KR20230001208A - Acyclic nucleic acid mimetics containing five-membered heterocyclic base - Google Patents

Abstract

The present invention relates to a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof, which, by inhibiting the replication of an RNA virus by being integrated as a nucleotide derivative into a polymerase of the RNA virus and inducing inhibitory activity, suppresses the proliferation of influenza A, influenza B, dengue virus, West Nile virus, HIV, and the like, and thus can be used as a novel and effective anti-viral agent.

Description

Acyclic nucleic acid mimetics containing five-membered heterocyclic base}

The present invention relates to an acyclic nucleic acid mimetic containing a pentagonal base, and more particularly, to a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In the above formula,

L is substituted or unsubstituted nitrogen (N), substituted or unsubstituted oxygen (O), substituted or unsubstituted carbon (C), substituted or unsubstituted sulfur (S), substituted or unsubstituted boron (B ), substituted or unsubstituted phosphorus (P), substituted or unsubstituted selenium (Se), and substituted or unsubstituted silicon (Si).

R ₁ is a hydrogen atom, a halo group, a carboxyl group, a haloformyl group, a hydroxyl group, a carbonyl group, an aldehyde group, a carboxylic acid ester group, a carboxyl group, an ether group, an ester group, an amide group, a hydroxyamide group, or a hydroxyalkylamide. group, an amine group, a nitric acid group, a nitrile group, a nitro group, a phosphine group, a phosphoric acid group, a sulfone group, and a sulfonic acid group, and

n ₁ and n ₂ are each an integer from 0 to 5;

는 이중 결합 또는 단일 결합이고,

is a double bond or a single bond,

X, Y, Z are -CH- or -N-, respectively.)

RNA viruses whose genetic information is composed of ribonucleic acid (RNA) include Ebola virus, human immunodeficiency (HIV) virus, severe acute respiratory syndrome (SARS-CoV) virus, hepatitis C virus, and dengue virus.

The RNA virus is more than 1,000 times more likely to mutate than DNA viruses in the process of replicating genetic information for virus propagation after penetrating into the body, so vaccines and new drugs are more likely to occur than bacteria or DNA viruses. There is no situation.

Antiviral drugs used as drugs for the treatment of conventional RNA virus infections include Ribavirin, which is used for the treatment of hepatitis C, SARS, and Ebola virus infections, and Remedesivir, which is used for the treatment of Ebola virus and coronavirus. ), and acyclovir, which is used to treat herpes virus.

The above-mentioned conventional antiviral agents are used as antiviral therapeutics because they are similar to nucleotides to be integrated into DNA strands, but they affect not only viral polymerase but also mitochondrial DNA, resulting in side effects such as bone marrow suppression, and new drug resistance due to drug resistance. There is a problem that makes treatment using existing antiviral agents difficult due to the appearance of mutations. Therefore, there is a demand for development of pharmaceutical compositions effective against RNA viruses.

Focusing on the fact that most of the conventional nucleic acid mimics maintain the basic skeleton of purine and pyrimidine bases, the present inventors have developed a rare structure of acyclic nucleic acid mimetic compounds containing pentagonal bases that have not been studied in Korea. was devised, and a total of 61 derivatives were synthesized, and the acyclic nucleic acid derivative compound confirmed the inhibitory effect on RNA viruses such as dengue virus, influenza A and B viruses, West Nile virus, and HIV, and completed the present invention. did

Republic of Korea Patent No. 10-1681559

One object of the present invention is to provide a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In the above formula,

L is substituted or unsubstituted nitrogen (N), substituted or unsubstituted oxygen (O), substituted or unsubstituted carbon (C), substituted or unsubstituted sulfur (S), substituted or unsubstituted boron (B ), substituted or unsubstituted phosphorus (P), substituted or unsubstituted selenium (Se), and substituted or unsubstituted silicon (Si).

R ₁ is a hydrogen atom, a halo group, a carboxyl group, a haloformyl group, a hydroxyl group, a carbonyl group, an aldehyde group, a carboxylic acid ester group, a carboxyl group, an ether group, an ester group, an amide group, a hydroxyamide group, or a hydroxyalkylamide. group, an amine group, a nitric acid group, a nitrile group, a nitro group, a phosphine group, a phosphoric acid group, a sulfone group, and a sulfonic acid group, and

n ₁ and n ₂ are each an integer from 0 to 5;

는 이중 결합 또는 단일 결합이고,

is a double bond or a single bond,

X, Y, Z are -CH- or -N-, respectively.)

Another object of the present invention is to provide a method for preparing the above compound.

In order to achieve the above purpose,

The present invention provides a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In the above formula,

L is substituted or unsubstituted nitrogen (N), substituted or unsubstituted oxygen (O), substituted or unsubstituted carbon (C), substituted or unsubstituted sulfur (S), substituted or unsubstituted boron (B ), substituted or unsubstituted phosphorus (P), substituted or unsubstituted selenium (Se), and substituted or unsubstituted silicon (Si).

R ₁ is a hydrogen atom, a halo group, a carboxyl group, a haloformyl group, a hydroxyl group, a carbonyl group, an aldehyde group, a carboxylic acid ester group, a carboxyl group, an ether group, an ester group, an amide group, a hydroxyamide group, or a hydroxyalkylamide. group, an amine group, a nitric acid group, a nitrile group, a nitro group, a phosphine group, a phosphoric acid group, a sulfone group, and a sulfonic acid group, and

n ₁ and n ₂ are each an integer from 0 to 5;

는 이중 결합 또는 단일 결합이고,

is a double bond or a single bond,

X, Y, Z are -CH- or -N-, respectively.)

In addition, the present invention provides a method for preparing the compound.

The acyclic nucleic acid mimetic containing the pentagonal base of the present invention is integrated into RNA virus polymerase as a nucleotide derivative and induces inhibitory activity to inhibit RNA virus replication, thereby inhibiting influenza A, B, dengue virus, and West Nile virus , It can be used as an effective and new antiviral agent as it can confirm the proliferation inhibitory effect against HIV and the like.

Hereinafter, the present invention will be described in detail.

One aspect of the present invention provides a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In the above formula,

L is substituted or unsubstituted nitrogen (N), substituted or unsubstituted oxygen (O), substituted or unsubstituted carbon (C), substituted or unsubstituted sulfur (S), substituted or unsubstituted boron (B ), substituted or unsubstituted phosphorus (P), substituted or unsubstituted selenium (Se), and substituted or unsubstituted silicon (Si).

R ₁ is a hydrogen atom, a halo group, a carboxyl group, a haloformyl group, a hydroxyl group, a carbonyl group, an aldehyde group, a carboxylic acid ester group, a carboxyl group, an ether group, an ester group, an amide group, a hydroxyamide group, or a hydroxyalkylamide. group, an amine group, a nitric acid group, a nitrile group, a nitro group, a phosphine group, a phosphoric acid group, a sulfone group, and a sulfonic acid group, and

n ₁ and n ₂ are each an integer from 0 to 5;

는 이중 결합 또는 단일 결합이고,

is a double bond or a single bond,

X, Y, Z are -CH- or -N-, respectively.)

In one embodiment of the present invention, L is one selected from substituted or unsubstituted nitrogen (N), substituted or unsubstituted oxygen (O), and substituted or unsubstituted carbon (C), wherein R ₁ is one selected from a carbonyl group, an ester group, an ether group, an ester group, an amide group, a hydroxyamide group, and a hydroxyalkylamide group, and n ₁ and n ₂ may each be an integer of 0 to 3.

In one embodiment of the present invention, L is one of -O-, -NR ₂ -, -CH- and -CH ₂ -,

,

,

및

로부터 선택되는 1 종이고, 상기 R₂는 수소(H), tert-부톡시카보닐기(tert-butoxycarbonyl, BOC) 및 아세틸기(Acetyl, AC)로부터 선택되는 1 종일 수 있다. The R ₁ is

,

,

and

, and R ₂ may be one selected from hydrogen (H), a tert-butoxycarbonyl group (BOC), and an acetyl group (Acetyl, AC).

In addition, the compound represented by Formula 1 may be one selected from the group consisting of the following compounds.

1) 1-(2-(2-hydroxyethoxy)ethyl-1H-imidazole-4-carboxamide (1-(2-(2-Hydroxyethoxy)ethyl)-1H-imidazole-4-carboxamide);

2) methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-carboxylate (methyl 1-(2-(2-hydroxyethoxy)ethyl)- 1H-1,2,3-triazole-4-carboxylate);

3) N-hydroxy-1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-carboxamide (N-hydroxy-1-(2-( 2-hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-carboxamide);

4) 1-(2-(2-hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxamide (1-(2- (2-hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxamide);

5) 1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-carboxamide (1-(2-(2-hydroxyethoxy)ethyl)-1H- 1,2,3-triazole-4-carboxamide);

6) Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-3-carboxylate (methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-3- carboxylate);

7) 1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-3-carboxamide (1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-3-carboxamide) ;

8) (Z)-methyl 1-(4-hydroxybut-2-enyl)-1H-pyrazole-4-carboxylate ((Z)-methyl 1-(4-hydroxybut-2-enyl)-1H -pyrazole-4-carboxylate);

9) (Z)-1-(4-hydroxybut-2-enyl)-1H-pyrazole-4-carboxamide ((Z)-1-(4-hydroxybut-2-enyl)-1H-pyrazole -4-carboxamide);

10) Methyl (Z)-1-(4-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl)-1H-pyrazole-3-carboxylate (Methyl (Z)- 1-(4-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl)-1H-pyrazole-3-carboxylate);

11) (Z)-1-(4-Hydroxybut-2-enyl)-1H-pyrazole-3-carboxamide ((Z)-1-(4-Hydroxybut-2-en-1-yl) -1H-pyrazole-3-carboxamide);

12) (Z)-N-hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-pyrazole-3-carboxamide ((Z)-N-Hydroxy-1- (4-hydroxybut-2-en-1-yl)-1H-pyrazole-3-carboxamide);

13) (Z)-1-(4-hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide ((Z)-1 -(4-Hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide);

14) Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,4-triazole-3-carboxylate (Methyl 1-(2-(2-hydroxyethoxy)ethyl)- 1H-1,2,4-triazole-3-carboxylate);

15) Methyl (Z)-1-(4-hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxylate (Methyl (Z)-1-( 4-hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxylate);

16) (Z)-1-(4-hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxamide ((Z)-1-(4- Hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxamide);

17) (Z)-N-hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxamide ((Z)- N-Hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxamide);

18) Methyl (Z)-1-(4-hydroxybut-2-en-1-yl)-1H-imidazole-4-carboxylate (Methyl (Z)-1-(4-hydroxybut-2- en-1-yl)-1H-imidazole-4-carboxylate);

19) (Z)-1-(4-Hydroxybut-2-en-1-yl)-1H-imidazole-4-carboxamide ((Z)-1-(4-Hydroxybut-2-en- 1-yl)-1H-imidazole-4-carboxamide);

20) (Z)-N-hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-imidazole-4-carboxamide ((Z)-N-Hydroxy-1- (4-hydroxybut-2-en-1-yl)-1H-imidazole-4-carboxamide);

21) 1-(2-(2-hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-carboxamide (1-(2- (2-Hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-carboxamide);

22) Methyl 1-(6-hydroxyhexyl)-1H-1,2,4-triazole-3-carboxylate (Methyl 1-(6-hydroxyhexyl)-1H-1,2,4-triazole-3 -carboxylate);

23) N-(2-hydroxyethyl)-1-(5-hydroxypentyl)-1H-1,2,4-triazole-3-carboxamide (N-(2-Hydroxyethyl)-1-( 5-hydroxypentyl)-1H-1,2,4-triazole-3-carboxamide);

24) N-(2-hydroxyethyl)-1-(6-hydroxyhexyl)-1H-1,2,4-triazole-3-carboxamide (N-(2-Hydroxyethyl)-1-( 6-hydroxyhexyl)-1H-1,2,4-triazole-3-carboxamide);

25) N-hydroxy-1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,4-triazole-3-carboxamide (N-Hydroxy-1-(2-( 2-hydroxyethoxy)ethyl)-1H-1,2,4-triazole-3-carboxamide);

26) 1-(2-(2-hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-imidazole-4-carboxamide (1-(2-(2-Hydroxyethoxy)ethyl )-N-(2-hydroxyethyl)-1H-imidazole-4-carboxamide);

27) Methyl 1-(6-hydroxyhexyl)-1H-imidazole-4-carboxylate;

28) 1-(5-Hydroxypentyl)-1H-1,2,4-triazole-3-carboxamide (1-(5-Hydroxypentyl)-1H-1,2,4-triazole-3-carboxamide );

29) 1-(5-Hydroxypentyl)-1H-imidazole-4-carboxamide (1-(5-Hydroxypentyl)-1H-imidazole-4-carboxamide);

30) (Z)-1-(4-hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-imidazole-4-carboxamide ((Z)-1 -(4-Hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-imidazole-4-carboxamide);

31) N-(2-hydroxyethyl)-1-(6-hydroxyhexyl)-1H-imidazole-4-carboxamide (N-(2-Hydroxyethyl)-1-(6-hydroxyhexyl)-1H -imidazole-4-carboxamide);

32) (Z)-N-hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-pyrazole-4-carboxamide ((Z)-N-Hydroxy-1- (4-hydroxybut-2-en-1-yl)-1H-pyrazole-4-carboxamide);

33) (Z)-1-(4-hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide ((Z)-1 -(4-Hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide);

34) 1-(2-(2-hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide (1-(2-(2-Hydroxyethoxy)ethyl )-N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide);

35) Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-4-carboxylate (Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-4- carboxylate);

36) 1-(6-Hydroxyhexyl)-1H-imidazole-5-carboxamide (1-(6-Hydroxyhexyl)-1H-imidazole-5-carboxamide);

37) 1-(6-Hydroxyhexyl)-1H-pyrazole-4-carboxamide (1-(6-Hydroxyhexyl)-1H-pyrazole-4-carboxamide);

38) Methyl 1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxylate;

39) Methyl 1-(5-hydroxypentyl)-1H-imidazole-4-carboxylate;

40) N-(2-hydroxyethyl)-1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxamide (N-(2-Hydroxyethyl)-1-(6-hydroxyhexyl)-1H -pyrazole-4-carboxamide);

41) N-Hydroxy-1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxamide (N-Hydroxy-1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxamide);

42) (Z)-1-(4-hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-carboxamide ((Z)-1-(4-Hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-carboxamide);

43) Methyl 1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxylate (methyl 1-(2-(2-hydroxyethylamino)ethyl)- 1H-1,2,4-triazole-3-carboxylate);

44) methyl 1-(2-(tert-butoxycarbonyl(2-hydroxyethyl)amino)ethyl)-1H-1,2,4-triazole-3-carboxylate (methyl 1-(2- (tert-butoxycarbonyl(2-hydroxyethyl)amino)ethyl)-1H-1,2,4-triazole-3-carboxylate);

45) 1-(2-(N-(2-hydroxyethyl)acetamino)ethyl)-1H-1,2,4-triazole-3-carboxamide ((1-(2-(N-( 2-hydroxyethyl)acetamido)ethyl)-1H-1,2,4-triazole-3-carboxamide);

46) N-(2-hydroxyethyl)-1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide (N-(2- hydroxyethyl)-1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide);

47) N-hydroxy-1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide (N-hydroxy-1-(2-( 2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide);

48) 2-(2-(3-(hydroxycarbamoyl)-1H-1,2,4-triazol-1-yl)ethylamino)ethyl acetate (2-(2-(3-(hydroxycarbamoyl)- 1H-1,2,4-triazol-1-yl)ethylamino)ethyl acetate);

49) N-hydroxy-1-(2-(N-(2-hydroxyethyl)acetamido)ethyl)-1H-1,2,4-triazole-3-carboxamide (N-hydroxy- 1-(2-(N-(2-hydroxyethyl)acetamido)ethyl)-1H-1,2,4-triazole-3-carboxamide);

50) 1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide (1-(2-(2-hydroxyethylamino)ethyl)-1H- 1,2,4-triazole-3-carboxamide);

51) tert-butyl 2- (4-carbamoyl-1H-imidazol-1-yl) ethyl (2-hydroxyethyl) carbamate (tert-butyl 2- (4-carbamoyl-1H-imidazol-1-yl )ethyl(2-hydroxyethyl)carbamate);

52) 1-(2-(2-hydroxyethylamino)ethyl)-1H-imidazole-4-carboxamide (1-(2-(2-hydroxyethylamino)ethyl)-1H-imidazole-4-carboxamide) ;

53) N-Hydroxy-1-(2-((2-hydroxyethyl)amino)ethyl)-1H-imidazole-4-carboxamide (N-Hydroxy-1-(2-((2-hydroxyethyl )amino)ethyl)-1H-imidazole-4-carboxamide);

54) Methyl 1-(2-((tert-butoxycarbonyl)(2-hydroxyethyl)amino)ethyl)-1H-pyrazole-3-carboxylate (Methyl 1-(2-((tert- butoxycarbonyl)(2-hydroxyethyl)amino)ethyl)-1H-pyrazole-3-carboxylate);

55) tert-Butyl (2-(3-carbamoyl-1H-pyrazol-1-yl)ethyl)(2-hydroxyethyl)carbamate (tert-Butyl (2-(3-carbamoyl-1H-pyrazol- 1-yl)ethyl)(2-hydroxyethyl)carbamate);

56) tert-Butyl (2-(3-(hydroxycarbamoyl)-1H-pyrazol-1-yl)ethyl)(2-hydroxyethyl) carbamate (tert-Butyl (2-(3-(hydroxycarbamoyl) )-1H-pyrazol-1-yl)ethyl)(2-hydroxyethyl) carbamate);

57) N-Hydroxy-1-(2-((2-hydroxyethyl)amino)ethyl)-1H-pyrazole-3-carboxamide (N-Hydroxy-1-(2-((2-hydroxyethyl )amino)ethyl)-1H-pyrazole-3-carboxamide);

58) 1-(2-((2-hydroxyethyl)amino)ethyl)-1H-pyrazole-3-carboxamide (1-(2-((2-hydroxyethyl)amino)ethyl)-1H-pyrazole -3-carboxamide);

59) Methyl 1-(2-((tert-butoxycarbonyl)(2-hydroxyethyl)amino)ethyl)-1H-pyrazole-4-carboxylate (Methyl 1-(2-((tert- butoxycarbonyl)(2-hydroxyethyl)amino)ethyl)-1H-pyrazole-4-carboxylate);

60) Methyl 1-(2-((2-hydroxyethyl)amino)ethyl)-1H-pyrazole-4-carboxylate (Methyl 1-(2-((2-hydroxyethyl)amino)ethyl)-1H -pyrazole-4-carboxylate); and

61) 1-(2-((2-hydroxyethyl)amino)ethyl)-1H-pyrazole-4-carboxamide (1-(2-((2-Hydroxyethyl)amino)ethyl)-1H-pyrazole -4-carboxamide).

In one embodiment of the present invention, the compound represented by Formula 1 and a pharmaceutically acceptable salt thereof are nucleic acid mimics and may have antiviral activity.

One aspect of the present invention provides a method for preparing the compound of the above aspect.

The production method of the present invention, as shown in Scheme A below,

introducing a protecting group (R ₃ ) to an acyclic sugar represented by Compound A (Step 1); reacting an acyclic sugar (A′) into which a protecting group is introduced and a pentagonal base represented by compound Ba (step 2); and removing the protecting group (R ₃ ) introduced in step 1 (step 3); includes:

[Scheme A]

(In the above formula,

L is substituted or unsubstituted nitrogen (N), substituted or unsubstituted oxygen (O), substituted or unsubstituted carbon (C), substituted or unsubstituted sulfur (S), substituted or unsubstituted boron (B ), substituted or unsubstituted phosphorus (P), substituted or unsubstituted selenium (Se), and substituted or unsubstituted silicon (Si).

R ₁ 'is a hydrogen atom, a halo group, a carboxyl group, a haloformyl group, a hydroxyl group, an aldehyde group, an amide group, a hydroxyamide group, a hydroxyalkylamide group, an amine group, a nitrate group, a nitrile group, a nitro group, a phosphate group, It is one type selected from a pin group, a phosphoric acid group, a sulfone group, and a sulfonic acid group,

R ₃ is tert-butyldimethylsilyl (TBS), trimethylsilylethoxymethyl (SEM), methoxyethoxymethyl (MEM), methoxymethyl (MOM), tetrahydropyranyl (THP) and tetrahydropyranyl ( THE) is one selected from,

n ₁ and n ₂ are each an integer from 0 to 5;

는 이중 결합 또는 단일 결합이고,

is a double bond or a single bond,

X, Y, Z are -CH- or -N-, respectively.)

In one embodiment of the present invention, in the above Reaction Scheme A, the R ₁ 'may be included in R ₁ defined in Formula 1 of the above aspect, and the compound represented by 1a is a compound represented by Formula 1 of the above aspect can be included In addition, the compound represented by 1a' may have a form in which a protecting group (R ₃ ) is introduced into the compound represented by 1a.

In one embodiment of the present invention, L is one selected from substituted or unsubstituted nitrogen (N), substituted or unsubstituted oxygen (O), and substituted or unsubstituted carbon (C), wherein R ₁ is one selected from a carbonyl group, an ester group, an ether group, an ester group, an amide group, a hydroxyamide group, and a hydroxyalkylamide group, and n ₁ and n ₂ may each be an integer of 0 to 3.

In one embodiment of the present invention, the L may be one of -O-, -NR ₂ -, -CH- and -CH ₂ -.

In addition, in one embodiment of the present invention, the acyclic sugar represented by the compound A,

A1) dimethylene glycol;

A2) cis-2-butene-1,4-diol ;

A3) pentane-1,5-diol;

A4) Hexane-1,6-diol; and

A5) diethanolamine; may be one selected from the group consisting of;

In one embodiment of the present invention, the second step may be performed by a nucleophilic substitution reaction, and the nucleophilic substitution reaction may be a Mitsunobu reaction or a click reaction.

Another aspect of the present invention provides a method for preparing the compound of the above aspect.

The production method of the present invention, as shown in Scheme B below,

introducing a protecting group (R ₃ ) to an acyclic sugar represented by Compound A (Step 1); Reacting the acyclic sugar (A') into which a protecting group is introduced and the pentagonal base represented by Compound B' (Step 2); and removing the protecting group (R ₃ ) introduced in step 1 (step 3); includes:

[Scheme B]

(In the above formula,

L is substituted or unsubstituted nitrogen (N), substituted or unsubstituted oxygen (O), substituted or unsubstituted carbon (C), substituted or unsubstituted sulfur (S), substituted or unsubstituted boron (B ), substituted or unsubstituted phosphorus (P), substituted or unsubstituted selenium (Se), and substituted or unsubstituted silicon (Si).

R ₃ is tert-butyldimethylsilyl (TBS), trimethylsilylethoxymethyl (SEM), methoxyethoxymethyl (MEM), methoxymethyl (MOM), tetrahydropyranyl (THP) and tetrahydropyranyl ( THE) is one selected from,

n ₁ and n ₂ are each an integer from 0 to 5;

는 이중 결합 또는 단일 결합이고,

is a double bond or a single bond,

X, Y, Z are -CH- or -N-, respectively.)

In one embodiment of the present invention, the compound represented by 1b in Scheme B may be included in the compound represented by Formula 1 of the above embodiment. In addition, the compound represented by 1b' may have a form in which a protecting group (R ₃ ) is introduced into the compound represented by 1b.

In one embodiment of the present invention, the acyclic sugar represented by Compound A is

A1) dimethylene glycol;

A2) cis-2-butene-1,4-diol ;

A3) pentane-1,5-diol;

A4) Hexane-1,6-diol; and

A5) diethanolamine; may be one selected from the group consisting of;

In one embodiment of the present invention, the pentagonal base compound represented by the compound Bb,

B1) Methyl 1H-imidazole-4-carboxylate;

B2) Methyl 1H-pyrazole-3-carboxylate;

B3) Methyl 1H-pyrazole-4-carboxylate;

B4) Methyl 1H-1,2,4-triazole-3-carboxylate; and

B5) methyl 1H-1,2,3-triazole-4-carboxylate;

In one embodiment of the present invention, the second step may be performed by a nucleophilic substitution reaction, and the nucleophilic substitution reaction may be a Mitsunobu reaction or a click reaction.

In one embodiment of the present invention, after step 3, a nitrogen compound, for example, one selected from ammonia water, hydroxyamine, and ethanol amine is added to the resulting compound 1b to obtain a carboxylate of a pentagonal base compound. A step of substituting with an amine derivative (Step 4) may be further included.

pharmaceutically acceptable salts

The active substance of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt. The term “pharmaceutically acceptable salt” refers to a concentration that has an effective effect that is relatively non-toxic and harmless to patients. It means inorganic addition salt. For these salts, inorganic and organic acids can be used as free acids, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, perchloric acid, and phosphoric acid can be used as inorganic acids, and citric acid, acetic acid, lactic acid, maleic acid, and fumarin as organic acids. Acids, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, tartaric acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesul For example, phonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid or malonic acid may be used. In addition, these salts include alkali metal salts (sodium salt, potassium salt, etc.) and alkaline earth metal salts (calcium salt, magnesium salt, etc.) and the like. For example, acid addition salts include acetate, aspartate, benzate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, Gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, malic ates, malonates, mesylates, methyl sulfates, naphthylates, 2-naphsylates, nicotinates, nitrates, orotates, oxalates, palmitates, pamoates, phosphates/hydrogen phosphates/dihydrogen phosphates, saccharides Lates, stearates, succinates, tartrates, tosylates, trifluoroacetates, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, Potassium, sodium, tromethamine, zinc salts and the like may be included, of which hydrochloride or trifluoroacetate is preferred.

The acid addition salt according to the present invention is obtained by dissolving an active material in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. by a conventional method, for example, filtering and drying the precipitate produced by adding an organic or inorganic acid. It can be prepared by distillation of a solvent and excess acid under reduced pressure, followed by drying or crystallization in an organic solvent.

In addition, a pharmaceutically acceptable metal salt may be prepared using a base. An alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. Also, the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

Furthermore, the present invention includes not only active substances and pharmaceutically acceptable salts thereof, but also possible solvates, hydrates, isomers, optical isomers and the like that can be prepared therefrom.

Hereinafter, the present invention will be described in more detail by examples. These examples are merely for explaining the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.

Example. Preparation of acyclic nucleic acid mimetics

Using an acyclic sugar represented by compound A below and a pentagonal ring base compound represented by compound Ba or Bb below, by a nucleophilic substitution reaction through a Mitsunobu reaction or a click reaction, total 61 acyclic nucleic acid derivatives were synthesized:

[Compound A]

(In the above formula,

L is substituted or unsubstituted nitrogen (N), substituted or unsubstituted oxygen (O), substituted or unsubstituted carbon (C), substituted or unsubstituted sulfur (S), substituted or unsubstituted boron (B ), substituted or unsubstituted phosphorus (P), substituted or unsubstituted selenium (Se), and substituted or unsubstituted silicon (Si).

n ₁ and n ₂ are each an integer from 0 to 5;

는 이중 결합 또는 단일 결합이다.)

is a double bond or a single bond.)

[Compound Ba]

(In the above formula,

A hydrogen atom, a halo group, a carboxyl group, a haloformyl group, a hydroxyl group, an aldehyde group, an amide group, a hydroxyamide group, a hydroxyalkylamide group, an amine group, a nitric acid group, a nitrile group, a nitro group, a phosphine group, a phosphoric acid group, It is one kind selected from a sulfone group and a sulfonic acid group,

X, Y, and Z are -CH- or -N-, respectively.)

[Compound Bb]

(In the above formula,

X, Y, and Z are -CH- or -N-, respectively.)

Table 1 below shows specific examples of the acyclic sugar represented by Compound A and the pentagonal base compound represented by Compound B:

[Compound A1]

Diethylene glycol

Diethylene glycol [Compound B1]

methyl 1H-imidazole-4-carboxylate [Compound A2]

cis-2-Butene-1,4-diol [Compound B2]

methyl 1H-pyrazole-3-carboxylate [Compound A3]

Pentane-1,5-diol [Compound B3]

methyl 1H-pyrazole-4-carboxylate [Compound A4]

Hexane-1,6-diol [Compound B4]

methyl 1H-1,2,4-triazole-3-carboxylate [Compound A5]

Diethanolamine [Compound B5]

methyl 1H-1,2,3-triazole-4-carboxylate

Table 2 below shows the conditions of the reactants used for substitution of acyclic sugars, pentagonal base compounds and amine derivatives used in the synthesis of acyclic nucleic acid mimetics:

Example acyclic sugar base Reactants Used for Amine Derivative Substitution Example 1 (LAVD-87) A1 B1 NH ₄ OH (aq.) Example 2 (LAVD-58) A1 B5 - Example 3 (LAVD-67) A1 B5 NH ₂ OH Example 4 (LAVD-69) A1 B5 NH ₂ (CH 2 ) ₂ OH Example 5 (LAVD-60) A1 B5 NH ₄ OH (aq.) Example 6 (LAVD-44) A1 B2 - Example 7 (LAVD-49) A1 B2 NH ₄ OH (aq.) Example 8 (LAVD-59) A2 B3 - Example 9 (LAVD-63) A2 B3 NH ₄ OH (aq.) Example 10 (LAVD-48) A2 B2 - Example 11 (LAVD-53) A2 B2 NH ₄ OH (aq.) Example 12 (LAVD-50) A2 B2 NH ₂ OH Example 13 (LAVD-55) A2 B2 NH ₂ (CH 2 ) ₂ OH Example 14 (LAVD-1) A1 B4 - Example 15 (LAVD-3) A2 B4 - Example 16 (LAVD-11) A2 B4 NH ₄ OH (aq.) Example 17 (LAVD-12) A2 B4 NH ₂ OH Example 18 (LAVD-25) A2 B1 - Example 19 (LAVD-26) A2 B1 NH ₄ OH (aq.) Example 20 (LAVD-27) A2 B1 NH ₂ OH Example 21 (LAVD-31) A1 B4 NH ₂ (CH 2 ) ₂ OH Example 22 (LAVD-33) A4 B4 - Example 23 (LAVD-36) A3 B4 NH ₂ (CH 2 ) ₂ OH Example 24 (LAVD-37) A4 B4 NH ₂ (CH 2 ) ₂ OH Example 25 (LAVD-41) A1 B4 NH ₂ OH Example 26 (LAVD-42) A1 B1 NH ₂ (CH 2 ) ₂ OH Example 27 (LAVD-43) A4 B1 - Example 28 (LAVD-45) A3 B4 NH ₄ OH (aq.) Example 29 (LAVD-54) A3 B1 NH ₄ OH (aq.) Example 30 (LAVD-56) A2 B1 NH ₂ (CH 2 ) ₂ OH Example 31 (LAVD-57) A4 B1 NH ₂ (CH 2 ) ₂ OH Example 32 (LAVD-64) A2 B3 NH ₂ OH Example 33 (LAVD-66) A2 B3 NH ₂ (CH 2 ) ₂ OH Example 34 (LAVD-71) A1 B2 NH ₂ (CH 2 ) ₂ OH Example 35 (LAVD-74) A1 B3 - Example 36 (LAVD-76) A4 B1 NH ₄ OH (aq.) Example 37 (LAVD-83) A4 B3 NH ₄ OH (aq.) Example 38 (LAVD-84) A4 B3 - Example 39 (LAVD-85) A3 B1 - Example 40 (LAVD-86) A4 B3 NH ₂ (CH 2 ) ₂ OH Example 41 (LAVD-88) A4 B3 NH ₂ OH Example 42 (LAVD-89) A2 B4 NH ₂ (CH 2 ) ₂ OH Example 43 (LAVD-35) A5 B4 - Example 44 (LAVD-2) A5 B4 - Example 45 (LAVD-13) A5 B4 NH ₄ OH (aq.) Example 46 (LAVD-34) A5 B4 NH ₂ (CH 2 ) ₂ OH Example 47 (LAVD-14) A5 B4 NH ₂ OH Example 48 (LAVD-21) A5 B4 NH ₂ OH Example 49 (LAVD-32) A5 B4 NH ₂ OH Example 50 (LAVD-9) A5 B4 NH ₄ OH (aq.) Example 51 (LAVD-38) A5 B1 NH ₄ OH (aq.) Example 52 (LAVD-39) A5 B1 NH ₄ OH (aq.) Example 53 (LAVD-40) A5 B1 NH ₂ OH Example 54 (LAVD-46) A5 B2 - Example 55 (LAVD-47) A5 B2 NH ₄ OH (aq.) Example 56 (LAVD-51) A5 B2 NH ₂ OH Example 57 (LAVD-52) A5 B2 NH ₂ OH Example 58 (LAVD-61) A5 B2 NH ₄ OH (aq.) Example 59 (LAVD-65) A5 B3 - Example 60 (LAVD-70) A5 B3 - Example 61 (LAVD-75) A5 B3 NH ₄ OH (aq.)

Example 1. 1-(2-(2-hydroxyethoxy)ethyl-1H-imidazole-4-carboxamide (1-(2-(2-Hydroxyethoxy)ethyl)-1H-imidazole-4-carboxamide , synthesis of LAVD-87)

LAVD-87 was prepared through the Mitsunobu reaction of Scheme 2 below:

[Scheme 1]

a) Preparation of 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethan-1-ol (Compound 1-1)

In a dried 500 mL one-necked round flask, 5 g of dimethylene glycol was added in 150 mL dichloromethane solvent, at 0 ° C, triethylamine (Et ₃ N) (3 equivalents) was added, tert After adding -butyl dimethyl silyl chloride (TBSCl), the mixture was stirred at room temperature for 24 hours. The completion of the reaction was confirmed using thin-layer chromatography (TLC), the reaction mixture was concentrated using a vacuum concentrator, and the residue was adsorbed on silica, followed by silica gel chromatography (hexane: ethyl acetate = 10: 1 v/v) to obtain (2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethan-1-ol (Compound 1-1).

b) Preparation of Methyl 1-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethyl)-1H-imidazole-4-carboxylate (Compound 1-2)

Methyl-1H-imidazole-4-carboxylate (0.10 g, 0.81 mmol, 1.2 equiv.), triphenylphosphine (PPh ₃ ) (0.22 g, 1.02 mmol, 1.5 equiv.) was added to the compound 1-1 suspended in THF (13 mL). ) and diisopropyl azodicarboxylate (DIAD) (0.2 mL, 1.02 mmol, 1.5 equivalent) were added (-20 °C, N ₂ atmosphere), and the mixture was stirred at room temperature overnight. Purified using silica gel chromatography (hexane:EtOAc = 5:1, v/v) to obtain Methyl 1-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethyl)-1H-imidazole-4- A carboxylate (compound 1-2) (0.14 g, 0.41 mmol) was obtained.

c) Preparation of Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-imidazole-4-carboxylate (Compound 1-3)

NH ₄ F (0.78 g, 2.09 mmol) was added to the compound 1-2 (0.14 g, 0.41 mmol) suspended in MeOH (3 mL), and the mixture was stirred at 50 °C for 8 hours. The solvent was evaporated under reduced pressure and purified by silica gel chromatography (hexane:EtOAc = 1:1 to CH ₂ Cl ₂ :MeOH = 10:1, v/v) to obtain Methyl 1-(2-(2-hydroxyethoxy)ethyl ) -1H-imidazole-4-carboxylate (Compound 1-3) (0.07g, 0.36 mmol, 89%) was obtained.

d) 1-(2-(2-Hydroxyethoxy)ethyl-1H-imidazole-4-carboxamide (1-(2-(2-Hydroxyethoxy)ethyl)-1H-imidazole-4-carboxamide, LAVD Synthesis of -87) (Compound 1-4)

NH ₄ OH (aq.) (5 mL) was added to compound 1-3 (0.12 g, 0.38 mmol) suspended in MeOH (3 mL) at room temperature, and the mixture was stirred at 50 °C for 8 hours. The solvent was removed under reduced pressure, and purified by silica gel chromatography (hexane:EtOAc = 1:1 to CH ₂ Cl ₂ :MeOH = 10: 1, v/v) to obtain 1-(2-(2-hydroxyethoxy ) Ethyl-1H-imidazole-4-carboxamide (1-(2-(2-Hydroxyethoxy)ethyl)-1H-imidazole-4-carboxamide, LAVD-87) (Compound 1-4) (0.02 g, 0.06 mmol) was obtained:

¹ H NMR (400 MHz, CD ₃ OD) δ7.83 (s, 1H), 7.61 (s, 1H), 4.56 (t, J = 4.80 Hz, 2H), 3.76 (t, J = 4.80 Hz, 2H) , 3.60 (t, J = 4.80 Hz, 2H), 3.48 (t, J = 4.80 Hz, 2H)

- Examples 2 to 5

The following LAVD-58, LAVD-60, LAVD-67 and LAVD-69 were prepared through the click reaction of Reaction Scheme 2 below.

[Scheme 2]

Example 2. Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-carboxylate (Methyl 1-(2-(2-hydroxyethoxy)ethyl )-1H-1,2,3-triazole-4-carboxylate, LAVD-58) Synthesis

a) Preparation of 2-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)ethyl methanesulfonate (Compound 2-3)

To a suspension of compound 2-1 (0.80 g, 3.63 mmol) in anhydrous CH ₂ Cl ₂ (80 mL) was added MsCl (0.37 mL, 4.76 mmol, 1.5 equiv) and Et ₃ N (1.1 mL, 7.94 mmol, 2.5 equiv). was added (0 °C, N ₂ atmosphere). After stirring at 0 °C for 2 hours, the reaction mixture was purified with 0.5 N HCl solution (20 mL x 2). The organic layer was separated, washed with ether, dried over MgSO ₄ and concentrated under reduced pressure. Anhydrous DMF (61mL) and NaN ₃ (0.65g, 10.05mmol, 3 equivalents) were directly added to compound 2-2 (1.0g, 3.35mmol) (room temperature, N ₂ atmosphere). After stirring at 80 ° C for 24 hours, the mixture was purified with cold ether and water (5:1, v/v), the organic layer was separated, and the aqueous layer was washed with ether. The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:EtOAc = 1:1, v/v) to obtain 2-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)ethyl methanesulfonate (Compound 2-3) (0.63 g, 2.56 mmol, 77.0 %) was obtained.

b) Preparation of Methyl 1-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethyl)-1H-1,2,3-triazole-4-carboxylate (Compound 2-4)

To compound 2-3 (0.30 g, 1.22 mmol) dissolved in THF (30 mL) was added CuI (1.16 g, 6.11 mmol, 5 equiv), methyl propiolate (0.43 mL, 4.89 mmol, 4 equiv) and Et ₃ N (0.51 mL, 3.67 mmol, 3 eqiuv.) was added (room temperature, N ₂ atmosphere) and stirred for 12 hours. The suspension was purified by silica gel chromatography (hexane:EtOAc = 8:1 to 1:1, v/v) to obtain Methyl 1-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethyl)-1H- 1,2,3-triazole-4-carboxylate (Compound 2-4) (0.29 g, 0.89 mmol, 73.0%) was obtained.

c) Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-carboxylate (Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H- Synthesis of 1,2,3-triazole-4-carboxylate, LAVD-58) (Compound 2-5)

NH ₄ F (0.17 g, 4.47 mmol, 5 equiv.) was added to compound 2-4 (0.29 g, 0.89 mmol) dissolved in 5 mL MeOH, stirred at 50 °C for 8 h, and the residue was purified by silica gel chromatography. (CH ₂ Cl ₂ :MeOH = 40:1 to 10:1, v/v) to obtain methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-tri Azole-4-carboxylate (Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-carboxylate, LAVD-58) (Compound 2-5) (0.12 g, 0.55 mmol, 63.0%) was obtained:

1H NMR (400 MHz, CDCl ³ ) _δ8.27 (s, 1H), 4.61 (t, J = 4.56 Hz, 2H), 3.92 (s, 3H) 3.89 (t, J = 4.00 Hz, 2H), 3.72 (t, J = 4.00 Hz, 2H), 3.56 (t, J = 4.40 Hz, 2H), 2.33 (br, 1H)

Example 3. N-hydroxy-1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-carboxamide (N-Hydroxy-1-(2 Synthesis of -(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-carboxamide, LAVD-67) (Compound 2-6)

Compound 2-5 (0.03 g, 0.13 mmol) dissolved in NH ₂ OH (0.2 mL) was stirred at 50 °C for 8 h. The residue was purified by silica gel chromatography (CH ₂ Cl ₂ :MeOH = 8:1 to 5:1, v/v) to obtain N-hydroxy-1-(2-(2-hydroxyethoxy)ethyl) -1H-1,2,3-triazole-4-carboxamide (N-Hydroxy-1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-carboxamide, LAVD -67) (compound 2-6) (0.01 g, 0.04 mmol, 35.0%) was obtained:

1H NMR (400 MHz, CD ³ OD) _δ8.42 (s, 1H), 4.65 (t, J = 4.99 Hz, 2H), 3.89 (t, J = 4.99 Hz, 1H), 3.66-3.53 (m, 5H)

Example 4. 1-(2-(2-hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxamide (1-( Synthesis of 2-(2-hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxamide, LAVD-69) (Compound 2-7)

Ethanolamine (NH ₂ (CH ₂ ) ₂ OH) (0.1 mL) was added to compound 2-5 (0.03 g, 0.13 mmol) dissolved in water (H ₂ O) (0.1 mL). After stirring at room temperature for 8 hours, the residue was purified by silica gel chromatography (CH ₂ Cl ₂ :MeOH = 8:1 to 5:1, v/v) to obtain 1-(2-(2-hydroxyethoxy )Ethyl)-N-(2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxamide (1-(2-(2-hydroxyethoxy)ethyl)-N-(2-hydroxyethyl )-1H-1,2,3-triazole-4-carboxamide, LAVD-69) (Compound 2-7) (0.02 g, 0.06 mmol, 50.0%) was obtained:

1H NMR (400 MHz, CD ³ OD) _δ8.41 (s, 1H), 4.64 (t, J = 5 Hz, 2H), 3.88 (t, J = 5 Hz, 2H), 3.70 (t, J = 5.75 Hz, 2H), 3.63 (t, J = 4.8 Hz, 2H), 3.53 (t, J = 7.8 Hz, 4H)

Example 5. 1-(2-(2-Hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-carboxamide (1-(2-(2-Hydroxyethoxy)ethyl)- Preparation of 1H-1,2,3-triazole-4-carboxamide, LAVD-60)

In Example ₃ , 1-(2-( _2- Hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-carboxamide (1-(2-(2-Hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4- carboxamide, LAVD-60) was prepared.

¹ H NMR (CD ₃ OD, 400 MHz) δ 8.43 (s, 1H), 4.66 (t, J = 4.8 Hz, 2H), 3.91 (t, J = 4.8 Hz, 2H), 3.65 (t, J = 4.8 Hz, 2H), 3.55 (t, J = 4.8 Hz, 2H)

- Examples 6 and 7

The following LAVD-44 and LAVD-49 were prepared through the Mitsunobu reaction of Scheme 3 below:

[Scheme 3]

Example 6. Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-3-carboxylate (methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole- Preparation of 3-carboxylate, LAVD-44) (Compound 3-3)

In c) of Example 1, methyl 1- (2-(2-hydroxyethoxy)ethyl)-1H-imidazole-4-carboxylate (Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-imidazole-4-carboxylate, LAVD-44 ) (compound 3-3) (0.20 g, 0.94 mmol, 74%) was obtained:

1H NMR (400 MHz, CD ³ Cl ₂ ) δ 7.52 (d, J = _2.00 , 1H), 7.85 (d, J = 2.00, 1H), 4.80 (t, J = 5.60 Hz, 2H), 3.89 (t , J = 5.2, 2H), 3.89 (s, 3H), 3.65 (t, J = 4.40 Hz, 2H), 3.57 (t, J = 4.40 Hz, 2H)

Example 7. 1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-3-carboxamide (1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-3- Preparation of carboxamide, LAVD-49) (Compound 3-4)

1-(2-( 2-hydroxyethoxy)ethyl)-1H-pyrazole-3-carboxamide (1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-3-carboxamide, LAVD-49) (Compound 3- 4) (0.01 g, 0.05 mmol, 27%) was obtained:

1H NMR (400 MHz, CD ³ OD) _δ7.50 (d, J = 2.0 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 4.74 (t, J = 5.60 Hz, 2H), 3.82 (t, J = 5.60 Hz, 2H), 3.59 (t, J = 4.80 Hz, 2H), 3.47 (t, J = 4.80 Hz, 2H)

- Examples 8 and 9

The following LAVD-59 and LAVD-63 were prepared through the Mitsunobu reaction of Scheme 4 below:

[Scheme 4]

Example 8. (Z)-methyl 1-(4-hydroxybut-2-enyl)-1H-pyrazole-4-carboxylate ((Z)-methyl 1-(4-hydroxybut-2-enyl) Synthesis of -1H-pyrazole-4-carboxylate, LAVD-59)

In c) of Example 1, except that cis-2-Butene-1,4-diol was used instead of dimethylene glycol and methyl 1H-pyrazole-4-carboxylate was used instead of methyl 1H-imidazole-4-carboxylate. (Z)-methyl 1-(4-hydroxybut-2-enyl)-1H-pyrazole-4-carboxylate ((Z)-methyl 1 -(4-hydroxybut-2-enyl)-1H-pyrazole-4-carboxylate, LAVD-59) (compound 4-3) (0.33 g, 1.67 mmol, 75%) was obtained:

1H NMR (400 MHz, CDCl ³ ) _δ7.91 (s, 1H), 7.89 (s, 1H), 5.99 (t, J = 5.20 Hz, 1H), 5.72 (d, J = 10.80 Hz, 1H), 4.84 (d, J = 7.60 Hz, 2H), 4.29 (d, J = 6.80 Hz, 2H), 3.79 (s, 3H), 3.29 (br, 1H)

Example 9. (Z)-1-(4-hydroxybut-2-enyl)-1H-pyrazole-4-carboxamide ((Z)-1-(4-hydroxybut-2-enyl)-1H Synthesis of -pyrazole-4-carboxamide, LAVD-63)

(Z)-1- (4-hydroxybut-2-enyl)-1H-pyrazole-4-carboxamide ((Z)-1-(4-hydroxybut-2-enyl)-1H-pyrazole-4-carboxamide, LAVD-63 ) (Compound 4-4) (0.04 g, 0.21 mmol, 81%) was obtained:

¹ H NMR (400 MHz, CD ₃ OD) δ8.10 (s, 1H), 7.91 (s, 1H), 5.87 (dd, J = 6.00, 4.80, Hz, 1H), 5.70 (d, J = 10.80 Hz , 1H), 4.88 (d, J = 6.00 Hz, 2H), 4.26 (d, J = 6.00 Hz, 2H)

- Examples 10 to 42

According to the conditions shown in Table 2, the types of reactants used for substitution with acyclic sugars, bases and amine derivatives are varied, and LAVD-48, LAVD-53, LAVD- 50, LAVD-55, LAVD-1, LAVD-3, LAVD-11, LAVD-12, LAVD-25, LAVD-26, LAVD-27, LAVD-31, LAVD-33, LAVD-36, LAVD-37, LAVD-41, LAVD-42, LAVD-43, LAVD-45, LAVD-54, LAVD-56, LAVD-57, LAVD-64, LAVD-66, LAVD-71, LAVD-74, LAVD-76, LAVD- 83, LAVD-84, LAVD-85, LAVD-86, LAVD-88 and LAVD-89 were synthesized.

Example 10. Methyl (Z)-1-(4-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl)-1H-pyrazole-3-carboxylate (Methyl (Z Synthesis of )-1-(4-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl)-1H-pyrazole-3-carboxylate, LAVD-48)

a) Preparation of (Z)-4-((tert-Butyldimethylsilyl)oxy)but-2-en-1-ol

To a dried 500 mL one-necked round flask was added 5 g of cis-2-Butene-1,4-diol under 150 mL dichloromethane solvent, and triethylamine (Et ₃ N) (3 equivalents) was added at 0 °C. After adding tert-butyl dimethyl silyl chloride (TBSCl), the mixture was stirred at room temperature for 24 hours. The completion of the reaction was confirmed using thin-layer chromatography (TLC), the reaction mixture was concentrated using a vacuum concentrator, and the residue was adsorbed on silica, followed by silica gel chromatography (hexane: ethyl acetate = 10: 1 v/v) to obtain (Z)-4-((tert-Butyldimethylsilyl)oxy)but-2-en-1-ol.

b) Preparation of (Z)-methyl 1-(4-(tert-butyldimethylsilyloxy)but-2-enyl)-1H-pyrazole-3-carboxylate

Methyl 1H-pyrazole-3-carboxylate (0.26 g, 2.0 mmol, 1.2 equiv.) PPh3 (0.68 g, 2.6 mmol, 1.5 equiv.) and DIAD (0.5 mL, 2.6 mmol, 1.5 equiv.) were added to the suspension (-10 °C N ₂ atmosphere), stirred overnight at room temperature, The solvent was evaporated under reduced pressure. The mixture was purified by silica gel chromatography (hexane:EtOAc = 5:1 to EtOAc, v/v) to obtain (Z)-methyl 1-(4-(tert-butyldimethylsilyloxy)but-2-enyl)-1H-pyrazole-3 -carboxylate (0.43 g, 1.38 mmol, 80%) was obtained.

c) methyl (Z)-1-(4-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl)-1H-pyrazole-3-carboxylate (Methyl (Z)- Synthesis of 1-(4-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl)-1H-pyrazole-3-carboxylate, LAVD-48)

Suspension of Methyl (Z)-1-(4-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl)-1H-pyrazole-3-carboxylate (0.31 g, 0.99 mmol) in MeOH (5 mL) NH ₄ F (0.18 g, 4.93 mmol, 5 equivalents) was added (N ₂ atmosphere), stirred at 50 °C under N ₂ atmosphere overnight, and then the solvent was evaporated under reduced pressure. The mixture was purified by silica gel chromatography (hexane:EtOAc = 1:1 to 1:2, v/v) to obtain methyl (Z)-1-(4-((tert-butyldimethylsilyl)oxy)but-2 -En-1-yl)-1H-pyrazole-3-carboxylate (Methyl (Z)-1-(4-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl)-1H- pyrazole-3-carboxylate, LAVD-48) was obtained:

1H NMR (400 MHz, CDCl ³ ) δ7.49 ( _d , J = 1.6 Hz, 1H), 6.83 (d, J = 1.6 Hz, 1H), 5.91-5.87 (m, 1H), 5.71-5.69 (m , 1H), 5.30 (d, J = 7.2 Hz, 2H), 4.31 (d, J = 6.8 Hz, 2H), 3.87 (s, 3H), 2.80 (br, 1H)

Example 11. (Z)-1-(4-Hydroxybut-2-enyl)-1H-pyrazole-3-carboxamide ((Z)-1-(4-Hydroxybut-2-en-1- Synthesis of yl)-1H-pyrazole-3-carboxamide, LAVD-53)

NH ₄ OH (50% aq. soln.) (2 mL) was added to the above LAVD-48 (0.06 g, 0.29 mmol) solution, and the mixture was stirred at 50 °C for 12 hours. The residue was purified by silica gel chromatography (CH ₂ Cl ₂ :MeOH = 5:1, v/v) to obtain (Z)-1-(4-hydroxybut-2-enyl)-1H-pyrazole-3- Carboxamide ((Z)-1-(4-Hydroxybut-2-en-1-yl)-1H-pyrazole-3-carboxamide, LAVD-53) (0.01 g, 0.06 mmol, 20.0%) was obtained:

1H NMR (400 MHz, CD ³ OD) _δ7.49 (d, J = 2.0 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H), 5.76-5.70 (m, 1H), 5.64-5.58 ( m, 1H), 5.27 (d, J = 6.8H, 2H), 4.27 (d, J = 6.8 Hz, 2H)

Example 12. (Z)-N-hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-pyrazole-3-carboxamide ((Z)-N-Hydroxy- Synthesis of 1-(4-hydroxybut-2-en-1-yl)-1H-pyrazole-3-carboxamide (LAVD-50)

In Example 11, (Z) -N-hydride was obtained in the same manner as in Example 11, except that NH ₂ OH (50% aq. soln.) (0.5 mL) was used instead of NH ₄ OH. Roxy-1-(4-hydroxybut-2-en-1-yl)-1H-pyrazole-3-carboxamide ((Z)-N-Hydroxy-1-(4-hydroxybut-2-en- 1-yl)-1H-pyrazole-3-carboxamide, LAVD-50) (0.04 g, 0.19 mmol, 72.0%) was obtained:

1H NMR (400 MHz, CD ³ OD) _δ7.46 (d, J = 1.6 Hz, 1H), 6.61 (d, J = 1.6 Hz, 1H), 5.73-5.67 (m, 1H), 5.60-5.54 ( m, 1H), 5.19 (d, J = 6.8 Hz, 2H), 4.24 (d, J = 6.4 Hz, 2H)

Example 13. (Z)-1-(4-hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide ((Z) Synthesis of -1-(4-Hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide (LAVD-55)

Ethanolamine (NH ₂ (CH ₂ ) ₂ OH) (0.1 mL) was added to the above LAVD-48 (0.05 g, 0.26 mmol) dissolved in MeOH (0.1 mL), and the mixture was stirred at 50° C. for 12 hours. The residue was purified by silica gel chromatography (CH ₂ Cl ₂ :MeOH = 5:1, v/v) to obtain (Z)-1-(4-hydroxybut-2-en-1-yl)-N- (2-hydroxyethyl)-1H-pyrazole-3-carboxamide ((Z)-1-(4-Hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-pyrazole -3-carboxamide, LAVD-55) (0.05 g, 0.20 mmol, 78.0 %) was obtained:

1H NMR (400 MHz, CDCl ³ ) δ7.46 ( _d , J = 1.2 Hz, 1H), 6.68 (s, 1H), 6.56 (d, J = 1.2 Hz, 1H), 5.89 (d, J = 10.4 Hz, 1H), 5.70 (d, J = 7.2 Hz, 1H), 5.28 (d, J = 7.2 Hz, 2H), 4.26 (d, J = 7.2 Hz, 2H), 3.79 (t, J = 4.8 Hz, 2H), 3.56 (t, J = 5.2 Hz, 2H), 2.80 (br, 1H)

Example 14. Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,4-triazole-3-carboxylate (Methyl 1-(2-(2-hydroxyethoxy)ethyl Synthesis of )-1H-1,2,4-triazole-3-carboxylate, LAVD-1)

According to the conditions of Table 2 in Examples 10 to 13, the reactant used for substituting the acyclic sugar, base or amine derivative was changed to obtain methyl 1-(2-(2-hydroxyethoxy)ethyl) -1H-1,2,4-triazole-3-carboxylate (Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,4-triazole-3-carboxylate, LAVD-1) was obtained:

1H NMR (400 MHz, CDCl ³ ) _δ7.99 (s, 1H), 4.84 (t, J = 4.8 Hz, 2H), 4.00 (s, 3H), 3.91 (t, J = 5.2 Hz, 2H), 3.65 (t, J = 4.80 Hz, 2H), 3.55 (d, J = 5.20 Hz, 2H)

Example 15. Methyl (Z) -1- (4-hydroxybut-2-en-1-yl) -1H-1,2,4-triazole-3-carboxylate (Methyl (Z) -1 -(4-hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxylate, LAVD-3)

According to the conditions of Table 2 in Examples 10 to 13, the reactant used for substituting the acyclic sugar, base or amine derivative was changed to obtain methyl (Z)-1-(4-hydroxybut-2- En-1-yl) -1H-1,2,4-triazole-3-carboxylate (Methyl (Z) -1- (4-hydroxybut-2-en-1-yl) -1H-1,2 ,4-triazole-3-carboxylate, LAVD-3) was obtained:

¹ H NMR (400 MHz, CDCl ₃ ) δ7.97 (s, 1H), 5.92 (m, 1H), 5.69 (m, 1H), 5.33 (d, J = 6.80 Hz, 2H), 4.34 (d, J = 6.80 Hz, 2H), 3.98 (s, 3H), 2.75 (br, 1H)

Example 16. (Z)-1-(4-hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxamide ((Z)-1-( Synthesis of 4-Hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxamide, LAVD-11)

According to the conditions of Table 2 in Examples 10 to 13, (Z) -1- (4-hydroxybut-2-ene -1-yl)-1H-1,2,4-triazole-3-carboxamide ((Z)-1-(4-Hydroxybut-2-en-1-yl)-1H-1,2,4 -triazole-3-carboxamide, LAVD-11) was obtained:

¹ H NMR (400 MHz, CD ₃ OD) δ 7.94 (s, 1H), 5.79 (m, 1H), 5.66 (m, 1H), 5.34 (d, J = 6.00 Hz, 2H), 4.29 (d, J = 6.00 Hz, 2H)

Example 17. (Z)-N-hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxamide ((Z Synthesis of )-N-Hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxamide, LAVD-12)

According to the conditions of Table 2 in Examples 10 to 13, (Z) -N-hydroxy-1- (4-hydroxy But-2-en-1-yl)-1H-1,2,4-triazole-3-carboxamide ((Z)-N-Hydroxy-1-(4-hydroxybut-2-en-1-yl )-1H-1,2,4-triazole-3-carboxamide, LAVD-12) was obtained:

¹ H NMR (400 MHz, CD ₃ OD) δ7.92 (s, 1H), 5.80 (m, 1H), 5.66 (m, 1H), 5.32 (d, J = 6.40 Hz, 2H), 4.30 (d, J = 6.40 Hz, 2H)

Example 18. Methyl (Z)-1-(4-hydroxybut-2-en-1-yl)-1H-imidazole-4-carboxylate (Methyl (Z)-1-(4-hydroxybut- 2-en-1-yl)-1H-imidazole-4-carboxylate, LAVD-25)

According to the conditions of Table 2 in Examples 10 to 13, the reactant used for substituting the acyclic sugar, base or amine derivative was changed to obtain methyl (Z)-1-(4-hydroxybut-2- Methyl (Z)-1-(4-hydroxybut-2-en-1-yl)-1H-imidazole-4-carboxylate, LAVD-25 ) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69 (s, 1H), 7.62 (s, 1H), 5.87 (m, 1H), 5.56 (m, 1H), 5.00 (d, J = 7.20 Hz, 2H) , 4.29 (d, J = 6.80 Hz, 2H), 3.81 (s, 3H), 3.05 (br, 1H)

Example 19. (Z)-1-(4-hydroxybut-2-en-1-yl)-1H-imidazole-4-carboxamide ((Z)-1-(4-Hydroxybut-2- Synthesis of en-1-yl)-1H-imidazole-4-carboxamide, LAVD-26)

According to the conditions of Table 2 in Examples 10 to 13, (Z) -1- (4-hydroxybut-2-ene -1-yl)-1H-imidazole-4-carboxamide ((Z)-1-(4-Hydroxybut-2-en-1-yl)-1H-imidazole-4-carboxamide, LAVD-26) obtained.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.82 (s, 1H), 7.61 (s, 1H), 5.79 (m, 1H), 5.66 (m, 1H), 5.09 (d, J = 6.80 Hz, 2H ), 4.26 (d, J = 6.40 Hz, 2H)

Example 20. (Z)-N-hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-imidazole-4-carboxamide ((Z)-N-Hydroxy- Synthesis of 1-(4-hydroxybut-2-en-1-yl)-1H-imidazole-4-carboxamide (LAVD-27)

According to the conditions of Table 2 in Examples 10 to 13, (Z) -N-hydroxy-1- (4-hydroxy But-2-en-1-yl)-1H-imidazole-4-carboxamide ((Z)-N-Hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-imidazole- 4-carboxamide, LAVD-27) was obtained.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.84 (s, 2H), 7.41 (s, 2H), 5.78 (m, 1H), 5.60 (m, 1H), 5.06 (d, J = 6.80 Hz, 2H ), 4.27 (d, J = 6.40 Hz, 2H)

Example 21. 1-(2-(2-hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-carboxamide (1-( Synthesis of 2-(2-Hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-carboxamide, LAVD-31)

According to the conditions of Table 2 in Examples 10 to 13, the reactant used for substituting the acyclic sugar, base or amine derivative was changed to obtain 1-(2-(2-hydroxyethoxy)ethyl)- N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-carboxamide (1-(2-(2-Hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H- 1,2,4-triazole-3-carboxamide, LAVD-31) was obtained:

¹ H NMR (400 MHz, CD ₃ OD) δ7.95 (s, 1H), 4.86-3.89 (m, 2H), 3.88 (t, J = 6.40 Hz, 2H), 3.70 (t, J = 6.40 Hz, 2H), 3.57 (t, J = 4.40 Hz, 2H), 3.51-3.47 (m, 4H)

Example 22. Methyl 1-(6-hydroxyhexyl)-1H-1,2,4-triazole-3-carboxylate (Methyl 1-(6-hydroxyhexyl)-1H-1,2,4-triazole Synthesis of -3-carboxylate, LAVD-33)

According to the conditions of Table 2 in Examples 10 to 13, the reactant used for substituting the acyclic sugar, base or amine derivative was changed to obtain methyl 1-(6-hydroxyhexyl)-1H-1,2 ,4-triazole-3-carboxylate (Methyl 1-(6-hydroxyhexyl)-1H-1,2,4-triazole-3-carboxylate, LAVD-33) was obtained:

1H NMR (400 MHz, CD ³ OD) δ 8.05 ₍ s, 1H), 4.62 (t, J = 7.20 Hz, 2H), 3.09 (s, 3H), 3.54 (t, J = 6.4 Hz, 2H), 1.89 (t, 6.4 Hz, 2H), 1.52 (t, J = 6.4 Hz, 2H), 1.42-1.28 (m, 4H)

Example 23. N-(2-hydroxyethyl)-1-(5-hydroxypentyl)-1H-1,2,4-triazole-3-carboxamide (N-(2-Hydroxyethyl)-1 Synthesis of -(5-hydroxypentyl)-1H-1,2,4-triazole-3-carboxamide, LAVD-36)

According to the conditions of Table 2 in Examples 10 to 13, reactants used for substitution of acyclic sugars, bases or amine derivatives were changed to obtain N-(2-hydroxyethyl)-1-(5-hydroxy N-(2-Hydroxyethyl)-1-(5-hydroxypentyl)-1H-1,2,4-triazole-3-carboxamide , LAVD-36) was obtained:

1H NMR (400 MHz, CD ³ OD) _δ7.93 (s, 1H), 4.65 (t, J = 7.2 Hz, 2H), 3.69 (t, J = 6.00 Hz, 2H), 3.54-3.48 (m, 4H), 1.92-1.85 (m, 2H), 1.59-1.52 (m, 2H), 1.40-1.32 (m, 2H)

Example 24. N-(2-hydroxyethyl)-1-(6-hydroxyhexyl)-1H-1,2,4-triazole-3-carboxamide (N-(2-Hydroxyethyl)-1 Synthesis of -(6-hydroxyhexyl)-1H-1,2,4-triazole-3-carboxamide, LAVD-37)

In Examples 10 to 13, N-(2-hydroxyethyl)-1-(6-hydroxy N-(2-Hydroxyethyl)-1-(6-hydroxyhexyl)-1H-1,2,4-triazole-3-carboxamide , LAVD-37) was obtained:

1H NMR (400 MHz, CD ³ OD) δ _7.93 (s, 1H), 4.64 (t, J = 7.2 Hz, 2H), 3.69 (t, J = 5.6 Hz, 2H), 3.54-3.47 (m, 4H) ), 1.91-1.83 (m, 2H), 1.55-1.48 (m, 2H), 1.42-1.28 (m, 4H)

Example 25. N-hydroxy-1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,4-triazole-3-carboxamide (N-Hydroxy-1-(2 Synthesis of -(2-hydroxyethoxy)ethyl)-1H-1,2,4-triazole-3-carboxamide, LAVD-41)

According to the conditions of Table 2 in Examples 10 to 13, reactants used for substitution of acyclic sugars, bases, or amine derivatives were changed to obtain N-hydroxy-1-(2-(2-hydroxy) N-Hydroxy-1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,4-triazole-3 -carboxamide, LAVD-41) was obtained:

1H NMR (400 MHz, CD ³ OD) δ 7.85 ₍ s, 1H), 4.80 (t, J = 5.2 Hz, 2H), 3.85 (t, J = 5.6 Hz, 2H), 3.58 (t, J = 4.8 Hz, 2H), 3.48 (t, J = 4.8 Hz, 2H)

Example 26. 1-(2-(2-hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-imidazole-4-carboxamide (1-(2-(2-Hydroxyethoxy Synthesis of )ethyl)-N-(2-hydroxyethyl)-1H-imidazole-4-carboxamide, LAVD-42)

According to the conditions of Table 2 in Examples 10 to 13, the reactant used for substituting the acyclic sugar, base or amine derivative was changed to obtain 1-(2-(2-hydroxyethoxy)ethyl)- N-(2-hydroxyethyl)-1H-imidazole-4-carboxamide (1-(2-(2-Hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-imidazole-4-carboxamide, LAVD-42) was obtained.

¹ H NMR (CD ₃ OD, 400 MHz) δ 7.81 (s, 1H), 7.55 (s, 1H), 4.56 (t, J = 4.8 Hz, 2H), 3.77 (t, J = 4.8 Hz, 2H), 3.68 (t, J = 6.0 Hz, 2H), 3.61 (t, J = 4.8 Hz, 2H), 3.48 (t, J =4.8 Hz, 2H), 3.44 (t, J = 5.6 Hz, 2H)

Example 27. Synthesis of Methyl 1-(6-hydroxyhexyl)-1H-imidazole-4-carboxylate (LAVD-43)

According to the conditions of Table 2 in Examples 10 to 13, the reactant used for substituting the acyclic sugar, base or amine derivative was changed to obtain methyl 1-(6-hydroxyhexyl)-1H-imidazole- 4-carboxylate (Methyl 1-(6-hydroxyhexyl)-1H-imidazole-4-carboxylate, LAVD-43) was obtained.

¹ H NMR (CD ₃ OD, 400 MHz) δ 7.88 (s, 1H), 7.66 (s, 1H), 4.37 (t, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.55 (t, J = 6.4 Hz, 2H), 1.81 (t, J = 7.2 Hz, 2H), 1.54 (t, J = 7.2 Hz, 2H), 1.41–1.32 (m, 4H)

Example 28. 1-(5-Hydroxypentyl)-1H-1,2,4-triazole-3-carboxamide (1-(5-Hydroxypentyl)-1H-1,2,4-triazole-3 Synthesis of -carboxamide, LAVD-45)

According to the conditions of Table 2 in Examples 10 to 13, reactants used for substituting acyclic sugars, bases or amine derivatives were changed to obtain 1-(5-hydroxypentyl)-1H-1,2, 4-triazole-3-carboxamide (1-(5-Hydroxypentyl)-1H-1,2,4-triazole-3-carboxamide, LAVD-45) was obtained:

1H NMR (400 MHz, DMSO ^- d6) δ 8.13 (br, 1H), 8.03 (s, 1H), 7.90 (br, 1H), 4.54 (t, J = 7.2 Hz, 2H), 3.34 (t, J = 6.4 Hz, 2H), 3.15 (d, J = 5.2 Hz, 1H), 1.78-1.71 (m, 2H), 1.43-1.37 (m, 2H), 1.25-1.19 (m, 2H)

Example 29. Synthesis of 1-(5-hydroxypentyl)-1H-imidazole-4-carboxamide (1-(5-Hydroxypentyl)-1H-imidazole-4-carboxamide, LAVD-54)

According to the conditions of Table 2 in Examples 10 to 13, reactants used for substituting acyclic sugars, bases or amine derivatives were changed to obtain 1-(5-hydroxypentyl)-1H-imidazole-4 -Carboxamide (1-(5-Hydroxypentyl)-1H-imidazole-4-carboxamide, LAVD-54) was obtained.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.80 (s, 1H), 7.61 (s, 1H), 4.37 (t, J = 7.20 Hz, 2H), 3.53 (t, J = 6.40 Hz, 2H), 1.81 (m, 2H), 1.56 (m, 2H), 1.36 (m, 2H)

Example 30. (Z)-1-(4-hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-imidazole-4-carboxamide ((Z) Synthesis of -1-(4-Hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-imidazole-4-carboxamide (LAVD-56)

According to the conditions of Table 2 in Examples 10 to 13, (Z) -1- (4-hydroxybut-2-ene -1-yl)-N-(2-hydroxyethyl)-1H-imidazole-4-carboxamide ((Z)-1-(4-Hydroxybut-2-en-1-yl)-N-( 2-hydroxyethyl)-1H-imidazole-4-carboxamide, LAVD-56) was obtained.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.80 (s, 1H), 7.56 (s, 1H), 5.77 (m, 1H), 5.62 (m, 1H), 5.08 (d, J = 6.80 Hz, 2H ), 4.26 (d, J = 6.00 Hz, 2H), 3.66 (t, J = 6.00 Hz, 2H), 3.42 (t, J = 6.00 Hz, 2H), 2.72 (s. 1H)

Example 31. N-(2-hydroxyethyl)-1-(6-hydroxyhexyl)-1H-imidazole-4-carboxamide (N-(2-Hydroxyethyl)-1-(6-hydroxyhexyl) Synthesis of -1H-imidazole-4-carboxamide, LAVD-57)

In Examples 10 to 13, N-(2-hydroxyethyl)-1-(6-hydroxy Oxyhexyl)-1H-imidazole-4-carboxamide (N-(2-Hydroxyethyl)-1-(6-hydroxyhexyl)-1H-imidazole-4-carboxamide, LAVD-57) was obtained.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.79 (s, 1H), 7.56 (s, 1H), 4.37 (t, J = 7.2 Hz, 2H), 3.68 (t, J = 6.0 Hz, 2H), 3.54 (t, J = 6.0 Hz, 2H), 3.45 (t, J = 6.0 Hz, 2H), 1.79 (t, J = 7.2 Hz, 2H), 1.53 (t, J = 7.2 Hz, 2H), 1.48- 1.33 (m, 4H)

Example 32. (Z)-N-hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-pyrazole-4-carboxamide ((Z)-N-Hydroxy- Synthesis of 1-(4-hydroxybut-2-en-1-yl)-1H-pyrazole-4-carboxamide (LAVD-64)

According to the conditions of Table 2 in Examples 10 to 13, (Z) -N-hydroxy-1- (4-hydroxy But-2-en-1-yl)-1H-pyrazole-4-carboxamide ((Z)-N-Hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-pyrazole- 4-carboxamide, LAVD-64) was obtained.

Example 32 (LAVD-64)

1H NMR (400 MHz, CD ³ OD) δ 8.04 ₍ s, 1H), 7.82 (s, 1H), 5.87 (m, 1H), 5.72 (m, 1H), 4.89 (d, J = 6.40 Hz, 2H ), 4.25 (d, J = 6.40 Hz, 2H)

Example 33. (Z)-1-(4-hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide ((Z) Synthesis of -1-(4-Hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide (LAVD-66)

According to the conditions of Table 2 in Examples 10 to 13, (Z) -1- (4-hydroxybut-2-ene -1-yl)-N-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide ((Z)-1-(4-Hydroxybut-2-en-1-yl)-N-( 2-hydroxyethyl)-1H-pyrazole-4-carboxamide, LAVD-66) was obtained.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.08 (s, 1H), 7.89 (s, 1H), 5.89 (m, 1H), 5.73 (m, 1H), 4.89 (d, J = 7.2 0 Hz, 2H), 4.26 (d, J = 6.40 Hz, 2H), 3.66 (t, J = 6.00 Hz, 2H), 3.43 (t, J = 6.00 Hz, 2H)

Example 34. 1-(2-(2-hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide (1-(2-(2-Hydroxyethoxy Synthesis of )ethyl)-N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide, LAVD-71)

According to the conditions of Table 2 in Examples 10 to 13, the reactant used for substituting the acyclic sugar, base or amine derivative was changed to obtain 1-(2-(2-hydroxyethoxy)ethyl)- N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide (1-(2-(2-Hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide, LAVD-71) was obtained.

¹ H NMR (CD ₃ OD, 400 MHz) δ 7.49 (s, 1H), 6.75 (s, 1H), 4.71 (t, J = 5.2 Hz, 2H), 3.82 (t, J = 5.2 Hz, 2H), 3.69 (t, J = 5.2 Hz, 2H), 3.58 (t, J = 4.4 Hz, 2H), 3.47 (t, J = 4.8 Hz, 4H)

Example 35. Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-4-carboxylate (Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole- Synthesis of 4-carboxylate, LAVD-74)

According to the conditions of Table 2 in Examples 10 to 13, the reactant used for substituting the acyclic sugar, base or amine derivative was changed to obtain methyl 1-(2-(2-hydroxyethoxy)ethyl) -1H-pyrazole-4-carboxylate (Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-4-carboxylate, LAVD-74) was obtained.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.97 (s, 1H), 7.92 (s, 1H), 4.34 (t, J = 4.8 Hz, 2H), 3.89 (t, J = 5.2 Hz, 2H), 3.82 (s, 3H), 3.70 (t, J = 4.4 Hz, 2H), 3.56 (t, J = 4.4 Hz, 2H)

Example 36. Synthesis of 1-(6-hydroxyhexyl)-1H-imidazole-5-carboxamide (1-(6-Hydroxyhexyl)-1H-imidazole-5-carboxamide, LAVD-76)

According to the conditions of Table 2 in Examples 10 to 13, reactants used for substitution of acyclic sugars, bases or amine derivatives were changed to obtain 1-(6-hydroxyhexyl)-1H-imidazole-5 -Carboxamide (1-(6-Hydroxyhexyl)-1H-imidazole-5-carboxamide, LAVD-76) was obtained.

¹ H NMR (CD ₃ OD, 400 MHz) δ 7.79 (s, 1H), 7.60 (s, 1H), 4.38 (t, J = 7.2 Hz, 2H), 3.53 (t, J = 6.4 Hz, 2H), 1.79 (t, J = 7.2 Hz, 2H), 1.53 (t, J = 7.2 Hz, 2H), 1.33-1.28 (m, 4H)

Example 37. Synthesis of 1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxamide (1-(6-Hydroxyhexyl)-1H-pyrazole-4-carboxamide, LAVD-83)

According to the conditions of Table 2 in Examples 10 to 13, reactants used for substitution of acyclic sugars, bases or amine derivatives were changed to obtain 1-(6-hydroxyhexyl)-1H-pyrazole-4 -Carboxamide (1-(6-Hydroxyhexyl)-1H-pyrazole-4-carboxamide, LAVD-83) was obtained.

¹ H NMR (CD ₃ OD, 400 MHz) δ 8.09 (s, 1H), 7.90 (s, 1H), 4.17 (t, J = 6.8 Hz, 2H), 3.53 (t, J = 6.4 Hz, 2H), 1.89 (t, J = 3.6 Hz, 2H), 1.53 (t, J = 6.8 Hz, 2H), 1.43-1.31 (m, 4H)

Example 38. Synthesis of Methyl 1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxylate (LAVD-84)

According to the conditions of Table 2 in Examples 10 to 13, reactants used for substitution of acyclic sugars, bases or amine derivatives were changed to obtain methyl 1-(6-hydroxyhexyl)-1H-pyrazole- 4-carboxylate (Methyl 1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxylate, LAVD-84) was obtained.

1H NMR _{(CDCl 3} ^, 400 MHz) δ 7.87 (s, 1H), 7.86 (s, 1H), 4.13 (t, J = 7.2 Hz, 2H), 3.79 (s, 3H), 3.60 (t, J = 6.4 Hz, 2H), 1.90-1.82 (m, 2H), 1.54-1.49 (m, 2H), 1.41-1.34 (m, 2H), 1.32-1.26 (m, 2H)

Example 39. Synthesis of Methyl 1-(5-hydroxypentyl)-1H-imidazole-4-carboxylate (LAVD-85)

According to the conditions of Table 2 in Examples 10 to 13, the reactant used for substituting the acyclic sugar, base or amine derivative was changed to obtain methyl 1-(5-hydroxypentyl)-1H-imidazole- 4-carboxylate (Methyl 1-(5-hydroxypentyl)-1H-imidazole-4-carboxylate, LAVD-85) was obtained.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.89 (s, 1H), 7.67 (s, 1H), 4.37 (t, J = 7.20 Hz, 2H), 3.85 (s, 3H), 3.54 (t, J = 6.40 Hz, 2H), 1.85 (m, 2H), 1.57 (m, 2H), 1.38 (m, 2H)

Example 40. N-(2-hydroxyethyl)-1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxamide (N-(2-Hydroxyethyl)-1-(6-hydroxyhexyl) Synthesis of -1H-pyrazole-4-carboxamide, LAVD-86)

In Examples 10 to 13, N-(2-hydroxyethyl)-1-(6-hydroxy Roxyhexyl)-1H-pyrazole-4-carboxamide (N-(2-Hydroxyethyl)-1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxamide, LAVD-86) was obtained.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.07 (s, 1H), 7.92 (s, 1H), 4.18 (t, J = 7.2 Hz, 2H), 3.68 (t, J = 6.0 Hz, 2H), 3.54 (t, J = 6.4 Hz, 2H), 3.45 (t, J = 6.0 Hz, 2H), 1.90-1.83 (m, 2H), 1.55-1.48 (m, 2H), 1.42-1.35 (m, 2H) , 1.30-1.25 (m, 2H)

Example 41. N-hydroxy-1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxamide (N-Hydroxy-1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxamide, Synthesis of LAVD-88)

In Examples 10 to 13, N-hydroxy-1-(6-hydroxyhexyl)-1H was obtained by differentiating the reactant used for substituting the acyclic sugar, base or amine derivative according to the conditions of Table 2 above. -Pyrazole-4-carboxamide (N-Hydroxy-1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxamide, LAVD-88) was obtained.

1H NMR (400 MHz, CD ³ OD) δ 8.13 ₍ s, 1H), 7.86 (s, 1H), 4.19 (t, J = 7.2 Hz, 2H), 3.54 (t, J = 6.4 Hz, 2H), 1.90-1.83 (m, 2H), 1.55-1.48 (m, 2H), 1.43-1.35 (m, 2H), 1.33-1.26 (m, 2H)

Example 42. (Z)-1-(4-hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-car copymid ((Z)-1-(4-Hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-carboxamide, LAVD-89) synthesis

According to the conditions of Table 2 in Examples 10 to 13, (Z) -1- (4-hydroxybut-2-ene -1-yl)-N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-carboxamide ((Z)-1-(4-Hydroxybut-2-en-1- yl)-N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-carboxamide, LAVD-89) was obtained:

¹ H NMR (400 MHz, CD ₃ OD) δ 8.07 (s, 1H), 5.81 (t, J = 4.8 Hz, 1H), 5.68 (t, J = 4.8 Hz, 1H), 5.34 (t, J = 5.6 Hz, 2H), 4.30 (d, J = 6.0 Hz, 2H), 3.70 (s, 2H), 3.50 (s, 2H)

Example 43. Methyl 1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxylate (methyl 1-(2-(2-hydroxyethylamino)ethyl )-1H-1,2,4-triazole-3-carboxylate, LAVD-35) Synthesis

LAVD-35 was synthesized through the Mitsunobu reaction shown in Scheme 5 below:

[Scheme 5]

a) Preparation of tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(2-hydroxyethyl)carbamate (Compound 5-2)

2,2'-azanediylbis(ethan-1-ol) (compound 5-1) (12.6 g, 47.55 mmol) and imidazole (3.23 g, 47.55 mmol) dissolved in DMF (30 mL) in TBSCl (4.77 g, 31.70 mmol) was added (0 °C, N ₂ atmosphere), stirred at room temperature for 12 hours, and then stirred in MeOH (1.0 mL) for 30 minutes. The reaction solution was poured into saturated NH ₄ Cl aqueous solution and EtOAc (100 mL, 1:1 v/v), and the organic layer was separated. The aqueous layer was washed with EtOAc (100 mL x 4). The organic layers were mixed, dried over Na ₂ SO ₄ , filtered, and the remaining solution was concentrated under reduced pressure and purified with a silica gel pad (hexane:EtOAc = 1:1 to EtOAc, v/v) to obtain a silylated compound, 6.4 g, 0.029 mmol, 61 %) was obtained.

Et ₃ N (7.3 g, 72.9 mmol) and (Boc) ₂ O (13.6 g, 55.6 mmol) were added (0 ℃, N ₂ atmosphere), and stirred at room temperature for 12 hours. The reaction solution was treated with saturated aqueous NH ₄ Cl (10.0 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was dried over Na ₂ SO ₄ , filtered, and the residual solution was concentrated under reduced pressure and purified with a silica gel pad (hexane:EtOAc = 5:1 to EtOAc, v/v) to obtain tert-butyl 2-( tert-butyldimethylsilyloxy)ethyl(2-hydroxyethyl)carbamate (Compound 5-2) (3.6 g, 0.43 mmol, 39 %) was obtained.

b) Preparation of methyl 1-(2-(tert-butoxycarbonyl(2-(tert-butyldimethylsilyloxy)ethyl)amino)ethyl)-1H-imidazole-4-carboxylate (Compound 5-3)

Using the Mitsunobu reaction mechanism of Examples 10 to 13, and different reactants used for substitution of acyclic sugars, bases or amine derivatives, methyl 1-(2-(tert-butoxycarbonyl(2-(tert- butyldimethylsilyloxy)ethyl)amino)ethyl)-1H-imidazole-4-carboxylate (Compound 5-3) (0.68 g, 1.52 mmol, 82%) was obtained.

c) Preparation of methyl 1-(2-(tert-butoxycarbonyl(2-hydroxyethyl)amino)ethyl)-1H-imidazole-4-carboxylate (Compound 5-4)

TBAF (0.66 mL, 2.28 mmol) was added to a solution of compound 5-3 dissolved in THF (10 mL) (0 °C, N ₂ atmosphere), and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, purified with a silica gel pad (hexane: EtOAc = 1:1 to EtOAc v/v), and methyl 1-(2-(tert-butoxycarbonyl(2-hydroxyethyl)amino)ethyl)-1H- To obtain imidazole-4-carboxylate (Compound 5-4) (0.40 g, 1.30 mmol, 85%).

d) methyl 1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxylate (methyl 1-(2-(2-hydroxyethylamino)ethyl)- Synthesis of 1H-1,2,4-triazole-3-carboxylate, LAVD-35)

An excess of HCl (in MeOH (25.0 mL)) was added to compound 5-4 (0.08 g, 0.25 mmol) dissolved in MeOH (10 mL) (0 °C), and the mixture was stirred at room temperature for 12 hours. Solvents and volatiles were removed under reduced pressure at 35 °C (bath temperature) and purified with a silica gel pad (CH ₂ Cl ₂ :MeOH = 8:1 v/v) to obtain methyl 1-(2-(2-hydroxyethylamino )ethyl)-1H-1,2,4-triazole-3-carboxylate (methyl 1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxylate, LAVD -35) (compound 5-5) (0.05 g, 0.25 mmol, 100%) was obtained:

¹ H NMR (400 MHz, CD ₃ OD) δ 8.45 (s, 1H), 7.96 (s, 1H), 3.92 (s, 3H), 3.81 (s, 2H), 3.58 (s, 2H), 3.33 (s , 2H), 3.2 (s, 2H).

Examples 44 to 61

Through the mechanism shown in Scheme 6 below, LAVD-2, LAVD-9, LAVD-13, LAVD-14, LAVD-21, LAVD-32, LAVD-34, LAVD-38, LAVD-39, LAVD-40, LAVD-46, LAVD-47, LAVD-51, LAVD-52, LAVD-61, LAVD-65, LAVD-70 and LAVD-75 were synthesized:

[Scheme 6]

Example 44. Methyl 1-(2-(tert-butoxycarbonyl(2-hydroxyethyl)amino)ethyl)-1H-1,2,4-triazole-3-carboxylate (methyl 1-( Synthesis of 2-(tert-butoxycarbonyl(2-hydroxyethyl)amino)ethyl)-1H-1,2,4-triazole-3-carboxylate, LAVD-2)

methyl 1-(2-(tert-butoxycarbonyl(2-(tert-butyldimethylsilyloxy)ethyl)amino)ethyl)-1H-1,2,4-triazole-3-carboxylate (compound 6- 1) (0.24 g, 0.7 mmol) was added with TBAF (1.0 mL, 1.07 mmol) (0 °C, N ₂ atmosphere), and stirred at room temperature for 12 hours. The residual solution was concentrated under reduced pressure and purified on a pad of silica gel (hexane:EtOAc = 1:1 to EtOAc v/v) to yield methyl 1-(2-(tert-butoxycarbonyl(2-hydroxyethyl)amino)ethyl )-1H-1,2,4-triazole-3-carboxylate (methyl 1-(2-(tert-butoxycarbonyl(2-hydroxyethyl)amino)ethyl)-1H-1,2,4-triazole-3 -carboxylate, LAVD-2) (compound 6-3) (0.11 g, 0.03 mmol, 50%) was obtained:

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89-7.83 (s, 1H), 4.89-4.85 (m, 2H), 3.77-3.73 (m, 4H), 3.37-3.32 (m, 2H), 1.36-1.23 (s, 9H).

Example 45. 1-(2-(N-(2-hydroxyethyl)acetamino)ethyl)-1H-1,2,4-triazole-3-carboxamide ((1-(2-(N Synthesis of -(2-hydroxyethyl)acetamido)ethyl)-1H-1,2,4-triazole-3-carboxamide, LAVD-13)

a) Preparation of tert-butyl 2-(3-carbamoyl-1H-1,2,4-triazol-1-yl)ethyl(2-hydroxyethyl)carbamate (Compound 6-4)

methyl 1-(2-(tert-butoxycarbonyl(2-(tert-butyldimethylsilyloxy)ethyl)amino)ethyl)-1H-1,2,4-triazole-3-carboxylate (Compound 6-1) (0.11 g, 0.26 mmol ) was dissolved in MeOH (2.5 mL), treated with NH ₄ F (0.05 g, 1.31 mmol) (room temperature, Ar atmosphere), stirred at 50 ° C. for 18 hours, and then volatiles were removed with an evaporator. The residue was adsorbed on silica gel and purified by silica gel column chromatography to obtain the product in quantitative yield. The product (0.06 g, 0.14 mmol) was dissolved in 5 mL of MeOH, and NH ₄ OH (50% aq. soln ., 10 mL), stirred for 12 hours while heating at 80 °C, adsorbed on silica gel, and purified by silica gel chromatography (CH ₂ Cl ₂ :MeOH = 5:1 v/v), tert- Butyl 2-(3-carbamoyl-1H-1,2,4-triazol-1-yl)ethyl(2-hydroxyethyl)carbamate (Compound 6-4) (0.02 g, 0.07 mmol, 50%) was obtained.

b) 1-(2-(N-(2-hydroxyethyl)acetamino)ethyl)-1H-1,2,4-triazole-3-carboxamide ((1-(2-(N-( Synthesis of 2-hydroxyethyl)acetamido)ethyl)-1H-1,2,4-triazole-3-carboxamide, LAVD-13) (Compound 6-6)

BzCl (0.07 mL, 0.63 mmol) was added to Et ₃ N (0.17 mL, 1.25 mmol) and compound 6-4 (0.16 g, 0.05 mmol) dissolved in CH ₂ Cl ₂ (2.5 mL) (Ar atmosphere). , and stirred (room temperature, 1 hour). The reaction solution was treated with MeOH (1.0 mL), stirred for an additional 30 minutes, adsorbed onto silica gel, and purified with a silica gel pad to obtain 2-(tert-butoxycarbonyl(2-(3-carbamoyl-1H-1,2,4 -triazol-1-yl)ethyl)amino)ethyl benzoate (Compound 6-5) (0.02 g, 0.045 mmol, 90%) was obtained.

The compound 6-5 was treated with HCl (in MeOH) (0 °C, N ₂ atmosphere), stirred (room temperature, 12 hours), the resulting solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. After purification to obtain a purified compound 6-5 (0.01 g, 0.037 mmol, 82%), dissolved in CH ₂ Cl ₂ (4.0 mL), acetyl chloride (0.01 mL, 0.18 mmol) and Et ₃ N (0.02 mL, 0.18 mmol) was added (0 ℃, Ar atmosphere), and after stirring at room temperature for 20 hours, the mixture was adsorbed on silica gel and purified with a silica column to obtain an acetyl compound (0.05 g, 0.13 mmol, 69%). obtained.

The above acetyl compound (0.05 g, 0.13 mmol) was dissolved in 1.5 mL of MeOH and K ₂ CO ₃ (0.02 g, 0.13 mmol), and stirred at 0 °C for 12 hours. The solution was neutralized to pH 6-7 with HCl (in MeOH), adsorbed on silica gel, and purified on a silica gel column to obtain 1-(2-(N-(2-hydroxyethyl)acetamino)ethyl)-1H- 1,2,4-triazole-3-carboxamide ((1-(2-(N-(2-hydroxyethyl)acetamido)ethyl)-1H-1,2,4-triazole-3-carboxamide, LAVD- 13) (Compound 6-6) (0.014 g, 0.06 mmol, 50%) was obtained:

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.92 (s, 0.5H), 7.86 (s, 0.5H), 4.92 (t, J = 6.4 Hz, 1H), 4.90 (t, J = 6.4 Hz, 0.5H) ) or 4.93-4.88 (m, 2H), 3.87-3.81 (m, 2H), 3.80 (t, J = 5.6 Hz, 1H), 3.74 (t, J = 5.6 Hz, 1H), 3.53 (t, J = 4.8 Hz, 1H), 3.42 (t, J = 4.8 Hz, 1H), 2.05 (s, 1.5H), 1.87 (s, 1.5H).

Example 46. N-(2-hydroxyethyl)-1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide (N-( Synthesis of 2-hydroxyethyl)-1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide, LAVD-34)

In Example 4, N-(2-hydroxyethyl)-1-(2-(2-hydroxy Ethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide (N-(2-hydroxyethyl)-1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2, 4-triazole-3-carboxamide, LAVD-34) (Compound 6-2) (0.015 g, 0.006 mmol, 34%) was obtained.

1H NMR (400 MHz, CD ³ OD) δ 7.96 ( _d , J = 18.8 Hz, 1H), 4.93 (t, J = 5.6 Hz, 2H), 3.72 (t, J = 4.8 Hz, 1H), 3.65 ( t, J = 4.8 Hz, 1H), 3.53 (t, J = 5.6 Hz, 1H), 3.44 (t, J = 5.6 Hz, 1H), 3.27 (s, 1H), 3.13 (t, J = 4.8 Hz, 1H), 2.92 (s, 2H), 2.79 (s, 2H).

Example 47. N-hydroxy-1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide (N-hydroxy-1-(2 Synthesis of -(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide, LAVD-14)

Step 1 of synthesizing an intermediate product according to the conditions of Table 2 in Example 2 by differentiating the reactant of the reaction of the acyclic sugar, base or amine derivative; and NHOH (aq.) (2 mL) was added to the above intermediate (0.06 g, 0.2 mmol) suspended in MeOH (3 mL), stirred overnight (55 °C), the residue was evaporated under reduced pressure, and hexane and, in two steps of solidification in a co-solvent of EtOAc; through, N-hydroxy-1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carb Copymid (N-hydroxy-1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide, LAVD-14) (Compound 6-7) (0.04 g, 0.18 mmol , 37%) was obtained.

1H NMR (400 MHz, CD ³ OD) δ 8.07 ₍ s, 1H), 5.31 (t, J = 5.2 Hz, 2H), 4.05-4.02 (m, 2H), 3.81-3.76 (m, 2H), 3.73 -3.69 (m, 2H)

Example 48. 2-(2-(3-(hydroxycarbamoyl)-1H-1,2,4-triazol-1-yl)ethylamino)ethyl acetate (2-(2-(3-(hydroxycarbamoyl) Synthesis of )-1H-1,2,4-triazol-1-yl)ethylamino)ethyl acetate, LAVD-21)

In Example 3, according to the conditions of Table 2, the reactant of the reaction of the acyclic sugar, base or amine derivative was made different, 2-(2-(3-(hydroxycarbamoyl)-1H-1,2, 4-triazol-1-yl)ethylamino)ethyl acetate (2-(2-(3-(hydroxycarbamoyl)-1H-1,2,4-triazol-1-yl)ethylamino)ethyl acetate (LAVD-21) (Compound 6-8) (0.04 g, 0.16 mmol, 90%) was obtained.

1H NMR (400 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 4.50 (t, J = 6.0 Hz, 2H), 4.35 (t, J = 5.2 Hz, 2H), 3.97-3.94 (m, 2H), 3.87 (t, J = 5.2 Hz, 2H), 2.07 (s, 3H)

Example 49. N-Hydroxy-1-(2-(N-(2-hydroxyethyl)acetamido)ethyl)-1H-1,2,4-triazole-3-carboxamide (N- Synthesis of hydroxy-1-(2-(N-(2-hydroxyethyl)acetamido)ethyl)-1H-1,2,4-triazole-3-carboxamide, LAVD-32)

a) Preparation of 1-(2-(2-(tert-butyldimethylsilyloxy)ethylamino)ethyl)-N-hydroxy-1H-1,2,4-triazole-3-carboxamide

Compounds 6-7 (0.30 g, 1.39 mmol) and imidazole (0.14 g, 2.09 mmol) dissolved in DMF (4 mL) and CH ₂ Cl ₂ (10 mL) co-solvent were added to TBSCL (0.23 g, 1.53 g). mmol) was added (0 °C, Ar atmosphere), and the mixture was stirred at room temperature for 13 hours. The resulting solution was treated with MeOH (1.0 mL) and stirred for an additional 30 min. The solution was concentrated under reduced pressure and purified with a silica gel pad (hexane:EtOAc = 1:2 v/v) to obtain 1-(2-(2-(tert-butyldimethylsilyloxy)ethylamino)ethyl)-N-hydroxy-1H-1,2, 4-triazole-3-carboxamide (Compound 6-9) (0.23 g, 0.70 mmol, 50%) was obtained.

b) N-hydroxy-1-(2-(N-(2-hydroxyethyl)acetamido)ethyl)-1H-1,2,4-triazole-3-carboxamide (N-hydroxy- Synthesis of 1-(2-(N-(2-hydroxyethyl)acetamido)ethyl)-1H-1,2,4-triazole-3-carboxamide, LAVD-32)

NMI (0.05 mL, 0.56 mmol) and AcCl (0.02 mL, 0.28 mmol) were added to a solution of compound 6-9 (0.08 g, 0.25 mmol) dissolved in 3 mL of CH- ₃ -CN (0 °C, Ar atmosphere). ) was done. After stirring for 13 hours, the completion of the reaction was confirmed by TLC, and the mixture was concentrated under reduced pressure. The residue was dissolved in MeOH, absorbed on silica gel and purified (DCM:MeOH = 8:1) to obtain N-hydroxy-1-(2-(N-(2-hydroxyethyl)acetamido)ethyl) -1H-1,2,4-triazole-3-carboxamide (N-hydroxy-1-(2-(N-(2-hydroxyethyl)acetamido)ethyl)-1H-1,2,4-triazole- 3-carboxamide, LAVD-32) (Compound 6-10) (0.06 g, 0.23 mmol, 90%) was obtained:

1H NMR (400 MHz, CD ³ OD) δ 8.14 ₍ s, 1H), 4.45 (t, J = 6.4 Hz, 2H), 4.19 (t, J = 5.6 Hz, 2H), 3.91 (t, J = 6.4 Hz, 2H), 3.71 (t, J = 5.6 Hz, 2H), 1.98 (s, 3H).

Example 50. 1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide (1-(2-(2-hydroxyethylamino)ethyl)- Synthesis of 1H-1,2,4-triazole-3-carboxamide, LAVD-9)

In Example 47, according to the conditions of Table 2, the reactant used for substituting the acyclic sugar, base or amine derivative was changed to obtain 1-(2-(2-hydroxyethylamino)ethyl)-1H-1 ,2,4-triazole-3-carboxamide (1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide, LAVD-9) was obtained:

1H NMR (400 MHz, DMSO ^- d6) δ 8.14 (br, 1H), 8.02 (s, 1H), 7.89 (br, 1H), 4.62 (t, J = 6.40 Hz, 2H), 4.44 (br, 1H) ), 3.36 (m, 2H), 2.91 (t, J = 6.40 Hz, 2H), and 2.52 (t, J = 5.80 Hz, 2H).

Example 51. tert-butyl 2- (4-carbamoyl-1H-imidazol-1-yl) ethyl (2-hydroxyethyl) carbamate (tert-butyl 2- (4-carbamoyl-1H-imidazol-1 Synthesis of -yl)ethyl(2-hydroxyethyl)carbamate, LAVD-38)

In Example 45, tert-butyl 2-(4-carbamoyl-1H-imidazol-1-yl ) Ethyl (2-hydroxyethyl) carbamate (tert-butyl 2- (4-carbamoyl-1H-imidazol-1-yl) ethyl (2-hydroxyethyl) carbamate, LAVD-38) was obtained.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.73 (s, 1H), 7.68 (s, 1H), 4.54 (t, J = 6.4 Hz, 2 H), 3.73 (t, J = 5.2 Hz , 1H) , 3.64 (t, J = 5.2 Hz, 2H), 3.56 (t, J = 2.8 Hz, 1H), 3.48 (t, J = 5.6 Hz, 1H), 1.42 (s, 3H), 1.30 (s, 6H).

Example 52. 1-(2-(2-hydroxyethylamino)ethyl)-1H-imidazole-4-carboxamide (1-(2-(2-hydroxyethylamino)ethyl)-1H-imidazole-4- Synthesis of carboxamide, LAVD-39)

In Example 47, according to the conditions of Table 2, reactants used for substituting acyclic sugars, bases or amine derivatives were different, and 1-(2-(2-hydroxyethylamino)ethyl)-1H-alimine Dazole-4-carboxamide (1-(2-(2-hydroxyethylamino)ethyl)-1H-imidazole-4-carboxamide, LAVD-39) was obtained.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.93 (s, 1H), 7.82 (s, 1H), 7.69 (d, J = 0.8 Hz, 1H), 7.50 (d, J = 0.8 Hz , 1H), 4.72-4.68 (tt, 4H), 3.81-3.77 (tt, 4H), 3.53-3.48 (tt, 4H), 3.16 (t, J = 5.2 Hz, 2H), 3.11 (t, J = 5.2 Hz, 2H) .

Example 53. N-Hydroxy-1-(2-((2-hydroxyethyl)amino)ethyl)-1H-imidazole-4-carboxamide (N-Hydroxy-1-(2-((2 Synthesis of -hydroxyethyl)amino)ethyl)-1H-imidazole-4-carboxamide, LAVD-40)

In Example 47, N-hydroxy-1-(2-((2-hydroxyethyl)amino )Ethyl)-1H-imidazole-4-carboxamide (N-Hydroxy-1-(2-((2-hydroxyethyl)amino)ethyl)-1H-imidazole-4-carboxamide, LAVD-40) was obtained. .

1H NMR (400 MHz, CD ³ OD) δ 8.58 ₍ s, 1H), 7.87 (s, 1H), 4.86 (t, J = 6.4 Hz, 2H), 3.82 (t, J = 5.2 Hz , 2H) , 3.60 (t, J = 6.4 Hz, 2H), 3.21 (t, J = 5.2 Hz, 2H)

Example 54. Methyl 1-(2-((tert-butoxycarbonyl)(2-hydroxyethyl)amino)ethyl)-1H-pyrazole-3-carboxylate (Methyl 1-(2-(( Synthesis of tert-butoxycarbonyl)(2-hydroxyethyl)amino)ethyl)-1H-pyrazole-3-carboxylate, LAVD-46)

In Example 44, methyl 1-(2-((tert-butoxycarbonyl)(2-hydroxy Methyl 1-(2-((tert-butoxycarbonyl)(2-hydroxyethyl)amino)ethyl)-1H-pyrazole-3-carboxylate, LAVD -46) was obtained.

1H NMR (400 MHz, CDCl ³ ) δ 7.54 ( _d , J = 12.4 Hz, 1H), 6.91 (d, J = 15.2 Hz, 1H), 4.73 (t, J = 5.6 Hz , 2H), 3.89 (d , J = 4.4 Hz , 3H), 3.75–3.68 (m, 2H), 3.61 (t, J = 5.6 Hz , 1H), 3.56 (t, J = 6.4 Hz , 1H), 1.39 (d, J = 6.4 Hz) , 9H).

Example 55. tert-Butyl (2-(3-carbamoyl-1H-pyrazol-1-yl)ethyl)(2-hydroxyethyl)carbamate (tert-Butyl (2-(3-carbamoyl-1H- Synthesis of pyrazol-1-yl)ethyl)(2-hydroxyethyl)carbamate, LAVD-47)

In Example 45, tert-butyl (2-(3-carbamoyl-1H-pyrazole-1- yl)ethyl)(2-hydroxyethyl)carbamate (tert-Butyl (2-(3-carbamoyl-1H-pyrazol-1-yl)ethyl)(2-hydroxyethyl)carbamate, LAVD-47) was obtained.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.42 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 6.0 Hz, 1H), 4.59 (s, J = 5.2 Hz, 2 H), 3.73 -3.66 (tt , 2H), 3.61-3.59 (tt, 2H), 3.19 (t, J = 5.6 Hz , 1H), 3.13 (t, J = 5.6 Hz , 1H), 1.40 (s, 4H), 1.31 (s, 5H).

Example 56. tert-Butyl (2-(3-(hydroxycarbamoyl)-1H-pyrazol-1-yl)ethyl)(2-hydroxyethyl) carbamate (tert-Butyl (2-(3-(hydroxycarbamoyl)- Synthesis of 1H-pyrazol-1-yl)ethyl)(2-hydroxyethyl) carbamate, LAVD-51)

In Example 45, tert-butyl (2-(3-(hydroxycarbamoyl)-1H-pyra tert-Butyl (2-(3-(hydroxycarbamoyl)-1H-pyrazol-1-yl)ethyl)(2-hydroxyethyl) carbamate, LAVD- 51) was obtained.

1H NMR (400 MHz, CD ³ OD) δ 7.42 ( _d , J = 7.6 Hz, 1H), 6.56 (s, 1H), 4.78-4.70 (br, 2H), 3.77 (s , 1H), 3.70 ( t, J = 5.2 Hz, 2H), 3.37 (br, 1H), 3.28 (br, 2H), 1.32 (s, 9H).

Example 57. N-Hydroxy-1-(2-((2-hydroxyethyl)amino)ethyl)-1H-pyrazole-3-carboxamide (N-Hydroxy-1-(2-((2 Synthesis of -hydroxyethyl)amino)ethyl)-1H-pyrazole-3-carboxamide, LAVD-52)

In Example 47, N-hydroxy-1-(2-((2-hydroxyethyl)amino )Ethyl)-1H-pyrazole-3-carboxamide (N-Hydroxy-1-(2-((2-hydroxyethyl)amino)ethyl)-1H-pyrazole-3-carboxamide, LAVD-52) was obtained. .

1H NMR (400 MHz, CD ³ OD) δ 7.55 ( _d , J = 6.0 Hz, 1H), 6.80 (d, J = 10.0 Hz, 1H), 4.59 (s, 1H), 3.76 (t , J = 5.6 Hz 2H), 3.53 (t, J = 5.6 Hz, 2H), 3.14 (t, J = 4.8 Hz, 2H), 2.66 (s, 1H).

Example 58. 1-(2-((2-Hydroxyethyl)amino)ethyl)-1H-pyrazole-3-carboxamide (1-(2-((2-Hydroxyethyl)amino)ethyl)-1H Synthesis of -pyrazole-3-carboxamide, LAVD-61)

In Example 47, according to the conditions of Table 2, the reactant used for substituting the acyclic sugar, base or amine derivative was changed to obtain 1-(2-((2-hydroxyethyl)amino)ethyl)-1H -Pyrazole-3-carboxamide (1-(2-((2-Hydroxyethyl)amino)ethyl)-1H-pyrazole-3-carboxamide, LAVD-61) was obtained.

1H NMR (400 MHz, CD ³ OD) δ 7.59 ( _d , J = 2.0 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 4.88 (t, J = 3.6 Hz, 1H), 3.80 ( t , J = 5.2 Hz, 2H), 3.56 (t, J = 5.2 Hz, 2H), 3.18 (t, J = 5.2 Hz, 2H).

Example 59. Methyl 1-(2-((tert-butoxycarbonyl)(2-hydroxyethyl)amino)ethyl)-1H-pyrazole-4-carboxylate (Methyl 1-(2-(( Synthesis of tert-butoxycarbonyl)(2-hydroxyethyl)amino)ethyl)-1H-pyrazole-4-carboxylate, LAVD-65)

In Example 44, methyl 1-(2-((tert-butoxycarbonyl)(2-hydroxy Methyl 1-(2-((tert-butoxycarbonyl)(2-hydroxyethyl)amino)ethyl)-1H-pyrazole-4-carboxylate, LAVD -65) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (s, 2H), 4.35 (d, J = 17.2, 2H), 3.80 (s, 2H), 3.65 (br, 4H), 3.40 (br, OH), 3.22 (br, 1H), 3.15 (br, 1H), 1.36 (s, 4H), 1.32(s, 5H).

Example 60. Methyl 1-(2-((2-hydroxyethyl)amino)ethyl)-1H-pyrazole-4-carboxylate (Methyl 1-(2-((2-hydroxyethyl)amino)ethyl) Synthesis of -1H-pyrazole-4-carboxylate, LAVD-70)

In Example 44, methyl 1-(2-((2-hydroxyethyl)amino)ethyl)- 1H-pyrazole-4-carboxylate (Methyl 1-(2-((2-hydroxyethyl)amino)ethyl)-1H-pyrazole-4-carboxylate, LAVD-70) was obtained.

1H NMR (400 MHz, CD ³ OD) δ 8.27 ₍ s, 1H), 7.96 (s, 1H), 4.59 (t, J = 5.6, 2H), 3.81 (t, J = 4.8 Hz, 5H), 3.56 (t , J = 5.6 Hz, 2H), 3.21 (t, J = 5.2 Hz, 2H)

Example 61. 1-(2-((2-Hydroxyethyl)amino)ethyl)-1H-pyrazole-4-carboxamide (1-(2-((2-Hydroxyethyl)amino)ethyl)-1H Synthesis of -pyrazole-4-carboxamide, LAVD-75)

In Example 47, according to the conditions of Table 2, the reactant used for substituting the acyclic sugar, base or amine derivative was changed to obtain 1-(2-((2-hydroxyethyl)amino)ethyl)-1H -Pyrazole-4-carboxamide (1-(2-((2-Hydroxyethyl)amino)ethyl)-1H-pyrazole-4-carboxamide, LAVD-75) was obtained.

1H NMR (CD3OD, 400 MHz) δ 8.43 (s, 1H), 4.66 (t, J = 4.8 Hz, 2H), 3.91 (t, J = 4.8 Hz, 2H), 3.65 (t, J = 4.8 Hz, 2H) ), 3.55 (t, J = 4.8 Hz, 2H)

The structures and names of synthesized acyclic nucleic acid mimetics are shown in Table 3 below:

structure designation Example 1 (LAVD-87)

1-(2-(2-hydroxyethoxy)ethyl-1H-imidazole-4-carboxamide (1-(2-(2-Hydroxyethoxy)ethyl)-1H-imidazole-4-carboxamide) Example 2 (LAVD-58)

Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-carboxylate (methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H- 1,2,3-triazole-4-carboxylate) Example 3 (LAVD-67)

N-hydroxy-1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-carboxamide (N-hydroxy-1-(2-(2- hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-carboxamide) Example 4 (LAVD-69)

1-(2-(2-hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxamide (1-(2-(2 -hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxamide) Example 5 (LAVD-60)

1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-carboxamide (1-(2-(2-hydroxyethoxy)ethyl)-1H-1, 2,3-triazole-4-carboxamide) Example 6 (LAVD-44)

Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-3-carboxylate (methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-3-carboxylate Example 7 (LAVD-49)

1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-3-carboxamide (1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-3-carboxamide) Example 8 (LAVD-59)

(Z)-methyl 1-(4-hydroxybut-2-enyl)-1H-pyrazole-4-carboxylate ((Z)-methyl 1-(4-hydroxybut-2-enyl)-1H-pyrazole -4-carboxylate) Example 9 (LAVD-63)

(Z)-1-(4-hydroxybut-2-enyl)-1H-pyrazole-4-carboxamide ((Z)-1-(4-hydroxybut-2-enyl)-1H-pyrazole-4 -carboxamide) Example 10 (LAVD-48)

Methyl (Z)-1-(4-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl)-1H-pyrazole-3-carboxylate (Methyl (Z)-1- (4-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl)-1H-pyrazole-3-carboxylate) Example 11 (LAVD-53)

(Z)-1-(4-Hydroxybut-2-enyl)-1H-pyrazole-3-carboxamide ((Z)-1-(4-Hydroxybut-2-en-1-yl)-1H -pyrazole-3-carboxamide) Example 12 (LAVD-50)

(Z)-N-hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-pyrazole-3-carboxamide ((Z)-N-Hydroxy-1-(4 -hydroxybut-2-en-1-yl)-1H-pyrazole-3-carboxamide) Example 13 (LAVD-55)

(Z)-1-(4-hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide ((Z)-1-( 4-Hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide) Example 14 (LAVD-1)

Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,4-triazole-3-carboxylate (Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H- 1,2,4-triazole-3-carboxylate) Example 15 (LAVD-3)

Methyl (Z)-1-(4-hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxylate (Methyl (Z)-1-(4- hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxylate) Example 16 (LAVD-11)

(Z)-1-(4-hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxamide ((Z)-1-(4-Hydroxybut- 2-en-1-yl)-1H-1,2,4-triazole-3-carboxamide) Example 17 (LAVD-12)

(Z)-N-hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxamide ((Z)-N- Hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxamide) Example 18 (LAVD-25)

Methyl (Z)-1-(4-hydroxybut-2-en-1-yl)-1H-imidazole-4-carboxylate (Methyl (Z)-1-(4-hydroxybut-2-en- 1-yl)-1H-imidazole-4-carboxylate) Example 19 (LAVD-26)

(Z)-1-(4-Hydroxybut-2-en-1-yl)-1H-imidazole-4-carboxamide ((Z)-1-(4-Hydroxybut-2-en-1- yl)-1H-imidazole-4-carboxamide) Example 20 (LAVD-27)

(Z)-N-hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-imidazole-4-carboxamide ((Z)-N-Hydroxy-1-(4 -hydroxybut-2-en-1-yl)-1H-imidazole-4-carboxamide) Example 21 (LAVD-31)

1-(2-(2-hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-carboxamide (1-(2-(2 -Hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-carboxamide) Example 22 (LAVD-33)

Methyl 1-(6-hydroxyhexyl)-1H-1,2,4-triazole-3-carboxylate ) Example 23 (LAVD-36)

N-(2-hydroxyethyl)-1-(5-hydroxypentyl)-1H-1,2,4-triazole-3-carboxamide (N-(2-Hydroxyethyl)-1-(5- hydroxypentyl)-1H-1,2,4-triazole-3-carboxamide) Example 24 (LAVD-37)

N-(2-hydroxyethyl)-1-(6-hydroxyhexyl)-1H-1,2,4-triazole-3-carboxamide (N-(2-Hydroxyethyl)-1-(6- hydroxyhexyl)-1H-1,2,4-triazole-3-carboxamide) Example 25 (LAVD-41)

N-hydroxy-1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,4-triazole-3-carboxamide (N-Hydroxy-1-(2-(2- hydroxyethoxy)ethyl)-1H-1,2,4-triazole-3-carboxamide) Example 26 (LAVD-42)

1-(2-(2-hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-imidazole-4-carboxamide (1-(2-(2-Hydroxyethoxy)ethyl)- N-(2-hydroxyethyl)-1H-imidazole-4-carboxamide) Example 27 (LAVD-43)

Methyl 1-(6-hydroxyhexyl)-1H-imidazole-4-carboxylate (Methyl 1-(6-hydroxyhexyl)-1H-imidazole-4-carboxylate) Example 28 (LAVD-45)

1-(5-Hydroxypentyl.)-1H-1,2,4-triazole-3-carboxamide (1-(5-Hydroxypentyl)-1H-1,2,4-triazole-3-carboxamide) Example 29 (LAVD-54)

1-(5-hydroxypentyl)-1H-imidazole-4-carboxamide (1-(5-Hydroxypentyl)-1H-imidazole-4-carboxamide) Example 30 (LAVD-56)

(Z)-1-(4-hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-imidazole-4-carboxamide ((Z)-1-( 4-Hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-imidazole-4-carboxamide) Example 31 (LAVD-57)

N-(2-hydroxyethyl)-1-(6-hydroxyhexyl)-1H-imidazole-4-carboxamide (N-(2-Hydroxyethyl)-1-(6-hydroxyhexyl)-1H-imidazole -4-carboxamide) Example 32 (LAVD-64)

(Z)-N-hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-pyrazole-4-carboxamide ((Z)-N-Hydroxy-1-(4 -hydroxybut-2-en-1-yl)-1H-pyrazole-4-carboxamide) Example 33 (LAVD-66)

(Z)-1-(4-hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide ((Z)-1-( 4-Hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide) Example 34 (LAVD-71)

1-(2-(2-hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide (1-(2-(2-Hydroxyethoxy)ethyl)- N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide) Example 35 (LAVD-74)

Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-4-carboxylate (Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-4-carboxylate Example 36 (LAVD-76)

1-(6-Hydroxyhexyl)-1H-imidazole-5-carboxamide (1-(6-Hydroxyhexyl)-1H-imidazole-5-carboxamide) Example 37 (LAVD-83)

1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxamide (1-(6-Hydroxyhexyl)-1H-pyrazole-4-carboxamide) Example 38 (LAVD-84)

Methyl 1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxylate (Methyl 1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxylate) Example 39 (LAVD-85)

Methyl 1-(5-hydroxypentyl)-1H-imidazole-4-carboxylate (Methyl 1-(5-hydroxypentyl)-1H-imidazole-4-carboxylate) Example 40 (LAVD-86)

N-(2-hydroxyethyl)-1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxamide (N-(2-Hydroxyethyl)-1-(6-hydroxyhexyl)-1H-pyrazole -4-carboxamide) Example 41 (LAVD-88)

N-Hydroxy-1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxamide (N-Hydroxy-1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxamide) Example 42 (LAVD-89)

(Z)-1-(4-hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-carboxamide (( Z)-1-(4-Hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-carboxamide) Example 43 (LAVD-35)

Methyl 1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxylate (methyl 1-(2-(2-hydroxyethylamino)ethyl)-1H- 1,2,4-triazole-3-carboxylate) Example 44 (LAVD-2)

Methyl 1-(2-(tert-butoxycarbonyl(2-hydroxyethyl)amino)ethyl)-1H-1,2,4-triazole-3-carboxylate (methyl 1-(2-(tert -butoxycarbonyl(2-hydroxyethyl)amino)ethyl)-1H-1,2,4-triazole-3-carboxylate) Example 45 (LAVD-13)

1-(2-(N-(2-hydroxyethyl)acetamino)ethyl)-1H-1,2,4-triazole-3-carboxamide ((1-(2-(N-(2- hydroxyethyl)acetamido)ethyl)-1H-1,2,4-triazole-3-carboxamide) Example 46 (LAVD-34)

N-(2-hydroxyethyl)-1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide (N-(2-hydroxyethyl) -1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide) Example 47 (LAVD-14)

N-hydroxy-1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide (N-hydroxy-1-(2-(2- hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide) Example 48 (LAVD-21)

2-(2-(3-(hydroxycarbamoyl)-1H-1,2,4-triazol-1-yl)ethylamino)ethyl acetate (2-(2-(3-(hydroxycarbamoyl)-1H- 1,2,4-triazol-1-yl)ethylamino)ethyl acetate) Example 49 (LAVD-32)

N-hydroxy-1-(2-(N-(2-hydroxyethyl)acetamido)ethyl)-1H-1,2,4-triazole-3-carboxamide (N-hydroxy-1- (2-(N-(2-hydroxyethyl)acetamido)ethyl)-1H-1,2,4-triazole-3-carboxamide) Example 50 (LAVD-9)

1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide (1-(2-(2-hydroxyethylamino)ethyl)-1H-1, 2,4-triazole-3-carboxamide) Example 51 (LAVD-38)

tert-butyl 2- (4-carbamoyl-1H-imidazol-1-yl) ethyl (2-hydroxyethyl) carbamate (tert-butyl 2- (4-carbamoyl-1H-imidazol-1-yl) ethyl (2-hydroxyethyl)carbamate) Example 52 (LAVD-39)

1-(2-(2-hydroxyethylamino)ethyl)-1H-imidazole-4-carboxamide (1-(2-(2-hydroxyethylamino)ethyl)-1H-imidazole-4-carboxamide Example 53 (LAVD-40)

N-Hydroxy-1-(2-((2-hydroxyethyl)amino)ethyl)-1H-imidazole-4-carboxamide (N-Hydroxy-1-(2-((2-hydroxyethyl)amino )ethyl)-1H-imidazole-4-carboxamide) Example 54 (LAVD-46)

Methyl 1-(2-((tert-butoxycarbonyl)(2-hydroxyethyl)amino)ethyl)-1H-pyrazole-3-carboxylate (Methyl 1-(2-((tert-butoxycarbonyl) (2-hydroxyethyl)amino)ethyl)-1H-pyrazole-3-carboxylate) Example 55 (LAVD-47)

tert-butyl (2-(3-carbamoyl-1H-pyrazol-1-yl)ethyl)(2-hydroxyethyl)carbamate (tert-Butyl (2-(3-carbamoyl-1H-pyrazol-1- yl)ethyl)(2-hydroxyethyl)carbamate) Example 56 (LAVD-51)

tert-Butyl (2-(3-(hydroxycarbamoyl)-1H-pyrazol-1-yl)ethyl)(2-hydroxyethyl) carbamate (tert-Butyl (2-(3-(hydroxycarbamoyl)- 1H-pyrazol-1-yl)ethyl)(2-hydroxyethyl)carbamate) Example 57 (LAVD-52)

N-Hydroxy-1-(2-((2-hydroxyethyl)amino)ethyl)-1H-pyrazole-3-carboxamide (N-Hydroxy-1-(2-((2-hydroxyethyl)amino )ethyl)-1H-pyrazole-3-carboxamide) Example 58 (LAVD-61)

1-(2-((2-Hydroxyethyl)amino)ethyl)-1H-pyrazole-3-carboxamide (1-(2-((2-Hydroxyethyl)amino)ethyl)-1H-pyrazole-3 -carboxamide) Example 59 (LAVD-65)

Methyl 1-(2-((tert-butoxycarbonyl)(2-hydroxyethyl)amino)ethyl)-1H-pyrazole-4-carboxylate (Methyl 1-(2-((tert-butoxycarbonyl) (2-hydroxyethyl)amino)ethyl)-1H-pyrazole-4-carboxylate) Example 60 (LAVD-70)

Methyl 1-(2-((2-hydroxyethyl)amino)ethyl)-1H-pyrazole-4-carboxylate (Methyl 1-(2-((2-hydroxyethyl)amino)ethyl)-1H-pyrazole -4-carboxylate) Example 61 (LAVD-75)

1-(2-((2-Hydroxyethyl)amino)ethyl)-1H-pyrazole-4-carboxamide (1-(2-((2-Hydroxyethyl)amino)ethyl)-1H-pyrazole-4 -carboxamide)

Experimental Example 1. Investigation of physiological inhibitory activity of influenza virus

Influenza virus physiological inhibitory activity of the compounds prepared in Example 1, Example 16, Example 17, Example 45, Example 47 and Example 50 was investigated and shown in Table 4 below:

Example Toxicity CC ₅₀ (μM) Antiviral activity (EC ₅₀ : μM) Selectivity index (SI) FluA FluA FluB FluA FluA FluB H1N1 H3N2 - H1N1 H3N2 - PR8 HongKong Lee PR8 HongKong Lee Example 50 (LAVD-9) > 100.0 > 100.0 > 100.0 > 100.0 ND ND ND Example 16 (LAVD-11) > 100.0 > 100.0 > 100.0 > 100.0 ND ND ND Example 17 (LAVD-12) > 100.0 > 100.0 > 100.0 > 100.0 ND ND ND Example 1 (LAVD-87) > 100.0 25 > 100.0 > 100.0 > 4.0 ND ND Example 45 (LAVD-13) > 100.0 > 100.0 88.9 > 100.0 ND > 1.1 ND Example 47 (LAVD-14) > 100.0 > 100.0 > 100.0 > 100.0 ND ND ND

Referring to Table 4, it was confirmed that the compound of Example 1 had an EC50 value of 25 and a selectivity index (SI) of 4 or more for the influenza A virus subtype H1N1 of the compound of Example 1, and the influenza A virus H3N2 of the compound of Example 45 For subtypes, it was confirmed that the EC50 value was 88.9 and the SI was 1.1 or more. Therefore, the compound of Example 1 and the compound of Example 45 exhibited activity against type A influenza cancer cells, and since both compounds had high selectivity indexes, it could be confirmed that they were compounds capable of inhibiting influenza virus.

Manufacturing example of drug

The active substance according to the present invention can be formulated in various forms depending on the purpose. The following exemplifies some formulation methods containing the active substance according to the present invention as an active ingredient, but the present invention is not limited thereto.

<Pharmaceutical Preparation Example 1> Preparation of powder

active substance 2g

lactose 1 g

After mixing the above ingredients, the powder was prepared by filling in airtight bags.

<Pharmaceutical Preparation Example 2> Preparation of tablets

active substance 100 mg

corn starch 100 mg

Lactose 100 mg

magnesium stearate 2 mg

After mixing the above components, tablets were prepared by tableting according to a conventional tablet manufacturing method.

<Pharmaceutical Preparation Example 3> Preparation of capsules

active substance 100 mg

corn starch 100 mg

Lactose 100 mg

magnesium stearate 2 mg

After mixing the above ingredients, capsules were prepared by filling gelatin capsules according to a conventional capsule preparation method.

<Pharmaceutical Preparation Example 4> Preparation of Injections

active substance 10 μg/mL

dilute hydrochloric acid BP until pH 3.5

Sodium Chloride BP for Injection up to 1 ml

The active substance according to the present invention was dissolved in an appropriate volume of sodium chloride BP for injection, the pH of the resulting solution was adjusted to pH 3.5 with dilute hydrochloric acid BP, the volume was adjusted with sodium chloride BP for injection, and mixed thoroughly. . The solution was filled into a 5 ml type I ampoule made of transparent glass, sealed under an upper grid of air by dissolving the glass, and sterilized by autoclaving at 120° C. for 15 minutes or longer to prepare an injection solution.

<Pharmaceutical Preparation Example 5> Preparation of Nasal Spray

active substance 1.0g

sodium acetate 0.3g

Methylparaben 0.1 g

Propylparaben 0.02g

sodium chloride Appropriate amount

HCl or NaOH pH Adjustment Appropriate amount

Purified water Appropriate amount

According to the conventional method for preparing nasal absorbents, saline (0.9% NaCl, w/v, solvent is purified water) is prepared to contain 3 mg of active substance per 1 mL, filled in an opaque spray container and sterilized to prepare nasal absorbents. manufactured.

<Pharmaceutical Preparation Example 6> Preparation of liquid formulation

active substance 100 mg

Lee Seonghwadang 10g

mannitol 5g

Purified water Appropriate amount

According to the conventional method for preparing liquids, each component is dissolved in purified water, lemon flavor is added, the above components are mixed, and purified water is added to adjust the total volume to 100 mL, and then filled in a brown bottle and sterilized to prepare a liquid formulation. did

So far, the present invention has been looked at with respect to its preferred embodiments. Those skilled in the art to which the present invention pertains will be able to understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative rather than a limiting point of view. The scope of the present invention is particularly indicated in the claims rather than the foregoing description, and all differences within the equivalent range should be construed as being included in the present invention.

Claims (16)

A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In the above formula,
L is substituted or unsubstituted nitrogen (N), substituted or unsubstituted oxygen (O), substituted or unsubstituted carbon (C), substituted or unsubstituted sulfur (S), substituted or unsubstituted boron (B ), substituted or unsubstituted phosphorus (P), substituted or unsubstituted selenium (Se), and substituted or unsubstituted silicon (Si).
R ₁ is a hydrogen atom, a halo group, a carboxyl group, a haloformyl group, a hydroxyl group, a carbonyl group, an aldehyde group, a carboxylic acid ester group, a carboxyl group, an ether group, an ester group, an amide group, a hydroxyamide group, or a hydroxyalkylamide. group, an amine group, a nitric acid group, a nitrile group, a nitro group, a phosphine group, a phosphoric acid group, a sulfone group, and a sulfonic acid group, and
n ₁ and n ₂ are each an integer from 0 to 5;

is a double bond or a single bond,
X, Y, Z are -CH- or -N-, respectively.)
According to claim 1,
Wherein L is one selected from substituted or unsubstituted nitrogen (N), substituted or unsubstituted oxygen (O), and substituted or unsubstituted carbon (C),
R ₁ is one selected from a carbonyl group, an ester group, an ether group, an ester group, an amide group, a hydroxyamide group, and a hydroxyalkylamide group;
wherein n ₁ and n ₂ are each an integer of 0 to 3, or a pharmaceutically acceptable salt thereof.
According to claim 2,
L is one of -O-, -NR ₂ -, -CH- and -CH ₂ -;
The R ₁ is

,

,

and

It is one species selected from
Wherein R ₂ is hydrogen (H), a tert-butoxycarbonyl group (tert-butoxycarbonyl, BOC) and an acetyl group (Acetyl, AC), characterized in that a compound or a pharmaceutically acceptable salt thereof.
According to claim 1,
A compound or a pharmaceutically acceptable salt thereof, characterized in that the compound represented by Formula 1 is one selected from the group consisting of the following compounds:
1) 1-(2-(2-hydroxyethoxy)ethyl-1H-imidazole-4-carboxamide (1-(2-(2-Hydroxyethoxy)ethyl)-1H-imidazole-4-carboxamide;
2) methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-carboxylate (methyl 1-(2-(2-hydroxyethoxy)ethyl)- 1H-1,2,3-triazole-4-carboxylate);
3) N-hydroxy-1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-carboxamide (N-hydroxy-1-(2-( 2-hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-carboxamide);
4) 1-(2-(2-hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxamide (1-(2- (2-hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxamide);
5) 1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-carboxamide (1-(2-(2-hydroxyethoxy)ethyl)-1H- 1,2,3-triazole-4-carboxamide);
6) Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-3-carboxylate (methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-3- carboxylate);
7) 1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-3-carboxamide (1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-3-carboxamide) ;
8) (Z)-methyl 1-(4-hydroxybut-2-enyl)-1H-pyrazole-4-carboxylate ((Z)-methyl 1-(4-hydroxybut-2-enyl)-1H -pyrazole-4-carboxylate);
9) (Z)-1-(4-hydroxybut-2-enyl)-1H-pyrazole-4-carboxamide ((Z)-1-(4-hydroxybut-2-enyl)-1H-pyrazole -4-carboxamide);
10) Methyl (Z)-1-(4-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl)-1H-pyrazole-3-carboxylate (Methyl (Z)- 1-(4-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl)-1H-pyrazole-3-carboxylate);
11) (Z)-1-(4-Hydroxybut-2-enyl)-1H-pyrazole-3-carboxamide ((Z)-1-(4-Hydroxybut-2-en-1-yl) -1H-pyrazole-3-carboxamide);
12) (Z)-N-hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-pyrazole-3-carboxamide ((Z)-N-Hydroxy-1- (4-hydroxybut-2-en-1-yl)-1H-pyrazole-3-carboxamide);
13) (Z)-1-(4-hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide ((Z)-1 -(4-Hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide);
14) Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,4-triazole-3-carboxylate (Methyl 1-(2-(2-hydroxyethoxy)ethyl)- 1H-1,2,4-triazole-3-carboxylate);
15) Methyl (Z)-1-(4-hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxylate (Methyl (Z)-1-( 4-hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxylate);
16) (Z)-1-(4-hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxamide ((Z)-1-(4- Hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxamide);
17) (Z)-N-hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxamide ((Z)- N-Hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-1,2,4-triazole-3-carboxamide);
18) Methyl (Z)-1-(4-hydroxybut-2-en-1-yl)-1H-imidazole-4-carboxylate (Methyl (Z)-1-(4-hydroxybut-2- en-1-yl)-1H-imidazole-4-carboxylate);
19) (Z)-1-(4-Hydroxybut-2-en-1-yl)-1H-imidazole-4-carboxamide ((Z)-1-(4-Hydroxybut-2-en- 1-yl)-1H-imidazole-4-carboxamide);
20) (Z)-N-hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-imidazole-4-carboxamide ((Z)-N-Hydroxy-1- (4-hydroxybut-2-en-1-yl)-1H-imidazole-4-carboxamide);
21) 1-(2-(2-hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-carboxamide (1-(2- (2-Hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-carboxamide);
22) Methyl 1-(6-hydroxyhexyl)-1H-1,2,4-triazole-3-carboxylate (Methyl 1-(6-hydroxyhexyl)-1H-1,2,4-triazole-3 -carboxylate);
23) N-(2-hydroxyethyl)-1-(5-hydroxypentyl)-1H-1,2,4-triazole-3-carboxamide (N-(2-Hydroxyethyl)-1-( 5-hydroxypentyl)-1H-1,2,4-triazole-3-carboxamide);
24) N-(2-hydroxyethyl)-1-(6-hydroxyhexyl)-1H-1,2,4-triazole-3-carboxamide (N-(2-Hydroxyethyl)-1-( 6-hydroxyhexyl)-1H-1,2,4-triazole-3-carboxamide);
25) N-hydroxy-1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,4-triazole-3-carboxamide (N-Hydroxy-1-(2-( 2-hydroxyethoxy)ethyl)-1H-1,2,4-triazole-3-carboxamide);
26) 1-(2-(2-hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-imidazole-4-carboxamide (1-(2-(2-Hydroxyethoxy)ethyl )-N-(2-hydroxyethyl)-1H-imidazole-4-carboxamide);
27) Methyl 1-(6-hydroxyhexyl)-1H-imidazole-4-carboxylate;
28) 1-(5-hydroxypentyl)-1H-1,2,4-triazole-3-carboxamide (1-(5-Hydroxypentyl)-1H-1,2,4-triazole-3-carboxamide );
29) 1-(5-Hydroxypentyl)-1H-imidazole-4-carboxamide (1-(5-Hydroxypentyl)-1H-imidazole-4-carboxamide);
30) (Z)-1-(4-hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-imidazole-4-carboxamide ((Z)-1 -(4-Hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-imidazole-4-carboxamide);
31) N-(2-hydroxyethyl)-1-(6-hydroxyhexyl)-1H-imidazole-4-carboxamide (N-(2-Hydroxyethyl)-1-(6-hydroxyhexyl)-1H -imidazole-4-carboxamide);
32) (Z)-N-hydroxy-1-(4-hydroxybut-2-en-1-yl)-1H-pyrazole-4-carboxamide ((Z)-N-Hydroxy-1- (4-hydroxybut-2-en-1-yl)-1H-pyrazole-4-carboxamide);
33) (Z)-1-(4-hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide ((Z)-1 -(4-Hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide);
34) 1-(2-(2-hydroxyethoxy)ethyl)-N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide (1-(2-(2-Hydroxyethoxy)ethyl )-N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide);
35) Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-4-carboxylate (Methyl 1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-4- carboxylate);
36) 1-(6-Hydroxyhexyl)-1H-imidazole-5-carboxamide (1-(6-Hydroxyhexyl)-1H-imidazole-5-carboxamide);
37) 1-(6-Hydroxyhexyl)-1H-pyrazole-4-carboxamide (1-(6-Hydroxyhexyl)-1H-pyrazole-4-carboxamide);
38) Methyl 1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxylate;
39) Methyl 1-(5-hydroxypentyl)-1H-imidazole-4-carboxylate;
40) N-(2-hydroxyethyl)-1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxamide (N-(2-Hydroxyethyl)-1-(6-hydroxyhexyl)-1H -pyrazole-4-carboxamide);
41) N-Hydroxy-1-(6-hydroxyhexyl)-1H-pyrazole-4-carboxamide;
42) (Z)-1-(4-hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-carboxamide ((Z)-1-(4-Hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-carboxamide);
43) Methyl 1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxylate (methyl 1-(2-(2-hydroxyethylamino)ethyl)- 1H-1,2,4-triazole-3-carboxylate);
44) methyl 1-(2-(tert-butoxycarbonyl(2-hydroxyethyl)amino)ethyl)-1H-1,2,4-triazole-3-carboxylate (methyl 1-(2- (tert-butoxycarbonyl(2-hydroxyethyl)amino)ethyl)-1H-1,2,4-triazole-3-carboxylate);
45) 1-(2-(N-(2-hydroxyethyl)acetamino)ethyl)-1H-1,2,4-triazole-3-carboxamide ((1-(2-(N-( 2-hydroxyethyl)acetamido)ethyl)-1H-1,2,4-triazole-3-carboxamide);
46) N-(2-hydroxyethyl)-1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide (N-(2- hydroxyethyl)-1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide);
47) N-hydroxy-1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide (N-hydroxy-1-(2-( 2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide);
48) 2-(2-(3-(hydroxycarbamoyl)-1H-1,2,4-triazol-1-yl)ethylamino)ethyl acetate (2-(2-(3-(hydroxycarbamoyl)- 1H-1,2,4-triazol-1-yl)ethylamino)ethyl acetate);
49) N-hydroxy-1-(2-(N-(2-hydroxyethyl)acetamido)ethyl)-1H-1,2,4-triazole-3-carboxamide (N-hydroxy- 1-(2-(N-(2-hydroxyethyl)acetamido)ethyl)-1H-1,2,4-triazole-3-carboxamide);
50) 1-(2-(2-hydroxyethylamino)ethyl)-1H-1,2,4-triazole-3-carboxamide (1-(2-(2-hydroxyethylamino)ethyl)-1H- 1,2,4-triazole-3-carboxamide);
51) tert-butyl 2-(4-carbamoyl-1H-imidazol-1-yl)ethyl(2-hydroxyethyl)carbamate (tert-butyl 2-(4-carbamoyl-1H-imidazol-1-yl )ethyl(2-hydroxyethyl)carbamate);
52) 1-(2-(2-hydroxyethylamino)ethyl)-1H-imidazole-4-carboxamide (1-(2-(2-hydroxyethylamino)ethyl)-1H-imidazole-4-carboxamide ;
53) N-Hydroxy-1-(2-((2-hydroxyethyl)amino)ethyl)-1H-imidazole-4-carboxamide (N-Hydroxy-1-(2-((2-hydroxyethyl )amino)ethyl)-1H-imidazole-4-carboxamide);
54) Methyl 1-(2-((tert-butoxycarbonyl)(2-hydroxyethyl)amino)ethyl)-1H-pyrazole-3-carboxylate (Methyl 1-(2-((tert- butoxycarbonyl)(2-hydroxyethyl)amino)ethyl)-1H-pyrazole-3-carboxylate);
55) tert-Butyl (2-(3-carbamoyl-1H-pyrazol-1-yl)ethyl)(2-hydroxyethyl)carbamate (tert-Butyl (2-(3-carbamoyl-1H-pyrazol- 1-yl)ethyl)(2-hydroxyethyl)carbamate);
56) tert-Butyl (2-(3-(hydroxycarbamoyl)-1H-pyrazol-1-yl)ethyl)(2-hydroxyethyl)carbamate (tert-Butyl (2-(3-(hydroxycarbamoyl) )-1H-pyrazol-1-yl)ethyl)(2-hydroxyethyl) carbamate);
57) N-Hydroxy-1-(2-((2-hydroxyethyl)amino)ethyl)-1H-pyrazole-3-carboxamide (N-Hydroxy-1-(2-((2-hydroxyethyl )amino)ethyl)-1H-pyrazole-3-carboxamide);
58) 1-(2-((2-hydroxyethyl)amino)ethyl)-1H-pyrazole-3-carboxamide (1-(2-((2-hydroxyethyl)amino)ethyl)-1H-pyrazole -3-carboxamide);
59) Methyl 1-(2-((tert-butoxycarbonyl)(2-hydroxyethyl)amino)ethyl)-1H-pyrazole-4-carboxylate (Methyl 1-(2-((tert- butoxycarbonyl)(2-hydroxyethyl)amino)ethyl)-1H-pyrazole-4-carboxylate);
60) Methyl 1-(2-((2-hydroxyethyl)amino)ethyl)-1H-pyrazole-4-carboxylate (Methyl 1-(2-((2-hydroxyethyl)amino)ethyl)-1H -pyrazole-4-carboxylate); and
61) 1-(2-((2-Hydroxyethyl)amino)ethyl)-1H-pyrazole-4-carboxamide (1-(2-((2-Hydroxyethyl)amino)ethyl)-1H-pyrazole -4-carboxamide).
According to claim 1,
A compound characterized by having antiviral activity or a pharmaceutically acceptable salt thereof.
As shown in Scheme A below,
introducing a protecting group (R ₃ ) to an acyclic sugar represented by Compound A (Step 1);
reacting an acyclic sugar (A′) into which a protecting group is introduced and a pentagonal base represented by compound Ba (step 2); and
removing the protecting group (R ₃ ) introduced in step 1 (step 3);
A method for preparing the compound of claim 1 comprising:
[Scheme A]

(In the above formula,
L is substituted or unsubstituted nitrogen (N), substituted or unsubstituted oxygen (O), substituted or unsubstituted carbon (C), substituted or unsubstituted sulfur (S), substituted or unsubstituted boron (B ), substituted or unsubstituted phosphorus (P), substituted or unsubstituted selenium (Se), and substituted or unsubstituted silicon (Si).
R ₁ 'is a hydrogen atom, a halo group, a carboxyl group, a haloformyl group, a hydroxyl group, an aldehyde group, an amide group, a hydroxyamide group, a hydroxyalkylamide group, an amine group, a nitrate group, a nitrile group, a nitro group, a phosphate group, It is one type selected from a pin group, a phosphoric acid group, a sulfone group, and a sulfonic acid group,
R ₃ is tert-butyldimethylsilyl (TBS), trimethylsilylethoxymethyl (SEM), methoxyethoxymethyl (MEM), methoxymethyl (MOM), tetrahydropyranyl (THP) and tetrahydropyranyl ( THE) is one selected from,
n ₁ and n ₂ are each an integer from 0 to 5;

is a double bond or a single bond,
X, Y, Z are -CH- or -N-, respectively.)
According to claim 6,
The acyclic sugar represented by the compound A,
A1) dimethylene glycol;
A2) cis-2-butene-1,4-diol ;
A3) pentane-1,5-diol;
A4) Hexane-1,6-diol; and
A5) diethanolamine (Diethanolamine); characterized in that the production method is one selected from the group consisting of.
According to claim 6,
The second step is carried out by a nucleophilic substitution reaction,
The production method, characterized in that the nucleophilic substitution reaction is a Mitsunobu reaction or a click reaction.
As shown in Scheme B below,
introducing a protecting group (R ₃ ) to an acyclic sugar represented by Compound A (Step 1);
Reacting the acyclic sugar (A') into which a protecting group is introduced and the pentagonal base represented by Compound B' (Step 2); and
removing the protecting group (R ₃ ) introduced in step 1 (step 3);
A method for preparing the compound of claim 1 comprising:
[Scheme B]

(In the above formula,
L is substituted or unsubstituted nitrogen (N), substituted or unsubstituted oxygen (O), substituted or unsubstituted carbon (C), substituted or unsubstituted sulfur (S), substituted or unsubstituted boron (B ), substituted or unsubstituted phosphorus (P), substituted or unsubstituted selenium (Se), and substituted or unsubstituted silicon (Si).
R ₃ is tert-butyldimethylsilyl (TBS), trimethylsilylethoxymethyl (SEM), methoxyethoxymethyl (MEM), methoxymethyl (MOM), tetrahydropyranyl (THP) and tetrahydropyranyl ( THE) is one selected from,
n ₁ and n ₂ are each an integer from 0 to 5;

is a double bond or a single bond,
X, Y, Z are -CH- or -N-, respectively.)
According to claim 9,
The acyclic sugar represented by the compound A,
A1) dimethylene glycol;
A2) cis-2-butene-1,4-diol ;
A3) pentane-1,5-diol;
A4) Hexane-1,6-diol; and
A5) diethanolamine (Diethanolamine); characterized in that the production method is one selected from the group consisting of.
According to claim 9,
The pentagonal base compound represented by the compound Bb,
B1) Methyl 1H-imidazole-4-carboxylate;
B2) Methyl 1H-pyrazole-3-carboxylate;
B3) Methyl 1H-pyrazole-4-carboxylate;
B4) Methyl 1H-1,2,4-triazole-3-carboxylate; and
B5) methyl 1H-1,2,3-triazole-4-carboxylate (Methyl 1H-1,2,3-triazole-4-carboxylate);
According to claim 9,
The second step is carried out by a nucleophilic substitution reaction,
The production method, characterized in that the nucleophilic substitution reaction is a Mitsunobu reaction or a click reaction.
According to claim 9,
After step 3 above,
Adding a nitrogen compound to the resulting compound 1b to replace the carboxylate of the pentagonal base compound with an amine derivative (step 4); manufacturing method characterized in that it further comprises.
According to claim 13,
The nitrogen compound added in step 4 is a manufacturing method, characterized in that one selected from ammonia water, hydroxyamine and ethanolamine.
A medicament comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.
A use for the preparation of a medicament comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.