WO2007034846A1 - Cardiotonic agent comprising grk inhibitor - Google Patents

Abstract

It is intended to provide a novel cardiotonic agent (a drug for ameliorating acute cardiac contraction) which contains a compound having an inhibitory effect on G protein-coupled receptor kinase (GRK), its prodrug or a salt thereof (a GRK inhibitor).

Description

 Specification

 Cardiotonic drugs composed of GRK inhibitors

 The present invention relates to G protein-coupled receptor kinase, (G protein-coupled receptor phosphatase; GRK) inhibitory compound or a prodrug thereof (hereinafter sometimes abbreviated as GRK. Inhibitor). Concerning cardiotonic drugs (acute cardiac strength improving drugs). Background art

Heart failure is a general term for pathological conditions caused by the inability to beat blood that meets the demand for peripheral organ tissue due to abnormal cardiac function. Very Umate prognosis among diseases of the circulatory system is one of the bad disease, the 5-year survival rate of about ^50% (the American Heart Association Statistics

1997), it is said that the survival rate of male patients over 65 years of age is 20% (American Heart Association Total 2004). Of the total population in the United States, 5 million people of more than 2% are suffering from this disease, patients ^ number ¹ is to further increase Caro trend. Heart failure treatment has two objectives: improving acute symptoms and improving chronic life prognosis.Currently, as a pharmacotherapy, we expect catecholamines 'diuretics' digitalis Antibiotics such as PDE inhibitors are expected to improve chronic prognosis and survival. Angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists '] 3 blockers' aldosterone ^ It has been. However, the therapeutic effects of these drugs are far from satisfactory and the only radical treatment that can truly recover from a heart failure state is heart transplantation.

Drugs that act directly on the heart and improve the cardiac contractile force immediately after drug administration are called `` cardiotonic drugs'', focusing on the aforementioned digitalis' catecholamines and PDE inhibitors, especially in the treatment of heart failure, especially in the acute phase A category is formed as an essential drug for the improvement of symptoms. However, catecholamines, PDE inhibitors, etc. can It is known to increase life prognosis in the long run rather by accelerating and increasing the frequency of fatal cardiac arrhythmias. In addition, digitalis has a known fatal serious side effect called “digitalis intoxication”, and placebo-controlled, soil-blind, other large-scale clinical trials in 6800 patients with heart failure. Even in the DIG trial, the survival rate was not improved (New England Journal 'Ob' Medesin, 336, 525-S33). In other words, at present, there is no `` cardiotonic drug '' that clearly has an effect of improving the safety and prognosis of chronic administration, and a new strength that shows a better drug efficacy profile based on a new mechanism of action: It has been demanded.

On the other hand, in 1983, GRK2 (G protein-coupled receptor phosphorylase-2, also known as receptor phosphorylation enzyme) is considered to be one of the causes of decreased cardiac function in heart failure pathology. As a result, it is clarified what happens due to receptor phosphorylation by the gene.By using gene modification techniques, long-term inhibition of the heart's GRK2 action can improve both cardiac function and survival in heart failure model animals. Many findings have been reported (Nature Biotechnology :, Vol. 14, pp. 283-286 and Toren's “In-force Ludiovascular Medi. Sin, Vol. 9, pp. 77-81) . further, in heart failure model animal Ya human heart failure patients reported an increase in cardiac GRK2 protein onset amount that has (Saki configuration research, Vol. ^{74, 2} 0 ⁶ _ ² 1; 3 pages). etc., of GRK Inhibition is pre-existing heart failure For example, Harding et al. Have developed a model animal for dilated cardiomyopathy, calcequestrin-overexpressing heart failure mouse, which has been attracting attention as a new mechanism that can improve both cardiac function and long-term prognosis. , A GRK inhibitor protein] 3 By crossing mice that overexpressed ARKct in the myocardium, the heart GRK was chronically inhibited from birth, and at 7 weeks of age, cardiac contractility and relaxation (American Academy of Sciences, Vol. 98, pages 5809-5814), White et al., Shaha et al. Inhibition of cardiac GRK by introducing 3 ARKct into the heart of a heart failure Usagi after myocardial infarction improves cardiac function 1-3 weeks after gene transfer (USA. Scientific Academies, Bulletin 97, pp. 97: 5428-5433 and Circulation, pp. 103, 1311-113 ρ).

 However, in the laboratory using these genetic modification methods, it was observed because the introduced gene required several hours to several 0 until it expressed inhibitory protein and actually showed inhibition. It is not possible to identify whether the event occurred more directly in the inhibition of GRK or indirectly through another route. In particular, regarding the effects of acute ifi damage to the heart GRK, it is possible to obtain an effect of directly improving acute cardiac contractility, that is, whether GRK inhibition is a new `` cardiotonic '' mechanism. Therefore, it was impossible to confirm that there was no low molecular weight compound that could inhibit GRK action selectively and acutely, and it was completely unknown. … :::.

 Therefore, although there was a vague expectation that long-term inhibition of GRK would eventually lead to improved cardiac function via multiple pathways, GRK inhibitors acted directly on the heart and became acute immediately after drug administration. It was never known to those skilled in the art to have a “medicine use as a“ cardiotonic agent ”” to improve the cardiac contractility.

Disclosure of the invention:

 As mentioned above, at present, there are no `` cardiotonic drugs '' that clearly have safety and prognosis-improving effects in chronic administration, and the creation of new cardiotonic drugs that exhibit better medicinal profiles based on new mechanisms of action Was demanded.

In the process of diligently searching for drugs that can selectively inhibit GRK by applying to cells, organ specimens, and living organisms, the present inventors have found that a compound having a triazole skeleton has a strong GRK inhibitory action in the enzyme assembly. It was found that GRK can be inhibited through the cell membrane even when applied from outside the cell. Furthermore, when this compound is applied directly to the isolated perfused heart preparation, the contractile force increases immediately after drug administration, and its effect is further increased in the presence of catecholamine, and the heart rate is almost increased. Not Was revealed. In addition, when the compound is administered intranasally to anesthetized rats, immediately after drug administration, only the systolic force is selectively enhanced with little effect on blood pressure and heart rate, and it can be recovered by administration interruption. Found έ

 Based on the above results, it is clear that GRK inhibition acts directly on the 'heart) ¾ and becomes an acute mechanism immediately after drug administration;

 [Where,

 Ring A represents an optionally substituted aromatic ring.

 Ring B represents an optionally substituted 5-membered ^ nitrogen aromatic heterocycle,

 Ring C represents an optionally substituted nitrogen-containing aromatic heterocycle, and

 X represents an optionally substituted Ci-4 alkylene group,

 Y represents an optionally substituted imino group, 1 O— or 1 S (0) n— (n represents Q, 1 or 2). ]

 A cardiotonic drug according to (2), which is a GRK2 inhibitor comprising a compound represented by the formula:

 (4) A method for treating heart failure in a mammal, comprising administering an effective amount of the cardiotonic agent according to (1) to the mammal suffering from heart failure;

 Etc.

Based on a new mechanism different from that of known drugs, GRK inhibitors act as a “cardiac agent” that acts directly on the heart and improves cardiac contraction force immediately after drug administration. First time to have: Based on what was revealed, "We were able to provide a cardiotonic drug J that does not contain a GRK inhibitor.

 In addition, GRK inhibitors have been confirmed to have a φ characteristic with little increase in heart rate, and are expected to have a chronic life prognostic effect as well as an action mechanism. That is, according to the present invention, an excellent “cardiotonic drug” is provided by the present invention, and the GRK inhibitor is based on its medicinal properties as a “cardiac drug” and heart failure (especially symptomatic heart failure). It has been demonstrated for the first time that it can be applied as: prevention, treatment, amelioration of symptoms of heart failure, left ventricular function improving agent in patients with heart failure, etc.

 '

 Brief Description of Drawings'

 Figure 1 shows the results of observing the effect of acute GRK inhibition by the test compound (1) on rat cardiovascular dynamics. Best form for applying the invention to the cold

The GRK inhibitor J used in the present invention is not particularly limited as long as it is a compound having a GRK inhibitory action, but is a low molecular weight compound, a nucleic acid, a protein, a peptide, a prodrug thereof, or a compound thereof. Any of salt, etc. can be used, but it is advantageous in practice of the present invention to use one having a strong GRK inhibitory action, for example, by the method disclosed in Test Examples 1 and 8 described later. When the inhibitory activity of GRK2 is measured, it is recommended to use an IC of ₅ or less, more preferably 0.3 iM or less, and still more preferably 0.1 M or less. This is advantageous in the practice of the invention, but is not limited thereto.

 In addition, the “GRK inhibitor” used in the present invention may have a pharmacological action other than the GRK inhibitory action, but it has a high selectivity to the GRK inhibitory action, and in particular, it is selected for the GRK2 inhibitory action. It is advantageous in the practice of the present invention to use a material having high properties.

Examples of the GRK inhibitor used in the present invention include International Application No. PCT / JP2005 / 005995 (W02005 / Ri 90328), a compound represented by the following formula (I), or the American Chemical Society, 231st National Meeting ), And the compounds represented by the formula (II) described later. A GRK inhibitor can be appropriately selected from these to implement the present invention. The following compounds are given as examples of GRK inhibitors only, and are not intended to be limiting. .

,

,

. Show the ring

S () n _ (n is 0, 1 or

 In the formula (I), ring A represents an optionally substituted aromatic ring. .

 Examples of the aromatic ring in the “optionally substituted aromatic ring” represented by ring A include (i) aromatic cyclic hydrocarbon, and (ii) nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom. An aromatic heterocycle containing preferably 1 to 3 heteroatoms selected from 1 or 2 is mentioned.

As the "aromatic cyclic hydrocarbon", for example, benzene, naphthalene, C 6 etc. _- include _{1 4} aromatic cyclic hydrocarbons.

Examples of the “aromatic heterocycle” include 5- to 6-membered aromatic monocyclic compounds such as furan, thiophene, pyridine, pyridazine, pyrimidine, pyrazine, and triazine. Treatment: For example, benzofuran, indole, etc., 8 to 16 membered. (Preferably 8 to 12 membered) aromatic condensed heterocycle (preferably 5 to 6 membered aromatic Monocyclic heterogeneous heterocycles of 1 to 2 (preferably: 1) fused with a benzene ring to 2 好 ま し く (preferably 1), or as described above. A heterocyclic ring in which the same ^ "of a cyclic heterocyclic ring or 2 to 3 different heterocyclic rings, preferably 2) are fused, and the like.

 Here, examples of the substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring may have include a halogen atom, an optionally substituted hydrocarbon: group, and a substituted Mole, heterocyclic group, optionally substituted amino group, optionally substituted imidoyl group, optionally substituted amidino group, optionally substituted hydroxyl group, substituted Optionally substituted cyanore group: sia / group, nitro group, nitrozo group, sulfo group, optionally substituted rubamoyl group, .substituted samoyl group, esterified The optional carboxyl group may be substituted with 1 to 5 (preferably 1 to 3) of these optional substituents at substitutable positions.

 Examples of the “halogen atom” as the substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have include fluorine, silicon, bromine, and iodine. It is done.

 The “hydrocarbon group” in the “optionally substituted hydrocarbon group” as the substituent that the ring may have in the “optionally substituted aromatic ring” represented by ring A is Examples thereof include an aliphatic chain hydrocarbon group, an alicyclic hydrocarbon group (non-aromatic cyclic hydrocarbon group), and an aryl group (aromatic hydrocarbon group).

 Examples of the “aliphatic chain hydrocarbon group” as an example of the hydrocarbon group include linear or branched aliphatic hydrocarbon groups such as an alkyl group, an alkenyl group, and an alkynyl group.

Here, examples of the “alkyl group” include C ₁₀ alkyl groups (preferably C ^ alkyl etc.) such as methyl, ethyl, n-propyl, isopropyl, etc. Leaking. ..,,

 Examples of the “alkenyl group” include vinyl, allyl, isopropenyl, etc.

C ₂ _ ₆ .alkenyl S and the like. , —— '

. 'As "alkynyl group", for example,' Echuru, 1 Purobyuru, 2-propyl sulfonyl, C ₂ etc. - include ₆ alkynyl group.. -.

 Examples of the “alicyclic hydrocarbon group” as an example of the hydrocarbon group include saturated or unsaturated alicyclic hydrocarbon groups such as a cycloalkyl group, a cycloalkenyl group, and a chloralkadienyl group. . .

Here, the "cycloalkyl group J, for example, Shikuropuropinore, Shikurobu chill, C ₃ _ ₉ cycloalkyl grave or the like and the like.

Ho as "cycloalkenyl group", for example, 2- Shikuropenchin one 1-I le, 3-cyclopentene -.. 1 I Le, C ₃ _ ₉ consequent equal Roaruke group, and the like.

Examples of the “cycloalkadienyl group” include, for example, 2,4-cyclopentagen 1-yl, 2,4-cyclohexahexan 1-yl, 2,5-cyclopentahexagen 1 A C _4-6 cycloalkadienyl group such as —yl; .

Examples of the “aryl group” as an example of the hydrocarbon group include monocyclic or condensed polycyclic aromatic hydrocarbon groups, such as C _6-14 aryl groups such as phenyl, naphthyl, etc. Among them, a 'C _6:12 aryl group and the like are particularly preferable.

 Further, as examples of the hydrocarbon group, the same or different 2 to 3 groups constituting a group selected from the above-described alicyclic hydrocarbon group and aryl group, such as 1,2-di-7dronaphtyl, indanyl and the like. And a bi- or tricyclic hydrocarbon group derived from the condensation of a ring (preferably two or more rings). Furthermore, a bridged hydrocarbon group such as adamantyl is also included.

 The “hydrocarbon group” in the “optionally substituted hydrocarbon group” as the substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have Examples of the substituent that may be used include:

(i) a nitro group; (ii) a hydroxy group, oxo ¾;

 (iii) a siaso group;

 (iv) Power ruby radical; '.

. (V) mono- or di - C Medicine ₄ alkyl - force Rubamoiru group (the alkyl group is halogen atom, seven Dorokishi group, C _{1 4} alkoxy group it may also be substituted with such les.), Mono - or di -C ₂ _ ₄ Arukeeru - power Rubamoiru group (該A / Rekeniru group halogen atom, arsenic Dorokishi group, optionally substituted by C _1-4 alkoxy £ etc.), mono- or di one phenylene Rucarbyl group, mono- or diaralkyl one-strength rubamoy: ru group, C — ₄ alkoxy monocarbonyl, force rubermoyl group, C ₄ alkylsulfo: nyl-strength rubamoinole group, c _1-4 alkoxy-strength rubamoin group , Amino-carbamoyl group, mono- or di-C _1-4 nalalkylamino-strength rubermoyl group, mono- or diphenyleno-strength rubermoyl group;

 (vi) cal; ^ xyl group;

 (vii) — 4 Ananoloxy monocarbonyl group;

(viii) Snorejo group;

 (ix) a halogen atom;

(X) optionally halogenated C [physicians have ₄ alkoxy groups, human Dorokishi g conversion which may C ₁ even though _-4 alkoxy group group may be substituted with a carboxyl group

_{A 4} alkoxy group, an alkoxy group optionally substituted with ₄ alkoxy 1 carbonyl groups, — 4 alkoxy 1 C ₄ alkoxy groups, I ₄ alkoxy 1 Ci ₄ alkoxy 1 Ci alkoxy group;

(xi) phenoxy group, phenoxy ten preparative ₄ alkyl group, phenoxy one C physician ₄ alkoxy group, CI- 4 alkyl one carbonyl O alkoxy group, a force Rubamoiruokishi group, mono- or di-C _1-4 alkyl - force Rubamoiruokishi group;

(xii) a halogen atom, optionally halogenated C _{[1 -4} alkyl group, optionally halogenated C [Medicine ₄ alkoxy groups, optionally substituted by human Dorokishi C,. ₄ alkyl group and phenyl C optionally substituted with a substituent selected from the group ₆ ” ₁₂ reel base; ',:,...

(xiii) Soso halogenated which may phenyl one also be an alkyl group, an optionally halogenated phenyl _ C ₂ _ ₄ even though Aruke group, Seo, 'halogenated which may be phenoxy group, Pirijiruokishi groups, C ^. Cycloalkyl - Jii ₄ alkoxy group, C ₃ - ₁₀ Non Black alkyl one ₄ alkyl group;

(xiv) human Dorokishiru may be substituted with a group C ₃ - _10, down Roarukiru group, C. _ ₁₀ Bicyclic hydrocarbon group condensed with cycloalkyl group and benzene (for example, indal etc.), Bridged hydrocarbon group (for example, adayantyl etc.);

(XV) halogenated expired they may Ji alkyl group, /, halogenated which may be C ₂ _ ₆ alkenyl group, an optionally C _1-4 alkylthio group which may be halogenated, substituted with human Dorokishi group It may be substituted with a d- ₄ alkyl group or a hydroxy group. ₄ alkylthio groups;

 (xvi) mercapto group, thixo group;

(xvii) an benzyloxy group or a benzylthio group optionally substituted with a substituent selected from a halogen atom, a carboxyl group, and a _-4 alkoxy monocarbonyl group;

(xviii) optionally halogenated phenylthio group, pyridylthio group, phenylo- — ₄ alkyl group, pyridylthio-C _1-4 alkyl group;

(xix) an optionally halogenated C _1-4 alkylsulfier group;

(XX) optionally halogenated C _1-4 anoleno ^ / sunorephoninole group, phenenolesnorephonyl group, phenylsenorephonyl-to- ₄ arenoalkyl group;

(xxi) Sno referencing Moi Honoré group, mono one or di- Jii ₄ § Honoré Kino less Roh referencing Moi Honoré group (the alkyl group is a halogen atom, arsenic Dorokishi group, optionally substituted with C _1-4 alkoxy group May be);

(xxii) amino group, C _t - ₁₀ Ashiru primary amino group [C physician ₁₀ Ashiru halogen atom, arsenic Dorokishi group, may be substituted with a carboxyl group or the like], benzyl O carboxymethyl Cal Boniruamino, halogenated C ₆ alkoxy-carbonylamino , Rubamoylamino groups, mono- or di-, C _1-4 alkyl monocarbamoamino groups;

. (xxiii) mono- - or di one C ^ ₄ alkylamino group (^ alkyl group is a halogen atom, arsenic Dorokishi group may be substituted with C ₄ alkoxy S, etc.), phenyl Amino, benzyl T Mino; ' :.

 (xxiv) a 4- to 6-membered cyclic amino group, a 4- to 6-membered cyclic amino monocarbonyl ¾,

, 4- to 6-membered cyclic aminoaminocarbonyl group, 4- to 6-membered cyclic amino group / repulol-amino group, 4-membered), 6-membered cyclic aminosulfonyl group, 4- to 6-membered cyclic amino group. Preparative ₄ alkyl group;

(XXV) C _1-6 acyl group or benzoyl group each optionally substituted by a substituent selected from a halogen atom, a force / repoxyl group and a C _1-4 aroxy-carbonyl group · No,.

 (xxvi) a benzoyl group optionally substituted by a halogen atom;

(xxvii) 5 to 10-membered Hajime Tamaki (said heterocyclic group 〇 ₄ 'Rere good be substituted by an alkyl group);''

 (xxviii) a 5- to 10-membered heterocyclic-carbonyl group (the heterocyclic group may be substituted with an alkyl group or the like);

 (XX ix) a hydroxyimino group, a Ci-4 alkoxyimino group;

(XXX) a linear or branched C _1-4 alkylenedioxy group which may be halogenated;

 Etc.

 The “hydrocarbon group” may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) of these substituents at substitutable positions. When having the above, the substituents may be the same or different.

The “heterocyclic group” in the “optionally substituted heterocyclic group” as the substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have, for example, The atoms that make up the ring system (ring atoms) are oxygen atoms, sulfur atoms And at least one (preferably 1 or 2) preferably 1 to 3 kinds of atom atoms selected from nitrogen insulators, etc. An aromatic heterocyclic group, a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) and the like can be mentioned. : ''

 Examples of the “aromatic heterocyclic group” include 5- to 6-membered aromatic monocyclic heterocyclic groups such as furyl, .cenyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, .triazinyl and the like. For example, benzofuranyl, indolyl, imidazo

 [1, 5-a) Pyridyl, etc. 8: ~ 16-membered (preferably 8-: 12-membered) aromatic ^ condensed hetero-groups (preferably the 5-6 membered fragrance described above A heterocyclic group in which an aromatic monocyclic heterocyclic group is condensed with a benzene ring, or a heterocyclic group in which the same or different heterocyclic rings of the 5- to 6-membered aromatic monocyclic heterocyclic group are condensed. More preferably, the 5- to 6-membered aromatic monocyclic heterocyclic group is a heterocyclic group condensed with a benzene ring).

 Examples of the “non-aromatic heterocyclic group” include pyrrolidinyl, piperidyl, tetrahydro, pyrael, morpholinyl, thiomorpholiel (the sulfur atom may be oxidized), piperazinyl and the like. (Preferably 5- to 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group), etc .; or 1, 2, 3, 4-tetrahydroquinolinole, 1, 2, Non-aromatic heterocyclic groups in which some or all double bonds of the aromatic monocyclic heterocyclic group or aromatic condensed heterocyclic group described above are saturated, such as 3,4-tetrahydroisoquinolinole, etc. Is mentioned.

The “heterocyclic group” in the “optionally substituted heterocyclic group” as the substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have. Examples of the substituent that may be included include, for example, the “hydrocarbon group” in the “optionally substituted hydrocarbon group” as the substituent of the “optionally substituted aromatic ring” represented by ring A. And the same number of the same groups as the substituents which may be present. The “optionally substituted amino group” or the “optionally substituted amino group” as the substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have. An imidoyl group ”,“ optionally substituted amidino, group ”,“ optionally substituted, hydroxyl group ”,“ optionally substituted thiol group ”, Examples of the substituent that each of the imidazole group, amidino, hydroxy, thione group and thiol group may have include:

(i) Halogen, C ₆ alkylthio, phenyl, which may be halogenated

(The phenyl is halogen atom, Nono Gen of which may flicking ₆ even if. Alkyl, Bruno, may be substituted with halogenated which may be C ^ e-alkoxy, etc.), it has been Nono port Gen of May be naphthyl and C ₃ . Cigroalkyl is selected; a lower alkyl group optionally substituted with a substituent, etc .;

 (i i) a phenyl group which may be halogenated and is;

(iii) an optionally halogenated C _{3 10} cycloalkyl group;

(iv) an acyl group (optionally halogenated C i-s ananolecsyl, phenylacetyl '(the phenyl may be substituted with a halogen atom, an optionally halogenated C ₆ alkyl, etc. .), Nzoiru base may be halogenated, Nono halogenated which may be ς doctor ₆ alkylsulfonyl group, Nono halogenated which may be benzenesulfonyl, torr ^ Nsuruho two les, etc.);

(V) Soso halogenated which may c be the _{1 - 6} alkoxy - carbonyl group, a substituted c Medical ₆ optionally alkoxy carbonyl group phenyl;

(vi) mono- or diaralkyl one-strength rubermoyl group, mono- or _six- alkyl _six- strength rubermoyl group;

 (vi i) Heterocyclic group (for example, in the previously mentioned “optionally substituted heterocyclic group”

The same as “heterocyclic group”);

Etc. The “amino group” in the “optionally substituted amino group” as a substituent is an optionally substituted imidoyl group (for example, 〇 ₆ alkylimidoyl, C _{t 6} alkoxyimidoyl, alkylthioimidoyl). , Amidino and the like), an amino group which may be substituted with 1 to 2 alkyls, and the like. In addition, in the case of “optionally substituted amino group”, “optionally substituted imino group J and“ optionally substituted amidino group ”, two substituents are combined with the nitrogen atom. In this case, examples of the cyclic amino group include 1-azedinyl, 1-pyrrolidinyl, piperidine, thiomorpholino, kirolino, 1-piperazinyl, and A cyclic amino group having a lower alkyl group, an aralkyl group, an aryl group, etc. at the 4-position, such as 1-piperajurule, 1 pyrolithule, 1 imidazolyl, etc., preferably 3 to 8 members. Etc. ,: .. Two or more substituents present adjacent to each other on the aromatic ring in the “optionally substituted aromatic ring” represented by ring A are combined to form a linear or branched C! An alkylene dioxy group or the like may be formed.

 In the “optionally substituted aromatic ring” represented by ring A, the “optionally substituted strong rubermoyl group” as the substituent that the aromatic ring may have includes In addition to the / vamoyl group, N-mono.substitutional force ruberamoyl¾ and N, N-disubstitutional force / levermoinole group are fisted.

 Examples of the substituent of “N-mono-substituted rubamoyl group” include, for example, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, and an optionally substituted amino. .

 Examples of the “optionally substituted hydrocarbon group” as an example of the substituent of “N-mono-substituted rubamoyl group” include substitution in the “optionally substituted aromatic ring” represented by ring A Examples thereof include the same groups as the “optionally substituted hydrocarbon group” as the group.

 Examples of the “optionally substituted heterocyclic group” as an example of the substituent of “N-mono-substituted rubamoyl group” include substitution in the “optionally substituted aromatic ring” represented by ring A Examples thereof include the same groups as the “optionally substituted heterocyclic group” as the group.

The “optionally substituted amino group” as an example of the substituent of “N-mono-substituted rubamoyl group” is the “optionally substituted aromatic ring” represented by ring A. Examples of the substituent are the same groups such as “amino group which may be substituted and τ”.

“Ν, Ν—di-substituted rubamoyl group” means two force rubamoyl groups on the ¾ atom (one example of such a substituent is as described above; etc. substituents in N- monosubstituted force Rubamoiru group "Chile include the same ^, is to the other examples, for instance, a lower alkyl group, ₃ - ₆ cycloalkyl group, C _{1 ()} Ararukiru group and the like In some cases, two substituents may be combined with a nitrogen atom to form a cyclic amino group.In such a case, examples of the cyclic aminocarbamoinole group include .1. Azetidinylcarbonyl, ビ -bilolizinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholino force carbonyl / le (sulfur atoms may be oxidized), 1-piperazylcarbonyl , And 4-position lower alkyl group, aralkyl And a 3- to 8-membered (preferably 5- to 6-membered) cyclic amino-carbonyl group such as' 1_piperazylcarbonyl, etc., which may have an aryl group, etc. Examples of the “optionally substituted sulfamoyl group” as the substituent that the aromatic ring in the optionally substituted aromatic ring J may have include an unsubstituted sulfamoyl group, as well as an N-monosubstituted sulfamoyl group. Groups and N, N-disubstituted sulfamoyl groups.

 Examples of the substituent of “N-quino-substituted sulfamoyl group” include the same groups as the substituent of “N-mono-substituted rubamoyl group”.

“N, N-disubstituted sulfamoyl group” means a sulfamoyl group having two substituents on the nitrogen atom, and one example of the substituent is the above-mentioned “N-mono substituted sulfamoyl group” include those similar to the substituents, it is in the other examples, for example, a lower alkyl group, C ₃ _ ₆ cycloalkyl group, such as C ₇ _ _{1 0} Ararukiru group. In some cases, two substituents together with a nitrogen atom form a cyclic amino group. In such a case, examples of the cyclic aminosulfamoyl group include 1-azetidylsulfonyl, 1 Monopyrrolidinylsulfonyl, piperidinosulfonyl, morpholinosulfonyl, thiomorpholinosulfoninole (sulfur atom may be oxidized), 1-piperazinylsulfonyl, and lower alkyl at position 4 A 3- to 8-membered (preferably 5- to 6-membered) cyclic amino-sulfonyl group, such as 1-piperazinylsulfonyl, which may have an alkyl group, an aralkyl group, an aryl group, etc.

'You can get lost. .

 The “optionally esterified carboxyl group” as the substituent that the aromatic ring in the “optionally substituted” ring represented by ring A may have is a free carboxyl In addition to the groups, examples include lower alkoxycarbonyl group, aryl, oxycarbonyl group, aralkyloxycarbonyl group and the like.

. Examples of the "lower alkoxycarbonyl ^ le group", for example, main butoxy Rubo sulfonyl, E-butoxycarbonyl, propoxycarbonyl, C etc. -. ₆ Anorekokishi one carbonylation Honoré, and among them C _L - ₃ alkoxy one Carbonyl and the like are preferred.

 Examples of “Aryl talented xycarbonyl groups” include, for example, phenoxycarbonyl,

1-naphthoxycarbonyl, 2-naphthoxycarbonyl C ₆ .- _{1 2} Ariru one O alkoxycarbonyl, such as carbonyl, etc. are preferable.

The "§ Lal Kill O alkoxycarbonyl group", for example ', benzyl O propoxycarbonyl sulfonyl, phenethyl' O carboxymethyl Kano repo sulfonyl etc. C ₇ - _{1 ()} Ararukiru - O butoxycarbonyl, etc. (preferably, C _{6 - 1} Aryl 1 C ₄ alkoxy 1 carbonyl, etc.) are preferred.

 The “lower alkoxycarbonyl group”, “aryloxycarbonyl group”, and “aralkyloxycarbonyl group” may have a substituent, and as the substituent, the “substituted alkoxy group represented by ring A” The same number of the same groups as those mentioned as the substituents that the “hydrocarbon group” in the “optionally substituted hydrocarbon group” as the substituent in the “optionally aromatic ring” may have. Used.

 As the “acyl group” as the substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have, a carboxylic acid-derived asil group, a sulfinic acid-derived acyl group And an acyl group derived from sulfonic acid and an acyl group derived from phosphonic acid.

As the “carboxylic acid-derived acyl group”, a hydrogen atom, which may be substituted A hydrocarbon group (for example, the same group as the “optionally substituted hydrocarbon group” as a substituent in the “optionally substituted aromatic ring” in ring A) or may be substituted A silicon ring group (for example, “optionally substituted heterocyclic group” as a substituent in the “optionally substituted aromatic ring” represented by ring A and similar groups) and carbonyl (-C (O)-) and a group bonded thereto, for example, formyl, acetyl, propionyl, butyryl, isotoptyl, norrelyl, isovaleryl, hydr. Kisanoinore to server Roinore, Shikurobudan carbonyl, consequent emission Tan carbonyl, hexane force Lupo two Honoré cyclohexane, black doo two Honoré, I be halogen of such Torifuruo port Asechiru: There linear or cyclic c ₂ _ ₈ Arukanoiru; Benzoiru, nicotinyl Noiru, Isonikodjinoi ^, and among them, § Se chill, propionyl, flop styryl, valeryl, c ₂ such as pivaloyl _{-.. 5} Arukanoiru like.

The “sulfinic acid-derived acyl group” includes an optionally substituted hydrocarbon group (for example, a “substituted” as a g-substituted group in the “optionally substituted aromatic ring” represented by ring A. The same group as “optionally substituted hydrocarbon group” or a heterocyclic group which may be substituted (eg, ring. Indicated by A. Substituent in “optionally substituted aromatic ring” All of which may be substituted, similar to the heterocyclic group, etc.) and sulfiel (-S (0)-), such as methanesulfinyl, ethanesole A chain or cyclic C ₆ alkyl sulfiere that may be arogenized, such as finyl, proso, sulfanyl, cyclopropanesulfinyl, cyclopentanesulfinisole, cyclohexanesulfinyl, etc .; Benzene Fini Norre, such as door Norre Enns Norre Fini Norre and the like.

The “sulfonic acid-derived acyl group” is an optionally substituted hydrocarbon group (for example, “substituted” as a substituent in the “optionally substituted aromatic ring” represented by ring A. The same as the “hydrocarbon group” or a heterocyclic group which may be substituted (for example, “substituted” as the substituent in the “optionally substituted aromatic ring” represented by ring A) A group similar to “optionally substituted heterocyclic group”) and sulfonyl (—s (o) ₂ —), for example, methanesulfonyl, ethane Sunole Honinole, Prono. Nsnorejo 'Ninore ,. Chain, cyclic alkyl _6- cyclosulfoneole, which may be halogenated, such as benzenesulfonyl, toluenesulfonyl, and the like.

The phosphonic acid-derived acyl group includes, for example, 'dimethylphosphoso, jetylphosphono, diisopropylphosphono, dibutylphosphono, .2-oxide 1: 3,2-dioxaphosphinan-1 Examples of such compounds that may form cocoons, such as rutile, di-C _1-4 teralkyl, phosphoso and the like.

 As the substituent that the aromatic ring in ring A may have,

A neurogenic atom;

C ₆ alkyl group (wherein the c _1-6 alkyl group is a halogen atom, hydroxy, carbamoyl, mono- or di-benzylcarbamoinole, moso- or di-phenethylol-rubamoyl, carboxyl, di- ₄ Anorekokishi one carbonylation Honoré. Nono halogenated which may be C _{1 -4} alkoxy, amino, mono- one or di- _C _1-4 Arukirua amino, C ^ alkanoyloxy Noi Rua amino, may be Nono halogenated Substituted with phenyl, optionally halogenated benzoyl, etc.);

C _2-6 alkenyl group (the C ₂ _ ₆ alkenyl group may be substituted with may be Benzoiru like halogenated) .;

A phenylol group (the phenylol is a hydrogen atom, a log atom, a hydroxyloxy, a canolamoyl, a carboxyl, a sulfo group, an alkoxy monocarbonyl, an optionally halogenated _4- alkoxy, an optionally halogenated d— ₄ alkyl, amino, mono- one or di- one C ^ Arukiruamino may be substituted with C _{1 -6} alkanoyloxy Noi Rua amino, etc.);

 A non-aromatic heterocyclic group (preferably oxazoline, the non-aromatic heterocyclic group may be substituted with an oxo group or the like);

An amino group (the amino group is an optionally halogenated C ^ alkyl, an optionally halogenated C _1-6 alkanol, an optionally halogenated ben; Zoyl, phenylacetyl (the phenyl may be substituted with a halogen atom, which may be halogenated, such as Ci-e alkyl), .. mono- or di-benzylcarbamoyl group, mono- or di- . full energy chill carbamoylthiopheno group, it may be replacement by phenylene Le - ₆ alkoxy one carbonyl group, Bruno, halogenated which may be optionally C _{1 - 6} alkylsulfonyl is substituted by an Izu, also 'Hydroxy group (the hydroxy block is phenyl, the phenyl is a halogen atom,

, I be substituted with a halogenated or may be substituted by may be C i _ ₆ alkyl such as optionally) and optionally halogenated selected from a naphthyl substituents: There C ^ alkyl, May be substituted with an optionally halogenated phenyl, etc.);

C _4- alkylene dioxy group;

A thiol group (the thiol group may be substituted with a halogen atom or an optionally halogenated phenyl group, substituted with a _6- alkylenoleole, a nitrogenated L. or an optionally substituted phenyl group, etc.) It may be.);

 Force rubamoire group;

 N—Mono-substituted rubamoyl group (eg “

 N—C ^ e alkyl '(wherein the alkyl may be substituted with a halogen atom, a hydride, etc.)

N-phenyl (wherein the phenyl may be substituted with a halogen atom, optionally halogenated C _1-4 alkyl, etc.) —strength rubamoyl group;

 N—non-aromatic heterocycle (preferably tetrahydrobiranyl)

 N—bi- or tricyclic hydrocarbon (preferably tetrahydronaphthyl, indanolanol, fluorenyl, the dicyclic or tricyclic hydrocarbon may be substituted with hydroxy, etc.)

N _ C ₆ _ _{1 2} aryl (the aryl is a halogen atom, optionally halogenated C ₄ alkyl, optionally halogenated C ₄ alkoxy, hydro May be substituted with xyl — ₄ may be substituted with alkyl, phenyl, etc.) monoalkyl (the C _1-6 alkyl may be substituted with hydroxy, rubermoyl, etc.) ) —Force rubermoyl group;

N—5 to 10-membered heterocycle (preferably pyridyl, furyl, chenyl, indolyl. The heterocycle may be substituted with C anolole.kill, etc.) 1 C ₆ azorequinole 1canole vamoire Group;

, NC _{3 10} cycloalkyl (said cycloalkyl may be replacement by such human Dorokishi.) Have one C, alkyl - force Rubamoiru group.;

N—I2 cyclic charcoal hydrogen—C- ₆ alkyl rubamoyl;

 N-adamantyl— a Cn alkyl-powered rubermoyl group;

N-phenoxy-C- ₆ alkyl rubamoyl group;

N-phenylamino-C ^ ₆ alkyl-strengthened rubamoyl group, etc.);

N, N-, substituted rubermoyl groups (eg, N—C ₆ alkyl-N-phenyl-Cu arnolequinol / canolevamoi / re groups; to.

 5- to 6-membered cyclic amino (preferably, forming a piperidine ring) monocarbonyl group (preferably 1, 2, 3, 4-tetrahydroisoquinoline 1- 2-ylcarbonyl) etc.);

 Snolefamoyl group;

N-monosubstituted snorefamoinole group (for example, N-phenol (this phenyl may be substituted with a non-ogen atom, a hydrogenated Ci-alkyl, etc.) Ji ₆ alkyl monosulfamoyl);

 Canolepoxyl group;

d_ ₆ alkoxy - carbonyl group;

An optionally halogenated C ₂ _ ₈ Arukanoiru group;

A _6- alkylsulfinyl group that may be halogenated;

 A benzylsulfinyl group;

An alkylsulfonyl group which may be halogenated; '' Benzinores norehoninole group ''; ■,. '■

 Etc. are preferred. '.

 Ring A is preferably an optionally substituted benzene ring or an optionally substituted pyridine ring, among which an optionally substituted benzene ring is more preferred, and a halogen atom (preferably , Silicon, bromine, etc.) The 3-position is substituted with a benzene ring which may be substituted with, or a rubamoyl group which may be substituted with τ.

A good benzene ring is particularly preferred. In particular, a cisene ring, which may be substituted at the 3 • position with a mono-substituted rubamoyl group, is most preferable. .. ..

 In the formula (Γ), X may be substituted. An alkylene group is shown.

0. The C _1-4 § alkylene group in the "optionally substituted C _1-4 alkylene group" represented by X, methylene, ethylene, trimethylene, Te Toramechiren, main Chirumechiren, Echinoremechiren, dimethylcarbamoyl Honoré methylene. Examples thereof include linear or branched C ^ ₄ alkylene groups such as propylene and dimethylenoethylene. Of these, methylene, methylmethylene, ethylmethylene and the like are preferable.

Examples of the substituent that the o ₄ alkylene group may have include “substitution” as the substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have. The hydrocarbon group in “optionally substituted hydrocarbon group” includes the same group as the substituent which may have (however, it is preferably not an oxo group), and these substituents can be substituted. 1 to 3 (preferably 1) may be substituted at any position. Examples of the substituent that the Ci alkylene group may have include a halogen atom;

 A hydroxyl group;

 Force rubamoire group;

 Carboxyl group;

A C _1-4 alkoxy monocarbonyl group;

D ₄ alkoxy group which may be halogenated;

An alkyl group which may be halogenated; May be halogenated! /, A raenyl group;

 Amino group;

Mono- or di-C _1-4 alkylamino group (in addition, the C, ^ alkyl may be substituted with phenenyl, pyridyl, etc.);

Etc. are preferred. Among these, an amino group, a mono- or C _1-4 alkylamino group (methylamino., Ethylamino; /, etc.) which may be substituted with phenyl or pyridyl is particularly preferable. .

 X is preferably substituted and more preferably methylene, especially unsubstituted methylene.

 In formula (I), ring B represents an optionally substituted 5-membered nitrogen-containing aromatic heterocycle. Examples of the “5-membered nitrogen aromatic silicon ring” include, for example, roll, oxazole, isoxazol, thiazole, isothiazole, imidazole, pyrazole, oxadiazole (1, 2, 3-oxadiazole, 1, 2 , 4-Oxadiazole, 1, 3, 4 oxadiazole), furazane, thiadiazole (1, 2, 3-thiadiazole, 1, 2, 4-thiadiazole, 1, 3, 4-thiadiazole), triazole ( 1,2,3-triazole, .1,2,4-triazole), and tetrazole. Preferred are pyrrolinole, pyrazole, imidazole, triazole, thiazole, isooxazole, oxadiazole and thiadiazole. Examples of the substituent that the “5-membered nitrogen-containing aromatic heterocyclic ring” may have include the same groups as the substituents in the “optionally substituted aromatic ring” represented by the above ring A, etc. 1 to 3 (preferably 1) of these substituents may be substituted at any substitutable position. As the substituent that the “5-membered nitrogen-containing aromatic heterocycle” may have,

 A halogen atom;

Alkyl group (the C ^ alkyl group, a halogen atom, arsenic Dorokishi, Cal Bamoinore, carboxyl, optionally phenyl optionally halogenated, C physician ₄ Anoreko carboxymethyl Ichiriki Noreboninore, Surufamoinore, Sunoreho group may be Harogenihi C !: ₄ alkoxy, Benjiruokishi, Amino, mono- one or di- one ₄ Arukirua amino, C _{1 - 6} alk Noi Rua amino, may be halogenated - 4 alkyl Chio, C doctor ₄ Arukirusu be halogenated / Refinyl, optionally substituted with C _1-4 alkylsulfonyl which may be halogenated),

 An optionally halogenated file;-and the like are preferable.

 Ring B may be bonded to ring C and X at any substitutable position of the “5-membered nitrogen-containing aromatic heterocycle”: The carbon of the “heterocycle”: Rings C and X are preferably bonded to the elementary atom. .

Above all, in the formula (I.), the formula:

(Wherein R ¹ represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl group; R ² and R ³ each independently represents a hydrogen atom, a halogen atom; Atom (eg, fluorine, chlorine, bromine, iodine), optionally substituted hydrocarbon group, optionally substituted heterocyclic group, optionally substituted amino group, optionally substituted hydroxy Group, nitro group, cyano group, carboxyl group which may be esterified, rubamoyl group or acyl group which may be substituted And X is as defined above. .

 Above all,.

NN R ^z

 -Ν-Ν '. +' '

^-^ s ^ or-^ s ^ x. (wherein R ¹ and R ² are as defined above, and X is as defined above).

, An optionally substituted hydrocarbon group represented by R ¹ includes an optionally substituted aromatic ring in the “optionally substituted aromatic ring” represented by ring A. And the same groups as the “optionally substituted hydrocarbon group”. ..

As the “optionally substituted heterocyclic group” represented by R ¹ , the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may be substituted. Examples thereof include the same groups as the “optionally substituted heterocyclic group”.

The “acyl group” represented by R ¹ is a substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring A. The group of the visitor is mentioned.

The R ^1,.

 Hydrogen atom; \

C ^ ₆ alkyl group (the C ₆ alkyl group is a halogen atom, hydroxy, strong rubamoyl, carboxyl, phenyl, optionally substituted phenyl, C ₄ alkoxycarboninole, snolefa Moinole, Snorejo group, optionally halogenated C ^ 4 alkoxy, benzyloxy, amino, mono- or di C _1-4 alkylamino, C ₆ alkanoylamino, optionally halogenated C _{1 -4} alkylthio, optionally halogenated — optionally substituted with 4 alkylsulfinyl, optionally halogenated Ci-4 alkylsulfonyl, etc.);

 Optionally halogenated phenyl;

 Etc. are preferred.

Among them, hydrogen atom, halogen atom (fluorine atom, etc.), alkoxy Shi (methoxy, etc.) Particularly preferred are C ₆ alkyl groups (such as methylethyl) which may be substituted with ^ 4 allyl, monocarbonyl (such as ethoxycarbonyl).

And the optionally substituted hydrogen group represented by R ³ is a ring

Examples thereof include the same groups as the “optionally substituted hydrocarbon group” as the substituent that the aromatic ring in the “optionally substituted V, aromatic ring” represented by A may have. . ..

The “optionally substituted silicon ring group” represented by R ² , R ² and R ³ may have an aromatic ring in the “optionally substituted aromatic ring” represented by ring A. V, the same as the “optionally substituted heterocyclic group” as the substituted S, and the like. As represented by R ² and R ³ , the `` optionally substituted amino group '' may have an aromatic ring in the `` optionally substituted aromatic ring '' represented by ring A. Examples of good substituents include “optionally substituted amino group” and the like.

The “optionally substituted hydroxy group” represented by R ² and R ³ may have an aromatic ring in the “optionally substituted aromatic ring” represented by ring A. Examples thereof include the same groups as the “optionally substituted hydroxy group” as a substituent.

As the “optionally esterified canoleboxyl group” represented by R ² and R ³ , the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may be substituted. Examples of the group include the same groups as the “optionally esterified carboxyl group”.

As the “optionally substituted strong rubamoyl group” represented by R ² and R ³ , the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may be The same groups as the “optionally substituted rubamoyl group” in the above are listed.

The “acyl group” represented by R ² and R ³ is an “acyl group” as a substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have. And the like groups. R ^{2 and} R ³ are each preferably a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, or the like.

 Hydrogen atom;

 A halogen atom;

An alkyl group (the C _1-6 alkyl group is a halo-gen atom, a hydroxy, a strong ruby moinole, a carboxyl, an optionally halogenated file, a C ₄ alkoxy;

, Single carbonyl, sulfamoinole, sulfo group, and may be nonogenated

₄ alkoxy, benzyloxy, amino, mono or di C _1-4 . Alkylamino, C! -E ar: canylamino, optionally halogenated C _1-4 alkylthio, optionally halogenated C ₄ alkylsulfiel, optionally substituted with Ci-4 alkylsulfonyl, etc.).

 Optionally halogenated phenol;

 Are particularly preferred, and a hydrogen atom is most preferred.

 In the formula (I), Y represents an optionally substituted imino group, O— or one S (0) n— (n represents 0, 1, or 2).

The “optionally substituted imino group” represented by Y is represented by the formula: 1 N (R ⁴ ) 1 (wherein R ⁴ is a hydrogen atom, an optionally substituted hydrocarbon group, a substituted And a divalent group represented by the following: a preferable heterocyclic group, an optionally esterified carboxyl group, an optionally substituted rubamoyl group or an acyl group.

As the “optionally substituted hydrocarbon group” represented by R ⁴ , the aromatic ring in the “optionally substituted aromatic ring” represented by ring A is an optionally substituted aromatic ring. And the same groups as the “optionally substituted hydrocarbon group”. .

As the “optionally substituted heterocyclic group” represented by R ⁴ , the “optionally substituted aromatic ring” represented by ring A as “the optionally substituted aromatic ring” Examples thereof include the same groups as the “optionally substituted heterocyclic group”.

Examples of the “optionally esterified carboxyl group” represented by R ⁴ include a ring The same as the “optionally esterified carboxyl group” as the i substituent which the aromatic ring in the “optionally substituted aromatic ring” represented by Α · And the like. · ——

'. The “optionally substituted rubamoyl group” represented by R ⁴ is represented by ring A. The aromatic ring in the “optionally substituted aromatic ring” may have And the like and the same group as the “optionally substituted rubamoyl group”. , R ⁴ is an “acyl group”, and is represented by ring A. “An acyl group in the aromatic ring that may be substituted” The same as above. .

. The Y, optionally substituted Imino group (e.g., formula: _N (R) - is a group represented by) are preferred, among them, C - ₄ Argyle groups are substitution with C _1-4 alkoxy ^ group May be phenyl group, rubamoyl group, norogenated,

An imino group optionally substituted by a C ₂ L ₈ arnoyl group, a benzoyl group or the like (ie,

-N (R ⁴⁾ - In, R ⁴ forces a hydrogen atom, _d-4 alkyl group, alkoxy Hue Le group have be substituted with a group, the force Rubamoiru group, optionally halogenated and C ₂ - ₈ An alkanoyl group, a benzoyl group, and the like are more preferable, and R ⁴ , a hydrogen atom, and a _4- alkyl group are particularly preferable. Above all, R ⁴ .

^^ Most preferred to be a child. ,

 When Y is a substituted imi / group, the substituent of the imino group and the substituent of the “aromatic ring” in ring A may be combined to form a ring (eg, tetrahydroquinoline).

 In the formula (I), ring C represents an optionally substituted nitrogen-containing aromatic heterocycle.

Examples of the “nitrogen-containing aromatic heterocycle” in the “optionally substituted nitrogen-containing aromatic heterocycle” represented by ring C include pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, Thiadiazole (1, 2, 4-thiadiazole, 1, 3, 4-thiadiazole, 1, 2, 5-thiadiazole), triazole (1, 2, 3-triazole, 1, 2, 4 monotriazole), Tetrazole, pyridine, pyridazine, pyrimidine., Pyrazine, triazine (1,2,4-triazine, 1,3,5-triazi) 5- to 6-membered nitrogen-containing aromatic monocyclic heterocycles such as rings; Isoindole, pyrazo mouth [.1, 5-a) Pyridine, imidazo [l, 2-a] Pyridine, imidazo [1, 5-a] pyridin, imidazo [l, 2-b] Imidazo [1, 2-a] pyrimidine, .1

Containing ⁸ to 16 members (preferably ⁸ to 12 members) such as 2,4-triazolo [4,3-a] pyridine, 1,2,4-triazolo [4,3-, b] pyridazine, etc. Examples thereof include nitrogen-aromatic fused complex rings, and 5 to 6-membered nitrogen-containing nitrogen-containing aromatic monocyclic heterocycles are preferable. Examples of the substituent that the nitrogen-containing aromatic heterocyclic ring may have include the same groups as the substituent in the “optionally substituted aromatic ring” represented by the ring A described above. These substituents may be substituted at any substitutable position by 1 to 4 (preferably 1 or 2 are preferred). As the substituent that the “nitrogen-containing aromatic heterogeneous prefecture” may have,

 A halogen atom;

 A hydroxyl group;

 Canolevainole group;

 Carboxyl group;

d- ₆ alkoxy monocarbonyl group

 Snorefamoinole group;

 Snorejo group;

An optionally halogenated C _1-6 alkoxy group;

C, _ ₆ alkyl group (the C _t _ ₆ alkyl group, a halogen atom, arsenic Dorokishi group, may be substituted by Cal Bamoiruokishi group);

 An optionally halogenated phenyl group;

 An amino group;

Mono- or di-C ^ alkylamino group (the alkyl group, halogen atom, be halogenation C -! ₆ alkoxy, optionally Nono halogenated C ₆ alkylthio, phenyl (Fu, enyl may be substituted with a halogon atom, no, C ^ alkyl which may be genated, C _1-6 alkoxy which may be optionally halogenated, etc.), May be substituted with a substituent selected from C _{3 10} ^ chloroalkyl);

 Mono or diphenylamino group (the phenyl may be halogenated);

, Mono one or di- one C ₃ _ ₁₀ Siglo alkylamino group;:

Bruno, Yo be Rogge of Le, C _r - ₆ alk Noi Rua amino group;

 Benzoylamino group, which may be halogenated; Phenylorecetinoleamino group;

 Mono- or di-C ^ -e alkyl rubamoylamino groups

 Optionally phenoxyl ruberamoylamino group;

 An optionally halogenated phenyl-rubberyl group;

 Aromatic heterocycles (preferably thiophene) —forced ruby groups;

An optionally halogenated ₆ alkylthio group;

An optionally parogenated C ₆ alkylsulfinyl group;

Optionally C ₆ alkylsulfonyl group;

 Etc. are preferred.

In addition, when the “nitrogen-containing aromatic heterocycle” in the “optionally substituted nitrogen-containing aromatic heterocycle” represented by ring C has two or more substituents adjacent to each other, the substituents are bonded to each other. ring (e.g., cyclopentane, cyclohexane, C ₄ cycloheptane, etc. - ₈ cycloalkane ring, a benzene ring) may form a.

 ring. May be bonded to ring B at any substitutable position of the “nitrogen-containing aromatic heterocycle”, and in particular, is bonded to ring B at a constituent carbon atom of the “nitrogen-containing aromatic heterocycle”. It is preferable.

Ring C is preferably an optionally substituted pyridine ring, an optionally substituted pyrimidine ring, or an optionally substituted thiadiazole ring. Formula (i).

 The group represented by

'·.

N -C-.. NC " ^X ) ~~

 -\ — / Or \ ― I.

 [Wherein ring C 'and ring C "may each be substituted.] Is preferred.

 Examples of the substituent that each of ring C ′ and ring C ″ may have include the same groups as the substituent S that ring C may have:

 The nitrogen atom constituting the pyridine ring may be oxidized and tau. .

 Specific examples of the compound represented by (Γ) include the following. Ν—Benzyl 1 3— [[[5— (4-Pyridyl) 1 1H— 1, 2, 4— Triazol 3—yl] Methyl] Amino] benzamide,

 4—Black mouth 3—Feluceamide Ν— [[5- (4-Pyri-dyl)-1 Η — 1, 2, 4-triazole 1-yl] methyl] aniline,

 Ν-Benzyl 1 _ [[[[5- (4-Pyridyl) isoxar _ 3-yl] methenorecoamino] benzamide, ..

 Ν—Benzyl N ′ — [3— [[[5_ (4-Pyridyl) 1 1 H— 1, 2, 4-Triazol-3-yl] methyl] amino] phenyl] urea,

 4_Chloro Ν— [[5 -— (4-Pyridyl) pyrazole-3-yl] methyl] aniline,

 Ν—Benzyl-3-[[[[5_ (4-Pyridyl) pyrazole-3-yl] methyl] amino] benzamide,

 3— (Methylthio) — Ν— [[5— (4-Pyridyl) 1 1 Η_ 1, 2, 4— Triazol / Lee 3—yl] methyl] aniline,

Ν— (3-Methoxybenzyl) 1 3— [[[5— (4-Pyridyl) 1 H 1, 2, 4-Triazol-3-yl] methyl] amino] benzamide,

 3— [[[4 ■ —Methyl 1 5— (4 -Pyridyl) 1 4H— 1, 2, 4— Triazole _ 3—yl] methyl] Amino] — N— [2—. (Trifunoleolomethyl) Benzyl] benzamide,

 N-benzyl-1-3-[[[4-methyl-1-5- (4-pyridyl) pyrazole-3-yl] methyl] amino] benzamide,

 N— (1-Indanyl) 1 3— [[[4— (2, 2, 2-trifluoroethyl) 1

3— (4-Pyridyl) 1 4 H- 1, 2, 4, 4-Triazol-5-yl] methyl] amino] benzami

 N— [2, 6-Difluorobenzyl] — 3— [[[4 Monomethyl 1 3- (4-Pyrimidyl) 14H— 1, 2, 4-Triazole _ 5—yl] Methyl 1 amino] Benz Amide,.

 , (2, 6-diplobenzyl) 1-3— [[[4-propyl-1 3- (4-pyrimidyl)-4 H-1, 2, 4- triazole-5-yl] methyl] amino ] Ben Zami.

 N— [(R) — 1 monophenyl] 1 3 — [[[5 — (4 _pyridyl) thiazol 2 ynole] methyl] amino] benzamide,

 N- [(R) 1 1-phenylethyl] 1 3— [[[5— (4-pyridyl) 1 1, 3, 4-thiadiazole 1-yl] methyl] amino] benzamide,

 N- (1-Indanyl) — 3— [[[4 Monomethyl 1 3- (4-Pyridyl) 1 4H— 1, 2, 4_Triazole 1 5 _yl] methyl] Amino] benzamide,

 N— [2-(Trifnoleolomethinole) benzyl] — 3— [[[4-Ethinole 3— (4 —Pyridyl) 1 4H— 1, 2, 4, 4-Triazole 1-5-yl] methyl] amino] Benzamide,

 N- (2-Methoxybenzyl) 1 3— [[[4-Ethyl 1 3— (4-Pyridyl) 1

4 H-1, 2, 4, 4_triazol-5-inole] methyl] amino] benzamide, N- [5-Fnoroleol 2-benzyl (trinoleolomethinole) benzyl] one-three-[[[4- Til 1- (4-pyridyl) 1 4, H— 1, 2, 4—driazol.5-yl] methyl] amiso] benzamide,

'N- [5-Fluoro-2- (trifluoromethyl) benzyl] — 3— [[[4-. (2-Methoxychetyl) 1 3- (4 ”pyridyl) 1 4 _ 1, 2, 4 1 Triazo 5—yl] methyl ”.amino] benzamide, 'N— (biphenyl 2-ylmethyl) 1 3— [[[[4-(2-methoxychetyl) 1 3-(4-pyridyl) -4H- 1, 2, 4 1 Triazol / Lay 5—yl] methyl] amino] .. benzamide,. ',.' ::

 [2-(Trifluoromethyl) benzyl] — 3— [. [[[4- [(Ethoxycarbonyl) methyl] — 3—. (4 monopyridyl) 1 4H— 1, .2, 4_Triazol 5 _ i Lu] methyl] amino benzamide, '

 1-Phenylamino 1-Ethylamino 1- [3- (4-Pyridyl) 1 1H- 1, 2, 4-Triazolene _ 5-Inole] ethane,.

 1-phenylamino 1- (2-phenylethyl) amino 1- [3- (4-pyridyl) 1 1 H— 1, 2, 4 triazole 1-yl] ethane,

 1-phenylamino 1- [[..2-pyridylmethyl) amino]-1-[3- (4 monopyridyl)-1 H-1, 2, 4- triazole 1-yl] ethane,

• 2_Amino 7- 1-[(4_Black-Fuel) Amino] — 1 1 [3- (4-Pyrimidyl) 1 1H— 1, 2, .4— Triazole 5—yl ]

 (1 R) 1 2-Amino 1 1 [(4-Clophenyl) amino] — 1— [3— (4 —Pyrimidyl) 1 1 H— 1, 2, 4— Triazole 1-5-yl] ethane ,

 (1 R) — 2—Amino 1— [(4-Bromophenyl) amino] — 1— [3— (4 1 Pyrimidyl) 1 1 H— 1, 2, 4— Triazole 1-5-yl] ethane,

 2—Amino 1— [(4 1-phenyl) Amino] _ 1 1 [3— (1, 2, 5—thiadiazole—3-yl) — 1 H— 1, 2, 4-triazol 5— Le] Tan,

4—Chloro N — [[5— (4-Pyridyl) 1 1H— 1, 2, 4— Triazole ― 3-yl] methyl] aline Formula (II):

,

 R i represents a hydrogen atom, an optionally substituted alkyl group, an alkoxy group, a benzyloxy group, an alkylthio group, a sulfamoyl group, a halogen ^ atom, a nitro group, a cyano group, or an N-monosubstituted optionally substituted rubermoyl group. Group, an optionally substituted phenoxy group, a pyridyloxy group, or an esterified carboxyl group. ].

Or a salt thereof. Examples of the “alkyl group” in the “optionally substituted alkyl group” of C include, for example, C, _δ alkyl groups (preferably C _1-4 alkyl, etc.) such as methyl, ethyl, η-propyl, isopropyl, etc. Can be mentioned.

As "alkoxy group", for example, main butoxy, etc. 〇 I ₄ § alkoxy groups ethoxy, and the like.

The "alkylthio group", for example methylthio, C ₁ such Echiruchio _- like ₄ § alkylthio group.

 Examples of the “halogen atom” include fluorine, chlorine, bromine, and iodine.

Examples of the substituent of the “optionally substituted alkyl group” for R _t include fluorine, Halogen atoms such as chlorine, bromine and iodine. .

Examples of the convertible group of “N-mono-substituted rubamoyl ¾” of R _t include, for example, a C _1-6 ′ alkyl group, a phenyl group, a pyridyl group and the like which may be substituted with a morpholino group. Can be mentioned.

The substituent of the “optionally substituted phenoxy group” in C may be a C ₆ alkyl group, a halogen atom, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), C ^ ₄ alkoxy groups (for example: methoxy, edoxy, etc.) and the like. ',

アルコキシカルボニル基等が挙げられる。 For example, “an optionally esterified carboxyl group” includes a free carboxyl group, for example,

An alkoxycarbonyl group etc. are mentioned.

が好ましい。 As a trap,

Is preferred.

 Ri is preferably a naroxy group, and most preferably a methoxy group. The compounds of formula (I I) include 2 — [(3-methoxyphenyl) amino] — N ′

-((1 E) —4-Pyridinylmethylene) acetohydrazide is the most preferred.

Further, as the GRK inhibitor used in the present invention, in addition to the compound of the above formula (I) or the formula (Γ I), for example, 3-amino-1-((4-monophenyl) amino] — 1— (3-morpholino 1 H—1, 2, 4—triazole 1-5-inole) Propane is preferred. Examples of the salt of the compound (I) or (II) include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. Can be mentioned. Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, an alkali metal salt (eg, sodium salt, strong rhodium salt, etc.), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium) In the case of having a salt functional group in the compound, for example, with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. . salts or acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric _acid,;:. maleic acid, 'Kuen acid, succinic acid, methanesulfonic acid, P- dollar ene organic acids and salts thereof Chireru such as a sulfonic acid. ■ '' —. .. ■ '· The above compounds (I) or (ίΐ) etc. can be obtained, for example, by the method described in International Application No., PCT / JP2005 / 005995 (W02005 / 090328), American chemical Society 23 1 rejuvenated ^s annual (American chemical Society, 231st National meeting ) '.' ί this'. Oite published methods, methods toying disclosed in reference example 1 to reference example 8 to be described later, the other A method usually used in organic synthesis can be appropriately applied and produced. Compound (I) or (Π) may be used as a prodrug. Compounds ■ Prodrugs such as (I) or (Π) are compounds that convert to compounds (I) or (II) by reaction with enzymes, gastric acid, etc. under physiological conditions in vivo, ie enzymatically oxidized , A compound that undergoes reduction, hydrolysis, etc. and changes to a compound (I) or (Π), etc., or a compound that undergoes hydrolysis or the like by gastric acid ^ and changes to a τ compound (I) or (π), etc.

 When a GRK inhibitor is used as a cardiotonic drug based on the present invention, the pharmacologically acceptable carrier is used alone or in accordance with conventional methods (for example, the method described in the Japanese Pharmacopoeia). For example, tablets (including sugar-coated tablets, film-coating tablets), powders, granules, capsules, liquids, emulsions, suspensions, injections, suppositories, sustained-release agents, As a patch, etc., it can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration, continuous intravenous administration, etc.).

 The content of the GRK inhibitor in the pharmaceutical composition is about 0.01 to 11% by weight of the total composition, preferably about 2 to 8.5% by weight.

The dose of GRK inhibitor varies depending on the subject of administration, administration route, disease, etc. For example, when administered as an oral agent to an adult (body weight of about 6 O kg), it is about as a GRK inhibitor that is an active ingredient. 1 to 1 00 Omg, preferably about 3 to 300 mg, More preferably, it is about 10 to ² , 0 O rag and can be administered in 1 to several times. These can be adjusted appropriately according to the strength of action and the molecular weight of the GRK inhibitor used. ',

 In addition, the “cardiotonic drug containing a GRK inhibitor” of the present invention is a drug that is usually used for the treatment of heart failure, for example, digitalis, catecholamine (eg, dobutamine, 'nomin, denopamine, zamoterol, etc.) ,] 3 blockers (pisoprolol, carbegi, rolls, etc.), nitrates (nitronitroserine, etc.), seven doraradi, Ca antagonists (Am mouth dipine, etc.), ACE inhibitors (enalapril, etc.), Al antagonists (force) Ndesartan, etc.), diuretics (such as larosemide), PDE-inhibited cold (such as milrinone), Ca sensitizers (such as pimobendan), thrombolytic agents (such as t-PA), anticoagulants (heparin,.ヮ Rufaline, etc.), anti-blood platelets (aspirin, etc.), antiarrhythmic drugs (amiodarone, etc.), HMG-CoA reductase inhibitors (Attoguchi pastatin, sympastatin, etc.), α blockade (Brazosi) ), Atrial diuretic peptide, sputum inhibitor (such as fascytril), endothelin antagonist (such as bocentan), aldosterone antagonist (such as spironolactone), vasopressin antagonist (such as coninoptane), .matrix meta-oral protea These pharmaceutical ingredients can be used in combination as appropriate, in combination with a zease inhibitor, etc. Due to the combination of strength and strength, a synergistic effect can be expected compared to when administered alone. Furthermore, it can be used in combination with non-pharmacotherapy for severe heart failure, for example, assisted circulation (intra-aortic balloon pumping, assisting heart, etc.), batista surgery, heart transplantation, etc. ■

Furthermore, the “cardiotonic drug containing a GRK inhibitor” of the present invention can be used in combination with a biologic (eg, antibody, vaccine preparation, etc.) when applied to each of the above diseases. It can also be applied as a combination therapy in combination with gene therapy. Examples of antibodies and vaccine preparations include vaccine preparations against angiotensin II, vaccine preparations against CETP, CETP antibodies, antibodies against TNFa antibodies and other site-in, amyloid] 3 vaccine preparations, type 1 diabetes vaccines ( In addition to Peptor's DIAPEP-277, etc.), site-in, renin angiotensin-based enzymes and their products or vaccines, enzymes involved in blood lipid metabolism Antibodies or mactin preparations for proteins, coagulation in blood, antibodies or vaccines for enzymes and proteins that contribute to the lysis system, antibodies to vaccines involved in glucose metabolism resistance, vaccine preparations, etc. In addition, gene therapy methods include, for example, site force-in, renici 'angiotensin enzymes and their related products: gene therapy, ø receptor: signal transmission such as duty cycle. Treatment using genes related to the system, treatment using genes related to j3 ARKct, / 3 arrestin, etc.6, treatment using DNA decoys such as NF KB decoy, treatment using antisense, Related to enzymes and proteins involved in blood lipid metabolism: for example, cholesterol or triglyceride or HDL-cholesterol Genes related to metabolism, excretion, and absorption of blood phospholipids). Enzymes and proteins involved in angiogenesis therapy for treatment, peripheral ductal obstruction, etc. (eg, HGF, VEGF, etc.) Such as growth factors, etc.); treatments using genes related to sugars, treatments using genes related to proteins involved in insulin resistance, antisenses against cytodynamic ins such as TNF, etc. . In addition, various organ regeneration methods such as heart regeneration, kidney regeneration, sputum regeneration, and blood vessel regeneration, bone marrow cells (bone marrow mononuclear cells, bone marrow stem cells, etc.) and other cells that have the ability to differentiate into muscle (embryonic stem cells, myoblasts) It can also be used in combination with blood vessel and myocardial neoplasia using cell transplantation.

'For example, (1) administration of a single formulation obtained by simultaneously formulating a GRK inhibitor and a concomitant drug, (2) obtained by separately formulating a GRK inhibitor and a concomitant drug (3) Administration of two preparations obtained by separately formulating a GRK inhibitor and a concomitant drug at different times in the same administration route, ( 4) Simultaneous administration of two different preparations obtained by separately formulating a GRK inhibitor and a concomitant drug through different administration routes, (5) Obtained by separately formulating a GRK inhibitor and a concomitant drug 2 Administration of different types of preparations at different time intervals (for example, administration in the order of concomitant drugs after administration of a GRK inhibitor, or administration in the reverse order). The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of GRK inhibitor and concomitant drug is determined according to the subject of administration, administration route, It can be selected as appropriate depending on the condition, symptom, combination, etc. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the GRK inhibitor. ''

Cold application ■-,

 The drug a test results using an example of simultaneous ij of the present invention are shown below. In addition, this Example is only an illustration, Comprising: The scope of the present invention is not limited at all.

Reference example: Γ.

The production method of the test compound (1) used in the pharmacological test is shown below. .3 — [[[[4-Methyl-5- (4-Pyridyl) 1 4 H— 1, 2, 4-Triazole 1 3 _yl] methyl] Amino] — N— [2— (Trifluoromethyl Benzile] benzamide; test compound (1)...

3-[[[4-Methyl-1-5- (4-Pyridyl) 1-4H- l, 2, 4 Triazol 3-reyl] Methyl] amino] Benzoic acid (155 mg), 2- (Trifluoromethinole) Benzenoreamine (1 75 mg), 1-ethenoleyl 3- (3-dimethinoreaminopropyl) carbodiimidate (144 mg) and 1-hydroxy 1 H-benzotriazole hydrate (7.7 mg) in DMF ( 2.0 mL) and stirred at room temperature for 18 hours. Ethyl oxalate (100 mL) was added to the reaction mixture, and the mixture was washed with water (2 X 30 mL) and then with saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. did. The residue was purified by silica gel column chromatography (ethyl acetate → ethyl acetate: methanol = 2: 1) to give 225 mg (yield 96%) of the title compound as a colorless amorphous substance. ^L H-NMR (300 MHz, Me ₂ SO-d ₆ ), δ, 3.78 (3H, s), 4.55 (2H, d, J = 5.7 Hz), 4.64 (2H, d, J-5.4 Hz), 6.50 (1H, t, J = 5.4 Hz)., 6.95 (1H,. D, J = 6.6 Hz), 7.16. (1H, d, J = 7.5 Hz)., 7.22 (1H, t, J = .. 7.8 Hz), 7. '29 (1H, s), 7.47 (1H, t, J = 7.8 Hz), 7.51 (1H, d, J = 7: 8 Hz), 7.66 (1H, t, J = 7.7 Hz) , 7.72-7.75 (3H, m), 8.76 (2H, dd, J = 5. "3, 0.8 Hz), 8.94 (1H, t, J-5.7 Hz). Anal. Calcd. For C ₂₄ H ₂₁ F ₃ N ₆ 0-1.2H ₂ 0: C, 59.06; H, 4.83; N,, 17.22. Found: C, 59.16; H, 4.84; N, 16.84.

 The production method of the test compound (13) used in the pharmacological test is shown below.

 1-phenylamino 1- (2-Laenylethyl) amino 1- [3- (.4-pyridyl) — 1 H— 1, 2, 4-triazol-5 _yl] ethane; test compound (1 3).

 a) (2 S)-2-(Benzylo cycanoreboninole) amino 1- [N_ · (tert -butoxycarbonyl) — N— (2-phenylethyl) amino] methyl propionate

IsT, 0.0_bis (trimethylsilyl) acetamide (8.8 mL) was added to a solution of 2-phenylethylamine (8.2 g) in acetonitrile (15 OmL.) And stirred at room temperature for 1 hour. (S) -benzyloxycarbonyl serine β-lactone (10 g) was added, and the mixture was stirred at room temperature under an argon atmosphere for 24 hours. After evaporating the solvent under reduced pressure, a solution prepared from thiochloride (13 mL) and methanol (65 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 4 hours. After the reaction solution was concentrated, the residue was neutralized by adding saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The resulting extract was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol (10 OmL), di-tert-butyl dicarbonate (1 OmL) was added, and the mixture was stirred for 1 hour at room temperature. After concentrating the reaction solution, the obtained residue was subjected to silica gel chromatography (eluent; hexane: ethyl acetate = 1) The title compound was obtained as a colorless oily substance (13.6 g) after purification in 1). :

 1H NMR (300 MHz, CDC 13) 6 1.41 (9H, s), 2.79 '(2H, m), 3.40 (4H, m), 3.73 (3H, s), 4.4 (1H, m), 5.10 ( 2H, m), 5.97 (1H, br), 7.14—7.32 (10H, m).

 b) (2 S) — 2—Phenylamino 3 -— [N— (t e r t-butoxycarbo, ru) — N— (2-Fieruetino) amino] methyl propionate

 (2 S) — 2— (Penzinoloxycarbonyl), amino-3 _ [N— (tert;,. —Butoxycanolol) 1 Ν— (2-phenylethyl) amino] propion fermentation methyl (1 3. 6 g) of methanol (20 OmL) was added with 10% palladium on carbon (2. O g), and the catalyst was removed using seraite that was stirred for 2 hours at room temperature under 5 atm hydrogen pressure. Thereafter, the solvent was distilled off under reduced pressure. Acetonitrile (5 mL) was added to the resulting residue to give a solution, and this solution was then added to phenylboronic acid (7.3 g), copper oxalate monohydrate (0.6 g) and molecular sieves 4 A (30 g). ) In dichloromethane (30 OmL) and heated and stirred at 40 ° C. for 24 hours in an oxygen atmosphere. After the reaction solution is filtered through celite, the filtrate is concentrated, and the resulting residue is purified by silica gel chromatography: γ— (eluent: hexane: ethyl acetate =: 1) ^: The title compound was obtained as a colorless oil (6.7 g).

 1H NMR (300 MHz, CDC13) δ 1.44 (9H, s), 2.77 (2H, m), 3.28-3.46 (4H, m), 3.72 (3H, s), 4.26 (1H, m), 4.70 (1H, br), 6.57 (2H, d, J = 7.8 Hz), 6.71 (1H, m), 7.12-7.33 (7H, m).

 c) 1-phenylamino 2_ [N— (tert-butoxycarbonyl) 1 N— (2-phenylethyl) amino] — 1— [3— (4 monopyridyl) — 1 H— 1, 2, 4-triazole 1— Ill]

(2 S) — 2—Phenylphenylamino 3— [N— (tert-butoxycarbonyl) 1 N— (2-phenylethyl) amino] in a solution of methyl propionate (6.7 g) in ethanol (15 OmL) Add hydrazine monohydrate (1 OmL) and add 24 After heating under reflux for a period of time, the solvent was distilled off under reduced pressure. As a result, (2 S) — ² ^ ”phenylnaminol 3— [N- (tert-butoxycarbonyl) 1 N—. (Letyl) amino]. Propionic acid hydrazide was obtained as a colorless oil '. Obtained (2 • S) — 2 _Phenylamino 1- [N- (tert-butoxycarbo; l) 1 N ― ( 2 Bueniruechiru) Amino]: propionic acid ratio hydrazide and 4 Shianobi lysine (5. ethanol (20 shed mL of 2 g)) was added ≥ 0% sodium E Toki, Sydow ethanol solution (7. OML) was added, ^{for 24} hours After concentrating the reaction solution, the resulting residue was neutralized with 1 N hydrochloric acid and extracted with ethyl acetate: The resulting leachate was washed with water and dried over magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography (dissolved). . Liquid; hexane: acetic acid Echiru = 1: 1) was purified by colorless title compound an oil (5. 2 g) as a

·.Obtained. ■ ■...;

 1H NMR (3.00 MHz, CDC 13) δ 1.45 (9H, s), 2.80 (2Η, m), 3.41 (2H, m), 3.58 (1H, m), 3.98 (1H, m), 4.73 (1H, m ), 5.82 (1H, br), 6.52 (2H, d, J = 7.8 Hz), 6.78. (1H, t, J = 7.8 Hz), 7.07-7.25 (7H, m), 7.98 (2H, d, J = 6.0 Hz), 8.71 (2H, d, J. = 6.0.Hz).

 d) 1 _Phenylamino 1- (2-Phenylrutil) Amino 1 1 [3— (4 —Pyridyl) _ 1 H— 1, 2, 4— Triazole 1 5-yl] ethane

 1-phenylamino 1- [N— (tert-ptoxycarboninole). 1 N— (2-phenylethyl) amino] — 1— [3— (4-pyridyl) 1 1 H— 1, 2, 4 1 triazole— To a solution of 5-yl] ethane (0.6 g) in ethyl acetate (1 OmL) was added 4 N hydrogen chloride-ethyl acetate solution (l OmL), and the mixture was stirred at room temperature for 24 hours. The reaction solution was neutralized by sequentially adding water and a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The resulting extract was washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The compound was obtained as a colorless solid (19 Omg).

1H NMR (300 MHz, CDC13) 6 2.77 (2H, t, J = 6.6 Hz), 2.91 (2H, t, J = 6.6 Hz), 3.18 (2H, ra), 4.68 (1H, m), 4.83 (1H , br), 6.55 (2H, d, J = 8.4 Ηζ), 6.78 (1H, t, J = 8.4 Hz), 7.13-7.31 (7H,. M), 7.95 (2H,. D, J = 6.0 Hz), 8.67 (2H, d, J = 6.0 Hz) .

'Reference Example 3

 The production method of the test compound (14)-used in the pharmacological test is shown below. '1-Phenylamino 2-[[(2' -Pyridinolemethyl) amino]] — 1— [3-(4, —Pyridyl) 1 1 1— 1, 2, 4-Triazole 1-5-inole] ethane; Test compound ( 14) . ,

 a) (2 S) 1.2- (Benzyloxycarbonyl) amino 1- [N- (tert-butoxycarbonyl) _N— (2-pyridylmethyl) amino] methyl propionate:

 Add 2- (aminomethyl) pyridine (2.2 g) to acetonitrile (60 mL) with N, Q-bis (trimethinoresylinore) acetamide (2.7 mL) at room temperature. After stirring for a period of time, (S) -dioxycarbonylserine 1 / 3-latatin was added, and the mixture was stirred at room temperature for 24 hours under an argon atmosphere. After distilling off the solvent under reduced pressure, a solution prepared from thiochloride (4 mL) and methanol (20 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 4 hours. After the reaction solution was concentrated, the residue was neutralized by adding a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The resulting extract was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. . The obtained residue was dissolved in ethanol (50 mL), di-tert-butyl dicarbonate (3 mL) was added, and the mixture was stirred for 1 hour at room temperature. After concentrating the reaction solution, the resulting residue was purified by silica gel chromatography (eluent; hexane: ethyl acetate = 3: 1) to give the title compound as a colorless oil (5.0 g). .

 1H NMR (300 MHz, CDC13) δ 2.30, (9Η, s), 3.63 (1H, m), 3.71 (3H, s), 3.87 (1H, m), 4.47 (2H, s), 4.59 (1H, m ), 5.12 (2H, s), 7.01 (1H, m), 7.15 (1H, m), 7.34 (5H, m), 7.62 (1H, m), 8.50 (1H, ra).

b) (2 S)-2-phenylamino 1- [N— (tert-butoxycarbodi 1) N— (2-Pyridylmeter) amino] methyl propionate

(2 S).-2-(Benzyloxycarbonyl) amino-3- [N— (tert-butoxycarbonyl) 1 N— (2-pyridylmethyl) amino] methyl propionate (5. O g) in methanol 10% palladium-carbon (1.Og) was added to the (10OmL) solution and stirred at room temperature for 2 hours under 5 atm hydrogen pressure. After removing the catalyst using celite, the solvent was distilled off under reduced pressure. Acetonitri and Nore (5 mL) were added to the resulting residue to make a solution, and this solution was then added to the boronic boronic acid (2.8 g), copper acetate monohydrate (0.2.3 g) and Molecule 1 Buzz 4 A. (14 g) was added to a suspension of dichloromethane (1500 mL) and heated at 40 ° C for 24 hours under an oxygen atmosphere: stirred. After the reaction solution was filtered through cerite, the filtrate was concentrated, and the resulting residue was purified by silica gel chromatography (eluent; hexacy: ethyl acetate = 2: 1). The title compound was obtained as a colorless oil (1.5 g).

 1H MR (300 MHz, CDC13) δ 1.38 (9H, s), 3.63 (1Η, m), 3.71 (3H, s), 3.91 (1H, m), 4.35 (1H, m), 4.54 (2H, s) , 5.00 (1H, br), 6.57 (2H, d, J = 8.4 Hz), 6.71 (1H, m), 7.15 (4H, m), 7.58 (1H, m), 8.53 (1H, m).

 c) 1— [N—Fuel N- (trifluoroacetyl) amino] 2— [N— (tert-Butoxycarbonyl) 1 N— (2-Pyridylmethyl) amino] — 1 — [3— (4— 1 Pyridyl) 1 H— 1, 2, 4— Triazole 1 5-yl]

(2S) -2-phenylamine 3_ [N_ (tert-butoxycanoleboninole) -N- (2-pyridylmethyl) amino] methyl propionate (1.5 g) in ethanol (5 OmL) After adding drazine monohydrate (1.8 mL) and heating to reflux for 24 hours, the solvent was distilled off under reduced pressure, and (2 S) — 2-phenylaminomino 3 _ [N- (tert-butoxycarbonyl ) 1 N- (2-Pyridylmethinole) amino] Propionic acid hydrazide was obtained as a colorless oil. The obtained (2 S) -2-phenylamine 3- [N— (tert-butoxycarbonyl) 1 N- (2-pyridylmethyl) amino] propionate hydrazide and 4-syanobi To a solution of lysine (1.2 g) in ethanol (5 OmL), 20% sodium ethoxide-ethanol solution (1.5 mL) was added and heated to reflux for 24 hours. After concentrating the reaction solution, the resulting residue was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The obtained extract was washed with water and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. After the obtained residue was dissolved in tetrahydrofuran (5 OmL), triethylamine (0.6 mL) and trifluoroacetic anhydride (0.6 mL) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. Was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (eluent; hexane: ethyl acetate = 1: 1) to give the title compound as a colorless oil (1 g).

 1H NMR (300 MHz, GDC13). Δ 1.24 (9Η, s), 3.87 (1H, m), 4.64 (2H, m), 4.73 (1H, m), 5.89 (1H, m), 7.45 (7H, m ), 7.88 (1H, m), 8.44. (2H, d, J. = 5.4 Hz), 8.63 (1H, m), 8.85 (2H, d, J = 5.4 Hz) ...

 d) 1-Phenylamino 2 -— [(2-Pyridylmethyl) amino] — 1— [3 -— (4-Pyridyl)-1 H-1, 2, 4 1. Triazole 1 '5-yl] ethane

 1 1 LN—Fenirium N— (Trifnoleoloacetyl) amino] — 2— [N- (tert-Butoxycarboi) 1 N— (2-Pyridylmethyl) amino] _ 1 1 [3— (4 —Pyridyl)-1 H-1, 2, 4— Triazole _ 5—yl] Ethanol (1.0 g) in ethanol (5 Om.L) was added with 1 N aqueous sodium hydroxide solution (1 5 mL). 3. Stir at room temperature for 3 hours. The reaction mixture was concentrated, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The resulting extract was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. A 4 N hydrogen chloride-ethyl acetate solution (15 mL) was added to a solution of the resulting residue in ethyl acetate (3 OmL), and the mixture was stirred at room temperature for 24 hours. Water and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution in order to neutralize it, followed by extraction with ethyl acetate. The resulting extract was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The title compound was obtained as a colorless solid (0.5 1 g).

1H NMR (300 MHz, CDC13) δ 3.24 (2Η, m), 3.96 (2Η, m), 4.79 (1H, m), 5.01 (1H, br), 6.58 (2H, d, J = 8.1Hz), 6.73 (1H, t, J = 7.5 Hz), 7.12 (2H, t, J = 7.5 Hz), 7.19 (2H, m), 7.65 (1H,, ni), 7.94 (2H, d, J = 5.4 Hz), 8.59 (1H, m), 8.63 (2H, d , J = 5.4 Hz) ... 4

 The production method of the test food (15): used in the pharmacological test is shown below.

 3-Amino 1- [(4-Raphlolaenyl) Amino] — 1— (3-Morpholino 1 Η— 1, 2, 4, 4-Triazol-Lu 5-yl) Propane; Test compound (1 5) a ) (2 S) — 2— (4-C, lorophenyl) amino 1- [(tert-butoxycarbonyl) amino] methyl butanoate ..

 (2 S). — 2—Amino _4— [(tert-butoxycarbonyl) amino] Amberlist A— 2 1 in a suspension of methyl butanoic acid hydrochloride (10. 05 g) in acetonitrile (30 OmL) (40 g) was added, and the mixture was stirred at room temperature for 30 minutes and filtered. After concentrating the obtained filtrate, acetonitrile was added to form a solution, and this solution was added to 4__________________________________. (0.76 g) and molecular sieves 4 A (40 g) in dichloromethane (30 OmL) were suspended in oxygen at 4: 0 ° C for 20 hours. The reaction mixture was filtered through celite, the filtrate was concentrated, and the resulting residue was purified by silica gel chromatography (eluent; hexane: ethyl acetate = 7: 3) to give the title compound 9 02 g (yield 7%) was obtained as a colorless oil.

 1H NMR (300 MHz, CDC13) δ 1.44 (9 Η, s), 1.92—2.08 (2), m), 3.27 (2 Η, q, J = 6.3 Hz), 3.72 (3H, s), .4.03-4.10 (1H m), 4.24 (1H, br), 4.68 (1H, br), 6.52 (2H, d, J = 9.0 Hz), 7.11 (2H, d, J = 9.0 Hz).

 b) 2— (4—Black mouth) Amino 4-— [(t e r t-Butoxycarbonole) Amino] Butanoic acid

(2 S) — 2— (4—Black mouth fuel) Amino 1- [(tert-Butoxy Carbon) Amino] Methyl butanoate (7.99 g) in methanol (1 00 mL) in 28% sodium methoxide Add 1 methanol solution (1 1. 25 g) It was heated to reflux overnight. The reaction mixture was concentrated to about half volume, diluted with tedravidrofuran (30 mL) and water (30 mL), and stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction solution under reduced pressure was diluted with water (50 mL), adjusted to pH = 4 by adding 1N hydrochloric acid, and extracted with black mouth form (3 × 50 mL). The organic layer was washed with saturated brine (5 QmL), dried over magnesium sulfate, and-The solvent was distilled off under reduced pressure to give 5.67 g (yield 74%) of the title compound as pale yellow amorphous. Obtained as a sex substance. ; 1H NMR (300 MHz, CDC13) δ 1.44 (9Η, s), 1.92-2.08 (2Η, ra), 3.27 (2Η, q,-J = 6.3 Hz), 3.72 (3H, s) 4.03-4.11 (1H , m), 4.24 (1H, br), 4.68 (1Ή, br), 6:52 (2H, d, J = 9.0 Hz), 7.11 (2H, d, J = 9.0 Hz),

 c) 3 — [(tert-butoxycarbonyl) amino] — 1- (4-chlorophenyl) amino 1 _ (3-morpholino 1 H— 1 ', 2, 4-triazole-5 _yl) propane.

2— (4-Chroosome Phenylsole) Amino 4-[(tert-Butoxycarbonyl) Amiso] Butanoic acid (5.6 6 g), Morpholine 4-Carbohydrazone amide. Hydrogen ¾. (5 6 1 g) and 1-Hydroxybenzotriazol, monohydrate (3.15 g) in a solution of N, N-dimethylformamide: 50 (50 mL) in 1-ethyl — 3— (3 —Dimethylaminopropyl) Carposiimide hydrochloride (3.95 g) was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed successively with water (100 mL) and saturated brine (100 mL), dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. A solution of the residue and acetic acid (15 mL) in ethanol (15 OmL) was heated to reflux for 12 hours. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was diluted with water (8 OmL), adjusted to pH = 8 by adding saturated aqueous sodium hydrogen carbonate solution, and extracted with black mouth form (3 × 8 OmL). The organic layer was washed with saturated brine (8 OmL), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 1: 2) to give 2.03 g (27% yield) of the title compound as a pale-carbon yellow amorphous substance. . 1H NR (300 MHz, CDC13) δ 1..46 (9H, s), 1.99-2.05 (2H, m), 3.22 (2H, br), 4.07 (1H, br), 4.95 (1H, br), 6.55 (2H, d, J = 8,1 Hz), 6.74 (1H, br), 7.12 (2H, d, J = 8.1 Hz).

 d) 3-Amino-11 [(4-Chronophenyl) amino] — 1— (3-Morpholino-1 H-1, 2, 4— 卜 riazol 5-yl) Propane

 3— [(tert-Butoxycarbonyl) amino] _ 1 (4—Black-mouthed Fe, 2) Amino 1— (3 —Morpholino 1 H— 1, 2, 4—.Triazol-5 —yl) Propane (2 03 g), concentrated hydrochloric acid (: 1 OmL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethanol (5 mL), and the solvent was distilled off under reduced pressure. The residue was diluted with water (5 OmL), adjusted to pH = 9 by adding 2N aqueous sodium hydroxide solution, and extracted with 10% methanol / chloroform form solution (3 × 5 OmL). The organic layer was washed with saturated brine (5 OmL). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl ether monoethyl acetate to give the title compound 6 1 1 mg. (Yield 39%) ′ as colorless crystals. 1H NMR (300 MHz, 'CDC13) 6 2.02-2.04 (2H, m), 2.79-2.81 (2H, m), 3.23 (4Η, br), 3.25-3.60 (2Η, m), 3.65 (4Η, br) 4.46-4.49 (1Η, m), 6.21 (1H, d, J = 6.9 Hz), 6.63 (2H, d, J = 8.7 Hz), 7,05 (2H, d, J = '8.7 Hz), 7.80-9.20 (1H, br). Reference Example 5

 The production method of the test compound (16) used in the pharmacological test is shown below.

 2-Amino 1- [(4-Flophenyl) amino] — 1— [3— (4-Pyrimidyl) — 1 H— 1, 2, 4 _triazole-5 _yl] ethane trihydrochloride; Test compound (1 6)

 a) (2 S)-3-[(tert-butoxycarbonyl) amino] — 2— [(4— black-phenyl) amino] methyl propionate

(2 S) — 2-amino 1- [(tert-butoxycarbonyl) amino.] Methyl pionate hydrochloride ^: (9, 9, 8 g), 4 p-p-phenylboronic acid (1 8

45 g), copper acetate (I I) (7.84 g) and molecular, 4 A (29.

5 g) was mixed with dichloromethane (3 OmL), triethylamine (7.95 g) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture 'was treated with ² N ammonia Ichime methanol solution (26 OmL), Celite Application: were filtered through. The filtrate was concentrated under reduced pressure and ethyl acetate (50 OmL) ′ was added. The mixture was washed with water (30 OmL × 2) and then with saturated brine (l OQmL). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. ¾ Distillate was purified by silica gel column chromatography (elution. Liquid; hexane: ethyl acetate = 2: 1). The title compound 1.38 g (yield 1 1%) was obtained as a pale yellow oily substance. . What

 1H NR (300 MHz, CDC13) δ 1.44 (9Η, s), 3.54. (2Η, br t, J = 6.3 Hz); 3.76 (3H, s), 4.11-4.15 (1H, m), 4.55. 1H, br d, J = 6.3 Hz), 4.88 (1H, br s), 6.55 (2H, d, J = 8.7 Hz), 7.12 (2H, d, J = 8.7 Hz),

 b) (2 S) 1 3 _ [(tert-butoxycarbonyl) amiso]-2- [(4-phenyl) amino] propionic acid.

 (2 S) 1 3 — [(. Tert-toxylanol) amino] — 2 _ [(4-Gulphenyl) amino] Enol (30 mL) of methyl propionate (1.3 g) To the mixture was added IN aqueous sodium hydroxide solution (3 OmL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, acidified with 1N hydrochloric acid, and extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (5 OmL), dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 1.4 g of the title compound as crystals.

 1H NMR (300 MHz, CDC13) 8 1.44 (9H, s), 3.61 (2H, m), 4.11 (1Η, m), 5.04 (1H, br), 6.57 (2H, m), 7.15 (1H, d, J = 8.7 Hz),

 c) 2— (tert-butoxycarbonylamino) 1 1— [(4 1-phloyl 2-amino) amino] 1 1 1 [3— (4-pyrimidyl) 1 1 H— 1, 2, 4-triazolone 1-5—Inore] Ethane

Pyrimidine 1-carbohydrazone (0.65 g), (2 S)-3-[(t ert—Butoxycarbonyl) .Amino] — 2— [(4—Mouth Mouth Fell) Amino] Mouth Pionic Acid (1.4 g), 1—Bidoxybenzotrihydrate (2 90 mg) 1-Ethyl 3- (3 ^ dimethylaminopropyl) carbodiimide hydrochloride (1.0 g) was added to a solution of acetononitrile (5 mL) and stirred overnight at room temperature. After concentrating the reaction solution, ethanol / ethyl was added to the resulting residue and the resulting solid was collected by filtration. Ethanol (10 OmL) and acetic acid (20 mL) were added to the obtained solid and heated at reflux for a while. After concentrating the reaction solution, the resulting residue was purified by basic silica gel column chromatography (eluent; ethyl acetate: methanol = ⁴ : 1). Title: Compound 0.8.8: 8 g Was obtained as an oil.

 1H NMR (300 MHz, CDC 13) δ 1.43 (9Η, s), 3,76 (2H, m), 4.82 (1H, m), 5.33 (1H, m), 5.40 (1H, br), 6.52 ( 2H, d, J = 8.7 Hz), 7.06 (2H, d, J = 8.7 Hz), 8.10 (1H, d, J = 5.1 Hz), 8.89 (1H, d, J, = 5..1 Hz), 9.31 (1H, s).

 d) 2-Amino _ 1— [(4—Black mouth phenyl) amino /] '— 1— [3- (4-Pyrimidyl) — 1 H— 1, 2, 4, 4-Triazol-5-yl] Ethani hydrochloride salt

 2— (tert-Butoxycarbonylamino) 1 1 _ [(4—Black mouth phenyl) amine] — 1— [3— (4-Pyrimidyl) _ 1 H— 1, 2, 4— Triazol Nore 5-yl] ethane (88 8 Og). To 12 N hydrochloric acid (2 mL) was added and the mixture was stirred at room temperature for 15 minutes. Ethanol (50 mL) was added to the reaction mixture and mixed, and the solvent was evaporated under reduced pressure. The residue was treated with ethanol-jetyl ether, and the resulting precipitate was collected by filtration. The precipitate was washed with jetyl ether (20 mL) and dried under reduced pressure to give 0.66 g of the title compound as a pale yellow powder. It was.

1H NMR (300 MHz, Me2S0-d6) δ 3.35 (2Η, m), 5.04 (1H, m), 6.76 (2H, d, J = 8.7 Hz), 7.14 (2H, d, J = 8.7 Hz), 8.09 (1H, d, J = 5.1 Hz), 8.36 (3H, br), 8.99 (1H, d, J = 5.1 Hz), 9.32 (1H, s) Reference Example 6 The preparation method of the test compound (17) used in the pharmacological test is shown below.

 (1 R) 1 2-Amino 1- [(4-Clophenyl) amino] 1 1- [3- (4 1-pyrimidyl) 1 1 H— 1, 2, 4-triazole — '5—yl] Ethane Trihydrochloride-Test Compound (1 7)

 a) (2 R) — 3— [(t e r t-butoxycarbonyl) amino] — 2— [(4-phenyl phenyl) amino] Pro t. Methyl onate

,. (2 R) — 2-Amino 1 3— [(t e. Rt-Butoxycarbonyl) Amino] Methyl propionate (7. 3 ^ g), 4-chloropheninorepolonic acid (1 0. 48 g ), Copper (II) acetate hydrate (0.68 g) and molecular sieves 4 A (33.5 g) were mixed with dichloromethane (0.2 mL) and stirred at 40 ° C. for 12 hours. The reaction mixture was treated with 2N ammonia in methanol solution (20 OmL) and filtered through celite. The filtrate was concentrated under reduced pressure and ethyl acetate (50 OmL) was added. The mixture was washed with water (300 mL × 2) and then with saturated brine (10 OmL), the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane: ethyl acetate = 4: 1) to obtain 1.20 g (yield 11%) of the title compound as a pale yellow oily substance.

 1H thigh (300 MHz, CDC13) δ 1.44 (9H, s), 3.52—3.56 (2H, m), 3.76 (3H, s), 4.15 (1H, t, J = 4.2 Hz), 4.55 (lH ,. br , J = 6.9 Hz), 4,87 (1H, br), 6.55 (2H, d, J = 9.0 Hz), 7.12 (2H, d, J-9.0 Hz).

 b) (2 R)-3- [(ter t-butoxycarbonyl) amino] — 2— [(4-phenyl) amino] propionic acid

(2 R) — 3— [(tert-butoxycarbonyl) amino] _ 2— [(4 chlorophenyl) amino] Methyl propionate (1.12 g) in methanol (3 mL) and tetrahydrofuran (3 mL) 2N Aqueous sodium hydroxide solution (3.4 mL) was added to the solution dissolved in, and the mixture was stirred at 0 ° C for 1 hr. The residue obtained by concentrating the reaction solution under reduced pressure was diluted with water (10 mL), adjusted to pH 4 with 1N hydrochloric acid, and extracted with a 20% methanol-chloroform solution (3 XI OmL). . Saturated organic layer After washing with Japanese salt water (1 OmL) and drying over magnesium sulfate, the solvent was removed under reduced pressure. The obtained residue was crystallized from diisopropyl ether to give the title compound (983 mg, yield 9.2%) as colorless crystals. '

1H NR (300 MHz, CDC13) δ 1.45 (9H, s), 3.40-3.60 (2H, m), 4.04-4.15 (2H, m), 5.04 (1H, br s), 6.00-6.60 (1H, br) ^; , 6.55 (2H, br s), 7.13 (2H, d, J = 8.4 Hz).

 , c) (1 R) — 2— [(tert-butoxycarbonyl) amino] — 1 1 (4-chlorophenol) ANO 1 _. [3— (4-Pyrimidyl) 1 1 H— 1, 2 , 4—Triazonore 1—5-inole]

 (2 R) — 3— [(tert-Butoxycarbonyl) .Amino] — 2— [(4—Chlorophenyl). Amino] propionic acid (668 mg), Pyri: Midishi 4-Carbohydrazone (346 mg) and 1-hydroxy> zoi, riazole hydrate (193 mg) in a solution of 1-ethyl 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (483 mg) ) Was added and stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate (80 mL), washed with water (5.0 mL) and saturated brine (5 OmL), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was heated under reflux for 12 hours in a solution of acetic acid (2.5 mL) and ethanol (25 mL). The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was diluted with water (5 OmL), adjusted to pH 8 by adding saturated aqueous sodium hydrogen carbonate solution, and extracted with black mouth form (3 X 5 OmL). The organic layer was washed with saturated brine (10 OmL), dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 17: 3) to give 347 mg (yield 40%) of the title compound as a pale yellow amorphous substance.

1H NMR (300 MHz, CDC13) 8 1.43 (9H, s), 3.68-3.84 (2H, m), 4.80 (1H, br), 5.21 (1H, br), 5.24-5.50 (1H, br), 6.53 ( 2H, d, J = 8.4 Hz), 7.07 (2H, d, J = 8.4 Hz), 8.07 (1H, d, J = 5.1 Hz), 8.88 (1H, d, J = 5.1 Hz), 9.30 (1H, s), 12.20-12.80 (1H, .br).

 d) (1 R)-2-Amino 1- [(4-Flophenyl) amino] — 1— [3— (4-Pyrimidyl) 1 1 H— 1,: 2, 4— Triazo “Lu 5 —Inole] Ethane trisalt

• Acid salt

 (lR) —, 2— [(tert-butoxycarbo-nole) .Amino:] — 1— (4-chlorophenyl) amino 1— [3— (4-pyrimidyl)-1 H-1, 2, 4— Concentrated hydrochloric acid (2 mL) was added to triazol-5-yl) ethane (345 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction was diluted with ethanol (5 mL) and the solvent was removed under reduced pressure. The residue was diluted again with ethanol (5 mL), and the solvent was distilled off under reduced pressure. Jetyl ether (5 mL) was added to the residue obtained, and the precipitate was collected by filtration and dried under reduced pressure to give the title compound (19 lmg, yield 91%) as a white powder. ,.

 1H NMR (300 MHz, Me2S0- 36) δ 3.30-3.38 (2H, m), 3.70-4.40 (4Η, br), 4.97-5.02 (1Η, m), 6.30-6.70 (1Η, br), 6.74 ( 2H, 'd,. J = 8.7 Hz), 7.15 (2H, d, J = 8.7 Hz), 8.07 (1H, d, J. = 5.4 Hz), 8.15 (2H, br), 9.00 (1H, d, J = 5.4 Hz), 9.33 (1H, s). Reference Example 7.

 The production method of the test compound (18) used in the pharmacological test is shown below.

 (1 R) — 2—Amino 1 1 [(4-Bromophenyl) Amino] — 1 1 [3— (4 —Pyrimidyl) 1 1 H_ 1, 2, 4, 4-Triazole 1 5— ^ Tl] ethane 3 Hydrochloride: Test compound (1 8)

 a) (2 R) — 3— [(t e r t-butoxycarbonyl) amino] — 2— [(4-Promophenyl) amino] methyl propionate

(2 R) — 2-Amino-3-[(tert-butoxycarbonyl) amino] Propionate methyl (8.95 g), 4-Monophenylboronic acid (16 · 47 g), Copper acetate ( II) Hydrate (0.82 g) and Molecular Sieves 4 A (40 g) was mixed with dichloromethane (30 Om.L) and stirred at 40 ° C. for 13 hours under an oxygen atmosphere. To the reaction mixture was added acetyl acetate (500 mL), and the mixture was filtered through celite. The filtrate was washed with 5% aqueous ammonia (30 mL) and then saturated brine (200 mL). The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 3: 1) to give 2.88 g (yield 19%) of the title compound as a pale yellow powder. , 1H NMR (300 MHz, CDC13) 8 1.44 (9H, s), 3.52—3.57 (2H, m), 3.76 (3Η, s) 4.14 (1Η, t, J = 5.4 Hz),, 4.30, 75 (1H , Br), 4.86 (1H, br), 6.52 (2H, d J = 9.0 Hz), 7.26 (2H, d, J = 9.0 Hz).

 b) (2 R), 3— [(t er. t _butoxycarbonyl). Amino] — 2— [(4-Bromophenyl) amino] propionic acid

 (2 R) — 3— [(tert-Butoxycarbole): Γmino] — 2— [(4-Bromophenyl) amino] Methyl propionate (2. 88 g) was added to methanol (5 mL) and tetrahydrofuran ( To a solution dissolved in 1 mL) was added 0.2N aqueous sodium hydroxide solution (7. 7 mL), and the mixture was stirred at room temperature for 3 hours. The residue obtained by concentrating the reaction solution under reduced pressure was diluted with water (10 mL), adjusted to pH 4 by adding 1N hydrochloric acid, and extracted with ethyl acetate (3 X 1 OmL). . The organic layer was washed with saturated brine (10 mL), dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was crystallized from disopropyl ether monohexane to give 2.46 g (yield 89 ° / o) of the title compound as colorless crystals.

 1H NR (300 MHz, CDC13) δ 1.45 (9H, s), 3.40-3.61 (2H, m), 4.00 (1H, br s), 4.05-4.20 (1H, br), 5.02 (1H, br), 6.53 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz).

 c) (1 R)-2-[(tert-butoxycarbonyl) amino] — 1 _ (4-Bromophenyl) amino 1- [3- (4-pyrimidyl) 1 1 H— 1, 2, 4— Triazonole 1—Inore]

(2 R)-3-[(tert-ptoxycarbol) amino] — 2— [(4- Lomophenyl) amino] propio, acid (3 59 mg), pyrimidine- .4-cal ^ hydrazone amide (1 6 5 mg) and 1 hydrated oxybenzo. Triazo monoruohydrate (68 mg) 1-ethyl 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (230 mg) was added to a solution of DMF (3 mL) in water and stirred at room temperature for 1. hour. · The reaction solution was diluted with ethyl acetate (50 mL), washed with 50 mL water and saturated brine (50 mL), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. . The residue was dissolved in acetic acid (5 mL) and ethanol (25 mL). The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was diluted with water .. (5 OmL), adjusted to pH = 8 by adding saturated aqueous sodium hydrogen carbonate solution, and extracted with Glow mouth form (3 X 5 OmL). The organic ^layer: was washed with saturated brine (1 0 OML}, dried over magnesium sulfate, the solvent was distilled off under reduced pressure .. the residue was purified by silica gel force column chromatography (eluent; chloroform...:. By purifying with methanol = 7: 1), the title compound 2 1 6 mg was obtained as a pale yellow amorphous substance: 1H NR (300 MHz, CDC13) δ 1.43 (9Η, s), 3.65—3.85 ( 2Η, m), 4.79 (1Η, br) :, 5.21 (1Η, br), 5.30—5.70 (1Η, br), .6. '48 (2Η, br, J = 9.0 Hz), 7.22 (2H, d , J = 9.0 Hz), 8.09 (1H, dd, J = 5 1, 1.2 Hz), 8.91 (1H, d, J = 5.1 Hz), 9; 32 (1H, d, J = 1.2 Hz), 12.20- 12.60 (1H, br).

 d) (1 R) — 2-Amino 1- [(4-Bromophenyl) amino] — 1- [3, (4 Pyrimidyl) 1 1 H ^ 1, 2, .4-Triazole 1 5-Inole] Ethane trihydrochloride

(1 R) — 2— [(tert-Butoxycarbonyl) amino] — 1 _ (4-Promophenyl) Amino 1 — [3— (4-Pyrimidyl) 1 1 H— 1, 2, 4-triazole Concentrated hydrochloric acid (lmL) was added to 15-yl] ethane (200mg), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethanol (5 mL), and the solvent was distilled off under reduced pressure. The residue was again diluted with ethanol (15 mL) and the solvent was removed under reduced pressure. Jetyl ether (15 mL) was added to the obtained residue, and the precipitate was collected by filtration and dried under reduced pressure to give 162 mg of the title compound as a pale yellow powder. 1H NMR (300 MHz, Me2S0-d6) δ 3.30— 3.41 (2H, m), 5.01 (1H, .br), 5.40—

6.70 (4H, br), 6.70 (2H, d, J = 8.7 Hz), 7.25 (2H, d, .j = 8.7 Hz), 8.09

(1H, dd, J = 5.4, 1.2 Hz), 8.25 (3H, br), 8.99 (1H, d, J. = 5.4 Hz), 9.32 (1H, d, J = 1.2 Hz).

 ■ .- + ■.. ';.

 The production method of the test compound (19) used in the pharmacological test is shown below.

 2—Amino 1— [(4-Qui-Phenyl) Amino] — 1— [3— (1, 2, 5-Thiadiale— 3 _il) _ 1 Η— 1, 2, 4—Triazole _ 5 _Il] ethane dihydrochloride; test compound (1 9)

 a) 1, 2, 5-Thiadiazole 1-Strong rubonic acid:

 To the mixture of disulfur dichloride (288 g) in DMF (3.4 OmL) was added 2,, 3-diaminopropionate hydrochloride (50 g) little by little at 0 ° C, and the mixture was stirred at room temperature 3 Stir for hours. Water (25 OmL) was added dropwise to the reaction solution at 0 ° C, and the resulting mixture was extracted with dimethyl ether (20 OmLX 2). The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. . The residue was dissolved in a saturated aqueous sodium hydrogen carbonate solution (250 mL), and the resulting solution was washed with jetyl ether (10 OmLX 2). To the aqueous layer was added 12 N hydrochloric acid at 0 ° C. until pH = 0.2, and the mixture was extracted with ethyl acetate (20 OmLX 2). The organic layers were combined, washed with saturated brine (200 mL), dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 18.7 g (yield 40%) of the title compound as a pale yellow solid. Obtained.

 1H NMR (300 MHz, CDC13) δ 5.20—6.40 (1Η, br), 9.15 (1H, s).

 b) 1, 2, 5-Thiadiazole 3-Methanol

1, 2, 5—Thiadiazole 3-strong rubonic acid (18.7 g) was added in portions to THF solution of borane / THF complex (1 M, 288 mL) at 0 ° C, and the mixture was heated at room temperature. Stir for 2 hours. The reaction solution was poured into ice water (30 OmL), and 12N hydrochloric acid was added to adjust to pH = 2, and then the mixture was stirred at room temperature for 1 hour. 8N Hydroxic acid at 0 ° C to the mixture After adding aqueous sodium nitrite solution to pH = 8, the mixture was extracted with ethyl oxalate (30m LX 2). The organic layer was washed with saturated brine (SO 2 OmL) and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound 1'6 .. O g (yield 96%) as a brown liquid. Obtained.

 1H N R (200 MHz, CDC 13) 6 2.64 (1H, t, J-= 6.0 Hz), 5.00 (2H, d, J. = 6.0 Hz), 8.60 (1H, s).

, c) 1, 2, 5—thiadiazo ^ —3—carbohi drazone amide

1, 2, 5—thiadiazole _ 3—methanol (8. 0 g) in water (1 60 mL). To a mixture of diammonium cerium nitrate (IV) (80 g) and 80 ° C For 30 minutes. To the mixture was added diammonium cerium nitrate (IV) (40 g), and stirred at 80 ° C for 30 minutes. The skin solution was cooled to room temperature and extracted with diethyl ether (100 mL X 3). The organic layer was combined and washed with saturated brine (250 mL), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give crude 1, 2, 5-thiadiazole 3-carbaldehyde (4 3 g) was obtained as a brown liquid. The obtained crude i, 2,5-thiadiazole_3-carbaldehyde (4: 3 g) in solution with acetonitrile (5 OmL) was dissolved in hydroxyramine hydrochloride (5.2 g). A solution of C in 8N aqueous sodium hydroxide (9.4 mL) was added dropwise at room temperature, and the mixture was stirred at room temperature for 3.0 minutes. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate (10 mL). The organic shoulder was washed with saturated saline (SOmL) and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. N, N ′ monocarbodidiimidazole (12.2 g) was added to a solution of the obtained residue in THF (5 OmL), and the mixture was stirred at 60 ° C. for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. Water (5 OmL) was added to the residue, and the mixture was extracted with ethyl acetate (5 OmL). The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue (crude 1, 2, 5-thiadiazole _ 3-carbonitryl) was dissolved in ethanol (5 OmL) and anhydrous hydrazine. (3.6 g) was added and the mixture was stirred at 60 ° C. for 3 hours. The reaction solution is cooled to room temperature, and the resulting crystals are collected by filtration and washed with ethanol (5 mL). After purification, it was dried under reduced pressure to obtain 2.1 g (yield 21 ° / ₀ ) of the title compound as pale yellow crystals. .. ..

 1H 删 R (200MHz, Me2S0-d6) δ · 5.57 (2Η, br), 5.78 (2H, br), .8.92 (1H). D) 2— [(tert-butoxycarbonyl) amino;] — 1— [ (4—Black mouth phenyl) Amino] — 1— [3— (1, 2, 5—Thiadiazol 1-3 —yl) 1 1 H— 1, 2, 4 4 Tricool 1-5 —yl] ethane

 1, .2, 5—Thiadiazol 3-Carbohydrazone amide (3.44 mg), 3- [(tert-Butoxycarbonyl) amino] — 2— L (4-Gulophenyl) amino] Propionic acid (63 Qmg ) And 1— .Hydroxybenzotriazole hydrate (1 35 mg) to acetonitrile (1 OmL) [Add this mixture to 1-ethyl 3- (3-dimethylaminopropinole) carbodi] Midhydrochloride (46 O.mg). Was added at room temperature and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, water (5 OmL) was added to the residue, and the mixture was extracted with ethyl acetate (5 OmL). The organic layer was washed with saturated brine (50 mL), dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in edanol (2 OmL) and acetic acid (5 mL), and the resulting solution was heated to reflux for 16 hours. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (15 mL) was added to the residue, and the mixture was extracted with ethyl acetate (5 OmL). The organic layer was washed with saturated brine (5 OmL) and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 9: 1 → 1: 1) to give 460 mg (55% yield) of the title compound as a pale yellow amorphous substance. Got as.

 1H NMR (200 MHz, CDC13) δ 1.43 (9Η, s), 3.68-3.87 (2H, m), 4.81 (1H, br), 5.38 (1H, br), 5.54 (1H, br), 6.48 (2H, d, J = 6.0Hz), 7.06 (2H, d, J = 6.0 Hz), 9.13 (1H, s).

e) 2-Amino _ 1 [(4—Black mouth phenyl) amino] — 1— [3— (1, 2, 5—Thiadiazole— 3—yl) 1 1 H— 1, 2, 4—Triazole 5—i Nore] Etani hydrochloride 2-[(tert-Butoxygalbornyl) amino] 1 1- [(4 mouthful ferrule) amino] — .1 1 [3— (1, 2, 5 -thiadiazole 3-yl) 1 1 H_ A solution of 1,2,4-triazol-5-yl] ethane. (460 mg) in 12 N hydrochloric acid (2 mL) at room temperature was stirred at room temperature for 15 minutes. Ethanol (1 QmL) was added to the mixture and the solvent was distilled off under reduced pressure. The residue was treated with _{Etanoru Rougetyl} Edel, and the resulting precipitate was collected by filtration. The precipitate was washed with _Jetyl ether (5 mL) and then reduced and dried under the _{shovel to} give 265 mg of the title compound as a pale yellow powder.

 1H NMR (200MHz, Me2S0-d6), δ 3.29-3.48 (2Η, m), 5.12 (1Η, t, J = 4.6Hz), 6.77 (2H, d, J = 6.0 Hz), Ί.14 (2H, d, J = 6.0 Hz), 8.48 (3H, br), 9.34 (1H, s). According to the test example described below, it is substantially GRK-inhibited. It was demonstrated that the test compounds (1) to (20), which were confirmed to exhibit GRK inhibitory action, applied directly to the heart and improved the contractile force.

 Therefore, it is clear that the GRK inhibitory action is an essential action for improving the systolic force, and it was demonstrated that the GRK inhibitor is useful as a cardiotonic drug. Test example 1

 The following experiment was conducted for the purpose of evaluating the kinase inhibitory action of the test compound (1) on GRK2, PKC, PKA, R0Kα at the enzyme level.

Enzyme inhibitory activity against GRK2 was measured using tubulin as a substrate with reference to a report by Pitcher et al. (Journal 'Ob' Biological Chemistry, Vol. 273, pages 12316-12324). 0.15 / ζΜ purified ushi GRK2, 0.9 μM purified ushi tubulin, 0.5 μΜ ΑΤΡ (including 0.1 / iCi [γ- ³² P] ATP), 2 mM EDTA, lOraM MgCl ₂ , A test compound of an appropriate concentration is added to 20 mM Tris-HCl (pH 7.5) containing ImM DTT to make a 25 L mixed solution, which is reacted at 30 ° (:, 1 hour. 20% Trichrome After stopping the reaction by adding mouth acetic acid solution (TCA), the TCA precipitate produced was collected on a GF / C filter. The radioactivity on the filter was measured using a scintillation counter and a Yon counter and used as an index of tubulin phosphorylation. '' Normalized tubulin phosphorylation with 0% count in the absence of GRK2 and 100% in the absence of test compound ^ 100%, and the concentration of the test compound exhibiting 50% phosphorylation inhibitory activity as the IC _5Q value Calculated. The enzyme inhibitory activity against PKCc, PKA, and ROKa is 6 μg / mL purified human PKCa or 8 / g / m purified Ushi PKA catalyst subunit, or 0., ⁴ U / mL of purified rat ROKa was measured in the same manner as described above using 20 μg / mL purified ushimyelin basic protein as a substrate. The results are shown in Table 1.

 Table 1 Kinase inhibitory effects of test compound (1) on GRK2, PKCa, PKA, R0K

,·for .. .·..'.

Kinase .. ic ₅ . value

 GRK2 35nM '.

 PKCa,> 2000nM.

 PKA> 2000nM

 ROKa> 2000nM

From the results in Table 1, it can be seen that Compound (1) exhibits selective GRK inhibition ^^.

Test example 2

The following experiment was conducted for the purpose of evaluating the affinity of the test compound (1) for the adrenergic 3 receptor, dopamine receptor, endothelin receptor, calcium channel (CaCh) and sodium channel (NaCh). That is, the human i receptor to prepare a high expression was membrane preparation from Rex 16 cells, 5QmM containing Asukorubin acid 1.4 mM, 0.001% of © shea serum albumin, 1.5 mM CaCl _2, 5 m EDTA and 120 mM NaCl Tris- Incubate with 0.03 nM ¹²⁵ 1-Cyanopindolol in HC1 (pH 7.4) for 2 hours at 25 ° C. I did. The test compound (1) was dissolved in DMS0 (final concentration 1%) and added to a final concentration of 10 / ζ. After incubation, the reaction solution was filtered through a GF / B filter, and the radioactivity on the filter was measured using an inversion counter. Nonspecific binding was defined as the amount of binding in the presence of 100 / i M S (-) -Propranolol, and the inhibition rate for the specific binding amount in the absence of 5 test compounds was determined. β ₂ receptor, receptor, D ₂₁ _ receptor, D _{2 S} receptor, D ₃ receptor, D receptor, ET _A receptor, ET _B .receptor .., affinity for CaCh and NaCh It measured by the method of. The source of the specimen is human j3 _2> D or D ₂ D _{2 S} , D ₃ , D ₅ , ΕΤ _Α ′, and CH0 cells or rat cerebrum highly expressing ET _B receptors. And NaCh), and the label ligand is 0.2 nM ³ H- CGP-12177 (] 3 ₂ ), 1.4 nM ³ H-SCH-23390 (Dj) _Λ 0. 16n 3H-Spiperone (D _{2 2 S} ), .0.7 nM ³ H Spiperone '(D ₃ ), 2 nM ³ H-SCH-23390 (D ₅ ), 0.03 nM ¹²⁵ I-Endothelin-l (ET _A ), 0. InM ¹²⁵ 1— Endothelin-1 (ET _B ), 2 nM 3H-: Diltiazem (CaCh) and 5riM 3H-Batrachotoxin (NaCh) were used. Incubation conditions were 25 ° C for 1 hour, (] 3 ₂ ), 37 ° C for 2 hours (D D D ₅ , 5 ET _A ), 25 ° C 2 h (D ₂ D D _{2 S} , .ET _B ), 4 ° C for 3 hours (CaCh) and 37 ° C for 1 hour (NaCh). Furthermore, non-specific binding is 10 / iM. ICI-118, 551 (β ₂ ), 10 μM (+)-Butaclamol (Ό _ι ) 10 μM Haloperidol (D _{2 L} , D _{2 S} ), 25 μ MS (-)-Sulpiride (D ₃ ), 10 μ, cis-Flupentixbl (D ₅ ) 0. 1 μ.M Endothelin-1 (ET ET _B ), 10 μ Μ Diltiazem (CaCh) and 100 μ M It was defined as 0 using Veratridine (NaCh). The results are shown in Table 2.

Table 2 Affinity of test compound (1) for adrenergic receptor, dopamine receptor ^: and endoserine receptor

Receptor inhibition rate

 β 5%

 <5%

 5%

D _{2 L} 5%

D _{2 S} '5%

 ¾.: <5% "

D ₅ <5%.

ET _A <5%

ET _B 5%.

 CaCh 6%

 From the results in Table 2, it is clear that test compound (1) has no affinity for various receptors and ion channels involved in myocardial contractility. Test example 3

The following experiment was conducted to evaluate the inhibitory activity of the test compound (1) against Na / K-ATPase and phosphodiesterase (PDE). In other words, Na / K-ATPase prepared from kidney kidney was pretreated for 15 minutes at 37 ° C in 80 mM Tris-HCl (pH 7.4) containing 1.3 mM EDTA, 25 mM KC1, 5.3 mM MgCl ₂ , and 160 mM NaCl. The enzyme reaction was started by incubating and then adding 2 mM ATP. Test compound (1) was dissolved in DMS0 (final concentration 1%) and added to a final concentration of ΙΟμΜ. After a reaction time of 15 minutes, the reaction was stopped by adding 2.5 of HC10 ₄ and adding (NH ₄ ) ₆ Mo ₇ 0 _{2 4} -H ₂ S0 ₄ and Fiske-Subbarow reagent. Colorimetric determination of Pi produced in It was a finger slip. The inhibition rate of the compound was calculated with the enzyme activity in the absence of the test compound as 0%. The inhibitory activity against PDE was measured as follows. That is, PDE3 prepared from human platelets was preincubated for 15 minutes at 25 ° C in lQmM ^: Tris-HC1 (pH 7.5) containing Im gCl ₂ and then 'cAMP 1 / x containing ³ H-cAMP. Enzyme reaction was started with M. Test compound (1) was dissolved in DMS0 (final concentration 1%) and added to a final concentration of 10 μΜ. After the reaction time of 20 minutes, stop the reaction by heating at 100 ° C for 2 minutes, add snake venom, and incubate at 37 ° C for 10 minutes. Converted to 3H-Adenosine After removing unreacted cAMP with AG1 2 resin, the radioactivity in the reaction solution was measured, and the enzyme activity in the absence of the test compound was used as an index of enzyme activity. The inhibitory rate of the compound was calculated with PED4 and PDE5 as the enzyme source, and the enzyme source was hydrated U931 cells (PDE4) and human platelets (PDE5). Was measured in the same manner using 3 μ-cGMP containing 3H-cGMP instead of 3H-cAMP / cAMP.

 The results are shown in Table 3. '

 Table 3. Enzyme inhibitory activity of test compound (1) on Na / K-ATPase and phosphodiesterase

 Enzyme inhibition rate

 Na / K-ATPase 5%

 PDE3: <5%

 PDE4 <5%

 PDE5 <5% The results in Table 3 indicate that test compound (1) has no enzyme inhibitory activity against Na / K-ATPase and PDE involved in myocardial contractility. Test example 4

In order to evaluate the GRK inhibitory action of the test compound (1) in the cell line, The experiment was conducted. .

Based on studies using the GRK inhibitor protein] 3 ARKct, the accumulation of intracellular cAMP produced by isoproterenol at concentrations that cause sufficient receptor desensitization suppresses the GRK-dependent desensitization reaction. It has been shown to be augmented by ί (Journal · Ob · Clinical · Investigation, Vol. 99, pp. 288-296). Therefore, to assess the human / 3 put in ₂ receptor highly expressed was the HEK293 cells (HEK B2 cells), Ru isopropoxy D Telenor enhancing effect on cAMP accumulation after stimulation index of GRK inhibitory effects in cell lines It was. That is, HEK-B2 cells suspended in D_PBS (+) solution containing ³ -isobutyl-1-methyl-xantine (IBMX, ImM) and L-ascorbic acid (0.01%). Compounds were added and incubated at 37 ° C for 20 minutes. Then, add enough isoproterenol ^^ (ΙηΜ) to induce a / 3 receptor desensitization reaction and incubate at 37 ° C for 20 minutes. Induced (Atsusy capacity ²⁰ / L). The cAMP production reaction was stopped by adding the same volume of Tris-EDTA buffer (pH 8.0) and heating at 95 ° C. The amount of cAMP produced was measured using an ALPHA-Screen cAMP detection kit (Perkin Elma). As a control, the same reaction was carried out by adding only the solvent (N, dimethylformamide, final concentration 0.3%) without ^ S test compound. The results are shown by normalizing the amount of cAMP accumulated with the amount of cAMP accumulated in the absence of the compound as 100%. The results are shown in Table 4.

Table 4. Potentiating effect of test compound (1) on cAMP accumulation after isoproterenol stimulation in HEK293 cells with high expression of human / 3 ₂ receptor

 Compound concentration c AMP accumulation

 Ι μ Μ 9%

 3 μ Μ 24%

 10 52%

30 u M 137% From the results in Table 4, it can be seen that the test compound () shows concentration-dependent cAMP accumulation enhancing action, that is, for GRK inhibition, by extracellular application. Test example 5

 To confirm that the inhibitory effect of the receptor desensitization by GRK inhibition of the test compound (1) confirmed in Test Example 4 also occurs at the heart organ level. The following experiment was conducted using this.

10- to 11-week-old male Wistar rats, the heart was removed and a force tape was inserted into the aortic root and attached to a Langendorf device maintained at 37 ° C, mixed gas (95% 0 ₂ -5% C0 ₂ ). Crep and solution (composition (mM): NaCl 113, KC1 4.6, CaCl ₂ 1.2, NaH ₂ P0 _{4 2.5} , MgCl ₂ 1.2, Thigh C0 ₃ 22, glucose 10) was perfused at a constant pressure (75 mmHg). After the stabilization period, the solvent (Ν, Ν-dimethylformamide, final concentration 0.1%) or compound (1) 10 // Μ is applied for 20 minutes, after which a receptor ^ sensitization occurs. For this purpose, 10 / ζ テ レ of isoproterenol (Iso) was used in combination for another 20 minutes. ] 3 Controls that did not cause receptor desensitization. In the (control) group, no isoproterenol was applied. The heart after drug application was frozen in liquid nitrogen and stored at -80 ° C until the following experiment. The preparation of the pericardial membrane was in accordance with Drazna et al.'S method (Jana Norreov Clinical Ishivestigation, 99 pp. 288-296). That is, thaw the heartbeat in lysis buffer (25 raM Tris-HC1, 5 mM EDTA, 5 mM EGTA, pH 7.4 at 37 ° C), homogenize, and centrifuge at 500 xg to obtain the nuclear fraction. The supernatant obtained was centrifuged at 40,000 xg to precipitate the membrane fraction. The obtained membrane fraction was resuspended in a binding buffer (75 mM Tris-HC1, 12.5 mM MgCl ₂ , 2 raM EDTA, pH 7.4 at 37 ° C.). [3] Receptor reactivity of membrane specimens was measured using isoproterenol-dependent adenylate cyclase (AC) activity as an indicator. In other words, suspend the membrane specimen in the presence of 0.5 mM IBMX, 53 μM GTP, 2.7 mM pyruvate, 4 IU / mL pyruvate kinase, 20 IU / mL myokinase, solvent, 0. isoproterenol or 10 mM fluoride. Add 0.12 mM ATP in the presence of sodium (NaF) CAMP. Was produced by incubation at 37 ° C. The reaction was stopped by the addition of triclomouth oxalate, and after deproteinization and TCA removal, the cAMP produced was measured using the ALPHA-Screen cAMP detection kit. The results were normalized with the amount of cAMP obtained in the presence of NaF as 100%, and are shown as the mean value and standard error of 8 cases. The results are shown in Table 5. ;

 Table 5. Inhibition of Compound (1) on Receptor Reactivity (Desensitization) by Application of High Concentration of Isoproterenol in Isolated Rat Heart Samples.

 ;

 Action "(% of lOmM NaF).

 Control .5.7 ± 0.6%

 Solvent + Iso 3.3 ± 0.6% '

 Test compound (1) + Iso 5.3 ± 0.2% As shown in Table 5, the reduction in receptor responsiveness (desensitization) caused by the application of high-concentration isoproterenol in rat isolated perfused heart specimens was 10 / M Was significantly inhibited by pretreatment with the test compound (1). This indicates that the inhibitory action of the 3 receptor desensitization by GRK inhibition of the test compound (1) confirmed in Test Example 4 occurs at the heart level. Test Example 6

 In order to observe the effect of acute GRK inhibition using test compound (1) on the contractility of isolated perfused heart specimens, the following experiment was conducted.

10-11 were excised heart Male Wistar rats weeks old, by inserting a force Tete Le aortic HajimeHajime unit, mounted on a Langendorff apparatus, which is kept at 37 ° C, a mixed gas (95% 0 ₂ - 5% C0 ₂ ) aerated crepes solution (composition (mM): NaCl 113, KC1 4.6, CaCl ₂ 1.2, NaH ₂ P0 ₄ 2.5, MgCl ₂ 1.2, NaHC0 ₃ 22, glucose 10) was constant pressure perfused (75 mmHg) . The left ventricular pressure, an index of cardiac contraction force, is the balloon force inserted from the left atrial appendage. It is measured from a taper through a pressure transducer. The heart rate was measured from the left ventricular pressure using a tachometer (Nihon Kohden). After the stabilization period, the compound dissolved in N, N-dimethylformamide (1): was applied to the perfusate mixed at a rate of 0.1%. After 15 minutes of drug perfusion, isoproterenol InM dissolved in distillate was simultaneously perfused for 15 minutes to investigate the action of compound (1) in the presence of catecholamine. As a control, only the solvent was perfused for 15 minutes, and then the same observation was performed using InM isoproterenol for 15 minutes. Compound (1) When applied alone and in combination with isoprodelenol: Change in each parameter that occurred at time (+ Iso) is shown as a change rate from the pre-drug value in 4-5 cases (^ average value) The results are shown in Table 6. Table 6 Effect of test compound (1) on cardiac contractility in rat isolated perfused heart preparation Left ventricular pressure HR:

 Single + Iso Single + Iso-,

 Solvent 9% 33% 2% 28%

 ! ¾ 匕 (1) Ι μΜ 20% 39%. 4% ''22% ■

Test compound (1). 10 _W M 45% 97% 2% 35% As shown in Table 6, the cardiac contractile force depending on the compound concentration is shown by selective inhibition of cardiac GRK by test compound (1). It has been clarified that the potentiating effect appears immediately after drug administration, and that the effect increases in the presence of catecholamine. The working concentration of test compound (1) was not inconsistent with the effective concentration of GRK inhibitory action obtained in the cell line. Interestingly, this potentiation of cardiac contractility by acute GRK inhibition was hardly accompanied by an increase in heart rate. Test Example 7

 In order to observe the effect of acute GRK inhibition using the test compound (1) on in vivo cardiovascular dynamics, the following experiment was conducted.

Male Wistar rats (350-450g) were anesthetized with inactin (100mg / kg, ip) A force gauge for blood pressure (MBP) measurement and drug administration was placed in the left femoral artery and vein, respectively. A mirror catheter with a pressure sensor was placed in the left ventricle from the right carotid artery, and the left ventricular pressure (LVP) was measured. By differentiating LVP, the maximum left ventricular pressure first derivative (LVdP / (Jt _ma '; _[ ), which is an index of systolic force, and the minimum left ventricular pressure first derivative (LVdP / it calculates dt _min). heart rate (HR) were measured via Takome one loaders from the left ventricular pressure. after the stabilization period, test compounds (1) port containing iN HC1, triethylene glycol (PEG) 400 And then diluted with physiological saline to make a lOmg / mL solution (final PEG concentration 30%, HC1 concentration 0.02N), and administered intravenously at a dose of lmg / kg / min for 30 minutes. Cardiovascular changes were recorded until 20 minutes after the end of administration. In the control group, a compound-free solvent ( ³⁰ % PEG / HC1 / saline) was administered in the same manner. The data obtained in Fig. 1 is shown as the average change rate and standard error of the 4 cases as the rate of change from the value before starting drug administration. As shown in Fig. 1, similar to the results in isolated perfused heart specimens (Test Example 5) by selectively suppressing GRK in vivo by continuous intravenous administration of the test compound (1.) Immediately after drug administration, only the systolic force was enhanced with little effect on blood pressure and heart rate, and the effect was restored by discontinuation of administration. This result clearly shows that inhibition of GRK provides a new mechanism for “cardiotonic drugs” that acutely improve cardiac contractility. Test Example 8

Test compounds of the following structural formulas (2) to (20), except that 0.06 / xg / mL of purified human PKC and 0.6U / mL of purified rat R0K were used as enzymes. Using the same method as in 1, experiments were conducted to evaluate enzyme-level kinase inhibitory effects on GRK2, PKCa, PKA, and R0Kα.

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The unit is nM (where ND indicates no data).

Table 7 Kinase inhibitory effects on GRK2, PKCa, PKA, ROK ct

Compound No .. GRK2 ROKa PKC and PKA

 (2) 87 360.> 2000 'ND

 (3) 32〉 2000〉 2000 ND

 (4) 27 510 '> 2000 670

 (5) .30 1100> 2000 ND

 (6) 21 470-〉 2000 790

 (7) '24, 1600〉 2000 ND

 (8) '34> 2000> 2000 ND

 (9) 62 1400〉 2000 ND

 (10) 27 27 620> 2000 ND

 (11) 32. 680 1300 •; ND

 (12) 51 600 1800 ND

 (13) 170 720〉 2000 .120

 (14), 270> 2000) 2000. 250

 (15) 250〉 2000> 2000 1100

 (16) 92 1000〉 2000 33! 0

 (17) 110 470.> 2000 72

 (18) 71 470〉 2000 54

 (19) .220> 2000.> 2000 420

 (20) 91 200> 2000 200 From the results in Table 7, it can be seen that the compounds (2) to (20) show a selective GRK inhibitory action in the same manner as the compound (1). Test Example 9

Test compounds (2) to (20) used in Test Example 8 were almost the same as Test Example 7. In the same way, an experiment was conducted to evaluate the strong effect of cardiac contraction force it in anesthetized rats. Each test compound was dissolved in polyethylene glycol (PEG) 400. containing IN HC1 and then diluted with physiological saline (final PEG concentration 30%, HC1 concentration. 0.02-0., 04N). Intravenous administration (ImL / kg): The results are shown in Table 8. The effect of enhancing cardiac contraction force in the table is the maximum LVdP / dt _{ra ax} after each test compound administration when the maximum left ventricular pressure first derivative value (LVdP / d) immediately before the test compound administration is taken as the reference (100%). The amount of change (%) is shown. ;;;

表 8の結果は、 化合物 （2) 〜（20)が、 すべて 20%以上の心収縮力増強作 用を有することを示しており、 化合物 （2) 〜（20)が、 急性に心収縮力を改善 する強心薬として有用であることが示されている。 製剤例 1 本発明における 「GRK.阻害剤を含有してなる強心薬」 は、 例えば、..次のような 具体的な処方を有する医薬組 β¾物の形態で実施することができる.（但し、 これら に限定されるものではない）。

The results in Table 8 indicate that all of compounds (2) to (20) have a cardiac contractility enhancing action of 20% or more, and compounds (2) to (20) have acute cardiac contractility. It has been shown to be useful as a cardiotonic agent to improve Formulation Example 1 In the present invention, “a cardiotonic drug containing a GRK inhibitor” can be implemented, for example, in the form of a pharmaceutical group β¾ having the following specific formulation (however, Not limited).

 In addition, in the following prescription, components (additives) other than the active ingredient may be those listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Pharmaceutical Standards or the Pharmaceutical Additives Standard, etc. '

 1. Capsule

 (1) Test compound (1) No .: 4 Omg

 (2) Lactose 7 Omg

 (3) Microcrystalline cellulose 9 mg

 (4) Magnesium stearate: .1 mg

 1 Capsenore 1 2 Omg

 Mix (1/2) of (1), (2) and (3) and (4) and granulate. Add the rest of (4) to this and enclose the whole in a gelatin capsule. .

2.Tablet IJ

 (1) Test compound (1) 4 Omg.

 (2) Rata Koichisu "· ''.

 (3) Corn starch. 1 8mg

 (4) Microcrystalline cellulose, .3.5 mg

 (5) Magnesium stearate 0.5 mg

 1 tablet 1 2 Omg

 Mix 2/3 of (1), (2), (3), (4) and 1-2 of (5) and granulate. The remaining (4) and (5) are added to the granules and pressed into tablets. Industrial applicability

It was first demonstrated by the present invention that a GRK inhibitor has an excellent cardiotonic effect. The agent of the present invention comprising a GRK inhibitor is useful as a cardiotonic drug, The utility value in the field of industry is extremely high.

 This application is based on Japanese Patent Application No. 200'5-276 782 filed in Japan, the contents of which are incorporated herein.

Claims

The scope of the claims GRK (G protein-coupled receptor kinase) P and a cardiotonic drug containing a harmful agent The cardiotonic agent according to claim 1, wherein the GRK inhibitor is a GRK2 inhibitor. 3. The GRK2 inhibitor is of formula (I)

[Where,  Ring A represents an optionally substituted aromatic ring.  Ring B represents an optionally substituted 5-membered nitrogen-containing aromatic heterocycle,  Ring C represents an optionally substituted nitrogen-containing aromatic heterocycle,  X represents an optionally substituted CH alkylene group,  Y represents an optionally substituted imino group, 1 O— or _S (O) n— (n represents 0, 1 or 2). ]  The cardiotonic agent according to claim 2, which is a GRK2 inhibitor comprising a compound represented by the formula: 4. A method for treating heart failure in a mammal, comprising administering an effective amount of the cardiotonic agent according to claim 1 to the mammal suffering from heart failure.