JP2010070502A - Antifungal triazolopyridine derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound specifically or selectively exhibiting antifungal activity based on the action mechanism of inhibiting the synthesis of 1,6-β-glucan. <P>SOLUTION: The compound specifically or 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. ]
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 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,
A dialkylamino group having the same or different alkyl chain and a total carbon number of 2 to 4,
Means a halogenomethyl group or an alkoxymethyl group having an alkoxy group having 1 to 3 carbon atoms;
R ⁴ and R ⁵ are each independently a halogen atom, or both may be combined to form an oxo group;
R ⁶ is
Hydrogen atom,
An alkyl group having 1 to 6 carbon atoms,
An alkoxymethyl group having 2 to 7 carbon atoms,
Aromatic heterocyclic group or the following formula:
^{-C (= O) -N (-R} 61) R 62
(Wherein, R ⁶¹ and R ⁶² 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). Means
These alkyl group, alkoxymethyl group, and aromatic heterocyclic group may have one or more groups that may be selected in an overlapping manner from [Substituent group 3];
[Substituent group 3]:
Halogen atoms,
An alkoxy group having 1 to 6 carbon atoms,
Aromatic heterocyclic group and the following formula:
^{-N (-R 63) -C (=} O) R 64
A group represented by: wherein R ⁶³ on the nitrogen atom and R ⁶⁴ on the carbon atom each independently represents an alkyl group having 1 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,
1. A saturated or partially saturated heterocyclic group containing a heteroatom 1 or 2 which may be selected from a heteroatom of the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. 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. 1. R ⁴ and R ⁵ together are an oxo group. To 9. The compound as described in any one of these, its salt, or those hydrates.
11. 1. R ⁴ and R ⁵ are both halogen atoms. To 9. The compound as described in any one of these, its salt, or those hydrates.
12 The compound according to any one of claims 1 to 11, wherein R ⁶ is an optionally substituted alkyl group having 1 to 6 carbon atoms or an alkoxymethyl group having 2 to 7 carbon atoms. , Its salts, or their 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 ⁶ .

  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.

  “Aryl group” means a monovalent group obtained by removing one hydrogen atom from an aromatic ring of an aromatic hydrocarbon compound. 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 one ^{N (-R 81) R 82} or ^{-N (-R 81) - (CH} (-R 71) R 72) means a substituent represented by _n2,
b represents an integer of 0, 1, or 2;
n2 represents an integer of 0, 1 or 2;
R ⁸¹ and R ⁸² 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.
R ⁸¹ and R ⁸² are 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.
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 heterocyclic groups, and means what is called “aromatic heterocycle”. For example, a 5-membered or 6-membered monocyclic ring, a bicyclic benzo-fused ring system or a heterocyclic-heterocyclic fused ring system, a 5-6 fused ring system, a 6-6 fused 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, bivaloyl 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 [a] to [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,
A halogenoalkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkoxymethyl 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 or bicyclic heterocyclic group having 2 to 10 carbon atoms 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 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. Furthermore, it is preferable that a fluorine atom is bonded to a carbon atom adjacent to the carbon atom to which the basic substituent is bonded.

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 of the group represented by [a] or [b] is preferred, and among them, the basic substitution on the group of the group represented by [a] A structure having a group is particularly preferred. Specifically, it has the following structure.

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

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. The phenyl group may have a substituent, and one or more hydroxyl groups, amino groups, halogen atoms, nitrile groups, alkyl groups having 1 to 3 carbon atoms, alkoxy groups having 1 to 3 carbon atoms, etc. May be substituted. 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 heteroatoms. 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.

Among these, as R ³ , an alkyl group and a halogen atom are preferable, and specifically, a methyl group and a chloro group are preferable.

R ⁴ and R ⁵ are each independently a halogen atom, or both may be integrated to form an oxo group.

As R ⁴ and R ⁵ , both are preferably fluorine atoms, and it is also preferable that both are integrated to form an oxo group.

R ⁶ is
Hydrogen atom,
An alkyl group having 1 to 6 carbon atoms,
An alkoxymethyl group having 1 to 6 carbon atoms,
Aromatic heterocyclic group or the following formula:
^{-C (= O) -N (-R} 61) R 62
(Wherein, R ⁶¹ and R ⁶² 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). Means
These alkyl group, alkoxymethyl group, and aromatic heterocyclic group may have one or more groups that may be selected in an overlapping manner from [Substituent group 3];
[Substituent group 3]:
Halogen atoms,
An alkoxy group having 1 to 6 carbon atoms,
Aromatic heterocyclic group and the following formula:
^{-N (-R 63) -C (=} O) R 64
(Wherein R ⁶³ on the nitrogen atom and R ⁶⁴ on the carbon atom each independently represents an alkyl group having 1 to 6 carbon atoms).

R ⁶ includes an alkyl group having 1 to 6 carbon atoms,
A methyl group substituted with a halogen atom,
A methyl group substituted by the formula: —N (—R ⁶³ ) —C (═O) R ⁶⁴ (wherein R ⁶³ and R ⁶⁴ each represent an alkyl group having 1 to 6 carbon atoms);
A methyl group substituted by an aromatic heterocyclic group,
An alkoxymethyl group having 1 to 6 carbon atoms,
A C1-C6 alkoxymethyl group substituted with a C1-C6 alkoxy group, or an aromatic heterocyclic group is preferable.

Specifically, methyl group, fluoromethyl group, ethyl group, isopropyl group, —CH ₂ —N (CH ₃ ) —C (═O) —CH ₃ , methyl group substituted by triazolyl group, methoxymethyl group, An ethoxymethyl group, a methoxyethoxymethyl group, and a triazolyl group are preferable.

  More preferred are an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 1 to 6 carbon atoms, and an alkoxymethyl group substituted with an alkoxy group having 1 to 6 carbon atoms. Specifically, a methyl group, an ethyl group, an isopropyl group, a methoxymethyl group, an ethoxymethyl group, and a methoxyethoxymethyl group 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) a halogen atom, (2) a substituent selected from the group of oxo groups formed by integration of both; R ⁶ (1) an alkyl group having 1 to 6 carbon atoms, (2) a methyl group substituted with a halogen atom, (3) a formula: —N (—R ⁶³ ) —C (═O) R ⁶⁴ (wherein R ⁶³ and R ⁶⁴ each independently represents an alkyl group having 1 to 6 carbon atoms.), (4) a methyl group substituted with an aromatic heterocyclic group, and (5) a carbon number of 1 (6) an alkoxymethyl group having 1 to 6 carbon atoms A combination of; conversion has been alkoxymethyl group having a carbon number of 1, (7) a substituent selected from the group of the group of the heterocyclic group.

In one more preferred embodiment, R ² is an aryl group; R ¹ is a 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 Saturated nitrogen-containing heterocyclic group or cyclic hydrocarbon group; R ³ is an alkyl group having 1 to 3 carbon atoms; R ⁴ and R ⁵ are both (1) a halogen atom, and (2) both are integrated A substituent selected from a group of substituents selected from an oxo group; R ⁶ is (1) an alkyl group having 1 to 6 carbon atoms, (2) an alkoxymethyl group having 1 to 6 carbon atoms, and (3) carbon. A substituent selected from the group of the alkoxymethyl group having 1 to 6 carbon atoms substituted with an alkoxymethyl group having 1 to 6 carbon atoms.

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 , pyrrolidinyl group substituted with an alkylamino group or dialkylamino group having 1 to 6 carbon atoms; is R ^3, a methyl group; is R ⁴ and R ^5, together fluorine or both oxo group formed integrally, A substituent selected from the group of groups; R ⁶ is a substituent selected from the group of the group of methyl group, methyl fluoride group, ethyl group, isopropyl group, methoxymethyl group, ethoxymethyl group, methoxyethoxymethyl group; It is a combination.

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. R ³ is a methyl group; R ⁴ and R ⁵ are both fluorine atoms, or a substituent selected from the group of oxo groups formed by integration of both; R ⁶ is methyl A substituent selected from the group consisting of a group, an ethyl group, an isopropyl group, a methoxymethyl group, an ethoxymethyl group, and a methoxyethoxymethyl group.

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. Moreover, the definition of R ¹ to R ⁶ in the following production method is the same as the definition of the substituent of formula (I), and X represents a halogen atom.

Manufacturing method 1

(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.

  Manufacturing method 2

On the other hand, the substituents (R ⁴ , R ⁵ , R ⁶ ) on the acetonitrile derivative of triazole can be converted to the target substituents afterwards as ester groups, as shown below. R ⁷ includes alkyl groups (methyl group, ethyl group, t-butyl group and the like), phenyl groups and substituted derivatives thereof such as 4-methoxyphenyl group, allyl group, vinyl group, benzyl group, 4-methoxybenzyl group and the like. The substituted derivatives of are used. Preferred are lower alkyl groups such as a methyl group and an ethyl group.

Step 4 is a step of producing the primary alcohol body (7) by reducing the ester group. As a reducing reagent, a reducing reagent capable of selectively reducing an ester group in the presence of a nitrile group, for example, LiAlH ₄ , i-Bu ₂ AlH, LiB (Et) ₃ H, NaCNBH ₃ , NaBH ₄ , Zn (BH ₄ ) ₂ , Red-Al, B ₂ H _{6 and the} like. NaBH ₄ is preferable.

  Step 5 is a step of producing an aldehyde form (8) by oxidizing the primary alcohol form (7). As oxidizing reagents, such as Dess-Martin periodinane, chromic acid derivatives (pyridinium chlorochromate, pyridinium dichromate, chromium oxide, etc.), DMSO oxidation (such as Swern oxidation, etc.), etc. If it is.

Further, as shown in Step 6, the ester group of compound (6) can be directly converted to aldehyde group (8) without going through compound (7). Examples of the reducing reagent used include i-Bu ₂ AlH.

Step 7 is a step of producing a secondary alcohol (9) by introducing an alkyl group to the aldehyde group (8). Examples of the alkylating reagent used in this step include alkyl lithium (R ⁶ Li), alkyl magnesium halide (R ⁶ MgX), alkyl titanium trialkoxide (R ⁶ Ti (OR) ₃ ), and dialkyl zinc (R ⁶ ₂ Zn). Etc.

  Step 8 is a step of producing a ketone body (10) by oxidizing the secondary alcohol (9). As an oxidizing reagent, such as Dess-Martin periodinane, chromic acid derivatives (pyridinium chlorochromate, pyridinium dichromate, chromium oxide, etc.), DMSO oxidation (Swern oxidation etc.), etc. are generally used to convert secondary hydroxyl groups to ketones. If it is.

Step 9 is a difluorination step of the ketone body (10). As the fluorinating reagent, dialkylaminosulfur trifluorides (Et ₂ NSF ₃ , (CH ₂ OCH ₂ CH ₂ ) ₂ NSF _3, etc.) are preferably used.

  Production method 3

(In the formula, R ⁷ is the same as described above, R ⁸ is O or CH ₂ , and R ⁹ and R ¹⁰ are each independently an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms.)
On the other hand, the secondary alcohol (9) can also be synthesized via the epoxide (13) shown in Step 10.

  At that time, the epoxide (13) can be produced by reacting the aldehyde (9) with a base such as trimethylsulfoxonium iodozide and sodium hydride. Moreover, it can manufacture also by making a peroxide (example: mCPBA etc.) act on a vinyl body (12).

  Step 11 is a step of producing a secondary alcohol (9) by allowing a nucleophile to act on the epoxide (13). As the nucleophile, sodium salt or potassium salt of alcohol, amines, alkyl magnesium halide in the presence of copper salt, mono- or dialkyl copper lithium, etc. are used.

  The ester body (6) can be derived into the ketone body (10) by direct alkylation to the amide (14) as shown in the step 13, regardless of the route shown in the steps 4 to 11.

  That is, step 12 is a step of producing amide (14) by hydrolyzing ester body (6) to carboxylic acid and then condensing with secondary amine. The amide (14) can also be directly produced by reacting an ester amide (6) with an aluminum amide obtained from a secondary amine and a trialkylaluminum represented by trimethylaluminum. The secondary amine used here is preferably N, O-dimethylhydroxylamine.

Step 13 is a step of producing ketone body (10) by alkylating amide (14). Examples of the alkylating reagent used in this step include alkyl lithium (R ⁶ Li), alkyl magnesium halide (R ⁶ MgX), and dialkyl zinc (R ⁶ ₂ Zn).

Manufacturing method 4

The substituent (R ⁴ , R ⁵ , R ⁶ ) on the acetonitrile derivative of triazole may be converted to an alkyloxymethyl group (R ¹¹ OCH ₂ ) and then converted to the desired substituent as shown below. it can. As R ¹¹ , an alkyl group (methyl group, ethyl group, t-butyl group and the like), a phenyl group and a substituted derivative thereof such as a 4-methoxyphenyl group, and a substituted derivative such as a benzyl group and a 4-methoxybenzyl group are used. It is done.

Step 14 is a step of producing the primary alcohol (7) by removing the alkyl group of the compound (15). When R ¹¹ is an alkyl group (methyl group, ethyl group, t-butyl group, etc.), as a dealkylating reagent, Lewis acids such as BBr ₃ and AlCl ₃ are used, and R ¹¹ is a phenyl group and a 4-methoxyphenyl group. In the case of substituted derivatives thereof such as cerium ammonium nitrate, and in the case where R ¹¹ is a substituted derivative such as benzyl group and 4-methoxybenzyl group, by hydrogenation in the presence of Pd, Rh, etc., or 4-methoxybenzyl In the case of a group or the like, DDQ or the like is used.

Manufacturing method 5

When R ² is hydrogen, the compound of the present invention represented by the formula (I) can also be produced via the compound (17).

Step 15 is a step of halogenating (for example, Cl, Br, I) the compound (16) in which R ² is hydrogen.

Step 16 is a step of producing the compound of the present invention represented by the formula (I) from a product obtained by utilizing R ² for the halogen compound (17) by Suzuki cross coupling reaction or Stille cross coupling reaction. It is.

Manufacturing method 6

When R ¹ is a cycloalkenyl group, a cycloalkyl group, or an alkyl group, a compound represented by the formula (I) is directly represented from the acetonitrile derivative of triazole as the compound (I) and the diketone derivative as the compound (18). Inventive compounds can also be produced.

  The substituent introduced in Step 1 to Step 17 can be appropriately protected with a functional group, removed with a protective group, or converted into a functional group as 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, those 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 salts, sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, ammonium salts, triethylamine salts, N-methylglucamine salts, tris salts. -(Hydroxymethyl) aminomethane salt and the like may be either inorganic salt or organic salt 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]
Ethyl imino (isopropoxy) acetate hydrochloride (I-1)

Ethyl cyanoformate (100 g, 1.01 mol) and isopropanol (77.2 ml, 1.01 mol) were dissolved in diethyl ether (880 ml) and cooled to -5 ° C. Hydrochloric acid gas was bubbled into this solution for 4 hours, being careful not to let the internal temperature exceed 10 ° C. After gently stirring at the same temperature for 24 hours, the solvent was distilled off under reduced pressure. Toluene (500 ml) was added to the obtained residue, and azeotropic distillation was performed under reduced pressure. This operation was repeated once more. The obtained residue was dried well under reduced pressure, and diisopropyl ether (500 ml) was added thereto for sonication. The insoluble solid was collected by filtration with washing with diisopropyl ether and then dried well under reduced pressure to obtain 188.22 g (95%) of the title compound as a colorless solid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.27 (3H, t, J = 7.1 Hz), 1.32 (6H, d, J = 6.1 Hz), 4.28 (2H, q, J = 7.1 Hz), 5.23 ( 1H, dq, J = 6.1, 6.1 Hz), 11.78 (1H, br s).
[Reference Example 2]
Ethyl 5- (cyanomethyl) -1H-1,2,4-triazole-3-carboxylate (I-2)

Ethylimino (isopropoxy) acetate hydrochloride (I-1) (94 g, 430.38 mmol) was suspended in diethyl ether (1500 ml), and triethylamine (70.3 ml, 504.4 mmol) was slowly added over 10 minutes at 0 ° C. It was dripped. The suspension was stirred for 19 hours while gradually warming to room temperature. The insoluble material was filtered off while washing with diethyl ether, and the filtrate was concentrated under reduced pressure. When normal hexane (300 ml) was added to the obtained residue and sonication was performed, a colorless solid precipitated. The solid was filtered off while washing with normal hexane, and the filtrate was concentrated again under reduced pressure. Ethanol (1200 ml) was added to the obtained residue (oil), and cyanoacetohydrazide (49.1 g, 480.38 mmol) was slowly added at 0 ° C. After stirring this solution at room temperature for 69.5 hours, the solvent was distilled off under reduced pressure. Acetic acid (1200 ml) was added to the residue, and the solution was stirred at 130 ° C. for 4 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. Toluene (500 ml) was added to the residue and distilled off azeotropically under reduced pressure. The obtained residue was purified twice by silica gel column chromatography (first time: mobile phase: chloroform: methanol = 9: 1, v / v; second time: mobile phase: chloroform: methanol = 95: 5, v / v) The title compound 74.23 g (86%) was obtained as a pale yellow solid.
ESI-MS m / z: 181 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.39 (3H, t, J = 7.1 Hz), 4.12 (2H, s), 4.47 (2H, q, J = 7.1 Hz), 11.05 (1H, br).
[Reference Example 3]
Ethyl 8-cyano-7-methyl-5-oxo-6-phenyl-1,5-dihydro [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-3)

Ethyl 5- (cyanomethyl) -1H-1,2,4-triazole-3-carboxylate (I-2) (20 g, 111.0 mmol), ethyl 2-phenylacetoacetate (25.96 g, 122.1 mmol) and ammonium acetate (17.97 g, 233.13 mmol) was mixed and gently stirred at 80 ° C. for 4.75 hours. The reaction temperature was then raised to 100 ° C. and further heated for 23 hours. After the mixture was cooled to room temperature, it was heated to 90 ° C. under reduced pressure and dried for 2.5 hours. Diisopropyl ether (300 ml) was added to the obtained residue, and sonication / spatula pulverization was repeated to make the solid powder. The solid was then collected by filtration with washing with diisopropyl ether (200 ml) and dried under reduced pressure at 60 ° C. for 3 hours and then at room temperature for 60.5 hours to give 34.8 g (97%) of the title compound as a brown powdery solid. Obtained.
ESI-MS m / z: 323 (M + 1) ⁺ .
¹ H-NMR (DMSO-d ₆ ) δ: 1.35 (3H, t, J = 7.1 Hz), 2.13 (3H, s), 4.36 (2H, q, J = 7.1 Hz), 7.20-7.29 (3H, m ), 7.34-7.40 (2H, m).
[Reference Example 4]
Ethyl 5-chloro-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-4)

Ethyl 8-cyano-7-methyl-5-oxo-6-phenyl-1,5-dihydro [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-3) (40 g, 124.1 mmol) was suspended in phosphorus oxychloride (400 ml) and heated to reflux for 9 hours (dissolved gradually when heated). The reaction solution was cooled to room temperature and concentrated under reduced pressure. Toluene (400 ml) was added to the obtained residue, and azeotropic distillation was performed under reduced pressure. The residue was purified by silica gel column chromatography (silica gel: 400 g; mobile phase: chloroform: methanol = 98: 2, v / v) to obtain an ocher solid. Diisopropyl ether (500 ml) was added thereto, sonicated, and the solid was collected by suction filtration while washing with diisopropyl ether. The solid was collected and dried under reduced pressure to give 38.3 g (91%) of the title compound as a brown powdery solid.
ESI-MS m / z: 341 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.50 (3H, t, J = 7.1 Hz), 2.48 (3H, s), 4.59 (2H, q, J = 7.1 Hz), 7.24-7.27 (2H, m), 7.52-7.60 (3H, m).
[Reference Example 5]
Ethyl 5-{(3S) -3-[(tert-butoxycarbonyl) (methyl) amino] -3-methylpyrrolidin-1-yl} -8-cyano-7-methyl-6-phenyl [1,2,4 ] Triazolo [1,5-a] pyridine-2-carboxylate (I-5)

Of ethyl 5-chloro-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-4) (2.1 g, 6.16 mmol) To a tetrahydrofuran (20 ml) solution was added tert-butylmethyl [(3S) -3-methylpyrrolidin-3-yl] carbamate (synthesized according to the method described in WO2007 / 020936) (1.58 g, 7.40 mmol) and triethylamine ( 1.29 ml, 9.24 mmol) was added, and the mixture was stirred on an oil bath at 50 ° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 1: 1, v / v), 3.20 g (100%) of the title compound was obtained as a colorless solid.
¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, s), 1.42 (9H, s), 1.47 (3H, t, J = 7.1 Hz), 1.87-2.07 (2H, m), 2.30 (3H, s ), 2.75 (3H, s), 3.10-3.22 (1H, m), 3.46-3.74 (3H, m), 4.53 (2H, q, J = 7.1 Hz), 7.09-7.54 (5H, m).
[Reference Example 6]
tert-Butyl {(3S) -1- [8-Cyano-2- (hydroxymethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3-Methylpyrrolidin-3-yl} methylcarbamate (I-6)

Ethyl 5-{(3S) -3-[(tert-butoxycarbonyl) (methyl) amino] -3-methylpyrrolidin-1-yl} -8-cyano-7-methyl-6-phenyl [1,2,4 ] Triazolo [1,5-a] pyridine-2-carboxylate (I-5) (5.00 g, 9.64 mmol) in methanol (100 ml) at room temperature, sodium borohydride (3.28 g, 86.8 mmol) And tetrahydrofuran (50 ml) were added, and the mixture was stirred at the same temperature for 5 hours. Under ice-cooling, a saturated aqueous ammonium chloride solution was added to the reaction solution, and water was added to the residue obtained by concentration under reduced pressure, followed by extraction with chloroform. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 1: 1, v / v), 4.01 g (87%) of the title compound was obtained as a pale yellow foam.
HRESI-MS m / z: 477.2580 (Calcd for C ₂₆ H ₃₃ N ₆ O ₃ 477.2614).
¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, s), 1.42 (9H, s), 1.87-2.06 (2H, m), 2.28 (3H, s), 2.56 (1H, t, J = 6.0 Hz ), 2.75 (3H, s), 3.10-3.18 (1H, m), 3.52-3.65 (3H, m), 4.93 (2H, d, J = 6.0 Hz), 7.09-7.13 (1H, m), 7.26- 7.31 (1H, m), 7.40-7.52 (3H, m).
[Reference Example 7]
tert-butyl {(3S) -1- [8-cyano-2-formyl-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3- Methylpyrrolidin-3-yl} methylcarbamate (I-7)

tert-Butyl {(3S) -1- [8-Cyano-2- (hydroxymethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] Dess-Martin periodinane (9.35 g, 22.0 mmol) was added to a solution of -3-methylpyrrolidin-3-yl} methylcarbamate (I-6) (3.50 g, 7.34 mmol) in dichloromethane (50 ml) under ice-cooling. And stirred at room temperature for 4 hours. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution and a 10% aqueous sodium thiosulfate solution were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with chloroform, and the resulting organic phase was dried over anhydrous sodium sulfate. Insoluble materials were filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography. (Eluent; chloroform: ethyl acetate = 1: 1, v / v), 3.42 g (98%) of the title compound was obtained as a pale yellow solid.
HRESI-MS m / z: 475.2479 (Calcd for C ₂₆ H ₃₁ N ₆ O ₃ 475.2458).
¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, s), 1.42 (9H, s), 1.92-2.04 (2H, m), 2.32 (3H, s), 2.75 (3H, s), 3.17-3.24 (1H, m), 3.58-3.70 (3H, m), 7.12-7.14 (1H, m), 7.25-7.33 (1H, m), 7.42-7.54 (3H, m), 10.23 (1H, s).
[Reference Example 8]
tert-butyl {(3S) -1- [8-cyano-2- (1-hydroxyethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-5- Yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-8)

tert-butyl {(3S) -1- [8-cyano-2-formyl-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3- To a solution of methylpyrrolidin-3-yl} methylcarbamate (I-7) (1.0 g, 2.11 mmol) in tetrahydrofuran (20 ml), ice-cooled methylmagnesium bromide (0.97 mol tetrahydrofuran solution) (2.61 ml, 2.53 mmol) ) Was added and stirred at 0 ° C. for 1 hour. Further, methylmagnesium bromide (0.97 mol tetrahydrofuran solution) (2.61 ml, 2.53 mmol) was added to the reaction solution, and the mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 2 hours. Under ice-cooling, 1N aqueous hydrochloric acid solution was added to the reaction mixture, this was extracted with ethyl acetate, and the resulting organic phase was washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: normal hexane: ethyl acetate). = 1: 1, v / v), and 535 mg (52%) of the title compound was obtained as a pale yellow solid.
HRESI-MS m / z: 491.2723 (Calcd for C ₂₇ H ₃₅ N ₆ O ₃ 491.2771).
¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, s), 1.41-1.43 (9H, m), 1.67-1.71 (3H, m), 1.87-2.04 (2H, m), 2.27-2.29 (3H, m), 2.75 (3H, s), 2.88-2.93 (1H, m), 3.09-3.16 (1H, m), 3.47-3.56 (1H, m), 3.61-3.66 (2H, m), 5.09-5.17 ( 1H, m), 7.08-7.13 (1H, m), 7.26-7.30 (1H, m), 7.40-7.52 (3H, m).
[Reference Example 9]
tert-butyl [(3S) -1- (2-acetyl-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3- Methylpyrrolidin-3-yl] methylcarbamate (I-9)

tert-butyl {(3S) -1- [8-cyano-2- (1-hydroxyethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-5- [Ils] -3-methylpyrrolidin-3-yl} methylcarbamate (I-8) (100 mg, 0.20 mmol) in dichloromethane (2 ml) under ice-cooling, Dess-Martin periodinane (259 mg, 0.61 mmol) And stirred at room temperature for 30 minutes. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution and a 10% aqueous sodium thiosulfate solution were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with chloroform, and the resulting organic phase was dried over anhydrous sodium sulfate. Insoluble matters were filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography. (Eluent; chloroform: ethyl acetate = 2: 1, v / v), 100 mg (100%) of the title compound was obtained as a pale yellow solid.
HRESI-MS m / z: 489.2577 (Calcd for C ₂₇ H ₃₃ N ₆ O ₃ 489.2614).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, s), 1.42 (9H, s), 1.89-2.06 (2H, m), 2.31 (3H, s), 2.75 (3H, s), 2.80 (3H , s), 3.14-3.22 (1H, m), 3.52-3.62 (1H, m), 3.63-3.72 (2H, m), 7.10-7.14 (1H, m), 7.29-7.33 (1H, m), 7.41 -7.54 (3H, m).
[Example 1]
2-Acetyl-7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl [1,2,4] triazolo [1,5-a] Pyridine-8-carbonitrile (# 1)

tert-butyl [(3S) -1- (2-acetyl-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3- Trifluoroacetic acid (1 ml) was added to a solution of methylpyrrolidin-3-yl] methylcarbamate (I-9) (80 mg, 0.16 mmol) in dichloromethane (2 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with chloroform. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated, and the resulting residue was purified by preparative TLC (eluent; chloroform: methanol = 10: 1, v / v) and 41.0 mg (64%) of the title compound were obtained as a pale yellow solid.
ESI-MS m / z: 389 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, s), 1.61-1.67 (1H, m), 1.76-1.83 (1H, m), 2.28 (3H, s), 2.31 (3H, s), 2.81 (3H, s), 3.22 (1H, d, J = 10.5 Hz), 3.30-3.43 (3H, m), 7.18-7.24 (2H, m), 7.44-7.53 (3H, m).
IR (ATR): 2968, 2212, 1706, 1607, 1533, 1504, 1471, 1438, 1395, 1374, 1351, 1268, 1251, 1156, 1118, 1073, 1021, 956, 873 cm ^-1 .
Anal. Calcd for C ₂₂ H ₂₄ N ₆ O ・ 0.25H ₂ O: C, 67.24; H, 6.28; N, 21.39. Found: C, 67.52; H, 6.28; N, 21.59.
[Reference Example 10]
Benzyl (3R) -3-[(tert-butoxycarbonyl) (methyl) amino] -4-fluoro-3-methylpyrrolidine-1-carboxylate (I-10)

Benzyl (3R) -3-[(tert-butoxycarbonyl) amino] -4-fluoro-3-methylpyrrolidine-1-carboxylate (synthesized according to the method described in WO2006 / 123792) (234 mg, 0.64 mmol) and Dissolve methyl iodide (62 μl, 1.0 mmol) in N, N-dimethylformamide (3 ml), add sodium hydride (55% in paraffin liquid) (34.8 mg, 0.80 mmol) under ice cooling. Stir at temperature for 1 hour. Under ice-cooling, 10% aqueous citric acid solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic phase was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble material was filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 4: 1, v / v → 2: 1, v / v), and 236 mg (97%) of the title compound was obtained as a colorless oil.
ESI-MS m / z: 389 (M + 23) ⁺ .
HRESI-MS m / z: 367.2018 (Calcd for C ₁₉ H ₂₈ FN ₂ O ₄ 367.2033).
¹ H-NMR (CDCl ₃ ) δ: 1.40 (3H, dd, J = 9.5, 2.4 Hz), 1.46 (9H, d, J = 7.6 Hz), 2.87 (3H, d, J = 2.4 Hz), 3.51 ( 1H, ddd, J = 22.0, 12.3, 4.3 Hz), 3.67-3.86 (3H, m), 5.14 (2H, s), 5.26-5.55 (1H, m), 7.21-7.40 (5H, m).
IR (ATR): 2976, 2939, 2891, 1695, 1587, 1454, 1421, 1390, 1352, 1250, 1157, 1115, 1090, 1057, 1014, 966, 866, 768 cm ^-1 .
[Reference Example 11]
tert-Butyl [(3R) -4-fluoro-3-methylpyrrolidin-3-yl] methylcarbamate (I-11)

Benzyl (3R) -3-[(tert-butoxycarbonyl) (methyl) amino] -4-fluoro-3-methylpyrrolidine-1-carboxylate (I-10) (235 mg, 0.64 mmol) was converted to 1,4- The mixture was dissolved in dioxane (6 ml), palladium hydroxide catalyst (20% on carbon) (50 mg) was added, and the mixture was stirred at room temperature for 17 hours in a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (149 mg, 100%) as a colorless oil.
ESI-MS m / z: 233 (M + 23) ⁺ .
HRESI-MS m / z: 233.1640 (Calcd for C ₁₁ H ₂₂ FN ₂ O ₂ 233.1665).
¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, d, J = 4.6 Hz), 1.47 (9H, s), 2.92-2.90 (3H, m), 3.08 (1H, ddd, J = 23.9, 13.0, 3.5 Hz), 3.18-3.31 (3H, m), 5.28 (1H, dq, J = 53.6, 3.5 Hz).
IR (ATR): 2976, 2931, 2873, 1689, 1477, 1456, 1365, 1352, 1254, 1157, 1130, 1111, 1053, 1011, 924, 868, 777 cm ^-1 .
[Reference Example 12]
Ethyl 5-{(3R) -3-[(tert-butoxycarbonyl) (methyl) amino] -4-fluoro-3-methylpyrrolidin-1-yl} -8-cyano-7-methyl-6-phenyl [1 , 2,4] Triazolo [1,5-a] pyridine-2-carboxylate (I-12)

Of ethyl 5-chloro-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-11) (1.40 g, 4.11 mmol) To a tetrahydrofuran (20 ml) solution was added tert-butyl [(3R) -4-fluoro-3-methylpyrrolidin-3-yl] methylcarbamate (1.0 g, 4.31 mmol) and triethylamine (744 μl, 5.34 mmol). Stir at 50 ° C. for 17 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and the obtained organic phase was washed with water and saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 1: 1, v / v) to give 1.34 g (61%) of the title compound as a colorless solid.
HRESI-MS m / z: 537.2599 (Calcd for C ₂₈ H ₃₄ FN ₆ O ₄ 537.2626).
¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 2.7 Hz), 1.43 (9H, s), 1.48 (3H, t, J = 7.1 Hz), 2.32 (3H, s), 2.84 ( 3H, d, J = 1.5 Hz), 3.42 (1H, ddd, J = 21.6, 11.8, 4.0 Hz), 3.59-3.80 (3H, m), 4.54 (2H, q, J = 7.1 Hz), 5.22-5.42 (1H, m), 7.18-7.25 (2H, m), 7.43-7.54 (3H, m).
[Reference Example 13]
tert-butyl {(3R) -1- [8-cyano-2- (hydroxymethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -4-Fluoro-3-methylpyrrolidin-3-yl} methylcarbamate (I-13)

Ethyl 5-{(3R) -3-[(tert-butoxycarbonyl) (methyl) amino] -4-fluoro-3-methylpyrrolidin-1-yl} -8-cyano-7-methyl-6-phenyl [1 , 2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-12) (510 mg, 0.95 mmol) in methanol (2 ml) and tetrahydrofuran (10 ml) under ice cooling, Sodium borohydride (55% in paraffin liquid) (71.9 mg, 1.90 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Under ice-cooling, a 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography. (Eluent: normal hexane: ethyl acetate = 1: 1, v / v), 216 mg (46%) of the title compound was obtained as a colorless solid.
HRESI-MS m / z: 495.2473 (Calcd for C ₂₆ H ₃₂ FN ₆ O ₃ 495.2520).
¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, d, J = 2.4 Hz), 1.43 (9H, s), 2.30 (3H, s), 2.52-2.60 (1H, m), 2.82 (3H, s ), 3.44-3.70 (4H, m), 4.94 (2H, d, J = 5.4 Hz), 5.20-5.40 (1H, m), 7.16-7.22 (2H, m), 7.42-7.52 (3H, m).
[Reference Example 14]
tert-butyl {(3R) -1- [8-cyano-2- (1-hydroxyethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-5- Yl] -4-fluoro-3-methylpyrrolidin-3-yl} methylcarbamate (I-14)

tert-Butyl {(3R) -1- [8-Cyano-2- (hydroxymethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] 4-fluoro-3-methylpyrrolidin-3-yl} methylcarbamate (I-13) (216 mg, 0.44 mmol) in dichloromethane (5 ml) under ice-cooling, Dess-Martin periodinane (556 mg, 1.31 mmol) was added and stirred at room temperature for 2 hours. Under ice-cooling, a saturated aqueous sodium bicarbonate solution and a 10% aqueous sodium thiosulfate solution were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, and the obtained organic phase was washed with water and saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated.To a solution of the aldehyde in tetrahydrofuran (5 ml) was added methylmagnesium bromide (0.97 mol) under ice-cooling. Tetrahydrofuran solution) (1.08 ml, 1.05 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour. Under ice-cooling, 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic phase was washed with water and saturated brine. The obtained 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: ethyl acetate = 1: 1, v / v) and 191 mg (86%) of the title compound were obtained as a colorless solid.
HRESI-MS m / z: 509.2616 (Calcd for C ₂₇ H ₃₄ FN ₆ O ₃ 509.2676).
¹ H-NMR (CDCl ₃ ) δ: 1.27-1.31 (3H, m), 1.42 (9H, s), 1.70 (3H, d, J = 6.6 Hz), 2.30 (3H, s), 2.81-2.84 (3H , m), 2.87-2.99 (1H, m), 3.41-3.70 (4H, m), 5.14 (1H, q, J = 6.5 Hz), 5.30 (1H, dt, J = 53.2, 4.8 Hz), 7.16- 7.22 (2H, m), 7.41-7.53 (3H, m).
[Reference Example 15]
tert-butyl {(3R) -1- [2-acetyl-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -4- Fluoro-3-methylpyrrolidin-3-yl} methylcarbamate (I-15)

tert-butyl {(3R) -1- [8-cyano-2- (1-hydroxyethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-5- [Il] -4-fluoro-3-methylpyrrolidin-3-yl} methylcarbamate (I-14) (191 mg, 0.38 mmol) in dichloromethane (4 ml) under ice-cooling, Dess-Martin periodinane (478 mg , 1.13 mmol) was added and stirred at room temperature for 1 hour. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution and a 10% aqueous sodium thiosulfate solution were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate, and the resulting organic phase was washed with water and saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 4: 1, v / v), 190 mg (100%) of the title compound were obtained as a colorless solid.
HRESI-MS m / z: 507.2495 (Calcd for C ₂₇ H ₃₂ FN ₆ O ₃ 506.2520).
_{^{1 H-NMR (CDCl 3)}} δ: 1.31 (3H, d, J = 2.7 Hz), 1.43 (9H, s), 2.33 (3H, s), 2.81 (3H, s), 2.82-2.85 (3H, m ), 3.41-3.73 (4H, m), 5.32 (1H, dt, J = 53.5, 4.9 Hz), 7.21-7.23 (2H, m), 7.44-7.55 (3H, m).
[Example 2]
2-acetyl-5-[(3R) -4-fluoro-3-methyl-3- (methylamino) pyrrolidin-1-yl] -7-methyl-6-phenyl [1,2,4] triazolo [1, 5-a] pyridine-8-carbonitrile (# 2)

tert-butyl {(3R) -1- [2-acetyl-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -4- To a solution of fluoro-3-methylpyrrolidin-3-yl} methylcarbamate (I-15) (190 mg, 0.38 mmol) in dichloromethane (4 ml) is added trifluoroacetic acid (2 ml) under ice-cooling, and the mixture is brought to 0 ° C. And stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, dissolved in chloroform, and the obtained organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, the insoluble material was filtered off, and the residue obtained by concentration was purified by silica gel column chromatography (eluent; chloroform: methanol = 10: 1, v / v )did. Further, the purified product was purified by slurry with diisopropyl ether to obtain 125 mg (82%) of the title compound as a pale yellow solid.
ESI-MS m / z: 407 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, d, J = 2.9 Hz), 2.31 (3H, s), 2.33 (3H, s), 2.82 (3H, s), 3.17 (1H, dd, J = 10.7, 2.2 Hz), 3.25-3.38 (2H, m), 4.18 (1H, ddd, J = 37.8, 12.7, 4.2 Hz), 4.61 (1H, dd, J = 53.0, 4.15 Hz), 7.12-7.17 ( 1H, m), 7.26-7.30 (1H, m), 7.45-7.56 (3H, m).
IR (ATR): 3355, 3053, 2942, 2883, 2807, 2212, 1709, 1606, 1534, 1500, 1457, 1376, 1352, 1324, 1266, 1216, 1174, 1161, 1093, 1073, 1052, 1024, 1005 , 958, 876 cm ^-1 .
Anal. Calcd for C ₂₂ H ₂₃ FN ₆ O: C, 65.01; H, 5.70; N, 20.68; F, 4.67. Found: C, 64.68; H, 5.78; N, 20.54; F, 4.80.
[Reference Example 16]
tert-Butyl [(3S) -1- {8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-5 -Il} -3-Methylpyrrolidin-3-yl] methylcarbamate (I-16)

N, O-dimethylhydroxylamine hydrochloride (113 mg, 1.16 mmol) was suspended in dichloromethane (2 ml), and trimethylaluminum (1.05 molar normal hexane solution) (1.1 ml, 1.16 mmol) was added dropwise at 0 ° C. The mixture was stirred at the same temperature for 15 minutes and then at room temperature for 1 hour. After cooling to 0 ° C again, ethyl 5-{(3S) -3- [tert-butoxycarbonyl] (methyl) amino} -3-methylpyrrolidin-1-yl} -8-cyano-7-methyl was added to the solution. A solution of -6-phenyl [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-5) (200 mg, 0.39 mmol) in dichloromethane (3 ml) was added dropwise for 4 hours. Stir. A saturated aqueous sodium hydrogen carbonate solution (15 ml) was added to this solution, and the mixture was stirred for 20 minutes, and then extracted with dichloromethane three times. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by preparative TLC (mobile phase: chloroform: methanol = 98: 2, v / v) to obtain 161 mg (78%) of the title compound as a colorless solid.
ESI-MS m / z: 534 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, s), 1.41 (9H, s), 1.88-2.03 (2H, m), 2.30 (3H, s), 2.75 (3H, s), 3.21 (1H , t, J = 9.0 Hz), 3.35-3.75 (6H, m), 3.90 (3H, s), 7.08-7.13 (1H, m), 7.27-7.32 (1H, m), 7.40-7.53 (3H, m ).
[Reference Example 17]
tert-butyl [(3S) -1- (8-cyano-7-methyl-6-phenyl-2-propionyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3- Methylpyrrolidin-3-yl] methylcarbamate (I-17)

tert-Butyl [(3S) -1- {8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-5 -Il} -3-methylpyrrolidin-3-yl] methylcarbamate (I-16) (150 mg, 0.28 mmol) was dissolved in dichloromethane (4 ml) and ethylmagnesium bromide (1 Molar tetrahydrofuran solution) (562 μl, 0.56 mmol) was added. After stirring at the same temperature for 2 hours, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was further stirred for 10 minutes. The mixture was extracted 3 times with dichloromethane. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by preparative TLC (mobile phase: chloroform: methanol = 95: 5, v / v) to obtain 124 mg (88%) of the title compound as a pale yellow solid.
ESI-MS m / z: 503 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, s), 1.28 (3H, t, J = 7.3 Hz), 1.42 (9H, s), 1.90-2.12 (2H, m), 2.30 (3H, s ), 2.76 (3H, s), 3.15-3.22 (1H, m), 3.25 (2H, dq, J = 1.7, 7.3 Hz), 3.56 (1H, dt, J = 6.8, 10.7 Hz), 3.65-3.75 ( 2H, m), 7.10-7.15 (2H, m), 7.30-7.34 (1H, m), 7.41-7.54 (3H, m).
[Example 3]
7-Methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl-2-propionyl [1,2,4] triazolo [1,5-a] Pyridine-8-carbonitrile (# 3)

tert-butyl [(3S) -1- (8-cyano-7-methyl-6-phenyl-2-propionyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3- Methylpyrrolidin-3-yl] methylcarbamate (I-17) (124 mg, 0.25 mmol) was dissolved in dichloromethane (3 ml), and trifluoroacetic acid (1.5 ml) was added at room temperature. The solution was stirred at the same temperature for 9 hours, and then the solvent was distilled off under reduced pressure. The obtained residue was dissolved in dichloromethane (15 ml), saturated aqueous sodium hydrogen carbonate solution (15 ml) was added thereto at room temperature, and the mixture was vigorously stirred for 10 minutes. The aqueous phase was separated and extracted twice more with dichloromethane. The organic phases were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by preparative TLC (mobile phase: chloroform: methanol = 9: 1, v / v) to obtain 75 mg (76%) of the title compound as a pale yellow solid.
ESI-MS m / z: 403 (M + 1) ⁺ .
HRESI-MS m / z: 403.22355 (Calcd for C ₂₃ H ₂₇ N ₆ O 403.22463).
¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, s), 1.28 (3H, t, J = 7.1 Hz), 1.65-1.73 (1H, m), 1.85-2.05 (2H, m), 2.32 (3H , s), 2.40 (3H, s), 3.14 (1H, d, J = 10.7 Hz), 3.18-3.23 (1H, m), 3.27 (2H, q, J = 7.1 Hz), 3.40-3.46 (1H, m), 3.62-3.67 (1H, m), 7.18-7.25 (2H, m), 7.45-7.53 (3H, m).
IR (ATR): 2216, 1703, 1607, 1502, 1475, 1439, 1334, 1250, 1111, 942, 706 cm ^-1 .
Anal.Calcd for C ₂₃ H ₂₆ N ₆ O ・ 0.25H ₂ O: C, 67.87; H, 6.56; N, 20.65. Found: C, 67.99; H, 6.52; N, 20.42.
[Reference Example 18]
tert-butyl [(3S) -1- (8-cyano-2-isobutyl-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3- Methylpyrrolidin-3-yl] methylcarbamate (I-18)

tert-butyl [(3S) -1- (8-cyano-2-formyl-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3- Methylpyrrolidin-3-yl] methylcarbamate (I-7) (177 mg, 0.37 mmol) was dissolved in dichloromethane (4 ml) and isopropylmagnesium bromide (0.78 molar tetrahydrofuran solution) (1.08 mol) at 0 ° C under a nitrogen stream. ml, 0.75 mmol) was added dropwise. After stirring at the same temperature for 3 hours, a saturated aqueous ammonium chloride solution was added to this solution, and the mixture was further stirred for 10 minutes. This mixture was extracted three times with dichloromethane. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The residue was roughly purified by preparative TLC (mobile phase: chloroform: ethyl acetate = 1: 1, v / v) to obtain 76 mg of an alcohol containing impurities.
ESI-MS m / z: 519 (M + 1) ⁺ .
The alcohol obtained above was dissolved in dichloromethane (3 ml), and Dess-Martin periodinane (123 mg, 0.29 mmol) was added at 0 ° C. under a nitrogen stream. The mixture was stirred at the same temperature for 10 minutes and then at room temperature for 3.5 hours. The suspension was cooled again to 0 ° C., saturated aqueous sodium thiosulfate solution (5 ml) was added, and the mixture was subsequently stirred for 30 min. The mixture was fractionated with dichloromethane and saturated aqueous sodium bicarbonate. The aqueous phase was separated and extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by preparative TLC (mobile phase: chloroform: acetone = 95: 5, v / v) to obtain 47 mg (24%) of the title compound as a colorless solid.
ESI-MS m / z: 517 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, s), 1.29 (3H, d, J = 7.1 Hz), 1.30 (3H, d, J = 7.1 Hz), 1.42 (9H, s), 1.90- 1.97 (1H, m), 2.02 (1H, q, J = 10.5 Hz), 2.30 (3H, s), 2.76 (3H, s), 3.18 (1H, t, J = 10.5 Hz), 3.54 (1H, dt , J = 6.8, 10.5 Hz), 3.65-3.75 (2H, m), 3.83-3.91 (1H, m), 7.10-7.15 (1, m), 7.30-7.33 (1H, m), 7.42-7.56 (3H , m).
[Example 4]
2-Isobutyl-7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl [1,2,4] triazolo [1,5-a] Pyridine-8-carbonitrile (# 4)

tert-butyl [(3S) -1- (8-cyano-2-isobutyl-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3- Methylpyrrolidin-3-yl] methylcarbamate (I-18) (46 mg, 0.09 mmol) was dissolved in dichloromethane (2 ml), and trifluoroacetic acid (1 ml) was added at 0 ° C. The reaction solution was stirred at the same temperature for 2 hours, and then the solvent was distilled off under reduced pressure. Dichloromethane (10 ml) and saturated aqueous sodium hydrogen carbonate solution (10 ml) were added to the obtained residue, and the mixture was vigorously stirred for 10 minutes. The aqueous phase was separated and extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by preparative TLC (mobile phase: chloroform: methanol = 9: 1, v / v) to obtain 29 mg (78%) of the title compound as a light brown solid.
ESI-MS m / z: 417 (M + 1) ⁺ .
HRESI-MS m / z: 417.23688 (Calcd for C ₂₄ H ₂₉ N ₆ O 417.24028).
¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, s), 1.30 (6H, d, J = 7.1 Hz), 1.65 (1H, dt, J = 7.6, 12.0 Hz), 1.80-1.95 (2H, m ), 2.30 (3H, s), 2.31 (3H, s), 3.21 (1H, d, J = 10.5 Hz), 3.31 (1H, ddd, J = 6.1, 7.6, 10.5 Hz), 3.38-3.45 (1H, m), 3.46 (1H, d, J = 10.5 Hz), 3.80-3.92 (1H, m), 7.20-7.25 (2H, m), 7.43-7.55 (3H, m).
IR (ATR): 2213, 1709, 1608, 1498, 1475, 1432, 1343, 1253, 1054, 959, 698 cm ^-1 .
Anal. Calcd for C ₂₄ H ₂₈ N ₆ O0.5H ₂ O: C, 67.74; H, 6.87; N, 19.75. Found: C, 67.86; H, 7.00; N, 19.24.
[Reference Example 19]
1-Methyl-1H-1,2,4-triazole (I-19)

1H-1,2,4-triazole (10 g, 144 mmol) was dissolved in tetrahydrofuran (50 ml) and cooled to 0 ° C. To this solution, 1,8-diazabicyclo [5,4,0] undec-7-ene (26 ml, 174 mmol) and methyl iodide (12.6 ml, 203 mmol) were added and stirred at room temperature for 24 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 resulting residue was distilled to obtain 5.1 g (43%) of the title compound as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 3.94 (3H, s), 7.93 (1H, s), 8.09 (1H, s).
[Reference Example 20]
tert-Butyl [(3S) -1- {8-cyano-7-methyl-2-[(1-methyl-1H-1,2,4-triazolo-5-yl) carbonyl] -6-phenyl [1, 2,4] Triazolo [1,5-a] pyridin-5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-20)

1-Methyl-1H-1,2,4-triazole (I-19) (311 mg, 3.2 mmol) was dissolved in tetrahydrofuran (4 ml). The solution was cooled to −78 ° C., and normal butyl lithium (1.63 molar normal hexane solution) (2.5 ml, 4.1 mmol) was added dropwise under a nitrogen atmosphere, followed by stirring at −78 ° C. for 30 minutes. This solution was tert-butyl [(3S) -1- {8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] Pyridine-5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (400 mg, 0.75 mmol) (I-16) in dichloromethane (5 ml) was added dropwise at −78 ° C. under a nitrogen stream at 0 ° C. For 3 hours. 1N Aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (eluent; ethyl acetate: normal hexane = 1: 1, v / v) to obtain 60 mg (14%) of the title compound as a pale yellow solid.
ESI-MS m / z: 556 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, s), 1.37 (9H, s), 1.76 (1H, s), 1.92-2.06 (2H, m), 2.32 (3H, s), 2.76 (3H , s), 3.15-3.23 (1H, m), 3.51-3.61 (1H, m), 3.63-3.75 (2H, m), 4.32 (3H, s), 7.13 (1H, d, J = 7.3 Hz), 7.31 (1H, d, J = 7.3 Hz), 7.42-7.55 (3H, m).
[Example 5]
7-Methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -2-[(1-methyl-1H-1,2,4-triazolo-5-yl) Carbonyl] -6-phenyl [1,2,4] triazolo [1,5-a] pyridine-8-carbonitrile (# 5)

tert-Butyl [(3S) -1- {8-cyano-7-methyl-2-[(1-methyl-1H-1,2,4-triazolo-5-yl) carbonyl] -6-phenyl [1, 2,4] Triazolo [1,5-a] pyridin-5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-20) (60 mg, 0.11 mmol) dissolved in dichloromethane (2 ml) did. To this solution was added trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was diluted with chloroform. This was washed with a saturated aqueous sodium hydrogen carbonate solution and 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 31 mg (62%) of the title compound as a pale yellow solid.
ESI-MS m / z: 556 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, s), 1.59-1.69 (1H, m), 1.86-1.96 (1H, m), 2.33 (6H, d, J = 6.1 Hz), 3.12-3.20 (1H, m), 3.24 (1H, d, J = 11.0 Hz), 3.40-3.48 (1H, m), 3.76 (1H, d, J = 11.0 Hz), 4.32 (3H, s), 7.21-7.26 ( 2H, m), 7.44-7.55 (3H, m).
IR (ATR): 2940, 2206 1678, 1604, 1506, 1474, 1279, 1095, 1013, 904, 705 cm ^-1 .
Anal.Calcd for C ₂₄ H ₂₅ N ₉ O ・ 1.25H ₂ O: C, 60.30; H, 5.80; N, 26.37. Found: C, 60.89; H, 5.28; N, 25.92.
[Reference Example 21]
tert-butyl [(3S) -1- (8-cyano-7-methyl-2-oxiran-2-yl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl ) -3-Methylpyrrolidin-3-yl] methylcarbamate (I-21)

Sodium hydride (55% in paraffin liquid) (55.2 mg, 1.26 mmol) was added to a solution of trimethylsulfoxonium iodide (301 mg, 1.37 mmol) in dimethyl sulfoxide (10 ml), and the mixture was stirred at room temperature for 1 hour. . To this solution, tert-butyl {(3S) -1- [8-cyano-2-formyl-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl ] -Methylpyrrolidin-3-yl} methylcarbamate (I-7) (500 mg, 1.05 mmol) in dimethyl sulfoxide (10 ml) was added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate. The obtained organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography. (Eluent; normal hexane: ethyl acetate = 1: 1, v / v), 290 mg (56%) of the title compound was obtained as a colorless solid.
ESI-MS m / z: 489 (M + 1) ⁺ .
HRESI-MS m / z: 489.2575 (Calcd for C ₂₇ H ₃₃ N ₆ O ₃ 489.2614).
¹ H-NMR (CDCl ₃ ) δ: 1.20-1.22 (3H, m), 1.42-1.43 (9H, m), 1.87-2.04 (2H, m), 2.27-2.28 (3H, m), 2.74-2.76 ( 3H, m), 3.07-3.16 (1H, m), 3.22-3.25 (1H, m), 3.45-3.69 (4H, m), 4.15-4.18 (1H, m), 7.08-7.12 (1H, m), 7.26-7.30 (1H, m), 7.40-7.52 (3H, m).
[Reference Example 22]
tert-butyl [(3S) -1- {8-cyano-2- [1-hydroxy-2- (1H-1,2,4-triazol-1-yl) ethyl] -7-methyl-6-phenyl [ 1,2,4] Triazolo [1,5-a] pyridin-5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-22)

Add N, N-dimethylformamide (2 ml) to 1,2,4-triazole (28 mg, 0.41 mmol) and sodium hydride (55% in paraffin liquid) (27 mg, 0.62 mmol) at room temperature. For 30 minutes. To this solution, tert-butyl {(3S) -1- [8-cyano-7-methyl-2- (oxiran-2-yl) -6-phenyl dissolved in N, N-dimethylformamide (2 ml) [1,2,4] Triazolo [1,5-a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-21) (100 mg, 0.21 mmol) was added dropwise, and 80 Stir for 3 hours at ° C. 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 = 2: 1, v / v) to obtain 60 mg (53%) of the title compound as a yellow oil.
ESI-MS m / z: 558 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, s), 1.41 (9H, s), 1.88-2.02 (2H, m), 2.27 (3H, s), 2.73 (3H, s), 2.88 (3H , s), 3.09-3.18 (1H, m), 3.43-3.50 (1H, m), 3.54-3.66 (1H, m), 4.72-4.87 (2H, m), 5.40-5.46 (1H, m), 7.09 -7.14 (1H, m), 7.28-7.31 (1H, m), 7.39-7.53 (3H, m), 7.93 (1H, d, J = 2.9 Hz), 8.25 (1H, s).
[Reference Example 23]
tert-Butyl {(3S) -1- [8-Cyano-7-methyl-6-phenyl-2- (1H-1,2,4-triazol-1-ylacetyl) [1,2,4] triazolo [1 , 5-a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-23)

tert-butyl [(3S) -1- {8-cyano-2- [1-hydroxy-2- (1H-1,2,4-triazol-1-yl) ethyl] -7-methyl-6-phenyl [ 1,2,4] Triazolo [1,5-a] pyridin-5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-22) (450 mg, 0.81 mmol) in dichloromethane (30 ml) Dissolved in. The solution was cooled to 0 ° C., Dess-Martin periodinane (1.03 g, 2.43 mmol) was added, and the mixture was stirred at room temperature for 3 hours. A 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes. Ethyl acetate was added to the mixture 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 silica gel column chromatography (eluent; ethyl acetate: normal hexane = 2: 1, v / v) to obtain 323 mg (72%) of the title compound as a pale yellow solid.
ESI-MS m / z: 556 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, s), 1.41 (9H, s), 1.92-2.05 (2H, m), 2.31 (3H, s), 2.75 (3H, s), 3.21-3.29 (1H, m), 3.51-3.81 (3H, m), 5.92 (2H, dd, J = 18.6, 29.5 Hz), 7.14-7.18 (1H, m), 7.34-7.39 (1H, m), 7.43-7.56 (3H, m), 8.01 (1H, s), 8.32 (1H, s).
[Example 6]
7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl-2- (1H-1,2,4-triazol-1-ylacetyl) [ 1,2,4] triazolo [1,5-a] pyridine-8-carbonitrile (# 6)

tert-butyl {(3S) -1- [8-cyano-7-methyl-6-phenyl-2- (1H-1,2,4-triazol-1-ylacetyl) [1,2,4] triazolo [1 , 5-a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-23) (300 mg, 0.54 mmol) was dissolved in dichloromethane (2 ml). To this solution was added trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with chloroform, and then washed with a saturated aqueous sodium bicarbonate 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 using preparative TLC (eluent; chloroform: methanol = 4: 1, v / v) to obtain 23 mg (9%) of the title compound as a pale yellow solid.
ESI-MS m / z: 456 (M + 1) ⁺ .
HRESI-MSm / z: 456.22617 (Calcd for C ₂₄ H ₂₆ N ₉ O 456.22603).
¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, s), 1.59-1.70 (1H, m), 1.80-1.90 (1H, m), 2.31 (3H, s), 2.32 (3H, s), 3.19 (1H, d, J = 10.5 Hz), 3.25-3.34 (1H, m), 3.40-3.53 (2H, m), 5.92 (2H, s), 7.21-7.26 (2H, m), 7.44-7.54 (3H , m), 8.02 (1H, s), 8.32 (1H, s).
IR (ATR): 2926, 2215, 1725, 1605, 1504, 1271, 705, 677 cm ^-1 .
[Reference Example 24]
tert-Butyl [(3S) -1- {8-cyano-2- [1-hydroxy-2- (methylamino) ethyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5 -a] pyridin-5-yl} -methylpyrrolidin-3-yl] methylcarbamate (I-24)

tert-butyl {(3S) -1- [8-cyano-7-methyl-2- (oxiran-2-yl) -6-phenyl [1,2,4] triazolo [1,5-a] pyridine-5 -Yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-21) (1.0 g, 2.1 mmol) was added with 40% methylamine methanol solution (10 ml) and microwave irradiation (100 ° C, 30 Min) Subsequently, this reaction liquid was concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (eluent; chloroform: methanol = 95: 5, v / v) to obtain 432 mg (41%) of the title compound as a yellow oil.
ESI-MS m / z: 520 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, s), 1.42 (9H, s), 1.87-2.05 (2H, m), 2.27 (3H, s), 2.53 (3H, s), 2.75 (3H , s), 3.09-3.20 (3H, m), 3.51-3.66 (3H, m), 5.06-5.11 (1H, m), 7.08-7.12 (1H, m), 7.27-7.30 (1H, m), 7.39 -7.53 (3H, m).
[Reference Example 25]
tert-Butyl [(3S) -1- (2- {2- [acetyl (methyl) amino] -1-hydroxyethyl} -8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [ 1,5-a] pyridin-5-yl) -3-methylpyrrolidin-3-yl] methylcarbamate (I-25)

tert-butyl [(3S) -1- {8-cyano-2- [1-hydroxy-2- (methylamino) ethyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5 -a] pyridin-5-yl} -methylpyrrolidin-3-yl] methylcarbamate (I-24) (432 mg, 0.83 mmol) was dissolved in acetic anhydride (5 ml). To this solution was added saturated aqueous sodium hydrogen carbonate solution (0.5 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in methanol (5 ml). To this solution was added lithium hydroxide monohydrate (173 mg, 4.2 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed with saturated brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: normal hexane = 2: 1, v / v) to obtain 464 mg (99%) of the title compound as a pale yellow solid.
ESI-MS m / z: 562 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, s), 1.39 (9H, s), 1.88-2.04 (3H, m), 2.12 (3H, s), 2.12-2.17 (1H, m), 2.24 (3H, s), 2.72 (3H, s), 3.13 (3H, s), 3.40-3.75 (3H, m), 3.85-3.96 (2H, m), 5.16-5.25 (1H, m), 7.07-7.14 (1H, m), 7.25-7.33 (1H, m), 7.38-7.50 (3H, m).
[Reference Example 26]
tert-Butyl {(3S) -1- [2- (N-acetyl-N-methylglycyl) -8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine -5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-25)

tert-Butyl [(3S) -1- (2- {2- [acetyl (methyl) amino] -1-hydroxyethyl} -8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [ 1,5-a] pyridin-5-yl) -3-methylpyrrolidin-3-yl] methylcarbamate (I-25) (464 mg, 0.83 mmol) was dissolved in dichloromethane (20 ml). The solution was cooled to 0 ° C., Dess-Martin periodinane (1.63 g, 3.8 mmol) was added, and the mixture was stirred at room temperature for 3 hours. A 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes. Chloroform was further added thereto, and this was washed with saturated saline. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: normal hexane = 1: 1, v / v) to obtain 268 mg (58%) of the title compound as a colorless solid.
ESI-MS m / z: 560 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, s), 1.39 (9H, s), 1.89-2.03 (3H, m), 2.19 (2H, s), 2.29 (3H, s), 2.73 (3H , d, J = 3.2 Hz), 3.14 (3H, s), 3.16-3.22 (1H, m), 3.49-3.73 (2H, m), 4.95-5.12 (2H, m), 7.08-7.13 (1H, m ), 7.28-7.33 (1H, m), 7.41-7.53 (3H, m).
[Example 7]
N- (2- {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} -2-oxoethyl) -N-methylacetamide (# 7)

tert-Butyl {(3S) -1- [2- (N-acetyl-N-methylglycyl) -8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine -5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-26) (200 mg, 0.36 mmol) was dissolved in dichloromethane (10 ml). To this solution was added trifluoroacetic acid (10 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and diluted with chloroform. This was washed with a saturated aqueous sodium hydrogen carbonate 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 using preparative TLC (eluent; chloroform: methanol = 10: 1, v / v) to obtain 140 mg (85%) of the title compound as a colorless solid.
ESI-MS m / z: 460 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.11 (3H, s), 1.55-1.65 (1H, m), 1.73-1.82 (1H, m), 2.02 (1H, s), 2.16 (2H, s), 2.24 (1H, s), 2.26 (2H, s), 2.99 (1H, s), 3.11 (2H, s), 3.14-3.23 (2H, m), 3.26-3.55 (2H, m), 4.93-5.09 (2H , m), 7.14-7.21 (1H, m), 7.23-7.27 (1H, m), 7.38-7.50 (3H, m).
IR (ATR): 2963, 2217, 1720, 1645, 1605, 1504, 1474, 1091, 958, 706 cm ^-1 .
Anal.Calcd for C ₂₅ H ₂₉ N ₇ O ₂・ 1.0H ₂ O: C, 62.88; H, 6.54; N, 20.53.Found: C, 63.56; H, 6.56; N, 19.65.
[Reference Example 27]
Ethyl 5-chloro-8-cyano-7-methyl [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-27)

Ethyl 3-oxobutanoate (6.5 g, 50.0 mmol), ethyl 5- (cyanomethyl) -1H-1,2,4-triazole-3-carboxylate (7.5 g, 41.6 mmol), ammonium acetate (6.4 g, 83.3 mmol) ) Was stirred at 80 ° C. for 30 minutes. The reaction mixture was then heated at 100 ° C. for 17 hours to give a solid. The obtained solid was returned to room temperature and diethyl ether was added. This was filtered to obtain a powdery solid (11.8 g). Phosphorous oxychloride (100 ml) was added to the obtained powder (9.84 g), and this solution was stirred at 100 ° C. for 18 hours. The reaction mixture was returned to room temperature and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction obtained from an eluent of 5% ethyl acetate-dichloromethane was concentrated under reduced pressure to obtain the title compound (8.14 g) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.49 (3H, t, J = 7.1 Hz), 2.77 (3H, s), 4.58 (2H, q, J = 7.2 Hz), 7.25 (1H, s).
[Reference Example 28]
Ethyl 5-{(3S) -3-[(tert-butoxycarbonyl) (methyl) amino] -3-methylpyrrolidin-1-yl} -8-cyano-7-methyl [1,2,4] triazolo [1 , 5-a] pyridine-2-carnoxylate (I-28)

Ethyl 5-chloro-8-cyano-7-methyl [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-27) (957 mg, 3.62 mmol) in dichloromethane (20 ml ), Triethylamine (756 μl, 5.42 mmol) at 0 ° C. under nitrogen flow, and then tert-butylmethyl [(3S) -3-methylpyrrolidin-3-yl] carbamate (783 mg, 3.65 mmol) in dichloromethane ( 10 ml) solution was added. After the solution was stirred at room temperature for 13.5 hours, a solution of tert-butyl methyl [(3S) -3-methylpyrrolidin-3-yl] carbamate (233 mg, 1.08 mmol) in dichloromethane (4 ml) was added again. Stir at warm for 4 hours. Triethylamine (756 μl, 5.42 mmol) was added to this solution, and the mixture was further stirred for 2 hours and then cooled to 0 ° C. Saturated aqueous ammonium chloride solution (30 ml) was added to the reaction mixture, and the mixture was stirred for 10 min. The mixture was extracted 3 times with dichloromethane. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by medium pressure liquid chromatography (stationary phase: silica gel; mobile phase: chloroform: acetone = 95: 5, v / v) to obtain 1.404 g (88%) of the title compound as a colorless solid. .
¹ H-NMR (CDCl ₃ ) δ: 1.40 (3H, t, J = 7.1 Hz), 1.52 (9H, s), 2.18 (1H, dd, J = 6.3, 11.7 Hz), 2.30 (1H, q, J = 11.7 Hz), 2.57 (3H, s), 2.93 (3H, s), 3.95-4.40 (4H, m), 4.48-4.55 (2H, m), 5.90 (1H, s).
[Reference Example 29]
Ethyl 6-bromo-5-{(3S) -3-[(tert-butoxycarbonyl) (methyl) amino] -3-methylpyrrolidin-1-yl} -8-cyano-7-methyl [1,2,4 ] Triazolo [1,5-a] pyridine-2-carboxylate (I-29)

Ethyl 5-{(3S) -3-[(tert-butoxycarbonyl) (methyl) amino] -3-methylpyrrolidin-1-yl} -8-cyano-7-methyl [1,2,4] triazolo [1 , 5-a] pyridine-2-carboxylate (I-28) (1.30 g, 2.94 mmol) in dichloromethane (26 ml) at 0 ° C under nitrogen flow at 0 ° C with N-bromosuccinimide (680 mg, 3.82 mmol) Was added. After stirring at 0 ° C. for 6 hours, a saturated aqueous sodium hydrogen carbonate solution (40 ml) was added to the reaction solution. After stirring for 10 minutes at the same temperature, the mixture was extracted three times with dichloromethane. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by medium pressure liquid chromatography (stationary phase: silica gel; mobile phase: chloroform: acetone = 97: 3, v / v) to give 1.362 g (89%) of the title compound as a pale yellow solid. It was.
ESI-MS m / z: 521, 523 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.47 (3H, t, J = 7.1 Hz), 1.47 (9H, s), 1.43 (3H, s), 2.20-2.28 (1H, m), 2.39 (1H, q , J = 10.5 Hz), 2.78 (3H, s), 2.95 (3H, s), 3.74 (1H, t, J = 10.5 Hz), 4.00 (1H, d, J = 10.5 Hz), 4.45 (1H, d , J = 10.5 Hz), 4.53 (2H, q, J = 7.1 Hz), 4.87 (1H, dt, J = 7.1, 10.5 Hz).
[Reference Example 30]
tert-Butyl [(3S) -1- {6-bromo-8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl [1,2,4] triazolo [1,5-a] pyridine-5 -Il} -3-Methylpyrrolidin-3-yl] methylcarbamate (I-30)

N, O-dimethylhydroxylamine hydrochloride (765 mg, 7.84 mmol) was suspended in dichloromethane (15 ml), and trimethylaluminum (1.05 molar hexane solution) (7.5 ml, 7.84 mmol) was suspended at 0 ° C under a nitrogen stream. It was dripped. The solution was stirred at the same temperature for 15 minutes, then warmed to room temperature and further stirred for 1 hour. The solution was then cooled to 0 ° C. and then ethyl 6-bromo-5-{(3S) -3-[(tert-butoxycarbonyl) (methyl) amino] -3-methylpyrrolidin-1-yl} -8 A solution of -cyano-7-methyl [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-29) (1.362 g, 2.61 mmol) in dichloromethane (25 ml) was added dropwise. The solution was stirred at the same temperature for 6 hours, and then a saturated aqueous sodium hydrogen carbonate solution (50 ml) was slowly added while paying attention to foaming. The mixture was extracted 3 times with dichloromethane. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by medium pressure liquid chromatography (stationary phase: silica gel; mobile phase: chloroform: acetone = 95: 5, v / v) to obtain 1.219 g (87%) of the title compound as a colorless solid. .
ESI-MS m / z: 536, 538 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, s), 1.47 (9H, s), 2.22 (1H, dd, J = 7.1, 11.7 Hz), 2.36 (1H, q, J = 10.2 Hz), 2.77 (3H, s), 2.93 (3H, s), 3.35-3.60 (3H, br), 3.72 (1H, dt, J = 2.0, 10.2 Hz), 3.87 (3H, s), 3.97 (1H, br d , J = 10.2 Hz), 4.43 (1H, d, J = 10.2 Hz), 4.57 (1H, dt, J = 7.1, 10.2 Hz).
[Reference Example 31]
tert-butyl [(3S) -1- {8-cyano-6- (3-fluorophenyl) -2- [methoxy (methyl) carbamoyl] -7-methyl [1,2,4] triazolo [1,5- a] Pyridin-5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-31)

tert-Butyl [(3S) -1- {6-bromo-8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl [1,2,4] triazolo [1,5-a] pyridine-5 -Il} -3-methylpyrrolidin-3-yl] methylcarbamate (I-30) (140 mg, 0.26 mmol), 3-fluorophenylboronic acid (73 mg, 0.52 mmol), tetrakistriphenylphosphine palladium (30 mg , 0.03 mmol) and potassium carbonate (144 mg, 1.04 mmol) in 1,4-dioxane (5 ml) were heated to reflux for 14 hours. The reaction mixture was returned to room temperature, water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 20% ethyl acetate-normal hexane was concentrated under reduced pressure to obtain 50 mg (35%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.21-1.25 (3H, m), 1.41 (9H, s), 1.89-2.08 (2H, m), 2.30, 2.31 (3H, sx 2), 2.73-2.78 (3H , m), 3.23-3.94 (7H, m), 3.91 (3H, s), 6.82-7.71 (4H, m).
[Reference Example 32]
tert-butyl {(3S) -1- [2-acetyl-8-cyano-6- (3-fluorophenyl) -7-methyl [1,2,4] triazolo [1,5-a] pyridine-5- Yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-32)

tert-butyl [(3S) -1- {8-cyano-6- (3-fluorophenyl) -2- [methoxy (methyl) carbamoyl] -7-methyl [1,2,4] triazolo [1,5- a] pyridin-5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-31) (65 mg, 0.12 mmol) in dichloromethane (5 ml) and ice-cooled methylmagnesium bromide (5 ml) 0.97 molar tetrahydrofuran solution: 0.25 ml) was added and stirred at the same temperature for 6.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 10% ethyl acetate-dichloromethane was concentrated under reduced pressure to obtain 48 mg (80%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.24, 1.25 (3H, sx 2), 1.42 (9H, s), 1.91-2.10 (2H, m), 2.31, 2.32 (3H, sx 2), 2.78 (3H, s), 2.81 (3H, s), 3.21-3.31 (1H, m), 3.57-3.77 (3H, m), 6.84-7.20 (3H, m), 7.41-7.55 (1H, m).
[Example 8]
2-acetyl-6- (3-fluorophenyl) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] [1,2,4] triazolo [1 , 5-a] pyridine-8-carbonitrile (# 8)

tert-butyl {(3S) -1- [2-acetyl-8-cyano-6- (3-fluorophenyl) -7-methyl [1,2,4] triazolo [1,5-a] pyridine-5- [Il] -3-methylpyrrolidin-3-yl} methylcarbamate (I-32) (48 mg, 0.09 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (0.5 ml) and stirred at room temperature for 2 hours. did. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution was added. This was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from the eluent of 4% methanol-chloroform was concentrated under reduced pressure to obtain 27 mg (70%) of the title compound as a solid.
ESI-MS m / z: 407 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.18, 1.19 (3H, sx 2), 1.63-1.88 (2H, m), 2.30, 2.32 (3H, sx 2), 2.32 (3H, s), 2.81 (3H, s), 3.25-3.48 (4H, m), 6.93-7.06 (2H, m), 7.15-7.22 (1H, m), 7.44-7.53 (1H, m).
IR (ATR): 2966, 2884, 2213, 1707, 1607, 1580, 1507, 1471, 1433, 1374, 1350, 1273, 1260, 1206, 1153, 956, 802, 784, 759, 749, 655 cm ^-1 .
Anal. Calcd for C ₂₂ H ₂₃ FN ₆ O ・ 0.25H ₂ O: C, 64.30; H, 5.76; N, 20.45. Found: C, 64.39; H, 5.41; N, 20.10.
[Reference Example 33]
tert-Butyl [(3S) -1- {8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl-6- (3-methylphenyl) [1,2,4] triazolo [1,5- a] Pyridin-5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-33)

tert-Butyl [(3S) -1- {6-bromo-8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl [1,2,4] triazolo [1,5-a] pyridine-5 -Il} -3-methylpyrrolidin-3-yl] methylcarbamate (I-30) (203 mg, 0.38 mmol), 3-methylphenylboronic acid (103 mg, 0.76 mmol), tetrakistriphenylphosphine palladium (44 mg , 0.04 mmol) and potassium carbonate (209 mg, 1.51 mmol) in 1,4-dioxane (5 ml) were heated to reflux for 24 hours. To this suspension were added 3-methylphenylboronic acid (51 mg, 0.38 mmol), tetrakistriphenylphosphine palladium (44 mg, 0.04 mmol), and potassium carbonate (104 mg, 0.76 mmol), and the mixture was heated to reflux for 24 hours. The suspension was returned to room temperature, water was added, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. 1,4-Dioxane (5 ml) of the obtained residue, 3-methylphenylboronic acid (103 mg, 0.76 mmol), tetrakistriphenylphosphine palladium (44 mg, 0.04 mmol), potassium carbonate (209 mg, 1.51 mmol) The suspension was heated to reflux for 20 hours. The suspension was returned to room temperature, water was added, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 50% ethyl acetate-normal hexane was concentrated under reduced pressure to give the title compound (116 mg, 56%) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.18-1.23 (3H, m), 1.40, 1.42 (9H, sx 2), 1.86-2.05 (2H, m), 2.30, 2.31 (3H, sx 2), 2.38, 2.43 (3H, sx 2), 2.74 (3H, sx 2), 3.11-3.24 (1H, m), 3.34-3.79 (6H, m), 3.90, 3.91 (3H, sx 2), 6.87-6.93 (1H, m), 7.07-7.12 (1H, m), 7.20-7.41 (2H, m).
[Reference Example 34]
tert-butyl {(3S) -1- [2-acetyl-8-cyano-7-methyl-6- (3-methylphenyl) [1,2,4] triazolo [1,5-a] pyridine-5- Yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-34)

tert-Butyl [(3S) -1- {8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl-6- (3-methylphenyl) [1,2,4] triazolo [1,5- a] Pyridin-5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-33) (116 mg, 0.21 mmol) in dichloromethane (6 ml) in methylmagnesium bromide (0.97 molar tetrahydrofuran solution: 0.43 ml) was added under ice cooling. The reaction was stirred at the same temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution under ice cooling, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 10% ethyl acetate-dichloromethane was concentrated under reduced pressure to give the title compound (98 mg, 92%) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.19-1.25 (3H, m), 1.41, 1.43 (9H, sx 2), 1.88-2.08 (2H, m), 2.31 (3H, sx 2), 2.39, 2.43 ( 3H, sx 2), 2.76, 2.78 (3H, sx 2), 2.80 (3H, s), 3.09-3.90 (4H, m), 6.88-6.94 (1H, m), 7.08-7.12 (1H, m), 7.22-7.28 (1H, m), 7.31-7.42 (1H, m).
[Example 9]
2-acetyl-7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6- (3-methylphenyl) [1,2,4] triazolo [1 , 5-a] pyridine-8-carbonitrile (# 9)

tert-butyl {(3S) -1- [2-acetyl-8-cyano-7-methyl-6- (3-methylphenyl) [1,2,4] triazolo [1,5-a] pyridine-5- [Il] -3-methylpyrrolidin-3-yl} methylcarbamate (I-34) (98 mg, 0.19 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (1 ml) and stirred at room temperature for 2.5 hours. did. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from the eluent of 5% methanol-chloroform was concentrated under reduced pressure to obtain a solid. Normal hexane was added to the obtained solid, and the resulting solid was collected by filtration. After drying it under reduced pressure, 59 mg (75%) of the title compound was obtained as a powder.
ESI-MS m / z: 403 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.16, 1.18 (3H, sx 2), 1.60-1.86 (2H, m), 2.30 (3H, sx 2), 2.32 (3H, sx 2), 2.41 (3H, s ), 2.81 (3H, s), 3.21-3.52 (4H, m), 6.98-7.04 (2H, m), 7.24-7.28 (1H, m), 7.34-7.41 (1H, m).
IR (ATR): 2967, 2885, 2847, 2215, 1704, 1610, 1503, 1471, 1443, 1429, 1373, 1346, 1271, 1250, 1156, 958, 779, 761 cm ^-1 .
Anal. Calcd for C ₂₃ H ₂₆ N ₆ O: C, 68.63; H, 6.51; N, 20.88. Found: C, 68.30; H, 6.61; N, 20.69.
[Reference Example 35]
tert-butyl [(3S) -1- {8-cyano-2-[(dimethylamino) (oxo) acetyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] Pyridin-5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-35)

Ethyl 5-{(3S) -3-[(tert-butoxycarbonyl) (methyl) amino] -3-methylpyrrolidin-1-yl} -8-ethynyl-7-methyl-6-phenyl [1,2,4 ] Triazolo [1,5-a] pyridine-2-carboxylate (I-5) (214 mg, 0.41 mmol) in dichloromethane (4.0 ml) at room temperature with (dimethylamino) acetonitrile (64 μl, 0.62 mmol) ) And lithium bis (trimethylsilyl) amide (1.0 mol tetrahydrofuran solution, 1.0 ml) was added under ice cooling. After stirring at the same temperature for 40 minutes, 5% sodium hypochlorite solution (1.5 ml) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium sulfite solution was added to the reaction solution under ice-cooling, and the mixture was stirred for 30 minutes, and then extracted with dichloromethane-methanol (10/1, v / v). 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 using preparative TLC (eluent; dichlorometa: methanol = 20: 1). , v / v), 23 mg (10%) of the title compound was obtained as a yellow solid.
ESI-MS m / z: 446 (M-99) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, s), 1.42 (9H, s), 1.89-2.06 (2H, m), 2.31 (3H, s), 2.75 (3H, s), 3.06 (3H , s), 3.10-3.19 (4H, m), 3.46-3.77 (3H, m), 7.07-7.15 (1H, m), 7.27-7.32 (1H, m), 7.41-7.55 (3H, m).
[Example 10]
2- {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, N-dimethyl-2-oxoacetamide (# 10)

tert-Butyl [(3S) -1- {8-cyano-2-[(dimethylamino) (oxo) acetyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] Pyridine-5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-35) (23 mg, 0.04 mmol) in dichloromethane (2.0 ml) was added trifluoroacetic acid (1.0 ml) under ice-cooling. The mixture was further stirred for 1.5 hours. After the reaction solution was concentrated, a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and this was extracted with dichloromethane / methanol (10/1, v / v). The organic phase was dried over anhydrous sodium sulfate, insolubles were filtered off, and the filtrate was concentrated under reduced pressure to give a residue obtained by preparative TLC (eluent: dichloromethane: methanol = 10: 1, v / v) The title compound 13 mg (66%) was obtained as a yellow solid.
HRFAB-MS m / z: 446.23045 (Calcd for C ₂₄ H ₂₈ N ₇ O ₂ 446.22835).
¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, s), 1.61-1.67 (1H, m), 1.74-1.84 (1H, m), 2.28 (3H, s), 2.31 (3H, s), 3.06 (3H, s), 3.15 (3H, s), 3.18-3.30 (2H, m), 3.30-3.39 (1H, m), 3.45 (1H, d, J = 10.7 Hz), 7.18-7.24 (2H, m ), 7.45-7.54 (3H, m). No NH observed [Reference Example 36]
tert-butyl {(3S) -1- [8-cyano-2- (difluoromethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3-Methylpyrrolidin-3-yl} methylcarbamate (I-36)

tert-Butyl [(3S) -1- (8-cyano-2-formyl-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3- (Diethylamino) sulfur trifluoride (164 μl, 1.25 mmol) in a dichloromethane solution (3.0 ml) of methylpyrrolidin-3-yl] methylcarbamate (I-7) (99 mg, 0.21 mmol) in an argon atmosphere under ice-cooling ) Was added and stirred at room temperature for 23.5 hours. Under ice-cooling, the reaction was quenched with saturated aqueous sodium hydrogen carbonate solution, water was added thereto, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to medium pressure liquid chromatography (stationary phase: silica gel; mobile phase: dichloromethane: ethyl acetate = 20: 1, v / v) to obtain 82 mg (79%) of the title compound as a pale yellowish white solid.
ESI-MS m / z: 497 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, s), 1.43 (9H, s), 1.87-1.96 (1H, m), 1.96-2.06 (1H, m), 2.29 (3H, s), 2.76 (3H, s), 3.11-3.21 (1H, m), 3.40-3.57 (1H, m), 3.63-3.79 (2H, m), 6.87 (1H, t, J = 53.6 Hz), 7.10-7.16 (1H , m), 7.29-7.35 (1H, m), 7.41-7.56 (3H, m).
[Example 11]
2- (Difluoromethyl) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl [1,2,4] triazolo [1,5 -a] pyridine-8-carbonitrile (# 11)

tert-butyl {(3S) -1- [8-cyano-2- (difluoromethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] Trifluoroacetic acid (2.0 ml) was added to a dichloromethane solution (2.0 ml) of -3-methylpyrrolidin-3-yl} methylcarbamate (I-36) (82 mg, 0.16 mmol) under ice cooling, and the mixture was stirred at room temperature for 2 hours. Stir. After the reaction solution was concentrated, a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and this was extracted with dichloromethane / methanol (10/1, v / v). 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 subjected to medium pressure liquid chromatography (stationary phase: silica gel; mobile phase: dichloromethane: methanol = 40). : 1, v / v to 20: 1, v / v) to obtain 52 mg (80%) of the title compound as a colorless solid.
ESI-MS m / z: 397 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, s), 1.58-1.68 (1H, m), 1.74-1.85 (1H, m), 2.26-2.32 (6H, m), 3.16 (1H, d, J = 10.5 Hz), 3.25-3.34 (1H, m), 3.35-3.46 (2H, m), 6.88 (1H, t, J = 53.4 Hz), 7.18-7.24 (2H, m), 7.43-7.54 (3H m). NH not observed
IR (ATR): 2961, 2211, 1608, 1539, 1496, 1472, 1440, 1369, 1335, 1269, 1182, 1144, 1118, 1057 cm ^-1 .
Anal.Calcd for C ₂₁ H ₂₂ F ₂ N ₆ : C, 63.62; H, 5.59; N, 21.20; F, 9.58. Found: C, 63.86; H, 5.71; N, 20.71; F, 8.84.
[Reference Example 37]
tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine- 5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-37)

tert-butyl {(3S) -1- [2-acetyl-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3- (Diethylamino) sulfur trifluoride (107 μl, 0.82 mmol) in dichloromethane (3.0 ml) of methylpyrrolidin-3-yl} methylcarbamate (I-9) (99.6 mg, 0.20 mmol) in a nitrogen atmosphere under ice-cooling And stirred at room temperature for 14.5 hours. (Diethylamino) sulfur trifluoride (267 μl, 2.0 mmol) was added under ice cooling, the solution was further stirred at room temperature for 10 hours, and then the reaction was quenched by adding water under ice cooling. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (3.0 ml), and (diethylamino) sulfur trifluoride (267 μl, 2.0 mmol) was added under ice cooling. After stirring at room temperature for 26 hours, the reaction solution was quenched by adding a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, water was further added, and this was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to medium pressure liquid chromatography (stationary phase: silica gel; mobile phase: dichloromethane: ethyl acetate = 20). : 1, v / v) to obtain 85 mg (81%) of the title compound as a pale yellowish white solid.
ESI-MS m / z: 511 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, s), 1.42 (9H, s), 1.85-1.95 (1H, m), 1.96-2.05 (1H, m), 2.08-2.24 (3H, m) , 2.28 (3H, s), 2.76 (3H, s), 3.08-3.19 (1H, m), 3.34-3.51 (1H, m), 3.66-3.81 (2H, m), 7.08-7.16 (1H, m) , 7.28-7.34 (1H, m), 7.41-7.56 (3H, m).
[Example 12]
2- (1,1-Difluoroethyl) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl [1,2,4] triazolo [1,5-a] pyridine-8-carbonitrile (# 12)

tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine- Trifluoroacetic acid (2 ml) was added to a dichloromethane solution (2 ml) of 5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-37) (85 mg, 0.17 mmol) under ice-cooling. . After stirring at room temperature for 2 hours, the reaction mixture was concentrated, dichloromethane was added to the resulting residue, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution. After drying over anhydrous sodium sulfate, the residue obtained by concentration was subjected to medium pressure liquid chromatography (stationary phase: silica gel; mobile phase: dichloromethane: methanol = 40: 1, v / v to 20: 1, v / v). To give 56 mg (80%) of the title compound as a pale yellowish white solid.
ESI-MS m / z: 411 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, s), 1.58-1.68 (1H, m), 1.75-1.82 (1H, m), 2.17 (3H, dt, J = 1.8, 18.6 Hz), 2.26 -2.31 (6H, m), 3.17 (1H, d, J = 10.5 Hz), 3.23-3.32 (1H, m), 3.32-3.41 (1H, m), 3.44 (1H, d, J = 10.5 Hz), 7.17-7.23 (2H, m), 7.41-7.54 (3H, m). No NH observed
IR (ATR): 2964, 2213, 1609, 1512, 1472, 1441, 1387, 1373, 1364, 1340, 1278, 1184, 1134 cm ^-1 .
Anal. Calcd for C ₂₂ H ₂₄ F ₂ N ₆・ 0.2H ₂ O: C, 64.21; H, 6.26; N, 19.91; F, 8.62. Found: C, 63.82; H, 5.94; N, 20.30; F, 9.18.
[Reference Example 38]
tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoropropyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine- 5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-38)

tert-butyl [(3S) -1- (8-cyano-7-methyl-6-phenyl-2-propionyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3- Methylpyrrolidin-3-yl] methylcarbamate (I-17) (138 mg, 0.27 mmol) was dissolved in dichloromethane (3 ml), and (diethylamino) sulfur trifluoride (363 μl, 2.75 mmol) at 0 ° C under nitrogen flow ) Was added. The mixture was stirred for 87 hours while gradually warming from 0 ° C to room temperature. The mixture was cooled again to 0 ° C., saturated aqueous sodium hydrogen carbonate solution (10 ml) was added dropwise to the solution, and the mixture was stirred at the same temperature for 10 min. The mixture was extracted 3 times with dichloromethane. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by medium pressure liquid chromatography (stationary phase: silica gel; mobile phase: chloroform: acetone = 99: 1, v / v) to give 103 mg (72%) of the title compound as a pale yellow solid. It was.
ESI-MS m / z: 525 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 7.6 Hz), 1.20 (3H, s), 1.43 (9H, s), 1.85-1.93 (1H, m), 1.96-2.05 (1H , m), 2.29 (3H, s), 2.40-2.55 (2H, m), 2.76 (3H, s), 3.13 (1H, t, J = 9.5 Hz), 3.35-3.50 (1H, br), 3.70 ( 1H, d, J = 9.5 Hz), 3.73-3.83 (1H, br), 7.10-7.14 (1H, m), 7.30 (1H, d, J = 7.6 Hz), 7.42-7.54 (3H, m).
[Example 13]
2- (1,1-Difluoropropyl) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl [1,2,4] triazolo [1,5-a] pyridine-8-carbonitrile (# 13)

tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoropropyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine- 5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-38) (102 mg, 0.19 mmol) was dissolved in dichloromethane (3 ml), and trifluoroacetic acid (1.5 ml) was dissolved at 0 ° C. added. After stirring at the same temperature for 5 hours, the solvent was distilled off under reduced pressure. Chloroform (10 ml) and saturated aqueous sodium hydrogen carbonate solution (10 ml) were added to the residue, and the mixture was vigorously stirred for 10 minutes. The aqueous phase was separated and extracted twice with chloroform. These organic phases were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by preparative TLC (mobile phase: chloroform: methanol = 9: 1, v / v) to obtain 67 mg (81%) of the title compound as a light brown solid.
ESI-MS m / z: 425 (M + 1) ⁺ .
HRESI-MS m / z: 425.22911 (Calcd for C ₂₃ H ₂₇ F ₂ N ₆ 425.22653).
_{^{1 H-NMR (CDCl 3)}} δ: 1.13 (3H, t, J = 7.6 Hz), 1.16 (3H, s), 1.60-1.70 (1H, m), 1.77-1.87 (1H, m), 2.29 (3H , s), 2.30 (3H, s), 2.40-2.55 (2H, m), 3.15 (1H, d, J = 10.5 Hz), 3.23-3.30 (1H, m), 3.38 (1H, dt, J = 7.8 , 10.5 Hz), 3.48 (1H, d, J = 10.5 Hz), 7.18-7.23 (2H, m), 7.42-7.52 (3H, m).
IR (ATR): 2215, 1611, 1508, 1474, 1443, 1346, 1270, 1120, 977, 946, 933, 769, 700 cm ^-1 .
Anal. Calcd for C ₂₃ H ₂₆ F ₂ N ₆・ 0.25H ₂ O: C, 64.39; H, 6.23; N, 19.59; F, 8.86. Found: C, 64.53; H, 6.32; N, 19.43; F, 8.66.
[Reference Example 39]
tert-Butyl [(3S) -1- {8-cyano-2- [difluoro (1-methyl-1H-1,2,4-triazolo-5-yl) methyl] -7-methyl-6-phenyl [1 , 2,4] Triazolo [1,5-a] pyridin-5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-39)

tert-Butyl [(3S) -1- {8-cyano-7-methyl-2-[(1-methyl-1H-1,2,4-triazolo-5-yl) carbonyl] -6-phenyl [1, 2,4] Triazolo [1,5-a] pyridin-5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-20) (80 mg, 0.14 mmol) dissolved in dichloromethane (10 ml) did. The solution was cooled to 0 ° C., [bis (2-methoxyethyl) amino] sulfur trifluoride (265 μl, 1.4 mmol) was added dropwise, and the mixture was stirred at room temperature for 20 hours. Chloroform was added to the reaction solution, 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 55 mg (66%) of the title compound as a pale yellow solid.
ESI-MS m / z: 578 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, s), 1.40 (9H, s), 1.85-2.03 (2H, m), 2.29 (3H, s), 2.74 (3H, s), 3.14 (1H , d, J = 9.2 Hz), 3.38-3.49 (1H, m), 3.66-3.73 (2H, m), 4.23 (3H, m), 7.07-7.12 (1H, m), 7.28-7.31 (2H, m ), 7.41-7.54 (2H, m), 7.88 (1H, s).
[Example 14]

2- [Difluoro (1-methyl-1H-1,2,4-triazol-5-yl) methyl] -7-methyl-5
-[(3S) -3-Methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl [1,2,4] triazolo [1,5-a] pyridine-8-carbonitrile (# 14 )

tert-Butyl [(3S) -1- {8-cyano-2- [difluoro (1-methyl-1H-1,2,4-triazolo-5-yl) methyl] -7-methyl-6-phenyl [1 , 2,4] Triazolo [1,5-a] pyridin-5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-39) (55 mg, 0.10 mmol) in dichloromethane (2 ml) Dissolved. To this solution was added trifluoroacetic acid (2 ml) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The obtained residue was diluted with chloroform, and this was washed with a saturated aqueous sodium hydrogen carbonate solution and 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 (63%) of the title compound as a colorless solid.
ESI-MS m / z: 478 (M + 1) ⁺ .
HRESI-MSm / z: 478.22704 (Calcd for C ₂₄ H ₂₆ F ₂ N ₉ 478.22792).
¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, s), 1.62-1.71 (1H, m), 1.85-1.95 (1H, m), 2.30 (3H, s), 2.36 (3H, s), 3.13 -3.21 (2H, m), 3.30-3.39 (1H, m), 3.64 (1H, d, J = 10.7 Hz), 3.72 (1H, br s), 4.22 (3H, s), 7.16-7.24 (2H, m), 7.43-7.53 (3H, m), 7.88 (1H, s).
IR (ATR): 2968, 2220 1672, 1610, 1506, 1203, 1125, 933, 704 cm ^-1 .
[Reference Example 40]
tert-butyl {(3S) -1- [8-cyano-2- (1-hydroxy-2-methoxyethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] Pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-40)

tert-butyl [(3S) -1- (8-cyano-7-methyl-2-oxiran-2-yl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl ) -3-Methylpyrrolidin-3-yl] methylcarbamate (I-21) (290 mg, 0.59 mmol) in methanol (10 ml) was added sodium methoxide (128 mg, 2.37 mmol) at room temperature, The mixture was heated to reflux on an oil bath at 80 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The obtained organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography. (Eluent; normal hexane: ethyl acetate = 1: 2, v / v), 282 mg (91%) of the title compound was obtained as a colorless solid.
HRESI-MS m / z: 521.2852 (Calcd for C ₂₈ H ₃₇ N ₆ O ₄ 521.2876).
¹ H-NMR (CDCl ₃ ) δ: 1.18-1.22 (3H, m), 1.41-1.43 (9H, m), 1.86-2.05 (2H, m), 2.26-2.29 (3H, m), 2.75 (3H, s), 3.09-3.17 (2H, m), 3.44-3.66 (6H, m), 3.89-3.93 (2H, m), 5.17 (1H, q, J = 5.2 Hz), 7.07-7.12 (1H, m) , 7.24-7.30 (1H, m), 7.39-7.53 (3H, m).
[Reference Example 41]
tert-butyl {(3S) -1- [8-cyano-2- (methoxyacetyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3-Methylpyrrolidin-3-yl} methylcarbamate (I-41)

tert-butyl {(3S) -1- [8-cyano-2- (1-hydroxy-2-methoxyethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] Pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-40) (281 mg, 0.540 mmol) in dichloromethane (6 ml) at room temperature in Dess-Martin periodinane (687 mg, 1.62 mmol) was added and the mixture was stirred at room temperature for 2 hours. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution and a 10% aqueous sodium thiosulfate solution were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate, and the resulting organic phase was washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: normal hexane: ethyl acetate). = 1: 2, v / v), and 201 mg (72%) of the title compound was obtained as a pale yellow solid.
HRESI-MS m / z: 519.2716 (Calcd for C ₂₈ H ₃₅ N ₆ O ₄ 519.2720).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, s), 1.43 (9H, s), 1.88-2.08 (2H, m), 2.30 (3H, s), 2.76 (3H, s), 3.13-3.22 (1H, m), 3.51-3.75 (6H, m), 5.00 (2H, s), 7.08-7.14 (1H, m), 7.28-7.33 (1H, m), 7.40-7.55 (3H, m).
[Reference Example 42]
tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoro-2-methoxyethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5- a] Pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-42)

tert-butyl {(3S) -1- [8-cyano-2- (methoxyacetyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-41) (110 mg, 0.21 mmol) in dichloromethane (3 ml) under ice-cooling (diethylamino) sulfur trifluoride (278 μl, 2.12 mmol) And stirred at room temperature for 17 hours. Under ice-cooling, water and a saturated aqueous sodium hydrogen carbonate solution were added to the solution, this was extracted with ethyl acetate, and the resulting organic phase was washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: normal hexane: ethyl acetate). = 2: 1, v / v), and 83.0 mg (72%) of the title compound was obtained as a colorless solid.
HRESI-MS m / z: 541.2751 (Calcd for C ₂₈ H ₃₅ F ₂ N ₆ O ₃ 541.2739).
¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, s), 1.42 (9H, s), 1.84-2.04 (2H, m), 2.29 (3H, s), 2.76 (3H, s), 3.08-3.19 (1H, m), 3.36-3.79 (6H, m), 4.19 (2H, t, J = 13.1 Hz), 7.07-7.13 (1H, m), 7.23-7.31 (1H, m), 7.40-7.55 (3H , m).
[Example 15]
2- (1,1-Difluoro-2-methoxyethyl) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl [1,2 , 4] Triazolo [1,5-a] pyridine-8-carbonitrile (# 15)

tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoro-2-methoxyethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5- Add trifluoroacetic acid (1 ml) to a solution of a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-42) (83.0 mg, 0.15 mmol) in dichloromethane (2 ml) Stir at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with chloroform. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated, and the resulting residue was purified by preparative TLC (eluent; chloroform: methanol = 10: 1, v / v) and 57 mg (84%) of the title compound were obtained as a colorless solid.
ESI-MS m / z: 441 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, s), 1.54-1.83 (2H, m), 2.28 (3H, s), 2.29 (3H, s), 3.19 (1H, d, J = 10.7 Hz ), 3.22-3.41 (2H, m), 3.45 (1H, d, J = 10.7 Hz), 3.52 (3H, s), 4.19 (2H, t, J = 13.1 Hz), 7.15-7.22 (2H, m) , 7.41-7.53 (3H, m).
IR (ATR): 3283, 3060, 2966, 2928, 2903, 2819, 2799, 2212, 1610, 1536, 1509, 1475, 1445, 1429, 1390, 1379, 1367, 1345, 1276, 1253, 1208, 1187, 1169 , 1150, 1123, 1109, 1073, 1021, 980 cm ^-1 .
Anal. Calcd for C ₂₃ H ₂₆ F ₂ N ₆ O: C, 62.71; H, 5.95; N, 19.08; F, 8.63. Found: C, 62.66; H, 5.88; N, 18.85; F, 8.60.
[Reference Example 43]
tert-butyl {(3S) -1- [8-cyano-2- (2-ethoxy-1-hydroxyethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] Pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-43)

tert-butyl [(3S) -1- (8-cyano-7-methyl-2-oxiran-2-yl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl ) -3-Methylpyrrolidin-3-yl] methylcarbamate (I-21) (222 mg, 0.45 mmol) in ethanol (8 ml) was added sodium ethoxide (124 mg, 1.82 mmol) at room temperature, The mixture was heated and refluxed on a 90 ° C. oil bath for 1.5 hours. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, insolubles were filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (elution). Liquid; normal hexane: ethyl acetate = 1: 2, v / v), and 160 mg (66%) of the title compound was obtained as a colorless foam.
HRESI-MS m / z: 535.3010 (Calcd for C ₂₉ H ₃₉ N ₆ O ₄ 535.3033).
¹ H-NMR (CDCl ₃ ) δ: 1.18-1.26 (6H, m), 1.41-1.43 (9H, m), 1.86-2.06 (2H, m), 2.27 (3H, s), 2.75 (3H, s) , 3.09-3.21 (2H, m), 3.49-3.68 (5H, m), 3.87-3.99 (2H, m), 5.12-5.20 (1H, m), 7.07-7.13 (1H, m), 7.25-7.31 ( 1H, m), 7.39-7.53 (3H, m).
[Reference Example 44]
tert-butyl {(3S) -1- [8-cyano-2- (ethoxyacetyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3-Methylpyrrolidin-3-yl} methylcarbamate (I-44)

tert-butyl {(3S) -1- [8-cyano-2- (2-ethoxy-1-hydroxyethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] Dess-Martin periodinane (381 mg, pyridin-5-yl) -3-methylpyrrolidin-3-yl} methylcarbamate (I-43) (160 mg, 0.30 mmol) in dichloromethane (4 ml) at room temperature 0.90 mmol) was added and stirred at room temperature for 14 hours. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution and a 10% aqueous sodium thiosulfate solution were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate, and the resulting organic phase was washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: normal hexane: ethyl acetate). = 1: 1, v / v), and 121 mg (76%) of the title compound was obtained as a pale yellow solid.
HRESI-MS m / z: 533.2844 (Calcd for C ₂₉ H ₃₇ N ₆ O ₄ 533.2876).
¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, s), 1.33 (3H, t, J = 7.1 Hz), 1.42 (9H, s), 1.87-2.08 (2H, m), 2.30 (3H, s ), 2.75 (3H, s), 3.13-3.21 (1H, m), 3.52-3.77 (5H, m), 5.04 (2H, s), 7.08-7.13 (1H, m), 7.27-7.33 (1H, m ), 7.39-7.56 (3H, m).
[Reference Example 45]
tert-Butyl {(3S) -1- [8-cyano-2- (2-ethoxy-1,1-difluoroethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5- a] Pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-45)

tert-butyl {(3S) -1- [8-cyano-2- (ethoxyacetyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-44) (121 mg, 0.23 mmol) in dichloromethane (3 ml) under ice-cooling, (diethylamino) sulfur trifluoride (298 μl, 2.27 mmol) And stirred at room temperature for 16 hours. Under ice-cooling, water and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, this was extracted with ethyl acetate, and the resulting organic phase was washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: normal hexane: ethyl acetate). = 2: 1, v / v), and 100 mg (79%) of the title compound was obtained as a pale yellow solid.
HRESI-MS m / z: 555.2836 (Calcd for C ₂₉ H ₃₇ F ₂ N ₆ O ₃ 555.2895).
¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, s), 1.21 (3H, t, J = 7.1 Hz), 1.42 (9H, s), 1.88-2.04 (2H, m), 2.29 (3H, s ), 2.76 (3H, s), 3.09-3.19 (1H, m), 3.38-3.57 (1H, m), 3.66-3.75 (4H, m), 4.22 (2H, t, J = 13.3 Hz), 7.08- 7.14 (1H, m), 7.24-7.31 (1H, m), 7.39-7.55 (3H, m).
[Example 16]
2- (2-Ethoxy-1,1-difluoroethyl) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl [1,2 , 4] Triazolo [1,5-a] pyridine-8-carbonitrile (# 16)

tert-Butyl {(3S) -1- [8-cyano-2- (2-ethoxy-1,1-difluoroethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5- a] Pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-45) (100 mg, 0.18 mmol) in dichloromethane (2 ml) under ice cooling with trifluoroacetic acid (1 ml) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with chloroform. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matter was 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 65 mg (79%) of the title compound was obtained as a pale yellow solid.
ESI-MS m / z: 455 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, s), 1.22 (3H, t, J = 7.1 Hz), 1.57-1.67 (1H, m), 1.75-1.81 (1H, m), 2.28 (3H , s), 2.29 (3H, s), 3.18 (1H, d, J = 10.5 Hz), 3.24-3.41 (2H, m), 3.44 (1H, d, J = 10.5 Hz), 3.72 (2H, q, J = 7.1 Hz), 4.22 (2H, t, J = 13.3 Hz), 7.16-7.24 (2H, m), 7.41-7.53 (3H, m).
IR (ATR): 2975, 2900, 2800, 2211, 1609, 1536, 1508, 1474, 1447, 1429, 1377, 1365, 1342, 1270, 1254, 1206, 1185, 1150, 1097, 1020, 1004, 956, 935 cm ^-1 .
Anal.Calcd for C ₂₄ H ₂₈ F ₂ N ₆ O ・ 0.25H ₂ O: C, 62.80; H, 6.26; N, 18.31; F, 8.28. Found: C, 63.02; H, 6.11; N, 18.30; F , 8.35.
[Reference Example 46]
tert-Butyl [(3S) -1- {8-cyano-2- [1-hydroxy-2- (2-methoxyethoxy) ethyl] -7-methyl-6-phenyl [1,2,4] triazolo [1 , 5-a] pyridin-5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-46)

tert-butyl [(3S) -1- (8-cyano-7-methyl-2-oxiran-2-yl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl ) -3-Methylpyrrolidin-3-yl] methylcarbamate (I-21) (200 mg, 0.41 mmol) in 2-methoxyethanol (4 ml) under ice cooling with sodium hydride (55% in paraffin liquid ) (107 mg, 2.46 mmol) was added, and the mixture was heated to reflux for 1 hour on an oil bath at 60 ° C. A saturated aqueous ammonium chloride solution and water were added to the reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 1: 2, v / v) and 154 mg (67%) of the title compound were obtained as a pale yellow solid.
ESI-MS m / z: 565 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, m), 1.42 (9H, s), 1.86-2.05 (2H, m), 2.27 (3H, s), 2.74 (3H, s), 3.14 (1H , m), 3.40 (3H, s), 3.51-3.64 (6H, m), 3.74-3.79 (2H, m), 3.92-4.09 (2H, m), 5.16-5.24 (1H, m), 7.06-7.13 (1H, m), 7.24-7.30 (1H, m), 7.37-7.54 (3H, m).
[Reference Example 47]
tert-Butyl [(3S) -1- {8-cyano-2-[(2-methoxyethoxy) acetyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine -5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-47)

tert-Butyl [(3S) -1- {8-cyano-2- [1-hydroxy-2- (2-methoxyethoxy) ethyl] -7-methyl-6-phenyl [1,2,4] triazolo [1 , 5-a] pyridin-5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-46) (154 mg, 0.27 mmol) in dichloromethane (3 ml) at room temperature in Dess-Martin periodinane (347 mg, 0.82 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution and a 10% aqueous sodium thiosulfate solution were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate, and the resulting organic phase was washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 2: 1, v / v) and 105 mg (68%) of the title compound were obtained as a pale yellow solid.
HRESI-MS m / z: 563.2978 (Calcd for C ₃₀ H ₃₉ N ₆ O ₅ 563.2982).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, s), 1.42 (9H, s), 1.88-2.07 (2H, m), 2.31 (3H, s), 2.75 (3H, s), 3.14-3.23 (1H, m), 3.41 (3H, s), 3.55-3.69 (5H, m), 3.83-3.87 (2H, m), 5.11 (2H, s), 7.08-7.14 (1H, m), 7.23-7.33 (1H, m), 7.42-7.54 (3H, m).
[Reference Example 48]
tert-Butyl [(3S) -1- {8-cyano-2- [1,1-difluoro-2- (2-methoxyethoxy) ethyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-48)

tert-Butyl [(3S) -1- {8-cyano-2-[(2-methoxyethoxy) acetyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine -5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-47) (105 mg, 0.19 mmol) in dichloromethane (2 ml) under ice-cooling (diethylamino) sulfur trifluoride (245 μl, 1.87 mmol) was added and stirred at room temperature for 15 hours. To this solution, water and a saturated aqueous sodium hydrogen carbonate solution were added under ice-cooling, this was extracted with ethyl acetate, and the resulting organic phase was washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 3: 1, v / v) and 83 mg (76%) of the title compound were obtained as a pale yellow solid.
HRESI-MS m / z: 585.2912 (Calcd for C ₃₀ H ₃₉ F ₂ N ₆ O ₄ 585.3001).
¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, s), 1.42 (9H, s), 1.85-2.07 (2H, m), 2.29 (3H, s), 2.76 (3H, s), 3.06-3.19 (1H, m), 3.36-4.36 (12H, m), 7.07-7.13 (1H, m), 7.24-7.33 (1H, m), 7.40-7.55 (3H, m).
[Example 17]
2- [1,1-Difluoro-2- (2-methoxyethoxy) ethyl] -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6- Phenyl [1,2,4] triazolo [1,5-a] pyridine-8-carbonitrile (# 17)

tert-Butyl [(3S) -1- {8-cyano-2- [1,1-difluoro-2- (2-methoxyethoxy) ethyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-48) (83.0 mg, 0.14 mmol) in dichloromethane (2 ml) under ice-cooling, Trifluoroacetic acid (1 ml) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with chloroform. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated, and the resulting residue was purified by preparative TLC (eluent; chloroform: methanol = 10: 1, v / v), 37 mg (54%) of the title compound was obtained as a pale yellow solid.
ESI-MS m / z: 485 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, s), 1.56-1.67 (1H, m), 1.71-1.82 (1H, m), 2.28 (3H, s), 2.29 (3H, s), 3.18 (1H, d, J = 10.7 Hz), 3.24-3.40 (2H, m), 3.37 (3H, s), 3.44 (1H, d, J = 10.7 Hz), 3.52-3.59 (2H, m), 3.81- 3.87 (2H, m), 4.31 (2H, t, J = 13.3 Hz), 7.14-7.54 (5H, m).
IR (ATR): 2877, 2213, 1610, 1537, 1509, 1473, 1431, 1366, 1342, 1279, 1253, 1207, 1162, 1140, 1099, 1030, 1008, 958, 934 cm ^-1 .
Anal. Calcd for C ₂₅ H ₃₀ F ₂ N ₆ O ₂ : C, 61.97; H, 6.24; N, 17.34; F, 7.84. Found: C, 62.00; H, 6.27; N, 17.30; F, 7.35.
[Reference Example 49]
tert-butyl {(3S) -1- [8-cyano-2- (2-fluoro-1-hydroxyethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] Pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-49)

tert-butyl [(3S) -1- (8-cyano-7-methyl-2-oxiran-2-yl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl ) -3-Methylpyrrolidin-3-yl] methylcarbamate (I-21) (145 mg, 0.30 mmol) was added triethylamine trihydrofluoride (5 ml), and the mixture was heated to reflux for 15 hours on an oil bath at 90 ° C. did. Water and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, which was extracted with chloroform. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 1: 1, v / v), and 50 mg (33%) of the title compound were obtained as a colorless solid.
ESI-MS m / z: 509 (M + 1) ⁺ .
HRESI-MS m / z: 509.2660 (Calcd for C ₂₇ H ₃₄ FN ₆ O ₃ 509.2676).
¹ H-NMR (CDCl ₃ ) δ: 1.19-1.22 (3H, m), 1.41-1.43 (9H, m), 1.86-2.03 (2H, m), 2.27-2.30 (3H, m), 2.75 (3H, s), 3.09-3.17 (1H, m), 3.23 (1H, t, J = 6.3 Hz), 3.46-3.56 (1H, m), 3.58-3.71 (2H, m), 4.75-4.98 (2H, m) , 5.17-5.32 (1H, m), 7.07-7.13 (1H, m), 7.25-7.31 (1H, m), 7.39-7.54 (3H, m).
[Reference Example 50]
tert-butyl {(3S) -1- [8-cyano-2- (fluoroacetyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3-Methylpyrrolidin-3-yl} methylcarbamate (I-50)

tert-butyl {(3S) -1- [8-cyano-2- (2-fluoro-1-hydroxyethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] Pyridine-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-49) (40 mg, 0.08 mmol) in dichloromethane (1 ml) at room temperature with Dess-Martin periodinane (100 mg, 0.24 mmol) was added and stirred at room temperature for 15 hours. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution and a 10% aqueous sodium thiosulfate solution were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate, and the resulting organic phase was washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: normal hexane: ethyl acetate). = 1: 1, v / v), and 29 mg (73%) of the title compound was obtained as a pale yellow solid.
HRESI-MS m / z: 507.2548 (Calcd for C ₂₇ H ₃₂ FN ₆ O ₃ 507.2520).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, s), 1.43 (9H, s), 1.89-2.05 (2H, m), 2.31 (3H, s), 2.75 (3H, s), 3.14-3.22 (1H, m), 3.52-3.74 (3H, m), 5.80 (2H, d, J = 46.9 Hz), 7.09-7.13 (1H, m), 7.29-7.33 (1H, m), 7.42-7.54 (3H , m).
[Reference Example 51]
tert-butyl {(3S) -1- [8-cyano-7-methyl-6-phenyl-2- (1,1,2-trifluoroethyl) [1,2,4] triazolo [1,5-a ] Pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-51)

tert-butyl {(3S) -1- [8-cyano-2- (fluoroacetyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-50) (28 mg, 0.06 mmol) in dichloromethane (1 ml) under ice-cooling, (diethylamino) sulfur trifluoride (72 μl, 0.6 mmol) And stirred at room temperature for 16 hours. Under ice-cooling, water and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, this was extracted with ethyl acetate, and the resulting organic phase was washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: normal hexane: ethyl acetate). = 2: 1, v / v) and 28 mg (96%) of the title compound were obtained as a colorless solid.
HRESI-MS m / z: 529.2528 (Calcd for C ₂₇ H ₃₂ F ₃ N ₆ O ₂ 529.2539).
¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, s), 1.42 (9H, s), 1.85-2.06 (2H, m), 2.30 (3H, s), 2.76 (3H, s), 3.09-3.19 (1H, m), 3.32-3.51 (1H, m), 3.67-3.82 (2H, m), 5.04 (2H, dt, J = 12.0, 46.1 Hz), 7.07-7.14 (1H, m), 7.27-7.32 (1H, m), 7.40-7.55 (3H, m).
[Example 18]
7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl-2- (1,1,2-trifluoroethyl) [1,2, 4] Triazolo [1,5-a] pyridine-8-carbonitrile (# 18)

tert-butyl {(3S) -1- [8-cyano-7-methyl-6-phenyl-2- (1,1,2-trifluoroethyl) [1,2,4] triazolo [1,5-a ] Trifluoroacetic acid (0.5 ml) was added to a solution of [pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-51) (28.0 mg, 0.05 mmol) in dichloromethane (1 ml) at room temperature. For 2 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with chloroform. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated, and the resulting residue was purified by preparative TLC (eluent; chloroform: methanol = 10: 1, v / v) and 10 mg (44%) of the title compound were obtained as a colorless solid.
ESI-MS m / z: 429 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, s), 1.59-1.88 (2H, m), 2.30 (3H, s), 2.31 (3H, s), 3.17 (1H, d, J = 10.5 Hz ), 3.23-3.29 (1H, m), 3.34-3.40 (1H, m), 3.50 (1H, d, J = 10.5 Hz), 5.04 (2H, dt, J = 12.1, 46.1 Hz), 7.16-7.24 ( 2H, m), 7.42-7.53 (3H, m).
IR (ATR): 3057, 2965, 2892, 2808, 2667, 2456, 2213, 1610, 1534, 1511, 1473, 1439, 1391, 1374, 1341, 1279, 1261, 1205, 1170, 1118, 1085, 1052, 1021 , 998 cm ^-1 .
Anal. Calcd for C ₂₂ H ₂₃ F ₃ N ₆ : C, 61.67; H, 5.41; N, 19.61.Found: C, 61.76; H, 5.36; N, 19.37.
[Reference Example 52]
tert-butyl {(3R) -1- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine- 5-yl] -4-fluoro-3-methylpyrrolidin-3-yl} methylcarbamate (I-52)

tert-butyl [(3R) -1- (2-acetyl-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -4- Fluoro-3-methylpyrrolidin-3-yl] methylcarbamate (I-15) (146 mg, 0.29 mmol) in dichloromethane (3.0 ml) under ice-cooling, (diethylamino) sulfur trifluoride (377 μl, 2.88 mmol) And stirred at room temperature for 16 hours. The reaction solution was quenched by adding a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and extracted with dichloromethane. 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 subjected to medium pressure liquid chromatography (stationary phase: silica gel; mobile phase: dichloromethane: methanol = 50). : 1, v / v) to obtain 140 mg (92%) of the title compound as a light brown white solid.
ESI-MS m / z: 529 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.27-1.32 (3H, m), 1.43 (9H, s), 2.16 (3H, t, J = 18.5 Hz), 2.30 (3H, s), 2.82-2.86 (3H , m), 3.34-3.49 (1H, m), 3.54-3.68 (1H, m), 3.69-3.77 (2H, m), 5.19-5.42 (1H, m), 7.19-7.24 (2H, m), 7.44 -7.55 (3H, m).
[Example 19]
2- (1,1-Difluoroethyl) -5-[(3R) -4-fluoro-3-methyl-3- (methylamino) pyrrolidin-1-yl] -7-methyl-6-phenyl [1,2 , 4] Triazolo [1,5-a] pyridine-8-carbonitrile (# 19)

tert-butyl {(3R) -1- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine- Add trifluoroacetic acid (3.0 ml) to a dichloromethane solution (3.0 ml) of 5-yl] -4-fluoro-3-methylpyrrolidin-3-yl} methylcarbamate (140 mg, 0.27 mmol) under ice cooling, and For 1.5 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with dichloromethane: methanol (10: 1, v / v). The organic phase was dried over anhydrous sodium sulfate, insolubles were filtered off, and the filtrate was concentrated under reduced pressure to give a residue obtained by preparative TLC (eluent: dichloromethane: methanol = 15: 1, v / v) To give 99 mg (87%) of the title compound as an off-white solid.
ESI-MS m / z: 429 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, d, J = 2.8 Hz), 2.16 (3H, t, J = 18.6 Hz), 2.29 (3H, s), 2.32 (3H, s), 3.16 ( 1H, dd, J = 11.0, 2.1 Hz), 3.29 (1H, dd, J = 26.4, 12.6 Hz), 3.41 (1H, d, J = 11.0 Hz), 4.11 (1H, ddd, J = 37.0, 12.8, 4.1 Hz), 4.60 (1H, dd, J = 53.0, 3.9 Hz), 7.12-7.21 (1H, m), 7.25-7.33 (1H, m), 7.43-7.57 (3H, m).
IR (ATR): 3362, 2971, 2212, 1610, 1512, 1433, 1377, 1328, 1266, 1201, 1182, 1134, 1082, 1050cm ^-1 .
Anal. Calcd for C ₂₂ H ₂₃ F ₃ N ₆・ 0.2H ₂ O: C, 61.16; H, 5.46; N, 19.45; F, 13.19. Found: C, 61.13; H, 5.40; N, 19.13; F, 13.21.
[Reference Example 53]
tert-butyl {3-[(1S) -1-phenylethyl] -3-azabicyclo [3.1.0] hex-1-yl} carbamate (I-53)

3-[(1S) -1-phenylethyl] -3-azabicyclo [3.1.0] normal hexane-1-carbonitrile (synthesized by the method described in WO98 / 13370) (3.0 g, 14.1 mmol) was converted to methanol ( 30 ml), 2N aqueous sodium hydroxide solution (30 ml) was added at room temperature, and the mixture was heated to 105 ° C. and stirred for 23 hours. After cooling to room temperature, 2N aqueous hydrochloric acid (30 ml) was added dropwise to the reaction mixture at 0 ° C., and the mixture was further stirred for 10 min. The residue obtained by concentrating the mixture under reduced pressure was roughly purified by subjecting to silica gel column chromatography, and 3-[(1S) -1-phenylethyl] -3-azabicyclo [3.1.0] normal hexane- 1-carboxylic acid (4.113 g: weight with impurities) was obtained as brown amorphous. The acid obtained above was dissolved in tert-butanol (100 ml), and triethylamine (3.2 ml, 22.56 mmol) and diphenylphosphoric acid azide (4.3 ml, 19.74 mmol) were added at room temperature. The reaction was heated to reflux for 24 hours and then cooled to room temperature. The solvent of this solution was distilled off under reduced pressure, and the resulting residue was fractionated with ethyl acetate and water. The aqueous phase was separated and it was extracted twice more with ethyl acetate. These organic phases were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 2.38 g (56%) of the title compound was obtained as a pale yellow gel from normal hexane: ethyl acetate = 3: 1, v / v fraction.
ESI-MS m / z: 303 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 0.65-0.73 (1H, m), 1.26 (3H, d, J = 6.6 Hz), 1.20-1.32 (1H, m), 1.39 (9H, s), 1.48-1.58 (1H, m), 2.31 (1H, d, J = 8.3 Hz), 2.55-2.72 (1H, br), 2.78 (1H, d, J = 7.6 Hz), 3.09 (1H, d, J = 7.6 Hz) , 3.34 (1H, q, J = 6.6 Hz), 4.65-5.05 (1H, br), 7.17-7.30 (5H, m).
[Reference Example 54]
tert-butyl {3-[(1S) -1-phenylethyl] -3-azabicyclo [3.1.0] hex-1-yl} carbamate (I-54)

tert-butyl {3-[(1S) -1-phenylethyl] -3-azabicyclo [3.1.0] hex-1-yl} carbamate (I-53) (2.30 g, 7.61 mmol) in dichloromethane (10 ml) And carbobenzyloxychloride (6.5 ml, 45.63 mmol) was added at room temperature. The mixed solution was heated to reflux for 17 hours and then cooled to room temperature. The solution was then fractionated with dichloromethane and saturated brine. The organic phase was dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by medium pressure liquid chromatography (stationary phase: silica gel; mobile phase: normal hexane: ethyl acetate = 4: 1, v / v), and 1.345 g (52%) of the title compound was obtained as a colorless solid. Obtained.
HRESI-MS m / z: 333.18144 (Calcd for C ₁₈ H ₂₅ N ₂ O ₄ 333.18143).
¹ H-NMR (CDCl ₃ ) δ: 0.70 (1H, q, J = 5.4 Hz), 1.05 (1H, dd, J = 5.4, 7.1 Hz), 1.44 (9H, s), 1.60-1.73 (1H, br ), 3.40-3.71 (3H, m), 3.80 (1H, d, J = 10.3 Hz), 4.90-5.10 (1H, br), 5.08 (1H, d, J = 12.5 Hz), 5.12 (1H, d, J = 12.5 Hz), 7.27-7.38 (5H, m).
IR (ATR): 3334, 1689, 1417, 1363, 1167, 1113 cm ^-1 .
[Reference Example 55]
Benzyl 1-[(tert-butoxycarbonyl) amino] -3-azabicyclo [3.1.0] normal hexane-3-carboxylate (I-55)

tert-Butyl {3-[(1S) -1-phenylethyl] -3-azabicyclo [3.1.0] hex-1-yl} carbamate (I-54) (500 mg, 1.50 mmol) was replaced with N, N-dimethyl Dissolved in formamide (10 ml), methyl iodide (113 μl, 1.81 mmol) and then sodium hydride (55% in paraffin liquid) (85 mg, 1.96 mmol) were added at 0 ° C. After stirring at the same temperature for 3.5 hours, a saturated aqueous ammonium chloride solution was added to the reaction solution. The mixture was extracted 3 times with ethyl acetate. The organic phases were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by medium pressure liquid chromatography (stationary phase: silica gel; mobile phase: normal hexane: ethyl acetate = 3: 1, v / v), and 482 mg (92%) of the title compound was obtained as a colorless gel. Obtained.
HRESI-MS m / z: 347.19712 (Calcd for C ₁₉ H ₂₇ N ₂ O ₄ 347.19708).
¹ H-NMR (CDCl ₃ ) δ: 0.72 (1H, t, J = 5.9 Hz), 1.07 (1H, dd, J = 5.9, 7.6 Hz), 1.46 (9H, s), 1.65-1.82 (1H, br ), 2.86 (3H, d, J = 6.1 Hz), 3.30-3.40 (1H, br), 3.53-3.64 (2H, m), 3.80 (1H, dd, J = 10.3, 23.2 Hz), 5.11 (2H, t, J = 14.2 Hz), 7.28-7.39 (5H, m).
IR (ATR): 1693, 1416, 1358, 1155, 1107, 770, 698 cm ^-1 .
[Reference Example 56]
Ethyl 5- {1-[(tert-butoxycarbonyl) (methyl) amino] -3-azabicyclo [3.1.0] hex-3-yl} -8-cyano-7-methyl-6-phenyl [1,2, 4] Triazolo [1,5-a] pyridine-2-carboxylate (I-56)

Benzyl 1-[(tert-butoxycarbonyl) (methyl) amino] -3-azabicyclo [3.1.0] hexane-3-carboxylate (I-55) (395 mg, 1.14 mmol) dissolved in ethanol (8 ml) Then, palladium hydroxide (20% on carbon) (119 mg) was added at room temperature. This suspension was stirred at room temperature under a normal pressure hydrogen stream for 2.5 hours. The catalyst was filtered off while washing with ethanol, and the filtrate was concentrated under reduced pressure. The obtained residue was mixed with dichloromethane (8 ml), triethylamine (477 μl, 3.42 mmol), ethyl 5-chloro-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5- a] Pyridine-2-carboxylate (I-4) (427 mg, 1.25 mmol) was added. The solution was stirred at room temperature for 12 hours and then heated to reflux for 12 hours. The mixture was further stirred at room temperature for 9 days. A saturated aqueous ammonium chloride solution was added to this solution at 0 ° C., and the mixture was stirred for 10 minutes. The mixture was extracted three times with dichloromethane. The organic phases were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by medium pressure liquid chromatography (stationary phase: silica gel; mobile phase: normal hexane: ethyl acetate = 3: 1, v / v) to obtain 287 mg (49%) of the title compound as a pale yellow solid. .
ESI-MS m / z: 517 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 0.91 (1H, t, J = 7.1 Hz), 1.08-1.15 (1H, br), 1.42 (9H, s), 1.48 (3H, t, J = 7.1 Hz), 1.38-1.50 (1H, br), 1.59-1.67 (1H, br), 2.32 (3H, s), 2.79 (3H, s), 2.89 (1H, br d, J = 8.8 Hz), 3.15-3.30 (1H , br), 3.79 (1H, br d, J = 8.8 Hz), 3.92 (1H, d, J = 9.8 Hz), 4.54 (2H, q, J = 7.1 Hz), 7.19-7.27 (2H, m), 7.45-7.56 (3H, m).
[Reference Example 57]
tert-butyl (3- {8-cyano-2- [methoxy (methyl) carbonyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl}- 3-Azabicyclo [3.1.0] hex-1-yl) methylcarbamate (I-57)

N, O-dimethylhydroxylamine hydrochloride (162 mg, 1.66 mmol) was suspended in dichloromethane (2.5 ml), and trimethylaluminum (1.05 molar normal hexane solution) (1.58 ml, 1.66 mmol) was added dropwise at 0 ° C. The solution was stirred at the same temperature for 15 minutes and then at room temperature for 1 hour, and then cooled to 0 ° C. again. 3.1.0] Hex-3-yl} -8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-56) (286 mg, 0.55 mmol) in dichloromethane (4.5 ml) was added dropwise and stirred for 6 hours and 40 minutes. A saturated aqueous sodium hydrogen carbonate solution (10 ml) was added to this solution at 0 ° C., and the mixture was stirred for 15 minutes, and then extracted with dichloromethane three times. The organic phases were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by preparative TLC (mobile phase: chloroform: acetone = 95: 5, v / v) to obtain 290 mg (98%) of the title compound as a colorless solid.
ESI-MS m / z: 532 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 0.88 (1H, dd, J = 6.1, 7.6 Hz), 1.08-1.17 (1H, br), 1.40 (9H, s), 1.55-1.65 (1H, br), 2.33 (3H, s), 2.73-2.80 (1H, br), 2.77 (3H, s), 3.05-3.15 (1H, br), 3.40-3.50 (3H, br), 3.76 (1H, d, J = 9.0 Hz ), 3.90 (3H, s), 3.95-4.03 (1H, br), 7.15-7.23 (2H, m), 7.43-7.54 (3H, m).
[Reference Example 58]
tert-Butyl [3- (2-acetyl-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3-azabicyclo [3.1. 0] Hex-1-yl] methylcarbamate (I-58)

tert-butyl (3- {8-cyano-2- [methoxy (methyl) carbonyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl}- 3-Azabicyclo [3.1.0] hex-1-yl) methylcarbamate (I-57) (290 mg, 0.55 mmol) was dissolved in dichloromethane (6 ml) and methylmagnesium bromide ( 0.97 molar tetrahydrofuran solution) (1.1 ml, 1.09 mmol) was added. After stirring at the same temperature for 3.5 hours, a saturated aqueous sodium hydrogen carbonate solution was added to this solution, and the mixture was further stirred for 15 minutes. The mixture was extracted 3 times with dichloromethane. The organic phases were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by preparative TLC (mobile phase: chloroform: acetone = 95: 5, v / v) to obtain 186 mg (70%) of the title compound as a pale yellow solid.
ESI-MS m / z: 487 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 0.92 (1H, dd, J = 6.1, 7.6 Hz), 1.14 (1H, br s), 1.42 (9H, s), 1.64 (1H, br s), 2.33 (3H , s), 2.79 (3H, s), 2.81 (3H, s), 2.78-2.90 (1H, br), 3.13-3.28 (1H, br), 3.75 (1H, d, J = 9.0 Hz), 3.94 ( 1H, d, J = 9.0 Hz), 7.17-7.25 (2H, m), 7.45-7.55 (3H, m).
[Reference Example 59]
tert-butyl {3- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3-Azabicyclo [3.1.0] hex-1-yl} methylcarbamate (I-59)

tert-Butyl [3- (2-acetyl-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3-azabicyclo [3.1. 0] Hex-1-yl] methylcarbamate (I-58) (185 mg, 0.38 mmol) was dissolved in dichloromethane (4 ml), and (diethylamino) sulfur trifluoride (502 μl, 3.80) at 0 ° C under a nitrogen stream. mmol) was added. The solution was stirred for 17 hours while gradually warming from 0 ° C. to room temperature, cooled again to 0 ° C., saturated aqueous sodium hydrogen carbonate solution (15 ml) was added dropwise, and the mixture was stirred at the same temperature for 15 minutes. The mixture was extracted 3 times with dichloromethane. The organic phases were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by preparative TLC (stationary phase: silica gel; mobile phase: chloroform: acetone = 95: 5, v / v) to obtain 186 mg (96%) of the title compound as a pale yellow solid.
HRESI-MS m / z: 509.24503 (Calcd for C ₂₇ H ₃₁ F ₂ N ₆ O ₂ 509.24765).
¹ H-NMR (CDCl ₃ ) δ: 0.89 (1H, t, J = 7.6 Hz), 1.10 (1H, t, J = 4.4 Hz), 1.41 (9H, s), 1.55-1.65 (1H, br), 2.17 (3H, t, J = 18.5 Hz), 2.33 (3H, s), 2.78 (3H, s), 2.84 (1H, d, J = 9.0 Hz), 3.10-3.20 (1H, br), 3.78 (1H , d, J = 9.0 Hz), 3.86 (1H, d, J = 9.0 Hz), 7.15-7.22 (2, m), 7.43-7.55 (3H, m).
[Example 20]
2- (1,1-Difluoroethyl) -7-methyl-5- [1- (methylamino) -3-azabicyclo [3.1.0] hex-3-yl] -6-phenyl [1,2,4] Triazolo [1,5-a] pyridine-8-carbonitrile (# 20)

tert-butyl {3- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3-Azabicyclo [3.1.0] hex-1-yl} methylcarbamate (I-59) (185 mg, 0.36 mmol) was dissolved in dichloromethane (4 ml), and trifluoroacetic acid (2 ml) was dissolved at room temperature. added. The solution was stirred at the same temperature for 5 hours, and then the solvent was distilled off under reduced pressure. The obtained residue was dissolved in chloroform (15 ml), saturated aqueous sodium hydrogen carbonate solution (10 ml) was added thereto at room temperature, and the mixture was vigorously stirred for 10 minutes. The aqueous phase was separated and extracted three more times with chloroform. The organic phases were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by preparative TLC (mobile phase: chloroform: methanol = 9: 1, v / v) to obtain 113 mg (76%) of the title compound as a yellow solid.
ESI-MS m / z: 409 (M + 1) ⁺ .
HRESI-MS m / z: 409.19418 (Calcd for C ₂₂ H ₂₃ F ₂ N ₆ 409.19523).
_{^{1 H-NMR (CDCl 3)}} δ: 0.75-0.95 (2H, m), 1.20-1.40 (2H, m), 2.17 (3H, t, J = 18.3 Hz), 2.33 (3H, s), 2.35 (3H , s), 2.97 (1H, d, J = 9.3 Hz), 3.05 (1H, d, J = 9.3 Hz), 3.67 (1H, d, J = 9.3 Hz), 3.95 (1H, d, J = 9.3 Hz) ), 7.15-7.25 (2H, m), 7.45-7.60 (3H, m).
IR (ATR): 2213, 1612, 1510, 1502, 1441, 1269, 1181, 1149, 938, 914, 769, 705 cm ^-1 .
Anal. Calcd for C ₂₂ H ₂₂ F ₂ N ₆・ 0.25H ₂ O: C, 63.99; H, 5.49; N, 20.35; F, 9.20. Found: C, 64.16; H, 5.37; N, 20.13; F, 9.03.
[Reference Example 60]
tert-Butyl 3-ethyl-5-oxo-1-[(1R) -1-phenylethyl] pyrrolidine-3-carboxylate (I-60)

tert-butyl 5-oxo-1-[(1R) -1-phenylethyl] pyrrolidine-3-carboxylate (synthesized by the method described in WO2006 / 12379241) (27.2 g, 94.0 mmol) and ethyl iodide (18.8 ml, 235 mmol) in N, N-dimethylformamide (190 ml) under ice-cooling, sodium hydride (55% in paraffin liquid) (10.25 g, 235 mmol) was added and stirred at room temperature for 3 hours . The reaction solution was poured into a 10% aqueous citric acid solution under ice cooling, and the resulting mixture was extracted with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, insolubles were filtered off, and the filtrate was concentrated to purify the residue by silica gel column chromatography ( Eluent: normal hexane: ethyl acetate = 3: 1, v / v), title compound (I-60a, low polarity, 7.44 g, 25%, pale yellow oil) and (I-60b, high polarity, 9.53 g , 32%, colorless solid).
I-60a
¹ H-NMR (CDCl ₃ ) δ: 0.72 (3H, t, J = 7.4 Hz), 1.45 (9H, s), 1.52 (3H, d, J = 7.1 Hz), 1.51-1.61 (2H, m), 2.30 (1H, d, J = 17.1 Hz), 2.73 (1H, d, J = 10.3 Hz), 2.89 (1H, d, J = 17.1 Hz), 3.63 (1H, d, J = 10.3 Hz), 5.50 ( 1H, q, J = 7.1 Hz), 7.26-7.37 (5H, m).
I-60b
¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t, J = 7.6 Hz), 1.34 (9H, s), 1.51 (3H, d, J = 7.1 Hz), 1.59-1.82 (2H, m), 2.31 (1H, d, J = 17.1 Hz), 2.93 (1H, d, J = 17.1 Hz), 3.11 (1H, d, J = 10.3 Hz), 3.32 (1H, d, J = 10.3 Hz), 5.49 ( 1H, q, J = 7.1 Hz), 7.24-7.35 (5H, m).
[Reference Example 61]
3-Ethyl-5-oxo-1-[(1R) -1-phenylethyl] pyrrolidine-3-carboxylic acid (I-61)

To a solution of tert-butyl 3-ethyl-5-oxo-1-[(1R) -1-phenylethyl] pyrrolidine-3-carboxylate (I-60a) (1.10 g, 3.47 mmol) in dichloromethane (40 ml), Under ice cooling, trifluoroacetic acid (20 ml) was added, and the mixture was stirred at room temperature for 6 hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in chloroform and washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble material was filtered off, and the filtrate was concentrated to obtain 905 mg (100%) of the title compound as a colorless oily substance.
ESI-MS m / z: 262 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 0.76 (3H, t, J = 7.3 Hz), 1.53 (3H, d, J = 7.1 Hz), 1.57-1.72 (2H, m), 2.42 (1H, d, J = 17.1 Hz), 2.81 (1H, d, J = 10.3 Hz), 2.98 (1H, d, J = 17.1 Hz), 3.73 (1H, d, J = 10.3 Hz), 5.51 (1H, q, J = 7.3 Hz), 7.25-7.38 (5H, m).
[Reference Example 62]
tert-butyl {3-ethyl-5-oxo-1-[(1R) -1-phenylethyl] pyrrolidin-3-yl} carbamate (I-62)

3-Ethyl-5-oxo-1-[(1R) -1-phenylethyl] pyrrolidine-3-carboxylic acid (I-61) (905 mg, 3.46 mmol) was dissolved in toluene (30 ml) and triethylamine ( 965 μl, 6.93 mmol) and diphenylphosphoric acid azide (822 μl, 3.81 mmol) were added, and the mixture was stirred at room temperature for 30 minutes and then on an oil bath at 125 ° C. for 2.5 hours. To this reaction solution was added tert-butanol (30 ml), and the mixture was stirred on an oil bath at 100 ° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 1: 2, v / v), and 524 mg (46%) of the title compound was colorless. Obtained as an oil.
ESI-MS m / z: 333 (M + 1) ⁺ .
HRESI-MS m / z: 333.2176 (Calcd for C ₁₉ H ₂₉ N ₂ O ₃ 333.2178).
¹ H-NMR (CDCl ₃ ) δ: 0.74 (3H, t, J = 7.3 Hz), 1.43 (9H, s), 1.52 (3H, d, J = 7.3 Hz), 1.40-1.60 (1H, m), 1.69-1.89 (1H, m), 2.43 (1H, d, J = 16.6 Hz), 2.58 (1H, d, J = 16.6 Hz), 2.92 (1H, d, J = 10.3 Hz), 3.58-3.78 (1H , m), 4.49-4.66 (1H, m), 5.53 (1H, q, J = 7.3 Hz), 7.23-7.36 (5H, m).
[Reference Example 63]
tert-butyl {3-ethyl-5-oxo-1-[(1R) -1-phenylethyl] pyrrolidin-3-yl} methylcarbamate (I-63)

tert-butyl {3-ethyl-5-oxo-1-[(1R) -1-phenylethyl] pyrrolidin-3-yl} carbamate (I-62) (524 mg, 1.58 mmol) and methyl iodide (128 μl , 2.05 mmol) was dissolved in N, N-dimethylformamide (10 ml), sodium hydride (55% in paraffin liquid) (82.5 mg, 1.89 mmol) was added under ice cooling, and the mixture was stirred under ice cooling for 1 hour. did. Under ice-cooling, a saturated aqueous ammonium chloride solution was added to the reaction solution, this was extracted with ethyl acetate, and the resulting organic phase was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble material was filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: normal hexane: ethyl acetate = 1: 1, v / v) and 500 mg (92%) of the title compound were obtained as a colorless oil.
HRESI-MS m / z: 347.2368 (Calcd for C ₂₀ H ₃₁ N ₂ O ₃ 347.2335).
¹ H-NMR (CDCl ₃ ) δ: 0.61 (3H, t, J = 7.6 Hz), 1.39-1.60 (2H, m), 1.41 (9H, s), 1.53 (3H, d, J = 7.1 Hz), 2.50 (1H, d, J = 16.4 Hz), 2.77-2.83 (4H, m), 3.17-3.40 (1H, m), 3.56 (1H, d, J = 10.5 Hz), 5.50 (1H, q, J = 7.1 Hz), 7.22-7.37 (5H, m).
[Reference Example 64]
tert-butyl {3-ethyl-1-[(1R) -1-phenylethyl] pyrrolidin-3-yl} methylcarbamate (I-64)

tert-butyl {3-ethyl-5-oxo-1-[(1R) -1-phenylethyl] pyrrolidin-3-yl} methylcarbamate (I-63) (500 mg, 1.44 mmol) in tetrahydrofuran (10 ml) Then, borane-tetrahydrofuran complex (1.03 molar tetrahydrofuran solution) (5.60 ml, 5.77 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 15 hours. Ethanol (10 ml), triethylamine (3 ml) and water (3 ml) were added to the reaction solution, and the mixture was stirred on an oil bath at 90 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate and washed with saturated brine. This was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 1: 1). , v / v), and 452 mg (94%) of the title compound was obtained as a colorless oil.
HRESI-MS m / z: 333.2545 (Calcd for C ₂₀ H ₃₃ N ₂ O ₂ 333.2542).
¹ H-NMR (CDCl ₃ ) δ: 0.83 (3H, t, J = 7.6 Hz), 1.35 (3H, d, J = 6.6 Hz), 1.42 (9H, s), 1.76-1.97 (3H, m), 2.13-2.24 (1H, m), 2.44 (1H, q, J = 7.9 Hz), 2.53-2.63 (1H, m), 2.72 (1H, d, J = 10.0 Hz), 2.79 (1H, d, J = 10.3 Hz), 2.84 (3H, s), 3.22 (1H, q, J = 6.5 Hz), 7.19-7.33 (5H, m).
[Reference Example 65]
tert-Butyl (3-ethylpyrrolidin-3-yl) methylcarbamate (I-65)

tert-butyl {3-ethyl-1-[(1R) -1-phenylethyl] pyrrolidin-3-yl} methylcarbamate (I-64) (452 mg, 1.36 mmol) in 1,4-dioxane (10 ml) Then, palladium hydroxide catalyst (20% on carbon) (100 mg) was added, and the mixture was stirred for 3 hours on an oil bath at 70 ° C. in a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (297 mg, 96%) as a colorless oil.
ESI-MS m / z: 229 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 0.89 (3H, t, J = 7.5 Hz), 1.46 (9H, s), 1.65-1.87 (2H, m), 1.92-2.01 (1H, m), 2.03-2.15 (1H, m), 2.90 (3H, s), 2.91-3.06 (2H, m), 3.12 (1H, d, J = 11.7 Hz), 3.19 (1H, d, J = 11.7 Hz).
[Reference Example 66]
Ethyl 5- {3-[(tert-butoxycarbonyl) (methyl) amino] -3-ethylpyrrolidin-1-yl} -8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1 , 5-a] pyridine-2-carboxylate (I-66)

Of ethyl 5-chloro-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-4) (403 mg, 1.18 mmol) To a dichloromethane (10 ml) solution, add tert-butyl (3-ethylpyrrolidin-3-yl) methylcarbamate (I-65) (297 mg, 1.30 mmol) and triethylamine (214 μl, 1.54 mmol) at room temperature. Stir for 15 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate, and this was washed with water and saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 4: 1, v / v) and 546 mg (87%) of the title compound were obtained as a colorless solid.
HRESI-MS m / z: 533.2861 (Calcd for C ₂₉ H ₃₇ N ₆ O ₄ 533.2876).
¹ H-NMR (CDCl ₃ ) δ: 0.84 (3H, t, J = 7.5 Hz), 1.42 (9H, s), 1.48 (3H, t, J = 7.1 Hz), 1.52-1.60 (1H, m), 1.72-1.87 (1H, m), 1.99-2.08 (2H, m), 2.30 (3H, s), 2.77 (3H, s), 3.10-3.23 (1H, m), 3.34-3.64 (1H, m), 3.65-3.77 (2H, m), 4.54 (2H, q, J = 7.1 Hz), 7.13-7.52 (5H, m).
[Reference Example 67]
tert-butyl (1- {8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl}- 3-Ethylpyrrolidin-3-yl) methylcarbamate (I-67)

To a suspension of N, O-dimethylhydroxylamine hydrochloride (103 mg, 1.05 mmol) in toluene (3 ml) was added trimethylaluminum (1.05 molar hexane solution) (1.00 ml, 1.05 mmol) at room temperature. For 1 hour. Ethyl 5- {3-[(tert-butoxycarbonyl) (methyl) amino] -3-ethylpyrrolidin-1-yl} -8-cyano-7-methyl-6-phenyl [1,2,4] A solution of triazolo [1,5-a] pyridine-2-carboxylate (I-66) (224 mg, 0.42 mmol) in dichloromethane (2 ml) was added, and the mixture was stirred at room temperature for 15 hours. Under ice-cooling, 1N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, insolubles were filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (elution). Liquid: chloroform: ethyl acetate = 1: 2, v / v), and 230 mg (100%) of the title compound was obtained as a pale yellow oily substance.
ESI-MS m / z: 548 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 0.81 (3H, t, J = 7.6 Hz), 1.41 (9H, s), 1.53-1.64 (1H, m), 1.71-1.86 (1H, m), 1.97-2.06 (2H, m), 2.29 (3H, s), 2.75 (3H, s), 3.17-3.25 (1H, m), 3.18 (3H, s), 3.23 (3H, s), 3.49-3.70 (3H, m ), 7.09-7.14 (1H, m), 7.25-7.30 (1H, m), 7.40-7.54 (3H, m).
[Reference Example 68]
tert-Butyl [1- (2-acetyl-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3-ethylpyrrolidine-3 -Il] methylcarbamate (I-68)

tert-butyl (1- {8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl}- To a solution of 3-ethylpyrrolidin-3-yl) methylcarbamate (I-67) (230 mg, 0.42 mmol) in dichloromethane (3 ml), ice-cooled methylmagnesium bromide (0.97 mol tetrahydrofuran) (866 μl, 0.84 mmol) was added, and the mixture was stirred at 0 ° C. for 2 hours. Under ice-cooling, saturated ammonium chloride was added to the reaction solution, this was extracted with ethyl acetate, and the resulting organic phase was washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 3: 1, v / v), 135 mg (64%) of the title compound were obtained as a pale yellow solid.
HRESI-MS m / z: 503.2742 (Calcd for C ₂₈ H ₃₅ N ₆ O ₃ 503.2771).
¹ H-NMR (CDCl ₃ ) δ: 0.84 (3H, t, J = 7.6 Hz), 1.42 (9H, s), 1.50-1.61 (1H, m), 1.74-1.89 (1H, m), 2.00-2.08 (2H, m), 2.30 (3H, s), 2.77 (3H, s), 2.81 (3H, s), 3.16-3.24 (1H, m), 3.45-3.57 (1H, m), 3.64-3.74 (2H , m), 7.09-7.55 (5H, m).
[Reference Example 69]
tert-butyl {1- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3-Ethylpyrrolidin-3-yl} methylcarbamate (I-69 )

tert-Butyl [1- (2-acetyl-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3-ethylpyrrolidine-3 -Diyl] methylcarbamate (I-68) (134 mg, 0.27 mmol) in dichloromethane (2 ml) was added (diethylamino) sulfur trifluoride (349 μl, 2.67 mmol) under ice-cooling, and the mixture was stirred at room temperature for 15 Stir for hours. Under ice-cooling, water and a saturated aqueous sodium hydrogen carbonate solution were added to this solution, this was extracted with ethyl acetate, and the resulting organic phase was washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 4: 1, v / v), and 104 mg (74%) of the title compound was obtained as a pale yellow solid.
HRESI-MS m / z: 525.2778 (Calcd for C ₂₈ H ₃₅ F ₂ N ₆ O ₂ 525.2790).
¹ H-NMR (CDCl ₃ ) δ: 0.84 (3H, t, J = 7.6 Hz), 1.42 (9H, s), 1.48-1.60 (1H, m), 1.73-1.85 (1H, m), 1.97-2.06 (2H, m), 2.17 (3H, t, J = 18.7 Hz), 2.29 (3H, s), 2.78 (3H, s), 3.08-3.19 (1H, m), 3.30-3.44 (1H, m), 3.68-3.77 (2H, m), 7.09-7.53 (5H, m).
[Example 21]
2- (1,1-Difluoroethyl) -5- [3-ethyl-3- (methylamino) pyrrolidin-1-yl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5 -a] pyridine-8-carbonitrile (# 21)

tert-butyl {1- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] To a solution of -3-ethylpyrrolidin-3-yl} methylcarbamate (I-69) (104 mg, 0.20 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (1 ml) under ice cooling, and at room temperature. Stir for 2 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with chloroform. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matter was 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 69 mg (82%) of the title compound was obtained as a pale yellow solid.
ESI-MS m / z: 425 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 0.80 (3H, t, J = 7.3 Hz), 1.40-1.53 (2H, m), 1.53-1.64 (1H, m), 1.68-1.78 (1H, m), 2.17 (3H, t, J = 18.6 Hz), 2.21 (3H, s), 2.29 (3H, s), 3.19-3.26 (2H, m), 3.32-3.46 (2H, m), 7.15-7.25 (2H, m ), 7.41-7.52 (3H, m).
IR (ATR): 3361, 3058, 2969, 2941, 2880, 2862, 2799, 2211, 1609, 1536, 1510, 1471, 1443, 1386, 1366, 1347, 1311, 1270, 1247, 1237, 1201, 1178, 1135 , 1097, 1073, 1042, 1024, 1003, 968 cm ^-1 .
Anal. Calcd for C ₂₃ H ₂₆ F ₂ N ₆ : C, 65.08; H, 6.17; N, 19.80; F, 8.95. Found: C, 64.96; H, 6.11; N, 19.58; F, 8.74.
[Reference Example 70]
3-Ethyl-5-oxo-1-[(1R) -1-phenylethyl] pyrrolidine-3-carboxylic acid (I-70)

To a solution of tert-butyl 3-ethyl-5-oxo-1-[(1R) -1-phenylethyl] pyrrolidine-3-carboxylate (I-60b) (1.14 g, 3.59 mmol) in dichloromethane (40 ml), Under ice cooling, trifluoroacetic acid (20 ml) was added, and the mixture was stirred at room temperature for 17 hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in chloroform and washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated to obtain 938 mg (100%) of the title compound as a colorless oily substance.
ESI-MS m / z: 262 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 7.4 Hz), 1.53 (3H, d, J = 7.3 Hz), 1.75-1.85 (2H, m), 2.47 (1H, d, J = 17.3 Hz), 2.98 (1H, d, J = 17.3 Hz), 3.18 (1H, d, J = 10.5 Hz), 3.36 (1H, d, J = 10.5 Hz), 5.49 (1H, q, J = 7.3 Hz), 7.21-7.38 (5H, m).
[Reference Example 71]
tert-butyl {3-ethyl-5-oxo-1-[(1R) -1-phenylethyl] pyrrolidin-3-yl} carbamate (I-71)

3-ethyl-5-oxo-1-[(1R) -1-phenylethyl] pyrrolidine-3-carboxylic acid (I-70) (938 mg, 3.59 mmol) was dissolved in toluene (30 ml) and triethylamine ( 1.00 ml, 7.18 mmol) and diphenylphosphoric acid azide (813 μl, 3.77 mmol) were added, and the mixture was stirred at room temperature for 2 hours. To this reaction solution, tert-butanol (30 ml) was added, and the mixture was stirred on an oil bath at 100 ° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate and washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: normal hexane: ethyl acetate). = 1: 2, v / v), and 481 mg (40%) of the title compound was obtained as a colorless oil.
ESI-MS m / z: 333 (M + 1) ⁺ .
HRESI-MS m / z: 333.2203 (Calcd for C ₁₉ H ₂₉ N ₂ O ₃ 333.2178).
¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t, J = 7.5 Hz), 1.35 (9H, s), 1.51 (3H, d, J = 7.1 Hz), 1.63-1.81 (2H, m), 2.46-2.64 (2H, m), 3.20-3.35 (2H, m), 4.38-4.54 (1H, m), 5.45-5.59 (1H, m), 7.21-7.41 (5H, m).
[Reference Example 72]
tert-butyl {3-ethyl-5-oxo-1-[(1R) -1-phenylethyl] pyrrolidin-3-yl} methylcarbamate (I-72)

tert-butyl {3-ethyl-5-oxo-1-[(1R) -1-phenylethyl] pyrrolidin-3-yl} carbamate (I-71) (481 mg, 1.45 mmol) and methyl iodide (117 μl , 1.88 mmol) was dissolved in N, N-dimethylformamide (6 ml), sodium hydride (55% in paraffin liquid) (76 mg, 1.74 mmol) was added under ice cooling, and the mixture was stirred at the same temperature for 6 hours. . A saturated aqueous ammonium chloride solution was added to the reaction solution under ice-cooling, this was extracted with ethyl acetate, and the resulting organic phase was washed with saturated brine. After drying over anhydrous sodium sulfate, the insoluble material was filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: normal hexane: ethyl acetate = 1: 2, v / v) and 270 mg (54%) of the title compound were obtained as a colorless oil.
HRESI-MS m / z: 347.2342 (Calcd for C ₂₀ H ₃₁ N ₂ O ₃ 347.2335).
¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 7.5 Hz), 1.39 (9H, s), 1.52 (3H, d, J = 7.3 Hz), 1.66-1.80 (1H, m), 1.83-1.97 (1H, m), 2.53 (1H, d, J = 16.1 Hz), 2.75 (1H, d, J = 16.1 Hz), 2.76 (3H, s), 3.18 (1H, d, J = 10.5 Hz ), 3.43-3.71 (1H, m), 5.52 (1H, q, J = 7.3 Hz), 7.23-7.39 (5H, m).
[Reference Example 73]
tert-butyl {3-ethyl-1-[(1R) -1-phenylethyl] pyrrolidin-3-yl} methylcarbamate (I-73)

tert-butyl {3-ethyl-5-oxo-1-[(1R) -1-phenylethyl] pyrrolidin-3-yl} methylcarbamate (I-72) (269 mg, 0.78 mmol) in tetrahydrofuran (5 ml) Borane-tetrahydrofuran complex (1.03 mol tetrahydrofuran solution) (3.02 ml, 3.11 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 18 hours. Ethanol (20 ml), triethylamine (5 ml) and water (5 ml) were added to the reaction solution, and the mixture was stirred on an oil bath at 90 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: normal hexane: ethyl acetate). = 2: 1, v / v), and 211 mg (82%) of the title compound was obtained as a colorless oil.
HRESI-MS m / z: 333.2556 (Calcd for C ₂₀ H ₃₃ N ₂ O ₂ 333.2542).
¹ H-NMR (CDCl ₃ ) δ: 0.79 (3H, t, J = 7.6 Hz), 1.32 (3H, d, J = 6.6 Hz), 1.38 (9H, s), 1.77-2.00 (3H, m), 2.11-2.21 (1H, m), 2.38 (1H, dt, J = 9.0, 5.9 Hz), 2.57-2.65 (1H, m), 2.71 (1H, d, J = 9.8 Hz), 2.74-2.84 (1H, m), 2.82 (3H, s), 3.21 (1H, q, J = 6.6 Hz), 7.19-7.34 (5H, m).
[Reference Example 74]
tert-Butyl (3-ethylpyrrolidin-3-yl) methylcarbamate (I-74)

tert-butyl {3-ethyl-1-[(1R) -1-phenylethyl] pyrrolidin-3-yl} methylcarbamate (I-73) (211 mg, 0.64 mmol) in 1,4-dioxane (6 ml) Then, palladium hydroxide catalyst (20% on carbon) (40 mg) was added, and the mixture was stirred for 3 hours on a 70 ° C. oil bath in a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (139 mg, 96%) as a colorless oil.
ESI-MS m / z: 229 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 0.89 (3H, t, J = 7.6 Hz), 1.46 (9H, s), 1.65-1.87 (2H, m), 1.92-2.00 (1H, m), 2.04-2.14 (1H, m), 2.90 (3H, s), 2.91-3.05 (2H, m), 3.11 (1H, d, J = 11.7 Hz), 3.18 (1H, d, J = 11.7 Hz).
[Reference Example 75]
Ethyl 5- {3-[(tert-butoxycarbonyl) (methyl) amino] -3-ethylpyrrolidin-1-yl} -8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1 , 5-a] pyridine-2-carboxylate (I-75)

Of ethyl 5-chloro-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-4) (187 mg, 0.55 mmol) To a dichloromethane (4 ml) solution, add tert-butyl (3-ethylpyrrolidin-3-yl) methylcarbamate (I-74) (138 mg, 0.60 mmol) and triethylamine (99.4 μl, 0.71 mmol) at room temperature. Stir for 15 hours. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and washed with saturated brine. The obtained 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: ethyl acetate = 4: 1, v / v) to give 259 mg (89%) of the title compound as a colorless solid.
HRESI-MS m / z: 533.2855 (Calcd for C ₂₉ H ₃₇ N ₆ O ₄ 533.2876).
¹ H-NMR (CDCl ₃ ) δ: 0.84 (3H, t, J = 7.3 Hz), 1.42 (9H, s), 1.47 (3H, t, J = 7.1 Hz), 1.51-1.63 (1H, m), 1.72-1.86 (1H, m), 1.99-2.07 (2H, m), 2.30 (3H, s), 2.77 (3H, s), 3.10-3.22 (1H, m), 3.37-3.76 (3H, m), 4.54 (2H, q, J = 7.1 Hz), 7.10-7.17 (1H, m), 7.24-7.30 (1H, m), 7.40-7.54 (3H, m).
[Reference Example 76]
tert-butyl (1- {8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl}- 3-Ethylpyrrolidin-3-yl) methylcarbamate (I-76)

To a suspension of N, O-dimethylhydroxylamine hydrochloride (118 mg, 1.21 mmol) in toluene (4 ml) was added trimethylaluminum (1.05 molar hexane solution) (1.15 ml, 1.21 mmol) at room temperature. Stir at temperature for 1 hour. In this solution, ethyl 5- {3-[(tert-butoxycarbonyl) (methyl) amino] -3-ethylpyrrolidin-1-yl} -8-cyano-7-methyl-6-phenyl [1,2,4] A solution of triazolo [1,5-a] pyridine-2-carboxylate (I-75) (258 mg, 0.48 mmol) in dichloromethane (3 ml) was added, and the mixture was stirred at room temperature for 25 hours. Under ice-cooling, 1N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, insolubles were filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (elution). Liquid: chloroform: ethyl acetate = 1: 2, v / v), and 204 mg (77%) of the title compound was obtained as a colorless foam.
HRESI-MS m / z: 548.2979 (Calcd for C ₂₉ H ₃₈ N ₇ O ₄ 548.2985).
¹ H-NMR (CDCl ₃ ) δ: 0.81 (3H, t, J = 7.5 Hz), 1.41 (9H, s), 1.50-1.60 (1H, m), 1.74-1.82 (1H, m), 1.99-2.05 (2H, m), 2.30 (3H, s), 2.75 (3H, s), 3.18-3.26 (1H, m), 3.34-3.70 (6H, m), 3.91 (3H, s), 7.09-7.14 (1H , m), 7.24-7.30 (1H, m), 7.40-7.53 (3H, m).
[Reference Example 77]
tert-Butyl [1- (2-acetyl-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3-ethylpyrrolidine-3 -Il] methylcarbamate (I-77)

tert-butyl (1- {8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl}- To a solution of 3-ethylpyrrolidin-3-yl) methylcarbamate (I-76) (204 mg, 0.37 mmol) in dichloromethane (3 ml) was added ice-cooled methylmagnesium bromide (0.97 mol tetrahydrofuran) (768 μl, 0.75 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour. Under ice-cooling, saturated ammonium chloride was added to the reaction solution, this was extracted with ethyl acetate, and the resulting organic phase was washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: normal hexane: ethyl acetate). = 1: 1, v / v), and 156 mg (83%) of the title compound was obtained as a colorless solid.
HRESI-MS m / z: 503.2760 (Calcd for C ₂₈ H ₃₅ N ₆ O ₃ 503.2771).
¹ H-NMR (CDCl ₃ ) δ: 0.84 (3H, t, J = 7.5 Hz), 1.42 (9H, s), 1.51-1.62 (1H, m), 1.75-1.88 (1H, m), 2.01-2.08 (2H, m), 2.30 (3H, s), 2.77 (3H, s), 2.81 (3H, s), 3.17-3.24 (1H, m), 3.47-3.56 (1H, m), 3.63-3.75 (2H , m), 7.10-7.15 (1H, m), 7.24-7.31 (1H, m), 7.41-7.54 (3H, m).
[Reference Example 78]
tert-butyl {1- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3-Ethylpyrrolidin-3-yl} methylcarbamate (I-78)

tert-butyl [1- (2-acetyl-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3-ethylpyrrolidine-3 -Diyl] methylcarbamate (I-78) (156 mg, 0.31 mmol) in dichloromethane (3 ml) was added (diethylamino) sulfur trifluoride (407 μl, 3.10 mmol) under ice-cooling, and the mixture was stirred at room temperature for 15 Stir for hours. Under ice-cooling, water and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, which was extracted with ethyl acetate, and the resulting organic phase was washed with saturated brine. The obtained 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: ethyl acetate = 4: 1, v / v) and 153 mg (94%) of the title compound were obtained as a pale yellow solid.
HRESI-MS m / z: 525.2809 (Calcd for C ₂₈ H ₃₅ F ₂ N ₆ O ₂ 525.2790).
¹ H-NMR (CDCl ₃ ) δ: 0.84 (3H, t, J = 7.5 Hz), 1.42 (9H, s), 1.49-1.60 (1H, m), 1.73-1.86 (1H, m), 1.98-2.05 (2H, m), 2.17 (3H, t, J = 18.6 Hz), 2.29 (3H, s), 2.78 (3H, s), 3.08-3.20 (1H, m), 3.31-3.43 (1H, m), 3.69-3.77 (2H, m), 7.09-7.15 (1H, m), 7.24-7.30 (1H, m), 7.40-7.54 (3H, m).
[Example 22]
2- (1,1-Difluoroethyl) -5- [3-ethyl-3- (methylamino) pyrrolidin-1-yl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5 -a] pyridine-8-carbonitrile (# 22)

tert-butyl {1- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] To a solution of -3-ethylpyrrolidin-3-yl} methylcarbamate (I-78) (152 mg, 0.29 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (1 ml) under ice-cooling, and the mixture was brought to 0 ° C. And stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with chloroform. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matters 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), 94 mg (76%) of the title compound was obtained as a pale yellow solid.
ESI-MS m / z: 425 (M + 1) ⁺ .
_{^{1 H-NMR (CDCl 3)}} δ: 0.80 (3H, t, J = 7.5 Hz), 1.43-1.63 (3H, m), 1.73-1.77 (1H, m), 2.17 (3H, t, J = 18.6 Hz ), 2.22 (3H, s), 2.29 (3H, s), 3.19-3.25 (2H, m), 3.34-3.45 (2H, m), 7.14-7.25 (2H, m), 7.41-7.52 (3H, m ).
IR (ATR): 3058, 2968, 2941, 2880, 2862, 2799, 2211, 1609, 1536, 1510, 1471, 1443, 1386, 1367, 1347, 1311, 1270, 1247, 1236, 1201, 1179, 1136, 1097 , 1073, 1042, 1024, 1003, 967 cm ^-1 .
Anal. Calcd for C ₂₃ H ₂₆ F ₂ N ₆ : C, 65.08; H, 6.17; N, 19.80; F, 8.95. Found: C, 65.06; H, 6.18; N, 19.66; F, 8.92.
[Reference Example 79]
Ethyl 5-{(3S) -3-[(tert-butoxycarbonyl) (ethyl) amino] pyrrolidin-1-yl} -8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1 , 5-a] pyridine-2-carboxylate (I-79)

Of ethyl 5-chloro-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-4) (200 mg, 0.59 mmol) (3S)-(−)-3- (Ethylamino) pyrrolidine (94.7 μl, 0.76 mmol) and triethylamine (123 μl, 0.88 mmol) were added to a dichloromethane (5 ml) solution, and the mixture was stirred at room temperature for 15 hours. Di-tert-butyl dicarbonate (384 mg, 1.76 mmol) and triethylamine (123 μl, 0.88 mmol) were added to the reaction solution at room temperature, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and washed with saturated brine. The obtained 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: ethyl acetate = 2: 1, v / v), and 304 mg (100%) of the title compound was obtained as a colorless solid.
HRESI-MS m / z: 519.2673 (Calcd for C ₂₈ H ₃₅ N ₆ O ₄ 519.2720).
¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, t, J = 7.1 Hz), 1.12 (3H, t, J = 7.1 Hz), 1.41-1.51 (9H, m), 1.79-2.08 (2H, m ), 2.32 (3H, s), 3.04-3.63 (7H, m), 4.54 (2H, q, J = 7.1 Hz), 7.10-7.18 (1H, m), 7.25-7.31 (1H, m), 7.40- 7.55 (3H, m).
[Reference Example 80]
tert-Butyl [(3S) -1- {8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-5 -Il} pyrrolidin-3-yl] ethylcarbamate (I-80)

To a suspension of N, O-dimethylhydroxylamine hydrochloride (143 mg, 1.47 mmol) in toluene (6 ml) was added trimethylaluminum (1.05 molar hexane solution) (1.40 ml, 1.47 mmol) at room temperature. For 1 hour. To this solution ethyl 5-{(3S) -3-[(tert-butoxycarbonyl) (ethyl) amino] pyrrolidin-1-yl} -8-cyano-7-methyl-6-phenyl [1,2,4] A solution of triazolo [1,5-a] pyridine-2-carboxylate (I-79) (304 mg, 0.59 mmol) in dichloromethane (4 ml) was added, and the mixture was stirred at room temperature for 15 hours. Under ice-cooling, 1N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, insolubles were filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (elution). Liquid: chloroform: ethyl acetate = 2: 1, v / v), and 271 mg (87%) of the title compound was obtained as a colorless oily substance.
HRESI-MS m / z: 534.2843 (Calcd for C ₂₈ H ₃₆ N ₇ O ₄ 534.2829).
¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, t, J = 7.0 Hz), 1.35-1.45 (2H, m), 1.43 (9H, s), 1.73-1.99 (2H, m), 2.31 (3H , s), 2.97-3.12 (2H, m), 3.18 (3H, s), 3.25 (3H, s), 3.27-3.41 (2H, m), 4.34-4.63 (1H, m), 7.08-7.17 (1H , m), 7.24-7.30 (1H, m), 7.40-7.53 (3H, m).
[Reference Example 81]
tert-Butyl [(3S) -1- (2-acetyl-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) pyrrolidine-3 -Il] ethyl carbamate (I-81)

tert-Butyl [(3S) -1- {8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-5 -Il} pyrrolidin-3-yl] ethylcarbamate (I-80) (270 mg, 0.51 mmol) in dichloromethane (5 ml) under ice cooling with methylmagnesium bromide (0.97 mol tetrahydrofuran) (1.04 ml, 1.01 mmol) was added, and the mixture was stirred at 0 ° C. for 2 hours. Under ice-cooling, saturated ammonium chloride was added to the reaction solution, this was extracted with ethyl acetate, and the resulting organic phase was washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 3: 1, v / v), and 163 mg (66%) of the title compound was obtained as a pale yellow solid.
HRESI-MS m / z: 489.2579 (Calcd for C ₂₇ H ₃₃ N ₆ O ₃ 489.2614).
¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, t, J = 7.1 Hz), 1.39-1.57 (2H, m), 1.44 (9H, s), 1.78-2.03 (2H, m), 2.32 (3H , s), 2.81 (3H, s), 3.02-3.13 (2H, m), 3.28-3.42 (2H, m), 4.38-4.61 (1H, m), 7.10-7.19 (1H, m), 7.25-7.30 (1H, m), 7.41-7.55 (3H, m).
[Reference Example 82]
tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine- 5-yl] pyrrolidin-3-yl} ethylcarbamate (I-82)

tert-Butyl [(3S) -1- (2-acetyl-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) pyrrolidine-3 -Diyl] ethylcarbamate (I-81) (163 mg, 0.33 mmol) in dichloromethane (3 ml) was added (diethylamino) sulfur trifluoride (437 μl, 3.34 mmol) under ice-cooling, and the mixture was stirred at room temperature. Stir for hours. Under ice-cooling, water and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, which was extracted with ethyl acetate, and the resulting organic phase was washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 4: 1, v / v), and 137 mg (80%) of the title compound was obtained as a pale yellow solid.
HRESI-MS m / z: 511.2615 (Calcd for C ₂₇ H ₃₃ F ₂ N ₆ O ₂ 511.2633).
¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, t, J = 7.1 Hz), 1.35-1.45 (1H, m), 1.44 (9H, s), 1.78-2.00 (2H, m), 2.17 (3H , t, J = 18.7 Hz), 2.31 (3H, s), 3.02-3.15 (2H, m), 3.24-3.65 (3H, m), 4.35-4.64 (1H, m), 7.09-7.16 (1H, m ), 7.24-7.29 (1H, m), 7.41-7.54 (3H, m).
[Example 23]
2- (1,1-Difluoroethyl) -5-[(3S) -3- (ethylamino) pyrrolidin-1-yl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5 -a] pyridine-8-carbonitrile (# 23)

tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine- To a solution of 5-yl] pyrrolidin-3-yl} ethylcarbamate (I-82) (137 mg, 0.27 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (1 ml) under ice-cooling, and the mixture was brought to 0 ° C. And stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with chloroform. The obtained organic phase was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated, and the resulting residue was purified by preparative TLC (eluent; chloroform: methanol = 10: 1, v / v), and 84.0 mg (76%) of the title compound was obtained as a pale yellow solid.
ESI-MS m / z: 411 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.08 (3H, t, J = 7.1 Hz), 1.58-1.69 (1H, m), 1.91-2.04 (1H, m), 2.17 (3H, t, J = 18.7 Hz ), 2.29 (3H, s), 2.52-2.63 (2H, m), 3.22-3.55 (5H, m), 7.15-7.24 (2H, m), 7.41-7.52 (3H, m).
IR (ATR): 3055, 2965 , 2933, 2878, 2209, 1610, 1534, 1512, 1498, 1444, 1422, 1383, 1367, 1339, 1270, 1185, 1142, 1075, 1022, 1010 cm -1.
Anal. Calcd for C ₂₂ H ₂₄ F ₂ N ₆ : C, 64.37; H, 5.89; N, 20.47; F, 9.26. Found: C, 64.35; H, 5.97; N, 20.27; F, 9.16.
[Reference Example 83]
Tributyl [3- (methoxymethoxy) cyclopent-1-en-1-yl] stannane (I-83)

3- (Tributylstannyl) cyclopent-2-en-1-ol (synthesized according to the method described in WO2003 / 064422) (11.6 g, 31.1 mmol) and chloromethyl methyl ether (2.83 ml, 37.3 mmol) in dichloromethane ( To the solution, diisopropylethylamine (7.58 ml, 43.5 mmol) and dimethylaminopyridine (380 mg, 3.11 mmol) were added under ice-cooling, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the obtained residue, and the mixture was washed with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 4: 1 v / v) and 12.0 g (93%) of the title compound were obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.73-1.05 (15H, m), 1.24-1.35 (6H, m), 1.39-1.57 (6H, m), 1.71-1.80 (1H, m), 2.12-2.20 ( 1H, m), 2.31-2.41 (1H, m), 2.55-2.65 (1H, m), 3.38 (3H, s), 4.68-4.77 (3H, m), 5.90-6.01 (1H, m).
[Reference Example 84]
Ethyl 8-cyano-5- [3- (methoxymethyl) cyclopent-1-en-1-yl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-2 -Carboxylate (I-84)

Ethyl 5-chloro-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-4) (1.0 g, 2.93 mmol), Tributyl [3- (methoxymethoxy) cyclopent-1-en-1-yl] stannane (I-83) (1.47 g, 3.52 mmol), 2,6-di-tert-butyl-4-methylphenol (65 mg, A solution of 0.29 μmol) and dichlorobis (triphenylphosphine) palladium (II) (206 mg, 0.29 μmol) in 1,4-dioxane (30 ml) was stirred at 80 ° C. for 24 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (eluent: chloroform: ethyl acetate = 1: 1, v / v) to give 1.06 g (84%) of the title compound. Obtained as a pale yellow solid.
HRESI-MS m / z: 433.1873 (Calcd for C ₂₄ H ₂₅ N ₄ O ₄ 433.1876).
¹ H-NMR (CDCl ₃ ) δ: 1.48 (3H, t, J = 7.07 Hz), 1.77-1.86 (1H, m), 2.23-2.32 (1H, m), 2.44 (3H, s), 2.58-2.63 (2H, m), 3.26 (3H, s), 4.44-4.58 (4H, m), 4.64-4.69 (1H, m), 6.00-6.02 (1H, m), 7.15-7.21 (2H, m), 7.43 -7.50 (3H, m).
[Reference Example 85]
8-Cyano-N-methoxy-5- [3- (methoxymethoxy) cyclopent-1-en-1-yl] -N, 7-dimethyl-6-phenyl [1,2,4] triazolo [1,5- a] pyridine-2-carboxamide (I-85)

Ethyl 8-cyano-5- [3- (methoxymethyl) cyclopent-1-en-1-yl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-2 -Carboxylate (I-84) (1.06 g, 2.45 mmol) in ethanol (24 ml) was added with 1N aqueous sodium hydroxide solution (3.68 ml, 3.68 mmol) under ice-cooling and stirred at room temperature for 14 hours. did. A 10% aqueous citric acid solution was added to the residue obtained by concentrating the reaction solution under reduced pressure, and this was extracted with chloroform. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a pale yellow foamy substance in dichloromethane (24 ml). Dissolved. On the other hand, under ice cooling, N, O-dimethylhydroxylamine hydrochloride (359 mg, 3.68 mmol), 1-hydroxybenzotriazole (497 mg, 3.68 mmol), 1-ethyl-3- (3-dimethylaminopropyl) ) Carbodiimide (705 mg, 3.68 mmol) and triethylamine (1.02 ml, 7.35 mmol) were added, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate was added to the reaction solution, which was washed with water and saturated brine. The organic layer 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 = 20: 1, v / v), 960 mg (88%) of the title compound was obtained as a pale yellow foam.
HRESI-MS m / z: 448.2020 (Calcd for C ₂₄ H ₂₆ N ₅ O ₄ 448.1985).
¹ H-NMR (CDCl ₃ ) δ: 1.74-1.87 (1H, m), 2.18-2.32 (1H, m), 2.43 (3H, s), 2.50-2.68 (2H, m), 3.24 (3H, s) , 3.37-3.46 (3H, m), 3.90 (3H, s), 4.40-4.55 (2H, m), 4.59-4.68 (1H, m), 5.94-6.02 (1H, m), 7.14-7.21 (2H, m), 7.42-7.49 (3H, m).
[Reference Example 86]
2-Acetyl-5- [3- (methoxymethoxy) cyclopent-1-en-1-yl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-8- Carbonitrile (I-86)

8-cyano-N-methoxy-5- [3- (methoxymethoxy) cyclopent-1-en-1-yl] -N, 7-dimethyl-6-phenyl [1,2,4] triazolo [1,5- a] To a solution of pyridine-2-carboxamide (I-85) (960 mg, 2.15 mmol) in dichloromethane (20 ml), ice-cooled methylmagnesium bromide (0.97 mol tetrahydrofuran solution) (4.42 ml, 4.29 mmol). In addition, the mixture was stirred at 0 ° C. for 2 hours. Under ice-cooling, a saturated aqueous ammonium chloride solution was added to the reaction solution, this was extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 4: 1, v / v), and the title compound (735 mg, 85%) was obtained as a pale yellow solid.
HRESI-MS m / z: 403.1782 (Calcd for C ₂₃ H ₂₃ N ₅ O ₃ 403.1770).
¹ H-NMR (CDCl ₃ ) δ: 1.78-1.89 (1H, m), 2.22-2.35 (1H, m), 2.44 (3H, s), 2.53-2.71 (2H, m), 2.81 (3H, s) , 3.25 (3H, s), 4.46 (1H, d, J = 6.8 Hz), 4.52 (1H, d, J = 6.8 Hz), 4.63-4.69 (1H, m), 5.98 (1H, d, J = 2.0 Hz), 7.14-7.21 (2H, m), 7.42-7.51 (3H, m).
[Reference Example 87]
2- (1,1-Difluoroethyl) -5- [3- (methoxymethoxy) cyclopent-1-en-1-yl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5 -a] pyridine-8-carbonitrile (I-87)

2-Acetyl-5- [3- (methoxymethoxy) cyclopent-1-en-1-yl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-8- (Diethylamino) sulfur trifluoride (2.39 ml, 18.2 mmol) was added to a solution of carbonitrile (I-86) (734 mg, 1.82 mmol) in dichloromethane (20 ml) under ice cooling, and the mixture was stirred at room temperature for 18 hours. . Under ice-cooling, water and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, which was extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 2: 1, v / v) and the title compound 590 mg (76%) was obtained as a pale yellow solid.
HRESI-MS m / z: 425.1801 (Calcd for C ₂₃ H ₂₃ F ₂ N ₄ O ₂ 425.1789).
¹ H-NMR (CDCl ₃ ) δ: 1.77-1.87 (1H, m), 2.17 (3H, t, J = 18.5 Hz), 2.22-2.31 (1H, m), 2.43 (3H, s), 2.50-2.70 (2H, m), 3.25 (3H, s), 4.45 (1H, d, J = 6.8 Hz), 4.52 (1H, d, J = 6.8 Hz), 4.61-4.68 (1H, m), 5.96-5.99 ( 1H, m), 7.12-7.19 (2H, m), 7.42-7.49 (3H, m).
[Reference Example 88]
2- (1,1-Difluoroethyl) -5- (3-hydroxycyclopent-1-en-1-yl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a ] Pyridine-8-carbonitrile (I-88)

2- (1,1-Difluoroethyl) -5- [3- (methoxymethoxy) cyclopent-1-en-1-yl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5 To a solution of -a] pyridine-8-carbonitrile (I-87) (200 mg, 0.47 mmol) in tetrahydrofuran (10 ml) was added 1N aqueous hydrochloric acid (7 ml), and the mixture was stirred at 60 ° C for 5.5 hours. The reaction solution was returned to room temperature, water was added, and this was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 20% ethyl acetate / dichloromethane was concentrated under reduced pressure to obtain the title compound (117 mg, 65%) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.68-1.79 (1H, m), 2.17 (3H, t, J = 18.7 Hz), 2.28-2.39 (1H, m), 2.45 (3H, s), 2.59-2.76 (2H, m), 4.71-4.80 (1H, m), 5.83-5.86 (1H, m), 7.11-7.21 (2H, m), 7.44-7.49 (3H, m).
[Reference Example 89]
2- (1,1-Difluoroethyl) -7-methyl-5- (3-oxocyclopent-1-en-1-yl) -6-phenyl [1,2,4] triazolo [1,5-a ] Pyridine-8-carbonitrile (I-89)

2- (1,1-Difluoroethyl) -5- (3-hydroxycyclopent-1-en-1-yl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a Dess-Martin periodinane (195 mg, 0.46 mmol) was added to a solution of pyridine-8-carbonitrile (I-88) (117 mg, 0.31 mmol) in dichloromethane (5 ml), and the mixture was stirred at room temperature for 90 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and this was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 40% ethyl acetate / hexane was concentrated under reduced pressure to obtain 85 mg (73%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 2.17 (3H, t, J = 18.7 Hz), 2.43-2.48 (5H, m), 2.90-2.96 (2H, m), 6.16-6.19 (1H, m), 7.12 -7.19 (2H, m), 7.45-7.51 (3H, m).
[Reference Example 90]
2- (1,1-Difluoroethyl) -5- (4-fluoro-3-oxocyclopent-1-en-1-yl) -7-methyl-6-phenyl [1,2,4] triazolo [1 , 5-a] pyridine-8-carbonitrile (I-90)

2- (1,1-Difluoroethyl) -7-methyl-5- (3-oxocyclopent-1-en-1-yl) -6-phenyl [1,2,4] triazolo [1,5-a ] To a solution of pyridine-8-carbonitrile (I-89) (160 mg, 0.42 mmol) in tetrahydrofuran (8 ml) at −78 ° C. was added lithium bis (trimethylsilyl) amide (1.0 molar tetrahydrofuran solution: 0.63 ml), Stir at -78 ° C for 15 minutes. To this reaction solution, a solution of N-fluorobenzenesulfonimide (146 mg, 0.46 mmol) in tetrahydrofuran (5 ml) was added at -78 ° C. The reaction solution was stirred at −78 ° C. for 30 minutes, and water was added thereto, followed by returning to room temperature. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluate of 25% ethyl acetate / normal hexane was concentrated under reduced pressure to obtain 34 mg (20%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 2.17 (3H, t, J = 18.5 Hz), 2.48 (3H, s), 2.82-2.97 (1H, m), 3.29-3.40 (1H, m), 4.93-5.12 (1H, m), 6.26-6.30 (1H, m), 7.12-7.22 (2H, m), 7.48-7.54 (3H, m).
[Reference Example 91]
tert-butyl {3- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -5-Fluorocyclopent-2-en-1-yl} methylcarbamate (I-91)

  2- (1,1-Difluoroethyl) -5- (4-fluoro-3-oxocyclopent-1-en-1-yl) -7-methyl-6-phenyl [1,2,4] triazolo [1 , 5-a] pyridine-8-carbonitrile (I-90) (34 mg, 0.09 mmol) in dichloromethane (3 ml) in methylamine (2 molar tetrahydrofuran solution: 20 μl), titanium tetraisopropoxide (37 mg, 0.13 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. Sodium triacetoxyhydroborate (36 mg, 0.17 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from the eluent of 5% methanol / dichloromethane was concentrated under reduced pressure.

To a solution of the obtained residue in dichloromethane (3 ml) were added ditert-butyl dicarbonate (28 mg, 0.13 mmol) and triethylamine (25 μl), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 20% ethyl acetate / normal hexane was concentrated under reduced pressure to give the title compound (25 mg, 57%) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 2.09-2.35 (6H, m), 2.43 (3H, s), 2.62-2.68 (1H, m), 3.09-3.58 (1H, m) , 5.01-5.32 (2H, m), 5.77-5.91 (1H, m), 7.09-7.15 (1H, m), 7.24-7.27 (1H, m), 7.39-7.54 (3H, m).
[Example 24]
2- (1,1-Difluoroethyl) -5- [4-fluoro-3- (methylamino) cyclopent-1-en-1-yl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-8-carbonitrile (# 24)

tert-butyl {3- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] Trifluoroacetic acid (0.5 ml) was added to a solution of -5-fluorocyclopent-2-en-1-yl} methylcarbamate (I-91) (25 mg, 0.05 mmol) in dichloromethane (3 ml) at room temperature. Stir for 1 hour. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from the eluent of 4% methanol / dichloromethane was concentrated under reduced pressure to obtain a solid. Diethyl ether-normal hexane was added to the obtained solid, and the solid was collected by filtration and dried to give 8 mg (40%) of the title compound as a powder.
ESI-MS m / z: 411 (M + 1) ⁺ .
HRESI-MS m / z: 412.17665 (Calcd for C ₂₂ H ₂₁ F ₃ N ₅ 412.17490).
¹ H-NMR (CDCl ₃ ) δ: 2.17 (3H, t, J = 18.7 Hz), 2.40 (3H, s), 2.46 (3H, s), 2.68-2.82 (1H, m), 3.14-3.33 (1H , m), 3.70-3.81 (1H, m), 5.13-5.32 (1H, m), 5.75 (1H, s), 7.08-7.14 (1H, m), 7.17-7.22 (1H, m), 7.43-7.50 (3H, m).
IR (ATR): 2963, 2941, 1852, 2801, 2227, 1610, 1539, 1484, 1450, 1422, 1389, 1337, 1270, 1183, 1139, 931, 911, 875, 844 cm ^-1 .
[Reference Example 92]
(2-Methyl-1,3-dioxolan-2-yl) (phenyl) ethyl acetate (I-92)

A toluene solution of ethyl 3-oxo-2-phenylbutanoate (1.14 g, 5.53 mmol), ethylene glycol (1.5 ml, 27.6 mmol) and p-toluenesulfonic acid monohydrate (0.10 g, 0.55 mmol) was added to Dean Stark. And heated to reflux for 4.5 hours. Ethylene glycol (0.6 ml, 11.1 mmol) was added to the reaction solution, and the mixture was further heated to reflux for 1.5 hours. The reaction solution was returned to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 10% ethyl acetate / normal hexane was concentrated under reduced pressure to give the title compound (1.11 g, 80%) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.21-1.27 (3H, m), 1.39 (3H, s), 3.80-3.99 (5H, m), 4.08-4.26 (2H, m), 7.27-7.35 (3H, m), 7.46-7.52 (2H, m).
[Reference Example 93]
N-methoxy-N-methyl-2- (2-methyl-1,3-dioxolan-2-yl) -2-phenylacetamide (I-93)

(2-Methyl-1,3-dioxolan-2-yl) (phenyl) ethyl acetate (I-92) (844 mg, 3.37 mmol), 1N aqueous sodium hydroxide solution (5 ml) in ethanol (15 ml) Was stirred at 70 ° C. for 17 hours. The reaction mixture was allowed to cool to room temperature, 1N aqueous hydrochloric acid solution (6 ml) and water were added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue, N, O-dimethylamine hydrochloride (493 mg, 5.06 mmol), 1-hydroxybenzotriazole monohydrate (516 mg, 3.37 mmol), 1-ethyl-3- (3-dimethylaminopropyl) ) A solution of carbodiimide hydrochloride (970 mg, 5.06 mmol) and N-methylmorpholine (1.1 ml, 10.1 mmol) in dichloromethane (50 ml) was stirred at room temperature for 2 hours. N, O-dimethylamine hydrochloride (493 mg, 5.06 mmol) and N-methylmorpholine (0.55 ml, 5.06 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 6 hours. N, O-dimethylamine hydrochloride (493 mg, 5.06 mmol) and N-methylmorpholine (0.55 ml, 5.06 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with water and a saturated aqueous sodium hydrogen carbonate solution in this order. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 40% ethyl acetate / normal hexane was concentrated under reduced pressure to give the title compound (763 mg, 85%) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, s), 3.19 (3H, s), 3.47 (3H, s), 3.76-3.98 (4H, m), 4.47 (1H, s), 7.24-7.33 (3H, m), 7.47-7.53 (2H, m).
[Reference Example 94]
tert-Butyl methyl {3-[(2-methyl-1,3-dioxolan-2-yl) (phenyl) acetyl] cyclopent-2-en-1-yl} carbamate (I-94)

To a solution of tert-butyl methyl [3- (tributylstannyl) cyclopent-2-en-1-yl] carbamate (synthesized according to the method described in WO2007 / 020936) (1.82 g, 3.74 mmol) in tetrahydrofuran (50 ml) Butyl lithium (1.63 molar normal hexane solution: 2.3 ml) was added at -78 ° C. The reaction was stirred at -78 ° C for 15 minutes. To this reaction solution was added N-methoxy-N-methyl-2- (2-methyl-1,3-dioxolan-2-yl) -2-phenylacetamide (I-93) (763 mg, 2.88) at -78 ° C. mmol) in tetrahydrofuran (10 ml) was added. The reaction mixture was stirred at -78 ° C for 2 hours, saturated aqueous ammonium chloride solution was added, and the temperature was returned to room temperature. The reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 25% ethyl acetate / normal hexane was concentrated under reduced pressure to give the title compound (798 mg, 69%) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.38-1.48 (12H, m), 1.58-1.75 (1H, m), 2.13-2.75 (6H, m), 3.70-3.96 (4H, m), 4.58 (1H, s), 5.08-5.56 (1H, m), 6.37-6.45 (1H, m), 7.24-7.42 (5H, m).
[Reference Example 95]
tert-Butyl methyl {3-[(2-methyl-1,3-dioxolan-2-yl) (phenyl) acetyl] cyclopentyl} carbamate (I-95)

tert-Butyl methyl {3-[(2-methyl-1,3-dioxolan-2-yl) (phenyl) acetyl] cyclopent-2-en-1-yl} carbamate (I-94) (921 mg, 2.29 mmol ), A suspension of 10% palladium on carbon (wet: 90 mg) in ethanol (30 ml) was stirred under a hydrogen atmosphere for 16 hours. The reaction suspension was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 25% ethyl acetate / normal hexane was concentrated under reduced pressure to give the title compound (850 mg, 92%) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.34-1.46 (12H, m), 1.51-2.15 (6H, m), 2.65-2.74 (3H, m), 2.87-3.10 (1H, m), 3.74-3.97 ( 4H, m), 4.13-4.17 (1H, m), 4.28-4.60 (1H, m), 7.24-7.40 (5H, m).
[Reference Example 96]
tert-Butyl methyl [3- (3-oxo-2-phenylbutanoyl) cyclopentyl] carbamate (I-96)

tert-Butylmethyl {3-[(2-methyl-1,3-dioxolan-2-yl) (phenyl) acetyl] cyclopentyl} carbamate (I-95) (850 mg, 2.11 mmol) in water (5 ml) / Concentrated hydrochloric acid (2 ml) was added to a mixed solution of 1,4-dioxane (15 ml), and the mixture was stirred at room temperature for 2 hours. Concentrated hydrochloric acid (1 ml) was added to the reaction mixture solution, and the mixture was stirred at room temperature for 17 hours. Further, concentrated hydrochloric acid (1 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 5 hours, then ice-cooled, and saturated aqueous sodium hydrogen carbonate solution was added to make it alkaline. To this mixed solution was added a solution of 1,4-dioxane (4 ml) in tert-butyl dicarbonate (690 mg, 3.16 mmol) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture solution was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 10% ethyl acetate / normal hexane was concentrated under reduced pressure to give the title compound (696 mg, 92%) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 1.51-2.19 (10H, m), 2.52-2.81 (4H, m), 4.21-4.64 (1H, m), 7.11-7.20 (2H, m), 7.31-7.42 (3H, m).
[Reference Example 97]
Ethyl 5- {3-[(tert-butoxycarbonyl) (methyl) amino] cyclopentyl} -8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-2 -Carboxylate (I-97)

tert-Butylmethyl [3- (3-oxo-2-phenylbutanoyl) cyclopentyl] carbamate (I-96) (590 mg, 1.64 mmol), ethyl 5- (cyanomethyl) -1H-1,2,4-triazole -3-Carboxylate (I-2) (355 mg, 1.97 mmol) and ammonium acetate (253 mg, 3.28 mmol) were stirred at 80 ° C. for 1 hour. The reaction mixture was stirred at 110 ° C. for 24 hours and then returned to room temperature. This was dissolved in chloroform and subjected to flash silica gel column chromatography, and the fraction obtained from the eluent of 5% methanol / chloroform was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from the eluent of 30% ethyl acetate / normal hexane was concentrated under reduced pressure to give 37 mg (4.5%) of the title compound (diastereomer mixture) as a solid. Got as.
¹ H-NMR (CDCl ₃ ) δ: 1.39-1.50 (12H, m), 1.66-1.81 (3H, m), 2.24-2.40 (5H, m), 2.58-2.71 (1H, m), 2.92 (3H, s), 3.24-3.42 (1H, m), 4.43-4.66 (3H, m), 7.11-7.22 (2H, m), 7.50-7.58 (3H, m).
[Reference Example 98]
tert-butyl [(1S *, 3R *)-3- {8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a ] Pyridin-5-yl} cyclopentyl] methylcarbamate (I-98a) and tert-butyl [(1S *, 3S *)-3- {8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl- 6-Phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl} cyclopentyl] methylcarbamate (I-98b)

Ethyl 5- {3-[(tert-butoxycarbonyl) (methyl) amino] cyclopentyl} -8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-2 Lithium hydroxide monohydrate (6 mg, 0.15 mmol) was added to a mixed solution of -carboxylate (I-97) (37 mg, 0.07 mmol) in tetrahydrofuran (5 ml) / water (2 ml) at room temperature. Stir for 1 hour. A 1N aqueous hydrochloric acid solution (0.5 ml) was added to the reaction mixture solution, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue, N, O-dimethylamine hydrochloride (11 mg, 0.11 mmol), 1-hydroxybenzotriazole (10 mg, 0.07 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride A solution of (21 mg, 0.11 mmol) and N-methylmorpholine (24 μl, 0.22 mmol) in dichloromethane (5 ml) was stirred at room temperature for 17 hours and concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from the eluent of 40% ethyl acetate / normal hexane was concentrated under reduced pressure to give the title compound (less polar: I-98a) 25 mg (66%) Was obtained as a solid, and 2 mg (5%) of the title compound (more polar: I-98b) was obtained as an amorphous substance.
(I-98a)
ESI-MS m / z: 519 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 1.63-1.83 (3H, m), 2.16-2.43 (5H, m), 2.63 (1H, q, J = 11.4 Hz), 2.84 (3H , s), 3.25-3.57 (4H, m), 3.89 (3H, s), 4.39-4.66 (1H, m), 7.11-7.19 (2H, m), 7.50-7.56 (3H, m).
(I-98b)
ESI-MS m / z: 519 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.41 (9H, s), 1.58-1.74 (3H, m), 1.91-2.06 (2H, m), 2.35 (3H, s), 2.47-2.60 (2H, m) , 2.64 (3H, s), 3.32-3.48 (3H, m), 3.89 (3H, s), 4.95 (1H, br s), 7.15-7.20 (2H, m), 7.50-7.57 (3H, m).
[Reference Example 99]
tert-Butyl [(1S ^* , 3S ^* )-3- (2-acetyl-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl ) Cyclopentyl] methyl carbamate (I-99)

tert-butyl [(1S *, 3S *)-3- {8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a ] Pyridin-5-yl} cyclopentyl] methylcarbamate (I-98b) (112 mg, 0.22 mmol) was dissolved in dichloromethane (5 ml). This solution was cooled to 0 ° C., methylmagnesium bromide (0.97 mol tetrahydrofuran solution) (444 μl, 0.43 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 2 hr. An aqueous ammonium chloride solution and chloroform were added to the reaction solution, and the organic phase was washed with saturated brine. The obtained organic phase was dried over anhydrous magnesium sulfate, and then 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 86 mg (84%) of the title compound as a colorless solid.
ESI-MS m / z: 474 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.41 (9H, s), 1.63-1.78 (3H, m), 2.01-2.09 (1H, m), 2.34 (3H, s), 2.41-2.54 (2H, m) , 2.67 (3H, s), 2.86 (3H, s), 3.35-3.46 (1H, m), 5.08 (1H, br s), 7.17-7.22 (2H, m), 7.51-7.58 (3H, m).
[Reference Example 100]
tert-butyl {(1S ^* , 3S ^* )-3- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5- a] Pyridin-5-yl] cyclopentyl} methylcarbamate (I-100)

tert-Butyl [(1S *, 3S *)-3- (2-acetyl-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl ) Cyclopentyl] methylcarbamate (I-99) (86 mg, 0.18 mmol) was dissolved in dichloromethane (4 ml). The solution was cooled to 0 ° C., (diethylamino) sulfur trifluoride (96 μl, 0.7 mmol) was added dropwise, and the mixture was stirred at room temperature for 3 hours. Water and chloroform were added to the reaction solution, and the organic phase was washed with saturated brine. The obtained organic phase was dried over anhydrous magnesium sulfate, and then 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 77 mg (86%) of the title compound as a colorless solid.
ESI-MS m / z: 496 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 1.59-1.74 (3H, s), 1.99-2.06 (1H, m), 2.20 (3H, t, J = 18.5 Hz), 2.33 (3H , s), 2.40-2.54 (2H, m), 2.66 (3H, s), 3.32-3.43 (1H, m), 4.98 (1H, br s), 7.15-7.20 (2H, m), 7.50-7.57 ( 3H, m).
[Example 25]
2- (1,1-Difluoroethyl) -7-methyl-5-[(1S ^* , 3S ^* )-3- (methylamino) cyclopentyl] -6-phenyl [1,2,4] triazolo [1,5 -a] pyridine-8-carbonitrile (# 25)

tert-butyl {(1S *, 3S *)-3- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5- a] Pyridin-5-yl] cyclopentyl} methyl carbamate (I-100) (91 mg, 0.18 mmol) was dissolved in dichloromethane (2 ml). To this solution was added trifluoroacetic acid (2 ml) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was diluted with chloroform. This was washed with a saturated aqueous sodium hydrogen carbonate solution and 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 = 5: 1, v / v) to obtain 55 mg (76%) of the title compound as a colorless solid.
ESI-MS m / z: 396 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.39-1.58 (2H, m), 1.74-1.83 (1H, m), 1.88-1.96 (1H, m), 2.17 (3H, t, J = 21.1 Hz), 2.33 (3H, s), 2.35 (3H, s), 2.35-2.36 (2H, m), 2.50-2.59 (1H, m), 3.44-3.58 (2H, m), 7.13-7.18 (2H, m), 7.48 -7.54 (3H, m).
IR (ATR): 2945, 2227, 1617, 1483, 1386, 1188, 1138, 910, 708 cm ^-1 .
Anal. Calcd for C ₂₂ H ₂₃ F ₂ N ₅・ 0.25H ₂ O: C, 66.07; H, 5.92; N, 17.51; F, 9.50. Found: C, 65.98; H, 5.67; N, 17.23; F, 9.61.
[Reference Example 101]
tert-butyl [(1S *, 3R *)-3- (2-acetyl-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl ) Cyclopentyl] methyl carbamate (I-101)

tert-butyl [(1S *, 3R *)-3- {8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl-6-phenyl [1,2,4] triazolo [1,5-a ] Methylmagnesium bromide (0.97 mol tetrahydrofuran solution: 0.13 ml) was added to a solution of [pyridin-5-yl} cyclopentyl] methylcarbamate (I-98a) (25 mg, 0.05 mmol) in dichloromethane (5 ml) with ice cooling. And stirred for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution under ice cooling, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by flash silica gel column chromatography to obtain 20 mg (88%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.64-1.91 (3H, m), 2.25-2.42 (2H, m), 2.36 (3H, s), 2.57-2.70 (1H, m) , 2.82-2.94 (6H, m), 3.28-3.43 (1H, m), 4.44-4.68 (1H, m), 7.11-7.24 (2H, m), 7.5-7.60 (3H, m).
[Reference Example 102]
tert-butyl {(1S *, 3R *)-3- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5- a] Pyridin-5-yl] cyclopentyl} methylcarbamate (I-102)

tert-butyl [(1S *, 3R *)-3- (2-acetyl-8-cyano-7-methyl-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl ) Cyclopentyl] methylcarbamate (I-101) (20 mg, 0.04 mmol) in dichloromethane (5 ml) was added with (diethylamino) sulfur trifluoride (55 μl, 0.42 mmol) under ice-cooling, followed by 14 at room temperature. Stir for hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution under ice cooling, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. (Diethylamino) sulfur trifluoride (166 μl, 1.27 mmol) was added to a solution of the obtained residue in dichloromethane (3 ml) with ice cooling, and the mixture was stirred at room temperature for 7 hours. Further, (diethylamino) sulfur trifluoride (166 μl, 1.27 mmol) was added to this solution under ice cooling, and the mixture was stirred at room temperature for 16 hours, followed by addition of a saturated aqueous sodium hydrogen carbonate solution under ice cooling. Extracted in The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 5% ethyl acetate / normal hexane was concentrated under reduced pressure to obtain 18 mg (86%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.60-1.84 (3H, m), 2.12-2.37 (8H, m), 2.55-2.67 (1H, m), 2.85 (3H, s) , 3.24-3.36 (1H, m), 4.44-4.69 (1H, m), 7.09-7.18 (2H, m), 7.49-7.56 (3H, m).
[Example 26]
2- (1,1-Difluoroethyl) -7-methyl-5-[(1R *, 3S *)-3- (methylamino) cyclopentyl] -6-phenyl [1,2,4] triazolo [1,5 -a] pyridine-8-carbonitrile (# 26)

tert-butyl {(1S *, 3R *)-3- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6-phenyl [1,2,4] triazolo [1,5- To a solution of a] pyridin-5-yl] cyclopentyl} methylcarbamate (I-102) (104 mg, 0.21 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from the eluent of 7N ammonia methanol solution / chloroform (5/95, v / v) was concentrated under reduced pressure to give 51 mg (62% ) Was obtained as a solid.
ESI-MS m / z: 396 (M + 1) ⁺ .
HRESI-MS m / z: 396.20178 (Calcd for C ₂₂ H ₂₄ F ₂ N ₅ 396.19998).
¹ H-NMR (CDCl ₃ ) δ: 1.68-1.81 (2H, m), 1.91-2.05 (2H, m), 2.13-2.26 (4H, m), 2.34 (3H, s), 2.42 (3H, s) , 2.45-2.55 (1H, m), 3.02-3.32 (2H, m), 7.14-7.21 (2H, m), 7.50-7.57 (3H, m).
IR (ATR): 2952, 2783, 1618, 1484, 1443, 1386, 1330, 1270, 1187, 1140, 925, 911, 780, 769 cm ^-1 .
Anal. Calcd for C ₂₂ H ₂₃ F ₂ N ₅ : C, 66.82; H, 5.86; F, 9.61; N, 17.71. Found: C, 66.76; H, 5.72; F, 9.24; N, 17.76.
[Reference Example 103]
Ethyl 8-cyano-7-hydroxy-5-oxo-6-phenyl-1,5-dihydro [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-103)

Ethyl 5- (cyanomethyl) -1H-1,2,4-triazole-3-carboxylate (I-2) (835 mg, 4.6 mmol) and bis (2,4,6-trichlorophenyl) phenylpropanedioate ( 2.5 g, 4.6 mmol) was slowly stirred at 150 ° C. for 18 hours. Toluene and diethyl ether were added to the reaction solution, and the resulting solid was collected by filtration. The solid was purified using silica gel column chromatography (eluent; chloroform: methanol = 4: 1, v / v) to obtain 190 mg (13%) of the title compound as a yellow solid.
ESI-MS m / z: 325 (M + 1) ⁺ .
[Reference Example 104]
Ethyl 5,7-dichloro-8-cyano-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-104)

Ethyl 8-cyano-7-hydroxy-5-oxo-6-phenyl-1,5-dihydro [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-103) (190 mg, 0.59 mmol) was added phosphorus oxychloride (4 ml) and refluxed for 31 hours. The reaction mixture was concentrated under reduced pressure, and ice water was added to the resulting residue, followed by dilution with chloroform. This was washed with a saturated aqueous solution of sodium bicarbonate 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; chloroform: methanol = 95: 5, v / v) to obtain 30 mg (14%) of the title compound as a colorless solid.
ESI-MS m / z: 361 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.51 (3H, t, J = 7.1 Hz), 4.60 (2H, q, J = 7.1 Hz), 7.30-7.34 (2H, m), 7.56-7.60 (3H, m ).
[Reference Example 105]
Ethyl 5-{(3S) -3-[(tert-butoxycarbonyl) (methyl) amino] -3-methylpyrrolidin-1-yl} -7-chloro-8-cyano-6-phenyl [1,2,4 ] Triazolo [1,5-a] pyridine-2-carboxylate (I-105)

Ethyl 5,7-dichloro-8-cyano-6-phenyl [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-104) (40 mg, 0.11 mmol) was added to tetrahydrofuran ( 1 ml) and dimethyl sulfoxide (1 ml). The mixture was added and stirred at 80 ° C. for 2 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: normal hexane = 1: 1, v / v) to obtain 48 mg (80%) of the title compound as a colorless solid.
ESI-MS m / z: 539 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, s), 1.43 (9H, s), 1.47 (3H, t, J = 7.2 Hz), 1.90-2.08 (2H, m), 2.75 (3H, s ), 3.21-3.31 (2H, m), 3.51-3.66 (2H, m), 3.76 (2H, br s), 4.54 (2H, q, J = 7.1 Hz), 7.12-7.18 (1H, m), 7.37 -7.41 (1H, m), 7.44-7.55 (3H, m).
[Reference Example 106]
tert-Butyl [(3S) -1- {7-chloro-8-cyano-2- [methoxy (methyl) carbamoyl] -6-phenyl [1,2,4] triazolo [1,5-a] pyridine-5 -Il} -3-Methylpyrrolidin-3-yl] methylcarbamate (I-106)

Ethyl 5-{(3S) -3-[(tert-butoxycarbonyl) (methyl) amino] -3-methylpyrrolidin-1-yl} -7-chloro-8-cyano-6-phenyl [1,2,4 ] Triazolo [1,5-a] pyridine-2-carboxylate (I-105) (220 mg, 0.41 mmol) was dissolved in water (5 ml) and tetrahydrofuran (5 ml). Lithium hydroxide monohydrate (21 mg, 0.49 mmol) was added to this solution and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was neutralized with 1N aqueous hydrochloric acid, and extracted with chloroform. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in dichloromethane (30 ml). To this solution was added N, O-dimethylhydroxyamine hydrochloride (60 mg, 0.6 mmol), 1-hydroxybenzotriazole (83 mg, 0.6 mmol), triethylamine (86 μl, 0.6 mmol) and 1- (dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (118 mg, 0.6 mmol) was added and stirred at room temperature for 3 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: normal hexane = 1: 1, v / v) to obtain 80 mg (35%) of the title compound as a colorless amorphous.
ESI-MS m / z: 554 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, s), 1.41 (9H, s), 1.89-2.04 (2H, m), 2.73 (3H, s), 3.27-3.35 (2H, m), 3.37 -3.46 (2H, m), 3.57-3.76 (3H, m), 3.90 (3H, s), 7.12-7.17 (1H, m), 7.37-7.54 (4H, m).
[Reference Example 107]
tert-Butyl [(3S) -1- (2-acetyl-7-chloro-8-cyano-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3- Methylpyrrolidin-3-yl] methylcarbamate (I-107)

tert-Butyl [(3S) -1- {7-chloro-8-cyano-2- [methoxy (methyl) carbamoyl] -6-phenyl [1,2,4] triazolo [1,5-a] pyridine-5 -Il} -3-methylpyrrolidin-3-yl] methylcarbamate (I-106) (80 mg, 0.14 mmol) was dissolved in dichloromethane (5 ml). The solution was cooled to 0 ° C., methylmagnesium bromide (0.97 mol tetrahydrofuran solution) (297 μl, 0.29 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 2 hr. To this reaction solution, an aqueous ammonium chloride solution and chloroform were added, 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: 1, v / v) to obtain 71 mg (97%) of the title compound as a colorless solid.
ESI-MS m / z: 509 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, s), 1.43 (9H, s), 1.55-1.64 (1H, m), 1.90-2.08 (2H, m), 2.76 (3H, s), 2.79 (3H, s), 3.24-3.32 (1H, m), 3.55-3.64 (1H, m), 3.74-3.83 (2H, m), 7.12-7.18 (1H, m), 7.38-7.56 (4H, m) .
[Reference Example 108]
tert-Butyl {(3S) -1- [7-Chloro-8-cyano-2- (1,1-difluoroethyl) -6-phenyl [1,2,4] triazolo [1,5-a] pyridine- 5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-108)

tert-Butyl [(3S) -1- (2-acetyl-7-chloro-8-cyano-6-phenyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3- Methylpyrrolidin-3-yl] methylcarbamate (I-107) (90 mg, 0.17 mmol) was dissolved in dichloromethane (10 ml). The solution was cooled to 0 ° C., (diethylamino) sulfur trifluoride (183 μl, 1.4 mmol) was added dropwise, and the mixture was stirred at room temperature for 18 hours. Water and chloroform were 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 51 mg (48%) of the title compound as a colorless solid.
ESI-MS m / z: 531 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, s), 1.43 (9H, s), 1.87-2.07 (2H, m), 2.16 (3H, t, J = 18.6 Hz), 2.77 (3H, s ), 3.17-3.26 (1H, m), 3.38-3.54 (1H, m), 3.78-3.84 (2H, m), 7.11-7.17 (1H, m), 7.36-7.55 (4H, m).
[Example 27]
7-Chloro-2- (1,1-difluoroethyl) -5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-phenyl [1,2,4] triazolo [1,5-a] pyridine-8-carbonitrile (# 27)

tert-Butyl {(3S) -1- [7-Chloro-8-cyano-2- (1,1-difluoroethyl) -6-phenyl [1,2,4] triazolo [1,5-a] pyridine- 5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-108) (51 mg, 0.1 mmol) was dissolved in dichloromethane (4 ml). To this solution was added trifluoroacetic acid (4 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and diluted with chloroform, and then washed with saturated aqueous sodium hydrogen carbonate solution and 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 32 mg (77%) of the title compound as a colorless solid.
ESI-MS m / z: 431 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, s), 1.65-1.74 (1H, m), 1.80-1.91 (1H, m), 2.14 (3H, dt, J = 3.3, 18.7 Hz), 2.29 (3H, br s), 3.26-3.57 (3H, m), 3.69-3.75 (1H, m), 7.33-7.38 (1H, m), 7.41-7.46 (1H, m), 7.49-7.55 (3H, m ).
Anal. Calcd for C ₂₁ H ₂₁ ClF ₂ N ₆・ 0.75 H ₂ O: C, 56.76; H, 5.10; N, 18.91; F, 8.55; Cl, 7.98. Found: C, 57.25; H, 5.06; N, 18.31; F, 9.20; Cl, 8.30.
[Reference Example 109]
tert-butyl [(3S) -1- {8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl [1,2,4] triazolo [1,5-a] pyridin-5-yl}- 3-Methylpyrrolidin-3-yl] methylcarbamate (I-109)

Ethyl 5-{(3S) -3-[(tert-butoxycarbonyl) (methyl) amino] -3-methylpyrrolidin-1-yl} -8-cyano-7-methyl [1,2,4] triazolo [1 , 5-a] pyridine-2-carboxylate (I-28) (932 mg, 2.11 mmol) in tetrahydrofuran (20 ml) / water (4 ml) solution in lithium hydroxide monohydrate (106 mg, 2.53 mmol) ) Was added and stirred at room temperature for 3 hours. Chloroform and 1N hydrochloric acid were added to this reaction solution, and this was extracted with 2% methanol / chloroform. The organic layer was dried over anhydrous magnesium sulfate, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue, N, O-dimethylamine hydrochloride (308 mg, 3.16 mmol), 1-hydroxybenzotriazole (284 mg, 2.11 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride A solution of (606 mg, 3.16 mmol) and N-methylmorpholine (695 μl, 6.32 mmol) in dichloromethane (20 ml) was stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and this was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 70% ethyl acetate / normal hexane was concentrated under reduced pressure to obtain 802 mg (83%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.39 (3H, s), 1.51 (9H, s), 2.11-2.32 (2H, m), 2.57 (3H, s), 2.91 (3H, s), 3.33-3.45 (2H, m), 3.89 (3H, s), 3.90-4.38 (5H, m), 5.86 (1H, s).
[Reference Example 110]
tert-Butyl [(3S) -1- (2-acetyl-8-cyano-7-methyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3-methylpyrrolidine-3 -Il] methylcarbamate (I-110)

tert-butyl [(3S) -1- {8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl [1,2,4] triazolo [1,5-a] pyridin-5-yl}- To a solution of 3-methylpyrrolidin-3-yl] methylcarbamate (I-109) (5.60 g, 12.2 mmol) in dichloromethane (120 ml) was added methylmagnesium bromide (0.97 mol tetrahydrofuran solution) (15.1 ml) with ice cooling. added. The reaction mixture was stirred for 90 minutes under ice-cooling, and methylmagnesium bromide (0.97 molar tetrahydrofuran solution) (3.8 ml) was added. The reaction mixture was stirred for 30 minutes under ice-cooling, and saturated aqueous sodium hydrogen carbonate solution was added. The reaction mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 65% ethyl acetate / normal hexane was concentrated under reduced pressure to obtain 4.76 g (94%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.41 (3H, s), 1.51 (9H, s), 2.15-2.35 (2H, m), 2.58 (3H, s), 2.78 (3H, s), 2.93 (3H , s), 3.91-4.42 (4H, m), 5.90 (1H, s).
[Reference Example 111]
tert-Butyl {(3S) -1- [8-Cyano-2- (1,1-difluoroethyl) -7-methyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] -3-Methylpyrrolidin-3-yl} methylcarbamate (I-111)

tert-Butyl [(3S) -1- (2-acetyl-8-cyano-7-methyl [1,2,4] triazolo [1,5-a] pyridin-5-yl) -3-methylpyrrolidine-3 -Ile] methylcarbamate (I-110) (4.76 g, 11.5 mmol) in dichloromethane (120 ml) was added (diethylamino) sulfur trifluoride (6.1 ml, 46.1 mmol) at -78 ° C and gradually brought to room temperature. The mixture was stirred for 17 hours while returning. The reaction mixture was ice-cooled and saturated aqueous sodium hydrogen carbonate solution was added. The reaction mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (120 ml), (diethylamino) sulfur trifluoride (6.1 ml, 46.1 mmol) was added at −78 ° C., and the mixture was stirred for 17 hours while gradually returning to room temperature. The reaction mixture was ice-cooled and saturated aqueous sodium hydrogen carbonate solution was added. The reaction mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 50% ethyl acetate / normal hexane was concentrated under reduced pressure to give the title compound (3.66 g, 73%) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.40 (3H, s), 1.51 (9H, s), 2.07-2.35 (5H, m), 2.57 (3H, s), 2.93 (3H, s), 3.94-4.38 (4H, m), 5.86 (1H, s).
[Reference Example 112]
tert-butyl {(3S) -1- [6-bromo-8-cyano-2- (1,1-difluoroethyl) -7-methyl [1,2,4] triazolo [1,5-a] pyridine- 5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-112)

tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoroethyl) -7-methyl [1,2,4] triazolo [1,5-a] pyridin-5-yl] N-bromosuccinimide (1.80 g, 10.1 mmol) was added to a solution of -3-methylpyrrolidin-3-yl} methylcarbamate (I-111) (3.66 g, 8.42 mmol) in dichloromethane (100 ml) at room temperature. Stir for 1 hour and concentrate under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from the eluent of 20% ethyl acetate / normal hexane was concentrated under reduced pressure to obtain a solid. Diethyl ether-normal hexane was added to the obtained solid, and the resulting solid was collected by filtration and dried to obtain 1.56 g (36%) of the title compound as a powder.
¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, s), 1.47 (9H, s), 2.09-2.41 (5H, m), 2.77 (3H, s), 2.94 (3H, s), 3.65-3.75 (1H, m), 3.99 (1H, d, J = 10.5 Hz), 4.43 (1H, d, J = 10.5 Hz), 4.49-4.59 (1H, m).
[Example 28]
6-Bromo-2- (1,1-difluoroethyl) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] [1,2,4] triazolo [1,5-a] pyridine-8-carbonitrile (# 28)

tert-butyl {(3S) -1- [6-bromo-8-cyano-2- (1,1-difluoroethyl) -7-methyl [1,2,4] triazolo [1,5-a] pyridine- 5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-112) (80 mg, 0.16 mmol) was dissolved in dichloromethane (5 ml). To this solution was added trifluoroacetic acid (5 ml) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and diluted with chloroform. This was washed with a saturated aqueous sodium hydrogen carbonate solution and 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 23 mg (36%) of the title compound as a pale yellow oil.
ESI-MS m / z: 413 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.40 (3H, s), 1.93-2.04 (1H, m), 2.15 (3H, t, J = 21.1 Hz), 2.19-2.21 (1H, m), 2.45 (3H , s), 2.77 (3H, s), 3.71 (1H, d, J = 10.2 Hz), 3.91 (2H, d, J = 10.2 Hz), 4.02-4.19 (2H, m).
IR (ATR): 2964, 2219, 1607, 1511, 1473, 1376, 1178, 1145, 916 cm ^-1 .
[Reference Example 113]
Ethyl 8-cyano-5-oxo-7- (trifluoromethyl) -1,5-dihydro [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-113)

Ethyl 5- (cyanomethyl) -1H-1,2,4-triazole-3-carboxylate (I-2) (4.0 g, 22.2 mmol), ethyl 4,4,4-trifluoro-3-oxobutanoate (3.9 ml, 26.6 mmol) and ammonium acetate (3.42 g, 44.4 mmol) were stirred slowly at 80 ° C. for 30 minutes. Furthermore, it stirred slowly at 100 degreeC for 18 hours. This reaction solution was directly purified using silica gel column chromatography (eluent; ethyl acetate: normal hexane = 1: 2, v / v) to obtain 1.0 g (15%) of the title compound as a yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.33-1.38 (3H, m), 4.38 (2H, q, J = 7.2 Hz).
[Reference Example 114]
Ethyl 5-chloro-8-cyano-7- (trifluoromethyl) [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-114)

Ethyl 8-cyano-5-oxo-7- (trifluoromethyl) -1,5-dihydro [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-113) (2.0 g, 16.7 mmol) was added phosphorus oxychloride (20 ml), and the mixture was refluxed for 3 hours. The reaction solution was concentrated under reduced pressure and diluted with chloroform. This was washed with a saturated aqueous sodium hydrogen carbonate solution and 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 337 mg (97%) of the title compound as a colorless solid.
ESI-MS m / z: 319 (M + 1) ⁺ .
[Reference Example 115]
Ethyl 5-{(3S) -3-[(tert-butoxycarbonyl) (methyl) amino] -3-methylpyrrolidin-1-yl} -8-cyano-7- (trifluoromethyl) [1,2,4 ] Triazolo [1,5-a] pyridine-2-carboxylate (I-115)

Ethyl 5-chloro-8-cyano-7- (trifluoromethyl) [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-114) (830 mg, 2.6 mmol) Dissolve in dichloromethane (20 ml), add triethylamine (544 μl, 3.9 mmol) and tert-butyl methyl [(3S) -3-methylpyrrolidin-3-yl] carbamate (669 mg, 3.1 mmol) and bring to room temperature. And stirred for 18 hours. Chloroform 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 1.06 g (69%) of the title compound as a colorless solid.
ESI-MS m / z: 497 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, s), 1.45-1.49 (3H, s), 1.52 (9H, s), 1.64 (3H, s), .1.9-2.41 (2H, m), 2.94 (3H, s), 4.04-4.30 (2H, m), 4.32-4.47 (1H, m), 4.48-4.57 (2H, m), 6.25 (1H, s).
[Reference Example 116]
Ethyl 6-bromo-5-{(3S) -3-[(tert-butoxycarbonyl) (methyl) amino] -3-methylpyrrolidin-1-yl} -8-cyano-7- (trifluoromethyl) [1 , 2,4] Triazolo [1,5-a] pyridine-2-carboxylate (I-116)

Ethyl 5-{(3S) -3-[(tert-butoxycarbonyl) (methyl) amino] -3-methylpyrrolidin-1-yl} -8-cyano-7- (trifluoromethyl) [1,2,4 ] Triazolo [1,5-a] pyridine-2-carboxylate (I-115) (1 g, 2 mmol) was dissolved in acetic acid (10 ml). N-bromosuccinimide (427 mg, 2.4 mmol) was added to this solution and stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure and diluted with ethyl acetate, and then washed with saturated aqueous sodium hydrogen carbonate solution and 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: 3, v / v) to obtain 1.01 g (88%) of the title compound as a pale yellow amorphous.
ESI-MS m / z: 575 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.46-1.50 (5H, s), 2.26-2.47 (2H, m), 2.97 (3H, s), 3.80-3.88 (1H, m) , 4.06-4.13 (1H, m), 4.51-4.62 (3H, m), 4.70-4.80 (1H, m).
[Reference Example 117]
tert-Butyl [(3S) -1- {6-Bromo-8-cyano-2- [methoxymethyl (methyl) carbonyl] -7- (trifluoromethyl) [1,2,4] triazolo [1,5- a] Pyridin-5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-117)

N, O-dimethylhydroxyamine hydrochloride (506 mg, 5.2 mmol) was dissolved in dichloromethane (15 ml). The solution was cooled to 0 ° C., trimethylaluminum (1.03 molar normal hexane solution) (5.0 ml, 5.2 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 30 minutes. After 30 minutes, ethyl 6-bromo-5-{(3S) -3-[(tert-butoxycarbonyl) (methyl) amino] -3-methylpyrrolidin-1-yl dissolved in dichloromethane (5 ml) was dissolved in this solution. } -8-cyano-7- (trifluoromethyl) [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-116) (1.0 g, 1.73 mmol) was added dropwise, Stir at room temperature for 18 hours. The reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in dichloromethane (100 ml), triethylamine (482 μl, 3.5 mmol) and di-tert-butyl dicarbonate (567 mg, 2.6 mmol) were added, and the mixture was stirred at room temperature for 18 hours. Chloroform 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 747 mg (73%) of the title compound as a colorless solid.
¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, s), 1.47 (9H, s), 1.86 (1H, s), 2.21-2.29 (1H, m), 2.33-2.43 (1H, m), 2.94 (3H, s), 3.41 (3H, s), 3.75-3.83 (1H, m), 3.88 (3H, s), 4.00-4.08 (1H, m), 4.55 (1H, d, J = 10.7 Hz), 4.69-4.78 (1H, m).
[Reference Example 118]
tert-Butyl {(3S) -1- [2-acetyl-6-bromo-8-cyano-7- (trifluoromethyl) [1,2,4] triazolo [1,5-a] pyridin-5-yl ] -3-Methylpyrrolidin-3-yl} methylcarbamate (I-118)

tert-Butyl [(3S) -1- {6-Bromo-8-cyano-2- [methoxymethyl (methyl) carbonyl] -7- (trifluoromethyl) [1,2,4] triazolo [1,5- a] Pyridin-5-yl} -3-methylpyrrolidin-3-yl] methylcarbamate (I-117) (745 mg, 1.26 mmol) was dissolved in dichloromethane (15 ml). The solution was cooled to 0 ° C., methylmagnesium bromide (0.97 mol tetrahydrofuran solution) (2 ml, 1.9 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 4 hours. An aqueous ammonium chloride solution and chloroform were 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 90 mg (13%) of the title compound as a pale yellow amorphous.
ESI-MS m / z: 545 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, s), 1.47 (9H, s), 2.23-2.43 (2H, m), 2.83 (3H, s), 2.95 (3H, s), 3.76-3.83 (1H, m), 4.04-4.11 (1H, m), 4.57 (1H, d, J = 11.0 Hz), 4.68-4.79 (1H, m).
[Reference Example 119]
tert-Butyl {(3S) -1- [6-Bromo-8-cyano-2- (1,1-difluoroethyl) -7- (trifluoromethyl) [1,2,4] triazolo [1,5- a] Pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-119)

tert-Butyl {(3S) -1- [2-acetyl-6-bromo-8-cyano-7- (trifluoromethyl) [1,2,4] triazolo [1,5-a] pyridin-5-yl ] -3-Methylpyrrolidin-3-yl} methylcarbamate (I-118) (90 mg, 0.17 mmol) was dissolved in dichloromethane (10 ml). [Bis (2-methoxyethyl) amino] sulfur trifluoride (304 μl, 1.7 mmol) was added dropwise to this solution and stirred at room temperature for 18 hours. Chloroform was added to the reaction solution, 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 using silica gel column chromatography (eluent; ethyl acetate: normal hexane = 1: 2, v / v) to obtain 45 mg (48%) of the title compound as a pale yellow solid.
ESI-MS m / z: 567 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, s), 1.47 (9H, s), 2.22-2.29 (1H, m), 2.32-2.42 (1H, m), 2.95 (3H, s), 3.72 -3.80 (1H, m), 4.06 (1H, d, J = 10.5 Hz), 4.53-4.58 (1H, m), 4.64-4.73 (1H, m).
[Example 29]
6-Bromo-2- (1,1-difluoroethyl) -5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -7- (trifluoromethyl) [1,2 , 4] Triazolo [1,5-a] pyridine-8-carbonitrile (# 29)

tert-butyl {(3S) -1- [6-bromo-8-cyano-2- (1,1-difluoroethyl) -7- (trifluoromethyl) [1,2,4] triazolo [1,5- a] Pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-119) (80 mg, 0.14 mmol) was dissolved in dichloromethane (5 ml). To this solution was added trifluoroacetic acid (5 ml) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and diluted with chloroform, and this was washed with a saturated aqueous sodium bicarbonate 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 using preparative TLC (eluent; chloroform: methanol = 10: 1, v / v) to obtain 89 mg (55%) of the title compound as a colorless solid.
ESI-MS m / z: 467 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.41 (3H, s), 1.97-2.05 (1H, m), 2.12-2.23 (4H, m), 2.44 (3H, s), 3.83 (1H, d, J = 10.5 Hz), 3.97 (1H, d, J = 10.5 Hz), 4.11-4.19 (1H, m), 4.25-4.33 (1H, m).
IR (ATR): 2968, 2228, 1629, 1596, 1525, 1379, 1180, 1139, 937, 909 cm ^-1 .
[Reference Example 120]
tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoroethyl) -6- (3-fluorophenyl) -7-methyl [1,2,4] triazolo [1,5 -a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-120)

tert-butyl {(3S) -1- [6-bromo-8-cyano-2- (1,1-difluoroethyl) -7-methyl [1,2,4] triazolo [1,5-a] pyridine- 5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-112) (91 mg, 0.18 mmol), 3-fluorophenylboronic acid (50 mg, 0.35 mmol), tetrakistriphenylphosphine palladium (20 mg, 0.02 mmol) and potassium carbonate (98 mg, 0.71 mmol) in 1,4-dioxane (5 ml) were heated to reflux for 9 hours. Dichloromethane and water were added to the reaction suspension, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from the eluent of 30% ethyl acetate / normal hexane followed by 20% ethyl acetate / normal hexane was concentrated under reduced pressure to give the title compound 46 mg (49 %) As a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.22, 1.23 (3H, sx 2), 1.42 (9H, s), 1.89-2.09 (2H, m), 2.05 (3H, s), 2.16 (3H, t, J = 18.7 Hz), 2.30, 2.31 (3H, sx 2), 2.78 (3H, sx 2), 3.15-3.26 (1H, m), 3.50-3.77 (3H, m), 6.83-7.20 (3H, m), 7.41-7.54 (1H, m).
[Example 30]
2- (1,1-Difluoroethyl) -6- (3-fluorophenyl) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] [1, 2,4] Triazolo [1,5-a] pyridine-8-carbonitrile (# 30)

tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoroethyl) -6- (3-fluorophenyl) -7-methyl [1,2,4] triazolo [1,5 -a] Pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-120) (49 mg, 0.09 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (0.5 ml) And stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 5% methanol / chloroform was concentrated under reduced pressure to obtain 31 mg (83%) of the title compound as a solid.
ESI-MS m / z: 429 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, sx 2), 1.61-1.86 (2H, m), 2.17 (3H, t, J = 18.5 Hz), 2.29-2.32 (6H, m), 3.21- 3.51 (4H, m), 6.92-7.04 (2H, m), 7.14-7.21 (1H, m), 7.43-7.51 (1H, m).
IR (ATR): 2969, 2210, 1609, 1580, 1538, 1511, 1471, 1437, 1382, 1367, 1336, 1275, 1261, 1207, 1182, 1136, 930, 907, 878, 800, 783, 769, 740 cm ^-1 .
Anal.Calcd for C ₂₂ H ₂₃ F ₃ N ₆・ 0.25H ₂ O: C, 61.03; H, 5.47; N, 19.41.Found: C, 60.83; H, 5.23; N, 19.17.
[Reference Example 121]
tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6- (3-methylphenyl) [1,2,4] triazolo [1,5 -a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-121)

tert-butyl {(3S) -1- [6-bromo-8-cyano-2- (1,1-difluoroethyl) -7-methyl [1,2,4] triazolo [1,5-a] pyridine- 5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-112) (93 mg, 0.18 mmol), 3-methylphenylboronic acid (62 mg, 0.45 mmol), tetrakistriphenylphosphine palladium (21 mg, 0.02 mmol) and potassium carbonate (100 mg, 0.72 mmol) in 1,4-dioxane (5 ml) were heated to reflux for 11 hours. To this reaction suspension, 3-methylphenylboronic acid (62 mg, 0.45 mmol), tetrakistriphenylphosphine palladium (21 mg, 0.02 mmol) and potassium carbonate (100 mg, 0.72 mmol) were added and heated to reflux for 5.5 hours. . The mixture was cooled to room temperature, water was added, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 20% ethyl acetate / normal hexane was concentrated under reduced pressure to obtain 51 mg (54%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.19, 1.21 (3H, sx 2), 1.42, 1.43 (9H, sx 2), 1.84-2.07 (2H, m), 2.17 (3H, t, J = 18.6 Hz) , 2.29, 2.30 (3H, sx 2), 2.39, 2.43 (3H, sx 2), 2.77, 2.78 (3H, sx 2), 3.03-3.56 (2H, m), 3.67-3.99 (2H, m), 6.87 -7.12 (2H, m), 7.27-7.42 (2H, m).
[Example 31]
2- (1,1-Difluoroethyl) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6- (3-methylphenyl) [1, 2,4] Triazolo [1,5-a] pyridine-8-carbonitrile (# 31)

tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6- (3-methylphenyl) [1,2,4] triazolo [1,5 To a solution of -a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-121) (51 mg, 0.10 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (0.5 ml). The mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the residue obtained by concentrating the reaction solution under reduced pressure, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from the eluent of 4% methanol / chloroform was concentrated under reduced pressure to obtain a solid. Normal hexane was added to the obtained solid, and the resulting solid was collected by filtration and dried to obtain 28 mg (68%) of the title compound as a powder.
ESI-MS m / z: 425 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.15, 1.17 (3H, sx 2), 1.60-1.85 (2H, m), 2.17 (3H, t, J = 18.7 Hz), 2.31 (6H, s), 2.41 ( 3H, s), 3.16-3.57 (4H, m), 6.97-7.02 (2H, m), 7.23-7.40 (2H, m).
IR (ATR): 2968, 2213, 1609, 1537, 1508, 1471, 1449, 1388, 1364, 1344, 1280, 1187, 1133, 922, 912, 771, 748 cm ^-1 .
Anal. Calcd for C ₂₃ H ₂₆ F ₂ N ₆ : C, 65.08; H, 6.17; N, 19.80. Found: C, 64.93; H, 6.33; N, 19.40.
[Reference Example 122]
tert-butyl {(3S) -1- [6- (3-chlorophenyl) -8-cyano-2- (1,1-difluoroethyl) -7-methyl [1,2,4] triazolo [1,5- a] Pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-122)

tert-butyl {(3S) -1- [6-bromo-8-cyano-2- (1,1-difluoroethyl) -7-methyl [1,2,4] triazolo [1,5-a] pyridine- 5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-112) (95 mg, 0.19 mmol), 3-chlorophenylboronic acid (72 mg, 0.46 mmol), tetrakistriphenylphosphine palladium (21 mg , 0.02 mmol), and a suspension of potassium carbonate (102 mg, 0.74 mmol) in 1,4-dioxane (5 ml) were heated to reflux for 15 hours. To this reaction suspension were added 3-chlorophenylboronic acid (30 mg, 0.19 mmol), tetrakistriphenylphosphine palladium (22 mg, 0.02 mmol), and potassium carbonate (67 mg, 0.49 mmol), and the mixture was heated to reflux for 7 hours. The mixture was cooled to room temperature, water was added, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 20% ethyl acetate / normal hexane was concentrated under reduced pressure to obtain 56 mg (56%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.22, 1.23 (3H, sx 2), 1.43 (9H, s), 1.87-2.09 (2H, m), 2.16 (3H, t, J = 18.5 Hz), 2.30 ( 3H, s), 2.79 (3H, sx 2), 3.09-3.92 (4H, m), 6.98-7.53 (4H, m).
[Example 32]
6- (3-Chlorophenyl) -2- (1,1-difluoroethyl) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] [1,2 , 4] Triazolo [1,5-a] pyridine-8-carbonitrile (# 32)

tert-butyl {(3S) -1- [6- (3-chlorophenyl) -8-cyano-2- (1,1-difluoroethyl) -7-methyl [1,2,4] triazolo [1,5- To a solution of a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-122) (56 mg, 0.10 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (0.5 ml), Stir at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from the eluent of 5% methanol / chloroform was concentrated under reduced pressure to obtain a solid. Normal hexane was added to the obtained solid, and the resulting solid was collected by filtration and dried to obtain 35 mg (77%) of the title compound as a powder.
ESI-MS m / z: 445 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, s), 1.63-1.89 (2H, m), 2.17 (3H, t, J = 18.6 Hz), 2.30-2.34 (6H, m), 3.16-3.60 (4H, m), 7.09-7.16 (1H, m), 7.22 (1H, s), 7.41-7.48 (2H, m).
IR (ATR): 2966, 2686 , 2212, 1610, 1538, 1510, 1471, 1446, 1376, 1364, 1339, 1275, 1184, 1136, 1096, 1080, 930, 911, 797, 770, 750, 719 cm - ¹ .
Anal. Calcd for C ₂₃ H ₂₃ ClF ₂ N ₆・ 0.25H ₂ O: C, 55.80; H, 5.27; Cl, 7.89; F, 8.45; N, 18.70. Found: C, 58.91; H, 5.14; Cl, 7.73; F, 8.93; N, 18.60.
[Reference Example 123]
tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoroethyl) -6- (3-methoxyphenyl) -7-methyl [1,2,4] triazolo [1,5 -a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-123)

tert-butyl {(3S) -1- [6-bromo-8-cyano-2- (1,1-difluoroethyl) -7-methyl [1,2,4] triazolo [1,5-a] pyridine- 5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-112) (97 mg, 0.19 mmol), 3-methoxyphenylboronic acid (72 mg, 0.47 mmol), tetrakistriphenylphosphenine palladium A suspension of (22 mg, 0.02 mmol) and potassium carbonate (104 mg, 0.76 mmol) in 1,4-dioxane (5 ml) was heated to reflux for 17 hours. Add 3-methoxyphenylboronic acid (29 mg, 0.19 mmol), tetrakistriphenylphosphenine palladium (22 mg, 0.02 mmol), potassium carbonate (65 mg, 0.47 mmol) to the reaction suspension and heat for 3 hours. Refluxed. The mixture was cooled to room temperature, water was added, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 25% ethyl acetate / normal hexane was concentrated under reduced pressure to obtain 53 mg (52%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, s), 1.42, 1.43 (9H, sx 2), 1.87-2.08 (2H, m), 2.16 (3H, t, J = 18.6 Hz), 2.30, 2.32 (3H, sx 2), 2.78 (3H, s), 3.17 (1H, m), 3.37-3.59 (1H, m), 3.69-3.92 (2H, m), 3.82, 3.85 (3H, sx 2), 6.62-7.00 (3H, m), 7.34-7.45 (1H, m).
[Example 33]
2- (1,1-Difluoroethyl) -6- (3-methoxyphenyl) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] [1, 2,4] Triazolo [1,5-a] pyridine-8-carbonitrile (# 33)

tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoroethyl) -6- (3-methoxyphenyl) -7-methyl [1,2,4] triazolo [1,5 To a solution of -a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (53 mg, 0.10 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (0.5 ml) at room temperature. Stir for hours. A saturated aqueous sodium hydrogen carbonate solution was added to the residue obtained by concentrating the reaction solution under reduced pressure, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from the eluent of 5% methanol / chloroform was concentrated under reduced pressure to obtain a solid. Normal hexane was added to the obtained solid, and the resulting solid was collected by filtration and dried to obtain 34 mg (79%) of the title compound as a powder.
ESI-MS m / z: 441 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, s), 1.60-1.86 (2H, m), 2.17 (3H, t, J = 18.7 Hz), 2.31 (3H, s), 2.32 (3H, sx 2), 3.21-3.41 (3H, m), 3.54 (1H, d, J = 10.7 Hz), 3.84 (3H, s), 6.71-7.01 (3H, m), 7.37-7.43 (1H, m).
IR (ATR): 2967, 2213, 1607, 1509, 1470, 1388, 1364, 1278, 1236, 1185, 1135, 1028, 922, 906, 805, 781, 771 cm ^-1 .
Anal. Calcd for C ₂₃ H ₂₆ F ₂ N ₆ O: C, 62.71; H, 5.95; N, 19.08. Found: C, 62.59; H, 5.76; N, 18.57.
[Reference Example 124]
tert-butyl {(3S) -1- [6- (3-aminophenyl) -8-cyano-2- (1,1-difluoroethyl) -7-methyl [1,2,4] triazolo [1,5 -a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-124)

tert-butyl {(3S) -1- [6-bromo-8-cyano-2- (1,1-difluoroethyl) -7-methyl [1,2,4] triazolo [1,5-a] pyridine- 5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-112) (93 mg, 0.18 mmol), 3-aminophenylboronic acid (70 mg, 0.45 mmol), tetrakistriphenylphosphine palladium (21 mg, 0.02 mmol) and potassium carbonate (100 mg, 0.72 mmol) in 1,4-dioxane (5 ml) were heated to reflux for 19 hours. To this reaction suspension, 3-aminophenylboronic acid (28 mg, 0.18 mmol), tetrakistriphenylphosphine palladium (21 mg, 0.02 mmol), potassium carbonate (50 mg, 0.36 mmol) was added and heated to reflux for 6.5 hours. . The mixture was cooled to room temperature, water was added, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 40% ethyl acetate / normal hexane was concentrated under reduced pressure to give the title compound (59 mg, 62%) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.22, 1.23 (3H, sx 2), 1.43 (9H, sx 2), 1.86-2.09 (2H, m), 2.16 (3H, t, J = 18.5 Hz), 2.32 , 2.33 (3H, sx 2), 2.79 (3H, sx 2), 3.09-3.21 (1H, m), 3.33-3.55 (1H, m), 3.63-4.06 (4H, m), 6.37-7.27 (4H, m).
[Example 34]
6- (3-Aminophenyl) -2- (1,1-difluoroethyl) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] [1, 2,4] Triazolo [1,5-a] pyridine-8-carbonitrile (# 34)

tert-butyl {(3S) -1- [6- (3-aminophenyl) -8-cyano-2- (1,1-difluoroethyl) -7-methyl [1,2,4] triazolo [1,5 To a solution of -a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-124) (59 mg, 0.11 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (0.5 ml). And stirred at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the residue obtained by concentrating the reaction solution under reduced pressure, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 5% methanol / chloroform followed by 10% methanol / chloroform was concentrated under reduced pressure to obtain a solid. Normal hexane was added to the obtained solid, and the resulting solid was collected by filtration and dried to obtain 33 mg (69%) of the title compound as a powder.
ESI-MS m / z: 426 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.19, 1.20 (3H, sx 2), 1.63-1.89 (2H, m), 2.17 (3H, t, J = 18.6 Hz), 2.31-2.37 (6H, m), 3.23-3.66 (4H, m), 3.80 (2H, s), 6.48 (1H, s), 6.55 (1H, d, J = 7.6 Hz), 6.71-6.79 (1H, m), 7.21-7.27 (1H, m).
IR (ATR): 3453, 3340, 3190, 2966, 2212, 1607, 1508, 1471, 1447, 1387, 1366, 1340, 1275, 1185, 1133, 922, 907, 770, 749 cm ^-1 .
Anal. Calcd for C ₂₂ H ₂₅ F ₂ N ₇・ 0.5H ₂ O: C, 60.82; H, 6.03; F, 8.75; N, 22.57. Found: C, 61.09; H, 5.97; F, 8.76; N, 22.61.
[Reference Example 125]
tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoroethyl) -6- (3,5-difluorophenyl) -7-methyl [1,2,4] triazolo [1 , 5-a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-125)

tert-butyl {(3S) -1- [6-bromo-8-cyano-2- (1,1-difluoroethyl) -7-methyl [1,2,4] triazolo [1,5-a] pyridine- 5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-112) (100 mg, 0.19 mmol), 3,5-difluorophenylboronic acid (77 mg, 0.49 mmol), tetrakistriphenylphosphine palladium A suspension of (23 mg, 0.02 mmol) and potassium carbonate (108 mg, 0.78 mmol) in 1,4-dioxane (5 ml) was heated to reflux for 16 hours. The reaction suspension was cooled to room temperature, water was added, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 20% ethyl acetate / normal hexane was concentrated under reduced pressure to obtain 68 mg (64%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, s), 1.43 (9H, s), 1.92-2.10 (2H, m), 2.16 (3H, t, J = 18.6 Hz), 2.32 (3H, s ), 2.80 (3H, s), 3.23-3.81 (4H, m), 6.66-6.72 (1H, m), 6.86-6.96 (2H, m).
[Example 35]
2- (1,1-Difluoroethyl) -6- (3,5-difluorophenyl) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] [ 1,2,4] triazolo [1,5-a] pyridine-8-carbonitrile (# 35)

tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoroethyl) -6- (3,5-difluorophenyl) -7-methyl [1,2,4] triazolo [1 , 5-a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-125) (68 mg, 0.12 mmol) in dichloromethane (3 ml) in trifluoroacetic acid (1 ml) And stirred at room temperature for 4 days. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the residue obtained by concentrating the reaction solution under reduced pressure, and this was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from the eluent of 4% methanol / chloroform was concentrated under reduced pressure to obtain a solid. Normal hexane was added to the resulting solid, and the resulting solid was collected by filtration and dried to give 38 mg (68%) of the title compound as a powder.
ESI-MS m / z: 447 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, s), 1.65-1.91 (2H, m), 2.17 (3H, t, J = 18.7 Hz), 2.32 (3H, s), 2.33 (3H, s ), 3.27-3.57 (4H, m), 6.75-6.82 (2H, m), 6.90-7.00 (1H, m).
IR (ATR): 2970, 2212, 1608, 1587, 1514, 1471, 1432, 1379, 1370, 1342, 1278, 1238, 1183, 1137, 1119, 983, 930, 909, 857, 770, 723 cm ^-1 .
Anal. Calcd for C ₂₂ H ₂₂ F ₄ N ₆ : C, 59.19; H, 4.97; F, 17.02; N, 18.82. Found: C, 59.21; H, 4.70; F, 17.16; N, 18.83.
[Reference Example 126]
tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoroethyl) -6- (3,5-dimethylphenyl) -7-methyl [1,2,4] triazolo [1 , 5-a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-126)

tert-butyl {(3S) -1- [6-bromo-8-cyano-2- (1,1-difluoroethyl) -7-methyl [1,2,4] triazolo [1,5-a] pyridine- 5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-112) (105 mg, 0.20 mmol), 3,5-dimethylphenylboronic acid (61 mg, 0.41 mmol), tetrakistriphenylphosphine palladium A suspension of (24 mg, 0.02 mmol) and potassium carbonate (113 mg, 0.82 mmol) in 1,4-dioxane (5 ml) was heated to reflux for 19 hours. Add 3,5-dimethylphenylboronic acid (31 mg, 0.20 mmol), tetrakistriphenylphosphine palladium (24 mg, 0.02 mmol), potassium carbonate (57 mg, 0.41 mmol) to this reaction suspension, and heat for 5 hours. Refluxed. The mixture was cooled to room temperature, water was added, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 20% ethyl acetate / normal hexane was concentrated under reduced pressure to obtain 39 mg (35%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, s), 1.43 (9H, s), 1.85-1.94 (1H, m), 1.97-2.07 (1H, m), 2.16 (3H, t, J = 18.5 Hz), 2.31 (3H, s), 2.34 (3H, s), 2.38 (3H, s), 2.79 (3H, s), 3.07 (1H, t, J = 9.1 Hz), 3.19-3.32 (1H, m), 3.75 (1H, d, J = 10.7 Hz), 3.89-4.03 (1H, m), 6.70 (1H, s), 6.89 (1H, s), 7.05 (1H, s).
[Example 36]
2- (1,1-Difluoroethyl) -6- (3,5-dimethylphenyl) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] [ 1,2,4] triazolo [1,5-a] pyridine-8-carbonitrile (# 36)

tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoroethyl) -6- (3,5-dimethylphenyl) -7-methyl [1,2,4] triazolo [1 , 5-a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-126) (66 mg, 0.12 mmol) in dichloromethane (3 ml) in trifluoroacetic acid (1 ml) And stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the residue obtained by concentrating the reaction solution under reduced pressure, and this was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from the eluent of 5% methanol / chloroform was concentrated under reduced pressure to obtain a solid. Normal hexane was added to the obtained solid, and the resulting solid was collected by filtration and dried to obtain 41 mg (76%) of the title compound as a powder.
ESI-MS m / z: 439 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, s), 1.59-1.84 (2H, m), 2.17 (3H, t, J = 19.0 Hz), 2.31 (6H, sx 2), 2.36 (6H, s), 3.11-3.26 (2H, m), 3.34 (1H, d, J = 10.7 Hz), 3.56 (1H, d, J = 10.7 Hz), 6.79 (2H, s), 7.07 (1H, s).
IR (ATR): 2970, 2915, 2213, 1608, 1506, 1470, 1448, 1388, 1365, 1347, 1279, 1187, 1132, 920, 905, 857, 772 cm ^-1 .
Anal. Calcd for C ₂₄ H ₂₈ F ₂ N ₆ : C, 65.73; H, 6.44; F, 8.66; N, 19.16.Found: C, 65.75; H, 6.45; F, 8.63; N, 19.02.
[Reference Example 127]
tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6-pyridin-3-yl [1,2,4] triazolo [1,5- a] Pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-127)

tert-butyl {(3S) -1- [6-bromo-8-cyano-2- (1,1-difluoroethyl) -7-methyl [1,2,4] triazolo [1,5-a] pyridine- 5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-112) (98 mg, 0.19 mmol), (pyridin-3-yl) boronic acid (59 mg, 0.48 mmol), tetrakistriphenylphosphine A suspension of palladium (22 mg, 0.02 mmol) and potassium carbonate (106 mg, 0.76 mmol) in 1,4-dioxane (5 ml) was heated to reflux for 17 hours. (Pyridin-3-yl) boronic acid (59 mg, 0.48 mmol), tetrakistriphenylphosphine palladium (22 mg, 0.02 mmol), potassium carbonate (106 mg, 0.76 mmol) were added to this reaction suspension for 2 days. Heated to reflux. The mixture was cooled to room temperature, water was added, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The residue obtained, (4-pyridin-3-yl) boronic acid (59 mg, 0.48 mmol), tetrakistriphenylphosphine palladium (22 mg, 0.02 mmol), potassium carbonate (106 mg, 0.76 mmol) in 1,4-dioxane The suspension (5 ml) / water (0.5 ml) was heated to reflux for 5.5 hours. The suspension was cooled to room temperature, water was added, and this was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from an eluent of 50% ethyl acetate / chloroform was concentrated under reduced pressure to obtain 41 mg (42%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.19, 1.24 (3H, sx 2), 1.41, 1.43 (9H, sx 2), 1.88-2.07 (2H, m), 2.17 (3H, t, J = 18.5 Hz) , 2.29, 2.30 (3H, sx 2), 2.76, 2.78 (3H, sx 2), 3.19-3.77 (4H, m), 7.41-8.74 (4H, m).
[Example 37]
2- (1,1-Difluoroethyl) -7-methyl-5-[(3S) -3-methyl-3- (methylamino) pyrrolidin-1-yl] -6-pyridin-3-yl [1,2 , 4] Triazolo [1,5-a] pyridine-8-carbonitrile (# 37)

tert-butyl {(3S) -1- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6-pyridin-3-yl [1,2,4] triazolo [1,5- To a solution of a] pyridin-5-yl] -3-methylpyrrolidin-3-yl} methylcarbamate (I-127) (63 mg, 0.12 mmol) in dichloromethane (3 ml), add trifluoroacetic acid (1 ml), Stir at room temperature for 90 minutes. A 1N aqueous sodium hydroxide solution was added to the residue obtained by concentrating the reaction solution under reduced pressure, and this was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography, and the fraction obtained from the eluent of 15% methanol / chloroform was concentrated under reduced pressure to obtain a solid. A mixed solution of diethyl ether-normal hexane was added to the obtained solid, and the resulting solid was collected by filtration and dried to obtain 32 mg (63%) of the title compound as a powder.
ESI-MS m / z: 412 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.17, 1.21 (3H, sx 2), 1.65-1.91 (2H, m), 2.17 (3H, t, J = 18.6 Hz), 2.31 (3H, sx 2), 2.33 (3H, s), 3.13-3.59 (4H, m), 7.44-7.50 (1H, m), 7.55-7.62 (1H, m), 8.51 (1H, s), 8.72 (1H, d, J = 3.9 Hz ).
IR (ATR): 2966, 2887, 2213, 1610, 1512, 1472, 1442, 1408, 1379, 1366, 1343, 1277, 1201, 1183, 1134, 1099, 1020, 929, 909, 871, 770 cm ^-1 .
Anal.Calcd for C ₂₁ H ₂₃ F ₂ N ₇・ 0.25H ₂ O: C, 60.64; H, 5.69; F, 9.13; N, 23.57. Found: C, 60.79; H, 5.78; F, 8.93; N, 23.46.
[Reference Example 127]
Ethyl 8-cyano-7-methyl-6- (2-methyl-1,3-thiazol-4-yl) -5-oxo-1,5-dihydro [1,2,4] triazolo [1,5-a ] Pyridine-2-carboxylate (I-127)

Ethyl 2- (2-methyl-1,3-thiazol-4-yl) -3-oxobutanoate (synthesized according to the method of WO2005 / 077948) (1.0 g, 4.42 mmol) was added to toluene (10 ml) and acetic acid Dissolved in (1 ml), added ammonium acetate (2.04 g, 26.5 mmol) at room temperature, then heated to reflux for 19 hours under a nitrogen stream. After cooling to room temperature, water (15 ml) was added to the reaction solution, and this was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure to obtain a dark brown oily substance. To this was added ethyl 5- (cyanomethyl) -1H-1,2,4-triazole-3-carboxylate (I-2) (955 mg, 5.30 mmol) and ammonium acetate (511 mg, 6.63 mmol). Heated to 100 ° C. with stirring for 12 hours. The mixture was cooled to room temperature, dissolved in chloroform containing 10% methanol, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by medium pressure liquid chromatography (stationary phase: silica gel; mobile phase: chloroform: methanol = 95: 5, v / v → 85: 15, v / v), and the title compound 416 mg (27 %) As a brown solid.
ESI-MS m / z: 344 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.1 Hz), 2.31 (3H, s), 2.73 (3H, s), 4.46 (2H, q, J = 7.1 Hz), 7.31 ( 1H, s), 7.89 (1H, s).
[Reference Example 128]
Ethyl 5-chloro-8-cyano-7-methyl-6- (2-methyl-1,3-thiazol-4-yl) [1,2,4] triazolo [1,5-a] pyridine-2-carboxy Rate (I-128)

Ethyl 8-cyano-7-methyl-6- (2-methyl-1,3-thiazol-4-yl) -5-oxo-1,5-dihydro [1,2,4] triazolo [1,5-a Pyridine-2-carboxylate (I-127) (416 mg, 1.21 mmol) was suspended in phosphorus oxychloride (12 ml) and heated to reflux for 12 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Toluene (30 ml) was added to the obtained residue, and azeotropic distillation was performed under reduced pressure. The residue was dissolved in chloroform (20 ml), saturated aqueous sodium hydrogen carbonate solution (20 ml) was added thereto, and the mixture was vigorously stirred. The aqueous phase was separated and extracted twice with chloroform. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by medium pressure liquid chromatography (stationary phase: silica gel; mobile phase: chloroform: acetone = 98: 2, v / v) to obtain 183 mg (42%) of the title compound as a light brown gel. It was.
ESI-MS m / z: 362 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.50 (3H, t, J = 7.1 Hz), 2.57 (3H, s), 4.59 (2H, q, J = 7.1 Hz), 7.37 (1H, s).
[Reference Example 129]
Ethyl 5-{(3R) -3-[(tert-butoxycarbonyl) (methyl) amino] -4-fluoro-3-methylpyrrolidin-1-yl} -8-cyano-7-methyl-6- (2- Methyl-1,3-thiazol-4-yl) [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-129)

Ethyl 5-chloro-8-cyano-7-methyl-6- (2-methyl-1,3-thiazol-4-yl) [1,2,4] triazolo [1,5-a] pyridine-2-carboxy Rate (I-128) (183 mg, 0.51 mmol) and tert-butyl [(3R) -4-fluoro-3-methylpyrrolidin-3-yl] methylcarbamate (I-11) (141 mg, 0.61 mmol) It melt | dissolved in tetrahydrofuran (6 ml), and triethylamine (445 microliters, 3.19 mmol) was added at room temperature under nitrogen stream. The solution was heated to reflux for 13 hours. Then, dimethyl sulfoxide (4 ml) was added at room temperature, heated again to 80 ° C. and stirred for 11 hours. The reaction mixture was cooled to 0 ° C., saturated aqueous sodium hydrogen carbonate solution (15 ml) was added, and the mixture was stirred at the same temperature for 10 min. This mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by medium pressure liquid chromatography (stationary phase: silica gel; mobile phase: chloroform: acetone = 95: 5, v / v) to give 258 mg (92%) of the title compound as a light brown solid. It was.
ESI-MS m / z: 558 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, d, J = 2.7 Hz), 1.45 (9H, s), 1.46 (3H, t, J = 7.1 Hz), 2.35 (3H, s), 2.81 ( 3H, s), 2.88 (3H, s), 3.45-3.95 (4H, br), 4.53 (2H, q, J = 7.1 Hz), 5.40 (1H, dt, J = 4.8, 53.4 Hz), 7.17 (1H , s).
[Reference Example 130]
tert-butyl [(3R) -1- {8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl-6- (2-methyl-1,3-thiazol-4-yl) [1,2 , 4] Triazolo [1,5-a] pyridin-5-yl} -4-fluoro-3-methylpyrrolidin-3-yl] methylcarbamate (I-130)

N, O-dimethylhydroxylamine hydrochloride (135 mg, 1.39 mmol) was suspended in dichloromethane (5 ml), and trimethylaluminum (1.05 molar normal hexane solution) (1.3 ml, 1.39 mmol) was added dropwise at 0 ° C. After stirring at the same temperature for 1 hour, ethyl 5-{(3R) -3-[(tert-butoxycarbonyl) (methyl) amino] -4-fluoro-3-methylpyrrolidin-1-yl}-was added to this solution. 8-cyano-7-methyl-6- (2-methyl-1,3-thiazol-4-yl) [1,2,4] triazolo [1,5-a] pyridine-2-carboxylate (I-129 ) (258 mg, 0.46 mmol) in dichloromethane (5 ml) was added dropwise and stirred for 5 hours. A saturated aqueous sodium hydrogen carbonate solution (15 ml) was added to this solution, and the mixture was stirred for 15 minutes, and then extracted three times with dichloromethane. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by medium pressure liquid chromatography (stationary phase: silica gel; mobile phase: chloroform: acetone = 95: 5, v / v) to obtain 185 mg (70%) of the title compound as a colorless gel. .
ESI-MS m / z: 573 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.35 (3H, d, J = 2.4 Hz), 1.44 (9H, s), 2.35 (3H, s), 2.80 (3H, s), 2.85 (3H, s), 3.35-3.39 (11H, m), 5.40 (1H, d, J = 53.0 Hz), 7.10 (1H, s).
[Reference Example 131]
tert-butyl {(3R) -1- [2-acetyl-8-cyano-7-methyl-6- (2-methyl-1,3-thiazol-4-yl) [1,2,4] triazolo [1 , 5-a] pyridin-5-yl] -4-fluoro-3-methylpyrrolidin-3-yl} methylcarbamate (I-131)

tert-butyl [(3R) -1- {8-cyano-2- [methoxy (methyl) carbamoyl] -7-methyl-6- (2-methyl-1,3-thiazol-4-yl) [1,2 , 4] Triazolo [1,5-a] pyridin-5-yl} -4-fluoro-3-methylpyrrolidin-3-yl] methylcarbamate (I-130) (185 mg, 0.32 mmol) in dichloromethane (5 ml ) And methylmagnesium bromide (0.97 mol tetrahydrofuran solution) (670 μl, 1.09 mmol) was added at 0 ° C. under a nitrogen stream. The reaction solution was stirred at the same temperature for 4 hours, a saturated aqueous ammonium chloride solution was added, and the mixture was further stirred for 10 minutes. The mixture was extracted 3 times with dichloromethane. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by preparative TLC (mobile phase: chloroform: acetone = 95: 5, v / v) to obtain 139 mg (82%) of the title compound as a light brown gel.
ESI-MS m / z: 528 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.38 (3H, d, J = 2.4 Hz), 1.45 (9H, s), 2.35 (3H, s), 2.80 (3H, s), 2.81 (3H, s), 2.88 (3H, d, J = 1.0 Hz), 3.50-3.90 (4H, m), 5.40 (1H, dt, J = 4.9, 53.7 Hz), 7.15 (1H, s).
[Reference Example 132]
tert-butyl {(3R) -1- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6- (2-methyl-1,3-thiazol-4-yl) [1, 2,4] Triazolo [1,5-a] pyridin-5-yl] -4-fluoro-3-methylpyrrolidin-3-yl} methylcarbamate (I-132)

tert-butyl {(3R) -1- [2-acetyl-8-cyano-7-methyl-6- (2-methyl-1,3-thiazol-4-yl) [1,2,4] triazolo [1 , 5-a] pyridin-5-yl] -4-fluoro-3-methylpyrrolidin-3-yl} methylcarbamate (I-131) (139 mg, 0.26 mmol) in dichloromethane (5 ml) and nitrogen (Diethylamino) sulfur trifluoride (348 μl, 2.63 mmol) was added at 0 ° C. under a stream of air. The reaction mixture was stirred for 36 hours while gradually warming from 0 ° C. to room temperature, then cooled again to 0 ° C., saturated aqueous sodium hydrogen carbonate solution (20 ml) was added dropwise, and the mixture was stirred at the same temperature for 10 min. The mixture was extracted 3 times with dichloromethane. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by medium pressure liquid chromatography (stationary phase: silica gel; mobile phase: chloroform: acetone = 95: 5, v / v) to obtain 111 mg (77%) of the title compound as a colorless gel. .
ESI-MS m / z: 550 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, d, J = 2.7 Hz), 1.45 (9H, s), 2.16 (3H, t, J = 18.5 Hz), 2.81 (3H, s), 2.81 ( 3H, s), 2.88 (3H, d, J = 1.2 Hz), 3.40-3.95 (4H, m), 5.37 (1H, dt, J = 4.9, 53.4 Hz), 7.11 (1H, s).
[Example 38]
2- (1,1-Difluoroethyl) -5-[(3R) -4-fluoro-3-methyl-3- (methylamino) pyrrolidin-1-yl] -7-methyl-6- (2-methyl- 1,3-thiazol-4-yl) [1,2,4] triazolo [1,5-a] pyridine-8-carbonitrile (# 38)

tert-butyl {(3R) -1- [8-cyano-2- (1,1-difluoroethyl) -7-methyl-6- (2-methyl-1,3-thiazol-4-yl) [1, 2,4] Triazolo [1,5-a] pyridin-5-yl] -4-fluoro-3-methylpyrrolidin-3-yl} methylcarbamate (I-132) (111 mg, 0.20 mmol) in dichloromethane (4 ml) and trifluoroacetic acid (2 ml) was added at room temperature. After stirring this reaction liquid at the same temperature for 2.5 hours, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in chloroform (15 ml), saturated aqueous sodium hydrogen carbonate solution (15 ml) was added thereto at room temperature, and the mixture was vigorously stirred for 10 minutes. The aqueous phase was separated and extracted twice more with chloroform. These organic phases were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by preparative TLC (mobile phase: chloroform: methanol = 9: 1, v / v) to obtain 73 mg (80%) of the title compound as a colorless amorphous.
ESI-MS m / z: 450 (M + 1) ⁺ .
HRESI-MS m / z: 450.16972 (Calcd for C ₂₀ H ₂₃ F ₃ N ₇ S 450.16877).
¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, d, J = 2.7 Hz), 2.16 (3H, t, J = 18.6 Hz), 2.34 (3H, s), 2.35 (3H, s), 2.81 ( 3H, s), 3.33 (1H, d, J = 11.0 Hz), 3.42 (1H, dd, J = 13.0, 26.0 Hz), 3.57 (1H, d, J = 11.0 Hz), 4.08 (1H, ddd, J = 3.9, 13.0, 37.8 Hz), 4.65 (1H, ddd, J = 3.9, 52.7 Hz), 7.13 (1H, s).
IR (ATR): 2221, 1609, 1522, 1500, 1454, 1380, 1274, 1189, 1172, 1142, 1052, 936, 914, 881, 729 cm ^-1 .
Anal. Calcd for C ₂₀ H ₂₂ F ₃ N ₇ S: C, 53.44; H, 4.93; N, 21.81; F, 12.68; S, 7.13. Found: C, 53.37; H, 4.97; N, 21.27; F, 12.94; S, 7.21.
[Test Example 1] Measurement of antifungal activity It was carried out by a micro liquid dilution method using a 96-well flat bottom plate.
That is, cells cultured on Sabouraud dextrose agar medium at 30 ° C. for 24 hours are diluted with YPD20 medium (1% yeast extract, 2% peptone, 20% glucose), and the final bacterial solution concentration is 1 × 10 ³ to 1 × 10 ⁴ cells. 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 culturing at 37 ° C. for 16 to 30 hours, and the growth without addition of the drug was 80% The minimum concentration to inhibit was calculated and taken as the GI 80 value (μg / mL).

[Test Example 2] Treatment effect in infected mouse model-Preparation of inoculum solution albicans ATCC 90028 strain (C. albicans sensitive strain) and C. albicans. S. albicans ATCC MYA-573 strain (C. albicans resistant strain) was inoculated on Sabouraud dextrose agar (SDA), followed by static culture at 30 ° C. overnight. Thereafter, the bacteria in the agar medium were collected and suspended using a sterilized physiological saline (sterile T / S) containing 0.1% polyoxyethylene sorbitan monooleate (Tween 80) (suspension). In addition, C.I. For glabrata ATCC48435 strain (C. glabrata), the bacterium was inoculated in a Sabouraud dextrose liquid medium (SDB) and cultured overnight at 30 ° C. with shaking, and then a suspension was prepared using sterile physiological saline. Further, the number of viable bacteria in the suspension was measured using a hemocytometer. 5-6 × 10 ⁵ cfu / mL for C. albicans sensitive strains, C.I. 3 × 10 ⁶ cfu / mL for C. albicans resistant strains, and C.I. In glabrata, the bacterial concentration was adjusted to 1 × 10 ⁹ cfu / mL and used as the respective inoculum solution.
-Infectious treatment treatment Cyclophosphamide was intraperitoneally administered to healthy ICR female mice (5-6 weeks old) at a rate of 100 mg / kg 4 and 1 day before infection.
-Infection ECR female mice (6 weeks old) that were easily infected were inoculated with 0.2 mL of the inoculum from the tail vein (C. albicans: 1 x 10 < ⁵ > cfu / mouse, C. glabrata: 2 x 10 < ⁸ > cfu / mouse).
-Treatment A 0.1% lactic acid-containing glucose aqueous solution was added to the test compound and dissolved, and a 1N sodium hydroxide aqueous solution was appropriately added to prepare a pH 4-5 administration solution.

The dosing solution was administered subcutaneously immediately after inoculation and 6 hours after inoculation. The treatment period was the day of infection, and the dose was 0.1 mL per 10 g of mouse. The infection control group was similarly administered with a 5% glucose aqueous solution.
-Judgment of effect As an index of drug efficacy, the life and death until the 14th day of infection were observed, the average survival days of each group were calculated, and those of the infection control group and the test compound administration group were respectively compared. The number of animals was 10 per group for both the infection control group and the treatment group.
(5) Test results The compound of the present invention showed a therapeutic effect against any of fluconazole-sensitive bacteria, low-sensitivity bacteria, and resistant bacteria.

[Test Example 3] Examination of effects on synthesis of cell wall constituents (method) albicans ATCC 90028 strain was inoculated into Sabouraud Dextrose (SD) medium, cultured at 30 ° C. to the logarithmic growth phase, and collected by centrifugation. This was suspended in RPMI1640 medium (RPMI1640 (with L-glutamine, withsodium bicarbonate), 0.165M 3-morpholinopropanolic acid, PH 7.0), and the bacterial solution was adjusted so that OD ₅₉₅ = 0.7. Each concentration of compound and [ ¹⁴ C] glucose (final concentration 1 μCi / mL) were simultaneously added to this bacterial solution, and after shaking culture at 30 ° C. for 60 minutes, 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%.
(Result) The compound of the present invention selectively exhibited a β-1,6-glucan synthase inhibitory action.
[Test Example 4] Mice intravenous injection single dose toxicity test (Method) Necessary amounts of each compound were weighed and dissolved in 5% glucose containing 1% lactic acid to a concentration of 10 mg / ml. The 5 mg / ml solution was prepared by diluting the 10 mg / ml solution twice with 5% glucose containing 1% lactic acid. The solution thus prepared was administered intravenously once at the required amount of 0.2 ml / min, and then observed to determine the mortality (number of deaths / number of doses).
(Results) None of the compounds of Examples 3 and 12 died in any of the three administration groups.

  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 solvate 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. ]
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 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,
A dialkylamino group having the same or different alkyl chain and a total carbon number of 2 to 4,
Means a halogenomethyl group or an alkoxymethyl group having an alkoxy group having 1 to 3 carbon atoms;
R ⁴ and R ⁵ are each independently a halogen atom, or both may be combined to form an oxo group;
R ⁶ is
Hydrogen atom,
An alkyl group having 1 to 6 carbon atoms,
An alkoxymethyl group having 2 to 7 carbon atoms,
Aromatic heterocyclic group or the following formula:
^{-C (= O) -N (-R} 61) R 62
(Wherein, R ⁶¹ and R ⁶² 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). Means
The alkyl group, alkoxymethyl group, and aromatic heterocyclic group of R ⁶ may have one or more groups which may be selected in an overlapping manner from [Substituent group 3];
[Substituent group 3]:
Halogen atoms,
An alkoxy group having 1 to 6 carbon atoms,
Aromatic heterocyclic group and the following formula:
^{-N (-R 63) -C (=} O) R 64
A group represented by: wherein R ⁶³ on the nitrogen atom and R ⁶⁴ on the carbon atom each independently represents an alkyl group having 1 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
Having a basic substituent,
A saturated or partially saturated heterocyclic group containing a heteroatom 1 or 2 that may be selected from a heteroatom of the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. The described compound, a salt thereof, or a hydrate thereof. 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, a cyclopentyl group, or a 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, a salt thereof, or a hydrate thereof, wherein R ⁴ and R ⁵ are together an oxo group. The compound according to any one of claims 1 to 9, a salt thereof, or a hydrate thereof, wherein R ⁴ and R ⁵ are both halogen atoms. The compound according to any one of claims 1 to 11, wherein R ⁶ is an optionally substituted alkyl group having 1 to 6 carbon atoms or an alkoxymethyl group having 2 to 7 carbon atoms. , 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.