KR100793095B1 - Novel Sulfone Amide Derivatives Capable Of Inhibiting BACE - Google Patents

Novel Sulfone Amide Derivatives Capable Of Inhibiting BACE Download PDF

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KR100793095B1
KR100793095B1 KR1020030068187A KR20030068187A KR100793095B1 KR 100793095 B1 KR100793095 B1 KR 100793095B1 KR 1020030068187 A KR1020030068187 A KR 1020030068187A KR 20030068187 A KR20030068187 A KR 20030068187A KR 100793095 B1 KR100793095 B1 KR 100793095B1
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amino
methyl
hydroxy
benzamide
carbonyl
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KR1020030068187A
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KR20050032177A (en
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오영수
최덕영
조영락
윤숙경
서상원
임동철
민경식
이태수
이선화
정경하
김병문
배성진
이종선
이대원
정모세
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주식회사 프로메디텍
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Priority to PCT/KR2004/002523 priority patent/WO2005030709A1/en
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Abstract

본 발명은 BACE(또는 베타-세크리타제)의 효소활동을 저해하는 하기 화학식의 신규한 술폰 아미드 유도체에 관한 것이다. 상기 술폰 아미드 유도체는 BACE의 효소활동을 저해함으로써, 베타-아밀로이드 생성으로 인해 유발되는 알츠하이머 질환 또는 그와 유사한 질병을 치료하거나 예방하는데 효과적으로 사용될 수 있다.The present invention relates to novel sulfonamide derivatives of the formulas that inhibit the enzymatic activity of BACE (or beta-secretase). The sulfonamide derivatives can be effectively used to treat or prevent Alzheimer's disease or similar diseases caused by beta-amyloid production by inhibiting the enzyme activity of BACE.

Figure 112003036743077-pat00001
Figure 112003036743077-pat00001

(상기 식에서, A, R1, R2, R3 및 X 는 명세서에 정의되어 있음)(Wherein A, R 1 , R 2 , R 3 and X are defined in the specification)

Description

ＢＡＣＥ 저해효능을 가진 신규한 술폰 아미드 유도체 {Novel Sulfone Amide Derivatives Capable Of Inhibiting BACE}Novel Sulfone Amide Derivatives Capable Of Inhibiting BACE

도 1은 본 발명에 따른 실시예 88 및 89의 화합물들(화합물 1 및 화합물 2)과 종래의 화합물(화합물 3)을 각각 쥐에 경구 투여한 후의 혈장 중 약물 농도와 시간과의 관계를 보여주는 그래프이다.1 is a graph showing the relationship between plasma drug concentration and time after oral administration of the compounds of Examples 88 and 89 (Compounds 1 and 2) and the conventional compounds (Compound 3), respectively, according to the present invention. to be.

본 발명은 베타-아밀로이드 전구 단백질 분해 효소(β-amyloid precursor protein cleaving enzyme) 또는 베타-세크리타제(β-secretase)라고 불리는 효소(BACE)에 대해 저해효능을 가진 신규한 구조의 술폰 아미드 유도체에 관한 것이다. 본 발명에 따른 술폰 아미드 유도체는 BACE의 작용으로 인하여 발생하는 알츠하이머 질환 또는 그와 유사한 질병을 치료하거나 예방하는데 효과적으로 사용될 수 있다.The present invention relates to a sulfonamide derivative having a novel structure having an inhibitory effect on a beta-amyloid precursor protein cleaving enzyme or an enzyme called beta-secretase (BACE). will be. The sulfonamide derivatives according to the present invention can be effectively used to treat or prevent Alzheimer's disease or similar diseases caused by the action of BACE.

알츠하이머 질환(노인성 치매)은 나이가 들면서 점진적으로 진행되는 신경질환으로서 전체 치매환자의 약 50∼70%에 이르는 질병이다. 주된 증세로서는 기억력 감퇴, 인지 기능 및 판단력 상실, 정서 불안 등으로 나타나며, 통계적으로 볼 때 대부분이 약 65 세를 전후해서 발병하며, 약 9 년 정도의 진행 이후에 사망하는 것으로 나타난다. 이 알츠하이머 질환은 점점 사회가 발전하여 노령화되어 갈수록 그 환자 수가 증가되고 있는데, 향후 10 년 이내에 미국내에서만 약 600만 명의 환자가 나타날 것으로 추정되며, 이는 시간이 갈수록 점점 더 증가할 것으로 추정된다. 우리 사회 또한 노인 연령층이 증가하고 있는 추세이며, 특히 노인성 치매 환자로 인해 야기되는 사회적 문제 또한 심각하게 대두되고 있다. Alzheimer's disease (senile dementia) is a neurological disease that develops gradually with age, accounting for about 50-70% of all dementia patients. The main symptoms are memory loss, loss of cognitive function and judgment, emotional anxiety, and statistically, most of them develop around 65 years of age and die after about 9 years of progression. The number of patients with Alzheimer's disease is increasing as society develops and ages, and it is estimated that there will be about 6 million patients in the United States within the next 10 years, which will increase over time. Korean society is also on the rise of the elderly, especially social problems caused by senile dementia patients.

그러나, 현재까지는 알츠하이머 질환의 근본적인 발병원인을 치료할 수 있는 치료제는 개발되지 못하고 있으며, 일반적인 치료제로서 사용가능한 것으로는 아세틸콜린 에스테라제 저해제가 유일한 실정이다. 그 예로서, 파이자(Pfizer)사의 Aricept(상표), 노바티스(Norvatis)사의 Exelon(상표), 그리고 얀센(Jasnssen)사의 Reminyl(상표) 정도가 그 대표적인 치료제로 통용되고 있다. 상기 아세틸콜린 에스테라제 저해제의 경우는 알츠하이머 질환의 근본적인 발병 원인을 치료하지는 못하며, 단지 일부 환자의 경우(약 40∼50%)에서 일시적인 증세 완화의 효과를 보이며, 그 약효가 오래 지속되지 못하므로, 엄밀한 의미에서의 치료제로서 정의하기는 어렵다. 또한, 질환의 특성상 장기복용을 요하게 되는데, 상기 의약품들의 경우 간 독성을 비롯한 여러 가지의 부작용을 수반하는 문제점도 가지고 있다. 따라서, 질환의 진행과정을 막아줄 수 있는 치료제의 개발이 시급한 과제로 대두되고 있다. However, until now, therapies that can treat the underlying cause of Alzheimer's disease have not been developed, and acetylcholine esterase inhibitors are the only ones that can be used as general therapeutic agents. For example, Pfizer's Aricept (trademark), Novartis (Norvatis) brand Exelon (trademark), and Janssen (reminyl) brand are commonly used as the representative treatments. The acetylcholine esterase inhibitor does not cure the underlying cause of Alzheimer's disease, and only some patients (about 40 to 50%) show temporary relief of symptoms, and the drug does not last long. However, it is difficult to define it as a cure in the strict sense. In addition, the nature of the disease requires long-term use, the drug has a problem that is accompanied by a number of side effects, including liver toxicity. Therefore, the development of therapeutic agents that can prevent the progress of the disease is emerging as an urgent task.

따라서, 많은 제약회사들이 이 분야의 연구개발에 막대한 투자를 하고 있으며, 특히 알츠하이머 질환의 근본적인 발병원인으로 추정되고 있는 42개의 아미노산으로 구성된 베타-아밀로이드(beta-amyloid)의 생성량을 감소시키는 베타-세크리 타제 저해제의 개발이 그 주종을 이루고 있다.As a result, many pharmaceutical companies are investing heavily in research and development in this area, especially beta-secret, which reduces the production of beta-amyloid, which is composed of 42 amino acids, which are believed to be the primary cause of Alzheimer's disease. The development of other inhibitors is the main cause.

알츠하이머 질환(이하, 때때로 "AD"로 약칭하기도 함)에 걸린 환자들의 경우, 그 뇌와 대뇌 혈관에 베타-아밀로이드 침착(deposits)과 혈관증(angiopathy)이 각각 나타나며, 뇌세포 내부에 신경섬유 응집(neurofibrillar tangle)과 같은 병변들이 나타난다. 이와 같은 병변들은 AD 환자의 경우에 기억과 인지 기능에 중요한 작용을 하는 뇌 부위들에 대량으로 발견되며, 알츠하이머 질환 증세를 보이지 않는 정상적인 경우에도 나이 든 사람들의 뇌에서는 소량 발견되는 것으로 알려져 있다. 베타-아밀로이드 침착과 혈관증은 알츠하이머 질환 이외에도 다운 증후군(Down's syndrome; Trisomy 21)과 유전성 대뇌 출혈증(Hereditary Cerebral Hemorrhage)과 같은 베타 유전분 침착증(beta amyloiodsis) 관련 질환들에 걸린 환자의 뇌에서도 발견이 된다.In patients with Alzheimer's disease (hereinafter sometimes abbreviated as "AD"), beta-amyloid deposits and angiopathy are present in the brain and cerebral vessels, respectively, and nerve fiber aggregation inside the brain cells Lesions such as the (neurofibrillar tangle) appear. These lesions are found in large quantities in areas of the brain that play an important role in memory and cognitive function in AD patients, and are found in small amounts in older people's brains even in normal cases without Alzheimer's disease. In addition to Alzheimer's disease, beta-amyloid deposition and vasculosis are found in the brains of patients with beta amyloiodsis-related diseases such as Down's syndrome (Trisomy 21) and Hereditary Cerebral Hemorrhage. do.

베타-아밀로이드 침착은 알츠하이머 질환의 대표적인 징후이며, 이 질환의 발병 원인(causative factor)으로 간주되고 있는데, 주로 베타-아밀로이드 펩티드가 그 주성분이다. APP-695, APP 751, APP-770 등과 같은 여러 가지 유형의 베타-아밀로이드 전구체 단백질(beta-amyloid precursor protein, 이하 "APP"로 약칭함)이 알려져 있으며, 각각 695, 751 및 770개의 아미노산으로 이루어져 있다. 상기 APP 유전자 상의 돌연변이는 유전적인 조기 발병 알츠하이머 질환(familial early on-set AD)을 일으키는 것으로 알려져 있다. 예를 들어, 595번째 아미노산인 라이신(Lys)과 596번째 아미노산인 메티오닌(Met)이 각각 아스팔틱산(Asp)과 류신(Leu)으로 바뀐 스웨덴형 돌연변이(Swedish, SW)와, 717번째 아미노산인 발린(Val)이 글 리신(Gly) 이소류신(Ile) 그리고 페닐 알라닌 (Phe)으로 바뀐 경우 등이 있다.Beta-amyloid deposition is a representative sign of Alzheimer's disease and is considered a causative factor of the disease, with beta-amyloid peptides as its main component. Several types of beta-amyloid precursor proteins (abbreviated as "APP") are known, such as APP-695, APP 751, APP-770, and are composed of 695, 751 and 770 amino acids, respectively. have. Mutations on the APP gene are known to cause hereditary early onset Alzheimer's disease. For example, the 595th amino acid lysine (Lys) and the 596th amino acid methionine (Met) are changed to aspartic acid (Asp) and leucine (Seu), Swedish mutation (Swedish, SW), and the 717th amino acid Val is replaced by glycine (Gly) isoleucine (Ile) and phenyl alanine (Phe).

베타-아밀로이드 단백질들은 신경세포 내에서 만들어지는 Amyloid Precursor Protein (APP)이라는 큰 분자량의 전구체로부터 3 가지의 단백질 분해 효소(secretase)들에 의한 일련의 절단과정을 거쳐서 만들어지며, 39∼42개의 아미노산으로 구성되어 있다. 이 과정은 신경세포의 세포질 내에 있는 Golgi(또는 Endosome)이라는 membrane vesicle 내에서 이루어지는 과정이며, 상기 APP와 그 단백분해 효소들인 세크리타제들은 그 막(membrane)에 위치해서 작용한다. 베타-아밀로이드의 N-말단은 APP의 C-말단으로부터 99째 아미노산에 해당되며, 이 부위가 베타-세크리타제에 의해서 절단되며, 막 내에 위치하는 베타-아밀로이드의 C-말단이 감마-세크리타제에 의해 절단됨으로써 베타-아밀로이드 단백질이 만들어지고, 이어서 신경 세포 밖으로 분비된다. APP 전구체는, 이와는 별도의 경로를 통해 전혀 다른 위치에서 절단될 수도 있는데, 알파-세크리타제에 의해서 베타-아밀로이드의 중간 부위(N-말단으로부터 16번째와 17번째 아미노산 사이)가 절단되면, 큰 분자량의 sAPP 알파가 만들어져서 분비되며 더 이상의 베타-아밀로이드가 만들어지지 않게 된다. Beta-amyloid proteins are produced by a series of cleavage by three secretases from a large molecular weight precursor called Amyloid Precursor Protein (APP), which is made in neurons, and contains 39-42 amino acids. Consists of. This process occurs in the membrane vesicle called Golgi (or Endosome) in the cytoplasm of neurons, and APP and its proteases, secretases, are located in the membrane. The N-terminus of beta-amyloid corresponds to the 99th amino acid from the C-terminus of APP, and this site is cleaved by beta-secretase and the C-terminus of beta-amyloid located in the membrane is directed to gamma-secretase. Cleavage results in the production of beta-amyloid proteins, which are then secreted out of nerve cells. The APP precursor may be cleaved at an entirely different position via a separate pathway, with a large molecular weight if the intermediate site (between the 16th and 17th amino acids from the N-terminus) of the beta-amyloid is cleaved by alpha-secretase. SAPP alpha is produced and secreted and no more beta-amyloid is produced.

상기 BACE와 감마-세크리타제에 의해서 여러 길이의 베타-아밀로이드 단백질이 만들어지는데, 아미노산 40개 짜리와 아미노산 42개 짜리가 주종을 이룬다. 40개와 42개 짜리의 베타-아밀로이드는 정상적인 환경에서는 약 9:1 의 비율로 만들어진다. 또한, 배양된 신경세포로부터 42개의 베타-아밀로이드가 생성되어 그 배양액으로 분비되는 것이 밝혀졌을 뿐만 아니라, 실제 정상적인 사람과 알츠하이머 질환 환자의 뇌 척수액(cerebrospinal fluid)에서도 베타-아밀로이드가 측정된다 (참조, Seubert et al., Nature 359:325-327 (1992)). 42 베타-아밀로이드의 경우, 40 베타-아밀로이드와는 달리, 좀 더 쉽게 응집되는 경향을 보이며, 환자의 뇌 속에 축적될 경우 amyloid plaque의 형성을 촉진하게 되며, 이는 그 주변 부위의 신경세포가 서서히 괴사하게 만드는데, 이것이 알츠하이머 질환의 주된 발병 기작으로서 추정되고 있다. 전체적으로 두 유형의 아밀로이드 단백질의 합성량이 증가하거나, Presenilin 1 & 2 유전자의 돌연변이에 의해서 42 베타-아밀로이드의 합성이 선택적으로 증가하게 되면, 알츠하이머 질환의 발병이 더 촉진되며, 그 증세 또한 심각하게 나타나는 것으로 알려져 있다 (참조, Selkoe et al., Neuron 6:487 (1991)). 따라서, 42 베타-아밀로이드의 합성을 감소시킴으로써 알츠하이머 질환을 위한 치료가 가능할 것으로 전망되며, 특히 베타- 또는 감마-세크리타제 저해제의 경우 알츠하이머 질환에 대한 치료제로서 개발이 가능하다.Beta-amyloid proteins of various lengths are produced by BACE and gamma-secretase, with 40 amino acids and 42 amino acids predominantly. 40 and 42 beta-amyloids are produced at a ratio of about 9: 1 under normal conditions. In addition, 42 beta-amyloids were produced from cultured neurons and secreted into the culture medium, and beta-amyloid is also measured in the cerebrospinal fluid of normal humans and Alzheimer's disease patients. Seubert et al., Nature 359: 325-327 (1992)). Unlike 40 beta-amyloid, 42 beta-amyloid tends to aggregate more easily, and when accumulated in the patient's brain, it promotes the formation of amyloid plaque, which causes the necrotic cells in the surrounding area to slowly necrosis. This is presumed to be the main pathogenesis of Alzheimer's disease. Overall, increased synthesis of both types of amyloid protein, or selective increase in the synthesis of 42 beta-amyloid by mutations in the Presenilin 1 & 2 gene, further promotes the onset of Alzheimer's disease, and the symptoms are also severe. Known (see Selkoe et al., Neuron 6: 487 (1991)). Therefore, it is expected that treatment for Alzheimer's disease will be possible by reducing the synthesis of 42 beta-amyloid, and in particular, beta- or gamma-secretase inhibitors may be developed as therapeutic agents for Alzheimer's disease.

베타- 및 감마-세크리타제는 둘 다 aspartic protease로 알려져 있으며, 막에 부착된 형태로 존재하는 것으로 알려져 있다. 그러나, 감마-세크리타제 저해제의 경우는 아직 그 유전자가 제대로 규명이 되어있지 않다. 또한, 그 기질이 APP에 한정되어 있지 않고, 분화 과정 중 cell-fate decision에 대단히 중요한 역할을 하는 것으로 알려져 있는 Notch 단백질의 절단 과정에도 관여하는 것으로 알려져 있다. 특히, 감마-세크리타제 유전자 자체를 제거한 형질전환 동물이 태내에서 사망하는 것으로 나타났을 뿐만 아니라, 최근 감마-세크리타제 저해제의 임상실험 결과에서도 상당한 독성을 수반함으로써, 그 전망이 불투명하다. 따라서, 감마-세크 리타제 저해제가 알츠하이머 질환에 대한 안전한 치료제로 개발 가능한지에 대해서는, 아직도 많은 부분이 입증되지 않고 있는 실정이다. Both beta- and gamma-secretases are known as aspartic proteases and are known to be present in the form attached to the membrane. However, in the case of gamma-secretase inhibitors, the gene is not well defined. In addition, the substrate is not limited to APP, and is known to be involved in the cleavage of Notch protein, which is known to play an important role in cell-fate decision during differentiation. In particular, transgenic animals from which the gamma-secretase gene itself has been removed have not only been shown to die in the fetus, but the prospects are unclear because of the recent clinical trial results of gamma-secretase inhibitors. Thus, much remains to be known about whether gamma-secretase inhibitors can be developed as safe treatments for Alzheimer's disease.

그러나, 베타-세크리타제의 경우 다양한 방법을 통해 그 유전자가 규명되었으며, 실제 생체내에서 베타-세크리타제로서의 활성을 나타낸다는 것이 1999년도에 발표된 바 있다 (참조, Sinha et al. Nature 402:537-554). 또한, 그 X-ray 결정구조가 밝혀졌으며, 이에 대한 높은 친화도의 펩티드 저해제 또한 잘 알려져 있다. 특히, 유전자 결핍 형질전환 동물이 전혀 이상이 없는 정상적인 형질을 나타냄으로써, 베타-세크리타제 특이 저해제가 좀 더 안전하고도 효율적인 치매 치료제로서의 개발이 가능함을 시사해 준 바 있다. However, in the case of beta-secretase, the gene was identified through various methods, and it was published in 1999 that it shows activity as a beta-secretase in vivo (see Sinha et al. Nature 402: 537). -554). In addition, the X-ray crystal structure has been found, and a high affinity peptide inhibitor for this is also well known. In particular, the genetically deficient transgenic animals showed normal traits with no abnormalities, suggesting that beta-secretase specific inhibitors could be developed as a safer and more effective treatment for dementia.

베타-세크리타제를 저해하여 알츠하이머를 치료하고자 하는 예가 최근에 시작되었는데, 많은 경우에 있어서 천연 아미노산을 이용하여 펩티드 결합으로 이루어진 것이 대부분이다 (참조, Ghosh et al. J. Am. Chem. Soc. 122:3522-3523, Ghosh et al. J. Med. Chem. 44:2865-2868, Tung et. al. J. Med. Chem. 45:259-262). 그러나, 미국의 Elan Pharmaceutical에서 N-말단과 C-말단이 천연 아미노산에서 벗어난 보다 진보된 저해제를 발표하기 시작하였다. 구체적으로 살펴보면, N-말단은 이소프탈산(isophthalic acid)을 이용한 펩티드 결합으로 이루어져 있고, C-말단은 벤질아민을 이용한 비펩티드성으로 되어 있다.In recent years, there have been many attempts to treat Alzheimer's by inhibiting beta-secretase, which in many cases consists mostly of peptide bonds using natural amino acids (see Ghosh et al. J. Am. Chem. Soc. 122). : 3522-3523, Ghosh et al. J. Med. Chem. 44: 2865-2868, Tung et. Al. J. Med. Chem. 45: 259-262). However, Elan Pharmaceutical of the United States has begun to publish more advanced inhibitors in which the N- and C-terminus deviate from natural amino acids. Specifically, the N-terminus is composed of peptide bonds using isophthalic acid, and the C-terminus is nonpeptidic using benzylamine.

이에, 본 발명자들은 지금까지 보고된 저해제와는 근본적으로 다른 화학구조를 가지는 화합물들을 새로 디자인하여 합성한 후, BACE에 대한 바인딩을 측정하 고, 유사한 효소들에 대한 높은 선택성을 가지도록 하였으며, 그 결과 하기 화학식 1로 표시되는 화합물이 본 발명의 소기 목적에 부합됨을 발견하고, 본 발명을 완성하기에 이르렀다.Therefore, the inventors of the present invention have newly designed and synthesized compounds having radically different chemical structures from those reported so far, measured binding to BACE, and had high selectivity for similar enzymes. As a result, it was found that the compound represented by the following Chemical Formula 1 meets the intended purpose of the present invention, and the present invention was completed.

따라서, 본 발명은 BACE에 대해 높은 저해효능을 가진 하기 화학식 1로 표시되는 신규한 술폰 아미드 유도체를 제공함을 목적으로 한다.Accordingly, an object of the present invention is to provide a novel sulfonamide derivative represented by the following Chemical Formula 1 having a high inhibitory effect on BACE.

본 발명은 또한, 화학식 1의 술폰 아미드 유도체를 제조하는 방법을 제공함을 목적으로 한다. It is another object of the present invention to provide a method for preparing a sulfonamide derivative of formula (1).

본 발명은 또한, 화학식 1의 술폰 아미드 유도체를 활성성분으로 함유하고 있는 것을 특징으로 하는 BACE 저해제 조성물을 제공함을 목적으로 한다.It is another object of the present invention to provide a BACE inhibitor composition comprising the sulfonamide derivative of formula (1) as an active ingredient.

본 발명은 또한, 화학식 1의 술폰 아미드 유도체를 활성성분으로 사용하여, 베타-아밀로이드 생성으로 인해 유발되는 알츠하이머 질환 또는 그와 유사한 질병을 치료 또는 예방하는 방법을 제공함을 목적으로 한다.It is another object of the present invention to provide a method for treating or preventing Alzheimer's disease or similar diseases caused by beta-amyloid production by using the sulfonamide derivative of Formula 1 as an active ingredient.

본 발명의 내용을 구체적으로 설명하기에 앞서, 본 명세서에 사용된 몇가지 용어들을 다음과 같이 정의한다.Prior to describing the contents of the present invention in detail, some terms used herein are defined as follows.

a) 알킬(alkyl) 그룹: 탄소수 1∼10개로 구성된 것으로서, 직선형(linear) 또는 가지형(branched), 포화 또는 불포화된 탄화수소로 이루어진 경우도 포함한다. 하나 또는 여러 개의 수소가 다음에 따로 정의되는 치환체로 치환될 수 있으며, 치환체는 다음에 정의된 것들 중에서 순서와 종류에 관계없이 치환가능한 수만큼 최대한 치환될 수 있다. 상기 치환체는 다음과 같다: 아실(acyl), 아미노(amino), 카르보알콕시(carboalkoxy), 카르복시(carboxy), 카르복시아미노(carboxyamino), 시아노(cyano), 할로(halo), 하이드록시(hydroxy), 니트로(nitro), 티오(thio), 알킬(alkyl), 시클로알킬(cycloalkyl), 알콕시(alkoxy), 아릴옥시(aryloxy), 술폭시(sulfoxy), 구아니도(guanido) 그룹이다.a) alkyl group: consisting of 1 to 10 carbon atoms, including linear or branched, saturated or unsaturated hydrocarbons. One or several hydrogens may be substituted with substituents defined separately, and the substituents may be substituted with the maximum number of substituents defined in the following regardless of order and type. The substituents are as follows: acyl, amino, carboalkoxy, carboxy, carboxyamino, cyano, halo, hydroxy ), Nitro, thio, alkyl, cycloalkyl, alkoxy, aryloxy, sulfoxy and guanido groups.

b) 시클로알킬(cycloalkyl) 그룹: 포화 또는 부분적으로 불포화된 탄소수소를 포함하는 고리 구조로서, 0∼5개의 산소, 황, 질소 등의 헤테로 원자(heteroatom)를 가질 수 있다. 상기 고리는 3각∼12각형으로 구성되어지며, 단순고리(single ring) 또는 융합고리(fused ring)형의 화합물이다. 하나 또는 여러 개의 수소가 다음에 따로 정의되는 치환체로 치환될 수 있으며, 상기 치환체는 다음에 정의된 것들 중에서 순서와 종류에 관계없이 치환가능한 수만큼 최대한 치환될 수 있다. 치환체는 다음과 같다: 아실(acyl), 아미노(amino), 카르보알콕시(carboalkoxy), 카르복시(carboxy), 카르복시아미노(carboxyamino), 시아노(cyano), 할로(halo), 하이드록시(hydroxy), 니트로(nitro), 티오(thio), 알킬(alkyl), 시클로알킬(cycloalkyl), 알콕시(alkoxy), 아릴옥시(aryloxy), 술폭시(sulfoxy), 구아니도(guanido) 그룹이다. 상기 시클로알킬 그룹의 구체적인 예로는 시클로프로필(cyclopropyl), 시클로부틸(cyclobutyl), 시클로펜틸(cyclopentyl), 시크로헥실(cyclohehexyl), 시클로헵틸(cycloheptyl), 시클로옥틸(cyclooctyl), 몰포리닐(morpholinyl), 호모몰포리닐(homomorpholinyl), 티오몰포리닐(thiomorpholinyl), 호모티오몰포리닐(homothiomorpholinyl), 티오몰 포리닐 S-oxide(thiomorpholinyl S-oxide), 티오몰포리닐 S,S-dioxide(thiomorpholinyl S,S-dioxide), 피페리디닐(piperidinyl), 호모피페리디닐(homopiperidinyl), 피페라지닐(piperazinyl), 호모피페라지닐(homopiperazinyl), 피롤리디닐(pyrrolidinyl), 피롤리닐(pyrrolinyl), 테트라하이드로피라닐(tetrahydropyranyl), 테트라하이드로푸라닐(tetrahydrofuranyl), 테트라하이드로티에닐(tetrahydrothienyl), 옥사졸리디노닐(oxazolidinonyl), 디히드로피라졸릴(dihydropyrazolyl), 디히드로피롤릴(dihydropyrrolyl), 디히드로피라지닐(dihydropyrazinyl), 디히드로피리디닐(dihydropyridinyl), 디히드로피리미디닐(dihydropyrimidinyl), 디히드로푸릴(dihydrofuryl), 디히드로피라닐(dihydropyranyl) 등이 있다.b) Cycloalkyl group: A ring structure containing saturated or partially unsaturated hydrogen, which may have 0 to 5 heteroatoms such as oxygen, sulfur and nitrogen. The ring is composed of triangular to octagonal, and is a compound of a single ring or fused ring type. One or several hydrogens may be substituted with substituents defined separately, and the substituents may be substituted with the maximum number of substituents defined in the following regardless of order and type. Substituents are as follows: acyl, amino, carboalkoxy, carboxy, carboxyamino, cyano, halo, hydroxy , Nitro, thio, alkyl, cycloalkyl, alkoxy, aryloxy, sulfoxy, guanido groups. Specific examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohehexyl, cycloheptyl, cyclooctyl, morpholinyl ), Homomorpholinyl, thiomorpholinyl, homothiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S, S-dioxide (thiomorpholinyl S, S-dioxide), piperidinyl, homopiperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolidinyl (pyrrolidinyl) pyrrolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl , Dihydropyrazinyl (d ihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, and the like.

c) 아릴(aryl group) 그룹: 아로메틱 그룹과 헤테로아로메틱 그룹을 모두 포함한다. 상기 아로메틱 그룹은 단순 또는 융합 고리형이며 고리는 5각∼15각형으로 이루어져 있는 불포화 탄화수소이다. 한 개 또는 그 이상의 수소가 다음에서 선택된 그룹으로 치환될 수 있다: 아실(acyl), 아미노(amino), 카르보알콕시(carboalkoxy), 카르복시(carboxy), 카르복시아미노(carboxyamino), 시아노(cyano), 할로(halo), 하이드록시(hydroxy), 니트로(nitro), 티오(thio), 알킬(alkyl), 시클로알킬(cycloalkyl), 알콕시(alkoxy), 아릴옥시(aryloxy), 술폭시(sulfoxy), 구아니도(guanido) 그룹. 상기 헤테로아로메틱 그룹은 1∼5개의 산소, 황, 질소 등의 헤테로 원자(heteroatom)를 가진 아로메틱 그룹이다. 역시 한 개 또는 그 이상의 수소가 다음에서 선택된 그룹으로 치환될 수 있다: 아실(acyl), 아미노(amino), 카르보알콕시(carboalkoxy), 카르복시(carboxy), 카르복시아미노(carboxyamino), 시아노(cyano), 할로(halo), 하이드록시(hydroxy), 니트로(nitro), 티오(thio), 알킬(alkyl), 시클로알킬(cycloalkyl), 알콕시(alkoxy), 아릴옥시(aryloxy), 술폭시(sulfoxy), 구아니도(guanido) 그룹. 상기 아릴 그룹의 예로는 페닐(phenyl), 1-나프틸(1-naphtyl), 2-나프틸(2-naphtyl), 피리디닐(pyridinyl), 피리미디닐(pyrimidinyl), 퀴놀리닐(quinolinyl), 벤조티에닐(benzothienyl), 인돌릴(indolyl), 피라지닐(pyrazinyl), 이소인돌릴(isoindolyl), 이소퀴놀릴(isoquinolyl), 퀴나졸리닐(qunazolinyl),(quinoxalinyl), 프탈라지닐(phthalazinyl), 이미다졸리닐(imidazolinyl), 이속사졸리닐(isoxazolyl), 피라졸릴(pyrazolyl), 옥사졸릴(oxazolyl), 티아졸릴(thiazolyl), 인돌리지닐(indolizinyl), 인다졸릴(indazolyl), 벤조티아졸릴(benzothiazolyl), 벤즈이미다졸릴(benzimidazolyl), 벤조푸라닐(benzofuranyl), 티에닐(thienyl), 피롤릴(pyrrolyl), 옥사디아졸릴(oxadiazolyl), 티아디아졸릴(thiadiazolyl), 트리아졸릴(triazolyl), 테트라졸릴(tetrazolyl), 옥사졸로피리디닐(oxazolopyridinyl), 이미다조피리디닐(imidazopyridinyl), 이소티아졸릴(isothiazolyl), 시놀리닐(cinnolinyl), 카바졸릴(carbazolyl), 이소크로마닐(isochromanyl), 크로마닐(chromanyl), 테트라히드로이소퀴놀리닐(tetrahydroisoquinolinyl), 이소인돌리닐(isoindolinyl), 이소벤조테트라히드로푸라닐(isobenzotetrahydrofuranyl), 이소벤조테트라히드로티에닐(isobenzotetrahydrothienyl), 이소벤조티에닐(isobenzothienyl), 벤조옥사졸리닐(benzoxazolyl), 피리도피리디닐(pyridopyridinyl), 벤조테트라히드로푸라닐(benzotetrahydrofuranyl), 벤조테트라히드로티에닐(benzotetrahydrothienyl), 푸리닐(purinyl), 벤조디옥솔릴(benzodioxolyl), 트리아지닐(triazinyl), 페녹사지닐(phenoxazinyl), 페노티아지닐(phenothiazinyl), 프테리디닐(pteridinyl), 벤조티아졸릴(benzothiazolyl), 이미다조피리디닐(imidazopyridinyl), 이미다조티아졸릴(imidazothiazolyl), 디히드로벤즈이속사지닐(dihydrobenzisoxazinyl), 벤즈이속사지닐(benzisoxazinyl), 벤즈옥사지닐(benzoxazinyl), 디히드로벤즈이소티오피라닐(dihydrobenzisothiopyranyl), 벤조피라닐(benzopyranyl), 벤조티오피라닐(benzothiopyranyl), 쿠마리닐(coumarinyl), 이소쿠마리닐(isocoumarinyl), 크로모닐(chromonyl), 크로마노닐(chromanonyl), 피리딜-N-옥사이드(pyridinyl-N-oxide), 테트라하이드로퀴놀리닐-N-옥사이드(tetrahydroquinolinyl-N-oxide), 디히드로퀴놀리닐(dihydroquinolinyl), 디하이드로퀴놀리닐(dihydroquinolinonyl), 디하이드로이소퀴놀리노닐(dihydroisoquinolinonyl), 디하이드로쿠마리닐(dihydrocoumarinyl), 디하이드로이소쿠마리닐(dihydroisocoumarinyl), 이소인돌리노닐(isoindolinonyl), 벤조디옥사닐(benzodioxanyl), 벤조옥사졸리노닐(benzoxazolinonyl), 피로릴-N-옥사이드(pyrrolyl-N-oxide), 피리미디닐-N-옥사이드(pyrimidinyl-N-oxide), 피라지 닐-N-옥사이드(pyrazinyl-N-oxide), 퀴놀리닐-N-옥사이드(quinolinyl-N-oxide), 인도릴-N-옥사이드(indolyl-N-oxide), 인도리닐-N-옥사이드(indolinyl-N-oxide), 피라지닐-N-옥사이드(pyrazinyl-N-oxide), 이소퀴노릴-N-옥사이드(isoquinolyl-N-oxide), 쿠나조리닐-N-옥사이드(qunazolinyl-N-oxide), 퀴녹사리닐-N-옥사이드(quinoxalinyl-N-oxide), 프탈라지닐-N-옥사이드(phthalazinyl-N-oxide), 이미다졸리닐-N-옥사이드(imidazolinyl-N-oxide), 이속사조릴-N-옥사이드(isoxazolyl-N-oxide), 옥사조릴-N-옥사이드(oxazolyl-N-oxide), 티아조릴-N-옥사이드(thiazolyl-N-oxide), 인돌리지닐-N-옥사이드(indolizinyl-N-oxide), 인다조릴-N-옥사이드(indazolyl-N-oxide), 벤조티아조릴-N-옥사이드(benzothiazolyl-N-oxide), 벤지이미다조릴-N-옥사이드(benzimidazolyl-N-oxide), 피로릴-N-옥사이드(pyrrolyl-N-oxide), 옥사디아조릴-N-옥사이드(oxadiazolyl-N-oxide), 티아디아조릴-N-옥사이드(thiadiazolyl-N-oxide), 티아조릴-N-옥사이드(triazolyl-N-oxide), 테트라조릴-N-옥사이드(tetrazolyl-N-oxide) 등이다.
c) aryl group: includes both an aromatic group and a heteroaromatic group. The aromatic group is a simple or fused cyclic ring, and the ring is an unsaturated hydrocarbon consisting of 5 to 15 hexagons. One or more hydrogens may be substituted with a group selected from: acyl, amino, carboalkoxy, carboxy, carboxyamino, cyano , Halo, hydroxy, nitro, thio, alkyl, cycloalkyl, alkoxy, aryloxy, sulfoxy, Guanido group. The heteroaromatic group is an aromatic group having 1 to 5 heteroatoms such as oxygen, sulfur, and nitrogen. One or more hydrogens may also be substituted with a group selected from: acyl, amino, carboalkoxy, carboxy, carboxyamino, cyano ), Halo, hydroxy, nitro, thio, alkyl, cycloalkyl, alkoxy, aryloxy, sulfoxy , Guanido group. Examples of the aryl group include phenyl, 1-naphtyl, 2-naphtyl, pyridinyl, pyrimidinyl, and quinolinyl. , Benzothienyl, indolyl, pyrazinyl, isoindolyl, isoquinolyl, isoquinolyl, qunazolinyl, (quinoxalinyl), phthalazinyl ), Imidazolinyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, indazolyl, benzo Benzothiazolyl, benzimidazolyl, benzofuranyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, and cynoliny l), carbazolyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, Isobenzotetrahydrothienyl, isobenzothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzotetrahydrothienyl ), Purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenoxiazinyl, pterididinyl, benzothiazolyl, benzothiazolyl, Dazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, benzoxazinyl Robbenzisothiopyranyl, benzopyranyl, benzothiopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromonyl, chromonyl, chromanonyl, Pyridinyl-N-oxide, tetrahydroquinolinyl-N-oxide, dihydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, di Dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, Pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyrazinyl-N-oxide, quinolinyl-N- Oxide (quinolinyl-N-oxide), indolyl-N-oxide, indolee Indolinyl-N-oxide, pyrazinyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N-oxide -N-oxide, quinoxalinyl-N-oxide, phthalazinyl-N-oxide, imidazolinyl-N-oxide ), Isoxazolyl-N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, indolizinyl-N Indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide N-oxide, pyrrolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, thia Triazolyl-N-oxide, tetrazolyl-N-oxide, and the like.

본 명세서에서 자주 등장하는 용어를 설명의 편의를 위하여 다음과 같이 약칭한다.Terms frequently appearing in the present specification are abbreviated as follows for convenience of description.

N-메틸몰포린(N-methylmorporline) : NMMN-methylmorporline: NMM

N,N-디메틸포름아미드(N,N-dimethyl formamide) : DMF N, N-dimethyl formamide: DMF                     

1-(3-디메틸아미노프로필)-3-에틸카르보디이미드{1-(3-dimethylaminopropyl)-3-ethylcarbodiimide}: EDC1- (3-dimethylaminopropyl) -3-ethylcarbodiimide {1- (3-dimethylaminopropyl) -3-ethylcarbodiimide}: EDC

1-히드록시벤조트리아졸 수화물(1-hydroxybenzotriazole hydrate) : HOBt1-hydroxybenzotriazole hydrate: HOBt

트리플로로아세트산(trifluoroacetic acid) : TFA Trifluoroacetic acid: TFA

t-부틸옥시카르보닐(t-butoxycarbonyl) : Boct-Butyloxycarbonyl: Boc

벤질옥시카르보닐(benzyloxycarbonyl) : CbzBenzyloxycarbonyl: Cbz

메틸(methyl) : MeMethyl: Me

에틸(ethyl) : EtEthyl: Et

당량(equivalent) : Eq
Equivalent: Eq

본 발명은 BACE에 대해 저해효능을 지니는 하기 화학식 1로 표시되는 신규한 술폰 아미드 유도체를 제공한다.The present invention provides a novel sulfonamide derivative represented by the following formula (1) having an inhibitory effect on BACE.

Figure 112003036743077-pat00002
Figure 112003036743077-pat00002

상기 식에서, 각종 치환체에 대한 구체적인 정의는 다음과 같다.In the above formula, specific definitions for the various substituents are as follows.

(Ⅰ) A 는 벤젠고리에 치환된 그룹을 나타내는 것으로서, 수소, 할로겐, 시아노, 니트로, 치환 또는 비치환 알킬, 치환 또는 비치환 에스테르, 치환 또는 비치환 아미드, 치환 또는 비치환 아민, 또는 치환 또는 비치환 알콕시 그룹을 나타 낸다. 상기 치환된 알킬, 에스테르, 아미드, 아민 및 알콕시 그룹은 바람직하게는 할로겐으로 치환된 경우를 들 수 있다. 상기 할로겐으로 치환된 알킬 그룹의 바람직한 예로는 트리플루오르메틸 그룹(-CF3)을 들 수 있다. 상기 비치환 에스테르 그룹의 바람직한 예로는 메틸 에스테르 그룹(-CO2-CH3)과 벤질 에스테르 그룹(-CO2 -CH2-C6H5)을 들 수 있다. 상기 A 자체 또는 알킬 등의 치환기로서의 할로겐의 바람직한 예로는 불소, 염소 및 브롬을 들 수 있다.(I) A represents a group substituted in the benzene ring, hydrogen, halogen, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted ester, substituted or unsubstituted amide, substituted or unsubstituted amine, or substituted Or an unsubstituted alkoxy group. The substituted alkyl, ester, amide, amine and alkoxy groups are preferably substituted with halogen. Preferred examples of the alkyl group substituted with halogen include trifluoromethyl group (-CF 3 ). Preferred examples of the unsubstituted ester group include methyl ester group (-CO 2 -CH 3 ) and benzyl ester group (-CO 2 -CH 2 -C 6 H 5 ). Preferred examples of halogen as a substituent such as A itself or alkyl include fluorine, chlorine and bromine.

(Ⅱ) R1 은 단순한 알킬 그룹(-SAC)이거나, 알릴(allyl)을 포함하는 이중결합이 치환된 알킬, 시클로알킬(-SCAC), 아로마틱(-Ar), 아로마틱으로 치환된 알킬(-SAC-Ar) 또는 수소를 나타내며, 바람직하게는 아로마틱으로 치환된 알킬을 나타낸다. 또한, R1 과 R2 는 단순한 알킬그룹으로 고리화를 이룰 수 있다.(II) R 1 is a simple alkyl group (-SAC) or an alkyl substituted with a double bond containing allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted with aromatic (-SAC) -Ar) or hydrogen, preferably alkyl substituted with aromatic. R 1 and R 2 may also be cyclized to simple alkyl groups.

(Ⅲ) R2 는 단순한 알킬그룹(-SAC)이거나, 알릴(allyl)을 포함하는 이중결합이 치환된 알킬, 시클로알킬(-SCAC), 아로마틱(-Ar), 아로마틱으로 치환된 알킬(-SAC-Ar) 또는 수소를 나타내며, 바람직하게는 단순한 알킬그룹을 나타낸다. 또한, R1 과 R2 는 단순한 알킬그룹으로 고리화를 이룰 수 있다.(III) R 2 is a simple alkyl group (-SAC) or an alkyl substituted with a double bond containing allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted with aromatic (-SAC) -Ar) or hydrogen, preferably a simple alkyl group. R 1 and R 2 may also be cyclized to simple alkyl groups.

(Ⅳ) R3 는 -SAC, 알릴(allyl)을 포함하는 이중결합이 치환된 알킬, -SCAC, -Ar, -SAC-Ar 또는 수소일 수 있으며, 모든 천연 아미노산의 곁가지(side chain residue)를 포함한다. R3 로 인하여 인접 위치가 스테레오 센터가 되는 경우 두가 지 경우의 입체 화합물이 모두 포함되며, 두 가지형의 화합물이 공존하는 경우(디아스테레오머릭 혼합물을 의미함)도 포함된다. R3 가 아미노산의 곁가지로서 카르복실산 또는 염기로 구성되어 있을 경우, 단순 에스테르 등으로 보호기가 붙어 있는 경우와, 약제학적으로 허용되는 염(salt) 형태로 존재하는 경우도 포함된다. (IV) R 3 may be -SAC, alkyl substituted with a double bond containing allyl, -SCAC, -Ar, -SAC-Ar or hydrogen, and the side chain residues of all natural amino acids Include. In the case where the adjacent position becomes a stereo center due to R 3 , both stereo compounds are included, and in the case where two types of compounds coexist (meaning a diastereomeric mixture). When R 3 is composed of a carboxylic acid or a base as a side chain of an amino acid, a case in which a protecting group is attached by a simple ester or the like and a case in which the R 3 is present in the form of a pharmaceutically acceptable salt are included.

(Ⅴ) X 는 하기 화학식 2 내지 4 중의 어느 하나의 치환기이다.(V) X is a substituent in any one of following formula (2-4).

Figure 112003036743077-pat00003
Figure 112003036743077-pat00003

Figure 112003036743077-pat00004
Figure 112003036743077-pat00004

Figure 112003036743077-pat00005
Figure 112003036743077-pat00005

상기 화학식 2 내지 4에서,In Chemical Formulas 2 to 4,

n 은 0 또는 1 이다.n is 0 or 1;

R4 는 독립적으로 -SAC, 알릴(allyl)을 포함하는 이중결합이 치환된 알 킬, -SCAC, -Ar, -SAC-Ar 또는 수소일 수 있으며, 모든 천연 아미노산의 곁가지를 포함한다. R4 로 인하여 인접 위치가 스테레오 센터가 되는 경우 두가지 경우의 입체 화합물이 모두 포함되며, 두가지 유형의 화합물이 공존하는 경우(디아스테레오머릭 혼합물을 의미함)도 포함된다. R4 가 아미노산의 곁가지로서 카르복실산 또는 염기로 구성되어 있을 경우, 단순 에스테르 등으로 보호기가 붙어있는 경우와 약제학적으로 허용되는 염 형태로 존재하는 경우도 포함된다. R4 는 다음의 특별한 경우도 포함한다. 즉, -(CH2)nOR (R = -SAC, -SCAC, -Ar, -SAC-Ar: n = 1,2) 및 -(CH2)nOC(=O)R (R = -SAC, -SCAC, -Ar, -SAC-Ar: n=1,2).R 4 may independently be -SAC, allyl substituted double bonds including allyl, -SCAC, -Ar, -SAC-Ar or hydrogen, including all branching of natural amino acids. Both cases of steric compounds are included when the adjacent position becomes a stereo center due to R 4 , and also when two types of compounds coexist (meaning diastereomeric mixtures). When R 4 is composed of a carboxylic acid or a base as a side chain of an amino acid, a case in which a protecting group is attached by a simple ester or the like and a case in which the R 4 is present in a pharmaceutically acceptable salt form are included. R 4 also includes the following special cases: That is,-(CH 2 ) n OR (R = -SAC, -SCAC, -Ar, -SAC-Ar: n = 1,2) and-(CH 2 ) n OC (= O) R (R = -SAC, -SCAC, -Ar, -SAC-Ar: n = 1,2).

R5 는 단순한 알킬그룹(-SAC)이거나, 알릴(allyl)을 포함하는 이중결합이 치환된 알킬, 시클로알킬(-SCAC), 아로마틱(-Ar), 아로마틱으로 치환된 알킬(-SAC-Ar) 또는 수소를 나타내며, 바람직하게는 단순한 알킬그룹을 나타낸다.R 5 is a simple alkyl group (-SAC) or an alkyl substituted with a double bond containing allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted by aromatic (-SAC-Ar) Or hydrogen, preferably a simple alkyl group.

R6 는 단순한 알킬그룹(-SAC)이거나, 알릴(allyl)을 포함하는 이중결합이 치환된 알킬, 시클로알킬(-SCAC), 아로마틱(-Ar), 아로마틱으로 치환된 알킬(-SAC-Ar) 또는 수소를 나타낸다. 또한, R6 는 하기 화학식 5 또는 6으로 표시되는 그룹을 포함한다.R 6 is a simple alkyl group (-SAC) or an alkyl substituted with a double bond containing allyl, cycloalkyl (-SCAC), aromatic (-Ar), aromatic substituted alkyl (-SAC-Ar) Or hydrogen. In addition, R 6 includes a group represented by the following formula (5) or (6).

Figure 112003036743077-pat00006
Figure 112003036743077-pat00006

Figure 112003036743077-pat00007
Figure 112003036743077-pat00007

상기 화학식 5 및 6에서,In Chemical Formulas 5 and 6,

R7 은 독립적으로 -SAC, 알릴(allyl)을 포함하는 이중결합이 치환된 알킬, -SCAC, -Ar, -SAC-Ar 또는 수소일 수 있으며, 모든 천연 아미노산의 곁가지를 포함한다. R7 로 인하여 인접 위치가 스테레오 센터가 되는 경우 두가지 경우의 입체 화합물이 모두 포함되며, 두가지 유형의 화합물이 공존하는 경우(디아스테레오머릭 혼합물을 의미함)도 포함된다. R7 이 아미노산의 곁가지로서 카르복실산 또는 염기로 구성되어 있을 경우, 단순 에스테르 등으로 보호기가 붙어 있는 경우와 약제학적으로 허용되는 염 형태로 존재하는 경우도 포함된다. R 7 may independently be -SAC, alkyl substituted with a double bond including allyl, -SCAC, -Ar, -SAC-Ar or hydrogen, including all branching of natural amino acids. Both cases of steric compounds are included when the adjacent position becomes a stereo center due to R 7, and when both types of compounds coexist (meaning diastereomeric mixtures). When R 7 is composed of a carboxylic acid or a base as a side chain of an amino acid, a case in which a protecting group is attached by a simple ester or the like and a case in which the R 7 is present in a pharmaceutically acceptable salt form are included.

R8 및 R9 은 각각 독립적으로 단순한 알킬그룹(-SAC)이거나, 알릴(allyl)을 포함하는 이중결합이 치환된 알킬, 시클로알킬(-SCAC), 아로마틱(-Ar), 아로마틱으로 치환된 알킬(-SAC-Ar) 카르복스산이 치환된 아로마틱으로 치환된 알킬 또는 수소를 나타낸다. R 8 and R 9 are each independently a simple alkyl group (-SAC) or an alkyl substituted with a double bond containing allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted with aromatic (-SAC-Ar) Carboxylic acid represents alkyl substituted with substituted aromatics or hydrogen.

R10 은 독립적으로 단순한 알킬그룹(-SAC)이거나, 알릴(allyl)을 포함하는 이중결합이 치환된 알킬, 시클로알킬(-SCAC), 아로마틱(-Ar), 아로마틱으로 치환된 알킬(-SAC-Ar) 또는 수소를 나타내며, 바람직하게는 단순한 알킬그룹을 나타낸다.R 10 is independently a simple alkyl group (-SAC) or an alkyl substituted with a double bond containing allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted with aromatic (-SAC- Ar) or hydrogen, preferably a simple alkyl group.

R11 은 독립적으로 단순한 알킬그룹(-SAC)이거나, 알릴(allyl)을 포함하는 이중결합이 치환된 알킬, 시클로알킬(-SCAC), 아로마틱(-Ar), 알킬 또는 알콕시로 치환된 아로마틱, 알킬 또는 알콕시로 치환된 헤테로아로마틱 또는 알콕시로 치환된 헤테로시클로알킬을 나타낸다.R 11 is independently a simple alkyl group (-SAC) or an aromatic, alkyl substituted with a double bond containing allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl or alkoxy Or heteroaromatic substituted with alkoxy or heterocycloalkyl substituted with alkoxy.

따라서, 본 발명에 따른 화학식 1의 술폰 아미드 유도체에 대한 본 명세서(특허청구범위 포함)에서의 정의에는 그것의 염들과 이성질체들이 모두 포함된다.Thus, the definitions herein (including claims) for the sulfonamide derivatives of formula 1 according to the invention include both salts and isomers thereof.

화학식 1에서의 정의에 따라, 본 발명의 술폰 아미드 유도체는 하기 화학식 7 내지 9 중의 어느 하나의 화합물일 수 있다.According to the definition in Formula 1, the sulfone amide derivative of the present invention may be a compound of any one of Formulas 7 to 9 below.

Figure 112003036743077-pat00008
Figure 112003036743077-pat00008

Figure 112003036743077-pat00009
Figure 112003036743077-pat00009

Figure 112003036743077-pat00010
Figure 112003036743077-pat00010

상기 식에서, n, A, R1, R2, R3, R4, R5, R6 , R10 및 R11 은 화학식 1에서와 동일하다.
Wherein n, A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 10 and R 11 are the same as in formula (1).

본 발명에 따른 술폰 아미드 유도체 중의 특히 바람직한 예로는 하기 (1) 내지 (153)의 화합물을 들 수 있다.Particularly preferred examples of the sulfonamide derivatives according to the present invention include the compounds of the following (1) to (153).

(1) 4-[({(2S)-2-[((2R,4S,5S)-5-{[3-(1,1-디옥소-1λ6-이소치아졸리딘-2-일)벤조일]아미노}-4-히드록시-2,7-디메틸옥타노일)아미노]프로파노일}아미노)메틸]벤조산(1) 4-[({(2 S ) -2-[((2 R , 4 S , 5 S ) -5-{[3- (1,1-dioxo-1λ 6 -isothiazolidine- 2-yl) benzoyl] amino} -4-hydroxy-2,7-dimethyloctanoyl) amino] propanoyl} amino) methyl] benzoic acid

(2) N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠)-1-메틸-2,2,4-트리옥소-1,2,3,4-테트라히드로-2λ6,1-벤조치아진-7-카르복스아미드(2) N -(( 1S , 2S , 4R ) -5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl) -1-methyl-2,2,4-trioxo-1,2,3,4-tetrahydro-2λ 6 , 1-benzothiazin-7- Carboxamide

(3) 4-{[((2S)-2-{[(2R,4S,5S)-4-히드록시-2,7-디메틸-5-({3-[(프로필술포닐)아미노]벤조일}아미노)옥타노일]아미노}프로파노일)아미노]메틸}벤조산
(3) 4-{[((2 S ) -2-{[(2 R , 4 S , 5 S ) -4-hydroxy-2,7-dimethyl-5-({3-[(propylsulfonyl ) Amino] benzoyl} amino) octanoyl] amino} propanoyl) amino] methyl} benzoic acid

(4) 4-{[((2S)-2-{[(2R,4S,5S)-4-히드록시-2,7-디메틸-5-({3-[(페닐술포닐)아미노] 벤조일}아미노)옥타노일]아미노}프로파노일)아미노]메틸}벤조산
(4) 4-{[((2 S ) -2-{[(2 R , 4 S , 5 S ) -4-hydroxy-2,7-dimethyl-5-({3-[(phenylsulfonyl ) Amino] benzoyl} amino) octanoyl] amino} propanoyl) amino] methyl} benzoic acid

(5) 4-{[((2S)-2-{[(2R,4S,5S)-4-히드록시-2,7-디메틸-5-({3-[(2-치에닐술포닐)아미노]벤조일}아미노)옥타노일]아미노}프로파노일)아미노]메틸}벤조산
(5) 4 - {[( (2 S) -2 - {[(2 R, 4 S, 5 S) -4- hydroxy-2,7-dimethyl-5 - ({3 - [(2-value Enylsulfonyl) amino] benzoyl} amino) octanoyl] amino} propanoyl) amino] methyl} benzoic acid

(6) 4-{[((2S)-2-{[(2R,4S,5S)-4-히드록시-2,7-디메틸-5-({3-[메틸(프로필술포닐)아미노]벤조일}아미노)옥타노일]아미노}프로파노일)아미노]메틸}벤조산
(6) 4-{[((2 S ) -2-{[(2 R , 4 S , 5 S ) -4-hydroxy-2,7-dimethyl-5-({3- [methyl (propylsulphur) Phenyl) amino] benzoyl} amino) octanoyl] amino} propanoyl) amino] methyl} benzoic acid

(7) 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[에틸(프로필술포닐)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}프로파노일)아미노]메틸}벤조산
(7) 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5-({3- [ethyl (propylsulfonyl) amino] benzoyl} amino) -4- Hydroxy-2,7-dimethyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid

(8) 4-{[((2S)-2-{[(2R,4S,5S)-4-히드록시-2,7-디메틸-5-({3-[프로필(프로필술포닐)아미노]벤조일}아미노)옥타노일]아미노}프로파노일)아미노]메틸}벤조산
(8) 4-{[((2 S ) -2-{[(2 R , 4 S , 5 S ) -4-hydroxy-2,7-dimethyl-5-({3- [propyl (propylsulphate) Phenyl) amino] benzoyl} amino) octanoyl] amino} propanoyl) amino] methyl} benzoic acid

(9) 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[벤질(프로필술포닐)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}프로파노일)아미노]메틸}벤조산
(9) 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5-({3- [benzyl (propylsulfonyl) amino] benzoyl} amino) -4- Hydroxy-2,7-dimethyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid

(10) 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(에틸술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}프로파노일)아미노]메틸}벤조산
(10) 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5-({3-[(ethylsulfonyl) (methyl) amino] benzoyl} amino)- 4-hydroxy-2,7-dimethyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid

(11) 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(부칠술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}프로파노일)아미노]메틸}벤조산
(11) 4 - {[( (2 S) -2 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( Fanning sulfonyl) (methyl) amino] benzoyl} amino) - 4-hydroxy-2,7-dimethyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid

(12) 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}프로파노일)아미노]메틸}벤조산
(12) 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino)- 4-hydroxy-2,7-dimethyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid

(13) 4-[({(2S)-2-[((2R,4S,5S)-4-히드록시-2,7-디메틸-5-{[3-(메틸{[2-(1-나프틸)에틸]술포닐}아미노)벤조일]아미노}옥타노일)아미노]프로파노일}아미노)메틸]벤조산
(13) 4-[({(2 S ) -2-[((2 R , 4 S , 5 S ) -4-hydroxy-2,7-dimethyl-5-{[3- (methyl {[2 -(1-naphthyl) ethyl] sulfonyl} amino) benzoyl] amino} octanoyl) amino] propanoyl} amino) methyl] benzoic acid

(14) N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠)-3-[메틸(2-치에닐술포닐)아미노]벤즈아미드
(14) N -(( 1S , 2S , 4R ) -5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl) -3- [methyl (2-chienylsulfonyl) amino] benzamide

(15) N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠)-3-[메틸(페닐술포닐)아미노]벤즈아미드
(15) N -(( 1S , 2S , 4R ) -5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl) -3- [methyl (phenylsulfonyl) amino] benzamide

(16) N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠)-3-[메틸(1-나프틸술포닐)아미노]벤즈아미드
(16) N -(( 1S , 2S , 4R ) -5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl) -3- [methyl (1-naphthylsulfonyl) amino] benzamide

(17) N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-베틸-2-옥소에틸]아미노}-2-히드록 시-1-이소부칠-4-메틸-5-옥소펜칠)-3-[메틸(2-나프틸술포닐)아미노]벤즈아미드
 (17) N - ((1 S, 2 S, 4 R) -5 - {[(1 S) -2- ( benzylamino) -1-betil-oxoethyl] amino} -2-hydroxy -1-isobutyl-4-methyl-5-oxopentyl) -3- [methyl (2-naphthylsulfonyl) amino] benzamide

(18) N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠)-3-[{[5-(디메틸아미노)-1-나프틸]술포닐}(메틸)아미노]벤즈아미드
(18) N -(( 1S , 2S , 4R ) -5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl) -3-[{[5- (dimethylamino) -1-naphthyl] sulfonyl} (methyl) amino] benzamide

(19) 3-[{[2-(아세틸아미노)-4-메틸-1,3-치아졸-5-일]술포닐}(메틸)아미노]-N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠)벤즈아미드
(19) 3-[{[2- (acetylamino) -4-methyl-1,3-thiazol-5-yl] sulfonyl} (methyl) amino] -N -((1 S , 2 S , 4 R) -5 - {[(1 S) -2- ( benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1-isopropyl-4-methyl-5-oxo penchil Fanning) Benzamide

(20) N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠)-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
(20) N -(( 1S , 2S , 4R ) -5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide

(21) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소펜칠-4-메틸-5-옥소펜칠]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
(21) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isopentyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide

(22) N-[(1S,2S,4S)-4-({[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}카르보닐)-2-히드록시-1-이소부칠-5-메틸헥실]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
(22) N -[( 1S , 2S , 4S ) -4-({[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} carbonyl) -2 -Hydroxy-1-isobutyl-5-methylhexyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide

(23) N-{(1S,2S,4S)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카 르보닐]-2-히드록시-1-이소부칠-5-메틸헥실}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
(23) N -{( 1S , 2S , 4S ) -4-[({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl]- 2-hydroxy-1-isobutyl-5-methylhexyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide

(24) N-[(1S,2S,4R)-4-({[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}카르보닐)-2-히드록시-1-이소부칠-6-헵테닐]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
(24) N -[( 1S , 2S , 4R ) -4-({[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} carbonyl) -2 -Hydroxy-1-isobutyl-6-heptenyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide

(25) N-{(1S,2S,4R)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-히드록시-1-이소부칠-6-헵테닐}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
(25) N -{( 1S , 2S , 4R ) -4-[({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2 -Hydroxy-1-isobutyl-6-heptenyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide

(26) 4-({[(2S)-2-({(2R)-2-[(2S,3S)-3-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-2-히드록시-5-메틸헥실]-4-펜테노일}아미노)프로파노일]아미노}메틸)벤조산
(26) 4-({[( 2S ) -2-({( 2R ) -2-[( 2S , 3S ) -3-({3-[(benzylsulfonyl) (methyl) amino] Benzoyl} amino) -2-hydroxy-5-methylhexyl] -4-pentenoyl} amino) propanoyl] amino} methyl) benzoic acid

(27) 4-({[(2S)-2-({(2R)-2-[(2S,3S)-3-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-2-히드록시-5-메틸헥실]-4-펜테노일}아미노)-3-메틸부타노일]아미노}메틸)벤조산
(27) 4-({[( 2S ) -2-({( 2R ) -2-[( 2S , 3S ) -3-({3-[(benzylsulfonyl) (methyl) amino] Benzoyl} amino) -2-hydroxy-5-methylhexyl] -4-pentenoyl} amino) -3-methylbutanoyl] amino} methyl) benzoic acid

(28) 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-3-메틸부타노일)아미노]메틸}벤조산
(28) 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino)- 4-hydroxy-2,7-dimethyloctanoyl] amino} -3-methylbutanoyl) amino] methyl} benzoic acid

(29) 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-7-메틸-2-프로필옥타노일]아미노}프로파노일)아미노]메틸}벤조산
(29) 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino)- 4-hydroxy-7-methyl-2-propyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid

(30) N-{(1S,2S,4R)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-히드록시-1-이소부칠헵칠}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
(30) N -{(1 S , 2 S , 4 R ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2 -Hydroxy-1-isobutylheptyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide

(31) 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-7-메틸-2-프로필옥타노일]아미노}-3-메틸부타노일)아미노]메틸}벤조산
(31) 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino)- 4-hydroxy-7-methyl-2-propyloctanoyl] amino} -3-methylbutanoyl) amino] methyl} benzoic acid

(32) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠]-3-[메틸(2-치에닐술포닐)아미노]벤즈아미드
(32) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3- [methyl (2-chienylsulfonyl) amino] benzamide

(33) N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠)-3-[메틸(프로필술포닐)아미노]벤즈아미드
(33) N -(( 1S , 2S , 4R ) -5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl) -3- [methyl (propylsulfonyl) amino] benzamide

(34) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠]-3-[메틸(프로필술포닐)아미노]벤즈아미드
(34) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3- [methyl (propylsulfonyl) amino] benzamide

(35) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2- 히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-5-[(벤질술포닐)(메틸)아미노]-2-클로로벤즈아미드
(35) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -5-[(benzylsulfonyl) (methyl) amino] -2-chlorobenzamide

(36) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-5-(트리플루오로메틸)벤즈아미드
(36) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -5- (trifluoromethyl) benzamide

(37) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-5-브로모벤즈아미드
(37) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -5-bromobenzamide

(38) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-5-니트로벤즈아미드
(38) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -5-nitrobenzamide

(39) 3-아미노-N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-5-[(벤질술포닐)(메틸)아미노]벤즈아미드
(39) 3-amino- N -[(1 S , 2 S , 4 R ) -5-({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2 -Hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -5-[(benzylsulfonyl) (methyl) amino] benzamide

(40) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2- 히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-5-시아노벤즈아미드
(40) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -5-cyanobenzamide

(41) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-5-메틸벤즈아미드
(41) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -5-methylbenzamide

(42) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-5-클로로벤즈아미드
(42) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -5-chlorobenzamide

(43) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-5-[(벤질술포닐)(메틸)아미노]이소프탈아미드
(43) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -5-[(benzylsulfonyl) (methyl) amino] isophthalamide

(44) 메틸 3-({[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]아미노}카르보닐)-5-[(벤질술포닐)(메틸)아미노]벤조에이트
(44) Methyl 3-({[(1 S , 2 S , 4 R ) -5-({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2- Hydroxy-1-isobutyl-4-methyl-5-oxopentyl] amino} carbonyl) -5-[(benzylsulfonyl) (methyl) amino] benzoate

(45) 벤질 3-({[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미 노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]아미노}카르보닐)-5-[(벤질술포닐)(메틸)아미노]벤조에이트
(45) benzyl 3-({[(1 S , 2 S , 4 R ) -5-({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2 -Hydroxy-1-isobutyl-4-methyl-5-oxopentyl] amino} carbonyl) -5-[(benzylsulfonyl) (methyl) amino] benzoate

(46) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-4-메톡시벤즈아미드
(46) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -4-methoxybenzamide

(47) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-4-플루오로벤즈아미드
(47) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -4-fluorobenzamide

(48) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-4-클로로벤즈아미드
(48) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -4-chlorobenzamide

(49) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-5-[(벤질술포닐)(메틸)아미노]-2-메톡시벤즈아미드
(49) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -5-[(benzylsulfonyl) (methyl) amino] -2-methoxybenzamide

(50) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2- 히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-{메틸[(2-니트로벤질)술포닐]아미노}벤즈아미드
(50) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3- {methyl [(2-nitrobenzyl) sulfonyl] amino} benzamide

(51) 3-[[(2-아미노벤질)술포닐](메틸)아미노]-N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]벤즈아미드
(51) 3-[[(2-aminobenzyl) sulfonyl] (methyl) amino] -N -[(1 S , 2 S , 4 R ) -5-({(1 S ) -1-[(benzyl Amino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] benzamide

(52) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-{메틸[(2-메틸벤질)술포닐]아미노}벤즈아미드
(52) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3- {methyl [(2-methylbenzyl) sulfonyl] amino} benzamide

(53) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-{메틸[(3-메틸벤질)술포닐]아미노}벤즈아미드
(53) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3- {methyl [(3-methylbenzyl) sulfonyl] amino} benzamide

(54) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틴]-3-{메틸[(4-메틸벤질)술포닐]아미노}벤즈아미드
(54) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentin] -3- {methyl [(4-methylbenzyl) sulfonyl] amino} benzamide

(55) N-{(1S,2S,4R)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카 르보닐]-2-히드록시-1-이소부틸-6-헵틴일}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
(55) N -{( 1S , 2S , 4R ) -4-[({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl]- 2-hydroxy-1-isobutyl-6-heptinyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide

(56) N-{(1S,2S,4Z)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-히드록시-1-이소부틸-4-헥센일}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
(56) N -{(1 S , 2 S , 4 Z ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2 -Hydroxy-1-isobutyl-4-hexenyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide

(57) N-{(1S,2S,4R)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-히드록시-1-이소부틸헥실}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
(57) N -{( 1S , 2S , 4R ) -4-[({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2 -Hydroxy-1-isobutylhexyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide

(58) N-{(1S,2S,4S)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-히드록시-1-이소부틸헥실}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
(58) N -{( 1S , 2S , 4S ) -4-[({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2 -Hydroxy-1-isobutylhexyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide

(59) 메틸 (2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-3-메틸부타노에이트
59 methyl (2 S) -2 - {[ (2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy -2,7-dimethyloctanoyl] amino} -3-methylbutanoate

(60) (2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-3-메틸부탄산
 (60) (2 S) -2 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy- 2,7-dimethyloctanoyl] amino} -3-methylbutanoic acid

(61) N-((1S,2S,4R)-5-{[(1S)-1-(아미노카르보닐)-2-메틸프로필]아미노}-2-히드록 시-1-이소부틸-4-메틸-5-옥소펜틸)-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
(61) N -(( 1S , 2S , 4R ) -5-{[( 1S ) -1- (aminocarbonyl) -2-methylpropyl] amino} -2-hydroxy-1- Isobutyl-4-methyl-5-oxopentyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide

(62) (2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}부탄산
 (62) (2 S) -2 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy- 2,7-dimethyloctanoyl] amino} butanoic acid

(63) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
(63) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] propyl} amino) -2-hydroxy-1-isobutyl -4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide

(64) (2S,3R)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-3-메틸펜탄산
(64) ( 2S , 3R ) -2-{[( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4- Hydroxy-2,7-dimethyloctanoyl] amino} -3-methylpentanoic acid

(65) N-[(1S,2S,4R)-5-({(1S,2R)-1-[(벤질아미노)카르보닐]-2-메틸부틸}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
(65) N -[( 1S , 2S , 4R ) -5-({( 1S , 2R ) -1-[(benzylamino) carbonyl] -2-methylbutyl} amino) -2- Hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide

(66) 메틸 (2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-3,3-디메틸부타노에이트
66 methyl (2 S) -2 - {[ (2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy -2,7-dimethyloctanoyl] amino} -3,3-dimethylbutanoate

(67) (2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-3,3-디메틸부탄산
(67) (2 S) -2 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy- 2,7-dimethyloctanoyl] amino} -3,3-dimethylbutanoic acid

(68) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2,2-디메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
 (68) N - [(1 S, 2 S, 4 R) -5 - ({(1 S) -1 - [( benzylamino) carbonyl] -2,2- dimethylpropyl} amino) -2-hydroxy Roxy-1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide

(69) N-[(1S,2S,4R)-5-({(1R)-1-[(벤질아미노)카르보닐]-2,2-디메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
 (69) N - [(1 S, 2 S, 4 R) -5 - ({(1 R) -1 - [( benzylamino) carbonyl] -2,2- dimethylpropyl} amino) -2-hydroxy Roxy-1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide

(70) N-[(1S,2S,4R)-5-({1-[(벤질아미노)카르보닐]사이클로펜틸}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
(70) N - [(1 S, 2 S, 4 R) -5 - ({1 - [( benzylamino) carbonyl] cyclopentyl} amino) -2-hydroxy-1-isobutyl-4-methyl -5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide

(71) (2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥탄산
 (71) (2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyl-octanoic acid

(72) 3-[(벤질술포닐)(메틸)아미노]-N-((1S,2S,4R)-2-히드록시-1-이소부틸-4-메틸-5-옥소-5-{[(3R)-2-옥소피페리딘일]아미노}펜틸)벤즈아미드
(72) 3-[(benzylsulfonyl) (methyl) amino] -N -(( 1S , 2S , 4R ) -2-hydroxy-1-isobutyl-4-methyl-5-oxo-5 -{[( 3R ) -2-oxopiperidinyl] amino} pentyl) benzamide

(73) 3-[(벤질술포닐)(메틸)아미노]-N-((1S,2S,4R)-2-히드록시-1-이소부틸-4-메틸-5-옥소-5-{[(3S)-2-옥소피페리딘일]아미노}펜틸)벤즈아미드
(73) 3-[(benzylsulfonyl) (methyl) amino] -N -(( 1S , 2S , 4R ) -2-hydroxy-1-isobutyl-4-methyl-5-oxo-5 - {[(3 S) -2- oxpiperidin- each optionally substituted; amino} cyclopentyl) benzamide

(74) 메틸 4-({[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디베틸옥타노일]아미노}메틸)사이클로헥산카르복실레이트
74 methyl 4 - ({[(2 R , 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy -2,7 -Dibetayloctanoyl] amino} methyl) cyclohexanecarboxylate

(75) 4-({[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}메틸)사이클로헥산카르복실산
(75) 4 - ({[ (2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7 Dimethyloctanoyl] amino} methyl) cyclohexanecarboxylic acid

(76) 메틸 4-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}사이클로헥산카르복실레이트
(76) methyl 4 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7 Dimethyloctanoyl] amino} cyclohexanecarboxylate

(77) 4-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}사이클로헥산카르복실산
(77) 4 - {[( 2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyl Octanoyl] amino} cyclohexanecarboxylic acid

(78) 메틸 3-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}사이클로헥산카르복실레이트
(78) methyl 3 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7 Dimethyloctanoyl] amino} cyclohexanecarboxylate

(79) 3-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}사이클로헥산카르복실산
(79) 3 - {[( 2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyl Octanoyl] amino} cyclohexanecarboxylic acid

(80) 메틸 5-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}펜타노에이트
80-methyl-5 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7 Dimethyloctanoyl] amino} pentanoate

(81) 5-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}펜탄산
(81) 5 - {[( 2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyl Octanoyl] amino} pentanoic acid

(82) 에틸 3-((1S)-1-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-2-메틸프로필)-4,5-디히드로-5-이소옥사졸카르복실레이트
(82) ethyl 3-(( 1S ) -1-{[( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4 -Hydroxy-2,7-dimethyloctanoyl] amino} -2-methylpropyl) -4,5-dihydro-5-isoxazolecarboxylate

(83) 3-[(벤질술포닐)(메틸)아미노]-N-((1S,2S,4R)-5-{[(1S)-1-시아노-2-메틸프로필]아미노}-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸)벤즈아미드
(83) 3-[(benzylsulfonyl) (methyl) amino] -N -((1 S , 2 S , 4 R ) -5-{[(1 S ) -1-cyano-2-methylpropyl] Amino} -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl) benzamide

(84) 메틸 (2S)-2-{[(3S,4S)-4-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-3-히드록시-6-메틸헵타노일]아미노}-3-메틸부타노에이트
84 methyl (2 S) -2 - {[ (3 S, 4 S) -4 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -3-hydroxy-6 Methylheptanoyl] amino} -3-methylbutanoate

(85) (2S)-2-{[(3S,4S)-4-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-3-히드록시-6-메틸헵타노일]아미노}-3-메틸부탄산
(85) (2 S) -2 - {[(3 S, 4 S) -4 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -3-hydroxy-6-methyl Heptanoyl] amino} -3-methylbutanoic acid

(86) N-[(1S,2S)-4-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-옥소부틸]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
(86) N -[( 1S , 2S ) -4-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-iso Butyl-4-oxobutyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide

(87) 4-{[((2S)-2-{[(3S,4S)-4-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-3-히드록시-6-메틸헵타노일]아미노}-3-메틸부타노일)아미노]메틸}벤조산
(87) 4-{[(( 2S ) -2-{[( 3S , 4S ) -4-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -3-hydrate Oxy-6-methylheptanoyl] amino} -3-methylbutanoyl) amino] methyl} benzoic acid

(88) N-{(1S,2R)-1-벤질-2-히드록시-3-[(3-메톡시벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (88) N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(3-methoxybenzyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide amides

(89) N-{(1S)-1-[(5R)-3-(3-메톡시벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}-3-[메틸(프로필술포닐)아미노]벤즈아미드
(89) N -{( 1S ) -1-[( 5R ) -3- (3-methoxybenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [Methyl (propylsulfonyl) amino] benzamide

(90) N-{(1S,2R)-1-벤질-2-히드록시-3-[(3-메틸벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (90) N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(3-methylbenzyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide

(91) N-{(1S)-1-[(5R)-3-(3-메틸벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}-3-[메틸(프로필술포닐)아미노]벤즈아미드
(91) N -{( 1S ) -1-[( 5R ) -3- (3-methylbenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [ Methyl (propylsulfonyl) amino] benzamide

(92) N-{(1S,2R)-1-벤질-2-히드록시-3-[(2-피리디닐메틸)아미노]프로필}-3-[메틸( 프로필술포닐)아미노]벤즈아미드
 (92) N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(2-pyridinyl methyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide amides

(93) N-{(1S,2R)-1-벤질-3-[(3-에틸벤질)아미노]-2-히드록시프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
(93) N - {(1 S, 2 R) -1- benzyl-3 - [(3-ethylbenzyl) amino] -2-hydroxypropyl} -3- [methyl (propyl-sulfonyl) amino] benzamide

(94) N-{(1S)-1-[(5R)-3-(3-에틸벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}-3-[메틸(프로필술포닐)아미노]벤즈아미드
(94) N -{( 1S ) -1-[( 5R ) -3- (3-ethylbenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [ Methyl (propylsulfonyl) amino] benzamide

(95) N-[(1S,2R)-1-벤질-3-(벤질아미노)-2-히드록시프로필]-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (95) N - [(1 S, 2 R) -1- benzyl-3- (benzylamino) -2-hydroxypropyl] -3- [methyl (propyl-sulfonyl) amino] benzamide

(96) N-{(1S)-1-[(5R)-3-벤질-1,3-옥사졸리딘-5-일]-2-페닐에틸}-3-[메틸(프로필술포닐)아미노]벤즈아미드
(96) N -{( 1S ) -1-[( 5R ) -3-benzyl-1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [methyl (propylsulfonyl ) Amino] benzamide

(97) N-((1S,2R)-1-벤질-2-히드록시-3-{[(1R)-1-페닐프로필]아미노}프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드
(97) N - ((1 S, 2 R) -1- benzyl-2-hydroxy -3 - {[(1 R) -1- phenylpropyl] amino} propyl) -3- [methyl (propyl-sulfonyl ) Amino] benzamide

(98) 3-[메틸(프로필술포닐)아미노]-N-((1S)-2-페닐-1-{(5R)-3-[(1R)-1-페닐프로필]-1,3-옥사졸리딘-5-일}에틸)벤즈아미드
(98) 3- [methyl (propylsulfonyl) amino] -N -(( 1S ) -2-phenyl-1-{( 5R ) -3-[( 1R ) -1-phenylpropyl] -1 , 3-oxazolidin-5-yl} ethyl) benzamide

(99) N-((1S,2R)-1-벤질-2-히드록시-3-{[(1S)-1-페닐프로필]아미노}프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드
(99) N - ((1 S, 2 R) -1- benzyl-2-hydroxy -3 - {[(1 S) -1- phenylpropyl] amino} propyl) -3- [methyl (propyl-sulfonyl ) Amino] benzamide

(100) 3-[메틸(프로필술포닐)아미노]-N-((1S)-2-페닐-1-{(5R)-3-[(1S)-1-페닐프로필]-1,3-옥사졸리딘-5-일}에틸)벤즈아미드
(100) 3- [methyl (propylsulfonyl) amino] -N -(( 1S ) -2-phenyl-1-{( 5R ) -3-[( 1S ) -1-phenylpropyl] -1 , 3-oxazolidin-5-yl} ethyl) benzamide

(101) N-((1S,2R)-1-벤질-2-히드록시-3-{[(1R)-1-(3-메톡시페닐)에틸]아미노}프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드
(101) N - ((1 S, 2 R) -1- benzyl-2-hydroxy -3 - {[(1 R) -1- (3- methoxyphenyl) ethyl] amino} propyl) -3 [Methyl (propylsulfonyl) amino] benzamide

(102) N-((1S)-1-{(5R)-3-[(1R)-1-(3-메톡시페닐)에틸]-1,3-옥사졸리딘-5-일}-2-페닐에틸)-3-[메틸(프로필술포닐)아미노]벤즈아미드
(102) N -(( 1S ) -1-{( 5R ) -3-[( 1R ) -1- (3-methoxyphenyl) ethyl] -1,3-oxazolidin-5-yl } -2-phenylethyl) -3- [methyl (propylsulfonyl) amino] benzamide

(103) N-((1S,2R)-1-벤질-2-히드록시-3-{[(1S)-1-(3-메톡시페닐)에틸]아미노}프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드
(103) N - ((1 S, 2 R) -1- benzyl-2-hydroxy -3 - {[(1 S) -1- (3- methoxyphenyl) ethyl] amino} propyl) -3 [Methyl (propylsulfonyl) amino] benzamide

(104) N-((1S)-1-{(5R)-3-[(1S)-1-(3-메톡시페닐)에틸]-1,3-옥사졸리딘-5-일}-2-페닐에틸)-3-[메틸(프로필술포닐)아미노]벤즈아미드
(104) N -(( 1S ) -1-{( 5R ) -3-[( 1S ) -1- (3-methoxyphenyl) ethyl] -1,3-oxazolidin-5-yl } -2-phenylethyl) -3- [methyl (propylsulfonyl) amino] benzamide

(105) N-{(1S,2R)-1-벤질-2-히드록시-3-[(3-메톡시벤질)아미노]프로필}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
(105) N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(3-methoxybenzyl) amino] propyl} -3 - [(benzyl-sulfonyl) (methyl) amino ] Benzamide

(106) 3-[(벤질술포닐)(메틸)아미노]-N-{(1S)-1-[(5R)-3-(3-메톡시벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}벤즈아미드
(106) 3-[(benzylsulfonyl) (methyl) amino] -N -{( 1S ) -1-[( 5R ) -3- (3-methoxybenzyl) -1,3-oxazolidine -5-yl] -2-phenylethyl} benzamide

(107) 3-[(부틸술포닐)(메틸)아미노]-N-{(1S)-1-[(5R)-3-(3-메톡시벤질)-1,3-옥소졸리딘-5-일]-2-페닐에틸}벤즈아미드
(107) 3-[(butylsulfonyl) (methyl) amino] -N -{( 1S ) -1-[( 5R ) -3- (3-methoxybenzyl) -1,3-oxozolidine -5-yl] -2-phenylethyl} benzamide

(108) 3-[(에틸술포닐)(메틸)아미노]-N-{(1S)-1-[(5R)-3-(3-메톡시벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}벤즈아미드
(108) 3-[(ethylsulfonyl) (methyl) amino] -N -{( 1S ) -1-[( 5R ) -3- (3-methoxybenzyl) -1,3-oxazolidine -5-yl] -2-phenylethyl} benzamide

(109) N-{(1S)-1-[(5R)-3-(3-메톡시벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}-3-[메틸(메틸술포닐)아미노]벤즈아미드
(109) N -{( 1S ) -1-[( 5R ) -3- (3-methoxybenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [Methyl (methylsulfonyl) amino] benzamide

(110) N-{(1S,2R)-1-벤질-2-히드록시-3-[(3-메톡시벤조일)아미노]프로필}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
(110) N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(3-methoxybenzoyl) amino] propyl} -3 - [(benzyl-sulfonyl) (methyl) amino ] Benzamide

(111) N-{(1S,2R)-1-벤질-2-히드록시-3-[(페닐술포닐)아미노]프로필}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
 (111) N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(phenylsulfonyl) amino] propyl} -3 - [(benzyl-sulfonyl) (methyl) amino] benzamide amides

(112) N-((1S,2R)-1-벤질-2-히드록시-3-{[2-(트리플루오로메틸)벤질]아미노}프로 필)-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
(112) N - ((1 S, 2 R) -1- benzyl-2-hydroxy-3 - {[2- (trifluoromethyl) benzyl] amino} profiles) -3 - [(benzyl-sulfonyl ) (Methyl) amino] benzamide

(113) N-((1S,2R)-1-벤질-2-히드록시-3-{[3-(투리플루오로메틸)벤질]아미노}프로필)-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
(113) N - ((1 S, 2 R) -1- benzyl-2-hydroxy-3 - {[3- (2-fluoro Turi) benzyl] amino} propyl) -3 - [(benzyl-sulfonyl) (Methyl) amino] benzamide

(114) N-{(1S,2R)-1-벤질-3-[(3-브로모벤질)아미노]-2-히드록시프로필}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드
 (114) N - {(1 S, 2 R) -1- benzyl-3 - [(3-bromobenzyl) amino] -2-hydroxypropyl} -3 - [(benzyl-sulfonyl) (methyl) amino ] Benzamide

(115) N-((1S,2R)-1-벤질-2-히드록시-3-{[3-(트리플루오로메톡시)벤질]아미노}프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (115) N - ((1 S, 2 R) -1- benzyl-2-hydroxy-3 - {[3- (trifluoromethoxy) benzyl] amino} propyl) -3- [methyl (propyl-sulfonyl ) Amino] benzamide

(116) N-{(1S,2R)-1-벤질-2-히드록시-3-[(3-페녹시벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (116) N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(3-phenoxybenzyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide amides

(117) N-{(1S,2R)-1-벤질-2-히드록시-3-[(3-히드록시벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (117) N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(3-hydroxybenzyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide amides

(118) N-{(1S,2R)-1-벤질-2-히드록시-3-[(4-메톡시벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (118) N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(4-methoxybenzyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide amides

(119) N-{(1S,2R)-1-벤질-2-히드록시-3-[(2-메톡시벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (119) N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(2-methoxybenzyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide amides

(120) N-{(1S,2R)-1-벤질-3-[(3-에톡시벤질)아미노]-2-히드록시프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
(120) N - {(1 S, 2 R) -1- benzyl-3 - [(3-ethoxy-benzyl) amino] -2-hydroxypropyl} -3- [methyl (propyl-sulfonyl) amino] benzamide amides

(121) N-((1S,2R)-3-{[3-(알릴옥시)벤질]아미노}-1-벤질-2-히드록시프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드
(121) N - ((1 S, 2 R) -3 - {[3- ( allyloxy) benzyl] amino} -1-benzyl-2-hydroxypropyl) -3- [methyl (propyl-sulfonyl) amino ] Benzamide

(122) N-((1S,2R)-1-벤질-3-{[3-(벤질옥시)벤질]아미노}-2-히드록시프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드
(122) N - ((1 S, 2 R) -1- benzyl-3 - {[3- (benzyloxy) benzyl] amino} -2-hydroxypropyl) -3- [methyl (propyl-sulfonyl) amino ] Benzamide

(123) 3-({[(2R,3S)-2-히드록시-3-({3-[메틸(프로필술포닐)아미노]벤조일}아미노)-4-페닐부틸]아미노}메틸)페닐 벤조에이트
(123) 3 - ({[ (2 R, 3 S) -2- hydroxy-3 - ({3- [methyl (propyl-sulfonyl) amino] benzoyl} amino) -4-phenylbutyl] amino} methyl) Phenyl benzoate

(124) N-((1S,2R)-1-벤질-3-{[3-(디메틸아미노)벤질]아미노}-2-히드록시프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (124) N - ((1 S, 2 R) -1- benzyl-3 - {[3- (dimethylamino) benzyl] amino} -2-hydroxypropyl) -3- [methyl (propyl-sulfonyl) amino ] Benzamide

(125) N-[(1S,2R)-1-벤질-2-히드록시-3-(펜에틸아미노)프로필]-3-[메틸(프로필술포닐)아미노]벤즈아미드
(125) N - [(1 S, 2 R) -1- benzyl-2-hydroxy-3- (phenethyl-amino) propyl] -3- [methyl (propyl-sulfonyl) amino] benzamide

(126) N-((1S,2R)-1-벤질-3-{[(5-에틸-2-퓨릴)메틸]아미노}-2-히드록시프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (126) N - ((1 S, 2 R) -1- benzyl-3 - {[(5-ethyl-2-furyl) methyl] amino} -2-hydroxypropyl) -3- [methyl (propyl alcohol Phenyl) amino] benzamide

(127) N-((1S,2R)-1-벤질-3-{[(5-에틸-2-치에닐)메틸]아미노}-2-히드록시프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드
(127) N - ((1 S, 2 R) -1- benzyl-3 - {[(5-ethyl-2-on value carbonyl) methyl] amino} -2-hydroxypropyl) -3- [methyl ( Propylsulfonyl) amino] benzamide

(128) N-[(1S,2R)-1-벤질-2-히드록시-3-({[5-(히드록시메틸)-2-퓨릴]메틸}아미노)프로필]-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (128) N - [(1 S, 2 R) -1- benzyl-2-hydroxy-3 - ({[5- (hydroxymethyl) -2-furyl] methyl} amino) propyl] -3- [ Methyl (propylsulfonyl) amino] benzamide

(129) N-((1S,2R)-1-벤질-3-{[(5-브로모-2-치에닐)메틸]아미노}-2-히드록시프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (129) N - ((1 S, 2 R) -1- benzyl-3 - {[(5-bromo-2 value to carbonyl) methyl] amino} -2-hydroxypropyl) -3- [methyl (Propylsulfonyl) amino] benzamide

(130) N-{(1S,2R)-1-벤질-3-[(3-클로로벤질)아미노]-2-히드록시프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
(130) N - {(1 S, 2 R) -1- benzyl-3 - [(3-chlorobenzyl) amino] -2-hydroxypropyl} -3- [methyl (propyl-sulfonyl) amino] benzamide

(131) N-{(1S,2R)-1-벤질-3-[(3-브로모벤질)아미노]-2-히드록시프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
(131) N - {(1 S, 2 R) -1- benzyl-3 - [(3-bromobenzyl) amino] -2-hydroxypropyl} -3- [methyl (propyl-sulfonyl) amino] benzamide amides

(132) N-{(1S,2R)-1-벤질-2-히드록시-3-[(3-아이오도벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (132) N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(3-iodo-benzyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide amides

(133) N-((1S,2R)-1-벤질-2-히드록시-3-{[3-(트리플루오로메틸)벤질]아미노}프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (133) N - ((1 S, 2 R) -1- benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl) -3- [methyl (propyl-sulfonyl ) Amino] benzamide

(134) N-{(1S,2R)-1-벤질-2-히드록시-3-[(3-메틸벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (134) N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(3-methylbenzyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide

(135) N-{(1S,2R)-3-[(1,3-벤조디옥솔-5-일메틸)아미노]-1-벤질-2-히드록시프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
(135) N - {(1 S, 2 R) -3 - [(1,3- benzodioxol-5-ylmethyl) amino] -1-benzyl-2-hydroxypropyl} -3- [methyl ( Propylsulfonyl) amino] benzamide

(136) N-{(1S,2R)-1-벤질-3-[(3,5-디메톡시벤질)아미노]-2-히드록시프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (136) N - {(1 S, 2 R) -1- benzyl-3 - [(3,5-dimethoxybenzyl) amino] -2-hydroxypropyl} -3- [methyl (propyl-sulfonyl) amino ] Benzamide

(137) N-{(1S,2R)-1-벤질-2-히드록시-3-[(2-히드록시-3-메톡시벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (137) N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(2-hydroxy-3-methoxybenzyl) amino] propyl} -3- [methyl (propyl alcohol Phenyl) amino] benzamide

(138) N-{(1S,2R)-1-벤질-3-[(2,3-디메톡시벤질)아미노]-2-히드록시프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (138) N - {(1 S, 2 R) -1- benzyl-3 - [(2,3-dimethoxybenzyl) amino] -2-hydroxypropyl} -3- [methyl (propyl-sulfonyl) amino ] Benzamide

(139) N-{(1S,2R)-1-벤질-2-히드록시-3-[(2-히드록시-5-메톡시벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
(139) N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(2-hydroxy-5-methoxybenzyl) amino] propyl} -3- [methyl (propyl alcohol Phenyl) amino] benzamide

(140) N-{(1S,2R)-1-벤질-3-[(2,5-디메톡시벤질)아미노]-2-히드록시프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (140) N - {(1 S, 2 R) -1- benzyl-3 - [(2,5-dimethoxybenzyl) amino] -2-hydroxypropyl} -3- [methyl (propyl-sulfonyl) amino ] Benzamide

(141) N-{(1S,2R)-1-벤질-2-히드록시-3-[(1-나프틸메틸)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (141) N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(1-naphthylmethyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide amides

(142) N-{(1S,2R)-3-[(1,3-벤조디옥솔-4-일메틸)아미노]-1-벤질-2-히드록시프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
(142) N - {(1 S, 2 R) -3 - [(1,3- benzodioxol-4-ylmethyl) amino] -1-benzyl-2-hydroxypropyl} -3- [methyl ( Propylsulfonyl) amino] benzamide

(143) N-[(1S,2R)-1-벤질-2-히드록시-3-(1H-피라졸-1-일)프로필]-3-[메틸(프로필술포닐)아미노]벤즈아미드
(143) N - [(1 S, 2 R) -1-benzyl-2-hydroxy-3- (1 H - pyrazol-1-yl) propyl] -3- [methyl (propyl-sulfonyl) amino] Benzamide

(144) N-[(1S,2R)-1-벤질-3-(3-벤질-1H-피라졸-1-일)-2-히드록시프로필]-3-[메틸(프로필술포닐)아미노]벤즈아미드
(144) N - [(1 S, 2 R) -1-benzyl-3- (3-benzyl -1 H - pyrazol-1-yl) -2-hydroxypropyl] -3- [methyl (propyl alcohol Phenyl) amino] benzamide

(145) N-[(1S,2R)-1-벤질-2-히드록시-3-(3-이소프로필-1H-피라졸-1-일)프로필]-3-[메틸(프로필술포닐)아미노]벤즈아미드
(145) N - [(1 S, 2 R) -1-benzyl-2-hydroxy-3- (3-isopropyl -1 H - pyrazol-1-yl) propyl] -3- [methyl (propyl Sulfonyl) amino] benzamide

(146) N-((1S,2R)-1-벤질-2-히드록시-3-{3-[(E)-2-페닐에테닐]-1H-피라졸-1-일}프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드
(146) N - ((1 S, 2 R) -1- benzyl-2-hydroxy-3- {3 - [the (E) -2-phenylethenyl] -1 H-pyrazol-1-yl} Propyl) -3- [methyl (propylsulfonyl) amino] benzamide

(147) N-[(1S,2R)-1-벤질-2-히드록시-3-(3-펜에틸-1H-피라졸-1-일)프로필]-3-[메틸(프로필술포닐)아미노]벤즈아미드
(147) N - [(1 S, 2 R) -1-benzyl-2-hydroxy-3- (3-phenethyl--1 H - pyrazol-1-yl) propyl] -3- [methyl (propyl Sulfonyl) amino] benzamide

(148) N-{(1S,2R)-1-벤질-2-히드록시-3-[(3-메톡시벤질)(메틸)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
(148) N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(3-methoxybenzyl) (methyl) amino] propyl} -3- [methyl (propyl-sulfonyl) Amino] benzamide

(149) N-{(1S,2R)-3-[아세틸(3-메톡시벤질)아미노]-1-벤질-2-히드록시프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
 (149) N - {(1 S, 2 R) -3- [ acetyl (3-methoxybenzyl) amino] -1-benzyl-2-hydroxypropyl} -3- [methyl (propyl-sulfonyl) amino] Benzamide

(150) N-((1S)-1-{(1R)-1-히드록시-2-[(3-메톡시벤질)아미노]에틸}-3-메틸부틸)-3- [메틸(프로필술포닐)아미노]벤즈아미드
(150) N -(( 1S ) -1-{( 1R ) -1-hydroxy-2-[(3-methoxybenzyl) amino] ethyl} -3-methylbutyl) -3- [methyl ( Propylsulfonyl) amino] benzamide

(151) N-{(1S,2S)-1-벤질-2-히드록시-3-[(3-메톡시벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
(151) N -{( 1S , 2S ) -1-benzyl-2-hydroxy-3-[(3-methoxybenzyl) amino] propyl} -3- [methyl (propylsulfonyl) amino] benz amides

(152) N-{(1S)-1-[(5S)-3-(3-메톡시벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}-3-[메틸(프로필술포닐)아미노]벤즈아미드
(152) N -{( 1S ) -1-[( 5S ) -3- (3-methoxybenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [Methyl (propylsulfonyl) amino] benzamide

(153) N-{(1S,2S)-1-벤질-2-히드록시-3-[(3-메톡시벤질)(메틸)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드
(153) N -{( 1S , 2S ) -1-benzyl-2-hydroxy-3-[(3-methoxybenzyl) (methyl) amino] propyl} -3- [methyl (propylsulfonyl) Amino] benzamide

본 발명은 또한 화학식 1의 술폰 아미드 유도체의 제조방법을 제공한다. 본 발명이 속한 분야에서 화합물 합성에 관한 통상의 지식을 가진 자라면, 공지의 화합물들, 또는 그것으로부터 손쉽게 제조할 수 있는 화합물들을 사용하여, 본 발명에 따른 화학식 1의 술폰 아미드 유도체를 제조하는 것이 가능할 것이다. 따라서, 제조방법과 관련한 하기 설명은, 하나의 예시적인 방법들을 개시하는 것에 지나지 않으며, 단위조작의 순서 등이 필요에 따라 바뀔 수 있으므로, 그러한 제조방법만으로 본 발명의 범주가 한정되는 것은 아니다.The present invention also provides a method for preparing the sulfon amide derivative of formula (I). Those of ordinary skill in the art to which the present invention pertains can make a sulfonamide derivative of formula (I) according to the present invention using known compounds or compounds which can be easily prepared therefrom. It will be possible. Accordingly, the following description of the manufacturing method is merely to disclose one exemplary method, and the order of the unit operation and the like may be changed as necessary, and thus the scope of the present invention is not limited only to the manufacturing method.

우선, 화학식 1에서 X 가 화학식 2의 치환기인 술폰 아미드 유도체(화학식 7의 유도체)의 제조방법을 하기 반응식 1을 참조하여 설명한다. First, a method of preparing a sulfonamide derivative (derivative of Chemical Formula 7) in which X is a substituent of Chemical Formula 2 will be described with reference to Scheme 1 below.                     

Figure 112003036743077-pat00011
Figure 112003036743077-pat00011

우선, 공지의 방법(J. Am. Chem. Soc. 2000, 122, 3522-3523)에 의하여, 아미노기가 보호된(BocNH-) 아미노산을 이용하여 락톤 화합물(1)을 얻을 수 있다. 이 화합물을 무수테트라히드로퓨란 용액에서 리튬 비스(트리메틸실릴)아미드(바람직하게는, 1.0 M)와 아이오도메탄을 이용하여 알킬이 치환된 락톤(2)를 얻을 수 있다. 락톤(2)를 수산화리튬 수용액(바람직하게는, 1.0 N)으로 처리한 후 이미다졸과 t-부칠디메틸실릴 클로라이드를 사용하여 O-프로텍티드된 카르복실산 화합물(3)을 얻을 수 있다. 화합물(3)을 아민과 커플링시켜 화합물(4)를 얻고, 이것의 프로텍션 그룹을 제거한 후 술폰 아미드가 치환된 벤조산과 커플링시켜 화합물(5)를 얻을 수 있다. 마지막 단계로서 O-프로텍션 그룹을 제거하여 소망하는 최종 화합물(6)을 얻을 수 있다.First, the lactone compound (1) can be obtained by a well-known method ( J. Am. Chem. Soc. 2000, 122, 3522-3523) using the amino acid in which the amino group was protected (BocNH-). This compound can be obtained by using lithium bis (trimethylsilyl) amide (preferably 1.0 M) and iodomethane in anhydrous tetrahydrofuran solution to obtain an alkyl substituted lactone (2). The lactone (2) can be treated with an aqueous lithium hydroxide solution (preferably 1.0 N) and then the O-protected carboxylic acid compound (3) can be obtained using imidazole and t -butyldimethylsilyl chloride. Compound (3) can be coupled with an amine to give compound (4), and after removal of its protection group, coupling with sulfonic amide-substituted benzoic acid can yield compound (5). As a final step, the O-protection group can be removed to give the desired final compound (6).

상기 술폰 아미드가 치환된 벤조산(술폰아미드-치환 벤조산)은 다음에 설명하는 방법으로 합성할 수 있다. 우선, 고리화된 술폰 아미드 유도체를 제조하기 위한 술폰아미드-치환 벤조산은 하기 반응식 2로 합성될 수 있다.The benzoic acid (sulfonamide-substituted benzoic acid) substituted with the sulfonamide can be synthesized by the method described below. First, sulfonamide-substituted benzoic acid for preparing cyclized sulfonamide derivatives can be synthesized by the following scheme 2.

Figure 112003036743077-pat00012
Figure 112003036743077-pat00012

상업적으로 수득가능한 에틸-3-아미노벤조에이트(7)을 3-클로로프로판술포닐 클로라이드와 반응시켜 에틸 3-{비스[(3-클로로프로필)술포닐]아미노}벤조에이트(8)을 얻을 수 있다. 얻어진 화합물(8)을 N,N-디메틸포름아미드 용매하에 수산화나트륨 수용액(바람직하게는, 1 N)을 사용하여 고리화된 화합물(9)를 얻고, 이것을 테트라히드로퓨란 및 메탄올 용매하에서 수산화리튬 수용액(바람직하게는, 1 N)을 사용하여 화합물(10)을 합성할 수 있다.   Commercially available ethyl-3-aminobenzoate (7) can be reacted with 3-chloropropanesulfonyl chloride to give ethyl 3- {bis [(3-chloropropyl) sulfonyl] amino} benzoate (8). have. The obtained compound (8) was cyclized using N, N-dimethylformamide solvent in an aqueous sodium hydroxide solution (preferably 1 N) to obtain a cyclized compound (9), which was dissolved in tetrahydrofuran and methanol in an aqueous solution of lithium hydroxide. (Preferably, 1 N) can be used to synthesize compound (10).

고리화되지 않은 술폰 아미드 유도체를 제조하기 위한 술폰아미드-치환 벤조 산은, 상기와 마찬가지로, 화합물(7)과 알킬술포닐 크로라이드를 사용하여 에틸 알킬술포닐아미노벤조에이트를 얻은 후, 수산화리튬 수용액으로 가수분해하여 합성할 수 있다.The sulfonamide-substituted benzoic acid for preparing an uncyclized sulfonamide derivative was obtained in the same manner as above, after obtaining ethyl alkylsulfonylaminobenzoate using compound (7) and alkylsulfonyl chloride, followed by aqueous lithium hydroxide solution. It can be synthesized by hydrolysis.

또한, 화학식 1에서 X 가 화학식 3 또는 4의 치환기인 술폰 아미드 유도체(화학식 8과 9의 유도체)의 제조방법을 하기 반응식 3을 참조하여 설명하면 다음과 같다.In addition, in Formula 1, a method for preparing a sulfonamide derivative (a derivative of Formulas 8 and 9) in which X is a substituent of Formula 3 or 4 will be described with reference to Scheme 3 below.

Figure 112003036743077-pat00013
Figure 112003036743077-pat00013

우선, 공지의 방법(Tetrahedron Letters 1999, 36, 5453-5456)에 의하여, 아미노기가 보호된(BocNH-) 아미노산을 이용하여 epoxide 화합물(11)을 얻을 수 있다. 이 화합물(11)을 이소프로판올 용액에서 해당 아민과 반응시켜 화합물(12)를 얻을 수 있다. 화합물(12)에서 보호기를 제거한 후 해당 알킬술포닐아미노 벤조산 과 커플링시켜 화합물(14)(화학식 8의 화합물)을 얻는다. 여기서 화합물(14)의 일부 치환기(-OH 와 =N-R4 사이)를 고리화하고자 할 때에는, 테트라하이드로퓨란 용매하에서 포르말린과 교반함으로서 화합물(15)(화학식 9의 화합물)를 얻는다.
First, an epoxide compound (11) can be obtained by using a known amino acid (Tocrahedron Letters 1999, 36, 5453-5456) using an amino group protected (BocNH-). Compound (11) can be reacted with the amine in an isopropanol solution to give compound (12). The protecting group is removed from compound (12) and then coupled with the alkylsulfonylamino benzoic acid to obtain compound (14) (compound of formula 8). In the case where it is desired to cyclize some substituents (between -OH and = NR 4 ) of compound (14), compound (15) (compound of formula 9) is obtained by stirring with formalin in a tetrahydrofuran solvent.

본 발명에 따른 화학식 1의 화합물은, 추후 설명하는 실험예들의 결과로부터 알 수 있듯이, BACE 저해효능(억제활성)을 지니고 있고, 그에 따라 베타-아밀로이드 생성의 차단효과를 발휘한다. 따라서, 본 발명은, 약제학적으로 허용되는 담체와, 화학식 1로 표시되는 술폰 아미드 유도체를 약리학적 유효량으로 함유하는 것을 특징으로 하는 BACE 저해제 조성물, 구체적으로는 베타-아밀로이드 생성 저해제 조성물을 제공한다.Compound of formula 1 according to the present invention, as can be seen from the results of the experimental examples to be described later, has a BACE inhibitory effect (inhibitory activity), thereby exhibiting a blocking effect of beta-amyloid production. Accordingly, the present invention provides a BACE inhibitor composition, specifically a beta-amyloid production inhibitor composition, which comprises a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a sulfone amide derivative represented by the formula (1).

화학식 1의 술폰 아미드 유도체는 목적하는 바에 따라 다양한 약제학적 투여형태로 제형화될 수 있다. 본 발명에 따른 약제학적 조성물을 제조함에 있어서, 활성성분, 구체적으로, 화학식 1의 술폰 아미드 유도체를 제조하고자 하는 제형에 따라 선택될 수 있는 다양한 약제학적으로 허용되는 담체와 함께 혼합한다.The sulfone amide derivatives of Formula 1 may be formulated in various pharmaceutical dosage forms as desired. In preparing the pharmaceutical compositions according to the invention, the active ingredient, specifically the sulfonamide derivative of formula 1, is mixed with various pharmaceutically acceptable carriers which may be selected according to the formulation to be prepared.

활성성분은, 목적하는 바에 따라, 주사용 제제, 경피용 제제 또는 경구용 제제로 제형화될 수 있으며, 투여의 용이성 및 용량의 균일성 측면에서 바람직하게는 단일 투여형(unit dosage form)으로 제조된다.The active ingredient may be formulated as an injectable, transdermal or oral preparation, as desired, and is preferably prepared in unit dosage form in view of ease of administration and uniformity of dosage. do.

경구용 제제를 제조하는 경우에는 통상의 약제학적 담체를 사용할 수 있다. 예를 들어, 현탁액, 시럽제, 엘릭시르 밀 용액제와 같은 경구용 액체 제제의 경우 에는 물, 글리콜, 오일, 알콜 등을 담체로 사용할 수 있고, 산제, 환제, 캅셀제 및 정제와 같은 고체 제제의 경우에는 전분, 설탕, 카올린, 윤활제, 결합제, 붕해제 등을 사용할 수 있다. 투여의 용이성으로 인하여 정제 및 캅셀제가 가장 편리한 복용 형태이며, 정제 및 환제는 장피제로 제조하는 것이 바람직하다.When preparing oral preparations, conventional pharmaceutical carriers can be used. For example, water, glycols, oils, alcohols and the like may be used as carriers for oral liquid preparations such as suspensions, syrups, elixirs mill solutions, and solid preparations such as powders, pills, capsules and tablets. Starch, sugar, kaolin, lubricants, binders, disintegrants and the like can be used. Because of their ease of administration, tablets and capsules are the most convenient dosage forms, and tablets and pills are preferably prepared with enteric preparations.

비경구 제제의 경우, 담체로는 통상 멸균수를 사용하며, 용해 보조제와 같은 다른 성분도 포함시킬 수 있다. 주사용 제제, 예를 들어, 멸균 주사용 수성 또는 유성 현탁액은 공지된 기술에 따라 적합한 분산제, 습윤제 또는 현탁제를 사용하여 제조할 수 있다. 여기에 사용될 수 있는 용매에는, 물, 링거액 및 등장성 NaCl 용액이 있으며, 멸균 고정오일도 통상적으로 용매 또는 현탁 매질로서 사용한다. 모노-, 디-글리세라이드를 포함하여 어떠한 무자극성 고정오일도 이러한 목적으로 사용될 수 있으며, 또한 올레산과 같은 지방산도 주사용 제제에 사용할 수 있다.In the case of parenteral preparations, sterile water is usually used as a carrier, and other ingredients such as dissolution aids may also be included. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be prepared using suitable dispersants, wetting agents or suspending agents according to known techniques. Solvents that can be used here include water, Ringer's solution and isotonic NaCl solution, and sterile fixed oils are also commonly used as solvents or suspending media. Any non-irritating fixed oil may be used for this purpose, including mono- and diglycerides, and fatty acids such as oleic acid may also be used in the preparation of injectables.

경피 제제의 경우에는, 담체로서 침투 촉진제 및/또는 적당한 습윤제를 임의로 피부에 대한 자극성이 없는 적당한 첨가제와 함께 사용할 수 있다. 첨가제로는 피부를 통한 투여를 촉진시키고/시키거나 목적하는 조성물을 제조하는데 도움이 되는 것을 선택한다. 경피 제제는 경피용 패취, 크림 또는 연고와 같은 다양한 방식으로 투여된다.In the case of transdermal formulations, penetration promoters and / or suitable humectants can be used as carriers, optionally with suitable additives that are not irritating to the skin. The additives are selected to facilitate the administration through the skin and / or to help prepare the desired composition. Transdermal formulations are administered in a variety of ways such as transdermal patches, creams or ointments.

활성성분이 체내에서 빠르게 제거되는 것을 방지하기 위하여, 본 발명에 따른 조성물은 서방성 제제의 형태로 만들어질 수도 있는데, 이때 사용될 있는 담체로는 당업계에 공지되어 있는 삽입물(implant), 마이크로캡슐화 전달계(miroencapsulated delivery system), 생분해성/생체적합성 고분자(biodegradable/biocompatible polymers) 등이 포함된다. In order to prevent the active ingredient from being rapidly removed from the body, the composition according to the present invention may be made in the form of a sustained release preparation, in which a carrier to be used is an implant, a microencapsulated delivery system known in the art. (miroencapsulated delivery system), biodegradable / biocompatible polymers, and the like.

상기 약리학적 유효량(therapeutically effective amount)이란, 치료를 요하는 병의 증상을 경감 또는 줄이거나 예방을 요하는 병의 임상학적 마커 또는 증상의 개시를 줄이거나 지연시키는데 유효한 활성성분의 량을 의미한다. 약리학적 유효량은 치료를 요하는 병에 대한 공지된 생체내(in vivo) 및 생체외(in vitro) 모델 시스템에서 화합물을 실험함으로써 경험적으로 결정될 수 있다.The therapeutically effective amount means the amount of active ingredient effective to reduce or reduce the symptoms of a disease requiring treatment or to reduce or delay the onset of a clinical marker or condition of a disease requiring prevention. Pharmacologically effective amounts can be determined empirically by testing the compounds in known in vivo and in vitro model systems for diseases in need of treatment.

활성성분, 구체적으로 화학식 1의 술폰 아미드 유도체를 임상적인 목적으로 투여시, 단일 용량 또는 분리용량으로 숙주에게 투여될 총 1 일 용량은 체중 1 ㎏ 당 0.1∼100 ㎎의 범위가 바람직하지만, 특정 환자에 대한 특이 용량 수준은 사용될 특정 화합물, 환자의 체중, 성, 건강상태, 식이, 약제의 투여시간, 투여 방법, 배설률, 약제 혼합 및 질환의 중증도 등에 따라 변화될 수 있다.When the active ingredient, specifically the sulfonamide derivative of Formula 1, is administered for clinical purposes, the total daily dose to be administered to the host in a single dose or in separate doses is preferably in the range of 0.1 to 100 mg per kg of body weight, but in certain patients Specific dosage levels for may vary depending on the particular compound to be used, the weight of the patient, sex, health condition, diet, time of administration of the drug, method of administration, rate of excretion, drug mixing and severity of the disease, and the like.

경우에 따라서는, 화학식 1의 술폰 아미드 유도체는 그것의 프로드럭(prodrug) 등의 형태로 유효한 제약 조성물을 제형화하는데 사용될 수도 있다.In some cases, the sulfone amide derivative of formula 1 may be used to formulate an effective pharmaceutical composition in the form of its prodrug or the like.

앞서 설명한 바와 같이, 화학식 1로 표시되는 술폰 아미드 유도체에는 제약학적으로 허용되는 염(pharmaceutically acceptable salts)이 포함되는데, 상기 염은 투여 대상인 객체에서 모 화합물(parent compound)의 활성을 유지하고 바람직하지 못한 효과를 유발하지 않는 염이라면 특별히 제한되는 것은 아니다. 그러한 염에는 무기염과 유기염이 포함되며, 바람직하게는 다음과 같은 산들의 염을 들 수 있다: acetic, nitric, aspartic, sulfonic, sulfuric, maleic, glutamic, formic, succinic, phosphoric, phthalic, tannic, tartaric, hydrobromic, propionic, benzenesulfonic, benzoic, stearic, esyl, lactic, bicarbonic, bisulfuric, bitartaric, oxalic, butyric, calcium edetate, camsylic, carbonic, chlorobenzoic, citric, edetic, toluenesulfonic, edisylic, esylic, fumaric, gluceptic, pamoic, gluconic, glycollylarsanilic, methylnitric, polygalactouronic, hexylresorcinoic, malonic, hydrabamic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactobionic, mandelic, estolic, methylsulfuric, mucic, napsylic, muconic, p-nitromethanesulfonic, hexamic, pantothenic, monohyrogen phosphoric, dihyrogen phosphoric, salicylic, sulfamic, sulfanilic, methanesulfonic, teoclic, acid 등. As described above, sulfone amide derivatives represented by Formula 1 include pharmaceutically acceptable salts, which maintain the activity of the parent compound in the subject being administered and are undesirable. The salt which does not cause an effect is not particularly limited. Such salts include inorganic and organic salts, preferably salts of the following acids: acetic, nitric, aspartic, sulfonic, sulfuric, maleic, glutamic, formic, succinic, phosphoric, phthalic, tannic, tartaric, hydrobromic, propionic, benzenesulfonic, benzoic, stearic, esyl, lactic, bicarbonic, bisulfuric, bitartaric, oxalic, butyric, calcium edetate, camsylic, carbonic, chlorobenzoic, citric, edetic, toluenesulfonic, edisylic, esylicluc fu pamoic , gluconic, glycollylarsanilic, methylnitric, polygalactouronic, hexylresorcinoic, malonic, hydrabamic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactobionic, mandelic, estolic, methylsulfuric, mucic, napsylic, muconic, p-nitromicsonic panthegenothenic , salicylic, sulfamic, sulfanilic, methanesulfonic, teoclic, acid etc.

본 발명에 따른 BACE 저해제 조성물에는, 활성성분의 작용을 저해하지 않거나 활성성분의 작용을 보조하는 기타 성분들이 더 포함될 수 있으며, 기타 당업계에 공지된 다양한 형태로 제형화될 수 있다.
The BACE inhibitor composition according to the present invention may further include other ingredients that do not inhibit the action or assist the action of the active ingredient, and may be formulated in various forms known in the art.

본 발명은 또한, 화학식 1로 표시되는 술폰 아미드 유도체를 유효성분으로 사용하여, 베타-아밀로이드 생성으로 인해 유발되는 병을 치료하거나 예방하는 방법을 제공한다. 상기 베타-아밀로이드 생성으로 인한 병의 대표적인 예는, 앞서의 설명과 같이, 알츠하이머 질환을 들 수 있지만, 그것만으로 한정되는 것은 아니며, 다운 증후군(Down's syndrome), 유전성 대뇌 출혈증(Hereditary Cerebral Hemorrhage) 등과 같이 알츠하이머 질환에 유사한 질병들도 포함된다. 따라서, 본 발명에 따른 화학식 1의 술폰 아미드 유도체 등이 약리학적 유효량으로 인간 등에게 투여될 때에는, BACE(또는 베타-세크리타제)의 작용을 저해함으로써, BACE의 효소작용으로 인한 베타-아밀로이드 생성을 억제하여, 알츠하이머 질환 또는 그와 유사한 질병의 치료 및 예방에 효과적이다. 상기 "치료"란 발병 증상을 보이는 객체에 사용될 때 병의 진행을 중단 또는 지연시키는 것을 의미하며, 상기 예방이란 발병 증상을 보이지는 않지만 그러한 위험성이 높은 객체에 사용될 때 발병 징후를 중단 또는 지연시키는 것을 의미한다.
The present invention also provides a method for treating or preventing a disease caused by beta-amyloid production by using a sulfonamide derivative represented by Formula 1 as an active ingredient. Representative examples of the disease caused by the beta-amyloid production, as described above, Alzheimer's disease, but is not limited thereto, Down's syndrome, Hereditary Cerebral Hemorrhage, etc. Similar diseases include Alzheimer's disease. Therefore, when the sulfonamide derivative of formula 1 according to the present invention is administered to humans or the like in a pharmacologically effective amount, by inhibiting the action of BACE (or beta-secretase), beta-amyloid production due to the enzymatic action of BACE Inhibitors are effective in the treatment and prevention of Alzheimer's disease or similar diseases. The term "treatment" means stopping or delaying the progression of the disease when used in a subject exhibiting symptoms of onset, and the prophylaxis means stopping or delaying the onset of disease when used in a subject who does not exhibit symptoms but has a high risk of developing the disease. it means.

이하, 본 발명의 내용을 하기 실시예를 참조하여 보다 구체적으로 설명하지만, 이들 실시예는 본 발명에 대한 이해를 돕기 위한 것일 뿐, 어떤 의미로도 본 발명의 범위를 제한하는 것은 아니다.Hereinafter, the content of the present invention will be described in more detail with reference to the following examples, but these examples are provided only to assist the understanding of the present invention and do not limit the scope of the present invention in any sense.

[제조예 1][Production Example 1]

tert-부틸 (1S)-3-메틸-1-[(2R)-5-옥소테트라히드로-2-퓨라닐]부틸카르바메이트의 제조: tert-butyl (1S)-3-methyl-1-[(2R)-5-oxotetrahydro-2-furanyl]butylcarbamate tert - butyl (1 S) -3- methyl -1 - [(2 R) -5- oxo-tetrahydro-2-furanyl]-butyl carbamate: tert -butyl (1 S) -3 -methyl- 1 - [(2 R) -5 -oxotetrahydro-2-furanyl] butylcarbamate

공지의 방법(J. Am. Chem. Soc. 2000, 122, 3522-3523)에 따라, t-부톡시카르보닐-(S)-루이신으로부터 표제 화합물을 합성할 수 있었다. According to known methods ( J. Am. Chem. Soc. 2000, 122, 3522-3523), the title compound could be synthesized from t -butoxycarbonyl- ( S ) -leucine.

1H NMR (500 MHz, CDCl3) ; 4.50 (1H, t), 4.41 (1H, d), 3.84 (1H, m), 2.52 (2H, t), 2.22 (1H, m), 2.11 (1H, m), 1.65 (1H, m), 1.55 (1H, m), 1.43 (9H, s), 1.33 (1H, m), 0.93 (3H, d), 0.92 (3H, d)
1 H NMR (500 MHz, CDCl 3 ); 4.50 (1H, t), 4.41 (1H, d), 3.84 (1H, m), 2.52 (2H, t), 2.22 (1H, m), 2.11 (1H, m), 1.65 (1H, m), 1.55 (1H, m), 1.43 (9H, s), 1.33 (1H, m), 0.93 (3H, d), 0.92 (3H, d)

[제조예 2] [Production Example 2]

tert-부틸 (1S)-3-메틸-1-[(2R,4R)-4-메틸-5-옥소테트라히드로-2-퓨라닐]부틸카르바메이트의 제조: tert-butyl (1S)-3-methyl-1-[(2R,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butylcarbamate tert-butyl (1 S) -3- methyl-1 - Preparation of [(2 R, 4 R) -4- methyl-5-oxo-tetrahydro-2-furanyl] butyl carbamate: tert -butyl (1 S ) -3-methyl-1-[(2 R , 4 R ) -4-methyl-5-oxotetrahydro-2-furanyl] butylcarbamate

상기 제조예 1에서 얻은 화합물 20.67 g(76.17 mmol)을 무수 테트라히드로퓨란 350 ㎖에 녹여 -78℃로 냉각한 후 1.0 M 리튬 비스(트리메틸실릴)아미드 152 ㎖(167.57 mmol, 테트라히드로퓨란용액)를 가하였다. 30 분 동안 교반한 후, 아이오도메탄 10.4 ㎖(167.57 mmol)를 가하여 1 시간 동안 교반하였다. 포화염화암모늄 수용액으로 반응을 종결하여 용매를 감압증류하여 제거하고 에틸아세테이트로 용출하여 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음 에틸아세테이트와 헥산의 1:5 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 15.35 g을 71% 수율로 얻을 수 있었다.20.67 g (76.17 mmol) of the compound obtained in Preparation Example 1 was dissolved in 350 ml of anhydrous tetrahydrofuran, cooled to -78 ° C, and 152 ml (167.57 mmol, tetrahydrofuran solution) of 1.0 M lithium bis (trimethylsilyl) amide was added. Was added. After stirring for 30 minutes, 10.4 mL (167.57 mmol) of iodomethane was added and stirred for 1 hour. The reaction was terminated with a saturated aqueous ammonium chloride solution, and the solvent was distilled off under reduced pressure, eluted with ethyl acetate and washed with brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a 1: 5 mixture of ethyl acetate and hexane to obtain 15.35 g of the title compound in 71% yield.

1H NMR (500 MHz, CDCl3) ; 4.47 (1H, s), 4.37 (1H, d), 3.82 (1H, m), 2.66 (1H, m), 2.39 (1H, m), 1.91 (1H, m), 1.63 (1H, m), 1.53 (1H, m), 1.41 (9H, s), 1.32 (1H, m), 1.25 (3H, d), 0.92 (3H, d), 0.90 (3H, d)
1 H NMR (500 MHz, CDCl 3 ); 4.47 (1H, s), 4.37 (1H, d), 3.82 (1H, m), 2.66 (1H, m), 2.39 (1H, m), 1.91 (1H, m), 1.63 (1H, m), 1.53 (1H, m), 1.41 (9H, s), 1.32 (1H, m), 1.25 (3H, d), 0.92 (3H, d), 0.90 (3H, d)

[제조예 3] [Production Example 3]                     

에틸 3-{비스[(3-클로로프로필)술포닐]아미노}벤조에이트의 제조: ethyl 3-{bis[(3-chloropropyl)sulfonyl]amino}benzoatePreparation of ethyl 3- {bis [(3-chloropropyl) sulfonyl] amino} benzoate: ethyl 3- {bis [(3-chloropropyl) sulfonyl] amino} benzoate

에틸-3-아미노벤조에이트 0.83 g(5 mmol)과 3-클로로프로판술포닐 클로라이드 1.52 ㎖(12.5 mmol)를 디클로로메탄 25 ㎖에 녹인 후 0℃로 냉각하였다. 트리에틸아민 2.09 ㎖(15 mmol)를 넣고 상온으로 온도를 올려서 2 시간 동안 교반하였다. 용매를 감압증류하여 제거하고 에틸아세테이트로 용출한 후 포화탄산수소나트륨과 소금물로 씻어 주었다. 용매를 감압 증류하여 제거한 후 디에틸에테르를 이용하여 고체화시켜 여과하여 표제 화합물 1.02 g을 46% 수율로 얻을 수 있었다. 0.83 g (5 mmol) of ethyl-3-aminobenzoate and 1.52 mL (12.5 mmol) of 3-chloropropanesulfonyl chloride were dissolved in 25 mL of dichloromethane, and then cooled to 0 ° C. 2.09 mL (15 mmol) of triethylamine was added thereto, and the reaction mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, eluted with ethyl acetate, and then washed with saturated sodium bicarbonate and brine. The solvent was distilled off under reduced pressure, and then solidified with diethyl ether to obtain 1.02 g of the title compound in 46% yield.

1H NMR (500 MHz, CDCl3) ; 8.17 (1H, m), 8.03 (1H, s), 7.56 (2H, d), 4.40 (2H, q), 3.76 (4H, t), 3.67 (4H, t), 2.42-2.37 (4H, m), 1.40 (3H, t)
1 H NMR (500 MHz, CDCl 3 ); 8.17 (1H, m), 8.03 (1H, s), 7.56 (2H, d), 4.40 (2H, q), 3.76 (4H, t), 3.67 (4H, t), 2.42-2.37 (4H, m) , 1.40 (3H, t)

[제조예 4][Production Example 4]

3-(1,1-디옥소-1λ6-이소치아졸리딘-2-일)벤조산의 제조: 3-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid3- (1,1-dioxo -1λ 6 - isopropyl teeth Jolly-2-yl) benzoic acid: 3- (1,1-dioxo-1λ 6 -isothiazolidin-2-yl) benzoic acid

상기 제조예 3에서 얻은 화합물 1.0 g(2.24 mmol)을 N,N-디메틸포름아미드 4 ㎖와 1.0 N 수산화나트륨 수용액 4.5 ㎖에 넣고 2 시간 동안 교반하였다. 용매를 감압증류하여 제거하고 에틸아세테이트로 용출한 후 소금물로 씻어 주었다. 용매를 감압증류하여 얻어진 화합물에 다시 테트라히드로퓨란 10 ㎖, 메탄올 2 ㎖, 1.0 N 수산화리튬 수용액 6 ㎖에 녹여서 5 시간 동안 교반하였다. 용매를 감압증류하 여 제거한 후 물로 희석시켜서, 1.0 N 염산 수용액으로 산성화하여 생성된 고체를 여과하여 표제 화합물 0.35 g을 64% 수율로 얻을 수 있었다.1.0 g (2.24 mmol) of the compound obtained in Preparation Example 3 was added to 4 ml of N, N-dimethylformamide and 4.5 ml of 1.0 N aqueous sodium hydroxide solution, followed by stirring for 2 hours. The solvent was distilled off under reduced pressure, eluted with ethyl acetate and washed with brine. The solvent was further distilled under reduced pressure, and the resultant was dissolved in 10 ml of tetrahydrofuran, 2 ml of methanol, and 6 ml of 1.0 N lithium hydroxide aqueous solution and stirred for 5 hours. The solvent was removed by distillation under reduced pressure, diluted with water, acidified with 1.0 N aqueous hydrochloric acid, and the resulting solid was filtered to give 0.35 g of the title compound in 64% yield.

1H NMR (500 MHz, CD3OD) ; 7.88 (1H, s), 7.78 (1H, d), 7.52-7.43 (2H, m), 3.83 (2H, t), 3.46 (2H, t), 2.56-2.50 (2H, m)
1 H NMR (500 MHz, CD3 OD); 7.88 (1H, s), 7.78 (1H, d), 7.52-7.43 (2H, m), 3.83 (2H, t), 3.46 (2H, t), 2.56-2.50 (2H, m)

[제조예 5]Production Example 5

3-(1,1-디옥소-1λ6-이소치아졸리딘-2-일)-N-{(1S)-3-메틸-1-[(2R,4R)-4-메틸-5-옥소테트라히드로-2-퓨라닐]부틸}벤즈아미드의 제조: 3-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-N-{(1S)-3-methyl-1-[(2R,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butyl}benzamide3- (1,1-dioxo -1λ6- isopropyl teeth Jolly-2-yl) - N - {(1 S ) -3- methyl -1 - [(2 R, 4 R) -4- methyl-5 -oxo-tetrahydro-2-furanyl] butyl} benzamide Preparation of: 3- (1,1-dioxo-1λ 6 -isothiazolidin-2-yl) - N - {(1 S) -3-methyl-1- [(2 R , 4 R ) -4-methyl-5-oxotetrahydro-2-furanyl] butyl} benzamide

상기 제조예 2에서 얻은 화합물 0.29 g(1.0 mmol)을 에틸아세테이트에 묽혀진 4.0 N 염산용액 5 ㎖에 녹여서 1 시간 동안 교반하였다. 용매를 감압증류하여 농축한 후 N,N-디메틸포름아미드 5 ㎖에 녹여서 0℃로 냉각하여, 상기 제조예 4에서 얻은 화합물 0.29 g(1.2 mmol), EDC 0.23 g(1.2 mmol), HOBT 0.2 g(1.5 mmol)을 가하였다. 여기에, N,N-디이소프로필에틸아민 1.05 ㎖(6.0 mmol)를 가하고 상온으로 온도를 올려 하룻밤 동안 교반하였다. 감압증류하여 용매를 제거한 다음, 에틸아세테이트에 녹여서 물, 1.0 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류하여 제거한 후, 에틸아세테이트를 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.4 g을 97% 수율로 얻을 수 있었다. 0.29 g (1.0 mmol) of the compound obtained in Preparation Example 2 was dissolved in 5 ml of 4.0 N hydrochloric acid solution diluted in ethyl acetate, and stirred for 1 hour. The solvent was distilled under reduced pressure, concentrated, and then dissolved in 5 ml of N, N-dimethylformamide and cooled to 0 ° C., 0.29 g (1.2 mmol) of the compound obtained in Preparation Example 4, 0.23 g (1.2 mmol) of EDC, and 0.2 g of HOBT. (1.5 mmol) was added. 1.05 mL (6.0 mmol) of N, N-diisopropylethylamine was added thereto, and the temperature was raised to room temperature, followed by stirring overnight. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, 1.0 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was distilled off under reduced pressure, and then purified by column chromatography using ethyl acetate to obtain 0.4 g of the title compound in 97% yield.                     

1H NMR (500 MHz, CDCl3) ; 7.57 (1H, d), 7.52 (1H, s),7.45-7.38 (2H, m), 6.02 (1H, d), 4.62 (1H, m), 4.47 (1H, m), 3.82 (2H, t), 3.40 (2H, t), 2.66-2.52 (3H, m), 2.43 (1H, m), 1.99 (1H, m), 1.73 (1H, m), 1.62 (1H, m), 1.47 (1H, m), 1.25 (3H, d), 0.95 (6H, d)
1 H NMR (500 MHz, CDCl 3 ); 7.57 (1H, d), 7.52 (1H, s), 7.45-7.38 (2H, m), 6.02 (1H, d), 4.62 (1H, m), 4.47 (1H, m), 3.82 (2H, t) , 3.40 (2H, t), 2.66-2.52 (3H, m), 2.43 (1H, m), 1.99 (1H, m), 1.73 (1H, m), 1.62 (1H, m), 1.47 (1H, m ), 1.25 (3H, d), 0.95 (6H, d)

[제조예 6][Manufacture example 6]

(2R,4S,5S)-4-{[tert-부틸(디메틸)실릴]옥시}-5-{[3-(1,1-디옥소-1λ6-이소치아졸리딘-2-일)벤조일]아미노}-2,7-디메틸옥탄산의 제조 : (2R,4S,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-{[3-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoyl]amino}-2,7-dimethyloctanoic acid (2 R, 4 S, 5 S) -4 - {[tert - butyl (dimethyl) silyl] oxy} -5 - {[3- (1,1-dioxo -1λ 6-isopropyl-2-teeth Jolly yl) benzoyl] amino} 2,7-dimethyl-octanoic acid Preparation of: (2 R, 4 S, 5 S) -4 - {[tert -butyl (dimethyl) silyl] oxy} -5 - {[3- ( 1,1-dioxo-1λ 6 -isothiazolidin-2-yl) benzoyl] amino} -2,7-dimethyloctanoic acid

상기 제조예 5에서 얻은 화합물0.4 g(0.97 mmol)을 테트라히드로퓨란 5 ㎖에 녹인 후 1.0 N 수산화리튬 수용액 5 ㎖를 가하여 1 시간 동안 교반하였다. 용매를 감압증류하여 제거한 후 물로 희석하여 25% 시트르산 수용액으로 산성화하여 에틸아세테이트로 용출해 소금물로 씻어 주었다. 용매를 상온이하에서 감압증류하여 제거한 다음 N,N-디메틸포름아미드 10 ㎖에 녹여 이미다졸1.32 g(19.34 mmol)과 t-부틸디메틸실릴 클로라이드 1.46 g(9.67 mmol)을 가하여 하룻밤 동안 교반하였다. 메탄올 4 ㎖를 가하여 2 시간 동안 교반한 후 25% 시트르산 수용액을 가하여 에틸아세테이트로 용출해서 물과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음 메탄올과 디클로로메탄 5:95 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.45 g을 86% 수율로 얻을 수 있었다.0.4 g (0.97 mmol) of the compound obtained in Preparation Example 5 was dissolved in 5 ml of tetrahydrofuran, and 5 ml of 1.0 N lithium hydroxide aqueous solution was added thereto, followed by stirring for 1 hour. The solvent was distilled off under reduced pressure, diluted with water, acidified with 25% aqueous citric acid solution, eluted with ethyl acetate, and washed with brine. The solvent was removed by distillation under reduced pressure at room temperature and then dissolved in 10 ml of N, N-dimethylformamide. Then, 1.32 g (19.34 mmol) of imidazole and 1.46 g (9.67 mmol) of t -butyldimethylsilyl chloride were added and stirred overnight. 4 ml of methanol was added thereto, stirred for 2 hours, 25% aqueous citric acid solution was added thereto, eluted with ethyl acetate and washed with water and brine. The solvent was removed by distillation under reduced pressure, and then purified by column chromatography using methanol and dichloromethane 5:95 mixture to obtain 0.45 g of the title compound in 86% yield.

1H NMR (500 MHz, CDCl3); 7.56 (1H, m), 7.53 (1H, s), 7.41 (2H, d), 6.33 (1H, d), 4.27 (1H, m), 3.84-3.77 (3H, m), 3.39 (2H, t), 2.65 (1H, m), 2.57-2.52 (2H, m), 1.87 (1H, m), 1.64 (1H, m), 1.56-1.36 (3H, m), 1.20 (3H, d), 0.96 (3H, d), 0.95 (3H, d), 0.91 (9H, s), 0.12 (3H, s), 0.10 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 7.56 (1H, m), 7.53 (1H, s), 7.41 (2H, d), 6.33 (1H, d), 4.27 (1H, m), 3.84-3.77 (3H, m), 3.39 (2H, t) , 2.65 (1H, m), 2.57-2.52 (2H, m), 1.87 (1H, m), 1.64 (1H, m), 1.56-1.36 (3H, m), 1.20 (3H, d), 0.96 (3H , d), 0.95 (3H, d), 0.91 (9H, s), 0.12 (3H, s), 0.10 (3H, s)

[제조예 7][Manufacture example 7]

벤질 4-{[(tert-부톡시카르보닐)아미노]메틸}벤조에이트의 제조: benzyl 4-{[(tert-butoxycarbonyl)amino]methyl}benzoateBenzyl 4 - {[(tert - butoxycarbonyl) amino] methyl} benzoate Preparation of: benzyl 4 - {[(tert -butoxycarbonyl) amino] methyl} benzoate

4-(t-부톡시카르보닐아미노-메틸)-벤조산 5.03 g(20 mmol)과 탄산칼륨 4.15 g(30 mmol)을 N,N-디메틸포름아미드 100 ㎖에 녹인 후, 벤질 브로마이드 2.85 ㎖를 가하여 5 시간 동안 교반하였다. 감압증류하여 용매를 제거한 후, 에틸아세테이트에 녹여서 물과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음 에틸아세테이트와 헥산의 1:3 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 6.5 g을 99% 수율로 얻을 수 있었다.5.03 g (20 mmol) of 4- ( t -butoxycarbonylamino-methyl) -benzoic acid and 4.15 g (30 mmol) of potassium carbonate were dissolved in 100 ml of N, N-dimethylformamide, followed by adding 2.85 ml of benzyl bromide. Stir for 5 hours. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a 1: 3 mixture of ethyl acetate and hexane to obtain 6.5 g of the title compound in 99% yield.

1H NMR (500 MHz, CDCl3); 8.03 (2H, d), 7.44 (2H, d), 7.38 (2H, t), 7.35-7.32 (3H, m), 5.35 (2H, s), 4.91 (1H, br), 4.36 (2H, d), 1.45 (9H, s)
1 H NMR (500 MHz, CDCl 3 ); 8.03 (2H, d), 7.44 (2H, d), 7.38 (2H, t), 7.35-7.32 (3H, m), 5.35 (2H, s), 4.91 (1H, br), 4.36 (2H, d) , 1.45 (9H, s)

[제조예 8] [Manufacture example 8]                     

벤질 4-[({(2S)-2-[(tert-부톡시카르보닐)아미노]프로파노일}아미노)메틸]벤조에이트의 제조: benzyl 4-[({(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl}amino)methyl]benzoateBenzyl 4 - [({(2 S ) -2 - [(tert - butoxycarbonyl) amino] propanoyl} amino) methyl] benzoate prepared: benzyl 4 - [({( 2 S) -2- [( tert -butoxycarbonyl) amino] propanoyl} amino) methyl] benzoate

상기 제조예 7에서 얻은 화합물 1.71 g(5.0 mmol)을 에틸아세테이트에 묽혀진 4.0 N 염산용액 15 ㎖에 녹여서 3 시간 동안 교반하였다. 용매를 감압증류하여 농축한 후, N,N-디메틸포름아미드 25 ㎖에 녹여서 0℃로 냉각하여, t-부톡시카르보닐-(S)-알라닌1.04 g(5.5 mmol), EDC 1.15 g(6.0 mmol), HOBT 1.01 g(7.5 mmol)을 가하였다. 여기에, N,N-디이소프로필에틸아민 5.23 ㎖(30.0 mmol)를 가하고 상온으로 온도를 올려 하룻밤 동안 교반하였다. 감압증류하여 용매를 제거한 다음 에틸아세테이트에 녹여서, 물, 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류하여 제거한 후 디에틸에테르에서 고체화하여 표제 화합물 1.78 g을 86% 수율로 얻을 수 있었다.1.71 g (5.0 mmol) of the compound obtained in Preparation Example 7 was dissolved in 15 mL of 4.0 N hydrochloric acid solution diluted in ethyl acetate, and stirred for 3 hours. The solvent was concentrated by distillation under reduced pressure, and then dissolved in 25 ml of N, N-dimethylformamide and cooled to 0 ° C., 1.04 g (5.5 mmol) of t -butoxycarbonyl- ( S ) -alanine and 1.15 g (6.0) of EDC. mmol), and 1.01 g (7.5 mmol) of HOBT were added. 5.23 ml (30.0 mmol) of N, N-diisopropylethylamine was added thereto, and the temperature was raised to room temperature and stirred overnight. After distillation under reduced pressure to remove the solvent, the resultant was dissolved in ethyl acetate, washed with water, 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was distilled off under reduced pressure and then solidified in diethyl ether to obtain 1.78 g of the title compound in 86% yield.

1H NMR (500 MHz, CDCl3); 8.01 (2H, d), 7.43 (2H, d), 7.38 (2H, t), 7.34 (1H, d), 7.31 (2H, d), 6.68 (1H, br), 5.35 (2H, s), 4.94 (1H, br), 4.49 (2H, br), 4.18 (1H, br), 1.41 (9H, s), 1.38 (3H, d)
1 H NMR (500 MHz, CDCl 3 ); 8.01 (2H, d), 7.43 (2H, d), 7.38 (2H, t), 7.34 (1H, d), 7.31 (2H, d), 6.68 (1H, br), 5.35 (2H, s), 4.94 (1H, br), 4.49 (2H, br), 4.18 (1H, br), 1.41 (9H, s), 1.38 (3H, d)

[제조예 9][Manufacture example 9]

벤질 4-[(4S,7R,9S)-9-((1S)-1-{[3-(1,1-디옥소-1λ6-이소치아졸리딘-2-일)벤조일]아미노}-3-메틸부틸)-4,7,11,11,12,12-헥사메틸-3,6-디옥소-10-옥사-2,5-디아자-11-실라트리덱-1-일]벤조에이트의 제조: benzyl 4-[(4S,7R,9S)-9-((1S)-1-{[3-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoyl]amino}-3-methylbutyl)-4,7,11,11,12,12-hexamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl]benzoateBenzyl 4-[(4 S , 7 R , 9 S ) -9-((1 S ) -1-{[3- (1,1-dioxo-1λ 6 -isothiazolidin-2-yl) benzoyl ] Amino} -3-methylbutyl) -4,7,11,11,12,12-hexamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1 Preparation of -yl] benzoate: benzyl 4-[(4 S , 7 R , 9 S ) -9-((1 S ) -1-{[3- (1,1-dioxo-1λ 6 -isothiazolidin-2 -yl) benzoyl] amino} -3-methylbutyl) -4,7,11,11,12,12-hexamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl ] benzoate

상기 제조예 8에서 얻은 화합물 59 ㎎(0.144 mmol)을 에틸아세테이트에 묽혀진 4.0 N 염산용액 3 ㎖에 녹여서 2 시간 동안 교반하였다. 용매를 감압증류하여 농축한 후 N,N-디메틸포름아미드 3 ㎖에 녹여서 0℃로 냉각하여, 상기 제조예 6에서 얻은 화합물 65 ㎎(0.12 mmol)과 HATU 55 ㎎(0.144 mmol)을 가하였다. 여기에, N,N-디이소프로필에틸아민 0.5 ㎖(과량)를 가하고 상온으로 온도를 올려 4 시간 동안 교반하였다. 감압증류하여 용매를 제거한 다음 에틸아세테이트에 녹여서 물, 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음 메탄올과 디클로로메탄의 5:95 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 71 ㎎을 71% 수율로 얻을 수 있었다.59 mg (0.144 mmol) of the compound obtained in Preparation Example 8 was dissolved in 3 ml of 4.0 N hydrochloric acid solution diluted in ethyl acetate, and stirred for 2 hours. The solvent was concentrated by distillation under reduced pressure, dissolved in 3 ml of N, N-dimethylformamide, cooled to 0 ° C, and 65 mg (0.12 mmol) of the compound obtained in Preparation Example 6 and 55 mg (0.144 mmol) of HATU were added thereto. 0.5 ml (excess) of N, N-diisopropylethylamine was added thereto, and the temperature was raised to room temperature and stirred for 4 hours. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a 5:95 mixture of methanol and dichloromethane to obtain 71 mg of the title compound in 71% yield.

1H NMR (500 MHz, CDCl3); 8.00 (2H, d), 7.59 (1H, s), 7.55 (1H, d), 7.45-7.32 (7H, m), 7.30 (2H, d), 7.03 (1H, t), 6.97 (1H, d), 6.28 (1H, d), 5.35 (2H, s), 4.52-4.28 (4H, m), 3.80-3.70 (3H, m), 3.36 (2H, t), 2.58-2.48 (3H, m), 1.68-1.54 (3H, m), 1.48 (1H, m), 1.34 (1H, m), 1.15 (3H, d), 1.11 (3H, d), 0.95 (3H, d), 0.94 (3H, d), 0.91 (9H, s), 0.10 (3H, s), 0.09 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 8.00 (2H, d), 7.59 (1H, s), 7.55 (1H, d), 7.45-7.32 (7H, m), 7.30 (2H, d), 7.03 (1H, t), 6.97 (1H, d) , 6.28 (1H, d), 5.35 (2H, s), 4.52-4.28 (4H, m), 3.80-3.70 (3H, m), 3.36 (2H, t), 2.58-2.48 (3H, m), 1.68 -1.54 (3H, m), 1.48 (1H, m), 1.34 (1H, m), 1.15 (3H, d), 1.11 (3H, d), 0.95 (3H, d), 0.94 (3H, d), 0.91 (9H, s), 0.10 (3H, s), 0.09 (3H, s)

[실시예 1]Example 1

4-[({(2S)-2-[((2R,4S,5S)-5-{[3-(1,1-디옥소-1λ6-이소치아졸리딘-2-일)벤조일]아미노}-4-히드록시-2,7-디메틸옥타노일)아미노]프로파노일}아미노)메틸]벤조산의 제조: 4-[({(2S)-2-[((2R,4S,5S)-5-{[3-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoyl]amino}-4-hydroxy-2,7-dimethyloctanoyl)amino]propanoyl}amino)methyl]benzoic acid4-[({(2 S ) -2-[((2 R , 4 S , 5 S ) -5-{[3- (1,1-dioxo-1λ 6 -isothiazolidin-2-yl ) Benzoyl] amino} -4-hydroxy-2,7-dimethyloctanoyl) amino] propanoyl} amino) methyl] benzoic acid: 4-[({( 2S ) -2-[(( 2R , 4 S , 5 S ) -5-{[3- (1,1-dioxo-1λ 6 -isothiazolidin-2-yl) benzoyl] amino} -4-hydroxy-2,7-dimethyloctanoyl) amino] propanoyl} amino ) methyl] benzoic acid

상기 제조예 9에서 얻은 화합물 68 ㎎(0.081 mmol)을 메탄올 3 ㎖에 녹인 후, 활성 탄소에 흡착된 팔라듐(10%)을 가하고, 수소공기 하에서 하룻밤 동안 교반하였다. 셀라이트를 이용한 감압여과로 고체를 제거한 다음, 감압증류로 용매를 제거하여 얻은 화합물을 테트라히드로퓨란 3 ㎖에 녹였다. 1.0 M 테트라부틸암모늄플루오라이드 0.24 ㎖(0.24 mmol, 테트라히드로퓨란용액)를 가하여 하룻밤 동안 교반하였다. 용매를 감압증류로 제거하여 메탄올과 디클로로메탄의 15:85 혼합액을 이용한 컬럼크로마토그래피로 정제한 후, 디에틸에테르를 이용하여 고체화시켜 여과하여 표제 화합물 46 ㎎을 90% 수율로 얻을 수 있었다.68 mg (0.081 mmol) of the compound obtained in Preparation Example 9 was dissolved in 3 ml of methanol, and palladium (10%) adsorbed on activated carbon was added thereto, and the mixture was stirred overnight under hydrogen air. The solid was removed by vacuum filtration using Celite, and then the solvent was removed by distillation under reduced pressure. The obtained compound was dissolved in 3 ml of tetrahydrofuran. 0.24 mL (0.24 mmol, tetrahydrofuran solution) of 1.0 M tetrabutylammonium fluoride was added and stirred overnight. The solvent was removed by distillation under reduced pressure, purified by column chromatography using a 15:85 mixture of methanol and dichloromethane, and then solidified with diethyl ether to obtain 46 mg of the title compound in 90% yield.

1H NMR (500 MHz, CD3OD); 7.92 (2H, d), 7.65 (1H, s), 7.57 (1H, d), 7.50-7.41 (2H, m), 7.30 (2H, d), 4.41 (2H, q), 4.33 (1H, q), 4.17 (1H, m), 3.84 (2H, t), 3.59 (1H, m), 3.44 (2H, t), 2.68 (1H, m), 2.50 (2H, m), 1.83 (1H, m), 1.68-1.62 (2H, m), 1.48-1.36 (2H, m), 1.32 (3H, d), 1.13 (3H, d), 0.96 (3H, d), 0.94 (3H, d)1 H NMR (500 MHz, CD3 OD); 7.92 (2H, d), 7.65 (1H, s), 7.57 (1H, d), 7.50-7.41 (2H, m), 7.30 (2H, d), 4.41 (2H, q), 4.33 (1H, q) , 4.17 (1H, m), 3.84 (2H, t), 3.59 (1H, m), 3.44 (2H, t), 2.68 (1H, m), 2.50 (2H, m), 1.83 (1H, m), 1.68-1.62 (2H, m), 1.48-1.36 (2H, m), 1.32 (3H, d), 1.13 (3H, d), 0.96 (3H, d), 0.94 (3H, d)

ESI MS (m/e) = 631 [M+H]+
ESI MS (m / e) = 631 [M + H] < + >

[제조예 10][Production Example 10]

(2R,4S,5S)-5-[(tert-부톡시카르보닐)아미노]-4-{[tert-부틸(디메틸)실릴]옥시}-2,7-디메틸옥탄산의 제조: (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-{[ tert-butyl(dimethyl)silyl]oxy}-2,7-dimethyloctanoic acid (2 R, 4 S, 5 S) -5 - [(tert - butoxycarbonyl) amino] -4 - {[tert - butyl (dimethyl) silyl] oxy} Preparation of 2,7-dimethyl-octanoic acid: (2 R , 4 S , 5 S ) -5-[( tert -butoxycarbonyl) amino] -4-{[ tert -butyl (dimethyl) silyl] oxy} -2,7-dimethyloctanoic acid

상기 제조예 5에서 얻은 화합물 대신에 상기 제조예 2에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 6과 동일한 방법으로 실시하여, 표제 화합물 9.1 g을 90% 수율로 얻을 수 있었다.In the same manner as in Preparation Example 6, except that the compound obtained in Preparation Example 2 was used instead of the compound obtained in Preparation Example 5, 9.1 g of the title compound was obtained in a 90% yield.

1H NMR (500 MHz, DMSO, d6); 6.57 (1H, d), 3.63 (1H, m), 3.47 (1H, m), 2.42 (1H, br), 1.77 (1H, m), 1.53 (1H, m), 1.36 (9H, s), 1.30-1.15 (3H, m), 1.07 (3H, d), 0.86 (9H, s), 0.84 (3H, d), 0.79 (3H, d), 0.09 (3H, s), 0.03 (3H, s)
1 H NMR (500 MHz, DMSO, d 6); 6.57 (1H, d), 3.63 (1H, m), 3.47 (1H, m), 2.42 (1H, br), 1.77 (1H, m), 1.53 (1H, m), 1.36 (9H, s), 1.30 -1.15 (3H, m), 1.07 (3H, d), 0.86 (9H, s), 0.84 (3H, d), 0.79 (3H, d), 0.09 (3H, s), 0.03 (3H, s)

[제조예 11][Production Example 11]

tert-부틸 (1S)-2-(벤질아미노)-1-메틸-2-옥소에틸카르바메이트의 제조: tert-butyl (1S)-2-(benzylamino)-1-methyl-2-oxoethylcarbamate tert - butyl (1 S) -2- (benzylamino) Preparation of 1-methyl-2-oxo-ethylcarbamate: tert -butyl (1 S) -2- (benzylamino) -1-methyl-2-oxoethylcarbamate

t-부톡시카르보닐-(S)-알라닌 3.78 g(20 mmol)을 N,N-디메틸포름아미드 100 ㎖에 녹여서 0℃로 냉각하고, 벤질아민 4.37 ㎖(40 mmol), EDC 4.6 g(24 mmol), HOBT 3.24 g(24 mmol)을 가하였다. 여기에, N,N-디이소프로필에틸아민 20.9 ㎖(120 mmol)를 가하고 상온으로 온도를 올려 하룻밤 동안 교반하였다. 감압증류 하여 용매를 제거한 다음 에틸아세테이트에 녹여서, 물, 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음, 에틸아세테이트와 헥산의 1:2 혼합액을 이용한 컬럼크로마토그래피로 정제하여, 표제 화합물 3.88 g을 70% 수율로 얻을 수 있었다.3.78 g (20 mmol) of t -butoxycarbonyl- ( S ) -alanine was dissolved in 100 mL of N, N-dimethylformamide, cooled to 0 ° C., 4.37 mL (40 mmol) of benzylamine, and 4.6 g (24) of EDC. mmol), and 3.24 g (24 mmol) of HOBT were added. 20.9 mL (120 mmol) of N, N-diisopropylethylamine was added thereto, and the mixture was stirred at room temperature overnight. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was removed by distillation under reduced pressure, and then purified by column chromatography using a 1: 2 mixture of ethyl acetate and hexane to obtain 3.88 g of the title compound in 70% yield.

1H NMR (500 MHz, CDCl3); 7.33-7.23 (5H, m), 6.56 (1H, br), 5.02 (1H, br), 4.42 (2H, d), 4.18 (1H, br), 1.40 (9H, s), 1.37 (3H, d)
1 H NMR (500 MHz, CDCl 3 ); 7.33-7.23 (5H, m), 6.56 (1H, br), 5.02 (1H, br), 4.42 (2H, d), 4.18 (1H, br), 1.40 (9H, s), 1.37 (3H, d)

[제조예 12][Manufacture example 12]

tert-부틸 (1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-{[tert-부틸(디메틸)실릴]옥시}-1-이소부틸-4-메틸-5-옥소펜틸카르바메이트의 제조: tert-butyl (1S,2S,4R)-5-{[(1S)-2-(benzylamino)-1-methyl-2-oxoethyl]amino}-2-{[tert-butyl(dimethyl)silyl]oxy}-1-isobutyl-4-methyl-5-oxopentylcarbamate tert - butyl (1 S, 2 S, 4 R) -5 - {[(1 S) -2- ( benzylamino) -1-methyl-2-oxoethyl] amino} -2 - {[tert - butyl ( Dimethyl) silyl] oxy} -1-isobutyl-4-methyl-5-oxopentylcarbamate: tert- butyl (1 S , 2 S , 4 R ) -5-{[(1 S ) -2 -(benzylamino) -1-methyl-2-oxoethyl] amino} -2-{[ tert -butyl (dimethyl) silyl] oxy} -1-isobutyl-4-methyl-5-oxopentylcarbamate

상기 제조예 11에서 얻은 화합물 1.34 g(4.8 mmol)을 에틸아세테이트에 묽혀진 4.0 N 염산용액 20 ㎖에 녹여서 2 시간 동안 교반하였다. 용매를 감압증류하여 농축한 후 N,N-디메틸포름아미드 20 ㎖에 녹여서 0℃로 냉각하여 상기 제조예 10에서 얻은 화합물 1.67 g(4.0 mmol), EDC 0.92 g(4.8 mmol)과 HOBT 0.81 g(6.0 mmol)을 가하였다. 여기에, N,N-디이소프로필에틸아민 4.18 ㎖(24.0 mmol)를 가하고 상온으로 온도를 올려 하룻밤동안 교반하였다. 감압증류하여 용매를 제거한 다음 에 틸아세테이트에 녹여서 물, 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음 메탄올과 디클로로메탄의 2:98 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 2.06 g을 89% 수율로 얻을 수 있었다.1.34 g (4.8 mmol) of the compound obtained in Preparation Example 11 was dissolved in 20 mL of 4.0 N hydrochloric acid solution diluted in ethyl acetate, and stirred for 2 hours. The solvent was concentrated by distillation under reduced pressure, dissolved in 20 ml of N, N-dimethylformamide, and cooled to 0 ° C. to obtain 1.67 g (4.0 mmol) of the compound obtained in Preparation Example 10, 0.92 g (4.8 mmol) of EDC, and 0.81 g of HOBT. 6.0 mmol) was added. 4.18 mL (24.0 mmol) of N, N-diisopropylethylamine was added thereto, the temperature was raised to room temperature, and the mixture was stirred overnight. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a 2:98 mixture of methanol and dichloromethane to obtain 2.06 g of the title compound in 89% yield.

1H NMR (400 MHz, CDCl3); 7.28-7.16 (5H, m), 6.66 (1H, br), 6.45 (1H, d), 4.46 (1H, d), 4.41 (1H, d), 4.36 (2H, dd), 3.64 (1H, m), 3.56 (1H, dd), 2.43 (1H, m), 1.69-1.52 (2H, m), 1.43-1.35 (2H, m), 1.38 (9H, s), 1.31 (3H, d), 1.14 (1H, m), 1.01 (3H, d), 0.87 (3H, d), 0.85 (3H, d), 0.83 (9H, s), 0.01 (6H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.28-7.16 (5H, m), 6.66 (1H, br), 6.45 (1H, d), 4.46 (1H, d), 4.41 (1H, d), 4.36 (2H, dd), 3.64 (1H, m) , 3.56 (1H, dd), 2.43 (1H, m), 1.69-1.52 (2H, m), 1.43-1.35 (2H, m), 1.38 (9H, s), 1.31 (3H, d), 1.14 (1H , m), 1.01 (3H, d), 0.87 (3H, d), 0.85 (3H, d), 0.83 (9H, s), 0.01 (6H, s)

[제조예 13][Production Example 13]

tert-부틸 (1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸카르바메이트의 제조 : tert-butyl (1S,2S,4R )-5-{[(1S)-2-(benzylamino)-1-methyl-2-oxoethyl]amino}-2-hydroxy-1-isobutyl-4-methyl-5-oxopentylcarbamate tert -butyl (1 S , 2 S , 4 R ) -5-{[(1 S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1-iso Preparation of Butyl-4-methyl-5-oxopentylcarbamate: tert- butyl (1 S , 2 S , 4 R ) -5-{[(1 S ) -2- (benzylamino) -1-methyl-2 -oxoethyl] amino} -2-hydroxy-1-isobutyl-4-methyl-5-oxopentylcarbamate

상기 제조예 12에서 얻은 화합물 2.06 g(3.56 mmol)을 테트라히드로퓨란 20 ㎖에 녹인 후 1.0 M 테트라부틸암모늄플루오라이드 7.12 ㎖(7.12 mmol, 테트라히드로퓨란 용액)를 가하여 하룻밤 동안 교반하였다. 용매를 감압증류로 제거하고 에틸아세테이트를 이용한 컬럼크로마토그래피로 정제한 후 헥산을 이용하여 고체화시 켜 여과하여 표제 화합물 1.56 g을 95% 수율로 얻을 수 있었다.2.06 g (3.56 mmol) of the compound obtained in Preparation Example 12 was dissolved in 20 mL of tetrahydrofuran, and then, 7.12 mL (7.12 mmol, tetrahydrofuran solution) of 1.0 M tetrabutylammonium fluoride was added and stirred overnight. The solvent was removed by distillation under reduced pressure, purified by column chromatography using ethyl acetate, and then filtered through solidification with hexane to obtain 1.56 g of the title compound in 95% yield.

1H NMR (500 MHz, CDCl3); 7.33-7.21 (5H, m), 6.69 (1H, br), 6.56 (1H, d), 4.62 (1H, d), 4.48 (1H, dd), 4.40 (2H, d), 3.53 (2H, br), 2.60 (1H, m), 1.76-1.58 (4H, m), 1.42 (9H, s), 1.38 (3H, d),1.25 (1H, m), 1.12 (3H, d), 0.90 (6H, d)
1 H NMR (500 MHz, CDCl 3 ); 7.33-7.21 (5H, m), 6.69 (1H, br), 6.56 (1H, d), 4.62 (1H, d), 4.48 (1H, dd), 4.40 (2H, d), 3.53 (2H, br) , 2.60 (1H, m), 1.76-1.58 (4H, m), 1.42 (9H, s), 1.38 (3H, d), 1.25 (1H, m), 1.12 (3H, d), 0.90 (6H, d )

[실시예 2]Example 2

N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸)-1-메틸-2,2,4-트리옥소-1,2,3,4-테트라히드로-2λ6,1-벤조치아진-7-카르복스아미드의 제조: N-((1S,2S,4R)-5-{[(1S)-2-(benzylamino)-1-methyl-2-oxoethyl]amino}-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl)-1-methyl-2,2,4-trioxo-1,2,3,4-tetrahydro-2λ6,1-benzothiazine-7-carboxamide N -(( 1S , 2S , 4R ) -5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1-iso butyl-4-methyl-5-oxo-pentyl) -1-methyl-2,2,4-tree-oxo-1,2,3,4-tetrahydro--2λ 6, 1- benzo tooth Jean-7-carboxamide Preparation of: N -((1 S , 2 S , 4 R ) -5-{[(1 S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1-isobutyl -4-methyl-5-oxopentyl) -1-methyl-2,2,4-trioxo-1,2,3,4-tetrahydro-2λ 6 , 1-benzothiazine-7-carboxamide

상기 제조예 13에서 얻은 화합물 93 ㎎(0.2 mmol)을 20% 트리플루오로아세트산 2.5 ㎖(디클로로메탄용액)에 녹여서 30 분 동안 교반하였다. 상온이하에서 용매를 감압증류하여 농축한 후 N,N-디메틸포름아미드 5 ㎖에 녹여서 0℃로 냉각하여 1-메틸-2,2,4-트리옥소-테트라히드로-2λ6,1-벤조치아진-7-카르복실산 77 ㎎(0.3 mmol)과 HATU 114 ㎎(0.3 mmol)을 가하였다. 여기에, N,N-디이소프로필에틸아민 0.5 ㎖(과량)를 가하고 상온으로 온도를 올려 4 시간 동안 교반하였다. 감압증류하여 용매를 제거한 다음 에틸아세테이트에 녹여서 물, 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음 에틸아세테이트와 헥산의 3:1 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 53 ㎎을 44% 수율로 얻을 수 있었다.93 mg (0.2 mmol) of the compound obtained in Preparation Example 13 was dissolved in 2.5 ml (dichloromethane solution) of 20% trifluoroacetic acid, and stirred for 30 minutes. The solvent was distilled under reduced pressure under normal temperature, concentrated, dissolved in 5 ml of N, N-dimethylformamide, cooled to 0 ° C., and then cooled to 0 ° C. in 1-methyl-2,2,4-trioxo-tetrahydro-2λ 6 , 1-benzothia. 77 mg (0.3 mmol) of gin-7-carboxylic acid and 114 mg (0.3 mmol) of HATU were added. 0.5 ml (excess) of N, N-diisopropylethylamine was added thereto, and the temperature was raised to room temperature and stirred for 4 hours. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a 3: 1 mixture of ethyl acetate and hexane to obtain 53 mg of the title compound in 44% yield.

1H NMR (400 MHz, CD3OD); 8.15 (1H, d), 7.77 (1H, s), 7.66 (1H, d), 7.33-7.21 (5H, m), 4.91 (2H, s), 4.43-4.31 (3H, m), 4.20 (1H, m), 3.60 (1H, m), 3.51 (3H,s), 2.71 (1H, m), 1.86 (1H, m), 1.70-1.62 (2H, m), 1.49-1.42 (2H, m), 1.32 (3H, d), 1.15 (3H, d), 0.97 (3H, d), 0.96 (3H, d)1 H NMR (400 MHz, CD3OD); 8.15 (1H, d), 7.77 (1H, s), 7.66 (1H, d), 7.33-7.21 (5H, m), 4.91 (2H, s), 4.43-4.31 (3H, m), 4.20 (1H, m), 3.60 (1H, m), 3.51 (3H, s), 2.71 (1H, m), 1.86 (1H, m), 1.70-1.62 (2H, m), 1.49-1.42 (2H, m), 1.32 (3H, d), 1.15 (3H, d), 0.97 (3H, d), 0.96 (3H, d)

ESI MS (m/e) = 601 [M+H]+
ESI MS (m / e) = 601 [M + H] < + >

[제조예 14]Production Example 14

에틸 3-[(프로필술포닐)아미노]벤조에이트의 제조: ethyl 3-[(propylsulfonyl)amino]benzoatePreparation of ethyl 3-[(propylsulfonyl) amino] benzoate: ethyl 3-[(propylsulfonyl) amino] benzoate

에틸 3-아미노벤조에이트 1.65 g(10 mmol)과 프로판술포닐클로라이드 2.81 ㎖(25 mmol)를 디클로로메탄 50 ㎖에 녹인 후 0℃로 냉각하였다. 트리에틸아민4.18 ㎖(30 mmol)를 넣고 상온으로 온도를 올려서 2 시간 동안 교반하였다. 용매를 감압증류로 제거하여 에틸아세테이트로 용출한 후 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 감압증류하여 얻어진 화합물을 N,N-디메틸포름아미드50 ㎖에 녹인 후 1.0 N 수산화나트륨 수용액 20 ㎖를 넣고 2 시간 동안 교반하였다. 감압증류하여 용매를 제거한 다음 1.0 N 염산 수용액으로 산성화하여 에틸아세테이트로 용출한 후 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다 음 에틸아세테이트와 헥산의 1:3 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 2.5 g을 92% 수율로 얻을 수 있었다.1.65 g (10 mmol) of ethyl 3-aminobenzoate and 2.81 mL (25 mmol) of propanesulfonyl chloride were dissolved in 50 mL of dichloromethane and cooled to 0 ° C. 4.18 mL (30 mmol) of triethylamine was added thereto, and the reaction mixture was heated to room temperature and stirred for 2 hours. The solvent was removed by distillation under reduced pressure, eluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution and brine. The compound obtained by distillation under reduced pressure was dissolved in 50 ml of N, N-dimethylformamide, and 20 ml of 1.0 N aqueous sodium hydroxide solution was added thereto, followed by stirring for 2 hours. After distillation under reduced pressure to remove the solvent, acidified with 1.0 N aqueous hydrochloric acid solution, eluted with ethyl acetate and washed with brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a 1: 3 mixture of ethyl acetate and hexane to obtain 2.5 g of the title compound in 92% yield.

1H NMR (500 MHz, CDCl3); 7.84 (1H, d), 7.80 (1H, s), 7.51 (1H, d), 7.43 (1H, t), 6.59 (1H, s), 4.39 (2H, q), 3.09 (2H, t), 1.87 (2H, m), 1.40 (3H, t), 1.03 (3H, t)
1 H NMR (500 MHz, CDCl 3 ); 7.84 (1H, d), 7.80 (1H, s), 7.51 (1H, d), 7.43 (1H, t), 6.59 (1H, s), 4.39 (2H, q), 3.09 (2H, t), 1.87 (2H, m), 1.40 (3H, t), 1.03 (3H, t)

[제조예 15][Production Example 15]

3-[(프로필술포닐)아미노]벤조산의 제조 : 3-[(propylsulfonyl)amino]benzoic acidPreparation of 3-[(propylsulfonyl) amino] benzoic acid: 3-[(propylsulfonyl) amino] benzoic acid

상기 제조예 14에서 얻어진 화합물 0.41 g(1.52 mmol)을 테트라히드로퓨란 10 ㎖, 메탄올 2 ㎖, 1.0 N 수산화리튬 수용액 6 ㎖에 녹여서 5 시간 동안 교반하였다. 용매를 감압증류하여 제거한 후 물로 희석하여 1.0 N 염산 수용액으로 산성화하여 생성된 고체를 여과하여 표제 화합물 0.33 g을 89% 수율로 얻을 수 있었다.0.41 g (1.52 mmol) of the compound obtained in Preparation Example 14 was dissolved in 10 ml of tetrahydrofuran, 2 ml of methanol, and 6 ml of an aqueous 1.0 N lithium hydroxide solution, followed by stirring for 5 hours. The solvent was distilled off under reduced pressure, diluted with water, acidified with 1.0 N aqueous hydrochloric acid, and the resulting solid was filtered to obtain 0.33 g of the title compound in 89% yield.

1H NMR (500 MHz, CD3OD); 7.89 (1H, s), 7.76 (1H, d), 7.47 (1H, d), 7.42 (1H, t), 3.07 (2H, t), 1.80 (2H, m), 1.00 (3H, t)
1 H NMR (500 MHz, CD3 OD); 7.89 (1H, s), 7.76 (1H, d), 7.47 (1H, d), 7.42 (1H, t), 3.07 (2H, t), 1.80 (2H, m), 1.00 (3H, t)

[제조예 16][Production Example 16]

N-{(1S)-3-메틸-1-[(2R,4R)-4-메틸-5-옥소테트라히드로-2-퓨라닐]부틸}-3-[(프로필술포닐)아미노]벤즈아미드의 제조 : N-{(1S)-3-methyl-1-[(2R,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butyl}-3-[(propylsulfonyl)amino]benzamide N -{( 1S ) -3-methyl-1-[(2 R , 4R ) -4-methyl-5-oxotetrahydro-2-furanyl] butyl} -3-[(propylsulfonyl) amino ] Preparation of benzamide: N -{(1 S ) -3-methyl-1-[(2 R , 4 R ) -4-methyl-5-oxotetrahydro-2-furanyl] butyl} -3-[(propylsulfonyl) amino] benzamide

상기 제조예 4에서 얻은 화합물 대신에 상기 제조예 15에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 5와 동일한 방법으로 실시하여, 표제 화합물 0.38 g을 93% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 15 instead of the compound obtained in Preparation Example 4, it was carried out in the same manner as in Preparation Example 5, it was possible to obtain 0.38 g of the title compound in 93% yield.

1H NMR (500 MHz, CDCl3); 7.80 (1H, s), 7.72 (1H, s), 7.59 (1H, m), 7.41 (2H, d), 6.22 (1H, d), 4.66 (1H, m), 4.57 (1H, m), 3.09 (2H, t), 2.62 (1H, m), 2.42 (1H, m), 2.04 (1H, m), 1.92-1.82 (2H, m), 1.78-1.63 (2H, m), 1.50 (1H, m), 1.25 (3H, d), 1.01 (3H, t), 0.95 (6H, d)
1 H NMR (500 MHz, CDCl 3 ); 7.80 (1H, s), 7.72 (1H, s), 7.59 (1H, m), 7.41 (2H, d), 6.22 (1H, d), 4.66 (1H, m), 4.57 (1H, m), 3.09 (2H, t), 2.62 (1H, m), 2.42 (1H, m), 2.04 (1H, m), 1.92-1.82 (2H, m), 1.78-1.63 (2H, m), 1.50 (1H, m ), 1.25 (3H, d), 1.01 (3H, t), 0.95 (6H, d)

[제조예 17][Production Example 17]

(2R,4S,5S)-4-{[tert-부틸(디메틸)실릴]옥시}-2,7-디메틸-5-({3-[(프로필술포닐)아미노]벤조일}아미노)옥탄산의 제조: (2R,4S,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,7-dimethyl-5-({3-[(propylsulfonyl)amino]benzoyl}amino)octanoic acid (2 R, 4 S, 5 S) -4 - {[tert - butyl (dimethyl) silyl] oxy} 2,7-dimethyl-5 - ({3 - [(propyl-sulfonyl) amino] benzoyl} amino) Preparation of octanoic acid: (2 R, 4 S, 5 S) -4 - {[tert -butyl (dimethyl) silyl] oxy} -2,7-dimethyl-5 - ({3 - [(propylsulfonyl) amino] benzoyl } amino) octanoic acid

상기 제조예 5에서 얻은 화합물 대신에 상기 제조예 16에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 6과 동일한 방법으로 실시하여, 표제 화합물 0.45 g을 91% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 16 instead of the compound obtained in Preparation Example 5, it was carried out in the same manner as in Preparation Example 6, 0.45 g of the title compound could be obtained in 91% yield.

1H NMR (500 MHz, CDCl3); 8.56 (1H, s), 7.87 (1H, s), 7.64 (1H, d), 7.37 (1H, t), 7.29 (1H, d), 6.20 (1H, d), 4.36 (1H, m), 3.86 (1H, t), 3.06-2.94 (2H, m), 2.75 (1H, m), 1.90 (1H, m), 1.80-1.66 (3H, m), 1.56-1.46 (2H, m), 1.39 (1H, m), 1.21 (3H, d), 1.00 (3H, d), 0.99 (3H, d), 0.91 (9H, s), 0.82 (3H, t), 0.15 (3H, s), 0.09 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 8.56 (1H, s), 7.87 (1H, s), 7.64 (1H, d), 7.37 (1H, t), 7.29 (1H, d), 6.20 (1H, d), 4.36 (1H, m), 3.86 (1H, t), 3.06-2.94 (2H, m), 2.75 (1H, m), 1.90 (1H, m), 1.80-1.66 (3H, m), 1.56-1.46 (2H, m), 1.39 (1H , m), 1.21 (3H, d), 1.00 (3H, d), 0.99 (3H, d), 0.91 (9H, s), 0.82 (3H, t), 0.15 (3H, s), 0.09 (3H, s)

[제조예 18][Production Example 18]

벤질 4-{(4S,7R,9S)-4,7,11,11,12,12-헥사메틸-9-[(1S)-3-메틸-1-({3-[(프로필술포닐)아미노]벤조일}아미노)부틸]-3,6-디옥소-10-옥사-2,5-디아자-11-실라트리덱-1-일}벤조에이트의 제조: benzyl 4-{(4S,7R,9S)-4,7,11,11,12,12-hexamethyl-9-[(1S)-3-methyl-1-({3-[(propylsulfonyl)amino]benzoyl}amino)butyl]-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl}benzoateBenzyl 4-{(4 S , 7 R , 9 S ) -4,7,11,11,12,12-hexamethyl-9-[(1 S ) -3-methyl-1-({3-[( Propylsulfonyl) amino] benzoyl} amino) butyl] -3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate: benzyl 4- { (4 S , 7 R , 9 S ) -4,7,11,11,12,12-hexamethyl-9-[(1 S ) -3-methyl-1-({3-[(propylsulfonyl) amino] benzoyl } amino) butyl] -3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate

상기 제조예 6에서 얻은 화합물 대신에 상기 제조예 17에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 9와 동일한 방법으로 실시하여, 표제 화합물 91 ㎎을 83% 수율로 얻을 수 있었다.91 mg of the title compound was obtained in 83% yield by the same method as Preparation Example 9, except that the compound obtained in Preparation Example 17 was used instead of the compound obtained in Preparation Example 6.

1H NMR (500 MHz, CDCl3); 7.81 (2H, d), 7.43-7.28 (7H, m), 7.23 (1H, d), 7.16-7.10 (3H, m), 6.58 (2H, br), 5.31 (2H, s), 4.68 (1H, m), 4.42 (1H, dd), 4.25 (1H, m), 4.00 (1H, m), 3.67 (1H, m), 2.96-2.84 (2H, m), 2.47 (1H, m), 1.98 (1H, m), 1.80-1.64 (3H, m), 1.52-1.40 (2H, m), 1.47 (1H, m), 1.36 (3H, d), 1.27 (1H, m), 1.11 (3H, d), 0.96 (3H, d), 0.90 (9H, s), 0.90 (3H, d), 0.85 (3H, d), 0.11 (3H, s), 0.09 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 7.81 (2H, d), 7.43-7.28 (7H, m), 7.23 (1H, d), 7.16-7.10 (3H, m), 6.58 (2H, br), 5.31 (2H, s), 4.68 (1H, m), 4.42 (1H, dd), 4.25 (1H, m), 4.00 (1H, m), 3.67 (1H, m), 2.96-2.84 (2H, m), 2.47 (1H, m), 1.98 (1H) , m), 1.80-1.64 (3H, m), 1.52-1.40 (2H, m), 1.47 (1H, m), 1.36 (3H, d), 1.27 (1H, m), 1.11 (3H, d), 0.96 (3H, d), 0.90 (9H, s), 0.90 (3H, d), 0.85 (3H, d), 0.11 (3H, s), 0.09 (3H, s)

[실시예 3]Example 3

4-{[((2S)-2-{[(2R,4S,5S)-4-히드록시-2,7-디메틸-5-({3-[(프로필술포닐)아미노]벤조일}아미노)옥타노일]아미노}프로파노일)아미노]메틸}벤조산의 제조 : 4-{[((2S)-2-{[(2R,4S,5S)-4-hydroxy-2,7-dimethyl-5-({3-[(propylsulfonyl)amino]benzoyl}amino)octanoyl]amino}propanoyl)amino]methyl}benzoic acid4-{[((2 S ) -2-{[(2 R , 4 S , 5 S ) -4-hydroxy-2,7-dimethyl-5-({3-[(propylsulfonyl) amino] benzoyl} amino) octanoyl] amino} propanoyl) amino] methyl} benzoic acid: 4 - {[((2 S) -2 - {[(2 R, 4 S, 5 S) -4-hydroxy- 2,7-dimethyl-5-({3-[(propylsulfonyl) amino] benzoyl} amino) octanoyl] amino} propanoyl) amino] methyl} benzoic acid

상기 제조예 9에서 얻은 화합물 대신에 상기 제조예 18에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 실시하여, 표제 화합물 46 ㎎을 71% 수율로 얻을 수 있었다.46 mg of the title compound was obtained in 71% yield by the same method as Example 1 except for using the compound obtained in Preparation Example 18 instead of the compound obtained in Preparation Example 9.

1H NMR (500 MHz, CD3OD); 7.94 (2H, d), 7.64 (1H, s), 7.54 (1H, s), 7.41 (2H, d), 7.33 (2H, d), 4.43 (2H, d), 4.34 (1H, m), 4.15 (1H, m), 3.59 (1H, m), 3.09 (2H, t), 2.71 (1H, m), 1.88-1.76 (3H, m), 1.70-1.62 (2H, m), 1.48-1.38 (2H, m), 1.34 (3H, d), 1.14 (3H, d), 1.00 (3H, t), 0.96 (3H, d), 0.95 (3H, d)1 H NMR (500 MHz, CD3 OD); 7.94 (2H, d), 7.64 (1H, s), 7.54 (1H, s), 7.41 (2H, d), 7.33 (2H, d), 4.43 (2H, d), 4.34 (1H, m), 4.15 (1H, m), 3.59 (1H, m), 3.09 (2H, t), 2.71 (1H, m), 1.88-1.76 (3H, m), 1.70-1.62 (2H, m), 1.48-1.38 (2H , m), 1.34 (3H, d), 1.14 (3H, d), 1.00 (3H, t), 0.96 (3H, d), 0.95 (3H, d)

ESI MS (m/e) = 633 [M+H]+
ESI MS (m / e) = 633 [M + H] < + >

[제조예 19][Production Example 19]

에틸 3-[(페닐술포닐)아미노]벤조에이트의 제조: ethyl 3-[(phenylsulfonyl)amino]benzoatePreparation of ethyl 3-[(phenylsulfonyl) amino] benzoate: ethyl 3-[(phenylsulfonyl) amino] benzoate

에틸 3-아미노벤조에이트 0.83 g(5 mmol)과 벤젠술포닐클로라이드 1.32 g(7.5 mmol)를 N,N-디메틸포름아미드 25 ㎖에 녹인 후 0℃로 냉각하였다. N-메틸몰폴린 1.65 ㎖(15 mmol)를 넣고 상온으로 온도를 올려서 2 시간 동안 교반하였다. 용매를 감압증류로 제거하여 에틸아세테이트로 용출한 후 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음 에틸아세테이트와 헥산의 1:3 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 1.0 g을 65% 수율로 얻을 수 있었다.0.83 g (5 mmol) of ethyl 3-aminobenzoate and 1.32 g (7.5 mmol) of benzenesulfonyl chloride were dissolved in 25 mL of N, N-dimethylformamide and cooled to 0 ° C. 1.65 mL (15 mmol) of N-methylmorpholine was added thereto, and the mixture was stirred at room temperature for 2 hours. The solvent was removed by distillation under reduced pressure, eluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a 1: 3 mixture of ethyl acetate and hexane to obtain 1.0 g of the title compound in 65% yield.

1H NMR (500 MHz, CDCl3); 7.80-7.76 (3H, m), 7.64 (1H, s), 7.53 (1H, d), 7.44 (2H, t), 7.38 (1H, d), 7.33 (1H, t), 6.76 (1H, s), 4.34 (2H, q), 1.36 (3H, t)
1 H NMR (500 MHz, CDCl 3 ); 7.80-7.76 (3H, m), 7.64 (1H, s), 7.53 (1H, d), 7.44 (2H, t), 7.38 (1H, d), 7.33 (1H, t), 6.76 (1H, s) , 4.34 (2H, q), 1.36 (3H, t)

[제조예 20][Production Example 20]

3-[(페닐술포닐)아미노]벤조산의 제조: 3-[(phenylsulfonyl)amino]benzoic acidPreparation of 3-[(phenylsulfonyl) amino] benzoic acid: 3-[(phenylsulfonyl) amino] benzoic acid

상기 제조예 14에서 얻은 화합물 대신에 상기 제조예 19에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 15와 동일한 방법으로 실시하여, 표제 화합물 0.78 g을 86% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 19 instead of the compound obtained in Preparation Example 14, 0.78 g of the title compound could be obtained in 86% yield in the same manner as in Preparation Example 15.

1H NMR (500 MHz, CD3OD); 7.79-7.73 (3H, m), 7.69 (1H, m), 7.56 (1H, t), 7.48 (2H, t), 7.34-7.30 (2H, m)
1 H NMR (500 MHz, CD3 OD); 7.79-7.73 (3H, m), 7.69 (1H, m), 7.56 (1H, t), 7.48 (2H, t), 7.34-7.30 (2H, m)

[제조예 21] [Production Example 21]                     

N-{(1S)-3-메틸-1-[(2R,4R)-4-메틸-5-옥소테트라히드로-2-퓨라닐]부틸}-3-[(페닐술포닐)아미노]벤즈아미드의 제조: N-{(1S)-3-methyl-1-[(2R,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butyl}-3-[(phenylsulfonyl)amino]benzamide N -{( 1S ) -3-methyl-1-[(2 R , 4R ) -4-methyl-5-oxotetrahydro-2-furanyl] butyl} -3-[(phenylsulfonyl) amino ] Preparation of Benzamide: N -{(1 S ) -3-methyl-1-[(2 R , 4 R ) -4-methyl-5-oxotetrahydro-2-furanyl] butyl} -3-[(phenylsulfonyl) amino] benzamide

상기 제조예 4에서 얻은 화합물 대신에 상기 제조예 20에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 5와 동일한 방법으로 실시하여, 표제 화합물 0.42 g을 94% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 20 instead of the compound obtained in Preparation Example 4, 0.42 g of the title compound could be obtained in 94% yield in the same manner as in Preparation Example 5.

1H NMR (500 MHz, CDCl3); 7.81 (2H, d), 7.69 (1H, s), 7.58-7.42 (5H, m), 7.38 (1H, d), 6.06 (1H, d), 4.62 (1H, m), 4.55 (1H, m), 2.57 (1H, m), 2.40 (1H, m), 2.01 (1H, m), 1.69 (1H, m), 1.62 (1H, m), 1.47 (1H, m), 1.24 (3H, d), 0.94 (3H, d), 0.93 (3H, d)
1 H NMR (500 MHz, CDCl 3 ); 7.81 (2H, d), 7.69 (1H, s), 7.58-7.42 (5H, m), 7.38 (1H, d), 6.06 (1H, d), 4.62 (1H, m), 4.55 (1H, m) , 2.57 (1H, m), 2.40 (1H, m), 2.01 (1H, m), 1.69 (1H, m), 1.62 (1H, m), 1.47 (1H, m), 1.24 (3H, d), 0.94 (3H, d), 0.93 (3H, d)

[제조예 22][Production Example 22]

(2R,4S,5S)-4-{[tert-부틸(디메틸)실릴]옥시}-2,7-디메틸-5-({3-[(페닐술포닐)아미노]벤조일}아미노)옥탄산의 제조: (2R,4S,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,7-dimethyl-5-({3-[(phenylsulfonyl)amino]benzoyl}amino)octanoic acid (2 R, 4 S, 5 S) -4 - {[tert - butyl (dimethyl) silyl] oxy} 2,7-dimethyl-5 - ({3 - [(phenylsulfonyl) amino] benzoyl} amino) Preparation of octanoic acid: (2 R, 4 S, 5 S) -4 - {[tert -butyl (dimethyl) silyl] oxy} -2,7-dimethyl-5 - ({3 - [(phenylsulfonyl) amino] benzoyl } amino) octanoic acid

상기 제조예 5에서 얻은 화합물 대신에 상기 제조예 21에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 6과 동일한 방법으로 실시하여, 표제 화합물 0.47 g을 88% 수율로 얻을 수 있었다. Except for using the compound obtained in Preparation Example 21 instead of the compound obtained in Preparation Example 5, in the same manner as in Preparation Example 6, 0.47 g of the title compound could be obtained in 88% yield.                     

1H NMR (500 MHz, CDCl3); 8.55 (1H, br), 7.70 (2H, d), 7.65 (1H, s), 7.48 (1H, d), 7.39 (1H, t), 7.31-7.22 (4H, m), 6.18 (1H, d), 4.33 (1H, dd), 3.85 (1H, t), 2.71 (1H, m), 1.84 (1H, m), 1.68 (1H, m), 1.54-1.44 (2H, m), 1.39 (1H, m), 1.20 (3H, d), 0.99 (6H, d), 0.90 (9H, s), 0.14 (3H, s), 0.09 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 8.55 (1H, br), 7.70 (2H, d), 7.65 (1H, s), 7.48 (1H, d), 7.39 (1H, t), 7.31-7.22 (4H, m), 6.18 (1H, d) , 4.33 (1H, dd), 3.85 (1H, t), 2.71 (1H, m), 1.84 (1H, m), 1.68 (1H, m), 1.54-1.44 (2H, m), 1.39 (1H, m ), 1.20 (3H, d), 0.99 (6H, d), 0.90 (9H, s), 0.14 (3H, s), 0.09 (3H, s)

[제조예 23][Manufacture example 23]

벤질 4-{(4S,7R,9S)-4,7,11,11,12,12-헥사메틸-9-[(1S)-3-메틸-1-({3-[(페닐술포닐)아미노]벤조일}아미노)부틸]-3,6-디옥소-10-옥사-2,5-디아자-11-실라트리덱-1-일}벤조에이트의 제조: benzyl 4-{(4S,7R,9S)-4,7,11,11,12,12-hexamethyl-9-[(1S)-3-methyl-1-({3-[(phenylsulfonyl)amino]benzoyl}amino)butyl]-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl}benzoateBenzyl 4-{(4 S , 7 R , 9 S ) -4,7,11,11,12,12-hexamethyl-9-[(1 S ) -3-methyl-1-({3-[( Phenylsulfonyl) amino] benzoyl} amino) butyl] -3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate: benzyl 4- { (4 S , 7 R , 9 S ) -4,7,11,11,12,12-hexamethyl-9-[(1 S ) -3-methyl-1-({3-[(phenylsulfonyl) amino] benzoyl } amino) butyl] -3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate

상기 제조예 6에서 얻은 화합물 대신에 상기 제조예 22에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 9와 동일한 방법으로 실시하여, 표제 화합물 97 ㎎을 86% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 22 instead of the compound obtained in Preparation Example 6, it was carried out in the same manner as in Preparation Example 9, it was obtained 97 mg of the title compound in 86% yield.

1H NMR (500 MHz, CDCl3); 7.73 (2H, d), 7.70 (2H, br), 7.44-7.25 (12H, m), 7.20 (1H, t), 7.10 (1H, br), 7.04 (2H, br), 6.53 (2H, br), 5.31 (2H, s), 4.66 (1H, br), 4.33 (1H, m), 4.23 (1H, br), 4.05 (1H, br), 3.71 (1H, m), 2.49 (1H, m), 1.64 (1H, m), 1.52-1.42 (2H, m), 1.38-1.28 (2H, m), 1.12 (3H, d), 0.93 (6H, d), 0.90 (9H, s), 0.83 (3H, d), 0.12 (3H, s), 0.09 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 7.73 (2H, d), 7.70 (2H, br), 7.44-7.25 (12H, m), 7.20 (1H, t), 7.10 (1H, br), 7.04 (2H, br), 6.53 (2H, br) , 5.31 (2H, s), 4.66 (1H, br), 4.33 (1H, m), 4.23 (1H, br), 4.05 (1H, br), 3.71 (1H, m), 2.49 (1H, m), 1.64 (1H, m), 1.52-1.42 (2H, m), 1.38-1.28 (2H, m), 1.12 (3H, d), 0.93 (6H, d), 0.90 (9H, s), 0.83 (3H, d), 0.12 (3H, s), 0.09 (3H, s)

[실시예 4]Example 4

4-{[((2S)-2-{[(2R,4S,5S)-4-히드록시-2,7-디메틸-5-({3-[(페닐술포닐)아미노]벤조일}아미노)옥타노일]아미노}프로파노일)아미노]메틸}벤조산의 제조: 4-{[((2S)-2-{[(2R,4S,5S)-4-hydroxy-2,7-dimethyl-5-({3-[(phenylsulfonyl)amino]benzoyl}amino)octanoyl]amino}propanoyl)amino]methyl}benzoic acid4-{[((2 S ) -2-{[(2 R , 4 S , 5 S ) -4-hydroxy-2,7-dimethyl-5-({3-[(phenylsulfonyl) amino] benzoyl} amino) octanoyl] amino} propanoyl) amino] methyl} benzoic acid: 4 - {[((2 S) -2 - {[(2 R, 4 S, 5 S) -4-hydroxy- 2,7-dimethyl-5-({3-[(phenylsulfonyl) amino] benzoyl} amino) octanoyl] amino} propanoyl) amino] methyl} benzoic acid

상기 제조예 9에서 얻은 화합물 대신에 상기 제조예 23에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 실시하여, 표제 화합물 23 ㎎을 32% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 23 instead of the compound obtained in Preparation Example 9 it was carried out in the same manner as in Example 1, it was possible to obtain 23 mg of the title compound in 32% yield.

1H NMR (500 MHz, CD3OD); 7.95 (2H, d), 7.78 (2H, d), 7.57-7.44 (5H, m), 7.37-7.26 (4H, m), 4.43 (2H, d), 4.33 (1H, m), 4.12 (1H, m), 3.57 (1H, m), 2.68 (1H, m), 1.79 (1H, m), 1.70-1.58 (2H, m), 1.47-1.38 (2H, m), 1.31 (3H, d), 1.13 (3H, d), 0.94 (3H, d). 0.93 (3H, d)1 H NMR (500 MHz, CD3 OD); 7.95 (2H, d), 7.78 (2H, d), 7.57-7.44 (5H, m), 7.37-7.26 (4H, m), 4.43 (2H, d), 4.33 (1H, m), 4.12 (1H, m), 3.57 (1H, m), 2.68 (1H, m), 1.79 (1H, m), 1.70-1.58 (2H, m), 1.47-1.38 (2H, m), 1.31 (3H, d), 1.13 (3H, d), 0.94 (3H, d). 0.93 (3H, d)

ESI MS (m/e) = 667 [M+H]+
ESI MS (m / e) = 667 [M + H] < + >

[제조예 24][Manufacture example 24]

에틸 3-[(2-치에닐술포닐)아미노]벤조에이트의 제조: ethyl 3-[(2-thienylsulfonyl)amino]benzoatePreparation of ethyl 3-[(2-thienylsulfonyl) amino] benzoate: ethyl 3-[(2-thienylsulfonyl) amino] benzoate

벤젠술포닐클로라이드 대신에 2-치오펜술포닐클로라이드를 사용한 것을 제외 하고는, 제조예 19와 동일한 방법으로 실시하여, 표제 화합물 1.17 g을 75% 수율로 얻을 수 있었다.Except for using 2-thiophenesulfonylchloride instead of benzenesulfonylchloride, the same procedure as in Production Example 19 was carried out to obtain 1.17 g of the title compound in 75% yield.

1H NMR (500 MHz, CDCl3); 7.84 (1H, d), 7.70 (1H, s), 7.54 (1H, d), 7.51 (1H, d), 7.45 (1H, d), 7.38 (1H, t), 7.00 (1H, dd), 6.78 (1H, s), 4.36 (2H, q), 1.37 (3H, t)
1 H NMR (500 MHz, CDCl 3 ); 7.84 (1H, d), 7.70 (1H, s), 7.54 (1H, d), 7.51 (1H, d), 7.45 (1H, d), 7.38 (1H, t), 7.00 (1H, dd), 6.78 (1H, s), 4.36 (2H, q), 1.37 (3H, t)

[제조예 25]Production Example 25

3-[(2-치에닐술포닐)아미노]벤조산의 제조: 3-[(2-thienylsulfonyl)amino]benzoic acidPreparation of 3-[(2-thienylsulfonyl) amino] benzoic acid: 3-[(2-thienylsulfonyl) amino] benzoic acid

상기 제조예 14에서 얻은 화합물 대신에 상기 제조예 24에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 15와 동일한 방법으로 실시하여, 표제 화합물 0.96 g을 91% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 24 instead of the compound obtained in Preparation Example 14, 0.96 g of the title compound could be obtained in 91% yield in the same manner as in Preparation Example 15.

1H NMR (500 MHz, CD3OD); 7.79 (1H, s), 7.74 (1H, d), 7.71 (1H, d), 7.51 (1H, d), 7.39-7.33 (2H, m), 7.05 (1H, dd)
1 H NMR (500 MHz, CD3 OD); 7.79 (1H, s), 7.74 (1H, d), 7.71 (1H, d), 7.51 (1H, d), 7.39-7.33 (2H, m), 7.05 (1H, dd)

[제조예 26]Production Example 26

N-{(1S)-3-메틸-1-[(2R,4R)-4-메틸-5-옥소테트라히드로-2-퓨라닐]부틸}-3-[(2-치에닐술포닐)아미노]벤즈아미드의 제조: N-{(1S)-3-methyl-1-[(2R,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butyl}-3-[(2-thienylsulfonyl)amino]benzamide N -{( 1S ) -3-methyl-1-[(2 R , 4R ) -4-methyl-5-oxotetrahydro-2-furanyl] butyl} -3-[(2-chienylsul sulfonyl) amino] benzamide Preparation of: N - {(1 S) -3-methyl-1 - [(2 R, 4 R) -4-methyl-5-oxotetrahydro-2-furanyl] butyl} -3- [ (2-thienylsulfonyl) amino] benzamide

상기 제조예 4에서 얻은 화합물 대신에 상기 제조예 25에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 5와 동일한 방법으로 실시하여, 표제 화합물 0.45 g을 99% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 25 instead of the compound obtained in Preparation Example 4, 0.45 g of the title compound could be obtained in 99% yield in the same manner as in Preparation Example 5.

1H NMR (500 MHz, CDCl3); 8.22 (1H, s), 7.70 (1H, s), 7.57 (1H, d), 7.54 (1H, d), 7.52 (1H, d), 7.41 (1H, d), 7.36 (1H, t), 7.00 (1H, dd), 6.17 (1H, d), 4.64 (1H, m), 4.59 (1H, m), 2.58 (1H, m), 2.41 (1H, m), 2.04 (1H, m), 1.75-1.62 (2H, m), 1.49 (1H, m), 1.25 (3H, d), 0.95 (3H, d), 0.93 (3H, d)
1 H NMR (500 MHz, CDCl 3 ); 8.22 (1H, s), 7.70 (1H, s), 7.57 (1H, d), 7.54 (1H, d), 7.52 (1H, d), 7.41 (1H, d), 7.36 (1H, t), 7.00 (1H, dd), 6.17 (1H, d), 4.64 (1H, m), 4.59 (1H, m), 2.58 (1H, m), 2.41 (1H, m), 2.04 (1H, m), 1.75- 1.62 (2H, m), 1.49 (1H, m), 1.25 (3H, d), 0.95 (3H, d), 0.93 (3H, d)

[제조예 27][Production Example 27]

(2R,4S,5S)-4-{[tert-부틸(디메틸)실릴]옥시}-2,7-디메틸-5-({3-[(2-치에닐술포닐)아미노]벤조일}아미노)옥탄산의 제조: (2R,4S,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,7-dimethyl-5-({3-[(2-thienylsulfonyl)amino]benzoyl}amino)octanoic acid (2 R, 4 S, 5 S) -4 - {[tert - butyl (dimethyl) silyl] oxy} 2,7-dimethyl-5 - ({3 - [(2-Chi nilsul sulfonyl) amino] benzoyl } amino) octanoic acid Preparation of: (2 R, 4 S, 5 S) -4 - {[tert -butyl (dimethyl) silyl] oxy} -2,7-dimethyl-5 - ({3 - [(2- thienylsulfonyl) amino] benzoyl} amino) octanoic acid

상기 제조예 5에서 얻은 화합물 대신에 상기 제조예 26에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 6과 동일한 방법으로 실시하여, 표제 화합물 0.49 g을 87% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 26 instead of the compound obtained in Preparation Example 5, 0.49 g of the title compound could be obtained in 87% yield in the same manner as in Preparation Example 6.

1H NMR (500 MHz, CDCl3); 8.85 (1H, br), 7.69 (1H, s), 7.58 (1H, d), 7.42-7.28 (4H, m), 6.84 (1H, t), 6.19 (1H, d), 4.34 (1H, dd), 3.86 (1H, t), 2.72 (1H, m), 1.84 (1H, m), 1.70 (1H, m), 1.49 (2H, t), 1.38 (1H, m), 1.20 (3H, d), 0.98 (3H, d), 0.97 (3H, d), 0.90 (9H, s), 0.14 (3H, s), 0.09 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 8.85 (1H, br), 7.69 (1H, s), 7.58 (1H, d), 7.42-7.28 (4H, m), 6.84 (1H, t), 6.19 (1H, d), 4.34 (1H, dd) , 3.86 (1H, t), 2.72 (1H, m), 1.84 (1H, m), 1.70 (1H, m), 1.49 (2H, t), 1.38 (1H, m), 1.20 (3H, d), 0.98 (3H, d), 0.97 (3H, d), 0.90 (9H, s), 0.14 (3H, s), 0.09 (3H, s)

[제조예 28]Production Example 28

벤질 4-{(4S,7R,9S)-4,7,11,11,12,12-헥사메틸-9-[(1S)-3-메틸-1-({3-[(2-치에닐술포닐)아미노]벤조일}아미노)부틸]-3,6-디옥소-10-옥사-2,5-디아자-11-실라트리덱-1-일}벤조에이트의 제조: benzyl 4-{(4S,7R,9S)-4,7,11,11,12,12-hexamethyl-9-[(1S)-3-methyl-1-({3-[(2-thienylsulfonyl)amino]benzoyl}amino)butyl]-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl}benzoateBenzyl 4-{(4 S , 7 R , 9 S ) -4,7,11,11,12,12-hexamethyl-9-[(1 S ) -3-methyl-1-({3-[( 2-Chenylsulfonyl) amino] benzoyl} amino) butyl] -3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate Preparation: benzyl 4-{(4 S , 7 R , 9 S ) -4,7,11,11,12,12-hexamethyl-9-[(1 S ) -3-methyl-1-({3-[(2- thienylsulfonyl) amino] benzoyl} amino) butyl] -3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate

상기 제조예 6에서 얻은 화합물 대신에 상기 제조예 27에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 9와 동일한 방법으로 실시하여, 표제 화합물 79 ㎎을 75% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 27 instead of the compound obtained in Preparation Example 6, it was carried out in the same manner as in Preparation Example 9, 79 mg of the title compound could be obtained in 75% yield.

1H NMR (500 MHz, CDCl3); 7.71 (2H, br), 7.46-7.33 (11H, m), 7.22 (1H, t), 7.16-7.03 (3H, m), 6.88 (1H, t), 6.54 (1H, br), 6.39 (1H, br), 5.32 (2H, s), 4.61 (1H, br), 4.40 (1H, dd), 4.21 (1H, br), 4.03 (1H, br), 3.69 (1H, m), 2.50 (1H, m), 1.64 (1H, m), 1.50-1.42 (2H, m), 1.38-1.26 (2H, m), 1.16 (3H, d), 0.94 (6H, d), 0.90 (9H, s), 0.84 (3H, d), 0.11 (3H, s), 0.09 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 7.71 (2H, br), 7.46-7.33 (11H, m), 7.22 (1H, t), 7.16-7.03 (3H, m), 6.88 (1H, t), 6.54 (1H, br), 6.39 (1H, br), 5.32 (2H, s), 4.61 (1H, br), 4.40 (1H, dd), 4.21 (1H, br), 4.03 (1H, br), 3.69 (1H, m), 2.50 (1H, m ), 1.64 (1H, m), 1.50-1.42 (2H, m), 1.38-1.26 (2H, m), 1.16 (3H, d), 0.94 (6H, d), 0.90 (9H, s), 0.84 ( 3H, d), 0.11 (3H, s), 0.09 (3H, s)

[실시예 5]Example 5

4-{[((2S)-2-{[(2R,4S,5S)-4-히드록시-2,7-디메틸-5-({3-[(2-치에닐술포닐)아미노] 벤조일}아미노)옥타노일]아미노}프로파노일)아미노]메틸}벤조산의 제조: 4-{[((2S)-2-{[(2R,4S,5S)-4-hydroxy-2,7-dimethyl-5-({3-[(2-thienylsulfonyl)amino]benzoyl}amino)octanoyl]amino}propanoyl)amino]methyl}benzoic acid4-{[((2 S ) -2-{[(2 R , 4 S , 5 S ) -4-hydroxy-2,7-dimethyl-5-({3-[(2-chienylsulfonyl ) Amino] benzoyl} amino) octanoyl] amino} propanoyl) amino] methyl} benzoic acid: 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -4 -hydroxy-2,7-dimethyl-5-({3-[(2-thienylsulfonyl) amino] benzoyl} amino) octanoyl] amino} propanoyl) amino] methyl} benzoic acid

상기 제조예 28에서 얻은 화합물79 ㎎(0.09 mmol)을 테트라히드로퓨란 3 ㎖, 메탄올 0.5 ㎖, 1.0 N 수산화리튬 수용액 2 ㎖에 녹여서 5 시간 동안 교반하였다. 용매를 감압증류하여 제거한 후 물로 희석하여 1.0 N 염산 수용액으로 산성화하여 에틸아세테이트로 용출하였다. 소금물로 씻어 주고 감압증류로 용매를 제거하여 얻은 화합물을 테트라히드로퓨란 3 ㎖에 녹였다. 1.0 M 테트라부틸암모늄플루오라이드 0.27 ㎖(0.27 mmol, 테트라히드로퓨란용액)를 가하여 하룻밤 동안 교반하였다. 용매를 감압증류로 제거하여 메탄올과 디클로로메탄의 15:85 혼합액을 이용한 컬럼크로마토그래피로 정제한 후 디에틸에테르를 이용하여 고체화 시켜 여과하여 표제 화합물 28 ㎎을 46% 수율로 얻을 수 있었다.79 mg (0.09 mmol) of the compound obtained in Preparation Example 28 was dissolved in 3 ml of tetrahydrofuran, 0.5 ml of methanol, and 2 ml of a 1.0 N lithium hydroxide aqueous solution, followed by stirring for 5 hours. The solvent was distilled off under reduced pressure, diluted with water, acidified with 1.0 N aqueous hydrochloric acid, and eluted with ethyl acetate. The compound obtained by washing with brine and removing the solvent by distillation under reduced pressure was dissolved in 3 ml of tetrahydrofuran. 0.27 mL (0.27 mmol, tetrahydrofuran solution) of 1.0 M tetrabutylammonium fluoride was added and stirred overnight. The solvent was removed by distillation under reduced pressure, purified by column chromatography using a 15:85 mixture of methanol and dichloromethane, and then solidified using diethyl ether to obtain 28 mg of the title compound in 46% yield.

1H NMR (500 MHz, CD3OD); 7.94 (2H, d), 7.69 (1H, d), 7.55 (1H, s), 7.54-7.51 (2H, m), 7.37-7.30 (4H, m), 7.03 (1H, dd), 4.42 (2H, d), 4.33 (1H, dd), 4.13 (1H, m), 3.57 (1H, m), 2.67 (1H, m), 1.80 (1H, m), 1.70-1.58 (2H, m), 1.48-1.37 (2H, m), 1.32 (3H, d), 1.13 (3H, d), 0.95 (3H, d), 0.93 (3H, d)1 H NMR (500 MHz, CD3 OD); 7.94 (2H, d), 7.69 (1H, d), 7.55 (1H, s), 7.54-7.51 (2H, m), 7.37-7.30 (4H, m), 7.03 (1H, dd), 4.42 (2H, d), 4.33 (1H, dd), 4.13 (1H, m), 3.57 (1H, m), 2.67 (1H, m), 1.80 (1H, m), 1.70-1.58 (2H, m), 1.48-1.37 (2H, m), 1.32 (3H, d), 1.13 (3H, d), 0.95 (3H, d), 0.93 (3H, d)

ESI MS (m/e) = 673 [M+H]+
ESI MS (m / e) = 673 [M + H] < + >

[제조예 29] [Manufacture example 29]                     

3-[메틸(프로필술포닐)아미노]벤조산의 제조: 3-[methyl(propylsulfonyl)amino]benzoic acidPreparation of 3- [methyl (propylsulfonyl) amino] benzoic acid: 3- [methyl (propylsulfonyl) amino] benzoic acid

상기 제조예 14에서 얻은 화합물 1.86 g(6.85 mmol)과 탄산칼륨 1.89 g(13.7 mmol)을 N,N-디메틸포름아미드 20 ㎖에 녹인 후 아이오도메탄 2.13 ㎖(34.25 mmol)를 가하여 5 시간 동안 교반하였다. 감압증류하여 용매를 제거한 후 에틸아세테이트에 녹여서 물과 소금물로 씻어 주었다. 용매를 감압증류로 제거하여 얻어진 화합물을 테트라히드로퓨란 35 ㎖, 메탄올 7 ㎖, 1.0 N 수산화리튬 수용액 21 ㎖에 녹여서 5 시간 동안 교반하였다. 용매를 감압증류하여 제거한 후 물로 희석하여 1.0 N 염산 수용액으로 산성화하여 생성된 고체를 여과하여 표제 화합물 1.74 g을 99% 수율로 얻을 수 있었다.1.86 g (6.85 mmol) of the compound obtained in Preparation Example 14 and 1.89 g (13.7 mmol) of potassium carbonate were dissolved in 20 ml of N, N-dimethylformamide, followed by addition of 2.13 ml (34.25 mmol) of iodomethane and stirring for 5 hours. It was. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water and brine. The compound obtained by distillation of the solvent under reduced pressure was dissolved in 35 ml of tetrahydrofuran, 7 ml of methanol, and 21 ml of 1.0 N lithium hydroxide aqueous solution, followed by stirring for 5 hours. After distilling off the solvent under reduced pressure, the mixture was diluted with water and acidified with 1.0 N aqueous hydrochloric acid to filter the produced solid, thereby obtaining 1.74 g of the titled compound in 99% yield.

1H NMR (500 MHz, CD3OD); 8.05 (1H, s), 7.94 (1H, d), 7.67 (1H, d), 7.50 (1H, t), 3.35 (3H, s), 3.08 (2H, t), 1.86-1.74 (2H, m), 1.02 (3H, t)
1 H NMR (500 MHz, CD3 OD); 8.05 (1H, s), 7.94 (1H, d), 7.67 (1H, d), 7.50 (1H, t), 3.35 (3H, s), 3.08 (2H, t), 1.86-1.74 (2H, m) , 1.02 (3H, t)

[제조예 30]Production Example 30

N-{(1S)-3-메틸-1-[(2R,4R)-4-메틸-5-옥소테트라히드로-2-퓨라닐]부틸}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S)-3-methyl-1-[(2R,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S) -3-methyl -1 - [(2 R, 4 R) -4- methyl-5-oxo-tetrahydro-2-furanyl] butyl} -3- [methyl (propyl-sulfonyl) amino] benzamide Preparation of: N - {(1 S) -3-methyl-1 - [(2 R, 4 R) -4-methyl-5-oxotetrahydro-2-furanyl] butyl} -3- [methyl ( propylsulfonyl) amino] benzamide

상기 제조예 4에서 얻은 화합물 대신에 상기 제조예 29에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 5와 동일한 방법으로 실시하여, 표제 화합물 0.4 g을 94% 수율로 얻을 수 있었다. Except for using the compound obtained in Preparation Example 29 instead of the compound obtained in Preparation Example 4, it was carried out in the same manner as in Preparation Example 5, it was possible to obtain 0.4 g of the title compound in 94% yield.                     

1H NMR (500 MHz, CDCl3); 7.80 (1H, s), 7.61 (1H, d), 7.53 (1H, d), 7.45 (1H, t), 6.01 (1H, d), 4.63 (1H, m), 4.48 (1H, m), 3.37 (3H, s), 2.98 (2H, dd), 2.62 (1H, m), 2.43 (1H, m), 2.00 (1H, m), 1.90-1.82 (2H, m), 1.77-1.63 (2H, m), 1.49 (1H, m), 1.25 (3H, d), 1.03 (3H, t), 0.96 (6H, d)
1 H NMR (500 MHz, CDCl 3 ); 7.80 (1H, s), 7.61 (1H, d), 7.53 (1H, d), 7.45 (1H, t), 6.01 (1H, d), 4.63 (1H, m), 4.48 (1H, m), 3.37 (3H, s), 2.98 (2H, dd), 2.62 (1H, m), 2.43 (1H, m), 2.00 (1H, m), 1.90-1.82 (2H, m), 1.77-1.63 (2H, m ), 1.49 (1H, m), 1.25 (3H, d), 1.03 (3H, t), 0.96 (6H, d)

[제조예 31]Preparation Example 31

(2R,4S,5S)-4-{[tert-부틸(디메틸)실릴]옥시}-2,7-디메틸-5-({3-[메틸(프로필술포닐)아미노]벤조일}아미노)옥탄산의 제조: (2R,4S,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,7-dimethyl-5-({3-[methyl(propylsulfonyl)amino]benzoyl}amino)octanoic acid (2 R, 4 S, 5 S) -4 - {[tert - butyl (dimethyl) silyl] oxy} 2,7-dimethyl-5 - ({3- [methyl (propyl-sulfonyl) amino] benzoyl} amino ) Preparation of octanoic acid: (2 R, 4 S, 5 S) -4 - {[tert -butyl (dimethyl) silyl] oxy} -2,7-dimethyl-5 - ({3- [methyl (propylsulfonyl) amino ] benzoyl} amino) octanoic acid

상기 제조예 5에서 얻은 화합물 대신에 상기 제조예 30에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 6과 동일한 방법으로 실시하여, 표제 화합물 0.48 g을 95% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 30 instead of the compound obtained in Preparation Example 5, in the same manner as in Preparation Example 6, 0.48 g of the title compound could be obtained in 95% yield.

1H NMR (500 MHz, CDCl3); 7.80 (1H, s), 7.58 (2H, d), 7.44 (1H, s), 6.36(1H, d), 4.26 (1H, m), 3.82 (1H, t), 3.35 (3H, s), 2.96 (2H, dd), 2.64 (1H, m), 1.92-1.80 (3H, m), 1.64 (1H, m), 1.54-1.39 (3H, m), 1.20 (3H, d), 1.02 (3H, t), 0.97 (3H, d), 0.94 (3H, d), 0.90 (9H, s), 0.13 (3H, s), 0.11 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 7.80 (1H, s), 7.58 (2H, d), 7.44 (1H, s), 6.36 (1H, d), 4.26 (1H, m), 3.82 (1H, t), 3.35 (3H, s), 2.96 (2H, dd), 2.64 (1H, m), 1.92-1.80 (3H, m), 1.64 (1H, m), 1.54-1.39 (3H, m), 1.20 (3H, d), 1.02 (3H, t ), 0.97 (3H, d), 0.94 (3H, d), 0.90 (9H, s), 0.13 (3H, s), 0.11 (3H, s)

[제조예 32][Production Example 32]

벤질 4-{(4S,7R,9S)-4,7,11,11,12,12-헥사메틸-9-[(1S)-3-메틸-1-({3-[메틸(프로필술포닐)아미노]벤조일}아미노)부틸]-3,6-디옥소-10-옥사-2,5-디아자-11-실라트리덱-1-일}벤조에이트의 제조: benzyl 4-{(4S,7R,9S)-4,7,11,11,12,12-hexamethyl-9-[(1S)-3-methyl-1-({3-[methyl(propylsulfonyl)amino]benzoyl}amino)butyl]-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl}benzoateBenzyl 4-{(4 S , 7 R , 9 S ) -4,7,11,11,12,12-hexamethyl-9-[(1 S ) -3-methyl-1-({3- [methyl Preparation of (propylsulfonyl) amino] benzoyl} amino) butyl] -3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate: benzyl 4- {(4 S , 7 R , 9 S ) -4,7,11,11,12,12-hexamethyl-9-[(1 S ) -3-methyl-1-({3- [methyl (propylsulfonyl) amino ] benzoyl} amino) butyl] -3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate

상기 제조예 6에서 얻은 화합물 대신에 상기 제조예 31에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 9와 동일한 방법으로 실시하여, 표제 화합물 88 ㎎을 79% 수율로 얻을 수 있었다.In the same manner as in Preparation Example 9, except that the compound obtained in Preparation Example 31 was used instead of the compound obtained in Preparation Example 6, 88 mg of the title compound was obtained in a yield of 79%.

1H NMR (500 MHz, CDCl3); 8.01 (2H, d), 7.84 (1H, s), 7.58 (2H, t), 7.48-7.29 (8H, m), 6.95 (1H, t), 6.89 (1H, d), 6.27 (1H, d), 5.35 (2H, s), 4.54-4.31 (4H, m), 3.73 (1H, m), 3.34 (3H, s), 2.95 (2H, dd), 2.54 (1H, m), 1.87-1.78 (2H, m), 1.69-1.56 (3H, m), 1.49 (1H, m), 1.37 (1H, m), 1.17 (3H, d), 1.12 (3H, d), 1.01 (3H, t), 0.96 (3H, d), 0.94 (3H, d), 0.91 (9H, s), 0.11 (3H, s), 0.09 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 8.01 (2H, d), 7.84 (1H, s), 7.58 (2H, t), 7.48-7.29 (8H, m), 6.95 (1H, t), 6.89 (1H, d), 6.27 (1H, d) , 5.35 (2H, s), 4.54-4.31 (4H, m), 3.73 (1H, m), 3.34 (3H, s), 2.95 (2H, dd), 2.54 (1H, m), 1.87-1.78 (2H , m), 1.69-1.56 (3H, m), 1.49 (1H, m), 1.37 (1H, m), 1.17 (3H, d), 1.12 (3H, d), 1.01 (3H, t), 0.96 ( 3H, d), 0.94 (3H, d), 0.91 (9H, s), 0.11 (3H, s), 0.09 (3H, s)

[실시예 6]Example 6

4-{[((2S)-2-{[(2R,4S,5S)-4-히드록시-2,7-디메틸-5-({3-[메틸(프로필술포닐)아미노]벤조일}아미노)옥타노일]아미노}프로파노일)아미노]메틸}벤조산의 제조: 4- {[((2S)-2-{[(2R,4S,5S)-4-hydroxy-2,7-dimethyl-5-({3-[methyl(propylsulfonyl)amino]benzoyl}amino)octanoyl]amino}propanoyl)amino]methyl}benzoic acid4-{[((2 S ) -2-{[(2 R , 4 S , 5 S ) -4-hydroxy-2,7-dimethyl-5-({3- [methyl (propylsulfonyl) amino ] Benzoyl} amino) octanoyl] amino} propanoyl) amino] methyl} benzoic acid: 4-{[((2 S ) -2-{[(2 R , 4 S , 5 S ) -4-hydroxy -2,7-dimethyl-5-({3- [methyl (propylsulfonyl) amino] benzoyl} amino) octanoyl] amino} propanoyl) amino] methyl} benzoic acid

상기 제조예 9에서 얻은 화합물 대신에 상기 제조예 32에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 실시하여, 표제 화합물 52 ㎎을 80% 수율로 얻을 수 있었다.52 mg of the title compound was obtained in the same manner as in Example 1, except that the compound obtained in Preparation Example 32 was used instead of the compound obtained in Preparation Example 9.

1H NMR (500 MHz, CD3OD); 7.96 (2H, d), 7.87 (1H, s), 7.75 (1H, d), 7.60 (1H, d), 7.48 (1H, t), 7.36 (2H, d), 4.44 (2H, s), 4.33 (1H, m), 4.19 (1H, m), 3.60 (1H, m), 3.34 (3H, s), 3.09 (2H, dd), 2.71 (1H, m), 1.88-1.76 (3H, m), 1.70-1.61 (2H, m), 1.49-1.37 (2H, m), 1.33 (3H, d), 1.14 (3H, d), 1.02 (3H, t), 0.95 (3H, d), 0.94 (3H, d)1 H NMR (500 MHz, CD3 OD); 7.96 (2H, d), 7.87 (1H, s), 7.75 (1H, d), 7.60 (1H, d), 7.48 (1H, t), 7.36 (2H, d), 4.44 (2H, s), 4.33 (1H, m), 4.19 (1H, m), 3.60 (1H, m), 3.34 (3H, s), 3.09 (2H, dd), 2.71 (1H, m), 1.88-1.76 (3H, m), 1.70-1.61 (2H, m), 1.49-1.37 (2H, m), 1.33 (3H, d), 1.14 (3H, d), 1.02 (3H, t), 0.95 (3H, d), 0.94 (3H, d)

ESI MS (m/e) = 647 [M+H]+
ESI MS (m / e) = 647 [M + H] < + >

[제조예 33][Manufacture example 33]

3-[에틸(프로필술포닐)아미노]벤조산의 제조: 3-[ethyl(propylsulfonyl)amino]benzoic acidPreparation of 3- [ethyl (propylsulfonyl) amino] benzoic acid: 3- [ethyl (propylsulfonyl) amino] benzoic acid

아이오도메탄 대신에 아이오도에탄을 사용한 것을 제외하고는, 제조예 29와 동일한 방법으로 실시하여, 표제 화합물 0.25 g을 92% 수율로 얻을 수 있었다.Except for using iodoethane instead of iodomethane, the same procedure as in Preparation Example 29 was carried out to obtain 0.25 g of the title compound in 92% yield.

1H NMR (500 MHz, CDCl3); 8.07 (1H, d), 7.04 (1H, s), 7.64 (1H, d), 7.53 (1H, t), 3.80 (2H, q), 2.98 (2H, dd), 1.92-1.83 (2H, m), 1.15 (3H, t), 1.05 (3H, t)
1 H NMR (500 MHz, CDCl 3 ); 8.07 (1H, d), 7.04 (1H, s), 7.64 (1H, d), 7.53 (1H, t), 3.80 (2H, q), 2.98 (2H, dd), 1.92-1.83 (2H, m) , 1.15 (3H, t), 1.05 (3H, t)

[제조예 34][Manufacture example 34]

3-[에틸(프로필술포닐)아미노]-N-{(1S)-3-메틸-1-[(2R,4R)-4-메틸-5-옥소테트라히드로-2-퓨라닐]부틸}벤즈아미드의 제조: 3-[ethyl(propylsulfonyl)amino]-N-{(1S)-3-methyl-1-[(2R,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butyl}benzamide3- [ethyl (propylsulfonyl) amino] -N -{( 1S ) -3-methyl-1-[(2 R , 4R ) -4-methyl-5-oxotetrahydro-2-furanyl] Preparation of butyl} benzamide: 3- [ethyl (propylsulfonyl) amino] -N -{(1 S ) -3-methyl-1-[(2 R , 4 R ) -4-methyl-5-oxotetrahydro-2- furanyl] butyl} benzamide

상기 제조예 4에서 얻은 화합물 대신에 상기 제조예 33에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 5와 동일한 방법으로 실시하여, 표제 화합물 0.18 g을 83% 수율로 얻을 수 있었다.0.18 g of the title compound could be obtained in 83% yield in the same manner as in Preparation Example 5, except that the compound obtained in Preparation Example 33 was used instead of the compound obtained in Preparation Example 4.

1H NMR (500 MHz, CDCl3); 7.78 (1H, s), 7.59 (1H, d), 7.55 (1H, d), 7.47 (1H, t), 6.06 (1H, d), 4.63 (1H, m), 4.48 (1H, m), 3.78 (2H, q), 2.98 (2H, dd), 2.62 (1H, m), 2.43 (1H, m), 2.01 (1H, m), 1.92-1.82 (2H, m), 1.78-1.64 (2H, m), 1.50 (1H, m), 1.26 (3H, d), 1.14 (3H, t), 1.04 (3H, t), 0.96 (6H, d)
1 H NMR (500 MHz, CDCl 3 ); 7.78 (1H, s), 7.59 (1H, d), 7.55 (1H, d), 7.47 (1H, t), 6.06 (1H, d), 4.63 (1H, m), 4.48 (1H, m), 3.78 (2H, q), 2.98 (2H, dd), 2.62 (1H, m), 2.43 (1H, m), 2.01 (1H, m), 1.92-1.82 (2H, m), 1.78-1.64 (2H, m ), 1.50 (1H, m), 1.26 (3H, d), 1.14 (3H, t), 1.04 (3H, t), 0.96 (6H, d)

[제조예 35]Preparation Example 35

(2R,4S,5S)-4-{[tert-부틸(디메틸)실릴]옥시}-5-({3-[에틸(프로필술포닐)아미노]벤조일}아미노)-2,7-디메틸옥탄산의 제조: (2R,4S,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-({3-[ethyl(propylsulfonyl)amino]benzoyl}amino)- 2,7-dimethyloctanoic acid (2 R, 4 S, 5 S) -4 - {[tert - butyl (dimethyl) silyl] oxy} -5 - ({3- [ethyl (propyl-sulfonyl) amino] benzoyl} amino) 2,7 dimethyl octanoic acid Preparation of: (2 R, 4 S, 5 S) -4 - {[tert -butyl (dimethyl) silyl] oxy} -5 - ({3- [ethyl (propylsulfonyl) amino] benzoyl} amino) - 2,7-dimethyloctanoic acid

상기 제조예 5에서 얻은 화합물 대신에 상기 제조예 34에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 6과 동일한 방법으로 실시하여, 표제 화합물 0.22 g을 98% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 34 instead of the compound obtained in Preparation Example 5, it was carried out in the same manner as in Preparation Example 6, to obtain 0.22 g of the title compound in 98% yield.

1H NMR (500 MHz, CDCl3); 7.77 (1H, s), 7.66 (1H, d), 7.53 (1H, d), 7.48 (1H, t), 6.38 (1H, d), 4.28 (1H, m), 3.84-3.75 (3H, m), 2.97 (2H, dd), 2.65 (1H, m), 1.93-1.83 (3H, m), 1.66 (1H, m), 1.56-1.40 (3H, m), 1.21 (3H, d), 1.13 (3H, t), 1.03 (3H, t), 0.97 (3H, d), 0.95 (3H, d), 0.92 (9H, s), 0.11 (3H, s), 0.09 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 7.77 (1H, s), 7.66 (1H, d), 7.53 (1H, d), 7.48 (1H, t), 6.38 (1H, d), 4.28 (1H, m), 3.84-3.75 (3H, m) , 2.97 (2H, dd), 2.65 (1H, m), 1.93-1.83 (3H, m), 1.66 (1H, m), 1.56-1.40 (3H, m), 1.21 (3H, d), 1.13 (3H , t), 1.03 (3H, t), 0.97 (3H, d), 0.95 (3H, d), 0.92 (9H, s), 0.11 (3H, s), 0.09 (3H, s)

[제조예 36][Manufacture example 36]

벤질 4-{(4S,7R,9S)-9-[(1S)-1-({3-[에틸(프로필술포닐)아미노]벤조일}아미노)-3-메틸부틸]-4,7,11,11,12,12-헥사메틸-3,6-디옥소-10-옥사-2,5-디아자-11-실라트리덱-1-일}벤조에이트의 제조: benzyl 4-{(4S,7R,9S)-9-[(1S)-1-({3-[ethyl(propylsulfonyl)amino]benzoyl}amino)-3-methylbutyl]-4,7,11,11,12,12-hexamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl}benzoateBenzyl 4-{(4 S , 7 R , 9 S ) -9-[(1 S ) -1-({3- [ethyl (propylsulfonyl) amino] benzoyl} amino) -3-methylbutyl] -4 Preparation of 7,7,11,11,12,12-hexamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate: benzyl 4- {(4 S , 7 R , 9 S ) -9-[(1 S ) -1-({3- [ethyl (propylsulfonyl) amino] benzoyl} amino) -3-methylbutyl] -4,7,11,11 , 12,12-hexamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate

상기 제조예 6에서 얻은 화합물 대신에 상기 제조예 35에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 9와 동일한 방법으로 실시하여, 표제 화합물 89 ㎎을 71% 수율로 얻을 수 있었다. Except for using the compound obtained in Preparation Example 35 instead of the compound obtained in Preparation Example 6, it was carried out in the same manner as in Preparation Example 9, it was obtained 89 mg of the title compound in 71% yield.                     

1H NMR (500 MHz, CDCl3); 8.01 (2H, d), 7.80 (1H, s), 7.63 (1H, d), 7.54-7.29 (9H, m), 6.97 (1H, t), 6.89 (1H, d), 6.31 (1H, d), 5.35 (2H, d), 4.54-4.31 (4H, m), 3.82-3.70 (3H, m), 2.96 (2H, dd), 2.53 (1H, m), 1.89-1.81(2H, m), 1.70-1.55 (3H, m), 1.49 (1H, m), 1.38 (1H, m), 1.16 (3H, d), 1.12 (3H, t), 1.10 (3H, d), 1.02 (3H, t), 0.95 (3H, d), 0.94 (3H, d), 0.92 (9H, s), 0.11 (3H, s), 0.09 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 8.01 (2H, d), 7.80 (1H, s), 7.63 (1H, d), 7.54-7.29 (9H, m), 6.97 (1H, t), 6.89 (1H, d), 6.31 (1H, d) , 5.35 (2H, d), 4.54-4.31 (4H, m), 3.82-3.70 (3H, m), 2.96 (2H, dd), 2.53 (1H, m), 1.89-1.81 (2H, m), 1.70 -1.55 (3H, m), 1.49 (1H, m), 1.38 (1H, m), 1.16 (3H, d), 1.12 (3H, t), 1.10 (3H, d), 1.02 (3H, t), 0.95 (3H, d), 0.94 (3H, d), 0.92 (9H, s), 0.11 (3H, s), 0.09 (3H, s)

[실시예 7]Example 7

4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[에틸(프로필술포닐)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}프로파노일)아미노]메틸}벤조산의 제조: 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[ethyl(propylsulfonyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}propanoyl)amino]methyl}benzoic acid 4 - {[((2 S ) -2 - {[(2 R, 4 S, 5 S) -5 - ({3- [ ethyl (propyl-sulfonyl) amino] benzoyl} amino) -4-hydroxy- Preparation of 2,7-dimethyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid: 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5- ( {3- [ethyl (propylsulfonyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid

상기 제조예 9에서 얻은 화합물 대신에 상기 제조예 36에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 실시하여, 표제 화합물 43 ㎎을 66% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 36 instead of the compound obtained in Preparation Example 9, it was carried out in the same manner as in Example 1, whereby 43 mg of the title compound could be obtained in 66% yield.

1H NMR (500 MHz, CD3OD); 7.96 (2H, d), 7.84 (1H, s), 7.81 (1H, d), 7.56 (1H, d), 7.51 (1H, t), 7.37 (2H, d), 4.44 (2H, s), 4.34 (1H, m), 4.19 (1H, m), 3.79 (2H, q), 3.60 (1H, m), 3.09 (2H, dd), 2.71 (1H, m), 1.88-1.78 (2H, m), 1.72-1.63 (2H, m), 1.49-1.37 (3H, m), 1.33 (3H, d), 1.14 (3H, d), 1.10 (3H, t), 1.03 (3H, t), 0.96 (3H, d), 0.94 (3H, d)1 H NMR (500 MHz, CD3 OD); 7.96 (2H, d), 7.84 (1H, s), 7.81 (1H, d), 7.56 (1H, d), 7.51 (1H, t), 7.37 (2H, d), 4.44 (2H, s), 4.34 (1H, m), 4.19 (1H, m), 3.79 (2H, q), 3.60 (1H, m), 3.09 (2H, dd), 2.71 (1H, m), 1.88-1.78 (2H, m), 1.72-1.63 (2H, m), 1.49-1.37 (3H, m), 1.33 (3H, d), 1.14 (3H, d), 1.10 (3H, t), 1.03 (3H, t), 0.96 (3H, d), 0.94 (3H, d)

ESI MS (m/e) = 661 [M+H]+
ESI MS (m / e) = 661 [M + H] < + >

[제조예 37]Production Example 37

3-[프로필(프로필술포닐)아미노]벤조산의 제조: 3-[propyl(propylsulfonyl)amino]benzoic acidPreparation of 3- [propyl (propylsulfonyl) amino] benzoic acid: 3- [propyl (propylsulfonyl) amino] benzoic acid

아이오도메탄 대신에 아이오도프로판을 사용한 것을 제외하고는, 제조예 29와 동일한 방법으로 실시하여, 표제 화합물 0.27 g을 93% 수율로 얻을 수 있었다.Except for using iodopropane instead of iodomethane, the same procedure as in Preparation Example 29 was carried out to obtain 0.27 g of the title compound in 93% yield.

1H NMR (500 MHz, CDCl3); 8.08-8.03 (2H, m), 7.66 (1H, d), 7.52 (1H, t), 3.70 (2H, t), 2.98 (2H, dd), 1.92-1.83 (2H, m), 1.54-1.45 (2H, m), 1.04 (3H, t), 0.91 (3H, t)
1 H NMR (500 MHz, CDCl 3 ); 8.08-8.03 (2H, m), 7.66 (1H, d), 7.52 (1H, t), 3.70 (2H, t), 2.98 (2H, dd), 1.92-1.83 (2H, m), 1.54-1.45 ( 2H, m), 1.04 (3H, t), 0.91 (3H, t)

[제조예 38][Manufacture example 38]

N-{(1S)-3-메틸-1-[(2R,4R)-4-메틸-5-옥소테트라히드로-2-퓨라닐]부틸}-3-[프로필(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S)-3-methyl-1-[(2R,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butyl}-3-[propyl(propylsulfonyl)amino]benzamide N - {(1 S) -3-methyl -1 - [(2 R, 4 R) -4- methyl-5-oxo-tetrahydro-2-furanyl] butyl} -3- [propyl (propyl-sulfonyl) amino] benzamide Preparation of: N - {(1 S) -3-methyl-1 - [(2 R, 4 R) -4-methyl-5-oxotetrahydro-2-furanyl] butyl} -3- [propyl ( propylsulfonyl) amino] benzamide

상기 제조예 4에서 얻은 화합물 대신에 상기 제조예 37에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 5와 동일한 방법으로 실시하여, 표제 화합물 0.17 g을 75% 수율로 얻을 수 있었다. Except for using the compound obtained in Preparation Example 37 instead of the compound obtained in Preparation Example 4, it was carried out in the same manner as in Preparation Example 5, 0.17 g of the title compound could be obtained in 75% yield.                     

1H NMR (500 MHz, CDCl3); 7.79 (1H, s), 7.59 (1H, d), 7.55 (1H, d), 7.47 (1H, t), 6.14 (1H, d), 4.63 (1H, m), 4.48 (1H, m), 3.67 (2H, t), 2.97 (2H,dd), 2.61 (1H, m), 2.43 (1H, m), 2.00 (1H, m), 1.91-1.82 (2H, m), 1.77-1.64 (2H, m), 1.52-1.44 (3H, m), 1.26 (3H, d), 1.03 (3H, t), 0.95 (6H, d), 0.90 (3H, t)
1 H NMR (500 MHz, CDCl 3 ); 7.79 (1H, s), 7.59 (1H, d), 7.55 (1H, d), 7.47 (1H, t), 6.14 (1H, d), 4.63 (1H, m), 4.48 (1H, m), 3.67 (2H, t), 2.97 (2H, dd), 2.61 (1H, m), 2.43 (1H, m), 2.00 (1H, m), 1.91-1.82 (2H, m), 1.77-1.64 (2H, m ), 1.52-1.44 (3H, m), 1.26 (3H, d), 1.03 (3H, t), 0.95 (6H, d), 0.90 (3H, t)

[제조예 39][Manufacture example 39]

(2R,4S,5S)-4-{[tert-부틸(디메틸)실릴]옥시}-2,7-디메틸-5-({3-[프로필(프로필술포닐)아미노]벤조일}아미노)옥탄산의 제조: (2R,4S,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,7-dimethyl-5-({3-[propyl(propylsulfonyl)amino]benzoyl}amino)octanoic acid (2 R, 4 S, 5 S) -4 - {[tert - butyl (dimethyl) silyl] oxy} 2,7-dimethyl-5 - ({3- [propyl (propyl-sulfonyl) amino] benzoyl} amino ) Preparation of octanoic acid: (2 R, 4 S, 5 S) -4 - {[tert -butyl (dimethyl) silyl] oxy} -2,7-dimethyl-5 - ({3- [propyl (propylsulfonyl) amino ] benzoyl} amino) octanoic acid

상기 제조예 5에서 얻은 화합물 대신에 상기 제조예 38에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 6과 동일한 방법으로 실시하여, 표제 화합물 0.2 g을 97% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 38 instead of the compound obtained in Preparation Example 5, it was carried out in the same manner as in Preparation Example 6, 0.2 g of the title compound could be obtained in 97% yield.

1H NMR (500 MHz, CDCl3); 7.78 (1H, s), 7.65 (1H, d), 7.53 (1H, d), 7.47 (1H, t), 6.39 (1H, d), 4.28 (1H, m), 3.82 (1H, dd), 3.67 (2H, t), 2.96 (2H, dd), 2.66 (1H, m), 1.96-1.82 (3H, m), 1.66 (1H, m), 1.58-1.40 (5H, m), 1.21 (3H, d), 1.12 (3H, t), 0.97 (3H, d), 0.95 (3H, d), 0.92 (9H, s), 0.86 (3H, t), 0.13 (3H, s), 0.11 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 7.78 (1H, s), 7.65 (1H, d), 7.53 (1H, d), 7.47 (1H, t), 6.39 (1H, d), 4.28 (1H, m), 3.82 (1H, dd), 3.67 (2H, t), 2.96 (2H, dd), 2.66 (1H, m), 1.96-1.82 (3H, m), 1.66 (1H, m), 1.58-1.40 (5H, m), 1.21 (3H, d ), 1.12 (3H, t), 0.97 (3H, d), 0.95 (3H, d), 0.92 (9H, s), 0.86 (3H, t), 0.13 (3H, s), 0.11 (3H, s)

[제조예 40][Manufacture example 40]

벤질 4-{(4S,7R,9S)-4,7,11,11,12,12-헥사메틸-9-[(1S)-3-메틸-1-({3-[프로필(프로필술포닐)아미노]벤조일}아미노)부틸]-3,6-디옥소-10-옥사-2,5-디아자-11-실라트리덱-1-일}벤조에이트의 제조: benzyl 4-{(4S,7R,9S)-4,7,11,11,12,12-hexamethyl-9-[(1S)-3-methyl-1-({3-[propyl(propylsulfonyl)amino]benzoyl}amino)butyl]-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl}benzoateBenzyl 4-{(4 S , 7 R , 9 S ) -4,7,11,11,12,12-hexamethyl-9-[(1 S ) -3-methyl-1-({3- [propyl Preparation of (propylsulfonyl) amino] benzoyl} amino) butyl] -3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate: benzyl 4- {(4 S , 7 R , 9 S ) -4,7,11,11,12,12-hexamethyl-9-[(1 S ) -3-methyl-1-({3- [propyl (propylsulfonyl) amino ] benzoyl} amino) butyl] -3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate

상기 제조예 6에서 얻은 화합물 대신에 상기 제조예 39에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 9와 동일한 방법으로 실시하여, 표제 화합물 100 ㎎을 85% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 39 instead of the compound obtained in Preparation Example 6, it was carried out in the same manner as in Preparation Example 9, 100 mg of the title compound in 85% yield was obtained.

1H NMR (500 MHz, CDCl3); 8.02 (2H, d), 7.81 (1H, s), 7.63 (1H, d), 7.54 (1H, d), 7.48 (1H, d), 7.44 (2H, d), 7.39 (2H, t), 7.35 (1H, d), 7.31 (2H, d), 6.97 (1H, t), 6.91 (1H, d), 6.31 (1H, d), 5.30 (2H, s), 4.55-4.30 (4H, m), 3.77-3.60 (3H, m), 2.95 (2H, dd), 2.53 (1H, m), 1.90-1.80 (2H, m), 1.70-1.34 (7H, m), 1.17 (3H, d), 1.13 (3H, d), 1.02 (3H, t), 0.96 (3H, d), 0.95 (3H, d), 0.92 (9H, s), 0.88 (3H, t), 0.11 (3H, s), 0.10 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 8.02 (2H, d), 7.81 (1H, s), 7.63 (1H, d), 7.54 (1H, d), 7.48 (1H, d), 7.44 (2H, d), 7.39 (2H, t), 7.35 (1H, d), 7.31 (2H, d), 6.97 (1H, t), 6.91 (1H, d), 6.31 (1H, d), 5.30 (2H, s), 4.55-4.30 (4H, m), 3.77-3.60 (3H, m), 2.95 (2H, dd), 2.53 (1H, m), 1.90-1.80 (2H, m), 1.70-1.34 (7H, m), 1.17 (3H, d), 1.13 ( 3H, d), 1.02 (3H, t), 0.96 (3H, d), 0.95 (3H, d), 0.92 (9H, s), 0.88 (3H, t), 0.11 (3H, s), 0.10 (3H , s)

[실시예 8]Example 8

4-{[((2S)-2-{[(2R,4S,5S)-4-히드록시-2,7-디메틸-5-({3-[프로필(프로필술포닐)아 미노]벤조일}아미노)옥타노일]아미노}프로파노일)아미노]메틸}벤조산의 제조: 4-{[((2S)-2-{[(2R,4S,5S)-4-hydroxy-2,7-dimethyl-5-({3-[propyl(propylsulfonyl)amino]benzoyl}amino)octanoyl]amino}propanoyl)amino]methyl}benzoic acid4-{[((2 S ) -2-{[(2 R , 4 S , 5 S ) -4-hydroxy-2,7-dimethyl-5-({3- [propyl (propylsulfonyl) a Preparation of Mino] benzoyl} amino) octanoyl] amino} propanoyl) amino] methyl} benzoic acid: 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -4- hydroxy-2,7-dimethyl-5-({3- [propyl (propylsulfonyl) amino] benzoyl} amino) octanoyl] amino} propanoyl) amino] methyl} benzoic acid

상기 제조예 9에서 얻은 화합물 대신에 상기 제조예 40에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 실시하여, 표제 화합물 53 ㎎을 55% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 40 instead of the compound obtained in Preparation Example 9 was carried out in the same manner as in Example 1, 53 mg of the title compound in 55% yield was obtained.

1H NMR (500 MHz, CD3OD); 7.97 (2H, d), 7.87 (1H, s), 7.82 (1H, d), 7.58 (1H, d), 7.52 (1H, t), 7.38 (2H, d), 4.45 (2H, s), 4.35 (1H, m), 4.20 (1H, m), 3.71 (2H, t), 3.61 (1H, m), 3.08 (2H, t), 2.72 (1H, m), 1.89-1.78 (2H, m), 1.72-1.62 (2H, m), 1.51-1.38 (5H, m), 1.34 (3H, d), 1.15 (3H, d), 1.04 (3H, t), 0.96 (3H, d), 0.95 (3H, d), 0.91 (3H, t)1 H NMR (500 MHz, CD3 OD); 7.97 (2H, d), 7.87 (1H, s), 7.82 (1H, d), 7.58 (1H, d), 7.52 (1H, t), 7.38 (2H, d), 4.45 (2H, s), 4.35 (1H, m), 4.20 (1H, m), 3.71 (2H, t), 3.61 (1H, m), 3.08 (2H, t), 2.72 (1H, m), 1.89-1.78 (2H, m), 1.72-1.62 (2H, m), 1.51-1.38 (5H, m), 1.34 (3H, d), 1.15 (3H, d), 1.04 (3H, t), 0.96 (3H, d), 0.95 (3H, d), 0.91 (3H, t)

ESI MS (m/e) = 675 [M+H]+
ESI MS (m / e) = 675 [M + H] < + >

[제조예 41]Production Example 41

[3-[벤질(프로필술포닐)아미노]벤조산의 제조: 3-[benzyl(propylsulfonyl)amino]benzoic acidPreparation of [3- [benzyl (propylsulfonyl) amino] benzoic acid: 3- [benzyl (propylsulfonyl) amino] benzoic acid

아이오도메탄 대신에 벤질브로마이드를 사용한 것을 제외하고는, 제조예 29와 동일한 방법으로 실시하여, 표제 화합물 0.3 g을 90% 수율로 얻을 수 있었다.0.3 g of the titled compound was obtained in 90% yield by the same method as Preparation Example 29, except that benzylbromide was used instead of iodomethane.

1H NMR (500 MHz, CD3OD); 7.95 (1H, s), 7.88 (1H, d), 7.53 (1H, d), 7.40 (1H, t), 7.27-7.16 (5H, m), 4.92 (2H, s), 3.15 (2H, dd), 1.90-1.84 (2H, m), 1.06 (3H, t)
1 H NMR (500 MHz, CD3 OD); 7.95 (1H, s), 7.88 (1H, d), 7.53 (1H, d), 7.40 (1H, t), 7.27-7.16 (5H, m), 4.92 (2H, s), 3.15 (2H, dd) , 1.90-1.84 (2H, m), 1.06 (3H, t)

[제조예 42]Production Example 42

3-[벤질(프로필술포닐)아미노]-N-{(1S)-3-메틸-1-[(2R,4R)-4-메틸-5-옥소테트라히드로-2-퓨라닐]부틸}벤즈아미드의 제조: 3-[benzyl(propylsulfonyl)amino]-N-{(1S)-3-methyl-1-[(2R,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butyl}benzamide3- [benzyl (propylsulfonyl) amino] -N -{( 1S ) -3-methyl-1-[(2 R , 4R ) -4-methyl-5-oxotetrahydro-2-furanyl] Preparation of butyl} benzamide: 3- [benzyl (propylsulfonyl) amino] -N -{(1 S ) -3-methyl-1-[(2 R , 4 R ) -4-methyl-5-oxotetrahydro-2- furanyl] butyl} benzamide

상기 제조예 4에서 얻은 화합물 대신에 상기 제조예 41에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 5와 동일한 방법으로 실시하여, 표제 화합물 0.21 g을 85% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 41 instead of the compound obtained in Preparation Example 4, 0.21 g of the title compound could be obtained in 85% yield in the same manner as in Preparation Example 5.

1H NMR (500 MHz, CDCl3); 7.60 (1H, s), 7.54 (1H, d), 7.42 (1H, d), 7.37 (1H, t), 7.29-7.21 (5H, m), 5.92 (1H, d), 4.88 (2H, d), 4.61 (1H, m), 4.44 (1H, m), 3.04 (2H, dd), 2.56 (1H, m), 2.39 (1H, m), 2.02-1.86 (3H, m), 1.70 (1H, m), 1.61 (1H, m), 1.47 (1H, m), 1.25 (3H, d), 1.06 (3H, t), 0.95 (3H, d), 0.93 (3H, d)
1 H NMR (500 MHz, CDCl 3 ); 7.60 (1H, s), 7.54 (1H, d), 7.42 (1H, d), 7.37 (1H, t), 7.29-7.21 (5H, m), 5.92 (1H, d), 4.88 (2H, d) , 4.61 (1H, m), 4.44 (1H, m), 3.04 (2H, dd), 2.56 (1H, m), 2.39 (1H, m), 2.02-1.86 (3H, m), 1.70 (1H, m ), 1.61 (1H, m), 1.47 (1H, m), 1.25 (3H, d), 1.06 (3H, t), 0.95 (3H, d), 0.93 (3H, d)

[제조예 43]Production Example 43

(2R,4S,5S)-5-({3-[벤질(프로필술포닐)아미노]벤조일}아미노)-4-{[tert-부틸(디메틸)실릴]옥시}-2,7-디메틸옥탄산의 제조: (2R,4S,5S)-5-({3- [benzyl(propylsulfonyl)amino]benzoyl}amino)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,7-dimethyloctanoic acid( 2R , 4S , 5S ) -5-({3- [benzyl (propylsulfonyl) amino] benzoyl} amino) -4-{[ tert -butyl (dimethyl) silyl] oxy} -2,7- dimethyl octanoic acid Preparation of: (2 R, 4 S, 5 S) -5 - ({3- [benzyl (propylsulfonyl) amino] benzoyl} amino) -4 - {[tert -butyl (dimethyl) silyl] oxy} - 2,7-dimethyloctanoic acid

상기 제조예 5에서 얻은 화합물 대신에 상기 제조예 42에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 6과 동일한 방법으로 실시하여, 표제 화합물 0.25 g을 97% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 42 instead of the compound obtained in Preparation Example 5, it was carried out in the same manner as in Preparation Example 6, 0.25 g of the title compound could be obtained in 97% yield.

1H NMR (500 MHz, CDCl3); 7.68 (1H, s), 7.57 (1H, d), 7.39 (1H, d), 7.36 (1H, t), 7.27-7.19 (5H, m), 6.25 (1H, d), 4.88 (2H, dd), 4.24 (1H, m), 3.80 (1H, t), 3.03 (2H, dd), 2.64 (1H, m),1.96-1.80 (3H, m), 1.61 (1H, m), 1.53-1.38 (3H, m), 1.21 (3H, d), 1.05 (3H, t), 0.95 (6H, d), 0.92 (9H, s), 0.13 (3H, s), 0.10 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 7.68 (1H, s), 7.57 (1H, d), 7.39 (1H, d), 7.36 (1H, t), 7.27-7.19 (5H, m), 6.25 (1H, d), 4.88 (2H, dd) , 4.24 (1H, m), 3.80 (1H, t), 3.03 (2H, dd), 2.64 (1H, m), 1.96-1.80 (3H, m), 1.61 (1H, m), 1.53-1.38 (3H , m), 1.21 (3H, d), 1.05 (3H, t), 0.95 (6H, d), 0.92 (9H, s), 0.13 (3H, s), 0.10 (3H, s)

[제조예 44][Production Example 44]

벤질 4-{(4S,7R,9S)-9-[(1S)-1-({3-[벤질(프로필술포닐)아미노]벤조일}아미노)-3-메틸부틸]-4,7,11,11,12,12-헥사메틸-3,6-디옥소-10-옥사-2,5-디아자-11-실라트리덱-1-일}벤조에이트의 제조: benzyl 4-{(4S,7R,9S)-9-[(1S)-1-({3-[benzyl(propylsulfonyl)amino]benzoyl}amino)-3-methylbutyl]-4,7,11,11,12,12-hexamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl}benzoateBenzyl 4-{(4 S , 7 R , 9 S ) -9-[(1 S ) -1-({3- [benzyl (propylsulfonyl) amino] benzoyl} amino) -3-methylbutyl] -4 Preparation of 7,7,11,11,12,12-hexamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate: benzyl 4- {(4 S , 7 R , 9 S ) -9-[(1 S ) -1-({3- [benzyl (propylsulfonyl) amino] benzoyl} amino) -3-methylbutyl] -4,7,11,11 , 12,12-hexamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate

상기 제조예 6에서 얻은 화합물 대신에 상기 제조예 43에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 9와 동일한 방법으로 실시하여, 표제 화합물 91 ㎎을 78% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 43 instead of the compound obtained in Preparation Example 6, it was carried out in the same manner as in Preparation Example 9, it was obtained 91 mg of the title compound in 78% yield.

1H NMR (500 MHz, CDCl3); 8.01 (2H, d), 7.69 (1H, s), 7.57 (1H, d), 7.46-7.18 (14H, m), 6.95 (1H, t), 6.85 (1H, d), 6.19 (1H, d), 5.35 (2H, s), 4.87 (2H, dd), 4.54-4.26 (4H, m), 3.72 (1H, dd), 3.02 (2H, dd), 2.51 (1H, m), 1.94-1.85 (2H, m), 1.64-1.24 (5H, m), 1.11 (3H, d), 1.08-1.02 (6H, m), 0.99-0.90 (15H, m), 0.11 (3H, s), 0.10 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 8.01 (2H, d), 7.69 (1H, s), 7.57 (1H, d), 7.46-7.18 (14H, m), 6.95 (1H, t), 6.85 (1H, d), 6.19 (1H, d) , 5.35 (2H, s), 4.87 (2H, dd), 4.54-4.26 (4H, m), 3.72 (1H, dd), 3.02 (2H, dd), 2.51 (1H, m), 1.94-1.85 (2H , m), 1.64-1.24 (5H, m), 1.11 (3H, d), 1.08-1.02 (6H, m), 0.99-0.90 (15H, m), 0.11 (3H, s), 0.10 (3H, s )

[실시예 9]Example 9

4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[벤질(프로필술포닐)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}프로파노일)아미노]메틸}벤조산의 제조: 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[benzyl(propylsulfonyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}propanoyl)amino]methyl}benzoic acid 4 - {[((2 S ) -2 - {[(2 R, 4 S, 5 S) -5 - ({3- [ benzyl (propyl-sulfonyl) amino] benzoyl} amino) -4-hydroxy- Preparation of 2,7-dimethyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid: 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5- ( {3- [benzyl (propylsulfonyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid

상기 제조예 28에서 얻은 화합물 대신에 상기 제조예 44에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 5와 동일한 방법으로 실시하여, 표제 화합물 39 ㎎을 57% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 44 instead of the compound obtained in Preparation Example 28, it was carried out in the same manner as in Example 5, 39 mg of the title compound could be obtained in 57% yield.

1H NMR (500 MHz, CD3OD); 7.96 (2H, d), 7.79 (1H, s), 7.70 (1H, d), 7.46 (1H, d), 7.42-7.35 (3H, m), 7.30-7.16 (5H, m), 4.92 (2H, s), 4.44 (2H, s), 4.34 (1H, m), 4.16 (1H, m), 3.60 (1H, m), 3.18 (2H, t), 2.70 (1H, m), 1.94-1.77 (3H, m), 1.72-1.56 (2H, m), 1.50-1.36 (2H, m), 1.31 (3H, d), 1.14 (3H, d), 1.06 (3H, t), 0.96 (3H, d), 0.95 (3H, d)1 H NMR (500 MHz, CD3 OD); 7.96 (2H, d), 7.79 (1H, s), 7.70 (1H, d), 7.46 (1H, d), 7.42-7.35 (3H, m), 7.30-7.16 (5H, m), 4.92 (2H, s), 4.44 (2H, s), 4.34 (1H, m), 4.16 (1H, m), 3.60 (1H, m), 3.18 (2H, t), 2.70 (1H, m), 1.94-1.77 (3H , m), 1.72-1.56 (2H, m), 1.50-1.36 (2H, m), 1.31 (3H, d), 1.14 (3H, d), 1.06 (3H, t), 0.96 (3H, d), 0.95 (3H, d)

ESI MS (m/e) = 723 [M+H]+
ESI MS (m / e) = 723 [M + H] < + >

[제조예 45]Production Example 45

에틸 3-[(에틸술포닐)아미노]벤조에이트의 제조: ethyl 3-[(ethylsulfonyl)amino]benzoatePreparation of ethyl 3-[(ethylsulfonyl) amino] benzoate: ethyl 3-[(ethylsulfonyl) amino] benzoate

프로판술포닐클로라이드 대신에 에탄술포닐클로라이드를 사용한 것을 제외하고는, 제조예 14와 동일한 방법으로 실시하여, 표제 화합물 0.65 g을 61% 수율로 얻을 수 있었다.Except for using ethanesulfonylchloride instead of propanesulfonylchloride, the same procedure as in Production Example 14 was carried out to obtain 0.65 g of the title compound in 61% yield.

1H NMR (500 MHz, CDCl3); 7.86-7.82 (2H, m), 7.53 (1H, d), 7.43 (1H, t), 6.72 (1H, s), 4.39 (2H, q), 3.15 (2H, q), 1.40 (3H, t), 1.38 (3H, t)
1 H NMR (500 MHz, CDCl 3 ); 7.86-7.82 (2H, m), 7.53 (1H, d), 7.43 (1H, t), 6.72 (1H, s), 4.39 (2H, q), 3.15 (2H, q), 1.40 (3H, t) , 1.38 (3H, t)

[제조예 46]Preparation Example 46

에틸 3-[(에틸술포닐)아미노]벤조에이트의 제조: 3-[(ethylsulfonyl)(methyl)amino]benzoic acidPreparation of ethyl 3-[(ethylsulfonyl) amino] benzoate: 3-[(ethylsulfonyl) (methyl) amino] benzoic acid

상기 제조예 14에서 얻은 화합물 대신에 상기 제조예 45에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 29와 동일한 방법으로 실시하여, 표제 화합물 0.57 g을 92% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 45 instead of the compound obtained in Preparation Example 14, it was carried out in the same manner as in Preparation Example 29, it was possible to obtain 0.57 g of the title compound in 92% yield.

1H NMR (500 MHz, CDCl3); 8.07 (1H, s), 8.02 (1H, d), 7.72 (1H, d), 7.50 (1H, t), 3.41 (3H, s), 3.07 (2H, q), 1.38 (3H, t)
1 H NMR (500 MHz, CDCl 3 ); 8.07 (1H, s), 8.02 (1H, d), 7.72 (1H, d), 7.50 (1H, t), 3.41 (3H, s), 3.07 (2H, q), 1.38 (3H, t)

[제조예 47]Production Example 47

3-[(에틸술포닐)(메틸)아미노]-N-{(1S)-3-메틸-1-[(2R,4R)-4-메틸-5-옥소테트라히드로-2-퓨라닐]부틸}벤즈아미드의 제조: 3-[(ethylsulfonyl)(methyl)amino]-N-{(1S)-3-methyl-1-[(2R,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butyl}benzamide3-[(ethylsulfonyl) (methyl) amino] -N -{( 1S ) -3-methyl-1-[(2 R , 4R ) -4-methyl-5-oxotetrahydro-2-fue Preparation of ranyl] butyl} benzamide: 3-[(ethylsulfonyl) (methyl) amino] -N -{(1 S ) -3-methyl-1-[(2 R , 4 R ) -4-methyl-5- oxotetrahydro-2-furanyl] butyl} benzamide

상기 제조예 4에서 얻은 화합물 대신에 상기 제조예 46에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 5와 동일한 방법으로 실시하여, 표제 화합물 0.17 g을 81% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 46 instead of the compound obtained in Preparation Example 4, it was carried out in the same manner as in Preparation Example 5, 0.17 g of the title compound could be obtained in 81% yield.

1H NMR (500 MHz, CDCl3); 7.82 (1H, s), 8.60 (1H, d), 7.58 (1H, d), 7.43 (1H, t), 6.26 (1H, d), 4.63 (1H,m), 4.48 (1H, m), 3.37 (3H, s), 3.05 (2H, q), 2.61 (1H, m), 2.43 (1H, m), 1.99 (1H, m), 1.78-1.62 (2H, m), 1.49 (1H, m), 1.36 (3H, t), 1.24 (3H, d), 0.95 (6H, d)
1 H NMR (500 MHz, CDCl 3 ); 7.82 (1H, s), 8.60 (1H, d), 7.58 (1H, d), 7.43 (1H, t), 6.26 (1H, d), 4.63 (1H, m), 4.48 (1H, m), 3.37 (3H, s), 3.05 (2H, q), 2.61 (1H, m), 2.43 (1H, m), 1.99 (1H, m), 1.78-1.62 (2H, m), 1.49 (1H, m), 1.36 (3H, t), 1.24 (3H, d), 0.95 (6H, d)

[제조예 48][Manufacture example 48]

(2R,4S,5S)-4-{[tert-부틸(디메틸)실릴]옥시}-5-({3-[(에틸술포닐)(메틸)아미노]벤조일}아미노)-2,7-디메틸옥탄산의 제조: (2R,4S,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-({3-[(ethylsulfonyl)(methyl)amino]benzoyl}amino)-2,7-dimethyloctanoic acid (2 R, 4 S, 5 S) -4 - {[tert-butyl (dimethyl) silyl] oxy} -5 - ({3 - [(ethylsulfonyl) (methyl) amino] benzoyl} amino) -2, Preparation of 7-dimethyl-octanoic acid: (2 R, 4 S, 5 S) -4 - {[tert -butyl (dimethyl) silyl] oxy} -5 - ({3 - [(ethylsulfonyl) (methyl) amino] benzoyl } amino) -2,7-dimethyloctanoic acid

상기 제조예 5에서 얻은 화합물 대신에 상기 제조예 47에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 6과 동일한 방법으로 실시하여, 표제 화합물 0.2 g을 97% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 47 instead of the compound obtained in Preparation Example 5, it was carried out in the same manner as in Preparation Example 6, 0.2 g of the title compound could be obtained in 97% yield.

1H NMR (500 MHz, CDCl3); 7.81 (1H, s), 7.62-7.57 (2H, m), 7.45 (1H, t), 6.36 (1H, d), 4.28 (1H, m), 3.82 (1H, t), 3.37 (3H, s), 3.04 (2H, q), 2.64 (1H, m), 1.89 (1H, m), 1.64 (1H, m), 1.56-1.38 (3H, m), 1.36 (3H, t), 1.21 (3H, d), 0.97 (3H, d), 0.96 (3H, d), 0.90 (9H, s), 0.13 (3H, s), 0.11 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 7.81 (1H, s), 7.62-7.57 (2H, m), 7.45 (1H, t), 6.36 (1H, d), 4.28 (1H, m), 3.82 (1H, t), 3.37 (3H, s) , 3.04 (2H, q), 2.64 (1H, m), 1.89 (1H, m), 1.64 (1H, m), 1.56-1.38 (3H, m), 1.36 (3H, t), 1.21 (3H, d ), 0.97 (3H, d), 0.96 (3H, d), 0.90 (9H, s), 0.13 (3H, s), 0.11 (3H, s)

[제조예 49][Manufacture example 49]

벤질 4-{(4S,7R,9S)-9-[(1S)-1-({3-[(에틸술포닐)(메틸)아미노]벤조일}아미노)-3-메틸부틸]-4,7,11,11,12,12-헥사메틸-3,6-디옥소-10-옥사-2,5-디아자-11-실라트리덱-1-일}벤조에이트의 제조: benzyl 4-{(4S,7R,9S)-9-[(1S)-1-({3-[(ethylsulfonyl)(methyl)amino]benzoyl}amino)-3-methylbutyl]-4,7,11,11,12,12-hexamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl}benzoateBenzyl 4-{(4 S , 7 R , 9 S ) -9-[(1 S ) -1-({3-[(ethylsulfonyl) (methyl) amino] benzoyl} amino) -3-methylbutyl] Preparation of -4,7,11,11,12,12-hexamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate: benzyl 4-{(4 S , 7 R , 9 S ) -9-[(1 S ) -1-({3-[(ethylsulfonyl) (methyl) amino] benzoyl} amino) -3-methylbutyl] -4,7 , 11,11,12,12-hexamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate

상기 제조예 6에서 얻은 화합물 대신에 상기 제조예 48에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 9와 동일한 방법으로 실시하여, 표제 화합물 103 ㎎을 75% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 48 instead of the compound obtained in Preparation Example 6, it was carried out in the same manner as in Preparation Example 9, 103 mg of the title compound could be obtained in 75% yield.

1H NMR (500 MHz, CDCl3); 8.01 (2H, d), 7.85 (1H, s), 7.61 (1H, d), 7.57 (1H, d), 7.48-7.30 (8H, m), 6.97 (1H, t), 6.92 (1H, d), 6.29 (1H, d), 5.36 (2H, s), 4.55-4.32 (4H, m), 3.74 (1H, dd), 3.35 (3H, s), 3.03 (2H, q), 2.54 (1H, m), 1.70-1.56 (3H, m), 1.49 (1H, m), 1.39 (1H, m), 1.35 (3H, t), 1.17 (3H, d), 1.13 (3H, d), 0.90 (3H, d), 0.95 (3H, d), 0.92 (9H, s), 0.11 (3H, s), 0.09 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 8.01 (2H, d), 7.85 (1H, s), 7.61 (1H, d), 7.57 (1H, d), 7.48-7.30 (8H, m), 6.97 (1H, t), 6.92 (1H, d) , 6.29 (1H, d), 5.36 (2H, s), 4.55-4.32 (4H, m), 3.74 (1H, dd), 3.35 (3H, s), 3.03 (2H, q), 2.54 (1H, m ), 1.70-1.56 (3H, m), 1.49 (1H, m), 1.39 (1H, m), 1.35 (3H, t), 1.17 (3H, d), 1.13 (3H, d), 0.90 (3H, d), 0.95 (3H, d), 0.92 (9H, s), 0.11 (3H, s), 0.09 (3H, s)

[실시예 10]Example 10

4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(에틸술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}프로파노일)아미노]메틸}벤조산의 제조: 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(ethylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}propanoyl)amino]methyl}benzoic acid 4 - {[((2 S ) -2 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( ethylsulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy Preparation of Roxy-2,7-dimethyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid: 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5 -({3-[(ethylsulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid

상기 제조예 9에서 얻은 화합물 대신에 상기 제조예 49에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 실시하여, 표제 화합물 56 ㎎을 72% 수율로 얻을 수 있었다.In the same manner as in Example 1, except that the compound obtained in Preparation Example 49 was used instead of the compound obtained in Preparation Example 9, 56 mg of the title compound was obtained in a 72% yield.

1H NMR (500 MHz, CD3OD); 7.96 (2H, d), 7.88 (1H, s), 7.75 (1H, d), 7.61 (1H, d), 7.48 (1H, t), 7.37 (2H, d), 4.44 (2H,s), 4.34 (1H, m), 4.18 (1H, m), 3.60 (1H, m), 3.35 (3H, s), 3.14 (2H, q), 2.69 (1H, m), 1.84 (1H, m), 1.70-1.60 (2H, m), 1.48-1.36 (2H, m), 1.34-1.28 (6H, m), 1.14 (3H, d), 0.95 (3H, d), 0.94 (3H, d)1 H NMR (500 MHz, CD3 OD); 7.96 (2H, d), 7.88 (1H, s), 7.75 (1H, d), 7.61 (1H, d), 7.48 (1H, t), 7.37 (2H, d), 4.44 (2H, s), 4.34 (1H, m), 4.18 (1H, m), 3.60 (1H, m), 3.35 (3H, s), 3.14 (2H, q), 2.69 (1H, m), 1.84 (1H, m), 1.70- 1.60 (2H, m), 1.48-1.36 (2H, m), 1.34-1.28 (6H, m), 1.14 (3H, d), 0.95 (3H, d), 0.94 (3H, d)

ESI MS (m/e) = 633 [M+H]+
ESI MS (m / e) = 633 [M + H] < + >

[제조예 50][Production Example 50]

에틸 3-[(부틸술포닐)아미노]벤조에이트의 제조: ethyl 3-[(butylsulfonyl)amino]benzoatePreparation of ethyl 3-[(butylsulfonyl) amino] benzoate: ethyl 3-[(butylsulfonyl) amino] benzoate

벤젠술포닐클로라이드 대신에 1-부탄술포닐클로라이드를 사용한 것을 제외하고는, 제조예 19와 동일한 방법으로 실시하여, 표제 화합물 1.08 g을 76% 수율로 얻을 수 있었다.Except for using 1-butanesulfonylchloride instead of benzenesulfonylchloride, the same procedure as in Production Example 19 was carried out to obtain 1.08 g of the title compound in 76% yield.

1H NMR (500 MHz, CDCl3); 7.87-7.82 (2H, m), 7.53 (1H, d), 7.42 (1H, t), 6.96 (1H, s), 4.40 (2H, q), 3.11 (2H, dd), 1.86-1.78 (2H, m), 1.46-1.36 (5H, m), 0.89 (3H, t)
1 H NMR (500 MHz, CDCl 3 ); 7.87-7.82 (2H, m), 7.53 (1H, d), 7.42 (1H, t), 6.96 (1H, s), 4.40 (2H, q), 3.11 (2H, dd), 1.86-1.78 (2H, m), 1.46-1.36 (5H, m), 0.89 (3H, t)

[제조예 51]Production Example 51

3-[(부틸술포닐)(메틸)아미노]벤조산의 제조: 3-[(butylsulfonyl)(methyl)amino]benzoic acidPreparation of 3-[(butylsulfonyl) (methyl) amino] benzoic acid: 3-[(butylsulfonyl) (methyl) amino] benzoic acid

상기 제조예 14에서 얻은 화합물 대신에 상기 제조예 50에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 29와 동일한 방법으로 실시하여, 표제 화합물 0.96 g을 93% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 50 instead of the compound obtained in Preparation Example 14, 0.96 g of the title compound could be obtained in 93% yield in the same manner as in Preparation Example 29.

1H NMR (500 MHz, CD3OD); 8.05 (1H, s), 7.94 (1H, d), 7.66 (1H, d), 7.50 (1H, t), 3.35 (3H, s), 3.10 (2H, dd), 1.74-1.70 (2H, m), 1.46-1.42 (2H, m), 0.92 (3H, t)
1 H NMR (500 MHz, CD3 OD); 8.05 (1H, s), 7.94 (1H, d), 7.66 (1H, d), 7.50 (1H, t), 3.35 (3H, s), 3.10 (2H, dd), 1.74-1.70 (2H, m) , 1.46-1.42 (2H, m), 0.92 (3H, t)

[제조예 52]Production Example 52

3-[(부틸술포닐)(메틸)아미노]-N-{(1S)-3-메틸-1-[(2R,4R)-4-메틸-5-옥소테트라히드로-2-퓨라닐]부틸}벤즈아미드의 제조: 3-[(butylsulfonyl)(methyl)amino]-N-{(1S)-3-methyl-1-[(2R,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butyl}benzamide3-[(butylsulfonyl) (methyl) amino] -N -{( 1S ) -3-methyl-1-[(2 R , 4R ) -4-methyl-5-oxotetrahydro-2-fue Preparation of ranyl] butyl} benzamide: 3-[(butylsulfonyl) (methyl) amino] -N -{(1 S ) -3-methyl-1-[(2 R , 4 R ) -4-methyl-5- oxotetrahydro-2-furanyl] butyl} benzamide

상기 제조예 4에서 얻은 화합물 대신에 상기 제조예 51에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 5와 동일한 방법으로 실시하여, 표제 화합물 0.17 g을 79% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 51 instead of the compound obtained in Preparation Example 4, it was carried out in the same manner as in Preparation Example 5, 0.17 g of the title compound could be obtained in 79% yield.

1H NMR (500 MHz, CDCl3); 7.81 (1H, d), 7.59 (2H, dd), 7.42 (1H, t), 6.38 (1H, d), 4.63 (1H, dd), 4.48 (1H, m), 3.35 (3H, s), 2.99 (2H, dd), 2.61 (1H, m), 2.44 (1H, m), 1.99 (1H, m), 1.86-1.73 (3H, m), 1.66 (1H, m), 1.53-1.36 (3H, m), 1.23 (3H, d), 0.94 (6H, d), 0.90 (3H, t)
1 H NMR (500 MHz, CDCl 3 ); 7.81 (1H, d), 7.59 (2H, dd), 7.42 (1H, t), 6.38 (1H, d), 4.63 (1H, dd), 4.48 (1H, m), 3.35 (3H, s), 2.99 (2H, dd), 2.61 (1H, m), 2.44 (1H, m), 1.99 (1H, m), 1.86-1.73 (3H, m), 1.66 (1H, m), 1.53-1.36 (3H, m ), 1.23 (3H, d), 0.94 (6H, d), 0.90 (3H, t)

[제조예 53][Manufacture example 53]

(2R,4S,5S)-4-{[tert-부틸(디메틸)실릴]옥시}-5-({3-[(부틸술포닐)(메틸)아미노]벤조일}아미노)-2,7-디메틸옥탄산의 제조: (2R,4S,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-({3-[(butylsulfonyl)(methyl)amino]benzoyl}amino)-2,7-dimethyloctanoic acid(2 R, 4 S, 5 S) -4 - {[tert-butyl (dimethyl) silyl] oxy} -5 - ({3 - [(1-butylsulfonyl) (methyl) amino] benzoyl} amino) -2, Preparation of 7-dimethyl-octanoic acid: (2 R, 4 S, 5 S) -4 - {[tert -butyl (dimethyl) silyl] oxy} -5 - ({3 - [(butylsulfonyl) (methyl) amino] benzoyl } amino) -2,7-dimethyloctanoic acid

상기 제조예 5에서 얻은 화합물 대신에 상기 제조예 52에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 6과 동일한 방법으로 실시하여, 표제 화합물 0.2 g을 98% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 52 instead of the compound obtained in Preparation Example 5, it was carried out in the same manner as in Preparation Example 6, it was possible to obtain 0.2 g of the title compound in 98% yield.

1H NMR (500 MHz, CDCl3); 7.80 (1H, s), 7.62-7.57 (2H, m), 7.45 (1H, t), 6.36 (1H, d), 4.28 (1H, m), 3.82 (1H, dd), 3.36 (3H, s), 2.99 (2H, dd), 2.66 (1H, m), 1.88 (1H, m), 1.84-1.75 (2H, m), 1.65 (1H, m), 1.58-1.36 (5H, m), 1.21 (3H, d), 1.02-0.86 (18H, m), 0.13 (3H, s), 0.11 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 7.80 (1H, s), 7.62-7.57 (2H, m), 7.45 (1H, t), 6.36 (1H, d), 4.28 (1H, m), 3.82 (1H, dd), 3.36 (3H, s) , 2.99 (2H, dd), 2.66 (1H, m), 1.88 (1H, m), 1.84-1.75 (2H, m), 1.65 (1H, m), 1.58-1.36 (5H, m), 1.21 (3H , d), 1.02-0.86 (18H, m), 0.13 (3H, s), 0.11 (3H, s)

[제조예 54][Manufacture example 54]

벤질 4-{(4S,7R,9S)-9-[(1S)-1-({3-[(부틸술포닐)(메틸)아미노]벤조일}아미노)-3-메틸부틸]-4,7,11,11,12,12-헥사메틸-3,6-디옥소-10-옥사-2,5-디아자-11-실라트리덱-1-일}벤조에이트의 제조: benzyl 4-{(4S,7R,9S)-9-[(1S)-1-({3-[(butylsulfonyl)(methyl)amino]benzoyl}amino)-3-methylbutyl]-4,7,11,11,12,12-hexamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl}benzoateBenzyl 4-{(4 S , 7 R , 9 S ) -9-[(1 S ) -1-({3-[(butylsulfonyl) (methyl) amino] benzoyl} amino) -3-methylbutyl] Preparation of -4,7,11,11,12,12-hexamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate: benzyl 4-{(4 S , 7 R , 9 S ) -9-[(1 S ) -1-({3-[(butylsulfonyl) (methyl) amino] benzoyl} amino) -3-methylbutyl] -4,7 , 11,11,12,12-hexamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate

상기 제조예 6에서 얻은 화합물 대신에 상기 제조예 53에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 9와 동일한 방법으로 실시하여, 표제 화합물 113 ㎎을 80% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 53 instead of the compound obtained in Preparation Example 6, it was carried out in the same manner as in Preparation Example 9, it was possible to obtain 113 mg of the title compound in 80% yield.

1H NMR (500 MHz, CDCl3); 8.01 (2H, d), 7.84 (1H, s), 7.58 (2H, m), 7.49-7.29 (8H, m), 6.96 (1H, t), 6.90 (1H, d), 6.29 (1H, d), 5.35 (2H, s), 4.54-4.30 (4H, m), 3.74 (1H, dd), 3.34 (3H, s), 2.97 (2H, dd), 2.53 (1H, m), 1.82- 1.74 (2H, m), 1.72-1.56 (3H, m), 1.54-1.34 (4H, m), 1.17 (3H, d), 1.12 (3H, d), 1.02-0.86 (18H, m), 0.11 (3H, s), 0.09 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 8.01 (2H, d), 7.84 (1H, s), 7.58 (2H, m), 7.49-7.29 (8H, m), 6.96 (1H, t), 6.90 (1H, d), 6.29 (1H, d) , 5.35 (2H, s), 4.54-4.30 (4H, m), 3.74 (1H, dd), 3.34 (3H, s), 2.97 (2H, dd), 2.53 (1H, m), 1.82- 1.74 (2H , m), 1.72-1.56 (3H, m), 1.54-1.34 (4H, m), 1.17 (3H, d), 1.12 (3H, d), 1.02-0.86 (18H, m), 0.11 (3H, s ), 0.09 (3H, s)

[실시예 11]Example 11

4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(부틸술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}프로파노일)아미노]메틸}벤조산의 제조: 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(butylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}propanoyl)amino]methyl}benzoic acid 4 - {[((2 S ) -2 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( butyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy Preparation of Roxy-2,7-dimethyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid: 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5 -({3-[(butylsulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid

상기 제조예 9에서 얻은 화합물 대신에 상기 제조예 54에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 실시하여, 표제 화합물 63 ㎎을 74% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 54 instead of the compound obtained in Preparation Example 9, it was carried out in the same manner as in Example 1, it was obtained 63 mg of the title compound in 74% yield.

1H NMR (500 MHz, CD3OD); 7.96 (2H, d), 7.87 (1H, s), 7.75 (1H, d), 7.60 (1H, d), 7.48 (1H, t), 7.37 (2H, d), 4.44 (2H, s), 4.34 (1H, m), 4.18 (1H, m), 3.60 (1H, m), 3.35 (3H, s), 3.11 (2H, dd), 2.70 (1H, m), 1.84 (1H, m), 1.77-1.61 (4H, m), 1.49-1.38 (4H, m), 1.33 (3H, d), 1.14 (3H, d), 0.96 (3H, d), 0.94 (3H, d), 0.91 (3H, t)1 H NMR (500 MHz, CD3 OD); 7.96 (2H, d), 7.87 (1H, s), 7.75 (1H, d), 7.60 (1H, d), 7.48 (1H, t), 7.37 (2H, d), 4.44 (2H, s), 4.34 (1H, m), 4.18 (1H, m), 3.60 (1H, m), 3.35 (3H, s), 3.11 (2H, dd), 2.70 (1H, m), 1.84 (1H, m), 1.77- 1.61 (4H, m), 1.49-1.38 (4H, m), 1.33 (3H, d), 1.14 (3H, d), 0.96 (3H, d), 0.94 (3H, d), 0.91 (3H, t)

ESI MS (m/e) = 661 [M+H]+
ESI MS (m / e) = 661 [M + H] < + >

[제조예 55][Manufacture example 55]

에틸 3-[(벤질술포닐)아미노]벤조에이트의 제조: ethyl 3- [(benzylsulfonyl)amino]benzoatePreparation of ethyl 3-[(benzylsulfonyl) amino] benzoate: ethyl 3- [(benzylsulfonyl) amino] benzoate

프로판술포닐클로라이드 대신에 -톨루엔술포닐클로라이드를 사용한 것을 제외하고는, 제조예 14와 동일한 방법으로 실시하여, 표제 화합물 2.48 g을 78% 수율로 얻을 수 있었다.Except for using -toluenesulfonylchloride instead of propanesulfonylchloride, the same procedure as in Production Example 14 was carried out to obtain 2.48 g of the title compound in 78% yield.

1H NMR (500 MHz, CDCl3); 7.84 (1H, m), 7.71 (1H, s), 7.44-7.40 (2H, m), 7.38-7.32 (3H, m), 7.29-7.25 (2H, m), 6.36 (1H, s), 4.39 (2H, q), 4.36 (2H, s), 1.41 (3H, t)
1 H NMR (500 MHz, CDCl 3 ); 7.84 (1H, m), 7.71 (1H, s), 7.44-7.40 (2H, m), 7.38-7.32 (3H, m), 7.29-7.25 (2H, m), 6.36 (1H, s), 4.39 ( 2H, q), 4.36 (2H, s), 1.41 (3H, t)

[제조예 56][Manufacture example 56]

3-[(벤질술포닐)(메틸)아미노]벤조산의 제조: 3-[(benzylsulfonyl)(methyl)amino]benzoic acidPreparation of 3-[(benzylsulfonyl) (methyl) amino] benzoic acid: 3-[(benzylsulfonyl) (methyl) amino] benzoic acid

상기 제조예 14에서 얻은 화합물 대신에 상기 제조예 55에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 29와 동일한 방법으로 실시하여, 표제 화합물 2.3 g을 98% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 55 instead of the compound obtained in Preparation Example 14, it was carried out in the same manner as in Preparation Example 29, it was possible to obtain 2.3 g of the title compound in 98% yield.

1H NMR (500 MHz, CD3OD); 7.90-7.86 (2H, m), 7.49-7.32 (7H, m), 4.44 (2H, s), 3.24 (3H, s)
1 H NMR (500 MHz, CD3 OD); 7.90-7.86 (2H, m), 7.49-7.32 (7H, m), 4.44 (2H, s), 3.24 (3H, s)

[제조예 57][Manufacture example 57]

3-[(벤질술포닐)(메틸)아미노]-N-{(1S)-3-메틸-1-[(2R,4R)-4-메틸-5-옥소테트라히 드로-2-퓨라닐]부틸}벤즈아미드의 제조: 3-[(benzylsulfonyl)(methyl)amino]-N-{(1S)-3-methyl-1-[(2R,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butyl}benzamide3 - [(benzyl-sulfonyl) (methyl) amino] - N - {(1 S ) -3- methyl -1 - [(2 R, 4 R) -4- methyl-5-oxo-tetrahydro-2-Hi draw Preparation of furanyl] butyl} benzamide: 3-[(benzylsulfonyl) (methyl) amino] -N -{(1 S ) -3-methyl-1-[(2 R , 4 R ) -4-methyl-5 -oxotetrahydro-2-furanyl] butyl} benzamide

상기 제조예 4에서 얻은 화합물 대신에 상기 제조예 56에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 5와 동일한 방법으로 실시하여, 표제 화합물 0.2 g을 83% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 56 instead of the compound obtained in Preparation Example 4, it was carried out in the same manner as in Preparation Example 5, 0.2 g of the title compound could be obtained in 83% yield.

1H NMR (500 MHz, CDCl3); 7.56 (1H, s), 7.52 (1H, d), 7.43-7.36 (7H,m), 5.93 (1H, d), 4.63 (1H, m), 4.48 (1H, m), 4.31 (2H, s), 3.18 (3H, s), 2.61 (1H, m), 2.43 (1H, m), 2.00 (1H, m), 1.78-1.64 (2H, m), 1.51 (1H, m), 1.26 (3H, d), 0.98 (3H, d), 0.96 (3H, d)
1 H NMR (500 MHz, CDCl 3 ); 7.56 (1H, s), 7.52 (1H, d), 7.43-7.36 (7H, m), 5.93 (1H, d), 4.63 (1H, m), 4.48 (1H, m), 4.31 (2H, s) , 3.18 (3H, s), 2.61 (1H, m), 2.43 (1H, m), 2.00 (1H, m), 1.78-1.64 (2H, m), 1.51 (1H, m), 1.26 (3H, d ), 0.98 (3H, d), 0.96 (3H, d)

[제조예 58]Preparation Example 58

(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-{[tert-부틸(디메틸)실릴]옥시}-2,7-디메틸옥탄산의 제조: (2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,7-dimethyloctanoic acid( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-{[ tert -butyl (dimethyl) silyl] oxy} -2, Preparation of 7-dimethyl-octanoic acid: (2 R, 4 S, 5 S) -5 - ({3 - [(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4 - {[tert -butyl (dimethyl) silyl ] oxy} -2,7-dimethyloctanoic acid

상기 제조예 5에서 얻은 화합물 대신에 상기 제조예 57에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 6과 동일한 방법으로 실시하여, 표제 화합물 0.24 g을 97% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 57 instead of the compound obtained in Preparation Example 5, it was carried out in the same manner as in Preparation Example 6, to obtain 0.24 g of the title compound in 97% yield.

1H NMR (500 MHz, CDCl3); 7.68 (1H, s), 7.55 (1H, d), 7.45-7.33 (7H, m), 6.32 (1H, d), 4.34-4.25 (3H, m), 3.82 (1H, dd), 3.15 (3H, s), 2.66 (1H, m), 1.90 (1H, m), 1.65 (1H, m), 1.58-1.40 (3H, m), 1.21 (3H, d), 0.97 (3H, d), 0.96 (3H, d), 0.91 (9H, s), 0.13 (3H, s), 0.10 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 7.68 (1H, s), 7.55 (1H, d), 7.45-7.33 (7H, m), 6.32 (1H, d), 4.34-4.25 (3H, m), 3.82 (1H, dd), 3.15 (3H, s), 2.66 (1H, m), 1.90 (1H, m), 1.65 (1H, m), 1.58-1.40 (3H, m), 1.21 (3H, d), 0.97 (3H, d), 0.96 (3H , d), 0.91 (9H, s), 0.13 (3H, s), 0.10 (3H, s)

[제조예 59][Manufacture example 59]

벤질 4-{(4S,7R,9S)-9-[(1S)-1-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-3-메틸부틸]-4,7,11,11,12,12-헥사메틸-3,6-디옥소-10-옥사-2,5-디아자-11-실라트리덱-1-일}벤조에이트의 제조: benzyl 4-{(4S,7R,9S)-9-[(1S)-1-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-3-methylbutyl]-4,7,11,11,12,12-hexamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl}benzoateBenzyl 4-{(4 S , 7 R , 9 S ) -9-[(1 S ) -1-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -3-methylbutyl] Preparation of -4,7,11,11,12,12-hexamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate: benzyl 4-{(4 S , 7 R , 9 S ) -9-[(1 S ) -1-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -3-methylbutyl] -4,7 , 11,11,12,12-hexamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate

상기 제조예 6에서 얻은 화합물 대신에 상기 제조예 58에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 9와 동일한 방법으로 실시하여, 표제 화합물 83 ㎎을 73% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 58 instead of the compound obtained in Preparation Example 6, it was carried out in the same manner as in Preparation Example 9, it was obtained 83 mg of the title compound in 73% yield.

1H NMR (500 MHz, CDCl3); 8.01 (2H, d), 7.73 (1H, s), 7.54 (1H, d), 7.45-7.28 (14H, m), 6.93 (1H, t), 6.89 (1H, d), 6.25 (1H, d), 5.35 (2H, s), 4.53-4.30 (4H, m), 4.28 (2H, s), 3.73 (1H, dd), 3.17 (3H, s), 2.54 (1H, m), 1.70-1.56 (3H, m), 1.49 (1H, m), 1.38 (1H, m), 1.16 (3H, d), 1.13 (3H, d), 0.97 (3H, d), 0.96 (3H, d), 0.92 (9H, s), 0.11 (3H, s), 0.09 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 8.01 (2H, d), 7.73 (1H, s), 7.54 (1H, d), 7.45-7.28 (14H, m), 6.93 (1H, t), 6.89 (1H, d), 6.25 (1H, d) , 5.35 (2H, s), 4.53-4.30 (4H, m), 4.28 (2H, s), 3.73 (1H, dd), 3.17 (3H, s), 2.54 (1H, m), 1.70-1.56 (3H , m), 1.49 (1H, m), 1.38 (1H, m), 1.16 (3H, d), 1.13 (3H, d), 0.97 (3H, d), 0.96 (3H, d), 0.92 (9H, s), 0.11 (3H, s), 0.09 (3H, s)

[실시예 12]Example 12

4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}프로파노일)아미노]메틸}벤조산의 제조: 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}propanoyl)amino]methyl}benzoic acid 4 - {[((2 S ) -2 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy Preparation of Roxy-2,7-dimethyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid: 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5 -({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid

상기 제조예 9에서 얻은 화합물 대신에 상기 제조예 59에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 실시하여, 표제 화합물 23 ㎎을 38% 수율로 얻을 수 있었다.23 mg of the title compound could be obtained in 38% yield in the same manner as in Example 1 except that the compound obtained in Preparation Example 59 was used instead of the compound obtained in Preparation Example 9.

1H NMR (500 MHz, CD3OD); 7.95 (2H, d), 7.76 (1H, s), 7.71 (1H, d), 7.44-7.32 (9H, m), 4.46 (2H, s), 4.43 (2H, s), 4.33 (1H, m), 4.18 (1H, m), 3.61 (1H, m), 3.25 (3H, s), 2.70 (1H, m), 1.85 (1H, m), 1.70-1.62 (2H, m), 1.50-1.38 (2H, m), 1.33 (3H, d), 1.14 (3H, d), 0.96 (3H, d), 0.95 (3H, d)1 H NMR (500 MHz, CD3 OD); 7.95 (2H, d), 7.76 (1H, s), 7.71 (1H, d), 7.44-7.32 (9H, m), 4.46 (2H, s), 4.43 (2H, s), 4.33 (1H, m) , 4.18 (1H, m), 3.61 (1H, m), 3.25 (3H, s), 2.70 (1H, m), 1.85 (1H, m), 1.70-1.62 (2H, m), 1.50-1.38 (2H , m), 1.33 (3H, d), 1.14 (3H, d), 0.96 (3H, d), 0.95 (3H, d)

ESI MS (m/e) = 695 [M+H]+
ESI MS (m / e) = 695 [M + H] < + >

[제조예 60]Production Example 60

에틸 3-({[2-(1-나프틸)에틸]술포닐}아미노)벤조에이트의 제조: ethyl 3-({[2-(1-naphthyl)ethyl]sulfonyl}amino)benzoatePreparation of ethyl 3-({[2- (1-naphthyl) ethyl] sulfonyl} amino) benzoate: ethyl 3-({[2- (1-naphthyl) ethyl] sulfonyl} amino) benzoate

프로판술포닐클로라이드 대신에 2-(1-나프틸)에탄술포닐클로라이드를 사용한 것을 제외하고는, 제조예 14와 동일한 방법으로 실시하여, 표제 화합물 0.3 g을 99% 수율로 얻을 수 있었다. 0.3 g of the title compound was obtained in 99% yield by the same method as Preparation Example 14, except that 2- (1-naphthyl) ethanesulfonylchloride was used instead of propanesulfonylchloride.                     

1H NMR (500 MHz, CDCl3); 7.85 (1H, d), 7.80-7.74 (3H, m), 7.56 (1H, s), 7.48-7.29 (5H, m), 7.24 (1H, d), 6.30 (1H, s), 4.38 (2H, q), 3.65-3.44 (4H, m), 1.39 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 7.85 (1H, d), 7.80-7.74 (3H, m), 7.56 (1H, s), 7.48-7.29 (5H, m), 7.24 (1H, d), 6.30 (1H, s), 4.38 (2H, q), 3.65-3.44 (4H, m), 1.39 (3H, s)

[제조예 61]Production Example 61

3-(메틸{[2-(1-나프틸)에틸]술포닐}아미노)벤조산의 제조: 3-(methyl{[2-(1-naphthyl)ethyl]sulfonyl}amino)benzoic acidPreparation of 3- (methyl {[2- (1-naphthyl) ethyl] sulfonyl} amino) benzoic acid: 3- (methyl {[2- (1-naphthyl) ethyl] sulfonyl} amino) benzoic acid

상기 제조예 14에서 얻은 화합물 대신에 상기 제조예 60에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 29와 동일한 방법으로 실시하여, 표제 화합물 0.24 g을 83% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 60 instead of the compound obtained in Preparation Example 14, 0.24 g of the title compound could be obtained in 83% yield in the same manner as in Preparation Example 29.

1H NMR (500 MHz, CD3OD); 8.09 (1H, s), 7.94 (1H, d), 7.89 (1H, d), 7.86 (1H, d), 7.76 (1H, t), 7.67 (1H, d), 7.52-7.44 (3H, m), 7.39 (2H, d), 3.54-3.42 (4H, m), 3.38 (3H, s)
1 H NMR (500 MHz, CD3 OD); 8.09 (1H, s), 7.94 (1H, d), 7.89 (1H, d), 7.86 (1H, d), 7.76 (1H, t), 7.67 (1H, d), 7.52-7.44 (3H, m) , 7.39 (2H, d), 3.54-3.42 (4H, m), 3.38 (3H, s)

[제조예 62]Production Example 62

N-{(1S)-3-메틸-1-[(2R,4R)-4-메틸-5-옥소테트라히드로-2-퓨라닐]부틸}-3-(메틸{[2-(1-나프틸)에틸]술포닐}아미노)벤즈아미드의 제조: N-{(1S)-3-methyl-1-[(2R,4R )-4-methyl-5-oxotetrahydro-2-furanyl]butyl}-3-(methyl{[2-(1-naphthyl)ethyl]sulfonyl}amino)benzamide N - {(1 S) -3-methyl -1 - [(2 R, 4 R) -4- methyl-5-oxo-tetrahydro-2-furanyl] butyl} -3- (methyl {[2- ( Preparation of 1-naphthyl) ethyl] sulfonyl} amino) benzamide: N -{(1 S ) -3-methyl-1-[(2 R , 4 R ) -4-methyl-5-oxotetrahydro-2- furanyl] butyl} -3- (methyl {[2- (1-naphthyl) ethyl] sulfonyl} amino) benzamide

상기 제조예 4에서 얻은 화합물 대신에 상기 제조예 61에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 5와 동일한 방법으로 실시하여, 표제 화합물 0.28 g을 97% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 61 instead of the compound obtained in Preparation Example 4, it was carried out in the same manner as in Preparation Example 5, 0.28 g of the title compound could be obtained in 97% yield.

1H NMR (500 MHz, CDCl3); 7.91 (1H, d), 7.86 (1H, d), 7.83 (1H, s), 7.76 (1H, d), 7.60 (1H, d), 7.57 (1H, d), 7.55-7.42 (3H, m), 7.39 (1H, t), 7.34 (1H, d), 6.13 (1H, d), 4.62 (1H, m), 4.46 (1H, m), 3.63-3.55 (2H, m), 3.41 (3H, s), 3.38-3.32 (2H, m), 2.58 (1H, m), 2.40 (1H, m), 1.97 (1H, m), 1.78-1.58 (2H, m), 1.48 (1H, m), 1.22 (3H, d), 0.94 (6H, d)
1 H NMR (500 MHz, CDCl 3 ); 7.91 (1H, d), 7.86 (1H, d), 7.83 (1H, s), 7.76 (1H, d), 7.60 (1H, d), 7.57 (1H, d), 7.55-7.42 (3H, m) , 7.39 (1H, t), 7.34 (1H, d), 6.13 (1H, d), 4.62 (1H, m), 4.46 (1H, m), 3.63-3.55 (2H, m), 3.41 (3H, s ), 3.38-3.32 (2H, m), 2.58 (1H, m), 2.40 (1H, m), 1.97 (1H, m), 1.78-1.58 (2H, m), 1.48 (1H, m), 1.22 ( 3H, d), 0.94 (6H, d)

[제조예 63][Production Example 63]

(2R,4S,5S)-4-{[tert-부틸(디메틸)실릴]옥시}-2,7-디메틸-5-{[3-(메틸{[2-(1-나프틸)에틸]술포닐}아미노)벤조일]아미노}옥탄산의 제조: (2R,4S,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,7-dimethyl-5-{[3-(methyl{[2-(1-naphthyl)ethyl]sulfonyl}amino)benzoyl]amino}octanoic acid (2 R, 4 S, 5 S) -4 - {[tert - butyl (dimethyl) silyl] oxy} 2,7-dimethyl-5 - {[3- ({[2- (1-naphthyl) ethyl] sulfonyl} amino) benzoyl] amino} octanoic acid Preparation of: (2 R, 4 S, 5 S) -4 - {[tert -butyl (dimethyl) silyl] oxy} -2,7-dimethyl-5- {[3- (methyl {[2- (1-naphthyl) ethyl] sulfonyl} amino) benzoyl] amino} octanoic acid

상기 제조예 5에서 얻은 화합물 대신에 상기 제조예 62에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 6과 동일한 방법으로 실시하여, 표제 화합물 0.31 g을 93% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 62 instead of the compound obtained in Preparation Example 5, in the same manner as in Preparation Example 6, 0.31 g of the title compound could be obtained in 93% yield.

1H NMR (500 MHz, CDCl3); 7.91 (1H, d), 7.86 (1H, d), 7.82 (1H, s), 7.75 (1H, d), 7.62 (1H, d), 7.57 (1H, d), 7.55-7.42 (3H, m), 7.39 (1H, t), 7.33 (1H, d), 6.36 (1H, d), 4.26 (1H, m), 3.80 (1H, dd), 3.62-3.54 (2H, m), 3.40 (3H, s), 3.37-3.31 (2H, m), 2.63 (1H, m), 1.87 (1H, m), 1.63 (1H, m), 1.54-1.37 (3H, m), 1.18 (3H, d), 0.95 (3H, d), 0.94 (3H, d), 0.90 (9H, s), 0.12 (3H, s), 0.09 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 7.91 (1H, d), 7.86 (1H, d), 7.82 (1H, s), 7.75 (1H, d), 7.62 (1H, d), 7.57 (1H, d), 7.55-7.42 (3H, m) , 7.39 (1H, t), 7.33 (1H, d), 6.36 (1H, d), 4.26 (1H, m), 3.80 (1H, dd), 3.62-3.54 (2H, m), 3.40 (3H, s ), 3.37-3.31 (2H, m), 2.63 (1H, m), 1.87 (1H, m), 1.63 (1H, m), 1.54-1.37 (3H, m), 1.18 (3H, d), 0.95 ( 3H, d), 0.94 (3H, d), 0.90 (9H, s), 0.12 (3H, s), 0.09 (3H, s)

[제조예 64]Preparation Example 64

벤질 4-[(4S,7R,9S)-4,7,11,11,12,12-헥사메틸-9-((1S)-3-메틸-1-{[3-(메틸{[2-(1-나프틸)에틸]술포닐}아미노)벤조일]아미노}부틸)-3,6-디옥소-10-옥사-2,5-디아자-11-실라트리덱-1-일]벤조에이트의 제조: benzyl 4-[(4S,7R,9S)-4,7,11,11,12,12-hexamethyl-9-((1S)-3-methyl-1-{[3-(methyl{[2-(1-naphthyl)ethyl]sulfonyl}amino)benzoyl]amino}butyl)-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl]benzoateBenzyl 4-[(4 S , 7 R , 9 S ) -4,7,11,11,12,12-hexamethyl-9-((1 S ) -3-methyl-1-{[3- (methyl {[2- (1-naphthyl) ethyl] sulfonyl} amino) benzoyl] amino} butyl) -3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1- Preparation of benzoate: benzyl 4-[(4 S , 7 R , 9 S ) -4,7,11,11,12,12-hexamethyl-9-((1 S ) -3-methyl-1- {[3- (methyl {[2- (1-naphthyl) ethyl] sulfonyl} amino) benzoyl] amino} butyl) -3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1- yl] benzoate

상기 제조예 6에서 얻은 화합물 대신에 상기 제조예 63에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 9와 동일한 방법으로 실시하여, 표제 화합물 108 ㎎을 84% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 63 instead of the compound obtained in Preparation Example 6, it was carried out in the same manner as in Preparation Example 9, 108 mg of the title compound could be obtained in 84% yield.

1H NMR (500 MHz, CDCl3); 8.00 (2H, d), 7.93-7.83 (3H, m), 7.74 (1H, d), 7.62-7.56 (2H, m), 7.53-7.30 (10H, m), 7.28 (2H, d), 6.86 (1H, d), 6.85 (1H, t), 6.30 (1H, d), 5.35 (2H, s), 4.50-4.34 (3H, m), 4.26 (1H, m), 3.73 (1H, dd), 3.60-3.54 (2H, m), 3.38 (3H, s), 3.36-3.30 (2H, m), 2.51 (1H, m), 1.66- 1.54 (2H, m), 1.47 (1H, m), 1.37 (1H, m), 1.25 (1H, m), 1.11 (3H, d), 1.08 (3H, d), 0.94 (3H, d), 0.93 (3H, d), 0.90 (9H, s), 0.10 (3H, s), 0.08 (3H, s)
1 H NMR (500 MHz, CDCl 3 ); 8.00 (2H, d), 7.93-7.83 (3H, m), 7.74 (1H, d), 7.62-7.56 (2H, m), 7.53-7.30 (10H, m), 7.28 (2H, d), 6.86 ( 1H, d), 6.85 (1H, t), 6.30 (1H, d), 5.35 (2H, s), 4.50-4.34 (3H, m), 4.26 (1H, m), 3.73 (1H, dd), 3.60 -3.54 (2H, m), 3.38 (3H, s), 3.36-3.30 (2H, m), 2.51 (1H, m), 1.66- 1.54 (2H, m), 1.47 (1H, m), 1.37 (1H , m), 1.25 (1H, m), 1.11 (3H, d), 1.08 (3H, d), 0.94 (3H, d), 0.93 (3H, d), 0.90 (9H, s), 0.10 (3H, s), 0.08 (3H, s)

[실시예 13]Example 13

4-[({(2S)-2-[((2R,4S,5S)-4-히드록시-2,7-디메틸-5-{[3-(메틸{[2-(1-나프틸)에틸]술포닐}아미노)벤조일]아미노}옥타노일)아미노]프로파노일}아미노)메틸]벤조산의 제조: 4-[({(2S)-2-[((2R,4S,5S)-4-hydroxy-2,7-dimethyl-5-{[3-(methyl{[2-(1-naphthyl)ethyl]sulfonyl}amino)benzoyl]amino}octanoyl)amino]propanoyl}amino)methyl]benzoic acid4-[({(2 S ) -2-[((2 R , 4 S , 5 S ) -4-hydroxy-2,7-dimethyl-5-{[3- (methyl {[2- (1 Preparation of -naphthyl) ethyl] sulfonyl} amino) benzoyl] amino} octanoyl) amino] propanoyl} amino) methyl] benzoic acid: 4-[({( 2S ) -2-[(( 2R , 4 S , 5 S ) -4-hydroxy-2,7-dimethyl-5-{[3- (methyl {[2- (1-naphthyl) ethyl] sulfonyl} amino) benzoyl] amino} octanoyl) amino] propanoyl} amino) methyl] benzoic acid

상기 제조예 9에서 얻은 화합물 대신에 상기 제조예 64에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 실시하여, 표제 화합물 41 ㎎을 58% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 64 instead of the compound obtained in Preparation Example 9, the title compound was obtained in 58% yield in the same manner as in Example 1.

1H NMR (500 MHz, CD3OD); 7.98-7.84 (5H, m), 7.79-7.73 (2H, m), 7.62 (1H, d), 7.53-7.44 (3H, m),7.38 (2H, d), 7.35 (2H, d), 4.42 (2H, s), 4.31 (1H, m), 4.17 (1H, m), 3.59 (1H, m), 3.55-3.42 (4H, m), 3.39 (3H, s), 2.68 (1H, m), 1.81 (1H, m), 1.70-1.58 (2H, m), 1.48-1.36 (2H, m), 1.28 (3H, d), 1.10 (3H, d), 0.93 (6H, d)1 H NMR (500 MHz, CD3 OD); 7.98-7.84 (5H, m), 7.79-7.73 (2H, m), 7.62 (1H, d), 7.53-7.44 (3H, m), 7.38 (2H, d), 7.35 (2H, d), 4.42 ( 2H, s), 4.31 (1H, m), 4.17 (1H, m), 3.59 (1H, m), 3.55-3.42 (4H, m), 3.39 (3H, s), 2.68 (1H, m), 1.81 (1H, m), 1.70-1.58 (2H, m), 1.48-1.36 (2H, m), 1.28 (3H, d), 1.10 (3H, d), 0.93 (6H, d)

ESI MS (m/e) = 759 [M+H]+
ESI MS (m / e) = 759 [M + H] < + >

[제조예 65] Preparation Example 65                     

3-[메틸(2-치에닐술포닐)아미노]벤조산의 제조: 3-[methyl(2-thienylsulfonyl)amino]benzoic acidPreparation of 3- [methyl (2-thienylsulfonyl) amino] benzoic acid: 3- [methyl (2-thienylsulfonyl) amino] benzoic acid

상기 제조예 14에서 얻은 화합물 대신에 상기 제조예 24에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 29와 동일한 방법으로 실시하여, 표제 화합물 0.2 g을 95% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 24 instead of the compound obtained in Preparation Example 14, it was carried out in the same manner as in Preparation Example 29, it was possible to obtain 0.2 g of the title compound in 95% yield.

1H NMR (400 MHz, CDCl3); 8.01 (1H, d), 7.75 (1H, s), 7.61 (1H, d), 7.59 (1H, d), 7.46 (1H, t), 7.34 (1H, d), 7.10 (1H, dd), 3.28 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 8.01 (1H, d), 7.75 (1H, s), 7.61 (1H, d), 7.59 (1H, d), 7.46 (1H, t), 7.34 (1H, d), 7.10 (1H, dd), 3.28 (3H, s)

[실시예 14]Example 14

N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸)-3-[메틸(2-치에닐술포닐)아미노]벤즈아미드의 제조: N-((1S,2S,4R)-5-{[(1S)-2-(benzylamino)-1-methyl-2-oxoethyl]amino}-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl)-3-[methyl(2-thienylsulfonyl)amino]benzamide N -(( 1S , 2S , 4R ) -5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1-iso Preparation of Butyl-4-methyl-5-oxopentyl) -3- [methyl (2-chienylsulfonyl) amino] benzamide: N -((1 S , 2 S , 4 R ) -5-{[( 1 S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl) -3- [methyl (2-thienylsulfonyl) amino] benzamide

1-메틸-2,2,4-트리옥소-테트라히드로-2λ6,1-벤조치아진-7-카르복실산 대신에 상기 제조예 65에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 2와 동일한 방법으로 실시하여, 표제 화합물 74 ㎎을 57% 수율로 얻을 수 있었다.Example 2 except that the compound obtained in Preparation Example 65 was used instead of 1-methyl-2,2,4-trioxo-tetrahydro-2λ 6 , 1-benzothiazin-7-carboxylic acid. By the same procedure, 74 mg of the title compound was obtained in 57% yield.

1H NMR (400 MHz, CDCl3); 7.79 (1H, d), 7.60 (1H, d), 7.54 (1H, s), 7.43-7.21 (8H, m), 7.09 (1H, dd), 6.56 (1H, d), 6.51 (1H, t), 6.39 (1H, d), 4.46-4.36 (3H, m), 4.11 (1H, m), 3.86 (1H, br), 3.75 (1H, m), 3.25 (3H, s), 2.64 (1H, m), 1.78-1.55 (4H, m), 1.42 (1H, m), 1.32 (3H, d), 1.17 (3H, d), 0.95 (3H, d), 0.93 (3H, d)1 H NMR (400 MHz, CDCl 3 ); 7.79 (1H, d), 7.60 (1H, d), 7.54 (1H, s), 7.43-7.21 (8H, m), 7.09 (1H, dd), 6.56 (1H, d), 6.51 (1H, t) , 6.39 (1H, d), 4.46-4.36 (3H, m), 4.11 (1H, m), 3.86 (1H, br), 3.75 (1H, m), 3.25 (3H, s), 2.64 (1H, m ), 1.78-1.55 (4H, m), 1.42 (1H, m), 1.32 (3H, d), 1.17 (3H, d), 0.95 (3H, d), 0.93 (3H, d)

ESI MS (m/e) = 643 [M+H]+
ESI MS (m / e) = 643 [M + H] < + >

[제조예 66]Production Example 66

3-[메틸(페닐술포닐)아미노]벤조산의 제조: 3-[methyl(phenylsulfonyl)amino]benzoic acidPreparation of 3- [methyl (phenylsulfonyl) amino] benzoic acid: 3- [methyl (phenylsulfonyl) amino] benzoic acid

상기 제조예 14에서 얻은 화합물 대신에 상기 제조예 19에서 얻은 화합물을 사용한 것을 제외하고는 제조예 29와 동일한 방법으로 실시하여, 표제 화합물 0.2 g을 92% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 19 instead of the compound obtained in Preparation Example 14 in the same manner as in Preparation Example 29, 0.2 g of the title compound could be obtained in 92% yield.

1H NMR (400 MHz, CDCl3); 8.01 (1H, d), 7.71 (1H, s), 7.61 (1H, t), 7.58-7.42 (6H, m), 3.22 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 8.01 (1H, d), 7.71 (1H, s), 7.61 (1H, t), 7.58-7.42 (6H, m), 3.22 (3H, s)

[실시예 15]Example 15

N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸)-3-[메틸(페닐술포닐)아미노]벤즈아미드의 제조: N-((1S,2S,4R)-5-{[(1S)-2-(benzylamino)-1-methyl-2-oxoethyl]amino}-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl)-3-[methyl(phenylsulfonyl)amino]benzamide N -(( 1S , 2S , 4R ) -5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1-iso Preparation of Butyl-4-methyl-5-oxopentyl) -3- [methyl (phenylsulfonyl) amino] benzamide: N -((1 S , 2 S , 4 R ) -5-{[(1 S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl) -3- [methyl (phenylsulfonyl) amino] benzamide

1-메틸-2,2,4-트리옥소-테트라히드로-2λ6,1-벤조치아진-7-카르복실산 대신에 상기 제조예 66에서 얻은 화합물을 사용한 것을 제외하고는 실시예 2와 동일한 방법으로 실시하여, 표제 화합물 71 ㎎을 56% 수율로 얻을 수 있었다.Same as Example 2 except that the compound obtained in Preparation Example 66 was used instead of 1-methyl-2,2,4-trioxo-tetrahydro-2λ 6 , 1-benzothiazin-7-carboxylic acid. By the method, 71 mg of the title compound was obtained in 56% yield.

1H NMR (500 MHz, CDCl3); 7.67 (1H, d), 7.58 (1H, t), 7.54 (2H, d), 7.49 (1H, s), 7.45 (2H, t), 7.35 (1H, t), 7.29 (2H, d), 7.27-7.20 (4H, m), 6.65 (1H, d), 6.62 (1H, t), 6.40 (1H, d), 4.43 (1H, m), 4.39 (2H, d), 4.10 (1H, m), 3.92 (1H, d), 3.73 (1H, m), 3.17 (3H, s), 2.63 (1H, m), 1.76-1.58 (4H, m), 1.40 (1H, m), 1.31 (3H, d), 1.15 (3H, d), 0.93 (3H, d), 0.92 (3H, d)1 H NMR (500 MHz, CDCl 3 ); 7.67 (1H, d), 7.58 (1H, t), 7.54 (2H, d), 7.49 (1H, s), 7.45 (2H, t), 7.35 (1H, t), 7.29 (2H, d), 7.27 -7.20 (4H, m), 6.65 (1H, d), 6.62 (1H, t), 6.40 (1H, d), 4.43 (1H, m), 4.39 (2H, d), 4.10 (1H, m), 3.92 (1H, d), 3.73 (1H, m), 3.17 (3H, s), 2.63 (1H, m), 1.76-1.58 (4H, m), 1.40 (1H, m), 1.31 (3H, d) , 1.15 (3H, d), 0.93 (3H, d), 0.92 (3H, d)

ESI MS (m/e) = 637 [M+H]+
ESI MS (m / e) = 637 [M + H] < + >

[제조예 67]Preparation Example 67

에틸 3-[(1-나프틸술포닐)아미노]벤조에이트의 제조: ethyl 3-[(1-naphthylsulfonyl)amino]benzoatePreparation of ethyl 3-[(1-naphthylsulfonyl) amino] benzoate: ethyl 3-[(1-naphthylsulfonyl) amino] benzoate

벤젠술포닐클로라이드 대신에 1-나프탈렌술포닐클로라이드를 사용한 것을 제외하고는, 제조예 19와 동일한 방법으로 실시하여, 표제 화합물 0.53 g을 74% 수율로 얻을 수 있었다.Except for using 1-naphthalenesulfonylchloride instead of benzenesulfonylchloride, the same procedure as in Production Example 19 was carried out to obtain 0.53 g of the title compound in 74% yield.

1H NMR (400 MHz, CDCl3); 8.67 (1H, d), 8.22 (1H, d), 8.04 (1H, d), 7.94 (1H, d)7.74-7.65 (2H, m), 7.61 (1H, t), 7.52 (1H, s), 7.48 (1H, t), 7.24-7.18 (2H, m), 6.89 (1H, s), 4.29 (2H, q), 1.32 (3H, t)
1 H NMR (400 MHz, CDCl 3 ); 8.67 (1H, d), 8.22 (1H, d), 8.04 (1H, d), 7.94 (1H, d) 7.4-7.65 (2H, m), 7.61 (1H, t), 7.52 (1H, s), 7.48 (1H, t), 7.24-7.18 (2H, m), 6.89 (1H, s), 4.29 (2H, q), 1.32 (3H, t)

[제조예 68][Manufacture example 68]

3-[메틸(1-나프틸술포닐)아미노]벤조산의 제조: 3-[methyl(1-naphthylsulfonyl)amino]benzoic acidPreparation of 3- [methyl (1-naphthylsulfonyl) amino] benzoic acid: 3- [methyl (1-naphthylsulfonyl) amino] benzoic acid

상기 제조예 14에서 얻은 화합물 대신에 상기 제조예 67에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 29와 동일한 방법으로 실시하여, 표제 화합물 0.17 g을 100% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 67 instead of the compound obtained in Preparation Example 14, 0.17 g of the title compound could be obtained in 100% yield in the same manner as in Preparation Example 29.

1H NMR (400 MHz, CDCl3); 8.28 (1H, d), 8.13 (1H, d), 8.07 (1H, d), 7.96 (1H, d), 7.90 (1H, d), 7.70 (1H, s), 7.55-7.35 (5H, m), 3.25 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 8.28 (1H, d), 8.13 (1H, d), 8.07 (1H, d), 7.96 (1H, d), 7.90 (1H, d), 7.70 (1H, s), 7.55-7.35 (5H, m) , 3.25 (3H, s)

[실시예 16]Example 16

N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸)-3-[메틸(1-나프틸술포닐)아미노]벤즈아미드의 제조: N-((1S,2S,4R)-5-{[(1S)-2-(benzylamino)-1-methyl-2-oxoethyl]amino}-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl)-3-[methyl(1-naphthylsulfonyl)amino]benzamide N -(( 1S , 2S , 4R ) -5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1-iso Preparation of Butyl-4-methyl-5-oxopentyl) -3- [methyl (1-naphthylsulfonyl) amino] benzamide: N -((1 S , 2 S , 4 R ) -5-{[(1 S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl) -3- [methyl (1-naphthylsulfonyl) amino] benzamide

1-메틸-2,2,4-트리옥소-테트라히드로-2λ6,1-벤조치아진-7-카르복실산 대신에 상기 제조예 68에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 2와 동일한 방법으로 실시하여, 표제 화합물 72 ㎎을 53% 수율로 얻을 수 있었다.Example 2 except that the compound obtained in Preparation Example 68 was used instead of 1-methyl-2,2,4-trioxo-tetrahydro-2λ 6 , 1-benzothiazin-7-carboxylic acid. By the same procedure, 72 mg of the title compound was obtained in 53% yield.

1H NMR (400 MHz, CDCl3); 8.28 (1H, d), 8.11 (1H, d), 8.06 (1H, d), 7.89 (1H, d), 7.64 (1H, d), 7.54-7.36 (4H, m), 7.34-7.20 (7H, m), 6.70-6.62 (2H, m), 6.28 (1H, d), 4.44 (1H, m), 4.39 (2H, d), 4.06 (1H, m), 3.91 (1H, br), 3.48 (1H, m), 3.22 (3H, s), 2.63 (1H, m), 1.75-1.52 (4H, m), 1.38 (1H, m), 1.30 (3H, d), 1.15 (3H, d), 0.92 (6H, d)1 H NMR (400 MHz, CDCl 3 ); 8.28 (1H, d), 8.11 (1H, d), 8.06 (1H, d), 7.89 (1H, d), 7.64 (1H, d), 7.54-7.36 (4H, m), 7.34-7.20 (7H, m), 6.70-6.62 (2H, m), 6.28 (1H, d), 4.44 (1H, m), 4.39 (2H, d), 4.06 (1H, m), 3.91 (1H, br), 3.48 (1H , m), 3.22 (3H, s), 2.63 (1H, m), 1.75-1.52 (4H, m), 1.38 (1H, m), 1.30 (3H, d), 1.15 (3H, d), 0.92 ( 6H, d)

ESI MS (m/e) = 687 [M+H]+
ESI MS (m / e) = 687 [M + H] < + >

[제조예 69][Production Example 69]

에틸 3-[(2-나프틸술포닐)아미노]벤조에이트의 제조: ethyl 3-[(2-naphthylsulfonyl)amino]benzoatePreparation of ethyl 3-[(2-naphthylsulfonyl) amino] benzoate: ethyl 3-[(2-naphthylsulfonyl) amino] benzoate

벤젠술포닐클로라이드 대신에 2-나프탈렌술포닐클로라이드를 사용한 것을 제외하고는, 제조예 19와 동일한 방법으로 실시하여, 표제 화합물 0.57 g을 81% 수율로 얻을 수 있었다.Except for using 2-naphthalenesulfonylchloride instead of benzenesulfonylchloride, the same procedure as in Production Example 19 was carried out to obtain 0.57 g of the title compound in 81% yield.

1H NMR (400 MHz, CDCl3); 8.39 (1H, s), 7.89 (2H,d), 7.87 (1H, d), 7.75 (2H, t), 7.68 (1H, s), 7.66-7.56 (2H, m), 7.41 (1H, d), 7.31 (1H, t), 6.85 (1H, s), 4.32 (2H, q), 1.33 (3H, t)
1 H NMR (400 MHz, CDCl 3 ); 8.39 (1H, s), 7.89 (2H, d), 7.87 (1H, d), 7.75 (2H, t), 7.68 (1H, s), 7.66-7.56 (2H, m), 7.41 (1H, d) , 7.31 (1H, t), 6.85 (1H, s), 4.32 (2H, q), 1.33 (3H, t)

[제조예 70][Manufacture example 70]

3-[메틸(2-나프틸술포닐)아미노]벤조산의 제조: 3-[methyl(2-naphthylsulfonyl)amino]benzoic acidPreparation of 3- [methyl (2-naphthylsulfonyl) amino] benzoic acid: 3- [methyl (2-naphthylsulfonyl) amino] benzoic acid

상기 제조예 14에서 얻은 화합물 대신에 상기 제조예 69에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 29와 동일한 방법으로 실시하여, 표제 화합물 0.17 g을 99% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 69 instead of the compound obtained in Preparation Example 14, 0.17 g of the title compound could be obtained in 99% yield in the same manner as in Preparation Example 29.

1H NMR (400 MHz, CDCl3); 8.21 (1H, s), 8.01 (1H, d), 7.90 (3H, t), 7.76 (1H, s), 7.68-7.56 (2H, m), 7.53-7.41 (3H, m), 3.25 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 8.21 (1H, s), 8.01 (1H, d), 7.90 (3H, t), 7.76 (1H, s), 7.68-7.56 (2H, m), 7.53-7.41 (3H, m), 3.25 (3H, s)

[실시예 17]Example 17

N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-베틸-2-옥소에틸]아미노}-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸)-3-[메틸(2-나프틸술포닐)아미노]벤즈아미드의 제조: N-((1S,2S,4R)-5-{[(1S)-2-(benzylamino)-1-methyl-2-oxoethyl]amino}-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl)-3-[methyl(2-naphthylsulfonyl)amino]benzamide N - ((1 S, 2 S, 4 R) -5 - {[(1 S) -2- ( benzylamino) -1-betil-oxoethyl] amino} -2-hydroxy-1-isopropyl Preparation of Butyl-4-methyl-5-oxopentyl) -3- [methyl (2-naphthylsulfonyl) amino] benzamide: N -((1 S , 2 S , 4 R ) -5-{[(1 S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl) -3- [methyl (2-naphthylsulfonyl) amino] benzamide

1-메틸-2,2,4-트리옥소-테트라히드로-2λ6,1-벤조치아진-7-카르복실산 대신에 상기 제조예 70에서 얻은 화합물을 사용한 것을 제외하고는 실시예 2와 동일한 방법으로 실시하여, 표제 화합물 78 ㎎을 57% 수율로 얻을 수 있었다.Same as Example 2, except that the compound obtained in Preparation Example 70 was used instead of 1-methyl-2,2,4-trioxo-tetrahydro-2λ 6 , 1-benzothiazin-7-carboxylic acid. By the method, 78 mg of the title compound was obtained in 57% yield.

1H NMR (400 MHz, CDCl3); 8.20 (1H, s), 7.89 (3H, t), 7.72-7.56 (4H, m), 7.46 (1H, d), 7.38-7.18 (7H, m), 6.66 (1H, d), 6.63 (1H, t), 6.44 (1H, d), 4.42 (1H, m), 4.40 (2H, d), 4.10 (1H, m), 3.87 (1H, br), 3.71 (1H, m), 3.22 (3H, s), 2.63 (1H, m), 1.74-1.56 (4H, m), 1.39 (1H, m), 1.31 (3H, d), 1.15 (3H, d), 0.92 (3H, d), 0.90 (3H, d)1 H NMR (400 MHz, CDCl 3 ); 8.20 (1H, s), 7.89 (3H, t), 7.72-7.56 (4H, m), 7.46 (1H, d), 7.38-7.18 (7H, m), 6.66 (1H, d), 6.63 (1H, t), 6.44 (1H, d), 4.42 (1H, m), 4.40 (2H, d), 4.10 (1H, m), 3.87 (1H, br), 3.71 (1H, m), 3.22 (3H, s ), 2.63 (1H, m), 1.74-1.56 (4H, m), 1.39 (1H, m), 1.31 (3H, d), 1.15 (3H, d), 0.92 (3H, d), 0.90 (3H, d)

ESI MS (m/e) = 687 [M+H]+
ESI MS (m / e) = 687 [M + H] < + >

[제조예 71]Preparation Example 71

에틸 3-({[5-(디메틸아미노)-1-나프틸]술포닐}아미노)벤조에이트의 제조: ethyl 3-({[5-(dimethylamino)-1-naphthyl]sulfonyl}amino)benzoatePreparation of ethyl 3-({[5- (dimethylamino) -1-naphthyl] sulfonyl} amino) benzoate: ethyl 3-({[5- (dimethylamino) -1-naphthyl] sulfonyl} amino) benzoate

벤젠술포닐클로라이드 대신에 단실클로라이드를 사용한 것을 제외하고는 제조예 19와 동일한 방법으로 실시하여, 표제 화합물 0.31 g을 79% 수율로 얻을 수 있었다.0.31 g of the title compound was obtained in 79% yield, using the same method as in Preparation Example 19, except that monosil chloride was used instead of benzenesulfonyl chloride.

1H NMR (400 MHz, CDCl3); 8.50 (1H, d), 8.32 (1H, d), 8.21 (1H, d), 7.69 (1H, t), 7.58 (1H, t), 7.54 (1H, s), 7.44 (1H, t), 7.27-7.17 (3H, m), 6.95 (1H, s), 4.30 (2H, q), 2.87 (6H, s), 1.33 (3H, t)
1 H NMR (400 MHz, CDCl 3 ); 8.50 (1H, d), 8.32 (1H, d), 8.21 (1H, d), 7.69 (1H, t), 7.58 (1H, t), 7.54 (1H, s), 7.44 (1H, t), 7.27 -7.17 (3H, m), 6.95 (1H, s), 4.30 (2H, q), 2.87 (6H, s), 1.33 (3H, t)

[제조예 72][Manufacture example 72]

3-[{[5-(디메틸아미노)-1-나프틸]술포닐}(메틸)아미노]벤조산의 제조: 3-[{[5-(dimethylamino)-1-naphthyl]sulfonyl}(methyl)amino]benzoic acidPreparation of 3-[{[5- (dimethylamino) -1-naphthyl] sulfonyl} (methyl) amino] benzoic acid: 3-[{[5- (dimethylamino) -1-naphthyl] sulfonyl} (methyl) amino ] benzoic acid

상기 제조예 14에서 얻은 화합물 대신에 상기 제조예 71에서 얻은 화합물을 사용한 것을 제외하고는 제조예 29와 동일한 방법으로 실시하여, 표제 화합물 0.25 g을 87% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 71 instead of the compound obtained in Preparation Example 14 in the same manner as in Preparation Example 29, 0.25 g of the title compound could be obtained in 87% yield.

1H NMR (400 MHz, CDCl3); 8.55 (1H, d), 8.11 (1H, d), 7.99 (1H, d), 7.95 (1H, d), 7.70 (1H, s), 7.54-7.44 (2H, m), 7.39 (1H, t), 7.33 (1H, dd), 7.12 (1H, d), 3.26 (3H, s), 2.87 (6H, s)
1 H NMR (400 MHz, CDCl 3 ); 8.55 (1H, d), 8.11 (1H, d), 7.99 (1H, d), 7.95 (1H, d), 7.70 (1H, s), 7.54-7.44 (2H, m), 7.39 (1H, t) , 7.33 (1H, dd), 7.12 (1H, d), 3.26 (3H, s), 2.87 (6H, s)

[실시예 18]Example 18

N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸)-3-[{[5-(디메틸아미노)-1-나프틸]술포닐}(메틸)아미노]벤즈아미드의 제조: N-((1S,2S,4R)-5-{[(1S)-2-(benzylamino)-1-methyl-2-oxoethyl]amino}-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl)-3-[{[5-(dimethylamino)-1-naphthyl]sulfonyl}(methyl)amino]benzamide N -(( 1S , 2S , 4R ) -5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1-iso Preparation of Butyl-4-methyl-5-oxopentyl) -3-[{[5- (dimethylamino) -1-naphthyl] sulfonyl} (methyl) amino] benzamide: N -((1 S , 2 S , 4 R ) -5-{[(1 S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl) -3 -[{[5- (dimethylamino) -1-naphthyl] sulfonyl} (methyl) amino] benzamide

1-메틸-2,2,4-트리옥소-테트라히드로-2λ6,1-벤조치아진-7-카르복실산 대신에 상기 제조예 72에서 얻은 화합물을 사용한 것을 제외하고는 실시예 2와 동일한 방법으로 실시하여, 표제 화합물 69 ㎎을 47% 수율로 얻을 수 있었다.Same as Example 2, except that the compound obtained in Preparation Example 72 was used instead of 1-methyl-2,2,4-trioxo-tetrahydro-2λ 6 , 1-benzothiazine-7-carboxylic acid. By the method, 69 mg of the title compound was obtained in 47% yield.

1H NMR (400 MHz, CDCl3); 8.54 (1H, d), 8.09 (1H, d), 8.00 (1H, d), 7.65 (1H, d), 7.58 (1H, s), 7.46 (1H, t), 7.38-7.20 (8H, m), 7.11 (1H, d), 6.76 (1H, s), 6.75 (1H, s), 6.43 (1H, s), 4.43 (1H, m), 4.38 (2H, d), 4.09 (1H, m), 3.97 (1H, br), 3.71 (1H, m), 3.22 (3H, s), 2.87 (6H, s), 2.63 (1H, m), 1.74-1.56 (4H, m), 1.40 (1H, m), 1.29 (3H, d), 1.14 (3H, d), 0.93 (6H, d)1 H NMR (400 MHz, CDCl 3 ); 8.54 (1H, d), 8.09 (1H, d), 8.00 (1H, d), 7.65 (1H, d), 7.58 (1H, s), 7.46 (1H, t), 7.38-7.20 (8H, m) , 7.11 (1H, d), 6.76 (1H, s), 6.75 (1H, s), 6.43 (1H, s), 4.43 (1H, m), 4.38 (2H, d), 4.09 (1H, m), 3.97 (1H, br), 3.71 (1H, m), 3.22 (3H, s), 2.87 (6H, s), 2.63 (1H, m), 1.74-1.56 (4H, m), 1.40 (1H, m) , 1.29 (3H, d), 1.14 (3H, d), 0.93 (6H, d)

ESI MS (m/e) = 730 [M+H]+
ESI MS (m / e) = 730 [M + H] < + >

[제조예 73] Preparation Example 73                     

에틸 3-({[2-(아세틸아미노)-4-메틸-1,3-치아졸-5-일]술포닐}아미노)벤조에이트의 제조: ethyl 3-({[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]sulfonyl}amino)benzoatePreparation of ethyl 3-({[2- (acetylamino) -4-methyl-1,3-thiazol-5-yl] sulfonyl} amino) benzoate: ethyl 3-({[2- (acetylamino)- 4-methyl-1,3-thiazol-5-yl] sulfonyl} amino) benzoate

벤젠술포닐클로라이드 대신에 2-아세타미도-4-메틸-5-치아졸술포닐클로라이드를 사용한 것을 제외하고는 제조예 19와 동일한 방법으로 실시하여, 표제 화합물 0.18 g을 46% 수율로 얻을 수 있었다.0.18 g of the title compound was obtained in 46% yield by the same method as Preparation Example 19, except that 2-acetamido-4-methyl-5-thiazolesulfonylchloride was used instead of benzenesulfonylchloride. .

1H NMR (400 MHz, CDCl3); 9.12 (1H, s), 7.85 (1H, d), 7.74 (1H, s), 7.51 (1H, d), 7.38 (1H, t), 7.32 (1H, s), 4.36 (2H, q), 2.32 (3H, s), 2.26 (3H, s), 1.38 (3H, t)
1 H NMR (400 MHz, CDCl 3 ); 9.12 (1H, s), 7.85 (1H, d), 7.74 (1H, s), 7.51 (1H, d), 7.38 (1H, t), 7.32 (1H, s), 4.36 (2H, q), 2.32 (3H, s), 2.26 (3H, s), 1.38 (3H, t)

[제조예 74][Manufacture example 74]

3-[{[2-(아세틸아미노)-4-메틸-1,3-치아졸-5-일]술포닐}(메틸)아미노]벤조산의 제조: 3-[{[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]sulfonyl}(methyl)amino]benzoic acidPreparation of 3-[{[2- (acetylamino) -4-methyl-1,3-thiazol-5-yl] sulfonyl} (methyl) amino] benzoic acid: 3-[{[2- (acetylamino)- 4-methyl-1,3-thiazol-5-yl] sulfonyl} (methyl) amino] benzoic acid

상기 제조예 14에서 얻은 화합물 대신에 상기 제조예 73에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 29와 동일한 방법으로 실시하여, 표제 화합물 0.12 g을 75% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 73 instead of the compound obtained in Preparation Example 14, in the same manner as in Preparation Example 29, 0.12 g of the title compound could be obtained in 75% yield.

1H NMR (400 MHz, DMSO,d6); 13.05 (1H, br), 8.15 (1H, d), 7.72 (1H, t), 7.64 (1H, s), 7.35(2H, d), 3.06 (3H, s), 2.65 (3H, d), 1.73 (3H, s)
1 H NMR (400 MHz, DMSO, d 6); 13.05 (1H, br), 8.15 (1H, d), 7.72 (1H, t), 7.64 (1H, s), 7.35 (2H, d), 3.06 (3H, s), 2.65 (3H, d), 1.73 (3H, s)

[실시예 19]Example 19

3-[{[2-(아세틸아미노)-4-메틸-1,3-치아졸-5-일]술포닐}(메틸)아미노]-N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸)벤즈아미드의 제조: 3-[{[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]sulfonyl}(methyl)amino]-N-((1S,2S,4R)-5-{[(1S)-2-(benzylamino)-1-methyl-2-oxoethyl]amino}-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl)benzamide3-[{[2- (acetylamino) -4-methyl-1,3-thiazol-5-yl] sulfonyl} (methyl) amino] -N -((1 S , 2 S , 4 R )- 5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl) benzamide Preparation: 3-[{[2- (acetylamino) -4-methyl-1,3-thiazol-5-yl] sulfonyl} (methyl) amino] -N -((1 S , 2 S , 4 R ) -5 - {[(1 S) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl) benzamide

1-메틸-2,2,4-트리옥소-테트라히드로-2λ6,1-벤조치아진-7-카르복실산 대신에 상기 제조예 74에서 얻은 화합물을 사용한 것을 제외하고는 실시예 2와 동일한 방법으로 실시하여, 표제 화합물 65 ㎎을 45% 수율로 얻을 수 있었다.Same as Example 2, except that the compound obtained in Preparation Example 74 was used instead of 1-methyl-2,2,4-trioxo-tetrahydro-2λ 6 , 1-benzothiazin-7-carboxylic acid. By the method, 65 mg of the title compound was obtained in 45% yield.

1H NMR (400 MHz, CDCl3); 7.70 (1H, d), 7.53 (2H, d), 7.42 (1H, t), 7.36-7.22 (5H, m), 6.76 (1H, d), 6.55 (1H, t), 6.34 (1H, d), 6.23 (1H, d), 4.41 (2H, d), 4.16 (1H, m), 3.85-3.72 (2H, m), 3.29 (3H, s), 2.94 (3H, d), 2.64 (1H, m), 2.02 (3H, s), 1.80-1.54 (4H, m), 1.42 (1H, m), 1.32 (3H, d), 1.18 (3H, d), 0.96 (3H, d), 0.95 (3H, d)1 H NMR (400 MHz, CDCl 3 ); 7.70 (1H, d), 7.53 (2H, d), 7.42 (1H, t), 7.36-7.22 (5H, m), 6.76 (1H, d), 6.55 (1H, t), 6.34 (1H, d) , 6.23 (1H, d), 4.41 (2H, d), 4.16 (1H, m), 3.85-3.72 (2H, m), 3.29 (3H, s), 2.94 (3H, d), 2.64 (1H, m ), 2.02 (3H, s), 1.80-1.54 (4H, m), 1.42 (1H, m), 1.32 (3H, d), 1.18 (3H, d), 0.96 (3H, d), 0.95 (3H, d)

ESI MS (m/e) = 715 [M+H]+
ESI MS (m / e) = 715 [M + H] < + >

[실시예 20] Example 20                     

N-((1S,2S,4R)-5-{[(1S)-2-(benzylamino)-1-methyl-2-oxoethyl]amino}-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl)-3-[(benzylsulfonyl)(methyl)amino]benzamide의 제조: N-((1S,2S,4R)-5-{[(1S)-2-(benzylamino)-1-methyl-2-oxoethyl]amino}-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl)-3-[(benzylsulfonyl)(methyl)amino]benzamide N -((1 S , 2 S , 4 R ) -5-{[(1 S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1-isobutyl-4- Preparation of methyl-5-oxopentyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -((1 S , 2 S , 4 R ) -5-{[(1 S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide

1-메틸-2,2,4-트리옥소-테트라히드로-2λ6,1-벤조치아진-7-카르복실산 대신에 상기 제조예 56에서 얻은 화합물을 사용한 것을 제외하고는 실시예 2와 동일한 방법으로 실시하여, 표제 화합물 41 ㎎을 63% 수율로 얻을 수 있었다.Same as Example 2, except that the compound obtained in Preparation 56 was used instead of 1-methyl-2,2,4-trioxo-tetrahydro-2λ 6 , 1-benzothiazin-7-carboxylic acid. By the method, 41 mg of the title compound was obtained in 63% yield.

1H NMR (400 MHz, CD3OD); 7.77 (1H, s), 7.72 (1H, d), 7.46-7.21 (12H, m), 4.47 (2H, s), 4.36 (2H, d), 4.33 (1H, m), 4.19 (1H, m), 3.60 (1H, m), 3.26 (3H, s), 2.70 (1H, m), 1.82 (1H, m), 1.72-1.62 (2H, m), 1.52-1.36 (2H, m), 1.32 (3H, d), 1.14 (3H, d), 0.97 (6H, d)1 H NMR (400 MHz, CD3OD); 7.77 (1H, s), 7.72 (1H, d), 7.46-7.21 (12H, m), 4.47 (2H, s), 4.36 (2H, d), 4.33 (1H, m), 4.19 (1H, m) , 3.60 (1H, m), 3.26 (3H, s), 2.70 (1H, m), 1.82 (1H, m), 1.72-1.62 (2H, m), 1.52-1.36 (2H, m), 1.32 (3H , d), 1.14 (3H, d), 0.97 (6H, d)

ESI MS (m/e) = 651 [M+H]+
ESI MS (m / e) = 651 [M + H] < + >

[제조예 75][Manufacture example 75]

tert-부틸 (1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필카르바메이트의 제조: tert-butyl (1S)-1-[(benzylamino)carbonyl]-2-methylpropylcarbamate tert - butyl (1 S) -1 - [(benzylamino) carbonyl] Preparation of 2-methyl-propyl carbamate: tert -butyl (1 S) -1 - [(benzylamino) carbonyl] -2-methylpropylcarbamate

t-부톡시카르보닐-(S)-발린 4.35 g(20 mmol)을 N,N-디메틸포름아미드 100 ㎖에 녹여서 0℃로 냉각하여 벤질아민 2.62 ㎖(24 mmol), EDC 4.6 g(24 mmol), HOBT 1.05 g(30 mmol)을 가하였다. 여기에, N,N-디이소프로필에틸아민 20.9 ㎖(120 mmol)를 가하고 상온으로 온도를 올려 하룻밤 동안 교반하였다. 감압증류하여 용매를 제거한 다음 에틸아세테이트에 녹여서 물, 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음, 에틸아세테이트와 헥산을 이용하여 고체화하여 표제 화합물 4.57 g을 75% 수율로 얻을 수 있었다.4.35 g (20 mmol) of t -butoxycarbonyl- ( S ) -valine was dissolved in 100 mL of N, N-dimethylformamide, cooled to 0 ° C., 2.62 mL (24 mmol) of benzylamine, and 4.6 g (24 mmol) of EDC. ), HOBT 1.05 g (30 mmol) was added. 20.9 mL (120 mmol) of N, N-diisopropylethylamine was added thereto, and the mixture was stirred at room temperature overnight. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was removed by distillation under reduced pressure, and then solidified with ethyl acetate and hexane to obtain 4.57 g of the title compound in 75% yield.

1H NMR (400 MHz, CDCl3); 7.38-7.22 (5H, m), 6.25 (1H, br), 5.02 (1H, br), 4.46 (2H, d), 3.90 (1H, dd), 2.19 (1H, m), 1.43 (9H, s), 0.97 (3H, d), 0.93 (3H, d)
1 H NMR (400 MHz, CDCl 3 ); 7.38-7.22 (5H, m), 6.25 (1H, br), 5.02 (1H, br), 4.46 (2H, d), 3.90 (1H, dd), 2.19 (1H, m), 1.43 (9H, s) , 0.97 (3H, d), 0.93 (3H, d)

[제조예 76][Manufacture example 76]

tert-부틸 (1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-{[tert-부틸(디메틸)실릴]옥시}-1-이소부틸-4-메틸-5-옥소펜틸카르바메이트의 제조: tert-butyl (1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-isobutyl-4-methyl-5-oxopentylcarbamate tert - butyl (1 S, 2 S, 4 R) -5 - ({(1 S) -1 - [( benzylamino) carbonyl] -2-methylpropyl} amino) -2 - {[tert - butyl ( Dimethyl) silyl] oxy} -1-isobutyl-4-methyl-5-oxopentylcarbamate: tert- butyl (1 S , 2 S , 4 R ) -5-({(1 S ) -1 -[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-{[ tert -butyl (dimethyl) silyl] oxy} -1-isobutyl-4-methyl-5-oxopentylcarbamate

상기 제조예 11에서 얻은 화합물 대신에 상기 제조예 75에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 12와 동일한 방법으로 실시하여, 표제 화합물 1.73 g을 95% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 75 instead of the compound obtained in Preparation Example 11, by the same method as Preparation Example 12, 1.73 g of the title compound could be obtained in 95% yield.

1H NMR (400 MHz, CDCl3); 7.38-7.22 (5H, m), 6.43-6.32 (2H, m), 4.56-4.36 (3H, m), 4.11 (1H, t), 3.73 (1H, m), 3.66 (1H, m), 2.53 (1H, m), 2.17 (1H, m), 1.79 (1H, m), 1.50-1.38 (11H, m), 1.30-1.18 (2H, m), 1.09 (3H, d), 0.98-0.86 (21H, m), 0.08 (3H, s), 0.07 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.38-7.22 (5H, m), 6.43-6.32 (2H, m), 4.56-4.36 (3H, m), 4.11 (1H, t), 3.73 (1H, m), 3.66 (1H, m), 2.53 ( 1H, m), 2.17 (1H, m), 1.79 (1H, m), 1.50-1.38 (11H, m), 1.30-1.18 (2H, m), 1.09 (3H, d), 0.98-0.86 (21H, m), 0.08 (3H, s), 0.07 (3H, s)

[제조예 77][Manufacture example 77]

tert-부틸 (1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸카르바메이트의 제조: tert-butyl (1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentylcarbamate tert -butyl (1 S , 2 S , 4 R ) -5-({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-iso Preparation of Butyl-4-methyl-5-oxopentylcarbamate: tert -butyl (1 S , 2 S , 4 R ) -5-({(1 S ) -1-[(benzylamino) carbonyl] -2- methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentylcarbamate

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 76에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 1.27 g을 91% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation 76 instead of the compound obtained in Preparation 12, it was carried out in the same manner as in Preparation 13, it was possible to obtain 1.27 g of the title compound in 91% yield.

1H NMR (400 MHz, CDCl3); 7.36-7.18 (5H, m), 6.52 (1H, d), 6.45 (1H, s), 4.63 (1H, d), 4.48-4.34 (2H, m), 4.20 (1H, t), 3.62-3.42 (3H, m), 2.65 (1H, m), 2.15 (1H, m), 1.75-1.58 (4H, m), 1.43 (9H, s), 1.26 (1H, m), 1.15 (3H, d), 0.96 (3H, d), 0.94 (3H, d), 0.87 (6H, d)
1 H NMR (400 MHz, CDCl 3 ); 7.36-7.18 (5H, m), 6.52 (1H, d), 6.45 (1H, s), 4.63 (1H, d), 4.48-4.34 (2H, m), 4.20 (1H, t), 3.62-3.42 ( 3H, m), 2.65 (1H, m), 2.15 (1H, m), 1.75-1.58 (4H, m), 1.43 (9H, s), 1.26 (1H, m), 1.15 (3H, d), 0.96 (3H, d), 0.94 (3H, d), 0.87 (6H, d)

[실시예 21]Example 21

N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록 시-1-이소펜틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]benzamide N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1- Preparation of Isopentyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -[(1 S , 2 S , 4 R ) -5-({( 1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 77에서 얻은 화합물49 ㎎ (0.1 mmol)을 20% 트리플루오로아세트산 1.5 ㎖(디클로로메탄용액)에 녹여서 30 분 동안 교반하였다. 상온 이하에서 용매를 감압증류하여 농축한 후, N,N-디메틸포름아미드 3 ㎖에 녹여서 0℃로 냉각하여, 상기 제조예 56에서 얻은 화합물 46 ㎎(0.15 mmol)과 HATU 57 ㎎(0.15 mmol)을 가하였다. 여기에, N,N-디이소프로필에틸아민 0.5 ㎖(과량)를 가하고 상온으로 온도를 올려 4 시간 동안 교반하였다. 감압증류하여 용매를 제거한 다음 에틸아세테이트에 녹여서 물, 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음 에틸아세테이트와 헥산 3:1 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 41 ㎎을 60% 수율로 얻을 수 있었다.49 mg (0.1 mmol) of the compound obtained in Preparation Example 77 was dissolved in 1.5 mL (dichloromethane solution) of 20% trifluoroacetic acid, and stirred for 30 minutes. The solvent was distilled under reduced pressure under normal temperature, concentrated, dissolved in 3 ml of N, N-dimethylformamide, cooled to 0 ° C, and 46 mg (0.15 mmol) of the compound obtained in Preparation Example 56 and 57 mg (0.15 mmol) of HATU. Was added. 0.5 ml (excess) of N, N-diisopropylethylamine was added thereto, and the temperature was raised to room temperature and stirred for 4 hours. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a mixture of ethyl acetate and hexane 3: 1 to obtain 41 mg of the title compound in 60% yield.

1H NMR (400 MHz, CD3OD); 7.78 (1H, s), 7.73 (1H, d), 7.47-7.22 (12H, m), 4.48 (2H, s), 4.37 (2H, d), 4.22 (1H, m), 4.13 (1H, d), 3.63 (1H, m), 3.27 (3H, s), 2.77 (1H, m), 2.01 (1H, m), 1.87 (1H, m), 1.74-1.64 (2H, m), 1.52-1.40 (2H, m), 1.14 (3H, d), 0.98 (6H, d), 0.90 (3H, d), 0.88 (3H, d)1 H NMR (400 MHz, CD3OD); 7.78 (1H, s), 7.73 (1H, d), 7.47-7.22 (12H, m), 4.48 (2H, s), 4.37 (2H, d), 4.22 (1H, m), 4.13 (1H, d) , 3.63 (1H, m), 3.27 (3H, s), 2.77 (1H, m), 2.01 (1H, m), 1.87 (1H, m), 1.74-1.64 (2H, m), 1.52-1.40 (2H , m), 1.14 (3H, d), 0.98 (6H, d), 0.90 (3H, d), 0.88 (3H, d)

ESI MS (m/e) = 679 [M+H]+
ESI MS (m / e) = 679 [M + H] < + >

[제조예 78][Production Example 78]

tert-부틸 (1S)-1-[(2R,4S)-4-(1-히드록시-1-메틸에틸)-5-옥소테트라히드로-2-퓨라닐]-3-메틸부틸카르바메이트의 제조: tert-butyl (1S)-1-[(2R,4S)-4-(1-hydroxy-1-methylethyl)-5-oxotetrahydro-2-furanyl]-3-methylbutylcarbamate tert -butyl (1 S ) -1-[(2 R , 4 S ) -4- (1-hydroxy-1-methylethyl) -5-oxotetrahydro-2-furanyl] -3-methylbutylcar Preparation of Bamate: tert -butyl (1 S ) -1-[(2 R , 4 S ) -4- (1-hydroxy-1-methylethyl) -5-oxotetrahydro-2-furanyl] -3-methylbutylcarbamate

상기 제조예 1에서 얻은 화합물0.95 g(3.5 mmol)을 무수 테트라히드로퓨란 20 ㎖에 녹여 -78℃로 냉각한 후 1.0 M 리튬 비스(트리메틸실릴)아미드 10.5 ㎖(10.5 mmol, 테트라히드로퓨란용액)를 가했다. 30 분 동안 교반 후 아세톤 1.28 ㎖(17.5 mmol)를 가하여 1 시간 동안 교반하였다. 포화염화암모늄 수용액으로 반응을 종결하여 용매를 감압증류하여 제거하고 에틸아세테이트로 용출하여 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음 에틸아세테이트와 헥산의 1:2 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.72 g을 73% 수율로 얻을 수 있었다.0.95 g (3.5 mmol) of the compound obtained in Preparation Example 1 was dissolved in 20 mL of anhydrous tetrahydrofuran, cooled to −78 ° C., and then 10.5 mL (10.5 mmol, tetrahydrofuran solution) of 1.0 M lithium bis (trimethylsilyl) amide was added. Added. After stirring for 30 minutes, 1.28 mL (17.5 mmol) of acetone was added thereto, followed by stirring for 1 hour. The reaction was terminated with a saturated aqueous ammonium chloride solution, and the solvent was distilled off under reduced pressure, eluted with ethyl acetate and washed with brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a 1: 2 mixture of ethyl acetate and hexane to obtain 0.72 g of the title compound in 73% yield.

1H NMR (400 MHz, CDCl3); 4.49 (1H, m), 4.38 (1H, d), 3.85 (1H, m), 3.29 (1H, s), 2.73 (1H, dd), 2.39 (1H, m), 2.13 (1H, m), 1.64 (1H, m), 1.53-1.42 (11H, m), 1.27 (3H, s), 1.23 (3H, s), 0.93 (3H, d), 0.91 (3H, d)
1 H NMR (400 MHz, CDCl 3 ); 4.49 (1H, m), 4.38 (1H, d), 3.85 (1H, m), 3.29 (1H, s), 2.73 (1H, dd), 2.39 (1H, m), 2.13 (1H, m), 1.64 (1H, m), 1.53-1.42 (11H, m), 1.27 (3H, s), 1.23 (3H, s), 0.93 (3H, d), 0.91 (3H, d)

[제조예 79][Manufacture example 79]

tert-부틸 (1S)-1-[(2R,4S)-4-이소프로페닐-5-옥소테트라히드로-2-퓨라닐]-3-메틸부틸카르바메이트의 제조: tert-butyl (1S)-1-[(2R,4S)-4-isopropenyl-5- oxotetrahydro-2-furanyl]-3-methylbutylcarbamate Preparation of tert -butyl (1 S ) -1-[(2 R , 4 S ) -4-isopropenyl-5-oxotetrahydro-2-furanyl] -3-methylbutylcarbamate: tert -butyl (1 S ) -1-[(2 R , 4 S ) -4-isopropenyl-5-oxotetrahydro-2-furanyl] -3-methylbutylcarbamate

상기 제조예 78에서 얻은 화합물0.72 g(2.18 mmol)을 디클로로메탄 30 ㎖에 녹여 0℃로 냉각한 후 오염화인0.5 g(2.4 mmol)을 가하여 3 시간동안 교반하였다. 포화탄산수소나트륨 수용액을 가하여 디클로로메탄으로 용출한 후 감압증류하여 용매를 제거하고 에틸아세테이트와 헥산의 1:4 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.29 g을 43% 수율로 얻을 수 있었다.0.72 g (2.18 mmol) of the compound obtained in Preparation Example 78 was dissolved in 30 ml of dichloromethane, cooled to 0 ° C., and 0.5 g (2.4 mmol) of phosphorus pentachloride was added and stirred for 3 hours. Aqueous solution of saturated sodium hydrogen carbonate was added, eluted with dichloromethane, distilled under reduced pressure to remove the solvent, and the residue was purified by column chromatography using a 1: 4 mixture of ethyl acetate and hexane to obtain 0.29 g of the title compound in 43% yield.

1H NMR (400 MHz, CDCl3); 4.97 (1H, s), 4.90 (1H, s), 4.51 (1H, dd), 4.39 (1H, d), 3.86 (1H, m), 3.29 (1H, dd), 2.37 (1H, m), 2.22 (1H, m), 1.81 (3H, s), 1.67 (1H, m), 1.55 (1H, m), 1.44 (9H, s), 1.35 (1H, m), 0.93 (3H, d), 0.92 (3H, d)
1 H NMR (400 MHz, CDCl 3 ); 4.97 (1H, s), 4.90 (1H, s), 4.51 (1H, dd), 4.39 (1H, d), 3.86 (1H, m), 3.29 (1H, dd), 2.37 (1H, m), 2.22 (1H, m), 1.81 (3H, s), 1.67 (1H, m), 1.55 (1H, m), 1.44 (9H, s), 1.35 (1H, m), 0.93 (3H, d), 0.92 ( 3H, d)

[제조예 80][Production Example 80]

tert-부틸 (1S)-1-[(2R,4S)-4-이소프로필-5-옥소테트라히드로-2-퓨라닐]-3-메틸부틸카르바메이트의 제조: tert-butyl (1S)-1-[(2R,4S)-4-isopropyl-5-oxotetrahydro-2-furanyl]-3-methylbutylcarbamate Preparation of tert -butyl (1 S ) -1-[(2 R , 4 S ) -4-isopropyl-5-oxotetrahydro-2-furanyl] -3-methylbutylcarbamate: tert -butyl ( 1 S ) -1-[(2 R , 4 S ) -4-isopropyl-5-oxotetrahydro-2-furanyl] -3-methylbutylcarbamate

상기 제조예 79에서 얻은 화합물 0.28 g(0.9 mmol)을 메탄올 30 ㎖에 녹인 후, 활성 탄소에 흡착된 팔라듐(10%)을 가하고 수소공기 하에서 하룻밤 동안 교반하였다. 셀라이트를 이용한 감압여과로 고체를 제거한 다음 감압증류로 용매를 제거하여 에틸아세테이트와 헥산의 1:4 혼합액을 이용한 컬럼크로마토그래피로 정제 하여 표제 화합물 0.19 g을 68% 수율로 얻을 수 있었다.0.28 g (0.9 mmol) of the compound obtained in Preparation Example 79 was dissolved in 30 ml of methanol, and palladium (10%) adsorbed on activated carbon was added thereto, and the mixture was stirred overnight under hydrogen air. The solid was removed by vacuum filtration using celite, and the solvent was removed by distillation under reduced pressure, and purified by column chromatography using a 1: 4 mixture of ethyl acetate and hexane to obtain 0.19 g of the title compound in 68% yield.

1H NMR (400 MHz, CDCl3); 4.43 (1H, dd), 4.36 (1H, d), 3.84 (1H, m), 2.56 (1H, m), 2.26-2.02 (3H, m), 1.68 (1H, m), 1.52 (1H, m), 1.44 (9H, s), 1.34 (1H, m), 1.00 (3H, d), 0.96-0.90 (9H, m)
1 H NMR (400 MHz, CDCl 3 ); 4.43 (1H, dd), 4.36 (1H, d), 3.84 (1H, m), 2.56 (1H, m), 2.26-2.02 (3H, m), 1.68 (1H, m), 1.52 (1H, m) , 1.44 (9H, s), 1.34 (1H, m), 1.00 (3H, d), 0.96-0.90 (9H, m)

[제조예 81]Preparation Example 81

(2S,4S,5S)-5-[(tert-부톡시카르보닐)아미노]-4-{[tert-부틸(디메틸)실릴]옥시}-2-이소프로필-7-메틸옥탄산의 제조: (2S,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-2-isopropyl-7-methyloctanoic acid (2 S, 4 S, 5 S) -5 - [(tert - butoxycarbonyl) amino] -4 - {[tert - butyl (dimethyl) silyl] oxy} -2-isopropyl-7-methyl-octanoic acid Preparation of: (2 S, 4 S, 5 S) -5 - [(tert -butoxycarbonyl) amino] -4 - {[tert -butyl (dimethyl) silyl] oxy} -2-isopropyl-7-methyloctanoic acid

상기 제조예 5에서 얻은 화합물 대신에 상기 제조예 80에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 6과 동일한 방법으로 실시하여, 표제 화합물 0.21 g을 95% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 80 instead of the compound obtained in Preparation Example 5, it was carried out in the same manner as in Preparation Example 6, 0.21 g of the title compound could be obtained in 95% yield.

1H NMR (400 MHz, CDCl3); 4.52 (1H, d), 3.70-3.62(2H, m), 2.38 (1H, m), 1.94 (1H, m), 1.82 (1H, m), 1.62 (1H, m), 1.52 (1H, m), 1.45 (9H, s), 1.40-1.24 (2H, m), 0.98 (3H, d), 0.97 (3H, d), 0.95-0.90 (15H, m), 0.10 (6H, s)
1 H NMR (400 MHz, CDCl 3 ); 4.52 (1H, d), 3.70-3.62 (2H, m), 2.38 (1H, m), 1.94 (1H, m), 1.82 (1H, m), 1.62 (1H, m), 1.52 (1H, m) , 1.45 (9H, s), 1.40-1.24 (2H, m), 0.98 (3H, d), 0.97 (3H, d), 0.95-0.90 (15H, m), 0.10 (6H, s)

[제조예 82]Production Example 82

tert-부틸 (1S,2S,4S)-4-({[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}카르보닐)-2-{[tert-부틸(디메틸)실릴]옥시}-1-이소부틸-5-메틸헥실카르바메이트의 제조: tert-butyl (1S,2S,4S)-4-({[(1S)-2-(benzylamino)-1-methyl-2-oxoethyl]amino} carbonyl)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-isobutyl-5-methylhexylcarbamate tert -butyl (1 S , 2 S , 4 S ) -4-({[(1 S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} carbonyl) -2-{[ Preparation of tert -butyl (dimethyl) silyl] oxy} -1-isobutyl-5-methylhexylcarbamate: tert -butyl (1 S , 2 S , 4 S ) -4-({[(1 S )- 2- (benzylamino) -1-methyl-2-oxoethyl] amino} carbonyl) -2-{[ tert -butyl (dimethyl) silyl] oxy} -1-isobutyl-5-methylhexylcarbamate

상기 제조예 10에서 얻은 화합물 대신에 상기 제조예 81에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 12와 동일한 방법으로 실시하여, 표제 화합물 91 ㎎을 67% 수율로 얻을 수 있었다.91 mg of the title compound was obtained in a 67% yield by the same method as Preparation Example 12, except that the compound obtained in Preparation Example 81 was used instead of the compound obtained in Preparation Example 10.

1H NMR (400 MHz, CDCl3); 7.38-7.20 (5H, m), 6.97 (1H, s), 6.03 (1H, d), 4.52-4.40 (4H, m), 3.68-3.58 (2H, m), 2.11 (1H, m), 1.80-1.52 (4H, m), 1.43 (9H, s), 1.38 (3H, d), 1.30-1.22 (2H, m), 0.98-0.82 (21H, m), 0.10 (6H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.38-7.20 (5H, m), 6.97 (1H, s), 6.03 (1H, d), 4.52-4.40 (4H, m), 3.68-3.58 (2H, m), 2.11 (1H, m), 1.80- 1.52 (4H, m), 1.43 (9H, s), 1.38 (3H, d), 1.30-1.22 (2H, m), 0.98-0.82 (21H, m), 0.10 (6H, s)

[제조예 83][Manufacture example 83]

tert-부틸 (1S,2S,4S)-4-({[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}카르보닐)-2-히드록시-1-이소부틸-5-메틸헥실카르바메이트의 제조: tert-butyl (1S,2S,4S)-4-({[(1S)-2-(benzylamino)-1-methyl-2-oxoethyl]amino}carbonyl)-2-hydroxy-1-isobutyl-5-methylhexylcarbamate tert -butyl (1 S , 2 S , 4 S ) -4-({[(1 S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} carbonyl) -2-hydroxy Preparation of -1-Isobutyl-5-methylhexylcarbamate: tert -butyl (1 S , 2 S , 4 S ) -4-({[(1 S ) -2- (benzylamino) -1-methyl- 2-oxoethyl] amino} carbonyl) -2-hydroxy-1-isobutyl-5-methylhexylcarbamate

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 82에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 59 ㎎을 81% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 82 instead of the compound obtained in Preparation Example 12, it was carried out in the same manner as in Preparation Example 13, 59 mg of the title compound could be obtained in 81% yield.

1H NMR (400 MHz, CDCl3); 7.35-7.22 (5H, m), 6.58 (1H, s), 6.26 (1H, d), 4.58 (1H, d), 4.48 (1H, m), 4.41(2H, d), 3.50-3.42 (2H, m), 3.34 (1H, br), 2.12 (1H, m), 1.85 (1H, m), 1.77-1.52 (4H, m), 1.44 (9H, s), 1.41 (3H, d), 1.26 (1H, m), 0.94-0.86 (9H, m), 0.83 (3H, d)
1 H NMR (400 MHz, CDCl 3 ); 7.35-7.22 (5H, m), 6.58 (1H, s), 6.26 (1H, d), 4.58 (1H, d), 4.48 (1H, m), 4.41 (2H, d), 3.50-3.42 (2H, m), 3.34 (1H, br), 2.12 (1H, m), 1.85 (1H, m), 1.77-1.52 (4H, m), 1.44 (9H, s), 1.41 (3H, d), 1.26 (1H , m), 0.94-0.86 (9H, m), 0.83 (3H, d)

[실시예 22]Example 22

N-[(1S,2S,4S)-4-({[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}카르보닐)-2-히드록시-1-이소부틸-5-메틸헥실]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-[(1S,2S,4S)-4-({[(1S)-2-(benzylamino)-1-methyl-2-oxoethyl]amino}carbonyl)-2-hydroxy-1-isobutyl-5-methylhexyl]-3-[(benzylsulfonyl)(methyl)amino]benzamide N -[( 1S , 2S , 4S ) -4-({[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} carbonyl) -2-hydroxy Preparation of -1-Isobutyl-5-methylhexyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -[(1 S , 2 S , 4 S ) -4-({[( 1 S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} carbonyl) -2-hydroxy-1-isobutyl-5-methylhexyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 83에서 얻은 화합물49 ㎎(0.1 mmol)을 20% 트리플루오로아세트산 1.5 ㎖(디클로로메탄용액)에 녹여서 30 분 동안 교반하였다. 상온 이하에서 용매를 감압증류하여 농축한 후 N,N-디메틸포름아미드 3 ㎖에 녹여서 0℃로 냉각하여 상기 제조예 56에서 얻은 화합물 46 ㎎(0.15 mmol)과 HATU 57 ㎎(0.15 mmol)을 가하였다. 여기에, N,N-디이소프로필에틸아민 0.5 ㎖(과량)를 가하고 상온으로 온도를 올려 4 시간 동안 교반하였다. 감압증류하여 용매를 제거한 다음 에틸아세테이트에 녹여서 물, 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음 에틸아세테이트와 헥산의 3:1 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 48 ㎎을 71% 수율로 얻을 수 있었다. Compound 49 mg (0.1 mmol) obtained in Preparation Example 83 was dissolved in 1.5 ml (dichloromethane solution) of 20% trifluoroacetic acid, and stirred for 30 minutes. The solvent was distilled under reduced pressure under normal temperature, concentrated, dissolved in 3 ml of N, N-dimethylformamide, cooled to 0 ° C., and 46 mg (0.15 mmol) of the compound obtained in Preparation Example 56 and 57 mg (0.15 mmol) of HATU were added thereto. It was. 0.5 ml (excess) of N, N-diisopropylethylamine was added thereto, and the temperature was raised to room temperature and stirred for 4 hours. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a 3: 1 mixture of ethyl acetate and hexane to obtain 48 mg of the title compound in 71% yield.                     

1H NMR (400 MHz, CDCl3); 7.68 (1H, s), 7.61 (1H, d), 7.44-7.21 (12H, m), 6.62 (1H, t), 6.51 (1H, d), 6.48 (1H, d), 4.50-4.31 (3H, m), 4.29 (2H, s), 4.10 (1H, m), 3.71 (1H, d), 3.15 (3H, s), 2.14 (1H, m), 1.94-1.62 (5H, m), 1.44 (1H, m), 1.34 (3H, d), 0.96 (3H, d), 0.95 (3H, d), 0.91 (3H, d), 0.84 (3H, d)1 H NMR (400 MHz, CDCl 3 ); 7.68 (1H, s), 7.61 (1H, d), 7.44-7.21 (12H, m), 6.62 (1H, t), 6.51 (1H, d), 6.48 (1H, d), 4.50-4.31 (3H, m), 4.29 (2H, s), 4.10 (1H, m), 3.71 (1H, d), 3.15 (3H, s), 2.14 (1H, m), 1.94-1.62 (5H, m), 1.44 (1H , m), 1.34 (3H, d), 0.96 (3H, d), 0.95 (3H, d), 0.91 (3H, d), 0.84 (3H, d)

ESI MS (m/e) = 679 [M+H]+
ESI MS (m / e) = 679 [M + H] < + >

[제조예 84][Manufacture example 84]

tert-부틸 (1S,2S,4S)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-{[tert-부틸(디메틸)실릴]옥시}-1-이소부틸-5-메틸헥실카르바메이트의 제조: tert-butyl (1S,2S,4S)-4-[({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)carbonyl]-2-{[tert-butyl(dimethyl)silyl]oxy}-1-isobutyl-5-methylhexylcarbamate tert -butyl (1 S , 2 S , 4 S ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-{[ Preparation of tert -butyl (dimethyl) silyl] oxy} -1-isobutyl-5-methylhexylcarbamate: tert -butyl (1 S , 2 S , 4 S ) -4-[({(1 S )- 1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-{[ tert -butyl (dimethyl) silyl] oxy} -1-isobutyl-5-methylhexylcarbamate

상기 제조예 75에서 얻은 화합물103 ㎎(0.336 mmol)을 에틸아세테이트에 묽혀진 4.0 N 염산용액 5 ㎖에 녹여서 2 시간 동안 교반하였다. 용매를 감압증류하여 농축한 후 N,N-디메틸포름아미드 5 ㎖에 녹여서 0℃로 냉각하여 상기 제조예 81에서 얻은 화합물 100 ㎎(0.224 mmol)과 HATU 128 ㎎(0.336 mmol)을 가하였다. 여기에, N,N-디이소프로필에틸아민 0.5 ㎖(과량)를 가하고 상온으로 온도를 올려 4 시간 동안 교반하였다. 감압증류하여 용매를 제거한 다음 에틸아세테이트에 녹여 서 물, 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음 에틸아세테이트와 헥산 1:3 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 101 ㎎을 72% 수율로 얻을 수 있었다.103 mg (0.336 mmol) of the compound obtained in Preparation Example 75 was dissolved in 5 ml of 4.0 N hydrochloric acid solution diluted in ethyl acetate, and stirred for 2 hours. The solvent was concentrated by distillation under reduced pressure, dissolved in 5 ml of N, N-dimethylformamide, cooled to 0 ° C., and 100 mg (0.224 mmol) of the compound obtained in Preparation Example 81 and 128 mg (0.336 mmol) of HATU were added thereto. 0.5 ml (excess) of N, N-diisopropylethylamine was added thereto, and the temperature was raised to room temperature and stirred for 4 hours. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a mixture of ethyl acetate and hexane 1: 3 to obtain 101 mg of the title compound in 72% yield.

1H NMR (400 MHz, CDCl3); 7.36-7.23 (5H, m), 6.26 (1H, t), 6.07 (1H, d), 4.52-4.39 (3H, m), 4.18 (1H, m), 3.66 (1H, br), 3.58 (1H, br), 2.18-2.04 (2H, m), 1.84-1.50 (6H, m), 1.42 (9H, s), 1.00-0.80 (27H, m), 0.11 (6H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.36-7.23 (5H, m), 6.26 (1H, t), 6.07 (1H, d), 4.52-4.39 (3H, m), 4.18 (1H, m), 3.66 (1H, br), 3.58 (1H, br), 2.18-2.04 (2H, m), 1.84-1.50 (6H, m), 1.42 (9H, s), 1.00-0.80 (27H, m), 0.11 (6H, s)

[제조예 85]Preparation Example 85

tert-부틸 (1S,2S,4S)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-히드록시-1-이소부틸-5-메틸헥실카르바메이트의 제조: tert-butyl (1S,2S,4S)-4-[({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)carbonyl]-2-hydroxy-1-isobutyl-5-methylhexylcarbamate tert -butyl (1 S , 2 S , 4 S ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-hydroxy Preparation of -1-Isobutyl-5-methylhexylcarbamate: tert -butyl (1 S , 2 S , 4 S ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2 -methylpropyl} amino) carbonyl] -2-hydroxy-1-isobutyl-5-methylhexylcarbamate

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 84에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 63 ㎎을 79% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 84 instead of the compound obtained in Preparation Example 12, it was carried out in the same manner as in Preparation Example 13, it was obtained 63 mg of the title compound in 79% yield.

1H NMR (400 MHz, CDCl3); 7.38-7.20 (5H, m), 6.41 (2H, br), 4.63 (1H, d), 4.48-4.35 (2H, m), 4.21 (1H, t), 3.56-3.42 (3H, br), 2.20-2.12 (2H, m), 1.87 (1H, m), 1.80-1.40 (5H, m), 1.43 (9H, s), 0.97 (3H, d), 0.95 (3H, d), 0.94-0.88 (9H, m), 0.85 (3H, d)
1 H NMR (400 MHz, CDCl 3 ); 7.38-7.20 (5H, m), 6.41 (2H, br), 4.63 (1H, d), 4.48-4.35 (2H, m), 4.21 (1H, t), 3.56-3.42 (3H, br), 2.20- 2.12 (2H, m), 1.87 (1H, m), 1.80-1.40 (5H, m), 1.43 (9H, s), 0.97 (3H, d), 0.95 (3H, d), 0.94-0.88 (9H, m), 0.85 (3H, d)

[실시예 23]Example 23

N-{(1S,2S,4S)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-히드록시-1-이소부틸-5-메틸헥실}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-{(1S,2S,4S)-4-[({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)carbonyl]-2-hydroxy-1-isobutyl-5-methylhexyl}-3-[(benzylsulfonyl)(methyl)amino]benzamide N -{(1 S , 2 S , 4 S ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-hydroxy Preparation of -1-Isobutyl-5-methylhexyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -{(1 S , 2 S , 4 S ) -4-[({( 1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-hydroxy-1-isobutyl-5-methylhexyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 83에서 얻은 화합물 대신에 상기 제조예 85에서 얻은 화합물을 사용한 것을 제외하고는 실시예 22와 동일한 방법으로 실시하여, 표제 화합물 57 ㎎을 80% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 85 instead of the compound obtained in Preparation Example 83 was carried out in the same manner as in Example 22, to obtain 57 mg of the title compound in 80% yield.

1H NMR (400 MHz, CDCl3); 7.69 (1H, s), 7.58 (1H, d), 7.42-7.12 (12H, m), 6.96-6.88 (2H, m), 6.63 (1H, d), 4.46-4.20 (6H, m), 4.14 (1H, m), 3.70 (1H, d), 3.12 (3H, s), 2.21 (1H, m), 2.08 (1H, m), 1.94-1.82 (2H, m), 1.75-1.60 (3H, m), 1.45 (1H, m), 1.00-0.85 (15H, m), 0.82 (3H, d)1 H NMR (400 MHz, CDCl 3 ); 7.69 (1H, s), 7.58 (1H, d), 7.42-7.12 (12H, m), 6.96-6.88 (2H, m), 6.63 (1H, d), 4.46-4.20 (6H, m), 4.14 ( 1H, m), 3.70 (1H, d), 3.12 (3H, s), 2.21 (1H, m), 2.08 (1H, m), 1.94-1.82 (2H, m), 1.75-1.60 (3H, m) , 1.45 (1H, m), 1.00-0.85 (15H, m), 0.82 (3H, d)

ESI MS (m/e) = 707 [M+H]+
ESI MS (m / e) = 707 [M + H] < + >

[제조예 86][Manufacture example 86]

tert-부틸 (1S)-1-[(2R,4R)-4-알릴-5-옥소테트라히드로-2-퓨라닐]-3-메틸부틸카르바메이트의 제조: tert-butyl (1S)-1-[(2R,4R)-4-allyl-5-oxotetrahydro-2- furanyl]-3-methylbutylcarbamate Preparation of tert -butyl (1 S ) -1-[(2 R , 4 R ) -4-allyl-5-oxotetrahydro-2-furanyl] -3-methylbutylcarbamate: tert -butyl (1 S ) -1-[(2 R , 4 R ) -4-allyl-5-oxotetrahydro-2-furanyl] -3-methylbutylcarbamate

아이오도메탄 대신에 알릴브로마이드를 사용한 것을 제외하고는, 제조예 2와 동일한 방법으로 실시하여, 표제 화합물 0.86 g을 69% 수율로 얻을 수 있었다.Except for using allyl bromide instead of iodomethane, the same procedure as in Preparation Example 2 was carried out to obtain 0.86 g of the title compound in 69% yield.

1H NMR (400 MHz, CDCl3); 5.74 (1H, m), 5.13 (1H, d), 5.10 (1H, s), 4.47 (1H, m), 4.35 (1H, d), 3.84 (1H, m), 2.73 (1H, m), 2.54 (1H, m), 2.38-2.22 (2H, m), 2.02 (1H, m), 1.69-1.51 (2H, m), 1.43 (9H, s), 1.34 (1H, m), 0.93 (3H, d), 0.92 (1H, d)
1 H NMR (400 MHz, CDCl 3 ); 5.74 (1H, m), 5.13 (1H, d), 5.10 (1H, s), 4.47 (1H, m), 4.35 (1H, d), 3.84 (1H, m), 2.73 (1H, m), 2.54 (1H, m), 2.38-2.22 (2H, m), 2.02 (1H, m), 1.69-1.51 (2H, m), 1.43 (9H, s), 1.34 (1H, m), 0.93 (3H, d ), 0.92 (1H, d)

[제조예 87][Manufacture example 87]

N-{(1S)-1-[(2R,4R)-4-알릴-5-옥소테트라히드로-2-퓨라닐]-3-메틸부틸}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-{(1S)-1-[(2R,4R)-4-allyl-5-oxotetrahydro-2-furanyl]-3-methylbutyl}-3-[(benzylsulfonyl)(methyl)amino]benzamide N - {(1 S) -1 - [(2 R, 4 R) -4- allyl-5-oxo-tetrahydro-2-furanyl] -3-methylbutyl} -3 - [(benzyl-sulfonyl) ( Preparation of methyl) amino] benzamide: N -{(1 S ) -1-[(2 R , 4 R ) -4-allyl-5-oxotetrahydro-2-furanyl] -3-methylbutyl} -3-[( benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 86에서 얻은 화합물0.45 g(1.44 mmol)을 에틸아세테이트에 묽혀진 4.0 N 염산용액 8 ㎖에 녹여서 1 시간 동안 교반하였다. 용매를 감압증류하여 농축한 후 N,N-디메틸포름아미드 8 ㎖에 녹여서 0℃로 냉각하여 상기 제조예 56에서 얻은 화합물 0.53 g(1.73 mmol), EDC 0.33 g(1.73 mmol), HOBT 0.29 g(2.16 mmol)을 가하였다. 여기에, N,N-디이소프로필에틸아민 1.51 ㎖(8.64 mmol)를 가하고 상온으로 온도를 올려 하룻밤 동안 교반하였다. 감압증류하여 용매를 제거한 다음 에틸아세테이트에 녹여서 물, 1.0 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류하여 제거한 후 에틸아세테이트와 헥산에서 고체화하여 표제 화합물 0.69 g을 96% 수율로 얻을 수 있었다.0.45 g (1.44 mmol) of the compound obtained in Preparation Example 86 was dissolved in 8 ml of 4.0 N hydrochloric acid solution diluted in ethyl acetate, and stirred for 1 hour. The solvent was concentrated by distillation under reduced pressure, dissolved in 8 ml of N, N-dimethylformamide, cooled to 0 ° C., 0.53 g (1.73 mmol) of the compound obtained in Preparation Example 56, 0.33 g (1.73 mmol) of EDC, and 0.29 g of HOBT. 2.16 mmol) was added. 1.51 mL (8.64 mmol) of N, N-diisopropylethylamine was added thereto, and the temperature was raised to room temperature and stirred overnight. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, 1.0 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was distilled off under reduced pressure and then solidified in ethyl acetate and hexane to obtain 0.69 g of the title compound in 96% yield.

1H NMR (400 MHz, CDCl3); 7.58 7.38 (9H, m), 5.98 (1H, d), 5.74 (1H, m), 5.15-5.10 (2H, m), 4.61 (1H, m), 4.48 (1H, m), 4.33 (2H, s), 3.19 (3H, s), 2.67 (1H, m), 2.48 (1H, m), 2.31 (2H, m), 2.09 (1H, m), 1.79-1.47 (3H, m), 0.99 (3H, d), 0.97 (3H, d)
1 H NMR (400 MHz, CDCl 3 ); 7.58 7.38 (9H, m), 5.98 (1H, d), 5.74 (1H, m), 5.15-5.10 (2H, m), 4.61 (1H, m), 4.48 (1H, m), 4.33 (2H, s ), 3.19 (3H, s), 2.67 (1H, m), 2.48 (1H, m), 2.31 (2H, m), 2.09 (1H, m), 1.79-1.47 (3H, m), 0.99 (3H, d), 0.97 (3H, d)

[제조예 88][Production Example 88]

(2R)-2-((2S,3S)-3-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-2-{[tert-부틸(디메틸)실릴]옥시}-5-메틸헥실)-4-펜탄산의 제조: (2R)-2-((2S,3S)-3-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-2-{[tert-butyl(dimethyl)silyl]oxy}-5-methylhexyl)-4-pentenoic acid( 2R ) -2-(( 2S , 3S ) -3-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -2-{[ tert -butyl (dimethyl) silyl] oxy} -5-methylhexyl) Preparation of 4-pentanoic acid: (2 R) -2 - ( (2 S, 3 S) -3 - ({3 - [(benzylsulfonyl) (methyl) amino] benzoyl} amino ) -2-{[ tert -butyl (dimethyl) silyl] oxy} -5-methylhexyl) -4-pentenoic acid

상기 제조예 5에서 얻은 화합물 대신에 상기 제조예 87에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 6과 동일한 방법으로 실시하여, 표제 화합물 0.86 g을 100% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 87 instead of the compound obtained in Preparation Example 5, it was carried out in the same manner as in Preparation Example 6, it was possible to obtain 0.86 g of the title compound in 100% yield.

1H NMR (400 MHz, CDCl3); 7.69 (1H, s), 7.55 (1H, d), 7.43-7.37 (7H, m), 6.30 (1H, d), 5.77 (1H, m), 5.09 (1H, d), 5.06 (1H, d), 4.30 (2H, s), 4.26 (1H, m), 3.85 (1H, dd), 2.65 (1H, m), 2.44 (1H, m), 2.27 (1H, m), 1.85 (1H, m), 1.65-1.58 (2H, m), 1.50-1.44 (2H, m), 0.99 (3H, d), 0.97 (3H, d), 0.92 (9H, s), 0.14 (3H, s), 0.12 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.69 (1H, s), 7.55 (1H, d), 7.43-7.37 (7H, m), 6.30 (1H, d), 5.77 (1H, m), 5.09 (1H, d), 5.06 (1H, d) , 4.30 (2H, s), 4.26 (1H, m), 3.85 (1H, dd), 2.65 (1H, m), 2.44 (1H, m), 2.27 (1H, m), 1.85 (1H, m), 1.65-1.58 (2H, m), 1.50-1.44 (2H, m), 0.99 (3H, d), 0.97 (3H, d), 0.92 (9H, s), 0.14 (3H, s), 0.12 (3H, s)

[제조예 89][Manufacture example 89]

N-((1S,2S,4R)-4-({[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}카르보닐)-2-{[tert-부틸(디메틸)실릴]옥시}-1-이소부틸-6-헵테닐)-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-((1S,2S,4R)-4-({[(1S)-2-(benzylamino)-1-methyl-2-oxoethyl]amino}carbonyl)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-isobutyl-6-heptenyl)-3-[(benzylsulfonyl)(methyl)amino]benzamide N -(( 1S , 2S , 4R ) -4-({[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} carbonyl) -2-{[ Preparation of tert -butyl (dimethyl) silyl] oxy} -1-isobutyl-6-heptenyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -((1 S , 2 S , 4 R ) -4-({[(1 S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} carbonyl) -2-{[ tert -butyl (dimethyl) silyl] oxy} -1- isobutyl-6-heptenyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 10에서 얻은 화합물 대신에 상기 제조예 88에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 12와 동일한 방법으로 실시하여, 표제 화합물 66 ㎎을 66% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 88 instead of the compound obtained in Preparation Example 10, it was carried out in the same manner as Preparation Example 12, it was obtained 66 mg of the title compound in 66% yield.

1H NMR (400 MHz, CDCl3); 7.72 (1H, s), 7.55 (1H, d), 7.44-7.20 (12H, m), 6.74 (1H, d), 6.65 (1H, t), 6.24 (1H, d), 5.66 (1H, m), 4.99 (1H, d), 4.82 (1H, d), 4.45-4.30 (4H, m), 4.29 (2H, s), 3.79 (1H, dd), 3.16 (3H, s), 2.55-2.42 (2H, m), 2.16 (1H, m), 1.70-1.52 (4H, m), 1.40 (1H, m), 1.16 (3H, d), 0.98 (3H, d), 0.97 (3H, d), 0.92 (9H, s), 0.11 (3H, s), 0.10 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.72 (1H, s), 7.55 (1H, d), 7.44-7.20 (12H, m), 6.74 (1H, d), 6.65 (1H, t), 6.24 (1H, d), 5.66 (1H, m) , 4.99 (1H, d), 4.82 (1H, d), 4.45-4.30 (4H, m), 4.29 (2H, s), 3.79 (1H, dd), 3.16 (3H, s), 2.55-2.42 (2H , m), 2.16 (1H, m), 1.70-1.52 (4H, m), 1.40 (1H, m), 1.16 (3H, d), 0.98 (3H, d), 0.97 (3H, d), 0.92 ( 9H, s), 0.11 (3H, s), 0.10 (3H, s)

[실시예 24] Example 24                     

N-[(1S,2S,4R)-4-({[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}카르보닐)-2-히드록시-1-이소부틸-6-헵테닐]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-[(1S,2S,4R)-4-({[(1S)-2-(benzylamino)-1-methyl-2-oxoethyl]amino}carbonyl)-2-hydroxy-1-isobutyl-6-heptenyl]-3-[(benzylsulfonyl)(methyl)amino]benzamide N -[( 1S , 2S , 4R ) -4-({[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} carbonyl) -2-hydroxy Preparation of -1-Isobutyl-6-heptenyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -[(1 S , 2 S , 4 R ) -4-({[( 1 S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} carbonyl) -2-hydroxy-1-isobutyl-6-heptenyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 89에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 54 ㎎을 98% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 89 instead of the compound obtained in Preparation Example 12, it was carried out in the same manner as in Preparation Example 13, it was obtained 54 mg of the title compound in 98% yield.

1H NMR (400 MHz, CDCl3); 7.68 (1H, s), 7.62 (1H, d), 7.45-7.20 (12H, m), 6.67 (1H, d), 6.64 (1H, t), 6.49 (1H, d), 5.66 (1H, m), 4.98 (1H, d), 4.89 (1H, d), 4.45 (1H, m), 4.37 (2H, dd), 4.29 (2H, s), 4.11 (1H, m), 3.73 (1H, d), 3.16 (3H, s), 2.59 (1H, m), 2.37 (1H, m), 2.19 (1H, m), 1.84-1.62 (4H, m), 1.44 (1H, m), 1.32 (3H, d), 0.96 (3H, d), 0.94 (3H, d)1 H NMR (400 MHz, CDCl 3 ); 7.68 (1H, s), 7.62 (1H, d), 7.45-7.20 (12H, m), 6.67 (1H, d), 6.64 (1H, t), 6.49 (1H, d), 5.66 (1H, m) , 4.98 (1H, d), 4.89 (1H, d), 4.45 (1H, m), 4.37 (2H, dd), 4.29 (2H, s), 4.11 (1H, m), 3.73 (1H, d), 3.16 (3H, s), 2.59 (1H, m), 2.37 (1H, m), 2.19 (1H, m), 1.84-1.62 (4H, m), 1.44 (1H, m), 1.32 (3H, d) , 0.96 (3H, d), 0.94 (3H, d)

ESI MS (m/e) = 677 [M+H]+
ESI MS (m / e) = 677 [M + H] < + >

[제조예 90][Production Example 90]

N-((1S,2S,4R)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-{[tert-부틸(디메틸)실릴]옥시}-1-이소부틸-6-헵테틸)-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-((1S,2S,4R)-4-[({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)carbonyl]-2-{[tert- butyl(dimethyl)silyl]oxy}-1-isobutyl-6-heptenyl)-3-[(benzylsulfonyl)(methyl)amino]benzamide N -((1 S , 2 S , 4 R ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-{[ tert -butyl (dimethyl) silyl] oxy} -1-isobutyl-6-heptetyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide Preparation: N -((1 S , 2 S , 4 R ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-{[ tert -butyl (dimethyl) silyl] oxy} -1-isobutyl -6-heptenyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 75에서 얻은 화합물 55 ㎎(0.18 mmol)을 에틸아세테이트에 묽혀진 4.0 N 염산용액 3 ㎖에 녹여서 2 시간 동안 교반하였다. 용매를 감압증류하여 농축한 후 N,N-디메틸포름아미드 5 ㎖에 녹여서 0℃로 냉각하여 상기 제조예 88에서 얻은 화합물 95 ㎎(0.15 mmol), EDC(35 ㎎, 0.18 mmol)와 HOBT 30 ㎎(0.225 mmol)을 가하였다. 여기에, N,N-디이소프로필에틸아민 1.0 ㎖(과량)를 가하고 상온으로 온도를 올려 하룻밤동안 교반하였다. 감압증류하여 용매를 제거한 다음 에틸아세테이트에 녹여서 물, 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음 메탄올과 디클로로메탄의 5:95 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 80 ㎎을 65% 수율로 얻을 수 있었다.55 mg (0.18 mmol) of the compound obtained in Preparation Example 75 was dissolved in 3 ml of 4.0 N hydrochloric acid solution diluted in ethyl acetate, and stirred for 2 hours. The solvent was distilled under reduced pressure, concentrated, and then dissolved in 5 ml of N, N-dimethylformamide and cooled to 0 ° C. to obtain 95 mg (0.15 mmol), EDC (35 mg, 0.18 mmol) and HOBT 30 mg of the compound obtained in Preparation Example 88. (0.225 mmol) was added. To this was added 1.0 mL (excess) of N, N-diisopropylethylamine, the temperature was raised to room temperature, and the mixture was stirred overnight. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a 5:95 mixture of methanol and dichloromethane to obtain 80 mg of the title compound in 65% yield.

1H NMR (400 MHz, CDCl3); 7.77 (1H, s), 7.58 (1H, d), 7.42-7.20 (12H, m), 6.57 (1H, d), 6.38 (1H, t), 6.28 (1H, d), 5.72 (1H, m), 5.02 (1H, d), 4.88 (1H, d), 4.46-4.32 (3H, m), 4.26 (2H, s), 4.13 (1H, dd), 3.79 (1H, dd), 3.16 (3H, s), 2.62 (1H, m), 2.42 (1H, m), 2.20-2.04 (2H, m), 1.74-1.50 (4H, m), 1.43 (1H, m), 0.99 (3H, d), 0.97 (3H, d), 0.93 (9H, s), 0.71 (3H, d), 0.69 (3H, d), 0.12 (3H, s), 0.11 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.77 (1H, s), 7.58 (1H, d), 7.42-7.20 (12H, m), 6.57 (1H, d), 6.38 (1H, t), 6.28 (1H, d), 5.72 (1H, m) , 5.02 (1H, d), 4.88 (1H, d), 4.46-4.32 (3H, m), 4.26 (2H, s), 4.13 (1H, dd), 3.79 (1H, dd), 3.16 (3H, s ), 2.62 (1H, m), 2.42 (1H, m), 2.20-2.04 (2H, m), 1.74-1.50 (4H, m), 1.43 (1H, m), 0.99 (3H, d), 0.97 ( 3H, d), 0.93 (9H, s), 0.71 (3H, d), 0.69 (3H, d), 0.12 (3H, s), 0.11 (3H, s)

[실시예 25]Example 25

N-{(1S,2S,4R)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-히드록시-1-이소부틸-6-헵테닐}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-{(1S,2S,4R)-4-[({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)carbonyl]-2-hydroxy-1-isobutyl-6-heptenyl}-3-[(benzylsulfonyl)(methyl)amino]benzamide N -{(1 S , 2 S , 4 R ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-hydroxy Preparation of -1-Isobutyl-6-heptenyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -{(1 S , 2 S , 4 R ) -4-[({( 1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-hydroxy-1-isobutyl-6-heptenyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 90에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 58 ㎎을 87% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 90 instead of the compound obtained in Preparation Example 12, it was carried out in the same manner as in Preparation Example 13, it was obtained 58 mg of the title compound in 87% yield.

1H NMR (400 MHz, CDCl3); 7.69 (1H, s), 7.60 (1H, d), 7.40-7.17 (12H, m), 6.84 (1H, d), 6.78 (1H, t), 6.59 (1H, d), 5.65 (1H, m), 4.98 (1H, d), 4.88 (1H, d), 4.40-4.20 (4H, m), 4.28 (2H, s), 4.12 (1H, m), 3.73 (1H, d), 3.14 (3H, s), 2.66 (1H, m), 3.80 (1H, m), 2.22-2.10 (2H, m), 1.88-1.62 (4H, m), 1.43 (1H, m), 0.95 (3H, d), 0.94 (3H, d), 0.90 (3H, d), 0.88 (3H, d)1 H NMR (400 MHz, CDCl 3 ); 7.69 (1H, s), 7.60 (1H, d), 7.40-7.17 (12H, m), 6.84 (1H, d), 6.78 (1H, t), 6.59 (1H, d), 5.65 (1H, m) , 4.98 (1H, d), 4.88 (1H, d), 4.40-4.20 (4H, m), 4.28 (2H, s), 4.12 (1H, m), 3.73 (1H, d), 3.14 (3H, s ), 2.66 (1H, m), 3.80 (1H, m), 2.22-2.10 (2H, m), 1.88-1.62 (4H, m), 1.43 (1H, m), 0.95 (3H, d), 0.94 ( 3H, d), 0.90 (3H, d), 0.88 (3H, d)

ESI MS (m/e) = 705 [M+H]+
ESI MS (m / e) = 705 [M + H] < + >

[제조예 91][Manufacture example 91]

벤질 4-{(4S,7R,9S)-7-알릴-9-[(1S)-1-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-3-메틸부틸]-4,11,11,12,12-펜타메틸-3,6-디옥소-10-옥사-2,5-디아자-11-실라 트리덱-1-일}벤조에이트의 제조: benzyl 4-{(4S,7R,9S)-7-allyl-9-[(1S)-1-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-3-methylbutyl]-4,11,11,12,12-pentamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl}benzoateBenzyl 4-{(4 S , 7 R , 9 S ) -7-allyl-9-[(1 S ) -1-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -3 Preparation of -methylbutyl] -4,11,11,12,12-pentamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-sila tridec-1-yl} benzoate benzyl 4-{(4 S , 7 R , 9 S ) -7-allyl-9-[(1 S ) -1-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -3- methylbutyl] -4,11,11,12,12-pentamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate

상기 제조예 6에서 얻은 화합물 대신에 상기 제조예 88에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 9와 동일한 방법으로 실시하여, 표제 화합물 99 ㎎을 71% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 88 instead of the compound obtained in Preparation Example 6, it was carried out in the same manner as in Preparation Example 9, 99 mg of the title compound could be obtained in 71% yield.

1H NMR (400 MHz, CDCl3); 8.01 (2H, d), 7.71 (1H, s), 7.54 (1H, d), 7.45-7.29 (14H, m), 6.85 (1H, t), 6.78 (1H, d), 6.24 (1H, d), 5.65 (1H, m), 5.35 (2H, s), 4.98 (1H, d), 4.83 (1H, d), 4.43-4.29 (6H, m), 3.79 (1H, m), 3.15 (3H, s), 2.53-2.41 (2H, m), 2.15 (1H, m), 1.66-1.58 (4H, m), 1.41 (1H, m), 1.16 (3H, d), 0.98 (3H, d), 0.96 (3H, d), 0.92 (9H, s), 0.11 (3H, s), 0.09 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 8.01 (2H, d), 7.71 (1H, s), 7.54 (1H, d), 7.45-7.29 (14H, m), 6.85 (1H, t), 6.78 (1H, d), 6.24 (1H, d) , 5.65 (1H, m), 5.35 (2H, s), 4.98 (1H, d), 4.83 (1H, d), 4.43-4.29 (6H, m), 3.79 (1H, m), 3.15 (3H, s ), 2.53-2.41 (2H, m), 2.15 (1H, m), 1.66-1.58 (4H, m), 1.41 (1H, m), 1.16 (3H, d), 0.98 (3H, d), 0.96 ( 3H, d), 0.92 (9H, s), 0.11 (3H, s), 0.09 (3H, s)

[실시예 26]Example 26

4-({[(2S)-2-({(2R)-2-[(2S,3S)-3-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-2-히드록시-5-메틸헥실]-4-펜테노일}아미노)프로파노일]아미노}메틸)벤조산의 제조: 4-({[(2S)-2-({(2R)-2-[(2S,3S)-3-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-2-hydroxy-5-methylhexyl]-4-pentenoyl}amino)propanoyl]amino}methyl)benzoic acid 4-({[(2 S ) -2-({(2 R ) -2-[(2 S , 3 S ) -3-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino Preparation of) -2-hydroxy-5-methylhexyl] -4-pentenoyl} amino) propanoyl] amino} methyl) benzoic acid: 4-({[( 2S ) -2-({( 2R ) -2 - [(2 S, 3 S) -3 - ({3 - [(benzylsulfonyl) (methyl) amino] benzoyl} amino) -2-hydroxy-5-methylhexyl] -4-pentenoyl} amino) propanoyl] amino methyl) benzoic acid

상기 제조예 28에서 얻은 화합물 대신에 상기 제조예 91에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 5와 동일한 방법으로 실시하여, 표제 화합물 44 ㎎을 57% 수율로 얻을 수 있었다.44 mg of the title compound was obtained in 57% yield by the same method as Example 5 except for using the compound obtained in Preparation Example 91 instead of the compound obtained in Preparation Example 28.

1H NMR (400 MHz, CD3OD); 7.96 (2H, d), 7.75 (1H, s), 7.69 (1H, d), 7.48-7.32 (9H, m), 5.75 (1H, m), 5.10-4.80 (2H, overlap with the H2O), 4.46 (2H, s), 4.41 (2H, s), 4.36 (1H, m), 4.16 (1H, m), 3.60 (1H, d), 3.25 (3H, s), 2.67 (1H, m), 2.35 (1H, m), 2.18 (1H, m), 1.82 (1H, m), 1.68-1.50 (3H, m), 1.40 (1H, m), 1.34 (3H, d), 0.96 (6H, d)1 H NMR (400 MHz, CD3OD); 7.96 (2H, d), 7.75 (1H, s), 7.69 (1H, d), 7.48-7.32 (9H, m), 5.75 (1H, m), 5.10-4.80 (2H, overlap with the H 2 O) , 4.46 (2H, s), 4.41 (2H, s), 4.36 (1H, m), 4.16 (1H, m), 3.60 (1H, d), 3.25 (3H, s), 2.67 (1H, m), 2.35 (1H, m), 2.18 (1H, m), 1.82 (1H, m), 1.68-1.50 (3H, m), 1.40 (1H, m), 1.34 (3H, d), 0.96 (6H, d)

ESI MS (m/e) = 721 [M+H]+
ESI MS (m / e) = 721 [M + H] < + >

[제조예 92][Manufacture example 92]

벤질 4-[({(2S)-2-[(tert-부톡시카르보닐)아미노]-3-메틸부타노일}아미노)메틸]벤조에이트의 제조: benzyl 4-[({(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl}amino)methyl]benzoateBenzyl 4 - [({(2 S ) -2 - [(tert - butoxycarbonyl) amino] -3-methyl-butanoyl} amino) methyl] benzoate prepared: benzyl 4 - [({( 2 S) -2-[( tert -butoxycarbonyl) amino] -3-methylbutanoyl} amino) methyl] benzoate

t-부톡시카르보닐-(S)-알라닌 대신에 t-부톡시카르보닐-(S)-발린을 사용한 것을 제외하고는, 제조예 8과 동일한 방법으로 실시하여, 표제 화합물 3.71 g을 84% 수율로 얻을 수 있었다. t - butoxycarbonyl - (S) - a t-alanine instead of - butoxycarbonyl - (S) -, except that valine, conducted in the same manner as in Production Example 8, the title compound was 3.71 g 84% Yield was obtained.

1H NMR (400 MHz, CDCl3); 8.03 (2H, d), 7.46-7.34 (5H, m), 7.33 (2H, d), 6.37 (1H, br), 5.36 (2H, s), 4.98 (1H, br), 4.51 (2H, d), 3.89 (1H, dd), 2.18 (1H, m), 1.43 (9H, s), 0.97 (3H, d), 0.93 (3H, d)
1 H NMR (400 MHz, CDCl 3 ); 8.03 (2H, d), 7.46-7.34 (5H, m), 7.33 (2H, d), 6.37 (1H, br), 5.36 (2H, s), 4.98 (1H, br), 4.51 (2H, d) , 3.89 (1H, dd), 2.18 (1H, m), 1.43 (9H, s), 0.97 (3H, d), 0.93 (3H, d)

[제조예 93][Manufacture example 93]

벤질 4-{(4S,7R,9S)-7-알릴-9-[(1S)-1-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-3-메틸부틸]-4-이소프로필-11,11,12,12-테트라메틸-3,6-디옥소-10-옥사-2,5-디아자-11-실라트리덱-1-일}벤조에이트의 제조: benzyl 4-{(4S,7R,9S)-7-allyl-9-[(1S)-1-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-3-methylbutyl]-4-isopropyl-11,11,12,12-tetramethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl}benzoateBenzyl 4-{(4 S , 7 R , 9 S ) -7-allyl-9-[(1 S ) -1-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -3 -Methylbutyl] -4-isopropyl-11,11,12,12-tetramethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzo Preparation of eight: benzyl 4-{(4 S , 7 R , 9 S ) -7-allyl-9-[(1 S ) -1-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -3-methylbutyl] -4-isopropyl-11,11,12,12-tetramethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate

상기 제조예 75에서 얻은 화합물 대신에 상기 제조예 92에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 90과 동일한 방법으로 실시하여, 표제 화합물 107 ㎎을 75% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 92 instead of the compound obtained in Preparation Example 75, it was carried out in the same manner as in Preparation Example 90, to obtain 107 mg of the title compound in 75% yield.

1H NMR (400 MHz, CDCl3); 8.02 (2H, d), 7.75 (1H, s), 7.57 (1H, d), 7.48-7.25 (14H, m), 6.58 (1H, d), 6.55 (1H, t), 6.27 (1H, d), 5.71 (1H, m), 5.36 (2H, s), 5.02 (1H, d), 4.89 (1H, d), 4.50-4.30 (3H, m), 4.29 (2H, s), 4.12 (1H, dd), 3.78 (1H, dd), 3.15 (3H, s), 2.62 (1H, m), 2.43 (1H, m), 2.20-2.04 (2H, m), 1.74-1.50 (4H, m), 1.41 (1H, m), 0.98 (3H, d), 0.96 (3H, d), 0.92 (9H, s), 0.69 (6H, d), 0.12 (3H, s), 0.10 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 8.02 (2H, d), 7.75 (1H, s), 7.57 (1H, d), 7.48-7.25 (14H, m), 6.58 (1H, d), 6.55 (1H, t), 6.27 (1H, d) , 5.71 (1H, m), 5.36 (2H, s), 5.02 (1H, d), 4.89 (1H, d), 4.50-4.30 (3H, m), 4.29 (2H, s), 4.12 (1H, dd ), 3.78 (1H, dd), 3.15 (3H, s), 2.62 (1H, m), 2.43 (1H, m), 2.20-2.04 (2H, m), 1.74-1.50 (4H, m), 1.41 ( 1H, m), 0.98 (3H, d), 0.96 (3H, d), 0.92 (9H, s), 0.69 (6H, d), 0.12 (3H, s), 0.10 (3H, s)

[실시예 27]Example 27

4-({[(2S)-2-({(2R)-2-[(2S,3S)-3-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-2-히드록시-5-메틸헥실]-4-펜테노일}아미노)-3-메틸부타노일]아미노}메틸)벤조산의 제조: 4-({[(2S)-2-({(2R)-2-[(2S,3S)-3-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-2-hydroxy-5-methylhexyl]-4-pentenoyl}amino)-3-methylbutanoyl]amino}methyl)benzoic acid4-({[(2 S ) -2-({(2 R ) -2-[(2 S , 3 S ) -3-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino Preparation of) -2-hydroxy-5-methylhexyl] -4-pentenoyl} amino) -3-methylbutanoyl] amino} methyl) benzoic acid: 4-({[( 2S ) -2-({( 2 R ) -2-[(2 S , 3 S ) -3-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -2-hydroxy-5-methylhexyl] -4-pentenoyl} amino) -3-methylbutanoyl] amino} methyl) benzoic acid

상기 제조예 28에서 얻은 화합물 대신에 상기 제조예 93에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 5와 동일한 방법으로 실시하여, 표제 화합물 58 ㎎을 71% 수율로 얻을 수 있었다.58 mg of the title compound could be obtained in a yield of 71% by the same method as Example 5 except for using the compound obtained in Preparation Example 93 instead of the compound obtained in Preparation Example 28.

1H NMR (400 MHz, CD3OD); 7.95 (2H, d), 7.75 (1H, s), 7.70 (1H, d), 7.44-7.32 (9H, m), 5.72 (1H, m), 5.01 (1H, d), 4.95-4.75 (1H, overlap with the H2O), 4.46 (2H, s), 4.45-4.40 (2H, m), 4.22-4.12 (2H, m), 3.62 (1H, d), 3.25 (3H, s), 2.73 (1H, m), 2.34 (1H, m), 2.17 (1H, m), 2.02 (1H, m), 1.83 (1H, m), 1.68-1.58 (2H, m), 1.54 (1H, m), 1.41 (1H, m), 0.96 (3H, d), 0.95 (3H, d), 0.91 (3H, d), 0.89 (3H, d)1 H NMR (400 MHz, CD3OD); 7.95 (2H, d), 7.75 (1H, s), 7.70 (1H, d), 7.44-7.32 (9H, m), 5.72 (1H, m), 5.01 (1H, d), 4.95-4.75 (1H, overlap with the H 2 O), 4.46 (2H, s), 4.45-4.40 (2H, m), 4.22-4.12 (2H, m), 3.62 (1H, d), 3.25 (3H, s), 2.73 (1H , m), 2.34 (1H, m), 2.17 (1H, m), 2.02 (1H, m), 1.83 (1H, m), 1.68-1.58 (2H, m), 1.54 (1H, m), 1.41 ( 1H, m), 0.96 (3H, d), 0.95 (3H, d), 0.91 (3H, d), 0.89 (3H, d)

ESI MS (m/e) = 749 [M+H]+
ESI MS (m / e) = 749 [M + H] < + >

[제조예 94][Manufacture example 94]

벤질 4-{(4S,7R,9S)-9-[(1S)-1-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-3- 메틸부틸]-4-이소프로필-7,11,11,12,12-펜타메틸-3,6-디옥소-10-옥사-2,5-디아자-11-실라트리덱-1-일}벤조에이트의 제조: benzyl 4-{(4S,7R,9S)-9-[(1S)-1-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-3-methylbutyl]-4-isopropyl-7,11,11,12,12-pentamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl}benzoateBenzyl 4-{(4 S , 7 R , 9 S ) -9-[(1 S ) -1-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -3- methylbutyl] 4-isopropyl-7,11,11,12,12-pentamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate Preparation: benzyl 4-{(4 S , 7 R , 9 S ) -9-[(1 S ) -1-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -3-methylbutyl]- 4-isopropyl-7,11,11,12,12-pentamethyl-3,6-dioxo-10-oxa-2,5-diaza-11-silatridec-1-yl} benzoate

상기 제조예 92에서 얻은 화합물 83 ㎎(0.188 mmol)을 에틸아세테이트에 묽혀진 4.0 N 염산용액 3 ㎖에 녹여서 2 시간 동안 교반하였다. 용매를 감압증류하여 농축한 후 N,N-디메틸포름아미드 5 ㎖에 녹여서 0℃로 냉각하여 상기 제조예 58에서 얻은 화합물 95 ㎎(0.157 mmol), EDC(36 ㎎, 0.188 mmol)와 HOBT 32 ㎎(0.236 mmol)을 가하였다. 여기에 N,N-디이소프로필에틸아민 1.0 ㎖(과량)를 가하고 상온으로 온도를 올려 하룻밤동안 교반하였다. 감압증류하여 용매를 제거한 다음 에틸아세테이트에 녹여서 물, 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음 메탄올과 디클로로메탄의 5:95 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 108 ㎎을 74% 수율로 얻을 수 있었다.83 mg (0.188 mmol) of the compound obtained in Preparation Example 92 was dissolved in 3 ml of 4.0 N hydrochloric acid solution diluted in ethyl acetate, and stirred for 2 hours. The solvent was distilled under reduced pressure, concentrated, and dissolved in 5 ml of N, N-dimethylformamide. (0.236 mmol) was added. 1.0 mL (excess) of N, N-diisopropylethylamine was added thereto, the temperature was raised to room temperature, and the mixture was stirred overnight. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a 5:95 mixture of methanol and dichloromethane to obtain 108 mg of the title compound in 74% yield.

1H NMR (400 MHz, CDCl3); 8.01 (2H, d), 7.77 (1H, s), 7.57 (1H, d), 7.46-7.32 (12H, m), 7.30 (2H, d), 6.71 (1H, d), 6.55 (1H, t), 6.27 (1H, d), 5.36 (2H, s), 4.51-4.29 (3H, m), 4.29 (2H, s), 4.09 (1H, dd), 3.74 (1H, dd), 3.16 (3H, s), 2.65 (1H, m), 2.03 (1H, m), 1.76-1.48 (4H, m), 1.41 (1H, m), 1.14 (3H, d), 0.97 (3H, d), 0.96 (3H, d), 0.92 (9H, s), 0.74 (3H, d), 0.64 (3H, d), 0.12 (3H, s), 0.10 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 8.01 (2H, d), 7.77 (1H, s), 7.57 (1H, d), 7.46-7.32 (12H, m), 7.30 (2H, d), 6.71 (1H, d), 6.55 (1H, t) , 6.27 (1H, d), 5.36 (2H, s), 4.51-4.29 (3H, m), 4.29 (2H, s), 4.09 (1H, dd), 3.74 (1H, dd), 3.16 (3H, s ), 2.65 (1H, m), 2.03 (1H, m), 1.76-1.48 (4H, m), 1.41 (1H, m), 1.14 (3H, d), 0.97 (3H, d), 0.96 (3H, d), 0.92 (9H, s), 0.74 (3H, d), 0.64 (3H, d), 0.12 (3H, s), 0.10 (3H, s)

[실시예 28]Example 28

4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-3-메틸부타노일)아미노]메틸}벤조산의 제조: 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}-3-methylbutanoyl)amino]methyl}benzoic acid 4 - {[((2 S ) -2 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy Preparation of Roxy-2,7-dimethyloctanoyl] amino} -3-methylbutanoyl) amino] methyl} benzoic acid: 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyloctanoyl] amino} -3-methylbutanoyl) amino] methyl} benzoic acid

상기 제조예 9에서 얻은 화합물 대신에 상기 제조예 94에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 실시하여, 표제 화합물 36 ㎎을 43% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 94 instead of the compound obtained in Preparation Example 9 was carried out in the same manner as in Example 1, 36 mg of the title compound was obtained in 43% yield.

1H NMR (400 MHz, CD3OD); 7.95 (2H, d), 7.77 (1H, s), 7.71 (1H, d), 7.44-7.34 (9H, m), 4.46 (2H, s), 4.42 (2H, s), 4.20 (1H, m), 4.13 (1H, d), 3.62 (1H, m), 3.25 (3H, s), 2.76 (1H, m), 2.01 (1H, m), 1.86 (1H, m), 1.71-1.62 (2H, m), 1.49-1.39 (2H, m), 1.13 (3H, d), 0.96 (6H, d), 0.89 (3H, d), 0.87 (3H, d)1 H NMR (400 MHz, CD3OD); 7.95 (2H, d), 7.77 (1H, s), 7.71 (1H, d), 7.44-7.34 (9H, m), 4.46 (2H, s), 4.42 (2H, s), 4.20 (1H, m) , 4.13 (1H, d), 3.62 (1H, m), 3.25 (3H, s), 2.76 (1H, m), 2.01 (1H, m), 1.86 (1H, m), 1.71-1.62 (2H, m ), 1.49-1.39 (2H, m), 1.13 (3H, d), 0.96 (6H, d), 0.89 (3H, d), 0.87 (3H, d)

ESI MS (m/e) = 723 [M+H]+
ESI MS (m / e) = 723 [M + H] < + >

[실시예 29] Example 29                     

4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-7-메틸-2-프로필옥타노일]아미노}프로파노일)아미노]메틸}벤조산의 제조: 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-7-methyl-2-propyloctanoyl]amino}propanoyl)amino]methyl}benzoic acid 4 - {[((2 S ) -2 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy Preparation of Roxy-7-methyl-2-propyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid: 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-7-methyl-2-propyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid

상기 제조예 9에서 얻은 화합물 대신에 상기 제조예 91에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 실시하여, 표제 화합물 36 ㎎을 50% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 91 instead of the compound obtained in Preparation Example 9 was carried out in the same manner as in Example 1, 36 mg of the title compound could be obtained in 50% yield.

1H NMR (400 MHz, CD3OD); 8.04 (2H, d), 7.75 (1H, s), 7.70 (1H, d), 7.46-7.32 (9H, m), 4.46 (2H, s), 4.42 (2H, s), 4.37 (1H, m), 4.17 (1H, m), 3.58 (1H, m), 3.25 (3H, s), 2.59 (1H, m), 1.83 (1H, m), 1.68-1.55 (3H, m), 1.50 (1H, m), 1.43-1.22 (7H, m), 0.97 (3H, d), 0.95 (3H, d), 0.85 (3H, t)1 H NMR (400 MHz, CD3OD); 8.04 (2H, d), 7.75 (1H, s), 7.70 (1H, d), 7.46-7.32 (9H, m), 4.46 (2H, s), 4.42 (2H, s), 4.37 (1H, m) , 4.17 (1H, m), 3.58 (1H, m), 3.25 (3H, s), 2.59 (1H, m), 1.83 (1H, m), 1.68-1.55 (3H, m), 1.50 (1H, m ), 1.43-1.22 (7H, m), 0.97 (3H, d), 0.95 (3H, d), 0.85 (3H, t)

ESI MS (m/e) = 723 [M+H]+
ESI MS (m / e) = 723 [M + H] < + >

[실시예 30]Example 30

N-{(1S,2S,4R)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-히드록시-1-이소부틸헵칠}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-{(1S,2S,4R)-4-[({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)carbonyl]-2-hydroxy-1-isobutylheptyl}-3-[(benzylsulfonyl)(methyl)amino]benzamide N -{(1 S , 2 S , 4 R ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-hydroxy Preparation of -1-Isobutylheptyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -{(1 S , 2 S , 4 R ) -4-[({(1 S )- 1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-hydroxy-1-isobutylheptyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 실시예 25에서 얻은 화합물10 ㎎(0.014 mmol)을 메탄올 2 ㎖에 녹인 후, 활성 탄소에 흡착된 팔라듐(10%)을 가하고 수소공기하에서 하룻밤 동안 교반하였다. 셀라이트를 이용한 감압여과로 고체를 제거한 다음 감압증류로 용매를 제거하여 표제 화합물 10 ㎎을 100%수율로 얻을 수 있었다.10 mg (0.014 mmol) of the compound obtained in Example 25 was dissolved in 2 ml of methanol, and palladium (10%) adsorbed on activated carbon was added thereto, and the mixture was stirred overnight under hydrogen air. The solid was removed by vacuum filtration using celite, and then the solvent was removed by distillation under reduced pressure to obtain 10 mg of the title compound in 100% yield.

1H NMR (400 MHz, CDCl3); 7.69 (1H, s), 7.60 (1H, d), 7.39-7.21 (12H, m), 6.68 (1H, d), 6.54-6.48 (2H, m), 4.45-4.30 (2H, m), 4.29 (2H, s), 4.21 (1H, dd), 4.11 (1H, m), 3.74 (1H, m), 3.67 (1H, br), 3.16 (3H, s), 2.54 (1H, m), 2.09 (1H, m), 1.82-1.20 (9H, m), 0.97-0.84 (15H, m)1 H NMR (400 MHz, CDCl 3 ); 7.69 (1H, s), 7.60 (1H, d), 7.39-7.21 (12H, m), 6.68 (1H, d), 6.54-6.48 (2H, m), 4.45-4.30 (2H, m), 4.29 ( 2H, s), 4.21 (1H, dd), 4.11 (1H, m), 3.74 (1H, m), 3.67 (1H, br), 3.16 (3H, s), 2.54 (1H, m), 2.09 (1H , m), 1.82-1.20 (9H, m), 0.97-0.84 (15H, m)

ESI MS (m/e) = 707 [M+H]+
ESI MS (m / e) = 707 [M + H] < + >

[실시예 31]Example 31

4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-7-메틸-2-프로필옥타노일]아미노}-3-메틸부타노일)아미노]메틸}벤조산의 제조: 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-7-methyl-2-propyloctanoyl]amino}-3-methylbutanoyl)amino]methyl}benzoic acid 4 - {[((2 S ) -2 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy Preparation of Roxy-7-methyl-2-propyloctanoyl] amino} -3-methylbutanoyl) amino] methyl} benzoic acid: 4-{[(( 2S ) -2-{[( 2R , 4S , 5 S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-7-methyl-2-propyloctanoyl] amino} -3-methylbutanoyl) amino] methyl} benzoic acid

상기 실시예 25에서 얻은 화합물 대신에 상기 실시예 27에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 30과 동일한 방법으로 실시하여, 표제 화합물 10 ㎎을 100% 수율로 얻을 수 있었다.Except for using the compound obtained in Example 27 instead of the compound obtained in Example 25, it was carried out in the same manner as in Example 30, to obtain 10 mg of the title compound in 100% yield.

1H NMR (400 MHz, CD3OD); 8.49 (1H, s), 7.92 (2H, d), 7.75 (1H, s), 7.42-7.31 (9H, m), 4.46 (2H, s), 4.42-4.34 (2H, m), 4.20-4.12 (2H, m), 3.60 (1H, m), 3.26 (3H, s), 2.63 (1H, m), 1.99 (1H, m), 1.82 (1H, m),1.66-1.23 (8H, m), 0.96-0.83 (15H, m)1 H NMR (400 MHz, CD3OD); 8.49 (1H, s), 7.92 (2H, d), 7.75 (1H, s), 7.42-7.31 (9H, m), 4.46 (2H, s), 4.42-4.34 (2H, m), 4.20-4.12 ( 2H, m), 3.60 (1H, m), 3.26 (3H, s), 2.63 (1H, m), 1.99 (1H, m), 1.82 (1H, m), 1.66-1.23 (8H, m), 0.96 -0.83 (15H, m)

ESI MS (m/e) = 751 [M+H]+
ESI MS (m / e) = 751 [M + H] < + >

[실시예 32]Example 32

N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[메틸(2-치에닐술포닐)아미노]벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3-[methyl(2-thienylsulfonyl)amino]benzamide N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-iso Preparation of Butyl-4-methyl-5-oxopentyl] -3- [methyl (2-chienylsulfonyl) amino] benzamide: N -[(1 S , 2 S , 4 R ) -5-({( 1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3- [methyl (2-thienylsulfonyl) amino] benzamide

상기 제조예 56에서 얻은 화합물 대신에 상기 제조예 65에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표제 화합물 38 ㎎을 57% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 65 instead of the compound obtained in Preparation Example 56, it was carried out in the same manner as in Example 21, 38 mg of the title compound could be obtained in 57% yield.

1H NMR (400 MHz, CDCl3); 7.68 (1H, d), 7.60 (1H, d), 7.52 (1H, s), 7.40 (1H, t), 7.38-7.24 (7H, m), 7.09 (1H, t), 6.42 (1H, d), 6.35 (1H, d), 6.15 (1H, t), 4.50-4.36 (2H, m), 4.18-4.09 (2H, m), 3.88 (1H, d), 3.77 (1H, m), 3.25 (3H, s), 2.68 (1H, m), 2.09 (1H, m), 1.72-1.41 (5H, m), 1.21 (3H, d), 1.03 (3H, d), 1.01 (3H, d), 0.90 (3H, d), 0.86 (3H, d) 1 H NMR (400 MHz, CDCl 3 ); 7.68 (1H, d), 7.60 (1H, d), 7.52 (1H, s), 7.40 (1H, t), 7.38-7.24 (7H, m), 7.09 (1H, t), 6.42 (1H, d) , 6.35 (1H, d), 6.15 (1H, t), 4.50-4.36 (2H, m), 4.18-4.09 (2H, m), 3.88 (1H, d), 3.77 (1H, m), 3.25 (3H , s), 2.68 (1H, m), 2.09 (1H, m), 1.72-1.41 (5H, m), 1.21 (3H, d), 1.03 (3H, d), 1.01 (3H, d), 0.90 ( 3H, d), 0.86 (3H, d)

ESI MS (m/e) = 671 [M+H]+
ESI MS (m / e) = 671 [M + H] < + >

[실시예 33]Example 33

N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸)-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-((1S,2S,4R)-5-{[(1S)-2-(benzylamino)-1-methyl-2-oxoethyl]amino}-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl)-3-[methyl(propylsulfonyl)amino]benzamide N -(( 1S , 2S , 4R ) -5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1-iso Preparation of Butyl-4-methyl-5-oxopentyl) -3- [methyl (propylsulfonyl) amino] benzamide: N -((1 S , 2 S , 4 R ) -5-{[(1 S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl) -3- [methyl (propylsulfonyl) amino] benzamide

1-메틸-2,2,4-트리옥소-테트라히드로-2λ6,1-벤조치아진-7-카르복실산 대신에 상기 제조예 29에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 2와 동일한 방법으로 실시하여, 표제 화합물 36 ㎎을 60% 수율로 얻을 수 있었다.Example 2 except that the compound obtained in Preparation Example 29 was used instead of 1-methyl-2,2,4-trioxo-tetrahydro-2λ 6 , 1-benzothiazin-7-carboxylic acid. By the same method, 36 mg of the title compound was obtained in 60% yield.

1H NMR (400 MHz, CDCl3); 7.86 (1H, s), 7.65 (1H, d), 7.56 (1H, d), 7.42 (1H, t), 7.33-7.22 (5H, m), 6.72 (1H, d), 6.66 (1H, t), 6.57 (1H, d), 4.45-4.39 (3H, m), 4.14 (1H, m), 4.01 (1H, br), 3.74 (1H, m), 3.35 (3H, s), 2.97 (2H, t), 2.64 (1H, m), 1.87-1.66 (6H, m), 1.42 (1H, m), 1.32 (3H, d), 1.15 (3H, d), 1.02 (3H, t), 0.95 (3H, d), 0.94 (3H, d)1 H NMR (400 MHz, CDCl 3 ); 7.86 (1H, s), 7.65 (1H, d), 7.56 (1H, d), 7.42 (1H, t), 7.33-7.22 (5H, m), 6.72 (1H, d), 6.66 (1H, t) , 6.57 (1H, d), 4.45-4.39 (3H, m), 4.14 (1H, m), 4.01 (1H, br), 3.74 (1H, m), 3.35 (3H, s), 2.97 (2H, t ), 2.64 (1H, m), 1.87-1.66 (6H, m), 1.42 (1H, m), 1.32 (3H, d), 1.15 (3H, d), 1.02 (3H, t), 0.95 (3H, d), 0.94 (3H, d)

ESI MS (m/e) = 603 [M+H]+
ESI MS (m / e) = 603 [M + H] < + >

[실시예 34]Example 34

N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록 시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3-[methyl(propylsulfonyl)amino]benzamide N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1- Preparation of Isobutyl-4-methyl-5-oxopentyl] -3- [methyl (propylsulfonyl) amino] benzamide: N -[(1 S , 2 S , 4 R ) -5-({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3- [methyl (propylsulfonyl) amino] benzamide

상기 제조예 56에서 얻은 화합물 대신에 상기 제조예 29에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표제 화합물 45 ㎎을 71% 수율로 얻을 수 있었다.45 mg of the title compound was obtained in the yield of 71% by the same method as in Example 21, except that the compound obtained in Preparation Example 29 was used instead of the compound obtained in Preparation Example 56.

1H NMR (400 MHz, CDCl3+CD3OD); 7.84 (1H, s), 7.72 (1H, d), 7.55 (1H, d), 7.45 (1H, t), 7.34-7.23 (5H, m), 4.49-4.32 (2H, m), 4.16-4.06 (2H, m), 3.65 (1H, m), 3.36 (3H, s), 3.00 (2H, dd), 2.65 (1H, m), 2.02 (1H, m), 1.89-1.80 (2H, m), 1.75 (1H, m), 1.67-4.56 (3H, m), 1.42 (1H, m), 1.15 (3H, d), 1.04 (3H, t), 0.96-0.91 (6H, m), 0.89 (3H, d), 0.86 (3H, d)1 H NMR (400 MHz, CDCl 3 + CD 3 OD); 7.84 (1H, s), 7.72 (1H, d), 7.55 (1H, d), 7.45 (1H, t), 7.34-7.23 (5H, m), 4.49-4.32 (2H, m), 4.16-4.06 ( 2H, m), 3.65 (1H, m), 3.36 (3H, s), 3.00 (2H, dd), 2.65 (1H, m), 2.02 (1H, m), 1.89-1.80 (2H, m), 1.75 (1H, m), 1.67-4.56 (3H, m), 1.42 (1H, m), 1.15 (3H, d), 1.04 (3H, t), 0.96-0.91 (6H, m), 0.89 (3H, d ), 0.86 (3H, d)

ESI MS (m/e) = 631 [M+H]+
ESI MS (m / e) = 631 [M + H] < + >

[실시예 35]Example 35

N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-5-[(벤질술포닐)(메틸)아미노]-2-클로로벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-5- [(benzylsulfonyl)(methyl)amino]-2-chlorobenzamide N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-iso Butyl-4-methyl-5-oxopentyl] -5-[(benzylsulfonyl) (methyl) amino] -2-chlorobenzamide: N -[(1 S , 2 S , 4 R ) -5- ({(1 S) -1 - [(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -5- [(benzylsulfonyl) (methyl) amino ] -2-chlorobenzamide

상기 제조예 56에서 얻은 화합물 대신에 5-[(벤질술포닐)(메틸)아미노]-2-클로로벤조산을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표제 화합물 18 ㎎을 60% 수율로 얻을 수 있었다.Except for using 5-[(benzylsulfonyl) (methyl) amino] -2-chlorobenzoic acid instead of the compound obtained in Preparation 56, was carried out in the same manner as in Example 21, and 18 mg of the title compound was 60 mg. Yield in% yield.

1H-NMR (300 MHz, CDCl3); 7.48 (1H, d, J = 2.67), 7.39∼7.11 (12H, m), 6.60(1H,bs), 6.45 (1H, bs), 6.42∼6.32 (1H, m), 4.49∼4.31 (2H, m), 4.29 (2H, s), 4.12∼3.93 (3H, m), 3.82∼3.73 (1H, m), 3.12 (3H, s), 2.74∼2.60 (1H, m), 2.14∼1.98 (1H, m), 1.82∼1.49 (4H, m), 1.48∼1.31 (1H, m), 1.20 (3H, d, J = 6.99), 0.99∼0.78 (m, 12H)1 H-NMR (300 MHz, CDCl 3 ); 7.48 (1H, d, J = 2.67), 7.39-7.11 (12H, m), 6.60 (1H, bs), 6.45 (1H, bs), 6.42-6.32 (1H, m), 4.49-4.31 (2H, m ), 4.29 (2H, s), 4.12-3.93 (3H, m), 3.82-3.73 (1H, m), 3.12 (3H, s), 2.74-2.60 (1H, m), 2.14-1.98 (1H, m) ), 1.82-1.49 (4H, m), 1.48-1.31 (1H, m), 1.20 (3H, d, J = 6.99), 0.99-0.78 (m, 12H)

FAB MS (m/e) = 713 [M+H]+
FAB MS (m / e) = 713 [M + H] < + >

[실시예 36]Example 36

N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-5-(트리플루오로메틸)벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-5-(trifluoromethyl)benzamide N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-iso Preparation of Butyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -5- (trifluoromethyl) benzamide: N -[(1 S , 2 S , 4 R ) -5-({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl ) (methyl) amino] -5- (trifluoromethyl) benzamide

상기 제조예 56에서 얻은 화합물 대신에 3-[(벤질술포닐)(메틸)아미노]-5-(트리플루오로메틸)벤조산을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표제 화합물 17 ㎎을 55% 수율로 얻을 수 있었다.The same procedure as in Example 21 was carried out except that 3-[(benzylsulfonyl) (methyl) amino] -5- (trifluoromethyl) benzoic acid was used instead of the compound obtained in Preparation Example 56, 17 mg of compound could be obtained in 55% yield.

1H-NMR (300 MHz, CDCl3); 7.86∼7.83 (2H, m)7.39∼7.20 (m, 11H), 6.70 (1H, d, J= 8.58), 6.58 (1H, d, J= 9.34), 6.52∼6.41 (1H, m), .4.52∼4.27 (4H, m), 4.26∼4.09 (3H, m), 3.83∼3.69 (1H, m), 3.22 (3H, s), 2.69∼2.60 (1H, m), 2.19∼1.98 (1H, m), 1.82∼1.51 (4H, m), 1.48∼1.31 (1H, m), 1.20 (3H, d, J = 6.60), 1.07∼0.70 (m, 12H)1 H-NMR (300 MHz, CDCl 3 ); 7.86-7.83 (2H, m) 7.39-7.20 (m, 11H), 6.70 (1H, d, J = 8.58), 6.58 (1H, d, J = 9.34), 6.52-6.61 (1H, m), .4.52 -4.27 (4H, m), 4.26-4.09 (3H, m), 3.83-3.69 (1H, m), 3.22 (3H, s), 2.69-2.60 (1H, m), 2.19-1.98 (1H, m) , 1.82 to 1.51 (4H, m), 1.48 to 1.31 (1H, m), 1.20 (3H, d, J = 6.60), 1.07 to 0.70 (m, 12H)

FAB MS (m/e) = 747 [M+H]+
FAB MS (m / e) = 747 [M + H] < + >

[실시예 37]Example 37

N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-5-브로모벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-5-bromobenzamide N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-iso Butyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -5-bromobenzamide: N -[(1 S , 2 S , 4 R ) -5 - ({(1 S) -1 - [(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3 - [(benzylsulfonyl) (methyl) amino] -5-bromobenzamide

상기 제조예 56에서 얻은 화합물 대신에 3-[(벤질술포닐)(메틸)아미노]-5-브로모벤조산을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표제 화합물 20 ㎎을 63% 수율로 얻을 수 있었다.20 mg of the title compound was obtained in the same manner as in Example 21, except that 3-[(benzylsulfonyl) (methyl) amino] -5-bromobenzoic acid was used instead of the compound obtained in Preparation Example 56. Obtained in 63% yield.

1H-NMR (300 MHz, CDCl3); 7.71 (1H, s), 7.59 (1H, s), 7.44∼7.13 (11H, m), 6.80 (1H, d, J = 8.68), 6.63∼6.52 (1H, m), 6.50 (1H, d, J= 9.54), 4.46∼4.02 (7H, m), 3.80∼3.67 (1H, m), 3.13 (3H, s), 2.72∼2.58 (1H, m), 2.18∼1.93 (1H, m), 1.81∼1.49 (4H, m), 1.48∼1.33 (1H, m), 1.16 (3H, d, J= 6.90), 1.01∼0.69 (m, 12H)1 H-NMR (300 MHz, CDCl 3 ); 7.71 (1H, s), 7.59 (1H, s), 7.44-7.13 (11H, m), 6.80 (1H, d, J = 8.68), 6.63-6.62 (1H, m), 6.50 (1H, d, J = 9.54), 4.46-4.02 (7H, m), 3.80-3.67 (1H, m), 3.13 (3H, s), 2.72-2.58 (1H, m), 2.18-1.93 (1H, m), 1.81-1.49 (4H, m), 1.48-1.33 (1H, m), 1.16 (3H, d, J = 6.90), 1.01-0.96 (m, 12H)

FAB MS (m/e) = 757 [M+H]+
FAB MS (m / e) = 757 [M + H] < + >

[실시예 38]Example 38

N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-5-니트로벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-5-nitrobenzamide N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-iso Butyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -5-nitrobenzamide: N -[(1 S , 2 S , 4 R ) -5- ({(1 S) -1 - [(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3 - [(benzylsulfonyl) (methyl) amino ] -5-nitrobenzamide

상기 제조예 56에서 얻은 화합물 대신에 3-[(벤질술포닐)(메틸)아미노]-5-니트로벤조산을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표제 화합물 19 ㎎을 52% 수율로 얻을 수 있었다.Except for using 3-[(benzylsulfonyl) (methyl) amino] -5-nitrobenzoic acid instead of the compound obtained in Preparation 56, by the same method as in Example 21, 19 mg of the title compound was 52 mg. Yield in% yield.

1H-NMR (300 MHz, CDCl3); 8.31 (1H, s), 7.97 (1H, s), 7.87 (1H, s), 7.43∼7.10 (10H, m), 7.05 (1H, d, J = 8.78), 6.98∼6.83 (2H, m), 4.48∼4.08 (7H, m), 3.82∼3.69 (1H, m), 3.20 (3H, s), 2.78∼2.59 (1H, m), 2.17∼1.93 (1H, m), 1.90∼1.52 (4H, m), 1.51∼1.38 (1H, m), 1.15 (3H, d, J = 6.80), 1.06∼0.75 (m, 12H) 1 H-NMR (300 MHz, CDCl 3 ); 8.31 (1H, s), 7.97 (1H, s), 7.87 (1H, s), 7.43-7.10 (10H, m), 7.05 (1H, d, J = 8.78), 6.98-6.83 (2H, m), 4.48 to 4.08 (7H, m), 3.82 to 3.69 (1H, m), 3.20 (3H, s), 2.78 to 2.59 (1H, m), 2.17 to 1.93 (1H, m), 1.90 to 1.52 (4H, m ), 1.51 to 1.38 (1H, m), 1.15 (3H, d, J = 6.80), 1.06 to 0.75 (m, 12H)

FAB MS (m/e) = 724 [M+H]+
FAB MS (m / e) = 724 [M + H] < + >

[실시예 39]Example 39

3-아미노-N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-5-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: 3-amino-N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-5-[(benzylsulfonyl)(methyl)amino]benzamide3-amino- N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy Preparation of -1-Isobutyl-4-methyl-5-oxopentyl] -5-[(benzylsulfonyl) (methyl) amino] benzamide: 3-amino- N -[(1 S , 2 S , 4 R ) -5-({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -5-[(benzylsulfonyl) (methyl) amino] benzamide

상기 실시예 38에서 얻은 화합물 10 ㎎(0.014 mmol)과 10% Pd-C 5 ㎎을 95% 에탄올 1 ㎖에 녹인 후 수소가스하에서 16 시간 동안 교반하였다. Celite를 사용하여 여과 후 용매를 감압증류하여 표제 화합물 9 ㎎을 90% 수율로 얻을 수 있었다.10 mg (0.014 mmol) of the compound obtained in Example 38 and 5 mg of 10% Pd-C were dissolved in 1 ml of 95% ethanol, followed by stirring for 16 hours under hydrogen gas. After filtration using Celite, the solvent was distilled under reduced pressure to obtain 9 mg of the title compound in 90% yield.

1H-NMR (300 MHz, CDCl3); 7.45∼7.09 (11H, m), 6.97∼6.79 (2H, m), 6.69∼6.38 (3H, m), 4.48∼3.99 (7H, m), 3.79∼3.62 (1H, m), 3.12 (3H, s), 2.78∼2.59 (1H, m), 2.21∼1.93 (1H, m), 1.90∼1.49 (4H, m), 1.48∼1.12 (3H, m), 1.15 (3H, J = 5.35, d), 1.03∼0.68 (m, 12H)1 H-NMR (300 MHz, CDCl 3 ); 7.45-7.09 (11H, m), 6.97-6.69 (2H, m), 6.69-6.38 (3H, m), 4.48-3.99 (7H, m), 3.79-3.62 (1H, m), 3.12 (3H, s ), 2.78-2.59 (1H, m), 2.21-1.93 (1H, m), 1.90-1.49 (4H, m), 1.48-1.12 (3H, m), 1.15 (3H, J = 5.35, d), 1.03 -0.68 (m, 12H)

FAB MS (m/e) = 694 [M+H]+
FAB MS (m / e) = 694 [M + H] < + >

[실시예 40] Example 40                     

N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-5-시아노벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-5-cyanobenzamide N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-iso Butyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -5-cyanobenzamide: N -[(1 S , 2 S , 4 R ) -5 - ({(1 S) -1 - [(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3 - [(benzylsulfonyl) (methyl) amino] -5-cyanobenzamide

상기 제조예 56에서 얻은 화합물 대신에 3-[(벤질술포닐)(메틸)아미노]-5-시아노벤조산을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표제 화합물 12 ㎎을 40% 수율로 얻을 수 있었다.12 mg of the title compound was obtained in the same manner as in Example 21, except that 3-[(benzylsulfonyl) (methyl) amino] -5-cyanobenzoic acid was used instead of the compound obtained in Preparation Example 56. 40% yield was obtained.

1H-NMR (300 MHz, CDCl3); 7.89∼7.75(2H, m), 7.48∼7.06(11H, m), 6.80(1H, bs), 6.72∼6.55(2H, m), 4.49∼4.02(7H, m), 3.79∼3.66(1H, m), 3.21(3H, s), 2.74∼2.59(1H, m), 2.19∼1.91(1H, m), 1.86∼1.51(4H, m), 1.50∼1.33(1H, m), 1.17(3H, d, J = 6.93), 1.06∼0.72(m, 12H)1 H-NMR (300 MHz, CDCl 3 ); 7.89-7.75 (2H, m), 7.48-7.06 (11H, m), 6.80 (1H, bs), 6.72-6.65 (2H, m), 4.49-4.02 (7H, m), 3.79-3.66 (1H, m) ), 3.21 (3H, s), 2.74-2.59 (1H, m), 2.19-1.91 (1H, m), 1.86-1.51 (4H, m), 1.50-1.33 (1H, m), 1.17 (3H, d , J = 6.93), 1.06-0.72 (m, 12H)

FAB MS (m/e) = 704 [M+H]+
FAB MS (m / e) = 704 [M + H] < + >

[실시예 41]Example 41

N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-5-메틸벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3- [(benzylsulfonyl)(methyl)amino]-5-methylbenzamide N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-iso Butyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -5-methylbenzamide: N -[(1 S , 2 S , 4 R ) -5- ({(1 S) -1 - [(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3- [(benzylsulfonyl) (methyl) amino ] -5-methylbenzamide

상기 제조예 56에서 얻은 화합물 대신에 3-[(벤질술포닐)(메틸)아미노]-5-메틸벤조산을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표제 화합물 21 ㎎을 73% 수율로 얻을 수 있었다.Except for using 3-[(benzylsulfonyl) (methyl) amino] -5-methylbenzoic acid instead of the compound obtained in Preparation 56, by the same method as in Example 21, 21 mg of the title compound was 73 mg. Yield in% yield.

1H-NMR (300 MHz, CDCl3); 7.54∼7.15 (12H, m), 7.11 (1H, s), 6.72 (1H, bs), 6.52∼6.33 (2H, m), 4.48∼4.99 (7H, m), 3.76∼3.63 (1H, m), 3.14 (3H, s), 2.75∼2.56 (1H, m), 2.33 (3H, s), 2.18∼1.97 (1H, m), 1.82∼1.49 (4H, m), 1.16 (3H, d, J = 6.92), 1.01∼0.63 (12H, m)1 H-NMR (300 MHz, CDCl 3 ); 7.54-7.15 (12H, m), 7.11 (1H, s), 6.72 (1H, bs), 6.52-6.63 (2H, m), 4.48-4.99 (7H, m), 3.76-3.63 (1H, m), 3.14 (3H, s), 2.75 to 2.56 (1H, m), 2.33 (3H, s), 2.18 to 1.97 (1H, m), 1.82 to 1.49 (4H, m), 1.16 (3H, d, J = 6.92 ), 1.01 to 0.63 (12H, m)

FAB MS (m/e) = 693 [M+H]+
FAB MS (m / e) = 693 [M + H] < + >

[실시예 42]Example 42

N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-5-클로로벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-5-chlorobenzamide N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-iso Butyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -5-chlorobenzamide: N -[(1 S , 2 S , 4 R ) -5- ({(1 S) -1 - [(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3 - [(benzylsulfonyl) (methyl) amino ] -5-chlorobenzamide

상기 제조예 56에서 얻은 화합물 대신에 3-[(벤질술포닐)(메틸)아미노]-5-클로로벤조산을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표제 화합물 19 ㎎을 64% 수율로 얻을 수 있었다. Example 19, except that 3-[(benzylsulfonyl) (methyl) amino] -5-chlorobenzoic acid was used instead of the compound obtained in Preparation 56, 19 mg of the titled compound was 64 mg. Yield in% yield.                     

1H-NMR (300 MHz, CDCl3); 7.56∼7.53 (2H, m), 7.30∼7.09 (m, 11H), 6.64 (1H, bs), 6.44∼6.34 (2H, m), 4.48∼4.18 (6H, m), 4.16∼4.05 (1H, m), 3.80∼3.68 (1H, bs), 3.09 (3H, s), 2.75∼2.60 (1H, m), 1.82∼1.51 (5H, m), 1.17 (3H, d, J = 6.78), 0.99∼0.68 (12H, m)1 H-NMR (300 MHz, CDCl 3 ); 7.56 to 7.53 (2H, m), 7.30 to 7.09 (m, 11H), 6.64 (1H, bs), 6.44 to 6.34 (2H, m), 4.48 to 4.18 (6H, m), 4.16 to 4.05 (1H, m ), 3.80 to 3.68 (1H, bs), 3.09 (3H, s), 2.75 to 2.60 (1H, m), 1.82 to 1.51 (5H, m), 1.17 (3H, d, J = 6.78), 0.99 to 0.68 (12H, m)

FAB MS (m/e) = 713 [M+H]+
FAB MS (m / e) = 713 [M + H] < + >

[실시예 43]Example 43

N1-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-5-[(벤질술포닐)(메틸)아미노]이소프탈아미드의 제조: N1-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-5-[(benzylsulfonyl)(methyl)amino]isophthalamide N 1-[(1 S , 2 S , 4 R ) -5-({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1- Preparation of Isobutyl-4-methyl-5-oxopentyl] -5-[(benzylsulfonyl) (methyl) amino] isophthalamide: N 1-[(1 S , 2 S , 4 R ) -5- ( {(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -5-[(benzylsulfonyl) (methyl) amino] isophthalamide

상기 제조예 56에서 얻은 화합물 대신에 3-(아미노카르보닐)-5-[(벤질술포닐)(메틸)아미노]벤조산을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표제 화합물 17 ㎎을 57% 수율로 얻을 수 있었다.The title compound was carried out in the same manner as in Example 21, except that 3- (aminocarbonyl) -5-[(benzylsulfonyl) (methyl) amino] benzoic acid was used instead of the compound obtained in Preparation Example 56. 17 mg was obtained in 57% yield.

1H-NMR (300 MHz, CDCl3); 8.41 (1H, s), 7.92 (1H, s), 7.65 (1H, s), 7.50∼7.26 (11H, m), 6.40 (2H, m), 4.63∼4.48 (6H, m), 4.37∼4.32 (4H, m), 3.23∼3.19 (3H, bs), 2.79∼2.59 (1H, m), 2.59∼2.45 (1H, m), 2.01∼1.51 (5H, m), 1.39∼1.36 (3H, d, J = 9.09), 0.99∼0.68 (12H, m) 1 H-NMR (300 MHz, CDCl 3 ); 8.41 (1H, s), 7.92 (1H, s), 7.65 (1H, s), 7.50-7.26 (11H, m), 6.40 (2H, m), 4.63-4.48 (6H, m), 4.37-4.32 ( 4H, m), 3.23 to 3.19 (3H, bs), 2.79 to 2.59 (1H, m), 2.59 to 2.45 (1H, m), 2.01 to 1.51 (5H, m), 1.39 to 1.36 (3H, d, J = 9.09), 0.99-0.68 (12H, m)

FAB MS (m/e) = 722 [M+H]+
FAB MS (m / e) = 722 [M + H] < + >

[실시예 44]Example 44

메틸 3-({[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]아미노}카르보닐)-5-[(벤질술포닐)(메틸)아미노]벤조에이트의 제조: methyl 3-({[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]amino}carbonyl)-5-[(benzylsulfonyl)(methyl)amino]benzoateMethyl 3-({[(1 S , 2 S , 4 R ) -5-({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- Preparation of 1-isobutyl-4-methyl-5-oxopentyl] amino} carbonyl) -5-[(benzylsulfonyl) (methyl) amino] benzoate: methyl 3-({[(1 S , 2 S , 4 R ) -5-({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] amino} carbonyl) -5-[(benzylsulfonyl) (methyl) amino] benzoate

상기 제조예 56에서 얻은 화합물 대신에 3-[(벤질술포닐)(메틸)아미노]-5-(메톡시카르보닐)벤조산을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표제 화합물 19 ㎎을 63% 수율로 얻을 수 있었다.The procedure of Example 21 was repeated except that 3-[(benzylsulfonyl) (methyl) amino] -5- (methoxycarbonyl) benzoic acid was used instead of the compound obtained in Preparation Example 56, 19 mg of compound could be obtained in 63% yield.

1H-NMR (300 MHz, CDCl3); 8.25 (1H, s), 7.93 (2H, d, J = 8.81), 7.28∼7.19 (11H, m), 6.69∼6.49 (1H, m), 6.49∼6.30 (1H, m), 4.58∼4.18 (6H, m), 3.90 (3H, s), 3.80∼3.71 (1H, m), 3.18 (3H, s), 2.75∼2.60 (1H, m), 2.18∼1.51 (5H, m), 1.18 (3H, d, J = 6.89), 0.99∼0.68 (12H, m)1 H-NMR (300 MHz, CDCl 3 ); 8.25 (1H, s), 7.93 (2H, d, J = 8.81), 7.28-7.19 (11H, m), 6.69-6.69 (1H, m), 6.49-6.30 (1H, m), 4.58-4.18 (6H , m), 3.90 (3H, s), 3.80-3.71 (1H, m), 3.18 (3H, s), 2.75-2.60 (1H, m), 2.18-1.51 (5H, m), 1.18 (3H, d , J = 6.89), 0.99-0.68 (12H, m)

FAB MS (m/e) = 737 [M+H]+
FAB MS (m / e) = 737 [M + H] < + >

[실시예 45]Example 45

벤질 3-({[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)- 2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]아미노}카르보닐)-5-[(벤질술포닐)(메틸)아미노]벤조에이트의 제조: benzyl 3-({[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]amino}carbonyl)-5-[(benzylsulfonyl)(methyl)amino]benzoateBenzyl 3-({[(1 S , 2 S , 4 R ) -5-({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2 -hydroxy- Preparation of 1-isobutyl-4-methyl-5-oxopentyl] amino} carbonyl) -5-[(benzylsulfonyl) (methyl) amino] benzoate: benzyl 3-({[(1 S , 2 S , 4 R ) -5-({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] amino} carbonyl) -5-[(benzylsulfonyl) (methyl) amino] benzoate

상기 제조예 56에서 얻은 화합물 대신에 3-[(벤질옥시)카르보닐]-5-[(벤질술포닐)(메틸)아미노]벤조산을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표제 화합물 19 ㎎을 56% 수율로 얻을 수 있었다.The procedure of Example 21 was repeated except that 3-[(benzyloxy) carbonyl] -5-[(benzylsulfonyl) (methyl) amino] benzoic acid was used instead of the compound obtained in Preparation Example 56. 19 mg of the title compound were obtained in 56% yield.

1H-NMR (300 MHz, CDCl3); 8.03∼7.90 (1H, m), 7.80∼7.60 (2H, m)7.49∼7.10 (15H, m), 6.65∼6.20 (3H, m), 4.65∼4.46 (3H, m), 4.45∼4.18 (6H, m), 4.16∼4.05 (1H, m), 3.76∼3.66 (1H, bs), 3.17 (3H, s), 2.75∼2.60 (1H, m), 1.82∼1.51 (5H, m), 1.02 (3H, d, J = 6.82), 0.99∼0.68 (12H, m)1 H-NMR (300 MHz, CDCl 3 ); 8.03 to 7.90 (1H, m), 7.80 to 7.60 (2H, m) 7.49 to 7.10 (15H, m), 6.65 to 6.30 (3H, m), 4.65 to 4.66 (3H, m), 4.45 to 4.18 (6H, m), 4.16 to 4.05 (1H, m), 3.76 to 3.66 (1H, bs), 3.17 (3H, s), 2.75 to 2.60 (1H, m), 1.82 to 1.51 (5H, m), 1.02 (3H, d, J = 6.82), 0.99-0.68 (12H, m)

FAB MS (m/e) = 813 [M+H]+
FAB MS (m / e) = 813 [M + H] < + >

[실시예 46]Example 46

N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-4-메톡시벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-4-methoxybenzamide N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-iso Preparation of Butyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -4-methoxybenzamide: N -[(1 S , 2 S , 4 R ) -5 - ({(1 S) -1 - [(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3 - [(benzylsulfonyl) (methyl) amino] -4-methoxybenzamide

상기 제조예 56에서 얻은 화합물 대신에 3-[(벤질술포닐)(메틸)아미노]-4-메톡시벤조산을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표제 화합물 19 ㎎을 66% 수율로 얻을 수 있었다.19 mg of the title compound was obtained in the same manner as in Example 21, except that 3-[(benzylsulfonyl) (methyl) amino] -4-methoxybenzoic acid was used instead of the compound obtained in Preparation Example 56. Obtained at 66% yield.

1H-NMR (300 MHz, CDCl3); 7.83 (1H, d, J = 8.70), 7.56 (1H, s), 7.49∼7.22 (10H, m), 6.97 (1H, d, J= 8.73), 6.67 (1H, bs), 6.59∼6.48 (1H, m), 6.35 (1H, bs), 4.48∼4.22 (4H, m), 4.21∼4.03 (2H, m), 3.96 (3H, s), 3.92∼3.77 (1H, m), 3.75∼3.62 (1H, m), 3.09 (3H, s), 2.74∼2.58 (1H, m), 2.19∼1.98 (1H, m), 1.82∼1.48 (4H, m), 1.15 (3H, d, J = 6.92), 1.01∼0.69 (12H, m)1 H-NMR (300 MHz, CDCl 3 ); 7.83 (1H, d, J = 8.70), 7.56 (1H, s), 7.49-7.22 (10H, m), 6.97 (1H, d, J = 8.73), 6.67 (1H, bs), 6.59-6.68 (1H , m), 6.35 (1H, bs), 4.48-4.22 (4H, m), 4.21-4.03 (2H, m), 3.96 (3H, s), 3.92-3.77 (1H, m), 3.75-3.62 (1H , m), 3.09 (3H, s), 2.74 to 2.58 (1H, m), 2.19 to 1.98 (1H, m), 1.82 to 1.48 (4H, m), 1.15 (3H, d, J = 6.92), 1.01 -0.69 (12H, m)

FAB MS (m/e) = 709 [M+H]+
FAB MS (m / e) = 709 [M + H] < + >

[실시예 47]Example 47

N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-4-플루오로벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-4-fluorobenzamide N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-iso Preparation of Butyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -4-fluorobenzamide: N -[(1 S , 2 S , 4 R ) -5 - ({(1 S) -1 - [(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3 - [(benzylsulfonyl) (methyl) amino] -4-fluorobenzamide

상기 제조예 56에서 얻은 화합물 대신에 3-[(벤질술포닐)(메틸)아미노]-4-플루오로벤조산을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표제 화합물 20 ㎎을 69% 수율로 얻을 수 있었다.20 mg of the title compound was obtained in the same manner as in Example 21, except that 3-[(benzylsulfonyl) (methyl) amino] -4-fluorobenzoic acid was used instead of the compound obtained in Preparation Example 56. Yield was 69% yield.

1H-NMR (300 MHz, CDCl3); 7.83∼7.61 (2H, m), 7.53∼7.09 (11H, m), 6.84 (1H, bs), 6.79∼6.65 (1H, m), 6.49 (1H, bs), 4.50∼4.01 (7H, m), 3.74∼3.62 (1H, m), 3.09 (3H, s), 2.77∼2.58 (1H, m), 2.12∼1.92 (1H, m), 1.85∼1.51 (4H, m), 1.50∼1.32 (1H, m), 1.14 (3H, d, J = 6.93), 1.01∼0.68 (12H, m)1 H-NMR (300 MHz, CDCl 3 ); 7.83-7.61 (2H, m), 7.53-7.09 (11H, m), 6.84 (1H, bs), 6.79-6.65 (1H, m), 6.49 (1H, bs), 4.50-4.01 (7H, m), 3.74-3.62 (1H, m), 3.09 (3H, s), 2.77-2.58 (1H, m), 2.12-1.92 (1H, m), 1.85-1.51 (4H, m), 1.50-1.32 (1H, m ), 1.14 (3H, d, J = 6.93), 1.01-0.68 (12H, m)

FAB MS (m/e) = 697 [M+H]+
FAB MS (m / e) = 697 [M + H] < + >

[실시예 48]Example 48

N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-4-클로로벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-4-chlorobenzamide N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-iso Preparation of Butyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -4-chlorobenzamide: N -[(1 S , 2 S , 4 R ) -5- ({(1 S) -1 - [(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3 - [(benzylsulfonyl) (methyl) amino ] -4-chlorobenzamide

상기 제조예 56에서 얻은 화합물 대신에 3-[(벤질술포닐)(메틸)아미노]-4-클로로벤조산을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표제 화합물 18 ㎎을 60% 수율로 얻을 수 있었다.Except for using 3-[(benzylsulfonyl) (methyl) amino] -4-chlorobenzoic acid instead of the compound obtained in Preparation 56, by the same method as in Example 21, 18 mg of the title compound was 60 mg. Yield in% yield.

1H-NMR (300 MHz, CDCl3); 7.71∼7.56 (2H, m), 7.49∼7.10 (11H, m), 6.80 (1H, bs), 6.73∼6.62 (1H, m), 6.49 (1H, bs), 4.43∼4.02 (7H, m), 3.76∼3.61 (1H, m), 3.11 (3H, s), 2.72∼2.58 (1H, m), 2.11∼1.92 (1H, m), 1.81∼1.48 (4H, m), 1.46∼1.32 (1H, m), 1.14 (3H, d, J= 6.90), 0.99∼0.67 (12H, m)1 H-NMR (300 MHz, CDCl 3 ); 7.71 to 7.56 (2H, m), 7.49 to 7.10 (11H, m), 6.80 (1H, bs), 6.73 to 6.62 (1H, m), 6.49 (1H, bs), 4.43 to 4.02 (7H, m), 3.76-3.61 (1H, m), 3.11 (3H, s), 2.72-2.58 (1H, m), 2.11-1.92 (1H, m), 1.81-1.48 (4H, m), 1.46-1.32 (1H, m) ), 1.14 (3H, d, J = 6.90), 0.99-0.67 (12H, m)

FAB MS (m/e) = 713 [M+H]+
FAB MS (m / e) = 713 [M + H] < + >

[실시예 49]Example 49

N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-5-[(벤질술포닐)(메틸)아미노]-2-메톡시벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-5-[(benzylsulfonyl)(methyl)amino]-2-methoxybenzamide N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-iso Butyl-4-methyl-5-oxopentyl] -5-[(benzylsulfonyl) (methyl) amino] -2-methoxybenzamide: N -[(1 S , 2 S , 4 R ) -5 - ({(1 S) -1 - [(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -5 - [(benzylsulfonyl) (methyl) amino] -2-methoxybenzamide

상기 제조예 56에서 얻은 화합물 대신에 5-[(벤질술포닐)(메틸)아미노]-2-메톡시벤조산을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표제 화합물 18 ㎎을 61% 수율로 얻을수 있었다.18 mg of the title compound was obtained in the same manner as in Example 21, except that 5-[(benzylsulfonyl) (methyl) amino] -2-methoxybenzoic acid was used instead of the compound obtained in Preparation Example 56. Yield 61% yield.

1H-NMR (300 MHz, CDCl3); 8.39 (1H, d, J = 8.40), 8.04 (1H, s), 7.49∼7.15 (13H, m), 6.9 7(1H, d, J = 8.97), 6.50∼6.30 (1H, m), .4.48∼4.18 (5H, m), 4.24 (2H, s), 3.98 (3H, s), 3.12 (3H, s), 2.75∼2.60 (1H, m), 1.82∼1.51 (5H, m), 1.16 (3H, d, J = 7.08), 0.99∼0.68 (12H, m)1 H-NMR (300 MHz, CDCl 3 ); 8.39 (1H, d, J = 8.40), 8.04 (1H, s), 7.49-7.15 (13H, m), 6.9 7 (1H, d, J = 8.97), 6.50-6.30 (1H, m), .4.48 -4.18 (5H, m), 4.24 (2H, s), 3.98 (3H, s), 3.12 (3H, s), 2.75-2.60 (1H, m), 1.82-1.51 (5H, m), 1.16 (3H , d, J = 7.08), 0.99 to 0.68 (12H, m)

FAB MS (m/e) = 709 [M+H]+
FAB MS (m / e) = 709 [M + H] < + >

[실시예 50] Example 50                     

N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-{메틸[(2-니트로벤질)술포닐]아미노}벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3-{methyl[(2-nitrobenzyl)sulfonyl]amino}benzamide N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-iso Butyl-4-methyl-5-oxopentyl] -3- {methyl [(2-nitrobenzyl) sulfonyl] amino} benzamide: N -[(1 S , 2 S , 4 R ) -5- ( {(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3- {methyl [(2-nitrobenzyl) sulfonyl ] amino} benzamide

상기 제조예 56에서 얻은 화합물 대신에 3-{메틸[(2-니트로벤질)술포닐]아미노}벤조산을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표제 화합물 19 ㎎을 63% 수율로 얻을 수 있었다.Except for using 3- {methyl [(2-nitrobenzyl) sulfonyl] amino} benzoic acid in place of the compound obtained in Preparation Example 56, 63% of the title compound was obtained in the same manner as in Example 21. Yield was obtained.

1H-NMR (300 MHz, CDCl3); 8.09∼7.91 (1H, m), 7.77 (1H, s), 7.70∼7.12 (10H, m), 7.00 (1H, bs), 6.93∼6.81 (1H, m), 6.64 (1H, bs), 4.85 (2H, s), 4.42∼4.03 (5H, m), 3.78∼3.64 (1H, m), 3.30 (3H, s), 2.78∼2.69 (1H, m), 2.15∼1.97 (1H, m), 1.87∼1.64 (4H, m), 1.47∼1.32 (1H, m), 1.12 (3H, d, J = 6.81), 1.01∼0.70 (12H, m)1 H-NMR (300 MHz, CDCl 3 ); 8.09 to 7.91 (1H, m), 7.77 (1H, s), 7.70 to 7.72 (10H, m), 7.00 (1H, bs), 6.93 to 6.81 (1H, m), 6.64 (1H, bs), 4.85 ( 2H, s), 4.42 to 4.03 (5H, m), 3.78 to 3.64 (1H, m), 3.30 (3H, s), 2.78 to 2.69 (1H, m), 2.15 to 1.97 (1H, m), 1.87 to 1.64 (4H, m), 1.47-1.32 (1H, m), 1.12 (3H, d, J = 6.81), 1.01-0.70 (12H, m)

FAB MS (m/e) = 724 [M+H]+
FAB MS (m / e) = 724 [M + H] < + >

[실시예 51]Example 51

3-[[(2-아미노벤질)술포닐](메틸)아미노]-N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]벤즈아미드의 제조: 3-[[(2-aminobenzyl)sulfonyl](methyl)amino]-N-[(1S,2S,4R)-5- ({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]benzamide3-[[(2-aminobenzyl) sulfonyl] (methyl) amino] -N -[(1 S , 2 S , 4 R ) -5-({(1 S ) -1-[(benzylamino) car Preparation of Bonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] benzamide: 3-[[(2-aminobenzyl) sulfonyl] (methyl) amino ] -N -[(1 S , 2 S , 4 R ) -5- ({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4 -methyl-5-oxopentyl] benzamide

상기 실시예 38에서 얻은 화합물 대신에 상기 실시예 50에서 얻은 화합물 사용한 것을 제외하고는, 실시예 39와 동일한 방법으로 실시하여, 표제 화합물 8 ㎎을 80% 수율로 얻을 수 있었다.In the same manner as in Example 39, except that the compound obtained in Example 50 was used instead of the compound obtained in Example 38, 8 mg of the title compound could be obtained in 80% yield.

1H-NMR (300 MHz, CDCl3); 7.79∼7.52 (2H, m), 7.43∼6.88 (10H, m), 6.85∼6.39 (4H, m), 4.53∼4.01 (7H, m), 3.80∼3.60 (1H, m), 3.24 (3H, s), 2.76∼2.58 (1H, m), 2.21∼1.94(1H, m), 1.88∼1.51 (4H, m), 1.48∼1.19 (3H, m), 1.13 (3H, d, J = 6.28), 1.02∼0.62 (12H, m)1 H-NMR (300 MHz, CDCl 3 ); 7.79-7.52 (2H, m), 7.43-6.88 (10H, m), 6.85-6.39 (4H, m), 4.53-4.01 (7H, m), 3.80-3.60 (1H, m), 3.24 (3H, s ), 2.76 to 2.58 (1H, m), 2.21 to 1.94 (1H, m), 1.88 to 1.51 (4H, m), 1.48 to 1.19 (3H, m), 1.13 (3H, d, J = 6.28), 1.02 -0.62 (12H, m)

FAB MS (m/e) = 694 [M+H]+
FAB MS (m / e) = 694 [M + H] < + >

[실시예 52]Example 52

N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-{메틸[(2-메틸벤질)술포닐]아미노}벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3-{methyl[(2-methylbenzyl)sulfonyl]amino}benzamide N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-iso Preparation of Butyl-4-methyl-5-oxopentyl] -3- {methyl [(2-methylbenzyl) sulfonyl] amino} benzamide: N -[(1 S , 2 S , 4 R ) -5- ( {(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3- {methyl [(2-methylbenzyl) sulfonyl ] amino} benzamide

상기 제조예 56에서 얻은 화합물 대신에 3-{메틸[(2-메틸벤질)술포닐]아미노}벤조산을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표 제 화합물 19 ㎎을 65% 수율로 얻을 수 있었다.Except for using 3- {methyl [(2-methylbenzyl) sulfonyl] amino} benzoic acid in place of the compound obtained in Preparation Example 56, the same procedure as in Example 21 was carried out to obtain 19 mg of the title compound. Yield in% yield.

1H-NMR (300 MHz, CDCl3); 8.04 (1H, d, J = 8.40), 7.68 (1H, d, J = 8.34), 7.56 (2H, t, J = 6.96), 7.49∼7.09 (11H, m), 7.01 (1H, bs), 6.80∼6.70 (1H, m), 4.70∼4.60 (1H, m), 4.48∼4.18 (7H, m), 3.89 (3H, s), 3.76∼3.66 (1H, m), 3.05 (3H, s), 2.75∼2.40 (1H, m), 2.01∼1.51 (5H, m), 1.15 (3H, d, J = 6.93), 0.99∼0.68 (12H, m)1 H-NMR (300 MHz, CDCl 3 ); 8.04 (1H, d, J = 8.40), 7.68 (1H, d, J = 8.34), 7.56 (2H, t, J = 6.96), 7.49-7.09 (11H, m), 7.01 (1H, bs), 6.80 -6.70 (1H, m), 4.70-4.60 (1H, m), 4.48-4.18 (7H, m), 3.89 (3H, s), 3.76-3.66 (1H, m), 3.05 (3H, s), 2.75 -2.40 (1H, m), 2.01-1.51 (5H, m), 1.15 (3H, d, J = 6.93), 0.99-0.68 (12H, m)

FAB MS (m/e) = 693 [M+H]+
FAB MS (m / e) = 693 [M + H] < + >

[실시예 53]Example 53

N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-{메틸[(3-메틸벤질)술포닐]아미노}벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3-{methyl[(3-methylbenzyl)sulfonyl]amino}benzamide N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-iso Preparation of Butyl-4-methyl-5-oxopentyl] -3- {methyl [(3-methylbenzyl) sulfonyl] amino} benzamide: N -[(1 S , 2 S , 4 R ) -5- ( {(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3- {methyl [(3-methylbenzyl) sulfonyl ] amino} benzamide

상기 제조예 56에서 얻은 화합물 대신에 3-{메틸[(3-메틸벤질)술포닐]아미노}벤조산을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표제 화합물 14 ㎎을 50% 수율로 얻을 수 있었다.Except for using 3- {methyl [(3-methylbenzyl) sulfonyl] amino} benzoic acid in place of the compound obtained in Preparation Example 56, 50% of the title compound was carried out in the same manner as in Example 21. Yield was obtained.

1H-NMR (300 MHz, CDCl3); 7.76 (1H, s), 7.69∼7.55 (1H, m), 7.48∼6.99 (13H, m), 6.78∼6.59 (1H, m), 4.49∼4.02 (7H, m), 3.79∼3.63 (1H, m), 3.16 (3H, s), 2.79∼2.56 (1H, m), 2.32 (3H, s), 2.18∼1.93 (1H, m), 1.82∼1.49 (4H, m), 1.47∼1.32 (1H, m), 1.11 (3H, d, J = 6.15), 1.01∼0.62 (12H, m)1 H-NMR (300 MHz, CDCl 3 ); 7.76 (1H, s), 7.69 to 7.55 (1H, m), 7.48 to 6.99 (13H, m), 6.78 to 6.69 (1H, m), 4.49 to 4.02 (7H, m), 3.79 to 3.63 (1H, m ), 3.16 (3H, s), 2.79 to 2.56 (1H, m), 2.32 (3H, s), 2.18 to 1.93 (1H, m), 1.82 to 1.49 (4H, m), 1.47 to 1.32 (1H, m) ), 1.11 (3H, d, J = 6.15), 1.01-0.62 (12H, m)

FAB MS (m/e) = 693 [M+H]+
FAB MS (m / e) = 693 [M + H] < + >

[실시예 54]Example 54

N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틴]-3-{메틸[(4-메틸벤질)술포닐]아미노}벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3-{methyl[(4-methylbenzyl)sulfonyl]amino}benzamide N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-iso butyl-4-methyl-5-oxo-pentyne] -3- {methyl [(4-methylbenzyl) sulfonyl] amino} benzamide Preparation of: N - [(1 S, 2 S, 4 R) -5- ( {(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3- {methyl [(4-methylbenzyl) sulfonyl ] amino} benzamide

상기 제조예 56에서 얻은 화합물 대신에 3-{메틸[(4-메틸벤질)술포닐]아미노}벤조산을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표제 화합물 19 ㎎을 65% 수율로 얻을 수 있었다.Except for using 3- {methyl [(4-methylbenzyl) sulfonyl] amino} benzoic acid in place of the compound obtained in Preparation Example 56, 65% of the title compound was obtained in the same manner as in Example 21. Yield was obtained.

1H-NMR (300 MHz, CDCl3); 8.04 (1H, d, J = 8.40), 7.68 (1H, d, J = 8.34), 7.56 (2H, t, J = 6.96), 7.51∼7.10 (11H, m), 7.01 (1H, bs), 6.93∼6.71 (1H, m), 4.70∼4.18 (7H, m), 3.88 (3H, s), 3.76∼3.66 (1H, m), 3.04 (3H, s), 2.75∼2.40 (1H, m), 2.01∼1.51 (5H, m), 1.15 (3H, d, J = 6.93), 0.97∼0.66 (12H, m)1 H-NMR (300 MHz, CDCl 3 ); 8.04 (1H, d, J = 8.40), 7.68 (1H, d, J = 8.34), 7.56 (2H, t, J = 6.96), 7.51-7.10 (11H, m), 7.01 (1H, bs), 6.93 -6.71 (1H, m), 4.70-4.18 (7H, m), 3.88 (3H, s), 3.76-3.66 (1H, m), 3.04 (3H, s), 2.75-2.40 (1H, m), 2.01 -1.51 (5H, m), 1.15 (3H, d, J = 6.93), 0.97-0.66 (12H, m)

FAB MS (m/e) = 693 [M+H]+
FAB MS (m / e) = 693 [M + H] < + >

[제조예 95][Manufacture example 95]

tert-부틸 (1S)-3-메틸-1-[(2R,4R)-5-옥소-4-(2-프로핀일)테트라히드로-2-퓨라닐]부틸카르바메이트의 제조: tert-butyl (1S)-3-methyl-1-[(2R,4R)-5-oxo-4-(2-propynyl)tetrahydro-2-furanyl]butylcarbamatePreparation of tert -butyl (1 S ) -3-methyl-1-[(2 R , 4 R ) -5-oxo-4- (2-propynyl) tetrahydro-2-furanyl] butylcarbamate: tert -butyl (1 S ) -3-methyl-1-[(2 R , 4 R ) -5-oxo-4- (2-propynyl) tetrahydro-2-furanyl] butylcarbamate

아이오도메탄 대신에 프로파질브로마이드를 사용한 것을 제외하고는, 제조예 2와 동일한 방법으로 실시하여, 표제 화합물 0.32 g을 52% 수율로 얻을 수 있었다.0.32 g of the title compound was obtained in a 52% yield, using the same method as in Preparation Example 2, except that propazylbromide was used instead of iodomethane.

1H NMR (400 MHz, CDCl3); 4.57 (1H, t), 4.33 (1H, d), 3.88 (1H, m), 2.84 (1H, m), 2.65-2.50 (2H, m), 2.44 (1H, m), 2.30 (1H, m), 2.02 (1H, t), 1.66 (1H, m), 1.52 (1H, m), 1.44 (9H, s), 1.35 (1H, m), 0.94 (3H, d), 0.92 (3H, d)
1 H NMR (400 MHz, CDCl 3 ); 4.57 (1H, t), 4.33 (1H, d), 3.88 (1H, m), 2.84 (1H, m), 2.65-2.50 (2H, m), 2.44 (1H, m), 2.30 (1H, m) , 2.02 (1H, t), 1.66 (1H, m), 1.52 (1H, m), 1.44 (9H, s), 1.35 (1H, m), 0.94 (3H, d), 0.92 (3H, d)

[제조예 96][Production Example 96]

3-[(벤질술포닐)(메틸)아미노]-N-{(1S)-3-메틸-1-[(2R,4R)-5-옥소-4-(2-프로핀일)테트라히드로-2-퓨라닐]부틸}벤즈아미드의 제조: 3-[(benzylsulfonyl)(methyl)amino]-N-{(1S)-3-methyl-1-[(2R,4R)-5-oxo-4-(2-propynyl)tetrahydro-2-furanyl]butyl}benzamide3 - [(benzyl-sulfonyl) (methyl) amino] - N - {(1 S ) -3- methyl -1 - [(2 R, 4 R) -5- oxo-4- (2-propynyl) tetrahydro Preparation of hydro-2-furanyl] butyl} benzamide: 3-[(benzylsulfonyl) (methyl) amino] -N -{(1 S ) -3-methyl-1-[(2 R , 4 R ) -5 -oxo-4- (2-propynyl) tetrahydro-2-furanyl] butyl} benzamide

상기 제조예 86에서 얻은 화합물 대신에 상기 제조예 95에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 87과 동일한 방법으로 실시하여, 표제 화합물 0.42 g을 81% 수율로 얻을 수 있었다. Except for using the compound obtained in Preparation Example 95 instead of the compound obtained in Preparation Example 86, in the same manner as in Preparation Example 87, 0.42 g of the title compound could be obtained in 81% yield.                     

1H NMR (400 MHz, CDCl3); 7.57 (1H, s), 7.52 (1H, d), 7.43-7.32 (7H, m), 5.95 (1H, d), 4.71 (1H, m), 4.50 (1H, m), 4.32 (2H, s), 3.18 (3H, s), 2.76 (1H, m), 2.65-2.33 (4H, m), 2.03 (1H, m), 1.70-1.63 (2H, m), 1.51 (1H, m), 0.98 (3H, d), 0.97 (3H, d)
1 H NMR (400 MHz, CDCl 3 ); 7.57 (1H, s), 7.52 (1H, d), 7.43-7.32 (7H, m), 5.95 (1H, d), 4.71 (1H, m), 4.50 (1H, m), 4.32 (2H, s) , 3.18 (3H, s), 2.76 (1H, m), 2.65-2.33 (4H, m), 2.03 (1H, m), 1.70-1.63 (2H, m), 1.51 (1H, m), 0.98 (3H , d), 0.97 (3H, d)

[제조예 97]Preparation Example 97

(2R)-2-((2S,3S)-3-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-2-{[tert-부틸(디메틸)실릴]옥시}-5-베칠헥실)-4-펜틴산의 제조: (2R)-2-((2S,3S)-3-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-2-{[tert-butyl(dimethyl)silyl]oxy}-5-methylhexyl)-4-pentynoic acid( 2R ) -2-(( 2S , 3S ) -3-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -2-{[ tert -butyl (dimethyl) silyl] oxy} -5-bechil hexyl) Preparation of 4-pentyn acid: (2 R) -2 - ( (2 S, 3 S) -3 - ({3 - [(benzylsulfonyl) (methyl) amino] benzoyl} amino ) -2-{[ tert -butyl (dimethyl) silyl] oxy} -5-methylhexyl) -4-pentynoic acid

상기 제조예 5에서 얻은 화합물 대신에 상기 제조예 96에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 6과 동일한 방법으로 실시하여, 표제 화합물 0.45 g을 85% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 96 instead of the compound obtained in Preparation Example 5, in the same manner as in Preparation Example 6, 0.45 g of the title compound could be obtained in 85% yield.

1H NMR (400 MHz, CDCl3); 7.68 (1H, s), 7.56 (1H, d), 7.44-7.33 (7H, m), 6.31 (1H, d), 4.34 (1H, m), 4.30 (2H, s), 3.16 (3H, s), 2.83 (1H, m), 2.64-2.43 (2H, m), 2.04 (1H, t), 1.91 (1H, m), 1.76 (1H, m), 1.66 (1H, m), 1.56 (1H, m), 1.45 (1H, m), 0.98 (6H, d), 0.93 (9H, s), 0.15 (3H, s), 0.14 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.68 (1H, s), 7.56 (1H, d), 7.44-7.33 (7H, m), 6.31 (1H, d), 4.34 (1H, m), 4.30 (2H, s), 3.16 (3H, s) , 2.83 (1H, m), 2.64-2.43 (2H, m), 2.04 (1H, t), 1.91 (1H, m), 1.76 (1H, m), 1.66 (1H, m), 1.56 (1H, m ), 1.45 (1H, m), 0.98 (6H, d), 0.93 (9H, s), 0.15 (3H, s), 0.14 (3H, s)

[제조예 98] [Manufacture example 98]                     

N-((1S,2S,4R)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-{[tert-부틸(디메틸)실릴]옥시}-1-이소부틸-6-헵틴일)-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-((1S,2S,4R)-4-[({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)carbonyl]-2-{[tert-butyl(dimethyl)silyl]oxy}-1-isobutyl-6-heptynyl)-3-[(benzylsulfonyl)(methyl)amino]benzamide N -((1 S , 2 S , 4 R ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-{[ tert -Butyl (dimethyl) silyl] oxy} -1-isobutyl-6-heptinyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide Preparation : N -((1 S , 2 S , 4 R ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-{[ tert -butyl (dimethyl) silyl] oxy} -1-isobutyl -6-heptynyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 88에서 얻은 화합물 대신에 상기 제조예 97에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 90과 동일한 방법으로 실시하여, 표제 화합물 0.1 g을 84% 수율로 얻을 수 있었다.0.1 g of the title compound could be obtained in 84% yield in the same manner as in Example 90, except that the compound obtained in Preparation Example 97 was used instead of the compound obtained in Preparation Example 88.

1H NMR (400 MHz, CDCl3); 7.75 (1H, s), 7.37 (1H, d), 7.42-7.21 (12H, m), 6.72 (1H, d), 6.45 (1H, t), 6.21 (1H, d), 4.42 (1H, m), 4.40 (2H, d), 4.30 (3H, s), 4.16 (1H, dd), 3.92 (1H, dd), 3.16 (3H, s), 2.85 (1H, m), 2.54 (1H, m), 2.33 (1H, m), 2.14 (1H, m), 1.82-1.52 (5H, m), 1.38 (1H, m), 0.98 (3H, d), 0.96 (3H, d), 0.93 (9H, s), 0.71 (3H, d), 0.69 (3H, d), 0.12 (3H, s), 0.11 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.75 (1H, s), 7.37 (1H, d), 7.42-7.21 (12H, m), 6.72 (1H, d), 6.45 (1H, t), 6.21 (1H, d), 4.42 (1H, m) , 4.40 (2H, d), 4.30 (3H, s), 4.16 (1H, dd), 3.92 (1H, dd), 3.16 (3H, s), 2.85 (1H, m), 2.54 (1H, m), 2.33 (1H, m), 2.14 (1H, m), 1.82-1.52 (5H, m), 1.38 (1H, m), 0.98 (3H, d), 0.96 (3H, d), 0.93 (9H, s) , 0.71 (3H, d), 0.69 (3H, d), 0.12 (3H, s), 0.11 (3H, s)

[실시예 55]Example 55

N-{(1S,2S,4R)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-히드록시-1-이소부틸-6-헵틴일}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-{(1S,2S,4R)-4-[({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)carbonyl]-2-hydroxy-1-isobutyl-6-heptynyl}-3-[(benzylsulfonyl)(methyl)amino]benzamide N -{(1 S , 2 S , 4 R ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-hydroxy Preparation of -1-Isobutyl-6-heptinyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -{(1 S , 2 S , 4 R ) -4-[({( 1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-hydroxy-1-isobutyl-6-heptynyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 98에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 81 ㎎을 91% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 98 instead of the compound obtained in Preparation Example 12, it was carried out in the same manner as in Preparation Example 13, it was obtained 81 mg of the title compound in 91% yield.

1H NMR (400 MHz, CD3OD); 7.75 (1H. s), 7.69 (1H, d), 7.48-7.15 (12H, m), 4.46 (2H, s), 4.35 (2H, s), 4.24-4.13 (2H, m), 3.66 (1H, m), 3.25 (3H, s), 2.88 (1H, m), 2.44 (1H, m), 2.32 (1H, m), 2.14 (1H, t), 2.06 (1H, m), 1.85 (1H, m), 1.73-1.57 (2H, m), 1.42 (1H, m), 0.96 (3H, d), 0.95 (3H, d), 0.90 (3H, d), 0.88 (3H, d)1 H NMR (400 MHz, CD3OD); 7.75 (1H.s), 7.69 (1H, d), 7.48-7.15 (12H, m), 4.46 (2H, s), 4.35 (2H, s), 4.24-4.13 (2H, m), 3.66 (1H, m), 3.25 (3H, s), 2.88 (1H, m), 2.44 (1H, m), 2.32 (1H, m), 2.14 (1H, t), 2.06 (1H, m), 1.85 (1H, m ), 1.73-1.57 (2H, m), 1.42 (1H, m), 0.96 (3H, d), 0.95 (3H, d), 0.90 (3H, d), 0.88 (3H, d)

ESI MS (m/e) = 703 [M+H]+
ESI MS (m / e) = 703 [M + H] < + >

[제조예 99][Manufacture example 99]

tert-부틸 (1S)-1-[(2R)-4-(1-히드록시메틸)-5-옥소테트라히드로-2-퓨라닐]-3-메틸부틸카르바메이트의 제조: tert-butyl (1S)-1-[(2R)-4-(1-hydroxyethyl)-5-oxotetrahydro-2-furanyl]-3-methylbutylcarbamate tert - butyl (1 S) -1 - [( 2 R) -4- (1- hydroxymethyl) -5-oxo-tetrahydro-2-furanyl] -3-methyl-butyl Preparation of carbamate: tert - butyl (1 S ) -1-[(2 R ) -4- (1-hydroxyethyl) -5-oxotetrahydro-2-furanyl] -3-methylbutylcarbamate

아세톤 대신에 아세트알데히드를 사용한 것을 제외하고는, 제조예 78과 동일한 방법으로 실시하여, 표제 화합물 1.33 g을 85% 수율로 얻을 수 있었다. Except for using acetaldehyde instead of acetone, it was carried out in the same manner as in Preparation 78 to obtain 1.33 g of the title compound in 85% yield.                     

1H NMR (400 MHz, CDCl3); 4.60-4.54 (2H, m), 4.35 (1H, d), 3.85 (1H, m), 2.87 (1H, m), 2.51-2.32 (2H, m), 1.66-1.50 (6H, m), 1.42 (9H, s), 0.93-0.91 (6H, m)
1 H NMR (400 MHz, CDCl 3 ); 4.60-4.54 (2H, m), 4.35 (1H, d), 3.85 (1H, m), 2.87 (1H, m), 2.51-2.32 (2H, m), 1.66-1.50 (6H, m), 1.42 ( 9H, s), 0.93-0.91 (6H, m)

[제조예 100][Production Example 100]

tert-부틸 (1S)-1-{(2R)-4-[(E)에틸리덴]-5-옥소테트라히드로-2-퓨라닐}-3-메틸부틸카르바메이트의 제조: tert-butyl (1S)-1-{(2R)-4-[(E)ethylidene]-5-oxotetrahydro-2-furanyl}-3-methylbutylcarbamate tert - butyl (1 S) -1 - Preparation of - {(2 R) -4 [ (E) ethylidene] -5-oxo-tetrahydro-2-furanyl} -3-methyl-butyl carbamate: tert - butyl (1 S ) -1-{(2 R ) -4-[( E ) ethylidene] -5-oxotetrahydro-2-furanyl} -3-methylbutylcarbamate

상기 제조예 78에서 얻은 화합물 대신에 상기 제조예 99에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 79와 동일한 방법으로 실시하여, 표제 화합물 0.33 g을 25% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 99 instead of the compound obtained in Preparation Example 78 was carried out in the same manner as Preparation Example 79, it was possible to obtain 0.33 g of the title compound in 25% yield.

1H NMR (400 MHz, CDCl3); 6.75 (1H, m), 4.55 (1H, m), 4.35 (1H, d), 3.88 (1H, m), 2.85-2.80 (2H, m), 1.82 (3H, d), 1.62-1.56 (3H, m), 1.39 (9H, s), 0.93 (3H, d), 0.92 (3H, d)
1 H NMR (400 MHz, CDCl 3 ); 6.75 (1H, m), 4.55 (1H, m), 4.35 (1H, d), 3.88 (1H, m), 2.85-2.80 (2H, m), 1.82 (3H, d), 1.62-1.56 (3H, m), 1.39 (9H, s), 0.93 (3H, d), 0.92 (3H, d)

[제조예 101][Production Example 101]

3-[(벤질술포닐)(메틸)아미노]-N-((1S)-1-{(2R)-4-[(E)에틸리덴]-5-옥소테트라히드로-2-퓨라닐}-3-메틸부틸)벤즈아미드의 제조: 3-[(benzylsulfonyl)(methyl)amino]-N-((1S)-1-{(2R)-4-[(E)ethylidene]-5-oxotetrahydro-2-furanyl}-3- methylbutyl)benzamide3-[(benzylsulfonyl) (methyl) amino] -N -(( 1S ) -1-{( 2R ) -4-[( E ) ethylidene] -5-oxotetrahydro-2-furanyl } -3-Methylbutyl) benzamide Preparation: 3-[(benzylsulfonyl) (methyl) amino] -N -((1 S ) -1-{(2 R ) -4-[( E ) ethylidene] -5 -oxotetrahydro-2-furanyl} -3-methylbutyl) benzamide

상기 제조예 86에서 얻은 화합물 대신에 상기 제조예 100에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 87과 동일한 방법으로 실시하여, 표제 화합물 0.29 g을 54% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 100 instead of the compound obtained in Preparation Example 86, it was carried out in the same manner as in Preparation Example 87, to obtain 0.29 g of the title compound in 54% yield.

1H NMR (400 MHz, CDCl3); 7.50 (1H, t), 7.46 (1H, m), 7.41-7.33 (7H, m), 6.71 (1H, m), 5.98 (1H, d), 4.68 (1H, m), 4.54 (1H, m), 4.30 (2H, s), 3.16 (3H, s), 2.80 (1H, m), 2.77 (1H, m), 1.76 (3H, d), 1.74-1.65 (2H, m), 1.53 (1H, m), 0.97 (6H, d)
1 H NMR (400 MHz, CDCl 3 ); 7.50 (1H, t), 7.46 (1H, m), 7.41-7.33 (7H, m), 6.71 (1H, m), 5.98 (1H, d), 4.68 (1H, m), 4.54 (1H, m) , 4.30 (2H, s), 3.16 (3H, s), 2.80 (1H, m), 2.77 (1H, m), 1.76 (3H, d), 1.74-1.65 (2H, m), 1.53 (1H, m ), 0.97 (6H, d)

[제조예 102]Production Example 102

(Z)-2-((2S,3S)-3-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-2-{[tert-부틸(디메틸)실릴]옥시}-5-메틸헥실)-2-부텐산의 제조: (Z)-2-((2S,3S)-3-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-2-{[tert-butyl(dimethyl)silyl]oxy}-5-methylhexyl)-2-butenoic acid( Z ) -2-(( 2S , 3S ) -3-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -2-{[ tert -butyl (dimethyl) silyl] oxy Preparation of} -5-methylhexyl) -2-butenoic acid: ( Z ) -2-((2 S , 3 S ) -3-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino)- 2-{[ tert -butyl (dimethyl) silyl] oxy} -5-methylhexyl) -2-butenoic acid

상기 제조예 5에서 얻은 화합물 대신에 상기 제조예 101에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 6과 동일한 방법으로 실시하여, 표제 화합물 0.30 g을 81% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 101 instead of the compound obtained in Preparation Example 5, it was carried out in the same manner as in Preparation Example 6, it was possible to obtain 0.30 g of the title compound in 81% yield.

1H NMR (400 MHz, CDCl3); 7.73 (1H, t), 7.56 (1H, m), 7.45-7.34 (7H, m), 7.14 (1H, q), 6.63 (1H, d), 4.29 (2H, s), 4.10 (1H, m), 4.02 (1H, m), 3.17 (3H, s), 2.58-2.43 (2H, m), 1.81 (3H, d), 1.60 (1H, m), 1.47-1.43 (2H, m), 0.96-0.88 (15H, m), 0.15 (6H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.73 (1H, t), 7.56 (1H, m), 7.45-7.34 (7H, m), 7.14 (1H, q), 6.63 (1H, d), 4.29 (2H, s), 4.10 (1H, m) , 4.02 (1H, m), 3.17 (3H, s), 2.58-2.43 (2H, m), 1.81 (3H, d), 1.60 (1H, m), 1.47-1.43 (2H, m), 0.96-0.88 (15H, m), 0.15 (6H, s)

[제조예 103]Preparation Example 103

N-((1S,2S,4Z)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-{[tert-부틸(디메틸)실릴]옥시}-1-이소부틸-4-헥센일)-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-((1S,2S,4Z)-4-[({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)carbonyl]-2-{[tert-butyl(dimethyl)silyl]oxy}-1-isobutyl-4-hexenyl)-3-[(benzylsulfonyl)(methyl)amino]benzamide N -((1 S , 2 S , 4 Z ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-{[ Preparation of tert -butyl (dimethyl) silyl] oxy} -1-isobutyl-4-hexenyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -((1 S , 2 S , 4 Z ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-{[ tert -butyl (dimethyl) silyl] oxy} -1-isobutyl -4-hexenyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 88에서 얻은 화합물 대신에 상기 제조예 102에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 90과 동일한 방법으로 실시하여, 표제 화합물 0.20 g을 51% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 102 instead of the compound obtained in Preparation Example 88, it was carried out in the same manner as in Preparation Example 90, 0.20 g of the title compound could be obtained in 51% yield.

1H NMR (400 MHz, CDCl3); 7.83 (1H, t), 7.61 (1H, m), 7.37-7.26 (12H, m),6.85 (1H, d), 6.48 (1H, d), 6.43 (1H, t), 6.34 (1H, q), 4.48 (1H, dd), 4.37 (1H, dd), 4.29 (2H, s), 4.27 (1H, m), 4.10 (1H, m), 4.00 (1H, m), 3.16 (3H, s), 2.61-2.52 (2H, m), 2.11 (1H, m), 1.76 (3H, d), 1.62 (1H, m), 1.47-1.42 (2H, m), 0.94-0.87 (21H, m), 0.14 (3H, s), 0.13 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.83 (1H, t), 7.61 (1H, m), 7.37-7.26 (12H, m), 6.85 (1H, d), 6.48 (1H, d), 6.43 (1H, t), 6.34 (1H, q) , 4.48 (1H, dd), 4.37 (1H, dd), 4.29 (2H, s), 4.27 (1H, m), 4.10 (1H, m), 4.00 (1H, m), 3.16 (3H, s), 2.61-2.52 (2H, m), 2.11 (1H, m), 1.76 (3H, d), 1.62 (1H, m), 1.47-1.42 (2H, m), 0.94-0.87 (21H, m), 0.14 ( 3H, s), 0.13 (3H, s)

[실시예 56]Example 56

N-{(1S,2S,4Z)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-히드록시-1-이소부틸-4-헥센일}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-{(1S,2S,4Z)-4-[({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)carbonyl]-2-hydroxy-1-isobutyl-4-hexenyl}-3-[(benzylsulfonyl)(methyl)amino]benzamide N -{(1 S , 2 S , 4 Z ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-hydroxy Preparation of -1-Isobutyl-4-hexenyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -{(1 S , 2 S , 4 Z ) -4-[({( 1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-hydroxy-1-isobutyl-4-hexenyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 103에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 54 ㎎을 59% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 103 instead of the compound obtained in Preparation Example 12, it was carried out in the same manner as in Preparation Example 13, it was obtained 54 mg of the title compound in 59% yield.

1H NMR (400 MHz, CDCl3); 7.68 (1H, t), 7.61 (1H, m), 7.43-7.23 (12H, m), 6.67 (1H, d), 6.61 (1H, d), 6.33 (1H, q), 6.26 (1H, t), 4.48 (1H, dd), 4.36 (1H, dd), 4.29 (2H, s), 4.26 (1H, m), 4.19 (1H, m), 3.72 (1H, m), 3.16 (3H, s), 2.62 (1H, m), 2.32 (1H, m), 2.08 (1H, m), 1.81 (3H, d), 1.77-1.66 (2H, m), 1.46 (1H, m), 1.00-0.87 (12H, m)1 H NMR (400 MHz, CDCl 3 ); 7.68 (1H, t), 7.61 (1H, m), 7.43-7.23 (12H, m), 6.67 (1H, d), 6.61 (1H, d), 6.33 (1H, q), 6.26 (1H, t) , 4.48 (1H, dd), 4.36 (1H, dd), 4.29 (2H, s), 4.26 (1H, m), 4.19 (1H, m), 3.72 (1H, m), 3.16 (3H, s), 2.62 (1H, m), 2.32 (1H, m), 2.08 (1H, m), 1.81 (3H, d), 1.77-1.66 (2H, m), 1.46 (1H, m), 1.00-0.87 (12H, m)

ESI MS (m/e) = 691 [M+H]+
ESI MS (m / e) = 691 [M + H] < + >

[제조예 104][Production Example 104]

N-((1S,2S,4R or 4S)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-{[tert-부틸(디메틸)실릴]옥시}-1-이소부틸헥실)-3-[(벤질술포닐)(메틸) 아미노]벤즈아미드의 제조: N-((1S,2S,4R or 4S)-4-[({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)carbonyl]-2-{[tert-butyl(dimethyl)silyl]oxy}-1-isobutylhexyl)-3-[(benzylsulfonyl)(methyl)amino]benzamide N -((1 S , 2 S , 4 R or 4 S ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2 Preparation of-{[ tert -butyl (dimethyl) silyl] oxy} -1-isobutylhexyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -((1 S , 2 S , 4 R or 4 S ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-{[ tert -butyl (dimethyl) silyl] oxy} -1 -isobutylhexyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 103에서 얻은 화합물0.20 g(0.25 mmol)을 메탄올 20 ㎖에 녹인 후, 활성 탄소에 흡착된 팔라듐(10%)을 가하고 수소공기 하에서 하룻밤 동안 교반하였다. 셀라이트를 이용한감압여과로 고체를 제거한 다음 감압증류로 용매를 제거하여 에틸아세테이트와 헥산의 2:3 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 54 ㎎을 27% 수율로 얻을 수 있었다.0.20 g (0.25 mmol) of the compound obtained in Preparation Example 103 was dissolved in 20 ml of methanol, and palladium (10%) adsorbed on activated carbon was added thereto, and the mixture was stirred overnight under hydrogen air. The solid was removed by reduced pressure filtration using celite, and the solvent was removed by distillation under reduced pressure, and purified by column chromatography using a 2: 3 mixture of ethyl acetate and hexane to obtain 54 mg of the title compound in 27% yield.

1H NMR (400 MHz, CDCl3); 7.79 (1H, t), 7.60 (1H, m), 7.41-7.23 (12H, m), 6.58 (1H, d), 6.43 (1H, t), 6.31 (1H, d), 4.47-4.34 (3H, m), 4.30 (2H, s), 4.13 (1H, m), 3.75 (1H, m), 3.17 (3H, s), 2.40 (1H, m), 2.03 (1H, m), 1.76-1.61 (4H, m), 1.62-1.42 (3H, m), 1.01-0.83 (24H, m), 0.13 (3H, s), 0.11 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.79 (1H, t), 7.60 (1H, m), 7.41-7.23 (12H, m), 6.58 (1H, d), 6.43 (1H, t), 6.31 (1H, d), 4.47-4.34 (3H, m), 4.30 (2H, s), 4.13 (1H, m), 3.75 (1H, m), 3.17 (3H, s), 2.40 (1H, m), 2.03 (1H, m), 1.76-1.61 (4H , m), 1.62-1.42 (3H, m), 1.01-0.83 (24H, m), 0.13 (3H, s), 0.11 (3H, s)

[실시예 57]Example 57

N-{(1S,2S,4R or 4S)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-히드록시-1-이소부틸헥실}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-{(1S,2S,4R or 4S)-4-[({(1S)-1-[(benzylamino)carbonyl]-2- methylpropyl}amino)carbonyl]-2-hydroxy-1-isobutylhexyl}-3-[(benzylsulfonyl)(methyl)amino]benzamide N -{(1 S , 2 S , 4 R or 4 S ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2 Preparation of -hydroxy-1-isobutylhexyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -{(1 S , 2 S , 4 R or 4 S ) -4-[( {(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-hydroxy-1-isobutylhexyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 104에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 25 ㎎을 54% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 104 instead of the compound obtained in Preparation Example 12, it was carried out in the same manner as in Preparation Example 13, it was obtained 25 mg of the title compound in 54% yield.

1H NMR (400 MHz, CDCl3); 7.69 (1H, t), 7.60 (1H, m), 7.39-7.21 (12H, m), 6.65 (1H, d), 6.49-6.45 (2H, m), 4.45-4.31 (3H, m), 4.29 (2H, s), 4.22 (1H, m), 4.13 (1H, m), 3.75 (1H, m), 3.16 (3H, s), 2.45 (1H, m), 2.08 (1H, m), 1.85-1.41 (7H, m), 0.98-0.84 (15H, m)1 H NMR (400 MHz, CDCl 3 ); 7.69 (1H, t), 7.60 (1H, m), 7.39-7.21 (12H, m), 6.65 (1H, d), 6.49-6.45 (2H, m), 4.45-4.31 (3H, m), 4.29 ( 2H, s), 4.22 (1H, m), 4.13 (1H, m), 3.75 (1H, m), 3.16 (3H, s), 2.45 (1H, m), 2.08 (1H, m), 1.85-1.41 (7H, m), 0.98-0.84 (15H, m)

ESI MS (m/e) = 693 [M+H]+
ESI MS (m / e) = 693 [M + H] < + >

[제조예 105][Production Example 105]

N-((1S,2S,4R or 4S)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-{[tert-부틸(디메틸)실릴]옥시}-1-이소부틸헥실)-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-((1S,2S,4R or 4S)-4-[({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)carbonyl]-2-{[tert-butyl(dimethyl)silyl]oxy}-1-isobutylhexyl)-3-[(benzylsulfonyl)(methyl)amino]benzamide N -((1 S , 2 S , 4 R or 4 S ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2 Preparation of-{[ tert -butyl (dimethyl) silyl] oxy} -1-isobutylhexyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -((1 S , 2 S , 4 R or 4 S ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-{[ tert -butyl (dimethyl) silyl] oxy} -1 -isobutylhexyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 104에서 상기 제조예 104와는 반대 이성질체인 표제 화합물 37 ㎎을 19% 수율로 분리하여 얻을 수 있었다. In Preparation 104, 37 mg of the title compound which was the opposite isomer as in Preparation 104 was obtained by separation in 19% yield.

1H NMR (400 MHz, CDCl3); 7.70 (1H, t), 7.54 (1H, m), 7.44-7.28 (12H, m), 6.35 (1H, d), 6.29 (1H, t), 6.23 (1H, d), 4.55 (1H, dd), 4.35 (1H, dd), 4.30 (2H, s), 4.27 (1H, m)4.23 (1H, m), 3.73 (1H, m), 3.18 (3H, s), 2.29 (1H, m), 2.16 (1H, m), 1.82-1.37 (7H, m), 1.01-0.85 (24H, m), 0.14 (3H, s), 0.10 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.70 (1H, t), 7.54 (1H, m), 7.44-7.28 (12H, m), 6.35 (1H, d), 6.29 (1H, t), 6.23 (1H, d), 4.55 (1H, dd) , 4.35 (1H, dd), 4.30 (2H, s), 4.27 (1H, m) 4.23 (1H, m), 3.73 (1H, m), 3.18 (3H, s), 2.29 (1H, m), 2.16 (1H, m), 1.82-1.37 (7H, m), 1.01-0.85 (24H, m), 0.14 (3H, s), 0.10 (3H, s)

[실시예 58]Example 58

N-{(1S,2S,4R or 4S)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-히드록시-1-이소부틸헥실}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-{(1S,2S,4R or 4S)-4-[({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)carbonyl]-2-hydroxy-1-isobutylhexyl}-3-[(benzylsulfonyl)(methyl)amino]benzamide N -{(1 S , 2 S , 4 R or 4 S ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2 Preparation of -hydroxy-1-isobutylhexyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -{(1 S , 2 S , 4 R or 4 S ) -4-[( {(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2-hydroxy-1-isobutylhexyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 105에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 16 ㎎을 50% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 105 instead of the compound obtained in Preparation Example 12, it was carried out in the same manner as in Preparation Example 13, 16 mg of the title compound could be obtained in 50% yield.

1H NMR (400 MHz, CDCl3); 7.68 (1H, t), 7.60 (1H, m), 7.41-7.24 (12H, m), 6.65 (1H, t), 6.30 (1H, d), 6.13 (1H. d), 4.40 (2H, d), 4.32-4.28 (3H, m), 4.14 (1H, m), 3.68 (1H, m), 3.35 (1H, d), 3.17 (3H, s), 2.30-2.21 (2H, m), 1.94-1.31 (7H, m), 0.98-0.87 (15H, m)1 H NMR (400 MHz, CDCl 3 ); 7.68 (1H, t), 7.60 (1H, m), 7.41-7.24 (12H, m), 6.65 (1H, t), 6.30 (1H, d), 6.13 (1H.d), 4.40 (2H, d) , 4.32-4.28 (3H, m), 4.14 (1H, m), 3.68 (1H, m), 3.35 (1H, d), 3.17 (3H, s), 2.30-2.21 (2H, m), 1.94-1.31 (7H, m), 0.98-0.87 (15H, m)

ESI MS (m/e)= 693 [M+H]+
ESI MS (m / e) = 693 [M + H] < + >

[제조예 106][Manufacture example 106]

메틸 (2S)-2-[((2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-{[tert-부틸(디메틸)실릴]옥시}-2,7-디메틸옥타노일)아미노]-3-메틸부타노에이트의 제조: methyl (2S)-2-[((2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,7-dimethyloctanoyl)amino]-3-methylbutanoateMethyl ( 2S ) -2-[(( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-{[ tert -butyl Preparation of (dimethyl) silyl] oxy} -2,7-dimethyloctanoyl) amino] -3-methylbutanoate: methyl (2 S ) -2-[((2 R , 4 S , 5 S ) -5 -({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-{[ tert -butyl (dimethyl) silyl] oxy} -2,7-dimethyloctanoyl) amino] -3-methylbutanoate

상기 제조예 58에서 얻은 화합물 70 ㎎(0.116 mmol)을 N,N-디메틸포름아미드 5 ㎖에 녹여서 0℃로 냉각한 후 (S)-발린메틸에스터히드로클로라이드 25 ㎎(0.151 mmol)과 HATU(57 ㎎, 0.151 mmol)를 가하였다. 여기에 N,N-디이소프로필에틸아민 0.5 ㎖(과량)를 가하고 상온으로 온도를 올려 3 시간동안 교반하였다. 감압증류하여 용매를 제거한 다음 에틸아세테이트에 녹여서 물, 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음 메탄올과 디클로로메탄의 5:95 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 72 ㎎을 87% 수율로 얻을 수 있었다.70 mg (0.116 mmol) of the compound obtained in Preparation Example 58 was dissolved in 5 ml of N, N-dimethylformamide, and cooled to 0 ° C., followed by 25 mg (0.151 mmol) of ( S ) -valine methyl ester hydrochloride and HATU (57). Mg, 0.151 mmol) was added. 0.5 ml (excess) of N, N-diisopropylethylamine was added thereto, and the temperature was raised to room temperature, followed by stirring for 3 hours. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a 5:95 mixture of methanol and dichloromethane to obtain 72 mg of the title compound in 87% yield.

1H NMR (400 MHz, CDCl3); 7.74 (1H, s), 7.56 (1H, m), 7.43-7.33 (7H, m), 6.57 (1H, d), 6.22 (1H, d), 4.44-4.34 (2H, m), 4.29 (2H, s), 3.78 (1H, d), 3.70 (3H, s), 3.16 (3H, s), 2.66 (1H, m), 1.96 (1H, m), 1.80-1.49 (4H, m), 1.41 (1H, m), 1.16 (3H, d), 0.99 (3H, d), 0.97 (3H, d), 0.93 (9H, s), 0.72 (3H, d), 0.69 (3H, d), 0.12 (3H, s), 0.11 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.74 (1H, s), 7.56 (1H, m), 7.43-7.33 (7H, m), 6.57 (1H, d), 6.22 (1H, d), 4.44-4.34 (2H, m), 4.29 (2H, s), 3.78 (1H, d), 3.70 (3H, s), 3.16 (3H, s), 2.66 (1H, m), 1.96 (1H, m), 1.80-1.49 (4H, m), 1.41 (1H , m), 1.16 (3H, d), 0.99 (3H, d), 0.97 (3H, d), 0.93 (9H, s), 0.72 (3H, d), 0.69 (3H, d), 0.12 (3H, s), 0.11 (3H, s)

[실시예 59]Example 59

메틸 (2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-3-메틸부타노에이트의 제조: methyl (2S)-2-{[(2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}-3-methylbutanoateMethyl (2 S) -2 - {[ (2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2, 7-dimethyl-octanoyl] amino} -3-methyl butanoate of the prepared: methyl (2 S) -2 - {[(2 R, 4 S, 5 S) -5 - ({3 - [(benzylsulfonyl) ( methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyloctanoyl] amino} -3-methylbutanoate

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 106에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 54 ㎎을 92% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 106 instead of the compound obtained in Preparation Example 12, it was carried out in the same manner as in Preparation Example 13, it was obtained 54 mg of the title compound in 92% yield.

1H NMR (400 MHz, CDCl3); 7.66 (1H, s), 7.61 (1H, d), 7.44-7.34 (7H, m), 6.37 (1H, d), 6.23 (1H, d), 4.50 (1H, dd), 4.30 (2H, s), 4.14 (1H, m), 4.01 (1H, d), 3.82 (1H, m), 3.74 (3H, s), 3.17 (3H, s), 2.72 (1H, m), 2.11 (1H, m), 1.82-1.62 (4H, m), 1.46 (1H, m), 1.25 (3H, d), 0.98 (3H, d), 0.96 (3H, d), 0.87 (3H, d), 0.84 (3H, d)1 H NMR (400 MHz, CDCl 3 ); 7.66 (1H, s), 7.61 (1H, d), 7.44-7.34 (7H, m), 6.37 (1H, d), 6.23 (1H, d), 4.50 (1H, dd), 4.30 (2H, s) , 4.14 (1H, m), 4.01 (1H, d), 3.82 (1H, m), 3.74 (3H, s), 3.17 (3H, s), 2.72 (1H, m), 2.11 (1H, m), 1.82-1.62 (4H, m), 1.46 (1H, m), 1.25 (3H, d), 0.98 (3H, d), 0.96 (3H, d), 0.87 (3H, d), 0.84 (3H, d)

ESI MS (m/e) = 604 [M+H]+
ESI MS (m / e) = 604 [M + H] < + >

[실시예 60]Example 60

(2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-3-메틸부탄산의 제조: (2S)-2-{[(2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}-3-methylbutanoic acid (2 S) -2 - {[ (2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy -2,7 -dimethyl octanoyl] amino} Preparation of 3-methyl butanoic acid: (2 S) -2 - { [(2 R, 4 S, 5 S) -5 - ({3 - [(benzylsulfonyl) (methyl) amino ] benzoyl} amino) -4-hydroxy-2,7-dimethyloctanoyl] amino} -3-methylbutanoic acid

상기 실시예 59에서 얻은 화합물 49 ㎎(0.081 mmol)을 테트라히드로퓨란 3 ㎖와 메탄올 0.5 ㎖에 녹인 후 1.0 N 수산화리튬 수용액 2 ㎖를 가하여 2 시간 동안 교반하였다. 용매를 감압증류하여 제거한 후 물로 희석하여 1.0 N 염산 수용액으로 산성화하여 생성된 고체를 여과하여 표제 화합물 34 ㎎을 71% 수율로 얻을 수 있었다.49 mg (0.081 mmol) of the compound obtained in Example 59 was dissolved in 3 ml of tetrahydrofuran and 0.5 ml of methanol, and 2 ml of 1.0 N lithium hydroxide aqueous solution was added thereto, followed by stirring for 2 hours. The solvent was distilled off under reduced pressure, diluted with water, acidified with 1.0 N aqueous hydrochloric acid, and the resulting solid was filtered to afford 34 mg of the title compound in 71% yield.

1H NMR (400 MHz, CD3OD); 7.94 (1H, d), 7.76 (1H, s), 7.47-7.31 (7H, m), 4.67 (2H, s), 4.29 (1H, m), 4.20 (1H, m), 3.62 (1H, m), 3.26 (3H, s), 2.76 (1H, m), 2.11 (1H, m), 1.86 (1H, m), 1.73-1.58 (2H, m), 1.50-1.34 (2H, m), 1.15 (3H, d), 0.96 (6H, d), 0.90 (6H, d)1 H NMR (400 MHz, CD3OD); 7.94 (1H, d), 7.76 (1H, s), 7.47-7.31 (7H, m), 4.67 (2H, s), 4.29 (1H, m), 4.20 (1H, m), 3.62 (1H, m) , 3.26 (3H, s), 2.76 (1H, m), 2.11 (1H, m), 1.86 (1H, m), 1.73-1.58 (2H, m), 1.50-1.34 (2H, m), 1.15 (3H , d), 0.96 (6H, d), 0.90 (6H, d)

ESI MS (m/e) = 590 [M+H]+
ESI MS (m / e) = 590 [M + H] < + >

[제조예 107][Manufacture example 107]

N-((1S,2S,4R)-5-{[(1S)-1-(아미노카르보닐)-2-메틸프로필]아미노}-2-{[ tert-부틸(디메틸)실릴]옥시}-1-이소부틸-4-메틸-5-옥소펜틸)-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-((1S,2S,4R)-5-{[(1S)-1-(aminocarbonyl)-2- methylpropyl]amino}-2-{[tert-butyl(dimethyl)silyl]oxy}-1-isobutyl-4-methyl-5-oxopentyl)-3-[(benzylsulfonyl)(methyl)amino]benzamide N -(( 1S , 2S , 4R ) -5-{[( 1S ) -1- (aminocarbonyl) -2-methylpropyl] amino} -2-{[ tert -butyl (dimethyl) silyl ] Oxy} -1-isobutyl-4-methyl-5-oxopentyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -((1 S , 2 S , 4 R ) -5 - {[(1 S) -1- (aminocarbonyl) -2- methylpropyl] amino} -2 - {[tert -butyl (dimethyl) silyl] oxy} -1-isobutyl-4-methyl-5-oxopentyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide

(S)-발린메틸에스터 히드로클로라이드 대신에 (S)-발린아미드를 사용한 것을 제외하고는, 제조예 106과 동일한 방법으로 실시하여, 표제 화합물 62 ㎎을 74% 수율로 얻을 수 있었다. (S) - valine methyl ester hydrochloride in place of (S) -, except that the valine amide, conducted in the same manner as in Preparation Example 106, to obtain a 62 ㎎ was obtained in 74% yield.

1H NMR (400 MHz, CDCl3); 7.77 (1H, s), 7.58 (1H, d), 7.47-7.32 (7H, m), 6.70 (1H, d), 6.29 (1H, d), 6.10 (1H, s), 5.34 (1H, s), 4.38 (1H, m), 4.31 (2H, s), 4.15 (1H, dd), 3.76 (1H, dd), 3.18 (3H, s), 2.66 (1H, m), 2.00 (1H, m), 1.82-1.48 (4H, m), 1.41 (1H, m), 1.17 (3H, d), 0.98 (3H, d), 0.97 (3H, d), 0.93 (9H, s), 0.76 (3H, d), 0.66 (3H, d), 0.12 (3H, s), 0.11 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.77 (1H, s), 7.58 (1H, d), 7.47-7.32 (7H, m), 6.70 (1H, d), 6.29 (1H, d), 6.10 (1H, s), 5.34 (1H, s) , 4.38 (1H, m), 4.31 (2H, s), 4.15 (1H, dd), 3.76 (1H, dd), 3.18 (3H, s), 2.66 (1H, m), 2.00 (1H, m), 1.82-1.48 (4H, m), 1.41 (1H, m), 1.17 (3H, d), 0.98 (3H, d), 0.97 (3H, d), 0.93 (9H, s), 0.76 (3H, d) , 0.66 (3H, d), 0.12 (3H, s), 0.11 (3H, s)

[실시예 61]Example 61

N-((1S,2S,4R)-5-{[(1S)-1-(아미노카르보닐)-2-메틸프로필]아미노}-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸)-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-((1S,2S,4R)-5-{[(1S)-1-(aminocarbonyl)-2-methylpropyl]amino}-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl)-3-[(benzylsulfonyl)(methyl)amino]benzamide N -(( 1S , 2S , 4R ) -5-{[( 1S ) -1- (aminocarbonyl) -2-methylpropyl] amino} -2-hydroxy-1-isobutyl-4 Preparation of -methyl-5-oxopentyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -((1 S , 2 S , 4 R ) -5-{[(1 S )- 1- (aminocarbonyl) -2-methylpropyl] amino} -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 107에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 41 ㎎을 82% 수율로 얻을 수 있었다. Except for using the compound obtained in Preparation Example 107 instead of the compound obtained in Preparation Example 12, it was carried out in the same manner as Preparation Example 13, it was obtained 41 mg of the title compound in 82% yield.                     

1H NMR (400 MHz, CD3OD); 7.76 (1H, s), 7.71 (1H, d), 7.45-7.33 (7H, m), 4.47 (2H, s), 4.20 (1H, m), 4.16 (1H, d), 3.62 (1H, m), 3.26 (3H, s), 2.76 (1H, m), 2.00 (1H, m), 1.86 (1H, m), 1.73-1.60 (2H, m), 1.50-1.36 (2H, m), 1.14 (3H, d), 0.96 (6H, d), 0.91 (3H, d), 0.89 (3H, d)1 H NMR (400 MHz, CD3OD); 7.76 (1H, s), 7.71 (1H, d), 7.45-7.33 (7H, m), 4.47 (2H, s), 4.20 (1H, m), 4.16 (1H, d), 3.62 (1H, m) , 3.26 (3H, s), 2.76 (1H, m), 2.00 (1H, m), 1.86 (1H, m), 1.73-1.60 (2H, m), 1.50-1.36 (2H, m), 1.14 (3H , d), 0.96 (6H, d), 0.91 (3H, d), 0.89 (3H, d)

ESI MS (m/e) = 589 [M+H]+
ESI MS (m / e) = 589 [M + H] < + >

[제조예 108][Manufacture example 108]

메틸 (2S)-2-[((2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-{[tert-부틸(디메틸)실릴]옥시}-2,7-디메틸옥타노일)아미노]부타노에이트의 제조: methyl (2S)-2-[((2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,7-dimethyloctanoyl)amino]butanoateMethyl ( 2S ) -2-[(( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-{[ tert -butyl Preparation of (dimethyl) silyl] oxy} -2,7-dimethyloctanoyl) amino] butanoate: methyl (2 S ) -2-[((2 R , 4 S , 5 S ) -5-({3 -[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-{[ tert -butyl (dimethyl) silyl] oxy} -2,7-dimethyloctanoyl) amino] butanoate

(S)-발린메틸에스터 히드로클로라이드 대신에 메틸 (2S)-2-아미노부타네이트 히드로클로라이드를 사용한 것을 제외하고는, 제조예 106과 동일한 방법으로 실시하여, 표제 화합물 91 ㎎을 86% 수율로 얻을 수 있었다. (S) - and it is subjected to the same procedures as in Preparation Example 106, except for using the valine methyl ester hydrochloride in place of (2 S) -2- amino nobuta carbonate hydrochloride, the title compound in 86% yield 91 ㎎ Could get

1H NMR (400 MHz, CDCl3); 7.75 (1H, s), 7.56 (1H, t), 7.43-7.33 (7H, m), 6.67 (1H, d), 6.23 (1H, d), 4.40 (1H, m), 4.29 (2H, s), 3.78 (1H, dd), 3.70 (3H. s), 3.17 (3H, s), 2.61 (1H, m), 1.78-1.46 (6H, m), 1.40 (1H, m), 1.17 (3H, d), 0.99 (3H, d), 0.97 (3H, d), 0.92 (9H, s), 0.67 (3H, t), 0.12 (3H, s), 0.11 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.75 (1H, s), 7.56 (1H, t), 7.43-7.33 (7H, m), 6.67 (1H, d), 6.23 (1H, d), 4.40 (1H, m), 4.29 (2H, s) , 3.78 (1H, dd), 3.70 (3H.s), 3.17 (3H, s), 2.61 (1H, m), 1.78-1.46 (6H, m), 1.40 (1H, m), 1.17 (3H, d ), 0.99 (3H, d), 0.97 (3H, d), 0.92 (9H, s), 0.67 (3H, t), 0.12 (3H, s), 0.11 (3H, s)

[제조예 109]Preparation Example 109

메틸 (2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}부타노에이트의 제조: methyl (2S)-2-{[(2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}butanoateMethyl (2 S) -2 - {[ (2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2, Preparation of 7-dimethyloctanoyl] amino} butanoate: methyl (2 S ) -2-{[(2 R , 4 S , 5 S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyloctanoyl] amino} butanoate

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 108에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 66 ㎎을 90% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 108 instead of the compound obtained in Preparation Example 12, it was carried out in the same manner as in Preparation Example 13, it was obtained 66 mg of the title compound in 90% yield.

1H NMR (400 MHz, CDCl3); 7.67 (1H, s), 7.61 (1H, d), 7.44-7.35 (7H, m), 6.38 (1H. d), 6.28 (1H, d), 4.51 (1H, m), 4.30 (2H, s), 4.14 (1H, m), 4.00 (1H, s), 3.81 (1H, m), 3.74 (3H, s), 3.17 (3H, s), 2.69 (1H, m), 1.84 (1H, m), 1.78-1.62 (5H, m), 1.47 (1H, m), 1.25 (3H, d), 0.98 (3H, d), 0.96 (3H, d), 0.84 (3H, t)
1 H NMR (400 MHz, CDCl 3 ); 7.67 (1H, s), 7.61 (1H, d), 7.44-7.35 (7H, m), 6.38 (1H.d), 6.28 (1H, d), 4.51 (1H, m), 4.30 (2H, s) , 4.14 (1H, m), 4.00 (1H, s), 3.81 (1H, m), 3.74 (3H, s), 3.17 (3H, s), 2.69 (1H, m), 1.84 (1H, m), 1.78-1.62 (5H, m), 1.47 (1H, m), 1.25 (3H, d), 0.98 (3H, d), 0.96 (3H, d), 0.84 (3H, t)

[실시예 62]Example 62

(2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}부탄산의 제조: (2S)-2-{[(2R,4S,5S)-5-({3- [(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}butanoic acid (2 S) -2 - {[ (2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy -2,7 -dimethyl octanoyl] amino} part Preparation of acid: (2 S) -2 - { [(2 R, 4 S, 5 S) -5 - ({3- [(benzylsulfonyl) (methyl) amino] benzoyl} amino ) -4-hydroxy-2,7-dimethyloctanoyl] amino} butanoic acid

상기 실시예 59에서 얻은 화합물 대신에 상기 제조예 109에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 60과 동일한 방법으로 실시하여, 표제 화합물 44 ㎎을 68% 수율로 얻을 수 있었다.44 mg of the title compound was obtained in 68% yield by the same method as Example 60 except for using the compound obtained in Preparation Example 109 instead of the compound obtained in Example 59.

1H NMR (400 MHz, CD3OD); 7.76 (1H, s), 7.71 (1H, m), 7.46-7.32 (7H, m), 4.46 (2H, s), 4.26 (1H, dd), 4.19 (1H, m), 3.61 (1H, m), 3.26 (3H, s), 2.73 (1H, m), 1.92-1.77 (2H, m), 1.73-1.59 (3H, m), 1.50-1.36 (2H, m), 1.16 (3H, d), 0.96 (6H, d), 0.89 (3H, t)1 H NMR (400 MHz, CD3OD); 7.76 (1H, s), 7.71 (1H, m), 7.46-7.32 (7H, m), 4.46 (2H, s), 4.26 (1H, dd), 4.19 (1H, m), 3.61 (1H, m) , 3.26 (3H, s), 2.73 (1H, m), 1.92-1.77 (2H, m), 1.73-1.59 (3H, m), 1.50-1.36 (2H, m), 1.16 (3H, d), 0.96 (6H, d), 0.89 (3H, t)

ESI MS (m/e) = 576 [M+H]+
ESI MS (m / e) = 576 [M + H] < + >

[실시예 63]Example 63

N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]propyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]benzamide N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] propyl} amino) -2-hydroxy-1-isobutyl-4- Preparation of Methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -[(1 S , 2 S , 4 R ) -5-({(1 S ) -1 -[(benzylamino) carbonyl] propyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 실시예 62에서 얻은 화합물 18 ㎎(0.031 mmol)을 N,N-디메틸포름아미드 3 ㎖에 녹여서 0℃로 냉각한 후 벤질아민 5 ㎎(0.047 mmol)과 HATU(18 ㎎, 0.047 mmol)를 가하였다. 여기에, N,N-디이소프로필에틸아민 0.5 ㎖(과량)를 가하고 상온으로 온도를 올려 3 시간동안 교반하였다. 감압증류하여 용매를 제거한 다음 에 틸아세테이트에 녹여서 물, 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음 에틸아세테이트와 헥산의 5:1 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 18 ㎎을 86% 수율로 얻을 수 있었다.18 mg (0.031 mmol) of the compound obtained in Example 62 was dissolved in 3 ml of N, N-dimethylformamide, and cooled to 0 ° C. Then, 5 mg (0.047 mmol) of benzylamine and HATU (18 mg, 0.047 mmol) were added thereto. It was. 0.5 mL (excess) of N, N-diisopropylethylamine was added thereto, and the temperature was raised to room temperature, followed by stirring for 3 hours. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a 5: 1 mixture of ethyl acetate and hexane to obtain 18 mg of the title compound in 86% yield.

1H NMR (400 MHz, CD3OD); 7.77 (1H. s), 7.71 (1H, m), 7.44-7.18 (12H, m), 4.45 (2H. s), 4.36 (2H, dd), 4.26-4.12 (2H, m), 3.60 (1H, m), 3.25 (3H, s), 2.72 (1H, m), 1.90-1.56 (5H, m), 1.51-1.35 (2H, m), 1.13 (3H, d), 0.97 (3H, d), 0.95 (3H, d), 0.87 (3H, t)1 H NMR (400 MHz, CD3OD); 7.77 (1H.s), 7.71 (1H, m), 7.44-7.18 (12H, m), 4.45 (2H.s), 4.36 (2H, dd), 4.26-4.12 (2H, m), 3.60 (1H, m), 3.25 (3H, s), 2.72 (1H, m), 1.90-1.56 (5H, m), 1.51-1.35 (2H, m), 1.13 (3H, d), 0.97 (3H, d), 0.95 (3H, d), 0.87 (3H, t)

ESI MS (m/e) = 665 [M+H]+
ESI MS (m / e) = 665 [M + H] < + >

[제조예 110][Production Example 110]

메틸 (2S,3R)-2-[((2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-{[tert-부틸(디메틸)실릴]옥시}-2,7-디메틸옥타노일)아미노]-3-메틸펜타노에이트의 제조: methyl (2S,3R)-2-[((2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,7-dimethyloctanoyl)amino]-3-methylpentanoateMethyl ( 2S , 3R ) -2-[(( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-{[ Preparation of tert -butyl (dimethyl) silyl] oxy} -2,7-dimethyloctanoyl) amino] -3-methylpentanoate: methyl (2 S , 3 R ) -2-[((2 R , 4 S , 5 S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-{[ tert -butyl (dimethyl) silyl] oxy} -2,7-dimethyloctanoyl) amino] -3 -methylpentanoate

(S)-발린메틸에스터 히드로클로라이드 대신에 메틸 (2S,3R)-2-아미노-3-메틸펜타노에이트 히드로클로라이드를 사용한 것을 제외하고는, 제조예 106과 동일한 방법으로 실시하여, 표제 화합물 91 ㎎을 83% 수율로 얻을 수 있었다. The same procedure as in Preparation Example 106 was carried out except that methyl ( 2S , 3R ) -2-amino-3-methylpentanoate hydrochloride was used instead of ( S ) -valinemethylester hydrochloride. 91 mg of compound could be obtained in 83% yield.

1H NMR (400 MHz, CDCl3); 7.73 (1H, s), 7.57 (1H, m), 7.44-7.33 (7H, m), 6.58 (1H, d), 6.21 (1H, d), 4.50-4.35 (2H, m), 4.29 (2H, s), 3.78 (1H, m), 3.69 (3H, s), 3.17 (3H, s), 2.65 (1H, m), 1.79-1.47 (6H, m), 1.40 (1H, m), 1.23 (1H, m), 1.16 (3H, d), 0.99 (3H, d), 0.97 (3H, d), 0.93 (9H, s), 0.69 (3H, d), 0.65 (3H, t), 0.12 (3H, s), 0.11 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.73 (1H, s), 7.57 (1H, m), 7.44-7.33 (7H, m), 6.58 (1H, d), 6.21 (1H, d), 4.50-4.35 (2H, m), 4.29 (2H, s), 3.78 (1H, m), 3.69 (3H, s), 3.17 (3H, s), 2.65 (1H, m), 1.79-1.47 (6H, m), 1.40 (1H, m), 1.23 (1H , m), 1.16 (3H, d), 0.99 (3H, d), 0.97 (3H, d), 0.93 (9H, s), 0.69 (3H, d), 0.65 (3H, t), 0.12 (3H, s), 0.11 (3H, s)

[제조예 111][Production Example 111]

메틸 (2S,3R)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-3-메틸펜타노에이트의 제조: methyl (2S,3R)-2-{[(2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}-3-methylpentanoateMethyl (2 S, 3 R) -2 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy Preparation of -2,7-dimethyloctanoyl] amino} -3-methylpentanoate: methyl (2 S , 3 R ) -2-{[(2 R , 4 S , 5 S ) -5-({3 -[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyloctanoyl] amino} -3-methylpentanoate

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 108에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 65 ㎎을 85% 수율로 얻을 수 있었다.65 mg of the title compound was obtained in 85% yield by the same method as Preparation Example 13, except that the compound obtained in Preparation Example 108 was used instead of the compound obtained in Preparation Example 12.

1H NMR (400 MHz, CDCl3); 7.66 (1H, s), 7.61 (1H, d), 7.45-7.35 (7H, m), 6.37 (1H, d), 6.25 (1H, d), 4.55 (1H, dd), 4.30 (2H, s), 4.13 (1H, m), 4.00 (1H, d), 3.81 (1H, m), 3.73 (3H, s), 3.17 (3H, s), 2.71 (1H, m), 1.85 (1H, m), 1.78-1.62 (4H, m), 1.47 (1H, m), 1.36 (1H, m), 1.24 (3H, d), 1.12 (1H, m), 0.98 (3H, d), 0.96 (3H, d), 0.85 (3H, t), 0.84 (3H, d)
1 H NMR (400 MHz, CDCl 3 ); 7.66 (1H, s), 7.61 (1H, d), 7.45-7.35 (7H, m), 6.37 (1H, d), 6.25 (1H, d), 4.55 (1H, dd), 4.30 (2H, s) , 4.13 (1H, m), 4.00 (1H, d), 3.81 (1H, m), 3.73 (3H, s), 3.17 (3H, s), 2.71 (1H, m), 1.85 (1H, m), 1.78-1.62 (4H, m), 1.47 (1H, m), 1.36 (1H, m), 1.24 (3H, d), 1.12 (1H, m), 0.98 (3H, d), 0.96 (3H, d) , 0.85 (3H, t), 0.84 (3H, d)

[실시예 64]Example 64

(2S,3R)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-3-메틸펜탄산의 제조: (2S,3R)-2-{[(2R,4S,5 S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}-3-methylpentanoic acid (2 S, 3 R) -2 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy- Preparation of 2,7-dimethyloctanoyl] amino} -3-methylpentanoic acid: ( 2S , 3R ) -2-{[( 2R , 4S , 5S ) -5-({3-[( benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyloctanoyl] amino} -3-methylpentanoic acid

상기 실시예 59에서 얻은 화합물 대신에 상기 제조예 111에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 60과 동일한 방법으로 실시하여, 표제 화합물 62 ㎎을 98% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 111 instead of the compound obtained in Example 59, the title compound was obtained in the same manner as in Example 60, and 62 mg of the title compound was obtained in 98% yield.

1H NMR (400 MHz, CD3OD); 7.76 (1H, s), 7.70 (1H, m), 7.48-7.27 (7H, m), 4.46 (2H, s), 4.33 (1H, m), 4.20 (1H, m), 3.60 (1H, m), 3.26 (3H, s), 2.77 (1H, m), 1.93-1.76 (2H, m), 1.73-1.58 (2H, m), 1.52-1.35 (3H, m), 1.29 (1H, m), 1.14 (3H, d), 0.96 (6H, d), 0.88 (3H, d), 0.83 (3H, t)1 H NMR (400 MHz, CD3OD); 7.76 (1H, s), 7.70 (1H, m), 7.48-7.27 (7H, m), 4.46 (2H, s), 4.33 (1H, m), 4.20 (1H, m), 3.60 (1H, m) , 3.26 (3H, s), 2.77 (1H, m), 1.93-1.76 (2H, m), 1.73-1.58 (2H, m), 1.52-1.35 (3H, m), 1.29 (1H, m), 1.14 (3H, d), 0.96 (6H, d), 0.88 (3H, d), 0.83 (3H, t)

ESI MS (m/e) = 604 [M+H]+
ESI MS (m / e) = 604 [M + H] < + >

[실시예 65]Example 65

N-[(1S,2S,4R)-5-({(1S,2R)-1-[(벤질아미노)카르보닐]-2-메틸부틸}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S,2R)-1-[(benzylamino)carbonyl]-2-methylbutyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3- [(benzylsulfonyl)(methyl)amino]benzamide N - [(1 S, 2 S, 4 R) -5 - ({(1 S, 2 R) -1 - [( benzylamino) carbonyl] -2-methylbutyl} amino) -2-hydroxy- Preparation of 1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -[(1 S , 2 S , 4 R ) -5- ( {(1 S , 2 R ) -1-[(benzylamino) carbonyl] -2-methylbutyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3- [(benzylsulfonyl) (methyl ) amino] benzamide

상기 실시예 62에서 얻은 화합물 대신에 상기 실시예 64에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 63과 동일한 방법으로 실시하여, 표제 화합물 20 ㎎을 63% 수율로 얻을 수 있었다.In the same manner as in Example 63, except that the compound obtained in Example 64 was used instead of the compound obtained in Example 62, 20 mg of the title compound could be obtained in 63% yield.

1H NMR (400 MHz, CD3OD); 7.77 (1H, s), 7.71 (1H, m), 7.45-7.18 (12H, m), 4.45 (2H, s), 4.35 (2H, dd), 4.23-4.12 (2H, m), 3.61 (1H, m), 3.25 (3H, s), 2.75 (1H, m), 1.90-1.58 (4H, m), 1.52-1.37 (3H, m), 1.12 (3H, d), 1.11 (1H, m), 0.96 (6H, d), 0.84 (3H, d), 0.78 (3H, t)1 H NMR (400 MHz, CD3OD); 7.77 (1H, s), 7.71 (1H, m), 7.45-7.18 (12H, m), 4.45 (2H, s), 4.35 (2H, dd), 4.23-4.12 (2H, m), 3.61 (1H, m), 3.25 (3H, s), 2.75 (1H, m), 1.90-1.58 (4H, m), 1.52-1.37 (3H, m), 1.12 (3H, d), 1.11 (1H, m), 0.96 (6H, d), 0.84 (3H, d), 0.78 (3H, t)

ESI MS (m/e) = 693 [M+H]+
ESI MS (m / e) = 693 [M + H] < + >

[제조예 112][Production Example 112]

메틸 (2S)-2-[((2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-{[tert-부틸(디메틸)실릴]옥시}-2,7-디메틸옥타노일)아미노]-3,3-디메틸부타노에이트의 제조: methyl (2S)-2-[((2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,7-dimethyloctanoyl)amino]-3,3-dimethylbutanoateMethyl ( 2S ) -2-[(( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-{[ tert -butyl Preparation of (dimethyl) silyl] oxy} -2,7-dimethyloctanoyl) amino] -3,3-dimethylbutanoate: methyl (2 S ) -2-[((2 R , 4 S , 5 S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-{[ tert -butyl (dimethyl) silyl] oxy} -2,7-dimethyloctanoyl) amino] -3,3-dimethylbutanoate

(S)-발린메틸에스터 히드로클로라이드 대신에 메틸 (2S)-2-아미노-3,3-디메틸부타노에이트 히드로클로라이드를 사용한 것을 제외하고는, 제조예 106과 동일한 방법으로 실시하여, 표제 화합물 93 ㎎을 85% 수율로 얻을 수 있었다. (S) - and it is subjected to the same procedures as in Preparation Example 106, except for using the valine methyl ester hydrochloride in place of methyl chloride (2 S) -2- amino-3,3-dimethyl butanoate hydrochloride, the title compound 93 mg could be obtained in 85% yield.

1H NMR (400 MHz, CDCl3); 7.72 (1H, s), 7.56 (1H, d), 7.43-7.33 (7H, m), 6.52 (1H, d), 6.19 (1H, d), 4.38 (1H, m), 4.32 (1H, d), 4.29 (2H, s), 3.79 (1H, dd), 3.68 (3H, s), 3.16 (3H, s), 2.70 (1H, m), 1.80-1.50 (4H, m), 1.40 (1H, m), 1.14 (3H, d), 0.99 (3H, d), 0.97 (3H, d), 0.93 (9H, s), 0.77 (9H, s), 0.12 (3H, s), 0.11 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.72 (1H, s), 7.56 (1H, d), 7.43-7.33 (7H, m), 6.52 (1H, d), 6.19 (1H, d), 4.38 (1H, m), 4.32 (1H, d) , 4.29 (2H, s), 3.79 (1H, dd), 3.68 (3H, s), 3.16 (3H, s), 2.70 (1H, m), 1.80-1.50 (4H, m), 1.40 (1H, m ), 1.14 (3H, d), 0.99 (3H, d), 0.97 (3H, d), 0.93 (9H, s), 0.77 (9H, s), 0.12 (3H, s), 0.11 (3H, s)

[실시예 66]Example 66

메틸 (2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-3,3-디메틸부타노에이트의 제조: methyl (2S)-2-{[(2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}-3,3-dimethylbutanoateMethyl (2 S) -2 - {[ (2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2, Preparation of 7-dimethyloctanoyl] amino} -3,3-dimethylbutanoate: methyl (2 S ) -2-{[(2 R , 4 S , 5 S ) -5-({3-[(benzylsulfonyl ) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyloctanoyl] amino} -3,3-dimethylbutanoate

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 112에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 74 ㎎을 95% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 112 instead of the compound obtained in Preparation Example 12, it was carried out in the same manner as in Preparation Example 13, 74 mg of the title compound could be obtained in 95% yield.

1H NMR (400 MHz, CDCl3); 7.65 (1H, s), 7.59 (1H, d), 7.44-7.34 (7H, m), 6.33 (1H, d), 6.24 (1H, d), 4.41 (1H, d), 4.30 (2H, s), 4.13 (1H, m), 3.97 (1H, d), 3.83 (1H, m), 3.72 (3H, s), 3.17 (3H, s), 2.72 (1H, m), 1.82-1.62 (4H, m), 1.46 (1H, m), 1.24 (3H, d), 0.98 (3H, d), 0.96 (3H, d), 0.91 (9H, s)1 H NMR (400 MHz, CDCl 3 ); 7.65 (1H, s), 7.59 (1H, d), 7.44-7.34 (7H, m), 6.33 (1H, d), 6.24 (1H, d), 4.41 (1H, d), 4.30 (2H, s) , 4.13 (1H, m), 3.97 (1H, d), 3.83 (1H, m), 3.72 (3H, s), 3.17 (3H, s), 2.72 (1H, m), 1.82-1.62 (4H, m ), 1.46 (1H, m), 1.24 (3H, d), 0.98 (3H, d), 0.96 (3H, d), 0.91 (9H, s)

ESI MS (m/e) = 618 [M+H]+
ESI MS (m / e) = 618 [M + H] < + >

[실시예 67]Example 67

(2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-3,3-디메틸부탄산의 제조: (2S)-2-{[(2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}-3,3-dimethylbutanoic acid (2 S) -2 - {[ (2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy -2,7 -dimethyl octanoyl] amino} Preparation of 3,3-dimethyl butanoic acid: (2 S) -2 - { [(2 R, 4 S, 5 S) -5 - ({3 - [(benzylsulfonyl) (methyl ) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyloctanoyl] amino} -3,3-dimethylbutanoic acid

상기 실시예 59에서 얻은 화합물 대신에 상기 실시예 66에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 60과 동일한 방법으로 실시하여, 표제 화합물 60 ㎎을 91% 수율로 얻을 수 있었다.Except for using the compound obtained in Example 66 instead of the compound obtained in Example 59, it was carried out in the same manner as in Example 60, to obtain 60 mg of the title compound in 91% yield.

1H NMR (400 MHz, CDCl3); 7.68 (1H, s), 7.63 (1H, m), 7.42-7.33 (7H, m), 6.64 (1H, d), 6.60 (1H, d), 4.38 (1H, d), 4.31 (2H, s), 4.12 (1H, m), 3.84 (1H, m), 3.16 (3H, s), 2.73 (1H, m), 1.82-1.58 (4H, m), 1.46 (1H, m), 1.19 (3H, d), 0.95 (9H, s), 0.89 (3H, d), 0.87 (3H, d)1 H NMR (400 MHz, CDCl 3 ); 7.68 (1H, s), 7.63 (1H, m), 7.42-7.33 (7H, m), 6.64 (1H, d), 6.60 (1H, d), 4.38 (1H, d), 4.31 (2H, s) , 4.12 (1H, m), 3.84 (1H, m), 3.16 (3H, s), 2.73 (1H, m), 1.82-1.58 (4H, m), 1.46 (1H, m), 1.19 (3H, d ), 0.95 (9H, s), 0.89 (3H, d), 0.87 (3H, d)

ESI MS (m/e) = 604 [M+H]+
ESI MS (m / e) = 604 [M + H] < + >

[실시예 68]Example 68

N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2,2-디메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2,2- dimethylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]benzamide N - [(1 S, 2 S, 4 R) -5 - ({(1 S) -1 - [( benzylamino) carbonyl] -2,2-dimethyl-propyl} amino) -1-hydroxy-2 Preparation of -isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -[(1 S , 2 S , 4 R ) -5-({ (1 S) -1 - [( benzylamino) carbonyl] -2,2- dimethylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3 - [(benzylsulfonyl) (methyl) amino benzamide

상기 실시예 62에서 얻은 화합물 대신에 상기 실시예 67에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 63과 동일한 방법으로 실시하여, 표제 화합물 39 ㎎을 49% 수율로 얻을 수 있었다.Except for using the compound obtained in Example 67 instead of the compound obtained in Example 62, it was carried out in the same manner as in Example 63, it was obtained 39 mg of the title compound in 49% yield.

1H NMR (400 MHz, CDCl3); 7.69 (1H, s), 7.60 (1H, d), 7.44-7.18 (12H, m), 6.59 (1H, d), 6.44 (1H, d), 6.22 (1H, t), 4.48-4.27 (2H, m), 4.29 (2H, s), 4.22 (1H, d), 4.13 (1H, m), 4.09 (1H, d), 3.79 (1H, m), 3.16 (3H, s), 2.71 (1H, m), 1.78 (1H, m), 1.74-1.60 (3H, m), 1.45 (1H, m), 1.19 (3H, d), 0.97 (3H, d), 0.94 (3H, d), 0.93 (9H, s)1 H NMR (400 MHz, CDCl 3 ); 7.69 (1H, s), 7.60 (1H, d), 7.44-7.18 (12H, m), 6.59 (1H, d), 6.44 (1H, d), 6.22 (1H, t), 4.48-4.27 (2H, m), 4.29 (2H, s), 4.22 (1H, d), 4.13 (1H, m), 4.09 (1H, d), 3.79 (1H, m), 3.16 (3H, s), 2.71 (1H, m ), 1.78 (1H, m), 1.74-1.60 (3H, m), 1.45 (1H, m), 1.19 (3H, d), 0.97 (3H, d), 0.94 (3H, d), 0.93 (9H, s)

ESI MS (m/e) = 693 [M+H]+
ESI MS (m / e) = 693 [M + H] < + >

[실시예 69]Example 69

N-[(1S,2S,4R)-5-({(1R)-1-[(벤질아미노)카르보닐]-2,2-디메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-[(1S,2S,4R)-5-({(1S)-1-[(benzylamino)carbonyl]-2,2-dimethylpropyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]benzamide N - [(1 S, 2 S, 4 R) -5 - ({(1 R) -1 - [( benzylamino) carbonyl] -2,2-dimethyl-propyl} amino) -1-hydroxy-2 Preparation of -isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -[(1 S , 2 S , 4 R ) -5-({ (1 S) -1 - [( benzylamino) carbonyl] -2,2-dimethylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3 - [(benzylsulfonyl) (methyl) amino benzamide

상기 실시예 68에서 부산물로 표제 화합물 7 ㎎을 9% 수율로 얻을 수 있었 다.In Example 68, 7 mg of the title compound was obtained as a by-product in 9% yield.

1H NMR (400 MHz, CDCl3); 7.71 (1H, s), 7.59 (1H, d), 7.44-7.18 (12H, m), 6.46 (1H, d), 6.33 (1H, d), 6.19 (1H, t), 4.50-4.30 (2H, m), 4.29 (2H, s), 4.20 (1H, d), 4.08 (1H, m), 4.07 (1H, d), 3.60 (1H, m), 3.18 (3H, s), 2.68 (1H, m), 1.78-1.53 (4H, m), 1.33 (1H, m), 1.21 (3H, d), 1.00 (9H, s), 0.94 (3H, d), 0.92 (3H, d)1 H NMR (400 MHz, CDCl 3 ); 7.71 (1H, s), 7.59 (1H, d), 7.44-7.18 (12H, m), 6.46 (1H, d), 6.33 (1H, d), 6.19 (1H, t), 4.50-4.30 (2H, m), 4.29 (2H, s), 4.20 (1H, d), 4.08 (1H, m), 4.07 (1H, d), 3.60 (1H, m), 3.18 (3H, s), 2.68 (1H, m ), 1.78-1.53 (4H, m), 1.33 (1H, m), 1.21 (3H, d), 1.00 (9H, s), 0.94 (3H, d), 0.92 (3H, d)

ESI MS (m/e) = 693 [M+H]+
ESI MS (m / e) = 693 [M + H] < + >

[제조예 113][Production Example 113]

tert-부틸 1-[(벤질아미노)카르보닐]사이클로펜틸카르바메이트: tert-butyl 1-[(benzylamino)carbonyl]cyclopentylcarbamate tert -butyl 1-[(benzylamino) carbonyl] cyclopentylcarbamate: tert -butyl 1-[(benzylamino) carbonyl] cyclopentylcarbamate

t-부톡시카르보닐 (S)-발린 대신에 1-[(t-부톡시카르보닐)아미노]사이클로펜탄카르복실산을 사용한 것을 제외하고는, 제조예 75와 동일한 방법으로 실시하여, 표제 화합물 133 ㎎을 48% 수율로 얻을 수 있었다. The title compound was carried out in the same manner as in Production Example 75, except that 1-[( t -butoxycarbonyl) amino] cyclopentanecarboxylic acid was used instead of t -butoxycarbonyl ( S ) -valine. 133 mg could be obtained in 48% yield.

1H NMR (400 MHz, CDCl3); 7.35-7.20 (5H, m), 7.02 (1H, br), 4.73 (1H, br), 4.46 (2H, d), 2.40-2.25 (2H, m), 1.98-1.66 (6H, m), 1.39 (9H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.35-7.20 (5H, m), 7.02 (1H, br), 4.73 (1H, br), 4.46 (2H, d), 2.40-2.25 (2H, m), 1.98-1.66 (6H, m), 1.39 ( 9H, s)

[제조예 114][Production Example 114]

N-((1S,2S,4R)-5-({1-[(벤질아미노)카르보닐]사이클로펜틸}아미노)-2-{[tert -부틸( 디메틸)실릴]옥시}-1-이소부틸-4-메틸-5-옥소펜틸)-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-((1S,2S,4R)-5-({1-[(benzylamino)carbonyl]cyclopentyl}amino)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-isobutyl-4-methyl-5-oxopentyl)-3-[(benzylsulfonyl)(methyl)amino]benzamide N -((1 S , 2 S , 4 R ) -5-({1-[(benzylamino) carbonyl] cyclopentyl} amino) -2-{[ tert -butyl (dimethyl) silyl] oxy} -1 Preparation of -Isobutyl-4-methyl-5-oxopentyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -((1 S , 2 S , 4 R ) -5-({ 1-[(benzylamino) carbonyl] cyclopentyl} amino) -2-{[ tert -butyl (dimethyl) silyl] oxy} -1-isobutyl-4-methyl-5-oxopentyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 113에서 얻은 화합물 72 ㎎(0.225 mmol)을 에틸아세테이트에 묽혀진 4.0 N 염산용액 3 ㎖에 녹여서 2 시간 동안 교반하였다. 용매를 감압증류하여 농축한 후 N,N-디메틸포름아미드 5 ㎖에 녹여서 0℃로 냉각하여 상기 제조예 58에서 얻은 화합물 91 ㎎(0.15 mmol), EDC(43 ㎎, 0.225 mmol)와 HOBT 41 ㎎(0.3 mmol)을 가하였다. 여기에, N,N-디이소프로필에틸아민 0.5 ㎖(과량)를 가하고 상온으로 온도를 올려 하룻밤동안 교반하였다. 감압증류하여 용매를 제거한 다음 에틸아세테이트에 녹여서 물, 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음 메탄올과 디클로로메탄의 5:95 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 51 ㎎을 42% 수율로 얻을 수 있었다.72 mg (0.225 mmol) of the compound obtained in Preparation Example 113 was dissolved in 3 ml of 4.0 N hydrochloric acid solution diluted in ethyl acetate, and stirred for 2 hours. The solvent was distilled under reduced pressure, concentrated, and then dissolved in 5 ml of N, N-dimethylformamide and cooled to 0 ° C. to obtain 91 mg (0.15 mmol), EDC (43 mg, 0.225 mmol) and 41 mg HOBT obtained in Preparation Example 58. (0.3 mmol) was added. To this was added 0.5 ml (excess) of N, N-diisopropylethylamine, the temperature was raised to room temperature and the mixture was stirred overnight. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a 5:95 mixture of methanol and dichloromethane to obtain 51 mg of the title compound in 42% yield.

1H NMR (400 MHz, CDCl3); 7.69 (1H, s), 7.52-7.29 (9H, m), 7.20-7.14 (5H, m), 6.84 (1H, s), 6.17 (1H, d), 4.43-4.14 (5H, m), 3.73 (1H, dd), 3.19 (3H, s), 2.55 (1H, m), 2.33 (1H, m), 2.20 (1H, m), 2.10-1.92 (2H, m), 1.72-1.31 (9H, m), 1.12 (3H, d), 0.97 (6H, d), 0.91 (9H, s), 0.10 (3H, s), 0.06 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.69 (1H, s), 7.52-7.29 (9H, m), 7.20-7.14 (5H, m), 6.84 (1H, s), 6.17 (1H, d), 4.43-4.14 (5H, m), 3.73 ( 1H, dd), 3.19 (3H, s), 2.55 (1H, m), 2.33 (1H, m), 2.20 (1H, m), 2.10-1.92 (2H, m), 1.72-1.31 (9H, m) , 1.12 (3H, d), 0.97 (6H, d), 0.91 (9H, s), 0.10 (3H, s), 0.06 (3H, s)

[실시예 70]Example 70

N-[(1S,2S,4R)-5-({1-[(벤질아미노)카르보닐]사이클로펜틸}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-[(1S,2S,4R)-5-({1-[(benzylamino)carbonyl]cyclopentyl}amino)-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]benzamide N - [(1 S, 2 S, 4 R) -5 - ({1 - [( benzylamino) carbonyl] cyclopentyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5 Preparation of oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -[(1 S , 2 S , 4 R ) -5-({1-[(benzylamino) carbonyl] cyclopentyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 114에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 40 ㎎을 93% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 114 instead of the compound obtained in Preparation Example 12, it was carried out in the same manner as in Preparation Example 13, 40 mg of the title compound could be obtained in 93% yield.

1H NMR (400 MHz, CDCl3); 7.66 (1H, s), 7.55 (1H, t), 7.43-7.33 (7H, m), 7.30-7.13 (6H, m), 6.34 (1H, s), 6.19 (1H, d), 4.44-4.22 (4H, m), 4.09 (1H, m), 3.64 (1H, m), 3.26 (1H, d), 3.18 (3H, s), 2.59 (1H, m), 2.35-2.17 (2H, m), 2.08 (1H, m), 1.89 (1H, m), 1.78-1.50 (8H, m), 1.34 (1H, m), 1.13 (3H, d), 0.94 (3H, d), 0.93 (3H, d)1 H NMR (400 MHz, CDCl 3 ); 7.66 (1H, s), 7.55 (1H, t), 7.43-7.33 (7H, m), 7.30-7.13 (6H, m), 6.34 (1H, s), 6.19 (1H, d), 4.44-4.22 ( 4H, m), 4.09 (1H, m), 3.64 (1H, m), 3.26 (1H, d), 3.18 (3H, s), 2.59 (1H, m), 2.35-2.17 (2H, m), 2.08 (1H, m), 1.89 (1H, m), 1.78-1.50 (8H, m), 1.34 (1H, m), 1.13 (3H, d), 0.94 (3H, d), 0.93 (3H, d)

ESI MS (m/e) = 691 [M+H]+
ESI MS (m / e) = 691 [M + H] < + >

[실시예 71]Example 71

(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥탄산의 제조: (2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoic acid (2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) Preparation of 4-hydroxy-2,7-dimethyl-octanoic acid: (2 R , 4 S , 5 S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyloctanoic acid

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 58에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 10 ㎎을 33% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 58 instead of the compound obtained in Preparation Example 12, it was carried out in the same manner as in Preparation Example 13, 10 mg of the title compound in 33% yield was obtained.

1H NMR (400 MHz, CD3OD); 7.74 (1H, s), 7.71 (1H, m), 7.46-7.32 (7H, m), 4.47 (2H, s), 4.17 (1H, m), 3.63 (1H, m), 3.26 (3H, s), 2.68 (1H, m), 1.83 (1H, m), 1.72-1.59 (2H, m), 1.50-1.34 (2H, m), 1.15 (3H, d), 0.97 (6H, d)1 H NMR (400 MHz, CD3OD); 7.74 (1H, s), 7.71 (1H, m), 7.46-7.32 (7H, m), 4.47 (2H, s), 4.17 (1H, m), 3.63 (1H, m), 3.26 (3H, s) , 2.68 (1H, m), 1.83 (1H, m), 1.72-1.59 (2H, m), 1.50-1.34 (2H, m), 1.15 (3H, d), 0.97 (6H, d)

ESI MS (m/e) = 491 [M+H]+
ESI MS (m / e) = 491 [M + H] < + >

[제조예 115][Manufacture example 115]

3-아미노-2-피페리디논 히드로클로라이드의 제조: 3-amino-2-piperidinone hydrochloridePreparation of 3-amino-2-piperidinone hydrochloride: 3-amino-2-piperidinone hydrochloride

공지의 방법(Tetrahedron 2002, 58, 3137-3143)에 따라 표제 화합물을 합성할 수 있었다. The title compound can be synthesized according to known methods (Tetrahedron 2002, 58, 3137-3143).

1H NMR (400 MHz, DMSO,d6); 8.28 (3H, s), 8.04 (1H, s), 3.71 (1H, m), 3.20-3.03 (2H, m), 2.13 (1H, m), 1.90-1.62 (3H, m)
1 H NMR (400 MHz, DMSO, d 6); 8.28 (3H, s), 8.04 (1H, s), 3.71 (1H, m), 3.20-3.03 (2H, m), 2.13 (1H, m), 1.90-1.62 (3H, m)

[제조예 116][Production Example 116]

3-[(벤질술포닐)(메틸)아미노]-N-((1S,2S,4R)-2-{[tert-부틸(디메틸)실릴]옥시}-1-이소부틸-4-메틸-5-옥소-5-{[(3R or 3S)-2-옥소피페리딘일]아미노}펜틸)벤즈아미드 의 제조: 3-[(benzylsulfonyl)(methyl)amino]-N-((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-isobutyl-4-methyl-5-oxo-5-{[(3R or 3S)-2-oxopiperidinyl]amino}pentyl)benzamide3-[(benzylsulfonyl) (methyl) amino] -N -((1 S , 2 S , 4 R ) -2-{[ tert -butyl (dimethyl) silyl] oxy} -1-isobutyl-4- methyl-5-oxo -5 - {[(3 R or 3 S) -2- oxpiperidin- each optionally substituted; amino} pentyl) benzamide Preparation of: 3 - [(benzylsulfonyl) ( methyl) amino] - N - (( 1 S , 2 S , 4 R ) -2-{[ tert -butyl (dimethyl) silyl] oxy} -1-isobutyl-4-methyl-5-oxo-5-{[(3 R or 3 S ) -2 -oxopiperidinyl] amino} pentyl) benzamide

상기 제조예 58에서 얻은 화합물 91 ㎎(0.15 mmol)을 N,N-디메틸포름아미드 5 ㎖에 녹여서 0℃로 냉각한 후 상기 제조예 115에서 얻은 화합물 34 ㎎(0.225 mmol)과 HATU(86 ㎎, 0.225 mmol)를 가하였다. 여기에, N,N-디이소프로필에틸아민 0.5 ㎖(과량)를 가하고 상온으로 온도를 올려 3 시간동안 교반하였다. 감압증류하여 용매를 제거한 다음 에틸아세테이트에 녹여서 물, 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음 메탄올과 디클로로메탄의 5:95 혼합액을 이용한 컬럼크로마토그래피로 정제하여 광학적으로 순수한 이성질체인 표제 화합물 21 ㎎을 20% 수율로 얻을 수 있었다.91 mg (0.15 mmol) of the compound obtained in Preparation Example 58 was dissolved in 5 ml of N, N-dimethylformamide, cooled to 0 ° C., and 34 mg (0.225 mmol) of the compound obtained in Preparation Example 115 and HATU (86 mg, 0.225 mmol) was added. 0.5 mL (excess) of N, N-diisopropylethylamine was added thereto, and the temperature was raised to room temperature, followed by stirring for 3 hours. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a 5:95 mixture of methanol and dichloromethane to obtain 21 mg of the title compound as an optically pure isomer in 20% yield.

1H NMR (400 MHz, CDCl3); 7.82 (1H, s), 7.59(1H, d), 7.45-7.33 (7H, m), 6.79 (1H, d), 6.27 (1H, d), 5.48 (1H, s), 4.50-4.20 (4H, m), 3.80 (1H, m), 3.23 (3H, s), 3.22-3.12 (2H, m), 2.54 (1H, m), 2.28 (1H, m), 1.97 (1H, m), 1.92-1.48 (6H, m), 1.39 (1H, m), 1.17 (3H, d), 0.98 (3H, d), 0.97 (3H, d), 0.91 (9H, s), 0.12 (3H, s), 0.11 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.82 (1H, s), 7.59 (1H, d), 7.45-7.33 (7H, m), 6.79 (1H, d), 6.27 (1H, d), 5.48 (1H, s), 4.50-4.20 (4H, m), 3.80 (1H, m), 3.23 (3H, s), 3.22-3.12 (2H, m), 2.54 (1H, m), 2.28 (1H, m), 1.97 (1H, m), 1.92-1.48 (6H, m), 1.39 (1H, m), 1.17 (3H, d), 0.98 (3H, d), 0.97 (3H, d), 0.91 (9H, s), 0.12 (3H, s), 0.11 ( 3H, s)

[실시예 72]Example 72

3-[(벤질술포닐)(메틸)아미노]-N-((1S,2S,4R)-2-히드록시-1-이소부틸-4-메틸-5-옥 소-5-{[(3R or 3S)-2-옥소피페리딘일]아미노}펜틸)벤즈아미드의 제조: 3-[(benzylsulfonyl)(methyl)amino]-N-((1S,2S,4R)-2-hydroxy-1-isobutyl-4-methyl-5-oxo-5-{[(3R or 3S)-2-oxopiperidinyl]amino}pentyl)benzamide3-[(benzylsulfonyl) (methyl) amino] -N -((1 S , 2 S , 4 R ) -2-hydroxy-1-isobutyl-4-methyl-5-oxo-5- { [(3 R or 3 S) -2- oxpiperidin- each optionally substituted; amino} pentyl) benzamide Preparation of: 3 - [(benzylsulfonyl) ( methyl) amino] - N - ((1 S, 2 S, 4 R) -2-hydroxy-1-isobutyl-4-methyl-5-oxo-5-{[(3 R or 3 S ) -2-oxopiperidinyl] amino} pentyl) benzamide

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 116에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 13 ㎎을 76% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 116 instead of the compound obtained in Preparation Example 12, it was carried out in the same manner as in Preparation Example 13, 13 mg of the title compound could be obtained in 76% yield.

1H NMR (400 MHz, CDCl3); 7.73 (1H, s), 7.65 (1H, m), 7.45-7.32 (7H, m), 6.58 (1H, d), 6.41 (1H, d), 6.03 (1H, s), 4.67 (1H, br), 4.46 (1H, m), 4.32 (2H, s), 4.16 (1H, m), 3.75 (1H, br), 3.28 (2H, br), 3.16 (3H, s), 2.60 (1H, m), 2.31 (1H, m), 1.98-1.50 (7H, m), 1.39 (1H, m), 1.18 (3H, d), 0.96 (3H, d), 0.93 (3H, d)1 H NMR (400 MHz, CDCl 3 ); 7.73 (1H, s), 7.65 (1H, m), 7.45-7.32 (7H, m), 6.58 (1H, d), 6.41 (1H, d), 6.03 (1H, s), 4.67 (1H, br) , 4.46 (1H, m), 4.32 (2H, s), 4.16 (1H, m), 3.75 (1H, br), 3.28 (2H, br), 3.16 (3H, s), 2.60 (1H, m), 2.31 (1H, m), 1.98-1.50 (7H, m), 1.39 (1H, m), 1.18 (3H, d), 0.96 (3H, d), 0.93 (3H, d)

ESI MS (m/e) = 587 [M+H]+
ESI MS (m / e) = 587 [M + H] < + >

[제조예 117]Preparation Example 117

3-[(벤질술포닐)(메틸)아미노]-N-((1S,2S,4R)-2-{[tert-부틸(디메틸)실릴]옥시}-1-이소부틸-4-메틸-5-옥소-5-{[(3R or 3S)-2-옥소피페리딘일]아미노}펜틸)벤즈아미드의 제조: 3-[(benzylsulfonyl)(methyl)amino]-N-((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-isobutyl-4-methyl-5-oxo-5-{[(3R or 3S)-2-oxopiperidinyl]amino}pentyl)benzamide 3-[(benzylsulfonyl) (methyl) amino] -N -((1 S , 2 S , 4 R ) -2-{[ tert -butyl (dimethyl) silyl] oxy} -1-isobutyl-4- methyl-5-oxo -5 - {[(3 R or 3 S) -2- oxpiperidin- each optionally substituted; amino} pentyl) benzamide Preparation of: 3 - [(benzylsulfonyl) ( methyl) amino] - N - (( 1 S , 2 S , 4 R ) -2-{[ tert -butyl (dimethyl) silyl] oxy} -1-isobutyl-4-methyl-5-oxo-5-{[(3 R or 3 S ) -2 -oxopiperidinyl] amino} pentyl) benzamide

제조예 116의 정제과정에서 제조예 116과는 반대 이성질체인 표제 화합물 36 ㎎을 34% 수율로 얻을 수 있었다.During the purification of Preparation 116, 36 mg of the title compound as an isomer of Preparation 116 was obtained in a 34% yield.

1H NMR (400 MHz, CDCl3); 7.81 (1H, s), 7.53 (1H, d), 7.43-7.33 (6H, m), 7.30 (1H, m), 6.81 (1H, d), 6.27 (1H, d), 5.69 (1H, s), 4.37 (1H, m), 4.34 (2H, s), 4.17 (1H, m), 3.77 (1H, m), 3.28-3.18 (2H, m), 3.19 (3H, s), 2.55 (1H, m), 2.26 (1H, m), 1.82-1.34 (8H, m), 1.17 (3H, d), 0.98 (3H, d), 0.96 (3H, d), 0.92 (9H, s), 0.13 (3H, s), 0.11 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.81 (1H, s), 7.53 (1H, d), 7.43-7.33 (6H, m), 7.30 (1H, m), 6.81 (1H, d), 6.27 (1H, d), 5.69 (1H, s) , 4.37 (1H, m), 4.34 (2H, s), 4.17 (1H, m), 3.77 (1H, m), 3.28-3.18 (2H, m), 3.19 (3H, s), 2.55 (1H, m ), 2.26 (1H, m), 1.82-1.34 (8H, m), 1.17 (3H, d), 0.98 (3H, d), 0.96 (3H, d), 0.92 (9H, s), 0.13 (3H, s), 0.11 (3H, s)

[실시예 73]Example 73

3-[(벤질술포닐)(메틸)아미노]-N-((1S,2S,4R)-2-히드록시-1-이소부틸-4-메틸-5-옥소-5-{[(3R or 3S)-2-옥소피페리딘일]아미노}펜틸)벤즈아미드의 제조: 3-[(benzylsulfonyl)(methyl)amino]-N-((1S,2S,4R)-2-hydroxy-1-isobutyl-4-methyl-5-oxo-5-{[(3R or 3S)-2-oxopiperidinyl]amino}pentyl)benzamide3-[(benzylsulfonyl) (methyl) amino] -N -((1 S , 2 S , 4 R ) -2-hydroxy-1-isobutyl-4-methyl-5-oxo-5-{[ (3 R or 3 S) -2- oxpiperidin- each optionally substituted; amino} pentyl) benzamide Preparation of: 3 - [(benzylsulfonyl) ( methyl) amino] - N - ((1 S, 2 S, 4 R) - 2-hydroxy-1-isobutyl-4-methyl-5-oxo-5-{[(3 R or 3 S ) -2-oxopiperidinyl] amino} pentyl) benzamide

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 117에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 28 ㎎을 99% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 117 instead of the compound obtained in Preparation Example 12, 28 mg of the title compound could be obtained in 99% yield in the same manner as in Preparation Example 13.

1H NMR (400 MHz, CDCl3); 7.71 (1H, s), 7.65 (1H, m), 7.43-7.33 (7H, m), 6.76 (1H, d), 6.62 (1H, d), 5.99 (1H, s), 4.59 (1H, br), 4.31 (2H, s), 4.18-4.03 (2H, m), 3.80 (1H, m), 3.39-3.24 (2H, m), 3.17 (3H, s), 2.65 (1H, m), 2.36 (1H, m), 1.96-1.57 (7H, m), 1.44 (1H, m), 1.21 (3H, d), 0.97 (3H, d), 0.95 (3H, d)1 H NMR (400 MHz, CDCl 3 ); 7.71 (1H, s), 7.65 (1H, m), 7.43-7.33 (7H, m), 6.76 (1H, d), 6.62 (1H, d), 5.99 (1H, s), 4.59 (1H, br) , 4.31 (2H, s), 4.18-4.03 (2H, m), 3.80 (1H, m), 3.39-3.24 (2H, m), 3.17 (3H, s), 2.65 (1H, m), 2.36 (1H , m), 1.96-1.57 (7H, m), 1.44 (1H, m), 1.21 (3H, d), 0.97 (3H, d), 0.95 (3H, d)

ESI MS (m/e) = 587 [M+H]+
ESI MS (m / e) = 587 [M + H] < + >

[제조예 118]Preparation Example 118

메틸 trans-4-{[(tert-부톡시카르보닐)아미노]메틸}사이클로헥산카르복실레이트의 제조: methyl 4-{[(tert-butoxycarbonyl)amino]methyl}cyclohexanecarboxylatePreparation of methyl trans- 4-{[( tert -butoxycarbonyl) amino] methyl} cyclohexanecarboxylate: methyl 4-{[( tert -butoxycarbonyl) amino] methyl} cyclohexanecarboxylate

trans-4-{[(tert-부톡시카르보닐)아미노]메틸}사이클로헥산카르복실산 1.23 g(4.78 mmol)과 탄산칼륨 1.98 g(14.34 mmol)을 N,N-디메틸포름아미드 20 ㎖에 녹인 후 아이오도메탄 0.89 ㎖(14.34 mmol)를 가하여 3 시간 동안 교반하였다. 감압증류하여 용매를 제거한 후 에틸아세테이트에 녹여서 물과 소금물로 씻어 주었다. 용매를 감압증류로 제거하여 표제 화합물 1.2 g을 92% 수율로 얻을 수 있었다. trans- 4-{[( tert -butoxycarbonyl) amino] methyl} cyclohexanecarboxylic acid 1.23 g (4.78 mmol) and potassium carbonate 1.98 g (14.34 mmol) were dissolved in 20 ml of N, N-dimethylformamide. 0.89 mL (14.34 mmol) of iodomethane was added thereto, followed by stirring for 3 hours. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water and brine. The solvent was removed by distillation under reduced pressure to obtain 1.2 g of the title compound in 92% yield.

1H NMR (400 MHz, CDCl3); 4.56 (1H, br), 3.66 (3H, s), 2.98 (2H, t), 2.24 (1H, m), 2.00 (2H, d), 1.82 (2H, d), 1.44 (9H, s), 1.50-1.34 (3H, m), 1.03-0.88 (2H, m)
1 H NMR (400 MHz, CDCl 3 ); 4.56 (1H, br), 3.66 (3H, s), 2.98 (2H, t), 2.24 (1H, m), 2.00 (2H, d), 1.82 (2H, d), 1.44 (9H, s), 1.50 -1.34 (3H, m), 1.03-0.88 (2H, m)

[제조예 119][Production Example 119]

메틸 4-{[((2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-{[tert -부틸(디메틸)실릴]옥시}-2,7-디메틸옥타노일)아미노]메틸}사이클로헥산카르복실레 이트의 제조: methyl 4-{[((2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,7-dimethyloctanoyl)amino]methyl}cyclohexanecarboxylateMethyl 4-{[((2 R , 4 S , 5 S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-{[ tert -butyl (dimethyl) silyl ] Oxy} -2,7-dimethyloctanoyl) amino] methyl} cyclohexanecarboxylate: methyl 4-{[((2 R , 4 S , 5 S ) -5-({3-[( benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-{[ tert -butyl (dimethyl) silyl] oxy} -2,7-dimethyloctanoyl) amino] methyl} cyclohexanecarboxylate

상기 제조예 113에서 얻은 화합물 대신에 상기 제조예 118에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 114와 동일한 방법으로 실시하여, 표제 화합물 89 ㎎을 78% 수율로 얻을 수 있었다.
Except for using the compound obtained in Preparation Example 118 instead of the compound obtained in Preparation Example 113, it was carried out in the same manner as Preparation Example 114, it was obtained 89 mg of the title compound in 78% yield.

[실시예 74]Example 74

메틸 4-({[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디베틸옥타노일]아미노}메틸)사이클로헥산카르복실레이트의 제조: methyl 4-({[(2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}methyl)cyclohexanecarboxylateMethyl 4 - ({[(2 R , 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-betil octanoyl] amino} methyl) Preparation of cyclohexane-carboxylate: methyl 4 - ({[( 2 R, 4 S, 5 S) -5 - ({3 - [(benzylsulfonyl) (methyl) amino] benzoyl} amino ) -4-hydroxy-2,7-dimethyloctanoyl] amino} methyl) cyclohexanecarboxylate

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 119에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 52 ㎎을 68% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 119 instead of the compound obtained in Preparation Example 12, it was carried out in the same manner as in Preparation Example 13, 52 mg of the title compound could be obtained in 68% yield.

1H NMR (400 MHz, CDCl3); 7.65 (1H, s), 7.60 (1H, m), 7.43-7.33 (7H, m), 6.36 (1H, d), 5.86 (1H, t), 4.31 (2H, s), 4.18 (1H, d), 4.14 (1H, m), 3.81 (1H, m), 3.65 (3H, s), 3.17 (3H, s), 3.16-2.98 (2H, m), 2.60 (1H, m), 2.19 (1H, m), 2.00-1.88 (2H, m), 1.81-1.61 (6H, m), 1.52-1.26 (6H, m), 1.23 (3H, d), 0.98 (3H, d), 0.96 (3H, d)1 H NMR (400 MHz, CDCl 3 ); 7.65 (1H, s), 7.60 (1H, m), 7.43-7.33 (7H, m), 6.36 (1H, d), 5.86 (1H, t), 4.31 (2H, s), 4.18 (1H, d) , 4.14 (1H, m), 3.81 (1H, m), 3.65 (3H, s), 3.17 (3H, s), 3.16-2.98 (2H, m), 2.60 (1H, m), 2.19 (1H, m ), 2.00-1.88 (2H, m), 1.81-1.61 (6H, m), 1.52-1.26 (6H, m), 1.23 (3H, d), 0.98 (3H, d), 0.96 (3H, d)

ESI MS (m/e) = 587 [M+H]+
ESI MS (m / e) = 587 [M + H] < + >

[실시예 75]Example 75

4-({[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}메틸)사이클로헥산카르복실산의 제조: 4-({[(2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}methyl)cyclohexanecarboxylic acid 4 - ({[(2 R , 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyl-octanoyl Preparation of] amino} methyl) cyclohexanecarboxylic acid: 4-({[(2 R , 4 S , 5 S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4 -hydroxy-2,7-dimethyloctanoyl] amino} methyl) cyclohexanecarboxylic acid

상기 실시예 59에서 얻은 화합물 대신에 상기 실시예 74에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 60과 동일한 방법으로 실시하여, 표제 화합물 36 ㎎을 80% 수율로 얻을 수 있었다.Except for using the compound obtained in Example 74 instead of the compound obtained in Example 59, it was carried out in the same manner as in Example 60, 36 mg of the title compound could be obtained in 80% yield.

1H NMR (400 MHz, CD3OD); 7.75 (1H, s), 7.71 (1H, d), 7.50-7.30 (7H, m), 4.47 (2H, s), 4.18 (1H, m), 3.58 (1H, m), 3.26 (3H, s), 3.12-2.90(2H, m), 2.65 (1H, m), 2.15 (1H, m), 2.00-1.58 (8H, m), 1.50-1.21 (6H, m), 1.13 (3H, d), 0.97 (6H, d)1 H NMR (400 MHz, CD3OD); 7.75 (1H, s), 7.71 (1H, d), 7.50-7.30 (7H, m), 4.47 (2H, s), 4.18 (1H, m), 3.58 (1H, m), 3.26 (3H, s) , 3.12-2.90 (2H, m), 2.65 (1H, m), 2.15 (1H, m), 2.00-1.58 (8H, m), 1.50-1.21 (6H, m), 1.13 (3H, d), 0.97 (6H, d)

ESI MS (m/e) = 630 [M+H]+
ESI MS (m / e) = 630 [M + H] < + >

[제조예 120]Production Example 120

메틸 4-[(tert-부톡시카르보닐)아미노]사이클로헥산카르복실레이트의 제조: methyl 4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylatePreparation of Methyl 4-[( tert -butoxycarbonyl) amino] cyclohexanecarboxylate: methyl 4-[( tert- butoxycarbonyl) amino] cyclohexanecarboxylate

trans-4-{[(tert-부톡시카르보닐)아미노]메틸}사이클로헥산카르복실산 대신에 4-[(tert-부톡시카르보닐)아미노]사이클로헥산카르복실산을 사용한 것을 제외하고는, 제조예 118과 동일한 방법으로 실시하여, 표제 화합물 0.89 g을 98% 수율로 얻을 수 있었다.except that 4-[( tert -butoxycarbonyl) amino] cyclohexanecarboxylic acid was used in place of trans- 4-{[( tert -butoxycarbonyl) amino] methyl} cyclohexanecarboxylic acid, By the same method as in Preparation 118, 0.89 g of the title compound was obtained in 98% yield.

1H NMR (400 MHz, CDCl3); 4.56 (1H, br), 3.68 (3H, s), 3.63 (1H, m), 2.47 (1H, m), 2.12-1.48 (5H, m), 1.44 (9H, s)
1 H NMR (400 MHz, CDCl 3 ); 4.56 (1H, br), 3.68 (3H, s), 3.63 (1H, m), 2.47 (1H, m), 2.12-1.48 (5H, m), 1.44 (9H, s)

[제조예 121][Production Example 121]

메틸 4-[((2R,4S,5S)-5-({3-[(벤젠술포닐)(메틸)아미노]벤조일}아미노)-4-{[tert -부틸(디메틸)실릴]옥시}-2,7-디메틸옥타노일)아미노]사이클로헥산카르복실레이트의 제조: methyl 4-[((2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,7-dimethyloctanoyl)amino]cyclohexanecarboxylateMethyl 4-[(( 2R , 4S , 5S ) -5-({3-[(benzenesulfonyl) (methyl) amino] benzoyl} amino) -4-{[ tert -butyl (dimethyl) silyl] Preparation of oxy} -2,7-dimethyloctanoyl) amino] cyclohexanecarboxylate: methyl 4-[((2 R , 4 S , 5 S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-{[ tert -butyl (dimethyl) silyl] oxy} -2,7-dimethyloctanoyl) amino] cyclohexanecarboxylate

상기 제조예 113에서 얻은 화합물 대신에 상기 제조예 120에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 114와 동일한 방법으로 실시하여, 표제 화합물 84 ㎎을 75% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 120 instead of the compound obtained in Preparation Example 113, it was carried out in the same manner as Preparation Example 114, it was obtained 84 mg of the title compound in 75% yield.

1H NMR (400 MHz, CDCl3); 7.64 (1H, s), 7.58 (1H, m), 7.46-7.32 (7H, m), 6.24 (1H, d), 6.20 (1H, d), 4.38 (1H, m), 4.31 (2H, s), 3.80-3.68 (2H, m), 3.65 (3H, s), 3.21 (3H, s), 2.51-2.36 (2H, m), 1.98-1.83 (2H, m), 1.73-1.30 (11H, m), 1.14 (3H, d), 0.98 (3H, d), 0.97 (3H, d)
1 H NMR (400 MHz, CDCl 3 ); 7.64 (1H, s), 7.58 (1H, m), 7.46-7.32 (7H, m), 6.24 (1H, d), 6.20 (1H, d), 4.38 (1H, m), 4.31 (2H, s) , 3.80-3.68 (2H, m), 3.65 (3H, s), 3.21 (3H, s), 2.51-2.36 (2H, m), 1.98-1.83 (2H, m), 1.73-1.30 (11H, m) , 1.14 (3H, d), 0.98 (3H, d), 0.97 (3H, d)

[실시예 76]Example 76

메틸 4-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}사이클로헥산카르복실레이트의 제조: methyl 4-{[(2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}cyclohexanecarboxylateMethyl 4-{[(2 R , 4 S , 5 S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyloctanoyl Preparation of] amino} cyclohexanecarboxylate: methyl 4-{[(2 R , 4 S , 5 S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy -2,7-dimethyloctanoyl] amino} cyclohexanecarboxylate

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 121에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 65 ㎎을 92% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 121 instead of the compound obtained in Preparation Example 12, it was carried out in the same manner as in Preparation Example 13, it was obtained 65 mg of the title compound in 92% yield.

1H NMR (400 MHz, CDCl3); 7.65 (1H, s), 7.60 (1H, d), 7.45-7.34 (7H, m), 6.38 (1H, d), 5.77 (1H, d), 4.38 (1H, s), 4.31 (2H, s), 4.13 (1H, m), 3.91-3.26 (2H, m), 3.67 (3H, s), 3.18 (3H, s), 1.96-1.81 (2H, m), 1.77-1.48 (10H, m), 1.27 (1H, m), 1.22 (3H, d), 0.98 (3H, d), 0.96 (3H, d)1 H NMR (400 MHz, CDCl 3 ); 7.65 (1H, s), 7.60 (1H, d), 7.45-7.34 (7H, m), 6.38 (1H, d), 5.77 (1H, d), 4.38 (1H, s), 4.31 (2H, s) , 4.13 (1H, m), 3.91-3.26 (2H, m), 3.67 (3H, s), 3.18 (3H, s), 1.96-1.81 (2H, m), 1.77-1.48 (10H, m), 1.27 (1H, m), 1.22 (3H, d), 0.98 (3H, d), 0.96 (3H, d)

ESI MS (m/e) = 630 [M+H]+
ESI MS (m / e) = 630 [M + H] < + >

[실시예 77] Example 77                     

4-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}사이클로헥산카르복실산의 제조: 4-{[(2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}cyclohexanecarboxylic acid 4 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyl-octanoyl; Preparation of amino} cyclohexanecarboxylic acid: 4-{[(2 R , 4 S , 5 S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2 , 7-dimethyloctanoyl] amino} cyclohexanecarboxylic acid

상기 실시예 59에서 얻은 화합물 대신에 상기 실시예 76에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 60과 동일한 방법으로 실시하여, 표제 화합물 61 ㎎을 87% 수율로 얻을 수 있었다.Except for using the compound obtained in Example 76 instead of the compound obtained in Example 59, the title compound was obtained in 87% yield in the same manner as in Example 60, 61 mg.

1H NMR (400 MHz, CD3OD); 7.75 (1H, s), 7.70 (1H, m), 7.48-7.30 (7H, m), 4.47 (2H, s), 4.16 (1H, m), 3.73 (1H, m), 3.57 (1H, m), 3.26 (3H, s), 2.63 (1H, m), 2.46 (1H, m), 2.03-1.78 (3H, m), 1.72-1.33 (10H, m), 1.12 (3H, d), 0.96 (6H, d)1 H NMR (400 MHz, CD3OD); 7.75 (1H, s), 7.70 (1H, m), 7.48-7.30 (7H, m), 4.47 (2H, s), 4.16 (1H, m), 3.73 (1H, m), 3.57 (1H, m) , 3.26 (3H, s), 2.63 (1H, m), 2.46 (1H, m), 2.03-1.78 (3H, m), 1.72-1.33 (10H, m), 1.12 (3H, d), 0.96 (6H , d)

ESI MS (m/e) = 616 [M+H]+
ESI MS (m / e) = 616 [M + H] < + >

[제조예 122]Production Example 122

메틸 3-[(tert-부톡시카르보닐)아미노]사이클로헥산카르복실레이트의 제조: methyl 3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylatePreparation of Methyl 3-[( tert -butoxycarbonyl) amino] cyclohexanecarboxylate: methyl 3-[( tert- butoxycarbonyl) amino] cyclohexanecarboxylate

trans-4-{[(tert-부톡시카르보닐)아미노]메틸}사이클로헥산카르복실산 대신에 3-[(tert-부톡시카르보닐)아미노]사이클로헥산카르복실산을 사용한 것을 제외하고는, 제조예 118과 동일한 방법으로 실시하여, 표제 화합물 0.44 g을 90% 수율로 얻을 수 있었다. except that 3-[( tert -butoxycarbonyl) amino] cyclohexanecarboxylic acid was used in place of trans- 4-{[( tert -butoxycarbonyl) amino] methyl} cyclohexanecarboxylic acid, By the same method as in Preparation 118, 0.44 g of the title compound could be obtained in 90% yield.

1H NMR (400 MHz, CDCl3); 4.40 (1H, br), 3.66 (3H, s), 3.46 (1H, m), 2.40 (1H, m), 2.24 (1H, d), 2.02-1.80 (3H, m), 1.45 (9H, s), 1.41-1.17 (3H, m), 1.04 (1H, m)
1 H NMR (400 MHz, CDCl 3 ); 4.40 (1H, br), 3.66 (3H, s), 3.46 (1H, m), 2.40 (1H, m), 2.24 (1H, d), 2.02-1.80 (3H, m), 1.45 (9H, s) , 1.41-1.17 (3H, m), 1.04 (1H, m)

[제조예 123][Production Example 123]

메틸 3-[((2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-{[tert -부틸(디메틸)실릴]옥시}-2,7-디메틸옥타노일)아미노]사이클로헥산카르복실레이트의 제조: methyl 3-[((2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,7-dimethyloctanoyl)amino]cyclohexanecarboxylateMethyl 3-[(( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-{[ tert -butyl (dimethyl) silyl] Preparation of oxy} -2,7-dimethyloctanoyl) amino] cyclohexanecarboxylate: methyl 3-[((2 R , 4 S , 5 S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-{[ tert -butyl (dimethyl) silyl] oxy} -2,7-dimethyloctanoyl) amino] cyclohexanecarboxylate

상기 제조예 113에서 얻은 화합물 대신에 상기 제조예 122에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 114와 동일한 방법으로 실시하여, 표제 화합물 91 ㎎을 81% 수율로 얻을 수 있었다.91 mg of the title compound was obtained in 81% yield by the same method as Preparation Example 114, except that the compound obtained in Preparation Example 122 was used instead of the compound obtained in Preparation Example 113.

1H NMR (400 MHz, CDCl3); 7.71-7.52 (2H, m), 7.46-7.32 (7H, m), 6.34-6.18 (2H, m), 4.40 (1H, m), 4.31 (2H, s), 3.75 (1H, m), 3.64 (1H, m), 3.64, 3.56 (3H, two set of s), 3.18, 3.17 (3H, two set of s), 2.47-2.17 (2H, m), 1.98-1.76 (2H, m), 1.73-1.46 (7H, m), 1.42-1.00 (4H, m), 1.14 (3H, d), 0.99 (3H, d), 0.97 (3H, d), 0.92 (9H, s), 0.12 (3H, s), 0.10 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.71-7.52 (2H, m), 7.46-7.32 (7H, m), 6.34-6.18 (2H, m), 4.40 (1H, m), 4.31 (2H, s), 3.75 (1H, m), 3.64 ( 1H, m), 3.64, 3.56 (3H, two set of s), 3.18, 3.17 (3H, two set of s), 2.47-2.17 (2H, m), 1.98-1.76 (2H, m), 1.73-1.46 (7H, m), 1.42-1.00 (4H, m), 1.14 (3H, d), 0.99 (3H, d), 0.97 (3H, d), 0.92 (9H, s), 0.12 (3H, s), 0.10 (3H, s)

[실시예 78]Example 78

메틸 3-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}사이클로헥산카르복실레이트의 제조: methyl 3-{[(2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}cyclohexanecarboxylateMethyl 3 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyl-octanoyl ] Amino} cyclohexanecarboxylate Preparation: methyl 3-{[(2 R , 4 S , 5 S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy -2,7-dimethyloctanoyl] amino} cyclohexanecarboxylate

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 123에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 74 ㎎을 96% 수율로 얻을 수 있었다.In the same manner as in Preparation Example 13, except that the compound obtained in Preparation Example 123 was used instead of the compound obtained in Preparation Example 12, 74 mg of the title compound was obtained in a yield of 96%.

1H NMR (400 MHz, CDCl3); 7.65 (1H, s), 7.62 (1H, m), 7.46-7.33 (7H, m), 5.84, 5.79 (1H, two set of d), 4.31 (2H, s), 4.24, 4.10 (1H, two set of d), 4.14 (1H, m), 3.86-3.68 (2H, m), 3.66, 3.63 (3H, two set of s), 3.17 (3H, s), 2.55 (1H, m), 2.41 (1H, m), 2.19, 2.06 (1H, two set of d), 1.97-1.60 (7H, m), 1.47 (1H, m), 1.40-1.02 (7H, m), 0.98 (3H, d), 0.96 (3H, d)1 H NMR (400 MHz, CDCl 3 ); 7.65 (1H, s), 7.62 (1H, m), 7.46-7.33 (7H, m), 5.84, 5.79 (1H, two set of d), 4.31 (2H, s), 4.24, 4.10 (1H, two set of d), 4.14 (1H, m), 3.86-3.68 (2H, m), 3.66, 3.63 (3H, two set of s), 3.17 (3H, s), 2.55 (1H, m), 2.41 (1H, m), 2.19, 2.06 (1H, two set of d), 1.97-1.60 (7H, m), 1.47 (1H, m), 1.40-1.02 (7H, m), 0.98 (3H, d), 0.96 (3H , d)

ESI MS (m/e) = 630 [M+H]+
ESI MS (m / e) = 630 [M + H] < + >

[실시예 79]Example 79

3-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}사이클로헥산카르복실산의 제조: 3-{[(2R,4S,5S)-5-({3- [(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}cyclohexanecarboxylic acid 3 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyl-octanoyl; Preparation of amino} cyclohexanecarboxylic acid: 3-{[(2 R , 4 S , 5 S ) -5-({3- [(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2 , 7-dimethyloctanoyl] amino} cyclohexanecarboxylic acid

상기 실시예 59에서 얻은 화합물 대신에 상기 실시예 78에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 60과 동일한 방법으로 실시하여, 표제 화합물 60 ㎎을 86% 수율로 얻을 수 있었다.Except for using the compound obtained in Example 78 instead of the compound obtained in Example 59, it was carried out in the same manner as in Example 60, to obtain 60 mg of the title compound in 86% yield.

1H NMR (400 MHz, CD3OD); 7.75 (1H, s), 7.71 (1H, m), 7.48-7.27 (7H, m), 4.47 (2H, s), 4.17 (1H, m), 3.70-3.52 (2H, m), 3.26 (3H, s), 2.60 (1H, m), 2.32 (1H, m), 2.08 (1H, d), 1.97-1.74 (4H, m), 1.72-1.58 (2H, m), 1.49-1.17 (6H, m), 1.13 (3H, d), 0.97 (6H, d)1 H NMR (400 MHz, CD3OD); 7.75 (1H, s), 7.71 (1H, m), 7.48-7.27 (7H, m), 4.47 (2H, s), 4.17 (1H, m), 3.70-3.52 (2H, m), 3.26 (3H, s), 2.60 (1H, m), 2.32 (1H, m), 2.08 (1H, d), 1.97-1.74 (4H, m), 1.72-1.58 (2H, m), 1.49-1.17 (6H, m) , 1.13 (3H, d), 0.97 (6H, d)

ESI MS (m/e) = 616 [M+H]+
ESI MS (m / e) = 616 [M + H] < + >

[제조예 124][Production Example 124]

메틸 5-[(tert-부톡시카르보닐)아미노]펜타노에이트의 제조: methyl 5-[(tert-butoxycarbonyl)amino]pentanoatePreparation of Methyl 5-[( tert -butoxycarbonyl) amino] pentanoate: methyl 5-[( tert- butoxycarbonyl) amino] pentanoate

trans-4-{[(tert-부톡시카르보닐)아미노]메틸}사이클로헥산카르복실산 대신에 5-[(tert-부톡시카르보닐)아미노]펜탄산을 사용한 것을 제외하고는, 제조예 118과 동일한 방법으로 실시하여, 표제 화합물 0.5 g을 95% 수율로 얻을 수 있었다.Preparation Example 118 except that 5-[( tert -butoxycarbonyl) amino] pentanoic acid was used instead of trans- 4-{[( tert -butoxycarbonyl) amino] methyl} cyclohexanecarboxylic acid By the same method as in, 0.5 g of the title compound could be obtained in 95% yield.

1H NMR (400 MHz, CDCl3); 4.54 (1H, br), 3.67 (3H, s), 3.13 (2H, dd), 2.34 (2H, t), 1.71-1.60 (2H, m), 1.56-1.47 (2H, m), 1.44 (9H, s)
1 H NMR (400 MHz, CDCl 3 ); 4.54 (1H, br), 3.67 (3H, s), 3.13 (2H, dd), 2.34 (2H, t), 1.71-1.60 (2H, m), 1.56-1.47 (2H, m), 1.44 (9H, s)

[제조예 125][Production Example 125]

메틸 5-[((2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-{[tert -부틸(디메틸)실릴]옥시}-2,7-디메틸옥타노일)아미노]펜타노에이트의 제조: methyl 5-[((2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-{[tert -butyl(dimethyl)silyl]oxy}-2,7-dimethyloctanoyl)amino]pentanoateMethyl 5-[(( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-{[ tert -butyl (dimethyl) silyl] Preparation of oxy} -2,7-dimethyloctanoyl) amino] pentanoate: methyl 5-[((2 R , 4 S , 5 S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-{[ tert -butyl (dimethyl) silyl] oxy} -2,7-dimethyloctanoyl) amino] pentanoate

상기 제조예 113에서 얻은 화합물 대신에 상기 제조예 124에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 114와 동일한 방법으로 실시하여, 표제 화합물 75 ㎎을 84% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 124 instead of the compound obtained in Preparation Example 113, it was carried out in the same manner as Preparation Example 114, it was obtained 75 mg of the title compound in 84% yield.

1H NMR (400 MHz, CDCl3); 7.67 (1H, s), 7.56 (1H, d), 7.45-7.33 (7H, m), 6.35 (1H, t), 6.24 (1H, d), 4.40 (1H, m), 4.31 (2H, s), 3.76 (1H, dd), 3.62 (3H, s), 3.17 (3H, s), 3.24-3.03 (2H, m), 2.44 (1H, m), 2.20 (2H, t), 1.74-1.33 (9H, m), 1.16 (3H, d), 0.99 (3H, d), 0.97 (3H, d)
1 H NMR (400 MHz, CDCl 3 ); 7.67 (1H, s), 7.56 (1H, d), 7.45-7.33 (7H, m), 6.35 (1H, t), 6.24 (1H, d), 4.40 (1H, m), 4.31 (2H, s) , 3.76 (1H, dd), 3.62 (3H, s), 3.17 (3H, s), 3.24-3.03 (2H, m), 2.44 (1H, m), 2.20 (2H, t), 1.74-1.33 (9H , m), 1.16 (3H, d), 0.99 (3H, d), 0.97 (3H, d)

[실시예 80]Example 80

메틸 5-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}펜타노에이트의 제조: methyl 5-{[(2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7- dimethyloctanoyl]amino}pentanoateMethyl 5 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyl-octanoyl ] Amino} pentanoate preparation: methyl 5-{[(2 R , 4 S , 5 S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2 , 7-dimethyloctanoyl] amino} pentanoate

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 125에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 57 ㎎을 92% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 125 instead of the compound obtained in Preparation Example 12, it was carried out in the same manner as Preparation Example 13, it was obtained 57 mg of the title compound in 92% yield.

1H NMR (400 MHz, CDCl3); 7.67 (1H, s), 7.61 (1H, m), 7.44-7.34 (7H, m), 6.46 (1H, d), 5.91 (1H, t), 4.30 (2H, s), 4.26 (1H, d), 4.13 (1H, m), 3.79 (1H, m), 3.65 (3H, s), 3.29 (1H, m), 3.17 (3H, s), 3.16 (1H, m), 2.60 (1H, m), 2.31 (2H, t), 1.79-1.36 (9H, m), 1.22 (3H, d), 0.98 (3H, d), 0.96 (3H, d)1 H NMR (400 MHz, CDCl 3 ); 7.67 (1H, s), 7.61 (1H, m), 7.44-7.34 (7H, m), 6.46 (1H, d), 5.91 (1H, t), 4.30 (2H, s), 4.26 (1H, d) , 4.13 (1H, m), 3.79 (1H, m), 3.65 (3H, s), 3.29 (1H, m), 3.17 (3H, s), 3.16 (1H, m), 2.60 (1H, m), 2.31 (2H, t), 1.79-1.36 (9H, m), 1.22 (3H, d), 0.98 (3H, d), 0.96 (3H, d)

ESI MS (m/e) = 604 [M+H]+
ESI MS (m / e) = 604 [M + H] < + >

[실시예 81]Example 81

5-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}펜탄산의 제조: 5-{[(2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}pentanoic acid 5 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyl-octanoyl; Preparation of amino} pentanoic acid: 5-{[(2 R , 4 S , 5 S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7- dimethyloctanoyl] amino} pentanoic acid

상기 실시예 59에서 얻은 화합물 대신에 상기 실시예 80에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 60과 동일한 방법으로 실시하여, 표제 화합물 49 ㎎을 96% 수율로 얻을 수 있었다.In the same manner as in Example 60, except that the compound obtained in Example 80 was used instead of the compound obtained in Example 59, 49 mg of the title compound could be obtained in 96% yield.

1H NMR (400 MHz, CD3OD); 7.75 (1H, s), 7.71 (1H, d), 7.50-7.28 (7H, m), 4.46 (2H, s), 4.17 (1H, m), 3.57 (1H, m), 3.26 (3H, s), 3.22-3.07 (2H, m), 2.62 (1H, m), 2.26 (2H, t), 1.84 (1H, m), 1.73-1.35 (8H, m), 1.13 (2H, d), 0.96 (6H, d)1 H NMR (400 MHz, CD3OD); 7.75 (1H, s), 7.71 (1H, d), 7.50-7.28 (7H, m), 4.46 (2H, s), 4.17 (1H, m), 3.57 (1H, m), 3.26 (3H, s) , 3.22-3.07 (2H, m), 2.62 (1H, m), 2.26 (2H, t), 1.84 (1H, m), 1.73-1.35 (8H, m), 1.13 (2H, d), 0.96 (6H , d)

ESI MS (m/e) = 590 [M+H]+
ESI MS (m / e) = 590 [M + H] < + >

[제조예 126][Manufacture example 126]

에틸 3-{(1S)-1-[(tert-부톡시카르보닐)아미노]-2-메틸프로필}-4,5-디히드로-5-이소옥사졸카르복실레이트의 제조: ethyl 3-{(1S)-1-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-4,5-dihydro-5-isoxazolecarboxylateEthyl 3 - {(1 S) -1 - [(tert - butoxycarbonyl) amino] -2-methylpropyl} Preparation of 4,5-dihydro-5-isopropyl-oxazol-carboxylate: ethyl 3- {(1 S ) -1-[( tert -butoxycarbonyl) amino] -2-methylpropyl} -4,5-dihydro-5-isoxazolecarboxylate

공지의 방법(J. Chem. Soc., Perkin Trans. 1, 1998, 359-365)에 따라 t-부톡시카르보닐-(S)-발린으로부터 표제 화합물을 합성할 수 있었다. The title compound can be synthesized from t -butoxycarbonyl- ( S ) -valine according to known methods ( J. Chem. Soc., Perkin Trans. 1 , 1998, 359-365).

1H NMR (500 MHz, CDCl3); 5.01 (1H, t), 4.39 (1H, br), 4.25 (2H, q), 3.26 (1H, t), 2.08 (1H, m), 1.47 (9H, s), 1.32 (3H, t), 1.01 (3H, t), 0.95 (3H, dd)
1 H NMR (500 MHz, CDCl 3 ); 5.01 (1H, t), 4.39 (1H, br), 4.25 (2H, q), 3.26 (1H, t), 2.08 (1H, m), 1.47 (9H, s), 1.32 (3H, t), 1.01 (3H, t), 0.95 (3H, dd)

[제조예 127][Production Example 127]

에틸 3-{(1S)-1-[((2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-{[tert-부틸(디메틸)실릴]옥시}-2,7-디메틸옥타노일)아미노]-2-메틸프로필}-4,5-디히드로-5-이소옥사졸카르복실레이트의 제조: ethyl 3-{(1S)-1-[((2R,4S,5S)-5-({3- [(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,7-dimethyloctanoyl)amino]-2-methylpropyl}-4,5-dihydro-5-isoxazolecarboxylateEthyl 3-{(1 S ) -1-[((2 R , 4 S , 5 S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-{[ tert -Butyl (dimethyl) silyl] oxy} -2,7-dimethyloctanoyl) amino] -2-methylpropyl} -4,5-dihydro-5-isoxazolecarboxylate: ethyl 3- { (1 S ) -1-[((2 R , 4 S , 5 S ) -5-({3- [(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-{[ tert -butyl (dimethyl) silyl] oxy} -2,7-dimethyloctanoyl) amino] -2-methylpropyl} -4,5-dihydro-5-isoxazolecarboxylate

상기 제조예 113에서 얻은 화합물 대신에 상기 제조예 126에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 114와 동일한 방법으로 실시하여, 표제 화합물 133 ㎎을 83% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 126 instead of the compound obtained in Preparation Example 113, it was carried out in the same manner as Preparation Example 114, it was possible to obtain the title compound 133 mg in 83% yield.

1H NMR (400 MHz, CDCl3); 7.74 (1H, d), 7.52 (1H, m), 7.43-7.32 (7H, m), 6.65 (1H, t), 6.22 (1H, d), 4.95 (1H, m), 4.58 (1H, m), 4.30 (2H, s), 4.21 (2H, q), 3.76 (1H, dd), 3.26 (2H, d), 3.18 (3H, s), 2.60 (1H, m), 1.98-1.48 (5H, m), 1.40 (1H, m), 1.28 (3H, t), 1.15 (3H, d), 0.98 (3H, d), 0.96 (3H, d), 0.92 (9H, s), 0.75 (3H, t), 0.65 (3H, t), 0.11 (3H, s), 0.10 (3H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.74 (1H, d), 7.52 (1H, m), 7.43-7.32 (7H, m), 6.65 (1H, t), 6.22 (1H, d), 4.95 (1H, m), 4.58 (1H, m) , 4.30 (2H, s), 4.21 (2H, q), 3.76 (1H, dd), 3.26 (2H, d), 3.18 (3H, s), 2.60 (1H, m), 1.98-1.48 (5H, m ), 1.40 (1H, m), 1.28 (3H, t), 1.15 (3H, d), 0.98 (3H, d), 0.96 (3H, d), 0.92 (9H, s), 0.75 (3H, t) , 0.65 (3H, t), 0.11 (3H, s), 0.10 (3H, s)

[실시예 82]Example 82

에틸 3-((1S)-1-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-2-메틸프로필)-4,5-디히드로-5-이소옥사졸카르복실레이트: ethyl 3-((1S)-1-{[(2R,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7-dimethyloctanoyl]amino}-2-methylpropyl)-4,5-dihydro-5-isoxazolecarboxylateEthyl 3 - ((1 S) -1 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy -2,7-dimethyloctanoyl] amino} -2-methylpropyl) -4,5-dihydro-5-isoxazolecarboxylate: ethyl 3-((1 S ) -1-{[(2 R , 4 S , 5 S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyloctanoyl] amino} -2-methylpropyl) -4,5- dihydro-5-isoxazolecarboxylate

상기 제조예 12에서 얻은 화합물 대신에 상기 제조예 127에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 13과 동일한 방법으로 실시하여, 표제 화합물 5 ㎎을 4% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 127 instead of the compound obtained in Preparation Example 12, it was carried out in the same manner as in Preparation Example 13, to obtain 5 mg of the title compound in 4% yield.

1H NMR (400 MHz, CDCl3); 7.68 (1H, s), 7.61 (1H, d), 7.48-7.30 (7H, m), 6.38 (1H, d), 6.33 (1H, d), 5.00 (1H, m), 4.68 (1H, m), 4.31 (2H, s), 4.30-4.10 (3H, m), 3.99-3.68 (2H, m), 3.25 (2H, t), 3.18 (3H, s), 2.70 (1H, m), 2.05 (1H, m), 1.84-1.62 (4H, m), 1.46 (1H, m), 1.30 (3H, t), 1.22 (3H, d), 0.98 (3H, d), 0.96 (3H, d), 0.91 (3H, t), 0.83 (3H, d)1 H NMR (400 MHz, CDCl 3 ); 7.68 (1H, s), 7.61 (1H, d), 7.48-7.30 (7H, m), 6.38 (1H, d), 6.33 (1H, d), 5.00 (1H, m), 4.68 (1H, m) , 4.31 (2H, s), 4.30-4.10 (3H, m), 3.99-3.68 (2H, m), 3.25 (2H, t), 3.18 (3H, s), 2.70 (1H, m), 2.05 (1H , m), 1.84-1.62 (4H, m), 1.46 (1H, m), 1.30 (3H, t), 1.22 (3H, d), 0.98 (3H, d), 0.96 (3H, d), 0.91 ( 3H, t), 0.83 (3H, d)

ESI MS (m/e) = 687 [M+H]+
ESI MS (m / e) = 687 [M + H] < + >

[실시예 83]Example 83

3-[(벤질술포닐)(메틸)아미노]-N-((1S,2S,4R)-5-{[(1S)-1-시아노-2-메틸프로필]아미노}-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸)벤즈아미드의 제조: 3-[(benzylsulfonyl)(methyl)amino]-N-((1S,2S,4R)-5-{[(1S)-1-cyano-2-methylpropyl]amino}-2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl)benzamide3-[(benzylsulfonyl) (methyl) amino] -N -((1 S , 2 S , 4 R ) -5-{[(1 S ) -1-cyano-2-methylpropyl] amino}- Preparation of 2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl) benzamide: 3-[(benzylsulfonyl) (methyl) amino] -N -((1 S , 2 S , 4 R )- 5 - {[(1 S) -1-cyano-2-methylpropyl] amino} -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl) benzamide

상기 실시예 82 과정에서 부산물로 표제 화합물 4 ㎎을 4% 수율로 얻을 수 있었다.As a by-product of Example 82, 4 mg of the title compound was obtained in a 4% yield.

1H NMR (400 MHz, CDCl3)7.64 (1H, s), 7.61 (1H, d), 7.46-7.30 (7H, m), 6.75 (1H, d), 6.30 (1H, d), 4.68 (1H, dd), 4.32 (2H, s), 4.20 (1H, m), 3.74 (1H, m), 3.17 (3H, s), 2.98 (1H, d), 2.70 (1H, m), 1.94 (1H, m), 1.80-1.54 (4H, m), 1.45 (1H, m), 1.21 (3H, d), 1.03-0.93 (9H, m), 0.92 (3H, d)1 H NMR (400 MHz, CDCl 3 ) 7.64 (1H, s), 7.61 (1H, d), 7.46-7.30 (7H, m), 6.75 (1H, d), 6.30 (1H, d), 4.68 (1H, dd), 4.32 (2H, s), 4.20 (1H, m), 3.74 (1H, m), 3.17 (3H, s), 2.98 (1H, d), 2.70 (1H, m), 1.94 (1H, m ), 1.80-1.54 (4H, m), 1.45 (1H, m), 1.21 (3H, d), 1.03-0.93 (9H, m), 0.92 (3H, d)

ESI MS (m/e)= 571 [M+H]+
ESI MS (m / e) = 571 [M + H] < + >

[제조예 128][Production Example 128]

에틸 (3S,4S)-4-[(tert-부톡시카르보닐)아미노]-3-히드록시-6-메틸헵타노에이트의 제조: Ethyl (3 S, 4 S) -4 - [(tert - butoxycarbonyl) amino] Preparation of 3-hydroxy-6-methyl heptanoate:

ethyl (3S,4S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-6-methylheptanoateethyl (3 S , 4 S ) -4-[( tert -butoxycarbonyl) amino] -3-hydroxy-6-methylheptanoate

공지의 방법(Tetrahedron 57, 2001, 8521-8530)에 따라, t-부톡시카르보닐-(S)-루이신알로부터 표제 화합물을 합성할 수 있었다. According to the known method ( Tetrahedron 57, 2001, 8521-8530), the title compound could be synthesized from t -butoxycarbonyl- ( S ) -leucine.

1H NMR (400 MHz, CDCl3); 4.69 (1H, d), 4.17 (2H, q), 4.01 (1H, m), 3.61 (1H, m), 3.25 (1H, d), 2.55-2.45 (2H, m), 1.67-1.48 (3H, m), 1.44 (9H, s), 1.27 (3H, t), 0.93 (6H, d)
1 H NMR (400 MHz, CDCl 3 ); 4.69 (1H, d), 4.17 (2H, q), 4.01 (1H, m), 3.61 (1H, m), 3.25 (1H, d), 2.55-2.45 (2H, m), 1.67-1.48 (3H, m), 1.44 (9H, s), 1.27 (3H, t), 0.93 (6H, d)

[제조예 129][Manufacture example 129]

에틸 (3S,4S)-4-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-3-히드록시-6-메틸헵타노에이트의 제조: ethyl (3S,4S)-4-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-3-hydroxy-6-methylheptanoateEthyl (3 S, 4 S) -4 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) Preparation of 3-hydroxy-6-methyl heptanoate: ethyl (3 S, 4 S ) -4-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -3-hydroxy-6-methylheptanoate

상기 제조예 77에서 얻은 화합물 대신에 상기 제조예 128을 사용한 것을 제외하고는, 실시예 21과 동일한 방법으로 실시하여, 표제 화합물 3.09 g을 73% 수율 로 얻을 수 있었다.Except for using the preparation 128 in place of the compound obtained in Preparation 77, by the same method as in Example 21, 3.09 g of the title compound could be obtained in 73% yield.

1H NMR (400 MHz, CDCl3); 7.64-7.59 (2H, m), 7.43-7.36 (7H, m), 6.38 (1H, d), 4.31 (2H, s), 4.24 (1H, m), 4.20-4.09 (3H, m), 3.17 (3H, s), 2.56-2.52 (2H, m), 1.76-1.66 (2H, m), 1.49 (1H, m), 1.25 (3H, t), 0.98 (3H, d), 0.96 (3H, d)
1 H NMR (400 MHz, CDCl 3 ); 7.64-7.59 (2H, m), 7.43-7.36 (7H, m), 6.38 (1H, d), 4.31 (2H, s), 4.24 (1H, m), 4.20-4.09 (3H, m), 3.17 ( 3H, s), 2.56-2.52 (2H, m), 1.76-1.66 (2H, m), 1.49 (1H, m), 1.25 (3H, t), 0.98 (3H, d), 0.96 (3H, d)

[제조예 130][Production Example 130]

(3S,4S)-4-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-3-히드록시-6-메틸헵탄산의 제조: (3 S, 4 S) -4 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) Preparation of 3-hydroxy-6-methyl-heptanoic acid:

(3S,4S)-4-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-3-hydroxy-6-methylheptanoic acid(3 S , 4 S ) -4-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -3-hydroxy-6-methylheptanoic acid

상기 실시예 59에서 얻은 화합물 대신에 상기 제조예 129에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 60과 동일한 방법으로 실시하여, 표제 화합물 1.27 g을 95% 수율로 얻을 수 있었다.In the same manner as in Example 60, except that the compound obtained in Preparation Example 129 was used instead of the compound obtained in Example 59, 1.27 g of the title compound could be obtained in 95% yield.

1H NMR (500 MHz, DMSO-d6); 7.94 (1H, d), 7.75-7.74 (2H, m), 7.43-7.35 (7H, m), 4.99 (1H, brs), 4.57 (2H, s), 4.11 (1H, m), 3.95 (1H, m), 3.28 (3H, s), 2.41 (1H, dd), 2.18 (1H, dd), 1.60-1.55 (2H, m), 1.35 (1H, m), 0.90 (3H, d), 0.86 (3H, d)
1 H NMR (500 MHz, DMSO-d 6); 7.94 (1H, d), 7.75-7.74 (2H, m), 7.43-7.35 (7H, m), 4.99 (1H, brs), 4.57 (2H, s), 4.11 (1H, m), 3.95 (1H, m), 3.28 (3H, s), 2.41 (1H, dd), 2.18 (1H, dd), 1.60-1.55 (2H, m), 1.35 (1H, m), 0.90 (3H, d), 0.86 (3H , d)

[실시예 84]Example 84

메틸 (2S)-2-{[(3S,4S)-4-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-3-히드록시-6-메틸헵타노일]아미노}-3-메틸부타노에이트의 제조: methyl (2S)-2-{[(3S,4S)-4-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-3-hydroxy-6-methylheptanoyl]amino}-3-methylbutanoateMethyl (2 S) -2 - {[ (3 S, 4 S) -4 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -3-hydroxy-6-methyl-heptanoic Russo Preparation of] amino} -3-methylbutanoate: methyl (2 S ) -2-{[(3 S , 4 S ) -4-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -3-hydroxy-6-methylheptanoyl] amino} -3-methylbutanoate

상기 제조예 58에서 얻은 화합물 대신에 상기 제조예 130에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 106과 동일한 방법으로 실시하여, 표제 화합물 207 ㎎을 73% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 130 instead of the compound obtained in Preparation Example 58, it was carried out in the same manner as Preparation Example 106, it was obtained in 207 mg of the title compound in 73% yield.

1H NMR (400 MHz, CDCl3); 7.66 (1H, t), 7.62 (1H, m), 7.42-7.36 (7H, m), 6.42 (1H, d), 6.38 (1H, d), 4.50 (1H, m), 4.33 (1H, d), 4.31 (2H, s), 4.22 (1H, m), 4.12 (1H, m), 3.75(3H, s), 3.17 (3H, s), 2.46 (2H, d), 2.14 (1H, m), 1.76-1.67 (2H, m), 1.49 (1H, m), 0.99-0.86 (12H, m)1 H NMR (400 MHz, CDCl 3 ); 7.66 (1H, t), 7.62 (1H, m), 7.42-7.36 (7H, m), 6.42 (1H, d), 6.38 (1H, d), 4.50 (1H, m), 4.33 (1H, d) , 4.31 (2H, s), 4.22 (1H, m), 4.12 (1H, m), 3.75 (3H, s), 3.17 (3H, s), 2.46 (2H, d), 2.14 (1H, m), 1.76-1.67 (2H, m), 1.49 (1H, m), 0.99-0.86 (12H, m)

ESI MS (m/e) = 576 [M+H]+
ESI MS (m / e) = 576 [M + H] < + >

[실시예 85]Example 85

(2S)-2-{[(3S,4S)-4-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-3-히드록시-6-메틸헵타노일]아미노}-3-메틸부탄산의 제조: (2S)-2-{[(3S,4S)-4-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-3-hydroxy-6-methylheptanoyl]amino}-3-methylbutanoic acid (2 S) -2 - {[ (3 S, 4 S) -4 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -3-hydroxy-6-methyl-heptanoic Noil; Preparation of methyl 3-amino} butanoic acid: (2 S) -2 - { [(3 S, 4 S) -4 - ({3 - [(benzylsulfonyl) (methyl) amino] benzoyl} amino) -3- hydroxy-6-methylheptanoyl] amino} -3-methylbutanoic acid

상기 실시예 59에서 얻은 화합물 대신에 상기 실시예 84에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 60과 동일한 방법으로 실시하여, 표제 화합물 0.15 g을 77 % 수율로 얻을 수 있었다.In the same manner as in Example 60, except that the compound obtained in Example 84 was used instead of the compound obtained in Example 59, 0.15 g of the title compound could be obtained in a 77% yield.

1H NMR (400 MHz, DMSO-d6)12.5 (1H, s), 8.00 (1H, d), 7.96 (1H, d), 7.77-7.74 (2H, m), 7.43-7.33 (7H, m), 4.91 (1H, brs), 4.55 (2H, s), 4.15-4.11 (2H, m), 3.90 (1H, m). 3.23 (3H, s), 2.31-2.25 (2H, m), 2.00 (1H, m), 1.61-1.58 (2H, m), 1.32 (1H, m), 0.89-0.81 (12H, m)1 H NMR (400 MHz, DMSO-d6) 12.5 (1H, s), 8.00 (1H, d), 7.96 (1H, d), 7.77-7.74 (2H, m), 7.43-7.33 (7H, m), 4.91 (1H, brs), 4.55 (2H, s), 4.15-4.11 (2H, m), 3.90 (1H, m). 3.23 (3H, s), 2.31-2.25 (2H, m), 2.00 (1H, m), 1.61-1.58 (2H, m), 1.32 (1H, m), 0.89-0.81 (12H, m)

ESI MS (m/e) = 561 [M+H]+
ESI MS (m / e) = 561 [M + H] < + >

[실시예 86]Example 86

N-[(1S,2S)-4-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-옥소부틸]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-[(1S,2S)-4-({(1S)-1-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-1-isobutyl-4-oxobutyl]-3-[(benzylsulfonyl)(methyl)amino]benzamide N -[( 1S , 2S ) -4-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4 Preparation of -oxobutyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide: N -[(1 S , 2 S ) -4-({(1 S ) -1-[(benzylamino) carbonyl ] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-oxobutyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide

t-부톡시카르보닐-(S)-알라닌 대신에 상기 실시예 85에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 11과 동일한 방법으로 실시하여, 표제 화합물 87 ㎎을 65% 수율로 얻을 수 있었다.87 mg of the title compound was obtained in 65% yield by the same method as Preparation Example 11 except for using the compound obtained in Example 85 instead of t -butoxycarbonyl- ( S ) -alanine. .

1H NMR (500 MHz, CDCl3); 7.65 (1H, t), 7.62 (1H, m), 7.42-7.36 (7H, m), 7.34-7.25 (5H, m), 6.52-6.47 (3H, m), 4.45-4.38 (3H,m), 4.31 (2H, s), 4.23- 4.10 (3H, m), 3.16 (3H, s), 2.47-2.45 (2H, m), 2.11 (1H, m), 1.76-1.64 (2H, m), 1.49 (1H, m), 0.97-0.88 (12H, m)1 H NMR (500 MHz, CDCl 3 ); 7.65 (1H, t), 7.62 (1H, m), 7.42-7.36 (7H, m), 7.34-7.25 (5H, m), 6.52-6.47 (3H, m), 4.45-4.38 (3H, m), 4.31 (2H, s), 4.23- 4.10 (3H, m), 3.16 (3H, s), 2.47-2.45 (2H, m), 2.11 (1H, m), 1.76-1.64 (2H, m), 1.49 ( 1H, m), 0.97-0.88 (12H, m)

ESI MS (m/e) = 651 [M+H]+
ESI MS (m / e) = 651 [M + H] < + >

[제조예 131]Preparation Example 131

벤질 4-{[((2S)-2-{[(3S,4S)-4-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-3-히드록시-6-메틸헵타노일]아미노}-3-메틸부타노일)아미노]메틸}벤조에이트의 제조: benzyl 4-{[((2S)-2-{[(3S,4S)-4-({3-[(benzylsulfonyl)(methyl)amino]benzoyl} amino)-3-hydroxy-6-methylheptanoyl]amino}-3-methylbutanoyl)amino]methyl}benzoateBenzyl 4 - {[((2 S ) -2 - {[(3 S, 4 S) -4 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -3-hydroxy- 6-methyl-heptanoic alkanoyl] amino} Preparation of 3-methyl-butanoyl) amino] methyl} benzoate: benzyl 4 - {[(( 2 S) -2 - {[(3 S, 4 S) -4- ( {3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -3-hydroxy-6-methylheptanoyl] amino} -3-methylbutanoyl) amino] methyl} benzoate

상기 제조예 92에서 얻은 화합물 99 ㎎(0.225 mmol)을 에틸아세테이트에 묽혀진 4.0 N 염산용액 3 ㎖에 녹여서 2 시간 동안 교반하였다. 용매를 감압증류하여 농축한 후 N,N-디메틸포름아미드 5 ㎖에 녹여서 0℃로 냉각하여 상기 제조예 130에서 얻은 화합물 69 ㎎(0.15 mmol)와 HATU(86 ㎎, 0.225 mmol)을 가하였다. 여기에, N,N-디이소프로필에틸아민 0.5 ㎖(과량)를 가하고 상온으로 온도를 올려 하룻밤동안 교반하였다. 감압증류하여 용매를 제거한 다음 에틸아세테이트에 녹여서 물, 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음 메탄올과 디클로로메탄의 5:95 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 85 ㎎을 72% 수율로 얻을 수 있었다. 99 mg (0.225 mmol) of the compound obtained in Preparation Example 92 was dissolved in 3 ml of 4.0 N hydrochloric acid solution diluted in ethyl acetate, and stirred for 2 hours. The solvent was concentrated by distillation under reduced pressure, dissolved in 5 ml of N, N-dimethylformamide, cooled to 0 ° C., and 69 mg (0.15 mmol) of the compound obtained in Preparation Example 130 and HATU (86 mg, 0.225 mmol) were added thereto. To this was added 0.5 ml (excess) of N, N-diisopropylethylamine, the temperature was raised to room temperature and the mixture was stirred overnight. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a 5:95 mixture of methanol and dichloromethane to obtain 85 mg of the title compound in 72% yield.                     

1H NMR (400 MHz, CDCl3); 8.01 (2H, d), 7.64-7.56 (2H, m), 7.47-7.56 (14H, m), 6.75 (1H, t), 6.44 (1H, d), 6.40 (1H, d), 5.35 (2H, s), 4.48 (2H, d), 4.30 (2H, s), 4.22 (1H, dd), 4.12 (1H, m), 4.08 (1H, d), 3.15 (3H, s), 2.54-2.38 (2H, s), 2.14 (1H, m), 1.80-1.58 (2H, m), 1.47 (1H, m), 0.98-0.80 (12H, m)
1 H NMR (400 MHz, CDCl 3 ); 8.01 (2H, d), 7.64-7.56 (2H, m), 7.47-7.56 (14H, m), 6.75 (1H, t), 6.44 (1H, d), 6.40 (1H, d), 5.35 (2H, s), 4.48 (2H, d), 4.30 (2H, s), 4.22 (1H, dd), 4.12 (1H, m), 4.08 (1H, d), 3.15 (3H, s), 2.54-2.38 (2H , s), 2.14 (1H, m), 1.80-1.58 (2H, m), 1.47 (1H, m), 0.98-0.80 (12H, m)

[실시예 87]Example 87

4-{[((2S)-2-{[(3S,4S)-4-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-3-히드록시-6-메틸헵타노일]아미노}-3-메틸부타노일)아미노]메틸}벤조산의 제조: 4-{[((2S)-2-{[(3S,4S)-4-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-3-hydroxy-6-methylheptanoyl]amino}-3-methylbutanoyl)amino]methyl}benzoic acid4-{[((2 S ) -2-{[(3 S , 4 S ) -4-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -3-hydroxy-6 Preparation of -Methylheptanoyl] amino} -3-methylbutanoyl) amino] methyl} benzoic acid: 4-{[(( 2S ) -2-{[( 3S , 4S ) -4-({3- [(benzylsulfonyl) (methyl) amino] benzoyl} amino) -3-hydroxy-6-methylheptanoyl] amino} -3-methylbutanoyl) amino] methyl} benzoic acid

상기 제조예 131에서 얻은 화합물 85 ㎎(0.108 mmol)을 테트라히드로퓨란 3 ㎖와 메탄올 0.5 ㎖에 녹인 후 1.0 N 수산화리튬 수용액 2 ㎖를 가하여 2 시간 동안 교반하였다. 용매를 감압증류하여 제거한 후 물로 희석하여 1.0 N 염산 수용액으로 산성화하여 생성된 고체를 여과하한 후 메탄올과 디클로로메탄의 5:95 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 72 ㎎을 96% 수율로 얻을 수 있었다.85 mg (0.108 mmol) of the compound obtained in Preparation Example 131 was dissolved in 3 ml of tetrahydrofuran and 0.5 ml of methanol, and 2 ml of 1.0 N lithium hydroxide aqueous solution was added thereto, followed by stirring for 2 hours. After distilling off the solvent under reduced pressure, the mixture was diluted with water and acidified with 1.0 N aqueous hydrochloric acid solution. The resulting solid was filtered and purified by column chromatography using 5:95 mixture of methanol and dichloromethane to obtain 72 mg of the title compound in 96% yield. Could get

1H NMR (400 MHz, CD3OD); 7.96 (2H, d), 7.76 (1H, s),7.70 (1H, m), 7.47-7.29 (9H, m), 4.58-4.38 (2H, m), 4.44 (2H, s), 4.30-4.09 (3H, m), 3.23 (3H, s), 2.60-2.40 (2H, m), 2.20 (1H, m), 1.78-1.54 (2H, m), 1.42 (1H, m), 1.01-0.81 (12H, m)1 H NMR (400 MHz, CD3OD); 7.96 (2H, d), 7.76 (1H, s), 7.70 (1H, m), 7.47-7.29 (9H, m), 4.58-4.38 (2H, m), 4.44 (2H, s), 4.30-4.09 ( 3H, m), 3.23 (3H, s), 2.60-2.40 (2H, m), 2.20 (1H, m), 1.78-1.54 (2H, m), 1.42 (1H, m), 1.01-0.81 (12H, m)

ESI MS (m/e) = 695 [M+H]+
ESI MS (m / e) = 695 [M + H] < + >

[제조예 132][Production Example 132]

tert-부틸 (1S)-1-[(2S)옥시라닐]-2-페닐에틸카르바메이트의 제조: tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate tert - butyl (1 S) -1 - [( 2 S) oxiranyl] Preparation of 2-phenyl ethyl carbamate: tert -butyl (1 S) -1 - [(2 S) oxiranyl] -2-phenylethylcarbamate

공지의 방법(Tetrahedron Letters 36(31), 1999, 5453-5456)에 따라, t-부톡시카르보닐-(S)-페닐알라닌으로부터 표제 화합물을 합성할 수 있었다. According to the known method ( Tetrahedron Letters 36 (31), 1999, 5453-5456), the title compound could be synthesized from t -butoxycarbonyl- ( S ) -phenylalanine.

1H NMR (400 MHz, CDCl3); 7.36-7.18 (5H, m), 4.43 (1H, br), 3.69 (1H, br), 3.02-2.82 (3H, m), 2.80 (1H, t), 2.76 (1H, m), 1.38 (9H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.36-7.18 (5H, m), 4.43 (1H, br), 3.69 (1H, br), 3.02-2.82 (3H, m), 2.80 (1H, t), 2.76 (1H, m), 1.38 (9H, s)

[제조예 133]Preparation Example 133

벤질 (2R,3S)-3-[(tert-부톡시카르보닐)아미노]-2-히드록시-4-페닐부틸(3-메톡시벤질)카르바메이트의 제조: benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl(3-methoxybenzyl)carbamateBenzyl (2 R, 3 S) -3 - [(tert - butoxycarbonyl) amino] Preparation of 2-hydroxy-4-phenylbutyl (3-methoxybenzyl) carbamate: benzyl (2 R, 3 S ) -3-[( tert -butoxycarbonyl) amino] -2-hydroxy-4-phenylbutyl (3-methoxybenzyl) carbamate

제조예 132에서 얻은 화합물 0.74 g(2.81 mmol)과 3-메톡시벤질아민 1.93 g(14.05 mmol)을 이소프로판올 60 ㎖ 에 녹여서 하룻밤 동안 환류시켰다. 온도를 상온으로 식혀서 용매를 감압증류하여 제거한 후 디클로로메탄 15 ㎖ 와 1.0 N NaOH 수용액 14 ㎖에 녹였다. 벤질클로로포메이트 4.79 g(28.1 mmol)을 가하여 1 시간 동안 교반한 후 디클로로메탄에 희석하여 물과 소금물로 닦아주었다. 용매를 감압증류로 제거한 다음 에틸아세테이트와 헥산의 1:3 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 1.34 g을 89% 수율로 얻을 수 있었다.0.74 g (2.81 mmol) of the compound obtained in Preparation Example 132 and 1.93 g (14.05 mmol) of 3-methoxybenzylamine were dissolved in 60 ml of isopropanol and refluxed overnight. After cooling to room temperature, the solvent was distilled off under reduced pressure and then dissolved in 15 mL of dichloromethane and 14 mL of 1.0 N NaOH aqueous solution. 4.79 g (28.1 mmol) of benzylchloroformate was added thereto, stirred for 1 hour, diluted with dichloromethane, and washed with water and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a 1: 3 mixture of ethyl acetate and hexane to obtain 1.34 g of the title compound in 89% yield.

1H NMR (400 MHz, CDCl3); 7.42-7.02 (12H, m), 6.88-6.58 (3H, m), 5.20 (2H, s), 4.52 (2H, s), 4.30 (1H, s), 3.82 (2H, br), 3.70 (3H, s), 3.52-3.13 (2H, m), 3.00-2.60 (2H, m), 1.33 (9H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.42-7.02 (12H, m), 6.88-6.58 (3H, m), 5.20 (2H, s), 4.52 (2H, s), 4.30 (1H, s), 3.82 (2H, br), 3.70 (3H, s), 3.52-3.13 (2H, m), 3.00-2.60 (2H, m), 1.33 (9H, s)

[제조예 134][Production Example 134]

벤질 (2R,3S)-2-히드록시-3-({3-[메틸(프로필술포닐)아미노]벤조일}아미노)-4-페닐부틸(3-메톡시벤질)카르바메이트의 제조: benzyl (2R,3S)-2-hydroxy-3-({3-[methyl(propylsulfonyl)amino]benzoyl}amino)-4-phenylbutyl(3-methoxybenzyl)carbamateBenzyl (2 R, 3 S) -2- hydroxy-3 - ({3- [methyl (propyl-sulfonyl) amino] benzoyl} amino) -4-phenylbutyl (3-methoxybenzyl) Preparation of carbamate benzyl (2 R , 3 S ) -2-hydroxy-3-({3- [methyl (propylsulfonyl) amino] benzoyl} amino) -4-phenylbutyl (3-methoxybenzyl) carbamate

제조예 133에서 얻은 화합물 500 ㎎(0.935 mmol)을 디클로로메탄 10 ㎖와 트리플루오로아세트산 5 ㎖에 녹여서 1 시간 동안 교반하였다. 용매를 감압증류하여 농축한 후 N,N-디메틸포름아미드 10 ㎖에 녹여서 0℃로 냉각하여 상기 제조예 29에서 얻은 화합물 289 ㎎(1.122 mmol)와 PyBob 730 ㎎(1.403 mmol)을 가하였다. 여기에 N,N-디이소프로필에틸아민 0.98 ㎖(5.61 mmol)를 가하고 상온으로 온도를 올려 1 시간 30 분 동안 교반하였다. 감압증류하여 용매를 제거한 다음 에틸아세테 이트에 녹여서 물, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음 에틸아세테이트와 헥산의 1:1 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 508 ㎎을 81% 수율로 얻을 수 있었다.500 mg (0.935 mmol) of the compound obtained in Preparation Example 133 was dissolved in 10 ml of dichloromethane and 5 ml of trifluoroacetic acid and stirred for 1 hour. The solvent was concentrated by distillation under reduced pressure, dissolved in 10 ml of N, N-dimethylformamide, cooled to 0 ° C., and 289 mg (1.122 mmol) of the compound obtained in Preparation Example 29 and 730 mg (1.403 mmol) of PyBob were added thereto. 0.98 mL (5.61 mmol) of N, N-diisopropylethylamine was added thereto, and the temperature was raised to room temperature, followed by stirring for 1 hour 30 minutes. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a 1: 1 mixture of ethyl acetate and hexane to obtain 508 mg of the title compound in 81% yield.

1H NMR (400 MHz, DMSO,d6); 8.33 (1H, dd), 7.73 (1H, s), 7.63-7.38 ( 3H, m), 7.36-7.12 (10H, m), 7.10 (1H, t), 6.84-6.65 (3H, m), 5.31 (1H, dd), 5.20-4.97 (2H, m), 4.69 (1H, dd), 4.46 (1H, d), 4.06 (1H, m), 3.86 (1H, m), 3.66 (3H, s), 3.24 (3H, d), 3.20-2.97 (5H, m), 2.76 (1H, m), 1.72-7.55 (2H, m), 1.00-0.93 (3H, m)
1 H NMR (400 MHz, DMSO, d 6); 8.33 (1H, dd), 7.73 (1H, s), 7.63-7.38 (3H, m), 7.36-7.12 (10H, m), 7.10 (1H, t), 6.84-6.65 (3H, m), 5.31 ( 1H, dd), 5.20-4.97 (2H, m), 4.69 (1H, dd), 4.46 (1H, d), 4.06 (1H, m), 3.86 (1H, m), 3.66 (3H, s), 3.24 (3H, d), 3.20-2.97 (5H, m), 2.76 (1H, m), 1.72-7.55 (2H, m), 1.00-0.93 (3H, m)

[실시예 88]Example 88

N-{(1S,2R)-1-벤질-2-히드록시-3-[(3-메톡시벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(3-methoxybenzyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide Preparation of : N -{(1 S , 2 R ) -1-benzyl-2-hydroxy-3-[(3-methoxybenzyl) amino] propyl} -3- [methyl (propylsulfonyl) amino] benzamide

상기 제조예 134에서 얻은 화합물 505 ㎎(0.749 mmol)을 메탄올 10 ㎖에 녹인 후, 활성 탄소에 흡착된 팔라듐(10%)을 가하고 수소공기 하에서 1 시간 동안 교반하였다. 셀라이트를 이용한 감압여과로 고체를 제거하고 감압증류로 용매를 제거 한 후 메탄올과 디클로로메탄의 5:95 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 355 ㎎을 88% 수율로 얻을 수 있었다.505 mg (0.749 mmol) of the compound obtained in Preparation Example 134 was dissolved in 10 ml of methanol, and palladium (10%) adsorbed on activated carbon was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure, and then purified by column chromatography using a 5:95 mixture of methanol and dichloromethane to obtain 355 mg of the title compound in 88% yield.

1H NMR (400 MHz, CDCl3); 7.69 (1H, s), 7.55 (1H, d), 7.43 (1H, d), 7.35 (1H, d), 7.33-7.18 (6H, m), 7.13 (1H, d), 6.93-6.87 (2H, m), 6.81 (1H, dd), 4.42 (1H, m), 3.88-3.73 (5H, m), 3.71 (1H, m), 3.33 (3H, s), 3.10-2.78 (6H, m), 1.90-1.77 (2H, m), 1.02 (3H, t)1 H NMR (400 MHz, CDCl 3 ); 7.69 (1H, s), 7.55 (1H, d), 7.43 (1H, d), 7.35 (1H, d), 7.33-7.18 (6H, m), 7.13 (1H, d), 6.93-6.87 (2H, m), 6.81 (1H, dd), 4.42 (1H, m), 3.88-3.73 (5H, m), 3.71 (1H, m), 3.33 (3H, s), 3.10-2.78 (6H, m), 1.90 -1.77 (2H, m), 1.02 (3H, t)

ESI MS (m/e)= 540 [M+H]+
ESI MS (m / e) = 540 [M + H] < + >

[실시예 89]Example 89

N-{(1S)-1-[(5R)-3-(3-메톡시벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S)-1-[(5R)-3-(3-methoxybenzyl)-1,3-oxazolidin-5-yl]-2-phenylethyl}-3-[methyl(propylsulfonyl)amino]benzamide N -{( 1S ) -1-[( 5R ) -3- (3-methoxybenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [methyl ( Preparation of propylsulfonyl) amino] benzamide: N -{(1 S ) -1-[(5 R ) -3- (3-methoxybenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [methyl (propylsulfonyl) amino] benzamide

상기 실시예 88에서 얻은 화합물 164 ㎎(0.304 mmol)을 테트라히드로퓨란 5 ㎖ 에 녹인 후 35% 포르말린 104 ㎎(1.216 mmol)을 가하여 하룻밤 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트와 헥산의 2:1 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 150 ㎎을 89% 수율로 얻을 수 있었다.164 mg (0.304 mmol) of the compound obtained in Example 88 was dissolved in 5 ml of tetrahydrofuran, and 104 mg (1.216 mmol) of 35% formalin was added thereto, followed by stirring overnight. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a 2: 1 mixture of ethyl acetate and hexane to obtain 150 mg of the title compound in 89% yield.

1H NMR (400 MHz, CDCl3); 7.75 (1H, s), 7.56 (1H, d), 7.46 (1H, d), 7.41 (1H, d), 7.34-7.18 (6H, m), 6.92 (1H, d), 6.91 (1H, s),6.83 (1H, d), 6.78 (1H, d), 4.56 (1H, d), 4.43 (1H, m), 4.20 (1H, d), 4.14 (1H, m), 3.88-3.58 (5H, m), 3.35 (3H, s), 3.20 (1H, dd), 3.07 (1H, dd), 2.98-2.82 (4H, m), 1.90-1.78 (2H, m), 1.02 (3H, t) 1 H NMR (400 MHz, CDCl 3 ); 7.75 (1H, s), 7.56 (1H, d), 7.46 (1H, d), 7.41 (1H, d), 7.34-7.18 (6H, m), 6.92 (1H, d), 6.91 (1H, s) , 6.83 (1H, d), 6.78 (1H, d), 4.56 (1H, d), 4.43 (1H, m), 4.20 (1H, d), 4.14 (1H, m), 3.88-3.58 (5H, m ), 3.35 (3H, s), 3.20 (1H, dd), 3.07 (1H, dd), 2.98-2.82 (4H, m), 1.90-1.78 (2H, m), 1.02 (3H, t)

ESI MS (m/e) = 552 [M+H]+
ESI MS (m / e) = 552 [M + H] < + >

[제조예 135]Preparation Example 135

벤질 (2R,3S)-3-[(tert-부톡시카르보닐)아미노]-2-히드록시-4-페닐부틸(3-메틸벤질)카르바메이트의 제조: benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl(3-methylbenzyl)carbamateBenzyl (2 R, 3 S) -3 - [(tert - butoxycarbonyl) amino] Preparation of 2-hydroxy-4-phenylbutyl (3-methylbenzyl) carbamate: benzyl (2 R, 3 S ) -3-[( tert -butoxycarbonyl) amino] -2-hydroxy-4-phenylbutyl (3-methylbenzyl) carbamate

3-메톡시벤질아민 대신에 3-메틸벤질아민을 사용한 것을 제외하고는, 제조예 133과 동일한 방법으로 실시하여, 표제 화합물 86 ㎎을 83% 수율로 얻을 수 있었다.86 mg of the title compound was obtained in 83% yield by the same method as Preparation Example 133, except that 3-methylbenzylamine was used instead of 3-methoxybenzylamine.

1H NMR (400 MHz, CDCl3); 7.43-6.87 (15H, m), 5.21 (2H, s), 4.65-4.43 (3H, m), 4.30 (1H, m), 3.88-3.62 (2H, m), 3.55-3.37 (2H, m), 3.02-2.70 (2H, m), 2.28 (3H, s), 1.33 (9H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.43-6.87 (15H, m), 5.21 (2H, s), 4.65-4.43 (3H, m), 4.30 (1H, m), 3.88-3.62 (2H, m), 3.55-3.37 (2H, m), 3.02-2.70 (2H, m), 2.28 (3H, s), 1.33 (9H, s)

[제조예 136]Preparation Example 136

벤질 (2R,3S)-2-히드록시-3-({3-[메틸(프로필술포닐)아미노]벤조일}아미노)-4-페닐부틸(3-메틸벤질)카르바메이트의 제조: benzyl (2R,3S)-2-hydroxy-3-({3-[methyl(propylsulfonyl)amino]benzoyl}amino)-4-phenylbutyl(3-methylbenzyl)carbamateBenzyl (2 R, 3 S) -2- hydroxy-3 - ({3- [methyl (propyl-sulfonyl) amino] benzoyl} amino) -4-phenylbutyl (3-methylbenzyl) Preparation of carbamate: benzyl (2 R , 3 S ) -2-hydroxy-3-({3- [methyl (propylsulfonyl) amino] benzoyl} amino) -4-phenylbutyl (3-methylbenzyl) carbamate

상기 제조예 133에서 얻은 화합물 대신에 상기 제조예 135에서 얻은 화합물 을 사용한 것을 제외하고는, 제조예 134와 동일한 방법으로 실시하여, 표제 화합물 98 ㎎을 90% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 135 instead of the compound obtained in Preparation Example 133, it was carried out in the same manner as in Preparation Example 134, it was possible to obtain 98 mg of the title compound in 90% yield.

1H NMR (400 MHz, CDCl3); 7.64 (1H, s), 7.55 (1H, d), 7.48-6.88 (16H, m), 6.60 (1H, d), 5.20 (2H, dd), 4.53 (2H, dd), 4.38 (1H, br), 4.25 (1H, br), 3.94 (1H, br), 3.35 (2H, d), 3.33 (3H, s), 3.03-2.86 (4H, m), 2.25 (3H, s), 1.90-1.77 (2H, m), 1.01 (3H, t)
1 H NMR (400 MHz, CDCl 3 ); 7.64 (1H, s), 7.55 (1H, d), 7.48-6.88 (16H, m), 6.60 (1H, d), 5.20 (2H, dd), 4.53 (2H, dd), 4.38 (1H, br) , 4.25 (1H, br), 3.94 (1H, br), 3.35 (2H, d), 3.33 (3H, s), 3.03-2.86 (4H, m), 2.25 (3H, s), 1.90-1.77 (2H , m), 1.01 (3H, t)

[실시예 90]Example 90

N-{(1S,2R)-1-벤질-2-히드록시-3-[(3-메틸벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methylbenzyl)amino]propyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(3-methylbenzyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide Preparation of: N -{(1 S , 2 R ) -1-benzyl-2-hydroxy-3-[(3-methylbenzyl) amino] propyl} -3- [methyl (propylsulfonyl) amino] benzamide

상기 제조예 134에서 얻은 화합물 대신에 상기 제조예 136에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 88과 동일한 방법으로 실시하여, 표제 화합물 63 ㎎을 82% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 136 instead of the compound obtained in Preparation Example 134 by the same method as in Example 88, 63 mg of the title compound could be obtained in 82% yield.

1H NMR (400 MHz, CDCl3); 7.69 (1H, t), 7.53 (1H, m), 7.42 (1H, d), 7.37-7.18 (7H, m), 7.16-7.06 (4H, m), 4.42 (1H, m), 3.80 (2H, dd), 3.72 (1H, m), 3.33 (3H, s), 3.10-2.78 (6H, m), 2.33 (3H, s), 1.90-1.77 (2H, m), 1.02 (3H, t)1 H NMR (400 MHz, CDCl 3 ); 7.69 (1H, t), 7.53 (1H, m), 7.42 (1H, d), 7.37-7.18 (7H, m), 7.16-7.06 (4H, m), 4.42 (1H, m), 3.80 (2H, dd), 3.72 (1H, m), 3.33 (3H, s), 3.10-2.78 (6H, m), 2.33 (3H, s), 1.90-1.77 (2H, m), 1.02 (3H, t)

ESI MS (m/e) = 524 [M+H]+
ESI MS (m / e) = 524 [M + H] < + >

[실시예 91]Example 91

N-{(1S)-1-[(5R)-3-(3-메틸벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S)-1-[(5R)-3-(3-methylbenzyl)-1,3-oxazolidin-5-yl]-2-phenylethyl}-3-[methyl(propylsulfonyl)amino]benzamide N -{( 1S ) -1-[( 5R ) -3- (3-methylbenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [methyl (propyl Preparation of sulfonyl) amino] benzamide: N -{(1 S ) -1-[(5 R ) -3- (3-methylbenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl}- 3- [methyl (propylsulfonyl) amino] benzamide

상기 실시예 88에서 얻은 화합물 대신에 상기 실시예 90에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 89와 동일한 방법으로 실시하여, 표제 화합물 19 ㎎을 79% 수율로 얻을 수 있었다.In the same manner as in Example 89, except that the compound obtained in Example 90 was used instead of the compound obtained in Example 88, 19 mg of the title compound could be obtained in 79% yield.

1H NMR (400 MHz, CDCl3); 7.75 (1H, s), 7.57 (1H, d), 7.48-7.18 (7H, m), 7.17-7.06 (4H, m), 6.78 (1H, d), 4.54 (1H, d), 4.42 (1H, m), 4.20 (1H, d), 4.14 (1H, m), 3.70 (2H, dd), 3.35 (3H, s), 3.20 (1H, dd), 3.06 (1H, dd), 2.98-2.81 (4H, m), 2.33 (3H, s), 1.90-1.77 (2H, m), 1.02 (3H, t)1 H NMR (400 MHz, CDCl 3 ); 7.75 (1H, s), 7.57 (1H, d), 7.48-7.18 (7H, m), 7.17-7.06 (4H, m), 6.78 (1H, d), 4.54 (1H, d), 4.42 (1H, m), 4.20 (1H, d), 4.14 (1H, m), 3.70 (2H, dd), 3.35 (3H, s), 3.20 (1H, dd), 3.06 (1H, dd), 2.98-2.81 (4H , m), 2.33 (3H, s), 1.90-1.77 (2H, m), 1.02 (3H, t)

ESI MS (m/e) = 536 [M+H]+
ESI MS (m / e) = 536 [M + H] < + >

[제조예 137][Production Example 137]

벤질 (2R,3S)-3-[(tert-부톡시카르보닐)아미노]-2-히드록시-4-페닐부틸(2-피리디닐메틸)카르바메이트의 제조: benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl(2-pyridinylmethyl)carbamateBenzyl (2 R, 3 S) -3 - [(tert - butoxycarbonyl) amino] Preparation of 2-hydroxy-4-phenyl-butyl (2-pyridinyl methyl) carbamate: benzyl (2 R, 3 S ) -3-[( tert -butoxycarbonyl) amino] -2-hydroxy-4-phenylbutyl (2-pyridinylmethyl) carbamate

3-메톡시벤질아민 대신에 2-(아미노메틸)-피리딘을 사용한 것을 제외하고는, 제조예 133과 동일한 방법으로 실시하여, 표제 화합물 40 ㎎을 40% 수율로 얻을 수 있었다.40 mg of the title compound was obtained in 40% yield by the same method as Preparation Example 133, except that 2- (aminomethyl) -pyridine was used instead of 3-methoxybenzylamine.

1H NMR (400 MHz, CDCl3); 8.51 (1H, m), 7.72, 7.57 (1H, two set of t), 7.40-6.93 (13H, m), 5.06 (1H, m), 4.96 (1H, s), 4.77-4.32 (3H, m), 3.96-3.78 (2H, m), 3.33 (1H, m), 3.05 (1H, m), 2.90 (1H, m), 1.32 (9H, s)
1 H NMR (400 MHz, CDCl 3 ); 8.51 (1H, m), 7.72, 7.57 (1H, two set of t), 7.40-6.93 (13H, m), 5.06 (1H, m), 4.96 (1H, s), 4.77-4.32 (3H, m) , 3.96-3.78 (2H, m), 3.33 (1H, m), 3.05 (1H, m), 2.90 (1H, m), 1.32 (9H, s)

[제조예 138]Preparation Example 138

벤질 (2R,3S)-2-히드록시-3-({3-[메틸(프로필술포닐)아미노]벤조일}아미노)-4-페닐부틸(2-피리디닐메틸)카르바메이트의 제조: benzyl (2R,3S)-2-hydroxy-3-({3-[methyl(propylsulfonyl)amino]benzoyl}amino)-4-phenylbutyl(2-pyridinylmethyl)carbamateBenzyl (2 R, 3 S) -2- hydroxy-3 - ({3- [methyl (propyl-sulfonyl) amino] benzoyl} amino) -4-phenyl-butyl (2-pyridinyl methyl) carbamate Preparation of benzyl (2 R , 3 S ) -2-hydroxy-3-({3- [methyl (propylsulfonyl) amino] benzoyl} amino) -4-phenylbutyl (2-pyridinylmethyl) carbamate

상기 제조예 133에서 얻은 화합물 대신에 상기 제조예 137에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 134와 동일한 방법으로 실시하여, 표제 화합물 26 ㎎을 51% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 137 instead of the compound obtained in Preparation Example 133, 26 mg of the title compound could be obtained in 51% yield in the same manner as in Preparation Example 134.

1H NMR (400 MHz, CDCl3); 8.50 (1H, dd), 7.77-6.92 (17H, m), 6.60, 6.26 (1H, two set of d), 5.01 (1H, d), 4.94 (1H, s), 4.71-4.32 (3H, m), 4.04 (1H, m), 3.86 (1H, m), 3.41 (1H, m), 3.32 (3H, d), 3.23-3.07 (2H, m), 2.97-2.88 (2H, m), 1.89-1.77 (2H, m), 1.01 (3H, t)
1 H NMR (400 MHz, CDCl 3 ); 8.50 (1H, dd), 7.77-6.92 (17H, m), 6.60, 6.26 (1H, two set of d), 5.01 (1H, d), 4.94 (1H, s), 4.71-4.32 (3H, m) , 4.04 (1H, m), 3.86 (1H, m), 3.41 (1H, m), 3.32 (3H, d), 3.23-3.07 (2H, m), 2.97-2.88 (2H, m), 1.89-1.77 (2H, m), 1.01 (3H, t)

[실시예 92]Example 92

N-{(1S,2R)-1-벤질-2-히드록시-3-[(2-피리디닐메틸)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-pyridinylmethyl)amino]propyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(2-pyridinyl methyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide Preparation of : N -{(1 S , 2 R ) -1-benzyl-2-hydroxy-3-[(2-pyridinylmethyl) amino] propyl} -3- [methyl (propylsulfonyl) amino] benzamide

상기 제조예 134에서 얻은 화합물 대신에 상기 제조예 138에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 88과 동일한 방법으로 실시하여, 표제 화합물 11 ㎎을 55% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 138 instead of the compound obtained in Preparation Example 134 by the same method as in Example 88, 11 mg of the title compound could be obtained in 55% yield.

1H NMR (400 MHz, CDCl3); 8.54 (1H, d), 7.70 (1H, t), 7.66 (1H, dd), 7.53 (1H, m), 7.47 (1H, d), 7.36-7.13 (9H, m), 4.47 (1H, m), 4.02 (2H, s), 3.80 (1H, m), 3.32 (3H, s), 3.15-2.88 (6H, m), 1.89-1.76 (2H, m), 1.02 (3H, t)1 H NMR (400 MHz, CDCl 3 ); 8.54 (1H, d), 7.70 (1H, t), 7.66 (1H, dd), 7.53 (1H, m), 7.47 (1H, d), 7.36-7.13 (9H, m), 4.47 (1H, m) , 4.02 (2H, s), 3.80 (1H, m), 3.32 (3H, s), 3.15-2.88 (6H, m), 1.89-1.76 (2H, m), 1.02 (3H, t)

ESI MS (m/e) = 511 [M+H]+
ESI MS (m / e) = 511 [M + H] < + >

[제조예 139][Production Example 139]

벤질 (2R,3S)-3-[(tert-부톡시카르보닐)아미노]-2-히드록시-4-페닐부틸(3-에틸벤질)카르바메이트의 제조: benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl(3-ethylbenzyl)carbamateBenzyl (2 R, 3 S) -3 - [(tert - butoxycarbonyl) amino] Preparation of 2-hydroxy-4-phenylbutyl (3-ethylbenzyl) carbamate: benzyl (2 R, 3 S ) -3-[( tert -butoxycarbonyl) amino] -2-hydroxy-4-phenylbutyl (3-ethylbenzyl) carbamate

3-메톡시벤질아민 대신에 3-에틸벤질아민을 사용한 것을 제외하고는, 제조예 133과 동일한 방법으로 실시하여, 표제 화합물 154 ㎎을 74% 수율로 얻을 수 있었다. Except for using 3-ethylbenzylamine instead of 3-methoxybenzylamine, the same procedure as in Preparation Example 133 was carried out to obtain 154 mg of the title compound in 74% yield.                     

1H NMR (400 MHz, CDCl3); 7.38-7.18 (11H, m), 7.09-7.07 (2H, m), 6.96 (1H, s), 5.21 (2H, s), 4.52-4.31 (3H, m), 3.85-3.70 (2H, m), 3.45-3.34 (2H, m), 2.94-2.79 (2H, m), 2.57 (2H, q), 1.33 (9H, s), 1.18 (3H, t)
1 H NMR (400 MHz, CDCl 3 ); 7.38-7.18 (11H, m), 7.09-7.07 (2H, m), 6.96 (1H, s), 5.21 (2H, s), 4.52-4.31 (3H, m), 3.85-3.70 (2H, m), 3.45-3.34 (2H, m), 2.94-2.79 (2H, m), 2.57 (2H, q), 1.33 (9H, s), 1.18 (3H, t)

[제조예 140][Production Example 140]

벤질 3-에틸벤질[(2R,3S)-2-히드록시-3-({3-[매칠(프로필술포닐)아미노]벤조일}아미노)-4-페닐부틸]카르바메이트의 제조: benzyl 3-ethylbenzyl[(2R,3S)-2-hydroxy-3-({3-[methyl(propylsulfonyl)amino]benzoyl}amino)-4-phenylbutyl]carbamateBenzyl 3-ethyl-benzyl [(2 R, 3 S) -2- hydroxy-3 - ({3- [maechil (propyl-sulfonyl) amino] benzoyl} amino) -4-phenylbutyl] Preparation of carbamate: benzyl 3-ethylbenzyl [(2 R , 3 S ) -2-hydroxy-3-({3- [methyl (propylsulfonyl) amino] benzoyl} amino) -4-phenylbutyl] carbamate

상기 제조예 133에서 얻은 화합물 대신에 상기 제조예 139에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 134와 동일한 방법으로 실시하여, 표제 화합물 71 ㎎을 35% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 139 instead of the compound obtained in Preparation Example 133 by the same method as Preparation Example 134, 71 mg of the title compound could be obtained in 35% yield.

1H NMR (400 MHz, CDCl3); 7.96-6.87 (18H, m), 6.62 (1H, d), 5.10 (2H, dd), 4.45 (2H, dd), 4.31 (1H, m), 3.88 (1H, m), 3.40-3.33 (2H, m), 3.27 (3H, s), 2.90-2.78 (4H, m), 2.45 (2H, q), 1.79-1.68 (2H, m), 1.06 (3H, t), 0.91 (3H, t)
1 H NMR (400 MHz, CDCl 3 ); 7.96-6.87 (18H, m), 6.62 (1H, d), 5.10 (2H, dd), 4.45 (2H, dd), 4.31 (1H, m), 3.88 (1H, m), 3.40-3.33 (2H, m), 3.27 (3H, s), 2.90-2.78 (4H, m), 2.45 (2H, q), 1.79-1.68 (2H, m), 1.06 (3H, t), 0.91 (3H, t)

[실시예 93]Example 93

N-{(1S,2R)-1-벤질-3-[(3-에틸벤질)아미노]-2-히드록시프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-3 - [(3-ethylbenzyl) amino] -2-hydroxypropyl} -3- [methyl (propyl-sulfonyl) amino] benzamide Preparation of: N -{(1 S , 2 R ) -1-benzyl-3-[(3-ethylbenzyl) amino] -2-hydroxypropyl} -3- [methyl (propylsulfonyl) amino] benzamide

상기 제조예 134에서 얻은 화합물 대신에 상기 제조예 140에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 88과 동일한 방법으로 실시하여, 표제 화합물 56 ㎎을 94% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 140 instead of the compound obtained in Preparation Example 134, it was carried out in the same manner as in Example 88, 56 mg of the title compound could be obtained in 94% yield.

1H NMR (400 MHz, CDCl3); 7.70 (1H, t), 7.53-6.97 (13H, m), 4.41 (1H, m), 3.83-3.68 (2H, m), 3.32 (3H, s), 3.05-3.00 (2H, m), 2.97-2.81 (5H, m), 2.62 (2H, q), 1.81 (2H, m), 1.21 (3H, t), 1.01 (3H, t)1 H NMR (400 MHz, CDCl 3 ); 7.70 (1H, t), 7.53-6.97 (13H, m), 4.41 (1H, m), 3.83-3.68 (2H, m), 3.32 (3H, s), 3.05-3.00 (2H, m), 2.97- 2.81 (5H, m), 2.62 (2H, q), 1.81 (2H, m), 1.21 (3H, t), 1.01 (3H, t)

ESI MS (m/e) = 538 [M+H]+
ESI MS (m / e) = 538 [M + H] < + >

[실시예 94]Example 94

N-{(1S)-1-[(5R)-3-(3-에틸벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S)-1-[(5R)-3-(3-ethylbenzyl)-1,3-oxazolidin-5-yl]-2-phenylethyl}-3-[methyl(propylsulfonyl)amino]benzamide N -{( 1S ) -1-[( 5R ) -3- (3-ethylbenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [methyl (propyl Preparation of sulfonyl) amino] benzamide: N -{(1 S ) -1-[(5 R ) -3- (3-ethylbenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl}- 3- [methyl (propylsulfonyl) amino] benzamide

상기 실시예 88에서 얻은 화합물 대신에 상기 실시예 93에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 89와 동일한 방법으로 실시하여, 표제 화합물 30 ㎎을 60% 수율로 얻을 수 있었다.In the same manner as in Example 89, except that the compound obtained in Example 93 was used instead of the compound obtained in Example 88, 30 mg of the title compound could be obtained in 60% yield.

1H NMR (400 MHz, CDCl3); 7.76 (1H, t), 7.58-7.55 (1H, m), 7.49-7.47 (1H, m), 7.43-7.08 (10H, m), 6.83 (1H, d), 4.55 (1H, d), 4.44 (1H, m), 4.21 (1H, d), 4.15 (1H, m), 3.73 (2H, dd), 3.35 (3H, s), 3.19 (1H, m), 3.07 (1H, m), 2.97-2.86 (4H, m), 2.63 (2H, q), 1.87-1.81 (2H, m), 1.22 (3H, t), 1.03 (3H, t)1 H NMR (400 MHz, CDCl 3 ); 7.76 (1H, t), 7.58-7.55 (1H, m), 7.49-7.47 (1H, m), 7.43-7.08 (10H, m), 6.83 (1H, d), 4.55 (1H, d), 4.44 ( 1H, m), 4.21 (1H, d), 4.15 (1H, m), 3.73 (2H, dd), 3.35 (3H, s), 3.19 (1H, m), 3.07 (1H, m), 2.97-2.86 (4H, m), 2.63 (2H, q), 1.87-1.81 (2H, m), 1.22 (3H, t), 1.03 (3H, t)

ESI MS (m/e) = 550 [M+H]+
ESI MS (m / e) = 550 [M + H] < + >

[제조예 141]Preparation Example 141

벤질 벤질{(2R,3S)-3-[(tert-부톡시카르보닐)아미노]-2-히드록시-4-페닐부틸}카르바메이트의 제조: benzyl benzyl{(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl}carbamatePreparation of benzyl benzyl {(2 R, 3 S) -3 - - [(tert -butoxycarbonyl) amino] -2-hydroxy-4-phenylbutyl} carbamate: benzyl benzyl {(2 R, 3 S ) -3-[( tert -butoxycarbonyl) amino] -2-hydroxy-4-phenylbutyl} carbamate

3-메톡시벤질아민 대신에 벤질아민을 사용한 것을 제외하고는, 제조예 133과 동일한 방법으로 실시하여, 표제 화합물 74 ㎎을 73% 수율로 얻을 수 있었다.Except for using benzylamine instead of 3-methoxybenzylamine, the same procedure as in Preparation Example 133 was carried out to obtain 74 mg of the title compound in 73% yield.

1H NMR (400 MHz, CDCl3); 7.43-7.00 (15H, m), 5.21 (2H, s), 4.72-4.40 (3H, m), 4.30 (1H, m), 3.87-3.62 (2H, m), 3.53-3.28 (2H, m), 3.01-2.70 (2H, m), 1.33 (9H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.43-7.00 (15H, m), 5.21 (2H, s), 4.72-4.40 (3H, m), 4.30 (1H, m), 3.87-3.62 (2H, m), 3.53-3.28 (2H, m), 3.01-2.70 (2H, m), 1.33 (9H, s)

[제조예 142][Production Example 142]

벤질 벤질[(2R,3S)-2-히드록시-3-({3-[메틸(프로필술포닐)아미노]벤조일}아미노)-4-페닐부틸]카르바메이트의 제조: benzyl benzyl[(2R,3S)-2-hydroxy-3-({3-[methyl(propylsulfonyl)amino]benzoyl}amino)-4-phenylbutyl]carbamateBenzyl benzyl - Preparation of [(2 R, 3 S) -2- hydroxy-3 ({3- [methyl (propyl-sulfonyl) amino] benzoyl} amino) -4-phenylbutyl] carbamate: benzyl benzyl [ (2 R, 3 S) -2 -hydroxy-3 - ({3- [methyl (propylsulfonyl) amino] benzoyl} amino) -4-phenylbutyl] carbamate

상기 제조예 133에서 얻은 화합물 대신에 상기 제조예 141에서 얻은 화합물 을 사용한 것을 제외하고는, 제조예 134와 동일한 방법으로 실시하여, 표제 화합물 86 ㎎을 91% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 141 instead of the compound obtained in Preparation Example 133, 86 mg of the title compound could be obtained in 91% yield in the same manner as in Preparation Example 134.

1H NMR (400 MHz, CDCl3); 7.64 (1H, s), 7.56 (1H, d), 7.51-7.04 (17H, m), 6.53 (1H, s), 5.20 (2H, dd), 4.57 (2H, dd), 4.38 (1H, m), 3.93 (1H, m), 3.46 (2H, d), 3.33 (3H, s), 3.07-2.83 (4H, m), 1.92-1.75 (2H, m), 1.01 (3H, t)
1 H NMR (400 MHz, CDCl 3 ); 7.64 (1H, s), 7.56 (1H, d), 7.51-7.04 (17H, m), 6.53 (1H, s), 5.20 (2H, dd), 4.57 (2H, dd), 4.38 (1H, m) , 3.93 (1H, m), 3.46 (2H, d), 3.33 (3H, s), 3.07-2.83 (4H, m), 1.92-1.75 (2H, m), 1.01 (3H, t)

[실시예 95]Example 95

N-[(1S,2R)-1-벤질-3-(벤질아미노)-2-히드록시프로필]-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-[(1S,2R)-1-benzyl-3-(benzylamino)-2-hydroxypropyl]-3-[methyl(propylsulfonyl)amino]benzamide N - [(1 S, 2 R) -1- benzyl-3- (benzylamino) -2-hydroxypropyl] -3-Preparation of [methyl (propyl-sulfonyl) amino] benzamide: N - [(1 S , 2 R ) -1-benzyl-3- (benzylamino) -2-hydroxypropyl] -3- [methyl (propylsulfonyl) amino] benzamide

상기 제조예 134에서 얻은 화합물 대신에 상기 제조예 142에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 88과 동일한 방법으로 실시하여, 표제 화합물 41 ㎎을 60% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 142 instead of the compound obtained in Preparation Example 134, the title compound was obtained in 60% yield in the same manner as in Example 88.

1H NMR (400 MHz, CDCl3); 7.68 (1H, t), 7.53 (1H, m), 7.42 (dt), 7.37-7.18 (11H, m), 7.01 (1H, d), 4.42 (1H, m), 3.87 (2H, dd), 3.74 (1H, m), 3.33 (3H, s), 3.13-2.80 (6H, m), 1.91-1.78 (2H, m), 1.02 (3H, t)1 H NMR (400 MHz, CDCl 3 ); 7.68 (1H, t), 7.53 (1H, m), 7.42 (dt), 7.37-7.18 (11H, m), 7.01 (1H, d), 4.42 (1H, m), 3.87 (2H, dd), 3.74 (1H, m), 3.33 (3H, s), 3.13-2.80 (6H, m), 1.91-1.78 (2H, m), 1.02 (3H, t)

ESI MS (m/e) = 510 [M+H]+
ESI MS (m / e) = 510 [M + H] +

[실시예 96] Example 96                     

N-{(1S)-1-[(5R)-3-벤질-1,3-옥사졸리딘-5-일]-2-페닐에틸}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S)-1-[(5R)-3-benzyl-1,3-oxazolidin-5-yl]-2-phenylethyl}-3-[methyl(propylsulfonyl)amino]benzamide N -{( 1S ) -1-[( 5R ) -3-benzyl-1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [methyl (propylsulfonyl) amino] Preparation of Benzamide: N -{(1 S ) -1-[(5 R ) -3-benzyl-1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [methyl (propylsulfonyl) amino] benzamide

상기 실시예 88에서 얻은 화합물 대신에 상기 실시예 95에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 89와 동일한 방법으로 실시하여, 표제 화합물 26 ㎎을 70% 수율로 얻을 수 있었다.Except for using the compound obtained in Example 95 instead of the compound obtained in Example 88, it was carried out in the same manner as in Example 89, whereby 26 mg of the title compound could be obtained in 70% yield.

1H NMR (400 MHz, CDCl3); 7.75 (1H, t), 7.56 (1H, m), 7.46 (1H, dt), 7.39 (1H, t), 7.37-7.18 (10H, m), 6.78(1H, d), 4.55 (1H, d), 4.43 (1H, m), 4.19 (1H, d), 4.15 (1H, m), 3.73 (2H, dd), 3.35 (3H, s), 3.19 (1H, dd), 3.07 (1H, dd), 3.00-2.82 (4H, m), 1.91-1.78 (2H, m), 1.02 (3H, t)1 H NMR (400 MHz, CDCl 3 ); 7.75 (1H, t), 7.56 (1H, m), 7.46 (1H, dt), 7.39 (1H, t), 7.37-7.18 (10H, m), 6.78 (1H, d), 4.55 (1H, d) , 4.43 (1H, m), 4.19 (1H, d), 4.15 (1H, m), 3.73 (2H, dd), 3.35 (3H, s), 3.19 (1H, dd), 3.07 (1H, dd), 3.00-2.82 (4H, m), 1.91-1.78 (2H, m), 1.02 (3H, t)

ESI MS (m/e) = 522 [M+H]+
ESI MS (m / e) = 522 [M + H] < + >

[제조예 143][Production Example 143]

벤질 (2R,3S)-3-[(tert-부톡시카르보닐)아미노]-2-히드록시-4-페닐부틸[(1R)-1-페닐프로필]카르바메이트의 제조: benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl[(1R)-1-phenylpropyl]carbamateBenzyl (2 R, 3 S) -3 - [(tert - butoxycarbonyl) amino] -2-hydroxy-4-phenyl-butyl [(1 R) -1- phenylpropyl] Preparation of carbamate: benzyl (2 R , 3 S ) -3-[( tert -butoxycarbonyl) amino] -2-hydroxy-4-phenylbutyl [(1 R ) -1-phenylpropyl] carbamate

3-메톡시벤질아민 대신에 (R)-1-페닐프로필아민을 사용한 것을 제외하고는, 제조예 133과 동일한 방법으로 실시하여, 표제 화합물 87 ㎎을 81% 수율로 얻을 수 있었다. 87 mg of the title compound was obtained in 81% yield by the same method as the Preparation Example 133, except that ( R ) -1-phenylpropylamine was used instead of 3-methoxybenzylamine.

1H NMR (400 MHz, CDCl3); 7.46-6.98 (15H, m), 5.25 (2H, s), 5.16 (1H, m), 4.95 (1H, br), 4.71 (1H, d), 3.70-3.28 (2H, m), 3.04 (1H, d), 2.83-2.53 (2H, m), 2.00-1.80 (3H, m), 1.62 (1H, t), 1.40 (9H, s), 0.90 (3H, t)
1 H NMR (400 MHz, CDCl 3 ); 7.46-6.98 (15H, m), 5.25 (2H, s), 5.16 (1H, m), 4.95 (1H, br), 4.71 (1H, d), 3.70-3.28 (2H, m), 3.04 (1H, d), 2.83-2.53 (2H, m), 2.00-1.80 (3H, m), 1.62 (1H, t), 1.40 (9H, s), 0.90 (3H, t)

[제조예 144]Preparation Example 144

벤질 (2R,3S)-2-히드록시-3-({3-[메틸(프로필술포닐)아미노]벤조일}아미노)-4-페닐부틸[(1R)-1-페닐프로필]카르바메이트의 제조: benzyl (2R,3S)-2-hydroxy-3-({3-[methyl(propylsulfonyl)amino]benzoyl}amino)-4-phenylbutyl[(1R)-1-phenylpropyl]carbamateBenzyl (2 R, 3 S) -2- hydroxy-3 - ({3- [methyl (propyl-sulfonyl) amino] benzoyl} amino) -4-phenylbutyl [(1 R) -1- phenyl-propyl] carbamic Preparation of bamate: benzyl (2 R , 3 S ) -2-hydroxy-3-({3- [methyl (propylsulfonyl) amino] benzoyl} amino) -4-phenylbutyl [(1 R ) -1-phenylpropyl] carbamate

상기 제조예 133에서 얻은 화합물 대신에 상기 제조예 143에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 134와 동일한 방법으로 실시하여, 표제 화합물 65 ㎎을 61% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 143 instead of the compound obtained in Preparation Example 133, 65 mg of the title compound was obtained in 61% yield in the same manner as in Preparation Example 134.

1H NMR (400 MHz, CDCl3); 7.61 (1H, s), 7.57 (1H, d), 7.45-6.90 (17H, m), 5.66 (1H, d), 5.25 (2H, s), 5.13 (1H, m), 4.10 (1H, m), 3.40 (1H, m), 3.35 (3H, s), 3.08-2.80 (6H, m), 1.95-1.75 (4H, m), 1.03 (3H, t), 0.88 (3H, t)
1 H NMR (400 MHz, CDCl 3 ); 7.61 (1H, s), 7.57 (1H, d), 7.45-6.90 (17H, m), 5.66 (1H, d), 5.25 (2H, s), 5.13 (1H, m), 4.10 (1H, m) , 3.40 (1H, m), 3.35 (3H, s), 3.08-2.80 (6H, m), 1.95-1.75 (4H, m), 1.03 (3H, t), 0.88 (3H, t)

[실시예 97]Example 97

N-((1S,2R)-1-벤질-2-히드록시-3-{[(1R)-1-페닐프로필]아미노}프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1R)- 1-phenylpropyl]amino}propyl)-3-[methyl(propylsulfonyl)amino]benzamide N - ((1 S, 2 R) -1- benzyl-2-hydroxy -3 - {[(1 R) -1- phenylpropyl] amino} propyl) -3- [methyl (propyl-sulfonyl) amino] Preparation of Benzamide: N -((1 S , 2 R ) -1-benzyl-2-hydroxy-3-{[(1 R ) -1-phenylpropyl] amino} propyl) -3- [methyl (propylsulfonyl) amino benzamide

상기 제조예 134에서 얻은 화합물 대신에 상기 제조예 144에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 88과 동일한 방법으로 실시하여, 표제 화합물 48 ㎎을 92% 수율로 얻을 수 있었다.48 mg of the title compound was obtained in 92% yield by the same method as Example 88 except for using the compound obtained in Preparation Example 144 instead of the compound obtained in Preparation Example 134.

1H NMR (400 MHz, CDCl3); 7.70 (1H, t), 7.55 (1H, m), 7.48 (1H, d), 7.39 (1H, t), 7.35-7.13 (10H, m), 7.09 (1H, d), 4.39 (1H, m), 3.63 (1H, dd), 3.47 (1H, t), 3.35(3H, s), 3.01-2.89 (3H, m), 2.82 (1H, dd), 2.72-2.55 (2H, m), 1.92-1.77 (3H, m), 1.72 (1H, m), 1.03 (3H, t), 0.85 (3H, t)1 H NMR (400 MHz, CDCl 3 ); 7.70 (1H, t), 7.55 (1H, m), 7.48 (1H, d), 7.39 (1H, t), 7.35-7.13 (10H, m), 7.09 (1H, d), 4.39 (1H, m) , 3.63 (1H, dd), 3.47 (1H, t), 3.35 (3H, s), 3.01-2.89 (3H, m), 2.82 (1H, dd), 2.72-2.55 (2H, m), 1.92-1.77 (3H, m), 1.72 (1H, m), 1.03 (3H, t), 0.85 (3H, t)

ESI MS (m/e) = 538 [M+H]+
ESI MS (m / e) = 538 [M + H] < + >

[실시예 98]Example 98

3-[메틸(프로필술포닐)아미노]-N-((1S)-2-페닐-1-{(5R)-3-[(1R)-1-페닐프로필]-1,3-옥사졸리딘-5-일}에틸)벤즈아미드의 제조: 3-[methyl(propylsulfonyl)amino]-N-((1S)-2-phenyl-1-{(5R)-3-[(1R)-1-phenylpropyl]-1,3-oxazolidin-5-yl}ethyl)benzamide3- [methyl (propylsulfonyl) amino] -N -(( 1S ) -2-phenyl-1-{( 5R ) -3-[( 1R ) -1-phenylpropyl] -1,3- oxazolidin-5-yl} ethyl) benzamide Preparation of: 3- [methyl (propylsulfonyl) amino ] - N - ((1 S) -2-phenyl-1 - {(5 R) -3 - [(1 R ) -1-phenylpropyl] -1,3-oxazolidin-5-yl} ethyl) benzamide

상기 실시예 88에서 얻은 화합물 대신에 상기 실시예 97에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 89와 동일한 방법으로 실시하여, 표제 화합물 34 ㎎을 76% 수율로 얻을 수 있었다.In the same manner as in Example 89, except that the compound obtained in Example 97 was used instead of the compound obtained in Example 88, 34 mg of the title compound was obtained in 76% yield.

1H NMR (400 MHz, CDCl3); 7.80 (1H, t), 7.62-7.14 (13H, m), 7.06 (1H, d), 4.68 (1H, d), 4.38 (1H, m), 4.11 (1H, m), 4.09 (1H, d), 3.36 (3H, s), 3.22-3.11 (2H, m), 3.01-2.68 (5H, m), 1.92-1.68 (4H, m), 1.03 (3H, t), 0.69 (3H, t)1 H NMR (400 MHz, CDCl 3 ); 7.80 (1H, t), 7.62-7.14 (13H, m), 7.06 (1H, d), 4.68 (1H, d), 4.38 (1H, m), 4.11 (1H, m), 4.09 (1H, d) , 3.36 (3H, s), 3.22-3.11 (2H, m), 3.01-2.68 (5H, m), 1.92-1.68 (4H, m), 1.03 (3H, t), 0.69 (3H, t)

ESI MS (m/e) = 550 [M+H]+
ESI MS (m / e) = 550 [M + H] < + >

[제조예 145][Production Example 145]

벤질 (2R,3S)-3-[(tert-부톡시카르보닐)아미노]-2-히드록시-4-페닐부틸[(1S)-1-페닐프로필]카르바메이트의 제조: benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl[(1S)-1-phenylpropyl]carbamateBenzyl (2 R, 3 S) -3 - [(tert - butoxycarbonyl) amino] -2-hydroxy-4-phenyl-butyl [(1 S) -1- phenylpropyl] Preparation of carbamate: benzyl (2 R , 3 S ) -3-[( tert -butoxycarbonyl) amino] -2-hydroxy-4-phenylbutyl [(1 S ) -1-phenylpropyl] carbamate

3-메톡시벤질아민 대신에 (S)-1-페닐프로필아민을 사용한 것을 제외하고는, 제조예 133과 동일한 방법으로 실시하여, 표제 화합물 73 ㎎을 68% 수율로 얻을 수 있었다.73 mg of the title compound was obtained in 68% yield by the same method as Preparation Example 133, except that ( S ) -1-phenylpropylamine was used instead of 3-methoxybenzylamine.

1H NMR (400 MHz, CDCl3); 7.49-7.01 (15H, m), 5.23 (2H, s), 5.14 (1H, m), 4.71 (1H, s), 4.64 (1H, m), 3.78-3.47 (2H, m), 3.33-2.70 (3H, m), 2.04-1.73 (3H, m), 1.63 (1H, m), 1.32 (9H, s), 0.94 (3H, t)
1 H NMR (400 MHz, CDCl 3 ); 7.49-7.01 (15H, m), 5.23 (2H, s), 5.14 (1H, m), 4.71 (1H, s), 4.64 (1H, m), 3.78-3.47 (2H, m), 3.33-2.70 ( 3H, m), 2.04-1.73 (3H, m), 1.63 (1H, m), 1.32 (9H, s), 0.94 (3H, t)

[제조예 146]Preparation Example 146

벤질 (2R,3S)-2-히드록시-3-({3-[메틸(프로필술포닐)아미노]벤조일}아미노)-4-페닐부틸[(1S)-1-페닐프로필]카르바메이트의 제조: benzyl (2R,3S)-2-hydroxy-3-({3- [methyl(propylsulfonyl)amino]benzoyl}amino)-4-phenylbutyl[(1S)-1-phenylpropyl]carbamateBenzyl (2 R, 3 S) -2- hydroxy-3 - ({3- [methyl (propyl-sulfonyl) amino] benzoyl} amino) -4-phenyl-butyl [(1 S) -1- phenyl-propyl] carbamic Preparation of the bamate: benzyl (2 R , 3 S ) -2-hydroxy-3-({3- [methyl (propylsulfonyl) amino] benzoyl} amino) -4-phenylbutyl [(1 S ) -1-phenylpropyl] carbamate

상기 제조예 133에서 얻은 화합물 대신에 상기 제조예 145에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 134와 동일한 방법으로 실시하여, 표제 화합물 58 ㎎을 63% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 145 instead of the compound obtained in Preparation Example 133, 58 mg of the title compound could be obtained in 63% yield in the same manner as in Preparation Example 134.

1H NMR (400 MHz, CDCl3); 7.64 (1H, s), 7.55 (1H, d), 7.50-7.10 (17H, m), 6.64 (1H, m), 5.24 (1H, s), 5.19 (1H, m), 4.27 (1H, m), 3.70 (1H, m), 3.33 (3H, s), 3.28-3.10 (2H, m), 2.98-2.81 (4H, m), 1.96 (1H, m), 1.91-1.76 (3H, m), 1.02 (3H, t), 0.93 (3H, t)
1 H NMR (400 MHz, CDCl 3 ); 7.64 (1H, s), 7.55 (1H, d), 7.50-7.10 (17H, m), 6.64 (1H, m), 5.24 (1H, s), 5.19 (1H, m), 4.27 (1H, m) , 3.70 (1H, m), 3.33 (3H, s), 3.28-3.10 (2H, m), 2.98-2.81 (4H, m), 1.96 (1H, m), 1.91-1.76 (3H, m), 1.02 (3H, t), 0.93 (3H, t)

[실시예 99]Example 99

N-((1S,2R)-1-벤질-2-히드록시-3-{[(1S)-1-페닐프로필]아미노}프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1S)-1-phenylpropyl]amino}propyl)-3-[methyl(propylsulfonyl)amino]benzamide N - ((1 S, 2 R) -1- benzyl-2-hydroxy -3 - {[(1 S) -1- phenylpropyl] amino} propyl) -3- [methyl (propyl-sulfonyl) amino] Preparation of Benzamide: N -((1 S , 2 R ) -1-benzyl-2-hydroxy-3-{[(1 S ) -1-phenylpropyl] amino} propyl) -3- [methyl (propylsulfonyl) amino benzamide

상기 제조예 134에서 얻은 화합물 대신에 상기 제조예 146에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 88과 동일한 방법으로 실시하여, 표제 화합물 44 ㎎을 96% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 146 instead of the compound obtained in Preparation Example 134, it was carried out in the same manner as in Example 88, 44 mg of the title compound could be obtained in 96% yield.

1H NMR (400 MHz, CDCl3); 7.66 (1H, t), 7.54 (1H, m), 7.44 (1H, dt), 7.39 (1H, t), 7.35-7.17 (10H, m), 6.70(1H, d), 4.39 (1H, m), 3.54 (1H, m), 3.49 (1H, t), 3.34 (3H, s), 3.10-2.90 (4H, m), 2.72-2.59 (2H, m), 1.92-1.78 (3H, m), 1.74 (1H, m), 1.03 (3H, t), 0.84 (3H, t)1 H NMR (400 MHz, CDCl 3 ); 7.66 (1H, t), 7.54 (1H, m), 7.44 (1H, dt), 7.39 (1H, t), 7.35-7.17 (10H, m), 6.70 (1H, d), 4.39 (1H, m) , 3.54 (1H, m), 3.49 (1H, t), 3.34 (3H, s), 3.10-2.90 (4H, m), 2.72-2.59 (2H, m), 1.92-1.78 (3H, m), 1.74 (1H, m), 1.03 (3H, t), 0.84 (3H, t)

ESI MS (m/e) = 538 [M+H]+
ESI MS (m / e) = 538 [M + H] < + >

[실시예 100]Example 100

3-[메틸(프로필술포닐)아미노]-N-((1S)-2-페닐-1-{(5R)-3-[(1S)-1-페닐프로필]-1,3-옥사졸리딘-5-일}에틸)벤즈아미드의 제조: 3-[methyl(propylsulfonyl)amino]-N-((1S)-2-phenyl-1-{(5R)-3-[(1S)-1-phenylpropyl]-1,3-oxazolidin-5-yl}ethyl)benzamide3- [methyl (propylsulfonyl) amino] -N -(( 1S ) -2-phenyl-1-{( 5R ) -3-[( 1S ) -1-phenylpropyl] -1,3- oxazolidin-5-yl} ethyl) benzamide Preparation of: 3- [methyl (propylsulfonyl) amino ] - N - ((1 S) -2-phenyl-1 - {(5 R) -3 - [(1 S ) -1-phenylpropyl] -1,3-oxazolidin-5-yl} ethyl) benzamide

상기 실시예 88에서 얻은 화합물 대신에 상기 실시예 99에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 89와 동일한 방법으로 실시하여, 표제 화합물 15 ㎎을 37% 수율로 얻을 수 있었다.15 mg of the title compound was obtained in 37% yield by the same method as Example 89 except for using the compound obtained in Example 99 instead of the compound obtained in Example 88.

1H NMR (400 MHz, CDCl3); 7.80 (1H, t), 7.61 (1H, m), 7.55 (1H, dt), 7.44 (1H, t), 7.36-7.17 (10H, m), 7.10 (1H, d), 4.40 (1H, m), 4.24 (1H, d), 4.20 (1H, m), 3.93 (1H, d), 3.36 (3H, s), 3.27 (1H, dd), 3.19 (1H, dd), 3.13 (1H, dd), 2.99-2.91 (2H, m), 2.87 (1H, m), 2.73 (1H, m), 2.00-1.70 (4H, m), 1.02 (3H, t), 0.71 (3H, t)1 H NMR (400 MHz, CDCl 3 ); 7.80 (1H, t), 7.61 (1H, m), 7.55 (1H, dt), 7.44 (1H, t), 7.36-7.17 (10H, m), 7.10 (1H, d), 4.40 (1H, m) , 4.24 (1H, d), 4.20 (1H, m), 3.93 (1H, d), 3.36 (3H, s), 3.27 (1H, dd), 3.19 (1H, dd), 3.13 (1H, dd), 2.99-2.91 (2H, m), 2.87 (1H, m), 2.73 (1H, m), 2.00-1.70 (4H, m), 1.02 (3H, t), 0.71 (3H, t)

ESI MS (m/e) = 550 [M+H]+
ESI MS (m / e) = 550 [M + H] < + >

[제조예 147][Production Example 147]

벤질 (2R,3S)-3-[(tert-부톡시카르보닐)아미노]-2-히드록시-4-페닐부틸[(1R)-1-(3-메톡시페닐)에틸]카르바메이트의 제조: benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl[(1R)-1-(3-methoxyphenyl)ethyl]carbamateBenzyl (2 R, 3 S) -3 - [(tert - butoxycarbonyl) amino] -2-hydroxy-4-phenyl-butyl [(1 R) -1- (3- methoxyphenyl) ethyl] carbamic Preparation of bamate: benzyl (2 R , 3 S ) -3-[( tert -butoxycarbonyl) amino] -2-hydroxy-4-phenylbutyl [(1 R ) -1- (3-methoxyphenyl) ethyl] carbamate

3-메톡시벤질아민 대신에 (R)-1-(3-메톡시페닐)에틸아민을 사용한 것을 제외하고는, 제조예 133과 동일한 방법으로 실시하여, 표제 화합물 81 ㎎을 74% 수율로 얻을 수 있었다.Except for using ( R ) -1- (3-methoxyphenyl) ethylamine instead of 3-methoxybenzylamine, the same procedure as in Production Example 133 was carried out to obtain 81 mg of the title compound in 74% yield. Could.

1H NMR (400 MHz, CD3OD); 7.41-7.08 (11H, m), 6.90-6.73 (3H, m), 5.32 (1H, m), 5.15 (2H, s), 3.70 (3H, s), 3.78-3.56 (2H, m), 3.38 (1H, m), 3.12-2.83 (2H, br), 2.53 (1H, t), 1.60 (3H, d), 1.27 (9H, s)
1 H NMR (400 MHz, CD3OD); 7.41-7.08 (11H, m), 6.90-6.73 (3H, m), 5.32 (1H, m), 5.15 (2H, s), 3.70 (3H, s), 3.78-3.56 (2H, m), 3.38 ( 1H, m), 3.12-2.83 (2H, br), 2.53 (1H, t), 1.60 (3H, d), 1.27 (9H, s)

[제조예 148][Production Example 148]

벤질 (2R,3S)-2-히드록시-3-({3-[메틸(프로필술포닐)아미노]벤조일}아미노)-4-페닐부틸[(1R)-1-(3-메톡시페닐)에틸]카르바메이트의 제조: benzyl (2R,3S)-2-hydroxy-3-({3-[methyl(propylsulfonyl)amino]benzoyl}amino)-4-phenylbutyl[(1R)-1-(3-methoxyphenyl)ethyl]carbamateBenzyl (2 R, 3 S) -2- hydroxy-3 - ({3- [methyl (propyl-sulfonyl) amino] benzoyl} amino) -4-phenylbutyl [(1 R) -1- (3-methoxy Preparation of oxyphenyl) ethyl] carbamate: benzyl (2 R , 3 S ) -2-hydroxy-3-({3- [methyl (propylsulfonyl) amino] benzoyl} amino) -4-phenylbutyl [(1 R ) -1- (3-methoxyphenyl) ethyl] carbamate

상기 제조예 133에서 얻은 화합물 대신에 상기 제조예 147에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 134와 동일한 방법으로 실시하여, 표제 화합물 83 ㎎을 83% 수율로 얻을 수 있었다. Except for using the compound obtained in Preparation Example 147 instead of the compound obtained in Preparation Example 133, 83 mg of the title compound could be obtained in the same manner as in Preparation Example 134, in 83% yield.                     

1H NMR (400 MHz, CDCl3); 7.68 (1H, s), 7.57 (1H, d), 7.45-7.10 (12H, m), 6.97 (1H, br), 6.78-6.59 (3H, m), 6.02 (1H, br), 5.35 (1H, m), 5.23 (1H, d), 4.73 (1H, br), 4.13 (1H, m), 3.64 (3H, s), 3.35 (3H, s), 3.42-3.24 (2H, m), 3.15 (1H, d), 3.02-2.83 (4H, m), 1.92-1.78 (2H, m), 1.45 (3H, d), 1.03 (3H, t)
1 H NMR (400 MHz, CDCl 3 ); 7.68 (1H, s), 7.57 (1H, d), 7.45-7.10 (12H, m), 6.97 (1H, br), 6.78-6.59 (3H, m), 6.02 (1H, br), 5.35 (1H, m), 5.23 (1H, d), 4.73 (1H, br), 4.13 (1H, m), 3.64 (3H, s), 3.35 (3H, s), 3.42-3.24 (2H, m), 3.15 (1H , d), 3.02-2.83 (4H, m), 1.92-1.78 (2H, m), 1.45 (3H, d), 1.03 (3H, t)

[실시예 101]Example 101

N-((1S,2R)-1-벤질-2-히드록시-3-{[(1R)-1-(3-메톡시페닐)에틸]아미노}프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1R)-1-(3-methoxyphenyl)ethyl]amino}propyl)-3-[methyl(propylsulfonyl)amino]benzamide N - ((1 S, 2 R) -1- benzyl-2-hydroxy -3 - {[(1 R) -1- (3- methoxyphenyl) ethyl] amino} propyl) -3- [methyl ( Preparation of Propylsulfonyl) amino] benzamide: N -((1 S , 2 R ) -1-benzyl-2-hydroxy-3-{[(1 R ) -1- (3-methoxyphenyl) ethyl] amino} propyl) -3- [methyl (propylsulfonyl) amino] benzamide

상기 제조예 134에서 얻은 화합물 대신에 상기 제조예 148에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 88과 동일한 방법으로 실시하여, 표제 화합물 60 ㎎을 90% 수율로 얻을 수 있었다.60 mg of the title compound was obtained in the same manner as in Example 88, except that the compound obtained in Preparation Example 148 was used instead of the compound obtained in Preparation Example 134.

1H NMR (400 MHz, CDCl3); 7.70 (1H, t), 7.55 (1H, m), 7.49 (1H, dt), 7.39 (1H, t), 7.31-7.13 (7H, m), 6.90 (1H, d), 6.88 (1H, t), 6.79 (1H, m), 4.42 (1H, m), 3.77(3H, s), 3.73 (1H, m), 3.65 (1H, dd), 3.35 (3H, s), 3.02-2.89 (3H, m), 2.85 (1H, dd), 2.72 (1H, dd), 2.64 (1H, dd), 1.92-1.78 (2H, m), 1.44 (3H, d), 1.03 (3H, t) 1 H NMR (400 MHz, CDCl 3 ); 7.70 (1H, t), 7.55 (1H, m), 7.49 (1H, dt), 7.39 (1H, t), 7.31-7.13 (7H, m), 6.90 (1H, d), 6.88 (1H, t) , 6.79 (1H, m), 4.42 (1H, m), 3.77 (3H, s), 3.73 (1H, m), 3.65 (1H, dd), 3.35 (3H, s), 3.02-2.89 (3H, m ), 2.85 (1H, dd), 2.72 (1H, dd), 2.64 (1H, dd), 1.92-1.78 (2H, m), 1.44 (3H, d), 1.03 (3H, t)

ESI MS (m/e) = 554 [M+H]+
ESI MS (m / e) = 554 [M + H] < + >

[실시예 102]Example 102

N-((1S)-1-{(5R)-3-[(1R)-1-(3-메톡시페닐)에틸]-1,3-옥사졸리딘-5-일}-2-페닐에틸)-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-((1S)-1-{(5R)-3-[(1R)-1-(3-methoxyphenyl)ethyl]-1,3-oxazolidin-5-yl}-2-phenylethyl)-3-[methyl(propylsulfonyl)amino]benzamide N -(( 1S ) -1-{( 5R ) -3-[( 1R ) -1- (3-methoxyphenyl) ethyl] -1,3-oxazolidin-5-yl} -2 Preparation of -phenylethyl) -3- [methyl (propylsulfonyl) amino] benzamide: N -(( 1S ) -1-{( 5R ) -3-[( 1R ) -1- (3- methoxyphenyl) ethyl] -1,3-oxazolidin-5-yl} -2-phenylethyl) -3- [methyl (propylsulfonyl) amino] benzamide

상기 실시예 88에서 얻은 화합물 대신에 상기 실시예 101에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 89와 동일한 방법으로 실시하여, 표제 화합물 28 ㎎을 74% 수율로 얻을 수 있었다.Except for using the compound obtained in Example 101 instead of the compound obtained in Example 88, 28 mg of the title compound could be obtained in a 74% yield in the same manner as in Example 89.

1H NMR (400 MHz, CDCl3); 7.80 (1H, t), 7.62-7.56 (2H, m), 7.45 (1H, t), 7.30-7.16 (6H, m), 7.12 (1H, d), 6.91 (1H, d), 6.89 (1H, s), 6.82 (1H, dd), 4.68 (1H, d), 4.38 (1H, m), 4.14 (1H, m), 4.12 (1H, d), 3.75 (3H, s), 3.42-3.31 (4H, m), 3.20 (1H, dd), 3.01-2.92 (2H, m), 2.86 (1H, dd), 2.74 (1H, dd), 2.65 (1H, dd), 1.92-1.78 (2H, m), 1.40 (3H, d), 1.03 (3H, t)1 H NMR (400 MHz, CDCl 3 ); 7.80 (1H, t), 7.62-7.56 (2H, m), 7.45 (1H, t), 7.30-7.16 (6H, m), 7.12 (1H, d), 6.91 (1H, d), 6.89 (1H, s), 6.82 (1H, dd), 4.68 (1H, d), 4.38 (1H, m), 4.14 (1H, m), 4.12 (1H, d), 3.75 (3H, s), 3.42-3.31 (4H , m), 3.20 (1H, dd), 3.01-2.92 (2H, m), 2.86 (1H, dd), 2.74 (1H, dd), 2.65 (1H, dd), 1.92-1.78 (2H, m), 1.40 (3H, d), 1.03 (3H, t)

ESI MS (m/e) = 566 [M+H]+
ESI MS (m / e) = 566 [M + H] < + >

[제조예 149][Production Example 149]

벤질 (2R,3S)-3-[(tert-부톡시카르보닐)아미노]-2-히드록시-4-페닐부틸[(1S)-1-(3- 메톡시페닐)에틸]카르바메이트의 제조: benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl[(1S)-1-(3-methoxyphenyl)ethyl]carbamateBenzyl (2 R, 3 S) -3 - [(tert - butoxycarbonyl) amino] -2-hydroxy-4-phenyl-butyl [(1 S) -1- (3- methoxyphenyl) ethyl] carbamic Preparation of bamate: benzyl (2 R , 3 S ) -3-[( tert -butoxycarbonyl) amino] -2-hydroxy-4-phenylbutyl [(1 S ) -1- (3-methoxyphenyl) ethyl] carbamate

3-메톡시벤질아민 대신에 (S)-1-(3-메톡시페닐)에틸아민을 사용한 것을 제외하고는, 제조예 133과 동일한 방법으로 실시하여, 표제 화합물 75 ㎎을 68% 수율로 얻을 수 있었다.Except for using ( S ) -1- (3-methoxyphenyl) ethylamine instead of 3-methoxybenzylamine, the same procedure as in Production Example 133 was carried out to obtain 75 mg of the title compound in 68% yield. Could.

1H NMR (400 MHz, CDCl3); 7.44-7.10 (11H, m), 6.90-6.64 (3H, m), 5.35 (1H, br), 5.20 (2H, dd), 4.74 (1H, br), 4.58 (1H, br), 3.82-3.60 (4H, m), 3.37 (1H, br), 3.11 (1H, br), 3.02-2.71 (2H, m), 1.50 (3H, d), 1.31 (9H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.44-7.10 (11H, m), 6.90-6.64 (3H, m), 5.35 (1H, br), 5.20 (2H, dd), 4.74 (1H, br), 4.58 (1H, br), 3.82-3.60 ( 4H, m), 3.37 (1H, br), 3.11 (1H, br), 3.02-2.71 (2H, m), 1.50 (3H, d), 1.31 (9H, s)

[제조예 150][Production Example 150]

벤질 (2R,3S)-2-히드록시-3-({3-[메틸(프로필술포닐)아미노]벤조일}아미노)-4-페닐부틸[(1S)-1-(3-메톡시페닐)에틸]카르바메이트의 제조: benzyl (2R,3S)-2-hydroxy-3-({3-[methyl(propylsulfonyl)amino]benzoyl}amino)-4-phenylbutyl[(1S)-1-(3-methoxyphenyl)ethyl]carbamateBenzyl (2 R, 3 S) -2- hydroxy-3 - ({3- [methyl (propyl-sulfonyl) amino] benzoyl} amino) -4-phenyl-butyl [(1 S) -1- (3-methoxy Preparation of oxyphenyl) ethyl] carbamate: benzyl (2 R , 3 S ) -2-hydroxy-3-({3- [methyl (propylsulfonyl) amino] benzoyl} amino) -4-phenylbutyl [(1 S ) -1- (3-methoxyphenyl) ethyl] carbamate

상기 제조예 133에서 얻은 화합물 대신에 상기 제조예 149에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 134와 동일한 방법으로 실시하여, 표제 화합물 80 ㎎을 85% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 149 instead of the compound obtained in Preparation Example 133, 80 mg of the title compound could be obtained in 85% yield in the same manner as in Preparation Example 134.

1H NMR (400 MHz, CD3OD)7.62-7.53 (2H, m), 7.50-7.38 (2H, m), 7.33-7.08 (12H, m), 6.87-6.72 (3H, m), 5.24-5.07 (3H, m), 4.20 (1H, m), 3.78 (1H, m), 3.66 (3H, s), 3.50 (1H, m), 3.40-3.17 (5H, m), 3.04 (2H, dd), 2.76 (1H, dd), 1.85-1.70 (2H, m), 1.64 (3H, d), 1.00 (3H, t)
1 H NMR (400 MHz, CD3OD) 7.82-7.53 (2H, m), 7.50-7.38 (2H, m), 7.33-7.08 (12H, m), 6.87-6.72 (3H, m), 5.24-5.07 (3H, m), 4.20 (1H, m), 3.78 (1H, m), 3.66 (3H, s), 3.50 (1H, m), 3.40-3.17 (5H, m), 3.04 (2H, dd), 2.76 (1H , dd), 1.85-1.70 (2H, m), 1.64 (3H, d), 1.00 (3H, t)

[실시예 103]Example 103

N-((1S,2R)-1-벤질-2-히드록시-3-{[(1S)-1-(3-메톡시페닐)에틸]아미노}프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1S)-1-(3-methoxyphenyl)ethyl]amino}propyl)-3-[methyl(propylsulfonyl)amino]benzamide N - ((1 S, 2 R) -1- benzyl-2-hydroxy -3 - {[(1 S) -1- (3- methoxyphenyl) ethyl] amino} propyl) -3- [methyl ( Preparation of propylsulfonyl) amino] benzamide: N -((1 S , 2 R ) -1-benzyl-2-hydroxy-3-{[(1 S ) -1- (3-methoxyphenyl) ethyl] amino} propyl) -3- [methyl (propylsulfonyl) amino] benzamide

상기 제조예 134에서 얻은 화합물 대신에 상기 제조예 150에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 88과 동일한 방법으로 실시하여, 표제 화합물 60 ㎎을 94% 수율로 얻을 수 있었다.60 mg of the title compound was obtained in the yield of 94% by the same method as in Example 88, except that the compound obtained in Preparation Example 150 was used instead of the compound obtained in Preparation Example 134.

1H NMR (400 MHz, CDCl3); 7.68 (1H, t), 7.54 (1H, m), 7.45 (1H, dt), 7.38 (1H,t), 7.33-7.18 (6H, m), 6.92-6.83 (3H, m), 3.78 (1H, m), 4.39 (1H, m), 3.80 (3H, s), 3.75 (1H, m), 3.59 (1H, dd), 3.34 (3H, s), 3.11-2.90 (4H, m), 2.77-2.62 (2H, m), 1.90-1.78 (2H, m), 1.43 (3H, d), 1.03 (3H, t)1 H NMR (400 MHz, CDCl 3 ); 7.68 (1H, t), 7.54 (1H, m), 7.45 (1H, dt), 7.38 (1H, t), 7.33-7.18 (6H, m), 6.92-6.83 (3H, m), 3.78 (1H, m), 4.39 (1H, m), 3.80 (3H, s), 3.75 (1H, m), 3.59 (1H, dd), 3.34 (3H, s), 3.11-2.90 (4H, m), 2.77-2.62 (2H, m), 1.90-1.78 (2H, m), 1.43 (3H, d), 1.03 (3H, t)

ESI MS (m/e) = 554 [M+H]+
ESI MS (m / e) = 554 [M + H] < + >

[실시예 104] Example 104                     

N-((1S)-1-{(5R)-3-[(1S)-1-(3-메톡시페닐)에틸]-1,3-옥사졸리딘-5-일}-2-페닐에틸)-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-((1S)-1-{(5R)-3-[(1S)-1-(3-methoxyphenyl)ethyl]-1,3-oxazolidin-5-yl}-2-phenylethyl)-3-[methyl(propylsulfonyl)amino]benzamide N -(( 1S ) -1-{( 5R ) -3-[( 1S ) -1- (3-methoxyphenyl) ethyl] -1,3-oxazolidin-5-yl} -2 Preparation of -phenylethyl) -3- [methyl (propylsulfonyl) amino] benzamide: N -(( 1S ) -1-{( 5R ) -3-[( 1S ) -1- (3- methoxyphenyl) ethyl] -1,3-oxazolidin-5-yl} -2-phenylethyl) -3- [methyl (propylsulfonyl) amino] benzamide

상기 실시예 88에서 얻은 화합물 대신에 상기 실시예 103에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 89와 동일한 방법으로 실시하여, 표제 화합물 33 ㎎을 87% 수율로 얻을 수 있었다.Except for using the compound obtained in Example 103 instead of the compound obtained in Example 88, the same procedure as in Example 89 was carried out, and 33 mg of the title compound was obtained in 87% yield.

1H NMR (400 MHz, CDCl3); 7.80 (1H, t), 7.60 (1H, m), 7.55 (1H, dt), 7.45 (1H, t), 7.34-7.17 (6H, m), 7.09 (1H, d), 6.91-6.84 (2H, m), 6.78 (1H, m), 4.41 (1H, m), 4.29 (1H, d), 4.21 (1H, m), 3.99 (1H, d), 3.76 (3H, s), 3.36 (3H, s), 3.34 (1H, m), 3.26 (1H, dd), 3.14 (1H, dd), 3.00-2.92 (2h, m), 2.88 (1H, dd), 2.75 (1H, dd), 1.91-1.78 (2H, m), 1.44 (3H, d), 1.02 (3H, t)1 H NMR (400 MHz, CDCl 3 ); 7.80 (1H, t), 7.60 (1H, m), 7.55 (1H, dt), 7.45 (1H, t), 7.34-7.17 (6H, m), 7.09 (1H, d), 6.91-6.84 (2H, m), 6.78 (1H, m), 4.41 (1H, m), 4.29 (1H, d), 4.21 (1H, m), 3.99 (1H, d), 3.76 (3H, s), 3.36 (3H, s ), 3.34 (1H, m), 3.26 (1H, dd), 3.14 (1H, dd), 3.00-2.92 (2h, m), 2.88 (1H, dd), 2.75 (1H, dd), 1.91-1.78 ( 2H, m), 1.44 (3H, d), 1.02 (3H, t)

ESI MS (m/e) = 566 [M+H]+
ESI MS (m / e) = 566 [M + H] < + >

[제조예 151][Manufacture Example 151]

벤질 (2R,3S)-3-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-2-히드록시-4-페닐부틸(3-메톡시벤질)카르바메이트의 제조: benzyl (2R,3S)-3-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-2-hydroxy-4-phenylbutyl(3-methoxybenzyl)carbamate Benzyl (2 R, 3 S) -3 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -2-hydroxy-4-phenylbutyl (3-methoxybenzyl) carbamate Preparation of: benzyl (2 R , 3 S ) -3-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -2-hydroxy-4-phenylbutyl (3-methoxybenzyl) carbamate

상기 제조예 29에서 얻은 화합물 대신에 상기 제조예 56에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 134와 동일한 방법으로 실시하여, 표제 화합물 75 ㎎을 93% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 56 instead of the compound obtained in Preparation Example 29, it was carried out in the same manner as in Preparation Example 134, 75 mg of the title compound could be obtained in 93% yield.

1H NMR (400 MHz, CDCl3); 7.52-7.10 (20H, m), 6.77 (1H, dd), 6.72 (1H, d), 6.68 (1H, s), 6.49 (1H, d), 5.19 (2H, dd), 4.55 (2H, dd), 4.38 (1H, m), 4.26 (2H, s), 3.95 (1H, dd), 3.68 (3H, s), 3.47 (2H, d), 3.13 (3H, s), 3.00 (2H, d)
1 H NMR (400 MHz, CDCl 3 ); 7.52-7.10 (20H, m), 6.77 (1H, dd), 6.72 (1H, d), 6.68 (1H, s), 6.49 (1H, d), 5.19 (2H, dd), 4.55 (2H, dd) , 4.38 (1H, m), 4.26 (2H, s), 3.95 (1H, dd), 3.68 (3H, s), 3.47 (2H, d), 3.13 (3H, s), 3.00 (2H, d)

[실시예 105]Example 105

N-{(1S,2R)-1-벤질-2-히드록시-3-[(3-메톡시벤질)아미노]프로필}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[(benzylsulfonyl)(methyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(3-methoxybenzyl) amino] propyl} -3 - [(benzyl-sulfonyl) (methyl) amino] benzamide Preparation of: N -{(1 S , 2 R ) -1-benzyl-2-hydroxy-3-[(3-methoxybenzyl) amino] propyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 151에서 얻은 화합물 52 ㎎(0.072 mmol)을 디클로로메탄 5 ㎖ 에 녹인 후 아이오도트리메틸틸실란 72 ㎎(0.36 mmol)을 넣어 30 분 동안 교반하였다. 디클로로메탄에 희석하여 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 다음 메탄올과 디클로로메탄의 5:95 혼합액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 13 ㎎을 31% 수율로 얻을 수 있었다.52 mg (0.072 mmol) of the compound obtained in Preparation Example 151 was dissolved in 5 mL of dichloromethane, and 72 mg (0.36 mmol) of iodotrimethyltylsilane was added thereto, followed by stirring for 30 minutes. Diluted in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography using a 5:95 mixture of methanol and dichloromethane to obtain 13 mg of the title compound in 31% yield.

1H NMR (400 MHz, CDCl3); 7.60 (1H, s), 7.46 (1H, m), 7.38-7.16 (13H, m), 7.09 (1H, s), 7.06 (1H, d), 7.01 (1H, d), 6.87 (1H, dd), 4.38 (1H, m), 4.29 (2H, s), 4.14 (1H, d), 4.12 (1H, m), 3.99 (1H, d), 3.78 (3H, s), 3.24 (1H, dd), 3.13 (3H, s), 3.10 (1H, s), 3.08 (1H, d), 2.94 (1H, dd)1 H NMR (400 MHz, CDCl 3 ); 7.60 (1H, s), 7.46 (1H, m), 7.38-7.16 (13H, m), 7.09 (1H, s), 7.06 (1H, d), 7.01 (1H, d), 6.87 (1H, dd) , 4.38 (1H, m), 4.29 (2H, s), 4.14 (1H, d), 4.12 (1H, m), 3.99 (1H, d), 3.78 (3H, s), 3.24 (1H, dd), 3.13 (3H, s), 3.10 (1H, s), 3.08 (1H, d), 2.94 (1H, dd)

ESI MS (m/e) = 588 [M+H]+
ESI MS (m / e) = 588 [M + H] < + >

[실시예 106]Example 106

3-[(벤질술포닐)(메틸)아미노]-N-{(1S)-1-[(5R)-3-(3-메톡시벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}벤즈아미드의 제조: 3-[(benzylsulfonyl)(methyl)amino]-N-{(1S)-1-[(5R)-3-(3-methoxybenzyl)-1,3-oxazolidin-5-yl]-2-phenylethyl}benzamide3-[(benzylsulfonyl) (methyl) amino] -N -{( 1S ) -1-[( 5R ) -3- (3-methoxybenzyl) -1,3-oxazolidine-5- general Preparation of 2-phenyl-ethyl} -benzamide: 3 - [(benzylsulfonyl) ( methyl) amino] - N - {(1 S) -1 - [(5 R) -3- (3-methoxybenzyl) -1 , 3-oxazolidin-5-yl] -2-phenylethyl} benzamide

상기 실시예 88에서 얻은 화합물 대신에 상기 실시예 105에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 89와 동일한 방법으로 실시하여, 표제 화합물 6 ㎎을 60% 수율로 얻을 수 있었다.Except for using the compound obtained in Example 105 instead of the compound obtained in Example 88, it was carried out in the same manner as in Example 89, whereby 6 mg of the title compound could be obtained in 60% yield.

1H NMR (400 MHz, CDCl3); 7.59 (1H, t), 7.47-7.18 (14H, m), 6.93 (1H, d), 6.91 (1H, s), 6.82 (1H, dd), 6.67 (1H, d), 4.56 (1H, d), 4.43 (1H, m), 4.27 (2H, s), 4.23 (1H, d), 4.14 (1H, m), 3.78 (3H, s), 3.72 (2H, dd), 3.19 (1H, dd), 3.15 (3H, s), 3.05 (1H, dd), 2.98-2.83 (2H, m)1 H NMR (400 MHz, CDCl 3 ); 7.59 (1H, t), 7.47-7.18 (14H, m), 6.93 (1H, d), 6.91 (1H, s), 6.82 (1H, dd), 6.67 (1H, d), 4.56 (1H, d) , 4.43 (1H, m), 4.27 (2H, s), 4.23 (1H, d), 4.14 (1H, m), 3.78 (3H, s), 3.72 (2H, dd), 3.19 (1H, dd), 3.15 (3H, s), 3.05 (1H, dd), 2.98-2.83 (2H, m)

ESI MS (m/e) = 600 [M+H]+
ESI MS (m / e) = 600 [M + H] +

[제조예 152][Production Example 152]

tert-부틸 (1S,2R)-1-벤질-3-[[(9H-퓨렌-9-일메톡시)카르보닐](3-메톡시벤질)아미노]-2-히드록시프로필카르바메이트의 제조: tert-butyl (1S,2R)-1-benzyl-3-[[(9H -fluoren-9-ylmethoxy)carbonyl](3-methoxybenzyl)amino]-2-hydroxypropylcarbamate tert - butyl (1 S, 2 R) -1- benzyl -3 - [[(9 H - pyuren-9-ylmethoxy) carbonyl] (3-methoxybenzyl) amino] -2-hydroxypropyl carbamate Preparation of mate: tert -butyl (1 S, 2 R) -1-benzyl-3 - [[(9 H -fluoren-9-ylmethoxy) carbonyl] (3-methoxybenzyl) amino] -2-hydroxypropylcarbamate

상기 제조예 132에서 얻은 화합물(500 ㎎, 1.90 mmol)을 이소프로판올 (9 ㎖)에 녹인 후 3-메톡시벤질아민(0.27 ㎖, 2.09 mmol)을 상온에서 넣어 주었다. 반응용액을 16 시간 동안 환류시킨 후 용매를 감압증류하여 제거하였다. 잔여물을 테트라하이드로퓨란(9 ㎖)에 녹인 후 0 C로 냉각하였다. 이 반응용액에 트리에틸아민(0.29 ㎖, 2.09 mmol)과 9-플루오레닐메틸 클로로포름산(541 ㎎, 2.09 mmol)을 넣고 1 시간 동안 교반하였다. 반응용액을 에틸아세테이트로 희석하고, 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류하여 제거한 후 컬럼크로마토그래피로 정제하여 표제 화합물 1.90 g을 60%의 수율로 얻었다.The compound (500 mg, 1.90 mmol) obtained in Preparation Example 132 was dissolved in isopropanol (9 mL), and 3-methoxybenzylamine (0.27 mL, 2.09 mmol) was added at room temperature. The reaction solution was refluxed for 16 hours and then the solvent was removed by distillation under reduced pressure. The residue was taken up in tetrahydrofuran (9 mL) and cooled to 0 C. Triethylamine (0.29 mL, 2.09 mmol) and 9-fluorenylmethyl chloroform acid (541 mg, 2.09 mmol) were added to the reaction solution, and the mixture was stirred for 1 hour. The reaction solution was diluted with ethyl acetate and washed with 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography to obtain 1.90 g of the title compound in a yield of 60%.

1H-NMR (300 MHz, CDCl3); 7.78∼7.49(3H, m), 7.47∼6.99(12H, m), 6.82∼6.54(3H, m), 4.75(1H, bs), 4.58∼4.31(4H, m), 4.29∼4.10(2H, m), 3.90∼3.70(1H, m), 3.75(3H, s), 3.50∼3.30(2H, m), 3.03∼2.78(2H, m), 1.32(9H, s)
1 H-NMR (300 MHz, CDCl 3 ); 7.78-7.49 (3H, m), 7.47-6.99 (12H, m), 6.82-6.64 (3H, m), 4.75 (1H, bs), 4.58-4.31 (4H, m), 4.29-4.10 (2H, m) ), 3.90-3.70 (1H, m), 3.75 (3H, s), 3.50-3.30 (2H, m), 3.03-2.78 (2H, m), 1.32 (9H, s)

[실시예 107] Example 107                     

3-[(부틸술포닐)(메틸)아미노]-N-{(1S)-1-[(5R)-3-(3-메톡시벤질)-1,3-옥소졸리딘-5-일]-2-페닐에틸}벤즈아미드의 제조: 3-[(butylsulfonyl)(methyl)amino]-N-{(1S)-1-[(5R)-3-(3-methoxybenzyl)-1,3-oxazolidin-5-yl]-2-phenylethyl}benzamide3-[(butylsulfonyl) (methyl) amino] -N -{( 1S ) -1-[( 5R ) -3- (3-methoxybenzyl) -1,3-oxozolidine-5- general Preparation of 2-phenyl-ethyl} -benzamide: 3 - [(butylsulfonyl) ( methyl) amino] - N - {(1 S) -1 - [(5 R) -3- (3-methoxybenzyl) -1 , 3-oxazolidin-5-yl] -2-phenylethyl} benzamide

상기 제조예 95에서 얻은 화합물(90 ㎎, 0.144 mmol)을 에틸아세테이트에 묽혀진 4.0 N 염산용액(3 ㎖)에 녹여서 2 시간 동안 교반하였다. 용매를 감압증류하여 농축한 후 N,N-디메틸포름아미드(3 ㎖)에 녹여서 0℃로 냉각하여 상기 제조예 51에서 얻은 화합물 37 ㎎(0.12 mmol)과 HATU 55 ㎎(0.144 mmol)를 가하였다. 여기에 디이소프로필에틸아민 0.5 ㎖(과량)을 가하고 상온으로 온도를 올려 4 시간 동안 교반하였다. 감압증류하여 용매를 제거한 다음 에틸아세테이트에 녹여서 물, 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 후, 잔여물을 메틸렌클로라이드 1 ㎖에 녹이고 피페리딘 0.1 ㎖을 가한 후 1 시간 동안 교반하였다. 감압증류하여 용매를 제거한 후 컬럼크로마토그래피로 정제하여 표제 화합물 36 ㎎을 50%의 수율로 얻었다.The compound (90 mg, 0.144 mmol) obtained in Preparation Example 95 was dissolved in 4.0 N hydrochloric acid solution (3 mL) diluted in ethyl acetate, and stirred for 2 hours. The solvent was concentrated by distillation under reduced pressure, dissolved in N, N-dimethylformamide (3 ml), cooled to 0 ° C., and 37 mg (0.12 mmol) of the compound obtained in Preparation Example 51 and 55 mg (0.144 mmol) of HATU were added thereto. . 0.5 ml (excess) of diisopropylethylamine was added thereto, and the temperature was raised to room temperature, followed by stirring for 4 hours. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. After the solvent was removed by distillation under reduced pressure, the residue was dissolved in 1 ml of methylene chloride, 0.1 ml of piperidine was added, and stirred for 1 hour. After distillation under reduced pressure to remove the solvent, the residue was purified by column chromatography to obtain 36 mg of the title compound in a yield of 50%.

1H-NMR (300 MHz, CDCl3); 7.75 (1H, s), 7.56∼7.72 (1H, m), 7.45∼7.40 (2H, m), 7.30∼7.21 (5H, m), 6.92∼6.90 (2H, m), 6.85∼6.75 (2H, m), 4.56∼4.54 (1H, d, J = 3.87), 4.45∼4.35 (1H, m), 4.20∼4.18 (1H, d, J = 3.90), 3.78 (3H, s), 3.75∼3.65 (2H, m), 3.34 (3H, s), 3.25∼3.10 (1H, m), 3.08∼3.00 (1H, m), 2.98∼2.84 (5H, m), 1.80∼1.75 (2H, m), 1.41∼1.36 (2H, m), 1.01 (3H, t, J = 7.29) 1 H-NMR (300 MHz, CDCl 3 ); 7.75 (1H, s), 7.56-7.72 (1H, m), 7.45-7.40 (2H, m), 7.30-7.71 (5H, m), 6.92-6.70 (2H, m), 6.85-6.75 (2H, m ), 4.56 to 4.44 (1H, d, J = 3.87), 4.45 to 4.35 (1H, m), 4.20 to 4.18 (1H, d, J = 3.90), 3.78 (3H, s), 3.75 to 3.65 (2H, m), 3.34 (3H, s), 3.25 to 3.10 (1H, m), 3.08 to 3.00 (1H, m), 2.98 to 2.84 (5H, m), 1.80 to 1.75 (2H, m), 1.41 to 1.36 ( 2H, m), 1.01 (3H, t, J = 7.29)

FAB MS (m/e) = 566 [M+H]+
FAB MS (m / e) = 566 [M + H] < + >

[실시예 108]Example 108

3-[(에틸술포닐)(메틸)아미노]-N-{(1S)-1-[(5R)-3-(3-메톡시벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}벤즈아미드의 제조: 3-[(ethylsulfonyl)(methyl)amino]-N-{(1S)-1-[(5R)-3-(3-methoxybenzyl)-1,3-oxazolidin-5-yl]-2-phenylethyl}benzamide3-[(ethylsulfonyl) (methyl) amino] -N -{( 1S ) -1-[( 5R ) -3- (3-methoxybenzyl) -1,3-oxazolidine-5- general Preparation of 2-phenyl-ethyl} -benzamide: 3 - [(ethylsulfonyl) ( methyl) amino] - N - {(1 S) -1 - [(5 R) -3- (3-methoxybenzyl) -1 , 3-oxazolidin-5-yl] -2-phenylethyl} benzamide

상기 제조예 56에서 얻은 화합물 대신에 상기 제조예 46에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 107과 동일한 방법으로 실시하여, 표제 화합물 16 ㎎을 49% 수율로 얻었다.Except for using the compound obtained in Preparation Example 46 instead of the compound obtained in Preparation Example 56, the same procedure as in Example 107 was carried out to obtain 16 mg of the title compound in 49% yield.

1H-NMR (300 MHz, CDCl3); 7.76∼7.54 (2H, m), 7.45∼7.40 (2H, m), 7.30∼7.21 (5H, m), 6.92∼6.90 (2H, m), 6.85∼6.75 (2H, m), 4.56∼4.54 (1H, d, J = 3.87), 4.45∼4.35 (1H, m), 4.20∼4.18 (1H, d, J = 3.90), 3.78 (3H, s), 3.75∼3.65 (2H, m), 3.35 (3H, s), 3.25∼3.10 (1H, m), 3.08∼3.00 (1H, m), 3.00∼2.86 (4H, m), 2.79 (1H, s), 1.34 (3H, t, J = 7.39)1 H-NMR (300 MHz, CDCl 3 ); 7.76 to 7.74 (2H, m), 7.45 to 7.40 (2H, m), 7.30 to 7.21 (5H, m), 6.92 to 6.70 (2H, m), 6.85 to 6.75 (2H, m), 4.56 to 4.54 (1H) , d, J = 3.87), 4.45-4.35 (1H, m), 4.20-4.18 (1H, d, J = 3.90), 3.78 (3H, s), 3.75-3.65 (2H, m), 3.35 (3H, s), 3.25 to 3.10 (1H, m), 3.08 to 3.00 (1H, m), 3.00 to 2.86 (4H, m), 2.79 (1H, s), 1.34 (3H, t, J = 7.39)

FAB MS (m/e) = 538 [M+H]+
FAB MS (m / e) = 538 [M + H] < + >

[실시예 109]Example 109

N-{(1S)-1-[(5R)-3-(3-메톡시벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}-3-[메틸(메틸술포닐)아미노]벤즈아미드의 제조: N-{(1S)-1-[(5R)-3-(3-methoxybenzyl)-1,3- oxazolidin-5-yl]-2-phenylethyl}-3-[methyl(methylsulfonyl)amino]benzamide N -{( 1S ) -1-[( 5R ) -3- (3-methoxybenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [methyl ( Preparation of Methylsulfonyl) amino] benzamide: N -{(1 S ) -1-[(5 R ) -3- (3-methoxybenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [methyl (methylsulfonyl) amino] benzamide

상기 제조예 56에서 얻은 화합물 대신에 3-[메틸(메틸술포닐)아미노]벤조산을 사용한 것을 제외하고는, 실시예 107과 동일한 방법으로 실시하여, 표제 화합물 12 ㎎을 40% 수율로 얻었다.Except for using 3- [methyl (methylsulfonyl) amino] benzoic acid instead of the compound obtained in Preparation Example 56, the same procedure as in Example 107 was carried out to obtain 12 mg of the title compound in 40% yield.

1H-NMR (300 MHz, CDCl3); 7.75 (1H, s), 7.56∼7.54 (1H, m), 7.49∼7.41 (3H, m), 7.37∼7.22 (5H, m), 6.92∼6.90 (2H, m), 6.83∼6.81 (1H, m), 4.56∼4.54 (1H, d, J = 3.87), 4.45∼4.35 (1H, m), 4.20∼4.18 (1H, d, J = 3.90), 3.78 (3H, s), 3.75∼3.65 (3H, m), 3.33 (3H, s), 3.25∼3.10 (1H, m), 3.08∼3.00 (1H, m), 2.98∼2.84 (2H, m), 2.82 (3H, s)1 H-NMR (300 MHz, CDCl 3 ); 7.75 (1H, s), 7.56 to 7.54 (1H, m), 7.49 to 7.41 (3H, m), 7.37 to 7.72 (5H, m), 6.92 to 6.70 (2H, m), 6.83 to 6.81 (1H, m ), 4.56 to 4.44 (1H, d, J = 3.87), 4.45 to 4.35 (1H, m), 4.20 to 4.18 (1H, d, J = 3.90), 3.78 (3H, s), 3.75 to 3.65 (3H, m), 3.33 (3H, s), 3.25 to 3.10 (1H, m), 3.08 to 3.00 (1H, m), 2.98 to 2.84 (2H, m), 2.82 (3H, s)

FAB MS (m/e) = 524 [M+H]+
FAB MS (m / e) = 524 [M + H] < + >

[제조예 153]Preparation Example 153

tert-부틸 (1S,2R)-3-아지도-1-벤질-2-히드록시프로필카르바메이트의 제조: tert -butyl (1S,2R)-3-azido-1-benzyl-2-hydroxypropylcarbamate tert - butyl (1 S, 2 R) -3- azido-1-benzyl-2-hydroxy propyl carbamate Preparation of: tert -butyl (1 S, 2 R) -3-azido-1-benzyl- 2-hydroxypropylcarbamate

상기 제조예 132에서 얻은 화합물 500 ㎎(1.90 mmol)을 메탄올 8.6 ㎖과 증류수 1.1 ㎖에 녹이고, 암모늄클로라이드 221 ㎎(4.13 mmol)와 소듐아자이드 610 ㎎(9.39 mmol)을 상온에서 넣었다. 40℃에서 16 시간 교반 후 물로 희석하고 에틸아세테이트로 추출하였다. 감압증류하여 용매를 제거한 후 컬럼크로마토그래피로 정제하여 표제 화합물 523 ㎎을 90% 수율로 얻었다 500 mg (1.90 mmol) of the compound obtained in Preparation Example 132 was dissolved in 8.6 ml of methanol and 1.1 ml of distilled water, and 221 mg (4.13 mmol) of ammonium chloride and 610 mg (9.39 mmol) of sodium azide were added at room temperature. After stirring for 16 hours at 40 ℃ diluted with water and extracted with ethyl acetate. After distillation under reduced pressure to remove the solvent, the residue was purified by column chromatography to obtain the title compound (523 mg) in 90% yield.                     

1H-NMR (300 MHz, CDCl3); 7.33∼7.11 (5H, m), 4.60 (1H. d, J = 8.07), 3.92∼3.69 (2H, m), 3.43∼3.30 (2H, m), 2.96∼2.72 (2H, m), 1.37(9H, s)
1 H-NMR (300 MHz, CDCl 3 ); 7.33 to 7.11 (5H, m), 4.60 (1H.d, J = 8.07), 3.92 to 3.69 (2H, m), 3.43 to 3.30 (2H, m), 2.96 to 2.72 (2H, m), 1.37 (9H , s)

[제조예 154][Production Example 154]

N-[(1S,2R)-3-아지도-1-벤질-2-히드록시프로필]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-[(1S,2R)-3-azido-1-benzyl-2-hydroxypropyl]-3-[(benzylsulfonyl)(methyl)amino]benzamide N - [(1 S, 2 R) -3- azido-1-benzyl-2-hydroxypropyl] -3 - Preparation of [(benzyl-sulfonyl) (methyl) amino] benzamide: N - [(1 S , 2 R ) -3-azido-1-benzyl-2-hydroxypropyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 153에서 얻은 화합물 44 ㎎(0.144 mmol)을 에틸아세테이트에 묽혀진 4.0 N 염산용액 3 ㎖에 녹여서 2 시간 동안 교반하였다. 용매를 감압증류하여 농축한 후 N,N-디메틸포름아미드 2 ㎖에 녹여서 0℃로 냉각하여 상기 제조예 56에서 얻은 화합물 37 ㎎(0.12 mmol)과 HATU 55 ㎎(0.144 mmol)을 가하였다. 여기에, N,N-디이소프로필에틸아민 0.5 ㎖(과량)를 가하고 상온으로 온도를 올려 4 시간 동안 교반하였다. 감압증류하여 용매를 제거한 다음 에틸아세테이트에 녹여서 물, 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 후 컬럼크로마토그래피로 정제하여 표제 화합물 47 ㎎을 80% 수율로 얻었다. 44 mg (0.144 mmol) of the compound obtained in Preparation Example 153 was dissolved in 3 ml of 4.0 N hydrochloric acid solution diluted in ethyl acetate, and stirred for 2 hours. The solvent was concentrated by distillation under reduced pressure, dissolved in 2 ml of N, N-dimethylformamide, cooled to 0 ° C., and 37 mg (0.12 mmol) of the compound obtained in Preparation Example 56 and 55 mg (0.144 mmol) of HATU were added thereto. 0.5 ml (excess) of N, N-diisopropylethylamine was added thereto, and the temperature was raised to room temperature and stirred for 4 hours. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography to give 47 mg of the title compound in 80% yield.

1H-NMR (300 MHz, CDCl3); 7.51∼7.16 (14H, m), 6.45 (1H, d, J = 7.82), 4.42∼4.25 (1H, m), 4.27 (2H, s), 4.00∼3.86 (2H, m), 3.52∼3.35 (2H, m), 3.11 (3H, s), 3.05∼2.95 (1H, m)
1 H-NMR (300 MHz, CDCl 3 ); 7.51 to 7.16 (14H, m), 6.45 (1H, d, J = 7.82), 4.42 to 4.25 (1H, m), 4.27 (2H, s), 4.00 to 3.86 (2H, m), 3.52 to 3.35 (2H , m), 3.11 (3H, s), 3.05-2.95 (1H, m)

[제조예 155][Production Example 155]

N-[(1S,2R)-3-아미노-1-벤질-2-히드록시프로필]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-[(1S,2R)-3-amino-1-benzyl-2-hydroxypropyl]-3-[(benzylsulfonyl)(methyl)amino]benzamide N - [(1 S, 2 R) -3- amino-1-benzyl-2-hydroxypropyl] -3 - Preparation of [(benzyl-sulfonyl) (methyl) amino] benzamide: N - [(1 S , 2 R ) -3-amino-1-benzyl-2-hydroxypropyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 실시예 38에서 얻은 화합물 대신에 상기 제조예 154에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 39와 동일한 방법으로 실시하여, 표제 화합물 40 ㎎을 90% 수율로 얻었다.40 mg of the title compound was obtained in 90% yield by the same method as Example 39 except for using the compound obtained in Preparation Example 154 instead of the compound obtained in Example 38.

1H-NMR (300 MHz, CDCl3); 7.56 (1H, s), 7.54∼7.10 (14H, m), 5.31 (3H, bs), 4.45∼3.85 (4H, m), 3.20∼2.78 (4H, m), 2.98 (3H, s)
1 H-NMR (300 MHz, CDCl 3 ); 7.56 (1H, s), 7.54-7.10 (14H, m), 5.31 (3H, bs), 4.45-3.85 (4H, m), 3.20-2.78 (4H, m), 2.98 (3H, s)

[실시예 110]Example 110

N-{(1S,2R)-1-벤질-2-히드록시-3-[(3-메톡시벤조일)아미노]프로필}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzoyl)amino]propyl}-3-[(benzylsulfonyl)(methyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(3-methoxybenzoyl) amino] propyl} -3 - [(benzyl-sulfonyl) (methyl) amino] benzamide Preparation of: N -{(1 S , 2 R ) -1-benzyl-2-hydroxy-3-[(3-methoxybenzoyl) amino] propyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide

상기 제조예 155에서 얻은 화합물 20 ㎎(0.0428 mmol)을 디클로로메탄 (1 ㎖)에 녹이고 0℃로 냉각하여, 트리에틸아민 11.9 ㎖(0.0856 mmol)과 3-메톡시벤조일 클로라이드 6.3 ㎖(0.0449 mmol)를 가했다. 4 시간 동안 교반한 후 디클로로메탄으로 희석하고 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 후 컬럼크로마토그래피로 정제하여 표제 화합물 15 ㎎을 58% 수율로 얻었다.20 mg (0.0428 mmol) of the compound obtained in Preparation Example 155 was dissolved in dichloromethane (1 mL), cooled to 0 ° C., and 11.9 mL (0.0856 mmol) of triethylamine and 6.3 mL (0.0449 mmol) of 3-methoxybenzoyl chloride were obtained. Added. After stirring for 4 hours, the mixture was diluted with dichloromethane and washed with 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography to give 15 mg of the title compound in 58% yield.

1H-NMR (300 MHz, CDCl3); 7.89∼7.76 (1H, m), 7.52∼7.18 (17H, m), 7.10∼6.98 (1H, m), 6.34∼6.21 (1H, m), 4.78∼4.51 (1H, m), 4.48∼4.32 (1H, m), 4.27 (2H, s), 4.19∼4.12 (1H, m), 3.86 (3H, s), 3.82∼3.76 (1H, m), 3.29∼3.08 (6H, m)1 H-NMR (300 MHz, CDCl 3 ); 7.89-7.72 (1H, m), 7.52-7.18 (17H, m), 7.10-6.98 (1H, m), 6.34-6.21 (1H, m), 4.78-4.51 (1H, m), 4.48-4.32 (1H) , m), 4.27 (2H, s), 4.19-4.12 (1H, m), 3.86 (3H, s), 3.82-3.76 (1H, m), 3.29-3.08 (6H, m)

FAB MS (m/e) = 602 [M+H]+
FAB MS (m / e) = 602 [M + H] < + >

[실시예 111]Example 111

N-{(1S,2R)-1-벤질-2-히드록시-3-[(페닐술포닐)아미노]프로필}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(phenylsulfonyl)amino]propyl}-3-[(benzylsulfonyl)(methyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(phenylsulfonyl) amino] propyl} -3 - [(benzyl-sulfonyl) (methyl) amino] benzamide Preparation of : N -{(1 S , 2 R ) -1-benzyl-2-hydroxy-3-[(phenylsulfonyl) amino] propyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide

3-메톡시벤조일 클로라이드 대신에 벤젠술포닐클로라이드를 사용한 것을 제외하고는, 실시예 110과 동일한 방법으로 실시하여, 표제 화합물 14 ㎎을 48% 수율로 얻었다.14 mg of the title compound was obtained in 48% yield by the same method as Example 110 except that benzenesulfonylchloride was used instead of 3-methoxybenzoyl chloride.

1H-NMR (300 MHz, CDCl3); 7.92∼7.79 (2H, m), 7.58∼7.17 (17H, m), 6.30 (1H, d, J = 8.19), 6.08∼5.91 (1H, m), 4.39∼4.18 (1H, m), 4.27 (2H, s), 3.88∼3.73 (1H, m), 3.24∼2.86 (4H, m), 3.12 (3H, s)1 H-NMR (300 MHz, CDCl 3 ); 7.92-7.79 (2H, m), 7.58-7.17 (17H, m), 6.30 (1H, d, J = 8.19), 6.08-5.91 (1H, m), 4.39-4.18 (1H, m), 4.27 (2H , s), 3.88 to 3.73 (1H, m), 3.24 to 2.86 (4H, m), 3.12 (3H, s)

FAB MS (m/e) = 608 [M+H]+
FAB MS (m / e) = 608 [M + H] < + >

[실시예 112]Example 112

N-((1S,2R)-1-벤질-2-히드록시-3-{[2-(트리플루오로메틸)벤질]아미노}프로필)-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(trifluoromethyl)benzyl]amino}propyl)-3-[(benzylsulfonyl)(methyl)amino]benzamide N - ((1 S, 2 R) -1- benzyl-2-hydroxy-3 - {[2- (trifluoromethyl) benzyl] amino} propyl) -3 - [(benzyl-sulfonyl) (methyl) Preparation of amino] benzamide: N -((1 S , 2 R ) -1-benzyl-2-hydroxy-3-{[2- (trifluoromethyl) benzyl] amino} propyl) -3-[(benzylsulfonyl) (methyl ) amino] benzamide

상기 제조예 155에서 얻은 화합물 20 ㎎(0.0428 mmol)과 2-트리플루오로벤즈알데히드 6 ㎎(0.0342 mmol)를 1,2-디클로로에탄 0.5 ㎖에 녹였다. 이 반응용액에 소듐 트리아세톡시보로하이드라이드 11 ㎎(0.0514 mmol)를 넣은 후 상온에서 16 시간 동안 교반하였다. 에틸아세테이트로 묽힌 후, 포화탄산나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 후 컬럼크로마토그래피로 정제하여 표제 화합물 16 ㎎을 60% 수율로 얻었다.20 mg (0.0428 mmol) of the compound obtained in Preparation Example 155 and 6 mg (0.0342 mmol) of 2-trifluorobenzaldehyde were dissolved in 0.5 ml of 1,2-dichloroethane. 11 mg (0.0514 mmol) of sodium triacetoxyborohydride was added to the reaction solution, followed by stirring at room temperature for 16 hours. After diluting with ethyl acetate, the mixture was washed with saturated aqueous sodium carbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography to give 16 mg of the title compound in 60% yield.

1H-NMR (300 MHz, CDCl3); 7.71∼7.08 (17H, m), 6.75 (1H, d, J = 7.68), 4.49∼4.30 (1H, m), 4.26 (2H, s), 3.99 (2H, s), 3.78∼3.62 (1H, m), 3.13 (3H, s), 3.12∼2.93 (2H, m), 2.90∼2.78 (2H, m), 2.33 (2H, bs)1 H-NMR (300 MHz, CDCl 3 ); 7.71-7.08 (17H, m), 6.75 (1H, d, J = 7.68), 4.49-4.30 (1H, m), 4.26 (2H, s), 3.99 (2H, s), 3.78-3.62 (1H, m ), 3.13 (3H, s), 3.12-2.93 (2H, m), 2.90-2.78 (2H, m), 2.33 (2H, bs)

FAB MS (m/e) = 626 [M+H]+
FAB MS (m / e) = 626 [M + H] < + >

[실시예 113]Example 113

N-((1S,2R)-1-벤질-2-히드록시-3-{[3-(투리플루오로메틸)벤질]아미노}프로필)-3-[( 벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-3-[(benzylsulfonyl)(methyl)amino]benzamide N - ((1 S, 2 R) -1- benzyl-2-hydroxy-3 - {[3- (2-fluoro Turi) benzyl] amino} propyl) -3 - [(benzyl-sulfonyl) (methyl) Preparation of amino] benzamide: N -((1 S , 2 R ) -1-benzyl-2-hydroxy-3-{[3- (trifluoromethyl) benzyl] amino} propyl) -3-[(benzylsulfonyl) (methyl ) amino] benzamide

2-트리플루오로벤즈알데히드 대신에 3-트리플루오로벤즈알데히드를 사용한 것을 제외하고는, 실시예 112와 동일한 방법으로 실시하여, 표제 화합물 15 ㎎을 58% 수율로 얻었다.15 mg of the title compound was obtained in 58% yield by the same method as Example 112 except that 3-trifluorobenzaldehyde was used instead of 2-trifluorobenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.69∼7.17 (17H, m), 6.72 (1H, d, J = 8.58), 4.43∼4.28 (1H, m), 4.27 (2H, s), 3.93∼3.78 (2H, m), 3.73∼3.61 (1H, m), 3.13 (3H, s), 3.02∼2.90 (2H, m), 2.80∼2.71 (2H, m), 2.39 (2H, bs)1 H-NMR (300 MHz, CDCl 3 ); 7.69 to 7.17 (17H, m), 6.72 (1H, d, J = 8.58), 4.43 to 4.28 (1H, m), 4.27 (2H, s), 3.93 to 3.78 (2H, m), 3.73 to 3.61 (1H , m), 3.13 (3H, s), 3.02-2.90 (2H, m), 2.80-2.71 (2H, m), 2.39 (2H, bs)

FAB MS (m/e) = 626 [M+H]+
FAB MS (m / e) = 626 [M + H] < + >

[실시예 114]Example 114

N-{(1S,2R)-1-벤질-3-[(3-브로모벤질)아미노]-2-히드록시프로필}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-3-[(3-bromobenzyl)amino]-2-hydroxypropyl}-3-[(benzylsulfonyl)(methyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-3 - [(3-bromobenzyl) amino] -2-hydroxypropyl} -3 - [(benzyl-sulfonyl) (methyl) amino] benzamide Preparation of: N -{(1 S , 2 R ) -1-benzyl-3-[(3-bromobenzyl) amino] -2-hydroxypropyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide

2-트리플루오로벤즈알데히드 대신에 3-브로모벤즈알데히드를 사용한 것을 제외하고는, 실시예 112와 동일한 방법으로 실시하여, 표제 화합물 18 ㎎을 65% 수율로 얻었다.18 mg of the title compound was obtained in 65% yield by the same method as Example 112 except that 3-bromobenzaldehyde was used instead of 2-trifluorobenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.60∼7.11 (17H, m), 6.81 (1H, d, J = 8.38), 4.46∼4.30 (1H, m), 4.27 (2H, s), 3.89∼3.61 (3H, m), 3.13 (3H, s), 3.09∼2.97 (2H, m), 2.83∼2.72 (2H, m), 2.45 (2H, bs)1 H-NMR (300 MHz, CDCl 3 ); 7.60-7.71 (17H, m), 6.81 (1H, d, J = 8.38), 4.46-4.30 (1H, m), 4.27 (2H, s), 3.89-3.61 (3H, m), 3.13 (3H, s ), 3.09 to 2.97 (2H, m), 2.83 to 2.72 (2H, m), 2.45 (2H, bs)

FAB MS (m/e) = 636 [M+H]+
FAB MS (m / e) = 636 [M + H] < + >

[제조예 156][Production Example 156]

N-[(1S,2R)-3-아지도-1-벤질-2-히드록시프로필]-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-[(1S,2R)-3-azido-1-benzyl-2-hydroxypropyl]-3-[methyl(propylsulfonyl)amino]benzamide N - [(1 S, 2 R) -3-azido-1-benzyl-2-hydroxypropyl] -3-Preparation of [methyl (propyl-sulfonyl) amino] benzamide: N - [(1 S, 2 R ) -3-azido-1-benzyl-2-hydroxypropyl] -3- [methyl (propylsulfonyl) amino] benzamide

상기 제조예 56에서 얻은 화합물 대신에 상기 제조예 29에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 154와 동일한 방법으로 실시하여, 표제 화합물 45 ㎎을 85% 수율로 얻었다.45 mg of the title compound was obtained in 85% yield by the same method as Preparation Example 154, except that the compound obtained in Preparation Example 29 was used instead of the compound obtained in Preparation Example 56.

1H-NMR (300 MHz, CDCl3); 7.64 (1H, s), 7.53 (1H, d, J = 7.42), 7.42∼7.14 (7H, m), 6.38 (1H, d, J = 7.59), 4.43∼4.30 (1H, m), 3.99∼3.83 (1H, m), 3.76∼3.66 (1H, m), 3.49∼3.35 (2H, m), 3.32 (3H, s), 3.04∼2.82 (4H, m), 1.89∼1.71 (2H, m), 1.03 (3H, t, J = 7.43)
1 H-NMR (300 MHz, CDCl 3 ); 7.64 (1H, s), 7.53 (1H, d, J = 7.42), 7.42-7.14 (7H, m), 6.38 (1H, d, J = 7.59), 4.43-4.30 (1H, m), 3.99-3.83 (1H, m), 3.76-3.66 (1H, m), 3.49-3.35 (2H, m), 3.32 (3H, s), 3.04-2.82 (4H, m), 1.89-1.71 (2H, m), 1.03 (3H, t, J = 7.43)

[제조예 157]Preparation Example 157

N-[(1S,2R)-3-아미노-1-벤질-2-히드록시프로필]-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-[(1S,2R)-3-amino-1-benzyl-2-hydroxypropyl]-3- [methyl(propylsulfonyl)amino]benzamide N - Preparation of [(1 S, 2 R) -3-amino-1-benzyl-2-hydroxypropyl] -3- [methyl (propyl-sulfonyl) amino] benzamide: N - [(1 S, 2 R ) -3-amino-1-benzyl-2-hydroxypropyl] -3- [methyl (propylsulfonyl) amino] benzamide

상기 실시예 38에서 얻은 화합물 대신에 상기 제조예 156에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 39와 동일한 방법으로 실시하여, 표제 화합물 35 ㎎을 91% 수율로 얻었다.Except for using the compound obtained in Preparation Example 156 instead of the compound obtained in Example 38, the same procedure as in Example 39 was carried out to obtain 35 mg of the title compound in 91% yield.

1H-NMR (300 MHz, CDCl3); 7.64 (1H, s), 7.56∼7.40 (2H, m), 7.39∼7.05 (7H, m), 4.48∼4.39 (1H, m), 3.65∼3.50 (1H, m), 3.31 (3H, s), 3.10∼2.78 (6H, m), 2.70 (3H, bs), 1.91∼1.71 (2H, m), 1.01 (3H, t, J = 7.44)
1 H-NMR (300 MHz, CDCl 3 ); 7.64 (1H, s), 7.56-7.40 (2H, m), 7.39-7.05 (7H, m), 4.48-4.39 (1H, m), 3.65-3.50 (1H, m), 3.31 (3H, s), 3.10-2.78 (6H, m), 2.70 (3H, bs), 1.91-2.71 (2H, m), 1.01 (3H, t, J = 7.44)

[실시예 115]Example 115

N-((1S,2R)-1-벤질-2-히드록시-3-{[3-(트리플루오로메톡시)벤질]아미노}프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethoxy)benzyl]amino}propyl)-3-[methyl(propylsulfonyl)amino]benzamide N - ((1 S, 2 R) -1- benzyl-2-hydroxy-3 - {[3- (trifluoromethoxy) benzyl] amino} propyl) -3- [methyl (propyl-sulfonyl) amino] Preparation of Benzamide: N -((1 S , 2 R ) -1-benzyl-2-hydroxy-3-{[3- (trifluoromethoxy) benzyl] amino} propyl) -3- [methyl (propylsulfonyl) amino] benzamide

상기 제조예 157에서 얻은 화합물 20 ㎎(0.0477 mmol)과 3-트리플루오로메톡시벤즈알데히드 7 ㎎(0.0342 mmol)를 1,2-디클로로에탄 0.5 ㎖에 녹였다. 이 반응용액에 소듐 트리아세톡시보로하이드라이드 11 ㎎(0.0514 mmol)를 넣은 후 상온에서 16 시간 동안 교반하였다. 에틸아세테이트로 묽힌 후, 포화탄산나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 후 컬럼크로마토그래피로 정제하여 표제 화합물 20 ㎎을 71% 수율로 얻었다. 20 mg (0.0477 mmol) of the compound obtained in Preparation Example 157 and 7 mg (0.0342 mmol) of 3-trifluoromethoxybenzaldehyde were dissolved in 0.5 ml of 1,2-dichloroethane. 11 mg (0.0514 mmol) of sodium triacetoxyborohydride was added to the reaction solution, followed by stirring at room temperature for 16 hours. After diluting with ethyl acetate, the mixture was washed with saturated aqueous sodium carbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography to give 20 mg of the title compound in 71% yield.                     

1H-NMR (300 MHz, CDCl3); 7.71∼7.61 (1H, m), 7.56∼7.09 (13H, m), 6.99∼6.89 (1H, m), 4.48∼4.30 (1H, m), 3.91∼3.60 (3H, m), 3.33 (3H, s), 3.07∼2.81 (4H, m), 2.80∼2.71 (2H, m), 2.71 (2H, bs), 1.91∼1.71 (2H, m), 1.02 (3H, t, J = 7.45)1 H-NMR (300 MHz, CDCl 3 ); 7.71-7.61 (1H, m), 7.56-7.09 (13H, m), 6.99-6.89 (1H, m), 4.48-4.30 (1H, m), 3.91-3.60 (3H, m), 3.33 (3H, s ), 3.07 to 2.81 (4H, m), 2.80 to 2.71 (2H, m), 2.71 (2H, bs), 1.91 to 1.71 (2H, m), 1.02 (3H, t, J = 7.45)

FAB MS (m/e) = 594 [M+H]+
FAB MS (m / e) = 594 [M + H] < + >

[실시예 116]Example 116

N-{(1S,2R)-1-벤질-2-히드록시-3-[(3-페녹시벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-phenoxybenzyl)amino]propyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(3-phenoxybenzyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide Preparation of : N -{(1 S , 2 R ) -1-benzyl-2-hydroxy-3-[(3-phenoxybenzyl) amino] propyl} -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 3-페녹시벤즈알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 20 ㎎을 70% 수율로 얻었다.20 mg of the title compound was obtained in 70% yield by the same method as Example 115 except for using 3-phenoxybenzaldehyde instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.68 (1H, s), 7.58∼7.39 (2H, m), 7.38∼7.15 (13H, m), 7.14∼6.82 (3H, m), 4.48∼4.32 (1H, m), 3.85∼3.59 (3H, m), 3.32 (3H, s), 3.09∼2.83 (4H, m), 2.82∼2.74 (2H, m), 2.47 (2H, bs), 1.89∼1.72 (2H, m), 1.01 (3H, t, J = 7.42)1 H-NMR (300 MHz, CDCl 3 ); 7.68 (1H, s), 7.58-7.39 (2H, m), 7.38-7.15 (13H, m), 7.14-6.82 (3H, m), 4.48-4.32 (1H, m), 3.85-3.59 (3H, m ), 3.32 (3H, s), 3.09 to 2.83 (4H, m), 2.82 to 2.74 (2H, m), 2.47 (2H, bs), 1.89 to 1.72 (2H, m), 1.01 (3H, t, J = 7.42)

FAB MS (m/e) = 602 [M+H]+
FAB MS (m / e) = 602 [M + H] < + >

[실시예 117]Example 117

N-{(1S,2R)-1-벤질-2-히드록시-3-[(3-히드록시벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-hydroxybenzyl)amino]propyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(3-hydroxybenzyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide Preparation of : N -{(1 S , 2 R ) -1-benzyl-2-hydroxy-3-[(3-hydroxybenzyl) amino] propyl} -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 3-히드록시벤즈알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 17 ㎎을 71% 수율로 얻었다.17 mg of the title compound was obtained in 71% yield by the same method as Example 115 except for using 3-hydroxybenzaldehyde instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.65 (1H, s), 7.52∼7.37 (2H, m), 7.36∼7.06 (8H, m), 6.89∼6.68 (3H, m), 4.45∼4.29 (1H, m), 3.80∼3.58 (3H, m), 3.60 (2H, bs), 3.48 (1H, s), 3.29 (3H, s), 2.99∼2.84 (4H, m), 2.83∼2.72 (2H, m), 1.89∼1.70 (2H, m), 1.01 (3H, t, J = 7.41)1 H-NMR (300 MHz, CDCl 3 ); 7.65 (1H, s), 7.52-7.37 (2H, m), 7.36-7.06 (8H, m), 6.89-6.68 (3H, m), 4.45-4.29 (1H, m), 3.80-3.58 (3H, m ), 3.60 (2H, bs), 3.48 (1H, s), 3.29 (3H, s), 2.99-2.84 (4H, m), 2.83-2.72 (2H, m), 1.89-1.70 (2H, m), 1.01 (3H, t, J = 7.41)

FAB MS (m/e) = 526 [M+H]+
FAB MS (m / e) = 526 [M + H] < + >

[실시예 118]Example 118

N-{(1S,2R)-1-벤질-2-히드록시-3-[(4-메톡시벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(4-methoxybenzyl)amino]propyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(4-methoxybenzyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide Preparation of : N -{(1 S , 2 R ) -1-benzyl-2-hydroxy-3-[(4-methoxybenzyl) amino] propyl} -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 4-메톡시벤즈알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 16 ㎎을 65% 수율로 얻었다.16 mg of the title compound was obtained in 65% yield by the same method as Example 115 except that 4-methoxybenzaldehyde was used instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.69 (1H, s), 7.55∼7.08 (11H, m), 6.91∼6.78 (2H, m), 4.45∼4.29 (1H, m), 3.86∼3.59 (3H, m), 3.79 (3H, s), 3.32 (3H, s), 3.12∼2.79 (8H, m), 1.90∼1.69 (2H, m), 1.01 (3H, t, J = 7.41)1 H-NMR (300 MHz, CDCl 3 ); 7.69 (1H, s), 7.55-7.08 (11H, m), 6.91-6.68 (2H, m), 4.45-4.29 (1H, m), 3.86-3.59 (3H, m), 3.79 (3H, s), 3.32 (3H, s), 3.12-2.79 (8H, m), 1.90-1.69 (2H, m), 1.01 (3H, t, J = 7.41)

FAB MS (m/e) = 540 [M+H]+
FAB MS (m / e) = 540 [M + H] < + >

[실시예 119]Example 119

N-{(1S,2R)-1-벤질-2-히드록시-3-[(2-메톡시벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-methoxybenzyl)amino]propyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(2-methoxybenzyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide Preparation of : N -{(1 S , 2 R ) -1-benzyl-2-hydroxy-3-[(2-methoxybenzyl) amino] propyl} -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 2-메톡시벤즈알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 17 ㎎을 68% 수율로 얻었다.17 mg of the title compound was obtained in 68% yield by the same method as Example 115 except for using 2-methoxybenzaldehyde instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.70 (1H, s), 7.62∼7.49 (2H, m), 7.48∼7.12 (9H, m), 7.01∼6.82 (2H, m), 4.52∼4.36 (1H, m), 3.93∼3.63 (3H, m), 3.80 (3H, s), 3.31 (3H, s), 3.18∼2.71 (8H, m), 1.90∼1.68 (2H, m), 1.01 (3H, t, J = 7.38)1 H-NMR (300 MHz, CDCl 3 ); 7.70 (1H, s), 7.62-7.49 (2H, m), 7.48-7.72 (9H, m), 7.01-6.82 (2H, m), 4.52-4.36 (1H, m), 3.93-3.63 (3H, m ), 3.80 (3H, s), 3.31 (3H, s), 3.18-2.71 (8H, m), 1.90-1.68 (2H, m), 1.01 (3H, t, J = 7.38)

FAB MS (m/e) = 540 [M+H]+
FAB MS (m / e) = 540 [M + H] < + >

[제조예 158][Production Example 158]

3-에톡시벤즈알데히드의 제조: 3-EthoxybenzaldehydePreparation of 3-ethoxybenzaldehyde: 3-Ethoxybenzaldehyde

3-히드록시벤즈알데히드 1.0 g(8.19 mmol)를 N,N-디메틸포름알데히드 40 ㎖에 녹인 후 탄산칼륨 1.29 g(16.31 mmol)과 아이오도에탄 1.95 ㎖(9.00 mmol)을 넣었다. 상온에서 16 시간 동안 교반한 후 감압 증류하여 용매를 제거하였다. 농축액을 에틸아세테이트에 녹이고 물과 소금물로 씻었다. 감압 증류하여 용매를 제거한 후 농축액을 컬럼크로마토그래피로 정제하여 표제 화합물 1.05 g을 85% 수율로 얻었다. 1.0 g (8.19 mmol) of 3-hydroxybenzaldehyde was dissolved in 40 ml of N, N-dimethylformaldehyde, followed by adding 1.29 g (16.31 mmol) of potassium carbonate and 1.95 ml (9.00 mmol) of iodoethane. After stirring for 16 hours at room temperature, the solvent was removed by distillation under reduced pressure. The concentrate was dissolved in ethyl acetate and washed with water and brine. After distillation under reduced pressure to remove the solvent, the concentrate was purified by column chromatography to give 1.05 g of the title compound in 85% yield.

1H-NMR (300 MHz, CDCl3); 9.62 (1H, s), 7.50∼7.31 (3H, m), 7.22∼7.10 (1H, m), 4.09 (2H, q, J = 6.97), 1.44 (3H, t, J = 6.99)
1 H-NMR (300 MHz, CDCl 3 ); 9.62 (1H, s), 7.50-7.31 (3H, m), 7.22-7.10 (1H, m), 4.09 (2H, q, J = 6.97), 1.44 (3H, t, J = 6.99)

[실시예 120]Example 120

N-{(1S,2R)-1-벤질-3-[(3-에톡시벤질)아미노]-2-히드록시프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-3-[(3-ethoxybenzyl)amino]-2-hydroxypropyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-3 - [amino (3-ethoxy-benzyl) -2-hydroxy-propyl} Preparation of 3- [methyl (propyl-sulfonyl) amino] benzamide : N -{(1 S , 2 R ) -1-benzyl-3-[(3-ethoxybenzyl) amino] -2-hydroxypropyl} -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 제조예 158에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 17 ㎎을 65% 수율로 얻었다.17 mg of the title compound was obtained in 65% yield by the same method as Example 115 except for using the compound obtained in Preparation Example 158 instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.69 (1H, s), 7.58∼7.02 (10H, m), 6.92∼6.71 (3H, m), 4.48∼4.31 (1H, m), 3.40 (2H, q, J = 6.87), 3.87∼3.56 (3H, m), 3.33 (3H, s), 3.07∼2.69 (6H, m), 2.62 (2H, bs), 1.90∼1.70 (2H, m), 1.40 (3H, t, J = 6.93), 1.02 (3H, t, J = 7.35)1 H-NMR (300 MHz, CDCl 3 ); 7.69 (1H, s), 7.58-7.02 (10H, m), 6.92-6.71 (3H, m), 4.48-4.31 (1H, m), 3.40 (2H, q, J = 6.87), 3.87-3.56 (3H , m), 3.33 (3H, s), 3.07-2.69 (6H, m), 2.62 (2H, bs), 1.90-1.70 (2H, m), 1.40 (3H, t, J = 6.93), 1.02 (3H , t, J = 7.35)

FAB MS (m/e) = 554 [M+H]+
FAB MS (m / e) = 554 [M + H] < + >

[제조예 159][Production Example 159]

3-(알릴옥시)벤즈알데히드의 제조: 3-(allyloxy)benzaldehydePreparation of 3- (allyloxy) benzaldehyde: 3- (allyloxy) benzaldehyde

아이오도에탄 대신에 알릴브로마이드를 사용한 것을 제외하고는, 제조예 158과 동일한 방법으로 실시하여, 표제 화합물 1.14 g을 86% 수율로 얻었다.Except for using allyl bromide instead of iodoethane, the same procedure as in Production Example 158 was carried out to obtain 1.14 g of the title compound in 86% yield.

1H-NMR (300 MHz, CDCl3); 9.97 (1H, s), 7.49∼7.31 (3H, m), 7.24∼7.11 (1H, m), 6.14∼5.95 (1H, m), 5.48∼5.19 (2H, m), 4.66∼4.52 (2H, m)
1 H-NMR (300 MHz, CDCl 3 ); 9.97 (1H, s), 7.49-7.31 (3H, m), 7.24-7.71 (1H, m), 6.14-5.95 (1H, m), 5.48-5.19 (2H, m), 4.66-4.52 (2H, m )

[실시예 121]Example 121

N-((1S,2R)-3-{[3-(알릴옥시)벤질]아미노}-1-벤질-2-히드록시프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-((1S,2R)-3-{[3-(allyloxy)benzyl]amino}-1-benzyl-2-hydroxypropyl)-3-[methyl(propylsulfonyl)amino]benzamide N - ((1 S, 2 R) -3 - {[3- ( allyloxy) benzyl] amino} -1-benzyl-2-hydroxypropyl) -3- [methyl (propyl-sulfonyl) amino] benzamide Preparation of: N -((1 S , 2 R ) -3-{[3- (allyloxy) benzyl] amino} -1-benzyl-2-hydroxypropyl) -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 제조예 159에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 19 ㎎을 69% 수율로 얻었다. 19 mg of the title compound was obtained in 69% yield by the same method as Example 115 except for using the compound obtained in Preparation Example 159 instead of 3-trifluoromethoxybenzaldehyde.                     

1H-NMR (300 MHz, CDCl3); 7.69 (1H, s), 7.58∼7.01 (10H, m), 6.94∼6.70 (3H, m), 6.12∼5.92 (1H, m), 5.45∼5.20 (2H, m), 4.55∼4.31 (3H, m), 3.95∼3.59 (3H, m), 3.32 (3H, s), 3.10∼2.61 (8H, m), 1.01 (3H, t, J = 7.37)1 H-NMR (300 MHz, CDCl 3 ); 7.69 (1H, s), 7.58-7.01 (10H, m), 6.94-6.70 (3H, m), 6.12-5.92 (1H, m), 5.45-5.20 (2H, m), 4.55-4.31 (3H, m ), 3.95-3.59 (3H, m), 3.32 (3H, s), 3.10-2.61 (8H, m), 1.01 (3H, t, J = 7.37)

FAB MS (m/e) = 566 [M+H]+
FAB MS (m / e) = 566 [M + H] < + >

[제조예 160][Production Example 160]

3-(벤질옥시)벤즈알데히드의 제조: 3-(benzyloxy)benzaldehydePreparation of 3- (benzyloxy) benzaldehyde: 3- (benzyloxy) benzaldehyde

아이오도에탄 대신에 벤질브로마이드를 사용한 것을 제외하고는, 제조예 158과 동일한 방법으로 실시하여, 표제 화합물 1.46 g을 84% 수율로 얻었다.Except for using benzyl bromide instead of iodoethane, the same procedure as in Production Example 158 was carried out to obtain 1.46 g of the title compound in 84% yield.

1H-NMR (300 MHz, CDCl3); 9.95 (1H, s), 7.50∼7.18 (9H, m), 5.10 (2H, s)
1 H-NMR (300 MHz, CDCl 3 ); 9.95 (1H, s), 7.50-7.18 (9H, m), 5.10 (2H, s)

[실시예 122]Example 122

N-((1S,2R)-1-벤질-3-{[3-(벤질옥시)벤질]아미노}-2-히드록시프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-((1S,2R)-1-benzyl-3-{[3-(benzyloxy)benzyl]amino}-2-hydroxypropyl)-3-[methyl(propylsulfonyl)amino]benzamide N - (benzyl -1- -3 (1 S, 2 R) - {[3- ( benzyloxy) benzyl] amino} -2-hydroxypropyl) -3- [methyl (propyl-sulfonyl) amino] benzamide Preparation of: N -((1 S , 2 R ) -1-benzyl-3-{[3- (benzyloxy) benzyl] amino} -2-hydroxypropyl) -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 제조예 160에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 19 ㎎을 69% 수율로 얻었다. 19 mg of the title compound was obtained in 69% yield by the same method as Example 115 except for using the compound obtained in Preparation Example 160 instead of 3-trifluoromethoxybenzaldehyde.                     

1H-NMR (300 MHz, CDCl3); 7.69 (1H, s), 7.53∼7.07 (15H, m), 7.02∼6.81 (3H, m), 5.04 (2H, s), 4.48∼4.30 (1H, m), 3.88∼3.61 (3H, m), 3.30 (3H, s), 3.09∼2.62 (8H, m), 1.90∼1.72 (2H, m), 1.40 (3H, t, J = 6.93), 1.01 (3H, t, J = 7.41)1 H-NMR (300 MHz, CDCl 3 ); 7.69 (1H, s), 7.53-7.07 (15H, m), 7.02-6.81 (3H, m), 5.04 (2H, s), 4.48-4.30 (1H, m), 3.88-3.61 (3H, m), 3.30 (3H, s), 3.09-2.62 (8H, m), 1.90-1.72 (2H, m), 1.40 (3H, t, J = 6.93), 1.01 (3H, t, J = 7.41)

FAB MS (m/e) = 616 [M+H]+
FAB MS (m / e) = 616 [M + H] < + >

[제조예 161][Manufacture Example 161]

3-포르밀페닐 벤조에이트의 제조: 3-formylphenyl benzoatePreparation of 3-formylphenyl benzoate: 3-formylphenyl benzoate

아이오도에탄 대신에 벤조일클로라이드를 사용한 것을 제외하고는, 제조예 158과 동일한 방법으로 실시하여, 표제 화합물 1.24 g을 67% 수율로 얻었다.Except for using benzoyl chloride instead of iodoethane, the same procedure as in Production Example 158 was carried out to obtain 1.24 g of the title compound in 67% yield.

1H-NMR (300 MHz, CDCl3); 10.04 (1H, s), 8.24∼7.93 (2H, m), 7.82∼7.40 (7H, m)
1 H-NMR (300 MHz, CDCl 3 ); 10.04 (1H, s), 8.24 to 7.73 (2H, m), 7.82 to 7.40 (7H, m)

[실시예 123]Example 123

3-({[(2R,3S)-2-히드록시-3-({3-[메틸(프로필술포닐)아미노]벤조일}아미노)-4-페닐부틸]아미노}메틸)페닐 벤조에이트의 제조: 3-({[(2R,3S)-2-hydroxy-3-({3-[methyl(propylsulfonyl)amino]benzoyl}amino)-4-phenylbutyl]amino}methyl)phenyl benzoate 3 - ({[(2 R , 3 S) -2- hydroxy-3 - ({3- [methyl (propyl-sulfonyl) amino] benzoyl} amino) -4-phenylbutyl] amino} methyl) phenyl benzoate Preparation of: 3 - ({[(2 R, 3 S) -2-hydroxy-3 - ({3- [methyl (propylsulfonyl) amino] benzoyl} amino) -4-phenylbutyl] amino} methyl) phenyl benzoate

3-트리플루오로메톡시벤즈알데히드 대신에 제조예 161에서 얻은 화합물을 사 용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 21 ㎎을 70% 수율로 얻었다.21 mg of the title compound was obtained in 70% yield by the same method as Example 115 except for using the compound obtained in Preparation Example 161 instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 8.20∼8.16 (2H, m), 7.70∼6.96 (17H, m), 4.48∼4.32 (1H, m), 3.88 (1H, d, J =14.51), 3.84 (1H, d, J= 14.49), 3.72∼3.60 (1H, m), 3.31 (3H, s), 3.11∼2.78 (6H, m), 2.00 (2H, bs), 1.89∼1.73 (2H, m), 1.01 (3H, t, J = 7.44)1 H-NMR (300 MHz, CDCl 3 ); 8.20-8.16 (2H, m), 7.70-6.96 (17H, m), 4.48-4.32 (1H, m), 3.88 (1H, d, J = 14.51), 3.84 (1H, d, J = 14.49), 3.72 -3.60 (1H, m), 3.31 (3H, s), 3.11-2.78 (6H, m), 2.00 (2H, bs), 1.89-1.73 (2H, m), 1.01 (3H, t, J = 7.44)

FAB MS (m/e) = 630 [M+H]+
FAB MS (m / e) = 630 [M + H] < + >

[제조예 162][Production Example 162]

3-(디메틸아미노)벤즈알데히드: 3-(dimethylamino)benzaldehyde3- (dimethylamino) benzaldehyde: 3- (dimethylamino) benzaldehyde

3-디메틸아미노벤질알코올 0.3 g(1.98 mmol)을 디클로로메탄 10 ㎖에 녹이고 피리디늄 디크로메이트 1.11 g(2.97 mmol)를 상온에서 넣었다. 20 시간 동안 교반 후 혼합물을 에테르로 희석하고 침전물을 걸러주었다. 여과액을 감압 농축 후 농축액을 컬럼크로마토그래피로 정제하여 표제 화합물 221 ㎎을 75% 수율로 얻었다. 0.3 g (1.98 mmol) of 3-dimethylaminobenzyl alcohol was dissolved in 10 mL of dichloromethane, and 1.11 g (2.97 mmol) of pyridinium dichromate was added at room temperature. After stirring for 20 hours the mixture was diluted with ether and the precipitate was filtered off. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to give 221 mg of the title compound in 75% yield.

1H-NMR (300 MHz, CDCl3); 9.95 (1H, s), 7.38 (1H, t, J = 7.89), 7.20∼7.18 (2H, m), 6.99∼6.96 (1H, m), 3.01 (6H, s)
1 H-NMR (300 MHz, CDCl 3 ); 9.95 (1H, s), 7.38 (1H, t, J = 7.89), 7.20-7.18 (2H, m), 6.99-6.96 (1H, m), 3.01 (6H, s)

[실시예 124]Example 124

N-((1S,2R)-1-벤질-3-{[3-(디메틸아미노)벤질]아미노}-2-히드록시프로필)-3-[메틸( 프로필술포닐)아미노]벤즈아미드의 제조: N-((1S,2R)-1-benzyl-3-{[3-(dimethylamino)benzyl]amino}-2-hydroxypropyl)-3-[methyl(propylsulfonyl)amino]benzamide N - ((1 S, 2 R) -1- benzyl-3 - {[3- (dimethylamino) benzyl] amino} -2-hydroxypropyl) -3- [methyl (propyl-sulfonyl) amino] benzamide Preparation of: N -((1 S , 2 R ) -1-benzyl-3-{[3- (dimethylamino) benzyl] amino} -2-hydroxypropyl) -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 제조예 162에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 13 ㎎을 50% 수율로 얻었다.13 mg of the title compound was obtained in 50% yield by the same method as Example 115 except for using the compound obtained in Preparation Example 162 instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.69 (1H, s), 7.57∼7.49 (1H, m), 7.45∼7.40 (1H, m), 7.35∼7.19 (7H, m), 6.67∼6.66 (3H, m), 4.50∼4.35 (1H, m), 3.85∼3.71 (3H, m), 3.32 (3H, s), 3.12∼2.86 (6H, m), 2.92 (6H, s), 1.84∼1.81 (2H, m), 1.01 (3H, t, J = 7.41)1 H-NMR (300 MHz, CDCl 3 ); 7.69 (1H, s), 7.57 to 7.49 (1H, m), 7.45 to 7.40 (1H, m), 7.35 to 7.19 (7H, m), 6.67 to 6.66 (3H, m), 4.50 to 4.35 (1H, m ), 3.85 to 3.71 (3H, m), 3.32 (3H, s), 3.12 to 2.86 (6H, m), 2.92 (6H, s), 1.84 to 1.81 (2H, m), 1.01 (3H, t, J = 7.41)

FAB MS (m/e) = 553 [M+H]+
FAB MS (m / e) = 553 [M + H] < + >

[실시예 125]Example 125

N-[(1S,2R)-1-벤질-2-히드록시-3-(펜에틸아미노)프로필]-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-[(1S,2R)-1-benzyl-2-hydroxy-3-(phenethylamino)propyl]-3-[methyl(propylsulfonyl)amino]benzamide N - [(1 S, 2 R) -1- benzyl-2-hydroxy-3- (phenethyl-amino) propyl] -3 Preparation of [methyl (propyl-sulfonyl) amino] benzamide: N - [( 1 S , 2 R ) -1-benzyl-2-hydroxy-3- (phenethylamino) propyl] -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 페닐아세트알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 15 ㎎을 60% 수율로 얻었다. 15 mg of the title compound was obtained in 60% yield by the same method as Example 115 except for using phenylacetaldehyde instead of 3-trifluoromethoxybenzaldehyde.                     

1H-NMR (300 MHz, CDCl3); 7.68∼7.67 (1H, m), 7.55∼7.52 (1H, m), 7.43∼7.38 (2H, m), 7.30∼7.17 (9H, m), 6.93∼6.91 (1H, m), 4.45∼4.35 (1H, m), 3.71∼3.67 (1H, m), 3.33 (3H, s), 3.06∼3.00 (2H, m), 2.96∼2.91 (4H, m), 2.85∼2.80 (4H, m), 1.87∼1.81 (2H, m), 1.01 (3H, t, J = 7.41)1 H-NMR (300 MHz, CDCl 3 ); 7.68 to 7.57 (1H, m), 7.55 to 7.72 (1H, m), 7.43 to 7.38 (2H, m), 7.30 to 7.71 (9H, m), 6.93 to 6.61 (1H, m), 4.45 to 4.35 (1H , m), 3.71 to 3.67 (1H, m), 3.33 (3H, s), 3.06 to 3.00 (2H, m), 2.96 to 2.91 (4H, m), 2.85 to 2.80 (4H, m), 1.87 to 1.81 (2H, m), 1.01 (3H, t, J = 7.41)

FAB MS (m/e) = 524 [M+H]+
FAB MS (m / e) = 524 [M + H] < + >

[실시예 126]Example 126

N-((1S,2R)-1-벤질-3-{[(5-에틸-2-퓨릴)메틸]아미노}-2-히드록시프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-((1S,2R)-1-benzyl-3-{[(5-ethyl-2-furyl)methyl]amino}-2-hydroxypropyl)-3-[methyl(propylsulfonyl)amino]benzamide N - ((1 S, 2 R) -1- benzyl-3 - {[(5-ethyl-2-furyl) methyl] amino} -2-hydroxypropyl) -3- [methyl (propyl-sulfonyl) amino ] Preparation of Benzamide: N -((1 S , 2 R ) -1-benzyl-3-{[(5-ethyl-2-furyl) methyl] amino} -2-hydroxypropyl) -3- [methyl (propylsulfonyl ) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 5-에틸퓨란-2-카브알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 17 ㎎을 68% 수율로 얻었다.17 mg of the title compound was obtained in 68% yield by the same method as Example 115 except for using 5-ethylfuran-2-carbaldehyde instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.72 (1H, s), 7.58∼7.42 (2H, m), 7.41∼7.14 (7H, m), 6.10 (1H, d, J = 2.96), 5.90 (1H, d, J = 2.99), 4.49∼4.32 (1H, m), 3.84∼3.63 (3H, m), 3.33 (3H, s), 3.09∼2.74 (6H, m), 2.58 (2H, q, J = 7.48), 2.48 (2H, bs), 1.90∼1.72 (2H, m), 1.18 (3H,t, J = 7.54), 1.02 (3H, t, J = 7.44)1 H-NMR (300 MHz, CDCl 3 ); 7.72 (1H, s), 7.58-7.42 (2H, m), 7.41-7.14 (7H, m), 6.10 (1H, d, J = 2.96), 5.90 (1H, d, J = 2.99), 4.49-4.32 (1H, m), 3.84-3.63 (3H, m), 3.33 (3H, s), 3.09-2.74 (6H, m), 2.58 (2H, q, J = 7.48), 2.48 (2H, bs), 1.90 -1.72 (2H, m), 1.18 (3H, t, J = 7.54), 1.02 (3H, t, J = 7.44)

FAB MS (m/e) = 528 [M+H]+
FAB MS (m / e) = 528 [M + H] < + >

[실시예 127]Example 127

N-((1S,2R)-1-벤질-3-{[(5-에틸-2-치에닐)메틸]아미노}-2-히드록시프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-((1S,2R)-1-benzyl-3-{[(5-ethyl-2-thienyl)methyl]amino}-2-hydroxypropyl)-3-[methyl(propylsulfonyl)amino]benzamide N - ((1 S, 2 R) -1- benzyl-3 - {[(5-ethyl-2-on value carbonyl) methyl] amino} -2-hydroxypropyl) -3- [methyl (propyl-sulfonyl Preparation of Amino] benzamide: N -((1 S , 2 R ) -1-benzyl-3-{[(5-ethyl-2-thienyl) methyl] amino} -2-hydroxypropyl) -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 5-에틸치오펜-2-카브알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 18 ㎎을 71% 수율로 얻었다.18 mg of the title compound was obtained in 71% yield by the same method as Example 115 except for using 5-ethylthiophen-2-carbaldehyde instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.71 (1H, s), 7.58∼7.40 (2H, m), 7.39∼7.16 (7H, m), 7.58∼7.40 (2H, m), 6.74 (1H, d, J = 3.24), 6.61 (1H, d, J = 3.30), 4.49∼4.32 (2H, m), 3.76∼3.61 (1H, m), 3.33 (3H, s), 3.12∼2.56 (6H, m), 2.68 (2H, bs), 1.90∼1.69 (2H, m), 1.28 (3H, t, J = 7.50), 1.02 (3H, t, J = 7.41)1 H-NMR (300 MHz, CDCl 3 ); 7.71 (1H, s), 7.58-7.40 (2H, m), 7.39-7.16 (7H, m), 7.58-7.40 (2H, m), 6.74 (1H, d, J = 3.24), 6.61 (1H, d , J = 3.30), 4.49 to 4.32 (2H, m), 3.76 to 3.61 (1H, m), 3.33 (3H, s), 3.12 to 2.56 (6H, m), 2.68 (2H, bs), 1.90 to 1.69 (2H, m), 1.28 (3H, t, J = 7.50), 1.02 (3H, t, J = 7.41)

FAB MS (m/e) = 544 [M+H]+
FAB MS (m / e) = 544 [M + H] < + >

[실시예 128]Example 128

N-[(1S,2R)-1-벤질-2-히드록시-3-({[5-(히드록시메틸)-2-퓨릴]메틸}아미노)프로필]-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-[(1S,2R)-1-benzyl-2- hydroxy-3-({[5-(hydroxymethyl)-2-furyl]methyl}amino)propyl]-3-[methyl(propylsulfonyl)amino]benzamide N - [(1 S, 2 R) -1- benzyl-2-hydroxy-3 - ({[5- (hydroxymethyl) -2-furyl] methyl} amino) propyl] -3- [methyl (propyl Preparation of sulfonyl) amino] benzamide: N -[(1 S , 2 R ) -1-benzyl-2-hydroxy-3-({[5- (hydroxymethyl) -2-furyl] methyl} amino) propyl] -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 5-히드록시메틸퓨란-2-카브알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 15 ㎎을 62% 수율로 얻었다.15 mg of the title compound was obtained in 62% yield by the same method as Example 115 except for using 5-hydroxymethylfuran-2-carbaldehyde instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.68 (1H, s), 7.55∼7.40 (2H, m), 7.39∼7.14 (6H, m), 7.02 (1H, d, J = 8.30), 6.18 (1H, d, J = 3.09), 6.13 (1H, d, J= 3.12), 4.50 (2H, s), 4.42∼4.38 (1H, m), 3.84 (1H, d, J = 14.50), 3.74 (1H, d, J = 14.49), 3.64∼3.51 (1H, m), 3.33 (3H, s), 3.09∼2.87 (4H, m), 2.85∼2.72 (2H, m), 2.57 (3H, bs), 1.89∼1.72 (2H, m), 1.03 (3H, t, J= 7.44)1 H-NMR (300 MHz, CDCl 3 ); 7.68 (1H, s), 7.55-7.40 (2H, m), 7.39-7.14 (6H, m), 7.02 (1H, d, J = 8.30), 6.18 (1H, d, J = 3.09), 6.13 (1H , d, J = 3.12), 4.50 (2H, s), 4.42-4.38 (1H, m), 3.84 (1H, d, J = 14.50), 3.74 (1H, d, J = 14.49), 3.64-3.51 ( 1H, m), 3.33 (3H, s), 3.09-2.87 (4H, m), 2.85-2.72 (2H, m), 2.57 (3H, bs), 1.89-1.72 (2H, m), 1.03 (3H, t, J = 7.44)

FAB MS (m/e) = 530 [M+H]+
FAB MS (m / e) = 530 [M + H] < + >

[실시예 129]Example 129

N-((1S,2R)-1-벤질-3-{[(5-브로모-2-치에닐)메틸]아미노}-2-히드록시프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-((1S,2R)-1-benzyl-3-{[(5-bromo-2-thienyl)methyl]amino}-2-hydroxypropyl)-3-[methyl(propylsulfonyl)amino]benzamide N - ((1 S, 2 R) -1- benzyl-3 - {[(5-bromo-2 to the parent value carbonyl) methyl] amino} -2-hydroxypropyl) -3- [methyl (propyl alcohol Preparation of Ponyyl) Amino] Benzamide: N -((1 S , 2 R ) -1-benzyl-3-{[(5-bromo-2-thienyl) methyl] amino} -2-hydroxypropyl) -3- [ methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 5-브로모치오펜-2-카브알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 17 ㎎을 63% 수율로 얻었다.17 mg of the title compound was obtained in 63% yield by the same method as Example 115 except for using 5-bromothiophen-2-carbaldehyde instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.69 (1H, s), 7.59∼7.28 (8H, m), 6.91∼6.82 (2H, m), 6.69 (1H, d, J = 3.64), 4.47∼4.31 (1H, m), 3.96 (1H, d, J = 14.50), 3.92 (1H, d, J = 14.49), 3.72∼3.60 (1H, m), 3.34 (3H, s), 3.10∼2.86 (4H, m), 2.85∼2.76 (2H, m), 1.99 (2H, bs), 1.89∼1.73 (2H, m), 1.02 (3H, t, J = 7.46)1 H-NMR (300 MHz, CDCl 3 ); 7.69 (1H, s), 7.59-7.28 (8H, m), 6.91-6.82 (2H, m), 6.69 (1H, d, J = 3.64), 4.47-4.31 (1H, m), 3.96 (1H, d , J = 14.50), 3.92 (1H, d, J = 14.49), 3.72-3.60 (1H, m), 3.34 (3H, s), 3.10-2.86 (4H, m), 2.85-2.76 (2H, m) , 1.99 (2H, bs), 1.89-1.73 (2H, m), 1.02 (3H, t, J = 7.46)

FAB MS (m/e) = 594 [M+H]+
FAB MS (m / e) = 594 [M + H] < + >

[실시예 130]Example 130

N-{(1S,2R)-1-벤질-3-[(3-클로로벤질)아미노]-2-히드록시프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-3-[(3-chlorobenzyl)amino]-2-hydroxypropyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-3 - [(3-chlorobenzyl) amino] -2-hydroxypropyl} -3- [methyl (propyl-sulfonyl) amino] benzamide Preparation of: N -{(1 S , 2 R ) -1-benzyl-3-[(3-chlorobenzyl) amino] -2-hydroxypropyl} -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 3-클로로벤즈알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 17 ㎎을 67% 수율로 얻었다.17 mg of the title compound was obtained in 67% yield by the same method as Example 115 except for using 3-chlorobenzaldehyde instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.68 (1H, s), 7.55∼7.12 (12H, m), 6.98∼6.88 (1H, m), 4.46∼4.32 (1H, m), 3.84∼3.60 (3H, m), 3.33 (3H, s), 3.09∼2.82 (4H, m), 2.81∼2.70 (2H, m), 2.02 (2H, s), 1.90∼1.73 (2H, m), 1.02 (3H, t, J = 7.41) 1 H-NMR (300 MHz, CDCl 3 ); 7.68 (1H, s), 7.55-7.72 (12H, m), 6.98-6.88 (1H, m), 4.46-4.32 (1H, m), 3.84-3.60 (3H, m), 3.33 (3H, s), 3.09-2.82 (4H, m), 2.81-2.70 (2H, m), 2.02 (2H, s), 1.90-1.73 (2H, m), 1.02 (3H, t, J = 7.41)

FAB MS (m/e) = 544 [M+H]+
FAB MS (m / e) = 544 [M + H] < + >

[실시예 131]Example 131

N-{(1S,2R)-1-벤질-3-[(3-브로모벤질)아미노]-2-히드록시프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-3-[(3-bromobenzyl)amino]-2-hydroxypropyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-3 - [(3-bromobenzyl) amino] -2-hydroxypropyl} -3- [methyl (propyl-sulfonyl) amino] benzamide Preparation of : N -{(1 S , 2 R ) -1-benzyl-3-[(3-bromobenzyl) amino] -2-hydroxypropyl} -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 3-브로모벤즈알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 16 ㎎을 60% 수율로 얻었다.16 mg of the title compound was obtained in 60% yield by the same method as Example 115 except for using 3-bromobenzaldehyde instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.68 (1H, s), 7.56∼7.13 (12H, m), 6.98∼6.89 (1H, m), 4.46∼4.32 (1H, m), 3.84∼3.59 (3H, m), 3.33 (3H, s), 3.09∼2.88 (4H, m), 2.81∼2.71 (2H, m), 2.21 (2H, bs), 1.90∼1.70 (2H, m), 1.02 (3H, t, J = 7.42)1 H-NMR (300 MHz, CDCl 3 ); 7.68 (1H, s), 7.56 to 7.13 (12H, m), 6.98 to 6.89 (1H, m), 4.46 to 4.32 (1H, m), 3.84 to 3.59 (3H, m), 3.33 (3H, s), 3.09 to 2.88 (4H, m), 2.81 to 2.71 (2H, m), 2.21 (2H, bs), 1.90 to 1.70 (2H, m), 1.02 (3H, t, J = 7.42)

FAB MS (m/e) = 588 [M+H]+
FAB MS (m / e) = 588 [M + H] < + >

[실시예 132]Example 132

N-{(1S,2R)-1-벤질-2-히드록시-3-[(3-아이오도벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(3-iodo-benzyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide Preparation of : N -{(1 S , 2 R ) -1-benzyl-2-hydroxy-3-[(3-iodobenzyl) amino] propyl} -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 3-아이오도벤즈알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 18 ㎎을 61% 수율로 얻었다.18 mg of the title compound was obtained in 61% yield by the same method as Example 115 except for using 3-iodobenzaldehyde instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.74∼7.14 (12H, m), 7.09∼6.89 (2H, m), 4.47∼4.31 (1H, m), 3.86∼3.62 (3H, m), 3.33 (3H, s), 3.08∼2.86 (4H, m), 2.82∼2.72 (2H, m), 2.12 (2H, bs), 1.91∼1.72 (2H, m), 1.02 (3H, t, J = 7.42)1 H-NMR (300 MHz, CDCl 3 ); 7.74-7.14 (12H, m), 7.09-6.89 (2H, m), 4.47-4.31 (1H, m), 3.86-3.62 (3H, m), 3.33 (3H, s), 3.08-2.86 (4H, m ), 2.82-2.72 (2H, m), 2.12 (2H, bs), 1.91-1.72 (2H, m), 1.02 (3H, t, J = 7.42)

FAB MS (m/e) = 636 [M+H]+
FAB MS (m / e) = 636 [M + H] < + >

[실시예 133]Example 133

N-((1S,2R)-1-벤질-2-히드록시-3-{[3-(트리플루오로메틸)벤질]아미노}프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-3-[methyl(propylsulfonyl)amino]benzamide N - ((1 S, 2 R) -1- benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl) -3- [methyl (propyl-sulfonyl) amino] Preparation of Benzamide: N -((1 S , 2 R ) -1-benzyl-2-hydroxy-3-{[3- (trifluoromethyl) benzyl] amino} propyl) -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 3-트리플루오로메틸벤즈알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 19 ㎎을 70% 수율로 얻었다.19 mg of the title compound was obtained in 70% yield by the same method as Example 115 except for using 3-trifluoromethylbenzaldehyde instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.76∼7.16 (13H, m), 6.96 (1H, d, J = 8.52), 4.48∼4.31 (1H, m), 3.99∼3.62 (3H, m), 3.33 (3H, s), 3.10∼2.72 (6H, m), 2.78 (2H, bs), 1.91∼1.71 (2H, m), 1.02 (3H, t, J = 7.41) 1 H-NMR (300 MHz, CDCl 3 ); 7.76 to 7.16 (13H, m), 6.96 (1H, d, J = 8.52), 4.48 to 4.31 (1H, m), 3.99 to 3.62 (3H, m), 3.33 (3H, s), 3.10 to 2.72 (6H , m), 2.78 (2H, bs), 1.91-1.71 (2H, m), 1.02 (3H, t, J = 7.41)

FAB MS (m/e) = 578 [M+H]+
FAB MS (m / e) = 578 [M + H] < + >

[실시예 134]Example 134

N-{(1S,2R)-1-벤질-2-히드록시-3-[(3-메틸벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methylbenzyl)amino]propyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(3-methylbenzyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide Preparation of: N -{(1 S , 2 R ) -1-benzyl-2-hydroxy-3-[(3-methylbenzyl) amino] propyl} -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 3-메틸벤즈알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 17 ㎎을 69% 수율로 얻었다.17 mg of the title compound was obtained in 69% yield by the same method as Example 115 except for using 3-methylbenzaldehyde instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.70 (1H, s), 7.60∼7.02 (13H, m), 4.49∼4.35 (1H, m), 3.90∼3.70 (3H, m), 3.32 (3H, s), 3.12∼2.62 (8H, m), 2.33 (3H, s), 1.91∼1.73 (2H, m), 1.02 (3H, t, J = 7.36)1 H-NMR (300 MHz, CDCl 3 ); 7.70 (1H, s), 7.60-7.02 (13H, m), 4.49-4.35 (1H, m), 3.90-3.70 (3H, m), 3.32 (3H, s), 3.12-2.62 (8H, m), 2.33 (3H, s), 1.91-1.73 (2H, m), 1.02 (3H, t, J = 7.36)

FAB MS (m/e) = 524 [M+H]+
FAB MS (m / e) = 524 [M + H] < + >

[실시예 135]Example 135

N-{(1S,2R)-3-[(1,3-벤조디옥솔-5-일메틸)아미노]-1-벤질-2-히드록시프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-3-[(1,3-benzodioxol-5-ylmethyl)amino]-1-benzyl-2-hydroxypropyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -3 - [(1,3- benzodioxol-5-ylmethyl) amino] -1-benzyl-2-hydroxypropyl} -3- [methyl (propyl-sulfonyl Preparation of Amino] benzamide: N -{(1 S , 2 R ) -3-[(1,3-benzodioxol-5-ylmethyl) amino] -1-benzyl-2-hydroxypropyl} -3- [methyl ( propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 피페로날을 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 17 ㎎을 66% 수율로 얻었다.17 mg of the title compound was obtained in 66% yield by the same method as Example 115 except for using piperonal instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.69 (1H, s), 7.61∼7.12 (9H, m), 6.83 (1H, s), 6.79∼6.70 (2H, m), 5.94 (2H, s), 4.46∼4.33 (1H, m), 3.81∼3.60 (2H, m), 3.33 (3H, s), 3.07∼2.88 (4H, m), 2.87∼2.72 (2H, m), 2.52 (2H, bs), 1.89∼1.72 (2H, m), 1.02 (3H, t, J = 7.42)1 H-NMR (300 MHz, CDCl 3 ); 7.69 (1H, s), 7.61-7.72 (9H, m), 6.83 (1H, s), 6.79-6.70 (2H, m), 5.94 (2H, s), 4.46-4.33 (1H, m), 3.81- 3.60 (2H, m), 3.33 (3H, s), 3.07-2.88 (4H, m), 2.87-2.72 (2H, m), 2.52 (2H, bs), 1.89-1.72 (2H, m), 1.02 ( 3H, t, J = 7.42)

FAB MS (m/e) = 554 [M+H]+
FAB MS (m / e) = 554 [M + H] < + >

[실시예 136]Example 136

N-{(1S,2R)-1-벤질-3-[(3,5-디메톡시벤질)아미노]-2-히드록시프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-3-[(3,5-dimethoxybenzyl)amino]-2-hydroxypropyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-3 - [(3,5-dimethoxybenzyl) amino] -2-hydroxypropyl} -3- [methyl (propyl-sulfonyl) amino] benzamide Preparation of: N -{(1 S , 2 R ) -1-benzyl-3-[(3,5-dimethoxybenzyl) amino] -2-hydroxypropyl} -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 3,5-디메톡시벤즈알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 20 ㎎을 76% 수율로 얻었다.20 mg of the title compound was obtained in 76% yield by the same method as Example 115 except for using 3,5-dimethoxybenzaldehyde instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3)7.69 (1H, s), 7.59∼7.13 (10H, m), 6.58∼6.31 (3H, m), 4.46∼4.30 (1H, m), 3.88∼3.62 (3H, m), 3.76 (6H, s), 3.32 (3H, s), 3.07∼2.69 (8H, m), 1.90∼1.70 (2H, m), 1.01 (3H, t, J = 7.38)1 H-NMR (300 MHz, CDCl 3 ) 7.69 (1H, s), 7.59 to 7.13 (10H, m), 6.58 to 6.31 (3H, m), 4.46 to 4.30 (1H, m), 3.88 to 3.62 (3H, m), 3.76 (6H, s), 3.32 (3H, s), 3.07-2.69 (8H, m), 1.90-1.70 (2H, m), 1.01 (3H, t, J = 7.38)

FAB MS (m/e) = 570 [M+H]+
FAB MS (m / e) = 570 [M + H] < + >

[실시예 137]Example 137

N-{(1S,2R)-1-벤질-2-히드록시-3-[(2-히드록시-3-메톡시벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-hydroxy-3-methoxybenzyl)amino]propyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(2-hydroxy-3-methoxybenzyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino ] Preparation of benzamide: N -{(1 S , 2 R ) -1-benzyl-2-hydroxy-3-[(2-hydroxy-3-methoxybenzyl) amino] propyl} -3- [methyl (propylsulfonyl) amino benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 2-히드록시-3-메톡시벤즈알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 16 ㎎을 61% 수율로 얻었다.16 mg of the title compound was obtained in 61% yield by the same method as Example 115 except for using 2-hydroxy-3-methoxybenzaldehyde instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.66 (1H, s), 7.59∼7.46 (2H, m), 7.40∼7.15 (m, 6H), 7.17∼6.97 (1H, m), 6.85∼6.69 (3H, m), 4.38∼4.25 (1H, m), 4.09∼3.89 (3H, m), 3.84 (3H, s), 3.82 (3H, bs), 3.32 (3H, s), 3.05∼2.78 (1H, m), 1.89∼1.72 (2H, m), 1.02 (3H, t, J = 7.41)1 H-NMR (300 MHz, CDCl 3 ); 7.66 (1H, s), 7.59-7.46 (2H, m), 7.40-7.15 (m, 6H), 7.17-6.97 (1H, m), 6.85-6.69 (3H, m), 4.38-4.25 (1H, m) ), 4.09 to 3.89 (3H, m), 3.84 (3H, s), 3.82 (3H, bs), 3.32 (3H, s), 3.05 to 2.78 (1H, m), 1.89 to 1.72 (2H, m), 1.02 (3H, t, J = 7.41)

FAB MS (m/e) = 556 [M+H]+
FAB MS (m / e) = 556 [M + H] < + >

[실시예 138]Example 138

N-{(1S,2R)-1-벤질-3-[(2,3-디메톡시벤질)아미노]-2-히드록시프로필}-3-[메틸(프로 필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-3-[(2,3-dimethoxybenzyl)amino]-2-hydroxypropyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-3 - [(2,3-dimethoxybenzyl) amino] -2-hydroxypropyl} -3- [methyl (prop pilsul sulfonyl) amino] benzamide Preparation of: N -{(1 S , 2 R ) -1-benzyl-3-[(2,3-dimethoxybenzyl) amino] -2-hydroxypropyl} -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 2,3-디메톡시벤즈알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 19 ㎎을 75% 수율로 얻었다.19 mg of the title compound was obtained in 75% yield by the same method as Example 115 except for using 2,3-dimethoxybenzaldehyde instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.71 (1H, s), 7.56∼7.46 (1H, m), 7.45∼7.14 (8H, m), 7.06∼6.98 (1H, m), 6.90∼6.81 (2H, m), 4.49∼4.35 (1H, m), 3.88∼3.78 (8H, m), 3.77∼3.68 (1H, m), 3.32 (3H, s), 3.09∼2.82 (6H, m), 2.65 (2H, bs), 1.91∼1.75 (2H, m), 1.02 (3H, t, J = 7.41)1 H-NMR (300 MHz, CDCl 3 ); 7.71 (1H, s), 7.56-7.46 (1H, m), 7.45-7.14 (8H, m), 7.06-6.98 (1H, m), 6.90-6.81 (2H, m), 4.49-4.35 (1H, m) ), 3.88 to 3.78 (8H, m), 3.77 to 3.68 (1H, m), 3.32 (3H, s), 3.09 to 2.82 (6H, m), 2.65 (2H, bs), 1.91 to 1.75 (2H, m ), 1.02 (3H, t, J = 7.41)

FAB MS (m/e) = 570 [M+H]+
FAB MS (m / e) = 570 [M + H] < + >

[실시예 139]Example 139

N-{(1S,2R)-1-벤질-2-히드록시-3-[(2-히드록시-5-메톡시벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-hydroxy-5-methoxybenzyl)amino]propyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(2-hydroxy-5-methoxybenzyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino ] Preparation of benzamide: N -{(1 S , 2 R ) -1-benzyl-2-hydroxy-3-[(2-hydroxy-5-methoxybenzyl) amino] propyl} -3- [methyl (propylsulfonyl) amino benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 2-히드록시-5-메톡시벤즈알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 17 ㎎을 62% 수율로 얻었다.17 mg of the title compound was obtained in 62% yield by the same method as Example 115 except for using 2-hydroxy-5-methoxybenzaldehyde instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.64 (1H, s), 7.57∼7.17 (9H, m), 6.84∼6.68 (2H, m), 6.67∼6.52 (2H, m), 4.35∼4.21 (1H, m), 4.05 (1H, d, J = 14.52), 3.97 (1H, d, J = 14.48), 3.88∼3.78 (8H, m), 3.75 (3H, s), 3.77∼3.68 (1H, m), 3.34 (3H, s), 3.14 (3H, bs), 3.12∼2.75 (6H, m), 1.91∼1.72 (2H, m), 1.04 (3H, t, J = 7.49)1 H-NMR (300 MHz, CDCl 3 ); 7.64 (1H, s), 7.57 to 7.17 (9H, m), 6.84 to 6.68 (2H, m), 6.67 to 6.62 (2H, m), 4.35 to 4.21 (1H, m), 4.05 (1H, d, J = 14.52), 3.97 (1H, d, J = 14.48), 3.88-3.78 (8H, m), 3.75 (3H, s), 3.77-3.68 (1H, m), 3.34 (3H, s), 3.14 (3H , bs), 3.12-2.75 (6H, m), 1.91-1.72 (2H, m), 1.04 (3H, t, J = 7.49)

FAB MS (m/e) = 556 [M+H]+
FAB MS (m / e) = 556 [M + H] < + >

[실시예 140]Example 140

N-{(1S,2R)-1-벤질-3-[(2,5-디메톡시벤질)아미노]-2-히드록시프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-3-[(2,5-dimethoxybenzyl)amino]-2-hydroxypropyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-3 - [(2,5-dimethoxybenzyl) amino] -2-hydroxypropyl} -3- [methyl (propyl-sulfonyl) amino] benzamide Preparation of: N -{(1 S , 2 R ) -1-benzyl-3-[(2,5-dimethoxybenzyl) amino] -2-hydroxypropyl} -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 2,5-디메톡시벤즈알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 19 ㎎을 71% 수율로 얻었다.19 mg of the title compound was obtained in 71% yield by the same method as Example 115 except for using 2,5-dimethoxybenzaldehyde instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.69 (1H, s), 7.53 (1H, d, J = 7.93), 7.45 (1H, d, J = 7.76), 7.40∼7.12 (7H, m), 6.84∼6.71 (3H, m), 4.61 (2H, bs), 4.50∼4.37 (1H, m), 3.95 (1H, d, J = 13.52), 3.86 (1H, d, J = 13.01), 3.77 (3H, s), 3.74 (3H, s), 3.31 (3H, s), 3.77∼3.68 (1H, m), 3.11∼2.78 (6H, m), 1.90∼1.73 (2H, m), 1.02 (3H, t, J = 7.40)1 H-NMR (300 MHz, CDCl 3 ); 7.69 (1H, s), 7.53 (1H, d, J = 7.93), 7.45 (1H, d, J = 7.76), 7.40-7.72 (7H, m), 6.84-6.71 (3H, m), 4.61 (2H , bs), 4.50-4.37 (1H, m), 3.95 (1H, d, J = 13.52), 3.86 (1H, d, J = 13.01), 3.77 (3H, s), 3.74 (3H, s), 3.31 (3H, s), 3.77-3.68 (1H, m), 3.11-2.78 (6H, m), 1.90-1.73 (2H, m), 1.02 (3H, t, J = 7.40)

FAB MS (m/e) = 570 [M+H]+
FAB MS (m / e) = 570 [M + H] < + >

[실시예 141]Example 141

N-{(1S,2R)-1-벤질-2-히드록시-3-[(1-나프틸메틸)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(1-naphthylmethyl)amino]propyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(1-naphthylmethyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide Preparation of : N -{(1 S , 2 R ) -1-benzyl-2-hydroxy-3-[(1-naphthylmethyl) amino] propyl} -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 나프탈렌-1-카브알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 18 ㎎을 69% 수율로 얻었다.18 mg of the title compound was obtained in 69% yield by the same method as Example 115 except for using naphthalene-1-carbaldehyde instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 8.15∼8.10 (1H, m), 7.90∼7.88 (1H, m), 7.85∼7.78 (1H, m), 7.66∼7.65 (1H, m), 7.51∼7.41 (5H, m), 7.30∼7.05 (7H, m), 4.50∼4.45 (1H, m), 4.28∼4.25 (2H, m), 3.85∼3.78 (1H, m), 3.33 (3H, s), 2.98∼2.89 (6H, m), 1.87∼1.81 (2H, m), 1.00 (3H, t, J = 7.41)1 H-NMR (300 MHz, CDCl 3 ); 8.15-8.10 (1H, m), 7.90-7.88 (1H, m), 7.85-7.78 (1H, m), 7.66-7.75 (1H, m), 7.51-7.41 (5H, m), 7.30-7.05 (7H , m), 4.50 to 4.45 (1H, m), 4.28 to 4.25 (2H, m), 3.85 to 3.78 (1H, m), 3.33 (3H, s), 2.98 to 2.89 (6H, m), 1.87 to 1.81 (2H, m), 1.00 (3H, t, J = 7.41)

FAB MS (m/e) = 560 [M+H]+
FAB MS (m / e) = 560 [M + H] < + >

[실시예 142]Example 142

N-{(1S,2R)-3-[(1,3-벤조디옥솔-4-일메틸)아미노]-1-벤질-2-히드록시프로필}-3-[메 틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-3-[(1,3-benzodioxol-4-ylmethyl)amino]-1-benzyl-2-hydroxypropyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -3 - [(1,3- benzodioxol-4-ylmethyl) amino] -1-benzyl-2-hydroxypropyl} -3- [methyl (propyl alcohol Preparation of Ponyl) amino] benzamide: N -{(1 S , 2 R ) -3-[(1,3-benzodioxol-4-ylmethyl) amino] -1-benzyl-2-hydroxypropyl} -3- [methyl (propylsulfonyl) amino] benzamide

3-트리플루오로메톡시벤즈알데히드 대신에 2,3-(메틸렌디옥시)벤즈알데히드를 사용한 것을 제외하고는, 실시예 115와 동일한 방법으로 실시하여, 표제 화합물 17 ㎎을 64% 수율로 얻었다.17 mg of the title compound was obtained in 64% yield by the same method as Example 115 except for using 2,3- (methylenedioxy) benzaldehyde instead of 3-trifluoromethoxybenzaldehyde.

1H-NMR (300 MHz, CDCl3); 7.69 (1H, s), 7.55∼7.49 (1H, m), 7.47∼7.43 (1H, m), 7.40∼7.20 (6H, m), 6.79∼6.75 (3H, m), 5.8 9(2H, s), 4.50∼4.45 (1H, m), 3.89∼3.76 (2H, m), 3.75∼3.69 (1H, m), 3.32 (3H, s), 2.98∼2.89 (6H, m), 1.87∼1.81 (2H, m), 1.02 (3H, t, J = 7.38)1 H-NMR (300 MHz, CDCl 3 ); 7.69 (1H, s), 7.55-7.49 (1H, m), 7.47-7.43 (1H, m), 7.40-7.20 (6H, m), 6.79-6.75 (3H, m), 5.8 9 (2H, s) , 4.50 to 4.45 (1H, m), 3.89 to 3.76 (2H, m), 3.75 to 3.69 (1H, m), 3.32 (3H, s), 2.98 to 2.89 (6H, m), 1.87 to 1.81 (2H, m), 1.02 (3H, t, J = 7.38)

FAB MS (m/e) = 554 [M+H]+
FAB MS (m / e) = 554 [M + H] < + >

[실시예 143]Example 143

N-[(1S,2R)-1-벤질-2-히드록시-3-(1H-피라졸-1-일)프로필]-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-[(1S,2R)-1-benzyl-2-hydroxy-3-(1H-pyrazol-1-yl)propyl]-3-[methyl(propylsulfonyl)amino]benzamide N - [(1 S, 2 R) -1-benzyl-2-hydroxy-3- (1 H - pyrazol-1-yl) propyl] -3- [methyl (propyl-sulfonyl) amino] benzamide in Preparation: N -[(1 S , 2 R ) -1-benzyl-2-hydroxy-3- (1 H -pyrazol-1-yl) propyl] -3- [methyl (propylsulfonyl) amino] benzamide

상기 제조예 132에서 얻은 화합물 19 ㎎(0.07 mmol)과 피라졸 0.07 mmol을 이소프로판올 1 ㎖에 녹인 후 트리에틸아민 0.10 mmol을 가하고 반응 용액을 70℃에서 12 시간 동안 교반하였다. 반응 용액을 에틸아세테이트로 희석하고 1N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻었다. 용매를 감압증류하여 제거한 후 농축액을 디클로로메탄 1 ㎖에 녹이고 트리플루오로아세트산 100 ㎖을 가했다. 상온에서 1 시간 교반한 후 반응 용액을 감압 농축하였다. 농축액과 상기 제조예 29에서 얻은 화합물 16 ㎎(0.06 mmol)을 N,N-디메틸포름아미드 1 ㎖에 녹이고 0℃로 냉각한 후 EDC 11.5 ㎎(0.06 mmol), HOBT 8.1 ㎎(0.06 mmol)와 트리에틸아민 0.06 mmol을 가한 후 상온에서 10 시간 동안 교반하였다. 반응용액을 에틸아세테이트로 희석하고 1N 염산 용액, 포화탄산수소나트륨 용액과 소금물로 씻어 주었다. 용매를 감압증류하여 제거한 후 컬럼크로마토그래피로 정제하여 표제 화합물 13 ㎎을 40% 수율로 얻었다.19 mg (0.07 mmol) of the compound obtained in Preparation Example 132 and 0.07 mmol of pyrazole were dissolved in 1 ml of isopropanol, and 0.10 mmol of triethylamine was added thereto, and the reaction solution was stirred at 70 ° C. for 12 hours. The reaction solution was diluted with ethyl acetate and washed with 1N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. After distilling off the solvent under reduced pressure, the concentrated solution was dissolved in 1 ml of dichloromethane and 100 ml of trifluoroacetic acid was added thereto. After stirring for 1 hour at room temperature, the reaction solution was concentrated under reduced pressure. The concentrated solution and 16 mg (0.06 mmol) of the compound obtained in Preparation Example 29 were dissolved in 1 ml of N, N-dimethylformamide, cooled to 0 ° C., and then EDC 11.5 mg (0.06 mmol), HOBT 8.1 mg (0.06 mmol) and tree After adding 0.06 mmol of ethylamine, the mixture was stirred at room temperature for 10 hours. The reaction solution was diluted with ethyl acetate and washed with 1N hydrochloric acid solution, saturated sodium bicarbonate solution and brine. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography to obtain 13 mg of the title compound in 40% yield.

1H-NMR (300 MHz, CDCl3); 7.76 (1H, s), 7.41∼7.61 (4H, m), 7.11∼7.32 (5H, m), 6.67 (1H, d, J = 8.64), 6.23 (1H, m), 4.68 (1H, bs), 4.42 (1H, m), 4.26 (2H, d, J = 5.59), 4.05 (1H, m), 3.31 (3H, s), 2.94 (4H, m), 1.81 (2H, m), 1.12 (3H, t, J = 7.36)1 H-NMR (300 MHz, CDCl 3 ); 7.76 (1H, s), 7.41-7.61 (4H, m), 7.11-7.72 (5H, m), 6.67 (1H, d, J = 8.64), 6.23 (1H, m), 4.68 (1H, bs), 4.42 (1H, m), 4.26 (2H, d, J = 5.59), 4.05 (1H, m), 3.31 (3H, s), 2.94 (4H, m), 1.81 (2H, m), 1.12 (3H, t, J = 7.36)

FAB MS (m/e) = 471 [M+H]+
FAB MS (m / e) = 471 [M + H] < + >

[실시예 144]Example 144

N-[(1S,2R)-1-벤질-3-(3-벤질-1H-피라졸-1-일)-2-히드록시프로필]-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-[(1S,2R)-1-benzyl-3-(3-benzyl-1H-pyrazol-1-yl)-2-hydroxypropyl]-3-[methyl(propylsulfonyl)amino]benzamide N - [(1 S, 2 R) -1-benzyl-3- (3-benzyl -1 H - pyrazol-1-yl) -2-hydroxypropyl] -3- [methyl (propyl-sulfonyl) amino ] Benzamide Preparation: N -[(1 S , 2 R ) -1-benzyl-3- (3-benzyl-1 H -pyrazol-1-yl) -2-hydroxypropyl] -3- [methyl (propylsulfonyl) amino] benzamide

피라졸 대신에 3-벤질피라졸을 사용한 것을 제외하고는, 실시예 143과 동일한 방법으로 실시하여, 표제 화합물 17 ㎎을 45% 수율로 얻었다.17 mg of the title compound was obtained in 45% yield by the same method as Example 143 except for using 3-benzylpyrazole instead of pyrazole.

1H-NMR (300 MHz, CDCl3); 7.78 (1H, s), 7.21∼7.73 (12H, m), 7.04 (1H, m), 6.64 (1H, m), 6.05 (1H, m), 4.52 (2H, bs), 4.34 (1H, m), 4.21 (2H, m), 3.98 (2H, m), 3.34 (3H, s), 3.01 (4H, m), 1.78 (2H, m), 1.12 (3H, t, J = 7.43)1 H-NMR (300 MHz, CDCl 3 ); 7.78 (1H, s), 7.21-7.73 (12H, m), 7.04 (1H, m), 6.64 (1H, m), 6.05 (1H, m), 4.52 (2H, bs), 4.34 (1H, m) , 4.21 (2H, m), 3.98 (2H, m), 3.34 (3H, s), 3.01 (4H, m), 1.78 (2H, m), 1.12 (3H, t, J = 7.43)

FAB MS (m/e) = 561 [M+H]+
FAB MS (m / e) = 561 [M + H] < + >

[실시예 145]Example 145

N-[(1S,2R)-1-벤질-2-히드록시-3-(3-이소프로필-1H-피라졸-1-일)프로필]-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-[(1S,2R)-1-benzyl-2-hydroxy-3-(3-isopropyl-1H-pyrazol-1-yl)propyl]-3-[methyl(propylsulfonyl)amino]benzamide N - [(1 S, 2 R) -1-benzyl-2-hydroxy-3- (3-isopropyl -1 H - pyrazol-1-yl) propyl] -3- [methyl (propyl-sulfonyl) Preparation of amino] benzamide: N -[(1 S , 2 R ) -1-benzyl-2-hydroxy-3- (3-isopropyl-1 H -pyrazol-1-yl) propyl] -3- [methyl ( propylsulfonyl) amino] benzamide

피라졸 대신에 3-이소프로필피라졸을 사용한 것을 제외하고는, 실시예 143과 동일한 방법으로 실시하여, 표제 화합물 14 ㎎을 41% 수율로 얻었다.14 mg of the title compound was obtained in 41% yield by the same method as Example 143 except for using 3-isopropylpyrazole instead of pyrazole.

1H-NMR (300 MHz, CDCl3); 7.68 (1H, m), 7.55 (1H, m), 7.39 (2H, m), 7.25 (5H, m), 6.52 (1H, d, J = 8.74), 6.05 (1H, m), 4.92 (1H, bs), 4.43 (1H, m), 4.21 (2H, d, J = 5.27), 4.13 (1H, m), 3.32 (3H, s), 2.93 (5H, m), 1.85 (2H, m), 1.20 (6H, m), 1.05 (3H, t, J = 7.43)1 H-NMR (300 MHz, CDCl 3 ); 7.68 (1H, m), 7.55 (1H, m), 7.39 (2H, m), 7.25 (5H, m), 6.52 (1H, d, J = 8.74), 6.05 (1H, m), 4.92 (1H, bs), 4.43 (1H, m), 4.21 (2H, d, J = 5.27), 4.13 (1H, m), 3.32 (3H, s), 2.93 (5H, m), 1.85 (2H, m), 1.20 (6H, m), 1.05 (3H, t, J = 7.43)

FAB MS (m/e) = 513 [M+H]+
FAB MS (m / e) = 513 [M + H] < + >

[실시예 146]Example 146

N-((1S,2R)-1-벤질-2-히드록시-3-{3-[(E)-2-페닐에테닐]-1H-피라졸-1-일}프로필)-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-((1S,2R)-1-benzyl-2-hydroxy-3-{3-[(E)-2-phenylethenyl]-1H-pyrazol-1-yl}propyl)-3-[methyl(propylsulfonyl)amino]benzamide N - ((1 S, 2 R) -1-benzyl-2-hydroxy -3- {3 - [(E) -2-phenylethenyl] -1 H-pyrazol-1-yl} propyl) Preparation of 3- [methyl (propylsulfonyl) amino] benzamide: N -((1 S , 2 R ) -1-benzyl-2-hydroxy-3- {3-[( E ) -2-phenylethenyl]- 1 H -pyrazol-1-yl} propyl) -3- [methyl (propylsulfonyl) amino] benzamide

피라졸 대신에 3-스타이릴피라졸을 사용한 것을 제외하고는, 실시예 143과 동일한 방법으로 실시하여, 표제 화합물 18 ㎎을 44% 수율로 얻었다.18 mg of the title compound was obtained in 44% yield by the same method as Example 143 except for using 3-styrylpyrazole instead of pyrazole.

1H-NMR (300 MHz, CDCl3); 7.65 (1H, m), 7.16∼7.58 (14H, m), 7.05 (1H, s), 6.48 (1H, d, J = 8.70), 6.41 (1H, m), 4.80 (1H, bs), 4.45 (1H, m), 4.32 (2H, d, J = 5.38), 4.08 (1H, m), 3.28 (3H,s), 2.89 (4H, m), 1.83 (2H, m), 0.95 (3H, m) 1 H-NMR (300 MHz, CDCl 3 ); 7.65 (1H, m), 7.16 to 7.58 (14H, m), 7.05 (1H, s), 6.48 (1H, d, J = 8.70), 6.41 (1H, m), 4.80 (1H, bs), 4.45 ( 1H, m), 4.32 (2H, d, J = 5.38), 4.08 (1H, m), 3.28 (3H, s), 2.89 (4H, m), 1.83 (2H, m), 0.95 (3H, m)

FAB MS (m/e) = 573 [M+H]+
FAB MS (m / e) = 573 [M + H] < + >

[실시예 147]Example 147

N-[(1S,2R)-1-벤질-2-히드록시-3-(3-펜에틸-1H-피라졸-1-일)프로필]-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-[(1S,2R)-1-benzyl-2-hydroxy-3-(3-phenethyl-1H-pyrazol-1-yl)propyl]-3-[methyl(propylsulfonyl)amino]benzamide N - [(1 S, 2 R) -1-benzyl-2-hydroxy-3- (3-phenethyl--1 H - pyrazol-1-yl) propyl] -3- [methyl (propyl-sulfonyl) Preparation of amino] benzamide: N -[(1 S , 2 R ) -1-benzyl-2-hydroxy-3- (3-phenethyl-1 H -pyrazol-1-yl) propyl] -3- [methyl ( propylsulfonyl) amino] benzamide

피라졸 대신에 3-펜에틸피라졸을 사용한 것을 제외하고는, 실시예 143과 동 일한 방법으로 실시하여, 표제 화합물 18 ㎎을 45% 수율로 얻었다.18 mg of the title compound was obtained in 45% yield by the same method as Example 143 except that 3-phenethylpyrazole was used instead of pyrazole.

1H-NMR (300 MHz, CDCl3); 7.80 (1H, m), 7.55 (1H, m), 7.43 (2H, m), 7.12∼7.33 (9H, m), 7.01 (1H, m), 6.42 (1H, d, J = 8.70), 6.05 (1H, d, J = 2.20), 4.70 (1H, bs), 4.35 (1H, m), 4.16 (1H, d, J = 5.20), 3.93 (2H, m), 3.33 (3H, s), 2.88 (8H, m), 1.82 (2H, m), 1.03 (3H, m)1 H-NMR (300 MHz, CDCl 3 ); 7.80 (1H, m), 7.55 (1H, m), 7.43 (2H, m), 7.12-7.73 (9H, m), 7.01 (1H, m), 6.42 (1H, d, J = 8.70), 6.05 ( 1H, d, J = 2.20), 4.70 (1H, bs), 4.35 (1H, m), 4.16 (1H, d, J = 5.20), 3.93 (2H, m), 3.33 (3H, s), 2.88 ( 8H, m), 1.82 (2H, m), 1.03 (3H, m)

FAB MS (m/e) = 575 [M+H]+
FAB MS (m / e) = 575 [M + H] < + >

[제조예 163][Production Example 163]

tert-부틸 (1S,2R)-1-벤질-2-히드록시-3-[(3-메톡시벤질)(메틸)아미노]프로필카르바메이트의 제조: tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)(methyl)amino]propylcarbamatePreparation of tert -butyl (1 S , 2 R ) -1-benzyl-2-hydroxy-3-[(3-methoxybenzyl) (methyl) amino] propylcarbamate: tert -butyl (1 S , 2 R ) -1-benzyl-2-hydroxy-3-[(3-methoxybenzyl) (methyl) amino] propylcarbamate

40% 메틸아민 수용액 0.5 ㎖(12.53 mmol)과 상기 제조예 132에서 얻은 화합물 100 ㎎(0.38 mmol)을 이소프로판올 3 ㎖에 녹인 후 상온에서 16 시간 동안 교반하였다. 감압 증류로 용매를 제거한 후 농축액과 3-메톡시벤즈알데히드 41 ㎎(0.34 mmol)를 1,2-디클로로에탄 2 ㎖에 녹였다. 이 반응용액에 소듐 트리아세톡시보로하이드라이드 108 ㎎(0.51 mmol)를 넣은 후 상온에서 16 시간 동안 교반하였다. 에틸아세테이트로 묽힌 후 포화탄산나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 후 컬럼크로마토그래피로 정제하여 표제 화합물 118 ㎎을 75% 수율로 얻었다. 0.5 mL (12.53 mmol) of 40% aqueous methylamine solution and 100 mg (0.38 mmol) of the compound obtained in Preparation Example 132 were dissolved in 3 mL of isopropanol, followed by stirring at room temperature for 16 hours. After the solvent was removed by distillation under reduced pressure, the concentrated solution and 41 mg (0.34 mmol) of 3-methoxybenzaldehyde were dissolved in 2 ml of 1,2-dichloroethane. 108 mg (0.51 mmol) of sodium triacetoxyborohydride was added to the reaction solution, followed by stirring at room temperature for 16 hours. Dilute with ethyl acetate and wash with saturated aqueous sodium carbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography to give 118 mg of the title compound in 75% yield.                     

1H-NMR (300 MHz, CDCl3); 7.29∼7.18 (6H, m), 6.87∼6.78 (3H, m), 5.70∼5.60 (1H, m), 3.80 (3H, s), 3.79∼3.74 (1H, m), 3.63∼3.59 (2H, m), 3.44∼3.40 (1H, m), 2.95∼2.85 (2H, m), 2.42∼2.32 (2H, m), 2.21 (3H, s), 1.34 (9H, s)
1 H-NMR (300 MHz, CDCl 3 ); 7.29 to 7.18 (6H, m), 6.87 to 6.68 (3H, m), 5.70 to 5.60 (1H, m), 3.80 (3H, s), 3.79 to 3.74 (1H, m), 3.63 to 3.59 (2H, m ), 3.44-3.40 (1H, m), 2.95-2.85 (2H, m), 2.42-2.32 (2H, m), 2.21 (3H, s), 1.34 (9H, s)

[실시예 148]Example 148

N-{(1S,2R)-1-벤질-2-히드록시-3-[(3-메톡시벤질)(메틸)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)(methyl)amino]propyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(3-methoxybenzyl) (methyl) amino] propyl} -3- [methyl (propyl-sulfonyl) amino] benzamide Preparation of Amide: N -{(1 S , 2 R ) -1-benzyl-2-hydroxy-3-[(3-methoxybenzyl) (methyl) amino] propyl} -3- [methyl (propylsulfonyl) amino] benzamide

상기 제조예 163에서 얻은 화합물 20 ㎎(0.0482 mmol)을 에틸아세테이트에 묽혀진 4.0 N 염산용액 1 ㎖에 녹여서 2 시간 동안 교반하였다. 용매를 감압증류하여 농축한 후 N,N-디메틸포름아미드 1 ㎖에 녹여서 0℃로 냉각하여 상기 제조예 29에서 얻은 화합물 13 ㎎(0.0482 mmol)과 HATU 20 ㎎(0.0530 mmol)을 가하였다. 여기에 디이소프로필에틸아민 0.2 ㎖(과량)를 가하고 상온으로 온도를 올려 4 시간 동안 교반하였다. 감압증류하여 용매를 제거한 다음 에틸아세테이트에 녹여서 물, 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류로 제거한 후 컬럼크로마토그래피로 정제하여 표제 화합물 20 ㎎을 75% 수율로 얻었다.20 mg (0.0482 mmol) of the compound obtained in Preparation Example 163 was dissolved in 1 ml of 4.0 N hydrochloric acid solution diluted in ethyl acetate, and stirred for 2 hours. The solvent was concentrated by distillation under reduced pressure, dissolved in 1 ml of N, N-dimethylformamide, cooled to 0 ° C., and 13 mg (0.0482 mmol) of the compound obtained in Preparation Example 29 and 20 mg (0.0530 mmol) of HATU were added thereto. 0.2 ml (excess) of diisopropylethylamine was added thereto, and the temperature was raised to room temperature and stirred for 4 hours. After distillation under reduced pressure to remove the solvent, it was dissolved in ethyl acetate and washed with water, 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was removed by distillation under reduced pressure and purified by column chromatography to obtain 20 mg of the title compound in 75% yield.

1H-NMR (300 MHz, CDCl3); 7.65∼7.64 (1H, m), 7.55∼7.50 (1H, m), 7.40∼7.39 (2H, m), 7.36∼7.21 (5H, m), 6.88∼6.82 (3H, m), 6.56∼6.50 (1H, m), 4.49∼4.45 (1H, m), 3.85∼3.78 (1H, m), 3.79 (3H, s), 3.65∼3.60 (1H, m),3.47∼3.42 (1H, m), 3.32 (3H, s), 2.99∼2.90 (4H, m), 2.65∼2.46 (2H, m), 2.26 (3H, s), 1.87∼1.79 (2H, m), 1.02 (3H, t, J = 7.44)1 H-NMR (300 MHz, CDCl 3 ); 7.65 to 7.74 (1H, m), 7.55 to 7.50 (1H, m), 7.40 to 7.39 (2H, m), 7.36 to 7.21 (5H, m), 6.88 to 6.82 (3H, m), 6.56 to 6.50 (1H) , m), 4.49-4.45 (1H, m), 3.85-3.78 (1H, m), 3.79 (3H, s), 3.65-3.60 (1H, m), 3.47-3.42 (1H, m), 3.32 (3H , s), 2.99-2.90 (4H, m), 2.65-2.46 (2H, m), 2.26 (3H, s), 1.87-1.79 (2H, m), 1.02 (3H, t, J = 7.44)

FAB MS (m/e) = 554 [M+H]+
FAB MS (m / e) = 554 [M + H] < + >

[제조예 164][Production Example 164]

tert-부틸 (1S,2R)-3-[아세틸(3-메톡시벤질)아미노]-1-벤질-2-히드록시프로필카르바메이트의 제조: tert-butyl (1S,2R)-3-[acetyl(3-methoxybenzyl)amino]-1-benzyl-2-hydroxypropylcarbamatePreparation of tert -butyl (1 S , 2 R ) -3- [acetyl (3-methoxybenzyl) amino] -1-benzyl-2-hydroxypropylcarbamate: tert -butyl (1 S , 2 R ) -3- [acetyl (3-methoxybenzyl) amino] -1-benzyl-2-hydroxypropylcarbamate

상기 제조예 132에서 얻은 화합물 65 ㎎(0.249 mmol)을 이소프로판올 2 ㎖에 녹인 후, 3-메톡시벤질아민 35 ㎖(0.274 mmol)을 상온에서 넣어 주었다. 반응용액을 16 시간 동안 환류시킨 후 용매를 감압증류하여 제거하였다. 농축물을 디클로로메탄 2 ㎖에 녹인 후 0 C로 냉각하였다. 이 반응용액에 트리에틸아민 70 ㎖(0.498 mmol)과 아세틱안하이드라이드 21 ㎖(0.274 mmol)을 넣고 1 시간 동안 교반하였다. 반응용액을 에틸아세테이트로 희석하고 0.5 N 염산 수용액, 포화탄산수소나트륨 수용액과 소금물로 씻어 주었다. 용매를 감압증류하여 제거한 후 컬럼크로마토그래피로 정제하여 표제 화합물 90 ㎎을 76% 수율로 얻었다.65 mg (0.249 mmol) of the compound obtained in Preparation Example 132 was dissolved in 2 ml of isopropanol, and 35 ml (0.274 mmol) of 3-methoxybenzylamine was added at room temperature. The reaction solution was refluxed for 16 hours and then the solvent was removed by distillation under reduced pressure. The concentrate was taken up in 2 ml of dichloromethane and cooled to 0 C. 70 mL (0.498 mmol) of triethylamine and 21 mL (0.274 mmol) of acetic anhydride were added to the reaction solution, and the mixture was stirred for 1 hour. The reaction solution was diluted with ethyl acetate and washed with 0.5 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography to obtain 90 mg of the title compound in 76% yield.

1H-NMR (300 MHz, CDCl3); 7.28∼7.13 (6H, m), 6.82∼6.65 (3H, m), 4.55 (3H, m), 3.78 (3H, s), 3.71∼3.62 (2H, m), 3.40∼3.36 (1H, m), 2.99∼2.81 (2H, m), 2.16 (3H, s), 1.30 (9H, s)1 H-NMR (300 MHz, CDCl 3 ); 7.28-7.13 (6H, m), 6.82-6.65 (3H, m), 4.55 (3H, m), 3.78 (3H, s), 3.71-3.62 (2H, m), 3.40-3.36 (1H, m), 2.99 to 2.81 (2H, m), 2.16 (3H, s), 1.30 (9H, s)

FAB MS (m/e) = 443 [M+H]+
FAB MS (m / e) = 443 [M + H] < + >

[실시예 149]Example 149

N-{(1S,2R)-3-[아세틸(3-메톡시벤질)아미노]-1-벤질-2-히드록시프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2R)-3-[acetyl(3-methoxybenzyl)amino]-1-benzyl-2-hydroxypropyl}-3-[methyl(propylsulfonyl)amino]benzamide N - {(1 S, 2 R) -3- [ acetyl (3-methoxybenzyl) amino] -1-benzyl-2-hydroxypropyl} -3- [methyl (propyl-sulfonyl) amino] benzamide in Preparation: N -{(1 S , 2 R ) -3- [acetyl (3-methoxybenzyl) amino] -1-benzyl-2-hydroxypropyl} -3- [methyl (propylsulfonyl) amino] benzamide

상기 제조예 163에서 얻은 화합물 대신에 상기 제조예 164에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 148과 동일한 방법으로 실시하여, 표제 화합물 20 ㎎을 75% 수율로 얻었다.20 mg of the title compound was obtained in 75% yield by the same method as Example 148 except for using the compound obtained in Preparation Example 164 instead of the compound obtained in Preparation Example 163.

1H-NMR (300 MHz, CDCl3); 7.78 (1H, s), 7.56∼7.53 (1H, d, J = 7.44), 7.43∼7.34 (2H, m), 7.27∼7.22 (5H, m), 6.81∼6.64 (4H, m), 4.75∼4.65 (1H, m), 4.60∼4.55 (2H, m), 4.40∼4.30 (1H, m), 3.97∼3.87 (1H, m), 3.76 (3H, s), 3.45∼3.44 (1H, m), 3.32 (3H, s), 3.03∼3.02 (2H, d, J = 5.53), 2.95∼2.90 (2H, m), 2.14 (3H, s), 1.86∼1.81 (2H, m), 1.01 (3H, t, J = 7.36).1 H-NMR (300 MHz, CDCl 3 ); 7.78 (1H, s), 7.56 to 7.53 (1H, d, J = 7.44), 7.43 to 7.74 (2H, m), 7.27 to 7.72 (5H, m), 6.81 to 6.64 (4H, m), 4.75 to 4.65 (1H, m), 4.60 to 4.55 (2H, m), 4.40 to 4.30 (1H, m), 3.97 to 3.87 (1H, m), 3.76 (3H, s), 3.45 to 3.44 (1H, m), 3.32 (3H, s), 3.03-3.02 (2H, d, J = 5.53), 2.95-2.90 (2H, m), 2.14 (3H, s), 1.86-1.81 (2H, m), 1.01 (3H, t, J = 7.36).

FAB MS (m/e) = 582 [M+H]+
FAB MS (m / e) = 582 [M + H] < + >

[제조예 165][Production Example 165]

tert-부틸 (1S)-3-메틸-1-[(2S)옥시라닐]부틸카르바메이트의 제조: tert-butyl (1S)-3-methyl-1-[(2S)oxiranyl]butylcarbamate tert - butyl (1 S) -3- methyl -1 - [(2 S) oxiranyl] Preparation of butyl carbamate: tert -butyl (1 S) -3 -methyl-1 - [(2 S) oxiranyl] butylcarbamate

공지의 방법(Tetrahedron Letters 36(31), 1999, 5453-5456)에 따라, t-부톡시카르보닐-(S)-루이신으로부터 표제 화합물을 합성할 수 있었다. According to known methods ( Tetrahedron Letters 36 (31), 1999, 5453-5456), the title compound can be synthesized from t -butoxycarbonyl- ( S ) -leucine.

1H NMR (500 MHz, CDCl3); 4.38 (1H, br), 3.52 (1H, br), 2.85 (1H, m), 2.77 (2H, d), 1.75 (1H, m), 1.45 (9H, s), 1.45-1.32 (2H, m), 0.95 (3H, d), 0.92 (3H, d)
1 H NMR (500 MHz, CDCl 3 ); 4.38 (1H, br), 3.52 (1H, br), 2.85 (1H, m), 2.77 (2H, d), 1.75 (1H, m), 1.45 (9H, s), 1.45-1.32 (2H, m) , 0.95 (3H, d), 0.92 (3H, d)

[제조예 166][Production Example 166]

벤질 (2R,3S)-3-[(tert-부톡시카르보닐)아미노]-2-히드록시-5-메틸헥실(3-메톡시벤질)카르바메이트의 제조: benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-5-methylhexyl(3-methoxybenzyl)carbamateBenzyl (2 R, 3 S) -3 - [(tert - butoxycarbonyl) amino] Preparation of 2-hydroxy-5-methylhexyl (3-methoxybenzyl) carbamate: benzyl (2 R, 3 S ) -3-[( tert -butoxycarbonyl) amino] -2-hydroxy-5-methylhexyl (3-methoxybenzyl) carbamate

상기 제조예 132에서 얻은 화합물 대신에 상기 제조예 165에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 133과 동일한 방법으로 실시하여, 표제 화합물 98 ㎎을 51% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 165 instead of the compound obtained in Preparation Example 132 by the same method as Preparation Example 133, 98 mg of the title compound could be obtained in 51% yield.

1H NMR (500 MHz, CDCl3); 7.39-7.27 (5H, m), 7.21 (1H, t), 6.80 (1H, dd), 6.76 (1H, d), 6.71 (1H, s), 5.18 (2H, s), 4.56 (2H, dd), 3.97 (1H, br), 3.83-3.58 (5H, m), 3.40 (1H, m), 3.26 (1H, d), 2.63 (1H, m), 1.41 (9H, s), 1.48- 1.24 (2H, m), 0.91 (3H, d), 0.88 (3H, d)
1 H NMR (500 MHz, CDCl 3 ); 7.39-7.27 (5H, m), 7.21 (1H, t), 6.80 (1H, dd), 6.76 (1H, d), 6.71 (1H, s), 5.18 (2H, s), 4.56 (2H, dd) , 3.97 (1H, br), 3.83-3.58 (5H, m), 3.40 (1H, m), 3.26 (1H, d), 2.63 (1H, m), 1.41 (9H, s), 1.48-1.24 (2H , m), 0.91 (3H, d), 0.88 (3H, d)

[제조예 167][Production Example 167]

벤질 (2R,3S)-2-히드록시-5-메틸-3-({3-[메틸(프로필술포닐)아미노]벤조일}아미노)헥실(3-메톡시벤질)카르바메이트의 제조: benzyl (2R,3S)-2-hydroxy-5-methyl-3-({3-[methyl(propylsulfonyl)amino]benzoyl}amino)hexyl(3-methoxybenzyl)carbamateBenzyl (2 R, 3 S) -2- hydroxy-5-methyl-3 - ({3- [methyl (propyl-sulfonyl) amino] benzoyl} amino) hexyl Preparation of (3-methoxybenzyl) carbamate : benzyl (2 R , 3 S ) -2-hydroxy-5-methyl-3-({3- [methyl (propylsulfonyl) amino] benzoyl} amino) hexyl (3-methoxybenzyl) carbamate

상기 제조예 133에서 얻은 화합물 대신에 상기 제조예 166에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 134와 동일한 방법으로 실시하여, 표제 화합물 70 ㎎을 56% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 166 instead of the compound obtained in Preparation Example 133, it was carried out in the same manner as in Preparation Example 134, 70 mg of the title compound could be obtained in 56% yield.

1H NMR (400 MHz, CDCl3); 7.85 (1H, s), 7.63 (2H, dd), 7.45 (1H, t), 7.38-7.23 (5H, m), 7.20 (1H, t), 6.84-6.65 (4H, m), 5.18 (2H, dd), 4.54 (2H, dd), 4.28 (1H, m), 3.93 (1H, br), 3.71 (3H, s), 3.50-3.30 (5H, m), 2.97 (2H,dd), 1.92-1.78 (2H, m), 1.68-1.48 (2H, m), 1.32 (1H, m), 1.02 (3H, t), 0.91 (6H, d)
1 H NMR (400 MHz, CDCl 3 ); 7.85 (1H, s), 7.63 (2H, dd), 7.45 (1H, t), 7.38-7.23 (5H, m), 7.20 (1H, t), 6.84-6.65 (4H, m), 5.18 (2H, dd), 4.54 (2H, dd), 4.28 (1H, m), 3.93 (1H, br), 3.71 (3H, s), 3.50-3.30 (5H, m), 2.97 (2H, dd), 1.92-1.78 (2H, m), 1.68-1.48 (2H, m), 1.32 (1H, m), 1.02 (3H, t), 0.91 (6H, d)

[실시예 150]Example 150

N-((1S)-1-{(1R)-1-히드록시-2-[(3-메톡시벤질)아미노]에틸}-3-메틸부틸)-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-((1S)-1-{(1R)-1-hydroxy-2-[(3- methoxybenzyl)amino]ethyl}-3-methylbutyl)-3-[methyl(propylsulfonyl)amino]benzamide N -(( 1S ) -1-{( 1R ) -1-hydroxy-2-[(3-methoxybenzyl) amino] ethyl} -3-methylbutyl) -3- [methyl (propylsulfonyl Preparation of Amino] benzamide: N -((1 S ) -1-{(1 R ) -1-hydroxy-2-[(3-methoxybenzyl) amino] ethyl} -3-methylbutyl) -3- [methyl (propylsulfonyl) amino] benzamide

상기 제조예 134에서 얻은 화합물 대신에 상기 제조예 167에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 88과 동일한 방법으로 실시하여, 표제 화합물 51 ㎎을 92% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 167 instead of the compound obtained in Preparation Example 134, the title compound was obtained in 92% yield in the same manner as in Example 88.

1H NMR (400 MHz, CDCl3); 7.85 (1H, t), 7.58 (2H, dd), 7.39 (1H, t), 7.26 (1H, m), 7.08 (1H, d), 6.94-6.88 (2H, m), 6.83 (1H, dd), 4.30 (1H, m), 3.92-3.71 (6H, m), 3.37 (3H, s), 3.02-2.88 (3H, m), 2.80 (1H, dd), 1.92-1.80 (2H, m), 1.67 (1H, m), 1.57-1.40 (2H, m), 1.03 (3H, t), 0.95 (6H, d)1 H NMR (400 MHz, CDCl 3 ); 7.85 (1H, t), 7.58 (2H, dd), 7.39 (1H, t), 7.26 (1H, m), 7.08 (1H, d), 6.94-6.88 (2H, m), 6.83 (1H, dd) , 4.30 (1H, m), 3.92-3.71 (6H, m), 3.37 (3H, s), 3.02-2.88 (3H, m), 2.80 (1H, dd), 1.92-1.80 (2H, m), 1.67 (1H, m), 1.57-1.40 (2H, m), 1.03 (3H, t), 0.95 (6H, d)

ESI MS (m/e) = 506 [M+H]+
ESI MS (m / e) = 506 [M + H] < + >

[제조예 168][Production Example 168]

tert-부틸 (1S)-1-[(2R)옥시라닐]-2-페닐에틸카르바메이트의 제조: tert-butyl (1S)-1-[(2R)oxiranyl]-2-phenylethylcarbamate tert - butyl (1 S) -1 - [( 2 R) oxiranyl] -2-phenyl Preparation of ethyl carbamate: tert -butyl (1 S) -1 - [(2 R) oxiranyl] -2-phenylethylcarbamate

공지의 방법(Tetrahedron 55(49), 1999, 14145-14160)에 따라 tert-부틸 (1S,2R)-1-벤질-2,3-디히드록시프로필카르바메이트로부터 표제 화합물을 합성할 수 있었다.Synthesis of the title compound from tert -butyl (1 S , 2 R ) -1-benzyl-2,3-dihydroxypropylcarbamate according to known methods ( Tetrahedron 55 (49), 1999, 14145-14160). Could.

1H NMR (400 MHz, CDCl3); 7.35-7.16 (5H, m), 4.47 (1H, br), 4.12 (1H, dd), 3.05-2.82 (3H, m), 2.69 (1H, t), 2.59 (1H, br), 1.39 (9H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.35-7.16 (5H, m), 4.47 (1H, br), 4.12 (1H, dd), 3.05-2.82 (3H, m), 2.69 (1H, t), 2.59 (1H, br), 1.39 (9H, s)

[제조예 169]Preparation Example 169

벤질 (2S,3S)-3-[(tert-부톡시카르보닐)아미노]-2-히드록시-4-페닐부틸(3-메톡시벤질)카르바메이트의 제조: benzyl (2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl(3-methoxybenzyl)carbamateBenzyl (2 S, 3 S) -3 - [(tert - butoxycarbonyl) amino] Preparation of 2-hydroxy-4-phenylbutyl (3-methoxybenzyl) carbamate: benzyl (2 S, 3 S ) -3-[( tert -butoxycarbonyl) amino] -2-hydroxy-4-phenylbutyl (3-methoxybenzyl) carbamate

상기 제조예 132에서 얻은 화합물 대신에 상기 제조예 168에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 133과 동일한 방법으로 실시하여, 표제 화합물 611 ㎎을 94% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 168 instead of the compound obtained in Preparation Example 132 by the same method as in Preparation Example 133, 611 mg of the title compound could be obtained in 94% yield.

1H NMR (400 MHz, CDCl3); 7.40-7.13 (11H, m), 6.83-6.56 (3H, m), 5.16 (2H, s), 4.93 (1H,br), 4.43 (2H, dd), 4.01 (1H, br), 3.70-3.55 (5H, m), 3.06 (1H, d), 2.92-2.72 (2H, m), 1.37 (9H, s)
1 H NMR (400 MHz, CDCl 3 ); 7.40-7.13 (11H, m), 6.83-6.56 (3H, m), 5.16 (2H, s), 4.93 (1H, br), 4.43 (2H, dd), 4.01 (1H, br), 3.70-3.55 ( 5H, m), 3.06 (1H, d), 2.92-2.72 (2H, m), 1.37 (9H, s)

[제조예 170][Production Example 170]

벤질 (2S,3S)-2-히드록시-3-({3-[메틸(프로필술포닐)아미노]벤조일}아미노)-4-페닐부틸(3-메톡시벤질)카르바메이트의 제조: benzyl (2S,3S)-2-hydroxy-3-({3-[methyl(propylsulfonyl)amino]benzoyl}amino)-4-phenylbutyl(3-methoxybenzyl)carbamateBenzyl (2 S, 3 S) -2- hydroxy-3 - ({3- [methyl (propyl-sulfonyl) amino] benzoyl} amino) -4-phenylbutyl (3-methoxybenzyl) Preparation of carbamate benzyl (2 S , 3 S ) -2-hydroxy-3-({3- [methyl (propylsulfonyl) amino] benzoyl} amino) -4-phenylbutyl (3-methoxybenzyl) carbamate

상기 제조예 133에서 얻은 화합물 대신에 상기 제조예 169에서 얻은 화합물을 사용한 것을 제외하고는, 제조예 134와 동일한 방법으로 실시하여, 표제 화합물 117 ㎎을 87% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 169 instead of the compound obtained in Preparation Example 133 by the same method as in Preparation Example 134, 117 mg of the title compound could be obtained in 87% yield.

1H NMR (400 MHz, CDCl3); 7.73 (1H, s), 7.59 (1H, d), 7.53 (1H, d), 7.41 (1H, t), 7.36-7.18 (10H, m), 7.14 (1H, t), 6.80-6.59 (4H, m), 5.16 (2H, s), 4.43 (2H, s), 4.16 (1H, dd), 3.81 (1H, m), 3.69 (3H, s), 3.62 (1H, m), 3.35 (3H, s), 3.14 (1H, d), 3.07-2.87 (4H, m), 1.90-1.78 (2H, m), 1.02 (3H, t)
1 H NMR (400 MHz, CDCl 3 ); 7.73 (1H, s), 7.59 (1H, d), 7.53 (1H, d), 7.41 (1H, t), 7.36-7.18 (10H, m), 7.14 (1H, t), 6.80-6.59 (4H, m), 5.16 (2H, s), 4.43 (2H, s), 4.16 (1H, dd), 3.81 (1H, m), 3.69 (3H, s), 3.62 (1H, m), 3.35 (3H, s ), 3.14 (1H, d), 3.07-2.87 (4H, m), 1.90-1.78 (2H, m), 1.02 (3H, t)

[실시예 151]Example 151

N-{(1S,2S)-1-벤질-2-히드록시-3-[(3-메톡시벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2S)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[methyl(propylsulfonyl)amino]benzamidePreparation of N -{( 1S , 2S ) -1-benzyl-2-hydroxy-3-[(3-methoxybenzyl) amino] propyl} -3- [methyl (propylsulfonyl) amino] benzamide : N -{(1 S , 2 S ) -1-benzyl-2-hydroxy-3-[(3-methoxybenzyl) amino] propyl} -3- [methyl (propylsulfonyl) amino] benzamide

상기 제조예 134에서 얻은 화합물 대신에 상기 제조예 170에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 88과 동일한 방법으로 실시하여, 표제 화합물 73 ㎎을 86% 수율로 얻을 수 있었다.Except for using the compound obtained in Preparation Example 170 instead of the compound obtained in Preparation Example 134, 73 mg of the title compound could be obtained in 86% yield in the same manner as in Example 88.

1H NMR (400 MHz, CDCl3); 7.76 (1H, t), 7.58 (1H, m), 7.51 (1H, d), 7.41 (1H, t), 7.33-7.17 (6H, m), 6.84-6.76 (3H, m), 6.71 (1H, d), 4.27 (1H, m), 3.81-3.63 (6H, m), 3.36 (3H, s), 3.11-2.91 (4H, m), 2.73 (1H, dd), 2.58 (1H, dd), 1.91-0.78 (2H, m), 1.03 (3H, t)1 H NMR (400 MHz, CDCl 3 ); 7.76 (1H, t), 7.58 (1H, m), 7.51 (1H, d), 7.41 (1H, t), 7.33-7.17 (6H, m), 6.84-6.76 (3H, m), 6.71 (1H, d), 4.27 (1H, m), 3.81-3.63 (6H, m), 3.36 (3H, s), 3.11-2.91 (4H, m), 2.73 (1H, dd), 2.58 (1H, dd), 1.91 -0.78 (2H, m), 1.03 (3H, t)

ESI MS (m/e) = 540 [M+H]+
ESI MS (m / e) = 540 [M + H] < + >

[실시예 152]Example 152

N-{(1S)-1-[(5S)-3-(3-메톡시벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S)-1-[(5S)-3-(3-methoxybenzyl)-1,3-oxazolidin-5-yl]-2-phenylethyl}-3-[methyl(propylsulfonyl)amino]benzamide N -{( 1S ) -1-[( 5S ) -3- (3-methoxybenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [methyl ( Preparation of propylsulfonyl) amino] benzamide: N -{(1 S ) -1-[(5 S ) -3- (3-methoxybenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [methyl (propylsulfonyl) amino] benzamide

상기 실시예 88에서 얻은 화합물 대신에 상기 실시예 151에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 89와 동일한 방법으로 실시하여, 표제 화합물 14 ㎎을 82% 수율로 얻을 수 있었다.14 mg of the title compound could be obtained in 82% yield in the same manner as in Example 89, except that the compound obtained in Example 151 was used instead of the compound obtained in Example 88.

1H NMR (400 MHz, CDCl3); 7.84 (1H, t), 7.63-7.57 (2H, m), 7.45 (1H, t), 7.35-7.18 (5H, m), 7.14 (1H, t), 6.94 (1H, d), 6.82-6.73 (3H, m), 4.53 (1H, d), 4.29 (1H, m), 4.19 (1H, d), 4.16 (1H, m), 3.72 (3H, s), 3.62 (2H, dd), 3.37 (3H, s), 3.14 (1H, dd), 3.01-2.90 (3H, m), 2.80 (2H, d), 1.90-1.78 (2H, m), 1.02 (3H, t)1 H NMR (400 MHz, CDCl 3 ); 7.84 (1H, t), 7.63-7.57 (2H, m), 7.45 (1H, t), 7.35-7.18 (5H, m), 7.14 (1H, t), 6.94 (1H, d), 6.82-6.73 ( 3H, m), 4.53 (1H, d), 4.29 (1H, m), 4.19 (1H, d), 4.16 (1H, m), 3.72 (3H, s), 3.62 (2H, dd), 3.37 (3H , s), 3.14 (1H, dd), 3.01-2.90 (3H, m), 2.80 (2H, d), 1.90-1.78 (2H, m), 1.02 (3H, t)

ESI MS (m/e) = 552 [M+H]+
ESI MS (m / e) = 552 [M + H] < + >

[제조예 171]Preparation Example 171

tert-부틸 (1S,2S)-1-벤질-2-히드록시-3-[(3-메톡시벤질)(메틸)아미노]프로필카르바메이트의 제조: tert-butyl (1S,2S)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)(methyl)amino]propylcarbamatePreparation of tert -butyl (1 S , 2 S ) -1-benzyl-2-hydroxy-3-[(3-methoxybenzyl) (methyl) amino] propylcarbamate: tert -butyl (1 S , 2 S ) -1-benzyl-2-hydroxy-3-[(3-methoxybenzyl) (methyl) amino] propylcarbamate

상기 제조예 132에서 얻은 화합물 대신에 상기 제조예 168에서 얻은 화합물 을 사용한 것을 제외하고는, 제조예 163과 동일한 방법으로 실시하여, 표제 화합물 110 ㎎을 70% 수율로 얻었다.Except for using the compound obtained in Preparation Example 168 instead of the compound obtained in Preparation Example 132 by the same method as Preparation Example 163, 110 mg of the title compound was obtained in 70% yield.

1H-NMR (300 MHz, CDCl3); 7.35∼7.18 (6H, m), 6.85∼6.78 (3H, m), 5.00∼4.90 (1H, m), 3.85∼3.78 (3H, s), 3.78∼3.58 (3H, m), 3.45∼3.38 (1H, m), 2.98∼2.85 (2H, m), 2.65∼2.46 (1H, m), 2.21∼2.15 (1H, m), 2.18 (3H, s), 1.43 (9H, s)
1 H-NMR (300 MHz, CDCl 3 ); 7.35-7.18 (6H, m), 6.85-6.68 (3H, m), 5.00-4.90 (1H, m), 3.85-3.78 (3H, s), 3.78-3.58 (3H, m), 3.45-3.38 (1H) , m), 2.98-2.85 (2H, m), 2.65-2.46 (1H, m), 2.21-2.15 (1H, m), 2.18 (3H, s), 1.43 (9H, s)

[실시예 153]Example 153

N-{(1S,2S)-1-벤질-2-히드록시-3-[(3-메톡시벤질)(메틸)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드의 제조: N-{(1S,2S)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)(methyl)amino]propyl}-3-[methyl(propylsulfonyl)amino]benzamide N -{( 1S , 2S ) -1-benzyl-2-hydroxy-3-[(3-methoxybenzyl) (methyl) amino] propyl} -3- [methyl (propylsulfonyl) amino] benz Preparation of Amide: N -{(1 S , 2 S ) -1-benzyl-2-hydroxy-3-[(3-methoxybenzyl) (methyl) amino] propyl} -3- [methyl (propylsulfonyl) amino] benzamide

상기 제조예 163에서 얻은 화합물 대신에 상기 제조예 171에서 얻은 화합물을 사용한 것을 제외하고는, 실시예 148과 동일한 방법으로 실시하여, 표제 화합물 16 ㎎을 70% 수율로 얻었다.Except for using the compound obtained in Preparation Example 171 instead of the compound obtained in Preparation Example 163 by the same method as in Example 148, 16 mg of the title compound was obtained in 70% yield.

1H-NMR (300 MHz, CDCl3); 7.75 (1H, s), 7.57∼7.56 (1H, m), 7.38 (1H, t, J = 7.89), 7.30∼7.26 (5H, m), 7.18∼7.13 (1H, m), 6.81∼6.73 (3H, m), 6.60∼6.55 (1H, m), 4.30∼4.10 (1H, m), 3.85∼3.78 (1H, m), 3.74 (3H, s), 3.64∼3.60 (1H, d, J = 12.96), 3.37∼3.33 (1H, m), 3.35 (3H, s), 3.04∼2.92 (4H, m), 2.52 (1H, m), 2.25∼2.21 (1H, m), 2.22 (3H, s), 1.87∼1.81 (2H, m), 1.02 (3H, t, J = 7.45)1 H-NMR (300 MHz, CDCl 3 ); 7.75 (1H, s), 7.57 to 7.56 (1H, m), 7.38 (1H, t, J = 7.89), 7.30 to 7.26 (5H, m), 7.18 to 7.13 (1H, m), 6.81 to 6.73 (3H , m), 6.60 to 6.55 (1H, m), 4.30 to 4.10 (1H, m), 3.85 to 3.78 (1H, m), 3.74 (3H, s), 3.64 to 3.60 (1H, d, J = 12.96) , 3.37 to 3.33 (1H, m), 3.35 (3H, s), 3.04 to 2.92 (4H, m), 2.52 (1H, m), 2.25 to 2.21 (1H, m), 2.22 (3H, s), 1.87 -1.81 (2H, m), 1.02 (3H, t, J = 7.45)

FAB MS (m/e) = 554 [M+H]+
FAB MS (m / e) = 554 [M + H] < + >

[실험예 1] 베타-세크리타제 저해제의 생물학적 활성 측정 Experimental Example 1 Measurement of Biological Activity of Beta-Secretase Inhibitor

(1) 재조합 베타-세크리타제 발현 벡터의 제조(1) Preparation of recombinant beta-secretase expression vector

기존의 public data base인 Genebank에 공지된 사람 BACE 유전자 염기서열(accession #: AF190725)을 기초로 합성한 primer를 사용하는 PCR 방법으로 사람 태아 cDNA 라이브러리(Human placental cDNA library)(Clonetech)로부터 BACE 유전자 cDNA를 클로닝하였다. 상기 BACE 전체 유전자 중에서 세포막 투과 부분(transmembrane domain)과 세포질 부분(cytoplasmic domain)을 제외한 아미노산 서열 1∼460에 해당하는 부분, 즉 ectodomain만을 다시 클로닝한 다음, 그것의 3' 말단에 사람 면역 글로불린 G(hIgG)의 아미노산 230개(아미노산 서열 1∼460)에 해당하는 Fc 부분 염기서열을 붙였다. 상기 BACE (ectodomain)-IgG Fc(이하, "BACE-Fc"로 칭함)를 포유동물 발현 벡터인 pCDNA3(Invitrogen)의 BamHI과 EcoR I 사이에 접합(ligation)시켜 넣음으로써, BACE-Fc 단백질 발현 벡터(이하, "pCDNA3 BACE Fc"로 칭함)를 제조하였다.
BACE gene cDNA from human placental cDNA library (Clonetech) by PCR using primers synthesized on the basis of the human BACE gene sequence (accession #: AF190725) known from Genebank, an existing public data base. Was cloned. In the entire BACE gene, only the portion corresponding to amino acid sequences 1 to 460 except for the transmembrane domain and the cytoplasmic domain, ie, the ectodomain, was cloned again, and then human immunoglobulin G ( The Fc partial nucleotide sequence corresponding to 230 amino acids (amino acid sequence 1-460) of hIgG) was attached. BACE-Fc protein expression vector by ligation of BACE (ectodomain) -IgG Fc (hereinafter referred to as "BACE-Fc") between BamHI and EcoR I of pCDNA3 (Invitrogen), a mammalian expression vector (Hereinafter referred to as "pCDNA3 BACE Fc") was prepared.

(2) BACE-Fc 융합 단백질 발현 포유동물 세포주 제조(2) Preparation of BACE-Fc Fusion Protein Expressing Mammalian Cell Line

HEK(human embryonic kidney) 293T 세포(ATCC Accession# CRL1573)를 10%의 소 태아 혈청(fetal bovine serum (FBS) (GIBCO-BRL))을 함유한 DMEM(Dulbecco's minimum essential medium) (GIBCO-BRL) 배양액으로 배양한 다음, 6-well culture plate로 옮기고, 세포가 배양 용기 바닥을 덮을 정도로 자란 뒤에, Lipofectamine Plus(Life Technologies)를 사용하여 상기 pCDNA3 BACE Fc로 형질전환시켰다. 형질전환된 세포들은 1 ㎎/㎖의 Geneticin(G418 sulfate) (GIBCO-BRL)을 함유한 배양액으로 매 4 일마다 교체해 주면서 선택배양 하였고, 그 중 60여 개의 클론을 각각 분리한 다음, 다시 6-well culture plate에서 분리 배양하였다. 분리된 클론들 중 세포 성장 속도가 양호한 13개의 클론들을 동일한 세포수(2 × 105 cells/㎖/24-well)로 맞추어서 24-well culture plate에서 다시 3 일 동안 배양하였다. 배양액으로 분비된 BACE-Fc 단백질의 양을 염소 유래 항 사람 IgG(Goat anti-human Igg(Pierce))를 사용하는 ELISA 방법으로 정량하였다. 그 결과로서, 가장 빠른 성장속도와 BACE-Fc 발현양(1 ℓ 배양시 약 20 ㎎)을 나타내는 클론 #8-3을 선별하였다.
Dulbecco's minimum essential medium (DMEM) containing human embryonic kidney (HEK) 293T cells (ATCC Accession # CRL1573) containing 10% fetal bovine serum (FBS) (GIBCO-BRL) (GIBCO-BRL) culture, then transferred to a 6-well culture plate, cells were grown to cover the bottom of the culture vessel, and then transformed into the pCDNA3 BACE Fc using Lipofectamine Plus (Life Technologies). Transformed cells were selected and cultured every 4 days with a culture medium containing 1 mg / ml Geneticin (G418 sulfate) (GIBCO-BRL). The cells were separated and cultured in well culture plates. Thirteen clones with good cell growth rate among the isolated clones were incubated for 3 days in a 24-well culture plate with the same cell number (2 × 10 5 cells / ml / 24-well). The amount of BACE-Fc protein secreted into the culture was quantified by ELISA using goat anti-human IgG (Pierce). As a result, clone # 8-3 showing the fastest growth rate and the amount of BACE-Fc expression (about 20 mg in 1 L culture) was selected.

(3) BACE-Fc 융합 단백질 생산 및 정제(3) BACE-Fc fusion protein production and purification

HEK 293T BACE-Fc #8-3 세포주를 10%의 FBS를 함유한 DMEM 배양액 250 ㎖이 있는 roller bottle에 2 × 105 cells/㎖이 되게 넣고, Roll-In 세포 배양기(Bellco)에서 40 rpm의 속도로 회전시키면서 37℃ 온도하에서 4 일 동안 배양하였다. 세포가 배양용기를 완전히 덮을 정도로 자랐을 때, 250 ㎖의 무혈청 배지(SFII; GIBCO-BRL)로 1 회 세척해 준 다음, 다시 500 ㎖의 인슐린(0.5 ㎍/㎖) (SIGMA)을 함유한 무혈청 배지를 넣고 3 일 동안 배양하였다. 배양액을 수거한 후, 다시 500 ㎖의 무혈청 배지를 넣고 3 일 동안 배양하는 과정을 2 회 반복한 다음, 수거된 모든 세포 배양액(conditioned media)을 7000 rpm에서 20 분 동안 원심분리(Beckman, JA 10 rotor)한 뒤, 세정액만을 분리하였다. 상기 세정액을 0.45 ㎛ 필터에 통과시킨 후, 20 mM sodium phosphata buffer(pH 7.0)로 평형화시킨 Protein A sepharose 크로마토그래피 컬럼(Pharmacia)에 통과시키고, 다시 20 mM sodium phosphata buffer(pH 7.0)로 세척함으로써, 흡착되지 않은 모든 단백질을 제거하였다. 100 mM sodium acetate 완충액(pH 3.5)을 가하여 흡착된 단백질을 떨어뜨려 냄으로써, 순도 95% 이상의 BACE-Fc 단백질(M.W 100 KDa.)을 얻을 수 있었다. 상기의 방법으로 제조된 BACE-Fc 융합 단백질은, 대장균에서 발현시킨 후 refolding 시킨 경우와는 달리, 완전히 당화된 형태이며, 실제 생체내에서 분리 및 정제된 BACE 단백질과 그 기질 특이도에 있어서 동일한 양상을 나타냄이 보고된 바 있다 (Citron et al., Neuron 14: 661-670 (1999)).
The HEK 293T BACE-Fc # 8-3 cell line was placed in a roller bottle containing 250 ml of DMEM medium containing 10% FBS at 2 x 10 5 cells / ml and loaded at 40 rpm in a Roll-In cell incubator (Bellco). Incubated at 37 ° C. for 4 days while rotating at speed. When cells were grown to completely cover the culture vessel, they were washed once with 250 ml serum-free medium (SFII; GIBCO-BRL) and then again with 500 ml insulin (0.5 μg / ml) (SIGMA) Serum medium was added and incubated for 3 days. After the cultures were collected, 500 ml of serum-free medium was added again, followed by culturing for three days, and then all collected cell cultures were centrifuged at 7000 rpm for 20 minutes (Beckman, JA). 10 rotor), and only the washing liquid was separated. After passing through the 0.45 μm filter, the washing solution was passed through a Protein A sepharose chromatography column (Pharmacia) equilibrated with 20 mM sodium phosphata buffer (pH 7.0), and washed again with 20 mM sodium phosphata buffer (pH 7.0). All protein that was not adsorbed was removed. By adding 100 mM sodium acetate buffer (pH 3.5) to drop the adsorbed protein, BACE-Fc protein (MW 100 KDa.) With a purity of 95% or more was obtained. The BACE-Fc fusion protein prepared by the above method is completely glycosylated, unlike the expression and refolding in Escherichia coli, and is identical in its substrate specificity to the BACE protein isolated and purified in vivo. Has been reported (Citron et al., Neuron 14: 661-670 (1999)).

(4) 형광 표지 특이 기질을 사용한 베타-세크리타제 활성도 검정(4) Beta-secretase activity assay using fluorescent label specific substrate

베타-세크리타제의 효소 활성도와 합성 화합물들의 저해 효능을 측정하기 위하여, 상기 정제된 BACE-Fc 융합 단백질과 형광 표지 베타-세크리타제 특이 기질을 사용한 Fluorescence Resonance Energy Transfer(FRET) 효소 활성도 측정법을 확립하였다. 이를 간략히 서술하면 다음과 같다. 세포내 베타-세크리타제 특이 기질로 알려져 있는 Amyloid precursor protein(APP)의 전체 아미노산 서열 중, 베타- 세크리타제 절제 부분을 포함하는 10개 아미노산 부위에 해당하는 펩티드 특이 기질을, 형광 발색체(Fluorophore)인 EDANS와 Quenching group인 DABCYL을 부착시킨 형태로 합성한다. 이 형광 표지 기질을 BACE-Fc와 같이 반응시켜, BACE 작용 부위가 절단되면서 quenching group이 떨어져 나가고, EDANS는 350 nM의 excitation light에 의해 510 nm 파장의 형광을 나타내게 되는데, 그 양을 측정함으로써 반응 진행 정도를 민감하고도 간편하게 측정할 수 있다. 각 합성 화합물들은 10 mM 의 농도로 DMSO에 용해시켜서 20℃에서 보관한다. 활성도를 측정하기 위해서는, 먼저 100 μM DMSO 용액을 96 well plate 가장 오른쪽 열에 넣은 뒤, 동일한 양의 DMSO로 2 배 희석하는 단계를 9 단계까지 순차적으로 실행한다. 15 ㎕의 반응 완충액(100 mM sodiumacetate, pH 5.0, 0.05% CHAPS)과 10 ㎕의 50% DMSO에 용해되어있는 600 μM 형광 표지 BACE 기질을 넣어둔 96-well assay plate에 상기 희석 화합물 용액 5 ㎕를 첨가함으로써, 최종 DMSO 농도는 10%가 되게 하고 저해제 처리 농도는 5 μM부터 9 단계의 2 배 희석이 되게 한다. 70 ㎕의 상기 정제된 BACE-Fc 융합단백질 용액을 최종농도 0.2 μM이 되게 가한 뒤, 상온에서 1 시간 동안 반응을 진행시킨다. 반응 결과물의 생성량은 fluorescent plate reader(SpectraMax Gemini XS, Molecular Device)를 사용하여 350 nM excitation 과 510 nm emission 파장에서 나타나는 형광으로써 측정한다. 이 측정값을 합성화합물이 첨가되지 않은 대조군에서의 측정값과 비교함으로써, 상기 베타-세크리타제 활성도의 50%를 저해하는 합성 화합물의 농도, 즉, IC50와 Ki를 결정한다. 실험 결과, 본 발명에 따 른 화학식 1의 술폰 아미드 유도체의 IC50 값은 0.1∼50 μM의 활성을 나타내며, Ki 값은 0.01∼50 μM의 범위에 속하였다.
In order to measure the enzyme activity of the beta-secretase and the inhibitory effect of the synthetic compounds, Fluorescence Resonance Energy Transfer (FRET) enzyme activity assay using the purified BACE-Fc fusion protein and the fluorescently labeled beta-secretase specific substrate was established. . This is briefly described as follows. Among the entire amino acid sequence of Amyloid precursor protein (APP), which is known as an intracellular beta-secretase specific substrate, a peptide specific substrate corresponding to a 10 amino acid site including a beta-secretase ablation portion is identified by a fluorescent fluorophore. It is synthesized by attaching EDANS and quenching group DABCYL. The fluorescence-labeled substrate is reacted with BACE-Fc, and the quenching group is detached as the BACE action site is cleaved, and EDANS exhibits 510 nm wavelength fluorescence by 350 nM excitation light. The accuracy can be measured sensitively and simply. Each synthetic compound is dissolved in DMSO at a concentration of 10 mM and stored at 20 ° C. To measure activity, first add 100 μM DMSO solution to the rightmost column of the 96 well plate, then dilute twice with the same amount of DMSO up to 9 steps sequentially. 5 μl of the diluted compound solution on a 96-well assay plate containing 600 μl fluorescent labeled BACE substrate dissolved in 15 μl of reaction buffer (100 mM sodiumacetate, pH 5.0, 0.05% CHAPS) and 10 μl of 50% DMSO. By addition, the final DMSO concentration is 10% and the inhibitor treatment concentration is 2-fold dilution from 5 μM to 9 steps. 70 μl of the purified BACE-Fc fusion protein solution was added to a final concentration of 0.2 μM, followed by reaction at room temperature for 1 hour. The amount of reaction product produced was measured by fluorescence at 350 nM excitation and 510 nm emission wavelength using a fluorescent plate reader (SpectraMax Gemini XS, Molecular Device). By comparing this measurement with that in the control without the addition of the synthetic compound, the concentrations of the synthetic compound that inhibit 50% of the beta-secretase activity, namely IC50 and K i, are determined. As a result, the IC 50 value of the sulfonamide derivative of formula 1 according to the present invention shows an activity of 0.1-50 μM, and the K i value is in the range of 0.01-50 μM.

[실험예 2] 세포내 베타-세크리타제 활성도 측정 Experimental Example 2 Measurement of Intracellular Beta-Secretase Activity

아밀로이드 전구체(APP)로부터 베타-아밀로이드 펩티드를 만드는 사람 세포주를 이용하여 합성 화합물들의 세포내 베타-세크리타제 활성의 저해도를 측정할 수 있다. Inhibition of intracellular beta-secretase activity of synthetic compounds can be measured using human cell lines that make beta-amyloid peptides from amyloid precursors (APP).

(1) 베타-세크리타제와 아밀로이드 전구체를 생산하는 영구 세포주 확립(1) Establishment of permanent cell lines producing beta-secretase and amyloid precursors

BACE 전체 유전자는 포유동물 발현 벡터인 pcDNA3.1(+)Zeo (Invitrogen)에 클로닝하였고, C-말단에 두 개의 라이신을 첨부한 swedish 돌연 변이형 아밀로이드 전구체(APP swe) 유전자(APPswe KK)는 다른 포유동물 발현 벡터인 pcDNA3.1(+)Neo (Invitrogen)에 클로닝하였다. HEK(human embryonic kidney) 293T 세포(ATCC Accession# CRL1573)를 10%의 FBS를 함유한 DMEM(Dulbecco's minimum essential medium) (GIBCO-BRL) 배양액으로 배양한 다음 6-well culture plate로 옮기고, 세포가 배양 용기 바닥을 덮을 정도로 자란 뒤에, Lipofectamine 2000(Life Technologies)을 사용하여, 상기 pcDNA3.1(+)Zeo BACE와 pcDNA3 (+)Neo APP swe KK 발현 벡터로 형질전환시켰다. 형질전환된 세포들은 1 ㎎/㎖의 Geneticin(G418 sulfate) (GIBCO-BRL)을 함유한 배양액으로 매 4 일마다 교체해 주면서 선택하였고, 각 클론들을 각각 분리한 다음, 다시 6-well culture plate에서 분리 배양하였 다. 선택된 클론들 중 세포 성장 속도가 양호한 76개의 클론들을 동일한 세포 수(2 × 105 cells/㎖/24-well)로 맞춰서, 24-well culture plate에서 새로 2 일 동안 배양한 다음, 10%의 fetal bovine serum(FBS) (GIBCO-BRL)을 함유한 OPTI-MEM(GIBCO-BRL) 배양액으로 교환해 준 다음, 48 시간 동안 배양하면서 배양액으로 분비된 베타-아밀로이드 펩티드의 양을 베타-아밀로이드 펩티드에 선택적인 항체를 사용한 ELISA 방법으로 정량하였다. 그 결과로서, 가장 빠른 성장속도와 가장 많은 베타-아밀로이드 펩티드 발현 양을 나타내는 클론 #28을 선별하였다.
The entire BACE gene was cloned into the mammalian expression vector pcDNA3.1 (+) Zeo (Invitrogen), and the swedish mutant amyloid precursor (APP swe) gene (APPswe KK) with two lysines attached at the C-terminus was different. It was cloned into the mammalian expression vector pcDNA3.1 (+) Neo (Invitrogen). Human embryonic kidney (HEK) 293T cells (ATCC Accession # CRL1573) were incubated with Dulbecco's minimum essential medium (DMEM) culture medium containing 10% FBS (GIBCO-BRL) and then transferred to a 6-well culture plate. After growing to the bottom of the vessel, Lipofectamine 2000 (Life Technologies) was used to transform the pcDNA3.1 (+) Zeo BACE and pcDNA3 (+) Neo APP swe KK expression vectors. Transformed cells were selected by replacing every 4 days with a culture medium containing 1 mg / ml Geneticin (G418 sulfate) (GIBCO-BRL), each clone isolated, and then again in a 6-well culture plate. Incubated. Of the clones selected, 76 clones with good cell growth rate were set to the same cell number (2 × 10 5 cells / ml / 24-well), incubated for 2 days in a 24-well culture plate, and then 10% fetal. Exchange with OPTI-MEM (GIBCO-BRL) cultures containing bovine serum (FBS) (GIBCO-BRL), and select the beta-amyloid peptides with the amount of beta-amyloid peptide secreted into the cultures for 48 hours. Quantitation was performed by ELISA method using antibodies. As a result, clone # 28 was selected that exhibited the fastest growth rate and the highest amount of beta-amyloid peptide expression.

(2) 베타-아밀로이드 펩티드 ELISA 분석법(2) Beta-amyloid peptide ELISA assay

상기 BACE와 C-말단에 두 개의 라이신을 첨부한 swedish 돌연 변이형 아밀로이드 전구체를 영구 발현시키는 세포주인 HEK BACE APPswe KK # 28 세포를 24-well 배양용기에 각 well 당 1 × 105 개의 세포로 넣고 6% CO2의 존재하에서 37℃ 배양기에서 48 시간 동안 배양하였다. 세포가 배양용기를 완전히 덮을 정도로 자랐을 때, 300 ㎕의 10% FBS를 함유한 Opti-MEM (GIBCO-BRL)으로 교환해 준 뒤, 다시 48 시간 동안 배양하였다. 상기 배양액으로 분비된 베타-아밀로이드 펩티드 발현양은 베타-아밀로이드 펩티드에 특이적인 두 개의 항체를 사용한 sandwich ELISA 방법을 통하여 측정하였는데, 이를 간략히 기술하면 다음과 같다. HEK BACE APPswe KK # 28 cells, which are cell lines permanently expressing swedish mutant amyloid precursors with two lysines attached to the BACE and C-terminus, were put into 1 × 10 5 cells per well in a 24-well culture vessel. Incubated for 48 hours in a 37 ° C. incubator in the presence of 6% CO 2 . When the cells were grown to completely cover the culture vessel, the cells were exchanged with Opti-MEM (GIBCO-BRL) containing 300 μl of 10% FBS, and then incubated for another 48 hours. The expression level of the beta-amyloid peptide secreted into the culture solution was measured by sandwich ELISA using two antibodies specific for the beta-amyloid peptide, which is briefly described as follows.

먼저 베타-아밀로이드 펩티드 아미노산 17∼24에 특이적으로 반응하는 단일 클론 항체 4G8(signet)를 PBS로 10 ㎍/㎖이 되게 희석한 다음, 100 ㎕ 씩 Maxisorp 96 well immuno plate(NUNC)의 각 well 에 넣고, 상온에서 2 시간 이상(또는 4℃에서 하루 이상) 방치함으로써 표면을 코팅하였다. 상기 플레이트는 상온에서 1 시간 동안 200 ㎕의 Superblock(PIERCE)을 처리함으로써 비특이적인 흡착이 일어나지 않도록 하고, 100 ㎕의 각 농도로 희석된 베타-아밀로이드 펩티드 1∼40 또는 1 × RIPA가 되도록 조절한 세포 배양액을 첨가하고, 상온에서 2 시간 반응시켰다. 세척액(0.05% Tween20가 첨가된 PBS)으로 5 회 세척해 준 다음, 0.1 × Superblock (PIERCE)으로 500 배 희석한 중합 클론 항체인 anti-Ab1-40 또는 anti-Ab 1-42(Biosource International) 100 ㎕를 첨가한 뒤, 상온에서 2 시간 반응시켰다. 세척액으로 5 회 세척해 준 다음, 0.1 × Superblock(PIERCE)으로 2,000 배 희석한 HRP(horse radish peroxidase) 부착 항토끼 IgG 항체(goat anti-rabbit IgG antibody conjugated with HRP (horse radish peroxidase) (Amersham)) 100 ㎕를 첨가한 뒤, 상온에서 1 시간 반응시켰다. 세척액으로 5 회 세척해 준 다음, 100 mM sodium citrate(pH 4.5)에 용해시킨 O-phenylnediamine dihydrochloride(SIGMA) 용액 100 ㎕를 가하고, 상온에서 30 분 동안 반응시킨 뒤, microplate reader(SpectraMax 340, Molecular Device)를 사용하여 450 nm에서의 흡광도를 측정하였다. 이 측정값을 합성 화합물이 첨가되지 않고 0.5 %의 DMSO만을 처리한 대조군에서의 측정값과 비교함으로써, 세포내 베타-세크리타제 활성도의 50%를 저해 하는 합성 화합물의 농도, 즉 IC50를 결정하였다. 실험 결과, 본 발명에 따른 화학식 1의 술폰 아미드 유도체의 IC50 값은 0.5∼50 μM의 활성을 나타내었다.
First, the monoclonal antibody 4G8 (signet) that specifically reacts with beta-amyloid peptide amino acids 17-24 was diluted to 10 ㎍ / ml with PBS, and then 100 µl was added to each well of the Maxisorp 96 well immunoplate (NUNC). The surface was coated by placing and leaving at room temperature for at least 2 hours (or at least 4 days at 4 ° C.). The plate was treated with 200 μl of Superblock (PIERCE) for 1 hour at room temperature to prevent nonspecific adsorption and adjusted to 1-40 or 1 × RIPA of beta-amyloid peptide diluted to 100 μl of each concentration. The culture solution was added and reacted at room temperature for 2 hours. After washing five times with washing solution (PBS with 0.05% Tween20), anti-Ab1-40 or anti-Ab 1-42 (Biosource International) 100, a polymeric clone antibody diluted 500-fold with 0.1 × Superblock (PIERCE) 100 After the addition of μl, the reaction was carried out at room temperature for 2 hours. After washing 5 times with washing solution, goat anti-rabbit IgG antibody conjugated with horse radish peroxidase (HRP) (Amersham) diluted 2,000-fold with 0.1 × Superblock (PIERCE) After 100 μl was added, the reaction was carried out at room temperature for 1 hour. After washing 5 times with washing solution, 100 μl of a solution of O-phenylnediamine dihydrochloride (SIGMA) dissolved in 100 mM sodium citrate (pH 4.5) was added, and reacted at room temperature for 30 minutes, followed by a microplate reader (SpectraMax 340, Molecular Device). ), The absorbance at 450 nm was measured. By comparing this measurement with that in the control treated with only 0.5% DMSO without addition of the synthetic compound, the concentration of the synthetic compound, i.e., IC 50 , which inhibits 50% of intracellular beta-secretase activity is determined. . As a result, the IC 50 value of the sulfone amide derivative of the formula 1 according to the present invention showed an activity of 0.5-50 μM.

[실험예 3] 쥐에서의 약물동력학 시험Experimental Example 3 Pharmacokinetic Test in Rats

본 시험에 사용한 약물은, 본 발명의 실시예 88의 화합물인 N-{(1S,2R)-1-벤질-2-히드록시-3-[(3-메톡시벤질)아미노]프로필}-3-[메틸(프로필술포닐)아미노]벤즈아미드(이하, "화합물 1"이라 함), 실시예 89의 화합물인 N-{(1S)-1-[(5R)-3-(3-메톡시벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}-3-[메틸(프로필술포닐)아미노]벤즈아미드(이하, "화합물 2"라 함)를 사용하였다. 또한, 비교 실험용 화합물로서, Elan Pharmaceutical의 PCT 국제출원 WO 02/098849호의 N1-{1-벤질-2-히드록시-3-[(3-메톡시벤질)아미노]프로필}-N3,N3-디프로필이소프탈아미드(이하, "화합물 3"이라 함)을 사용하였다.Drugs used in this test, the compounds of the invention of Example 88 N - {(1 S, 2 R) -1- benzyl-2-hydroxy-3 - [(3-methoxybenzyl) amino] propyl} -3- [methyl (propylsulfonyl) amino] benzamide (hereinafter referred to as "Compound 1"), the compound of Example 89, N -{( 1S ) -1-[( 5R ) -3- ( 3-methoxybenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [methyl (propylsulfonyl) amino] benzamide (hereinafter referred to as "Compound 2") Used. Further, as a comparative experimental compound, Elan Pharmaceutical the PCT International Application WO 02/098849 favor N 1 - {1- benzyl-2-hydroxy-3 - [(3-methoxybenzyl) amino] propyl} -N 3, N 3 -dipropylisophthalamide (hereinafter referred to as "Compound 3") was used.

약물 투여 18 시간 전부터 절식한 쥐(250∼300 g, 한국, 바이오 제노믹스)에 PEG400에 녹인 약물을 경구존대를 사용하여 20 ㎎/㎏ 용량으로 투여하였다. 약물 투여 전(control)과, 약물 투여 후 30, 60, 120, 240 및 360 분에 각각 쥐꼬리 정맥에서 헤파린 처리한 주사기로 대략 200 ㎕의 혈액을 채취하였다. 채취한 혈액을 원심분리하여 혈장을 분리한 다음, 제단백하여 원심분리 후 상층액을 취하여 HPLC로 분석하였다. 검량선은 약물의 0.10∼5.0 g/㎖ 농도 범위에서 시행하였다. 약물은 Shiseido Capcell-Pak C18 역상 column으로 분석하였다. HPLC는 Class-LC10A system control software, CBM-10A communication bus module, two LC-10AD pumps, SIL-10AXL autoinjector with sample cooler, SPD-10AV ultraviolet detector(Shimadzu, 동경, 일본), GLP-2050+ laser printer(LG 전자, 서울, 한국)의 장치로 구성되어 있다. 화합물 3은 210 nm의 파장에서 자외선 램프로 분석하였고, 유속은 분당 1 ㎖로 하였다. 이동상으로는 acetonitrile과 0.1% trifluoroacetic acid 용액을 각각 36%와 64%로 사용하였다. 약물의 retention time은 대략 11 분이었다. 화합물 1과 화합물 2는 228 nm의 파장에서 자외선 램프로 분석하였고, 유속은 분당 1 ㎖로 하였다. 이동상으로는 acetonitrile과 0.1% trifluoroacetic acid 용액을 각각 35%와 65%로 사용하였다. 약물의 retention time은 대략 8 분이었다. 데이터는 혈장 중 약물 농도와 시간과의 관계 그래프로 표시하였고(도 1 참조), Win-Nonlin program(Scientific Consultion사, 미국)을 이용하여 non-compartment model에 적용하여 약동력학 파라미터를 계산하였다. 약물 투여 후의 혈장 중 최고농도(Cmax), 최고농도의 시간(Tmax), 무한대 시간까지 추정된 혈장 중 농도-시간 곡선 하 면적(AUCinf), 약물 투여 후 6 시간까지의 혈장 중 농도-시간 곡선 하 면적(AUC0-6hr)을 계산한 결과, 화합물 1과 화합물 2가 Cmax, AUCinf와 AUCO-6hr 등의 모든 값에서 화합물 3보다 높은 값을 나타내어, 쥐에서의 경구흡수가 잘되었음을 확인할 수 있었다.A drug dissolved in PEG400 was administered at a dose of 20 mg / kg using an oral zone in fasted rats (250-300 g, Biogenome, Korea) 18 hours before drug administration. Approximately 200 μl of blood was collected with heparinized syringes in rat tail veins before and after drug administration and at 30, 60, 120, 240 and 360 minutes after drug administration, respectively. The collected blood was centrifuged to separate plasma, and then the protein was centrifuged and the supernatant was collected and analyzed by HPLC. The calibration curve was performed in the concentration range of 0.10 to 5.0 g / ml of the drug. The drug was analyzed by Shiseido Capcell-Pak C18 reversed phase column. HPLC uses Class-LC10A system control software, CBM-10A communication bus module, two LC-10AD pumps, SIL-10AXL autoinjector with sample cooler, SPD-10AV ultraviolet detector (Shimadzu, Tokyo, Japan), GLP-2050 + laser printer ( LG Electronics, Seoul, South Korea). Compound 3 was analyzed by an ultraviolet lamp at a wavelength of 210 nm and the flow rate was 1 ml per minute. As the mobile phase, acetonitrile and 0.1% trifluoroacetic acid solution were used in 36% and 64%, respectively. The retention time of the drug was approximately 11 minutes. Compound 1 and compound 2 were analyzed by an ultraviolet lamp at a wavelength of 228 nm, and the flow rate was 1 ml per minute. As mobile phase, acetonitrile and 0.1% trifluoroacetic acid solution were used in 35% and 65%, respectively. The retention time of the drug was approximately 8 minutes. The data is presented as a graph of the relationship between drug concentration and time in plasma (see FIG. 1). Pharmacokinetic parameters were calculated by applying the non-compartment model to the Win-Nonlin program (Scientific Consultion, USA). Plasma concentrations after drug administration (C max ), peak concentration time (T max ), estimated plasma concentrations to infinity time-area under time curve (AUC inf ), plasma concentrations up to 6 hours after drug administration- The area under the time curve (AUC0-6hr) was calculated to show that Compound 1 and Compound 2 showed higher values than Compound 3 at all values such as C max , AUC inf and AUCO-6hr. I could confirm it.

(쥐에 화합물 1, 화합물 2, 화합물 3을 경구 투여한 후의 약동력학 파라미터 값)(Pharmacokinetic parameter values after oral administration of Compound 1, Compound 2, and Compound 3 to rats) 화합물compound 화합물 1Compound 1 화합물 2Compound 2 화합물 3Compound 3 Cmax (㎍/㎖)C max (μg / ml) 0.210.21 0.270.27 0.090.09 Tmax (min)T max (min) 3838 6060 4545 AUCinf (㎍·min/㎖)AUC inf (µgmin / ml) -- 4646 1414 AUC0-6hr (㎍·min/㎖)AUC0-6hr (μgmin / ml) 1717 3434 1010

본 발명은 위의 실시예와 실험예에서 구체적으로 기술된 바와 같이 구조적 특이성을 가지며, 베타세크리타아제에 대한 활성이 높고, 약동력학적으로도 경구 투여가 가능한 약물이다. The present invention is a drug having structural specificity, high activity against beta secretase, and pharmacokinetic oral administration as described in detail in Examples and Experimental Examples above.

본 발명이 속한 분야에서 통상의 지식을 가진 자라면 상기 내용을 바탕으로 본 발명의 범주내에서 다양한 응용 및 변형을 행하는 것이 가능할 것이다.Those skilled in the art to which the present invention pertains will be able to perform various applications and modifications within the scope of the present invention based on the above contents.

Claims (15)

하기 화학식 1로 표시되는 술폰 아미드 유도체.Sulfonamide derivatives represented by the following formula (1).
Figure 112007047617983-pat00014
(1)
Figure 112007047617983-pat00014
(One) 상기 식에서, Where (Ⅰ) A 는 벤젠고리에 치환된 그룹을 나타내는 것으로서, 수소, 할로겐, 시아노, 니트로, 치환 또는 비치환 알킬, 치환 또는 비치환 에스테르, 치환 또는 비치환 아미드, 치환 또는 비치환 아민, 또는 치환 또는 비치환 알콕시 그룹이고;(I) A represents a group substituted in the benzene ring, hydrogen, halogen, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted ester, substituted or unsubstituted amide, substituted or unsubstituted amine, or substituted Or an unsubstituted alkoxy group; (Ⅱ) R1 은 단순한 알킬 그룹(-SAC), 알릴(allyl)을 포함하는 이중결합이 치환된 알킬, 시클로알킬(-SCAC), 아로마틱(-Ar), 아로마틱으로 치환된 알킬(-SAC-Ar), 또는 수소이고;(II) R 1 is a simple alkyl group (-SAC), alkyl substituted with a double bond containing allyl, cycloalkyl (-SCAC), aromatic (-Ar), aromatic substituted alkyl (-SAC- Ar), or hydrogen; (Ⅲ) R2 는 단순한 알킬그룹(-SAC), 알릴(allyl)을 포함하는 이중결합이 치환된 알킬, 시클로알킬(-SCAC), 아로마틱(-Ar), 아로마틱으로 치환된 알킬(-SAC-Ar), 또는 수소이고, R1 과 R2 는 단순한 알킬그룹으로 고리화를 이룰 수 있으며;(III) R 2 is a simple alkyl group (-SAC), a double bond substituted alkyl including allyl, cycloalkyl (-SCAC), aromatic (-Ar), aromatic substituted alkyl (-SAC- Ar), or hydrogen, and R 1 and R 2 may be cyclized to simple alkyl groups; (Ⅳ) R3 는 -SAC, 알릴(allyl)을 포함하는 이중결합이 치환된 알킬, -SCAC, -Ar, -SAC-Ar, 또는 수소이고, 모든 천연 아미노산의 곁가지(side chain residue)를 포함하며, R3 로 인하여 인접 위치가 스테레오 센터가 되는 경우 두가지 유형의 입체 화합물이 모두 포함되고, 아미노산의 곁가지로서 카르복실산 또는 염기로 구성되어 있을 경우 단순 에스테르 보호기가 붙어 있는 경우와 약제학적으로 허용되는 염(salt) 형태가 포함되며;(IV) R 3 is -SAC, alkyl substituted with a double bond containing allyl, -SCAC, -Ar, -SAC-Ar, or hydrogen, including side chain residues of all natural amino acids When the adjacent position becomes a stereo center due to R 3 , both types of steric compounds are included, and when a carboxylic acid or a base is included as a side chain of an amino acid, a simple ester protecting group is attached and pharmaceutically acceptable. Included salt forms; (Ⅴ) X 는 하기 화학식 2 또는 4의 치환기이고;(V) X is a substituent of Formula 2 or 4 below;
Figure 112007047617983-pat00015
(2)
Figure 112007047617983-pat00015
(2)
Figure 112007047617983-pat00017
(4)
Figure 112007047617983-pat00017
(4) 상기 화학식 2 또는 4에서,In Chemical Formula 2 or 4, n 은 0 또는 1 이며;n is 0 or 1; R4 는 독립적으로 -SAC, 알릴(allyl)을 포함하는 이중결합이 치환된 알킬, -SCAC, -Ar, -SAC-Ar 또는 수소이고, 모든 천연 아미노산의 곁가지를 포함하며, R4 로 인하여 인접 위치가 스테레오 센터가 되는 경우 두가지 유형의 입체 화합물이 모두 포함되며, 아미노산의 곁가지로서 카르복실산 또는 염기로 구성되어 있는 경우 단순 에스테르 보호기가 붙어있는 경우와 약제학적으로 허용되는 염 형태로 존재하는 경우가 포함되며, -(CH2)nOR (R = -SAC, -SCAC, -Ar, -SAC-Ar: n = 1,2) 또는 -(CH2)nOC(=O)R (R = -SAC, -SCAC, -Ar, -SAC-Ar: n=1,2)인 것이 또한 포함되며;R 4 is independently —SAC, alkyl substituted with a double bond containing allyl, —SCAC, —Ar, —SAC-Ar, or hydrogen, which includes a side chain of all natural amino acids and is adjacent due to R 4 When the position is a stereo center, both types of steric compounds are included, and the side chains of amino acids are composed of carboxylic acids or bases, and have simple ester protecting groups and are present in pharmaceutically acceptable salt form. Contains-(CH 2 ) n OR (R = -SAC, -SCAC, -Ar, -SAC-Ar: n = 1,2) or-(CH 2 ) n OC (= O) R (R = -SAC, -SCAC, -Ar, -SAC-Ar: n = 1,2) are also included; R5 는 단순한 알킬그룹(-SAC)이거나, 알릴(allyl)을 포함하는 이중결합이 치환된 알킬, 시클로알킬(-SCAC), 아로마틱(-Ar), 아로마틱으로 치환된 알킬(-SAC-Ar) 또는 수소이고; R 5 is a simple alkyl group (-SAC) or an alkyl substituted with a double bond containing allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted by aromatic (-SAC-Ar) Or hydrogen; R6 는 단순한 알킬그룹(-SAC)이거나, 알릴(allyl)을 포함하는 이중결합이 치환된 알킬, 시클로알킬(-SCAC), 아로마틱(-Ar), 아로마틱으로 치환된 알킬(-SAC-Ar) 또는 수소이고, 하기 화학식 5 또는 6으로 표시되는 치환기가 포함되며;R 6 is a simple alkyl group (-SAC) or an alkyl substituted with a double bond containing allyl, cycloalkyl (-SCAC), aromatic (-Ar), aromatic substituted alkyl (-SAC-Ar) Or hydrogen and a substituent represented by the following Chemical Formula 5 or 6;
Figure 112007047617983-pat00018
(5)
Figure 112007047617983-pat00018
(5)
Figure 112007047617983-pat00019
(6)
Figure 112007047617983-pat00019
(6) 상기 화학식 5 및 6에서,In Chemical Formulas 5 and 6, R7 은 독립적으로 -SAC, 알릴(allyl)을 포함하는 이중결합이 치환된 알킬, -SCAC, -Ar, -SAC-Ar 또는 수소이고, 모든 천연 아미노산의 곁가지를 포함하며, R7 로 인하여 인접 위치가 스테레오 센터가 되는 경우 두가지 유형의 입체 화합물이 모두 포함되며, 아미노산의 곁가지로서 카르복실산 또는 염기로 구성되어 있는 경우 단순 에스테르 보호기가 붙어있는 경우와 약제학적으로 허용되는 염 형태로 존재하는 경우도 포함되며;R 7 is independently —SAC, alkyl substituted with a double bond containing allyl, —SCAC, —Ar, —SAC-Ar, or hydrogen, including all natural amino acids, and adjacent to R 7 When the position is a stereo center, both types of steric compounds are included, and the side chains of amino acids are composed of carboxylic acids or bases, and have simple ester protecting groups and are present in pharmaceutically acceptable salt form. Also included; R8 및 R9 은 각각 독립적으로 단순한 알킬그룹(-SAC)이거나, 알릴(allyl)을 포함하는 이중결합이 치환된 알킬, 시클로알킬(-SCAC), 아로마틱(-Ar), 아로마틱으로 치환된 알킬(-SAC-Ar) 카르복스산이 치환된 아로마틱으로 치환된 알킬 또는 수소이며; R 8 and R 9 are each independently a simple alkyl group (-SAC) or an alkyl substituted with a double bond containing allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted with aromatic (-SAC-Ar) carboxylic acid is alkyl substituted with substituted aromatic or hydrogen; R10 은 독립적으로 단순한 알킬그룹(-SAC), 알릴(allyl)을 포함하는 이중결합이 치환된 알킬, 시클로알킬(-SCAC), 아로마틱(-Ar), 아로마틱으로 치환된 알킬(-SAC-Ar) 또는 수소이고; R 10 is independently a simple alkyl group (-SAC), a double bond substituted alkyl including allyl, cycloalkyl (-SCAC), aromatic (-Ar), aromatic substituted alkyl (-SAC-Ar ) Or hydrogen; R11 은 독립적으로 단순한 알킬그룹(-SAC), 알릴(allyl)을 포함하는 이중결합이 치환된 알킬, 시클로알킬(-SCAC), 아로마틱(-Ar), 알킬 또는 알콕시로 치환된 아로마틱, 알킬 또는 알콕시로 치환된 헤테로아로마틱, 또는 알콕시로 치환된 헤테로시클로알킬이다.R 11 independently represents an aromatic, alkyl or substituted with a simple alkyl group (-SAC), a double bond substituted alkyl including allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl or alkoxy Heteroaromatic substituted by alkoxy, or heterocycloalkyl substituted by alkoxy. 제 1 항에 있어서, R1 은 아로마틱으로 치환된 알킬기이고, R2 는 단순한 알킬이며, R5 는 단순한 알킬이고, R10 은 단순한 알킬기인 것을 특징으로 하는 술폰 아미드 유도체.The sulfonamide derivative of claim 1 wherein R 1 is an aromatic substituted alkyl group, R 2 is simple alkyl, R 5 is simple alkyl, and R 10 is a simple alkyl group. 제 1 항에 있어서, 상기 유도체는 하기 화학식 7로 표시되는 화합물인 것을 특징으로 하는 술폰 아미드 유도체.The sulfone amide derivative according to claim 1, wherein the derivative is a compound represented by the following Chemical Formula 7.
Figure 112003036743077-pat00020
(7)
Figure 112003036743077-pat00020
(7) 상기 식에서, n, A, R1, R2, R3, R4, R5 및 R6 는 화학식 1에서와 동일하다.Wherein n, A, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as in formula (1). 삭제delete 제 1 항에 있어서, 상기 유도체는 하기 화학식 9로 표시되는 화합물인 것을 특징으로 하는 술폰 아미드 유도체.The sulfone amide derivative according to claim 1, wherein the derivative is a compound represented by the following Chemical Formula 9.
Figure 112003036743077-pat00022
(9)
Figure 112003036743077-pat00022
(9) 상기 식에서, n, A, R1, R2, R3, R10 및 R11 은 화학식 1에서와 동일하다.Wherein n, A, R 1 , R 2 , R 3 , R 10 and R 11 are the same as in formula (1). 제 1 항에 있어서, 상기 유도체는 하기 (1) 내지 (153)의 화합물들에서 선택되는 것을 특징으로 하는 술폰 아미드 유도체.The sulfone amide derivative according to claim 1, wherein the derivative is selected from the following compounds (1) to (153). (1) 4-[({(2S)-2-[((2R,4S,5S)-5-{[3-(1,1-디옥소-1λ6-이소치아졸리딘-2-일)벤조일]아미노}-4-히드록시-2,7-디메틸옥타노일)아미노]프로파노일}아미노)메틸]벤조산(1) 4-[({(2 S ) -2-[((2 R , 4 S , 5 S ) -5-{[3- (1,1-dioxo-1λ 6 -isothiazolidine- 2-yl) benzoyl] amino} -4-hydroxy-2,7-dimethyloctanoyl) amino] propanoyl} amino) methyl] benzoic acid (2) N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠)-1-메틸-2,2,4-트리옥소-1,2,3,4-테트라히드로-2λ6,1-벤조치아진-7-카르복스아미드(2) N -(( 1S , 2S , 4R ) -5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl) -1-methyl-2,2,4-trioxo-1,2,3,4-tetrahydro-2λ 6 , 1-benzothiazin-7- Carboxamide (3) 4-{[((2S)-2-{[(2R,4S,5S)-4-히드록시-2,7-디메틸-5-({3-[(프로필술포닐)아미노]벤조일}아미노)옥타노일]아미노}프로파노일)아미노]메틸}벤조산 (3) 4-{[((2 S ) -2-{[(2 R , 4 S , 5 S ) -4-hydroxy-2,7-dimethyl-5-({3-[(propylsulfonyl ) Amino] benzoyl} amino) octanoyl] amino} propanoyl) amino] methyl} benzoic acid (4) 4-{[((2S)-2-{[(2R,4S,5S)-4-히드록시-2,7-디메틸-5-({3-[(페닐술포닐)아미노]벤조일}아미노)옥타노일]아미노}프로파노일)아미노]메틸}벤조산 (4) 4-{[((2 S ) -2-{[(2 R , 4 S , 5 S ) -4-hydroxy-2,7-dimethyl-5-({3-[(phenylsulfonyl ) Amino] benzoyl} amino) octanoyl] amino} propanoyl) amino] methyl} benzoic acid (5) 4-{[((2S)-2-{[(2R,4S,5S)-4-히드록시-2,7-디메틸-5-({3-[(2-치에닐술포닐)아미노]벤조일}아미노)옥타노일]아미노}프로파노일)아미노]메틸}벤조산(5) 4 - {[( (2 S) -2 - {[(2 R, 4 S, 5 S) -4- hydroxy-2,7-dimethyl-5 - ({3 - [(2-value Enylsulfonyl) amino] benzoyl} amino) octanoyl] amino} propanoyl) amino] methyl} benzoic acid (6) 4-{[((2S)-2-{[(2R,4S,5S)-4-히드록시-2,7-디메틸-5-({3-[메틸(프로필술포닐)아미노]벤조일}아미노)옥타노일]아미노}프로파노일)아미노]메틸}벤조산 (6) 4-{[((2 S ) -2-{[(2 R , 4 S , 5 S ) -4-hydroxy-2,7-dimethyl-5-({3- [methyl (propylsulphur) Phenyl) amino] benzoyl} amino) octanoyl] amino} propanoyl) amino] methyl} benzoic acid (7) 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[에틸(프로필술포닐)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}프로파노일)아미노]메틸}벤조산(7) 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5-({3- [ethyl (propylsulfonyl) amino] benzoyl} amino) -4- Hydroxy-2,7-dimethyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid (8) 4-{[((2S)-2-{[(2R,4S,5S)-4-히드록시-2,7-디메틸-5-({3-[프로필(프로필술포닐)아미노]벤조일}아미노)옥타노일]아미노}프로파노일)아미노]메틸}벤조산(8) 4-{[((2 S ) -2-{[(2 R , 4 S , 5 S ) -4-hydroxy-2,7-dimethyl-5-({3- [propyl (propylsulphate) Phenyl) amino] benzoyl} amino) octanoyl] amino} propanoyl) amino] methyl} benzoic acid (9) 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[벤질(프로필술포닐)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}프로파노일)아미노]메틸}벤조산 (9) 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5-({3- [benzyl (propylsulfonyl) amino] benzoyl} amino) -4- Hydroxy-2,7-dimethyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid (10) 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(에틸술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}프로파노일)아미노]메틸}벤조산 (10) 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5-({3-[(ethylsulfonyl) (methyl) amino] benzoyl} amino)- 4-hydroxy-2,7-dimethyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid (11) 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(부칠술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}프로파노일)아미노]메틸}벤조산(11) 4 - {[( (2 S) -2 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( Fanning sulfonyl) (methyl) amino] benzoyl} amino) - 4-hydroxy-2,7-dimethyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid (12) 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}프로파노일)아미노]메틸}벤조산(12) 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino)- 4-hydroxy-2,7-dimethyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid (13) 4-[({(2S)-2-[((2R,4S,5S)-4-히드록시-2,7-디메틸-5-{[3-(메틸{[2-(1-나프틸)에틸]술포닐}아미노)벤조일]아미노}옥타노일)아미노]프로파노일}아미노)메틸]벤조산 (13) 4-[({(2 S ) -2-[((2 R , 4 S , 5 S ) -4-hydroxy-2,7-dimethyl-5-{[3- (methyl {[2 -(1-naphthyl) ethyl] sulfonyl} amino) benzoyl] amino} octanoyl) amino] propanoyl} amino) methyl] benzoic acid (14) N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠)-3-[메틸(2-치에닐술포닐)아미노]벤즈아미드(14) N -(( 1S , 2S , 4R ) -5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl) -3- [methyl (2-chienylsulfonyl) amino] benzamide (15) N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠)-3-[메틸(페닐술포닐)아미노]벤즈아미드(15) N -(( 1S , 2S , 4R ) -5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl) -3- [methyl (phenylsulfonyl) amino] benzamide (16) N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠)-3-[메틸(1-나프틸술포닐)아미노]벤즈아미드(16) N -(( 1S , 2S , 4R ) -5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl) -3- [methyl (1-naphthylsulfonyl) amino] benzamide (17) N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-베틸-2-옥소에틸]아미노}-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠)-3-[메틸(2-나프틸술포닐)아미노]벤즈아미드 (17) N - ((1 S, 2 S, 4 R) -5 - {[(1 S) -2- ( benzylamino) -1-betil-oxoethyl] amino} -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl) -3- [methyl (2-naphthylsulfonyl) amino] benzamide (18) N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠)-3-[{[5-(디메틸아미노)-1-나프틸]술포닐}(메틸)아미노]벤즈아미드(18) N -(( 1S , 2S , 4R ) -5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl) -3-[{[5- (dimethylamino) -1-naphthyl] sulfonyl} (methyl) amino] benzamide (19) 3-[{[2-(아세틸아미노)-4-메틸-1,3-치아졸-5-일]술포닐}(메틸)아미노]-N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠)벤즈아미드(19) 3-[{[2- (acetylamino) -4-methyl-1,3-thiazol-5-yl] sulfonyl} (methyl) amino] -N -((1 S , 2 S , 4 R) -5 - {[(1 S) -2- ( benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy-1-isopropyl-4-methyl-5-oxo penchil Fanning) Benzamide (20) N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠)-3-[(벤질술포닐)(메틸)아미노]벤즈아미드(20) N -(( 1S , 2S , 4R ) -5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide (21) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소펜칠-4-메틸-5-옥소펜칠]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드 (21) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isopentyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide (22) N-[(1S,2S,4S)-4-({[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}카르보닐)-2-히드록시-1-이소부칠-5-메틸헥실]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드 (22) N -[( 1S , 2S , 4S ) -4-({[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} carbonyl) -2 -Hydroxy-1-isobutyl-5-methylhexyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide (23) N-{(1S,2S,4S)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-히드록시-1-이소부칠-5-메틸헥실}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드 (23) N -{( 1S , 2S , 4S ) -4-[({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2 -Hydroxy-1-isobutyl-5-methylhexyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide (24) N-[(1S,2S,4R)-4-({[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}카르보닐)-2-히드록시-1-이소부칠-6-헵테닐]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드 (24) N -[( 1S , 2S , 4R ) -4-({[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} carbonyl) -2 -Hydroxy-1-isobutyl-6-heptenyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide (25) N-{(1S,2S,4R)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-히드록시-1-이소부칠-6-헵테닐}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드(25) N -{( 1S , 2S , 4R ) -4-[({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2 -Hydroxy-1-isobutyl-6-heptenyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide (26) 4-({[(2S)-2-({(2R)-2-[(2S,3S)-3-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-2-히드록시-5-메틸헥실]-4-펜테노일}아미노)프로파노일]아미노}메틸)벤조산(26) 4-({[( 2S ) -2-({( 2R ) -2-[( 2S , 3S ) -3-({3-[(benzylsulfonyl) (methyl) amino] Benzoyl} amino) -2-hydroxy-5-methylhexyl] -4-pentenoyl} amino) propanoyl] amino} methyl) benzoic acid (27) 4-({[(2S)-2-({(2R)-2-[(2S,3S)-3-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-2-히드록시-5-메틸헥실]-4-펜테노일}아미노)-3-메틸부타노일]아미노}메틸)벤조산 (27) 4-({[( 2S ) -2-({( 2R ) -2-[( 2S , 3S ) -3-({3-[(benzylsulfonyl) (methyl) amino] Benzoyl} amino) -2-hydroxy-5-methylhexyl] -4-pentenoyl} amino) -3-methylbutanoyl] amino} methyl) benzoic acid (28) 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-3-메틸부타노일)아미노]메틸}벤조산(28) 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino)- 4-hydroxy-2,7-dimethyloctanoyl] amino} -3-methylbutanoyl) amino] methyl} benzoic acid (29) 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-7-메틸-2-프로필옥타노일]아미노}프로파노일)아미노]메틸}벤조산 (29) 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino)- 4-hydroxy-7-methyl-2-propyloctanoyl] amino} propanoyl) amino] methyl} benzoic acid (30) N-{(1S,2S,4R)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-히드록시-1-이소부칠헵칠}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드 (30) N -{(1 S , 2 S , 4 R ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2 -Hydroxy-1-isobutylheptyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide (31) 4-{[((2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-7-메틸-2-프로필옥타노일]아미노}-3-메틸부타노일)아미노]메틸}벤조산(31) 4-{[(( 2S ) -2-{[( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino)- 4-hydroxy-7-methyl-2-propyloctanoyl] amino} -3-methylbutanoyl) amino] methyl} benzoic acid (32) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠]-3-[메틸(2-치에닐술포닐)아미노]벤즈아미드 (32) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3- [methyl (2-chienylsulfonyl) amino] benzamide (33) N-((1S,2S,4R)-5-{[(1S)-2-(벤질아미노)-1-메틸-2-옥소에틸]아미노}-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠)-3-[메틸(프로필술포닐)아미노]벤즈아미드 (33) N -(( 1S , 2S , 4R ) -5-{[( 1S ) -2- (benzylamino) -1-methyl-2-oxoethyl] amino} -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl) -3- [methyl (propylsulfonyl) amino] benzamide (34) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부칠-4-메틸-5-옥소펜칠]-3-[메틸(프로필술포닐)아미노]벤즈아미드(34) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3- [methyl (propylsulfonyl) amino] benzamide (35) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-5-[(벤질술포닐)(메틸)아미노]-2-클로로벤즈아미드 (35) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -5-[(benzylsulfonyl) (methyl) amino] -2-chlorobenzamide (36) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-5-(트리플루오로메틸)벤즈아미드 (36) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -5- (trifluoromethyl) benzamide (37) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-5-브로모벤즈아미드 (37) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -5-bromobenzamide (38) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-5-니트로벤즈아미드 (38) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -5-nitrobenzamide (39) 3-아미노-N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-5-[(벤질술포닐)(메틸)아미노]벤즈아미드 (39) 3-amino- N -[(1 S , 2 S , 4 R ) -5-({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2 -Hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -5-[(benzylsulfonyl) (methyl) amino] benzamide (40) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-5-시아노벤즈아미드 (40) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -5-cyanobenzamide (41) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-5-메틸벤즈아미드 (41) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -5-methylbenzamide (42) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-5-클로로벤즈아미드 (42) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -5-chlorobenzamide (43) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-5-[(벤질술포닐)(메틸)아미노]이소프탈아미드 (43) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -5-[(benzylsulfonyl) (methyl) amino] isophthalamide (44) 메틸 3-({[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]아미노}카르보닐)-5-[(벤질술포닐)(메틸)아미노]벤조에이트 (44) Methyl 3-({[(1 S , 2 S , 4 R ) -5-({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2- Hydroxy-1-isobutyl-4-methyl-5-oxopentyl] amino} carbonyl) -5-[(benzylsulfonyl) (methyl) amino] benzoate (45) 벤질 3-({[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]아미노}카르보닐)-5-[(벤질술포닐)(메틸)아미노]벤조에이트 (45) benzyl 3-({[(1 S , 2 S , 4 R ) -5-({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2- Hydroxy-1-isobutyl-4-methyl-5-oxopentyl] amino} carbonyl) -5-[(benzylsulfonyl) (methyl) amino] benzoate (46) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-4-메톡시벤즈아미드 (46) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -4-methoxybenzamide (47) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-4-플루오로벤즈아미드 (47) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -4-fluorobenzamide (48) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]-4-클로로벤즈아미드 (48) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] -4-chlorobenzamide (49) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-5-[(벤질술포닐)(메틸)아미노]-2-메톡시벤즈아미드 (49) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -5-[(benzylsulfonyl) (methyl) amino] -2-methoxybenzamide (50) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-{메틸[(2-니트로벤질)술포닐]아미노}벤즈아미드(50) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3- {methyl [(2-nitrobenzyl) sulfonyl] amino} benzamide (51) 3-[[(2-아미노벤질)술포닐](메틸)아미노]-N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]벤즈아미드(51) 3-[[(2-aminobenzyl) sulfonyl] (methyl) amino] -N -[(1 S , 2 S , 4 R ) -5-({(1 S ) -1-[(benzyl Amino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl] benzamide (52) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-{메틸[(2-메틸벤질)술포닐]아미노}벤즈아미드(52) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3- {methyl [(2-methylbenzyl) sulfonyl] amino} benzamide (53) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-{메틸[(3-메틸벤질)술포닐]아미노}벤즈아미드(53) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentyl] -3- {methyl [(3-methylbenzyl) sulfonyl] amino} benzamide (54) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틴]-3-{메틸[(4-메틸벤질)술포닐]아미노}벤즈아미드(54) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy- 1-isobutyl-4-methyl-5-oxopentin] -3- {methyl [(4-methylbenzyl) sulfonyl] amino} benzamide (55) N-{(1S,2S,4R)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-히드록시-1-이소부틸-6-헵틴일}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드(55) N -{( 1S , 2S , 4R ) -4-[({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2 -Hydroxy-1-isobutyl-6-heptinyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide (56) N-{(1S,2S,4Z)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-히드록시-1-이소부틸-4-헥센일}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드(56) N -{(1 S , 2 S , 4 Z ) -4-[({(1 S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2 -Hydroxy-1-isobutyl-4-hexenyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide (57) N-{(1S,2S,4R)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-히드록시-1-이소부틸헥실}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드(57) N -{( 1S , 2S , 4R ) -4-[({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2 -Hydroxy-1-isobutylhexyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide (58) N-{(1S,2S,4S)-4-[({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)카르보닐]-2-히드록시-1-이소부틸헥실}-3-[(벤질술포닐)(메틸)아미노]벤즈아미드(58) N -{( 1S , 2S , 4S ) -4-[({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) carbonyl] -2 -Hydroxy-1-isobutylhexyl} -3-[(benzylsulfonyl) (methyl) amino] benzamide (59) 메틸 (2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-3-메틸부타노에이트 59 methyl (2 S) -2 - {[ (2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy -2,7-dimethyloctanoyl] amino} -3-methylbutanoate (60) (2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-3-메틸부탄산 (60) (2 S) -2 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy- 2,7-dimethyloctanoyl] amino} -3-methylbutanoic acid (61) N-((1S,2S,4R)-5-{[(1S)-1-(아미노카르보닐)-2-메틸프로필]아미노}-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸)-3-[(벤질술포닐)(메틸)아미노]벤즈아미드(61) N -(( 1S , 2S , 4R ) -5-{[( 1S ) -1- (aminocarbonyl) -2-methylpropyl] amino} -2-hydroxy-1-iso Butyl-4-methyl-5-oxopentyl) -3-[(benzylsulfonyl) (methyl) amino] benzamide (62) (2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}부탄산 (62) (2 S) -2 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy- 2,7-dimethyloctanoyl] amino} butanoic acid (63) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드(63) N -[( 1S , 2S , 4R ) -5-({( 1S ) -1-[(benzylamino) carbonyl] propyl} amino) -2-hydroxy-1-isobutyl -4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide (64) (2S,3R)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-3-메틸펜탄산 (64) ( 2S , 3R ) -2-{[( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4- Hydroxy-2,7-dimethyloctanoyl] amino} -3-methylpentanoic acid (65) N-[(1S,2S,4R)-5-({(1S,2R)-1-[(벤질아미노)카르보닐]-2-메틸부틸}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드 (65) N -[( 1S , 2S , 4R ) -5-({( 1S , 2R ) -1-[(benzylamino) carbonyl] -2-methylbutyl} amino) -2- Hydroxy-1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide (66) 메틸 (2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-3,3-디메틸부타노에이트66 methyl (2 S) -2 - {[ (2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy -2,7-dimethyloctanoyl] amino} -3,3-dimethylbutanoate (67) (2S)-2-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-3,3-디메틸부탄산 (67) (2 S) -2 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy- 2,7-dimethyloctanoyl] amino} -3,3-dimethylbutanoic acid (68) N-[(1S,2S,4R)-5-({(1S)-1-[(벤질아미노)카르보닐]-2,2-디메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드 (68) N - [(1 S, 2 S, 4 R) -5 - ({(1 S) -1 - [( benzylamino) carbonyl] -2,2- dimethylpropyl} amino) -2-hydroxy Roxy-1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide (69) N-[(1S,2S,4R)-5-({(1R)-1-[(벤질아미노)카르보닐]-2,2-디메틸프로필}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드 (69) N - [(1 S, 2 S, 4 R) -5 - ({(1 R) -1 - [( benzylamino) carbonyl] -2,2- dimethylpropyl} amino) -2-hydroxy Roxy-1-isobutyl-4-methyl-5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide (70) N-[(1S,2S,4R)-5-({1-[(벤질아미노)카르보닐]사이클로펜틸}아미노)-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드 (70) N - [(1 S, 2 S, 4 R) -5 - ({1 - [( benzylamino) carbonyl] cyclopentyl} amino) -2-hydroxy-1-isobutyl-4-methyl -5-oxopentyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide (71) (2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥탄산 (71) (2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyl-octanoic acid (72) 3-[(벤질술포닐)(메틸)아미노]-N-((1S,2S,4R)-2-히드록시-1-이소부틸-4-메틸-5-옥소-5-{[(3R)-2-옥소피페리딘일]아미노}펜틸)벤즈아미드 (72) 3-[(benzylsulfonyl) (methyl) amino] -N -(( 1S , 2S , 4R ) -2-hydroxy-1-isobutyl-4-methyl-5-oxo-5 -{[( 3R ) -2-oxopiperidinyl] amino} pentyl) benzamide (73) 3-[(벤질술포닐)(메틸)아미노]-N-((1S,2S,4R)-2-히드록시-1-이소부틸-4-메틸-5-옥소-5-{[(3S)-2-옥소피페리딘일]아미노}펜틸)벤즈아미드 (73) 3-[(benzylsulfonyl) (methyl) amino] -N -(( 1S , 2S , 4R ) -2-hydroxy-1-isobutyl-4-methyl-5-oxo-5 - {[(3 S) -2- oxpiperidin- each optionally substituted; amino} cyclopentyl) benzamide (74) 메틸 4-({[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디베틸옥타노일]아미노}메틸)사이클로헥산카르복실레이트74 methyl 4 - ({[(2 R , 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy -2,7 -Dibetayloctanoyl] amino} methyl) cyclohexanecarboxylate (75) 4-({[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}메틸)사이클로헥산카르복실산(75) 4 - ({[ (2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7 Dimethyloctanoyl] amino} methyl) cyclohexanecarboxylic acid (76) 메틸 4-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}사이클로헥산카르복실레이트(76) methyl 4 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7 Dimethyloctanoyl] amino} cyclohexanecarboxylate (77) 4-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}사이클로헥산카르복실산 (77) 4 - {[( 2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyl Octanoyl] amino} cyclohexanecarboxylic acid (78) 메틸 3-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}사이클로헥산카르복실레이트(78) methyl 3 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7 Dimethyloctanoyl] amino} cyclohexanecarboxylate (79) 3-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}사이클로헥산카르복실산 (79) 3 - {[( 2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyl Octanoyl] amino} cyclohexanecarboxylic acid (80) 메틸 5-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}펜타노에이트 80-methyl-5 - {[(2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7 Dimethyloctanoyl] amino} pentanoate (81) 5-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}펜탄산 (81) 5 - {[( 2 R, 4 S, 5 S) -5 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -4-hydroxy-2,7-dimethyl Octanoyl] amino} pentanoic acid (82) 에틸 3-((1S)-1-{[(2R,4S,5S)-5-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-4-히드록시-2,7-디메틸옥타노일]아미노}-2-메틸프로필)-4,5-디히드로-5-이소옥사졸카르복실레이트(82) ethyl 3-(( 1S ) -1-{[( 2R , 4S , 5S ) -5-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -4 -Hydroxy-2,7-dimethyloctanoyl] amino} -2-methylpropyl) -4,5-dihydro-5-isoxazolecarboxylate (83) 3-[(벤질술포닐)(메틸)아미노]-N-((1S,2S,4R)-5-{[(1S)-1-시아노-2-메틸프로필]아미노}-2-히드록시-1-이소부틸-4-메틸-5-옥소펜틸)벤즈아미드 (83) 3-[(benzylsulfonyl) (methyl) amino] -N -((1 S , 2 S , 4 R ) -5-{[(1 S ) -1-cyano-2-methylpropyl] Amino} -2-hydroxy-1-isobutyl-4-methyl-5-oxopentyl) benzamide (84) 메틸 (2S)-2-{[(3S,4S)-4-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-3-히드록시-6-메틸헵타노일]아미노}-3-메틸부타노에이트84 methyl (2 S) -2 - {[ (3 S, 4 S) -4 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -3-hydroxy-6 Methylheptanoyl] amino} -3-methylbutanoate (85) (2S)-2-{[(3S,4S)-4-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-3-히드록시-6-메틸헵타노일]아미노}-3-메틸부탄산 (85) (2 S) -2 - {[(3 S, 4 S) -4 - ({3 - [( benzyl-sulfonyl) (methyl) amino] benzoyl} amino) -3-hydroxy-6-methyl Heptanoyl] amino} -3-methylbutanoic acid (86) N-[(1S,2S)-4-({(1S)-1-[(벤질아미노)카르보닐]-2-메틸프로필}아미노)-2-히드록시-1-이소부틸-4-옥소부틸]-3-[(벤질술포닐)(메틸)아미노]벤즈아미드(86) N -[( 1S , 2S ) -4-({( 1S ) -1-[(benzylamino) carbonyl] -2-methylpropyl} amino) -2-hydroxy-1-iso Butyl-4-oxobutyl] -3-[(benzylsulfonyl) (methyl) amino] benzamide (87) 4-{[((2S)-2-{[(3S,4S)-4-({3-[(벤질술포닐)(메틸)아미노]벤조일}아미노)-3-히드록시-6-메틸헵타노일]아미노}-3-메틸부타노일)아미노]메틸}벤조산(87) 4-{[(( 2S ) -2-{[( 3S , 4S ) -4-({3-[(benzylsulfonyl) (methyl) amino] benzoyl} amino) -3-hydrate Oxy-6-methylheptanoyl] amino} -3-methylbutanoyl) amino] methyl} benzoic acid (89) N-{(1S)-1-[(5R)-3-(3-메톡시벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}-3-[메틸(프로필술포닐)아미노]벤즈아미드(89) N -{( 1S ) -1-[( 5R ) -3- (3-methoxybenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [Methyl (propylsulfonyl) amino] benzamide (91) N-{(1S)-1-[(5R)-3-(3-메틸벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}-3-[메틸(프로필술포닐)아미노]벤즈아미드(91) N -{( 1S ) -1-[( 5R ) -3- (3-methylbenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [ Methyl (propylsulfonyl) amino] benzamide (94) N-{(1S)-1-[(5R)-3-(3-에틸벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}-3-[메틸(프로필술포닐)아미노]벤즈아미드(94) N -{( 1S ) -1-[( 5R ) -3- (3-ethylbenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [ Methyl (propylsulfonyl) amino] benzamide (96) N-{(1S)-1-[(5R)-3-벤질-1,3-옥사졸리딘-5-일]-2-페닐에틸}-3-[메틸(프로필술포닐)아미노]벤즈아미드(96) N -{( 1S ) -1-[( 5R ) -3-benzyl-1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [methyl (propylsulfonyl ) Amino] benzamide (98) 3-[메틸(프로필술포닐)아미노]-N-((1S)-2-페닐-1-{(5R)-3-[(1R)-1-페닐프로필]-1,3-옥사졸리딘-5-일}에틸)벤즈아미드(98) 3- [methyl (propylsulfonyl) amino] -N -(( 1S ) -2-phenyl-1-{( 5R ) -3-[( 1R ) -1-phenylpropyl] -1 , 3-oxazolidin-5-yl} ethyl) benzamide (100) 3-[메틸(프로필술포닐)아미노]-N-((1S)-2-페닐-1-{(5R)-3-[(1S)-1-페닐프로필]-1,3-옥사졸리딘-5-일}에틸)벤즈아미드(100) 3- [methyl (propylsulfonyl) amino] -N -(( 1S ) -2-phenyl-1-{( 5R ) -3-[( 1S ) -1-phenylpropyl] -1 , 3-oxazolidin-5-yl} ethyl) benzamide (102) N-((1S)-1-{(5R)-3-[(1R)-1-(3-메톡시페닐)에틸]-1,3-옥사졸리딘-5-일}-2-페닐에틸)-3-[메틸(프로필술포닐)아미노]벤즈아미드 (102) N -(( 1S ) -1-{( 5R ) -3-[( 1R ) -1- (3-methoxyphenyl) ethyl] -1,3-oxazolidin-5-yl } -2-phenylethyl) -3- [methyl (propylsulfonyl) amino] benzamide (104) N-((1S)-1-{(5R)-3-[(1S)-1-(3-메톡시페닐)에틸]-1,3-옥사졸리딘-5-일}-2-페닐에틸)-3-[메틸(프로필술포닐)아미노]벤즈아미드 (104) N -(( 1S ) -1-{( 5R ) -3-[( 1S ) -1- (3-methoxyphenyl) ethyl] -1,3-oxazolidin-5-yl } -2-phenylethyl) -3- [methyl (propylsulfonyl) amino] benzamide (106) 3-[(벤질술포닐)(메틸)아미노]-N-{(1S)-1-[(5R)-3-(3-메톡시벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}벤즈아미드(106) 3-[(benzylsulfonyl) (methyl) amino] -N -{( 1S ) -1-[( 5R ) -3- (3-methoxybenzyl) -1,3-oxazolidine -5-yl] -2-phenylethyl} benzamide (107) 3-[(부틸술포닐)(메틸)아미노]-N-{(1S)-1-[(5R)-3-(3-메톡시벤질)-1,3-옥소졸리딘-5-일]-2-페닐에틸}벤즈아미드(107) 3-[(butylsulfonyl) (methyl) amino] -N -{( 1S ) -1-[( 5R ) -3- (3-methoxybenzyl) -1,3-oxozolidine -5-yl] -2-phenylethyl} benzamide (108) 3-[(에틸술포닐)(메틸)아미노]-N-{(1S)-1-[(5R)-3-(3-메톡시벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}벤즈아미드(108) 3-[(ethylsulfonyl) (methyl) amino] -N -{( 1S ) -1-[( 5R ) -3- (3-methoxybenzyl) -1,3-oxazolidine -5-yl] -2-phenylethyl} benzamide (109) N-{(1S)-1-[(5R)-3-(3-메톡시벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}-3-[메틸(메틸술포닐)아미노]벤즈아미드(109) N -{( 1S ) -1-[( 5R ) -3- (3-methoxybenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [Methyl (methylsulfonyl) amino] benzamide (152) N-{(1S)-1-[(5S)-3-(3-메톡시벤질)-1,3-옥사졸리딘-5-일]-2-페닐에틸}-3-[메틸(프로필술포닐)아미노]벤즈아미드.(152) N -{( 1S ) -1-[( 5S ) -3- (3-methoxybenzyl) -1,3-oxazolidin-5-yl] -2-phenylethyl} -3- [Methyl (propylsulfonyl) amino] benzamide. 삭제delete 화학식 1에서 X 가 화학식 2의 치환기인 술폰 아미드 유도체(화학식 7의 유도체)를 하기 단계들을 포함하는 과정에 의해 제조하는 것을 특징으로 하는 방법.A process according to claim 1, wherein X is a sulfonamide derivative (derivative of formula 7) wherein X is a substituent of formula (2). (ⅰ) 아미노기가 보호된(BocNH-) 아미노산을 이용하여 락톤 화합물(1)을 얻는 단계;  (Iii) obtaining a lactone compound (1) using an amino group having a protected (BocNH-) amino group; (ⅱ) 화합물(1)을 무수테트라히드로퓨란 용액에서 리튬 비스(트리메틸실릴)아미드와 아이오도메탄을 이용하여 알킬이 치환된 락톤(2)를 얻는 단계;(Ii) obtaining the alkyl substituted lactone (2) using lithium bis (trimethylsilyl) amide and iodomethane in anhydrous tetrahydrofuran solution; (ⅲ) 락톤(2)를 수산화리튬 수용액으로 처리한 후 이미다졸과 t-부칠디메틸실릴 클로라이드를 사용하여 O-프로텍티드된 카르복실산 화합물(3)을 얻는 단계;(Iii) treating lactone (2) with an aqueous lithium hydroxide solution to obtain an O-protected carboxylic acid compound (3) using imidazole and t -butyldimethylsilyl chloride; (ⅳ) 화합물(3)을 아민과 커플링시켜 화합물(4)를 얻는 단계;(Iii) coupling compound (3) with an amine to obtain compound (4); (ⅴ) 화합물(4)의 프로텍션 그룹을 제거한 후, 술폰 아미드가 치환된 벤조산(술폰아미드-치환 벤조산)과 커플링시켜 화합물(5)를 얻는 단계; 및(Iv) removing the protection group of compound (4), and then coupling with sulfonic amide-substituted benzoic acid (sulfonamide-substituted benzoic acid) to obtain compound (5); And (ⅵ) 화합물(5)의 O-프로텍션 그룹을 제거하여 화합물(6)(화학식 7의 유도체)를 얻는 단계.(Iii) removing the O-protecting group of compound (5) to obtain compound (6) (derivative of formula 7).
Figure 112007015528338-pat00023
Figure 112007015528338-pat00023
 제 8 항에 있어서, 상기 술폰아미드-치환 벤조산 중, 고리화된 술폰 아미드 유도체를 제조하기 위한 술폰아미드-치환 벤조산은 하기 단계들을 포함하는 과정에 의해 제조되는 것을 특징으로 하는 방법.9. The method of claim 8, wherein in the sulfonamide-substituted benzoic acid, sulfonamide-substituted benzoic acid for preparing a cyclized sulfonamide derivative is prepared by a process comprising the following steps. (ⅶ) 에틸-3-아미노벤조에이트(7)을 3-클로로프로판술포닐 클로라이드와 반응시켜 에틸 3-{비스[(3-클로로프로필)술포닐]아미노}벤조에이트(8)을 얻는 단계;(Iii) reacting ethyl-3-aminobenzoate (7) with 3-chloropropanesulfonyl chloride to obtain ethyl 3- {bis [(3-chloropropyl) sulfonyl] amino} benzoate (8); (ⅷ) 화합물(8)을 N,N-디메틸포름아미드 용매하에 수산화나트륨 수용액을 사용하여 고리화된 화합물(9)를 얻는 단계; 및(Iii) obtaining Compound (8) by cyclization of Compound (9) using an aqueous sodium hydroxide solution in a N, N-dimethylformamide solvent; And (ⅸ) 화합물(9)를 테트라히드로퓨란 및 메탄올 용매하에서 수산화리튬 수용액을 사용하여 화합물(10)을 얻는 단계.(Iii) obtaining compound (9) from compound of tetrahydrofuran and methanol using aqueous lithium hydroxide solution.
Figure 112003036743077-pat00024
Figure 112003036743077-pat00024
 제 8 항에 있어서, 상기 술폰아미드-치환 벤조산 중, 고리화되지 않은 술폰 아미드 유도체를 제조하기 위한 술폰아미드-치환 벤조산은 하기 단계들을 포함하는 과정에 의해 제조되는 것을 특징으로 하는 방법.10. The method of claim 8, wherein in the sulfonamide-substituted benzoic acid, sulfonamide-substituted benzoic acid for preparing an uncyclized sulfonamide derivative is prepared by a process comprising the following steps. (ⅶ) 화합물(7)과 알킬술포닐 크로라이드를 사용하여 에틸 알킬술포닐아미노벤조에이트를 얻는 단계; 및(Iii) obtaining ethyl alkylsulfonylaminobenzoate using compound (7) and alkylsulfonyl chloride; And (ⅷ) 에틸 알킬술포닐아미노벤조에이트를 수산화리튬 수용액으로 가수분해하여 술폰아미드-치환 벤조산을 얻는 단계.(Iii) hydrolyzing ethyl alkylsulfonylaminobenzoate with an aqueous lithium hydroxide solution to obtain sulfonamide-substituted benzoic acid. 삭제delete 약제학적으로 허용되는 담체와, 제 1 항에 따른 화학식 1의 술폰 아미드 유도체를 약리학적 유효량으로 함유하는 알츠하이머 질환의 예방 또는 치료용 조성물.A composition for the prophylaxis or treatment of Alzheimer's disease, comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of the sulfonamide derivative of formula 1 according to claim 1. 제 12 항에 있어서, 상기 조성물은 경구용 제제, 비경구용 제제 또는 경피용 제제로 제형화되는 것을 특징으로 하는 알츠하이머 질환의 예방 또는 치료용 조성물.13. The composition for preventing or treating Alzheimer's disease according to claim 12, wherein the composition is formulated as an oral preparation, a parenteral preparation or a transdermal preparation. 삭제delete 삭제delete
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