KR101169359B1 - Novel Oxazolidinone derivatives with cyclic amidrazone and Pharmaceutical Compositions thereof - Google Patents

Abstract

본 발명은 하기 화학식 1로 표시되는 신규한 옥사졸리디논 유도체, 특히 사이클릭 아미드라존 기를 가지는 신규한 옥사졸리디논 화합물에 관한 것이다.
[화학식 1]

[상기 식에서 R, X 및 Q는 발명의 상세한 설명에 정의된 바와 동일하다.]
또한 본 발명은 상기 화학식 1의 신규한 옥사졸리디논 유도체, 이의 프로드럭, 이의 수화물, 이의 용매화물, 이의 이성질체 및 이의 약제학적으로 허용되는 염을 유효성분으로 함유하는 항생제용 의약 조성물에 관한 것이다.
본 발명에 따른 신규한 옥사졸리디논 유도체, 이의 프로드럭, 이의 수화물, 이의 용매화물, 이의 이성질체 및 이의 약제학적으로 허용되는 염은 내성균에 대한 항균 스펙트럼이 넓고, 독성이 낮으며, 그람양성 및 그람음성균에 강한 항균효과를 나타내므로, 항생제로 유용하게 사용될 수 있다.The present invention relates to novel oxazolidinone derivatives represented by the following general formula (1), in particular novel oxazolidinone compounds having cyclic amidrazon groups.
[Formula 1]

[Where R, X and Q are the same as defined in the detailed description of the invention]
The present invention also relates to a pharmaceutical composition for antibiotics containing a novel oxazolidinone derivative of Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, and a pharmaceutically acceptable salt thereof as an active ingredient.
The novel oxazolidinone derivatives, prodrugs thereof, hydrates thereof, solvates thereof, isomers thereof and pharmaceutically acceptable salts thereof according to the present invention have a broad antimicrobial spectrum, low toxicity, gram positive and gram resistance to resistant bacteria. Since it shows strong antibacterial effect against negative bacteria, it can be usefully used as an antibiotic.

Description

사이클릭 아미드라존 기를 가지는 신규한 옥사졸리디논 유도체 및 이를 함유하는 의약 조성물 {Novel Oxazolidinone derivatives with cyclic amidrazone and Pharmaceutical Compositions thereof}Novel Oxazolidinone derivatives with cyclic amidrazone and Pharmaceutical Compositions etc.

본 발명은 하기 화학식 1로 표시되는 새로운 옥사졸리디논 유도체, 특히 사이클릭 아미드라존 기를 포함하는 신규한 옥사졸리디논 유도체에 관한 것이다.The present invention relates to novel oxazolidinone derivatives represented by the following general formula (1), in particular novel oxazolidinone derivatives comprising cyclic amidrazon groups.

[화학식 1][Formula 1]

또한 본 발명은 화학식 1로 표시되는 신규한 옥사졸리디논 유도체, 이의 프로드럭, 이의 수화물, 이의 용매화물, 이의 이성질체 또는 이의 약제학적으로 허용되는 염을 유효성분으로 함유하는 항생제용 의약 조성물에 관한 것이다.The present invention also relates to a pharmaceutical composition for antibiotics containing a novel oxazolidinone derivative represented by Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. .

옥사졸리디논 항생제인 리네졸리드가 1984년 처음 보고된 이후(유럽 특허공개 제 127,902호), 여러 제약회사들에 의하여 다양한 옥사졸리디논 유도체들이 보고되고 있다. 그러나 아직 개발 중인 약물 중에는 리네졸리드 (제품명: 자이복스)보다 독성이 적으면서도 효능이 뛰어난 약물은 없는 실정이다. 이러한 문제점은 MRSA 에 대한 치료에서 반코마이신을 대체할 수 있는 최선의 수단으로 리네졸리드가 주목을 받고 있으나, 최근 보고되고 있는 리네졸리드 내성균이 더 확산된다면 이의 치료제는 거의 없어지는 아주 심각한 문제가 생기게 된다.Since oxazolidinone antibiotic Lineezolide was first reported in 1984 (European Patent Publication No. 127,902), various oxazolidinone derivatives have been reported by several pharmaceutical companies. However, none of the drugs under development is less toxic and more potent than Linezolid (product name: XIVOX). This problem has been receiving attention by Linezolid as the best alternative to vancomycin in the treatment of MRSA. However, if more recently spread of Lineezolide resistant bacteria has been reported, there is a very serious problem that its treatment is almost eliminated. .

이러한 이유로 리네졸리드보다 효과나 독성 측면에서 뛰어나며, 리네졸리드 내성균에 대해서도 효과가 있는 약물의 개발은 아주 시급한 실정이다. 본 발명자는 2008년 9월 24일 출원한 대한민국 특허 10-2008-0093712 에 사이클릭 아미드라존 또는 사이클릭 아미독심 기를 가지는 옥사졸리디논 항생제가 약효나 독성 측면에서 리네졸리드 보다 우수한 특성을 보임을 발표하였으며, 사이클릭 아미드라존 기를 도입함으로 많은 장점을 가짐을 보고하였다. For this reason, it is very urgent to develop drugs that are superior to linezolide in terms of efficacy and toxicity, and are effective against linezolide resistant bacteria. The inventors of the Korean Patent No. 10-2008-0093712 filed Sep. 24, 2008 show that oxazolidinone antibiotics having a cyclic amidrazone or cyclic amidoxime group have superior properties to linezolid in terms of efficacy and toxicity. It has been reported that it has many advantages by introducing cyclic amidrazone groups.

특히 사이클릭 아미드라존 기는 약한 염기성을 띄게 되어 염의 형태를 만들 수 있으며, 염산염의 경우 pKa 가 5 정도로 아세트 산과 유사한 정도의 산성도를 나타낸다. 이러한 정도의 약산성 성질에 의해 항균능력은 떨어지지 않으면서 물에 대한 용해도를 크게 증가 시킬 수 있게 된다.In particular, the cyclic amidrazon group may have a weak basicity to form a salt, and in the case of hydrochloride, pKa is about 5, and has an acidity similar to acetic acid. Due to this weak acidic properties, the solubility in water can be greatly increased without degrading the antibacterial ability.

이에, 본 발명자들은 기존의 항생제보다 우수한 항균력을 가지며 경구 및 주사제로의 개발을 용이하게 하기 위하여 높은 용해도를 가지는 항생제를 개발하기 위하여 신규한 옥사졸리디논 유도체를 합성하였으며, 본 발명에 따른 신규한 옥사졸리디논 유도체들은 항균 효과가 우수하고 항균 스펙트럼이 월등히 향상됨을 확인하고 본 발명을 완성하였다. Accordingly, the present inventors have synthesized a novel oxazolidinone derivative to develop an antibiotic having a high solubility in order to facilitate the development of oral and injectables, and has a superior antimicrobial activity than conventional antibiotics, the novel oxa according to the present invention Zolidinone derivatives were confirmed that the antimicrobial effect is excellent and the antibacterial spectrum is significantly improved and completed the present invention.

특히 본 발명의 화합물과 같은 사이클릭 아미드라존 화합물에 대해서는 연구가 되어있지 않은 새로운 구조이다. 사이클릭 아미드라존 기를 옥사졸리디논 항생제에 도입함으로 흡수도를 크게 개선시킬 수 있었으며, 적당한 염기도를 가짐으로 인해 염의 형태를 만들 수 있어 물에 대한 용해도를 크게 증가시킬 수 있었다. 이러한 물에 대한 용해도의 증가로 굳이 프로드럭의 형태를 취하지 않고도 주사제를 만들 수 있으며, 독성도 크게 나타나지 않는 것을 확인 하였다.In particular, cyclic amidrazone compounds such as the compounds of the present invention are new structures that have not been studied. Incorporation of cyclic amidrazon groups into the oxazolidinone antibiotics could greatly improve the absorbency and, with the proper basicity, could form salts, which greatly increased the solubility in water. The increased solubility in water makes it possible to make injections without taking the form of prodrugs and does not show much toxicity.

따라서, 본 발명의 목적은 신규한 옥사졸리디논 유도체, 특히 사이클릭 아미드라존 기를 도입하여 용해도를 증가시킨 신규한 옥사졸리디논 화합물 및 이의 제조방법을 제공하는 것이다.It is therefore an object of the present invention to provide novel oxazolidinone derivatives, in particular novel oxazolidinone compounds which have increased solubility by introducing cyclic amidrazone groups and methods for their preparation.

본 발명의 다른 목적은 신규한 옥사졸리디논 유도체, 이의 프로드럭, 이의 수화물, 이의 용매화물, 이의 이성질체 또는 이의 약제학적으로 허용되는 염을 유효성분으로 함유하는 항생제용 의약 조성물을 제공하는 것이다. Another object of the present invention is to provide a pharmaceutical composition for antibiotics containing a novel oxazolidinone derivative, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

본 발명에 따른 신규한 옥사졸리디논 유도체들은 원내획득폐렴, 사회획득 폐렴, 복합성 피부 및 연조직 감염, 단순성 피부 및 연조직 감염, 항생제 내성균주, 특히 VRE (반코마이신 내성 엔테로코쿠스 패슘) 혹은 리네졸리드 내성 엔테로코쿠스 패칼리스에 의한 패혈증 등의 감염, 병원균에 그람 (-)균이 포함된 경우의 병용요법 등의 치료제로 사용 되어질 수 있다.The novel oxazolidinone derivatives according to the present invention are in vitro acquired pneumonia, socially acquired pneumonia, complex skin and soft tissue infections, simple skin and soft tissue infections, antibiotic resistant strains, in particular VRE (vancomycin resistant enterococcus fascium) or linezolide resistant It can be used as a therapeutic agent for infections such as sepsis caused by Enterococcus faecalis and combination therapy when gram (-) bacteria are included in pathogens.

본 발명은 하기 화학식 1로 표시되는 신규한 옥사졸리디논 유도체, 특히 사이클릭 아미드라존 기를 가지는 신규한 옥사졸리디논 화합물에 관한 것이다. 또한, 본 발명은 하기 화학식 1의 신규한 옥사졸리디논 유도체, 이의 프로드럭, 이의 수화물, 이의 용매화물, 이의 이성질체 또는 이의 약제학적으로 허용되는 염을 유효성분으로 함유하는 항생제용 의약 조성물에 관한 것이다.The present invention relates to novel oxazolidinone derivatives represented by the following general formula (1), in particular novel oxazolidinone compounds having cyclic amidrazon groups. The present invention also relates to a pharmaceutical composition for antibiotics containing a novel oxazolidinone derivative of Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. .

[화학식 1][Formula 1]

[상기 식에서, [In the above formula,

X 는 화학결합, -(CH₂)_n- 또는 -(CH₂)_nC(=O)- 이며; X is a chemical bond,-(CH ₂ ) _n -or-(CH ₂ ) _n C (= 0)-;

n 은 0 내지 2의 정수이고;n is an integer from 0 to 2;

R 은 하기 구조에서 선택되는 5원 혹은 6원 헤테로 고리이며:R is a 5 or 6 membered hetero ring selected from the structure:

상기 R₁ 내지 R₂₅ 는 서로 독립적으로 수소, (C₁-C₆)알킬, (C₃-C₆)사이클로알킬, -OH, -NR₃₁R₃₂, -C(=O)R₃₃, -(CH₂)_mOH, -C=NOH, -CN, -NO₂ 또는 할로겐이며;R ₁ to R ₂₅ are each independently hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, -OH, -NR ₃₁ R ₃₂ , -C (= 0) R ₃₃ ,- (CH ₂ ) _m OH, —C═NOH, —CN, —NO ₂ or halogen;

R₃₁ 및 R₃₂는 서로 독립적으로 수소, (C₁-C₆) 알킬 또는 -C(=O)H이며;R ₃₁ and R ₃₂ are independently of each other hydrogen, (C ₁ -C ₆ ) alkyl, or —C (═O) H;

R₃₃은 수소, -OH, -NH₂ 또는 (C₁-C₆)알킬이며;R ₃₃ is hydrogen, —OH, —NH ₂ or (C ₁ -C ₆ ) alkyl;

m은 1 내지 6의 정수이며;m is an integer from 1 to 6;

Q는 -OH, -NHC(=O)R₄₁ 또는 -NHC(=O)OR₄₁이며;Q is -OH, -NHC (= 0) R ₄₁ or -NHC (= 0) OR ₄₁ ;

R₄₁은 (C₁-C₆)알킬이다.]
R ₄₁ is (C ₁ -C ₆ ) alkyl.]

본 명세서에서 사용되는 용어 '알킬'은 직쇄 및 분지쇄형 구조를 포함한다. 예를 들어, (C₁-C₆)알킬은 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, tert-부틸, 펜틸 및 헥실 등 모든 가능한 위치 및 기하 이성질체를 포함한다. The term 'alkyl' as used herein includes both straight and branched chain structures. For example, (C ₁ -C ₆ ) alkyl includes all possible positions and geometric isomers such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl.

(C₃-C₆)사이클로알킬의 예는 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실 및 사이클로프로필메틸 등 모든 고리 형태의 가능한 위치 및 기하 이성질체를 포함한다.
Examples of (C ₃ -C ₆ ) cycloalkyl include the possible positions and geometric isomers of all ring forms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclopropylmethyl.

본 발명에 따른 상기 화학식 1의 옥사졸리디논 유도체의 바람직한 예로는 하기 화학식 2 내지 화학식 4로부터 선택되는 화합물이다.Preferred examples of the oxazolidinone derivative of Chemical Formula 1 according to the present invention are compounds selected from Chemical Formulas 2 to 4.

[화학식 2][Formula 2]

[화학식 3](3)

[화학식 4][Formula 4]

[상기 화학식 2 내지 4에서, R 과 Q 는 상기 화학식 1에서의 정의와 동일하다.]
[In Formulas 2 to 4, R and Q are the same as defined in Formula 1 above.]

본 발명에 따른 상기 화학식 1의 옥사졸리디논 유도체의 더욱 바람직한 예로는 하기 화학식 5 내지 화학식 10으로부터 선택되는 화합물이다.More preferred examples of the oxazolidinone derivative of Formula 1 according to the present invention are compounds selected from the following Formulas 5 to 10:

[화학식 5][Chemical Formula 5]

[화학식 6][Formula 6]

[화학식 7][Formula 7]

[화학식 8][Formula 8]

[화학식 9][Chemical Formula 9]

[화학식 10][Formula 10]

[상기 화학식 5 내지 10에서 R은 상기 화학식 1에서의 정의와 동일하다.]
[R in Formulas 5 to 10 is the same as defined in Formula 1]

본 발명에 따른 신규한 옥사졸리디논 유도체는 하기의 화합물들로 예시될 수 있으나, 하기의 화합물이 본 발명을 한정하는 것은 아니다. The novel oxazolidinone derivatives according to the present invention may be exemplified by the following compounds, but the following compounds do not limit the present invention.

본 발명에 따른 신규한 옥사졸리디논 유도체는 사이클릭 아미드라존 기를 가짐으로써 생체내 흡수를 증진시키거나 용해도를 증가시키기 위하여 프로드럭, 수화물, 용매화물, 이성질체 및 약제학적으로 허용되는 염의 형태로 만들어 사용할 수 있으므로, 상기의 프로드럭, 수화물, 용매화물, 이성질체 및 약제학적으로 허용되는 염 역시 본 발명의 범위에 속한다.
The novel oxazolidinone derivatives according to the invention are made in the form of prodrugs, hydrates, solvates, isomers and pharmaceutically acceptable salts in order to enhance absorption in vivo or to increase solubility by having cyclic amidrazone groups. As such, prodrugs, hydrates, solvates, isomers and pharmaceutically acceptable salts thereof are also within the scope of the present invention.

본 발명에 따른 신규한 옥사졸리디논 유도체는 약제학적으로 허용되는 염의 형태로 사용할 수 있으며, 약제학적으로 허용되는 염은 예컨대 HCl, HBr, HI, 설페이트(sulfate), 포스페이트(phosphate), 아세테이트(acetate), 프로피오네이트(propionate), 락테이트(lactate), 메실레이트(mesylate), 말레에이트(maleate), 말레이트(malate), 숙시네이트(succinate), 타르트레이트(tartrate), 시트레이트(citrate), 퓨마레이트(fumarate), 2-하이드록시에틸술포네이트(2-hydroxyethyl sulfonate) 등을 포함한다. 또한 이러한 염은 수하물 형태 일 수 있다.
The novel oxazolidinone derivatives according to the invention can be used in the form of pharmaceutically acceptable salts, the pharmaceutically acceptable salts being for example HCl, HBr, HI, sulfate, phosphate, acetate ), Propionate, lactate, mesylate, maleate, maleate, succinate, tartrate, citrate , Fumarate, 2-hydroxyethyl sulfonate, and the like. Such salts may also be in the form of baggage.

본 발명의 옥사졸리디논 유도체는 용매화된 형태, 예를 들어 수화된 형태 및 비용매화 형태로 존재할 수 있으며, 본 발명에 따른 옥사졸리디논 유도체 화합물의 용매화물은 제약 활성을 갖는 모든 용매화된 형태를 포함하는 것이다.
The oxazolidinone derivatives of the present invention may exist in solvated forms, for example hydrated forms and unsolvated forms, and solvates of the oxazolidinone derivative compounds according to the present invention are all solvated forms having pharmaceutical activity. It will include.

본 발명의 옥사졸리디논 유도체는 인간 또는 동물의 체내에서 분해되어 본 발명의 화합물을 제공하는 프로드럭의 형태로 투여될 수 있다. 프로드럭은 모 화합물의 물리적 및(또는) 약동학적 프로파일을 변경 또는 개선하는데 사용될 수 있고 모 화합물이 프로드럭을 형성하도록 유도될 수 있는 적합한 기 또는 치환체를 함유할 경우 형성될 수 있다. 프로드럭의 예는 본 발명에 따른 화합물의 생체 내 가수분해 가능한 에스테르 및 이의 제약상 허용되는 염을 포함한다.
The oxazolidinone derivatives of the invention can be administered in the form of prodrugs that are degraded in the human or animal body to provide the compounds of the invention. Prodrugs can be used to alter or improve the physical and / or pharmacokinetic profile of the parent compound and can be formed if the parent compound contains suitable groups or substituents that can be induced to form the prodrug. Examples of prodrugs include in vivo hydrolyzable esters of the compounds according to the invention and pharmaceutically acceptable salts thereof.

프로드럭의 다양한 형태는 당업계에 공지되어 있는데, 예를 들어:Various forms of prodrugs are known in the art, for example:

a) 문헌 [Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) 및 Methods in Enzymology, Vol. 42, p.309-396, edited by K. Widder, et al. (Academic press, 1985)];a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic press, 1985);

b) 문헌 [A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991)];b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991);

c) 문헌 [H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992)];c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

d) 문헌 [H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988)]; 및d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); And

e) 문헌 [N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984)]e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984)].

등의 문헌을 참조할 수 있다.
See et al.

본 발명에 따른 프로드럭의 예로는 아래와 같은 화합물을 들 수 있다.Examples of prodrugs according to the present invention include the following compounds.

위의 예시에서와 같이 하이드록시기에 포스포네이트를 붙이거나 아세틸기를 붙여서 흡수되고 난 뒤에는 활성을 가지는 형태로 돌아가게 하는 형태로 만들거나, 아미노산을 붙이거나 카보네이트 형태로 만드는 방법 등이 가능하다. 이러한 프로드럭은 용해도가 비교적 낮거나 흡수도가 낮은 경우에 주로 이용되며 프로드럭으로 바꿀 경우 용해도 및 흡수가 증가함은 물론, ADME(absorption, distribution, metabolism, excretion)와 PK 프로파일이 향상 되기도 한다.As in the above example, after being absorbed by attaching a phosphonate to an hydroxy group or by attaching an acetyl group, a form of returning to an active form, or adding an amino acid or a carbonate form is possible. These prodrugs are mainly used when the solubility is relatively low or the absorption is low, and the conversion to prodrug increases the solubility and absorption, as well as improves ADME (absorption, distribution, metabolism, excretion) and PK profile.

본 발명의 화합물은 옥사졸리디논 고리의 C-5 위치에 키랄 센터를 갖는다. 본 발명에 따른 옥사졸리디논 유도체 화합물의 바람직한 부분입체 이성질체는 [화학식 1]에 나타낸 것과 같으며 화학식 1b와 같은 에피머와 비교하여 더 유리한 MAO 프로파일을 나타낸다.Compounds of the invention have a chiral center at the C-5 position of the oxazolidinone ring. Preferred diastereomers of the oxazolidinone derivative compounds according to the invention are as shown in [Formula 1] and exhibit a more favorable MAO profile compared to epimers such as Formula 1b.

[화학식 1b][Chemical Formula 1b]

옥사졸리디논 키랄 센터 상의 에피머의 임의의 혼합물이 사용될 경우, 거울상 이성질체를 단독으로 사용하는 경우와 제약상 활성이 있는 동일한 효과를 얻기 위해서는 부분 입체 이성질체의 비율을 감안하여 그 사용량을 조절할 수 있다.When any mixture of epimers on the oxazolidinone chiral center is used, its amount can be adjusted in consideration of the proportion of the diastereoisomers in order to obtain the same effect with pharmacological activity alone as with the enantiomer alone.

본 발명에서 화학식 1의 화합물 또는 이의 염은 호변이성질화(tautomer) 현상을 나타낼 수 있으므로, 비록 본 명세서 내의 화학식 또는 반응식 들이 하나의 가능성 있는 호변이성질체 형태만을 표현하고 있다 하더라도, 본 발명은 항균 활성을 갖는 임의의 호변이성질체 형태를 포함하고 단순히 화학식 또는 반응식 내에 사용된 하나의 호변이성질체 형태에만 국한되는 것은 아니다.
In the present invention, since the compound of Formula 1 or a salt thereof may exhibit tautomer phenomenon, although the formula or schemes in the present specification express only one possible tautomeric form, the present invention exhibits antimicrobial activity. It includes, but is not limited to, only one tautomeric form having any tautomeric form having it in the formula or scheme.

본 발명의 특정 화합물은, 또한, 동질이상 (polymorphism)을 나타낼 수 있으며, 항균 활성을 갖는 임의의 동질이상 화합물도 모두 본 발명에 포함된다.Certain compounds of the present invention may also exhibit polymorphisms, and any homogenous compounds having antimicrobial activity are also included in the present invention.

본 발명에 따른 신규한 옥사졸리디논 유도체 화합물은 그 치환체의 종류에 따라 알려진 다양한 방법으로 제조될 수 있는데, 예를 들어, 하기 반응식 1 과 2에 예시된 방법에 따라 제조될 수 있다. 하기 반응식 1 또는 2에 제시된 제조방법은 예시일 뿐이며 특정의 치환체에 따라 당업자에 의해 용이하게 변형될 수 있음 자명하므로 하기 반응식 1 또는 2에 예시된 방법이 본 발명에 따른 옥사졸리디논 화합물을 제조하는 방법을 한정하는 것은 아니며, 달리 언급이 없는 한 하기 반응식의 치환체의 정의는 상기 화학식 1에서의 정의와 동일하다.The novel oxazolidinone derivative compounds according to the present invention can be prepared by various known methods depending on the kind of substituents thereof, for example, can be prepared according to the methods illustrated in Schemes 1 and 2. The preparation method shown in Scheme 1 or 2 is only an example and can be easily modified by those skilled in the art according to specific substituents. Thus, the method illustrated in Scheme 1 or 2 is prepared to prepare an oxazolidinone compound according to the present invention. It does not limit the method, and unless otherwise stated, the definition of substituents in the following scheme is the same as defined in the formula (1).

본 발명에 따른 상기 화학식 1의 옥사졸리디논 유도체 화합물은 Q 에 따라 각각 다른 방법으로 합성 할 수 있으며, Q 가 OH 인 경우에 있어 대표적인 합성 방법을 다음의 반응식1에 나타내었으며, Q 가 N-acetyl 인 경우는 반응식 2에 나타내었다.
The oxazolidinone derivative compounds of Chemical Formula 1 according to the present invention can be synthesized in different ways according to Q. In the case of Q is OH, a typical synthesis method is shown in Scheme 1 below, and Q is N-acetyl. In the case of is shown in Scheme 2.

아래의 반응식 1에 나타낸 바와 같이, 다이플루오로나이트로벤젠을 에탄올아민과 반응시켜 화합물 I 을 합성하고, 알코올과 아민을 각각 TBS (t-butyldimethylsilyl) 와 boc 으로 보호한 뒤 (화합물 II), 나이트로 기를 Pd/C 을 이용하여 아민으로 환원시키고 (화합물 III), Cbz-Cl 를 사용하여 cbz 기를 붙여 화합물 IV를 합성하였다. 이 화합물을 (R)-glycidyl butyrate 와 BuLi 으로 반응시켜 chiral 한 화합물 V 를 합성하였다. 화합물 V에서 알코올기를 먼저 벤조일로 보호한 다음 염산으로 boc과 tbs 보호기를 제거하고 (화합물 VI), 메질레이션(mesylation)시켜 화합물 VII 을 합성하였다. 이 화합물을 하이드라진과 반응시키고, 다시 트리메틸오르소포메이트와 반응시켜 사이클릭 아미드라존 화합물 VIII 을 합성하였다. 포밀기를 제거하고 (화합물 IX) 연결부분인 X와 다양한 R을 도입하여 화학식 1의 화합물을 얻을 수 있었으며 각각의 자세한 예는 실시예에 기술하였다.As shown in Scheme 1 below, difluoronitrobenzene was reacted with ethanolamine to synthesize Compound I, and the alcohol and amine were protected with TBS (t-butyldimethylsilyl) and boc, respectively (Compound II), The group was reduced to an amine using Pd / C (Compound III), and the compound was synthesized by attaching a cbz group using Cbz-Cl. This compound was reacted with (Li) -glycidyl butyrate and BuLi to synthesize chiral compound V. In compound V, the alcohol group was first protected with benzoyl, and then boc and tbs protecting groups were removed with hydrochloric acid (compound VI), and mesolysis (mesylation) to synthesize compound VII. This compound was reacted with hydrazine and again with trimethylorthoformate to synthesize cyclic amidrazone compound VIII. By removing the formyl group (Compound IX) and introducing the linking portion X and various Rs, the compound of Formula 1 was obtained, and detailed examples of each were described in the Examples.

[반응식 1][Reaction Scheme 1]

화학식 1에서 Q 가 N-acetyl 인 경우는 하기 반응식 2에 나타내었다. 상기 반응식 1에서 합성한 화합물 V 를 메탄술포닐 클로라이드 (Ms-Cl) 와 반응시키고, 다시 소디움 아자이드 (NaN₃) 와 반응시켜 화합물 X 을 합성하였다. 이 화합물을 수소가스 하에서 Pd/C 로 아민으로 만든 뒤 다시 Cbz-Cl 를 사용하여 cbz 기를 붙여 화합물 XII 를 합성하였다. 이 화합물을 염산으로 처리하여 보호기 boc 과 tbs 를 제거하고, 다시 메탄술포닐 클로라이드 (Ms-Cl) 와 반응시켜 화합물 XIII 을 합성하였다. 이 화합물을 하이드라진과 반응시키고 트리메틸오르소포메이트와 반응시켜 사이클릭 아미드라존 화합물 XIV 를 합성하였다. 이 화합물에서 보호기인 cbz 를 제거하고 아세틸 기를 도입한 뒤 (화합물 XV), 포밀기를 제거하고 다양한 R 그룹을 도입하여 화학식 1의 화합물을 얻을 수 있었다. 각각의 자세한 예는 실시예에 기술하였다.In the case of Q in Formula 1, N-acetyl is shown in Scheme 2 below. Compound V synthesized in Scheme 1 was reacted with methanesulfonyl chloride (Ms-Cl), and then reacted with sodium azide (NaN ₃ ) to synthesize compound X. The compound was made of amine under Pd / C under hydrogen gas, and then cbz group was attached using Cbz-Cl to synthesize Compound XII. The compound was treated with hydrochloric acid to remove the protective groups boc and tbs, and then reacted with methanesulfonyl chloride (Ms-Cl) to synthesize Compound XIII. This compound was reacted with hydrazine and with trimethylorthoformate to synthesize cyclic amidrazone compound XIV. From this compound, the protective group cbz was removed, an acetyl group was introduced (Compound XV), a formyl group was removed, and various R groups were introduced to obtain a compound of Formula 1. Each detailed example is described in the Examples.

[반응식 2]Scheme 2

본 발명의 조성물은 경구용으로 적합한 형태 (예를 들면, 정제, 로렌지, 경질 또는 연질 캅셀제, 수성 또는 오일상 현탁제, 유제, 분산성 산제 또는 과립제, 시럽제 또는 엘릭서제), 국부용으로 적합한 형태 (예를 들면, 크림, 연고, 젤, 또는 수성 또는 오일상 용제 또는 현탁제), 안과 투여용으로 적합한 형태, 흡입 투여용으로 적합한 형태 (예를 들면, 미분화 산제 또는 액상 에어로졸), 주입 투여용으로 적합한 형태 (예를 들면, 미분화 산제) 또는 비경구 투여용으로 적합한 형태 (예를 들면, 정맥내, 피하, 설하, 근육내 또는 근육내 투약용 멸균성 수성 또는 오일상 용제로서, 또는 직장 투약용 좌제로서)일 수 있다. Compositions of the present invention are suitable for oral use (e.g. tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), suitable for topical use. Forms (e.g. creams, ointments, gels or aqueous or oily solvents or suspensions), forms suitable for ophthalmic administration, forms suitable for inhalation administration (e.g. micronized powder or liquid aerosol), infusion administration Suitable forms for use (eg, undifferentiated powders) or suitable forms for parenteral administration (eg, as sterile aqueous or oily solvents for intravenous, subcutaneous, sublingual, intramuscular or intramuscular administration, or rectal As a suppository for administration).

본 발명의 화합물 이외에도, 본 발명의 제약 조성물은 기타 임상적으로 유용한 항균제 (예를 들면, β-락탐, 매크롤리드, 퀴놀론 또는 아미노글리코시드) 및/또는 기타 항감염제 (예를 들면, 항진균성 트리아졸 또는 암포테리신) 중에서 선택된 한 가지 이상의 공지된 약물을 함유할 수 있거나 (즉, 함께 제형화함으로써 이루어짐) 또는 이들 한 가지 이상의 공지된 약물과 공동으로 투여할 수 있다. 이들은 치료 효능을 확대시키기 위해, 카바페넴, 예를 들면, 메로페넴 또는 이미페넴을 포함할 수 있다. 본 발명의 화합물은 또한, 그람 음성 세균과 항미생물제에 대해 내성인 세균에 대해 활성을 증진시키기 위해, 살균성/투과-증가성 단백질 (BPI) 생성물 또는 유출 펌프 억제제와 함께 제형화하거나 이와 공동으로 투여할 수 있다. In addition to the compounds of the present invention, the pharmaceutical compositions of the present invention may contain other clinically useful antibacterial agents (e.g., β-lactams, macrolides, quinolones or aminoglycosides) and / or other anti-infective agents (e.g., antifungal agents One or more known drugs selected from sexual triazoles or amphotericins) (ie, by formulating together) or co-administered with one or more known drugs. These may include carbapenems, for example meropenem or imipenem, to broaden the therapeutic efficacy. The compounds of the present invention may also be formulated or co-administered with bactericidal / permeable-increasing protein (BPI) products or effluent pump inhibitors to enhance activity against gram negative bacteria and bacteria that are resistant to antimicrobial agents. can do.

본 발명의 화합물은 비타민, 예를 들면, 비타민 B, 예를 들어, 비타민 B2, 비타민 B6, 비타민 B12 및 엽산과 함께 제형화하거나 이와 공동으로 투여할 수도 있다. 본 발명의 화합물은 사이클로옥시게나제 (COX) 억제제, 특히 COX-2 억제제와 함께 제형화하거나 이와 공동으로 투여할 수도 있다. 또한 본 발명의 화합물을 그람-양성 세균, 그람-음성 세균에 대항해 활성인 항균제와 함께 제형화 및 공동투여 할 수 있다. The compounds of the present invention may also be formulated with or coadministered with vitamins such as vitamin B such as vitamin B2, vitamin B6, vitamin B12 and folic acid. The compounds of the present invention may also be formulated or co-administered with cyclooxygenase (COX) inhibitors, in particular COX-2 inhibitors. The compounds of the invention can also be formulated and coadministered with antimicrobial agents active against Gram-positive bacteria, Gram-negative bacteria.

본 발명의 조성물은 당해 분야에 널리 공지되어 있는 통상적인 제약 부형제를 사용하여 통상적인 과정에 의해 수득할 수 있다. 따라서, 경구 투여용으로 의도된 조성물은 예를 들어, 한 가지 이상의 착색제, 감미제, 향미제 및/또는 방부제를 함유 할 수 있다. 정맥내 투여될 제약 조성물은 유리하게는 (예를 들어, 안정성을 증강시키기 위함), 적합한 살균제, 산화방지제 또는 환원제, 또는 적합한 격리제를 함유할 수 있다. The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients which are well known in the art. Thus, a composition intended for oral administration may contain, for example, one or more colorants, sweeteners, flavors and / or preservatives. Pharmaceutical compositions to be administered intravenously may advantageously contain (eg, to enhance stability) suitable bactericides, antioxidants or reducing agents, or suitable sequestrants.

경구 투여용 조성물은 활성 성분을 불활성 고형 희석제, 예를 들면, 탄산칼슘, 인산칼슘 또는 카올린과 혼합한 경질 젤라틴 캅셀제 형태, 또는 활성 성분을 물 또는 오일, 예를 들면, 땅콩유, 액상 파라핀 또는 올리브유와 혼합한 연질 젤라틴 캅셀제 형태일 수 있다. Compositions for oral administration may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or the active ingredient in water or oil such as peanut oil, liquid paraffin or olive oil. It may be in the form of a soft gelatin capsule mixed with.

수성 현탁제는 일반적으로, 한 가지 이상의 현탁화제, 예를 들면, 나트륨 카복시메틸셀룰로스, 메틸셀룰로스, 하이드록시프로필메틸셀룰로스, 나트륨 알지네이트, 폴리비닐-피롤리돈, 트라가칸드 검 및 아카시아 검; 분산제 또는 습윤제, 예를 들면, 레시틴, 또는 알킬렌 옥사이드와 지방산과의 축합 생성물 (예를 들면, 폴리옥시에틸렌 스테아레이트), 또는 에틸렌 옥사이드와 장쇄 지방족 알코올과의 축합 생성물, 예를 들면, 헵타데카에틸렌옥시세타놀, 또는 에틸렌 옥사이드와 지방산 및 헥시톨로부터 유도된 부분 에스테르와의 축합 생성물, 예를 들면, 폴리옥시에틸렌 솔비톨 모노올레에이트, 또는 에틸렌 옥사이드와 장쇄 지방족 알코올과의 축합 생성물, 예를 들면, 헵타데카에틸렌옥시세타놀, 또는 에틸렌 옥사이드와 지방산 및 헥시톨로부터 유도된 부분 에스테르와의 축합 생성물, 예를 들면, 폴리옥시에틸렌 솔비톨 모노올레에이트, 또는 에틸렌 옥사이드와 지방산 및 헥시톨 무수물로부터 유도된 부분 에스테르와의 축합 생성물, 예를 들면, 폴리에틸렌 솔비탄 모노올레에이트와 함께, 미분화 형태의 활성 성분을 함유한다. 수성 현탁제는 한 가지 이상의 방부제 (예를 들면, 에틸 또는 프로필 p-하이드록시벤조에이트), 산화방지제 (예를 들면, 아스코르브산), 착색제, 향미제, 및/또는 감미제 (예를 들면, 슈크로스, 삭카린 또는 아스파르탐)을 함유할 수도 있다. Aqueous suspending agents generally include one or more suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, tragacand gum and acacia gum; Dispersing or wetting agents, for example lecithin or condensation products of alkylene oxides with fatty acids (eg polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadeca Condensation products of ethyleneoxycetanol or partial esters derived from fatty acids and hexitols, for example polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example , Heptadecaethyleneoxycetanol, or a condensation product of ethylene oxide with partial esters derived from fatty acids and hexitol, for example polyoxyethylene sorbitol monooleate, or ethylene oxide derived from fatty acids and hexitol anhydrides Condensation products with partial esters, for example polyethylene sorbbi Together with tan monooleate, it contains the active ingredient in micronized form. Aqueous suspending agents include one or more preservatives (eg, ethyl or propyl p-hydroxybenzoate), antioxidants (eg, ascorbic acid), colorants, flavors, and / or sweetening agents (eg, shoe Cross, saccharin or aspartame).

오일상 현탁제는 활성 성분을 식물성 오일 (예를 들면, 아라키스 오일, 올리브유, 참깨유 또는 코코넛 오일) 또는 광유 (예를 들면, 액상 파라핀) 중에 현탁시킴으로써 제형화할 수 있다. 오일상 현탁제는 증점제, 예를 들면, 밀랍, 경질 파라핀 또는 세틸 알코올을 함유할 수도 있다. 상기 언급된 바와 같은 감미제, 및 향미제를 가하여 맛좋은 경구용 제제를 제공할 수 있다. 이들 조성물은 아스코르산과 같은 산화방지제를 부가함으로써 보존시킬 수 있다. Oily suspensions can be formulated by suspending the active ingredient in vegetable oils (eg arachis oil, olive oil, sesame oil or coconut oil) or mineral oils (eg liquid paraffin). Oily suspensions may contain thickening agents, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents as mentioned above, and flavoring agents may be added to provide a delicious oral preparation. These compositions can be preserved by adding antioxidants such as ascorbic acid.

물을 부가함으로써 수성 현탁제를 제조하는데 적합한 분산성 산제 및 과립제는 분산 또는 습윤제, 현탁화제 및 한 가지 이상의 방부제와 함께 활성 성분을 함유한다. 적합한 분산 또는 습윤제 및 현탁화제는 앞서 언급된 바와 같이 예시된다. 감미제, 향미제 및 착색제와 같은 부가의 부형제가 존재할 수도 있다.
Dispersible powders and granules suitable for preparing an aqueous suspending agent by adding water contain the active ingredient together with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified as mentioned above. Additional excipients may also be present, such as sweetening, flavoring and coloring agents.

제형에 관한 추가의 정보에 대해서는 하기 문헌을 참조할 수 있다 [참조: Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990].
For further information regarding formulations, reference may be made to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

단일 투여 형태를 생성시키기 위해 하나 이상의 부형제와 배합되는 활성 성분의 양은 물론, 치료받고 있는 숙주와 특정한 투여 경로에 따라서 다양할 것이다. 예를 들어, 인간에게 경구 투여하고자 하는 제형은 일반적으로, 50 mg 내지 5 g의 활성제 화합물을 편리한 적당량의 부형제 (이는 조성물의 총 중량을 기준하여 약 5 내지 약 98％일 수 있다)와 함께 함유할 수 있다. 투여 단위 형태는 일반적으로, 약 200 mg 내지 약 2 g의 활성 성분을 함유할 것이다. 투여 경로 및 투여량 섭생에 관한 추가의 정보에 대해서는, 하기 문헌을 참조할 수 있다 [참조: Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990]. The amount of active ingredient combined with one or more excipients to produce a single dosage form will of course vary depending upon the host being treated and the particular route of administration. For example, formulations intended for oral administration to humans generally contain 50 mg to 5 g of active compound with a convenient suitable amount of excipient, which may be about 5 to about 98% based on the total weight of the composition. can do. Dosage unit forms will generally contain about 200 mg to about 2 g of active ingredient. For further information regarding the route of administration and dosage regimen, reference may be made to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

본 발명의 적합한 제약 조성물은 단위 투여 형태로 경구 투여하기에 적합한 형태, 예를 들면, 본 발명의 화합물을 0.1 mg 내지 1 g, 바람직하게는 100 mg 내지 1 g 함유하는 정제 또는 캅셀제이다. 특히 바람직한 것은 본 발명의 화합물을 50 mg 내지 800 mg, 특히 100 mg 내지 500 mg 함유하는 정제 또는 캅셀제이다.
Suitable pharmaceutical compositions of the invention are tablets or capsules containing 0.1 mg to 1 g, preferably 100 mg to 1 g of a compound of the invention, in a form suitable for oral administration in unit dosage form. Especially preferred are tablets or capsules containing 50 mg to 800 mg, in particular 100 mg to 500 mg of the compounds of the invention.

또한, 본 발명의 제약 조성물은 정맥내, 피하 또는 근육내 주사용으로 적합한 형태, 예를 들면, 본 발명의 화합물을 0.1％ w/v 내지 50％ w/v (1 mg/ml 내지 500 mg/ml) 함유하는 주사제이다.
In addition, the pharmaceutical composition of the present invention may be in a form suitable for intravenous, subcutaneous or intramuscular injection, for example 0.1% w / v to 50% w / v (1 mg / ml to 500 mg / ml) injection.

각 환자에게, 예를 들어, 본 발명의 화합물을 1일 0.1 mg/kg 내지 20 mg/kg씩 정맥내, 피하 또는 근육내 투여할 수 있으며, 해당 조성물을 1일 1회 내지 4회 투여한다. 또 다른 양태에서는, 본 발명의 화합물을 1일 1 mg/kg 내지 20 mg/kg씩 투여한다. 정맥내, 피하 및 근육내 용량은 거환 주사함으로써 제공할 수 있다. 또 다른 한편, 정맥내 용량은 일정 시간에 걸쳐 연속적으로 주입함으로써 제공할 수 있다. 또 다른 한편, 각 환자에게 1일 비경구 용량과 대략 등가일 수 있는 1일 경구 용량을 투여할 수 있으며, 해당 조성물을 1일 1 내지 4회 투여한다.
Each patient may be administered intravenously, subcutaneously or intramuscularly, for example, from 0.1 mg / kg to 20 mg / kg of a compound of the invention, and the composition is administered once to four times daily. In another embodiment, the compound of the present invention is administered 1 mg / kg to 20 mg / kg per day. Intravenous, subcutaneous and intramuscular doses can be given by bolus injection. Alternatively, intravenous doses can be given by continuous infusion over time. Alternatively, each patient may be administered a daily oral dose, which may be approximately equivalent to a daily parenteral dose, and the composition is administered 1 to 4 times per day.

본 발명의 옥사졸리디논 유도체는 현재 시판 중인 리네졸리드에 비하여 훨씬 낮은 농도에서 기존 항생제에 내성을 갖는 스타필로코커스 아우레우스와 엔테로코쿠스 패칼리스 등의 그람 양성균 및 해모필루스 인플루엔재, 모락셀라 카타랄리스 등의 그람 음성균에 대해 항균력을 나타내며, 특히 리네졸리드 내성 엔테로코쿠스 패슘에 대해 탁월한 항균력을 보여준다.
The oxazolidinone derivatives of the present invention are Gram-positive bacteria and Haemophilus influenza, such as Staphylococcus aureus and Enterococcus faecalis, which are resistant to conventional antibiotics at much lower concentrations than commercially available linezolids. It shows antimicrobial activity against Gram-negative bacteria such as Moraxella catarrhalis, and especially against linezolide resistant enterococcus fascia.

이상에서 살펴본 바와 같이, 본 발명의 신규한 옥사졸리디논 유도체는 MRSA, VRE를 비롯한 내성균에 대한 항균 스펙트럼이 넓고, 해모필루스 인플루엔자와 같은 그람 음성균에도 활성을 보여주어 2세대 옥사졸리디논계 항생제로 유용하게 사용될 수 있다. 또한 본 발명의 화합물들은 사이클릭 아미드라존 기를 포함하고 있어 염의 형태를 만들 수 있으므로 기존에 알려진 화합물보다 물에 대한 용해도가 높아 경구용 혹은 주사제로의 개발이 용이하다.
As described above, the novel oxazolidinone derivative of the present invention has a broad antimicrobial spectrum against resistant bacteria including MRSA and VRE, and also shows activity against Gram-negative bacteria such as Haemophilus influenza and is a second-generation oxazolidinone-based antibiotic. It can be usefully used. In addition, the compounds of the present invention contain cyclic amidrazon groups, which can form salts, so that the solubility in water is higher than that of the conventionally known compounds, so it is easy to develop oral or injectables.

이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예 및 실험예를 제시한다. 그러나 하기의 실시예 및 실험예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples and experimental examples are presented to help understand the present invention. However, the following examples and experimental examples are provided only to more easily understand the present invention, and the contents of the present invention are not limited by the following examples.

[제조예 1] 화합물 I 의 제조Preparation Example 1 Preparation of Compound I

3,4-다이플루오르니트로벤젠 (158 g, 0.99 mol)을 아세토니트릴 (800 mL)에 녹인 후 에탄올아민 (117 g, 1.9 mol)을 넣고 4시간 동안 환류 교반했다. 상기 반응물을 상온으로 식힌 후, 감압농축하고 다이에틸이서(diethylether)로 고체화(trituration) 한 뒤 여과하여 노란색의 화합물 I (199 g, 0.99 mol, 100%)을 얻었다.3,4-Difluoronitrobenzene (158 g, 0.99 mol) was dissolved in acetonitrile (800 mL), ethanolamine (117 g, 1.9 mol) was added thereto, and the mixture was stirred under reflux for 4 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, triturated with diethylether and filtered to obtain yellow Compound I (199 g, 0.99 mol, 100%).

¹H NMR (400 MHz, chloroform-d₁) δ 7.97 (d, 1H, J = 8.8Hz), 7.87 (dd, 1H, J ₁ = 11.6 Hz, J ₂ = 2.4 Hz), 6.65 (t, 1H, J = 8.8 Hz), 5.10-4.87 (bs, 1H), 3.97-3.83(m, 2H), 3.43-3.37(m, 2H).
¹ H NMR (400 MHz, chloroform-d ₁ ) δ 7.97 (d, 1H, J = 8.8 Hz), 7.87 (dd, 1H, J ₁ = 11.6 Hz, J ₂ = 2.4 Hz), 6.65 (t, 1H, J = 8.8 Hz), 5.10-4.87 (bs, 1H), 3.97-3.83 (m, 2H), 3.43-3.37 (m, 2H).

[제조예 2] 화합물 II 의 제조Preparation Example 2 Preparation of Compound II

화합물 I (100 g, 0.5 mol), TBS-Cl (t-butyldimethylsilyl chloride, 97g, 0.65 mol) 및 이미다졸 (51 g, 0.75 mol)을 0℃에서 다이클로로메탄 (700 mL)에 녹인 뒤 서서히 상온으로 올려 밤새 교반하였다. 상기 반응물을 감압농축 한 다음, 에틸아세테이트에 녹여 0.5 N HCl 로 세척하고, 중탄산나트륨 포화수용액, 염화나트륨 포화수용액(brine)으로 순차적으로 씻어주고 무수황산나트륨을 이용하여 탈수시켜 감압농축하여 알코올에 tbs 기가 붙은 화합물을 정량적으로 얻었다. 이 화합물을 THF (500 mL)에 녹인 뒤, 1.2 당량의 Boc₂O 와 0.1 당량의 DMAP (4-dimethylaminopyridine)를 넣어주고 3시간 동안 상온에서 교반 시킨 뒤, 암모니아 수 (30 mL)를 넣고 다시 20분간 교반 시키고 감압농축 하였다. 농축액을 다시 에틸아세테이트에 녹인 뒤, 0.5 N HCl, 중탄산나트륨 포화수용액, 염화나트륨 포화수용액(brine)으로 순차적으로 씻어주고, 무수황산나트륨을 이용하여 탈수시켜 감압농축하여 화합물 II 를 정량적으로 얻었다. Compound I (100 g, 0.5 mol), TBS-Cl (t-butyldimethylsilyl chloride, 97g, 0.65 mol) and imidazole (51 g, 0.75 mol) were dissolved in dichloromethane (700 mL) at 0 ° C and then slowly cooled to room temperature. Raised and stirred overnight. The reaction product was concentrated under reduced pressure, and then dissolved in ethyl acetate, washed with 0.5 N HCl, washed sequentially with saturated sodium bicarbonate solution and saturated sodium chloride solution (brine), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to attach a tbs group to alcohol. The compound was obtained quantitatively. After dissolving the compound in THF (500 mL), 1.2 equivalents of Boc ₂ O and 0.1 equivalents of DMAP (4-dimethylaminopyridine) were added thereto, stirred at room temperature for 3 hours, and ammonia water (30 mL) was added thereto. The mixture was stirred for 5 minutes and concentrated under reduced pressure. The concentrated solution was again dissolved in ethyl acetate, washed sequentially with 0.5 N HCl, saturated sodium bicarbonate solution and saturated sodium chloride solution (brine), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Compound II quantitatively.

¹H NMR (600 MHz, chloroform-d₁) δ 8.06-7.98 (m, 1H), 7.95 (dd, 1H, J ₁ = 10.2 Hz, J ₂ = 2.4 Hz), 7.57 (t, 1H, J = 7.8 Hz), 3.80 (t, 2H, J = 5.4 Hz), 3.73 (t, 2H, J = 4.8 Hz), 1.42 (s, 9H), 0.81 (s, 9H), 0.01 (s, 6H).
¹ H NMR (600 MHz, chloroform-d ₁ ) δ 8.06-7.98 (m, 1H), 7.95 (dd, 1H, J ₁ = 10.2 Hz, J ₂ = 2.4 Hz), 7.57 (t, 1H, J = 7.8 Hz), 3.80 (t, 2H, J = 5.4 Hz), 3.73 (t, 2H, J = 4.8 Hz), 1.42 (s, 9H), 0.81 ( s, 9H), 0.01 (s, 6H).

[제조예 3] 화합물 III 의 제조Preparation Example 3 Preparation of Compound III

화합물 II (92 g, 0.22 mol)을 메탄올 (600 mL)에 녹인 뒤 Pd/C (6 g)을 넣고 수소가스 풍선하에서 4시간 동안 교반하였다, 셀라이트(celite)를 이용하여 여과 한 후 감압농축하여 무색의 오일 화합물 III (86g)을 정량적으로 얻었다. Compound II (92 g, 0.22 mol) was dissolved in methanol (600 mL) and Pd / C (6 g) was added thereto, and the mixture was stirred for 4 hours under a hydrogen gas balloon. The mixture was filtered through celite, concentrated under reduced pressure, and colorless. Oil compound III (86 g) was obtained quantitatively.

¹H NMR (400 MHz, chloroform-d₁) δ 6.99 (t, 1H, J = 12.0 Hz), 6.44-6.30 (m, 2H), 3.81-3.63 (m, 4H), 3.63-3.52 (m, 2H), 1.50 (s, 3H), 1.35 (s, 6H), 0.86 (s, 9H), 0.03 (s, 6H).
¹ H NMR (400 MHz, chloroform-d ₁ ) δ 6.99 (t, 1H, J = 12.0 Hz), 6.44-6.30 (m, 2H), 3.81-3.63 (m, 4H), 3.63-3.52 (m, 2H ), 1.50 (s, 3H), 1.35 (s, 6H), 0.86 (s, 9H), 0.03 (s, 6H).

[제조예 4] 화합물 IV 의 제조Preparation Example 4 Preparation of Compound IV

화합물 III (86 g, 0.22 mol)을 다이클로로메탄 (300 mL)에 녹인 뒤 1N NaOH 수용액 (300 mL)을 넣고 교반하면서 서서히 Cbz-Cl (benzyl chloroformate, 38 mL, 0.27 mol)를 적가 하였다. 상온에서 1시간동안 교반 한 후, 유기층을 분리하여 물로 두번 세척하고, 무수황산나트륨을 이용하여 탈수시켜 감압농축하여 노란색 오일 화합물 IV (116 g)를 정량적으로 얻었다. Compound III (86 g, 0.22 mol) was dissolved in dichloromethane (300 mL), 1N NaOH aqueous solution (300 mL) was added thereto, and slowly added dropwise Cbz-Cl (benzyl chloroformate, 38 mL, 0.27 mol) while stirring. After stirring for 1 hour at room temperature, the organic layer was separated, washed twice with water, dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to yield yellow oil compound IV (116 g) quantitatively.

¹H NMR (600 MHz, chloroform-d₁) δ 7.44-7.32 (m, 6H), 7.18 (t, 1H, J = 8.1 Hz), 6.96 (d, 1H, J = 8.4 Hz), 6.84-6.66 (bs, 1H), 5.20 (s, 2H), 3.82-3.63 (m, 2H), 3.63-3.58 (m, 2H), 1.51 (s, 3H), 1.35 (s, 6H), 0.86 (s, 9H), 0.02 (s, 6H).
¹ H NMR (600 MHz, chloroform-d ₁ ) δ 7.44-7.32 (m, 6H), 7.18 (t, 1H, J = 8.1 Hz), 6.96 (d, 1H, J = 8.4 Hz), 6.84-6.66 ( bs, 1H), 5.20 (s, 2H), 3.82-3.63 (m, 2H), 3.63-3.58 (m, 2H), 1.51 (s, 3H), 1.35 (s, 6H), 0.86 (s, 9H) , 0.02 (s, 6H).

[제조예 5] 화합물 V 의 제조Preparation Example 5 Preparation of Compound V

화합물 IV (116 g, 0.22 mol)을 THF (400 mL)에 녹인 뒤, n-부틸리튬(n-butyllithium, 2.5M solution in n-Hexane) (90 mL, 0.23 mol)을 -78℃에서 서서히 적가하고 20분간 교반하였다. (R)-글리시딜 부티레이트 ((R)-Glycidyl butyrate, 31.5 mL, 0.23 mol)를 넣은 뒤, 서서히 상온으로 올리며 3시간 동안 교반하고 암모늄 클로라이드 수용액으로 pH 를 6 정도로 맞춘 뒤 감압농축하였다. 농축액을 80% 에틸아세테이트/헥산으로 녹인 뒤, 물과 염화나트륨 포화수용액(brine)으로 순차적으로 씻어주고 무수황산나트륨을 이용하여 탈수시켜 감압농축하였다. 이 농축액을 40% 에틸아세테이트/헥산 용액으로 컬럼크로마토그래피를 이용하여 분리하여 무색 오일 화합물 V (45 g, 0.093 mol, 42%)를 얻었다. Compound IV (116 g, 0.22 mol) was dissolved in THF (400 mL), then n-butyllithium (2.5M solution in n-Hexane) (90 mL, 0.23 mol) was slowly added dropwise at -78 ° C and 20 Stirred for a minute. After adding (R) -glycidyl butyrate ((R) -Glycidyl butyrate, 31.5 mL, 0.23 mol), the mixture was slowly raised to room temperature, stirred for 3 hours, adjusted to pH 6 with aqueous ammonium chloride solution, and concentrated under reduced pressure. The concentrated solution was dissolved in 80% ethyl acetate / hexane, washed sequentially with water and saturated aqueous sodium chloride (brine), and concentrated under reduced pressure by dehydration using anhydrous sodium sulfate. This concentrate was separated by column chromatography using 40% ethyl acetate / hexane solution to give a colorless oil compound V (45 g, 0.093 mol, 42%).

¹H NMR (600MHz, CDCl3) δ 7.50-7.48(m, 1H), 7.30-7.28(m, 1H), 7.17-7.16(m, 1H), 4.74-4.70(m, 1H), 4.03-4.02(m, 1H), 3.98(m, 2H), 3.75(m, 3H), 3.65(m, 2H), 1.51(s, 3H), 1.36(s, 6H), 0.85(s, 9H), 0.02(s, 6H).
¹ H NMR (600 MHz, CDCl 3) δ 7.50-7.48 (m, 1H), 7.30-7.28 (m, 1H), 7.17-7.16 (m, 1H), 4.74-4.70 (m, 1H), 4.03-4.02 (m , 1H), 3.98 (m, 2H), 3.75 (m, 3H), 3.65 (m, 2H), 1.51 (s, 3H), 1.36 (s, 6H), 0.85 (s, 9H), 0.02 (s, 6H).

[제조예 6] 화합물 VI 의 제조Preparation Example 6 Preparation of Compound VI

화합물 V (26 g, 0.053 mol)을 다이클로로메탄 (180 mL)에 녹인 뒤, DIPEA (diisopropylethylamine, 13 mL, 0.079 mol)과 벤조일 클로라이드 (Bz-Cl, 7.4 mL, 0.064 mol)를 0℃에서 순차적으로 서서히 적가하고 10분간 교반하였다. 상온으로 올린 뒤 소량의 DMAP(4-dimethylaminopyridine)를 넣고 2시간 동안 교반하였다. 이 용액을 감압농축하여 에틸아세테이트에 녹이고 중탄산나트륨 포화수용액, 염화나트륨 포화수용액(brine)으로 순차적으로 씻어주고, 무수황산나트륨을 이용하여 탈수시켜 감압농축하여 벤조일이 붙은 화합물 (31g, 0.053 mol)를 정량적으로 얻었다. 이 화합물을 다이클로로메탄 (100 mL)에 녹인 뒤 4N HCl in dioxane 용액 (130 mL)을 넣고 상온에서 3 시간 교반한 뒤 감압농축하여 화합물 VI 을 정량적으로 얻었다. Compound V (26 g, 0.053 mol) was dissolved in dichloromethane (180 mL), and then DIPEA (diisopropylethylamine, 13 mL, 0.079 mol) and benzoyl chloride (Bz-Cl, 7.4 mL, 0.064 mol) were added sequentially at 0 ° C. It was slowly added dropwise and stirred for 10 minutes. After raising to room temperature, a small amount of DMAP (4-dimethylaminopyridine) was added thereto, followed by stirring for 2 hours. The solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution (brine), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to give benzoyl compound. (31 g, 0.053 mol) was obtained quantitatively. The compound was dissolved in dichloromethane (100 mL), 4N HCl in dioxane solution (130 mL) was added thereto, stirred at room temperature for 3 hours, and concentrated under reduced pressure to obtain Compound VI quantitatively.

¹H NMR (600 MHz, DMSO-d₆) δ 7.88 (d, J = 7.8 Hz, 2H), 7.63 (t, 1H, J = 7.2 Hz), 7.46 (t, 2H, J = 7.2 Hz), 7.41 (dd, 1H, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz), 7.11 (d, 1H, J = 9.0 Hz), 6.88 (t, 1H, J = 9.0 Hz), 5.02 (m, 1H), 4.54-4.45 (m, 2H), 4.16 (t, 1H, J = 9.0 Hz), 3.88 (m, 1H), 3.54 (t, 2H, J = 6.0 Hz), 3.13 (t, 2H, J = 6.0 Hz).
¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.88 (d, J = 7.8 Hz, 2H), 7.63 (t, 1H, J = 7.2 Hz), 7.46 (t, 2H, J = 7.2 Hz), 7.41 (dd, 1H, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz), 7.11 (d, 1H, J = 9.0 Hz), 6.88 (t, 1H, J = 9.0 Hz), 5.02 (m, 1H), 4.54 -4.45 (m, 2H), 4.16 (t, 1H, J = 9.0 Hz), 3.88 (m, 1H), 3.54 (t, 2H, J = 6.0 Hz), 3.13 (t, 2H, J = 6.0 Hz) .

[제조예 7] 화합물 VII 의 제조Preparation Example 7 Preparation of Compound VII

화합물 VI (19.8 g, 0.053 mol)을 다이클로로메탄 (300 mL)에 녹인 뒤, 트리에틸아민 (17.3 mL, 0.123 mol)과 메탄술포닐 클로라이드 (MsCl, 4.8 mL, 0.062 mol)를 0℃에서 순차적으로 서서히 적가하고 10분간 교반하였다. 상온으로 올린 뒤 2시간 동안 교반하고 다이클로로메탄으로 묽힌 뒤, 물, 중탄산나트륨 포화수용액, 염화나트륨 포화수용액(brine)으로 순차적으로 씻어주고, 무수황산나트륨을 이용하여 탈수시켜 감압농축하였다. 이렇게 얻은 고체를 다이에틸이서(diethylether) 용매로 다시 고체화(trituration)시키고 여과하여 흰색 고체 화합물 X (18.6 g, 0.041 mol, 77%)를 얻었다. Compound VI (19.8 g, 0.053 mol) was dissolved in dichloromethane (300 mL), and then triethylamine (17.3 mL, 0.123 mol) and methanesulfonyl chloride (MsCl, 4.8 mL, 0.062 mol) were added slowly at 0 ° C. It was added dropwise and stirred for 10 minutes. After raising to room temperature, the mixture was stirred for 2 hours, diluted with dichloromethane, washed sequentially with water, saturated sodium bicarbonate solution and saturated sodium chloride solution (brine), and concentrated under reduced pressure by dehydration using anhydrous sodium sulfate. The solid thus obtained was triturated again with diethylether solvent and filtered to give white solid Compound X (18.6 g, 0.041 mol, 77%).

¹H NMR (600MHz, CDCl₃) δ 8.02-8.00 (m, 2H), 7.58 (m, 1H), 67.44-7.40 (m, 3H), 7.05 (m, 1H), 6.70 (t, 1H, J = 9.0 Hz), 4.99 (m, 1H), 4.62-4.54 (m, 2H), 4.39 (t, 2H, J = 5.4Hz), 4.18 (br s, 1H), 4.15 (t, 1H, J = 9.0 Hz), 3.86 (m, 1H), 3.55 (br t, 2H), 3.02 (s, 3H).
¹ H NMR (600 MHz, CDCl ₃ ) δ 8.02-8.00 (m, 2H), 7.58 (m, 1H), 67.44-7.40 (m, 3H), 7.05 (m, 1H), 6.70 (t, 1H, J = 9.0 Hz), 4.99 (m, 1H), 4.62-4.54 (m, 2H), 4.39 (t, 2H, J = 5.4 Hz), 4.18 (br s, 1H), 4.15 (t, 1H, J = 9.0 Hz ), 3.86 (m, 1 H), 3.55 (br t, 2 H), 3.02 (s, 3 H).

[제조예 8] 화합물 VIII 의 제조Preparation Example 8 Preparation of Compound VIII

화합물 VII (18.6 g, 0.041 mol)를 에탄올 (100 mL)에 넣고 하이드라진 모노하이드레이트 (H₂NNH₂-H₂O, 50 mL)를 첨가하고 60℃에서 2시간 동안 교반하였다. 이 용액을 감압농축하여 오일 형태의 화합물을 정량적으로 얻었다. Compound VII (18.6 g, 0.041 mol) was added to ethanol (100 mL) and hydrazine monohydrate (H ₂ NNH ₂ -H ₂ O, 50 mL) was added and stirred at 60 ° C. for 2 hours. The solution was concentrated under reduced pressure to quantitatively obtain an oily compound.

이렇게 얻은 화합물을 아세트 산 (200 mL)에 넣고 트리메틸오르소포메이트(trimethylorthoformate, 100 mL)를 첨가하고 8시간동안 환류(reflux)시켰다. 이 용액을 감압증류 한 뒤, 다이클로로메탄으로 녹이고 중탄산나트륨 포화수용액, 염화나트륨 포화수용액(brine)으로 순차적으로 씻어주고, 무수황산나트륨을 이용하여 탈수시켜 감압농축하였다. 이 농축액을 5% 메탄올/다이클로로메탄 용액으로 컬럼크로마토그래피를 이용하여 분리하여 흰색 고체 화합물 VIII (4.2 g, 0.013 mol, 32%)를 얻었다.The compound thus obtained was added to acetic acid (200 mL), trimethylorthoformate (100 mL) was added and refluxed for 8 hours. After distilling under reduced pressure, the solution was dissolved in dichloromethane, washed sequentially with a saturated aqueous sodium bicarbonate solution and a saturated sodium chloride solution (brine), and then dehydrated using anhydrous sodium sulfate and concentrated under reduced pressure. This concentrate was separated by column chromatography with 5% methanol / dichloromethane solution to give white solid compound VIII (4.2 g, 0.013 mol, 32%).

¹H NMR (600MHz, CDCl₃) δ = 8.55 (s, 1H), 7.61 (dd, J ₁ = 13 Hz, J ₂ = 2.4 Hz, 1H), 7.25 (dd, J ₁ = 9.0 Hz, J ₂ = 2.7 Hz, 1H), 7.14 (t, J = 8.4 Hz, 1H), 6.90 (s, 1H), 4.79 (m, 1H), 4.04-3.99 (m, 5H), 3.79-3.73 (m, 3H), 2.58 (br s, 1H); LCMS: C₁₄H₁₅-FN₄O₄ 에 대하여 323 (M+H⁺)
¹ H NMR (600 MHz, CDCl ₃ ) δ = 8.55 (s, 1H), 7.61 (dd, J ₁ = 13 Hz, J ₂ = 2.4 Hz, 1H), 7.25 (dd, J ₁ = 9.0 Hz, J ₂ = 2.7 Hz, 1H), 7.14 (t, J = 8.4 Hz, 1H), 6.90 (s, 1H), 4.79 (m, 1H), 4.04-3.99 (m, 5H), 3.79- 3.73 (m, 3 H), 2.58 (br s, 1 H); LCMS: 323 (M + H ⁺ ) for C ₁₄ H ₁₅ -FN ₄ O ₄

[제조예 9] 화합물 IX 의 제조Preparation Example 9 Preparation of Compound IX

화합물 VIII (8.8 g, 27 mmol)을 메탄올 (150 mL)에 녹인 뒤, 1,4-다이옥산에 녹여진 4N-염산 (15 mL)을 넣고 2시간 동안 교반하였다. 상기 반응물을 감압 농축하고 다이에틸이서(diethylether)로 고체화(trituration)하여 연노란 고체 화합물을 정량적으로 얻었다 (8.72g, 27 mmol, 100%). Compound VIII (8.8 g, 27 mmol) was dissolved in methanol (150 mL), and then 4N-hydrochloric acid (15 mL) dissolved in 1,4-dioxane was added thereto, followed by stirring for 2 hours. The reaction mass was concentrated under reduced pressure and triturated with diethylether to give a pale yellow solid. Compound was obtained quantitatively (8.72 g, 27 mmol, 100%).

¹H NMR (600MHz, DMSO-d₆) δ = 7.73 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.60 (t, J = 9 Hz, 1H), 7.45 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 4.75 (m, 1H), 4.11 (t, J = 9.0 Hz, 1H), 3.88 (m, 1H), 3.78 (t, J = 4.8 Hz, 2H), 3.70-3.55 (m, 2H), 3.36 (t, J = 4.8 Hz, 2H); LCMS: C₁₃H₁₅-FN₄O₃ 에 대하여 295 (M+H⁺) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.73 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.60 (t, J = 9 Hz, 1H), 7.45 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 4.75 (m, 1H), 4.11 (t, J = 9.0 Hz, 1H), 3.88 (m, 1H), 3.78 (t, J = 4.8 Hz, 2H) , 3.70-3.55 (m, 2H), 3.36 (t, J = 4.8 Hz, 2H); LCMS: 295 (M + H ⁺ ) for C ₁₃ H ₁₅ -FN ₄ O ₃

이 화합물을 다시 제조예 2와 같은 방법으로 TBS-Cl 와 반응시켜 화합물 IX를 정량적으로 얻었다.This compound was reacted with TBS-Cl again in the same manner as in Preparation Example 2 to obtain compound IX quantitatively.

¹H NMR (400MHz, CDCl₃) δ = 7.53 (dd, J ₁ = 13.6 Hz, J ₂ = 2.4 Hz, 1H), 7.21 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 6.89 (br s, 1H), 4.89 (br S, 1H), 4.69 (m, 1H), 4.03-3.78 (m, 6H), 3.31 (t, J = 4.6 Hz, 2H), 0.85 (s, 9H), 0.09 (s, 6H)
¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.53 (dd, J ₁ = 13.6 Hz, J ₂ = 2.4 Hz, 1H), 7.21 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 6.89 (br s, 1H), 4.89 (br S, 1H), 4.69 (m, 1H), 4.03- 3.78 (m, 6H), 3.31 (t, J = 4.6 Hz, 2H), 0.85 (s, 9H), 0.09 (s, 6H)

[제조예 10] 화합물 X 의 제조Preparation Example 10 Preparation of Compound X

화합물 V (45 g, 0.093 mol)을 다이클로로메탄 (300 mL)에 녹인 뒤, 트리에틸아민 (26 mL, 0.186 mol)과 메탄술포닐 클로라이드(MsCl, 10.9 mL, 0.14 mol)를 0℃에서 순차적으로 서서히 적가하고 20분간 교반하였다. 상온으로 올린 뒤 1시간 동안 교반하고 감압농축하였다. 농축액을 에틸아세테이트로 녹인 뒤, 0.5 N HCl, 중탄산나트륨 포화수용액, 염화나트륨 포화수용액(brine)으로 순차적으로 씻어주고, 무수황산나트륨을 이용하여 탈수시켜 감압농축하여 노란색 오일 화합물 X (50g, 0.089 mol, 96%)를 얻었다. Compound V (45 g, 0.093 mol) was dissolved in dichloromethane (300 mL), then triethylamine (26 mL, 0.186 mol) and methanesulfonyl chloride (MsCl, 10.9 mL, 0.14 mol) were added sequentially at 0 ° C. It was slowly added dropwise and stirred for 20 minutes. After raising to room temperature, the mixture was stirred for 1 hour and concentrated under reduced pressure. The concentrated solution was dissolved in ethyl acetate, washed sequentially with 0.5 N HCl, saturated sodium bicarbonate solution and saturated sodium chloride solution (brine), dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow oil compound X (50 g, 0.089 mol, 96%). %) Was obtained.

¹H NMR (400MHz, CDCl₃) δ 7.46(dd, 1H, J ₁=11.6Hz, J ₂=2.4Hz), 7.29(m, 1H), 7.13(m, 1H), 4.94-4.88(m, 1H), 4.50-4.39(m, 2H), 4.12(m, 1H), 3.92(m, 1H), 3.72(m, 2H), 3.64-3.62(m, 2H), 3.08(s, 3H), 1.49(s, 3H), 1.34(s, 6H), 0.83(s, 9H), 0.00(s, 6H).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46 (dd, 1H, J ₁ = 11.6 Hz, J ₂ = 2.4 Hz), 7.29 (m, 1H), 7.13 (m, 1H), 4.94-4.88 (m, 1H ), 4.50-4.39 (m, 2H), 4.12 (m, 1H), 3.92 (m, 1H), 3.72 (m, 2H), 3.64-3.62 (m, 2H), 3.08 (s, 3H), 1.49 ( s, 3H), 1.34 (s, 6H), 0.83 (s, 9H), 0.00 (s, 6H).

[제조예 11] 화합물 XI 의 제조Preparation Example 11 Preparation of Compound XI

화합물 X (50 g, 0.089 mol)을 DMF (200 mL)에 녹인 뒤, NaN₃ (7.16 g, 0.11 mol)를 넣고 80℃에서 3시간 교반하였다. 상온으로 식힌 뒤 에틸아세테이트로 묽히고, 물, 중탄산나트륨 포화수용액, 염화나트륨 포화수용액(brine)으로 순차적으로 씻어주고, 무수황산나트륨을 이용하여 탈수시켜 감압농축하여 무색의 오일성 고체 화합물 XI (47g, 0.089 mol)를 정량적으로 얻었다. Compound X (50 g, 0.089 mol) was dissolved in DMF (200 mL), NaN ₃ (7.16 g, 0.11 mol) was added thereto, and the mixture was stirred at 80 ° C. for 3 hours. After cooling to room temperature, diluted with ethyl acetate, washed sequentially with water, saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution (brine), dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to give a colorless oily solid compound XI (47 g, 0.089 mol). ) Was obtained quantitatively.

¹H NMR (600MHz, CDCl₃) δ 7.48(dd, J ₁=8.2Hz, J ₂=1.4Hz) 7.30(m, 1H), 7.16(m, 1H), 4.81-4.79(m, 1H), 4.09-4.08(m, 1H), 3.86(m, 1H), 3.74(m, 2H), 3.62-3.59(m, 1H), 1.51(s, 3H), 1.36(s, 6H), 0.85(s, 9H), 0.02(s, 6H).
¹ H NMR (600MHz, CDCl ₃ ) δ 7.48 (dd, J ₁ = 8.2 Hz, J ₂ = 1.4 Hz) 7.30 (m, 1H), 7.16 (m, 1H), 4.81-4.79 (m, 1H), 4.09-4.08 (m, 1H), 3.86 ( m, 1H), 3.74 (m, 2H), 3.62-3.59 (m, 1H), 1.51 (s, 3H), 1.36 (s, 6H), 0.85 (s, 9H), 0.02 (s, 6H).

[제조예 12] 화합물 XII 의 제조Preparation Example 12 Preparation of Compound XII

화합물 XI (47 g, 0.089 mol)을 메탄올 (400 mL)에 녹인 뒤 Pd/C (3.5 g)을 넣고 수소가스 풍선하에서 4시간 동안 교반하였다, 셀라이트(celite)를 이용하여 여과한 후 감압농축하였다. 이 농축액을 다이클로로메탄 (130 mL)에 녹인 뒤 1N NaOH 수용액 (130 mL)을 넣고 교반하면서 서서히 Cbz-Cl (15.5 mL, 0.11 mol)를 적가 하였다. 상온에서 2시간동안 교반 한 후, 유기층을 분리하여 물과 염화나트륨 포화수용액(brine)으로 세척하고, 무수황산나트륨을 이용하여 탈수시킨 후 감압농축하고, 20% 에틸아세테이트/헥산 용액으로 컬럼크로마토그래피를 이용하여 분리하여 연노란색 오일 화합물 XII (50.5 g, 0.082 mol, 92%)를 얻었다. Compound XI (47 g, 0.089 mol) was dissolved in methanol (400 mL), Pd / C (3.5 g) was added thereto, and the mixture was stirred for 4 hours under a hydrogen gas balloon. The mixture was filtered using celite and concentrated under reduced pressure. The concentrate was dissolved in dichloromethane (130 mL), 1N NaOH aqueous solution (130 mL) was added thereto, and Cbz-Cl (15.5 mL, 0.11 mol) was slowly added dropwise with stirring. After stirring for 2 hours at room temperature, the organic layer was separated, washed with water and saturated aqueous sodium chloride (brine), dehydrated using anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography was performed with 20% ethyl acetate / hexane solution. It was separated to give a light yellow oil compound XII (50.5 g, 0.082 mol, 92%).

¹H NMR (400MHz, CDCl₃) δ 7.46-7.43(m, 1H), 7.36-7.35(m, 1H), 7.31(s, 6H), 7.11(m, 1H), 5.09(s, 2H), 4.75(m, 1H), 4.01(t, 1H, J=8.4Hz), 3.76-3.50(m, 1H), 1.49(s, 3H), 1.34(s, 6H), 0.83(s, 9H), 0.01(s, 6H).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46-7.43 (m, 1H), 7.36-7.35 (m, 1H), 7.31 (s, 6H), 7.11 (m, 1H), 5.09 (s, 2H), 4.75 (m, 1H), 4.01 (t, 1H, J = 8.4 Hz), 3.76-3.50 (m, 1H), 1.49 (s, 3H), 1.34 (s, 6H), 0.83 (s, 9H), 0.01 ( s, 6H).

[제조예 13] 화합물 XIII 의 제조Preparation Example 13 Preparation of Compound XIII

화합물 XII (50.5 g, 0.082 mol)을 다이클로로메탄 (100 mL)에 녹인 뒤 4N HCl in dioxane 용액 (130 mL)을 넣고 상온에서 3 시간 교반한 뒤 감압농축하여 흰색 고체 화합물 (36 g, 0.082 mol)를 정량적으로 얻었다. Compound XII Dissolve (50.5 g, 0.082 mol) in dichloromethane (100 mL), add 4N HCl in dioxane solution (130 mL), stir at room temperature for 3 hours, and concentrate under reduced pressure to give a white solid compound (36 g, 0.082 mol). Obtained quantitatively.

¹H NMR (400MHz, DMSO-d₆) δ 7.69(t, 1H, J=6.0Hz), 7.44-7.40(m, 1H), 7.32(s, 6H), 7.09-7.07(m, 1H), 6.88(t, 1H, J=9.2Hz), 5.03(s, 2H), 4.71-4.68(m, 1H), 4.08-4.03(m, 2H), 3.73-3.69(m, 1H), 3.60-3.57(m, 3H), 3.39-3.34(m, 2H), 3.18-3.15(m, 2H). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.69 (t, 1H, J = 6.0 Hz), 7.44-7.40 (m, 1H), 7.32 (s, 6H), 7.09-7.07 (m, 1H), 6.88 (t, 1H, J = 9.2 Hz), 5.03 (s, 2H), 4.71-4.68 (m, 1H), 4.08-4.03 (m, 2H), 3.73-3.69 (m, 1H), 3.60-3.57 (m , 3H), 3.39-3.34 (m, 2H), 3.18-3.15 (m, 2H).

이렇게 얻은 화합물 (36 g, 0.082 mol)을 다이클로로메탄 (300 mL)에 녹인 뒤, 트리에틸아민 (34.5 mL, 0.245 mol)과 메탄술포닐 클로라이드 (MsCl, 9.5 mL, 0.123 mol)를 0℃에서 순차적으로 서서히 적가하고 10분간 교반하였다. 상온으로 올린 뒤 2시간 동안 교반하고 다이클로로메탄으로 묽힌 뒤, 물, 중탄산나트륨 포화수용액, 염화나트륨 포화수용액(brine)으로 순차적으로 씻어주고, 무수황산나트륨을 이용하여 탈수시켜 감압농축하였다. 이렇게 얻은 고체를 다이에틸이서(diethylether) 용매로 다시 고체화(trituration)시키고 여과하여 흰색 고체 화합물 XIII (30.5 g, 0.063 mol, 77%)를 얻었다.Thus obtained compound (36 g, 0.082 mol) was dissolved in dichloromethane (300 mL), triethylamine (34.5 mL, 0.245 mol) and methanesulfonyl chloride (MsCl, 9.5 mL, 0.123 mol) were added at 0 ° C. The mixture was slowly added dropwise and stirred for 10 minutes. After raising to room temperature, the mixture was stirred for 2 hours, diluted with dichloromethane, washed sequentially with water, saturated sodium bicarbonate solution and saturated sodium chloride solution (brine), and concentrated under reduced pressure by dehydration using anhydrous sodium sulfate. The solid thus obtained was triturated again with a diethylether solvent and filtered to give a white solid compound XIII. (30.5 g, 0.063 mol, 77%) was obtained.

¹H NMR (600MHz, CDCl₃) δ 7.39-7.32 (m, 6H), 7.01 (m, 1H), 6.68 (t, 1H, J = 9.0Hz), 5.24 (t, 1H, J = 6.0 Hz), 5.11 (s, 2H), 4.75 (m, 1H), 4.40 (t, 2H, J = 5.4Hz), 4.17 (br t, 1H), 3.99 (t, 1H, J = 8.7 Hz), 3.75-3.52 (m, 5H), 3.03 (s, 3H).
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.39-7.32 (m, 6H), 7.01 (m, 1H), 6.68 (t, 1H, J = 9.0 Hz), 5.24 (t, 1H, J = 6.0 Hz), 5.11 (s, 2H), 4.75 (m, 1H), 4.40 (t, 2H, J = 5.4Hz), 4.17 (br t, 1H), 3.99 (t, 1H, J = 8.7 Hz), 3.75-3.52 ( m, 5H), 3.03 (s, 3H).

[제조예 14] 화합물 XIV 의 제조Preparation Example 14 Preparation of Compound XIV

화합물 XIII (20 g, 0.042 mol)를 에탄올 (100 mL)에 넣고 하이드라진 모노하이드레이트 (H₂NNH₂-H₂O, 50 mL)를 첨가하고 60℃에서 2시간 동안 교반하였다. 이 용액을 감압농축하여 오일 형태의 화합물 (17.4 g, 0.042 mol)을 얻었다. Compound XIII (20 g, 0.042 mol) was added to ethanol (100 mL) and hydrazine monohydrate (H ₂ NNH ₂ -H ₂ O, 50 mL) was added and stirred at 60 ° C for 2 h. The solution was concentrated under reduced pressure to give an oil compound. (17.4 g, 0.042 mol) was obtained.

이렇게 얻은 화합물을 아세트 산 (200 mL)에 넣고 트리메틸오르소포메이트(trimethylorthoformate, 100 mL)를 첨가하고 8시간동안 환류(reflux)시켰다. 이 용액을 감압증류 한 뒤, 다이클로로메탄으로 녹이고 중탄산나트륨 포화수용액, 염화나트륨 포화수용액(brine)으로 순차적으로 씻어주고, 무수황산나트륨을 이용하여 탈수시켜 감압농축하였다. 이 농축액을 5% 메탄올/다이클로로메탄 용액으로 컬럼크로마토그래피를 이용하여 분리하여 흰색 고체 화합물 XIV (5.8 g, 0.013 mol, 31%)를 얻었다.The compound thus obtained was added to acetic acid (200 mL), trimethylorthoformate (100 mL) was added and refluxed for 8 hours. After distilling under reduced pressure, the solution was dissolved in dichloromethane, washed sequentially with a saturated aqueous sodium bicarbonate solution and a saturated sodium chloride solution (brine), and then dehydrated using anhydrous sodium sulfate and concentrated under reduced pressure. This concentrate was separated by column chromatography with 5% methanol / dichloromethane solution to give white solid compound XIV (5.8 g, 0.013 mol, 31%).

¹H NMR (600MHz, CDCl₃) δ = 8.52 (s, 1H), 7.55-7.53 (m, 1H), 7.30-7.28 (m, 6H), 7.19-7.18 (m, 1H), 7.11-7.08 (m, 1H), 6.86 (s, 1H), 5.27 (t, J = 6 Hz, 1H), 5.08 (s, 2H), 4.77 (m, 1H), 4.03-4.00 (m, 1H), 3.97 (t, J = 4.8Hz, 2H), 3.81- 3.76 (m, 1H), 3.70 (t, J = 5.1 Hz, 2H), 3.65-3.60 (m, 1H), 3.59-3.54 (m, 1H).
¹ H NMR (600 MHz, CDCl ₃ ) δ = 8.52 (s, 1H), 7.55-7.53 (m, 1H), 7.30-7.28 (m, 6H), 7.19-7.18 (m, 1H), 7.11-7.08 (m , 1H), 6.86 (s, 1H), 5.27 (t, J = 6 Hz, 1H), 5.08 (s, 2H), 4.77 (m, 1H), 4.03-4.00 (m, 1H), 3.97 (t, J = 4.8 Hz, 2H), 3.81-3.76 (m, 1H), 3.70 (t, J = 5.1 Hz, 2H), 3.65-3.60 (m, 1H), 3.59-3.54 (m, 1H).

[제조예 15] 화합물 XV 의 제조Preparation Example 15 Preparation of Compound XV

화합물 XIV (5 g, 0.011 mol)을 메탄올 (100 mL)에 녹인 뒤 Pd/C (0.5 g)을 넣고 수소가스 풍선하에서 4시간 동안 교반하였다. 셀라이트(celite)를 이용하여 여과 한 후 감압농축하여 오일릭 고체 화합물 (3.2 g, 0.010 mol, 91%)를 얻었다. Compound XIV (5 g, 0.011 mol) was dissolved in methanol (100 mL), Pd / C (0.5 g) was added thereto, and the mixture was stirred for 4 hours under a hydrogen gas balloon. Filtration using celite followed by concentration under reduced pressure afforded an oily solid compound (3.2 g, 0.010 mol, 91%).

¹H NMR (600MHz, DMSO-d₆) δ = 8.43 (s, 1H), 7.65-7.63 (m, 1H), 7.40-7.36 (m, 2H), 7.12 (s, 1H), 4.65-4.62 (m, 1H), 4.09-4.06 (m, 1H), 3.89-3.86 (m, 1H), 3.85 (t, J = 5.1 Hz, 2H), 3.70 (t, J = 4.8 Hz, 2H),2.88-2.85 (m, 1H), 2.82-2.79 (m, 1H). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 8.43 (s, 1H), 7.65-7.63 (m, 1H), 7.40-7.36 (m, 2H), 7.12 (s, 1H), 4.65-4.62 (m , 1H), 4.09-4.06 (m, 1H), 3.89-3.86 (m, 1H), 3.85 (t, J = 5.1 Hz, 2H), 3.70 (t, J = 4.8 Hz, 2H), 2.88-2.85 ( m, 1H), 2.82-2.79 (m, 1H).

이렇게 얻은 화합물 (0.1 g, 0.31 mmol)을 다이클로로메탄 (3 mL)에 녹인 뒤, DIPEA (0.1 mL, 0.6 mmol) 및 Ac₂O (0.06 mL, 0.6 mmol)를 순차적으로 적가하고 2시간 동안 상온에서 교반 한 후, 감압 농축 하여 컬럼크로마토그래피을 이용하여 백색고체로 화합물 XV (0.098 g, 0.27 mmol, 87%)을 얻었다.So obtained Compound (0.1 g, 0.31 mmol) was dissolved in dichloromethane (3 mL), and then DIPEA (0.1 mL, 0.6 mmol) and Ac ₂ O (0.06 mL, 0.6 mmol) were added dropwise sequentially and stirred at room temperature for 2 hours. After concentration under reduced pressure, compound XV was obtained as a white solid using column chromatography. (0.098 g, 0.27 mmol, 87%) was obtained.

¹H NMR (400MHz, chloroform-d₄) δ = 8.54(s, 1H), 7.59(dd J=13.6, 2.4Hz, 1H), 7.20(dd, J =13.6, 2.4Hz, 1H), 7.13(t J=8.8, Hz, 1H), 6.88(s, 1H), 6.19(t, J =6.0Hz, 1H), 4.81(m, 1H), 4.05(t, J =8Hz, 1H), 3.99(t, J=4.8Hz, 2H), 3.80(dd, J =8.8, 6.8Hz, 1H), 3.73(t, J =4.8Hz, 2H), 3.69(m, 2H), 2.03(s, 3H); LCMS: C₁₆H₁₈FN₅O₄ 에 대하여 364(M+H⁺)
¹ H NMR (400 MHz, chloroform-d ₄ ) δ = 8.54 (s, 1H), 7.59 (dd J = 13.6, 2.4 Hz, 1H), 7.20 (dd, J = 13.6, 2.4 Hz, 1H), 7.13 (t J = 8.8, Hz, 1H), 6.88 (s, 1H), 6.19 (t, J = 6.0 Hz, 1H), 4.81 (m, 1H), 4.05 (t, J = 8 Hz, 1H), 3.99 (t, J = 4.8 Hz, 2H), 3.80 (dd, J = 8.8, 6.8 Hz, 1H), 3.73 (t, J = 4.8 Hz, 2H), 3.69 (m, 2H), 2.03 (s, 3H); LCMS: 364 (M + H ⁺ ) for C ₁₆ H ₁₈ FN ₅ O ₄

[제조예 16] 화합물 XVI 의 제조Preparation Example 16 Preparation of Compound XVI

화합물 XV (0.7 g, 1.93 mmol), 1,4-다이옥산에 녹여진 4N-염산 (3 mL, 12 mmol), Pd/C (70 mg)을 THF (20 mL)에 첨가 후 수소가스 하에서 2시간 동안 교반 한 후, 상기 반응물을 셀라이트을 이용하여 여과하고 감압 농축하여 백색고체로 화합물 XVI (0.72g, 1.93mmol, 100%)을 얻었다. Compound XV (0.7 g, 1.93 mmol), 4N-hydrochloric acid (3 mL, 12 mmol) dissolved in 1,4-dioxane, Pd / C (70 mg) was added to THF (20 mL), followed by 2 hours under hydrogen gas. After stirring for a while, the reaction mixture was filtered through celite and concentrated under reduced pressure to yield compound XVI as a white solid. (0.72 g, 1.93 mmol, 100%) was obtained.

¹H NMR (400MHz, DMSO-d₆) δ = 8.34-8.31(m, 2H), 7.68(dd J=13.6, 2.4Hz, 1H), 7.56(t, J =8.8Hz, 1H), 7.41(dd J=13.6, 2.4Hz, 1H), 4.76(m, 1H), 4.15(t, J =8.8Hz, 1H), 3.78(m, 3H), 3.46(m, 2H), 3.35(t, J =8.4Hz, 2H), 1.83(s, 3H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.34-8.31 (m, 2H), 7.68 (dd J = 13.6, 2.4 Hz, 1H), 7.56 (t, J = 8.8 Hz, 1H), 7.41 (dd J = 13.6, 2.4 Hz, 1H), 4.76 (m, 1H), 4.15 (t, J = 8.8 Hz, 1H), 3.78 (m, 3H), 3.46 (m, 2H), 3.35 (t, J = 8.4 Hz, 2H), 1.83 (s, 3H)

LCMS: C₁₅H₁₈FN₅O₃ 에 대하여 336(M+H⁺)
LCMS: 336 (M + H ⁺ ) for C ₁₅ H ₁₈ FN ₅ O ₃

상기 제조예 1 내지 16에서 제조된 중간체로부터 최종 화합물들의 합성법을 하기 실시예에 나타내었다.Synthesis of the final compounds from the intermediates prepared in Preparation Examples 1 to 16 is shown in the following Examples.

[실시예 1] 화합물 1 의 제조Example 1 Preparation of Compound 1

상기 제조예 8에서 만든 화합물 VIII (4.4 g, 0.013 mol)을 DIPEA(4.3ml, 0.024mol), DMAP(0.15g)와 함께 다이클로로메탄 (60 mL)에 녹인 뒤 벤조일클로라이드(1.37ml, 0.020mol)을 0℃에서 dropwise하고 상온에서 1시간 동안 교반하고 다이클로로메탄으로 녹이고 0.5N-염산수용액, 중탄산나트륨 포화수용액, 염화나트륨 포화수용액(brine)으로 순차적으로 씻어주고, 무수황산나트륨을 이용하여 탈수시켜 감압농축하였다. 이 농축액을 100%에틸아세테이트 용액으로 컬럼크로마토그래피를 이용하여 분리하여 흰색 고체 화합물 XVII (3.2 g, 0.007mol, 55%)를 얻었다. Compound VIII made in Preparation Example 8 (4.4 g, 0.013 mol) is dissolved in dichloromethane (60 mL) with DIPEA (4.3 ml, 0.024 mol) and DMAP (0.15 g), and then benzoyl chloride (1.37 ml, 0.020 mol) is dropwise at 0 ° C. and room temperature The mixture was stirred for 1 hour, dissolved in dichloromethane, washed sequentially with 0.5N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride (brine), and concentrated under reduced pressure by using anhydrous sodium sulfate. This concentrate was separated by column chromatography with 100% ethyl acetate solution to obtain a white solid compound XVII. (3.2 g, 0.007 mol, 55%) was obtained.

이 화합물 XVII (3.2 g, 0.007 mol)을 40 mL 메탄올에 녹인 뒤, 4 M HCl in dioxane 용액 8 mL 을 넣고 상온에서 1시간 교반한 뒤 농축하고 다이에틸이서(diethylether)로 고체화(trituration)하여 흰색고체 화합물 XVIII (3.35g, 정량적)을 얻었다.This compound XVII Dissolve (3.2 g, 0.007 mol) in 40 mL methanol, add 8 mL of 4 M HCl in dioxane solution, stir at room temperature for 1 hour, concentrate and triturate with diethylether to give white solid compound XVIII (3.35 g, quantitative).

이렇게 얻은 화합물 화합물 XVIII (1 g, 2.30 mmol)과 중탄산나트륨 포화수용액(20ml)을 클로로포름(20ml)에 넣은 후 사이오포스진(thiophosgen, 0.2 mL, 2.6 mmol)을 0℃에서 dropwise한 뒤, 상온에서 1시간 교반 후 암모니아수용액(8ml)을 상온에서 넣고 다시 2시간 동안 교반하고 다이에틸이서(100ml)로 고체화(trituration)하여 아이보리 고체 화합물 XIX (0.8g, 1.75mmol, 76%) 를 얻었다.The obtained compound compound XVIII (1 g, 2.30 mmol) and saturated aqueous sodium bicarbonate solution (20 ml) were added to chloroform (20 ml), and then thiophosgen (0.2 mL, 2.6 mmol) was dropwise at 0 ° C., and then stirred at room temperature for 1 hour. Aqueous ammonia solution (8 ml) was added at room temperature, stirred for 2 hours, and triturated with diethyl ether (100 ml) to obtain an ivory solid compound XIX (0.8 g, 1.75 mmol, 76%).

이렇게 얻은 화합물 XIX (0.2 g, 0.43 mmol) 을 4 mL 에탄올에 녹인 뒤, 50% 클로로아세트알데하이드 수용액 (0.11ml, 0.87mmol) 을 넣고 12 시간 동안 환류시켰다. 이 용액을 감압농축하고 컬럼크로마토그래피 (eluent : 5% MeOH/MC)하여 벤조일 화합물을 얻은 뒤, 5 mL 에탄올에 녹인 후 암모니아 수용액 2ml을 넣고 90분간 환류교반시켜 벤조일 그룹을 제거하였다. 이 용액을 감압농축하고 컬럼크로마토그래피 (eluent : 5% MeOH/MC)하여 표제 화합물 1 (23mg, 0.06mmol, 14%) 을 얻었다.Thus obtained compound XIX (0.2 g, 0.43 mmol) was dissolved in 4 mL ethanol, and 50% aqueous chloroacetaldehyde solution (0.11 ml, 0.87 mmol) was added and refluxed for 12 hours. The solution was concentrated under reduced pressure, column chromatography (eluent: 5% MeOH / MC) to obtain a benzoyl compound, dissolved in 5 mL ethanol, 2 ml of aqueous ammonia solution and refluxed for 90 minutes to remove the benzoyl group. The solution was concentrated under reduced pressure and column chromatography (eluent: 5% MeOH / MC) afforded the title compound 1 (23 mg, 0.06 mmol, 14%).

¹H NMR (600MHz, DMSO-d₆) δ = 7.65 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.41 (t, J = 9 Hz, 1H), 7.37 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.21 (d, J = 3.6 Hz, 1H), 7.18 (d, J = 1.8 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H), 5.23 (br s, 1H), 4.72 (m, 1H), 4.09 (t, J = 9.0 Hz, 1H), 4.02 (t, J = 4.8 Hz, 2H), 3.86-3.83 (m, 3H), 3.68 (dd, J ₁ = 12.6 Hz, J ₂ = 3.0 Hz, 1H ), 3.56 (dd, J ₁ = 12.6 Hz, J ₂ = 3.8 Hz, 1H ) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.65 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.41 (t, J = 9 Hz, 1H), 7.37 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.21 (d, J = 3.6 Hz, 1H), 7.18 (d, J = 1.8 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H), 5.23 (br s, 1H), 4.72 (m, 1H), 4.09 (t, J = 9.0 Hz, 1H), 4.02 (t, J = 4.8 Hz, 2H), 3.86-3.83 (m, 3H), 3.68 (dd , J ₁ = 12.6 Hz, J ₂ = 3.0 Hz, 1H), 3.56 (dd, J ₁ = 12.6 Hz, J ₂ = 3.8 Hz, 1H)

LCMS: C₁₆H₁₆-FN₅O₃S 에 대하여 378 (M+H⁺)
LCMS: 378 (M + H ⁺ ) for C ₁₆ H ₁₆ -FN ₅ O ₃ S

[실시예 2] 화합물 2 의 제조Example 2 Preparation of Compound 2

화합물 XIX 로부터 클로로아세트알데하이드 대신 클로로아세톤을 사용하여 상기 실시예 1과 동일한 방법으로 아이보리색 고체의 표제화합물 2 (66mg, 0.17mmol, 40%) 를 얻었다.The title compound 2 (66 mg, 0.17 mmol, 40%) was obtained in the same manner as in Example 1, using chloroacetone instead of chloroacetaldehyde from compound XIX .

¹H NMR (600MHz, CDCl₃) δ = 7.61 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.36 (t, J = 9 Hz, 1H), 7.33 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.11 (s, 1H), 6.38 (s, 1H), 5.20 (t, J = 5.4 Hz, 1H), 4.68 (m, 1H), 4.05 (t, J = 9.0 Hz, 1H), 3.96 (t, J = 4.8 Hz, 2H), 3.81-3.78 (m, 3H), 3.66-3.51 (m, 2H) ¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.61 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.36 (t, J = 9 Hz, 1H), 7.33 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.11 (s, 1H), 6.38 (s, 1H), 5.20 (t, J = 5.4 Hz, 1H), 4.68 (m, 1H), 4.05 (t, J = 9.0 Hz, 1H), 3.96 (t, J = 4.8 Hz, 2H), 3.81-3.78 (m, 3H), 3.66-3.51 (m, 2H)

LCMS: C₁₇H₁₈-FN₅O₃S 에 대하여 392 (M+H⁺)
LCMS: 392 (M + H ⁺ ) for C ₁₇ H ₁₈ -FN ₅ O ₃ S

[실시예 3] 화합물 3 의 제조Example 3 Preparation of Compound 3

화합물 XIX 로부터 클로로아세트 알데하이드 대신 에틸브로모아세테이트를 사용하여 상기 실시예 1과 동일한 방법으로 연한노란색 고체의 표제화합물 3 (53mg, 0.13mmol, 30%)을 얻었다.The title compound 3 (53 mg, 0.13 mmol, 30%) as a pale yellow solid was obtained from the compound XIX using ethyl bromoacetate instead of chloroacetaldehyde in the same manner as in Example 1.

¹H NMR (600MHz, DMSO-d₆) δ = 7.67 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.47 (s, 1H), 7.44 (t, J = 9 Hz, 1H), 7.39 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 5.22 (t, J = 5.6 Hz, 1H), 4.73 (m, 1H), 4.22 (t, J = 5.6 Hz, 2H), 4.10 (t, J = 8.8 Hz, 1H), 3.87 (s, 2H), 3.85-3.82 (m, 3H), 3.71-3.53 (m, 2H) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.67 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.47 (s, 1H), 7.44 (t, J = 9 Hz, 1H), 7.39 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 5.22 (t, J = 5.6 Hz, 1H), 4.73 (m, 1H), 4.22 (t, J = 5.6 Hz, 2H), 4.10 (t, J = 8.8 Hz, 1H), 3.87 (s, 2H), 3.85-3.82 (m, 3H), 3.71-3.53 (m, 2H)

LCMS: C₁₆H₁₆-FN₅O₄S 에 대하여 394 (M+H⁺)
LCMS: 394 (M + H ⁺ ) for C ₁₆ H ₁₆ -FN ₅ O ₄ S

[실시예 4] 화합물 4 의 제조Example 4 Preparation of Compound 4

화합물 XIX 로부터 클로로아세트 알데하이드 대신 에틸브로모피루베이트를 사용하여 상기 실시예 1과 동일한 방법으로 연갈색 고체의 표제화합물 4 (53mg, 0.13mmol, 30%)을 얻었다.The title compound 4 (53 mg, 0.13 mmol, 30%) was obtained as a light brown solid, in the same manner as in Example 1, using ethyl bromopyruvate instead of chloroacetaldehyde from compound XIX .

¹H NMR (600MHz, DMSO-d₆) δ = 7.65 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.45-7.23 (m, 6H), 5.26 (br s, 1H), 4.73 (m, 1H), 4.10-3.57 (m, 8H) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.65 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.45-7.23 (m, 6H), 5.26 (br s, 1H), 4.73 (m, 1H), 4.10-3.57 (m, 8H)

LCMS: C₁₇H₁₇-FN₆O₄S 에 대하여 421 (M+H⁺)
LCMS: 421 (M + H ⁺ ) for C ₁₇ H ₁₇ -FN ₆ O ₄ S

[실시예 5] 화합물 5 의 제조Example 5 Preparation of Compound 5

상기 제조예 8에서 만든 화합물 VIII (8.8 g, 27 mmol)을 메탄올 (150 mL)에 녹인 뒤, 1,4-다이옥산에 녹여진 4N-염산 (15 mL)을 넣고 2시간 동안 교반하였다. 상기 반응물을 감압 농축하고 다이에틸이서로 고체화(trituration)하여 연노란 고체 화합물 XX을 정량적으로 얻었다 (8.72g, 27 mmol, 100%).Made in Preparation Example 8 Compound VIII (8.8 g, 27 mmol) was dissolved in methanol (150 mL), and then 4N-hydrochloric acid (15 mL) dissolved in 1,4-dioxane was added thereto, followed by stirring for 2 hours. The reaction was concentrated under reduced pressure and triturated with diethyl to quantitatively obtain a pale yellow solid compound XX (8.72 g, 27 mmol, 100%).

이렇게 얻은 화합물 XX (100mg, 0.30 mmol) 을 3 mL 다이클로로메탄에 녹인 뒤, 클로로아세틸클로라이드 (0.048ml, 0.6mmol), 트리에틸아민(0.127ml, 0.9mmol)을 넣고 상온에서 30분간 교반 하였다. 이 용액을 50 mL 다이클로로메탄으로 희석 시키고 중탄산나트륨 포화수용액으로 세척한 뒤, 다시 농축시켰다. 이 혼합물을 5 mL 에탄올에 녹인 뒤, 싸이오우레아(thiourea, 0.068g, 0.9mmol) 을 넣고 3시간 동안 환류교반한 뒤 다시 농축하였다. 이 용액을 50 mL 다이클로로메탄으로 희석 시키고 중탄산나트륨 포화수용액으로 세척 한 뒤 컬럼크로마토그래피로 분리하여 (eluent : 10%MeOH/MC) 노란색 고체의 표제화합물 5 (0.01g, 0.021mmol, 8%) 를 얻었다. Compound XX thus obtained (100 mg, 0.30 mmol) was dissolved in 3 mL dichloromethane, and chloroacetyl chloride (0.048 ml, 0.6 mmol) and triethylamine (0.127 ml, 0.9 mmol) were added and stirred at room temperature for 30 minutes. The solution was diluted with 50 mL dichloromethane, washed with saturated aqueous sodium bicarbonate solution and concentrated again. The mixture was dissolved in 5 mL ethanol, thiourea (0.068 g, 0.9 mmol) was added thereto, and the mixture was stirred under reflux for 3 hours and then concentrated again. The solution was diluted with 50 mL dichloromethane, washed with saturated aqueous sodium bicarbonate solution, separated by column chromatography (eluent: 10% MeOH / MC) to give the title compound 5 as a yellow solid (0.01 g, 0.021 mmol, 8%). Got.

¹H NMR (600MHz, CDCl₃) δ = 7.63 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.29 (m, 1H), 7.16 (t, J = 9 Hz, 1H), 7.08 (s, 1H), 5.0 (br s, 1H), 4.78 (m, 1H), 4.36-4.34 (m, 2H), 4.07-4.02 (m, 3H), 3.88 (s, 2H), 3.84-3.75 (m, 3H) ¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.63 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.29 (m, 1H), 7.16 (t, J = 9 Hz, 1H), 7.08 (s, 1H), 5.0 (br s, 1H), 4.78 (m , 1H), 4.36-4.34 (m, 2H), 4.07-4.02 (m, 3H), 3.88 (s, 2H), 3.84-3.75 (m, 3H)

LCMS: C₁₆H₁₆-FN₅O₄S 에 대하여 394 (M+H⁺)
LCMS: 394 (M + H ⁺ ) for C ₁₆ H ₁₆ -FN ₅ O ₄ S

[실시예 6] 화합물 6 의 제조Example 6 Preparation of Compound 6

상기 제조예 9에서 만든 화합물 IX (100mg, 0.24mmol)을 다이클로로메탄(5ml)에 녹인 후에 디이소프로필아민 (0.06ml, 0.36mmol) 를 넣고 0 ℃ -에서 에틸말로닐클로라이드(Ethyl malonyl chloride, 0.037ml, 0.29mmol) 를 다이클로메탄 (3ml)에 묽혀서 넣어 주었다. 10 분간 교반한 후에 실온으로 온도를 올려주고 20분간 다시 실온에서 교반하였다. 이 용액에 다이클로로메탄 50ml를 넣어서 묽혀 준 후에 물 50ml로 씻어주고, 무수황산나트륨을 이용하여 탈수시켜 감압농축하여 연 노란색 오일을 얻었다. 이것을 다이에틸이서로 고체화(trituration)하여 연 노란색 고체 화합물 XXI (90mg 71.7%)를 얻었다. Made in Preparation Example 9 Compound IX Dissolve (100mg, 0.24mmol) in dichloromethane (5ml), add diisopropylamine (0.06ml, 0.36mmol), and add ethyl malonyl chloride (0.037ml, 0.29mmol) at 0 ℃. Diluted in chlormethane (3ml). After stirring for 10 minutes, the temperature was raised to room temperature and stirred for another 20 minutes at room temperature. 50 ml of dichloromethane was added to the solution, diluted with water, washed with 50 ml of water, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to give a pale yellow oil. This was triturated with diethyl to give a pale yellow solid compound XXI (90 mg 71.7%).

이렇게 얻은 화합물 XXI (160mg, 0.306mmol)에 톨루엔(3ml)을 넣고 Lawesson's reagent (148.6mg, 0.367mmol)을 넣어 준 후에 1시간 동안 환류 교반하였다. 실온으로 식혀 준 후에 감압 농축하고 3% 메탄올/다이클로로메탄 용액으로 컬럼크로마토그래피를 이용하여 분리하여 연노란색 고체 화합물 XXII (104mg, 63%)를 얻었다.Compound XXI thus obtained Toluene (3ml) was added to (160mg, 0.306mmol), Lawesson's reagent (148.6mg, 0.367mmol) was added thereto, and the mixture was stirred under reflux for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure and separated by column chromatography with 3% methanol / dichloromethane solution to obtain a pale yellow solid compound XXII (104 mg, 63%).

이렇게 얻은 화합물 XXII (50mg, 0.093mmol)을 에탄올 (1ml) 넣어서 현탁시켜 준 후에 하이드라진 (0.48ml, 0.093mmol)을 에탄올(10ml)에 묽혀서 넣어 준 뒤, 60 ℃ 에서 1시간 교반하였다. 생성된 고체를 감압여과 한 후에 에탄올로 씻어주고 감압 건조하여서 흰색고체 화합물 XXIII (35mg, 76.7%)를 얻었다.The compound XXII (50 mg, 0.093 mmol) thus obtained was suspended in ethanol (1 ml), hydrazine (0.48 ml, 0.093 mmol) was diluted in ethanol (10 ml), and stirred at 60 ° C for 1 hour. The resulting solid was filtered under reduced pressure, washed with ethanol and dried under reduced pressure to obtain a white solid compound XXIII (35mg, 76.7%).

이렇게 얻은 화합물 XXIII (35mg, 0.07mmol)을 다이클로로메탄 (3ml) 넣어서 녹여 준 후에 4M HCl in dioxane 용액 (0.2ml, 0.8mmol)을 넣어 주었다. 실온 -에서 1시간 교반 한 후에 감압농축 해서 흰색고체의 표제화합물 6을 정량적으로 얻었다.Thus obtained compound XXIII (35mg, 0.07mmol) was dissolved in dichloromethane (3ml) and 4M HCl in dioxane solution (0.2ml, 0.8mmol) was added. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to obtain the title compound 6 as a white solid.

¹H NMR (600MHz, DMSO-d₆) δ = 7.66 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.44 (t, J = 9 Hz, 1H), 7.39 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.26 (s, 1H), 5.34 (s, 1H), 4.73 (m, 1H), 4.09 (t, J = 9.0 Hz, 1H), 3.86-3.55 (m, 9H) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.66 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.44 (t, J = 9 Hz, 1H), 7.39 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.26 (s, 1H), 5.34 (s, 1H), 4.73 (m, 1H), 4.09 (t, J = 9.0 Hz, 1H), 3.86-3.55 ( m, 9H)

LCMS: C₁₆H₁₇-FN₆O₄ 에 대하여 377 (M+H⁺)
LCMS: 377 (M + H ⁺ ) for C ₁₆ H ₁₇ -FN ₆ O ₄

[실시예 7] 화합물 7 의 제조Example 7 Preparation of Compound 7

상기 실시예 5에서 만든 화합물 XX (500mg, 1.50mmol)을 다이클로로메탄 (30mL)에 녹인 뒤, 중탄산나트륨 포화수용액 (10mL)을 넣고 0 ℃ 에서 사이오포스진 (thiophosgene, 0.14mL , 1.80mmol)을 천천히 넣고 40분간 교반후, 유기층을 모아서 무수황산나트륨을 이용하여 탈수시켰다. 이 용액을 감압증류한 뒤 THF (30mL)에 녹이고 하이드라진 (H₂NNH₂.H₂O, 31mL, 6.25mmol)을 넣고 상온에서 12시간동안 교반하였다. 이 용액을 감압증류하고 다이에틸이서로 고체화(trituration)하여 여과하여 흰색의 고체 화합물 XXIV (520mg, 83%)를 얻었다. Compound XX (500mg, 1.50mmol) prepared in Example 5 was dissolved in dichloromethane (30mL), and then saturated sodium bicarbonate solution (10mL) was added and thiophosgene (thiophosgene, 0.14mL, 1.80mmol) at 0 ° C. The mixture was slowly added thereto, stirred for 40 minutes, and the organic layers were collected and dehydrated using anhydrous sodium sulfate. The solution was distilled under reduced pressure, dissolved in THF (30 mL), hydrazine (H ₂ NNH ₂ .H ₂ O, 31 mL, 6.25 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The solution was distilled under reduced pressure, triturated with diethyl and filtered to give white solid compound XXIV (520 mg, 83%).

이렇게 얻은 화합물 XXIV (260mg, 0.71mmol)을 폼산(formic acid, 5mL), 트리메틸오르소포르메이트(TMOF, 2.5mL)에 넣고 9시간 동안 교반환류시켰다. 상온으로 식히고 용매를 감압농축하여 다이클로로메탄 (60mL)에 묽히고 중탄산나트륨 포화수용액 (50mL)로 씻어주고 무수황산나트륨으로 탈수시킨 뒤, 컬럼크로마토그래피 (eluent : 5%MeOH/MC)로 분리하여 표제화합물 7 (66.5mg, 25%)을 얻었다.Thus obtained compound XXIV (260mg, 0.71mmol) was added to formic acid (formic acid, 5mL), trimethyl ortho formate (TMOF, 2.5mL) and refluxed for 9 hours. To cool to room temperature and concentrated under reduced pressure, the solvent dichloromethane after diluted with (60mL) and washed with saturated aqueous sodium bicarbonate solution (50mL) was dehydrated over anhydrous sodium sulfate, and purified by column chromatography (eluent: 5% MeOH / MC ) to separate the title Compound 7 (66.5 mg, 25%) was obtained.

¹H NMR (400MHz, DMSO-d₆) δ = 8.85 (s, 1H), 7.66 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.43 (t, J = 9 Hz, 1H), 7.38 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.25 (s, 1H), 5.24 (t, J = 5.6 Hz, 1H), 4.73 (m, 1H), 4.12-3.52 (m, 8H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.85 (s, 1H), 7.66 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.43 (t, J = 9 Hz, 1H), 7.38 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.25 (s, 1H), 5.24 (t, J = 5.6 Hz, 1H), 4.73 (m, 1H), 4.12-3.52 (m, 8H)

LCMS: C₁₅H₁₅-FN₆O₃S 에 대하여 379 (M+H⁺)
LCMS: 379 (M + H ⁺ ) for C ₁₅ H ₁₅ -FN ₆ O ₃ S

[실시예 8] 화합물 8 의 제조Example 8 Preparation of Compound 8

상기 실시예 7에서 만든 화합물 XXIV (260 mg, 0.71 mmol), 아세트산 (5 mL) 및 트리에틸오소아세테이트 (TEOA, 2.5 mL)를 혼합하고 9시간 동안 환류 교반시켰다. 상온으로 식힌 뒤 감압농축하고 다이클로로메탄 (60 mL)에 묽혀 중탄산나트륨 포화수용액 (50 mL)로 씻어주고 무수황산나트륨으로 탈수시켰다. 이 용액을 감압증류한 뒤 디에틸이서로 고체화(trituration)하여 표제화합물 8 (51mg, 19%)을 얻었다. Compound XXIV (260 mg, 0.71 mmol), acetic acid (5 mL) and triethyloacetate (TEOA, 2.5 mL) prepared in Example 7 were mixed and stirred at reflux for 9 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, diluted with dichloromethane (60 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL), and dehydrated with anhydrous sodium sulfate. The solution was distilled under reduced pressure and triturated with diethyl to give the title compound 8 (51 mg, 19%).

¹H NMR (400MHz, DMSO-d₆) δ = 7.66 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.42 (t, J = 9 Hz, 1H), 7.37 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.21 (s, 1H), 5.24 (t, J = 5.6 Hz, 1H), 4.72 (m, 1H), 4.12-3.52 (m, 8H), 2.52 (s, 3H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.66 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.42 (t, J = 9 Hz, 1H), 7.37 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.21 (s, 1H), 5.24 (t, J = 5.6 Hz, 1H), 4.72 (m, 1H), 4.12-3.52 (m, 8H), 2.52 ( s, 3 H)

LCMS: C₁₆H₁₇-FN₆O₃S 에 대하여 393 (M+H⁺)
LCMS: 393 (M + H ⁺ ) for C ₁₆ H ₁₇ -FN ₆ O ₃ S

[실시예 9] 화합물 9 의 제조Example 9 Preparation of Compound 9

상기 실시예 7에서 만든 화합물 XXIV (0.3 g, 0.63 mmol)을 THF (10 mL)에 녹인 뒤 카보닐다이이미다졸 (CDI, 0.12g, 0.73mmol)을 넣고 상온에서 5시간동안 교반하였다. 이 용액을 농축한 뒤 다이클로로메탄에 녹여 다이에틸이서로 고체화 한 뒤 여과하고 메탄올과 다이에틸이서로 고체화(trituration)하여 백색고체 표제화합물 9 (240mg, 0.61mmol, 97%)을 얻었다. Compound XXIV (0.3 g, 0.63 mmol) prepared in Example 7 was dissolved in THF (10 mL), and carbonyldiimidazole (CDI, 0.12 g, 0.73 mmol) was added thereto, followed by stirring at room temperature for 5 hours. The solution was concentrated, dissolved in dichloromethane, solidified with diethyl ether, filtered, and triturated with methanol and diethyl to give the white solid title compound 9 (240 mg, 0.61 mmol, 97%).

¹H NMR (600MHz, DMSO-d₆) δ = 11.81 (s, 1H), 7.64 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.39 (t, J = 9 Hz, 1H), 7.36 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.12 (s, 1H), 5.24 (t, J = 5.6 Hz, 1H), 4.72 (m, 1H), 4.09 (t, J = 9.0 Hz, 1H), 3.84-3.54 (m, 7H) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 11.81 (s, 1H), 7.64 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.39 (t, J = 9 Hz, 1H), 7.36 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.12 (s, 1H), 5.24 (t, J = 5.6 Hz, 1H), 4.72 (m, 1H), 4.09 (t, J = 9.0 Hz, 1H) , 3.84-3.54 (m, 7H)

LCMS: C₁₅H₁₅-FN₆O₄S 에 대하여 395 (M+H⁺)
LCMS: 395 (M + H ⁺ ) for C ₁₅ H ₁₅ -FN ₆ O ₄ S

[실시예 10] 화합물 10, 11 의 제조Example 10 Compound 10 , Manufacture of 11

상기 실시예 7에서 만든 화합물 XXIV (100mg, 0.21mmol) 을 DMF (3 mL)에 녹인 뒤, 에틸클로로옥소아세테이트(ethyl chlorooxoacetate, 0.05mL, 0.41mmol)을 천천히 넣고 상온에서 1시간 교반후 80 ℃로 가열하여 14시간 교반시켰다. 상온으로 낮추고 에틸아세테이트 (60mL)로 묽히고 물 (50mL)로 3회 씻어주었다. 유기층은 무수황산나트륨을 이용하여 탈수시키고 컬럼크로마토그래피 (eluent : 에틸아세테이트)로 분리하여 노란색 고체 (55mg, 47%)를 얻었다.Dissolve compound XXIV (100mg, 0.21mmol) prepared in Example 7 in DMF (3 mL), slowly add ethyl chlorooxoacetate (0.05 mL, 0.41 mmol), and stir at room temperature for 1 hour to 80 ° C. Heated and stirred for 14 h. Lowered to room temperature, diluted with ethyl acetate (60mL) and washed three times with water (50mL). The organic layer was dehydrated using anhydrous sodium sulfate and separated by column chromatography (eluent: ethyl acetate) to obtain a yellow solid (55 mg, 47%).

이렇게 얻은 화합물 (50mg, 0.09mmol)을 THF (1mL)와 MeOH (2mL)의 혼합용매에 녹인 뒤 암모니아수(4mL)을 넣고 14시간 동안 교반환류시켰다. 용매를 감압농축하고 컬럼크로마토그래피 (eluent : 물/ AN = 2/8)로 분리하여 표제화합물 10 (3.8 mg), 표제화합물 11 (11 mg)을 각각 얻었다.
Thus obtained compound (50mg, 0.09mmol) was dissolved in a mixed solvent of THF (1mL) and MeOH (2mL) and ammonia water (4mL) was added and stirred under reflux for 14 hours. The solvent was concentrated under reduced pressure and separated by column chromatography (eluent: water / AN = 2/8) to obtain the title compound 10 (3.8 mg) and the title compound 11 (11 mg), respectively.

<화합물 10> < Compound 10>

¹H NMR (600MHz, DMSO-d₆) δ = 8.20 (s, 1H), 7.80 (s, 1H), 7.67 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.43 (t, J = 9 Hz, 1H), 7.38 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.35 (s, 1H), 5.26 (br t, 1H), 4.73 (m, 1H), 4.16 (t, J = 4.8 Hz, 2H), 4.10 (t, J = 9.0 Hz, 1H), 3.88-3.55 (m, 5H) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 8.20 (s, 1H), 7.80 (s, 1H), 7.67 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.43 (t, J = 9 Hz, 1H), 7.38 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.35 (s, 1H), 5.26 (br t, 1H), 4.73 (m, 1H), 4.16 (t, J = 4.8 Hz, 2H), 4.10 (t , J = 9.0 Hz, 1H), 3.88-3.55 (m, 5H)

LCMS: C₁₆H₁₆FN₇O₄S 에 대하여 422 (M+H⁺)
LCMS: 422 (M + H ⁺ ) for C ₁₆ H ₁₆ FN ₇ O ₄ S

<화합물 11><Compound 11>

¹H NMR (600MHz, DMSO-d₆) δ = 7.65 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.41 (t, J = 9 Hz, 1H), 7.37 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.21 (s, 1H), 5.25 (t, J = 5.6 Hz, 1H), 4.72 (m, 1H), 4.09 (t, J = 9.0 Hz, 1H), 4.03 (t, J = 5.2 Hz, 2H), 3.87-3.51 (m, 5H) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.65 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.41 (t, J = 9 Hz, 1H), 7.37 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.21 (s, 1H), 5.25 (t, J = 5.6 Hz, 1H), 4.72 (m, 1H), 4.09 (t, J = 9.0 Hz, 1H) , 4.03 (t, J = 5.2 Hz, 2H), 3.87-3.51 (m, 5H)

LCMS: C₁₆H₁₅-FN₆O₅S 에 대하여 423 (M+H⁺)
LCMS: 423 (M + H ⁺ ) for C ₁₆ H ₁₅ -FN ₆ O ₅ S

[실시예 11] 화합물 12, 13 의 제조Example 11 Compound 12 , 13 , manufacturing

상기 실시예 1에서 만든 화합물 XVIII (1 g, 2.30 mmol)을 다이클로로메탄 (5 mL)에 녹인 뒤 트리에틸아민 (0.97 mL, 6.9 mmol), 시아노겐브로마이드(cyanogen bromide, 0.3 mL, 3 mmol) 을 넣고 0 ℃ 에서 90분간 교반하였다. 이 용액을 다이클로로메탄 (50 mL)로 묽힌 뒤 중탄산나트륨 포화수용액 (50 mL)로 씻어주고 무수황산나트륨으로 탈수시켰다. 이 용액을 감압농축하고 컬럼크로마토그래피 (eluent : 50% EA/Hex)로 분리하여 연노란색 고체 화합물 XXV (0.21g, 0.5mmol, 22%)를 얻었다. Compound XVIII made in Example 1, above (1 g, 2.30 mmol) was dissolved in dichloromethane (5 mL), triethylamine (0.97 mL, 6.9 mmol) and cyanogen bromide (0.3 mL, 3 mmol) were added and stirred at 0 ° C. for 90 minutes. It was. The solution was diluted with dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL) and dehydrated with anhydrous sodium sulfate. The solution was concentrated under reduced pressure and separated by column chromatography (eluent: 50% EA / Hex) to give a pale yellow solid compound XXV (0.21 g, 0.5 mmol, 22%).

이렇게 얻은 화합물 화합물 XXV (0.21 g, 0.5 mmol)을 DMF (3 mL)에 녹인 뒤 암모늄클로라이드 (80 mg, 1.5 mmol), NaN₃ (48 mg, 0.75 mmol)를 넣고 120 ℃ 에서 2.5 시간 가열교반하였다. 이 용액을 에틸아세테이트 (50 mL)로 묽힌 뒤 중탄산나트륨 포화수용액 (50 mL)로 씻어주고 무수황산나트륨으로 탈수시켰다. 이 용액을 감압농축하고 다이에틸이서로 고체화(trituration)하여 흰색 고체 화합물 XXVI (0.08g, 0.18mmol, 36%)를 얻었다.The obtained compound compound XXV (0.21 g, 0.5 mmol) was dissolved in DMF (3 mL), followed by ammonium chloride (80 mg, 1.5 mmol), NaN ₃ (48 mg, 0.75 mmol) was added thereto and stirred at 120 ° C. for 2.5 hours. The solution was diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL) and dehydrated with anhydrous sodium sulfate. The solution was concentrated under reduced pressure and triturated with diethyl to afford the white solid compound XXVI (0.08 g, 0.18 mmol, 36%).

이렇게 얻은 화합물 화합물 XXVI (0.08g, 0.18mmol)을 DMF (1 mL)에 녹인 뒤 KOH (25 mg, 0.45 mmol), 요오드메탄 (0.045 mL, 0.73 mmol)를 넣고 상온에서 2 시간 교반하였다. 이 용액을 다이클로로메탄 (50 mL)로 묽힌 뒤 중탄산나트륨 포화수용액 (50 mL)로 씻어주고 무수황산나트륨으로 탈수시켰다. 이 용액을 감압농축하고 에탄올에 녹여 암모니아수 (2 mL)를 넣고 1시간동안 환류교반 시켰다. 이 용액을 감압농축 후 컬럼크로마토그래피로 분리하여 연노란색 고체 표제화합물 12 (23mg, 0.06mmol, 33%), 아이보리색 고체 표제화합물 13 (23mg, 0.06mmol, 33%)을 각각 얻었다.
The obtained compound compound XXVI (0.08 g, 0.18 mmol) was dissolved in DMF (1 mL), KOH (25 mg, 0.45 mmol) and iodine methane (0.045 mL, 0.73 mmol) were added thereto, and the resultant was stirred at room temperature for 2 hours. The solution was diluted with dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL) and dehydrated with anhydrous sodium sulfate. The solution was concentrated under reduced pressure, dissolved in ethanol, ammonia water (2 mL) was added, and the mixture was stirred under reflux for 1 hour. The solution was concentrated under reduced pressure and separated by column chromatography to obtain a pale yellow solid title compound 12 (23 mg, 0.06 mmol, 33%) and an ivory solid title compound 13 (23 mg, 0.06 mmol, 33%), respectively.

<화합물 12><Compound 12>

LCMS: C₁₅H₁₇-FN₈O₃ 에 대하여 377 (M+H⁺)
LCMS: 377 (M + H ⁺ ) for C ₁₅ H ₁₇ -FN ₈ O ₃

<화합물 13><Compound 13>

¹H NMR (600MHz, DMSO-d₆) δ = 7.64 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.40 (t, J = 9 Hz, 1H), 7.36 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.10 (s, 1H), 5.24 (br t, 1H), 4.73 (m, 1H), 4.21 (s, 3H), 4.09 (t, J = 9.0 Hz, 1H), 3.86-3.55 (m, 7H) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.64 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.40 (t, J = 9 Hz, 1H), 7.36 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.10 (s, 1H), 5.24 (br t, 1H), 4.73 (m, 1H), 4.21 (s, 3H), 4.09 (t, J = 9.0 Hz , 1H), 3.86-3.55 (m, 7H)

LCMS: C₁₅H₁₇-FN₈O₃ 에 대하여 377 (M+H⁺)
LCMS: 377 (M + H ⁺ ) for C ₁₅ H ₁₇ -FN ₈ O ₃

[실시예 12] 화합물 14 의 제조Example 12 Preparation of Compound 14

상기 제조예 9에서 만든 화합물 IX (140mg, 0.34mmol)을 DMF (5 mL)에 녹인 후에 다이아이소프로필아민 (DIEA, 0.11 mL, 0.68 mmol), 2-클로로-5-니트로피리딘 (81.5 mg, 0.51 mmol)을 넣어 주었다. 상온에서 12시간 교반한 뒤, 10% 헥산/에틸아세테이트 100 mL를 넣어서 묽혀 준 후에 물 50 mL 로 두 번 씻어주고, 무수황산나트륨을 이용하여 탈수시켜 감압농축 하여 노란색 고체 화합물 (140mg 77.6%)을 얻었다. Made in Preparation Example 9 Compound IX (140mg, 0.34mmol) was dissolved in DMF (5 mL), and then diisopropylamine (DIEA, 0.11 mL, 0.68 mmol) and 2-chloro-5-nitropyridine (81.5 mg, 0.51 mmol) were added thereto. After stirring for 12 hours at room temperature, 100 mL of 10% hexane / ethyl acetate was added to the mixture, and the mixture was diluted with water, washed twice with 50 mL of water, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow solid compound (140mg 77.6%). .

이렇게 얻은 화합물 (90 mg, 0.17 mmol)에 메탄올 (2 mL)을 넣고 Pd/C (36 mg)을 넣고 수소가스 풍선하에서 4시간 동안 교반하였다. 셀라이트(celite)를 이용하여 여과 한 후 감압농축하여 노란색 오일 화합물 (40mg, 47%)를 얻었다.Methanol (2 mL) was added to the compound (90 mg, 0.17 mmol), and Pd / C (36 mg) was added thereto. The mixture was stirred under a hydrogen gas balloon for 4 hours. Filtration using celite followed by concentration under reduced pressure gave a yellow oil compound (40 mg, 47%).

이렇게 얻은 화합물 (40mg, 0.079mmol)을 THF (2 mL)에 녹여 니트로실 테트라플루오로보르산(nitrosyl tetrafluoroborate, 10 mg, 0.087 mmol)을 넣고 상온에서 1시간 교반하였다. 감압 농축한 후에 디에틸에테르를 넣어서 생성된 고체를 감압여과 후, 톨루엔 (3 mL)에 넣어 12시간동안 환류 교반하였다. 감압 농축한 후에 10% 메탄올/다이클로로메탄 용액으로 컬럼크로마토그래피를 이용하여 분리하여 노란색 고체 표제화합물 14 (4mg, 14%)를 얻었다.The compound thus obtained (40 mg, 0.079 mmol) was dissolved in THF (2 mL), and nitrosyl tetrafluoroborate (10 mg, 0.087 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, diethyl ether was added, and the resulting solid was filtered under reduced pressure, and then poured into toluene (3 mL), followed by stirring under reflux for 12 hours. Concentration under reduced pressure and then separated by column chromatography in 10% methanol / dichloromethane solution to give the yellow solid title compound 14 (4mg, 14%).

¹H NMR (600MHz, acetone-d₆) δ = 8.17 (s, 1H), 7.76-7.73 (m, 2H), 7.45-7.38 (m, 3H), 7.19 (br s, 1H), 6.83 (br s, 1H), 4.81(m, 1H), 4.40 (br s, 1H), 4.26-3.28 (m, 8H) ¹ H NMR (600 MHz, acetone-d ₆ ) δ = 8.17 (s, 1H), 7.76-7.73 (m, 2H), 7.45-7.38 (m, 3H), 7.19 (br s, 1H), 6.83 (br s , 1H), 4.81 (m, 1H), 4.40 (br s, 1H), 4.26-3.28 (m, 8H)

LCMS: C₁₈H₁₈-FN₅O₃ 에 대하여 372 (M+H⁺)
LCMS: 372 (M + H ⁺ ) for C ₁₈ H ₁₈ -FN ₅ O ₃

[실시예 13] 화합물 15 의 제조Example 13 Preparation of Compound 15

상기 실시예 5에서 만든 화합물 XX (60 mg, 0.18 mmol)을 다이클로로에탄 (3 mL)에 녹인 후 트리에틸아민 (0.02 mL, 0.18 mmol), 5-메틸푸르푸랄(5-methyl furfural, 0.02 mL, 0.22 mmol), 아세트산 (0.01mL, 0.18mmol), 소듐 트리아세톡시보로하이드라이드(sodium triacetoxyborohydride, 46 mg, 0.22 mmol)을 넣고 실온에서 2시간 교반하였다. 반응물에 물 2mL를 넣고 교반한 후에 탄산수소나트륨 포화 수용액 20 mL를 넣고 다이클로로메탄 20mL로 두 번 추출하였다. 무수황산나트륨을 이용하여 탈수시켜 감압 농축한 후에 7% 메탄올/다이클로로메탄 용액으로 컬럼크로마토그래피를 이용하여 분리하여 옅은 노란색 고체 표제화합물 15 (43mg, 61%)를 얻었다. Compound XX (60 mg, 0.18 mmol) prepared in Example 5 was dissolved in dichloroethane (3 mL), followed by triethylamine (0.02 mL, 0.18 mmol) and 5-methyl furfural (0.02 mL). , 0.22 mmol), acetic acid (0.01 mL, 0.18 mmol) and sodium triacetoxyborohydride (46 mg, 0.22 mmol) were added thereto, and the resultant was stirred at room temperature for 2 hours. 2 mL of water was added to the reaction mixture, followed by stirring. 20 mL of saturated aqueous sodium hydrogen carbonate solution was added thereto, and extracted twice with 20 mL of dichloromethane. Dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography with 7% methanol / dichloromethane solution to give a pale yellow solid title compound 15 (43mg, 61%).

¹H NMR (600MHz, DMSO-d₆) δ = 7.58 (d, J = 15 Hz, 1H), 7.31-7.28 (m, 2H), 6.87 (br s, 1H), 6.18 (br d, 1H), 6.00 (br s, 1H), 5.23 (t, J = 5.4 Hz, 1H), 4.70 (m, 1H), 4.07 (t, J = 9.0 Hz, 1H), 3.91 (s, 2H), 3.82-3.54 (m, 5H), 2.91 (br t, 2H), 2.24 (s, 3H) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.58 (d, J = 15 Hz, 1H), 7.31-7.28 (m, 2H), 6.87 (br s, 1H), 6.18 (br d, 1H), 6.00 (br s, 1H), 5.23 (t, J = 5.4 Hz, 1H), 4.70 (m, 1H), 4.07 (t, J = 9.0 Hz, 1H), 3.91 (s, 2H), 3.82-3.54 ( m, 5H), 2.91 (br t, 2H), 2.24 (s, 3H)

LCMS: C₁₉H₂₁-FN₄O₄ 에 대하여 389 (M+H⁺)
LCMS: 389 (M + H ⁺ ) for C ₁₉ H ₂₁ -FN ₄ O ₄

[실시예 14] 화합물 16 의 제조Example 14 Preparation of Compound 16

상기 실시예 5에서 만든 화합물 XX (50 mg, 0.17 mmol), 5-니트로-퓨란-2-카브알데하이드(29 mg, 0.20 mmol)을 DCE(dichloroethane, 3 mL)에 넣고 녹인뒤 AcOH (0.01 mL, 0.17 mmol)을 넣고 NaBH(OAc)₃를 넣고 상온에서 2시간 교반시켰다. 다이클로로메탄 (50 mL)로 묽히고 중탄산나트튬 포화수용액 (40 mL), 염화나트륨 포화수용액 (40 mL)로 순차적으로 씻어주고 무수황산나트륨을 이용하여 탈수시키고 5% MeOH/MC로 컬럼크로마토그래피를 이용하여 분리하여 노란색 고체 표제화합물 16 (44mg, 62%)를 얻었다. Compound XX (50 mg, 0.17 mmol) and 5-nitro-furan-2-carbaldehyde (29 mg, 0.20 mmol) prepared in Example 5 were dissolved in DCE (dichloroethane, 3 mL) and dissolved in AcOH (0.01 mL, 0.17 mmol) was added and NaBH (OAc) ₃ was added thereto and stirred at room temperature for 2 hours. Dilute with dichloromethane (50 mL), wash sequentially with saturated sodium bicarbonate solution (40 mL), saturated aqueous sodium chloride solution (40 mL), dehydrate with anhydrous sodium sulfate, and use column chromatography with 5% MeOH / MC. Isolate to give a yellow solid title compound 16 (44mg, 62%).

¹H NMR (400MHz, CDCl₃) δ = 7.54 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 7.20 (dd, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz, 1H), 7.10 (t, J = 8.8 Hz, 1H), 6.89 (s, 1H), 6.62 (d, J = 3.6 Hz, 1H), 4.77 (m, 1H), 4.18 (s, 2H), 4.04-3.96 (m, 3H), 3.84 (t, J = 4.8 Hz, 2H), 3.77 (m, 1H), 3.11 (t, J = 4.8 Hz, 2H), 2.04 (t, J = 6.6 Hz, 1H) ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.54 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 7.20 (dd, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz, 1H), 7.10 (t, J = 8.8 Hz, 1H), 6.89 (s, 1H), 6.62 (d, J = 3.6 Hz, 1H), 4.77 (m, 1H) , 4.18 (s, 2H), 4.04-3.96 (m, 3H), 3.84 (t, J = 4.8 Hz, 2H), 3.77 (m, 1H), 3.11 (t, J = 4.8 Hz, 2H), 2.04 ( t, J = 6.6 Hz, 1H)

LCMS: C₁₈H₁₈FN₅O₆ 에 대하여 420 (M+H⁺)
LCMS: 420 (M + H ⁺ ) for C ₁₈ H ₁₈ FN ₅ O ₆

[실시예 15] 화합물 17 의 제조Example 15 Preparation of Compound 17

상기 실시예 5에서 만든 화합물 XX (100 mg, 0.30 mmol)을 다이클로로에탄 (5 mL)에 녹인 후에 트리에틸아민 (0.04 mL, 0.30 mmol) 를 넣고 퓨란-2,5-다이카브알데하이드 (75 mg, 0.36 mmol), 아세트산 (0.02 mL, 0.30 mmol), 소듐 트리아세톡시보로하이드라이드 (77 mg, 0.36 mmol)을 넣어 주고 실온에서 2시간 교반하였다. 반응물에 물 2 mL를 넣고 교반한 후에 탄산수소나트륨 포화 수용액 20 mL를 넣고 다이클로로메탄 20 mL로 두 번 추출하였다. 무수황산나트륨을 이용하여 탈수시켜 감압 농축한 후에 7% 메탄올/다이클로로메탄 용액으로 컬럼크로마토그래피를 이용하여 분리하여 노란색 고체 표제화합물 17 (55mg, 45%)를 얻었다. Compound XX (100 mg, 0.30 mmol) prepared in Example 5 was dissolved in dichloroethane (5 mL), and triethylamine (0.04 mL, 0.30 mmol) was added thereto, and furan-2,5-dicarbaldehyde (75 mg) was used. , 0.36 mmol), acetic acid (0.02 mL, 0.30 mmol) and sodium triacetoxyborohydride (77 mg, 0.36 mmol) were added thereto, and the resulting mixture was stirred at room temperature for 2 hours. 2 mL of water was added to the reaction mixture, followed by stirring. 20 mL of saturated aqueous sodium hydrogen carbonate solution was added thereto, and extracted twice with 20 mL of dichloromethane. Dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography with 7% methanol / dichloromethane solution to give a yellow solid title compound 17 (55mg, 45%).

¹H NMR (400MHz, CDCl₃) δ = 9.61 (s, 1H), 7.53 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.24 (d, J = 3.6 Hz, 1H), 7.20 (dd, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz, 1H), 7.09 (t, J = 8.8 Hz, 1H), 6.90 (s, 1H), 6.59 (d, J = 3.6 Hz, 1H), 4.77 (m, 1H), 4.20 (s, 2H), 4.04-3.96 (m, 3H), 3.83 (t, J = 4.8 Hz, 2H), 3.77 (m, 1H), 3.09 (t, J = 4.8 Hz, 2H), 2.17 (br t, 1H) ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.61 (s, 1H), 7.53 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.24 (d, J = 3.6 Hz, 1H), 7.20 (dd, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz, 1H), 7.09 (t, J = 8.8 Hz, 1H), 6.90 (s, 1H), 6.59 (d, J = 3.6 Hz, 1H), 4.77 (m, 1H) , 4.20 (s, 2H), 4.04-3.96 (m, 3H), 3.83 (t, J = 4.8 Hz, 2H), 3.77 (m, 1H), 3.09 (t, J = 4.8 Hz, 2H), 2.17 ( br t, 1H)

LCMS: C₁₉H₁₉FN₄O₅ 에 대하여 403 (M+H⁺)
LCMS: 403 (M + H ⁺ ) for C ₁₉ H ₁₉ FN ₄ O ₅

[실시예 16] 화합물 18 의 제조Example 16 Preparation of Compound 18

상기 실시예 5에서 만든 화합물 XX (100 mg, 0.30 mmol)을 다이클로로에탄 (5 mL)에 녹인 후에 트리에틸아민 (0.04 mL, 0.30 mmol)를 넣고 5-(하이드록시메틸)푸르푸랄 (46 mg, 0.36 mmol), 아세트산 (0.02 mL, 0.30 mmol), 소듐 트리아세톡시보로하이드라이드 (77 mg, 0.36 mmol)을 넣어주고 실온에서 1시간 교반하였다. 반응물에 물 2mL를 넣고 교반한 후에 탄산수소나트륨 포화 수용액 20 mL를 넣고 다이클로로메탄 20 mL로 두 번 추출하였다. 무수황산나트륨을 이용하여 탈수시켜 감압 농축한 후에 7% 메탄올/다이클로로메탄 용액으로 컬럼크로마토그래피를 이용하여 분리하여 노란색 고체 표제화합물 18 (95mg, 78%)를 얻었다. Compound XX (100 mg, 0.30 mmol) prepared in Example 5 was dissolved in dichloroethane (5 mL), and triethylamine (0.04 mL, 0.30 mmol) was added thereto, and 5- (hydroxymethyl) furfural (46 mg , 0.36 mmol), acetic acid (0.02 mL, 0.30 mmol) and sodium triacetoxyborohydride (77 mg, 0.36 mmol) were added thereto, followed by stirring at room temperature for 1 hour. 2 mL of water was added to the reaction mixture, followed by stirring. 20 mL of saturated aqueous sodium hydrogen carbonate solution was added thereto and extracted twice with 20 mL of dichloromethane. Dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography with 7% methanol / dichloromethane solution to give a yellow solid title compound 18 (95mg, 78%).

¹H NMR (600MHz, DMSO-d₆) δ = 7.58 (d, J = 15 Hz, 1H), 7.31-7.28 (m, 2H), 6.87 (br s, 1H), 6.24 (d, J = 3.0 Hz, 1H), 6.21 (d, J = 3.0 Hz, 1H), 5.22 (t, J = 5.4 Hz, 1H), 5.18 (t, J = 5.4 Hz, 1H), 4.70 (m, 1H), 4.35 (d, J = 5.4 Hz, 2H), 4.07 (t, J = 9.0 Hz, 1H), 3.95 (s, 2H), 3.82-3.53 (m, 5H), 2.93 (t, J = 4.8 Hz, 2H) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.58 (d, J = 15 Hz, 1H), 7.31-7.28 (m, 2H), 6.87 (br s, 1H), 6.24 (d, J = 3.0 Hz , 1H), 6.21 (d, J = 3.0 Hz, 1H), 5.22 (t, J = 5.4 Hz, 1H), 5.18 (t, J = 5.4 Hz, 1H), 4.70 (m, 1H), 4.35 (d , J = 5.4 Hz, 2H), 4.07 (t, J = 9.0 Hz, 1H), 3.95 (s, 2H), 3.82-3.53 (m, 5H), 2.93 (t, J = 4.8 Hz, 2H)

LCMS: C₁₉H₂₁-FN₄O₅ 에 대하여 405 (M+H⁺)
LCMS: 405 (M + H ⁺ ) for C ₁₉ H ₂₁ -FN ₄ O ₅

[실시예 17] 화합물 19 의 제조Example 17 Preparation of Compound 19

상기 실시예 5에서 만든 화합물 XX (100 mg, 0.30 mmol)을 다이클로로에탄 (5 mL)에 녹인 후에 트리에틸아민 (0.04 mL, 0.30 mmol) 를 넣고 5-니트릴-2-티오펜카브알데하이드 (57 mg, 0.36 mmol), 아세트산 (0.02 mL, 0.30 mmol), 소듐 트리아세톡시보로하이드라이드 (49 mg, 0.36 mmol)을 넣어주고 실온에서 1시간 교반하였다. 반응물에 물 2 mL를 넣고 교반한 후에 탄산수소나트륨 포화 수용액 20 mL를 넣고 다이클로로메탄 20mL로 두 번 추출하였다. 무수황산나트륨을 이용하여 탈수시켜 감압 농축한 후에 10% 메탄올/다이클로로메탄 용액으로 컬럼크로마토그래피를 이용하여 분리하여 노란색 고체 표제화합물 19 (92.3mg, 73%)를 얻었다. Compound XX (100 mg, 0.30 mmol) prepared in Example 5 was dissolved in dichloroethane (5 mL), and triethylamine (0.04 mL, 0.30 mmol) was added thereto, and 5-nitrile-2-thiophencarbaldehyde (57 mg, 0.36 mmol), acetic acid (0.02 mL, 0.30 mmol) and sodium triacetoxyborohydride (49 mg, 0.36 mmol) were added thereto, followed by stirring at room temperature for 1 hour. 2 mL of water was added to the reaction mixture, followed by stirring. 20 mL of saturated aqueous sodium hydrogen carbonate solution was added thereto, and extracted twice with 20 mL of dichloromethane. Dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography with 10% methanol / dichloromethane solution to give a yellow solid title compound 19 (92.3mg, 73%).

¹H NMR (600MHz, CDCl₃) δ = 7.55 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.51 (d, J = 3.6 Hz, 1H), 7.19 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.12 (t, J = 9 Hz, 1H), 7.00 (d, J = 3.6 Hz, 1H), 6.94 (s, 1H), 4.77 (m, 1H), 4.32 (s, 2H), 4.04-3.96 (m, 3H), 3.83 (t, J = 4.8 Hz, 2H), 3.77 (dd, J ₁ = 12.6 Hz, J ₂ = 3.6 Hz, 1H), 2.99 (t, J = 4.8 Hz, 2H) ¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.55 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.51 (d, J = 3.6 Hz, 1H), 7.19 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.12 (t, J = 9 Hz, 1H), 7.00 (d, J = 3.6 Hz, 1H), 6.94 (s, 1H), 4.77 (m, 1H) , 4.32 (s, 2H), 4.04-3.96 (m, 3H), 3.83 (t, J = 4.8 Hz, 2H), 3.77 (dd, J ₁ = 12.6 Hz, J ₂ = 3.6 Hz, 1H), 2.99 (t, J = 4.8 Hz, 2H)

LCMS: C₁₉H₁₈-FN₅O₃S 에 대하여 416 (M+H⁺)
LCMS: 416 (M + H ⁺ ) for C ₁₉ H ₁₈ -FN ₅ O ₃ S

[실시예 18] 화합물 20 의 제조Example 18 Preparation of Compound 20

상기 실시예 5에서 만든 화합물 XX (100 mg, 0.30 mmol)을 다이클로로에탄 (5 mL)에 녹인 후에 트리에틸아민 (0.04 mL, 0.30 mmol) 를 넣고 2,5-티오펜다이카브알데하이드 (85 mg, 0.36 mmol), 아세트산 (0.02 mL, 0.30 mmol), 소듐 트리아세톡시보로하이드라이드 (77 mg, 0.36 mmol)을 넣어주고 실온에서 2시간 교반하였다. 반응물에 물 2 mL를 넣고 교반한 후에 탄산수소나트륨 포화 수용액 20 mL를 넣고 다이클로로메탄 20mL로 두 번 추출하였다. 무수황산나트륨을 이용하여 탈수시켜 감압 농축한 후에 7% 메탄올/다이클로로메탄 용액으로 컬럼크로마토그래피를 이용하여 분리하여 노란색 고체 표제화합물 20 (95 mg, 75%)를 얻었다. Compound XX (100 mg, 0.30 mmol) prepared in Example 5 was dissolved in dichloroethane (5 mL), and triethylamine (0.04 mL, 0.30 mmol) was added thereto to give 2,5-thiophendicarbaldehyde (85 mg). , 0.36 mmol), acetic acid (0.02 mL, 0.30 mmol) and sodium triacetoxyborohydride (77 mg, 0.36 mmol) were added thereto, and the resulting mixture was stirred at room temperature for 2 hours. 2 mL of water was added to the reaction mixture, followed by stirring. 20 mL of saturated aqueous sodium hydrogen carbonate solution was added thereto, and extracted twice with 20 mL of dichloromethane. Dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography with 7% methanol / dichloromethane solution to give the title compound 20 (95 mg, 75%).

¹H NMR (600MHz, CDCl₃) δ = 9.88 (s, 1H), 7.67 (d, J = 3.6 Hz, 1H), 7.55 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.19 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.13-7.10 (m, 2H), 6.94 (s, 1H), 4.77 (m, 1H), 4.35 (s, 2H), 4.04-3.96 (m, 3H), 3.82 (t, J = 4.8 Hz, 2H), 3.77 (dd, J ₁ = 12.6 Hz, J ₂ = 3.6 Hz, 1H), 3.01 (t, J = 4.8 Hz, 2H) ¹ H NMR (600 MHz, CDCl ₃ ) δ = 9.88 (s, 1H), 7.67 (d, J = 3.6 Hz, 1H), 7.55 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.19 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.13-7.10 (m, 2H), 6.94 (s, 1H), 4.77 (m, 1H), 4.35 (s, 2H), 4.04-3.96 (m, 3H ), 3.82 (t, J = 4.8 Hz, 2H), 3.77 (dd, J ₁ = 12.6 Hz, J ₂ = 3.6 Hz, 1H), 3.01 (t, J = 4.8 Hz, 2H)

LCMS: C₁₉H₁₉FN₄O₄S 에 대하여 419 (M+H⁺)
LCMS: 419 (M + H ⁺ ) for C ₁₉ H ₁₉ FN ₄ O ₄ S

[실시예 19] 화합물 21 의 제조Example 19 Preparation of Compound 21

상기 실시예 5에서 만든 화합물 XX (100 mg, 0.30 mmol)을 다이클로로에탄 (5 mL)에 녹인 후에 트리에틸아민 (0.04 mL, 0.30 mmol) 를 넣고 5-니트로-2-티오펜카브알데하이드(57 mg, 0.36 mmol), 아세트산 (0.02 mL, 0.30 mmol), 소듐 트리아세톡시보로하이드라이드 (77 mg, 0.36 mmol)을 넣어주고 실온에서 1시간 교반하였다. 반응물에 물 2 mL를 넣고 교반한 후에 탄산수소나트륨 포화 수용액 20 mL를 넣고 다이클로로메탄 20 mL로 두 번 추출한다. 무수황산나트륨을 이용하여 탈수시켜 감압 농축한 후에 5% 메탄올/다이클로로메탄 용액으로 컬럼크로마토그래피를 이용하여 분리하여 노란색 고체 표제화합물 21 (68mg, 51%)를 얻었다. Compound XX (100 mg, 0.30 mmol) prepared in Example 5 was dissolved in dichloroethane (5 mL), and triethylamine (0.04 mL, 0.30 mmol) was added thereto, and 5-nitro-2-thiophencarbaldehyde (57 mg, 0.36 mmol), acetic acid (0.02 mL, 0.30 mmol) and sodium triacetoxyborohydride (77 mg, 0.36 mmol) were added thereto, followed by stirring at room temperature for 1 hour. 2 mL of water was added to the reaction mixture, followed by stirring. 20 mL of saturated aqueous sodium hydrogen carbonate solution was added thereto and extracted twice with 20 mL of dichloromethane. Dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography with 5% methanol / dichloromethane solution to give a yellow solid title compound 21 (68mg, 51%).

¹H NMR (400MHz, CDCl₃) δ = 7.82 (d, J = 4.4 Hz, 1H), 7.56 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.20 (dd, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz, 1H), 7.13 (t, J = 8.8 Hz, 1H), 6.95-6.94 (m, 2H), 4.77 (m, 1H), 4.29 (s, 2H), 4.05-3.96 (m, 3H), 3.84 (t, J = 4.8 Hz, 2H), 3.76 (m, 1H), 3.03 (t, J = 4.8 Hz, 2H), 2.01 (t, J = 6.0 Hz, 1H) ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.82 (d, J = 4.4 Hz, 1H), 7.56 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.20 (dd, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz, 1H), 7.13 (t, J = 8.8 Hz, 1H), 6.95-6.94 (m, 2H), 4.77 (m, 1H), 4.29 (s, 2H), 4.05- 3.96 (m, 3H), 3.84 (t, J = 4.8 Hz, 2H), 3.76 (m, 1H), 3.03 (t, J = 4.8 Hz, 2H), 2.01 (t, J = 6.0 Hz, 1H)

LCMS: C₁₈H₁₈FN₅O₅S 에 대하여 436 (M+H⁺)
LCMS: 436 (M + H ⁺ ) for C ₁₈ H ₁₈ FN ₅ O ₅ S

[실시예 20] 화합물 22 의 제조Example 20 Preparation of Compound 22

상기 실시예 18에서 만든 화합물 20 (60 mg, 0.14 mmol)을 메탄올 (3 mL)에 녹인 후에 하이드록실아민하이드로클로라이드 (15 mg, 0.21 mmol), 트리에틸아민 (0.1 mL, 0.67 mmol) 을 넣고 실온에서 12시간 교반하였다. 반응물을 감압 농축한 후에 나온 고체를 물과 다이에틸이서와 다이클로로에탄으로 세척하여 연노란색 고체 표제화합물 22 (30.3 mg, 35%)를 얻었다. Compound 20 (60 mg, 0.14 mmol) prepared in Example 18 was dissolved in methanol (3 mL), and then hydroxylamine hydrochloride (15 mg, 0.21 mmol) and triethylamine (0.1 mL, 0.67 mmol) were added thereto. Stir at 12 h. The reaction mixture was concentrated under reduced pressure, and the solid was washed with water, diethyl ether and dichloroethane to give a pale yellow solid, the title compound 22 (30.3 mg, 35%).

¹H NMR (400MHz, DMSO-d₆) δ = 11.76 (s, 0.5H), 11.1 (s, 0.5H), 8.26 (s, 0.5H), 7.76 (s, 0.5H), 7.59 (d, J = 14 Hz, 1H), 7.31-6.93 (m, 4H), 5.23 (t, J = 5.6 Hz, 1H), 4.70 (m, 1H), 4.29-4.05 (m, 3H), 3.83-3.53 (m, 5H), 2.89 (br t, 2H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.76 (s, 0.5H), 11.1 (s, 0.5H), 8.26 (s, 0.5H), 7.76 (s, 0.5H), 7.59 (d, J = 14 Hz, 1H), 7.31-6.93 (m, 4H), 5.23 (t, J = 5.6 Hz, 1H), 4.70 (m, 1H), 4.29-4.05 (m, 3H), 3.83-3.53 (m, 5H), 2.89 (br t, 2H)

LCMS: C₁₉H₂₀-FN₅O₄S 에 대하여 434 (M+H⁺)
LCMS: 434 (M + H ⁺ ) for C ₁₉ H ₂₀ -FN ₅ O ₄ S

[실시예 21] 화합물 23 의 제조Example 21 Preparation of Compound 23

상기 제조예 9에서 만든 화합물 IX (80 mg, 0.20 mmol)을 DMF (2 mL)에 녹인 뒤, 5-(클로로메틸)-1-메틸-1H-테트라졸(78 mg, 0.59 mmol), DIEA (0.1 mL, 0.59 mmol)을 넣고 60 ℃에서 7시간동안 교반하였다. 이 용액을 에틸아세테이트 (50 mL)로 묽히고 물 (40 mL)로 2회 씻어주고 무수황산나트륨을 이용하여 탈수시키고 80% EA/Hexane 으로 컬럼 크로마토그래피로 분리하여 tbs 보호기가 붙어있는 화합물 (20 mg, 20%)을 얻었다.Made in Preparation Example 9 Compound IX (80 mg, 0.20 mmol) was dissolved in DMF (2 mL), 5- (chloromethyl) -1-methyl-1H-tetrazole (78 mg, 0.59 mmol) and DIEA (0.1 mL, 0.59 mmol) were added thereto. Stir at 60 ° C. for 7 hours. The solution was diluted with ethyl acetate (50 mL), washed twice with water (40 mL), dehydrated with anhydrous sodium sulfate and separated by column chromatography with 80% EA / Hexane (20 mg). , 20%).

이 화합물 (20 mg, 0.04 mmol)을 THF (2 mL)에 녹인 후, TBAF (0.06 mL, 0.06 mmol)을 넣고 1시간 동안 상온에서 교반시켰다. 이 용액을 감압농축하고 다이클로로메탄 (20 mL)로 묽히고 물 (20 mL)로 씻어주고 무수황산나트륨을 이용하여 탈수시키고 10% MEOH/EA로 컬럼 크로마토그래피로 분리하여 표제화합물 23 (9 mg, 58%)을 얻었다.After dissolving this compound (20 mg, 0.04 mmol) in THF (2 mL), TBAF (0.06 mL, 0.06 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure, diluted with dichloromethane (20 mL), washed with water (20 mL), dehydrated with anhydrous sodium sulfate, separated by column chromatography with 10% MEOH / EA, and the title compound 23 (9 mg, 58%).

¹H NMR (600MHz, CDCl₃) δ = 7.52 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.17 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.07 (t, J = 9 Hz, 1H), 6.89 (s, 1H), 4.76 (m, 1H), 4.39 (s, 2H), 4.37 (s, 3H), 4.02-3.96 (m, 3H), 3.84 (t, J = 4.8 Hz, 2H), 3.76 (dd, J ₁ = 12.2 Hz, J ₂ = 3.0 Hz, 1H), 3.17 (t, J = 4.8 Hz, 2H) ¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.52 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.17 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.07 (t, J = 9 Hz, 1H), 6.89 (s, 1H), 4.76 (m, 1H), 4.39 (s, 2H), 4.37 (s, 3H), 4.02-3.96 (m, 3H), 3.84 (t, J = 4.8 Hz, 2H), 3.76 (dd, J ₁ = 12.2 Hz, J ₂ = 3.0 Hz, 1H), 3.17 (t, J = 4.8 Hz, 2H)

LCMS: C₁₆H₁₉-FN₈O₃ 에 대하여 391 (M+H⁺)
LCMS: 391 (M + H ⁺ ) for C ₁₆ H ₁₉ -FN ₈ O ₃

[실시예 22] 화합물 24 의 제조Example 22 Preparation of Compound 24

상기 실시예 5에서 만든 화합물 XX (100mg, 0.34mmol)을 DMF에 녹인뒤 DIEA (0.65 mL, 0.34 mmol), 클로로메틸사이클릭아미독심 (56 mg, 0.37 mmol)을 넣고 상온에서 5시간 교반후, 80 ℃에서 13시간 동안 교반시켰다. 상온으로 식힌후 다이클로로메탄 (50 mL)로 묽히고 증류수 (40 mL)로 씻어주고 무수황산나트륨을 이용하여 탈수시키고 10% MeOH/MC로 컬럼 크로마토그래피 분리하여 아이보리색 고체 표제화합물 24 (56mg, 41%)를 얻었다.After dissolving Compound XX (100mg, 0.34mmol) prepared in Example 5 in DMF, DIEA (0.65 mL, 0.34 mmol) and chloromethylcyclic amidoxime (56 mg, 0.37 mmol) were added and stirred at room temperature for 5 hours. Stirred at 80 ° C for 13 h. After cooling to room temperature, dilute with dichloromethane (50 mL), wash with distilled water (40 mL), dehydrate with anhydrous sodium sulfate, and column chromatography with 10% MeOH / MC to separate ivory-colored solid title compound 24 (56mg, 41). %) Was obtained.

¹H NMR (600MHz, CDCl₃) δ = 7.54 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.19 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 6.87 (s, 1H), 4.77 (m, 1H), 4.04-4.00 (m, 5H), 3.79-3.62 (m, 5H) 3.34 (t, J = 4.8 Hz, 2H), 3.10 (s, 3H), 3.08-3.04 (m, 2H), 2.80 (br s, 1H) ¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.54 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.19 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 6.87 (s, 1H), 4.77 (m, 1H), 4.04-4.00 (m, 5H), 3.79- 3.62 (m, 5H) 3.34 (t, J = 4.8 Hz, 2H), 3.10 (s, 3H), 3.08-3.04 (m, 2H), 2.80 (br s, 1H)

LCMS: C₁₈H₂₃-FN₆O₄ 에 대하여 407 (M+H⁺)
LCMS: 407 (M + H ⁺ ) for C ₁₈ H ₂₃ -FN ₆ O ₄

[실시예 23] 화합물 25 의 제조Example 23 Preparation of Compound 25

상기 제조예 9에서 만든 화합물 IX (70mg, 0.17mmol)과 알데하이드를 다이클로로메탄 (4mL)에 넣고 교반하면서 AcOH (0.01mL, 0.17mmol), NaBH(OAc)₃ (43mg, 0.20mmol)을 넣고 상온에서 교반하였다. 이 용액을 다이클로로메탄으로 묽히고 중탄산 나트륨 포화수용액으로 씻어주고 무수황산나트륨을 이용하여 탈수시키고 10% MeOH/MC 으로 컬럼 크로마토그래피로 분리하여 갈색고체 (60mg, 68%)를 얻었다. Made in Preparation Example 9 Compound IX AcOH (0.01 mL, 0.17 mmol) and NaBH (OAc) ₃ (43 mg, 0.20 mmol) were added to the mixture (70 mg, 0.17 mmol) and aldehyde in dichloromethane (4 mL), followed by stirring. The solution was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, dehydrated with anhydrous sodium sulfate and separated by column chromatography with 10% MeOH / MC to give a brown solid (60 mg, 68%).

이 화합물 (60mg, 0.12mmol)을 다이클로로메탄 (3mL), 4M HCl (0.5mL)을 넣고 상온에서 40분간 교반하였다. 용매를 감압농축하고 다이클로로메탄으로 고체화(trituration)하고 여과하여 갈색의 고체 표제화합물 25 (49mg, 96%)를 얻었다 This compound (60mg, 0.12mmol) was added dichloromethane (3mL) and 4M HCl (0.5mL) and stirred for 40 minutes at room temperature. The solvent was concentrated under reduced pressure, triturated with dichloromethane and filtered to obtain a brown solid title compound 25 (49 mg, 96%).

¹H NMR (600MHz, DMSO-d₆) δ = 9.31 (br s, 2H), 7.67 (d, J = 14 Hz, 1H), 7.47-7.39 (m, 2H), 7.31 (s, 1H), 4.73 (m, 1H), 4.13 (s, 2H), 4.09 (t, J = 9.0 Hz, 1H), 3.86-3.55 (m, 5H), 3.12 (br t, 2H) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 9.31 (br s, 2H), 7.67 (d, J = 14 Hz, 1H), 7.47-7.39 (m, 2H), 7.31 (s, 1H), 4.73 (m, 1H), 4.13 (s, 2H), 4.09 (t, J = 9.0 Hz, 1H), 3.86-3.55 (m, 5H), 3.12 (br t, 2H)

LCMS: C₁₇H₁₉-FN₆O₃S 에 대하여 407 (M+H⁺)
LCMS: 407 (M + H ⁺ ) for C ₁₇ H ₁₉ -FN ₆ O ₃ S

[실시예 24] 화합물 26 의 제조Example 24 Preparation of Compound 26

상기 제조예 9에서 만든 화합물 IX (100mg, 0.24mmol), 아미노티아졸 (68mg, 0.37mmol)을 아세토나이트릴 (4mL)에 넣고 DIPEA (0.13mL, 0.72mmol)을 넣고 9시간동안 환류교반하였다. 상온으로 냉각 후 용매를 감압농축하고 다이클로로메탄으로 묽히고 물, 브린으로 순차적으로 씻어주고 무수황산나트륨을 이용하여 탈수시키고 10% MeOH/MC로 컬럼 크로마토그래피로 분리하여 갈색고체 (40mg, 32%)를 얻었다.Made in Preparation Example 9 Compound IX (100 mg, 0.24 mmol) and aminothiazole (68 mg, 0.37 mmol) were added to acetonitrile (4 mL), and DIPEA (0.13 mL, 0.72 mmol) was added and stirred under reflux for 9 hours. After cooling to room temperature, the solvent was concentrated under reduced pressure, diluted with dichloromethane, washed sequentially with water and brine, dehydrated with anhydrous sodium sulfate, separated by column chromatography with 10% MeOH / MC, and brown solid (40mg, 32%). Got.

이 화합물 (40mg, 0.08mmol)을 다이클로로메탄 (2.5mL), 4M HCl (0.4mL)을 넣고 상온에서 40분간 교반하였다. 용매를 감압농축하고 다이클로로메탄으로 고체화(trituration)하여 여과한 고체를 MeOH로 녹여내어 감압농축 후 EA로 고체화(trituration)하고 여과하여 갈색의 고체 표제화합물 26 (24mg, 70%)를 얻었다. This compound (40mg, 0.08mmol) was added dichloromethane (2.5mL) and 4M HCl (0.4mL) and stirred for 40 minutes at room temperature. The solvent was concentrated under reduced pressure, triturated with dichloromethane, the filtered solid was dissolved in MeOH, concentrated under reduced pressure, triturated with EA, and filtered to obtain a brown solid title compound 26 (24 mg, 70%).

¹H NMR (600MHz, DMSO-d₆) δ = 9.17 (br s, 2H), 7.72 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.60 (t, J = 9.0 Hz, 1H), 7.44 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 6.90 (s, 1H), 4.74 (m, 1H), 4.11 (t, J = 9.0 Hz, 1H), 4.06 (s, 2H), 3.89-3.55 (m, 5H), 3.29 (br t, 2H) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 9.17 (br s, 2H), 7.72 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.60 (t, J = 9.0 Hz, 1H), 7.44 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 6.90 (s, 1H), 4.74 (m, 1H), 4.11 (t, J = 9.0 Hz, 1H), 4.06 (s, 2H), 3.89-3.55 ( m, 5H), 3.29 (br t, 2H)

LCMS: C₁₇H₁₉-FN₆O₃S 에 대하여 407 (M+H⁺)
LCMS: 407 (M + H ⁺ ) for C ₁₇ H ₁₉ -FN ₆ O ₃ S

[실시예 25] 화합물 27 의 제조Example 25 Preparation of Compound 27

상기 실시예 5에서 만든 화합물 XX (100mg, 0.34mmol)을 DMF에 넣고 교반하면서 포밀사이아졸아세트 산 (127mg, 0.68mmol), DIPEA (0.12mL, 0.68mmol), PyBoP (265mg, 0.51mmol)을 넣고 3시간 동안 교반하였다. 다이클로로메탄 (70mL)로 묽히고 물 (70mL)로 3회 세척한 후 중탄산나트륨 포화 수용액으로 세척하고 무수 황산나트륨을 이용하여 탈수시켜 감압농축하여 10% MeOH/MC로 컬럼 크로마토그래피로 분리하여 표제화합물 27 (22mg, 14%)를 얻었다. Compound XX (100mg, 0.34mmol) prepared in Example 5 was added to DMF, followed by stirring with formylthiazolacetic acid (127mg, 0.68mmol), DIPEA (0.12mL, 0.68mmol), and PyBoP (265mg, 0.51mmol). Stir for 3 hours. Dilute with dichloromethane (70mL), wash three times with water (70mL), wash with saturated aqueous sodium bicarbonate solution, dehydrate with anhydrous sodium sulfate, concentrate under reduced pressure and separate by column chromatography with 10% MeOH / MC to give the title compound. 27 (22 mg, 14%) was obtained.

¹H NMR (600MHz, DMSO-d₆) δ = 12.20 (s, 1H), 8.45 (s, 1H), 7. 65 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.40-7.36 (m, 2H), 7.11 (d, J = 1.8 Hz, 1H), 6.94 (s, 1H), 5.23 (t, J = 5.4 Hz, 1H), 4.72 (m, 1H), 4.09 (t, J = 9.0 Hz, 1H), 4.00 (s, 2H), 3.92 (t, J = 4.8 Hz, 2H), 3.83 (m, 1H), 3.71 (t, J = 4.8 Hz, 2H), 3.69-3.54 (m, 2H) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 12.20 (s, 1H), 8.45 (s, 1H), 7. 65 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.40-7.36 (m, 2H), 7.11 (d, J = 1.8 Hz, 1H), 6.94 (s, 1H), 5.23 (t, J = 5.4 Hz, 1H), 4.72 (m, 1H), 4.09 (t, J = 9.0 Hz, 1H), 4.00 (s, 2H), 3.92 (t, J = 4.8 Hz, 2H), 3.83 (m, 1H), 3.71 ( t, J = 4.8 Hz, 2H), 3.69-3.54 (m, 2H)

LCMS: C₁₉H₁₉-FN₆O₅S 에 대하여 463 (M+H⁺)
LCMS: 463 (M + H ⁺ ) for C ₁₉ H ₁₉ -FN ₆ O ₅ S

[실시예 26] 화합물 28 의 제조Example 26 Preparation of Compound 28

상기 실시예 25에서 만든 화합물 27 (30mg, 0.06mmol)을 MeOH (6mL)에 녹인 뒤 4M HCl (0.4mL)을 넣고 상온에서 2시간동안 교반시켰다. 용매를 감압농축하고 디에틸이서로 고체화(trituration)하여 여과하여 아이보리색 고체 표제화합물 28 (20mg, 66%)을 얻었다. Compound 27 (30mg, 0.06mmol) prepared in Example 25 was dissolved in MeOH (6mL), 4M HCl (0.4mL) was added thereto, and the resultant was stirred at room temperature for 2 hours. The solvent was concentrated under reduced pressure, triturated with diethyl ether and filtered to obtain an ivory-colored solid title compound 28 (20 mg, 66%).

¹H NMR (400MHz, DMSO-d₆) δ = 9.19 (br s, 2H), 7. 65 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.40-7.38 (m, 2H), 7.18 (d, J = 2.0 Hz, 1H), 6.71 (s, 1H), 4.73 (m, 1H), 4.09 (t, J = 9.0 Hz, 1H), 4.00 (s, 2H), 3.93 (t, J = 4.8 Hz, 2H), 3.84 (m, 1H), 3.71 (t, J = 4.8 Hz, 2H), 3.69-3.54 (m, 2H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.19 (br s, 2H), 7. 65 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.40-7.38 (m, 2H), 7.18 (d, J = 2.0 Hz, 1H), 6.71 (s, 1H), 4.73 (m, 1H), 4.09 ( t, J = 9.0 Hz, 1H), 4.00 (s, 2H), 3.93 (t, J = 4.8 Hz, 2H), 3.84 (m, 1H), 3.71 (t, J = 4.8 Hz, 2H), 3.69- 3.54 (m, 2 H)

LCMS: C₁₈H₁₉-FN₆O₄S 에 대하여 435 (M+H⁺)
LCMS: 435 (M + H ⁺ ) for C ₁₈ H ₁₉ -FN ₆ O ₄ S

[실시예 27] 화합물 29 의 제조Example 27 Preparation of Compound 29

상기 제조예 16에서 만든 화합물 XVI 로부터 상기 실시예 7과 동일한 방법으로 반응시켜 아이보리색 고체 표제화합물 29 (158mg, 77%)를 얻었다.The compound XVI prepared in Preparation Example 16 was reacted in the same manner as in Example 7, to obtain an ivory-colored solid title compound 29 (158 mg, 77%).

¹H NMR (400MHz, CDCl₃) δ = 8.54 (s, 1H), 7.59 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.21 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.15 (t, J = 9 Hz, 1H), 6.98 (s, 1H), 5.99 (t, J = 6.0 Hz, 1H), 4.80 (m, 1H), 4.26 (t, J = 4.8 Hz, 2H), 4.06 (t, J = 9.0 Hz, 1H), 3.90 (t, J = 4.8 Hz, 2H), 3.82-3.61 (m, 3H), 2.03 (s, 3H) ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.54 (s, 1H), 7.59 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.21 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.15 (t, J = 9 Hz, 1H), 6.98 (s, 1H), 5.99 (t, J = 6.0 Hz, 1H), 4.80 (m, 1H) , 4.26 (t, J = 4.8 Hz, 2H), 4.06 (t, J = 9.0 Hz, 1H), 3.90 (t, J = 4.8 Hz, 2H), 3.82-3.61 (m, 3H), 2.03 (s, 3H)

LCMS: C₁₇H₁₈-FN₇O₃S 에 대하여 420 (M+H⁺)
LCMS: 420 (M + H ⁺ ) for C ₁₇ H ₁₈ -FN ₇ O ₃ S

[실시예 28] 화합물 30 의 제조Example 28 Preparation of Compound 30

상기 제조예 16에서 만든 화합물 XVI 로부터 상기 실시예 10과 같이 반응시켜 노란색 고체 표제화합물 29 (19 mg, 16%)를 얻었다.From the compound XVI prepared in Preparation Example 16, the reaction was carried out as in Example 10, to obtain a yellow solid title compound 29 (19 mg, 16%).

¹H NMR (600MHz, DMSO-d₆) δ = 8.23 (t, J = 5.4 Hz, 1H), 8.16 (s, 1H), 7.76 (s, 1H), 7.60 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.40 (t, J = 9 Hz, 1H), 7.32-7.30 (m, 2H), 4.71 (m, 1H), 4.13-4.08 (m, 3H), 3.84-3.69 (m, 3H), 3.38 (t, J = 5.6Hz, 2H), 1.80 (s, 3H) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 8.23 (t, J = 5.4 Hz, 1H), 8.16 (s, 1H), 7.76 (s, 1H), 7.60 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.40 (t, J = 9 Hz, 1H), 7.32-7.30 (m, 2H), 4.71 (m, 1H), 4.13-4.08 (m, 3H), 3.84-3.69 (m, 3H), 3.38 (t, J = 5.6 Hz, 2H), 1.80 (s, 3H)

LCMS: C₁₈H₁₉FN₈O₄S 에 대하여 463 (M+H⁺)
LCMS: 463 (M + H ⁺ ) for C ₁₈ H ₁₉ FN ₈ O ₄ S

[실시예 29] 화합물 31 의 제조Example 29 Preparation of Compound 31

상기 제조예 16에서 만든 화합물 XVI 로부터 상기 실시예 3과 동일한 방법으로 반응시켜 노란색 고체 표제화합물 31 (63mg, 21%)를 얻었다. Compound XVI prepared in Preparation Example 16 was reacted in the same manner as in Example 3, to obtain a yellow solid title compound 31 (63 mg, 21%).

¹H NMR (600MHz, DMSO-d₆) δ = 8.23 (t, J = 5.8 Hz, 1H), 7.64 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.48 (s, 1H), 7.45 (t, J = 9.0 Hz, 1H), 7.35 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 4.75 (m, 1H), 4.22 (t, J = 5.2 Hz, 2H), 4.13 (t, J = 9.0 Hz, 1H), 3.87 (s, 2H), 3.84-3.73 (m, 3H), 3.42 (t, J = 5.2 Hz, 2H), 1.83 (s, 3H) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 8.23 (t, J = 5.8 Hz, 1H), 7.64 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.48 (s, 1H), 7.45 (t, J = 9.0 Hz, 1H), 7.35 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 4.75 (m, 1H), 4.22 (t, J = 5.2 Hz, 2H), 4.13 (t, J = 9.0 Hz, 1H), 3.87 (s, 2H) , 3.84-3.73 (m, 3H), 3.42 (t, J = 5.2 Hz, 2H), 1.83 (s, 3H)

LCMS: C₁₈H₁₉FN₆O₄S 에 대하여 435 (M+H⁺)
LCMS: 435 (M + H ⁺ ) for C ₁₈ H ₁₉ FN ₆ O ₄ S

[실시예 30] 화합물 32 의 제조Example 30 Preparation of Compound 32

상기 제조예 16에서 만든 화합물 XVI (100 mg, 0.27 mmol)을 클로로포름 (3mL)에 녹인 뒤, 중탄산나트륨 포화수용액 (3 mL)을 넣고 0 ℃ 에서 싸이오포스진(thiophosgene) (0.021 mL, 0.27 mmol)을 천천히 넣고 30분간 교반후, 분액 funnel을 이용하여 유기층을 모아서 암모니아수 (3mL), THF (5mL)을 넣고 상온에서 12시간 교반후 유기용매를 감압증류하였다. 이 혼합물을 다이에틸이서로 고체화(trituration)하고 여과하여 흰색의 고체 (80mg, 76%)를 얻었다. Compound XVI (100 mg, 0.27 mmol) prepared in Preparation Example 16 was dissolved in chloroform (3 mL), and then saturated aqueous sodium bicarbonate solution (3 mL) was added thereto and thiophosgene (0.021 mL, 0.27 mmol) at 0 ° C. ) Was slowly added and stirred for 30 minutes. The organic layer was collected using a separating funnel, ammonia water (3 mL) and THF (5 mL) were added thereto, and the organic solvent was distilled under reduced pressure after stirring at room temperature for 12 hours. The mixture was triturated with diethyl and filtered to give a white solid (80 mg, 76%).

이렇게 얻은 고체 (37 mg, 0.09 mmol)을 EtOH (2mL)에 넣고 클로로아세트알데하이드 (0.024 mL, 0.18 mmol)을 넣고 12시간 동안 환류교반시켰다. 용매를 감압증류하여 다이에틸이서로 고체화(trituration)하여 연한 갈색의 고체 표제화합물 32 (33 mg, 89%)을 얻었다.The solid (37 mg, 0.09 mmol) was added to EtOH (2 mL), and chloroacetaldehyde (0.024 mL, 0.18 mmol) was added and stirred under reflux for 12 hours. The solvent was distilled under reduced pressure to triturate with diethyl to give the title compound 32 (33 mg, 89%) as a light brown solid.

¹H NMR (600MHz, DMSO-d₆) δ = 8.30 (t, J = 5.4 Hz, 1H), 7.65 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.45 (t, J = 9.0 Hz, 1H), 7.37 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 7.30 (s, 1H), 6.96 (d, J = 3.6 Hz, 1H), 4.77 (m, 1H), 4.16 (t, J = 9.0 Hz, 1H), 4.09 (t, J = 4.8 Hz, 2H), 3.90-3.75 (m, 3H), 3.44 (t, J = 4.8 Hz, 2H), 1.86 (s, 3H) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 8.30 (t, J = 5.4 Hz, 1H), 7.65 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.45 (t, J = 9.0 Hz, 1H), 7.37 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 7.30 (s, 1H), 6.96 (d, J = 3.6 Hz, 1H), 4.77 (m, 1H) , 4.16 (t, J = 9.0 Hz, 1H), 4.09 (t, J = 4.8 Hz, 2H), 3.90-3.75 (m, 3H), 3.44 (t, J = 4.8 Hz, 2H), 1.86 (s, 3H)

LCMS: C₁₈H₁₉FN₆O₃S 에 대하여 419 (M+H⁺)
LCMS: 419 (M + H ⁺ ) for C ₁₈ H ₁₉ FN ₆ O ₃ S

[실시예 31] 화합물 33 의 제조Example 31 Preparation of Compound 33

상기 제조예 16에서 만든 화합물 XVI 로부터 클로로아세트알데하이드 대신 에틸브로모피루베이트를 사용하여 실시예 30과 동일한 방법으로 반응시켜 흰색 고체 표제화합물 33 (148 mg, 84%)를 얻었다.The white solid title compound 33 (148 mg, 84%) was obtained by the same method as in Example 30, using ethyl bromopyruvate instead of chloroacetaldehyde from Compound XVI prepared in Preparation Example 16.

¹H NMR (600MHz, CDCl₃) δ = 7.56 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.54 (s, 1H), 7.18 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.13 (t, J = 9 Hz, 1H), 6.95 (s, 1H), 5.98 (t, J = 6.0 Hz, 1H), 4.78 (m, 1H), 4.35 (q, J = 7.2 Hz, 2H), 4.22 (t, J = 4.8 Hz, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.84 (t, J = 4.8 Hz, 2H), 3.79-3.60 (m, 3H), 2.01 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H) ¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.56 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.54 (s, 1H), 7.18 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.13 (t, J = 9 Hz, 1H), 6.95 (s, 1H), 5.98 (t, J = 6.0 Hz, 1H), 4.78 (m, 1H) , 4.35 (q, J = 7.2 Hz, 2H), 4.22 (t, J = 4.8 Hz, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.84 (t, J = 4.8 Hz, 2H), 3.79 -3.60 (m, 3H), 2.01 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H)

LCMS: C₂₁H₂₃-FN₆O₅S 에 대하여 491 (M+H⁺)
LCMS: 491 (M + H ⁺ ) for C ₂₁ H ₂₃ -FN ₆ O ₅ S

[실시예 32] 화합물 34, 35 의 제조Example 32 Preparation of Compounds 34 and 35

상기 제조예 16에서 만든 화합물 33 (140mg, 0.29mmol) 을 MeOH (7 mL)에 녹인 뒤 암모니아수 (14 mL)을 넣고 12 시간 동안 환류교반 시켰다. 용매를 감압농축하고 컬럼크로마토그래피 (eluent : 7% MeOH in MC )로 분리하여 연노란색 고체 표제화합물 34 (30.2mg, 0.06mmol, 22%), 표제화합물 35 (19.7mg, 0.04mmol, 15%) 를 각각 얻었다.
Compound 33 (140mg, 0.29mmol) prepared in Preparation Example 16 was dissolved in MeOH (7 mL), and ammonia water (14 mL) was added thereto, and the mixture was stirred under reflux for 12 hours. The solvent was concentrated under reduced pressure and separated by column chromatography (eluent: 7% MeOH in MC) to give a pale yellow solid title compound 34 (30.2mg, 0.06mmol, 22%), title compound 35 (19.7mg, 0.04mmol, 15%) Were obtained respectively.

<표제화합물 34><Title Compound 34>

¹H NMR (400MHz, DMSO-d₆) δ = 8.24 (t, J = 5.6 Hz, 1H), 7.61 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.44-7.40 (m, 4H), 7.33 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.22 (d, J = 1.6 Hz, 1H), 4.73 (m, 1H), 4.14-4.08 (m, 3H), 3.87-3.71 (m, 3H), 3.41 (t, J = 5.6 Hz, 2H), 1.82 (s, 3H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.24 (t, J = 5.6 Hz, 1H), 7.61 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.44-7.40 (m, 4H), 7.33 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.22 (d, J = 1.6 Hz, 1H), 4.73 (m, 1H), 4.14-4.08 (m, 3H), 3.87-3.71 (m, 3H), 3.41 (t, J = 5.6 Hz, 2H), 1.82 (s, 3H)

LCMS: C₁₉H₂₀FN₇O₄S 에 대하여 462 (M+H⁺)
LCMS: 462 (M + H ⁺ ) for C ₁₉ H ₂₀ FN ₇ O ₄ S

<표제화합물 35><Title Compound 35>

¹H NMR (400MHz, DMSO-d₆) δ = 8.22 (t, J = 5.6 Hz, 1H), 7.57 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.38 (t, J = 9.2 Hz, 1H), 7.31-7.28 (m, 2H), 7.14 (d, J = 2.0 Hz, 1H), 4.70 (m, 1H), 4.11-3.97 (m, 3H), 3.80-3.68 (m, 3H), 3.37 (t, J = 5.6 Hz, 2H), 1.79 (s, 3H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.22 (t, J = 5.6 Hz, 1H), 7.57 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.38 (t, J = 9.2 Hz, 1H), 7.31-7.28 (m, 2H), 7.14 (d, J = 2.0 Hz, 1H), 4.70 (m, 1H), 4.11-3.97 (m, 3H), 3.80-3.68 (m, 3H), 3.37 (t, J = 5.6 Hz, 2H), 1.79 (s, 3H)

LCMS: C₁₉H₁₉FN₆O₅S 에 대하여 463 (M+H⁺)
LCMS: 463 (M + H ⁺ ) for C ₁₉ H ₁₉ FN ₆ O ₅ S

[실시예 33] 화합물 36 의 제조Example 33 Preparation of Compound 36

상기 제조예 16에서 만든 화합물 XVI 로부터 에틸클로로옥소아세테이트 대신 에틸브로모아세테이트를 사용하여 상기 실시예 10과 동일한 방법으로 반응시켜 연노란색 고체 표제화합물 36 (11mg, 0.025mmol, 23%)를 얻었다. Compound XVI prepared in Preparation Example 16 was reacted in the same manner as in Example 10 using ethyl bromoacetate instead of ethylchlorooxoacetate to obtain a pale yellow solid title compound 36 (11 mg, 0.025 mmol, 23%).

¹H NMR (600MHz, DMSO-d₆) δ = 10.59 (s, 1H), 8.25 (t, J = 5.8 Hz, 1H), 7.59 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.37 (t, J = 9.0 Hz, 1H), 7.31 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.06 (s, 1H), 4.73 (m, 1H), 4.12 (t, J = 9.0 Hz, 1H), 3.77-3.7 (m, 5H), 3.41 (t, J = 5.4 Hz, 2H), 3.39 (s, 2H), 1.83 (s, 3H) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 10.59 (s, 1H), 8.25 (t, J = 5.8 Hz, 1H), 7.59 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.37 (t, J = 9.0 Hz, 1H), 7.31 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.06 (s, 1H), 4.73 (m, 1H), 4.12 (t, J = 9.0 Hz, 1H), 3.77-3.7 (m, 5H), 3.41 ( t, J = 5.4 Hz, 2H), 3.39 (s, 2H), 1.83 (s, 3H)

LCMS: C₁₈H₂₀FN₇O₄S 에 대하여 450 (M+H⁺)
LCMS: 450 (M + H ⁺ ) for C ₁₈ H ₂₀ FN ₇ O ₄ S

[실시예 34] 화합물 37 의 제조Example 34 Preparation of Compound 37

상기 제조예 16에서 만든 화합물 XVI 로부터 상기 실시예 11과 같이 CNBr 과 반응시키고 하이드라진으로 처리한 뒤, 상기 실시예 9와 동일한 방법으로 반응시켜 흰색 고체 표제화합물 37 (10mg, 0.02mmol, 16%) 를 얻었다.The compound XVI prepared in Preparation Example 16 was reacted with CNBr as in Example 11, treated with hydrazine, and reacted in the same manner as in Example 9, to obtain a white solid title compound 37 (10 mg, 0.02 mmol, 16%). Got it.

¹H NMR (400MHz, DMSO-d₆) δ = 11.17 (s, 1H), 10.61 (s, 1H), 8.25 (t, J = 5.6 Hz, 1H), 7.64-7.01 (m, 4H), 4.74 (m, 1H), 4.12 (t, J = 8.8 Hz, 1H), 3.86-3.37 (m, 7H), 1.83 (s, 3H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.17 (s, 1H), 10.61 (s, 1H), 8.25 (t, J = 5.6 Hz, 1H), 7.64-7.01 (m, 4H), 4.74 ( m, 1H), 4.12 (t, J = 8.8 Hz, 1H), 3.86-3.37 (m, 7H), 1.83 (s, 3H)

LCMS: C₁₇H₁₉FN₈O₄ 에 대하여 419 (M+H⁺)
LCMS: 419 (M + H ⁺ ) for C ₁₇ H ₁₉ FN ₈ O ₄

[실시예 35] 화합물 38 의 제조Example 35 Preparation of Compound 38

상기 제조예 16에서 만든 화합물 XVI 로부터 상기 실시예 11과 같이 CNBr 과 반응시키고 하이드록실아민으로 처리한 뒤, 상기 실시예 9와 동일한 방법으로 반응시켜 흰색 고체 표제화합물 38 (10mg, 0.02mmol, 24%) 를 얻었다.The compound XVI prepared in Preparation Example 16 was reacted with CNBr as in Example 11, treated with hydroxylamine, and reacted in the same manner as in Example 9 to give a white solid title compound 38 (10 mg, 0.02 mmol, 24%). )

¹H NMR (400MHz, DMSO-d₆) δ = 12.28 (s, 1H), 8.20 (t, J = 5.6 Hz, 1H), 7.56 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.37 (t, J = 9.2 Hz, 1H), 7.29 (dd, J ₁ = 9.2 Hz, J ₂ = 2.4 Hz, 1H), 7.13 (s, 1H), 4.70 (m, 1H), 4.08 (t, J = 8.8 Hz, 1H), 3.77-3.36 (m, 7H), 1.71 (s, 3H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.28 (s, 1H), 8.20 (t, J = 5.6 Hz, 1H), 7.56 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.37 (t, J = 9.2 Hz, 1H), 7.29 (dd, J ₁ = 9.2 Hz, J ₂ = 2.4 Hz, 1H), 7.13 (s, 1H), 4.70 (m, 1H), 4.08 (t, J = 8.8 Hz, 1H), 3.77-3.36 (m, 7H), 1.71 ( s, 3 H)

LCMS: C₁₇H₁₈FN₇O₅ 에 대하여 420 (M+H⁺)
LCMS: 420 (M + H ⁺ ) for C ₁₇ H ₁₈ FN ₇ O ₅

[실시예 36] 화합물 39 의 제조Example 36 Preparation of Compound 39

상기 제조예 16에서 만든 화합물 XVI 로부터 상기 실시예 17과 동일한 방법으로 반응시켜 흰색 고체 표제화합물 39 (0.048 g, 0.11mmol, 83%) 를 얻었다.The white solid title compound 39 (0.048 g, 0.11 mmol, 83%) was obtained by reaction in the same manner as in Example 17 from compound XVI prepared in Preparation Example 16.

¹H NMR (600MHz, CDCl₃) δ = 7.51 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.31-7.16 (m, 3H), 7.14 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.09 (t, J = 9 Hz, 1H), 6.93 (s, 1H), 5.97 (t, J = 6.0 Hz, 1H), 4.79 (m, 1H), 4.03 (t, J = 9.0 Hz, 1H), 3.79-3.61 (m, 5H), 2.93 (t, J = 4.8 Hz, 2H), 2.03 (s, 3H) ¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.51 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.31-7.16 (m, 3H), 7.14 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.09 (t, J = 9 Hz, 1H), 6.93 (s, 1H), 5.97 (t, J = 6.0 Hz, 1H), 4.79 (m, 1H) , 4.03 (t, J = 9.0 Hz, 1H), 3.79-3.61 (m, 5H), 2.93 (t, J = 4.8 Hz, 2H), 2.03 (s, 3H)

LCMS: C₂₀H₂₂-FN₅O₃S 에 대하여 432 (M+H⁺)
LCMS: 432 (M + H ⁺ ) for C ₂₀ H ₂₂ -FN ₅ O ₃ S

[실시예 37] 화합물 40 의 제조Example 37 Preparation of Compound 40

상기 제조예 16에서 만든 화합물 XVI 로부터 상기 실시예 13과 동일한 방법으로 반응시켜 흰색 고체 표제화합물 40 (0.021 g, 0.05mmol, 37%) 를 얻었다. Compound XVI prepared in Preparation Example 16 was reacted in the same manner as in Example 13, to obtain white solid title compound 40 (0.021 g, 0.05 mmol, 37%).

¹H NMR (600MHz, CDCl₃) δ = 7.51 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.44 (s, 1H), 7.41 (d, J = 1.8 Hz, 1H), 7.14 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.09 (t, J = 9 Hz, 1H), 6.93 (s, 1H), 6.49 (s, 1H), 5.94 (t, J = 6.0 Hz, 1H), 4.79 (m, 1H), 4.03 (t, J = 9.0 Hz, 1H), 3.98 (s, 2H), 3.79 (t, J = 4.8 Hz, 2H), 3.78-3.60 (m, 3H), 2.95 (t, J = 4.8 Hz, 2H), 2.03 (s, 3H) ¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.51 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.44 (s, 1H), 7.41 (d, J = 1.8 Hz, 1H), 7.14 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.09 (t, J = 9 Hz, 1H), 6.93 (s, 1H), 6.49 (s, 1H), 5.94 (t, J = 6.0 Hz, 1H) , 4.79 (m, 1H), 4.03 (t, J = 9.0 Hz, 1H), 3.98 (s, 2H), 3.79 (t, J = 4.8 Hz, 2H), 3.78-3.60 (m, 3H), 2.95 ( t, J = 4.8 Hz, 2H), 2.03 (s, 3H)

LCMS: C₂₀H₂₂-FN₅O₄ 에 대하여 416 (M+H⁺)
LCMS: 416 (M + H ⁺ ) for C ₂₀ H ₂₂ -FN ₅ O ₄

[실시예 38] 화합물 41 의 제조Example 38 Preparation of Compound 41

상기 제조예 16에서 만든 화합물 XVI 로부터 상기 실시예 13과 동일한 방법으로 반응시켜 흰색 고체 표제화합물 41 (0.044 g, 0.10mmol, 76%) 를 얻었다.The white solid title compound 41 (0.044 g, 0.10 mmol, 76%) was obtained by reaction in the same manner as in Example 13 from compound XVI prepared in Preparation Example 16.

¹H NMR (600MHz, CDCl₃) δ = 7.76 (d, J = 3.0 Hz, 1H), 7.52 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.33 (d, J = 3.0 Hz, 1H), 7.15 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.11 (t, J = 9 Hz, 1H), 6.96 (s, 1H), 5.97 (t, J = 6.0 Hz, 1H), 4.79 (m, 1H), 4.50 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.83 (t, J = 4.8 Hz, 2H), 3.78-3.60 (m, 3H), 3.08 (t, J = 4.8 Hz, 2H), 2.03 (s, 3H) ¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.76 (d, J = 3.0 Hz, 1H), 7.52 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.33 (d, J = 3.0 Hz, 1H), 7.15 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.11 (t, J = 9 Hz, 1H), 6.96 (s, 1H), 5.97 (t, J = 6.0 Hz, 1H), 4.79 (m, 1H) , 4.50 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.83 (t, J = 4.8 Hz, 2H), 3.78-3.60 (m, 3H), 3.08 (t, J = 4.8 Hz, 2H), 2.03 (s, 3H)

LCMS: C₁₉H₂₁-FN₆O₃S 에 대하여 433 (M+H⁺)
LCMS: 433 (M + H ⁺ ) for C ₁₉ H ₂₁ -FN ₆ O ₃ S

[실시예 39] 화합물 42 의 제조Example 39 Preparation of Compound 42

상기 제조예 16에서 만든 화합물 XVI 로부터 상기 실시예 13과 동일한 방법으로 반응시켜 흰색 고체 표제화합물 42 (0.043 g, 0.10mmol, 74%) 를 얻었다.The white solid title compound 42 (0.043 g, 0.10 mmol, 74%) was obtained by reaction in the same manner as in Example 13 from compound XVI prepared in Preparation Example 16.

¹H NMR (600MHz, CDCl₃) δ = 7.51 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.14 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.08 (t, J = 9 Hz, 1H), 6.98 (s, 1H), 6.89 (s, 1H), 6.88 (s, 1H), 5.98 (t, J = 6.0 Hz, 1H), 4.79 (m, 1H), 4.21 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.79 (s, 3H), 3.78-3.60 (m, 5H), 3.01 (t, J = 4.8 Hz, 2H), 2.03 (s, 3H) ¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.51 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.14 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.08 (t, J = 9 Hz, 1H), 6.98 (s, 1H), 6.89 (s, 1H), 6.88 (s, 1H), 5.98 (t, J = 6.0 Hz, 1H), 4.79 (m, 1H), 4.21 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.79 (s, 3H), 3.78-3.60 (m, 5H), 3.01 (t, J = 4.8 Hz, 2H), 2.03 (s, 3H)

LCMS: C₂₀H₂₄-FN₇O₃ 에 대하여 430 (M+H⁺)
LCMS: 430 (M + H ⁺ ) for C ₂₀ H ₂₄ -FN ₇ O ₃

[실시예 40] 화합물 43 의 제조Example 40 Preparation of Compound 43

상기 제조예 16에서 만든 화합물 XVI 로부터 상기 실시예 23과 동일한 방법으로 반응시켜 흰색 고체 표제화합물 43 (0.004 g, 0.01mmol, 7%) 를 얻었다.The white solid title compound 43 (0.004 g, 0.01 mmol, 7%) was obtained from the compound XVI prepared in Preparation Example 16 in the same manner as in Example 23.

¹H NMR (600MHz, CDCl₃) δ = 7.51 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.14-7.09 (m, 4H), 6.94 (s, 1H), 6.23 (s, 1H), 4.79 (m, 1H), 4.20 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.78-3.60 (m, 5H), 3.10 (t, J = 4.8 Hz, 2H), 2.73 (s, 3H), 2.03 (s, 3H) ¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.51 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.14-7.09 (m, 4H), 6.94 (s, 1H), 6.23 (s, 1H), 4.79 (m, 1H), 4.20 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.78-3.60 (m, 5H), 3.10 (t, J = 4.8 Hz, 2H), 2.73 (s, 3H), 2.03 (s, 3H)

LCMS: C₂₀H₂₃-FN₆O₃S 에 대하여 447 (M+H⁺)
LCMS: 447 (M + H ⁺ ) for C ₂₀ H ₂₃ -FN ₆ O ₃ S

[실시예 41] 화합물 44 의 제조Example 41 Preparation of Compound 44

상기 제조예 16에서 만든 화합물 XVI (150 mg, 0.40 mmol)을 아세토나이트릴 (5 mL)에 녹인뒤 DIPEA (0.22 mL, 0.61 mmol)을 넣고 트리틸-아미노싸이아졸 화합물 (237mg, 0.61mmol)을 넣고 5시간동안 환류교반시켰다. 이 용액을 상온으로 낮추어 용매를 감압증류하고 다이클로로메탄 (40 mL)로 묽히고 물 (40 mL)로 씻어주고 유기층은 무수황산타트륨을 이용하여 탈수시킨 뒤, 5%MeOH/MC로 컬럼 크로마토그래피 분리하여 갈색의 고체 (8 2mg, 30%)을 얻었다. 이 화합물 (80 mg, 0.12 mmol)을 TFA (8 mL)에 넣고 3시간 동안 환류교반시킨후 상온으로 식히고 용매를 감압농축 후 물:아세토니트릴=3:7로 컬럼 크로마토그래피 분리하여 갈색의 고체 표제화합물 44 (40 mg, 60%)를 얻었다. Compound XVI (150 mg, 0.40 mmol) prepared in Preparation Example 16 was dissolved in acetonitrile (5 mL), and then DIPEA (0.22 mL, 0.61 mmol) was added to the trityl-aminothiazole compound (237 mg, 0.61 mmol). The mixture was refluxed for 5 hours. The solution was cooled to room temperature, the solvent was distilled under reduced pressure, diluted with dichloromethane (40 mL), washed with water (40 mL), and the organic layer was dehydrated with anhydrous titanium sulfate, followed by column chromatography with 5% MeOH / MC. The chromatography separated to give a brown solid (8 2 mg, 30%). The compound (80 mg, 0.12 mmol) was added to TFA (8 mL), stirred at reflux for 3 hours, cooled to room temperature, the solvent was concentrated under reduced pressure, and the residue was concentrated by column chromatography with water: acetonitrile = 3: 7 to give a brown solid title. Compound 44 (40 mg, 60%) was obtained.

¹H NMR (400MHz, DMSO-d₆) δ = 8.26 (t, J = 5.6 Hz, 1H), 7.57 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.36 (t, J = 9.2 Hz, 1H), 7.30 (dd, J ₁ = 9.2 Hz, J ₂ = 2.4 Hz, 1H), 7.12 (s, 1H), 6.56 (s, 1H), 4.73 (m, 1H), 4.11 (t, J = 8.8 Hz, 1H), 3.86 (s, 2H), 3.74-3.01 (m, 7H), 1.83 (s, 3H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.26 (t, J = 5.6 Hz, 1H), 7.57 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.36 (t, J = 9.2 Hz, 1H), 7.30 (dd, J ₁ = 9.2 Hz, J ₂ = 2.4 Hz, 1H), 7.12 (s, 1H), 6.56 (s, 1H), 4.73 (m, 1H), 4.11 (t, J = 8.8 Hz, 1H), 3.86 (s, 2H), 3.74-3.01 (m, 7H), 1.83 (s, 3H)

LCMS: C₁₉H₂₂-FN₇O₃S 에 대하여 448 (M+H⁺)
LCMS: 448 (M + H ⁺ ) for C ₁₉ H ₂₂ -FN ₇ O ₃ S

[실시예 42] 화합물 45 의 제조Example 42 Preparation of Compound 45

상기 제조예 16에서 만든 화합물 XVI 로부터 상기 실시예 22와 동일한 방법으로 반응시켜 흰색 고체 표제화합물 45 (0.003 g, 0.01mmol, 4%)를 얻었다.The white solid title compound 45 (0.003 g, 0.01 mmol, 4%) was obtained from the compound XVI prepared in Preparation Example 16 in the same manner as in Example 22.

¹H NMR (400MHz, DMSO-d₆) δ = 8.26 (t, J = 5.6 Hz, 1H), 7.57 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.34 (t, J = 9.2 Hz, 1H), 7.29 (dd, J ₁ = 9.2 Hz, J ₂ = 2.4 Hz, 1H), 6.91 (s, 1H), 4.73 (m, 1H), 4.11 (t, J = 8.8 Hz, 1H), 3.83 (t, J = 4.8 Hz, 2H), 3.73-3.28 (m, 7H), 2.97 (s, 3H), 2.93 (t, J = 4.8 Hz, 2H), 1.83 (s, 3H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.26 (t, J = 5.6 Hz, 1H), 7.57 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.34 (t, J = 9.2 Hz, 1H), 7.29 (dd, J ₁ = 9.2 Hz, J ₂ = 2.4 Hz, 1H), 6.91 (s, 1H), 4.73 (m, 1H), 4.11 (t, J = 8.8 Hz, 1H), 3.83 (t, J = 4.8 Hz, 2H) , 3.73-3.28 (m, 7H), 2.97 (s, 3H), 2.93 (t, J = 4.8 Hz, 2H), 1.83 (s, 3H)

LCMS: C₂₀H₂₆-FN₇O₄S 에 대하여 448 (M+H⁺)
LCMS: 448 (M + H ⁺ ) for C ₂₀ H ₂₆ -FN ₇ O ₄ S

[실시예 43] 화합물 46 의 제조Example 43 Preparation of Compound 46

상기 제조예 16에서 만든 화합물 XVI (0.2 g, 0.54 mmol), 클로로아세토니트릴 (0.07 mL, 1.08 mmol), 탄산칼륨 (0.074 g, 0.54 mmol), NaI (0.081 g, 0.54 mmol)을 DMF (6 mL)에 첨가 후 60 ℃에서 3시간 반응키킨 뒤, 유기층을 추출 하여 컬럼 크로마토그래피 분리하여 중간체 화합물 (0.141 g, 0.38mmol, 70%)을 얻었다. 이 화합물 (0.124 g, 0.33 mmol)을 암모니움 클로라이드 용액 (0.089 mL, 1.65 mmol), 소듐아자이드 (0.108 g, 1.65 mmol)과 함께 DMF (3 mL)에 녹인 후 12시간 동안 환류교반하고 고체화(trituration)하여 표제화합물 46 (0.074 g, 0.146mmol, 44%)을 얻었다. Compound XVI (0.2 g, 0.54 mmol), chloroacetonitrile (0.07 mL, 1.08 mmol), potassium carbonate (0.074 g, 0.54 mmol), NaI (0.081 g, 0.54 mmol) prepared in Preparation Example 16 was added to DMF (6 mL). After the reaction was carried out for 3 hours at 60 ° C., the organic layer was extracted and the column chromatography was separated to give an intermediate compound. (0.141 g, 0.38 mmol, 70%) was obtained. This compound (0.124 g, 0.33 mmol) was dissolved in DMF (3 mL) with ammonium chloride solution (0.089 mL, 1.65 mmol) and sodium azide (0.108 g, 1.65 mmol), and then stirred under reflux for 12 hours to solidify ( trituration) gave the title compound 46 (0.074 g, 0.146 mmol, 44%).

¹H NMR (400MHz, DMSO-d₆) δ = 8.25 (t, J = 5.6 Hz, 1H), 7.55 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.35-7.27 (m, 2H), 6.87 (s, 1H), 4.72 (m, 1H), 4.13-2.92 (m, 10H), 1.83 (s, 3H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.25 (t, J = 5.6 Hz, 1H), 7.55 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.35-7.27 (m, 2H), 6.87 (s, 1H), 4.72 (m, 1H), 4.13-2.92 (m, 10H), 1.83 (s, 3H )

LCMS: C₁₇H₂₀-FN₉O₃S 에 대하여 418 (M+H⁺)
LCMS: 418 (M + H ⁺ ) for C ₁₇ H ₂₀ -FN ₉ O ₃ S

[실시예 44] 화합물 47 의 제조Example 44 Preparation of Compound 47

상기 제조예 16에서 만든 화합물 XVI 로부터 상기 실시예 13과 동일한 방법으로 5-메틸푸르푸랄 대신 퓨란-2-카브알데하이드를 사용하여 반응시켜 흰색 고체 표제화합물 47 (0.030 g, 0.07mmol, 54%) 를 얻었다.The white solid title compound 47 (0.030 g, 0.07 mmol, 54%) was reacted with furan-2-carbaldehyde instead of 5-methylfurfural in the same manner as in Example 13 from compound XVI prepared in Preparation Example 16. Got it.

¹H NMR (400MHz, CDCl₃) δ = 7.51 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.41 (m, 1H)7.14 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.08 (t, J = 9 Hz, 1H), 6.92 (s, 1H), 6.36-6.33 (m, 2H), 5.93 (t, J = 6.0 Hz, 1H), 4.78 (m, 1H), 4.12 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.81 (t, J = 4.8 Hz, 2H), 3.78-3.56 (m, 3H) 3.02 (t, J = 4.8 Hz, 2H), 2.02 (s, 3H) ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.51 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.41 (m, 1H) 7.14 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.08 (t, J = 9 Hz, 1H), 6.92 (s, 1H), 6.36-6.33 (m, 2H), 5.93 (t, J = 6.0 Hz, 1H), 4.78 (m, 1H), 4.12 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.81 (t, J = 4.8 Hz, 2H), 3.78-3.56 (m, 3H) 3.02 (t, J = 4.8 Hz, 2H), 2.02 (s, 3H)

LCMS: C₂₀H₂₂-FN₅O₄ 에 대하여 416 (M+H⁺)
LCMS: 416 (M + H ⁺ ) for C ₂₀ H ₂₂ -FN ₅ O ₄

[실시예 45] 화합물 48 의 제조Example 45 Preparation of Compound 48

상기 제조예 16에서 만든 화합물 XVI 로부터 상기 실시예 13과 동일한 방법으로 5-메틸푸르푸랄 대신 5-니트로퓨란-2-카브알데하이드를 사용하여 반응시켜 흰색 고체 표제화합물 48 (0.040 g, 0.08mmol, 64%) 를 얻었다. Compound XVI prepared in Preparation Example 16 was reacted with 5-nitrofuran-2-carbaldehyde instead of 5-methylfurfural in the same manner as in Example 13, to obtain a white solid title compound 48 (0.040 g, 0.08 mmol, 64 %) Was obtained.

¹H NMR (600MHz, CDCl₃) δ = 7.53 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 7.15 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.10 (t, J = 9 Hz, 1H), 6.89 (s, 1H), 6.62 (d, J = 3.6 Hz, 1H), 5.92 (t, J = 6.0 Hz, 1H), 4.79 (m, 1H), 4.18 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.84 (t, J = 4.8 Hz, 2H), 3.78-3.61 (m, 3H) 3.11 (t, J = 4.8 Hz, 2H), 2.03 (s, 3H) ¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.53 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 7.15 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.10 (t, J = 9 Hz, 1H), 6.89 (s, 1H), 6.62 (d, J = 3.6 Hz, 1H), 5.92 (t, J = 6.0 Hz, 1H), 4.79 (m, 1H), 4.18 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.84 (t, J = 4.8 Hz, 2H), 3.78-3.61 (m, 3H) 3.11 (t, J = 4.8 Hz, 2H), 2.03 (s, 3H)

LCMS: C₂₀H₂₁-FN₆O₆ 에 대하여 461 (M+H⁺)
LCMS: 461 (M + H ⁺ ) for C ₂₀ H ₂₁ -FN ₆ O ₆

[실시예 46] 화합물 49 의 제조Example 46 Preparation of Compound 49

상기 제조예 16에서 만든 화합물 XVI 로부터 상기 실시예 13과 동일한 방법으로 5-메틸푸르푸랄 대신 5-클로로퓨란-2-카브알데하이드를 사용하여 반응시켜 연노란색 고체 표제화합물 49 (44 mg, 72%) 를 얻었다.The pale yellow solid title compound 49 (44 mg, 72%) was reacted with 5-chlorofuran-2-carbaldehyde instead of 5-methylfurfural by the same method as Example 13 from compound XVI prepared in Preparation Example 16. Got.

¹H NMR (600MHz, CDCl₃) δ = 7.53 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.14 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.10 (t, J = 9 Hz, 1H), 6.94 (s, 1H), 6.35 (d, J = 2.4 Hz, 1H), 6.13 (d, J = 2.4 Hz, 1H), 5.99 (t, J = 6.0 Hz, 1H), 4.79 (m, 1H), 4.07 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.82 (t, J = 4.8 Hz, 2H), 3.78-3.60 (m, 3H) 3.15 (t, J = 4.8 Hz, 2H), 2.03 (s, 3H) ¹ H NMR (600 MHz, CDCl ₃ ) δ = 7.53 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.14 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.10 (t, J = 9 Hz, 1H), 6.94 (s, 1H), 6.35 (d, J = 2.4 Hz, 1H), 6.13 (d, J = 2.4 Hz, 1H), 5.99 (t, J = 6.0 Hz, 1H), 4.79 (m, 1H), 4.07 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.82 (t, J = 4.8 Hz, 2H), 3.78-3.60 (m, 3H) 3.15 (t, J = 4.8 Hz, 2H), 2.03 (s, 3H)

LCMS: C₂₀H₂₁-ClFN₅O₄ 에 대하여 450 (M+H⁺)
LCMS: 450 (M + H ⁺ ) for C ₂₀ H ₂₁ -ClFN ₅ O ₄

[실시예 47] 화합물 50 의 제조Example 47 Preparation of Compound 50

상기 제조예 16에서 만든 화합물 XVI 로부터 상기 실시예 13과 동일한 방법으로 5-메틸푸르푸랄 대신 2,4-다이하이드록시-6-메틸피리미딘-5-카브알데하이드를 사용하여 반응시켜 흰색 고체 표제화합물 50 (33mg, 52%)를 얻었다.The white solid title compound was reacted by using 2,4-dihydroxy-6-methylpyrimidine-5-carbaldehyde instead of 5-methylfurfural in the same manner as in Example 13 from compound XVI prepared in Preparation Example 16. 50 (33 mg, 52%) was obtained.

¹H NMR (600MHz, DMSO-d₆) δ = 10.99 (s, 1H), 10.81 (s, 1H), 8.27 (t, J = 6.0 Hz, 1H), 7.55 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.32 (t, J = 9.0 Hz, 1H), 7.27 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 6.85 (s, 1H), 4.73 (m, 1H), 4.11 (t, J = 9.0 Hz, 1H), 3.74-3.67 (m, 5H), 3.41 (t, J = 4.8 Hz, 2H), 2.87 (t, J = 4.8 Hz, 2H), 2.20 (s, 3H), 1.84 (s, 3H) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 10.81 (s, 1H), 8.27 (t, J = 6.0 Hz, 1H), 7.55 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.32 (t, J = 9.0 Hz, 1H), 7.27 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 6.85 (s, 1H), 4.73 (m, 1H), 4.11 (t, J = 9.0 Hz, 1H), 3.74-3.67 (m, 5H), 3.41 ( t, J = 4.8 Hz, 2H), 2.87 (t, J = 4.8 Hz, 2H), 2.20 (s, 3H), 1.84 (s, 3H)

LCMS: C₂₁H₂₄-ClFN₇O₅ 에 대하여 474 (M+H⁺)
LCMS: 474 (M + H ⁺ ) for C ₂₁ H ₂₄ -ClFN ₇ O ₅

[실시예 48] 화합물 51 의 제조Example 48 Preparation of Compound 51

상기 제조예 16에서 만든 화합물 XVI 로부터 상기 실시예 13과 동일한 방법으로 5-메틸푸르푸랄 대신 피콜린알데하이드(picolinaldehyde)를 사용하여 반응시켜 흰색 고체 표제화합물 51 (0.039 g, 0.09 mmol, 68%) 를 얻었다 The white solid title compound 51 (0.039 g, 0.09 mmol, 68%) was reacted by using picolinaldehyde instead of 5-methylfurfural in the same manner as in Example 13 from compound XVI prepared in Preparation Example 16. Got

¹H NMR (600MHz, CDCl₃) δ = 8.59 (d, J = 4.8 Hz, 1H), 7.69 (m, 1H), 7.53-7.50 (m, 2H), 7.20 (m, 1H), 7.14 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.10 (t, J = 9 Hz, 1H), 6.93 (s, 1H), 5.94 (t, J = 6.0 Hz, 1H), 4.78 (m, 1H), 4.24 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.83 (t, J = 4.8 Hz, 2H), 3.77-3.59 (m, 3H), 3.09 (t, J = 4.8 Hz, 2H), 2.03 (s, 3H) ¹ H NMR (600 MHz, CDCl ₃ ) δ = 8.59 (d, J = 4.8 Hz, 1H), 7.69 (m, 1H), 7.53-7.50 (m, 2H), 7.20 (m, 1H), 7.14 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.10 (t, J = 9 Hz, 1H), 6.93 (s, 1H), 5.94 (t, J = 6.0 Hz, 1H), 4.78 (m, 1H) , 4.24 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.83 (t, J = 4.8 Hz, 2H), 3.77-3.59 (m, 3H), 3.09 (t, J = 4.8 Hz, 2H), 2.03 (s, 3H)

LCMS: C₂₁H₂₃-FN₆O₃ 에 대하여 427 (M+H⁺)
LCMS: 427 (M + H ⁺ ) for C ₂₁ H ₂₃ -FN ₆ O ₃

[실시예 49] 화합물 52 의 제조Example 49 Preparation of Compound 52

상기 제조예 16에서 만든 화합물 XVI 로부터 상기 실시예 9와 동일한 방법으로 반응시켜 흰색 고체 표제화합물 52 (3.2 mg, 6%)를 얻었다.The white solid title compound 52 (3.2 mg, 6%) was obtained by reacting the same method as in Example 9 from Compound XVI prepared in Preparation Example 16.

¹H NMR (600MHz, DMSO-d₆) δ = 11.80 (s, 1H), 8.26 (t, J = 5.8 Hz, 1H), 7.61 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.39 (t, J = 9.0 Hz, 1H), 7.33 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.12 (s, 1H), 4.74 (m, 1H), 4.12 (t, J = 9.0 Hz, 1H), 3.80-3.71 (m, 5H), 3.41 (t, J = 5.2 Hz, 2H), 1.83 (s, 3H) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 11.80 (s, 1H), 8.26 (t, J = 5.8 Hz, 1H), 7.61 (dd, J ₁ = 13.8 Hz, J ₂ = 2.4 Hz, 1H), 7.39 (t, J = 9.0 Hz, 1H), 7.33 (dd, J ₁ = 9.0 Hz, J ₂ = 2.4 Hz, 1H), 7.12 (s, 1H), 4.74 (m, 1H), 4.12 (t, J = 9.0 Hz, 1H), 3.80-3.71 (m, 5H), 3.41 ( t, J = 5.2 Hz, 2H), 1.83 (s, 3H)

LCMS: C₁₇H₁₈FN₇O₄S 에 대하여 436 (M+H⁺)
LCMS: 436 (M + H ⁺ ) for C ₁₇ H ₁₈ FN ₇ O ₄ S

[실험예 1] 시험관 내 항균활성 측정Experimental Example 1 Measurement of In Vitro Antimicrobial Activity

상기 실시예 1 내지 48에서 합성한 옥사졸리디논 유도체의 항균력을 알아보기 위하여 시험관 내 활성 검사를 하기와 같은 방법으로 수행하였다.In order to determine the antimicrobial activity of the oxazolidinone derivatives synthesized in Examples 1 to 48 in vitro activity test was carried out in the following manner.

본 발명의 실시예 1 내지 48의 옥사졸리디논 유도체들의 시험관 내 항균 활성은 분광 측정에 의한 약물 비처리 대조군 성장과 비교하여 균의 성장을 90%까지 억제할 수 있는 항생제의 최소 농도인 90% 억제 농도(MIC₉₀, ug/mL)를 측정하는 것으로 평가하였다. MIC₉₀는 CLSI 표준[참고 : Clinical and Laboratory Standards Institute Document.(2000) Methods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobically-Fifth Edition:M7-A5. CLSI, Villanova, PA]에 기초한 브로스 마이크로 희석법(Broth microdilution method)로 측정하였다.
In vitro antimicrobial activity of the oxazolidinone derivatives of Examples 1 to 48 of the present invention is 90% inhibition, which is the minimum concentration of antibiotic that can inhibit the growth of bacteria by 90% compared to drug-untreated control growth by spectroscopic measurements. The concentration (MIC ₉₀ , ug / mL) was evaluated by measuring. MIC ₉₀ is a CLSI standard [Clinical and Laboratory Standards Institute Document. (2000) Methods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobically-Fifth Edition: M7-A5. CLSI, Villanova, PA] was measured by the Broth microdilution method.

1) 시험 균주1) test strain

메티실린 감수성 스타필로코커스 아우레우스(MSSA, methicillin susceptible Staphylococcus aureus), 메티실린 내성 스타필로코커스 아우레우스(MRSA, methicillin resistant Staphylococcus aureus), 반코마이신 내성 엔테로코카이(VRE, Vancomycin resistant Enterococci), 반코마이신-리네졸리드 내성 엔테로코쿠스 패칼리스 (VLRE, Vancomycin - Linezolid Resistant Enterococcus faecalis), 해모필루스 인플루엔자(Haemophilus Influenzae)와 모락셀라(moraxella)등 모두 14개 균주 (S. aureus , S. aureus ^MR , S. epidermidis , S.epidermidis ^MR , E. faecalis , E.faecalis ^VanA , E. faecalis ^VanA LR, E. faecium ^VanA , E. faecium , E. coli , P. aeruginosa , K.pneumoniae, H. influenzae , M. catarrhalis)를 사용하여 항균력을 측정하였으며, 그 중 중요한 11 개 균주의 결과를 표 1에 나타내었다.
Methicillin susceptible Staphylococcus aureus (MSSA, methicillin susceptible Staphylococcus aureus ), methicillin resistant Staphylococcus aureus (MRSA, methicillin resistant Staphylococcus aureus ), vancomycin-resistant enterocokai (VRE, Vancomycin) resistant Enterococci ), vancomycin-linezolide resistant enterococcus faecalis (VLRE, Vancomycin - Linezolid Resistant Enterococcus faecalis ), Haemophilus Influenzae and moraxella were all 14 strains ( S. aureus , S. aureus ^MR , S. epidermidis , S.epidermidis ^MR , E. faecalis , E.faecalis ^VanA , E. faecalis ^VanA LR , E. faecium ^VanA , E. faecium , E. coli , P. aeruginosa , K.pneumoniae, H. influenzae , M. catarrhalis ) were used to determine the antimicrobial activity. Shown in

2) 시험물질 제조법2) Test substance manufacturing method

시험물질(실시예 1 내지 48에서 합성한 본 발명에 따른 옥사졸리디논 유도체 화합물 1 내지 51)을 10240 ug/mL의 농도로 DMSO에 녹인 후 2배(fold)씩 희석하여 멸균된 3차 증류수로 20배(fold) 희석하였다. 항균 실험 시 최종농도는 최고 128ug/mL에서 최저 0.0625ug/mL이었으며, 부형제로 사용된 DMSO의 농도는 최종적으로 2.5%(V/V)였다. 대조물질로는 파마시아 앤 업존의 리네졸리드(화학식 B)의 화합물을 사용하여 항균활성을 비교하여 그 결과를 하기 표 1에 나타내었다.The test substance (oxazolidinone derivative compounds 1 to 51 according to the present invention synthesized in Examples 1 to 48) was dissolved in DMSO at a concentration of 10240 ug / mL, and then diluted twice by fold to sterilized tertiary distilled water. Diluted 20fold. In the antimicrobial experiment, the final concentration was from 128 ug / mL to 0.0625 ug / mL, and the concentration of DMSO used as excipient was 2.5% (V / V). As a control material, the antibacterial activity was compared using the compound of Pharmazolide (Formula B) of Pharmacia & Upzone and the results are shown in Table 1 below.

[화학식 B][Formula B]

[표 1] 화학식 1의 화합물들의 항균력 (MIC₉₀, ug/mL)Table 1 Antimicrobial activity of compounds of formula 1 (MIC ₉₀ , ug / mL)

1. 스타필로코쿠스 아우레우스 (Staphylococcus aureus)1.Staphylococcus aureus

2. 메티실린 내성 스타필로코쿠스 아우레우스 (Methicillin Resistant Staphylococcus aureus)2. Methicillin Resistant Staphylococcus aureus

3. 스타필로코쿠스 에피더미디스 (Staphylococcus epidermidis)3. Staphylococcus epidermidis

4. 메티실린 내성 스타필로코쿠스 에피더미디스 (Methicillin Resistant Staphylococcus epidermidis)4. Methicillin Resistant Staphylococcus epidermidis

5. 엔테로코쿠스 패칼리스 (Enterococcus faecalis)5. Enterococcus faecalis

6. 반코마이신 내성 엔테로코쿠스 패칼리스 (Vancomycin Resistant Enterococcus faecalis)6. Vancomycin Resistant Enterococcus faecalis

7. 리네졸리드, 반코마이신 내성 엔테로코쿠스 패칼리스 (Linezolid and Vancomycin Resistant Enterococcus faecalis)7. Linezolid and Vancomycin Resistant Enterococcus faecalis

8. 엔테로코쿠스 패슘 (Enterococcus faecium)8. Enterococcus faecium

9. 반코마이신 내성 엔테로코쿠스 패슘 (Vancomycin Resistant Enterococcus faecium)9. Vancomycin Resistant Enterococcus faecium

10. 해모필루스 인플루엔재 (Haemophilus influenzae)10. Haemophilus influenzae

11. 모락셀라 카타랄리스 (Moraxella catarrhalis)
11.Moraxella catarrhalis

상기 표 1에 나타난 바와 같이, 본 발명의 옥사졸리디논 유도체는 대조물질인 리네졸리드에 비하여 훨씬 낮은 농도에서 그람 양성균, 특히 기존 항생제에 내성을 갖는 그람양성균 (MRSA, VRE 등)에 효과적이며, 해모필루스 인플루엔자(Haemophilus Influenzae)와 모락셀라(moraxella)와 같은 그람 음성균에도 효과적임을 알 수 있다. 특히 리네졸리드 내성 엔테로코쿠스 패칼리스에 대해서도 높은 항균력을 보여주고 있어 최근 발현하기 시작하여 앞으로 큰 문제가 될 수 있는 리네졸리드 내성균에도 유용하게 사용 될 수 있음을 보여준다.As shown in Table 1, the oxazolidinone derivatives of the present invention are effective against Gram-positive bacteria, particularly Gram-positive bacteria (MRSA, VRE, etc.), which are resistant to gram-positive bacteria, especially existing antibiotics, at much lower concentrations than the control linerazole. Haemophilus It is also effective for Gram-negative bacteria such as Influenzae ) and moraxella . In particular, it shows high antimicrobial activity against Linezolide resistant Enterococcus faecalis, which shows that it can be useful for Linezolide resistant bacteria that can start to manifest recently and become a big problem in the future.

따라서, 본 발명의 옥사졸리디논 유도체는 그람 양성균에 대한 브로드 스펙트럼(broad spectrum)을 가지는 항생제로 유용하게 사용될 수 있음을 알 수 있다.Therefore, it can be seen that the oxazolidinone derivative of the present invention can be usefully used as an antibiotic having a broad spectrum for Gram-positive bacteria.

Claims (5)

하기 화학식 1로 표시되는 신규한 옥사졸리디논 유도체, 이의 수화물, 이의 용매화물, 이의 이성질체 또는 이들의 약제학적으로 허용되는 염.
[화학식 1]

[상기 식에서,
X 는 화학결합, -(CH₂)_n- 또는 -(CH₂)_nC(=O)- 이며;
n 은 0 내지 2의 정수이고;
R 은 하기 구조에서 선택되는 5원 혹은 6원 헤테로 고리이며:

상기 R₁ 내지 R₂₅ 는 서로 독립적으로 수소, (C₁-C₆)알킬, (C₃-C₆)사이클로알킬, -OH, -NR₃₁R₃₂, -C(=O)R₃₃, -(CH₂)_mOH, -C=NOH, -CN, -NO₂ 또는 할로겐이며;
R₃₁ 및 R₃₂는 서로 독립적으로 수소, (C₁-C₆) 알킬 또는 -C(=O)H이며;
R₃₃은 수소, -OH, -NH₂ 또는 (C₁-C₆)알킬이며;
m은 1 내지 6의 정수이며;
Q는 -OH, -NHC(=O)R₄₁ 또는 -NHC(=O)OR₄₁이며;
R₄₁은 (C₁-C₆)알킬이다.]A novel oxazolidinone derivative represented by the following formula (1), a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof.
[Formula 1]

[Wherein,
X is a chemical bond,-(CH ₂ ) _n -or-(CH ₂ ) _n C (= 0)-;
n is an integer from 0 to 2;
R is a 5 or 6 membered hetero ring selected from the structure:

R ₁ to R ₂₅ are each independently hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, -OH, -NR ₃₁ R ₃₂ , -C (= 0) R ₃₃ ,- (CH ₂ ) _m OH, —C═NOH, —CN, —NO ₂ or halogen;
R ₃₁ and R ₃₂ are independently of each other hydrogen, (C ₁ -C ₆ ) alkyl, or —C (═O) H;
R ₃₃ is hydrogen, —OH, —NH ₂ or (C ₁ -C ₆ ) alkyl;
m is an integer from 1 to 6;
Q is -OH, -NHC (= 0) R ₄₁ or -NHC (= 0) OR ₄₁ ;
R ₄₁ is (C ₁ -C ₆ ) alkyl.] 제 1항에 있어서,
하기 화학식 2 내지 4로 표시되는 신규한 옥사졸리디논 유도체, 이의 수화물, 이의 용매화물, 이의 이성질체 또는 이들의 약제학적으로 허용되는 염.
[화학식 2]

[화학식 3]

[화학식 4]

[상기 화학식 2 내지 4에서, R 및 Q 는 청구항 제1항에서의 정의와 동일하다.]The method of claim 1,
Novel oxazolidinone derivatives represented by the following Chemical Formulas 2 to 4, hydrates thereof, solvates thereof, isomers thereof, or pharmaceutically acceptable salts thereof.
(2)

(3)

[Chemical Formula 4]

[In Formulas 2 to 4, R and Q are the same as defined in claim 1.] 제 2항에 있어서,
하기 화학식 5 내지 10으로 표시되는 신규한 옥사졸리디논 유도체, 이의 수화물, 이의 용매화물, 이의 이성질체 또는 이들의 약제학적으로 허용되는 염.
[화학식 5]

[화학식 6]

[화학식 7]

[화학식 8]

[화학식 9]

[화학식 10]

[상기 화학식 5 내지 10에서 R은 청구항 제1항에서의 정의와 동일하다.]The method of claim 2,
A novel oxazolidinone derivative, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof represented by the following Chemical Formulas 5 to 10.
[Chemical Formula 5]

[Chemical Formula 6]

(7)

[Chemical Formula 8]

[Chemical Formula 9]

[Formula 10]

[In Formulas 5 to 10, R is the same as defined in claim 1] 제 3항에 있어서,
하기 화합물들로부터 선택되는 것을 특징으로 하는 옥사졸리디논 유도체, 이의 수화물, 이의 용매화물, 이의 이성질체 또는 이의 약제학적으로 허용되는 염.

The method of claim 3, wherein
An oxazolidinone derivative, a hydrate thereof, a solvate thereof, an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from the following compounds.

제 1항 내지 제 4항에서 선택되는 어느 한 항에 따른 신규한 옥사졸리디논 유도체, 이의 수화물, 이의 용매화물, 이의 이성질체 또는 이들의 약제학적으로 허용되는 염을 유효성분으로 하는 항생제용 의약 조성물.A pharmaceutical composition for antibiotics comprising the novel oxazolidinone derivative, hydrate thereof, solvate thereof, isomer thereof or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 as an active ingredient.