JP2009501740A - Phenyl-substituted piperazine derivatives as plasminogen activator inhibitor-I (PAI-I) - Google Patents

Abstract

  The present invention relates to substituted pyridinecarboxamides, methods for their production, and their use for the manufacture of a medicament for the treatment and / or prevention of diseases, particularly thrombosis in humans and animals.

Description

  The present invention relates to substituted pyridinecarboxamides, processes for their preparation and their use for the manufacture of medicaments for the treatment and / or prevention of human and animal diseases, in particular thrombosis.

  Plasminogen activator inhibitor-1 (PAI-1) is the most important regulatory component of the plasminogen-plasmin system. The fibrinolytic system contains the proenzyme plasminogen which is converted to the active enzyme plasmin by two plasminogen activators, tPA and uPA. PAI-1 is a major physiological inhibitor of both tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). One of the main functions of plasmin in the fibrinolytic system is to degrade fibrin at the site of vascular injury. The fibrinolytic system, however, is not only involved in removing fibrin from the blood circulation, but also in various other processes including ovulation, embryogenesis, intimal proliferation, angiogenesis, tumorigenesis and atherosclerosis. concern.

  Elevated plasma PAI-1 levels are associated with many diseases and conditions that cause impairment of the fibrinolytic system. Thus, for example, elevated plasma PAI-1 levels, for example, a thrombus characterized by the occurrence of a thrombus that locally decreases vascular blood flow or separates and embolizes to obstruct downstream blood flow (Krishnamurti, Blood, 69, 798 (1987); Reilly, Arteriosclerosis and Thrombosis, 11, 1276 (1991); Carmeliet, Journal of Clinical Investigations, 92, 2756 (1993); Rocha, Fibrinolysis, 8 , 294, 1994; Aznar, Haemostasis, 24, 243 (1994)). Neutralizing antibodies of PAI-1 activity result in a fast rate of endogenous fibrinolysis and perfusion (Biemond, Circulation, 91, 1175 (1995); Levi, Circulation, 85, 305 (1992)).

  Accordingly, one object of the present invention is to provide novel PAI-1 inhibitors for the treatment of thrombotic diseases in humans and animals.

  Structures similar to the compounds of the present invention are described in WO 03/080060 and WO 03/080564 as PAI-1 inhibitors for the treatment of thrombotic diseases. WO95 / 33750 describes inter alia substituted pyridinecarboxamides as corticotropin releasing factor (CRF) antagonists for the treatment of diseases of the central nervous system, and WO03 / 061387 to control algae by using substituted pyridinecarboxamides. The method is described.

〔式中、
Ｘは式

｛ここで、
＊はカルボニル基に結合する位置であり、
＃は酸素原子に結合する位置であり、
そして
Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５は互いに独立して水素、ハロゲン、ヒドロキシ、アミノ、シアノ、ニトロ、トリフルオロメチル、Ｃ_１−Ｃ_４−アルキル、Ｃ_１−Ｃ_４−アルコキシ、Ｃ_１−Ｃ_６−アルキルアミノ、Ｃ_１−Ｃ_４−アルコキシカルボニルまたはＣ_１−Ｃ_６−アルキルアミノカルボニルである｝の基であり、
Ｙはフェニルまたはピリジルであり
｛ここで、フェニルおよびピリジルは１から３個の置換基により置換されていてもよい（ここで、置換基は互いに独立してハロゲン、ヒドロキシ、アミノ、シアノ、トリフルオロメチル、トリフルオロメトキシ、ヒドロキシカルボニル、アミノカルボニル、Ｃ_１−Ｃ_６−アルキル、Ｃ_１−Ｃ_６−アルコキシ、Ｃ_１−Ｃ_６−アルキルアミノ、Ｃ_１−Ｃ_６−アルキルカルボニル、Ｃ_１−Ｃ_６−アルコキシカルボニルおよびＣ_１−Ｃ_６−アルキルアミノカルボニルからなる群から選択される）｝、
ｎは０、１、２または３の数であり、
Ｒ^１はフェニルまたは５−もしくは６−員ヘテロアリールである
｛ここで、フェニルおよびヘテロアリールは１から３個の置換基により置換されていてもよい（ここで、置換基は互いに独立してハロゲン、ヒドロキシ、アミノ、シアノ、トリフルオロメチル、トリフルオロメトキシ、ヒドロキシカルボニル、アミノカルボニル、Ｃ_１−Ｃ_６−アルキル、Ｃ_１−Ｃ_６−アルコキシ、Ｃ_１−Ｃ_６−アルキルアミノ、Ｃ_１−Ｃ_６−アルキルカルボニル、Ｃ_１−Ｃ_６−アルコキシカルボニル、Ｃ_１−Ｃ_６−アルキルアミノカルボニルおよびＣ_１−Ｃ_６−アルキルスルホニルアミノからなる群から選択される）｝〕
で示される化合物およびそれらの塩、水和物、塩の水和物および溶媒和物に関する。 The present invention has the formula

[Where,
X is the formula

{here,
* Is the position bonded to the carbonyl group,
# Is the position of bonding to the oxygen atom,
R ² , R ³ , R ⁴ and R ⁵ are independently of each other hydrogen, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₆ -alkylamino, C ₁ -C ₄ -alkoxycarbonyl or C ₁ -C ₆ -alkylaminocarbonyl}
Y is phenyl or pyridyl {wherein phenyl and pyridyl may be substituted by 1 to 3 substituents, where the substituents are independently of one another halogen, hydroxy, amino, cyano, trifluoro; , trifluoromethoxy, hydroxycarbonyl, _{aminocarbonyl,} C 1 -C ₆ - _alkyl, C 1 -C ₆ - _alkoxy, C 1 -C ₆ - _alkylamino, C 1 -C ₆ - _{alkylcarbonyl,} C 1 -C Selected from the group consisting of ₆ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl)},
n is a number 0, 1, 2 or 3;
R ¹ is phenyl or 5- or 6-membered heteroaryl {wherein phenyl and heteroaryl may be substituted by 1 to 3 substituents, wherein the substituents are independently of one another halogen , hydroxy, amino, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, _{aminocarbonyl,} C 1 -C ₆ - _alkyl, C 1 -C ₆ - _alkoxy, C 1 -C ₆ - _alkylamino, C 1 -C _6- alkylcarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkylaminocarbonyl and C ₁ -C ₆ -alkylsulfonylamino)}]
And a salt, hydrate, salt hydrate and solvate thereof.

  The compounds of the present invention include compounds of formula (I) and their salts, solvates and salt solvates, compounds encompassed by formula (I) of the following formula and their salts, solvates and salts Solvates, and compounds encompassed by formula (I) and described below as typical embodiments, and salts, solvates and solvates of the salts thereof (compounds encompassed by formula (I) described below) Is not already a salt, solvate or salt solvate).

  Depending on the structure, the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The present invention therefore includes the enantiomers or diastereomers and their respective mixtures. Stereoisomerically pure constituents can be isolated by known methods from such mixtures of enantiomers and / or diastereomers.

  When the compounds of the present invention can give rise to tautomers, the present invention encompasses all tautomeric forms.

Preferred salts for the purposes of the invention are physiologically acceptable salts of the compounds of the invention. However, salts which are unsuitable for pharmaceutical applications, but can be used, for example, to isolate or purify the compounds of the invention are also included.

  Physiologically acceptable salts of the compounds of the invention are acid addition salts of mineral acids, carboxylic acids and sulfonic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfone. Including salts of acids, benzenesulfonic acid, naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

  Physiologically acceptable salts of the compounds according to the invention are also customary base salts, such as preferably alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts). And ammonia or an organic amine containing 1 to 16 C atoms, for example, preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dica Including ammonium salts derived from benzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

A solvate means, for the purposes of the present invention, a form of a compound of the invention which forms a solid or liquid complex through coordination with solvent molecules. Hydrates are a specific form of solvates in which coordination occurs with water.

For the purposes of the present invention, substituents have the following meanings unless otherwise indicated:
Alkyl itself and “alk” and “alkyl” of alkoxy, alkylamino, alkylcarbonyl, alkylaminocarbonyl, alkoxycarbonyl and alkylsulfonylamino usually have 1 to 6, preferably 1 to 4, particularly preferably 1 Represents a straight-chain or branched alkyl group having from 3 to 3 carbon atoms, for example, preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxy represents, for example, preferably methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylamino is one or two alkyl substituents (selected independently of one another), for example, preferably methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentyl Amino, n-hexylamino, N, N-dimethylamino, N, N-diethylamino, N, N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl Represents an alkylamino group having -Nn-propylamino, N-tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino. C ₁ -C ₄ -alkylamino is, for each alkyl substituent, for example a monoalkylamino group having 1 to 4 carbon atoms or a dialkylamino having 1 to 4 carbon atoms in each alkyl substituent Represents a group.

Alkylcarbonyl represents, for example, preferably methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl and n-hexylcarbonyl.

Alkylaminocarbonyl represents an alkylaminocarbonyl group having 1 or 2 alkyl substituents (selected independently of one another). C ₁ -C ₃ -alkylaminocarbonyl has in each alkyl substituent, for example, a monoalkylaminocarbonyl group having 1 to 3 carbon atoms or 1 to 3 carbon atoms in each alkyl substituent. Represents a dialkylaminocarbonyl group. For example, preferably: methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N, N -Dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl-Nn-propylaminocarbonyl, N-tert- Examples include butyl-N-methylaminocarbonyl, N-ethyl-Nn-pentylaminocarbonyl, and Nn-hexyl-N-methylaminocarbonyl.

Alkoxycarbonyl represents, for example, preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Alkylsulfonylamino represents, for example, preferably methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, n-pentylsulfonylamino and n-hexylsulfonylamino.

A heteroaryl is typically an aromatic monocyclic group having 5 or 6 ring atoms and up to 4, preferably up to 3, heteroatoms from the group S, O and N, for example, preferably Represents thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl and pyridazinyl.

Halogen represents fluorine, chlorine, bromine and iodine.

In the formula of the group representing X, the end of the line where * or # is present does not mean a carbon atom or a CH ₂ group, but forms a carbonyl group to which X is bonded or a part of an oxygen atom. .

When groups of the compounds of the invention are substituted , the groups may be substituted with the same or different one or more substituents, unless otherwise specified. Substitution with up to 3 identical or different substituents is preferred. Even more particularly preferred is substitution with one substituent.

｛ここで、
＊はカルボニル基に結合する位置であり、
＃は酸素原子に結合する位置であり、
そして
Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５は互いに独立して水素、ハロゲン、ヒドロキシ、アミノ、シアノ、ニトロ、トリフルオロメチル、Ｃ_１−Ｃ_４−アルキル、Ｃ_１−Ｃ_４−アルコキシ、Ｃ_１−Ｃ_６−アルキルアミノ、Ｃ_１−Ｃ_４−アルコキシカルボニルまたはＣ_１−Ｃ_６−アルキルアミノカルボニルである｝の基であり、
Ｙがフェニルであり
｛ここで、フェニルは１から３個の置換基により置換されていてもよい（ここで、置換基は互いに独立してハロゲン、ヒドロキシ、アミノ、シアノ、トリフルオロメチル、トリフルオロメトキシ、ヒドロキシカルボニル、アミノカルボニル、Ｃ_１−Ｃ_６−アルキル、Ｃ_１−Ｃ_６−アルコキシ、Ｃ_１−Ｃ_６−アルキルアミノ、Ｃ_１−Ｃ_６−アルキルカルボニル、Ｃ_１−Ｃ_６−アルコキシカルボニルおよびＣ_１−Ｃ_６−アルキルアミノカルボニルからなる群から選択される）｝、
ｎが０の数であり、
Ｒ^１がフェニルである
｛ここで、フェニルは１から３個の置換基により置換されていてもよい（ここで、置換基は互いに独立してハロゲン、ヒドロキシ、アミノ、シアノ、トリフルオロメチル、トリフルオロメトキシ、ヒドロキシカルボニル、アミノカルボニル、Ｃ_１−Ｃ_６−アルキル、Ｃ_１−Ｃ_６−アルコキシ、Ｃ_１−Ｃ_６−アルキルアミノ、Ｃ_１−Ｃ_６−アルキルカルボニル、Ｃ_１−Ｃ_６−アルコキシカルボニル、Ｃ_１−Ｃ_６−アルキルアミノカルボニルおよびＣ_１−Ｃ_６−アルキルスルホニルアミノからなる群から選択される）｝
式（Ｉ）の化合物、およびそれらの塩、水和物、塩の水和物および溶媒和物である。 Preferably,
X is an expression

{here,
* Is the position bonded to the carbonyl group,
# Is the position of bonding to the oxygen atom,
R ² , R ³ , R ⁴ and R ⁵ are independently of each other hydrogen, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₆ -alkylamino, C ₁ -C ₄ -alkoxycarbonyl or C ₁ -C ₆ -alkylaminocarbonyl}
Y is phenyl {wherein the phenyl may be substituted by 1 to 3 substituents (wherein the substituents are independently of one another halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoro methoxy, hydroxycarbonyl, _{aminocarbonyl,} C 1 -C ₆ - _alkyl, C 1 -C ₆ - _alkoxy, C 1 -C ₆ - _alkylamino, C 1 -C ₆ - _{alkylcarbonyl,} C 1 -C ₆ - alkoxycarbonyl And C ₁ -C ₆ -alkylaminocarbonyl)}
n is a number of 0;
R ¹ is phenyl {wherein the phenyl may be substituted by 1 to 3 substituents (wherein the substituents are independently of one another halogen, hydroxy, amino, cyano, trifluoromethyl, tri trifluoromethoxy, hydroxycarbonyl, _{aminocarbonyl,} C 1 -C ₆ - _alkyl, C 1 -C ₆ - _alkoxy, C 1 -C ₆ - _alkylamino, C 1 -C ₆ - _{alkylcarbonyl,} C 1 -C ₆ - alkoxy Selected from the group consisting of carbonyl, C ₁ -C ₆ -alkylaminocarbonyl and C ₁ -C ₆ -alkylsulfonylamino)}
Compounds of formula (I) and their salts, hydrates, salt hydrates and solvates.

｛ここで、
＊はカルボニル基に結合する位置であり、
＃は酸素原子に結合する位置であり、
そして
Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５は水素である｝の基であり、
Ｙがフェニルであり
｛ここで、フェニルは１から２個の置換基により置換されていてもよい（ここで、置換基は互いに独立してハロゲンおよびＣ_１−Ｃ_４−アルコキシからなる群から選択される）｝、
ｎが０の数であり、
Ｒ^１がフェニルである
｛ここで、フェニルは１から３個の置換基により置換されていてもよい（ここで、置換基は互いに独立してハロゲン、シアノ、トリフルオロメチル、メチル、メトキシおよびメチルスルホニルアミノからなる群から選択される）｝
式（Ｉ）の化合物、およびそれらの塩、水和物、塩の水和物および塩の溶媒和物である。 Preferably also
X is an expression

{here,
* Is the position bonded to the carbonyl group,
# Is the position of bonding to the oxygen atom,
And R ² , R ³ , R ⁴ and R ⁵ are hydrogen}
Y is phenyl {wherein phenyl is optionally substituted by 1 to 2 substituents, wherein the substituents are selected from the group consisting of halogen and C ₁ -C ₄ -alkoxy independently of each other )},
n is a number of 0;
R ¹ is phenyl {wherein phenyl is optionally substituted by 1 to 3 substituents, where the substituents are independently of one another halogen, cyano, trifluoromethyl, methyl, methoxy and methyl Selected from the group consisting of sulfonylamino)}
Compounds of formula (I) and their salts, hydrates, salt hydrates and salt solvates.

｛ここで、
＊はカルボニル基に結合する位置であり、
＃は酸素原子に結合する位置であり、
そして
Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５は水素である｝の基である
式（Ｉ）の化合物である。 Preferably also
X is an expression

{here,
* Is the position bonded to the carbonyl group,
# Is the position of bonding to the oxygen atom,
And R ² , R ³ , R ⁴ and R ⁵ are hydrogen} is a compound of formula (I).

Preference is also given to compounds of the formula (I) in which R ² and R ³ are hydrogen.
Preference is also given to compounds of the formula (I) in which R ⁴ and R ⁵ are hydrogen.
Preference is also given to compounds of the formula (I) in which Y is phenyl.
Preference is also given to compounds of the formula (I) in which n is the number 0.
Preference is also given to compounds of the formula (I) in which R ¹ is phenyl, where phenyl is substituted once by trifluoromethyl.

〔式中、ＸおよびＲ^１は上記の意味を有する〕
で示される化合物を
式

〔式中、Ｘおよびｎは上記の意味を有する〕
で示される化合物と反応させることを特徴とする、式（Ｉ）の化合物を製造するための方法に関する。 The present invention further provides a formula

[Wherein X and R ¹ have the above-mentioned meanings]
A compound represented by the formula

[Wherein X and n have the above-mentioned meanings]
To a process for preparing a compound of formula (I), characterized in that it is reacted with a compound of formula (I).

  The reaction is generally carried out in an inert solvent in the presence of a base, preferably at atmospheric pressure from room temperature to the reflux temperature of the solvent.

  Examples of inert solvents are ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide or acetonitrile, with dimethyl sulfoxide being preferred.

  Examples of bases are alcoholates such as sodium or potassium methanolate, or sodium or potassium ethanolate or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or organometallic compounds, For example, butyl lithium or phenyl lithium, or other bases such as sodium hydride or DBU, with sodium hydride being preferred.

〔式中、Ｒ^１は上記で示される意味を有する〕
で示される化合物を式

〔式中、Ｘは上記で示される意味を有する〕
で示される化合物と反応させる事により製造することができる。 Compounds of formula (II) are known or of formula

[Wherein R ¹ has the meaning indicated above]
A compound represented by the formula

[Wherein X has the meaning indicated above]
It can manufacture by making it react with the compound shown by these.

  The reaction is generally carried out in an inert solvent, in the presence of a dehydrating agent, when appropriate, in the presence of a base, preferably at atmospheric pressure and at a temperature between −30 ° C. and 50 ° C.

  Examples of inert solvents are halohydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, nitromethane, dioxane, dimethylformamide or acetonitrile. It is likewise possible to use a mixture of solvents. Dichloromethane or dimethylformamide is particularly preferred.

  Examples of bases are alkali metal carbonates such as sodium or potassium carbonate, or bicarbonates, or organic bases such as trialkylamines such as triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylamino. Pyridine or diisopropylethylamine.

  Examples of suitable dehydrating agents in this connection are carbodiimides such as N, N′-diethyl-, N, N′-dipropyl-, N, N′-diisopropyl, N, N′-dicyclohexylcarbodiimide, N- ( 3-dimethylaminoisopropyl) -N′-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N′-propyloxymethylpolystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2- Oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulfate or 2-tert-butyl-5-methylisoxazolium perchloric acid, or acylamino compounds such as 2-ethoxy-1 -Ethoxycarbonyl-1,2-dihydroxy Phosphorus, or propanephosphonic anhydride, or isobutyl chloroformate, or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or O- (benzotriazol-1-yl) -N, N, N ′, N′— Tetramethyluronium hexafluorophosphate (HBTU), 2- (2-oxo-1- (2H) -pyridyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O- ( Benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium tetrafluoroborate (TBTU) or O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or Zotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), or benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), or N-hydroxysuccinimide, or a mixture thereof , And base.

  The condensation is preferably carried out with TBTU in the presence of diisopropylethylamine.

  Compounds of formula (III), (IV) and (V) are known per se to the person skilled in the art or can be prepared by conventional methods known from the literature.

スキーム２：

The production of the compounds of the present invention can be clarified by the following synthetic scheme.
Scheme 1:

Scheme 2:

  The compounds of the present invention exhibit an unexpected and valuable range of pharmacological and pharmacokinetic effects.

  It is therefore suitable for use as a medicament for the treatment and / or prevention of diseases in humans and animals.

  The pharmaceutical activity of the compounds of the present invention can be explained by their action as PAI-1 inhibitors.

  The invention further relates to the use of the compounds according to the invention for the treatment and / or prevention of diseases, preferably thrombotic diseases.

  The compounds of the present invention are thrombotic diseases such as venous and arterial thrombosis, pulmonary thrombosis, cerebral thrombosis, thromboembolism and deep vein thrombosis, or coronary heart disease, cardiac fibrillation, pulmonary fibrosis, cystic fibrosis, Thromboembolic complications or strokes such as thrombotic and thromboembolic stroke, or transient ischemic stroke, reocclusion and restenosis after coronary surgery (reocclusion and restenosis after percutaneous coronary surgery, Reocclusion and restenosis after coronary artery bypass surgery), disseminated intravascular coagulation syndrome, or surgery, eg pulmonary embolism, stroke, vascular surgery, vascular replacement, stent placement, organisation, tissue and cell implementation ) And transplants, or cardiovascular diseases such as myocardial infarction, arteriosclerotic plaque formation, cardiac infarction, stable and unstable angina, or chronic obstructive pulmonary disease, renal fibrosis, polycystic Nest syndrome, Alzheimer's disease, osteolysis induced by estrogen deficiency, diabetes, obesity, chronic periodontitis, lymphoma, extracellular matrix accumulation-related diseases, inflammatory diseases such as asthma, septic shock, kidney disease, For the prevention and / or treatment of obesity, insulin resistance, angiogenesis-related diseases or cancers, eg vascular damage due to leukemia, malignancy or infection, and high uPA level-related diseases such as breast cancer and ovarian cancer Is appropriate.

  The compounds of the present invention can further influence atherosclerotic vascular diseases such as restenosis, coronary heart disease, cerebral ischemia and peripheral arterial occlusive disease to influence wound healing to support thrombolytic therapy Prevention of degenerative diseases such as neurodegenerative diseases and osteoporosis, heart failure, hypertension, inflammatory diseases such as asthma, inflammatory lung disease, glomerulonephritis, inflammatory bowel disease and rheumatic diseases of the motor system And can be used in treatment.

  The compounds of the present invention may be used in the processing of blood and blood products used for dialysis and blood storage in the liquid phase, particularly for ex vivo platelet aggregation. The compounds can also be added to human plasma during blood chemistry analysis under hospital conditions to determine fibrinolytic capacity.

  The compounds of the present invention can also be used in combination with prothrombolytic agents, fibrinolytic agents and anticoagulants.

  The invention further relates to the use of the compounds according to the invention for the prevention and / or treatment of diseases, in particular the above mentioned pathologies.

  The invention further relates to the use of the compounds according to the invention for the manufacture of a medicament for the prevention and / or treatment of diseases, in particular the above mentioned pathologies.

  The present invention further relates to a method for preventing and / or treating diseases, especially the diseases mentioned above, by using an amount having a cardiovascular activity of a compound of the invention.

  The invention further relates to a medicament comprising a compound of the invention in combination with one or more further active ingredients, in particular for preventing and / or treating the abovementioned diseases.

  The compounds of the invention can act systemically and / or locally. For this purpose, they are suitable in a suitable way, for example orally, parenterally, pulmonary, nasally, sublingually, lingually, buccal, rectally, dermally, transdermally. Can be administered by the conjunctival or transauricular route, or as an implant or stent.

  The compounds of the present invention can be administered by any route suitable for these routes.

  Suitable for oral administration are dosage forms that function according to the prior art, deliver the compounds of the invention in a rapid and / or modified manner, and contain the compounds of the invention in crystalline and / or amorphous and / or dissolved forms. For example, a tablet (uncoated or, for example, an enteric coating or a coated tablet with a coating that is insoluble or that dissolves slowly and controls the release of the compounds of the invention), in the mouth Quickly disintegrating tablets or film / cache, film / lyophilizer, capsule (eg, hard or soft gelatin capsule), dragee, granule, pellet, powder, emulsion, suspension, aerosol, or liquid is there.

  Parenteral administration avoids the absorption phase (eg intravenous, intraarterial, intracardiac, spinal or lumbar) or includes absorption (eg intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal) be able to. Suitable dosage forms for parenteral administration are, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.

  Other suitable administration routes are, for example, pharmaceutical forms for inhalation (especially powder inhalers, nebulizers), nasal drops, liquids, sprays; tablets for tongue, sublingual or buccal administration, films / oblates or capsules, suppositories , Eye or ear formulations, vaginal capsules, aqueous suspensions (lotions, stirred mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, sprays A dusting powder, an implant or a stent.

  The compounds of the invention can be converted into the stated administration forms. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable auxiliaries. These adjuvants include, inter alia, carriers (eg, microcrystalline cellulose, lactose, mannitol), solvents (eg, liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (eg, sodium dodecyl sulfate, polyoxysorbitan oleate). , Binders (eg, polyvinylpyrrolidone), synthetic and natural polymers (eg, albumin), stabilizers (eg, antioxidants, eg, ascorbic acid), colorants (eg, inorganic pigments, eg, iron oxide) and flavors And / or an odor masking agent.

  The present invention further comprises a medicament comprising at least one compound of the present invention, preferably together with one or more inert, non-toxic, pharmaceutically suitable auxiliaries, and for the above purposes Relating to their use.

  To obtain the desired results, a total amount of about 0.01 to about 700, preferably 0.01 to 100 mg / kg body weight of a compound of the invention is administered every 24 hours in multiple single dosage forms when appropriate. Proved to be generally advantageous in human and veterinary drugs. Single dosage forms preferably contain the compound of the invention in an amount of about 0.1 to about 80, in particular 0.1 to 30 mg / kg body weight.

  Nevertheless, it may be necessary to deviate from the stated amounts when appropriate, depending in particular on body weight, mode of administration, individual response to the active ingredient, the nature of the formulation and the time or interval of administration. Thus, doses lower than the minimum amount may be sufficient, while the upper limit described may have to be exceeded. When administered in large amounts, it may be desirable to divide these into multiple individual doses over the day.

  Unless otherwise stated, the% data in the following tests and examples are percentages by weight; parts are parts by weight. Liquid / liquid solution solvent ratios, dilution ratios and concentration data are based on volume in each case.

A. Example
Abbreviations:

３００ｍｇ（２.０６ｍｍｏｌ）の２−フルオロニコチン酸を、丸底フラスコ中の１０ｍｌのジクロロメタンに入れ、９９３ｍｇ（３.０９ｍｍｏｌ）のＴＢＴＵを加える。０.５３９ｍｌ（３.０９ｍｍｏｌ）のジイソプロピルエチルアミンを滴下し、その後室温で１０分間撹拌し、次いで５３２.９６ｍｇ（２.２７ｍｍｏｌ）の３−ピペラジノベンゾトリフルオリドを加える。混合物を室温で１６時間撹拌し、溶媒を完全に除去する。分取ＨＰＬＣによる精製で６５２ｍｇ（理論値の８９％）の生成物を得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝３５４（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 8.37 (d, 1H), 8.08 (t, 1H), 7.49 (t, 1H), 7.43 (d, 1H), 7.24 (d, 1H), 7.21 (s, 1H), 7.11 (d, 1H), 3.80 (t, 2H), 3.34-3.40 (m, 4H), 3.23 (t, 2H)。 Starting compound
Example 1A
1-[(2-Fluoropyridin-3-yl) carbonyl] -4- [3- (trifluoromethyl) phenyl] piperazine

300 mg (2.06 mmol) of 2-fluoronicotinic acid is placed in 10 ml of dichloromethane in a round bottom flask and 993 mg (3.09 mmol) of TBTU is added. 0.539 ml (3.09 mmol) of diisopropylethylamine is added dropwise followed by stirring for 10 minutes at room temperature and then 532.96 mg (2.27 mmol) of 3-piperazinobenzotrifluoride are added. The mixture is stirred at room temperature for 16 hours and the solvent is completely removed. Purification by preparative HPLC gives 652 mg (89% of theory) of product.
MS (ESIpos): m / z = 354 (M + H) ^<+> .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.37 (d, 1H), 8.08 (t, 1H), 7.49 (t, 1H), 7.43 (d, 1H), 7.24 (d, 1H), 7.21 (s, 1H), 7.11 (d, 1H), 3.80 (t, 2H), 3.34-3.40 (m, 4H), 3.23 (t, 2H).

１５０ｍｇ（１.０４ｍｍｏｌ）の２−フルオロ−４−ピリジンカルボン酸を丸底フラスコ中の１０ｍｌのジクロロメタンに入れ、５０２ｍｇ（１.５６ｍｍｏｌ）のＴＢＴＵを加える。０.２７２ｍｌ（１.５６ｍｍｏｌ）のジイソプロピルエチルアミンを滴下し、その後室温で１０分間撹拌し、次いで３６７ｍｇ（１.５６ｍｍｏｌ）の３−ピペラジノベンゾトリフルオリドを加える。混合物を室温で１６時間撹拌し、溶媒を完全に除去する。分取ＨＰＬＣによる精製で２７２ｍｇ（理論値の７４％）の生成物を得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝３５４（Ｍ＋Ｈ）^＋。
¹H-NMR (300MHz, DMSO-d₆): δ= 8.35 (d, 1H), 7.4-7.69 (m, 2H), 7.30 (s, 1H), 7.24 (d, 1H), 7.19 (s, 1H), 7.11 (d, 1H), 3.78 (m, 2H), 3.39 (m, 4H), 3.26 (m, 2H)。 Example 2A
1- (2-Fluoroisonicotinoyl) -4- [3- (trifluoromethyl) phenyl] piperazine

150 mg (1.04 mmol) of 2-fluoro-4-pyridinecarboxylic acid is placed in 10 ml of dichloromethane in a round bottom flask and 502 mg (1.56 mmol) of TBTU is added. Add 0.272 ml (1.56 mmol) of diisopropylethylamine dropwise, then stir at room temperature for 10 minutes, then add 367 mg (1.56 mmol) of 3-piperazinobenzotrifluoride. The mixture is stirred at room temperature for 16 hours and the solvent is completely removed. Purification by preparative HPLC gives 272 mg (74% of theory) of product.
MS (ESIpos): m / z = 354 (M + H) ^<+> .
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 8.35 (d, 1H), 7.4-7.69 (m, 2H), 7.30 (s, 1H), 7.24 (d, 1H), 7.19 (s, 1H ), 7.11 (d, 1H), 3.78 (m, 2H), 3.39 (m, 4H), 3.26 (m, 2H).

１００ｍｇ（０.７１ｍｍｏｌ）の２−フルオロニコチン酸を丸底フラスコ中の８ｍｌのジクロロメタンに入れ、３３１ｍｇ（１.０３ｍｍｏｌ）のＴＢＴＵを加える。０.１８ｍｌ（１.０３ｍｍｏｌ）のジイソプロピルエチルアミンを滴下し、その後室温で１０分間撹拌し、次いで１７４.１ｍｇ（０.７５６ｍｍｏｌ）の１−（４−トリフルオロメチルフェニル）ピペラジンを加える。混合物を室温で１６時間撹拌し、溶媒を完全に除去する。分取ＨＰＬＣによる精製で２２８ｍｇ（理論値の９４％）の生成物を固体として得る。
ＭＳ（ＤＣＩ、ＮＨ_３）：ｍ／ｚ＝３７１（Ｍ＋ＮＨ_４）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 8.36 (d, 1H), 8.08 (dt, 1H), 7.53 (d, 2H), 7.48-7.51 (m, 1H), 7.08 (d, 2H), 3.80 (t, 2H), 3.39-3.43 (m, 4H), 3.30 (s, 2H)。 Example 3A
1-[(2-Fluoropyridin-3-yl) carbonyl] -4- [4- (trifluoromethyl) phenyl] piperazine

100 mg (0.71 mmol) of 2-fluoronicotinic acid is placed in 8 ml of dichloromethane in a round bottom flask and 331 mg (1.03 mmol) of TBTU is added. 0.18 ml (1.03 mmol) of diisopropylethylamine is added dropwise, followed by stirring at room temperature for 10 minutes, and then 174.1 mg (0.756 mmol) of 1- (4-trifluoromethylphenyl) piperazine is added. The mixture is stirred at room temperature for 16 hours and the solvent is completely removed. Purification by preparative HPLC gives 228 mg (94% of theory) of the product as a solid.
_{MS (DCI, NH 3):} m / z = 371 (M + NH 4) +.
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.36 (d, 1H), 8.08 (dt, 1H), 7.53 (d, 2H), 7.48-7.51 (m, 1H), 7.08 (d, 2H ), 3.80 (t, 2H), 3.39-3.43 (m, 4H), 3.30 (s, 2H).

１００ｍｇ（０.７１ｍｍｏｌ）の２−フルオロニコチン酸を、実施例３Ａを製造するための方法と同様に１７５ｍｇ（０.７５６ｍｍｏｌ）の１−（３,４−ジクロロフェニル）ピペラジンと反応させ、対応するアミドを得る。分取ＨＰＬＣによる精製で２３６ｍｇ（理論値の９７％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝３５４（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 8.36 (d, 1H), 8.07 (dt, 1H), 7.47-7.51 (m, H), 7.42 (d, 1H), 7.16 (d, 1H), 6.95 (dd, 1H), 3.77 (t, 2H), 3.35-3.39 (m, 4H), 3.15-3.21 (m, 2H)。 Example 4A
1- (3,4-Dichlorophenyl) -4-[(2-fluoropyridin-3-yl) carbonyl] piperazine

100 mg (0.71 mmol) of 2-fluoronicotinic acid was reacted with 175 mg (0.756 mmol) of 1- (3,4-dichlorophenyl) piperazine analogously to the method for preparing Example 3A to give the corresponding amide. Get. Purification by preparative HPLC gives 236 mg (97% of theory) of the product as a solid.
MS (ESIpos): m / z = 354 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.36 (d, 1H), 8.07 (dt, 1H), 7.47-7.51 (m, H), 7.42 (d, 1H), 7.16 (d, 1H ), 6.95 (dd, 1H), 3.77 (t, 2H), 3.35-3.39 (m, 4H), 3.15-3.21 (m, 2H).

１００ｍｇ（０.７１ｍｍｏｌ）の２−フルオロニコチン酸を、実施例３Ａを製造するための方法と同様に２２５ｍｇ（０.７５６ｍｍｏｌ）の１−［３,５−ビス（トリフルオロメチル）フェニル］ピペラジンと反応させ、対応するアミドを得る。分取ＨＰＬＣによる精製で２１５ｍｇ（理論値の７４％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝４２２（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 8.36 (d, 1H), 8.08 (dt, 1H), 7.47-7.53 (m, 3H), 7.36 (s, 1H), 3.80 (t, 2H), 3.50 (m, 2H), 3.35-3.42 (m, 4H)。 Example 5A
1- [3,5-Bis (trifluoromethyl) phenyl] -4-[(2-fluoropyridin-3-yl) carbonyl] piperazine

100 mg (0.71 mmol) of 2-fluoronicotinic acid and 225 mg (0.756 mmol) of 1- [3,5-bis (trifluoromethyl) phenyl] piperazine as in the method for preparing Example 3A. React to obtain the corresponding amide. Purification by preparative HPLC gives 215 mg (74% of theory) of the product as a solid.
MS (ESIpos): m / z = 422 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.36 (d, 1H), 8.08 (dt, 1H), 7.47-7.53 (m, 3H), 7.36 (s, 1H), 3.80 (t, 2H ), 3.50 (m, 2H), 3.35-3.42 (m, 4H).

１００ｍｇ（０.７１ｍｍｏｌ）の２−フルオロニコチン酸を、実施例３Ａを製造するための方法と同様に１４８.７ｍｇ（０.７５６ｍｍｏｌ）の１−（２−クロロフェニル）ピペラジンと反応させ、対応するアミドを得る。分取ＨＰＬＣによる精製で２０８ｍｇ（理論値の９５％）の生成物を油状物として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝３２０（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 8.35 (d, 1H), 8.08 (dt, 1H), 7.49 (m, 1H), 7.43 (dd, 1H), 7.32 (t, 1H), 7.18 (dd, 1H), 7.08 (t, 1H), 3.82 (t, 2H), 3.41 (t, 2H), 3.05 (t, 2H), 2.95 (t, 2H)。 Example 6A
1- (2-Chlorophenyl) -4-[(2-fluoropyridin-3-yl) carbonyl] piperazine

100 mg (0.71 mmol) of 2-fluoronicotinic acid was reacted with 148.7 mg (0.756 mmol) of 1- (2-chlorophenyl) piperazine analogously to the method for preparing Example 3A to give the corresponding amide. Get. Purification by preparative HPLC gives 208 mg (95% of theory) of the product as an oil.
MS (ESIpos): m / z = 320 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.35 (d, 1H), 8.08 (dt, 1H), 7.49 (m, 1H), 7.43 (dd, 1H), 7.32 (t, 1H), 7.18 (dd, 1H), 7.08 (t, 1H), 3.82 (t, 2H), 3.41 (t, 2H), 3.05 (t, 2H), 2.95 (t, 2H).

１００ｍｇ（０.７１ｍｍｏｌ）の２−フルオロニコチン酸を、実施例３Ａを製造するための方法と同様に１４１.６ｍｇ（０.７５６ｍｍｏｌ）の４ピペラジン−１−イル−ベンゾニトリルと反応させ、対応するアミドを得る。分取ＨＰＬＣによる精製で２０１ｍｇ（理論値の９４％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝３１１（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 8.36 (d, 1H), 8.08 (dt, 1H), 7.61 (d, 2H), 7.46-7.52 (m, 1H), 7.03 (d, 2H), 3.78 (t, 2H), 3.48 (t, 2H), 3.35-3.41 (m, 4H)。 Example 7A
4- {4-[(2-Fluoropyridin-3-yl) carbonyl] piperazin-1-yl} benzonitrile

100 mg (0.71 mmol) of 2-fluoronicotinic acid is reacted with 141.6 mg (0.756 mmol) of 4-piperazin-1-yl-benzonitrile analogously to the method for preparing Example 3A and the corresponding Obtain the amide. Purification by preparative HPLC gives 201 mg (94% of theory) of the product as a solid.
MS (ESIpos): m / z = 311 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.36 (d, 1H), 8.08 (dt, 1H), 7.61 (d, 2H), 7.46-7.52 (m, 1H), 7.03 (d, 2H ), 3.78 (t, 2H), 3.48 (t, 2H), 3.35-3.41 (m, 4H).

１００ｍｇ（０.７１ｍｍｏｌ）の２−フルオロニコチン酸を、実施例３Ａを製造するための方法と同様に１４８.７ｍｇ（０.７５６ｍｍｏｌ）の１−（４−クロロフェニル）ピペラジンと反応させ、対応するアミドを得る。分取ＨＰＬＣによる精製で１９０ｍｇ（理論値の８６％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝３２０（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 8.35 (d, 1H), 8.07 (dt, 1H), 7.48 (m, 1H), 7.25 (d, 2H), 6.97 (d, 2H), 3.79 (t, 2H), 3.38 (t, 2H), 3.24 (t, 2H), 3.12 (t, 2H)。 Example 8A
1- (4-Chlorophenyl) -4-[(2-fluoropyridin-3-yl) carbonyl] piperazine

100 mg (0.71 mmol) of 2-fluoronicotinic acid was reacted with 148.7 mg (0.756 mmol) of 1- (4-chlorophenyl) piperazine analogously to the method for preparing Example 3A to give the corresponding amide. Get. Purification by preparative HPLC gives 190 mg (86% of theory) of the product as a solid.
MS (ESIpos): m / z = 320 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.35 (d, 1H), 8.07 (dt, 1H), 7.48 (m, 1H), 7.25 (d, 2H), 6.97 (d, 2H), 3.79 (t, 2H), 3.38 (t, 2H), 3.24 (t, 2H), 3.12 (t, 2H).

１００ｍｇ（０.７１ｍｍｏｌ）の２−フルオロニコチン酸を、実施例３Ａを製造するための方法と同様に１７４.８ｍｇ（０.７５６ｍｍｏｌ）の１−（３,５−ジクロロフェニル）ピペラジンと反応させ、対応するアミドを得る。分取ＨＰＬＣによる精製で２０７ｍｇ（理論値の８５％）の生成物を固体として得る。
ＭＳ（ＤＣＩ、ＮＨ_３）：ｍ／ｚ＝３７１（Ｍ＋ＮＨ_４）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 8.35 (d, 1H), 8.07 (dt, 1H), 7.49 (m, 1H), 6.97 (s, 2H), 6.91 (s, 1H), 3.76 (t, 2H), 3.34-3.39 (m, 4H), 3.21-3.26 (m, 2H)。 Example 9A
1- (3,5-dichlorophenyl) -4-[(2-fluoropyridin-3-yl) carbonyl] piperazine

100 mg (0.71 mmol) of 2-fluoronicotinic acid was reacted with 174.8 mg (0.756 mmol) of 1- (3,5-dichlorophenyl) piperazine analogously to the method for preparing Example 3A To obtain an amide. Purification by preparative HPLC gives 207 mg (85% of theory) of the product as a solid.
_{MS (DCI, NH 3):} m / z = 371 (M + NH 4) +.
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.35 (d, 1H), 8.07 (dt, 1H), 7.49 (m, 1H), 6.97 (s, 2H), 6.91 (s, 1H), 3.76 (t, 2H), 3.34-3.39 (m, 4H), 3.21-3.26 (m, 2H).

１００ｍｇ（０.７１ｍｍｏｌ）の２−フルオロニコチン酸を、実施例３Ａを製造するための方法と同様に１７４.８ｍｇ（０.７５６ｍｍｏｌ）の１−（２,３−ジクロロフェニル）ピペラジンと反応させ、対応するアミドを得る。分取ＨＰＬＣによる精製で２１８ｍｇ（理論値の９０％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝３５４（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 8.35 (d, 1H), 8.08 (dt, 1H), 7.47-7.51 (m, 1H), 7.30-7.36 (m, 2H), 7.15-7.20 (m, 1H), 3.83 (t, 2H), 3.42 (t, 2H), 3.07 (t, 2H), 3.96 (t, 2H)。 Example 10A
1- (2,3-Dichlorophenyl) -4-[(2-fluoropyridin-3-yl) carbonyl] piperazine

100 mg (0.71 mmol) of 2-fluoronicotinic acid was reacted with 174.8 mg (0.756 mmol) of 1- (2,3-dichlorophenyl) piperazine analogously to the method for preparing Example 3A To obtain an amide. Purification by preparative HPLC gives 218 mg (90% of theory) of the product as a solid.
MS (ESIpos): m / z = 354 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.35 (d, 1H), 8.08 (dt, 1H), 7.47-7.51 (m, 1H), 7.30-7.36 (m, 2H), 7.15-7.20 (m, 1H), 3.83 (t, 2H), 3.42 (t, 2H), 3.07 (t, 2H), 3.96 (t, 2H).

１００ｍｇ（０.７１ｍｍｏｌ）の２−フルオロニコチン酸を、実施例３Ａを製造するための方法と同様に１７４.１ｍｇ（０.７５６ｍｍｏｌ）の１−［２−（トリフルオロメチル）フェニル］ピペラジンと反応させ、対応するアミドを得る。分取ＨＰＬＣによる精製で２２３ｍｇ（理論値の９２％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝３５４（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 8.35 (d, 1H), 8.09 (dt, 1H), 7.68 (t, 2H), 7.59 (d, 1H), 7.47-7.51 (m, 1H), 7.38 (t, 1H), 3.78 (m, 2H), 3.34-3.39 (m, 2H), 2.95 (t, 2H), 2.84 (t, 2H)。 Example 11A
1-[(2-Fluoropyridin-3-yl) carbonyl] -4- [2- (trifluoromethyl) phenyl] piperazine

Reaction of 100 mg (0.71 mmol) of 2-fluoronicotinic acid with 174.1 mg (0.756 mmol) of 1- [2- (trifluoromethyl) phenyl] piperazine analogously to the method for preparing Example 3A To give the corresponding amide. Purification by preparative HPLC gives 223 mg (92% of theory) of the product as a solid.
MS (ESIpos): m / z = 354 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.35 (d, 1H), 8.09 (dt, 1H), 7.68 (t, 2H), 7.59 (d, 1H), 7.47-7.51 (m, 1H ), 7.38 (t, 1H), 3.78 (m, 2H), 3.34-3.39 (m, 2H), 2.95 (t, 2H), 2.84 (t, 2H).

１００ｍｇ（０.７１ｍｍｏｌ）の２−フルオロニコチン酸を、実施例３Ａを製造するための方法と同様に１４５.４ｍｇ（０.７５６ｍｍｏｌ）の１−（４−メトキシフェニル）ピペラジンと反応させ、対応するアミドを得る。分取ＨＰＬＣによる精製で１４８ｍｇ（理論値の６７％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝３１６（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 8.35 (d, 1H), 8.07 (dt, 1H), 7.48 (m, 1H), 6.92 (d, 2H), 6.83 (d, 2H), 3.79 (t, 2H), 3.38 (t, 2H), 3.09 (t, 2H), 3.97 (t, 2H)。 Example 12A
1-[(2-Fluoropyridin-3-yl) carbonyl] -4- (4-methoxyphenyl) piperazine

100 mg (0.71 mmol) of 2-fluoronicotinic acid is reacted with 145.4 mg (0.756 mmol) of 1- (4-methoxyphenyl) piperazine analogously to the method for preparing Example 3A and the corresponding Obtain the amide. Purification by preparative HPLC gives 148 mg (67% of theory) of the product as a solid.
MS (ESIpos): m / z = 316 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.35 (d, 1H), 8.07 (dt, 1H), 7.48 (m, 1H), 6.92 (d, 2H), 6.83 (d, 2H), 3.79 (t, 2H), 3.38 (t, 2H), 3.09 (t, 2H), 3.97 (t, 2H).

１００ｍｇ（０.７１ｍｍｏｌ）の２−フルオロニコチン酸を、実施例３Ａを製造するための方法と同様に１６９.２ｍｇ（０.７５６ｍｍｏｌ）の３ピペラジン−１−イル−ベンゾニトリルヒドロクロライドと反応させ、対応するアミドを得る。しかしながら、３当量のジイソプロピルエチルアミンを塩基添加として使用する。分取ＨＰＬＣによる精製で２０１ｍｇ（理論値の９３％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝３１１（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 8.36 (d, 1H), 8.08 (dt, 1H), 7.49 (m, 1H), 7.41 (t, 1H), 7.37 (s, 1H), 7.29 (dd, 1H), 7.20 (d, 1H), 3.79 (t, 2H), 3.30-3.41 (m, 4H), 3.23 (t, 2H)。 Example 13A
3- {4-[(2-Fluoropyridin-3-yl) carbonyl] piperazin-1-yl} benzonitrile

100 mg (0.71 mmol) of 2-fluoronicotinic acid was reacted with 169.2 mg (0.756 mmol) of 3-piperazin-1-yl-benzonitrile hydrochloride in a manner similar to the method for preparing Example 3A; The corresponding amide is obtained. However, 3 equivalents of diisopropylethylamine are used as base addition. Purification by preparative HPLC gives 201 mg (93% of theory) of the product as a solid.
MS (ESIpos): m / z = 311 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.36 (d, 1H), 8.08 (dt, 1H), 7.49 (m, 1H), 7.41 (t, 1H), 7.37 (s, 1H), 7.29 (dd, 1H), 7.20 (d, 1H), 3.79 (t, 2H), 3.30-3.41 (m, 4H), 3.23 (t, 2H).

１００ｍｇ（０.７１ｍｍｏｌ）の２−フルオロニコチン酸を、実施例３Ａを製造するための方法と同様に１８８.４ｍｇ（０.７５６ｍｍｏｌ）の１−（４−メチルフェニル）ピペラジンジヒドロクロライドと反応させ、対応するアミドを得る。しかしながら、４.５当量のジイソプロピルエチルアミンを塩基添加として使用する。分取ＨＰＬＣによる精製で１７９ｍｇ（理論値の８７％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝３００（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 8.36 (d, 1H), 8.07 (dt, 1H), 7.49 (m, 1H), 7.04 (d, 2H), 6.86 (d, 2H), 3.79 (t, 2H), 3.33-3.40 (m, 2H), 3.16 (t, 2H), 3.04 (t, 2H)。 Example 14A
1-[(2-Fluoropyridin-3-yl) carbonyl] -4- (4-methylphenyl) piperazine

100 mg (0.71 mmol) of 2-fluoronicotinic acid was reacted with 188.4 mg (0.756 mmol) of 1- (4-methylphenyl) piperazine dihydrochloride in a manner similar to the method for preparing Example 3A; The corresponding amide is obtained. However, 4.5 equivalents of diisopropylethylamine is used as a base addition. Purification by preparative HPLC gives 179 mg (87% of theory) of the product as a solid.
MS (ESIpos): m / z = 300 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.36 (d, 1H), 8.07 (dt, 1H), 7.49 (m, 1H), 7.04 (d, 2H), 6.86 (d, 2H), 3.79 (t, 2H), 3.33-3.40 (m, 2H), 3.16 (t, 2H), 3.04 (t, 2H).

１００ｍｇ（０.７１ｍｍｏｌ）の２−フルオロニコチン酸を、実施例３Ａを製造するための方法と同様に１７３ｍｇ（０.７５６ｍｍｏｌ）の１−（２−メトキシフェニル）ピペラジンヒドロクロライドと反応させ、対応するアミドを得る。しかしながら、３当量のジイソプロピルエチルアミンを塩基添加として使用する。分取ＨＰＬＣによる精製で１９０ｍｇ（８８％理論値の）の生成物を樹脂として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝３１６（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 8.35 (d, 1H), 8.07 (m, 1H), 7.48 (m, 1H), 6.93-7.02 (m, 2H), 6.85-6.92 (m, 2H), 3.78-3.81 (m, 2H), 3.78 (s, 3H), 3.38 (t, 2H), 3.03 (t, 2H), 2.92 (t, 2H)。 Example 15A
1-[(2-Fluoropyridin-3-yl) carbonyl] -4- (2-methoxyphenyl) piperazine

100 mg (0.71 mmol) of 2-fluoronicotinic acid is reacted with 173 mg (0.756 mmol) of 1- (2-methoxyphenyl) piperazine hydrochloride analogously to the method for preparing Example 3A and the corresponding Obtain the amide. However, 3 equivalents of diisopropylethylamine are used as base addition. Purification by preparative HPLC gives 190 mg (88% of theory) of product as a resin.
MS (ESIpos): m / z = 316 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.35 (d, 1H), 8.07 (m, 1H), 7.48 (m, 1H), 6.93-7.02 (m, 2H), 6.85-6.92 (m , 2H), 3.78-3.81 (m, 2H), 3.78 (s, 3H), 3.38 (t, 2H), 3.03 (t, 2H), 2.92 (t, 2H).

１００ｍｇ（０.７１ｍｍｏｌ）の２−フルオロニコチン酸を、実施例３Ａを製造するための方法と同様に２４８.２ｍｇ（０.７５６ｍｍｏｌ）のＮ−（２−ピペラジン−１−イルフェニル）メタンスルホンアミドジヒドロクロライドと反応させ、対応するアミドを得る。しかしながら、４.５当量のジイソプロピルエチルアミンを塩基添加として使用する。分取ＨＰＬＣによる精製で９８ｍｇ（理論値の２７％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝３７９（Ｍ＋Ｈ）^＋。 Example 16A
N- (2- {4-[(2-fluoropyridin-3-yl) carbonyl] piperazin-1-yl} phenyl) methanesulfonamide

100 mg (0.71 mmol) of 2-fluoronicotinic acid was converted to 248.2 mg (0.756 mmol) of N- (2-piperazin-1-ylphenyl) methanesulfonamide analogously to the method for preparing Example 3A. React with dihydrochloride to give the corresponding amide. However, 4.5 equivalents of diisopropylethylamine is used as a base addition. Purification by preparative HPLC gives 98 mg (27% of theory) of the product as a solid.
MS (ESIpos): m / z = 379 (M + H) ^<+> .

１００ｍｇ（０.７１ｍｍｏｌ）の２−フルオロニコチン酸を、実施例３Ａを製造するための方法と同様に１４９.９ｍｇ（０.７８ｍｍｏｌ）の１−（３−メトキシフェニル）ピペラジンと反応させ、対応するアミドを得る。分取ＨＰＬＣによる精製で１５７ｍｇ（理論値の６８％）の生成物を樹脂として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝３１６（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 8.36 (d, 1H), 8.07 (dt, 1H), 7.49 (hept, 1H), 7.13 (t, 1H), 6.54 (dd, 1H), 6.48 (t, 1H), 6.41 (dd, 1H), 3.78 (t, 2H), 3.71 (s, 3H), 3.37 (t, 2H), 3.23 (t, 2H), 3.11 (t, 2H)。 Example 17A
1-[(2-Fluoropyridin-3-yl) carbonyl] -4- (3-methoxyphenyl) piperazine

100 mg (0.71 mmol) of 2-fluoronicotinic acid is reacted with 149.9 mg (0.78 mmol) of 1- (3-methoxyphenyl) piperazine analogously to the method for preparing Example 3A and the corresponding Obtain the amide. Purification by preparative HPLC gives 157 mg (68% of theory) of product as a resin.
MS (ESIpos): m / z = 316 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.36 (d, 1H), 8.07 (dt, 1H), 7.49 (hept, 1H), 7.13 (t, 1H), 6.54 (dd, 1H), 6.48 (t, 1H), 6.41 (dd, 1H), 3.78 (t, 2H), 3.71 (s, 3H), 3.37 (t, 2H), 3.23 (t, 2H), 3.11 (t, 2H).

１００ｍｇ（０.７１ｍｍｏｌ）の２−フルオロニコチン酸を、実施例３Ａを製造するための方法と同様に１８０.２３ｍｇ（０.７８ｍｍｏｌ）の１−（４−フルオロフェニル）ピペラジンと反応させ、対応するアミドを得る。分取ＨＰＬＣによる精製で１９９ｍｇ（理論値の９２％）の生成物を油状物として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝３０４（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 8.35 (d, 1H), 8.06 (hept, 1H), 7.49 (hept, 1H), 7.07 (d, 2H), 6.99 (d, 1H), 6.98 (d, 1H), 3.79 (t, 2H), 3.38 (t, 2H), 3.17 (t, 2H), 3.05 (t, 2H)。 Example 18A
1- (4-Fluorophenyl) -4-[(2-fluoropyridin-3-yl) carbonyl] piperazine

100 mg (0.71 mmol) of 2-fluoronicotinic acid is reacted with 180.23 mg (0.78 mmol) of 1- (4-fluorophenyl) piperazine analogously to the method for preparing Example 3A and the corresponding Obtain the amide. Purification by preparative HPLC gives 199 mg (92% of theory) of the product as an oil.
MS (ESIpos): m / z = 304 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.35 (d, 1H), 8.06 (hept, 1H), 7.49 (hept, 1H), 7.07 (d, 2H), 6.99 (d, 1H), 6.98 (d, 1H), 3.79 (t, 2H), 3.38 (t, 2H), 3.17 (t, 2H), 3.05 (t, 2H).

１００ｍｇ（０.７１ｍｍｏｌ）の２−フルオロニコチン酸を、実施例３Ａを製造するための方法と同様に２０６.３４ｍｇ（０.７８ｍｍｏｌ）の１−［４−クロロ−３−（トリフルオロメチル）フェニル］ピペラジンと反応させ、対応するアミドを得る。分取ＨＰＬＣによる精製で２７１ｍｇ（理論値の９９％）の生成物を樹脂として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝３８８（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 8.37 (d, 1H), 8.08 (hept, 1H), 7.52 (d, 1H), 7.49 (hept, 1H), 7.29 (d, 1H), 7.23 (dd, 1H), 3.79 (t, 2H), 3.38 (m, 4H), 3.24 (t, 2H)。 Example 19A
1- [4-Chloro-3- (trifluoromethyl) phenyl] -4-[(2-fluoropyridin-3-yl) carbonyl] piperazine

100 mg (0.71 mmol) of 2-fluoronicotinic acid was converted to 206.34 mg (0.78 mmol) of 1- [4-chloro-3- (trifluoromethyl) phenyl as in the method for preparing Example 3A. Reaction with piperazine gives the corresponding amide. Purification by preparative HPLC gives 271 mg (99% of theory) of product as a resin.
MS (ESIpos): m / z = 388 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.37 (d, 1H), 8.08 (hept, 1H), 7.52 (d, 1H), 7.49 (hept, 1H), 7.29 (d, 1H), 7.23 (dd, 1H), 3.79 (t, 2H), 3.38 (m, 4H), 3.24 (t, 2H).

３７.５３ｍｇ（０.２７２ｍｍｏｌ）の４−ヒドロキシ安息香酸を４ｍｌの乾燥ＤＭＳＯに入れ、２２.６４ｍｇ（０.５７ｍｍｏｌ）の水素化ナトリウム（６０％）を加える。室温、アルゴン雰囲気下で１０分間撹拌後、実施例１Ａ由来の８０ｍｇ（０.２２６ｍｍｏｌ）の２−フルオロニコチンアミドを加える。混合物を８０℃で１時間加熱し、前駆体がまだ存在するため１２０℃でさらに１６時間加熱する。約１ｍｌの水を慎重に加える。分取ＨＰＬＣによる精製で３６ｍｇ（理論値の３４％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝４７２（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 8.25 (dd, 1H), 7.97 (d, 2H), 7.94 (dd, 1H), 7.44 (t, 1H), 7.31 (dd, 1H), 7.25 (d, 2H), 7.19 (d, 2H), 7.10 (d, 1H), 3.80 (t, 2H), 3.48 (m, 2H), 3.32 (m, 2H), 3.15 (m, 2H)。 Exemplary embodiments
Example 1
4-{[3-({4- [3- (trifluoromethyl) phenyl] piperazin-1-yl} carbonyl) pyridin-2-yl] oxy} benzoic acid

37.53 mg (0.272 mmol) of 4-hydroxybenzoic acid is placed in 4 ml of dry DMSO and 22.64 mg (0.57 mmol) of sodium hydride (60%) is added. After stirring for 10 minutes at room temperature under argon atmosphere, 80 mg (0.226 mmol) of 2-fluoronicotinamide from Example 1A is added. The mixture is heated at 80 ° C. for 1 hour and is further heated at 120 ° C. for 16 hours since the precursor is still present. Carefully add about 1 ml of water. Purification by preparative HPLC gives 36 mg (34% of theory) of the product as a solid.
MS (ESIpos): m / z = 472 (M + H) ^<+> .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.25 (dd, 1H), 7.97 (d, 2H), 7.94 (dd, 1H), 7.44 (t, 1H), 7.31 (dd, 1H), 7.25 (d, 2H), 7.19 (d, 2H), 7.10 (d, 1H), 3.80 (t, 2H), 3.48 (m, 2H), 3.32 (m, 2H), 3.15 (m, 2H).

４６.９ｍｇ（０.３４ｍｍｏｌ）の４−ヒドロキシ安息香酸を４ｍｌの乾燥ＤＭＳＯに入れ、２８.３ｍｇ（０.７１ｍｍｏｌ）の水素化ナトリウム（６０％）を加える。室温、アルゴン雰囲気下で１０分間撹拌後、実施例２Ａ由来の１００ｍｇ（０.２８ｍｍｏｌ）のイソニコチンアミドを加える。混合物を１３０℃で１６時間加熱し、冷却後、１Ｎの塩酸で中和する。分取ＨＰＬＣによる精製で５７ｍｇ（理論値の４３％）の生成物を得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝４７２（Ｍ＋Ｈ）^＋。
¹H-NMR (300MHz, DMSO-d₆): δ = 12.88 (s, 幅広い, 1H), 8.28 (d, 1H), 7.99 (d, 2H), 7.45 (t, 1H), 7.08-7.29 (m, 7H), 3.78 (m, 2H), 3.47 (m, 2H), 3.37 (m, 4H)。 Example 2
4-{[4-({4- [3- (trifluoromethyl) phenyl] piperazin-1-yl} carbonyl) pyridin-2-yl] oxy} benzoic acid

46.9 mg (0.34 mmol) of 4-hydroxybenzoic acid is placed in 4 ml of dry DMSO and 28.3 mg (0.71 mmol) of sodium hydride (60%) is added. After stirring for 10 minutes at room temperature under an argon atmosphere, 100 mg (0.28 mmol) of isonicotinamide from Example 2A is added. The mixture is heated at 130 ° C. for 16 hours, cooled and neutralized with 1N hydrochloric acid. Purification by preparative HPLC gives 57 mg (43% of theory) of product.
MS (ESIpos): m / z = 472 (M + H) ^<+> .
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 12.88 (s, broad, 1H), 8.28 (d, 1H), 7.99 (d, 2H), 7.45 (t, 1H), 7.08-7.29 (m , 7H), 3.78 (m, 2H), 3.47 (m, 2H), 3.37 (m, 4H).

３７.１８ｍｇ（０.２５５ｍｍｏｌ）の４−ヒドロキシ安息香酸を６ｍｌの乾燥ＤＭＳＯに入れ、２８.５ｍｇ（０.７１３ｍｍｏｌ）の水素化ナトリウム（６０％）を加える。室温、アルゴン雰囲気下で１０分間撹拌後、実施例３Ａ由来の６０ｍｇ（０.１７ｍｍｏｌ）の２−フルオロニコチンアミドを加える。混合物を１２０℃で１６時間加熱する。ｐＨがわずかに酸性になるまで約１ｍｌの２Ｎの塩酸を慎重に加える。分取ＨＰＬＣによる精製で５８ｍｇ（理論値の７２％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝４７２（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 8.24 (dd, 1H), 7.97 (d, 2H), 7.94 (dd, 1H), 7.52 (d, 2H), 7.30 (dd, 1H), 7.24 (d, 2H), 7.06 (d, 2H), 3.79 (t, 2H), 3.48 (m, 2H), 3.34 (m, 4H)。 Example 3
4-{[3-({4- [4- (trifluoromethyl) phenyl] piperazin-1-yl} carbonyl) pyridin-2-yl] oxy} benzoic acid

37.18 mg (0.255 mmol) of 4-hydroxybenzoic acid is placed in 6 ml of dry DMSO and 28.5 mg (0.713 mmol) of sodium hydride (60%) is added. After stirring for 10 minutes at room temperature under an argon atmosphere, 60 mg (0.17 mmol) of 2-fluoronicotinamide from Example 3A is added. The mixture is heated at 120 ° C. for 16 hours. Carefully add about 1 ml of 2N hydrochloric acid until the pH is slightly acidic. Purification by preparative HPLC gives 58 mg (72% of theory) of the product as a solid.
MS (ESIpos): m / z = 472 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.24 (dd, 1H), 7.97 (d, 2H), 7.94 (dd, 1H), 7.52 (d, 2H), 7.30 (dd, 1H), 7.24 (d, 2H), 7.06 (d, 2H), 3.79 (t, 2H), 3.48 (m, 2H), 3.34 (m, 4H).

実施例４Ａ由来の８０ｍｇ（０.２２６ｍｍｏｌ）の２−フルオロニコチンアミドを、実施例３を製造するための方法と同様に４６.７９ｍｇ（０.３３９ｍｍｏｌ）の４−ヒドロキシ安息香酸と反応させ、対応するエーテルを得る。分取ＨＰＬＣによる精製で７７ｍｇ（理論値の７２％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝４７２（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 12.93 (s, 幅広い, 1H), 8.24 (dd, 1H), 7.98 (d, 2H), 7.94 (dd, 1H), 7.41 (d, 2H), 7.30 (dd, 1H), 7.14 (d, 2H), 6.93 (dd, 1H), 3.76 (t, 2H), 3.45 (m, 2H), 3.28 (m, 2H), 3.19 (m, 2H)。 Example 4
4-[(3-{[4- (3,4-Dichlorophenyl) piperazin-1-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

80 mg (0.226 mmol) of 2-fluoronicotinamide from Example 4A was reacted with 46.79 mg (0.339 mmol) of 4-hydroxybenzoic acid in a manner similar to the method for preparing Example 3 To obtain ether. Purification by preparative HPLC gives 77 mg (72% of theory) of the product as a solid.
MS (ESIpos): m / z = 472 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.93 (s, broad, 1H), 8.24 (dd, 1H), 7.98 (d, 2H), 7.94 (dd, 1H), 7.41 (d, 2H ), 7.30 (dd, 1H), 7.14 (d, 2H), 6.93 (dd, 1H), 3.76 (t, 2H), 3.45 (m, 2H), 3.28 (m, 2H), 3.19 (m, 2H) .

実施例５Ａ由来の８０ｍｇ（０.１９ｍｍｏｌ）の２−フルオロニコチンアミドを、実施例３を製造するための方法と同様に３９.３４ｍｇ（０.２８５ｍｍｏｌ）の４−ヒドロキシ安息香酸と反応させ、対応するエーテルを得る。分取ＨＰＬＣによる精製で７５ｍｇ（理論値の７３％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝５４０（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 12.92 (s, 幅広い, 1H), 8.25 (dd, 1H), 7.98 (d, 2H), 7.95 (dd, 1H), 7.48 (s, 2H), 7.34 (s, 1H), 7.31 (dd, 1H), 7.25 (d, 2H), 3.80 (m, 2H), 3.47 (m, 4H), 3.37 (m, 2H)。 Example 5
4-{[3-({4- [3,5-Bis (trifluoromethyl) phenyl] piperazin-1-yl} carbonyl) pyridin-2-yl] oxy} benzoic acid

80 mg (0.19 mmol) of 2-fluoronicotinamide from Example 5A was reacted with 39.34 mg (0.285 mmol) of 4-hydroxybenzoic acid in a manner similar to the method for preparing Example 3 To obtain ether. Purification by preparative HPLC gives 75 mg (73% of theory) of the product as a solid.
MS (ESIpos): m / z = 540 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.92 (s, broad, 1H), 8.25 (dd, 1H), 7.98 (d, 2H), 7.95 (dd, 1H), 7.48 (s, 2H ), 7.34 (s, 1H), 7.31 (dd, 1H), 7.25 (d, 2H), 3.80 (m, 2H), 3.47 (m, 4H), 3.37 (m, 2H).

実施例６Ａ由来の８０ｍｇ（０.２５ｍｍｏｌ）の２−フルオロニコチンアミドを、実施例３を製造するための方法と同様に５１.８ｍｇ（０.３７５ｍｍｏｌ）の４−ヒドロキシ安息香酸と反応させ、対応するエーテルを得る。分取ＨＰＬＣによる精製で７８ｍｇ（理論値の７１％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝４３８（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 12.93 (s, 幅広い, 1H), 8.24 (dd, 1H), 7.98 (d, 2H), 7.94 (dd, 1H), 7.42 (dd, 1H), 7.30 (dd, 1H), 7.27 (d, 1H), 7.26 (d, 2H), 7.11 (dd, 1H), 7.07 (dt, 1H), 3.81 (m, 2H), 3.49 (m, 2H), 3.0 (m, 4H)。 Example 6
4-[(3-{[4- (2-Chlorophenyl) piperazin-1-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

80 mg (0.25 mmol) of 2-fluoronicotinamide from Example 6A was reacted with 51.8 mg (0.375 mmol) of 4-hydroxybenzoic acid in a manner similar to the method for preparing Example 3 To obtain ether. Purification by preparative HPLC gives 78 mg (71% of theory) of the product as a solid.
MS (ESIpos): m / z = 438 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.93 (s, broad, 1H), 8.24 (dd, 1H), 7.98 (d, 2H), 7.94 (dd, 1H), 7.42 (dd, 1H ), 7.30 (dd, 1H), 7.27 (d, 1H), 7.26 (d, 2H), 7.11 (dd, 1H), 7.07 (dt, 1H), 3.81 (m, 2H), 3.49 (m, 2H) , 3.0 (m, 4H).

実施例７Ａ由来の８０ｍｇ（０.２５８ｍｍｏｌ）の２−フルオロニコチンアミドを、実施例３を製造するための方法と同様に５３.４１ｍｇ（０.３８７ｍｍｏｌ）の４−ヒドロキシ安息香酸と反応させ、対応するエーテルを得る。分取ＨＰＬＣによる精製で７１ｍｇ（理論値の６４％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝４２９（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 12.94 (s, 幅広い, 1H), 8.25 (dd, 1H), 7.97 (d, 2H), 7.95 (dd, 1H), 7.60 (d, 2H), 7.30 (dd, 1H), 7.25 (d, 2H), 7.01 (d, 2H), 3.77 (t, 2H), 3.46 (m, 4H), 3.35 (m, 2H)。 Example 7
4-[(3-{[4- (4-Cyanophenyl) piperazin-1-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

80 mg (0.258 mmol) of 2-fluoronicotinamide from Example 7A was reacted with 53.41 mg (0.387 mmol) of 4-hydroxybenzoic acid in a similar manner to the preparation of Example 3 To obtain ether. Purification by preparative HPLC gives 71 mg (64% of theory) of the product as a solid.
MS (ESIpos): m / z = 429 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.94 (s, broad, 1H), 8.25 (dd, 1H), 7.97 (d, 2H), 7.95 (dd, 1H), 7.60 (d, 2H ), 7.30 (dd, 1H), 7.25 (d, 2H), 7.01 (d, 2H), 3.77 (t, 2H), 3.46 (m, 4H), 3.35 (m, 2H).

実施例８Ａ由来の８０ｍｇ（０.２５ｍｍｏｌ）の２−フルオロニコチンアミドを、実施例３を製造するための方法と同様に５１.８３ｍｇ（０.３７５ｍｍｏｌ）の４−ヒドロキシ安息香酸と反応させ、対応するエーテルを得る。分取ＨＰＬＣによる精製で８４ｍｇ（理論値の７７％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝４３８（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 12.95 (s, 幅広い, 1H), 8.24 (dd, 1H), 7.97 (d, 2H), 7.94 (dd, 1H), 7.30 (dd, 1H), 7.24 (dd, 4H), 6.94 (d, 2H), 3.78 (t, 2H), 3.46 (m, 2H), 3.21 (m, 2H), 3.12 (m, 2H)。 Example 8
4-[(3-{[4- (4-Chlorophenyl) piperazin-1-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

80 mg (0.25 mmol) of 2-fluoronicotinamide from Example 8A was reacted with 51.83 mg (0.375 mmol) of 4-hydroxybenzoic acid in a manner similar to the method for preparing Example 3 and To obtain ether. Purification by preparative HPLC gives 84 mg (77% of theory) of the product as a solid.
MS (ESIpos): m / z = 438 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.95 (s, broad, 1H), 8.24 (dd, 1H), 7.97 (d, 2H), 7.94 (dd, 1H), 7.30 (dd, 1H ), 7.24 (dd, 4H), 6.94 (d, 2H), 3.78 (t, 2H), 3.46 (m, 2H), 3.21 (m, 2H), 3.12 (m, 2H).

実施例９Ａ由来の８０ｍｇ（０.２６６ｍｍｏｌ）の２−フルオロニコチンアミドを、実施例３を製造するための方法と同様に４６.８ｍｇ（０.３３９ｍｍｏｌ）の４−ヒドロキシ安息香酸と反応させ、対応するエーテルを得る。分取ＨＰＬＣによる精製で７０ｍｇ（理論値の６６％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝４７２（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 12.94 (s, 幅広い, 1H), 8.25 (dd, 1H), 7.98 (d, 2H), 7.94 (dd, 1H), 7.30 (dd, 1H), 7.24 (d, 2H), 6.95 (d, 2H), 6.90 (t, 1H), 3.75 (t, 2H), 3.43 (m, 2H), 3.33 (m, 2H), 3.31 (m, 2H)。 Example 9
4-[(3-{[4- (3,5-dichlorophenyl) piperazin-1-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

80 mg (0.266 mmol) of 2-fluoronicotinamide from Example 9A was reacted with 46.8 mg (0.339 mmol) of 4-hydroxybenzoic acid in a manner similar to the method for preparing Example 3 To obtain ether. Purification by preparative HPLC gives 70 mg (66% of theory) of the product as a solid.
MS (ESIpos): m / z = 472 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.94 (s, broad, 1H), 8.25 (dd, 1H), 7.98 (d, 2H), 7.94 (dd, 1H), 7.30 (dd, 1H ), 7.24 (d, 2H), 6.95 (d, 2H), 6.90 (t, 1H), 3.75 (t, 2H), 3.43 (m, 2H), 3.33 (m, 2H), 3.31 (m, 2H) .

実施例１０Ａ由来の８０ｍｇ（０.２６６ｍｍｏｌ）の２−フルオロニコチンアミドを、実施例３を製造するための方法と同様に４６.８ｍｇ（０.３３９ｍｍｏｌ）の４−ヒドロキシ安息香酸と反応させ、対応するエーテルを得る。分取ＨＰＬＣによる精製で７３ｍｇ（理論値の６８％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝４７２（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 12.94 (s, 幅広い, 1H), 8.24 (dd, 1H), 7.98 (d, 2H), 7.94 (dd, 1H), 7.22-7.36 (m, 5H), 7.11 (dd, 1H), 3.82 (m, 2H), 3.50 (m, 2H), 2.9-3.1 (m, 4H)。 Example 10
4-[(3-{[4- (2,3-dichlorophenyl) piperazin-1-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

80 mg (0.266 mmol) of 2-fluoronicotinamide from Example 10A was reacted with 46.8 mg (0.339 mmol) of 4-hydroxybenzoic acid in a manner similar to the method for preparing Example 3 To obtain ether. Purification by preparative HPLC gives 73 mg (68% of theory) of the product as a solid.
MS (ESIpos): m / z = 472 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.94 (s, broad, 1H), 8.24 (dd, 1H), 7.98 (d, 2H), 7.94 (dd, 1H), 7.22-7.36 (m , 5H), 7.11 (dd, 1H), 3.82 (m, 2H), 3.50 (m, 2H), 2.9-3.1 (m, 4H).

実施例１１Ａ由来の８０ｍｇ（０.２２６ｍｍｏｌ）の２−フルオロニコチンアミドを、実施例３を製造するための方法と同様に４６.９１ｍｇ（０.３４ｍｍｏｌ）の４−ヒドロキシ安息香酸と反応させ、対応するエーテルを得る。分取ＨＰＬＣによる精製で５１ｍｇ（理論値の４８％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝４７２（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 12.94 (s, 幅広い, 1H), 8.24 (dd, 1H), 7.99 (d, 2H), 7.95 (dd, 1H), 7.65 (dd, 2H), 7.49 (d, 1H), 7.36 (t, 1H), 7.31 (dd, 1H), 7.26 (d, 2H), 3.77 (m, 2H), 3.44 (t, 2H), 2.73-2.98 (m, 4H)。 Example 11
4-{[3-({4- [2- (trifluoromethyl) phenyl] piperazin-1-yl} carbonyl) pyridin-2-yl] oxy} benzoic acid

80 mg (0.226 mmol) of 2-fluoronicotinamide from Example 11A was reacted with 46.91 mg (0.34 mmol) of 4-hydroxybenzoic acid in a manner similar to the method for preparing Example 3 To obtain ether. Purification by preparative HPLC gives 51 mg (48% of theory) of the product as a solid.
MS (ESIpos): m / z = 472 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.94 (s, broad, 1H), 8.24 (dd, 1H), 7.99 (d, 2H), 7.95 (dd, 1H), 7.65 (dd, 2H ), 7.49 (d, 1H), 7.36 (t, 1H), 7.31 (dd, 1H), 7.26 (d, 2H), 3.77 (m, 2H), 3.44 (t, 2H), 2.73-2.98 (m, 4H).

実施例１２Ａ由来の８０ｍｇ（０.２５４ｍｍｏｌ）の２−フルオロニコチンアミドを、実施例３を製造するための方法と同様に５２.５６ｍｇ（０.３８１ｍｍｏｌ）の４−ヒドロキシ安息香酸と反応させ、対応するエーテルを得る。分取ＨＰＬＣによる精製で６３ｍｇ（理論値の５４％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝４３４（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 12.92 (s, 幅広い, 1H), 8.24 (dd, 1H), 7.98 (d, 2H), 7.93 (dd, 1H), 7.30 (dd, 1H), 7.24 (d, 2H), 6.89 (d, 2H), 6.81 (d, 2H), 3.78 (m, 2H), 3.68 (s, 3H), 3.45 (m, 2H), 2.90-3.1 (m, 4H)。 Example 12
4-[(3-{[4- (4-Methoxyphenyl) piperazin-1-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

80 mg (0.254 mmol) of 2-fluoronicotinamide from Example 12A was reacted with 52.56 mg (0.381 mmol) of 4-hydroxybenzoic acid in a manner similar to the method for preparing Example 3 To obtain ether. Purification by preparative HPLC gives 63 mg (54% of theory) of the product as a solid.
MS (ESIpos): m / z = 434 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.92 (s, broad, 1H), 8.24 (dd, 1H), 7.98 (d, 2H), 7.93 (dd, 1H), 7.30 (dd, 1H ), 7.24 (d, 2H), 6.89 (d, 2H), 6.81 (d, 2H), 3.78 (m, 2H), 3.68 (s, 3H), 3.45 (m, 2H), 2.90-3.1 (m, 4H).

実施例１３Ａ由来の８０ｍｇ（０.２５８ｍｍｏｌ）の２−フルオロニコチンアミドを、実施例３を製造するための方法と同様に５３.４１ｍｇ（０.３８７ｍｍｏｌ）の４−ヒドロキシ安息香酸と反応させ、対応するエーテルを得る。分取ＨＰＬＣによる精製で６６ｍｇ（理論値の６０％）の生成物を固体として得る。
ＭＳ（ＤＣＩ、ＮＨ_３）：ｍ／ｚ＝４４６（Ｍ＋ＮＨ_４）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 12.93 (s, 幅広い, 1H), 8.25 (dd, 1H), 7.98 (d, 2H), 7.94 (dd, 1H), 7.40 (t, 1H), 7.26-7.36 (m, 5H), 7.19 (d, 1H), 3.78 (t, 2H), 3.46 (m, 2H), 3.30 (m, 2H), 3.24 (m, 2H)。 Example 13
4-[(3-{[4- (3-Cyanophenyl) piperazin-1-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

80 mg (0.258 mmol) of 2-fluoronicotinamide from Example 13A was reacted with 53.41 mg (0.387 mmol) of 4-hydroxybenzoic acid in a manner similar to the method for preparing Example 3 To obtain ether. Purification by preparative HPLC gives 66 mg (60% of theory) of the product as a solid.
_{MS (DCI, NH 3):} m / z = 446 (M + NH 4) +.
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.93 (s, broad, 1H), 8.25 (dd, 1H), 7.98 (d, 2H), 7.94 (dd, 1H), 7.40 (t, 1H ), 7.26-7.36 (m, 5H), 7.19 (d, 1H), 3.78 (t, 2H), 3.46 (m, 2H), 3.30 (m, 2H), 3.24 (m, 2H).

実施例１４Ａ由来の８０ｍｇ（０.２６７ｍｍｏｌ）の２−フルオロニコチンアミドを、実施例３を製造するための方法と同様に５５.３７ｍｇ（０.４ｍｍｏｌ）の４−ヒドロキシ安息香酸と反応させ、対応するエーテルを得る。分取ＨＰＬＣによる精製で７６ｍｇ（理論値の６８％）の生成物を固体として得る。
ＭＳ（ＤＣＩ、ＮＨ_３）：ｍ／ｚ＝４１８（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 12.92 (s, 幅広い, 1H), 8.23 (d, 1H), 7.97 (d, 2H), 7.93 (d, 1H), 7.30 (dd, 1H), 7.24 (d, 2H), 7.02 (d, 2H), 6.83 (d, 2H), 3.78 (m, 2H), 3.45 (m, 2H), 3.23-3.18 (m, 4H), 2.19 (s, 3H)。 Example 14
4-[(3-{[4- (4-Methylphenyl) piperazin-1-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

80 mg (0.267 mmol) of 2-fluoronicotinamide from Example 14A was reacted with 55.37 mg (0.4 mmol) of 4-hydroxybenzoic acid in a manner similar to the method for preparing Example 3 and To obtain ether. Purification by preparative HPLC gives 76 mg (68% of theory) of the product as a solid.
_{MS (DCI, NH 3):} m / z = 418 (M + H) +.
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.92 (s, broad, 1H), 8.23 (d, 1H), 7.97 (d, 2H), 7.93 (d, 1H), 7.30 (dd, 1H ), 7.24 (d, 2H), 7.02 (d, 2H), 6.83 (d, 2H), 3.78 (m, 2H), 3.45 (m, 2H), 3.23-3.18 (m, 4H), 2.19 (s, 3H).

実施例１５Ａ由来の８０ｍｇ（０.２５４ｍｍｏｌ）の２−フルオロニコチンアミドを、実施例３を製造するための方法と同様に５２.５６ｍｇ（０.３８１ｍｍｏｌ）の４−ヒドロキシ安息香酸と反応させ、対応するエーテルを得る。分取ＨＰＬＣによる精製で２ｍｇ（理論値の２％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝４３４（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 12.92 (s, 幅広い), 8.36 (dd), 8.24 (dd), 8.07 (t), 7.98 (d), 7.93 (d), 7.48 (t), 7.30 (dd), 7.25 (d), 6.92-7.01 (m), 6.81-6.91 (m), 3.77 (s), 3.45 (m), 3.39 (m,), 3.03 (m), 2.92 (m)。 Example 15
4-[(3-{[4- (2-methoxyphenyl) piperazin-1-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

80 mg (0.254 mmol) of 2-fluoronicotinamide from Example 15A was reacted with 52.56 mg (0.381 mmol) of 4-hydroxybenzoic acid in a manner similar to the method for preparing Example 3 To obtain ether. Purification by preparative HPLC gives 2 mg (2% of theory) of the product as a solid.
MS (ESIpos): m / z = 434 (M + H) ^<+> .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 12.92 (s, broad), 8.36 (dd), 8.24 (dd), 8.07 (t), 7.98 (d), 7.93 (d), 7.48 (t ), 7.30 (dd), 7.25 (d), 6.92-7.01 (m), 6.81-6.91 (m), 3.77 (s), 3.45 (m), 3.39 (m,), 3.03 (m), 2.92 (m ).

実施例１６Ａ由来の４０ｍｇ（０.１０６ｍｍｏｌ）の２−フルオロニコチンアミドを、実施例３を製造するための方法と同様に２１.９ｍｇ（０.１５９ｍｍｏｌ）の４−ヒドロキシ安息香酸と反応させ、対応するエーテルを得る。分取ＨＰＬＣによる精製で２７ｍｇ（理論値の４９％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝４９７（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 12.92 (s, 幅広い, 1H), 8.6 (s, 1H), 8.24 (dd, 1H), 7.99 (d, 2H), 7.96 (m, 1H), 7.37 (dd, 1H), 7.30 (dd, 1H), 7.45 (d, 2H), 7.08-7.19 (m, 3H), 3.86 (m, 2H), 3.53 (m, 1H), 3.45 (m, 1H), 3.1 (s, 3H), 2.83-2.94 (m, 2H), 2.70-2.82 (m, 2H)。 Example 16
4-({3-[(4- {2-[(methylsulfonyl) amino] phenyl} piperazin-1-yl) carbonyl] pyridin-2-yl} oxy) benzoic acid

40 mg (0.106 mmol) of 2-fluoronicotinamide from Example 16A was reacted with 21.9 mg (0.159 mmol) of 4-hydroxybenzoic acid in a manner similar to the method for preparing Example 3 To obtain ether. Purification by preparative HPLC gives 27 mg (49% of theory) of the product as a solid.
MS (ESIpos): m / z = 497 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.92 (s, broad, 1H), 8.6 (s, 1H), 8.24 (dd, 1H), 7.99 (d, 2H), 7.96 (m, 1H ), 7.37 (dd, 1H), 7.30 (dd, 1H), 7.45 (d, 2H), 7.08-7.19 (m, 3H), 3.86 (m, 2H), 3.53 (m, 1H), 3.45 (m, 1H), 3.1 (s, 3H), 2.83-2.94 (m, 2H), 2.70-2.82 (m, 2H).

実施例１７Ａ由来の４６ｍｇ（０.１４６ｍｍｏｌ）の２−フルオロニコチンアミドを、実施例３を製造するための方法と同様に３０.２２ｍｇ（０.２１９ｍｍｏｌ）の４−ヒドロキシ安息香酸と反応させ、対応するエーテルを得る。分取ＨＰＬＣによる精製で１７ｍｇ（理論値の２５％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝４３４（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 12.91 (s, 幅広い, 1H), 8.24 (dd, 1H), 7.97 (d, 2H), 7.94 (dd, 1H), 7.30 (dd, 1H), 7.24 (d, 2H), 7.12 (t, 1H), 6.51 (dd, 1H), 6.45 (t, 1H), 6.39 (dd, 1H), 3.77 (t, 2H), 3.70 (s, 3H), 3.45 (m, 2H), 3.20 (m, 2H), 3.11 (m, 2H)。 Example 17
4-[(3-{[4- (3-methoxyphenyl) piperazin-1-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

46 mg (0.146 mmol) of 2-fluoronicotinamide from Example 17A was reacted with 30.22 mg (0.219 mmol) of 4-hydroxybenzoic acid in a manner similar to the method for preparing Example 3 To obtain ether. Purification by preparative HPLC gives 17 mg (25% of theory) of the product as a solid.
MS (ESIpos): m / z = 434 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.91 (s, broad, 1H), 8.24 (dd, 1H), 7.97 (d, 2H), 7.94 (dd, 1H), 7.30 (dd, 1H ), 7.24 (d, 2H), 7.12 (t, 1H), 6.51 (dd, 1H), 6.45 (t, 1H), 6.39 (dd, 1H), 3.77 (t, 2H), 3.70 (s, 3H) 3.45 (m, 2H), 3.20 (m, 2H), 3.11 (m, 2H).

実施例１８Ａ由来の４６ｍｇ（０.１５２ｍｍｏｌ）の２−フルオロニコチンアミドを、実施例３を製造するための方法と同様に３１.４２ｍｇ（０.２２７ｍｍｏｌ）の４−ヒドロキシ安息香酸と反応させ、対応するエーテルを得る。分取ＨＰＬＣによる精製で４７ｍｇ（理論値の７４％）の生成物を得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝４２２（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 12.92 (s, 幅広い, 1H), 8.24 (dd, 1H), 7.97 (d, 2H), 7.94 (dd, 1H), 7.30 (dd, 1H), 7.24 (d, 2H), 7.06 (t, 2H), 6.97 (d, 1H), 6.95 (dd, 1H), 3.78 (t, 2H), 3.46 (m, 2H), 3.13 (m, 2H), 3.05 (m, 2H)。 Example 18
4-[(3-{[4- (4-Fluorophenyl) piperazin-1-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

46 mg (0.152 mmol) of 2-fluoronicotinamide from Example 18A was reacted with 31.42 mg (0.227 mmol) of 4-hydroxybenzoic acid analogously to the method for preparing Example 3 and To obtain ether. Purification by preparative HPLC gives 47 mg (74% of theory) of product.
MS (ESIpos): m / z = 422 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.92 (s, broad, 1H), 8.24 (dd, 1H), 7.97 (d, 2H), 7.94 (dd, 1H), 7.30 (dd, 1H ), 7.24 (d, 2H), 7.06 (t, 2H), 6.97 (d, 1H), 6.95 (dd, 1H), 3.78 (t, 2H), 3.46 (m, 2H), 3.13 (m, 2H) , 3.05 (m, 2H).

実施例１９Ａ由来の８０ｍｇ（０.２１ｍｍｏｌ）の２−フルオロニコチンアミドを、実施例３を製造するための方法と同様に４２.７ｍｇ（０.３１ｍｍｏｌ）の４−ヒドロキシ安息香酸と反応させ、対応するエーテルを得る。分取ＨＰＬＣによる精製で１００ｍｇ（理論値の９６％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝５０６（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 12.94 (s, 幅広い, 1H), 8.25 (dd, 1H), 7.97 (d, 2H), 7.94 (dd, 1H), 7.51 (d, 1H), 7.30 (d, 1H), 7.27 (d, 1H), 7.25 (d, 2H), 7.21 (dd, 1H), 3.78 (t, 2H), 3.47 (m, 2H), 3.30 (m, 2H), 3.24 (m, 2H)。 Example 19
4-{[3-({4- [4-Chloro-3- (trifluoromethyl) phenyl] piperazin-1-yl} carbonyl) pyridin-2-yl] oxy} benzoic acid

80 mg (0.21 mmol) of 2-fluoronicotinamide from Example 19A was reacted with 42.7 mg (0.31 mmol) of 4-hydroxybenzoic acid in the same manner as for the preparation of Example 3 To obtain ether. Purification by preparative HPLC gives 100 mg (96% of theory) of the product as a solid.
MS (ESIpos): m / z = 506 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.94 (s, broad, 1H), 8.25 (dd, 1H), 7.97 (d, 2H), 7.94 (dd, 1H), 7.51 (d, 1H ), 7.30 (d, 1H), 7.27 (d, 1H), 7.25 (d, 2H), 7.21 (dd, 1H), 3.78 (t, 2H), 3.47 (m, 2H), 3.30 (m, 2H) , 3.24 (m, 2H).

実施例１Ａ由来の４０ｍｇ（０.１１ｍｍｏｌ）の２−フルオロニコチンアミドを、実施例３を製造するための方法と同様に２６.５ｍｇ（０.１７ｍｍｏｌ）の３−フルオロ−４−ヒドロキシ安息香酸と反応させ、対応するエーテルを得る。分取ＨＰＬＣによる精製で１５ｍｇ（理論値の２６％）の生成物を固体として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝４９０（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 13.28 (s, 幅広い, 1H), 8.20 (dd, 1H), 7.96 (dd, 1H), 7.84 (s, 1H), 7.81 (d, 1H), 7.48 (t, 1H), 7.44 (t, 1H), 7.30 (dd, 1H), 7.23 (d, 1H), 7.20 (s, 1H), 7.10 (d, 1H), 3.82 (t, 2H), 3.47 (m, 2H), 3.33 (m, 2H), 3.27 (m, 2H)。 Example 20
3-Fluoro-4-{[3-({4- [3- (trifluoromethyl) phenyl] piperazin-1-yl} carbonyl) pyridin-2-yl] oxy} benzoic acid

40 mg (0.11 mmol) of 2-fluoronicotinamide from Example 1A were combined with 26.5 mg (0.17 mmol) of 3-fluoro-4-hydroxybenzoic acid in a manner similar to the method for preparing Example 3. React to obtain the corresponding ether. Purification by preparative HPLC gives 15 mg (26% of theory) of the product as a solid.
MS (ESIpos): m / z = 490 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 13.28 (s, broad, 1H), 8.20 (dd, 1H), 7.96 (dd, 1H), 7.84 (s, 1H), 7.81 (d, 1H ), 7.48 (t, 1H), 7.44 (t, 1H), 7.30 (dd, 1H), 7.23 (d, 1H), 7.20 (s, 1H), 7.10 (d, 1H), 3.82 (t, 2H) 3.47 (m, 2H), 3.33 (m, 2H), 3.27 (m, 2H).

実施例１Ａ由来の４０ｍｇ（０.１１３ｍｍｏｌ）の２−フルオロニコチンアミドを、実施例３を製造するための方法と同様に２９.３ｍｇ（０.１７ｍｍｏｌ）の３−クロロ−４−ヒドロキシ安息香酸と反応させ、対応するエーテルを得る。分取ＨＰＬＣによる精製で１８ｍｇ（理論値の３１％）の生成物を樹脂として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝５０６（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 13.31 (s, 幅広い, 1H), 8.19 (dd, 1H), 8.04 (dd, 1H), 7.95 (dt, 2H), 7.44 (d, 2H), 7.30 (dd, 1H), 7.23 (d, 1H), 7.20 (s, 1H), 7.10 (d, 1H), 3.82 (t, 2H), 3.51 (m, 2H), 3.36 (m, 2H), 3.28 (m, 2H)。 Example 21
3-Chloro-4-{[3-({4- [3- (trifluoromethyl) phenyl] piperazin-1-yl} carbonyl) pyridin-2-yl] oxy} benzoic acid

40 mg (0.113 mmol) of 2-fluoronicotinamide from Example 1A were combined with 29.3 mg (0.17 mmol) of 3-chloro-4-hydroxybenzoic acid in a manner similar to the method for preparing Example 3. React to obtain the corresponding ether. Purification by preparative HPLC gives 18 mg (31% of theory) of product as a resin.
MS (ESIpos): m / z = 506 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 13.31 (s, broad, 1H), 8.19 (dd, 1H), 8.04 (dd, 1H), 7.95 (dt, 2H), 7.44 (d, 2H ), 7.30 (dd, 1H), 7.23 (d, 1H), 7.20 (s, 1H), 7.10 (d, 1H), 3.82 (t, 2H), 3.51 (m, 2H), 3.36 (m, 2H) , 3.28 (m, 2H).

実施例１Ａ由来の４０ｍｇ（０.１１３ｍｍｏｌ）の２−フルオロニコチンアミドを、実施例３を製造するための方法と同様に２８.６ｍｇ（０.１７ｍｍｏｌ）のバニリン酸（vannilinic acid）と反応させ、対応するエーテルを得る。分取ＨＰＬＣによる精製で１２ｍｇ（理論値の２１％）の生成物を油状物として得る。
ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝５０１（Ｍ＋Ｈ）^＋。
¹H-NMR (400MHz, DMSO-d₆): δ = 13.01 (s, 幅広い, 1H), 8.12 (dd, 1H), 8.08 (t, 1H), 7.89 (dd, 1H), 7.61 (m, 1H), 7.49 (hept, 1H), 7.44 (d, 1H), 7.25 (m, 2H), 7.20 (s, 1H), 7.11 (t, 1H), 3.8 (t, 2H), 3.75 (s, 3H), 3.38 (m, 2H), 3.35 (m, 2H), 3.22 (m, 2H)。 Example 22
3-methoxy-4-{[3-({4- [3- (trifluoromethyl) phenyl] piperazin-1-yl} carbonyl) pyridin-2-yl] oxy} benzoic acid

40 mg (0.113 mmol) of 2-fluoronicotinamide from Example 1A was reacted with 28.6 mg (0.17 mmol) of vannilinic acid in a manner similar to the method for preparing Example 3; The corresponding ether is obtained. Purification by preparative HPLC gives 12 mg (21% of theory) of the product as an oil.
MS (ESIpos): m / z = 501 (M + H) ^<+> .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 13.01 (s, broad, 1H), 8.12 (dd, 1H), 8.08 (t, 1H), 7.89 (dd, 1H), 7.61 (m, 1H ), 7.49 (hept, 1H), 7.44 (d, 1H), 7.25 (m, 2H), 7.20 (s, 1H), 7.11 (t, 1H), 3.8 (t, 2H), 3.75 (s, 3H) , 3.38 (m, 2H), 3.35 (m, 2H), 3.22 (m, 2H).

本発明の化合物のインビトロ効果を下記において示すことができる：
１．血漿線維素溶解アッセイ
ラットにおけるプラスミノーゲン活性化因子阻害因子−１（ＰＡＩ−１）の阻害剤の同定および本明細書に記載されている物質の活性の定量化を血漿−ベース線維素溶解アッセイを使用して行う。線溶系の阻害をα_２−アンチプラスミンもしくはα_２−マクログロブリンによるプラスミンレベルまたはＰＡＩ−１によるプラスミノーゲン活性化因子レベルのいずれかで行うことができる。 B. Assessment of physiological activity
Abbreviations:

The in vitro effects of the compounds of the invention can be shown below:
1. Plasma fibrinolysis assay Identification of inhibitors of plasminogen activator inhibitor-1 (PAI-1) in rats and quantification of the activity of the substances described herein in plasma-based fibrinolysis assay To do that. Inhibition of fibrinolysis alpha ₂ - antiplasmin or alpha ₂ - can be carried out either by plasmin levels or PAI-1 by macroglobulin plasminogen activator level.

  The addition of human α-thrombin leads to the development of a fibrin network with a three-dimensional structure through several intermediate steps. This fibrin network is disrupted by the serine protease plasmin, which is previously formed from the inactive proenzyme plasminogen by the plasminogen activator tPA. The activity of tPA is controlled by plasminogen activator inhibitor-1 (PAI-1). Inhibition of PAI-1 results in an increased rate of disruption of the fibrin network.

Assay Method: Recombinant Rat Plasminogen Activator Inhibitor 1 (PAI-1; Molecular Innovations Inc., MI, USA) (final concentration: 8.25 nM; 50 mM HEPES, pH 6.2; 50 mM NaCl; 1% PEG 6000) in a volume of 12 μl is incubated for 3 minutes at room temperature in a 96-well microtiter plate with the substance to be tested or a suitable solvent in a concentration range of 100 μM to 10 nM. Human platelet poor plasma (Blutspendedienst Deutsches Rotes Kreuz, Hagen, Germany) is diluted 1: 3 with buffer (150 mM NaCl; 20 mM HEPES, pH 7.4). Add 183 μl of plasma / buffer mixture per batch to the protein / substance mixture. Then 8 μl calcium chloride (final concentration: 10 mM), human tissue plasminogen activator (tPA; final concentration: 7.5 nM; Chromogenix, Moelndal, Sweden) and α-thrombin (final concentration: 25 nM; Kordia, Leiden, Netherlands) mixture, mix thoroughly, and transfer 2 portions of 80 μl to 384-well microtiter plate. Fibrin clot formation and subsequent lysis is followed by absorption measurements at a wavelength of 405 nm. The reaction rate is measured at 37 ° C. at 2 min intervals for at least 3 hours (Tecan Saphire, Tecan Germany GmbH, Crailsheim, Germany).

Data analysis: Clot lysis time (CLT) is the time to reach half of the maximum and minimum absorption values. The CTL value found in the absence of PAI-1 is defined as “0% PAI-1 activity” and in the presence of 8.25 nM as “100% activity”. The CLT ₅₀ value indicates the concentration of test substance at which the clot lysis time is reduced by half.
Representative in vitro data for the activity of the compounds of the invention is shown in Table A:
Table A:

2. Selectivity comparison with other serine proteases
2.1 Plasminogen activator t-PA and urokinase
Assay Method: Substances are characterized by a comparison of effects on tPA (tissue plasminogen activator) and urokinase. For this purpose, PAI-1 inhibitor is added to human tPA (Sigma Aldrich Chemie GmbH, Taufkirchen, Germany; final concentration: 1 nM) or human urokinase (Sigma Aldrich Chemie GmbH, Taufkirchen, Germany; final concentration: 2.5 nM) to 50 mM. Incubate in buffer with TRIS pH 7.5, 140 mM NaCl and 0.1% PEG 6000 for 10 minutes at room temperature. Enzyme activity is measured as an increase due to cleavage of specific peptide substrates (final concentration 10 μM; 444XF for tPA and 244XF for urokinase; American Diagnostica) in SPECTRAFluor Plus (Tecan, Maennedorf, Switzerland). The highest concentration is 10 μM.

Analysis: Fluorescence values obtained without substance addition are adjusted to 100% and then all other values are related to this 100%. Dose activity plots and IC ₅₀ values are calculated from percentages using the GraphPad Prism computer program.

2.2. Coagulation factors FX, FXa, FIXaβ, FVIIa, FXIa and serine proteases plasmin and trypsin
Assay Method: Coagulation factors Factor X (FX), Factor Xa (FXa), Factor IXaβ (FIXaβ), Factor VIIa (FVIIa), Factor XIa (FXIa) and thrombin and serine proteases plasmin and trypsin were tested. Use for. Common fluorogenic substrates are I-1100 (Boc-Ile-Glu-Gly-Arg-AMC), I-1575 (Boc-Glu (OBzl) -Ala-Arg-AMC HCl), I-1560 (Boc-Asp). (OBzl) -Pro-Arg-AMC HCl), and I-1275 (MeOSuc-Ala-Phe-Lys-AMC TFA). All these substrates can be obtained from Bachem (Bubendorf, Switzerland). All experiments are performed in 50 millimolar (mM) Tris, 100 mM sodium chloride, 5 mM calcium chloride, 0.1% BSA, pH 7.4, room temperature. The final volume in all experiments is 100 microliters (μl).

  In each mixture, 10 nM FXa 5 μM substrate I-1100, 0.3 nM FXIa 5 μM I-1575, 0.1 nM trypsin 5 μM I-1100, 0.002 nM thrombin 5 μM I-1560 and 0.012 nM plasmin are mixed with 50 μM I-1275. For the combined assay system, 8.8 nM FIXaβ or 1 pM FVIIa is mixed with 9.5 nM FXa and 50 μM substrate I-1100 in each case. The test compound is prepared as a 10 mmol (mM) solution in dimethyl sulfoxide (DMSO). These 10 mM stock solutions are first diluted 1: 5 in DMSO and then 1: 100 in assay medium. Eight serial dilutions are made from this 20 μM solution with each subsequent concentration corresponding to 1/3 of the initial concentration. 30 μl of these individual dilution mixtures were added at the highest substance concentration of this enzyme / substance mixture of 10 μM, then in order 3.3 μM, 1.1 μM, 0.37 μM, 0.12 μM, 0.04 μM, 0.012 μM and 0. Add to 30 μl cell to correspond to 0.004 μM. These test substances diluted in this way are added to the individual enzyme assay system. After incubation for 60 minutes, the amidolytic activity of the enzyme is measured with SPECTRAFluor Plus (Tecan, Maennedorf, Switzerland) at wavelengths of 360 nm (excitation) and 465 nm (emission).

Analysis: Fluorescence values obtained without substance addition are adjusted to 100% and then all other values are related to this 100%. Thus, comparative experiments can be performed on different days. Dose activity plots and IC ₅₀ values are calculated from percentages using the GraphPad Prism computer program.

2.3 Inhibition of serine protease
2.3.1 α ₂ -antiplasmin serine protease inhibitor α ₂ -antiplasmin can inhibit serine protease plasmin in addition to α ₂ -macroglobulin.

Assay Method: Human α ₂ -antiplasmin (Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany; final concentration: 50 nM; 50 mM TrisHCl pH 7.3; 200 mM NaCl; 0.2% BSA) in a volume of 10 microliters Incubate 5 minutes at room temperature in a 96-well microtiter plate with the substance to be tested or a suitable solvent in a concentration range of 100 to 10 μM Add 20 μl of human plasmin (Merck Biosciences, Schwalbach / Taunus, Germany; final concentration: 5 nM) per batch to the α ₂ -antiplasmin / substance mixture and incubate at 37 ° C. for 15 minutes. 20 μl of fluorescent plasmin substrate I1275 (Bachem, Weil am Rhein, Germany; final concentration: 15 μM; 50 mM TRIS pH 7.3, 200 mM NaCl; 0.02% BSA) is then added. After incubation for 40 minutes at a temperature of 37 ° C., the fluorescence signal is measured (Tecan Saphire, Tecan Deutschland GmbH, Crailsheim, Germany; excitation: 360 nm; emission: 465 nm; gain 50).

Analysis of data: The fluorescence value found in the absence of α ₂ -antiplasmin (released at 465 nm) is defined as “0% inhibition” and defined as “100% inhibition” in the presence of 50 nM. IC ₅₀ values indicate the concentration of test substance at which the emitted fluorescence was reduced by half.

2.3.2 α ₁ -antitrypsin serine protease inhibitor α ₁ -antitrypsin can inhibit serine protease trypsin.

Assay Method: Human α ₁ -antitrypsin (Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany; final concentration: 2 μM; 50 mM TrisHCl pH 7.3; 100 mM NaCl; 5 mM calcium chloride; 0.5% BSA) 10 Incubate for 5 minutes at room temperature in a 96-well microtiter plate with the substance to be tested or a suitable solvent in a concentration range of 100 to 10 μM in a microliter volume. Add 20 μl of human trypsin (Sigma-Aldrich, Taufkirchen, Germany; final concentration: 500 nM) per batch to the α ₁ -antitrypsin / substance mixture and incubate at 37 ° C. for 15 minutes. 20 μl of fluorescent trypsin substrate I1100 (Bachem, Weil am Rhein, Germany; final concentration: 1 μM; 50 mM TRIS pH 7.3, 200 mM NaCl; 0.02% BSA) is then added. After incubation for 40 minutes at a temperature of 37 ° C., the fluorescence signal is measured (Tecan Saphire, Tecan Deutschland GmbH, Crailsheim, Germany; excitation: 360 nm; emission: 465 nm; gain 50).

Analysis of data: The fluorescence value found in the absence of α ₁ -antitrypsin (released at 465 nm) is defined as “0% inhibition” and is defined as “100% inhibition” in the presence of 2 μM. IC ₅₀ values indicate the concentration of test substance at which the emitted fluorescence was reduced by half.

The suitability of the compounds of the invention for treating thrombosis can be found in the following animal models:
The compounds of the invention can be studied in a thrombosis model in which fibrinolysis is mediated by a PAI-1-dependent mechanism (see: Clozel, J Cardiovasc Pharmacol 12: 520-5 (1998); Levi, Circulation 85: 305 -12 (1992); Biemond, Circulation 91: 1175-81 (1995); Friederich, Circulation 96: 916-21 (1997)). Furthermore, the compounds of the invention can be characterized in terms of inhibition or reduction in PAI-1 activity in vivo (see: Crandall, BBRC 311: 904-908 (2003)).

The half-life of the compounds of the present invention can be found in the following assay:
To measure the apparent half-life in vivo, test substances are dissolved in various formulated compositions (eg, plasma, ethanol, DMSO, PEG400, etc.) or a mixture of such solubilizers, Administered intravenously. The dose administered is in the range of 0.1 to 1 mg / kg. Blood samples are removed by means of catheters or by killing at various time points over a period of up to 26 hours. Quantitative measurement of the substance in the test sample is performed in plasma via an assay sample conditioned in plasma. Proteins present in the plasma are removed by precipitation with acetonitrile. Samples are then fractionated by HPLC on a 2300 HTLC system (Cohesive Technologies, Franklin, MA, USA) using a reverse phase column. The HPLC system is coupled to an API 3000 Triple Quadropole mass spectrometer (Applied Biosystems, Darmstadt, Germany) via a turbo ion spray interface. Plasma concentration over time is analyzed using an effective kinetic analysis program.

C. Exemplary Embodiments of Pharmaceutical Compositions The compounds of the present invention can be converted into pharmaceutical products in the following manner:
tablet:
Composition:
100 mg of a compound of the invention, 50 mg lactose (monohydrate), 50 mg corn starch (natural), 10 mg polyvinylpyrrolidone (PVP25) (BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate.
Tablet weight 212 mg. Diameter 8mm, curvature radius 12mm.
Manufacturing:
A mixture of the compound of the invention, lactose and starch is granulated with a 5% strength solution (m / m) of PVP in water. The granules are dried and then mixed with magnesium stearate for 5 minutes. The mixture is tableted with a conventional tablet press (see tablet format above). As per the guidelines, a tableting force of 15 kN is used for tableting.

Oral suspension:
Composition:
1000 mg of the compound of Example 1, 1000 mg ethanol (96%), 400 mg Rhodigel (FMC, xanthan gum from USA) and 99 g water.
Oral suspension of 10ml is equivalent to a single dose of a compound of the invention 100 mg.
Manufacturing:
Rhodigel is suspended in ethanol and the compound of the invention is added to the suspension. Add water with stirring. The mixture is stirred for about 6 hours until the expansion of the Rhodigel is complete.

Solutions that can be administered intravenously:
Composition:
1 mg of a compound of the invention, 15 g polyethylene glycol 400 and 250 g water for injection.
Manufacturing:
The compound of the invention is dissolved in water with stirring with polyethylene glycol 400. The solution is sterilized by filtration (pore diameter 0.22 μm) and dispensed into heat-sterilized infusion bottles under aseptic conditions. These are sealed with an injection stopper and a crimp cap.

Claims (11)

formula

[Where,
X is the formula

{here,
* Is the position bonded to the carbonyl group,
# Is the position of bonding to the oxygen atom,
R ² , R ³ , R ⁴ and R ⁵ are independently of each other hydrogen, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₆ -alkylamino, C ₁ -C ₄ -alkoxycarbonyl or C ₁ -C ₆ -alkylaminocarbonyl}
Y is phenyl or pyridyl {wherein phenyl and pyridyl may be substituted by 1 to 3 substituents, where the substituents are independently of one another halogen, hydroxy, amino, cyano, trifluoro; , trifluoromethoxy, hydroxycarbonyl, _{aminocarbonyl,} C 1 -C ₆ - _alkyl, C 1 -C ₆ - _alkoxy, C 1 -C ₆ - _alkylamino, C 1 -C ₆ - _{alkylcarbonyl,} C 1 -C Selected from the group consisting of ₆ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl)},
n is a number 0, 1, 2 or 3;
R ¹ is phenyl or 5- or 6-membered heteroaryl {wherein phenyl and heteroaryl may be substituted by 1 to 3 substituents, wherein the substituents are independently of one another halogen , hydroxy, amino, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, _{aminocarbonyl,} C 1 -C ₆ - _alkyl, C 1 -C ₆ - _alkoxy, C 1 -C ₆ - _alkylamino, C 1 -C _6- alkylcarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkylaminocarbonyl and C ₁ -C ₆ -alkylsulfonylamino)}]
Or a salt, solvate or solvate of a salt thereof. X is an expression

{here,
* Is the position bonded to the carbonyl group,
# Is the position of bonding to the oxygen atom,
R ² , R ³ , R ⁴ and R ⁵ are independently of each other hydrogen, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₆ -alkylamino, C ₁ -C ₄ -alkoxycarbonyl or C ₁ -C ₆ -alkylaminocarbonyl}
Y is phenyl {wherein the phenyl may be substituted by 1 to 3 substituents (wherein the substituents are independently of one another halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoro methoxy, hydroxycarbonyl, _{aminocarbonyl,} C 1 -C ₆ - _alkyl, C 1 -C ₆ - _alkoxy, C 1 -C ₆ - _alkylamino, C 1 -C ₆ - _{alkylcarbonyl,} C 1 -C ₆ - alkoxycarbonyl And C ₁ -C ₆ -alkylaminocarbonyl)}
n is a number of 0;
R ¹ is phenyl {wherein the phenyl may be substituted by 1 to 3 substituents (wherein the substituents are independently of one another halogen, hydroxy, amino, cyano, trifluoromethyl, tri trifluoromethoxy, hydroxycarbonyl, _{aminocarbonyl,} C 1 -C ₆ - _alkyl, C 1 -C ₆ - _alkoxy, C 1 -C ₆ - _alkylamino, C 1 -C ₆ - _{alkylcarbonyl,} C 1 -C ₆ - alkoxy Selected from the group consisting of carbonyl, C ₁ -C ₆ -alkylaminocarbonyl and C ₁ -C ₆ -alkylsulfonylamino)}
A compound according to claim 1, or one of its salts, solvates or solvates of salts. X is an expression

{here,
* Is the position bonded to the carbonyl group,
# Is the position of bonding to the oxygen atom,
And R ² , R ³ , R ⁴ and R ⁵ are hydrogen}
Y is phenyl {wherein phenyl is optionally substituted by 1 to 2 substituents, wherein the substituents are selected from the group consisting of halogen and C ₁ -C ₄ -alkoxy independently of each other )},
n is a number of 0;
R ¹ is phenyl {wherein phenyl is optionally substituted by 1 to 3 substituents, where the substituents are independently of one another halogen, cyano, trifluoromethyl, methyl, methoxy and methyl Selected from the group consisting of sulfonylamino)}
A compound according to claim 1 or claim 2, or a salt, solvate or solvate of a salt thereof. formula

[Wherein X and R ¹ have the meanings given in claim 1]
A compound represented by
formula

[Wherein X and n have the meanings given in claim 1]
A process for the preparation of a compound of formula (I) according to claim 1 or a salt, solvate or solvate of a salt thereof, characterized in that it is reacted with a compound of formula (I).   4. A compound according to any one of claims 1 to 3 for the treatment and / or prevention of disease.   Use of a compound according to any of claims 1 to 3 for the manufacture of a medicament for the treatment and / or prevention of diseases.   Use of a compound according to any of claims 1 to 3 for the manufacture of a medicament for the treatment and / or prevention of thrombotic diseases.   A medicament comprising at least one compound according to any of claims 1 to 3 together with a further active ingredient.   A medicament comprising at least one compound according to any one of claims 1 to 3 together with at least one inert, non-toxic, pharmaceutically suitable adjuvant.   10. A medicament according to claim 8 or claim 9 for the treatment and / or prevention of thrombotic diseases.   A thrombotic disorder in humans and animals via administration of a pharmaceutically effective amount of at least one compound according to any one of claims 1 to 3 or a drug according to any one of claims 8 to 10. How to control.