JP2010070503A - Antifungal 2-amino-triazolopyridine derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound specifically and selectively exhibiting antifungal activity based on the action mechanism of inhibiting the synthesis of 1,6-β-glucan. <P>SOLUTION: The compound specifically and selectively exhibiting the antifungal activity in wide spectrum based on the action mechanism of inhibiting the synthesis of the 1,6-β-glucan is provided. The medicine, especially the antifungal agent, contains such the compound, a salt thereof or a hydrate thereof. Concretely, the compound is the one represented by formula (I), or the salt thereof or the hydrate thereof. The medicine or the antifungal agent contains the compound, the salt thereof or the hydrate thereof as an active ingredient. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a compound having an antifungal action against pathogenic fungi, a salt thereof, or a hydrate thereof. Moreover, it is related with the antifungal agent containing these.

  Fungi are known to cause various diseases by infecting humans, animals, plants and the like. For example, in addition to causing superficial mycosis on the epidermal stratum corneum of human skin, keratinized tissues such as nails and hair, and mucosal epithelium such as oral cavity, deep skin fungi also against skin tissue located deep from the body surface Cause deep mycosis in deep tissues such as the esophagus, internal organs, and brain. Candida, Cryptococcus, Aspergillus, etc. are known as the main pathogenic fungi that cause deep mycosis by infecting humans. Superficial mycosis infects the skin, oral cavity, vagina, etc. Candida spp., Ringworm that infects the skin of hands and feet, etc. are considered to be the main ones. Various other fungi exist and are thought to infect animals and plants.

  Due to the rapid progress of research and development on antibiotics and chemotherapeutic drugs since 1950, and their widespread use, many therapeutic drugs for bacterial infections have been developed. Similarly, great efforts have been made toward the development of antifungal drugs, but compared to the development of antibacterial chemotherapeutic agents, there are few compounds currently in clinical use. On the other hand, the use of compromised hosts with reduced immunity due to the frequent use of antibacterial drugs (antibiotics and chemotherapeutic agents) in medical practice, malignant tumors, leukemia, organ and bone marrow transplantation, and acquired immune deficiency syndrome Due to the increase, deep mycosis has increased in recent years and has become a problem.

  The main antifungal agents currently used in clinical settings include polyene macrolides, fluoropyrimidines, and azoles. For the treatment of superficial mycosis, it is mainly used as a topical product, including various azole drugs, polyene macrolide nystatin, griseofulvin, terbinafine hydrochloride, butenafine hydrochloride, amorolfine hydrochloride, etc. Yes. On the other hand, azole fluconazole, itraconazole, voriconazole and posaconazole are frequently used in the treatment of deep mycosis, which has been increasing remarkably in recent years, but drug interactions have been reported. In addition, amphotericin B, which is a polyene macrolide, has a wide antibacterial spectrum and high effectiveness, but has a problem in terms of toxicity (side effects). Furthermore, flucytosine, which is a fluoropyrimidine, has low toxicity but easily causes fungal resistance. As described above, there are very few drugs currently used for the treatment of deep mycosis that have high medical satisfaction from the viewpoint of antibacterial spectrum, efficacy, safety and the like. In addition, fluconazole, which is particularly frequently used among these anti-deep fungi, is less susceptible to pathogenic fungi such as Candida glabrata, Candida tropicalis, Candida crusei, etc. Bacteria are also emerging. Therefore, there is a long-awaited clinical antifungal drug that overcomes these problems.

  On the other hand, for the development of mycosis therapy in recent years and the development of new antifungal agents, a test method for scientific evaluation of usefulness has been established, and it is more effective in combination with the progress of research on the mechanism of action. And safe drug development is desired. From the viewpoint of overcoming the problem of resistant bacteria, the development of antifungal agents having a novel mechanism of action is also awaited.

  Furthermore, because of safety issues, since fungi are different from bacteria (prokaryotic cells) and are eukaryotic cells similar to humans, compounds that specifically (selectively) damage fungal cells will be developed. There is a need.

  Under such circumstances, synthesis of major cell wall constituents of fungi, drugs that inhibit the so-called cell wall polysaccharide synthesis system, that is, antifungal agents whose target molecules are cell wall polysaccharide synthases that exist specifically in fungi Is expected in terms of novelty and selective toxicity. As polysaccharides constituting the fungal cell wall, β-glucan, chitin or chitosan, and mannan are known. Of these, β-glucan, which is the main component of the fungal cell wall, is 1,3-β-glucan. And 1,6-β-glucan.

  Examples of 1,3-β-glucan synthase inhibitors include papracandins (Non-patent Document 1), echinocandins (Non-patent Document 2), pneumocandins (Non-patent Document 3), and acreasins (non-patent documents). Reference 4) has been reported. Caspofungin (Non-Patent Document 5), Mikafungin (Non-Patent Document 6) and the like have been developed and marketed. However, all of these are only injections, and a novel antifungal agent effective even for oral administration is desired.

  As 1,6-β-glucan synthase inhibitors, tricyclic imidazo [1,2-a] pyridine derivatives (Patent Document 1), dibenzofuran and benzofuropyridine derivatives (Patent Document 4) have been reported. Therefore, it is necessary to develop a 1,6-β-glucan synthase inhibitor having a broad spectrum of pathogenic fungi, which has stronger growth inhibition.

  On the other hand, as pyridine derivatives having a bicyclic skeleton, imidazopyridine, triazolopyridine, pyrazolopyridine and its derivatives are known to have pharmacological activity in a very wide range of regions, and imidazopyrimidine and pyrazolopyridine are known. There are reports that pyrimidine derivatives show antifungal action against fungi causing plant diseases (Patent Documents 2 and 3 and Non-Patent Document 7).

Also, benzoxazole derivatives have been reported as 1,6-β-glucan synthase inhibitors (Patent Document 5).
US Patent Application Publication No. 2005/0113397 US Pat. No. 7,211,545 US Patent Application Publication No. 2007-0191395 Japanese Patent Laid-Open No. 19-204458 European Patent Application Publication No. 1932837 Journal of Antibiotics, 36, 1539 (1983) Journal of Medicinal Chemistry, 38, 3271 (1995) Journal of Antibiotics, 45, 1875 (1992) Journal of Biochemistry, Volume 105, 606 (1989) Journal of Medicinal Chemistry, 37, 222 (1994) Journal of Antibiotics, Vol. 52, p. 674 (1999) Journal of Medicinal Chemistry, Vol. 18, page 1253 (1975)

  An object of the present invention is to provide a compound capable of specifically or selectively expressing an antifungal action based on an action mechanism of 1,6-β-glucan synthesis inhibition, such a compound, a salt thereof, or a compound thereof. It is providing the antifungal agent containing the hydrate of this.

The present inventors conducted a search for a compound for the purpose of obtaining a compound exhibiting antifungal activity by inhibiting 1,6-β-glucan synthase, and used it as an index of [ ¹⁴ C] -glucose uptake. Through a molecular synthesis inhibition test, a compound having an inhibitory action on 1,6-β-glucan synthesis was found. It was verified whether a group of compounds structurally similar to the compound exhibits antifungal action (growth inhibitory activity) against pathogenic fungi, and as a result, a triazolopyridine derivative represented by the formula (I), and It has been found that the salts and hydrates exhibit an antifungal action whose action mechanism is inhibition of 1,6-β-glucan synthesis. In particular, it has been found that it exhibits antifungal activity against Candida, which is a typical causative bacterium of deep mycosis, and has completed the present invention.

That is, the present invention includes the following aspects.
1. A compound represented by the following formula (I), a salt thereof, or a hydrate thereof.

{ ^Where R ^l is
1) an amino group,
2) an alkylamino group having an alkyl group having 1 to 6 carbon atoms,
3) a dialkylamino group having an alkyl group having 1 to 6 carbon atoms, which may be the same or different,
4) an aminomethyl group,
5) an alkylaminomethyl group having an alkyl group having 1 to 6 carbon atoms, or 6) a dialkylaminomethyl group having an alkyl group having 1 to 6 carbon atoms which may be the same or different,
Represents a group selected from the following [a] to [c] having a basic substituent:
[A]: a saturated or partially saturated heterocyclic group containing a hetero atom 1 or 2 which may be selected from a hetero atom of a group consisting of a nitrogen atom, an oxygen atom and a sulfur atom,
[B]: a 5-membered or 6-membered cyclic hydrocarbon group which may contain a double bond,
[C]: The following formula:
-X ¹ - (alkyl group having 1 to 6 carbon atoms)
(Wherein, ^{X 1} is an oxygen atom, a sulfur atom, -CH ₂ -, or the formula:
Means a structure represented by -N ( ^-Rll )-,
R ^ll on the nitrogen atom represents hydrogen, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group or an aralkyl group having 7 to 9 carbon atoms, from 3 to 6 carbon atoms. Wherein the heterocyclic group and the cyclic hydrocarbon group in [a] or [b] may be selected from [Substituent Group 1] redundantly, or one or more groups May have
[Substituent group 1]:
Halogen atoms,
Hydroxyl group,
A carboxy group,
An alkyl group having 1 to 6 carbon atoms,
A halogenoalkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkoxymethyl group having 2 to 7 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms,
An aralkyloxy group having 7 to 9 carbon atoms,
An aralkyloxycarbonyl group having 8 to 10 carbon atoms, and the following formula:
^{-C (= O) -N (-R} 12) R 13
(Wherein, R ¹² and R ¹³ on the nitrogen atom each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms). ;
R ² is
Halogen atoms,
A hydroxymethyl group,
Formyl group,
A dialkylamino group having 1 to 6 carbon atoms which may be the same or different,
An alkyl group having 1 to 8 carbon atoms,
An alkenyl group having 2 to 8 carbon atoms,
An alkynyl group having 2 to 8 carbon atoms,
An alkoxycarbonyl group having 2 to 8 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms,
A cycloalkenyl group having 5 to 6 carbon atoms,
Monocyclic or bicyclic aryl groups,
A monocyclic or bicyclic heteroaryl group (including 1 to 4 heteroatoms which may be selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, or the following formula:
-X ² -R ²¹
[Wherein, X ² represents —C (═O) —, — (CH ₂ ) _n —, —C (═O) —N (—R ²² ) —, or —N (—R ²³ ) —C ( = O)-
n means any integer from 1 to 3,
R ²¹ is a monocyclic or bicyclic aryl group, or a monocyclic or bicyclic heteroaryl group (overlapping selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom) 1 to 4 heteroatoms that may be present.)
R ²² and R ²³ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. ] Represents a group represented by
These alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, and heteroaryl group have one or more groups that may be selected from [Substituent Group 2]. May be;
[Substituent group 2]:
Halogen atoms,
An amino group,
Hydroxyl group,
A carboxy group,
Nitrile group,
A halogenomethyl group,
A hydroxymethyl group,
An alkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms and the following formula:
^{-C (= O) -N (-R} 24) R 25
(Wherein, R ²⁴ Oyobi R ²⁵ on the nitrogen atom are each independently hydrogen atom, an aryl group an alkyl group or a C 6 to 10, from 1 to 6 carbon atoms.) Represented by Group;
Here, the amino group of [Substituent group 2] is an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 7 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms. 1 or 2 selected from the group consisting of an aralkyl group having 7 to 12 carbon atoms, an aromatic heterocyclic group, an alkylsulfonyl group having 1 to 6 carbon atoms, and an arylsulfonyl group having 6 to 10 carbon atoms A group may be substituted as a substituent, and when the amino group has two substituents, they may be bonded to each other to form a cyclic structure;
R ³ is
Hydrogen atom,
Halogen atoms,
A linear or branched alkyl group having 1 to 4 carbon atoms,
A cyclic alkyl group having 3 or 4 carbon atoms,
An alkoxy group having 1 to 4 carbon atoms,
Means a dialkylamino group, a halogenomethyl group, or an alkoxymethyl group having a C1 to C3 alkoxy group having the same or different alkyl chain and having a total of 2 to 4 carbon atoms;
R ⁴ and R ⁵ are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a monocyclic or bicyclic aryl group, a monocyclic or bicyclic ring A heteroaryl group of the formula, a group represented by the formula: —C (═O) —R ⁴¹ (wherein R ⁴¹ represents an alkyl group having 1 to 6 carbon atoms), or both And may include a nitrogen atom to which R ⁴ and R ⁵ are bonded to form a saturated, partially saturated or unsaturated ring having 3 to 7 carbon atoms, and a nitrogen atom or oxygen atom in the ring. , And one or more heteroatoms selected from the group consisting of sulfur atoms may be included, but this ring structure may have a substituent;
Provided that R ⁴ and R ⁵ are simultaneously hydrogen atoms;
Here, the alkyl group, the cycloalkyl group, the aryl group, the heteroaryl group, and the saturated ring, the partially saturated ring, or the unsaturated ring of R ⁴ or R ⁵ described above are duplicated from [Substituent group 3]. May have one or more groups which may be selected;
[Substituent group 3]:
Halogen atoms,
An amino group,
Hydroxyl group,
Formyl group,
A carboxy group,
Nitrile group,
A halogenomethyl group,
A hydroxymethyl group,
An alkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms;
X ¹ and X ² are each independently
A nitrogen atom or
Halogen atoms,
An alkoxy group having 1 to 6 carbon atoms,
An optionally substituted alkyl group having 1 to 6 carbon atoms,
Or it means a carbon atom that may be substituted with an ester group,
Either ^one of X ¹ and X ² is necessarily a nitrogen atom;
Here, the substituent of the alkyl group is one or more groups selected from the following group of substituents;
Halogen atoms,
An amino group,
Nitro group,
Hydroxyl group,
Mercapto group,
A carboxy group,
A cyano group,
An alkoxy group having 1 to 6 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms and an aryl group having 6 to 10 carbon atoms;
When the substituent on the carbon atom is an ester, these are
An alkyl ester having 1 to 6 carbon atoms,
Aryl esters having 6 to 10 carbon atoms,
Or an aralkyl ester composed of an alkyl group having 1 to 6 carbon atoms and an aryl group having 6 to 10 carbon atoms;
Furthermore, the aryl moiety of these aryl esters and aralkyl groups may be substituted with one or more groups selected from the group of the following substituents;
Halogen atoms,
An amino group,
Nitro group,
Hydroxyl group,
Mercapto group,
A carboxy group,
A cyano group,
An alkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms and an aryl group having 6 to 10 carbon atoms;
Means. }
2. 1. X ¹ and X ² are both nitrogen atoms. Or a salt thereof, or a hydrate thereof.
3. R ¹ has a basic substituent, a nitrogen atom, an oxygen atom, and a heteroatom of the group consisting of sulfur atoms, including a good heteroatom 1 or 2 is selected overlap, saturated or partially saturated heterocyclic 1. a ring group, Or 2. Or a salt thereof, or a hydrate thereof.
4). 1. R ¹ is a nitrogen-containing heterocyclic group having a basic substituent. Or 2. Or a salt thereof, or a hydrate thereof.
5). 1. R ¹ is a pyrrolidinyl group, cyclopentyl group, or cyclopentenyl group having a basic substituent. Or 2. Or a salt thereof, or a hydrate thereof.
6). 1. R ² is an aryl group which may have a substituent. To 5. The compound as described in any one of these, its salt, or those hydrates.
7). 1. R ² is a phenyl group which may have a substituent. To 5. The compound as described in any one of these, its salt, or those hydrates.
8). 1. R ³ is an alkyl group having 1 to 4 carbon atoms which may have a substituent. To 7. The compound as described in any one of these, its salt, or those hydrates.
9. 1. R ³ is a methyl group. To 7. The compound as described in any one of these, its salt, or those hydrates.
10. Any one of R ⁴ and R ⁵ is an alkyl group having 1 to 6 carbon atoms which may have a substituent; To 9. The compound as described in any one of these, its salt, or those hydrates.
11. Any one of R ⁴ and R ⁵ is an acyl group having 2 to 7 carbon atoms which may have a substituent; To 9. The compound as described in any one of these, its salt, or those hydrates.
12 1. R ⁴ and R ⁵ are a saturated or aromatic ring having 3 to 7 carbon atoms and containing a nitrogen atom to which R ⁴ and R ⁵ are bonded together. To 9. The compound as described in any one of these, its salt, or those hydrates.
13. Above 1. To 12. A medicament comprising the compound according to any one of the above, a salt thereof, or a hydrate thereof.
14 Above 1. To 12. An infectious disease therapeutic agent comprising the compound according to any one of the above, a salt thereof, or a hydrate thereof.
15. Above 1. To 12. The antifungal agent containing the compound as described in any one of these, its salt, or those hydrates.
16. Above 1. To 12. A method for treating an infection using the compound according to any one of the above, a salt thereof, or a hydrate thereof.
17. Above 1. To 12. Use for the treatment of the infection which uses the compound as described in any one of these, its salt, or those hydrates.

  The present invention provides a compound that can exhibit an antifungal action based on the action mechanism of 1,6-β-glucan synthesis inhibition in a broad spectrum and specifically or selectively, and such a compound, salt thereof Or a medicament containing the hydrate thereof, particularly an infectious disease therapeutic agent or an antifungal agent.

Definitions of terms used in the present specification are as follows. Among these, it may be selected from these according to the limitation of each of the substituents R ¹ to R ⁵ .

  The alkyl moiety in the “alkyl group” or a substituent containing an alkyl moiety (for example, an alkoxy group, etc.) may be either linear or branched. Specifically, as an alkyl group, methyl group, ethyl group, normal propyl group, normal butyl group, normal pentyl group, normal hexyl group, normal heptyl group, normal octyl group, normal nonyl group, normal undecyl group, Normal dodecyl group, normal tridecyl group, normal tetradecyl group, normal pentadecyl group, normal hexadecyl group, normal heptadecyl group, normal octadecyl group, isopropyl group, isobutyl group, secondary butyl group, tertiary butyl group , Isopentyl group, neopentyl group, tertiary pentyl group, isohexyl group, 1,1-dimethylpropyl group, n-heptyl group, n-octyl group and the like.

  “Cycloalkyl group” means a monocyclic or bicyclic cyclic alkyl group, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a bicyclo [3.2.1] oct-2. -An yl group etc. can be mentioned.

  The “alkenyl group” may be linear or branched and has one or more carbon-carbon double bonds. Specifically, vinyl group, propenyl group, buten-1-yl group, isobutenyl group, penten-1-yl group, 2-methylbuten-1-yl group, 3-methylbuten-1-yl group, hexene-1 -Yl group, hepten-1-yl group, octen-1-yl group and the like can be mentioned.

  “Cycloalkenyl group” refers to a monocyclic or bicyclic alkenyl group such as 1-cyclopenten-1-yl group, 1,3-cyclopentadien-1-yl group, 2-norbornene-2- Yl group and the like.

  The “alkynyl group” may be linear or branched and has one or more carbon-carbon triple bonds. Specific examples include an ethynyl group and a propynyl group.

  “Halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

The “aryl group” means a monovalent group obtained by removing one hydrogen atom from an aromatic ring of an aromatic hydrocarbon. The aromatic ring constituting the aryl group may be either a single ring or a condensed ring.
For example, a phenyl group, a naphthyl group, an anthryl group, an azulenyl group, etc. can be mentioned.

  The “aralkyl group” means a group in which one or more hydrogen atoms of an alkyl group are substituted with the above aryl group. For example, a benzyl group, a benzhydryl group, a trityl group, etc. can be mentioned.

  “Heterocyclic group” means a group derived from a saturated, partially saturated, or unsaturated heterocyclic compound, and may be monocyclic, bicyclic, or spirocyclic. Examples of the heterocyclic compound that gives a heterocyclic group include aziridine, azetidine, pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazole, triazole, tetrazole, pyrazole, imidazolidine, pyrazolidine, oxazole, isoxazole, thiazole, Examples include isothiazole, pyridine, dihydropyridine, tetrahydropyran, piperidine, pyridazine, pyrimidine, triazine, pyrazine, piperazine, pyrrolidone, dioxane, pyran, morpholine, benzofuran, indolizine, benzothiophene, indole, naphthyridine, quinoxaline, quinazoline, and chroman. Furthermore, what is represented by the following formula can be illustrated.

(In the formula, R ⁵¹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, or a cycloalkyl group having 3 to 6 carbon atoms. formula:
-(C (-R ⁷¹ ) R ⁷² ) _n2 means a substituent represented by N (-R ⁶¹ ) R ⁶² or -N (-R ⁸¹ )-(CH (-R ⁷¹ ) R ⁷² ) _n2 ,
b represents an integer of 0, 1, or 2;
n2 represents an integer of 0, 1 or 2;
R ⁶¹ and R ⁶² are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a halogenoalkyl group having 1 to 6 carbon atoms, an amino acid, a dipeptide, or 3 to 5 amino acids. Means the polypeptide
R ⁷¹ and R ⁷² are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 6 carbon atoms, or an amino group having 1 to 6 carbon atoms. An alkyl group, an alkoxyalkyl group having 2 to 12 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an optionally substituted phenyl group, or an optionally substituted carbon group having 3 to 10 carbon atoms A heteroaryl group is meant. )
R ⁵¹ is preferably a hydrogen atom or an alkyl group, and the alkyl group is preferably a methyl group, an ethyl group, a normal propyl group, or an isopropyl group.
The R ⁶¹ and R ^62, a hydrogen atom or an alkyl group is preferable, as the alkyl group, methyl group, ethyl group, normal propyl group or an isopropyl group, is preferred.
R ⁷¹ and R ⁷² are each independently preferably a hydrogen atom, an alkyl group, a halogenoalkyl group, an alkoxylalkyl group, a cycloalkyl group, or a phenyl group. Among these, a hydrogen atom, a methyl group, an ethyl group, a fluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a methoxymethyl group, a cyclopropyl group, a cyclobutyl group, or a phenyl group is more preferable.

R ⁷¹ and R ⁷² may be integrated to form a polymethylene chain, and may include a carbon atom to which they are bonded to form a ring structure having 3 to 6 carbon atoms. Further, this ring may contain a nitrogen atom as an atom constituting the ring. Preferred ring structures include cyclopropyl, cyclobutyl, or cyclopentyl.

  The “heteroaryl group” particularly means a group having aromaticity (or aromaticity) among the above-described heterocyclic groups, and means a group called “aromatic heterocycle”. For example, a 5-membered or 6-membered monocyclic ring, a bicyclic benzo-fused ring system or a hetero-heterocyclic ring system, a 5-6 condensed ring system, or a 6-6 condensed ring system The thing etc. can be mentioned. For example, pyrrolyl group, furyl group, thienyl group, imidazolyl group, triazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, tetrazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, triazinyl group, pyrazinyl group, A benzofuryl group, an indolyl group, a naphthyridinyl group, a quinoxalinyl group, a quinazolinyl group, etc. can be mentioned.

  Further, in the present specification, the “aromatic heterocyclic group” is a monocyclic 5-membered ring or 6-membered ring among the above heteroaryl groups, and a group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. In particular, it means one containing 1 to 4 heteroatoms selected from For example, pyrrolyl, furyl, thienyl, imidazolyl, triazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, triazinyl, pyrazinyl, etc. Can do.

  In the present specification, regarding the amino group, hydroxyl group, mercapto group, etc., the “protecting group” in the case of “may be protected by a protecting group” is not particularly limited as long as it is widely used in this field. Are, for example, alkoxycarbonyl groups such as tertiary butoxycarbonyl group and 2,2,2-trichloroethoxycarbonyl group; aralkyloxy such as benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group and paranitrobenzyloxycarbonyl group Carbonyl groups; acyl groups such as acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group; tertiary butyl group, benzyl group, paranitrobenzyl group, paramethoxy Alkyl groups such as benzyl group and triphenylmethyl group; Are aralkyl groups; ethers such as methoxymethyl group, tertiary butoxymethyl group, tetohydropyranyl group, 2,2,2-trichloroethoxymethyl group; trimethylsilyl group, isopropyldimethylsilyl group, tertiary butyldimethyl group Mention may be made of (alkyl and / or aralkyl) substituted silyl groups such as silyl groups, tribenzylsilyl groups, tertiary butyldiphenylsilyl groups. Further, the amino group may be protected as phthalimide.

  “Amino acid, dipeptide, or group derived from a polypeptide consisting of 3 to 5 amino acids” or “amino acid, dipeptide, or polypeptide consisting of 3 to 5 amino acids bound to an amino group” For example, amino acids, dipeptides, and tripeptides, or substituted carbonyl groups derived therefrom. That is, amino acids such as glycine, alanine, aspartic acid, dipeptides such as glycine-glycine, glycine-alanine, alanine-alanine, and tripeptides such as glycine-glycine-alanine, glycine-alanine-alanine, or from these Mention may be made of substituted carbonyl groups which are derived.

The partial structure and substituent of the compound represented by (I) of the present invention will be described.
Formula (I):

In a compound represented by:
R ^l is a basic group. That is, any group may be used as long as the basic group shown as the group of groups [c] to the group of groups [c] below is substituted with a basic substituent. Examples of the basic substituent constituting the basic group include the following. Ie;
1) an amino group,
2) an alkylamino group having an alkyl group having 1 to 6 carbon atoms,
3) a dialkylamino group having an alkyl group having 1 to 6 carbon atoms, which may be the same or different,
4) an aminomethyl group,
5) an alkylaminomethyl group having an alkyl group having 1 to 6 carbon atoms, or 6) a dialkylaminomethyl group having an alkyl group having 1 to 6 carbon atoms which may be the same or different,
It is.

  Examples of 2) include a methylamino group, an ethylamino group, a normal propylamino group, an isopropylamino group, a normal butylamino group, an isobutylamino group, and a secondary butylamino group. The alkyl group substituted for the amino group may be either linear or branched.

  As an example of 3), the nitrogen atom of the alkylamino group shown in 2) may be further alkylated with an alkyl group having 1 to 6 carbon atoms. Such a second alkyl group may be a methyl group. , Ethyl group, normal propyl group, isopropyl group, normal butyl group, isobutyl group and sec-butyl group. Two alkyl groups may be the same or different.

Aminomethyl group and dialkylamino methyl group described in 5) and 6), the above 2) and 3) alkylamino group or a dialkylamino group and a methylene group described in (-CH 2 _-) because those composed Good.

  The basic substituent is preferably an alkylamino group or a dialkylamino group. Specifically, a methylamino group, an ethylamino group, and a dimethylamino group are preferable.

The basic group constituting the basic group is a group of groups shown as the following [a] to [c]. A basic substituent is substituted on these groups to form a basic group.
[A]: a saturated or partially saturated heterocyclic group containing a hetero atom 1 or 2 which may be selected from a hetero atom of a group consisting of a nitrogen atom, an oxygen atom and a sulfur atom,
[B]: a 5-membered or 6-membered cyclic hydrocarbon group which may contain a double bond,
[C]:
The following formula:
-X ¹ - (alkyl group having 1 to 6 carbon atoms)
(Wherein, ^{X 1} is an oxygen atom, a sulfur atom, -CH ₂ -, or the formula:
-N ( ^-Rll )-
Means structure represented by the, R ^ll on the nitrogen atom means a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aralkyl group having 7 to 9 carbon atoms . )
A group represented by
Here, the heterocyclic group and cyclic hydrocarbon group of [a] and [b] may have one or one or more groups which may be selected from [Substituent Group 1]. ;
[Substituent group 1]:
Halogen atoms,
Hydroxyl group,
A carboxy group,
An alkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms,
An aralkyloxy group having 7 to 9 carbon atoms,
Aralkyloxycarbonyl group having 8 to 10 carbon atoms, or the following formula:
^{-C (= O) -N (-R} 12) R 13
(Wherein R ¹² and R ¹³ on the nitrogen atom each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms.)
A group represented by

The saturated or partially saturated heterocyclic group shown in [a] is selected from the heterocyclic groups shown above.
1. The heteroatom is a heteroatom 1 or 2 that may be selected from a group consisting of a nitrogen atom, an oxygen atom and a sulfur atom,
2. Saturated or partially saturated, and
3. A monocyclic 4- to 6-membered heterocyclic group may be selected.

  For example, an azetidinyl group, a pyrrolidinyl group, and a piperidinyl group can be exemplified, and among these, a pyrrolidinyl group and a piperidinyl group can include a heterocyclic group having a sulfur atom or an oxygen atom as a second heteroatom.

  Of these, a 4-membered or 5-membered heterocyclic group having a nitrogen atom as a heteroatom and being a saturated ring is preferable. Further, this heterocyclic group is preferably bonded to the bicyclic mother nucleus at the nitrogen atom.

  As the cyclic hydrocarbon group shown in [b], a cyclopentyl group or a cyclohexyl group, or those containing one double bond in them is preferable, and a cyclopentenyl group or a cyclohexenyl group is preferable. The double bond is preferably located at a position where the carbon atom bonded to the bicyclic mother nucleus becomes one carbon atom of the double bond and is conjugated with the bicyclic mother nucleus.

  With respect to these groups [a] and [b], the substitution position of the basic substituent is preferably the 2-position or the 3-position (the substitution position of [a] and [b] to the bicyclic mother nucleus is 1). And). As the group [a] or [b] having a basic substituent, a 4-membered or 5-membered saturated heterocyclic ring having an alkylamino group, a dialkylamino group, an alkylaminomethyl group, or a dialkylaminomethyl group Or a cyclic hydrocarbon group having a saturated or double bond 1 is preferred. More specifically, a 1-pyrrolidinyl group, 1-cyclopentyl group, or 1-cyclopentenyl group each having a methylamino group or a dimethylamino group at the 3-position; a methylaminomethyl group or a dimethylaminomethyl group at the 2-position, respectively. The 1-pyrrolidinyl group, 1-azetidinyl group, or 1-cyclopentyl group is preferable.

  The carbon atom to which the basic substituent is bonded may further have a substituent. As such a substituent, an alkyl group having 1 to 6 carbon atoms is preferable, a methyl group or an ethyl group is preferable, and a methyl group is more preferable. The basic group constituted as described above is shown below.

Of the chemical formula 4, the chemical formula 4-1 is more preferable.

The group represented by [c] is an alkyl group having X ¹ (nitrogen atom, oxygen atom, methylene, sulfur atom or the like) as a linker with a bicyclic mother nucleus. The alkyl moiety has 1 to 6 carbon atoms and may be linear or branched. The position of the basic substituent on the alkyl may be any, but the one at the end of the alkyl chain is more preferable.

  The linker is preferably a nitrogen atom, and further preferably has an alkyl group as a substituent on the nitrogen atom. The chain length including the linker moiety is preferably a chain length of 3 or 4 atoms.

Things as the basic group of R ^l having a cyclic structure is more preferable. That is, a structure having a basic substituent on the group represented by [a] or [b] is preferable, and specifically, the structure mentioned above.
R ² is
Halogen atoms,
A hydroxymethyl group,
Formyl group,
A dialkylamino group having 1 to 6 carbon atoms which may be the same or different,
An alkyl group having 1 to 8 carbon atoms,
An alkenyl group having 2 to 8 carbon atoms,
An alkynyl group having 2 to 8 carbon atoms,
An alkoxycarbonyl group having 2 to 8 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms,
A cycloalkenyl group having 5 to 6 carbon atoms,
Monocyclic or bicyclic aryl groups,
A monocyclic or bicyclic heteroaryl group (including 1 to 4 heteroatoms which may be selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, or the following formula:
-X ² -R ²¹
[Wherein, X ² represents —C (═O) —, — (CH ₂ ) _n —, —C (═O) —N (—R ²² ) —, or —N (—R ²³ ) —C ( = O)-
n means any integer from 1 to 3,
R ²¹ is a monocyclic or bicyclic aryl group, or a monocyclic or bicyclic heteroaryl group (overlapping selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom) 1 to 4 heteroatoms that may be present.)
R ²² and R ²³ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. ]
Means a group represented by
These alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group and heteroaryl group have one or more groups which may be selected from [Substituent Group 2]. May be;
[Substituent group 2]:
Halogen atoms,
An amino group,
Hydroxyl group,
A carboxy group,
Nitrile group,
A halogenomethyl group,
A hydroxymethyl group,
An alkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms and the following formula:
^{-C (= O) -N (-R} 24) R 25
(Wherein R ²⁴ and R ²⁵ on the nitrogen atom each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms). ;
Here, the amino group of [Substituent group 2] is an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 7 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms. 1 or 2 selected from the group consisting of an aralkyl group having 7 to 12 carbon atoms, an aromatic heterocyclic group, an alkylsulfonyl group having 1 to 6 carbon atoms, and an arylsulfonyl group having 6 to 10 carbon atoms A group may be present as a substituent, and when the amino group has two substituents, they may be bonded to each other to form a cyclic structure.

  Among these, a monocyclic or bicyclic aryl group, or a monocyclic or bicyclic heteroaryl group (which may be selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom redundantly) 1 to 4 heteroatoms are preferred.).

  As the aryl group, a monocyclic group is preferable, and a phenyl group is preferable. This phenyl group may have a substituent, and one or more hydroxyl groups, amino groups, halogen atoms, nitrile groups, alkyls having 1 to 3 carbon atoms, alkoxy groups having 1 to 3 carbon atoms, and the like are substituted. You may do it. The position at which these substituents are substituted is preferably ortho-position or meta-position, particularly preferably meta-position. These are shown below.

The heteroaryl group is preferably a monocyclic 5- or 6-membered heteroaryl group. The 5- or 6-membered heteroaryl group contains 1 or 2 heteroatoms, which may be selected from a nitrogen atom, an oxygen atom, and a sulfur atom as a heteroatom. Examples thereof include a furyl group, a thiazolyl group, a pyridyl group, a pyrimidyl group, and a pyridazyl group.
Of these, a 5-membered heteroaryl group is preferable, and examples include 4-thiazolyl group, 2-furyl group, 3-furyl group, 2-thienyl group, 3-thienyl group, and 1-pyrrole group. Can do. These are shown below.

The heteroaryl group may have a substituent, and an alkyl group having 1 to 6 carbon atoms may be substituted. The alkyl group is preferably a methyl group, and examples thereof include a 2-methyl-4-thiazolyl group and a 3-methyl-4-thienyl group.

R ² is more preferably a phenyl group, a 3-methylphenyl group, a 3-fluorophenyl group, or a 2-methyl-4-thiazolyl group.

As R ^2, an aryl group, preferably a halogen atom other than a heteroaryl group, a bromine atom.

R ³ is
Hydrogen atom,
A linear or branched alkyl group having 1 to 4 carbon atoms,
A cyclic alkyl group having 3 or 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms,
It means an alkoxymethyl group having the same or different alkyl chain and having a dialkylamino group having 2 to 4 carbon atoms in total, a halogenomethyl group, or an alkoxy group having 1 to 3 carbon atoms.

R ³ is preferably a bulky group having about 1 to 4 carbon atoms. For example, methyl group, ethyl group, isopropyl group, cyclopropyl group, cyclobutyl group, dimethylamino group, ethylmethylamino group, diethylamino group, trifluoromethyl group, methoxymethyl group, ethoxymethyl group, methoxyethyl group and the like.

Of these, R ³ is preferably an alkyl group, specifically a methyl group.

R ⁴ and R ⁵ are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a monocyclic or bicyclic aryl group, a monocyclic or bicyclic ring A heteroaryl group of the formula, a group represented by the formula: —C (═O) —R ⁴¹ (wherein R ⁴¹ represents an alkyl group having 1 to 6 carbon atoms), or both To form a saturated, partially saturated or unsaturated ring having 3 to 7 carbon atoms, including a nitrogen atom to which R ⁴ and R ⁵ are bonded, and a nitrogen atom, an oxygen atom, and One or more heteroatoms selected from the group consisting of sulfur atoms may be contained, but this ring structure may further have a substituent. However, the case where R ⁴ and R ⁵ are simultaneously hydrogen atoms is excluded.

Here, the alkyl group, the cycloalkyl group, the aryl group, the heteroaryl group, and the saturated ring, the partially saturated ring, or the unsaturated ring of R ⁴ or R ⁵ described above are duplicated from [Substituent group 3]. May have one or more groups which may be selected;
[Substituent group 3]:
Halogen atoms,
An amino group,
Hydroxyl group,
Formyl group,
A carboxy group,
Nitrile group,
A halogenomethyl group,
A hydroxymethyl group,
An alkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms;
R ⁴ and R ⁵ are each independently preferably a hydrogen atom or an alkyl group, preferably a hydrogen atom, a methyl group, or an ethyl group. Alternatively, they may be a saturated ring group having 3 to 7 carbon atoms, a partially saturated ring group, or an unsaturated ring group containing a nitrogen atom to which R ⁴ and R ⁵ are bonded together. What is shown.

[Wherein R ⁸¹ is a hydrogen atom, a halogen atom, a hydroxyl group, a thiol group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 7 carbon atoms, an alkynyl group having 2 to 7 carbon atoms, or a group having 1 carbon atom. An alkoxy group having 6 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a bicycloalkyl group having 3 to 6 carbon atoms which may have a halogen atom, or a halogen atom; Represents an optionally spirocycloalkyl group, and X represents a carbon atom, an oxygen atom, a sulfur atom, a nitrogen atom, or a phosphorus atom. ]
Of these,

The following are more preferable.

X ¹ and X ² are each independently a nitrogen atom, a halogen atom, an alkoxy group having 1 to 6 carbon atoms, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an ester This means a carbon atom which may be substituted with a group, but one of X ¹ and X ² is necessarily a nitrogen atom.

Here, the substituent of the alkyl group is one or more groups selected from the group of the following substituent group;
Halogen atom, amino group, nitro group, hydroxyl group, mercapto group, carboxy group, cyano group, alkoxy group having 1 to 6 carbon atoms, alkylthio group having 1 to 6 carbon atoms, acyl group having 2 to 7 carbon atoms, carbon number 2 An alkoxycarbonyl group having from 7 to 7, a cycloalkyl group having 3 to 6 carbon atoms, and an aryl group having 6 to 10 carbon atoms;
When the substituent on the carbon atom is an ester, these are alkyl esters having 1 to 6 carbon atoms, aryl esters having 6 to 10 carbon atoms, or alkyl groups having 1 to 6 carbon atoms and aryl groups having 6 to 10 carbon atoms. An aralkyl ester composed of:
Furthermore, the aryl moiety of these aryl esters and aralkyl groups may be substituted by one or more groups selected from the group of the following substituent groups;
Halogen atom, amino group, nitro group, hydroxyl group, mercapto group, carboxy group, cyano group, alkyl group having 1 to 6 carbon atoms, alkoxy group having 1 to 6 carbon atoms, alkylthio group having 1 to 6 carbon atoms, carbon number 2 To C7 acyl group, C2 to C7 alkoxycarbonyl group, C3 to C6 cycloalkyl group, and C6 to C10 aryl group.

X ¹ and X ² are preferably both nitrogen atoms.

One of the preferred combinations of each substituent of the compound represented by the formula (I) of the present invention is as follows: R ² is an aryl group; R ¹ is a saturated or partially saturated cyclic substituent having a substituent; R ³ is an alkyl group having 1 to 3 carbon atoms; R ⁴ and R ⁵ are (1) each independently a hydrogen atom or an alkyl group (except when both are hydrogen atoms), (2) both are integrated A substituent selected from a substituent group selected from a saturated, partially saturated, or unsaturated ring having 3 to 7 carbon atoms, including the nitrogen atom to which R ⁴ and R ⁵ are bonded.

In one more preferred embodiment, R ² is an aryl group; R ¹ is saturated or partially substituted with an alkyl group having 1 to 6 carbon atoms, an amino group, an alkylamino group having 1 to 6 carbon atoms or a dialkylamino group A saturated nitrogen-containing heterocyclic group or a cyclic hydrocarbon group; R ³ is an alkyl group having 1 to 3 carbon atoms; R ⁴ and R ⁵ are each independently (1) a hydrogen atom or an alkyl group (both are hydrogen atoms) (Except in some cases), (2) a group of substituents selected from a saturated, partially saturated, or unsaturated ring having 3 to 7 carbon atoms, including a nitrogen atom to which R ⁴ and R ⁵ are bonded together. A substituent selected from the group consisting of:

One of the preferable specific embodiments of the preferred combinations of the substituents of the compound represented by the formula (I) of the present invention is as follows: R ² is a phenyl group; R ¹ is an alkyl group having 1 to 6 carbon atoms, an amino group A pyrrolidinyl group substituted with an alkylamino group having 1 to 6 carbon atoms or a dialkylamino group; R ³ is a methyl group; R ⁴ and R ⁵ are a hydrogen atom and an ethyl group, both a methyl group, both an ethyl group, or The following formula is formed by integrating both:

(Wherein R ⁸¹ has the same definition as described above.)
A substituent selected from the group consisting of:

One of the more preferable specific embodiments of a preferable combination of each substituent of the compound represented by the formula (I) of the present invention is as follows: R ² is a phenyl group; R ¹ is a methyl group or an ethyl group, and a methylamino group. A pyrrolidinyl group substituted with: R ³ is a methyl group; R ⁴ and R ⁵ are a hydrogen atom and an ethyl group, both methyl groups, both ethyl groups, or a combination of the following formulas:

(Wherein R ⁸¹ has the same definition as described above.)
A substituent selected from the group consisting of:

The compound of the present invention represented by the formula (I) can be produced by various methods. As a preferable example, a typical production method in which both X ¹ and X ² are nitrogen atoms is shown and described below. However, it is not limited to these. In the reaction, the substituent is protected with a protecting group as necessary, and the conversion order of each substituent (functional group) is not particularly limited. In addition, the definitions of R ¹ to R ⁵ in the following production methods are the same as the definition of the substituent of formula (I).

(In the formula, R ′ is an alkyl group having 1 to 6 carbon atoms.)
Step 1 is a step of producing compound (3) by allowing a acetonitrile derivative of triazole as compound (1) and a β-ketoester derivative as compound (2) to act and condense and cyclize.

  Step 2 is a step of producing compound (4) using the hydroxyl group of compound (3) as a leaving group. Examples of the leaving group X include halogens (Cl, Br, I, F), sulfonic acid esters (methanesulfonyl, benzenesulfonyl, toluenesulfonyl, trifluoromethanesulfonyl, etc.), ethers (methyl ether, ethyl ether, etc.) Aromatic ethers such as alkyl ethers or phenyl ethers, etc.) and esters (acetates, propionates, benzoates, etc.) are used. Preferred are halogens, and more preferred is a chloro group.

Step 3 is a step of producing the compound of the present invention represented by formula (I) by reacting compound (4) with amine derivative (5). When R ¹ is a cycloalkenyl group, a cycloalkyl group, or an alkyl group, Suzuki cross-coupling reaction (Chem. Rev., 95, 2457, 1995), Stille cross-coupling reaction (Angew. Chem. Int. Ed. Engl., 25, 508, 1986) and the like.

On the other hand, the substituent on the acetonitrile derivative of triazole can be converted to the target substituent by the following production method using an ester group. R ⁶ includes alkyl groups (methyl group, ethyl group, tert-butyl group and the like), phenyl groups and substituted derivatives thereof such as 4-methoxyphenyl group, allyl group, vinyl group, benzyl group and 4-methoxybenzyl group. Substituted derivatives thereof such as Preferred are lower alkyl groups such as a methyl group and an ethyl group.

  Process 4 is a process which manufactures a carboxylic acid body (7) by hydrolyzing an ester group.

  Step 5 is a step of producing the amine body (8) by the Curtius rearrangement reaction or the Hoffman rearrangement reaction of the carboxyl group of (7).

  Step 6 is a step for producing the compound of the present invention represented by (I) by modification such as alkylation or acylation of compound (8).

  On the other hand, the compound of the present invention represented by (I) can also be synthesized via the halogen derivative (9) shown in Step 7. The halogen compound (9: X = Cl, Br, I) can be produced by using the amino compound (8) by utilizing the Sandmeyer reaction or the like.

  Step 8 is a step for producing the compound of the present invention represented by (I) by substituting a primary or secondary amine for the halogen compound (9).

The substituent on the acetonitrile derivative of triazole can be converted to an alkyloxymethyl group (R ⁷ OCH ₂ ) and then converted to the desired substituent by the production method shown below. R ⁷ includes alkyl groups (methyl group, ethyl group, tert-butyl group and the like), phenyl groups and substituted derivatives thereof such as 4-methoxyphenyl group, and substituted derivatives such as benzyl group and 4-methoxybenzyl group. Used.

Step 9 is a step of producing the primary alcohol (11) by removing the alkyl group of the compound (10). When R ⁷ is an alkyl group (methyl group, ethyl group, tert-butyl group, etc.), the dealkylating reagent includes Lewis acids such as BBr ₃ and AlCl ₃ , R ⁷ is a phenyl group and 4-methoxyphenyl In the case of substituted derivatives thereof such as cerium ammonium nitrate, and in the case where R ⁷ is a substituted derivative such as benzyl group and 4-methoxybenzyl group, by hydrogenation in the presence of Pd, Rh or the like, or 4-methoxy In the case of a benzyl group or the like, DDQ or the like is used.

  Step 10 is a step of producing a carboxylic acid body (7) by oxidizing the hydroxyl group of the compound (11).

  On the other hand, the carboxylic acid form (7) can also be produced from the compound (10) via the halogen form (12: X = Cl, Br, I) as shown in Step 11.

  Step 12 is a step of producing the carboxylic acid body (7) by oxidizing the halogen body (12).

(Wherein R ⁶ and R ⁷ are the same as defined in the above-mentioned production methods 2 and 4, respectively.)
When R ¹ is a cycloalkenyl group, a cycloalkyl group, or an alkyl group, an acetonitrile derivative of triazole (R ⁸ = —C (O) OR ⁶ , —CH ₂ OR ⁷ , —NR ⁴ ) as the compound (1) The compound of the present invention represented by the formula (I) can also be produced directly from the diketone derivative which is R ⁵ ) and the compound (14).

  The substituents introduced in Step 1 to Step 13 can be appropriately protected with a functional group, removed with a protective group, or converted into a functional group, if necessary.

  The compounds of the present invention exhibit an antifungal action specifically (selective) and are active against fungi that cause various fungal infections to treat and prevent diseases caused by these pathogens. Or can be mitigated.

  Examples of fungi in which the compounds of the present invention are effective include Candida albicans, Candida glabrata, Candida crusei, Candida tropicalis and other Candida species, Cryptococcus neoformans and other Cryptococcus spp., Aspergillus fumigatus, Aspergillus・ Plascoccidioides such as Aspergius genus such as Flabusus, Pneumocystis carinii, Kumonskabi genus, Absidia genus, Histoplasma genus such as Histoplasma capsultrum, Coccidioides genus such as Coccidioides imitis, Blast Myces genus, Paracoccidioides brasiliensis etc. Genus, Penicillium, Pseudolesia, Sporotrix, Black Fungus, Trichophyton, Microsporum, Epidermophyton, Malassezia, Ho Senkaea genus Fusarium, Paecilomyces spp, Trichosporon such Trichosporon Kutaneumu, Hiarohora genus can be exemplified Cladosporium and the like. Furthermore, Saccharomyces cerevisiae, Candida albicans, Candida glabrata, Candida crusei, Candida tropicalis, Cryptocox neoformans, Trichosporon tantaneum, Aspergillus fumigatus and the like can be exemplified.

  In addition, diseases caused by these pathogens include visceral mycosis (deep mycosis) such as candidiasis, cryptococcosis, aspergillus (filamentous fungi), actinomyces (actinomycosis), nocardiosis, Mucormycosis (zygomycosis), geotrichumosis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, blastomysosis, penicillosis, etc. Specifically, mycosis, respiratory mycosis, digestive mycosis, urinary tract Mycosis, fungal meningitis, etc., deep dermatomycosis, sporotricosis, chromomycosis (melanocytic mycosis), mycoma (mysetoma), etc. Examples include deep ringworm, refractory ringworm, onychomycosis, folding screen, cutaneous candidiasis, oral candidiasis and the like.

The administration method, dose, and administration frequency of the medicament of the present invention are not particularly limited, and can be appropriately selected according to various conditions such as the type of pathogenic fungus, the age, weight, and symptoms of the patient. Usually, for an adult, 0.1 to 100 mg / kg may be divided into 1 to several times a day by oral or parenteral (injection, infusion, etc.) administration.
The compounds of the present invention are also effective against various fungi that cause fungal infections in animals.

  Utilizing the antifungal action of the compound of the present invention against pathogenic fungi, the compound containing the compound of the present invention, a salt thereof, or a hydrate thereof can be used as an agent for treating infectious diseases or an antifungal agent It can also be applied to animal drugs, marine products, or antifungal preservatives.

  You may use the compound of this invention, its salt, or these hydrates for the manufacture of the pharmaceutical containing these, an infectious disease therapeutic agent, or an antifungal agent. For example, the compound of the present invention, a salt thereof, or a hydrate thereof may be used for the production of an injection or solution provided in a solution state. In addition, a pharmaceutical, an infectious disease treatment agent, or an antifungal agent is produced by a conventional method of formulation such as compounding the compound of the present invention, a salt thereof, or a hydrate thereof and adding an additive as necessary. can do.

Examples of the dosage form of the antifungal agent comprising the compound of the present invention as a salt thereof or a hydrate thereof include tablets, powders, granules, or capsules, solutions, syrups, elixirs, or oily or aqueous. Can be exemplified as an oral preparation.
As injections, stabilizers, preservatives, or solubilizing agents may be used in the preparation. After storing a solution that may contain these adjuvants in a container, use as a solid preparation by lyophilization or the like. It may be a preparation for preparation.

  Examples of the preparation for external use include solutions, suspensions, emulsions, ointments, gels, creams, lotions, and sprays.

  The solid preparation may contain a pharmaceutically acceptable additive together with the compound of the present invention, a salt thereof, or a hydrate thereof. For example, fillers, extenders, binders, disintegrants Further, dissolution promoters, wetting agents, lubricants, and the like can be selected and mixed as necessary to prepare a formulation.

  Examples of liquid preparations include solutions, suspensions, emulsions, and the like, but additives may include suspending agents, emulsifiers, and the like.

  The method of administering the compound of the present invention, a salt thereof, or a hydrate thereof to an animal can be administered directly or mixed into the feed and orally, or after it is made into a solution, directly or in drinking water or feed Examples of such a method include oral administration after addition to the above and administration by injection.

  As a preparation for administering the compound of the present invention, a salt thereof, or a hydrate thereof to an animal, a powder, a fine granule, a soluble powder, or a syrup is appropriately used according to a technique usually used in this field. , Solution or injection.

  When the compound represented by the formula (I) of the present invention has a structure in which an enantiomer (enantiomer) exists, each enantiomer, a racemate that is a mixture of the 1: 1 ratio, and each enantiomer are appropriately mixed. Any enantiomeric mixture present in ratio and having an optical purity of less than 100% is encompassed by the compounds of the invention. Furthermore, when the compound represented by the formula (I) has a structure in which a diastereomer exists, the compound of the present invention includes a single diastereomer and a mixture of diastereomers.

  When the compound represented by the formula (I) has a structure in which an enantiomer is present, it is desirable to administer a compound consisting of a single enantiomer when the compound of the present invention is administered to humans or animals. The term “consisting of a single enantiomer” is understood to include not only the case where the other enantiomer (enantiomer) is not contained at all, but also the case where it can be usually said that it is chemically pure. That is, it is understood that the other enantiomer (enantiomer) may be included as long as it does not affect the physical constant and physiological activity.

  Furthermore, when the compound represented by formula (I) has a structure in which diastereomers are present, it is desirable to administer a compound consisting of a single diastereomer when the compound of the present invention is administered to humans or animals. . The term “consisting of a single diastereomer” is understood to include not only the case where no other diastereomer is contained, but also a case where it can be usually said that it is chemically pure. That is, it is understood that other diastereomers may be included as long as they do not affect physical constants and physiological activities.

  In addition, “stereochemically single” means that an asymmetric carbon atom is contained in a compound or the like, so that it is composed of only one of them when it is in an isomer relation. Indicates. In this case as well, this “single” interpretation is considered in the same manner as described above.

When the compound represented by the formula (I) is an acid derivative having a phenolic hydroxyl group, a carboxy group (carboxylic acid derivative), or a sulfo group (sulfonic acid derivative) in an arbitrary substituent moiety, these acid derivatives are Although it may be in a free form, it may be a salt of a phenolic hydroxyl group, a carboxy group, or a sulfo group.
Examples of these salts include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salt, triethylamine salt and N-methylglucamine salt, Any of inorganic salts and organic salts such as tris- (hydroxymethyl) aminomethane salt may be used. In addition, free forms and salts of these acid derivatives may exist as hydrates.

  On the other hand, when the compound represented by the formula (I) is a basic derivative having an amino group or an amine structure at an arbitrary substituent moiety, these basic derivatives may remain in a free form, but acid addition salts It is good.

  Examples of acid addition salts include hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides, phosphates and other inorganic acid salts, or methanesulfonates and benzenesulfonates. And organic acid salts such as paratoluenesulfonate (sulfonate), acetate, citrate, maleate, fumarate, lactate, and tartrate (carboxylate). Moreover, the free body and salt of these basic derivatives may exist as a hydrate.

  When the compound represented by the formula (I) is a carboxylic acid compound, the derivative in which the carboxylic acid moiety is an ester is useful as a synthetic intermediate or prodrug. For example, alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters and phenyl esters are useful as synthetic intermediates.

  In addition, when the carboxylic acid compound of the present invention is used for antifungal purposes, the ester used as a prodrug is an ester that is easily cleaved in vivo to produce a free form of carboxylic acid, for example, Acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyl ester, choline ester, dimethylaminoethyl ester, 5-indanyl ester and phthalidinyl ester, 5-alkyl-2-oxo-1,3-dioxol-4-yl Mention may be made of methyl esters and oxoalkyl esters such as 3-acetoxy-2-oxobutyl ester.

  Furthermore, the compound represented by the formula (I) is a basic compound having an amino group, and a derivative in which an amino group, a dipeptide or a tripeptide is bound to the amino group is useful as a prodrug.

  As amino acids, dipeptides, and tripeptides used as prodrugs, peptide bonds formed from these carboxy groups and the amino group of formula (I), which is a compound of the present invention, are easily cleaved in vivo to release amines. For example, amino acids such as glycine, alanine, aspartic acid, dipeptides such as glycine-glycine, glycine-alanine, alanine-alanine, and glycine-glycine-alanine, glycine-alanine- Mention may be made of tripeptides such as alanine.

Next, the present invention will be described with reference to examples and reference examples, but the present invention is not limited thereto.
[Reference Example 1]
2- (Methoxymethyl) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl [1,2,4] triazolo [1,5 -a] pyridine-8-carbonitrile (I-1)

tert-Butylmethyl [(3S) -3-methylpyrrolidin-3-yl] carbamate (synthesized according to the method described in WO2007 / 020936) (106 mg, 0.495 mmol) was added to 4N hydrochloric acid-1 at room temperature. , 4-Dioxane solution (4 ml) was added and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was converted into 5-chloro-2- (methoxymethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine- In addition to a solution of 8-carbonitrile (synthesized according to the method described in WO2005 / 077948) (129 mg, 0.41 mmol) and triethylamine (287 μl, 2.06 mmol) in dimethyl sulfoxide (2 ml), an oil bath at 110 ° C. Stir for 3 hours above. After the reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in chloroform, and this was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, insolubles were filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 10: 1). , v / v) and 140 mg (87%) of the title compound were obtained as a brown solid.
ESI-MS m / z: 391 (M + 1) ⁺ .
_{^{1 H-NMR (CDCl 3)}} δ: 1.13 (3H, s), 1.53-1.67 (1H, m), 1.72-1.83 (1H, m), 2.27 (3H, s), 2.28 (3H, s), 3.16 (1H, d, J = 10.5 Hz), 3.20-3.30 (1H, m), 3.31-3.40 (1H, m), 3.42 (1H, d, J = 10.5 Hz), 3.56 (3H, s), 4.75 ( 2H, s), 7.15-7.24 (2H, m), 7.39-7.52 (3H, m).
IR (ATR): 3313, 3057, 2969, 2925, 2879, 2212, 1716, 1606, 1537, 1500, 1495, 1473, 1427, 1365, 1335, 1269, 1188, 1113, 1065, 1016, 966 cm ^-1 .
_{. Anal Calcd for C 22 H 26} N 6 O · 0.25H 2 O:. C, 66.90; H, 6.76; N, 21.28 Found: C, 67.14; H, 6.69; N, 21.70.
[Reference Example 2]
N-{(3S) -1- [8-Cyano-2- (methoxymethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl]- 3-Methylpyrrolidin-3-yl} -N-methyl-2-nitrobenzenesulfonamide (I-2)

2- (Methoxymethyl) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl [1,2,4] triazolo [1,5 -a] Pyridine-8-carbonitrile (I-1) (1.2 g, 3.07 mmol) in pyridine (30 ml) at room temperature with 4-dimethylaminopyridine (75.1 mg, 0.62 mmol) and 2-nitrobenzenesulfonyl Chloride (4.09 g, 18.4 mmol) was added and stirred at 60 ° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in ethyl acetate, and the obtained organic phase was washed with 1N aqueous hydrochloric acid and saturated brine. The organic phase was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 2: 1, v / v), 1.35 g (76%) of the title compound were obtained as a yellow foam.
HRESI-MS m / z: 576.2040 (Calcd for C ₂₈ H ₂₉ N ₇ O ₅ S 576.2029).
¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, s), 1.85-2.08 (2H, m), 2.27 (3H, s), 2.86 (3H, s), 3.28 (1H, d, J = 10.7 Hz ), 3.36-3.53 (2H, m), 3.55 (3H, s), 3.76 (1H, d, J = 10.7 Hz), 4.69 (2H, s), 7.11-7.22 (2H, m), 7.39-7.63 ( 6H, m), 7.90-7.96 (1H, m).
IR (ATR): 2924, 2854, 2218, 1724, 1606, 1541, 1504, 1479, 1444, 1342, 1267, 1215, 1161, 1105, 1016, 960 cm ^-1 .
[Reference Example 3]
N-{(3S) -1- [2- (Bromomethyl) -8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3 -Methylpyrrolidin-3-yl} -N-methyl-2-nitrobenzenesulfonamide (I-3)

N-{(3S) -1- [8-Cyano-2- (methoxymethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl]- 3-methylpyrrolidin-3-yl} -N-methyl-2-nitrobenzenesulfonamide (I-2) (1.35 g, 2.35 mmol) in dichloromethane (12 ml) at room temperature with boron tribromide (1.0 mol) (Dichloromethane solution) (3.52 ml, 3.52 mmol) was added, and the mixture was stirred at room temperature for 20 hours. Saturated brine was added to the reaction solution, this was extracted with ethyl acetate, and the resulting organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 10: 1, v / v), 1.08 g (74%) of the title compound was obtained as a yellow foam.
HRESI-MS m / z: 624.1005, 626.0992 (Calcd for C ₂₇ H ₂₆ BrN ₇ O ₄ S 624.1029, 626.1008).
¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, s), 1.86-1.94 (1H, m), 1.98-2.09 (1H, m), 2.26 (3H, s), 2.87 (3H, s), 3.29 -3.46 (3H, m), 3.78 (1H, d, J = 11.0 Hz), 4.58 (2H, d, J = 1.7 Hz), 7.11-7.22 (2H, m), 7.41-7.52 (3H, m), 7.59-7.67 (3H, m), 7.94-7.96 (1H, m).
IR (ATR): 2925, 2854, 2218, 1724, 1606, 1541, 1504, 1479, 1439, 1367, 1340, 1265, 1217, 1159, 1120, 1076, 1016, 962 cm ^-1 .
[Reference Example 4]
8-cyano-7-methyl-5-((3S) -3-methyl-3- {methyl [(2-nitrophenyl) sulfonyl] amino} pyrrolidin-1-yl) -6-phenyl [1,2,4 ] Triazolo [1,5-a] pyridine-2-carboxylic acid (I-4)

N-{(3S) -1- [2- (Bromomethyl) -8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3 -Methylpyrrolidin-3-yl} -N-methyl-2-nitrobenzenesulfonamide (I-3) (1.08 g, 1.73 mmol) in dimethylsulfoxide (15 ml) at room temperature with acetic acid (990 μl, 17.3 mmol ) And sodium nitrite (358 mg, 5.19 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the residue obtained by concentrating the reaction solution under reduced pressure, this was extracted with ethyl acetate, and the resulting organic phase was washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate, insolubles were filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform: methanol: water = 8). : 3: 0.5, v / v), and 407 mg (41%) of the title compound was obtained as a yellow foam.
ESI-MS m / z: 576 (M + 1) ⁺ .
[Reference Example 5]
tert-butyl {8-cyano-7-methyl-5-[(3S) -3-methyl-3- {methyl [(2-nitrophenyl) sulfonyl] amino} pyrrolidin-1-yl] -6-phenyl [1 , 2,4] Triazolo [1,5-a] pyridin-2-yl} carbamate (I-5)

8-cyano-7-methyl-5-[(3S) -3-methyl-3- {methyl [(2-nitrophenyl) sulfonyl] amino} pyrrolidin-1-yl] -6-phenyl [1,2,4 ] To a solution of triazolo [1,5-a] pyridine-2-carboxylic acid (I-4) (1.0 g, 1.74 mmol) in toluene (17 ml), diphenylphosphoric acid azide (450 μl, 2.08 mmol), triethylamine (484 μl, 3.47 mmol) and tert-butanol (3.3 ml) were added and the mixture was stirred on an oil bath at 100 ° C. for 14 hours. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in ethyl acetate, and this was washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 2). : 1, v / v), and 745 mg (66%) of the title compound was obtained as a pale yellow foam.
¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, s), 1.54 (9H, s), 1.93-2.07 (2H, m), 2.24 (3H, s), 2.88 (3H, s), 3.34 (1H , d, J = 10.7 Hz), 3.40-3.47 (2H, m), 3.86 (1H, d, J = 10.7 Hz), 7.10-7.22 (2H, m), 7.36-7.50 (4H, m), 7.55- 7.64 (2H, m), 7.93-7.99 (1H, m).
[Reference Example 6]
N-[(3S) -1- (2-Amino-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3-methyl Pyrrolidin-3-yl] -N-methyl-2-nitrobenzenesulfonamide (I-6)

tert-butyl {8-cyano-7-methyl-5-[(3S) -3-methyl-3- {methyl [(2-nitrophenyl) sulfonyl] amino} pyrrolidin-1-yl] -6-phenyl [1 , 2,4] Triazolo [1,5-a] pyridin-2-yl} carbamate (I-5) (745 mg, 1.15 mmol) in dichloromethane (4 ml) under ice-cooling, trifluoroacetic acid (4 ml) was added, and the mixture was refluxed for 2 hours on an oil bath at 50 ° C. Saturated sodium hydrogen carbonate was added to the reaction solution at room temperature, and this was extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate, insolubles were filtered off, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 10: 1, v / v), and 431 mg (69%) of the title compound was obtained as a pale yellow solid.
HRESI-MS m / z: 547.1865 (Calcd for C ₂₆ H ₂₇ N ₈ O ₄ S 547.1876).
¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, s), 1.81-1.90 (1H, m), 1.95-2.06 (1H, m), 2.21 (3H, s), 2.88 (3H, s), 3.17 (1H, dd, J = 1.0, 10.5 Hz), 3.24-3.32 (1H, m), 3.35-3.43 (1H, m), 3.71 (1H, d, J = 10.5 Hz), 4.61 (2H, s), 7.10-7.19 (2H, m), 7.37-7.48 (3H, m), 7.55-7.66 (3H, m), 7.92-7.97 (1H, m).
[Example 1]
2-Amino-7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl [1,2,4] triazolo [1,5-a] Pyridine-8-carbonitrile (# 1)

N-[(3S) -1- (2-Amino-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3-methyl Pyrrolidin-3-yl] -N-methyl-2-nitrobenzenesulfonamide (I-6) (100 mg, 0.18 mmol) was dissolved in N, N-dimethylformamide (5 ml) and potassium carbonate was dissolved. (76 mg, 0.55 mmol) and thiophenol (38 μl, 0.37 mmol) were added, followed by stirring at room temperature for 2 hours. The residue obtained by concentrating the reaction solution under reduced pressure was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified using preparative TLC (eluent; chloroform: methanol = 10: 1, v / v) to obtain 28 mg (42%) of the title compound as a colorless solid.
ESI-MS: m / z: 362 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, s), 1.56-1.66 (1H, m), 1.83-1.92 (1H, m), 2.23 (3H, s), 2.33 (3H, s), 2.93 (1H, d, J = 10.7 Hz), 3.07-3.16 (1H, m), 3.40-3.50 (2H, m), 4.82 (2H, brs), 7.19-7.24 (2H, m), 7.39-7.50 (3H , m).
IR (ATR): 3313, 2974, 1656, 1606, 1546, 1477, 1376, 1264, 1147, 762, 701 cm ^-1 .
Anal. Calcd for C ₃₀ H ₂₃ N ₇・ 1.5H ₂ O: C, 61.84; H, 6.75; N, 25.24. Found: C, 62.76; H, 6.13; N, 24.57.
[Reference Example 7]
N-{(3S) -1- [8-Cyano-2- (dimethylamino) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl]- 3-Methylpyrrolidin-3-yl} -N-methyl-2-nitrobenzenesulfonamide (I-7)

N-[(3S) -1- (2-Amino-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3-methyl Pyrrolidin-3-yl] -N-methyl-2-nitrobenzenesulfonamide (I-6) (200 mg, 0.37 mmol) in methanol (3 ml) and chloroform (3 ml) in acetic acid (126 μl , 2.20 mmol), 37% formalin (178 μl, 2.20 mmol) and sodium cyanoborohydride (82.8 mg, 1.32 mmol) were added, and the mixture was stirred at room temperature for 2 hours. To this solution, acetic acid (126 μl, 2.20 mmol), 37% formalin (178 μl, 2.20 mmol) and sodium cyanoborohydride (82.8 mg, 1.32 mmol) were added at room temperature, and this operation was performed every 30 minutes. Repeated a total of 6 times. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate, insolubles were filtered off, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 1). : 1, v / v), and 142 mg (67%) of the title compound was obtained as a pale yellow foam.
ESI-MS m / z: 575 (M + 1) ⁺ .
HRESI-MS m / z: 575.2176 (Calcd for C ₂₈ H ₃₁ N ₈ O ₄ S 575.2189).
¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, s), 1.82-1.90 (1H, m), 1.93-2.04 (1H, m), 2.21 (3H, s), 2.87 (3H, s), 3.13 (6H, s), 3.24 (1H, d, J = 10.5 Hz), 3.28-3.44 (2H, m), 3.67 (1H, d, J = 10.5 Hz), 7.12-7.15 (2H, m), 7.35- 7.62 (6H, m), 7.92 (1H, dd, J = 1.3, 7.9 Hz).
[Example 2]
2- (Dimethylamino) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl [1,2,4] triazolo [1,5 -a] pyridine-8-carbonitrile (# 2)

N-{(3S) -1- [8-Cyano-2- (dimethylamino) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl]- Carbonate 3-methylpyrrolidin-3-yl} -N-methyl-2-nitrobenzenesulfonamide (I-7) (141 mg, 0.25 mmol) in N, N-dimethylformamide (2 ml) at room temperature. Potassium (102 mg, 0.74 mmol) and thiophenol (37.5 μl, 0.37 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in chloroform, and the obtained organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, insolubles were filtered off, and the filtrate was concentrated, and the resulting residue was purified by preparative TLC (eluent; chloroform: methanol = 10: 1, The colorless solid obtained in v / v) was purified by slurry with diisopropyl ether. The precipitated solid was collected by filtration to give 61.0 mg (63%) of the title compound as a colorless solid.
ESI-MS m / z: 390 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, s), 1.54-1.63 (1H, m), 1.72-1.81 (1H, m), 2.23 (3H, s), 2.27 (3H, s), 3.05 (1H, d, J = 10.3 Hz), 3.12-3.20 (1H, m), 3.15 (6H, s), 3.30-3.37 (2H, m), 7.14-7.20 (2H, m), 7.36-7.48 (3H , m).
IR (ATR): 3343, 3054, 2968, 2942, 2884, 2794, 2205, 1601, 1571, 1531, 1502, 1468, 1439, 1418, 1390, 1369, 1338, 1307, 1271, 1209, 1152, 1092, 1062 , 1017, 976, 932, 900 cm ^-1 .
Anal.Calcd for C ₂₂ H ₂₇ N ₇・ 0.25H ₂ O: C, 67.06; H, 7.04; N, 24.88. Found: C, 67.84; H, 6.99; N, 24.75.
[Reference Example 8]
N-{(3S) -1- [8-Cyano-7-methyl-6-phenyl-2- (1H-pyrrol-1-yl) [1,2,4] triazolo [1,5-a] pyridine- 5-yl] pyrrolidin-3-yl} -N-methyl-2-nitrobenzenesulfonamide (I-8)

N-[(3S) -1- (2-Amino-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) pyrrolidine-3- [Il] -N-methyl-2-nitrobenzenesulfonamide (I-6) (240 mg, 0.39 mmol) was dissolved in acetic acid (10 ml). To this solution was added 2,5-dimethoxytetrahydrofuran (175 μl, 1.36 mmol) at room temperature, and the mixture was stirred at 100 ° C. for 3 hours. Ethyl acetate was added to the residue obtained by concentrating the reaction solution under reduced pressure, and this was washed with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: normal hexane = 0: 100, v / v → 100: 0, v / v), and the title compound 175 mg (67%) Was obtained as a colorless solid.
ESI-MS m / z: 583 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.82-1.94 (1H, m), 2.01-2.10 (1H, m), 2.31 (3H, s), 2.86 (3H, s), 2.97-3.06 (1H, m) , 3.19-3.26 (1H, m), 3.41-3.49 (1H, m), 3.61-3.68 (1H, m), 4.56-4.65 (1H, m), 6.33-6.37 (2H, m), 7.12-7.17 ( 1H, m), 7.19-7.24 (1H, m), 7.44-7.53 (3H, m), 7.55-7.58 (2H, m), 7.61-7.74 (3H, m), 8.02-8.07 (1H, m).
[Example 3]
7-Methyl-5-[(3S) -3- (methylamino) pyrrolidin-1-yl] -6-phenyl-2- (1H-pyrrol-1-yl) [1,2,4] triazolo [1, 5-a] pyridine-8-carbonitrile (# 3)

N-{(3S) -1- [8-Cyano-7-methyl-6-phenyl-2- (1H-pyrrol-1-yl) [1,2,4] triazolo [1,5-a] pyridine- 5-yl] pyrrolidin-3-yl} -N-methyl-2-nitrobenzenesulfonamide (I-8) (140 mg, 0.24 mmol) was dissolved in N, N-dimethylformamide (10 ml). Potassium carbonate (99.5 mg, 0.72 mmol) and thiophenol (49 μl, 0.48 mmol) were added to the solution, followed by stirring at room temperature for 2 hours. The residue obtained by concentrating the reaction solution under reduced pressure was diluted with ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified using preparative TLC (eluent; chloroform: methanol = 10: 1, v / v) to obtain 62 mg (65%) of the title compound as a colorless solid.
ESI-MS m / z: 398 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.58-1.69 (1H, m), 1.90-2.00 (1H, m), 2.23 (3H, m), 2.35 (3H, s), 3.11-3.18 (1H, m) , 3.21-3.34 (2H, m), 3.40-3.51 (2H, m), 6.30-6.34 (2H, m), 7.16-7.22 (2H, m), 7.38-7.48 (3H, m), 7.57-7.60 ( 2H, m).
IR (ATR): 2965, 2208, 1614, 1557, 1526, 1509, 1450, 1296, 1178, 1083, 727 cm ^-1 .
Anal.Calcd for C ₂₃ H ₂₃ N ₇・ 0.25H ₂ O: C, 68.72; H, 5.89; N, 24.39. Found: C, 68.92; H, 5.69; N, 23.99.
[Reference Example 9]
N- {8-cyano-7-methyl-5-[(3S) -3-methyl-3- {methyl [(2-nitrophenyl) sulfonyl] amino} pyrrolidin-1-yl] -6-phenyl [1, 2,4] Triazolo [1,5-a] pyridin-2-yl} -4-hydroxybutanamide (I-9)

N-[(3S) -1- (2-Amino-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) pyrrolidine-3- [Il] -N-methyl-2-nitrobenzenesulfonamide (I-6) (383 mg, 0.70 mmol) was dissolved in dichloromethane (10 ml). Trimethylaluminum (1.03 molar normal hexane solution) (2.1 ml, 2.1 mmol) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. To this solution was added γ-butyrolactone (161 μl, 2.1 mmol), and the mixture was stirred at 50 ° C. for 5 hours. Ethyl acetate was added to the reaction solution, which was washed with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 260 mg (59%) of the title compound as a colorless solid.
ESI-MS m / z: 633 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.24-1.28 (2H, m), 1.35 (3H, s), 1.89-2.04 (4H, m), 2.23 (3H, s), 2.85 (3H, s), 3.33 -3.48 (3H, m), 3.75 (2H, t, J = 6.0 Hz), 3.84-3.91 (1H, m), 7.14-7.24 (2H, m), 7.38-7.49 (3H, m), 7.56-7.68 (3H, m), 7.94-7.99 (1H, m).
[Reference Example 10]
N-{(3S) -1- [8-Cyano-7-methyl-2- (2-oxopyrrolidin-1-yl) -6-phenyl [1,2,4] triazolo [1,5-a] pyridine -5-yl] -3-methylpyrrolidin-3-yl} -N-methyl-2-nitrobenzenesulfonamide (I-10)

N- {8-cyano-7-methyl-5-[(3S) -3-methyl-3- {methyl [(2-nitrophenyl) sulfonyl] amino} pyrrolidin-1-yl] -6-phenyl [1, 2,4] Triazolo [1,5-a] pyridin-2-yl} -4-hydroxybutanamide (I-9) (260 mg, 0.48 mmol) was dissolved in tetrahydrofuran (2 ml). To this solution were added tri-n-butylphosphine (356 μl, 1.43 mmol) and diisopropyl azodicarboxylate (282 μl, 1.43 mmol), and the mixture was stirred at room temperature for 3 days. Ethyl acetate was added to the residue obtained by concentrating the reaction solution under reduced pressure, and this was washed with saturated brine. The organic phase was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: normal hexane = 0: 100, v / v → 100: 0, v / v), and 98 mg (33%) of the title compound. Was obtained as a colorless solid.
ESI-MS m / z: 615 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.38 (3H, s), 1.39-1.45 (1H, m), 1.96-2.01 (1H, m), 2.26 (3H, s), 2.21-2.28 (2H, m) , 2.65 (2H, t, J = 8.1 Hz), 2.88 (3H, s), 3.32-3.39 (2H, m), 3.50 (1H, d, J = 11.0 Hz), 3.93 (1H, d, J = 11.0 Hz), 4.10-4.18 (2H, m), 7.11-7.16 (1H, m), 7.19-7.23 (1H, m), 7.38-7.50 (3H, m), 7.54-7.64 (3H, m), 7.96- 8.01 (1H, m).
[Example 4]
7-Methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -2- (2-oxopyrrolidin-1-yl) -6-phenyl [1,2,4 ] Triazolo [1,5-a] pyridine-8-carbonitrile (# 4)

N-{(3S) -1- [8-Cyano-7-methyl-2- (2-oxopyrrolidin-1-yl) -6-phenyl [1,2,4] triazolo [1,5-a] pyridine -5-yl] -3-methylpyrrolidin-3-yl} -N-methyl-2-nitrobenzenesulfonamide (I-10) (98 mg, 0.16 mmol) in N, N-dimethylformamide (5 ml) Then, potassium carbonate (66 mg, 0.48 mmol) and thiophenol (33 μl, 0.32 mmol) were added thereto, followed by stirring at room temperature for 1 hour. The residue obtained by concentrating the reaction solution under reduced pressure was diluted with ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified using preparative TLC (eluent; chloroform: methanol = 10: 1, v / v) to obtain 29 mg (43%) of the title compound as a colorless solid.
ESI-MS m / z: 430 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, s), 1.56-1.66 (1H, m), 1.91-2.01 (1H, m), 2.20-2.28 (2H, m), 2.29 (3H, s) , 2.40 (3H, s), 2.63-2.69 (2H, m), 3.00-3.08 (1H, m), 3.15 (1H, d, J = 11.0 Hz), 3.40-3.48 (1H, m), 3.85-3.94 (1H, m), 4.14-4.21 (2H, m), 7.15-7.25 (2H, m), 7.40-7.50 (3H, m).
IR (ATR): 2962, 2214, 1731, 1671, 1610, 1538, 1504, 1440, 1200, 940, 847 cm ^-1 .
Anal.Calcd for C ₂₄ H ₂₇ N ₇ O ・ 1.25H ₂ O: C, 63.77; H, 6.58; N, 21.69.Found: C, 64.04; H, 6.48; N, 21.19.
[Reference Example 11]
N-{(3S) -1- [8-Cyano-2- (diethylamino-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3- Methylpyrrolidin-3-yl} -N-methyl-2-nitrobenzenesulfonamide (I-11a) and N-{(3S) -1- [8-cyano-2- (ethylamino-7-methyl-6-phenyl) [1,2,4] Triazolo [1,5-a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} -N-methyl-2-nitrobenzenesulfonamide (I-11b)

N-[(3S) -1- (2-Amino-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3-methyl Pyrrolidin-3-yl] -N-methyl-2-nitrobenzenesulfonamide (I-6) (160 mg, 0.29 mmol) was dissolved in dichloromethane (5 ml) and methanol (5 ml). Acetaldehyde (329 μl, 5.9 mmol), molecular sieves 4A (100 mg), acetic acid (100 μl) and sodium cyanoborohydride (110 mg, 1.76 mmol) were added to the solution, and the mixture was stirred at room temperature for 24 hours. Ethyl acetate was added to the residue obtained by concentrating the reaction solution under reduced pressure, and this was washed with saturated brine. The organic phase was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: normal hexane = 2: 1, v / v), and the title compound (I-11a) 40 mg (11%), (I -11b) 120 mg (36%) were obtained as a colorless solid.
(I-11a)
ESI-MS m / z: 603 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.20-1.28 (6H, m), 1.37 (3H, s), 1.83-1.96 (2H, m), 2.20 (3H, s), 2.85 (3H, s), 3.26 -3.41 (3H, m), 3.54-3.62 (4H, m), 3.77-3.85 (1H, m), 7.11-7.17 (2H, m), 7.35-7.47 (3H, m), 7.52-7.65 (3H, m), 7.88-7.92 (1H, m).
(I-11b)
ESI-MS m / z: 575 (M + 1) ⁺ .
¹ H-NMR (CDCl3) δ: 1.24-1.32 (3H, m), 1.36 (3H, s), 1.86-2.03 (2H, m), 2.20 (3H, s), 2.86 (3H, s), 3.25 ( 1H, d, J = 10.5 Hz), 3.35-3.45 (3H, m), 3.65 (1H, d, J = 10.5 Hz), 4.63-4.69 (1H, m), 7.12-7.18 (2H, m), 7.37 -7.65 (6H, m), 7.89-7.94 (1H, m).
[Example 5]
2- (Ethylamino) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl [1,2,4] triazolo [1,5 -a] pyridine-8-carbonitrile (# 5)

N-{(3S) -1- [8-Cyano-2- (ethylamino-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3 -Methylpyrrolidin-3-yl} -N-methyl-2-nitrobenzenesulfonamide (I-11b) (60 mg, 0.10 mmol) was dissolved in N, N-dimethylformamide (5 ml). Potassium carbonate (43 mg, 0.48 mmol) and thiophenol (21 μl, 0.21 mmol) were added to the mixture, and the mixture was stirred at room temperature for 2 hours. The organic phase was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure, and the resulting residue was purified using preparative TLC. (Eluent; chloroform: methanol = 10: 1, v / v), 25 mg (62%) of the title compound was obtained as a colorless solid.
ESI-MS m / z: 390 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, s), 1.28 (3H, t, J = 7.2 Hz), 1.57-1.67 (1H, m), 1.86-1.95 (1H, m), 2.22 (3H , s), 2.33 (3H, s), 2.91-2.96 (1H, m), 3.39-3.56 (4H, m), 4.96-5.02 (1H, m), 7.13-7.18 (1H, m), 7.21-7.26 (1H, m), 7.38-7.49 (3H, m).
IR (ATR): 3266, 2967, 2214, 1572, 1500, 1467, 1442, 1335, 1258, 1143, 1015, 704 cm ^-1 .
Anal. Calcd for C ₂₂ H ₂₇ N ₇・ 1.0H ₂ O: C, 64.84; H, 7.17; N, 24.04. Found: C, 65.70; H, 7.04; N, 23.15.
[Example 6]
2- (Diethylamino) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl [1,2,4] triazolo [1,5- a] pyridine-8-carbonitrile (# 6)

N-{(3S) -1- [8-Cyano-2- (diethylamino-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3- Methylpyrrolidin-3-yl} -N-methyl-2-nitrobenzenesulfonamide (I-11a) (126 mg, 0.16 mmol) was dissolved in N, N-dimethylformamide (5 ml) Potassium (87 mg, 0.63 mmol) and thiophenol (43 μl, 0.42 mmol) were added and stirred at room temperature for 18 hours.The reaction mixture was concentrated under reduced pressure, and the residue obtained was diluted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure, and the resulting residue was purified using preparative TLC (elution). Liquid: chloroform: methanol = 10: 1, v / v), and 29 mg (43%) of the title compound was obtained as a colorless solid.
ESI-MS m / z: 418 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, s), 1.23 (6H, t, J = 7.1 Hz), 1.56-1.66 (1H, m), 1.79-1.88 (1H, m), 2.22 (3H , s), 2.30 (3H, s), 2.64 (2H, br s), 3.01 (1H, d, J = 10.2 Hz), 3.13-3.21 (1H, m), 3.33 (1H, d, J = 10.2 Hz ), 3.37-3.46 (1H, m), 3.59 (4H, q, J = 7.1 Hz), 7.14-7.20 (2H, m), 7.37-7.49 (3H, m).
IR (ATR): 2962, 2211, 1614, 1562, 1504, 1449, 1366, 1346, 759, 701 cm ^-1 .
Anal.Calcd for C ₂₄ H ₂₇ N ₇ O ・ 0.75H ₂ O: C, 66.87; H, 7.60; N, 22.75. Found: C, 67.08; H, 7.52; N, 21.85.
[Reference Example 12]
N- {8-cyano-7-methyl-5-[(3S) -3-methyl-3- {methyl [(2-nitrophenyl) sulfonyl] amino} pyrrolidin-1-yl] -6-phenyl [1, 2,4] Triazolo [1,5-a] pyridin-2-yl} -N-ethylacetamide (I-12)

N-{(3S) -1- [8-Cyano-2- (ethylamino-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3 -Methylpyrrolidin-3-yl} -N-methyl-2-nitrobenzenesulfonamide (I-11b) (160 mg, 0.29 mmol) was dissolved in pyridine (5 ml) and acetic anhydride (41 μl, 0.43 The mixture was stirred for 24 hours at 100 ° C. Chloroform was added to the residue obtained by concentrating the reaction solution under reduced pressure, and this was washed with a 1N aqueous hydrochloric acid solution and then with a saturated saline solution. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (eluent; ethyl acetate: normal hexane = 1: 1, v / v). The title compound (110 mg, 62%) was obtained as a colorless solid.
ESI-MS m / z: 617 (M + 1) ⁺ .
1H-NMR (CDCl3) δ: 1.22-1.29 (3H, s), 1.36 (3H, s), 1.91-2.00 (2H, m), 2.27 (3H, s), 2.46 (3H, s), 2.78 (3H , s), 3.17-3.26 (1H, m), 3.30-3.42 (1H, m), 3.48-3.55 (1H, m), 3.68-3.74 (1H, m), 4.05-4.14 (2H, m), 7.11 -7.16 (1H, m), 7.22-7.27 (1H, m), 7.40-7.52 (3H, m), 7.58-7.74 (3H, m), 7.91-7.96 (1H, m).
[Example 7]
N- {8-Cyano-7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl [1,2,4] triazolo [1,5 -a] pyridin-2-yl} -N-ethylacetamide (# 7)

N- {8-cyano-7-methyl-5-[(3S) -3-methyl-3- {methyl [(2-nitrophenyl) sulfonyl] amino} pyrrolidin-1-yl] -6-phenyl [1, 2,4] Triazolo [1,5-a] pyridin-2-yl} -N-ethylacetamide (I-12) (110 mg, 0.18 mmol) dissolved in N, N-dimethylformamide (5 ml) To this, potassium carbonate (74 mg, 0.53 mmol) and thiophenol (37 μl, 0.36 mmol) were added, followed by stirring at room temperature for 2 hours. The residue obtained by concentrating the reaction solution under reduced pressure was diluted with ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified using preparative TLC (eluent; chloroform: methanol = 10: 1, v / v) to obtain 56 mg (62%) of the title compound as a colorless solid.
ESI-MS m / z: 432 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, s), 1.26 (3H, t, J = 7.1 Hz), 1.59-1.68 (1H, m), 1.78-1.87 (1H, m), 2.06 (1H , br), 2.28 (6H, s), 2.48 (3H, s), 3.13 (1H, d, J = 10.2 Hz), 3.27-3.43 (3H, m), 4.10 (2H, q, J = 7.1 Hz) , 7.19-7.23 (2H, m), 7.43-7.52 (3H, m).
IR (ATR): 2969, 2212, 1685, 1502, 1431, 1256, 1177, 996, 700 cm ^-1 .
Anal. Calcd for C ₂₄ H ₂₉ N ₇ O ・ 0.5H ₂ O: C, 65.43; H, 6.86; N, 22.26. Found: C, 65.43; H, 6.83; N, 21.83.
[Reference Example 13]
N- {8-cyano-7-methyl-5-[(3S) -3-methyl-3- {methyl [(2-nitrophenyl) sulfonyl] amino} pyrrolidin-1-yl] -6-phenyl [1, 2,4] Triazolo [1,5-a] pyridin-2-yl} acetamide (I-13)

N-[(3S) -1- (2-Amino-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3-methyl Pyrrolidin-3-yl] -N-methyl-2-nitrobenzenesulfonamide (I-6) (200 mg, 0.37 mmol) was dissolved in pyridine (5 ml). Acetic anhydride (103 μl, 1.1 mmol) was added to this solution, followed by stirring at 100 ° C. for 18 hours. Chloroform was added to the residue obtained by concentrating the reaction solution under reduced pressure, and this was washed with a 1N aqueous hydrochloric acid solution and then with a saturated saline solution. The organic phase was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: normal hexane = 1: 1, v / v) to obtain 61 mg (28%) of the title compound as a colorless solid.
ESI-MS m / z: 589 (M + 1) +.
¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, s), 1.60-1.85 (1H, br), 1.93-2.03 (2H, m), 2.25 (3H, s), 2.34-2.47 (3H, m) , 2.85 (3H, br s), 3.30-3.34 (2H, m), 3.47 (1H, d, J = 10.7 Hz), 3.84-3.93 (1H, m), 7.12-7.16 (1H, m), 7.20- 7.24 (1H, m), 7.40-7.50 (3H, m), 7.57-7.69 (3H, m), 7.96-8.01 (1H, m).
[Example 8]
N- {8-Cyano-7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl [1,2,4] triazolo [1,5 -a] pyridin-2-yl} acetamide (# 8)

N- {8-cyano-7-methyl-5-[(3S) -3-methyl-3- {methyl [(2-nitrophenyl) sulfonyl] amino} pyrrolidin-1-yl] -6-phenyl [1, 2,4] Triazolo [1,5-a] pyridin-2-yl} acetamide (I-13) (74 mg, 0.18 mmol) was dissolved in N, N-dimethylformamide (5 ml). Potassium carbonate (52 mg, 0.38 mmol) and thiophenol (26 μl, 0.25 mmol) were added to the solution, followed by stirring at room temperature for 24 hours. The residue obtained by concentrating the reaction solution under reduced pressure was diluted with ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified using preparative TLC (eluent; chloroform: methanol = 10: 1, v / v) to obtain 21 mg (41%) of the title compound as a colorless solid.
ESI-MS m / z: 404 (M + 1) ⁺ .
_{^{1 H-NMR (CD 3 OD}} ) δ: 1.29 (3H, s), 1.69-1.79 (1H, m), 2.01-2.11 (1H, m), 2.25 (3H, br), 2.31 (3H, s), 2.52 (3H, br), 2.93-3.02 (2H, m), 3.30-3.35 (1H, m), 3.98-4.13 (1H, m), 7.26-7.39 (2H, m), 7.44-7.56 (3H, m ).
IR (ATR): 2965, 2215, 1712, 1503, 1490, 1240, 1004, 778, 721 cm ^-1 .
Anal.Calcd for C ₂₂ H ₂₅ N ₇ O ・ 2.25H ₂ O: C, 59.51; H, 6.70; N, 22.08. Found: C, 59.23; H, 6.26; N, 21.45.
[Reference Example 14]
N-[(3S) -1- (2-Bromo-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3-methyl Pyrrolidin-3-yl] -N-methyl-2-nitrobenzenesulfonamide (I-14)

N-[(3S) -1- (2-Amino-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3-methyl Pyrrolidin-3-yl] -N-methyl-2-nitrobenzenesulfonamide (I-6) (300 mg, 0.55 mmol) and copper bromide (208 mg, 0.93 mmol) were dissolved in anhydrous acetonitrile (12 ml). The solution was cooled to 0 ° C., tert-butyl nitrite (91 μl, 0.77 mmol) was added, and the mixture was stirred at 0 ° C. for 3 hr. Ethyl acetate was added to the reaction solution, which was washed with saturated brine. The organic phase was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: normal hexane = 1: 1, v / v) to obtain 270 mg (81%) of the title compound as a pale yellow solid.
APCI-MS m / z: 610 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.35 (3H, s), 1.86-1.94 (1H, m), 1.99-2.09 (1H, m), 2.26 (3H, s), 2.87 (3H, br s), 3.28-3.47 (3H, m), 3.76 (1H, d, J = 10.7 Hz), 7.12-7.16 (1H, m), 7.18-7.22 (1H, m), 7.41-7.52 (3H, m), 7.57- 7.65 (3H, m), 7.95-7.99 (1H, m).
[Reference Example 15]
N-{(3S) -1- [2- (azetidin-1-yl) -8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-5- Yl] -3-methylpyrrolidin-3-yl} -N-methyl-2-nitrobenzenesulfonamide (I-15)

N-[(3S) -1- (2-Bromo-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3-methyl Pyrrolidin-3-yl] -N-methyl-2-nitrobenzenesulfonamide (I-14) (200 mg, 0.33 mmol) was dissolved in dimethyl sulfoxide (10 ml). Azetidine (45 μl, 0.66 mmol) and N, N-diisopropylethylamine (224 μl, 1.32 mmol) were added to the solution, and the mixture was stirred at 150 ° C. for 1 hour. Ethyl acetate was added to the residue obtained by concentrating the reaction solution under reduced pressure, and this was washed with saturated brine. The organic phase was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: normal hexane = 1: 2, v / v) to obtain 40 mg (19%) of the title compound as a pale yellow solid.
ESI-MS m / z: 587 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.35 (3H, s), 2.21 (3H, s), 2.39-2.49 (2H, m), 2.86 (3H, s), 2.95-3.05 (1H, m), 3.20 (1H, d, J = 10.0 Hz), 3.30-3.44 (3H, m), 3.67 (1H, d, J = 10.0 Hz), 4.14-4.20 (4H, m), 7.09-7.18 (2H, m), 7.37-7.64 (6H, m), 7.89-7.92 (1H, m).
[Example 9]
2- (Azetidin-1-yl) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl [1,2,4] triazolo [ 1,5-a] pyridine-8-carbonitrile (# 9)

N-{(3S) -1- [2- (azetidin-1-yl) -8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-5- Yl] -3-methylpyrrolidin-3-yl} -N-methyl-2-nitrobenzenesulfonamide (I-15) (40 mg, 0.07 mmol) was dissolved in N, N-dimethylformamide (3 ml). To this, potassium carbonate (28 mg, 0.2 mmol) and thiophenol (21 μl, 0.2 mmol) were added, followed by stirring at room temperature for 2 hours. The residue obtained by concentrating the reaction solution under reduced pressure was diluted with ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified using preparative TLC (eluent; chloroform: methanol = 10: 1, v / v) to obtain 20 mg (74%) of the title compound as a colorless solid.
ESI-MS m / z: 402 (M + 1) ⁺ .
HRESI-MS m / z: 402.24064 (Calcd for C ₂₂ H ₂₈ N ₇ 402.24062).
¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, s), 1.58-1.64 (1H, m), 1.82-1.95 (1H, m), 2.24 (3H, s), 2.32 (3H, s), 2.40 -2.49 (2H, m), 2.95 (1H, d, J = 10.5 Hz), 3.03-3.09 (1H, m), 3.30-3.39 (1H, m), 3.47 (1H, d, J = 10.5 Hz), 4.20 (4H, t, J = 7.6 Hz), 7.14-7.19 (2H, m), 7.38-7.48 (3H, m).
[Reference Example 16]
1- (Diphenylmethyl) -3-methoxyazetidine (I-16)

1- (Diphenylmethyl) azetidin-3-ol (5 g, 20.9 mmol) was dissolved in N, N-dimethylformamide (3 ml). After cooling the solution to 0 ° C, sodium hydride (55% in paraffin liquid) (1.37 g, 31.4 mmol) was added, followed by methyl iodide (3.9 ml, 62.7 mmol) and 3 hours at room temperature. Stir. Ethyl acetate was added to the reaction solution, which was washed with saturated brine. The organic phase was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: normal hexane = 1: 2, v / v) to obtain 3.27 g (62%) of the title compound as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 2.88-2.93 (2H, m), 3.21 (3H, s), 3.45-3.51 (2H, m), 4.00-4.07 (1H, m), 4.35 (1H, s) , 7.14-7.20 (2H, m), 7.22-7.28 (4H, m), 7.37-7.42 (4H, m).
[Reference Example 17]
3-Methoxyazetidine hydrochloride (I-17)

1- (Diphenylmethyl) -3-methoxyazetidine (I-16) (3.2 g, 12.6 mmol) was dissolved in ethanol (100 ml). To this solution was added palladium hydroxide (20% on carbon) (1.6 g), and the mixture was stirred at room temperature for 6 hours in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was distilled off under reduced pressure. 4N Hydrochloric acid / 1,4-dioxane solution was added to the obtained residue, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, normal hexane was added to the resulting residue, the solvent was decanted off, the residue was concentrated under reduced pressure, dried under reduced pressure, and the title compound 1.2 g (77%) Was obtained as a colorless solid.
¹ H-NMR (CD ₃ OD) δ: 3.89-3.96 (2H, m), 4.22-4.35 (3H, m), 4.83 (3H, s).
[Reference Example 18]
N-{(3S) -1- [8-Cyano-2- (3-methoxyazetidin-1-yl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] Pyridin-5-yl] -3-methylpyrrolidin-3-yl} -N-methyl-2-nitrobenzenesulfonamide (I-18)

N-[(3S) -1- (2-Bromo-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3-methyl Pyrrolidin-3-yl] -N-methyl-2-nitrobenzenesulfonamide (I-14) (500 mg, 0.82 mmol) was dissolved in dimethyl sulfoxide (5 ml). To this solution were added 3-methoxyazetidine hydrochloride (I-17) (202 mg, 1.64 mmol) and N, N-diisopropylethylamine (696 μl, 4.1 mmol), and the mixture was stirred at 150 ° C. for 18 hours. Ethyl acetate was added to the residue obtained by concentrating the reaction solution under reduced pressure, and this was washed with saturated brine. The organic phase was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: normal hexane = 1: 2, v / v) to obtain 170 mg (34%) of the title compound as a pale yellow solid.
ESI-MS m / z: 617 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.35 (3H, s), 1.84-2.06 (2H, m), 2.22 (3H, s), 2.86 (3H, s), 3.16 (1H, d, J = 10.5 Hz ), 3.34 (3H, s), 3.33-3.36 (1H, m), 3.40-3.49 (1H, m), 3.66 (1H, d, J = 10.5 Hz), 4.02-4.08 (2H, m), 4.31- 4.40 (3H, m), 7.12-7.15 (2H, m), 7.39-7.51 (3H, m), 7.57-7.65 (3H, m), 7.92-7.89 (1H, m).
[Example 10]
2- (Methoxyazetidin-1-yl) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl [1,2,4] Triazolo [1,5-a] pyridine-8-carbonitrile (# 10)

N-{(3S) -1- [8-Cyano-2- (3-methoxyazetidin-1-yl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] Pyridin-5-yl] -3-methylpyrrolidin-3-yl} -N-methyl-2-nitrobenzenesulfonamide (I-18) (170 mg, 0.28 mmol) was added to N, N-dimethylformamide (5 ml ), Potassium carbonate (114 mg, 0.83 mmol) and thiophenol (85 μl, 0.83 mmol) were added thereto, followed by stirring at room temperature for 2 hours. The residue obtained by concentrating the reaction solution under reduced pressure was diluted with ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified using preparative TLC (eluent; chloroform: methanol = 10: 1, v / v) to obtain 47 mg (40%) of the title compound as a colorless solid.
ESI-MS m / z: 432 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.22-1.28 (1H, br), 1.40 (3H, s), 1.74-1.83 (1H, m), 2.24 (3H, s), 2.26-2.30 (1H, m) , 2.55 (3H, s), 2.92-3.00 (1H, m), 2.98 (1H, d, J = 11.0 Hz), 3.33 (3H, s), 3.43-3.52 (1H, m), 3.88 (1H, d , J = 11.0 Hz), 4.02-4.08 (2H, m), 4.33-4.40 (3H, m), 7.14-7.23 (2H, m), 7.40-7.52 (3H, m).
IR (ATR): 2924, 2741, 2215, 1553, 1502, 1366, 1122, 1095, 761, 732 cm ^-1 .
Anal.Calcd for C ₂₄ H ₂₇ N ₇ O ・ 1.0H ₂ O: C, 64.12; H, 6.95; N, 21.81. Found: C, 64.62; H, 6.61; N, 20.86.
[Test Example 1]
It was performed by a micro liquid dilution method using a 96-well flat bottom plate.
In other words, cells cultured on Sabouraud dextrose agar medium at 30 ° C for 24 hours are diluted with YPD20 medium (1% yaest extract, 2% peptone, 20% glucose), and the final concentration of bacterial cells is 1X10 ³ to 1x10 ⁴ cell It adjusted so that it might become / mL. After 2 μl of the drug solution prepared by 11-fold 2-fold dilution and the bacterial solution were mixed on a 96-well plate, the absorbance (600 nm) was measured after incubation for 16 to 30 hours at 37 ° C. The minimum concentration at which% inhibition occurs was calculated and taken as the GI80 value (μg / mL).

  The results are shown in the following table.

The compounds of the present invention showed excellent antifungal activity.
[Test Example 2] Examination of effects on cell wall composition
C. albicans ATCC90028 strain was inoculated into Sabouraud Dextrose (SD) medium, cultured at 30 ° C. until the logarithmic growth phase, and collected by centrifugation. This, RPMI1640 medium (RPMI1640 (with L-glutamine, without sodium bicarbonates), 0.165M 3-morpholinopropanesulfonic acid, PH7.0) was suspended in, to prepare a bacterial liquid such as a OD ₅₉₅ = 0.7. Each concentration of compound and [ ¹⁴ C] glucose (final concentration 1 μCi / mL) were added simultaneously to this bacterial solution, and after shaking culture at 30 ° C. for 60 min, each cell wall component (β-1,3-glucan, β-1 , 6-glucan, chitin, mannan). The radioactivity of each fraction was measured, and the uptake ratio (% control) was calculated with the value when no compound was added as 100%.

  The compound of the present invention specifically exhibited β-1,6-glucan synthase inhibitory action.

  The present invention provides a compound that can exhibit an antifungal action based on the action mechanism of 1,6-β-glucan synthesis inhibition in a broad spectrum and specifically or selectively, and such a compound, salt thereof Or an antifungal agent containing the hydrate thereof.

Claims (17)

A compound represented by the following formula (I), a salt thereof, or a hydrate thereof.

{ ^Where R ^l is
1) an amino group,
2) an alkylamino group having an alkyl group having 1 to 6 carbon atoms,
3) a dialkylamino group having an alkyl group having 1 to 6 carbon atoms, which may be the same or different,
4) an aminomethyl group,
5) an alkylaminomethyl group having an alkyl group having 1 to 6 carbon atoms, or 6) a dialkylaminomethyl group having an alkyl group having 1 to 6 carbon atoms which may be the same or different,
Represents a group selected from the following [a] to [c] having a basic substituent:
[A]: a saturated or partially saturated heterocyclic group containing a hetero atom 1 or 2 which may be selected from a hetero atom of a group consisting of a nitrogen atom, an oxygen atom and a sulfur atom,
[B]: a 5-membered or 6-membered cyclic hydrocarbon group which may contain a double bond,
[C]: The following formula:
-X ¹ - (alkyl group having 1 to 6 carbon atoms)
(Wherein, ^{X 1} is an oxygen atom, a sulfur atom, -CH ₂ -, or the formula:
Means a structure represented by -N ( ^-Rll )-,
R ^ll on the nitrogen atom represents hydrogen, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group or an aralkyl group having 7 to 9 carbon atoms, from 3 to 6 carbon atoms. Wherein the heterocyclic group and the cyclic hydrocarbon group in [a] or [b] may be selected from [Substituent Group 1] redundantly, or one or more groups May have
[Substituent group 1]:
Halogen atoms,
Hydroxyl group,
A carboxy group,
An alkyl group having 1 to 6 carbon atoms,
A halogenoalkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkoxymethyl group having 2 to 7 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms,
An aralkyloxy group having 7 to 9 carbon atoms,
An aralkyloxycarbonyl group having 8 to 10 carbon atoms, and the following formula:
^{-C (= O) -N (-R} 12) R 13
(Wherein, R ¹² and R ¹³ on the nitrogen atom each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms). ;
R ² is
Halogen atoms,
A hydroxymethyl group,
Formyl group,
A dialkylamino group having 1 to 6 carbon atoms which may be the same or different,
An alkyl group having 1 to 8 carbon atoms,
An alkenyl group having 2 to 8 carbon atoms,
An alkynyl group having 2 to 8 carbon atoms,
An alkoxycarbonyl group having 2 to 8 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms,
A cycloalkenyl group having 5 to 6 carbon atoms,
Monocyclic or bicyclic aryl groups,
A monocyclic or bicyclic heteroaryl group (including 1 to 4 heteroatoms which may be selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, or the following formula:
-X ² -R ²¹
[Wherein, X ² represents —C (═O) —, — (CH ₂ ) _n —, —C (═O) —N (—R ²² ) —, or —N (—R ²³ ) —C ( = O)-
n means any integer from 1 to 3,
R ²¹ is a monocyclic or bicyclic aryl group, or a monocyclic or bicyclic heteroaryl group (overlapping selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom) 1 to 4 heteroatoms that may be present.)
R ²² and R ²³ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. ] Represents a group represented by
These alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, and heteroaryl group have one or more groups that may be selected from [Substituent Group 2]. May be;
[Substituent group 2]:
Halogen atoms,
An amino group,
Hydroxyl group,
A carboxy group,
Nitrile group,
A halogenomethyl group,
A hydroxymethyl group,
An alkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms and the following formula:
^{-C (= O) -N (-R} 24) R 25
(Wherein, R ²⁴ Oyobi R ²⁵ on the nitrogen atom are each independently hydrogen atom, an aryl group an alkyl group or a C 6 to 10, from 1 to 6 carbon atoms.) Represented by Group;
Here, the amino group of [Substituent group 2] is an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 7 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms. 1 or 2 selected from the group consisting of an aralkyl group having 7 to 12 carbon atoms, an aromatic heterocyclic group, an alkylsulfonyl group having 1 to 6 carbon atoms, and an arylsulfonyl group having 6 to 10 carbon atoms A group may be substituted as a substituent, and when the amino group has two substituents, they may be bonded to each other to form a cyclic structure;
R ³ is
Hydrogen atom,
Halogen atoms,
A linear or branched alkyl group having 1 to 4 carbon atoms,
A cyclic alkyl group having 3 or 4 carbon atoms,
An alkoxy group having 1 to 4 carbon atoms,
Means a dialkylamino group, a halogenomethyl group, or an alkoxymethyl group having a C1 to C3 alkoxy group having the same or different alkyl chain and having a total of 2 to 4 carbon atoms;
R ⁴ and R ⁵ are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a monocyclic or bicyclic aryl group, a monocyclic or bicyclic ring A heteroaryl group of the formula, a group represented by the formula: —C (═O) —R ⁴¹ (wherein R ⁴¹ represents an alkyl group having 1 to 6 carbon atoms), or both And may include a nitrogen atom to which R ⁴ and R ⁵ are bonded to form a saturated, partially saturated or unsaturated ring having 3 to 7 carbon atoms, and a nitrogen atom or oxygen atom in the ring. , And one or more heteroatoms selected from the group consisting of sulfur atoms may be included, but this ring structure may have a substituent;
Provided that R ⁴ and R ⁵ are simultaneously hydrogen atoms;
Here, the alkyl group, the cycloalkyl group, the aryl group, the heteroaryl group, and the saturated ring, the partially saturated ring, or the unsaturated ring of R ⁴ or R ⁵ described above are duplicated from [Substituent group 3]. May have one or more groups which may be selected;
[Substituent group 3]:
Halogen atoms,
An amino group,
Hydroxyl group,
Formyl group,
A carboxy group,
Nitrile group,
A halogenomethyl group,
A hydroxymethyl group,
An alkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms;
X ¹ and X ² are each independently
A nitrogen atom or
Halogen atoms,
An alkoxy group having 1 to 6 carbon atoms,
An optionally substituted alkyl group having 1 to 6 carbon atoms,
Or it means a carbon atom that may be substituted with an ester group,
Either ^one of X ¹ and X ² is necessarily a nitrogen atom;
Here, the substituent of the alkyl group is one or more groups selected from the following group of substituents;
Halogen atoms,
An amino group,
Nitro group,
Hydroxyl group,
Mercapto group,
A carboxy group,
A cyano group,
An alkoxy group having 1 to 6 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms and an aryl group having 6 to 10 carbon atoms;
When the substituent on the carbon atom is an ester, these are
An alkyl ester having 1 to 6 carbon atoms,
Aryl esters having 6 to 10 carbon atoms,
Or an aralkyl ester composed of an alkyl group having 1 to 6 carbon atoms and an aryl group having 6 to 10 carbon atoms;
Furthermore, the aryl moiety of these aryl esters and aralkyl groups may be substituted with one or more groups selected from the group of the following substituents;
Halogen atoms,
An amino group,
Nitro group,
Hydroxyl group,
Mercapto group,
A carboxy group,
A cyano group,
An alkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms and an aryl group having 6 to 10 carbon atoms;
Means. } The compound according to claim 1, a salt thereof, or a hydrate thereof, wherein X ¹ and X ² are both nitrogen atoms. R ¹ is a saturated or partially saturated complex containing a hetero atom 1 or 2 which may be selected from a hetero atom of the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom having a basic substituent. The compound according to claim 1, a salt thereof, or a hydrate thereof, which is a cyclic group. The compound, its salt, or those hydrates of Claim 1 or 2 whose R < ¹ > is a nitrogen-containing heterocyclic group which has a basic substituent. The compound according to claim 1 or 2, a salt thereof, or a hydrate thereof, wherein R ¹ is a pyrrolidinyl group, cyclopentyl group, or cyclopentenyl group having a basic substituent. R ² is substituted it is also an aryl group, a compound according to any one of claims 1 to 5, a salt or hydrate thereof. R ² is substituted it is also a phenyl group, a compound according to any one of claims 1 to 5, a salt or hydrate thereof. The compound, its salt, or those hydrates as described in any one of Claims 1-7 whose R < ³ > is the C1-C4 alkyl group which may have a substituent. The compound according to any one of claims 1 to 7, a salt thereof, or a hydrate thereof, wherein R ³ is a methyl group. The compound according to any one of claims 1 to 9, or a salt thereof, wherein any one of R ⁴ and R ⁵ is an optionally substituted alkyl group having 1 to 6 carbon atoms. Their hydrates. The compound according to any one of claims 1 to 9, or a salt thereof, wherein any one of R ⁴ and R ⁵ is an optionally substituted acyl group having 2 to 7 carbon atoms. Their hydrates. Integrated is R ⁴ and R ⁵ includes a nitrogen atom R ⁴ and R ⁵ are attached, a saturated or aromatic ring of 3 to 7 carbon atoms, a compound according to any one of claims 1 9 , Its salts, or their hydrates. The pharmaceutical containing the compound as described in any one of Claims 1-12, its salt, or those hydrates. The infectious disease therapeutic agent containing the compound as described in any one of Claims 1-12, its salt, or those hydrates. The antifungal agent containing the compound as described in any one of Claims 1-12, its salt, or those hydrates. The treatment method of the infectious disease using the compound, its salt, or those hydrates as described in any one of Claims 1-12. Use for the treatment of an infectious disease which uses the compound as described in any one of Claims 1-12, its salt, or those hydrates.