 H, d, J = 5.4 Hz), 10.39 (l H, b r.s), 13.63 (l H ₅ b r.s) .IR (KB r): 3 1 20, 1689, 1595, 1546, 1517, 1437 1416 cm " ¹ .

Yu I fi 0

 5-dichloro 2.3-dihi: dro 2-methyl-N— (1H-villa, black “3.4-bl pyridine-14-yl” 1-benzo- ”bl-furan-1 7-carboxamide

 Production was carried out in the same manner as in Example 2, except that 5-chloro-2,3-dihydro-2-methyl-benzo [b] furan-17-carboxylic acid was used instead of 2-methylbenzoic acid. Melting point> 270 ° C

Elementary analysis: as C ₁₆ H ₁₃ C1N ₄ 0 ₂

 C (%) H () N (%)

Calculated value: 5 8. 45 3. 9 9 17. 04

Measured value: 5 8. 05 4. 07 1 7. 00

MS (EI): 329 (M +). ¹ H-NMR (40 OMH z DMS 0-d ₆ ) δ (ppm): 1.54 (3 H, d, J = 5.9 Hz), 3. 42-3.49 (2 H, m), 5.27-5.30 (lH, m), 7.54 (1 H, s), 7.61 (1 H, s), 7.87 (1H, d, J = 5.3Hz), 8.21 (1H, s), 8.43 (1H, d, J = 5.3Hz), 10.0.39 (1 H, br.s) 13.65 (1H, br.s) .IR (KB r): 2976, 1690, 1626, 1592, 1545, 1514, 1446, 1 385 cm- ¹ .

Example 6 1 6—Black mouth 3.4—Dihydro N— N. H—Pyrazo mouth “3.4—b Pyridine-1—4-yl) -2H—1.4—Ben, zo'oxazine-1 8—Carboxami · 1 / 4 f k Japanese

6-chloro-1,4-dihydro-1H-2,1,4-pentoxoxazine-18-carbonic acid (1.0 g), 4-aminobiazolo [3,4-b] pyridine (1.0 g) and triethylamine ( To a solution of 1.1 g) in DMF (2 OmL) was added cyanide getylphosphate (1. Og), and the mixture was stirred for 1 hour and left at room temperature for 24 hours. The resulting solution was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with ethyl acetate to give the title compound (110. Omg) as pale-yellow crystals. Melting point> 270 ° C Elemental analysis: C ₁₅ H ₁₂ C1N ₅ 0 ₂ · 1 / 4H ₂ 0

 C (%) H () N (%)

Calculated value: 53.90 3.77 20.95

Measured value: 53.84 3.72 20.67

MS (EI): 329 (M ⁺ ). ¹ H-NMR (40 OMH z, DMS 0-d ₆ ) δ (p pm): 3.62 (2 H, br .t), 4.31 (2 H t), 645 (1H, s), 6.75 (1H, d, J = 2.5 Hz) ₃ 6.82 (1H, d: J = 2.5 Hz), 7. _{85 (1 H 3 d, J} = 4. 5 H z), 8. 34 (1 H, s): 8. 39 (1H, d, J = 5. 4Hz), 10. 74 (1 H, br. .. s), 13. 5 3 (1 H 3 br s) IR (KB r): 3298, 1684, 1622, 159 3, 1520 cm "1.

赛 Example β 2

 6-chloro-one 3.4-dihydro-2.2-dimethyl-1- (1Η-pyrazo-mouth [34-blpyridine-14-yl) -1 2H—] .4-ben, couoxazine-18-carbo Kisamide 1 / 47t Japanese

6-Chloro-3,4-dihydro-2H-1,4-benzoxazine-18 instead of 8-carboxylic acid 6-chloro-1,4-dihydro-1,2,2-dimethyl-1 2H-1 Produced in the same manner as in Example 61, except that 4-benzoxazine-18-carboxylic acid was used. Melting point> 280 ° C

Elemental analysis: C ₁₇ H ₁₆ N ₅ 0 ₂ C1 · 1 / 4H ₂₀

 C () H (%) N (%)

Calculated value: 56.51 4.32 19.38

Measured value: 56.56 4.77 18.99

MS (EI):. 357 ( M + + 1) 1 H-NMR (40 OMH z DMS Od 6) δ (ppm): 1. 33 (6 H, s), 3. 12 (2 H, s) 6 56 (1H, br .s), 6.80 (1H, d, J = 2.9Hz), 6.92 (1Hs), 7.88 (1H, d, J = 5.4Hz), _{8. 28 (1 H 5 s)} , 8. 41 (1H, d, J = 4. 8Hz), 10. 57 (1 H, br. s), 13. 62 (1 H br. s). IR ( KBr): 3358, 1665, 1620, 1590, 15 40, 1512, 1312 cm " ¹ .

卖 Example 63

 6—Black mouth 3. 4-Dihydro-1-methyl-N— —Pillar mouth Γ3.4—bl Pyridine-1-4yl)-2 H-1..4 Benzoxazine-1 8-Carboxy iJi

 6-Chloro-3,4-dihydro-1H- 1,4-benzoxazine-18-Carbonic acid instead of 6-chloro-1,3,4-dihydro-14-methyl-1H-1,4-benzobenzoxazine Produced in the same manner as in Example 61, except that 8-carboxylic acid was used. Melting point> 270 ° C

Elemental analysis: as C ₁₆ H ₁₄ N ₅ 0 ₂ C 1

 C (%) H (%) N (%)

Calculated value: 55. 90 4. 10 20. 37

Measured value: 55. 30 4. 20 20. 61

MS (EI): 343 (M ⁺ ). ¹ H-NMR (400 MHz, DMS 0-d ₆ ) δ (ppm): 2.91 (3H, s), 3.35 (2H, t, J = 4 .4H z) 4.38 (2H, br.t), 6.84 (1H, d, J = 2.5 Hz), 6.87 (1H, s), 7.85 (1H, d, J = 5. 4Hz), 8.36 (1H, s), 8.39 (1H, d, J = 5.4Hz), 10.75 (1H, br.s), 13.57 (IE, br.s ) .IR (KBr): 3325, 1684, 1620, 159 1, 1539, 1516, 1263 cm- ¹ .

rn m β A

fi-black mouth 3.4-dihydro, mouth 2.4-dityl N-(1 ττ-pyrazo mouth "3 4-bl pyridine 1-4 -yl)-2 H-1.4-benzoxazine-8 —Carbo Kisamide '

 6-chloro-1,3,4-dihydro-2H-1,4-benzobenzoxazine-18 instead of carboxylic acid 6_chloro-1,3,4-dihydro-1,2,4-dimethyl-2H-14,4-pentozoxazine-8 _ Manufacture was carried out in the same manner as in Example 61 except that rubric acid was used. Melting point> 260 ° C

Elementary analysis: as _{C 17 H 16 N 5 0 2} C1

 C (%) H (%) N (%)

Calculated: 57. 07 4. 51 19. 57

Measured value: 57.52 4.68 19.65

MS (EI): 357 (M ⁺ ). ¹ H-NMR (40 OMH z DMS 0-d ₆ ) ((p pm): 1.29 (3 H, d, J = 8.0 Hz), 2 86 (3H, s) 3.03 (1H, m), 3.41 (1H, m), 4.47 (1H, br.s),

6.85 (1H, d, J = 4.0Hz), 6.91 (1H, d, J = 4.0Hz)

7.88 (1H, d, J = 8.0Hz), 8.35 (1H, s), 8.40 (1H, d, J = 8. OHz), 10.66 (1H, br.s) , 13.59 (1 Hbr.s). IR (KBr): 3317, 1678, 1591, 1512, 1329 cm— ¹ .

 rn 65

6-Black mouth _4— (4-Black mouth benzyl) 1,3,4-Dihydro-1N— (1 H-pi Lazolo "3.4-b pyridine-1 4-yl) 1 2H-1.4-benzoxazine--8-carboxamide '1 / 27k

 6-Black 3,4-dihydro-1 2 H-1,4-Penoxoxazine-18-Carbonic acid 6-Black 4- (4-pentyl) 1,3-Dihydro-2 Production was carried out in the same manner as in Example 61 except that H-1,4-pentoxazine-18-carboxylic acid was used. 250 ° C

Elementary analysis: as _{C 22 H 17 C1 2 N 5} 0 2 · 1/2 H 2 0

 C (%) H (%) N (%)

Calculated value: 57. 63 3. 9 1 15. 12

Measured value: 57.40 3.94 15.24

¹ H-NMR (400 MHz, DMS 0-d ₆ ) 6 (ppm): 3.52 (2 H, s), 4.39 (2 H, s), 4.59 (2 H, s), 6. 77 (1H, s), 6.83 (1H, s), 7.34 (2H, d, J = 8.3Hz), 7.44 (2H, d, J = 8.3Hz) , 7. 85 (l H, m ), 8. 37 (1 H, s), 8 40 (1 H 5 d, J = 5. 4Hz), 10. 79 (1 H, br. s), 13. Five

7 (1 H ₃ br. S). IR (KB r): 3333, 1685, 15 16, 14

89, 1263 cm- ¹ .

荬 Example 66

 6-Promo 3.4-Dihydro-1-methyl-N- (1H-pyrazo, mouth "3,4-b" 1 pyridine-4-yl) 1-2H-1.4-ben, zooxazine-18-carboxa JJ1

 6-Chloro-3,4-dihydro-1 2H-1, 4_benzoxazine-18-Carbonic acid instead of 6-promo-3,4-dihydro-14-methyl-1 2H-1, 4-benzobenzoxazine-1 The production was carried out in the same manner as in Example 61, except that carboxylic acid was used.

U MR (400MHz, DMSO-d 6) δ (ppm): 2. 49 (3H, s), 2. 9 1 (2H, s), 4. 38 (2 H, s), 6. 89 (1 H , s), 6. 99 (1H, s), 7. 85 (1 H 3 d, J = 4. 9Hz), 8. 36 (1 H, s), 8. 40 (1H, d, J = 5. 4Hz), 10.75 (1H, br.s), 13.57 (1H, br.s).

rn m 67 '

 3,4-dihydro-1-6-methoxy-4-N- (1H-pyrazo-mouth "3.4-b, pyridine-4-yl")-2H-1.4-benzobenzoxazine-18-carboxy Samid

 6-Chloro-3,4-dihydro-1 2H-1, 4-benzoxazine-1 Instead of 8-carboxylic acid 3,4 dihydro-6-methoxy-1 4-methyl-1H- 1,4 1-benzoxazine Except for using 8-carboxylic acid, it was produced in the same manner as in Example 61. Melting point> 260 ° C

Elementary analysis: as C ₁₇ H ₁₇ N ₅ 0 ₃

 C (%) H (%) N (%)

Calculated value: 60. 12 5. 05 20. 64

Measured value: 59. 82 5. 03 20. 31

MS (EI):. 339 ( M +) 1 H-NMR (40 OMH z, DMSO- d 6) δ (ppm): 2. 89 (3H, s), 3. 32 (. 2 H, br t), 3.72 (3Η, s), .38 (2H, br.t), 6.42 (1H, d, J = 2.9 Hz), 6.52 (1H, d, J = 2.9H) z), 7. 88 (1 H , d, J = 5 4Hz), 8. 34 (1H, s), 8. 39 (1H, d, J = 5. 3Hz), 10. 72 (1 H 3 br ... s), 13. 57 (1 H 5 br s) IR (KBr): 331 7, 1680, 1595, 1543, 1518, 1379, 1332, 1273 cm "1.

卖 Example 68

3. 4-dihydro-1-methyl-6-methylthio-1-N- (1H-birazolo "3.4-bl pyridine-1-yl") -2H-1.4-ben, zooxazine-18-carboxami Do 6-Chloro-3,4-dihydro-1-H- 1,4-benzoxazine-18-carboxylic acid instead of 3,4-dihydro-4-methyl-6-methylthio-2H-1,4-benzoxazine-18-carboxyl Except that an acid was used, it was produced in the same manner as in Example 61. Melting point 2 63-2 65 ° C

Elementary analysis: as _{C 17 H 17 N 5 0 2} S

 C (%) H (%) N (%)

Calculated value: 57. 45 4. 82 1 8. 70

Measured value: 57. 5 6 4. 88 1 8. 93

MS (EI): 355 (M +). ¹ H-NMR (40 OMH z, DMSO—d ₆ ) δ (ppm): 2.49 (3 H, s), 2.90 (3 H, s), 3 32 (2 H m), 4.38 (2 H, m), 6.75 (1 H, s), 6.82 (1 H, d, J = 2.5 Hz), 7.87 (1H, d, J = 4.8Hz), 8.36 (1H, s) 8.38 (1H, d, J = 4.9Hz), 10.72 (1H, br) s), 1359 (1H, br.s) .IR (KBr): 3321, 1680, 1591, 1541, 1332, 1269 cm- ¹ .

Example 69

 6-chloro-1-3.4-dihydro-1-methyl-1-3-oxo-1-N- (1TT-pyrazo-mouth "3,4-blpyridine-14-yl) -2H-1.4-ben; Zoxazine-1 8 Carboxami K · 17k D ^ l

 6-chloro-3,4-dihydro-1 2H— 1,4-benzoxazine-18-carbonic acid instead of 6-chloro-1,3,4-dihydro-14-methyl-13-oxo-1 2H- Production was carried out in the same manner as in Example 61 except that 1,4-benzoxazine-18-carboxylic acid was used. Melting point> 270 ° C

Elemental analysis: C ₁₆ H ₁₂ C 1 N ₅ 0 ₃ · H ₂₀

 C (%) H (%) N (%)

Calculated value: 5 2.40 3.57 19.1 0

Measured value: 5 2. 7 1 3. 37 18. 6 9 MS (FAB): 358 (M ⁺ + 1). ¹ H-NMR (40 OMH z, DMSO-d ₆ ) δ (ppm): 3.3 1 (3H, s), 4.86 (2 H, s), 7.38 (1 H, d, J = l. 9 Hz) ₃ 7.45 (1 H, d, J = 2.0 Hz), 7.85 (1 H, d, J = 5 4Hz), 8.36 (1H, s), 8.41 (1H, dJ = 5.2Hz), 10.89 (1H, br.s), 13. 5 9 (1H, br.s) .IR (KB r): 3342, 3101, 1691, 1585, 1529,

1466, 1 37 1 cm " ¹ .

Transfusion 70

 2-Methoxy-N- (1-Methyl-1-H-pyrazo-mouth "3.4-bl pyridine-14-yl" benzamide

 2-Methoxy N- (1H-pyrazo [3,4-b] pyridin-141-yl) obtained in Example 7 benzamide (50 Omg) and potassium hydroxide-t-butoxide (6

To a solution of 27 mg) in DMF (18 ml) was added methyl iodide (1 g), and the mixture was stirred at room temperature for 2 hours. The resulting solution was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the precipitated crystals were washed with diisopropyl ether to obtain the title compound (23 mg) as white crystals. Melting point 17 6— 1 78 ° C

Elementary analysis: as C ₁₅ H ₁₄ N ₄ 0 ₂

 C (%) H (%) N (%)

Calculated value: 6 3.82 5.00 1 9.85

Measured value: 63.76 5.05 1 9.75

MS (EI) 282 (M ⁺ ). ¹ H-NMR (40 OMH z, DMS 0-d ₆ ) S (ppm) 3.93 (3 H, s), 4.03 (3 H, s), 7 . 1 0 (1 H dd, J = 7. 3 and 7. 8 H z), 7. 23 (1 H 5 d, J = 8. 3 H z), 7. 5 5 (l H, dd, J = 6.8 and 6.8 Hz), 7.69 (1 H, d, J = 7.8 Hz), 7.92 (1 H, d, J = 5.3 Hz), 8.35 (1 H, d, J = 5.4 Hz), 8.44 (1 H, d, J = 5.4 Hz), 10.77 (1H, br. S). IR (KB r): 3325, 1682, 16 1 4, 1537, 1336, 1302 cm " ¹ .

荬 Example Ί 1

 2-Methoxy-N- (1H-Pyrazo Mouth "3.4-dl Pyrimidine-1- 4-benzamide, 1/5

Except that 2-methoxybenzoic acid was used instead of 2-methylbenzoic acid, and 4-aminobirazolo [3,4-d] pyrimidine was used instead of 4-aminobirazolo [3,4-1b] pyridine It was manufactured in the same manner as in Example 2. Mp 259 ° C Elementary analysis: CuHuNsOz 'as 1Z5H ₂ 0

 C (%) H (%) N (%)

Calculated value: 57. 22 4. 2 1 25. 67

Measured value: 57. 04 4. 43 25. 68

MS (EI): 269 (M ⁺ ). ¹ H-NMR (40 OMHz, DMS 0-d ₆ ) δ (ppm): 3.99 (3H, s), 7.14 (lH, t, J = 7.3Hz), 7.27 (1H, d, J = 6.0Hz), 7.62 (lH, t, J = 7.3Hz) 7.92 (1H, d, J = 6.0Hz), 8.58 (1H, s), 8.64 (1H, s), 11.05 (1H, br.s), 13.96 (1H, br.s). IR (KB r): 1703, 1 59 9, 1503, 148 1, 1466, 1440 1286 cm- ¹ .

Example 72

 2-Methoxy N-M H-Pyro mouth “2.3-bl Pyridine 4-yl) Pen's amide

 .2 Use 2-methoxybenzoic acid instead of methylbenzoic acid and use 4-amino-1H-pyro [2,3-b] pyridine instead of 4-aminobiazolo [3,4-b] pyridine Except for using, was produced in the same manner as in Example 2. Melting point 25 2 ° C

Elementary analysis: as C ₁₅ H ₁₃ N ₃ 0 ₂ C (%) H (%) N (%)

Calculated value: 67.40 4.90 1 5.72

Measured value: 67.32 4.93 15.6 1

MS (EI): 267 (M ⁺ ). ¹ H-NMR (400 MHz, DMS 0-d ₆ ) δ (ppm): 4.02 (3 H, s), 6.64 (1 H, d , J = l. 4 Hz) 7.13 (lH, t, J = 7.3 Hz), 7.26 (1H, d, J = 8.3 Hz) 7.40 (1 H, t, J = 3.0Hz), 7.55-7.60 (1H, m), 7.85 (1H, dd, J = 1.4 and 7.3Hz), 7 97 (1H, d, J = 5.3Hz), 8.15 (1H, d, J = 5.3Hz), 10.43 (1H, br. S), 1 1.68 (1 H, br. S) .IR (KB r): 307 1, 300 6, 1 680, 1 6 1 3, 1 592, 1 538, 1 5 12, 1496, 1 53 8, 1 5 12, 149 6, 1482, 1 338 cm " ¹ .

Raw material synthesis example 1

 4-Azido:!, H-pyro mouth "2,3-bl pyridine"

 To a solution of 4-HCl-1H-pyrro [2,3-b] pyridin (16.0 g) in dimethylformamide (150 ml) obtained by the existing method was added sodium azide. (10.2 g) and ammonium chloride (8 · 40 g) were added, and the mixture was stirred at 100 ° C for 8 hours. The reaction solution was returned to room temperature, water (300 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain the desired 4-azido 1 H-pyro [2,3-b] pyridine 11.3 g was obtained as a brown solid.

— NMR (400 MHz, DMS 0-d ₆ ) δ: 6.45 (d, J = 3 Hz, 1 H), 6.88 (d, J = 5 Hz, 1 H), 7.45 ( d, J = 4Hz, 1H), 8.17 (d, J = 5Hz, lH), 1.85 (s,: Raw material platform example 2

 4-amino 1 — “2-ditrimethylsilyl) ethoxymethyl 1 — 1-pyromouth

"2.3-bl pyridine

 At 0 ° C, a solution of 4-azido 1H-pyro [2,3-b] pyridine (10.0 g) in dimethylformamide (75 ml) was added with diisopropylethylamine (16.

4 ml) and 2- (trimethylsilyl) ethoxymethyl chloride (12.6 g) were added, and the mixture was stirred at room temperature for 5 hours. Thereafter, water (300 ml) was added to the reaction solution, and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated saline. The solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off.

Thus, 18.2 g of a crude product of [2- (trimethylsilyl) ethoxymethyl] -1H-pyro [2,3-b] pyridine was obtained.

 The crude product of 4-azido-1- [2- (trimethylsilyl) ethoxymethyl] -1H-pyro [2,3-b] pyridine was converted to isopropyl alcohol (1

50 ml) and sodium borohydride (2.35 g) was added slowly at room temperature. After stirring the reaction solution at room temperature for 6 hours, water (200 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was purified by silica gel column chromatography, and recrystallized from ethyl acetate-hexane to give the desired 4-amino-1- [2- (trimethylsilyl) ethoxymethyl] 1-1H— Pillow mouth

[2,3-b] Pyridine 12.2 g was obtained as pale brown crystals.

^ -NM (400 MHz, DMSO— d ₆ ) δ-0.09 (s, 9 H), 0.81 (t, J = 8 Hz, 2 H), 3.47 (t, J = 8 Hz, 2H), 5. 48 (s, 2H), 6.19 (d, J = 5 Hz, 1 H), 6.20 (s, 2

H), 6.56 (d, J = 4 Hz, 1H), 7.19 (d, J = 4 Hz ₅ ), 7.76 (d, J = 5 Hz, 1 H)

 73

 2-Fluoro N— (1H—pyro mouth “2.3-bl pyridine-1-41”) benzamide,

 At room temperature, 4-amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H monopyrro [2,3-b] pyridine (500mg) and triethylamine (634mg) in tetrahydrofuran (20ml) 2-Fluorobenzoyl chloride (497 mg) was added. After the mixture was stirred at room temperature for 4 hours, water (50 ml) was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2-fluoro-N- {1- [2- (trimethylsilyl) ethoxymethyl] -1-H-pyrole [2, 727 mg of 3-b] pyridine-4-yl} benzamide was obtained as colorless crystals.

 To this 2-fluoro-N- {1- [2- (trimethylsilyl) ethoxymethyl] -1H-pyro [2,3-b] viridine-4-yl} benzamide was added 4N hydrochloric acid in dioxane (30 ml). The mixture was stirred at room temperature for 4 hours. After water was added to the reaction solution, potassium carbonate was added until the reaction solution became alkaline, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and water (30 ml) and methanol (15 m

I) and sodium acetate (6.00 g) were added, and the mixture was stirred under reflux for 1 hour. After adding water (100 ml), the mixture was extracted with ethyl acetate, and the obtained organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate / hexane to give the desired 2-fluoro-N- (1H-pyro [2,3-b] pyridine-4-yl). ) 225 mg of benzamide were obtained as colorless crystals. 235-237 ° C (decomposition) MS (EI): 255 (M +).

^ -NMR (400MHz, DMS 0- d 6) δ (p pm): 6. 7 9 (1 H s), 7. 30 - 7. 40 (3H, m), 7. 60 (1 H 5 br. q, J = 7 Hz, 7.71 (1 H, t, J = 7 Hz), 7.84 (1 H, d, J = 5 Hz) 8.15 (1 H, d, J = 5 Hz), 10.54 (1H, s), 11.63 (1H, br.s).

荬 Example Ί4

 N— (1H—pyro mouth “2.3-bl pyridine-1-yl”) benzamide,

 4-Amino 1_ [2- (trimethylsilyl) ethoxymethyl] _1H-Pyro mouth [2,3-b] Pyridine (300mg) and Benzoylc mouth light (162mg) The same reaction as in Example 73 By performing the above operation, 103 mg of the desired N— (1 H-pyrro [2,3-b] pyridin-4-yl) benzamide was obtained as pale yellow crystals. 234-235 ° C (decomposition)

MS (E I): 237 (M +)

丄 11 NMR (400 MHz, DMS 0-d ₆ ) δ (p pm): 6.80 (1 H s), 7.37 (1 H, s), 7.50-7.65 (3H, m ), 7. 69 (1 H, d, J = 5Hz), 7. 98 (2 H, d, J = 7Hz), 8. 16 (1 H 5 d, J = 5Hz), 10. 39 (1 H , S), 11.5 1 (1 H ₃ br. S).

2-N- (N- (1H-pyro- mouth "2.3-bi pyridine-41-yl") Penzamide 1/3 hydrate

4-amino-1- (2- (trimethylsilyl) ethoxymethyl] —1H-pyro [2,3-b] pyridine (500 mg) and 2-chlorobenzoicylamide (659 mg) By performing the same reaction procedure as in Example 73, the desired 2-monochloro-N_ (1H-pyrro [2,3-b] pyridin-14-yl) penzamide-1/3 hydrate was pale yellow 272 mg was obtained as crystals. Melting point> 225 ° C (decomposition) MS (EI): 271, 273 (M +).

^ -NMR (400 MHz, DMS 0-d ₆ ) δ (ppm): 6.82 (1 H s), 7.35 (1 H, s), 7.45-7.65 (4H, m), 7 86 (1H, br.s), 8.15 (1H, d, J = 5Hz), 10.70 (1H, s) 11.63 (1H, br.s).

赛 Example 76

 2—Promote N— ΠΗ—Pyro mouth “2.3-bl Pyridine 1 4 ^^ T) Benza U1

 4-Amino 1- [2- (trimethylsilyl) ethoxymethyl] -1H-Pyro [2,3-b] Pyridine (300 mg) and 2-Promobenzoyl-cylinder (302 mg) The same reaction procedure as in Example 73 was carried out to obtain 157 mg of the target 2 -promo N- (1H-pyroport [2,3-b] pyridine-14-yl) penzamide as colorless crystals. 239-241 ° C (decomposition)

MS (E I): 315, 317 (M +).

^ -NMR (400 MHz, DMS 0-d ₆ ) δ (ppm): 6.81 (1 Hs), 7.34 (1H, br.s), 7.44 (1H, t, J = 6 Hz), 7.51 (1H, t, J = 7Hz), 7.59 (1H, d, J = 6Hz), 7.73 (1H, d, J = 8Hz), 7.85 (1H, d , J = 5Hz), 8.15 (1H, d, J = 5Hz), 10.68 (1H, s), 11.61 (1H, br.s).

 rnm 77

 2-Methyl-N- (1H-pyro mouth “2.3-bl pyridine-14-yl benza”

Example using 4-amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-pyrro [2,3-b] pyridine (500 mg) and 2-methylbenzoylcopene (584 mg) By performing the same reaction procedure as in 73, the desired 2 -methyl-N- (1H-pyro mouth [2,3-b] pyridine-14-yl) 148 mg was obtained as colorless crystals. Melting point 240-241 ° C

MS (EI): 351 (M ⁺ ).

丄 11 NMR (400 MHz, DMSO-d ₆ ) δ (p pm): 2.42 (3H: s), 6.84 (1H, s), 7.34 (3H, br.s), 7.42 (1H, d, J = 8 Hz), 7.51 (1H, d, J = 8 Hz), 7.85 (1 H, br, s), 8.15 (1H, br.s), 10 50 (1H, s.), 11.59 (1H, br.s).

Example 78

 2-Trifluoromethyl-N— (1H—pyro-opened “2.3-bl pyridine-14-yl”) benzamide 2,3 trihydrate

 Using 4-amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-pyro [2,3-b] pyridine (300 mg) and 2-trifluoromethylbenzoyl oleide (240 mg) By performing the same reaction procedure as in Example 73, the desired 2-trifluoromethyl-N— (1H—pyro [2,3-b] pyridin-4-yl) benzamide · 2Z3 water 156 mg of the product as colorless crystals <mp 239-241 ° C

MS (E I): 305 (M +).

— NMR (400MHz, DMSO— d ₆ ) δ (p pm): 6.78 (1H d, J = 3Hz), 7.36 (1H, d, J = 3Hz), 7.70- 7.90 (5H, m), 8.16 (1H, d, J = 5Hz), 10.77 (1H, s), 11.65 (1H, br.s).

rn m Ί 9

 2-Nitro-N- (1H-Pyro mouth "2.3-bl pyridine-1-yl") Penza Ui

 4-Amino-1- [2- (trimethylsilyl) ethoxymethyl] -1-H-pyro [2,3-b] pyridine (472 mg) and 2-nitrobenzoyl alk (3

35 mg), and the same reaction procedure as in Example 73 was carried out. There was obtained 103 mg of N- (1H-pyro [2,3-b] pyridine-14-yl) benzamide as yellow crystals. Melting point> 270 ° C (decomposition)

MS (E I): 282 (M +).

^ -NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 6.74 (1H, s), 7.37 (1 H, d, J = 3 Hz), 7.75-7.85 (3H, m ), 7.91 (1H, t, J = 7Hz), 8.17 (1H, d, J = 5Hz), 8.22 (1H, d, J = 8Hz), 10.81 (1H, s), 11.65 (1H, br.s).

Example 80

 2,6-difluoro-1-N- (1H-pyro-mouth "2.3-bl pyridine-1-41") benzamide

4-Amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-pyro [2,3-b] pyridine (1.00 g) and 2,6-difluorobenzoyl chloride (724 mg) By carrying out the same reaction procedure as in Example 73, the desired 2,6-difluoro-N- (1H-pyroport [2,3-b] pyridin-4-yl) benzamide was converted to colorless crystals. 442 mg were obtained. Melting point> 250 ° C MS (EI): 273 (M ⁺ ).

_{^ -NMR (400MHz, DMSO- d 6} ) δ (pm): 6. 76 (1 H s), 7. 27 (2 H, t, J = 8Hz), 7. 37 (1 H, d, J = 3H z) 7.55-7.65 (lH, m), 7.86 (1H, d, J = 5Hz), 8.17 (1H, d, J = 5Hz), 10.93 (1H, s), 11.68 (1H, br.s).

荬 Example 81

 2. 3,6-Trifluoro-N— (1. H-pyro mouth “2,3-bl pyridine-14-yl”) benzamide

4-Amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-pyro [2,3-b] pyridine (670mg) and 2,3,6-trifluorobenzoyl By performing the same reaction operation as in Example 73 using chloride (500 mg), the desired 2,3,6-trifluoro-N— (1H-pyromouth [2,3-b] pyridine) was obtained. 4-yl) 159 mg of benzamide was obtained as colorless crystals. Melting point> 2 50 ° C (decomposition)

 MS (EI): 291 (M +).

NMR (400 MHz, DMS 0-d ₆ ) <5 (p pm): 6.75 (1 H s), 7.35 (1H, br .t, J = 8 Hz), 7.41 (1H, t, J = 3 Hz), 7.65-7.80 (1H, m), 7.86 (1H, d, J = 5Hz) 8.19 (1H, d, J = 5Hz), 11. 02 (1 H, s), 11.73 (1 H, br.

rn m 82

 2. 3-Difluoro-N-MH-pyro-mouth "2.3-b, pyridine-41-yl) benzamide

 4-amino-1— [2- (trimethylsilyl ') ethoxymethyl] —1H—pyro [2,3-b] pyridine (815 mg) and 3-chloro-1,2,6-difluorobenzoylc (656) mg)) to give the desired 3-chloro-2,6-difluoro-N— (1H-pyro [2 3-b] pyridine-4-yl) penzami Obtained as colorless crystals, melting point> 270 ° C (decomposition)

MS (E I): 307,309 (M +).

^ -NM (400 MHz, DMS 0-d ₆ ) δ (p pm): 6.84 (1 Hs), 7.45-7.55 (2H, m), 7.96 (2H, br.d, J = 5H z), 8. 29 (1 H, d, J = 5Hz), 11. 10 (1 H, s), 11. 8 2 (1 H 3 br. s).

赛 Example 83

2. 6-Difluoro-3-methyl-1-N-MH-pyro mouth “2.3-bl pyridine-4-ylbenzamide · 1 Z57k 4-Amino 1- [2- (trimethylsilyl) ethoxymethyl] -1H-pyrro [2,3-b] pyridine (500 mg) and 2,6-difluoro-3-methyl-benzoyl oxide And performing the same reaction procedure as in Example 73 to obtain the desired 2,6-difluoro-3-methyl-N- (1H-birolo [2,3-b] pyridin-4-yl) benzami 257 mg of dodecane pentahydrate was obtained as colorless crystals. Melting point> 260. C (decomposition)

MS (EI): 287 (M ⁺ ).

^X H-NM (400MHz, DMS 0-d ₆ ) δ (p pm): 6.87 (1H s), 7.26 (1H, t, J = 8Hz), 7.47 (1H, s), _{7. 58 (1H, q 3 J} = 7Hz), 7. 96 (1H, d, J = 5Hz), 8. 27 (1 H, d, J = 5Hz), 11. 00 (1H, s), 11 77 (1H, br. S).

Example 84

 Cyl 2 -——— (1 H—Pyrazo mouth—3.4—bl pyridine-1- 4-yl-pyruvamoyl 1-benzoate ”hydrochloride

 Under water cooling, thionyl chloride (775〃1) was added to methanol (20 ml) and stirred for 15 minutes. The 2- [N- (1H-pyrazo port [3,

4-b] Pyridine-4-yl) lubamoyl] benzoic acid (1.0 g) was added, and the mixture was stirred at room temperature for 1.5 hours. The crystals precipitated in the reaction solution are collected by filtration and washed with methanol to give the desired methyl 2- [N- (1H-birazolo [3,4-b] pyridin-14-yl) -force rubamoyl ] Benzoate 'hydrochloride as white crystals.

64 g were obtained. Melting point 167—170 ° C (decomposition)

— NMR (400MHz, DMS 0-d ₆ ) (5: 3.15 (3H ₅ s), 4.

50-5.50 (2 H, brs), 7.64-7.68 (2H, m), 7.72-7.76 (1H, m), 7.98-8.10 (2H, m) , 8.61 (1H, m), 8.71 (lH, m), 11.58 (1H, brs).

卖 Example 85 2. 5-Dichro mouth _N— Pyro mouth “2.3-bl pyridine-1-yl) Benzamide

 4-amino-1_ [2- (trimethylsilyl) ethoxymethyl] -1H-pyro [2,3-b] pyridine (25 Omg) and 2,5-dichlorobenzoylylide (200mg) By performing the same reaction operation as in Example 73 using, the desired 2,5-dichloro-1-N- (1H-pyro-port [2,3-b] pyridine-14-yl) penzamide Was obtained as white crystals (47 mg). Mp> 260 ° C (decomposition) MS (EI): 305, 307 (M +).

^ -NMR (400 MHz, DMS O-d ₆ ) <5 (p pm): 6.79 (1 H s), 7.37 (1 H, t, J = 2.9 Hz), 7. 62 (1 H, s), 7. 6 3 (1 H 5 s), 7. 79 (1 H, s), 7. 85 (1 H, d, J = 4. 9 H z), 8. 1 6 (1 H, d, J = 5.4 Hz), 10.7 5 (1 H, s), 1 16 5 (1 H, s).

Example 86

 5-bromo-1-N-—pyro mouth “2.3-bl pyridine-1-yl” benzamide

 4-Amino 1- [2- (trimethylsilyl) ethoxymethyl] -1H-Pyro [2,3-b] pyridine (25 Omg) and 5-bromo-12-chloro benzoyl lip mouth (24 Omg) By performing the same reaction operation as in Example 73 using, the desired 5-bromo-12-chloro-N- (1H-pyro [2,3-b] pyridin-4 44 mg of benzamide was obtained as white crystals. Melting point> 2 60 ° C (decomposition)

 MS (EI): 349, 351 (M +).

NMR (400 MHz, DMS 0-d ₆ ) <5 (p pm): 6.79 (1 H dd, J = 2.0, 3.5 Hz), 7.37 (1 H, t, J = 2.9 Hz, 756 (1 H, d, J = 8.3 Hz), 7.74 (1 H, dd, J = 2.5, 8.3 Hz), 7. 8 5 (1 H, d, J = 4.9 Hz), 7.89 (1 H, d, J = 2.4 Hz), 8.16 (1H, d, J = 5.4Hz), 10.75 (1H, s), 11.65 (1H, s).

 rnm 87

 2-Chloro-5-nitro-N- (1H-Pyro mouth "2.3-bl pyridine-4-yl" benzamide

 Using 4-amino-1_ [2- (trimethylsilyl) ethoxymethyl] -1H-pyrro [2,3-b] pyridine (250 mg) and 2-chloro-5-ditropenzoyl mouth (21 Omg) By performing the same reaction procedure as in Example 73, the desired 2-chloro-5-nitro-1-N_ (1H-pyro [2,3-b] viridin-41-yl) benzamide was obtained. 7 mg were obtained as pale yellow crystals. Melting point> 250 ° C (decomposition)

 MS (EI): 316, 318 (M +).

— NMR (400MHz, DMS 0-d ₆ ) δ (p pm): 6.77 (1 H s), 7.38 (1H, m), 7.87 (1H, d, J = 4.8 Hz), 7. 9

2 (1H, d, J = 8.8Hz), 8.18 (1H, d, J = 5.3Hz), 8

37 (1H, dd, J = 2.9, 8.8Hz), 8.53 (1H, d, J = 2.9Hz), 10.85 (1H, s), 11.68 (1H, s ).

rnmrn 88

 2—Azido N— (1. H—Bilazo, Mouth “3.4-bl Pyridine 1-4-yl) Benzamide

 To a 3N hydrochloric acid solution (15 mL) of 2-amino-N- (1H-pyrazo-mouth [3,4-b] pyridin-1_4_yl) penzamide (2.0 g) obtained in Example 18 was added. Under ice-cooling, sodium nitrite (0.61 g) was added. After stirring for 10 minutes, sodium azide (0.58 g) was added and the mixture was stirred for 1 hour. After basification with sodium methoxide, the title compound (45 Omg) was obtained by silica gel column chromatography. Melting point 196 ° C

Elemental analysis: as C ₁₃ H ₉ N ₇₀ C (%) Η (%) Ν (%)

 S7 5 5.9 1 3.25 35.1 1

Measured value: 5 5. 87 3. 55 35. 12

 MS (EI): 279 (M +).

— NMR (400 MHz, DMS 0-d ₆ ) 6 (p pm): 7.34 (1 Ht, J = 7.3 Hz), 7.48 (1 H, d, J = 7.3 Hz) ), 7.62-766 (2 H, m), 7.85 (1 H, d, J = 5.4 Hz), 8.41 (1 H, d, J = 5.4 Hz), 1 0.94 (1H, br.s), 13.58 (1H, br.s).

IR (KB r): 33 16, 23 16, 16 87, 1620, 1596, 1531, 1511, 1331 cm ^-1 .

卖 Example 89

 2-Acetylamino-N— (1H—Pyrazo mouth “3. 4-bl pyridine-14-yl”) Benzamide

 In a DMF (6 mL) solution of 2-amino-N- (1H-pyrazo [3,4-b] pyridin-141-yl) benzamide (0.6 g) obtained in Example 18 was added Triethylamine (0.372 g) and acetyl chloride (0.37 g) were added. After stirring for 4 hours, ethyl acetate (50 ml) was added, and the mixture was washed with saturated saline, and the organic layer was dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give the title compound (50 mg). Melting point> 2 60 ° C

MS (EI): 2 95 (M ⁺ ).

^ -NMR (400 MHz, DMS 0-d ₆ ) δ (p pm): 1.99 (1 H s), 7.27 (1 H, t, J = 7.3 Hz), 7.54 (1 H, d, J = 7.3 Hz), 7.7 1 -7. 73 (2 H ₃ m), 7.82 (1 H, d, J = 5.4 Hz), 8.40 ( 1 H, d, J = 5.4H z), 10.08 (1 H, br.s), 10.0.92 (1 H, b r.s), 1 3.5 1 (1 H, br. s). 卖 Example 90

 N-—Pyrazo mouth “3.4-b] Pyridine-1 4-yl) 1-Thiophene lipoxamide

 The production was carried out in the same manner as in Example 1 except that thiophene-2-carbonyl chloride was used instead of penzoyl sulfide. Melting point 244 ° C

Elemental analysis value:

As S

 C () H (%) N (%)

Calculated value: 54. 0 9 3. 30 22. 94

Measured value: 54.05 3.50 2 2.75

MS (EI): 244 (M ⁺ ). ¹ H-NMR (400 MHz, DMS 0-d ₆ ) δ (ppm): 7.28 (1 H, dd ₅ J = 4.9 and 3.4 H z ), 759 (1H, d, J = 5.4Hz), 7.95 (1H, dd, J = 4.9 and

1. 0H z), 8. 1 6 (1 H 5 dd, J = 3. 4 and 1. 0H z), 8. 37 (1 H, s), 8. 40 (1 H, d, J = 5 4H z), 10.71 (1 H, b r.s), 13.55 (l H, b r.s).

The structural formulas of the compounds obtained by the above examples are as shown below.

08

ZCC0 / T0df / X3d

Z8

ZCC0 / T0df / X3d S8

ZCC0 / T0df / X3d 8

ZCC0 / T0df / X3d s 8 / io OAV S8

ZCC0 / T0df / X3d 98

ΙΟΗ

ZCC0 / T0df / X3d

Example 1

 0.5 part of the compound of Example 1, 25 parts of lactose, 35 parts of crystalline cellulose and 3 parts of corn starch were thoroughly mixed, and then kneaded well with a binder made with 2 parts of corn starch. The kneaded mixture is sieved with 16 mesh, dried in an oven at 50 ° C, and sieved with 24 mesh. The kneaded powder obtained here was thoroughly mixed with 8 parts of corn starch, 11 parts of crystal cell mouth and 9 parts of talc, and then pressed to give tablets containing 0.5 mg of active ingredient per tablet. Obtained.

mm ^ 2

 Compound of Example 1 1. Omg and sodium chloride 9. Dissolve Omg in water for injection, remove the pyrogen by filtration, transfer the filtrate aseptically to an ampoule, sterilize, melt and seal to obtain the active ingredient An injection containing 1.0 mg was obtained.

 Experimental example

 The effect of the compound of the present invention on daricogen synthase kinase 13 (GSK-33) was evaluated and confirmed as follows.

87 GSK-3 buffer solution containing 1% dimethyl sulfoxide (2 Ommo 1 / L-Tris-HCl (PH7.5), 1 Ommo 1 / L · magnesium chloride, 5 mmol / L · dithiothreitol) in 25 zL 4 . 6 nmo 1 · CREB phospho peptide, 0.5 units' Usagi GSK- 3, 5 nmo 1 · ATP N 12. 3 kBq - [ § - ³² P] ATP-and test compound for 20 minutes at 30 ° C It was allowed to react. 10 μL of the reaction product was adsorbed on ion-exchange paper P81, washed with 10 Ommo 1 / L phosphoric acid, and then cpm was measured in a scintillation counter. As a result, as shown in Table 1 below, the compounds of the present invention exhibited an IC ₅₀ value of 0. 1~ 100 mo 1 / L. The CREB phosphopeptide is Lys-Arg-Arg-Glu-IleLeu-Ser-Arg-ArgProSer (P) -Tr-Arg.

 table 1

 Test compound GSK— 3/5 inhibitory effect

 I C 50 (〃mo 1 / L) Example 5 5.2

 Example 7 0.12 Example 10 1.3

 Example 49 5.2

 Example 79 9.5 Μ2: harmful effect of 沲 3 to Κ day on rat

Embryonic day 18 rat brain hippocampal neurons were collected and cultured for 7 days. Tau protein phosphorylation was induced by exposing cultured neurons to 5-amyloid (25-35) 20〃mo1 / L and a test compound (GSK13? Inhibitor) for 3 hours. . After completion of the culture, the phosphorylation level of tau protein was measured by EIA using an antibody recognizing phosphorylated tau protein (phosphorylation site by GSK-3?), And the GSK-3? The GSK-35 inhibitory effect was evaluated. As a result, the compound of Example 7 showed significant intracellular GSK- 3-showed inhibitory effect.

Test Example 3: Effect of amyloid on citrus dysfunction in citrus cells cultured on horses

 Embryonic day 18 rat brain hippocampal neurons were collected and cultured for 7 days. Cultured nerve cells are exposed to amyloid (25-35) 2 Ojumo 1 / L and a test compound (GSK-3? Inhibitor), and cultured for 24 hours for neuropathy (extracellular LDH activity). Increased and decreased intracellular reductase activity). After completion of the culture, extracellular LDH activity and intracellular reductase activity were measured, and the effect of the GSK-3; 5 inhibitor on 5-amiloid-induced neuropathy was evaluated. As a result, the compound of Example 7 showed a significant inhibitory effect on ^ -amyloid-induced neuropathy at 1 mol / L. MM 4: 391! Harmful effects in gerbil H tfn model

 The test compound (GSK-35 inhibitor) was intraperitoneally administered to gerbils, and 30 minutes later, the common carotid artery was subjected to ischemia for 4 minutes to induce phosphorylation of brain tau protein. The hippocampus was collected 3 hours after cerebral ischemia, and the level of tau protein phosphorylation was measured by Western blotting using a phosphorylated tau protein-recognizing antibody (phosphorylated site by GSK-3 / 5). We evaluated the inhibitory effect of a 3 — inhibitor on GSK-3 3 in gerbil brain. As a result, the compound of Example 7 showed a significant intracerebral GSK-3 ^ inhibitory effect at 30 mg / kg when administered intraperitoneally 30 minutes before cerebral ischemia.

 Industrial applicability

 The compound of the present invention is a compound showing a selective and strong inhibitory action on glycogen synthase kinase-3 ぺ yose (GSK-3β). Therefore, the compound of the present invention is a prophylactic or therapeutic drug for diabetes, complications of diabetes, Alzheimer's dementia, neurodegenerative diseases (AIDS encephalopathy, Huntington's disease, Parkinson's disease, cerebral ischemia), manic depression, etc. Useful as This application is based on a patent application No. 2000-111998 filed in Japan, the contents of which are incorporated in full herein.

Claims

 The scope of the claims

 General formula (I)

Wherein Z ₂ is the same or different and each represents CH or N.

 I also represents hydrogen or alkyl.

 Ar is selected from naphthyl which may have a substituent or a group represented by the following formulas (11), (II 1), (IV), (V), (VI) and (VI I) Represents a group.

 (IV) (V)

 (VI)

(Wherein, represents C—R ¹ or N. Y represents CH ₂ , N—R ⁷ , ◦ or S. RR ² , R ³ , R ⁴ , R ⁵ , R ⁶ may be the same or Differently, respectively, hydrogen, alkyl, alkoxy, phenoxy, phenylalkoxy, hydroxy, mercapto, alkylthio, amino, acylamino, alkylamino, carboxy, halogen, haloalkyl, phenylalkyl, cyano, phenyl, nitro, cycloalkoxy , Aminoalkoxy, alkylaminoalkoxy, alkoxycarbo Represents nil or azide. R ⁷ represents hydrogen, alkyl or phenylalkyl. H ⁸ and R ^g are the same or different and each represents hydrogen, alkyl or oxo. n represents 1 or 2 carbon atoms. )]

Or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 2. —The aromatic amide compound, the pharmaceutically acceptable salt, or the hydrate thereof according to claim 1, wherein in the general formula (I), k is CH and R is hydrogen. ·

 3. The aromatic amide according to claim 1, wherein in the general formula (I), Ar is a group represented by the formula (II), (111), (IV;), (V) or (VI). A compound, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

 4. The aromatic amide compound according to claim 1, wherein in the general formula (I), Ar is an optionally substituted naphthyl or a group represented by the formula (VII), Acceptable salts or hydrates thereof.

5. In the formula (II) of Ar, R ² , R ³ヽ R \ R ⁵ , R ⁶ are the same or different and are each hydrogen, alkyl, alkoxy, alkylthio, halogen, amino, alkyl or nitro. 2. The aromatic amide compound according to claim 1, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

6. The aromatic compound according to claim ¹ , wherein in the formula (VI) of Ar, Y is 0 or S, and X is C—R ¹ (R ¹ has the same meaning as in claim 1) or N ^. An amide compound, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

7. In the formula (VI I) of Ar, X is CH, Y is CH ₂ or N—R ⁷ (R ⁷ is defined as defined in claim 1), and n is 1 or 2. 2. The aromatic amide compound according to claim 1, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

8. 2-Fluoro-N— (1H-birazolo [3,4-b] pyridine-14 ml) benzamide; << 2-N- (IH-Bilazolo [3,4-b] pyridine-4-yl) benzamide,

 2—METHOD ^ — N— (1H—Pyrazo Mouth [3,4-b] Pyridine-1-4-yl) Benzamide, '

 2-ethoxy, N- (1H-birazolo [3,4-b] pyridine-14-yl) benzamide,

 2-propyl-oxy-N- (1H-pyrazo [3,4-b] pyridine-4-yl) benzamide,

 2-isopropyloxy-N- (1H-pyrazo-mouth [3,4-b] pyridine-41-yl) benzamide,

 2—Trifluoromethyl-N— (1H—Pyrazo mouth [3,4-b] pyridine-14-yl) benzamide,

 2-nitro-N- (1H-lazolo [3,4-b] pyridine-14-yl) benzamide,

 2-Methylthio-1-N— (1H—Pyrazo mouth [3,4-b] pyridine-4-41) benzamido, de,

 4-chloromethyl-N- (1H-birazolo [3,4-b] pyridine-14-yl) benzamide,

 4 1-Promomethyl-1-N— (1H—Pyrazo mouth [3,4-b] pyridine-14-yl) benzamide,

 4-trifluoromethyl-N- (1H-birazolo [3,4-b] pyridine-14-yl) benzamide,

 2,6-difluoro-N— (1H-pyrazo-mouth [3,4-b] pyridine-14-yl) benzamide,

 N— (1H—Pyrazo mouth [3,4-b] pyridine-1.4-^-f) 13-pyridine power Lupoxamide,

2-Methylthio-1-N— (1H—Pyrazo mouth [3,4-b] pyridine-4-yl) — 3-—Pyridinecarboxamide,

 2-Methyl-N— (1 H—Pyrazo mouth [3,4-b] pyridine-14-yl) 13-furancarboxamide,

 5-Methyl-N- (1H-pyrazo-mouth [3,4-b] pyridine-14-yl) 14-Isoxazolecarboxamide,

 3,4-dihydro-14-methyl-1-6-methylthio-1N— (1H—pyrazo [34-b] pyridine-14-yl) -1,2H—1,4-benzoxazine—8-carboxamide,

 2-N- (1-H-pyro [2,3-b] pyridin-4-yl) benzamide,

 2-nitro-N- (1H-pyrro [2,3-b] pyridin-4-yl) penzamide,

 2,6-difluoro-N- (1H-pyro [2,3-b] pyridin-4-yl) benzamide,

 2,3-difluoro-N— (1H—pyro [2,3-b] pyridin-4-yl) benzamide,

 2,6-difluoro-3-methyl-1-N— (1H-pyro [2,3-b] pyridin-4-yl) benzamide,

 2,5-dichroic N- (1 H-pyro [2,3-b] pyridin-4-yl) benzamide,-

5-bromo-1-N- (1H-pyrrolo [2,3-b] pyridine-4-yl) benzamide,

 2-chloro-5-nitro-N- (1H-pyro [2,3-b] pyridin-4-yl) benzamide, and

 N- (1H-pyrazo-mouth [3,4-b] pyridine-14-yl) -12-thiophene carboxamide

The aromatic amide compound according to claim 1, which is selected from the group consisting of: Salts or hydrates thereof.

 9. A medicament comprising the aromatic amide compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

 10. A pharmaceutical composition comprising the aromatic amide compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable additive. object.

 11. A GSK-3? Inhibitor comprising the aromatic amide compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

 12. An antidiabetic agent comprising the aromatic amide compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.

13. An agent for treating diabetes complications, comprising the aromatic amide compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.

 14. A therapeutic agent for Alzheimer's dementia, comprising as an active ingredient the aromatic amide compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

 15. A therapeutic drug for neurodegenerative diseases, comprising the aromatic amide compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.

 16. An agent for preventing or treating manic depression, comprising the aromatic amide compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

17. An immunostimulant comprising the aromatic amide compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. Claims of amendment

 [September 19, 2001 (1 September 09, 01) Accepted by the International Bureau: Claims originally filed

 1 has been amended; other claims remain unchanged. (Page 1)]

1. (after correction) General formula (I)

[Where τ Ζ ₂ is the same or different and represents CH or そ れ, respectively.

 R represents hydrogen or alkyl.

 Ar is selected from naphthyl which may have a substituent or a group represented by the following formulas (11), (II 1), (IV) s (V), (VI) and (VI I) Represents a group.

 (ll) (IV) (V)

(VI) (VII)

(In the formula, X represents C—R ¹ or N. Y represents CH ₂ , N—R ⁷ , 0 or S. I ¹ , R \ R ³ , R ⁴ , and RR ⁶ may be the same or Differently, respectively, hydrogen, alkyl, alkoxy, phenoxy, phenylalkoxy, hydroxy, mercapto, alkylthio, amino, acylamino, alkylamino, carboxy, halogen, haloalkyl, phenylalkyl, cyano, phenyl, nitro, cycloalkoxy, Aminoalkoxy, alkylaminoalkoxy, alkoxycarbo

95

 Corrected form (Article 19 of the Convention)