KR101564425B1 - Novel bicyclic nitroimidazole carbamate compounds, process for preparation thereof and pharmaceutical composition for preventing or treating tuberculosis containing the same as an active ingredient - Google Patents

Abstract

상기 화학식 1에서, R₁ 및 R₂는 각각 발명의 상세한 설명에서 정의한 바와 같다.
본 발명의 바이사이클릭 니트로이미다졸 카바메이트 화합물은 활동성 및 비활동성 결핵균에 대해 우수한 억제 효과를 나타내므로, 결핵의 치료에 유용하게 사용될 수 있다.The present invention relates to a bicyclic nitroimidazole carbamate compound represented by the following formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof, a method for producing the same, and a medicament for preventing or treating tuberculosis disease ≪ / RTI >
[Chemical Formula 1]

In Formula 1, R ₁ and R ₂ are each as defined in the description of the invention.
The bicyclic nitroimidazole carbamate compound of the present invention exhibits an excellent inhibitory effect on active and inactive Mycobacterium tuberculosis, and thus can be usefully used for the treatment of tuberculosis.

Description

TECHNICAL FIELD The present invention relates to a novel bicyclic nitroimidazole carbamate compound, a process for producing the same, and a pharmaceutical composition for preventing or treating tuberculosis disease containing the same as an active ingredient. treating tuberculosis containing the same active ingredient < RTI ID = 0.0 >

The present invention relates to a novel bicyclic nitroimidazole carbamate compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition for preventing or treating tuberculosis disease containing the same as an active ingredient will be.

PA-824 with antituberculous effect is currently in clinical trials as a nitroimidazole-based compound (C. Kendall Stover et al., Nature 2000, 405, 962-966), [Pipeline of TB Alliance, www.tballiance.org , 2013), another nitroimidazole compound, OPC-67683, is also in clinical trials earlier than PA-824 as anti-tuberculosis drug, and TBA-354 compound is currently in preclinical development stage (Hirofumi Sasaki et al. , J. Med. Chem . 2006, 49, 7854-7860], [Pilho Kim et al ., J. Med . Chem . 2009, 52, 1329-1344], Andrew M. Thompson et al ., J. Med . , 54, 6563-6585], [Adrian Blaser et al ., J. Med . Chem . 2012, 55, 312-326], [Jiricek, Jan et al ., WO2007 / 075872], [Ding, Charles, , Dennyl, William, Alexander et al., WO2011 / 014774, Thompson, Andrew, M. et al WO2011 / 014776).

Nitromimidazole compounds have shown good efficacy against inactive tubercle bacillus, one of the factors considered important for the shortening of the treatment period. Tuberculosis is an intractable disease that requires a long treatment period to be cured. In particular, bicyclic click nitroimidazoles have been studied in recent years (William Denny et al., J. Med. Chem. 2010, 53, 282-294; Kawano, Yoshikazu et al., WO 2012/141338) (See J. Kim et al., J. Med. Chem. 2009, 52, 1317-1328) and Korean Patent Application No. 2009-103041 have also been reported on the anti-tuberculosis effect of nitroimidazole-based compounds ).

Under these circumstances, the present inventors have completed the present invention by discovering a novel bicyclo-nitroimidazole carbamate compound which shows an excellent inhibitory effect on Mycobacterium tuberculosis, particularly inactive tubercle bacilli, as compared with existing monocyclic nitrimidazole-based compounds.

WO2007 / 075872 WO2009 / 120789 WO2011 / 014774 WO2011 / 014776 WO 2012/141338 Korean Patent Application No. 2009-103041

 C. Kendall Stover et al., Nature 2000, 405, 962-966  Pipeline of TB Allience, www.tballiance.org, 2013  Hirofumi Sasaki et al., J. Med. Chem. 2006, 49, 7854-7860  Pilho Kim et al., J. Med. Chem. 2009, 52, 1329-1344  Andrew M. Thompson et al., J. Med. Chem. 2011, 54, 6563-6585  Adrian Blaser et al., J. Med. Chem. 2012, 55, 312-326  William Denny et al., J. Med. Chem. 2010, 53, 282-294  Kim, P., et al., J. Med. Chem. 2009, 52, 1317-1328

Accordingly, an object of the present invention is to provide a novel bicyclo-nitroimidazole carbamate compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for producing the above-mentioned bicyclo- nitroimidazole carbamate compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating tuberculosis diseases containing the above-mentioned bicyclo-nitroimidazole carbamate compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to solve the above problems, the present invention provides a bicyclic nitroimidazole carbamate compound represented by the following formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

In Formula 1,

R ₁ and R ₂ are each independently hydrogen, (C1-C10) alkyl, (C6-C20) aryl, (C6-C20) which are (C1-C10) alkyl, (C6-C20) aryloxy (C6-C20) aryl, (C6-C20) aralkyl (C1-C10) alkyloxy (C6-C20) aryl, (C3-C20) alkenyl, or SO ₂ R ₃ heteroaryl, (C3-C20) cycloalkyl, (C2-C7) Or R ₁ and R ₂ may be linked with -L ₁ -N (R ₄ ) -L ₂ - to form a ring, provided that R ₁ and R ₂ are not simultaneously hydrogen;

R ₃ is (C 1 -C 10) alkyl or (C 6 -C 20) aryl;

L ₁ and L ₂ are each independently (C ₁ -C 5) alkylene;

R ₄ is selected from the group consisting of (C 6 -C 20) aryl, (C 6 -C 20) aryl (C 6 -C 20) alkyl, (C 6 -C 20) C1-C10) alkyloxy (C1-C10) alkyl;

Wherein R ₁ and R ₂ of the aryl, aralkyl, aryloxyalkyl, aryl, aralkyloxy aryl, of R _3, aryl, the R ₄ aryl, aralkyl, aralkyloxy aryl, aralkyl oxyalkyl are each independently ( (C1-C10) alkyl, (C1-C10) alkoxy, halogen, (C1-C10) alkoxycarbonyl, halo (C6-C20) arylcarbonyl, (C2-C7) alkenyl, (C3-C20) cycloalkyl, 5 to 7 membered carbocyclyl, cyano, hydroxy, amino, (C4-C20) heteroaryl, and nitro; and R < 2 >

Wherein said heterocycloalkyl and heteroaryl comprise at least one heteroatom selected from N, O and S;

In order to achieve the above other objects, the present invention provides a method for producing the bicyclic nitroimidazole carbamate compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

In order to accomplish the above object, the present invention provides a pharmaceutical composition for preventing or treating a tuberculosis disease containing the bicyclic nitroimidazole carbamate compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient .

The novel bicyclic nitroimidazole carbamate compound, its optical isomer or pharmaceutically acceptable salt thereof of the present invention exhibits an excellent inhibitory effect on active and inactive Mycobacterium tuberculosis, and thus can be useful for the treatment of tuberculosis.

Hereinafter, the present invention will be described in more detail. Unless otherwise defined, technical terms and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the following description, And a description of the known function and configuration will be omitted.

Hereinafter, the present invention will be described in detail.

The present invention provides a bicyclic nitroimidazole carbamate compound represented by the following general formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

In Formula 1,

R ₁ and R ₂ are each independently hydrogen, (C1-C10) alkyl, (C6-C20) aryl, (C6-C20) aralkyl (C1-C10) alkyl, (C6-C20) aryloxy (C6-C20) aryl, (C6-C20) aralkyl (C1-C10) alkyloxy (C6-C20) aryl, (C3-C20) alkenyl, or SO ₂ R ₃ heteroaryl, (C3-C20) cycloalkyl, (C2-C7) Or R ₁ and R ₂ may be linked with -L ₁ -N (R ₄ ) -L ₂ - to form a ring, provided that R ₁ and R ₂ are not simultaneously hydrogen;

R ₃ is (C 1 -C 10) alkyl or (C 6 -C 20) aryl;

L ₁ and L ₂ are each independently (C ₁ -C 5) alkylene;

R ₄ is selected from the group consisting of (C 6 -C 20) aryl, (C 6 -C 20) aryl (C 6 -C 20) alkyl, (C 6 -C 20) C1-C10) alkyloxy (C1-C10) alkyl;

Wherein R ₁ and R ₂ of the aryl, aralkyl, aryloxyalkyl, aryl, aralkyloxy aryl, of R _3, aryl, the R ₄ aryl, aralkyl, aralkyloxy aryl, aralkyl oxyalkyl are each independently ( (C1-C10) alkyl, (C1-C10) alkoxy, halogen, (C1-C10) alkoxycarbonyl, halo (C6-C20) arylcarbonyl, (C2-C7) alkenyl, (C3-C20) cycloalkyl, 5 to 7 membered carbocyclyl, cyano, hydroxy, amino, (C4-C20) heteroaryl, and nitro; and R < 2 >

Wherein said heterocycloalkyl and heteroaryl comprise at least one heteroatom selected from N, O and S;

The bicyclic nitroimidazole carbamate derivative according to the present invention can be represented by the following formula 2 or 3:

(2)

(3)

In the general formulas (2) and (3), R ₂ and R ₄ are the same as defined in the general formula (1).

Preferably, R ₂ is selected from the group consisting of (C6-C20) aryl, (C6-C20) ar (C1-C10) alkyl, (C6- C20) aryloxy -C10) alkyloxy (C6-C20) aryl, or SO ₂ R ₃ and, R ₃ is (C6-C20) aryl, R ₄ is a (C6-C20) aryl, (C6-C20) aralkyl (C1-C10) alkyl, (C6-C20) aralkyl (C1-C10) alkyloxy (C6-C20) aryl or (C6-C20) aralkyl (C1-C10) alkyloxy (C1-C10) alkyl, aryl, aralkyl in the R ₂ alkyl, aryloxy aryl, aralkyloxy aryl, of R ₃ aryl, and aryl, aralkyl, aralkyloxy aryl or aralkyloxy alkyl of R ₄ are each independently (C1-C10) alkyl, (C1-C10) May be further substituted with one or more substituents selected from the group consisting of halogen, (C1-C10) alkoxycarbonyl, halo (C1-C10) alkoxy, halo (C1-C10) alkyl and nitro.

Wherein R ₂ is phenyl, naphthyl, biphenyl, phenoxyphenyl, benzyloxy or phenylsulfonyl, R ₄ is benzyl, benzyloxyphenyl, benzyloxyethyl or phenyl and R ₂ of the phenyl, naphthyl, biphenyl, phenoxyphenyl, benzyloxyphenyl, benzyl, or phenylsulfonyl, and benzyl of R _4, benzyloxyphenyl, benzyloxy ethyl or phenyl, methoxy, chloromethyl, each independently, Which may be further substituted with one or more selected from the group consisting of fluoro, nitro, trifluoromethyl, ethoxycarbonyl, trifluoromethoxy.

Specific examples of the more preferable compound as the bicyclic nitroimidazole carbamate compound of Formula 1 according to the present invention are as follows:

1) (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin-7-yl) methyl m-tolylcarbamate,

2) (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin-7-yl) methyl 4-methoxyphenylcarbamate,

3) (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin-7-yl) methyl 4-chlorophenylcarbamate,

4) (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin-7-yl) methyl 2,4-dichlorophenylcarbamate,

5) Preparation of ethyl 3 - (((2-nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin-7-yl) methoxy) carbonylamino) Eight,

6) (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin-7-yl) methyl 4-chlorophenylsulfonylcarbamate,

7) dihydro-5H-imidazo [2,1-b] [1,3] oxazin-7-yl) methyl 4 '- (trifluoromethoxy) biphenyl- 4-yl carbamate,

8) (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin-7-yl) methyl 4- (4- (trifluoromethoxy) Yl) phenylcarbamate,

9) (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin-7-yl) methyl 4- (4- (trifluoromethyl) benzyl Oxy) phenylcarbamate,

10) (R) - (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin- Benzyloxy) phenylcarbamate, < RTI ID = 0.0 >

11) (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin-7-yl) methyl 4- (4-fluorobenzyl) piperazine- 1-carboxylate,

12) (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin-7-yl) methyl 4- (4- Methyl) benzyloxy) phenyl) piperazine-1-carboxylate,

13) (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin- Methyl) benzyloxy) ethyl) piperazine-1-carboxylate,

14) (R) - (2- nitro-6,7-dihydro -5 H - to the imidazo [2,1-b] [1,3] oxazin-7-yl) methyl 4- (4-fluoro Phenyl) piperazine-1-carboxylate,

15) (R) - (2- nitro-6,7-dihydro -5 H - to the imidazo [2,1-b] [1,3] oxazin-7-yl) methyl 4- (Tryp Luo Methyl) benzyl carbamate,

16) (R) - (2- nitro-6,7-dihydro -5 H - imidazo [2,1-b] [1,3] oxazin-7-yl) methyl methyl 4- (4-trifluoromethyl ) Phenyl carbamate,

17) (R) - (2- nitro-6,7-dihydro -5 H - imidazo [2,1-b] [1,3] oxazin-7-yl) methyl-4- (trifluoromethoxy ) Phenyl carbamate,

18) (R) - (2- nitro-6,7-dihydro -5 H - imidazo [2,1-b] [1,3] oxazin-7-yl) methyl-1-yl-carbamate ,

19) (R) - (2- nitro-6,7-dihydro -5 H - Photo-7-yl-imidazo [2,1-b] [1,3] octanoic) methyl 4-nitrophenyl carbamate,

20) (R) - (2- nitro-6,7-dihydro -5 H - imidazo [2,1-b] [1,3] oxazin-7-yl) methyl-phenyl-carbamate,

21) (R) - (2- nitro-6,7-dihydro -5 H - imidazo [2,1-b] [1,3] oxazin-7-yl) phenyl carbamate of methyl 3-fluoro And

22) (R) - (2- nitro-6,7-dihydro -5 H - imidazo [2,1-b] [1,3] oxazin-7-yl) methyl-methyl-3- (trifluoromethyl ) Phenylcarbamate.

The bicyclic nitroimidazole carbamate compound of Formula 1 of the present invention can be used in the form of a solvate, a hydrate, and a pharmaceutically acceptable salt for enhancing in vivo absorption or increasing solubility. Therefore, Cargo, hydrates and pharmaceutically acceptable salts are also within the scope of the present invention. In addition, the present invention encompasses both racemates and stereoisomers of the bicyclic nitroimidazole carbamate compounds represented by Formula 1 above.

The term " halo "or" halogen "as used herein means fluoro, bromo, chloro or iodo.

The term "alkyl" as used herein means a linear or branched saturated C1 to C10 hydrocarbon radical chain. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl and hexyl.

As used herein, the term "alkoxy" means an-ORa group wherein Ra is alkyl as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and the like.

The term "aryl" as used herein includes fused groups such as naphthyl, phenanthrenyl, and the like, as well as monocyclic or bicyclic aromatic rings such as phenyl, substituted phenyl, and the like.

The term "heteroaryl ", as used herein, refers to a straight or branched chain alkyl group having from 5 to 10 member atoms, such as furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isooxazolyl, pyrrolyl, Thiazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, Thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-tri Pyridinyl, 6,7-dihydro-5H- [1] pyridinyl, or 5,6,7,8-tetramethylpiperazin- Benzothiazolyl, benzimidazolyl, benzanthiazolyl, benzothiazolyl, benzo [b] thiophenyl, benzisothiazolyl, benzisoxazole, benzimidazolyl, thianaphthenyl, isothiocyanato, Anaphthyl, benzofuranyl, isobenzofuranyl, iso 3,4-b] pyridinyl, benzoxazinyl, and the like can be prepared by reacting a compound represented by the general formula .

The term "cycloalkyl" as used herein means a polycyclic alkyl group fused with two or more monocyclic alkyls as well as monocyclic alkyl groups having 3 to 6 carbon ring atoms. Specific examples thereof include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term "alkenyl " as used herein means a linear or branched hydrocarbon radical chain having two or more carbon-carbon double bonds. Examples of "alkenyl" as used herein include, but are not limited to, ethenyl and propenyl.

"Pharmaceutically acceptable salts" of the compounds of formula 1 may be prepared by conventional methods in the art and include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sodium hydrogen sulphate, phosphoric acid, nitric acid, And salts with the same inorganic acids, such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestic acid, fumaric acid, lactobionic acid, salicylic acid, Salts with organic acids such as silicic acid (aspirin), salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, asparaginic acid, glutamine, lysine, arginine, tyrosine, proline and the like, , A salt with a sulfonic acid such as ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid, a metal salt with a reaction with an alkali metal such as sodium or potassium or a salt with an ammonium ion It should.

The present invention also provides a process for preparing a bicyclic nitroimidazole carbamate compound of formula (1).

According to a preferred embodiment of the present invention, the bicyclic nitroimidazole carbamate compound of formula (I) of the present invention is prepared by reacting a bicyclo nitroimidazole oxazine compound of formula (Ia) with an isocyanate derivative compound of formula Can be obtained by reacting the same piperazine derivative compounds with amine derivative compounds such as the formula (7).

[Formula 1a]

[Chemical Formula 4]

R ₂ -NCO

[Chemical Formula 5]

(7)

Wherein R, R ₁ and R ₂ are each independently hydrogen, (C1-C10) alkyl, (C6-C20) aryl, (C6-C20) aralkyl (C1-C20) alkyl, (C6-C20) aryloxy (C6 (C3-C20) cycloalkyl, (C2-C7) alkenyl or SO (C6-C60) aryl ₂ R _3, or R ₁ and R ₂ may be linked to -L ₁ -N (R ₄ ) -L ₂ - to form a ring, provided that R ₁ and R ₂ are not simultaneously hydrogen;

R ₃ is (C 1 -C 20) alkyl or (C 6 -C 20) aryl;

L ₁ and L ₂ are each independently (C ₁ -C 5) alkylene;

R ₄ is selected from the group consisting of (C 6 -C 20) aryl, (C 6 -C 20) aryl (C 6 -C 20) alkyl, (C 6 -C 20) C1-C20) alkyloxy (C1-C20) alkyl;

Wherein R ₁ and R ₂ of the aryl, aralkyl, aryloxyalkyl, aryl, aralkyloxy aryl, of R _3, aryl, the R ₄ aryl, aralkyl, aralkyloxy aryl, aralkyl oxyalkyl are each independently ( (C 1 -C 20) alkyl, (C 1 -C 20) alkoxy, halogen, (C 1 -C 20) alkoxycarbonyl, halo (C 1 -C 20) alkoxy, halo (C6-C20) arylcarbonyl, (C2-C7) alkenyl, (C3-C20) cycloalkyl, 5 to 7 membered carbocyclyl, cyano, hydroxy, amino, (C4-C20) heteroaryl, and nitro. The term " aryl "

Specifically, the bicyclic nitroimidazole carbamate compounds of formula (I) according to the present invention can be prepared according to the synthetic route represented by the following reaction schemes.

First, the bicyclo nitroimidazole oxazine compound of formula (1a) can be prepared according to the synthesis route shown in the following reaction scheme 1:

[Reaction Scheme 1]

As shown in Reaction Scheme 1, the preparation method of Compound A of the present invention will be described in detail as follows. First, 2-bromo-4-nitro- 1H -imidazole, which is an intermediate compound 1a , was prepared by using 4-nitro- 1H -imidazole as starting material, and 2- (2,2- Dioxolane-4-yl) ethanol was reacted to prepare the target compound A.

Compound B, which is a stereoisomer of the bicyclo nitroimidazole oxazine compound of formula (1a), may be prepared according to the following synthetic route:

[Reaction Scheme 2]

As shown in Scheme 2, preparation of the compounds of the invention B is (R) -2- a bromide a (2,2-dimethyl-1,3-dioxolane-4-yl) ethanol (2a) Bromo-4-nitro-1H-imidazole ( 1a ) in the same manner as in Scheme 1, to give the desired compound B as a stereoisomer of Compound A.

The preparation methods of the bicyclic nitroimidazole carbamate compounds of the formula (1) of the present invention are shown in the following reaction formula (3).

[Reaction Scheme 3]

As shown in Reaction Scheme 3, Compound ( A ) can be reacted with copper chloride and isocyanate compounds in an anhydrous N, N-dimethylformamide solvent to obtain A1 compounds as a carbamate-type final compound, (a) Preparation of the chloroformate compounds and 4-methylmorpholine and the reaction was then substituted amine compounds to yield final compound of cover A1 and A2 compounds of the formate form in anhydrous dichloromethane, or the compound (a) Was reacted with triphosgene in the presence of triethylamine in anhydrous tetrahydrofuran solvent and then the piperazine compounds were reacted with this intermediate compound to give the final compound A2 compounds in the form of piperazine carbamate.

In addition, each of the preparation methods of each of the derivative compounds used in the reaction is, for example, but not limited to the following.

[Reaction Scheme 4]

As shown in Reaction Scheme 4, the preparation method of the substituted phenoxyphenyl isocyanate intermediate C and the substituted biphenyl isocyanate intermediate D compounds will be described in detail as follows. Nitrobenzene substituted with halogen is reacted with potassium carbonate in a N, N -dimethylformamide solvent with a phenol compound substituted with derivatives at 120 ° C for 5.5 hours to prepare C1 derivative compounds, while substituted phenylboron If acid compounds with dioxane as palladium in a water solvent, the reaction for 7.5 hours at 80 ℃ with potassium carbonate is made to D1 derivatives. The obtained nitro derivative compounds of C1 and D1 are added with 2 to 3 drops of concentrated hydrochloric acid together with iron in a solvent of ethanol and water, and then reacted at 110 DEG C for 4 hours to obtain C2 and D2 compounds. Then, C2 and D2 compounds were added with triethylamine in tetrahydrofuran and methylene chloride solvent, the phosgene solution (toluene) was slowly added at 0 ° C, and the mixture was reacted at room temperature for 3 hours to obtain final intermediate compounds C and D.

[Reaction Scheme 5]

As shown in Reaction Scheme 5, the preparation method of the substituted benzyloxyphenyl isocyanate intermediate E compounds will be described in detail as follows. Nitrophenol was slowly added to the sodium hydride in N, N -dimethylformamide solvent at 0 < 0 > C, and after 1 hour, the substituted benzylhalogen compounds were added and reacted overnight at room temperature to obtain intermediate compound E1 . The resulting intermediate compound E1 was reduced to iron as in Scheme 4 and reacted with phosgene to give the final intermediate compound E.

[Reaction Scheme 6]

As shown in Scheme 6, the method for preparing the substituted piperazine intermediate F compounds will be described in detail as follows. Substituted piperazine having an alcohol group is reacted with di-tert-butyldicarbonate in methanol to give F1 , an intermediate compound in which the amine group is protected, which is then reacted with sodium hydride in N, N -dimethylformamide After the next hour, the substituted benzyl halide compounds were added and reacted overnight at room temperature to give intermediate compound F2 . This was removed from methanol using hydrochloric acid to remove the BOC to obtain the substituted piperazine compound F as a final intermediate compound in hydrochloride form.

The preparation methods of the respective derivative compounds used in the reaction are described in detail in each of the following examples.

Meanwhile, the present invention provides a pharmaceutical composition for the prevention or treatment of tuberculosis diseases, which comprises, as an active ingredient, a bicyclic nitroimidazole carbamate compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition comprising the bicyclic nitroimidazole carbamate compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof according to the present invention can be administered orally or parenterally at the time of clinical administration and can be administered in the form of a general pharmaceutical preparation And when it is formulated, it can be prepared by using a commonly used diluent such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, or an excipient.

Solid formulations for oral administration may be prepared by mixing at least one excipient, such as starch, calcium carbonate, sucrose, lactose, or gelatin, in one or more of the nitroimidazole compounds of the present invention . In addition to simple excipients, lubricants such as magnesium stearate or talc may also be used.

Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. Various excipients such as wetting agents, sweetening agents, perfumes or preservatives can be used in addition to water and liquid paraffin, which are commonly used simple diluents. have.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations or suppositories. Examples of the non-aqueous solvent or suspending agent include vegetable oil such as propylene glycol, polyethylene glycol or olive oil, injectable ester such as ethyl oleate, etc. Examples of the suppository include withexol, macrogol, tween 61, Cacao butter, laurin butter, glycerol or gelatin.

In addition, the human body dose of the pharmaceutical composition for the prevention or treatment of tuberculosis disease according to the present invention may be varied depending on the age, weight, sex, dosage form, health condition and disease severity of the patient, , It is generally 0.1 to 1000 mg / day, preferably 1 to 500 mg / day, and may be dividedly administered once to several times a day at predetermined time intervals.

Hereinafter, the present invention will be described in more detail with reference to examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention more specifically and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention.

Example  1: (2-Nitro-6,7- Dihydro -5H- Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  m- Tolyl carbamate  (1)

(2-nitro-6,7-dihydro - 5H - imidazo [2,1-b] [1,3] oxazin-7-yl) in dry methanol (Compound A), 199mg (1mmol), N, N- And 0.15 ml (1.2 mmol) of m-tolyl isocyanate and 11.8 mg (0.12 mmol) of copper chloride were added thereto, followed by reaction at room temperature overnight. When the reaction was completed, 40 ml of ethyl acetate was added and washed twice with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent, chloroform / methanol = 40/1) to give the desired compound 1, which was purified by methanol / Obtained as a brown solid (137 mg, 41.2%).

^{1 H-NMR (300 MHz,} DMSO): δ 2.07 (m, 2H), 2.22 (s, 3H), 4.06 (m, 2H), 4.35 (m, 2H), 4.76 (m, 1H), 6.78 (d 1H, J = 7.1 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 7.23 (m, 2H), 8.06 (s, 1H), 9.74 MS (EI, m / e) = 332 (M ^< ^{+ &} gt ^; ).

Example  2: (2-Nitro-6,7- Dihydro - 5H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  4- Methoxyphenylcarbamate  (2)

199 mg (1 mmol) of the compound A and 0.155 ml (1.2 mmol) of 4-methoxyphenyl isocyanate were reacted in the same manner as in Example 1 to obtain the desired compound 2 as a gray solid (156 mg, 44.8%).

^{1 H-NMR (300 MHz,} DMSO): δ 2.08 (m, 1H), 2.24 (m, 1H), 3.69 (s, 3H), 4.10 (m, 2H), 4.36 (m, 2H), 4.78 (m 1H), 6.85 (d, J = 8.7 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 8.07 (s, 1H), 9.64 MS (EI, m / e) = 348 (M ^< ^{+ &} gt ^; ).

Example  3: (2-Nitro-6,7- Dihydro - 5H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  4- Chlorophenylcarbamate  (5)

199 mg (1 mmol) of the compound A and 184 mg (1.2 mmol) of 4-chlorophenyl isocyanate were reacted in the same manner as in Example 1 to obtain the desired compound 3 as a off-white solid (185 mg, 52.5%).

^{1 H-NMR (300 MHz,} DMSO): δ 2.10 (m, 1H), 2.24 (m, 1H), 4.11 (m, 2H), 4.38 (m, 2H), 4.80 (m, 1H), 7.33 (d , J = 8.8 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 8.07 (s, 1H), 10.01 (s, 1H); MS (EI, m / e) = 352 (M ^< ^{+ &} gt ^; ).

Example  4: (2-Nitro-6,7- Dihydro - 5H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  2,4- Dichlorophenylcarbamate  (4)

199 mg (1 mmol) of the compound A and 225 mg (1.2 mmol) of 2,4-dichlorophenyl isocyanate were reacted in the same manner as in Example 1 to obtain the target compound 4 as a white solid (58 mg, 15%).

^{1 H-NMR (300 MHz,} DMSO): δ 2.10 (m, 1H), 2.24 (m, 1H), 4.09 (m, 2H), 4.38 (m, 2H), 4.80 (m, 1H), 7.41 (dd J = 8.2 Hz, 2.3 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.65 (d, J = 2.1 Hz, 1H), 8.08 (s, 1H), 9.44 (s, 1H).

Example  5: ethyl 3 - (((2-nitro-6,7- Dihydro - 5H - Imidazo [2,1-b] [1,3] oxazine -7 days) Methoxy ) Carbonylamino ) Benzoate  (5)

199 mg (1 mmol) of the compound A and 0.198 ml (1.2 mmol) of ethyl-2-isocyanate benzoate were reacted in the same manner as in Example 1 to obtain the target compound 5 as a white solid (11 mg, 2.8%).

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.37 (t, J = 7.1Hz, 3H), 2.29 (m, 2H), 4.12 (m, 2H), 4.36 (q, J = 7.1Hz, 2H) , 4.46 (m, 2H), 4.70 (m, 1H), 7.38 (d, J = 8.1Hz, 1H), 7.48 (s, 1H), 7.70 (m, 1H), 7.77 (d, J = 7.8Hz, 1H), < / RTI > 7.99 (s, 1H); LC / MS (m / e) = 391 (M + 1).

Example  6: (2-Nitro-6,7- Dihydro - 5H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  4- Chlorophenyl Sulfonylcarbamate  (6)

199 mg (1 mmol) of the compound A and 0.25 ml (1.2 mmol) of 4-chlorobenzenesulfonyl isocyanate were reacted in the same manner as in Example 1 to obtain the target compound 6 as a white solid (83 mg, 19.9%).

^{1 H-NMR (300 MHz,} DMSO): δ 1.91 (m, 1H), 2.11 (m, 1H), 4.03 (m, 2H), 4.23 (m, 1H), 4.33 (m, 1H), 4.68 (m , 7.67 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 8.5 Hz, 2H), 8.04 (s, 1H).

Example  7: (2-Nitro-6,7- Dihydro - 5H - Imidazo [2,1-b] [1,3] oxazine -7 days) Me Yl 4 '- ( Trifluoromethoxy ) -1,1'- Biphenyl -4- Yl carbamate  (7)

Step 1: 4-Nitro-4 '- ( Trifluoromethoxy ) -1,1'- Biphenyl  (7a)

2.47 g (12 mmol) of 4- (trifluoromethoxy) phenylboronic acid and 2.02 g (10 mmol) of 1-bromo-4-nitrobenzene were dissolved in 40 ml of 1,4-dioxane and 48 ml of distilled water, 4.14 g ) And 0.53 g (0.5 mmol) of 10% palladium were added and reacted at 80 ° C for 7.5 hours. After cooling to room temperature, the mixture was filtered while passing through celite, and ethyl acetate was added to the residue. The organic layer was separated and dried with anhydrous magnesium sulfate The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 20/1) to obtain the desired compound 7a as a white solid (2.4 g, 84%).

^{1 H-NMR (300 MHz,} CDCl 3): δ 7.35 (d, J = 8.1Hz, 2H), 7.65 (d, J = 8.6Hz, 2H), 7.72 (d, J = 8.8Hz, 2H), 8.32 (d, J = 9.0 Hz, 2H); MS (EI, m / e) = 283 (M ^< ^{+ &} gt ^; ).

Step 2: 4 ' - ( Trifluoromethoxy ) -1,1'- Biphenyl -4-amine < / RTI > (7b)

40 ml of ethanol and 10 ml of distilled water were added to 2.2 g (7.7 mmol) of 4-nitro-4'- (trifluoromethoxy) -1,1'-biphenyl ( 7a ), and 4.33 g (77 mmol) 3 drops were added and reacted at 110 DEG C for 4 hours. When the reaction is complete and filtered through the Celite and concentrated under reduced pressure and then the residue was purified by silica gel column chromatography (eluent, ethyl acetate / n-hexane = 1/4) to give the to give the desired compound 7b as a brown solid (2g, Quantitative).

^{1 H-NMR (300 MHz,} CDCl 3): δ 3.74 (br s, 2H), 6.75 (d, J = 8.4Hz, 2H), 7.22 (d, J = 8.3Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H).

Step 3: 4 ' - ( Trifluoromethoxy ) -1,1'- Biphenyl -4-isocyanate (7c)

12 ml of anhydrous tetrahydrofuran and 3 ml of methylene chloride were added to 506 mg (2 mmol) of 4 '- (trifluoromethoxy) -1,1'-biphenyl-4-amine ( 7b ) and 0.36 ml mmol), 1.26 ml (2.4 mmol) of a 20% phosgene solution (toluene) was added slowly, and the mixture was allowed to react at room temperature for 3 hours. When the reaction was completed, the reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3/1) to obtain the desired compound 7c as a yellow liquid (400 mg, 71%).

^{1 H-NMR (300MHz, CDCl} 3): δ 7.53 (q, J = 7.7Hz, 4H), 7.28 (d, J = 3.6Hz, 2H), 7.16 (d, J = 8.4Hz, 2H).

Step 4: (2-Nitro-6,7- Dihydro - 5H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  4 '- Reflux Romero Ethoxy) -1,1'- Biphenyl -4- Yl carbamate  (7)

Compound A 0.237mg (1.2mmol) and 4 '- (trifluoromethoxy) -1,1'-biphenyl-4-isocyanate were reacted in the (7c) method such as a 400mg (1.4mmol) as in Example 1, the desired compound 7 as a white solid (51 mg, 7.4%).

^{1 H-NMR (300 MHz,} DMSO): δ 2.12 (m, 1H), 2.27 (m, 1H), 4.13 (m, 2H), 4.43 (m, 2H), 4.84 (m, 1H), 7.42 (d , J = 9.4Hz, 2H), 7.58 (d, J = 9.4Hz, 2H), 7.64 (d, J = 8.8Hz, 2H), 7.75 (d, J = 8.9Hz, 2H), 8.09 (s, 1H ), 10.01 (s, 1 H); LC / MS (m / e) = 479 (M + 1).

Example  8: (2-Nitro-6,7- Dihydro - 5H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  4- (4- ( Trifluoromethoxy ) Phenoxy ) Phenyl carbamate  (8)

Step 1: 1-Nitro-4- (4- ( Trifluoromethoxy ) Phenoxy ) Preparation of benzene (8a)

N -dimethylformamide (40 ml) was added to 2.59 ml (20 mmol) of 4- (trifluoromethoxy) phenol and 2.12 ml (20 mmol) of 1-fluoro-4-nitrobenzene, 5.52 g And the reaction was carried out at 120 ° C for 5.5 hours. When the reaction was completed, the reaction mixture was cooled to room temperature, and 150 ml of ethyl acetate was added to the reaction mixture. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated. The residue was purified by silica gel column chromatography (eluent ethyl acetate / n-hexane = 1/20) to obtain the desired compound 8a as a light yellow liquid (6.06 g, quantitative).

^{1 H-NMR (300 MHz,} CDCl 3): δ 7.03 (d, J = 9.1Hz, 2H), 7.11 (d, J = 9.0Hz, 2H), 7.29 (d, J = 8.8Hz, 2H), 8.22 (d, J = 9.1 Hz, 2H).

Step 2: 4- (4- ( Trifluoromethoxy ) Phenoxy ) Preparation of aniline (8b)

5.9 g (19.3 mmol) of 1-nitro-4- (4- (trifluoromethoxy) phenoxy) benzene ( 8a ) were reacted in the same manner as in the step 2 of Example 7 to obtain the target compound 8b as a brown liquid (5.1 g, 97%).

^{1 H-NMR (300 MHz,} CDCl 3): δ 3.60 (br s, 2H), 6.68 (d, J = 8.7Hz, 2H), 6.86 (d, J = 8.6Hz, 2H), 6.90 (d, J = 9.2 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H).

Step 3: 1- Isocianeto -4- (4- ( Trifluoromethoxy ) Phenoxy ) Preparation of benzene (8c)

538 mg (2 mmol) of 4- (4- (trifluoromethoxy) phenoxy) aniline ( 8b ) were reacted in the same manner as in the step 3 of Example 7 to obtain the objective compound 8c as a yellow liquid (420 mg, 71% .

^{1 H-NMR (300MHz, CDCl} 3): δ 7.37 (d, J = 5.2Hz, 1H), 7.20 (t, J = 4.6Hz, 2H), 7.10 (d, J = 5.2Hz, 1H), 6.92 ( m, 4H).

Step 4: (2-Nitro-6,7- Dihydro - 5H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  4- (4- Reflux Methoxy) Phenoxy ) Phenyl carbamate  (8)

Compound A 199mg (1mmol) and 1-isocyanato-4- (4- (trifluoromethoxy) phenoxy) benzene (8c) 8 The desired compound was reacted in the same way as a 354mg (1.2mmol) as in Example 1 (75 mg, 5.06%) as a white solid.

^{1 H-NMR (300 MHz,} DMSO): δ 2.12 (m, 1H), 2.27 (m, 1H), 4.13 (m, 2H), 4.40 (m, 2H), 4.82 (m, 1H), 7.05 (m , 4H), 7.35 (d, J = 8.6Hz, 2H), 7.51 (d, J = 9.4Hz, 2H), 8.09 (s, 1H), 8.09 (s, 1H), 9.92 (s, 1H).

Example  9: (2-Nitro-6,7- Dihydro - 5H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  4- (4- ( Trifluoromethyl ) Benzyloxy ) Phenyl carbamate  (9)

Step 1: 1-Nitro-4- (4- ( Trifluoromethyl ) Benzyloxy ) Preparation of benzene (9a)

1.39 g (10 mmol) of 4-nitrophenol was dissolved in 20 ml of anhydrous N, N -dimethylformamide, and 0.48 g (12 mmol) of 60% sodium hydride was added slowly at 0 ° C. After 1 hour, 2.86 g (12 mmol) of 4- (trifluoromethyl) benzyl bromide was added at the same temperature, and the mixture was reacted at room temperature overnight. When the reaction was completed, water was added at 0 ° C to terminate the reaction. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The residue was concentrated and the residue was purified by silica gel column chromatography (eluent, ethyl acetate / Hexane = 1/7 - > 1/4) to give the desired compound 9a as a light off-white solid (3.35 g, quantitative).

^{1 H-NMR (300 MHz,} CDCl 3): δ 5.22 (s, 2H), 7.03 (d, J = 9.2Hz, 2H), 7.55 (d, J = 8.1Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 8.22 (d, J = 9.2 Hz, 2H).

Step 2: 4- (4- ( Trifluoromethyl ) Benzyloxy ) Preparation of aniline (9b)

3.3 g (11.1 mmol) of 1-nitro-4- (4- (trifluoromethyl) benzyloxy) benzene ( 9a ) were reacted in the same manner as in the step 2 of Example 7 to obtain the desired compound 9b as a brown solid 2.4 g, 80.9%).

^{1 H-NMR (300 MHz,} CDCl 3): δ 3.43 (brs, 2H), 5.04 (s, 2H), 6.63 (d, J = 8.7Hz, 2H), 6.79 (d, J = 8.7Hz, 2H) , 7.52 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H).

Step 3: 1- Isocianeto -4- (4- ( Trifluoromethyl ) Benzyloxy ) Preparation of benzene (9c)

267 mg (1 mmol) of 4- (4- (trifluoromethyl) benzyloxy) aniline ( 9b ) was reacted by the same procedure with step 3 of Example 7 to obtain the desired compound 9c as a pink solid (274 mg, 88% .

^{1 H-NMR (300 MHz,} CDCl 3): δ 7.64 (d, J = 8.0Hz, 2H), 7.53 (d, J = 8.0Hz, 2H), 7.02 (d, J = 8.7Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 5.10 (s, 2H).

Step 4: (2-Nitro-6,7- Dihydro - 5H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  4- (4- Reflux Lt; / RTI > Benzyloxy ) Phenyl carbamate  (9)

Compound A 97mg (0.48mmol) and 1-isocyanato-4- (4- (trifluoromethyl) benzyloxy) benzene (9c) 172mg (0.58mmol) were reacted in the same manner as in Example 1, the desired compound 9 as a white solid (107 mg, 44.47%).

^{1 H-NMR (300 MHz,} DMSO): δ 2.12 (m, 1H), 2.27 (m, 1H), 4.13 (m, 2H), 4.38 (m, 2H), 4.82 (m, 1H), 5.19 (s , 2H), 6.98 (m, J = 9.0Hz, 2H), 7.39 (d, J = 7.7Hz, 2H), 7.67 (d, J = 8.1Hz, 2H), 7.77 (d, J = 8.3Hz, 2H ), 8.11 (s, 1 H), 9.71 (s, 1 H); MS (EI, m / e) = 492 (M ^< ^{+ &} gt ^; ).

Example  10: ( R ) - (2-nitro-6,7- Dihydro - 5H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  4- (4- ( Trifluoromethyl ) Benzyloxy ) Phenyl carbamate  (10)

(R) - (2- nitro-6,7-dihydro - 5H - imidazo [2,1-b] [1,3] oxazin-7-yl) methanol (B) 146mg (0.73mmol) and 1 216 mg (0.73 mmol) of isocyanato-4- (4- (trifluoromethyl) benzyloxy) benzene ( 9c ) was reacted in the same manner as in Example 1 to obtain the title compound 10 as a pink solid 13 mg, 3.58%).

^{1 H-NMR (300 MHz,} DMSO): δ 2.10 (m, 1H), 2.25 (m, 1H), 4.12 (m, 2H), 4.38 (m, 2H), 4.81 (m, 1H), 5.18 (s , 2H), 6.96 (t, J = 8.0Hz, 2H), 7.36 (d, J = 8.0Hz, 2H), 7.66 (d, J = 8.0Hz, 2H), 7.76 (d, J = 7.7Hz, 2H ), 8.08 (s, 1 H), 9.67 (s, 1 H).

Example  11: (2-Nitro-6,7- Dihydro - 5H - Imidazo [2,1-b] [1,3] oxazine Yl) methyl < RTI ID = 0.0 > 4- (4- Fluorobenzyl ) Piperazin-l- Of the carboxylate (11)  Produce

Step 1: Rat -Butyl 4- Benzylpiperazine -One- Carboxylate  (11a)

5 g (28.3 mmol) of 1-benzylpiperazine was dissolved in 50 ml of methanol, 7.43 g (34 mmol) of di-tert-butyl dicarbonate was added, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/4 -> 1/2) to obtain desired compound 11a as a white solid (8 g, quantitative) .

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.47 (s, 9H), 2.40 (m, 4H), 3.44 (m, 4H), 3.53 (s, 2H), 7.22 (m, 2H), 7.33 ( m, 3H); MS (EI, m / e) = 276 (M ^< ^{+ &} gt ^; ).

Step 2: Rat -Butylpiperazin-l- Carboxylate  (11b)

Tert-butyl-4-benzylpiperazine-1-carboxylate ( 11a ) 7.6 g (27.5 mmol) was dissolved in 55 ml of methanol, 1.52 g (20 wt%) of 10% palladium was added, and the mixture was reacted at room temperature overnight under a hydrogen balloon. When the reaction is complete and filtered through the celite and the residue was purified by silica gel column chromatography and then concentrated under reduced pressure (eluent, ethyl acetate -> ethyl acetate / methanol = 10/1 -> 5/1) to give the desired compound 11b Obtained as a white solid (4.2 g, 82%).

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.46 (s, 9H), 2.80 (m, 4H), 3.38 (m, 4H); MS (EI, m / e) = 186 (M ^< ^{+ &} gt ^; ).

Step 3: Rat -Butyl 4- (4- Fluorobenzyl ) Piperazin-l- Carboxylate  (11c)

Tert-butylpiperazine-1-carboxylate ( 11b ) Was dissolved in 10 ml of anhydrous methylene chloride. To the mixture was then added 0.97 ml (6.9 mmol) of triethylamine at 0 ° C, and 0.8 ml (6.4 mmol) of 4-fluorobenzyl bromide was gradually added thereto, followed by reaction at room temperature overnight. When the reaction is complete, add 100 ml of methylene chloride to the reaction mixture and wash with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue thus obtained was purified by silica gel column chromatography (eluent, ethyl acetate / n-hexane = 1/4? 1/1) to obtain desired compound 11c as a off-white solid (1.5 g, 98.3%).

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.45 (s, 9H), 2.36 (m, 4H), 3.41 (m, 4H), 3.46 (s, 2H), 7.00 (t, J = 8.6Hz, 2H), 7.26 (m, 2H).

Step 4: 1- (4- Fluorobenzyl ) Piperazine Hydrochloride  (11d)

Tert-butyl-4- (4-fluorobenzyl) piperazine-1-carboxylate ( 11c ) Was dissolved in 20 ml of anhydrous methanol, and 3.8 ml (15 mmol) of a 4 molar solution of hydrochloric acid, 1, 4-dioxane was slowly added thereto at 0 占 폚 and reacted at room temperature overnight. When the reaction was completed, 30 ml of ethyl acetate was added to the reaction mixture, and the mixture was further stirred for 30 minutes. The formed solid was filtered to obtain the desired compound 11d as a white solid (1 g, 85.9%).

^{1 H-NMR (300 MHz,} D 2 O): δ 3.41 (brs, 8H), 4.27 (s, 2H), 7.07 (t, J = 8.7Hz, 2H), 7.36 (m, 2H).

Step 5: (2-Nitro-6,7- Dihydro - 5H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  4- (4- Luo Luo Benzyl) piperazin-l- Carboxylate  (11)

199 mg (1 mmol) of Compound A was dissolved in 6 ml of anhydrous tetrahydrofuran, and 0.278 ml (2 mmol) of triethylamine and 148 mg (0.5 mmol) of triphosgene were added thereto at 0 ° C. and reacted at room temperature for 2 hours. (1.02 mmol) of piperazine hydrochloride ( 11d ) was dissolved in 4 ml of anhydrous tetrahydrofuran and 0.30 ml (2.2 mmol) of triethylamine, followed by slow addition. After the reaction was completed at room temperature overnight, when the reaction was completed, 50 ml of ethyl acetate was added to the reaction mixture and the reaction mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the residue was purified by silica gel column chromatography (eluent, methylene chloride / methanol = 20/1? 10/1) to give a solid. The solid was recrystallized from methanol and ethyl acetate To give the desired compound 11 as a white solid (103 mg, 24.2%).

^{1 H-NMR (300 MHz,} DMSO): δ 2.19 (m, 1H), 2.27 (m, 1H), 2.39 (brs, 4H), 3.47 (s, 6H), 4.13 (m, 2H), 4.31 (d , J = 6.0Hz, 0.3H), 4.35 (d, J = 6.0Hz, 0.7H), 4.41 (d, J = 3.6Hz, 0.7H), 4.45 (d, J = 3.6Hz, 0.3H), 4.65 (m, 1H), 7.00 (t, J = 8.6 Hz, 2H), 7.26 (m, 2H), 7.43 (s, 1H); MS (EI, m / e) = 419 (M ^< ^{+ &} gt ^; ).

Example  12: (2-Nitro-6,7- Dihydro - 5H - Imidazo [2,1-b] [1,3] oxazine -7-yl) methyl 4- (4- (4- ( Trifluoromethyl ) Benzyloxy ) Phenyl ) Piperazin-l- Carboxylate  (12)

Step 1: ( Rat -Butyl 4- (4- Hydroxyphenyl ) Piperazin-l- Carboxylate  (12a)

(20 mmol) of 1- (4-hydroxyphenol) piperazine was dissolved in 20 ml of anhydrous methanol, and 5.23 g (24 mmol) of di-tert-butyldicarboxylate was added thereto, followed by reaction at room temperature overnight. When the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 20 /) to obtain the title compound 12a as a light brown solid (6.06 g, quantitative).

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.48 (s, 9H), 2.99 (s, 2H), 3.57 (s, 2H), 5.31 (brs, 1H), 6.67 (d, J = 7.3Hz, 2H), 6.87 (d, J = 7.6 Hz, 2H); MS (EI, m / e) = 278 (M ^< ^{+ &} gt ^; ).

Step 2: ( Rat -Butyl-4- (4- Hydroxyphenyl ) Piperazin-l- Carboxylate  (12b)

(Tert-butyl-4- (4-hydroxyphenyl) piperazine-l-carboxylate (12a) 2.78g (10mmol) in anhydrous N, N in - 60% 0 ℃ dissolve in dimethylformamide 20ml sodium hydride (12 mmol) of 4- (trifluoromethyl) benzyl bromide was added to the reaction mixture, and the mixture was reacted overnight at room temperature. When the reaction was completed, water was slowly added to the reaction mixture at 0 And the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent, methylene chloride / ethyl acetate = 20/1 -> 10/1) Purification yielded the desired compound 12b as a white solid (3.68 g, 84.4%).

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.48 (s, 9H), 3.01 (t, J = 4.8Hz, 4H), 3.57 (t, J = 4.8Hz, 4H), 5.07 (s, 2H) , 6.89 (s, 4H), 7.53 (d, J = 7.9 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H).

Step 3: 1- (4- (4- ( Trifluoromethyl ) Benzyloxy ) Phenyl ) Piperazine Hydrochloride  (12c)

(8.4 mmol) of tert-butyl-4- (4-hydroxyphenyl) piperazine-1-carboxylate ( 12b ) was dissolved in 33 ml of anhydrous methanol and 6.3 ml of a 4 molar solution of 1,4- After completion of the reaction, 30 ml of ethyl acetate was added, and the resulting solid was filtered to obtain the target compound 12c as a white solid (2.77 g, 88.2%).

^{1 H-NMR (300 MHz,} D 2 O): δ 3.55 (s, 8H), 5.06 (s, 2H), 6.92 (d, J = 9.6Hz, 2H), 7.07 (d, J = 9.5Hz, 2H ), 7.44 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.6 Hz, 2H).

Step 4: (2-Nitro-6,7- Dihydro - 5H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  4- (4- (4- Reflux O-methyl) Benzyloxy ) Phenyl ) Piperazin-l- Carboxylate  (12)

745 mg (2 mmol) of the compound A and 395 mg (2 mmol) of 1- (4- (4- (trifluoromethyl) benzyloxy) phenyl) piperazine hydrochloride ( 12c ) were reacted in the same manner as in Step 5 of Example 11 The desired compound 12 was obtained as a white solid (0.258 g, 22.9%).

^{1 H-NMR (300 MHz,} DMSO): δ 2.09 (m, 1H), 2.25 (m, 1H), 2.99 (t, J = 4.6Hz, 4H), 3.52 (t, J = 3.9Hz, 4H), 4.10 (m, 2H), 4.27 (d, J = 5.7Hz, 0.3H), 4.31 (d, J = 5.7Hz, 0.7H), 4.35 (d, J = 3.2Hz, 0.7H), 4.39 (d, J = 3.2Hz, 0.3H), 4.78 (m, 1H), 5.15 (s, 2H), 6.91 (s, 4H), 7.64 (d, J = 8.1Hz, 2H), 7.75 (d, J = 8.1Hz , ≪ / RTI > 2H), 8.07 (s, 1H); MS (EI, m / e) = 561 (M ^< ^{+ &} gt ^; ).

Example  13: (2-Nitro-6,7- Dihydro - 5H - Imidazo [2,1-b] [1,3] oxazine -7-yl) methyl 4- (2- (4- ( Trifluoromethyl ) Benzyloxy ) Ethyl) piperazin-l- Carboxylate  (13)

Step 1: Rat -Butyl 4- (2- Hydroxyethyl ) Piperazin-l- Carboxylate  (13a)

2.6 g (20 mmol) of 1- (2-hydroxyethyl) piperazine was dissolved in 20 ml of anhydrous methanol, and 5.23 g (24 mmol) of di-tert-butyl dicarbonate was added and reacted overnight. When the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 20/1) to obtain the title compound 13a as a white solid (5.23 g, quantitative).

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.46 (s, 9H), 2.45 (m, 4H), 2.55 (m, 2H), 2.70 (brs, 1H), 3.44 (m, 4H), 3.63 ( m, 2H); MS (EI, m / e) = 230 (M ^< ^{+ &} gt ^; ).

Step 2: Rat -Butyl-4- (2- (4- ( Trifluoromethyl ) Benzyloxy ) Ethyl) piperazin-l- Carboxylate  (13b)

230 mg (1 mmol) of tert-butyl-4- (2-hydroxyethyl) piperazine-1-carboxylate ( 13a ) was dissolved in anhydrous N, N- dimethylformamide, and 48 mg ) Was slowly added thereto, and the mixture was stirred for 30 minutes. 286 mg (1.2 mmol) of 4- (trifluoromethyl) benzyl bromide was added in small portions at 0 ° C, and the mixture was reacted at room temperature overnight. When the reaction was completed, water was slowly added to the reaction mixture at 0 to terminate the reaction. The reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated and the residue was purified by silica gel column chromatography (eluent: methylene chloride / Ethyl acetate = 20/1? 10/1) to obtain the desired compound 13b as a colorless liquid (377 mg, 97%).

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.45 (s, 9H), 2.44 (t, J = 4.2Hz, 4H), 2.64 (t, J = 5.6Hz, 2H), 2.88 (s, 0.5H ), 2.95 (s, 0.5H) , 3.44 (t, J = 3.9Hz, 4H), 3.61 (t, J = 5.5Hz, 2H), 4.59 (s, 2H), 7.44 (d, J = 8.1Hz, 2H), 7.60 (d, J = 7.7 Hz, 2H); MS (EI, m / e) = 388 (M ^< ^{+ &} gt ^; ).

Step 3: 1- (2- (4- ( Trifluoromethyl ) Benzyloxy ) Ethyl) piperazine Hydrochloride  (13c)

(9 mmol) of tert-butyl-4- (2- (4- (trifluoromethyl) benzyloxy) ethyl) piperazine-1-carboxylate 13b was dissolved in 40 ml of anhydrous methanol, 6.7 ml (27 mmol) of 4-dioxane solution was added thereto, followed by reaction at room temperature overnight. When the reaction is completed, the filtrate is concentrated under reduced pressure, and 50 ml of ethyl acetate is added to the residue. The resulting solid was filtered to obtain the desired compound 13c as a white solid (2.9 g, 97%).

^{1 H-NMR (300 MHz,} D 2 O): δ 3.38 (t, J = 4.8Hz, 4H), 3.48 (brs, 8H), 3.74 (t, J = 4.8Hz, 2H), 4.53 (s, 2H ), 7.42 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H).

Step 4: (2-Nitro-6,7- Dihydro - 5H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  4- (2- (4- Reflux O-methyl) Benzyloxy ) Ethyl) piperazin-l- Carboxylate  (13)

(2 mmol) of Compound A and 649 mg (2 mmol) of 1- (2- (4- (trifluoromethyl) benzyloxy) ethyl) piperazine hydrochloride ( 13c ) were reacted in the same manner as in Step 5 of Example 11 The desired compound 13 was obtained as a white solid (88 mg, 8.5%).

^{1 H-NMR (300 MHz,} DMSO): δ 2.09 (m, 1H), 2.23 (m, 1H), 2.41 (m, 4H), 2.56 (t, J = 5.6Hz, 2H), 3.37 (m, 4H ), 3.58 (t, J = 5.6Hz, 2H), 4.09 (m, 2H), 4.23 (d, J = 5.7Hz, 0.3H), 4.27 (d, J = 5.7Hz, 0.7H), 4.32 (d , J = 3.1Hz, 0.7H), 4.36 (d, J = 3.2Hz, 0.3H), 4.58 (s, 2H), 4.76 (m, 1H), 7.54 (d, J = 8.0Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 8.07 (s, 1H).

Example  14: ( R ) - (2-nitro-6,7- Dihydro -5 H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  4- (4- Fluorophenyl ) Piperazin-l- Carbosylate  (14)

From 0 ℃ (R) - (2- nitro-6,7-dihydro - 5H - imidazo [2,1-b] [1,3] oxazin-7-yl) methanol (B) 150mg (0.75mmol (0.75 mmol) of 4-nitrophenyl chloroformate and 90 μl (0.825 mmol) of 4-methylmorpholine were added to the reaction mixture, and the reaction mixture was added with N, N -dimethylform Amide was added, and 149 mg (0.825 mmol) of 1- (4-fluorophenyl) piperazine and 0.27 ml (3 mmol) of N, N -diisopropylethylamine (DIPEA) were added and reacted at room temperature for 30 minutes. After completion of the reaction, ethyl acetate and water were added to the reaction mixture, and the reaction was terminated. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: methylene chloride / Ol = 40/1) to obtain the target compound 14 (83 mg, 27%).

^{1 H-NMR (300 MHz,} CDCl 3): δ 2.18 (s, 2H), 3.07 (d, J = 6.5Hz, 4H), 3.64 (t, J = 5.2Hz, 4H), 4.14 (dt, J = (Dd, J = 12.0, 3.2 Hz, 1H), 4.67 (dd, J = 9.9, 5.3 Hz, 1H), 6.93 (m, 4H) 7.45 (s, 1 H).

Example  15: ( R ) - (2-nitro-6,7- Dihydro -5 H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  4-( Trifluoromethyl )benzyl Carbamate  (15)

From 0 ℃ (R) - (2- nitro-6,7-dihydro - 5H - imidazo [2,1-b] [1,3] oxazin-7-yl) methanol (B) 150mg (0.75mmol N, N - dimethylaminopyridine was added to the reaction mixture, followed by the addition of 6 ml of anhydrous dichloromethane, 151 mg (0.75 mmol) of 4-nitrophenylcarbonyl chlorodate and 90 μl (0.825 mmol) 3 ml of dimethylformamide was added, and 0.12 ml (0.825 mmol) of 4- (trifluoromethyl) benzylamine and 0.27 ml (3 mmol) of N, N -diisopropylethylamine (DIPEA) were added and reacted at room temperature for 30 minutes. After completion of the reaction, ethyl acetate and water were added to the reaction mixture, and the reaction was terminated. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: methylene chloride / Ol = 40/1) to obtain the desired compound 15 (126 mg, 42%).

^{1 H-NMR (300 MHz,} CDCl 3): δ 2.23 (dd, J = 16.1, 8.3Hz, 2H), 4.13 (dt, J = 10.3, 5.2Hz, 1H), 4.38 (m, 4H), 4.63 ( d, J = 10.2 Hz, 1H), 5.52 (s, 1H), 7.40 (m, 3H), 7.60 (d, J = 8.0 Hz, 2H).

Example  16: ( R ) - (2-nitro-6,7- Dihydro -5 H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  4-( Trifluoromethyl ) Phenyl Carbamate  (16)

(R) - (2- nitro-6,7-dihydro - 5H - imidazo [2,1-b] [1,3] oxazin-7-yl) methanol (B) 150mg (0.75mmol) and 4 - (trifluoromethyl) phenyl isocyanate were reacted in the same manner as in Example 1 to obtain the desired compound 16 (261 mg, 90%).

^{1 H-NMR (300 MHz,} CDCl 3): δ 2.29 (dtt, J = 20.2, 9.8, 5.6Hz, 2H), 4.18 (m, 2H), 4.48 (m, 2H), 4.86 (d, J = 0.8 Hz, 1 H), 7.60 (m, 4 H), 7.79 (s, 1 H).

Example  17: ( R ) - (2-nitro-6,7- Dihydro -5 H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  4-( Trifluoromethoxy ) Phenyl Carbamate  (17)

(R) - (2- nitro-6,7-dihydro - 5H - imidazo [2,1-b] [1,3] oxazin-7-yl) methanol (B) 150mg (0.75mmol) and 4 - (trifluoromethoxy) phenyl isocyanate were reacted in the same manner as in Example 1 to obtain the object compound 17 (140 mg, 46%).

^{1 H-NMR (300 MHz,} Methanol-d 4): δ 2.29 (m, 2H), 4.19 (m, 2H), 4.45 (m, 2H), 4.80 (d, J = 6.9Hz, 1H), 7.19 ( d, J = 8.7 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.78 (s, 1H).

Example  18: ( R ) - (2-nitro-6,7- Dihydro -5 H - Imidazo [2,1-b] [1,3] oxazine -7-yl) methylnaphthalene-1- Yl carbamate  (18)

(R) - (2- nitro-6,7-dihydro - 5H - imidazo [2,1-b] [1,3] oxazin-7-yl) methanol (B) 100mg (0.5mmol) and 1 (0.615 mmol) of naphthyl isocyanate were reacted in the same manner as in Example 1 to obtain the desired compound 18 (56 mg, 30%).

^{1 H-NMR (300 MHz,} DMSO): δ 2.11 (s, 1H), 2.22 (s, 1H), 4.10 (m, 2H), 4.40 (qd, J = 12.6, 4.5Hz, 2H), 4.82 (d , J = 9.2Hz, 1H), 7.51 (m, 4H), 7.73 (dd, J = 7.8, 1.6Hz, 1H), 7.89 (dd, J = 6.4, 3.3Hz, 1H), 8.03 (d, J = 13.1 Hz, 2H), 9.71 (d, J = 2.3 Hz, 1H).

Example  19: ( R ) - (2-nitro-6,7- Dihydro -5 H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  4- Nitrophenyl Carbamate  (19)

(R) - (2- nitro-6,7-dihydro - 5H - imidazo [2,1-b] [1,3] oxazin-7-yl) methanol (B) 100mg (0.5mmol) and 4 (0.615 mmol) of nitrophenyl isocyanate were reacted in the same manner as in Example 1 to obtain the object compound 19 (91 mg, 50%).

^{1 H-NMR (300 MHz,} DMSO): δ 2.12 (td, J = 10.8, 6.4Hz, 1H), 2.24 (t, J = 8.4 Hz, 1H), 4.18 - 4.00 (m, 2H), 4.60 - 4.31 (m, 2H), 4.75 ( s, 1H), 7.30 (d, J = 7.1 Hz, 1H), 7.46 (t, J = 7.4 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.86 (s, 1 H), 8.03 (s, 1 H), 10.2 (s, 1 H).

Example  20: ( R ) - (2-nitro-6,7- Dihydro -5 H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl Phenyl Carbamate  (20)

(R) - (2- nitro-6,7-dihydro - 5H - imidazo [2,1-b] [1,3] oxazin-7-yl) methanol (B) 100mg (0.5mmol) and phenyl 73.2 mg (0.615 mmol) of isocyanate were reacted in the same manner as in Example 1 to obtain the target compound 20 (44 mg, 27%).

^{1 H-NMR (300 MHz,} DMSO): δ 2.13 (td, J = 11.1, 6.2Hz, 1H), 2.26 (t, J = 8.6Hz, 1H), 4.12 (m, 2H), 4.43 (m, 2H ), 4.82 (s, 1H) , 7.01 (t, J = 7.4Hz, 1H), 7.29 (t, J = 7.7Hz, 2H), 7.47 (d, J = 7.9Hz, 2H), 8.08 (s, 1H ), 9.83 (s, 1 H).

Example  21: ( R ) - (2-nitro-6,7- Dihydro -5 H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  3- Fluorophenyl Carbamate  (21)

(R) - (2- nitro-6,7-dihydro - 5H - imidazo [2,1-b] [1,3] oxazin-7-yl) methanol (B) 100mg (0.5mmol) and 3 (0.615 mmol) of fluorophenyl isocyanate were reacted in the same manner as in Example 1 to give the desired compound 21 (24 mg, 14%).

¹ H-NMR (300 MHz, CDCl ₃ ):? 2.24 (m, IH), 4.15 (m, 2H), 3.4 m, 2H), 7.07 (d, J = 7.3 Hz, 1H), 7.34 (m, 1H), 7.47 (s, 1H).

Example  22: ( R ) - (2-nitro-6,7- Dihydro -5 H - Imidazo [2,1-b] [1,3] oxazine -7 days) methyl  3- ( Trifluoromethyl ) Phenyl Carbamate  (22)

(R) - (2- nitro-6,7-dihydro - 5H - imidazo [2,1-b] [1,3] oxazin-7-yl) methanol (B) 100mg (0.5mmol) and 3 (Trifluoromethyl) phenyl isocyanate were reacted in the same manner as in Example 1 to give the desired compound 22 (57 mg, 29%).

¹ H-NMR (300 MHz, CDCl ₃ ):? 2.31 (m, 2H), 4.19 (m, 2H), 4.39 1H), 7.56 (m, 2H), 7.59 (d, J = 0.51 Hz, 1H), 7.78 (s, 1H).

[ Experimental Example  One]

The efficacy of the compounds obtained in Examples 1 to 22 on Mycobacterium tuberculosis was confirmed as follows, and the results are shown in Table 1 below.

1) Efficacy for Mycobacterium tuberculosis

In order to evaluate the efficacy of the compounds of the present invention against the anti-tubercle bacilli, the following tests were carried out using the method of measuring the minimum inhibitory concentration of Mycobacterium tuberculosis (MIC) as follows.

The test substances obtained in Examples 1 to 22 were serially diluted 2 fold in a medium broth 7H9 liquid medium (Difco, USA), and then 50 uL each in a 96-well microplate Respectively. Mycobacterium tuberculosis, a standard strain of Mycobacterium tuberculosis tuberculosis ) H37Rv broth Frozen stocks were inoculated into Middlebrook 7H9 liquid medium and cultured for 5 days. Diluted at an absorbance of 0.5 at a wavelength of 600 nanometers, the final bacterial count was 2 to 5 × 10 ⁵ colonies / ml. 50ul of the drug dilution plate was inoculated. After the test plates were incubated at 37 ° C for 7 days, 10 μl of Allamac blue indicator was added to each well. After 24 hours, the change in the fluorescence of each well was observed, and the lowest concentration remaining in blue was determined as the minimum inhibitory concentration. The results are shown in Table 1 below.

compound
number rescue Molecular Weight MIC
(ug / mL) One

332.31 0.25 2

348.31 0.5 3

352.73 0.125 4

387.17 0.5 5

390.35 0.5 6

416.79 200 7

478.38 0.039063 8

494.38 <0.39 9

492.40 0.03125 10

492.40 0.019531 11

419.41 1.25 12

561.51 0.078125 13

513.47 0.3125 14

405.38 0.5 15

400.31 0.5 16

386.28 0.125 17

402.28 0.125 18

368.34 0.25 19

363.28 0.5 20

318.28 0.125 21

336.28 0.125 22

386.28 0.5

359.26 0.125

Compounds 3, 11, 16, 17, 20 and 21 showed the same effect as the PA-824 compound. Compounds 7, 9, 10 and 12 showed the same effect as PA-824 It was confirmed that the compound exerts a more excellent effect on M. tuberculosis than the compound. Accordingly, the bicyclic nitroimidazole carbamate compound according to the present invention is expected to be useful for the development of a therapeutic agent for tuberculosis.

Claims (9)

delete A bicyclic nitroimidazole carbamate compound represented by the following formula (2) or (3), an optical isomer thereof or a pharmaceutically acceptable salt thereof.
(2)

(3)

In Formula 2 and 3, R ₂ is a (C6-C20) aryl, (C6-C20) aralkyl (C1-C10) alkyl, (C6-C20) aryloxy (C6-C20) aryl, (C6-C20) aralkyl and (C1-C10) alkyloxy (C6-C20) aryl, or SO ₂ R _3, R ₃ is (C6-C20) aryl, R ₄ is a (C6-C20) aryl, (C6-C20) aralkyl (C1- C10) alkyl, (C6-C20) aralkyl (C1-C10) alkyloxy (C6-C20) aryl or (C6-C20) aralkyl (C1-C10) alkyl-oxy (C1-C10) alkyl, aryl in the R ₂ , aralkyl, aryloxyalkyl, aryl, aralkyloxy aryl, the aryl of R _3, and R ₄ of the aryl, aralkyl, aralkyloxy aryl or aralkyl oxyalkyl are each independently (C1-C10) alkyl, (C1- (C1-C10) alkoxy, halogen, (C1-C10) alkoxycarbonyl, halo (C1-C10) alkoxy, halo (C1-C10) alkyl and nitro.
delete 3. The method of claim 2,
A bicyclic nitroimidazole carbamate compound selected from the following compounds, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
1) (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin-7-yl) methyl m-tolylcarbamate,
2) (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin-7-yl) methyl 4-methoxyphenylcarbamate,
3) (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin-7-yl) methyl 4-chlorophenylcarbamate,
4) (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin-7-yl) methyl 2,4-dichlorophenylcarbamate,
5) Preparation of ethyl 3 - (((2-nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin-7-yl) methoxy) carbonylamino) Eight,
6) (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin-7-yl) methyl 4-chlorophenylsulfonylcarbamate,
7) dihydro-5H-imidazo [2,1-b] [1,3] oxazin-7-yl) methyl 4 '- (trifluoromethoxy) biphenyl- 4-yl carbamate,
8) (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin-7-yl) methyl 4- (4- (trifluoromethoxy) Yl) phenylcarbamate,
9) (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin-7-yl) methyl 4- (4- (trifluoromethyl) benzyl Oxy) phenylcarbamate,
10) (R) - (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin- Benzyloxy) phenylcarbamate, &lt; RTI ID = 0.0 &gt;
11) (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin-7-yl) methyl 4- (4-fluorobenzyl) piperazine- 1-carboxylate,
12) (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin-7-yl) methyl 4- (4- Methyl) benzyloxy) phenyl) piperazine-1-carboxylate,
13) (2-Nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazin- Methyl) benzyloxy) ethyl) piperazine-1-carboxylate,
14) (R) - (2- nitro-6,7-dihydro -5 H - to the imidazo [2,1-b] [1,3] oxazin-7-yl) methyl 4- (4-fluoro Phenyl) piperazine-1-carboxylate,
15) (R) - (2- nitro-6,7-dihydro -5 H - to the imidazo [2,1-b] [1,3] oxazin-7-yl) methyl 4- (Tryp Luo Methyl) benzyl carbamate,
16) (R) - (2- nitro-6,7-dihydro -5 H - imidazo [2,1-b] [1,3] oxazin-7-yl) methyl methyl 4- (4-trifluoromethyl ) Phenyl carbamate,
17) (R) - (2- nitro-6,7-dihydro -5 H - imidazo [2,1-b] [1,3] oxazin-7-yl) methyl-4- (trifluoromethoxy ) Phenyl carbamate,
18) (R) - (2- nitro-6,7-dihydro -5 H - imidazo [2,1-b] [1,3] oxazin-7-yl) methyl-1-yl-carbamate ,
19) (R) - (2- nitro-6,7-dihydro -5 H - Photo-7-yl-imidazo [2,1-b] [1,3] octanoic) methyl 4-nitrophenyl carbamate,
20) (R) - (2- nitro-6,7-dihydro -5 H - imidazo [2,1-b] [1,3] oxazin-7-yl) methyl-phenyl-carbamate,
21) (R) - (2- nitro-6,7-dihydro -5 H - imidazo [2,1-b] [1,3] oxazin-7-yl) phenyl carbamate of methyl 3-fluoro , And
22) (R) - (2- nitro-6,7-dihydro -5 H - imidazo [2,1-b] [1,3] oxazin-7-yl) methyl-methyl-3- (trifluoromethyl ) Phenylcarbamate.
A process for preparing a bicyclic nitroimidazole carbamate compound of the formula (2) by reacting a bicyclo nitroimidazole oxazine compound represented by the formula (1a) and an isocyanate compound represented by the formula (4).
[Formula 1a]

[Chemical Formula 4]
R ₂ -NCO
(2)

Wherein, R ₂ is a (C6-C20) aryl, (C6-C20) aralkyl (C1-C10) alkyl, (C6-C20) aryloxy (C6-C20) aryl, (C6-C20) aralkyl (C1-C10 ) alkyloxy (C6-C20) aryl, or SO ₂ R _3, and;
R &lt; ₃ &gt; is (C6-C20) aryl;
Of the R ₂ aryl, aralkyl, aryloxyalkyl, aryl, aralkyloxy aryl, and aryl of R ₃ are each independently (C1-C10) alkyl, (C1-C10) alkoxy, halogen, (C1-C10) alkoxycarbonyl Which may be further substituted with one or more substituents selected from the group consisting of halogen, halo (C1-C10) alkoxy, halo (C1-C10) alkyl and nitro.
A process for preparing a bicyclonitroimidazole carbamate compound of the formula (3) by reacting a bicyclo nitroimidazole oxazine compound represented by the following formula (1a), triphosgene and a piperazine compound represented by the formula (5).
[Formula 1a]

[Chemical Formula 5]

(3)

Wherein, R ₄ is a (C6-C20) aryl, (C6-C20) aralkyl (C1-C10) alkyl, (C6-C20) aralkyl (C1-C10) alkyloxy (C6-C20) aryl or (C6-C20 (C1-C10) alkyloxy (C1-C10) alkyl;
Each aryl, aralkyl, aralkyloxy aryl, aralkyl oxyalkyl of said R ₄ is independently (C1-C10) alkyl, (C1-C10) alkoxy, halogen, (C1-C10) alkoxycarbonyl, halo (C1 (C1-C10) alkoxy, halo (C1-C10) alkyl and nitro.
A method for preparing a bicyclonitroimidazole carbamate compound represented by the formula (1) by reacting a bicyclo nitroimidazole oxazine compound represented by the following formula (1a), a chloroformate compound represented by the formula (6) and an amine compound represented by the formula (7)
[Formula 1a]

[Chemical Formula 6]

(7)

[Chemical Formula 1]

In this formula,
R &lt; ₁ &gt; is hydrogen; R ₂ is (C6-C20) aryl (C6-C20) aryl (C1-C10) (C6-C20) aryl, or SO ₂ R _3, and;
R &lt; ₃ &gt; is (C6-C20) aryl;
Of the R ₂ aryl, aralkyl, aryloxyalkyl, aryl, aralkyloxy aryl, R ₃ of the aryl are each independently (C1-C10) alkyl, (C1-C10) alkoxy, halogen, (C1-C10) alkoxycarbonyl , Halo (C1-C10) alkoxy, halo (C1-C10) alkyl and nitro;
R 'is (C1-C10) alkyl, (C2-C20) alkenyl, (C6-C20) aryl or (C6- The aralkyl may be further substituted with one or more selected from the group consisting of halogen, (C1-C10) alkyl, (C6-C20) aryl, halo (C1-C10) alkyl and nitro.
A medicament for the prophylaxis or treatment of a tuberculosis disease containing, as an active ingredient, a bicyclic nitroimidazole carbamate compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 2 or 4 Gt;
A process for producing a bicyclonitroimidazole carbamate compound of the formula (3) by reacting a bicyclo nitroimidazole oxazine compound represented by the following formula (1a), a chloroformate compound of the formula (6) and a piperazine compound represented by the formula .
[Formula 1a]

[Chemical Formula 6]

[Chemical Formula 5]

(3)

In this formula,
R ₄ is selected from the group consisting of (C 6 -C 20) aryl, (C 6 -C 20) aryl (C 6 -C 20) alkyl, (C 6 -C 20) C1-C10) alkyloxy (C1-C10) alkyl;
Each aryl, aralkyl, aralkyloxy aryl, aralkyl oxyalkyl of said R ₄ is independently (C1-C10) alkyl, (C1-C10) alkoxy, halogen, (C1-C10) alkoxycarbonyl, halo (C1 (C1-C10) alkoxy, halo (C1-C10) alkyl and nitro;
R 'is (C1-C10) alkyl, (C2-C20) alkenyl, (C6-C20) aryl or (C6- The aralkyl may be further substituted with one or more selected from the group consisting of halogen, (C1-C10) alkyl, (C6-C20) aryl, halo (C1-C10) alkyl and nitro.