JP4403105B2 - Imidazopyridazine derivatives - Google Patents

Description

  The present invention relates to a novel herbicide containing a fused heterocyclic sulfonylurea compound, a method for controlling weeds in paddy fields, and a novel fused heterocyclic sulfonylurea compound. In particular, the herbicide of the present invention has a very excellent selectivity for paddy rice by applying at the time of transplanting or after transplanting rice, and exhibits a high herbicidal effect on sulfonylurea-based herbicide-resistant weeds, The present invention relates to a method for controlling sulfonylurea herbicide-resistant weeds using the same and a novel condensed heterocyclic sulfonylurea compound.

Until now, many sulfonylurea compounds have been put to practical use for paddy fields, and they have been widely used as a mixture containing two or more active ingredients with various grass weed control agents effective against grass weeds. However, in recent years, the emergence of weeds having resistance to sulfonylurea herbicides such as bensulfuron-methyl, pyrazosulfuron-ethyl, and imazosulfuron has been observed, and its control has become a problem.
In general, ALS inhibitors including sulfonylurea herbicides having acetolactate synthase (ALS) as an action point are known to exhibit cross resistance in sulfonylurea herbicide resistant weeds. However, the conventional control method was a method of adding an active ingredient effective to a sulfonylurea herbicide-resistant weed to an existing mixture and increasing the number of active ingredients in the mixture to control (for example, (See Patent Documents 1 to 3.) Under such circumstances, there is a need for a herbicide that has a satisfactory herbicidal effect on sulfonylurea-based herbicide-resistant weeds and that can reduce the number of active ingredients in the mixture.
JP-A-10-287513 Japanese Patent Laid-Open No. 11-228307 Japanese Patent Application Laid-Open No. 11-349411

  One of the objects of the present invention is herbicidal which has no phytotoxicity on paddy rice, has an excellent herbicidal effect on sulfonylurea herbicide-resistant weeds, and can reduce the number of active ingredients in the mixture. Is the development of drugs. In addition to sulfonylurea herbicide-resistant weeds, herbicides have an excellent herbicidal effect on annual broad-leaved weeds and perennial weeds other than resistant weeds, and have a broad herbicidal spectrum with no phytotoxicity to paddy rice The development of this is one of the objects of the present invention.

As a result of repeated research aimed at developing an excellent herbicide having a broad herbicidal spectrum and having no phytotoxicity, the present inventors have found that the condensed heterocyclic sulfonylurea compound of Japanese Patent Application Laid-Open No. 64-38091. Within the range, it has been found that a compound represented by the following formula (I) or a salt thereof has a high herbicidal effect on a wide range of sulfonylurea-based herbicide-resistant weeds, compared to other compounds, The present invention has been completed.
Surprisingly, the compound of the following formula (I) in which the substituent Q is Q1 to Q3 and R3 is hydrogen shows a high herbicidal effect on sulfonylurea herbicide-sensitive weeds. On the other hand, R3 is a compound having the following substituents and Q is a group represented by Q4, and the same herbicidal effect on sensitive weeds as well as sulfonylurea herbicide-resistant weeds It turns out that it maintains.

（式中、Ｒ１はハロゲン原子を、Ｒ２は水素原子を、Ｒ３はC_２−４アルキル基またはシクロプロピル基を示す。）で表される化合物またはその塩、
（２）Ｒ１が塩素原子である上記（１）記載の化合物またはその塩、
（３）Ｒ３がエチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基またはイソブチル基である上記（２）記載の化合物またはその塩、
（４）式：

（式中、Ｒ１はハロゲン原子を、Ｒ２は水素原子を、Ｒ３はC_２−４アルキル基またはシクロプロピル基を示す。）で表される化合物またはその塩、
（５）Ｒ１が塩素原子である上記（４）記載の化合物またはその塩、
（６）Ｒ３がエチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基またはイソブチル基である上記（５）記載の化合物またはその塩、
（７）Ｒ１がフッ素原子、Ｒ２が水素原子およびＲ３がｎ−プロピル基である上記（４）記載の化合物またはその塩、
（８）式：

（式中、Ｒ１はハロゲン原子を、Ｒ２は水素原子を、Ｒ３はC_２−４アルキル基またはシクロプロピル基を示す。）で表される化合物またはその塩、
（９）Ｒ１が塩素原子である上記（８）記載の化合物またはその塩、
（１０）Ｒ３がエチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基またはイソブチル基である上記（９）記載の化合物またはその塩、
（１１）Ｒ１が塩素原子、Ｒ２が水素原子およびＲ３がｎ−プロピル基である上記（８）記載の化合物またはその塩、
（１２）Ｒ１がフッ素原子、Ｒ２が水素原子およびＲ３がｎ−プロピル基である上記（８）記載の化合物またはその塩、
（１３）式：

（式中、Ｒ１はハロゲン原子を、Ｒ２は水素原子を、Ｒ３はC_２−４アルキル基またはシクロプロピル基を示す。）で表される化合物またはその塩、
（１４）Ｒ１が塩素原子である上記（１３）記載の化合物またはその塩、
（１５）Ｒ３がエチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基またはシクロプロピル基である上記（１４）記載の化合物またはその塩、
（１６）Ｒ１がフッ素原子、Ｒ２が水素原子およびＲ３がｎ−プロピル基である上記（１３）記載の化合物またはその塩、
（１７）式

〔式中、Ｑは、式

（式中、Ｒ１は水素原子、ハロゲン原子、シアノ基、ニトロ基、ハロゲンで置換されていてもよい低級アルキル基、ハロゲンで置換されていてもよい低級アルコキシ基、低級アルキルチオ基、低級アルキルスルフィニル基、低級アルキルスルホニル基、アミノ基、低級アルキルアミノ基またはジ低級アルキルアミノ基を、
Ｒ２は、水素原子、ハロゲン原子またはハロゲンで置換されていてもよい低級アルキル基を、
Ｒ３は、ハロゲン原子、シアノ基、ニトロ基、ハロゲンで置換されていてもよい低級アルキル基、ハロゲンもしくは低級アルキル基で置換されていてもよい低級シクロアルキル基、ハロゲンで置換されていてもよい低級アルケニル基、ハロゲンで置換されていてもよい低級アルキニル基、ハロゲンで置換されていてもよい低級アルコキシ基、低級アルキルチオ基、低級アルキルスルフィニル基、低級アルキルスルホニル基、アミノ基、低級アルキルアミノ基またはジ低級アルキルアミノ基を示す。）で表される縮合複素環基を、
ＸおよびＹは、同一または異なって、それぞれハロゲンで置換されていてもよい低級アルキル基、ハロゲンで置換されていてもよい低級アルコキシ基またはハロゲン原子を示す。〕で表される化合物（以下、化合物（Ｉ）と称する場合がある）またはその塩を含有するスルホニル尿素系除草剤抵抗性雑草用の除草剤、
（１８）Ｒ１がハロゲン原子、ハロゲンで置換されていてもよい低級アルキル基、低級アルキルチオ基、低級アルキルスルフィニル基または低級アルキルスルホニル基を、Ｒ３がハロゲン原子、ハロゲンで置換されていてもよい低級アルキル基、ハロゲンもしくは低級アルキル基で置換されていてもよい低級シクロアルキル基、ハロゲンで置換されていてもよい低級アルコキシ基、低級アルキルチオ基、低級アルキルスルフィニル基、低級アルキルスルホニル基、低級アルキルアミノ基またはジ低級アルキルアミノ基を、ＸおよびＹが、それぞれハロゲンで置換されていてもよい低級アルコキシ基である上記（１７）記載の除草剤、
（１９）Ｒ１がハロゲン原子またはハロゲンで置換されていてもよい低級アルキル基を、Ｒ２が水素原子を、Ｒ３がハロゲン原子、ハロゲンで置換されていてもよい低級アルキル基、ハロゲンもしくは低級アルキル基で置換されていてもよい低級シクロアルキル基、ハロゲンで置換されていてもよい低級アルコキシ基、低級アルキルチオ基、低級アルキルスルフィニル基、低級アルキルスルホニル基、低級アルキルアミノ基またはジ低級アルキルアミノ基を、ＸおよびＹが、それぞれハロゲンで置換されていてもよい低級アルキル基またはハロゲンで置換されていてもよい低級アルコキシ基を示す上記（１７）記載の除草剤、
（２０）Ｑが、上記式Ｑ１またはＱ４で表される縮合複素環基である上記（１７）記載の除草剤、
（２１）式

（式中、Ｒ１はハロゲン原子またはハロゲンで置換されていてもよい低級アルキル基を、Ｒ２は水素原子を、Ｒ３はハロゲンで置換されていてもよいＣ_２−４アルキル基またはハロゲンもしくは低級アルキル基で置換されていてもよい低級シクロアルキル基を、ＸおよびＹは、それぞれハロゲンで置換されていてもよい低級アルキル基またはハロゲンで置換されていてもよい低級アルコキシ基を示す。）で表される化合物またはその塩（以下、化合物（Ｉａ）と称する場合がある）、
（２２）Ｒ１がハロゲン原子であり、Ｒ３がＣ_２−４アルキル基または低級シクロアルキル基であり、ＸおよびＹがそれぞれメトキシ基である上記（２１）記載の化合物またはその塩、
（２３）上記（２１）記載の化合物またはその塩を含有するスルホニル尿素系除草剤抵抗性雑草用の除草剤、
（２４）上記（２２）記載の化合物またはその塩を含有するスルホニル尿素系除草剤抵抗性雑草用の除草剤、
（２５）スルホニル尿素系除草剤抵抗性雑草に卓効を示す上記（１７）〜（２０）、（２３）または（２４）のいずれか１に記載の除草剤、
（２６）上記（１７）〜（２０）、（２３）または（２４）のいずれか１に記載の除草剤を適用することを特徴とするスルホニル尿素系除草剤抵抗性雑草の防除方法、および
（２７）上記（１７）〜（２０）、（２３）または（２４）のいずれか１に記載の除草剤を適用することを特徴とする水田の雑草の防除方法を提供するものである。 That is, the present invention
(1) Formula:

Wherein R1 represents a halogen atom, R2 represents a hydrogen atom, and R3 represents a C _2-4 alkyl group or a cyclopropyl group, or a salt thereof,
(2) The compound according to the above (1) or a salt thereof, wherein R1 is a chlorine atom,
(3) The compound or a salt thereof according to the above (2), wherein R3 is an ethyl group, n-propyl group, isopropyl group, n-butyl group or isobutyl group,
(4) Formula:

Wherein R1 represents a halogen atom, R2 represents a hydrogen atom, and R3 represents a C _2-4 alkyl group or a cyclopropyl group, or a salt thereof,
(5) The compound according to (4) or a salt thereof, wherein R1 is a chlorine atom,
(6) The compound or a salt thereof according to the above (5), wherein R3 is an ethyl group, n-propyl group, isopropyl group, n-butyl group or isobutyl group,
(7) The compound or a salt thereof according to the above (4), wherein R1 is a fluorine atom, R2 is a hydrogen atom and R3 is an n-propyl group,
(8) Formula:

Wherein R1 represents a halogen atom, R2 represents a hydrogen atom, and R3 represents a C _2-4 alkyl group or a cyclopropyl group, or a salt thereof,
(9) The compound according to (8) or a salt thereof, wherein R1 is a chlorine atom,
(10) The compound or a salt thereof according to the above (9), wherein R3 is an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group or an isobutyl group,
(11) The compound or a salt thereof according to the above (8), wherein R1 is a chlorine atom, R2 is a hydrogen atom and R3 is an n-propyl group,
(12) The compound or a salt thereof according to the above (8), wherein R1 is a fluorine atom, R2 is a hydrogen atom and R3 is an n-propyl group,
(13) Formula:

Wherein R1 represents a halogen atom, R2 represents a hydrogen atom, and R3 represents a C _2-4 alkyl group or a cyclopropyl group, or a salt thereof,
(14) The compound according to (13) or a salt thereof, wherein R1 is a chlorine atom,
(15) The compound or a salt thereof according to the above (14), wherein R3 is an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a cyclopropyl group,
(16) The compound or a salt thereof according to the above (13), wherein R1 is a fluorine atom, R2 is a hydrogen atom and R3 is an n-propyl group,
(17) Formula

[Where Q is the formula

(Wherein R1 represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a lower alkyl group optionally substituted with halogen, a lower alkoxy group optionally substituted with halogen, a lower alkylthio group, or a lower alkylsulfinyl group. A lower alkylsulfonyl group, an amino group, a lower alkylamino group or a di-lower alkylamino group,
R2 represents a hydrogen atom, a halogen atom or a lower alkyl group which may be substituted with a halogen,
R3 represents a halogen atom, a cyano group, a nitro group, a lower alkyl group which may be substituted with halogen, a lower cycloalkyl group which may be substituted with halogen or a lower alkyl group, or a lower group which may be substituted with halogen. Alkenyl group, lower alkynyl group optionally substituted with halogen, lower alkoxy group optionally substituted with halogen, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, amino group, lower alkylamino group or di A lower alkylamino group is shown. A condensed heterocyclic group represented by
X and Y are the same or different and each represents a lower alkyl group which may be substituted with halogen, a lower alkoxy group which may be substituted with halogen, or a halogen atom. A sulfonylurea-based herbicide-resistant herbicide containing a compound represented by the following formula (hereinafter sometimes referred to as compound (I)) or a salt thereof:
(18) R1 is a halogen atom, a lower alkyl group which may be substituted with halogen, a lower alkylthio group, a lower alkylsulfinyl group or a lower alkylsulfonyl group, and R3 is a lower alkyl which may be substituted with a halogen atom or halogen. Group, lower cycloalkyl group optionally substituted with halogen or lower alkyl group, lower alkoxy group optionally substituted with halogen, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylamino group or The herbicide according to (17) above, wherein the di-lower alkylamino group is a lower alkoxy group in which X and Y are each optionally substituted with a halogen;
(19) R1 is a halogen atom or a lower alkyl group which may be substituted with halogen, R2 is a hydrogen atom, R3 is a halogen atom or a lower alkyl group which may be substituted with halogen, a halogen or a lower alkyl group A lower cycloalkyl group which may be substituted, a lower alkoxy group which may be substituted with halogen, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylamino group or a di-lower alkylamino group; The herbicide according to the above (17), wherein Y and Y each represent a lower alkyl group optionally substituted with halogen or a lower alkoxy group optionally substituted with halogen;
(20) The herbicide according to the above (17), wherein Q is a condensed heterocyclic group represented by the above formula Q1 or Q4,
(21) Formula

(Wherein R1 is a halogen atom or a lower alkyl group optionally substituted with halogen, R2 is a hydrogen atom, R3 is a _C2-4 alkyl group optionally substituted with halogen, or a halogen or lower alkyl group. X and Y each represents a lower alkyl group which may be substituted with a halogen or a lower alkoxy group which may be substituted with a halogen. Compound or a salt thereof (hereinafter sometimes referred to as Compound (Ia)),
(22) The compound or a salt thereof according to the above (21), wherein R 1 is a halogen atom, R 3 is a C _2-4 alkyl group or a lower cycloalkyl group, and X and Y are each a methoxy group,
(23) A sulfonylurea-based herbicide-resistant weed killer containing the compound of the above (21) or a salt thereof,
(24) A sulfonylurea-based herbicide-resistant weed killer containing the compound of the above (22) or a salt thereof,
(25) The herbicide according to any one of the above (17) to (20), (23) or (24), which exhibits a superior effect on a sulfonylurea-based herbicide-resistant weed,
(26) A method for controlling a sulfonylurea herbicide-resistant weed, characterized by applying the herbicide according to any one of (17) to (20), (23) or (24), and ( 27) Provided is a method for controlling weeds in paddy fields, characterized by applying the herbicide according to any one of (17) to (20), (23) or (24).

  The herbicide of the present invention is useful for controlling weeds including sulfonylurea herbicide-resistant weeds in paddy fields, and is also useful for reducing the number of active ingredients in the mixture.

In the present specification, “lower” in a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a lower alkylthio group, etc. means that the hydrocarbon moiety has 1 or 2 to 6 carbon atoms, preferably 1 or 2 to 4 It is composed of carbon atoms. Examples thereof include a linear or branched C _1-6 alkyl group, a C _2-6 alkenyl group, a C _1-6 alkoxy group, a C _1-6 alkylthio group, and the like.
R1 in the condensed heterocyclic group represented by Q of compound (I) is a hydrogen atom, a halogen atom, a cyano group, a nitro group, a lower alkyl group which may be substituted with halogen, or a lower group which may be substituted with halogen. An alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an amino group, a lower alkylamino group or a di-lower alkylamino group;
Examples of the “halogen atom” in R1 include fluorine, chlorine, bromine, iodine and the like.
The “lower alkyl group” in R1 is a linear or branched alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t -Butyl etc. are mentioned. The “halogen” in the “lower alkyl group optionally substituted with halogen” includes, for example, fluorine, chlorine, bromine, iodine, etc., and the lower alkyl group is preferably one or more, preferably at a substitutable position. May be substituted by 1 to 3 halogens.
Examples of the “lower alkoxy group” for R 1 include linear or branched alkoxy groups having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, t-butoxy and the like. Examples of the “halogen” in the “lower alkoxy group optionally substituted with halogen” include the same as those in the case of the lower alkyl group, and the lower alkoxy group is preferably one or more, preferably at the substitutable position. It may be substituted by 1 to 3 halogens.
The “lower alkyl” in the “lower alkylthio group”, “lower alkylsulfinyl group”, “lower alkylsulfonyl group”, “lower alkylamino group” and “di-lower alkylamino group” of R1 is the above-mentioned “lower alkyl group” And the like.

R2 represents a hydrogen atom, a halogen atom or a lower alkyl group which may be substituted with a halogen. Examples of the “halogen atom”, “halogen” and “lower alkyl group” include those similar to the above R1. The lower alkyl group may be substituted with 1 or more, preferably 1 to 3 halogens at substitutable positions.
R3 represents a halogen atom, a cyano group, a nitro group, a lower alkyl group which may be substituted with a halogen, a lower cycloalkyl group which may be substituted with a halogen or a lower alkyl group, or a lower group which may be substituted with a halogen. Alkenyl group, lower alkynyl group optionally substituted with halogen, lower alkoxy group optionally substituted with halogen, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, amino group, lower alkylamino group or di A lower alkylamino group is shown. Examples of the “halogen atom”, “halogen”, “lower alkyl group” and “lower alkoxy group” are the same as those described above for R1. These lower alkyl group and lower alkoxy group may also be substituted with one or more, preferably 1 to 3 halogens at substitutable positions. Examples of the “lower cycloalkyl group” include cyclopropyl, cyclobutyl and the like, and examples of the “lower alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 1,2-propadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl and the like can be mentioned, and examples of the “lower alkynyl” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl and 2-butynyl. The “lower alkyl” in the “lower alkylthio group”, “lower alkylsulfinyl group”, “lower alkylsulfonyl group”, “lower alkylamino group” and “di-lower alkylamino group” is the “lower alkyl” described in R1 above. The same thing as "group" is mentioned.
The condensed heterocyclic group represented by Q includes an imidazo [1,2-b] pyridazine group represented by formula Q1 and a pyrazolo represented by formula Q3 because of its high activity against sulfonylurea herbicide-resistant weeds. A 1,5-a] pyrimidine group and a pyrazo [1,5-b] thiazole group represented by formula Q4 are preferred. In particular, the group represented by the formula Q1 is particularly preferable.

In compound (I), X and Y are the same or different and each represents a lower alkyl group which may be substituted with halogen, a lower alkoxy group which may be substituted with halogen, or a halogen atom. As these “halogen”, “lower alkyl group”, “lower alkoxy group” and “halogen atom”, those similar to the above R 1 can be mentioned. These lower alkyl group and lower alkoxy group may also be substituted with one or more, preferably 1 to 3 halogens at substitutable positions. X and Y are preferably a lower alkoxy group which may be substituted with a halogen, and more preferably a methoxy group.
In the compound (I), Q represents Q1, (a) R1 is a halogen atom or a lower alkyl group which may be substituted with halogen, and R2 may be substituted with a hydrogen atom, a halogen atom or halogen. A lower alkyl group, R3 is a halogen atom, a lower alkyl group which may be substituted with halogen, a lower cycloalkyl group which may be substituted with halogen or a lower alkyl group, a lower alkoxy group which may be substituted with halogen , A lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylamino group or a di-lower alkylamino group, wherein X and Y are each substituted with a lower alkyl group or halogen optionally substituted with halogen. And a lower alkoxy group which may be A halogen atom or a lower alkyl group which may be substituted with a halogen, R2 is a hydrogen atom, R3 is a halogen atom or a lower alkyl group which may be substituted with a halogen, a halogen or a lower alkyl group A preferred lower cycloalkyl group, a lower alkoxy group optionally substituted with halogen, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylamino group or a di-lower alkylamino group, wherein X and Y are each More preferably, it represents a lower alkoxy group which may be substituted with halogen, and in particular, as in (C) Compound (Ia), R1 represents a halogen atom, R2 represents a hydrogen atom, and R3 represents a _C2-4 alkyl. A group or a lower cycloalkyl group wherein X and Y each represents a methoxy group Preferred.

Representative examples of compound (I) include
(1) Compound (I) wherein Q is Q1, R1 is ethyl, R2 is a hydrogen atom, R3 is methylthio, X and Y are methoxy,
(2) Compound (I) wherein Q is Q1, R1 is methyl, R2 is a hydrogen atom, R3 is ethyl, X and Y are methoxy,
(3) Compound (I) wherein Q is Q1, R1 is methyl, R2 is a hydrogen atom, R3 is ethylthio, X and Y are methoxy,
(4) Compound (I) wherein Q is Q1, R1 is methyl, R2 is a hydrogen atom, R3 is methylthio, X and Y are methoxy,
(5) Compound (I) wherein Q is Q2, R1 is methyl, R2 is ethoxy, X and Y are methoxy,
(6) Compound (I) wherein Q is Q3, R1 is methyl, R2 is a hydrogen atom, R3 is methoxy, X and Y are methoxy,
(7) Compound (I) wherein Q is Q3, R1 is methyl, R2 is a hydrogen atom, R3 is ethoxy, X and Y are methoxy,
(8) Compound (I) wherein Q is Q4, R1 is methylsulfonyl, X and Y are methoxy,
(9) Compound (I) wherein Q is Q1, R1 is methyl, R2 is a hydrogen atom, R3 is n-propyl, X and Y are methoxy,
(10) Compound (I) wherein Q is Q1, R1 is a chlorine atom, R2 is a hydrogen atom, R3 is ethyl, X and Y are methoxy,
(11) Compound (I) wherein Q is Q1, R1 is a chlorine atom, R2 is a hydrogen atom, R3 is n-propyl, X and Y are methoxy,
(12) Compound (I) wherein Q is Q1, R1 is methyl, R2 is a hydrogen atom, R3 is i-propyl, X and Y are methoxy,
(13) Compound (I) in which Q is Q1, R1 is a chlorine atom, R2 is a hydrogen atom, R3 is i-propyl, and X and Y are methoxy.
(14) Compound (I) in which Q is Q1, R1 is a chlorine atom, R2 is a hydrogen atom, R3 is cyclopropyl, and X and Y are methoxy.
(15) Compound (I) in which Q is Q1, R1 is a fluorine atom, R2 is a hydrogen atom, R3 is n-propyl, and X and Y are methoxy.

Compound (I) may exist as optical isomers, diastereomers, and / or geometric isomers, and the present invention includes each isomer and a mixture thereof.
Compound (I) can form an agrochemically acceptable base salt with an acidic group such as a sulfo group or a carboxyl group in a substituent in the molecule together with an inorganic base or an organic base. A basic nitrogen atom and a basic group such as an amino acid group in a substituent can form an acid addition salt that is agrochemically acceptable with an inorganic acid, an organic acid or the like. Examples of inorganic base salts include salts such as alkali metals (eg, sodium, potassium, etc.), alkaline earth metals (eg, calcium, etc.), ammonia, and organic base salts such as dimethylamine, triethylamine, N, N-dimethylaniline, piperazine, pyrrolidine, piperidine, pyridine, 2-phenylethylamine, benzylamine, ethanolamine, diethanolamine, 1,8-diazabicyclo [5,4,0] undecene (hereinafter abbreviated as DBU), etc. And the like are used. Examples of the inorganic acid addition salt of compound (I) include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, etc., and organic acid addition of compound (I). Examples of the salt include salts with formic acid, acetic acid, propionic acid, succinic acid, succinic acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid and the like.
Compound (I) can be produced, for example, according to the method described in JP-A No. 64-38091, and the specific method is shown in the following examples.
When compound (I) is a crystal, compound (I) becomes a crystalline polymorph or pseudocrystalline polymorph depending on the conditions at which the crystal is crystallized, and different infrared absorptions even for chemical structures that give the same nuclear magnetic resonance spectrum May give a spectrum. The present invention includes not only each crystal form of a compound exhibiting such crystal polymorphism or pseudocrystal polymorphism, but also mixed crystals thereof.

Compound (I) or a salt thereof has particularly excellent selectivity for paddy rice when applied during or after transplanting of paddy rice, and exhibits a high herbicidal effect on sulfonylurea herbicide-resistant weeds.
When the compound (I) or a salt thereof is used as an agrochemical, particularly as a herbicide, a general pesticide can take a form, that is, one or more of the compound (I) or a salt thereof is an appropriate liquid depending on the purpose of use. Dissolved or dispersed in a carrier, or mixed or adsorbed with a suitable solid carrier, for example, emulsion, oil, spray, wettable powder, powder, DL (driftless) type powder, granule, fine granule, It is used as preparations such as fine granules F, flowables, dry fullables, jumbo granules and tablets. These preparations may contain an emulsifier, a dispersant, a spreading agent, a penetrating agent, a wetting agent, a mucilage agent, a stabilizer and the like, if necessary, and can be prepared by a method known per se.
Examples of the liquid carrier (solvent) to be used include water, alcohols (eg, methanol, ethanol, 1-propanol, 2-propanol, etherene glycol, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), ethers, and the like. (Eg, dioxane, tetrahydrofuran, ethylene glycol monomethyl ether, diethylene glycol monomethyl ether, propylene glycol monomethyl ether, etc.), aliphatic hydrocarbons (eg, kerosene, fuel oil, machine oil, etc.), aromatic hydrocarbons (eg, benzene) , Toluene, xylene, solvent naphtha, methylnaphthalene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride, etc.), acid amides (eg, dimethylformamide, dimethylacetamide, etc.), esters (eg, Acetic acid Solvents such as chill esters, butyl acetates, fatty acid glycerin esters, etc.) and nitriles (eg, acetonitrile, propionitrile, etc.) are suitable, and these are used singly or in combination of two or more. . Solid carriers (dilution / extension agents) include vegetable powders (eg, soybean powder, tobacco powder, wheat flour, wood flour, etc.), mineral powders (eg, kaolin, bentonite, acid clay, clays such as clay, talc Talc such as powder and wax stone powder, silica such as diatomaceous earth and mica powder, etc.), alumina, sulfur powder, activated carbon, etc. are suitable, and these are used by mixing one or more kinds in an appropriate ratio. . The liquid carrier or solid carrier is usually used in an amount of about 1 to 99% by weight, preferably about 1 to 80% by weight, based on the whole preparation.

Surfactants used as emulsifiers, spreading agents, penetrants, dispersants, etc. include soaps, polyoxyethylene alkylaryl ethers (eg, Neugen ^TM , EA 142 (E, A 142) as necessary. ^TM and TM are registered trademarks. The same applies hereinafter; manufactured by Daiichi Kogyo Seiyaku Co., Ltd.), polyoxyethylene aryl esters (eg, Nonal ^TM ; manufactured by Toho Chemical Co., Ltd.), alkyl sulfates ( Examples, Yumar 10 ^TM , Yumar 40 ^TM ; manufactured by Kao Soap Co., Ltd., alkyl sulfonates (eg, Neogen ^TM , Neogen T ^TM ; manufactured by Daiichi Kogyo Seiyaku Co., Ltd., Neoperex ^TM ; Kao Soap Co., Ltd.) Ltd.), polyethylene glycol ethers (e.g., Nonipol ^{85 TM,} Nonipol ^{100 TM,} Nonipol ^{160 TM;} Sanyo Kasei Co., Ltd.), multi Alcohol esters (e.g., Tween ^{20 TM,} Tween ^{80 TM;} Kao Soap Corp.) non ionic and anionic surfactants such as are used. The surfactant can be used usually in an amount of about 0.1 to about 50%, preferably about 0.1 to 25% with respect to the whole preparation.
The content of the compound (I) or a salt thereof in the herbicide is suitably about 1 to 90% by weight for emulsions, wettable powders, etc., and 0.01 for oils, powders, DL (driftless) type powders, etc. About 10 to 10% by weight is suitable, and about 0.05 to 10% by weight is suitable for the fine granules F and granules, but these concentrations may be appropriately changed depending on the purpose of use. Emulsions, wettable powders, and the like are sprayed after being appropriately diluted with water or the like (for example, 100 to 100,000 times).
The amount of compound (I) or a salt thereof used as a herbicide varies depending on the application scene, application period, application method, target weed, cultivated crop, etc., but generally as an active ingredient (compound (I) or a salt thereof) It is about 0.05 to 50 g, preferably about 0.1 to 5 g per paddy field, and about 0.04 to 10 g, preferably about 0.08 to 5 g, per field are.
The compound (I) or a salt thereof can be used as a pre-emergence soil treatment or a foliage and soil treatment agent for upland weeds. For example, the herbicide of the present invention can be used safely without causing phytotoxicity even after 2-3 weeks.

  The herbicide containing the compound (I) of the present invention or a salt thereof may be one or more (preferably 1 to 3) other herbicides, plant growth regulators, fungicides, It can be applied simultaneously with insecticides, acaricides, nematicides and the like. In addition, one or two or more (preferably 1 to 3) other herbicides, plant growth regulators, fungicides, insecticides, acaricides, nematicides, etc. are mixed and used. You can also. Other herbicides (herbicidal active ingredients) include, for example, (1) sulfonylurea herbicides [chlorsulfuron, sulfometuron-methyl, chlorimuron-ethyl, Triasulfuron, amidosulfuron, oxasulfuron, tribenuron-methyl, prosulfuron, ethametsulfuron-methyl, triflusulfuron-methyl (triflusulfuron-methyl), thifensulfuron-methyl, flusasulfuron, rimsulfuron, nicosulfuron, flupirsulfuron, bensulfuron-methy1 , Pyrazosulfuron-ethy1, imazosulfuron, sulfosulfuron (sul fosu1furon), sinosulfuron (cinosulfuron), azimsulfuron (azimsulfuron), metsulfuron methyl (metsu1furon-methy1), halosulfuron methyl (ha1osulfuron-methy1), ethoxysulfuron, cyclosulfamuron (cyc1osulfamuron), iodosulfururon (Iodosulfuron), etc.], (2) pyrazole herbicides [pyraflufen-ethyl, pyrazolate, pyrazoxifene, benzofenap, etc.], (3) carbamate herbicides (Di-allate, butyrate, tri-allate, phenmedipham, chloropropham, ashram, phenisopham, benthiocarb, Molinate, esprocarb, pyributicarb, dimepipate erate), swep, etc.], (4) chloroacetanilide herbicides [propachlor, metazachlor, alachlor, acetochlor, metolachlor, butachlor (butachlor), pretilachlor, tenyl chlor (theny1ch1or, etc.), (5) diphenyl ether herbicides [acifluorfen, oxyfluorfen, lactofen, lactomefen, flonsafen, aclonifen ), Chlomethoxyni1, bifenox, CNP, etc.), (6) Triazine herbicides [simazine, atrazine, proprazine, cyanazine, amethrin, cimetrin (simetryn), dimethametryn, promethrin, etc.], (7) Fe Noxic acid or benzoic acid herbicides [2,3,6-TBA, dicamba, quinclorac, quinmerac, clopyralid, picloram, triclopyr, fluroxypyr (fluroxypyr), benazolin, diclohopop-methyl, fluazifop-butyl, haloxyfop-methyl, quizalofop-ethyl, cyhalo Cyhalohop-butyl, 2,4-PA, MCP, MCPB, phenothiol, etc.], (8) acid amide or urea herbicides [Isoxaben, diflufenican, diuron ( diuron), linuron, fluometuron, difenoxuron, methyl-daimuron, isoproturon, isouron, tebuthiuron (teb) uthiuron, metabenzothiazuron, propanil, mefenacet, clomeprop, naproanilide, bromobutide, daimuron, cumy1urond, etozad ), Oxazichlomefone, etc.], (9) organophosphorus herbicides [glyphosate, bialaphos, amiprofos-methyl, anilofos, bensulide, piperophos ( piperophos, butamifos, anilofos, etc.], (10) dinitroaniline herbicides [bromoxynil, ioxynil, dinoseb, trifluralin, prodiamine, etc. ] (11) Cyclohexanedione herbicide [alloxydim, setoki Sethoxydim, cloproxydim, clethodim, cycloxydim, tralkoxydim, etc.], (12) imidazoline herbicides [imazamethabenz, imazapyr, imazaapyr] ), Imazethapyr, imazamox, imazaquin, etc.], (13) bipyridium herbicides [paraquat, diquat, etc.], (14) other herbicides [bentazones] (bentazon), tridiphane, indanofan, amitrole, carfentrazon-ethyl, sulfentrazon, fenchlorazole-ethyl, fentolazamide ( fentrazamide), isoxaflutole, clomazone, maleic acid Hydrazide (maleic hydrazide), pyridate, chloridazon, norflurazon, pyrithiobac, bromacil, terbacil, terbacil, metribuzin, oxaziclomefone, oxaziclomefone Flumiclorac-pentyl, cinidon-ethyl, flumioxazin, fluthiacet-methyl, azafenidin, benfuresate, oxadiazon, oxadiargyl (oxadiargy1), pentoxazone, cyhalofop-butyl, caffenstrole, pyriminobac-methy1, bispyribac-sodium, pyribenzoxim, pyriftalide (Pyriftalid), fe Fentrazamide, indanofan, ACN, benzobicyclon, dithiopyr, da1apon, chlorthiamid, etc.).

Examples of plant growth regulators (plant growth regulating active ingredients) include, for example, hymexazole (hymexazo1), paclobutrazole (pac1obutrazo1), uniconazole-P (uniconazole-P), inabenfide (inabenfide), prohexadione- ca1cium). As bactericides (bactericidal active ingredients), for example, (1) polyhaloalkylthio fungicides [captan etc.], (2) organophosphorus fungicides [IBP, EDDP, tolc1ofos-methy1) Etc.], (3) benzimidazole fungicides [benomyl, carbendazim, thiophanate methyl (thiophanate-methy1), etc.], (4) carboxamide fungicides [meproni1, flutolanil (f1uto1anil) ), Thifluzamid, furametpyr, teclophthalam (tec1oftha1am), pencyclon (Pencycuron), carpropamid, diclosimet (dic1ocymet, etc.)], (5) acylalanine fungicides [metalaxyl (metalaxy1), etc.] (6) Azole fungicides [triflumizo1e, ipconazo1e, pefazoate, prochloraz, etc.] (7) Methoxyacrylic acid fungicides [azoxystrobin, mettominostrobin, etc.], (8) Antibiotic fungicides [validamycin A, blasticidin S (blasticidin S) ), Kasugamycin, polyoxin (po1yoxin, etc.), (9) other fungicides [fthalide, probenazo1e, isoprothiolane, tricyclazole, pyroquiron, ferrimzone (ferimzone), acibnzolar S-methy1, dic1omezine, oxo1inic acid, phenazine oxide, TPN, iprodione, and the like. Insecticides (insecticidal active ingredients) include, for example, (1) organophosphorus insecticides [fenthion, fenitrothion, pirimiphos-methy1, diazinon, quinalphos, isoxathion ( isoxathion), pyridafenthion, chlorpyrifos-methyl, bamidothion, malathion, phenthoate, dimethoate, disulfoton, monocrotophos, monocrotophos, monocrotophos Phos (tetrach1orvinphos), chlorfenvinphos (ch1orfenvinphos), propaphos (propaphos), acephate (acephate), trichlorphon (trichlorphon), EPN, pyraclorfos (pyraclorfos) etc.], (2) carbamate insecticide [carbaryl (carbary1), Metolcarb, isoprocarb, BPMC, Propoxur, XMC, carbofuran, carbosulfan, benfuracarb, furathiocarb, methomyl, thiodicarb, etc.], (3) synthetic pyrethroid insecticides [ Cycloprothrin, etofenprox, etc.], (4) nereistoxin insecticides [cartap, bensu1tap, thiocyclam, etc.], (5) neonicotinoids Insecticides [imidacloprid (imidac1oprid), nitenpyram (nitenpyram), acetamiprid (acetamiprid), thiamethoxam (thiamethoxam), thiacloprid, dinotefuran (dinotefuran), clothianidin (clothianidin, etc.), insecticide (6) buprofezin), tebufenozide, fipronil, etiprol ethiprole), etc.], and the like. Examples of acaricides (miticidal active ingredients) include hexythiazox, pyridaben, fenpyroximate, tebufenpyrad, chlorfenapyr, etoxazole, pyrimidifen and the like. can give. Examples of the nematicide (nematicidal active ingredient) include fosthiazate and the like. Such other pesticidal active ingredients (eg, herbicidal active ingredients, plant growth regulating active ingredients, bactericidal active ingredients, insecticidal active ingredients, acaricidal active ingredients, nematicidal active ingredients, etc.) are usually about 0 for the entire formulation. About 1 to 20% by weight, preferably about 0.1 to 10% by weight can be used.
The herbicide containing the compound (I) or a salt thereof of the present invention further includes a synergist (eg, piperonyl butoxide etc.), an attractant (eg, eugenol etc.), a repellent (eg, Creosote, etc.), pigments (eg, edible blue No. 1 etc.), fertilizers (eg, urea, etc.), etc. may be mixed as appropriate.

Hereinafter, the present invention will be described in more detail with reference to examples (synthesis examples of synthesis intermediates (compounds (IIa) to (IId))), synthesis examples, formulation examples, and test examples. However, the present invention is not limited to these examples. Is not to be done.
Solvents observed by TLC (thin layer chromatography) were used as elution solvents in the column chromatography of Examples and Synthesis Examples. The TLC observation, silica gel 60F ₂₅₄ TLC plates Merck (Merck) Co., was used a UV detector as a detection direction. Silica gel 60 (0.063-0.200 mm) manufactured by Merck was used as the silica gel for the column. When a mixed solvent was used as an elution solvent, the volume mixing ratio of each solvent is shown in parentheses.
Proton nuclear magnetic resonance spectra ( ¹ H NMR) were measured with a Bruker AC-200P (200 MHz) and Bruker AV-400 (400 MHz) spectrometer using tetramethylsilane as an internal standard, and all delta values are shown in ppm. It was. Fluorine nuclear magnetic resonance spectra ( ¹⁹ F NMR) were measured with a Bruker AC-200P (188 MHz) and Bruker AV-400 (376 MHz) spectrometer using fluorotrichloromethane as an internal standard, and all delta values are shown in ppm. It was.
The infrared absorption spectrum (IR) was measured with a Perkin Elmer Paragon 100 type FT-IR spectrometer, and the absorption band position was indicated by wave number (cm ⁻¹ ). The melting point was measured using a Yanagimoto micro melting point measuring device.
The abbreviations used in the following examples, synthesis examples, and tables have the following meanings.
Me: methyl group, Et: ethyl group, n-Pr: normal propyl group, i-Pr: isopropyl group, c-Pr: cyclopropyl group, n-Bu: normal butyl group, i-Bu: isobutyl group, TMS: Trimethylsilyl group, s: singlet, d: doublet, t: triplet, q: quartet, br: broad, m: multiplet, dd: double triplet, dt: double triplet, tt: triple triplet, dq: double quartet, tq: Triple quartet, brs: broad singlet, J: coupling constant, CDCl ₃ : deuterated chloroform, DMSO-d ₆ : deuterated dimethyl sulfoxide, mp: melting point, dec .: decomposition, Hz: hertz, THF: tetrahydrofuran, DMF: N, N-dimethylformamide, dppp: 1,3-bis (diphenylphosphino) propane

６−クロロ−２−メチルイミダゾ［１，２−ｂ］ピリダジン (5.00 g, 29.8 mmol)と ［１，３−ビス（ジフェニルホスフィノ）プロパン］ニッケル（II）ジクロリド (0.08 g, 0.15 mmol)を乾燥エーテル (40 ml)−乾燥THF (20 ml)に懸濁し、氷冷下で攪拌しながらエチルマグネシウムブロミドエーテル溶液 (3M,15 ml, 45 mmol)を５分間で滴下した(内温１０℃以下)。反応液を室温まで昇温し、同温度で２時間、加熱還流下３時間攪拌した。反応液を攪拌しながら室温まで放冷し、水 (30 ml)を徐々に加えた。さらに室温で攪拌しながら濃塩酸でｐH=５〜６くらいに調節した。有機層と水層を分離し、水層を酢酸エチルで抽出した（70 ml ×2）。有機層を合して水洗した (250 ml ×3)。有機層を硫酸マグネシウムで乾燥、濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：酢酸エチル＝２：１→１：１）で精製し、得られた粗オイルをさらにシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し、目的物を淡紅色オイルとして得た。収量1.32 g(27.4%)
¹H NMR (CDCl₃, δ): 1.33 (3H,t,J=7.5 Hz), 2.48 (3H,s), 2.82 (2H,q,J=7.5 Hz), 6.87 (1H,d,J=9.2 Hz), 7.65 (1H,s), 7.72 (1H,d,J=9.2 Hz)
IR (Neat, cm^-1) : 2973, 2934, 2876, 1543, 1460, 1382, 1333, 1300, 1263, 1155, 1125, 1057, 1000, 820 ,726, 699 Synthesis of 6-ethyl-2-methylimidazo [1,2-b] pyridazine

6-chloro-2-methylimidazo [1,2-b] pyridazine (5.00 g, 29.8 mmol) and [1,3-bis (diphenylphosphino) propane] nickel (II) dichloride (0.08 g, 0.15 mmol). Suspended in dry ether (40 ml) -dry THF (20 ml) and stirred dropwise under ice cooling, ethylmagnesium bromide ether solution (3M, 15 ml, 45 mmol) was added dropwise over 5 minutes (internal temperature below 10 ° C). ). The reaction solution was warmed to room temperature and stirred at the same temperature for 2 hours and with heating under reflux for 3 hours. The reaction mixture was allowed to cool to room temperature with stirring, and water (30 ml) was gradually added. Further, the pH was adjusted to about 5 to 6 with concentrated hydrochloric acid while stirring at room temperature. The organic layer and the aqueous layer were separated, and the aqueous layer was extracted with ethyl acetate (70 ml × 2). The organic layers were combined and washed with water (250 ml × 3). The organic layer is dried over magnesium sulfate and concentrated. The residue is purified by silica gel column chromatography (chloroform: ethyl acetate = 2: 1 → 1: 1), and the resulting crude oil is further purified by silica gel column chromatography (ethyl acetate). To obtain the desired product as a light red oil. Yield 1.32 g (27.4%)
¹ H NMR (CDCl ₃ , δ): 1.33 (3H, t, J = 7.5 Hz), 2.48 (3H, s), 2.82 (2H, q, J = 7.5 Hz), 6.87 (1H, d, J = 9.2 Hz), 7.65 (1H, s), 7.72 (1H, d, J = 9.2 Hz)
IR (Neat, cm ^-1 ): 2973, 2934, 2876, 1543, 1460, 1382, 1333, 1300, 1263, 1155, 1125, 1057, 1000, 820, 726, 699

６−エチル−２−メチルイミダゾ［１，２−ｂ］ピリダジン (2.70 g, 16.7 mmol)を１，２−ジクロロエタン (30 ml)に溶解し、室温で攪拌しながらクロロスルホン酸 (1.27 g, 18.5 mmol)を加え、加熱還流下５時間攪拌した。反応液を約７０℃に下げた後、トリエチルアミン (2.38 g, 23.5 mmol)を１分間で滴下した。滴下終了後、反応液を加熱還流下で２０分間攪拌した。その後、反応液を７０℃くらいまで冷却し、オキシ塩化リン (3.86 g, 25.2 mmol)を１分間で滴下した。滴下終了後、加熱還流下で２時間攪拌した。反応液を約５０℃まで放冷し、温水（５０℃程度）50 mlに注ぎ入れた。これを５分間攪拌した後有機層を分取した。水層をクロロホルムで抽出した(50 ml ×2)。有機層を合して水洗後、硫酸マグネシウムで乾燥、濃縮した。残渣をアセトニトリル(40 ml)に溶解し、室温で攪拌しながら１４規定アンモニア水(7 ml)を加え、室温で２時間攪拌した。反応終了後、反応液を氷水(150 ml)にあけ、濃塩酸を用いてｐＨ＝４くらいに調節すると結晶が生成したのでこれを濾取、水洗後減圧下で乾燥した。その後、結晶をシリカゲルカラムクロマトグラフィー（クロロホルム：アセトン=９：１→４：１）で精製した。目的物を白色結晶として得た。収量1.8 g(44.7%)
mp 215.0-215.5℃
¹H NMR (DMSO-d₆, δ): 1.30 (3H,t,J=7.5 Hz), 2.57 (3H,s), 2.93 (2H,q,J=7.5 Hz), 7.39 (1H,d,J=9.3 Hz), 7.47 (2H,brs), 8.08 (1H,d,J=9.3 Hz)
IR (Nujol, cm^-1) : 3304, 3177, 3090, 1546, 1540, 1507, 1463, 1389, 1362, 1341, 1309, 1201, 1166, 1127, 1086, 1057, 959, 900, 9864, 824, 772, 686, 670, 652, 591, 525 Synthesis of 6-ethyl-2-methylimidazo [1,2-b] pyridazine-3-sulfonamide

6-Ethyl-2-methylimidazo [1,2-b] pyridazine (2.70 g, 16.7 mmol) was dissolved in 1,2-dichloroethane (30 ml) and stirred at room temperature with chlorosulfonic acid (1.27 g, 18.5 mmol) was added and stirred for 5 hours under reflux. After the reaction solution was lowered to about 70 ° C., triethylamine (2.38 g, 23.5 mmol) was added dropwise over 1 minute. After completion of the dropping, the reaction solution was stirred for 20 minutes under heating and reflux. Thereafter, the reaction solution was cooled to about 70 ° C., and phosphorus oxychloride (3.86 g, 25.2 mmol) was added dropwise over 1 minute. After completion of the dropwise addition, the mixture was stirred for 2 hours with heating under reflux. The reaction solution was allowed to cool to about 50 ° C. and poured into 50 ml of warm water (about 50 ° C.). After stirring this for 5 minutes, the organic layer was separated. The aqueous layer was extracted with chloroform (50 ml × 2). The organic layers were combined, washed with water, dried over magnesium sulfate, and concentrated. The residue was dissolved in acetonitrile (40 ml), 14N aqueous ammonia (7 ml) was added with stirring at room temperature, and the mixture was stirred at room temperature for 2 hr. After completion of the reaction, the reaction solution was poured into ice water (150 ml), and the pH was adjusted to about 4 using concentrated hydrochloric acid. Crystals were formed. The crystals were collected by filtration, washed with water and dried under reduced pressure. Thereafter, the crystals were purified by silica gel column chromatography (chloroform: acetone = 9: 1 → 4: 1). The target product was obtained as white crystals. Yield 1.8 g (44.7%)
mp 215.0-215.5 ℃
¹ H NMR (DMSO-d ₆ , δ): 1.30 (3H, t, J = 7.5 Hz), 2.57 (3H, s), 2.93 (2H, q, J = 7.5 Hz), 7.39 (1H, d, J = 9.3 Hz), 7.47 (2H, brs), 8.08 (1H, d, J = 9.3 Hz)
IR (Nujol, cm ^-1 ): 3304, 3177, 3090, 1546, 1540, 1507, 1463, 1389, 1362, 1341, 1309, 1201, 1166, 1127, 1086, 1057, 959, 900, 9864, 824, 772 , 686, 670, 652, 591, 525

窒素気流下、100 ml 三口フラスコに、２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジン (1.6 g, 8.5 mmol)、［１，３−ビス（ジフェニルホスフィノ）プロパン］ニッケル（II）ジクロリド（触媒量）および脱水テトラヒドロフラン (20 ml)をいれ氷冷下撹拌し、プロピルマグネシウムクロリドテトラヒドロフラン溶液 (2M,6.4 ml, 12.8 mmol)を１０℃以下で滴下した。滴下終了後、同温度で１時間、室温で１時間、５０〜６０℃で２時間撹拌した。反応終了後、反応液を放冷し、水 (50 ml)をいれ撹拌後、酢酸エチルで抽出した (20 ml×2)。有機相を合して水洗後、硫酸マグネシウムで乾燥、濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１）で精製して、目的物を橙色結晶（少量の不純物を含む）として得た。収量 0.8 g(48.2 %)
mp 未測定
¹H NMR (CDCl₃, δ): 1.01 (3H,t,J=7.3 Hz), 1.7-1.9 (2H,m), 2.79 (2H,t,J=7.6 Hz), 6.96 (1H,d,J=9.3 Hz), 7.75 (1H,d,J=9.3 Hz), 8.19 (1H,d,J=9.4 Hz) Synthesis of 2-chloro-6-n-propylimidazo [1,2-b] pyridazine

In a 100 ml three-necked flask under a nitrogen stream, 2,6-dichloroimidazo [1,2-b] pyridazine (1.6 g, 8.5 mmol), [1,3-bis (diphenylphosphino) propane] nickel (II) dichloride (Catalyst amount) and dehydrated tetrahydrofuran (20 ml) were added and stirred under ice cooling, and propylmagnesium chloride tetrahydrofuran solution (2M, 6.4 ml, 12.8 mmol) was added dropwise at 10 ° C. or lower. After completion of dropping, the mixture was stirred at the same temperature for 1 hour, at room temperature for 1 hour, and at 50 to 60 ° C. for 2 hours. After completion of the reaction, the reaction mixture was allowed to cool, poured into water (50 ml), stirred, and extracted with ethyl acetate (20 ml × 2). The organic phases are combined, washed with water, dried over magnesium sulfate and concentrated. The residue is purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the target product as orange crystals (containing a small amount of impurities). Got as. Yield 0.8 g (48.2%)
mp not measured
¹ H NMR (CDCl ₃ , δ): 1.01 (3H, t, J = 7.3 Hz), 1.7-1.9 (2H, m), 2.79 (2H, t, J = 7.6 Hz), 6.96 (1H, d, J = 9.3 Hz), 7.75 (1H, d, J = 9.3 Hz), 8.19 (1H, d, J = 9.4 Hz)

200 ml ナスフラスコに、２−クロロ−６−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジン(0.8 g, 4.1 mmol)およびジクロロエタン (10 ml)をいれ室温で撹拌し、クロロスルホン酸 (0.54 g, 4.5 mmol)を一気に加え、４時間加熱還流下撹拌した。反応液を７０℃付近まで冷却し、トリエチルアミン (0.5 g, 5 mmol)を一気に加え固体が溶解するまで撹拌した後、オキシ塩化リン (0.79 g, 5 mmol)を一気に加え、２時間加熱還流下撹拌した。反応終了後、反応液を放冷し、水 (50 ml)を加えて有機相を分取した。有機相を飽和食塩水で洗浄した後硫酸マグネシウムで乾燥、濃縮し、残渣にアセトニトリル (10 ml)および２８％アンモニア水 (4 ml)をいれ、室温で２時間撹拌した。反応終了後、水 (100 ml)を加え、希塩酸でｐＨ＝２位に調節し、生成している結晶を濾取、水およびクロロホルムで洗浄後、減圧下で乾燥して、目的物を淡褐色結晶として得た。収量 0.49 g(43.5%;3 step)
mp 174-5℃
¹H NMR (DMSO-d₆, δ): 0.96 (3H,t,J=7.4 Hz), 1.7-1.9 (2H,m), 2.8-3.0 (2H,m), 7.53 (1H,d,J=9.5 Hz), 7.82 (2H,brs), 8.19 (1H,d,J=9.4 Hz)
IR (Nujol, cm^-1) : 3377, 3324, 3189, 1545, 1364, 1322, 1187, 1166, 821, 680, 597 Synthesis of 2-chloro-6-n-propylimidazo [1,2-b] pyridazine-3-sulfonamide

In a 200 ml eggplant flask, 2-chloro-6-n-propylimidazo [1,2-b] pyridazine (0.8 g, 4.1 mmol) and dichloroethane (10 ml) were added and stirred at room temperature. Chlorosulfonic acid (0.54 g , 4.5 mmol) was added all at once, and the mixture was stirred for 4 hours under reflux. The reaction solution was cooled to around 70 ° C., triethylamine (0.5 g, 5 mmol) was added all at once and stirred until the solid was dissolved, and then phosphorus oxychloride (0.79 g, 5 mmol) was added all at once and stirred for 2 hours while heating under reflux. did. After completion of the reaction, the reaction solution was allowed to cool, water (50 ml) was added, and the organic phase was separated. The organic phase was washed with saturated brine, dried over magnesium sulfate and concentrated. Acetonitrile (10 ml) and 28% aqueous ammonia (4 ml) were added to the residue, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water (100 ml) was added, the pH was adjusted to position 2 with dilute hydrochloric acid, and the resulting crystals were collected by filtration, washed with water and chloroform, and then dried under reduced pressure to give the desired product as a light brown color. Obtained as crystals. Yield 0.49 g (43.5%; 3 step)
mp 174-5 ℃
¹ H NMR (DMSO-d ₆ , δ): 0.96 (3H, t, J = 7.4 Hz), 1.7-1.9 (2H, m), 2.8-3.0 (2H, m), 7.53 (1H, d, J = 9.5 Hz), 7.82 (2H, brs), 8.19 (1H, d, J = 9.4 Hz)
IR (Nujol, cm ^-1 ): 3377, 3324, 3189, 1545, 1364, 1322, 1187, 1166, 821, 680, 597

塩化亜鉛(2.04 g, 15.0 mmol)を真空下、１８０℃で２時間乾燥を行った後、室温まで冷却して無水テトラヒドロフラン(20.0 mL)を加えた。氷冷下、ｎ−ブチルリチウム(1.6M, 9.0 mL, 14.4 mmol)を約３０分間で滴下した後、氷冷下３０分間攪拌を続けて塩化ｎ−ブチル亜鉛のテトラヒドロフラン溶液を調製した。一方、窒素雰囲気下２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジン(1.88 g, 10.0 mmol)と［１，３−ビス（ジフェニルホスフィノ）プロパン］ニッケル（II）ジクロリド(0.16 g, 0.30 mmol)を無水テトラヒドロフラン(20.0 mL)に懸濁させた液を調製しておき、先に調製した塩化ｎ−ブチル亜鉛のテトラヒドロフラン溶液を3〜6℃を保ちながら３０分間で滴下した。氷冷下１５分間、室温下３時間攪拌した後、飽和食塩水に注ぎ希塩酸でｐＨ２とした。酢酸エチルで２回抽出した後、抽出液を合わせて無水硫酸マグネシウムで脱水して減圧下濃縮した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：４）で精製して、目的物を淡黄色結晶として得た。収量2.03 g(96.8%)
mp 61.0-63.0℃
¹H NMR (CDCl₃, δ): 0.96(3H, t, J=7.3 Hz),1.41(2H, tq, J=7.5, 7.3 Hz),1.73(2H, tt, J=7.8, 7.5 Hz), 2.81(2H, t, J=7.8 Hz), 6.96(1H, d, J=9.4 Hz), 7.74(1H, d, J=9.4 Hz), 7.79(1H, s).
IR(Nujol, cm^-1): 3115, 3061, 1545, 1466, 1378, 1326, 1276, 817. Synthesis of 6-n-butyl-2-chloroimidazo [1,2-b] pyridazine

Zinc chloride (2.04 g, 15.0 mmol) was dried under vacuum at 180 ° C. for 2 hours, cooled to room temperature, and anhydrous tetrahydrofuran (20.0 mL) was added. Under ice-cooling, n-butyllithium (1.6M, 9.0 mL, 14.4 mmol) was added dropwise over about 30 minutes, and stirring was continued for 30 minutes under ice-cooling to prepare a tetrahydrofuran solution of n-butylzinc chloride. On the other hand, 2,6-dichloroimidazo [1,2-b] pyridazine (1.88 g, 10.0 mmol) and [1,3-bis (diphenylphosphino) propane] nickel (II) dichloride (0.16 g, 0.30) under a nitrogen atmosphere. mmol) was suspended in anhydrous tetrahydrofuran (20.0 mL), and the previously prepared tetrahydrofuran solution of n-butylzinc chloride was added dropwise over 30 minutes while maintaining 3 to 6 ° C. The mixture was stirred for 15 minutes under ice-cooling and at room temperature for 3 hours, then poured into saturated brine and adjusted to pH 2 with dilute hydrochloric acid. After extracting twice with ethyl acetate, the extracts were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain the desired product as pale yellow crystals. Yield 2.03 g (96.8%)
mp 61.0-63.0 ℃
¹ H NMR (CDCl ₃ , δ): 0.96 (3H, t, J = 7.3 Hz), 1.41 (2H, tq, J = 7.5, 7.3 Hz), 1.73 (2H, tt, J = 7.8, 7.5 Hz), 2.81 (2H, t, J = 7.8 Hz), 6.96 (1H, d, J = 9.4 Hz), 7.74 (1H, d, J = 9.4 Hz), 7.79 (1H, s).
IR (Nujol, cm ^-1 ): 3115, 3061, 1545, 1466, 1378, 1326, 1276, 817.

６−ｎ−ブチル−２−クロロイミダゾ［１，２−ｂ］ピリダジン(1.00 g, 4.77 mmol)をクロロホルム(10.0 mL)に溶かし室温下攪拌しながら、クロロスルホン酸(0.35 mL, 5.27 mmol)を滴下した。その混合物を５時間加熱還流したがＴＬＣで原料残存を確認したのでクロロスルホン酸(0.35 mL, 5.27 mmol)を追加し更に４時間加熱還流を続けた。得られた懸濁液を室温まで放冷後、トリエチルアミン(2.50 mL, 17.9 mmol)とオキシ塩化リン(2.00 mL, 21.5 mmol)を加えて、再び４時間加熱還流を行った。室温まで冷やして水に注ぎクロロホルムで３回抽出した後、抽出液を合わせて無水硫酸マグネシウムで脱水して減圧下濃縮し暗赤色液体3.24 gを得た。この液体をアセトニトリル(10.0 mL)に溶かして、２５％アンモニア水(5.00 g, 73.5 mmol)をアセトニトリル(15.0 mL)に溶かした溶液に氷冷下滴下した。氷冷下３０分間、室温下１時間攪拌を続けた後、アセトニトリルを減圧下留去した。残渣に希塩酸を加えｐＨ２にした後、クロロホルムで２回抽出しクロロホルム層を合わせて無水硫酸マグネシウムで脱水して減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１→クロロホルム：エタノール＝２０：１）で精製して、目的化合物を白色結晶として得た。収量0.92 g(66.8%)
mp 165.5-166.5℃
¹H NMR(DMSO-d₆, δ): 0.93(3H, t, J=7.3 Hz), 1.37(2H, tq, J=7.5, 7.3 Hz), 1.72(2H, tt, J=7.9, 7.5 Hz), 2.93(2H, t, J=7.9 Hz), 7.53(1H, d, J=9.4 Hz), 7.80(2H, s), 8.18(1H, d, J=9.4 Hz).
IR(Nujol, cm^-1): 3412, 3360, 3287, 3197, 1546, 1464, 1376, 1321, 1172. Synthesis of 6-n-butyl-2-chloroimidazo [1,2-b] pyridazin-3-ylsulfonamide

While dissolving 6-n-butyl-2-chloroimidazo [1,2-b] pyridazine (1.00 g, 4.77 mmol) in chloroform (10.0 mL) and stirring at room temperature, chlorosulfonic acid (0.35 mL, 5.27 mmol) was added. It was dripped. The mixture was heated to reflux for 5 hours, but the residual material was confirmed by TLC, so chlorosulfonic acid (0.35 mL, 5.27 mmol) was added, and the mixture was further heated to reflux for 4 hours. The resulting suspension was allowed to cool to room temperature, triethylamine (2.50 mL, 17.9 mmol) and phosphorus oxychloride (2.00 mL, 21.5 mmol) were added, and the mixture was heated to reflux again for 4 hours. The mixture was cooled to room temperature, poured into water and extracted three times with chloroform. The extracts were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3.24 g of a dark red liquid. This liquid was dissolved in acetonitrile (10.0 mL) and added dropwise to a solution of 25% aqueous ammonia (5.00 g, 73.5 mmol) in acetonitrile (15.0 mL) under ice cooling. Stirring was continued for 30 minutes under ice cooling and 1 hour at room temperature, and then acetonitrile was distilled off under reduced pressure. Dilute hydrochloric acid was added to the residue to adjust the pH to 2, followed by extraction twice with chloroform. The chloroform layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1 → chloroform: ethanol = 20: 1) to obtain the target compound as white crystals. Yield 0.92 g (66.8%)
mp 165.5-166.5 ℃
¹ H NMR (DMSO-d ₆ , δ): 0.93 (3H, t, J = 7.3 Hz), 1.37 (2H, tq, J = 7.5, 7.3 Hz), 1.72 (2H, tt, J = 7.9, 7.5 Hz) ), 2.93 (2H, t, J = 7.9 Hz), 7.53 (1H, d, J = 9.4 Hz), 7.80 (2H, s), 8.18 (1H, d, J = 9.4 Hz).
IR (Nujol, cm ^-1 ): 3412, 3360, 3287, 3197, 1546, 1464, 1376, 1321, 1172.

Ｎ，Ｎ−ジイソブチルホルムアミド(5.44 g, 34.5 mmol)をクロロホルム(25.0 mL)に溶かし氷−食塩バスで冷却しながら、オキシ塩化リン(3.22 mL, 34.5 mmol)を−２℃以下で滴下した。−２℃以下で３０分間攪拌した後、２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミド(6.15 g, 23.0 mmol)を加えた。−１０℃で１０分間攪拌した後、トリエチルアミン(19.3 mL, 138 mmol)を５℃以下を保ちながら２０分間で滴下した。０℃以下で１時間、室温で１時間攪拌した後、飽和重曹水に注ぎクロロホルムで５回抽出した。抽出液を合わせて無水硫酸マグネシウムで脱水し減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝1：1）で精製して、目的物を淡黄色結晶として得た。収量5.58 g(59.6%)
mp 151.0-154.0℃
¹H NMR(CDCl₃, δ): 0.76(6H, d, J=6.7 Hz), 0.97 (6H, d, J=6.7 Hz), 1.90-2.10(2H, m), 3.23(2H, d, J=7.6 Hz), 3.28(2H, d, J=7.7 Hz), 7.26(1H, d, J=9.5 Hz), 7.90(1H, d, J=9.5 Hz), 8.51(1H, s).
IR(Nujol, cm^-1): 1615, 1456, 1324, 1311, 1146, 910, 858, 654. Synthesis of N ′-(2,6-dichloroimidazo [1,2-b] pyridazin-3-ylsulfonyl) -N, N-diisobutylformamidine

N, N-diisobutylformamide (5.44 g, 34.5 mmol) was dissolved in chloroform (25.0 mL), and phosphorus oxychloride (3.22 mL, 34.5 mmol) was added dropwise at −2 ° C. or lower while cooling with an ice-salt bath. After stirring at −2 ° C. or lower for 30 minutes, 2,6-dichloroimidazo [1,2-b] pyridazin-3-ylsulfonamide (6.15 g, 23.0 mmol) was added. After stirring at −10 ° C. for 10 minutes, triethylamine (19.3 mL, 138 mmol) was added dropwise over 20 minutes while maintaining the temperature at 5 ° C. or lower. After stirring at 0 ° C. or lower for 1 hour and at room temperature for 1 hour, the mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted five times with chloroform. The extracts were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the desired product as pale yellow crystals. Yield 5.58 g (59.6%)
mp 151.0-154.0 ℃
¹ H NMR (CDCl ₃ , δ): 0.76 (6H, d, J = 6.7 Hz), 0.97 (6H, d, J = 6.7 Hz), 1.90-2.10 (2H, m), 3.23 (2H, d, J = 7.6 Hz), 3.28 (2H, d, J = 7.7 Hz), 7.26 (1H, d, J = 9.5 Hz), 7.90 (1H, d, J = 9.5 Hz), 8.51 (1H, s).
IR (Nujol, cm ^-1 ): 1615, 1456, 1324, 1311, 1146, 910, 858, 654.

マグネシウム金属粉(0.27 g, 11.1 mmol)とヨウ素(5 mg)を混合し窒素雰囲気下、ドライヤーで加熱した後、室温まで戻し無水テトラヒドロフラン(15.0 mL)を加えた。この混合物を室温下攪拌しながら臭化シクロプロピル(1.33 g, 1.10 mmol)を２８〜３３℃を保ちながら滴下した後、室温で３０分間攪拌し続け淡黄灰色のシクロプロピルマグネシウムブロミドのテトラヒドロフラン溶液を調製した。一方、真空下１８０℃で４時間乾燥させた塩化亜鉛(1.50 g, 11.0 mmol)を窒素雰囲気下、無水テトラヒドロフラン(10.0mL)に溶かして氷−食塩バスで０℃以下を保ちながら、先に調製したシクロプロピルマグネシウムブロミドのテトラヒドロフラン溶液を滴下した。−１０℃付近で１５分間攪拌した後、得られた懸濁液に［１，３−ビス（ジフェニルホスフィノ）プロパン］ニッケル（II）ジクロリド(0.27 g, 0.50 mmol)を粉末のまま加え、続けてＮ’−（２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホニル）−Ｎ，Ｎ−ジイソブチルホルムアミジン(2.03 g, 5.00 mmol)を無水テトラヒドロフラン(10.0 mL)に溶かした溶液を滴下した。−１０℃で２時間、室温で１６時間攪拌した後、飽和食塩水に注ぎ希塩酸でｐＨ２にしてクロロホルムで４回抽出した。抽出液を合わせて無水硫酸マグネシウムで脱水して減圧濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１）で精製して、原料のＮ’−（２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホニル）−Ｎ，Ｎ−ジイソブチルホルムアミジンを0.64 g(31.5%)回収すると共に、目的物を淡黄色結晶として得た。収量0.94 g(45.7%)
mp 154.0-160.0℃
¹H NMR(CDCl₃, δ): 0.74(6H, d, J=6.7 Hz), 0.95(6H, d, J=6.7 Hz), 1.00-1.10(2H, m), 1.10-1.25(2H, m), 1.85-2.10(2H, m), 2.10-2.20(1H, m), 3.19(2H, d, J=7.5 Hz), 3.28(2H, d, J=7.5 Hz), 6.98(1H, d, J=9.4 Hz), 7.78(1H, d, J=9.4 Hz), 8.45(1H, s).
IR(Nujol)ν(cm^-1): 1613, 1464, 1334, 1318, 1143, 909, 859, 661. Synthesis of N ′-(2-chloro-6-cyclopropylimidazo [1,2-b] pyridazin-3-ylsulfonyl) -N, N-diisobutylformamidine

Magnesium metal powder (0.27 g, 11.1 mmol) and iodine (5 mg) were mixed and heated with a dryer in a nitrogen atmosphere, then returned to room temperature and anhydrous tetrahydrofuran (15.0 mL) was added. While stirring this mixture at room temperature, cyclopropyl bromide (1.33 g, 1.10 mmol) was added dropwise while maintaining the temperature at 28 to 33 ° C., and the mixture was then stirred at room temperature for 30 minutes to prepare a pale yellow gray solution of cyclopropylmagnesium bromide in tetrahydrofuran. Prepared. On the other hand, zinc chloride (1.50 g, 11.0 mmol) dried at 180 ° C. for 4 hours under vacuum was dissolved in anhydrous tetrahydrofuran (10.0 mL) under a nitrogen atmosphere, and prepared in advance while maintaining the temperature below 0 ° C. in an ice-salt bath. A solution of cyclopropylmagnesium bromide in tetrahydrofuran was added dropwise. After stirring at around −10 ° C. for 15 minutes, [1,3-bis (diphenylphosphino) propane] nickel (II) dichloride (0.27 g, 0.50 mmol) was added as a powder to the resulting suspension and continued. N '-(2,6-dichloroimidazo [1,2-b] pyridazin-3-ylsulfonyl) -N, N-diisobutylformamidine (2.03 g, 5.00 mmol) was dissolved in anhydrous tetrahydrofuran (10.0 mL). The solution was added dropwise. The mixture was stirred at −10 ° C. for 2 hours and at room temperature for 16 hours, poured into saturated brine, adjusted to pH 2 with dilute hydrochloric acid, and extracted four times with chloroform. The extracts were combined, dehydrated over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the starting N ′-(2,6-dichloroimidazo While recovering 0.64 g (31.5%) of [1,2-b] pyridazin-3-ylsulfonyl) -N, N-diisobutylformamidine, the desired product was obtained as pale yellow crystals. Yield 0.94 g (45.7%)
mp 154.0-160.0 ℃
¹ H NMR (CDCl ₃ , δ): 0.74 (6H, d, J = 6.7 Hz), 0.95 (6H, d, J = 6.7 Hz), 1.00-1.10 (2H, m), 1.10-1.25 (2H, m ), 1.85-2.10 (2H, m), 2.10-2.20 (1H, m), 3.19 (2H, d, J = 7.5 Hz), 3.28 (2H, d, J = 7.5 Hz), 6.98 (1H, d, J = 9.4 Hz), 7.78 (1H, d, J = 9.4 Hz), 8.45 (1H, s).
IR (Nujol) ν (cm ^-1 ): 1613, 1464, 1334, 1318, 1143, 909, 859, 661.

実施例８のシクロプロピルマグネシウムブロミドのテトラヒドロフラン溶液の代わりに市販のビニルマグネシウムブロミドのテトラヒドロフラン溶液を用い、［１，３−ビス（ジフェニルホスフィノ）プロパン］ニッケル（II）ジクロリドを原料のＮ’−（２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホニル）−Ｎ，Ｎ−ジイソブチルホルムアミジンに対して3 mol%使用して同様の反応を行うことにより、目的化合物を淡黄色結晶として得た。収率80.4%
mp 194.0-198.0℃
¹H NMR(CDCl₃, δ): 0.71(6H, d, J=6.7 Hz), 0.94(6H, d, J=6.6 Hz), 1.85-2.10(2H, m), 3.17(2H, d, J=7.5 Hz), 3.26(2H, d, J=7.7 Hz), 5.77(1H, d, J=11.1 Hz), 6.16(1H, d, J=17.8 Hz), 6.82(1H, dd, J=17.8, 11.1 Hz), 7.46(1H, d, J=9.5 Hz), 7.89(1H, d, J=9.5 Hz), 8.50(1H, s).
IR(Nujol, cm^-1): 1614, 1456, 1350, 1319, 1145, 913, 859, 664, 612. Synthesis of N ′-(2-chloro-6-ethenylimidazo [1,2-b] pyridazin-3-ylsulfonyl) -N, N-diisobutylformamidine

Instead of the tetrahydrofuran solution of cyclopropylmagnesium bromide in Example 8, a commercially available tetrahydrofuran solution of vinylmagnesium bromide was used, and [1,3-bis (diphenylphosphino) propane] nickel (II) dichloride was used as the starting material N ′-( By carrying out the same reaction using 3 mol% with respect to 2,6-dichloroimidazo [1,2-b] pyridazin-3-ylsulfonyl) -N, N-diisobutylformamidine, the target compound was pale yellow. Obtained as crystals. Yield 80.4%
mp 194.0-198.0 ℃
¹ H NMR (CDCl ₃ , δ): 0.71 (6H, d, J = 6.7 Hz), 0.94 (6H, d, J = 6.6 Hz), 1.85-2.10 (2H, m), 3.17 (2H, d, J = 7.5 Hz), 3.26 (2H, d, J = 7.7 Hz), 5.77 (1H, d, J = 11.1 Hz), 6.16 (1H, d, J = 17.8 Hz), 6.82 (1H, dd, J = 17.8 , 11.1 Hz), 7.46 (1H, d, J = 9.5 Hz), 7.89 (1H, d, J = 9.5 Hz), 8.50 (1H, s).
IR (Nujol, cm ^-1 ): 1614, 1456, 1350, 1319, 1145, 913, 859, 664, 612.

実施例８のシクロプロピルマグネシウムブロミドのテトラヒドロフラン溶液の代わりに市販の１−プロペニルマグネシウムブロミドのテトラヒドロフラン溶液を用い、［１，３−ビス（ジフェニルホスフィノ）プロパン］ニッケル（II）ジクロリドを原料のＮ’−（２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホニル）−Ｎ，Ｎ−ジイソブチルホルムアミジンに対して3 mol%使用して同様の反応を行うことにより、Ｅ，Ｚ混合(Ｅ：Ｚ＝５：３)の目的化合物を淡黄色結晶として得た。収率100%
mp Ｅ，Ｚ混合物の為未測定。
¹H NMR(CDCl₃, δ):［Ｅ体］0.72(6H, d, J=6.6 Hz), 0.94(6H, d, J=6.6 Hz), 1.85-2.10(2H, m), 2.00(3H, dd, J=6.9, 1.5 Hz), 3.17(2H, d, J=7.6 Hz), 3.26(2H, d, J=7.7 Hz), 6.51(1H, dq, J=16.0, 1.5 Hz), 6.71(1H, dq, J=16.0, 6.9 Hz), 7.35(1H, d, J=9.5 Hz), 7.82(1H, d, J=9.5 Hz), 8.50(1H, s).
¹H NMR(CDCl₃, δ):［Ｚ体］0.72(6H, d, J=6.6 Hz), 0.92(6H, d, J=6.6 Hz), 1.85-2.10(2H, m), 2.21(3H, dd, J=7.3, 1.8Hz), 3.12(2H, d, J=7.5 Hz), 3.25(2H, d, J=7.7 Hz), 6.23(1H, dq, J=11.9, 7.3 Hz), 6.40(1H, dq, J=11.9, 1.8 Hz), 7.19(1H, d, J=9.5 Hz), 7.85(1H, d, J=9.5 Hz), 8.43(1H, s).
IR(Nujol, cm^-1): 1609, 1456, 1351, 1319, 1144, 911. Synthesis of N ′-(2-chloro-6- (1-propenyl) imidazo [1,2-b] pyridazin-3-ylsulfonyl) -N, N-diisobutylformamidine

Instead of the tetrahydrofuran solution of cyclopropylmagnesium bromide in Example 8, a commercially available tetrahydrofuran solution of 1-propenylmagnesium bromide was used, and [1,3-bis (diphenylphosphino) propane] nickel (II) dichloride was used as a starting material N ′ By carrying out the same reaction using 3 mol% of (2,6-dichloroimidazo [1,2-b] pyridazin-3-ylsulfonyl) -N, N-diisobutylformamidine, E, Z The target compound (E: Z = 5: 3) was obtained as pale yellow crystals. Yield 100%
mp Not measured due to E, Z mixture.
¹ H NMR (CDCl ₃ , δ): [E form] 0.72 (6H, d, J = 6.6 Hz), 0.94 (6H, d, J = 6.6 Hz), 1.85-2.10 (2H, m), 2.00 (3H , dd, J = 6.9, 1.5 Hz), 3.17 (2H, d, J = 7.6 Hz), 3.26 (2H, d, J = 7.7 Hz), 6.51 (1H, dq, J = 16.0, 1.5 Hz), 6.71 (1H, dq, J = 16.0, 6.9 Hz), 7.35 (1H, d, J = 9.5 Hz), 7.82 (1H, d, J = 9.5 Hz), 8.50 (1H, s).
¹ H NMR (CDCl ₃ , δ): [Z-form] 0.72 (6H, d, J = 6.6 Hz), 0.92 (6H, d, J = 6.6 Hz), 1.85-2.10 (2H, m), 2.21 (3H , dd, J = 7.3, 1.8Hz), 3.12 (2H, d, J = 7.5 Hz), 3.25 (2H, d, J = 7.7 Hz), 6.23 (1H, dq, J = 11.9, 7.3 Hz), 6.40 (1H, dq, J = 11.9, 1.8 Hz), 7.19 (1H, d, J = 9.5 Hz), 7.85 (1H, d, J = 9.5 Hz), 8.43 (1H, s).
IR (Nujol, cm ^-1 ): 1609, 1456, 1351, 1319, 1144, 911.

（ａ）実施例８のシクロプロピルマグネシウムブロミドのテトラヒドロフラン溶液の代わりにリチウム トリメチルシリルアセチリドのテトラヒドロフラン溶液を用い、［１，３−ビス（ジフェニルホスフィノ）プロパン］ニッケル（II）ジクロリドを原料のＮ’−（２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホニル）−Ｎ，Ｎ−ジイソブチルホルムアミジンに対して3 mol%使用して同様の反応を行うことにより、Ｎ’−（２−クロロ−６−（トリメチルシリルエチニル）イミダゾ［１，２−ｂ］ピリダジン−３−イルスルホニル）−Ｎ，Ｎ−ジイソブチルホルムアミジンを淡黄色結晶として得た。収率32.9%
mp 180.0-182.0℃
¹H NMR(CDCl₃, δ): 0.30(9H, s), 0.73(6H, d, J=6.7 Hz), 0.97(6H, d, J=6.6 Hz), 1.85-2.10(2H, m), 3.24(2H, d, J=7.6 Hz), 3.27(2H, d, J=7.7 Hz), 7.30(1H, d, J=9.4 Hz), 7.86(1H, d, J=9.4 Hz), 8.56(1H, s).
IR(Nujol, cm^-1): 1614, 1455, 1339, 1314, 1302, 1140, 914, 864, 839.
（ｂ）Ｎ’−（２−クロロ−６−（トリメチルシリルエチニル）イミダゾ［１，２−ｂ］ピリダジン−３−イルスルホニル）−Ｎ，Ｎ−ジイソブチルホルムアミジン(2.31 g, 4.63 mmol)をテトラヒドロフラン−水（１０：１）の混合溶媒に溶かし氷冷下攪拌しながら、テトラブチルアンモニウムフルオリド水和物(1.50 g, 5.04 mmol)を加えた。氷冷下２０分間攪拌した後、テトラヒドロフランを減圧留去し、残留物を酢酸エチルに溶かした。酢酸エチル溶液を２回水洗した後、無水硫酸マグネシウムで脱水して減圧下濃縮乾固することにより目的物を淡黄色結晶として得た。収量1.96 g(100%)
mp 166.0-167.5℃
¹H NMR(DMSO-d₆, δ): 0.68(6H, d, J=6.6 Hz), 0.88(6H, d, J=6.6 Hz), 1.85-2.10(2H, m), 3.19(2H, d, J=7.6 Hz), 3.33(2H, d, J=7.6 Hz), 4.94(1H, s), 7.68(1H, d, J=9.4 Hz), 8.30(1H, d, J=9.4 Hz), 8.45(1H, s).
IR(Nujol, cm^-1): 3270, 2120, 1613, 1453, 1347, 1332, 1316, 1147, 870, 664. Synthesis of N ′-(2-chloro-6-ethynylimidazo [1,2-b] pyridazin-3-ylsulfonyl) -N, N-diisobutylformamidine

(A) A tetrahydrofuran solution of lithium trimethylsilylacetylide was used instead of the tetrahydrofuran solution of cyclopropylmagnesium bromide in Example 8, and [1,3-bis (diphenylphosphino) propane] nickel (II) dichloride was used as a starting material N′- By carrying out the same reaction using 3 mol% of (2,6-dichloroimidazo [1,2-b] pyridazin-3-ylsulfonyl) -N, N-diisobutylformamidine, N ′-( 2-Chloro-6- (trimethylsilylethynyl) imidazo [1,2-b] pyridazin-3-ylsulfonyl) -N, N-diisobutylformamidine was obtained as pale yellow crystals. Yield 32.9%
mp 180.0-182.0 ℃
¹ H NMR (CDCl ₃ , δ): 0.30 (9H, s), 0.73 (6H, d, J = 6.7 Hz), 0.97 (6H, d, J = 6.6 Hz), 1.85-2.10 (2H, m), 3.24 (2H, d, J = 7.6 Hz), 3.27 (2H, d, J = 7.7 Hz), 7.30 (1H, d, J = 9.4 Hz), 7.86 (1H, d, J = 9.4 Hz), 8.56 ( 1H, s).
IR (Nujol, cm ^-1 ): 1614, 1455, 1339, 1314, 1302, 1140, 914, 864, 839.
(B) N ′-(2-chloro-6- (trimethylsilylethynyl) imidazo [1,2-b] pyridazin-3-ylsulfonyl) -N, N-diisobutylformamidine (2.31 g, 4.63 mmol) was dissolved in tetrahydrofuran- Tetrabutylammonium fluoride hydrate (1.50 g, 5.04 mmol) was added while stirring in a mixed solvent of water (10: 1) and stirring under ice cooling. After stirring for 20 minutes under ice cooling, tetrahydrofuran was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed twice with water, dehydrated over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to obtain the desired product as pale yellow crystals. Yield 1.96 g (100%)
mp 166.0-167.5 ℃
¹ H NMR (DMSO-d ₆ , δ): 0.68 (6H, d, J = 6.6 Hz), 0.88 (6H, d, J = 6.6 Hz), 1.85-2.10 (2H, m), 3.19 (2H, d , J = 7.6 Hz), 3.33 (2H, d, J = 7.6 Hz), 4.94 (1H, s), 7.68 (1H, d, J = 9.4 Hz), 8.30 (1H, d, J = 9.4 Hz), 8.45 (1H, s).
IR (Nujol, cm ^-1 ): 3270, 2120, 1613, 1453, 1347, 1332, 1316, 1147, 870, 664.

Ｎ’−（２−クロロ−６−シクロプロピルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホニル）−Ｎ，Ｎ−ジイソブチルホルムアミジン(0.93 g, 2.26 mmol)をジオキサン(9.00 mL)に溶かして１００℃で攪拌しながら、３６％濃塩酸(9.0 mL, 107 mmol)を滴下した。１００〜１０５℃で１５時間加熱攪拌した後、室温まで放冷して結晶が出るまで減圧下濃縮した。残留物に水(30.0 mL)を注ぎ結晶を完全に析出させた後、ろ過して結晶を水洗、メタノール洗浄して、目的物を白色結晶として得た。収量0.31 g(50.4%)
mp 194.0-196.0℃
NMR(DMSO-d₆, δ): 1.10-1.25(4H, m), 2.30-2.45(1H, m), 7.36(1H, d, J=9.4 Hz), 7.78(2H, brs), 8.12(1H, d, J=9.4Hz).
IR(Nujol, cm^-1): 3348, 3247, 1553, 1468, 1455, 1358, 1316, 1170, 908, 825, 662. Synthesis of 2-chloro-6-cyclopropylimidazo [1,2-b] pyridazin-3-ylsulfonamide

N ′-(2-chloro-6-cyclopropylimidazo [1,2-b] pyridazin-3-ylsulfonyl) -N, N-diisobutylformamidine (0.93 g, 2.26 mmol) was dissolved in dioxane (9.00 mL). While stirring at 100 ° C., 36% concentrated hydrochloric acid (9.0 mL, 107 mmol) was added dropwise. After stirring with heating at 100 to 105 ° C. for 15 hours, the mixture was allowed to cool to room temperature and concentrated under reduced pressure until crystals appeared. Water (30.0 mL) was poured into the residue to completely precipitate crystals, followed by filtration to wash the crystals with water and methanol to obtain the desired product as white crystals. Yield 0.31 g (50.4%)
mp 194.0-196.0 ℃
NMR (DMSO-d ₆ , δ): 1.10-1.25 (4H, m), 2.30-2.45 (1H, m), 7.36 (1H, d, J = 9.4 Hz), 7.78 (2H, brs), 8.12 (1H , d, J = 9.4Hz).
IR (Nujol, cm ^-1 ): 3348, 3247, 1553, 1468, 1455, 1358, 1316, 1170, 908, 825, 662.

実施例１２のＮ’−（２−クロロ−６−シクロプロピルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホニル）−Ｎ，Ｎ−ジイソブチルホルムアミジンの代わりにＮ’−（２−クロロ−６−エテニルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホニル）−Ｎ，Ｎ−ジイソブチルホルムアミジンを用いて同様の反応を行った。得られた結晶をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製して、目的物を白色結晶として得た。収率42.1%
mp 229.0-233.0℃
¹H NMR(DMSO-d₆, δ): 5.87(1H, d, J=11.2 Hz), 6.50(1H, d, J=17.9 Hz), 6.86(1H, dd, J=17.9, 11.2 Hz), 7.89(2H, s), 7.96(1H, d, J=9.6 Hz), 8.26(1H, d, J=9.6 Hz).
IR(Nujol, cm^-1): 3316, 3183, 1466, 1368, 1321, 1167. Synthesis of 2-chloro-6-ethenylimidazo [1,2-b] pyridazin-3-ylsulfonamide

Instead of N ′-(2-chloro-6-cyclopropylimidazo [1,2-b] pyridazin-3-ylsulfonyl) -N, N-diisobutylformamidine in Example 12, N ′-(2-chloro- A similar reaction was performed using 6-ethenylimidazo [1,2-b] pyridazin-3-ylsulfonyl) -N, N-diisobutylformamidine. The obtained crystals were purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain the desired product as white crystals. Yield 42.1%
mp 229.0-233.0 ℃
¹ H NMR (DMSO-d ₆ , δ): 5.87 (1H, d, J = 11.2 Hz), 6.50 (1H, d, J = 17.9 Hz), 6.86 (1H, dd, J = 17.9, 11.2 Hz), 7.89 (2H, s), 7.96 (1H, d, J = 9.6 Hz), 8.26 (1H, d, J = 9.6 Hz).
IR (Nujol, cm ^-1 ): 3316, 3183, 1466, 1368, 1321, 1167.

実施例１２のＮ’−（２−クロロ−６−シクロプロピルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホニル）−Ｎ，Ｎ−ジイソブチルホルムアミジンの代わりにＥ，Ｚ混合物のＮ’−（２−クロロ−６−（１−プロペニル）イミダゾ［１，２−ｂ］ピリダジン−３−イルスルホニル）−Ｎ，Ｎ−ジイソブチルホルムアミジンを用いて同様の反応を行った。得られた結晶をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝２０：１）で精製して、目的物を白色結晶として得た。収率70.1%
mp 225.0-229.0℃
¹H NMR(DMSO-d₆, δ): 1.98(3H, dd, J=6.8, 1.7 Hz), 6.71(1H, dq, J=16.0, 1.7 Hz), 7.01(1H, dq, J=16.0, 6.8 Hz), 7.83(2H, s), 7.84(1H, d, J=9.5 Hz), 8.19(1H, d, J=9.6 Hz).
IR(Nujol, cm^-1): 3323, 3179, 1662, 1550, 1466, 1360, 1325, 1173. Synthesis of (E) -2-chloro-6- (1-propenyl) imidazo [1,2-b] pyridazin-3-ylsulfonamide

Instead of N ′-(2-chloro-6-cyclopropylimidazo [1,2-b] pyridazin-3-ylsulfonyl) -N, N-diisobutylformamidine of Example 12, N′- of the E, Z mixture A similar reaction was performed using (2-chloro-6- (1-propenyl) imidazo [1,2-b] pyridazin-3-ylsulfonyl) -N, N-diisobutylformamidine. The obtained crystals were purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain the desired product as white crystals. Yield 70.1%
mp 225.0-229.0 ℃
¹ H NMR (DMSO-d ₆ , δ): 1.98 (3H, dd, J = 6.8, 1.7 Hz), 6.71 (1H, dq, J = 16.0, 1.7 Hz), 7.01 (1H, dq, J = 16.0, 6.8 Hz), 7.83 (2H, s), 7.84 (1H, d, J = 9.5 Hz), 8.19 (1H, d, J = 9.6 Hz).
IR (Nujol, cm ^-1 ): 3323, 3179, 1662, 1550, 1466, 1360, 1325, 1173.

実施例１２のＮ’−（２−クロロ−６−シクロプロピルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホニル）−Ｎ，Ｎ−ジイソブチルホルムアミジンの代わりにＮ’−（２−クロロ−６−エチニルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホニル）−Ｎ，Ｎ−ジイソブチルホルムアミジンを用いて同様の反応を行った。得られた結晶をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１）で精製して、目的物のＥ体、Ｚ体それぞれを白色結晶として得た。Ｅ体の収率7.5%、Ｚ体の収率72.4%
Ｅ体の物性値
mp >240℃(decomp)
¹H NMR(DMSO-d₆, δ): 7.37(1H, d, J=13.8 Hz), 7.82(1H, d, J=9.6 Hz), 7.91(1H, d, J=13.8 Hz), 7.93(2H, brs), 8.29(1H, d, J=9.6 Hz).
IR(Nujol, cm^-1): 3329, 3182, 1616, 1467, 1361, 1324, 1169, 945.
Ｚ体の物性値
mp 197.0-200.0℃
¹H NMR(DMSO-d₆, δ): 7.14(1H, d, J=8.3 Hz), 7.20(1H, d, J=8.3 Hz), 7.83(2H, brs), 8.06(1H, d, J=9.6 Hz), 8.33(1H, d, J=9.6 Hz).
IR(Nujol, cm^-1): 3370, 3260, 1632, 1465, 1364, 1308, 1187, 1164, 842. Synthesis of 2-chloro-6- (2-chloroethenyl) imidazo [1,2-b] pyridazin-3-ylsulfonamide

Instead of N ′-(2-chloro-6-cyclopropylimidazo [1,2-b] pyridazin-3-ylsulfonyl) -N, N-diisobutylformamidine in Example 12, N ′-(2-chloro- A similar reaction was performed using 6-ethynylimidazo [1,2-b] pyridazin-3-ylsulfonyl) -N, N-diisobutylformamidine. The obtained crystals were purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the desired E form and Z form as white crystals. Y-form yield 7.5%, Z-form yield 72.4%
Physical properties of E body
mp> 240 ° C (decomp)
¹ H NMR (DMSO-d ₆ , δ): 7.37 (1H, d, J = 13.8 Hz), 7.82 (1H, d, J = 9.6 Hz), 7.91 (1H, d, J = 13.8 Hz), 7.93 ( 2H, brs), 8.29 (1H, d, J = 9.6 Hz).
IR (Nujol, cm ^-1 ): 3329, 3182, 1616, 1467, 1361, 1324, 1169, 945.
Physical properties of Z body
mp 197.0-200.0 ℃
¹ H NMR (DMSO-d ₆ , δ): 7.14 (1H, d, J = 8.3 Hz), 7.20 (1H, d, J = 8.3 Hz), 7.83 (2H, brs), 8.06 (1H, d, J = 9.6 Hz), 8.33 (1H, d, J = 9.6 Hz).
IR (Nujol, cm ^-1 ): 3370, 3260, 1632, 1465, 1364, 1308, 1187, 1164, 842.

Ｎ’−（２−クロロ−６−エチニルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホニル）−Ｎ，Ｎ−ジイソブチルホルムアミジン(792 mg, 2.00 mmol)をジオキサン(10.0 mL)に懸濁させ室温下攪拌しながら、２８％アンモニア水(4.00 g, 65.8 mmol)を滴下した。室温で３日間攪拌した後、濃縮してアンモニアを除き濃塩酸でｐＨ１とした。水を加えて希釈した後、酢酸エチルで抽出して、抽出液を無水硫酸マグネシウムで脱水し減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１）で精製して、目的物を淡黄色結晶として得た。収量71 mg(13.8%)
mp >234℃(dec.)
¹H NMR(DMSO-d₆, δ): 4.92(1H, s), 7.69(1H, d, J=9.4 Hz), 8.02(2H, brs), 8.32(1H, d, J=9.4 Hz).
IR(Nujol, cm^-1): 3359, 3294, 3242, 2123, 1464, 1356, 1312, 1170. Synthesis of 2-chloro-6-ethynylimidazo [1,2-b] pyridazin-3-ylsulfonamide

N ′-(2-chloro-6-ethynylimidazo [1,2-b] pyridazin-3-ylsulfonyl) -N, N-diisobutylformamidine (792 mg, 2.00 mmol) was suspended in dioxane (10.0 mL). While stirring at room temperature, 28% aqueous ammonia (4.00 g, 65.8 mmol) was added dropwise. After stirring at room temperature for 3 days, the mixture was concentrated to remove ammonia and adjusted to pH 1 with concentrated hydrochloric acid. The mixture was diluted with water and extracted with ethyl acetate. The extract was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the desired product as pale yellow crystals. Yield 71 mg (13.8%)
mp> 234 ° C (dec.)
¹ H NMR (DMSO-d ₆ , δ): 4.92 (1H, s), 7.69 (1H, d, J = 9.4 Hz), 8.02 (2H, brs), 8.32 (1H, d, J = 9.4 Hz).
IR (Nujol, cm ^-1 ): 3359, 3294, 3242, 2123, 1464, 1356, 1312, 1170.

窒素気流下、テトラヒドロフラン(80.0 ml) に、２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジン(10.0 g, 53.2 mmol)、［１，３−ビス（ジフェニルホスフィノ）プロパン］ニッケル（II）ジクロリド(0.43 g, 0.80 mmol)を加え氷冷下、ｎ−プロピルマグネシウムブロミドのテトラヒドロフラン溶液(2M, 31.9 ml, 63.8 mmol)を６０分かけてゆっくり滴下した。氷冷下、１０分間撹拌後、反応混合液を室温まで戻し、室温下２時間撹拌した。反応混合物に冷水(700 ml)を加え、濃塩酸で酸性とした後、析出した固体をろ取し、不溶の固体を希塩酸、ついで水で洗浄した。一方、ろ液を酢酸エチルで抽出、抽出液を合し、希塩酸、飽和食塩水、飽和炭酸水素ナトリウム水溶液、飽和食塩水の順で洗浄した。得られた有機層を無水硫酸マグネシウムで乾燥、ろ過、濃縮した。濃縮残渣とろ取した固体をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝３：７）で精製し、目的物を白色結晶として得た。収量9.21 g(88.5%)
mp 73.9-80.0℃
¹H NMR(CDCl₃, δ): 1.01(3H, t, J=7.4 Hz), 1.78(2H, m), 2.79(2H, t, J=7.6 Hz), 6.96 (1H, d, J=9.3 Hz), 7.75(1H, d, J=9.3 Hz), 7.80(1H, s).
IR(Nujol, cm^-1): 3122, 1466, 1377, 1314, 1302. Synthesis of 2-chloro-6-n-propylimidazo [1,2-b] pyridazine

Under a nitrogen stream, tetrahydrofuran (80.0 ml) was added to 2,6-dichloroimidazo [1,2-b] pyridazine (10.0 g, 53.2 mmol), [1,3-bis (diphenylphosphino) propane] nickel (II). Dichloride (0.43 g, 0.80 mmol) was added, and under ice cooling, a tetrahydrofuran solution of n-propylmagnesium bromide (2M, 31.9 ml, 63.8 mmol) was slowly added dropwise over 60 minutes. After stirring for 10 minutes under ice cooling, the reaction mixture was returned to room temperature and stirred at room temperature for 2 hours. Cold water (700 ml) was added to the reaction mixture, and the mixture was acidified with concentrated hydrochloric acid. The precipitated solid was collected by filtration, and the insoluble solid was washed with dilute hydrochloric acid and then with water. On the other hand, the filtrate was extracted with ethyl acetate, and the extracts were combined and washed in the order of dilute hydrochloric acid, saturated brine, saturated aqueous sodium bicarbonate, and saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated residue and the collected solid were purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7) to obtain the desired product as white crystals. Yield 9.21 g (88.5%)
mp 73.9-80.0 ℃
¹ H NMR (CDCl ₃ , δ): 1.01 (3H, t, J = 7.4 Hz), 1.78 (2H, m), 2.79 (2H, t, J = 7.6 Hz), 6.96 (1H, d, J = 9.3 Hz), 7.75 (1H, d, J = 9.3 Hz), 7.80 (1H, s).
IR (Nujol, cm ^-1 ): 3122, 1466, 1377, 1314, 1302.

実施例１７のｎ−プロピルマグネシウムブロミドのテトラヒドロフラン溶液の代わりにイソブチルマグネシウムブロミドのテトラヒドロフラン溶液を用いて同様の反応を行った。得られた粗製物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：４）で精製して、目的物を淡黄色結晶として得た。収量1.27 g(60.6%)
mp 71.0-72.5℃
¹H NMR(CDCl₃, δ): 0.98(6H, d, J=6.6 Hz), 2.09(1H, m), 2.68(2H, d, J=7.3 Hz), 6.94(1H, d, J=9.3 Hz), 7.75(1H, d, J=9.3 Hz), 7.81(1H,s).
IR(Nujol, cm^-1): 3126, 3059, 1545, 1466, 1369, 1331, 1320, 1279, 803. Synthesis of 2-chloro-6-isobutylimidazo [1,2-b] pyridazine

A similar reaction was carried out using a tetrahydrofuran solution of isobutylmagnesium bromide instead of the tetrahydrofuran solution of n-propylmagnesium bromide in Example 17. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain the desired product as pale yellow crystals. Yield 1.27 g (60.6%)
mp 71.0-72.5 ℃
¹ H NMR (CDCl ₃ , δ): 0.98 (6H, d, J = 6.6 Hz), 2.09 (1H, m), 2.68 (2H, d, J = 7.3 Hz), 6.94 (1H, d, J = 9.3 Hz), 7.75 (1H, d, J = 9.3 Hz), 7.81 (1H, s).
IR (Nujol, cm ^-1 ): 3126, 3059, 1545, 1466, 1369, 1331, 1320, 1279, 803.

実施例６の２−クロロ−６−ｎ−ブチルイミダゾ［１，２−ｂ］ピリダジンの代わりに２−クロロ−６−イソブチルイミダゾ［１，２−ｂ］ピリダジンを用いて同様の反応を行った。得られた反応混合物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１）で精製して、目的物を白色結晶として得た。収量1.12 g(64.0%)
mp 168.0-169.5℃
¹H NMR(DMSO-d₆, δ): 0.93(6H, d, J=6.6 Hz), 2.14(1H, m), 2.82(2H, d, J=7.4 Hz), 7.51(1H, d, J=9.4 Hz), 7.80(2H, s), 8.19(1H, d, J=9.4Hz).
IR(Nujol, cm^-1): 3316, 3180, 3117, 1548, 1469, 1362, 1336, 1321, 1200, 1173, 849, 678. Synthesis of 2-chloro-6-isobutylimidazo [1,2-b] pyridazin-3-ylsulfonamide

The same reaction was carried out using 2-chloro-6-isobutylimidazo [1,2-b] pyridazine instead of 2-chloro-6-n-butylimidazo [1,2-b] pyridazine of Example 6. . The resulting reaction mixture was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the desired product as white crystals. Yield 1.12 g (64.0%)
mp 168.0-169.5 ℃
¹ H NMR (DMSO-d ₆ , δ): 0.93 (6H, d, J = 6.6 Hz), 2.14 (1H, m), 2.82 (2H, d, J = 7.4 Hz), 7.51 (1H, d, J = 9.4 Hz), 7.80 (2H, s), 8.19 (1H, d, J = 9.4Hz).
IR (Nujol, cm ^-1 ): 3316, 3180, 3117, 1548, 1469, 1362, 1336, 1321, 1200, 1173, 849, 678.

２−クロロ−６−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジン(5.00 g, 25.6 mmol)を１，２−ジクロロエタン(30.0 ml)に溶解し、室温下クロロスルホン酸(3.40 ml, 51.1 mmol)を添加した。８．５時間加熱還流後、室温まで冷却しトリエチルアミン(7.84 ml, 56.2 mmol)及びオキシ塩化リン(5.24 ml, 56.2 mmol)を加え４時間加熱還流した。反応混合液に冷水を加えクロロホルムで抽出した。抽出液を合し、無水硫酸マグネシウムで乾燥、ろ過、濃縮した。濃縮残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝３：７）で精製し、目的物を淡黄色結晶として得た。収量7.40 g(98.4%)
mp 94.2-95.5℃
¹H NMR(CDCl₃, δ): 1.06(3H, t, J=7.4 Hz), 1.88(2H, m), 2.99(2H, t, J=7.6 Hz), 7.36 (1H, d, J=9.4 Hz), 7.95(1H, d, J=9.4 Hz).
IR(Nujol, cm^-1): 1464, 1436, 1386, 1314, 1166, 620, 573, 562, 550. Synthesis of 2-chloro-6-n-propylimidazo [1,2-b] pyridazin-3-ylsulfonyl chloride

2-Chloro-6-n-propylimidazo [1,2-b] pyridazine (5.00 g, 25.6 mmol) was dissolved in 1,2-dichloroethane (30.0 ml) and chlorosulfonic acid (3.40 ml, 51.1 mmol) at room temperature. ) Was added. After heating to reflux for 8.5 hours, the mixture was cooled to room temperature, triethylamine (7.84 ml, 56.2 mmol) and phosphorus oxychloride (5.24 ml, 56.2 mmol) were added, and the mixture was heated to reflux for 4 hours. Cold water was added to the reaction mixture, and the mixture was extracted with chloroform. The extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7) to obtain the desired product as pale yellow crystals. Yield 7.40 g (98.4%)
mp 94.2-95.5 ℃
¹ H NMR (CDCl ₃ , δ): 1.06 (3H, t, J = 7.4 Hz), 1.88 (2H, m), 2.99 (2H, t, J = 7.6 Hz), 7.36 (1H, d, J = 9.4 Hz), 7.95 (1H, d, J = 9.4 Hz).
IR (Nujol, cm ^-1 ): 1464, 1436, 1386, 1314, 1166, 620, 573, 562, 550.

乾燥フッ化カリウム(7.30 g, 130 mmol)、１８−クラウン−６(1.33 g, 5.03 mmol)および２−クロロ−６−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホニル クロリド(7.40 g, 25.2 mmol)をＤＭＦ(100 ml)中で３時間加熱還流させた後、室温で終夜放置した。反応混合物を減圧下濃縮し、濃縮残渣に冷水を加えクロロホルムで抽出した。抽出液を合し無水硫酸マグネシウムで乾燥、ろ過、濃縮した。濃縮残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝３：７）で精製したところ、未反応の原料を含む混合物が5.28 g得られた。そこで、乾燥フッ化カリウム(7.30 g, 130 mmol)、１８−クラウン−６(1.22 g, 4.61 mmol)および反応混合物 5.28 g をＤＭＦ(50.0 ml)中で５時間加熱還流させた後、１５０℃で終夜攪拌した。冷却後、反応混合物を減圧下、濃縮し、濃縮残渣に冷水を加え、クロロホルムで抽出した。抽出液を合し、無水硫酸マグネシウムで乾燥、ろ過、濃縮した後、濃縮残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝３：７）で精製し、目的物を白色結晶として得た。収量2.02 g(30.7%)
¹H NMR(CDCl₃, δ): 1.05(3H, t, J=7.3 Hz), 1.85(2H, m), 2.95(2H, t, J=7.7 Hz), 7.37 (1H, d, J=9.4 Hz), 7.93(1H, d, J=9.4 Hz).
IR(Nujol, cm^-1): 1538, 1434, 1310, 1240, 1220, 1188, 799, 765, 695, 613, 595. Synthesis of 2-fluoro-6-n-propylimidazo [1,2-b] pyridazin-3-ylsulfonyl fluoride

Dry potassium fluoride (7.30 g, 130 mmol), 18-crown-6 (1.33 g, 5.03 mmol) and 2-chloro-6-n-propylimidazo [1,2-b] pyridazin-3-ylsulfonyl chloride ( 7.40 g, 25.2 mmol) was heated to reflux in DMF (100 ml) for 3 hours, and then left at room temperature overnight. The reaction mixture was concentrated under reduced pressure, cold water was added to the concentrated residue, and the mixture was extracted with chloroform. The extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7) to obtain 5.28 g of a mixture containing unreacted raw materials. Accordingly, dry potassium fluoride (7.30 g, 130 mmol), 18-crown-6 (1.22 g, 4.61 mmol) and 5.28 g of the reaction mixture were heated to reflux in DMF (50.0 ml) for 5 hours, and then at 150 ° C. Stir overnight. After cooling, the reaction mixture was concentrated under reduced pressure, cold water was added to the concentrated residue, and the mixture was extracted with chloroform. The extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated, and then the concentrated residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7) to obtain the desired product as white crystals. Yield 2.02 g (30.7%)
¹ H NMR (CDCl ₃ , δ): 1.05 (3H, t, J = 7.3 Hz), 1.85 (2H, m), 2.95 (2H, t, J = 7.7 Hz), 7.37 (1H, d, J = 9.4 Hz), 7.93 (1H, d, J = 9.4 Hz).
IR (Nujol, cm ^-1 ): 1538, 1434, 1310, 1240, 1220, 1188, 799, 765, 695, 613, 595.

（ａ）２−フルオロ−６−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホニル フルオリド(1.00 g, 3.83 mmol)をアセトニトリル(20.0 ml)に希釈し、水(8.0 ml)に溶解した水酸化ナトリウム(0.23 g, 5.75 mmol)を加え、室温下４時間攪拌した。反応が完結していなかったため、水酸化ナトリウム(0.08 g, 2.00 mmol)を追加し、室温下１時間攪拌した。反応混合液を減圧下濃縮し、濃縮残渣に水を加え、濃塩酸で酸性とした。濃縮残渣にアセトンを加え、不溶の固体をろ過して除去した後、ろ液を減圧下濃縮し２−フルオロ−６−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホン酸を含む黄褐色油状物を1.18 g得た。
（ｂ）２−フルオロ−６−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホン酸を含む油状物(1.18 g)を１，２−ジクロロエタン(5.0 ml)に溶解し、室温下、オキシ塩化リン(0.70 ml, 7.66 mmol)を加え４時間加熱還流した。反応が完結していなかった為、オキシ塩化リン(0.70 ml , 7.66 mmol)を追加し更に２時間加熱還流した。反応混合液を冷却し、冷水を加えクロロホルムで抽出した。抽出液を合し、無水硫酸マグネシウムで乾燥、ろ過、濃縮した。濃縮残渣をアセトニトリル(2.0 ml)に希釈し、氷冷下２８％アンモニア水(8.0 ml)のアセトニトリル(5.0 ml)溶液に滴下し、室温下３時間攪拌した。反応混合液に水を加え希釈した後、濃塩酸を滴下し酸性とした。析出した固体をろ取、水洗し、固体をシリカゲルカラムクロマトグラフィー（アセトン：クロロホルム＝２：５）で精製し、目的物を淡黄白色結晶として得た。収量0.33 g (33.4%)
mp 147.8-148.0℃
¹H NMR(DMSO-d₆, δ): 0.97(3H, t, J=7.4 Hz), 1.76(2H, m), 2.89(2H, t, J=7.7 Hz), 7.56 (1H, d, J=9.4 Hz), 7.84(2H, s), 8.19(1H, d, J=9.4 Hz).
IR(Nujol, cm^-1): 3318, 1540, 1465, 1412, 1351, 1305, 1170, 609.
¹⁹F NMR(DMSO-d₆, δ): -114.3 Synthesis of 2-fluoro-6-n-propylimidazo [1,2-b] pyridazin-3-ylsulfonamide

(A) 2-Fluoro-6-n-propylimidazo [1,2-b] pyridazin-3-ylsulfonyl fluoride (1.00 g, 3.83 mmol) was diluted in acetonitrile (20.0 ml) and dissolved in water (8.0 ml). Dissolved sodium hydroxide (0.23 g, 5.75 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Since the reaction was not completed, sodium hydroxide (0.08 g, 2.00 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added to the concentrated residue, and the mixture was acidified with concentrated hydrochloric acid. Acetone is added to the concentrated residue, and the insoluble solid is removed by filtration. Then, the filtrate is concentrated under reduced pressure to contain 2-fluoro-6-n-propylimidazo [1,2-b] pyridazin-3-ylsulfonic acid. 1.18 g of a tan oil was obtained.
(B) An oily product (1.18 g) containing 2-fluoro-6-n-propylimidazo [1,2-b] pyridazin-3-ylsulfonic acid was dissolved in 1,2-dichloroethane (5.0 ml), and the solution was stirred at room temperature. , Phosphorus oxychloride (0.70 ml, 7.66 mmol) was added and the mixture was heated to reflux for 4 hours. Since the reaction was not completed, phosphorus oxychloride (0.70 ml, 7.66 mmol) was added and the mixture was further heated to reflux for 2 hours. The reaction mixture was cooled, cold water was added, and the mixture was extracted with chloroform. The extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated residue was diluted with acetonitrile (2.0 ml), added dropwise to a solution of 28% aqueous ammonia (8.0 ml) in acetonitrile (5.0 ml) under ice cooling, and stirred at room temperature for 3 hours. After diluting the reaction mixture with water, concentrated hydrochloric acid was added dropwise to make it acidic. The precipitated solid was collected by filtration and washed with water, and the solid was purified by silica gel column chromatography (acetone: chloroform = 2: 5) to obtain the desired product as pale yellowish white crystals. Yield 0.33 g (33.4%)
mp 147.8-148.0 ℃
¹ H NMR (DMSO-d ₆ , δ): 0.97 (3H, t, J = 7.4 Hz), 1.76 (2H, m), 2.89 (2H, t, J = 7.7 Hz), 7.56 (1H, d, J = 9.4 Hz), 7.84 (2H, s), 8.19 (1H, d, J = 9.4 Hz).
IR (Nujol, cm ^-1 ): 3318, 1540, 1465, 1412, 1351, 1305, 1170, 609.
¹⁹ F NMR (DMSO-d ₆ , δ): -114.3

水素化ナトリウム(60%, 0.73 g, 18.2 mmol)をＤＭＦ(10.0 ml)に氷冷下懸濁させ、エタンチオール(1.35 ml, 18.2 mmol)を滴下し、０℃で２時間攪拌した。２−クロロ−６−プロピルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミド(1.00 g, 3.64 mmol)を加え、１１０℃ で２．５時間加熱攪拌した。放冷後、反応混合液に水を加え希釈した後、濃塩酸を滴下し酸性とした。析出した固体をろ取、水洗後、固体をクロロホルム−酢酸エチルの混合溶液に懸濁させ、不溶の固体をろ取、固体をクロロホルムで洗浄し、目的物を灰色結晶として得た。収量0.45 g(41.2%)
mp 175.9-177.2℃
¹H NMR(DMSO-d₆, δ): 0.95(3H, t, J=7.4 Hz), 1.34(3H, t, J=7.3 Hz), 1.75(2H, m), 2.87(2H, t, J=7.7 Hz), 3.19(2H, q, J=7.3 Hz), 7.41 (1H, d, J=9.3 Hz), 7.56(2H, s), 8.12(1H, d, J=9.3 Hz).
IR(Nujol, cm^-1): 3309, 3188, 3059, 1466, 1430, 1348, 1325, 1165, 599. Synthesis of 2-ethylthio-6-n-propylimidazo [1,2-b] pyridazin-3-ylsulfonamide

Sodium hydride (60%, 0.73 g, 18.2 mmol) was suspended in DMF (10.0 ml) under ice-cooling, ethanethiol (1.35 ml, 18.2 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 2 hours. 2-Chloro-6-propylimidazo [1,2-b] pyridazin-3-ylsulfonamide (1.00 g, 3.64 mmol) was added, and the mixture was heated and stirred at 110 ° C. for 2.5 hours. After allowing to cool, the reaction mixture was diluted with water, and then concentrated hydrochloric acid was added dropwise to make it acidic. The precipitated solid was collected by filtration and washed with water, then the solid was suspended in a mixed solution of chloroform-ethyl acetate, the insoluble solid was collected by filtration, and the solid was washed with chloroform to obtain the desired product as gray crystals. Yield 0.45 g (41.2%)
mp 175.9-177.2 ℃
¹ H NMR (DMSO-d ₆ , δ): 0.95 (3H, t, J = 7.4 Hz), 1.34 (3H, t, J = 7.3 Hz), 1.75 (2H, m), 2.87 (2H, t, J = 7.7 Hz), 3.19 (2H, q, J = 7.3 Hz), 7.41 (1H, d, J = 9.3 Hz), 7.56 (2H, s), 8.12 (1H, d, J = 9.3 Hz).
IR (Nujol, cm ^-1 ): 3309, 3188, 3059, 1466, 1430, 1348, 1325, 1165, 599.

２−エチルチオ−６−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミド(0.30 g , 1.00 mmol) をアセトニトリル(1.0 ml)、水(4.0 ml)に懸濁させ、４５℃で過炭酸ナトリウム(有効酸素濃度12.2%, 0.33 g, 2.50 mmol)を加え、５０〜６０℃で２．５時間攪拌した。反応混合液を水にあけ、希塩酸で酸性にし、析出してきた不溶の固体をろ取、水洗して、目的物を白色結晶として得た。収量0.25 g(75.3%)
mp 232.3-233.0℃
¹H NMR(DMSO-d₆, δ): 0.97(3H, t, J=7.3 Hz), 1.21(3H, t, J=7.3 Hz), 1.78(2H, m), 2.96(2H, t, J=7.7 Hz), 3.62(2H, q, J=7.3 Hz), 7.62 (1H, d, J=9.4 Hz), 7.96(2H, s), 8.37(1H, d, J=9.4 Hz).
IR(Nujol, cm^-1): 3354, 3269, 1464, 1351, 1318, 1166, 1137, 743, 711, 452. Synthesis of 2-ethylsulfonyl-6-n-propylimidazo [1,2-b] pyridazin-3-ylsulfonamide

2-Ethylthio-6-n-propylimidazo [1,2-b] pyridazin-3-ylsulfonamide (0.30 g, 1.00 mmol) was suspended in acetonitrile (1.0 ml), water (4.0 ml), and 45 ° C. Sodium percarbonate (effective oxygen concentration 12.2%, 0.33 g, 2.50 mmol) was added and stirred at 50-60 ° C. for 2.5 hours. The reaction mixture was poured into water, acidified with dilute hydrochloric acid, and the precipitated insoluble solid was collected by filtration and washed with water to obtain the desired product as white crystals. Yield 0.25 g (75.3%)
mp 232.3-233.0 ℃
¹ H NMR (DMSO-d ₆ , δ): 0.97 (3H, t, J = 7.3 Hz), 1.21 (3H, t, J = 7.3 Hz), 1.78 (2H, m), 2.96 (2H, t, J = 7.7 Hz), 3.62 (2H, q, J = 7.3 Hz), 7.62 (1H, d, J = 9.4 Hz), 7.96 (2H, s), 8.37 (1H, d, J = 9.4 Hz).
IR (Nujol, cm ^-1 ): 3354, 3269, 1464, 1351, 1318, 1166, 1137, 743, 711, 452.

窒素気流下、テトラヒドロフラン(8.0 ml)に、エチル ６−クロロイミダゾ［１，２−ｂ］ピリダジン−２−イルカルボキシレート(1.00 g, 4.43 mmol)、［１，３−ビス（ジフェニルホスフィノ）プロパン］ニッケル（II）ジクロリド(0.24 g, 0.44 mmol)を加え氷冷下攪拌しながら、臭化ｎ−プロピル亜鉛のテトラヒドロフラン溶液(0.5M, 13.3 ml, 6.65 mmol)を滴下した。氷冷下で２０分間、室温下で０．５時間撹拌した後、反応混合物に冷水(50.0 ml)を加え、希塩酸で酸性とした。酢酸エチルで抽出し抽出液を合し、希塩酸、飽和食塩水で洗浄した。得られた有機層を無水硫酸マグネシウムで乾燥、ろ過、濃縮した。濃縮残渣をシリカゲルカラムクロマトグラフィー（アセトン：ヘキサン＝１：３）で精製し、目的物を白色結晶として得た。収量0.77 g(74.8%)
mp 54.0-54.5℃
¹H NMR(CDCl₃, δ): 1.02(3H, t, J=7.4 Hz), 1.44(3H, t, J=7.1 Hz), 1.80(2H, m), 2.81(2H, t, J=7.6 Hz), 4.47(2H, q, J=7.1 Hz), 7.00 (1H, d, J=9.5 Hz), 7.90(1H, d, J=9.5 Hz), 8.43(1H, s).
IR(Nujol, cm^-1): 3121, 1716, 1541, 1306, 1238, 1228, 1195. Synthesis of ethyl 6-n-propylimidazo [1,2-b] pyridazin-2-ylcarboxylate

Under nitrogen flow, tetrahydrofuran (8.0 ml) was charged with ethyl 6-chloroimidazo [1,2-b] pyridazin-2-ylcarboxylate (1.00 g, 4.43 mmol), [1,3-bis (diphenylphosphino) propane. Nickel (II) dichloride (0.24 g, 0.44 mmol) was added, and a solution of n-propylzinc bromide in tetrahydrofuran (0.5M, 13.3 ml, 6.65 mmol) was added dropwise with stirring under ice cooling. After stirring for 20 minutes under ice cooling and 0.5 hour at room temperature, cold water (50.0 ml) was added to the reaction mixture, and the mixture was acidified with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, and the extracts were combined and washed with dilute hydrochloric acid and saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated residue was purified by silica gel column chromatography (acetone: hexane = 1: 3) to obtain the desired product as white crystals. Yield 0.77 g (74.8%)
mp 54.0-54.5 ℃
¹ H NMR (CDCl ₃ , δ): 1.02 (3H, t, J = 7.4 Hz), 1.44 (3H, t, J = 7.1 Hz), 1.80 (2H, m), 2.81 (2H, t, J = 7.6 Hz), 4.47 (2H, q, J = 7.1 Hz), 7.00 (1H, d, J = 9.5 Hz), 7.90 (1H, d, J = 9.5 Hz), 8.43 (1H, s).
IR (Nujol, cm ^-1 ): 3121, 1716, 1541, 1306, 1238, 1228, 1195.

エチル ６−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジン−２−イルカルボキシレート(4.90 g, 21.0 mmol)をアセトニトリル(7.0 ml)に希釈し、２８％アンモニア水(10.0 ml)を加え、封管中１００℃で７時間攪拌した。室温まで冷却後、反応混合液に水(20.0 ml)を加え希釈した後、不溶の固体をろ取、水洗し、目的物を白色結晶として得た。収量3.39 g(79.0%)
mp 223.5-224.2℃
¹H NMR(CDCl₃, δ): 1.02(3H, t, J=7.4 Hz), 1.79(2H, m), 2.81(2H, t, J=7.6 Hz), 5.64(1H, brs), 7.01 (1H, d, J=9.4 Hz), 7.21(1H, brs), 7.81(1H, d, J=9.4 Hz), 8.43(1H, s).
IR(Nujol, cm^-1): 3437, 3175, 3104, 1632, 1542, 1319, 1294, 812, 682. Synthesis of 6-n-propylimidazo [1,2-b] pyridazin-2-ylcarboxamide

Ethyl 6-n-propylimidazo [1,2-b] pyridazin-2-ylcarboxylate (4.90 g, 21.0 mmol) is diluted in acetonitrile (7.0 ml), 28% aqueous ammonia (10.0 ml) is added and sealed. Stir in a tube at 100 ° C. for 7 hours. After cooling to room temperature, water (20.0 ml) was added to the reaction mixture for dilution, and the insoluble solid was collected by filtration and washed with water to obtain the desired product as white crystals. Yield 3.39 g (79.0%)
mp 223.5-224.2 ℃
¹ H NMR (CDCl ₃ , δ): 1.02 (3H, t, J = 7.4 Hz), 1.79 (2H, m), 2.81 (2H, t, J = 7.6 Hz), 5.64 (1H, brs), 7.01 ( 1H, d, J = 9.4 Hz), 7.21 (1H, brs), 7.81 (1H, d, J = 9.4 Hz), 8.43 (1H, s).
IR (Nujol, cm ^-1 ): 3437, 3175, 3104, 1632, 1542, 1319, 1294, 812, 682.

６−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジン−２−イルカルボキシアミド(3.38 g, 16.5 mmol) をピリジン(10.0 ml)に溶解し、氷冷下攪拌しながらトリフルオロ酢酸無水物(3.51 ml, 24.8 mmol)を加え、氷冷下０．５時間、室温下０．５時間攪拌した。反応混合液に水、濃塩酸を加え酸性とした後、不溶の固体をろ過して固体と水溶液に分けた。固体をエーテルに懸濁させ攪拌した後、不溶物を除きエーテル抽出液を得た。水溶液を食塩で飽和させた後、酢酸エチルで抽出して酢酸エチル抽出液を得た。エーテル抽出液と酢酸エチル抽出液を濃縮後、シリカゲルカラムクロマトグラフィー（酢酸エチル：クロロホルム＝２：５）で精製して、目的物を白色結晶として得た。収量2.41 g(78.2%)
mp 81.8-82.4℃
¹H NMR(CDCl₃, δ): 1.02(3H, t, J=7.4 Hz), 1.80(2H, m), 2.83(2H, t, J=7.6 Hz), 7.08(1H, d, J=9.4 Hz), 7.88(1H, d, J=9.4 Hz), 8.30(1H, s).
IR(Nujol, cm^-1): 3108, 2235, 1544, 1466, 1326, 1292, 1132, 984, 818. Synthesis of 6-n-propylimidazo [1,2-b] pyridazin-2-ylcarbonitrile

6-n-propylimidazo [1,2-b] pyridazin-2-ylcarboxamide (3.38 g, 16.5 mmol) was dissolved in pyridine (10.0 ml) and stirred under ice-cooling with trifluoroacetic anhydride (3.51 ml, 24.8 mmol) was added, and the mixture was stirred for 0.5 hour under ice cooling and 0.5 hour at room temperature. Water and concentrated hydrochloric acid were added to the reaction mixture to make it acidic, and then the insoluble solid was filtered to separate it into a solid and an aqueous solution. The solid was suspended in ether and stirred, and then insolubles were removed to obtain an ether extract. The aqueous solution was saturated with sodium chloride and then extracted with ethyl acetate to obtain an ethyl acetate extract. The ether extract and the ethyl acetate extract were concentrated and purified by silica gel column chromatography (ethyl acetate: chloroform = 2: 5) to obtain the desired product as white crystals. Yield 2.41 g (78.2%)
mp 81.8-82.4 ℃
¹ H NMR (CDCl ₃ , δ): 1.02 (3H, t, J = 7.4 Hz), 1.80 (2H, m), 2.83 (2H, t, J = 7.6 Hz), 7.08 (1H, d, J = 9.4 Hz), 7.88 (1H, d, J = 9.4 Hz), 8.30 (1H, s).
IR (Nujol, cm ^-1 ): 3108, 2235, 1544, 1466, 1326, 1292, 1132, 984, 818.

リチウム ジイソプロピルアミドのヘプタン−テトラヒドロフラン−エチルベンゼン溶液(2.0M, 3.22 ml, 6.44 mmol)をエーテル(30.0 ml)に希釈し、−６０℃以下で６−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジン−２−イルカルボニトリル(1.00 g, 5.37 mmol)のエーテル(20.0 ml)溶液を１２分間で滴下し、−６０℃で１．５時間攪拌した。未反応の原料が溶けずに残存していたのでテトラヒドロフラン(20.0 ml)を加え、−６０℃で１．５時間攪拌した。反応混合液に亜硫酸水素ナトリウムと濃硫酸により発生させた亜硫酸ガスを−６０℃以下で０．５時間かけて吹き込み、−６０℃以下で２０分攪拌し、その後ゆっくり０℃まで昇温した。析出した固体をろ取し、固体をエーテルで洗浄した。得られた固体を氷冷下、ジクロロメタン(20.0 ml)、水(20.0 ml)で溶解したＮ−クロロコハク酸イミド(1.15 g, 8.59 mmol)溶液に添加し、氷冷下１時間攪拌した。有機層を分離し、水層をクロロホルムで抽出した。有機層を合し、無水硫酸マグネシウムで乾燥、ろ過した後、ろ液を濃縮した。濃縮残渣をアセトニトリル(10.0 ml)に希釈し、氷冷下、２８％アンモニア水(2.0 ml)を加え、同温度で０．５時間攪拌した。反応混合液を濃縮後、水を加え、不溶の固体をろ取、固体を水で洗浄した。得られた固体をクロロホルムで洗浄して、目的物を白色結晶として得た。収量0.20 g(14.0%)
mp 237.4-243.8℃
¹H NMR(DMSO-d₆, δ): 0.97(3H, t, J=7.3 Hz), 1.78(2H, m), 2.82(2H, t, J=7.7 Hz), 7.64(1H, d, J=9.6 Hz), 8.20(2H, brs), 8.33(1H, d, J=9.6 Hz).
IR(Nujol, cm^-1): 3316, 3185, 2243, 1550, 1464, 1361, 1175, 606. Synthesis of 2-cyano-6-n-propylimidazo [1,2-b] pyridazin-3-ylsulfonamide

A solution of lithium diisopropylamide in heptane-tetrahydrofuran-ethylbenzene (2.0M, 3.22 ml, 6.44 mmol) is diluted in ether (30.0 ml), and 6-n-propylimidazo [1,2-b] pyridazine- A solution of 2-ylcarbonitrile (1.00 g, 5.37 mmol) in ether (20.0 ml) was added dropwise over 12 minutes, and the mixture was stirred at −60 ° C. for 1.5 hours. Since unreacted raw material remained without being dissolved, tetrahydrofuran (20.0 ml) was added, and the mixture was stirred at −60 ° C. for 1.5 hours. Sulfurous acid gas generated with sodium bisulfite and concentrated sulfuric acid was blown into the reaction mixture at −60 ° C. or lower for 0.5 hour, stirred at −60 ° C. or lower for 20 minutes, and then slowly heated to 0 ° C. The precipitated solid was collected by filtration, and the solid was washed with ether. The obtained solid was added to a solution of N-chlorosuccinimide (1.15 g, 8.59 mmol) dissolved in dichloromethane (20.0 ml) and water (20.0 ml) under ice cooling and stirred for 1 hour under ice cooling. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated. The concentrated residue was diluted with acetonitrile (10.0 ml), 28% aqueous ammonia (2.0 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 0.5 hr. The reaction mixture was concentrated, water was added, insoluble solid was collected by filtration, and the solid was washed with water. The obtained solid was washed with chloroform to obtain the desired product as white crystals. Yield 0.20 g (14.0%)
mp 237.4-243.8 ℃
¹ H NMR (DMSO-d ₆ , δ): 0.97 (3H, t, J = 7.3 Hz), 1.78 (2H, m), 2.82 (2H, t, J = 7.7 Hz), 7.64 (1H, d, J = 9.6 Hz), 8.20 (2H, brs), 8.33 (1H, d, J = 9.6 Hz).
IR (Nujol, cm ^-1 ): 3316, 3185, 2243, 1550, 1464, 1361, 1175, 606.

（ａ）５−メチル−４−オキソヘキサン酸(3.60 g, 25.0 mmol)と無水ヒドラジン(0.80 g, 26.0 mmol)をエタノール(36.0 ml)中で３時間加熱攪拌した。反応液を減圧濃縮した後、残渣にヘキサンを加えて結晶を析出させ、結晶をろ取して４，５−ジヒドロ−６−イソプロピル−３（２Ｈ）−ピリダジノンを結晶として得た。収量3.10 g
（ｂ）４，５−ジヒドロ−６−イソプロピル−３（２Ｈ）−ピリダジノン(3.10 g)を酢酸(30.0 ml)に溶かし１００℃で加熱攪拌しながら臭素(3.50 g, 22.0 mmol)を１０分間で滴下した。１時間加熱還流した後、酢酸を減圧留去して、残渣に水(100 ml)を加え酢酸エチルで５回抽出した。抽出液を合わせて無水硫酸マグネシウムで乾燥、濃縮して６−イソプロピル−３（２Ｈ）−ピリダジノンの粗生成物を得た。収量3.30 g
（ｃ）６−イソプロピル−３（２Ｈ）−ピリダジノン(3.30 g)とオキシ塩化リン(15.0 ml)を１時間加熱還流した。過剰のオキシ塩化リンを留去した後、残留物に氷水(200 ml)を加え、２０％水酸化ナトリウム水溶液でｐＨ６とした。酢酸エチルで３回抽出した後、抽出液を合わせて無水硫酸マグネシウムで乾燥し濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：クロロホルム＝１：２）で精製して目的物を淡赤色結晶として得た。収量1.60 g(５−メチル−４−オキソヘキサン酸を基準として40.8%)
mp 32-33℃
¹H NMR(CDCl₃, δ): 1.35-1.40(6H, m), 3.33(1H, sept, J=7.0 Hz), 7.34(1H, d, J=8.8 Hz), 7.44(1H, d, J=8.8Hz).
IR(Nujol, cm^-1): 1572, 1540, 1409, 1167, 1149, 1069, 1041, 854, 790. Synthesis of 3-chloro-6-isopropylpyridazine

(A) 5-Methyl-4-oxohexanoic acid (3.60 g, 25.0 mmol) and hydrazine anhydride (0.80 g, 26.0 mmol) were heated and stirred in ethanol (36.0 ml) for 3 hours. After the reaction solution was concentrated under reduced pressure, hexane was added to the residue to precipitate crystals, and the crystals were collected by filtration to obtain 4,5-dihydro-6-isopropyl-3 (2H) -pyridazinone as crystals. Yield 3.10 g
(B) 4,5-dihydro-6-isopropyl-3 (2H) -pyridazinone (3.10 g) was dissolved in acetic acid (30.0 ml), and bromine (3.50 g, 22.0 mmol) was added over 10 minutes while heating and stirring at 100 ° C. It was dripped. After heating under reflux for 1 hour, acetic acid was distilled off under reduced pressure, water (100 ml) was added to the residue, and the mixture was extracted 5 times with ethyl acetate. The extracts were combined, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product of 6-isopropyl-3 (2H) -pyridazinone. Yield 3.30 g
(C) 6-Isopropyl-3 (2H) -pyridazinone (3.30 g) and phosphorus oxychloride (15.0 ml) were heated to reflux for 1 hour. After excess phosphorus oxychloride was distilled off, ice water (200 ml) was added to the residue, and the pH was adjusted to 6 with a 20% aqueous sodium hydroxide solution. After extracting three times with ethyl acetate, the extracts were combined, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: chloroform = 1: 2) to obtain the desired product as pale red crystals. Yield 1.60 g (40.8% based on 5-methyl-4-oxohexanoic acid)
mp 32-33 ℃
¹ H NMR (CDCl ₃ , δ): 1.35-1.40 (6H, m), 3.33 (1H, sept, J = 7.0 Hz), 7.34 (1H, d, J = 8.8 Hz), 7.44 (1H, d, J = 8.8Hz).
IR (Nujol, cm ^-1 ): 1572, 1540, 1409, 1167, 1149, 1069, 1041, 854, 790.

３−クロロ−６−イソプロピルピリダジン(1.60 g, 10.2 mmol)と２８％アンモニア水(15.0 ml)を封管反応器に入れ１４０℃で２４時間、１６５℃で２５時間加圧下で加熱攪拌した。反応液を放冷後、水(30.0 ml)に注ぎｐＨ９に調節し、酢酸エチルで３回抽出した。抽出液を合わせて無水硫酸ナトリウムで乾燥、減圧濃縮して粗結晶を得た。この結晶をジイソプロピルエーテル−ヘキサンを加えて洗浄しながらろ過して、目的物を淡褐色結晶として得た。収量0.41 g(29.3%)
mp 131-132℃
¹H NMR(CDCl₃, δ): 1.30(6H, d, J=7.0 Hz), 3.17(1H, sept, J=7.0 Hz), 4.69(2H, brs), 6.72(1H, d, J=9.1 Hz), 7.12(1H, d, J=9.1 Hz).
IR(Nujol, cm^-1): 3312, 3139, 1645, 1608, 1555, 1056, 850, 840, 651. Synthesis of 3-amino-6-isopropylpyridazine

3-Chloro-6-isopropylpyridazine (1.60 g, 10.2 mmol) and 28% aqueous ammonia (15.0 ml) were placed in a sealed tube reactor and heated and stirred under pressure at 140 ° C. for 24 hours and at 165 ° C. for 25 hours. The reaction mixture was allowed to cool, poured into water (30.0 ml), adjusted to pH 9, and extracted three times with ethyl acetate. The extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude crystals. The crystals were filtered while adding diisopropyl ether-hexane, and the target product was obtained as light brown crystals. Yield 0.41 g (29.3%)
mp 131-132 ℃
¹ H NMR (CDCl ₃ , δ): 1.30 (6H, d, J = 7.0 Hz), 3.17 (1H, sept, J = 7.0 Hz), 4.69 (2H, brs), 6.72 (1H, d, J = 9.1 Hz), 7.12 (1H, d, J = 9.1 Hz).
IR (Nujol, cm ^-1 ): 3312, 3139, 1645, 1608, 1555, 1056, 850, 840, 651.

３−アミノ−６−イソプロピルピリダジン(0.41 g, 2.99 mmol)とブロモアセトン(0.53 g, 3.10 mmol)をアセトニトリル(5.0 ml)と混合し６時間過熱還流した。反応終了後、反応液に水(20.0 ml)を注ぎ、２０％水酸化ナトリウム水溶液でｐＨ９に調節した。酢酸エチルで２回抽出後、抽出液を合わせて無水硫酸ナトリウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：クロロホルム＝１：１）で精製して目的物を褐色オイルとして得た。収量0.30 g(57.2%)
¹H NMR(CDCl₃, δ): 1.33(6H, d, J=7.0 Hz), 2.48(3H, d, J=0.8 Hz), 3.09(1H, sept, J=7.0 Hz), 6.90(1H, d, J=9.4 Hz), 7.65-7.67(1H, m), 7.74(1H, d, J=9.4 Hz).
IR(Neat, cm^-1): 1539, 1327, 1289, 1123, 1084, 1042, 989, 815, 727. Synthesis of 6-isopropyl-2-methylimidazo [1,2-b] pyridazine

3-Amino-6-isopropylpyridazine (0.41 g, 2.99 mmol) and bromoacetone (0.53 g, 3.10 mmol) were mixed with acetonitrile (5.0 ml) and heated to reflux for 6 hours. After completion of the reaction, water (20.0 ml) was poured into the reaction solution, and the pH was adjusted to 9 with a 20% aqueous sodium hydroxide solution. After extraction twice with ethyl acetate, the extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: chloroform = 1: 1) to obtain the desired product as a brown oil. Yield 0.30 g (57.2%)
¹ H NMR (CDCl ₃ , δ): 1.33 (6H, d, J = 7.0 Hz), 2.48 (3H, d, J = 0.8 Hz), 3.09 (1H, sept, J = 7.0 Hz), 6.90 (1H, d, J = 9.4 Hz), 7.65-7.67 (1H, m), 7.74 (1H, d, J = 9.4 Hz).
IR (Neat, cm ^-1 ): 1539, 1327, 1289, 1123, 1084, 1042, 989, 815, 727.

実施例４の２−クロロ−６−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジンの代わりに６−イソプロピル−２−メチルイミダゾ［１，２−ｂ］ピリダジンを用いて同様の反応を行い、目的物を淡褐色結晶として得た。収率27.6%
mp 199-200℃
¹H NMR(DMSO-d₆, δ): 1.32(6H, d, J=6.9 Hz), 2.57(3H, s), 3.2-3.4(1H, m), 7.44(2H, brs), 7.47(1H, d, J=9.5 Hz), 8.11(1H, d, J=9.5 Hz).
IR(Nujol, cm^-1): 3338, 3067, 1543, 1347, 1332, 1162, 1047, 828, 763, 740, 606. Synthesis of 6-isopropyl-2-methylimidazo [1,2-b] pyridazin-3-ylsulfonamide

The same reaction was carried out using 6-isopropyl-2-methylimidazo [1,2-b] pyridazine instead of 2-chloro-6-n-propylimidazo [1,2-b] pyridazine of Example 4. The desired product was obtained as light brown crystals. Yield 27.6%
mp 199-200 ℃
¹ H NMR (DMSO-d ₆ , δ): 1.32 (6H, d, J = 6.9 Hz), 2.57 (3H, s), 3.2-3.4 (1H, m), 7.44 (2H, brs), 7.47 (1H , d, J = 9.5 Hz), 8.11 (1H, d, J = 9.5 Hz).
IR (Nujol, cm ^-1 ): 3338, 3067, 1543, 1347, 1332, 1162, 1047, 828, 763, 740, 606.

実施例３１の３−アミノ−６−イソプロピルピリダジンの代わりに３−アミノ−６−クロロピリダジンを用い、ブロモアセトンの代わりに１−クロロ−２−ペンタノンを用いて同様の反応を行い粗生成物を得た。これをシリカゲルカラムクロマトグラフィー（酢酸エチル：クロロホルム＝１：２）で精製して、目的物を肌色結晶として得た。収率43.7%
¹H NMR(CDCl₃, δ): 1.00(3H, t, J=7.4 Hz), 1.7-1.9(2H, m), 2.79(2H, t, J=7.6 Hz), 6.99(1H, d, J=9.4 Hz), 7.71(1H, s), 7.80(1H, d, J=9.4 Hz).
IR(Nujol, cm^-1): 1608, 1518, 1455, 1328, 1286, 1133, 1091, 987, 940, 818, 764, 708, 603, 508. Synthesis of 6-chloro-2-n-propylimidazo [1,2-b] pyridazine

The same reaction was carried out using 3-amino-6-chloropyridazine instead of 3-amino-6-isopropylpyridazine in Example 31 and 1-chloro-2-pentanone instead of bromoacetone. Obtained. This was purified by silica gel column chromatography (ethyl acetate: chloroform = 1: 2) to obtain the desired product as skin-colored crystals. Yield 43.7%
¹ H NMR (CDCl ₃ , δ): 1.00 (3H, t, J = 7.4 Hz), 1.7-1.9 (2H, m), 2.79 (2H, t, J = 7.6 Hz), 6.99 (1H, d, J = 9.4 Hz), 7.71 (1H, s), 7.80 (1H, d, J = 9.4 Hz).
IR (Nujol, cm ^-1 ): 1608, 1518, 1455, 1328, 1286, 1133, 1091, 987, 940, 818, 764, 708, 603, 508.

実施例６の２−クロロ−６−ｎ−ブチルイミダゾ［１，２−ｂ］ピリダジンの代わりに６−クロロ−２−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジンを用いて同様の反応を行い、目的物を白色結晶として得た。収率45.1%
mp 155-156℃(dec.)
¹H NMR(DMSO-d₆, δ): 0.94(3H, t, J=7.3 Hz), 1.7-1.8(2H, m), 2.98(2H, t, J=7.4 Hz), 7.59(1H, d, J=9.5 Hz), 7.75(2H, brs), 8.30(1H, d, J=9.5 Hz).
IR(Nujol, cm^-1): 3404, 3259, 1524, 1359, 1298, 1180, 1164, 1142, 818, 737, 612. Synthesis of 6-chloro-2-n-propylimidazo [1,2-b] pyridazin-3-ylsulfonamide

The same reaction was carried out using 6-chloro-2-n-propylimidazo [1,2-b] pyridazine instead of 2-chloro-6-n-butylimidazo [1,2-b] pyridazine in Example 6. The target product was obtained as white crystals. Yield 45.1%
mp 155-156 ° C (dec.)
¹ H NMR (DMSO-d ₆ , δ): 0.94 (3H, t, J = 7.3 Hz), 1.7-1.8 (2H, m), 2.98 (2H, t, J = 7.4 Hz), 7.59 (1H, d , J = 9.5 Hz), 7.75 (2H, brs), 8.30 (1H, d, J = 9.5 Hz).
IR (Nujol, cm ^-1 ): 3404, 3259, 1524, 1359, 1298, 1180, 1164, 1142, 818, 737, 612.

クロロ酢酸(0.32 g, 3.3 mmol)、トリエチルアミン(0.33 g, 3.3 mmol)、エタノール(5.0 ml)及び水(5.0 ml)を混合し室温下攪拌しながら、３−アミノ−６−イソプロピルピリダジン(0.45 g, 3.28 mmol)を加え８０〜９０℃で５時間加熱攪拌した後、反応液を濃縮乾固した。得られた固体とオキシ塩化リン(5.0 ml)を封管反応器中１５０℃で１２時間攪拌した。室温まで放冷後、４０〜５０℃の水(50.0 ml)に注ぎ過剰のオキシ塩化リンを分解させた。２０％水酸化ナトリウム水溶液でｐＨ７に調節した後、酢酸エチルで３回抽出し、抽出液を合わせて無水硫酸マグネシウムで乾燥し濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：クロロホルム＝１：２）で精製して、目的物を淡黄色結晶として得た。収量0.15 g(23.4%)
mp 69-71℃
¹H NMR(CDCl₃, δ): 1.34(6H, d, J=7.0 Hz), 3.11(1H, sept, J=7.0 Hz), 6.99(1H, d, J=9.4 Hz), 7.75-7.8(2H, m).
IR(Nujol, cm^-1): 3128, 3050, 1545, 1347, 1327, 1306, 1275, 1257, 1192, 1140, 1088, 1044, 961. Synthesis of 2-chloro-6-isopropylimidazo [1,2-b] pyridazine

While mixing chloroacetic acid (0.32 g, 3.3 mmol), triethylamine (0.33 g, 3.3 mmol), ethanol (5.0 ml) and water (5.0 ml) and stirring at room temperature, 3-amino-6-isopropylpyridazine (0.45 g , 3.28 mmol) was added and the mixture was heated and stirred at 80 to 90 ° C for 5 hours, and then the reaction solution was concentrated to dryness. The obtained solid and phosphorus oxychloride (5.0 ml) were stirred in a sealed tube reactor at 150 ° C. for 12 hours. After cooling to room temperature, the mixture was poured into 40-50 ° C. water (50.0 ml) to decompose excess phosphorus oxychloride. After adjusting the pH to 7 with a 20% aqueous sodium hydroxide solution, the mixture was extracted three times with ethyl acetate, and the combined extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: chloroform = 1: 2) to obtain the desired product as pale yellow crystals. Yield 0.15 g (23.4%)
mp 69-71 ℃
¹ H NMR (CDCl ₃ , δ): 1.34 (6H, d, J = 7.0 Hz), 3.11 (1H, sept, J = 7.0 Hz), 6.99 (1H, d, J = 9.4 Hz), 7.75-7.8 ( 2H, m).
IR (Nujol, cm ^-1 ): 3128, 3050, 1545, 1347, 1327, 1306, 1275, 1257, 1192, 1140, 1088, 1044, 961.

実施例４の２−クロロ−６−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジンの代わりに２−クロロ−６−イソプロピルイミダゾ［１，２−ｂ］ピリダジンを用いて同様の反応を行い、目的物を淡褐色結晶として得た。収率28.5%
mp 179-180℃(dec.)
¹H NMR(DMSO-d₆, δ): 1.33(6H, d, J=6.9 Hz), 3.28(1H, sept, J=6.9 Hz), 7.61(1H, d, J=9.5 Hz), 7.77(2H, brs), 8.21(1H, d, J=9.5 Hz).
IR(Nujol, cm^-1): 3347, 1549, 1460, 1379, 1366, 1357, 1331, 1317, 1254, 1174, 1166, 1069, 1036, 903, 826. Synthesis of 2-chloro-6-isopropylimidazo [1,2-b] pyridazin-3-ylsulfonamide

The same reaction was carried out using 2-chloro-6-isopropylimidazo [1,2-b] pyridazine instead of 2-chloro-6-n-propylimidazo [1,2-b] pyridazine of Example 4. The desired product was obtained as light brown crystals. Yield 28.5%
mp 179-180 ℃ (dec.)
¹ H NMR (DMSO-d ₆ , δ): 1.33 (6H, d, J = 6.9 Hz), 3.28 (1H, sept, J = 6.9 Hz), 7.61 (1H, d, J = 9.5 Hz), 7.77 ( 2H, brs), 8.21 (1H, d, J = 9.5 Hz).
IR (Nujol, cm ^-1 ): 3347, 1549, 1460, 1379, 1366, 1357, 1331, 1317, 1254, 1174, 1166, 1069, 1036, 903, 826.

実施例３のプロピルマグネシウムクロリドのテトラヒドロフラン溶液の代わりにエチルマグネシウムクロリドのテトラヒドロフラン溶液を用いて同様の反応を行い、目的物を淡黄色結晶として得た。収率66.2%
¹H NMR(CDCl₃, δ): 1.35(3H, t, J=7.6 Hz), 2.85(2H, q, J=7.6 Hz), 6.97(1H, d, J=9.3 Hz), 7.75(1H, d, J=9.3 Hz), 7.80(1H, s).
IR(Nujol, cm^-1): 3121, 3058, 1544, 1471, 1318, 1280, 1262, 1189, 1142, 1121, 1059, 983, 953, 822. Synthesis of 2-chloro-6-ethylimidazo [1,2-b] pyridazine

The same reaction was carried out using a tetrahydrofuran solution of ethylmagnesium chloride in place of the tetrahydrofuran solution of propylmagnesium chloride in Example 3 to obtain the desired product as pale yellow crystals. Yield 66.2%
¹ H NMR (CDCl ₃ , δ): 1.35 (3H, t, J = 7.6 Hz), 2.85 (2H, q, J = 7.6 Hz), 6.97 (1H, d, J = 9.3 Hz), 7.75 (1H, d, J = 9.3 Hz), 7.80 (1H, s).
IR (Nujol, cm ^-1 ): 3121, 3058, 1544, 1471, 1318, 1280, 1262, 1189, 1142, 1121, 1059, 983, 953, 822.

実施例４の２−クロロ−６−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジンの代わりに２−クロロ−６−エチルイミダゾ［１，２−ｂ］ピリダジンを用いて同様の反応を行い、目的物を淡褐色結晶として得た。収率74.1%
mp 204-205℃
¹H NMR(DMSO-d₆, δ): 1.31(3H, t, J=7.6 Hz), 2.95(2H, q, J=7.6 Hz), 7.54(1H, d, J=9.4 Hz), 7.82(2H, brs), 8.19(1H, d, J=9.4 Hz).
IR(Nujol, cm^-1): 3317, 3211, 1365, 1356, 1325, 1172, 829, 668. Synthesis of 2-chloro-6-ethylimidazo [1,2-b] pyridazin-3-ylsulfonamide

The same reaction was carried out using 2-chloro-6-ethylimidazo [1,2-b] pyridazine in place of 2-chloro-6-n-propylimidazo [1,2-b] pyridazine of Example 4. The desired product was obtained as light brown crystals. Yield 74.1%
mp 204-205 ℃
¹ H NMR (DMSO-d ₆ , δ): 1.31 (3H, t, J = 7.6 Hz), 2.95 (2H, q, J = 7.6 Hz), 7.54 (1H, d, J = 9.4 Hz), 7.82 ( 2H, brs), 8.19 (1H, d, J = 9.4 Hz).
IR (Nujol, cm ^-1 ): 3317, 3211, 1365, 1356, 1325, 1172, 829, 668.

実施例１のエチルマグネシウムブロミドのエーテル溶液の代わりにｎ−プロピルマグネシウムクロリドのエーテル溶液を用い、溶媒をエーテルとテトラヒドロフランの混合溶媒からテトラヒドロフラン溶媒に代えて同様の反応を行い、目的物を淡赤色油状物として得た。収率19.1%
¹H NMR(CDCl₃, δ): 1.00(3H, t, J=7.4 Hz), 1.7-1.9(2H, m), 2.48(3H, d, J=0.7 Hz), 2.77(2H, t, J=7.5 Hz), 6.85(1H, d, J=9.2 Hz), 7.66(1H, d, J=0.7 Hz), 7.72(1H, d, J=9.2 Hz).
IR(Nujol, cm^-1): 2961, 1541, 1464, 1326, 1296, 1153, 1124, 989, 816, 726. Synthesis of 2-methyl-6-n-propylimidazo [1,2-b] pyridazine

An ether solution of n-propylmagnesium chloride was used in place of the ether solution of ethylmagnesium bromide in Example 1, the solvent was changed from a mixed solvent of ether and tetrahydrofuran to a tetrahydrofuran solvent, and the same reaction was carried out. Obtained as a thing. Yield 19.1%
¹ H NMR (CDCl ₃ , δ): 1.00 (3H, t, J = 7.4 Hz), 1.7-1.9 (2H, m), 2.48 (3H, d, J = 0.7 Hz), 2.77 (2H, t, J = 7.5 Hz), 6.85 (1H, d, J = 9.2 Hz), 7.66 (1H, d, J = 0.7 Hz), 7.72 (1H, d, J = 9.2 Hz).
IR (Nujol, cm ^-1 ): 2961, 1541, 1464, 1326, 1296, 1153, 1124, 989, 816, 726.

実施例４の２−クロロ−６−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジンの代わりに２−メチル−６−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジンを用いて同様の反応を行い、目的物を淡褐色結晶として得た。収率14.6%
mp 178-179℃(dec.)
¹H NMR(DMSO-d₆, δ): 0.96(3H, t, J=7.3 Hz), 1.7-1.9(2H, m), 2.56(3H, s), 2.8-2.9(2H, m), 7.39(1H, d, J=9.3 Hz), 7.46(2H, brs), 8.08(1H, d, J=9.3 Hz).
IR(Nujol, cm^-1): 3384, 3327, 1543, 1508, 1420, 1348, 1327, 1309, 1162, 827. Synthesis of 2-methyl-6-n-propylimidazo [1,2-b] pyridazin-3-ylsulfonamide

The same reaction was carried out using 2-methyl-6-n-propylimidazo [1,2-b] pyridazine instead of 2-chloro-6-n-propylimidazo [1,2-b] pyridazine of Example 4. The target product was obtained as light brown crystals. Yield 14.6%
mp 178-179 ° C (dec.)
¹ H NMR (DMSO-d ₆ , δ): 0.96 (3H, t, J = 7.3 Hz), 1.7-1.9 (2H, m), 2.56 (3H, s), 2.8-2.9 (2H, m), 7.39 (1H, d, J = 9.3 Hz), 7.46 (2H, brs), 8.08 (1H, d, J = 9.3 Hz).
IR (Nujol, cm ^-1 ): 3384, 3327, 1543, 1508, 1420, 1348, 1327, 1309, 1162, 827.

実施例６の２−クロロ−６−ｎ−ブチルイミダゾ［１，２−ｂ］ピリダジンの代わりに６−クロロ−２−エチルイミダゾ［１，２−ｂ］ピリダジンを用いて同様の反応を行い、目的物を白色結晶として得た。収率11.5%
mp 201-203℃
¹H NMR(DMSO-d₆, δ): 1.27(3H, t, J=7.5 Hz), 3.01(2H, q, J=7.5 Hz), 7.59(1H, d, J=9.5 Hz), 7.74(2H, s), 8.30(1H, d, J=9.5 Hz).
IR(Nujol, cm^-1): 3347, 1520, 1503, 1462, 1448, 1346, 1298, 1171, 1134, 1076, 819, 737. Synthesis of 6-chloro-2-ethylimidazo [1,2-b] pyridazin-3-ylsulfonamide

The same reaction was carried out using 6-chloro-2-ethylimidazo [1,2-b] pyridazine instead of 2-chloro-6-n-butylimidazo [1,2-b] pyridazine of Example 6. The target product was obtained as white crystals. Yield 11.5%
mp 201-203 ℃
¹ H NMR (DMSO-d ₆ , δ): 1.27 (3H, t, J = 7.5 Hz), 3.01 (2H, q, J = 7.5 Hz), 7.59 (1H, d, J = 9.5 Hz), 7.74 ( 2H, s), 8.30 (1H, d, J = 9.5 Hz).
IR (Nujol, cm ^-1 ): 3347, 1520, 1503, 1462, 1448, 1346, 1298, 1171, 1134, 1076, 819, 737.

６０％水素化ナトリウム(0.19 g, 4.75 mmol)をＤＭＦ(5.0 ml)に懸濁させ攪拌しながらエタンチオール(0.29 g, 4.6 mmol)を加えた。水素の発生が収まってから、６−クロロ−２−エチルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミド(0.30 g, 1.15 mmol)を加え５０℃で３時間攪拌した。反応終了後、水(50.0 ml)に注ぎ希塩酸でｐＨ２に調節し、析出した結晶をろ過、水洗、エーテル洗浄を行い、目的物を淡黄色結晶として得た。収量0.19 g(57.3%)
mp 164-165℃
¹H NMR(DMSO-d₆, δ): 1.26(3H, t, J=7.5 Hz), 1.37(3H, t, J=7.3 Hz), 2.98(2H, q, J=7.5 Hz), 3.31(2H, q, J=7.3 Hz), 7.31(1H, d, J=9.5 Hz), 7.39(2H, s), 8.01(1H, d, J=9.5 Hz).
IR(Nujol, cm^-1): 3384, 1353, 1336, 1301, 1163. Synthesis of 2-ethyl-6-ethylthioimidazo [1,2-b] pyridazin-3-ylsulfonamide

60% sodium hydride (0.19 g, 4.75 mmol) was suspended in DMF (5.0 ml) and ethanethiol (0.29 g, 4.6 mmol) was added with stirring. After the evolution of hydrogen had ceased, 6-chloro-2-ethylimidazo [1,2-b] pyridazin-3-ylsulfonamide (0.30 g, 1.15 mmol) was added and stirred at 50 ° C. for 3 hours. After completion of the reaction, the reaction mixture was poured into water (50.0 ml) and adjusted to pH 2 with dilute hydrochloric acid, and the precipitated crystals were filtered, washed with water, and washed with ether to obtain the desired product as pale yellow crystals. Yield 0.19 g (57.3%)
mp 164-165 ℃
¹ H NMR (DMSO-d ₆ , δ): 1.26 (3H, t, J = 7.5 Hz), 1.37 (3H, t, J = 7.3 Hz), 2.98 (2H, q, J = 7.5 Hz), 3.31 ( 2H, q, J = 7.3 Hz), 7.31 (1H, d, J = 9.5 Hz), 7.39 (2H, s), 8.01 (1H, d, J = 9.5 Hz).
IR (Nujol, cm ^-1 ): 3384, 1353, 1336, 1301, 1163.

実施例４２の６−クロロ−２−エチルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドの代わりに６−クロロ−２−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドを、エタンチオールの代わりにメタンチオールを用いて同様の反応を行い、目的物を淡黄色結晶として得た。収率73.3%
mp 185-187℃
¹H NMR(DMSO-d₆, δ): 0.93(3H, t, J=7.4 Hz), 1.6-1.8(2H, m), 2.67(3H, s), 2.94(2H, t, J=7.4 Hz), 7.36(1H, d, J=9.5 Hz), 7.39(2H, brs), 8.01(1H, d, J=9.5 Hz).
IR(Nujol, cm^-1): 3378, 1536, 1446, 1307, 1171, 823, 616. Synthesis of 6-methylthio-2-n-propylimidazo [1,2-b] pyridazin-3-ylsulfonamide

Instead of 6-chloro-2-ethylimidazo [1,2-b] pyridazin-3-ylsulfonamide of Example 42, 6-chloro-2-n-propylimidazo [1,2-b] pyridazine-3- A similar reaction was carried out using ylsulfonamide using methanethiol instead of ethanethiol to obtain the desired product as pale yellow crystals. Yield 73.3%
mp 185-187 ℃
¹ H NMR (DMSO-d ₆ , δ): 0.93 (3H, t, J = 7.4 Hz), 1.6-1.8 (2H, m), 2.67 (3H, s), 2.94 (2H, t, J = 7.4 Hz ), 7.36 (1H, d, J = 9.5 Hz), 7.39 (2H, brs), 8.01 (1H, d, J = 9.5 Hz).
IR (Nujol, cm ^-1 ): 3378, 1536, 1446, 1307, 1171, 823, 616.

実施例４２の６−クロロ−２−エチルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドの代わりに６−クロロ−２−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドを、エタンチオールの代わりにエタノールを用いて同様の反応を行い、目的物を淡黄色結晶として得た。収率77.7%
mp 170-176℃
¹H NMR(DMSO-d₆, δ): 0.93(3H, t, J=7.4 Hz), 1.39(3H, t, J=7.0 Hz), 1.6-1.8(2H, m), 2.91(2H, t, J=7.4 Hz), 4.48(2H, q, J=7.0 Hz), 7.06(1H, d, J=9.7 Hz), 7.40(2H, brs), 8.06(1H, d, J=9.7 Hz).
IR(Nujol, cm^-1): 3351, 1551, 1504, 1346, 1166, 823, 629. Synthesis of 6-ethoxy-2-n-propylimidazo [1,2-b] pyridazin-3-ylsulfonamide

Instead of 6-chloro-2-ethylimidazo [1,2-b] pyridazin-3-ylsulfonamide of Example 42, 6-chloro-2-n-propylimidazo [1,2-b] pyridazine-3- The same reaction was carried out using ylsulfonamide in ethanol instead of ethanethiol to obtain the target product as pale yellow crystals. Yield 77.7%
mp 170-176 ℃
¹ H NMR (DMSO-d ₆ , δ): 0.93 (3H, t, J = 7.4 Hz), 1.39 (3H, t, J = 7.0 Hz), 1.6-1.8 (2H, m), 2.91 (2H, t , J = 7.4 Hz), 4.48 (2H, q, J = 7.0 Hz), 7.06 (1H, d, J = 9.7 Hz), 7.40 (2H, brs), 8.06 (1H, d, J = 9.7 Hz).
IR (Nujol, cm ^-1 ): 3351, 1551, 1504, 1346, 1166, 823, 629.

６−クロロ−２−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミド(0.50 g, 1.81 mmol)、５０％ジメチルアミン水溶液(1.0 ml)およびｔ−ブタノール(5.0 ml)の混合物を封管反応器中１００℃で８時間加熱攪拌した。室温まで放冷後、水(50.0 ml)に注ぎ希塩酸でｐＨ６として析出した結晶をろ過、水洗して、目的物を淡黄色結晶として得た。収量0.38 g(74.0%)
mp 215-217℃
¹H NMR(DMSO-d₆, δ): 0.92(3H, t, J=7.3 Hz), 1.6-1.8(2H, m), 2.87(2H, t, J=7.4 Hz), 3.00(6H, s), 7.13(2H, brs), 7.20(1H, d, J=10.0 Hz), 7.86(1H, d, J=10.0 Hz).
IR(Nujol, cm^-1): 3340, 1565, 1501, 1345, 1318, 1163, 810, 623. Synthesis of 6-dimethylamino-2-n-propylimidazo [1,2-b] pyridazin-3-ylsulfonamide

Of 6-chloro-2-n-propylimidazo [1,2-b] pyridazin-3-ylsulfonamide (0.50 g, 1.81 mmol), 50% aqueous dimethylamine (1.0 ml) and t-butanol (5.0 ml). The mixture was heated and stirred at 100 ° C. for 8 hours in a sealed tube reactor. After allowing to cool to room temperature, the mixture was poured into water (50.0 ml), and the precipitated crystals were adjusted to pH 6 with dilute hydrochloric acid and filtered and washed with water to obtain the desired product as pale yellow crystals. Yield 0.38 g (74.0%)
mp 215-217 ℃
¹ H NMR (DMSO-d ₆ , δ): 0.92 (3H, t, J = 7.3 Hz), 1.6-1.8 (2H, m), 2.87 (2H, t, J = 7.4 Hz), 3.00 (6H, s ), 7.13 (2H, brs), 7.20 (1H, d, J = 10.0 Hz), 7.86 (1H, d, J = 10.0 Hz).
IR (Nujol, cm ^-1 ): 3340, 1565, 1501, 1345, 1318, 1163, 810, 623.

６−クロロ−２−トリフルオロメチルイミダゾ［１，２−ｂ］ピリダジン(6.00 g, 27.1mmol)を１，１，２，２−テトラクロロエタン(60.0 ml)に溶かし室温で攪拌しながらクロロスルホン酸(97%, 2.80 ml, 40.7 mmol)を加えた。８時間加熱還流した後、室温に戻しトリエチルアミン(4.39 g, 43.4mmol)とオキシ塩化リン(7.47 g, 48.7 mmol)を滴下した。反応混合物を１２０℃で３時間加熱攪拌した後、５０℃まで冷却して水(150 ml)を加えた。分液後、水層よりクロロホルムで２回抽出を行い、有機層を全て合わせて２回水洗して無水硫酸マグネシウムで乾燥し減圧濃縮した。残留物をアセトニトリル(100 ml)に溶かし室温で攪拌しながらアンモニア水(14M, 9.00 ml, 126 mmol)を加えた。室温で２時間攪拌後、反応液を氷水(400 ml)に注ぎ濃塩酸でｐＨ２に調節して析出結晶をろ過、水洗した。結晶を乾燥後、シリカゲルカラムクロマトグラフィー（酢酸エチル：クロロホルム＝１：９→１：４→１：２）で精製して、目的物を無色結晶として得た。収量3.80 g(46.6%)
mp 223.0-223.5℃
¹H NMR(DMSO-d₆, δ): 7.77(1H, d, J=9.6 Hz), 8.20(2H, brs), 8.52(1H, d, J=9.6 Hz).
¹⁹F NMR(DMSO-d₆, δ): -58.48
IR(Nujol, cm^-1): 3177, 3104, 3089, 3069, 1568, 1530, 1452, 1385, 1371, 1361, 1307, 1243, 1173, 1157, 1133, 1119, 1041, 928, 840. Synthesis of 6-chloro-2-trifluoromethylimidazo [1,2-b] pyridazin-3-ylsulfonamide

6-Chloro-2-trifluoromethylimidazo [1,2-b] pyridazine (6.00 g, 27.1 mmol) was dissolved in 1,1,2,2-tetrachloroethane (60.0 ml) and stirred at room temperature with chlorosulfonic acid (97%, 2.80 ml, 40.7 mmol) was added. After heating to reflux for 8 hours, the temperature was returned to room temperature, and triethylamine (4.39 g, 43.4 mmol) and phosphorus oxychloride (7.47 g, 48.7 mmol) were added dropwise. The reaction mixture was stirred with heating at 120 ° C. for 3 hours, cooled to 50 ° C., and water (150 ml) was added. After separation, the aqueous layer was extracted twice with chloroform, and all the organic layers were combined, washed twice with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetonitrile (100 ml), and aqueous ammonia (14M, 9.00 ml, 126 mmol) was added with stirring at room temperature. After stirring at room temperature for 2 hours, the reaction solution was poured into ice water (400 ml), adjusted to pH 2 with concentrated hydrochloric acid, and the precipitated crystals were filtered and washed with water. The crystals were dried and purified by silica gel column chromatography (ethyl acetate: chloroform = 1: 9 → 1: 4 → 1: 2) to obtain the desired product as colorless crystals. Yield 3.80 g (46.6%)
mp 223.0-223.5 ℃
¹ H NMR (DMSO-d ₆ , δ): 7.77 (1H, d, J = 9.6 Hz), 8.20 (2H, brs), 8.52 (1H, d, J = 9.6 Hz).
¹⁹ F NMR (DMSO-d ₆ , δ): -58.48
IR (Nujol, cm ^-1 ): 3177, 3104, 3089, 3069, 1568, 1530, 1452, 1385, 1371, 1361, 1307, 1243, 1173, 1157, 1133, 1119, 1041, 928, 840.

６−クロロ−２−トリフルオロメチルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミド(1.00 g, 3.33 mmol)をｔ−ブチルアルコール(20.0 ml)に懸濁させ室温下攪拌しながらカリウムｔ−ブトキシド(80%, 1.40 g, 9.98 mmol)およびエタンチオール(0.54 ml, 7.29 mmol)を加えた。混合物を４時間加熱還流した後、室温まで放冷して氷水(200 ml)に注ぎｐＨ３に調節した。析出した結晶をろ過、水洗して、目的物を無色結晶として得た。収量0.54 g, 50.0%)
mp 208-210℃
¹H NMR(DMSO-d₆, δ): 1.38(3H, t, J=7.3 Hz), 3.35(2H, q, J=7.3 Hz), 7.48(1H, d, J=9.6 Hz), 7.83(2H, brs), 8.18(1H, d, J=9.6 Hz).
¹⁹F NMR(DMSO-d₆, δ): -58.22
IR(Nujol, cm^-1): 3368, 3198, 3100, 3061, 1598, 1540, 1532, 1455, 1375, 1360, 1320, 1210, 1182, 1162, 1130, 1112, 1038, 973, 916, 820. Synthesis of 6-ethylthio-2-trifluoromethylimidazo [1,2-b] pyridazin-3-ylsulfonamide

6-Chloro-2-trifluoromethylimidazo [1,2-b] pyridazin-3-ylsulfonamide (1.00 g, 3.33 mmol) was suspended in t-butyl alcohol (20.0 ml) and stirred at room temperature with potassium. t-Butoxide (80%, 1.40 g, 9.98 mmol) and ethanethiol (0.54 ml, 7.29 mmol) were added. The mixture was heated to reflux for 4 hours, allowed to cool to room temperature, poured into ice water (200 ml) and adjusted to pH 3. The precipitated crystals were filtered and washed with water to obtain the desired product as colorless crystals. (Yield 0.54 g, 50.0%)
mp 208-210 ℃
¹ H NMR (DMSO-d ₆ , δ): 1.38 (3H, t, J = 7.3 Hz), 3.35 (2H, q, J = 7.3 Hz), 7.48 (1H, d, J = 9.6 Hz), 7.83 ( 2H, brs), 8.18 (1H, d, J = 9.6 Hz).
¹⁹ F NMR (DMSO-d ₆ , δ): -58.22
IR (Nujol, cm ^-1 ): 3368, 3198, 3100, 3061, 1598, 1540, 1532, 1455, 1375, 1360, 1320, 1210, 1182, 1162, 1130, 1112, 1038, 973, 916, 820.

実施例４２の６−クロロ−２−エチルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドの代わりに６−クロロ−２−トリフルオロメチルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドを、エタンチオールの代わりにエタノールを用いて同様の反応を行い、目的物を淡黄色結晶として得た。収率83.1%
mp 191-192℃
¹H NMR(DMSO-d₆, δ): 1.41(3H, t, J=7.0 Hz), 4.55(2H, q, J=7.0 Hz), 7.25(1H, d, J=9.8 Hz), 7.88(2H, brs), 8.26(1H, d, J=9.8 Hz).
¹⁹F NMR(DMSO-d₆, δ): -58.17
IR(Nujol, cm^-1): 3370, 3266, 1618, 1558, 1522, 1493, 1473, 1388, 1371, 1324, 1315, 1296, 1234, 1203, 1180, 1165, 1147, 1122, 1041, 1024, 1003, 906, 828, 732. Synthesis of 6-ethoxy-2-trifluoromethylimidazo [1,2-b] pyridazin-3-ylsulfonamide

Instead of 6-chloro-2-ethylimidazo [1,2-b] pyridazin-3-ylsulfonamide of Example 42, 6-chloro-2-trifluoromethylimidazo [1,2-b] pyridazine-3- The same reaction was carried out using ylsulfonamide in ethanol instead of ethanethiol to obtain the target product as pale yellow crystals. Yield 83.1%
mp 191-192 ℃
¹ H NMR (DMSO-d ₆ , δ): 1.41 (3H, t, J = 7.0 Hz), 4.55 (2H, q, J = 7.0 Hz), 7.25 (1H, d, J = 9.8 Hz), 7.88 ( 2H, brs), 8.26 (1H, d, J = 9.8 Hz).
¹⁹ F NMR (DMSO-d ₆ , δ): -58.17
IR (Nujol, cm ^-1 ): 3370, 3266, 1618, 1558, 1522, 1493, 1473, 1388, 1371, 1324, 1315, 1296, 1234, 1203, 1180, 1165, 1147, 1122, 1041, 1024, 1003 , 906, 828, 732.

実施例４７のカリウムｔ−ブトキシドとエタンチオールの組み合わせの代わりにメタンチオールナトリウム塩の水溶液を用いて同様の反応を行い、目的物を無色結晶として得た。収率87.5%
mp 272-273℃
¹H NMR(DMSO-d₆, δ): 2.71(3H, s), 7.53(1H, d, J=9.6 Hz), 7.84(2H, brs), 8.18(1H, d, J=9.6 Hz).
¹⁹F NMR(DMSO-d₆, δ): -58.25
IR(Nujol, cm^-1): 3356, 3260, 3095, 3029, 1557, 1538, 1523, 1449, 1372, 1360, 1307, 1206, 1182, 1168, 1144, 1115, 1037, 929, 823. Synthesis of 6-methylthio-2-trifluoromethylimidazo [1,2-b] pyridazin-3-ylsulfonamide

The same reaction was carried out using an aqueous solution of sodium methanethiol instead of the combination of potassium t-butoxide and ethanethiol in Example 47 to obtain the desired product as colorless crystals. Yield 87.5%
mp 272-273 ℃
¹ H NMR (DMSO-d ₆ , δ): 2.71 (3H, s), 7.53 (1H, d, J = 9.6 Hz), 7.84 (2H, brs), 8.18 (1H, d, J = 9.6 Hz).
¹⁹ F NMR (DMSO-d ₆ , δ): -58.25
IR (Nujol, cm ^-1 ): 3356, 3260, 3095, 3029, 1557, 1538, 1523, 1449, 1372, 1360, 1307, 1206, 1182, 1168, 1144, 1115, 1037, 929, 823.

３−アミノ−６−メチルピリダジン(4.00 g, 27.5 mmol)と１−ブロモ−２−ブタノン(90%, 7.38 g, 44.0 mmol)を１−プロパノール(40.0 ml)中で１３時間加熱還流した。反応液を室温まで冷却し減圧濃縮した後、残留物をアセトン(50.0 ml)に溶かし２０％水酸化ナトリウム水溶液で中和した。減圧濃縮後、残留物をクロロホルムに溶かして無水硫酸マグネシウムで乾燥、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（イソプロパノール：ヘキサン＝１：２）で精製して目的物を灰色結晶として得た。収量2.33 g(39.4%)
mp 53-55℃
¹H NMR(CDCl₃, δ): 1.35(3H, t, J=7.5 Hz), 2.53(3H, s), 2.84(2H, q, J=7.5 Hz), 6.84(1H, d, J=9.2 Hz), 7.65(1H, s), 7.72(1H, d, J=9.2 Hz). Synthesis of 2-ethyl-6-methylimidazo [1,2-b] pyridazine

3-Amino-6-methylpyridazine (4.00 g, 27.5 mmol) and 1-bromo-2-butanone (90%, 7.38 g, 44.0 mmol) were heated to reflux in 1-propanol (40.0 ml) for 13 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was dissolved in acetone (50.0 ml) and neutralized with 20% aqueous sodium hydroxide solution. After concentration under reduced pressure, the residue was dissolved in chloroform, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (isopropanol: hexane = 1: 2) to obtain the desired product as gray crystals. Yield 2.33 g (39.4%)
mp 53-55 ℃
¹ H NMR (CDCl ₃ , δ): 1.35 (3H, t, J = 7.5 Hz), 2.53 (3H, s), 2.84 (2H, q, J = 7.5 Hz), 6.84 (1H, d, J = 9.2 Hz), 7.65 (1H, s), 7.72 (1H, d, J = 9.2 Hz).

実施例２の６−エチル−２−メチルイミダゾ［１，２−ｂ］ピリダジンの代わりに２−エチル−６−メチルイミダゾ［１，２−ｂ］ピリダジンを用いて同様の反応を行い、目的物を淡褐色結晶として得た。収率44.0%
mp 198-199℃
¹H NMR(DMSO-d₆, δ): 1.25(3H, t, J=7.5 Hz), 2.62(3H, s), 2.99(2H, q, J=7.5 Hz), 7.34(1H, d, J=9.3 Hz), 7.49(2H, brs), 8.08(1H, d, J=9.3 Hz).
IR(Nujol, cm^-1): 3312, 3195, 3061, 1578, 1546, 1489, 1397, 1383, 1363, 1342, 1306, 1202, 1169, 1133, 1083, 1036, 990, 906, 853, 818. Synthesis of 2-ethyl-6-methylimidazo [1,2-b] pyridazin-3-ylsulfonamide

The same reaction was carried out using 2-ethyl-6-methylimidazo [1,2-b] pyridazine instead of 6-ethyl-2-methylimidazo [1,2-b] pyridazine of Example 2 to obtain the desired product. Was obtained as light brown crystals. Yield 44.0%
mp 198-199 ℃
¹ H NMR (DMSO-d ₆ , δ): 1.25 (3H, t, J = 7.5 Hz), 2.62 (3H, s), 2.99 (2H, q, J = 7.5 Hz), 7.34 (1H, d, J = 9.3 Hz), 7.49 (2H, brs), 8.08 (1H, d, J = 9.3 Hz).
IR (Nujol, cm ^-1 ): 3312, 3195, 3061, 1578, 1546, 1489, 1397, 1383, 1363, 1342, 1306, 1202, 1169, 1133, 1083, 1036, 990, 906, 853, 818.

実施例４５の６−クロロ−２−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドの代わりに６−クロロ−２−エチルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドを用いて同様の反応を行い、目的物を無色結晶として得た。収率87.4%
mp 211-213℃
¹H NMR(DMSO-d₆, δ): 1.22(3H, t, J=7.5 Hz), 2.91(2H, q, J=7.5 Hz), 3.10(6H, s), 7.14(2H, brs), 7.19(1H, d, J=10.0 Hz), 7.85(1H, d, J=10.0 Hz).
IR(Nujol, cm^-1): 3318, 2695, 1629, 1604, 1556, 1504, 1462, 1429, 1406, 1375, 1363, 1349, 1334, 1323, 1312, 1276, 1221, 1183, 1163, 1148, 1100, 1061, 1049, 970. Synthesis of 2-ethyl-6-dimethylaminoimidazo [1,2-b] pyridazin-3-ylsulfonamide

Instead of 6-chloro-2-n-propylimidazo [1,2-b] pyridazin-3-ylsulfonamide of Example 45, 6-chloro-2-ethylimidazo [1,2-b] pyridazine-3- The same reaction was carried out using ylsulfonamide to obtain the desired product as colorless crystals. Yield 87.4%
mp 211-213 ℃
¹ H NMR (DMSO-d ₆ , δ): 1.22 (3H, t, J = 7.5 Hz), 2.91 (2H, q, J = 7.5 Hz), 3.10 (6H, s), 7.14 (2H, brs), 7.19 (1H, d, J = 10.0 Hz), 7.85 (1H, d, J = 10.0 Hz).
IR (Nujol, cm ^-1 ): 3318, 2695, 1629, 1604, 1556, 1504, 1462, 1429, 1406, 1375, 1363, 1349, 1334, 1323, 1312, 1276, 1221, 1183, 1163, 1148, 1100 , 1061, 1049, 970.

実施例４７の６−クロロ−２−トリフルオロメチルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドの代わりに６−クロロ−２−エチルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドを用い、カリウムｔ−ブトキシドとエタンチオールの組み合わせの代わりにメタンチオールナトリウム塩の水溶液を用いて同様の反応を行い、目的物を無色結晶として得た。収率78.3%
mp 196-197℃
¹H NMR(DMSO-d₆, δ): 1.26(3H, t, J=7.5 Hz), 2.67(3H, s), 2.98(2H, q, J=7.5 Hz), 7.36(1H, d, J=9.5 Hz), 7.40(2H, brs), 8.00(1H, d, J=9.5 Hz). Synthesis of 2-ethyl-6-methylthioimidazo [1,2-b] pyridazin-3-ylsulfonamide

Instead of 6-chloro-2-trifluoromethylimidazo [1,2-b] pyridazin-3-ylsulfonamide of Example 47, 6-chloro-2-ethylimidazo [1,2-b] pyridazine-3- The same reaction was performed using ylsulfonamide, using an aqueous solution of methanethiol sodium salt in place of the combination of potassium t-butoxide and ethanethiol, and the target product was obtained as colorless crystals. Yield 78.3%
mp 196-197 ℃
¹ H NMR (DMSO-d ₆ , δ): 1.26 (3H, t, J = 7.5 Hz), 2.67 (3H, s), 2.98 (2H, q, J = 7.5 Hz), 7.36 (1H, d, J = 9.5 Hz), 7.40 (2H, brs), 8.00 (1H, d, J = 9.5 Hz).

２−エチル−６−メチルチオイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミド(1.10 g, 4.04 mmol)をＤＭＦ(10.0 ml)に溶かし氷冷下攪拌しながら、ｍ−クロロ過安息香酸（略号：ｍＣＰＢＡ）(70%, 2.48 g, 10.1 mmol)を加えた。氷冷下１時間、室温下３時間攪拌した後、反応液を水(50.0 ml)に注ぎ入れ２５％アンモニア水(1.0 ml)を加えた。５分間攪拌を続けて析出した結晶をろ過、水洗して、目的物を無色結晶として得た。収量1.04 g(84.5%)
mp 225-226℃
¹H NMR(DMSO-d₆, δ): 1.29(3H, t, J=7.5 Hz), 3.09(2H, q, J=7.5 Hz), 3.63(3H, s), 7.89(2H, brs), 7.94(1H, d, J=9.5 Hz), 8.53(1H, d, J=9.5 Hz).
IR(Nujol, cm^-1): 3615, 3352, 3015, 1608, 1547, 1523, 1505, 1455, 1411, 1396, 1369, 1339, 1313, 1266, 1210, 1171, 1158, 1130, 1117, 1082, 1000, 969, 919, 826. Synthesis of 2-ethyl-6-methylsulfonylimidazo [1,2-b] pyridazin-3-ylsulfonamide

While dissolving 2-ethyl-6-methylthioimidazo [1,2-b] pyridazin-3-ylsulfonamide (1.10 g, 4.04 mmol) in DMF (10.0 ml), stirring with ice cooling, m-chloroperbenzoic acid was used. (Abbreviation: mCPBA) (70%, 2.48 g, 10.1 mmol) was added. After stirring for 1 hour under ice cooling and 3 hours at room temperature, the reaction mixture was poured into water (50.0 ml) and 25% aqueous ammonia (1.0 ml) was added. Stirring was continued for 5 minutes, and the precipitated crystals were filtered and washed with water to obtain the desired product as colorless crystals. Yield 1.04 g (84.5%)
mp 225-226 ℃
¹ H NMR (DMSO-d ₆ , δ): 1.29 (3H, t, J = 7.5 Hz), 3.09 (2H, q, J = 7.5 Hz), 3.63 (3H, s), 7.89 (2H, brs), 7.94 (1H, d, J = 9.5 Hz), 8.53 (1H, d, J = 9.5 Hz).
IR (Nujol, cm ^-1 ): 3615, 3352, 3015, 1608, 1547, 1523, 1505, 1455, 1411, 1396, 1369, 1339, 1313, 1266, 1210, 1171, 1158, 1130, 1117, 1082, 1000 , 969, 919, 826.

６−クロロ−２−エチルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミド(1.50 g, 5.75 mmol)をメタノール(30.0 ml)に懸濁させ室温で攪拌しながら、ナトリウムメトキシド(28%, 3.34 g, 17.3 mmol)を加えた。５時間加熱還流した後、反応液を氷水(200 ml)に注ぎ濃塩酸でｐＨ２に調節した。析出した結晶をろ過、水洗して、目的物を無色結晶として得た。収量1.02 g(69.3%)
mp 213-214℃
¹H NMR(DMSO-d₆, δ): 1.24(3H, t, J=7.5 Hz), 2.96(2H, q, J=7.5 Hz), 4.05(3H, s), 7.08(1H, d, J=9.6 Hz), 7.42(2H, brs), 8.06(1H, d, J=9.6 Hz). Synthesis of 2-ethyl-6-methoxyimidazo [1,2-b] pyridazin-3-ylsulfonamide

6-Chloro-2-ethylimidazo [1,2-b] pyridazin-3-ylsulfonamide (1.50 g, 5.75 mmol) was suspended in methanol (30.0 ml) and stirred at room temperature while sodium methoxide (28 %, 3.34 g, 17.3 mmol). After heating to reflux for 5 hours, the reaction mixture was poured into ice water (200 ml) and adjusted to pH 2 with concentrated hydrochloric acid. The precipitated crystals were filtered and washed with water to obtain the desired product as colorless crystals. Yield 1.02 g (69.3%)
mp 213-214 ℃
¹ H NMR (DMSO-d ₆ , δ): 1.24 (3H, t, J = 7.5 Hz), 2.96 (2H, q, J = 7.5 Hz), 4.05 (3H, s), 7.08 (1H, d, J = 9.6 Hz), 7.42 (2H, brs), 8.06 (1H, d, J = 9.6 Hz).

実施例５５のナトリウムメトキシドとメタノールの組み合わせの代わりにナトリウムエトキシドとエタノールの組み合わせを用いて同様の反応を行い、目的物を淡橙色結晶として得た。収率68.0%
mp 200-202℃
¹H NMR(DMSO-d₆, δ): 1.25(3H, t, J=7.5 Hz), 1.39(3H, t, J=7.1 Hz), 2.96(2H, q, J=7.5 Hz), 4.49(2H, q, 7.1 Hz), 7.05(1H, d, J=9.7 Hz), 7.40(2H, brs), 8.06(1H, d, J=9.7 Hz).
IR(Nujol, cm^-1): 3320, 1340, 1280, 1210, 1165, 825. Synthesis of 2-ethyl-6-ethoxyimidazo [1,2-b] pyridazin-3-ylsulfonamide

The same reaction was carried out using a combination of sodium ethoxide and ethanol in place of the combination of sodium methoxide and methanol in Example 55, and the target product was obtained as pale orange crystals. Yield 68.0%
mp 200-202 ℃
¹ H NMR (DMSO-d ₆ , δ): 1.25 (3H, t, J = 7.5 Hz), 1.39 (3H, t, J = 7.1 Hz), 2.96 (2H, q, J = 7.5 Hz), 4.49 ( 2H, q, 7.1 Hz), 7.05 (1H, d, J = 9.7 Hz), 7.40 (2H, brs), 8.06 (1H, d, J = 9.7 Hz).
IR (Nujol, cm ^-1 ): 3320, 1340, 1280, 1210, 1165, 825.

実施例５５の６−クロロ−２−エチルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドの代わりに６−クロロ−２−メチルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドを用い、ナトリウムメトキシドとメタノールの組み合わせの代わりにナトリウムエトキシドとエタノールの組み合わせを用いて同様の反応を行い、目的物を白色結晶として得た。収率92.0%
mp 225-226℃
¹H NMR(DMSO-d₆, δ): 1.39(3H, t, J=7.5 Hz), 2.55(3H, s), 4.50(2H, q, J=7.5 Hz), 7.03(1H, d, J=9.6 Hz), 7.38(2H, brs), 8.02(1H, d, J=9.6 Hz).
IR(Nujol, cm^-1): 3355, 1349, 1293, 1222, 1172, 826. Synthesis of 6-ethoxy-2-methylimidazo [1,2-b] pyridazin-3-ylsulfonamide

Instead of 6-chloro-2-ethylimidazo [1,2-b] pyridazin-3-ylsulfonamide of Example 55, 6-chloro-2-methylimidazo [1,2-b] pyridazin-3-ylsulfone Using amide, the same reaction was performed using a combination of sodium ethoxide and ethanol in place of the combination of sodium methoxide and methanol, and the target product was obtained as white crystals. Yield 92.0%
mp 225-226 ℃
¹ H NMR (DMSO-d ₆ , δ): 1.39 (3H, t, J = 7.5 Hz), 2.55 (3H, s), 4.50 (2H, q, J = 7.5 Hz), 7.03 (1H, d, J = 9.6 Hz), 7.38 (2H, brs), 8.02 (1H, d, J = 9.6 Hz).
IR (Nujol, cm ^-1 ): 3355, 1349, 1293, 1222, 1172, 826.

実施例４７の６−クロロ−２−トリフルオロメチルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドの代わりに６−クロロ−２−メチルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドを用いて同様の反応を行い、目的物を淡褐色結晶として得た。収率62.0%
mp 217-219℃
¹H NMR(DMSO-d₆, δ): 1.36(3H, t, J=7.2 Hz), 2.56(3H, s), 3.30(2H, q, J=7.2 Hz), 7.29(1H, d, J=9.3 Hz), 7.38(2H, brs), 7.97(1H, d, J=9.3 Hz).
IR(Nujol, cm^-1): 3380, 1343, 1303, 1169, 1141, 1068, 816. Synthesis of 6-ethylthio-2-methylimidazo [1,2-b] pyridazin-3-ylsulfonamide

Instead of 6-chloro-2-trifluoromethylimidazo [1,2-b] pyridazin-3-ylsulfonamide of Example 47, 6-chloro-2-methylimidazo [1,2-b] pyridazine-3- The same reaction was carried out using ylsulfonamide to obtain the desired product as light brown crystals. Yield 62.0%
mp 217-219 ℃
¹ H NMR (DMSO-d ₆ , δ): 1.36 (3H, t, J = 7.2 Hz), 2.56 (3H, s), 3.30 (2H, q, J = 7.2 Hz), 7.29 (1H, d, J = 9.3 Hz), 7.38 (2H, brs), 7.97 (1H, d, J = 9.3 Hz).
IR (Nujol, cm ^-1 ): 3380, 1343, 1303, 1169, 1141, 1068, 816.

実施例５４の２−エチル−６−メチルチオイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドの代わりに２−メチル−６−メチルチオイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドを用いて同様の反応を行い、目的物を淡黄色結晶として得た。収率84.0%
mp 245-246℃
¹H NMR(DMSO-d₆, δ): 2.69(3H, s), 3.63(3H, s), 7.88(2H, brs), 7.88(1H, d, J=9.6 Hz), 8.50(1H, d, J=9.6 Hz).
IR(Nujol, cm^-1): 3380, 1348, 1323, 1174, 1122, 778, 723. Synthesis of 2-methyl-6-methylsulfonylimidazo [1,2-b] pyridazin-3-ylsulfonamide

Instead of 2-ethyl-6-methylthioimidazo [1,2-b] pyridazin-3-ylsulfonamide of Example 54, 2-methyl-6-methylthioimidazo [1,2-b] pyridazin-3-ylsulfone The same reaction was carried out using amide to obtain the desired product as pale yellow crystals. Yield 84.0%
mp 245-246 ℃
¹ H NMR (DMSO-d ₆ , δ): 2.69 (3H, s), 3.63 (3H, s), 7.88 (2H, brs), 7.88 (1H, d, J = 9.6 Hz), 8.50 (1H, d , J = 9.6 Hz).
IR (Nujol, cm ^-1 ): 3380, 1348, 1323, 1174, 1122, 778, 723.

実施例５５の６−クロロ−２−エチルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドの代わりに２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドを用い、ナトリウムメトキシドとメタノールの組み合わせの代わりにナトリウムイソプロポキシドとイソプロパノールの組み合わせを用いて、目的物を白色結晶として得た。収率82.6%
mp 213-214℃
¹H NMR(DMSO-d₆, δ): 1.40(6H, d, J=6.0 Hz), 5.48(1H, sept, J=6.0 Hz), 7.10(1H, d, J=9.6 Hz), 7.74(2H, s), 8.09(1H, d, J=9.6 Hz). Synthesis of 2-chloro-6-isopropoxyimidazo [1,2-b] pyridazin-3-ylsulfonamide

Instead of 6-chloro-2-ethylimidazo [1,2-b] pyridazin-3-ylsulfonamide of Example 55, 2,6-dichloroimidazo [1,2-b] pyridazin-3-ylsulfonamide was used. Using the combination of sodium isopropoxide and isopropanol instead of the combination of sodium methoxide and methanol, the target product was obtained as white crystals. Yield 82.6%
mp 213-214 ℃
¹ H NMR (DMSO-d ₆ , δ): 1.40 (6H, d, J = 6.0 Hz), 5.48 (1H, sept, J = 6.0 Hz), 7.10 (1H, d, J = 9.6 Hz), 7.74 ( 2H, s), 8.09 (1H, d, J = 9.6 Hz).

２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミド(2.00 g, 7.50 mmol)とエチルアミン(50%, 10.0 ml)をアセトニトリル(100 ml)中、７０℃で８時間攪拌した。反応混合物を濃縮乾固し氷水(50.0 ml)に溶かして濃塩酸でｐＨ６に調節した。析出結晶をろ過、水洗することにより、目的物を淡黄色結晶として得た。収量1.10 g(53.3%)
mp 218-220℃
¹H NMR(DMSO-d₆, δ): 1.22(3H, t), 3.23-3.67(2H, m), 6.90(1H, d), 7.27(2H, brs), 7.67(1H, d). Synthesis of 2-chloro-6-ethylaminoimidazo [1,2-b] pyridazin-3-ylsulfonamide

2,6-Dichloroimidazo [1,2-b] pyridazin-3-ylsulfonamide (2.00 g, 7.50 mmol) and ethylamine (50%, 10.0 ml) were stirred in acetonitrile (100 ml) at 70 ° C. for 8 hours. did. The reaction mixture was concentrated to dryness, dissolved in ice water (50.0 ml), and adjusted to pH 6 with concentrated hydrochloric acid. The target crystal was obtained as a pale yellow crystal by filtering and washing the precipitated crystal with water. Yield 1.10 g (53.3%)
mp 218-220 ℃
¹ H NMR (DMSO-d ₆ , δ): 1.22 (3H, t), 3.23-3.67 (2H, m), 6.90 (1H, d), 7.27 (2H, brs), 7.67 (1H, d).

３−アミノ−６−クロロ−４−メチルピリダジン(5.50 g, 38.3 mmol)とブロモアセトン(6.90 g, 40.0 mmol)をアセトニトリル(50.0 ml)中で８時間加熱還流させた。反応液を減圧濃縮後、残渣に水(100 ml)を加え２０％水酸化ナトリウム水溶液でｐＨ９に調節し酢酸エチルで２回抽出した。抽出液を合わせて無水硫酸マグネシウムで乾燥し濃縮後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：クロロホルム＝１：２）で精製して、目的物を白色結晶として得た。収量3.80 g(54.6%)
mp 109-110℃
¹H NMR (CDCl₃, δ): 2.49-2.50(3H, m), 2.63-2.64(3H, m), 6.83-6.85(1H, m), 7.66(1H, s).
IR(Nujol, cm^-1): 3129, 1592, 1532, 1289, 1113, 1092, 985, 928, 843, 772. Synthesis of 6-chloro-2,8-dimethylimidazo [1,2-b] pyridazine

3-Amino-6-chloro-4-methylpyridazine (5.50 g, 38.3 mmol) and bromoacetone (6.90 g, 40.0 mmol) were heated to reflux in acetonitrile (50.0 ml) for 8 hours. The reaction mixture was concentrated under reduced pressure, water (100 ml) was added to the residue, pH was adjusted to 9 with 20% aqueous sodium hydroxide solution, and the mixture was extracted twice with ethyl acetate. The extracts were combined, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: chloroform = 1: 2) to obtain the desired product as white crystals. Yield 3.80 g (54.6%)
mp 109-110 ℃
¹ H NMR (CDCl ₃ , δ): 2.49-2.50 (3H, m), 2.63-2.64 (3H, m), 6.83-6.85 (1H, m), 7.66 (1H, s).
IR (Nujol, cm ^-1 ): 3129, 1592, 1532, 1289, 1113, 1092, 985, 928, 843, 772.

実施例２の６−エチル−２−メチルイミダゾ［１，２−ｂ］ピリダジンの代わりに６−クロロ−２，８−ジメチルイミダゾ［１，２−ｂ］ピリダジンを用いて同様の反応を行い、目的物を白色結晶として得た。収率51.1%
mp 247-248℃
¹H NMR(DMSO-d₆, δ): 2.59(6H, s), 7.5-7.6(1H, m), 7.71(2H, brs).
IR(Nujol, cm^-1): 3324, 3160, 3063, 1557, 1509, 1459, 1377, 1340, 1295, 1170, 1134, 1067, 933, 910, 863, 724, 613. Synthesis of 6-chloro-2,8-dimethylimidazo [1,2-b] pyridazin-3-ylsulfonamide

The same reaction was carried out using 6-chloro-2,8-dimethylimidazo [1,2-b] pyridazine instead of 6-ethyl-2-methylimidazo [1,2-b] pyridazine of Example 2. The target product was obtained as white crystals. Yield 51.1%
mp 247-248 ℃
¹ H NMR (DMSO-d ₆ , δ): 2.59 (6H, s), 7.5-7.6 (1H, m), 7.71 (2H, brs).
IR (Nujol, cm ^-1 ): 3324, 3160, 3063, 1557, 1509, 1459, 1377, 1340, 1295, 1170, 1134, 1067, 933, 910, 863, 724, 613.

実施例４５の６−クロロ−２−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドの代わりに６−クロロ−２，８−ジメチルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドを用いて同様の反応を行い、目的物を淡黄色結晶として得た。収率85.9%
mp 248-249℃
¹H NMR(DMSO-d₆, δ): 2.4-2.5(6H, m), 3.08(6H, s), 7.08(1H, s), 7.12(2H, brs).
IR(Nujol, cm^-1): 3349, 1611, 1525, 1352, 1320, 1184, 1166, 1135, 901, 763, 619. Synthesis of 2,8-dimethyl-6-dimethylaminoimidazo [1,2-b] pyridazin-3-ylsulfonamide

Instead of 6-chloro-2-n-propylimidazo [1,2-b] pyridazin-3-ylsulfonamide of Example 45, 6-chloro-2,8-dimethylimidazo [1,2-b] pyridazine- The same reaction was carried out using 3-ylsulfonamide to obtain the desired product as pale yellow crystals. Yield 85.9%
mp 248-249 ℃
¹ H NMR (DMSO-d ₆ , δ): 2.4-2.5 (6H, m), 3.08 (6H, s), 7.08 (1H, s), 7.12 (2H, brs).
IR (Nujol, cm ^-1 ): 3349, 1611, 1525, 1352, 1320, 1184, 1166, 1135, 901, 763, 619.

実施例４７の６−クロロ−２−トリフルオロメチルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドの代わりに６−クロロ−２，８−ジメチルイミダゾ［１，２−ｂ］ピリダジン−３−イルスルホンアミドを用い、エタンチオールとカリウムｔ−ブトキシドの組み合わせの代わりにメタンチオールナトリウム塩の水溶液を用いて同様の反応を行い、目的物を淡黄色結晶として得た。収率62.2%
mp 233-234℃
¹H NMR(DMSO-d₆, δ): 2.50(3H, s), 2.55(3H, s), 2.64(3H, s), 7.24-7.25(1H, m), 7.38(2H, brs).
IR(Nujol, cm^-1): 3373, 1346, 1292, 1179, 1138, 1127, 858, 730, 611. Synthesis of 2,8-dimethyl-6-methylthioimidazo [1,2-b] pyridazin-3-ylsulfonamide

Instead of 6-chloro-2-trifluoromethylimidazo [1,2-b] pyridazin-3-ylsulfonamide of Example 47, 6-chloro-2,8-dimethylimidazo [1,2-b] pyridazine- Using 3-ylsulfonamide, the same reaction was carried out using an aqueous solution of methanethiol sodium salt in place of the combination of ethanethiol and potassium t-butoxide to obtain the desired product as pale yellow crystals. Yield 62.2%
mp 233-234 ℃
¹ H NMR (DMSO-d ₆ , δ): 2.50 (3H, s), 2.55 (3H, s), 2.64 (3H, s), 7.24-7.25 (1H, m), 7.38 (2H, brs).
IR (Nujol, cm ^-1 ): 3373, 1346, 1292, 1179, 1138, 1127, 858, 730, 611.

Synthesis example 1

上記反応式に示すごとく、６−エチル−２−メチルイミダゾ[１，２−ｂ]ピリダジン−３−スルホンアミド（０．６０ｇ、２．５０ミリモル）およびフェニル Ｎ−（４，６−ジメトキシピリミジン−２−イル）カーバメート（０．７６ｇ、２．７６ミリモル）をアセトニトリル（１０ｍｌ）に懸濁し、氷冷下で撹拌しながらＤＢＵ（０．４６ｇ、３．０２ミリモル）を加えた。反応液を室温まで昇温し、同温で４時間撹拌した。反応液を氷水（１５０ｍｌ）に注ぎ入れ、濃塩酸でｐＨ３に調節した。室温で５分間撹拌後、析出した結晶を水、アセトニトリル、ジエチルエーテルの順で洗浄しながらろ取した。減圧乾燥後、目的物を無色結晶として得た。収量０．５５ｇ（５２％）、融点：１７２−１７４℃。
^１Ｈ NMR(DMSO-d₆, δppm)：1.02(3H, t, Ｊ=7.5Hz), 2.64(3H, s), 2.69(2H, q, Ｊ=7.5Hz), 3.97(6H, s), 6.03(1H, s), 7.44(1H, d, Ｊ=9.4Hz), 8.15(1H, d, Ｊ=9.4Hz), 10.56(1H, s), 13.21(1H, brs). Synthesis of 1- (4,6-dimethoxypyrimidin-2-yl) -3- (6-ethyl-2-methylmidazo [1,2-b] pyridazin-3-ylsulfonyl) urea (Compound No. 13)

As shown in the above reaction scheme, 6-ethyl-2-methylimidazo [1,2-b] pyridazine-3-sulfonamide (0.60 g, 2.50 mmol) and phenyl N- (4,6-dimethoxypyrimidine- 2-yl) carbamate (0.76 g, 2.76 mmol) was suspended in acetonitrile (10 ml) and DBU (0.46 g, 3.02 mmol) was added with stirring under ice cooling. The reaction solution was warmed to room temperature and stirred at the same temperature for 4 hours. The reaction mixture was poured into ice water (150 ml) and adjusted to pH 3 with concentrated hydrochloric acid. After stirring at room temperature for 5 minutes, the precipitated crystals were collected by filtration while washing with water, acetonitrile and diethyl ether in this order. After drying under reduced pressure, the desired product was obtained as colorless crystals. Yield 0.55 g (52%), melting point: 172-174 [deg.] C.
¹ H NMR (DMSO-d ₆ , δ ppm): 1.02 (3H, t, J = 7.5 Hz), 2.64 (3H, s), 2.69 (2H, q, J = 7.5 Hz), 3.97 (6H, s), 6.03 (1H, s), 7.44 (1H, d, J = 9.4Hz), 8.15 (1H, d, J = 9.4Hz), 10.56 (1H, s), 13.21 (1H, brs).

Synthesis example 2

上記反応式に示すごとく、２−エチル−６−エチルチオイミダゾ[１,２−ｂ]ピリダジン−3−スルホンアミド（０．１９ｇ、０．６６ミリモル）およびフェニル Ｎ−（４，６−ジメトキシピリミジン−２−イル）カーバメート（０．２０ｇ、０．７３ミリモル）をアセトニトリル(５ｍｌ)に懸濁し、室温で撹拌しながらＤＢＵ（０．１１ｇ、０．７３ミリモル）を加えた。室温で２時間撹拌後、反応液を水（５０ｍｌ）にあけ、希塩酸でｐＨ２に調節した。析出した結晶を濾取し、水、エーテルの順で結晶を洗浄した。減圧乾燥後、目的物を無色結晶として得た。収量０．１８ｇ（５８％）、融点：１６０−１６５℃（分解）。
^１Ｈ NMR(DMSO-d₆, δppm)：1.21(3H, t, Ｊ=7.5Hz), 1.31(3H, t, Ｊ=7.5Hz), 3.0-3.2(4H, m), 3.93(6H, s), 6.06(1H, s), 7.42(1H, d, Ｊ=9.5Hz), 8.09(1H, d, Ｊ=9.6Hz), 10.59(1H, brs), 12.9(1H, brs). 1- (4,6-dimethoxypyrimidin-2-yl) -3- (2-ethyl-6-ethylthioimidazo [1,2-b] pyridazin-3-ylsulfonyl) urea (compound (No. 7)) Composition

As shown in the above reaction scheme, 2-ethyl-6-ethylthioimidazo [1,2-b] pyridazine-3-sulfonamide (0.19 g, 0.66 mmol) and phenyl N- (4,6-dimethoxypyrimidine -2-yl) carbamate (0.20 g, 0.73 mmol) was suspended in acetonitrile (5 ml) and DBU (0.11 g, 0.73 mmol) was added with stirring at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was poured into water (50 ml) and adjusted to pH 2 with dilute hydrochloric acid. The precipitated crystals were collected by filtration and washed with water and ether in this order. After drying under reduced pressure, the desired product was obtained as colorless crystals. Yield 0.18 g (58%), melting point: 160-165 ° C. (decomposition).
¹ H NMR (DMSO-d ₆ , δ ppm): 1.21 (3H, t, J = 7.5 Hz), 1.31 (3H, t, J = 7.5 Hz), 3.0-3.2 (4H, m), 3.93 (6H, s ), 6.06 (1H, s), 7.42 (1H, d, J = 9.5Hz), 8.09 (1H, d, J = 9.6Hz), 10.59 (1H, brs), 12.9 (1H, brs).

Synthesis example 3

上記反応式に示すごとく、６−エトキシ−２−メチルイミダゾ[１，２−ａ]ピリジン−３−スルホンアミド（０．０４ｇ、０．１５６ミリモル）およびフェニル Ｎ−（４，６−ジメトキシピリミジン−２−イル）カーバメート（０．０４８ｇ、０．１７２ミリモル）をアセトニトリル（１ｍｌ）に懸濁し、室温で撹拌しながらＤＢＵ（０．０２６ｇ、０．１７２ミリモル）を加えた。室温で２時間撹拌後、反応液を水（２０ｍｌ）にあけ、希塩酸でｐＨ３に調節した。析出した結晶を濾取し、水、エーテルの順で結晶を洗浄した。減圧乾燥後、目的物を淡褐色結晶として得た。収量０．０６ｇ（８７％）、融点：１５９−１６４℃(分解)。
¹H NMR(DMSO-d₆, δppm)：1.38(3H, t, Ｊ=7.0Hz), 2.56(3H, s), 3.92(6H, s), 4.05(2H, q, Ｊ=6.9Hz), 6.00(1H, s), 7.3-7.5(1H, m), 7.65(1H, d, Ｊ=9.7Hz), 8.3-8.4(1H, m), 10.54(1H, brs), 12.7-13.0(1H, brs). Synthesis of 1- (4,6-dimethoxypyrimidin-2-yl) -3- (6-ethoxy-2-methylimidazo [1,2-a] pyridin-3-ylsulfonyl) urea (Compound No. 32)

As shown in the above reaction scheme, 6-ethoxy-2-methylimidazo [1,2-a] pyridine-3-sulfonamide (0.04 g, 0.156 mmol) and phenyl N- (4,6-dimethoxypyrimidine- 2-yl) carbamate (0.048 g, 0.172 mmol) was suspended in acetonitrile (1 ml) and DBU (0.026 g, 0.172 mmol) was added with stirring at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was poured into water (20 ml) and adjusted to pH 3 with dilute hydrochloric acid. The precipitated crystals were collected by filtration and washed with water and ether in this order. After drying under reduced pressure, the desired product was obtained as light brown crystals. Yield 0.06 g (87%), melting point: 159-164 ° C. (decomposition).
¹ H NMR (DMSO-d ₆ , δ ppm): 1.38 (3H, t, J = 7.0 Hz), 2.56 (3H, s), 3.92 (6H, s), 4.05 (2H, q, J = 6.9 Hz), 6.00 (1H, s), 7.3-7.5 (1H, m), 7.65 (1H, d, J = 9.7Hz), 8.3-8.4 (1H, m), 10.54 (1H, brs), 12.7-13.0 (1H, brs).

Similarly, the compounds shown in Tables 1 to 4 below and Compound No. 35 were synthesized. In addition, the compounds of Comparative 1 and 2 were also synthesized as control compounds used in later test examples. In the table, the above compound Nos. 13, 7 and 32 are also shown.

NMR data (DMSO-d ₆ , δppm)
Compound No. 1:
1.32 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 3.06 (2H, q, J = 7.5 Hz), 3.99 (6H, s), 6.02 (1H, s), 7.38 (1H, d , J = 9.3 Hz), 8.14 (1H, d, J = 9.3 Hz), 10.55 (1H, s), 13.26 (1H, brs).

Compound No. 2:
1.33 (3H, t, J = 7.5 Hz), 3.09 (2H, q, J = 7.5 Hz), 3.99 (6H, s), 6.00 (1H, s), 7.63 (1H, d, J = 9.6 Hz), 8.35 (1H, d, J = 9.6 Hz), 10.58 (1H, brs), 13.37 (1H, brs).

Compound No. 3:
1.00 (3H, t), 2.80-3.23 (2H, m), 3.96 (6H, s), 5.98 (1H, s), 6.93 (1H, d), 7.38 (1H, s), 7.80 (1H, d) , 10.60 (1H, brs), 13.02 (1H, brs).

Compound No. 4:
1.28 (3H, t, J = 7.5 Hz), 2.94 (6H, s), 2.98 (2H, q, J = 7.5 Hz), 3.92 (6H, s), 6.01 (1H, s), 7.22 (1H, d , J = 10.0 Hz), 7.90 (1H, d, J = 10.0 Hz), 10.53 (1H, s), 12.85 (1H, brs).

Compound No. 5:
1.24 (3H, t, J = 7.0 Hz), 1.31 (3H, t, J = 7.5 Hz), 3.03 (2H, q, J = 7.5 Hz), 3.94 (6H, s), 4.17 (2H, q, J = 7.0 Hz), 6.04 (1H, s), 7.11 (1H, d, J = 9.7 Hz), 8.12 (1H, d, J = 9.7 Hz), 10.57 (1H, brs), 13.00 (1H, brs).

Compound No. 6:
1.30 (3H, t, J = 7.5 Hz), 3.03 (2H, q, J = 7.5 Hz), 3.80 (3H, s), 3.92 (6H, s), 6.02 (1H, s), 7.15 (1H, d , J = 9.7 Hz), 8.10 (1H, d, J = 9.7 Hz), 10.56 (1H, s), 13.01 (1H, brs).

Compound No. 7: See Synthesis Example 2.

Compound No. 8:
1.31 (3H, t, J = 7.5 Hz), 2.47 (3H, s), 3.06 (2H, q, J = 7.5 Hz), 3.93 (6H, s), 6.04 (1H, s), 7.45 (1H, d , J = 9.6 Hz), 8.09 (1H, d, J = 9.6 Hz), 10.57 (1H, brs), 12.96 (1H, brs).

Compound No. 9:
1.36 (3H, t, J = 7.5 Hz), 3.18 (2H, q, J = 7.5 Hz), 3.26 (3H, s), 3.95 (6H, s), 5.99 (1H, s), 7.99 (1H, d , J = 9.5 Hz), 8.58 (1H, d, J = 9.5 Hz), 10.56 (1H, s), 13.34 (1H, brs).

Compound No. 10:
1.24 (3H, t, J = 7.0 Hz), 3.94 (6H, s), 4.20 (2H, q, J = 7.0 Hz), 6.06 (1H, s), 7.31 (1H, d, J = 9.8 Hz), 8.34 (1H, d, J = 9.8 Hz), 10.70 (1H, brs), 13.26 (1H, brs).

Compound No. 11:
1.24 (3H, t, J = 7.3 Hz), 3.08 (2H, q, J = 7.3 Hz), 3.94 (6H, s), 5.94 (1H, s), 7.58 (1H, d, J = 9.6 Hz), 8.28 (1H, d, J = 9.6 Hz), 10.69 (1H, brs), 13.21 (1H, brs).

Compound No. 12:
2.49 (3H, s), 3.93 (6H, s), 6.04 (1H, s), 7.63 (1H, d, J = 9.6 Hz), 8.29 (1H, d, J = 9.6 Hz), 10.69 (1H, brs ), 13.23 (1H, brs).

Compound No. 13: See Synthesis Example 1.

Compound No. 14:
2.55 (3H, s), 2.94 (6H, s), 3.92 (6H, s), 6.00 (1H, s), 7.21 (1H, d, J = 9.9 Hz), 7.85 (1H, d, J = 9.9 Hz ), 10.52 (1H, brs), 12.85 (1H, brs).

Compound No. 15:
2.46 (3H, s), 2.55 (3H, s), 2.92 (6H, s), 3.92 (6H, s), 6.02 (1H, s), 7.10-7.11 (1H, m), 10.52 (1H, s) , 12.83 (1H, s).

Compound No. 16:
1.26 (3H, t, J = 7.5 Hz), 2.63 (3H, s), 3.96 (6H, s), 4.21 (2H, q, J = 7.5 Hz), 6.02 (1H, s), 7.11 (1H, d , J = 9.9 Hz), 8.10 (1H, d, J = 9.9 Hz), 10.54 (1H, brs), 13.00 (1H, brs).

Compound No. 17:
2.60 (3H, s), 3.81 (3H, s), 3.92 (6H, s), 6.01 (1H, s), 7.14 (1H, d, J = 9.7 Hz), 8.10 (1H, d, J = 9.7 Hz ), 10.56 (1H, brs), 13.01 (1H, brs).

Compound No. 18:
1.23 (3H, t, J = 7.5 Hz), 2.63 (3H, s), 3.08 (2H, q, J = 7.5 Hz), 3.95 (6H, s), 5.99 (1H, s), 7.35 (1H, d , J = 9.6 Hz), 8.02 (1H, d, J = 9.6 Hz), 10.50 (1H, brs), 12.90 (1H, brs).

Compound No. 19:

Compound No. 20:
2.44 (3H, s), 2.50 (3H, s), 2.62 (3H, s), 3.93 (6H, s), 6.03 (1H, s), 7.32 (1H, s), 10.56 (1H, s), 12.93 (1H, s).

Compound No. 21:
2.75 (3H, s), 3.28 (3H, s), 3.96 (6H, s), 5.98 (1H, s), 7.98 (1H, d, J = 9.0 Hz), 8.56 (1H, d, J = 9.0 Hz ), 10.53 (1H, brs), 13.31 (1H, brs).

Compound No. 22:
2.97 (6H, s), 3.92 (6H, s), 5.96 (1H, s), 7.26 (1H, d, J = 10.0 Hz), 7.88 (1H, d, J = 10.0 Hz), 10.50 (1H, brs ), 12.90 (1H, brs).

Compound No. 25:
1.24 (3H, t, J = 7.3 Hz), 3.07 (2H, q, J = 7.3 Hz), 3.94 (6H, s), 6.04 (1H, s), 7.52 (1H, d, J = 9.6 Hz), 8.12 (1H, d, J = 9.6 Hz), 10.67 (1H, brs), 13.10 (1H, brs).

Compound No. 26:
2.47 (3H, s), 3.93 (6H, s), 6.03 (1H, s), 7.57 (1H, d, J = 9.6 Hz), 8.13 (1H, d, J = 9.6 Hz), 10.65 (1H, brs ), 13.12 (1H, brs).

Compound No. 27:
2.39 (3H, s), 2.48 (3H, s), 3.92 (3H, s), 6.58 (1H, s), 7.53 (1H, d, J = 9.5 Hz), 8.10 (1H, d, J = 9.5 Hz ), 10.74 (1H, brs), 13.75 (1H, brs).

Compound No. 28:
0.98 (3H, t, J = 7.4 Hz), 1.7-1.9 (2H, m), 3.04 (2H, t, J = 7.4 Hz), 3.99 (6H, s), 6.01 (1H, s), 7.63 (1H , d, J = 9.5 Hz), 8.35 (1H, d, J = 9.5 Hz), 10.58 (1H, s), 13.38 (1H, s).

Compound No. 29:
0.95 (3H, t, J = 7.3 Hz), 1.7-1.9 (2H, m), 2.9-3.0 (8H, m), 3.92 (6H, s), 6.03 (1H, s), 7.23 (1H, d, J = 10.0 Hz), 7.90 (1H, d, J = 10.0 Hz), 10.54 (1H, s), 12.9 (1H, s).

Compound No. 30:
0.97 (3H, t, J = 7.3 Hz), 1.22 (3H, t, J = 7.1 Hz), 1.7-1.9 (2H, m), 2.98 (2H, t, J = 7.4 Hz), 3.93 (6H, s ), 4.15 (2H, q, J = 7.0 Hz), 6.05 (1H, s), 7.12 (1H, d, J = 9.7 Hz), 8.13 (1H, d, J = 9.7 Hz), 10.58 (1H, s ), 13.0 (1H, s).

Compound No. 31:
0.97 (3H, t, J = 7.3 Hz), 1.7-1.9 (2H, m), 2.45 (3H, s), 3.00 (2H, t, J = 7.5 Hz), 3.93 (6H, s), 6.05 (1H , s), 7.45 (1H, d, J = 9.6 Hz), 8.09 (1H, d, J = 9.5 Hz), 10.58 (1H, s), 12.9-13.0 (1H, brs).

Compound No. 32: See Synthesis Example 3.

Synthesis example 4

25 ml ナスフラスコに、２−クロロ−６−ｎ−プロピルイミダゾ［１，２−ｂ］ピリダジン−３−スルホンアミド (0.49 g, 1.78 mmol)、フェニル Ｎ−（４，６−ジメトキシピリミジン−２−イル）カーバメート (0.55 g, 2 mmol)およびアセトニトリル（5 ml）をいれ室温で撹拌し、ＤＢＵ (0.31 g, 2 mmol)を一気に加え、室温で３時間撹拌した。反応終了後、反応液を水 (50 ml)にあけ、希塩酸でｐＨ＝２位に調節すると結晶が生成した。これを濾取し、水、アセトン、エーテルで順次洗浄した後減圧下で乾燥して目的物を淡褐色結晶として得た。収量 0.71 g(89.5%)
mp 199-201℃(dec.)
¹H NMR (DMSO-d₆, δ): 0.70(3H, t, J=7.3 Hz), 1.4-1.5(2H, m), 2.6-2.7(2H, m), 3.97(6H, s), 6.08(1H, s), 7.57(1H, d, J=9.4 Hz), 8.26(1H, d, J=9.4 Hz), 10.68(1H, brs), 13.4-13.5(1H, m).
IR (Nujol, cm^-1) : 3643, 1720, 1703, 1607, 1573, 1453, 1359, 1324, 1290, 1199, 1162, 1016, 888, 840, 629, 589, 514.
同様にして、以下の表５に示す化合物Ｎｏ．３６、３７および３９〜５２を合成した。表中には上記化合物Ｎｏ．３８も示す。 1- (2-chloro-6-n-propylimidazo [1,2-b] pyridazin-3-ylsulfonyl) -3- (4,6-dimethoxypyrimidin-2-yl) urea (Compound No. 38) Composition

To a 25 ml eggplant flask was added 2-chloro-6-n-propylimidazo [1,2-b] pyridazine-3-sulfonamide (0.49 g, 1.78 mmol), phenyl N- (4,6-dimethoxypyrimidine-2- Yl) carbamate (0.55 g, 2 mmol) and acetonitrile (5 ml) were added and stirred at room temperature. DBU (0.31 g, 2 mmol) was added all at once, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was poured into water (50 ml) and adjusted to pH = 2 with dilute hydrochloric acid to produce crystals. This was collected by filtration, washed successively with water, acetone and ether and then dried under reduced pressure to obtain the desired product as pale brown crystals. Yield 0.71 g (89.5%)
mp 199-201 ℃ (dec.)
¹ H NMR (DMSO-d ₆ , δ): 0.70 (3H, t, J = 7.3 Hz), 1.4-1.5 (2H, m), 2.6-2.7 (2H, m), 3.97 (6H, s), 6.08 (1H, s), 7.57 (1H, d, J = 9.4 Hz), 8.26 (1H, d, J = 9.4 Hz), 10.68 (1H, brs), 13.4-13.5 (1H, m).
IR (Nujol, cm ^-1 ): 3643, 1720, 1703, 1607, 1573, 1453, 1359, 1324, 1290, 1199, 1162, 1016, 888, 840, 629, 589, 514.
In the same manner, Compound No. 1 shown in Table 5 below. 36, 37 and 39-52 were synthesized. In the table, the above compound No. 38 is also shown.

ＮＭＲデータ(DMSO-d₆, δppm)
化合物No.３６：
0.71(3H, t, J=7.4 Hz), 1.4-1.5(2H, m), 2.6-2.7(5H, m), 3.97(6H, s), 6.05(1H, s), 7.43(1H, d, J=9.4 Hz), 8.15(1H, d, J=9.4 Hz), 10.5-10.6(1H, br), 13.2-13.3(1H, br).
化合物No.３７：
1.02(3H, t, J=7.5 Hz), 2.70(2H, q, J=7.5 Hz), 3.96(6H, s), 6.06(1H, s), 7.58(1H, d, J=9.4 Hz), 8.26(1H, d, J=9.4 Hz), 10.66(1H, brs), 13.39(1H, brs).

化合物No.３８：合成例４参照。

化合物No.３９：
1.09(6H, d, J=6.9 Hz), 2.64(3H, s), 2.96(1H, sept, J=6.9 Hz), 3.95(6H, s), 6.04(1H, s), 7.51(1H, d, J=9.4 Hz), 8.17(1H, d, J=9.4 Hz), 10.56(1H, brs), 13.1-13.2(1H, br).

化合物No.４０：
1.09(6H, d, J=7.0 Hz), 2.97(1H, sept, J=7.0 Hz), 3.95(6H, s), 6.06(1H, s), 7.65(1H, d, J=9.5 Hz), 8.28(1H, d, J=9.5 Hz), 10.66(1H, brs), 13.31(1H, brs).

化合物No.４１：
0.71(3H, t, J=7.4 Hz), 1.09(2H, sext, J=7.4 Hz), 1.39(2H, tt, 7.7, 7.4 Hz), 2.66(2H, t, J=7.7 Hz), 3.97(6H, s), 6.07(1H, s), 7.58(1H, d, J=9.4 Hz), 8.26(1H, d, J=9.4 Hz), 10.68(1H, brs), 13.42(1H, brs).

化合物No.４２：
0.66(6H, d, J=6.6 Hz), 1.88(1H, m), 2.53(2H, d, J=7.4 Hz), 3.97(6H, s), 6.09(1H, s), 7.56(1H, d, J=9.4 Hz), 8.26(1H, d, J=9.4 Hz), 10.68(1H, brs), 13.42(1H, brs).

化合物No.４３：
3.96(6H, s), 5.77(1H, d, J=11.0 Hz), 6.05(1H, s), 6.35(1H, d, J=17.7 Hz), 6.58(1H, dd, J=17.7, 11.0 Hz), 7.97(1H, d, Ｊ=9.6Hz), 8.32(1H, d, Ｊ=9.6Hz), 10.62(1H, brs), 13.34(1H, brs).

化合物No.４４：
0.75-0.90(2H, m), 0.90-1.05(2H, m), 2.05-2.15(1H, m), 3.96(6H, s), 6.06(1H, s), 7.53(1H, d, J=9.5 Hz), 8.19(1H, d, J=9.5 Hz), 10.64(1H, brs), 13.21(1H, brs).

化合物No.４５：
1.83(3H, dd, J=6.8, 1.6 Hz), 3.97(6H, s), 6.10(1H, s), 6.20(1H, dq, J=16.0, 1.6 Hz), 6.83(1H, dq, J=16.0, 6.8 Hz), 7.84(1H, d, J=9.6 Hz), 8.25(1H, d, J=9.6 Hz), 10.63(1H, brs), 13.36(1H, brs).

化合物No.４６：
0.72(3H, t, J=7.3 Hz), 1.48(2H, m), 2.67(2H, t, J=7.6 Hz), 3.97(6H, s), 6.06(1H, s), 7.60 (1H, d, J=9.4 Hz), 8.27(1H, d, J=9.4 Hz), 10.66(1H, s), 13.40(1H, s).

化合物No.４７：
0.73(3H, t, J=7.4 Hz), 1.51(2H, m), 2.71(2H, t, J=7.6 Hz), 3.97(6H, s), 6.08(1H, s), 7.66 (1H, d, J=9.5 Hz), 8.40(1H, d, J=9.5 Hz), 10.75(1H, brs), 13.4-13.8(1H, br).

化合物No.４８：
0.68(3H, t, J=7.3 Hz), 1.37(3H, t, J=7.3 Hz), 1.43(2H, m), 2.58(2H, t, J=7.7 Hz), 3.23(2H, q, J=7.3 Hz), 3.96(6H, s), 6.06(1H, s), 7.45 (1H, d, J=9.3 Hz), 8.18(1H, d, J=9.3 Hz), 10.57(1H, s), 13.24(1H, s).

化合物No.４９：
0.72(3H, t, J=7.3 Hz), 1.18(3H, t, J=7.3 Hz), 1.45(2H, m), 2.65(2H, t, J=7.9 Hz), 3.74(2H, q, J=7.3 Hz), 3.98(6H, s), 6.11(1H, s), 7.66 (1H, d, J=9.4 Hz), 8.45(1H, d, J=9.4 Hz), 10.77(1H, s), 13.60(1H, s).

化合物No.５０：
3.96(6H, s), 6.09(1H, s), 6.73(1H, d, J=13.7 Hz), 7.60(1H, d, J=13.7 Hz), 7.88(1H, d, J=9.6 Hz), 8.36(1H, d, J=9.6 Hz), 10.61(1H, brs), 13.31(1H, brs).

化合物No.５１：
3.94(6H, s), 6.03(1H, s), 6.85(1H, d, J=8.2 Hz), 7.01(1H, d, J=8.2 Hz), 7.92(1H, d, J=9.5 Hz), 8.38(1H, d, J=9.5 Hz), 10.62(1H, brs), 13.21(1H, brs).

化合物No.５２：
3.99(6H, s), 4.81(1H, s), 5.98(1H, s), 7.71(1H, d, J=9.4 Hz), 8.37(1H, d, J=9.4 Hz), 10.64(1H, brs), 13.52(1H, brs).

NMR data (DMSO-d ₆ , δppm)
Compound No. 36:
0.71 (3H, t, J = 7.4 Hz), 1.4-1.5 (2H, m), 2.6-2.7 (5H, m), 3.97 (6H, s), 6.05 (1H, s), 7.43 (1H, d, J = 9.4 Hz), 8.15 (1H, d, J = 9.4 Hz), 10.5-10.6 (1H, br), 13.2-13.3 (1H, br).
Compound No. 37:
1.02 (3H, t, J = 7.5 Hz), 2.70 (2H, q, J = 7.5 Hz), 3.96 (6H, s), 6.06 (1H, s), 7.58 (1H, d, J = 9.4 Hz), 8.26 (1H, d, J = 9.4 Hz), 10.66 (1H, brs), 13.39 (1H, brs).

Compound No. 38: See Synthesis Example 4.

Compound No. 39:
1.09 (6H, d, J = 6.9 Hz), 2.64 (3H, s), 2.96 (1H, sept, J = 6.9 Hz), 3.95 (6H, s), 6.04 (1H, s), 7.51 (1H, d , J = 9.4 Hz), 8.17 (1H, d, J = 9.4 Hz), 10.56 (1H, brs), 13.1-13.2 (1H, br).

Compound No. 40:
1.09 (6H, d, J = 7.0 Hz), 2.97 (1H, sept, J = 7.0 Hz), 3.95 (6H, s), 6.06 (1H, s), 7.65 (1H, d, J = 9.5 Hz), 8.28 (1H, d, J = 9.5 Hz), 10.66 (1H, brs), 13.31 (1H, brs).

Compound No. 41:
0.71 (3H, t, J = 7.4 Hz), 1.09 (2H, sext, J = 7.4 Hz), 1.39 (2H, tt, 7.7, 7.4 Hz), 2.66 (2H, t, J = 7.7 Hz), 3.97 ( 6H, s), 6.07 (1H, s), 7.58 (1H, d, J = 9.4 Hz), 8.26 (1H, d, J = 9.4 Hz), 10.68 (1H, brs), 13.42 (1H, brs).

Compound No. 42:
0.66 (6H, d, J = 6.6 Hz), 1.88 (1H, m), 2.53 (2H, d, J = 7.4 Hz), 3.97 (6H, s), 6.09 (1H, s), 7.56 (1H, d , J = 9.4 Hz), 8.26 (1H, d, J = 9.4 Hz), 10.68 (1H, brs), 13.42 (1H, brs).

Compound No. 43:
3.96 (6H, s), 5.77 (1H, d, J = 11.0 Hz), 6.05 (1H, s), 6.35 (1H, d, J = 17.7 Hz), 6.58 (1H, dd, J = 17.7, 11.0 Hz ), 7.97 (1H, d, J = 9.6Hz), 8.32 (1H, d, J = 9.6Hz), 10.62 (1H, brs), 13.34 (1H, brs).

Compound No. 44:
0.75-0.90 (2H, m), 0.90-1.05 (2H, m), 2.05-2.15 (1H, m), 3.96 (6H, s), 6.06 (1H, s), 7.53 (1H, d, J = 9.5 Hz), 8.19 (1H, d, J = 9.5 Hz), 10.64 (1H, brs), 13.21 (1H, brs).

Compound No. 45:
1.83 (3H, dd, J = 6.8, 1.6 Hz), 3.97 (6H, s), 6.10 (1H, s), 6.20 (1H, dq, J = 16.0, 1.6 Hz), 6.83 (1H, dq, J = 16.0, 6.8 Hz), 7.84 (1H, d, J = 9.6 Hz), 8.25 (1H, d, J = 9.6 Hz), 10.63 (1H, brs), 13.36 (1H, brs).

Compound No. 46:
0.72 (3H, t, J = 7.3 Hz), 1.48 (2H, m), 2.67 (2H, t, J = 7.6 Hz), 3.97 (6H, s), 6.06 (1H, s), 7.60 (1H, d , J = 9.4 Hz), 8.27 (1H, d, J = 9.4 Hz), 10.66 (1H, s), 13.40 (1H, s).

Compound No. 47:
0.73 (3H, t, J = 7.4 Hz), 1.51 (2H, m), 2.71 (2H, t, J = 7.6 Hz), 3.97 (6H, s), 6.08 (1H, s), 7.66 (1H, d , J = 9.5 Hz), 8.40 (1H, d, J = 9.5 Hz), 10.75 (1H, brs), 13.4-13.8 (1H, br).

Compound No. 48:
0.68 (3H, t, J = 7.3 Hz), 1.37 (3H, t, J = 7.3 Hz), 1.43 (2H, m), 2.58 (2H, t, J = 7.7 Hz), 3.23 (2H, q, J = 7.3 Hz), 3.96 (6H, s), 6.06 (1H, s), 7.45 (1H, d, J = 9.3 Hz), 8.18 (1H, d, J = 9.3 Hz), 10.57 (1H, s), 13.24 (1H, s).

Compound No. 49:
0.72 (3H, t, J = 7.3 Hz), 1.18 (3H, t, J = 7.3 Hz), 1.45 (2H, m), 2.65 (2H, t, J = 7.9 Hz), 3.74 (2H, q, J = 7.3 Hz), 3.98 (6H, s), 6.11 (1H, s), 7.66 (1H, d, J = 9.4 Hz), 8.45 (1H, d, J = 9.4 Hz), 10.77 (1H, s), 13.60 (1H, s).

Compound No. 50:
3.96 (6H, s), 6.09 (1H, s), 6.73 (1H, d, J = 13.7 Hz), 7.60 (1H, d, J = 13.7 Hz), 7.88 (1H, d, J = 9.6 Hz), 8.36 (1H, d, J = 9.6 Hz), 10.61 (1H, brs), 13.31 (1H, brs).

Compound No. 51:
3.94 (6H, s), 6.03 (1H, s), 6.85 (1H, d, J = 8.2 Hz), 7.01 (1H, d, J = 8.2 Hz), 7.92 (1H, d, J = 9.5 Hz), 8.38 (1H, d, J = 9.5 Hz), 10.62 (1H, brs), 13.21 (1H, brs).

Compound No. 52:
3.99 (6H, s), 4.81 (1H, s), 5.98 (1H, s), 7.71 (1H, d, J = 9.4 Hz), 8.37 (1H, d, J = 9.4 Hz), 10.64 (1H, brs ), 13.52 (1H, brs).

Formulation Example 1

  Compound No. 1 in Table 1 23 compounds 10.6 parts, ethylene glycol 5 parts, butylparaben 0.1 part, silicone emulsion (Antihome E20, Kao Corporation) 0.2 part, colloidal hydrous aluminum silicate (Kunipia F Kunimine Industry Co., Ltd.) )) 0.5 parts, sodium carboxymethylcellulose (Serogen 7A, Daiichi Kogyo Seiyaku Co., Ltd.) 0.3 parts, polyoxyalkylene allyl phenyl ether sulfate salt (Neugen EA-177, Daiichi Kogyo Seiyaku Co., Ltd.) 1 Parts, polyoxyalkylene distyryl phenyl ether (New Calgen FS-7, Takemoto Yushi Co., Ltd.) 1 part, rosin glycerin ester (Solpol 7518, Toho Chemical Co., Ltd.) 0.5 part, water 20.8 parts After mixing, wet milling with Dynomill KDL (Shinmaru Enterprise) and uniform This was made into a turbid solution, and 2 parts of sodium naphthalene sulfonate condensate (Neucalgen PS-P, Takemoto Yushi Co., Ltd.), 2 parts of didecyldimethylammonium chloride (Cathogen DDM, Daiichi Kogyo Seiyaku Co., Ltd.), polyoxy A uniform flowable agent was produced by adding a mixture of ethylene monolaurate (Emanon 1112, Kao Corporation) 15 parts and water 41 parts.

Formulation Example 2

  In Table 5, Compound No. 37 compounds 10.6 parts, ethylene glycol 5 parts, butylparaben 0.1 part, silicone emulsion (Antihome E20, Kao Corporation) 0.2 part, colloidal hydrous aluminum silicate (Kunipia F Kunimine Industry Co., Ltd.) )) 0.5 parts, sodium carboxymethylcellulose (Serogen 7A, Daiichi Kogyo Seiyaku Co., Ltd.) 0.3 parts, polyoxyalkylene allyl phenyl ether sulfate salt (Neugen EA-177, Daiichi Kogyo Seiyaku Co., Ltd.) 1 Parts, polyoxyalkylene distyryl phenyl ether (New Calgen FS-7, Takemoto Yushi Co., Ltd.) 1 part, rosin glycerin ester (Solpol 7518, Toho Chemical Co., Ltd.) 0.5 part, water 20.8 parts After mixing, wet milling with Dynomill KDL (Shinmaru Enterprise) and uniform This was made into a turbid solution, and 2 parts of sodium naphthalene sulfonate condensate (Neucalgen PS-P, Takemoto Yushi Co., Ltd.), 2 parts of didecyldimethylammonium chloride (Cathogen DDM, Daiichi Kogyo Seiyaku Co., Ltd.), polyoxy A uniform flowable agent was produced by adding a mixture of 12 parts of ethylene monolaurate (Emanon 1112, Kao Corporation) and 44 parts of water.

Formulation Example 3

  In Table 5, Compound No. 44 compounds 10.6 parts, ethylene glycol 10 parts, butylparaben 0.1 part, silicone emulsion (Antihome E20, Kao Corporation) 0.2 part, colloidal hydrous aluminum silicate (Kunipia F Kunimine Industry Co., Ltd.) )) 0.8 parts, 2 parts of polyoxyalkylene allyl phenyl ether sulfate salt (Neugen EA-177, Daiichi Kogyo Seiyaku Co., Ltd.), polyoxyalkylene distyryl phenyl ether (New Calgen FS-7, Takemoto Yushi Co., Ltd.) )) 2 parts, 1 part of rosin glycerin ester (Solpol 7518, Toho Chemical Co., Ltd.) and 73.3 parts of water were mixed, and then wet-pulverized with Dynomill KDL (manufactured by Shinmaru Enterprise) to form a uniform suspension (Flowable agent) was produced.

Formulation Example 4

  In Table 5, Compound No. 38 compounds 1.1 parts, bentonite (Kunigel V2, Kunimine Kogyo Co., Ltd.) 30 parts, calcium carbonate (charcoal Cal-O-430, Asahi Mineral Co., Ltd.) 66.4 parts, sodium polyacrylate (Toxanone GR -31A, Sanyo Chemical Industry Co., Ltd.) 2 parts and dioctyl sulfosuccinate sodium (Sanmorin OT, Sanyo Chemical Industries Co., Ltd.) 0.5 part were mixed and then mixed with water. Thereafter, this kneaded product was extruded and granulated using a screen having a diameter of 1.2 mm, dried at 60 ° C., and granules having a particle length of 0.5 to 1.7 mm were obtained.

Test example 1

結果を表７および表８に示す。 After filling the paddy field soil in a 5cm x 5cm Jiffy Pot ^TM, and receiving water, sulfonylurea herbicide-sensitive dog firefly, sulfonylurea herbicide-sensitive azena, sulfonylurea-sensitive American azena, sulfonylurea herbicide-resistant dog firefly, sulfonylurea The seeds of herbicide-resistant Azena and sulfonylurea-based herbicide-resistant American Azena are sown and cultivated under flooding conditions for a predetermined period. When the plant reaches the second leaf stage, the jiffy pot in which the plant grows is transferred to a square plastic pot having a predetermined number of 150 cm ² , and the water is made 3 cm, and then the drug diluted solution containing the compound becomes 1 g per 1 are. Apply in pot. The drug dilution solution was prepared by dissolving 1.5 g of the compound in 2 L of N, N-dimethylformamide (DMF) containing 2% (W / V) surfactant Tween 20 ^TM and diluting with water to a total volume of 10 L. It is.
The effect on various weeds is evaluated according to the criteria shown in Table 6 after 3 weeks of drug treatment.

The results are shown in Table 7 and Table 8.

Claims (16)

formula:

(Wherein R1 represents a halogen atom, R2 represents a hydrogen atom, and R3 represents a _C2-4 alkyl group or a cyclopropyl group) . The compound according to claim 1, wherein R1 is a chlorine atom . The compound according to claim 2, wherein R3 is an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group or an isobutyl group . formula:

(Wherein R1 represents a halogen atom, R2 represents a hydrogen atom, and R3 represents a _C2-4 alkyl group or a cyclopropyl group) . The compound according to claim 4, wherein R1 is a chlorine atom . 6. The compound according to claim 5, wherein R3 is an ethyl group, n-propyl group, isopropyl group, n-butyl group or isobutyl group . The compound according to claim 4, wherein R1 is a fluorine atom, R2 is a hydrogen atom, and R3 is an n-propyl group . formula:

(Wherein R1 represents a halogen atom, R2 represents a hydrogen atom, and R3 represents a _C2-4 alkyl group or a cyclopropyl group) . The compound according to claim 8, wherein R1 is a chlorine atom . The compound according to claim 9, wherein R3 is an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group or an isobutyl group . The compound according to claim 8, wherein R1 is a chlorine atom, R2 is a hydrogen atom, and R3 is an n-propyl group . The compound according to claim 8, wherein R1 is a fluorine atom, R2 is a hydrogen atom, and R3 is an n-propyl group . formula:

(Wherein R1 represents a halogen atom, R2 represents a hydrogen atom, and R3 represents a _C2-4 alkyl group or a cyclopropyl group) . The compound according to claim 13, wherein R1 is a chlorine atom . The compound according to claim 14, wherein R3 is an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, or a cyclopropyl group . The compound according to claim 13, wherein R1 is a fluorine atom, R2 is a hydrogen atom, and R3 is an n-propyl group .