KR930011304B1 - Pyridazinon derivatives - Google Patents

Abstract

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Description

Pyridazinone derivatives and preparation methods thereof

The present invention relates to a pyridazinone derivative and a method for preparing the same, in particular, the following general formula (I), which is effective for the treatment of cardiac circulatory disease, thrombosis and respiratory disease, It relates to a novel pyridazinone derivative represented and its preparation method.

Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, X and Y are each hydrogen atom, nitro group, cyano group, -NHCOR ₃ or -NHSO ₂ R ₄ , wherein R ₃ and R ₄ are each an alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted phenyl group or an alkyl group substituted with halogen, and R ₂ is a hydrogen atom, alkyl having 1 to 6 carbon atoms or side chain Is an alkyl, alkene, alkyne or alkyne group substituted with an alkyl, alkene, alkyne or alkynyl, alkene, alkyne or phenyl group.

The pyridazinone derivative represented by the general formula (I) according to the present invention has a selective inhibitory effect on cAMP phosphodiesterases in the myocardium, and exhibits a cardiac effect, and also has excellent physiological strength in contraction and blood pressure strengthening of heart muscle. It has activity and is a useful substance for treating hypertension or as a cerebrovascular agent. It also has antithrombotic effect, which is useful for the treatment of thrombosis. Accordingly, an object of the present invention is to provide a pyridazinone derivative represented by the general formula (I), which is effective for enhancing contractility and blood pressure of heart muscle, and useful for antithrombogenic effect, and a method of preparing the same.

Hereinafter, the present invention will be described in detail.

The present invention is a pyridazinone derivative represented by the general formula (I), the preparation method thereof is as follows.

That is, as a first embodiment for preparing the pyridazinone derivative (Ia) of the present invention, (A) keto-phenol (1) is reacted in the presence of a base with a derivative (2) having a leaving group A (3) ) And (b) reacting the keto derivative (3) with a vinegar derivative (4) having a leaving group B in the presence of a base to obtain a keto ester (5), and (c) the ketoester derivative (5). Reacted with hydrazine to obtain a pyridazinone derivative (6), and then (D) nitrating the pyridazinone derivative (6) to produce a compound represented by the following general formula (Ia) which is a pyridazinone derivative Will be.

Wherein R ₁ and R ₂ are as described above, R ₅ is a methyl group or an ethyl group, and A and B are each a halogen atom, tosylate or methanesulfonate.

In addition, as a second embodiment for preparing the pyridazinone derivative (Ia) of the present invention, the ketone-ester (5) is obtained in the same manner as in steps (a) to (b) of the first embodiment, and (c) The keto-ester derivative (5) was hydrolyzed to obtain a keto-organic acid derivative (7), and then (D) the keto-organic acid derivative (7) was reacted with hydrazine to obtain a pyridazinone derivative (6). When reacted in the same manner as step (d) of the first embodiment, a compound represented by the general formula (Ia), which is a pyridazinone derivative, is prepared.

In the above formula, R ₁ and R ₂ are as described above. In addition, a ketone-ester (5) is obtained in the same manner as the steps (a) to (b) of the third embodiment of the present invention for preparing the pyridazinone derivative (Ia), and (c) the ketone-ester derivative ( 5) to nitrate to obtain a ketone-ester derivative (8), and (d) when the ketone-ester derivative (8) is reacted with hydrazine to prepare a compound represented by the general formula (Ia), which is a pyridazinone derivative Will be.

In the above formula, R ₁ and R ₂ and R ₆ are as described above. In addition, as a fourth embodiment for preparing the pyridazinone derivative (Ia) of the present invention, ketone-ester (8) is obtained in the same manner as in steps (a) to (c) of the third embodiment, ) The ketone-ester derivative (8) is hydrolyzed to obtain a ketone-organic acid derivative (9), and then (e) when the ketone-organic acid derivative (9) is reacted with hydrazine, it is a pyridazinone derivative. The compound represented by Ia) is prepared.

In the above formula, R ₁ and R ₂ are as described above.

Further, as a fifth embodiment in which the pyridazinone derivative (Ia) of the present invention is produced via a common intermediate (10), (a) a phenol derivative (1) having a ketone group and a methyl derivative (2a) in which iodine is substituted The reaction was carried out in the presence of a base to obtain a ketone derivative (3a), (b) the ketone derivative (3) and the vinegar derivative (4) was reacted in the presence of a base to obtain a ketone-ester derivative (5a), and then (c) the The keto-ester derivative (5a) was hydrolyzed to obtain a keto-acid (7a), and then (d) the keto-acid (7a) was reacted in the presence of an acid to obtain a phenol-organic acid (10). The phenol-organic acid (10) and the derivative (2) substituted with the leaving group A in R ₂ are reacted in the presence of a base to obtain a mixture of the keto-ester (11) and the keto-organic acid (7). Treatment of a mixture of ester (11) and keto-lactic acid group (7) with a base yields a keto-organic acid (7), and (a) the keto-organic acid (7) And then reacted with deurajin obtained -pyridazinone (6), (G) a compound represented by the flutes when the nitro reaction times the Xenon (6) -pyridazinone derivative of the general formula (Ia) is to be prepared.

Wherein R ₁ , R ₂ , and R ₅ and A and B are as described above.

In addition, as a sixth embodiment of preparing a pyridazinone derivative of the present invention, a mixture of a keto-ester (11) and a keto organic acid (7) is obtained in the same manner as in steps (a) to (e) of the above embodiment. Thereafter, (f) the mixture of keto-ester (11) and keto organic acid (7) was obtained in the same manner as the keto-ester, and (f) the keto-ester (11) and keto-organic acid (7) mixtures were prepared. By reacting with hydrazine to obtain a pyridazinone (6), by the nitration reaction as in step (g) of the fifth embodiment, the compound represented by the general formula (Ia) of the pyridazinone derivative is prepared.

In addition, as a seventh embodiment in which the pyridazinone derivative (Ia) of the present invention is prepared through the common intermediate (12), (a) a phenol derivative (1) having a ketone group and isopropyl bromide (2b) Reacting in the presence of a ketone derivative (3b), (b) reacting the ketone-derivative (3b) with a vinegar acid derivative (4) in the presence of a base to obtain a keto-ester derivative (5b), and then (c) the The keto-ester derivative (5b) was nitrated to obtain a nitro-phenol derivative (12), and then (D) the nitro-phenol derivative (12) was reacted with a derivative (2) substituted with leaving group A in the presence of a base. Obtaining a keto-ester (8) and (e) reacting the keto-ester (8) with hydrazine produces a compound represented by the general formula (Ia), which is a pyridazinone derivative.

In the above formula, R ₁ , R ₂ and R ₅ are as described above.

In addition, as an eighth embodiment to prepare a pyridazinone derivative of the present invention, the keto-ester is obtained through the steps (a) to (d) of the seventh embodiment, and (e) the keto-ester (8) After hydrolysis to obtain a keto-organic acid (9), and (f) reacting the keto-organic acid (9) with hydrazine, the compound represented by the general formula (Ia), which is a pyridazinone derivative, is prepared.

In addition, as a ninth embodiment for preparing the pyridazinone derivative (Ib) of the present invention, the pyridazinone derivative (Ia) is obtained in the above embodiment, and the pyridazinone derivative (Ia) is once again nitrated. By doing this, pyridazinone derivatives represented by the following general formula (Ib) are obtained.

In the above formula, R ₁ and R ₂ are as described above.

In addition, as a tenth embodiment for producing pyridazinone derivatives (Ic) and (Id) of the present invention, a derivative represented by the general formula (Ia) is obtained. (A) reducing the pyridazinone derivative (Ia) to obtain an amino-pyridazinone derivative (IC), and (b) reacting the amino-pyridazinone derivative (Ic) with R ₃ COZ to pyrida A compound represented by the following general formula (Id) as a xenon derivative is prepared.

Wherein R ₁ and R ₂ are as defined above and Z is a halogen atom.

In addition, as an eleventh embodiment for preparing the pyridazinone derivative (Ie) of the present invention, a compound represented by the above general formula (Ic) is obtained by reacting in the same manner as in step (A) of the tenth embodiment, and then the compound When (Ic) is reacted with R ₄ SO ₂ Z, a compound represented by the following general formula (Ie), which is a pyridazinone derivative, is prepared.

Wherein R ₁ and R ₂ are as defined above and Z is a halogen atom.

In addition, as a twelfth embodiment for preparing the pyridazinone derivative (Ig) of the present invention, the compound represented by the general formula (Ic) is obtained by reacting in the same manner as in step (a) of the tenth embodiment, ) Reacted with HNO ₂ to obtain a diazonium salt derivative (If), and (c) when the diazonium salt derivative (If) is reacted with cyanocopper (14) through a sandmeyer reaction, it is represented by the following general formula (Ig). Pyridazinone derivatives are obtained.

In the above formula, R ₁ and R ₂ are as described above.

In addition, as a thirteenth embodiment for preparing the pyridazinone derivative (Ih) of the present invention, (a) after obtaining a phenol ester derivative (13) through esterification of the compound (10) obtained in the fifth embodiment , (B) reacting the phenol-ester derivative (13) with dibromomethane to halogen-react the α-bromomethyloxy derivative (5c) to obtain a vinyloxy derivative (5d), and (d) the vinyl When cyclooxylation of the oxy derivative (5d) to obtain a new cyclopropyl derivative (5e) and reacted in the same manner as in the embodiments 1 to 4, the compound represented by the following general formula (Ih) which is a pyridazinone derivative Will be produced.

In the above formula, R ₁ and R ₅ are as described above.

In addition, as a fourteenth embodiment of the preparation of pyridazinone derivative (Ii) of the present invention, (A) 4-hydroxy benzaldehyde (14) is reacted with a derivative having a leaving group A (2) in the presence of a base to form an aldehyde derivative ( 15), (b) oxidizing the aldehyde derivative (15) to obtain an organic acid derivative (16), and (c) condensing the organic acid derivative (16) with phenyl selenylphthalamide (17) to acyl selenium. A derivative 18 is obtained, and (d) an acyl radical is generated in the acyl selenium derivative 18 using a radical initiator and reacted with butenolide 19 to obtain a keto-lactone derivative 20. ) The keto-lactone derivative (20) is reacted with hydrazine to obtain a hydroxy-pyridazinone derivative (21), and (f) the nitridation reaction of the hydroxy-pyridazinone derivative (21) is carried out in general formula (Ii). Pyridazinone derivatives represented by) are prepared.

In the above formula, R ₂ and A are as described above.

In addition, as a fifteenth embodiment of preparing the pyridazinone derivative (Ii) of the present invention, the keto-lactone derivative (20) is obtained by the steps (a) to (d) of the fourteenth embodiment, and then (e) After nitrifying the keto-lactone derivative (20) to obtain a nitro-lactone derivative (22), and (f) reacting the nitro-lactone derivative (22) with hydrazine is a pyri represented by the general formula (Ii). Xenon derivatives will be prepared.

In the above formula, R ₂ is as described above.

In addition, as a sixteenth embodiment of preparing a pyridazinone derivative (Ii) of the present invention, an aldehyde derivative (15) is obtained by the step (a) of the fourteenth embodiment, and (b) the aldehyde derivative (15) and Propanedithiol (23) is reacted in the presence of an acid to obtain a dithiaene derivative (24), and then (c) the dithiaene derivative (24) is treated with a strong base and then buteneide (19) is added to the styrene. After obtaining the -lactone derivative (25), (d) the tauene-lactone derivative (25) was treated with an acid in the presence of metal to obtain a keto-lactone derivative (20), followed by (e) to (bar) The pyridazinone derivatives represented by the derivative (Ii) are prepared by the step).

In the above formula, R ₂ is as described above.

In addition, as a seventeenth embodiment for preparing the pyridazinone derivative (Ii) of the present invention, (a) 4-hydroxybenzaldehyde (14) and propanedithiol (23) are reacted in the presence of an acid to give didiene-phenol After obtaining the derivative (26), (b) reacting the dithiene-phenol derivative (26) with the derivative (2) having a leaving group A in the presence of a salt to obtain a dithiene derivative (24) and then the When the reaction is carried out by the steps (c) to (bar), pyridazinone derivatives represented by the general formula (Ii) are prepared.

In addition, an isopropyl derivative (19b) is obtained in the fourteenth to sixteenth embodiments as an eighteenth embodiment for preparing the pyridazinone derivative (Ii) of the present invention through a common intermediate (27). The propyl derivative (19b) was treated with an acid to obtain a keto-phenol derivative (27), and the keto-phenol derivative (27) was reacted in the presence of a base (2) containing a leaving group A in the presence of a new keto-lactone derivative. After obtaining (20), the reaction of the fifteenth embodiment (E) to (B) step to prepare the pyridazinone derivatives represented by the general formula (Ii).

As a nineteenth embodiment of preparing a pyridazinone derivative (Ij) of the present invention, the pyridazinone derivative (Ii) is obtained in the fourteenth to sixteenth embodiments, and then the pyridazinone derivative (Ii) is obtained. The halogenation reaction produces monohalogen derivatives (Ij), which are mono pyridazinone derivatives.

Wherein R ₂ is as described above and G is halogen.

In addition, as a twentieth embodiment for preparing a pyridazinone derivative (Ik) of the present invention, in the fourteenth to sixteenth embodiments, pyridazinone derivatives (Ii) are obtained, and then the hydroxy-pyrida. The nitro group is introduced into the xenon derivative (Ii) to prepare a nitrosyl-pyridazinone derivative represented by the general formula (Ik).

In the above formula, R ₂ is as described above.

In addition, as a Gen 21 embodiment for preparing the pyridazinone derivative (Ia) of the present invention, the ditaiane derivative 24 is obtained according to the 16th to 17th embodiments, and then (a) the dithiene derivative. (24) is reacted with a crotylic acid derivative (28) in the presence of a strong base to obtain a dithiene-organic acid derivative (29), and (b) treating the dithiene-organic acid derivative (29) with an acid in the presence of a metal to keto-organic acid. After obtaining a derivative (7) (c) reacting the keto-organic acid derivative (7) in the presence of hydrazide to obtain a pyridazinone derivative (30), and (d) nitrating the pyridazinone derivative (30) When the reaction is carried out, a pyridazinone compound represented by the following general formula (Ia) is prepared.

In the above formula, R ₁ and R ₂ are as described above.

In addition, as a twenty-second embodiment for preparing the pyridazinone derivative (Ia) of the present invention, keto-organic acid (7) is obtained by the steps (a) to (c) of the twenty-first embodiment. After nitrifying the keto-organic acid derivative (7) to obtain nitro-organic acid (31), (d) when the nitro-organic acid (31) is reacted in the presence of hydrazine, it is a pyri represented by the following general formula (Ia). Xenon derivatives are to be prepared.

In the above formula, R ₁ and R ₂ are as described above.

Further, as a twenty-third embodiment of the present invention, hydroxy-pyridazinone derivatives (Ii) or pyridazinone derivatives (Ij) and (Ik) are obtained in the 14th to 20th embodiments. Further nitrification of the diginone derivatives (Ii) (Ij) or (Ik) yields pyridazinone derivatives represented by the general formula (Im).

In the above formula, R ₂ is as described above, and K is a nitrosil, a halogen atom and a hydroxyl group.

In addition, as a twenty-fourth embodiment for preparing the pyridazinone derivative (In) of the present invention, after obtaining the pyridazinone derivatives (Ii) (Ij) or (Ik) in the 14th or 23rd embodiment, When the group is reduced, a pyridazinone derivative represented by the following general formula (In) is prepared.

In the above formula, R ₂ is as described above, and K is a nitrosil, a halogen atom and a hydroxyl group.

In addition, as a twenty-fifth embodiment for preparing the pyridazinone derivative (Io) of the present invention, a pyridazinone derivative (In) is obtained in the twenty-fourth embodiment, and the pyridazinone derivative (In) is R ₄ SO ₂ When reacted with X, a pyridazinone derivative represented by the following general formula (Io) is prepared.

In the above formula, R ₂ , R ₄ and K are as described above.

In addition, in the twenty-sixth embodiment of preparing a pyridazinone derivative (Ip) of the present invention, after obtaining a pyridazinone derivative (In) in the twenty-fourth embodiment, the pyridazinone derivative (In) is replaced with R ₃ COX. When reacted with, a pyridazinone derivative represented by the following general formula (Ip) is obtained.

In the above formula, R ₂ , R ₃ and K are as described above.

Further, as a twenty-seventh embodiment for preparing the pyridazinone derivative (Iq) of the present invention, after obtaining the amino-pyridazinone derivatives represented by the general formula (In), (a) the amino-pyridazinone ( After In) is made of a diazonium salt, and (b) substitution reaction of the diazonium salt derivative (Iq) with cyanocopper yields cyano-pyridazinone represented by the general formula (Ir).

All of the pyridazinone derivatives prepared above can be prepared with the respective optically active agents. Important intermediates are separated by the methods listed below, and the above-described embodiments Prepared by reactions. Separation of important intermediates into optically active agents is as described below.

As a twenty-eighth embodiment for preparing an optically active derivative of the pyridazinone derivative (Ia) of the present invention, the keto-organic acid derivative (7) is obtained by the steps (a) to (c) of the second embodiment. (D) reacting the keto-organic acid derivative (7) with an optically active alcohol (32) to obtain a keto-ester (33a) (33b), which is a diastereomer mixture, and (e) the keto-ester derivative. (33a) (33b) are separated into respective diastereomers (33a) (33b), and (f) hydrolyzing the optically active keto-ester derivatives (33a) (33b), respectively, to the scientifically active keto- When organic acids (7a) and (7b) are obtained and reacted by the steps (c) to (d) of the first embodiment, an optically active pyridazinone derivative represented by the following general formulas (Iaa) and (Iab) is obtained. Lose.

In the above formula, R ₁ , R ₂ are as described above.

Further, as a twenty-ninth embodiment for producing an optically active derivative of the pyridazinone derivative (Ii) of the present invention, after obtaining the pyridazinone derivative (21) according to the fourteenth embodiment to the fifteenth embodiment, A) reacting the pyridazinone derivative 21 with an optically active organic acid 34 to obtain pyridazinone-ester (35a) (35b) as a diastereomer mixture, and (b) the pyridazinone-ester The mixtures of derivatives 35a and 35b are separated into their respective optical isomers-esters 34a and 35b, and (b) the pyridazinone-ester derivatives 35a and 35b are then mixed into their respective optical isomers 35a. (B) and then (c) hydrolyzing the optically active pyridazinone esters (35a) (35b) to obtain optically active pyridazinone alcohols (21a) and (21b), respectively. (D) Pyridazinone represented by the following general formula (I-ia) (I-ib) when the pyridazinone-coals (21a) and (21b) are nitrated, respectively. Derivatives are obtained.

In addition, as a thirtieth embodiment for preparing an optically active derivative of the pyridazinone derivative (Ii) of the present invention, the pyridazinone derivative (Ii) is described in the steps (a) to (c) of the twenty-ninth embodiment. As can be separated directly.

In the above formula, R ₁ , R ₂ are as described above.

In the first embodiment of the present invention to prepare a pyridazinone derivative represented by the general formula (Ia) as described above, first, the leaving group A is substituted for the phenol derivative (I) having a ketone group and R2 as step (A). The ketone derivative (3) is prepared by reacting the derivative (2) in the presence of a base, wherein A is a halogen atom, tosylate or methanesulfonate, and the base includes sodium hydride, sodium alkoxide, and potassium carbonate. Acetone, difluoromethylformamide, difluoromethylsulfoxide and alcohol solvents are used as the solvent, and a catalytic amount of sodium iodide is required in some cases, and the reaction temperature is between 20 ° C and the boiling point of the solvent used. Until. In addition, (b) the ketone derivative (3) and the vinegar acid derivative (4) substituted with the leaving group B in the presence of a base to react ketone-ester derivative (5) to produce a bar, wherein B is a halogen atom As the base, sodium hydride, potassium t-butoxide, lithium diisopropylamide, lithium hexa methyl disilylamide, and the like are used, and the solvent is tetrahydrofuran, ethyl ether or benzene, and in some cases HMPA is used. Used as cosolvent. The reaction temperature is selected from temperatures between -78 ° C and room temperature. Subsequently, as step (c), pyridazinone derivative (6) is prepared by heating and refluxing the compound (5) in hydrazine and an organic solvent. The hydrazine is anhydrous or a hydrate, and the reaction solvent is an alcohol solvent. Reaction temperature is the boiling point of the solvent used. In the final step (d), when the pyridazinone derivative (6) is nitrated, a compound of the general formula (Ia), which is the target compound of the present invention, is obtained. A mixture of nitric acid and sulfuric acid, a mixture of nitric acid and vinegar acid, or ammonium nitrate and trifluoroacetic acid is used, and the reaction temperature is selected between -50 ° C and room temperature.

The preparation method of the compound as described above is represented by the following scheme.

In the above formula, R ₁ R ₂ and R ₅ and A and B are as described above.

In the second embodiment of the present invention, the compound (5) prepared as step (a) is subjected to hydrolysis in the presence of a base as described above in the same manner as in steps (a) to (c) of the first embodiment. Ketone-acid derivative (7) is prepared. The base used at this time is sodium hydroxide, potassium hydroxide or lithium hydroxide, and the like, water, alcohol or a mixture of water and acetone is used as the solvent. Subsequently, when (ke) reacts the keto-organic acid derivative (7) with hydrazine in the same manner as described above, a pyridazinone derivative (6) is obtained, and the final step is represented by the general formula (Ia). The compound is to be prepared. The above method for preparing these compounds is represented by a series of schemes.

In the above formula, R ₁ , R ₂ are as described above.

Further, as described above in the third embodiment of the present invention, the same reaction as in (a) to (b) of the first embodiment is carried out to obtain the keto-ester derivative (5), and then the keto-ester derivative (5 ) And the nitration reaction to obtain a keto-ester derivative (8), and reacting it with hydrazine to obtain the target compound represented by the general formula (Ia). At this time, the nitration reaction and the hydrazine reaction is the same as the above-described method. The preparation method of these compounds is represented by a series of schemes.

In the above formula, R ₁ , R ₂ and R ₅ are as described above.

Further, in the fourth embodiment of the present invention, after obtaining the keto-ester derivative (8) in the steps (a) to (b) of the third embodiment as described above, the compound (8) as (d) step Hydrolysis is performed to prepare the keto-organic acid derivative (9). The hydrolysis reaction at this time is carried out as described above, and when reacted with hydrazine, the target compound represented by the general formula (Ia) is obtained. The preparation method of these compounds is represented by a series of schemes.

In the above formula, R ₁ and R ₂ are as described above.

In addition, as a fifth embodiment of the present invention, by using R ₂ A as methyl iodide, in the same manner as steps (a) to (c) of the first embodiment, to obtain a keto-acid (7a), When the keto-organic acid (7a) is reacted in the presence of an acid as step), phenol-organic acid (10) is obtained. At this time, HBr, BBr ₃ , AlCl ₃ , Et ₃ NHCl, etc. are used as the acid, and dichloromethane, chloroform, difluoromethylformamide, etc. are used as the reaction solvent, and the reaction temperature is between -20 ° C. and the boiling point of the solvent. Will be selected.

Subsequently, as step (e), when the phenol-organic acid 10 and the R ₂ derivative substituted with leaving group A are reacted as described above, a new keto-ester 11 and a keto-organic acid 7 are formed. As a result, when the mixture is hydrolyzed as described above, a keto-organic acid (7) is obtained, which is reacted with hydrazine by the reaction of the above-described method to obtain a compound (6), and when it is nitrated, the general formula The target compound represented by (Ia) is obtained.

The preparation method of these compounds is represented by a series of schemes.

Wherein R ₁ , R ₂ and R ₃ and X and Y are as described above.

In addition, as a sixth embodiment of the present invention, the mixture of the new keto-organic acid (7) and the keto-ester (11) obtained by steps (a) to (e) of the fifth embodiment is the same as the method described above. When reacted with hydrazine, the target compound represented by the general formula (Ia) is obtained. The preparation method of these compounds is as follows.

In the above formula, R ₁ and R ₂ are as described above.

In addition, as a seventh embodiment of the present invention, by using R ₂ as isopropyl bromide (2b) to obtain a keto-ester derivative (5b) in the same manner as in step (a) to (c) of the first embodiment, When the compound (5b) is nitrated in the same manner as described above, a nitro-phenol derivative (12) is obtained.

Subsequently, in step (d), the nitro-phenol derivative (12) was obtained with a new keto-ester (8) in the same manner as described above with the derivative (2) substituted with the leaving group A, and the fourth embodiment described above. In the same manner as in the target compound represented by the general formula (Ia) can be prepared. A method of preparing these compounds is shown in the following scheme.

In the above formula, R ₃ and R ₅ are as described above.

In addition, as an eighth embodiment of the present invention, the keto-ester (8) obtained in the seventh embodiment is hydrolyzed to obtain a keto-organic acid (9), and then reacted with hydrazine as described above. The target compound represented by Ia) is obtained. The preparation method of these compounds is as follows.

In the above formula, R ₂ is as described above.

Further, in the ninth embodiment of the present invention, when the pyridazinone derivative represented by the general formula (Ia) is further nitrated, the target compound represented by the following general formula (Ib) is obtained. The nitration reaction is as described above, but is carried out using excess reagents. The preparation method of these compounds is as follows.

In the above formula, R ₁ , R ₂ are as described above.

Meanwhile, among the target compounds, the compound represented by the general formula (Ic) in which X is NHCOR ₂ is reduced to hydrogen in the presence of palladium or platinum catalyst as in the tenth embodiment. You can get it. At this time, the pressure of hydrogen is selected from atmospheric pressure to 5 atm and the solvent is an alcohol solvent or ethyl acetate, and the reaction temperature is room temperature.

In addition, when the amino compound represented by these (Ic) is reacted with capric acid, carboxylic acid halogen, or carboxylic anhydride, target compounds represented by the following general formula (Id) are obtained. In this case, as a catalyst for promoting the condensation reaction, dicyclohexylcarbodiamide, 4-difluoromethylaminopyridine or 1-hydroxybenzotriazole, etc. are used, and as a solvent, dichloromethane, ethyl acetate, pyridine and Benzene and the like are used, and the reaction temperature is from 20 ° C. to the boiling point of the solvent used. This is represented by a series of schemes.

In the above formula, R ₁ , R ₂ , R ₃ are as described above.

In addition, in the eleventh embodiment of the present invention, the target compound represented by the following general formula (Ie) can be prepared by combining the amino compound (Ic) with a sulfonic acid or a sulfonic acid halogen compound. At this time, the reaction temperature is selected between the boiling point of the solvent at 20 ° C. using a solvent such as difluoromethylformamide, ethyl ether, or tetrahydrofuran in the presence of an amine base. If this is expressed as a reaction scheme, it is as follows.

In the above formula, R ₁ , R ₂ and R ₄ are as described above.

As a twelfth embodiment of preparing a pyridazinone derivative represented by the following general formula (Ig) in the present invention, a compound represented by the general formula (Ic) is first obtained by the above method, and then (a) step The diazonium-pyridazinone derivative (If) is produced by the diazonation reaction of the compound (Ic). As the reaction conditions, sodium nitrite is added and reacted in the presence of concentrated HCl. As the solvent, water or water-dioxane, water-tetrahydrofuran and the like are used, and the reaction temperature is kept below 5 ° C. In the step (b), the diazonium compound (If) is substituted with a cyano group to prepare a cyano-pyridazinone compound (Ig). As a reagent for giving a cyano group, a cyanocopper is used in an aqueous KCN solution. Proceed with the reaction.

This can be expressed as a series of reactions:

In the above formula, R ₁ , R ₂ are as described above.

In addition, as a thirteenth embodiment of preparing a pyridazinone derivative represented by the following general formula (Ih) of the present invention, a compound (10) is obtained by the above-described reactions. ) Is converted into an ester, and reacted with diazomethane in an ether solvent or heated with an alcohol solvent in the presence of a mineral acid to obtain a compound (13), and (b) as a step, the phenol-ester derivative (13) And dibromomethane or bromomethanesulfonylmethane and the like are substituted to obtain α-bromomethyloxy derivative (5c). At this time, the reaction conditions are as described above, and in step (c), the α-bromomethyloxy derivative (5c) is removed to obtain a vinyloxy derivative (5d). At this time, bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like are used, and solvents include water-ether water-benzene and water-dichloromethane, and tetrabutylammonium chloride as a phase transfer catalyst. Triton-B is used as the base in dichloromethane solvent and the reaction temperature is from room temperature to the boiling point of the solvent. In the step (D), the vinyloxy derivative (5b) is cyclochlorolated to obtain a cyclooxy derivative (5e), wherein the reaction conditions are Simmon-Smith reaction, in the presence of diiomethane, zinc, zinc-copper Alloys, diethyl chloride, etc. are used, the reaction solvent is an ether solvent, and the reaction temperature is from room temperature to the boiling point of the solvent. Expressed as a series of general expressions:

In the above formula, R ₁ , R ₂ , R ₅ are as described above.

In the fourteenth embodiment of the present invention, the pyridazinone derivative represented by the general formula (Ii) is prepared. In the presence of the reaction to prepare a ketone derivative (15), where A is a halogen atom, tosylate or methanesulfonate, and the base is sodium hydride, sodium alkoxide, potassium carbonate, etc., the solvent is acetone or di Fluoromethylformamide and the like are used, and a catalytic amount of sodium iodide is necessary in some cases. The reaction temperature is 20 ° C. to the boiling point of the solvent used. Subsequently, the organic acid derivative (16) is obtained by oxidizing the aldehyde derivative (15) as step (b). As the oxidizing agent, potassium permanganate, chromium oxide, pyrididium chloro chromate, pyridinium dichromate, etc. are used. Water, difluoromethylformamide, dichloromethane, chloroform, tetrahydrofuran, dioxane and the like are used, and in some cases, a phosphate buffer solution is also required. The reaction temperature is selected between 0 ° C. and the boiling point of the solvent used. In the step (c), the organic acid derivative (16) is condensed with the phenyl selenyl phthalamide (17) to obtain an acyl selanium derivative (18). At this time, the reaction is carried out at room temperature using dichloromethane as the reaction solvent in the presence of trialkyl phosphine. Subsequently, in step (d), acyl selenide is produced from the acyl selenium derivative (18) and added to butenolide to obtain a keto-lactone derivative (20). As a radical initiator, AIBN, benzoyl peroxide is used as a solvent. The furnace is benzene or toluene, and the reaction temperature is selected between the boiling point of the solvent at room temperature. In the next step (e) to (bar) step by performing the reaction by the method as described above to obtain the target compound represented by the general formula (Ii). The preparation method of these compounds is represented by a series of schemes.

In the above formula, R ₂ and X are as described above.

Further, in the fifteenth embodiment of the present invention, as described above, the nitro compound (22) is subjected to the nitration reaction of the compound (20) in the same manner as described in the second embodiment and the third embodiment. When the nitro compound 22 is reacted with hydrazine as described above, the target compounds represented by the general formula (Ii) are obtained. The preparation method of these compounds is as follows.

In the above formula, R ₂ is as described above.

In addition, as a sixteenth embodiment of preparing a pyridazinone derivative (Ii) of the present invention, an aldehyde derivative 15 is obtained in the same manner as in step (a) of the fourteenth embodiment, and then (b) an aldehyde derivative as step (b). A protecting group (15) is introduced into didiene, which is obtained by reacting propanedithiol with an acid catalyst. In this case, brontrifluoro fluoride ether and lanthanide halide or mineral acid are used as a catalyst, and dichloromethane, chloroform, 1, 2 dichloroethane, etc. are used as a reaction solvent, and the reaction temperature is from -78 ° C to room temperature. Choose from. Subsequently, as a step (c), the dieneene derivative (24) is treated with a base to form an anion stabilized by sulfur, and the Michael reaction is performed on the butenolide (19) to obtain a styrene-lactone derivative (25). At this time, the base used is methyllithium, phenyllithium, butyllithium and the like, and the reaction solvent is tetrahydrofuran, tetrahydrofuran-HMPA mixture, ether and the like, the reaction temperature is selected from -78 ℃ to room temperature. Next, as the step (d), the tyene-lactone derivative (25) is treated with an acid to obtain a keto-lacto derivative (20). In the reaction conditions, in order to promote the reaction, in the presence of compounds such as mercury oxide and chloride, As the acid, boron trifluoride ether or hydrofluorobolic acid may be used. As a reaction solvent, a mixture of tetrahydrofuran and water is used, and the reaction temperature is from 0 ° C to room temperature. Subsequently, as described above, when reacted in the same manner as in steps (e) to (bar) of the twelfth embodiment, pyridazinone derivatives represented by the general formula (Ii) are obtained. The preparation method is as follows.

In the above formula, R ₂ is as described above.

In addition, the dithiene derivative (24) can be obtained by other routes. First, the 4-hydroxybenzaldehyde (14) and propanedithiol (23) in the step (a) described in the After reacting in the same manner as step) to obtain a phenol-didiene derivative (26), in step (b) the twelfth embodiment of the above-described derivative (2) having a diene-phenol derivative (26) and leaving group A When the reaction is carried out in the same manner as in step (A) of the example, the dithiene derivative 24 is obtained. Embodiment 17 The above method is represented by a series of reaction schemes.

In the above formula, R ₂ is as described above.

In addition, as an eighteenth embodiment for preparing the pyridazinone derivative (Ii) of the present invention through the common intermediate 27, the isopropyl derivative 19b is obtained in the fourteenth to sixteenth embodiments. When the propyl derivative 19b is treated with an acid, a keto-phenol derivative 27 is obtained. The acid used is 50% aqueous sulfuric acid solution and the reaction temperature is room temperature. As a next step, by reacting the keto-phenol derivative (27) with a derivative (2) containing a leaving group A in the same manner as in step (A) of the sixteenth embodiment described above to obtain a new keto-lactone derivative (20) , Pyridazinone derivatives represented by the general formula (Ii) are obtained through the reactions as described above (Example 18). This is represented by a series of schemes.

In the above formula, R and A are as described above.

Further, in the nineteenth embodiment for preparing the following general formula (Ii) of the present invention, it can be obtained by substituting the hydroxy group of the compound represented by the general formula (Ii). In this case, for the compound in which G is floro, DAST is used as a reagent, a solvent used is dichloromethane or chloroform, and the reaction temperature is selected from -78 ° C to room temperature. In addition, for the compound wherein G is chloro or bromo, carbon tetrachloride or sabromo carbon is used, respectively, trialkylphosphine is used together, the solvent is an ether solvent, and the reaction temperature is from room temperature to the boiling point of the solvent used. . This can be expressed as a series of reactions:

In the above formula, R ₂ is as described above.

In addition, as a twentieth embodiment of preparing a pyridazinone derivative represented by the following general formula (Ik) of the present invention, after obtaining a pyridazinone derivative (Ii) by the above-described reaction, the pyridazinone derivative is anhydrous. When reacted with concentrated nitric acid in a solvent of acetic acid, a pyridazinone derivative represented by the general formula (Ik) is prepared. At this time, the reaction temperature is selected between 0 ℃ and room temperature. If this is expressed as a reaction scheme, it is as follows.

In the above formula, R ₂ is as described above.

In addition, as a twenty-first embodiment in which the pyridazinone derivative (Ia) of the present invention is prepared, the titanene derivative (24) and the crotylic acid derivative (28) obtained by the above-mentioned steps as (a) are two equivalents of strong. Reaction in the presence of a base affords a dithiene-organic acid derivative (29). The reaction conditions are the same as those of step (c) of the sixteenth embodiment described above except that two equivalents of base are used. Thereafter, after step (d), when the reaction is carried out by the method described above in the sixteenth embodiment, the compounds represented by the general formula (Ia) are prepared. This preparation method is represented by a series of schemes as follows.

In the above formula, R ₁ and R ₂ are as described above.

Further, after obtaining the compound (30) in the same manner as in the twenty-first embodiment described above, and then nitrifying the compound (30) as the step (c) to obtain a nitro-organic acid (31), wherein the reaction conditions Is as described above. As described above, when reacted with hydrazine, a pyridazinone compound represented by the general formula (II) is obtained (Example 22). This can be expressed as a series of reactions:

In the above formula, R ₁ and R ₂ are as described above.

In addition, as a twenty-third embodiment for preparing pyridazinone represented by the following general formula (Im), the pyridazinone derivatives (Ii) (Ii) and (Ik) may be further nitrated by the reaction as described above. Dazinon derivative (Im) is to be prepared. This is represented by the following reaction scheme.

In the above formula, R ₂ and K are as described above.

In addition, when the pyridazinone derivative represented by the general formula (Ii) (Ij) or (Ia) is reduced, a pyridazinone derivative represented by the general formula (In) is prepared. Reduction is obtained by reduction with hydrogen in the presence of a palladium platinum catalyst, the input of which is selected between atmospheric and 5 atm (Example 24) and the above general formula (Io) wherein X is NHSO ₂ R ₄ and NHCO ₃ R ₃ in the target compound. In the preparation of the compound represented by (Ip), dehydrating agents such as carboxylic acid or sulfoic acid and dicyclohexyl carbodiamide, and catalysts such as 4-methyl amino pyridine and 1-hydroxybenzotriazole may be used. Catalysts such as dichloromethane, ethyl acetate, pyridine, 1-hydroxybenzotriazole may be used as the solvent, and dichloromethane, ethyl acetate, pyridine and benzene may be used as the solvent (Examples 25 and 26). When reacting the compound of Formula (Io) (Ip) with a carboxylic acid halogen compound or a sulfonic acid halogen compound, a solvent such as difluoromethylformamide, ethyl ether or tetrahydrofuran may be used in the presence of an amine base. And the reaction temperature is from 20 ° C. to the boiling point of the use temperature. This is represented by a series of schemes.

In the above formula, R ₂ , R ₅ and K are as described above.

In addition, as a twenty-seventh embodiment for preparing the pyridazinone derivative (Ir) of the present invention, a pyridazinone derivative represented by the general formula (In) is obtained by the method of Embodiment 24 described above, and then (A When the compound (In) is subjected to a diazotization reaction, a diazonium-pyridazinone derivative (Ir) is prepared. At this time, the reaction conditions of the two steps are used as described in the twelfth embodiment. This is represented by a series of schemes.

In the above formula, R ₂ is as described above.

Further, as a twenty-eighth embodiment for preparing an optically active derivative of the pyridazinone derivative (Ia) of the present invention, keto-organic acid derivative (7) is prepared by the steps (a) to (c) of the second embodiment described above. Hue was obtained, followed by step (d), wherein the keto-organic acid derivative (7) was reacted with an alcohol which is an optically active compound to obtain a keto-ester (33) which is a diastereomer mixture. Or methyl mandalate, and the like, and dehydrating agents such as dicyclohexyl carbodiamide and catalysts such as 4-methylamino pyridine and 1-hydroxybenzotriazole may be used, and solvents include dichloromethane, ethyl acetate, pyridine and benzene. Etc. are used. And (e) separating the keto-ester derivatives (33a) and (33b) into their respective diastereomers by column chromatography or recrystallization, followed by (f) the keto-ester derivatives (33a). And (33b) were respectively hydrolyzed to obtain respective optical isomers (7a) and (7b). As hydrolysis conditions, lithium hydroxide or potassium hydroxide is used in the alcohol solvent. Finally, each of the optical isomers (7a) and (7b) is reacted by the above-described method to produce the final targets (1-a-a) and (1-a-b), respectively. This is represented by a series of schemes.

In the above formula, R ₁ , R ₂ are as described above.

Further, as a twenty-ninth embodiment of obtaining a pyridazinone derivative which is the optically active substance of the present invention, after obtaining the pyridazinone derivative 21 by the reactions described in the fourteenth to fifteenth embodiments, When the pyridazinone derivative 21 is reacted with an organic acid which is an optically active compound, a mixture of diastereomers 35a and 35b is obtained. And dehydrating agents such as dicyclohexyl carbodiamide or catalysts such as 4-methyl amino pyridine and 1-hydroxybenzotriazole are commonly used together. It is commonly used. Subsequently, the diastereomeric mixture is separated (35a) and (35b) into respective optical isomers as a step (b). As a separation method, column chromatography or fractional recrystallization method is used. The reaction after step (bar) of the twenty-eighth embodiment can be carried out to obtain each of the optical isomers 21a and 21b. This is represented by a series of schemes.

In the above formula, R ₂ is as described above.

In addition, the pyridazinone derivative (Ii) can be separated from each of the optical isomers (Iia) and (Iib) by reacting in the same manner as described in the twenty-ninth embodiment (Example 30). This is represented by a series of schemes.

In the above formula, R ₁ and R ₂ are as described above.

Specific examples of the pyridazinone derivative of the general formula (I) which may be prepared according to the method as described above are as follows. These are each racemic mixtures or include respective optical isomers.

4, 5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-1),  4, 5-dihydro-6- (3-nitro-4-ethoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-2),  4, 5-dihydro-6- (3-nitro-4-isopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-3),  4, 5-dihydro-6- (3-nitro-4-t-butoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-4),  4, 5-dihydro-6- (3-nitro-4-phenoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-5),  4, 5-dihydro-6- (3-nitro-4-allyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-6),  4, 5-dihydro-6- (3-nitro-4-allyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-7),  4, 5-dihydro-6- (3-nitro-4-propazyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-8),  4, 5-dihydro-6- (3-nitro-4-cyclopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-9),  4, 5-dihydro-6- (3-nitro-4-cyclobutyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-10),  4, 5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-11),  4, 5-dihydro-6- (3-nitro-4-cyclohexyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-12),  4, 5-dihydro-6- (3-nitro-4- (2, 2, 2-trifluoroethyloxy) phenyl) -5-methyl-3 (2H) -pyridazinone (I-13),  4, 5-dihydro-6- (3-nitro-4-difluoromethyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-14),  4, 5-dihydro-6- (3, 5-dinitro-4-methoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-15),  4, 5-dihydro-6- (3, 5-dinitro-4-ethoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-16),  4, 5-dihydro-6- (3, 5-dinitro-4-isopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-17),  4, 5-dihydro-6- (3, 5-dinitro-4-t-butoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-18),  4, 5-dihydro-6- (3, 5-dinitro-4-phenoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-19),  4, 5-dihydro-6- (3, 5-dinitro-4-benzyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-20),  4, 5-dihydro-6- (3, 5-dinitro-4-allyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-21),  4, 5-dihydro-6- (3, 5-dinitro-4-propazyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-22),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-23),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclobutyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-24),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopentyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-25),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclohexyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-26),  4, 5-dihydro-6- (3, 5-dinitro-4- (2, 2, 2-trifluoroethyloxy) phenyl) -5-methyl-3 (2H) -pyridazinone (I-27),  4, 5-dihydro-6- (3, 5-dinitro-4-difluoromethyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-28),  4, 5-dihydro-6- (3-cyano-4-methoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-29),  4, 5-dihydro-6- (3-cyano-4-ethoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-30),  4, 5-dihydro-6- (3-cyano-4-isopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-31),  4, 5-dihydro-6- (3-cyano-4-t-butoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-32),  4, 5-dihydro-6- (3-cyano-4-phenoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-33),  4, 5-dihydro-6- (3-cyano-4-benzyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-34),  4, 5-dihydro-6- (3-cyano-4-allyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-35),  4, 5-dihydro-6- (3-cyano-4-propazyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-36),  4, 5-dihydro-6- (3-cyano-4-cyclopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-37),  4, 5-dihydro-6- (3-cyano-4-cyclobutyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-38),  4, 5-dihydro-6- (3-cyano-4-cyclopentyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-39),  4, 5-dihydro-6- (3-cyano-4-cyclohexyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-40),  4, 5-dihydro-6- (3-cyano-4- (2, 2, 2-trifluoroethyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-41),  4, 5-dihydro-6- (3-cyano-4-difluoromethyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-42),  4, 5-dihydro-6- (3-amino-4-methoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-43),  4, 5-dihydro-6- (3-amino-4-isopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-44),  4, 5-dihydro-6- (3-amino-4-cyclopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-45),  4, 5-dihydro-6- (3-amino-4-cyclopentyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-46),  4, 5-dihydro-6- (3-acetamido-4-difluoromethyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-47),  4, 5-dihydro-6- (3-acetamido-4-methoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-48),  4, 5-dihydro-6- (3-acetamido-4-isopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-49),  4, 5-dihydro-6- (3-acetamido-4-cyclopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-50),  4, 5-dihydro-6- (3-acetamido-4-cyclopentyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-51),  4, 5-dihydro-6- (3-acetamido-4-dichloromethyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-52),  4, 5-dihydro-6- (3-benzoylamido-4-methoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-53),  4, 5-dihydro-6- (3-benzoylamido-4-isopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-54),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-55),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopentyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-56),  4, 5-dihydro-6- (3-benzoylamido-4-diflomethyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-57),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido-4-methoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-58),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido-4-isopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-59),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido-4-cyclopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-60),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido-4-cyclopentyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-61),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido-4-difluoromethyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-62),  4, 5-dihydro-6- (3-trifluoroacetamido-4-methoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-63),  4, 5-dihydro-6- (3-trifluoroacetamido-4-isopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-64),  4, 5-dihydro-6- (3-trifluoroacetamido-4-cyclopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-65),  4, 5-dihydro-6- (3-trifluoroacetamido-4-cyclopentyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-66),  4, 5-dihydro-6- (3-trifluoroacetamido-4-difluoromethyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-67),  4, 5-dihydro-6- (3-methanesulfonamido-4-methoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-68),  4, 5-dihydro-6- (3-methanesulfonamido-4-isopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-69),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-70),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopentyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-71),  4, 5-dihydro-6- (3-methanesulfonamido-4-difluoromethyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-72),  4, 5-dihydro-6- (3-methanesulfonamido-4-methoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-73),  4, 5-dihydro-6- (3-methanesulfonamido-4-isopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-74),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-75),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopentyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-76),  4, 5-dihydro-6- (3-methanesulfonamido-4-difluoromethyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-77),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-methoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-78),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-isopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-79),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-80),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopentyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-81),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-difluoromethyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-82),  4, 5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-83),  4, 5-dihydro-6- (3-nitro-4-ethoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-84),  4, 5-dihydro-6- (3-nitro-4-isopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-85),  4, 5-dihydro-6- (3-nitro-4-t-butoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-86),  4, 5-dihydro-6- (3-nitro-4-phenoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-87),  4, 5-dihydro-6- (3-nitro-4-benzyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-88),  4, 5-dihydro-6- (3-nitro-4-allyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-89),  4, 5-dihydro-6- (3-nitro-4-propazyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-90),  4, 5-dihydro-6- (3-nitro-4-cyclopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-91),  4, 5-dihydro-6- (3-nitro-4-cyclobutyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-92),  4, 5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-93),  4, 5-dihydro-6- (3-nitro-4-cyclohexyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-94),  4, 5-dihydro-6- (3-nitro-4- (2, 2, 2-trifluoroethyloxy) phenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-95),  4, 5-dihydro-6- (3-nitro-4-difluoromethyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-96),  4, 5-dihydro-6- (3, 5-dinitro-4-methoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-97),  4, 5-dihydro-6- (3, 5-dinitro-4-ethoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-98),  4, 5-dihydro-6- (3, 5-dinitro-4-isopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-99),  4, 5-dihydro-6- (3, 5-dinitro-4-t-butoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-100),  4, 5-dihydro-6- (3, 5-dinitro-4-phenoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-101),  4, 5-dihydro-6- (3, 5-dinitro-4-benzyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-102),  4, 5-dihydro-6- (3, 5-dinitro-4-allyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-103),  4, 5-dihydro-6- (3, 5-dinitro-4-propazyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-104),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-105),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclobutyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-106),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopentyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-107),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclohexyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-108),  4, 5-dihydro-6- (3, 5-dinitro-4- (2, 2, 2-hydroxyethyloxy) phenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-109),  4, 5-dihydro-6- (3, 5-dinitro-4-difluoromethyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-110),  4, 5-dihydro-6- (3-sano-4-methoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-111),  4, 5-dihydro-6- (3-cyano-4-ethoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-112),  4, 5-dihydro-6- (3-cyano-4-isopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-113),  4, 5-dihydro-6- (3-cyano-4-t-butoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-114),  4, 5-dihydro-6- (3-cyano-4-phenoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-115),  4, 5-dihydro-6- (3-cyano-4-benzyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-116),  4, 5-dihydro-6- (3-cyano-4-allyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-117),  4, 5-dihydro-6- (3-cyano-4-propazyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-118),  4, 5-dihydro-6- (3-cyano-4-cyclopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-119),  4, 5-dihydro-6- (3-cyano-4-cyclobutyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-120),  4, 5-dihydro-6- (3-cyano-4-cyclopentyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-121),  4, 5-dihydro-6- (3-cyano-4-cyclohexyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-122),  4, 5-dihydro-6- (3-cyano-4- (2, 2, 2-trifluoroethyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-123),  4, 5-dihydro-6- (3-cyano-4-difluoromethyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-124),  4, 5-dihydro-6- (3-amino-4-methoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-125),  4, 5-dihydro-6- (3-amino-4-isopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-126),  4, 5-dihydro-6- (3-amino-4-cyclopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-127),  4, 5-dihydro-6- (3-amino-4-cyclopentyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-128),  4, 5-dihydro-6- (3-amino-4-difluoromethyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-129),  4, 5-dihydro-6- (3-acetamido-4-methoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-130),  4, 5-dihydro-6- (3-acetamido-4-isopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-131),  4, 5-dihydro-6- (3-acetamido-4-cyclopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-132),  4, 5-dihydro-6- (3-acetamido-4-cyclopentyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-133),  4, 5-dihydro-6- (3-acetamido-4-difluoromethyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-134),  4, 5-dihydro-6- (3-benzoylamido-4-methoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-135),  4, 5-dihydro-6- (3-benzoylamido-4-isopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-136),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-137),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopentyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-138),  4, 5-dihydro-6- (3-benzoylamido-4-difluoromethyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-139),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-methoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-140),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-isopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-141),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-cyclopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-142),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-cyclopentyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-143),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-difluoromethyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-144),  4, 5-dihydro-6- (3-trifluoroacetamido-4-methoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-145),  4, 5-dihydro-6- (3-trifluoroacetamido-4-isopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-146),  4, 5-dihydro-6- (3-trifluoroacetamido-4-cyclopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-147),  4, 5-dihydro-6- (3-trifluoroacetamido-4-cyclopentyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-148),  4, 5-dihydro-6- (3-trifluoroacetamido-4-difluoromethyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-149),  4, 5-dihydro-6- (3-methanesulfonamido-4-methoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-150),  4, 5-dihydro-6- (3-methanesulfonamido-4-isopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-151),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-152),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopentyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-153),  4, 5-dihydro-6- (3-methanesulfonamido-4-difluoromethyloxphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-154),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-methoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-155),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-isopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-156),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-cyclopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-157),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-cyclopentyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-158),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-difluoromethyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-159),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-methoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-160),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-isopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-161),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-162),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopentyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-163),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-difluoromethyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-164),  4, 5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-165),  4, 5-dihydro-6- (3-nitro-4-ethoxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-166),  4, 5-dihydro-6- (3-nitro-4-isopropyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-167),  4, 5-dihydro-6- (3-nitro-4-t-butoxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-168,  4, 5-dihydro-6- (3-nitro-4-phenoxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-169),  4, 5-dihydro-6- (3-nitro-4-benzyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-170),  4, 5-dihydro-6- (3-nitro-4-allyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-171),  4, 5-dihydro-6- (3-nitro-4-propazyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-172),  4, 5-dihydro-6- (3-nitro-4-cyclopropyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-173),  4, 5-dihydro-6- (3-nitro-4-cyclobutyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-174),  4, 5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-175),  4, 5-dihydro-6- (3-nitro-4-cyclohexyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-176),  4, 5-dihydro-6- (3-nitro-4- (2, 2, 2-trifluoroethyloxy) phenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-177),  4, 5-dihydro-6- (3-nitro-4-difluoromethyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-178),  4, 5-dihydro-6- (3, 5-dinitro-4-methoxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-179),  4, 5-dihydro-6- (3, 5-dinitro-4-ethoxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-180),  4, 5-dihydro-6- (3, 5-dinitro-4-isopropyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-181),  4, 5-dihydro-6- (3, 5-dinitro-4-t-butoxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-182),  4, 5-dihydro-6- (3, 5-dinitro-4-phenoxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-183),  4, 5-dihydro-6- (3, 5-dinitro-4-benzyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-184),  4, 5-dihydro-6- (3, 5-dinitro-4-allyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-185),  4, 5-dihydro-6- (3, 5-dinitro-4-propazyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-186),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopropyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-187),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclobutyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-188),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopentyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-189),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclohexyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-190),  4, 5-dihydro-6- (3, 5-dinitro-4- (2, 2, 2-trifluoroethyloxy) phenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-191),  4, 5-dihydro-6- (3, 5-dinitro-4-difluoromethyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-192),  4, 5-dihydro-6- (3-cyano-4-methoxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-193),  4, 5-dihydro-6- (3-cyano-4-ethoxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-194),  4, 5-dihydro-6- (3-cyano-4-isopropyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-195),  4, 5-dihydro-6- (3-cyano-4-t-butoxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-196),  4, 5-dihydro-6- (3-cyano-4-phenoxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-197),  4, 5-dihydro-6- (3-cyano-4-benzyloxphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-198),  4, 5-dihydro-6- (3-cyano-4-allyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-199),  4, 5-dihydro-6- (3-cyano-4-propazyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-200),  4, 5-dihydro-6- (3-cyano-4-cyclopropyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-201),  4, 5-dihydro-6- (3-cyano-4-cyclobutyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-202),  4, 5-dihydro-6- (3-cyano-4-cyclopentyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-203),  4, 5-dihydro-6- (3-cyano-4-cyclohexyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-204),  4, 5-dihydro-6- (3-cyano-4- (2, 2, 2-trifluoroethyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-205),  4, 5-dihydro-6- (3-cyano-4-difluoromethyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-206),  4, 5-dihydro-6- (3-amino-4-methoxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-207),  4, 5-dihydro-6- (3-amino-4-isopropyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-208),  4, 5-dihydro-6- (3-amino-4-cyclopropyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-209),  4, 5-dihydro-6- (3-amino-4-cyclopentyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-210),  4, 5-dihydro-6- (3-acetamido-4-difluoromethyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-211),  4, 5-dihydro-6- (3-acetamido-4-methoxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-212),  4, 5-dihydro-6- (3-acetamido-4-isopropyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-213),  4, 5-dihydro-6- (3-acetamido-4-cyclopropyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-214),  4, 5-dihydro-6- (3-acetamido-4-cyclopentyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-215),  4, 5-dihydro-6- (3-acetamido-4-difluoromethyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-216),  4, 5-dihydro-6- (3-benzoylamido-4-methoxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-217),  4, 5-dihydro-6- (3-benzoylamido-4-isopropyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-218),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopropyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-219),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopentyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-220),  4, 5-dihydro-6- (3-benzoylamido-4-difluoromethyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-221),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido-4-methoxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-222),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido-4-isopropyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-223),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido-4-cyclopropyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-224),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido-4-cyclopentyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-225),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido-4-difluoromethyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-226),  4, 5-dihydro-6- (3-trifluoroacetamido-4-methoxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-227),  4, 5-dihydro-6- (3-trifluoroacetamido-4-isopropyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-228),  4, 5-dihydro-6- (3-trifluoroacetamido-4-cyclopropyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-229),  4, 5-dihydro-6- (3-trifluoroacetamido-4-cyclopentyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-230),  4, 5-dihydro-6- (3-trifluoroacetamido-4-difluoromethyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-231),  4, 5-dihydro-6- (3-methanesulfonamido-4-methoxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-232),  4, 5-dihydro-6- (3-methanesulfonamido-4-isopropyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-233),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopropyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-234),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopentyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-235),  4, 5-dihydro-6- (3-methanesulfonamido-4-difluoromethyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-236),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-methoxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-237),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-isopropyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-238),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-cyclopropyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-239),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-cyclopentyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-240),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-difluoromethyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-241),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-methoxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-242),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-isopropyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-243),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopropyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-244),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopentyloxyphenyl) -5-nitrosylmethyl-3 (2H) -pyridazinone (I-245),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-difluoromethyloxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-246),  4, 5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-247),  4, 5-dihydro-6- (3-nitro-4-ethoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-248),  4, 5-dihydro-6- (3-nitro-4-isopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-249),  4, 5-dihydro-6- (3-nitro-4-t-butoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-250),  4, 5-dihydro-6- (3-nitro-4-phenoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-251),  4, 5-dihydro-6- (3-nitro-4-benzyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridinol (I-252),  4, 5-dihydro-6- (3-nitro-4-allyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-253),  4, 5-dihydro-6- (3-nitro-4-propazyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-254),  4, 5-dihydro-6- (3-nitro-4-cyclopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-255),  4, 5-dihydro-6- (3-nitro-4-cyclobutyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-256),  4, 5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-257),  4, 5-dihydro-6- (3-nitro-4-cyclohexyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-258),  4, 5-dihydro-6- (3-nitro-4- (2, 2, 2-trifluoroethyloxy) phenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-259),  4, 5-dihydro-6- (3-nitro-4-difluoromethyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-260),  4, 5-dihydro-6- (3, 5-dinitro-4-methoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-261),  4, 5-dihydro-6- (3, 5-dinitro-4-ethoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-262),  4, 5-dihydro-6- (3, 5-dinitro-4-isopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-263),  4, 5-dihydro-6- (3, 5-dinitro-4-t-butoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-264),  4, 5-dihydro-6- (3, 5-dinitro-4-phenoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-265),  4, 5-dihydro-6- (3, 5-dinitro-4-benzyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-266),  4, 5-dihydro-6- (3, 5-dinitro-4-allyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-267),  4, 5-dihydro-6- (3, 5-dinitro-4-propazyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-268),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-269),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclobutyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-270),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopentyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-271),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclohexyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-272),  4, 5-dihydro-6- (3, 5-dinitro-4- (2, 2, 2-trifluoroethyloxy) phenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-273),  4, 5-dihydro-6- (3, 5-dinitro-4-difluoromethyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-274),  4, 5-dihydro-6- (3-cyano-4-methoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-275),  4, 5-dihydro-6- (3-cyano-4-ethoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-276),  4, 5-dihydro-6- (3-cyano-4-isopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-277),  4, 5-dihydro-6- (3-cyano-4-t-butoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-278),  4, 5-dihydro-6- (3-cyano-4-phenoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-279),  4, 5-dihydro-6- (3-cyano-4-benzyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-280),  4, 5-dihydro-6- (3-cyano-4-allyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-281),  4, 5-dihydro-6- (3-cyano-4-propazyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-282),  4, 5-dihydro-6- (3-cyano-4-cyclopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-283),  4, 5-dihydro-6- (3-cyano-4-cyclobutyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-284),  4, 5-dihydro-6- (3-cyano-4-cyclopentyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-285),  4, 5-dihydro-6- (3-cyano-4-cyclohexyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-286),  4, 5-dihydro-6- (3-cyano-4- (2, 2, 2-trifluoroethyloxy) phenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-287),  4, 5-dihydro-6- (3-cyano-4-difluoromethyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-288),  4, 5-dihydro-6- (3-amino-4-methoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-289),  4, 5-dihydro-6- (3-amino-4-isopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-290),  4, 5-dihydro-6- (3-amino-4-cyclopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-291),  4, 5-dihydro-6- (3-amino-4-cyclopentyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-292),  4, 5-dihydro-6- (3-amino-4-difluoromethyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-293),  4, 5-dihydro-6- (3-acetamido-4-methoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-294),  4, 5-dihydro-6- (3-acetamido-4-isopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-295),  4, 5-dihydro-6- (3-acetamido-4-cyclopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-296),  4, 5-dihydro-6- (3-acetamido-4-cyclopentyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-297),  4, 5-dihydro-6- (3-acetamido-4-dichloromethyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-298),  4, 5-dihydro-6- (3-benzoylamido-4-methoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-299),  4, 5-dihydro-6- (3-benzoylamido-4-isopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-300),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-301),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopentyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-302),  4, 5-dihydro-6- (3-benzoylamido-4-difluoromethyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-303),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-methoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-304),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido-4-isopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-305),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido-4-cyclopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-306),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido-4-cyclopentyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-307),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido-4-dichloromethyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-308)

, 4,5-dihydro-6- (3-trifluoroacetamido-4-methoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-309), 4,5 -Dihydro-6- (3-trifluoroacetamido-4-isopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-310), 4,5-dihydro -6- (3-Trifluoroacetamido-4-cyclopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-311), 4,5-dihydro-6- (3-Trifluoroacetamido-4-cyclopentyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-312), 4,5-dihydro-6- (3- Trifluoroacetamido-4-difluoromethyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-313), 4,5-dihydro-6- (3-methane Sulfonamido-4-methoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-314), 4,5-dihydro-6- (3-methanesulfonamido-4- Isopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-315), 4,5-dihydro-6- (3-methanesulfone Mido-4-cyclopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-316), 4,5-dihydro-6- (3-methanesulfonamido-4-cyclo Pentyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-317), 4,5-dihydro-6- (3-methanesulfonamido-4-difluoromethyloxyphenyl ) -5-fluoromethyl-3 (2H) -pyridazinone (I-318), 4,5-dihydro-6- (3-trifluoromethylsulfonamido-4-methoxyphenyl) -5 -Fluoromethyl-3 (2H) -pyridazinone (I-319), 4,5-dihydro-6- (3-trifluoromethylsulfonamido-4-isopropyloxyphenyl) -5-fluoro Rhomethyl-3 (2H) -pyridazinone (I-320), 4,5-dihydro-6- (3-trifluoromethylsulfonamido-4-cyclopropyloxyphenyl) -5-fluoromethyl -3 (2H) -pyridazinone (I-321), 4,5-dihydro-6- (3-trifluoromethylsulfonamido-4-cyclopentyloxyphenyl) -5-fluoromethyl-3 (2H) -Pyridazinone (I-322), 4,5-dihydro-6- (3-trifluoromethylsulfonamido-4 -Difluoromethyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-323), 4,5-dihydro-6- (3-4'-tolylsulfonamido-4 -Methoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-324), 4,5-dihydro-6- (3-4'-tolylsulfonamido-4-isopropyl Oxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-325), 4,5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopropyloxyphenyl ) -5-fluoromethyl-3 (2H) -pyridazinone (I-326),

4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopentyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-327),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-difluoromethyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-328),  4, 5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-329),  4, 5-dihydro-6- (3-nitro-4-ethoxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-330),  4, 5-dihydro-6- (3-nitro-4-isopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-331),  4, 5-dihydro-6- (3-nitro-4-t-butoxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-332),  4, 5-dihydro-6- (3-nitro-4-phenoxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-333),  4, 5-dihydro-6- (3-nitro-4-benzyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-334),  4, 5-dihydro-6- (3-nitro-4-allyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-335),  4, 5-dihydro-6- (3-nitro-4-propazyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-336),  4, 5-dihydro-6- (3-nitro-4-cyclopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-337),  4, 5-dihydro-6- (3-nitro-4-cyclobutyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-338),  4, 5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-339),  4, 5-dihydro-6- (3-nitro-4-cyclohexyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-340),  4, 5-dihydro-6- (3-nitro-4- (2, 2, 2-trifluoroethyloxy) phenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-341),  4, 5-dihydro-6- (3-nitro-4-difluoromethyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-342),  4, 5-dihydro-6- (3, 5-dinitro-4-methoxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-343),  4, 5-dihydro-6- (3, 5-dinitro-4-ethoxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-344),  4, 5-dihydro-6- (3, 5-dinitro-4-isopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-345),  4, 5-dihydro-6- (3, 5-dinitro-4-t-butoxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-346),  4, 5-dihydro-6- (3, 5-dinitro-4-phenoxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-347),  4, 5-dihydro-6- (3, 5-dinitro-4-benzyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-348),  4, 5-dihydro-6- (3, 5-dinitro-4-allyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-349),  4, 5-dihydro-6- (3, 5-dinitro-4-propazyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-350),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-351),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopentyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-352),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopentyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-353),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclohexyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-354),  4, 5-dihydro-6- (3, 5-dinitro-4- (2, 2, 2-trifluoromethyloxy) phenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-355),  4, 5-dihydro-6- (3, 5-dinitro-4-difluoromethyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-356),  4, 5-dihydro-6- (3-sano-4-methoxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-357),  4, 5-dihydro-6- (3-cyano-4-ethoxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-358),  4, 5-dihydro-6- (3-cyano-4-isopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-359),  4, 5-dihydro-6- (3-cyano-4-t-butoxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-360),  4, 5-dihydro-6- (3-cyano-4-phenoxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-361),  4, 5-dihydro-6- (3-cyano-4-benzyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-362),  4, 5-dihydro-6- (3-cyano-4-allyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-363),  4, 5-dihydro-6- (3-cyano-4-propazyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-364),  4, 5-dihydro-6- (3-cyano-4-cyclopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-365),  4, 5-dihydro-6- (3-cyano-4-cyclobutyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-366),  4, 5-dihydro-6- (3-cyano-4-cyclopentyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-367),  4, 5-dihydro-6- (3-cyano-4-cyclohexyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-368),  4, 5-dihydro-6- (3-cyano-4- (2, 2, 2-trifluoromethyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-369),  4, 5-dihydro-6- (3-cyano-4-difluoromethyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-370),  4, 5-dihydro-6- (3-amino-4-methoxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-371),  4, 5-dihydro-6- (3-amino-4-isopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-372),  4, 5-dihydro-6- (3-amino-4-cyclopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-373),  4, 5-dihydro-6- (3-amino-4-cyclopentyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-374),  4, 5-dihydro-6- (3-amino-4-difluoromethyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-375),  4, 5-dihydro-6- (3-acetamido-4-methoxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-376),  4, 5-dihydro-6- (3-acetamido-4-isopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-377),  4, 5-dihydro-6- (3-acetamido-4-cyclopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-378),  4, 5-dihydro-6- (3-acetamido-4-cyclopentyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-379),  4, 5-dihydro-6- (3-acetamido-4-difluoromethyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-380),  4, 5-dihydro-6- (3-benzoylamido-4-methoxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-381),  4, 5-dihydro-6- (3-benzoylamido-4-isopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-382),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-383),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopentyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-384),  4, 5-dihydro-6- (3-benzoylamido-4-difluoromethyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-385),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-methoxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-386),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-isopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-387),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-cyclopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-388),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-cyclopentyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-389),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-difluoromethyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-390),  4, 5-dihydro-6- (3-trifluoroacetamido-4-methoxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-391),  4, 5-dihydro-6- (3-trifluoroacetamido-4-isopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-392),  4, 5-dihydro-6- (3-trifluoroacetamido-4-cyclopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-393),  4, 5-dihydro-6- (3-trifluoroacetamido-4-cyclopentyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-394),  4, 5-dihydro-6- (3-trifluoroacetamido-4-difluoromethyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-395),  4, 5-dihydro-6- (3-methanesulfonamido-4-methoxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-396),  4, 5-dihydro-6- (3-methanesulfonamido-4-isopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-397),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-398),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopentyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-399),  4, 5-dihydro-6- (3-methanesulfonamido-4-difluoromethyloxphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-400),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-methoxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-401),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-isopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-402),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-cyclopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-403),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-cyclopentyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-404),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-difluoromethyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-405),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-methoxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-406),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-isopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-407),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-408),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopentyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-409),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-difluoromethyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-410),  4, 5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-chlororomethyl-3 (2H) -pyridazinone (I-411),  4, 5-dihydro-6- (3-nitro-4-isopropyloxyphenyl) -5-chlororomethyl-3 (2H) -pyridazinone (I-412),  4, 5-dihydro-6- (3-nitro-4-cyclopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-413),  4, 5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-414),  4, 5-dihydro-6- (3-nitro-4-difluoromethyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-415),  4, 5-dihydro-6- (3, 5-dinitro-4-methoxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-416),  4, 5-dihydro-6- (3, 5-dinitro-4-isopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-417),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-418),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopentyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-419),  4, 5-dihydro-6- (3, 5-dinitro-4-difluoromethyloxyphenyl) -5-chlorolomethyl-3 (2H) -pyridazinone (I-420),  4, 5-dihydro-6- (3-cyano-4-methoxyphenyl) -5-chlororomethyl-3 (2H) -pyridazinone (I-421),  4, 5-dihydro-6- (3-cyano-4-isopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-422),  4, 5-dihydro-6- (3-cyano-4-cyclopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-423),  4, 5-dihydro-6- (3-cyano-4-cyclopentyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-424),  4, 5-dihydro-6- (3-cyano-4-difluoromethyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-425),  4, 5-dihydro-6- (3-amino-4-methoxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-426),  4, 5-dihydro-6- (3-amino-4-isopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-427),  4, 5-dihydro-6- (3-amino-4-cyclopropyloxyphenyl) -5-chlororomethyl-3 (2H) -pyridazinone (I-428),  4, 5-dihydro-6- (3-amino-4-cyclopentyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-429),  4, 5-dihydro-6- (3-amino-4-dichloromethyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-430),  4, 5-dihydro-6- (3-acetamido-4-methoxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-431),  4, 5-dihydro-6- (3-acetamido-4-isopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-432),  4, 5-dihydro-6- (3-acetamido-4-cyclopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-433),  4, 5-dihydro-6- (3-acetamido-4-cyclopentyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-434),  4, 5-dihydro-6- (3-acetamido-4-difluoromethyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-435),  4, 5-dihydro-6- (3-benzoylamido-4-methoxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-436),  4, 5-dihydro-6- (3-benzoylamido-4-isopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-437),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-438),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopentyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-439),  4, 5-dihydro-6- (3-benzoylamido-4-difluoromethyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-440),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-methoxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-441),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-isopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-442),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-cyclopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-443),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-cyclopentyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-444),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-difluoromethyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-445),  4, 5-dihydro-6- (3-trifluoroacetamido-4-methoxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-446),  4, 5-dihydro-6- (3-trifluoroacetamido-4-isopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-447),  4, 5-dihydro-6- (3-trifluoroacetamido-4-cyclopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-448),  4, 5-dihydro-6- (3-trifluoroacetamido-4-cyclopentyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-449),  4, 5-dihydro-6- (3-trifluoroacetamido-4-difluoromethyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-450),  4, 5-dihydro-6- (3-methanesulfonamido-4-methoxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-451),  4, 5-dihydro-6- (3-methanesulfonamido-4-isopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-452),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-453),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopentyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-454),  4, 5-dihydro-6- (3-methanesulfonamido-4-difluoromethyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-455),  4, 5-dihydro-6- (3-hydroxymethylsulfonamido-4-methoxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-456),  4, 5-dihydro-6- (3-hydroxymethylsulfonamido-4-isopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-457),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-cyclopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-458),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-cyclopentyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-459),  4, 5-dihydro-6- (3-hydroxymethylsulfonamido-4-difluoromethyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-460),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-methoxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-461),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-isopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-462),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-463),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopentyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-464),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-difluoromethyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-465),  4, 5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-466),  4, 5-dihydro-6- (3-nitro-4-isopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-467),  4, 5-dihydro-6- (3-nitro-4-cyclopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-468),  4, 5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-469),  4, 5-dihydro-6- (3-nitro-4-difluoromethyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-470),  4, 5-dihydro-6- (3, 5-dinitro-4-methoxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-471),  4, 5-dihydro-6- (3, 5-dinitro-4-isopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-472),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-473),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopentyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-474),  4, 5-dihydro-6- (3, 5-dinitro-4-difluoromethyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-475),  4, 5-dihydro-6- (3-cyano-4-methoxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-476),  4, 5-dihydro-6- (3-cyano-4-isopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-477),  4, 5-dihydro-6- (3-cyano-4-cyclopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-478),  4, 5-dihydro-6- (3-cyano-4-cyclopentyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-479),  4, 5-dihydro-6- (3-cyano-4-difluoromethyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-480),  4, 5-dihydro-6- (3-amino-4-methoxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-481),  4, 5-dihydro-6- (3-amino-4-isopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-482),  4, 5-dihydro-6- (3-amino-4-cyclopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-483),  4, 5-dihydro-6- (3-amino-4-cyclopentyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-484),  4, 5-dihydro-6- (3-amino-4-difluoromethyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-485),  4, 5-dihydro-6- (3-acetamido-4-methoxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-486),  4, 5-dihydro-6- (3-acetamido-4-isopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-487),  4, 5-dihydro-6- (3-acetamido-4-cyclopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-488),  4, 5-dihydro-6- (3-acetamido-4-cyclopentyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-489),  4, 5-dihydro-6- (3-acetamido-4-difluoromethyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-490),  4, 5-dihydro-6- (3-benzoylamido-4-methoxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-491),  4, 5-dihydro-6- (3-benzoylamido-4-isopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-492),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-493),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopentyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-494),  4, 5-dihydro-6- (3-benzoylamido-4-difluoromethyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-495),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-methoxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-496),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-isopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-497),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-cyclopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-498),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-cyclopentyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-499),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-difluoromethyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-500),  4, 5-dihydro-6- (3-trifluoroacetamido-4-methoxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-501),  4, 5-dihydro-6- (3-trifluoroacetamido-4-isopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-502),  4, 5-dihydro-6- (3-trifluoroacetamido-4-cyclopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-503),  4, 5-dihydro-6- (3-trifluoroacetamido-4-cyclopentyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-504),  4, 5-dihydro-6- (3-trifluoroacetamido-4-difluoromethyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-505),  4, 5-dihydro-6- (3-methanesulfonamido-4-methoxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-506),  4, 5-dihydro-6- (3-methanesulfonamido-4-isopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-507),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-508),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopentyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-509),  4, 5-dihydro-6- (3-methanesulfonamido-4-difluoromethyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-510),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-methoxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-511),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-isopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-512),  4, 5-dihydro-6- (3-hydroxymethylsulfonamido-4-cyclopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-513),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-cyclopentyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-514),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-difluoromethyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-515),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-methoxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-516),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-isopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-517),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopropyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-518),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopentyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-519),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-difluoromethyloxyphenyl) -5-trichloromethyl-3 (2H) -pyridazinone (I-520),  4, 5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-521),  4, 5-dihydro-6- (3-nitro-4-isopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-522),  4, 5-dihydro-6- (3-nitro-4-cyclopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-523),  4, 5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-524),  4, 5-dihydro-6- (3-nitro-4-difluoromethyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-525),  4, 5-dihydro-6- (3, 5-dinitro-4-methoxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-526),  4, 5-dihydro-6- (3, 5-dinitro-4-isopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-527),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-528),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopentyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-529),  4, 5-dihydro-6- (3, 5-dinitro-4-difluoromethyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-530),  4, 5-dihydro-6- (3-cyano-4-methoxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-531),  4, 5-dihydro-6- (3-cyano-4-isopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-532),  4, 5-dihydro-6- (3-cyano-4-cyclopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-533),  4, 5-dihydro-6- (3-cyano-4-cyclopentyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-534),  4, 5-dihydro-6- (3-cyano-4-difluoromethyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-535),  4, 5-dihydro-6- (3-amino-4-methoxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-536),  4, 5-dihydro-6- (3-amino-4-isopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-537),  4, 5-dihydro-6- (3-amino-4-cyclopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-538),  4, 5-dihydro-6- (3-amino-4-cyclopentyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-539),  4, 5-dihydro-6- (3-amino-4-difluoromethyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-540),  4, 5-dihydro-6- (3-acetamido-4-methoxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-541),  4, 5-dihydro-6- (3-acetamido-4-isopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-542),  4, 5-dihydro-6- (3-acetamido-4-cyclopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-543),  4, 5-dihydro-6- (3-acetamido-4-cyclopentyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-544),  4, 5-dihydro-6- (3-acetamido-4-difluoromethyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-545),  4, 5-dihydro-6- (3-benzoylamido-4-methoxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-546),  4, 5-dihydro-6- (3-benzoylamido-4-isopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-547),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-548),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopentyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-549),  4, 5-dihydro-6- (3-benzoylamido-4-difluoromethyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-550),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-methoxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-551),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-isopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-552),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-cyclopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-553),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-cyclopentyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-554),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-difluoromethyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-555),  4, 5-dihydro-6- (3-trifluoroacetamido-4-methoxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-556),  4, 5-dihydro-6- (3-trifluoroacetamido-4-isopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-557),  4, 5-dihydro-6- (3-trifluoroacetamido-4-cyclopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-558),  4, 5-dihydro-6- (3-trifluoroacetamido-4-cyclopentyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-559),  4, 5-dihydro-6- (3-trifluoroacetamido-4-difluoromethyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-560),  4, 5-dihydro-6- (3-methanesulfonamido-4-methoxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-561),  4, 5-dihydro-6- (3-methanesulfonamido-4-isopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-562),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-563),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopentyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-564),  4, 5-dihydro-6- (3-methanesulfonamido-4-difluoromethyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-565),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-methoxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-566),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-isopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-567),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-cyclopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-568),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-cyclopentyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-569),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-difluoromethyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-570),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-methoxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-571),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-isopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-572),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopropyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-573),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopentyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-574),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-difluoromethyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-575),  4, 5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-576),  4, 5-dihydro-6- (3-nitro-4-isopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-577),  4, 5-dihydro-6- (3-nitro-4-cyclopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-578),  4, 5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-579),  4, 5-dihydro-6- (3-nitro-4-difluoromethyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-580),  4, 5-dihydro-6- (3, 5-dinitro-4-methoxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-581),  4, 5-dihydro-6- (3, 5-dinitro-4-isopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-582),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-583),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopentyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-584),  4, 5-dihydro-6- (3, 5-dinitro-4-difluoromethyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-585),  4, 5-dihydro-6- (3-cyano-4-methoxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-586),  4, 5-dihydro-6- (3-cyano-4-isopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-587),  4, 5-dihydro-6- (3-cyano-4-cyclopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-588),  4, 5-dihydro-6- (3-cyano-4-cyclopentyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-589),  4, 5-dihydro-6- (3-cyano-4-difluoromethyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-590),  4, 5-dihydro-6- (3-amino-4-methoxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-591),  4, 5-dihydro-6- (3-amino-4-isopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-592),  4, 5-dihydro-6- (3-amino-4-cyclopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-593),  4, 5-dihydro-6- (3-amino-4-cyclopentyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-594),  4, 5-dihydro-6- (3-amino-4-difluoromethyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-595),  4, 5-dihydro-6- (3-acetamido-4-methoxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-596),  4, 5-dihydro-6- (3-acetamido-4-isopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-597),  4, 5-dihydro-6- (3-acetamido-4-cyclopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-598),  4, 5-dihydro-6- (3-acetamido-4-cyclopentyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-599),  4, 5-dihydro-6- (3-acetamido-4-difluoromethyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-600),  4, 5-dihydro-6- (3-benzoylamido-4-methoxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-601),  4, 5-dihydro-6- (3-benzoylamido-4-isopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-602),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopropyloxycyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-603),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopentyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-604),  4, 5-dihydro-6- (3-benzoylamido-4-difluoromethyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-605),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-methylcyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-606),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-isopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-607),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-cyclopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-608),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-cyclopentyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-609),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-difluoromethyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-610),  4, 5-dihydro-6- (3-trifluoroacetamido-4-methoxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-611),  4, 5-dihydro-6- (3-trifluoroacetamido-4-isopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-612),  4, 5-dihydro-6- (3-trifluoroacetamido) -4-cyclopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-613),  4, 5-dihydro-6- (3-trifluoroacetamido) -4-cyclopentyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-614),  4, 5-dihydro-6- (3-trifluoroacetamido-4-difluoromethyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-615),  4, 5-dihydro-6- (3-methanesulfonamido-4-methoxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-616),  4, 5-dihydro-6- (3-methanesulfonamido-4-isopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-617),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-618),  4, 5-dihydro-6- (3-methanesulfonamido) -4-cyclopentyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-619),  4, 5-dihydro-6- (3-methanesulfonamido) -4-difluoromethyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-620),  4, 5-dihydro-6- (3-hydroxymethylsulfonamido) -4-methoxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-621),  4, 5-dihydro-6- (3-hydroxymethylsulfonamido) -4-isopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-622),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-cyclopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-623),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-cyclopentyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-624),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido) -4-difluoromethyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-625),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-methoxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-626),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-isopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-627),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopropyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-628),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopentyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-629),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-difluoromethyloxyphenyl) -5-tribromomethyl-3 (2H) -pyridazinone (I-630),  4, 5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-631),  4, 5-dihydro-6- (3-nitro-4-isopropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-632),  4, 5-dihydro-6- (3-nitro-4-cyclopropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-633),  4, 5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-634),  4, 5-dihydro-6- (3-nitro-4-difluoromethyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-635),  4, 5-dihydro-6- (3, 5-difluoronitro-4-methoxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-636),  4, 5-dihydro-6- (3, 5-dinitro-4-isopropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-637),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-638),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopentyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-639),  4, 5-dihydro-6- (3, 5-dinitro-4-difluoromethyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-640),  4, 5-dihydro-6- (3-cyano-4-methoxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-641),  4, 5-dihydro-6- (3-cyano-4-isopropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-642),  4, 5-dihydro-6- (3-cyano-4-cyclopropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-643),  4, 5-dihydro-6- (3-cyano-4-cyclopentyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-644),  4, 5-dihydro-6- (3-cyino-4-difluoromethyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-645),  4, 5-dihydro-6- (3-amino-4-methoxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-646),  4, 5-dihydro-6- (3-amino-4-isopropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-647),  4, 5-dihydro-6- (3-amino-4-cyclopropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-648),  4, 5-dihydro-6- (3-amino-4-cyclopentyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-649),  4, 5-dihydro-6- (3-amino-4-diflomethyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-650),  4, 5-dihydro-6- (3-acetamido-4-methoxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-651),  4, 5-dihydro-6- (3-acetamido-4-ispropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-652),  4, 5-dihydro-6- (3-acetamido-4-cyclopropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-653),  4, 5-dihydro-6- (3-acetamido-4-cyclopentyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-654),  4, 5-dihydro-6- (3-acetamido-4-difluoromethyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-655),  4, 5-dihydro-6- (3-benzoylamido-4-methoxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-656),  4, 5-dihydro-6- (3-benzoylamido-4-isopropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-657),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-658),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopentyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-659),  4, 5-dihydro-6- (3-benzoylamido-4-difluoromethyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-660),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-methoxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-661),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-isopropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-662),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-cyclopropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-663),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-cyclopentyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-664),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-difluoromethyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-665),  4, 5-dihydro-6- (3-trifluoroacetamido-4-methoxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-666),  4, 5-dihydro-6- (3-trifluoroacetamido-4-isopropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-667),  4, 5-dihydro-6- (3-trifluoroacetamido) -4-cyclopentyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-668),  4, 5-dihydro-6- (3-trifluoroacetamido) -4-cyclopentyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-669),  4, 5-dihydro-6- (3-trifluoroacetamido) -4-difluoromethyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-670),  4, 5-dihydro-6- (3-methanesulfonamido-4-methoxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-671),  4, 5-dihydro-6- (3-methanesulfonamido-4-isopropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-672),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-673),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopentyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-674),  4, 5-dihydro-6- (3-methanesulfonamido-4-difluoromethyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-675),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-methoxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-676),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido) -4-isopropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-677),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-cyclopropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-678),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-cyclopentyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-679),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-difluoromethyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-680),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-methoxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-681),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-isopropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-682),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopropyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-683),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopentyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-684),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-difluoromethyloxyphenyl) -5-difluoromethyl-3 (2H) -pyridazinone (I-685),  4, 5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-686),  4, 5-dihydro-6- (3-nitro-4-isopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-687),  4, 5-dihydro-6- (3-nitro-4-cyclopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-688),  4, 5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-689),  4, 5-dihydro-6- (3-nitro-4-difluoromethyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-690),  4, 5-dihydro-6- (3, 5-dinitro-4-methoxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-691),  4, 5-dihydro-6- (3, 5-dinitro-4-isopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-692),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-693),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopentyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-694),  4, 5-dihydro-6- (3, 5-dinitro-4-difluoromethyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-695),  4, 5-dihydro-6- (3-cyano-4-methoxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-696),  4, 5-dihydro-6- (3-cyano-4-isopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-697),  4, 5-dihydro-6- (3-cyano-4-cyclopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-698),  4, 5-dihydro-6- (3-cyano-4-cyclopentyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-699),  4, 5-dihydro-6- (3-cyino-4-difluoromethyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-700),  4, 5-dihydro-6- (3-amino-4-methoxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-701),  4, 5-dihydro-6- (3-amino-4-isopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-702),  4, 5-dihydro-6- (3-amino-4-cyclopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-703),  4, 5-dihydro-6- (3-amino-4-cyclopentyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-704),  4, 5-dihydro-6- (3-amino-4-difluoromethyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-705),  4, 5-dihydro-6- (3-acetamido-4-methoxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-706),  4, 5-dihydro-6- (3-acetamido-4-isopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-707),  4, 5-dihydro-6- (3-acetamido-4-cyclopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-708),  4, 5-dihydro-6- (3-acetamido-4-cyclopentyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-709),  4, 5-dihydro-6- (3-acetamido-4-difluoromethyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-710),  4, 5-dihydro-6- (3-benzoylamido-4-methoxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-711),  4, 5-dihydro-6- (3-benzoylamido-4-isopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-712),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-713),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopentyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-714),  4, 5-dihydro-6- (3-benzoylamido-4-difluoromethyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-715),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-methoxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-716),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-isopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-717),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-cyclopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-718),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-cyclopentyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-719),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-difluoromethyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-720),  4, 5-dihydro-6- (3-trifluoroacetamido) -4-methoxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-721),  4, 5-dihydro-6- (3-trifluoroacetamido) -4-isopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-722),  4, 5-dihydro-6- (3-trifluoroacetamido-4-cyclopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-723),  4, 5-dihydro-6- (3-trifluoroacetamido-4-cyclopentyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-724),  4, 5-dihydro-6- (3-trifluoroacetamido-4-difluoromethyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-725),  4, 5-dihydro-6- (3-methanesulfonamido-4-methoxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-726),  4, 5-dihydro-6- (3-methanesulfonamido-4-isopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-727),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-728),  4, 5-dihydro-6- (3-methanesulfonamido-4-cyclopentyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-729),  4, 5-dihydro-6- (3-methanesulfonamido-4-difluoromethyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-730),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-methoxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-731),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-isopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-732),  4, 5-dihydro-6- (3-methylsulfonamido-4-cyclopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-733),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-cyclopentyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-734),  4, 5-dihydro-6- (3-trifluoromethylsulfonamido-4-difluoromethyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-735),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-methoxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-736),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-isopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-737),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopropyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-738),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopentyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-739),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-difluoromethyloxyphenyl) -5-dichloromethyl-3 (2H) -pyridazinone (I-740),  4, 5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-741),  4, 5-dihydro-6- (3-nitro-4-isopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-742),  4, 5-dihydro-6- (3-nitro-4-cyclopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-743),  4, 5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-744),  4, 5-dihydro-6- (3-nitro-4-difluoromethyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-745),  4, 5-dihydro-6- (3, 5-dinitro-4-methoxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-746),  4, 5-dihydro-6- (3, 5-dinitro-4-isopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-747),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-748),  4, 5-dihydro-6- (3, 5-dinitro-4-cyclopentyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-749),  4, 5-dihydro-6- (3, 5-dinitro-4-difluoromethyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-750),  4, 5-dihydro-6- (3-cyano-4-methoxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-751),  4, 5-dihydro-6- (3-cyano-4-isopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-752),  4, 5-dihydro-6- (3-cyano-4-cyclopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-753),  4, 5-dihydro-6- (3-cyano-4-cyclopentyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-754),  4, 5-dihydro-6- (3-cyino-4-difluoromethyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-755),  4, 5-dihydro-6- (3-amino-4-methoxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-756),  4, 5-dihydro-6- (3-amino-4-isopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-757),  4, 5-dihydro-6- (3-amino-4-cyclopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-758),  4, 5-dihydro-6- (3-amino-4-cyclopentyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-759),  4, 5-dihydro-6- (3-amino-4-difluoromethyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-760),  4, 5-dihydro-6- (3-acetamido-4-methoxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-761),  4, 5-dihydro-6- (3-acetamido-4-ispropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-762),  4, 5-dihydro-6- (3-acetamido-4-cyclopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-763),  4, 5-dihydro-6- (3-acetamido-4-cyclopentyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-764),  4, 5-dihydro-6- (3-acetamido-4-difluoromethyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-765),  4, 5-dihydro-6- (3-benzoylamido-4-methoxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-766),  4, 5-dihydro-6- (3-benzoylamido-4-isopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-767),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-768),  4, 5-dihydro-6- (3-benzoylamido-4-cyclopentyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-769),  4, 5-dihydro-6- (3-benzoylamido-4-difluoromethyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-770),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-methylcyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-771),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-isopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-772),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-cyclopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-773),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-cyclopentyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-774),  4, 5-dihydro-6- (3- (4-nitrobenzoylamido) -4-difluoromethyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-775),  4, 5-dihydro-6- (3-trifluoroacetamido) -4-methoxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-776),  4, 5-dihydro-6- (3-trifluoroacetamido) -4-isopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-777),  4, 5-dihydro-6- (3-trifluoroacetamido) -4-cyclopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-778),  4, 5-dihydro-6- (3-trifluoroacetamido) -4-cyclopentyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-779),  4, 5-dihydro-6- (3-trifluoroacetamido) -4-difluoromethyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-780),  4, 5-dihydro-6- (3-methanesulfonamido) -4-methoxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-781),  4, 5-dihydro-6- (3-methanesulfonamido) -4-isopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-782),  4, 5-dihydro-6- (3-methanesulfonamido) -4-cyclopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-783),  4, 5-dihydro-6- (3-methanesulfonamido) -4-cyclopentyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-784),  4, 5-dihydro-6- (3-methanesulfonamido) -4-difluoromethyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-785),  4, 5-dihydro-6- (3-methylsulfonamido) -4-methoxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-786),  4, 5-dihydro-6- (3-methylsulfonamido) -4-isopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-787),  4, 5-dihydro-6- (3-methylsulfonamido) -4-cyclopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-788),  4, 5-dihydro-6- (3-methylsulfonamido) -4-cyclopentyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-789),  4, 5-dihydro-6- (3-methylsulfonamido) -4-difluoromethyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-790),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-methoxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-791),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-isopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-792),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopropyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-793),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-cyclopentyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-794),  4, 5-dihydro-6- (3-4'-tolylsulfonamido-4-difluoromethyloxyphenyl) -5-dibromomethyl-3 (2H) -pyridazinone (I-795)

Example 1

Synthesis of 4,5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-methyl-3 (2H) pyridazinone (I-1)

<Step 1>

Synthesis of 4-methoxy propiophenone

50 g (0.33 mole) of 4-hydroxy propiophenone was dissolved in 300 mL of acetone, 60 g (0.43 mole) of calcium carbonate and 60 mL (0.96 mole) of iodomethane were added, followed by heating under reflux with stirring for 5 to 6 hours. . The reaction solvent was removed by evaporation under reduced pressure, diluted with 50 mL of ethyl acetate, washed with 200 mL of distilled water, and then washed with 100 mL of 0.5 N aqueous caustic soda solution and 100 mL of water, respectively. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 55 g of the target compound in 99% yield.

<Step 2>

Synthesis of 4-methoxy-α-ethoxycarbonylmethyl propiophenone

Dissolve 10 g (60.9 mmol) of the compound in tetrahydrofuran distilled to 100 mL (reaction vessel 1) in another vessel with 40 mL of tetrahydrofuran, and 15.4 mL (73.1 mmol) of 1,1,1,3,3, 3-nucleated methyldisilane was added and the mixture was cooled to -50 ° C using dry ice-acetone. Then, 29 mL (73.1 mmol) of normal-butyllithium (2.5 mole nucleic acid solution) was slowly added thereto, followed by stirring for 10 minutes ( Reaction vessel 2).

Cool down the reaction vessel 1 to -78 ° C and slowly transfer the contents of the reaction vessel 2 with a syringe, stir for 1 hour while maintaining the temperature below -50 ° C and 6.7 mL (60.9 mmol) of ethyl bromoacetate slowly After 30 minutes, the mixture was gradually raised to 0 ° C. and 20 mL of water was added to terminate the reaction. The reaction solution was diluted with 300 mL of ethyl acetate, washed twice with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The remaining liquid was purified by silica gel column chromatography to obtain 14.5 g of the target compound in 95% yield.

<Step 3>

Synthesis of 4,5-dihydro-6- (4-methoxyphenyl) -5-methyl-3 (2H) -pyridazinone

5 g (20 mmol) of the compound was dissolved in 30 mL of ethanol, 1.87 mL (30 mmol) of hydrazine hydrate (80% aqueous solution) was added, and the mixture was heated to reflux for 3 hours. The reaction solvent was removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 4.01 g of the target compound in 92% yield.

<Step 4>

Synthesis of 4,5-dihydro-6-(-3-nitro-4-methoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-1)

3 g (13.7 mmol) of the compound was dissolved in 20 mL of chloroform, 1.21 g (15.1 mmol) of ammonium nitrate and 4 mL of anhydrous trifluoroacetic acid were added thereto, and the mixture was stirred at room temperature for 3 hours. The reaction solvent was removed by evaporation under reduced pressure and purified by silica gel column chromatography to obtain 3.06 g of the desired final compound (I-1) in 85% yield.

m.p; 222-223 ° C

¹ HNMR; δ 1.3 (3H, d), 2.5-2.8 (2H, m), 3.3 (1H, m), 4.0 (3H, s), 7.1-8.4 (3H, m)

Example 2

Synthesis of 4,5-dihydro-6-(-3-nitro-4-cyclohexyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-12)

<Step 1>

Synthesis of 4-cyclohexyloxy propiophenone

20 g (0.133 mol) of 4-hydroxy propiophenone was dissolved in 150 mL of difluoromethylformamide, 27.6 g (0.20 mol) of calcium carbonate and 43.4 g (0.26 mol) of bromocyclohexane were added and heated to about 100 ° C. Stir for 5 hours. The reaction solution was diluted with 500 mL of ethyl ether, diluted, washed twice with 200 mL of water, and then washed again with 100 mL of saturated aqueous sodium carbonate solution and 100 mL of water. g was obtained.

<Step 2>

Synthesis of 4-cyclohexyloxy-α-ethoxycarbonylmethyl propiophenone

6.5 g (28.0 mmol) of the compound was dissolved in 60 mL of distilled tetrahydrofuran (reaction vessel 1), 30 mL of tetrahydrofuran was added to another vessel, and 5.4 g (33.6 mmol) of hexamethyldisilane was added, followed by dry ice-acetone. The mixture was cooled to -50 占 폚 or lower, 13.4 mL (33.6 mmol) of normal-butyllithium (2.5 mol nucleic acid solution) was slowly added dropwise, followed by stirring for about 10 minutes (reaction vessel 2).

The reaction vessel 1 was cooled to −78 ° C., and the contents of the reaction vessel 2 were slowly transferred thereto using a syringe, followed by stirring for about 1 hour while maintaining the reaction temperature at −50 ° C. or lower. Subsequently, 5.1 g (30.8 mmol) of ethyl bromoacetate was added slowly, and after 30 minutes of stirring, the reaction temperature was gradually raised to 0 ° C. and 10 mL of water was added to terminate the reaction. The reaction solution was added to 300 mL of ethyl acetate, diluted, washed twice with 100 mL of water, and then the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated by silica gel column chromatography to obtain 5.96 g of the target compound in 67% yield.

<Step 3>

Synthesis of 4-cyclohexane-α-carboxymethyl propiophenone

5 g (15.7 mmol) of the compound was dissolved in 60 mL of methanol, 10 mL of water and 2.0 g (47.1 mmol) of lithium hydroxide were added thereto, followed by stirring for 3 to 4 hours while heating to 50 ° C. 10% aqueous hydrochloric acid solution was added to make pH3, diluted with 200 mL of ethyl acetate, washed once with 100 mL of water, dried over anhydrous sodium sulfate, and filtered. Got it.

<Step 4>

Synthesis of 4,5-dihydro-6- (4-cyclohexyloxyphenyl) -5-methyl-3 (2H) -pyridazinone

4 g (13.8 mmol) of the compound was dissolved in 30 mL of ethanol, and 1.7 mL (27.6 mmol) of hydrazine 80% aqueous solution was added thereto, followed by heating to reflux for 3 hours. The reaction solvent was evaporated off under reduced pressure and purified using silica gel column chromatography to synthesize 2.97 g of the target compound in 75% yield.

<Step 5>

Synthesis of 4,5-dihydro-6- (3-nitro-4-cyclohexyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-12)

2.0 g (7.0 mmol) of the compound was dissolved in 20 mL of chloroform, and 0.61 g (7.7 mmol) of ammonium nitrate and 4 mL of anhydrous trifluoroacetic acid were added thereto, followed by stirring at room temperature for 3 hours. The reaction solution was diluted with 150 mL of methylene chloride, washed with 50 mL of water, the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by evaporation under reduced pressure. The remaining yellow solid was mixed with a methylene chloride-ethyl acetate (1: 1) mixture. Recrystallization gave 2.0 g of the target compound (I-12) in 88% yield.

m.p .; 184 ~ 185 ℃

¹ HNMR; δ 1.25 (3H, d), 1.3 to 2.0 (10 H, m), 2.5 (1 H, d), 2.74 (1 H, g), 3.32 (1 H, m), 4.55 (1 H, m), 7.13 (1 H, d), 7.93 (1H, d), 8.15 (1H, s), 8.60 (1H, s)

Example 3

Synthesis of 4,5-dihydro-6- (3-nitro-4-difluoromethyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-14)

<Step 1>

Synthesis of 4-difluoromethyloxypropiophenone

20.3 g (135 mmol) of 4-hydroxypropiophenone was dissolved in distilled tetrahydrofuran (100 mL), 5.4 g (135 mmol) of sodium hydride (60%) were added, followed by stirring at room temperature for 5 minutes. The reaction vessel was lowered to 0 ° C., dibromodifluoromethane (12.4 mL, 135 mmol) was added again, followed by stirring for 30 minutes. Water (10 mL) was added to the reaction mixture, and the solvent was removed under reduced pressure. The residue was extracted twice with dichloromethane (100 mL each), dried over MgSO ₄ anhydride, filtered and concentrated under reduced pressure to obtain the target compound in 63% yield in 17.01. g was prepared.

<Step 2>

Synthesis of 4-difluoromethyloxy-α-ethoxycarbonylmethyl propiophenone

6.0 mL (43 mmol) of diisopropylamine was dissolved in distilled tetrahydrofuran (40 mL) and the reaction vessel was lowered to 0 ° C. 2.7 M butyl lithium hexane solution (13.7 mL, 37 mmol) was slowly added thereto, followed by stirring for 20 minutes to form LDA. The LDA solution was cooled to −78 ° C. and 5.74 g (28.7 mmol) of the compound were added, followed by addition of ethyl bromomoacetate (3.6 mL, 32 mmol). The reaction solution was slowly heated to 0 ° C., water (10 mL) was added thereto, the tetrahydrofuran was removed under reduced pressure, and the residue was extracted twice with ethyl acetate (50 mL each), dried over MgSO ₄ anhydride, filtered, and under reduced pressure. The solvent was removed to prepare 8.1 g of the target compound in 66% yield.

<Step 3>

Synthesis of 3-nitro-4-difluoromethyloxy-α-ethoxycarbonylmethyl propiophenone

20 g (70 mmol) of the compound and ammonium nitrate (5.6 g, 70 mmol) were added to chloroform (100 mL), anhydrous trifluoro acetic acid (39.5 mL, 280 mmol) was added, followed by stirring at room temperature for 12 hours. Remove excess anhydrous trifluoro acetic acid and chloroform under reduced pressure, dissolve the residue in dichloromethane (50 mL), wash with water, dry with MgSO ₄ anhydride and concentrate the solvent under reduced pressure to give the target compound in 85% yield. 19.7 g were prepared.

<Step 4>

Synthesis of 4,5-dihydro-6- (3-nitro-4-difluoromethyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-14)

20 g (60.4 mmol) of the compound was dissolved in ethanol (100 mL), followed by addition of 7.6 mL (120.8 mmol) of hydrazine hydrate (80%). The mixture was heated to reflux for 18 hours, and then ethanol was removed under reduced pressure, and then the residue was dissolved in ethyl acetate (300 mL), washed with water, dried over MgSO ₄ anhydride, filtered, and the solvent was concentrated under reduced pressure. 15.5 g of Compound (I-14) was prepared in 86% yield.

m.p; 112 ~ 113 ℃

¹ HNMR; δ 1.3 (3H, d), 2.55 (1H, d), 2.75 (1H, g), 3.35 (1H, m), 6.4 ~ 7.0 (1H, d), 8.0 (1H, d), 8.3 (1H, s), 8.75 (1 H, s)

Example 4

Synthesis of 4,5-dihydro-6- (3-nitro-4- (2,2,2-trifluoromethyloxy) phenyl-5-methyl-3 (2H) -pyridazinone (I-13)

<Step 1>

Synthesis of 4- (2,2,2-trifluoro) -ethyloxy propiophenone

4-hydroxy propiophenone (5 g, 33 mmol) was dissolved in 40 mL of acetone, then potassium carbonate (6 g, 43 mmol) and 10 mL of 2,2,2-trifluoromethyl methanesulfonate were added, followed by heating for 18 hours. It was refluxed. The reaction solvent was removed by distillation under reduced pressure, diluted with ethyl acetate, washed with water and 1N aqueous solution of 1N-Gasodium, respectively. The organic layer was dried over Na ₂ SO ₄ anhydride, filtered and concentrated under reduced pressure to give the target compound in 90% yield in 6.89 g. Prepared.

<Step 2>

Synthesis of 4- (2,2,2-trifluoro) -ethyloxy-α-ethylcarboxymethyl-propiophenone

1,1,1,3,3,3-hexamethyldisilane (1.54 mL, 3 mmol) was added to 10 mL of tetrahydrofuran and cooled to -50 ° C or lower. Under argon atmosphere, normal butyllithium hexane solution (2.9 mL, 7.3 mmol) was slowly added, stirred for 10 minutes, cooled to -78 ° C, and after 30 minutes, the compound (1.6 g, 6.9 mmol) was added to 10 mL of tetrahydrofuran. The solution dissolved in was slowly added, stirred at -50 ° C. for 1 hour, ethyl bromoacetate (0.7 mL, 6.9 mmol) was added slowly, and the temperature was increased to 0 ° C. The reaction solution was extracted with water and acetate, the organic layer was washed with water, dried over Na ₂ SO ₄ or anhydride, filtered and concentrated under reduced pressure to give 1.6 g of the target compound in 73% yield.

<Step 3>

Synthesis of 3-nitro-4- (2,2,2, -trifluoro) -ethyloxy-α-ethylcarboxymethyl-preiophenone

The compound (2.23 g, 7 mmol) was dissolved in 20 mL of chloroform, ammonium nitrate (0.6 g, 7.5 mmol) and 2 mL of anhydrous trifluoroacetic acid were added, followed by stirring at room temperature for 8 hours. The reaction was extracted with saturated aqueous NaHCO ₃ solution and methylene chloride, and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 1.7 g of the target compound in 83% yield.

<Step 4>

Synthesis of 3-nitro-4- (2,2,2, -trifluoro) -ethyloxy-α-carboxy preiophenone

The compound (1.81 g, 5 mmol) was dissolved in 20 mL of ethanol, and 2N aqueous LiOH solution was added thereto, followed by stirring at room temperature for 12 hours. The reaction was adjusted to pH 2-3 using an aqueous 2N HCl solution, extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 1.28 g of the target compound in 97% yield.

<Step 5>

Of 4,5-dihydro-6- (3-nitro-4- (2,2,2-trifluoroethyloxy) phenyl-5-methyl-3 (2H))-pyridazinone (I-13) synthesis

The compound (0.66 g, 2 mmol) was dissolved in 10 mL of ethanol and 2 mL of hydrazine was added. The solution was heated to reflux for 12 hours, methanol was removed under reduced pressure, extracted with water and methylene chloride, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to prepare 0.44 g of the target compound in 85% yield. It was.

m.p .; 185 ~ 188 ℃

¹ HNMR (CDCl ₃ ); δ1.3 (3H, d), 2.5 (1H, d), 2.7 (1H, dd), 3.4 (1H, m), 4.6 (2H, q), 7.2 (1H, d), 8.0 (1H, dd) , 8.3 (1H, d), 8.9 (1H, s)

Example 5

Synthesis of 4,5-dihydro-6- (3-nitro-4-allyloxyphenyl) -5-methyl-3 (2H))-pyridazinone (I-7)

<Step 1>

Synthesis of 4-methoxy-α-carboxymethyl propiophenone

50.0 g (200 mmol) of 4-methoxy-α-methoxycarbonylmethyl propiophenone was dissolved in a mixed solution of 100 mL of methanol and 100 mL of water, and then lithium hydroxide hydrate (25.2 g, 600 mmol) was added thereto at room temperature. Stir for 1 hour. Methanol was removed under reduced pressure, adjusted to pH 2-3 using 1N HCl aqueous solution, extracted three times with ethyl acetate (200 mL each), the organic layer was dried over MgSO ₄ anhydrous, filtered and concentrated under reduced pressure. 42.18g was prepared by% yield.

<Step 2>

Synthesis of 4-hydroxy-α-carboxymethyl propiophenone

20.0 g (90 mmol) of the compound was dissolved in 100 mL of bromic acid (47%) and heated to reflux for 5 hours. After the reaction mixture was cooled, water (300 mL) was added thereto, extracted three times with ethyl acetate (100 mL each), the organic layer was dried over MgSO ₄ anhydride, filtered, and concentrated under reduced pressure to obtain 15.0 g of the target compound in 80% yield. .

<Step 3>

Synthesis of 4-allyloxy-α-carboxymethyl propiophenone and 4-allyloxy-α-allyloxycarbonylmethyl propiophenone

20 g (96.2 mmol) of the compound was dissolved in acetone (100 mL), potassium carbonate (26.6 g, 192 mmol) and allyl bromide (16.6 mL, 192 mmol) were added, and the mixture was heated to reflux for 14 hours. Remove acetone under reduced pressure, adjust to pH 2-3 using 1N HCl aqueous solution, extract three times with ethyl acetate (100 mL each), dry the organic layer with MgSO ₄ anhydride, filter, and remove the solvent under reduced pressure. 26.4 g of the mixture was prepared in 95% yield.

<Step 4>

Synthesis of 4-allyloxy-α-carboxymethyl propiophenone

30 g of the two mixtures were dissolved in a mixed solution of 100 mL of methanol and 100 mL of water, and lithium hydride hydrate (20 g, 476 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. Methanol was removed under reduced pressure, adjusted to pH 2-3 using 1N NCl aqueous solution, extracted three times with ethyl acetate (100 mL each), dried over MgSO ₄ anhydride, filtered and concentrated under reduced pressure to obtain the target compound in 98% yield. 25.2g was prepared.

<Step 5>

Synthesis of 4,5-dihydro-6- (4-allyloxyphenyl) -5-methyl-3 (2H) -pyridazinone

15 g (60.4 mmol) of the compound was dissolved in ethanol (100 mL), and then 7.6 mL (120.8 mmol) of hydrazine hydrate (80%) was added. The mixture was heated to reflux for 3 hours and then ethanol was removed under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with water, dried over MgSO ₄ anhydride, filtered, and the solvent was concentrated under reduced pressure to give 12.6 g of the target compound in 86% yield.

<Step 6>

Synthesis of 4,5-dihydro-6- (3-nitro-4-allyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-7)

17.1 g (70 mmol) of the compound and ammonium nitrate (5.6 g, 70 mmol) were added to chloroform (100 mL), trifluoroacetic anhydride (39.5 mL, 280 mmol) was added thereto, followed by stirring at room temperature for 14 hours. . Excess trifluoroacetic anhydride and chloroformum were removed under reduced pressure, and the residue was dissolved in dichloromethane (500 mL), washed with water, dried over MgSO ₄ anhydride, filtered, and the solvent was concentrated under reduced pressure to obtain 83% of the target compound. 16.0 g was prepared in yield.

m.p .; 185 ~ 186 ℃

¹ HNMR (CDCl ₃ ); δ 1.25 (3H, d), 2.5 (1H, d), 2.75 (1H, q), 3.35 (1H, m), 4.76 (2H, d), 5.35 ~ 5.58 (2H, q), 6.1 (1H, m), 7.15 (1H, d), 7.95 (1H, d), 8.25 (1H, s), 8.72 (1H, s)

Example 6

Synthesis of 4,5-dihydro-6- (3-nitro-4-propazyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-8)

<Step 1>

Synthesis of 4-propazyloxy-α-carboxymethylpropiophenone and 4-propazyloxy-α-propazyloxycarbonylmethyl propiophenone

20 g (96.2 mmol) of 4-hydroxy-α-carboxymethylpropiophenone are dissolved in difluoromethyl formaldehyde (50 mL), potassium carbonate (26.6 g, 192 mmol) and propazyl chloride (13.9 mL, 192 mmol). ) Was added and then heated to reflux for 18 hours. The mixture was adjusted to pH 2-3 using 1N aqueous HCl solution, extracted three times with ethyl acetate (100 mL each), washed with water, dried over anhydrous MgSo ₄ , and the solvent was removed under reduced pressure. g was prepared.

<Step 2>

Synthesis of 4,5-dihydro- (4-propazyloxyphenyl) -5-methyl-3 (2H) -pyridazinone

20 g of a mixture of the two compounds was dissolved in ethanol (100 mL), and then 15 mL (238 mmol) of hydrazine hydrate 980% were added. The mixture was heated to reflux for 18 hours, ethanol was removed under reduced pressure, and the residue was dissolved in ethyl acetate (300 mL), washed with water, dried over MgSO ₄ anhydrous, filtered, and the solvent was concentrated under reduced pressure to obtain the target compound. Prepared 17g in% yield.

<Step 3>

Synthesis of 4,5-dihydro-6- (3-nitro-4-propazyloxyphenyl) -5-methyl-3 (2H) -pyridazinone

16.0 g (70 mmol) of the compound and ammonium nitrate (5.6 g, 70 mmol) were added to chloroform (100 mL), trifluoroacetic anhydride (39.5 mL, 280 mmol) was added thereto, followed by stirring at room temperature for 14 hours. I was. Under reduced pressure, chloroform and excess trifluoroacetic anhydride were removed, the residue was dissolved in dichloromethane (500 mL), washed with water, dried over MgSO ₄ anhydride, filtered, and the solvent was concentrated under reduced pressure to give the target compound in 92% yield. 18.5g was prepared.

m.p .; 182 ~ 183 ℃

¹ HNMR (CDCl ₃ ); δ 1.25 (3H, d), 2.4 to 2.8 (1H, m), 3.4 (1H, m), 4.9 (2H, s), 7.1 to 8.3 (3H, m), 8.7 (1H, s)

Example 7

Synthesis of 4,5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-11)

<Step 1>

Synthesis of 4-isopropoxypropiophenone

20 g (0.133 mol) of 4-hydroxypropiophenone was dissolved in 200 mL of acetone, 27.6 g (0.20 mol) of potassium carbonate and 32.7 g (0.266 mol) of 2-bromopropane were added and stirred under reflux for 15 hours. . The reaction solvent was evaporated under reduced pressure, diluted with ethyl acetate (500 mL), washed with water (200 mL), washed with saturated aqueous sodium carbonate solution (100 mL) and water (100 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was Evaporation under reduced pressure afforded 24.6 g of the target compound in 96% yield.

<Step 2>

Synthesis of 4-isopropoxy-α-ethoxycarbonylmethyl propiophenone

Take 30 mL of tetrahydrofuran into the flask, add 5.4 g (33.6 mmol) of hexamethyldisilane, cool to below 50 ° C by using a dry ice-acetone container, and then 13.4 mL of n-butyllithium (2.5 mol hexane solution). 33.6 mmol) was slowly added dropwise and stirred for about 10 minutes (reaction vessel 1). In another flask, 7.4 g (28.0 mmol) of the compound was dissolved in tetrahydrofuran and cooled to minus 78 ° C. Then, the compound of Reaction Vessel 1 prepared above was dissolved in tetrahydrofuran using share gas, cooled to minus 78 ° C, and then reacted to the above. Slowly transfer all of the compounds from vessel 1 to the mixture using a syringe, and then cool the reaction temperature to -78 ° C. Then, slowly transfer all of the compounds from reaction vessel 1 prepared above using a syringe and keep the reaction temperature at -50 ° C. The mixture was stirred for about a minute and 51.g (30.8 mmol) of ethyl bromoacetate was added slowly. After stirring for 30 minutes, the dry ice-acetone vessel was removed, and the reaction temperature was gradually raised to 0 ° C., and 10 mL of water was added to terminate the reaction. The reaction mixture was diluted with 300 mL of ether, diluted twice with water, washed twice with water, and then the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated off under reduced pressure and purified by silica gel column chromatography to give the title compound in 65% yield. g was prepared.

<Step 3>

Synthesis of 4-hydroxy-α-ethoxycarbonylmethyl propiophenone

10 g (37.6 mmol) of the compound was dissolved in 100 mL of HBr (47%) and heated to reflux for 15 hours. 150 mL of ether was extracted twice, dried over anhydrous sodium sulfate, filtered and the solvent was evaporated off under reduced pressure to obtain 7.8 g of the target compound in 88% yield.

<Step 4>

Synthesis of 4-cyclopentyloxy-α-ethoxycarbonylmethyl propiophenone

Dissolve 2 g (8.4 mmol) of the compound in 10 mL of difluoromethylformamide, add 1.74 g (12.6 mmol) of potassium carbonate and 2.5 g (16.8 mmol) of cyclopentyl bromide and stir for 5 to 6 hours while heating to 100 ° C. It was. The reaction solution was added to 10 mL of ether, diluted, washed with 30 mL of water and 30 mL of saturated sodium carbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated off under reduced pressure to obtain 2.33 g of the target compound in 91% yield.

<Step 5>

Synthesis of 4-cyclopentyloxy-α-carboxymethyl propiophenone

1.2 g (5.71 mmol) of the compound was dissolved in 200 mL of methanol, 4 mL of water and 0.85 (17.1 mmol) of lithium hydroxide were added thereto, and the mixture was stirred for 4 hours while warming to 50 ° C. 10% aqueous solution of hydrochloric acid was added to adjust the pH to about 3, extracted with 100 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated off under reduced pressure to obtain 1.1 g of the target compound in 96% yield.

<Step 6>

Synthesis of 4,5-dihydro-6- (4-cyclopentyloxyphenyl) -5-methyl-3 (2H) -pyridazinone

1.0 g (4.76 mmol) of the compound was dissolved in 15 mL of ethanol, and 0.5 g (7.2 mmol) of hydrazine hydrate was added thereto, followed by heating to reflux for 3 hours. Subsequently, ethanol was removed by evaporation under reduced pressure, and the resulting solid was recrystallized from methylene chloride-hexane solution to prepare 0.84 g of the target compound in 85% yield.

<Step 7>

Synthesis of 4,5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-11) 0.7 g (3.38 mmol) of the compound It was dissolved in 5 mL of chloroform, and 0.3 g (3.72 mmol) of ammonium nitrate and 0.8 mL of trifluoroacetic anhydride were added, followed by stirring at room temperature for 3 hours. Subsequently, the reaction solvent was removed by evaporation under reduced pressure, and the remaining yellow solid was washed several times with distilled water, and then washed two or three times with ether to prepare 0.96 g of the final target compound (I-11) in 90% yield.

m.p .; 148 ~ 150 ℃

¹ HNMR; δ 1.25 (3H, d), 1.6 to 2.0 (8H, m), 2.5 (1H, d), 2.75 (1H, q), 3.35 (1H, m), 4.95 (1H, m), 7.1 (1H, d), 7.93 (1 H, d), 8.18 (1 H, s), 8.60 (1 H, s)

Example 8

Synthesis of 4,5-dihydro-6- (3-nitro-4-benzyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-6)

<Step 1>

Synthesis of 4-benzyloxy-α-ethoxycarbonylmethyl propiophenone

1.2 g (5.08 mmol) of 4-hydroxy-α-ethoxycarbonylmethyl propiophenone was dissolved in 10 mL of difluoromethylformamide, and 1.05 g (7.3 mmol) of potassium carbonate and 1.3 g (7.63 mmol) of benzyl bromide were dissolved. It was added and stirred for 5 hours while heating to 100 ° C. Subsequently, the reaction solution was diluted with 100 mL of ether, washed with 30 mL of water, the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 1.5 g of the target compound in 92% yield.

<Step 2>

Synthesis of 4-benzyloxy-α-ethoxycarbonylmethyl propiophenone

1.0 g (3.06 mmol) of the compound was dissolved in 10 mL of methanol, 2 mL of water and 0.42 g (9.2 mmol) of lithium hydroxide were added, followed by stirring for 4 hours while heating to 50 ° C. Subsequently, an aqueous 10% -HCl solution was added to adjust pH to about 3, extracted with 80 mL of ethyl acetate, dried over anhydrous sodium sulfate, and filtered to obtain 0.88 g of the target compound in 97% yield.

<Step 3>

Synthesis of 4,5-dihydro-6- (4-benzyloxyphenyl0-5-methyl-3 (2H) -pyridanone

0.7 g (2.35 mmol) of the compound was dissolved in 7 mL of ethanol, and 0.3 g (4.7 mmol) of hydrazine hydrate was added thereto, followed by heating to reflux for 2 hours. Subsequently, ethanol was evaporated under reduced pressure, and the resulting solid was recrystallized from a methylene chloride-hexane (1: 1) mixture to prepare 0.59 g of the target compound in 85% yield.

<Step 4>

Synthesis of 4,5-dihydro-6- (3-nitro-4-bendioxyphenyl) -5-methyl-3 (2H) -pyridazino (I-6)

0.52 g (1.76 mmol) of the compound was added to 4 mL of chloroform, and 0.15 g (1.94 mmol) of ammonium nitrate and 0.7 mL of mustrifluoroacetic acid were then stirred at room temperature for 3 hours. The reaction solvent was evaporated and removed under reduced pressure, and the remaining solid was washed 3-4 times with distilled water and 2-3 times with ether to prepare 0.53 g of the final target compound (I-6) in 88% yield.

m.p .; 187 ~ 188 ℃

¹ HNMR; δ-1.25 (3H, d), 2.5 (1H, d), 2.75 (1H, q), 3.34 (1H, m), 5.30 (2H, s), 7.15 (1H, d), 7.3 ~ 7.5 (5H, m), 7.92 (1 H, d), 8.25 (1 H, s), 8.67 (1 H, s)

Example 9

Synthesis of 4,5-dihydro-6- (3-nitro-4-cycloprooxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-9)

<Step 1>

Synthesis of 4-bromoethyloxy-α-ethoxycarbonylmethyl propiophenone

5.0 g (22.5 mmol) of 4-hydroxy-α-ethoxycarbonylmethyl propiophenone are dissolved in 50 mL of difluoromethylformamide, 9.3 g (67.5 mmol) of potassium carbonate and 9.7 mL (0.112 mmol) of dibromoethane. ) Was added followed by stirring with heating at 100 ° C. for 10 hours. Subsequently, 200 mL of distilled water was added to the reaction solution, followed by trituration with 100 mL of ether. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 5.8 g of the target compound in 79% yield.

<Step 2>

Synthesis of 4-vinyloxy-α-ethoxycarbonylmethyl propiophenone

1.0 g (3.04 mmol) of the compound was dissolved in 10 mL of benzene, 0.93 g (3.34 mmol) of tetrabutyl ammonium chloride and 3 mL of a 50% aqueous sodium hydroxide solution were added thereto, followed by stirring at room temperature for 3 hours. The reaction solution was diluted with 100 mL of ethyl acetate and washed twice with 30 mL of water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated off under reduced pressure. g was prepared.

<Step 3>

Synthesis of 4-cyclopropyloxy-α-ethoxycarbonylmethyl propiophenone

0.3 g (1.21 mmol) of the compound was dissolved in 5 mL of distilled ether, and 6 mL (6.0 mmol) of diethyl zinc (1.0 mol hexane solution) was slowly added, followed by slowly adding 0.5 mL (6.0 mmol) of diiomethane, and for 20 hours. It was heated to reflux with stirring. 1 mL of water was added to terminate the reaction. The mixture was diluted with 50 mL of ether, washed once with water, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The remaining residue was purified by silica gel column chromatography to give the title compound in 72% yield. 0.23 g was prepared.

<Step 4>

Synthesis of 4-cyclopropyloxy-α-carboxymethyl propiophenone

0.2 g (0.76 mmol) of the compound was dissolved in 5 mL of methanol, 3 mL (3.0 mmol) of 1N-LiOH was added thereto, followed by stirring at room temperature for 4 hours. Subsequently, diluted with 2 mL of distilled water, adjusted to pH 4 with 1N-HCl aqueous solution, extracted twice with 30 mL of ethyl acetate, dried over anhydrous sodium sulfate, and concentrated by filtration to remove the solvent to obtain the target compound (9-5) in 95% yield in 0.18% yield. g was prepared.

<Step 5>

Synthesis of 4,5-dihydro-6- (4-cyclopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone

0.18 g (0.73 mmol) of the compound was dissolved in 5 mL of ethanol, and 0.14 mL (2.19 mmol) of hydrazine and hydrate (80%) were added, followed by heating under reflux for 3 hours. Ethanol as a reaction solvent was removed by evaporation under reduced pressure, and the remaining solid was recrystallized using a methylene chloride-hexane (1: 1) solvent to prepare 0.16 g of the target compound in 90.3% yield.

<Step 6>

Synthesis of 4,5-dihydro-6- (3-nitro-4-cyclopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone

0.16 g (0.65 mmol) of the compound was dissolved in 3 mL of chloroform, and 0.16 g (0.17 mmol) of ammonium nitrate and 0.5 mL of trifluoroacetic anhydride were added thereto, followed by stirring at room temperature for 3 hours. The reaction solvent was removed by evaporation under reduced pressure, and the remaining yellow solid was washed several times with distilled water and then washed 3-4 times with ether to prepare 0.2 g of the final target compound in 65% yield.

¹ HNMR; δ 0.9 (4H, d), 1.3 (3H, d), 2.5 to 2.8 (2H, m), 3.4 to 3.9 (2H, m), 7.5 to 8.3 (3H, m),

<Step 7>

Synthesis of 4,5-dihydro-6- (3,5-dinitro-4-cyclopropyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-9)

0.2 g (0.82 mmol) of the intermediate compound (9-6) synthesized above were dissolved in 3 mL of chloroform, 0.26 g (3.28 mmol) of ammonium nitrate and 0.6 mL of trifluoroacetic anhydride were added thereto, followed by stirring at room temperature for 3 hours. Subsequently, the reaction solvent was removed by evaporation under reduced pressure, and the remaining solid was dissolved in 50 mL of methylene chloride, washed once with water, and then the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated to remove the mixture. Recrystallization gave 0.23 g of the target compound in 85% yield.

m.p .; 208 ~ 209 ℃

¹ HNMR (CDCl ₃ ); δ 0.9 (4H, d), 1.3 (3H, d), 2.5-2.8 (2H, m), 3.4 (1H, m), 3.9 (1H, m), 8.5 (2H, s)

Example 10

4,5-Dihydro-6- (3-methylsulfonamido-4-isopropoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-69) and 4,5-dihydro- Synthesis of 6- (3-amino-4-isopropoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-44)

<Step 1>

Synthesis of 4,5-dihydro-6- (3-amino-4-isopropoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-44)

0.8 g (2.75 mmol) of 4,5-dihydro-6- (3-nitro-4-isopropoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-3) was dissolved in 10 mL of ethanol. Then, 0.08 g of palladium (10%) was added thereto and reacted at a hydrogen pressure of 40 to 50 psi for 20 minutes. The reaction solution was filtered through silica gel, and the solvent was concentrated under reduced pressure to prepare 0.75 g of the target compound (I-44) in 98% yield.

M.P .; 143-145 ° C

¹ HNMR (CDCl ₃ ); δ1.3 (3H, d), 1.4 (6H, d), 2.4-2.8 (2H, q), 3.4 (1H, m), 4.6 (1H, m), 6.8-7.3 (3H, m)

<Step 2>

Synthesis of 4,5-dihydro-6- (3-methylsulfonamido-4-isopropoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-69)

0.1 g (0.38 mmol) of the compound was dissolved in 5 mL of difluoromethylformamide, 0.08 mL of triethylamine was further added thereto, cooled to 0 DEG C, and slowly added 0.4 mL of methanesulfonyl chloride for 30 minutes. Stirred. The reaction solution was added to 50 mL of ethyl acetate, washed with distilled water, and the organic layer was distilled under reduced pressure to purify the material by column chromatography to obtain 0.11 g of the target compound (I-69) as a white solid in 87% yield.

m.p .; 130 ~ 132 ℃

¹ HNMR (CDCl ₃ ); δ 1.3 (3H, d), 1.4 (6H, d), 2.5-2.8 (2H, m), 3.0 (3H, s), 3.4 (1H, m), 4.7 (1H, m), 6.9-8.5 ( 5H, m)

Example 11

4,5-Dihydro-6- (3-amino-4-cyclopentyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-46) and 4,5-dihydro-6- ( Synthesis of 3-benzoylamido-4-cyclopentyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-56)

<Step 1>

Synthesis of 4,5-dihydro-6- (3-amino-4-cyclopentyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-11)

1.0 g (3.15 mmol) of 4,5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-11) was dissolved in 15 mL of ethanol. 0.10 g of paradue (10% on C) was added thereto, followed by reaction for 20 minutes after adjusting the hydrogen pressure to 40 to 50 psi. The reaction solution was filtered through silica gel, and the solvent was concentrated under reduced pressure to obtain 0.88 g of the target compound (I-46) in 98% yield.

¹ HNMR (CDCl ₃ ); δ1.3 (3H, d), 2.2 (8H, d), 3.7 (1H, m), 4.55 (2H, m), 4.75 (1H, m), 7.2-8.2 (3H, m), 9.2 (1H, s)

<Step 2>

Synthesis of 4,5-dihydro-6- (3-benzoylamino-4-cyclopentyloxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-11)

0.1 g (0.34 mmol) of the compound was dissolved in 5 mL of tetrahydrofuran, and 0.01 mL of triethylamine was further added, and then 0.1 g of benzoyl chloride was slowly added and reacted at room temperature for 20 minutes. Subsequently, the solvent was concentrated under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, washed with distilled water, and the solvent was concentrated under reduced pressure. Then, 0.13 g of the target compound (I-56) was prepared in 95% yield.

¹ HNMR (CDCl ₃ ); δ1.2 (3H, d), 2.2 (8H, d), 3.7 (1H, m), 4.55 (2H, m), 4.7 (1H, m), 7.2 to 9.0 (10H, m)

Example 12

Synthesis of 4,5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-94)

<Step 1>

Synthesis of 4-cyclohexyloxy- (β-hydroxy-α-ethoxycarbonylmethyl) -propiophenone

Take 600 mL of distilled tetrahydrofuran into the reaction flask, add 10.1 mL (47.9 mmol) of hexamethyldisilazane, cool to -50 DEG C or lower using a dry ice-acetone container, and n-butyllithium 2.5 mol hexane solution) 19.2 mL (47.9 mmol) was added slowly (reaction vessel 1). Subsequently, 5.4 g (21.77 mmol) of the intermediate compound 4-cyclopropyloxy-β-hydroxypropiophenone synthesized above were dissolved in 100 mL of distilled tetrahydrofuran and cooled to -78 ° C in a dry ice-acetone container. Then, the solution of Reaction Vessel 1 made above was slowly removed using a syringe, and then transferred. Subsequently, after stirring at about -50 ° C for about 30 minutes, 3.6 g (21.77 mmol) of ethyl bromoacetate was slowly added thereto, stirred at this temperature for 1 hour, and then slowly raised to -20 ° C, and 10 mL of water was added to terminate the reaction. The solution was added to 300 mL of ethyl acetate solution, diluted, washed twice with water, the organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the target compound in 55% yield. 3.96 g was prepared.

<Step 2>

Synthesis of 4,5-dihydro-6- (4-cyclohexyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone

2.4 g (7.18 mmol) of the compound was dissolved in 30 mL of ethanol, 0.67 mL (10.78 mmol) of hydrazine hydrate was added and then heated to reflux with stirring for 3 days. Ethanol as a solvent was removed by evaporation under reduced pressure, and the remaining solid was washed several times with water, followed by ether and dried to prepare 1.86 g of the target compound in 86% yield.

<Step 3>

Synthesis of 4,5-dihydro-6- (3-nitro-4-cyclohexyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-94)

1.0 g (3.02 mmol) of the compound was dissolved in 10 mL of chloroform, and 0.26 g (3.32 mmol) of ammonium nitrate and 1 mL of trifluoroacetic anhydride were added thereto, followed by stirring at room temperature for 4 to 5 hours. The solvent was then evaporated off under reduced pressure and the remaining yellow solid was washed several times with water and then recrystallized from a methylene chloride-hexane (1: 1) mixture to prepare 0.91 g of the pure target compound in 87% yield.

¹ HNMR (CDCl ₃ ); δ 1.3 to 2.0 (10H, d), 2.5 to 2.8 (2H, m), 3.4 (1H, m), 3.6 (2H, m), 4.5 (1H, m), 7.2 to 8.3 (3H, m), 8.7 (1H, s)

Example 13

Synthesis of 4,5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-83)

<Step 1>

Synthesis of 4-methoxybenzaldehyde

10.g (81.9 mmol) of 4-hydroxybenzaldehyde was dissolved in difluoromethylformaldehyde (50 mL), followed by the addition of 22.64 g (163.8 mmol) potassium carbonate and methane iodide (7.6 mL, 122 mmol) Heated to reflux for hours. After cooling the mixture, distilled water (1500 mL) was added, extracted three times with ether (100 mL each), washed three times with distilled water (100 m each), water was removed with anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the target compound in 95% yield. 10.6 g was prepared.

<Step 2>

Synthesis of 4-methoxybenzoic Acid

5.6 g (41 mmol) of the compound was dissolved in tertiary butyl alcohol (246 mL) and 1.25 M KH ₂ SO ₄ buffer solution (164 mL) was added. Again, 1M KMnO ₄ aqueous solution (246mL) was added thereto, followed by stirring for 30 minutes at room temperature. Then, saturated aqueous Na ₂ SO ₃ solution (200mL) was added to the mixture, and the mixture was adjusted to pH 3 using 1N HCl aqueous solution, followed by ethyl acetate 2 Ash (100 mL each), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 5.6 g of the target compound in 90% yield.

<Step 3>

Synthesis of 4-methoxybenzoyl phenyl selenide

Potassium phthalimide 30.0 g (162 mmol) and phenyl selenyl chloride (28.7 g 150 mmol) were added to anhydrous hexane (150 mL) and stirred vigorously at room temperature for 2 hours. Anhydrous dichloromethane (1000 mL) was added thereto, the solids were filtered off, the solids were filtered out, the remaining solution was concentrated under reduced pressure, and anhydrous hexane (800 mL) was added thereto. The resulting solid was washed with anhydrous hexane (500 mL) to prepare phenylselenyl phthalamide.

25 g (166 mmol) of the compound and phenyl selenyl phthalamide (50 g, 166 mmol) were added to distilled tetrahydrofuran (300 mL), and tributylphosphine (41 mL, 166 mmol) was added thereto and stirred at room temperature for 1 hour. I was. Then, the solvent was removed under reduced pressure to give 32.8 g of the target compound in 68% yield.

<Step 4>

3- (4'-methoxybenzoyl) -butyrolactone

20 g (68.7 mmol) of the compound and 2 (5H) -furanone (29 g, 345 mmol) were added and then heated to reflux. Tributyl tin hydride (26 mL, 89.3 mmol) was added little by little over 1 hour, and then the reaction mixture was cooled, distilled water (10 mL) was added, benzene was removed under reduced pressure, and the residue was dissolved in ethyl acetate (30 mL). I was. The resulting solution was washed with water, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and purified by silica gel column chromatography to obtain 6.8 g of the target compound in 45% yield.

<Step 5>

Synthesis of 4,5-dihydro-6- (4-methoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone

40 g (182 mmol) of the compound was dissolved in ethanol (150 mL) and 20 g (320 mmol) of hydrazine hydrate (80%) was added thereto. The mixture was heated to reflux for 2 hours, then ethanol was removed under reduced pressure and the residue was dissolved in ethyl acetate (50 mL). The organic layer was washed with water, water was removed with anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 33.2 g of the target compound in 78% yield.

<Step 6>

Synthesis of 4,5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-83)

30 g (128 mmol) of the compound and ammonium nitrate (10 g, 128 mmol) were added to chloroform (150 mL), and tributylfluoroacetic anhydride (73 mL, 517 mmol) was added thereto, followed by stirring at room temperature for 16 hours. Excess trifluoroacetic anhydride and chloroform were removed under reduced pressure to give a sulfuric acid solid. The sulfuric acid solid was washed, water was removed with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 32.9 g of the target compound (I-83) in 92% yield.

m.p .; 235 ~ 237 ℃

¹ HNMR (CDCl ₃ ); δ 2.4 to 2.8 (2H, m), 3.2 to 3.6 (3H, m), 3.93 (3H, s), 4.9 (1H, t), 7.12 (1H, d), 7.97 (1H, d), 8.2 ( 1H, s), 10.68 (1H, s)

Example 14

Synthesis of 4,5-dihydro-6- (3-nitro-4-isopropoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-85)

<Step 1>

Synthesis of 4-isopropoxy benzaldehyde

Dissolve 10.0 g (81.9 mmol) of 4-hydroxybenzaldehyde in difluoromethylformaldehyde (50 mL), and then add potassium carbonate (22.64 g, 163.8 mmol) and 2-bromopropane (11.5 mL, 122 mmol). It was heated to reflux for about 10 hours. After cooling the mixture, distilled water (150 mL) was added, extracted three times with ether (100 mL each), washed three times with distilled water (100 mL each), water was removed with MgSO ₄ anhydride, filtered and concentrated under reduced pressure. 11.15g was prepared by% yield.

<Step 2>

Synthesis of 4-isopropoxy benzoic acid

6.72 g (41 mmol) of the compound was dissolved in tertiary butyl alcohol (246 mL) and 1.25 M KH ₂ O ₄ buffer aqueous solution (164 mL) was added. Again 1M KMnO ₄ aqueous solution (246mL) was added thereto, followed by stirring at room temperature for 30 minutes.

Na ₂ SO ₃ saturated aqueous solution (200 mL) was added to the mixture, adjusted to pH 3 using 1N HCl aqueous solution, extracted twice with ethyl acetate (100 mL each), dried over MgSO ₄ anhydride, filtered and concentrated under reduced pressure. 6.26 g of the compound was prepared in 85% yield.

<Step 3>

Synthesis of 4-isopropoxybenzoyl phenyl selenide

29.9 g (166 mmol) of the compound and phenyl selenylphthalimide (50 g, 166 mmol) were distilled into tetrahydrofuran (300 mL), and tributylphosphine (41 mL, 166 mmol) was added thereto for 1 hour at room temperature. Stirred. The solvent was removed under reduced pressure to give 42.2 g of the target compound in 42.2% yield.

<Step 4>

Synthesis of 3- (4-isopropoxybenzoyl) butyrolactone

21.9 g (68.7 mmol) and 2 (5H) -furanone (29 g, 345 mmol) of the compound were dissolved in distilled benzene (100 mL), and then AIBN (1.0 g, 6.8 mmol) was added thereto and then heated to reflux. Tributyl tin hydride (26 mL, 89.3 mmol) was added thereto little by little over 1 hour. After cooling the reaction mixture, distilled water (10 mL) was added thereto, benzene was removed under reduced pressure, and the residue was dissolved in ethyl acetate (300 mL). It was washed with water, dried over MgSO ₄ anhydride, filtered and the solvent was removed under reduced pressure to give 11.9 g of the target compound in 70% yield.

<Step 5>

Synthesis of 3- (3-nitro-4-isopropoxyphenyl) benzoyl butyrolactone

31.7 g (128 mmol) of the compound and ammonium nitrate (10 g, 128 mmol) were added to chloroform (150 mL), trichloroacetic anhydride (73 mL, 517 mmol) was added thereto, and the mixture was stirred at room temperature for 16 hours. Excess trifluoroacetic anhydride and chloroform were removed under reduced pressure, and the residue was dissolved in ethyl acetate (500 mL). It was washed with water, dried over MgSO ₄ anhydride, filtered and the solvent was removed under reduced pressure to obtain 20 g of the target compound in 75% yield.

<Step 6>

Synthesis of 4,5-dihydro-6- (3-nitro-4-isopropoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-85)

53.3 g (215 mmol) of the compound was dissolved in ethanol and 20 g (320 mmol) of hydrazine hydrate (80%) was added thereto. The mixture was heated to reflux for 2 days, then ethanol was removed under reduced pressure and the residue was dissolved in ethyl acetate (500 mL). It was washed with water, removed with MgSO ₄ anhydride, filtered and the solvent was removed under reduced pressure to give 48.7 g of the target compound (I-85) in 75% yield.

Example 15

Synthesis of 4,5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-hydroxymethyl-3- (2H) -pyridazinone (I-93)

<Step 1>

Synthesis of 4-cyclopentyloxybenzaldehyde

After dissolving 70 g (4-573 mmol) of 4-hydroxybenzaldehyde in 150 mL of DMF, 96 g (687 mmol) of K ₂ CO ₃ and 61.7 mL (573 mmol) of cyclopentyl bromide were added, followed by stirring at room temperature for about 24 hours. Extracted with ether five times (100 mL each), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to prepare 104 g of the target compound in 95% yield.

<Step 2>

Synthesis of 2- (4-cyclopentyloxyphenyl) -1,3-didiene

60 g (312 mmol) of the compound was dissolved in 150 mL of chloroform, and then 37.2 mL (342 mmol) of 1,3 propanedithiol and 4.44 mL (31.2 mmol) of borontripolide-etherate were added and stirred for about 1 hour, followed by chloroform. The obtained compound was removed under reduced pressure and recrystallized with 200 mL of hexane to prepare 78 g of the target compound in 90% yield.

<Step 3>

Synthesis of 2- (4-cyclopentyloxyphenyl) -2- (γ-butyrolactonyl) -1,3-didiene

40 g (142.86 mmol) of the compound was dissolved in 200 mL of tetrahydrofuran, and 1.6 M n-BuLi 89.28 mL (142.86 mmol) was added thereto, followed by stirring at -78 for 30 minutes. After about 30 minutes, 12 g (141.86 mmol) of furanone was added and stirred for about 10 minutes. Then, tetrahydrofuran was removed under reduced pressure, extracted five times with ethyl acetate (100 mL each), dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure to give 31.2 g of the target compound in 60% yield.

<Step 4>

Synthesis of 3- (4-cyclopentioxybenzoyl) -butyrolactone

25 g (68.68 mmol) of the compound was dissolved in 150 mL of tetrahydrofuran and 50 mL of distilled water, 29.74 g (137.4 mmol) of mercury oxide was added, and then 17.95 mL (137.4 mmol) of 48% hydrofluorobolic acid solution was added thereto, followed by stirring for about 10 minutes. Subsequently, 100 mL of saturated NaHCO ₃ aqueous solution and 200 mL of ethyl ether were added, extracted, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 15.5 g of the target compound in 85% yield.

<Step 5>

Synthesis of 4,5-dihydro-6- (4-cyclopentyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone

15 g (55 mmol) of the compound was dissolved in 50 mL of ethanol, and then 6.9 mL (110 mmol) of 85% hydrazinylated mole was added and heated to reflux for about 48 hours. Ethanol was then removed under reduced pressure and recrystallized from 100 mL of dichloromethane to prepare 11.8 g of the target compound in 75% yield.

<Step 6>

Synthesis of 4,5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-hydroxymethyl-3- (2H) -pyridazinone (I-93)

After dissolving 11 g (38.5 mmol) of the compound in 50 mL of chloroform, anhydrous 16.3 mL (115.5 mmol) was added thereto, and 3.35 g (38.5 mmol) of ammonium nitrate was added thereto, followed by stirring for about 30 minutes. 50 mL of 1N lithium hydroxide aqueous solution and 100 mL of dichloromethane were added thereto, stirred for about 5 minutes, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the target compound (I-93) in 80% yield. 10.1 g was prepared.

m.p .; 170 ~ 171 ℃

¹ HNMR (CDCl ₃ ); δ 2.2 (8H, m), 2.5 to 2.8 (2H, m), 3.4 (1H, s), 3.6 (2H, m), 4.5 (1H, m), 7.2 to 8.4 (3H, m), 8.8 ( 1H, s)

Example 16

Synthesis of 4,5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-hydroxymethyl-3- (2H) -pyridazinone (I-91)

<Step 1>

Synthesis of 2- (4-hydroxyphenyl) -1,3-didiene

20 g (164 mmol) of 4-hydroxybenzaldehyde was dissolved in 100 mL of chloroform, and then 19.6 mL (180.4 mmol) of 1,3-propanedithiol and 2.3 mL (164 mmol) of BF ₃ -Et ₂ O were added. After stirring, the chloroform was removed under reduced pressure, and the residue was recrystallized from 100 mL of hexane to prepare 20.6 g of the target compound as a solid in 90% yield.

<Step 2>

Synthesis of 2- (4-α-bromoethyloxyphenyl) -1,3-didiene

20 g (111 mmol) of the compound was dissolved in 100 mL of DMF, and 45.86 g (333 mmol) of K ₂ CO ₃ and 28.8 mL (333 mmol) of dibromoethane were added thereto, followed by stirring while heating at 100 ° C. for 10 hours. 200 mL of distilled water was added to the reaction solution, extracted three times with ether (100 mL each), concentrated to dryness with anhydrous Na ₂ SO ₄ , and separated to prepare 24 g of the target compound in 79% yield.

<Step 3>

Synthesis of 2- (4-vinyloxyphenyl) -1,3-didiene

20 g (70 mmol) of the compound was dissolved in 100 mL of benzene, 21.3 g (76.6 mmol) of tetrabutylammonium chloride and 50 mL of 50% NaOH solution were added thereto, stirred at room temperature for about 3 hours, and the reaction solution was diluted with 100 mL of ethyl acetate. After washing with distilled water (30 mL each), the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to prepare 7.1 g of the target compound in 45% yield.

<Step 4>

Synthesis of 2- (4-cyclopropyloxyphenyl) -1,3-didiene

6.0 g (29.1 mmol) of the compound was added 25 mL (145.5 mmol) of diethyl zinc (1.0 mol hexane solution), and then 12.1 mL (145.5 mmol) of diiodomethane was added thereto, followed by heating to reflux for 20 hours. The reaction was terminated, diluted with 100 mL of ether, washed once with water, dried over anhydrous Na ₂ SO ₄ , filtered to remove the ether under reduced pressure, and purified to give 4.5 g of the target compound in 72% yield.

<Step 5>

Synthesis of 2- (4-cyclopropyloxyphenyl) -2- (r-butyrolactinyl) -1,3-didiene

4.5 g (20.45 mmol) of the compound was dissolved in 50 mL of tetrahydrofuran, followed by addition of 12.78 mL (20.45 mmol) of 1.6 M n-butyllithium, followed by stirring at −78 ° C. for about 30 minutes, followed by adding 1.92 g of furanone (20.45 mmol) in tetra After dissolving in 5 mL of hydrofuran, adding the solution and stirring it for about 10 minutes, 5 mL of distilled water was added to terminate the reaction, diluted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to produce 3.13 g of the target compound in 60% yield. It was.

<Step 6>

Synthesis of 3- (4-isopropyloxybenzoyl) -butyrolactone

305 g (11.5 mmol) of the compound was dissolved in 50 mL of tetrahydrofuran and 10 mL of water, and 4.98 g (23 mmol) of mercury oxide was added thereto, and then 3.0 mL (23 mmol) of 40% aqueous HBF ₄ solution was slowly added thereto. After stirring for about 10 minutes, the reaction was terminated, 50 mL of saturated NaHCO ₃ aqueous solution and 100 mL of ether ether were added, and the organic layer obtained by filtration was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The isolate was prepared to yield 1.77 g of the target compound in 85% yield.

<Step 7>

Synthesis of 3-3 (-nitro-4-isopropyloxy benzoyl) -butyrolactone

2.4 g (9.75 mmol) of the compound was dissolved in 15 mL of chloroform, 4.1 mL (29.25 mmol) of trifluoroacetic anhydride was added thereto, and 0.85 g (29.25 mmol) of ammonium nitrate was added thereto, followed by stirring at room temperature for about 30 minutes. 20 mL of 1N LiOH aqueous solution and 50 mL of dichloromethane were added thereto, the mixture was stirred for about 5 minutes, the organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure to obtain a residue, which was 2.3g in 80% yield. .

<Step 8>

Synthesis of 4,5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-91)

2.0 g (6.87 mmol) of the compound was dissolved in 10 mL of ethanol, 0.86 mL (13.74 mmol) of 85% hydrazine hydrate was added thereto, and the residue obtained by heating under reflux for 48 hours was recrystallized with 10 mL of dichloromethane to obtain 80% of the target compound in the solid state. Prepared 2.0g in yield.

¹ HNMR (CDCl ₃ ); δ 0.9 (4H, d), 2.5 to 2.9 (2H, m), 3.4 to 3.8 (3H, m), 4.0 (1H, m), 4.8 (1H, t), 7.5 to 8.2 (3H, m), 8.7 (1H, s)

Example 17

Synthesis of 4,5-dihydro-6- (3-nitro-4-benzyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-88)

<Step 1>

Synthesis of 4-isopropyloxyoxybenzaldehyde

20 g (164 mmol) of 4-hydroxybenzaldehyde was dissolved in 100 mL of difluoromethylformamide, followed by the addition of 30.25 g (246 mmol) of 2-bromopropane and 27 g (196 mmol) of K ₂ CO _3. Stirred for time. When the reaction was completed, the mixture was extracted three times with ethyl ether (100 mL each), and the organic layer was dried over anhydrous MgSO _4, and ethyl ether was removed under reduced pressure to obtain 23 g of the target compound in 95% yield.

<Step 2>

Synthesis of 4-isopropyloxybenzaldehyde

20 g (90 mmol) of the compound was dissolved in 100 mL of chloroform, 10.7 mL (99 mmol) of 1,3-propanedithiol was added at room temperature, and 2.28 mL (9.0 mmol) of BF ₃ Ft ₂ O was added thereto. After stirring for about 1 hour, the reaction was terminated, chloroform was removed under reduced pressure, and the remaining residue was recrystallized from 100 mL of hexane, washed several times with hexane to prepare 20.6 g of the target compound in 90% yield.

<Step 3>

20 g (78.7 mmol) of the compound was dissolved in 200 mL of tetrahydrofuran, and 49.3 mL (78.7 mmol) of 1.6 M n-butyllithium hexane solution was added thereto, followed by stirring at −78 ° C. for about 30 minutes, followed by 6.6 g (78.7 mmol) of furanone. Was dissolved in 20 mL of tetrahydrofuran and added slowly. After stirring for about 10 minutes, 10 mL of distilled water was added to terminate the reaction, tetrahydrofuran was removed under reduced pressure, extracted three times with ethyl acetate (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained product was separated to prepare 16 g in 60% yield of the target compound.

<Step 4>

15 g (44.4 mmol) of the compound was dissolved in 100 mL of tetrahydrofuran and 500 mL of distilled water, and then 19.2 g (88.8 mmol) of mercury oxide and 11.6 mL (88.8 mmol) of 40% HBF ₄ aqueous solution were added thereto. After stirring for about 10 minutes at room temperature, the reaction was terminated, 100 mL of saturated NaHCO ₃ aqueous solution and 200 mL of ether ether were added, and the separated organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the target compound in 9.5% yield. g was prepared.

<Step 5>

Synthesis of 3- (3-nitro-4-hydroxy benzoyl) -butyrolactone

5.6 g (25.45 mmol) of the compound was dissolved in 50 mL of concentrated sulfuric acid, maintained at -30 ° C using a dry ice-acetone container, and 2.84 g (28.0 mmol) of nitric acid was further stirred at about -10 ° C for 20 minutes. Subsequently, the reaction solution was carefully dropped into 300 mL of ice water, extracted twice with 150 mL of ether, the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure to prepare 4.4 g of the target compound in 96% yield.

<Step 6>

Synthesis of 3- (3-nitro-4-benzyloxy benzoyl) -butyrolactone

3.2 g (15.3 mmol) of the compound was dissolved in 30 mL of difluoromethylformamide, and 4.23 g (30.6 mmol) of potassium carbonate and 2.7 mL (22.9 mmol) of benzyl bromide were added thereto, followed by heating with stirring at 100 ° C. for 5 to 6 hours. It was. Subsequently, the reaction solution was diluted with 200 mL of ether, washed twice with 80 mL of water, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure to prepare 4.16 g of the target compound in 90% yield.

<Step 7>

Synthesis of 4,5-dihydro-6- (3-nitro-4-benzyloxyphenyl) -5-hydroxymethyl-3- (2H) -pyridazinone (I-88)

2.5 g (7.89 mmol) of the compound was dissolved in 30 mL of ethanol, 1.0 mL (16.0 mmol) of hydrazine hydrate was added, followed by stirring under reflux for 3 days. Ethanol was evaporated off under reduced pressure and the remaining yellow solid was washed several times with water and then with ether and methylene chloride to give 1.9 g of pure target compound (I-88) in 75% yield.

Example 18

Synthesis of 4,5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-247)

500 mg of 4,5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-83) was dissolved in 15 mL of dichloromethane and then DAST 200 mL was added slowly at 0 ° C. After the reaction was performed for 20 minutes, 2 drops of water was added to terminate the reaction, the solvent was removed under reduced pressure, and the residue was separated and purified by silica gel column chromatography to prepare 0.21 g of the target compound (I-247) in 42% yield.

m.p .; 198 ~ 199 ℃

¹ HNMR (CDCl ₃ ); δ2.8 (2H, m), 3.65 (1H, m), 4.05 (3H, s), 4.4 to 4.7 (2H, m), 7.15 (1H, d), 8.0 (1H, d), 8.25 (1H, s), 8.64 (1 H, s)

Example 19

Synthesis of 4,5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-nitrosilmethyl-3 (2H) -pyridazinone (I-165)

300 mg of 4,5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-88) was dissolved in 5 mL of acetic anhydride and concentrated. After adding 0.1 mL of nitric acid, the mixture was stirred well at room temperature for 1 hour. The reaction solution was dissolved in 200 mL of ethyl acetate, washed with water and saturated aqueous sodium carbonate solution, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure to prepare 0.11 g of the target compound (I-165) in 32% yield.

¹ HNMR (CDCl ₃ ); δ2.7 to 3.1 (2H, m), 4.1 (3H, s), 4.3 to 4.7 (3H, m), 7.28 (2H, m), 8.2 (1H, d), 8.45 (1H, s)

Example 20

Synthesis of 4,5-dihydro-6- (3,5-dinitro-4-isopropoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-99)

0.1 g of 4,5-dihydro-6- (3-nitro-4-isopropoxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-85) 0.5 trifluoroacetic anhydride After dissolving in mL and 2 mL of chloroform, 0.10 g of ammonium nitrate was added and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel to prepare 0.1 g of the target compound (I-99) in 80% yield.

m.p .; 140 to 142 ° C

¹ HNMR (CDCl ₃ ); δ1.5 (6H, m), 2.8 (2H, d), 3.65 (1H, m), 4.52 (2H, m), 4.75 (1H, m), 8.2 (2H, s), 9.1 (1H, s)

Example 21

Synthesis of 4,5-dihydroxy-6- (3,5-dinitro-4-cyclopentyloxyphenyl) -5-fluoromethyl-pyridazinone (I-271)

0.08 g of 4,5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-257) was added 0.5 trichloroacetic anhydride. After dissolving in mL and 2 mL of chloroform, 0.13 g of ammonium nitrate was added and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain 0.084 g of the target compound (I-271) in 80% yield.

m.p .; 145 ~ 147 ℃

¹ HNMR (CDCl ₃ ); δ2.2 (8H, m), 2.8 (2H, d), 3.65 (1H, m), 4.6 (2H, m), 4.7 (1H, m), 8.3 (2H, s), 8.8 (1H, s)

Example 22

Synthesis of 4,5-dihydroxy-6- (3'-dinitro-4'-isopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-331)

<Step 1>

Synthesis of 2- (4-isopropyloxyphenyl) -2- (β-carboxyl-α-trofluoromethylethyl) -1,3-didiene

(1.27 g, 5 mmol) was dissolved in 15 mL of tetrahydrofuran and cooled to -78 ° C. Normal butyllithium hexane solution (2 mL, 5 mmol) was added slowly and stirred at the same temperature for about 30 minutes, and then 4,4,4-trifluoro-2-butene acid (0.37 g, 2.6 mmol) was added to 5 mL of tetrahydrofuran. The dissolved solution was added slowly. The reaction was stirred at -78 ° C for 10 minutes, the temperature was gradually raised to 0 ° C, adjusted to pH 2 with 2N aqueous HCl solution, extracted with methylene chloride (50 mL each), dried over Na ₂ SO ₄ anhydride, filtered, and depressurized. Concentration gave 1.6 g of the target compound in 80% yield.

<Step 2>

Synthesis of 4'-isopropyloxyphenyl-α-carboxymethyl-β, β, β-trifluoropropiophenone

The compound (0.66 g, 1.57 mmol) and mercury oxide (0.72 g, 3.33 mmol) were added to 9 mL of tetrahydrofuran, and 48% HBF ₄ aqueous solution (1.33 mL) and 0.5 mL of water were added thereto. When the yellow color of the orange suspension turns into a clear solution (within about 5 minutes), the solution is poured into 50 mL, extracted with methylene chloride (80 mL each), dried over Na ₂ SO ₄ anhydrous, filtered and concentrated under reduced pressure to yield the target compound in 75% yield. 0.41 g was prepared.

<Step 3>

Synthesis of 4,5-dihydro-6- (4-isopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone

The compound (0.68 g, 2.3 mmol) with 0,2 M hydrazine-methanol solution (23 mL) was heated to reflux for 3 days and then concentrated. The remaining solid was dissolved in methylene chloride (100 mL), and the filtered solution was depressurized again to obtain 0.75 g of the target compound in 57% yield.

<Step 4>

Synthesis of 4,5-dihydro-6- (3'-nitro-4'-isopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-331)

The compound (124 mg, 0.41 mmol) was dissolved in 16 mL of chloroform, ammonium nitrate (34 mg, 0.42 mmol) and trifluoro acetic anhydride (0.66 mL) were added at room temperature, followed by stirring for 24 hours. After adding the reaction solution to 50 mL of saturated NaHCO ₃ aqueous solution, methylene chloride (50 mL each) was extracted, dried over anhydrous Na ₂ SO _4, and concentrated under reduced pressure to prepare 92 mg of the target compound (I-331) in 65% yield.

m.p ,; 191-193 ℃

¹ HNMR (CDCl ₃ + CD ₃ OD / 5: 1); δ 1.4 (6H, d), 2.9 (1H, dd), 3.0 (1H, m) 4.0 (1H, m), 4.2 (1H, m), 7.2 (1H, d), 8.0 (1H, dd), 8.3 (1H, d)

Example 23

Synthesis of 4,5-dihydro-6- (3'-nitro-4'-cyclopentyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-339)

<Step 1>

Synthesis of 2- (4-cyclopentyloxyphenyl) -2- (a-trifluoro-β-carboxyethyl) -1,3-didiene

(3.96 g, 14.1 mmol) was dissolved in 50 mL of tetrahydrofuran and cooled to -78 ° C. n-butyllithium hexane solution (5.7 mL, 14.2 mmol) was added slowly and stirred at the same temperature for about 30 minutes, then 4,4,4-trifluoro-2-butene acid (0.91 g, 6.5 mmol) was added to tetrahydro The solution dissolved in 8 mL of furan was slowly added. The reaction mixture was stirred at -78 ° C for 10 minutes, the temperature was gradually raised to 0 ° C, adjusted to pH 2 using 2N HC1 aqueous solution, extracted with methylene chloride (100mL each), dried over Na ₂ SO ₄ anhydride, filtered, and concentrated under reduced pressure. To prepare 2.9g of the target compound in 50% yield.

<Step 2>

Synthesis of 4'-cyclopentyloxy-α-carboxymethyl-β, β, β-trifluoro propionphenone

The compound (2.18 g, 5.2 mmol) and the oxidation water temperature (2.3 g, 11 mmol) were added to 30 mL of tetrahydrofuran, and 48% HBF ₄ aqueous solution (4.4 mL) and 1.7 mL of water were added at room temperature. When the orange suspension turns into a yellow transparent solution within 5 minutes, the solution is poured into 100 mL of water, extracted with methylene chloride (100 mL each), dried over Na ₂ SO ₄ anhydrous, filtered, and concentrated under reduced pressure to give 1.34 g of the target compound in 80% yield. Prepared.

<Step 3>

Synthesis of 4,5-dihydro-6- (3'-nitro-4'-cyclooxyphenyl) -carboxymethyl-β, β, β-trifluoropropiophenone

The compound (0.55 g, 1.7 mmol) was dissolved in 60 mL of chloroform, ammonium nitrate (143 mg, 1.8 mmol) and trifluoro acetic anhydride (2.7 mL) were added at room temperature, followed by stirring for 24 hours. After adding the reaction solution to 100 mL of saturated NaHCO ₃ aqueous solution, methylene chloride (100 mL each) was extracted, dried over anhydrous Na ₂ SO _4, and concentrated under reduced pressure to prepare 0.42 g of the target compound in 75% yield.

<Step 4>

Synthesis of 4,5-dihydro-6- (3'-nitro-4'-isopropyloxyphenyl) -5-trifluoromethyl-3 (2H) -pyridazinone (I-339)

0.2 M hydrazine-methanol solution (57 mL) was added to the compound (1.9 g, 5.75 mmol), heated to reflux for 3 days, and then concentrated. The remaining solid was dissolved in methylene chloride (150 mL), and the filtered solution was concentrated under reduced pressure again to prepare 1.04 g of the target compound in 55% yield.

m.p; 203 ~ 205 ℃

¹ HNMR (CDCl ₃ + CD ₃ OD / 5: 1); δ 1.2 to 2.0 (8H, m) 2.90 (1H, m), 3.0 (1H, m), 4.0 (1H, m), 4.2 (1H, m), 7.2 (1H, d), 8.0 (1H, d) , 8.0 (1H, dd), 8.3 (1H, d)

Example 24

Synthesis of 4,5-dihydro-6- (3-amino-4-isopropoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-290)

0.5 g of 4,5-dihydro-6- (3-nitro-4-isopropoxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-249) was dissolved in 8 mL of ethanol, 0.05 g of palladium (10% on C) was added thereto, followed by reaction under hydrogen pressure of 40 to 50 psi. The reaction solution was filtered through silica gel, and the solvent was concentrated under reduced pressure to prepare 0.43 of the target compound (I-290) in 90% yield.

¹ HNMR (CDCl ₃ ); δ 1.4 (6H, d) 2.8 (2H, m), 3.7 (1H, m), 4.8 (1H, m), 4.5-4.7 (2H, m), 6.8-7.3 (3H, m), 8.9 (1H, s)

Example 25

Synthesis of 4,5-dihydro-6- (3-p-tolinesulfonamide-4-cyclopentyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-327)

1.0 g of 4,5-dihydro-6- (3-amino-4-cyclopentyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-292) was diluted with difluoromethylformami 5 mL of trimethylamine was added thereto, cooled to 0 ° C, 0.5 g of p-tolylsulfonylchloride was added, and stirred for 30 minutes. 50 mL of ethyl acetate was added to the reaction solution, washed with brine, washed with 1N HCl aqueous solution, the organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure to prepare 1.22 g of the target compound (I-327) in 82% yield. It was.

¹ HNMR (CDCl ₃ ); δ 2.2 (8H, m) 2.4 (3H, s), 2.8 (2H, m), 3.7 (2H, m), 4.5-4.7 (2H, m), 6.9-8.5 (9H, m)

Example 25

Synthesis of 4,5-dihydro-6- (3-nitro-4-isopropyloxyphenyl) -5-chloromethyl-3 (2H) -pyridazinone (I-412)

20 g (65.2 mmol) of 4,5-dihydro-6- (3-nitro-4-isopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-85) benzene (150 mL ) And thionyl chloride (9.5 mL, 130.3 mmol) were added thereto, followed by stirring at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, and benzene was removed under reduced pressure. The residue was extracted three times with ethyl acetate (200 mL each), washed with water, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure to obtain 14.9 g of the target compound in 70% yield.

¹ HNMR (CDCl ₃ ); δ 1.5 (6H, d) 2.8 (2H, m), 3.7 (1H, m), 4.5 (2H, m), 4.7 (1H, m), 7.1 (1H, d), 8.0 (1H, dd), 8.3 (1H, d), 8.7 (1H, d).

Example 27

Synthesis of 4,5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-bromomethyl-3 (2H) -pyridazinone (I-524)

4,5-dihydro-6- (3-nitro-4-cyclopentyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-93) 20.0 g (60 mmol) with tetrabromide 23.9 g (72 mmol) of carbon was dissolved in dichloromethane (200 mL), and triphenylphosphine (18.9 g 73 mmol) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was dissolved in dichloromethane (500 mL), washed with water, dried over MgSO ₄ anhydride, and the solvent was removed under reduced pressure to obtain 19 g of the target compound in 80% yield.

¹ HNMR (CDCl ₃ ); δ 1.5 to 2.0 (2H, m) 2.85 (2H, m), 3.8 (1H, m), 4.6 (2H, m), 5.0 (1H, m), 7.0 (1H, d), 8.0 (1H, dd) , 8.4 (1H, d), 8.8 (1H, d).

Example 28

Synthesis of 4,5-dihydro-6- (3-trifluoroacetamino-4-cyclopentyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-312)

0.1 g of the compound (I-292) was dissolved in 5 mL of tetrahydrofuran, and 0.10 mL of triethylamine was further added, and then 0.10 g of trifluoroacetate chloride was slowly added and reacted at room temperature for 20 minutes. Subsequently, the solvent was concentrated under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, washed with distilled water, and the solvent was further concentrated under reduced pressure to obtain 0.085 of the target compound (I-312) in 82% yield.

¹ HNMR (CDCl ₃ ); δ 1.5 to 2.0 (8H, m) 2.7 (2H, m), 3.7 (1H, m), 4.5 (2H, m), 5.0 (1H, m), 6.9 (1H, s), 7.1 (1H, d) , 8.0 (1H, dd), 8.2 (1H, d), 8.8 (1H, d).

Example 29

Synthesis of 4,5-dihydro-6- (3-cyano-methoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-29)

4,5-Dihydro-6- (3-amino-methoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-43) 0.932 (4 mmol) was dissolved in 20 mL of methanol and at 0 ° C. 3 mL of 2N nitrous acid aqueous solution was added. After stirring for 15 minutes, the mixture was adjusted to pH 7 with saturated NaHCO ₃ solution, and an aqueous solution (Ca, 5 mL) in which CuCN (0.448 g, 5 mmol) was dissolved was added at 0 ° C., and the temperature was gradually raised to room temperature, followed by water and methylene Extracted with chloride and concentrated the organic layer to dryness to prepare 0.72g of the target compound in 72% yield.

¹ HNMR (CDCl ₃ ); δ 1.3 (3H, d) 2.5 to 2.8 (2H, m), 3.3 (1H, m), 4.0 (3H, s), 7.0 to 8.1 (3H, m), 8.8 (1H, s).

Example 30

Synthesis of 4,5-dihydro-6- (3-amino-4-cyclopentyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-285)

0.303 g (1 mmol) of 4,5-dihydro-6- (3-cyano-4-cyclopentyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-292) After dissolving in 10 mL, 2 mL of 2N nitrite aqueous solution was added at 0 ° C., then stirred for 15 minutes, neutralized with saturated aqueous sodium hydrogen solution, and then dissolved in CuCN (0.11 g, 1.2 mmol) at 0 ° C. (2 mL) was added thereto. . The temperature was gradually raised to room temperature, after 2 hours, extracted with water and methylene chloride, and the organic layer was dried and concentrated to prepare 0.22 g of the target compound in 70% yield.

¹ HNMR (CDCl ₃ ); δ 2.2 (8H, m) 2.8 (2H, m), 3.7 (2H, m), 4.4-4.6 (2H, m), 7.0-8.1 (3H, m), 8.8 (1H, s).

Example 31

Optical activators (+) and (-) 4,5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-1-a) And (I-1-b)

<Step 1>

Synthesis of 3-nitro-4-methoxy-α-carboxymethylpropiophenone

15 g (0.068 mol) of 3-nitro-4-methoxy-α-ethoxycarbonylmethyl propionphenone was dissolved in 150 mL of concentrated sulfuric acid, which was kept at minus 30 ° C in a dry ice-acetone container, followed by nitric acid. 7.58 g (0.075 mol) diluted with 30 mL of sulfuric acid was slowly added and stirred at a temperature of minus 25 ° C for 30 minutes. This was slowly dropped in ice water to terminate the reaction. The precipitated solid was washed several times with distilled water, and then washed with an ether: hexane (1: 1) mixed solvent and dried to prepare 17.2 g of the target compound in 95% yield.

<Step 2>

Synthesis and Separation and Purification of 3-nitro-4-methoxy-α- (α'-carbomethoxybenzyloxy) carbonyl propiophenone, a mixture of diastereomers

10 g (37.45 mmol) of the compound was dissolved in 150 mL of methylene chloride, 6.22 g (37.45 mmol) of R-(-)-methylmandelaide, 9.3 g (44.94 mmol) of 1,2-dicyclohexylcarbodiimide, and 4- 0.5 g (3.74 mmol) of difluoromethylaminopyridine was added and stirred at room temperature for 1 hour. Subsequently, the reaction solution was filtered to remove the precipitated solid, the solvent was evaporated under reduced pressure, and the remaining residue was separated and purified several times using silica gel column chromatography using benzene: ethyl acetate (100: 1) as a developing solvent. Each of (+) and (-) was obtained as 6.6 g of pure optical isomer in 42.5% yield of (+) (-) respectively.

<Step 3>

Synthesis of (+) and (-) 3-nitro-4-methoxy-α-carboxymethyl propiophenone

6.6 g (16.0 mmol) of the compounds (+) and (-) isomers were dissolved in 60 mL of tetrahydrafuran, cooled to 0 ° C. using an ice water bath, and then 47 mL of IN-LiOH aqueous solution was added thereto, followed by stirring for 2-3 minutes. Immediately add 10% aqueous hydrochloric acid solution to pH 3, dilute with 200 mL of ethyl acetate, wash twice with water, dry with anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure to give 6.5 g of the target compound in 98% yield. Prepared.

<Step 4>

(+), (-) 4,5-dihydro-6- (3-nitro-4-methoxyphenyl) -5-methyl-3 (2H) -pyridazinone (I-1-a) (I- Synthesis of 1-b)

6.5 g (16.0 mmol) of each of the isomers of the compounds (+) and (-) were dissolved in 50 mL of ethanol, 2.0 mL (32 mmol) of hydrazine hydrate was added thereto, and then heated to reflux for 3 hours. The reaction solvent, ethanol, was removed by evaporation under reduced pressure, and the remaining yellow solid was washed several times with water, again with ether several times and dried to obtain 2.5 g of the target compound, each of (+) and (-) pure optical isomers, in 60% yield. Got it.

(I-1-a) (+) m.p; 178 ~ 179 ℃

[a] _D ^{15 °} = +338.5

(I-1-b) (−) m.p; 177 ~ 178 ℃

[a] _D ^{15 °} = -340.7

¹ HNMR (CDCl ₃ ); δ 1.3 (3H, d), 2.5 to 2.8 (2H, m), 3.3 (1H, m), 4.0 (3H, s), 7.1 to 8.4 (3H, m).

Example 32

With (+) (-) 4,5-dihydro-6- (3-nitro-4-isopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-249-a) Synthesis of (I-249-b)

<Step 1>

Synthesis of 4,5-dihydro-6- (4-isopropyloxyphenyl) -5- (2 ', 2'-methoxymethyl-3 (2H) -pyrazinone

12.5 g (42.58 mmol) of (+) (-) 4,5-dihydro-6- (4-isopropyloxyphenyl) -5-hydroxyphenyl-3 (2H) -pyridazinone was dissolved in 100 mL of ethyl acetate. 6.78 g (40.58 mmol) of (s)-(+)-a.2-methoxyphenylacetic acid, 10 g (48.69 mmol) of 1,3-dicyclohexylcarbodiimide and 0.24 g of 4-difluoromethylaminopyridine ( 2.02 mmol) was added, the mixture was stirred at room temperature for about 30 minutes, and the residue obtained by terminating the reaction was separated by silica gel chromatography (Hex / EX = 2: 1), and the respective isomers of (+) and (-) were each 95. 7.48 g was prepared in% yield.

<Step 2>

Synthesis of (+) (-) 4,5-dihydro-6- (4-isopropyloxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone

8.0 g (17.5 mmol) of each compound was dissolved in 500 mL of tetrahydrofuran and 50 mL of distilled water, 2.4 g of LiOH was added thereto, stirred for about 5 minutes, and the reaction was terminated. Three times (500 mL) were extracted with ethyl acetate and anhydrous MgSO ₄ After drying with filtration and concentration under reduced pressure, 4.95 g of a yellow solid compound were respectively prepared in 95% yield.

<Step 3>

Synthesis of (+) (-) 4,5-dihydro-6- (4-isopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone

After dissolving 4.5 g (17.17 mmol) of the compound in 500 mL of methylene chloride, 2.49 mL (18.87 mmol) of diethylaminosulfate fluoride was added at 0 ° C., stirred for about 25 minutes, and 1 mL of water was added to terminate the reaction. Methylene chloride was removed and separated by silica gel column chromatography (Hex / EA = 1: 1) to prepare 1.8 g of the target compound in 40% yield.

<Step 4>

Synthesis of (+) (-) 4,5-dihydro-6- (4-isopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone

2.5 g (9.45 mmol) of the compound was dissolved in 30 mL chloroform, 5.17 mL (57.24 mmol) of trifluoroacetic anhydride and 0.8 g (9.54 mmol) of ammonium nitrate were added thereto, followed by stirring at room temperature for about 30 minutes and then chloroform under reduced pressure. The mixture was extracted with ethyl acetate three times (200 mL each), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to prepare 2.3 g of the target compound in 80% yield.

m.p; 145 ~ 146 ℃

[α24] (C = 1) = + 237 °

= -234 °

¹ HNMR (CDCl ₃ ); δ 1.5 (6H, d), 2.8 (2H, d), 3.65 (1H, m), 4.52 (2H, m), 4.75 (1H, m), 7.1-8.2 (3H, m), 9.1 (1H, s ).

Example 33

With (+) (-) 4,5-dihydro-6- (3-nitro-4-cycloprooxyphenyl) -5-hydroxymethyl-3 (2H) -pyridazinone (I-91-α) Synthesis of (I-91-b)

<Step 1>

(+) (-) 4,5-dihydro-6- (3-nitro-4-cyclopropyl-oxyphenyl-5- (5-α-methoxy-α-phenyl) acetoxymethyl-3 (2H) Synthesis of Pyridazinone

5.0 g (18.18 mmol) of racemic mixture (I-91) was dissolved in 50 mL of ethyl acetate, and then 3.03 g (18.18 mmol) of (R)-(-)-a-methoxyphenylacetic acid was added thereto. 5.65 (21.8 mmol) of clohexylamide and 10.5 mg (0.09 mmol) of 4-dimethylaminopyridine were added, stirred for about 20 minutes at room temperature, ethyl acetate was removed under reduced pressure, and the resulting residue was separated by silica gel column chromatography to obtain respective isomers. 3.3 g of (+) and (−) compounds were prepared in 95% yield, respectively.

<Step 2>

With (+) (-) 4,5-dihydro-6- (3-nitro-4-cyclopropyloxyphenyl) -5-hydroxyphenyl-3 (2H) -pyridazinone (I-91-a) Synthesis of (I-91-b)

30 mL of 1N LiOH and 50 mL of tetrahydrofuran were added to 3.0 g (6.6 mmol) of the compound, followed by stirring for about 10 minutes. The obtained residue was separated with ethyl acetate (50 mL each), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a yellow solid product. 2.0 g each was prepared in 95% yield.

<Step 3>

(+) (-) 4,5-Dihydro-6- (3-nitro-4-cyclopropyloxyphenyl) -5-fluoromethyl-3 (2H) -pyridazinone (I-255a) and (I- 255b) synthesis

Dissolve 3.0 g (9.0 mmol) of each compound in 50 mL of methylene chloride, add 1.3 mL (9.9 mmol) of diethylaminosulfur trifluoride at 0 ° C., stir at 0 ° C. for about 25 minutes, and terminate the reaction. Was separated by methylene chloride (50 mL x 3) to obtain 1.2 g (40% yield) of the target compound.

The physiological effect of the compound prepared according to the method of 1 to 33 in the above Example was measured through the following test.

[exam]

Left ventricle of SD rats or guinea pigs was extracted, homogenized, centrifuged and dialyzed, and then PDE isozyme with sodium acetate gradient buffer (pH 6.5) containing 50 mM mercaptoethanol in DEAE cellulose column (1 × 30 cm). isozyme) were isolated. AMP generated by reacting each enzyme with the test drug [ ³ H] cAMP and snake venom (5'-nucleotides) were reacted, and the resulting adenosine was separated by an anion exchanger by batch method. Afterwards, the effect of the drug on the enzyme was measured by β-scintillation counting.

In addition to the above-described method, the cardiac contractile force of the drug may be measured by measuring the contractile force of the left atrium when the stimulus is electrically applied.

In this case, as a test drug, the compounds prepared in Examples and others were used and measured for imazodan for comparison. The representative results are shown in the following Table 1, and the measurement results for the test drug are expressed in EC (Effective Concentration: Effective Concentration), EC ₅₀ ) means the concentration of the test drug to increase the shrinkage force by 50%. The unit of concentration is moles / liter and a lower EC _{50 means} that the drug has a stronger contractile force.

TABLE 1

Claims (50)

A pyridazinone derivative represented by the following structural formula (I). Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, X and Y are each hydrogen atom, nitro group, cyano group-NHCOR ₃ or -NHSO ₂ R ₄ , wherein R ₃ and R ₄ are each an alkyl group having 1 to 6 carbon atoms, a substituted or alkyl or unsubstituted panyl group or an alkyl group substituted with halogen, and R ₂ is a hydrogen atom, alkyl having 1 to 6 carbon atoms or Alkyl, alkene, alkyne groups substituted with alkyl, alkene, alkyne or phenyl groups substituted with branched alkyl, cyclic alkyl, alkene, alkyne or halogen groups. The pyridazinone derivative according to claim 1, represented by the following structural formula (Ia). Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, alkyl having 1 to 6 carbon atoms or cyclic alkyl group, cyclic alkyl group , Alkyl, alkene, alkyne group substituted with an alkene, alkyne group or a substituted alkyl, alkene, alkyne or phenyl group. The pyridazinone derivative according to claim 1, represented by the following structural formula (Ib). In the above formula, R ₁ is methyl, hydroxymethyl, nitrosylmethyl, dihalomethyl, monohalomethyl, trihalomethyl, R ₂ is a hydrogen atom, alkyl of 1 to 6 carbon atoms or branched alkyl group, cyclic alkyl group , Alkyl, alkene, alkyne group substituted with alkyl, alkene, alkyne or phenyl group substituted with alkene, alkyne group or halogen. The pyridazinone derivative according to claim 1, represented by the following structural formula (Ic). Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, an alkyl group of 1 to 6 carbon atoms or an alkyl group of a side chain group, a ring Alkyl, alkene, alkyne, or halogen-substituted alkyl, alkene, alkyne, or phenyl-substituted alkyl alkene, alkyne groups. The pyridazinone derivative according to claim 1, represented by the following structural formula (id). Wherein R ₁ is methyl, hydroxymethyl, nitromethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, an alkyn or phenyl group having 1 to 6 carbon atoms Substituted alkyl alkene, alkyne group, R ₃ is an alkyl group having 1 to 6 carbon atoms, a substituted or branched alkyl group, an alkene, alkyne group or an alkyl alken substituted with a halogen, an alkyl or unsubstituted phenyl group or a halogen substituted alkyl group to be. The pyridazinone derivative according to claim 1, represented by the following structural formula (Ie). Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, alkyl having 1 to 6 carbon atoms or cyclic alkyl group, cyclic alkyl group Is an alkyl, alkene, alkyne, or a phenyl group substituted with an alkyl, alkene, alkyne or a phenyl group substituted with alkene, alkyne or alkyn, and R ₄ is an alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted phenyl group or substituted with halogen Alkyl group. The pyridazinone derivative according to claim 1, represented by the following structural formula (Ig). Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, alkyl having 1 to 6 carbon atoms or cyclic alkyl group, cyclic alkyl group Alkyl, alkene, alkyne or alkyne substituted by alkyl, alkene, alkyne or phenyl. The pyridazinone derivative according to claim 1, represented by the following structural formula (Ih). Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl. The pyridazinone derivative according to claim 1, represented by the following structural formula (Ii). Wherein R ₂ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkyl group having a cyclic group, an alkyl, alkene, alkyne group substituted with an alkyl, alkene, alkyne or phenyl group substituted with an alkene, alkyne or halogen group. The pyridazinone derivative according to claim 1, represented by the following structural formula (Ij). Wherein R2 is a hydrogen atom, an alkyl having 1 to 6 carbon atoms or an alkyl group having a side chain, a cyclic alkyl group, an alkene, alkyne group or an alkyl, alkene, alkyne or phenyl group substituted with a halogen. G is halogen. The pyridazinone derivative according to claim 1, represented by the following structural formula (Ik). Wherein R ₂ is a hydrogen atom, an alkyl, alkene, alkyne group substituted with an alkyl, alkene, alkyne or phenyl group substituted with an alkyn or branched alkyl group, a cyclic alkyl group, an alkene, alkyne group or a halogen group with 1 to 6 carbon atoms. The pyridazinone derivative according to claim 1, represented by the following structural formula (Im). Wherein R ₂ is a hydrogen atom, an alkyl, alkene, alkyne group substituted with an alkyl, alkene, alkyne or phenyl group substituted with an alkyn or branched alkyl group, a cyclic alkyl group, an alkene, alkyne group or a halogen group, having 1 to 6 carbon atoms, K is a nitrosyl, a halogen atom and a hydroxyl group. The pyridazinone derivative according to claim 1, represented by the following structural formula (In). Wherein R ₂ is a hydrogen atom, an alkyl, alkene, alkyne group substituted with an alkyl, alkene, alkyne or phenyl group substituted with a cyclic alkyl group, alkene, alkyne group or a halogen group with alkyn or branched alkyl group of 1 to 6 carbon atoms, K Are nitrosyl, a halogen atom and a hydroxyl group. The pyridazinone derivative according to claim 1, represented by the following structural formula (Io). Wherein R ₂ is a hydrogen atom, an alkyl, alkene, alkyne group substituted with an alkyl, alkene, alkyne or phenyl group substituted with a cyclic alkyl group, alkene, alkyne group or a halogen group with alkyn or branched alkyl group of 1 to 6 carbon atoms, R ₄ is an alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted phenyl group, or an alkyl group substituted with halogen, and K is a nitrosyl, halogen atom and hydroxy group. The pyridazinone derivative according to claim 1, represented by the following structural formula (Ip). Wherein R ₂ is a hydrogen atom, an alkyl, alkene, alkyne group substituted with an alkyl, alkene, alkyne or phenyl group substituted with a cyclic alkyl group, alkene, alkyne group or a halogen group with alkyn or branched alkyl group of 1 to 6 carbon atoms, R ₃ is an alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted phenyl group or an alkyl group substituted with halogen, and K is a nitrosyl, halogen atom and hydroxy group. The pyridazinone derivative according to claim 1, represented by the following structural formula (Ir). Wherein R ₂ is a hydrogen atom, an alkyl, alkene, alkyne group substituted with an alkyl, alkene, alkyne or phenyl group substituted with a cyclic alkyl group, alkene, alkyne group or a halogen group with alkyn or branched alkyl group of 1 to 6 carbon atoms, K Are nitrosyl, a halogen atom and a hydroxyl group. (A) Keto-phenol (1) and a derivative (2) having leaving group A are reacted in the presence of a base to obtain a keto derivative (3), and (B) the keto derivative (3) is subjected to vinegar acid having a leaving group B After reacting the derivative (4) with a base to obtain a keto ester (5), (c) reacting the keto-ester derivative (5) with hydrazine to obtain a pyridazinone derivative (6), and then (d) the A method for producing a pyridazinone derivative represented by the following general formula (Ia) obtained by reacting a dizinon derivative (6) with nitro ash. In the above formula, R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, alkyn or branched alkyl cyclic alkyl group, alkene having 1 to 6 carbon atoms Is an alkyl, alkene, alkyne or alkyne group substituted with an alkyn group or a halogen, an alkene group, an alkyn group, R ₅ is a methyl group or an ethyl group, and A and B are halogen atoms, tosylate or methanesulfonate, respectively. (A) Keto-phenol (1) and a derivative (2) having leaving group A are reacted in the presence of a base to obtain a keto derivative (3), and (B) the keto derivative (3) is subjected to vinegar acid having a leaving group B Reacting the derivative (4) with a base in the presence of a base to obtain a keto ester (5) (c) hydrolyzing the keto-ester derivative (5) to obtain a keto-organic acid derivative (7), and (d) the keto-organic acid The derivative (7) is reacted with hydrazine to obtain a pyridazinone derivative (6), and then (e) a pyridine represented by the following general formula (Ia) to be prepared by nitrating the pyridazinone derivative (6). Method for preparing xenon derivatives. In the above formula, R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, alkyn or branched alkyl cyclic alkyl group, alkene having 1 to 6 carbon atoms Is an alkyl, alkene, alkyne or alkyne group substituted with an alkyn group or a halogen, an alkene group, an alkyn group, R ₅ is a methyl group or an ethyl group, and A and B are halogen atoms, tosylate or methanesulfonate, respectively. (A) Keto-phenol (1) is reacted with a derivative (2) having a leaving group A in the presence of a base to obtain a ke derivative (3), and (B) the keto derivative (3) is a vinegar acid having a leaving group B After reacting the derivative (4) in the presence of a base to obtain a keto-ester (5) (c) The keto-ester derivative (5) is nitrated to obtain a ketone-ester derivative (8), and then (a) the ketone -A method for producing a pyridazinone derivative represented by the following one way (Ia) by reacting an ester derivative (8) with hydrazine. In the above formula, R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, alkyn or branched alkyl cyclic alkyl group, alkene having 1 to 6 carbon atoms Is an alkyl, alkene, alkyne or alkyne group substituted with an alkyn group or a halogen, an alkene group, an alkyn group, R ₅ is a methyl group or an ethyl group, and A and B are halogen atoms, tosylate or methanesulfonate, respectively. (A) Keto-phenol (1) and a derivative (2) having leaving group A are reacted in the presence of a base to obtain a keto derivative (3), and (B) the keto derivative (3) is subjected to vinegar acid having a leaving group B After reacting the derivative (4) with a base to obtain a ketoester (5), (c) nitrifying the keto-ester derivative (5) to obtain a ketone-ester derivative (8), and then (d) the ketone- The ester derivative (8) was hydrolyzed to obtain a ketone-organic acid derivative (9), and (e) to prepare a pyridazinone derivative represented by the following general formula (Ia) by reacting the ketone-organic acid (9) with hydrazine. Way. In the above formula, R ₁ is methyl, hydroxymethyl, nitromethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, alkyn or branched alkyl group cyclic alkyl group, alkene, An alkyl, alkene, alkyne, or phenyl group substituted by an alkyne group or a halogen is an alkyl, alkene, alkyne group, R ₅ is a methyl group or an ethyl group, and A and B are each a halogen atom, tosylate or methanesulfonate. (A) a phenol derivative (1) having a ketone group and a methyl derivative (2a) substituted with iodine are reacted in the presence of a base to obtain a ketone derivative (3a), and (b) the ketone derivative (3a) and a vinegar derivative (4). ) Is reacted in the presence of a base to obtain a keto-ester derivative (5a), and then (c) hydrolyze the keto-ester derivative (5a) to obtain a catto-acid (7a), and (d) the keto-acid (7a) is reacted in the presence of an acid to obtain a phenol-organic acid (10), and (e) the phenol-organic acid (10) is reacted with a derivative (2) in which the leaving group A is substituted for R ₂ in the presence of a base to carry out a keto- The mixture of ester (11) and keto-organic acid (7) was treated with a base to obtain a keto-organic acid (7), and (a) the keto-organic acid (7) was reacted with hydrazine to give pyridazinone (6). Then, (g) a method for producing a pyridazinone derivative represented by the following general formula (Ia) by nitrating the pyridazinone (6). Wherein R ₁ is methyl, hydroxymethyl, nitromethyl, monohalomethyl, dihalomethyl, trihalomethyl, and R ₂ is a hydrogen atom, an alkyn or branched alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group, an alkene Is an alkyl, alkene, alkyne or alkyne group substituted with an alkyn group or a halogen, an alkene group, an alkyn group, R ₅ is a methyl group or an ethyl group, and A and B are halogen atoms, tosylate or methanesulfonate, respectively. (A) a phenol derivative (1) having a ketone group and a methyl derivative (2a) substituted with iodine are reacted in the presence of a base to obtain a ketone derivative (3a), and (b) the ketone derivative (3a) and a vinegar derivative (4). ) Is reacted in the presence of a base to obtain a keto-ester derivative (5a), and then hydrolyze the keto-ester derivative (5a) to obtain a cato-acid (7a), and (d) the keto-acid (7a) Is reacted in the presence of an acid to obtain a phenol-organic acid (10), and (e) the phenol-organic acid (10) and a derivative (2) substituted with a leaving group A in R ₂ are reacted in the presence of a base to give a keto-ester (11). ) And a mixture of keto-organic acid (7), and (f) the mixture of keto-ester (11) and keto-organic acid (7) is reacted with hydrazine to obtain pyridazinone (6). ) A method for producing a pyridazinone derivative represented by the following general formula (Ia) by nitrating the pyridazinone (6). Wherein R ₁ is methyl, hydroxymethyl, nitromethyl, monohalomethyl, dihalomethyl, trihalomethyl, and R ₂ is a hydrogen atom, an alkyn or branched alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group, an alkene Is an alkyl, alkene, alkyne or alkyne group substituted with an alkyn group or a halogen, an alkene group, an alkyn group, R ₅ is a methyl group or an ethyl group, and A and B are halogen atoms, tosylate or methanesulfonate, respectively. (A) A phenol derivative (1) having a ketone group and isopropyl bromide (2b) were reacted in the presence of a base to obtain a ketone derivative (3b), and (B) the ketone derivative (3b) and a vinegar derivative (4) were used as a base. React in the presence of a keto-ester derivative (5b), and then (c) nitrate the keto-ester derivative (5b) to obtain a nitro-phenol derivative (12), and (d) the nitro-phenol derivative ( 12) is reacted with a derivative (2) substituted with leaving group A in the presence of a base to obtain a keto-ester (8), and (e) by reacting the keto-ester (8) with hydrazine, the following general formula (Ia) Method for producing a pyridazinone derivative represented by. Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₅ is methyl or ethyl, and A and B are halogen atom, tosylate or methane, respectively Sulfonate. (A) A phenol derivative (1) having a ketone group is reacted with isopropyl bromide (2b) in the presence of a base to obtain a ketone derivative (3b), and (B) the ketone derivative (3b) and a vinegar derivative (4) React in the presence of a keto-ester derivative (5b), and then (c) nitrate the keto-ester derivative (5b) to obtain a nitro-phenol derivative (12), and (d) the nitro-phenol derivative ( 12) was reacted with a derivative (2) substituted with leaving group A in the presence of a base to obtain a keto-ester (8), and (e) hydrolyzing the keto-ester (8) to obtain a keto-organic acid (9). And (f) a method for producing a pyridazinone derivative represented by the following general formula (Ia) by reacting the keto-organic acid (9) with hydrazine. Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, an alkyn or branched alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group, Alkyl, alkene, or alkyn substituted alkyl, alkene, alkyn, or phenyl substituted alkyl, alkene, alkyne, R ₅ is a methyl or ethyl group, and A and B are halogen atoms, tosylate or methanesulfonate, respectively . A method for producing a pyridazinone derivative represented by the following general formula (Id) by nitrating the pyridazinone derivative (Ia) according to claims 17 to 24. Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, an alkyn or branched alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group, Alkyl, alkene, alkyne or alkyne groups substituted with an alkene, alkyne or halogen substituted alkyl. A process for producing a -pyridazinone derivative represented by the following general formula (Ic) which is obtained by reducing the derivative (Ia) of pyridazinone according to claims 17 to 24. Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, an alkyn or branched alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group, Alkyl, alkene, alkyne or alkyne groups substituted with an alkene, alkyne or halogen substituted alkyl. (A) Reducing the pyridazinone derivative (Ia) according to claims 17 to 24 to obtain an amino-pyridazinone derivative (Ic), and (b) replacing the amino-pyridazinone derivative (Ic) with R _A method for producing a pyridazinone derivative represented by the following general formula (Id) which is reacted with ₃ CO 2. Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, an alkyn or branched alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group, An alkyl, alkene, alkyne, or phenyl group substituted with an alkene, alkyne, or halogen substituted alkyl, alkene, alkyne group, and Z is a halogen atom. (A) Reducing the pyridazinone derivative (Ia) according to claims 17 to 24 to obtain an amino-pyridazinone derivative (Ic), and (b) replacing the amino-pyridazinone derivative (Ic) with R4SO2Z. A method for producing a pyridazinone derivative represented by the following general formula (Ie) which is reacted with. Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, an alkyn or branched alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group, An alkyl, alkene, alkyne, or a phenyl group substituted with an alkene, alkyne or alkoxy substituted alkyl, alkene, alkyne group, Z is a halogen atom. (A) reducing the pyridazinone derivative (Ia) according to claims 17 to 24 to obtain an amino-pyridazinone derivative (Ic), and (b) converting the amino-pyridazinone derivative (Ic) to HNO. ₂ to obtain a diazonium salt derivative (If), and (c) to prepare a pyridazinone derivative represented by the following general formula (Ig) by subjecting the diazonium salt derivative (If) to a cyano copper sandsand reaction. Way. Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, an alkyn or branched alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group, Alkyl, alkene, alkyne or alkyne groups substituted with an alkene, alkyne or halogen substituted alkyl. (A) a phenol derivative (1) having a ketone group and a methyl derivative (2a) substituted with iodine are reacted in the presence of a base to obtain a ketone derivative (3a), and (b) the ketone derivative (3a) and a vinegar derivative (4). ) Is reacted in the presence of a base to obtain a keto-ester derivative (5a), and then the keto-ester derivative (5a) is hydrolyzed to obtain a keto-acid (7a), and (d) the keto-acid (7a). Is reacted in the presence of an acid to obtain a phenol-organic acid (10), (e) to obtain a phenol-ester derivative (13) through esterification of the keto-organic acid (10), and (f) the phenol-ester derivative. (13) was reacted with dibromomethane to obtain α-bromomethyloxy derivative (5c), and (g) the α-bromomethyloxy derivative (5c) was halogen-removed to give a vinyloxy derivative (5d). ), And (a) cyclopropane the vinyloxy derivative (5d) to form a cyclopropyl derivative (5e). (I) reacting the cyclopropyl derivative (5e) with hydrazine to obtain a pyridazinone derivative (6e), and then (typically) nitrating the pyridazinone derivative (6e) to the following general formula (Ih) Method for producing a pyridazinone derivative represented by). Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, an alkyn or branched alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group, An alkyl, alkene, alkyne or phenyl group substituted by an alkene, alkyne or alkene group, an alkyl, alkene, alkyne group, R ₅ is a methyl group or an ethyl group, and B is a halogen atom, tosylate or methanesulfonate. (A) a phenol derivative (1) having a ketone group and a methyl derivative (2a) substituted with iodine are reacted in the presence of a base to obtain a ketone derivative (3a), and (b) the ketone derivative (3a) and a vinegar derivative (4). ) In the presence of a base to obtain a keto-ester derivative (5a), and then (c) hydrolyze the keto-ester derivative (5a) to obtain a keto-acid (7a), and (d) the keto-acid (7a) is reacted in the presence of an acid to obtain a phenol-organic acid (10), (e) to obtain a phenol-ester derivative (13) through esterification of the phenol-organic acid (10), and then (f) the phenol -The ester derivative (13) is reacted with dibromomethane to obtain α-bromomethyloxy derivative (5c), and (g) the a-bromomethyloxy derivative (5c) is halogen-removed to give vinyloxy. Obtain derivative (5d), (a) Cyclopropylation of said vinyloxy derivative (5d), and cyclopropyl derivative (5e), (i) hydrolyze the cyclopropyl derivative (5e) to obtain a keto-organic acid derivative (7e), and then (second) react the keto-organic acid derivative (7e) with hydrazine to pyrida A method for producing a pyridazinone derivative represented by the following general formula (Ih) obtained by obtaining a xenon derivative (6e) and nitrating the pyridazinone derivative (6e). Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, an alkyn or branched alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group, An alkyl, alkene, alkyne, or phenyl group substituted by an alkene, alkyne or alkene substituted alkyl, alkene, alkyne group, R ₅ is a methyl group or an ethyl group, and B is a halogen atom, tosylate or methanesulfonate. (A) a phenol derivative (1) having a ketone group and a methyl derivative (2a) substituted with iodine are reacted in the presence of a base to obtain a ketone derivative (3a), and (b) the ketone derivative (3a) and a vinegar derivative (4). ) In the presence of a base to obtain a keto-ester derivative (5a), and then (c) hydrolyze the keto-ester derivative (5a) to obtain a keto-acid (7a), and (d) the keto-acid (7a) is reacted in the presence of an acid to obtain a phenol-organic acid (10), (e) to obtain a phenol-ester derivative (13) through esterification of the phenol-organic acid (10), and then (f) the phenol -The ester derivative (13) is reacted with dibromomethane to obtain α-bromomethyloxy derivative (5c), and (g) vinyl-oxygen is subjected to halogen removal reaction of the α-bromomethyloxy derivative (5c). Obtain derivative (5d) and (a) cyclopropane the vinyloxy derivative (5d) to induce cyclopropyl (5e), and then (i) nitration of the cyclopropyl derivative (5e) to obtain a keto-ester derivative (8e), and then (second) reacting the ketone-ester derivative (8e) with hydrazine. The manufacturing method of the pyridazinone derivative represented by general formula (Ih). Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, an alkyn or branched alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group, An alkyl, alkene, alkyne or phenyl group substituted with an alkene, alkyne or alkene group is an alkyl, alkene, alkyne group, R ₅ is a methyl group or an ethyl group, and B is a halogen atom, tosylate or methanesulfonate, respectively. (A) a phenol derivative (1) having a ketone group and a methyl derivative (2a) substituted with iodine are reacted in the presence of a base to obtain a ketone derivative (3a), and (b) the ketone derivative (3a) and a vinegar derivative (4). ) Is reacted in the presence of a base to obtain a keto-ester derivative (5a), and then (c) hydrolyze the keto-ester derivative to obtain a keto-acid (7a), and (d) the keto-acid (7a) Is reacted in the presence of an acid to obtain a phenol-organic acid (10), (e) to obtain a phenol-ester derivative (13) by esterification of the phenol-organic acid (10), and (f) the phenol-ester derivative. (13) was reacted with dibromomethane to obtain α-bromomethyloxy derivative (5c), and (g) the α-bromomethyloxy derivative (5c) was halogen-removed to give a vinyloxy derivative (5d). ), (A) the vinyloxy derivative (5d) to cyclopropane cyclopropyl derivative (5e) Next, (i) nitration of the cyclopropyl derivative (5e) to obtain a keto-ester derivative (8e), and (second) hydrolysis of the ketone-ester derivative (8e) to a ketone-organic acid derivative (9e) And (k) a method for producing a pyridazinone derivative represented by the following general formula (Ih) by reacting the ketone-organic acid derivative (9e) with hydrazine. Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, R ₂ is a hydrogen atom, alkyn or branched alkyl, cyclic alkyl, alkene, alkyne, or alkyl substituted by halogen , Alkene, alkyne or a phenyl group is substituted alkyl, alkene, alkyne group, R ₅ is a methyl group or an ethyl group, A and B are each a halogen atom, tosylate or methanesulfonate. (A) 4-hydroxy benzaldehyde (14) is reacted with a derivative (2) having a leaving group A in the presence of a base to obtain an aldehyde derivative (15), and (b) oxidizing the aldehyde derivative (15) to an organic acid derivative (16) was obtained, and (c) the organic acid derivative (16) was condensed with phenyl selenylphthalamide (17) to obtain an acyl selenium derivative (18), and (d) a radical initiator in the acyl selenium derivative (18). To generate an acyl radical and react with butenolide (19) to obtain a keto-lactone derivative (20), and then (e) react the keto-lactone derivative (20) with hydrazine to produce hydroxy-pyridazinone. A method for producing a pyridazinone derivative represented by the following structural formula (Ii) obtained by obtaining a derivative (21) and nitrating the hydroxy-pyridazinone derivative (21). Wherein R ₂ is a hydrogen atom, an alkyl, alkene, alkyne group substituted with an alkyl, alkene, alkyne or phenyl group substituted with an alkyn or branched alkyl group, a cyclic alkyl group, an alkene, alkyne group or a halogen group, having 1 to 6 carbon atoms, A is a halogen atom, tosylate or methanesulfonate. (A) 4-hydroxy benzaldehyde (14) is reacted with a derivative (2) having a leaving group A in the presence of a base to obtain an aldehyde derivative (15), and (b) oxidizing the aldehyde derivative (15) to an organic acid derivative (16) was obtained, and (c) the organic acid derivative (16) was condensed with phenyl selenyl phthalamide (17) to obtain an acyl selenium derivative (18), and (d) a radical initiator in the acyl selenium derivative (18). To generate acyl radicals and react with butenolide (19) to obtain keto-lactone derivatives (20), and (e) nitrate the keto-lactone derivatives (20) to nitro-lactone derivatives (22). (F) a method for producing a pyridazinone derivative represented by the following structural formula (Ii) obtained by reacting the nitro-lactone derivative (22) with hydrazine. Wherein R ₂ is a hydrogen atom, an alkyl, alkene, alkyne group substituted with an alkyl, alkene, alkyne or phenyl group substituted with an alkyn or branched alkyl group, a cyclic alkyl group, an alkene, alkyne group or a halogen group, having 1 to 6 carbon atoms, A is a halogen atom, tosylate or methanesulfonate. (A) 4-hydroxy benzaldehyde (14) is reacted with a derivative (2) having a leaving group A in the presence of a base to obtain an aldehyde derivative (15), and (b) the aldehyde derivative (15) and propanedithiol ( 23) is reacted in the presence of an acid to obtain a dithiene derivative (24), and (c) the dithiene derivative (24) is treated with a strong base, and then buteneide (19) is added to the styrene-lactone derivative (20). ) And (d) treating the pyene-lactone derivative (25) with an acid in the presence of a metal to obtain a keto-lactone derivative (20), and then (e) nitrifying the keto-lactone derivative (20) to nitro A method for producing a pyridazinone derivative represented by the following structural formula (Ii) obtained by obtaining a -lactone derivative (22) and reacting the nitro-lactone derivative (22) with hydrazine. Wherein R ₂ is a hydrogen atom, an alkyl, alkene, alkyne group substituted with an alkyl, alkene, alkyne or phenyl group substituted with an alkyn or branched alkyl group, a cyclic alkyl group, an alkene, alkyne group or a halogen group, having 1 to 6 carbon atoms, A is a halogen atom, tosylate or methanesulfonate. (A) 4-hydroxy benzaldehyde (14) and propanedithiol (23) are reacted in the presence of an acid to obtain a dithiene-phenol derivative (26), and (b) leaving the dithiene-phenol derivative (26). The derivative (2) having the group A was reacted in the presence of a base to obtain a dithiene derivative (24). (C) The dithiene derivative (24) was treated with a strong base and then added with butenolide (19). N-lactone derivatives (25) were obtained, (D) the tyene-lactone derivatives (25) were treated with an acid in the presence of gold to obtain a keto-lactone derivative (20), and (e) the keto-lactone derivatives (20 ) To obtain a nitro-lactone derivative (22), and (f) a method for producing a pyridazinone derivative represented by the following structural formula (Ii) by reacting the nitro-lactone derivative (22) with hydrazine. Wherein R ₂ is a hydrogen atom, an alkyl, alkene, alkyne group substituted with an alkyl, alkene, alkyne or phenyl group substituted with an alkyn or branched alkyl group, a cyclic alkyl group, an alkene, alkyne group or a halogen group, having 1 to 6 carbon atoms, A is a halogen atom, tosylate or methanesulfonate. (A) Treating the isopropyl derivative (19b) with an acid to obtain a ketophenol derivative (27), and (b) reacting the ketophenol derivative with a derivative (2) containing a leaving group A to obtain a ketolactone derivative ( 20), (c) nitrifying the keto-lactone derivative (20) to obtain a nitro-lactone derivative (22), and (d) reacting the nitro-lactone derivative (22) with hydrazine. A method for producing a pyridazinone derivative represented by Ii). Wherein R ₂ is a hydrogen atom, an alkyl, alkene, alkyne group substituted with an alkyl, alkene, alkyne or phenyl group substituted with an alkyn or branched alkyl group, a cyclic alkyl group, an alkene, alkyne group or a halogen group, having 1 to 6 carbon atoms, A is a halogen atom, tosylate or methanesulfonate. A process for producing a pyridazinone derivative represented by the following general formula (Ij) by halogenating a pyridazinone derivative (Ii) according to claim 34 to 36. Wherein R ₂ is a hydrogen atom, an alkyl, alkene, alkyne group substituted with an alkyl, alkene, alkyne or phenyl group substituted with an alkyn or branched alkyl group, a cyclic alkyl group, an alkene, alkyne group or a halogen group, having 1 to 6 carbon atoms, G is halogen. A method for producing a pyridazinone derivative represented by the following general formula (Ik) which is subjected to a nitration reaction of the pyridazinone derivative (Ii) according to claims 34 to 36. Wherein R ₂ is a hydrogen atom, an alkyl, alkene, alkyne group substituted with an alkyl, alkene, alkyne or phenyl group substituted with an alkyn or branched alkyl group, a cyclic alkyl group, an alkene, alkyne group or a halogen group with 1 to 6 carbon atoms. (A) reacting the dithione derivative (24) with the crotylic acid derivative (28) in the presence of a strong base to obtain a dithiene-organic acid derivative (29), and (b) the dithiene-organic acid derivative (29) in the presence of a metal. Acid to obtain a keto-organic acid derivative (7), and (c) reacting the keto-organic acid derivative (7) in the presence of hydrazine to obtain a pyridazinone derivative (30), and (d) the pyridazinone derivative A method for producing a pyridage derivative represented by the following general formula (Ia) which is subjected to nitration reaction (30). Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, alkyn or branched alkyl group of 1 to 6 carbon atoms, cyclic alkyl group , Alkyl, alkene, alkyne group substituted with alkyl, alkene, alkyne or phenyl group substituted with alkene, alkyne group or halogen. (A) reacting the dithione derivative (24) with the crotylic acid derivative (28) in the presence of a strong base to obtain a dithiene-organic acid derivative (29), and (b) the dithiene-organic acid derivative (29) in the presence of a metal. Treating with an acid to obtain a keto-organic acid derivative (7), and then (c) nitrifying the keto-organic acid derivative (7) to obtain a nitro-organic acid (31), and (d) the nitro-organic acid (31). A method for producing a pyridazinone derivative represented by the following general formula (Ia) by reacting with hydrazine. Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, alkyn or branched alkyl group of 1 to 6 carbon atoms, cyclic alkyl group , Alkyl, alkene, alkyne group substituted with alkyl, alkene, alkyne or phenyl group substituted with alkene, alkyne group or halogen. A process for producing a pyridazinone derivative represented by the following general formula (Im) obtained by nitrating a pyridazinone derivative (Ii), (Ij), and (Ik) according to claim 34 to 40. Wherein R ₂ is a hydrogen atom, an alkyl, alkene, alkyne group, substituted with an alkyl, alkene, alkyne or phenyl group substituted with an alkyn or branched alkyl group, a cyclic alkyl group, an alkene, alkyne group or a halogen group, having 1 to 6 carbon atoms; Are nitrosyl, halogen atom and hydroxy group. A process for producing a pyridazinone derivative represented by the following general formula (In) by reducing the nitro groups of the pyridazinone derivatives (Ii), (Ij) and (Ik) according to claim 34 to 40. Wherein R ₂ is a hydrogen atom, an alkyl, alkene, alkyne group substituted with an alkyl, alkene, alkyne or phenyl group substituted with an alkyn or branched alkyl group, a cyclic alkyl group, an alkene, alkyne group or a halogen group, having 1 to 6 carbon atoms, K is a nitrosyl, a halogen atom and a hydroxyl group. A process for preparing general formula (Io) by reacting a pyridazinone derivative (In) according to claim 44 with R ₄ SO ₂ X. Wherein R ₂ is a hydrogen atom, an alkyl, alkene, alkyne group substituted with an alkyl, alkene, alkyne or phenyl group substituted with an alkyn or branched alkyl group, a cyclic alkyl group, an alkene, alkyne group or a halogen group, having 1 to 6 carbon atoms, R ₄ is an alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted phenyl group or an alkyl group substituted with halogen, K is a nitrosil, a halogen atom and a hydroxyl group, and X is a halogen atom. A process for producing a pyridazinone derivative represented by the following general formula (Ip) by reacting a pyridazinone derivative (In) according to claim 44 with R ₃ COX. Wherein R ₂ is a hydrogen atom, an alkyl, alkene, alkyne group substituted with an alkyl, alkene, alkyne or phenyl group substituted with an alkyn or branched alkyl group, a cyclic alkyl group, an alkene, alkyne group or a halogen group, having 1 to 6 carbon atoms, R ₃ is an alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted phenyl group or an alkyl group substituted with halogen, K is a nitrosil, a halogen atom and a hydroxyl group, and X is a halogen atom. (A) The pyridazinone derivative (In) according to claim 44 is made of a diazonium salt derivative (Ir), and (b) the diazonium salt derivative (Iq) is substituted with cyanocopper to give the following general formula ( A method for producing a pyridazinone derivative represented by Ir). Wherein R ₂ is a hydrogen atom, an alkyl, alkene, alkyne group substituted with an alkyl, alkene, alkyne or phenyl group substituted with an alkyn or branched alkyl group, a cyclic alkyl group, an alkene, alkyne group or a halogen group, having 1 to 6 carbon atoms, K is a nitrosyl, a halogen atom and a hydroxyl group. (A) Keto-phenol (1) is reacted with a derivative (2) having a leaving group A in the presence of a base to obtain a keto derivative (3), and (B) the keto derivative (3) is a vinegar acid having a leaving group B After reacting the derivative (4) with a base to obtain a ketoester (4), (c) hydrolyzing the keto-ester derivative (5) to obtain a keto-organic acid derivative (7), and then (d) the keto The organic acid derivative (7) is reacted with an alcohol which is an optically active substance to obtain a keto-ester (33) which is a mixture of diastereomers, and (e) the keto-ester derivative (33a) is subjected to column chromatography or recrystallization, respectively. (E) hydrolyzing the keto-ester derivatives (33a) and (33b), respectively, to obtain respective optical isomers (7a) and (7b), and (g) the optical isomers. (7a) and (7b) were reacted with hydrazine, respectively, to yield pyridazinone derivatives (6a) and (6b). Is: (a) the pyridazinone derivative (6a), and how the flutes separating the optical isomers of the Xenon derivative represented by the following formula (Ia) are each separated by a nitration reaction (6b). Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R 2 is a hydrogen atom, an alkyn or branched alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group, Alkyl, alkene or alkyn substituted alkyl, alkene, alkyn or phenyl substituted alkyl, alkene, alkyne group, R ₅ is methyl or ethyl and A and B are halogen atom, tosylate or methanesulfonate, respectively . (A) 4-hydroxy benzaldehyde (14) is reacted with a derivative (2) having a leaving group A in the presence of a base to obtain an aldehyde derivative (15), and (b) oxidizing the aldehyde derivative (15) to an organic acid derivative (16) was obtained, and (c) the organic acid derivative (16) was condensed with phenyl selenylphthalamide (17) to obtain an acyl selenium derivative (18), and (d) a radical initiator in the acyl selenium derivative (18). To generate an acyl radical and react with butenolide (19) to obtain a keto-lactone derivative (20), and then (e) react the keto-lactone derivative (20) with hydrazine to produce hydroxy-pyridazinone. Obtaining a derivative (21), and (f) reacting the pyridazinone derivative (21) with an organic acid (34), which is an optically active substance, to obtain a mixture of diastereomers (35a) (35b), and (g) the diastereomer (35a) (35b) using column chromatography or fractional recrystallization After separating each optical isomer, (a) hydrolyzing the optical isomers 35a and 35b, respectively, to obtain isomers 21a and 21b, and then the optical isomers 21a and 21b. ) Is an optical isomer separation method of the pyridazinone derivative represented by the following general formula (Ii) to be separated by nitration reaction. Wherein R ₁ is methyl, hydroxymethyl, nitrosylmethyl, monohalomethyl, dihalomethyl, trihalomethyl, R ₂ is a hydrogen atom, alkyn or branched alkyl group of 1 to 6 carbon atoms, cyclic alkyl group Is an alkyl, alkene, alkyne, or a phenyl group substituted by an alkyl, alkene, alkyne or a phenyl group, and A is a halogen atom, tosylate or methanesulfonate. The pyridazinone derivative (Ii) according to claims 34 to 36 is (a) a mixture of an organic acid (34) which is an optically active compound and a diestereomer (36a, 36b), and (b) the diastereomer (36a) and (36b) are separated into their respective optical isomers using column chromatography or fractional recrystallization method, and (c) the optical isomers (36a) and (36b) are separated by hydrolysis, respectively. Optical isomer separation method of pyridazinone derivative represented by Ii). Wherein R ₂ is a hydrogen atom, an alkyl, alkene, alkyne group substituted with an alkyl, alkene, alkyne or phenyl group substituted with an alkyn or branched alkyl group, a cyclic alkyl group, an alkene, alkyne group or a halogen group with 1 to 6 carbon atoms.