KR20060035629A - Propionamide derivatives useful as androgen receptor modulators - Google Patents

Propionamide derivatives useful as androgen receptor modulators Download PDF

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KR20060035629A
KR20060035629A KR1020057024544A KR20057024544A KR20060035629A KR 20060035629 A KR20060035629 A KR 20060035629A KR 1020057024544 A KR1020057024544 A KR 1020057024544A KR 20057024544 A KR20057024544 A KR 20057024544A KR 20060035629 A KR20060035629 A KR 20060035629A
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methyl
nitrophenyl
hydroxy
alkyl
propionamide
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자리 라틸라이넨
아누 모일라넨
올리 토르마칸가스
아르자 카르잘라이넨
파아보 후흐탈라
저르드 워흘파흐르트
펙카 칼리오
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오리온 코포레이션
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Abstract

Compounds of formula (I) wherein R1 to R4, X and A are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds of formula (I) possess utility as tissue-selective androgen receptor modulators (SARM) and are useful in hormonal therapy, e.g. in the treatment or prevention of male hypogonadism and age-related conditions such as andropause.

Description

안드로젠 수용체 모듈레이터로 유용한 프로피온아마이드 유도체들 {PROPIONAMIDE DERIVATIVES USEFUL AS ANDROGEN RECEPTOR MODULATORS}Propionamide derivatives useful as androgen receptor modulators {PROPIONAMIDE DERIVATIVES USEFUL AS ANDROGEN RECEPTOR MODULATORS}

본 발명은 뉴클레어 수용체(nuclear receptor), 특히 스테로이드 수용체, 더욱 특별하게는 안드로젠 수용체(AR) 의존성 증후군들의 치료에 유용한 치료적으로 활성인 화합물들, 그 약학적으로 허용되는 염류 및 에스테르류 및 이러한 화합물들을 함유하는 약학적 조성물에 관한 것이다. 특히 본 발명은 조직-선택성 안드로젠 수용체 모듈레이터들(SARM)로서 유용성을 가지는 신규의 비스테로이드성 프로피온아닐라이드 구조를 가지는 화합물들에 관한 것이다. AR 아고니스트 활성을 가지는 본 발명의 화합물들은 남성휴지(andropause: 男性休止), 특히 같은 남성 성선기능저하증 및 노화관련 증후군들과 같은 증후군들의 예방과 치료에 호르몬성 요법에 유용하다.The present invention relates to therapeutically active compounds, pharmaceutically acceptable salts and esters thereof useful for the treatment of nucleus receptors, in particular steroid receptors, more particularly androgen receptor (AR) dependent syndromes and A pharmaceutical composition containing compounds is disclosed. In particular, the present invention relates to compounds having a novel nonsteroidal propionanilide structure having utility as tissue-selective androgen receptor modulators (SARM). Compounds of the present invention having AR agonist activity are useful for hormonal therapy in the prevention and treatment of androgens, in particular such as hypogonadism and aging related syndromes.

뉴클레어 호르몬 수용체들은 그 멤버들이 다중 생리적 및 개발적 기능들(multiple physiological and developmental functions)에 관여하는 리간드-유도 전사 인자들(ligand-inducible transcription factors)의 패밀리를 구성한다. 지난 20여년간 이들 패릴리에 속하는 구조적 및 기능적으로 관련된 단백질들이 확인되어 왔다. 뉴클레어 호르몬 수용체 패밀리는 분류적으로 스테로이드 수용체들(에스트로젠 수용체, 프로제스테론 수용체, 안드로젠 수용체, 글루코코르티코이드 수용체 및 미네랄로코르티코이드 수용체)이외에, 예를 들면 타이로이드 호르몬, 비타민 D 및 레티노이드류와 같은 수용체들을 포함한다. 더욱이, 지금까지 리간드들로 분류되지 않은, 소위 오펀 수용체들(orphan receptors)도 이 단백질 팰밀리에 속한한다(Mangelsdorf et al, Ceoo(1995) 83(6): 835-839 및 여기에 소개된 문헌들 참조.). 이들 단백질들에 대한 신규 모듈레이터를 찾아내는 데 연구가 집중되어 왔으며, 궁극적인 목표는 뉴클레어/스테로이드 수용체들에 의하여 조절되는 증후군과 질병들의 치료 및 요법들을 찾아내는 것이다. Nuclein hormone receptors form a family of ligand-inducible transcription factors whose members are involved in multiple physiological and developmental functions. Over the past two decades, structural and functionally related proteins belonging to these parrills have been identified. Nucleic hormone receptor families categorically include steroid receptors (estrogen receptor, progesterone receptor, androgen receptor, glucocorticoid receptor and mineralocorticoid receptor), for example receptors such as thyroid hormones, vitamin D and retinoids do. Moreover, so-called orphan receptors, which have not yet been classified as ligands, also belong to this protein family (Mangelsdorf et al, Ceoo (1995) 83 (6): 835-839 and the literature introduced herein). See them.). Research has focused on finding new modulators for these proteins, and the ultimate goal is to find treatments and therapies for syndromes and diseases regulated by nucleus / steroid receptors.

스테로이드성 안드로젠들은 수십년간 안드로젠 작용 결핍으로 야기되는 질병들의 치료에 사용되어 왔다. 그들은 남성수정능력의 규제에서 노년기 남성의 호르몬 대체 요법으로서 주목을 받아 왔다. 그러나 현재의 합성된 테스토스테론 및 그 유도체들과 같은 스테로이드성 안드로젠들은 심각한 제한을 가지고 있다. 테스토스테론은 간에서 급속하게 분해되어, 경구투여 후에 낮은 전신 생체이용성을 가진다. 더욱이, 메틸테스토스테론과 같은 경구용 테스토스테론 제제들은 간장기능에 변화를 가져오는 것과 연계가 있다. 여러 다른 시도들이 치료제로서의 스테로이드성 안드로젠들의 이러한 단점들을 극복하기 위한 시도들이 있었으나, 성공에 제한적이었다. 현재 테스토스테론 제제들은 임상적으로 주사제, 패취제 및 겔제로 사용된다.Steroidal androgens have been used for decades to treat diseases caused by androgen deprivation. They have received attention as a hormone replacement therapy for older men in the regulation of male fertility. However, steroidal androgens such as presently synthesized testosterone and derivatives thereof have serious limitations. Testosterone is rapidly degraded in the liver and has low systemic bioavailability after oral administration. Moreover, oral testosterone preparations, such as methyltestosterone, are associated with changes in hepatic function. Several other attempts have been made to overcome these shortcomings of steroidal androgens as therapeutics, but they have been limited to success. Testosterone preparations are currently used clinically as injections, patches and gels.

최근 수년동안, 치료적 용도로서 스테로이드 수용체용으로 비스테로이드성 모듈레이터들의 개발에 관심이 고조되고 있다. 비스테로이드성 리간드들이 더 우수한 수용체 선택성과 더 우수한 생리적, 약동력학적 및 약리적 특성들을 성취할 수 있음을 보여주고 있다. 안드로젠 수용체(AR)로서, 비스테로이드성 안타고니스트들(안티안드로젠들)이 임상적으로 과량의 안드로젠들의 바람직하지 않은 활성을 차단하기 위하여 사용된다. 대조적으로, 안드로젠 결핍으로 야기되는 질병들의 치료에 강력한 AR 아고니스트들이 최근에 보고되고 있다. 그러나, 최적의 아고니스트 활성 및 조직선택성을 가지는 비스테로이드성 리간드들의 구조적 요소들은 별로 없었다.In recent years, there has been a growing interest in the development of nonsteroidal modulators for steroid receptors as therapeutic uses. It has been shown that nonsteroidal ligands can achieve better receptor selectivity and better physiological, pharmacokinetic and pharmacological properties. As androgen receptor (AR), nonsteroidal antagonists (antiandrogens) are used to block the undesirable activity of clinically excess androgens. In contrast, AR agonists potent in the treatment of diseases caused by androgen deficiency have recently been reported. However, there are few structural elements of nonsteroidal ligands that have optimal agonist activity and tissue selectivity.

안드로젠 수용체 조적 활성을 가지는 비스테로이드성 프로피온아닐라이드들은 예를 들면, EP 100172, EP 253503, WO 98/53826 및 WO 02/16310에 기재되어 있다. 프로피온아닐라이드 구조를 가지는 AR 모듈레이터들의 디자인은 아닐라이드 링이 할로겐, 시아노, 트리풀루오로메틸 또는 니트로와 같은 두 전자-흡인 치환체들에 의하여 치환된 화합물들에 집중되어 왔으며, 이는 이러한 치환체가 리간드의 안드로젠 수용체 결합친화성을 증진시킨다고 보고되어 있기 때문이다. Tucker, H. et al., J. Med. Chem., 1988, 31, 954-959 참조.Nonsteroidal propionanilides with androgen receptor activating activity are described, for example, in EP 100172, EP 253503, WO 98/53826 and WO 02/16310. The design of AR modulators with a propionanilide structure has been concentrated on compounds in which the anilide ring is substituted by two electron-withdrawing substituents, such as halogen, cyano, trifluomethyl or nitro, which substituents It is reported that it enhances the androgen receptor binding affinity of the ligand. Tucker, H. et al., J. Med. See Chem., 1988, 31, 954-959.

구조식(I)의 화합물들이 강력한 뉴클레어 수용체 모듈레이트들, 특히 안드로젠 수용체 모듈레이터들임이 확인되었다. 구조식(I)의 화합물들은 안드로젠 수용체에 현저히 높은 친화성과 활성을 가지며, 조직-선택성 안드로젠 수용체 모듈레이터들(SARM)로서 유용성을 가진다. AR 아고니스트 활성을 가지는 구조식(I)의 화합물들 호르몬 요법, 특히 조직-선택성 남성불임 및 불임효과와 같은 남성휴지와 같은 남성 성기능저하 및 노년과 관련된 증후군들의 예방과 치료에 적합함이 발견되었다. 예를 들면, 본 발명의 한 바람직한 태양에 의하여, 전립선을 동시에 유해하게 자극함이 없이 유익한 안드로젠성 효과가 얻어진다. 본 발명의 화합물들은 일반적으로 또한 프로제스테론 수용체에 약하거나 중등도의 효과, 특히 안타고니스틱 효과를 가진다. 프로제스테론 안타고니즘을을 동시에 가지는 것은, 프로제스테론 안타고니즘이 특정 동물모델들에 있어서 글루코스 톨러런즈를 개선하기 때문에 유익하다. 본 발명의 화합물들은 우수한 안정성과 충분한 수용성을 가진다.It has been found that the compounds of formula (I) are potent nucleic receptor modulators, especially androgen receptor modulators. Compounds of formula (I) have a markedly high affinity and activity for androgen receptors and have utility as tissue-selective androgen receptor modulators (SARMs). Compounds of formula (I) having AR agonist activity have been found to be suitable for the prevention and treatment of hormonal therapy, in particular male hypogonadism and age-related syndromes such as male rest, such as tissue-selective male infertility and infertility effects. For example, with one preferred aspect of the present invention, a beneficial androgenic effect is obtained without simultaneously stimulating the prostate gland. The compounds of the invention generally also have a weak or moderate effect on the progesterone receptor, in particular an antagonistic effect. Having progesterone antagonism at the same time is beneficial because progesterone antagonism improves glucose tolerance in certain animal models. The compounds of the present invention have good stability and sufficient water solubility.

본 발명의 화합물들은 구조식(I)로 나타내는 구조를 가진 화합물, 그 약학적으로 허용되는 염류 및 에스테르류이다.The compounds of the present invention are compounds having the structure represented by formula (I), pharmaceutically acceptable salts and esters thereof.

Figure 112005075066351-PCT00001
Figure 112005075066351-PCT00001

여기에서 From here

R1 은 (C1-C7)알킬, 하이드록시(C1-C7)알킬 또는 - (CH2)n-CHO, 여기에서 n 은 0-6;R 1 Silver (C 1 -C 7 ) alkyl, hydroxy (C 1 -C 7 ) alkyl or-(CH 2 ) n -CHO, where n is 0-6;

R2는 니트로, 시아노 또는 할로겐;R 2 is nitro, cyano or halogen;

R3는 수소, (C1-C7)알킬 또는 할로 (C1-C7)알킬;R 3 is hydrogen, (C 1 -C 7 ) alkyl or halo (C 1 -C 7 ) alkyl;

R4는 수소, (C1-C7)알킬, COR10 또는 SO2R13;R 4 is hydrogen, (C 1 -C 7 ) alkyl, COR 10 or SO 2 R 13 ;

X는 O 또는 NH;X is O or NH;

A는 다음에서 선택된 그룹이다:A is the group selected from:

Figure 112005075066351-PCT00002
or
Figure 112005075066351-PCT00003
Figure 112005075066351-PCT00002
or
Figure 112005075066351-PCT00003

여기에서 R5, R6, R7, R8 및 R9은 각각 독립적으로 수소, 할로겐, 니트로, 시아노, (C1-C7)알킬, 할로(C1-C7)알킬, 시아노 (C1-C7)알킬, 아미노, 모노- 또는 디(C1-C7)알킬아미노, 아미노(C1-C7)알킬, 하이드록시(C1-C7)알킬, (C1-C7)알콕시 (C1-C7)알킬, -NHCOR10, -N(COR10)2, -COR11, -OR12, -OSO2R13, -SO2R14 또는 -SR15 또는 이미드 링; 이거나 또는 R5 및 R6, R6 및 R7, R7 및 R8 또는 R8 및 R9은 이들이 결합된 다른 링 원자(들)과 함께 5- 내지 7원의 지방족 또는 방향족 카보사이클릭 링이나 또는 N, O 및 S에서 선택된 1-3의 헤테로원자(들)을 포함하는 5- 내지 7-원 복소환링을 형성할 수 있다.;Wherein R 5 , R 6 , R 7 , R 8 and R 9 are each independently hydrogen, halogen, nitro, cyano, (C 1 -C 7 ) alkyl, halo (C 1 -C 7 ) alkyl, cyano (C 1 -C 7 ) alkyl, amino, mono- or di (C 1 -C 7 ) alkylamino, amino (C 1 -C 7 ) alkyl, hydroxy (C 1 -C 7 ) alkyl, (C 1- C 7 ) alkoxy (C 1 -C 7 ) alkyl, -NHCOR 10 , -N (COR 10 ) 2 , -COR 11 , -OR 12 , -OSO 2 R 13 , -SO 2 R 14 or -SR 15 or already De ring; Or R 5 and R 6 , R 6 and R 7 , R 7 And R 8 Or R 8 and R 9 together with other ring atom (s) to which they are attached represent a 5- to 7-membered aliphatic or aromatic carbocyclic ring or a heteroatom (s) of 1-3 selected from N, O and S; It can form a 5- to 7-membered heterocyclic ring comprising;

R10 및 R11은 각각 독립적으로 (C1-C7)알킬, (C2-C7)알케닐, 할로(C1-C7)알킬, 아미노(C1-C7)알킬, 모노- 또는 디-(C1-C7)알킬아미노(C1-C7)알킬, (C6-C10)아릴, -N(R16)2 또는 -OR17;R 10 and R 11 are each independently (C 1 -C 7 ) alkyl, (C 2 -C 7 ) alkenyl, halo (C 1 -C 7 ) alkyl, amino (C 1 -C 7 ) alkyl, mono- or di - (C 1 -C 7) alkylamino (C 1 -C 7) alkyl, (C 6 -C 10) aryl, -N (R 16) 2 or -OR 17;

R12 및 R15는 각각 독립적으로 수소, (C1-C7)알킬, (C2-C7)알케닐, 할로(C1-C7)알킬, 아미노(C1-C7)알킬, 모노- 또는 디-(C1-C7)알킬아미노(C1-C7)알킬, (C6-C10)아릴, 또는 -COR18;R 12 and R 15 are each independently hydrogen, (C 1 -C 7 ) alkyl, (C 2 -C 7 ) alkenyl, halo (C 1 -C 7 ) alkyl, amino (C 1 -C 7 ) alkyl, mono-or di - (C 1 -C 7) alkylamino (C 1 -C 7) alkyl, (C 6 -C 10) aryl, or -COR 18;

R13 및 R14는 각각 독립적으로 (C1-C7)알킬, (C2-C7)알케닐, 할로(C1-C7)알킬 또는 (C6-C10)아릴;R 13 and R 14 are each independently (C 1 -C 7 ) alkyl, (C 2 -C 7 ) alkenyl, halo (C 1 -C 7 ) alkyl or (C 6 -C 10 ) aryl;

R16 및 R17은 각각 독립적으로 수소, (C1-C7)알킬, (C2-C7)알케닐, 할로(C1-C7)알킬, 아미노(C1-C7)알킬 또는 (C6-C10)아릴;R 16 and R 17 are each independently hydrogen, (C 1 -C 7 ) alkyl, (C 2 -C 7 ) alkenyl, halo (C 1 -C 7 ) alkyl, amino (C 1 -C 7 ) alkyl or (C 6 -C 10 ) aryl;

R18은 (C1-C7)알킬, (C2-C7)알케닐, 할로(C1-C7)알킬 또는 (C6-C10)아릴;R 18 is (C 1 -C 7 ) alkyl, (C 2 -C 7 ) alkenyl, halo (C 1 -C 7 ) alkyl or (C 6 -C 10 ) aryl;

R19 및 R20은 각각 독립적으로 수소, 할로겐, (C1-C7)알킬 또는(C2-C7)알케닐;R 19 and R 20 are each independently hydrogen, halogen, (C 1 -C 7 ) alkyl or (C 2 -C 7 ) alkenyl;

및 여기에서 각각의 아릴 또는 링잔기는 치환될 수 있다.And wherein each aryl or ring residue may be substituted.

바람직한 화합물들의 다른 그룹에서 화합물들은 R1, R2, R3, R4, R5, R6, R7, R8 및 R9이 앞에서 정의된 구조식(Ib)의 화합물, 그 약학적으로 허용되는 염류 및 에스테르류이다. In another group of preferred compounds the compounds are those of the formula (Ib) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined above, pharmaceutically acceptable Salts and esters.

Figure 112005075066351-PCT00004
Figure 112005075066351-PCT00004

본 발명의 다른 바람직한 화합물을 다른 그룹은, R1이 메틸 또는 하이드록시메틸이고, R2 가 니트로 또는 시아노인 구조식(I) 또는 (Ib)의 화합물, 그 약학적으로 허용되는 염류 또는 에스테르류이다. 본 발명의 또 다른 바람직한 그룹은 R4가 수소이고, R3가 메틸인 구조식(I) 또는 (Ib)의 화합물, 그 약학적으로 허용되는 염류 또는 에스테르류이다. 본 발명의 다른 바람직한 화합물을 다른 그룹은 R5, R6, R7, R8 및 R9이 각각 독립적으로 수소, 할로겐, 니트로, 시아노, (C1-C7)알킬, (C1-C7)알콕시, 할로(C1-C7)알킬, 하이드록시(C1-C7)알킬 또는 -NHCOR10, 여기에서 R10은 (C1-C7)알킬, 할로(C1-C7)알킬, 하이드록시 또는 (C1-C7)알콕시이다. 특히 바람직한 구조식(I) 또는(Ib)화합물들은 R5, R6, R7, R8 및 R9중 적어도 하나가 할로겐, 바람직하게는 불소이다. 가장 바람직한 것은 R5, R6, R7, R8 및 R9중 적어도 두개가 할로겐, 바람직하게는 불소, 시아노 및 아세트아미도에서 선택된 화합물이다. 특히 바람직한 것은 R6가 할로겐, 바람직하게는 불소인 화합물이다. Another preferred compound of the invention is another group of compounds of formula (I) or (Ib) wherein R 1 is methyl or hydroxymethyl and R 2 is nitro or cyano, pharmaceutically acceptable salts or esters thereof . Another preferred group of the invention is a compound of formula (I) or (lb) wherein R 4 is hydrogen and R 3 is methyl, pharmaceutically acceptable salts or esters thereof. Other preferred compounds of this invention are those in which R 5 , R 6 , R 7 , R 8 And R 9 are each independently hydrogen, halogen, nitro, cyano, (C 1 -C 7 ) alkyl, (C 1 -C 7 ) alkoxy, halo (C 1 -C 7 ) alkyl, hydroxy (C 1- C 7 ) alkyl or —NHCOR 10 , wherein R 10 is (C 1 -C 7 ) alkyl, halo (C 1 -C 7 ) alkyl, hydroxy or (C 1 -C 7 ) alkoxy. Particularly preferred compounds of formula (I) or (lb) are R 5 , R 6 , R 7 , R 8 And at least one of R 9 is halogen, preferably fluorine. Most preferred are R 5 , R 6 , R 7 , R 8 And at least two of R 9 are compounds selected from halogen, preferably fluorine, cyano and acetamido. Especially preferred are compounds in which R 6 is halogen, preferably fluorine.

본 발명은 또한 구조식(I)의 화합물, 그 약학적으로 허용되는 염 또는 에스테르의 치료적으로 유효한 양을 필요한 환자에게 투여하는 것을 포함하는 호르몬 테라피의 방법을 제공하는 것이다.The present invention also provides a method of hormone therapy comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or ester thereof.

본 발명은 또한 구조식(I)의 화합물, 그 약학적으로 허용되는 염 또는 에스테르의 치료적으로 유효한 양을 필요한 환자에게 투여하는 것을 포함하는 안드로젠 수용체(AR) 의존성 증후군들의 예방 또는 치료방법을 제공하는 것이다. The invention also provides a method of preventing or treating androgen receptor (AR) dependent syndromes comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or ester thereof. will be.

본 발명은 또한 구조식(I)의 화합물, 그 약학적으로 허용되는염 또는 에스테르의 치료적으로 유효한 양을 필요한 환자에게 투여하는 것을 포함하는 안드로젠 결핍의 예방과 치료의 방법을 제공하는 것이다.The present invention also provides a method of preventing and treating androgen deficiency comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or ester thereof.

본 발명은 또한 구조식(I)의 화합물, 그 약학적으로 허용되는 염 또는 에스테르의 치료적으로 유효한 양을 필요한 환자에게 투여하는 것을 포함하는 남성휴지와 같은 남성 성기능저하증 및 노화와 관련된 증후군들의 예방과 치료방법을 제공하는 것이다.The invention also provides for the prevention of male hypogonadism and aging-related syndromes, such as male rest, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or ester thereof. To provide a treatment.

본 발명은 또한 구조식(I)의 화합물, 그 약학적으로 허용되는 염 또는 에스테르의 치료적으로 유효한 양을 필요한 환자에게 경구투여하는 것을 포함하는 안드로젠 결핍의 예방과 치료와 같은 호르몬 요법의 방법을 제공하는 것이다.The invention also provides a method of hormonal therapy such as the prevention and treatment of androgen deficiency comprising orally administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or ester thereof. It is.

본 발명은 또한 구조식(I)의 화합물, 그 약학적으로 허용되는 염 또는 에스테르를 약학적으로 허용되는 담체와 함께 포함하는 약학적 조성물을 제공하는 것이다.The present invention also provides a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt or ester thereof, together with a pharmaceutically acceptable carrier.

본 발명의 화합물들은 적당한 출발물질들을 사용하여 문헌에 공지인 방법 또는 이와 유사한 방법의 합성루트에 의하여 제조된다. 특히, 본 발명의 화합물들은 WO 98/53826호에 기술된 일반적인 방법에 유사하게 제조될 수 있다. 예를 들면, 본 발명의 화합물들은 반응 스킴 1 및 2에 따르거나 또는 그와 유사한 방법에 의하여 제조될 수 있다.The compounds of the present invention are prepared by synthetic routes of methods known in the art or similar methods using suitable starting materials. In particular, the compounds of the present invention can be prepared analogously to the general method described in WO 98/53826. For example, the compounds of the present invention may be prepared by methods according to or similar to reaction schemes 1 and 2.

스킴 1 (방법 A)Scheme 1 (Method A)

Figure 112005075066351-PCT00005
Figure 112005075066351-PCT00005

스킴 2 (방법 B)Scheme 2 (Method B)

Figure 112005075066351-PCT00006
Figure 112005075066351-PCT00006

그룹 A가 피리딘 링 또는 그 유도체인 구조식(I)의 화합물들은 적당한 하이드록실 피리딘 유도체들을 사용하여 스킴 1 또는 2에서 보여준 바와 같이 최종 스텝에서 제조될 수 있다. X가 -NH인 구조식(I)의 화합물들은 적당한 아닐린 유도체를 사용하여 스킴 1 또는 2에서 보여준 바와 같이 마지막 단계에서 제조될 수 있다.Compounds of formula (I), in which group A is a pyridine ring or derivatives thereof, can be prepared in the final step as shown in scheme 1 or 2 using suitable hydroxyl pyridine derivatives. Compounds of formula (I) wherein X is -NH can be prepared in the last step as shown in scheme 1 or 2 using suitable aniline derivatives.

약학적으로 허용되는 염류, 예를 들면 유기산 및 무기산들과의 산부가염들은 약학분야에서 잘 알려져 있으며, 이러한 예로서는 염화물, 브롬화물, 설페이트, 나티트레이트, 포스페이트, 설포네이트, 포메이트, 타트레이트, 말리에이트, 사이트레이트, 벤조에이트, 살리실레이트 및 아스코르베이트등을 예시할 수 있으나, 여기에 한정되는 것은 아니다. 약학적으로 허용되는 에스테르류는, 적용시에는 약학분야에서는 통상적인 약학적으로 허용되고, 유리형태의 약리적 특성을 가지는 산류를 사용하여 공지의 방법으로 제조될 수 있다. 이러한 예로는 예를 들면, 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, sec-부틸, tert-부틸 에스테르와 같은 지방족 또는 방향족 알콜류와의 에스테르를 예시할 수 있으나, 이들에 한정되는 것은 아니다. 포스페이트 에스테르류, 카보네이트 에스테르류들도 또한 본 발명의 범위내에 있다.Pharmaceutically acceptable salts, such as acid addition salts with organic and inorganic acids, are well known in the pharmaceutical arts, and examples thereof include chlorides, bromide, sulfates, natitrates, phosphates, sulfonates, formates, tartrates, Maleate, citrate, benzoate, salicylate, ascorbate and the like can be exemplified, but is not limited thereto. Pharmaceutically acceptable esters can be prepared by known methods using acids which, when applied, are conventionally pharmaceutically acceptable in the pharmaceutical art and have free pharmacological properties. Such examples may include, but are not limited to, esters with aliphatic or aromatic alcohols such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl esters. . Phosphate esters, carbonate esters are also within the scope of the present invention.

여기에서 사용된 용어들은 다음의 의미를 가진다.The terms used herein have the following meanings.

여기에서 또는 다른 그룹의 일부로서의 “할로” 또는 “할로겐”이란 용어는 염소, 브롬, 불소 또는 요드를 의미한다.The term "halo" or "halogen" herein or as part of another group means chlorine, bromine, fluorine or iodine.

여기에서 또는 다른 그룹의 일부로서의 “(C1-C7)알킬”이란 용어는 탄소수 1-7을 가지는 직쇄, 분지상 또는 환화된 체인 라디칼을 의미한다. (C1-C7)알킬의 대표적인 예로는 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, sec-부틸, tert-부틸, n-펜틸, 이소펜틸, 네오펜틸, n-헥실, 사이클로펜틸, 사이클로헥실 등을 예시할 수 있으나 여기에 한정되는 것은 아니다.The term “(C 1 -C 7 ) alkyl” herein or as part of another group refers to a straight, branched or cyclic chain radical having 1-7 carbon atoms. Representative examples of (C 1 -C 7 ) alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n- Hexyl, cyclopentyl, cyclohexyl, and the like can be exemplified, but is not limited thereto.

여기에서 또는 다른 그룹의 일부로서의 “(C2-C7)알케닐”이란 용어는 탄소수 2-7을 가지며, 하나 또는 둘이상의 이중결합을 가지는 직쇄, 분자상 또는 환상의 체인 라디칼을 의미한다.The term “(C 2 -C 7 ) alkenyl” herein or as part of another group refers to a straight chain, molecular or cyclic chain radical having 2 to 7 carbon atoms and having one or more double bonds.

여기에서 또는 다른 그룹의 일부로서의 “하이드록시”는 -OH 그룹을 의미한다.“Hydroxy” herein or as part of another group means an —OH group.

여기에서 또는 다른 그룹의 일부로서의 “하이드록시(C1-C7)알킬”이란 용어는 (C1-C7)알킬 그룹을 통하여 모분자 부위에 결합된 적이도 하나의 하이드록시 그룹을 의미한다. 대표적인 하이드록시(C1-C7)알킬은 하이드록시메틸, 2,2-디하이드록시에틸, 1-하이드록시에틸, 3-하이드록시프로필, 1-하이드록싶로필, 1-메틸-1-하이드록시에틸, 1-메틸-1-하이드록시프로필,등이나, 여기에 한정되는 것은 아니다.The term “hydroxy (C 1 -C 7 ) alkyl” herein or as part of another group means one hydroxy group which is bound to the parent molecule site via a (C 1 -C 7 ) alkyl group. . Representative hydroxy (C 1 -C 7 ) alkyls are hydroxymethyl, 2,2-dihydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-hydroxywanophyl, 1-methyl-1- Hydroxyethyl, 1-methyl-1-hydroxypropyl, and the like, but are not limited thereto.

여기에서 또는 다른 그룹의 일부로서의 “할로(C1-C7)알킬”이란 용어는 (C1-C7)알킬 그룹을 통하여 모분자 부위에 결합된 적이도 하나의 할로겐을 의미한다. 대표적인 할로(C1-C7)알킬의 예로는 풀루오로메틸, 디풀루오로메틸, 트리풀루오로메틸, 1-클로로에틸, 3-브로모프로필 등이며, 여기에 한정되는 것은 아니다.The term “halo (C 1 -C 7 ) alkyl” herein or as part of another group means one halogen that is also bonded to the parent molecular moiety through a (C 1 -C 7 ) alkyl group. Exemplary halo (C 1 -C 7 ) alkyls include, but are not limited to, pullulomethyl, difluomethyl, trifluomethyl, 1-chloroethyl, 3-bromopropyl, and the like.

여기에서 또는 다른 그룹의 일부로서의 “시아노”는 -CN 그룹을 의미한다."Cyano" as used herein or as part of another group means a -CN group.

여기에서 또는 다른 그룹의 일부로서의 “시아노(C1-C7)알킬”이란 용어는 (C1-C7)알킬 그룹을 통하여 모분자 부위에 결합된 적이도 하나의 시아노 그룹을 의미한다. 대표적인 시아노(C1-C7)알킬은 시아노메틸, 1-시아노에틸, 1-시아높로필, 2-시아노프로필, 등이다. 그러나 여기에 한정되는 것은 아니다.The term “cyano (C 1 -C 7 ) alkyl” herein or as part of another group refers to a cyano group that is never bonded to the parent molecule site via a (C 1 -C 7 ) alkyl group. . Representative cyano (C 1 -C 7 ) alkyl are cyanomethyl, 1-cyanoethyl, 1-cyanofluoro, 2-cyanopropyl, and the like. However, it is not limited to this.

여기에서 또는 다른 그룹의 일부로서의 “아미노”는 -NH2 그룹을 의미한다."Amino" here or as part of another group means a -NH 2 group.

여기에서 또는 다른 그룹의 일부로서의 “아미노(C1-C7)알킬”이란 용어는 (C1-C7)알킬 그룹을 통하여 모분자 부위에 결합된 적이도 하나의 아미노 그룹을 의미한다. 대표적인 아미노(C1-C7)알킬은 아미노메틸, 2-아메노에틸, 1-아미노에틸, 2,2-디아미노에틸, 3-아미노프로필, 2-아미노프로필, 4-아미노부틸, 1-메틸-1-아미노에틸, 등이며, 여기에 한정되는 것은 아니다.The term “amino (C 1 -C 7 ) alkyl” herein or as part of another group refers to an amino group that is ever bonded to the parent molecule site via a (C 1 -C 7 ) alkyl group. Representative amino (C 1 -C 7 ) alkyls are aminomethyl, 2-amenoethyl, 1-aminoethyl, 2,2-diaminoethyl, 3-aminopropyl, 2-aminopropyl, 4-aminobutyl, 1- Methyl-1-aminoethyl, and the like, but is not limited thereto.

여기에서 또는 다른 그룹의 일부로서의 “모노- 또는 디-(C1-C7)알킬아미노”이란 용어는 아미노 그룹을 통하여 모분자에 결합된 하나 또는 두 (C1-C7)알킬 그룹을을 의미한다. 대표적인 모노- 또는 디-(C1-C7)알킬아미노는 메틸아미노, 에틸아미노, 프로필아미노, 부틸아미노, 디메틸아미노, 디에틸아미노, N-에틸-N-메틸아미노, 등이며, 여기에 한정되는 것은 아니다.The term “mono- or di- (C 1 -C 7 ) alkylamino” herein or as part of another group refers to one or two (C 1 -C 7 ) alkyl groups bonded to the parent molecule through an amino group. it means. Representative mono-or di - and the like (C 1 -C 7) alkylamino are methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, N- ethyl -N- methylamino,, limited to It doesn't happen.

여기에서 또는 다른 그룹의 일부로서의 “모노- 또는 디-(C1-C7)알킬아미노(C1-C7)알킬”이란 용어는 (C1-C7)알킬 그룹을 통하여 모분자에 결합된 하나 또는 두 (C1-C7)알킬아미노 그룹을을 의미한다. 디표적인 모노- 또는 디-(C1-C7)알킬아미노(C1-C7)알킬 그룹은 N,N-디메틸아미노에틸, N,N-디에틸아메노메틸, N-메틸아미노에틸, N-메틸아미노프로필, N-에틸-N-메틸아미노메틸, 등이며, 여기에 한정되는 것은 아니다.The term “mono- or di- (C 1 -C 7 ) alkylamino (C 1 -C 7 ) alkyl” herein or as part of another group binds to the parent molecule through a (C 1 -C 7 ) alkyl group Mean one or two (C 1 -C 7 ) alkylamino groups. D, which is the target of a mono- or di - (C 1 -C 7) alkylamino (C 1 -C 7) alkyl group, N, N- dimethylaminoethyl, N, N- diethyl Ameno methyl, N- methylaminoethyl , N-methylaminopropyl, N-ethyl-N-methylaminomethyl, and the like, but are not limited thereto.

여기에서 또는 다른 그룹의 일부로서의 “(C1-C7)알콕시”이란 용어는 -O- (C1-C7) 그룹을 의미하며, (C1-C7)알킬 그룹은 전술한 바와 같다. 대표적인 (C1-C7)알콕시 그룹은 메톡시, 에톡시, 프로폭시, 부톡시, 이소부톡시, sec-부톡시, tert-부톡시, 등이며, 여기에 한정되는 것은 아니다.The term “(C 1 -C 7 ) alkoxy” herein or as part of another group means a —O— (C 1 -C 7 ) group, wherein the (C 1 -C 7 ) alkyl group is as described above. . Representative (C 1 -C 7 ) alkoxy groups are, but are not limited to, methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

여기에서 또는 다른 그룹의 일부로서의 “(C1-C7)알콕시(C1-C7)알킬”이란 용어는 (C1-C7)알킬 그룹을 통하여 모분자에 결합된 적어도 하나의 (C1-C7)알콕시 그룹을을 의미한다. 디표적인 (C1-C7)알콕시(C1-C7)알킬은 메톡시메틸, 에톡시메틸, 2-메톡시에틸, 2-에톡시에틸, 3,3-디메톡시프로필, 2,4-데메톡시부틸, 등이며, 여기에 한정되는 것은 아니다.The term “(C 1 -C 7 ) alkoxy (C 1 -C 7 ) alkyl” here or as part of another group refers to at least one (C) bonded to the parent molecule through a (C 1 -C 7 ) alkyl group. 1- C 7 ) alkoxy group. Ditargeting (C 1 -C 7 ) alkoxy (C 1 -C 7 ) alkyl is methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3,3-dimethoxypropyl, 2, 4-demethoxybutyl, etc. are not limited to this.

여기에서 또는 다른 그룹의 일부로서의 “(C6-C10)아릴”이란 용어는 링부분에 탄소수 6-10을 함유하는모노사이클릭 또는 비사이클릭 그룹을 의미한다. 대표적인 (C6-C10)아릴은 페닐, 나프틸, 등이며, 여기에 한정되는 것은 아니다.The term “(C 6 -C 10 ) aryl” herein or as part of another group refers to a monocyclic or acyclic group containing 6-10 carbon atoms in the ring portion. Representative (C 6 -C 10 ) aryl is phenyl, naphthyl, and the like, but is not limited thereto.

여기에서 또는 다른 그룹의 일부로서의 “(C2-C7)아실”이란 용어는 탄소수 2-7을 가지는 알킬카르보닐 또는 알케닐카르보닐 그룹을 의미한다. 대표적인 (C2-C7)아실은 아세틸, 프로파노일, 이소프로파노일, 부타노일, sec-부타노일, ter-부타노일 및 펜타노일 그룹이며, 여기에 한정되는 것은 아니다.The term “(C 2 -C 7 ) acyl” herein or as part of another group refers to an alkylcarbonyl or alkenylcarbonyl group having 2 to 7 carbon atoms. Representative (C 2 -C 7 ) acyls are, but are not limited to, acetyl, propanoyl, isopropanoyl, butanoyl, sec-butanoyl, ter-butanoyl and pentanoyl groups.

여러 잔기들과 관련하여 여기에서 사용된 “치환된”이란 용어는 불소, 염소, 브롬, 요드와 같은 할로겐 치환체, 또는 (C1-C7)알킬, 할로(C1-C7)알킬, 하이드록시, 아미노, (C1-C7)알콕시, (C2-C7)아실(C1-C7)알킬아미노, 아미노(C1-C7)알킬, 니트로, 시아노 또는 티올 치환체들을 의미한다.The term “substituted” as used herein in connection with various residues refers to halogen substituents such as fluorine, chlorine, bromine, iodine, or (C 1 -C 7 ) alkyl, halo (C 1 -C 7 ) alkyl, hydride Oxy, amino, (C 1 -C 7 ) alkoxy, (C 2 -C 7 ) acyl (C 1 -C 7 ) alkylamino, amino (C 1 -C 7 ) alkyl, nitro, cyano or thiol substituents do.

“치환된” 그룹은 전술한 치환체 1-3, 바람직하게는 1 또는 2, 가장 바람직하게는 하나의 치환체를 가진다.A “substituted” group has the substituents 1-3 described above, preferably 1 or 2, most preferably one substituent.

전술한 구조식(I)의 정의에서 화합물들은 화합물들의 모든 가능한 입체이성체들, 예를 들면 Z 및 E 이성체들(시스 및 트랜스 이성체들), 및 투공이성체들과 에난티오머들 및 예를 들면 포스페이트 에스테르 및 카보네이트 에스테르들과 같은 프러드러그 에스테르들을 포함한다. 더욱이, 본 발명은 각각의 이성체들과 예를 들면 라세미체들과 같은 이성체들의 혼합물들도 본 발명의 범위내에 포함된다. 각각의 이성체들은 출발물질들의 상응하는 이성체 형태를 사용하여 얻어질 수도 있으며, 합성된 후에 최종 화합물들을 통상의 분할 방법에 의하여 분할될 수도 있다. 에난티오머들과 같은 광학이성체들의 분할은 예를 들면 분별결장 등과 같은 통상의 분할방법에 의하여 분리될 수 있다.Compounds in the definition of formula (I) described above are all possible stereoisomers of the compounds, for example Z and E isomers (cis and trans isomers), and porous isomers and enantiomers and for example phosphate Prodrug esters such as esters and carbonate esters. Moreover, the invention also encompasses within its scope the respective isomers and mixtures of isomers such as racemates, for example. Each isomer may be obtained using the corresponding isomeric form of the starting materials, and after synthesis the final compounds may be partitioned by conventional partitioning methods. The cleavage of optical isomers such as enantiomers can be separated by conventional cleavage methods such as, for example, fractional colon.

바람직한 구조식(I) 화합물들은 다음의 화합물들, 그 약학적으로 허용되는 염류 및 에스테르류는 다음의 화합물을 포함한다.Preferred Structural Formula (I) compounds include the following compounds, pharmaceutically acceptable salts and esters thereof.

3-(4-아세틸아미노-3-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;3- (4-acetylamino-3-fluofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

2(S)-3-(4-아세틸아미노-3-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;2 (S) -3- (4-acetylamino-3-fulurofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

3-(4-아세틸아미노펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;3- (4-acetylaminophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

2(S)-3-(4-아세틸아미노펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;2 (S) -3- (4-acetylaminophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

3-(3-클로로-4-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;3- (3-chloro-4-fulurofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

3-(4-시아노펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;3- (4-cyanophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

3-(2-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;3- (2-fulurofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

3-(3-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;3- (3-Pluorofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

3-(3-클로로-4-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;3- (3-chloro-4-fulurofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

3-(3,4-디풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;3- (3,4-difluurofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

3-(4-클로로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;3- (4-chlorophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

2-하이드록시-3-(4-메톡시펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;2-hydroxy-3- (4-methoxyphenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

3-(2,4-디클로로-3,5-디메틸펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;3- (2,4-dichloro-3,5-dimethylphenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

3-(4-클로로-3-니트로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;3- (4-chloro-3-nitrophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

3-(4-시아노-3-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;3- (4-cyano-3-pululofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

3-(4-풀루오로페닐아미노)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;3- (4-Pluorophenylamino) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

3-[4-(3-클로로프로필)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;3- [4- (3-chloropropyl) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

2-하이드록시-3-(4-메톡시메틸펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;2-hydroxy-3- (4-methoxymethylphenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-피리딘-4-일옥소)프로피온아마이드;2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3-pyridin-4-yloxo) propionamide;

3-[4-(2-클로로에톡시)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;3- [4- (2-chloroethoxy) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

2-풀루오로-4-[2-하이드록시-2-(3-메틸-4-니트로페닐카바모일)프로폭시]-페닐카바민산 에틸에스테르;2-Pluoro-4- [2-hydroxy-2- (3-methyl-4-nitrophenylcarbamoyl) propoxy] -phenylcarbamic acid ethyl ester;

3-(4-사이노페닐아미노)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;3- (4-cyanophenylamino) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

(2S)-3-(4-시아노-3-풀루오로펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;(2S) -3- (4-cyano-3-pululofenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

3-(3-클로로-4-시아노페닐아미노)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;3- (3-chloro-4-cyanophenylamino) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

3-[4-(2-브로모에틸)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드;3- [4- (2-bromoethyl) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide;

3-(4-시아노-3-풀루오로펜옥시)-N-(3-에틸-4-니트로페닐)-2-하이드록시-2-메틸프로피온아마이드; 및3- (4-cyano-3-pululofenoxy) -N- (3-ethyl-4-nitrophenyl) -2-hydroxy-2-methylpropionamide; And

3-(3-클로로-4-시아노펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드.3- (3-Chloro-4-cyanophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide.

본 발명의 화합물들은 환자의 나이, 체중, 인종그룹, 상태등, 치료된 증후군의 상태, 투여경로 및 사용되는 안드로젠(AR) 모듈레이터에 따라서, 매일 약 0.1 내지 1000mg의 용량범위에 속하는 치료적으로 유효한 양을 환자에 투여할 수 있다. 본 발명의 화합물들은 문헌에 공지인 방법에 따라서 용량형태로 제형화 할 수 있다. 본 발명의 화합물들은 적당한 약학적 부형제들과 정제, 과립제, 캡슐제, 좌제, 유제, 현탁제 또는 액제의 형태로 환자에 투여할 수 있다. 조성물용 적당한 성분을 선택하는 것은 이 분야에서 통상의 지식을 가진 사람들에게는 루틴한 일이다. 이 분야의 기술에서 통상적으로 사용되는 적당한 담체, 용제, 겔형성제, 분산제, 항산화제, 착색제, 감미제, 습윤제 및 기타 성분들을 사용할 수 있음은 명확하다. 활성성분을 함유하는 조성물들은 경구적 또는 비경구적으로, 바람직한 경로를 선택하여 투여할 수 있다. 조성물중의 활성 화합물들의 양은 총 조성물 중량대비 약 0.5 - 100%, 바람직하게는 약 0.5 내지 약 20%이다.The compounds of the present invention are therapeutically effective in a dosage range of about 0.1 to 1000 mg daily, depending on the age, weight, ethnic group, condition, etc. of the patient, the condition of the syndrome treated, the route of administration and the androgen (AR) modulator used. The amount can be administered to the patient. The compounds of the present invention may be formulated in dosage form according to methods known in the literature. The compounds of the present invention can be administered to a patient in the form of tablets, granules, capsules, suppositories, emulsions, suspensions or solutions with suitable pharmaceutical excipients. Selecting suitable ingredients for the composition is routine for those of ordinary skill in the art. It is clear that suitable carriers, solvents, gel formers, dispersants, antioxidants, colorants, sweeteners, wetting agents and other ingredients commonly used in the art can be used. Compositions containing the active ingredient can be administered orally or parenterally, by selecting the preferred route. The amount of active compounds in the composition is about 0.5-100%, preferably about 0.5 to about 20% by weight of the total composition.

도 1은 미성숙한 숫컷 스프라그 다울리 래트의 거근(擧筋)의 항-근육(levator anti-muscle), 정액소포(seminal vesicle) 및 벤트랄 전립선(ventral prostate)에서 본 발명의 화합물의 안드로젠성 및 피임작용을 보여주는 도면이다.1 shows the androgenic properties of the compounds of the invention in the levator anti-muscle, seminal vesicle and ventral prostate of the immature male Sprague Dawley rats. And contraception.

본 발명은 다음의 실시예들에 의하여 더욱 상세히 설명한다. 실시예들은 본 발명의 목적을 위하여 예시되는 것이며, 이들 실시예들이 본 발명의 범위를 제한 하는 것은 아니다.The invention is explained in more detail by the following examples. The examples are illustrated for the purposes of the present invention and these examples do not limit the scope of the present invention.

실험예들Experimental Examples

실험예 1. AR 바인딩 어세이Experimental Example 1. AR Binding Assay

벤트랄 전립선들은 희생시키기 24시간전에 거세한 랫트들로부터 얻는다. 신선한 전립선을 잘게 썰고 완충액 A (Schilling and Liao, Prostate, 5:581-588, 1984)로 세척한다. 잘게 썬 것은 다음에 프로테아제 인히비터들을 함유하는 완충액 A(Complete, Mini, EDTA-free Roche) 3xvolume에서 호모지나이즈 한다. 호모지네이트를 30000g에서 30분간 원심분리한다. 결과로 얻어진 상등액을 덱스트란-코팅된 활성탄 액(12,5 g activated charcoal, 12,5 g dextran per liter of buffer A)으로 처리하여 내인성 스테로이드들을 제거한다. 시료들을 5분간 배양한 다음 160000g에서 10분간 원심분리한다. 활성탄-처리된 사이토솔(cytosol)의 소량을 취하고 안드로젠 수용체 분석을 행한다. 모든 공정들은 0-4℃에서 행한다. 사이토솔 안드로젠 수용체 농도는 문헌(Isomaa et al., Endocrinology, 111: 833-843, 1982)에 기술된 방법에 약간의 수정을 가하여 측정한다. 사이토솔 시료들은 앞에 기술된 바와 같이 제조하며, 결합되거나 또는 유리의 스테로이드들은 덱스트란-활성탄 현탁액의 같은 양으로 4℃에서 5분간 처리한 후, 160000g에서 10분간 원심분리하여 처리한다. .결합된 방사성 활성은 OptiPhase HiSafe3 나 또는 OptiPhase Supermix (PerkinElmer)의 1ml중에서 상등액 분획들을 카운팅하여 결정된다.Ventral prostates are obtained from rats castrated 24 hours before sacrifice. Chop fresh prostate and wash with Buffer A (Schilling and Liao, Prostate, 5: 581-588, 1984). Finely chopped is then homogenized in 3xvolume of Buffer A (Complete, Mini, EDTA-free Roche) containing protease inhibitors. Homogenate is centrifuged at 30000 g for 30 minutes. The resulting supernatant is treated with dextran-coated activated carbon liquid (12,5 g activated charcoal, 12,5 g dextran per liter of buffer A) to remove endogenous steroids. The samples are incubated for 5 minutes and then centrifuged at 160000 g for 10 minutes. Small amounts of activated carbon-treated cytosol are taken and an androgen receptor assay is performed. All processes are performed at 0-4 ° C. Cytosol androgen receptor concentrations are measured with minor modifications to the methods described in Isomaa et al., Endocrinology, 111: 833-843, 1982. Cytosol samples are prepared as described previously and bound or free steroids are treated with the same amount of dextran-activated carbon suspension at 4 ° C. for 5 minutes followed by centrifugation at 160000 g for 10 minutes. Bound radioactivity is determined by counting supernatant fractions in 1 ml of OptiPhase HiSafe3 or OptiPhase Supermix (PerkinElmer).

사이토솔 시료들은 1nM[3H]-mibolerone으로 0℃에서 하룻밤 처리(전체)하여 라벨링한다. 본 발명의 화합물들(test compounds)의 AR 결합활성을 측정하기 위하여, 테스트 화합물들의 [3H]7a,17a-디메틸--17b-하이드록시-4-에스트렌-3-온 ([3H]-mibolerone)과의 결합의 상경의 능력을 측정한다. 두 농도(0,2 and 2 uM)중의 1 nM [3H]-mibolerone과 테스트 화합물들을 0℃에서 하룻밤 배양한다. 비특이성 결합을 측정하기 위하여, 평행 배양들을 라벨하지 않은 테스토스테론의 500-배 초과 몰량과 함께 1nM 농도의 [3H]-mibolerone을 사용하여 수행한다. 각각의 시료ㄹ에 대하여 둘 내지 4 시료들을 사용한다. 배양후에, 결합 및 비결합 스테로이드들을 앞에 기술한 바와 같이 분리하고, 결합 방사성 활성을 측정한다. 테스트 화합물들의 AR 결합 능력은 1 nM [3H]-mibolerone으로 얻어진 결합된 방사성 활성에서 보다 감소한 것으로 보고되었다. 결과는 표 1에 나타낸다. 결과(% 억제)는 다음과 같이 계산한다.Cytosol samples are labeled with 1 nM [ 3 H] -mibolerone at 0 ° C. overnight (whole). In order to determine the AR binding activity of the test compounds of the present invention, [ 3 H] 7a, 17a-dimethyl-17b-hydroxy-4-estren-3-one ([ 3 H] -mibolerone) measures the ability of the upper phase of binding. Incubate overnight at 0 ° C. with 1 nM [ 3 H] -mibolerone at two concentrations (0, 2 and 2 uM). To measure nonspecific binding, parallel cultures are performed using [ 3 H] -mibolerone at a concentration of 1 nM with 500-fold greater molar amount of testosterone that is not labeled. Two to four samples are used for each sample. After incubation, bound and unbound steroids are isolated as previously described and bound radioactivity is measured. The AR binding capacity of the test compounds was reported to be lower in the bound radioactivity obtained with 1 nM [ 3 H] -mibolerone. The results are shown in Table 1. The result (% inhibition) is calculated as follows.

% inhibition = 100 - (100x(averagetest compound/averagetotal))% inhibition = 100-(100x (average test compound / average total ))

표 1. AR 결합 분석. 결합된 [3H]-mibolerone의 억제(%). Table 1. AR binding assays. % Inhibition of bound [3H] -mibolerone.

실시예 번호의 화합물 Compound of Example Number 0.2μM에서 결합된 [3H]-mibolerone의 억제(%)  % Inhibition of bound [3H] -mibolerone at 0.2 μM 2.0μM에서 결합된 [3H]-mibolerone의 억제(%)  % Inhibition of bound [3H] -mibolerone at 2.0 μM 1.One. 9191 101101 2.2. 9393 100100 3.3. 103103 115115 4.4. 9090 8888 5.5. 2525 7474 6.6. 6868 9595 7.7. 7474 9898 8.8. 9393 109109 9.9. 4141 102102 10.10. 55 8383 11.11. 9898 105105 12.12. 7777 101101 13.13. 7777 9090 14.14. 7575 9595 15.15. 4646 7777 16.16. 5050 9191 17.17. 9595 9898 18.18. 9090 9999 19.19. 8383 9999 20.20. 1313 8383 21.21. 2626 9191 23.23. 8888 9292 24.24. 7575 9393 25.25. 9696 9898 26.26. 6262 9292 27.27. 3434 8989 28.28. 9090 8888 29.29. 9292 9090 30.30. 8080 9999 31.31. 1818 7575 36.36. 33 5050 42.42. 8383 9797 43.43. 9595 9999 44.44. 8383 100100 50.50. 9696 9999 51.51. 7373 9292 52.52. 9090 115115 55.55. 8787 9999 56.56. 9090 9595 58.58. 8484 9393 63.63. 9292 9898 64.64. 7979 8989 66.66. 6969 9393 79.79. 8989 9898 80.80. 8787 9999 81.81. 8585 9898

실험예 2. 미성숙 숫컷 랫트들에서 AR 아고니즘 및 안타고니즘Experimental Example 2 AR Agonism and Antagonism in Immature Male Rats

실시예 3의 표제 화합물은 화합물 A로 약칭하며, 생체내 실험을 행하였다. 피하주사하여 투여한 화합물 A의 아고니즘과 안타고니즘을 미성숙한 숫컷 스프라그 다울리 랫트로 3-일간 분석을 벤트랄 전립선, 세미날 베시클, 및 레바토 안티-머슬(근육)의 상대 중량을 분석함으로서 실험을 행하였다. 테스토스테론 프로피오네이트는 대조 화합물로서 사용하였다.The title compound of Example 3 was abbreviated as Compound A and performed in vivo. Three-day analysis of the agonism and antagonism of Compound A administered by subcutaneous injection into immature male Sprague Dawley rats was performed to determine the relative weight of ventral prostate, seminal vesicle, and levato anti-muscle (muscle). The experiment was conducted by analyzing. Testosterone propionate was used as a control compound.

테스토스테론 프로피오네이트( TP로 약칭함.) 및 화합물 A는 먼저 DMSO에 용해시키고, 다음에 호마유(비히클)에 용해시키킨다. 체중 약 50g의 비처리된 스프라그-도울리 숫컷 랫트들(18-19일 된)을 실험에 하용하였다. 랫트들은 체중을 잭, 무작위적으로 각 그룹당 5필씩의 5 그룹으로 나눈다.(표 1). 화합물 A(용량 2 및 20mg/kg)과 테스토스테론 프로피오네이트(5mg/kg 용량)을 100microl 도싱 용액/동물/일의 일정량으로 동물의 목/등으로 피하주사한다. 동물들은 일일 1회 3일간 투여한 후, 투여하는 동안 임상적 현상을 기록한다. 연구 최종에는 동물들의 체중을 측정하고, 탄산가스로 마취 및 질식시킨다. 벤트랄 전립선, 세미날 베시클 및 레바토 안티-머슬을 적출해 내고, 냉각시킨 다음 무게를 잰다. 4회의 통계적 분석을 위하여 모든 장기들의 무게들을 체중에 맞추고 단일인자(single-factor) ANOVA에 의하여 통계적 유의성의 차이를 분석한다.Testosterone propionate (abbreviated TP) and Compound A are first dissolved in DMSO and then in horse oil (vehicle). Untreated Sprague-Dawley male rats (18-19 days old) weighing approximately 50 g were used for the experiment. Rats divide their weight into 5 groups of 5 randomly, 5 pills per group (Table 1). Compound A (doses 2 and 20 mg / kg) and testosterone propionate (5 mg / kg dose) are subcutaneously injected into the neck / back of the animal in a constant amount of 100 microl dosing solution / animal / day. Animals are administered once daily for 3 days and then the clinical phenomena recorded during the administration. At the end of the study animals are weighed, anesthetized and choked with carbon dioxide. Ventral prostate, seminal vesicles and levato anti-muscles are removed, cooled and weighed. For four statistical analyzes, the weights of all organs were weighed and the difference of statistical significance was analyzed by single-factor ANOVA.

표 2. 동물 그룹들 및 실험적 디자인Table 2. Animal Groups and Experimental Design

도스 그룹 및 그룹 수  DOS groups and number of groups 동물수 The number of animals 1. 비히클  1. Vehicle 5 5 2. 테스토스테론 프로피오네이트(TP) 5mg/kg s.c.  2. Testosterone Propionate (TP) 5 mg / kg s.c. 5 5 3. 화합물 A, 2 mg/kg  3. Compound A, 2 mg / kg 5 5 4. 화합물 A, 20 mg/kg  4. Compound A, 20 mg / kg 5 5 5. TP 5 mg/kg + 화합물 A, 20 mg/kg s.c.  5. TP 5 mg / kg + Compound A, 20 mg / kg s.c. 5 5

실험결과는 도 1에 나타내었다. 화합물 A는 안드로제닉 및 아나볼릭 활성을 보여주고 있다. 벤트랄 전립선, 세미날 베시클 및 레바토 안티-머슬의 상대적 체중은 테스토스테론 프로피오네이트의 투여와 함께 현저하게 증가하였다. 테스토스테론 프로피오네이트와 비교하여, 화합물 A는 조직 선택성을 보여주었다. 20mg/kg의 용량에서, 레바토 안티-머슬의 상대적 중량은 확실하게 증가하였으며, 세미날 베시클의 상대적 중량은 현저하게 증가하였다. 그러나, 전립선의 상대적 중량은 극히 미미하게 증가하였다. 더욱이, 화합물 A는 세미날 베시클에서 현저한 안타고니스트성 활성을 보여주었다. 테스토스테론 프로페오네이트나 화합물 A는 모두 체중(데이타는 보여주지 않음)에 영향을 주지 않았다. 도면에서, "a"는 아나고니즘을 의미하며, 비히클 그룹과 비교하여 p<0.01이였으며, "b"는 안타고니즘을 의미하며, 테스토스테론 그룹에 비하여 p<0.05이었다. 바는 ±SEM을 의미한다.The experimental results are shown in FIG. Compound A has shown androgenic and anabolic activity. Relative body weights of ventral prostate, seminal vesicle and levato anti-muscle increased significantly with administration of testosterone propionate. Compared to testosterone propionate, Compound A showed tissue selectivity. At a dose of 20 mg / kg, the relative weight of the levato anti-muscles increased reliably and the relative weight of the seminal vesicles increased significantly. However, the relative weight of the prostate grossly increased slightly. Moreover, Compound A showed significant antagonist activity in seminal vesicles. Neither Testosterone Propionate nor Compound A did not affect body weight (data not shown). In the figure, "a" refers to anagonism, p <0.01 compared to vehicle group, and "b" means antagonism, p <0.05 compared to testosterone group. Bar means ± SEM.

실시예들Examples ::

실시예 1.(방법 A)Example 1. (Method A)

3-(4-아세틸아미노펜옥시)-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드3- (4-acetylaminophenoxy) -2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide

a) 2-메틸-N-(3-메틸-4-니트로페닐)아크릴아마이드a) 2-methyl-N- (3-methyl-4-nitrophenyl) acrylamide

N,N-디메틸아세트아마이드(DMAC)(6ml) 중의 3-메틸-4-니트로아닐린(2.0g, 13mmol)을 질소분위기 중에서 메타크릴로일 클로라이드(2.0ml, 20.7mmol)의 냉각된 용액에 적가한다. 반응혼합물의 온도는 0-5℃로 유지한 다음, 용액을 실온으로 가온하고, 혼합물을 하룻밤 교반한다. 혼합물을 물(70ml)에 붓고, 초산에틸(40mlx4)로 추출한다. 유기상을 포화 탄산나트륨(20mlx3) 및 물(50mlx1)로 세척한 다음 망초로 건조시키고 증발시킨다. 조생성물 4.17g(DMA 이론양 2.9g)을 얻으며, 이것은 더 정제하지 않고 다음 단계에 사용된다.3-methyl-4-nitroaniline (2.0 g, 13 mmol) in N, N-dimethylacetamide (DMAC) (6 ml) was added dropwise to a cooled solution of methacryloyl chloride (2.0 ml, 20.7 mmol) in a nitrogen atmosphere. do. The temperature of the reaction mixture is kept at 0-5 ° C., then the solution is allowed to warm to room temperature and the mixture is stirred overnight. The mixture is poured into water (70 ml) and extracted with ethyl acetate (40 ml × 4). The organic phase is washed with saturated sodium carbonate (20mlx3) and water (50mlx1), then dried over forget-me-not and evaporated. 4.17 g of crude product (2.9 g of DMA theory) are obtained, which are used in the next step without further purification.

1H NMR (DMSO-d6): 1.97 (3H, s), 2.55 (3H, s), 5.62 (1H, m), 5.96 (1H, m), 7.80 (2H, m), 8.05 (1H, m), 10.22 (1H, s). 1 H NMR (DMSO-d 6 ): 1.97 (3H, s), 2.55 (3H, s), 5.62 (1H, m), 5.96 (1H, m), 7.80 (2H, m), 8.05 (1H, m ), 10.22 (1 H, s).

b) 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드b) 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide

m-클로로페벤조산(6.9g, 29.9mmol)을 60℃에서 2-메틸-N-(3-메틸-4-니트로페닐)아크릴아마이드(2.9g, 13.2mmol) 및 2,6-디-tert-부틸-4-메틸페놀(66mg)의 용액에 조금씩 가한다. 60℃에서 6시간 교반한 다음 반응혼합물을 실온으로 냉각시킨다. 침전된 m-클로로벤조산을 여과하고, 여엑을 1M 탄산나트륨(60mlx4)로 세척한다. 유기상을 황산나트륨으로 건조시키고 증발시킨다. 수율은 3.05g이다.m-chlorofebenzoic acid (6.9 g, 29.9 mmol) was treated with 2-methyl-N- (3-methyl-4-nitrophenyl) acrylamide (2.9 g, 13.2 mmol) and 2,6-di-tert- at 60 ° C. It is added little by little to a solution of butyl-4-methylphenol (66 mg). After stirring at 60 ° C. for 6 hours, the reaction mixture is cooled to room temperature. Precipitated m-chlorobenzoic acid is filtered off, and the filtrate is washed with 1M sodium carbonate (60mlx4). The organic phase is dried over sodium sulfate and evaporated. Yield 3.05 g.

1H NMR (DMSO-d6): 1.54 (3H, s), 2.51 (3H, s), 2.99 (1H, d, J=5.1 Hz), 3.05 (1H, d, J=5.1 Hz), 7.79 (2H, m), 8.01 (1H, m), 9.98 (1H, s). 1 H NMR (DMSO-d 6 ): 1.54 (3H, s), 2.51 (3H, s), 2.99 (1H, d, J = 5.1 Hz), 3.05 (1H, d, J = 5.1 Hz), 7.79 ( 2H, m), 8.01 (1H, m), 9.98 (1H, s).

c) 3-(4-아세틸아미노펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드c) 3- (4-acetylaminophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

TMF(60ml)중의 4-아세트아미도페놀(2.9g, 19mmol)을 교반하에 THF(60ml)에 현탁시킨 소디움 하이드라이드(미네랄오일에 분산시킨 60%, 0.46g, 19mmol)에 적가한다. 적가하는 동안 온도는 5℃이하로 유지한다. 혼합물을 10분간 교반하고, TMF(120ml)중의 2-메틸-옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드(3.05g, 13mmol)의 용액을 가한다. 혼합물을 60℃로 가열한 다음 이 온도에서 7시간 교반한 다음 실온으로 냉각시킨다. 용매를 증발시킨 잔유물을 물(150ml)와 초산에틸(150ml)의 혼합물에 용해시킨다. pH를 2M HCl로 2-3으로 조절한다. 상들을 분리하고, 물층을 초산에틸(150mlx4)로 추출하고, 추출액을 합하고 1M 탄산나트륨(100mlx5)용액으로 세척한 다음, 황산나트륨으로 건조시킨다음 증발시킨다. 오일상 잔유물을 초산에틸과 디에틸에테르(10:1)의 혼합물로 재결정한다. 조생성물을 초산에틸로 재결정하여 목적화합물 2.5g을 얻는다.4-acetamidophenol (2.9 g, 19 mmol) in TMF (60 ml) was added dropwise to sodium hydride (60%, 0.46 g, 19 mmol) dispersed in THF (60 ml) under stirring. During the dropping, the temperature is kept below 5 ° C. The mixture is stirred for 10 minutes and a solution of 2-methyl-oxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide (3.05 g, 13 mmol) in TMF (120 ml) is added. The mixture is heated to 60 ° C. and then stirred at this temperature for 7 hours and then cooled to room temperature. The solvent evaporated residue is dissolved in a mixture of water (150 ml) and ethyl acetate (150 ml). Adjust the pH to 2-3 with 2M HCl. The phases are separated, the water layer is extracted with ethyl acetate (150mlx4), the extracts are combined, washed with 1M sodium carbonate (100mlx5) solution, dried over sodium sulfate and evaporated. The oily residue is recrystallized from a mixture of ethyl acetate and diethyl ether (10: 1). The crude product is recrystallized from ethyl acetate to obtain 2.5 g of the target compound.

1H NMR (DMSO-d6): 1.42 (3H, s), 1.99 (3H, s), 2.53 (3H, s), 3.93 (1H, d, J=9.6 Hz), 4.16 (1H, d, J=9.6 Hz), 6.20 (1H, bs), 6.84 (2H, d, J=9.0 Hz), 7.44 (2H, d, J=9.0 Hz), 7.88 (1H, dd, J=9.0 Hz and 2.3 Hz), 7.93 (1H, d, J=2.3 Hz), 8.04 (1H, d, J=9.0 Hz), 9.76 (1H, s), 10.15 (1H, bs). 1 H NMR (DMSO-d 6 ): 1.42 (3H, s), 1.99 (3H, s), 2.53 (3H, s), 3.93 (1H, d, J = 9.6 Hz), 4.16 (1H, d, J = 9.6 Hz), 6.20 (1H, bs), 6.84 (2H, d, J = 9.0 Hz), 7.44 (2H, d, J = 9.0 Hz), 7.88 (1H, dd, J = 9.0 Hz and 2.3 Hz) , 7.93 (1H, d, J = 2.3 Hz), 8.04 (1H, d, J = 9.0 Hz), 9.76 (1H, s), 10.15 (1H, bs).

실시예 2Example 2

3-(4-아세틸아미노-3-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드3- (4-acetylamino-3-fulurofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

a) N-(2-풀루오로-4-하이드록시페닐)아세트아마이드a) N- (2-Pluoro-4-hydroxyphenyl) acetamide

아세틱안하이드라이드(13ml, 13.8mmol)을 아세트산(25ml) 중의 4-아미노-3-풀루오로페놀(1.0g,7.9mmol)의 용액에 실온에서 적가한다. 반응혼합물을 실온에서 2시간 교반한 다음, 물(2ml)를 가하고 실온에서 30분간 교반한다. 혼합물을 진공하에 증발시켜서 조성성물 1.3mg(100%)를 얻는다. 이것은 더 이상 정제없이 사용된다.Acetic anhydride (13 ml, 13.8 mmol) is added dropwise to a solution of 4-amino-3- pullurophenol (1.0 g, 7.9 mmol) in acetic acid (25 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then water (2 ml) was added and stirred at room temperature for 30 minutes. The mixture is evaporated in vacuo to yield 1.3 mg (100%) of the composition. It is used without further purification.

1H NMR (DMSO-d6): 2.00 (3H, s), 6.50-6.68 (2H, m), 7.39 (1H, m), 9.39 (1H, s), 9.72 (1H, s). 1 H NMR (DMSO-d 6 ): 2.00 (3H, s), 6.50-6.68 (2H, m), 7.39 (1H, m), 9.39 (1H, s), 9.72 (1H, s).

b) 3-(4-아세틸아미노-3-풀루오로펜옥시)-2-하이드록시-N-(3-메틸-4-니트로페닐)프로피온아마이드b) 3- (4-acetylamino-3- pullurofenoxy) -2-hydroxy-N- (3-methyl-4-nitrophenyl) propionamide

화합물은 실시예 1c에 기재된 공정에 의하여 N-(2-풀루오로-4-하이드록시페닐)아세트아마이드(0.5g, 3.0mmol)과 2-메틸옥시람-2-카르복실산(3-메틸-4-니트로페닐)아마이드(0.6g, 2.5mmol)을 출발물질로 사용하여 합성된다. 생성물은 초산에틸과 디에틸에테르(1:1)의 혼합물로 재결정한다. 수율은 0.39g이다.The compound was prepared using N- (2-fluoro-4-hydroxyphenyl) acetamide (0.5 g, 3.0 mmol) and 2-methyloxiram-2-carboxylic acid (3-methyl by the process described in Example 1c. Synthesized using 4-nitrophenyl) amide (0.6 g, 2.5 mmol) as starting material. The product is recrystallized from a mixture of ethyl acetate and diethyl ether (1: 1). The yield is 0.39 g.

1H NMR (DMSO-d6): 1.42 (3H, s), 2.02 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J=9.7 Hz), 4.21 (1H, d, J=9.7 Hz), 6.23 (1H, bs), 6.72 (1H, m), 6.90 (1H, m), 7.56 (1H, m), 7.88 (1H, dd, J=9.0 Hz and 2.2 Hz), 7.93 (1H, d, J=2.2 Hz), 8.03 (1H, d, J=9.0 Hz), 9.51 (1H, s), 10.15 (1H, bs). 1 H NMR (DMSO-d 6 ): 1.42 (3H, s), 2.02 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J = 9.7 Hz), 4.21 (1H, d, J = 9.7 Hz), 6.23 (1H, bs), 6.72 (1H, m), 6.90 (1H, m), 7.56 (1H, m), 7.88 (1H, dd, J = 9.0 Hz and 2.2 Hz), 7.93 ( 1H, d, J = 2.2 Hz), 8.03 (1H, d, J = 9.0 Hz), 9.51 (1H, s), 10.15 (1H, bs).

실시예 3 ( 방법 B)Example 3 (Method B)

(2S)-3-(4-아세틸아미노펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드(2S) -3- (4-acetylaminophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

a) (2R)-1-(2-메타크릴로일)피롤리딘-2-카르복실산a) (2R) -1- (2-methacryloyl) pyrrolidine-2-carboxylic acid

D-프롤린(5g, 43.4mmol)을 2M NaOH(26ml)에 용해시키고, 얼음욕에서 냉각시킨다. 용액을 아세톤(26ml)로 희석시킨다. 메타크릴로일 클로라이드(6.3ml, 65.1mmol)의 아세톤(26ml)의 용액과 2M NaOH 용액(34ml)을 동시에 1시간에 걸쳐서 D-프롤린 용액에 가한다. 결과로 얻어진 혼합물을 실온에서 3시간 교반한 다음, 혼합물을 40℃에서 증발시킨 다음 에테르(40mlx2)로 추출한다. 진한 HCl로 pH 2로 산성화시킨다, 결과로 얻어진 혼합물을 초산에틸(50mlx3)으로 추출하고, 추출액을 황산나트륨으로 건조시키고 증발시킨다. 수율은 11.5g(이론양 8.0g)이다. 이것은 더 정제하지 않고 다음의 공정에 사용된다.D-proline (5 g, 43.4 mmol) is dissolved in 2M NaOH (26 ml) and cooled in an ice bath. Dilute the solution with acetone (26 ml). A solution of acetone (26 ml) of methacryloyl chloride (6.3 ml, 65.1 mmol) and 2 M NaOH solution (34 ml) are added simultaneously to the D-proline solution over 1 hour. The resulting mixture is stirred at room temperature for 3 hours, then the mixture is evaporated at 40 ° C. and then extracted with ether (40 ml × 2). Acidify to pH 2 with concentrated HCl. The resulting mixture is extracted with ethyl acetate (50 ml × 3) and the extract is dried over sodium sulfate and evaporated. The yield is 11.5 g (8.0 g of theory). It is used in the next step without further purification.

b) (3R, 8aR)-3-브로모메틸-3-메틸테트라하이드로피롤로[2,1-c][1,4]옥사진-1,4-디온b) (3R, 8aR) -3-bromomethyl-3-methyltetrahydropyrrolo [2,1-c] [1,4] oxazine-1,4-dione

NBS(16g, 89.9mmol)을 DMF(50ml)에 용해시킨 다음, DMF(50ml)중의 (2R)-1-(2-메타크릴로일)피롤리딘-2-카르복실산(11.5g, 상응하는 출발물질 8.0g 함유, 43.4mmol)의 용액에 실온에서 가한다. 혼합물을 20시간 교반한 다음, 80-90℃ 에서 증발시킨다. 잔류물을 물(250ml)과 혼합하고, 초산에틸(80mlx4)로 추출한다. 추출액을 합하고 1M 탄산수소나트륨 용액(50mlx2) 및 물(50mlx1)로 차례로 세척한다. 유기층을 황산나트륨으로 건조시키고, 증발시킨다. 조 오일의 수율은 9.3g이다. 초산에틸(10ml)를 가하고, 혼합물을 얼음욕에서 교반한다. 침전된 생성물은 여과하고, 냉각된 초산에틸로 세척한다. 수율 1.2g.NBS (16 g, 89.9 mmol) was dissolved in DMF (50 ml) and then (2R) -1- (2-methacryloyl) pyrrolidine-2-carboxylic acid (11.5 g, corresponding) in DMF (50 ml) To a solution of 43.4 mmol) containing 8.0 g of the starting material at room temperature. The mixture is stirred for 20 hours and then evaporated at 80-90 ° C. The residue is mixed with water (250 ml) and extracted with ethyl acetate (80 ml × 4). The extracts are combined and washed sequentially with 1M sodium bicarbonate solution (50mlx2) and water (50mlx1). The organic layer is dried over sodium sulfate and evaporated. The yield of crude oil is 9.3 g. Ethyl acetate (10 ml) is added and the mixture is stirred in an ice bath. The precipitated product is filtered off and washed with cold ethyl acetate. Yield 1.2 g.

1H NMR (DMSO-d6): 1.58 (3H, s), 1.75-2.10 (3H, m), 2.25 (1H, m), 3.30-3.55 (2H, m), 3.87 (1H, d, J=11.4 Hz), 4.03 (1H, d, J=11.4 Hz), 4.70 (1H, m). 1 H NMR (DMSO-d 6 ): 1.58 (3H, s), 1.75-2.10 (3H, m), 2.25 (1H, m), 3.30-3.55 (2H, m), 3.87 (1H, d, J = 11.4 Hz), 4.03 (1H, d, J = 11.4 Hz), 4.70 (1H, m).

c) 2(R)-3-브로모-2-하이드록시-2-메틸프로피온산c) 2 (R) -3-bromo-2-hydroxy-2-methylpropionic acid

(3R, 8aR)-3-브로모메틸-3-메틸테트라하이드로피롤로[2,1-c][1,4]옥사진-1,4-디온(1.1g, 4.2mmol)을 진한 염산(10ml)에 용해시킨 다음 7시간 환류시킨다. 혼합물을 실온으로 냉각시키고, 물(20ml)를 가한다. 혼합물을 초산에틸(20mlx3)로 추출하고, 추출액을 합하고 증발시킨 잔류물을 톨루엔(5ml)와 혼합한다. 결정화된 생성물을 여과하고 톨루엔으로 세척한다. 수율 0.74g. (3R, 8aR) -3-bromomethyl-3-methyltetrahydropyrrolo [2,1-c] [1,4] oxazine-1,4-dione (1.1 g, 4.2 mmol) concentrated in hydrochloric acid ( 10 ml) and then refluxed for 7 hours. The mixture is cooled to room temperature and water (20 ml) is added. The mixture is extracted with ethyl acetate (20 ml × 3), the extracts are combined and the evaporated residue is mixed with toluene (5 ml). The crystallized product is filtered off and washed with toluene. Yield 0.74 g.

1H NMR (DMSO-d6): 1.37 (3H, s), 3.54 (1H, d, J=10.2 Hz), 3.64 (1H, d, J=10.2 Hz), 5.35 (1H, bs), 12.80 (1H, bs). 1 H NMR (DMSO-d 6 ): 1.37 (3H, s), 3.54 (1H, d, J = 10.2 Hz), 3.64 (1H, d, J = 10.2 Hz), 5.35 (1H, bs), 12.80 ( 1H, bs).

d) (2R)-3-브로모-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아미이드d) (2R) -3-bromo-2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide

티오닐클로라이드(0.48ml, 6.6mmol)을 DMA 10ml중의 (2R)-3-브로모-2-하이드록시-2-메틸프로피온산(1.0g, 5.5mmol)의 용액에 -5 내지 -10℃에서 적가한다. 혼합물을 2시간 교반하고, 이 혼합물에 DMA 7ml중의 3-메틸-4-니트로아닐린(0.83g, 5.5mmol)의 용액을 가한다. 결과로 얻어진 혼합물을 실온에서 3시간 교반한 다음, 물(250ml)에 붓는다. 물상을 초산에틸(50mlx4)로 추출한 다음, 황산나트륨으로 건조하고 증발시킨다. 원하는 화합물의 수율은 2.5g(DMA도 또한 함유한다. 이것은 더 정재하지 않고, 사용된다.Thionyl chloride (0.48 ml, 6.6 mmol) is added dropwise to a solution of (2R) -3-bromo-2-hydroxy-2-methylpropionic acid (1.0 g, 5.5 mmol) in 10 ml of DMA at -5 to -10 deg. do. The mixture is stirred for 2 hours, and to this mixture is added a solution of 3-methyl-4-nitroaniline (0.83 g, 5.5 mmol) in 7 ml of DMA. The resulting mixture is stirred for 3 hours at room temperature and then poured into water (250 ml). The aqueous phase is extracted with ethyl acetate (50mlx4), dried over sodium sulfate and evaporated. The yield of the desired compound also contains 2.5 g (DMA also. It is used without further purification.

1H NMR (DMSO-d6): 1.48 (3H, s), 2.53 (3H, s), 3.58 (1H, d, J=10.4 Hz), 3.82 (1H, d, J=10.4 Hz), 6.34 (1H, bs), 7.86 (1H, dd, J=9.0 Hz and 2.2 Hz), 7.91 (1H, d, J=2.2 Hz), 8.04 (1H, d, J=9.0 Hz), 10.09 (1H, bs). 1 H NMR (DMSO-d 6 ): 1.48 (3H, s), 2.53 (3H, s), 3.58 (1H, d, J = 10.4 Hz), 3.82 (1H, d, J = 10.4 Hz), 6.34 ( 1H, bs), 7.86 (1H, dd, J = 9.0 Hz and 2.2 Hz), 7.91 (1H, d, J = 2.2 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.09 (1H, bs) .

e) (2S)-3-(4-아세틸아미노펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드e) (2S) -3- (4-acetylaminophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

THF(7ml)중의 4-아세트아미도페놀(0.62g, 4.1mmol)의 용액을 THF(6ml)중의 소디움 하이드라이드(미네랄 오일에 현탁시킨 60%, 0.27g, 4.1mmol)의 현탁액에 교 반하면서 적가한다. 적가하는 동안 온도는 5℃이하로 유지한다. 혼합물을 10분간 교반하고, 여기에 THF(7ml)중의 (2R)-3-브로모-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아미이드(0.86g, 2.7mmol)의 용액을 가한다. 혼합물을 실온에서 30분간 교반하고, 60℃에서 5시간 교반한 다음, 실온으로 냉각시킨다. 용매를 증발시키고, 잔류물을 물(80ml)과 초산에틸(80ml)의 혼합물에 용해시키고, pH를 2M HCl로 2-3으로 조절한다. 상을 분리하고, 유기상을 1M 탄산나트륨(30mlx6)으로 세척한 다음, 황산나트륨으로 건조시킨 다음, 증발시킨다. 오일성 잔류물을 초산에틸로 결정화시킨다. 수율 0.27g.A solution of 4-acetamidophenol (0.62 g, 4.1 mmol) in THF (7 ml) was stirred with a suspension of sodium hydride (60% suspended in mineral oil, 0.27 g, 4.1 mmol) in THF (6 ml) Add it down. During the dropping, the temperature is kept below 5 ° C. The mixture was stirred for 10 minutes, to which (2R) -3-bromo-2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide (0.86) in THF (7 ml) was added. g, 2.7 mmol) is added. The mixture is stirred at room temperature for 30 minutes, stirred at 60 ° C. for 5 hours and then cooled to room temperature. The solvent is evaporated and the residue is dissolved in a mixture of water (80 ml) and ethyl acetate (80 ml) and the pH is adjusted to 2-3 with 2M HCl. The phases are separated and the organic phase is washed with 1M sodium carbonate (30mlx6), then dried over sodium sulfate and then evaporated. The oily residue is crystallized with ethyl acetate. Yield 0.27 g.

1H NMR (DMSO-d6): 1.42 (3H, s), 1.99 (3H, s), 2.53 (3H, s), 3.93 (1H, d, J=9.6 Hz), 4.16 (1H, d, J=9.6 Hz), 6.20 (1H, bs), 6.84 (2H, d, J=9.0 Hz), 7.44 (2H, d, J=9.0 Hz), 7.88 (1H, dd, J=9.0Hz and 2.3 Hz), 7.93 (1H, d, J=2.3 Hz), 8.04 (1H, d, J=9.0 Hz), 9.76 (1H, s), 10.15 (1H, bs). 1 H NMR (DMSO-d 6 ): 1.42 (3H, s), 1.99 (3H, s), 2.53 (3H, s), 3.93 (1H, d, J = 9.6 Hz), 4.16 (1H, d, J = 9.6 Hz), 6.20 (1H, bs), 6.84 (2H, d, J = 9.0 Hz), 7.44 (2H, d, J = 9.0 Hz), 7.88 (1H, dd, J = 9.0 Hz and 2.3 Hz) , 7.93 (1H, d, J = 2.3 Hz), 8.04 (1H, d, J = 9.0 Hz), 9.76 (1H, s), 10.15 (1H, bs).

실시예 4.Example 4.

(2S)-3-(4-아세틸아미노-3-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드(2S) -3- (4-acetylamino-3-pululofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

(2S)-3-(4-아세틸아미노-3-풀루오로펜옥시)-2-메틸-N-,(3-메틸-4-니트로페닐)프로피온아마이드는 실시예 3e에 기재된 방법B에 의하여 4-아세틸아미 노-3-풀루오로펜올과 N-[3-메틸-4-(니트로)페닐]-(2R)-3-브로모-2-하이드록시-2-메틸프로피온아마이드로부터 제조된다.(2S) -3- (4-acetylamino-3-pululofenoxy) -2-methyl-N-, (3-methyl-4-nitrophenyl) propionamide was prepared by Method B described in Example 3e. Prepared from 4-acetylamino-3-pululofenol and N- [3-methyl-4- (nitro) phenyl]-(2R) -3-bromo-2-hydroxy-2-methylpropionamide .

1H NMR (DMSO-d6): 1.42(3H, s), 2.02 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J=9.7 Hz), 4.21 (1H, d, J=9.7 Hz), 6.23 (1H, bs), 6.72 (1H, m), 6.90 (1H, m), 7.56 (1H, m), 7.88 (1H, dd, J=9.0 Hz and 2.2 Hz), 7.93 (1H, d, J=2.2 Hz), 8.03 (1H, d, J=9.0 Hz), 9.51 (1H, s), 10.15 (1H, bs). 1 H NMR (DMSO-d 6 ): 1.42 (3H, s), 2.02 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J = 9.7 Hz), 4.21 (1H, d, J = 9.7 Hz), 6.23 (1H, bs), 6.72 (1H, m), 6.90 (1H, m), 7.56 (1H, m), 7.88 (1H, dd, J = 9.0 Hz and 2.2 Hz), 7.93 ( 1H, d, J = 2.2 Hz), 8.03 (1H, d, J = 9.0 Hz), 9.51 (1H, s), 10.15 (1H, bs).

실시예 5Example 5

4-[2-하이드록시-2-(3-메틸-4-니트로페닐카바모일)프로폭시]벤즈아마이드4- [2-hydroxy-2- (3-methyl-4-nitrophenylcarbamoyl) propoxy] benzamide

4-[2-하이드록시-2-(3-메틸-4-니트로페닐카바모일)프로폭시]벤즈아마이드는 실시예 1에 기재된 방법에 의하여 4-하이드록시벤즈아마이드 및 1,2-에폭시-2-메틸-N-(3-메틸-4-니트로페닐)-2-프로피온아마이드로부터 제조된다.4- [2-hydroxy-2- (3-methyl-4-nitrophenylcarbamoyl) propoxy] benzamide was prepared by 4-hydroxybenzamide and 1,2-epoxy-2 by the method described in Example 1. It is prepared from -methyl-N- (3-methyl-4-nitrophenyl) -2-propionamide.

1H NMR (400 MHz, DMSO-d6): 1.45 (3H, s), 2.53 (3H, s), 4.04 (1H, d, J = 9.7 Hz), 4.28 (1H, d, J = 9.7 Hz), 6.26 (1H, s), 6.94-6.98 (2H, m), 7.19 (1 H, br s), 7.80-7.83 (3H, m), 7.89 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.95 (1H, d, J = 2.0 Hz), 8.05 (1H, d, J = 9.0 Hz), 10.19 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.45 (3H, s), 2.53 (3H, s), 4.04 (1H, d, J = 9.7 Hz), 4.28 (1H, d, J = 9.7 Hz) , 6.26 (1H, s), 6.94-6.98 (2H, m), 7.19 (1H, br s), 7.80-7.83 (3H, m), 7.89 (1H, dd, J = 9.0 Hz, J = 2.2 Hz ), 7.95 (1H, d, J = 2.0 Hz), 8.05 (1H, d, J = 9.0 Hz), 10.19 (1H, s).

실시예 6Example 6

3-(3,4-디클로로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드3- (3,4-Dichlorophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide

3-(3,4-디클로로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드는 실시예 1에 기재된 방법으로 3,4-디클로로-페놀과 1,2-에폭시-2-메틸-N-,(3-메틸-4-니트로페닐)-프로피온아마이드로부터 제조된다.3- (3,4-Dichlorophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide was prepared by the method described in Example 1 It is prepared from phenol and 1,2-epoxy-2-methyl-N-, (3-methyl-4-nitrophenyl) -propionamide.

1H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 4.02 (1H, d, J = 9.9 Hz), 4.28 (1H, d, J = 9.9 Hz), 6.27 (1H, s), 6.95 (1H, dd, J = 8,9 Hz, J = 2,8 Hz), 7.25 (1 H, d, J = 2,8 Hz), 7.49 (1 H, d, J = 8,9 Hz), 7.88 (1H, dd, J = 9.0 Hz, J = 2.3 Hz), 7.93 (1H, d, J = 2.0 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.17 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 4.02 (1H, d, J = 9.9 Hz), 4.28 (1H, d, J = 9.9 Hz) , 6.27 (1H, s), 6.95 (1H, dd, J = 8,9 Hz, J = 2,8 Hz), 7.25 (1 H, d, J = 2,8 Hz), 7.49 (1 H, d, J = 8,9 Hz), 7.88 (1H, dd, J = 9.0 Hz, J = 2.3 Hz), 7.93 (1H, d, J = 2.0 Hz) , 8.04 (1 H, d, J = 9.0 Hz), 10.17 (1 H, s).

실시예 7Example 7

4-[2-하이드록시-2-(3-메틸-4-니트로페닐카바모일)벤조산 에틸에스테르4- [2-hydroxy-2- (3-methyl-4-nitrophenylcarbamoyl) benzoic acid ethyl ester

4-[2-하이드록시-2-(3-메틸-4-니트로페닐카바모일)벤조산 에틸에스테르는 실시예 1에 기재된 방법으로 에틸 4-하이드록시-벤조에이트와 1,2-에폭시-2-메틸-N-(3-메틸-4-니트로페닐)-2-프로판아마이드로부터 제조된다.4- [2-hydroxy-2- (3-methyl-4-nitrophenylcarbamoyl) benzoic acid ethyl ester was prepared by the method described in Example 1, with ethyl 4-hydroxy-benzoate and 1,2-epoxy-2-. Prepared from methyl-N- (3-methyl-4-nitrophenyl) -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.30 (3H, t, J = 7.1 Hz), 1.45 (3H, s), 2.53 (3H, s), 4.07 (1H, d, J = 9.7 Hz), 4.26 (2H, q, J = 7.1 Hz), 4.30 (1H, d, J = 9.7 Hz), 6.29 (1H, s), 7.01-7.05 (2H, m), 7.86-7.91 (3H, m), 7.94 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.20 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.30 (3H, t, J = 7.1 Hz), 1.45 (3H, s), 2.53 (3H, s), 4.07 (1H, d, J = 9.7 Hz) , 4.26 (2H, q, J = 7.1 Hz), 4.30 (1H, d, J = 9.7 Hz), 6.29 (1H, s), 7.01-7.05 (2H, m), 7.86-7.91 (3H, m), 7.94 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.20 (1H, s).

실시예 8Example 8

3-(3-클로로-4-풀루오로펜옥시)-2-하이드록시-2-메틸-N-,(3-메틸-4-니트로페닐)프로피온아마이드3- (3-Chloro-4-fulurofenoxy) -2-hydroxy-2-methyl-N-, (3-methyl-4-nitrophenyl) propionamide

3-(3-클로로-4-풀루오로펜옥시)-2-하이드록시-2-메틸-N-,(3-메틸-4-니트로페닐)프로피온아마이드는 실시예 1에 기재된 방법으로 3-클로로-4-풀루오로페놀과 1,2-에폭시-2-메틸-N-(3-메틸-4-니트로페닐)-2-프로판아마이드로부터 제조된다.3- (3-Chloro-4-fulurofenoxy) -2-hydroxy-2-methyl-N-, (3-methyl-4-nitrophenyl) propionamide was prepared by the method described in Example 1. It is prepared from chloro-4-puluourophenol and 1,2-epoxy-2-methyl-N- (3-methyl-4-nitrophenyl) -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.42 (3H, s), 2.53 (3H, s), 4.00 (1H, d, J = 9.8 Hz), 4.25 (1H, d, J = 9.8 Hz), 6.21 (1H, s), 6.89-6.95(1H, m), 7.15-7.19 (1 H, m), 7.26-7.32 (1H, m), 7.87 (1H, dd, J = 8.9 Hz, J = 2.3 Hz), 7.91 (1H, d, J = 1.9 Hz), 8.03 (1H, d, J = 8.9 Hz), 10.12 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.42 (3H, s), 2.53 (3H, s), 4.00 (1H, d, J = 9.8 Hz), 4.25 (1H, d, J = 9.8 Hz) , 6.21 (1H, s), 6.89-6.95 (1H, m), 7.15-7.19 (1 H, m), 7.26-7.32 (1H, m), 7.87 (1H, dd, J = 8.9 Hz, J = 2.3 Hz), 7.91 (1H, d, J = 1.9 Hz), 8.03 (1H, d, J = 8.9 Hz), 10.12 (1H, s).

실시예 9Example 9

2-하이드록시-2-메틸-N--(3-메틸-4-니트로페닐)-3-(4-트리풀루오로메톡시펜옥시)프로피온아마이드2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl) -3- (4-trifluorofluoromethoxyphenoxy) propionamide

2-하이드록시-2-메틸-N--(3-메틸-4-니트로페닐)-3-(4-트리풀루오로메톡시펜옥시)프로피온아마이드는 실시예 1에 기재된 방법으로 4-9트리풀루오로메톡시)페놀과 1,2-에폭시-2-메틸-N-(3-메틸-4-니트로페닐)-2-프로판아마이드루부터 제조된다.2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl) -3- (4-trifluorofluoromethoxyphenoxy) propionamide was prepared by the method described in Example 1 and 4-9 tri It is prepared from pulluroromethoxy) phenol and 1,2-epoxy-2-methyl-N- (3-methyl-4-nitrophenyl) -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.44 (3H, s), 2.53 (3H, s), 4.01 (1H, d, J = 9.7 Hz), 4.24 (1H, d, J = 9.7 Hz), 6.24 (1H, s), 6.99-7.05(2H, m), 7.22-7.30 (2 H, m), 7.88 (1H, dd, J = 8.9 Hz, J = 2.3 Hz), 7.93 (1H, d, J = 1.9 Hz), 8.03 (1H, d, J = 8.9 Hz), 10.14 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.44 (3H, s), 2.53 (3H, s), 4.01 (1H, d, J = 9.7 Hz), 4.24 (1H, d, J = 9.7 Hz) , 6.24 (1H, s), 6.99-7.05 (2H, m), 7.22-7.30 (2H, m), 7.88 (1H, dd, J = 8.9 Hz, J = 2.3 Hz), 7.93 (1H, d, J = 1.9 Hz), 8.03 (1H, d, J = 8.9 Hz), 10.14 (1H, s).

실시예 10Example 10

3-(2,3-디클로로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드3- (2,3-Dichlorophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide

3-(2,3-디클로로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드는 실시예 1에 기재된 방법으로 2,3-디클로로-페놀과 1,2-에폭시-2-메틸-N-(3-메틸-4-니트로페닐)-2-프로판아마이드로부터 제조된다.3- (2,3-Dichlorophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide was prepared by the method described in Example 1 It is prepared from phenol and 1,2-epoxy-2-methyl-N- (3-methyl-4-nitrophenyl) -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.46 (3H, s), 2.53 (3H, s), 4.16 (1H, d, J = 9.8 Hz), 4.27 (1H, d, J = 9.8 Hz), 6.27 (1H, s), 7.16-7.21(2H, m), 7.27-7.33 (1 H, m), 7.87 (1H, dd, J = 8.9 Hz, J = 2.3 Hz), 7.91 (1H, d, J = 1.9 Hz), 8.03 (1H, d, J = 8.9 Hz), 10.14 (1H, s) 1 H NMR (400 MHz, DMSO-d 6 ): 1.46 (3H, s), 2.53 (3H, s), 4.16 (1H, d, J = 9.8 Hz), 4.27 (1H, d, J = 9.8 Hz) , 6.27 (1H, s), 7.16-7.21 (2H, m), 7.27-7.33 (1 H, m), 7.87 (1H, dd, J = 8.9 Hz, J = 2.3 Hz), 7.91 (1H, d, J = 1.9 Hz), 8.03 (1H, d, J = 8.9 Hz), 10.14 (1H, s)

실시예 11Example 11

3-(4-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드3- (4-Pluorofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide

3-(4-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드는 실시예 1에 기재된 방법으로 p-풀루오로페놀과 1,2-에폭시-2-메틸-N-[3-메틸-4-니트로페닐]-2-프로판아마이드루부터 제조된다.3- (4-Pluorofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide was prepared by the method described in Example 1 And 1,2-epoxy-2-methyl-N- [3-methyl-4-nitrophenyl] -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 3.96 (1H, d, J = 9.6 Hz), 4.20 (1H, d, J= 9.6 Hz), 6.21 (1H, s), 6.90-6.96 (2H, m), 7.06-7.12 (2H, m), 7.89 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.90 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.15 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 3.96 (1H, d, J = 9.6 Hz), 4.20 (1H, d, J = 9.6 Hz) , 6.21 (1H, s), 6.90-6.96 (2H, m), 7.06-7.12 (2H, m), 7.89 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.90 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.15 (1H, s).

실시예 12Example 12

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-p-톨릴옥시프로피온아마이드2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3-p-tolyloxypropionamide

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-p-톨릴옥시프로피온아마이드는실시예 1에 기재된 방법으로 p-메틸페놀과 1,2-에폭시-2-메틸-N-[3-메틸-4-니트로페닐]-2-프로판아마이드로부터 제조된다. 2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3-p-tolyloxypropionamide was prepared by the method described in Example 1 with p-methylphenol and 1,2-epoxy-2. It is prepared from -methyl-N- [3-methyl-4-nitrophenyl] -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.21 (3H, s), 2.53 (3H, s), 3.93 (1H, d, J = 9.6 Hz), 4.17 (1H, d, J = 9.5 Hz), 6.18 (1H, s), 8.53 (2H, d, J = 8.5 Hz), 7.06 (2H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 2.2 Hz, J = 9.0 Hz), 7.94 (1H, d, J = 1.8 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.14 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.21 (3H, s), 2.53 (3H, s), 3.93 (1H, d, J = 9.6 Hz), 4.17 (1H, d, J = 9.5 Hz), 6.18 (1H, s), 8.53 (2H, d, J = 8.5 Hz), 7.06 (2H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 2.2 Hz, J = 9.0 Hz), 7.94 (1H, d, J = 1.8 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.14 (1H, s).

실시예 13Example 13

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-[4-(2,2,2-트리풀루오로아세틸아미노)펜옥시]프로피온아마이드2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3- [4- (2,2,2-trifuluroacetylamino) phenoxy] propionamide

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-[4-(2,2,2-트리풀루오로아세틸아미노)펜옥시]프로피온아마이드는 실시예 1에 기재된 방법으로 p-N-트리풀루오로아세트아미도페놀과 1,2-에폭시-2-메틸-N-[3-메틸-4-니트로페닐]2-프로판아마이드로부터 제조된다.2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3- [4- (2,2,2-trifuluroacetylamino) phenoxy] propionamide is described in Example 1 It is prepared from pN-trifluorouroacetamidophenol and 1,2-epoxy-2-methyl-N- [3-methyl-4-nitrophenyl] 2-propaneamide by the method described in.

1H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 3.98 (1H, d, J = 9.6 Hz), 4.22 (1H, d, J = 9.6 Hz), 6.22 (1H, s), 6.93-6.98 (2H, m), 7.52-7.56 (2H, m), 7.88 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.93 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz). 1 H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 3.98 (1H, d, J = 9.6 Hz), 4.22 (1H, d, J = 9.6 Hz) , 6.22 (1H, s), 6.93-6.98 (2H, m), 7.52-7.56 (2H, m), 7.88 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.93 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz).

실시예 14Example 14

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-펜옥시프로피온아마이드2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3-phenoxypropionamide

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-펜옥시프로피온아마이드는 실시예 1에 기재된 방법으로 페놀과 1,2-에폭시-2-메틸-N-[3-메틸-4-니트로페닐]-프로판아마이드로부터 제조된다.2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3-phenoxypropionamide was prepared by the method described in Example 1 with phenol and 1,2-epoxy-2-methyl-N- Prepared from [3-methyl-4-nitrophenyl] -propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.44 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J = 9.6 Hz), 4.21 (1H, d, J = 9.6 Hz), 6.21 (1H, s), 6.90-6.95 (3H, m), 7.24-7.29 (2H, m), 7.89 (1H, dd, J = 2.3 Hz, J = 9.0 Hz), 7.94 (1H, d, J = 2.0 Hz), 8.04 (1H, d, 3 J = 9.0 Hz), 10.16 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.44 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J = 9.6 Hz), 4.21 (1H, d, J = 9.6 Hz) , 6.21 (1H, s), 6.90-6.95 (3H, m), 7.24-7.29 (2H, m), 7.89 (1H, dd, J = 2.3 Hz, J = 9.0 Hz), 7.94 (1H, d, J = 2.0 Hz), 8.04 (1H, d, 3 J = 9.0 Hz), 10.16 (1H, s).

실시예 15Example 15

2-하이드록시-2-메틸-N-(3-미틸-4-니트로페닐)-(3-(트리풀루오로메틸펜옥시) 프로피온아마이드2-hydroxy-2-methyl-N- (3-mityl-4-nitrophenyl)-(3- (trifuluromethylphenoxy) propionamide

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-(3-(트리풀루오로메틸펜옥시)프로피온아마이드는 실시예 1에 기재된 방법으로 p-하이드록시벤조트리풀루오라이드와 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 용출제로 헵탄/초산에틸(95:5)를 사용하여 플래시 크로마토그래피하여 정제한다. 결정화는 톨루엔에서 한다.2-Hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl)-(3- (trifuluromethylphenoxy) propionamide was prepared by the method described in Example 1 Prepared from pullolide and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide The crude product was subjected to flash chromatography using heptane / ethyl acetate (95: 5) as eluent. The crystallization is carried out in toluene.

1H NMR (400 MHz, CDCl3): 1.62 (3H, s), 2.65 (3H, s), 3.25 (1H, s, -OH), 4.05 (1H, d, 2 J gem = 9.1 Hz), 4.51 (1H, d, 2 J gem = 9.0 Hz), 7.00 (2H, d, 3 J = 8.8 Hz), 7.57 (2H, d, 3 J = 8.8 Hz), 7.58 (1H, dd, 3 J = 8.9 Hz, 4 J= 2.7 Hz), 7.66 (1H, d, 4 J = 2.2 Hz), 8.08 (1H, d, 3 J = 8.9 Hz), 8.9 (1H, broad s, -NHCO-). 1 H NMR (400 MHz, CDCl 3 ): 1.62 (3H, s), 2.65 (3H, s), 3.25 (1H, s, -OH), 4.05 (1H, d, 2 J gem = 9.1 Hz), 4.51 (1H, d, 2 J gem = 9.0 Hz), 7.00 (2H, d, 3 J = 8.8 Hz), 7.57 (2H, d, 3 J = 8.8 Hz), 7.58 (1H, dd, 3 J = 8.9 Hz , 4 J = 2.7 Hz), 7.66 (1H, d, 4 J = 2.2 Hz), 8.08 (1H, d, 3 J = 8.9 Hz), 8.9 (1H, broad s, -NHCO-).

실시예 16Example 16

3-(4-아세틸펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드3- (4-acetylphenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(4-아세틸펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드는 실시예 1에 기재된 방법으로 4‘-하이드록시-아세토페논과 2-메틸옥시 란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 용출제로 헵탄/초산에틸(95:5)를 사용하여 플래시 크로마토그래피하여 정제한다. 결정화는 톨루엔에서 한다. m.p. 153-155℃.3- (4-acetylphenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide was prepared by the method described in Example 1 with 4'-hydroxy-acetophenone. Prepared from 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography using heptane / ethyl acetate (95: 5) as eluent. Crystallization is done in toluene. m.p. 153-155 ° C.

1H NMR (400 MHz, CDCl3): 1.62 (3H, s), 2.57 (3H, s), 2.65 (3H, s), 3.26 (1H, s, -OH), 4.07 (1H, d, 2 J gem = 9.1 Hz), 4.53 (1H, d, 2 J gem = 9.1 Hz), 6.96 (2H, d, 3 J = 8.9 Hz), 7.58 (1H, dd, 3 J= 8.9 Hz, 4 J = 2.4 Hz), 7.66 (1H, d, 4 J = 2.3 Hz), 7.94 (2H, d, 3 J = 8.9 Hz), 8.09 (1H, d, 3 J= 9.0 Hz), 8.95 (1H, broad s, -NHCO-). 1 H NMR (400 MHz, CDCl 3 ): 1.62 (3H, s), 2.57 (3H, s), 2.65 (3H, s), 3.26 (1H, s, -OH), 4.07 (1H, d, 2 J gem = 9.1 Hz), 4.53 (1H, d, 2 J gem = 9.1 Hz), 6.96 (2H, d, 3 J = 8.9 Hz), 7.58 (1H, dd, 3 J = 8.9 Hz, 4 J = 2.4 Hz) , 7.66 (1H, d, 4 J = 2.3 Hz), 7.94 (2H, d, 3 J = 8.9 Hz), 8.09 (1H, d, 3 J = 9.0 Hz), 8.95 (1H, broad s, -NHCO- ).

실시예 17Example 17

3-(4-시아노펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드3- (4-cyanophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide

3-(4-시아노펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드는 실시예 1에 기재된 방법으로 4-시이노페놀과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 구배 용출제로 헵탄/초산에틸을 사용하여 플래시 크로마토그래피하여 정제한다. 결정화는 톨루엔에서 한다.3- (4-cyanophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide was prepared by the method described in Example 1 with 2-cyinophenol and 2- Prepared from methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography using heptane / ethyl acetate as the gradient eluent. Crystallization is done in toluene.

1H NMR (400 MHz, DMSO-d 6 ): 1.44 (3H, s), 2.53 (3H, s), 4.08 (1H, d, 2 J gem = 9.8 Hz), 4.33 (1H, d, 2 J gem = 9.9 Hz), about 6.3 (1H, broad s, -OH), 7.10 (2H, d, 3 J = 8.8 Hz), 7.75 (2H, d, 3 J = 8.8 Hz), 7.88 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.3 Hz), 7.93 (1H, d, 4 J = 2.0 Hz), 8.04 (1H, d, 3 J = 9.0 Hz), about 10.2 (1H, broad s, -NHCO-). 1 H NMR (400 MHz, DMSO-d 6 ): 1.44 (3H, s), 2.53 (3H, s), 4.08 (1H, d, 2 J gem = 9.8 Hz), 4.33 (1H, d, 2 J gem = 9.9 Hz), about 6.3 (1H, broad s, -OH), 7.10 (2H, d, 3 J = 8.8 Hz), 7.75 (2H, d, 3 J = 8.8 Hz), 7.88 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.3 Hz), 7.93 (1H, d, 4 J = 2.0 Hz), 8.04 (1H, d, 3 J = 9.0 Hz), about 10.2 (1H, broad s, -NHCO- ).

실시예 18Example 18

3-(3-풀로오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드3- (3-Pluorofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide

3-(3-풀로오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드는 실시예 1에 기재된 방법으로 3-풀루오로페놀과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 구배 용출제로 헵탄/초산에틸을 사용하여 플래시 크로마토그래피하여 정제한다. 결정화는 헵탄/초산에틸에서 한다. m.p. 83-86℃. 3- (3-Pluorofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide was prepared by the method described in Example 1 Prepared from 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography using heptane / ethyl acetate as the gradient eluent. Crystallization is done in heptane / ethyl acetate. m.p. 83-86 ° C.

1H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 3.99 (1H, d, 2 J gem = 9.7 Hz), 4.24 (1H, d, 2 J gem = 9.7 Hz), 6.26 (1H, broad s, -OH), 6.73-7.78 (2H, m), 6.81 (1H, m), 7.28 (1H, m), 7.89 (1H, dd, 3 J = 9.0 Hz, 4 J= 2.3 Hz), 7.94 (1H, d, 4 J = 2.0 Hz), 8.04 (1H, d, 3 J = 8.9 Hz), 10.17 (1H, broad s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.43 (3H, s), 2.53 (3H, s), 3.99 (1H, d, 2 J gem = 9.7 Hz), 4.24 (1H, d, 2 J gem = 9.7 Hz), 6.26 (1H, broad s, -OH), 6.73-7.78 (2H, m), 6.81 (1H, m), 7.28 (1H, m), 7.89 (1H, doublet of doublets, 3 J = 9.0 Hz, 4 J = 2.3 Hz), 7.94 (1H, d, 4 J = 2.0 Hz), 8.04 (1H, d, 3 J = 8.9 Hz), 10.17 (1H, broad s, -NHCO-).

실시예 19Example 19

3-(2-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드3- (2-Pluorofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide

3-(2-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드는 실시예 1에 기재된 방법으로 2-풀루오로페놀과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 용출제로 헵탄/초산에틸(90:10)를 사용하여 플래시 크로마토그래피하여 정제한다. 결정화는 초산에틸/헵탄에서 한다. m.p. 94-96℃. 3- (2-Pluorofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide was prepared by the method described in Example 1 And 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography using heptane / ethyl acetate (90:10) as eluent. Crystallization is in ethyl acetate / heptane. m.p. 94-96 ° C.

1H NMR (400 MHz, DMSO-d 6 ): 1.44 (3H, s), 2.53 (3H, s), 4.07 (1H, d, 2 J gem = 9.8 Hz), 4.27 (1H, d, 2 J gem = 9.8 Hz), 6.27 (1H, broad s, -OH), 6.93 (1H, m), 7.10 (1H, m), 7.14-7.21 (2H, m), 7.88 (1H, dd, 3 J = 9.0 Hz, 4 J= 2.2 Hz), 7.93 (1H, d, 4 J = 2.0 Hz), 8.04 (1H, d, 3 J = 9.0 Hz), 10.17 (1H, broad s, -NHCO-) 1 H NMR (400 MHz, DMSO- d 6 ): 1.44 (3H, s), 2.53 (3H, s), 4.07 (1H, d, 2 J gem = 9.8 Hz), 4.27 (1H, d, 2 J gem = 9.8 Hz), 6.27 (1H, broad s, -OH), 6.93 (1H, m), 7.10 (1H, m), 7.14-7.21 (2H, m), 7.88 (1H, dd, 3 J = 9.0 Hz , 4 J = 2.2 Hz), 7.93 (1H, d, 4 J = 2.0 Hz), 8.04 (1H, d, 3 J = 9.0 Hz), 10.17 (1H, broad s, -NHCO-)

실시예 20Example 20

2-하이드록시-3-[4-(2-하이드록시)펜옥시]-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드2-hydroxy-3- [4- (2-hydroxy) phenoxy] -2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

2-하이드록시-3-[4-(2-하이드록시)펜옥시]-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드는 실시예 1에 기재된 방법으로 4-하이드록시페닐 알코올(1.45 eq.), 소디움 하이드라이드(2.9eq.) 및 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드(1 eq.)를 사용하여 제조된다. 조생성물은 구배 용출제로 헵탄/초산에틸(9:1- 4:6)를 사용하여 플래시 크로마토그래피하여 정제한다.2-hydroxy-3- [4- (2-hydroxy) phenoxy] -2-methyl-N- (3-methyl-4-nitrophenyl) propionamide was prepared in 4-hydroxy by the method described in Example 1. It is prepared using phenyl alcohol (1.45 eq.), Sodium hydride (2.9eq.) And 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide (1 eq.). The crude product is purified by flash chromatography using heptane / ethyl acetate (9: 1- 4: 6) as the gradient eluent.

1H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 2.63 (2H, t, 3 J = 7.1 Hz), 3.53 (2H, m), 3.94 (1H, d, 2 J gem = 9.6 Hz), 4.17 (1H, d, 2 J gem = 9.6 Hz), 4.56 (1H, t, 3 J = 5.2 Hz, CH2OH), 6.17 (1H, broad s, -OH), 6.81 (2H, d, 3 J = 8.7 Hz), 7.09 (2H, d), 7.88 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.3 Hz), 7.93 (1H, d, 4 J = 1.9 Hz), 8.04 (1H, d, 3 J = 9.0 Hz), 10.13 (1H, broad s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.43 (3H, s), 2.53 (3H, s), 2.63 (2H, t, 3 J = 7.1 Hz), 3.53 (2H, m), 3.94 (1H , d, 2 J gem = 9.6 Hz), 4.17 (1H, d, 2 J gem = 9.6 Hz), 4.56 (1H, t, 3 J = 5.2 Hz, CH2O H ), 6.17 (1H, broad s, -OH ), 6.81 (2H, d, 3 J = 8.7 Hz), 7.09 (2H, d), 7.88 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.3 Hz), 7.93 (1H, d, 4 J = 1.9 Hz), 8.04 (1H, d, 3 J = 9.0 Hz), 10.13 (1H, broad s, -NHCO-).

실시예 21Example 21

3-(2,6-디클로로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드3- (2,6-Dichlorophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide

3-(2,6-디클로로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드는 실시예 1에 기재된 방법으로 2,6-디클로로페놀과 1,2-에폭시-2-메틸-N-(3-메틸-4-니트로페닐)-2-프로판아마이드로부터 제조된다.3- (2,6-dichlorophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide was prepared by the method described in Example 1 And 1,2-epoxy-2-methyl-N- (3-methyl-4-nitrophenyl) -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.47 (3H, s), 2.53 (3H, s), 4.12 (1H, d, J = 9.0 Hz), 4.18 (1H, d, J = 9.0 Hz), 6.14 (1H, s), 7.12-7.18 (1H, m), 7.43-7.46 (2 H, m), 7.86-7.90 (2H, m), 8.02-8.05 (1H, m), 10.11 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.47 (3H, s), 2.53 (3H, s), 4.12 (1H, d, J = 9.0 Hz), 4.18 (1H, d, J = 9.0 Hz) , 6.14 (1H, s), 7.12-7.18 (1H, m), 7.43-7.46 (2H, m), 7.86-7.90 (2H, m), 8.02-8.05 (1H, m), 10.11 (1H, s ).

실시예 22Example 22

3-(4-브로모-2-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드3- (4-Bromo-2-fulurofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(4-브로모-2-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드는 실시예 1에 기재된 방법으로 4-브로모-2-풀루오로페놀과 1,2-에폭시-2-메틸-N-(3-메틸-4-니트로페닐)-2-프로판아마이드로부터 제조된다.3- (4-Bromo-2-fulurofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide was prepared by the method described in Example 1. It is prepared from bromo-2-fulurophenol and 1,2-epoxy-2-methyl-N- (3-methyl-4-nitrophenyl) -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 4.08 (1H, d, J = 9.9 Hz), 4.28 (1H, d, J = 9.9 Hz), 6.26 (1H, s), 7.15-7.22 (1H, m), 7.29-7.33 (1 H, m), 7.46-7.50 (1H, m), 7.86 (1H, dd, J = 8.9 Hz, J = 2.3 Hz), 7.88 (1H, d, J = 1.9 Hz), 8.03 (1H, J = 8.9 Hz), 10.13 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 4.08 (1H, d, J = 9.9 Hz), 4.28 (1H, d, J = 9.9 Hz) , 6.26 (1H, s), 7.15-7.22 (1H, m), 7.29-7.33 (1H, m), 7.46-7.50 (1H, m), 7.86 (1H, dd, J = 8.9 Hz, J = 2.3 Hz), 7.88 (1H, d, J = 1.9 Hz), 8.03 (1H, J = 8.9 Hz), 10.13 (1H, s).

실시예 23Example 23

3-(4-클로로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드3- (4-Chlorophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide

3-(4-클로로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드는 실시예 1에 기재된 방법으로 p-클로로페놀과 1,2-에폭시-2-메틸-N-[3-메틸-4-니트로페닐]-2-프로판아마이드로부터 제조된다.3- (4-Chlorophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide was prepared by the method described in Example 1 with p-chlorophenol and 1,2 It is prepared from -epoxy-2-methyl-N- [3-methyl-4-nitrophenyl] -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 3.98 (1H, d, J = 9.7 Hz), 4.22 (1H, d, J = 9.7 Hz), 6.23 (1H, s), 6.93-7.00 (2H, m), 7.28-7.32 (2H, m), 7.88 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.93 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.51 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 3.98 (1H, d, J = 9.7 Hz), 4.22 (1H, d, J = 9.7 Hz) , 6.23 (1H, s), 6.93-7.00 (2H, m), 7.28-7.32 (2H, m), 7.88 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.93 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.51 (1H, s).

실시예 24Example 24

3-(4-브로모펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드3- (4-Bromophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide

3-(4-브로모펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드는 실시예 1에 기재된 방법으로 p-브로모페놀과 1,2-에폭시-2-메틸-N-[3-메틸-4-니트로페닐]-2-프로판아마이드로부터 제조된다.3- (4-Bromophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide was prepared by the method described in Example 1 with p-bromophenol and 1, It is prepared from 2-epoxy-2-methyl-N- [3-methyl-4-nitrophenyl] -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J = 9.7 Hz), 4.21 (1H, d, J= 9.7 Hz), 6.23 (1H, s), 6.88-6.93 (2H, m), 7.39-7.44 (2H, m), 7.88 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.93 (1H, d, J = 1.8 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.15 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J = 9.7 Hz), 4.21 (1H, d, J = 9.7 Hz) , 6.23 (1H, s), 6.88-6.93 (2H, m), 7.39-7.44 (2H, m), 7.88 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.93 (1H, d, J = 1.8 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.15 (1H, s).

실시예 25Example 25

2-하이드록시-3-(4-메톡시펜옥시)-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드2-hydroxy-3- (4-methoxyphenoxy) -2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide

2-하이드록시-3-(4-메톡시펜옥시)-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드는 실시예 1에 기재된 방법으로 p-메톡시페놀과 1,2-에폭시-2-메틸-N-[3-메틸-4-니트로페닐]-2-프로판아마이드로부터 제조된다.2-hydroxy-3- (4-methoxyphenoxy) -2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide was prepared in the same manner as in Example 1 with p-methoxyphenol and 1 , 2-epoxy-2-methyl-N- [3-methyl-4-nitrophenyl] -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.42 (3H, s), 2.53 (3H, s), 3.68 (3H, s), 3.91 (1H, d, J= 9.5 Hz), 4.15 (1H, d, J = 9.5 Hz), 6.17 (1H, s), 6.80-6.87 (4H, m), 7.88 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.93 (1H, d, J = 2.0 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.13 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.42 (3H, s), 2.53 (3H, s), 3.68 (3H, s), 3.91 (1H, d, J = 9.5 Hz), 4.15 (1H, d, J = 9.5 Hz), 6.17 (1H, s), 6.80-6.87 (4H, m), 7.88 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.93 (1H, d, J = 2.0 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.13 (1H, s).

실시예 26Example 26

3-(벤조[1,3]디옥솔-5-일옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드3- (benzo [1,3] dioxol-5-yloxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide

3-(벤조[1,3]디옥솔-5-일옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드는 실시예 1에 기재된 방법으로 3,4-메틸렌디옥시페놀과 1,2-에폭시-2-메틸-N-[3-메틸-4-니트로페닐]-2-프로판아마이드로부터 제조된다.3- (benzo [1,3] dioxol-5-yloxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide was prepared by the method described in Example 1. It is prepared from 3,4-methylenedioxyphenol and 1,2-epoxy-2-methyl-N- [3-methyl-4-nitrophenyl] -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.41 (3H, s), 2.53 (3H, s), 3.90 (1H, d, J = 9.6 Hz), 4.15 (1H, d, J= 9.6 Hz), 5.94 (2H, s), 6.18 (1H, s), 6.35 (1H, dd, J = 8.5 Hz, J = 2.5 Hz), 6.59 (1H, d, J = 2.5 Hz), 6.78 (1H, d, J = 8.5 Hz), 7.88 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.93 (1H, d, J = 1.6 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.13 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.41 (3H, s), 2.53 (3H, s), 3.90 (1H, d, J = 9.6 Hz), 4.15 (1H, d, J = 9.6 Hz) , 5.94 (2H, s), 6.18 (1H, s), 6.35 (1H, dd, J = 8.5 Hz, J = 2.5 Hz), 6.59 (1H, d, J = 2.5 Hz), 6.78 (1H, d, J = 8.5 Hz), 7.88 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.93 (1H, d, J = 1.6 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.13 (1H , s).

실시예 27Example 27

3-(3,4-디메톡시펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드3- (3,4-Dimethoxyphenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide

3-(3,4-디메톡시펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드는 실시예 1에 기재된 방법으로 3,4-디메톡시페놀과 1,2-에폭시-2-메틸-N-[3-메틸-4-니트로페닐]-2-프로판아마이드로부터 제조된다.3- (3,4-dimethoxyphenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide was prepared by the method described in Example 1 It is prepared from oxyphenol and 1,2-epoxy-2-methyl-N- [3-methyl-4-nitrophenyl] -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 3.67 (3H, s), 3.70 (3H, s), 3.91 (1H, d, J = 9.6 Hz), 4.17 (1H, d, J = 9.6 Hz), 6.17 (1H, s), 6.42 (1H, dd, J = 8.8 Hz, J = 2.8 Hz), 6.52 (1H, d, J = 2.8 Hz), 6.82 (1H, d, J = 8.8 Hz), 7.89 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.94 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.13 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 3.67 (3H, s), 3.70 (3H, s), 3.91 (1H, d, J = 9.6 Hz), 4.17 (1H, d, J = 9.6 Hz), 6.17 (1H, s), 6.42 (1H, dd, J = 8.8 Hz, J = 2.8 Hz), 6.52 (1H, d, J = 2.8 Hz) , 6.82 (1H, d, J = 8.8 Hz), 7.89 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.94 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.13 (1H, s).

실시예 28Example 28

3-(3,4-디풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드3- (3,4-Difluurofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide

3-(3,4-디풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프 로피온아마이드는 실시예 1에 기재된 방법으로 3,4-디풀루오로페놀과 1,2-에폭시-2-메틸-N-[3-메틸-4-니트로페닐]-2-프로판아마이드로부터 제조된다.3- (3,4-Difluurofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide was prepared by the method described in Example 1, It is prepared from 4-difluurophenol and 1,2-epoxy-2-methyl-N- [3-methyl-4-nitrophenyl] -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J = 9.8 Hz), 4.23 (1H, d, J = 9.8 Hz), 6.24 (1H, s), 6.72-6.79 (1H, m), 7.02-7.10 (1H, m), 7.20-7.33 (1H, m), 7.88 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.93 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.9 Hz), 10.15 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J = 9.8 Hz), 4.23 (1H, d, J = 9.8 Hz) , 6.24 (1H, s), 6.72-6.79 (1H, m), 7.02-7.10 (1H, m), 7.20-7.33 (1H, m), 7.88 (1H, dd, J = 9.0 Hz, J = 2.2 Hz ), 7.93 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.9 Hz), 10.15 (1H, s).

실시예 29Example 29

3-(2,4-디클로로-3,5-디메틸펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드3- (2,4-dichloro-3,5-dimethylphenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(2,4-디클로로-3,5-디메틸펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드는 실시예 1에 기재된 방법으로 2,4-디클로로-3,5-디메틸페놀과 1,2-에폭시-2-메틸-N-[3-메틸-4-니트로페닐]-2-프로판아마이드로부터 제조된다.3- (2,4-Dichloro-3,5-dimethylphenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide was prepared by the method described in Example 1 It is prepared from, 4-dichloro-3,5-dimethylphenol and 1,2-epoxy-2-methyl-N- [3-methyl-4-nitrophenyl] -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.46 (3H, s), 2.31 (3H, s), 2.36 (3H, s), 2.53 (3H, s), 4.41 (1H, d, J = 9.7 Hz), 4.21 (1H, d, J = 9.7 Hz), 6.25 (1H, s), 7.87 (1H, dd, J = 9.0 Hz, J = 2.3 Hz), 7.91 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.12 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.46 (3H, s), 2.31 (3H, s), 2.36 (3H, s), 2.53 (3H, s), 4.41 (1H, d, J = 9.7 Hz), 4.21 (1H, d, J = 9.7 Hz), 6.25 (1H, s), 7.87 (1H, dd, J = 9.0 Hz, J = 2.3 Hz), 7.91 (1H, d, J = 1.9 Hz) , 8.04 (1H, d, J = 9.0 Hz), 10.12 (1H, s).

실시예 30Example 30

3-(6-브로모나프탈렌-2-일옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드3- (6-bromonaphthalen-2-yloxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(6-브로모나프탈렌-2-일옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드는 실시예 1에 기재된 방법으로 6-브로모-2-나프톨과 1,2-에폭시-2-메틸-N-[3-메틸-4-니트로페닐]-2-프로판아마이드로부터 제조된다.3- (6-Bromonaphthalen-2-yloxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide was prepared in 6-bromo by the method described in Example 1. It is prepared from 2-naphthol and 1,2-epoxy-2-methyl-N- [3-methyl-4-nitrophenyl] -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.49 (3H, s), 2.53 (3H, s), 4.11 (1H, d, J = 9.7 Hz), 4.35 (1H, d, J = 9.7 Hz), 6.29 (1H, s), 7.18 (1H, dd, J = 9.0 Hz, J = 2.5 Hz), 7.41 (1H, d, J = 2.4 Hz), 7.57 (1H, dd, J = 8.7 Hz, J = 2.0 Hz), 7.77 (1H, d, J = 9.1 Hz), 7.80 (1H, d, J = 9.3 Hz), 7.90 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.95 (1H, d, 1.9 Hz), 8.05 (1H, d, J = 9.0 Hz), 8.10 (1H, d, J = 1.9 Hz), 10.21 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.49 (3H, s), 2.53 (3H, s), 4.11 (1H, d, J = 9.7 Hz), 4.35 (1H, d, J = 9.7 Hz) , 6.29 (1H, s), 7.18 (1H, dd, J = 9.0 Hz, J = 2.5 Hz), 7.41 (1H, d, J = 2.4 Hz), 7.57 (1H, dd, J = 8.7 Hz, J = 2.0 Hz), 7.77 (1H, d, J = 9.1 Hz), 7.80 (1H, d, J = 9.3 Hz), 7.90 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.95 (1H, d , 1.9 Hz), 8.05 (1H, d, J = 9.0 Hz), 8.10 (1H, d, J = 1.9 Hz), 10.21 (1H, s).

실시예 31Example 31

3-(4-아세틸아미노-3-트리풀루오로메틸펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드3- (4-acetylamino-3-trifluorofluoromethylphenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

a) 4-아미노-3-트리풀루오로메틸페놀a) 4-amino-3-trifluoromethylphenol

4-니트로-3-트리풀루오로메틸페놀(0.414g, 2.0mmol)을 빙초산 25ml에 용해시킨다. 아연말(2.62g, 40mmol)을 소량씩 10분간에 걸쳐서 가한 다음, 온도를40℃로 가온한다. 혼합물을 10분간 교반한 다음 여과한다. 아연말을 빙초산(10mlx3)으로 세척한 다음 여과한다. 여액을 증발시키고 건조시켜서 4-아미노-3-트리풀루오로메틸페놀 0.212g을 얻는다.4-Nitro-3-tripulouromethylphenol (0.414 g, 2.0 mmol) is dissolved in 25 ml of glacial acetic acid. Zinc powder (2.62 g, 40 mmol) is added in small portions over 10 minutes and then the temperature is warmed to 40 ° C. The mixture is stirred for 10 minutes and then filtered. The zinc powder is washed with glacial acetic acid (10mlx3) and then filtered. The filtrate is evaporated and dried to give 0.212 g of 4-amino-3-tripulofluoromethylphenol.

1H NMR (400 MHz, DMSO-d6): 4.86 (2H, s), 6.72 (1H, d, J = 8.7 Hz), 6.74 (1H, d, J = 2.6 Hz), 6.78 (1H, dd, J = 8.7 Hz, J = 2.7 Hz), 8.91 (1H, s) 1 H NMR (400 MHz, DMSO-d 6 ): 4.86 (2H, s), 6.72 (1H, d, J = 8.7 Hz), 6.74 (1H, d, J = 2.6 Hz), 6.78 (1H, dd, J = 8.7 Hz, J = 2.7 Hz), 8.91 (1H, s)

b) N-(4-하이드록시-2-트리풀루오로메틸페닐)아세트아마이드b) N- (4-hydroxy-2-trifluoromethylphenyl) acetamide

4-아미노-3-트리풀루오로메틸페놀 (0.212g, 1.2mmol)을 질소기류하에서 빙초산 10ml에 용해시킨다. 아세틱 안하이드라이드(0.3ml, 3.0mmol)을 가한 다음, 실온에서 1시간 교반한다. 반응혼합물에 물(0.5ml)를 가하고 증발건고시킨다. 여기에 톨루엔(50ml)을 가하고 증발시켜서 순수한 N-(4-하이드록시-2-트리풀루오로메틸페닐)아세트아마이드를 정량적으로 얻는다.4-amino-3-tripulouromethylphenol (0.212 g, 1.2 mmol) is dissolved in 10 ml of glacial acetic acid under a stream of nitrogen. Acetic anhydride (0.3 ml, 3.0 mmol) is added and then stirred at room temperature for 1 hour. Water (0.5 ml) was added to the reaction mixture and evaporated to dryness. Toluene (50 ml) was added thereto and evaporated to quantitatively obtain pure N- (4-hydroxy-2-trifluoromethylphenyl) acetamide.

1H NMR (400 MHz, DMSO-d6): 1.99 (3H, s), 7.01 (1H, dd, J = 8.6 Hz, J = 2.6 Hz), 7.02 (1H, d, J = 2.5 Hz), 7.19 (1H, d, J = 8.4 Hz), 9.33 (1H, s), 10.08 (1H, br s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.99 (3H, s), 7.01 (1H, dd, J = 8.6 Hz, J = 2.6 Hz), 7.02 (1H, d, J = 2.5 Hz), 7.19 (1H, d, J = 8.4 Hz), 9.33 (1H, s), 10.08 (1H, br s).

c) 3-(4-아세틸아미노-3-트리풀루오로메틸펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드c) 3- (4-acetylamino-3-trifluoromethylphenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(4-아세틸아미노-3-트리풀루오로메틸펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드는 실시예 1에 기재된 방법으로 N-(4-하이드록시-2-트리풀루오로페닐)아세트아마이드와 1,2-에폭시-2-메틸-N-[3-메틸-4-니트로페닐]-2-프로판아마이드로부터 제조된다. 3- (4-Acetylamino-3-trifluorofluoromethylphenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide was prepared by the method described in Example 1. It is prepared from N- (4-hydroxy-2-trifluorofluoro) acetamide and 1,2-epoxy-2-methyl-N- [3-methyl-4-nitrophenyl] -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.46 (3H, s), 2.00 (3H, s), 2.53 (3H, s), 4.07 (1H, d, J = 9.8 Hz), 4.32 (1H, d, J = 9.8 Hz), 6.27 (1H, s), 7.19 (1H, d, J = 2.7 Hz), 7.22 (1H, dd, J = 9.0 Hz, J = 2.5 Hz), 7.31 (1H, d, J = 8.7 Hz), 7.88 (1H, dd, J = 9.0 Hz, J = 2.3 Hz), 7.93 (1H, d, J = 2.0 Hz), 8.04 (1H, d, J = 9.0 Hz), 9.43 (1H, s), 10.17 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.46 (3H, s), 2.00 (3H, s), 2.53 (3H, s), 4.07 (1H, d, J = 9.8 Hz), 4.32 (1H, d, J = 9.8 Hz), 6.27 (1H, s), 7.19 (1H, d, J = 2.7 Hz), 7.22 (1H, dd, J = 9.0 Hz, J = 2.5 Hz), 7.31 (1H, d, J = 8.7 Hz), 7.88 (1H, dd, J = 9.0 Hz, J = 2.3 Hz), 7.93 (1H, d, J = 2.0 Hz), 8.04 (1H, d, J = 9.0 Hz), 9.43 (1H , s), 10.17 (1 H, s).

실시예 32Example 32

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-(3,4,5-트리풀루오로펜옥시)-프로피온아마이드2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3- (3,4,5-trifulurofenoxy) -propionamide

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-(3,4,5-트리풀루오로펜옥시)-프로피온아마이드는 실시예 1에 기재된 방법으로 3,4,5-트리풀루오로페놀과 1,2-에폭시-2-메틸-N-[3-메틸-4-니트로페닐]-2-프로판아마이드로부터 제조된다.2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3- (3,4,5-trifulurofenoxy) -propionamide was prepared by the method described in Example 1 It is prepared from, 4,5-tripulourophenol and 1,2-epoxy-2-methyl-N- [3-methyl-4-nitrophenyl] -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.42 (3H, s), 2.53 (3H, s), 3.98 (1H, d, J = 9.9 Hz), 4.26 (1H, d, J = 9.0 Hz), 6.27 (1H, s), 6.92-7.02 (2H, m), 7.88 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.92 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.14 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.42 (3H, s), 2.53 (3H, s), 3.98 (1H, d, J = 9.9 Hz), 4.26 (1H, d, J = 9.0 Hz) , 6.27 (1H, s), 6.92-7.02 (2H, m), 7.88 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.92 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.14 (1H, s).

실시예 33Example 33

2-하이드록시-3-(1H-인돌-5-일옥시)-2-메틸-N-(3-메텔-4-니트로페닐)-프로피온아마이드2-hydroxy-3- (1H-indol-5-yloxy) -2-methyl-N- (3-methel-4-nitrophenyl) -propionamide

2-하이드록시-3-(1H-인돌-5-일옥시)-2-메틸-N-(3-메텔-4-니트로페닐)-프로피온아마이드는 실시예 1에 기재된 방법으로 4-하이드록시인돌과 1,2-에폭시-2-메틸-N-[3-메틸-4-니트로페닐]-2-프로판아마이드로부터 제조된다.2-hydroxy-3- (1H-indol-5-yloxy) -2-methyl-N- (3-methel-4-nitrophenyl) -propionamide was prepared in 4-hydroxyindole by the method described in Example 1. And 1,2-epoxy-2-methyl-N- [3-methyl-4-nitrophenyl] -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.49 (3H, s), 2.53 (3H, s), 4.10 (1H, d, J = 9.4 Hz), 4.23 (1H, d, J = 9.4 Hz), 6.22 (1H, s), 6.31 (1H, d, J = 2.2 Hz), 6.47 (1H, dd, J = 6.8 Hz, J = 1.5 Hz), 6.93-7.00 (2H, m), 7.12-7.17 (1H, m), 7.92 (1H, dd, J = 9.0 Hz, J = 2.1 Hz), 7.98 (1H, d, J = 1.6 Hz), 8.05 (1H, d, J = 9.0 Hz), 10.24 (1H, s), 11.02 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.49 (3H, s), 2.53 (3H, s), 4.10 (1H, d, J = 9.4 Hz), 4.23 (1H, d, J = 9.4 Hz) , 6.22 (1H, s), 6.31 (1H, d, J = 2.2 Hz), 6.47 (1H, dd, J = 6.8 Hz, J = 1.5 Hz), 6.93-7.00 (2H, m), 7.12-7.17 ( 1H, m), 7.92 (1H, dd, J = 9.0 Hz, J = 2.1 Hz), 7.98 (1H, d, J = 1.6 Hz), 8.05 (1H, d, J = 9.0 Hz), 10.24 (1H, s), 11.02 (1 H, s).

실시예 34Example 34

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-(4-메틸설파닐-펜옥시)프로피온아마이드2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3- (4-methylsulfanyl-phenoxy) propionamide

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-(4-메틸설파닐-펜옥시)프로피온아마이드는 실시예 1에 기재된 방법으로 4-(메틸티오)페놀과 1,2-에폭시-2-메틸-N-[3-메틸-4-니트로페닐]-2-프로판아마이드로부터 제조된다. 2-Hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3- (4-methylsulfanyl-phenoxy) propionamide was prepared by the method described in Example 1 (4- (methylthio) It is prepared from phenol and 1,2-epoxy-2-methyl-N- [3-methyl-4-nitrophenyl] -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.41 (3H, s), 2.53 (3H, s), 3.96 (1H, d, J = 9.6 Hz), 4.20 (1H, d, J = 9.6 Hz), 6.21 (1H, s), 6.87-6.93 (2H, m), 7.17-7.25 (2H, m), 7.88 (1H, dd, J = 9.0 Hz, J = 2.3 Hz), 7.93 (1H, d, J = 2.0 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.15 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.41 (3H, s), 2.53 (3H, s), 3.96 (1H, d, J = 9.6 Hz), 4.20 (1H, d, J = 9.6 Hz), 6.21 (1H, s), 6.87-6.93 (2H, m), 7.17-7.25 (2H, m), 7.88 (1H, dd, J = 9.0 Hz, J = 2.3 Hz), 7.93 (1H, d, J = 2.0 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.15 (1H, s).

실시예 35Example 35

3-(3-풀루오로-4-니트로-펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드3- (3-Pluoro-4-nitro-phenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(3-풀루오로-4-니트로-펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드는 실시예 1에 기재된 방법으로 3-풀루오로-4-니트로페놀과 2-메틸-옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다.3- (3-Pluoro-4-nitro-phenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide was prepared by the method described in Example 1. It is prepared from pullouro-4-nitrophenol and 2-methyl-oxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide.

1H NMR (DMSO-d6): 1.46 (3H, s), 2.53 (3H, s), 4.16 (1H, d, J=10.1 Hz), 4.41 (1H, d, J=10.1 Hz), 6.36 (1H, bs), 6.96 (1H, m), 7.22 (1H, m), 7.88 (1H, dd, J=9.0 Hz and 2.1 Hz), 7.90 (1H, d, J=2.1 Hz), 8.04 (1H, d, J=9.0 Hz), 8.24 (1H, m), 10.19 (1H, s). 1 H NMR (DMSO-d 6 ): 1.46 (3H, s), 2.53 (3H, s), 4.16 (1H, d, J = 10.1 Hz), 4.41 (1H, d, J = 10.1 Hz), 6.36 ( 1H, bs), 6.96 (1H, m), 7.22 (1H, m), 7.88 (1H, dd, J = 9.0 Hz and 2.1 Hz), 7.90 (1H, d, J = 2.1 Hz), 8.04 (1H, d, J = 9.0 Hz), 8.24 (1H, m), 10.19 (1H, s).

실시예 36Example 36

3-[4-(4-클로로벤조일)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드3- [4- (4-chlorobenzoyl) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-[4-(4-클로로벤조일)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드는 실시예 1에 기재된 방법으로 4-클로로-4‘-하이드록시벤조페논과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조 생성물은 구배 용출제로 헵탄/초산에틸을 사용하는 플래시 크로마토그래피하여 정제한다. 결정화는 이소프로판올로 행한다.3- [4- (4-chlorobenzoyl) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide was prepared by the method described in Example 1 and 4-chloro- It is prepared from 4'-hydroxybenzophenone and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography using heptane / ethyl acetate as the gradient eluent. Crystallization is performed with isopropanol.

1H NMR (400 MHz, DMSO-d 6 ): 1.46 (3H, s), 2.53 (3H, s), 4.11 (1H, d, 2 J gem = 9.7 Hz), 4.33 (1H, d, 2 J gem = 9.7 Hz), about 6.3 (1H, broad s, -OH), 7.09 (2H, d, 3 J = 8.8 Hz), 7.62 (2H, d, 3 J = 8.5 Hz), 7.70 (2H, d, 3 J = 8.6 Hz), 7.72 (2H, d, 3 J= 9.0 Hz), 7.89 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.3 Hz), 7.94 (1H, d, 4 J = 2.2 Hz), 8.05 (1H, d, 3 J = 9.0 Hz), about 10.2 (1H, broad s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.46 (3H, s), 2.53 (3H, s), 4.11 (1H, d, 2 J gem = 9.7 Hz), 4.33 (1H, d, 2 J gem = 9.7 Hz), about 6.3 (1H, broad s, -OH), 7.09 (2H, d, 3 J = 8.8 Hz), 7.62 (2H, d, 3 J = 8.5 Hz), 7.70 (2H, d, 3 J = 8.6 Hz), 7.72 (2H, d, 3 J = 9.0 Hz), 7.89 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.3 Hz ), 7.94 (1 H, d, 4 J = 2.2 Hz), 8.05 (1H, d, 3 J = 9.0 Hz), about 10.2 (1H, broad s, -NHCO-).

실시예 37Example 37

3-(3-클로로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드3- (3-chlorophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(3-클로로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드는 실시예 1에 기재된 방법으로 3-클로로페놀과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조 생성물은 구배 용출제로 헵탄/초산에틸(10:90-40:90)을 사용하는 플래시 크로마토그래피하여 정제한다. 결정화는 톨루엔으로 행한다. m.p. 104-107℃.3- (3-Chlorophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide was prepared by 3-chlorophenol and 2-methyloxy by the method described in Example 1. Prepared from lan-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography using heptane / ethyl acetate (10: 90-40: 90) as gradient eluent. Crystallization is performed with toluene. m.p. 104-107 ° C.

1H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 4.00 (1H, d, 2 J gem = 9.8 Hz), 4.26 (1H, d, 2 J gem = 9.8 Hz), 6.25 (1H, broad s, -OH), 6.88-6.91 (1H, m), 6.97-7.00 (1H, m), 7.02 (1H, t, 4 J = 2.1 Hz), 7.28 (1H, t, 3 J = 8.2 Hz), 7.89 (1H, dd, 3 J= 9.0 Hz, 4 J = 2.3 Hz), 7.94 (1H, d, 4 J = 2.2 Hz), 8.04 (1H, d, 3 J = 9.0 Hz), 10.17 (1H, broad s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.43 (3H, s), 2.53 (3H, s), 4.00 (1H, d, 2 J gem = 9.8 Hz), 4.26 (1H, d, 2 J gem = 9.8 Hz), 6.25 (1H, broad s, -OH), 6.88-6.91 (1H, m), 6.97-7.00 (1H, m), 7.02 (1H, t, 4 J = 2.1 Hz), 7.28 (1H, t, 3 J = 8.2 Hz), 7.89 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.3 Hz), 7.94 (1H, d, 4 J = 2.2 Hz), 8.04 (1H, d, 3 J = 9.0 Hz), 10.17 (1H, broad s, -NHCO-) .

실시예 38Example 38

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-펜타풀루오로페닐옥시프로피온아마이드2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3-pentafluorofluorooxyoxypropionamide

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-펜타풀루오로페닐옥시프로피온아마이드는 실시예 1에 기재된 방법으로 펜타풀루오로페놀과 1,2-에폭시-2-메틸-N-[3-메틸-4-니트로페닐]-2-프로판아마이드로부터 제조된다. 2-Hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3-pentafulurophenyloxypropionamide was prepared by the method described in Example 1 with pentafulurophenol and 1,2- It is prepared from epoxy-2-methyl-N- [3-methyl-4-nitrophenyl] -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.40 (3H, s), 2.53 (3H, s), 4.24 (1H, d, J = 10,2 Hz), 4.44 (1H, d, J = 10,2 Hz), 6.28 (1H, s), 7.87 (1H, dd, J = 9.0 Hz, J = 2.1 Hz), 7.89 (1H, d, J = 2.1 Hz), 8.05 (1H, d, J = 8.9 Hz), 10.13 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.40 (3H, s), 2.53 (3H, s), 4.24 (1H, d, J = 10,2 Hz), 4.44 (1H, d, J = 10 , 2 Hz), 6.28 (1H, s), 7.87 (1H, dd, J = 9.0 Hz, J = 2.1 Hz), 7.89 (1H, d, J = 2.1 Hz), 8.05 (1H, d, J = 8.9 Hz), 10.13 (1H, s).

실시예 39Example 39

(2S)-3-(4-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드(2S) -3- (4-Pluorofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide

(2S)-3-(4-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-프로피온아마이드는 실시예 3에 기재된 방법으로 p-풀루오로페놀과 (2S)--3-브로모-2-하이드록시-2-메틸프로피온산으로부터 제조된다.(2S) -3- (4-Pluurofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -propionamide was prepared by the method described in Example 3 It is prepared from pullourophenol and (2S) -3-bromo-2-hydroxy-2-methylpropionic acid.

1H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 3.95 (1H, d, J = 9.6 Hz), 4.20 (1H, d, J = 9.6 Hz), 6.21 (1H, s), 6.90-6.97 (2H, m), 7.06-7.12 (2H, m), 7.88 (1H, dd, J = 9.0 Hz, J = 2.3 Hz), 7.93 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.15 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 3.95 (1H, d, J = 9.6 Hz), 4.20 (1H, d, J = 9.6 Hz) , 6.21 (1H, s), 6.90-6.97 (2H, m), 7.06-7.12 (2H, m), 7.88 (1H, dd, J = 9.0 Hz, J = 2.3 Hz), 7.93 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.15 (1H, s).

실시예 40Example 40

N-(4-시아노-3-메틸페닐)-3-(4-풀루오로펜옥시)-2-하이드록시-2-메틸-프로피온아마이드N- (4-cyano-3-methylphenyl) -3- (4-fulurofenoxy) -2-hydroxy-2-methyl-propionamide

a) 4-아미노-2-메틸벤조니트릴a) 4-amino-2-methylbenzonitrile

3-메틸-4-니트로벤조니트릴(1.0g, 6mmol)을 아세트산(15ml)에 용해시킨다. 물(3.75ml)을 가한 후, 혼합물을 90-95℃로 가열한다. 철 분말(2.5g)을 1.5시간에 걸쳐서 가한 다음, 결과로 얻어진 혼합물을 1시간동안 가열한다. 물(3.75ml)의 다른 부분을 가하고, 가열을 다시 2시간동안 계속한다. 용액을 실온으로 냉각시키고, 혼합물을 물(100ml)로 희석시킨다. 초산에틸(40mlx4)로 추출한다. 유기상을 합하고, 5% 탄산수소나트륨(50mlx1), 물(50mlx1)로 차례로 세척한다음, 황산나트륨으로 건조시킨 다음 증발시킨다. 조생성물은 더 정제하지 않고 사용된다.3-methyl-4-nitrobenzonitrile (1.0 g, 6 mmol) is dissolved in acetic acid (15 ml). After addition of water (3.75 ml), the mixture is heated to 90-95 ° C. Iron powder (2.5 g) is added over 1.5 hours, then the resulting mixture is heated for 1 hour. Add another portion of water (3.75 ml) and continue heating again for 2 hours. The solution is cooled to room temperature and the mixture is diluted with water (100 ml). Extract with ethyl acetate (40mlx4). The organic phases are combined, washed successively with 5% sodium hydrogen carbonate (50 ml × 1), water (50 ml × 1), dried over sodium sulphate and evaporated. The crude product is used without further purification.

1H NMR (DMSO-d6): 2.28 (3H, s), 6.04 (2H, bs), 6.44 (1H, m), 6.48 (1H, m), 7.31 (1H, m). 1 H NMR (DMSO-d 6 ): 2.28 (3H, s), 6.04 (2H, bs), 6.44 (1H, m), 6.48 (1H, m), 7.31 (1H, m).

b) N-(4-시아노-3-메틸페닐)-2-메틸아크릴아마이드b) N- (4-cyano-3-methylphenyl) -2-methylacrylamide

N-(4-시아노-3-메틸페닐)-2-메틸아크릴아마이드는 실시예 1에 기재된 방법으로 4-아미노-2-메틸벤조니트릴과 메타클로일클로라이드로부터 제조된다.N- (4-cyano-3-methylphenyl) -2-methylacrylamide is prepared from 4-amino-2-methylbenzonitrile and methacloylchloride by the method described in Example 1.

1H NMR (DMSO-d6): 1.96 (3H, s), 2.45 (3H, s), 5.60 (1H, m), 5.85 (1H, m), 7.70 (2H, m), 7.81 (1H, m), 10.12 (1H, s). 1 H NMR (DMSO-d 6 ): 1.96 (3H, s), 2.45 (3H, s), 5.60 (1H, m), 5.85 (1H, m), 7.70 (2H, m), 7.81 (1H, m ), 10.12 (1 H, s).

c) 메틸옥시란-2-카르복실산(4-시아노-3-메틸페닐)아마이드c) methyloxirane-2-carboxylic acid (4-cyano-3-methylphenyl) amide

메틸옥시란-2-카르복실산(4-시아노-3-메틸페닐)아마이드는 실시예 1에 기재된 방법으로 N-(4-시아노-3-메틸페닐)-2-메틸아크릴아마이드로부터 제조된다.Methyloxirane-2-carboxylic acid (4-cyano-3-methylphenyl) amide is prepared from N- (4-cyano-3-methylphenyl) -2-methylacrylamide by the method described in Example 1.

1H NMR (DMSO-d6): 1.54 (3H, s), 2.43 (3H, s), 2.99 (1H, d, J=5.1 Hz), 3.04 (1H, d, J=5.1 Hz), 7.70 (2H, m), 7.89 (1H, m), 9.77 (1H, s). 1 H NMR (DMSO-d 6 ): 1.54 (3H, s), 2.43 (3H, s), 2.99 (1H, d, J = 5.1 Hz), 3.04 (1H, d, J = 5.1 Hz), 7.70 ( 2H, m), 7.89 (1H, m), 9.77 (1H, s).

d) N-(4-시아노-3-메틸페닐)-3-(4-풀루오로펜옥시)-2-메틸-프로피온아마이드d) N- (4-cyano-3-methylphenyl) -3- (4-fulurofenoxy) -2-methyl-propionamide

N-(4-시아노-3-메틸페닐)-3-(4-풀루오로펜옥시)-2-메틸-프로피온아마이드는 실시예 1에 기재된 방법으로 4-풀루오로페놀과 메틸옥시란-2-카르복실산(4-시아노-3-메틸페닐)아마이드로부터 제조된다. N- (4-cyano-3-methylphenyl) -3- (4-pululofenoxy) -2-methyl-propionamide was prepared by the method described in Example 1, 4-fluorofluorophenol and methyloxirane- Prepared from 2-carboxylic acid (4-cyano-3-methylphenyl) amide.

1H NMR (DMSO-d6): 1.42 (3H, s), 2.44 (3H, s), 3.94 (1H, d, J=9.6 Hz), 4.18 (1H, d, J=9.6 Hz), 6.18 (1H, bs), 6.93 (2H, m), 7.08 (2H, m), 7.69 (1H, d, J=9.0 Hz), 7.78 (1H, dd, J=9.0 Hz and 2.1 Hz), 7.93 (1H, d, J=2.1 Hz), 10.02 (1H, s). 1 H NMR (DMSO-d 6 ): 1.42 (3H, s), 2.44 (3H, s), 3.94 (1H, d, J = 9.6 Hz), 4.18 (1H, d, J = 9.6 Hz), 6.18 ( 1H, bs), 6.93 (2H, m), 7.08 (2H, m), 7.69 (1H, d, J = 9.0 Hz), 7.78 (1H, dd, J = 9.0 Hz and 2.1 Hz), 7.93 (1H, d, J = 2.1 Hz), 10.02 (1H, s).

실시예 41Example 41

3-(4-아세틸아미노-3-푸루오로펜옥시)-N-(4-시아노-3-메틸페닐)-2-하이드록시-2-메틸프로피온아마이드3- (4-acetylamino-3-furoufenoxy) -N- (4-cyano-3-methylphenyl) -2-hydroxy-2-methylpropionamide

3-(4-아세틸아미노-3-푸루오로펜옥시)-N-(4-시아노-3-메틸페닐)-2-하이드록시-2-메틸프로피온아마이드는 실시예 1에 기재된 방법으로 N-(2-풀루오로-4-하이드록시페닐)아세트아마이드와 2-메틸옥시란-2-카르복실산(4-시아노-3-메틸페닐)아마이드로부터 제조된다.3- (4-acetylamino-3-furoufenoxy) -N- (4-cyano-3-methylphenyl) -2-hydroxy-2-methylpropionamide was prepared by the method described in Example 1 (2-Pluoro-4-hydroxyphenyl) acetamide and 2-methyloxirane-2-carboxylic acid (4-cyano-3-methylphenyl) amide.

1H NMR (DMSO-d6): 1.41 (3H, s), 2.02 (3H, s), 2.44 (3H, s), 3.95 (1H, d, J=9.8 Hz), 4.26 (1H, d, J=9.8 Hz), 6.21 (1H, bs), 6.72 (1H, m), 6.86 (1H, m), 7.56 (1H, m), 7.69 (1H, d, J=9.0 Hz), 7.78 (1H, dd, J=9.0 Hz and 2.2 Hz), 7.93 (1H, d, J=2.2 Hz), 9.51 (1H, s), 9.99 (1H, bs). 1 H NMR (DMSO-d 6 ): 1.41 (3H, s), 2.02 (3H, s), 2.44 (3H, s), 3.95 (1H, d, J = 9.8 Hz), 4.26 (1H, d, J = 9.8 Hz), 6.21 (1H, bs), 6.72 (1H, m), 6.86 (1H, m), 7.56 (1H, m), 7.69 (1H, d, J = 9.0 Hz), 7.78 (1H, dd , J = 9.0 Hz and 2.2 Hz), 7.93 (1H, d, J = 2.2 Hz), 9.51 (1H, s), 9.99 (1H, bs).

실시예 42Example 42

3-(4-시아노-3-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드3- (4-cyano-3-pululofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(4-시아노-3-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드는 실시예 1에 기재된 방법으로 2-풀루오로-4-하이드록시벤조니트릴과 2-메틸-옥시란-2-카르복실산(4-시아노-3-메틸페닐)아마이드로부터 제조된다. 3- (4-cyano-3-fulurofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide was prepared by the method described in Example 1. It is prepared from pullouro-4-hydroxybenzonitrile and 2-methyl-oxirane-2-carboxylic acid (4-cyano-3-methylphenyl) amide.

1H NMR (DMSO-d6): 1.46 (3H, s), 2.53 (3H, s), 4.11 (1H, d, J=10.1 Hz), 4.371 (1H, d, J=10.1 Hz), 6.33 (1H, bs), 6.96 (1H, m), 7.18 (1H, m), 7.80 (1H, m), 7.88 (1H, dd, J=9.0 Hz and 2.1 Hz), 7.91 (1H, d, J=2.1 Hz), 8.03 (1H, d, J=9.0 Hz), 10.21 (1H, s). 1 H NMR (DMSO-d 6 ): 1.46 (3H, s), 2.53 (3H, s), 4.11 (1H, d, J = 10.1 Hz), 4.371 (1H, d, J = 10.1 Hz), 6.33 ( 1H, bs), 6.96 (1H, m), 7.18 (1H, m), 7.80 (1H, m), 7.88 (1H, dd, J = 9.0 Hz and 2.1 Hz), 7.91 (1H, d, J = 2.1 Hz), 8.03 (1H, d, J = 9.0 Hz), 10.21 (1H, s).

실시예 43Example 43

(2S)--3-(4-시아노-3-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드(2S)-3- (4-cyano-3-pululofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

(2S)--3-(4-시아노-3-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드는 실시예 3에 기재된 방법으로 2-풀루오로-4-하이드록시벤조니트릴과 (2R)-3-브로모-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드로부터 다음의 공정으로 제조된다. 2-풀루오로-4-하이드록시벤조니트릴(0.2g, 1.4mmol)과 (2R)-3-브로모-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드(0.37g, 1.2mmol), 탄산칼륨(0.34g, 2.5mmol) 및 벤질트리에틸암모니움 클로라이드(0.028g, 0.1mmol)을 메틸에틸케톤(40ml)에 넣고, 5시간 환류시킨다. 혼합물을 실온으로 냉각시킨 다음, 증발시킨다. 잔류물을 초산에틸(50ml)와 물(50ml)에 분배시킨다. 유기상을 1M 탄산나트륨(20mlx4) 및 물(20mlx1)로 차례로 세척한 다음, 황산나트륨으로 건조시키고, 증발시킨다. 조 생성물은 플래시 크로마 토그래피(용출제 : 디클로로메탄)로 정제한다.(2S)-3- (4-cyano-3-pululofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide is described in Example 3. From 2-Pluoro-4-hydroxybenzonitrile and (2R) -3-bromo-2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide by the described method It is manufactured by the process of. 2-Pluoro-4-hydroxybenzonitrile (0.2 g, 1.4 mmol) and (2R) -3-bromo-2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) Propionamide (0.37 g, 1.2 mmol), potassium carbonate (0.34 g, 2.5 mmol) and benzyltriethylammonium chloride (0.028 g, 0.1 mmol) are added to methyl ethyl ketone (40 ml) and refluxed for 5 hours. The mixture is cooled to room temperature and then evaporated. The residue is partitioned between ethyl acetate (50 ml) and water (50 ml). The organic phase is washed sequentially with 1M sodium carbonate (20mlx4) and water (20mlx1), then dried over sodium sulfate and evaporated. The crude product is purified by flash chromatography (eluent: dichloromethane).

1H NMR (DMSO-d6): 1.46 (3H, s), 2.53 (3H, s), 4.11 (1H, d, J=10.1 Hz), 4.371 (1H, d, J=10.1 Hz), 6.33 (1H, bs), 6.96 (1H, m), 7.18 (1H, m), 7.80 (1H, m), 7.88 (1H, dd, J=9.0 Hz and 2.1 Hz), 7.91 (1H, d, J=2.1 Hz), 8.03 (1H, d, J=9.0 Hz), 10.21 (1H, s). 1 H NMR (DMSO-d 6 ): 1.46 (3H, s), 2.53 (3H, s), 4.11 (1H, d, J = 10.1 Hz), 4.371 (1H, d, J = 10.1 Hz), 6.33 ( 1H, bs), 6.96 (1H, m), 7.18 (1H, m), 7.80 (1H, m), 7.88 (1H, dd, J = 9.0 Hz and 2.1 Hz), 7.91 (1H, d, J = 2.1 Hz), 8.03 (1H, d, J = 9.0 Hz), 10.21 (1H, s).

실시예 44Example 44

3-(4-클로로-3-니트로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드3- (4-chloro-3-nitrophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(4-클로로-3-니트로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드는 실시예 1에 기재된 방법으로 4-클로로-3-니트로페놀과 2-메틸-옥시란-2-카르복실산(4-시아노-3-메틸페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-0.2% 메탄올)로 정제한다.3- (4-Chloro-3-nitrophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide was prepared in 4-chloro-3 by the method described in Example 1. Nitrophenol and 2-methyl-oxirane-2-carboxylic acid (4-cyano-3-methylphenyl) amide. The crude product is purified by flash chromatography (eluent: dichloromethane-0.2% methanol).

1H NMR (400 MHz, DMSO-d6): 1.45 (3H, s), 2.53 (3H, s), 4.10 (1H, d, J=9.9 Hz), 4.36 (1H, d, J= 9.9 Hz), 6.28 (1H, s), 7.28 (1H, dd, J=9.0 Hz, J=3.0 Hz), 7.62 (1H, d, J=9.0 Hz), 7.68 (1H, d, J=3.0 Hz), 7.88 (1H, dd, J=9.0 Hz, J=2.3 Hz), 7.92 (1H, d, J=2.0 Hz), 8.03 (1H, d, J=9.0 Hz), 10.15 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.45 (3H, s), 2.53 (3H, s), 4.10 (1H, d, J = 9.9 Hz), 4.36 (1H, d, J = 9.9 Hz) , 6.28 (1H, s), 7.28 (1H, doublet of doublets, J = 9.0 Hz, J = 3.0 Hz), 7.62 (1H, d, J = 9.0 Hz), 7.68 (1H, d, J = 3.0 Hz), 7.88 (1H, doublet of doublets, J = 9.0 Hz, J = 2.3 Hz), 7.92 (1H, d, J = 2.0 Hz), 8.03 (1H, d, J = 9.0 Hz), 10.15 (1H, s).

실시예 45Example 45

3-(4-풀루오로-3-트리풀루오로메틸펜옥시)-2-하이드록시-3-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드3- (4-Pluoro-3-trifuluromethylphenoxy) -2-hydroxy-3-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(4-풀루오로-3-트리풀루오로메틸펜옥시)-2-하이드록시-3-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드는 실시예 1에 기재된 방법으로 4-풀루오로-3-트리풀루오로메틸페놀과 2-메틸-옥시란-2-카르복실산(4-시아노-3-메틸페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-1% 메탄올)로 정제한다.3- (4-Pluoro-3-trifuluromethylphenoxy) -2-hydroxy-3-methyl-N- (3-methyl-4-nitrophenyl) propionamide is the method described in Example 1. To 4-pulluoro-3-tripulouromethylphenol and 2-methyl-oxirane-2-carboxylic acid (4-cyano-3-methylphenyl) amide. The crude product is purified by flash chromatography (eluant: dichloromethane-1% methanol).

1H NMR (400 MHz, DMSO-d6): 1.44 (3H, s), 2.53 (3H, s), 4.06 (1H, d, J=9.9 Hz), 4.32 (1H, d, J= 9.9 Hz), 6.23 (1H, s), 7.24-7.31 (2H, m), 7.38-7.43 (1H, m), 7.87 (1H, dd, J=9.0 Hz, J=2.1 Hz), 7.91 (1H, d, J=2.0 Hz), 8.03 (1H, d, J=9.0 Hz), 10.14 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.44 (3H, s), 2.53 (3H, s), 4.06 (1H, d, J = 9.9 Hz), 4.32 (1H, d, J = 9.9 Hz) , 6.23 (1H, s), 7.24-7.31 (2H, m), 7.38-7.43 (1H, m), 7.87 (1H, dd, J = 9.0 Hz, J = 2.1 Hz), 7.91 (1H, d, J = 2.0 Hz), 8.03 (1H, d, J = 9.0 Hz), 10.14 (1H, s).

실시예 46Example 46

2-하이드록시-3-[4-(2-메톡시에틸)펜옥시]-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드2-hydroxy-3- [4- (2-methoxyethyl) phenoxy] -2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

2-하이드록시-3-[4-(2-메톡시에틸)펜옥시]-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드는 실시예 1에 기재된 방법으로 4-메톡시에틸페놀과 2-메틸-옥시란-2-카르복실산(4-시아노-3-메틸페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-1% 메탄올)로 정제한다.2-hydroxy-3- [4- (2-methoxyethyl) phenoxy] -2-methyl-N- (3-methyl-4-nitrophenyl) propionamide was prepared by the method described in Example 1 It is prepared from oxyethylphenol and 2-methyl-oxirane-2-carboxylic acid (4-cyano-3-methylphenyl) amide. The crude product is purified by flash chromatography (eluant: dichloromethane-1% methanol).

1H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 2.71 (2H, t, J=6.8 Hz), 3.21 (3H, s), 3.45 (2H, t, J=6.8 Hz), 3.94 (1H, d, J=9.5 Hz), 4.17 (1H, d, J= 9.5 Hz), 6.20 (1H, s), 6.82 (2H, d, J=7.8 Hz), 7.10 (2H, d, J=8.0 Hz), 7.89 (1H, d, J=9.0 Hz), 7.94 (1H, s), 8.03 (1H, d, J=8.8 Hz), 10.16 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 2.71 (2H, t, J = 6.8 Hz), 3.21 (3H, s), 3.45 (2H, t, J = 6.8 Hz), 3.94 (1H, d, J = 9.5 Hz), 4.17 (1H, d, J = 9.5 Hz), 6.20 (1H, s), 6.82 (2H, d, J = 7.8 Hz) , 7.10 (2H, d, J = 8.0 Hz), 7.89 (1H, d, J = 9.0 Hz), 7.94 (1H, s), 8.03 (1H, d, J = 8.8 Hz), 10.16 (1H, s) .

실시예 47Example 47

3-(4-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(2-메틸-3-니트로페닐)프로피온아마이드3- (4-Pluorofenoxy) -2-hydroxy-2-methyl-N- (2-methyl-3-nitrophenyl) propionamide

a) 2-메틸-N-(2-메틸-3-니트로페닐)아크릴아마이드a) 2-methyl-N- (2-methyl-3-nitrophenyl) acrylamide

2-메틸-N-(2-메틸-3-니트로페닐)아크릴아마이드는 실시예 1a에 기재된 방법으로 2-메틸-3-니트로아닐린과 메타클로일 클로라이드로부터 제조된다2-methyl-N- (2-methyl-3-nitrophenyl) acrylamide is prepared from 2-methyl-3-nitroaniline and methacloyl chloride by the method described in Example 1a.

1H NMR (400 MHz, DMSO-d6):1.97 (3H, s), 2.23 (3H, s), 5.56 (1H, s), 5.90 (1H, s), 7.40-7.46 (1H, m), 7.57-7.60 (1H, m), 7.74-7.77 (1H, m), 9.71 (1H, s).. 1 H NMR (400 MHz, DMSO-d 6 ): 1.97 (3H, s), 2.23 (3H, s), 5.56 (1H, s), 5.90 (1H, s), 7.40-7.46 (1H, m), 7.57-7.60 (1 H, m), 7.74-7.77 (1 H, m), 9.71 (1 H, s) ..

b) 2-메틸옥시란-2-카르복실산(2-메틸-3-니트로페닐)아마이드b) 2-methyloxirane-2-carboxylic acid (2-methyl-3-nitrophenyl) amide

2-메틸옥시란-2-카르복실산(2-메틸-3-니트로페닐)아마이드는 실시예 1b에 기재된 방법으로 2-메틸-N-(2-메틸-3-니트로페닐)아크릴아마이드로부터 제조된다.2-Methyloxirane-2-carboxylic acid (2-methyl-3-nitrophenyl) amide is prepared from 2-methyl-N- (2-methyl-3-nitrophenyl) acrylamide by the method described in Example 1b. do.

1H NMR (400 MHz, DMSO-d6):1.54 (3H, s), 2.19 (3H, s), 2.99 (1H, d, J=5.1 Hz), 3.09 (1H, d, J=5.1 Hz), 7.40-7.45 (1H, m), 7.57-7.60 (1H, m), 7.74-7.77 (1H, m), 9.47 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.54 (3H, s), 2.19 (3H, s), 2.99 (1H, d, J = 5.1 Hz), 3.09 (1H, d, J = 5.1 Hz) , 7.40-7.45 (1 H, m), 7.57-7.60 (1 H, m), 7.74-7.77 (1 H, m), 9.47 (1 H, s).

c) 3-(4-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(2-메틸-3-니트로페닐)프로피온아마이드c) 3- (4-fulurofenoxy) -2-hydroxy-2-methyl-N- (2-methyl-3-nitrophenyl) propionamide

3-(4-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(2-메틸-3-니트로페닐)프로피온아마이드는 실시예 1c에 기재된 방법으로 4-풀루오로페놀과 2-메틸-옥시란-2-카르복실산(4-시아노-3-메틸페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-1% 메탄올)로 정제한다.3- (4-Pluorofenoxy) -2-hydroxy-2-methyl-N- (2-methyl-3-nitrophenyl) propionamide was prepared by the method described in Example 1c with 4-Pluorophenol. Prepared from 2-methyl-oxirane-2-carboxylic acid (4-cyano-3-methylphenyl) amide. The crude product is purified by flash chromatography (eluant: dichloromethane-1% methanol).

1H NMR (400 MHz, DMSO-d6): 1.44 (3H, s), 2.28 (3H, s), 3.96 (1H, d, J=9.5 Hz), 4.17 (1H, d, J= 9.5 Hz), 6.14 (1H, s), 6.93-6.97 (2H, m), 7.08-7.13 (2H, m), 7.41-7.45 (1H, m), 7.66-7.68 (1H, m), 7.72-7.75 (1H, m), 9.72 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.44 (3H, s), 2.28 (3H, s), 3.96 (1H, d, J = 9.5 Hz), 4.17 (1H, d, J = 9.5 Hz) , 6.14 (1H, s), 6.93-6.97 (2H, m), 7.08-7.13 (2H, m), 7.41-7.45 (1H, m), 7.66-7.68 (1H, m), 7.72-7.75 (1H, m), 9.72 (1 H, s).

실시예 48Example 48

3-(3-클로로-4-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(2-메틸-3-니트로페닐)프로피온아마이드3- (3-Chloro-4-fulurofenoxy) -2-hydroxy-2-methyl-N- (2-methyl-3-nitrophenyl) propionamide

3-(3-클로로-4-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(2-메틸-3-니트로페닐)프로피온아마이드는 실시예 1에 기재된 방법으로 3-클로로- 4-풀루오로페놀과 2-메틸옥시란-2-카르복실산(2-메틸-3-니트로페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-1% 메탄올)로 정제한다.3- (3-Chloro-4-fulurofenoxy) -2-hydroxy-2-methyl-N- (2-methyl-3-nitrophenyl) propionamide was prepared by the method described in Example 1. It is prepared from 4-pululourophenol and 2-methyloxirane-2-carboxylic acid (2-methyl-3-nitrophenyl) amide. The crude product is purified by flash chromatography (eluant: dichloromethane-1% methanol).

1H NMR (400 MHz, DMSO-d6): 1.44 (3H, s), 2.27 (3H, s), 3.99 (1H, d, J=9.8 Hz), 4.23 (1H, d, J= 9.8 Hz), 6.15 (1H, s), 6.92-6.97 (1H, m), 7.17-7.20 (1H, m), 7.29-7.35 (1H, m), 7.41-7.46 (1H, m), 7.66-7.69 (1H, m), 7.72-7.75 (1H, m), 9.72 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.44 (3H, s), 2.27 (3H, s), 3.99 (1H, d, J = 9.8 Hz), 4.23 (1H, d, J = 9.8 Hz) , 6.15 (1H, s), 6.92-6.97 (1H, m), 7.17-7.20 (1H, m), 7.29-7.35 (1H, m), 7.41-7.46 (1H, m), 7.66-7.69 (1H, m), 7.72-7.75 (1 H, m), 9.72 (1 H, s).

실시예 49Example 49

2-하이드록시-3-[4-(2-메톡시에틸)펜옥시]-2-메틸-N-(2-메텔-3-니트로페닐)프로피온아마이드)2-hydroxy-3- [4- (2-methoxyethyl) phenoxy] -2-methyl-N- (2-methel-3-nitrophenyl) propionamide)

2-하이드록시-3-[4-(2-메톡시에틸)펜옥시]-2-메틸-N-(2-메텔-3-니트로페닐)프로피온아마이드)는 실시예 1에 기재된 방법으로 4-메톡시에틸페놀과 2-메틸옥시란-2-카르복실산(2-메틸-3-니트로페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-2% 메탄올)로 정제한다.2-hydroxy-3- [4- (2-methoxyethyl) phenoxy] -2-methyl-N- (2-methel-3-nitrophenyl) propionamide) was prepared by the method described in Example 1. Prepared from methoxyethylphenol and 2-methyloxirane-2-carboxylic acid (2-methyl-3-nitrophenyl) amide. The crude product is purified by flash chromatography (eluant: dichloromethane-2% methanol).

1H NMR (400 MHz, DMSO-d6): 1.44 (3H, s), 2.28 (3H, s), 2.72 (2H, t, J=6.8 Hz), 3.22 (3H, s), 3.47 (2H, t, J=6.8 Hz), 3.94 (1H, d, J=9.4 Hz), 4.15 (1H,d, J= 9.4 Hz), 6.11 (1H, s), 6.84 (2H, d, J=7.9 Hz), 7.12 (2H, d, J=7.9 Hz), 7.41-7.45 (1H, m), 7.65-7.68 (1H, m), 7.72-7.75 (1H, m), 9.71 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.44 (3H, s), 2.28 (3H, s), 2.72 (2H, t, J = 6.8 Hz), 3.22 (3H, s), 3.47 (2H, t, J = 6.8 Hz), 3.94 (1H, d, J = 9.4 Hz), 4.15 (1H, d, J = 9.4 Hz), 6.11 (1H, s), 6.84 (2H, d, J = 7.9 Hz) 7.12 (2H, d, J = 7.9 Hz), 7.41-7.45 (1H, m), 7.65-7.68 (1H, m), 7.72-7.75 (1H, m), 9.71 (1H, s).

실시예 50Example 50

2-풀루로오-4-[2-하이드록시-2-(3-메틸-4-니트로페닐카바모일)프로폭시]-페닐카바민산 에틸에스테르2-Pluoro-4- [2-hydroxy-2- (3-methyl-4-nitrophenylcarbamoyl) propoxy] -phenylcarbamic acid ethyl ester

a) (2-풀루오로-4-하이드록시)페닐카바민산 에틸에스테르a) (2-Pluoro-4-hydroxy) phenylcarbamic acid ethyl ester

에틸 클로로포메이트(0.37ml, 3.9mmol)을 10% NaOH 2ml중의 4-아미노-3-풀루오로페놀(0.5g, 3.9mmol)의 용액을 교반하면서 여기에 가한다. 반응혼합물을 80℃에서 30분간 가열한다. 냉각시킨 후, 용액을 염화수소산으로 산성화시켜서 표제 생 성물을 얻는다.Ethyl chloroformate (0.37 ml, 3.9 mmol) is added to this with stirring of a solution of 4-amino-3- pullophenol (0.5 g, 3.9 mmol) in 2 ml of 10% NaOH. The reaction mixture is heated at 80 ° C. for 30 minutes. After cooling, the solution is acidified with hydrochloric acid to give the title product.

1H NMR (400 MHz, DMSO-d6):1.20 (3H, t, J=7.0 Hz), 4.06 (2H, q, J=7.0 Hz), 6.53-6.59 (2H, m), 7.16-7.21 (1H, m), 8.79 (1H, s), 9.72 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.20 (3H, t, J = 7.0 Hz), 4.06 (2H, q, J = 7.0 Hz), 6.53-6.59 (2H, m), 7.16-7.21 ( 1 H, m), 8.79 (1 H, s), 9.72 (1 H, s).

b) 2-풀루로오-4-[2-하이드록시-2-(3-메틸-4-니트로페닐카바모일)프로폭시]-페닐카바민산 에틸에스테르b) 2-Pluluo-4- [2-hydroxy-2- (3-methyl-4-nitrophenylcarbamoyl) propoxy] -phenylcarbamic acid ethyl ester

2-풀루로오-4-[2-하이드록시-2-(3-메틸-4-니트로페닐카바모일)프로폭시]-페닐카바민산 에틸에스테르는 실시예 1에 기재된 방법으로 (2-풀루오로-4-하이드록시)페닐카바민산 에틸에스테와 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-1.8% 메탄올)로 정제한다.2-Pluluo-4- [2-hydroxy-2- (3-methyl-4-nitrophenylcarbamoyl) propoxy] -phenylcarbamic acid ethyl ester was prepared by the method described in Example 1 (2-pulluo It is prepared from ro-4-hydroxy) phenylcarbamic acid ethyl ester and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography (eluent: dichloromethane-1.8% methanol).

1H NMR (400 MHz, DMSO-d6): 1.20 (3H, t, J=7.0 Hz), 1.43 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J=9.7 Hz), 4.07 (2H, q, J=7.0 Hz), 4.22 (1H, d, J= 9.7 Hz), 6.21 (1H, s), 6.71-6.73 (1H, m), 6.83-6.87 (1H, m), 7.31-7.35 (1H, m), 7.86-8.05 (3H, m), 8.95 (1H, s), 10.12 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.20 (3H, t, J = 7.0 Hz), 1.43 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J = 9.7 Hz) , 4.07 (2H, q, J = 7.0 Hz), 4.22 (1H, d, J = 9.7 Hz), 6.21 (1H, s), 6.71-6.73 (1H, m), 6.83-6.87 (1H, m), 7.31-7.35 (1H, m), 7.86-8.05 (3H, m), 8.95 (1H, s), 10.12 (1H, s).

실시예 51Example 51

3-(4-사이노-3-풀루오로펜옥시)-2-하이드록시-N-(3-하이드록시메틸-4-니트로페닐)-2-메틸프로피온아마이드3- (4-Sino-3-Pluorofenoxy) -2-hydroxy-N- (3-hydroxymethyl-4-nitrophenyl) -2-methylpropionamide

a) (5-아미노-2-니트로페닐)메탄올a) (5-amino-2-nitrophenyl) methanol

테트라하이드로퓨란 40ml중의 5-아미노-2-니트로벤조산(3.0g, 16.4mmol)의 용액에 보란-테트라하이드로퓨란 컴플렉스(THF중의 1.0M) 50ml를 가한다. 혼합물을 환류하에 1시간 가열한다. 통상의 처리방법에 의하여 표제 생성물을 얻는다.To a solution of 5-amino-2-nitrobenzoic acid (3.0 g, 16.4 mmol) in 40 ml of tetrahydrofuran, 50 ml of borane-tetrahydrofuran complex (1.0 M in THF) is added. The mixture is heated at reflux for 1 h. The title product is obtained by conventional processing methods.

1H NMR (400 MHz, DMSO-d6):4.79 (2H, d, J=5.4 Hz), 5.37 (1H, t, J=5.4 Hz), 6.48 (1H, dd, J=9.0 Hz, J=2.5 Hz), 6.68 (2H, s), 6.99 (1H, d, J=2.5 Hz), 7.94 (1H, d, J=9.0 Hz). 1 H NMR (400 MHz, DMSO-d 6 ): 4.79 (2H, d, J = 5.4 Hz), 5.37 (1H, t, J = 5.4 Hz), 6.48 (1H, dd, J = 9.0 Hz, J = 2.5 Hz), 6.68 (2H, s), 6.99 (1H, d, J = 2.5 Hz), 7.94 (1H, d, J = 9.0 Hz).

b) N-(3-하이드록시-4-니트로페닐)-2-메타크릴아마이드b) N- (3-hydroxy-4-nitrophenyl) -2-methacrylamide

N-(3-하이드록시-4-니트로페닐)-2-메타크릴아마이드는 실시예 1a에 기재된 방법에 의하여 (5-아미노-2-니트로페닐)메탄올과 메타클로일 클로라이드로부터 제조된다.N- (3-hydroxy-4-nitrophenyl) -2-methacrylamide is prepared from (5-amino-2-nitrophenyl) methanol and methacloyl chloride by the method described in Example 1a.

1H NMR (400 MHz, DMSO-d6):1.97 (3H, s), 4.85 (2H, d, J=5.2 Hz), 5.56 (1H, t, J=5.2 Hz), 5.61 (1H, s), 5.90 (1H, s), 7.93 (1H, dd, J=9.0 Hz, J=2.1 Hz), 8.11 (1H, d, J=9.0 Hz), 8.20 (1H, d, J=2.1 Hz), 10.32 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.97 (3H, s), 4.85 (2H, d, J = 5.2 Hz), 5.56 (1H, t, J = 5.2 Hz), 5.61 (1H, s) , 5.90 (1H, s), 7.93 (1H, dd, J = 9.0 Hz, J = 2.1 Hz), 8.11 (1H, d, J = 9.0 Hz), 8.20 (1H, d, J = 2.1 Hz), 10.32 (1H, s).

c) 메틸옥시란-2-카르복실산(3-하이드록시메틸-4-니트로페닐)아마이드c) methyloxirane-2-carboxylic acid (3-hydroxymethyl-4-nitrophenyl) amide

메틸옥시란-2-카르복실산(3-하이드록시메틸-4-니트로페닐)아마이드는 실시예 1b에 기재된 방법에 의하여 N-(3-하이드록시-4-니트로페닐)-2-메타크릴아마이드로부터 제조된다.Methyloxirane-2-carboxylic acid (3-hydroxymethyl-4-nitrophenyl) amide is prepared by N- (3-hydroxy-4-nitrophenyl) -2-methacrylamide by the method described in Example 1b. Is prepared from.

1H NMR (400 MHz, DMSO-d6): 1.55 (3H, s), 2.98 (1H, d, J=5.1 Hz), 3.07 (1H, d, J=5.1 Hz), 4.82 (2H, d, J=5.3 Hz), 5.53 (1H, t, J=5.3 Hz), 7.84 (1H, dd, J=8.9 Hz, J=2.4 Hz), 8.08 (1H, d, J=8.9 Hz), 8.24 (1H, d, J=2.4 Hz), 9.99 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.55 (3H, s), 2.98 (1H, d, J = 5.1 Hz), 3.07 (1H, d, J = 5.1 Hz), 4.82 (2H, d, J = 5.3 Hz), 5.53 (1H, t, J = 5.3 Hz), 7.84 (1H, dd, J = 8.9 Hz, J = 2.4 Hz), 8.08 (1H, d, J = 8.9 Hz), 8.24 (1H , d, J = 2.4 Hz), 9.99 (1H, s).

d) 3-(4-사이노-3-풀루오로펜옥시)-2-하이드록시-N-(3-하이드록시메틸-4-니트로페닐)-2-메틸프로피온아마이드d) 3- (4-cyano-3-pululofenoxy) -2-hydroxy-N- (3-hydroxymethyl-4-nitrophenyl) -2-methylpropionamide

3-(4-사이노-3-풀루오로펜옥시)-2-하이드록시-N-(3-하이드록시메틸-4-니트로페닐)-2-메틸프로피온아마이드는 실시예 1c에 기재된 방법에 의하여 2-풀루오로-4-하이드록시벤조니트릴과 2-메틸옥시란-2-카르복실산(3-하이드록시메틸-4-니트로페 닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-6.6% 메탄올)로 정제한다.3- (4-Cyno-3-pululofenoxy) -2-hydroxy-N- (3-hydroxymethyl-4-nitrophenyl) -2-methylpropionamide was prepared in the method described in Example 1c. 2-fluoroluo-4-hydroxybenzonitrile and 2-methyloxirane-2-carboxylic acid (3-hydroxymethyl-4-nitrofenyl) amide. The crude product is purified by flash chromatography (eluant: dichloromethane-6.6% methanol).

1H NMR (400 MHz, DMSO-d6): 1.45 (3H, s), 4.13 (1H, d, J=10.0 Hz), 4.38 (1H, d, J= 10.0 Hz), 4.83 (2H, d, J=5.4 Hz), 5.51 (1H, t, J=5.4 Hz), 6.25 (1H, s), 6.94-6.98 (1H, m), 7.16-7.20 (1H, m), 7.77-7.82 (1H, m), 7.88 (1H, dd, J=9.0 Hz, J=2.4 Hz), 8.09 (1H, d, J=9.0 Hz), 8.34 (1H, d, J=2.4 Hz), 10.24 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.45 (3H, s), 4.13 (1H, d, J = 10.0 Hz), 4.38 (1H, d, J = 10.0 Hz), 4.83 (2H, d, J = 5.4 Hz), 5.51 (1H, t, J = 5.4 Hz), 6.25 (1H, s), 6.94-6.98 (1H, m), 7.16-7.20 (1H, m), 7.77-7.82 (1H, m ), 7.88 (1H, doublet, J = 9.0 Hz, J = 2.4 Hz), 8.09 (1H, d, J = 9.0 Hz), 8.34 (1H, d, J = 2.4 Hz), 10.24 (1H, s).

실시예 52Example 52

3-(4-풀루오로페닐아미노)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드3- (4-Pluorophenylamino) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

아세토니트릴 2ml중의 2-메틸옥시란-2-카르복실산(3-하이드록시메틸-4-니트로페닐)아마이드(0.2g, 0.85mmol), 4-풀루오로아닐린(0.18g, 1.7mmol) 및 소디움퍼클로레이트(0.21g, 1.7mmol)의 혼합물을 환류하에 6시간 끓인다. 반응혼합물을 통상의 처리방법으로 처리하고, 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-1% 메탄올)로 정제한다.2-methyloxirane-2-carboxylic acid (3-hydroxymethyl-4-nitrophenyl) amide (0.2 g, 0.85 mmol), 4- pulloaniline (0.18 g, 1.7 mmol) in 2 ml of acetonitrile and A mixture of sodium perchlorate (0.21 g, 1.7 mmol) is boiled under reflux for 6 hours. The reaction mixture is treated by a conventional treatment method, and the crude product is purified by flash chromatography (eluent: dichloromethane-1% methanol).

1H NMR (400 MHz, DMSO-d6): 1.41 (3H, s), 2.51 (3H, s), 3.10 (1H, dd, J=12.7 Hz, J=4.6 Hz), 3.41 (1H, dd, J= 12.7 Hz, J=7.7 Hz), 5.26 (1H, m), 6.02 (1H, s), 6.62-6.66 (2H, m), 6.84-6.89 (2H, m), 7.79-7.83 (2H, m), 8.02 (1H, d, J=8.9 Hz), 9.99 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.41 (3H, s), 2.51 (3H, s), 3.10 (1H, dd, J = 12.7 Hz, J = 4.6 Hz), 3.41 (1H, dd, J = 12.7 Hz, J = 7.7 Hz), 5.26 (1H, m), 6.02 (1H, s), 6.62-6.66 (2H, m), 6.84-6.89 (2H, m), 7.79-7.83 (2H, m ), 8.02 (1H, d, J = 8.9 Hz), 9.99 (1H, s).

실시예 53Example 53

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-(4-트리풀루오로메틸페닐아미노)프로피온아마이드2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3- (4-trifluorofluoromethylphenylamino) propionamide

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-(4-트리풀루오로메틸페닐아미노)프로피온아마이드는 실시예 52에 기재된 방법에 의하여 4-(트리풀루오로메틸)아닐린과 2-메틸옥시란-2-카르복실산(3-하이드록시메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-1.5% 메탄올)로 정제한다.2-Hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3- (4-trifluorofluoromethylphenylamino) propionamide was prepared by the method described in Example 52. Prepared from fluoromethyl) aniline and 2-methyloxirane-2-carboxylic acid (3-hydroxymethyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography (eluent: dichloromethane-1.5% methanol).

1H NMR (400 MHz, DMSO-d6): 1.42 (3H, s), 2.51 (3H, s), 3.23 (1H, dd, J=13.3 Hz, J=5.0 Hz), 3.51 (1H, dd, J= 13.3 Hz, J=7.0 Hz), 6.06 (1H, s), 6.18 (1H, m), 6.77 (2H, d, J=8.4 Hz)), 7.31 (2H, d, J=8.4 Hz), 7.79-7.83 (2H, m), 8.01 (1H, d, J=8.9 Hz), 10.02 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.42 (3H, s), 2.51 (3H, s), 3.23 (1H, dd, J = 13.3 Hz, J = 5.0 Hz), 3.51 (1H, dd, J = 13.3 Hz, J = 7.0 Hz), 6.06 (1H, s), 6.18 (1H, m), 6.77 (2H, d, J = 8.4 Hz)), 7.31 (2H, d, J = 8.4 Hz), 7.79-7.83 (2H, m), 8.01 (1H, doublet, J = 8.9 Hz), 10.02 (1H, s).

실시예 54Example 54

2-하이드록시-3-(4-메톡시-3-트리풀루오로메틸페닐아미노)-2-메틸-N-(3- 메틸-4-니트로페닐)프로피온아마이드2-hydroxy-3- (4-methoxy-3-trifluoromethylphenylamino) -2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

2-하이드록시-3-(4-메톡시-3-트리풀루오로메틸페닐아미노)-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드는 실시예 52에 기재된 방법에 의하여 3-아미노-6-메톡시벤조트리풀루오라이드와 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-1.5% 메탄올)로 정제한다.2-hydroxy-3- (4-methoxy-3-trifluoromethylphenylamino) -2-methyl-N- (3-methyl-4-nitrophenyl) propionamide was prepared by the method described in Example 52. Prepared from 3-amino-6-methoxybenzotripulolide and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography (eluent: dichloromethane-1.5% methanol).

1H NMR (400 MHz, DMSO-d6): 1.41 (3H, s), 2.51 (3H, s), 3.12 (1H, dd, J=13.0 Hz, J=4.8 Hz), 3.45 (1H, dd, J=13.0 Hz, J=7.7 Hz), 3.71 (3H, s), 5.42 (1H, m), 6.00 (1H, s), 6.88 (1H, dd, J=8.9 Hz, J=2.7 Hz), 6.92 (1H, d, J=2.7 Hz), 6.97 (1H, d, J=8.9 Hz), 7.78 (1H, dd, J=8.9 Hz, J=2.3 Hz), 7.81 (1H, d, J=1.9 Hz), 8.00 (1H, d, J=8.9 Hz), 9.98 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.41 (3H, s), 2.51 (3H, s), 3.12 (1H, dd, J = 13.0 Hz, J = 4.8 Hz), 3.45 (1H, dd, J = 13.0 Hz, J = 7.7 Hz), 3.71 (3H, s), 5.42 (1H, m), 6.00 (1H, s), 6.88 (1H, dd, J = 8.9 Hz, J = 2.7 Hz), 6.92 (1H, d, J = 2.7 Hz), 6.97 (1H, d, J = 8.9 Hz), 7.78 (1H, dd, J = 8.9 Hz, J = 2.3 Hz), 7.81 (1H, d, J = 1.9 Hz ), 8.00 (1H, d, J = 8.9 Hz), 9.98 (1H, s).

실시예 55Example 55

3-(4-시아노페닐아미노)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드3- (4-cyanophenylamino) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(4-시아노페닐아미노)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드는 실시예 52에 기재된 방법에 의하여 4-아미노-벤조니트릴과 2-메틸 옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-5% 메탄올)로 정제한다3- (4-cyanophenylamino) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide was prepared by the method described in Example 52 with 4-amino-benzonitrile. Prepared from 2-methyl oxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography (eluent: dichloromethane-5% methanol).

1H NMR (400 MHz, DMSO-d6): 1.41 (3H, s), 2.52 (3H, s), 3.25 (1H, dd, J=13.5 Hz, J=5.3 Hz), 3.52 (1H, dd, J= 13.5 Hz, J=7.0 Hz), 6.08 (1H, s), 6.53 (1H, m), 6.75 (2H, d, J=8.8 Hz)), 7.39 (2H, d, J=8.8 Hz), 7.79-7.83 (2H, m), 8.01 (1H, d, J=8.9 Hz), 10.02 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.41 (3H, s), 2.52 (3H, s), 3.25 (1H, dd, J = 13.5 Hz, J = 5.3 Hz), 3.52 (1H, dd, J = 13.5 Hz, J = 7.0 Hz), 6.08 (1H, s), 6.53 (1H, m), 6.75 (2H, d, J = 8.8 Hz)), 7.39 (2H, d, J = 8.8 Hz), 7.79-7.83 (2H, m), 8.01 (1H, doublet, J = 8.9 Hz), 10.02 (1H, s).

실시예 56Example 56

3-(3-클로로-4-시아노페닐아미노)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드3- (3-chloro-4-cyanophenylamino) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(3-클로로-4-시아노페닐아미노)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드는 실시예 52에 기재된 방법에 의하여 4-아미노--2-클로로벤조니트릴과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-3% 메탄올)로 정제한다3- (3-Chloro-4-cyanophenylamino) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide was prepared in 4-amino by the method described in Example 52. It is prepared from 2-chlorobenzonitrile and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography (eluent: dichloromethane-3% methanol).

1H NMR (400 MHz, DMSO-d6): 1.40 (3H, s), 2.52 (3H, s), 3.27 (1H, dd, J=13.8 Hz, J=5.5 Hz), 3.55 (1H, dd, J=13.8 Hz, J=6.9 Hz), 6.12 (1H, s), 6.72 (1H, dd, J=8.8 Hz, J=2.2 Hz), 6.90 (1H, d, J=2.2 Hz), 6.95-6.98 (1H, m), 7.46 (1H, d, J=8.7 Hz), 7.80 (1H, dd, J=8.9 Hz, J=2.3 Hz), 7.83 (1H, d, J=2.0 Hz), 8.02 (1H, d, J=8.9 Hz), 10.05 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.40 (3H, s), 2.52 (3H, s), 3.27 (1H, dd, J = 13.8 Hz, J = 5.5 Hz), 3.55 (1H, dd, J = 13.8 Hz, J = 6.9 Hz), 6.12 (1H, s), 6.72 (1H, dd, J = 8.8 Hz, J = 2.2 Hz), 6.90 (1H, d, J = 2.2 Hz), 6.95-6.98 (1H, m), 7.46 (1H, d, J = 8.7 Hz), 7.80 (1H, dd, J = 8.9 Hz, J = 2.3 Hz), 7.83 (1H, d, J = 2.0 Hz), 8.02 (1H , d, J = 8.9 Hz), 10.05 (1H, s).

실시예 57Example 57

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-(피리딘-3-일옥소)프로피온아마이드2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3- (pyridin-3-yloxo) propionamide

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-(피리딘-3-일옥소)프로피온아마이드는 실시예 1에 기재된 방법에 의하여 3-하이드록시피리딘과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-9% 메탄올)로 정제한다2-Hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3- (pyridin-3-yloxo) propionamide was reacted with 3-hydroxypyridine and 2 by the method described in Example 1. -Methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography (eluent: dichloromethane-9% methanol).

1H NMR (400 MHz, DMSO-d6): 1.45 (3H, s), 2.53 (3H, s), 4.06 (1H, d, J=9.8 Hz), 4.31 (1H, d, J= 9.8 Hz), 6.26 (1H, s), 7.28-7.32 (1H, m), 7.38-7.41 (1H, m), 7.87-7.93 (2H, m), 8.03 (1H, d, J=8.9 Hz), 8.15-8.17 (1H, m), 8.26 (1H, d, J=2.4 Hz), 10.15 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.45 (3H, s), 2.53 (3H, s), 4.06 (1H, d, J = 9.8 Hz), 4.31 (1H, d, J = 9.8 Hz) , 6.26 (1H, s), 7.28-7.32 (1H, m), 7.38-7.41 (1H, m), 7.87-7.93 (2H, m), 8.03 (1H, d, J = 8.9 Hz), 8.15-8.17 (1H, m), 8.26 (1H, doublet, J = 2.4 Hz), 10.15 (1H, s).

실시예 58Example 58

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-(피리딘-4-일옥소)프로피온 아마이드2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3- (pyridin-4-yloxo) propion amide

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-(피리딘-4-일옥소)프로피온아마이드는 실시예 1에 기재된 방법에 의하여 4-하이드록시피리딘과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-7% 메탄올)로 정제한다2-Hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3- (pyridin-4-yloxo) propionamide was prepared from 2-hydroxypyridine and 2 by the method described in Example 1. -Methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography (eluent: dichloromethane-7% methanol).

1H NMR (400 MHz, CDCl3): 1.62 (3H, s), 2.63 (3H, s), 4.08 (1H, d, J=9.2 Hz), 4.46 (1H, d, J= 9.2 Hz), 6.79 (2H, d, J=5.1 Hz), 7.57 (1H, d, J=9.0 Hz), 7.66 (1H, s), 8.05 (1H, d, J=8.8 Hz), 8.35 (2H, d, J=5.1 Hz), 9.14 (1H, s). 1 H NMR (400 MHz, CDCl 3 ): 1.62 (3H, s), 2.63 (3H, s), 4.08 (1H, d, J = 9.2 Hz), 4.46 (1H, d, J = 9.2 Hz), 6.79 (2H, d, J = 5.1 Hz), 7.57 (1H, d, J = 9.0 Hz), 7.66 (1H, s), 8.05 (1H, d, J = 8.8 Hz), 8.35 (2H, d, J = 5.1 Hz), 9.14 (1 H, s).

실시예 59Example 59

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-(피리딘-2-일옥소)프로피온아마이드2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3- (pyridin-2-yloxo) propionamide

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-(피리딘-2-일옥소)프로피온아마이드는 실시예 1에 기재된 방법에 의하여 2-하이드록시피리딘과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-2% 메탄올)로 정제한다2-Hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3- (pyridin-2-yloxo) propionamide was reacted with 2-hydroxypyridine and 2 by the method described in Example 1. -Methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography (eluent: dichloromethane-2% methanol).

1H NMR (400 MHz, CDCl3): 1.53 (3H, s), 2.61 (3H, s), 4.58 (1H, d, J=12.3 Hz), 4.72 (1H, d, J= 12.3 Hz), 6.87 (1H, d, J=8.3 Hz), 7.00 (1H, t, J=6.1 Hz), 7.56 (1H, d, J=8.9 Hz), 7.64-7.69 (2H, m), 7.81 (1H, s), 8.03 (1H, d, J=8.9 Hz), 8.11 (1H, d, J=5.0 Hz), 9.33 (1H, s). 1 H NMR (400 MHz, CDCl 3 ): 1.53 (3H, s), 2.61 (3H, s), 4.58 (1H, d, J = 12.3 Hz), 4.72 (1H, d, J = 12.3 Hz), 6.87 (1H, d, J = 8.3 Hz), 7.00 (1H, t, J = 6.1 Hz), 7.56 (1H, d, J = 8.9 Hz), 7.64-7.69 (2H, m), 7.81 (1H, s) , 8.03 (1H, d, J = 8.9 Hz), 8.11 (1H, d, J = 5.0 Hz), 9.33 (1H, s).

실시예 60Example 60

3-(2-클로로피리딘-3-일옥소)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드3- (2-chloropyridin-3-yloxo) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(2-클로로피리딘-3-일옥소)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마이드는 실시예 1에 기재된 방법에 의하여 2-클로로-3-하이드록시피리딘과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-2% 메탄올)로 정제한다3- (2-Chloropyridin-3-yloxo) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide was prepared by the method described in Example 1. Prepared from 3-hydroxypyridine and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography (eluent: dichloromethane-2% methanol).

1H NMR (400 MHz, DMSO-d6): 1.47 (3H, s), 2.53 (3H, s), 4.18 (1H, d, J=9.9 Hz), 4.31 (1H, d, J= 9.9 Hz), 6.28 (1H, s), 7.35-7.39 (1H, m), 7.63 (1H, d, J=8.2 Hz), 7.77-7.97 (3H, m), 8.04 (1H, d, J=8.9 Hz), 10.13 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.47 (3H, s), 2.53 (3H, s), 4.18 (1H, d, J = 9.9 Hz), 4.31 (1H, d, J = 9.9 Hz) , 6.28 (1H, s), 7.35-7.39 (1H, m), 7.63 (1H, d, J = 8.2 Hz), 7.77-7.97 (3H, m), 8.04 (1H, d, J = 8.9 Hz), 10.13 (1 H, s).

실시예 61Example 61

N-(4-풀루오로-3-메틸페닐)-3-(4-풀루오로펜옥시)-2-하이드록시-2-메틸-프로피온아마이드N- (4-Pluoro-3-methylphenyl) -3- (4-fulurofenoxy) -2-hydroxy-2-methyl-propionamide

a) N-(4-풀루오로-3-메틸페닐)-2-메틸아크릴아마이드a) N- (4-Pluoro-3-methylphenyl) -2-methylacrylamide

N-(4-풀루오로-3-메틸페닐)-2-메틸아크릴아마이드는 실시예 1a에 기재된 방법으로 4-풀루오로-3-메틸아닐린과 메타클로일 클로라이드로부터 제조된다.N- (4-Pluoro-3-methylphenyl) -2-methylacrylamide is prepared from 4-Pluoro-3-methylaniline and methacloyl chloride by the method described in Example 1a.

1H NMR (400 MHz, DMSO-d6):1.94 (3H, s), 2.21 (3H, s), 5.50 (1H, s), 5.78 (1H, s), 7.05-7.10 (1H, m), 7.48-7.51 (1H, m), 7.57-7.59 (1H, m), 9.75 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.94 (3H, s), 2.21 (3H, s), 5.50 (1H, s), 5.78 (1H, s), 7.05-7.10 (1H, m), 7.48-7.51 (1 H, m), 7.57-7.59 (1 H, m), 9.75 (1 H, s).

b) 2-메틸옥시란-2-카르복실산(4-풀루오로-3-메틸페닐)아마이드b) 2-methyloxirane-2-carboxylic acid (4-pulluoro-3-methylphenyl) amide

2-메틸옥시란-2-카르복실산(4-풀루오로-3-메틸페닐)아마이드는 실시예 1b에 기재된 방법으로 N-(4-풀루오로-3-메틸페닐)-2-메틸아크릴아마이드로부터 제조된다.2-Methyloxirane-2-carboxylic acid (4-Pluoro-3-methylphenyl) amide is prepared by the method described in Example 1b with N- (4-Pluoro-3-methylphenyl) -2-methylacrylamide. Is prepared from.

1H NMR (400 MHz, DMSO-d6):1.52 (3H, s), 2.19 (3H, s), 2.94 (1H, d, J=5.3 Hz), 2.99 (1H, d, J=5.3 Hz), 7.02-7.07 (1H, m), 7.44-7.48 (1H, m), 7.56-7.59 (1H, m), 9.40 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.52 (3H, s), 2.19 (3H, s), 2.94 (1H, d, J = 5.3 Hz), 2.99 (1H, d, J = 5.3 Hz) , 7.02-7.07 (1H, m), 7.44-7.48 (1H, m), 7.56-7.59 (1H, m), 9.40 (1H, s).

c) N-(4-풀루오로-3-메틸페닐)-3-(4-풀루오로펜옥시)-2-하이드록시-2-메틸-프로피온아마이드c) N- (4-Pluoro-3-methylphenyl) -3- (4-fulurofenoxy) -2-hydroxy-2-methyl-propionamide

N-(4-풀루오로-3-메틸페닐)-3-(4-풀루오로펜옥시)-2-하이드록시-2-메틸-프로피온아마이드는 실시예 1c에 기재된 방법으로 4-풀루오로페놀과 2-메틸옥시란-2-카르복실산(4-풀루오로-3-메틸페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-1.4% 메탄올)로 정제한다N- (4-Pluoro-3-methylphenyl) -3- (4-Pluorophenoxy) -2-hydroxy-2-methyl-propionamide was prepared in 4-Pluoro by the method described in Example 1c. It is prepared from phenol and 2-methyloxirane-2-carboxylic acid (4-pulluoro-3-methylphenyl) amide. The crude product is purified by flash chromatography (eluent: dichloromethane-1.4% methanol).

1H NMR (400 MHz, DMSO-d6): 1.40 (3H, s), 2.20 (3H, s), 3.92 (1H, d, J=9.5 Hz), 4.17 (1H, d, J= 9.5 Hz), 6.03 (1H, s), 6.91-6.95 (2H, m), 7.03-7.10 (3H, m), 7.53-7.57 (1H, m), 7.66-7.68 (1H, m), 9.62 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.40 (3H, s), 2.20 (3H, s), 3.92 (1H, d, J = 9.5 Hz), 4.17 (1H, d, J = 9.5 Hz) , 6.03 (1H, s), 6.91-6.95 (2H, m), 7.03-7.10 (3H, m), 7.53-7.57 (1H, m), 7.66-7.68 (1H, m), 9.62 (1H, s) .

실시예 62Example 62

3-(4-아세틸아미노펜옥시)-N-(4-풀루오로-3-메틸페닐)-2-하이드록시-2-메틸프로피온아마아드3- (4-acetylaminophenoxy) -N- (4-fluorouro-3-methylphenyl) -2-hydroxy-2-methylpropion amide

3-(4-아세틸아미노펜옥시)-N-(4-풀루오로-3-메틸페닐)-2-하이드록시-2-메틸프로피온아마아드는 실시예 61c에 기재된 방법으로 4-아세트아미도페놀과 2-메틸옥시란-2-카르복실산(4-풀루오로-3-메틸페닐)아마이드로부터 제조된다.3- (4-Acetylaminophenoxy) -N- (4-fluorouro-3-methylphenyl) -2-hydroxy-2-methylpropionamide is prepared by the method described in Example 61c with 4-acetamidophenol. Prepared from 2-methyloxirane-2-carboxylic acid (4-fuluro-3-methylphenyl) amide.

1H NMR (400 MHz, DMSO-d6): 1.40 (3H, s), 2.00 (3H, s), 2.20 (3H, s), 3.90 (1H, d, J=9.5 Hz), 4.15 (1H, d, J= 9.5 Hz), 6.03 (1H, s), 6.84 (2H, d, J=8.7 Hz), 7.03-7.08 (1H, m), 7.44 (2H, d, J=8.7 Hz), 7.54-7.57 (1H, m), 7.67-7.69 (1H, m), 9.62 (1H, s), 9.75 (1H,s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.40 (3H, s), 2.00 (3H, s), 2.20 (3H, s), 3.90 (1H, d, J = 9.5 Hz), 4.15 (1H, d, J = 9.5 Hz), 6.03 (1H, s), 6.84 (2H, d, J = 8.7 Hz), 7.03-7.08 (1H, m), 7.44 (2H, d, J = 8.7 Hz), 7.54- 7.57 (1 H, m), 7.67-7.69 (1 H, m), 9.62 (1 H, s), 9.75 (1 H, s).

실시예 63Example 63

3-(3-클로로-4-시아노펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드3- (3-chloro-4-cyanophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(3-클로로-4-시아노펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 1에 기재된 방법에 의하여 2-클로로-4-하이드록시벤조니트릴과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-1.2% 메탄올)로 정제한다3- (3-Chloro-4-cyanophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide is 2-chloro by the method described in Example 1 Prepared from 4-hydroxybenzonitrile and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography (eluent: dichloromethane-1.2% methanol).

1H NMR (400 MHz, DMSO-d6): 1.44 (3H, s), 2.53 (3H, s), 4.13 (1H, d, J=10.1 Hz), 4.39 (1H, d, J= 10.1 Hz), 6.29 (1H, s), 7.09 (1H, dd, J=8.8 Hz, J=2.4 Hz), 7.36 (1H, d, J=2.4 Hz), 7.84-7.91 (3H, m), 8.03 (1H, d, J=8.9 Hz), 10.15 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.44 (3H, s), 2.53 (3H, s), 4.13 (1H, d, J = 10.1 Hz), 4.39 (1H, d, J = 10.1 Hz) , 6.29 (1H, s), 7.09 (1H, dd, J = 8.8 Hz, J = 2.4 Hz), 7.36 (1H, d, J = 2.4 Hz), 7.84-7.91 (3H, m), 8.03 (1H, d, J = 8.9 Hz), 10.15 (1H, s).

실시예 64Example 64

3-(4-시아노-3-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드3- (4-cyano-3-pululofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

a) 2-메틸-N-(2-메틸-4-니트로페닐)아크릴아마이드a) 2-methyl-N- (2-methyl-4-nitrophenyl) acrylamide

2-메틸-N-(2-메틸-4-니트로페닐)아크릴아마이드는 실시예 1a에 기재된 방법으로 2-메틸-4-니트로아닐린과 메티크릴로일 클로라아드로부터 제조된다.2-Methyl-N- (2-methyl-4-nitrophenyl) acrylamide is prepared from 2-methyl-4-nitroaniline and methacryloyl chlorad by the method described in Example 1a.

1H NMR (400 MHz, DMSO-d6):1.98 (3H, s), 2.34 (3H, s), 5.59 (1H, s), 5.91 (1H, s), 7.74 (1H, d, J=8.8 Hz), 8.07 (1H, dd, J=8.8 Hz, J=2.7 Hz), 8.15 (1H, d, J=2.6 Hz), 9.53 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.98 (3H, s), 2.34 (3H, s), 5.59 (1H, s), 5.91 (1H, s), 7.74 (1H, d, J = 8.8 Hz), 8.07 (1H, doublet of doublets, J = 8.8 Hz, J = 2.7 Hz), 8.15 (1H, d, J = 2.6 Hz), 9.53 (1H, s).

b) 2-메틸옥시란-2-카르복실산(2-메틸-4-니트로페닐)아마이드b) 2-methyloxirane-2-carboxylic acid (2-methyl-4-nitrophenyl) amide

2-메틸옥시란-2-카르복실산(2-메틸-4-니트로페닐)아마이드는 실시예 1b에 기재된 방법으로 2-메틸-N-(2-메틸-4-니트로페닐)-2-메틸아크릴아마이드로부터 제조된다.2-Methyloxirane-2-carboxylic acid (2-methyl-4-nitrophenyl) amide is prepared by the method described in Example 1b, 2-methyl-N- (2-methyl-4-nitrophenyl) -2-methyl. It is prepared from acrylamide.

1H NMR (400 MHz, DMSO-d6):1.55 (3H, s), 2.30 (3H, s), 3.03 (1H, d, J=5.1 Hz), 3.15 (1H, d, J=5.1 Hz), 7.86 (1H, d, J=8.9 Hz), 8.08 (1H, dd, J=8.9 Hz, J=2.6 Hz), 8.15 (1H, d, J=2.5 Hz), 9.13 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.55 (3H, s), 2.30 (3H, s), 3.03 (1H, d, J = 5.1 Hz), 3.15 (1H, d, J = 5.1 Hz) , 7.86 (1H, d, J = 8.9 Hz), 8.08 (1H, dd, J = 8.9 Hz, J = 2.6 Hz), 8.15 (1H, d, J = 2.5 Hz), 9.13 (1H, s).

c) 3-(4-시아노-3-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드c) 3- (4-cyano-3-pululofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(4-시아노-3-풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 1c에 기재된 방법으로 2-풀루오로-4-하이드록시벤조니트릴과 2-메틸옥시란-2-카르복실산(4-풀루오로-3-메틸페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-1.3% 메탄올)로 정제한다3- (4-cyano-3-pululofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamad was prepared by the method described in Example 1c. It is prepared from pullouro-4-hydroxybenzonitrile and 2-methyloxirane-2-carboxylic acid (4- pullouro-3-methylphenyl) amide. The crude product is purified by flash chromatography (eluent: dichloromethane-1.3% methanol).

1H NMR (400 MHz, DMSO-d6): 1.46 (3H, s), 2.37 (3H, s), 4.13 (1H, d, J=10.1 Hz), 4.37 (1H, d, J= 10.1 Hz), 6.51 (1H, s), 6.95-6.98 (1H, m), 7.17-7.21 (1H, m), 7.78-7.83 (1H, m), 8.05-8.12 (2H, m), 8.18 (1H, d, J=2.3 Hz), 9.57 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.46 (3H, s), 2.37 (3H, s), 4.13 (1H, d, J = 10.1 Hz), 4.37 (1H, d, J = 10.1 Hz) , 6.51 (1H, s), 6.95-6.98 (1H, m), 7.17-7.21 (1H, m), 7.78-7.83 (1H, m), 8.05-8.12 (2H, m), 8.18 (1H, d, J = 2.3 Hz), 9.57 (1 H, s).

실시예 65Example 65

3-(3-클로로-4-시아노펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드 3- (3-chloro-4-cyanophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(3-클로로-4-시아노펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 64c에 기재된 방법으로 2-클로로-4-하이드록시벤조니트릴과 2-메틸옥시란-2-카르복실산(4-풀루오로-3-메틸페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-1.3% 메탄올)로 정제한다 3- (3-Chloro-4-cyanophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide is 2-chloro- in the manner described in Example 64c. Prepared from 4-hydroxybenzonitrile and 2-methyloxirane-2-carboxylic acid (4-fuluro-3-methylphenyl) amide. The crude product is purified by flash chromatography (eluent: dichloromethane-1.3% methanol).

1H NMR (400 MHz, DMSO-d6): 1.46 (3H, s), 2.37 (3H, s), 4.15 (1H, d, J=10.1 Hz), 4.39 (1H, d, J= 10.1 Hz), 6.51 (1H, s), 7.10 (1H, dd, J=8.8 Hz, J=2.4 Hz), 7.37 (1H, d, J=2.4 Hz), 7.86 (1H, d, J=8.8 Hz), 8.05-8.12 (2H, m), 8.18 (1H, d, J=2.3 Hz), 9.56 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.46 (3H, s), 2.37 (3H, s), 4.15 (1H, d, J = 10.1 Hz), 4.39 (1H, d, J = 10.1 Hz) , 6.51 (1H, s), 7.10 (1H, dd, J = 8.8 Hz, J = 2.4 Hz), 7.37 (1H, d, J = 2.4 Hz), 7.86 (1H, d, J = 8.8 Hz), 8.05 -8.12 (2H, m), 8.18 (1H, doublet, J = 2.3 Hz), 9.56 (1H, s).

실시예 66Example 66

3-(4-시아노-3-풀루오로펜옥시)-N-(3-포밀-4-니트로페닐)-2-하이드록시-2-메틸프로피온아마아드3- (4-cyano-3-fulurofenoxy) -N- (3-formyl-4-nitrophenyl) -2-hydroxy-2-methylpropion amide

3-(4-시아노-3-풀루오로펜옥시)-2-하이드록시-N-(3-하이드록시메틸-4-니트로페닐)-2-메틸프로피온아마아드(0.2g, 0.51mmol)을 디클로로메탄(10ml)에 용해시키 고, 망가니스(IV)옥사이드(0.4g, 4.6mmol)을 가한다. 혼합물을 실온에서 48시간 교반한다. 고체 옥시단트는 여과하여 제거한 후, 용매를 증발시킨다. 조생성물은 플래시 크로마토그래피(용출제 : 디클로로메탄-3% 메탄올)로 정제한다3- (4-cyano-3-fulurofenoxy) -2-hydroxy-N- (3-hydroxymethyl-4-nitrophenyl) -2-methylpropionamide (0.2 g, 0.51 mmol) Is dissolved in dichloromethane (10 ml) and manganese (IV) oxide (0.4 g, 4.6 mmol) is added. The mixture is stirred for 48 hours at room temperature. Solid oxidant is removed by filtration and the solvent is evaporated. The crude product is purified by flash chromatography (eluent: dichloromethane-3% methanol).

1H NMR (400 MHz, DMSO-d6): 1.45 (3H, s), 4.13 (1H, d, J=10.0 Hz), 4.38 (1H, d, J= 10.0 Hz), 6.32 (1H, s), 6.94-6.97 (1H, m), 7.16-7.20 (1H, m), 7.77-7.82 (1H, m), 8.18-8.24 (2H, m), 8.36 (1H, d, J=2.1 Hz), 10.28 (1H, s), 10.55 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.45 (3H, s), 4.13 (1H, d, J = 10.0 Hz), 4.38 (1H, d, J = 10.0 Hz), 6.32 (1H, s) , 6.94-6.97 (1H, m), 7.16-7.20 (1H, m), 7.77-7.82 (1H, m), 8.18-8.24 (2H, m), 8.36 (1H, d, J = 2.1 Hz), 10.28 (1H, s), 10.55 (1H, s).

실시예 67Example 67

3-[4-(2-디메틸아미노에톡시)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드3- [4- (2-dimethylaminoethoxy) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

a) [2-(4-벤질옥시펜옥시)에틸]디메틸아민a) [2- (4-benzyloxyphenoxy) ethyl] dimethylamine

디메틸포름아마이드(15ml)중의 4-벤질옥시)페놀(2.89g, 0.01443mol)과 2-(디메틸아미노)에틸 클로라이드 염산염(2.32g, 0.01611mol)을 디메틸포름아마이드(5ml)중의 55-65% 미네랄오일에 분산시킨 소디움하이드라이드에 동시에 조금씩 0℃에서 가한다. 다음에, 혼합물을 90℃로 가열한 다음 1.5시간 교반한다. 냉각된 혼합물을 물에 붓는다. 결과로 얻어진 혼합물을 톨루엔으로 추출한 다. 추출액을 합하고 2.5M NaOH 및 물로 차례로 세척한 다음 황산나트륨으로 건조시킨 다음, 톨루엔을 증발시키고, 잔류 생성물을 다음 단계에 사용한다.4-benzyloxy) phenol (2.89 g, 0.01443 mol) and 2- (dimethylamino) ethyl chloride hydrochloride (2.32 g, 0.01611 mol) in dimethylformamide (15 ml) were 55-65% mineral in dimethylformamide (5 ml) To the sodium hydride dispersed in oil is added at the same time little by little at 0 ℃. The mixture is then heated to 90 ° C. and then stirred for 1.5 hours. Pour the cooled mixture into water. The resulting mixture is extracted with toluene. The extracts are combined, washed sequentially with 2.5M NaOH and water, dried over sodium sulfate, then toluene is evaporated and the residual product is used for the next step.

1H NMR (300 MHz, DMSO-d 6 ): 2.20 (6H, s), 2.58 (2H, t, 3 J = 5.9 Hz), 3.96 (2H, t, 3 J = 5.9 Hz), 5.03 (2H, s), 6.85 (2H, d, 3 J = 9.3 Hz), 6.92 (2H, d, 3 J = 9.3 Hz), 7.30-7.44 (5H, m). 1 H NMR (300 MHz, DMSO- d 6 ): 2.20 (6H, s), 2.58 (2H, t, 3 J = 5.9 Hz), 3.96 (2H, t, 3 J = 5.9 Hz), 5.03 (2H, s), 6.85 (2H, d, 3 J = 9.3 Hz), 6.92 (2H, d, 3 J = 9.3 Hz), 7.30-7.44 (5H, m).

b) 4-(2-디메틸아미노에톡시)페놀b) 4- (2-dimethylaminoethoxy) phenol

6M HCl(67ml)와 에탄올(33.5ml)의 혼합물중의 [2-(4-벤질옥시펜옥시)에틸]디메틸아닐린(3.36g, 0.01238mol)의 용액을 6.5시간 환류시킨다. 다음에 에탄올을 증류시키고, 2.5M NaOH로 pH를8로 조절한다. 생성물을 초산에틸로 추출한다. 추출액을 물로 세척하고 황산나트륨으로 건조시킨 다음, 감압하에 용매를 제거하여 표제 생성물을 얻는다. 이것은 구배 용출제로 헵탄/초산에틸(9:1-6:4)사용하여 실리카겔로 프래시 크로마토그리피하여 정제한다.A solution of [2- (4-benzyloxyphenoxy) ethyl] dimethylaniline (3.36 g, 0.01238 mol) in a mixture of 6M HCl (67 ml) and ethanol (33.5 ml) was refluxed for 6.5 hours. The ethanol is then distilled off and the pH adjusted to 8 with 2.5M NaOH. The product is extracted with ethyl acetate. The extract is washed with water, dried over sodium sulphate and the solvent is removed under reduced pressure to afford the title product. This is purified by flash chromatography on silica gel using heptane / ethyl acetate (9: 1-6: 4) as a gradient eluent.

1H NMR (300 MHz, DMSO-d 6 ): 2.20 (6H, s), 2.57 (2H, t, 3 J = 5.9 Hz), 3.92 (2H, t, 3 J = 5.9 Hz), 6.65 (2H, d, 3 J = 9.1 Hz), 6.74 (2H, d, 3 J = 9.0 Hz), 8.85 (1H, s, -OH). 1 H NMR (300 MHz, DMSO- d 6 ): 2.20 (6H, s), 2.57 (2H, t, 3 J = 5.9 Hz), 3.92 (2H, t, 3 J = 5.9 Hz), 6.65 (2H, d, 3 J = 9.1 Hz), 6.74 (2H, d, 3 J = 9.0 Hz), 8.85 (1H, s, -OH).

c) 3-[4-(2-디메틸아미노에톡시)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드c) 3- [4- (2-dimethylaminoethoxy) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-[4-(2-디메틸아미노에톡시)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 1c에 기재된 방법으로 4-(2-디메틸아미노에톡시)페놀과 2-메틸옥시란-2-카르복실산(4-풀루오로-3-메틸페닐)아마이드로부터 제조된다. 생성물은 pH 8에서 추출한다. 구배 용출제로 디클로로메탄/메탄올(0-20%)사용하여 플래시 크로마토그래피하여 정제한다.3- [4- (2-dimethylaminoethoxy) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamad is obtained by the method described in Example 1c. It is prepared from-(2-dimethylaminoethoxy) phenol and 2-methyloxirane-2-carboxylic acid (4-fuluro-3-methylphenyl) amide. The product is extracted at pH 8. Purify by flash chromatography using dichloromethane / methanol (0-20%) as gradient eluent.

1H NMR (400 MHz, DMSO-d 6 ): 1.42 (3H, s), 2.19 (6H, s), 2.53 (3H, s), 2.57 (2H, t, 3 J = 5.8 Hz), 3.90 (1H, d, 2 J gem = 9.6 Hz), 3.95 (2H, t, 3 J = 5.9 Hz), 4.14 (1H, d, 2 J gem = 9.5 Hz), 6.18 (1H, s, -OH), 6.83 (4H, s), 7.88 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.3 Hz), 7.93 (1H, d, 4 J = 1.8 Hz), 8.04 (1H, d, 3 J = 9.0 Hz), 10.14 (1H, s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.42 (3H, s), 2.19 (6H, s), 2.53 (3H, s), 2.57 (2H, t, 3 J = 5.8 Hz), 3.90 (1H , d, 2 J gem = 9.6 Hz, 3.95 (2H, t, 3 J = 5.9 Hz), 4.14 (1H, d, 2 J gem = 9.5 Hz), 6.18 (1H, s, -OH), 6.83 ( 4H, s), 7.88 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.3 Hz), 7.93 (1H, d, 4 J = 1.8 Hz), 8.04 (1H, d, 3 J = 9.0 Hz), 10.14 (1H, s, -NHCO-).

실시예 68Example 68

3-(4-시아노메틸펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드3- (4-cyanomethylphenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(4-시아노메틸펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 1c에 기재된 방법에 의하여 4-하이드록시-벤질시아나이드와 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 구배 용출제로 헵탄/초산에틸(9:1-7:3)을 사용하여 플래시 크로마토그래피하여 정제한다. m.p. 143-145℃.  3- (4-cyanomethylphenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamad is 4-hydroxy- by the method described in Example 1c. Benzyl cyanide and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography using heptane / ethyl acetate (9: 1-7: 3) as the gradient eluent. m.p. 143-145 ° C.

1H NMR (300 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 3.92 (2H, s), 3.98 (1H, d, 2 J gem = 9.7 Hz), 4.21 (1H, d, 2 J gem = 9.7 Hz), 6.17 (1H, broad s, -OH), 6.94 (2H, d, 3 J = 8.7 Hz), 7.23 (2H, d, 3 J = 8.7 Hz), 7.87 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.2 Hz), 7.92 (1H, s), 8.03 (1H, d, 3 J = 8.9 Hz), 10.09 (1H, broad s, -NHCO-). 1 H NMR (300 MHz, DMSO- d 6 ): 1.43 (3H, s), 2.53 (3H, s), 3.92 (2H, s), 3.98 (1H, d, 2 J gem = 9.7 Hz), 4.21 ( 1H, d, 2 J gem = 9.7 Hz, 6.17 (1H, broad s, -OH), 6.94 (2H, d, 3 J = 8.7 Hz), 7.23 (2H, d, 3 J = 8.7 Hz), 7.87 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.2 Hz), 7.92 (1H, s), 8.03 (1H, d, 3 J = 8.9 Hz), 10.09 (1H, broad s, -NHCO-).

실시예 69Example 69

3-[4-클로로에틸)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드3- [4-chloroethyl) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-[4-클로로에틸)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 1c에 기재된 방법에 의하여 4-(2-클로로에틸)페놀(A.C. Spivey et al. J.Org. Chem. 65(2000) 5253; P. G. Baraldi et al. J. Med. Chem. 45 (2002) 115)과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 구배 용출제로 헵탄/초산에틸(9:1-8:23)을 사용하여 2회 플래시 크로마토그래피하여 정제한다. 3- [4-Chloroethyl) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide is prepared by the method described in Example 1c according to the method described in Example 1c. Chloroethyl) phenol (AC Spivey et al. J. Org. Chem. 65 (2000) 5253; PG Baraldi et al. J. Med. Chem. 45 (2002) 115) and 2-methyloxirane-2-carboxyl Prepared from acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by two flash chromatography using heptane / ethyl acetate (9: 1-8: 23) as gradient eluent.

1H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 2.93 (2H, t, 3 J = 7.1 Hz), 3.77 (2H, t, 3 J = 7.1 Hz), 3.95 (1H, d, 2 J gem = 9.6 Hz), 4.19 (1H, d, 2 J gem = 9.6Hz), about 6.2 (1H, broad s, -OH), 6.85 (2H, d, 3 J = 8.6 Hz), 7.16 (2H, d, 3 J = 8.7 Hz), 7.89 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.3 Hz), 7.94(1H, d, 4 J = 2.2 Hz), 8.04 (1H, d, 3 J = 9.0 Hz), about 10.2 (1H, broad s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.43 (3H, s), 2.53 (3H, s), 2.93 (2H, t, 3 J = 7.1 Hz), 3.77 (2H, t, 3 J = 7.1 Hz), 3.95 (1H, d, 2 J gem = 9.6 Hz), 4.19 (1H, d, 2 J gem = 9.6 Hz), about 6.2 (1H, broad s, -OH), 6.85 (2H, d, 3 J = 8.6 Hz), 7.16 (2H, d, 3 J = 8.7 Hz), 7.89 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.3 Hz), 7.94 (1H, d, 4 J = 2.2 Hz), 8.04 (1H, d, 3 J = 9.0 Hz), about 10.2 (1H, broad s, -NHCO-).

실시예 70Example 70

2-하이드록시-3-(4-하이드록시메틸펜옥시)-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드2-hydroxy-3- (4-hydroxymethylphenoxy) -2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

2-하이드록시-3-(4-하이드록시메틸펜옥시)-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 1c에 기재된 방법에 의하여 4-하이드록시-벤질알콜과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성 물은 구배 용출제로 헵탄/초산에틸(95:25-25:75)을 사용하여 플래시 크로마토그래피하여 정제한다.2-Hydroxy-3- (4-hydroxymethylphenoxy) -2-methyl-N- (3-methyl-4-nitrophenyl) propionamad is 4-hydroxy- by the method described in Example 1c. Benzyl alcohol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography using heptane / ethyl acetate (95: 25-25: 75) as a gradient eluent.

1H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 3.95 (1H, d, 2 J gem = 9.6 Hz), 4.18 (1H, d, 2 J gem = 9.6 Hz), 4.39 (2H, d, 3 J = 5.3 Hz), 5.05 (1H, t, 3 J = 5.7 Hz), 6.22 (1H, s, -OH), 6.86 (2H, d, 3 J = 8.6 Hz), 7.19 (2H, d, 3 J = 8.8 Hz), 7.89 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.3 Hz), 7.94 (1H, d, 4 J = 2.2 Hz), 8.04 (1H, d, 3 J = 9.0 Hz), 10.16 (1H, s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.43 (3H, s), 2.53 (3H, s), 3.95 (1H, d, 2 J gem = 9.6 Hz), 4.18 (1H, d, 2 J gem = 9.6 Hz), 4.39 (2H, d, 3 J = 5.3 Hz), 5.05 (1H, t, 3 J = 5.7 Hz), 6.22 (1H, s, -OH), 6.86 (2H, d, 3 J = 8.6 Hz), 7.19 (2H, d, 3 J = 8.8 Hz), 7.89 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.3 Hz), 7.94 (1H, d, 4 J = 2.2 Hz), 8.04 (1H, d, 3 J = 9.0 Hz), 10.16 (1H, s, -NHCO-).

실시예 71Example 71

2-하이드록시-3-(4-하이드록시펜옥시)-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드2-hydroxy-3- (4-hydroxyphenoxy) -2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

2-하이드록시-3-(4-하이드록시펜옥시)-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 1c에 기재된 방법에 의하여 하이드로퀴논과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 구배 용출제로 헵탄/초산에틸(9:1-6:4)을 사용하여 플래시 크로마토그래피하여 정제한다.2-hydroxy-3- (4-hydroxyphenoxy) -2-methyl-N- (3-methyl-4-nitrophenyl) propionamad was hydroquinone and 2-methyl by the method described in Example 1c. It is prepared from oxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography using heptane / ethyl acetate (9: 1-6: 4) as a gradient eluent.

1H NMR (400 MHz, DMSO-d 6 ): 1.40 (3H, s), 2.53 (3H, s), 3.86 (1H, d, 2 J gem = 9.4 Hz), 4.10 (1H, d, 2 J gem = 9.4 Hz), 5.76 (1H, broad s, -OH), 6.63 (2H, d, 3 J = 9.0 Hz), 6.73 (2H, d, 3 J = 9.0 Hz), 7.88 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.4 Hz), 7.93 (1H, d, 4 J = 2.1 Hz), 8.04 (1H, d, 3 J = 9.0 Hz), 8.92 (1H, broad s, ArOH), 10.13 (1H, broad s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.40 (3H, s), 2.53 (3H, s), 3.86 (1H, d, 2 J gem = 9.4 Hz), 4.10 (1H, d, 2 J gem = 9.4 Hz), 5.76 (1H, broad s, -OH), 6.63 (2H, d, 3 J = 9.0 Hz), 6.73 (2H, d, 3 J = 9.0 Hz), 7.88 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.4 Hz), 7.93 (1H, d, 4 J = 2.1 Hz), 8.04 (1H, d, 3 J = 9.0 Hz), 8.92 (1H, broad s, ArO H ), 10.13 (1H, broad s, -NHCO-).

실시예 72Example 72

3-(3-시아노펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드3- (3-cyanophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(3-시아노펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 1c에 기재된 방법에 의하여 3-시아노페놀과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 구배 용출제로 헵탄/초산에틸을 사용하여 플래시 크로마토그래피하여 정제한다.m.p. 107-110℃3- (3-cyanophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamad was prepared by the method described in Example 1c and 2-cyanophenol and 2 -Methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography using heptane / ethyl acetate as the gradient eluant. 107-110 ℃

1H NMR (300 MHz, DMSO-d 6 ): 1.44 (3H, s), 2.53 (3H, s), 4.06 (1H, d, 2 J gem = 10.0 Hz), 4.31 (1H, d, 2 J gem = 9.9 Hz), about 6.3 (1H, broad s, -OH), 7.27 (1H, m), 7.38 (1H, dt, 3 J = 7.5 Hz, 4 J = 1.3 Hz), 7.43 (1H, m), 7.46 (1H, t, 3 J = 7.8 Hz), 7.87 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.3 Hz), 7.91 (1H, d, 4 J = 9.0 Hz, 4 J = 1.9 Hz), 8.03 (1H, d, 3 J = 9.0 Hz), about 10.1 (1H, broad s, -NHCO-). 1 H NMR (300 MHz, DMSO- d 6 ): 1.44 (3H, s), 2.53 (3H, s), 4.06 (1H, d, 2 J gem = 10.0 Hz), 4.31 (1H, d, 2 J gem = 9.9 Hz), about 6.3 (1H, broad s, -OH), 7.27 (1H, m), 7.38 (1H, dt, 3 J = 7.5 Hz, 4 J = 1.3 Hz), 7.43 (1H, m), 7.46 (1H, t, 3 J = 7.8 Hz), 7.87 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.3 Hz), 7.91 (1H, d, 4 J = 9.0 Hz, 4 J = 1.9 Hz), 8.03 (1H, d, 3 J = 9.0 Hz), about 10.1 (1H, broad s, -NHCO-).

실시예 73Example 73

3-(3-풀루오로메틸펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드3- (3-Pluoromethylphenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(3-풀루오로메틸펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 1c에 기재된 방법에 의하여 3-풀루오로-5-(트리풀루오로메틸)페놀과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 구배 용출제로 헵탄/초산에틸을 사용하여 플래시 크로마토그래피하여 정제한다. 결정화는 톨루엔/헵탄으로 행한다.3- (3-Pluoromethylphenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamad is obtained by the method described in Example 1c. It is prepared from rho-5- (trifuluromethyl) phenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography using heptane / ethyl acetate as the gradient eluent. Crystallization is carried out with toluene / heptane.

1H NMR (400 MHz, DMSO-d 6 ): 1.44 (3H, s), 2.53 (3H, s), 4.15 (1H, d, 2 J gem = 10.0 Hz), 4.37 (1H, d, 2 J gem = 10.0 Hz), 6.26 (1H, broad s, -OH), 7.12 (1H, s), 7.19 7.22 (2H, m), 7.87 (1H, dd, 3 J = 8.9 Hz, 4 J = 2.3 Hz), 7.92 (1H, d, 4 J = 1.9 Hz), 8.03 (1H, d, 3 J = 9.0 Hz), 10.15 (1H, broad s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.44 (3H, s), 2.53 (3H, s), 4.15 (1H, d, 2 J gem = 10.0 Hz), 4.37 (1H, d, 2 J gem = 10.0 Hz), 6.26 (1H, broad s, -OH), 7.12 (1H, s), 7.19 7.22 (2H, m), 7.87 (1H, dd, 3 J = 8.9 Hz, 4 J = 2.3 Hz), 7.92 (1H, d, 4 J = 1.9 Hz), 8.03 (1H, d, 3 J = 9.0 Hz), 10.15 (1H, broad s, -NHCO-).

실시예 74Example 74

3-(3,5-디풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드3- (3,5-difluurofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(3,5-디풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 1c에 기재된 방법에 의하여 3-(3,5-디풀루오)로페놀과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 구배 용출제로 헵탄/초산에틸(95:5-70:30)을 사용하여 플래시 크로마토그래피하여 정제한다.결정화는 톨우엔에서 행한다. m.p. 104 -106℃.3- (3,5-Difluurofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamad was obtained by the method described in Example 1c. 3,5-difluo) is prepared from phenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography using heptane / ethyl acetate (95: 5-70: 30) as a gradient eluent. Crystallization is carried out in toluene. m.p. 104-106 ° C.

1H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 4.01 (1H, d, 2 J gem = 9.9 Hz), 4.27 (1H, d, 2 J gem = 9.8 Hz), about 6.3 (1H, broad s, -OH), 6.71 (2H, dd, 3 J HF = 9.5 Hz, 4 J HH = 2.1 Hz), 6.76 (1H, tt, 3 J HF = 9.4 Hz, 4 J HH = 2.3 Hz), 7.87 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.4 Hz), 7.92 (1H, d, 4 J = 2.2 Hz), 8.04 (1H, d, 3 J = 9.0 Hz), about 10.1 (1H, broad s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.43 (3H, s), 2.53 (3H, s), 4.01 (1H, d, 2 J gem = 9.9 Hz), 4.27 (1H, d, 2 J gem = 9.8 Hz), about 6.3 (1H, broad s, -OH), 6.71 (2H, dd, 3 J HF = 9.5 Hz, 4 J HH = 2.1 Hz), 6.76 (1H, tt, 3 J HF = 9.4 Hz, 4 J HH = 2.3 Hz), 7.87 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.4 Hz), 7.92 (1H, d, 4 J = 2.2 Hz), 8.04 (1H, d, 3 J = 9.0 Hz), about 10.1 (1H, broad s, -NHCO-).

실시예 75Example 75

3-(2,3-디풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드3- (2,3-difluurofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(2,3-디풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 1c에 기재된 방법에 의하여 2,3-디풀루오로페놀과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 처음에 용출제로 헵탄/초산에틸(8:2)를 사용하고 다음에 디클로로메탄을 사용하여 플래시 크로마토그래피하여 정제한다. 결정화는 헵탄에서 행한다. m.p. 68-73℃3- (2,3-Difluurofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamad is 2,3 by the method described in Example 1c. It is prepared from difulurophenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is first purified by flash chromatography using heptane / ethyl acetate (8: 2) as eluent and then using dichloromethane. Crystallization is carried out in heptane. m.p. 68-73 ℃

1H NMR (300 MHz, DMSO-d 6 ): 1.44(3H, s), 2.53 (3H, s), 4.11 (1H, d, 2 J gem = 9.9 Hz), 4.31 (1H, d, 2 J gem = 9.8 Hz), 6.28 (1H, s, -OH), 6.93 7.14 (3H, m), 7.86 (1H, dd, 3 J = 8.9 Hz, 4 J = 2.3 Hz), 7.91 (1H, d, 4 J = 2.1 Hz), 8.03 (1H, d, 3 J = 8.9 Hz), 10.15 (1H, s, -NHCO-). 1 H NMR (300 MHz, DMSO- d 6 ): 1.44 (3H, s), 2.53 (3H, s), 4.11 (1H, d, 2 J gem = 9.9 Hz), 4.31 (1H, d, 2 J gem = 9.8 Hz), 6.28 (1H, s, -OH), 6.93 7.14 (3H, m), 7.86 (1H, dd, 3 J = 8.9 Hz, 4 J = 2.3 Hz), 7.91 (1H, d, 4 J = 2.1 Hz), 8.03 (1H, d, 3 J = 8.9 Hz), 10.15 (1H, s, -NHCO-).

실시예 76Example 76

3-(2,6-디풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드3- (2,6-difluurofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(2,6-디풀루오로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프 로피온아마아드는 실시예 1c에 기재된 방법에 의하여 2,6-디풀루오로페놀과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 구배 용출제로 헵탄/초산에틸(9:1-7:3)를 사용하여 플래시 크로마토그래피하여 정제한다. 3- (2,6-Difluurofenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide is prepared by the method described in Example 1c. , 6-difluurophenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography using heptane / ethyl acetate (9: 1-7: 3) as the gradient eluent.

1H NMR (400 MHz, DMSO-d 6 ): 1.40 (3H, s), 2.53 (3H, s), 4.16 (1H, d, 2 J gem = 10.0 Hz), 4.31 (1H, d, 2 J gem = 10.0 Hz), 6.18 (1H, broad s, -OH), 7.06 7.12 (3H, m), 7.86 (1H, dd, 3 J = 8.9 Hz, 4 J = 2.3 Hz), 7.88 (1H, d, 4 J = 2.3 Hz), 8.04 (1H, d, 3 J = 8.8 Hz), 10.08 (1H, broad s, -NHCO-) 1 H NMR (400 MHz, DMSO- d 6 ): 1.40 (3H, s), 2.53 (3H, s), 4.16 (1H, d, 2 J gem = 10.0 Hz), 4.31 (1H, d, 2 J gem = 10.0 Hz), 6.18 (1H, broad s, -OH), 7.06 7.12 (3H, m), 7.86 (1H, dd, 3 J = 8.9 Hz, 4 J = 2.3 Hz), 7.88 (1H, d, 4 J = 2.3 Hz), 8.04 (1H, d, 3 J = 8.8 Hz), 10.08 (1H, broad s, -NHCO-)

실시예 77Example 77

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-(3-트리풀루오로메틸-펜옥시)프로피온아마아드2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3- (3-trifluorofluoromethyl-phenoxy) propionamide

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-(3-트리풀루오로메틸-펜옥시)프로피온아마아드는 실시예 1c에 기재된 방법에 의하여 3-하이드록시벤조트리풀루오라이드와 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 구배 용출제로 헵탄/초산에틸(9:1-5:5)를 사용하여 플래시 크로마토그래피하여 정제한다. 결정화는 디클로로메탄/EtOH/헵탄에서 행한다.m.p. 84-87℃2-Hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3- (3-trifluorofluoromethyl-phenoxy) propionamide was prepared by the method described in Example 1c. It is prepared from hydroxybenzotrifluolide and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography using heptane / ethyl acetate (9: 1-5: 5) as the gradient eluent. Crystallization is carried out in dichloromethane / EtOH / heptane. M. 84-87 ℃

1H NMR (400 MHz, DMSO-d 6 ): 1.45 (3H, s), 2.53 (3H, s), 4.07 (1H, d, 2 J gem = 9.8 Hz), 4.33 (1H, d, 2 J gem = 9.8 Hz), 6.25 (1H, broad s, -OH), 7.23 (1H, s), 7.24 (1H, d, 3 J = 6.7 Hz,), 7.28 (1H, d, 3 J = 7.7 Hz,), 7.50 (1H, t, 3 J = 8.3 Hz,), 7.88 (1H, dd, 3 J = 8.9 Hz, 4 J = 2.3 Hz), 7.92 (1H, d, 4 J = 2.0 Hz), 8.03 (1H, d, 3 J = 9.0 Hz), 10.15 (1H, broad s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.45 (3H, s), 2.53 (3H, s), 4.07 (1H, d, 2 J gem = 9.8 Hz), 4.33 (1H, d, 2 J gem = 9.8 Hz), 6.25 (1H, broad s, -OH), 7.23 (1H, s), 7.24 (1H, d, 3 J = 6.7 Hz,), 7.28 (1H, d, 3 J = 7.7 Hz,) , 7.50 (1H, t, 3 J = 8.3 Hz,), 7.88 (1H, dd, 3 J = 8.9 Hz, 4 J = 2.3 Hz), 7.92 (1H, d, 4 J = 2.0 Hz), 8.03 (1H , d, 3 J = 9.0 Hz), 10.15 (1H, broad s, -NHCO-).

실시예 78Example 78

3-(3,5-디클로로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드3- (3,5-dichlorophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-(3,5-디클로로펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 1c에 기재된 방법에 의하여 3,5-디클로로페놀과2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 구배 용출제로 헵탄/초산에틸(9:1)를 사용하여 플래시 크로마토그래피하여 정제한다. 결정화는 톨루엔에서 행한다. m.p. 141 -143℃.3- (3,5-dichlorophenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamad is 3,5-dichloro by the method described in Example 1c. It is prepared from phenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography using heptane / ethyl acetate (9: 1) as the gradient eluent. Crystallization is carried out in toluene. m.p. 141 -143 ° C.

1H NMR (400 MHz, DMSO-d 6 ): 1.42(3H, s), 2.53 (3H, s), 4.05 (1H, d, 2 J gem = 10.1 Hz), 4.31 (1H, d, 2 J gem = 10.1 Hz), about 6.2 (1H, broad s, -OH), 7.04 (2H, distorted d, 4 J = 1.9 Hz), 7.13 (1H, distorted t, 4 J = 1.7 Hz), 7.87 (1H, d, 3 J = 8.9 Hz), 7.92 (1H, s), 8.04 (1H, d, 3 J = 8.90 Hz), about 10.1 (1H, broad s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.42 (3H, s), 2.53 (3H, s), 4.05 (1H, d, 2 J gem = 10.1 Hz), 4.31 (1H, d, 2 J gem = 10.1 Hz), about 6.2 (1H, broad s, -OH), 7.04 (2H, distorted d, 4 J = 1.9 Hz), 7.13 (1H, distorted t, 4 J = 1.7 Hz), 7.87 (1H, d , 3 J = 8.9 Hz), 7.92 (1 H, s), 8.04 (1 H, d, 3 J = 8.90 Hz), about 10.1 (1 H, broad s, -NHCO-).

실시예 79Example 79

3-[4-(3-클로로프로필)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드3- [4- (3-chloropropyl) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

a) 4-(3-클로로프로필)페놀a) 4- (3-chloropropyl) phenol

2-(4-하이드록시페닐)-1-프로판올(0.97g, 0.006374mol)과 진한 염산(20ml)를 100℃에서 14시간 가열한다. 냉각시킨 다음, 반응혼합물을 물에 붓고, 초산에틸로 추출한다. 추출액들을 합하고, 물로 추출하고 건조시킨 후 진공중에서 농축하여 조생성물을 얻는다. 조생성물은 용출제로 헵탄/초산에틸(9:1)을 사용하여 플래시 크로마토그래피하여 순수한 생성물(0.98g, 90%)을 얻는다. 2- (4-hydroxyphenyl) -1-propanol (0.97 g, 0.006374 mol) and concentrated hydrochloric acid (20 ml) are heated at 100 ° C. for 14 hours. After cooling, the reaction mixture is poured into water and extracted with ethyl acetate. The extracts are combined, extracted with water, dried and concentrated in vacuo to afford the crude product. The crude product is flash chromatographed using heptane / ethyl acetate (9: 1) as eluent to afford pure product (0.98 g, 90%).

1H NMR (400 MHz, DMSO-d 6 ): 1.95 (2H, quintet, 3 J = 7.0 Hz), 2.59 (2H, t, 3 J = 7.5 Hz), 3.58 (2H, t, 3 J = 6.5 Hz), 6.67 (2H, d, 3 J = 8.2 Hz), 6.99 (2H, d, 3 J = 8.2 Hz), 9.15 (1H, s, -OH). 1 H NMR (400 MHz, DMSO- d 6 ): 1.95 (2H, quintet, 3 J = 7.0 Hz), 2.59 (2H, t, 3 J = 7.5 Hz), 3.58 (2H, t, 3 J = 6.5 Hz ), 6.67 (2H, d, 3 J = 8.2 Hz), 6.99 (2H, d, 3 J = 8.2 Hz), 9.15 (1H, s, -OH).

b) 3-[4-(3-클로로프로필)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드b) 3- [4- (3-chloropropyl) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-[4-(3-클로로프로필)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 1c에 기재된 방법에 의하여 4-(3-클로로프로필페놀과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제로 처음에 디클로로메탄만을 사용하고, 다음에 헵탄/초산에틸(9:1)을 사용하여 정제한다. m.p. 110-112℃3- [4- (3-Chloropropyl) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamad was obtained by the method described in Example 1c. Prepared from (3-chloropropylphenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is flash chromatography (first using only dichloromethane as eluent, Then purified using heptane / ethyl acetate (9: 1) mp 110-112 ° C.

1H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 1.95 (2H, quintet, 3 J = 7.0 Hz), 2.53 (3H, s), 2.62 (2H, t, 3 J = 7.4 Hz), 3.58 (2H, t, 3 J = 6.5 Hz), 3.95 (1H, d, 2 J gem = 9.6 Hz), 4.18 (1H, d, 2 J gem = 9.5 Hz), 6.15 (1H, broad s, -OH), 6.84 (2H, d, 3 J = 8.5 Hz), 7.10 (2H, d, 3 J = 8.4 Hz), 7.88 (1H, d, 3 J = 9.1 Hz), 7.93 (1H, s), 8.03 (1H, d, 3 J = 9.0 Hz), 10.14(1H, broad s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.43 (3H, s), 1.95 (2H, quintet, 3 J = 7.0 Hz), 2.53 (3H, s), 2.62 (2H, t, 3 J = 7.4 Hz), 3.58 (2H, t, 3 J = 6.5 Hz), 3.95 (1H, d, 2 J gem = 9.6 Hz), 4.18 (1H, d, 2 J gem = 9.5 Hz), 6.15 (1H, broad s , -OH), 6.84 (2H, d, 3 J = 8.5 Hz), 7.10 (2H, d, 3 J = 8.4 Hz), 7.88 (1H, d, 3 J = 9.1 Hz), 7.93 (1H, s) , 8.03 (1H, doublet, 3 J = 9.0 Hz), 10.14 (1H, broad s, -NHCO-).

실시예 80Example 80

3-[4-(2-클로로프로필)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드3- [4- (2-chloropropyl) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-[4-(2-클로로프로필)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 1c에 기재된 방법에 의하여 4-(2-클로로에톡시)페놀(H. K. A. C. Coolen et al., Recueil des Travaux Chimiques des Pays-Bas 114(2) (1995) 65)과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 용출제로 헵탄/초산에틸(9:1)을 사용하여 플래시 크로마토그래피하여 정제한다. m.p. 131-133℃3- [4- (2-Chloropropyl) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamad was obtained by the method described in Example 1c. (2-Chloroethoxy) phenol (HKAC Coolen et al., Recueil des Travaux Chimiques des Pays-Bas 114 (2) (1995) 65) and 2-methyloxirane-2-carboxylic acid (3-methyl-4 -Nitrophenyl) amide. The crude product is purified by flash chromatography using heptane / ethyl acetate (9: 1) as eluent. m.p. 131-133 ℃

1H NMR (400 MHz, DMSO-d 6 ): 1.42 (3H, s), 2.53 (3H, s), 3.88-3.93 (3H, m), 4.14-4.18 (3H, m), about 6.2 (1H, broad s, -OH), 6.86 (4H, s), 7.88 (1H, d, 3 J = 9.0 Hz), 7.92 (1H, s), 8.04 (1H, d, 3 J = 9.0 Hz), about 10.1 (1H, broad s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.42 (3H, s), 2.53 (3H, s), 3.88-3.93 (3H, m), 4.14-4.18 (3H, m), about 6.2 (1H, broad s, -OH), 6.86 (4H, s), 7.88 (1H, d, 3 J = 9.0 Hz), 7.92 (1H, s), 8.04 (1H, d, 3 J = 9.0 Hz), about 10.1 ( 1H, broad s, -NHCO-).

실시예 81Example 81

2-하이드록시-3-(4-메톡시메틸펜옥시)-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드2-hydroxy-3- (4-methoxymethylphenoxy) -2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

2-하이드록시-3-(4-메톡시메틸펜옥시)-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 1c에 기재된 방법에 의하여 4-(메톡시메틸)페놀(J. M. Sa et al., J. Org. Chem. 53 (1988) 4263; D. R. Dimmel and D. Shepard, J. Org. Chem. 47 (1982) 22)과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 수회 플래시 크로마토그래피(구배 용출제로 디클로로메탄/메탄올 99:1; 헵탄/초산에틸 9:1-7:3; 및 디클로로메탄/메탄올 99.5:0.5)를 사용하여 플래시 크로마토그래피하여 정제한다.2-Hydroxy-3- (4-methoxymethylphenoxy) -2-methyl-N- (3-methyl-4-nitrophenyl) propionamad was obtained from 4- (methoxy by the method described in Example 1c. Methyl) phenol (JM Sa et al., J. Org. Chem. 53 (1988) 4263; DR Dimmel and D. Shepard, J. Org. Chem. 47 (1982) 22) and 2-methyloxirane-2- Prepared from carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography using several flash chromatography (dichloromethane / methanol 99: 1 as gradient eluent; heptane / ethyl acetate 9: 1-7: 3; and dichloromethane / methanol 99.5: 0.5).

1H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 3.22 (3H, s), 3.97 (1H, d, 2 J gem = 9.6 Hz), 4.20 (1H, d, 2 J gem = 9.5 Hz), 4.30 (2H, s), 6.19 (1H, broad s, -OH), 6.89 (2H, d, 3 J = 7.9 Hz), 7.20 (2H, d, 3 J = 8.2 Hz), 7.88 (1H, d, 3 J = 9.0 Hz), 7.93 (1H, s), 8.04 (1H, d, 3 J = 9.0 Hz), 10.13 (1H, broad s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.43 (3H, s), 2.53 (3H, s), 3.22 (3H, s), 3.97 (1H, d, 2 J gem = 9.6 Hz), 4.20 ( 1H, d, 2 J gem = 9.5 Hz), 4.30 (2H, s), 6.19 (1H, broad s, -OH), 6.89 (2H, d, 3 J = 7.9 Hz), 7.20 (2H, d, 3 J = 8.2 Hz), 7.88 (1H, d, 3 J = 9.0 Hz), 7.93 (1H, s), 8.04 (1H, d, 3 J = 9.0 Hz), 10.13 (1H, broad s, -NHCO-).

실시예 82Example 82

3-[4-(2-풀루오로에틸)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드3- [4- (2-Pluoroethyl) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

무수 디클로로메탄(3ml)중의 2-하이드록시-3-[4-(2-하이드록시-2메틸-N-(3- 메틸-4-니트로페닐)프로피온아마이드(실시예 20에서 제조된 것, 300mg, 0.0008012mol)의 용액을 무수 디클로로메탄(1ml)중의 Deoxo-Flour (195mg, 0.0008012mol)로 -15 내지 -10℃에서 처리한다. 용액을 0℃에서 2시간 교반한 다음, 실온에서 3일간 교반한다. 포화 탄산수소나트륨 용액을 가하고, 혼합물을 디클로로메탄으로 추출한다. 추출액을 합하고 물로 세척한 후, 황산나트륨으로 건조시킨다음, 여과하고, 진공증류시킨다. 조생성물은 용출제로 디클로로메탄을 사용하여 플래시 크로마토그래피하여 정제한다. 톨루엔으로 결정화시켜서 순수한 결정을 얻는다. m.p. 102-105℃2-hydroxy-3- [4- (2-hydroxy-2methyl-N- (3-methyl-4-nitrophenyl) propionamide in anhydrous dichloromethane (3 ml) (300 mg, prepared in Example 20) , 0.0008012 mol) was treated with Deoxo-Flour (195 mg, 0.0008012 mol) in anhydrous dichloromethane (1 ml) at -15 to -10 ° C. The solution was stirred at 0 ° C. for 2 hours and then at room temperature for 3 days Saturated sodium hydrogen carbonate solution is added and the mixture is extracted with dichloromethane The extracts are combined, washed with water, dried over sodium sulfate, filtered and vacuum distilled The crude product is flashed using dichloromethane as eluent. Purify by chromatography Crystallize with toluene to give pure crystals mp 102-105 ° C

1H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 2.88 (2H, dt, 3 J HF = 24.4 Hz, 3J = 6.4 Hz), 3.95 (1H, d, 2 J gem = 9.8 Hz), 4.18 (1H, d, 2 J gem = 9.5 Hz), 4.56 (2H, dt, 2 J HF = 47.4 Hz, 3 J = 6.4 Hz), 6.18 (1H, broad s, -OH), 6.85 (2H, d, 3J = 8.5 Hz), 7.15 (2H, d, 3 J = 8.4 Hz), 7.88 (1H, d, 3 J = 9.0 Hz), 7.93 (1H, s), 8.03 (1H, d, 3 J = 9.0 Hz), 10.13(1H, broad s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.43 (3H, s), 2.53 (3H, s), 2.88 (2H, dt, 3 J HF = 24.4 Hz, 3J = 6.4 Hz), 3.95 (1H, d, 2 J gem = 9.8 Hz), 4.18 (1H, d, 2 J gem = 9.5 Hz), 4.56 (2H, dt, 2 J HF = 47.4 Hz, 3 J = 6.4 Hz), 6.18 (1H, broad s, -OH), 6.85 (2H, d, 3J = 8.5 Hz), 7.15 (2H, d, 3 J = 8.4 Hz), 7.88 (1H, d, 3 J = 9.0 Hz), 7.93 (1H, s), 8.03 (1H, d, 3 J = 9.0 Hz), 10.13 (1H, broad s, -NHCO- ).

실시예 83Example 83

3-(4-풀루오로메틸)펜옥시)-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드3- (4-Pluoromethyl) phenoxy) -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

무수 디클로로메탄(6.5ml)중의 2-하이드록시-3-(4-하이드록시메틸펜옥시)-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드(실시예 70에서 제조된 것, 950mg, 0.002636mol)을 의 용액을 무수 디클로로메탄(3ml)중의 Deoxo-Flour (875mg, 0.003954mol)로 -76℃에서 처리한다. 용액을 -10℃에서 3시간 교반한다. 포화 탄산수소나트륨 용액을 가하고, 혼합물을 디클로로메탄으로 추출한다. 추출액을 합하고 물로 세척한 후, 황산나트륨으로 건조시킨다음, 여과하고, 진공증류시킨다. 조생성물은 구배 용출제로 헵탄/초산에틸(9:1-5:5)을 사용하여 플래시 크로마토그래피하여 정제한다. 디클로로메탄/헵탄으로 결정화시켜서 순수한 결정을 얻는다.2-hydroxy-3- (4-hydroxymethylphenoxy) -2-methyl-N- (3-methyl-4-nitrophenyl) propionamide in the anhydrous dichloromethane (6.5 ml) (prepared in Example 70) , 950 mg, 0.002636 mol) is treated with a solution of Deoxo-Flour (875 mg, 0.003954 mol) in anhydrous dichloromethane (3 ml) at -76 ° C. The solution is stirred at −10 ° C. for 3 hours. Saturated sodium hydrogen carbonate solution is added and the mixture is extracted with dichloromethane. The extracts are combined, washed with water, dried over sodium sulfate, filtered and vacuum distilled. The crude product is purified by flash chromatography using heptane / ethyl acetate (9: 1-5: 5) as the gradient eluent. Crystallization with dichloromethane / heptane gives pure crystals.

1H NMR (400 MHz, DMSO-d 6 ): 1.44 (3H, s), 2.53 (3H, s), 4.00 (1H, d, 2 J gem = 9.7 Hz), 4.24 (1H, d, 2 J gem = 9.6 Hz), 5.30 (2H, d, 2 J HF = 48.6 Hz), 6.21 (1H, s, -OH), 6.95 (2H, d, 3 J = 8.4 Hz), 7.34 (2H, d, 3 J = 8.6 Hz), 7.84 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.0 Hz), 7.93 (1H, broad s), 8.03 (1H, d, 3 J = 9.0 Hz), 10.14(1H, s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.44 (3H, s), 2.53 (3H, s), 4.00 (1H, d, 2 J gem = 9.7 Hz), 4.24 (1H, d, 2 J gem = 9.6 Hz, 5.30 (2H, d, 2 J HF = 48.6 Hz), 6.21 (1H, s, -OH), 6.95 (2H, d, 3 J = 8.4 Hz), 7.34 (2H, d, 3 J = 8.6 Hz), 7.84 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.0 Hz), 7.93 (1 H, broad s), 8.03 (1 H, d, 3 J = 9.0 Hz), 10.14 (1 H, s, -NHCO-).

실시예 84Example 84

3-[4-(2-브로모에틸)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드3- [4- (2-bromoethyl) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

a) 4-(2-브로모펜에틸)알콜a) 4- (2-bromophenethyl) alcohol

(4-하이드록시펜에틸)알콜(1.50g, 0.01086mol) 및 48wt% 브롬화수소산(10ml)를 100℃에서 1.5시간 가열한다. 냉각시킨 후, 반응혼합물을 물에 붓고, 초산에틸로 추출한다. 추출액을 물로 세척하고, 건조시킨 후, 진공 농축시켜서 조 생성물을 얻는다. 조생성물은 플래시 크로마토그래피(용출제 헵탄/초산에틸 9:1)하여 정제하여 순품(2.01g, 92%)을 얻는다.(4-hydroxyphenethyl) alcohol (1.50 g, 0.01086 mol) and 48 wt% hydrobromic acid (10 ml) are heated at 100 ° C. for 1.5 hours. After cooling, the reaction mixture is poured into water and extracted with ethyl acetate. The extract is washed with water, dried and concentrated in vacuo to afford the crude product. The crude product is purified by flash chromatography (eluent heptane / ethyl acetate 9: 1) to give the pure product (2.01 g, 92%).

1H NMR (400 MHz, DMSO-d 6 ): 2.99 (2H, t, 3 J = 7.4 Hz), 3.63 (2H, t, 3 J = 7.4 Hz), 6.68 (2H, d, 3 J = 8.5 Hz), 7.05 (2H, d, 3 J = 8.3 Hz), 9.24 (1H, s, -OH). 1 H NMR (400 MHz, DMSO- d 6 ): 2.99 (2H, t, 3 J = 7.4 Hz), 3.63 (2H, t, 3 J = 7.4 Hz), 6.68 (2H, d, 3 J = 8.5 Hz ), 7.05 (2H, d, 3 J = 8.3 Hz), 9.24 (1H, s, -OH).

b) 3-[4-(2-브로모에틸)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드b) 3- [4- (2-bromoethyl) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-[4-(2-브로모에틸)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 1c에 기재된 방법에 의하여 4-(2-브로모에틸)페놀과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제로 디클로로메탄/메탄올 99:1 또는 톨루엔/메탄올 99.5:0.5를 사용하고, 불순물이 포함된 생성물을 얻는다. 최종 정제는 제조용 HPLC를 사용하여 행한다.3- [4- (2-bromoethyl) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamad was prepared by the method described in Example 1c. It is prepared from-(2-bromoethyl) phenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is subjected to flash chromatography (dichloromethane / methanol 99: 1 or toluene / methanol 99.5: 0.5 as eluent to obtain the product containing impurities. Final purification is done using preparative HPLC.

1H NMR (400 MHz, CDCl3): 1.59 (3H, s), 2.63 (3H, s), 3.10 (2H, t, 3 J = 7.5 Hz), about 3.5 (-OH), 3.52 (2H, t, 3 J = 7.4 Hz), 3.98 (1H, d, 2 J gem = 9.0 Hz), 4.44 (1H, d, 2 J gem = 9.0 Hz), 6.87 (2H, d, 3 J = 8.6 Hz), 7.13 (2H, d, 3 J = 8.6 Hz), 7.57 (1H, dd, 3 J = 8.9 Hz, 4 J = 2.3 Hz), 7.65 (1H, d, 4 J = 2.2 Hz), 8.06 (1H, d, 3 J = 8.9 Hz), 9.00 (1H, s, -NHCO-). 1 H NMR (400 MHz, CDCl 3 ): 1.59 (3H, s), 2.63 (3H, s), 3.10 (2H, t, 3 J = 7.5 Hz), about 3.5 (-OH), 3.52 (2H, t , 3 J = 7.4 Hz), 3.98 (1H, d, 2 J gem = 9.0 Hz), 4.44 (1H, d, 2 J gem = 9.0 Hz), 6.87 (2H, d, 3 J = 8.6 Hz), 7.13 (2H, d, 3 J = 8.6 Hz), 7.57 (1H, dd, 3 J = 8.9 Hz, 4 J = 2.3 Hz), 7.65 (1H, d, 4 J = 2.2 Hz), 8.06 (1H, d, 3 J = 8.9 Hz), 9.00 (1H, s, -NHCO-).

실시예 85Example 85

2-하이드록시-3-(2-요도에틸)펜옥시]-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드2-hydroxy-3- (2-iodoethyl) phenoxy] -2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

a) 4-(2-요도에틸)페놀a) 4- (2-iodoethyl) phenol

트리페닐포스핀(1.57g, 0.006mol)과 이미다졸(0.41g, 0.006mol)을 무수 디클로로메탄(20ml) 에 가한다. 이미다졸이 용액이 되었을 때, 요드(1.52g, 0.006mol)을 가한다. 이미다졸 염산염이 침전되면, (4-하이드록시펜에틸)알콜(0.69g, 0.005mol)을 가한다. 혼합물을 실온에서 4시간 교반 한다음, 물을 가하고, 혼합물을 디클로로메탄으로 추출한다. 추출액을 물로 세척한 후, 건조시키고 진공농축하여 조생성물을 얻는다. 조생성물은 플래시 크로마토그래피(구배 용출제로 헵탄/초산에틸 9:1-6:4)하여 순품을 얻는다.Triphenylphosphine (1.57 g, 0.006 mol) and imidazole (0.41 g, 0.006 mol) are added to anhydrous dichloromethane (20 ml). When imidazole is in solution, iodine (1.52 g, 0.006 mol) is added. If imidazole hydrochloride precipitates, (4-hydroxyphenethyl) alcohol (0.69 g, 0.005 mol) is added. The mixture is stirred for 4 hours at room temperature, then water is added and the mixture is extracted with dichloromethane. The extract is washed with water, dried and concentrated in vacuo to afford the crude product. The crude product is subjected to flash chromatography (heptane / ethyl acetate 9: 1-6: 4 with gradient eluent) to obtain the pure product.

1H NMR (400 MHz, DMSO-d 6 ): 2.99 (2H, t, 3 J = 7.6 Hz), 3.38 (2H, t, 3 J = 7.6 Hz), 6.68 (2H, d, 3 J = 8.5 Hz), 7.03 (2H, d, 3 J = 8.5 Hz), 9.24 (1H, s, -OH). 1 H NMR (400 MHz, DMSO- d 6 ): 2.99 (2H, t, 3 J = 7.6 Hz), 3.38 (2H, t, 3 J = 7.6 Hz), 6.68 (2H, d, 3 J = 8.5 Hz ), 7.03 (2H, d, 3 J = 8.5 Hz), 9.24 (1H, s, -OH).

b) 2-하이드록시-3-(2-요도에틸)펜옥시]-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드b) 2-hydroxy-3- (2-iodoethyl) phenoxy] -2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

2-하이드록시-3-(2-요도에틸)펜옥시]-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 1c에 기재된 방법에 의하여 4-(2-브로모에틸)페놀과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(구배 용출제로 헵탄/초산에틸 9:1-6:4)하여 불순한 생성물을 얻는다. 최종 정제는 제조용 HPLC를 사용하여 행한다.2-Hydroxy-3- (2-iodoethyl) phenoxy] -2-methyl-N- (3-methyl-4-nitrophenyl) propionamad was obtained by the method described in Example 1c. Bromoethyl) phenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is flash chromatographed (heptane / ethyl acetate 9: 1-6: 4 with gradient eluent) to afford impure product. Final purification is done using preparative HPLC.

1H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 3.03 (2H, t, 3 J = 7.4 Hz), 3.40 (2H, t, 3 J = 7.4 Hz), 3.96 (1H, d, 2 J gem = 9.6 Hz), 4.19 (1H, d, 2 J gem = 9.6 Hz), 6.17 (1H, s, -OH), 6.85 (2H, d, 3 J = 8.6 Hz), 7.14 (2H, d, 3 J = 8.6 Hz), 7.88 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.2 Hz), 7.93 (1H, d, 4 J = 2.0 Hz), 8.03 (1H, d, 3 J = 9.0 Hz), 10.13 (1H, s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.43 (3H, s), 2.53 (3H, s), 3.03 (2H, t, 3 J = 7.4 Hz), 3.40 (2H, t, 3 J = 7.4 Hz), 3.96 (1H, d, 2 J gem = 9.6 Hz), 4.19 (1H, d, 2 J gem = 9.6 Hz), 6.17 ( 1H, s, -OH), 6.85 (2H, d, 3 J = 8.6 Hz), 7.14 (2H, d, 3 J = 8.6 Hz), 7.88 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.2 Hz), 7.93 (1H, d, 4 J = 2.0 Hz), 8.03 (1H, d, 3 J = 9.0 Hz), 10.13 (1H, s, -NHCO-).

실시예 86Example 86

3-[4-(2-브로모에톡시)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드3- [4- (2-bromoethoxy) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

a) 4-(2-브로모에톡시)페놀a) 4- (2-bromoethoxy) phenol

포타슘 카보네이트(7.53g, 0.05448mol)을 하이드로퀴논(2.00g, 0.01816mol)과 1,2-디브로모에탄(3.39g, 0.01805mol)의 아세톤 용액(50ml)에 가한다. 혼합물을 질소기류하에 6시간동안 환류시킨다. 혼합물을 여과하고, 물을 가한 다음 pH를 2-3으로 조절한다. 혼합물을 초산에틸로 추출한다. 추출액을 물로 세척하고 무수 황산나트륨으로 건조시킨 다음 여과하고 증발시킨다. Potassium carbonate (7.53 g, 0.05448 mol) is added to an acetone solution (50 ml) of hydroquinone (2.00 g, 0.01816 mol) and 1,2-dibromoethane (3.39 g, 0.01805 mol). The mixture is refluxed for 6 hours under a stream of nitrogen. The mixture is filtered, water is added and the pH is adjusted to 2-3. The mixture is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate, filtered and evaporated.

조생성물은 플래시 크로마토그래피(구배 용출제로 헵탄/초산에틸 95:5-70:30)하여 원하는 순수한 생성물을 백색결정으로 얻는다.The crude product is flash chromatographed (heptane / ethyl acetate 95: 5-70: 30 with gradient eluent) to afford the desired pure product as white crystals.

1H NMR (400 MHz, DMSO-d 6 ): 3.74 (2H, t, 3 J = 5.5 Hz), 4.19 (2H, t, 3 J = 5.5 Hz), 6.67 (2H, d, 3 J = 8.9 Hz), 6.78 (2H, d, 3 J = 8.9 Hz), 8.95 (1H, s, -OH). 1 H NMR (400 MHz, DMSO- d 6 ): 3.74 (2H, t, 3 J = 5.5 Hz), 4.19 (2H, t, 3 J = 5.5 Hz), 6.67 (2H, d, 3 J = 8.9 Hz ), 6.78 (2H, doublet, 3 J = 8.9 Hz), 8.95 (1H, s, -OH).

b) 3-[4-(2-브로모에톡시)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드b) 3- [4- (2-bromoethoxy) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-[4-(2-브로모에톡시)펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 1c에 기재된 방법에 의하여 4-(2-브로모에톡시)페놀과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 플래시 크로마토그래피(구배 용출제로 헵탄/초산에틸 9:1-6:4)하여 순품을 얻는다. 결정화는 디클로메탄에서 행한다. m.p. 135-138℃3- [4- (2-bromoethoxy) phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamad was prepared by the method described in Example 1c. It is prepared from-(2-bromoethoxy) phenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is subjected to flash chromatography (heptane / ethyl acetate 9: 1-6: 4 with gradient eluent) to obtain the pure product. Crystallization is carried out in dichloromethane. m.p. 135-138 ℃

1H NMR (400 MHz, DMSO-d 6 ): 1.42 (3H, s), 2.53 (3H, s), 3.75 (2H, t, 3 J = 5.5 Hz), 3.92 (1H, d, 2 J gem = 9.6 Hz), 4.15 (1H, d, 2 J gem = 9.5 Hz), 4.23 (2H, t, 3 J = 5.4 Hz), 6.16 (1H, broad s, -OH), 6.86 (4H, s), 7.88 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.2 Hz), 7.92 (1H, d, 4 J = 1.7 Hz), 8.04 (1H, d, 3 J = 8.9 Hz), 10.12 (1H, broad s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.42 (3H, s), 2.53 (3H, s), 3.75 (2H, t, 3 J = 5.5 Hz), 3.92 (1H, d, 2 J gem = 9.6 Hz), 4.15 (1H, d, 2 J gem = 9.5 Hz), 4.23 (2H, t, 3 J = 5.4 Hz), 6.16 (1H, broad s, -OH), 6.86 (4H, s), 7.88 (1H, doublet of doublets, 3 J = 9.0 Hz, 4 J = 2.2 Hz), 7.92 (1H, d, 4 J = 1.7 Hz), 8.04 (1H, d, 3 J = 8.9 Hz), 10.12 (1H, broad s, -NHCO-) .

실시예 87Example 87

3-[4-(2-클로로에틸)-3-플루오로펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드3- [4- (2-chloroethyl) -3-fluorophenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

a) 3-풀루오로-4-(2-하이드록시에틸)페놀a) 3-Pluoro-4- (2-hydroxyethyl) phenol

질소기류하에서, -10℃에서 무수 THF(40ml)중의 (2-풀루오로-4-하이드록시페닐)아세트산(P. C. Belanger et al. EP 106565 B1, 2.27 g, 0.01145 mol)의 용액에 보란-테트라하이드로퓨란 콤플렉스(THF중의 1.0M 용액, 22ml, 0.02200mol)을 적가한다. 결과로 얻어진 용액을 -10℃에서 2시간 교반한다. 물을 가하고, 생성물을 초산에틸로 추출한다. 추출액을 합하고 물로 세척한 후, 건조하고, 진공증류시켜서 생성물을 얻는다.Borane-tetra in a solution of (2-Pluoro-4-hydroxyphenyl) acetic acid (PC Belanger et al. EP 106565 B1, 2.27 g, 0.01145 mol) in dry THF (40 ml) at -10 ° C under nitrogen stream. Hydrofuran complex (1.0 M solution in THF, 22 ml, 0.02200 mol) is added dropwise. The resulting solution is stirred at −10 ° C. for 2 hours. Water is added and the product is extracted with ethyl acetate. The extracts are combined, washed with water, dried and vacuum distilled to afford the product.

1H NMR (400 MHz, DMSO-d 6 ): 2.62 (2H, t, 3 J = 7.2 Hz), 3.50 (2H, m), 4.63 (1H, t, 3 J = 5.4 Hz, -CH2OH), 6.47-6.53 (2H, m), 7.06 (1H, t, 3 J HH = 4 J HF = 8.5 Hz), 9.60 (1H, s, ArOH). 1 H NMR (400 MHz, DMSO- d 6 ): 2.62 (2H, t, 3 J = 7.2 Hz), 3.50 (2H, m), 4.63 (1H, t, 3 J = 5.4 Hz, -CH 2 O H ), 6.47-6.53 (2H, m), 7.06 (1H, t, 3 J HH = 4 J HF = 8 .5 Hz), 9.60 ( 1H, s, ArO H).

b) 4-(2-클로로에틸)-3-풀루오로페놀b) 4- (2-chloroethyl) -3-fulurophenol

4-(2-클로로에틸)-3-풀루오로페놀은 실시예 74a에 기재된 방법으로 3-풀루오 로-4-(2-하이드록시에틸)페놀으로부터 제조된다. 조생성물은 플래시 크로마토그래피(용출제로 헵탄/초산에틸 85:15)하여 정제한다.4- (2-Chloroethyl) -3-pluurophenol is prepared from 3-pluoro-4- (2-hydroxyethyl) phenol by the method described in Example 74a. The crude product is purified by flash chromatography (heptane / ethyl acetate 85:15 as eluent).

1H NMR (400 MHz, DMSO-d 6 ): 2.93 (2H, t, 3 J = 7.1 Hz), 3.74 (2H, t, 3 J = 7.1 Hz), 6.51-6.57 (2H, m), 7.13 (1H, t, 3 J HH = 4 J HF = 8.7 Hz), 9.75 (1H, s, ArOH). 1 H NMR (400 MHz, DMSO- d 6 ): 2.93 (2H, t, 3 J = 7.1 Hz), 3.74 (2H, t, 3 J = 7.1 Hz), 6.51-6.57 (2H, m), 7.13 ( 1H, t, 3 J HH = 4 J HF = 8 .7 Hz), 9.75 ( 1H, s, ArO H).

c) 4-(2-클로로에틸)-3-플루오로펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드c) 4- (2-chloroethyl) -3-fluorophenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

4-(2-클로로에틸)-3-플루오로펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 1c에 기재된 방법에 의하여 4-(2-클로로에틸)-3-풀루오로페놀과2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다. 조생성물은 용출제로 디클로로메탄을 사용하여 플래시 크로마토그래피하여 정제한다. 생성물은 디클로로메탄/헵탄으로 결정화한다. m.p. 77-79℃4- (2-Chloroethyl) -3-fluorophenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamad was prepared by the method described in Example 1c. Prepared from 4- (2-chloroethyl) -3-fulurophenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography using dichloromethane as eluent. The product is crystallized from dichloromethane / heptane. m.p. 77-79 ℃

1H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 2.97 (2H, t, 3 J = 6.9 Hz), 3.76 (2H, t, 3 J = 7.0 Hz), 3.98 (1H, d, 2 J gem = 9.8 Hz), 4.23 (1H, d, 2 J gem = 9.7 Hz), about 6.2 (1H, broad s, -OH), 6.73 (1H, dd, 3 J = 8.5 Hz, 4 J = 2.4 Hz), 6.80 (1H, dd, 3 J HF = 12.1 Hz, 4 J HH = 2.5 Hz), 7.24 (1H, t, 3 J HH = 4 J HF = 8.8 Hz), 7.87 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.3 Hz),7.92 (1H, d, 4 J = 2.0 Hz), 8.03 (1H, d, 3 J = 9.0 Hz), about 10.1 (1H, broad s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.43 (3H, s), 2.53 (3H, s), 2.97 (2H, t, 3 J = 6.9 Hz), 3.76 (2H, t, 3 J = 7.0 Hz), 3.98 (1H, d, 2 J gem = 9.8 Hz), 4.23 (1H, d, 2 J gem = 9.7 Hz), about 6.2 (1H, broad s, -OH), 6.73 (1H, dd, 3 J = 8.5 Hz, 4 J = 2.4 Hz), 6.80 (1H, dd, 3 J HF = 12.1 Hz, 4 J HH = 2.5 Hz), 7.24 (1H, t, 3 J HH = 4 J HF = 8.8 Hz), 7.87 (1H, dd, 3 J = 9.0 Hz , 4 J = 2.3 Hz), 7.92 (1H, d, 4 J = 2.0 Hz), 8.03 (1H, d, 3 J = 9.0 Hz), about 10.1 (1H, broad s, -NHCO-).

실시예 88Example 88

3-(4-시아노펜옥시)-N-(3-에틸-4-니트로페닐)-2-하이드록시-2-메틸-프로피온아마아드3- (4-cyanophenoxy) -N- (3-ethyl-4-nitrophenyl) -2-hydroxy-2-methyl-propionamide

a) N-(3-에틸-4-니트로페닐)-2-메틸아크릴아마이드a) N- (3-ethyl-4-nitrophenyl) -2-methylacrylamide

N-(3-에틸-4-니트로페닐)-2-메틸아크릴아마이드는 실시예 1a에 기재된 방법으로 3-에틸-4-니트로페닐아민(W. Pfleiderer et al. US 2002/0146737 A1)과 메타클로일 클로라이드로부터 제조된다. 조생성물은 용출제로 헵탄/초산에틸( 9:1)을 사용하여 플래시 크로마토그래피하여 정제한다.N- (3-ethyl-4-nitrophenyl) -2-methylacrylamide was treated with 3-ethyl-4-nitrophenylamine (W. Pfleiderer et al. US 2002/0146737 A1) in the manner described in Example 1a. Prepared from cloyl chloride. The crude product is purified by flash chromatography using heptane / ethyl acetate (9: 1) as eluent.

1H NMR (400 MHz, DMSO-d 6 ): 1.22 (3H, t, 3 J = 7.4 Hz), 1.97 (3H, s), 2.87 (2H, q, 3 J = 7.4 Hz), 5.62 (1H, s), 5.88 (1H, s), 7.81 (1H, dd, 3 J = 8.9 Hz, 4 J = 2.3 Hz), 7.83 (1H, d, 4 J = 2.2 Hz), 8.00 (1H, d, 3 J = 8.8 Hz), 10.21 (1H, s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.22 (3H, t, 3 J = 7.4 Hz), 1.97 (3H, s), 2.87 (2H, q, 3 J = 7.4 Hz), 5.62 (1H, s), 5.88 (1H, s), 7.81 (1H, dd, 3 J = 8.9 Hz, 4 J = 2.3 Hz), 7.83 (1H, d, 4 J = 2.2 Hz), 8.00 (1H, d, 3 J = 8.8 Hz), 10.21 (1H, s, -NHCO-).

b) 2-메틸옥시란-2-카르복실산(3-에틸-4-니트로페닐)아마이드b) 2-methyloxirane-2-carboxylic acid (3-ethyl-4-nitrophenyl) amide

디클로로메탄(180ml)중의 N-(3-에틸-4-니트로페닐)-2-메타크릴아마이드(6.68g, 0.02852mol)과 2,6-디-tert-부틸-4-메틸페놀(149mg)의 환류용액에 3-클로로퍼벤조산(14.71g, 0.08524mol)을 조금씩 가한다. 5시간 환류시키고, 반응혼합물을 실온으로 냉각시킨다. 침전된 3-클로로벤조산을 여과하고, 여액을 1M 탄산나트륨 용액 및 물로차례로 3회 추출한다. 유기층을 황사나트륨으로 건조시키고, 여과한 후 증발시킨다. 조생성물은 용출제로 디클로로메탄을 사용하여 플래시 크로마토그래피하여 정제한다.Of N- (3-ethyl-4-nitrophenyl) -2-methacrylamide (6.68 g, 0.02852 mol) and 2,6-di-tert-butyl-4-methylphenol (149 mg) in dichloromethane (180 ml) 3-chloroperbenzoic acid (14.71 g, 0.08524 mol) is added little by little to the reflux solution. It is refluxed for 5 hours and the reaction mixture is cooled to room temperature. The precipitated 3-chlorobenzoic acid is filtered off and the filtrate is extracted three times with 1M sodium carbonate solution and water. The organic layer is dried over sodium yellow sand, filtered and evaporated. The crude product is purified by flash chromatography using dichloromethane as eluent.

1H NMR (400 MHz, DMSO-d 6 ): 1.20 (3H, t, 3 J = 7.4 Hz), 1.55 (3H, s), 2.84 (2H, q, 3 J = 7.4 Hz), 2.99 (1H, d, 2 J gem = 5.1 Hz), 3.06 (1H, d, 2 J gem = 5.1 Hz), 7.81 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.3 Hz), 7.85 (1H, d, 4 J = 2.2 Hz), 7.97 (1H, d, 3 J = 9.0 Hz), 9.88 (1H, s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.20 (3H, t, 3 J = 7.4 Hz), 1.55 (3H, s), 2.84 (2H, q, 3 J = 7.4 Hz), 2.99 (1H, d, 2 J gem = 5.1 Hz), 3.06 (1H, d, 2 J gem = 5.1 Hz), 7.81 (1H, dd, 3 J = 9.0 Hz, 4 J = 2.3 Hz), 7.85 (1H, d, 4 J = 2.2 Hz), 7.97 (1H, d, 3 J = 9.0 Hz), 9.88 (1H, s, -NHCO-).

c) 3-(4-시아노펜옥시)-N-(3-에틸-4-니트로페닐)-2-하이드록시-2-메틸-프로피온아마아드c) 3- (4-cyanophenoxy) -N- (3-ethyl-4-nitrophenyl) -2-hydroxy-2-methyl-propionamide

3-(4-시아노펜옥시)-N-(3-에틸-4-니트로페닐)-2-하이드록시-2-메틸-프로피온아마아드는 실시예 1c에 기재된 방법에 의하여 4-시아노페놀과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다.조생성물은 플래시 크로마토그래피(구배 용출제로 헵탄/초산에틸 9:1-6:4)하여 정제한다.3- (4-cyanophenoxy) -N- (3-ethyl-4-nitrophenyl) -2-hydroxy-2-methyl-propionamade is treated with 4-cyanophenol by the method described in Example 1c. Prepared from 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography (heptane / ethyl acetate 9: 1-6: 4 as gradient eluent). do.

1H NMR (400 MHz, DMSO-d 6 ): 1.21 (3H, t, 3 J = 7.4 Hz), 1.45 (3H, s), 2.86 (2H, q, 3 J = 7.5 Hz), 4.09 (1H, d, 2 J gem = 9.9 Hz), 4.33 (1H, d, 2 J gem = 9.8 Hz), 6.26 (1H, broad s, -OH), 7.11 (2H, d, 3 J = 8.8 Hz), 7.74 (2H, d, 3 J = 8.7 Hz), 7.89 (1H, d, 3 J = 9.1 Hz), 7.94 (1H, s),7.98 (1H, d, 3 J = 8.9 Hz), 10.17 (1H, broad s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.21 (3H, t, 3 J = 7.4 Hz), 1.45 (3H, s), 2.86 (2H, q, 3 J = 7.5 Hz), 4.09 (1H, d, 2 J gem = 9.9 Hz), 4.33 (1H, d, 2 J gem = 9.8 Hz), 6.26 (1H, broad s, -OH), 7.11 (2H, d, 3 J = 8.8 Hz), 7.74 ( 2H, d, 3 J = 8.7 Hz), 7.89 (1H, d, 3 J = 9.1 Hz), 7.94 (1H, s), 7.98 (1H, d, 3 J = 8.9 Hz), 10.17 (1H, broad s , -NHCO-).

실시예 89Example 89

3-(4-시아노-3-풀루오로펜옥시)-N-(3-에틸-4-니트로페닐)-2-하이드록시-2-메틸-프로피온아마아드3- (4-cyano-3-pululofenoxy) -N- (3-ethyl-4-nitrophenyl) -2-hydroxy-2-methyl-propionamide

3-(4-시아노-3-풀루오로펜옥시)-N-(3-에틸-4-니트로페닐)-2-하이드록시-2-메틸-프로피온아마아드는 3- (4-cyano-3-pululofenoxy) -N- (3-ethyl-4-nitrophenyl) -2-hydroxy-2-methyl-propionamide

실시예 1c에 기재된 방법에 의하여 2-풀루오로-4-하이드록시벤조니트릴2-Pluoro-4-hydroxybenzonitrile by the method described in Example 1c

과 2-메틸옥시란-2-카르복실산(3-메틸-4-니트로페닐)아마이드로부터 제조된다.조생성물은 구배 용출제로 헵탄/초산에틸을 사용한 플래시 크로마토그래피하여 정제한다. 최종 정제는 제조용 HPLC로 행한다.And 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product is purified by flash chromatography using heptane / ethyl acetate as the gradient eluent. Final purification is done by preparative HPLC.

1H NMR (400 MHz, DMSO-d 6 ): 1.21 (3H, t, 3 J = 7.4 Hz), 1.44 (3H, s), 2.86 (2H, q, 3 J = 7.5 Hz), 4.12 (1H, d, 2 J gem = 10.0 Hz), 4.38 (1H, d, 2 J gem = 10.0 Hz), 6.30 (1H, broad s, -OH), 6.96 (1H, dd, 3 J = 8.7 Hz, 4 J = 2.2 Hz), 7.18 (1H, dd, 3 J HF = 11.8 Hz, 4 J HH = 2.3 Hz), 7.80 (1H, t, 3 J HH = 4 J HF = 8.3 Hz), 7.89 (1H, dd, 3 J = 8.9 Hz, 4 J = 2.2 Hz), 7.95 (1H, d, 4 J = 2.3 Hz), 7.98 (1H, d, 3 J = 9.0 Hz), 10.18 (1H, s, -NHCO-). 1 H NMR (400 MHz, DMSO- d 6 ): 1.21 (3H, t, 3 J = 7.4 Hz), 1.44 (3H, s), 2.86 (2H, q, 3 J = 7.5 Hz), 4.12 (1H, d, 2 J gem = 10.0 Hz), 4.38 (1H, d, 2 J gem = 10.0 Hz), 6.30 (1H, broad s, -OH), 6.96 (1H, dd, 3 J = 8.7 Hz, 4 J = 2.2 Hz), 7.18 (1H, dd, 3 J HF = 11.8 Hz, 4 J HH = 2.3 Hz), 7.80 (1H, t, 3 J HH = 4 J HF = 8.3 Hz), 7.89 (1H, dd, 3 J = 8.9 Hz, 4 J = 2.2 Hz), 7.95 (1H, d, 4 J = 2.3 Hz), 7.98 (1H, d, 3 J = 9.0 Hz), 10.18 (1H, s, -NHCO-).

실시예 90Example 90

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-(3-메틸-4-니트로페닐-아미노)프로피온아마아드2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3- (3-methyl-4-nitrophenyl-amino) propionamide

2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)-3-(3-메틸-4-니트로페닐-아미노)프로피온아마아드는 실시예 52에 기재된 방법으로 1,2-에폭시-2-메틸-N-[3- 메틸-4-니트로페닐]-2-프로판아마이드로부터 제조된다. 2-Hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) -3- (3-methyl-4-nitrophenyl-amino) propionamad was prepared as described in Example 52 by 1,2. -Epoxy-2-methyl-N- [3-methyl-4-nitrophenyl] -2-propaneamide.

1H-NMR (400 MHz, DMSO-d6): 1.62 (3H, s), 2.54 (3H, s), 2.60 (3H, s), 3,41 (1H, dd, J = 13.6 Hz, J = 6.0 Hz), 3.83 (1H, dd, J = 13.6 Hz, J = 6.9 Hz), 4.81 (1H, t, J = 6.3 Hz), 6.46 (1H, d, 2.1 Hz), 6.51 (1H, dd, J = 9.1 Hz, J = 2.5 Hz), 7.54 (1H, dd, J = 8.9 Hz, J = 2.2 Hz), 7.59 (1H, d, J = 1.8 Hz), 7.97 (1H, d, J = 9.0 Hz), 8.02 (1H, d, J = 8.9 Hz), 8.96 (1H, s). 1 H-NMR (400 MHz, DMSO-d 6 ): 1.62 (3H, s), 2.54 (3H, s), 2.60 (3H, s), 3,41 (1H, dd, J = 13.6 Hz, J = 6.0 Hz), 3.83 (1H, dd, J = 13.6 Hz, J = 6.9 Hz), 4.81 (1H, t, J = 6.3 Hz), 6.46 (1H, d, 2.1 Hz), 6.51 (1H, dd, J = 9.1 Hz, J = 2.5 Hz), 7.54 (1H, dd, J = 8.9 Hz, J = 2.2 Hz), 7.59 (1H, d, J = 1.8 Hz), 7.97 (1H, d, J = 9.0 Hz) , 8.02 (1H, d, J = 8.9 Hz), 8.96 (1H, s).

실시예 91Example 91

3-[4-(3,3-디메틸우레이도)-3-풀루오로펜옥시)-N-(3-에틸-4-니트로페닐)-2-하이드록시-2-메틸-프로피온아마아드3- [4- (3,3-dimethylureido) -3-fulurofenoxy) -N- (3-ethyl-4-nitrophenyl) -2-hydroxy-2-methyl-propionamide

a) 3-(2-풀루오로-4-하이드록시페닐)-1,1-디메틸우레아a) 3- (2-Pluoro-4-hydroxyphenyl) -1,1-dimethylurea

4-아미노-3-풀루오로페놀(0.47g, 3mmol)을 질소기류하에서 무수 THF(15ml)에 용해시킨 다음, 0℃로 냉각시킨다. 여기에 N,N'-디메틸카바모일클로라이드(0.28ml, 3.0mmol)을 적가한다. 반응혼합물을 실온으로 가온한다음 다시 0℃로 냉각시킨다음, 물 0.2ml를 가한 다음, 여과한다. 모액은 증발시키고, 초산체틸 25ml에 용해시킨다. 1M 탄산나트륨 10ml 및 물 10m씩으로 차례로 세척한 다음 황산나트륨으로 건조시킨다. 생성물을 크로마토그래피(용출제 : 초산에틸 : 톨루엔 1:1)로 정제한다. 4-Amino-3-Pluorophenol (0.47 g, 3 mmol) is dissolved in dry THF (15 ml) under a nitrogen stream and then cooled to 0 ° C. To this was added dropwise N, N'-dimethylcarbamoylchloride (0.28 ml, 3.0 mmol). The reaction mixture is allowed to warm to room temperature and then cooled to 0 ° C., then 0.2 ml of water is added and filtered. The mother liquor is evaporated and dissolved in 25 ml of ketyl acetate. Wash sequentially with 10 ml of 1 M sodium carbonate and 10 m of water, and then dry with sodium sulfate. The product is purified by chromatography (eluent: ethyl acetate: toluene 1: 1).

1H NMR (400 MHz, DMSO-d6): 2.88 (6H, s), 6.48-6.58 (2H, m), 7.02-7.10 (1H, m), 9.65 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 2.88 (6H, s), 6.48-6.58 (2H, m), 7.02-7.10 (1H, m), 9.65 (1H, s).

b) 3-[4-(3,3-디메틸우레이도)-3-풀루오로펜옥시)-N-(3-에틸-4-니트로페닐)-2-하이드록시-2-메틸-프로피온아마아드b) 3- [4- (3,3-dimethylureido) -3-fulurofenoxy) -N- (3-ethyl-4-nitrophenyl) -2-hydroxy-2-methyl-propionama Ad

3-[4-(3,3-디메틸우레이도)-3-풀루오로펜옥시)-N-(3-에틸-4-니트로페닐)-2-하이드록시-2-메틸-프로피온아마아드는 실시예 1에 기재된 방법으로 3-(2-풀루오로-4-하이드록시페닐)-1,1-디메틸우레아와 1,2-에폭시-2-메틸-N-[3-메틸-4-니트로페닐]-2-프로판아마이드로부터 제조된다. 3- [4- (3,3-Dimethylureido) -3-pululofenoxy) -N- (3-ethyl-4-nitrophenyl) -2-hydroxy-2-methyl-propionamide 3- (2-Pluoro-4-hydroxyphenyl) -1,1-dimethylurea and 1,2-epoxy-2-methyl-N- [3-methyl-4-nitro by the method described in Example 1 Phenyl] -2-propaneamide.

1H NMR (400 MHz, DMSO-d6): 1.42 (3H, s), 2.53 (3H, s), 2.88 (6H, s), 3.96 (1H, d, J = 9.7 Hz), 4.21 (1H, d, J= 9.7 Hz), 6.25 (1H, s), 6.68 (1H, dd, J = 8.8 Hz, J = 2.4 Hz), 6.81 (1H, dd, J = 12.3 Hz, J = 2.7 Hz), 7.10-7.30 (1H, m), 7.86 (1H, s), 7.88 (1H, dd, J = 9.1 Hz, J = 2.2 Hz), 7.93 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.15 (1H, s) 1 H NMR (400 MHz, DMSO-d 6 ): 1.42 (3H, s), 2.53 (3H, s), 2.88 (6H, s), 3.96 (1H, d, J = 9.7 Hz), 4.21 (1H, d, J = 9.7 Hz), 6.25 (1H, s), 6.68 (1H, dd, J = 8.8 Hz, J = 2.4 Hz), 6.81 (1H, dd, J = 12.3 Hz, J = 2.7 Hz), 7.10 -7.30 (1H, m), 7.86 (1H, s), 7.88 (1H, dd, J = 9.1 Hz, J = 2.2 Hz), 7.93 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.15 (1H, s)

실시예 92Example 92

3-[(3-풀루오로-4-메탄설포닐아미노).펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드3-[(3-Pluoro-4-methanesulfonylamino) .phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

a) N-(2-풀루오로-4-하이드록시페닐)메탄설폰아마이드a) N- (2-Pluoro-4-hydroxyphenyl) methanesulfonamide

질소기류하에서 무수 피리딘 10ml에 4-아미노-3-풀루오로페놀(0.254g, 2.0mmol)을 용해시킨 다음, 0℃로 냉각시킨다. 여기에 메탄솔포닐클로라이드(0.17ml, 2.1mmol)을 적가하고, 실온에서 3일간 교반한다. 반응혼합물을 증발시키고, 여기에 톨루엔 25ml를 가하고 교반한 후 다시 증발시킨다. 잔류물을 초산에틸 20ml에 용해시키고, 물 20ml로 세척한 다음 증발건고시켜서 적갈색 고체로 N-(2-풀루오로-4-하이드록시페닐)메탄설폰아마이드를 얻는다.Dissolve 4-amino-3-pulourophenol (0.254 g, 2.0 mmol) in 10 ml of anhydrous pyridine under a nitrogen stream, and then cool to 0 ° C. Methane sulphonyl chloride (0.17 ml, 2.1 mmol) is added dropwise thereto, and the mixture is stirred at room temperature for 3 days. The reaction mixture is evaporated, 25 ml of toluene is added thereto, stirred, and evaporated again. The residue is dissolved in 20 ml of ethyl acetate, washed with 20 ml of water and evaporated to dryness to afford N- (2-pullouro-4-hydroxyphenyl) methanesulfonamide as a reddish brown solid.

1H NMR (400 MHz, DMSO-d6): 2.93 (3H, s), 6.56-6.66 (2H, m), 7.14 (1H, t, J = 9.0 Hz), 9.17 (1H, s), 9.98 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 2.93 (3H, s), 6.56-6.66 (2H, m), 7.14 (1H, t, J = 9.0 Hz), 9.17 (1H, s), 9.98 ( 1H, s).

b) 3-[(3-풀루오로-4-메탄설포닐아미노).펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드b) 3-[(3-Pluoro-4-methanesulfonylamino) .phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

3-[(3-풀루오로-4-메탄설포닐아미노).펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드는 실시예 1에 기재된 방법으로 N-(2- 풀루오로-4-하이드록시페닐)메탄설폰아마이드와 1,2-에폭시-2-메틸-N-[3-메틸-4-니트로페닐]-2-프로판아마이드로부터 제조된다3-[(3-Pluoro-4-methanesulfonylamino). Penoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamad is Example 1 N- (2-Pluoro-4-hydroxyphenyl) methanesulfonamide and 1,2-epoxy-2-methyl-N- [3-methyl-4-nitrophenyl] -2-propaneamide by the method described in Is manufactured from

1H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 2.92 (3H, s), 3.99 (1H, d, J = 9.8 Hz), 4.24 (1H, d, J = 9.8 Hz), 6.25 (1H, s), 6.76 (1H, dd, J = 8.9 Hz, J = 2.0 Hz), 6.93 (1H, dd, J = 12.1 Hz, J = 2.7 Hz), 7.23 (1H, t, J = 9.1 Hz), 7.88 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.93 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz), 9.29 (1H, s), 10.16 (1H, s). 1 H NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 2.92 (3H, s), 3.99 (1H, d, J = 9.8 Hz), 4.24 (1H, d, J = 9.8 Hz), 6.25 (1H, s), 6.76 (1H, dd, J = 8.9 Hz, J = 2.0 Hz), 6.93 (1H, dd, J = 12.1 Hz, J = 2.7 Hz), 7.23 (1H, t, J = 9.1 Hz), 7.88 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.93 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz ), 9.29 (1 H, s), 10.16 (1 H, s).

실시예 93Example 93

3-[4-(2-아미노아세틸아미노)-3-풀루오로.펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드3- [4- (2-aminoacetylamino) -3-pululo.phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

a) [(2-풀루오로-4-하이드록시페닐카바모일)카바민산-tert-부틸에스테르a) [(2-Pluoro-4-hydroxyphenylcarbamoyl) carbamic acid-tert-butyl ester

질소기류하에 디클로로메탄 10ml중의 tert-부톡시카보닐아미노아세트산(=Boc-glycine)(0.256g, 2.0mmol)을 용해시킨다음 0℃로 냉각시킨다. 여기에 DCC(0.412g, 2.0mmol)을 가하고, 실온으로 가온한다. 4-아미노-3-풀루오로페놀(0.350g, 2.0mmol)을 디클로로메탄 10ml에 가하고 여기에 THF 5ml를 가한다. 두 용액을 합하고, 실온에서 2시간 교반한 다음, 2시간 환류시킨다. 다음에 실온에서 하루밤 교반한다. 반응혼합물을 증발하고 초산에틸 30ml에 용해시킨다, DCC로부터 생성된 잔류물(DHU)를 침전시키기 위하여 헵탄을 조금 가한다. 침전을 여과하고, 침전을 헵탄으로 세척한다. 여액 및 세척액을 합하고 증발시킨 잔류물을 초산에틸 10ml에 용해시킨다음, 톨루엔 2ml를 적가하여 침전을 생성시킨다. 여과한 후, 여액을 증발시켜서 [(2-풀루오로-4-하이드록시페닐카바모일)카바민산-tert-부틸에스테르를 얻는다.Dissolve tert-butoxycarbonylaminoacetic acid (= Boc-glycine) (0.256 g, 2.0 mmol) in 10 ml of dichloromethane under nitrogen stream and cool to 0 ° C. To this was added DCC (0.412 g, 2.0 mmol) and warmed to room temperature. 4-Amino-3-Pluorophenol (0.350 g, 2.0 mmol) is added to 10 ml of dichloromethane and 5 ml of THF is added thereto. The two solutions are combined, stirred at room temperature for 2 hours and then refluxed for 2 hours. Then it is stirred overnight at room temperature. The reaction mixture is evaporated and dissolved in 30 ml of ethyl acetate, a little heptane is added to precipitate the residue (DHU) produced from DCC. The precipitate is filtered off and the precipitate is washed with heptane. The filtrate and washings are combined and the evaporated residue is dissolved in 10 ml of ethyl acetate and then 2 ml of toluene is added dropwise to form a precipitate. After filtration, the filtrate is evaporated to obtain [(2-Pluoro-4-hydroxyphenylcarbamoyl) carbamic acid-tert-butylester.

1H-NMR (400 MHz, DMSO-d6): 1.39 (9H, s), 3.71 (2H, d, J = 6.0 Hz), 6.52-6.65 (2H, m), 7.00-7.07 (1H, m), 7.41-7.49 (1H, m), 9.34 (1H, s), 9.74 (1H, s). 1 H-NMR (400 MHz, DMSO-d 6 ): 1.39 (9H, s), 3.71 (2H, d, J = 6.0 Hz), 6.52-6.65 (2H, m), 7.00-7.07 (1H, m) , 7.41-7.49 (1 H, m), 9.34 (1 H, s), 9.74 (1 H, s).

b) (2-풀루오로-4-[2-하이드록시-2-(3-메틸-4-니트로페닐]카바모일메틸)카바민산-tert-부틸에스테르b) (2-Pluoro-4- [2-hydroxy-2- (3-methyl-4-nitrophenyl] carbamoylmethyl) carbamic acid-tert-butyl ester

(2-풀루오로-4-[2-하이드록시-2-(3-메틸-4-니트로페닐]카바모일메틸)카바민산-tert-부틸에스테르는 실시예 1에 기재된 방법으로 [(2-풀루오로-4-하이드록시페닐카바모일)카바민산-tert-부틸에스테르와 1,2-에폭시-2-메틸-N-[3-메틸-4-니트로페닐]-2-프로판아마이드로부터 제조된다.(2-Pluoro-4- [2-hydroxy-2- (3-methyl-4-nitrophenyl] carbamoylmethyl) carbamic acid-tert-butylester was prepared by the method described in Example 1 [(2- Pluoro-4-hydroxyphenylcarbamoyl) carbamic acid-tert-butylester and 1,2-epoxy-2-methyl-N- [3-methyl-4-nitrophenyl] -2-propaneamide .

1H-NMR (400 MHz, DMSO-d6): 1.39 (9H, s), 1.43 (3H, s), 2.53 (3H, s), 3.73 (2H, d, J = 5.4 Hz), 3.97 (1H, d, J = 9.8 Hz), 4.22 (1H, d, J = 9.8 Hz), 6.24 (1H, s), 6.74 (1H, d, J = 9.3 Hz), 6.89 (1H, d, J = 12.0 Hz), 7.00-7.10 (1H, m), 7.60 (1H, t, J = 8.9 Hz), 7.88 (1H, d, J = 9.0 Hz), 7.93 (1H, s), 8.04 (1H, d, J = 9.0 Hz), 9.46 (1H, s), 10.15 (1H, s). 1 H-NMR (400 MHz, DMSO-d 6 ): 1.39 (9H, s), 1.43 (3H, s), 2.53 (3H, s), 3.73 (2H, d, J = 5.4 Hz), 3.97 (1H , d, J = 9.8 Hz), 4.22 (1H, d, J = 9.8 Hz), 6.24 (1H, s), 6.74 (1H, d, J = 9.3 Hz), 6.89 (1H, d, J = 12.0 Hz ), 7.00-7.10 (1H, m), 7.60 (1H, t, J = 8.9 Hz), 7.88 (1H, d, J = 9.0 Hz), 7.93 (1H, s), 8.04 (1H, d, J = 9.0 Hz), 9.46 (1H, s), 10.15 (1H, s).

c) 3-[4-(2-아미노아세틸아미노)-3-풀루오로.펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드c) 3- [4- (2-aminoacetylamino) -3-pululo.phenoxy] -2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide

(2-풀루오로-4-[2-하이드록시-2-(3-메틸-4-니트로페닐]카바모일메틸)카바민산-tert-부틸에스테르(0.160g, 0.0mmol)을 질소기류하에서 디클로로메탄 5ml에 용해시킨다음 0℃로 냉각시킨다. 여기에 트리풀루오로아세트산(0.5ml)를 적가한 다음, 반응혼합물을 실온으로 가온하고 이 온도에서 2시간 교반한다. 반응혼합물을 증발건고시킨 잔류물을 초산에틸 25ml에 용해시키고, 물 10ml로 세척한다. 여기에 톨루엔(35ml)를 가하고 주의하여 증발시켜서 3-[4-(2-아미노아세틸아미노)-3-풀루오로.펜옥시]-2-하이드록시-2-메틸-N-(3-메틸-4-니트로페닐)프로피온아마아드를 얻는다.(2-Pluoro-4- [2-hydroxy-2- (3-methyl-4-nitrophenyl] carbamoylmethyl) carbamic acid-tert-butylester (0.160 g, 0.0 mmol) was dissolved in a nitrogen stream. It is dissolved in 5 ml of methane and cooled to 0 ° C. Trifluuroacetic acid (0.5 ml) is added dropwise, the reaction mixture is allowed to warm to room temperature and stirred at this temperature for 2 hours. Water is dissolved in 25 ml of ethyl acetate and washed with 10 ml of water, toluene (35 ml) is added thereto and carefully evaporated to 3- [4- (2-aminoacetylamino) -3- pullouro.phenoxy]- 2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl) propionamide is obtained.

1H-NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 3.75-3.85 (2H, m), 3.98 (1H, d, J = 9.1 Hz), 4.24 (1H, d, J = 9.3 Hz), 6.25 (1H, s), 6.78 (1H, d, J = 9.0 Hz), 6.95 (1H, d, J = 13.0 Hz), 7.60-7.72 (1H, m), 7.88 (1H, d, J = 8.8 Hz), 7.93 (1H, s), 8.00-8.15 (4H, m), 10.05 (1H, s), 10.12 (1H, s). 1 H-NMR (400 MHz, DMSO-d 6 ): 1.43 (3H, s), 2.53 (3H, s), 3.75-3.85 (2H, m), 3.98 (1H, d, J = 9.1 Hz), 4.24 (1H, d, J = 9.3 Hz), 6.25 (1H, s), 6.78 (1H, d, J = 9.0 Hz), 6.95 (1H, d, J = 13.0 Hz), 7.60-7.72 (1H, m) , 7.88 (1H, d, J = 8.8 Hz), 7.93 (1H, s), 8.00-8.15 (4H, m), 10.05 (1H, s), 10.12 (1H, s).

본 발명은 구조식(I)의 화합물, 그 약학적으로 허용되는 염 또는 에스테르의 치료적으로 유효한 양을 필요한 환자에게 투여하는 것을 포함하는 호르몬 테라피의 방법을 제공하는 것이다.The present invention provides a method of hormonal therapy comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or ester thereof.

본 발명은 또한 구조식(I)의 화합물, 그 약학적으로 허용되는 염 또는 에스테르의 치료적으로 유효한 양을 필요한 환자에게 투여하는 것을 포함하는 안드로젠 수용체(AR) 의존성 증후군들의 예방 또는 치료방법을 제공하는 것이다. The invention also provides a method of preventing or treating androgen receptor (AR) dependent syndromes comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or ester thereof. will be.

본 발명은 또한 구조식(I)의 화합물, 그 약학적으로 허용되는염 또는 에스테르의 치료적으로 유효한 양을 필요한 환자에게 투여하는 것을 포함하는 안드로젠 결핍의 예방과 치료의 방법을 제공하는 것이다.The present invention also provides a method of preventing and treating androgen deficiency comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or ester thereof.

본 발명은 또한 구조식(I)의 화합물, 그 약학적으로 허용되는 염 또는 에스테르의 치료적으로 유효한 양을 필요한 환자에게 투여하는 것을 포함하는 남성휴지와 같은 남성 성기능저하증 및 노화와 관련된 증후군들의 예방과 치료방법을 제공하는 것이다.The invention also provides for the prevention of male hypogonadism and aging-related syndromes, such as male rest, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or ester thereof. To provide a treatment.

본 발명은 또한 구조식(I)의 화합물, 그 약학적으로 허용되는 염 또는 에스 테르의 치료적으로 유효한 양을 필요한 환자에게 경구투여하는 것을 포함하는 안드로젠 결핍의 예방과 치료와 같은 호르몬 요법의 방법을 제공하는 것이다.The invention also provides methods of hormonal therapy such as the prevention and treatment of androgen deficiency comprising orally administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or ester thereof. To provide.

본 발명은 또한 구조식(I)의 화합물, 그 약학적으로 허용되는 염 또는 에스테르를 약학적으로 허용되는 담체와 함께 포함하는 약학적 조성물을 제공하는 것이다.The present invention also provides a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt or ester thereof, together with a pharmaceutically acceptable carrier.

Claims (11)

구조식 (I)의 화합물, 그 약학적으로 허용되는 염 및 에스테르Compounds of formula (I), pharmaceutically acceptable salts and esters thereof
Figure 112005075066351-PCT00007
Figure 112005075066351-PCT00007
 여기에서 R1 은 (C1-C7)알킬, 하이드록시(C1-C7)알킬 또는 - (CH2)n-CHO, 여기에서 n은 0-6;Wherein R 1 is (C 1 -C 7 ) alkyl, hydroxy (C 1 -C 7 ) alkyl or — (CH 2 ) n -CHO, where n is 0-6; R2는 니트로, 시아노 또는 할로겐;R 2 is nitro, cyano or halogen; R3는 수소, (C1-C7)알킬 또는 할로 (C1-C7)알킬;R 3 is hydrogen, (C 1 -C 7 ) alkyl or halo (C 1 -C 7 ) alkyl; R4는 수소, (C1-C7)알킬, COR10 또는 SO2R13;R 4 is hydrogen, (C 1 -C 7 ) alkyl, COR 10 or SO 2 R 13 ; X는 O 또는 NH;X is O or NH; A는 다음에서 선택된 그룹이다:A is the group selected from:
Figure 112005075066351-PCT00008
or
Figure 112005075066351-PCT00009
Figure 112005075066351-PCT00008
or
Figure 112005075066351-PCT00009
 여기에서 R5, R6, R7, R8 및 R9은 각각 독립적으로 수소, 할로겐, 니트로, 시아노, (C1-C7)알킬, 할로(C1-C7)알킬, 시아노 (C1-C7)알킬, 아미노, 모노- 또는 디(C1-C7)알킬아미노, 아미노(C1-C7)알킬, 하이드록시(C1-C7)알킬, (C1-C7)알콕시 (C1-C7)알킬, -NHCOR10, -N(COR10)2, -COR11, -OR12, -OSO2R13, -SO2R14 , -NHSO2R13 또는 -SR15 또는 이미드 링; 이거나 또는 R5 및 R6, R6 및 R7, R7 및 R8 또는 R8 및 R9은 이들이 결합된 다른 링 원자(들)과 함께 5- 내지 7원의 지방족 또는 방향족 카보사이클릭 링이나 또는 N, O 및 S에서 선택된 1-3의 헤테로원자(들)을 포함하는 5- 내지 7-원 복소환링을 형성할 수 있다.;Wherein R 5 , R 6 , R 7 , R 8 and R 9 are each independently hydrogen, halogen, nitro, cyano, (C 1 -C 7 ) alkyl, halo (C 1 -C 7 ) alkyl, cyano (C 1 -C 7 ) alkyl, amino, mono- or di (C 1 -C 7 ) alkylamino, amino (C 1 -C 7 ) alkyl, hydroxy (C 1 -C 7 ) alkyl, (C 1- C 7 ) alkoxy (C 1 -C 7 ) alkyl, -NHCOR 10 , -N (COR 10 ) 2 , -COR 11 , -OR 12 , -OSO 2 R 13 , -SO 2 R 14 , -NHSO 2 R 13 Or -SR 15 or an imide ring; Or R 5 and R 6 , R 6 And R 7 , R 7 and R 8 Or R 8 and R 9 together with other ring atom (s) to which they are attached represent a 5- to 7-membered aliphatic or aromatic carbocyclic ring or a heteroatom (s) of 1-3 selected from N, O and S; It can form a 5- to 7-membered heterocyclic ring comprising; R10 및 R11은 각각 독립적으로 (C1-C7)알킬, (C2-C7)알케닐, 할로(C1-C7)알킬, 아미노(C1-C7)알킬, 모노- 또는 디-(C1-C7)알킬아미노(C1-C7)알킬, (C6-C10)아릴, -N(R16)2 또는 -OR17;R 10 and R 11 are each independently (C 1 -C 7 ) alkyl, (C 2 -C 7 ) alkenyl, halo (C 1 -C 7 ) alkyl, amino (C 1 -C 7 ) alkyl, mono- or di - (C 1 -C 7) alkylamino (C 1 -C 7) alkyl, (C 6 -C 10) aryl, -N (R 16) 2 or -OR 17; R12 및 R15는 각각 독립적으로 수소, (C1-C7)알킬, (C2-C7)알케닐, 할로(C1-C7)알킬, 아미노(C1-C7)알킬, 모노- 또는 디-(C1-C7)알킬아미노(C1-C7)알킬, (C6-C10)아릴, 또는 -COR18;R 12 and R 15 are each independently hydrogen, (C 1 -C 7 ) alkyl, (C 2 -C 7 ) alkenyl, halo (C 1 -C 7 ) alkyl, amino (C 1 -C 7 ) alkyl, mono-or di - (C 1 -C 7) alkylamino (C 1 -C 7) alkyl, (C 6 -C 10) aryl, or -COR 18; R13 및 R14는 각각 독립적으로 (C1-C7)알킬, (C2-C7)알케닐, 할로(C1-C7)알킬 또는 (C6-C10)아릴;R 13 and R 14 are each independently (C 1 -C 7 ) alkyl, (C 2 -C 7 ) alkenyl, halo (C 1 -C 7 ) alkyl or (C 6 -C 10 ) aryl; R16 및 R17은 각각 독립적으로 수소, (C1-C7)알킬, (C2-C7)알케닐, 할로(C1-C7)알킬, 아미노(C1-C7)알킬 또는 (C6-C10)아릴;R 16 and R 17 are each independently hydrogen, (C 1 -C 7 ) alkyl, (C 2 -C 7 ) alkenyl, halo (C 1 -C 7 ) alkyl, amino (C 1 -C 7 ) alkyl or (C 6 -C 10 ) aryl; R18은 (C1-C7)알킬, (C2-C7)알케닐, 할로(C1-C7)알킬 또는 (C6-C10)아릴;R 18 is (C 1 -C 7 ) alkyl, (C 2 -C 7 ) alkenyl, halo (C 1 -C 7 ) alkyl or (C 6 -C 10 ) aryl; R19 및 R20은 각각 독립적으로 수소, 할로겐, (C1-C7)알킬 또는(C2-C7)알케닐이며, 여기에서 각각의 아릴 또는 링 잔기는 치환될 수 있다.R 19 and R 20 are each independently hydrogen, halogen, (C 1 -C 7 ) alkyl or (C 2 -C 7 ) alkenyl, wherein each aryl or ring moiety may be substituted. 제 1항에 있어서, R4가 수소이고 R3가 메틸인 화합물, 그 약학적으로 허용되는 염 및 에스테르.The compound according to claim 1, wherein R 4 is hydrogen and R 3 is methyl, pharmaceutically acceptable salts and esters thereof. 제 1　또는 제 2항에 있어서, X가 O인 화합물, 그 약학적으로 허용되는 염 및 에스테르.The compound according to claim 1 or 2, wherein X is O, pharmaceutically acceptable salts and esters thereof. 제 1항 내지 제 3항에 있어서, R1이 메틸 또는 하이드록시메틸이고, R2가 니트로 또는 시아노인 화합물, 그 약학적으로 허용되는 염 및 에스테르.The compound according to claim 1, wherein R 1 is methyl or hydroxymethyl and R 2 is nitro or cyano, pharmaceutically acceptable salts and esters thereof. 제 1항 내지 제 4항에 있어서, R5, R6, R7, R8 및 R9이 각각 독립적으로 수소, 할로겐, 니트로, 시아노, (C1-C7)알킬, (C1-C7)알콕시, 할로(C1-C7)알킬, 하이드록시(C1-C7)알킬 또는 -NHCOR10, 여기에서 R10은 (C1-C7)알킬, 할로(C1-C7)알킬, 하이드록시 또는 (C1-C7)알콕시인 화합물, 그 약학적으로 허용되는 염 및 에스테르.5. The compound of claim 1, wherein R 5 , R 6 , R 7 , R 8 and R 9 are each independently hydrogen, halogen, nitro, cyano, (C 1 -C 7 ) alkyl, (C 1- C 7 ) alkoxy, halo (C 1 -C 7 ) alkyl, hydroxy (C 1 -C 7 ) alkyl or -NHCOR 10 , wherein R 10 is (C 1 -C 7 ) alkyl, halo (C 1 -C 7 ) Compounds which are alkyl, hydroxy or (C 1 -C 7 ) alkoxy, pharmaceutically acceptable salts and esters thereof. 제 5항에 있어서, R5, R6, R7, R8 및 R9 중 적어도 하나가 할로겐인 화합물, 그 약학적으로 허용되는 염 및 에스테르.A compound according to claim 5 , wherein R 5 , R 6 , R 7 , R 8 and R 9. At least one of which is halogen, pharmaceutically acceptable salts and esters thereof. 제 6항에 있어서, R5, R6, R7, R8 및 R9 중 적어도 두개가 할로겐, 시아노 및 아세트아미도에서 선택된 화합물, 그 약학적으로 허용되는 염 및 에스테르.7. A compound according to claim 6, wherein R 5 , R 6 , R 7 , R 8 and R 9 At least two of which are selected from halogen, cyano and acetamido, pharmaceutically acceptable salts and esters thereof. 구조식(I)의 화합물, 그 약학적으로 허용되는 염 및 에스테르와 약학적으로 허용되는 담체를 함께 함유하는 약학적 조성물.A pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt and ester thereof, together with a pharmaceutically acceptable carrier. 구조식(I)의 화합물, 그 약학적으로 허용되는 염 및 에스테르의 치료적으로 유효량을 필요로 하는 환자에게 투여하는 것을 포함하는 호르몬적 치료방법.A method of hormonal treatment comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt and ester thereof. 구조식(I)의 화합물, 그 약학적으로 허용되는 염 및 에스테르의 치료적으로 유효량을 필요로 하는 환자에게 투여하는 것을 포함하는 안드로젠 수용체 의존성 증후군의 예방과 치료방법.A method of preventing and treating androgen receptor dependent syndrome comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt and ester thereof. 제 9항 또는 제 10항에 있어서, 구조식(I)의 화합물, 그 약학적으로 허용되는 염 및 에스테르의 치료적으로 유효량을 경구로 투여하는 방법.The method of claim 9 or 10, wherein the therapeutically effective amount of the compound of formula (I), a pharmaceutically acceptable salt and ester thereof is administered orally.
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