KR20080007764A - 1,2,5-TRIAZEPANE DERIVATIVES HAVING beta;-AMINO ACYL GROUP, ITS PHARMACEUTICAL ACCEPTABLE SALTS AND PREPARATION PROCESS THEREOF - Google Patents

Abstract

A 1,2,5-triazepane derivative showing excellent DPP-IV inhibitory activity is provided to be effectively used for preventing or treating diseases mediated by DPP-IV such as insulin-dependent, insulin non-dependent diabetes, arthritis, obesity, osteoporosis, and damaged glucose resistance. A 1,2,5-triazepane derivative having a beta-amino group is represented by the formula(1), wherein R1 is a group represented by the structural formula(1-1) or (1-2); R2 is H, C1-6 alkyl, or a group represented by the structural formula(1-3); R3 is H, C1-6 alkyl, C3-6 cycloalkyl, CH2CO2R^b, COCO2R^b, pyrazine, and a group represented by the structural formula(1-4), (1-5) or (1-6); R^a is independently H, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, OCF3, halogen, CN, CF3, COOR^b or NR^bR^c; each R^b and R^c is independently H, C1-6 alkyl or C3-6 cycloalkyl; R^d is C1-6 alkyl, trifluoromethyl, and a group represented by the structural formula(1-1), (1-7), (1-8), or (1-9); R^e is C1-6 alkyl, C3-6 cycloalkyl, and a group represented by the structural formula(1) or (2); R^f is H, halogen, NR^bR^c, tetrazole, proline, and a group represented by the structural formula(1-10), (1-11), (1-12), or (1-13); A is CH, N, O or S; B is H, C1-6 alkyl, C3-6 cycloalkyl, benzyl or CO2R^d; X is O or S; and n is 0 or 1. A method for preparing the 1,2,5-triazepane derivative comprises the steps of: (a) subjecting an amino acid represented by the formula(2) and 1,2,5-triazepane to a condensation reaction to prepare a compound represented by the formula(4); (b) reacting the compound of the formula(4) with an electrophilic compound substituted with R2 to prepare a compound represented by the formula(5); and (c) deprotecting the compound of the formula(5). A pharmaceutical composition for preventing or treating diseases mediated by DPP-IV comprises an effective amount of the 1,2,5-triazepane derivative or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

Description

1,2,5-TRIAZEPANE DERIVATIVES HAVING β-AMINO ACYL GROUP, ITS PHARMACEUTICAL ACCEPTABLE SALTS AND PREPARATION PROCESS THEREOF}

The present invention relates to a 1,2,5-triazane derivative having a betaamino group, a pharmaceutically acceptable salt thereof, and a method for preparing the same.

Dipeptidyl peptidase-IV (DPP-IV; hereafter referred to as “DPP-IV”) is involved in the regulation of the activity of several hormones. One such hormone is glucagon-like peptide 1 (GLP-1), which is involved in the regulation of post-prandial blood sugar levels, in which GLP-1 (7-36), which is active by DPP-IV, is inactive. (9-36) (Deacon, CF; Johnson, AH; Holst, JJJ Clin. Endocrinol. Metab. 1995, 80, 952).

However, in the case of diseases such as type 2 diabetes (insulin-independent diabetes mellitus) and impaired glucose tolerance, in which hyperglycemia can cause tissue damage, it enhances the effect of GLP-1 (7-36) in the active state. It is advantageous. Therefore, inhibitors of DPP-IV have been proposed as candidate drugs for the treatment of type 2 diabetes mellitus and impaired glucose tolerance, and research on them is being actively conducted.

In addition, it has been widely known that diseases such as type 1 diabetes (insulin dependent diabetes mellitus), arthritis, obesity or osteoporosis are also mediated by the activity of DPP-IV, and therefore, the inhibitory factor of the DPP-IV is Its importance is increasing as a candidate drug for the treatment of these diseases.

Meanwhile, for example, Merck, Novartis, Bristol-Myers Squibbs, Novo Nordisk, Ferring, Takeda, and Tanabe (for example) Tanabe, Wellide et al. Have studied and suggested various DPP-IV inhibitors. Such conventional DPP-IV inhibitory factors are disclosed in WO 95/15309, WO 95/34538, WO 98/19998, WO 99/38501, WO 99/67278, WO 00/34241, WO 01/34594. , WO 01/68603, WO 01/81304, WO 01/81337, WO 01/55105, WO 01/96295, WO 02/02560, WO 02/14271, WO 02/38541, WO 02/30890, WO 02/30891, WO 02/51836, WO 02/62764, WO 03/00180, WO 03/00181, WO 03/04498, WO 03/082817, WO 04 / 007446, WO 04/007468, WO 04/014860, WO 04/028524, WO 04/037169, WO 04/041795, WO 04/052850, WO 05/011581, WO 05/012312 WO 05/030751, WO 05/033099, WO 05/037828 and the like.

However, none of the above known documents discloses the fact that 1,2,5-triazane derivatives having betaamino groups exhibit DPP-IV inhibitory activity.

Therefore, the present inventors have completed the present invention by confirming that the 1,2,5-triazane derivative having a betaamino group, which has not been studied so far, shows excellent inhibitory activity in DPP-IV.

SUMMARY OF THE INVENTION An object of the present invention in consideration of the above-described prior art is to provide a 1,2,5-triazane derivative having a betaamino group having a novel structure or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preparing the 1,2,5-triazane derivative.

Still another object of the present invention is to provide a pharmaceutical composition comprising the 1,2,5-triazane derivative or a pharmaceutically acceptable salt thereof.

Technical problems to be achieved by the present invention are not limited to the technical problems mentioned above, and other technical problems not mentioned will be clearly understood by those skilled in the art from the following description.

In order to achieve the above object, the present invention provides a 1,2,5-triazane derivative having a betaamino group represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Formula 1]

또는

이고; R₂는 수소, C_1-6 알킬, 또는

이고; R₃은 수소, C_1-6 알킬, C_3-6 사이클로알킬,

,

, CH₂CO₂R^b, COCO₂R^b, 피라진 또는

이고; R^a는 하나 또는 그 이상으로 될 수 있고, 각각 독립적으로 수소, C_1-6 알킬, C_3-6 사이클로알킬, C_1-6 알콕시, OCF₃, 할로겐, CN, CF_3, COOR^b 또는 NR^bR^c이고; R^b 및 R^c는 각각 독립적으로 수소, C_1-6 알킬 또는 C_3-6 사이클로알킬이고; R^d는 C_1-6 알킬, 트리플루오르메틸,

,

,

또는

이고; R^e는 C_1-6 알킬, C_3-6 사이클로알킬,

또는

이고; R^f는 수소, 할로겐, NR^bR^c,

,

,

,

, 테트라졸 또는 프롤린이고; A는 CH, N, O 또는 S이고; B는 수소, C_1-6 알킬, C_3-6 사이클로알킬, 벤질 또는 CO₂R^d 이고; X는 O 또는 S이고; n은 0 또는 1의 정수이다. Wherein R ₁ is

or

ego; R ₂ is hydrogen, C _1-6 alkyl, or

ego; R ₃ is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl,

,

, CH ₂ CO ₂ R ^b , COCO ₂ R ^b , pyrazine or

ego; R ^a may be one or more and each independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, OCF ₃ , halogen, CN, CF _3, COOR ^b or NR ^b R ^c ; R ^b and Each R ^c is independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl; R ^d is C _1-6 alkyl, trifluoromethyl,

,

,

or

ego; R ^e is C _1-6 alkyl, C _3-6 cycloalkyl,

or

ego; R ^f is hydrogen, halogen, NR ^b R ^c ,

,

,

,

, Tetrazole or proline; A is CH, N, O or S; B is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, benzyl or CO ₂ R ^d ; X is O or S; n is an integer of 0 or 1.

The present invention also comprises the steps of condensation reaction of an amino acid of Formula 2 with 1,2,5-triazane of Formula 3 to produce a compound of Formula 4; Reacting an electrophilic compound substituted with R ₂ with a compound of Formula 4 to produce a compound of Formula 5; And deprotecting the compound of Formula 5, to provide a method for preparing the 1,2,5-triazane derivative of Formula 1 below:

Scheme 1

Wherein BOC represents a protecting group; R ₁ , R ₂ and R ₃ are as defined above.

In addition, the present invention comprises the steps of reacting a compound of formula 4 with chloroacetyl chloride to produce a compound of formula 6; Reacting a compound of Formula 6 with a nucleophile compound substituted with R ₂ to produce a compound of Formula 5; And deprotecting the compound of Formula 5, to provide a process for preparing the cyclized 1,2,5-triazane derivative of Formula 1 below:

Scheme 2

Wherein BOC represents a protecting group; R ₁ , R ₂ and R ₃ are as defined above.

The present invention also comprises the steps of condensation reaction of the amino acid of Formula 2 and the compound of Formula 7 to produce a compound of Formula 5; And deprotecting the compound of Formula 5, to provide a method for preparing the 1,2,5-triazane derivative of Formula 1 below:

Scheme 3

Wherein BOC represents a protecting group; R ₁ , R ₂ and R ₃ are as defined above.

The present invention also provides a pharmaceutical composition comprising an effective amount of the 1,2,5-triazane derivative of Formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In addition, the present invention provides a method for inhibiting DPP-IV comprising administering to a subject mammal a therapeutically effective amount of the 1,2,5-triazane derivative of Formula 1 or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for treating a disease mediated by DPP-IV comprising administering to a subject mammal a therapeutically effective amount of the 1,2,5-triazane derivative of Formula 1 or a pharmaceutically acceptable salt thereof. To provide.

Other specific details of the embodiments of the present invention are included in the following detailed description and the accompanying drawings.

Hereinafter, the configuration and operation of the present invention will be described in more detail.

As described above, the present invention basically provides a 1,2,5-triazane derivative having a betaamino group represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Formula 1]

또는

이고; R₂는 수소, C_1-6 알킬, 또는

이고; R₃은 수소, C_1-6 알킬, C_3-6 사이클로알킬,

,

, CH₂CO₂R^b, COCO₂R^b, 피라진 또는

이고; R^a는 하나 또는 그 이상으로 될 수 있고, 각각 독립적으로 수소, C_1-6 알킬, C_3-6 사이클로알킬, C_1-6 알콕시, OCF₃, 할로겐, CN, CF_3, COOR^b 또는 NR^bR^c이고; R^b 및 R^c는 각각 독립적으로 수소, C_1-6 알킬 또는 C_3-6 사이클로알킬이고; R^d는 C_1-6 알킬, 트리플루오르메틸,

,

,

또는

이고; R^e는 C_1-6 알킬, C_3-6 사이클로알킬,

또는

이고; R^f는 수소, 할로겐, NR^bR^c,

,

,

,

, 테트라졸 또는 프롤린이고; A는 CH, N, O 또는 S이고; B는 수소, C_1-6 알킬, C_3-6 사이클로알킬, 벤질 또는 CO₂R^d 이고; X는 O 또는 S이고; n은 0 또는 1의 정수이다. Wherein R ₁ is

or

ego; R ₂ is hydrogen, C _1-6 alkyl, or

ego; R ₃ is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl,

,

, CH ₂ CO ₂ R ^b , COCO ₂ R ^b , pyrazine or

ego; R ^a may be one or more and each independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, OCF ₃ , halogen, CN, CF _3, COOR ^b or NR ^b R ^c ; R ^b and Each R ^c is independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl; R ^d is C _1-6 alkyl, trifluoromethyl,

,

,

or

ego; R ^e is C _1-6 alkyl, C _3-6 cycloalkyl,

or

ego; R ^f is hydrogen, halogen, NR ^b R ^c ,

,

,

,

, Tetrazole or proline; A is CH, N, O or S; B is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, benzyl or CO ₂ R ^d ; X is O or S; n is an integer of 0 or 1.

As also supported by the test examples described later, the experimental results of the present inventors showed that the 1,2,5-triazane derivatives having the betaamino group of the general formula (1) showed very high inhibitory activity against DPP-IV. Thus, the 1,2,5-triazane derivative of Formula 1 is a disease mediated by the DPP-IV, for example, insulin dependent diabetes mellitus (type 1 diabetes), insulin independent diabetes mellitus (type 2 diabetes), arthritis It can be very useful for treating or preventing diseases such as obesity, osteoporosis or impaired glucose tolerance.

이고; R^g는 하나 또는 그 이상으로 될 수 있고, 각각 독립적으로 수소, C_1-6 알킬, C_1-6 알콕시, OCF₃, 할로겐, CN 또는 CF₃인 화합물로 될 수도 있다. 이 때, 상기 화학식 1의 1,2,5-트리아제판 유도체는, 상기 R^g는 하나 또는 그 이상의 할로겐인 화합물로 됨이 바람직하며, 이에 더하여, R₂는 또는

인 화합물로 됨이 보다 바람직하다. 또한, 더욱 바람직하게는, 상기 1,2,5-트리아제판 유도체는, 상기 R₂는

,

,

또는

이고; R^f는 수소, 염소,

,

,

,

,

,

,

,

,

,

,

,

,

,

또는

인 화합물로 될 수 있다. On the other hand, in view of the superior inhibitory activity for the DPP-IV, the 1,2,5-triazane derivative of Formula 1 is R ₁

ego; R ^g may be one or more and may each independently be a compound which is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, OCF ₃ , halogen, CN or CF ₃ . In this case, the 1,2,5-triazane derivative of Formula 1, wherein R ^g is preferably one or more halogen compounds, in addition, R ₂ or

It is more preferable to become a phosphorus compound. Further, more preferably, the 1,2,5-triazane derivative, R ₂ is

,

,

or

ego; R ^f is hydrogen, chlorine,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

Phosphorus compounds.

According to the preferred configuration of the 1,2,5-triazane derivative of Formula 1 as described above, it is possible to further enhance the inhibitory activity against DPP-IV and the therapeutic or prophylactic efficacy of diseases mediated by DPP-IV.

Meanwhile, the 1,2,5-triazane derivatives of the general formula (1) according to the present invention all contain at least one asymmetric stereocenter (for example, an amino group and a carbon to which R ₁ is bonded), and therefore, R coordination or The S configuration can take the form of specific enantiomers, diastereomers, or many other stereoisomers. By the way, in terms of inhibitory activity against DPP-IV, the 1,2,5-triazane derivative of Chemical Formula 1 is preferably in the form of R configuration in which the stereo center to which the amino group and R ₁ are bonded is formed. .

In addition, the 1,2,5-triazane derivative of Formula 1 may be in the form of an acid addition salt to which various organic acids are added, as well as in free form. At this time, the type of organic acid that can be added to the 1,2,5-triazane derivative is not particularly limited, but hydrochloride, sulfate, acetate, trifluoroacetate, phosphate, fumarate, maleate, citric acid More preferably, salt, methane sulfonate or lactate is added.

On the other hand, the present invention provides a method for preparing the 1,2,5-triazane derivative of the formula (1).

According to the first embodiment of the present invention, the 1,2,5-triazane derivative of Chemical Formula 1, as shown in Scheme 1 below, the amino acid of Chemical Formula 2 and 1,2,5-triazane of Chemical Formula 3 Condensation reaction to produce a compound of Formula 4; Reacting an electrophilic compound substituted with R ₂ with a compound of Formula 4 to produce a compound of Formula 5; And deprotecting the compound of Formula 5:

Scheme 1

Wherein BOC represents a protecting group and R ₁ , R ₂ and R ₃ are as defined above.

The method for preparing the 1,2,5-triazane derivative of Formula 1 according to the first embodiment is specifically examined for each step as follows.

First, the amino acid of Formula 2 can be easily synthesized by those skilled in the art from a known production method (see, eg, Kim, DS et. Al J. Med. Chem. 2005 , 48 , 141).

In addition, the 1,2,5-triazane of Formula 3 may be produced by a method as shown in Scheme 4:

Scheme 4

Wherein R ₁ , R ₂ and R ₃ are as defined above, Y and Z are different butoxycarbonyl or Cbz and X is Cl, Br, I or OTs.

That is, in preparing the 1,2,5-triazane of Formula 3, first, the compound of Formula 8 and the compound of Formula 9 are reacted. This reaction step is a reaction of a commercially available compound of formula 8 with a compound of formula 9 under known conditions (Boros, EE J. Heterocyclic Chem. 2001 , 38 , 613) to obtain a compound of formula 10, for example For example, the compound of Formula 8 and the compound of Formula 9 may proceed by reacting under basic conditions such as NaH or NaOH. In addition, if necessary, tetraethylammonium bromide, which is a phase transfer catalyst, may be added and reacted. The solvent for reacting the compound of Formula 8 and the compound of Formula 9 is not particularly limited, and N, N-dimethylformamide, toluene or water may be preferably used. In addition, the reaction between the compound of Formula 8 and the compound of Formula 9 is preferably performed for 5 to 20 hours at a reaction temperature of 100 to 200 ℃. The end point of this reaction is when all of the compound of Formula 8 is consumed, and can be confirmed by thin layer chromatography.

The compound of Formula 10 is produced by the reaction of the compound of Formula 8 and the compound of Formula 9, and then, by deprotecting Y or Z from the compound of Formula 10, when the compound of Formula 11 is deprotected. Or 1,2,5-triazane (Formula 3 wherein Z = R ₃ and deprotected Y). Such deprotection can be carried out, for example, in the presence of a deprotection reaction reagent such as hydrochloride, trifluoroacetic acid or Pd / C, and the amount of the deprotection reaction reagent is preferably about 5 to 10 equivalents. . In addition, as a solvent for the deprotection, although not particularly limited, 1,4-dioxane, dichloromethane, ethyl acetate, ethanol or methanol can be preferably used. In addition, the deprotection is preferably performed for 3 to 10 hours at a reaction temperature of 20 to 40 ℃.

When a compound of formula (11) produced through the deprotection, depending on the R ₃ type, by the reaction of a variety of electrophiles compound substituted with such a compound and R in the formula (11) ₃ (e. G., Depending on the type of R ₃ , An alkylation reaction, an arylation reaction, an acylation reaction, a sulfonation reaction or an electrophilic substitution reaction, etc.), and a compound of formula 12 is produced, and then, in the same manner as the deprotection reaction described above, Deprotection of Y from the compound may also yield 1,2,5-triazane of formula (3).

Meanwhile, after the amino acid of Formula 2 and 1,2,5-triase plate of Formula 3 are generated by the above-described method, the amino acid of Formula 2 and 1,2,5-triase plate of Formula 3 are condensed to react. To yield the compound of formula (4). Such condensation reactions include, for example, 1,1'-carbonyldiimidazole (CDI), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 1,3-dicyclo It can proceed in the presence of one or more condensing agents selected from the group consisting of hexylcarbodiimide (DCC), in addition to the presence of various condensing agents known to those skilled in the art. The amount of the condensing agent is preferably about 1 to 2 equivalents based on the amount of the 1,2,5-triazane of the formula (3). In addition, the amount of the amino acid of Formula 2 is preferably about 1 to 2 equivalents based on the amount of 1,2,5-triazepan of Formula 3, and the amount of 1,2,5-triazepan of Formula 3 Condensation of the amino acid of Formula 2 and 1,2,5-triazane of Formula 3 in the presence of about 2 to 5 equivalents of amine base is preferred. In addition, as a solvent for the condensation reaction, although not particularly limited, an aliphatic hydrocarbon solvent such as dichloromethane or chloroform may be preferably used, and the condensation reaction may be performed at a reaction temperature of 20 to 70 ° C. for 10 to 24 hours. It is preferable to proceed.

After generating the compound of Formula 4, an electrophilic compound substituted with R ₂ is reacted with a compound of Formula 4 to produce a compound of Formula 5. This reaction can proceed by stirring under a completely dried nitrogen atmosphere.

At this time, as the electrophile compound substituted with said R ₂ is can be used without limitation the electrophile compound known become apparent to those skilled in the art, preferably the acyl halide compound is substituted by R _2, a polyisocyanate compound substituted with R _2, or Sulfonyl chloride compounds substituted with R ₂ can be used. The amount of the electrophile is preferably about 1 to 3 equivalents based on the amount of the compound of Formula 4. Further, as the electrophile solvent for its compound and a compound of the reaction of formula (4) is substituted by the R ₂ include, but are not particularly limited, and an organic halogen solvent such as dichloromethane or chloroform may be preferably used, as the above R ₂ The reaction of the substituted electrophilic compound with the compound of Formula 4 is preferably performed for 5 to 24 hours at a reaction temperature of 20 to 70 ℃. And, the end point of the reaction is determined by the point at which all of the compound of Formula 4 is consumed, which can be confirmed by thin layer chromatography.

On the other hand, after the compound of Formula 5 is produced, the protecting group BOC is deprotected from the compound of Formula 5 to finally prepare the 1,2,5-triazane derivative of Formula 1.

At this time, the BOC may be any functional group well known to those skilled in the art as a protecting group of the amine group, but preferably a butoxycarbonyl group.

In addition, the deprotection may be performed, for example, in the presence of a deprotection reaction reagent such as hydrochloride or trifluoroacetic acid, and the amount of the deprotection reaction reagent is 5 based on the amount of the compound of Formula 5 About 10 equivalents are preferable. The solvent for deprotection is not particularly limited, but 1,4-dioxane, dichloromethane or ethyl acetate can be preferably used. In addition, the deprotection is preferably performed for 3 to 10 hours at a reaction temperature of 20 to 40 ℃. The end point of the deprotection reaction described above is determined by the point at which the compound of Formula 5 is completely consumed, which can be confirmed by thin layer chromatography.

On the other hand, unlike the manufacturing method according to the first embodiment described above, according to the second embodiment of the present invention, as shown in Scheme 2, by reacting the compound of formula 4 with chloroacetyl chloride of the formula Producing a compound; Reacting a compound of Formula 6 with a nucleophile compound substituted with R ₂ to produce a compound of Formula 5; And a 1,2,5-triazane derivative of the general formula (1) may be prepared by a manufacturing method comprising the step of deprotecting a compound of the general formula (5):

Scheme 2

Wherein BOC, R ₁ , R ₂ and R ₃ are as defined above.

At this time, as shown in Scheme 5, the compound of Formula 4 is condensation reaction of the amino acid of Formula 2 and 1,2,5-triazane of Formula 3 as in the manufacturing method according to the first embodiment Can be generated. However, since the specific constitution of the condensation reaction step has already been described above with respect to the manufacturing method according to the first embodiment, further description thereof will be omitted.

Scheme 5

Wherein BOC, R ₁ , R ₂ and R ₃ are as defined above.

In addition, in the preparation method according to the second embodiment, compared with the preparation method according to the first embodiment described above, the step of reacting the compound of Formula 4 with chloroacetyl chloride to produce a compound of Formula 6 In addition, this compound of formula 6 is reacted with a nucleophile compound substituted with R ₂ to produce a compound of formula 5.

The reaction of the compound of formula 4 with chloroacetyl chloride and the reaction of the compound of formula 6 with the nucleophile compound substituted with R ₂ are not particularly limited, but may preferably proceed under an organic halogen solvent, It is preferred to proceed for 5 to 24 hours at the reaction temperature.

In each of these reactions, a compound of formula 6, in which chloro acetyl is substituted, is produced by the reaction of the compound of formula 4 with chloroacetyl chloride, and then the compound of formula 6 is reacted with a nucleophilic compound substituted with R ₂ . To give a compound of formula (5).

On the other hand, with the nucleophile compound substituted with said R ₂ may work, without limitation, both the nucleophile compound apparent that known to those skilled in the art, preferably R ₂ a piperidine compound, a N- methyl piperazine substituted with R ₂ substituted with compound, there can be employed a pyrrolidine compound, a thio-dimethyl the morpholine compound substituted with an amine compound or R ₂ is substituted by R ₂ is substituted by R _2. The amount of the nucleophile compound is preferably about 1 to 3 equivalents based on the amount of the compound of Formula 6.

After the compound of Formula 5 is produced, the 1,2,5-triazane derivative of Formula 1 may be finally prepared by deprotecting the compound of Formula 5 as in the first embodiment.

On the other hand, unlike the first and second embodiments described above, according to the third embodiment of the present invention, condensation reaction of the amino acid of Formula 2 and the compound of Formula 7 to produce a compound of Formula 5; And a 1,2,5-triazane derivative of Chemical Formula 1 may be prepared by a preparation method comprising deprotecting the compound of Chemical Formula 5.

Scheme 3

Wherein BOC, R ₁ , R ₂ and R ₃ are as defined above

First, the compound of Formula 7 is produced by a method comprising the step of reacting a 1,2,5-triazane of Formula 3 with an electrophile compound substituted with R ₂ , as shown in Scheme 6 below, Other known methods can be readily produced by those skilled in the art:

Scheme 6

Wherein R ₂ and R ₃ are as defined above.

At this time, since the method for producing 1,2,5-triazane of Formula 3 has already been described in detail with respect to the first embodiment, further detailed description thereof will be omitted.

In addition, as the electrophile compound substituted with R ₂ reacted with the 1,2,5-triazane of Formula 3, all of the electrophile compounds known to those skilled in the art or commercially available can be used without limitation. For example, acetic anhydride substituted with R ₂ can be used.

In addition, the reaction between the cyclic hydrazine of Formula 3 and the electrophile compound substituted with R ₂ is not particularly limited, and may be preferably performed under a polar solvent such as acetone, N, N-dimethylformamide or water. It is preferred to proceed for 5 to 20 hours at a reaction temperature of room temperature to 50 ℃. And, the end point of the reaction is determined by the point at which the 1,2,5-triase plate of Formula 3 is completely consumed, which can be confirmed by thin layer chromatography.

As a result of this reaction, a compound of Formula 7 is produced, and the compound of Formula 7 is condensed with the amino acid of Formula 2 to produce a compound of Formula 5 under the same conditions as the first step of the first embodiment, and then the first As in the embodiment, the compound of Formula 5 may be deprotected to finally prepare the 1,2,5-triazane derivative of Formula 1.

On the other hand, the present invention provides a pharmaceutical composition comprising an effective amount of the 1,2,5-triazane derivative of Formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

As described above, the 1,2,5-triazane derivative having a betaamino group represented by Formula 1 and its pharmaceutically acceptable salts exhibit high inhibitory activity against DPP-IV, and thus include them as active ingredients. The pharmaceutical composition can be usefully used for the treatment or prevention of diseases mediated by DPP-IV, for example, insulin dependent diabetes mellitus, insulin independent diabetes mellitus, arthritis, obesity, osteoporosis or impaired glucose tolerance.

The pharmaceutical compositions may be formulated in various oral or parenteral dosage forms. For example, it may be in any dosage form for oral administration, such as tablets, pills, hard and soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs. Such oral dosage forms may contain, in addition to the active ingredient, a diluent such as, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, silica, talc, or the like according to the conventional composition of each formulation. And pharmaceutically acceptable carriers such as lubricants such as stearic acid and its magnesium or calcium salts and / or polyethylene glycols.

In addition, when the oral dosage form is a tablet, it may include a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, And, optionally, disintegrants such as starch, agar, alginic acid or sodium salts thereof, boiling mixtures and / or absorbents, colorants, flavoring or sweetening agents and the like.

In addition, the pharmaceutical composition may be formulated in a parenteral dosage form, in which case it is administered by parenteral administration methods such as subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. At this time, in order to formulate the formulation for parenteral administration, the pharmaceutical composition is an active ingredient, that is, 1,2,5-triazane derivative of Formula 1 or a pharmaceutically acceptable salt thereof with water or stabilizer or buffer Mixed to form a solution or suspension, which solution or suspension can be prepared in unit dosage forms of ampoules or vials.

In addition, the pharmaceutical composition may be sterile, or may further include adjuvants such as preservatives, stabilizers, hydrating or emulsifiers, salts and / or buffers for controlling osmotic pressure, and may further include other therapeutically useful substances. It may be formulated according to conventional methods of mixing, granulating or coating.

In addition, the active ingredient, that is, 1,2,5-triazane derivative of Formula 1 or a pharmaceutically acceptable salt thereof is 0.1 to 500 mg / kg (body weight) per day for mammals including humans. Preferably, the pharmaceutical composition may be included in the pharmaceutical composition in an effective amount of 0.5 to 100 mg / kg body weight, and the pharmaceutical composition may be divided once or twice a day and administered by oral or parenteral route.

On the other hand, the present invention also provides a method for inhibiting DPP-IV comprising administering to a subject mammal a therapeutically effective amount of the 1,2,5-triazane derivative of Formula 1 or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for treating a disease mediated by DPP-IV comprising administering to a subject mammal a therapeutically effective amount of the 1,2,5-triazane derivative of Formula 1 or a pharmaceutically acceptable salt thereof. To provide.

At this time, the disease mediated by DPP-IV may be, for example, insulin dependent diabetes mellitus, insulin independent diabetes mellitus, arthritis, obesity, osteoporosis or impaired glucose tolerance, and is associated with the activity of other DPP-IV. And any known disease.

In addition, the specific administration method and therapeutically effective amount of the 1,2,5-triazane derivative of Formula 1 or a pharmaceutically acceptable salt thereof may include the type of mammal, the type of disease, and 1,2,5 of Formula 1 The skilled person in the art can clearly determine the type of -triasepan derivative and thus the inhibitory activity of DPP-IV, and the like is not particularly limited.

Hereinafter, the present invention will be described in more detail with reference to preferred embodiments. However, this is presented by way of example of the present invention by any means is not limited by the scope of the present invention, the scope of the present invention is defined only in accordance with the claims to be described later.

Preparation Example 1

<Step 1>

Preparation of bis- (2-chloroethyl) carbamic acid benzyl ester

Dissolve bis- (2-chloroethyl) amine (26.7 g, 0.15 mol) in acetone (300 mL), cool to 0 ° C, add sodium carbonate (53 g, 0.5 mol) in distilled water (300 mL), and add benzyl chloro Formate (29.6 g, 0.165 mol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 5 hours, after completion of the reaction, extracted with ethyl acetate and washed with brine. Thereafter, the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated, and then separated by column chromatography to obtain the target product in the liquid phase (32.9 g, yield = 79%).

<Step 2>

Preparation of [1,2,5] triazane-1,2,5-tricarboxylic acid 5-benzyl ester 1,2-di-tert-butyl ester

Bis- (2-chloroethyl) carbamic acid benzyl ester (20 g, 72 mmol), di-tert-butylhydrazodiformate (10 g, 43 mmol), tetrabutylammonium in a 500 mL round flask equipped with a mechanical stirrer Bromide (4.8 g), toluene (150 mL) and 50% caustic soda (75 mL) were each added and heated to reflux for 6 hours with vigorous stirring. The reaction mixture was extracted with ethyl acetate and washed with brine. Then, dried over anhydrous sodium sulfate, filtered and concentrated and separated by column chromatography to give the target product as a white semi-solid (9.7 g, yield = 52%).

¹ H NMR (CDCl ₃ , 200 MHz) δ 7.36-7.34 (m, 5H), 5.14 (s, 2H), 4.21-4.02 (m, 2H), 3.98-3.65 (m, 1H), 3.52-3.04 (m , 5H), 1.49 (s, 18H).

<Step 3>

Preparation of [1,2,5] triazane-5-carboxylic acid benzyl ester.2HCl

[1,2,5] triazane-1,2,5-tricarboxylic acid benzyl ester di-tert-butyl ester (1.3 g, 2.99 mmol) was dissolved in ethyl acetate (1 mL) and 4M-HCl / 1,4 Dioxane (0.1 mL) was added followed by stirring at room temperature for 16 hours. Ethyl acetate was removed under reduced pressure, and then recrystallized from diethyl ether to obtain [1,2,5] triazane-5-carboxylic acid benzyl ester.2HCl as an ivory solid (400 mg, 43%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.37 (m, 5H), 5.09 (s, 2H), 4.20-3.00 (m, 8H).

<Step 4>

Preparation of (R) -1- [3-amino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5-carboxylic acid benzyl ester.2HCl

(R) -3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl) -butyric acid (333 mg, 1.00 mmol) was dissolved in methylene chloride (5 mL), [1,2,5] triazane-5-carboxylic acid benzyl ester.2HCl (369 mg, 1.20 mmol), EDCI (580 mg, 3.00 mmmol) and triethylamine (1 ml, 7.00 mmol) were added and 12 hours at room temperature. Was stirred. Extracted with methylene chloride, washed with brine and dried over anhydrous sodium sulfate. The liquid mixture concentrated under reduced pressure was separated by column chromatography (EtOAc: hexane = 1: 3) to obtain (R) -1- [3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro- Phenyl) -butyryl]-[1,2,5] triazane-5-carboxylic acid benzyl ester as a white solid (440 mg, 80%).

¹ H NMR (CDCl ₃ , 200 MHz) δ 7.35-7.32 (m, 5H), 7.12-6.99 (m, 1H), 6.88-6.81 (m, 1H), 5.48-5.32 (br, 1H), 5.12 (s , 2H), 4.14-4.10 (m, 1H), 3.73-3.46 (m, 8H), 3.00-2.70 (m, 4H), 1.36 (s, 9H).

(R) -1- [3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5-carboxylic acid Benzyl ester (20 mg, 0.036 mmol) was dissolved in ethyl acetate (1 ml), 4M-HCl / 1,4-dioxane (0.1 ml) was added, followed by stirring at room temperature for 16 hours. Ethyl acetate was removed under reduced pressure, and then recrystallized with diethyl ether to give (R) -1- [3-amino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2, 5] Triazepan-5-carboxylic acid benzyl ester.2HCl was obtained as a white solid (19 mg, 99%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.96 (br, 3H), 7.55-7.52 (m, 3H), 7.50-7.35 (m, 4H), 5.07 (s, 2H), 3.70-3.65 (m , 4H), 3.56-3.42 (m, 3H), 2.94-2.93 (m, 2H), 2.83-2.77 (m, 4H).

Preparation Example 2

Preparation of (R) -3-amino-1- [1,2,5] triazane-1-yl-4- (2,4,5-trifluoro-phenyl) -butan-1-one-3HCl

(R) -1- [3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5-carboxylic acid Benzyl ester (35 mg, 0.064 mmol) was dissolved in MeOH (2 ml) and 10% wt. Pd / C (7 mg, 20% wt) was added and stirred under hydrogen (H _2, 1 atm) for 10 hours. The reaction mixture was filtered through celite, and the concentrated mixture under reduced pressure was separated by column chromatography (EtOAc: MeOH = 2: 1) to obtain (R)-[3-oxo-3- [1,2,5] Triazane-1-yl-1- (2,4,5-trifluoro-benzyl) -propyl] -carbamic acid tert-butyl ester was obtained (24 mg, 90%).

¹ H NMR (CDCl ₃ , 200 MHz) δ 7.03-6.82 (m, 1H), 6.79-6.60 (m, 1H), 5.60-5.47 (br, 1H), 4.21-3.83 (m, 2H), 3.31-3.03 (m, 3H), 2.86-2.53 (m, 4H), 2.29-2.11 (m, 4H), 1.22 (s, 9H).

(R)-[3-oxo-3- [1,2,5] triazane-1-yl-1- (2,4,5-trifluoro-benzyl) -propyl] -carbamic acid tert-butyl ester (18 mg, 0.043 mmol) was dissolved in ethyl acetate (1 ml), 4M-HCl / 1,4-dioxane (0.1 ml) was added, followed by stirring at room temperature for 16 hours. Ethyl acetate was removed under reduced pressure, and then recrystallized from diethyl ether to give (R) -3-amino-1- [1,2,5] triazane-1-yl-4- (2,4,5-trifluoro -Phenyl) -butan-1-one.3HCl was obtained as a white solid (10 mg, 55%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.13 (br, 1H), 9.94, 9.08 (br, 1H), 8.00 (br, 2H), 7.37-7.34 (m, 2H), 4.61-4.35 (m , 1H), 4.17-4.14 (m, 1H), 3.94-3.89 (m, 1H), 3.76-3.14 (m, 5H), 2.79-2.76 (m, 2H), 2.60-2.53 (m, 3H).

Preparation Example 3

(R) -1-acetyl-2- [3-amino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triase plate-5-carboxylic acid benzyl Production of ester HCl

(R) -1- [3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5-carboxylic acid Benzyl ester (100 mg, 0.18 mmol) was dissolved in methylene chloride (1 ml), and then acetyl chloride (26 μl, 0.36 mmol) and triethylamine (75 μl, 0.54 mmol) were added and stirred at room temperature for 12 hours. Extracted with methylene chloride, washed with brine and dried over anhydrous sodium sulfate. The concentrated solution under reduced pressure was separated by column chromatography (EtOAc: hexane = 1: 1), and then (R) -1-acetyl-2- [3-tert-butoxycarbonylamino-4- (2,4,5- Trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5-carboxylic acid benzyl ester was obtained (66 mg, 88%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.40-7.35 (m, 5H), 7.05 (q, J = 8.4 Hz, 1H), 6.90 (q, J = 8.4 Hz, 1H), 5.14 (s, 2H) , 4.45-4.43 (m, 1H), 4.13-4.08 (m, 1H), 3.74-3.41 (m, 5H), 3.07-2.93 (m, 4H), 2.60-2.44 (m, 2H), 2.17-1.95 ( m, 3H), 1.37 (s, 9H).

(R) -1-acetyl-2- [3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane -5-carboxylic acid benzyl ester (66 mg, 0.02 mmol) was dissolved in ethyl acetate (1 ml), 4M-HCl / 1,4-dioxane (0.1 ml) was added, followed by stirring at room temperature for 16 hours. Ethyl acetate was removed under reduced pressure, and then recrystallized with diethyl ether to give (R) -1-acetyl-2- [3-amino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[ 1,2,5] triazane-5-carboxylic acid benzyl ester.HCl was obtained (6 mg, 57%).

1 H NMR (MeOD, 300 MHz) δ 7.54 (m, 2H), 7.36-7.35 (m, 5H), 5.09 (s, 2H), 4.26-3.90 (m, 2H), 3.71-3.35 (m, 5H), 3.20-3.10 (m, 1H), 3.05-2.95 (m, 3H), 2.65-2.64 (m, 2H), 2.00 (s, 3H).

Preparation Example 4

<Step 1>

Preparation of [1,2,5] triazane-1,2-dicarboxylic acid di-tert-butyl ester

[1,2,5] triazane-1,2,5-tricarboxylic acid 5-benzyl ester 1,2-di-tert-butyl ester (5.638 g, 12.9 mmol) was dissolved in methanol (100 mL), 10% -Pd / C (1.37 g, 10 mol%) was added and stirred for 5 h at room temperature under hydrogen (1 atm). The reaction mixture was filtered through celite and concentrated to afford the desired product as a colorless liquid (3.57 g, yield = 91%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 4.02-3.93 (m, 2H), 3.16-2.98 (m, 3H), 2.85-2.75 (m, 3H), 1.49 (s, 18H).

<Step 2>

Preparation of 5-methanesulfonyl- [1,2,5] triazane-1,2-dicarboxylic acid di-tert-butyl ester

[1,2,5] triazane-1,2-dicarboxylic acid di-tert-butyl ester (1 g, 3.3 mmol) was dissolved in methylene chloride (20 mL) and then triethylamine (0.4 g, 3.99 mmol) Was added and cooled to 0 ° C. Methanesulfonyl chloride (0.457 g, 3.99 mmol) was slowly added dropwise thereto and stirred at room temperature for 2 hours. Brine was added to the reaction mixture, and the mixture was extracted with methylene chloride, dried over anhydrous sodium sulfate, filtered and concentrated and separated by column chromatography to obtain the target product as a white solid (0.77 g, yield = 61%).

<Step 3>

Preparation of 5-methanesulfonyl- [1,2,5] triazane

5-methanesulfonyl- [1,2,5] triazane-1,2-dicarboxylic acid di-tert-butyl ester (800 mg, 2.1 mmol) was dissolved in methylene chloride (20 mL) and then 4M-HCl / Dioxane (10 mL) was added and stirred at rt for 12 h. After the reaction was completed, the resulting solid was filtered and dried to give the target product as a white solid (492 mg, yield = 92%).

<Step 4>

(R)-[3- (5-methanesulfonyl- [1,2,5] triasepan-1-yl) -3-oxo-1- (2,4,5-trifluoro-benzyl)- Propyl] -Carbamic Acid Tert-Butyl Ester Preparation

(R) -3-tert-butoxy carbonyl amino-4- (2,4,5-trifluoro-phenyl) -butyric acid (1.35 g, 4.0 mmol) was dissolved in methylene chloride, and then 1-ethyl- 3- (3-dimethylaminopropyl) carbodiimide.HCl (776.5 mg, 4.0 mmol) and 5-methanesulfonyl- (1,2,5) -triazane.2HCl (2.043 mg, 8.1 mmol). Triethylamine (5.65 ml, 40.5 mmol) was slowly added under stirring at 0 ° C. and stirred at room temperature for 12 hours. After that, the reaction mixture was washed with brine, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The concentrated solution under reduced pressure was separated by column chromatography (MeOH: EtOAc: hexane = 1: 4: 8), and the target compound (R)-[3- (5-methanesulfonyl- [1,2,5] triazane-1 -Yl) -3-oxo-1- (2,4,5-trifluoro-benzyl) -propyl] -carbamic acid tert-butyl ester as a white solid (1.65 g, 82%).

¹ H NMR (CDCl _3, 300 MHz) δ 7.11 to 7.03 (m, 1H), 6.95 to 6.85 (m, 1H), 5.75 (br, 1H), 5.41 (br, 1H), 4.16 to 4.09 (m, 1H) , 3.89 to 3.85 (m, 2H), 3.63 to 3.61 (m, 2H), 3.49 to 3.38 (m, 3H), 3.14 to 3.03 (m, 2H), 2.93 to 2.90 (m, 1H), 2.88 (s, 3H), 2.85-2.76 (m, 1H), 2.57-2.54 (m, 1H), 1.37 (s, 9H); EI-MS m / z (relative intensity) 494.53 (M ⁺ , 0.2), 394 (30), 232 (40), 179 (87), 100 (100).

<Step 5>

(R) -3-Amino-1- (5-methanesulfonyl- [1,2,5] triazane-1-yl) -4- (2,4,5-trifluoro-phenyl) -butane- Preparation of 1-one HCl

(R)-[3- (5-Methanesulfonyl- [1,2,5] triasepan-1-yl) -3-oxo-1- (2,4,5-trifluoro-benzyl) -propyl ] -Carbamic acid tert-butyl ester (20 mg, 0.040 mmol) was dissolved in ethyl acetate, 4M HCl / 1,4-dioxane (300 µl, excess) was added thereto, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove ethyl acetate and excess 4M HCl / 1,4-dioxane and recrystallized with ether to give the desired compound (R) -3-amino-1- (5-methanesulfonyl- [1,2,5] triazane-1-yl) -4- (2,4,5-trifluoro-phenyl) -butan-1-oneHCl was obtained as a white solid (18 mg, quantitative).

¹ H NMR (DMSO- d _3, 300 MHz) δ 8.07 (brs, 3H), 7.54-7.46 (m, 2H), 4.01 (br, 1H), 3.63-3.62 (m, 2H), 3.37-3.29 (m, 4H), 3.00-2.93 (m, 4H), 2.90 (s, 3H), 2.88-2.78 (m, 2H); EI-MS m / z (relative intensity) 430.87 (M ⁺ , 0.6), 148 (7), 84 (47), 72 (66), 59 (100).

Preparation Example 5

<Step 1>

(R)-[3- (2-acetyl-5-methanesulfonyl- [1,2,5] triazane-1-yl) -3-oxo-1- (2,4,5-trifluoro- Benzyl) -propyl] -carbamic acid tert-butyl ester

(R)-[3- (5-Methanesulfonyl- [1,2,5] triasepan-1-yl) -3-oxo-1- (2,4,5-trifluoro-benzyl) -propyl ] -Carbamic acid tert-butyl ester (30 mg, 0.061 mmol) was dissolved in methylene chloride, and then acetyl chloride (6.5 μl, 0.091 mmol) and TEA (17 μl, 0.121 mmol) were added and stirred at room temperature for 2 hours. Thereafter, the reaction mixture was washed with brine, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The concentrated solution under reduced pressure was separated by column chromatography (MeOH: EtOAc: hexane = 1: 4: 8) to obtain the title compound (R)-[3- (2-acetyl-5-methanesulfonyl- [1,2,5] Triazane-1-yl) -3-oxo-1- (2,4,5-trifluoro-benzyl) -propyl] -carbamic acid tert-butyl ester was obtained as a white solid (11.2 mg, 34%).

¹ H NMR (DMSO- d _3, 300 MHz) δ 7.58-7.39 (m, 2H), 4.93 (br, 1H), 4.37-4.21 (m, 3H), 3.69-3.28 (m, 4H), 3.07 (s, 3H), 3.05-2.68 (m, 4H), 2.40-2.28 (m, 1H), 2.40-2.28 (m, 1H), 2.10 (s, 3H), 2.06-1.99 (m, 1H), 1.37 (s, 9H); EI-MS m / z (relative intensity) 536.57 (M).

<Step 2>

(R) -1- (2-acetyl-5-methanesulfonyl- [1,2,5] triasepan-1-yl) -3-amino-4- (2,4,5-trifluoro-phenyl Production of) -butan-1-oneHCl

(R)-[3- (2-acetyl-5-methanesulfonyl- [1,2,5] triazane-1-yl) -3-oxo-1- (2,4,5-trifluoro- Benzyl) -propyl] -carbamic acid tert-butyl ester (7 mg, 0.013 mmol) was dissolved in ethyl acetate, and then added 4M HCl / 1,4-dioxane (100 µl, excess) and stirred at room temperature for 12 hours. . Thereafter, the reaction mixture was concentrated under reduced pressure to remove ethyl acetate and excess 4M HCl / 1,4-dioxane and recrystallized with ether to give the desired compound (R) -1- (2-acetyl-5-methanesulfonyl- [1,2,5] triazane-1-yl) -3-amino-4- (2,4,5-trifluoro-phenyl) -butan-1-oneHCl was obtained as a white solid (4 mg, 65%).

¹ H NMR (DMSO- d _3, 300 MHz) δ 8.14 (br, 3H), 7.59 to 7.58 (m, 2H), 4.24 to 4.19 (m, 2H), 3.85 to 3.78 (m, 1H), 3.60 to 3.36 ( m, 4H), 3.24 to 3.00 (m, 4H), 2.99 (s, 3H), 2.97 to 2.76 (m, 1H), 2.23 to 1.93 (m, 4H); EI-MS m / z (relative intensity) 472.91 (M).

Preparation Example 6

(R)-[3- [5-methanesulfonyl-2- (pyridine-3-carbonyl)-[1,2,5] triazane-1-yl] -3-oxo-1- (2,4 , 5-Trifluoro-benzyl) -propyl] -carbamic acid tert-butyl ester

(R)-[3- (5-Methanesulfonyl- [1,2,5] triasepan-1-yl) -3-oxo-1- (2,4,5-trifluoro-benzyl) -propyl ] -Carbamic acid tert-butyl ester (40 mg, 0.081 mmol) was dissolved in methylene chloride, then nicotinoyl chloride (43.2 mg, 0.242 mmol) and TEA (40 μl, 0.288 mmol) were added and stirred at room temperature for 2 hours. It was. Thereafter, the reaction mixture was washed with brine, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The concentrated solution under reduced pressure was separated by column chromatography (MeOH: EtOAc: hexane = 1: 4: 8), and the target compound (R)-[3- [5-methanesulfonyl-2- (pyridine-3-carbonyl)- [1,2,5] triazane-1-yl] -3-oxo-1- (2,4,5-trifluoro-benzyl) -propyl] -carbamic acid tert-butyl ester as a white solid ( 48.4 mg, 99%).

¹ H NMR (CDCl _3, 300 MHz) δ 8.99 (s, 1H), 8.50 to 8.48 (m, 1H), 8.15 to 8.12 (m, 1H), 7.46 to 7.38 (m, 1H), 7.32 to 7.28 (m, 1H), 6.80-6.68 (m, 1H), 4.30 (br, 1H), 4.12-4.00 (m, 1H), 3.77-3.20 (m, 6H), 3.01-2.94 (m, 4H), 2.61-2.40 ( m, 2H), 1.24 (s, 9H); EI-MS m / z (relative intensity) 599.62 (M).

(R) -3-amino-1- [5-methanesulfonyl-2- (pyridine-3-carbonyl)-[1,2,5] triazane-1-yl] -4- (2,4, Preparation of 5-trifluoro-phenyl) -butan-1-one-HCl

(R)-[3- [5-methanesulfonyl-2- (pyridine-3-carbonyl)-[1,2,5] triazane-1-yl] -3-oxo-1- (2,4 , 5-trifluoro-benzyl) -propyl] -carbamic acid tert-butyl ester (40 mg, 0.067 mmol) was dissolved in ethyl acetate, and then 4M HCl / 1,4-dioxane (500 µl, excess) was added thereto. Stir at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove ethyl acetate and excess 4M HCl / 1,4-dioxane and recrystallized with ether to give the desired compound (R) -3-amino-1- [5-methanesulfonyl- 2- (pyridine-3-carbonyl)-[1,2,5] triazane-1-yl] -4- (2,4,5-trifluoro-phenyl) -butan-1-one-HCl Obtained as a white solid (33 mg, 92%).

¹ H NMR (DMSO- d _3, 300 MHz) δ 9.14 (br, 1H), 8.90 to 8.77 (m, 1H), 8.50 to 8.47 (m, 1H), 8.32 (br, 3H), 7.77 to 7.72 (m, 1H), 7.69 to 7.52 (m, 2H), 4.01 to 3.39 (m, 9H), 3.29 to 3.03 (m, 9H), 3.02 to 2.83 (m, 4H); EI-MS m / z (relative intensity) 535.97 (M).

Preparation Example 7

(R)-{1- [3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5- Preparation of Il} -Acetic Acid Methyl Ester

(R) -3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl) -butyric acid (430 mg, 1.290 mmol) was dissolved in methylene chloride, and then 1-ethyl- 3- (3-dimethylaminopropyl) carbodiimide.HCl (495 mg, 2.580 mmol) and (1,2,5) triazane-5-yl-acetic acid methyl ester.2HCl (381 mg, 1.548 mmol) was added thereto. Triethylamine (1.80 ml, 12.901 mmol) was slowly added thereto under stirring at 0 ° C. and stirred at room temperature for 12 hours. Thereafter, the reaction mixture was washed with brine, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The concentrated solution under reduced pressure was separated by column chromatography (MeOH: EtOAc: hexane = 1: 4: 8) to obtain the target compound (R)-{1- [3-tert-butoxycarbonylamino-4- (2,4, 5-Trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5-yl} -acetic acid methyl ester was obtained as a white solid (225 mg, 36%).

¹ H NMR (CDCl _3, 300 MHz) δ 7.14 to 7.03 (m, 1H), 6.93 to 6.63 (m, 1H), 5.64 (br, 1H), 4.27 to 4.15 (m, 1H), 3.96 to 3.75 (m, 2H), 3.72 (s, 3H), 3.52 (s, 2H), 3.03 to 2.55 (m, 13H), 1.36 (s, 9H); EI-MS m / z (relative intensity) 488 (M ⁺ , 2), 388 (12), 155.9 (90), 115 (90), 59 (100).

(R)-{1- [3-Amino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5-yl} -acetic acid methyl ester Preparation of HCl

(R)-{1- [3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5- Japanese} -acetic acid methyl ester (20 mg, 0.041 mmol) was dissolved in ethyl acetate, 4M HCl / 1,4-dioxane (100 μl, excess) was added thereto, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove ethyl acetate and excess 4M HCl / 1,4-dioxane and recrystallized with ether to give the desired compound (R) -3 {1- [3-amino-4- (2). , 4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5-yl} acetic acid methyl ester.HCl as a white solid (16 mg, 92%).

¹ H NMR (DMSO- d _3, 300 MHz) δ 8.23 (brs, 3H), 7.62 to 7.51 (m, 2H), 4.32 (s, 2H), 3.86 to 3.26 (m, 11H), 3.00 to 2.63 (m, 6H); EI-MS m / z (relative intensity) 424.85 (M), 388 (1.8), 226 (10), 115 (50), 72 (64), 59 (100).

Preparation Example 8

(R)-{1-acetyl-2- [3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] tria Preparation of 5-enyl-5-yl} -acetic acid methyl ester

(R)-{1- [3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5- Japanese} -acetic acid methyl ester (60 mg, 0.123 mmol) was dissolved in methylene chloride, and then acetyl chloride (18 μl, 0.246 mmol) and TEA (56 μl, 0.368 mmol) were added and stirred at room temperature for 2 hours. Thereafter, the reaction mixture was washed with brine, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The concentrated liquid under reduced pressure was separated by column chromatography (EtOAc: hexane = 2: 1), and the target compound (R)-{1-acetyl-2- [3-tert-butoxycarbonylamino-4- (2,4, 5-Trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5-yl} -acetic acid methyl ester was obtained as a white solid (62.9 mg, 97%).

¹ H NMR (CDCl _3, 300 MHz) δ 7.11 to 7.02 (m, 1H), 6.94 to 6.85 (m, 1H), 5.41 (br, 1H), 4.39 to 4.31 (m, 2H), 4.18 to 4.00 (m, 1H), 3.72 (s, 3H), 3.48-3.45 (m, 2H), 3.20-2.93 (m, 6H), 2.80-2.49 (m, 4H), 2.01-1.94 (m, 3H), 1.36 (s, 9H); EI-MS m / z (relative intensity) 530.54 (M ⁺ , 1), 430 (3), 156 (36), 141 (46) 72 (60), 57 (100).

(R)-{1-acetyl-2- [3-amino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5-yl} Preparation of Acetic Acid Methyl Ester and HCl

(R)-{1-acetyl-2- [3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] tria Jepan-5-yl} -acetic acid methyl ester (10 mg, 0.019 mmol) was dissolved in ethyl acetate, 4M HCl / 1,4-dioxane (100 μl, excess) was added thereto, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove ethyl acetate and excess 4M HCl / 1,4-dioxane and recrystallized with ether to give the desired compound (R)-{1-acetyl-2- [3-amino-4 -(2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5-yl} acetic acid methyl esterHCl as a white solid (8 mg, 91% ).

¹ H NMR (DMSO- d _3, 300 MHz) δ 8.30 (br, 3H), 7.63 to 7.58 (m, 2H), 4.33 to 3.82 (m, 2H), 3.76 (s, 3H), 3.45 to 3.00 (m, 13H), 2.10-1.89 (m, 3H); EI-MS m / z (relative intensity) 466.88 (M), 430 (7) 156 (14), 72 (48), 59 (100).

Preparation Example 9

(R)-{1-acetyl-2- [3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] tria Preparation--5-yl} -acetic acid

(R)-{1-acetyl-2- [3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] tria Dissolve Gefan-5-yl} -acetic acid methyl ester (62 mg 0.117 mmol) in THF: MeOH = 1 ml: 0.5 ml, and dissolve LiOH.H ₂ O (10 mg, 0.234 mmol) in 0.5 ml of H ₂ O. It was added dropwise and stirred at room temperature for 3 hours. After the reaction was completed, the mixture was adjusted to 0 ° C., and slowly added dropwise with 1N-HCl, to about pH = 4. Washed with brine, extracted with methylene chloride, dried over NaSO ₄ , concentrated under reduced pressure, filtered, and the solid was washed with petroleum ether to afford the desired compound (R)-{1-acetyl-2- [3-tert-butoxycarbonyl Amino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5-yl} -acetic acid was obtained as a white solid (40.1 mg, 66%) .

¹ H NMR (CDCl _3, 300 MHz) δ 7.49 to 7.40 (m, 1H), 7.30 to 7.21 (m, 1H), 4.90 to 3.94 (m, 3H), 3.50 to 3.00 (m, 6H), 2.87 to 2.83 ( m, 4H), 2.62 to 2.52 (m, 4H), 1.95 (s, 2H), 1.37 (s, 9H); EI-MS m / z (relative intensity) 452.86 (M).

(R)-{1-acetyl-2- [3-amino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5-yl} Preparation of Acetic Acid and HCl

(R)-{1-acetyl-2- [3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] tria Jepan-5-yl} -acetic acid (32 mg, 0.062 mmol) was dissolved in ethyl acetate, 4M HCl / 1,4-dioxane (300 µl, excess) was added thereto, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove ethyl acetate and excess 4M HCl / 1,4-dioxane and recrystallized with ether to give the desired compound (R)-{1-acetyl-2- [3-amino-4 -(2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazpan-5-yl} -acetic acid.HCl was obtained as a white solid (27 mg, 97%).

¹ H NMR (DMSO- d _3, 300 MHz) δ 8.26 (brs, 3H), 7.57 to 7.35 (m, 2H), 4.71 to 4.26 (m, 2H), 4.94 to 2.83 (m, 14H), 2.18 to 1.91 ( m, 3H); EI-MS m / z (relative intensity) 452.86 (M).

Preparation Example 10

(R)-[3- [2- (2-Chloro-acetyl) -5-methanesulfonyl- [1,2,5] triazane-1-yl] -3-oxo-1- (2,4, Preparation of 5-trifluoro-benzyl) -propyl] -carbamic acid tert-butyl ester

(R)-[3- (5-Methanesulfonyl- [1,2,5] triasepan-1-yl) -3-oxo-1- (2,4,5-trifluoro-benzyl) -propyl ] -Carbamic acid tert-butyl ester (1.1 g, 2.224 mmol) was dissolved in methylene chloride, followed by addition of chloro acetyl chloride (531 μl, 6.673 mmol) and triethylamine (1.24 ml, 8.897 mmol) at room temperature for 3 hours. Stirred. Thereafter, the reaction mixture was washed with brine, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The concentrated solution under reduced pressure was separated by column chromatography (MeOH: EtOAc = 1: 12) to obtain the title compound (R)-[3- [2- (2-chloro-acetyl) -5-methanesulfonyl- [1,2, 5] triasepan-1-yl] -3-oxo-1- (2,4,5-trifluoro-benzyl) -propyl] -carbamic acid tert-butylester as a brown half oil (950 mg, 75 %).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.08 to 7.05 (m, 1H), 6.97 to 6.07 (m, 1H), 5.15 (br, 1H), 4.58 to 4.51 (m, 1H), 4.18 to 4.01 (m, 4H), 3.90-3.57 (m, 2H), 3.36-3.19 (m, 3H), 2.95-2.90 (m, 6H), 2.88-2.47 (m, 2H), 1.37 (s, 9H); EI-MS m / z (relative intensity) 571.2 (M ⁺ , 2), 471 (29), 369 (99), 259.9 (100).

(R) -3-amino-1- [2- (2-chloro-acetyl) -5-methanesulfonyl- [1,2,5] triazane-1-yl] -4- (2,4,5 Preparation of -trifluoro-phenyl) -butan-1-one-HCl

(R)-[3- [2- (2-Chloro-acetyl) -5-methanesulfonyl- [1,2,5] triazane-1-yl] -3-oxo-1- (2,4, 5-trifluoro-benzyl) -propyl] -carbamic acid tert-butyl ester (20 mg, 0.035 mmol) was dissolved in ethyl acetate, and then 4M HCl / 1,4-dioxane (200 µl, excess) was added to room temperature. Stirred for 12 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove ethyl acetate and excess 4M HCl / 1,4-dioxane, and then recrystallized with ether to give the desired compound (R) -3-amino-1- [2- (2- Chloro-acetyl) -5-methanesulfonyl- [1,2,5] triazane-1-yl] -4-(2,4,5-trifluoro-phenyl) -butan-1-one-HCl Obtained as a white solid (17 mg, 96%).

¹ H NMR (MeOH-d _4, 300 MHz) δ 7.36 to 7.33 (m, 1H), 7.27 to 7.22 (m, 1H), 4.47 to 4.21 (m, 4H), 3.85 to 3.54 (m, 2H), 3.52 ( s, 2H), 3.50-3.45 (m, 4H), 3.09-2.93 (m, 8H); EI-MS m / z (relative intensity) 507.36 (M).

Preparation Example 11

(R)-[3- [5-methanesulfonyl-2- (2-morpholin-4-yl-acetyl)-[1,2,5] triasepan-1-yl] -3-oxo-1- Preparation of (2,4,5-trifluoro-benzyl) -propyl] -carbamic acid tert-butyl ester

(R)-[3- [2- (2-Chloro-acetyl) -5-methanesulfonyl- [1,2,5] triazane-1-yl] -3-oxo-1- (2,4, 5-Trifluoro-benzyl) -propyl] -carbamic acid tert-butyl ester (30 mg, 0.053 mmol) was dissolved in THF, followed by morpholine (14 μL, 0.158 mmol), K ₂ CO ₃ (21.8 mg, 0.158). mmol) and KI (10 mg, 0.058 mmol) were added and stirred at room temperature for 1 hour. Thereafter, the reaction mixture was washed with brine, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The concentrated solution under reduced pressure was separated by column chromatography (EtOAc: MeOH = 12: 1), and the target compound (R)-[3- [5-methanesulfonyl-2- (2-morpholin-4-yl-acetyl)- [1,2,5] triazane-1-yl] -3-oxo-1- (2,4,5-trifluoro-benzyl) -propyl] -carbamic acid tert-butyl ester as a white solid ( 28 mg, 86%).

¹ H NMR (CDCl _3, 300 MHz) δ 7.11 to 7.02 (m, 1H), 6.97 to 6.07 (m, 1H), 5.25 (br, 1H), 4.25 to 4.00 (m, 2H), 3.75 to 3.71 (m, 5H), 3.58-3.24 (m, 6H), 3.20 (s, 2H), 3.04-2.87 (m, 5H), 2.66-2.48 (m, 6H), 1.37 (s, 9H); EI-MS m / z (relative intensity) 621.67 (M ⁺ , 0.04), 521 (0.05), 145 (60), 100 (100).

(R) -3-amino-1- [5-methanesulfonyl-2- (2-morpholin-4-yl-acetyl)-[1,2,5] triasepan-1-yl] -4- ( Preparation of 2,4,5-trifluoro-phenyl) -butan-1-oneHCl

(R)-[3- [5-methanesulfonyl-2- (2-morpholin-4-yl-acetyl)-[1,2,5] triasepan-1-yl] -3-oxo-1- (2,4,5-Trifluoro-benzyl) -propyl] -carbamic acid tert-butyl ester (20 mg, 0.032 mmol) was dissolved in ethyl acetate, and then 4M HCl / 1,4-dioxane (200 μl, excess) was added and stirred at room temperature for 12 hours. Thereafter, the reaction mixture was concentrated under reduced pressure to remove ethyl acetate and excess 4M HCl / 1,4-dioxane, and then recrystallized with ether to give the desired compound (R) -3-amino-1- [5-methanesulfonyl. -2- (2-Morpholin-4-yl-acetyl)-[1,2,5] triasepan-1-yl] -4- (2,4,5-trifluoro-phenyl) -butane-1 -ON-HCl was obtained as a white solid (18 mg, quantitative).

¹ H NMR (DMSO-d _6, 300 MHz) δ 8.45 (br, 3H), 7.68 to 7.56 (m, 2H), 4.98 to 4.62 (m, 3H), 4.33 to 3.82 (m, 7H), 3.64 to 3.39 ( m, 10H), 3.12-2.82 (m, 6H); EI-MS m / z (relative intensity) 521 (M ⁺ , 7), 376 (26), 127 (50), 100 (100).

Preparation Example 12

(R)-[3- {5-methanesulfonyl-2- [2- (thiazolo [5,4-b] pyridin-2-yl sulfanyl) -acetyl]-[1,2,5] triazane Preparation of -1-yl} -3-oxo-1- (2,4,5-trifluoro-benzyl) -propyl] -carbamic acid tert-butyl ester

(R)-[3- [2- (2-Chloro-acetyl) -5-methanesulfonyl- [1,2,5] triazane-1-yl] -3-oxo-1- (2,4, 5-Trifluoro-benzyl) -propyl] -carbamic acid tert-butyl ester (50 mg, 0.087 mmol) was dissolved in THF, followed by thiazolo [5,4-b] pyridine-2-thiol (17 mg, 0.1 mmol), K ₂ CO ₃ (42 mg, 0.3 mmol) and KI (15 mg, 0.087 mmol) were added and stirred at room temperature for 1 hour. Thereafter, the reaction mixture was washed with brine, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The concentrated solution under reduced pressure was separated by column chromatography (EtOAc: MeOH = 12: 1) to obtain the target product (R)-[3- {5-methanesulfonyl-2- [2- (thiazolo [5,4-b] Pyridin-2-yl sulfanyl) -acetyl]-[1,2,5] triasepan-1-yl} -3-oxo-1- (2,4,5-trifluoro-benzyl) -propyl]- Carbamic acid tert-butyl ester was obtained as a white solid (48 mg, 80%).

¹ H NMR (CDCl _3, 300 MHz) δ 8.45 (d, J = 4.5 Hz, 7.95 (m, 1H), 7.37 (m, 1H), 7.15-6.87 (m, 2H), 5.35 (br, 1H), 4.62 -2.70 (m, 18 H).

(R) -3-amino-1- {5-methanesulfonyl-2- [2- (thiazolo [5,4-b] pyridin-2-yl sulfanyl) -acetyl]-[1,2,5 ] Triazpan-1-yl} -4- (2,4,5-trifluoro-phenyl) -butan-1-one

(R)-[3- {5-methanesulfonyl-2- [2- (thiazolo [5,4-b] pyridin-2-yl sulfanyl) -acetyl]-[1,2,5] triazane -1-yl} -3-oxo-1- (2,4,5-trifluoro-benzyl) -propyl] -carbamic acid tert-butyl ester (23 mg, 0.032 mmol) in ethyl acetate, and then 4M. HCl / 1,4-dioxane (200 μl, excess) was added thereto and stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove ethyl acetate and excess 4M HCl / 1,4-dioxane, and then recrystallized with ether to give the desired compound (R) -3-amino-1- {5-methanesulfonyl. -2- [2- (thiazolo [5,4-b] pyridin-2-yl sulfanyl) -acetyl]-[1,2,5] triazane-1-yl} -4- (2,4, 5-Trifluoro-phenyl) -butan-1-one-HCl was obtained as a white solid (18 mg, quantitative).

¹ H NMR (DMSO-d _6, 300 MHz) δ 8.50 (m, 1H), 8.15-7.95 (m, 3H), 7.55-7.25 (m, 3H), 4.40-2.65 (m, 18H).

Preparation Example 13

(R) -1-Methyl-piperidin-4-one O- (2- {2- [3-amino-4- (2,4,5-trifluoro-phenyl) -butyryl] -5- Preparation of Methanesulfonyl- [1,2,5] triazane-1-yl} -2-oxo-ethyl) -oxime 2HCl

(R)-[3- {5-methanesulfonyl-2- [2- (1-methyl-piperidin-4-ylidene aminooxy) -acetyl]-[1,2,5] triazane-1 -Yl} -3-oxo-1- (2,4,5-trifluoro-benzyl) -propyl] -carbamic acid tert-butyl ester (8 mg, 0.012 mmol) in ethyl acetate, followed by 4M HCl / 1,4-dioxane (100 μl, excess) was added thereto and stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove ethyl acetate and excess 4M HCl / 1,4-dioxane and recrystallized with ether to afford the desired compound (R) -1-methyl-piperidin-4-one O-. (2- {2- [3-amino-4- (2,4,5-trifluoro-phenyl) -butyryl] -5-methanesulfonyl- [1,2,5] triazane-1-yl } -2-oxo-ethyl) -oxime.HCl was obtained as a white solid (7 mg, 97%).

¹ H NMR (DMSO-d _6, 300 MHz) δ 7.26 to 7.15 (m, 2H), 4.50 to 4.00 (m, 5H), 3.90 to 3.72 (m, 1H), 3.70 to 3.51 (m, 1H), 3.47 to 3.22 (m, 6H), 2.97 to 2.83 (m, 5H), 2.20 to 1.80 (m, 3H), 1.70 to 1.40 (m, 8H); EI-MS m / z (relative intensity) 635 (M).

Preparation Example 14

(R) -4- {1- [3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane- Preparation of 5-carbonyl} -benzoic acid

(R) -4- {1- [3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane- Dissolve 5-carbonyl} -benzoic acid methyl ester (90 mg, 0.156 mmol) in methylene chloride, add acetyl chloride (22 μl, 0.311 mmol) and TEA (65 μl, 0.467 mmol) and stir at room temperature for 36 hours. It was. Thereafter, the reaction mixture was washed with brine, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The concentrated solution under reduced pressure was separated by column chromatography (MeOH: EtOAc: hexane = 1: 4: 8), and the target compound (R) -4- {1-acetyl-2- [3-tert-butoxycarbonylamino-4 -(2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5-carbonyl} -benzoic acid methyl ester as a white solid (75 mg, 78% ).

^{_{1 H NMR (CDCl 3,,}} 300MHz) δ 8.12 ~ 8.04 (m, 2H), 7.53 ~ 7.43 (m, 2H), 7.12 ~ 7.03 (m, 1H), 6.93 ~ 6.91 (m, 1H), 5.25 (br , 1H), 4.59-4.40 (m, 1H), 4.38-4.29 (m, 1H), 4.26-4.13 (m, 1H), 4.11 (s, 3H), 3.95-3.42 (m, 4H), 3.01-2.94 (m, 3H), 2.64-2.49 (m, 2H), 2.30-1.98 (m, 3H), 1.37 (s, 9H); LC-MS m / z (relative intensity) 620 (M ⁺ ).

(R) -4- {1-acetyl-2- [3-amino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5- Production of carbonyl} -benzoic acid methyl ester, HCl

(R) -4- {1-acetyl-2- [3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5 ] Triazepan-5-carbonyl} -benzoic acid methyl ester (20 mg, 0.032 mmol) was dissolved in ethyl acetate, and then 4M HCl / 1,4-dioxane (200 µl, excess) was added for 12 hours at room temperature. Stirred. Thereafter, the reaction mixture was concentrated under reduced pressure to remove ethyl acetate and excess 4M HCl / 1,4-dioxane and recrystallized with ether to give the desired compound (R) -4- {1-acetyl-2- [3-amino. 4- (2,4,5-Trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5-carbonyl} -benzoic acid methyl esterHCl as a white solid (16 mg, 89%).

¹ H NMR (DMSO-d _6, 300 MHz) δ 8.08 (br, 3H), 7.95 (m, 2H), 7.50-7.47 (m, 4H), 4.21-4.09 (m, 2H), 3.81 (s, 3H) , 3.67-3.57 (m, 3H), 3.50 (s, 3H), 3.40-3.00 (m, 3H), 2.95-2.61 (m, 3H), 2.07-1.76 (m, 2H); LC-MS m / z relative intensity 521 (MH ⁺ ).

Preparation Example 15

(R) -4- {1-acetyl-2- [3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5 ] Triazane-5-carbonyl} -benzoic acid

(R) -4- {1-acetyl-2- [3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5 ] Triazepan-5-carbonyl} -benzoic acid methyl ester (50 mg, 0.081 mmol) was dissolved in THF (1 ml) and MeOH (1 ml), followed by LiOH.H ₂ O (1 ml) in water (1 ml). 7 mg, 0.161 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to remove THF and MeOH, cooled to 0 ° C., and slowly added dropwise 1N-HCl to pH = 4. Washed with brine, extracted with methylene chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, filtered and the solids were washed with ether to afford the desired compound (R) -4- {1-acetyl-2- [3-tert-butoxy Carbonylamino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5-carbonyl} -benzoic acid as a white solid (46.5 mg , 95%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.23 ~ 8.08 (m, 2H), 7.61 ~ 7.33 (m, 2H), 7.23 ~ 7.07 (m, 1H), 7.00 ~ 6.80 (m, 1H), 5.30 (br, 1H), 4.70 ~ 4.38 ( m, 2H), 3.90-3.38 (m, 7H), 3.03-2.64 (s, 3H), 2.80-2.26 (m, 4H), 1.38 (s, 9H); LC-MS m / z (relative intensity) 606 (M ⁺ ).

(R) -4- {1-acetyl-2- [3-amino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5- Production of carbonyl} -benzoic acid, HCl

(R) -4- {1-acetyl-2- [3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5 ] Triasepan-5-carbonyl} -benzoic acid (36 mg, 0.059 mmol) was dissolved in ethyl acetate, and then added 4M HCl / 1,4-dioxane (300 µl, excess) and stirred at room temperature for 12 hours. . Thereafter, the reaction mixture was concentrated under reduced pressure to remove ethyl acetate and excess 4M HCl / 1,4-dioxane and recrystallized with ether to give the desired compound (R) -4- {1-acetyl-2- [3-amino. 4- (2,4,5-Trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5-carbonyl} -benzoic acid-HCl as a white solid (30 mg, 93%).

¹ H NMR (DMSO-d _6, 300 MHz) δ 8.00-7.98 (m, 2H), 7.54-7.51 (m, 4H), 4.20-3.80 (m, 2H), 3.74-3.63 (m, 2H), 3.57 ( s, 3H), 3.41-3.30 (m, 5H), 3.17-2.78 (m, 3H), 2.08-1.84 (m, 2H); LC-MS m / z (relative intensity) 507 (MH ⁺ ).

Structures and NMR spectral data of representative examples of 1,2,5-triazane derivatives having a betaamino group of Formula 1, including a part of the 1,2,5-triazane derivatives obtained in Preparation Examples 1 to 15, are given in the following table 1 is shown. The 1,2,5-triazane derivatives shown in Table 1 below may be prepared by a method similar to Preparation Examples 1 to 15 described above.

TABLE 1

number Compound structure ^One H-NMR (DMSO- d _3, 300 MHz) δ One

7.96 (br, 3H), 7.55-7.52 (m, 3H), 7.50-7.35 (m, 4H), 5.07 (s, 2H), 3.70-3.65 (m, 4H), 3.56-3.42 (m, 3H), 2.94-2.93 (m, 2 H), 2.83-2.77 (m, 4 H). 2

δ 11.13 (br, 1H), 9.94, 9.08 (br, 1H), 8.00 (br, 2H), 7.37-7.34 (m, 2H), 4.61-4.35 (m, 1H), 4.17-4.14 (m, 1H) , 3.94-3.89 (m, 1H), 3.76-3.14 (m, 5H), 2.79-2.76 (m, 2H), 2.60-2.53 (m, 3H). 3

7.54 (m, 2H), 7.36-7.35 (m, 5H), 5.09 (s, 2H), 4.26-3.90 (m, 2H), 3.71-3.35 (m, 5H), 3.20-3.10 (m, 1H), 3.05-2.95 (m, 3H), 2.65-2.64 (m, 2H), 2.00 (s, 3H). 4

8.07 (brs, 3H), 7.54-7.46 (m, 2H), 4.01 (br, 1H), 3.63-3.62 (m, 2H), 3.37-3.29 (m, 4H), 3.00-2.93 (m, 4H), 2.90 (s, 3H), 2.88-2.78 (m, 2H) 5

 8.14 (br, 3H), 7.59 to 7.58 (m, 2H), 4.24 to 4.19 (m, 2H), 3.85 to 3.78 (m, 1H), 3.60 to 3.36 (m, 4H), 3.24 to 3.00 (m, 4H ), 2.99 (s, 3H), 2.97 to 2.76 (m, 1H), 2.23 to 1.93 (m, 4H) 6

9.14 (br, 1H), 8.90 to 8.77 (m, 1H), 8.50 to 8.47 (m, 1H), 8.32 (br, 3H), 7.77 to 7.72 (m, 1H), 7.69 to 7.52 (m, 2H), 4.01 to 3.39 (m, 9H), 3.29 to 3.03 (m, 9H), 3.02 to 2.83 (m, 4H) 7

8.23 (brs, 3H), 7.62 to 7.51 (m, 2H), 4.32 (s, 2H), 3.86 to 3.26 (m, 11H), 3.00 to 2.63 (m, 6H) 8

8.30 (br, 3H), 7.63 to 7.58 (m, 2H), 4.33 to 3.82 (m, 2H), 3.76 (s, 3H), 3.45 to 3.00 (m, 13H), 2.10 to 1.89 (m, 3H) 9

8.26 (brs, 3H), 7.57-7.35 (m, 2H), 4.71-4.26 (m, 2H), 4.94-2.83 (m, 14H), 2.18-1.91 (m, 3H) 10

7.36-7.33 (m, 1H), 7.27-7.22 (m, 1H), 4.47-4.21 (m, 4H), 3.85-3.54 (m, 2H), 3.52 (s, 2H), 3.50-3.45 (m, 4H ), 3.09 to 2.93 (m, 8H)

number Compound structure ^One H-NMR (DMSO- d _3, 300 MHz) δ 11

8.45 (br, 3H), 7.68 to 7.56 (m, 2H), 4.98 to 4.62 (m, 3H), 4.33 to 3.82 (m, 7H), 3.64 to 3.39 (m, 10H), 3.12 to 2.82 (m, 6H ) 12

 8.50 (m, 1 H), 8.15-7.95 (m, 3 H), 7.55-7.25 (m, 3 H), 4.40-2.65 (m, 18 H). 13

7.26 to 7.15 (m, 2H), 4.50 to 4.00 (m, 5H), 3.90 to 3.72 (m, 1H), 3.70 to 3.51 (m, 1H), 3.47 to 3.22 (m, 6H), 2.97 to 2.83 (m , 5H), 2.20-1.80 (m, 3H), 1.70-1.40 (m, 8H) 14

8.08 (br, 3H), 7.95 (m, 2H), 7.50-7.47 (m, 4H), 4.21-4.09 (m, 2H), 3.81 (s, 3H), 3.67-3.57 (m, 3H), 3.50 ( s, 3H), 3.40-3.00 (m, 3H), 2.95-2.61 (m, 3H), 2.07-1.76 (m, 2H) 15

8.00 ~ 7.98 (m, 2H), 7.54 ~ 7.51 (m, 4H), 4.20 ~ 3.80 (m, 2H), 3.74 ~ 3.63 (m, 2H), 3.57 (s, 3H), 3.41 ~ 3.30 (m, 5H ), 3.17-2.78 (m, 3H), 2.08-1.84 (m, 2H) 16

7.55-7.52 (m, 2H), 4.31-4.27 (m, 2H), 3.75-3.71 (m, 1H), 3.32-3.15 (m, 7H), 2.99-2.93 (m, 2H), 2.85-2.66 (m , 1H), 1.97 (s, 3H). 17

8.15-8.03 (brs, 3H), 7.42-7.02 (m, 12H), 4.91 (s, 2H), 4.38-4.15 (m, 1H), 3.93-3.21 (m, 8H), 3.08-3.06 (m, 2H ), 3.01-2.90 (m, 2H). 18

7.53-7.40 (m, 5H), 7.32-7.29 (m, 2H), 4.50-4.40 (m, 1H), 3.80-3.70 (m, 2H), 3.31-3.20 (m, 7H), 3.04-2.97 (m , 3H). 19

 8.91 to 8.60 (m, 2H), 8.34 (s, 1H), 8.14 (br, 3H), 7.62 to 7.43 (m, 3H), 4.71 to 3.36 (m, 14H), 2.97 to 2.40 (m, 4H) 20

 8.09 (brs, 3H), 7.54-7.49 (m, 2H), 3.78-3.35 (m, 8H), 2.98-2.92 (m, 4H), 2.81-2.79 (m, 2H)

number Compound structure ^One H-NMR (DMSO- d _3, 300 MHz) δ 21

8.14 (brs, 3H), 7.66 to 7.38 (m, 2H), 4.51 to 3.87 (m, 3H), 3.55 to 3.34 (m, 5H), 3.15 to 3.08 (m, 3H), 2.88 to 2.75 (m, 2H ), 2.21-2.02 (m, 3H) 22

9.10 to 8.75 (m, 2H), 8.55 to 8.30 (m, 3H), 8.06 to 8.00 (m, 2H), 7.43 to 7.71 (m, 2H), 4.83 to 4.75 (m, 1H), 4.65 to 4.40 (m , 1H), 4.30 to 3.57 (m, 6H), 3.56 to 3.20 (m, 3H), 3.10 to 2.50 (m, 4H) 23

8.56 (s, 1H), 7.81 (br, 1H), 7.27-7.18 (m, 1H), 7.15-7.06 (m, 1H), 4.11-3.86 (m, 6H), 3.69-3.63 (m, 2H), 2.99 to 2.94 (m, 6H), 2.78 to 2.72 (m, 2H) 24

8.29 (br, 3H), 7.57 to 7.43 (m, 2H), 4.39 to 3.63 (m, 4H), 3.54 to 3.27 (m, 10H), 3.09 to 2.80 (m, 9H), 2.40 to 1.58 (m, 5H ) 25

8.39 (br, 2H), 8.28 (brs, 1H), 7.61-7.53 (m, 2H), 4.24-4.08 (m, 5H), 3.70-3.37 (m, 15H), 3.12-2.96 (m, 9H), 2.89-2.80 (m, 5H) 26

8.45 (br, 2H), 8.34 (br, 1H), 7.26 to 7.56 (m, 2H), 4.60 to 4.21 (m, 3H), 4.00 to 3.70 (m, 2H), 3.57 to 3.37 (m, 5H), 3.24 to 2.97 (m, 10H), 2.09 to 1.91 (m, 6H) 27

8.45 (br, 3H), 7.65 to 7.60 (m, 2H), 4.31 to 4.00 (m, 3H), 3.85 to 3.78 (m, 2H), 3.64 to 3.40 (m, 6H), 3.18 to 3.04 (m, 8H ), 2.85-2.78 (m, 4H) 28

8.45 (br, 2H), 8.29 (br, 1H), 7.65-7.53 (m, 2H), 4.53-4.21 (m, 3H), 3.56-3.42 (m, 3H), 3.40-3.36 (m, 10H), 3.27 to 2.85 (m, 9H) 29

8.43-8.27 (m, 3H), 7.61-7.54 (m, 2H), 4.59-4.22 (m, 4H), 3.60-3.30 (m, 13H), 3.00-2.80 (m, 7H) 30

8.45 (br, 2H), 8.32 (br, 1H), 7.63-7.53 (m, 2H), 4.37-4.24 (m, 2H), 4.20-4.00 (m, 2H), 3.75 (s, 3H), 3.56- 3.16 (m, 8H), 3.05 to 2.97 (m, 6H), 2.20 to 2.10 (m, 1H), 2.09 to 1.91 (m, 5H)

number Compound structure ^One H-NMR (DMSO- d _3, 300 MHz) δ 31

8.43 (br, 2H), 8.33 (br, 1H), 7.65-7.55 (m, 1H), 4.29-4.22 (m, 3H), 3.76-3.63 (m, 6H), 3.51 (s, 2H), 3.48- 3.41 (m, 2H), 3.39 to 3.27 (m, 8H), 3.25 to 2.94 (m, 4H), 2.70 to 2.58 (m, 1H), 2.08 to 2.02 (m, 2H) 32

7.34 to 7.30 (m, 1H), 7.14 (m, 1H), 4.52 to 4.34 (m, 3H), 4.10 to 3.84 (m, 4H), 3.74 to 3.03 (m, 12H), 2.89 to 2.75 (m, 5H ), 2.41 to 1.90 (m, 4H) 33

7.32 (m, 1H), 7.15 (m, 1H), 4.40-3.78 (m, 6H), 3.65-3.40 (m, 8H), 3.20-2.95 (m, 6H), 2.89-2.85 (m, 4H), 2.70 ~ 2.60 (m, 2H), 2.12 ~ 1.89 (m, 4H) 34

8.20-8.10 (m, 3H), 7.80-7.30 (m, 6H), 4.50-2.80 (m, 18H) 35

8.11 (m, 3H), 7.6-7.50 (m, 2H), 4.55-2.66 (m, 21H) 36

8.06 (br, 3H), 7.93 (m, 2H), 7.47-7.45 (m, 4H), 3.81 (s, 3H), 3.70-3.33 (m, 7H), 3.30-3.28 (m, 2H), 3.15- 2.66 (m, 5H) 37

8.85 (br, 3H), 7.96-7.80 (m, 2H), 7.52-7.47 (m, 4H), 4.20-3.56 (m, 10H), 3.39-3.36 (m, 2H), 2.94-2.72 (m, 3H ) 38

8.22 (br, 3H), 7.70 ~ 7.64 (m, 2H), 5.98 (br, 1H), 4.41 ~ 4.36 (m, 3H), 3.85 ~ 3.63 (m, 4H), 3.30 ~ 2.92 (m, 7H), 1.38 (t, J = 7.2 Hz, 3H) 39

8.04 (br, 3H), 7.57 to 7.49 (m, 2H), 5.42 (br, 1H), 3.70 to 3.20 (m, 5H), 3.00 to 2.59 (m, 9H) 40

8.20 (br, 3H), 7.60-7.53 (m, 2H), 4.40-4.29 (m, 4H), 3.77-3.61 (m, 5H), 2.97-2.95 (m, 4H), 2.80-2.49 (m, 2H ), 2.03-1.91 (m, 3H)

The molecular structures of the 1,2,5-triazane derivatives shown in Preparation Examples 1 to 15 and Table 1 were confirmed by nuclear magnetic resonance spectra and mass spectrometry.

Formulation Example 1  : Preparation of Syrup

A syrup containing a 1,2,5-triazane derivative having a betaamino group of the present invention or a salt thereof as an active ingredient of 2% (weight / volume) was prepared by the following method.

Acid addition salts, sugars, and saccharin of 1,2,5-triazane derivatives having betaamino groups were dissolved in 80 g of warm water, and the solution was cooled. Then, a solution consisting of glycerin, saccharin, spices, sorbic acid, and water was prepared. Put in a bottle. Water was added to this mixture to make 100 mL. The addition salt may be replaced with another salt according to the above embodiment. The components and contents of the present syrup are shown in Table 2 below.

TABLE 2

Composition content (R) -4- {1-acetyl-2- [3-amino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5- Carbonyl} -benzoic acid, HCl 2 g saccharin 0.8 g Party 25.4 g glycerin 8.0 g Spice 0.04 g ethanol 4.0 g Sorbic acid 0.4 g Distilled water dose

Formulation Example 2  : Preparation of Tablet

A tablet containing 15 mg of the active ingredient was prepared by the following method.

(R) -4- {1-acetyl-2- [3-amino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5- 250 g of carbonyl} -benzoic acid and HCl were mixed with 175.9 g of lactose, 180 g of potato starch and 32 g of colloidal silicic acid. 10% gelatin solution was added to the mixture, which was then ground and passed through a 14 mesh sieve. It was dried and tablets were obtained by adding 160 g potato starch, 50 g talc and 5 g magnesium stearate to it. The components and contents of the tablets are shown in Table 3 below.

TABLE 3

Composition content (R) -4- {1-acetyl-2- [3-amino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5- Carbonyl} -benzoic acid, HCl 250 g Lactose 175.9 g Potato starch 180 g Colloidal silicic acid 32 g 10% gelatin solution Potato starch 160 g talc 50 g Magnesium Stearate 5 g

Formulation Example 3  : Preparation of Injection Solution

Injection solution containing 10 mg of the active ingredient was prepared by the following method.

(R) -4- {1-acetyl-2- [3-amino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5- 1 g of carbonyl} -benzoic acid, HCl, 0.6 g of sodium chloride and 0.1 g of ascorbic acid were dissolved in distilled water to make 100 ml. The solution was placed in a bottle and sterilized by heating at 20 ° C for 30 minutes. The components and contents of the injection solution are shown in Table 4 below.

TABLE 4

Composition content (R) -4- {1-acetyl-2- [3-amino-4- (2,4,5-trifluoro-phenyl) -butyryl]-[1,2,5] triazane-5- Carbonyl} -benzoic acid, HCl 1 g Sodium chloride 0.6 g Ascorbic acid 0.1 g Distilled water dose

In addition, pharmacological activity was searched to confirm that the compounds represented by the general formula (1) of the present invention showed excellent effects as inhibitors of DPP-IV action.

Test Example: Example of Pharmacological Activity Search

The inhibitory activity of DPP-IV was tested for the compound of Preparation Example 15 and its pharmaceutically acceptable acid addition salts as follows.

The inhibitory activity of DPP-IV was tested by measuring the inhibitory activity of test compounds on DPP-IV activity using extract of human colon carcinoma cell line (Caco-2) as an enzyme source. Human colon carcinoma cell lines were obtained from ATCC (American Type Culture Collection) and cultured for about 20 days. As a cell extract, 1 ml of lysate (10 mM Tris, 0.15 M NaCl, 1% TritonX 100, 10% glycerol) was added to the cultured cells, followed by centrifugation at 12,000 rpm for 10 minutes at 4 ° C. . DPP-IV inhibitory activity using Caco-2 cell lysate as enzyme source was measured in 96-well using 20 μl of Caco-2 cell lysate, 10 μl of test compound and 150 μl of incubation buffer (50 mM Tris-HCl, pH 7.5). It was added to the microtiter plate and 20 μl of Ala-Pro-AFC (final concentration 40 μM) was added and incubated at room temperature for 60 minutes before measurement. As in the above assay, the DPP-IV inhibitory effect of the test compound was calculated as an IC ₅₀ value and is shown in Table 5 below.

TABLE 5

compound Caco-2 DPP-IV Example 15 216 nM

As a result, it was confirmed that the compound of Preparation Example 15 and its pharmaceutically acceptable acid addition salts had DPP-IV inhibitory activity.

As such, the compound of Preparation Example 15 and its pharmaceutically acceptable acid addition salts thereof have inhibitory activity of DPP-IV, so insulin-dependent diabetes mellitus (type 1 diabetes), insulin-independent diabetes mellitus (type 2 diabetes), and immune related diseases It has been found that it can be used as a therapeutic agent. Typically, inhibition of DPP-IV in vivo results in an increase in blood concentrations of glucagon-like peptides (GLP-1, GLP-2), which stimulates insulin secretion from beta cells of the pancreas and suppresses glucagon secretion from alpha cells. It is effective in inducing and treating diabetes.

As a result of the above test, the 1,2,5-triazane derivative having a betaamino group represented by the formula (1) and its pharmaceutically acceptable salts show excellent DPP-IV inhibitory activity, and therefore, by DPP-IV It has been found that it can be effectively used for the treatment or prevention of mediated diseases.

According to the present invention, novel 1,2,5-triazane derivatives and pharmaceutically acceptable salts thereof that exhibit excellent DPP-IV inhibitory activity can be provided. Thus, these novel 1,2,5-triazane derivatives and the like are used to treat diseases mediated by DPP-IV, such as insulin dependent, insulin independent diabetes, arthritis, obesity, osteoporosis and impaired glucose tolerance. It can be effectively used for treatment or prevention.

In addition, according to the present invention, a method for preparing the novel 1,2,5-triazane derivative, a pharmaceutical composition comprising the same, a method for inhibiting DPP-IV using the same, and a method for treating a disease mediated by DPP-IV This may be provided.

Claims (17)

A 1,2,5-triazane derivative having a betaamino group represented by Formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1]

Where R ₁ is

or

ego; R ₂ is hydrogen, C _1-6 alkyl, or

ego; R ₃ is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl,

,

, CH ₂ CO ₂ R ^b , COCO ₂ R ^b , pyrazine or

ego; R ^a may be one or more and each independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, OCF ₃ , halogen, CN, CF _3, COOR ^b or NR ^b R ^c ; R ^b and Each R ^c is independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl; R ^d is C _1-6 alkyl, trifluoromethyl,

,

,

or

ego; R ^e is C _1-6 alkyl, C _3-6 cycloalkyl,

or

ego; R ^f is hydrogen, halogen, NR ^b R ^c ,

,

,

,

, Tetrazole or proline; A is CH, N, O or S; B is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, benzyl or CO ₂ R ^d ; X is O or S; n is an integer of 0 or 1. The method of claim 1, R ₁ is

ego; R ^g may be one or more, each independently a 1,2,5-triazane derivative or hydrogen, C _1-6 alkyl, C _1-6 alkoxy, OCF ₃ , halogen, CN or CF ₃ Pharmaceutically acceptable salts. The method of claim 2, R ^g is 1,2,5-triazane derivative or pharmaceutically acceptable salt thereof, wherein one or more halogen. The method of claim 3, wherein R ₂ is

or

Phosphorus 1,2,5-triazane derivatives or pharmaceutically acceptable salts thereof. The method of claim 4, wherein R ₂ is

,

,

or

ego; R ^f is hydrogen, chlorine,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

Phosphorus 1,2,5-triazane derivatives or pharmaceutically acceptable salts thereof. The 1,2,5-triazepane derivative according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the steric center to which the amino group and R ₁ are bonded is the R configuration. The 1,2 according to any one of claims 1 to 5, wherein hydrochloride, sulfate, acetate, trifluoroacetate, phosphate, fumarate, maleate, citrate, methane sulfonate or lactate are added. , 5-triazane derivative or a pharmaceutically acceptable salt thereof. A condensation reaction of an amino acid of Formula 2 with 1,2,5-triazane of Formula 3 to produce a compound of Formula 4; Reacting an electrophilic compound substituted with R ₂ with a compound of Formula 4 to produce a compound of Formula 5; And Method for preparing a 1,2,5-triazane derivative of formula (I) comprising the step of deprotecting a compound of formula (5): Scheme 1

Where BOC represents a protecting group; R ₁ is

or

ego; R ₂ is hydrogen, C _1-6 alkyl,

or

ego; R ₃ is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl,

,

, CH ₂ CO ₂ R ^b , COCO ₂ R ^b , pyrazine or

ego; R ^a may be one or more and each independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, OCF ₃ , halogen, CN, CF _3, COOR ^b or NR ^b R ^c ; R ^b and Each R ^c is independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl; R ^d is C _1-6 alkyl, trifluoromethyl,

,

,

or

ego; R ^e is C _1-6 alkyl, C _3-6 cycloalkyl,

or

ego; R ^f is hydrogen, halogen, NR ^b R ^c ,

,

,

,

, Tetrazole or proline; A is CH, N, O or S; B is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, benzyl or CO ₂ R ^d ; X is O or S; n is an integer of 0 or 1. Reacting a compound of Formula 4 with chloroacetyl chloride to produce a compound of Formula 6; Reacting a compound of Formula 6 with a nucleophile compound substituted with R ₂ to produce a compound of Formula 5; And Method for preparing a cyclized 1,2,5-triazane derivative of formula (I) comprising the step of deprotecting a compound of formula (5): Scheme 2

Where BOC represents a protecting group; R ₁ is

or

ego; R ₂ is hydrogen, C _1-6 alkyl,

or

ego; R ₃ is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl,

,

, CH ₂ CO ₂ R ^b , COCO ₂ R ^b , pyrazine or

ego; R ^a may be one or more and each independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, OCF ₃ , halogen, CN, CF _3, COOR ^b or NR ^b R ^c ; R ^b and Each R ^c is independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl; R ^d is C _1-6 alkyl, trifluoromethyl,

,

,

or

ego; R ^e is C _1-6 alkyl, C _3-6 cycloalkyl,

or

ego; R ^f is hydrogen, halogen, NR ^b R ^c ,

,

,

,

, Tetrazole or proline; A is CH, N, O or S; B is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, benzyl or CO ₂ R ^d ; X is O or S; n is an integer of 0 or 1. A condensation reaction of an amino acid of Formula 2 with a compound of Formula 7 to produce a compound of Formula 5; And Method for preparing a 1,2,5-triazane derivative of formula (I) comprising the step of deprotecting a compound of formula (5): Scheme 3

Where BOC represents a protecting group; R ₁ is

or

ego; R ₂ is hydrogen, C _1-6 alkyl,

or

ego; R ₃ is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl,

,

, CH ₂ CO ₂ R ^b , COCO ₂ R ^b , pyrazine or

ego; R ^a may be one or more and each independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, OCF ₃ , halogen, CN, CF _3, COOR ^b or NR ^b R ^c ; R ^b and Each R ^c is independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl; R ^d is C _1-6 alkyl, trifluoromethyl,

,

,

or

ego; R ^e is C _1-6 alkyl, C _3-6 cycloalkyl,

or

ego; R ^f is hydrogen, halogen, NR ^b R ^c ,

,

,

,

, Tetrazole or proline; A is CH, N, O or S; B is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, benzyl or CO ₂ R ^d ; X is O or S; n is an integer of 0 or 1. The method of claim 10, wherein the compound of Chemical Formula 4 is produced by condensation reaction of an amino acid of Chemical Formula 2 with 1,2,5-triazane of Chemical Formula 3. Scheme 5

A pharmaceutical composition comprising an effective amount of a 1,2,5-triazane derivative according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 12, which is used for the treatment or prevention of a disease mediated by DPP-IV. The pharmaceutical composition of claim 13, wherein the disease mediated by DPP-IV is insulin dependent diabetes mellitus, insulin independent diabetes mellitus, arthritis, obesity, osteoporosis or impaired glucose tolerance. A method of inhibiting DPP-IV comprising administering to a subject mammal a therapeutically effective amount of a 1,2,5-triazepane derivative according to claim 1 or a pharmaceutically acceptable salt thereof. A method for treating a disease mediated by DPP-IV comprising administering to a subject mammal a therapeutically effective amount of a 1,2,5-triazane derivative according to claim 1 or a pharmaceutically acceptable salt thereof. The method of claim 16, wherein the disease mediated by DPP-IV is insulin dependent diabetes mellitus, insulin independent diabetes mellitus, arthritis, obesity, osteoporosis or impaired glucose tolerance.