KR100674096B1 - Novel oxazolidinone derivatives containing pyrimidine moiety and method for preparation thereof - Google Patents

Novel oxazolidinone derivatives containing pyrimidine moiety and method for preparation thereof

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Publication number
KR100674096B1
KR100674096B1 KR1020000030896A KR20000030896A KR100674096B1 KR 100674096 B1 KR100674096 B1 KR 100674096B1 KR 1020000030896 A KR1020000030896 A KR 1020000030896A KR 20000030896 A KR20000030896 A KR 20000030896A KR 100674096 B1 KR100674096 B1 KR 100674096B1
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group
compound
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oxo
fluorophenyl
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KR1020000030896A
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KR20010110015A (en
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이재걸
임원빈
최성학
조종환
김동구
박상국
이태호
성현정
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동아제약주식회사
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Priority to AU5889701A priority patent/AU5889701A/en
Priority to CN01810697A priority patent/CN1433413A/en
Priority to BR0111280-5A priority patent/BR0111280A/en
Priority to CA002411859A priority patent/CA2411859A1/en
Priority to EP01932368A priority patent/EP1289984A4/en
Priority to JP2002501891A priority patent/JP2003535860A/en
Priority to US10/296,896 priority patent/US6689779B2/en
Priority to NZ522990A priority patent/NZ522990A/en
Priority to MXPA02012045A priority patent/MXPA02012045A/en
Priority to PCT/KR2001/000821 priority patent/WO2001094342A1/en
Priority to HU0301562A priority patent/HUP0301562A2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

본 발명은 하기 화학식 1로 표시되는 새로운 옥사졸리디논 (oxazolidinone)유도체와 약학적으로 허용되는 그의 염, 그의 제조방법 및 그를 포함하는 약학적 조성물에 관한 것으로서, 구체적으로 하기 화학식 1로 표시되는 본 발명의 피리미딘 고리를 포함하는 옥사졸리디논 유도체는 강한 항균력을 갖고 있을 뿐만 아니라 항균 스펙트럼이 넓고 생체내 효과가 뛰어나 항생제로서 유용하게 사용될 수 있다.
The present invention relates to a new oxazolidinone derivative represented by the following Chemical Formula 1, a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition comprising the same, and specifically, the present invention represented by the following Chemical Formula 1 The oxazolidinone derivative including the pyrimidine ring of has not only a strong antimicrobial activity but also a broad antibacterial spectrum and excellent in vivo effects, which can be usefully used as an antibiotic.

Figure 112000011447214-pat00015
Figure 112000011447214-pat00015

상기 화학식 1에서, R1 및 R2는 명세서에 기재된 바와 같다.In Formula 1, R 1 and R 2 are as described in the specification.

Description

피리미딘 고리를 포함하는 신규 옥사졸리디논 유도체와 그의 제조방법 {Novel oxazolidinone derivatives containing pyrimidine moiety and method for preparation thereof} Novel oxazolidinone derivatives containing pyrimidine ring and preparation method thereof {Novel oxazolidinone derivatives containing pyrimidine moiety and method for preparation according}             

본 발명은 항균효과를 갖는 하기 화학식 1로 표시되는 피리미딘을 포함하는 신규 옥사졸리디논 (oxazolidinone) 유도체 및 약학적으로 허용되는 그의 염, 그의 제조방법 및 그를 포함하는 조성물에 관한것이다.The present invention relates to a novel oxazolidinone derivative including pyrimidine represented by the following formula (1) having an antimicrobial effect, a pharmaceutically acceptable salt thereof, a preparation method thereof, and a composition comprising the same.

화학식 1Formula 1

Figure 112000011447214-pat00016
Figure 112000011447214-pat00016

상기 화학식 1에서, In Chemical Formula 1,

R1은 수소 또는 불소이고, R 1 is hydrogen or fluorine,

R2는 수소; C1-C4의 알콕시기; 아미노기; 또는 R3가 치환 또는 치환되지 않은 피페라지닐기이다. R 2 is hydrogen; An alkoxy group of C 1 -C 4 ; Amino group; Or R 3 is a substituted or unsubstituted piperazinyl group.

상기 R3는 수소; 트리페닐메틸기; 치환 또는 치환되지 않은 아세틸기; 치환 또는 치환되지 않은 벤조일기; 치환 또는 치환되지 않은 카보닐기; C1-C3의 알콕시페닐기; C1-C3의 알킬기가 치환 또는 치환되지 않은 아크릴로일기; 니코티노일기; 피발로일기; 크로토닐기 또는 n-발레릴기이다.
R 3 is hydrogen; Triphenylmethyl group; A substituted or unsubstituted acetyl group; Substituted or unsubstituted benzoyl group; Substituted or unsubstituted carbonyl group; An alkoxyphenyl group of C 1 -C 3 ; An acryloyl group, wherein the alkyl group of C 1 -C 3 is unsubstituted or substituted; Nicotinoyl group; Pivaloyl group; It is a crotonyl group or n-valeryl group.

옥사졸리디논(oxazolidinone) 화합물은 발효 산물이 아닌 경구 투여가 가능한 새로운 합성 항생제로서 다양한 구조의 유도체가 알려져 있다. 예를 들면 하나 또는 두개의 치환기를 가진 3-페닐-2-옥사졸리디논 유도체는 미국특허 USP 4,948,801, USP 4,461,773, USP 4,340,606, USP 4,476,136, USP 4,250,318, USP 4,128,654에 기술되어 있으며, 하기 화학식 2로 표시되는 3-[(모노치환된)페닐]-2-옥사졸리디논 유도체들은 유럽특허 EP 0312000, J. Med. Chem. 32, 1673(1989), J. Med. Chem. 33, 2569 (1990), Tetrahedron. 45,123(1989) 등에 언급되어 있다.Oxazolidinone compounds are known as new synthetic antibiotics that can be administered orally rather than as fermentation products, and derivatives of various structures are known. For example, 3-phenyl-2-oxazolidinone derivatives having one or two substituents are described in US Pat. 3-[(monosubstituted) phenyl] -2-oxazolidinone derivatives are described in European Patent EP 0312000, J. Med. Chem . 32, 1673 ( 1989 ), J. Med. Chem . 33, 2569 ( 1990 ), Tetrahedron . 45,123 ( 1989 ) and the like.

Figure 112000011447214-pat00003
Figure 112000011447214-pat00003

또한 파마시아 앤 업존 (Pharmacia & Upjohn)에서는 하기 화학식 3 및 4의 옥사졸리디논 유도체를 합성하였으며 (국제특허출원 WO 93/23384, WO 95/14684, WO 95/07271) 현재 하기 화학식 3의 화합물은 미국 식품의약품국 (FDA, Food and Drug Administration)의 허가를 얻어 발매를 앞두고 있다. 그러나 종래 합성된 옥사졸리디논 화합물들은 항균 스펙트럼이 광범위하지 못하고 독성이 있을 뿐만 아니라 생체내 (in vivo)에서 그 치료효과가 감소하는 단점을 가지고 있다.In addition, Pharmacia & Upjohn synthesized oxazolidinone derivatives of the following Chemical Formulas 3 and 4 (International Patent Application WO 93/23384, WO 95/14684, WO 95/07271). It is scheduled for release with the approval of the Food and Drug Administration (FDA). However, conventionally synthesized oxazolidinone compounds are disadvantageous in that the antimicrobial spectrum is not broad and toxic, and their therapeutic effect is reduced in vivo .

Figure 112000011447214-pat00004
Figure 112000011447214-pat00004

Figure 112000011447214-pat00005
Figure 112000011447214-pat00005

또한 국제특허출원 WO 93/09103에는 상기 화학식 1과 같이 페닐기의 4번 위치에 피리딘을 포함한 싸이아졸, 인돌, 옥사졸, 퀴놀 등과 같은 헤테로 고리로 치환된 옥사졸리디논 유도체가 알려져 있으나 헤테로 고리의 치환기들이 단순한 알킬기 또는 아미노기에 그치고 약효 또한 충분히 뛰어나지 않은 것으로 알려져 있다.
In addition, in International Patent Application WO 93/09103, an oxazolidinone derivative substituted with a hetero ring such as thiazole, indole, oxazole, quinol, etc. containing pyridine at position 4 of the phenyl group is known as Formula 1, but a substituent of a hetero ring is known. These are known to be simple alkyl or amino groups but not sufficiently effective.

이에 본 발명자들은 상기 문제점을 해결하기 위해 노력한 결과, 상기 화학식 1과 같이 페닐기의 4번 위치에 피리미딘 유도체가 치환되어 있는 다양한 옥사졸리 디논 유도체를 합성하였고 상기 화합물들의 항균력을 측정한 결과 그 항균 스펙트럼이 넓고 일부 화합물들은 생체내 (in vivo) 효과도 탁월함을 밝혀 본 발명을 완성하였다.
Accordingly, the present inventors have made efforts to solve the above problems, and synthesized various oxazolidinone derivatives in which pyrimidine derivatives are substituted at position 4 of the phenyl group as shown in Formula 1, and the antibacterial spectrum of the compounds was measured. This broad and some compound has also demonstrated excellent in vivo effects to complete the present invention.

본 발명의 목적은 강한 항균력을 갖는 상기 화학식 1로 표시되는 페닐기의 4번 위치에 피리미딘 유도체가 치환되어 있는 신규 옥사졸리디논 (oxazolidinone)유도체와 약학적으로 허용되는 그의 염 및 그들의 제조방법을 제공하는 것이다. SUMMARY OF THE INVENTION An object of the present invention is to provide a novel oxazolidinone derivative in which a pyrimidine derivative is substituted at position 4 of the phenyl group represented by Formula 1 having strong antibacterial activity, a pharmaceutically acceptable salt thereof, and a method for preparing the same. It is.

또한 본 발명의 목적은 화학식 1로 표시되는 옥사졸리디논 (oxazolidinone)유도체 및 약학적으로 허용되는 그의 염을 유효성분으로 하는 항생제용 약학적 조성물을 제공하는 것이다.
It is also an object of the present invention to provide a pharmaceutical composition for antibiotics comprising an oxazolidinone derivative represented by the formula (1) and a pharmaceutically acceptable salt thereof as an active ingredient.

상기 목적을 달성하기 위하여, 본 발명에서는 하기 화학식 1로 표시되는 페닐기의 4번 위치에 피리미딘을 포함하는 신규 옥사졸리디논 (oxazolidinone) 유도체 및 약학적으로 허용되는 그들의 염을 제공한다.In order to achieve the above object, the present invention provides novel oxazolidinone derivatives containing pyrimidine at position 4 of the phenyl group represented by the following formula (1), and pharmaceutically acceptable salts thereof.

화학식 1Formula 1

Figure 112000011447214-pat00017
Figure 112000011447214-pat00017

상기 화학식 1에서, In Chemical Formula 1,

R1은 수소 또는 불소이고, R 1 is hydrogen or fluorine,

R2는 수소; C1-C4의 알콕시기; 아미노기; 또는 R3가 치환 또는 치환되지 않은 피페라지닐기이다. R 2 is hydrogen; An alkoxy group of C 1 -C 4 ; Amino group; Or R 3 is a substituted or unsubstituted piperazinyl group.

상기 R3는 수소; 트리페닐메틸기; 치환 또는 치환되지 않은 아세틸기; 치환 또는 치환되지 않은 벤조일기; 치환 또는 치환되지 않은 카보닐기; C1-C3의 알콕시페닐기; C1-C3의 알킬기가 치환 또는 치환되지 않은 아크릴로일기; 니코티노일기; 피발로일기; 크로토닐기 또는 n-발레릴기이다.
R 3 is hydrogen; Triphenylmethyl group; A substituted or unsubstituted acetyl group; Substituted or unsubstituted benzoyl group; Substituted or unsubstituted carbonyl group; An alkoxyphenyl group of C 1 -C 3 ; An acryloyl group, wherein the alkyl group of C 1 -C 3 is unsubstituted or substituted; Nicotinoyl group; Pivaloyl group; It is a crotonyl group or n-valeryl group.

상기 치환된 아세틸기는 벤질옥시아세틸기, 아세톡시아세틸기, 히드록시아세틸기, C1-C3의 알킬아미노아세톡시아세틸기, 할로겐이 치환된 아세틸기, 몰포리-4-닐아세틸기, 이미다졸-1-일카보닐옥시아세틸기, C1-C3의 알콕시카보닐메틸아미노아세틸기, C1-C3의 알콕시아세틸기, t-부틸아세틸기; C1-C3의 알콕시기로 치환된 또는 치환되지않은 페닐아세틸기; 또는 C1-C3의 알콕시옥소아세틸기인 것이 바람직하다. The substituted acetyl group benzyloxyacetyl group, acetoxyacetyl group, hydroxyacetyl group, C 1 -C 3 alkylaminoacetoxyacetyl group, halogen-substituted acetyl group, morpholin-4-ylacetyl group, already Dazol-1-ylcarbonyloxyacetyl group, C 1 -C 3 alkoxycarbonylmethylaminoacetyl group, C 1 -C 3 alkoxyacetyl group, t -butylacetyl group; A phenylacetyl group substituted or unsubstituted with an alkoxy group of C 1 -C 3 ; Or a C 1 -C 3 alkoxyoxoacetyl group.

상기 치환된 벤조일기는 C1-C4의 알콕시벤조일기, 트리할로메틸벤조일기 또는 니트로벤조일기가 바람직하다.The substituted benzoyl group is preferably a C 1 -C 4 alkoxybenzoyl group, trihalomethylbenzoyl group or nitrobenzoyl group.

상기 치환된 카보닐기는 C1-C4의 할로알킬카보닐기, 페녹시카보닐기 또는 벤 질옥시카보닐기가 바람직하다.
The substituted carbonyl group is preferably a C 1 -C 4 haloalkylcarbonyl group, phenoxycarbonyl group or benzyloxycarbonyl group.

상기 화학식 1의 화합물들 중 바람직한 화합물로는 구체적으로 하기와 같은 화합물들이 있다.Preferred compounds among the compounds of Formula 1 include the following compounds.

1) (S)-[N-3-(4-피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 1의 화합물)1) (S)-[N-3- (4-pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide (compound of Example 1)

2) (S)-[N-3-(4-(2-메톡시피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 2의 화합물)2) (S)-[N-3- (4- (2-methoxypyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide (Example 2, compound)

3) (S)-[N-3-(4-(2-아미노피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 3의 화합물)3) (S)-[N-3- (4- (2-aminopyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide (Example 3 Compound of

4) (S)-[N-3-(4-(2-(4-트리페닐메틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 4의 화합물)4) (S)-[N-3- (4- (2- (4-triphenylmethylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5 -Oxazolindinyl] methyl acetamide (compound of Example 4)

5) (S)-[N-3-(4-(2-피페라진-1-일피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 염산염 (실시예 5의 화합물)5) (S)-[N-3- (4- (2-piperazin-1-ylpyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acet Amide Hydrochloride (Compound of Example 5)

6) (S)-[N-3-(4-(2-(4-아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 6의 화합물)6) (S)-[N-3- (4- (2- (4-acetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxa Zolindinyl] methyl acetamide (Compound of Example 6)

7) (S)-[N-3-(4-(2-(4-벤질옥시아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 7의 화합물)7) (S)-[N-3- (4- (2- (4-benzyloxyacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5 -Oxazolindinyl] methyl acetamide (compound of Example 7)

8) (S)-[N-3-(4-(2-(4-아세톡시아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 8의 화합물) 8) (S)-[N-3- (4- (2- (4-acetoxyacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5 -Oxazolindinyl] methyl acetamide (compound of Example 8)                     

9) (S)-[N-3-(4-(2-(4-히드록시아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 9의 화합물)9) (S)-[N-3- (4- (2- (4-hydroxyacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5 -Oxazolindinyl] methyl acetamide (compound of Example 9)

10) (S)-[N-3-(4-(2-(4-디메틸아미노아세톡시아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 10의 화합물)10) (S)-[N-3- (4- (2- (4-dimethylaminoacetoxyacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo -5-oxazolindinyl] methyl acetamide (compound of Example 10)

11) (S)-[N-3-(4-(2-(4-부로모아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 11의 화합물)11) (S)-[N-3- (4- (2- (4-bromoacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5 -Oxazolindinyl] methyl acetamide (compound of Example 11)

12) (S)-[N-3-(4-(2-(4-몰포린-4-일아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 12의 화합물)12) (S)-[N-3- (4- (2- (4-morpholin-4-ylacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2 -Oxo-5-oxazolindinyl] methyl acetamide (compound of Example 12)

13) (S)-[N-3-(4-(2-(4-이미다졸-1-일카보닐옥시아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 13의 화합물)13) (S)-[N-3- (4- (2- (4-imidazol-1-ylcarbonyloxyacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl ) -2-oxo-5-oxazolindinyl] methyl acetamide (compound of Example 13)

14) (S)-[N-3-(4-(2-(4-클로로아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 14의 화합물)14) (S)-[N-3- (4- (2- (4-chloroacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5- Oxazolindinyl] methyl acetamide (compound of Example 14)

15) (S)-[N-3-(4-(2-(4-메톡시카보닐메틸아미노아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 15의 화합물)15) (S)-[N-3- (4- (2- (4-methoxycarbonylmethylaminoacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2 -Oxo-5-oxazolindinyl] methyl acetamide (compound of Example 15)

16) (S)-[N-3-(4-(2-(4-(4-메톡시페닐피페라진-4-일)아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 16의 화합물) 16) (S)-[N-3- (4- (2- (4- (4-methoxyphenylpiperazin-4-yl) acetylpiperazin-1-yl) pyrimidin-5-yl) -3 -Fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide (compound of Example 16)                     

17) (S)-[N-3-(4-(2-(4-메톡시아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 17의 화합물)17) (S)-[N-3- (4- (2- (4-methoxyacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5 -Oxazolindinyl] methyl acetamide (compound of Example 17)

18) (S)-[N-3-(4-(2-(4-아크릴로일피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 18의 화합물)18) (S)-[N-3- (4- (2- (4-acryloylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5 -Oxazolindinyl] methyl acetamide (compound of Example 18)

19) (S)-[N-3-(4-(2-(4-에톡시옥소아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 19의 화합물)19) (S)-[N-3- (4- (2- (4-ethoxyoxoacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo- 5-oxazolindinyl] methyl acetamide (compound of Example 19)

20) (S)-[N-3-(4-(2-(4-니코티노일피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 20의 화합물)20) (S)-[N-3- (4- (2- (4-nicotinoylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5 -Oxazolindinyl] methyl acetamide (compound of Example 20)

21) (S)-[N-3-(4-(2-(4-피발로일피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 21의 화합물)21) (S)-[N-3- (4- (2- (4-pivaloylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5 -Oxazolindinyl] methyl acetamide (compound of Example 21)

22) (S)-[N-3-(4-(2-(4-t-부틸아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 22의 화합물)22) (S)-[N-3- (4- (2- (4- t -butylacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo- 5-oxazolindinyl] methyl acetamide (compound of Example 22)

23) (S)-[N-3-(4-(2-(4-(2,5-디메톡시페닐)아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 23의 화합물) 23) (S)-[N-3- (4- (2- (4- (2,5-dimethoxyphenyl) acetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl ) -2-oxo-5-oxazolindinyl] methyl acetamide (compound of Example 23)

24) (S)-[N-3-(4-(2-(4-(3,3-디메틸아크릴로일)피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 24의 화합물)24) (S)-[N-3- (4- (2- (4- (3,3-dimethylacryloyl) piperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl ) -2-oxo-5-oxazolindinyl] methyl acetamide (compound of Example 24)

25) (S)-[N-3-(4-(2-(4-(2,6-디메톡시벤조일)피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 25의 화합물; 25) (S)-[N-3- (4- (2- (4- (2,6-dimethoxybenzoyl) piperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide (compound of Example 25;                     

26) (S)-[N-3-(4-(2-(4-(2-트리플로로메틸벤조일)피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 26의 화합물)26) (S)-[N-3- (4- (2- (4- (2-trifluoromethylbenzoyl) piperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide (compound of Example 26)

27) (S)-[N-3-(4-(2-(4-(4-트리플로로메틸벤조일)피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 27의 화합물)27) (S)-[N-3- (4- (2- (4- (4-trifluoromethylbenzoyl) piperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide (compound of Example 27)

28) (S)-[N-3-(4-(2-(4-페닐아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 28의 화합물)28) (S)-[N-3- (4- (2- (4-phenylacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5- Oxazolindinyl] methyl acetamide (compound of Example 28)

29) (S)-[N-3-(4-(2-(4-(3,5-디니트로벤조일)피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 29의 화합물)29) (S)-[N-3- (4- (2- (4- (3,5-dinitrobenzoyl) piperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide (compound of Example 29)

30) (S)-[N-3-(4-(2-(4-크로토닐피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 30의 화합물)30) (S)-[N-3- (4- (2- (4-crotonylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5- Oxazolindinyl] methyl acetamide (compound of Example 30)

31) (S)-[N-3-(4-(2-(4-트리클로로아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸리딘일]메틸 아세트아마이드 (실시예 31의 화합물)31) (S)-[N-3- (4- (2- (4-trichloroacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5 -Oxazolidinyl] methyl acetamide (compound of Example 31)

32) (S)-[N-3-(4-(2-(4-n-발레릴피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸리딘일]메틸 아세트아마이드 (실시예 32의 화합물)32) (S)-[N-3- (4- (2- (4-n- valerylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo- 5-oxazolidinyl] methyl acetamide (compound of Example 32)

33) (S)-[N-3-(4-(2-(4-(1-부로모에틸카보닐)피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸리딘일]메틸 아세트아마이드 (실시예 33의 화합물)33) (S)-[N-3- (4- (2- (4- (1-bromoethylcarbonyl) piperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl acetamide (compound of Example 33)

34) (S)-[N-3-(4-(2-(4-페녹시카보닐피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸리딘일]메틸 아세트아마이드 (실시예 34의 화합물) 34) (S)-[N-3- (4- (2- (4-phenoxycarbonylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo- 5-oxazolidinyl] methyl acetamide (compound of Example 34)                     

35) (S)-[N-3-(4-(2-(4-벤질옥시카보닐피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸리딘일]메틸 아세트아마이드 (실시예 35의 화합물)
35) (S)-[N-3- (4- (2- (4-benzyloxycarbonylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo- 5-oxazolidinyl] methyl acetamide (compound of Example 35)

더욱 바람직하게는 상기 화학식 1의 화합물은 More preferably, the compound of Formula 1

1) (S)-[N-3-(4-피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 1의 화합물);1) (S)-[N-3- (4-pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide (compound of Example 1);

2) (S)-[N-3-(4-(2-메톡시피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 2의 화합물);2) (S)-[N-3- (4- (2-methoxypyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide (Example 2 compound);

3) (S)-[N-3-(4-(2-아미노피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 3의 화합물); 및3) (S)-[N-3- (4- (2-aminopyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide (Example 3 Compound of; And

4) (S)-[N-3-(4-(2-(4-부로모아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 11의 화합물)이다.
4) (S)-[N-3- (4- (2- (4-bromoacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5 -Oxazolindinyl] methyl acetamide (compound of Example 11).

하기 표 1은 화학식 1로 표시되는 본 발명의 옥사졸리디논 유도체의 구조식을 나타낸 것이다. Table 1 below shows structural formulas of the oxazolidinone derivatives of the present invention represented by the formula (1).                     

<표 1>TABLE 1

Figure 112000011447214-pat00007
Figure 112000011447214-pat00007

Figure 112000011447214-pat00008

Figure 112000011447214-pat00008

상기 화학식 1로 표시되는 본발명의 옥사졸리디논 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산 (free acid)에 의해 형성된 산부가염이 유용하다. 유리산으로는 무기산과 유기산을 사용할 수 있다. 무기산으로는 염산, 브롬산, 황산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 젖산, 주석산, 말레인산, 우마린산, 글루콘산, 메탄술폰 산, 글리콘산, 숙신산, 4-톨루엔술폰산, 갈룩투론산, 엠본산, 글루탐산, 또는 아스파르트산 등을 사용할 수 있다. 또한 화학식 1의 화합물은 염기로 인해 형성된 약학적으로 허용 가능한 금속염 특히 알칼리 금속염 일수도 있다. 이들의 예로는 나트륨염 및 칼륨염이 있다.
The oxazolidinone compound of the present invention represented by Chemical Formula 1 may 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 a salt. Inorganic acids and organic acids can be used as the free acid. Hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. may be used as the inorganic acid, and citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, umarin acid, gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, 4-toluene Sulfonic acid, galluxuronic acid, embonic acid, glutamic acid, aspartic acid and the like can be used. The compound of formula 1 may also be a pharmaceutically acceptable metal salt, in particular an alkali metal salt, formed due to the base. Examples of these are sodium salts and potassium salts.

또한 본 발명에서는 하기 반응식 1로 표시되는 화학식 1의 옥사졸리디논(oxazolidinone) 유도체의 제조방법을 제공한다.In another aspect, the present invention provides a method for preparing an oxazolidinone derivative of the formula (1) represented by Scheme 1.

Figure 112000011447214-pat00009
Figure 112000011447214-pat00009

상기 반응식에서 R1 및 R2는 화학식 1에서 정의한 바와 같다.

R 1 and in the above scheme R 2 is as defined in formula (1).

본 발명의 제조방법은The manufacturing method of the present invention

1) 구조식 (2)의 아닐린을 출발물질로 하여 아민기를 보호시킨 후 강염기 하에서 글리시딜부티레이트와 반응시켜 구조식 (3)의 하이드록시메틸 옥사졸리디논 유도체를 제조하는 단계 (제 1 단계);1) preparing a hydroxymethyl oxazolidinone derivative of formula ( 3 ) by protecting the amine group using aniline of formula ( 2 ) as a starting material and then reacting with glycidylbutyrate under a strong base (first step);

2) 상기 제 1 단계에서 제조된 화합물의 하이드록시기를 아민기로 변환시켜 구조식 (4)의 화합물을 제조하는 단계 (제 2 단계);2) preparing a compound of formula ( 4 ) by converting a hydroxy group of the compound prepared in the first step into an amine group (second step);

3) 상기 제 2 단계에서 제조된 구조식 (4)의 화합물을 아세틸화 반응시켜 구조식 (5)의 화합물을 얻는 단계 (제 3단계); 및3) acetylating the compound of formula ( 4 ) prepared in the second step to obtain a compound of formula ( 5 ) (third step); And

4) 상기 제 3 단계에서 제조된 구조식(5)의 화합물로부터 화학식 1의 피리미딘 고리를 포함하는 옥사졸리디논 유도체를 얻는 단계 (제 4단계)로 이루어진다.
4) obtaining a oxazolidinone derivative including a pyrimidine ring of formula ( 1 ) from the compound of formula ( 5 ) prepared in the third step (step 4).

구체적으로 상기 반응식 1에 도시한 바와 같이, 제 1 단계는 구조식 (2)로 표시되는 아닐린의 아민기에 Cbz (Benzyloxycarbonyl)기를 도입한 다음 글라시딜부티레이트와 강염기 하에서 반응시키는 것이 바람직하다. 강염기는 n-부틸리튬, sec-부틸리튬 또는 tert-부틸리튬를 사용하는 것이 바람직하며 더욱 바람직하게는 n-부틸리튬를 사용하는 것이다. 또한 상기 반응은 질소 하에 반응온도 -78℃에서 실시하는 것이 바람직하다.
Specifically, as shown in Scheme 1, in the first step, it is preferable to introduce a Cbz (Benzyloxycarbonyl) group into the amine group of the aniline represented by the formula ( 2 ), and then react with the glycidyl butyrate under a strong base. The strong base is preferably n -butyllithium, sec -butyllithium or tert -butyllithium, and more preferably n -butyllithium. In addition, the reaction is preferably carried out at a reaction temperature of -78 ℃ under nitrogen.

상기 제 2 단계에서는 구조식 (3)의 화합물의 하이드록시기를 아자이드로 쉽게 치환하기위해 우선 하이드록시기에 메탄술포닐기, 파라톨루엔술포닐기 또는 할 로겐을 도입한 후, 소디움아자이드와 반응시키고 생성된 아자이드를 팔라디움이나 트리페닐 포스핀을 사용하여 환원시켜 구조식 (4)의 화합물을 얻는다. In the second step, in order to easily replace the hydroxy group of the compound of formula ( 3 ) with azide, first, a methanesulfonyl group, paratoluenesulfonyl group, or halogen is introduced into the hydroxy group, and then reacted with sodium azide. Azide is reduced with palladium or triphenyl phosphine to give the compound of formula ( 4 ).

상기 구조식 (3)으로 표시되는 화합물의 히드록시기에 메탄술포닐기, 파라톨루엔술포닐기 또는 할로겐을 도입할 경우에는 반응온도 0℃에서 실시하는 것이 바람직하다. When introducing methanesulfonyl group, paratoluenesulfonyl group or halogen into the hydroxy group of the compound represented by the above structural formula ( 3 ), it is preferable to carry out at a reaction temperature of 0 ° C.

상기 메탄술포닐기, 파라톨루엔술포닐기 또는 할로겐이 도입된 화합물에 아자이드기를 도입하기 위해 소디움아자이드는 약 1∼3 당량 첨가하는 것이 바람직하다. 또한 반응온도는 90∼110℃ 범위가 바람직하며, 1∼2시간동안 반응시키는 것이 바람직하다. 반응용매로는 디메틸포름아마이드, 디메틸설프옥사이드 또는 1,4-디옥산 등을 사용할 수 있다.Sodium azide is preferably added in an amount of about 1 to 3 equivalents to introduce an azide group into the compound into which the methanesulfonyl group, paratoluenesulfonyl group, or halogen is introduced. In addition, the reaction temperature is preferably in the range of 90 to 110 ° C, and preferably for 1 to 2 hours. Dimethyl formamide, dimethyl sulfoxide or 1,4-dioxane can be used as the reaction solvent.

팔라디움을 사용하여 상기 아자이드 화합물을 환원할 경우에는 상온에서 수소 하에 반응을 실시하는 것이 바람직하다. 이때 반응용매는 테트라하이드로퓨란, 메탄올 등을 단독으로 또는 혼합하여 사용할 수 있다. 또한 트리페닐 포스핀을 사용하여 아자이드 화합물을 환원할 경우에는 테트라하이드로퓨란에 물을 소량 첨가한 후 2시간 가량 환류한다.When the azide compound is reduced using palladium, it is preferable to carry out the reaction under hydrogen at room temperature. At this time, the reaction solvent may be used alone or mixed with tetrahydrofuran, methanol. In addition, when triphenyl phosphine is used to reduce the azide compound, it is refluxed for about 2 hours after adding a small amount of water to tetrahydrofuran.

제 3 단계는 상기 제 2 단계에서 얻은 구조식(4)의 (S)-[N-3-(3-플로로페닐) -2-옥소-옥사졸린딘일]메틸 아민을 염기 하에 무수 아세트산과 반응시켜 아세틸화 반응시키는 단계로, 이때 적당한 염기로는 트리에틸아민, 피리딘, 디이소프로필에틸아민 등이 사용될 수 있다.
The third step is reacting (S)-[N-3- (3-fluorophenyl) -2-oxo-oxazolindinyl] methyl amine of Structural Formula ( 4 ) obtained in the second step with acetic anhydride under a base. In the step of acetylation, triethylamine, pyridine, diisopropylethylamine and the like may be used as a suitable base.

제 4 단계에서는 구조식(5)의 화합물로부터 화학식 1로 표시되는 본 발명의 옥사졸리디논 화합물을 얻는 단계로, 구조식(5)의 화합물을 할로겐화 반응시키고 유기스테닐 화합물과 반응시킨 다음 화학식 1로 표시되는 화합물의 적절한 치환기에 대응하는 브롬 또는 요오드로 치환된 피리미딘 유도체와 반응시켜 화학식 1의 화합물을 얻을 수 있다.The represented by the following formula (I) in which to obtain the oxazolidinone compound of the present invention, the compound of formula (5) halogenating reaction and the reaction with the organic Ste carbonyl compound in Step 4 of the formula 1 from a compound of formula (5) Compounds of formula (1) may be obtained by reaction with pyrimidine derivatives substituted with bromine or iodine corresponding to appropriate substituents of the compounds.

상기 할로겐화 반응은 요오드화 반응시키는 것이 바람직하며, 요오드화 반응은 아이오도 클로라이드 (iodochloride, ICl) 또는 트리플루오아세트산 은염 (CF3COOAg)과 요오드 존재 하에서 반응시키는 것이 바람직하다. 또한 상기 반응은 상온에서 실시하는 것이 바람직하다.The halogenation reaction is preferably iodized, and the iodide reaction is preferably reacted with iodochloride (ICl) or trifluoroacetic acid silver salt (CF 3 COOAg) in the presence of iodine. In addition, the reaction is preferably carried out at room temperature.

상기 구조식 (5)의 화합물을 요오드화 반응시켜 얻은 화합물은 팔라디움 촉매 하에 헥사메틸디틴과 반응시켜 요오드기가 트리메틸스테닐기로 치환된 화합물을 얻을 수 있다. 팔라디움 촉매로는 디클로로비스트리페닐포스핀 팔라디움(II) 또는 테트라키스트리페닐포스핀 팔라디움(0)을 사용할 수 있다. 반응용매로는 1,4-디옥산, 디메틸포름아마이드, 테트라하이드로퓨란 등을 사용할 수 있고 반응온도는 90∼120℃에서 실시하는 것이 바람직하다.
The compound obtained by the iodide reaction of the compound of formula ( 5 ) may be reacted with hexamethylditin under a palladium catalyst to obtain a compound in which an iodine group is substituted with a trimethylstenyl group. As the palladium catalyst, dichlorobistriphenylphosphine palladium (II) or tetrakistriphenylphosphine palladium (0) can be used. As a reaction solvent, 1, 4- dioxane, dimethylformamide, tetrahydrofuran, etc. can be used, It is preferable to carry out reaction temperature at 90-120 degreeC.

구체적으로 화학식 1로 표시되는 본 발명의 옥사졸리디논 화합물들은 하기 반응식 2에서 도시한 바와 같이, 트리메틸스테닐기를 도입한 하기 구조식 (6)의 화합물과 화학식 1로 표시되는 화합물들의 적절한 치환기에 대응하는 브롬 또는 아이 오딘으로 치환된 피리미딘 유도체를 팔라디움(0) 또는 팔라디움(II) 하에 반응시켜 얻는다. 상기 팔라디움 촉매로는 디클로로비스트리페닐포스핀 팔라디움(II) 또는 테트라키스트리페닐포스핀 팔라디움(0)을 사용할 수 있다. 반응온도는 90∼110 ℃ 범위에서 실시하는 것이 바람직하며, 반응시간은 약 2∼5시간이 바람직하다. 또한 반응용매로는 디메틸포름아마이드, 1,4-디옥산, 테트라히드로퓨란을 단독으로 또는 혼합하여 사용할 수 있다.
Specifically, the oxazolidinone compounds of the present invention represented by the general formula (1) correspond to the appropriate substituents of the compound represented by the following formula (6) and the compound represented by the general formula (1) in which a trimethylstenyl group is introduced, as shown in the following Scheme 2. The pyrimidine derivatives substituted with bromine or iodine are obtained by reaction under palladium (0) or palladium (II). As the palladium catalyst, dichlorobistriphenylphosphine palladium (II) or tetrakistriphenylphosphine palladium (0) may be used. The reaction temperature is preferably carried out in the range of 90 to 110 ° C, and the reaction time is preferably about 2 to 5 hours. As the reaction solvent, dimethylformamide, 1,4-dioxane and tetrahydrofuran may be used alone or in combination.

Figure 112000011447214-pat00010
Figure 112000011447214-pat00010

상기 식에서, R1 및 R2는 상기에서 정의한 바와 같다.
Wherein R 1 and R 2 are as defined above.

또한 하기 반응식 1에서 나타낸 바와 같이, 본 발명의 일부 화합물은 트리페닐메틸기로 보호되어있는 피페라진 피리미딘 중간체를 구조식 (7)의 화합물과 반응시켜 구조식 (8)의 화합물을 합성한 후 염산 용액을 사용하여 보호기를 제거하고 적당한 치환기와 반응시켜 구조식 (10)의 화합물을 합성할 수 있다. In addition, as shown in Scheme 1, some compounds of the present invention react the piperazine pyrimidine intermediate protected with a triphenylmethyl group with a compound of formula ( 7 ) to synthesize a compound of formula ( 8 ), and then To remove the protecting group and react with a suitable substituent to synthesize the compound of formula ( 10 ).

Figure 112000011447214-pat00011
Figure 112000011447214-pat00011

상기 식에서, R1 및 R2는 상기에서 정의한 바와 같으며, X는 할로겐 원자이다.
Wherein R 1 and R 2 are as defined above and X is a halogen atom.

또한 본 발명에서는 화학식 1의 화합물을 유효성분으로 함유하는 항생제용 약학적 조성물을 제공한다.    In another aspect, the present invention provides a pharmaceutical composition for antibiotics containing the compound of formula (1) as an active ingredient.

본 발명은 비독성, 불활성, 제약상 적합한 부형제 이외에, 본 발명에 따른 1종 이상의 화합물을 함유하거나, 또는 본 발명에 따른 1종 이상의 유효 화합물로 이루어지는 제약 조성물 및 이 조성물의 제조 방법을 제공한다.The present invention provides, in addition to non-toxic, inert, pharmaceutically suitable excipients, a pharmaceutical composition containing at least one compound according to the invention or consisting of at least one active compound according to the invention and a process for preparing the composition.

화학식 1의 화합물은 임상투여시에 경구 또는 비경구로 투여가 가능하며 일반적인 의약품제제의 형태로 사용될 수 있다. The compound of formula 1 may be administered orally or parenterally during clinical administration and may be used in the form of a general pharmaceutical preparation.                     

즉, 본 발명의 화학식 1의 화합물은 실제 임상투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있는데, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 하나 이상의 화학식 1의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트 (Calcium carbonate), 수크로스 (Sucrose) 또는 락토오스 (Lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜 (Propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.
That is, the compound of Formula 1 of the present invention may be administered in various oral and parenteral dosage forms during actual clinical administration, and when formulated, the commonly used fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. Prepared using diluents or excipients. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which form at least one excipient such as starch, calcium carbonate, It is prepared by mixing sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

일반적으로 의약품에 있어서, 본 발명에 의한 화학식 1로 표시되는 화합물의 유효 용량은 성인기준 1.2g/day 이고 하루 2~3회 투여될 수 있다. 그러나, 상기 투약량은 변화시킬 필요가 있으며, 특히 치료할 객체의 체질 특이성 및 체중, 질병의 종류 및 심도, 제형의 성질, 의약품 투여의 성질, 및 투여 기간 또는 간격을 고려해서 변화시킬 수 있다.
In general, in medicine, the effective dose of the compound represented by the formula (1) according to the present invention is 1.2 g / day for adults and may be administered 2-3 times a day. However, the dosage may need to be changed, and in particular, may be changed in consideration of the constitution specificity and weight of the subject to be treated, the type and depth of the disease, the nature of the formulation, the nature of the drug administration, and the duration or interval of administration.

본 발명의 옥사졸리디논 화합물의 항균력을 측정한 결과 항균 스펙트럼이 넓고 일부 화합물들은 생체내 (in vivo) 효과도 탁월한 것이 확인되었다. 또한 본 발명의 화합물은 기존 항생제에 내성을 가지는 스타필로코카이(Staphylococci), 엔테로코카이 (Enterococci), 스트렙토코카이 (Streptococci)와 같은 그람양성 호기성 박테리아뿐만 아니라, 박테로이데스 종 (Bacteroides), 클로스티리디아 종 (Clostridia)과 같은 혐기성 생물과 마이코박테리움 투베르쿨로시스 (Mycobacterium tuberculosis), 마이코 박테리움 아비움 (Mycobacterium avium) 등의 마아코 박테리움 종 (Mycobacterium )과 같은 항산성 미생물들을 포함하여 각종 사람 및 동물 병원균에 대해 강한 항균효과를 나타내었다.As a result of measuring the antimicrobial activity of the oxazolidinone compound of the present invention, it was confirmed that the antimicrobial spectrum was broad and some compounds also had excellent in vivo effects. In addition, compounds of the present invention are Staphylococcus Kokai (Staphylococci), those resistant to existing antibiotics, Enterobacter Kokai (Enterococci), streptomycin Kokai (Streptococci) Gram-positive aerobic bacteria teroyi, as well as foil des species (Bacteroides), such as a Claus tea Lydia Including anaerobic organisms such as Clostridia and acidic microorganisms such as Mycobacterium species such as Mycobacterium tuberculosis and Mycobacterium avium It showed strong antibacterial effect against human and animal pathogens.

이하 제조예와 실시예에 의하여 본 발명을 상세히 설명한다. 단 하기 실시예는 발명을 예시하는 것일 뿐 본 발명이 실시예에 의하여 한정되는 것은 아니다.
Hereinafter, the present invention will be described in detail by preparation examples and examples. However, the following examples are merely to illustrate the invention and the present invention is not limited by the examples.

<제조예 1> N-카보벤조옥시-3-플로로아닐린의 제조 Preparation Example 1 Preparation of N-Carbobenzooxy-3-fluoroaniline

3-플로로아닐린 100g(0.90 mole)을 1L의 테트라하이드로퓨란 (Tetrahydrofuran, THF)에 용해시키고 탄산수소나트륨(NaHCO3) 150g(1.8mol)을 첨가한 후 0℃로 냉각시킨 다음 상기 용액에 카보벤조옥시 크로라이드 (CbzCl, N- carbobenzyloxy chloride) 154ml(1.08mol)를 천천히 가하였다. 상기 반응 혼합물은 0℃를 유지시키면서 2시간 동안 교반시킨 다음 에틸아세테이트(ethylacetate) 0.5L를 가하여 추출하였다. 추출된 유기층은 소금물로 세척하고 무수 황산마그네슘 (MgSO4)으로 탈수한 후 감압농축하였다. 잔유물은 n-헥산으로 2번 세척하여 백색결정 132g (85%)의 표제 화합물을 얻었다.
Dissolve 100 g (0.90 mole) of 3-fluoroaniline in 1 L of tetrahydrofuran (THF), add 150 g (1.8 mol) of sodium bicarbonate (NaHCO 3 ), cool to 0 ° C., and then cabo to the solution. 154 ml (1.08 mol) of benzooxy chloride (CbzCl, N -carbobenzyloxy chloride) was slowly added. The reaction mixture was stirred for 2 hours while maintaining 0 ℃ and extracted by adding 0.5L ethylacetate (ethylacetate). The extracted organic layer was washed with brine, dehydrated with anhydrous magnesium sulfate (MgSO 4 ), and concentrated under reduced pressure. The residue was washed twice with n-hexane to give 132 g (85%) of the title compound as white crystals.

<제조예 2> (R)-[N-3-(3-플로로페닐)-2-옥소-5-옥사졸린딘일]메탄올의 제조 Preparation Example 2 Preparation of (R)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolindinyl] methanol

상기 제조예 1에서 얻은 N-카보벤조옥시-3-플로로아닐린 132g(0.54mol)을 1.3L의 테트라하이드로퓨란에 용해시키고 -78℃로 냉각시켰다. 질소 하에 n-부틸리튬(n-BuLi, 1.6M /n-헥산, 0.59mol) 370ml를 천천히 가한 다음 약 10분간 교반하였다. 상기 용액에 (R)-(-)-글리시딜부티레이트 84ml(1.1mol)를 천천히 가하고 반응혼합물을 동일 온도에서 2시간 교반시킨 후 상온에서 24시간 반응시켰다. 반응이 완결된 후 상온에서 반응용액에 암모늄 클로라이드(NH4CI) 용액을 가한 후 에틸아세테이트(0.5L)로 추출하였다. 추출된 유기 층은 소금물로 세척한 다음 무수 황산마그네슘으로 탈수하고 감압 증류하였다. 잔유물은 에틸아세테이트(100ml)로 용해시킨 후 n-헥산을 가하여 백색결정을 얻었다. 상기 백색 결정을 여과하여 원하는 표제 화합물 80g(70%)을 얻었다. 132 g (0.54 mol) of N-carbobenzooxy-3-fluoroaniline obtained in Preparation Example 1 was dissolved in 1.3 L of tetrahydrofuran and cooled to -78 ° C. 370 ml of n -butyllithium (n-BuLi, 1.6M / n -hexane, 0.59mol) was slowly added under nitrogen, followed by stirring for about 10 minutes. 84 ml (1.1 mol) of (R)-(-)-glycidyl butyrate was slowly added to the solution, and the reaction mixture was stirred at the same temperature for 2 hours and then reacted at room temperature for 24 hours. After the reaction was completed, ammonium chloride (NH 4 CI) solution was added to the reaction solution at room temperature, and extracted with ethyl acetate (0.5L). The extracted organic layer was washed with brine, dehydrated with anhydrous magnesium sulfate and distilled under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and n-hexane was added to give white crystals. The white crystals were filtered to give 80 g (70%) of the title compound.

1H NMR(DMSO-d6) 7.85(t,1H), 7.58(dd,1H), 7.23(dd,1H), 4.69(m,1H), 4.02(t,1H), 3.80(dd,1H), 3.60(br dd,2H).
1 H NMR (DMSO-d 6 ) 7.85 (t, 1H), 7.58 (dd, 1H), 7.23 (dd, 1H), 4.69 (m, 1H), 4.02 (t, 1H), 3.80 (dd, 1H) , 3.60 (br dd, 2H).

<제조예 3> (R)-[N-3-(3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 메탄술폰네이트의 제조 Preparation Example 3 Preparation of (R)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl methanesulfonate

(R)-[N-3-(3-플로로페닐)-2-옥소-5-옥사졸린딘일]메탄올 55.1g(0.26mol)을 메틸렌 클로라이드(300ml)에 녹이고 0℃에서 트리에틸아민 54.4ml(0.39mol)와 메탄술포닐 클로라이드 24ml(0.312mol)를 천천히 적가하였다. 0℃에서 약 40분가량 반응 혼합물을 교반한 후 물을 첨가하고 클로로포름으로 추출한 다음 무수 황산마그네슘으로 탈수하고 감압농축한 후 건조하여 표제 화합물 78.3g을 얻었다.
55.1 g (0.26 mol) of (R)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolindinyl] methanol is dissolved in methylene chloride (300 ml) and 54.4 ml of triethylamine at 0 ° C. (0.39 mol) and 24 ml (0.312 mol) of methanesulfonyl chloride were slowly added dropwise. After stirring the reaction mixture at 0 ° C. for about 40 minutes, water was added, extracted with chloroform, dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure, and dried to obtain 78.3 g of the title compound.

<제조예 4> (R)-[N-3-(3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아자이드의 제조 Preparation Example 4 Preparation of (R)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl azide

(R)-[N-3-(3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 메탄술폰네이트 78g(0.27mol)을 디메틸포름아마이드 800ml에 녹이고 소듐아자이드 26.3g (0.41mol)을 가한 후 100℃에서 2시간 교반하였다. 상기 반응 혼합물에 물을 첨가한 다음 에틸아세테이트로 추출하고 탈수한 후 감압 농축하고 건조하여 표제 화합물 70g을 얻었다.
78 g (0.27 mol) of (R)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl methanesulfonate was dissolved in 800 ml of dimethylformamide and 26.3 g (0.41) of sodium azide mol) was added and stirred at 100 ° C. for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate, dehydrated, concentrated under reduced pressure and dried to give 70 g of the title compound.

<제조예 5> (S)-[N-3-(3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아민의 제조 Preparation Example 5 Preparation of (S)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl amine

(R)-[N-3-(3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아자이드 70g을 테트라히드로퓨란 400ml와 메탄올 80ml의 혼합용매에 녹인 후 팔라듐 카본(Pd/C) 8g을 가하고 실온에서 수소 하에 24시간동안 교반한 다음 여과하고 감압농축하여 표제 화합물 54.6g을 얻었다.
70 g of (R)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl azide was dissolved in a mixed solvent of 400 ml of tetrahydrofuran and 80 ml of methanol, followed by palladium carbon (Pd / C) 8 g was added, stirred at room temperature under hydrogen for 24 hours, filtered and concentrated under reduced pressure to give 54.6 g of the title compound.

<제조예 6> (S)-[N-3-(3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조 Preparation Example 6 Preparation of (S)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide

(S)-[N-3-(3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아민 54.6g(0.26mol)을 메틸렌 클로라이드 500ml에 녹인 후 0℃에서 트리에틸아민 72.4ml(0.52mol)와 무수아세트산 36.8ml(0.39mol)을 가한 후 반응온도 0℃를 유지하면서 반응 혼합물을 1시간 교반한 다음 물을 가하고 클로로포름으로 추출하였다. 추출된 유기층은 소금물로 세척하고 탈수한 후 감압 농축하여 미색 분말을 얻었다. 생성된 미색 분말을 n-헥산으로 세 번 세척하여 표제 화합물 49.6g(76%)를 얻었다.
54.6 g (0.26 mol) of (S)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl amine was dissolved in 500 ml of methylene chloride, and then 72.4 ml of triethylamine at 0 ° C. (0.52 mol) and 36.8 ml (0.39 mol) of acetic anhydride were added thereto, the reaction mixture was stirred for 1 hour while maintaining the reaction temperature at 0 ° C., and water was added thereto, followed by extraction with chloroform. The extracted organic layer was washed with brine, dehydrated and concentrated under reduced pressure to obtain an off-white powder. The resulting off-white powder was washed three times with n-hexane to give 49.6 g (76%) of the title compound.

<제조예 7> (S)-[N-3-(4-아이오도-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조 Preparation Example 7 Preparation of (S)-[N-3- (4-iodo-3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide

(S)-[N-3-(3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 54.5g(0.22mol)을 아세트산 2.5L와 트리플로로아세트산 700ml의 혼합용매에 녹이고 아세트산 300ml에 녹인 아이오딘 모노클로라이드(ICl) 455.7g(2.8mol)을 실온에서 천천히 적가하였다. 실온에서 15시간동안 상기 반응 혼합물을 교반한 후 디에틸에테르를 첨가하여 고체를 생성시키고 이를 여과한 후 얻어진 고체를 클로로포름과 메탄올 혼합용매에 녹인 다음 소듐치오설패이트 용액과 탄산수소나트륨(NaHCO3)용액으로 세척하고 탈수하였다. 잔유물은 감압 농축한 후 건조하여 표제 화합물 59.5g(80.4%)을 얻었다.54.5 g (0.22 mol) of (S)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide was added to a mixed solvent of 2.5 L acetic acid and 700 ml of trifluoroacetic acid. 455.7 g (2.8 mol) of iodine monochloride (ICl) dissolved in 300 ml of acetic acid was slowly added dropwise at room temperature. After stirring the reaction mixture at room temperature for 15 hours, diethyl ether was added to form a solid, and the resultant solid was dissolved in a mixed solvent of chloroform and methanol, followed by sodium thiosulfate solution and sodium hydrogen carbonate (NaHCO 3 Washed with solution and dehydrated. The residue was concentrated under reduced pressure and dried to give 59.5 g (80.4%) of the title compound.

1H NMR(DMSO-d6) 8.23(t,1H), 7.82(dd,1H), 7.56(dd,1H), 7.18(dd,1H). 4.74(m,1H), 4.10(t,1H), 3.73(dd,1H), 3.40(br dd,2H), 1.83(s,3H)
 1 H NMR (DMSO-d 6 ) 8.23 (t, 1H), 7.82 (dd, 1H), 7.56 (dd, 1H), 7.18 (dd, 1H). 4.74 (m, 1H), 4.10 (t, 1H), 3.73 (dd, 1H), 3.40 (br dd, 2H), 1.83 (s, 3H)

<제조예 8> (S)-[N-3-(4-트리메틸스테닐-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조 Preparation Example 8 Preparation of (S)-[N-3- (4-trimethylstenyl-3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide

(S)-[N-3-(4-아이오도-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 50g을 1,4-디옥산 660ml에 녹이고 헥사메틸디틴 52g과 디클로로비스트리페닐포스핀 팔라디움(II) 9.3g을 가한 후 2시간 동안 환류하였다. 셀라이트(celite)를 사용하여 여과한 후 감압 농축하고 잔유물을 컬럼크로마토그래피로 정제하여 표제 화합물 45g을 분리하였다.
Dissolve 50 g of (S)-[N-3- (4-iodo-3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide in 660 ml of 1,4-dioxane and 52 g of hexamethylditin. And 9.3 g of dichlorobistriphenylphosphine palladium (II) were added and refluxed for 2 hours. Filtration was carried out using celite, concentrated under reduced pressure, and the residue was purified by column chromatography to separate 45 g of the titled compound.

<제조예 9> 2-피페라진-1-일-5-아이오도피리미딘의 제조Preparation Example 9 Preparation of 2-piperazin-1-yl-5-iodopyrimidine

1-(2-피리미딜)피페라진 2g을 초산 5ml, 물 1ml 및 황산 0.15ml의 혼합용매에 녹이고 과요오드산 0.38g과 요오드 0.86g을 실온에서 가한 후 100℃에서 6시간동안 교반하였다. 상기 반응 혼합물에 클로로포름을 가하고 탄산수소나트륨 용액과 소금물로 세척하였다. 유기층은 탈수, 여과 및 감압농축한 후 컬럼크로마토그래피 로 정제하여 표제 화합물 600mg을 얻었다.2 g of 1- (2-pyrimidyl) piperazine was dissolved in a mixed solvent of 5 ml of acetic acid, 1 ml of water, and 0.15 ml of sulfuric acid. 0.38 g of periodic acid and 0.86 g of iodine were added at room temperature, followed by stirring at 100 ° C. for 6 hours. Chloroform was added to the reaction mixture and washed with sodium hydrogen carbonate solution and brine. The organic layer was dehydrated, filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain 600 mg of the title compound.

H1NMR (CDCl3) 8.16(s,2H), 3.87(m,4H), 3.01(m,4H)
H 1 NMR (CDCl 3 ) 8.16 (s, 2H), 3.87 (m, 4H), 3.01 (m, 4H)

<제조예 10> 2-(4-트리페닐메틸피페라진-1-일)-5-아이오도피리미딘의 제조Preparation Example 10 Preparation of 2- (4-triphenylmethylpiperazin-1-yl) -5-iodopyrimidine

2-피페라진-1-일-5-아이오도피리미딘 13g을 메틸렌 클로라이드 100ml에 녹이고 트리페닐메틸클로라이드 15g과 트리에틸아민 16ml를 가한 후 1시간동안 실온에서 교반하였다. 상기 반응 혼합물에 메틸렌클로라이드를 가한 후 물과 소금물로 세척하고 세척된 유기층을 탈수, 여과 및 감압농축한 후 에틸아세테이트와 소량의 메탄올을 사용하여 정제하여 표제 화합물 10g 얻었다.13 g of 2-piperazin-1-yl-5-iodopyrimidine was dissolved in 100 ml of methylene chloride, 15 g of triphenylmethyl chloride and 16 ml of triethylamine were added, followed by stirring at room temperature for 1 hour. Methylene chloride was added to the reaction mixture, which was then washed with water and brine. The washed organic layer was dehydrated, filtered and concentrated under reduced pressure, and purified using ethyl acetate and a small amount of methanol to obtain 10 g of the title compound.

H1NMR (CDCl3) 8.13(s,2H), 7.49(m,5H), 7.23(m,10H), 3.86(m,4H), 2.33(m,4H)
H 1 NMR (CDCl 3 ) 8.13 (s, 2H), 7.49 (m, 5H), 7.23 (m, 10H), 3.86 (m, 4H), 2.33 (m, 4H)

<실시예 1> (S)-[N-3-(4-피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 1 Preparation of (S)-[N-3- (4-pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide

(S)-[N-3-(4-트리메틸스테닐-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 322mg을 디메틸포름아마이드 4ml에 녹이고 실온에서 5-아이오도피리미딘 400mg, 트리에틸아민 0.27ml 및 디클로로비스트리페닐포스핀 팔라디움(II) 0.22g을 각각 가한 후 4시간동안 100℃에서 교반하였다. 상기 반응 혼합물에 물을 가하고 에틸아세테이트로 추출한 후 유기층을 소금물로 세척하고 탈수, 여과 및 감 압농축한 다음 컬럼크로마토그래피로 정제하여 표제 화합물 100mg을 얻었다.322 mg of (S)-[N-3- (4-trimethylstenyl-3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide was dissolved in 4 ml of dimethylformamide and 5-iodopi at room temperature. 400 mg of limidine, 0.27 ml of triethylamine and 0.22 g of dichlorobistriphenylphosphine palladium (II) were respectively added, followed by stirring at 100 ° C. for 4 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dehydrated, filtered and concentrated under reduced pressure and purified by column chromatography to obtain 100 mg of the title compound.

H1NMR (CDCl3) 9.16(s,1H), 8.87(s,2H), 7.62(dd,1H), 7.43(t,1H), 7.33(dd,1H), 6.37(bt,1H), 4.82(m,1H), 4.08(t,1H), 3.84(dd,1H), 3.67(m,2H), 2.00(s,3H)
H 1 NMR (CDCl 3 ) 9.16 (s, 1H), 8.87 (s, 2H), 7.62 (dd, 1H), 7.43 (t, 1H), 7.33 (dd, 1H), 6.37 (bt, 1H), 4.82 (m, 1H), 4.08 (t, 1H), 3.84 (dd, 1H), 3.67 (m, 2H), 2.00 (s, 3H)

<실시예 2> (S)-[N-3-(4-(2-메톡시피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 2 (S)-[N-3- (4- (2-methoxypyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide Manufacture

출발물질로 5-아이오도피리미딘 대신 2-메톡시-5-아이오도피리미딘을 첨가하는 것을 제외하고 상기 실시예 1과 동일한 방법으로 표제 화합물을 얻었다.
The title compound was obtained in the same manner as in Example 1, except that 2-methoxy-5-iodopyrimidine was added instead of 5-iodopyrimidine as a starting material.

<실시예 3> (S)-[N-3-(4-(2-아미노피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 3 of (S)-[N-3- (4- (2-aminopyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide Produce

출발물질로 5-아이오도피리미딘 대신 2-아미노-5-부로모피리미딘을 168mg 첨가하는 것을 제외하고 상기 실시예 1과 동일한 방법으로 표제 화합물 45mg을 얻었다.45 mg of the title compound was obtained in the same manner as in Example 1, except that 168 mg of 2-amino-5-buromopyrimidine was added instead of 5-iodopyrimidine as a starting material.

H1NMR (DMSO-d6) 8.42(s,1H), 8.30(s,1H), 8.26(t,1H), 7.53(m,4H), 6.67(s,1H), 4.75(m,1H), 4.16(m,1H), 3.77(m,1H), 3.42(m,2H), 1.83(s,3H)
H 1 NMR (DMSO-d 6 ) 8.42 (s, 1H), 8.30 (s, 1H), 8.26 (t, 1H), 7.53 (m, 4H), 6.67 (s, 1H), 4.75 (m, 1H) , 4.16 (m, 1H), 3.77 (m, 1H), 3.42 (m, 2H), 1.83 (s, 3H)

<실시예 4> (S)-[N-3-(4-(2-(4-트리페닐메틸피페라진-1-일)피리미딘-5-일)-3-플 로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조의 제조Example 4 (S)-[N-3- (4- (2- (4-triphenylmethylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2- Preparation of Oxo-5-oxazolindinyl] methyl acetamide

(S)-[N-3-(4-트리메틸스테닐-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 400mg을 디메틸포름아마이드 5.6ml에 녹이고 실온에서 커퍼클로라이드 48mg과 2-(4-트리페닐메틸피페라진-1-일)-5-아이오도피리미딘 770mg을 각각 가한 후 1시간동안 80℃에서 교반하였다. 상기 반응 혼합물에 물을 가하고 에틸아세테이트(EA)로 추출한 후 유기층을 소금물로 세척하였다. 유기층은 탈수, 여과 및 감압농축한 후 컬럼크로마토그래피로 정제하여 표제 화합물 300mg을 얻었다.Dissolve 400 mg of (S)-[N-3- (4-trimethylstenyl-3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide in 5.6 ml of dimethylformamide and 48 mg of cupperchloride at room temperature And 770 mg of 2- (4-triphenylmethylpiperazin-1-yl) -5-iodopyrimidine were added, followed by stirring at 80 ° C. for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate (EA), and the organic layer was washed with brine. The organic layer was dehydrated, filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain 300 mg of the title compound.

H1NMR (DMSO-d6) 8.48(s,2H), 8.25(t,1H), 7.40(m,15H), 7.17(m,2H), 6.95(m,1H), 4.72(m,1H), 4.11(m,1H), 3.73(m,1H), 3.40(t,2H), 1.81(s,3H)
H 1 NMR (DMSO-d 6 ) 8.48 (s, 2H), 8.25 (t, 1H), 7.40 (m, 15H), 7.17 (m, 2H), 6.95 (m, 1H), 4.72 (m, 1H) , 4.11 (m, 1H), 3.73 (m, 1H), 3.40 (t, 2H), 1.81 (s, 3H)

<실시예 5> (S)-[N-3-(4-(2-피페라진-1-일피리미딘-5-일)-3-플로로페닐)-2-옥소 -5-옥사졸린딘일]메틸 아세트아마이드 염산염의 제조Example 5 (S)-[N-3- (4- (2-piperazin-1-ylpyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxazolindinyl ] Production of Methyl Acetamide Hydrochloride

(S)-[N-3-(4-(2-(4-트리페닐메틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 200mg을 테트라히드로퓨란에 녹이고 6N 염산용액 1ml를 실온에서 가한 후 24시간 동안 교반하였다. 상기 반응에서 생성된 고체를 여과하고 테트라히드로퓨란과 에틸에테르로 세척하여 표제 화합물 110mg을 얻었다.(S)-[N-3- (4- (2- (4-triphenylmethylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxa 200 mg of zolindinyl] methyl acetamide was dissolved in tetrahydrofuran, and 1 ml of 6N hydrochloric acid solution was added at room temperature, followed by stirring for 24 hours. The solid produced in the reaction was filtered and washed with tetrahydrofuran and ethyl ether to give 110 mg of the title compound.

H1NMR (DMSO-d6) 9.49(bs,1H), 8.63(s,2H), 8.33(t,1H), 7.49(m,4H), 4.74(m,1H), 4.13(t,1H), 4.02(m,4H), 3.78(dd,1H), 3.41(t,2H), 3.16(m,4H), 1.81(s,3H)
H 1 NMR (DMSO-d 6 ) 9.49 (bs, 1H), 8.63 (s, 2H), 8.33 (t, 1H), 7.49 (m, 4H), 4.74 (m, 1H), 4.13 (t, 1H) , 4.02 (m, 4H), 3.78 (dd, 1H), 3.41 (t, 2H), 3.16 (m, 4H), 1.81 (s, 3H)

<실시예 6> (S)-[N-3-(4-(2-(4-아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 6 (S)-[N-3- (4- (2- (4-acetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo- Preparation of 5-oxazolindinyl] methyl acetamide

(S)-[N-3-(4-(2-피페라진-1-일피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 염산염 30mg을 테트라히드로퓨란에 녹이고 아세틸클로라이드 10㎕와 트리에틸아민 30.3㎕를 실온에서 가한 후 30분동안 교반하였다. 상기 반응 혼합물에 클로로포름을 가한 후 물과 소금물로 세척하였다. 세척된 유기층은 탈수, 여과 및 감압농축하고 컬럼크로마토그라피로 정제하여 원하는 표제 화합물 30mg을 얻었다.(S)-[N-3- (4- (2-piperazin-1-ylpyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide hydrochloride 30 mg was dissolved in tetrahydrofuran, 10 µl of acetyl chloride and 30.3 µl of triethylamine were added at room temperature, followed by stirring for 30 minutes. Chloroform was added to the reaction mixture, which was then washed with water and brine. The washed organic layer was dehydrated, filtered and concentrated under reduced pressure and purified by column chromatography to obtain 30 mg of the title compound.

H1NMR (CDCl3) 8.47(s,2H), 7.53(dd,1H), 7.29(m,2H), 6.30(t,1H), 4.79(m,1H), 3.86(m,5H), 3.66(m,4H), 3.51(m,2H), 2.14(s,3H), 2.01(s,3H)
H 1 NMR (CDCl 3 ) 8.47 (s, 2H), 7.53 (dd, 1H), 7.29 (m, 2H), 6.30 (t, 1H), 4.79 (m, 1H), 3.86 (m, 5H), 3.66 (m, 4H), 3.51 (m, 2H), 2.14 (s, 3H), 2.01 (s, 3H)

<실시예 7> (S)-[N-3-(4-(2-(4-벤질옥시아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 7 (S)-[N-3- (4- (2- (4-benzyloxyacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2- Preparation of oxo-5-oxazolindinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 벤질옥시아세틸클로라이드 26.6㎕를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 30mg을 얻었다.30 mg of the title compound was obtained in the same manner as in Example 6, except that 26.6 μl of benzyloxyacetyl chloride was added instead of acetyl chloride as a starting material.

H1NMR (CDCl3) 8.48(s,2H), 7.52(dd,1H), 7.27(m,7H), 6.15(t,1H), 4.79(m,1H), 4.60(s,2H), 4.21(s,2H), 4.05(t,1H), 3.83(m,5H), 3.65(m,6H), 2.01(s,3H)
H 1 NMR (CDCl 3 ) 8.48 (s, 2H), 7.52 (dd, 1H), 7.27 (m, 7H), 6.15 (t, 1H), 4.79 (m, 1H), 4.60 (s, 2H), 4.21 (s, 2H), 4.05 (t, 1H), 3.83 (m, 5H), 3.65 (m, 6H), 2.01 (s, 3H)

<실시예 8> (S)-[N-3-(4-(2-(4-아세톡시아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 8 (S)-[N-3- (4- (2- (4-acetoxyacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2- Preparation of oxo-5-oxazolindinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 아세톡시아세틸클로라이드 16㎕를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 23mg을 얻었다.23 mg of the title compound was obtained in the same manner as in Example 6, except that 16 µl of acetoxyacetyl chloride was added instead of acetyl chloride as a starting material.

1H NMR(CDCl3) 8.49(d,2H), 7.56(dd,1H), 7.35(m,2H), 6.04(t,1H), 4.80(m,1H), 4.77(s,2H), 4.06(t,1H), 3.95(m,4H), 3.70(m,5H), 3.50(m,2H), 2.21(s,3H), 2.01(s,3H).
 1 H NMR (CDCl 3 ) 8.49 (d, 2H), 7.56 (dd, 1H), 7.35 (m, 2H), 6.04 (t, 1H), 4.80 (m, 1H), 4.77 (s, 2H), 4.06 (t, 1H), 3.95 (m, 4H), 3.70 (m, 5H), 3.50 (m, 2H), 2.21 (s, 3H), 2.01 (s, 3H).

<실시예 9> (S)-[N-3-(4-(2-(4-히드록시아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 9 (S)-[N-3- (4- (2- (4-hydroxyacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2- Preparation of oxo-5-oxazolindinyl] methyl acetamide

실시예 8의 표제화합물 220mg을 메탄올에 녹이고 1N KOH 수용액(1ml)을 가한후 실온에서 1시간 교반하였다. 과량의 메탄올을 감압농축한 후 물을 가하고 클로로포름으로 추출한 후 유기층을 탈수, 여과, 감압농축하고 컬럼크로마토그라피로 정제하여 표제화합물 189mg을 얻었다.220 mg of the title compound of Example 8 was dissolved in methanol, 1N aqueous KOH solution (1 ml) was added, and the mixture was stirred at room temperature for 1 hour. Excess methanol was concentrated under reduced pressure, water was added thereto, followed by extraction with chloroform. The organic layer was dehydrated, filtered, and concentrated under reduced pressure and purified by column chromatography to obtain 189 mg of the title compound.

H1NMR (CDCl3) 8.48(s,2H), 7.54(dd,1H), 7.34(t,1H), 7.26(dd,1H), 4.79(m,1H), 4.21(s,2H), 4.05(t,1H), 3.88(m,4H), 3.77(m,4H), 3.65(m,1H), 3.34(m,2H), 2.00(s,3H)
H 1 NMR (CDCl 3 ) 8.48 (s, 2H), 7.54 (dd, 1H), 7.34 (t, 1H), 7.26 (dd, 1H), 4.79 (m, 1H), 4.21 (s, 2H), 4.05 (t, 1H), 3.88 (m, 4H), 3.77 (m, 4H), 3.65 (m, 1H), 3.34 (m, 2H), 2.00 (s, 3H)

<실시예 10> (S)-[N-3-(4-(2-(4-디메틸아미노아세톡시아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 10 (S)-[N-3- (4- (2- (4-dimethylaminoacetoxyacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl)- Preparation of 2-oxo-5-oxazolindinyl] methyl acetamide

(S)-[N-3-(4-(2-(4-히드록시아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 50mg을 피리딘 2.5ml에 녹이고 실온에서 N,N-디메틸글리신 43.7mg, 1-(3-디메틸아미노프로필)-3-에틸카보디이미드 염산염 84mg, 4-디메틸아미노피리딘 20mg을 각각 적가한 후 15시간 동안 실온에서 교반하였다. 상기 반응 혼합물에 물을 가하고 에틸아세테이트로 추출한 후 유기층을 소금물로 세척하였다. 유기층은 탈수, 여과 및 감압농축하고 컬럼크로마토그라피로 정제하여 표제 화합물 22mg을 얻었다.(S)-[N-3- (4- (2- (4-hydroxyacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxa 50 mg of zolindinyl] methyl acetamide was dissolved in 2.5 ml of pyridine, and 43.7 mg of N, N-dimethylglycine, 84 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and 20 mg of 4-dimethylaminopyridine at room temperature. After each dropwise addition, the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine. The organic layer was dehydrated, filtered and concentrated under reduced pressure and purified by column chromatography to obtain 22 mg of the title compound.

H1NMR (CDCl3) 8.49(s,2H), 7.56(dd,1H), 7.34(t,1H), 7.27(dd,1H), 6.01(t,1H), 4.83(s,2H), 4.79(m,1H), 4.06(t,1H), 3.89(m,4H), 3.78(m,4H), 3.32(s,2H), 2.40(s,6H), 2.01(s,3H)
H 1 NMR (CDCl 3 ) 8.49 (s, 2H), 7.56 (dd, 1H), 7.34 (t, 1H), 7.27 (dd, 1H), 6.01 (t, 1H), 4.83 (s, 2H), 4.79 (m, 1H), 4.06 (t, 1H), 3.89 (m, 4H), 3.78 (m, 4H), 3.32 (s, 2H), 2.40 (s, 6H), 2.01 (s, 3H)

<실시예 11> (S)-[N-3-(4-(2-(4-부로모아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 11 (S)-[N-3- (4- (2- (4-Bromoacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2- Preparation of oxo-5-oxazolindinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 부로모아세틸클로라이드 63.06㎕를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 49mg을 얻었다. 49 mg of the title compound was obtained in the same manner as in Example 6, except that 63.06 μl of bromoacetyl chloride was added instead of acetyl chloride as a starting material.                     

H1NMR (CDCl3) 8.49(s,2H), 7.56(dd,1H), 7.34(t,1H), 7.26(dd,1H), 6.01(t,1H), 4.80(m,1H), 4.06(t,1H), 3.95(m,4H), 3.87(s,3.77(m,4H), 3.65(m,1H), 3.34(m,2H), 2.00(s,3H)
H 1 NMR (CDCl 3 ) 8.49 (s, 2H), 7.56 (dd, 1H), 7.34 (t, 1H), 7.26 (dd, 1H), 6.01 (t, 1H), 4.80 (m, 1H), 4.06 (t, 1H), 3.95 (m, 4H), 3.87 (s, 3.77 (m, 4H), 3.65 (m, 1H), 3.34 (m, 2H), 2.00 (s, 3H)

<실시예 12> (S)-[N-3-(4-(2-(4-몰포린-4-일아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 12 (S)-[N-3- (4- (2- (4-morpholin-4-ylacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl ) -2-oxo-5-oxazolindinyl] methyl acetamide

(S)-[N-3-(4-(2-(4-부로모아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 25mg을 테트라히드로퓨란에 녹이고 실온에서 트리에틸아민 19.3㎕와 몰포린 8㎕를 가한 후 실온에서 2시간 동안 교반하였다. 상기 반응 혼합물을 감압농축한 후 컬럼크로마토그라피로 정제하여 표제 화합물 25mg을 얻었다.(S)-[N-3- (4- (2- (4-bromoacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxa 25 mg of zolindinyl] methyl acetamide was dissolved in tetrahydrofuran, 19.3 μl of triethylamine and 8 μl of morpholine were added at room temperature, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to obtain 25 mg of the title compound.

1H NMR(CDCl3) 8.50(d,2H), 7.56(dd,1H), 7.35(m,2H), 5.99(t,1H), 4.79(m,1H), 4.06(t,1H), 3.89(m,5H), 3.73(m,10H), 2.55(m,4H), 2.01(s,3H).
 1 H NMR (CDCl 3 ) 8.50 (d, 2H), 7.56 (dd, 1H), 7.35 (m, 2H), 5.99 (t, 1H), 4.79 (m, 1H), 4.06 (t, 1H), 3.89 (m, 5H), 3.73 (m, 10H), 2.55 (m, 4H), 2.01 (s, 3H).

<실시예 13> (S)-[N-3-(4-(2-(4-이미다졸-1-일카보닐옥시아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 13 (S)-[N-3- (4- (2- (4-imidazol-1-ylcarbonyloxyacetylpiperazin-1-yl) pyrimidin-5-yl) -3- Florophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide

(S)-[N-3-(4-(2-(4-히드록시아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 30mg을 테트라히드로퓨란에 녹이 고 1,1-카보닐디이미다졸 34mg을 실온에서 가한 후 1시간 동안 교반하였다. 상기 반응 혼합물에 클로로포름을 첨가한 다음 탄산수소나트륨용액으로 세척하고 유기층을 탈수, 여과 및 감압농축한 다음 컬럼크로마토그라피로 정제하여 표제 화합물 28mg을 얻었다.(S)-[N-3- (4- (2- (4-hydroxyacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxa 30 mg of zolindinyl] methyl acetamide was dissolved in tetrahydrofuran and 34 mg of 1,1-carbonyldiimidazole was added at room temperature, followed by stirring for 1 hour. Chloroform was added to the reaction mixture, followed by washing with sodium hydrogen carbonate solution. The organic layer was dehydrated, filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain 28 mg of the title compound.

1H NMR(CDCl3) 8.50(d,2H), 8.19(s,1H), 7.56(dd,1H), 7.50(s,1H), 7.35(m,2H), 7.07(s,1H), 6.06(t,1H), 5.06(s,2H), 4.79(m,1H), 4.06(t,1H), 3.95(m,4H), 3.75(m,5H), 3.48(m,2H), 2.01(s,3H).
 1 H NMR (CDCl 3 ) 8.50 (d, 2H), 8.19 (s, 1H), 7.56 (dd, 1H), 7.50 (s, 1H), 7.35 (m, 2H), 7.07 (s, 1H), 6.06 (t, 1H), 5.06 (s, 2H), 4.79 (m, 1H), 4.06 (t, 1H), 3.95 (m, 4H), 3.75 (m, 5H), 3.48 (m, 2H), 2.01 ( s, 3H).

<실시예 14> (S)-[N-3-(4-(2-(4-클로로아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 14 (S)-[N-3- (4- (2- (4-chloroacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo Preparation of -5-oxazolindinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 클로로아세틸클로라이드 54.5㎕를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 102mg을 얻었다.102 mg of the title compound was obtained in the same manner as in Example 6, except that 54.5 μl of chloroacetyl chloride was added instead of acetyl chloride as a starting material.

H1NMR (CDCl3) 8.49(s,2H), 7.56(dd,1H), 7.39(t,1H), 7.27(dd,1H), 6.01(t,1H), 4.78(m,1H), 4.11(s,2H), 4.05(t,1H), 3.88(m,4H), 3.77(m,4H), 3.65(m,6H), 2.01(s,3H)
H 1 NMR (CDCl 3 ) 8.49 (s, 2H), 7.56 (dd, 1H), 7.39 (t, 1H), 7.27 (dd, 1H), 6.01 (t, 1H), 4.78 (m, 1H), 4.11 (s, 2H), 4.05 (t, 1H), 3.88 (m, 4H), 3.77 (m, 4H), 3.65 (m, 6H), 2.01 (s, 3H)

<실시예 15> (S)-[N-3-(4-(2-(4-메톡시카보닐메틸아미노아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 15 (S)-[N-3- (4- (2- (4-methoxycarbonylmethylaminoacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl ) -2-oxo-5-oxazolindinyl] methyl acetamide

실시예 14의 표제화합물 50mg을 메탄올에 녹이고 트리에틸아민 181㎕와 글라이신메틸에스테르 염산염 32mg을 가한 후 4시간동안 환류하였다. 과량의 메탄올은 감압농축하고 물을 가한 다음 클로로포름으로 추출한 후 유기층을 탈수, 여과, 감압농축하고 컬럼크로마토그라피로 정제하여 표제화합물 20mg을 얻었다.
50 mg of the title compound of Example 14 was dissolved in methanol, and 181 μl of triethylamine and 32 mg of glycinemethyl ester hydrochloride were added thereto, and the mixture was refluxed for 4 hours. Excess methanol was concentrated under reduced pressure, water was added, extraction was performed with chloroform, and the organic layer was dehydrated, filtered, and concentrated under reduced pressure and purified by column chromatography to obtain 20 mg of the title compound.

<실시예 16> (S)-[N-3-(4-(2-(4-(4-메톡시페닐피페라진-4-일)아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 16 (S)-[N-3- (4- (2- (4- (4-methoxyphenylpiperazin-4-yl) acetylpiperazin-1-yl) pyrimidin-5-yl ) -3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide

출발물질로 글라이신메틸에스테르 염산염 대신 메톡시페닐피페라진을 18mg 첨가하는 것을 제외하고 상기 실시예 15과 동일한 방법으로 표제 화합물 32mg을 얻었다.32 mg of the title compound was obtained in the same manner as in Example 15, except that 18 mg of methoxyphenyl piperazine was used instead of glycine methyl ester hydrochloride as a starting material.

1H NMR(CDCl3) 8.49(d,2H), 7.56(dd,1H), 7.35(m,2H), 6.86(q,4H), 6.04(t,1H), 4.79(m,1H), 4.06(t,1H), 3.88(m,5H), 3.74(s,3H), 3.70(m,8H), 2.01(s,3H).
 1 H NMR (CDCl 3 ) 8.49 (d, 2H), 7.56 (dd, 1H), 7.35 (m, 2H), 6.86 (q, 4H), 6.04 (t, 1H), 4.79 (m, 1H), 4.06 (t, 1H), 3.88 (m, 5H), 3.74 (s, 3H), 3.70 (m, 8H), 2.01 (s, 3H).

<실시예 17> (S)-[N-3-(4-(2-(4-메톡시아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 17 (S)-[N-3- (4- (2- (4-methoxyacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2- Preparation of oxo-5-oxazolindinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 메톡시아세틸클로라이드 13㎕를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 32mg을 얻었다. 32 mg of the title compound was obtained in the same manner as in Example 6, except that 13 µl of methoxyacetyl chloride was added instead of acetyl chloride as a starting material.                     

1H NMR(CDCl3) 8.48(d,2H), 7.56(dd,1H), 7.35(m,2H), 6.35(t,1H), 4.79(m,1H), 4.14(s,2H), 4.06(t,1H), 3.87(m,5H), 3.65(m,4H), 3.58(m,2H), 3.42(s,3H), 2.01(s,3H).
 1 H NMR (CDCl 3 ) 8.48 (d, 2H), 7.56 (dd, 1H), 7.35 (m, 2H), 6.35 (t, 1H), 4.79 (m, 1H), 4.14 (s, 2H), 4.06 (t, 1H), 3.87 (m, 5H), 3.65 (m, 4H), 3.58 (m, 2H), 3.42 (s, 3H), 2.01 (s, 3H).

<실시예 18> (S)-[N-3-(4-(2-(4-아크릴로일피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 18 (S)-[N-3- (4- (2- (4-acryloylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2- Preparation of oxo-5-oxazolindinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 아크릴로일클로라이드 14㎕를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 28mg을 얻었다.28 mg of the title compound was obtained in the same manner as in Example 6, except that 14 µl of acryloyl chloride was added instead of acetyl chloride as a starting material.

1H NMR(CDCl3) 8.49(d,2H), 7.56(dd,1H), 7.35(m,2H), 6.62(dd,1H), 6.36(dd,1H), 6.09(t,1H), 5.75(dd,1H), 4.80(m,1H), 4.06(t,1H), 3.97(m,4H), 3.85(m,3H), 3.68(m,4H), 2.01(s,3H).
 1 H NMR (CDCl 3 ) 8.49 (d, 2H), 7.56 (dd, 1H), 7.35 (m, 2H), 6.62 (dd, 1H), 6.36 (dd, 1H), 6.09 (t, 1H), 5.75 (dd, 1H), 4.80 (m, 1H), 4.06 (t, 1H), 3.97 (m, 4H), 3.85 (m, 3H), 3.68 (m, 4H), 2.01 (s, 3H).

<실시예 19> (S)-[N-3-(4-(2-(4-에톡시옥소아세틸피페라진-1-일)피리미딘-5-일) -3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 19 (S)-[N-3- (4- (2- (4-ethoxyoxoacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2 -Oxo-5-oxazolindinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 에틸클로로옥소아세테이트 16㎕를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 30mg을 얻었다.30 mg of the title compound was obtained in the same manner as in Example 6, except that 16 µl of ethylchlorooxoacetate was added instead of acetyl chloride as a starting material.

1H NMR(CDCl3) 8.50(d,2H), 7.56(dd,1H), 7.35(m,2H), 7.13(m,3H), 6.03(t,1H), 4.79(m,1H), 4.37(q,2H), 4.06(t,1H), 3.95(m,4H), 3.75(m,5H), 3.51(m,2H), 2.01(s,3H), 1.37(t,3H)
 1 H NMR (CDCl 3 ) 8.50 (d, 2H), 7.56 (dd, 1H), 7.35 (m, 2H), 7.13 (m, 3H), 6.03 (t, 1H), 4.79 (m, 1H), 4.37 (q, 2H), 4.06 (t, 1H), 3.95 (m, 4H), 3.75 (m, 5H), 3.51 (m, 2H), 2.01 (s, 3H), 1.37 (t, 3H)

<실시예 20> (S)-[N-3-(4-(2-(4-니코티노일피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 20 (S)-[N-3- (4- (2- (4-nicotinoylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2- Preparation of oxo-5-oxazolindinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 니코티노일클로라이드 염산염 26mg을 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 22mg을 얻었다.22 mg of the title compound was obtained in the same manner as in Example 6, except that 26 mg of nicotinoyl chloride hydrochloride was added instead of acetyl chloride as a starting material.

1H NMR(CDCl3) 8.70(s,2H), 8.50(s,2H), 7.82(d,1H), 7.56(dd,1H), 7.35(m,2H), 5.99(t,1H), 4.80(m,1H), 4.06(t,1H), 3.95(m,4H), 3.75(m,7H), 2.01(s,3H).
 1 H NMR (CDCl 3 ) 8.70 (s, 2H), 8.50 (s, 2H), 7.82 (d, 1H), 7.56 (dd, 1H), 7.35 (m, 2H), 5.99 (t, 1H), 4.80 (m, 1H), 4.06 (t, 1H), 3.95 (m, 4H), 3.75 (m, 7H), 2.01 (s, 3H).

<실시예 21> (S)-[N-3-(4-(2-(4-피발로일피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 21 (S)-[N-3- (4- (2- (4-pivaloylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2- Preparation of oxo-5-oxazolindinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 피발로일클로라이드를 17.4㎕를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 30mg을 얻었다.30 mg of the title compound was obtained in the same manner as in Example 6, except that 17.4 μl of pivaloyl chloride was added instead of acetyl chloride as a starting material.

1H NMR(CDCl3) 8.49(d,2H), 7.56(dd,1H), 7.35(m,2H), 6.05(t,1H), 4.79(m,1H), 4.06(t,1H), 3.88(m,4H), 3.65(m,7H), 2.01(s,3H), 1.30(s,9H)
 1 H NMR (CDCl 3 ) 8.49 (d, 2H), 7.56 (dd, 1H), 7.35 (m, 2H), 6.05 (t, 1H), 4.79 (m, 1H), 4.06 (t, 1H), 3.88 (m, 4H), 3.65 (m, 7H), 2.01 (s, 3H), 1.30 (s, 9H)

<실시예 22> (S)-[N-3-(4-(2-(4-Example 22 (S)-[N-3- (4- (2- (4-)) tt -부틸아세틸피페라진-1-일)피리미딘-5-일)-3-플 로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조-Butylacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 t-부틸아세틸클로라이드 20㎕를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 20mg을 얻었다.20 mg of the title compound was obtained in the same manner as in Example 6, except that 20 µl of t -butylacetyl chloride was added instead of acetyl chloride as a starting material.

1H NMR(CDCl3) 8.48(d,2H), 7.56(dd,1H), 7.35(m,2H), 6.27(t,1H), 4.79(m,1H), 4.05(t,1H), 3.87(m,4H), 3.69(m,4H), 3.58(m, 3H), 2.01(s,3H), 1.05(s,9H)
 1 H NMR (CDCl 3 ) 8.48 (d, 2H), 7.56 (dd, 1H), 7.35 (m, 2H), 6.27 (t, 1H), 4.79 (m, 1H), 4.05 (t, 1H), 3.87 (m, 4H), 3.69 (m, 4H), 3.58 (m, 3H), 2.01 (s, 3H), 1.05 (s, 9H)

<실시예 23> (S)-[N-3-(4-(2-(4-(2,5-디메톡시페닐)아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 23 (S)-[N-3- (4- (2- (4- (2,5-dimethoxyphenyl) acetylpiperazin-1-yl) pyrimidin-5-yl) -3- Florophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 2,5-디메톡시페닐아세틸클로라이드 30mg를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 36mg을 얻었다.36 mg of the title compound was obtained in the same manner as in Example 6, except that 30 mg of 2,5-dimethoxyphenylacetyl chloride was added instead of acetyl chloride as a starting material.

1H NMR(CDCl3) 8.48(d,2H), 7.55(dd,1H), 7.33(m,2H), 6.84(m,1H), 6.76(m,2H), 6.03(t,1H), 4.79(m,1H), 4.06(t,1H), 3.78(s,3H), 3.72(s,3H), 2.00(s,3H).
 1 H NMR (CDCl 3 ) 8.48 (d, 2H), 7.55 (dd, 1H), 7.33 (m, 2H), 6.84 (m, 1H), 6.76 (m, 2H), 6.03 (t, 1H), 4.79 (m, 1H), 4.06 (t, 1H), 3.78 (s, 3H), 3.72 (s, 3H), 2.00 (s, 3H).

<실시예 24> (S)-[N-3-(4-(2-(4-(3,3-디메틸아크릴로일)피페라진-1-일)피리미딘 -5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 24 (S)-[N-3- (4- (2- (4- (3,3-dimethylacryloyl) piperazin-1-yl) pyrimidin-5-yl) -3- Florophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 3,3-디메틸아크릴로일클로라이드 16㎕를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 20mg을 얻 었다.20 mg of the title compound was obtained in the same manner as in Example 6, except that 16 µl of 3,3-dimethylacryloyl chloride was added instead of acetyl chloride as a starting material.

1H NMR(CDCl3) 8.49(d,2H), 7.56(dd,1H), 7.34(m,2H), 6.04(t,1H), 5.81(s,1H), 4.79(m,1H), 4.06(t,1H), 3.85(m,5H), 3.70(m,5H), 3.62(m,2H), 2.01(s,3H).
 1 H NMR (CDCl 3 ) 8.49 (d, 2H), 7.56 (dd, 1H), 7.34 (m, 2H), 6.04 (t, 1H), 5.81 (s, 1H), 4.79 (m, 1H), 4.06 (t, 1H), 3.85 (m, 5H), 3.70 (m, 5H), 3.62 (m, 2H), 2.01 (s, 3H).

<실시예 25> (S)-[N-3-(4-(2-(4-(2,6-디메톡시벤조일)피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 25 (S)-[N-3- (4- (2- (4- (2,6-dimethoxybenzoyl) piperazin-1-yl) pyrimidin-5-yl) -3-flo Rophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 2,6-디메톡시벤조일클로라이드 29mg를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 27mg을 얻었다.27 mg of the title compound was obtained in the same manner as in Example 6, except that 29 mg of 2,6-dimethoxybenzoyl chloride was added instead of acetyl chloride as a starting material.

1H NMR(CDCl3) 8.48(d,2H), 7.56(dd,1H), 7.35(m,3H), 6.58(d,2H), 6.04(t,1H), 4.79(m,1H), 4.06(t,1H), 3.95(m,4H), 3.75(m,5H), 3.31(m,2H), 2.01(s,3H).
 1 H NMR (CDCl 3 ) 8.48 (d, 2H), 7.56 (dd, 1H), 7.35 (m, 3H), 6.58 (d, 2H), 6.04 (t, 1H), 4.79 (m, 1H), 4.06 (t, 1H), 3.95 (m, 4H), 3.75 (m, 5H), 3.31 (m, 2H), 2.01 (s, 3H).

<실시예 26> (S)-[N-3-(4-(2-(4-(2-트리플로로메틸벤조일)피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 26 (S)-[N-3- (4- (2- (4- (2-trifluoromethylbenzoyl) piperazin-1-yl) pyrimidin-5-yl) -3-flo Rophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 2-트리플로로메틸벤조일클로라이드 29㎕를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 36mg을 얻었다.36 mg of the title compound was obtained in the same manner as in Example 6, except that 29 µl of 2-trifluoromethylbenzoyl chloride was added instead of acetyl chloride as a starting material.

1H NMR(CDCl3) 8.47(d,2H), 7.74(d,1H), 7.57(m,3H), 7.38(m,2H), 7.34(m,1H), 6.07(t,1H), 4.79(m,1H), 4.06(t,1H), 3.95(m,6H), 3.64(m,2H) 3.25(m,2H), 2.01(s,3H).
 1 H NMR (CDCl 3 ) 8.47 (d, 2H), 7.74 (d, 1H), 7.57 (m, 3H), 7.38 (m, 2H), 7.34 (m, 1H), 6.07 (t, 1H), 4.79 (m, 1H), 4.06 (t, 1H), 3.95 (m, 6H), 3.64 (m, 2H) 3.25 (m, 2H), 2.01 (s, 3H).

<실시예 27> (S)-[N-3-(4-(2-(4-(4-트리플로로메틸벤조일)피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 27 (S)-[N-3- (4- (2- (4- (4-trifluoromethylbenzoyl) piperazin-1-yl) pyrimidin-5-yl) -3-flo Rophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 4-트리플로로메틸벤조일클로라이드 40㎕를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 35mg을 얻었다.35 mg of the title compound was obtained in the same manner as in Example 6, except that 40 µl of 4-trifluoromethylbenzoyl chloride was added instead of acetyl chloride as a starting material.

1H NMR(CDCl3) 8.50(d,2H), 7.72(d,2H), 7.57(m,3H), 7.35(m,2H), 6.01(t,1H), 4.79(m,1H), 4.09(t,1H), 3.95(m,4H), 3.75(m,7H), 2.01(s,3H).
 1 H NMR (CDCl 3 ) 8.50 (d, 2H), 7.72 (d, 2H), 7.57 (m, 3H), 7.35 (m, 2H), 6.01 (t, 1H), 4.79 (m, 1H), 4.09 (t, 1H), 3.95 (m, 4H), 3.75 (m, 7H), 2.01 (s, 3H).

<실시예 28> (S)-[N-3-(4-(2-(4-페닐아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 28 (S)-[N-3- (4- (2- (4-phenylacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo Preparation of -5-oxazolindinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 페닐아세틸클로라이드 20㎕를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 23mg을 얻었다.
23 mg of the title compound was obtained in the same manner as in Example 6, except that 20 µl of phenylacetyl chloride was added instead of acetyl chloride as a starting material.

<실시예 29> (S)-[N-3-(4-(2-(4-(3,5-디니트로벤조일)피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 29 (S)-[N-3- (4- (2- (4- (3,5-dinitrobenzoyl) piperazin-1-yl) pyrimidin-5-yl) -3-flo Rophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 3,5-디니트로벤조일클로라이드 20㎕를 첨 가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 20mg을 얻었다.20 mg of the title compound was obtained in the same manner as in Example 6, except that 20 µl of 3,5-dinitrobenzoyl chloride was added instead of acetyl chloride as a starting material.

1H NMR(CDCl3) 8.50(d,2H), 8.30(d,1H), 7.62(d,1H), 7.56(dd,1H), 7.35(m,1H), 7.27(dd,1H), 6.02(t,1H), 4.79(m,1H), 4.06(t,1H), 2.01(s,3H).
 1 H NMR (CDCl 3 ) 8.50 (d, 2H), 8.30 (d, 1H), 7.62 (d, 1H), 7.56 (dd, 1H), 7.35 (m, 1H), 7.27 (dd, 1H), 6.02 (t, 1H), 4.79 (m, 1H), 4.06 (t, 1H), 2.01 (s, 3H).

<실시예 30> (S)-[N-3-(4-(2-(4-크로토닐피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드의 제조Example 30 (S)-[N-3- (4- (2- (4-crotonylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo Preparation of -5-oxazolindinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 크로토닐클로라이드 14㎕를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 25mg을 얻었다.25 mg of the title compound was obtained in the same manner as in Example 6, except that 14 µl of crotonyl chloride was added instead of acetyl chloride as a starting material.

1H NMR(CDCl3) 8.49(d,2H), 7.56(dd,1H), 7.35(m,2H), 6.69(m,1H), 6.28(dd,1H), 6.01(t,1H), 4.79(m,1H), 4.06(t,1H), 3.95(m,4H), 3.75(m,7H), 2.01(s,3H), 1.90(dd,3H)
 1 H NMR (CDCl 3 ) 8.49 (d, 2H), 7.56 (dd, 1H), 7.35 (m, 2H), 6.69 (m, 1H), 6.28 (dd, 1H), 6.01 (t, 1H), 4.79 (m, 1H), 4.06 (t, 1H), 3.95 (m, 4H), 3.75 (m, 7H), 2.01 (s, 3H), 1.90 (dd, 3H)

<실시예 31> (S)-[N-3-(4-(2-(4-트리클로로아세틸피페라진-1-일)피리미딘-5-일) -3-플로로페닐)-2-옥소-5-옥사졸리딘일]메틸 아세트아마이드의 제조Example 31 (S)-[N-3- (4- (2- (4-trichloroacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2- Preparation of oxo-5-oxazolidinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 트리클로로아세틸클로라이드 32㎕를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 25mg을 얻었다.25 mg of the title compound was obtained in the same manner as in Example 6, except that 32 µl of trichloroacetyl chloride was added instead of acetyl chloride as a starting material.

1H NMR(CDCl3) 8.50(d,2H), 7.56(dd,1H), 7.37(m,2H), 6.03(t,1H), 4.80(m,1H), 4.06(t,1H), 3.95(m,4H), 3.75(m,7H), 2.01(s,3H).
 1 H NMR (CDCl 3 ) 8.50 (d, 2H), 7.56 (dd, 1H), 7.37 (m, 2H), 6.03 (t, 1H), 4.80 (m, 1H), 4.06 (t, 1H), 3.95 (m, 4H), 3.75 (m, 7H), 2.01 (s, 3H).

<실시예 32> (S)-[N-3-(4-(2-(4-n-발레릴피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸리딘일]메틸 아세트아마이드의 제조Example 32 (S)-[N-3- (4- (2- (4-n-Valerylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2 -Oxo-5-oxazolidinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 발레릴클로라이드 25㎕를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 35mg을 얻었다.
35 mg of the title compound was obtained in the same manner as in Example 6, except that 25 µl of valeryl chloride was added instead of acetyl chloride as a starting material.

<실시예 33> (S)-[N-3-(4-(2-(4-(1-부로모에틸카보닐)피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸리딘일]메틸 아세트아마이드의 제조Example 33 (S)-[N-3- (4- (2- (4- (1-Bromoethylcarbonyl) piperazin-1-yl) pyrimidin-5-yl) -3-flo Rophenyl) -2-oxo-5-oxazolidinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 부로모에틸카보닐클로라이드 12㎕를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 10mg을 얻었다.
10 mg of the title compound was obtained in the same manner as in Example 6, except that 12 µl of bromoethylcarbonyl chloride was added instead of acetyl chloride as a starting material.

<실시예 34> (S)-[N-3-(4-(2-(4-페녹시카보닐피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸리딘일]메틸 아세트아마이드의 제조Example 34 (S)-[N-3- (4- (2- (4-phenoxycarbonylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2 -Oxo-5-oxazolidinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 페닐클로로포르메이트 18㎕를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 15mg을 얻었다.15 mg of the title compound was obtained in the same manner as in Example 6, except that 18 µl of phenylchloroformate was added instead of acetyl chloride as a starting material.

1H NMR(CDCl3) 8.50(d,2H), 7.56(dd,1H), 7.35(m,4H), 7.13(m,3H), 6.00(t,1H), 4.79(m,1H), 4.06(t,1H), 3.95(m,4H), 3.75(m,7H), 2.01(s,3H).
 1 H NMR (CDCl 3 ) 8.50 (d, 2H), 7.56 (dd, 1H), 7.35 (m, 4H), 7.13 (m, 3H), 6.00 (t, 1H), 4.79 (m, 1H), 4.06 (t, 1H), 3.95 (m, 4H), 3.75 (m, 7H), 2.01 (s, 3H).

<실시예 35> (S)-[N-3-(4-(2-(4-벤질옥시카보닐피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸리딘일]메틸 아세트아마이드의 제조Example 35 (S)-[N-3- (4- (2- (4-benzyloxycarbonylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2 -Oxo-5-oxazolidinyl] methyl acetamide

출발물질로 아세틸클로라이드 대신 벤질옥시카보닐클로라이드 17㎕를 첨가하는 것을 제외하고 상기 실시예 6과 동일한 방법으로 표제 화합물 22mg을 얻었다.22 mg of the title compound was obtained in the same manner as in Example 6, except that 17 µl of benzyloxycarbonyl chloride was added instead of acetyl chloride as a starting material.

1H NMR(CDCl3) 8.47(d,2H), 7.55(dd,1H), 6.00(t,1H), 5.15(s,1H), 4.79(m,1H), 4.06(t,1H), 3.85(m,4H), 3.78(dd,1H), 3.58(m,4H), 2.00(s,3H)
 1 H NMR (CDCl 3 ) 8.47 (d, 2H), 7.55 (dd, 1H), 6.00 (t, 1H), 5.15 (s, 1H), 4.79 (m, 1H), 4.06 (t, 1H), 3.85 (m, 4H), 3.78 (dd, 1H), 3.58 (m, 4H), 2.00 (s, 3H)

<실험예 1> 시험관내 항균활성 측정Experimental Example 1 Measurement of In Vitro Antimicrobial Activity

본 발명에 의한 화합물의 항균력을 알아보기 위하여, 문헌에 기재된 한천희석법(agar dilution)을 이용하여 메티실린에 내성을 가지는 스타필로코커스 아우레우스 (MRSA, methicillin resistant Staphylococcus aureus)와 반코마이신에 내성을 가지는 엔테로코카이 (VRE, vancomycin resistant Enterococci)에 대한 항균력을 최소 발육저지 농도 (MIC, ㎍/㎖)로 나타내었으며 이때 화학식 3의 U-100766 화합물을 대조물질로 하여 항균 활성을 비교하였다(Chemotheraphy, 29(1), 76, (1981)). 그 결과는 하기 표 2에 나타낸 바와 같다. In order to examine the antimicrobial activity of the compounds according to the present invention, agar dilution described in the literature is resistant to methicillin and methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant The antimicrobial activity against enterocokai (VRE, vancomycin resistant Enterococci ) was expressed as the minimum growth inhibitory concentration (MIC, μg / ml), and the antimicrobial activity was compared with U-100766 compound of formula 3 as a control ( Chemotheraphy , 29 ( 1), 76, ( 1981 )). The results are as shown in Table 2 below.

<표 2>TABLE 2

화합물compound 항균력 (MIC50, μg/ml)Antimicrobial Activity (MIC 50 , μg / ml) 화합물compound 항균력 (MIC50, μg/ml)Antimicrobial Activity (MIC 50 , μg / ml) MRSAMRSA VREVRE MRSAMRSA VREVRE U-100766U-100766 3.133.13 1.561.56 1One 0.780.78 0.390.39 2121 >50> 50 3.133.13 22 1.561.56 0.390.39 2222 >50> 50 3.133.13 33 1.561.56 0.20.2 2323 6.256.25 3.133.13 44 >25> 25 >25> 25 2424 6.256.25 3.133.13 55 6.256.25 0.780.78 2525 6.256.25 3.133.13 66 3.133.13 0.780.78 2626 12.512.5 3.133.13 77 6.256.25 1.561.56 2727 >50> 50 6.256.25 88 3.133.13 1.561.56 2828 12.512.5 1.561.56 99 1.561.56 0.780.78 2929 >25> 25 12.512.5 1010 1.561.56 0.780.78 3030 3.133.13 1.561.56 1111 0.780.78 0.390.39 3131 >25> 25 3.133.13 1212 3.133.13 1.561.56 3232 3.133.13 1.561.56 1313 6.246.24 1.561.56 3333 6.256.25 0.780.78 1414 1.561.56 0.780.78 3434 2525 6.256.25 1515 6.256.25 1.561.56 3535 >25> 25 2525 1616 6.256.25 3.133.13 1717 6.256.25 1.561.56 1818 3.133.13 1.561.56 1919 6.256.25 3.133.13 2020 3.133.13 3.133.13 MRSA: 메티실린에 내성을 가지는 스타필로코커스 아우레우스 (methicillin resistantStaphylococcus aureus) VRE : 반코마이신에 내성을 가지는 엔테로코카이 (vancomycin resistantEnterococci) MRSA: methicillin resistant Staphylococcus aureus VRE: vancomycin resistant Enterococci resistant to vancomycin

상기 표 2에서 볼 수 있듯이, 본 발명의 화합물들이 미국 식품의약품국의 허가를 얻은 화학식 3의 U-100766 화합물에 비하여 기존 항생제에 내성을 갖는 스타틸로코커스와 엔테로코카이에 대해 훨씬 낮은 농도에서 강한 항균력을 보임을 알 수 있었다.
As can be seen in Table 2, the compounds of the present invention are stronger at much lower concentrations for staphylococcus and enterocokai resistant to conventional antibiotics than the U-100766 compound of Formula 3, which is licensed by the US Food and Drug Administration. It can be seen that the antimicrobial activity.

<실험예 2> 마우스에 대한 경구투여 급성독성 실험Experimental Example 2 Oral Acute Toxicity in Mice

본 발명에 의한 화합물의 급성 독성을 알아보기 위하여 하기와 같은 실험을 수행하였다. 본 발명의 화합물 각각 200mg을 1%의 HPMC(히드록시프로필메틸셀룰로 스) 배산체를 조제한 후 5주령의 웅성 ICR계 마우스(20g±2g) 5마리에 1g/10ml/kg으로 경구투여하고 2주간 사망율, 체중, 임상증상 등을 관찰하여 최소치사량(MLD)을 조사하였다. 그 결과는 하기 표 3에 나타내었다.In order to determine the acute toxicity of the compound according to the present invention was carried out the following experiment. 200 mg of each compound of the present invention was prepared by administering 1% HPMC (hydroxypropylmethylcellulose), and then orally administered at 1 g / 10 ml / kg to 5 male ICR mice (20 g ± 2 g) at 5 weeks of age. Minimum mortality (MLD) was examined by observing weekly mortality, body weight, and clinical symptoms. The results are shown in Table 3 below.

<표 3>TABLE 3

화합물compound 최소치사량(MLD, mg/kg)Minimum lethal dose (MLD, mg / kg) U-100766U-100766 >1000> 1000 실시예 1Example 1 >1000> 1000 실시예 2Example 2 >1000> 1000 실시예 3Example 3 >1000> 1000 실시예 11Example 11 >1000> 1000

경구투여 급성독성시험 결과, 상기 조제한 본 발명에 의한 시험 물질을 투여한 모든 마우스에서 특기할만한 임상증상은 없었고 폐사된 동물도 없었으며, 또한 체중변화, 혈액검사, 혈액생화학검사, 부검소견 등에서도 독성변화는 관찰되지 않았다. 상기 표 3에서 볼 수 있듯이, 화학식 1로 표시되는 본 발명의 화합물들은 항균효과가 뛰어날 뿐만 아니라 경구투여 최소치사량이 1g/kg 이상으로 안전한 물질로 판단되었다.
As a result of oral acute toxicity test, all mice administered the test substance according to the present invention had no clinical symptoms and no dead animals, and also toxicity in weight change, blood test, blood biochemical test, autopsy findings, etc. No change was observed. As can be seen in Table 3, the compounds of the present invention represented by the formula (1) was not only excellent in the antimicrobial effect, but was determined to be a safe substance with a minimum lethal dose of 1 g / kg or more.

이상에서 살펴본 바와 같이, 본 발명의 화학식 1로 표시되는 옥사졸리디논 화합물들은 항균 스펙트럼이 넓을 뿐만 아니라 생체내 (in vivo) 효과도 탁월하다. 또한 본 발명의 화합물은 기존 항생제에 내성을 가지는 스타필로코카이, 엔테로코카이, 스트렙토코카이와 같은 그람양성 호기성 박테리아 뿐만 아니라, 박테로이데 스 종, 클로스티리디아 종과 같은 혐기성 생물과 마이코박테리움 투베르쿨로시스, 마이코 박테리움 아비움 등의 마아코 박테리움 종과 같은 항산성 미생물들을 포함하여 각종 사람 및 동물 병원균에 우수한 항균 효과를 나타낼 수 있어 본 발명의 화합물들은 항생제로 유용하게 사용될 수 있다.As described above, the oxazolidinone compounds represented by Formula 1 of the present invention not only have broad antibacterial spectrum but also have excellent in vivo effects. In addition, the compounds of the present invention are not only Gram-positive aerobic bacteria, such as Staphylococcus, Enterocokai, and Streptococcus, which are resistant to conventional antibiotics, but also anaerobic organisms such as Bacteroides species and Clostridia species and Mycobacterium tutu Compounds of the present invention can be usefully used as antibiotics because they can exhibit excellent antimicrobial effects on various human and animal pathogens, including antimicrobial microorganisms such as Maculobacterium species such as Berculosis and Mycobacterium avium.

Claims (9)

하기 화학식 1로 표시되는 피리미딘 고리를 포함하는 옥사졸리디논 유도체 또는 약학적으로 허용되는 그의 염.An oxazolidinone derivative or a pharmaceutically acceptable salt thereof comprising a pyrimidine ring represented by the following formula (1). 화학식 1Formula 1
Figure 112006071630951-pat00018
Figure 112006071630951-pat00018
 상기 화학식 1에서, In Chemical Formula 1, R1은 수소 또는 불소이고, R 1 is hydrogen or fluorine, R2는 C1-C4의 알콕시기; 아미노기; 또는 R3가 치환 또는 치환되지 않은 피페라지닐기이다. R 2 is a C 1 -C 4 alkoxy group; Amino group; Or R 3 is a substituted or unsubstituted piperazinyl group. 상기 R3는 수소; 트리페닐메틸기; 치환 또는 치환되지 않은 아세틸기; 치환 또는 치환되지 않은 벤조일기; 치환 또는 치환되지 않은 카보닐기; C1-C3의 알콕시페닐기; C1-C3의 알킬기가 치환 또는 치환되지 않은 아크릴로일기; 니코티노일기; 피발로일기; 크로토닐기 또는 n-발레릴기이다.R 3 is hydrogen; Triphenylmethyl group; A substituted or unsubstituted acetyl group; Substituted or unsubstituted benzoyl group; Substituted or unsubstituted carbonyl group; An alkoxyphenyl group of C 1 -C 3 ; An acryloyl group, wherein the alkyl group of C 1 -C 3 is unsubstituted or substituted; Nicotinoyl group; Pivaloyl group; It is a crotonyl group or n-valeryl group. 제 1항에 있어서, 치환된 아세틸기는 벤질옥시아세틸기, 아세톡시아세틸기, 히드록시아세틸기, C1-C3의 알킬아미노아세톡시아세틸기, 할로겐이 치환된 아세틸기, 몰포린-4-일아세틸기, 이미다졸-1-일카보닐옥시아세틸기, C1-C3의 알콕시카보닐메틸아미노아세틸기, C1-C3의 알콕시아세틸기, t-부틸아세틸기; C1-C3의 알콕시기가 치환된 또는 치환되지않은 페닐아세틸기; 또는 C1-C3의 알콕시옥소아세틸기인 것을 특징으로 하는 옥사졸리디논 유도체 또는 약학적으로 허용되는 그의 염.The acetyl group according to claim 1, wherein the substituted acetyl group is benzyloxyacetyl group, acetoxyacetyl group, hydroxyacetyl group, C 1 -C 3 alkylaminoacetoxyacetyl group, halogen-substituted acetyl group, morpholine-4- Monoacetyl group, imidazol-1-ylcarbonyloxyacetyl group, C 1 -C 3 alkoxycarbonylmethylaminoacetyl group, C 1 -C 3 alkoxyacetyl group, t -butylacetyl group; C 1 phenylacetyl group -C 3 alkoxy groups are not substituted or substituted with a; Or a C 1 -C 3 alkoxyoxoacetyl group or a pharmaceutically acceptable salt thereof. 제 1항에 있어서, 치환된 벤조일기는 C1-C4의 알콕시벤조일기, 트리할로메틸벤조일기 또는 니트로벤조일기인 것을 특징으로 하는 옥사졸리디논 유도체 또는 약학적으로 허용되는 그의 염.The oxazolidinone derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein the substituted benzoyl group is a C 1 -C 4 alkoxybenzoyl group, trihalomethylbenzoyl group or nitrobenzoyl group. 제 1항에 있어서, 치환된 카보닐기는 C1-C4의 할로알킬카보닐기, 페녹시카보닐기 또는 벤질옥시카보닐기인 것을 특징으로 하는 옥사졸리디논 유도체 또는 약학적으로 허용되는 그의 염.The oxazolidinone derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein the substituted carbonyl group is a C 1 -C 4 haloalkylcarbonyl group, phenoxycarbonyl group or benzyloxycarbonyl group. 제 1 항에 있어서, 화학식 1의 화합물은The compound of claim 1 wherein 2) (S)-[N-3-(4-(2-메톡시피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 2의 화합물);2) (S)-[N-3- (4- (2-methoxypyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide (Example 2 compound); 3) (S)-[N-3-(4-(2-아미노피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 3의 화합물); 및3) (S)-[N-3- (4- (2-aminopyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5-oxazolindinyl] methyl acetamide (Example 3 Compound of; And 4) (S)-[N-3-(4-(2-(4-부로모아세틸피페라진-1-일)피리미딘-5-일)-3-플로로페닐)-2-옥소-5-옥사졸린딘일]메틸 아세트아마이드 (실시예 11의 화합물)인 것을 특징으로 하는 옥사졸리디논 유도체 또는 약학적으로 허용되는 그의 염.4) (S)-[N-3- (4- (2- (4-bromoacetylpiperazin-1-yl) pyrimidin-5-yl) -3-fluorophenyl) -2-oxo-5 -Oxazolidinyl] methyl acetamide (compound of Example 11), an oxazolidinone derivative or a pharmaceutically acceptable salt thereof. 1) 구조식 (2)의 플로로아닐린을 출발물질로하여 아민기를 보호시킨 후 강염기 하에서 글리시딜부티레이트와 반응시켜 구조식 (3)의 하이드록시메틸 옥사졸리디논 유도체를 제조하는 단계 (제 1 단계);1) preparing a hydroxymethyl oxazolidinone derivative of the formula ( 3 ) by protecting the amine group by using the fluoroaniline of the formula ( 2 ) as a starting material and reacting with glycidylbutyrate under a strong base (first step) ; 2) 상기 제 1 단계에서 제조된 화합물의 하이드록시기를 아민기로 변환시켜 구조식 (4)의 화합물을 제조하는 단계 (제 2 단계);2) preparing a compound of formula ( 4 ) by converting a hydroxy group of the compound prepared in the first step into an amine group (second step); 3) 상기 제 2 단계에서 제조된 구조식 (4)의 화합물은 아세틸화반응시켜 구조식(5)의 화합물을 얻는 단계 (제 3단계); 및3) acetylation of the compound of formula ( 4 ) prepared in the second step to obtain a compound of formula ( 5 ) (third step); And 4) 상기 제 3 단계에서 제조된 구조식 (5)의 화합물로부터 화학식 1의 옥사졸리디논 유도체를 얻는 단계 (제 4단계)로 이루어지는 것을 특징으로 하는 옥사졸리디논 유도체의 제조방법.4) A method of preparing an oxazolidinone derivative, comprising the step (fourth step) of obtaining an oxazolidinone derivative of the formula ( 1 ) from the compound of formula ( 5 ) prepared in the third step. 반응식 1Scheme 1
Figure 112006071630951-pat00013
Figure 112006071630951-pat00013
 (상기식에서, R1 및 R2는 상기 화학식 1에서 정의한 바와 같다.)(Wherein R 1 and R 2 are as defined in Formula 1 above) 제 6항에 있어서, 화학식 1의 옥사졸리디논 유도체는 팔라디움 촉매하에서 하기 구조식 (6)의 화합물과 할로겐으로 치환된 피리미딘 유도체를 반응시켜 옥사졸리디논 유도체를 제조하는 것을 특징으로 하는 옥사졸리디논 유도체의 제조방법.The oxazolidinone derivative according to claim 6, wherein the oxazolidinone derivative of formula ( 1 ) is reacted with a compound of the following structural formula ( 6 ) and a pyrimidine derivative substituted with halogen under a palladium catalyst to prepare an oxazolidinone derivative. Manufacturing method. 반응식 2Scheme 2
Figure 112006071630951-pat00014
Figure 112006071630951-pat00014
 (상기식에서, R1 및 R2는 상기 화학식 1에서 정의한 바와 같다.)(Wherein R 1 and R 2 are as defined in Formula 1 above) 제 7항에서, 팔라디움 촉매는 디클로로비스트리페닐포스핀 팔라디움 (II) 또는 테트라키스트리페닐포스핀 팔라디움 (0)인 것을 특징으로 하는 옥사졸리디논 유도체의 제조방법.8. The process for preparing oxazolidinone derivatives according to claim 7, wherein the palladium catalyst is dichlorobistriphenylphosphine palladium (II) or tetrakistriphenylphosphine palladium (0). 제 1항 내지 제 5항 중 어느 한 항의 옥사졸리디논 유도체 또는 약학적으로 허용되는 그의 염을 유효성분으로 함유하는 항생제용 약학적 조성물.A pharmaceutical composition for antibiotics comprising the oxazolidinone derivative of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.
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