JP2012512853A - 6-cycloamino-2,3-di-pyridinyl-imidazo [1,2-b] -pyridazine derivatives, their preparation and therapeutic use - Google Patents

Abstract

の６−シクロアミノ−３−（１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル）イミダゾ［１、２ｂ］ピリダジン誘導体に関する。本発明は、この調製、ならびにカゼインキナーゼ１εおよび／またはカゼインキナーゼ１δが関与する病気の治療または予防におけるこの治療用途にも関する。The present invention relates to general formula (I)

6-cycloamino-3- (1H-pyrrolo [2,3-b] pyridin-4-yl) imidazo [1,2b] pyridazine derivatives. The invention also relates to this preparation and its therapeutic use in the treatment or prevention of diseases involving casein kinase 1ε and / or casein kinase 1δ.

Description

  The present invention relates to a 6-cycloamino-2,3-dihydropyridylimidazo [1,2-b] pyridazine derivative, a process for its preparation and the treatment or prevention of diseases involving casein kinase 1ε and / or casein kinase 1δ. It relates to therapeutic use.

  One subject of the present invention is a compound corresponding to general formula (I):

式中
Ｒ_２は、ハロゲン原子およびＣ_１−６−アルキル基から選択される１つ以上の置換基で任意に置換されるピリジル基を表し；
Ｒ_３は、水素原子またはＣ_１−３−アルキル基を表し；
Ａは、１つまたは２つのＲ_ａ基で任意に置換されるＣ_１−７−アルキレン基を表し；
Ｂは、Ｒ_ｂ基で任意に置換されるＣ_１−７−アルキレン基を表し；
Ｌは、Ｒ_ｃ基またはＲ_ｄ基で任意に置換される窒素原子か、またはＲ_ｅ１基とＲ_ｄ基でもしくは２つのＲ_ｅ２基で置換される炭素原子のいずれかを表し；
ＡおよびＢの炭素原子は、１つ以上のＲ_ｆ基で任意に置換され、Ｒ_ｆ基は互いに同一であっても異なっていてもよく；
Ｒ_ａ、Ｒ_ｂ、およびＲ_ｃは、以下のように定義され：
２つのＲ_ａ基は、一緒になってＣ_１−６−アルキレン基を形成してもよく；
Ｒ_ａとＲ_ｂは、一緒になって結合またはＣ_１−６−アルキレン基を形成してもよく；
Ｒ_ａとＲ_ｃは、一緒になって結合またはＣ_１−６−アルキレン基を形成してもよく；
Ｒ_ｂとＲ_ｃは、一緒になって結合またはＣ_１−６−アルキレン基を形成してもよく；
Ｒ_ｄは、水素原子、ならびにＣ_１−６−アルキル基、Ｃ_３−７−シクロアルキル基、Ｃ_３−７−シクロアルキル−Ｃ_１−６−アルキル基、Ｃ_１−６−アルキルチオ−Ｃ_１−６−アルキル基、Ｃ_１−６−アルキルオキシ−Ｃ_１−６−アルキル基、Ｃ_１−６−フルオロアルキル基、ベンジル基、Ｃ_１−６−アシル基およびヒドロキシ−Ｃ_１−６−アルキル基から選択される基を表し；
Ｒ_ｅ１は、−ＮＲ_４Ｒ_５基または酸素原子を任意に含む環状モノアミンを表し、環状モノアミンは、フッ素原子、ならびにＣ_１−６−アルキル基、Ｃ_１−６−アルキルオキシ基およびヒドロキシル基から選択される１つ以上の置換基で任意に置換され；
２つのＲ_ｅ２基は、これらが結合した炭素原子と一緒に、酸素原子を任意に含む環状モノアミンを形成し、この環状モノアミンは１つ以上のＲ_ｆ基で任意に置換され、Ｒ_ｆ基は互いに同一であっても異なっていてもよく；
Ｒ_ｆは、Ｃ_１−６−アルキル基、Ｃ_３−７−シクロアルキル基、Ｃ_３−７−シクロアルキル−Ｃ_１−６−アルキル基、Ｃ_１−６−アルキルオキシ−Ｃ_１−６−アルキル基、ヒドロキシ−Ｃ_１−６−アルキル基、Ｃ_１−６−フルオロアルキル基またはベンジル基を表し；
Ｒ_４およびＲ_５は、互いに独立して、水素原子、またはＣ_１−６−アルキル基、Ｃ_３−７−シクロアルキル基、またはＣ_３−７−シクロアルキル−Ｃ_１−６−アルキル基を表し；
Ｒ_７およびＲ_８は、互いに独立して、水素原子またはＣ_１−６−アルキル基を表す。

In which R ₂ represents a pyridyl group optionally substituted with one or more substituents selected from a halogen atom and a C _1-6 -alkyl group;
R ₃ represents a hydrogen atom or a C _1-3 -alkyl group;
A represents a C _1-7 -alkylene group optionally substituted with one or two R _a groups;
B represents a C _1-7 -alkylene group optionally substituted with an R _b group;
L represents either a nitrogen atom optionally substituted with an R _c group or an R _d group, or a carbon atom substituted with an R _e1 group and an R _d group or with two R _e2 groups;
Carbon atoms of A and B is optionally substituted with one or more _the R _f group, _the R _f group may be the being the same or different;
R _a , R _b , and R _c are defined as follows:
Two R _a groups may be taken together to form a C _1-6 -alkylene group;
R _a and R _b together may form a bond or a C _1-6 -alkylene group;
R _a and R _c together may form a bond or a C _1-6 -alkylene group;
R _b and R _c together may form a bond or a C _1-6 -alkylene group;
R _d represents a hydrogen atom and a C _1-6 -alkyl group, a C _3-7 -cycloalkyl group, a C _3-7 -cycloalkyl-C _1-6 -alkyl group, a C _1-6 -alkylthio-C _{1. -6} -alkyl group, C _1-6 -alkyloxy-C _1-6 -alkyl group, C _1-6 -fluoroalkyl group, benzyl group, C _1-6 -acyl group and hydroxy-C _1-6 -alkyl Represents a group selected from the group;
R _e1 represents a —NR ₄ R ₅ group or a cyclic monoamine optionally containing an oxygen atom, and the cyclic monoamine is derived from a fluorine atom, and a C _1-6 -alkyl group, a C _1-6 -alkyloxy group and a hydroxyl group. Optionally substituted with one or more selected substituents;
The two R _e2 groups together with the carbon atom to which they are attached form a cyclic monoamine optionally containing an oxygen atom, which cyclic monoamine is optionally substituted with one or more R _f groups, wherein the R _f group is May be the same or different;
R _f represents a C _1-6 -alkyl group, a C _3-7 -cycloalkyl group, a C _3-7 -cycloalkyl-C _1-6 -alkyl group, a C _1-6 -alkyloxy-C _1-6- Represents an alkyl group, a hydroxy-C _1-6 -alkyl group, a C _1-6 -fluoroalkyl group or a benzyl group;
R ₄ and R ₅ each independently represent a hydrogen atom, or a C _1-6 -alkyl group, a C _3-7 -cycloalkyl group, or a C _3-7 -cycloalkyl-C _1-6 -alkyl group. Representation;
R ₇ and R ₈ each independently represent a hydrogen atom or a C _1-6 -alkyl group.

  The compound of formula (I) may contain one or more asymmetric carbon atoms. Thus, this compound can exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers and mixtures thereof including racemic mixtures also form part of the invention.

  The compounds of formula (I) can exist in the form of bases or acid addition salts. Such addition salts also form part of the present invention. These salts are advantageously prepared with pharmaceutically acceptable acids, but other acid salts useful, for example, for purifying or isolating compounds of formula (I) are also within the scope of the invention. Forming part.

  The compounds of formula (I) can also exist in the form of hydrates or solvates, ie in association or combination with one or more water molecules or solvents. Such hydrates and solvates also form part of the invention.

In the context of the present invention, the following definitions apply:
C _tz (wherein t and z can take values from 1 to 7): a carbon-based chain capable of containing from t to z carbon atoms, for example C _1-7 is 1 A carbon-based chain that can contain from 7 to 7 carbon atoms;
Alkyl: linear or branched saturated aliphatic group; for example, a C _1-6 -alkyl group is a carbon-based linear or branched chain of 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, tert-butyl, pentyl or hexyl);
Alkylene: A linear or branched saturated divalent alkyl group, such as a C _1-6 -alkylene group, is a carbon-based divalent linear or branched chain of 1 to 6 carbon atoms (eg, methylene, ethylene, 1 -Represents methylethylene or propylene);
Cycloalkyl: a cyclic alkyl group, eg, a C _3-7 -cycloalkyl group, represents a cyclic carbon-based group of 3 to 7 carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl);
Acyl: an alkyl-C (O)-group;
Hydroxyl: —OH group;
Cyclic monoamine: a saturated cyclic carbon-based chain containing one nitrogen atom;
Hydroxyalkyl: an alkyl group in which a hydrogen atom is replaced by a hydroxyl group;
Alkyloxy: —O-alkyl group;
Alkylthio: —S-alkyl group;
Fluoroalkyl: an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms;
Fluoroalkyloxy: an alkyloxy group in which one or more hydrogen atoms are replaced by fluorine atoms;
Halogen atom: fluorine atom, chlorine atom, bromine atom or iodine atom;
Aryl: A monocyclic or bicyclic aromatic group containing between 6 and 10 carbon atoms. Examples of the aryl group include a phenyl group and a naphthyl group.

  Non-limiting examples of cyclic amines or cyclic diamines formed with N, A, L and B may include in particular: aziridine, azetidine, pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, homopiperidine, decahydro Quinoline, decahydroisoquinoline, azabicycloheptane, azabicyclooctane, azabicyclononane, azaoxobicycloheptane, azathiabicycloheptane, azaoxobicyclooctane, azathiabicyclooctane, piperazine, homopiperazine, diazacyclooctane, diaza Cyclononane, diazacyclodecane, diazacycloundecane, octahydropyrrolopyrazine, octahydropyrrolodiazepine, octahydropyrrolopyrrole, octahydropyrrolopyridine, decahydride Naphthyridine, diazabicyclooctane heptane, diazabicyclooctane, diazabicyclononane, diaza spiro heptane, diaza spirooctane, diaza spiro-nonane, spiro diaza decane, diaza spiro-undecane and oxadiazine The spiro undecane.

Of the compounds of general formula (I) that are the subject of the present invention, the first group of compounds is composed of compounds of the formula:
L represents either a nitrogen atom optionally substituted with an R _c group or an R _d group, or represents a carbon atom substituted with an R _e1 group or an R _d group;
Other substituents are as defined above.

Of the compounds of general formula (I) that are the subject of the present invention, the second group of compounds is composed of compounds of the formula:
R ₂ represents a pyridyl group optionally substituted with one or more substituents selected from fluorine and methyl groups;
Other substituents are as defined above.

Of the compounds of general formula (I) that are the subject of the present invention, the third group of compounds is composed of compounds of the formula:
R ₃ represents a hydrogen atom or a methyl group;
Other substituents are as defined above.

Of the compounds of general formula (I) that are the subject of the present invention, the fourth group of compounds is composed of compounds of the formula:
R ₇ and R ₈ represent a hydrogen atom or a methyl group;
Other substituents are as defined above.

Of the compounds that are the subject of the present invention, the fifth group of compounds is composed of compounds of the formula:
A represents a C _1-7 -alkylene group optionally substituted with one or two R _a groups;
B represents a C _1-7 -alkylene group optionally substituted with an R _b group;
L represents a nitrogen atom optionally substituted with an R _c group or an R _d group;
Carbon atoms of A and B is optionally substituted with one or more _the R _f group, _the R _f group may be the being the same or different;
R _a , R _b and R _c are defined as follows:
Two R _a groups may be taken together to form a C _1-6 -alkylene group;
R _a and R _b together may form a bond or a C _1-6 -alkylene group;
R _a and R _c together may form a bond or a C _1-6 -alkylene group;
R _b and R _c together may form a bond or a C _1-6 -alkylene group;
R _d represents a hydrogen atom and a C _1-6 -alkyl group, a C _3-7 -cycloalkyl group, a C _3-7 -cycloalkyl-C _1-6 -alkyl group, a C _1-6 -alkylthio-C _{1- 6} -alkyl groups, C _1-6 -alkyloxy-C _1-6 -alkyl groups, C _1-6 -fluoroalkyl groups, benzyl groups, C _1-6 -acyl groups and hydroxy-C _1-6 -alkyl groups Represents a group selected from:
R _f represents a C _1-6 -alkyl group, a C _3-7 -cycloalkyl group, a C _3-7 -cycloalkyl-C _1-6 -alkyl group, a C _1-6 -alkyloxy-C _1-6- Represents an alkyl group, a hydroxy-C _1-6 -alkyl group, a C _1-6 -fluoroalkyl group or a benzyl group;
Other substituents are as defined above.

Of the compounds of general formula (I) that are the subject of the present invention, the sixth group of compounds is composed of compounds of the formula:
A represents a C _1-7 -alkylene group optionally substituted with one or two R _a groups;
B represents a C _1-7 -alkylene group optionally substituted with an R _b group;
L represents a carbon atom substituted with a R _e1 group and a R _d group;
Carbon atoms of A and B is optionally substituted with one or more _the R _f group, _the R _f group may be the being the same or different;
R _a , R _b and R _c are defined as follows:
Two R _a groups may be taken together to form a C _1-6 -alkylene group;
R _a and R _b together may form a bond or a C _1-6 -alkylene group;
R _a and R _c together may form a bond or a C _1-6 -alkylene group;
R _b and R _c together may form a bond or a C _1-6 -alkylene group;
R _d represents a hydrogen atom and a C _1-6 -alkyl group, a C _3-7 -cycloalkyl group, a C _3-7 -cycloalkyl-C _1-6 -alkyl group, a C _1-6 -alkylthio-C _{1- 6} -alkyl groups, C _1-6 -alkyloxy-C _1-6 -alkyl groups, C _1-6 -fluoroalkyl groups, benzyl groups, C _1-6 -acyl groups and hydroxy-C _1-6 -alkyl groups Represents a group selected from:
R _e1 represents a —NR ₄ R ₅ group or a cyclic monoamine optionally containing an oxygen atom, and the cyclic monoamine is derived from a fluorine atom, and a C _1-6 -alkyl group, a C _1-6 -alkyloxy group and a hydroxyl group. Optionally substituted with one or more selected substituents;
R _f represents a C _1-6 -alkyl group, a C _3-7 -cycloalkyl group, a C _3-7 -cycloalkyl-C _1-6 -alkyl group, a C _1-6 -alkyloxy-C _1-6- Represents an alkyl group, a hydroxy-C _1-6 -alkyl group, a C _1-6 -fluoroalkyl group or a benzyl group;
R ₄ and R ₅ each independently represent a hydrogen atom or a C _1-6 -alkyl group, a C _3-7 -cycloalkyl group or a C _3-7 -cycloalkyl-C _1-6 -alkyl group;
Other substituents are as defined above.

Of the compounds of general formula (I) that are the subject of the present invention, the seventh group of compounds is composed of compounds of the formula:
The cyclic amine formed by -N-A-LB- represents a piperazinyl or hexahydropyrrolopyrrolyl group optionally substituted with one or more C _1-6 -alkyl groups;
Other substituents are as defined above.

Of the compounds of general formula (I) that are the subject of the present invention, the eighth group of compounds is composed of compounds of the formula:
The cyclic amine formed by -N-A-L-B- represents a pyrrolidinylpiperidyl group;
R ₂ , R ₃ , R ₇ and R ₈ are as defined above.

Of the compounds of general formula (I) that are the subject of the present invention, the ninth group of compounds is composed of compounds of the formula:
The cyclic amine formed by -N-A-L-B- is (3S) -3-methylpiperazin-1-yl group, 3,3-dimethylpiperazin-1-yl group, 4-isopropylpiperazine-1- Yl, piperazin-1-yl, (3R) -3-isopropylpiperazin-1-yl or (cis) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl Represents;
Other substituents are as defined above.

Of the compounds of general formula (I) that are the subject of the present invention, the tenth group of compounds is composed of compounds of the formula:
The cyclic amine formed by -N-A-L-B- represents 4-pyrrolidin-1-ylpiperidin-1-yl;
Other substituents are as defined above.

Of the compounds of general formula (I) which are the subject of the present invention, the eleventh group of compounds is composed of compounds in the form of bases or acid addition salts, wherein:
The cyclic amine formed by -N-A-L-B- is (3S) -3-methylpiperazin-1-yl group, 3,3-dimethylpiperazin-1-yl group, 4-isopropylpiperazine-1- Yl group, piperazin-1-yl group, (3R) -3-isopropylpiperazin-1-yl group, (cis) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl group Or represents a 4-pyrrolidin-1-ylpiperidin-1-yl group;
R ₂ represents a pyridyl group optionally substituted with one or more substituents selected from fluorine and methyl groups;
R ₃ represents a hydrogen atom or a methyl group;
R ₇ and R ₈ represent a hydrogen atom or a methyl group.

Among the compounds that are the subject of the present invention, mention may be made in particular of the following:
6-[(3S) -3-methylpiperazin-1-yl] -3- (pyrid-4-yl) -2- (pyrid-3-yl) imidazo [1,2-b] pyridazine,
6-[(3S) -3-methylpiperazin-1-yl] -3- (2-methylpyrid-4-yl) -2- (pyrid-3-yl) imidazo [1,2-b] pyridazine,
6- (3,3-dimethylpiperazin-1-yl) -3- (pyrid-4-yl) -2- (pyrid-3-yl) imidazo [1,2-b] pyridazine,
6- (4-Isopropylpiperazin-1-yl) -3- (pyrid-4-yl) -2- (pyrid-3-yl) imidazo [1,2-b] pyridazine,
6- (4-Isopropylpiperazin-1-yl) -3- (2-methylpyrid-4-yl) -2- (pyrid-3-yl) imidazo [1,2-b] pyridazine,
2- (5-Fluoropyridin-3-yl) -6-[(3S) -3-methyl-piperazin-1-yl] -3- (pyrid-4-yl) -imidazo [1,2-b] pyridazine ,
2- (5-Fluoropyrid-3-yl) -6-[(3S) -3-methylpiperazin-1-yl] -3- (2-methylpyrid-4-yl) -imidazo [1,2-b] pyridazine ,
2- (5-fluoropyrid-3-yl) -6- (4-isopropylpiperazin-1-yl) -3- (pyrid-4-yl) imidazo [1,2-b] pyridazine,
6- (4-Isopropylpiperazin-1-yl) -3- (2-methylpyrid-4-yl) -2- (5-methylpyrid-3-yl) imidazo [1,2-b] pyridazine,
6-piperazin-1-yl-2,3-bis (pyrid-4-yl) imidazo [1,2-b] pyridazine,
6-[(3S) -3-methylpiperazin-1-yl] -3- (2-methylpyrid-4-yl) -2- (pyrid-4-yl) -imidazo [1,2-b] pyridazine,
6- (3,3-dimethylpiperazin-1-yl) -2,3-bis (pyrid-4-yl) imidazo [1,2-b] pyridazine,
6- (3,3-dimethylpiperazin-1-yl) -3- (2-methylpyrid-4-yl) -2- (pyrid-4-yl) imidazo [1,2-b] pyridazine,
6- (3,3-dimethylpiperazin-1-yl) -8-methyl-2,3-bis (pyrid-4-yl) imidazo [1,2-b] pyridazine,
6-[(3R) -3-isopropylpiperazin-1-yl] -2,3-bis (pyrid-4-yl) imidazo [1,2-b] pyridazine,
6- (4-Isopropylpiperazin-1-yl) -2,3-bis (pyrid-4-yl) imidazo [1,2-b] pyridazine,
6- (4-Isopropylpiperazin-1-yl) -3- (2-methylpyrid-4-yl) -2- (pyrid-4-yl) imidazo [1,2-b] pyridazine,
6-[(cis) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2-yl] -2,3-bis (pyrid-4-yl) imidazo [1,2-b] pyridazine,
2,3-bis (pyrid-4-yl) -6- (4-pyrrolidin-1-ylpiperidin-1-yl) -imidazo [1,2-b] pyridazine,
2- (2-fluoropyrid-4-yl) -6-[(3S) -3-methylpiperazin-1-yl] -3- (pyrid-4-yl) imidazo [1,2-b] pyridazine,
2- (2-fluoropyrid-4-yl) -6-[(3S) -3-methylpiperazin-1-yl] -3- (2-methylpyrid-4-yl) imidazo [1,2-b] pyridazine,
2- (2-fluoropyrid-4-yl) -6- (4-isopropylpiperazin-1-yl) -3- (pyrid-4-yl) imidazo [1,2-b] pyridazine,
2- (2-Fluoropyrid-4-yl) -6- (4-isopropylpiperazin-1-yl) -3- (2-methylpyrid-4-yl) imidazo [1,2-b] pyridazine.

  In accordance with the present invention, compounds of general formula (I) can be prepared according to the general methods described in Scheme 1 below.

一般に、スキーム１に示すとおり、一般式（Ｉ）の６−シクロアミノ−２，３−ジ−ピリジルイミダゾ［１，２−ｂ］ピリダジン誘導体（式中、Ｒ_２、Ｒ_３、Ａ、Ｌ、Ｂ、Ｒ_７およびＲ_８は上記で定義したとおりである。）は、一般式（ＩＩ）の３−（ピリド−４−イル）イミダゾ［１，２−ｂ］ピリダジン誘導体（式中、Ｒ_２、Ｒ_３、Ｒ_７およびＲ_８は上記で定義したとおりであり、Ｘ_６はハロゲンなどの脱離基を表す。）を、一般式（ＩＩａ）のアミン（式中、Ａ、Ｌ、およびＢはすでに定義したとおりである。）で処理することにより、調製することができる。この反応は、試薬を極性溶媒（ペンタノールまたはジメチルスルホキシドなど）中で加熱することにより行うことができる。

Generally, as shown in Scheme 1, 6-cycloamino-2,3-di-pyridylimidazo [1,2-b] pyridazine derivatives of general formula (I), wherein R ₂ , R ₃ , A, L, B, R ₇ and R ₈ are as defined above.) Is a 3- (pyrid-4-yl) imidazo [1,2-b] pyridazine derivative of general formula (II) wherein R ₂ , R ₃ , R ₇ and R ₈ are as defined above, X ₆ represents a leaving group such as halogen, etc., and an amine of the general formula (IIa) wherein A, L and B Can be prepared by treating with the above. This reaction can be carried out by heating the reagent in a polar solvent (such as pentanol or dimethyl sulfoxide).

The imidazo [1,2-b] pyridazine derivative of the general formula (II) is a 3-haloloymidazo [1,2-b] pyridazine derivative of the general formula (III) using a metal catalyst under Stille or Suzuki conditions ( Wherein R ₂ , X ₆ , R ₇ and R ₈ are as defined above, X ₃ represents a halogen such as bromine or iodine, more specifically iodine, and general formula (IIIa) Pyridine derivatives wherein R ₃ is as defined above and M is a trialkylstannyl group, usually a tributylstannyl group or a dihydroxyboryl or dialkyloxyboryl group, usually 4,4,5,5- Represents a tetramethyl-1,3,3,2-dioxaboran-2-yl group)).

  Coupling by the Stille method is performed, for example, by heating in a solvent (such as N, N-dimethylacetamide) in the presence of a catalyst (such as tetrakis (triphenylphosphine) palladium or copper iodide).

  The coupling by the Suzuki method is carried out in the presence of a catalyst (such as 1,1′-bis (diphenylphosphino) ferrocenedichloropalladium) and an inorganic base (such as cesium carbonate) in a mixed solvent (such as dioxane and water). Is done.

3-Haloimidazo [1,2-b] pyridazine derivatives of general formula (III) are imidazo [1,2-b] pyridazine derivatives of general formula (IV) (wherein R ₂ , X ₆ , R ₇ and R ₈ is as defined above) obtained by regioselective bromination or iodination. This reaction can be carried out using N-bromo or iodosuccinimide or iodine monochloride in a polar solvent (such as acetonitrile, tetrahydrofuran, methanol or chloroform).

  The imidazo [1,2-b] pyridazine derivatives of general formula (IV) are known (Journal of Heterocyclic Chemistry (2002), 39 (4), 737-742) or similar to methods known to those skilled in the art Can be prepared.

In a second alternative, according to Scheme 2, the 6-cycloamino-2,3-dipyridylimidazo [1,2-b] pyridazine derivative of general formula (I) as defined above is represented by the general formula (V) From the imidazo [1,2-b] pyridazine derivative (wherein R ₂ , A, L, B, R ₇ and R ₈ are as defined above).

第一のアプローチに従って、一般式（Ｖ）のイミダゾ［１，２−ｂ］ピリダジン誘導体を、一般式（Ｖａ）のピリジン誘導体（式中、Ｒ_３は上記で定義したとおりである。）とクロロギ酸アルキル（式中、アルキル基は、Ｃ_１−６−アルキルを表す、例えば、クロロギ酸エチルなど）の混合物と反応させて、一般式（ＶＩ）の誘導体（式中、Ｒ_２、Ａ、Ｌ、Ｂ、Ｒ_３、Ｒ_７およびＲ_８は上記で定義したとおりである。）とする。次いで、溶媒（トルエンなど）中、ｏｒｔｈｏ−クロラニルを用いて、一般式（ＶＩ）の誘導体を酸化して、一般式（Ｉ）の６−シクロアミノ−２，３−ビス−ピリジルイミダゾ［１，２−ｂ］ピリダジン誘導体を得る。

According to a first approach, an imidazo [1,2-b] pyridazine derivative of general formula (V) is replaced with a pyridine derivative of general formula (Va), wherein R ₃ is as defined above. Reaction with a mixture of acid alkyls (wherein the alkyl group represents C _1-6 -alkyl, for example, ethyl chloroformate, etc.) to give a derivative of general formula (VI) (wherein R ₂ , A, L , B, R ₃ , R ₇ and R ₈ are as defined above. The derivative of general formula (VI) is then oxidized with ortho-chloranil in a solvent (such as toluene) to give 6-cycloamino-2,3-bis-pyridylimidazo [1, 2-b] A pyridazine derivative is obtained.

According to a second approach, regioselective aromatic bromination or iodination of imidazo [1,2-b] pyridazine derivatives of general formula (V) leads to 3-bromo or iodoimidazo [1, 2-b] pyridazine derivatives wherein R ₂ , A, L, B, R ₇ and R ₈ are as defined above, X ₃ is a halogen such as bromine or iodine, more specifically iodine Represents). This reaction can be carried out using N-bromo or iodosuccinimide or iodine monochloride in a polar solvent (such as acetonitrile, tetrahydrofuran, methanol or chloroform).

  Then, a 3-bromo or iodoimidazo [1,2-b] pyridazine derivative of general formula (VII) and a pyridine derivative of general formula (IIIa) as defined above using a metal catalyst under Stille or Suzuki conditions The 6-cycloamino-2,3-di-pyridylimidazo [1,2-b] pyridazine derivative of general formula (I) is prepared by coupling with:

In a third alternative, according to Scheme 3, the 6-cycloamino-2,3-di-pyridylimidazo [1,2-b] pyridazine derivative of general formula (I) as defined above is represented by the general formula (I VIII) from 2-bromoimidazo [1,2-b] pyridazine derivatives (wherein A, L, B, R ₇ and R ₈ are as defined above) and can be prepared in 3 steps. .

Regioselective aromatic iodination of the imidazo [1,2-b] pyridazine derivative of the general formula (VIII) yields a 2-bromo-3-iodoimidazo [1,2-b] pyridazine derivative of the general formula (IX) ( In which A, L, B, R ₇ and R ₈ are as defined above). This reaction can be performed using N-iodosuccinimide or iodine monochloride in a polar solvent (such as acetonitrile, tetrahydrofuran, methanol, or chloroform).

Ｓｔｉｌｌｅまた鈴木条件下、一般式（ＩＸ）の２−ブロモ−３−ヨードイミダゾ［１，２−ｂ］ピリダジンと上記で定義したとおりの一般式（ＩＩＩａ）のピリジン誘導体との、金属触媒を用いた第一の位置選択的なカップリング反応により、一般式（Ｘ）の２−ブロモイミダゾ［１，２−ｂ］ピリダジン誘導体（式中、Ａ、Ｌ、Ｂ、Ｒ_３、Ｒ_７およびＲ_８は上記で定義したとおりである。）を得る。

A metal catalyst of 2-bromo-3-iodoimidazo [1,2-b] pyridazine of general formula (IX) and a pyridine derivative of general formula (IIIa) as defined above is used under Stille or Suzuki conditions. The first regioselective coupling reaction yielded a 2-bromoimidazo [1,2-b] pyridazine derivative of general formula (X) wherein A, L, B, R ₃ , R ₇ and R ₈ Is as defined above).

Finally, under Stille or Suzuki conditions, a 2-bromo-3-iodoimidazo [1,2-b] pyridazine derivative of general formula (X) and a pyridine derivative of general formula (Xa) (wherein R ₂ is As defined, M is a trialkylstannyl group, usually a tributylstannyl group or a dihydroxyboryl or dialkyloxyboryl group, usually 4,4,5,5-tetramethyl-1,3,3,2- Represents a 6-cycloamino-2,3-di-pyridyl of general formula (I) as defined above by a second coupling reaction using a metal catalyst with a dioxaboran-2-yl group) An imidazo [1,2-b] pyridazine derivative is obtained.

  Coupling by the Stille method is performed, for example, by heating in a solvent (such as N, N-dimethylacetamide) in the presence of (tetrakis (triphenylphosphine) palladium or copper iodide).

Precursor A 3-pyrid-4-ylimidazo [1,2-b] pyridazine derivative of general formula (V) as defined above is a pyridazin-3-ylamine derivative of general formula (XI) (wherein A, L, B, R ₇ and R ₈ are as defined above) and 2-bromo, chloro or iodoethane-1-one derivatives of general formula (XIa) wherein R ₂ is as defined above. And X represents a bromine, chlorine or iodine atom.) And can be prepared by condensation.

  The reaction can be performed by heating the reagent in a polar solvent (such as ethanol or butanol).

  Pyridazin-3-ylamine derivatives of general formula (XI) are known (Journal of Medicinal Chemistry (2008), 51 (12), 3507-3525) or are prepared analogously to methods known to those skilled in the art be able to.

  The 3-pyrid-4-ylimidazo [1,2-b] pyridazine derivative of general formula (V) as defined above is a 2-pyridazine derivative of general formula (VIII) as defined above under Stille or Suzuki conditions. It can also be prepared by a coupling reaction using a metal catalyst between a bromoimidazo [1,2-b] pyridazine derivative and a pyridine derivative of the general formula (Xa) as defined above.

The 2-bromo-imidazo [1,2-b] pyridazine derivative of the general formula (VIII) is a 2-bromoimidazo [1,2-b] pyridazine derivative of the general formula (XII) (wherein R ₇ and R ₈ Is as defined above, and X ₆ represents a leaving group such as halogen, more specifically chlorine.) By treating with an amine of general formula (IIa) as defined above. can do. This reaction can be performed by heating the reagent in a polar solvent (such as pentanol or dimethyl sulfoxide).

The 2-bromoimidazo [1,2-b] pyridazine derivative of the general formula (XII) is a 5-halopyridazin-3-ylamine of the general formula (XIV) (wherein X ₆ is a leaving group such as halogen, Specifically, it represents chlorine, and R ₇ and R ₈ are as defined above. Accordingly, alkylation of a 5-halopyridazin-3-ylamine derivative of general formula (XI) with 2-bromo or alkyl 2-chloroacetate (eg ethyl 2-bromoacetate) provides a general formula (XIII ) 6-amino-3-halo-1- (alkyloxycarbonylmethyl) pyridazine-1-ium hydrobromide or hydrochloride (wherein X ₆ is a leaving group such as halogen, more specifically, Represents chlorine, while R ₇ and R ₈ are as defined above). By cyclizing 6-amino-3-halo-1- (alkyloxycarbonylmethyl) pyridazine-1-ium hydrobromide or hydrochloride of general formula (XIII) with phosphorus oxybromide, A 2-bromo-3- (pyrid-4-yl) imidazo [1,2-b] pyridazine derivative of the general formula (XII) is obtained.

本明細書中上記の文章において、「脱離基」という用語は、ヘテロリシス結合開裂により、電子対を失いながら分子から容易に切断され得る基を意味する。従って、この基は、例えば、置換反応中に別の基に容易に置換することができる。このような脱離基として、例えば、ハロゲンまたは活性化ヒドロキシル基（メシル、トシル、トリフラート、アセチルなど）がある。脱離基の例、およびこれらを調製する参照は、「Ａｄｖａｎｃｅｓ ｉｎ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ」，Ｊ．Ｍａｒｃｈ，第３版，Ｗｉｌｅｙ Ｉｎｔｅｒｓｃｉｅｎｃｅ，３１０−３１６頁に見られる。

In the above text of this specification, the term “leaving group” means a group that can be easily cleaved from a molecule while losing an electron pair by heterolytic bond cleavage. Thus, this group can be easily substituted with another group, for example, during a substitution reaction. Such leaving groups include, for example, halogens or activated hydroxyl groups (mesyl, tosyl, triflate, acetyl, etc.). Examples of leaving groups, and the references to prepare them, are described in “Advanceds in Organic Chemistry”, J. MoI. March, 3rd edition, Wiley Interscience, pages 310-316.

Protecting group For compounds of general formula (I) or (IIa) as defined above, when the N-A-L-B group contains a primary or secondary amine functional group, this functional group is synthesized. In the meantime, it can be optionally protected with a protecting group (such as benzyl or t-butyloxycarbonyl).

  The following examples describe the preparation of specific compounds according to the present invention. These examples are not intended to be limiting, but only to illustrate the present invention. The numbers of the exemplified compounds indicate those given in Table 1 below in this specification. Table 1 shows the chemical structure and physical properties of a number of compounds described in the present invention.

( Compound 13): 6- (3,3-Dimethylpiperazin-1-yl) -3- (2-methylpyrid-4-yl) -2- (pyrid-4-yl) imidazo [1,2-b] pyridazine

工程１． １．６−クロロ−２−（ピリド−４−イル）イミダゾ［１，２−ｂ］ピリダジン

Step 1. 1.6-chloro-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine

還流エタノール１．５Ｌに３−アミノ−６−クロロピリダジン２４．０ｇ（８５．３ｍｍｏｌ）を加えた溶液に、４５分かけて、２−ブロモ−１−（ピリド−４−イル）エタノン臭化水素酸塩（ＣＡＳ ５４６９−６９−２）３３．２ｇ（２５６ｍｍｏｌ）を少しずつ加え、次いでトリエチルアミン１２．０ｍｌ（８５．４ｍｍｏｌ）を滴下する。混合物を３時間還流する。冷却してから、溶媒を減圧下エバポレートし、赤褐色残渣をクロロホルムと１Ｎ水酸化ナトリウム溶液３００ｍｌに取る。１５分撹拌後、混合物をろ過し、固体残渣をクロロホルムで洗う。有機層を分離し、水で洗い、硫酸ナトリウムで脱水し、溶媒をエバポレートして、褐色固体１３ｇを得る。残渣をシリカゲル５００ｇのカラムにかけ、ジクロロメタン、メタノール、およびアンモニア水の混合物（９７／３／０．３）で溶出させて精製し、ジイソプロピルエーテルに不要分を溶解させ、ろ過し、減圧下乾燥させて、６−クロロ−２−（ピリド−４−イル）イミダゾ［１，２−ｂ］ピリダジン１０．１ｇを暗ベージュ色固体として得る。

2-Bromo-1- (pyrid-4-yl) ethanone hydrogen bromide was added to a solution obtained by adding 24.0 g (85.3 mmol) of 3-amino-6-chloropyridazine to 1.5 L of refluxing ethanol over 45 minutes. 33.2 g (256 mmol) of the acid salt (CAS 5469-69-2) are added in portions and then 12.0 ml (85.4 mmol) of triethylamine are added dropwise. The mixture is refluxed for 3 hours. After cooling, the solvent is evaporated under reduced pressure and the reddish brown residue is taken up in chloroform and 300 ml of 1N sodium hydroxide solution. After stirring for 15 minutes, the mixture is filtered and the solid residue is washed with chloroform. The organic layer is separated, washed with water, dried over sodium sulfate, and the solvent is evaporated to give 13 g of a brown solid. The residue is applied to a column of 500 g of silica gel and purified by eluting with a mixture of dichloromethane, methanol, and aqueous ammonia (97/3 / 0.3). The unwanted portion is dissolved in diisopropyl ether, filtered, and dried under reduced pressure. 10.1 g of 6-chloro-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine is obtained as a dark beige solid.

m. p. 203-205 ° C
¹ H NMR (DMSO-d ₆ ) δ: 9.15 (s, 1H); 8.70 (d, 2H); 8.30 (d, 1H); 8.0 (d, 2H); 7.45 (D, 1H) ppm.

  Step 1. 2.6-Chloro-3-iodo-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine

６−クロロ−２−（ピリド−４−イル）イミダゾ［１，２−ｂ］ピリダジン１０．４ｇ（４５．１ｍｍｏｌ）をクロロホルム１Ｌに加えた溶液に、室温で、塩化ヨウ素２１．９ｇ（１３５ｍｍｏｌ）をメタノール１００ｍｌに加えたものを加える。２４時間反応させてから、混合物を飽和重炭酸ナトリウム溶液に注ぎ、得られる混合物に５％チオ硫酸ナトリウム水溶液を加えて脱色する。有機層を分離し、硫酸ナトリウムで脱水し、減圧濃縮し、アセトニトリル２００ｍｌで不要分を溶解させ、ろ過し、乾燥させて、６−クロロ−３−ヨード−２−（ピリド−４−イル）イミダゾ［１，２−ｂ］］ピリダジン１４．４ｇをベージュ色固体として得る。これは、６−クロロ−２−（ピリド−４−イル）イミダゾ［１，２−ｂ］ピリダジンを約１０％含有する。

To a solution of 10.4 g (45.1 mmol) of 6-chloro-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine in 1 L of chloroform was added 21.9 g (135 mmol) of iodine chloride at room temperature. Is added to 100 ml of methanol. After reacting for 24 hours, the mixture is poured into saturated sodium bicarbonate solution and the resulting mixture is decolorized by adding 5% aqueous sodium thiosulfate solution. The organic layer was separated, dehydrated with sodium sulfate, concentrated under reduced pressure, dissolved in 200 ml of acetonitrile, filtered and dried to give 6-chloro-3-iodo-2- (pyrid-4-yl) imidazo. 14.4 g of [1,2-b]] pyridazine are obtained as a beige solid. It contains about 10% 6-chloro-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine.

¹ H NMR (DMSO-d ₆ ) δ: 8.75 (d, 2H); 8.30 (d, 1H); 8.15 (d, 2H); 7.50 (d, 1H) ppm.

  Step 1.3. 6-Chloro-3- (2-methylpyrid-4-yl) -2- (pyrid-4-yl) imidazo [1,2-b] pyridazine

６−クロロ−２−（ピリド−４−イル）イミダゾ［１，２−ｂ］ピリダジン２．８５ｇ（６．３９ｍｍｏｌ）、（２−メチル−４−ピリジル）ボロン酸（ＣＡＳ ５７９４７６−６３−４）１．１４ｇ（６．１２ｍｍｏｌ）、および炭酸セシウム６．３ｇ（１９ｍｍｏｌ）を、テトラヒドロフランと水の混合物（９／１）４００ｍｌに加えた混合物を、アルゴンで脱気してから、これに１，１’−ビス（ジフェニルホスフィノ）フェロセンジクロロパラジウム（ＩＩ）（ＣＡＳ ７２２８７−２６−４）０．４７ｇ（０．５８ｍｍｏｌ）を加える。混合物を１８時間還流撹拌する。混合物を減圧濃縮し、残渣をクロロホルムに取る。有機相を水で洗い、硫酸ナトリウムで脱水し、溶媒を減圧下でエバポレートする。残渣をシリカゲル１１０ｇのカラムにかけ、ジクロロメタン、メタノール、およびアンモニアの混合物（９６／４／０．４）で溶出させて精製し、アセトニトリルに不要分を溶解させ、ろ過し、乾燥させて、６−クロロ−３−（２−メチルピリド−４−イル）−２−（ピリド−４−イル）イミダゾ［１，２−ｂ］ピリダジン１．３５ｇを白色粉末として得る。

6-chloro-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine 2.85 g (6.39 mmol), (2-methyl-4-pyridyl) boronic acid (CAS 579476-63-4) A mixture of 1.14 g (6.12 mmol) and 6.3 g (19 mmol) of cesium carbonate in 400 ml of a mixture of tetrahydrofuran and water (9/1) was degassed with argon, Add 0.47 g (0.58 mmol) of '-bis (diphenylphosphino) ferrocenedichloropalladium (II) (CAS 72287-26-4). The mixture is stirred at reflux for 18 hours. The mixture is concentrated under reduced pressure and the residue is taken up in chloroform. The organic phase is washed with water, dried over sodium sulfate and the solvent is evaporated under reduced pressure. Purify the residue on a 110 g column of silica gel and elute with a mixture of dichloromethane, methanol and ammonia (96/4 / 0.4), dissolve the unwanted portion in acetonitrile, filter, dry and dry with 6-chloro. 1.35 g of -3- (2-methylpyrid-4-yl) -2- (pyrid-4-yl) imidazo [1,2-b] pyridazine is obtained as a white powder.

m. p. : 218-222 ° C
¹ H NMR (DMSO-d ₆ ); δ: 8.60 (d, 1H); 8.55 (d, 2H); 7.95 (d, 1H); 7.50 (d, 2H); 35 (s, 1H); 7.25 (d, 1H); 7.15 (d, 1H); 2.60 (s, 3H) ppm.

  Step 1.4. 6- (3,3-Dimethylpiperazin-1-yl) -3- (2-methylpyrid-4-yl) -2- (pyrid-4-yl) imidazo [1,2-b] pyridazine

６−クロロ−３−（２−メチルピリド−４−イル）−２−（ピリド−４−イル）−イミダゾ［１，２−ｂ］ピリダジン０．５００ｇ（１．５５ｍｍｏｌ）および２，２−ジメチルピペラジン０．５２ｇ（４．７ｍｍｏｌ）をペンタノール５ｍｌに加えた混合物を、１５０℃で２４時間還流する。反応液を冷却し、２Ｎ塩酸水溶液に注ぐ。水相をジエチルエーテルで洗い、次いで２Ｎ水酸化ナトリウム水溶液で塩基性にし、生成物をクロロホルムで抽出する。有機層を硫酸ナトリウムで脱水し、溶媒を減圧下でエバポレートする。得られる固体をシリカゲル３５ｇにかけ、ジクロロメタン、メタノール、およびアンモニア水の混合物（９４／６／０．６）で溶出させて精製し、アセトニトリル１０ｍｌに溶解させてジエチルエーテルを加えて結晶化させ、ろ過し、乾燥させて、６−（３，３−ジメチルピペラジン−１−イル）−３−（２−メチルピリド−４−イル）−２−（ピリド−４−イル）イミダゾ［１，２−ｂ］ピリダジン０．１７ｇをベージュ色粉末として得る。

6-chloro-3- (2-methylpyrid-4-yl) -2- (pyrid-4-yl) -imidazo [1,2-b] pyridazine 0.500 g (1.55 mmol) and 2,2-dimethylpiperazine A mixture of 0.52 g (4.7 mmol) in 5 ml of pentanol is refluxed at 150 ° C. for 24 hours. Cool the reaction and pour into 2N aqueous hydrochloric acid. The aqueous phase is washed with diethyl ether, then basified with 2N aqueous sodium hydroxide solution and the product is extracted with chloroform. The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The resulting solid is applied to 35 g of silica gel and purified by eluting with a mixture of dichloromethane, methanol and aqueous ammonia (94/6 / 0.6), dissolved in 10 ml of acetonitrile, crystallized with diethyl ether and filtered. Dried, 6- (3,3-dimethylpiperazin-1-yl) -3- (2-methylpyrid-4-yl) -2- (pyrid-4-yl) imidazo [1,2-b] pyridazine 0.17 g is obtained as a beige powder.

m. p. 185-187 ° C
¹ H NMR (CDCl ₃ ); δ: 8.60 (m, 3H); 7.80 (d, 1H); 7.60 (d, 2H); 7.50 (s, 1H); 7.40 ( d, 2H); 6.95 (d, 1H); 3.45 (dd, 2H); 3.30 (s, 2H); 3.10 (dd, 2H); 2.65 (s, 3H); 1.2 (s, 6H) ppm.

(Compound 14): 6- (3,3-Dimethylpiperazin-1-yl) -8-methyl-2,3-bis (pyrid-4-yl) imidazo [1,2-b] pyridazine

  Step 2.1. 3-amino-6-chloro-4-methylpyridazine and 3-amino-6-chloro-5-methylpyridazine

オートクレーブ中、３，６−ジクロロ−４−メチルピリダジン５０．０ｇ（３０７ｍｍｏｌ）を３０％アンモニア水１７０ｍｌに加えた懸濁液を、１２０℃で１８時間加熱する。冷却してから、混合物を水２００ｍｌに注ぎ、固体をろ過して回収する。減圧下で乾燥させてから、生成物の混合物を酢酸エチルから再結晶して、３−アミノ−６−クロロ−４−メチルピリダジンと３−アミノ−６−クロロ−５−メチルピリダジンの混合物（３２／６８）４０ｇを得る。

A suspension obtained by adding 50.0 g (307 mmol) of 3,6-dichloro-4-methylpyridazine to 170 ml of 30% aqueous ammonia in an autoclave is heated at 120 ° C. for 18 hours. After cooling, the mixture is poured into 200 ml of water and the solid is recovered by filtration. After drying under reduced pressure, the product mixture was recrystallized from ethyl acetate to give a mixture of 3-amino-6-chloro-4-methylpyridazine and 3-amino-6-chloro-5-methylpyridazine (32 / 68) 40 g is obtained.

¹ H NMR (CDCl ₃ ): 7.15 and 6.75 (s and s, 1H); 5.0 (broad peak, 2H); 2.35 and 2.25 (s and s, 3H).

  Step 2.2. 6-amino-3-chloro-1-ethoxycarbonylmethyl-5-methylpyridazine-1-ium bromide and 6-amino-3-chloro-1-ethoxycarbonylmethyl-4-methylpyridazine-1-ium bromide

３−アミノ−６−クロロ−４−メチルピリダジンと３−アミノ−６−クロロ−５−メチルピリダジンの混合物（３２／６８）３６．０ｇ（２５１ｍｍｏｌ）を還流エタノール３５０ｍｌに加えた溶液に、２−ブロモ酢酸エチル３０．６ｍｌ（２７５ｍｍｏｌ）を少しずつ加え、加熱を２４時間続ける。冷却してから、反応溶媒を減圧下で部分濃縮し、次いでアセトン２００ｍｌで希釈し、懸濁液を０℃に冷却して、沈殿物をろ別する。次いで、ろ液を減圧下で部分濃縮し、アセトン１５０ｍｌで希釈し、懸濁液を再び０℃に冷却する。沈殿物をろ別し、最初の沈殿物と１つにまとめる。乾燥させてから、合計で、６−アミノ−３−クロロ−１−エトキシカルボニルメチル−４−メチルピリダジン−１−イウムブロミドと６−アミノ−３−クロロ−１−エトキシカルボニルメチル−５−メチルピリダジン−１−イウムブロミドの混合物（３０／７０）２９．８ｇを得る。

To a solution obtained by adding 36.0 g (251 mmol) of a mixture of 3-amino-6-chloro-4-methylpyridazine and 3-amino-6-chloro-5-methylpyridazine (32/68) to 350 ml of refluxing ethanol, 30.6 ml (275 mmol) of ethyl bromoacetate are added in portions and heating is continued for 24 hours. After cooling, the reaction solvent is partially concentrated under reduced pressure and then diluted with 200 ml of acetone, the suspension is cooled to 0 ° C. and the precipitate is filtered off. The filtrate is then partially concentrated under reduced pressure, diluted with 150 ml of acetone and the suspension is cooled again to 0 ° C. Filter the precipitate and combine with the first precipitate. In total, after drying, 6-amino-3-chloro-1-ethoxycarbonylmethyl-4-methylpyridazine-1-ium bromide and 6-amino-3-chloro-1-ethoxycarbonylmethyl-5-methylpyridazine- 29.8 g of a mixture of 1-ium bromide (30/70) are obtained.

¹ H NMR (MeOD): 7.90 and 7.55 (s and s, 1H); 5.30 and 5.25 (s and s, 2H); 4.35 (q, 2H); 2.50 and 2.45 (s and s, 3H); 1.35 (t, 3H).

  Step 2.3. 2-Bromo-6-chloro / bromo-7-methylimidazo [1,2-b] pyridazine and 2-bromo-6-chloro / bromo-8-methylimidazo [1,2-b] pyridazine

６−アミノ−３−クロロ−１−エトキシカルボニルメチル−４−メチルピリダジン−１−イウムと６−アミノ−３−クロロ−１−エトキシカルボニルメチル−５−メチルピリダジン−１−イウム（３０／７０）２７．８ｇ（８９．５ｍｍｏｌ）およびオキシ臭化リン８２ｇ（２８６ｍｍｏｌ）をトルエン１００ｍｌに加えた混合物を、密閉した管中で、１６０℃で１時間加熱する。冷却してから、壁面に析出した固体を剥がし、混合物を０℃で水５００ｍｌに注ぐ。次いで、水相にアンモニア水を加えて塩基性にし、１時間撹拌後、生成物をクロロホルムで溶解させる。有機層を分離し、硫酸ナトリウムで脱水し、減圧濃縮して、褐色固体２２ｇを得る。次いで、固体をシリカゲル４５０ｇのカラムにかけ、ジクロロメタンで溶出させるクロマトグラフィーで精製して、２，６−ジブロモ−８−メチルイミダゾ［１，２−ｂ］ピリダジンを含有する２−ブロモ−６−クロロ−８−メチルイミダゾ［１，２−ｂ］ピリダジン５．０ｇを白色粉末として得る（４１／５９）。

6-amino-3-chloro-1-ethoxycarbonylmethyl-4-methylpyridazine-1-ium and 6-amino-3-chloro-1-ethoxycarbonylmethyl-5-methylpyridazine-1-ium (30/70) A mixture of 27.8 g (89.5 mmol) and 82 g (286 mmol) phosphorus oxybromide in 100 ml toluene is heated in a sealed tube at 160 ° C. for 1 hour. After cooling, the solid deposited on the wall is peeled off, and the mixture is poured into 500 ml of water at 0 ° C. Next, aqueous ammonia is added to the aqueous phase to make it basic, and after stirring for 1 hour, the product is dissolved in chloroform. The organic layer is separated, dried over sodium sulfate and concentrated in vacuo to give 22 g of a brown solid. The solid is then applied to a column of 450 g silica gel and purified by chromatography eluting with dichloromethane to give 2-bromo-6-chloro- containing 2,6-dibromo-8-methylimidazo [1,2-b] pyridazine. 5.0 g of 8-methylimidazo [1,2-b] pyridazine is obtained as a white powder (41/59).

_{^{1 H NMR (CDCl 3):}} 7.80 (s, 1H); 6.85 and 7.00 (s and s, 1H); 2.55 (s , 3H).
Continuing elution with a mixture of dichloromethane, methanol, and aqueous ammonia (90/10/1), followed by 2-bromo-6-chloro containing 2,6-dibromo-7-methylimidazo [1,2-b] pyridazine / Bromo-7-methylimidazo [1,2-b] pyridazine 15.2 g is obtained as a pink powder.

¹ H NMR (CDCl ₃ ): 7.95 (s, 1H); 7.75 (s, 1H); 2.55 (s, 3H).

  Step 2.4. 2-Bromo-6- (3,3-dimethylpiperazin-1-yl) -8-methylimidazo [1,2-b] pyridazine

２，６−ジブロモ−８−メチルイミダゾ［１，２−ｂ］ピリダジンを含有する２−ブロモ−６−クロロ−８−メチルイミダゾ［１，２−ｂ］ピリダジン４．９５ｇ（約２０ｍｍｏｌ）、２，２−ジメチルピペラジン２．５ｇ（２２ｍｍｏｌ）、およびトリエチルアミン２．８ｍｌをペンタノール６０ｍｌに加えた混合物を、密閉した管中、１５０℃で３日間加熱する。冷却してから、反応液を１Ｎ塩酸水溶液に注ぐ。水相を酢酸エチルで洗い、次いでアンモニア水溶液で塩基性にし、生成物をジクロロメタンで抽出する。有機層を硫酸ナトリウムで脱水し、溶媒を減圧下でエバポレートする。得られるベージュ色固体を、シリカゲル８０ｇのカラムにかけ、ジクロロメタン、メタノール、およびアンモニア水の混合物（９５／６５／０．５）で溶出させて精製し、２−ブロモ−６−（３，３−ジメチルピペラジン−１−イル）−８−メチルイミダゾ［１，２−ｂ］ピリダジン４．６ｇを白色粉末として得る。

4.95 g (about 20 mmol) of 2-bromo-6-chloro-8-methylimidazo [1,2-b] pyridazine containing 2,6-dibromo-8-methylimidazo [1,2-b] pyridazine, 2 A mixture of 2.5 g (22 mmol) of 2-dimethylpiperazine and 2.8 ml of triethylamine in 60 ml of pentanol is heated in a sealed tube at 150 ° C. for 3 days. After cooling, the reaction mixture is poured into 1N aqueous hydrochloric acid. The aqueous phase is washed with ethyl acetate and then basified with aqueous ammonia and the product is extracted with dichloromethane. The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The resulting beige solid was purified on a column of 80 g silica gel, eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/65 / 0.5) to give 2-bromo-6- (3,3-dimethyl. 4.6 g of piperazin-1-yl) -8-methylimidazo [1,2-b] pyridazine are obtained as a white powder.

m. p. 139-141 ° C
¹ H NMR (CDCl ₃ ); δ: 7.65 (s, 1H); 7.65 (s, 1H); 3.5 (m, 2H); 3.30 (s, 2H); 3.10 ( m, 2H); 2.60 (s, 3H); 1.25 (s, 6H) ppm.

  Step 2.5. 6- (3,3-Dimethylpiperazin-1-yl) -8-methyl-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine

２−ブロモ−６−（３，３−ジメチルピペラジン−１−イル）−８−メチルイミダゾ［１，２−ｂ］ピリダジン４．６４ｇ（１４．３ｍｍｏｌ）および（４−ピリジル）ボロン酸（ＣＡＳ １６９２−１５−５）２．５ｇ（１７ｍｍｏｌ）をテトラヒドロフランと水の混合物（９／１）１００ｍｌに加えた混合物を、アルゴンで脱気してから、これに、炭酸セシウム１４ｇ（４３ｍｍｏｌ）および１，１’−ビス（ジフェニルホスフィノ）フェロセンジクロロパラジウム（ＩＩ）とジクロロメタンの錯体（ＰｄＣｌ_２（ｄｐｐｆ）・ＣＨ_２Ｃｌ_２）１．０５ｇ（１．２９ｍｍｏｌ）を加える。８時間還流撹拌してから、反応液を１Ｎ塩酸水溶液に注ぐ。水相を酢酸エチルで洗い、次いでアンモニア水溶液で塩基性にし、生成物をジクロロメタンで抽出する。有機層を硫酸ナトリウムで脱水し、溶媒を減圧下でエバポレートする。得られる黒色油状物を、シリカゲル１２０ｇのカラムにかけ、ジクロロメタン、メタノール、およびアンモニア水の混合物（９５／６５／０．５）で溶出させるクロマトグラフィーで精製し、６−（３，３−ジメチルピペラジン−１−イル）−８−メチル−２−（ピリド−４−イル）イミダゾ［１，２−ｂ］ピリダジン３．１ｇを油状物として得る。

2-Bromo-6- (3,3-dimethylpiperazin-1-yl) -8-methylimidazo [1,2-b] pyridazine 4.64 g (14.3 mmol) and (4-pyridyl) boronic acid (CAS 1692) -15-5) A mixture obtained by adding 2.5 g (17 mmol) to 100 ml of a mixture of tetrahydrofuran and water (9/1) was degassed with argon, and then 14 g (43 mmol) of cesium carbonate and 1,1 Add 1.05 g (1.29 mmol) of a complex of '-bis (diphenylphosphino) ferrocenedichloropalladium (II) and dichloromethane (PdCl ₂ (dppf) · CH ₂ Cl ₂ ). After stirring at reflux for 8 hours, the reaction solution is poured into 1N aqueous hydrochloric acid solution. The aqueous phase is washed with ethyl acetate and then basified with aqueous ammonia and the product is extracted with dichloromethane. The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The resulting black oil was purified by chromatography on a 120 g column of silica gel and eluted with a mixture of dichloromethane, methanol and aqueous ammonia (95/65 / 0.5) to give 6- (3,3-dimethylpiperazine- 3.1 g of 1-yl) -8-methyl-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine is obtained as an oil.

¹ H NMR (CDCl ₃ ); δ: 8.70 (d, 2H); 8.15 (s, 1H); 7.85 (d, 2H); 6.70 (s, 1H); 3.55 ( m, 2H); 3.30 (s, 2H); 3.15 (m, 2H); 2.70 (s, 3H); 1.30 (s, 6H) ppm.

  Step 2.6. 6- (3,3-Dimethylpiperazin-1-yl) -3-iodo-8-methyl-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine

６−（３，３−ジメチルピペラジン−１−イル）−８−メチル−２−（ピリド−４−イル）イミダゾ［１，２−ｂ］ピリダジン３．１３ｇ（９．７１ｍｍｏｌ）をジクロロメタン８０ｍｌに加えた溶液に、室温で、１Ｍ塩化ヨウ素ジクロロメタン溶液１９．４ｍｌ（１９．４ｍｍｏｌ）を加える。反応２時間後、溶液を水１５０ｍｌに注ぎ、重炭酸ナトリウムを加えて塩基性にし、得られる混合物にチオ硫酸ナトリウムを少しずつ加えて脱色する。有機層を分離し、硫酸ナトリウムで脱水し、減圧濃縮して褐色油状物を得る。この油状物を、シリカゲル１２０ｇのカラムにかけ、ジクロロメタン、メタノール、およびアンモニア水の混合物（９０／１０／１）で溶出させるクロマトグラフィーで精製して、６−（３，３−ジメチルピペラジン−１−イル）−３−ヨード−８−メチル−２−（ピリド−４−イル）イミダゾ［１，２−ｂ］ピリダジン３．３５ｇをベージュ色固体として得る。

6.13 g (9.71 mmol) of 6- (3,3-dimethylpiperazin-1-yl) -8-methyl-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine was added to 80 ml of dichloromethane. 19.4 ml (19.4 mmol) of 1M iodine chloride dichloromethane solution is added to the solution at room temperature. After 2 hours of reaction, the solution is poured into 150 ml of water, made basic by adding sodium bicarbonate, and decolorized by adding sodium thiosulfate little by little to the resulting mixture. The organic layer is separated, dried over sodium sulfate and concentrated in vacuo to give a brown oil. The oil was purified by chromatography on a 120 g column of silica gel and eluted with a mixture of dichloromethane, methanol and aqueous ammonia (90/10/1) to give 6- (3,3-dimethylpiperazin-1-yl. ) -3-Iodo-8-methyl-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine 3.35 g is obtained as a beige solid.

m. p. 153-155 ° C
¹ H NMR (CDCl ₃ ) δ: 8.75 (d, 2H); 8.15 (d, 2H); 6.75 (s, 1H); 3.70 (m, 2H); 3.40 (s , 2H); 3.20 (m, 2H); 2.70 (s, 3H); 1.30 (s, 6H) ppm.

  Step 2.7. 6- (3,3-Dimethylpiperazin-1-yl) -8-methyl-2,3-bis (pyrid-4-yl) imidazo [1,2-b] pyridazine

６−（３，３−ジメチルピペラジン−１−イル）−３−ヨード−８−メチル−２−（ピリド−４−イル）イミダゾ［１，２−ｂ］ピリダジン０．４０ｇ（０．８９ｍｍｏｌ）および（４−ピリジル）ボロン酸（ＣＡＳ １６９２−１５−５）０．１５５ｇ（１．０７ｍｍｏｌ）を、テトラヒドロフランと水の混合物（９／１）１５ｍｌに加えた混合物を、アルゴンで脱気してから、これに炭酸セシウム０．８７ｇ（２．７ｍｍｏｌ）および１，１’−ビス（ジフェニルホスフィノ）フェロセンジクロロパラジウム（ＩＩ）とジクロロメタンの錯体（ＰｄＣｌ_２（ｄｐｐｆ）・ＣＨ_２Ｃｌ_２−ＣＡＳ ８５１２３２−７１−８）０．０５７ｇ（０．０８ｍｍｏｌ）を加える。反応１８時間後、反応液を水１５０ｍｌに注ぎ、生成物をジクロロメタンで抽出する。有機層を硫酸ナトリウムで脱水し、溶媒を減圧下でエバポレートする。得られる黒色油状物を、シリカゲル４０ｇのカラムにかけ、ジクロロメタン、メタノール、およびアンモニア水の混合物（９５／６５／０．５）で溶出させるクロマトグラフィーで精製して、アセトニトリルから再結晶させ、ろ過し、乾燥させて、６−（３，３−ジメチルピペラジン−１−イル）−８−メチル−２，３−ビス（ピリド−４−イル）イミダゾ［１，２−ｂ］ピリダジン０．０３９ｇをベージュ色粉末として得る。

6- (3,3-dimethylpiperazin-1-yl) -3-iodo-8-methyl-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine 0.40 g (0.89 mmol) and A mixture obtained by adding 0.155 g (1.07 mmol) of (4-pyridyl) boronic acid (CAS 1692-15-5) to 15 ml of a mixture of tetrahydrofuran and water (9/1) was degassed with argon, To this, 0.87 g (2.7 mmol) of cesium carbonate and a complex of 1,1′-bis (diphenylphosphino) ferrocenedichloropalladium (II) and dichloromethane (PdCl ₂ (dppf) · CH ₂ Cl ₂ -CAS 851232-71 -8) Add 0.057 g (0.08 mmol). After 18 hours of reaction, the reaction mixture is poured into 150 ml of water and the product is extracted with dichloromethane. The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The resulting black oil is applied to a column of 40 g silica gel and purified by chromatography eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/65 / 0.5), recrystallized from acetonitrile, filtered, After drying, 0.039 g of 6- (3,3-dimethylpiperazin-1-yl) -8-methyl-2,3-bis (pyrid-4-yl) imidazo [1,2-b] pyridazine was beige Obtain as a powder.

m. p. = 211-213 ° C
¹ H NMR (CDCl ₃ ); δ: 8.70 (d, 2H); 8.60 (d, 2H); 7.60 (m, 4H); 6.75 (s, 1H); 3.45 ( m, 2H); 3.25 (s, 2H); 3.05 (m, 2H); 2.70 (s, 3H); 1.20 (s, 6H) ppm.

(Compound 12): 6- (3,3-Dimethylpiperazin-1-yl) -2,3-bis (pyrid-4-yl) imidazo [1,2-b] pyridazine

  Step 3.1. 6-Chloro-2- (pyrid-4-yl) -imidazo [1,2-b] pyridazine

３−アミノ−６−クロロピリダジン３．８０ｇ（２８．１ｍｍｏｌ）および２−ブロモ−１−（ピリド−４−イル）エタノン臭化水素酸塩５．００ｇ（１７．８ｍｍｏｌ）をエタノール５０ｍｌに加えた混合物を、マイクロ波により１４０℃で５０分間加熱する。冷却してから、溶媒を減圧下でエバポレートし、残渣を飽和炭酸水素ナトリウム水溶液に取る。固体をろ別し、水で洗い、次いでシリカゲルのカラムにかけ、ジクロロメタンとメタノールの混合物（９５／５）で溶出させるクロマトグラフィーで、６−クロロ−２−（ピリド−４−イル）イミダゾ［１，２−ｂ］ピリダジン１．９７ｇを黄色粉末として得る。

3.80 g (28.1 mmol) 3-amino-6-chloropyridazine and 5.00 g (17.8 mmol) 2-bromo-1- (pyrid-4-yl) ethanone hydrobromide were added to 50 ml ethanol. The mixture is heated by microwave at 140 ° C. for 50 minutes. After cooling, the solvent is evaporated under reduced pressure and the residue is taken up in saturated aqueous sodium hydrogen carbonate solution. The solid was filtered off, washed with water, then applied to a column of silica gel and chromatographed eluting with a mixture of dichloromethane and methanol (95/5) to give 6-chloro-2- (pyrid-4-yl) imidazo [1, 2-b] 1.97 g of pyridazine are obtained as a yellow powder.

LC / MS: M + H ⁺ = 231
¹ H NMR (CDCl ₃ ); δ: 8.71 (dd, 2H); 8.33 (d, 1H); 7.93 (dd, 1H); 7.82 (dd, 2H); 7.11 ( d, 1H).

  Step 3.2. 6- (3,3-Dimethylpiperazin-1-yl) -2- (pyrid-4-yl) imidazo [1,2-b] pyridazine

６−クロロ−２−（ピリド−４−イル）イミダゾ［１，２−ｂ］ピリダジン１．９５ｇ（８．４５ｍｍｏｌ）と２，２−ジメチルピペラジン２．４ｇ（２１ｍｍｏｌ）の混合物を、マイクロ波オーブン中、１５０℃で１３時間加熱する。次いで、その混合物を冷却し、溶媒を減圧下でエバポレートする。得られる橙色油状物をシリカゲルカラムにかけ、ジクロロメタンと１Ｍアンモニアメタノール溶液の混合物（９５／５）で溶出させるクロマトグラフィーで、６−（３，３−ジメチルピペラジン−１−イル）−２−（ピリド−４−イル）イミダゾ［１，２−ｂ］ピリダジン１．６３ｇを黄色発泡物として得る。

A mixture of 1.95 g (8.45 mmol) of 6-chloro-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine and 2.4 g (21 mmol) of 2,2-dimethylpiperazine was placed in a microwave oven. Heat at 150 ° C. for 13 hours. The mixture is then cooled and the solvent is evaporated under reduced pressure. The resulting orange oil is applied to a silica gel column and chromatographed eluting with a mixture of dichloromethane and 1M ammonia in methanol (95/5) to give 6- (3,3-dimethylpiperazin-1-yl) -2- (pyrido- 1.63 g of 4-yl) imidazo [1,2-b] pyridazine are obtained as a yellow foam.

LC / MS: M + H ⁺ = 309
¹ H NMR (DMSO-d ₆ ): 8.67 (d, 1H); 8.57 (dd, 2H); 7.86 (m, 3H); 7.23 (d, 1H); 3.41 ( m, 2H); 3.25 (s, 2H); 3.17 (d, 1H); 2.84 (m, 2H); 1.95 (bs, 1H); 1.07 (s, 6H).

  Step 3.3. 6- (3,3-Dimethylpiperazin-1-yl) -3-iodo-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine

６−（３，３−ジメチルピペラジン−１−イル）−２−（ピリド−４−イル）イミダゾ［１，２−ｂ］ピリダジン１．３７ｇ（４．４５ｍｍｏｌ）をクロロホルム２０ｍｌに加えた溶液に、一塩化ヨウ素１．８０ｇ（１１．１ｍｍｏｌ）をメタノール５ｍｌに加えた溶液を加える。得られる懸濁液を２時間撹拌する。飽和炭酸水素ナトリウム水溶液を加え、次いで反応液が黄色いままになるまで、チオ硫酸ナトリウムを少しずつ加える。固体をろ別し、風乾して、生成物６−（３，３−ジメチルピペラジン−１−イル）−３−ヨード−２−（ピリド−４−イル）イミダゾ［１，２−ｂ］ピリダジン１．９５ｇを黄色粉末として得る。

To a solution of 1.37 g (4.45 mmol) of 6- (3,3-dimethylpiperazin-1-yl) -2- (pyrid-4-yl) imidazo [1,2-b] pyridazine in 20 ml of chloroform, A solution of 1.80 g (11.1 mmol) iodine monochloride in 5 ml methanol is added. The resulting suspension is stirred for 2 hours. Saturated aqueous sodium bicarbonate solution is added and then sodium thiosulfate is added in portions until the reaction remains yellow. The solid was filtered off and air dried to give the product 6- (3,3-dimethylpiperazin-1-yl) -3-iodo-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine 1 .95 g is obtained as a yellow powder.

¹ H NMR (DMSO-d ₆ ): 9.0 (bs, 2H); 8.70 (d, 2H); 8.10 (d, 2H); 8.00 (d, 1H); 7.38 ( d, 1H); 3.85 (m, 2H); 3.70 (m, 2H); 3.3 (m, 2H); 1.40 (s, 6H).

  Step 3.4. 6- (3,3-Dimethylpiperazin-1-yl) -2,3-bis (pyrid-4-yl) imidazo [1,2-b] pyridazine

６−（３，３−ジメチルピペラジン−１−イル）−３−ヨード−２−（ピリド−４−イル）イミダゾ［１，２−ｂ］ピリダジン０．２８ｇ（０．５５ｍｍｏｌ）、（ピリド−４−イル）ボロン酸０．０９５ｇ（０．７７ｍｍｏｌ）、炭酸セシウム０．８９（２．７ｍｍｏｌ）および１，１’−ビス（ジフェニルホスフィノフェロセン）ジクロロパラジウム（ＩＩ）とジクロロメタンの錯体（ＰｄＣｌ_２（ｄｐｐｆ）・ＣＨ_２Ｃｌ_２−ＣＡＳ ８５１２３２−７１−８）４５ｍｇ（０．０５５ｍｍｏｌ）を、１，４−ジオキサンと水の混合物（７５／２）４ｍｌに加えた混合物を、脱気してから、マイクロ波オーブン中１０５℃で３０分間加熱する。冷却してから、混合物をジクロロメタンで希釈し水で洗う。次いで、有機層を硫酸マグネシウムで脱水し、ろ過し、溶媒をエバポレートする。得られる油状物を、シリカゲルにかけ、アンモニア１Ｍを含むメタノールとジクロロメタンの混合物（３／９７）で溶出させるクロマトグラフィーにかけて、黄色粉末０．０７０ｇを得る。

6- (3,3-dimethylpiperazin-1-yl) -3-iodo-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine 0.28 g (0.55 mmol), (pyrido-4 -Yl) boronic acid 0.095 g (0.77 mmol), cesium carbonate 0.89 (2.7 mmol) and 1,1′-bis (diphenylphosphinoferrocene) dichloropalladium (II) complex with dichloromethane (PdCl ₂ ( dppf) · CH ₂ Cl ₂ —CAS 851232-71-8) 45 mg (0.055 mmol) in 4 ml of a mixture of 1,4-dioxane and water (75/2) was degassed, Heat in a microwave oven at 105 ° C. for 30 minutes. After cooling, the mixture is diluted with dichloromethane and washed with water. The organic layer is then dehydrated with magnesium sulfate, filtered and the solvent is evaporated. The resulting oil is chromatographed on silica gel eluting with a mixture of methanol and dichloromethane (3/97) containing 1M ammonia to give 0.070 g of a yellow powder.

LC / MS: M + H ⁺ = 386
¹ H NMR (DMSO-d ₆ ): 8.70 (d, 2H); 8.54 (d, 2H); 7.96 (d, 1H); 7.60 (d, 2H); 7.51 ( d, 2H); 7.34 (d, 1H); 3.45-3.10 (m, 4H); 2.83 (m, 2H); 1.05 (6H).

(Compound 3): 6- (3,3-Dimethylpiperazin-1-yl) -2- (pyrid-3-yl) -3- (pyrid-4-yl) imidazo [1,2-b] pyridazine

  Step 4.1. 6-Chloro-2- (pyrid-3-yl) imidazo [1,2-b] pyridazine

３−アミノ−６−クロロピリダジン２．８０ｇ（１１．９ｍｍｏｌ）、２−ブロモ−１−（ピリド−３−イル）エタノン臭化水素酸塩３．６９ｇ（１３．２ｍｍｏｌ）およびトリエチルアミン３．７ｍｌ（２６ｍｍｏｌ）をエタノール４５ｍｌに加えた懸濁液を、マイクロ波により１４０℃で５０分間加熱する。冷却してから、溶媒を減圧下でエバポレートし、残渣をシリカゲル１２０ｇのカラムにかけ、ジクロロメタンとメタノールの混合物（９５／５）で溶出させるカラムクロマトグラフィーで精製して、ヘプタンに不要分を溶解し、ろ過し、減圧下乾燥させて、生成物０．７７ｇをベージュ色粉末として得る。

2.80 g (11.9 mmol) 3-amino-6-chloropyridazine, 3.69 g (13.2 mmol) 2-bromo-1- (pyrid-3-yl) ethanone hydrobromide and 3.7 ml triethylamine ( 26 mmol) in 45 ml of ethanol is heated in a microwave at 140 ° C. for 50 minutes. After cooling, the solvent was evaporated under reduced pressure and the residue was applied to a 120 g column of silica gel and purified by column chromatography eluting with a mixture of dichloromethane and methanol (95/5) to dissolve the unwanted portion in heptane, Filtration and drying under reduced pressure gives 0.77 g of product as a beige powder.

LC / MS: M + H ⁺ = 231
¹ H NMR (DMSO-d ₆ ): 9.25 (s, 1H); 9.00 (s, 1H); 8.60 (d, 1H); 8.40 (dt, 1H); 8.25 ( d, 1H); 7.50 (dd, 1H); 7.40 (d, 1H).

  Step 4.2. 6- (3,3-Dimethylpiperazin-1-yl) -2- (pyrid-3-yl) imidazo [1,2-b] pyridazine

６−クロロ−２−（ピリド−３−イル）イミダゾ［１，２−ｂ］ピリダジン０．７７ｇ（３．３ｍｍｏｌ）および２，２−ジメチルピペラジン１.１ｇ（９．６ｍｍｏｌ）をエタノール７ｍｌに加えた混合物を、マイクロ波オーブン中、１５０℃で１３時間加熱する。次いで、その混合物を冷却し、溶媒を減圧下でエバポレートする。得られる橙色油状物を、シリカゲルカラムにかけ、ジクロロメタンと１Ｍアンモニアメタノール溶液の混合物（９７／３）で溶出させるクロマトグラフィーにかけて、６−（３，３−ジメチルピペラジン−１−イル）−２−（ピリド−３−イル）イミダゾ［１，２−ｂ］ピリダジン０．８９ｇを黄色粉末として得る。

Add 0.77 g (3.3 mmol) of 6-chloro-2- (pyrid-3-yl) imidazo [1,2-b] pyridazine and 1.1 g (9.6 mmol) of 2,2-dimethylpiperazine to 7 ml of ethanol. The resulting mixture is heated in a microwave oven at 150 ° C. for 13 hours. The mixture is then cooled and the solvent is evaporated under reduced pressure. The resulting orange oil is chromatographed on a silica gel column and eluted with a mixture of dichloromethane and 1M ammonia in methanol (97/3) to give 6- (3,3-dimethylpiperazin-1-yl) -2- (pyrido). -3-yl) imidazo [1,2-b] pyridazine 0.89 g is obtained as a yellow powder.

LC / MS: M + H ⁺ = 309
¹ H NMR (DMSO-d ₆ ): 9.14 (d, 1H); 8.56 (s, 1H); 8.48 (d, 1H); 8.23 (d, 1H); 7.85 ( 7.45 (dd, 1H); 7.20 (d, 1H); 3.41 (t, 2H); 2.86 (t, 2H); 1.95 (bs, 2H); 1.08 (s, 6H).

  Step 4.3. 6- (3,3-Dimethylpiperazin-1-yl) -3-iodo-2- (pyrid-3-yl) imidazo [1,2-b] pyridazine

６−（３，３−ジメチルピペラジン−１−イル）−２−（ピリド−３−イル）イミダゾ［１，２−ｂ］ピリダジン０．８７０ｇ（２．８２ｍｍｏｌ）をクロロホルム１０ｍｌに加えた溶液に、一塩化ヨウ素０．６００ｇ（３．７０ｍｍｏｌ）をメタノール４ｍｌに加えた溶液を加える。次いで、橙色懸濁液を３時間撹拌し、溶媒を減圧下でエバポレートして、残渣を得る。次いで、飽和炭酸水素ナトリウム水溶液を加え、続いて、反応液が黄色いままになるまで、チオ硫酸ナトリウムを少しずつ加え続ける。固体をろ別し、風乾して、６−（３，３−ジメチルピペラジン−１−イル）−３−ヨード−２−（ピリド−３−イル）イミダゾ［１，２−ｂ］ピリダジン０．９０ｇをベージュ色粉末として得る。

To a solution of 0.870 g (2.82 mmol) of 6- (3,3-dimethylpiperazin-1-yl) -2- (pyrid-3-yl) imidazo [1,2-b] pyridazine in 10 ml of chloroform, A solution of iodine monochloride 0.600 g (3.70 mmol) in 4 ml of methanol is added. The orange suspension is then stirred for 3 hours and the solvent is evaporated under reduced pressure to give a residue. Saturated aqueous sodium bicarbonate solution is then added, followed by small portions of sodium thiosulfate until the reaction remains yellow. The solid was filtered off and air dried to give 0.90 g of 6- (3,3-dimethylpiperazin-1-yl) -3-iodo-2- (pyrid-3-yl) imidazo [1,2-b] pyridazine. Is obtained as a beige powder.

LC / MS: M + H ⁺ = 435
¹ H NMR (DMSO-d ₆ ): 9.26 (s, 1H); 8.57 (d, 1H); 8.39 (d, 1H); 7.92 (d, 1H); 7.52 ( dd, 1H); 7.31 (d, 1H); 3.75-3.10 (m, 6H); 1.25 (s, 6H).

  Step 4.4. 6- (3,3-Dimethylpiperazin-1-yl) -2,3-bis (pyrid-3-yl) imidazo [1,2-b] pyridazine

６−（３，３−ジメチルピペラジン−１−イル）−３−ヨード−２−（ピリド−３−イル）イミダゾ［１，２−ｂ］ピリダジン０．４００ｇ（０．９２ｍｍｏｌ）、（ピリド−４−イル）ボロン酸０．１５０ｇ（１．２２ｍｍｏｌ）、炭酸セシウム０．８９（２．７ｍｍｏｌ）および１，１’−ビス（ジフェニルホスフィノフェロセンジクロロパラジウム（ＩＩ）とジクロロメタンの錯体（ＰｄＣｌ_２（ｄｐｐｆ）・ＣＨ_２Ｃｌ_２）７５ｍｇ（０．０９２ｍｍｏｌ）を１，４−ジオキサンと水の混合物（３／１）６ｍｌに加えた混合物を、脱気してから、マイクロ波オーブン中１０５℃で３０分間加熱する。冷却してから、その混合物をジクロロメタンで希釈し、水で洗う。次いで、有機層を硫酸マグネシウムで脱水し、ろ過し、溶媒をエバポレートして緑色油状物を得る。得られる油状物を、シリカゲル２５ｇのカラムで、１Ｍアンモニアメタノール溶液とジクロロメタンの混合物（５／９５）で溶出させてクロマトグラフィーにかけて、６−（３，３−ジメチルピペラジン−１−イル）−２，３−ビス（ピリド−３−イル）イミダゾ［１，２−ｂ］ピリダジン０．１７０ｇを灰色粉末として得る。

6- (3,3-Dimethylpiperazin-1-yl) -3-iodo-2- (pyrid-3-yl) imidazo [1,2-b] pyridazine 0.400 g (0.92 mmol), (pyrido-4 -Yl) boronic acid 0.150 g (1.22 mmol), cesium carbonate 0.89 (2.7 mmol) and 1,1′-bis (diphenylphosphinoferrocenedichloropalladium (II) complex with dichloromethane (PdCl ₂ (dppf ) .CH ₂ Cl ₂ ) 75 mg (0.092 mmol) added to 6 ml of a mixture of 1,4-dioxane and water (3/1), degassed and then in a microwave oven at 105 ° C. for 30 minutes After cooling, the mixture is diluted with dichloromethane and washed with water, the organic layer is then dried over magnesium sulfate, filtered and the solvent is evaporated. Evaporate to give a green oil which is chromatographed on a 25 g column of silica gel eluting with a mixture of 1M ammonia in methanol and dichloromethane (5/95) to give 6- (3,3-dimethyl. 0.170 g of piperazin-1-yl) -2,3-bis (pyrid-3-yl) imidazo [1,2-b] pyridazine is obtained as a gray powder.

LC / MS: M + H ⁺ = 386
¹ H NMR (DMSO-d ₆ ): 8.70 (d, 1H); 8.67 (d, 2H); 8.52 (d, 1H); 7.96 (d, 1H); 7.90 ( 7.58 (d, 2H); 7.41 (dd, 1H); 7.33 (d, 1H); 3.40 (t, 2H); 3.25 (s, 2H); 2.84 (t, 2H); 1.06 (s, 6H).

(Compound 22): 2- (2-Fluoropyrid-4-yl) -6- (4-isopropylpiperazin-1-yl) -3- (pyrid-4-yl) imidazo [1,2-b] pyridazine

  Step 5.1. 6-amino-3-chloro-1- (ethoxycarbonylmethyl) pyridazine-1-ium bromide

３−アミノ−６−クロロピリダジン２５．６ｇ（１９８ｍｍｏｌ）を熱エタノール２３０ｍｌに加えた混合物を、ブロモ酢酸エチル３４．０ｇ（２０６ｍｍｏｌ）で処理する。２４時間還流後、その混合物を冷却し、結晶をろ別する。乾燥させて生成物３６．６ｇを得る。溶媒を減圧下エバポレートし、エタノールから再結晶してさらに７．１ｇを単離する。

A mixture of 25.6 g (198 mmol) 3-amino-6-chloropyridazine in 230 ml hot ethanol is treated with 34.0 g (206 mmol) ethyl bromoacetate. After refluxing for 24 hours, the mixture is cooled and the crystals are filtered off. Dry to give 36.6 g of product. Evaporate the solvent under reduced pressure and recrystallize from ethanol to isolate an additional 7.1 g.

¹ H NMR (DMSO-d ₆ ) δ: 9.8 (broad, 1H); 9.4 (broad, 1H); 8.0 (d, 1H); 7.7 (d, 1H); 5.3 (S, 1H); 4.1 (d, 2H); 1.2 (t, 3H) ppm.

  Step 5.2 2-Bromo-6-chloroimidazo [1,2-b] pyridazine and 2,6-dibromoimidazo [1,2-b] pyridazine

６−アミノ−３−クロロ−１−（エトキシカルボニルメチル）ピリダジン−１−イウムブロミド２０ｇ（６５ｍｍｏｌ）およびオキシ臭化リン６３ｇをトルエン５０ｍｌに加えた混合物を、１６０℃で３時間加熱する。次いで、その混合物を氷（３００ｍｌ）に注ぐ。撹拌してから、固体をろ過し、シリカゲル１２０ｇのカラムで、０から１０％メタノールを含むジクロロメタン混合物で溶出させるクロマトグラフィーで精製する。こうして２種の生成物の混合物８．０５ｇが得られるが、さらに精製することなくその後の合成に用いる。

A mixture of 6-amino-3-chloro-1- (ethoxycarbonylmethyl) pyridazine-1-ium bromide 20 g (65 mmol) and 63 g phosphorus oxybromide in 50 ml toluene is heated at 160 ° C. for 3 hours. The mixture is then poured onto ice (300 ml). After stirring, the solid is filtered and purified by chromatography on a 120 g column of silica gel, eluting with a dichloromethane mixture containing 0 to 10% methanol. This gives 8.05 g of a mixture of the two products, which is used for further synthesis without further purification.

¹ H NMR (CDCl ₃ ) δ: 7.92 (s, 1H); 7.83 (d, 1H); 7.1 (d, 1H)

  Step 5.3. 2-Bromo-6- (4-isopropylpiperazin-1-yl) imidazo [1,2-b] pyridazine

先の工程で得られる２−ブロモ−６−クロロイミダゾ［１，２−ｂ］ピリダジンと２，６−ジブロモイミダゾ［１，２−ｂ］ピリダジン３．９８ｇ（１４．４ｍｍｏｌ）および１−イソプロピルピペラジン３．７ｇ（２８．５ｍｍｏｌ）をエタノール１５ｍｌに加えた混合物を、密閉した管中、マイクロ波反応器で、１６０℃で８時間加熱する。その混合物をエタノールで希釈し、次いでろ過して２−ブロモ−６−（４−イソプロピルピペラジン−１−イル）イミダゾ［１，２−ｂ］ピリダジン２．４９ｇを得る。

2-Bromo-6-chloroimidazo [1,2-b] pyridazine obtained from the previous step, 3.98 g (14.4 mmol) of 2,6-dibromoimidazo [1,2-b] pyridazine and 1-isopropylpiperazine A mixture of 3.7 g (28.5 mmol) in 15 ml ethanol is heated in a microwave reactor at 160 ° C. for 8 hours in a sealed tube. The mixture is diluted with ethanol and then filtered to give 2.49 g of 2-bromo-6- (4-isopropylpiperazin-1-yl) imidazo [1,2-b] pyridazine.

¹ H NMR (CDCl ₃ ) δ: 7.62 (s, 1H); 7.60 (d, 1H); 6.9 (d, 1H); 3.5 (m, 4H); 2.73 (m , 1H); 2.64 (m, 4H); 1.1 (d, 6H)

  Step 5.4. 2-Bromo-3-iodo-6- (4-isopropylpiperazin-1-yl) imidazo [1,2-b] pyridazine

２−ブロモ−６−（４−イソプロピルピペラジン−１−イル）イミダゾ［１，２−ｂ］ピリダジン２．４５ｇ（７．５６ｍｍｏｌ）をクロロホルム２０ｍｌに加えた溶液に、０℃で、塩化ヨウ素２．４５ｇ（１４．８ｍｍｏｌ）をメタノール２ｍｌに加えた溶液を滴下する。その混合物を室温で４時間撹拌する。次いで、混合物をチオ硫酸ナトリウムと混合する。この混合物を、シリカゲル１５ｇとともに減圧下で濃縮する。残渣をシリカゲル８０ｇのカラムにのせ、０％から１０％への勾配でメタノールを含むジクロロメタンで溶出させるクロマトグラフィーで精製して、２−ブロモ−３−ヨード−６−（４−イソプロピルピペラジン−１−イル）イミダゾ［１，２−ｂ］ピリダジン２．０７ｇを橙色固体として得る。

To a solution of 2-bromo-6- (4-isopropylpiperazin-1-yl) imidazo [1,2-b] pyridazine 2.45 g (7.56 mmol) in 20 ml of chloroform at 0 ° C., iodine chloride 2. A solution of 45 g (14.8 mmol) in 2 ml of methanol is added dropwise. The mixture is stirred at room temperature for 4 hours. The mixture is then mixed with sodium thiosulfate. The mixture is concentrated under reduced pressure with 15 g of silica gel. The residue was applied to a column of 80 g silica gel and purified by chromatography eluting with dichloromethane containing methanol with a gradient from 0% to 10% to give 2-bromo-3-iodo-6- (4-isopropylpiperazine-1- Il) 2.07 g of imidazo [1,2-b] pyridazine is obtained as an orange solid.

¹ H NMR (CDCl ₃ ) δ: 7.5 (d, 1H); 6.9 (d, 1H); 3.55 (m, 4H); 3.19 (m, 4H); 3.17 (m , 1H); 1.32 (d, 6H)

  Step 5.5. 2-Bromo-6- (4-isopropylpiperazin-1-yl) -3- (pyrid-4-yl) -imidazo [1,2-b] pyridazine

２−ブロモ−３−ヨード−６−（４−イソプロピルピペラジン−１−イル）イミダゾ［１，２−ｂ］ピリダジン０．０５９ｇ（０．１２ｍｍｏｌ）、二塩化１，１’−ビス（ジフェニルホスフィノ）フェロセンパラジウム（ＣＡＳ ７２２８７−２６−４）３ｍｇ（０．００４ｍｍｏｌ）、ピリド−４−イルボロン酸（ＣＡＳ １６９２−１５−５）１８ｍｇ（０．１５ｍｍｏｌ）、２Ｍ炭酸セシウム水溶液０．９ｍｌおよび１，４−ジオキサン１．５ｍｌの混合物を密閉した管に入れ、マイクロ波オーブン中１１０℃で３０分間加熱する。飽和塩化ナトリウム溶液１ｍｌおよび酢酸エチル４ｍｌを加える。撹拌してから、混合物を硫酸ナトリウムカートリッジでろ過する。

2-Bromo-3-iodo-6- (4-isopropylpiperazin-1-yl) imidazo [1,2-b] pyridazine 0.059 g (0.12 mmol), 1,1′-bis (diphenylphosphino dichloride) ) Ferrocene palladium (CAS 72287-26-4) 3 mg (0.004 mmol), pyrid-4-ylboronic acid (CAS 1692-15-5) 18 mg (0.15 mmol), 2M aqueous cesium carbonate solution 0.9 ml and 1,4 -Place 1.5 ml of the dioxane mixture in a sealed tube and heat in a microwave oven at 110 ° C for 30 minutes. Add 1 ml of saturated sodium chloride solution and 4 ml of ethyl acetate. After stirring, the mixture is filtered through a sodium sulfate cartridge.

  Evaporate the solvent to dryness with silica gel. The adsorbed residue was loaded onto a 4 g column of silica gel and eluted with dichloromethane containing methanol and 1% aqueous ammonia in a gradient from 0% to 6% to give 2-bromo-6- (4-isopropylpiperazin-1-yl. ) -3- (Pyrid-4-yl) imidazo [1,2-b] pyridazine 8.5 mg is obtained.

¹ H NMR (CDCl ₃ ) δ: 8.74 (d, 2H); 7.94 (d, 2H); 7.7 (d, 1H); 6.93 (d, 1H); 3.5 (m , 4H); 2.75 (m, 1H); 2.65 (m, 4H); 1.10 (d, 6H).

  Step 5.6. 2- (2-Fluoropyrid-4-yl) -6- (4-isopropylpiperazin-1-yl) -3- (pyrid-4-yl) imidazo [1,2-b] pyridazine

２−ブロモ−６−（４−イソプロピルピペラジン−１−イル）−３−（ピリド−４−イル）−イミダゾ［１，２−ｂ］ピリダジン２．６５ｇ（６．６ｍｍｏｌ）、１，１’−ビス（ジフェニルホスフィノ）フェロセンパラジウム（ＣＡＳ ７２２８７−２６−４）０．４６ｇ（０．６５ｍｍｏｌ）、ピリジン−４−ボロン酸（ＣＡＳ １６９２１５−１５−５）１．１２ｇ（９．１０ｍｍｏｌ）および２Ｍ炭酸セシウム水溶液１５ｍｌを１，４−ジオキサン２５ｍｌに加えた混合物を密閉した管に入れ、１２０℃で２０分間加熱する。ピリジン−４−ボロン酸０．２３７ｇ（２．７ｍｍｏｌ）をさらに加え、反応液を１１０℃で３０分間加熱する。次いで、反応液を水で希釈し、生成物を酢酸エチルで抽出する。有機相を飽和塩化ナトリウム水溶液で洗い、次いで硫酸ナトリウムで脱水する。溶媒を減圧除去し、残渣をシリカゲルに吸着させる。生成物をシリカゲル８０ｇのカラムにかけ、０％から１０％への勾配でメタノールを含むジクロロメタンで溶出させるクロマトグラフィーで精製して、イソプロパノールから再結晶して、２−（２−フルオロピリド−４−イル）−６−（４−イソプロピルピペラジン−１−イル）−３−（ピリド−４−イル）−イミダゾ［１，２−ｂ］ピリダジン１．８５ｇを得る。

2-Bromo-6- (4-isopropylpiperazin-1-yl) -3- (pyrid-4-yl) -imidazo [1,2-b] pyridazine 2.65 g (6.6 mmol), 1,1′- Bis (diphenylphosphino) ferrocenepalladium (CAS 72287-26-4) 0.46 g (0.65 mmol), pyridine-4-boronic acid (CAS 169215-15-5) 1.12 g (9.10 mmol) and 2M carbonic acid A mixture of 15 ml of aqueous cesium solution added to 25 ml of 1,4-dioxane is placed in a sealed tube and heated at 120 ° C. for 20 minutes. An additional 0.237 g (2.7 mmol) of pyridine-4-boronic acid is added and the reaction is heated at 110 ° C. for 30 minutes. The reaction is then diluted with water and the product is extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is adsorbed onto silica gel. The product was applied to a column of 80 g silica gel, purified by chromatography eluting with methanol in dichloromethane with a gradient from 0% to 10%, recrystallized from isopropanol, and 2- (2-fluoropyrid-4-yl) 1.85 g of -6- (4-isopropylpiperazin-1-yl) -3- (pyrid-4-yl) -imidazo [1,2-b] pyridazine are obtained.

Melting point = 196-198 ° C.
¹ H NMR (CDCl ₃ ) δ: 8.74 (d, 2H); 8.15 (d, 1H); 7.80 (d, 1H); 7.56 (d, 2H); 7.39 (d 7.25 (d, 1H); 6.98 (d, 1H); 3.50 (m, 4H); 2.76 (m, 1H); 2.62 (m, 4H); 1 .08 (d, 6H).

  Table 1 below shows the chemical structures and physical properties of a number of compounds described in the present invention.

In this table:
The column “mp. ° C.” indicates the melting point of the product in degrees Celsius. “ND” indicates that the melting point cannot be measured.

The column “[α] _D ” shows the analysis results of the optical rotation of the compounds in the table at a wavelength of 589 nm. The solvent shown in parentheses corresponds to the solvent used to measure the optical rotation (degree), and the letter “c” indicates the concentration of the solvent in g / 100 ml. “NA” means that optical rotation measurement is not applicable,
The column of “m / z” is based on LC-MS (liquid chromatography-linked mass spectrometry) performed in the positive ESI mode with an Agilent LC-MSD Trap type apparatus, or the electron collision method with the DCl-NH3 method or the Waters GCT type apparatus. ² shows the molecular ion (M + H ⁺ ) observed in product analysis by mass spectrometry, either by direct introduction of MS (mass spectrometry) on an Autospec M (EBE) instrument using.

“CH ₃ —” means methyl,
“CH ₃ OH” means methanol,
“DMSO” means dimethyl sulfoxide,

Biological Examples The ability of the compounds of the invention to inhibit the phosphorylation of casein by casein kinase 1ε and δ can be evaluated according to the procedure described in document US2005 / 0131012.

ATP- ³³ P filter plate assay to screen for CK1ε inhibitors :
The effect of the compounds of the invention on the inhibition of casein phosphorylation by the enzyme casein kinase 1ε (CK1ε) is measured using a casein assay with in vitro filtration of ATP- ³³ P.

  Casein kinase 1ε (0.58 mg / ml) is obtained through fermentation and purification processes performed according to methods known to those skilled in the art, but may also be available from Invitrogen Corporation ™ (human CK1ε).

Compounds are tested at 5 different concentrations so that the IC ₅₀ is the compound concentration that can inhibit enzyme activity by 50%, or the percent inhibition at 10 micromolar concentrations is apparent.

  Prepare a “U” bottom Falcon plate by placing 5 μL of a compound solution according to the present invention at a concentration of 10, 1, 0.1, 0.01 or 0.001 μM into separate wells.

These different concentrations of the compound solution according to the invention are diluted in a 10 mM concentration of DMSO stock in test buffer (50 mM Tris (pH 7.5), 10 M MgCl ₂ , 2 mM DTT and 1 mM EGTA). To prepare. Then mixed with cold ATP, 5 μL of dephosphorylated casein at a final concentration of 0.2 μg / μL, 20 μL of CK1ε at a final concentration of 3 ng / ml and 20 μL of ATP- ³³ P at a final concentration of 0.02 μCi / μL (final) About 2 × 10 ⁶ CPM per 10 μM-1 well). The final total test volume per well is 50 μL.

  Vortex the above “U” bottom Falcon® test plate and then incubate for 2 hours at room temperature. After 2 hours, the reaction is stopped by adding an ice-cooled solution of 65 μL of cold ATP (2 mM) prepared in the test buffer.

  100 μL of the reaction mixture is then transferred from the “U” bottom Falcon® plate to a Millipore® MAPH filter plate pre-impregnated with 25 μL of ice-cold 100% TCA.

  The Millipore MAPH filter plate is gently shaken and allowed to stand at room temperature for at least 30 minutes to precipitate the protein.

  30 minutes later, 20% TCA 2 × 150 μL, 10% TCA 2 × 150 μL and 5% TCA 2 × 150 μL (total 6 washes per plate / 900 μL per well) and filtered sequentially To do.

  Allow the plates to dry overnight at room temperature. Then, 40 μL of Microscint-20 Packard® scintillation fluid is added per well and the plate is sealed to prevent leakage. The radiation emitted from each well is then measured with a Topcount NXT Packard® scintillation counter for 2 minutes. The scintillation counter measures the value of CPM / well.

The percent inhibition of the ability of the enzyme to phosphorylate the substrate (casein) is determined at each concentration of test compound. These inhibition data, expressed as percentages, are used to calculate an IC ₅₀ value for each compound compared to the control.

From kinetic studies, _{K M} value for ATP was determined to be 21μM in this test system.

Table 2 below shows IC ₅₀ values that inhibit phosphorylation of casein kinase 1ε for some of the compounds described in the present invention.

これらの条件下では、最も活性が高い本発明化合物は、１ｎＭから２μＭの間のＩＣ_５０値（カゼインキナーゼ１ε酵素活性を５０％阻害する濃度）を有する。

Under these conditions, the most active compounds of the present invention have IC ₅₀ values between 1 nM and 2 μM (concentrations that inhibit casein kinase 1ε enzyme activity by 50%).

  The ability of the compounds of the invention to inhibit the phosphorylation of casein by casein kinase 1ε and δ is determined according to the instructions using the “Z'Lyte ™ Kinase Assay Kit” (reference number PV3670, Invitrogen Corporation ™) FRET. It can be evaluated using (fluorescence resonance energy transfer).

  The casein kinase 1 used is obtained from Invitrogen Corporation (human CK1εPV3500 and human CK1δPV3665).

  In the presence of ATP, both ends were labeled with a fluorophore donor group (coumarin) and a fluorophore acceptor group (fluorescein) constituting the FRET system in the presence of ATP while increasing the concentration of the present compound present. Dephosphorylate the peptide substrate.

  The mixture is treated with a site-specific protease that specifically cleaves the substrate peptide to form two fluorescent fragments with a high fluorescence emission ratio.

  Thus, the observed fluorescence is associated with the ability of the compounds of the invention to inhibit phosphorylation of the substrate peptide by casein kinase 1ε or casein kinase 1δ.

The compound of the present invention was prepared by using a buffer solution (50 mM HEPS (pH 7.5) for casein kinase 1ε, 1 mM EGTA, 0.01% Brij-35, 10 mM MgCl ₂ ) starting from 10 mM DMSO stock solution. And diluted with Trizma Base (50 mM, pH 8.0), and NaN ₃ (final 0.01%) for casein kinase 1δ and dissolved at different concentrations.

Phosphorylation of the substrate peptide SER / THR11 obtained from Invitrogen Corporation ™ is performed at a final concentration of 2 μM. ATP concentration is 4 times the _{K M,} the value of _{K M} is 4μM for casein kinase 1Ipushiron 2 [mu] M for, and casein kinase I delta.

  Fluorescence emission is measured at wavelengths of 445 nm and 520 nm (excitation at 400 nm).

Table 3 below shows IC ₅₀ values for inhibition of phosphorylation of casein kinase 1δ for some of the compounds described in the present invention.

これらの条件下では、最も活性が高い本発明化合物は、１ｎＭから２μＭのＩＣ_５０値（カゼインキナーゼ１δ酵素活性を５０％阻害する濃度）を有する。

Under these conditions, the compound of the present invention having the highest activity has an IC ₅₀ value (concentration that inhibits the casein kinase 1δ enzyme activity by 50%) from 1 nM to 2 μM.

  Therefore, it can be seen that the compounds described in the present invention have inhibitory activity on the enzyme casein kinase 1ε and casein kinase 1δ.

Experimental protocol for circadian cell assay Mper1-luc Rat-1 (P2C4) fibroblast cultures were removed every 3 to 4 days in degassed 150 cm ² polystyrene tissue culture flasks (Falcon® # 35-5001). Prepared in aliquots (at approximately 10 to 20% confluence), culture medium [EMEM (Cellgro # 10-010-CV); 10% fetal bovine serum (FBS, at 37 ° C. and 5% CO ₂ ; Gibco # 16000-044) and 50I. U. / ML penicillin-streptomycin (Cellgro # 30-001-Cl)].

  Cells obtained from Rat-1 fibroblast cultures at 30-50% confluency as described above are subjected to a selectable marker for zeocin resistance to stable transfection and a luciferase reporter gene controlled by the mPer-1 promoter. Co-transfected with the containing vector. After 24-48 hours, cultures were split into 96-well plates and maintained in growth medium supplemented with 50-100 μg / ml Zeocin (Invitrogen® # 45-0430) for 10-14 days. Zeocin resistant stability by adding 100 μM luciferin (Promega® # E1603®) to the growth medium and assaying luciferase activity with a TopCount® scintillation counter (Packard Model # C384V00). Transfectants were evaluated for reporter expression. Rat-1 cell clones expressing both zeocin resistance and mPer1 regulated luciferase activity were synchronized with serum shock using 50% horse serum [HS (Gibco® # 16050-122)] Circadian reporter activity was evaluated. The P2C4 clone of fibroblast Mper1-luc Rat-1 was selected to test the compound.

40-50% confluent Mper1-luc Rat-1 (P2C4) fibroblasts obtained according to the above protocol were seeded in 96-well opaque tissue culture plates (Perkin Elmer® # 600005680). This is maintained in growth medium supplemented with 100 mg / mL Zeocin (Invitrogen # 45-0430) until the culture is 100% confluent (48-72 hours). Subsequently, conditioned medium [EMEM (Cellgro # 10-010-CV), 100I. U. Cultures were synchronized for 2 hours at 37 ° C. and 5% CO _{2 with} 100 μL / mL penicillin-streptomycin (Cellgro # 30-001-C1) 50% HS (Gibco # 16050-122)]. After synchronization, the culture was rinsed with 100 μL of EMEM (Cellgro # 10-010-CV) for 10 minutes at room temperature. After rinsing, the medium was mixed with CO ₂ -independent medium [CO ₂ I (Gibco # 18045-088), 2 mM L-glutamine (Cellgro # 25-005-C1), 100I. U. / ML penicillin-streptomycin (Cellgro # 30-001-C1), 100 μM luciferin (Promega # E1603)] and 300 μL. The compounds of the invention to be tested for circadian effects were added to CO ₂ -independent media at 0.3% (final concentration) in DMSO. The cultures were immediately sealed tightly with TopSeal-A® film (Packard # 60000515) and transferred for measurement of luciferase activity.

  After synchronization, the test plate was maintained at 37 ° C. in a tissue culture oven (Forma Scientific Model # 3914). In vivo luciferase activity was assessed by measuring relative luminescence with a TopCount scintillation counter (Packard Model # C384V00).

  Periodic analysis was performed either by determining the minimum interval of relative luminescence over several days or by Fourier transform. The two methods resulted in a substantially identical period estimate in the circadian period range. The output is given in ECδ (t + 1h), which is expressed as the effective micromolar concentration that induces a one hour extension of the cycle. Data represented by period change (y-axis) as a function of test compound concentration (x-axis) was analyzed by hyperbolic fitting with XLfit ™ software and ECδ (t + 1h) was interpolated from this curve.

  Table 4 below shows the EC δ (t + 1h) for some of the compounds described in the present invention.

これらの条件下では、最も活性が高い本発明化合物は、１ｎＭから２μＭの間のＥＣδ（ｔ＋１ｈ）（周期の１時間延長を誘導する有効マイクロモル濃度）を有する。

Under these conditions, the most active compounds of the invention have an ECδ (t + 1h) between 1 nM and 2 μM (effective micromolar concentration that induces a one hour extension of the cycle).

  By inhibiting the enzymes CK1ε and / or CK1δ, the compounds that are the subject of the present invention may be useful in treating circadian rhythm disorders because they modulate circadian rhythmicity.

  The compounds described in the present invention can be used in particular for the manufacture of a medicament for preventing or treating sleep disorders (circadian rhythm disorders, in particular due to jet lag or shift work).

  Among the sleep disorders that are particularly recognized are sleep failure (eg, primary insomnia), abnormal sleep behavior, hypersomnia (eg, excessive sleepiness), narcolepsy, sleep with sleep apnea Primary sleep disorders such as disorders, sleep disorders associated with circadian cycles, and other unlisted sleep disorders, sleep disorders associated with medical / psychiatric disorders.

  The compounds that are the subject of the present invention also cause a circadian phase shift, and such properties may be useful in the context of promising monotherapy or combination therapy that is clinically effective in the case of mood disorders.

  Among the mood disorders that are particularly recognized are depressive disorders (unipolar depression), bipolar disorders, mood disorders due to general medical conditions, and mood disorders induced by pharmacological substances. It is done.

  Among bipolar disorders, those that are particularly recognized include bipolar type I disorders, including seasonal affective disorders, and bipolar type II disorders.

  The compounds that are the subject of the present invention that modulate circadian periodicity can be particularly useful for the treatment of anxiety and depressive disorders caused by impaired secretion of CRF.

  Among the depressive disorders, those that are particularly recognized include major depressive disorders, dysthymic disorders, and other undocumented depressive disorders.

  The compounds that are the subject of the present invention that modulate circadian periodicity may be useful in the manufacture of a medicament for treating diseases associated with substance (cocaine, morphine, nicotine, ethanol, and cannabis) abuse dependence.

  By inhibiting casein kinase 1ε and / or casein kinase 1δ, the compounds described in the present invention can be used for the manufacture of a medicament, particularly for the manufacture of a medicament for the prevention or treatment of diseases associated with hyperphosphorylation of tau protein, particularly Alzheimer's disease. Can be used.

  These medicaments also find use in therapy, in particular in the treatment or prevention of diseases caused or exacerbated by cell proliferation, in particular tumor cell proliferation.

  As tumor cell growth inhibitors, these compounds are useful for liquid tumors (such as leukemia), solid tumors (both primary and metastatic), cell tumors, and cancer, particularly the following prevention and treatment: breast cancer , Lung cancer, small intestine cancer, colorectal cancer, airway cancer, oropharyngeal cancer, hypopharyngeal cancer, esophageal cancer, liver cancer, gastric cancer, bile duct cancer, gallbladder cancer, pancreatic cancer, urinary system (including kidney, urothelium, and bladder) .) Cancer, female genital cancer (including uterine cancer, cervical cancer, ovarian cancer, choriocarcinoma and trophoblastoma), male genital cancer (prostate cancer, seminal vesicle cancer, testicular cancer, and germ cells) Including tumors), endocrine gland cancer (including thyroid cancer, pituitary cancer, and adrenal cancer), skin cancer (including sarcomas including hemangioma, melanoma, and Kaposi's sarcoma), brain tumor, neuronal tumor , Eye tumor, or meningeal tumor (astrocytoma, glioma, nerve Including blastoma, retinoblastoma, schwannoma, neuroblastoma, Schwann cell tumor, and meningioma), hematopoietic tumor, leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) ), Chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL)), melanoma, plasmacytoma, T-cell or B-cell leukemia, Hodgkin or non-Hodgkin lymphoma, myeloma, and various malignant blood diseases.

  The compounds described in the present invention are used in the manufacture of pharmaceuticals, in particular inflammatory diseases, in particular central nervous system inflammatory diseases such as multiple sclerosis, encephalitis, myelitis, and encephalomyelitis and other inflammatory diseases. It can also be used for the manufacture of a medicament for the prevention or treatment of diseases such as vascular disease, atherosclerosis, arthritis, arthropathy, and rheumatoid arthritis.

  The compounds according to the invention can thus be used for the manufacture of a medicament, in particular for the manufacture of a medicament that inhibits casein kinase 1ε and / or casein kinase 1δ.

  Accordingly, in another aspect, the subject of the invention is a medicament comprising a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a hydrate or solvate of a compound of formula (I) It is.

  In another aspect, the invention relates to a pharmaceutical composition comprising as an active ingredient a compound according to the invention. Such a pharmaceutical composition comprises an effective amount of at least one compound according to the present invention or a pharmaceutically acceptable salt, hydrate or solvate of said compound, and at least one pharmaceutically acceptable. Excipients.

  Said excipients are selected from the usual excipients known to the person skilled in the art according to the pharmaceutical form and the desired mode of administration.

  In the pharmaceutical composition of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, topical, intratracheal, nasal, transdermal, or rectal administration, an active ingredient of the above formula (I), or This possible salt, hydrate, or solvate is administered to humans and animals for the prevention or treatment of the above disorders or diseases, in unit dosage form, as a mixture with conventional pharmaceutical excipients. Can do.

  Suitable unit dosage forms include oral dosage forms (tablets, soft or hard gel capsules, powders, granules, and oral solutions or suspensions), sublingual, buccal, intratracheal, intraocular, and nasal dosage forms , Inhaled forms, topical, transdermal, subcutaneous, intramuscular or intravenous dosage forms, rectal dosage forms, and implantable. For external use, the compounds of the invention can be used in creams, gels, ointments or lotions.

For example, a unit dosage form of a compound according to the invention in tablet form may contain the following components:
Compound described in the present invention: 50.0 mg
Mannitol: 223.75mg
Croscarmellose sodium: 6.0 mg
Corn starch: 15.0mg
Hydroxypropyl methylcellulose: 2.25mg
Magnesium stearate: 3.0mg
In the oral route, the dose of active ingredient administered per day is 0.1 to 20 mg / kg, the doses administered once or more.

  In some cases it may be appropriate to increase or decrease the dose. Such doses do not depart from the scope of the present invention. In accordance with normal practice, the appropriate dose for each patient is determined by the physician according to the mode of administration and the weight and response of the patient.

  In accordance with another aspect of the present invention, the present invention also relates to a method for treating the pathology shown above. This method comprises administering to a patient an effective amount of a compound according to the invention or a pharmaceutically acceptable salt or hydrate or solvate thereof.

Claims (14)

The following general formula (I) in the form of a base or acid addition salt:

In which R ₂ represents a pyridyl group optionally substituted with one or more substituents selected from a halogen atom and a C _1-6 -alkyl group;
R ₃ represents a hydrogen atom or a C _1-3 -alkyl group;
A represents a C _1-7 -alkylene group optionally substituted with one or two R _a groups;
B represents a C _1-7 -alkylene group optionally substituted with an R _b group;
L represents either a nitrogen atom optionally substituted with an R _c group or an R _d group, or a carbon atom substituted with an R _e1 group and an R _d group or with two R _e2 groups;
Carbon atoms of A and B is optionally substituted with one or more _the R _f group, _the R _f group may be the being the same or different;
R _a , R _b and R _c are defined as follows:
Two R _a groups may be taken together to form a C _1-6 -alkylene group;
R _a and R _b together may form a bond or a C _1-6 -alkylene group;
R _a and R _c together may form a bond or a C _1-6 -alkylene group;
R _b and R _c together may form a bond or a C _1-6 -alkylene group;
R _d represents a hydrogen atom and a C _1-6 -alkyl group, a C _3-7 -cycloalkyl group, a C _3-7 -cycloalkyl-C _1-6 -alkyl group, a C _1-6 -alkylthio-C _{1. -6} -alkyl group, C _1-6 -alkyloxy-C _1-6 -alkyl group, C _1-6 -fluoroalkyl group, benzyl group, C _1-6 -acyl group and hydroxy-C _1-6 -alkyl Represents a group selected from the group;
R _e1 represents a —NR ₄ R ₅ group or a cyclic monoamine optionally containing an oxygen atom, and the cyclic monoamine is derived from a fluorine atom and a C _1-6 -alkyl group, a C _1-6 -alkyloxy group, and a hydroxyl group. Optionally substituted with one or more selected substituents;
The two R _e2 groups together with the carbon atom to which they are attached form a cyclic monoamine optionally containing an oxygen atom, which cyclic monoamine is optionally substituted with one or more R _f groups, wherein the R _f group is May be the same or different;
R _f represents a C _1-6 -alkyl group, a C _3-7 -cycloalkyl group, a C _3-7 -cycloalkyl-C _1-6 -alkyl group, a C _1-6 -alkyloxy-C _1-6- Represents an alkyl group, a hydroxy-C _1-6 -alkyl group, a C _1-6 -fluoroalkyl group or a benzyl group;
R ₄ and R ₅ each independently represent a hydrogen atom, or a C _1-6 -alkyl group, a C _3-7 -cycloalkyl group or a C _3-7 -cycloalkyl-C _1-6 -alkyl group. ;
A compound in which R ₇ and R ₈ independently of each other represent a hydrogen atom or a C _1-6 -alkyl group. 2. The L according to claim 1, wherein L represents either a nitrogen atom optionally substituted with an R _c group or an R _d group or a carbon atom substituted with an R _e1 group and an R _d group. Compounds of general formula (I) R ₂ represents a pyridyl group optionally substituted with one or more substituents selected from fluorine and methyl groups, according to the general formula (1), A compound of I). The compound of general formula (I) according to any one of claims 1 to 3, characterized in that R ₇ and R ₈ represent a hydrogen atom or a C _1-6 -alkyl group. A represents a C _1-7 -alkylene group optionally substituted with one or two R _a groups;
B represents a C _1-7 -alkylene group optionally substituted with an R _b group;
L represents a nitrogen atom optionally substituted with an R _c group or an R _d group;
Carbon atoms of A and B is optionally substituted with one or more _the R _f group, _the R _f group may be the being the same or different;
R _a , R _b and R _c are defined as follows:
Two R _a groups may be taken together to form a C _1-6 -alkylene group;
R _a and R _b together may form a bond or a C _1-6 -alkylene group;
R _a and R _c together may form a bond or a C _1-6 -alkylene group;
R _b and R _c together may form a bond or a C _1-6 -alkylene group;
R _d represents a hydrogen atom and a C _1-6 -alkyl group, a C _3-7 -cycloalkyl group, a C _3-7 -cycloalkyl-C _1-6 -alkyl group, a C _1-6 -alkylthio-C _{1- 6} -alkyl groups, C _1-6 -alkyloxy-C _1-6 -alkyl groups, C _1-6 -fluoroalkyl groups, benzyl groups, C _1-6 -acyl groups and hydroxy-C _1-6 -alkyl groups Represents a group selected from:
R _f represents a C _1-6 -alkyl group, a C _3-7 -cycloalkyl group, a C _3-7 -cycloalkyl-C _1-6 -alkyl group, a C _1-6 -alkyloxy-C _1-6- It represents an alkyl group, a hydroxy-C _1-6 -alkyl group, a C _1-6 -fluoroalkyl group or a benzyl group, wherein the general formula (I) according to any one of claims 1 to 4 is represented. Compound. A represents a C _1-7 -alkylene group optionally substituted with one or two R _a groups;
B represents a C _1-7 -alkylene group optionally substituted with an R _b group;
L represents a carbon atom substituted with a R _e1 group and a R _d group;
Carbon atoms of A and B is optionally substituted with one or more _the R _f group, _the R _f group may be the being the same or different;
R _a , R _b and R _c are defined as follows:
Two R _a groups may be taken together to form a C _1-6 -alkylene group;
R _a and R _b together may form a bond or a C _1-6 -alkylene group;
R _a and R _c together may form a bond or a C _1-6 -alkylene group;
R _b and R _c together may form a bond or a C _1-6 -alkylene group;
R _d represents a hydrogen atom and a C _1-6 -alkyl group, a C _3-7 -cycloalkyl group, a C _3-7 -cycloalkyl-C _1-6 -alkyl group, a C _1-6 -alkylthio-C _{1- 6} -alkyl groups, C _1-6 -alkyloxy-C _1-6 -alkyl groups, C _1-6 -fluoroalkyl groups, benzyl groups, C _1-6 -acyl groups and hydroxy-C _1-6 -alkyl groups Represents a group selected from:
R _e1 represents a —NR ₄ R ₅ group or a cyclic monoamine optionally containing an oxygen atom, and the cyclic monoamine is derived from a fluorine atom and a C _1-6 -alkyl group, a C _1-6 -alkyloxy group, and a hydroxyl group. Optionally substituted with one or more selected substituents;
R _f represents a C _1-6 -alkyl group, a C _3-7 -cycloalkyl group, a C _3-7 -cycloalkyl-C _1-6 -alkyl group, a C _1-6 -alkyloxy-C _1-6- Represents an alkyl group, a hydroxy-C _1-6 -alkyl group, a C _1-6 -fluoroalkyl group or a benzyl group;
R ₄ and R ₅ each independently represent a hydrogen atom or a C _1-6 -alkyl group, a C _3-7 -cycloalkyl group or a C _3-7 -cycloalkyl-C _1-6 -alkyl group. A compound of general formula (I) according to any one of claims 1 to 5, characterized in that The cyclic amine formed by -N-A-L-B- is (3S) -3-methylpiperazin-1-yl group, 3,3-dimethylpiperazin-1-yl group, 4-isopropylpiperazine-1- Yl group, piperazin-1-yl group, (3R) -3-isopropylpiperazin-1-yl group, (cis) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl group Or represents a 4-pyrrolidin-1-ylpiperidin-1-yl group;
R ₂ represents a pyridyl group optionally substituted with one or more substituents selected from fluorine and methyl groups;
R ₃ represents a hydrogen atom or a methyl group;
R ₇ and R ₈ represent a hydrogen atom or a methyl group,
7. A compound of general formula (I) according to any one of claims 1 to 6, characterized in that it is in the form of a base or an acid addition salt. The following general formula (II):

In which R ₂ , R ₃ , R ₇ and R ₈ are as defined in claim 1, X ₆ represents halogen,
The compound of the following general formula (III):

Wherein A, L and B are as defined in claim 1;
A process for the preparation of a compound of general formula (I) according to claim 1, characterized in that it is reacted with an amine of The following general formula (V):

Wherein A, L, B, R ₂ , R ₇ and R ₈ are as defined in claim 1;
The compound of the following general formula (Va):

In which R ₃ is as defined in claim 1;
Is reacted with a mixture of a pyridine derivative of the above and an alkyl chloroformate (wherein the alkyl group represents C _1-6 -alkyl) to give the following general formula (VI):

Wherein A, L, B, R ₂ , R ₃ , R ₇ and R ₈ are as defined in claim 1;
A process for preparing a compound of general formula (I) according to claim 1, characterized in that the compound of general formula (VI) is obtained and then the compound of general formula (VI) is oxidized with ortho-chloranil. The following general formula (V):

Wherein A, L, B, R ₂ , R ₇ and R ₈ are as defined in claim 1;
Is reacted with an aromatic bromination reaction or iodination reaction to give the following general formula (VII):

In which A, L, B, R ₂ , R ₇ and R ₈ are as defined in claim 1, X ₃ represents a bromine atom or an iodine atom,
And then the resulting compound of general formula (VII) and the following general formula (IIIa):

In which R ₃ is as defined in claim 1 and M represents a trialkylstannyl group or a dihydroxyboryl group or a dialkyloxyboryl group,
The method for preparing a compound of the general formula (I) according to claim 1, wherein coupling with a pyridine derivative of is performed using a metal catalyst. a) The following general formula (VIII):

Wherein A, L, B, R ₇ and R ₈ are as defined in claim 1;
Are reacted by an aromatic iodination reaction to give the following general formula (IX):

Wherein A, L, B, R ₇ and R ₈ are as defined in claim 1;
To obtain a compound of
b) The compound of general formula (IX) obtained in a) is converted to the following general formula (IIIa):

In which R ₃ is as defined in claim 1 and M represents a trialkylstannyl group or a dihydroxyboryl group or a dialkyloxyboryl group,
The following general formula (X):

Wherein A, L, B, R ₃ , R ₇ and R ₈ are as defined in claim 1;
To obtain a compound of
c) In the presence of a catalyst, the compound of general formula (X) obtained in b) is converted to the following general formula (Xa):
R ₂ -M (Xa)
In which R ₂ is as defined in claim 1 and M represents a trialkylstannyl group or a dihydroxyboryl group or a dialkyloxyboryl group,
A process for the preparation of a compound of general formula (I) according to claim 1, characterized in that it is reacted with.   A medicament comprising a compound of formula (I) according to any one of claims 1 to 7 in the form of a base or in the form of a pharmaceutically acceptable acid addition salt.   8. A compound of formula (I) according to any one of claims 1 to 7, and at least one pharmaceutically acceptable excipient, in the form of a base or in the form of a pharmaceutically acceptable acid addition salt. A pharmaceutical composition comprising an agent.   Sleep disorders or circadian rhythm disorders, mood disorders, anxiety and depressive disorders, diseases associated with substance abuse dependence, diseases associated with tau protein hyperphosphorylation, diseases caused or exacerbated by cell proliferation, or inflammation Use of a compound of general formula (I) according to any one of claims 1 to 7 for the manufacture of a medicament for the prevention or treatment of sexually transmitted diseases.