KR101849775B1 - N-aroylureas derivatives, preparation method thereof and pharmaceutical compositions for the prevention and treatment of cancer containing the same as an active ingredient - Google Patents

N-aroylureas derivatives, preparation method thereof and pharmaceutical compositions for the prevention and treatment of cancer containing the same as an active ingredient Download PDF

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KR101849775B1
KR101849775B1 KR1020170049253A KR20170049253A KR101849775B1 KR 101849775 B1 KR101849775 B1 KR 101849775B1 KR 1020170049253 A KR1020170049253 A KR 1020170049253A KR 20170049253 A KR20170049253 A KR 20170049253A KR 101849775 B1 KR101849775 B1 KR 101849775B1
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carboxamide
pivaloylindoline
ethyl
ethylcarbamoyl
aroylurea
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KR1020170049253A
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Korean (ko)
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김인수
김형식
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성균관대학교산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol

Abstract

The present invention relates to a novel N-aroylurea derivative having anticancer activity, a preparation method of the same, and a pharmaceutical composition comprising the same as an effective component. More specifically, the present invention relates to an N-aroylurea derivative formed as a product of consecutive reactions of C-H amidation and C-N bond formation using a rhodium (III) catalyst, a preparation method of the same, and a composition for preventing or treating cancer comprising the same as an effective component. The novel N-aroylurea derivative according to the present invention shows excellent anticancer activities in various human cancer cell lines, and thus can be beneficially used as a pharmaceutical composition for preventing and treating cancer. In addition, the preparation method of an N-aroylurea derivative using a rhodium (III) catalyst can be applied to and incorporated into a wide range of functional groups, and as a reaction with regioselectivity and chemoselectivity, may be extremely beneficial in the synthesis of new drugs or compounds having biological activities.

Description

N-아로일우레아 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 암 예방 및 치료용 조성물 {N-aroylureas derivatives, preparation method thereof and pharmaceutical compositions for the prevention and treatment of cancer containing the same as an active ingredient}[0001] The present invention relates to a N-aroylurea derivative, a method for preparing the same, and a composition for preventing and treating cancer, which comprises the same as an active ingredient.

본 발명은 항암 활성을 갖는 신규 N-아로일우레아 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 약학적 조성물 등에 관한 것이다.The present invention relates to a novel N-aroyl urea derivative having an anticancer activity, a process for producing the same, and a pharmaceutical composition containing the same as an active ingredient.

질소를 포함하는 헤테로 사이클은 광범위한 의약 응용 분야를 가진 천연 제품 및 의약품에서 발견되는 필수 구조 단위 중 하나이다. 특히, N-헤테로사이클이 연결된 N-아실우레아는 항염증제, 진통제, 구충제, 살충제 및 항균성과 생물학적 활성을 보이면서, 의약학 및 식물화학 분야에서 주목되고 있다. 예를 들어, N-아실우레아 그룹을 갖는 천연 인돌 유사체인 카버골린(carbergoline)은 뇌하수체 프로락틴 세포에 대하여 장시간 지속되는 강력한 억제 효과를 나타내는 것으로 알려져있다. 또한, N-아실우레아 잔기는 살충제 및 항암제의 핵심 구조로 확인되었다. 상기와 같은 독특한 구조적 특징과 광범위한 의약 용도로 인해 유기화학 연구 분야에서는 N-아로일우레아를 합성하는 효율적인 방법에 대한 연구가 활발히 일어나고 있다. N-아실 또는 N-아로일우레아의 제조를 위한 전통적인 접근법은 카르복실산 유도체와 카르보디이미드 사이의 커플링 반응에 의해 제조하는 것이며, 아민과 아실 이소시아네이트의 축합 반응 역시 N-아실우레아 화합물을 제조하는 방법으로 알려져 있다. 최근, N-아로일우레아 유도체의 형성을 위한 대안적인 프로토콜은 CO 또는 Mo(CO)8의 존재 하에 아릴할라이드를 갖는 우레아의 마이크로파 조사에 의한 Pd(Ⅱ)-촉매 카르보닐화를 통해 이루어지는 것도 알려져 있다.Nitrogen containing heterocycles are one of the essential structural units found in natural products and pharmaceuticals with a wide range of medicinal applications. In particular, N-acylurea linked with N-heterocycles is attracting attention in the fields of medicine and phytochemistry, showing anti-inflammatory, analgesic, insect repellent, pesticide and antibacterial properties and biological activity. For example, carbergoline, a natural indole analog having an N-acylurea group, is known to exhibit potent inhibitory effects on prolonged pituitary prolactin cells. In addition, N-acylurea residues have been identified as core structures for pesticides and anticancer agents. Due to their unique structural features and their wide range of medicinal applications, research into efficient methods for synthesizing N-aroyl urea has been actively conducted in organic chemistry research. A conventional approach for the preparation of N-acyl or N-aroyl urea is to prepare by coupling reaction between a carboxylic acid derivative and a carbodiimide, and the condensation reaction of an amine with an acylisocyanate is also used to prepare an N- . Recently, it has also been known that an alternative protocol for the formation of N-aroylurea derivatives is via Pd (II) -catalyzon carbonylation of urea having an aryl halide in the presence of CO or Mo (CO) 8 by microwave irradiation have.

알켄, 알킨, 알렌 등과 같은 다양한 불포화물과의 새로운 C-C 결합 형성에 대한 효율적인 접근법을 제공하기 때문에, 전이금속 촉매에 의한 C-H 관능기화에 대해서는 많은 연구가 이루어져 왔다. 또한 C(sp2)-H 결합을 불포화 C=O 및 C=N 결합에 전이금속 촉매 하에 직접적으로 첨가하는 분야에서는 최근 진전을 보였는데, 특히, 이소시아네이트의 극성 π- 결합에 C-H 결합을 직접 삽입하는 것은 합성적으로 유용한 아미드 잔기를 제공하는 것에서 상당히 유용하다. 예를 들면, 방향족 알디민과 이소시아네이트의 Re(I)-촉매에 의한 분자 사이의 반응으로 프탈이미딘 유도체를 얻을 수 있다는 것이 알려져 있고, N-아실안트라닐 아미드와 β-엔아민 아미드의 합성을 위해 이소시아네이트를 첨가하여 아릴 및 비닐 C-H 결합을 Rh(Ⅲ)-촉매에 의해 아미드화 반응을 하는 것도 알려져 있다(Y. Kuninobu, Y. Tokunaga, A. Kawata, K. Takai, J. Am. Chem. Soc. 2006, 128, 202). 또한, 페닐피리딘, N-아릴피라졸, 옥심 및 벤조산 유도체와 같은 다양한 지향성기가 이소시아네이트와 효율적으로 결합되어 Rh, Ru, Re 및 Co와 같은 촉매 작용 하에 상응하는 오르토-아미드화 반응 또는 탠덤 고리화 생성물을 제공한다. Many studies have been made on CH functionalization by transition metal catalysts, since they provide an efficient approach to the formation of new CC bonds with various unsaturations such as alkenes, alkynes, allenes, and the like. Recent advances have also been made in the field of directly adding C (sp 2 ) -H bonds to unsaturated C═O and C═N bonds under transition metal catalysts, in particular by directly inserting CH bonds into the polar π-bonds of isocyanates Is quite useful in providing synthetically useful amide residues. For example, it is known that a phthalimidine derivative can be obtained by reaction between an aromatic aldimine and an isocyanate Re (I) -catalyzed molecule, and the synthesis of N-acylanthranilamide and? -Enamine amide It is also known that an isocyanate is added to cause an amidation reaction of aryl and vinyl CH bonds with Rh (Ⅲ) -catalyst (Y. Kuninobu, Y. Tokunaga, A. Kawata, K. Takai, J. Am. Chem. Soc., 2006, 128, 202). In addition, various directing groups such as phenylpyridine, N-arylpyrazole, oxime and benzoic acid derivatives can be efficiently combined with isocyanate to give the corresponding ortho-amidation reaction or tandem cyclization product under catalysis such as Rh, Ru, Re and Co .

한편, 인돌린의 C7 관능화 지향성기 그룹은 많은 생물학적 활성 천연물 및 의약품에서 발견되는 다양한 구조적 모티프로 이용될 수 있음이 알려지면서, 상기 인돌린의 C7-관능화에 대한 수요가 증가하고 있다. 특히, C7-아미드화 인돌린의 촉매적 합성은 유용한 생물학적 특성의 발견에 의해 상당한 관심을 끌고 있다. 이와 관련하여 Ru(Ⅱ), Ir(Ⅲ) 및 Rh(Ⅲ) 촉매 하에서 유기 아자이드, 디아졸론 및 안트라닐을 아미드화를 위한 공급원으로 사용하는 경우도 알려져 있다. On the other hand, it is known that the C7 functionalizing group of indolin can be used as various structural motifs found in many biologically active natural products and medicines, and the demand for the C7-functionalization of the indolin is increasing. In particular, catalytic synthesis of C7-amidated indolines has attracted considerable interest due to the discovery of useful biological properties. In this connection it is also known to use organic azides, diazoles and anthranyls as sources for amidation under Ru (II), Ir (III) and Rh (III) catalysts.

아울러, 최근 본 발명자들은 아조벤젠과 인돌과 이소시아네이트의 Rh(Ⅲ)-촉매에 의한 구역-선택적(site-selective)인 C-H 아미드화 반응을 제시한 바 있다. 그러나, 이소시아네이트를 사용하여 N-아로일우레아를 형성한 내용은 전혀 제시된 바 없다.In addition, recently, the present inventors have proposed C-H amidation reaction of azobenzene and indole and isocyanate with Rh (Ⅲ) -catalyzed site-selective. However, the content of N-aroyl urea formed using isocyanate has not been proposed at all.

본 발명은 상기와 같은 종래 기술상의 필요성을 해결하기 위해 안출된 것으로서, 본 발명자들은 항암 활성을 갖는 신규 N-아로일우레아 유도체를 제조하고, 이를 처리함으로써, 암 세포 증식의 억제를 통해 암에 대한 예방 또는 치료 효과를 확인한바, 이에 기초하여 본 발명을 완성하게 되었다.Disclosure of the Invention The present invention has been conceived to solve the above-described problems in the prior art, and the present inventors have found that a novel N-aroyl urea derivative having anticancer activity is produced and treated, Prevention or treatment effect of the present invention, the present invention has been completed on the basis thereof.

이에, 본 발명의 목적은 항암 활성을 갖는 신규 N-아로일우레아 유도체 및 이의 약학적 허용 가능한 염을 제공하는 것이다.Accordingly, an object of the present invention is to provide novel N-aroyl urea derivatives having an anticancer activity and pharmaceutically acceptable salts thereof.

또한, 본 발명의 다른 목적은 항암 활성을 갖는 신규 N-아로일우레아 유도체의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a process for producing novel N-aroyl urea derivatives having anticancer activity.

또한, 본 발명의 또 다른 목적은 항암 활성을 갖는 신규 N-아로일우레아 유도체 및 이의 약학적 허용 가능한 염을 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물을 제공하는 것이다.It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating cancer, which comprises a novel N-arylaurea derivative having an anticancer activity and a pharmaceutically acceptable salt thereof as an active ingredient.

그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.

상기와 같은 본 발명의 목적을 달성하기 위하여, 본 발명은 화학식 1로 표시되는 N-아로일우레아 유도체, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염을 제공한다.In order to achieve the object of the present invention, the present invention provides a N-aroylurea derivative represented by the general formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof.

[화학식 1][Chemical Formula 1]

Figure 112017037435453-pat00001
Figure 112017037435453-pat00001

이 때, 상기 화학식 1에 있어서,In this case, in Formula 1,

상기 R1 은 수소, 할로겐, C1-C6 알킬, 또는 CO2Me이고;Wherein R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or CO 2 Me;

상기 R2 는 수소 또는 C1-C6 알킬이며;R 2 is hydrogen or C 1 -C 6 alkyl;

상기 R3 는 C1-C6 알킬 또는 C6-C20 아릴이고; 및R 3 is C 1 -C 6 alkyl or C 6 -C 20 aryl; And

상기 R4 는 부틸, 펜틸, 헥실, 옥틸, 벤질, 페네틸, 사이클로펜틸, 페닐, 4-메틸페닐, 4-플루오로페닐, 또는 4-클로로페닐일 수 있다.R 4 may be butyl, pentyl, hexyl, octyl, benzyl, phenethyl, cyclopentyl, phenyl, 4-methylphenyl, 4-fluorophenyl, or 4-chlorophenyl.

또한, 본 발명은 로듐 촉매 존재 하에서, 하기 화학식 2로 표시되는 화합물을 하기 화학식 3으로 표시되는 이소시아네이트와 반응시키는 단계를 포함하는, 상기 화학식 1로 표시되는 N-아로일우레아 유도체의 제조방법을 제공한다:The present invention also provides a process for producing N-aroyl urea derivatives represented by the above formula (1), which comprises reacting a compound represented by the following formula (2) with an isocyanate represented by the following formula do:

[화학식 2](2)

Figure 112017037435453-pat00002
Figure 112017037435453-pat00002

이 때, 상기 화학식 2에 있어서,In this case, in Formula 2,

상기 R1 은 수소, 할로겐, C1-C6 알킬, 또는 CO2Me이고;Wherein R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or CO 2 Me;

상기 R2 는 수소 또는 C1-C6 알킬이며;R 2 is hydrogen or C 1 -C 6 alkyl;

상기 R3 는 C1-C6 알킬 또는 C6-C20 아릴이다. Wherein R 3 is C 1 -C 6 alkyl or C 6 -C 20 aryl.

[화학식 3](3)

Figure 112017037435453-pat00003
Figure 112017037435453-pat00003

이 때, 상기 화학식 3에 있어서,In this case, in Formula 3,

상기 R4 는 부틸, 펜틸, 헥실, 옥틸, 벤질, 페네틸, 사이클로펜틸, 페닐, 4-메틸페닐, 4-플루오로페닐, 또는 4-클로로페닐일 수 있다.R 4 may be butyl, pentyl, hexyl, octyl, benzyl, phenethyl, cyclopentyl, phenyl, 4-methylphenyl, 4-fluorophenyl, or 4-chlorophenyl.

본 발명의 다른 구현예로서, 상기 로듐 촉매는 C1-C5 알킬로 치환되거나, 또는 비치환된 사이클로펜타다이엔일(cyclopentadienyl) 로듐 (Ⅲ) 복합체 촉매일 수 있고, 보다 바람직하게는 펜타메틸사이클로펜타다이엔일로듐(Ⅲ) 클로라이드 이량체 (Pentamethylcyclopentadienylrhodium(Ⅲ) chloride dimer; [RhCp*Cl2]2) 촉매일 수 있다.In another embodiment of the present invention, the rhodium catalyst may be cyclopentadienyl rhodium (III) complex catalyst substituted with C 1 -C 5 alkyl or more preferably pentamethyl (RhCp * Cl 2 ) 2 ) catalyst. The catalyst may be a catalyst such as tetramethylcyclopentadienylrhodium (III) chloride dimer.

본 발명의 또 다른 구현예로서, 상기 반응은 첨가제를 더 포함하여 수행되는 것일 수 있다.In another embodiment of the present invention, the reaction may be carried out further comprising an additive.

본 발명의 또 다른 구현예로서, 상기 첨가제는 실버트리플루오로메틸설포닐이미드(silver tri(fluoromethylsulfonyl)imide, AgNTf2), 구리아세트산(Copper(Ⅱ) acetate; Cu(OAc)2) 또는 이들의 혼합물일 수 있다.As still another embodiment, the additive is methyl sulfonyl imide as silver trifluoroacetate (silver tri (fluoromethylsulfonyl) imide, AgNTf 2), copper acetate (Copper (Ⅱ) acetate; Cu (OAc) 2) , or their &Lt; / RTI &gt;

본 발명의 또 다른 구현예로서, 상기 제조방법은 다이클로로에테인(Dichloroethene; DCE), 또는 톨루엔(toluene) 용매에서 이루어질 수 있다.In another embodiment of the present invention, the process may be carried out in a dichloroethane (DCE) or toluene solvent.

본 발명의 또다른 구현예로서, 상기 제조방법은, 화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물의 반응 후, 하기 화학식 4로 표시되는 N-에틸-1-피발로일인돌린-7-카르복사마이드 화합물을 추가 생성하며, 상기 화학식 4로 표시되는 화합물은 화학식 3으로 표시되는 화합물과 반응하여 화학식 1로 표시되는 N-아로일우레아 유도체를 형성하는 것일 수 있다.In still another embodiment of the present invention, the above production method is characterized in that, after the reaction between the compound represented by the general formula (2) and the compound represented by the general formula (3), N-ethyl-1-pivaloylindoline- The compound represented by Formula 4 may be reacted with the compound represented by Formula 3 to form the N-aroyl urea derivative represented by Formula 1. Alternatively,

본 발명은 상기 화학식 1로 표시되는 N-아로일우레아 유도체, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating cancer, which comprises an N-araoyl urea derivative represented by Formula 1, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

본 발명의 일 구현예로서, 상기 암은 전립선암 또는 유방암일 수 있다.In one embodiment of the present invention, the cancer may be prostate cancer or breast cancer.

나아가, 본 발명은 상기 약학적 조성물을 개체에 투여하는 단계를 포함하는 암 예방 또는 치료 방법을 제공한다.Further, the present invention provides a method for preventing or treating cancer, comprising the step of administering the pharmaceutical composition to a subject.

뿐만 아니라, 본 발명은 상기 약학적 조성물의 암 예방 또는 치료 용도를 제공한다.In addition, the present invention provides the use of the pharmaceutical composition for the prevention or treatment of cancer.

본 발명에 따른 신규 N-아로일우레아 유도체는 다양한 인간 암 세포에 대해 우수한 항암 활성을 나타내는 바, 암 예방 및 치료를 위한 약학 조성물로 유용하게 사용될 수 있을 것으로 기대된다. The novel N-aroyl urea derivatives according to the present invention exhibit excellent anticancer activity against various human cancer cells and are expected to be useful as pharmaceutical compositions for cancer prevention and treatment.

또한, 본 발명에 따른 제조방법은, 로듐 촉매 하에서 두 번의 연속적인 이소시아네이트 결합반응을 통해 N-아로일우레아를 한번의 공정에 의해 합성하는 것으로, 탄소-수소 결합의 분해를 통해 인돌린 7번 위치에 N-아로일우레아가 도입된 화합물을 최초로 합성한 것에 해당한다. 이는 종래 제조방법이 다양한 합성방법을 통해 아마이드 화합물을 합성하고, 이후 이소시아네이트와의 결합을 통해 합성하는 다단계의 합성공정이 필요하며, 아마이드 화합물과 이소시아네이트와의 결합반응에서 과량의 염기가 필요했던 종래 기술상의 문제점을 극복한 것이다.In addition, the production process according to the present invention is characterized in that N-aroyl urea is synthesized by a single step through two successive isocyanate-bonding reactions under a rhodium catalyst, and the decomposition of carbon- Which is the first synthesis of a compound into which N-aroylurea is introduced. This is because the conventional production method requires a multi-step synthesis process in which an amide compound is synthesized through various synthetic methods and then synthesized through bonding with isocyanate. In the prior art method in which an excess amount of base is needed in the coupling reaction of an amide compound and isocyanate Which has been overcome.

이처럼 본 발명의 로듐 (Ⅲ) 촉매를 이용한 N-아로일우레아 유도체 제조방법은 광범위한 작용기에 적용 및 도입 가능하며, 위치선택성 및 화학선택성을 지닌 반응으로서, 새로운 의약품이나 생물학적 활성을 갖는 화합물의 합성에 있어 매우 유용할 것이다.As described above, the process for preparing N-aroyl urea derivatives using the rhodium (III) catalyst of the present invention can be applied and introduced into a wide range of functional groups, and is a reaction having positional selectivity and chemical selectivity. It will be very useful.

도 1은 본 발명의 로듐 (Ⅲ) 촉매를 이용한 N-아로일우레아 유도체의 제조방법(this work)과 종래 제조방법(previous work)을 나타낸 것이다.
도 2는 다양한 인돌린 화합물을 이용하여, 본 발명의 C-H 아미드화 및 연이은 C-N 결합 형성 반응 (C-H amidation 및 C-N bond formation reaction) 반응을 수행한 결과로 합성된 N-아로일우레아 유도체 및 수율을 나타낸 것이다.
도 3은 다양한 이소시아네이트 화합물을 이용하여, 본 발명의 C-H 아미드화 및 연이은 C-N 결합 형성 반응 (C-H amidation 및 C-N bond formation reaction) 반응을 수행한 결과로 합성된 N-아로일우레아 유도체 및 수율을 나타낸 것이다.
도 4는 본 발명에서 합성한 N-아로일우레아 유도체 3g(5-클로로-N-에틸-N-(에틸카르바모일)-1-피발로일인돌린-7-카르복사마이드)의 X-선 결정화 분석을 통해 분석한 구조를 나타낸 것이다.
도 5는 본 발명의 C-H 아미드화 및 연이은 C-N 결합 형성 반응을 통한 N-아로일우레아 형성 반응의 예상 메커니즘을 나타낸 것이다.1 shows a process for producing N-aroyl urea derivatives using the rhodium (III) catalyst of the present invention and a conventional process.
2 shows the N-arylaurea derivatives synthesized as a result of performing the CH amidation and the subsequent CN bond formation reaction (CH amidation and CN bond formation reaction) of the present invention using various indoline compounds and the yield will be.
FIG. 3 shows N-aroyl urea derivatives and yields obtained by performing CH-amidation and subsequent CN amidation and CN bond formation reaction according to the present invention using various isocyanate compounds .
4 shows the X-ray diffraction patterns of 3 g of 5-chloro-N-ethyl-N- (ethylcarbamoyl) -1-pivaloylindoline-7-carboxamide synthesized in the present invention The structure analyzed by crystallization analysis is shown.
Figure 5 shows the anticipated mechanism of the N-aroyl urea formation reaction through the CH amidation and subsequent CN bond formation reaction of the present invention.

본 발명은 항암 활성을 갖는 신규 N-아로일우레아 유도체, 이의 이성질체, 이의 약학적 허용 가능한 염 및 이를 유효성분으로 포함하는 암 예방 또는 치료용 조성물을 제공한다. 또한, 본 발명에 따른 화합물은 암 세포의 증식을 억제하여 암에 대한 예방 또는 치료 효과를 나타낸바, 암의 예방 또는 치료에 유용하게 활용할 수 있을 것이다.The present invention provides a novel N-aroyl urea derivative having an anticancer activity, an isomer thereof, a pharmaceutically acceptable salt thereof and a composition for preventing or treating cancer comprising the same as an active ingredient. In addition, the compound according to the present invention inhibits the proliferation of cancer cells and has a prophylactic or therapeutic effect on cancer, and thus can be usefully used for prevention or treatment of cancer.

이하, 본 발명에 대해 상세히 설명한다.Hereinafter, the present invention will be described in detail.

본 발명은 화학식 1로 표시되는 N-아로일우레아 유도체, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염을 제공한다.The present invention provides a N-aroylurea derivative represented by the general formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof.

[화학식 1][Chemical Formula 1]

Figure 112017037435453-pat00004
Figure 112017037435453-pat00004

이 때, 상기 화학식 1에 있어서,In this case, in Formula 1,

상기 R1 은 수소, 할로겐, C1-C6 알킬, 또는 CO2Me이고;Wherein R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or CO 2 Me;

상기 R2 는 수소 또는 C1-C6 알킬이며;R 2 is hydrogen or C 1 -C 6 alkyl;

상기 R3 는 C1-C6 알킬 또는 C6-C20 아릴이고; R 3 is C 1 -C 6 alkyl or C 6 -C 20 aryl;

상기 R4 는 부틸, 펜틸, 헥실, 옥틸, 벤질, 페네틸, 사이클로펜틸, 페닐, 4-메틸페닐, 4-플루오로페닐, 또는 4-클로로페닐일 수 있다.R 4 may be butyl, pentyl, hexyl, octyl, benzyl, phenethyl, cyclopentyl, phenyl, 4-methylphenyl, 4-fluorophenyl, or 4-chlorophenyl.

더욱 바람직하게는, 상기 화학식 1에 있어서, 상기 R1 은 수소, 메틸, 클로로, 브로모, 또는 CO2Me이고, 상기 R2 는 수소, 또는 메틸이며, 상기 R3 는 메틸, 페닐, 또는 터트-부틸일 수 있다.More preferably, R 1 is hydrogen, methyl, chloro, bromo or CO 2 Me, R 2 is hydrogen or methyl, R 3 is methyl, phenyl or tert- Butyl.

다음은 본 발명에 따른 화합물들을 제조하는 여러 가지 치환기의 정의를 설명한다.The following describes the definitions of the various substituents for preparing the compounds according to the invention.

본 발명에서 사용된 용어 "C1-C6 알킬"은 탄소원자수 1 내지 10의 1가 알킬기를 의미한다. 이 용어는 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸, tert-부틸, n-헥실 등과 같은 기능기를 예로 들 수 있다.The term "C 1 -C 6 alkyl" as used herein means a monovalent alkyl group of 1 to 10 carbon atoms. The term is exemplified by functional groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-hexyl and the like.

본 발명에서 사용된 용어 "C6-C20 아릴"은 단일링(예를 들면 페닐) 또는 복수의 축합링(예를 들면 나프틸)을 갖는 탄소원자수 6 내지 20의 불포화 방향족 고리화합물을 의미한다. 아릴은 페닐, 나프틸 등을 포함한다.The term "C 6 -C 20 aryl" as used herein refers to an unsaturated aromatic ring compound having from 6 to 20 carbon atoms and having a single ring (eg, phenyl) or multiple condensed rings (eg, naphthyl) . Aryl includes phenyl, naphthyl, and the like.

본 발명에 기재된 알킬, 및 그 외 알킬부분을 포함하는 치환체는 직쇄 또는 분쇄 형태를 모두 포함한다.The alkyls described in the present invention, as well as the substituents comprising other alkyl moieties, include both straight chain and branched forms.

본 발명에 따른 화학식 1로 표시되는 N-아로일우레아 유도체의 바람직한 구현 예는 하기와 같다:Preferred embodiments of the N-aroyl urea derivative represented by the formula (1) according to the present invention are as follows:

N-에틸-N-에틸카르바모일-1-피발로일인돌린-7-카르복사마이드(N-Ethyl-N-(ethylcarbamoyl)-1-pivaloylindoline-7-carboxamide) (3a);N-Ethyl-N-ethylcarbamoyl-1-pivaloyl-7-carboxamide (3a);

1-벤조일-N-에틸-N-(에틸카르바모일)인돌린-7-카르복사마이드(1-Benzoyl-N-ethyl-N-(ethylcarbamoyl)indoline-7-carboxamide) (3c);1-Benzoyl-N-ethyl-N- (ethylcarbamoyl) indolin-7-carboxamide (3c);

N-에틸-N-(에틸카르바모일)-4-메틸-1-피발로일인돌린-7-카르복사마이드(N-Ethyl-N-(ethylcarbamoyl)-4-methyl-1-pivaloylindoline-7-carboxamide) (3e);N-ethyl-N- (ethylcarbamoyl) -4-methyl-1-pivaloyl-7-carboxamide carboxamide) (3e);

N-에틸-N-(에틸카르바모일)-5-메틸-1-피발로일인돌린-7-카르복사마이드 (N-Ethyl-N-(ethylcarbamoyl)-5-methyl-1-pivaloylindoline-7-carboxamide) (3f);N-ethyl-N- (ethylcarbamoyl) -5-methyl-1-pivaloylindoline-7- carboxamide carboxamide) (3f);

5-클로로-N-에틸-N-(에틸카르바모일)-1-피발로일인돌린-7-카르복사마이드 (5-Chloro-N-ethyl-N-(ethylcarbamoyl)-1-pivaloylindoline-7-carboxamide) (3g);5-Chloro-N-ethyl-N- (ethylcarbamoyl) -1-pivaloylindoline-7- carboxamide) (3g);

5-브로모-N-에틸-N-(에틸카르바모일)-1-피발로일인돌린-7-카르복사마이드 (5-Bromo-N-ethyl-N-(ethylcarbamoyl)-1-pivaloylindoline-7-carboxamide) (3h);N-ethyl-N- (ethylcarbamoyl) -1-pivaloylindoline-7-carboxamide -carboxamide) (3h);

메틸7-(에틸(에틸카르바모일)카르바모일)-1-피발로일인돌린-5-카르복실레이트 (Methyl 7-(ethyl(ethylcarbamoyl)carbamoyl)-1-pivaloylindoline-5-carboxylate) (3i);(Ethyl (ethylcarbamoyl) carbamoyl) -1-pivaloylindoline-5-carboxylate (3 &lt;);

N-에틸-N-(에틸카르바모일)-6-메틸-1-피발로일인돌린-7-카르복사마이드 (N-Ethyl-N-(ethylcarbamoyl)-6-methyl-1-pivaloylindoline-7-carboxamide) (3j);N-ethyl-N- (ethylcarbamoyl) -6-methyl-1-pivaloyl-7-carboxamide carboxamide) (3j);

6-클로로-N-에틸-N-(에틸카르바모일)-1-피발로일인돌린-7-카르복사마이드 (6-Chloro-N-ethyl-N-(ethylcarbamoyl)-1-pivaloylindoline-7-carboxamide) (3k);(6-Chloro-N-ethyl-N- (ethylcarbamoyl) -1-pivaloylindoline-7-carboxamide carboxamide (3k);

N-에틸-N-(에틸카르바모일)-2-메틸-1-피발로일인돌린-7-카르복사마이드 (N-Ethyl-N-(ethylcarbamoyl)-2-methyl-1-pivaloylindoline-7-carboxamide) (3l);(Ethylcarbamoyl) -2-methyl-1-pivaloylindoline-7-carboxamide (N-ethyl-N-ethylcarbamoyl) carboxamide) (31);

5-클로로-N-에틸-N-(에틸카르바모일)-2-메틸-1-피발로일인돌린-7-카르복사마이드 (5-Chloro-N-ethyl-N-(ethylcarbamoyl)-2-methyl-1-pivaloylindoline-7-carboxamide) (3m);(5-Chloro-N-ethyl-N- (ethylcarbamoyl) -2-methyl-1-pivaloyl) methyl-1-pivaloylindoline-7-carboxamide) (3m);

N-에틸-N-(에틸카르바모일)-3-메틸-1-피발로일인돌린-7-카르복사마이드 (N-Ethyl-N-(ethylcarbamoyl)-3-methyl-1-pivaloylindoline-7-carboxamide) (3n);(Ethylcarbamoyl) -3-methyl-1-pivaloylindoline-7-carboxamide (N-ethyl-N-ethylcarbamoyl) carboxamide) (3n);

N-부틸-N-(부틸카르바모일)-1-피발로일인돌린-7-카르복사마이드 (N-Butyl-N-(butylcarbamoyl)-1-pivaloylindoline-7-carboxamide) (4b);N-butyl-N- (butylcarbamoyl) -1-pivaloyl-7-carboxamide (4b);

N-펜틸-N-(펜틸카르바모일)-1-피발로일인돌린-7-카르복사마이드 (N-Pentyl-N-(pentylcarbamoyl)-1-pivaloylindoline-7-carboxamide) (4c);N-Pentyl-N- (pentylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4c);

N-헥실-N-(헥실카르바모일)-1-피발로일인돌린-7-카르복사마이드 (N-Hexyl-N-(hexylcarbamoyl)-1-pivaloylindoline-7-carboxamide) (4d);N-hexyl-N- (hexylcarbamoyl) -1-pivaloyl-N- (hexylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4d);

N-옥틸-N-(옥틸카르바모일)-1-피발로일인돌린-7-카르복사마이드 (N-Octyl-N-(octylcarbamoyl)-1-pivaloylindoline-7-carboxamide) (4e);N-octyl-N- (octylcarbamoyl) -1-pivaloyl-N- (octylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4e);

N-페네틸-N-(패내틸카바모일)-1-피발로일인돌린-7-카르복사마이드 (N-Phenethyl-N-(phenethylcarbamoyl)-1-pivaloylindoline-7-carboxamide) (4f);N-phenethyl-N- (paratinylcarbamoyl) -1-pivaloyl-N- (phenethylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4f);

N-벤질-N-(벤질카바모일)-1-피발로일인돌린-7-카르복사마이드 (N-Benzyl-N-(benzylcarbamoyl)-1-pivaloylindoline-7-carboxamide) (4g);N-Benzyl-N- (benzylcarbamoyl) -1-pivaloyl-7-carboxamide (4 g);

N-사이클로펜틸-N-(사이클로펜틸카르바모일)-1-피발로일인돌린-7-카르복사마이드 (N-Cyclopentyl-N-(cyclopentylcarbamoyl)-1-pivaloylindoline-7-carboxamide) (4h);N-cyclopentyl-N- (cyclopentylcarbamoyl) -1-pivaloyl-N- (cyclopentylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4h);

N-페닐-N-(페닐카바모일)-1-피발로일인돌린-7-카르복사마이드 (N-Phenyl-N-(phenylcarbamoyl)-1-pivaloylindoline-7-carboxamide) (4i);N-Phenyl-N- (phenylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4i);

1-피발로일-N-(피-톨일)-N-(피-톨일카바모일)인돌린-7-카르복사마이드 (1-Pivaloyl-N-(p-tolyl)-N-(p-tolylcarbamoyl)indoline-7-carboxamide) (4j);1-pivaloyl-N- (p-tolyl) -N- (p-tolylcarbamoyl) indoline-7-carboxamide (1-Pivalyl- ) indoline-7-carboxamide) (4j);

N-(4-플루오로페닐)-N-((4-플루오로페닐)카바모일)-1-피발로일인돌린-7-카르복사마이드 (N-(4-Fluorophenyl)-N-((4-fluorophenyl)carbamoyl)-1-pivaloylindoline-7-carboxamide) (4k); 및N- (4-Fluorophenyl) -N - ((4-fluorophenyl) carbamoyl) -1-pivaloylindoline- -fluorophenyl) carbamoyl) -1-pivaloylindoline-7-carboxamide) (4k); And

N-(4-클로로페닐)-N-((4-클로로페닐)카바모일)-1-피발로일인돌린-7-카르복사마이드 (N-(4-Chlorophenyl)-N-((4-chlorophenyl)carbamoyl)-1-pivaloylindoline-7-carboxamide) (4l).N- (4-chlorophenyl) -N - ((4-chlorophenyl) carbamoyl) -1-pivaloylindoline- ) carbamoyl) -1-pivaloylindoline-7-carboxamide) (4l).

본 발명의 상기 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다.The compound of the present invention can be used in the form of a pharmaceutically acceptable salt. As the salt, acid addition salt formed by a pharmaceutically acceptable free acid is useful.

본 발명에서 사용되는 용어 "염"은 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함한다.As used herein, the term "salt" is useful as an acid addition salt formed by a pharmaceutically acceptable free acid. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.

본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 상기 화합물을 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다. 또한 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시키거나 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다.The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the above compound in an excess amount of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile . It may also be prepared by evaporating a solvent or excess acid in this mixture and then drying or by suction filtration of the precipitated salt.

또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수도 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면, 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염 (예, 질산은)과 반응시켜 얻는다.In addition, the base may be used to make a pharmaceutically acceptable metal salt. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

또한, 본 발명의 화합물은 약학적으로 허용되는 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 이성질체, 수화물 및 용매화물을 모두 포함한다.In addition, the compounds of the present invention include not only pharmaceutically acceptable salts, but also all salts, isomers, hydrates and solvates which can be prepared by conventional methods.

또한, 본 발명의 다른 양태로서, 본 발명은 로듐 촉매 존재 하에서, 하기 화학식 2로 표시되는 화합물을 화학식 3으로 표시되는 이소시아네이트와 반응시키는 단계를 포함하는, 상기 화학식 1로 표시되는 N-아로일우레아 유도체의 제조방법을 제공한다.In another aspect of the present invention, the present invention provides a process for producing N-aroyl urea represented by Formula 1, comprising reacting a compound represented by Formula 2 below with an isocyanate represented by Formula 3 in the presence of a rhodium catalyst A method for producing a derivative is provided.

[화학식 2](2)

Figure 112017037435453-pat00005
Figure 112017037435453-pat00005

[화학식 3](3)

Figure 112017037435453-pat00006
Figure 112017037435453-pat00006

이 때, 상기 화학식 2 및 3에서 R1, R2, R3, 및 R4는 상기 화학식 1에서 정의한 바와 같다.Herein, R 1 , R 2 , R 3 , and R 4 in the general formulas (2) and (3) are as defined in the above formula (1).

본 발명의 N-아로일우레아 유도체 제조방법은 상온 조건에서 로듐 촉매 하에서 두 번의 연속적인 이소시아네이트 결합반응을 통해 N-아로일우레아를 한번의 공정에 의해 합성하는 것으로, 탄소-수소 결합의 분해를 통해 인돌린 7번 위치에 N-아로일우레아가 도입된 화합물을 최초로 합성한 것이다. 이는 종래 제조방법이 다양한 합성방법을 통해 아마이드 화합물을 합성하고, 이후 이소시아네이트와의 결합을 통해 합성하는 다단계의 합성공정이 필요하며, 아마이드 화합물과 이소시아네이트와의 결합반응에서 과량의 염기가 필요했던 문제점을 극복한 것이다.The process for producing N-aroyl urea derivatives of the present invention is a process for synthesizing N-aroyl urea in a single step through two successive isocyanate-bonding reactions under a rhodium catalyst at room temperature, A compound in which N-aroylurea was introduced at the position 7 of indoline was first synthesized. This is because the conventional production method requires a multistage synthesis process in which an amide compound is synthesized through various synthesis methods and then synthesized through coupling with isocyanate and a problem that an excessive amount of base is needed in the coupling reaction of an amide compound and isocyanate It is overcome.

본 발명의 상기 제조방법은 상기 반응식 1에 의해 제조되는 것이다.The above-mentioned production method of the present invention is produced by the above-mentioned Reaction Scheme 1.

[반응식 1][Reaction Scheme 1]

Figure 112017037435453-pat00007
Figure 112017037435453-pat00007

본 발명의 로듐 촉매는 C1-C5 알킬로 치환되거나, 또는 비치환된 사이클로펜타다이엔일(cyclopentadienyl) 로듐 (Ⅲ) 복합체 촉매일 수 있고, 보다 바람직하게는 펜타메틸사이클로펜타다이엔일로듐(Ⅲ) 클로라이드 이량체 (Pentamethylcyclopentadienylrhodium(Ⅲ) chloride dimer; [RhCp*Cl2]2) 촉매일 수 있으며, 상기 화학식 2 화합물 1몰에 대해 1 내지 4 몰%, 바람직하게는 2 내지 3 몰로 사용될 수 있다.The rhodium catalyst of the present invention may be a C 1 -C 5 alkyl substituted or unsubstituted cyclopentadienyl rhodium (III) complex catalyst, more preferably pentamethylcyclopentadienylhodium (RhCp * Cl 2 ) 2 ) catalyst, and may be used in an amount of 1 to 4 mol%, preferably 2 to 3 mol, based on 1 mol of the compound of the formula (II) have.

본 발명의 제조방법에서, 상기 반응은 첨가제를 더 포함하여 수행되는 것이 바람직하다. 상기 첨가제는 실버트리플루오로메틸설포닐이미드(silver tri(fluoromethylsulfonyl)imide, AgNTf2), 구리아세트산(Copper(Ⅱ) acetate; Cu(OAc)2) 또는 이들의 혼합물인 것이 수득율 면에서 바람직하나, 이에 제한되는 것은 아니다.In the production process of the present invention, it is preferable that the reaction is carried out by further comprising an additive. The additive is preferably silver tri (fluoromethylsulfonyl) imide, AgNTf 2 , copper acetate (Cu (OAc) 2 ), or a mixture thereof, , But is not limited thereto.

본 발명의 일 실시예에 따른 반응은 유기용매 하에서 이루어 질 수 있으며, 상기 반응물질을 용해할 수 있는 것이라면 유기용매에 제한을 둘 필요는 없다. 상기 유기용매의 일례로는 다이클로로에테인(Dichloroethene; DCE), 테트라하이드로퓨란(tetrahydrofuran; THF), 아세토나이트릴(acetonitrile; MeCN), 톨루엔(toluene) 및 이들의 혼합물로 이루어진 군에서 선택되며 반응물의 용해성 및 제거의 용이성 또한 반응 효율면을 고려할 때 다이클로로에테인(DCE) 또는 톨루엔을 사용하는 것이 바람직하며, 더욱 바람직하게는 DCE를 사용할 수 있다.The reaction according to an embodiment of the present invention can be carried out in an organic solvent, and it is not necessary to limit the organic solvent as long as it can dissolve the reactant. Examples of the organic solvent include those selected from the group consisting of dichloroethane (DCE), tetrahydrofuran (THF), acetonitrile (MeCN), toluene, and mixtures thereof, Solubility and Ease of Removal It is preferable to use dichloroethane (DCE) or toluene, more preferably DCE, in view of the reaction efficiency.

본 발명에서, 상기 화학식 2로 표시되는 화합물과 상기 화학식 3으로 표시되는 화합물은 반응하여, 상기 화학식 1로 표시되는 화합물 외에, 하기 화학식 4로 표시되는 N-에틸-1-피발로일인돌린-7-카르복사마이드 화합물을 추가 생성한다. In the present invention, the compound represented by Chemical Formula 2 and the compound represented by Chemical Formula 3 may be reacted to produce a compound represented by Chemical Formula 4, which is represented by Chemical Formula 4, N-ethyl-1-pivaloylindoline-7 - carboxamide compound. &Lt; / RTI &gt;

하기 화학식 4로 표시되는 화합물은, 상기 화학식 3으로 표시되는 화합물과 반응하여 화학식 1로 표시되는 N-아로일우레아 유도체를 형성할 수 있다.The compound represented by the following general formula (4) can be reacted with the compound represented by the general formula (3) to form the N-aroyl urea derivative represented by the general formula (1).

[화학식 4][Chemical Formula 4]

Figure 112017037435453-pat00008
Figure 112017037435453-pat00008

본 발명의 일 실시예에서는 상기 화학식 1로 표시되는 N-아로일우레아 유도체를 제조한 후, NMR 또는 Mass 스펙트럼으로 구조를 분석 및 확인하였다(실시예 1 내지 8 참조).In one embodiment of the present invention, the N-aroyl urea derivative represented by Formula 1 was prepared, and its structure was analyzed and confirmed by NMR or Mass spectroscopy (see Examples 1 to 8).

또한, 본 발명의 다른 양태로서, 본 발명은 상기 화학식 1로 표시되는 N-아로일우레아 유도체, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 암 예방, 개선 또는 치료용 약학적 조성물을 제공한다.In another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing, ameliorating, or treating cancer comprising an N-araoyl urea derivative represented by the above formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient Lt; / RTI &gt;

본 발명에서 사용되는 용어, "예방"이란 본 발명에 따른 약학적 조성물의 투여에 의해 암을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.As used herein, the term "prophylactic " means any act that inhibits cancer or delays the onset of cancer by administration of the pharmaceutical composition according to the present invention.

본 발명에서 사용되는 용어, "치료"란 본 발명에 따른 약학적 조성물의 투여에 의해 암에 대한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.As used herein, the term "treatment" refers to any action that improves or alters the symptoms of cancer by the administration of the pharmaceutical composition according to the present invention.

본 발명의 조성물에 의한 예방, 치료 대상 질병인 "암"은 정상인 조직세포가 어떤 원인으로 무제한 증식하여 그 생체의 생활현상이나 주위의 조직상태 등에 관계없이 급속한 발육을 계속하는 질환으로 구분되며, 본 발명에서의 암은 바람직하게는 전립선암, 또는 유방암일 수 있으나, 상기 종류에 제한되지 않는다."Cancer" which is a preventive and therapeutic disease caused by the composition of the present invention is classified into diseases in which normal tissue cells proliferate unlimitedly for some reason and continue rapid development regardless of the life phenomenon of the living body or the surrounding tissue state. The cancer in the invention may preferably be prostate cancer, or breast cancer, but is not limited to this kind.

본 발명의 일 실시예에서는 본 발명의 제조방법에 따라 합성된 N-아로일우레아 유도체를 이용하여 다양한 인간 암 세포에 대한 항암 활성을 평가하였으며(실시예 9 참조), 본 발명의 화합물 4d 및 4e는 공지된 항암제인 시스플라틴보다 강력한 항암 활성을 나타낸 것을 확인하였다.In one embodiment of the present invention, the anticancer activity against various human cancer cells was evaluated using the N-arylyl urea derivatives synthesized according to the production method of the present invention (see Example 9), and the compounds 4d and 4e Showed stronger anticancer activity than the known anticancer drug cisplatin.

따라서 본 발명에 따른 상기 화학식 1로 표시되는 N-아로일우레아 유도체, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염은 이를 유효성분으로 포함하는 암의 예방, 개선 또는 치료용 약학적 조성물로 유용하게 사용될 수 있다.Accordingly, the N-aroyl urea derivative represented by the formula (I) according to the present invention, an isomer thereof or a pharmaceutically acceptable salt thereof may be useful as a pharmaceutical composition for preventing, improving or treating cancer, .

본 발명에 따른 약학적 조성물은 유효성분 이외에 약제학적으로 허용되는 담체를 포함할 수 있다. 이때, 약제학적으로 허용되는 담체는 제제 시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세 결정성셀룰로스, 폴리비닐피로리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필 히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일등을 포함하나, 이에 한정되는 것은 아니다. 또한, 상기성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다.The pharmaceutical composition according to the present invention may contain, in addition to the active ingredient, a pharmaceutically acceptable carrier. Herein, pharmaceutically acceptable carriers are those conventionally used at the time of formulation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose But are not limited to, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Further, in addition to the above components, a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like may be further included.

본 발명의 약제학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다.The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may vary depending on the condition and weight of the patient, The mode of administration, the route of administration, and the time, but may be appropriately selected by those skilled in the art.

본 발명의 약제학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명에 다른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the type of disease, severity, The sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, sequentially or concurrently with conventional therapeutic agents, and may be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.

구체적으로 본 발명의 약제학적 조성물의 유효량은 환자의 연령, 성별, 상태, 체중, 체내에 활성 성분의 흡수도, 불활성율 및 배설속도, 질병종류, 병용되는 약물에 따라 달라질 수 있으며, 일반적으로는 체중 1 kg 당 0.001 내지 150 ㎎, 바람직하게는 0.01 내지 100 ㎎을 매일 또는 격일 투여하거나, 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나 투여 경로, 비만의 중증도, 성별, 체중, 연령 등에 따라서 증감 될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, body weight, absorbency, inactivation rate and excretion rate of the active ingredient in the body, type of disease, 0.001 to 150 mg, preferably 0.01 to 100 mg, per kg of body weight may be administered daily or every other day, or one to three divided doses per day. However, the dosage may be varied depending on the route of administration, the severity of obesity, sex, weight, age, etc. Therefore, the dosage is not limited to the scope of the present invention by any means.

본 발명의 다른 양태로서, 본 발명은 상기 약학적 조성물을 개체에 투여하는 단계를 포함하는 암 치료 방법을 제공한다. 본 발명에서 "개체"란 질병의 치료를 필요로 하는 대상을 의미하고, 보다 구체적으로는, 인간 또는 비-인간인 영장류, 생쥐(mouse), 개, 고양이, 말 및 소 등의 포유류를 의미한다.In another aspect of the present invention, the present invention provides a method of treating cancer comprising administering the pharmaceutical composition to a subject. The term " individual "as used herein refers to a subject in need of treatment for a disease, and more specifically refers to a mammal such as a human or non-human primate, mouse, dog, cat, horse and cattle .

도 1에 나타낸 바와 같이, 본 발명의 로듐 (Ⅲ) 촉매를 이용한 반응 결과로 생성된 신규 N-아로일우레아 유도체는 다양한 인간 암 세포에 대해 우수한 항암 활성을 나타낸바, 암 예방 및 치료를 위한 약학 조성물로 유용하게 사용될 수 있을 것으로 기대된다. 또한, 본 발명의 로듐 (Ⅲ) 촉매를 이용한 N-아로일우레아 유도체 제조방법은 광범위한 작용기에 적용 및 도입 가능하며, 위치선택성 및 화학선택성을 지닌 반응으로서, 새로운 의약품이나 생물학적 활성을 갖는 화합물의 합성에 있어 매우 유용할 것이다.As shown in FIG. 1, the novel N-aroyl urea derivatives produced as a result of the reaction using the rhodium (III) catalyst of the present invention showed excellent anticancer activity against various human cancer cells, It is expected that it can be usefully used as a composition. In addition, the process for preparing N-aroyl urea derivatives using the rhodium (III) catalyst of the present invention can be applied and introduced into a wide range of functional groups, and is a reaction having positional selectivity and chemical selectivity. As a reaction for synthesizing a new drug or a compound having biological activity It will be very useful for.

이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.

[[ 실시예Example ]]

본 발명의 실시예에서는 별도로 언급하지 않는 한, 시판되는 시약을 추가 정제 없이 사용하였다. 밀폐된 튜브 (13 × 100 mm2)는 Fischer Scientific에서 구입하였고, 오븐에서 밤새 건조시킨 다음 사용 전에 실온에서 냉각시켜 사용하였고, 박층 크로마토 그래피는 Kieselgel 60F254 (Merck)로 코팅된 플레이트를 사용하여 수행하였으며, 플래시 칼럼 크로마토 그래피의 경우, E. Merck Kieselgel 60 (230-400 메쉬)을 사용 하였다. In the examples of the present invention, commercially available reagents were used without further purification unless otherwise stated. Closed tubes (13 x 100 mm 2 ) were purchased from Fischer Scientific, dried overnight in the oven and then cooled to room temperature prior to use and thin layer chromatography was performed using plates coated with Kieselgel 60F254 (Merck) And E. Merck Kieselgel 60 (230-400 mesh) for flash column chromatography.

핵자기 공명 스펙트럼 (1H 및 13C NMR)은 Bruker Unity 400 및 500 분광기에서 CDCl3 용액을 사용하여 기록된 것으로, 화학적 이동은 백만분율(ppm) 단위로 기재된 것이다. 공명 패턴은 s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sext (sextet) 및 m (multiplet)로 함께 표시되는 것이며, br는 넓은 신호를 나타내는 것에 사용된다. 커플링 상수(J)는 헤르쯔 (Hz)로 표시한다. Nuclear magnetic resonance spectra (1H and 13C NMR) were recorded using a CDCl 3 solution in a Bruker Unity 400 and 500 spectrometer with chemical shifts reported in parts per million (ppm). The resonance pattern is represented by s (singlet), d (doublet), t (triplet), q (quartet), quint Is used. The coupling constant (J) is expressed in hertz (Hz).

IR 스펙트럼은 Varian 2000 적외선 분광 광도계에서 기록되었고 cm-1로 기재하였다. 고해상도 질량 스펙트럼 (HRMS)은 JEOL JMS-600 분광기를 통해 분석된 것이다.IR spectra were recorded on a Varian 2000 infrared spectrophotometer and reported in cm -1 . High resolution mass spectra (HRMS) were analyzed using a JEOL JMS-600 spectrometer.

실시예Example 1. N- 1. N- 아로일우레아Aroylurea 유도체의 합성을 위한 최적 반응 조건 탐색 Search for Optimum Reaction Conditions for the Synthesis of Derivatives

본 실시예 1에서는 인돌린 및 이소시아네이트의 커플링 반응을 통한, 엔아로일우레아(N-aroylureas) 유도체 합성의 반응 최적 조건을 설정하고자, 하기 반응식 2에 도시된 바와 같이, 로듐 촉매 하에서 N-피발로일 인돌린(1a)와 에틸 이소시아네이트 (2a)의 커플 링 반응을 조사하여 최적화 조건을 도출하고자 하였다. 그 결과 표 1에 나타낸 것과 같이, [RhCp*Cl2]2와 AgSbF6에서 유래된 양이온성 로듐 복합체가 1a와 2a의 커플링 반응을 촉매하여 N-아로일우레아 3a(36 %)와 C7- 아미드화(amidated)된 인돌린 3aa(25%)를 형성한다는 것을 확인하였다. 항목 2에서는 [RhCp*Cl2]2를 사용하지 않았으며, 생성물이 생성되지 않았다.In Example 1, in order to set reaction optimum conditions for the synthesis of enoylurea (N-aroylureas) derivatives through the coupling reaction of indoline and isocyanate, as shown in the following Reaction Scheme 2, The aim of this study was to investigate the coupling reaction between valonyl indoline (1a) and ethyl isocyanate (2a). As a result, as shown in Table 1, a cationic rhodium complex derived from [RhCp * Cl 2 ] 2 and AgSbF 6 catalyzed the coupling reaction of 1a and 2a to form N-aroylurea 3a (36% To form amidated indoline 3aa (25%). Item 2 did not use [RhCp * Cl 2 ] 2 and no product was produced.

[반응식 2][Reaction Scheme 2]

Figure 112017037435453-pat00009
Figure 112017037435453-pat00009

EntryEntry Additive (mol %)Additive (mol%) SolventSolvent Yield (%)Yield (%) 3a3a 3aa3aa 1One AgSbF6(10)AgSbF 6 (10) DCEDCE 3636 2525 22 AgSbF6(10)AgSbF 6 (10) DCEDCE N.R.N.R. N.R.N.R. 33 AgSbF6(10),Cu(OAc)2(100)AgSbF 6 (10), Cu (OAc) 2 (100) DCEDCE 7575 55 44 Cu(OAc)2(100)Cu (OAc) 2 (100) DCEDCE N.R.N.R. N.R.N.R. 55 AgSbF6(10),Cu(OAc)2(30)AgSbF 6 (10), Cu (OAc) 2 (30) DCEDCE 7070 88 66 AgNTf2(10),Cu(OAc)2(30) AgNTf 2 (10), Cu ( OAc) 2 (30) DCEDCE 9292 44 77 AgPF6(10),Cu(OAc)2(30)AgPF 6 (10), Cu (OAc) 2 (30) DCEDCE 4545 1414 88 AgNTf2(10),Cu(OAc)2(10) AgNTf 2 (10), Cu ( OAc) 2 (10) DCEDCE 7272 1010 99 AgNTf2(10),NaOAc(30) AgNTf 2 (10), NaOAc ( 30) DCEDCE 5454 2121 1010 AgNTf2(10),CuOAc(30)AgNTf 2 (10), CuOAc (30) DCEDCE 7979 55 1111 AgNTf2(10),AgOAc(30) AgNTf 2 (10), AgOAc ( 30) DCEDCE 7878 1111 1212 AgNTf2(10),Cu(OAc)2(30) AgNTf 2 (10), Cu ( OAc) 2 (30) THFTHF 1212 2020 1313 AgNTf2(10),Cu(OAc)2(30) AgNTf 2 (10), Cu ( OAc) 2 (30) toluenetoluene 7070 55 1414 AgNTf2(10),Cu(OAc)2(30) AgNTf 2 (10), Cu ( OAc) 2 (30) MeCNMeCN N.R.N.R. N.R.N.R. 1515 AgNTf2(10),Cu(OAc)2(30) AgNTf 2 (10), Cu ( OAc) 2 (30) MeOHMeOH N.R.N.R. N.R.N.R. 1616 AgNTf2(10),Cu(OAc)2(30) AgNTf 2 (10), Cu ( OAc) 2 (30) DCEDCE 8686 33 1717 AgNTf2(10),Cu(OAc)2(30) AgNTf 2 (10), Cu ( OAc) 2 (30) DCEDCE 3131 2828 1818 AgNTf2(10),Cu(OAc)2(30) AgNTf 2 (10), Cu ( OAc) 2 (30) DCEDCE 2626 1313 1919 AgNTf2(10),Cu(OAc)2(30) AgNTf 2 (10), Cu ( OAc) 2 (30) DCEDCE N.R.N.R. N.R.N.R.

- 반응 조건 : 1a (0.2 mmol), 2a (0.6 mmol), [RhCp*Cl2]2 (2.5 mol %), 첨가제 (mol%, 표에 기재), 용매 (1 mL), 상온에서 20시간 동안 압력관(pressure tubes) 내에서 반응Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), [RhCp * Cl 2 ] 2 (2.5 mol%), additive (mol% Reaction in pressure tubes

- 수득율(Yield)는 flash column chromatography에 의해 도출Yield is derived by flash column chromatography

또한, Cu(OAc)2 첨가제를 첨가하자, 75% 수율로 3a의 현저한 개선된 형성을 보였으나(항목 3), 중성 Rh (Ⅲ) 촉매는 어떠한 커플링 생성물도 제공하지 못했다(항목 4). 흥미롭게도 30 mol%로 감소된 Cu(Ⅱ) 염의 양이 변환에서 비교 가능하다는 것이 발견되었다 (항목 5). 더욱이, 은 첨가제를 AgSbF6에서 AgNTf2로 교환하면, 원하는 N-아로일우레아 3a의 형성이 92% 수율로 증가되었다 (항목 6). Addition of the Cu (OAc) 2 additive also showed a significant improved formation of 3a at 75% yield (item 3), while the neutral Rh (III) catalyst did not provide any coupling products (item 4). Interestingly, it has been found that the amount of Cu (II) salt reduced to 30 mol% is comparable in conversion (item 5). Moreover, when the silver additive was changed from AgSbF 6 to AgNTf 2 , the formation of the desired N-aroylurea 3a was increased in 92% yield (item 6).

항목 7 내지 11에서 확인할 수 있는 것과 같이, 다른 종류의 은 첨가제 및 아세테이트 공급원의 조합은 본 발명의 커플링 반응에서 효과적이지 않다는 것을 확인하였다. 이에 일정 범위의 용매를 스크리닝한 후, 용매로 DCE를 사용하는 것이 3a의 형성에 대해 가장 높은 반응성을 나타내는 것을 확인하였다(항목 12 내지 15). As can be seen in items 7 to 11, it has been found that the combination of different kinds of silver additive and acetate source is not effective in the coupling reaction of the present invention. After screening a range of solvents, it was found that the use of DCE as solvent showed the highest reactivity to the formation of 3a (items 12-15).

이후 추가 조사를 통해, 2a를 5당량 사용하거나(항목 16), 2a를 1.5당량 사용한 결과(항목 17), 3 당량의 2a를 사용하는 것이 커플링 생성물 3a를 고수율을 형성하는 최적의 양인 것을 확인하였다. Further investigations have shown that using 5 equivalents of 2a (item 16) and 1.5 equivalents of 2a (item 17) and using 3 equivalents of 2a is the optimal amount of coupling product 3a to yield a high yield Respectively.

또한 다른 종류의 양이온성 촉매인 Ru(Ⅱ) 촉매([Ru(p-cymene)Cl2]2)를 사용하거나(항목 18) Co(Ⅲ) 촉매([CoCp*(CO)I2])를 사용할 경우(항목 19), 생성에 효과가 없다는 것을 확인하였다.It is also possible to use a different type of cationic catalyst, Ru (II) catalyst ([Ru (p-cymene) Cl 2 ] 2 ) or a Co (III) catalyst ([CoCp * (CO) I 2 ] (Item 19), it was confirmed that there was no effect on generation.

실시예Example 2. 다양한  2. Various 인돌린의Indolin 커플링 반응을 통한 N- N- 아로일우레아Aroylurea 유도체의 합성 Synthesis of derivatives

상기 실시예 1을 통해 결정된 커플링 반응 반응의 최적 조건에서, 다양한 화합물의 커플링 반응을 수행하였다. 보다 구체적으로, 하기 반응식 3에 도시한 바와 같이, 다양한 인돌린(1a 내지 1n)을 에틸이소시아네이트(2a)와 반응시켰다. 그 결과로 생성된 생성물(3a 내지 3n)를 도 2에 나타내었다.At the optimum conditions of the coupling reaction determined in Example 1 above, coupling reactions of various compounds were carried out. More specifically, as shown in the following Reaction Scheme 3, various indolines (1a to 1n) were reacted with ethyl isocyanate (2a). The resulting products 3a to 3n are shown in FIG.

[반응식 3][Reaction Scheme 3]

Figure 112017037435453-pat00010
Figure 112017037435453-pat00010

- 반응 조건 : 1a-1n (0.2 mmol), 2a (0.6 mmol), [RhCp*Cl2]2 (2.5 mol %), AgNTf2 (10 mol %), Cu(OAc)2 (30 mol %), DCE (1 mL), 상온에서 20시간 동안 압력관 내에서 반응- Reaction conditions: 1a-1n (0.2 mmol) , 2a (0.6 mmol), [RhCp * Cl 2] 2 (2.5 mol%), AgNTf 2 (10 mol%), Cu (OAc) 2 (30 mol%), DCE (1 mL), reaction in a pressure tube for 20 hours at room temperature

그 결과, N-아세틸인돌린(1b) 및 N-카바모일인돌린(1d)는 극미량의 N-아로 일우레아(3b 및 3d)를 제공하는 반면, N-벤조일 인돌린(1c)는 3c를 71 %의 수율로 제공하는 것이 확인되어, 본 발명의 커플링 반응에서 우수한 기질인 것이 확인되었다. C4- 및 C5- 치환 된 인돌린 1e 내지 1i의 경우에, 고수율로 목적하는 N-아로일우레아 부가물이 수득되었다. 특히, C5- 위치에서 전자 불충분 치환체 (Br, Cl 및 CO2Me)는 5 당량의 이소시아네이트 (2a) 사용 및/또는 연장된 반응 시간(40 시간) 조건에 의해 생성물 3g-3i를 제공하는 증가된 반응성을 나타내었다. 입체적으로 복잡한 구조를 가진 C6-치환된 인돌린 1j 및 1k는 약간 변형된 반응 조건 하에서 C7-관능화된 인돌린 3j 및 3k를 제공하는 것도 확인되었다. As a result, N-acetylindoline 1b and N-carbamoylindoline 1d provide trace amounts of N-aroylureas 3b and 3d, whereas N-benzoylindoline 1c provides 3c 71% yield, confirming that it is a good substrate in the coupling reaction of the present invention. In the case of C4- and C5-substituted indolines 1e to 1i, the desired N-aroylurea adduct was obtained in high yield. In particular, the electron insufficiency substituents (Br, Cl and CO 2 Me) at the C5- position are reduced by the use of 5 equivalents of isocyanate (2a) and / or an extended reaction time (40 hours) Lt; / RTI &gt; It has also been found that C6-substituted indolines 1j and 1k, which have a sterically complex structure, provide C7-functionalized indolines 3j and 3k under slightly modified reaction conditions.

메틸기로 치환된 인돌린의 경우, 출발 화합물 1j (68 %)의 대부분이 회수되었고, C7-아미드화된 인돌린 3ja의 형성이 관찰되지 않았다. 그러나 C6-클로로기로 치환된 인돌린 1k는 회수된 출발 물질 1k (52 %)과 함께 N-아로일 우레아 3k (29 %)와 C7-아미드화된 인돌린 3ka(11 %)의 혼합물을 제공하였다. In the case of the indoline substituted with a methyl group, most of the starting compound 1j (68%) was recovered and no formation of C7-amidated indoline 3ja was observed. However, indoline 1k substituted with a C6-chloro group provided a mixture of N-aroylurea 3k (29%) and C7-amidated indoline 3ka (11%) along with the recovered starting material 1k (52% .

놀랍게도, C6-치환된 N-아로일우레아 생성물 3j 및 3k의 부분 입체이성질체 E/Z 혼합물이 2.6 : 1 비율로 관찰되었다. 또한, C2- 및 C3-치환된 인돌린은 반응에서 양립 가능하여, 원하는 생성물 3l-3n을 고수율로 제공하는 것이 확인되었다.Surprisingly, the C6-substituted N-aroylurea products 3j and the diastereomeric E / Z mixture of 3k were observed in a 2.6: 1 ratio. In addition, it has been confirmed that C2- and C3-substituted indolines are compatible in the reaction and provide the desired products 3l-3n in high yield.

실시예Example 3. 다양한 이소시아네이트의 커플링 반응을 통한 N- 3. Coupling of various isocyanates to N- 아로일우레아Aroylurea 유도체의 합성 Synthesis of derivatives

이소시아네이트 반응물의 범위를 평가하기 위해, 하기 반응식 4에 나타낸 바와 같이, 다양한 이소시아네이트(2b 내지 2l) 및 N-피발로일인돌린(1a)의 고리 형성 반응을 수행하였다.In order to evaluate the range of isocyanate reactants, the ring forming reaction of various isocyanates (2b to 2l) and N-pivaloylindoline (1a) was carried out as shown in the following reaction scheme 4.

[반응식 4][Reaction Scheme 4]

Figure 112017037435453-pat00011
Figure 112017037435453-pat00011

- 반응 조건 : 1a (0.2 mmol), 2b-2l (0.6 mmol), [RhCp*Cl2]2 (2.5 mol %), AgNTf2 (10 mol %), Cu(OAc)2 (30 mol %), DCE (1 mL), 상온에서 20시간 동안 압력관 내에서 반응- Reaction conditions: 1a (0.2 mmol), 2b -2l (0.6 mmol), [RhCp * Cl 2] 2 (2.5 mol%), AgNTf 2 (10 mol%), Cu (OAc) 2 (30 mol%), DCE (1 mL), reaction in a pressure tube for 20 hours at room temperature

그 결과, 도 3에 도시한 바와 같이, 선형 알킬이소시아네이트 2b-2e를 1a와 성공적으로 결합시켜 고수율로 4b-4e를 제공하는 것을 확인하였다. 그러나, 페네틸이소시아네이트(2f) 및 벤질이소시아네이트(2g)는 최적 반응 조건 하에서 반응성이 낮았다. As a result, it was confirmed that linear alkyl isocyanate 2b-2e was successfully coupled with 1a to give 4b-4e in high yield, as shown in Fig. However, phenethyl isocyanate (2f) and benzyl isocyanate (2g) were less reactive under optimum reaction conditions.

이에 더하여, 2a 첨가 당량의 증가 (5 equiv.) 및/또는 연장된 반응시간 (40시간)이 상응하는 부가물 4f 및 4g를 증가된 수율로 형성한다는 것이 확인되었다. 대조적으로, 가지형 알킬이소시아네이트 2h는 약간 변형된 반응 조건 하에서 N-아로일우레아 생성물 4h (23 %)와 C7-아미드화된 인돌린 4ha(51 %)의 분리 가능한 혼합물을 제공하는 것으로 밝혀졌다. In addition, it was confirmed that an increase in the amount of added 2a (5 equiv.) And / or an extended reaction time (40 hours) formed the corresponding adducts 4f and 4g with increased yield. In contrast, the branched alkyl isocyanate 2h was found to provide a separable mixture of the N-araoyl urea product 4h (23%) and the C7-amidated indolin 4h (51%) under slightly modified reaction conditions.

또한, 아릴 이소시아네이트 2i-2l은 상기에서 결정된 반응조건 또는 약간 변형된 반응 조건 하에서도 생성된다는 것이 확인되었다. 전자가 풍부한 이소시아네이트 2j는 4j의 형성에 상대적으로 덜 반응하는 것이 확인되었는데, 미량의 C7-아미드화된 인돌린 4ja 및 출발 화합물 1a (30 %)가 검출되었다. 형성된 N-아실우레아 상의 아닐리드 그룹이 추가의 C(sp2)-H 아미드화 반응을 보조하지 않는 것이 확인되었다. 마지막으로, 높은 수율의 제품 (도 2 및 도 3)의 경우, 미량의 C7-아미드화된 인돌린 및 개시 물질뿐만 아니라, 특성 불명의 불순물의 혼합물이 관찰 되었다. 그러나, 3k, 4c 및 4h의 경우, C7-아미드화된 인돌린의 10-51 % 수율이 수득되었다.It has also been confirmed that the aryl isocyanate 2i-2l is also produced under the reaction conditions determined above or slightly modified reaction conditions. The electron enriched isocyanate 2j was found to be relatively less responsive to the formation of 4j, with trace amounts of C7-amidated indolin 4ja and starting compound 1a (30%) being detected. It was confirmed that the anilide group on the N-acylurea formed did not assist further C (sp 2 ) -H amidation reaction. Finally, for high yield products (Figures 2 and 3), a mixture of minor amounts of C7-amidated indoline and starting materials as well as mixtures of uncharacterized impurities were observed. However, for 3k, 4c and 4h, a 10-51% yield of C7-amidated indoline was obtained.

실시예Example 4. N- 4. N- 아로일우레아Aroylurea 유도체의 구조 확인 Identification of derivatives structure

생성된 N-아로일우레아 유도체의 구조를 확인하기 위해서, X-선 결정 분석을 통해 그 구조를 분석하였다.In order to confirm the structure of the resulting N-aroyl urea derivative, its structure was analyzed by X-ray crystallography.

그 결과, 도 4에 도시한 바와 같이, 인돌린 1g 및 이소시아네이트 2a의 커플링 반응을 거쳐, 5-Chloro-N-ethyl-N-(ethylcarbamoyl)-1-pivaloylindoline-7-carboxamide 화합물이 생성되었음을 확인할 수 있다.As a result, it was confirmed that 5-Chloro-N-ethyl-N- (ethylcarbamoyl) -1-pivaloylindoline-7-carboxamide compound was produced through the coupling reaction of 1 g of indoline and isocyanate 2a as shown in FIG. .

실시예Example 5. C7- 5. C7- 아미드화된Amidated 인돌린(N-Ethyl-1-pivaloylindoline-7-carboxamide)의 반응 조건에 따른 N- (N-ethyl-1-pivaloylindoline-7-carboxamide) 아로일우레아Aroylurea 유도체의 합성 Synthesis of derivatives

본 발명의 N-아로일우레아 유도체의 생성에 대한 기계론적 통찰을 얻기 위해, 먼저 하기 반응식 5와 같이 최적 반응 조건 하에서 3aa와 이소시아네이트 2a (3 당량)의 반응을 수행하였다. 고수율 (81%)로 N-아로일우레아 3a가 생성되었고, 7 % 수율로 출발 물질 3aa가 함께 형성되었다. In order to obtain a mechanistic insight into the production of the N-aroyl urea derivatives of the present invention, the reaction of 3aa with isocyanate 2a (3 eq.) Was carried out first under the optimum reaction conditions as shown in the following Reaction Scheme 5. N-Aroylurea 3a was produced in high yield (81%) and starting material 3aa was formed together at 7% yield.

[반응식 5][Reaction Scheme 5]

Figure 112017037435453-pat00012
Figure 112017037435453-pat00012

C7-아미드화된 인돌린 3aa로부터 N-아로일우레아 3a가 생성되는 반응을 이해하기 위해, 2개의 대조군 실험을 실시하였다. 첫째, 반응식 6에 도시한 것과 같이, Cu(OAc)2를 사용하지 않고, 양이온 Rh(Ⅲ) 복합체를 사용하는 C7-아미드화된 인돌린 3aa의 반응은, N- 아로일우레아 3a (70 %) 및 출발 물질 3aa (14 %)의 회수를 초래하였다. To understand the reaction of N-aroylurea 3a from C7-amidated indoline 3aa, two control experiments were performed. First, as shown in Scheme 6, Cu (OAc) 2 without the use of, a cationic Rh (Ⅲ) reaction of the amidated C7- indoline 3aa using the composite, N- aroyl urea 3a (70% ) And starting material 3aa (14%).

[반응식 6][Reaction Scheme 6]

Figure 112017037435453-pat00013
Figure 112017037435453-pat00013

이어서, 반응식 7에 도시한 것과 같이 3aa와 Cu(OAc)2의 반응을 수행하여 3a(56 %)를 수득하였고, 출발 물질 3aa (42 %)를 회수 하였다. 이러한 결과에 기초하여, 우레아의 형성은 양이온성 Rh(Ⅲ) 착물에 의해 개시될 수 있다는 것을 알 수 있다. 또한, 본 발명의 제조방법이 인돌린 1a 및/또는 C7-아미드화 인돌린 3aa로부터 N-아로일우레아 생성물 3a를 제공하기 위해서는 아세테이트 공급원과 염기의 역할을 하는 Cu(OAc)2가 필수적이라는 것을 확인하였다.The reaction of 3aa with Cu (OAc) 2 was then carried out as shown in Scheme 7 to give 3a (56%) and the starting material 3aa (42%) was recovered. Based on these results, it can be seen that the formation of urea can be initiated by a cationic Rh (III) complex. It is also noted that the process of the present invention requires Cu (OAc) 2 , which acts as a source of acetate and base, to provide the N-aroylurea product 3a from indolin-1a and / or C7-amidated indolin- Respectively.

[반응식 7][Reaction Scheme 7]

Figure 112017037435453-pat00014
Figure 112017037435453-pat00014

또한, 하기 반응식 8에 도시한 것과 같이 상기 반응 조건에서 온도를 120 ℃로 변경하여, 이소시아네이트를 첨가하지 않고, 3a의 반응을 진행한 결과, 인돌린 1a (40 %)와 함께 C7-아미드화된 인돌린 3aa (45 %)를 생성하는 것을 확인하였다. 이러한 결과는 N-아로일 유도체의 형성이 가역적 일 수 있음을 나타낸다. As shown in the following Reaction Scheme 8, the temperature was changed to 120 deg. C under the above reaction conditions and the reaction of 3a was carried out without adding isocyanate. As a result, it was confirmed that C7-amidated Indoleine 3aa (45%). These results indicate that the formation of N-aroyl derivatives may be reversible.

[반응식 8][Reaction Scheme 8]

Figure 112017037435453-pat00015
Figure 112017037435453-pat00015

실시예Example 6. N- 6. N- 아로일우레아Aroylurea 생성 반응 메커니즘확인 Identify the mechanism of production reaction

상기 실시예 1 내지 5로부터 본 발명의 N-아로일우레아 유도체의 생성 매커니즘을 도 5에 나타내었다. 도 5에 나타낸 것과 같이, [RhCp*Cl2]2를 AgNTf2와 Cu(OAc)2로 처리하면 양이온 Rh(Ⅲ) 촉매인 [RhCp*(OAc)][NTf2]가 C-H metallation 반응을 거쳐 고리형 다공성 복합체 A를 생성한다. 그 다음, 이소시아네이트 2a의 후속 이동성 첨가물의 배위는 로다사이클(rhodacycle) 중간체 C를 전달할 수 있고, 이는 AcOH와 양성자화가 C7-아미드화된 인돌린 3aa를 제공하는 것이다. N-아로일우레아 3a의 형성은 이소시아네이트 (2a)에 대한 친핵성 첨가 및 이어서 양성자화 공정(경로 a)을 통해 중간체 C로부터 유도될 수 있다. From the above Examples 1 to 5, the production mechanism of the N-aroyl urea derivative of the present invention is shown in Fig. As shown in FIG. 5, when [RhCp * Cl 2 ] 2 is treated with AgNTf 2 and Cu (OAc) 2 , [RhCp * (OAc)] [NTf 2 ], which is a cationic Rh To produce an annular porous composite A. The coordination of the subsequent mobile additive of isocyanate 2a can then transfer the rhodacycle intermediate C, which protonates to AcOH and provides C7-amidated indoline 3aa. Formation of N-aroylurea 3a can be derived from intermediate C via a nucleophilic addition to isocyanate (2a) and then a protonation step (path a).

대안적으로, 생성물 3a는 또한 아미드 3aa와 이소시아네이트 2a (경로 b) 사이의 금속-매개 및/또는 염기-매개 커플링 반응을 통해 형성될 수 있다. 이 반응 경로는 실시예 5의 결과에 의해 뒷받침되는 것이다. Alternatively, product 3a may also be formed via a metal-mediated and / or base-mediated coupling reaction between amide 3aa and isocyanate 2a (path b). This reaction path is supported by the results of Example 5.

실시예Example 7. N- 7. N- 아로일우레아의Aroylurea 전환 반응 확인 Confirm conversion response

본 실시예 7에서는 하기 반응식 9에 나타낸 것과 같이 C7-관능화된 인돌린에 대한 N-아로일우레아 작용기의 전환을 수행하였다. 3a를 100℃ 및 EtOH 하에서 NaOEt를 첨가하여 반응시킨 결과, C7-아미드화된 인돌린 3aa를 70 % 수율로 수득하였다. 또한, EtOH 용매 중 NaOH로 3a의 피바로일 및 카바모일기를 모두 제거하여 C7-아미드화프리-(NH)-인돌린(6a)을 86 %의 수율로 수득하였다. In this Example 7, conversion of N-aroylurea functional groups to C7-functionalized indoline was performed as shown in Scheme 9 below. 3a was reacted by addition of NaOEt at 100 &lt; 0 &gt; C and EtOH to give C7-amidated indoline 3aa in 70% yield. Further, the pivaloyl and carbamoyl groups of 3a were all removed with NaOH in EtOH solvent to give C7-amidated pre- (NH) -indolin (6a) in 86% yield.

[반응식 9][Reaction Scheme 9]

Figure 112017037435453-pat00016
Figure 112017037435453-pat00016

다음으로 하기 반응식 10에 나타낸 것과 같이, C7-아미드화된 인돌린 3aa의 순차적 C6-관능화를 조사하였다. 먼저, 실시예 1에서 결정된 반응 조건 하에서 알릴메틸카보네이트(7a)를 사용하여 알릴화 반응을 수행하여 C6-알릴화된 생성물 8a을 63%의 수율로 수득하였다. 또한, 3a 및 α-디아조에스테르(7b)로부터 유도된 이소퀴놀론 8b의 생성은 아미도 및 아세틸기 사이의 C6-알킬화 및 분자간 축합 반응에 의해 달성되었다.Next, sequential C6-functionalization of C7-amidated indoline 3aa was investigated, as shown in Scheme 10 below. First, an allylation reaction was performed using allylmethyl carbonate (7a) under the reaction conditions determined in Example 1 to obtain C6-allylated product 8a in a yield of 63%. In addition, the production of isoquinolone 8b derived from 3a and the alpha -diazo ester (7b) was achieved by C6-alkylation between the amido and acetyl groups and intermolecular condensation.

[반응식 10][Reaction Scheme 10]

Figure 112017037435453-pat00017
Figure 112017037435453-pat00017

이러한 N-아로일우레아 유도체의 합성 방법은, 다양한 작용기를 지닌 화합물에 적용 가능하여, 새로운 의약품이나 생물학적 활성을 갖는 화합물의 합성에 있어 매우 유용하다.The method of synthesizing such N-arylaurea derivatives is applicable to compounds having various functional groups and is very useful in the synthesis of new drugs and compounds having biological activity.

실시예 8. NMR 분석을 통한 신규 화합물의 구조 분석Example 8. Structural Analysis of New Compounds by NMR Analysis

8-1. N-Ethyl-N-(ethylcarbamoyl)-1-pivaloylindoline-7-carboxamide (3a)의 생성 및 구조 분석8-1. N-Ethyl-N- (ethylcarbamoyl) -1-pivaloylindoline-7-carboxamide (3a)

N-피발로일인돌린(1a) (40.7 mg, 0.2 mmol, 100 mol%), [RhCp*Cl2]2 (3.1 mg, 0.005 mmol, 2.5 mol %), Cu(OAc)2 (10.9 mg, 0.06 mmol, 30 mol %) 및 AgNTf2 (7.8 mg, 0.02 mmol, 10 mol %)가 포함된 용액에 에틸이소시아네이트 (2a) (42.6 mg, 0.6 mmol, 300 mol%) 및 DCE(1ml) 용매를 상온에서 첨가하였다. 반응 혼합물을 상온에서 20시간 동안 교반하였다. 반응 혼합물을 EtOAc(3 mL)로 희석시키고 진공 하에 농축시켰다. 잔류물을 플래시 컬럼 크로마토 그래피 (n- 헥산 / EtOAc = 3 : 1)로 정제하여 92.2 mg의 3a를 65.2 %의 수율로 수득하였으며, 이를 NMR 분석하여 하기에 나타내었다. 이하 3a 내지 3l 및 4b 내지 4l의 생성도 상기 조건에 따라 생성되었다.Turned feet yl N- blood (1a) (40.7 mg, 0.2 mmol, 100 mol%), [RhCp * Cl 2] 2 (3.1 mg, 0.005 mmol, 2.5 mol%), Cu (OAc) 2 (10.9 mg, 0.06 Ethyl isocyanate (2a) (42.6 mg, 0.6 mmol, 300 mol%) and DCE (1 ml) were added to a solution containing AgNTf 2 (7.8 mg, 0.02 mmol, 10 mol% . The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with EtOAc (3 mL) and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane / EtOAc = 3: 1) to give 92.2 mg of 3a in 65.2% yield, which was analyzed by NMR. The production of 3a to 31 and 4b to 4l was also produced according to the above conditions.

[화학식 3a][Chemical Formula 3]

Figure 112017037435453-pat00018
Figure 112017037435453-pat00018

63.5 mg (92%); white solid; mp = 119.3-120.9 oC; 1H NMR (400 MHz, CDCl3)δ 7.79 (br s, 1H), 7.25 (d, J = 6.2 Hz, 2H), 7.14 (d, J = 7.6 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 4.36 (br s, 1H), 4.11 (br s, 1H), 3.82 (br s, 1H), 3.31-2.91 (m, 4H), 1.34 (s, 9H), 1.22 (t, J = 7.0 Hz, 3H), 0.61 (br s, 3H); 13C NMR(100MHz,CDCl3) δ 179.2, 178.4, 156.1, 134.1, 134.1, 127.4, 125.9, 125.1, 124.2, 50.5, 39.8, 35.4, 35.2, 30.3, 27.8, 15.3, 13.6; IR(KBr) υ 3293, 3055, 2971, 2933, 2874, 2362, 1699, 1650, 1632, 1550, 1446, 1400, 1371, 1359, 1315, 1247, 1163, 1078, 1042, 902, 848, 751 cm-1; HRMS(orbitrap, ESI) calcd for C19H28N3O3 [M+H]+ 346.2130, found 346.2126.63.5 mg (92%); white solid; mp = 119.3-120.9 o C; 1 H NMR (400 MHz, CDCl 3) δ 7.79 (br s, 1H), 7.25 (d, J = 6.2 Hz, 2H), 7.14 (d, J = 7.6 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 4.36 (br s, 1H), 4.11 (br s, 1H), 3.82 (br s, 1H), 3.31-2.91 (m, 4H), 1.34 (s, 9H), 1.22 (t, J = 7.0 Hz, 3H), 0.61 (br s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 179.2, 178.4, 156.1, 134.1, 134.1, 127.4, 125.9, 125.1, 124.2, 50.5, 39.8, 35.4, 35.2, 30.3, 27.8, 15.3, 13.6; IR (KBr) υ 3293, 3055 , 2971, 2933, 2874, 2362, 1699, 1650, 1632, 1550, 1446, 1400, 1371, 1359, 1315, 1247, 1163, 1078, 1042, 902, 848, 751 cm - 1 ; HRMS (orbitrap, ESI) calcd for C 19 H 28 N 3 O 3 [M + H] + 346.2130, found 346.2126.

8-2. 1-Benzoyl-N-ethyl-N-(ethylcarbamoyl)indoline-7-carboxamide (3c)의 생성 및 구조 분석8-2. 1-Benzoyl-N-ethyl-N- (ethylcarbamoyl) indoline-7-carboxamide (3c)

[화학식 3c][Chemical Formula 3c]

Figure 112017037435453-pat00019
Figure 112017037435453-pat00019

51.8 mg (71%); yellow sticky solid; 1H NMR (400 MHz, CDCl3) δ 7.78 (br s, 1H), 7.67 (d, J = 7.2 Hz, 2H), 7.50 (d, J = 7.3 Hz, 1H), 7.45-7.41 (m, 2H), 7.29 (d, J = 7.4 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 4.20 (br s, 1H), 4.08 (br s, 1H), 3.80 (br s, 2H), 3.11-3.01 (m, 4H), 1.24-1.21 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 170.8, 168.5, 156.4, 139.4, 135.3, 135.2, 131.8, 128.7, 128.4, 127.8, 126.6, 125.4, 125.2, 53.3, 35.5, 29.8, 29.7, 14.0, 13.9; IR (KBr) υ 3286, 3058, 2924, 2853, 2304, 1697, 1634, 1549, 1448, 1390, 1330, 1249, 1191, 1077, 1025, 970, 883, 736 cm-1; HRMS (quadrupole, EI) calcd for C21H23N3O3 [M]+ 365.1739, found 365.1737.51.8 mg (71%); yellow sticky solid; 1 H NMR (400 MHz, CDCl 3) δ 7.78 (br s, 1H), 7.67 (d, J = 7.2 Hz, 2H), 7.50 (d, J = 7.3 Hz, 1H), 7.45-7.41 (m, 2H ), 7.29 (d, J = 7.4 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H) , 3.80 (br s, 2H), 3.11-3.01 (m, 4H), 1.24-1.21 (m, 6H); 13 C NMR (100 MHz, CDCl 3)? 170.8, 168.5, 156.4, 139.4, 135.3, 135.2, 131.8, 128.7, 128.4, 127.8, 126.6, 125.4, 125.2, 53.3, 35.5, 29.8, 29.7, 14.0, 13.9; IR (KBr) v 3286, 3058, 2924, 2853, 2304, 1697, 1634, 1549, 1448, 1390, 1330, 1249, 1191, 1077, 1025, 970, 883, 736 cm -1 ; HRMS (quadrupole, EI) calcd for C 21 H 23 N 3 O 3 [M] + 365.1739, found 365.1737.

8-3. N-Ethyl-N-(8-3. N-Ethyl-N- ( ethylcarbamoylethylcarbamoyl )-4-methyl-1-) -4-methyl-1- pivaloylindoline피발oylindoline -7-carboxamide (3e)의 생성 및 구조 분석-7-carboxamide (3e) and its structural analysis

[화학식 3e][Formula 3e]

Figure 112017037435453-pat00020
Figure 112017037435453-pat00020

68.4 mg (95%); white solid; mp = 130.1-133.7 oC; 1H NMR (500 MHz, CDCl3) δ 7.88 (br s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.34 (br s, 1H), 4.10 (br s, 1H), 3.78 (br s, 2H), 3.18-2.98 (m, 4H), 2.42 (s, 3H), 1.33 (s, 9H), 1.19 (t, J = 7.0 Hz, 3H), 0.70 (br s, 3H); 13C NMR (125 MHz, CDCl3) δ 179.0, 165.0, 156.2, 140.6, 135.8, 132.7, 132.6, 125.6, 125.1, 50.2, 39.8, 35.2, 29.0, 27.7, 18.7, 13.7 (two carbon overlap); IR (KBr) 3297, 3054, 2970, 2933, 2874, 2359, 2341, 1698, 1627, 1542, 1477, 1447, 1400, 1355, 1316, 1244, 1190, 1172, 1078, 1056, 1026, 897, 861, 813, 735 cm-1; HRMS (quadrupole, EI) calcd for C20H29N3O3 [M]+ 359.2209, found 359.2211.68.4 mg (95%); white solid; mp = 130.1-133.7 o C; 1 H NMR (500 MHz, CDCl 3) δ 7.88 (br s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.34 (br s, 1H) J = 7.0 Hz, 3H (m, IH), 4.08 (br s, IH) ), 0.70 (br s, 3H); 13 C NMR (125 MHz, CDCl 3 )? 179.0, 165.0, 156.2, 140.6, 135.8, 132.7, 132.6, 125.6, 125.1, 50.2, 39.8, 35.2, 29.0, 27.7, 18.7, 13.7 (two carbon overlap); IR (KBr) 3297, 3054, 2970, 2933, 2874, 2359, 2341, 1698, 1627, 1542, 1477, 1447, 1400, 1355, 1316, 1244, 1190, 1172, 1078, 1056, 1026, 813, 735 cm &lt; -1 & gt ;; HRMS (quadrupole, EI) calcd for C 20 H 29 N 3 O 3 [M] + 359.2209, found 359.2211.

8-4. N-Ethyl-N-(8-4. N-Ethyl-N- ( ethylcarbamoylethylcarbamoyl )-5-methyl-1-) -5-methyl-1- pivaloylindoline피발oylindoline -7--7- carboxamidecarboxamide (3f)의 생성 및 구조분석 (3f) and analysis of structure

[화학식 3f](3f)

Figure 112017037435453-pat00021
Figure 112017037435453-pat00021

50.4 mg (70%); light yellow solid; mp = 125.8-127.0 oC; 1H NMR (400 MHz, CDCl3) δ 7.83 (br s, 1H), 7.05 (s, 1H), 6.92 (s, 1H), 4.34 (br s, 1H), 4.06 (br s, 1H), 3.81 (br s, 2H), 3.18 (br s, 2H), 2.93 (br s, 2H), 2.25 (s, 3H), 1.32 (s, 9H), 1.20 (t, J = 6.7 Hz, 3H), 0.57 (br s, 3H); 13C NMR (100 MHz, CDCl3) δ 179.1, 168.3, 156.4, 138.7, 134.4, 127.3, 126.7, 125.5, 125.4, 50.8, 40.0, 39.5, 35.4, 30.5, 28.0, 21.0, 15.6, 13.8; IR (KBr) υ 3294, 3055, 2974, 2932, 2874, 2361, 1698, 1651, 1632, 1556, 1475, 1398, 1357, 1328, 1268, 1240, 1193, 1166, 1090, 1045, 910, 866, 741 cm-1; HRMS (quadrupole, EI) calcd for C20H29N3O3 [M]+ 359.2209, found 359.2209.50.4 mg (70%); light yellow solid; mp = 125.8-127.0 o C; 1 H NMR (400 MHz, CDCl 3 )? 7.83 (br s, IH), 7.05 (s, IH), 6.92 (s, 3H), 1.32 (s, 9H), 1.20 (t, J = 6.7 Hz, 3H), 0.57 (br s, 2H) (br s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 179.1, 168.3, 156.4, 138.7, 134.4, 127.3, 126.7, 125.5, 125.4, 50.8, 40.0, 39.5, 35.4, 30.5, 28.0, 21.0, 15.6, 13.8; IR (KBr) v 3294, 3055, 2974, 2932, 2874, 2361, 1698, 1651, 1632, 1556, 1475, 1398, 1357, 1328, 1268, 1240, 1193, 1166, 1090, 1045, 910, 866, 741 cm -1 ; HRMS (quadrupole, EI) calcd for C 20 H 29 N 3 O 3 [M] + 359.2209, found 359.2209.

8-5. 5-8-5. 5- ChloroChloro -N-ethyl-N-(-N-ethyl-N- ( ethylcarbamoylethylcarbamoyl )-1-)-One- pivaloylindoline피발oylindoline -7--7- carboxamidecarboxamide (3g)의 생성 및 구조분석 (3g) &lt; / RTI &gt;

[화학식 3g][Formula 3g]

Figure 112017037435453-pat00022
Figure 112017037435453-pat00022

50.0 mg (66%); yellow solid; mp = 128.2-128.7 oC; 1H NMR (400 MHz, CDCl3) δ 7.70 (br s, 1H), 7.21 (s, 1H), 7.11 (s, 1H), 4.36 (br s, 1H), 4.11 (br s, 1H), 3.79 (br s, 2H), 3.21 (br s, 2H), 2.98 (br s, 2H), 1.31 (s, 9H), 1.19 (t, J = 7.0 Hz, 3H), 0.66 (br s, 3H); 13C NMR (100 MHz, CDCl3) δ 179.5, 166.7, 155.8, 139.9, 136.3, 129.6, 128.4, 126.1, 125.0, 50.7, 40.0, 39.6, 35.5, 30.3, 29.9, 27.9, 13.8; IR (KBr) υ 3299, 3070, 2971, 2932, 2874, 2344, 1700, 1652, 1634, 1588, 1544, 1457, 1417, 1370, 1353, 1322, 1246, 1213, 1175, 1079, 905, 809, 737 cm-1; HRMS (quadrupole, EI) calcd for C19H26ClN3O3 [M]+ 379.1663, found 379.1665.50.0 mg (66%); yellow solid; mp = 128.2-128.7 o C; 1 H NMR (400 MHz, CDCl 3)? 7.70 (br s, IH), 7.21 (s, IH), 7.11 2H), 3.21 (br s, 2H), 2.98 (br s, 2H), 1.31 (s, 9H), 1.19 (t, J = 7.0 Hz, 3H), 0.66 (br s, 3H); 13 C NMR (100 MHz, CDCl 3) δ 179.5, 166.7, 155.8, 139.9, 136.3, 129.6, 128.4, 126.1, 125.0, 50.7, 40.0, 39.6, 35.5, 30.3, 29.9, 27.9, 13.8; IR (KBr) υ 3299, 3070, 2971, 2932, 2874, 2344, 1700, 1652, 1634, 1588, 1544, 1457, 1417, 1370, 1353, 1322, 1246, 1213, 1175, 1079, 905, 809, 737 cm -1 ; HRMS (quadrupole, EI) calcd for C 19 H 26 ClN 3 O 3 [M] + 379.1663, found 379.1665.

8-6. 5-8-6. 5- BromoBromo -N-ethyl-N-(-N-ethyl-N- ( ethylcarbamoylethylcarbamoyl )-1-)-One- pivaloylindoline피발oylindoline -7--7- carboxamidecarboxamide (3h)의 생성 및 구조분석 (3h) and analysis of structure

[화학식 3h][Chemical Formula 3h]

Figure 112017037435453-pat00023
Figure 112017037435453-pat00023

58.6 mg (69%); light yellow solid; mp = 124.9-125.7 oC; 1H NMR (400 MHz, CDCl3) δ 7.67 (br s, 1H), 7.36 (s, 1H), 7.25 (s, 1H), 4.35 (br s, 1H), 4.10 (br s, 1H), 3.80 (br s, 2H), 3.23 (br s, 2H), 2.99 (br s, 2H), 1.31 (s, 9H), 1.19 (t, J = 7.0 Hz, 3H), 0.67 (br s, 3H); 13C NMR (100 MHz, CDCl3) δ 179.4, 166.4, 155.8, 140.4, 136.6, 129.0, 128.8, 127.7, 116.9, 50.7, 40.0, 39.7, 35.5, 30.2, 29.9, 27.9, 13.8; IR (KBr) υ 3296, 3068, 2973, 2932, 2875, 2368, 1701, 1651, 1634, 1581, 1547, 1456, 1414, 1371, 1353, 1321, 1246, 1213, 1162, 1078, 1043, 906, 870, 808, 733 cm-1; HRMS (quadrupole, EI) calcd for C19H26BrN3O3 [M]+ 423.1158, found 423.1160.58.6 mg (69%); light yellow solid; mp = 124.9-125.7 o C; 1 H NMR (400 MHz, CDCl 3 )? 7.67 (br s, IH), 7.36 (s, IH), 7.25 2H), 3.23 (br s, 2H), 2.99 (br s, 2H), 1.31 (s, 9H), 1.19 (t, J = 7.0 Hz, 3H), 0.67 (br s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 179.4, 166.4, 155.8, 140.4, 136.6, 129.0, 128.8, 127.7, 116.9, 50.7, 40.0, 39.7, 35.5, 30.2, 29.9, 27.9, 13.8; IR (KBr) υ 3296, 3068, 2973, 2932, 2875, 2368, 1701, 1651, 1634, 1581, 1547, 1456, 1414, 1371, 1353, 1321, 1246, 1213, 1162, 1078, 1043, 906, 870 , 808, 733 cm &lt; -1 & gt ;; HRMS (quadrupole, EI) calcd for C 19 H 26 BrN 3 O 3 [M] + 423.1158, found 423.1160.

8-7. Methyl 7-(8-7. Methyl 7- ( ethyl(ethylcarbamoyl)carbamoylethyl (ethylcarbamoyl) carbamoyl )-1-)-One- pivaloylindoline피발oylindoline -5--5- carboxylatecarboxylate (3i)의 생성 및 구조분석 (3i) and its structural analysis

[화학식 3i][Formula 3i]

Figure 112017037435453-pat00024
Figure 112017037435453-pat00024

72.6mg (90%); yellow solid; mp = 124.4-125.7 oC; 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.80 (s, 1H), 7.56 (br s, 1H), 4.37 (br s, 1H), 4.17 (br s, 1H), 3.85 (s, 3H), 3.82 (br s, 2H), 3.27-2.92 (m, 4H), 1.32 (s, 9H), 1.20 (t, J = 7.0 Hz, 3H), 0.58 (br s, 3H); 13C NMR (100 MHz, CDCl3) δ 179.9, 167.3, 166.2, 155.8, 145.2, 134.6, 134.5, 127.2, 126.9, 126.0, 52.4, 50.9, 40.2, 39.6, 35.4, 30.0, 29.8, 27.8, 13.9; IR (KBr) υ 3298, 3057, 2965, 2927, 2873, 2364, 1701, 1650, 1540, 1437, 1417, 1355, 1326, 1288, 1242, 1207, 1176, 1120, 1082, 1044, 905, 816, 770, 733 cm-1; HRMS (quadrupole, EI) calcd for C21H29N3O5 [M]+ 403.2107, found 403.2109.72.6 mg (90%); yellow solid; mp = 124.4-125.7 o C; 1 H NMR (400 MHz, CDCl 3 )? 7.91 (s, IH), 7.80 (s, IH), 7.56 (br s, (s, 3H), 3.82 (br s, 2H), 3.27-2.92 (m, 4H), 1.32 (s, 9H), 1.20 (t, J = 7.0 Hz, 3H), 0.58 (br s, 3H); 13 C NMR (100 MHz, CDCl 3) δ 179.9, 167.3, 166.2, 155.8, 145.2, 134.6, 134.5, 127.2, 126.9, 126.0, 52.4, 50.9, 40.2, 39.6, 35.4, 30.0, 29.8, 27.8, 13.9; IR (KBr) υ 3298, 3057, 2965, 2927, 2873, 2364, 1701, 1650, 1540, 1437, 1417, 1355, 1326, 1288, 1242, 1207, 1176, 1120, 1082, 1044, 905, 816, 770 , 733 cm &lt; -1 & gt ;; HRMS (quadrupole, EI) calcd for C 21 H 29 N 3 O 5 [M] + 403.2107, found 403.2109.

8-8. N-Ethyl-N-(8-8. N-Ethyl-N- ( ethylcarbamoylethylcarbamoyl )-6-methyl-1-) -6-methyl-1- pivaloylindoline피발oylindoline -7--7- carboxamidecarboxamide (3j)의 생성 및 구조분석 (3j) and analysis of structure

[화학식 3j][Chemical formula 3j]

Figure 112017037435453-pat00025
Figure 112017037435453-pat00025

14.4 mg (20%, E:Z = 2.6:1); white solid; mp = 135.7-137.2 oC; 1H NMR (400 MHz, CDCl3) δ 7.79 (br s, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 4.35 (t, J = 9.0 Hz, 1H), 4.03-3.91 (m, 1H), 3.89-3.82 (m, 2H), 3.27-3.17 (m, 2H), 2.91-2.5 (m, 2H), 2.26 (s, 3H), 1.33 (s, 9H), 1.24 (t, J = 7.0 Hz, 3H), 0.59 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 179.6, 167.8, 156.2, 141.6, 134.1, 131.9, 127.1, 127.0, 125.1, 51.2, 40.0, 39.1, 35.3, 30.5, 28.0, 20.0, 13.8, 13.7; IR (KBr) υ 3284, 3059, 2973, 2928, 2370, 1699, 1645, 1540, 1456, 1402, 1372, 1316, 1245, 1166, 1079, 897, 808, 743 cm-1; HRMS (quadrupole, EI) calcd for C20H29N3O3 [M]+ 359.2209, found 359.2209.14.4 mg (20%, E: Z = 2.6: 1); white solid; mp = 135.7-137.2 o C; 1 H NMR (400 MHz, CDCl 3) δ 7.79 (br s, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 4.35 (t, J = 9.0 2H), 2.26 (s, 3H), 1.33 (m, 2H) s, 9H), 1.24 (t, J = 7.0 Hz, 3H), 0.59 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3) δ 179.6, 167.8, 156.2, 141.6, 134.1, 131.9, 127.1, 127.0, 125.1, 51.2, 40.0, 39.1, 35.3, 30.5, 28.0, 20.0, 13.8, 13.7; IR (KBr) ν 3284, 3059, 2973, 2928, 2370, 1699, 1645, 1540, 1456, 1402, 1372, 1316, 1245, 1166, 1079, 897, 808, 743 cm -1 ; HRMS (quadrupole, EI) calcd for C 20 H 29 N 3 O 3 [M] + 359.2209, found 359.2209.

8-9. 6-8-9. 6- ChloroChloro -N-ethyl-N-(-N-ethyl-N- ( ethylcarbamoylethylcarbamoyl )-1-)-One- pivaloylindoline피발oylindoline -7--7- carboxamidecarboxamide (3k)의 생성 및 구조분석 (3k) generation and structural analysis

[화학식 3k][Chemical Formula 3k]

Figure 112017037435453-pat00026
Figure 112017037435453-pat00026

13.7 mg (18%, E:Z = 2.6:1); white solid; mp = 152.8-153.5 oC; 1H NMR (400 MHz, CDCl3) δ 7.43 (br s, 1H), 7.12 (d, J = 8.1 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 4.37 (t, J = 9.2 Hz, 1H), 4.17 (t, J = 7.9 Hz, 1H), 3.99-3.87 (m, 1H), 3.85-3.76 (m, 1H), 3.32-3.22 (m, 2H), 2.97-2.87 (m, 2H), 1.33 (s, 9H), 1.23 (t, J = 6.9 Hz, 3H), 0.68 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 179.8, 165.2, 155.5, 143.1, 133.1, 130.0, 127.0, 125.8, 125.7, 51.2, 42.2, 39.3, 35.4, 30.4, 27.9, 13.9, 13.6; IR (KBr) υ 3307, 3055, 2965, 2924, 2361, 2342, 1701, 1645, 1540, 1445, 1401, 1373, 1313, 1267, 1244, 1161, 1099, 816, 742 cm-1; HRMS (orbitrap, ESI) calcd for C19H27ClN3O3 [M+H]+ 380.1735, found 380.1740.13.7 mg (18%, E: Z = 2.6: 1); white solid; mp = 152.8-153.5 o C; 1 H NMR (400 MHz, CDCl 3) δ 7.43 (br s, 1H), 7.12 (d, J = 8.1 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 4.37 (t, J = 9.2 (M, 2H), 2.97-2.87 (m, 1H), 3.85-3.76 (m, 2H), 1.33 (s, 9H), 1.23 (t, J = 6.9 Hz, 3H), 0.68 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3) δ 179.8, 165.2, 155.5, 143.1, 133.1, 130.0, 127.0, 125.8, 125.7, 51.2, 42.2, 39.3, 35.4, 30.4, 27.9, 13.9, 13.6; IR (KBr) v 3307, 3055, 2965, 2924, 2361, 2342, 1701, 1645, 1540, 1445, 1401, 1373, 1313, 1267, 1244, 1161, 1099, 816, 742 cm -1 ; HRMS (orbitrap, ESI) calcd for C 19 H 27 ClN 3 O 3 [M + H] + 380.1735, found 380.1740.

8-10. 6-Chloro-N-ethyl-1-pivaloylindoline-7-carboxamide (3ka)의 생성 및 구조분석8-10. Production and structural analysis of 6-Chloro-N-ethyl-1-pivaloylindoline-7-carboxamide (3ka)

[화학식 3ka][Formula 3ka]

Figure 112017037435453-pat00027
Figure 112017037435453-pat00027

6.8 mg (11%); light brown solid; mp = 174.2-178.9 oC; 1H NMR (400 MHz, CDCl3) δ 7.08 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.16 (br s, 1H), 4.14 (t, J = 8.0 Hz, 2H), 3.41-3.34 (m, 2H), 2.98 (t, J = 7.6 Hz, 2H), 1.29 (s, 9H), 1.21 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 178.6, 165.4, 143.2, 133.1, 129.4, 126.8, 125.6, 125.3, 50.9, 39.8, 34.8, 30.1, 27.9, 14.4; IR (KBr) υ 3333, 3055, 2970, 2932, 2876, 2361, 1644, 1589, 1540, 1443, 1421, 1401, 1355, 1267, 1187, 1158, 1097, 1056, 956, 917, 872, 806, 738 cm-1; HRMS (quadrupole, EI) calcd for C16H21ClN2O2 [M]+ 308.1292, found 308.1294.6.8 mg (11%); light brown solid; mp = 174.2-178.9 o C; 1 H NMR (400 MHz, CDCl 3) δ 7.08 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.16 (br s, 1H), 4.14 (t, J = 8.0 Hz, 2H), 3.41-3.34 (m, 2H), 2.98 (t, J = 7.6 Hz, 2H), 1.29 (s, 9H), 1.21 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3) δ 178.6, 165.4, 143.2, 133.1, 129.4, 126.8, 125.6, 125.3, 50.9, 39.8, 34.8, 30.1, 27.9, 14.4; IR (KBr)? 3333, 3055, 2970, 2932, 2876, 2361, 1644, 1589, 1540, 1443, 1421, 1401, 1355, 1267, 1187, 1158, 1097, 1056, 956, 917, 872, 806, 738 cm -1 ; HRMS (quadrupole, EI) calcd for C 16 H 21 ClN 2 O 2 [M] + 308.1292, found 308.1294.

8-11. N-Ethyl-N-(8-11. N-Ethyl-N- ( ethylcarbamoylethylcarbamoyl )-2-methyl-1-) -2-methyl-1- pivaloylindoline피발oylindoline -7--7- carboxamidecarboxamide (3l)의 생성 및 구조분석 (3l) &lt; / RTI &gt;

[화학식 3l]&Lt; EMI ID =

Figure 112017037435453-pat00028
Figure 112017037435453-pat00028

44.4 mg (62%); yellow sticky solid; 1H NMR (400 MHz, CDCl3) δ 7.92 (br s, 1H), 7.29 (d, J = 7.3 Hz, 1H), 7.18 (d, J = 7.3 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 4.87-4.81 (m, 1H), 3.82 (br s, 2H), 3.32 (q, J = 7.1 Hz, 1H), 3.09 (br s, 1H), 2.99 (br s, 1H), 2.58 (d, J = 15.0 Hz, 1H), 1.34 (s, 9H), 1.30 (d, J = 6.3 Hz, 3H), 1.20 (br s, 3H), 0.64 (br s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.7, 168.1, 156.1, 139.9, 133.9, 129.3, 126.5, 124.9, 124.6, 57.2, 40.0, 39.5, 37.7, 35.2, 28.4, 20.6, 13.6, 13.7; IR (KBr) υ 3291, 3070, 2963, 2923, 2853, 2366, 1700, 1653, 1629, 1589, 1551, 1442, 1400, 1373, 1358, 1324, 1247, 1189, 994, 831, 785, 749 cm-1; HRMS (orbitrap, ESI) calcd for C20H30N3O3 [M+H]+ 360.2282, found 360.2284.44.4 mg (62%); yellow sticky solid; 1 H NMR (400 MHz, CDCl 3) δ 7.92 (br s, 1H), 7.29 (d, J = 7.3 Hz, 1H), 7.18 (d, J = 7.3 Hz, 1H), 7.05 (t, J = 7.5 (Br s, 2H), 3.32 (q, J = 7.1 Hz, 1H), 3.09 (br s, 1H), 2.99 2.58 (d, J = 15.0 Hz, 1H), 1.34 (s, 9H), 1.30 (d, J = 6.3 Hz, 3H), 1.20 (br s, 3H), 0.64 (br s, 3H); 13 C NMR (100 MHz, CDCl 3) δ 177.7, 168.1, 156.1, 139.9, 133.9, 129.3, 126.5, 124.9, 124.6, 57.2, 40.0, 39.5, 37.7, 35.2, 28.4, 20.6, 13.6, 13.7; IR (KBr) υ 3291, 3070 , 2963, 2923, 2853, 2366, 1700, 1653, 1629, 1589, 1551, 1442, 1400, 1373, 1358, 1324, 1247, 1189, 994, 831, 785, 749 cm - 1 ; HRMS (orbitrap, ESI) calcd for C 20 H 30 N 3 O 3 [M + H] + 360.2282, found 360.2284.

8-12. 5-8-12. 5- ChloroChloro -N-ethyl-N-(-N-ethyl-N- ( ethylcarbamoylethylcarbamoyl )-2-methyl-1-) -2-methyl-1- pivaloylindoline피발oylindoline -7--7- carboxamidecarboxamide (3m)의 생성 및 구조분석 (3m) and analysis of structure

[화학식 3m][Formula 3m]

Figure 112017037435453-pat00029
Figure 112017037435453-pat00029

49.6 mg (63%); brown solid; mp = 121.0-122.1 oC; 1H NMR (400 MHz, CDCl3) δ 7.80 (br s, 1H), 7.26 (s, 1H), 7.16 (s, 1H), 4.88-4.82 (m, 1H), 3.80 (br s, 2H), 3.31 (q, J = 7.2 Hz, 1H), 3.21 (br s, 1H), 2.96 (br s, 1H), 2.57 (d, J = 15.2 Hz, 1H), 1.33 (s, 9H), 1.30 (d, J = 6.3 Hz, 3H), 1.18 (br s, 3H), 0.68 (br s, 3H); 13C NMR (100 MHz, CDCl3) δ δ 177.9, 166.3, 155.6, 138.6, 135.9, 130.1, 129.9, 126.6, 124.9, 57.4, 40.1, 39.5, 37.6, 35.3, 28.3, 20.6, 13.6 (two carbon overlap); IR (KBr) υ 3296, 3071, 2969, 2931, 2873, 2361, 1700, 1654, 1629, 1587, 1546, 1454, 1415, 1372, 1350, 1322, 1296, 1246, 1203, 1189, 1105, 1069, 995, 894, 848, 809, 728 cm-1; HRMS (orbitrap, ESI) calcd for C20H29ClN3O3 [M+H]+ 394.1892, found 394.1895.49.6 mg (63%); brown solid; mp = 121.0-122.1 o C; 1 H NMR (400 MHz, CDCl 3) δ 7.80 (br s, 1H), 7.26 (s, 1H), 7.16 (s, 1H), 4.88-4.82 (m, 1H), 3.80 (br s, 2H), (D, J = 15.2 Hz, 1H), 1.33 (s, 9H), 1.30 (br s, 1H) , J = 6.3 Hz, 3H), 1.18 (br s, 3H), 0.68 (br s, 3H); 13 C NMR (100 MHz, CDCl 3) δ δ 177.9, 166.3, 155.6, 138.6, 135.9, 130.1, 129.9, 126.6, 124.9, 57.4, 40.1, 39.5, 37.6, 35.3, 28.3, 20.6, 13.6 (two carbon overlap) ; IR (KBr) ν 3296, 3071, 2969, 2931, 2873, 2361, 1700, 1654, 1629, 1587, 1546, 1454, 1415, 1372, 1350, 1322, 1296, 1246, 1203, 1189, 1105, 1069, 995 , 894, 848, 809, 728 cm &lt; -1 & gt ;; HRMS (orbitrap, ESI) calcd for C 20 H 29 ClN 3 O 3 [M + H] + 394.1892, found 394.1895.

8-13. N-Ethyl-N-(8-13. N-Ethyl-N- ( ethylcarbamoylethylcarbamoyl )-3-methyl-1-) -3-methyl-1- pivaloylindoline피발oylindoline -7--7- carboxamidecarboxamide (3n)의 생성 및 구조분석 (3n) and analysis of structure

[화학식 3n](3n)

Figure 112017037435453-pat00030
Figure 112017037435453-pat00030

64.9 mg (90%); light yellow sticky solid; 1H NMR (500 MHz, CDCl3) δ 7.81 (br s, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 4.44-4.20 (m, 1H), 3.91-3.50 (m, 4H), 3.08-2.95 (m, 2H), 1.33 (s, 9H), 1.21 (t, J = 7.0 Hz, 6H), 0.60 (br s, 3H); 13C NMR (125 MHz, CDCl3) δ 178.7, 167.9, 155.9, 140.7, 139.8, 138.9, 127.3, 124.9, 124.4, 58.1, 39.6, 39.4, 36.8, 35.1, 27.6, 20.6, 16.5, 13.5; IR (KBr) υ 3286, 3057, 2969, 2933, 2874, 2362, 1700, 1633, 1589, 1550, 1439, 1401, 1359, 1315, 1246, 1078, 1048, 957, 901, 849, 732 cm-1; HRMS (quadrupole, EI) calcd for C20H29N3O3 [M]+ 359.2209, found 359.2208.64.9 mg (90%); light yellow sticky solid; 1 H NMR (500 MHz, CDCl 3) δ 7.81 (br s, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.02 (t, J = 7.5 2H), 1.33 (s, 9H), 1.21 (t, J = 7.0 Hz, 6H) , 0.60 (br s, 3H); 13 C NMR (125 MHz, CDCl 3) δ 178.7, 167.9, 155.9, 140.7, 139.8, 138.9, 127.3, 124.9, 124.4, 58.1, 39.6, 39.4, 36.8, 35.1, 27.6, 20.6, 16.5, 13.5; IR (KBr) ν 3286, 3057, 2969, 2933, 2874, 2362, 1700, 1633, 1589, 1550, 1439, 1401, 1359, 1315, 1246, 1078, 1048, 957, 901, 849, 732 cm -1 ; HRMS (quadrupole, EI) calcd for C 20 H 29 N 3 O 3 [M] + 359.2209, found 359.2208.

8-14. N-Butyl-N-(butylcarbamoyl)-1-pivaloylindoline-7-carboxamide (4b)의 생성 및 구조분석8-14. N-Butyl-N- (butylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4b)

[화학식 4b](4b)

Figure 112017037435453-pat00031
Figure 112017037435453-pat00031

70.6 mg (88%); brown sticky solid; 1H NMR (400 MHz, CDCl3) δ 7.86 (br s, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 4.37 (br s, 1H), 4.05 (br s, 1H), 3.75 (br s, 2H), 3.20-2.94 (m, 4H), 1.66-1.57 (m, 2H), 1.45-1.31 (m, 15H), 0.89 (br s, 6H); 13C NMR (100 MHz, CDCl3) δ 179.2, 168.4, 156.9, 141.1, 134.4, 127.9, 126.0, 125.1, 124.6, 50.7, 44.5, 40.4, 39.9, 30.9, 30.7, 30.5, 27.9, 20.2, 19.9, 14.1, 13.8; IR (KBr) υ 3288, 3057, 2958, 2930, 2872, 2372, 1700, 1651, 1633, 1590, 1552, 1446, 1401, 1361, 1327, 1266, 1227, 1208, 1161, 1095, 746 cm-1; HRMS (quadrupole, EI) calcd for C23H35N3O3 [M]+ 401.2678, found 401.2676.70.6 mg (88%); brown sticky solid; 1 H NMR (400 MHz, CDCl 3) δ 7.86 (br s, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 6.98 (t, J = 7.5 (M, 2H), 1.45-1.31 (m, 2H), 3.60 (s, 3H) (m, 15 H), 0.89 (br s, 6 H); 13 C NMR (100 MHz, CDCl 3) δ 179.2, 168.4, 156.9, 141.1, 134.4, 127.9, 126.0, 125.1, 124.6, 50.7, 44.5, 40.4, 39.9, 30.9, 30.7, 30.5, 27.9, 20.2, 19.9, 14.1 , 13.8; IR (KBr) ν 3288, 3057, 2958, 2930, 2872, 2372, 1700, 1651, 1633, 1590, 1552, 1446, 1401, 1361, 1327, 1266, 1227, 1208, 1161, 1095, 746 cm -1 ; HRMS (quadrupole, EI) calcd for C 23 H 35 N 3 O 3 [M] + 401.2678, found 401.2676.

8-15. N-Pentyl-N-(pentylcarbamoyl)-1-pivaloylindoline-7-carboxamide (4c)의 생성 및 구조분석8-15. N-Pentyl-N- (pentylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4c)

[화학식 4c][Chemical Formula 4c]

Figure 112017037435453-pat00032
Figure 112017037435453-pat00032

63.5 mg (74%); brown sticky solid; 1H NMR (400 MHz, CDCl3) δ 7.84 (br s, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 4.37 (br s, 1H), 4.09-4.02 (m, 1H), 3.74 (br s, 2H), 3.24-3.16 (m, 1H), 3.00-2.94 (m, 3H), 1.66-1.59 (m, 2H), 1.32 (s, 13H), 1.04 (br s, 3H), 0.85-0.71 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 179.0, 168.2, 156.8, 141.1, 134.3, 127.9, 126.1, 125.1, 124.6, 50.7, 44.7, 40.6, 39.9, 30.4, 29.1, 28.9, 28.8, 28.4, 27.9, 22.7, 22.4, 14.1, 14.0; IR (KBr) υ 3289, 3070, 2956, 2929, 2870, 2370, 1700, 1651, 1633, 1551, 1446, 1401, 1361, 1329, 1231, 1097, 902, 747 cm-1; HRMS (orbitrap, ESI) calcd for C25H40N3O3 [M+H]+ 430.3064, found 430.3066.63.5 mg (74%); brown sticky solid; 1 H NMR (400 MHz, CDCl 3) δ 7.84 (br s, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.98 (t, J = 7.5 (M, 3H), 1.66 (m, IH), 4.37 (br s, IH), 4.09-4.02 1.59 (m, 2H), 1.32 (s, 13H), 1.04 (br s, 3H), 0.85-0.71 (m, 9H); 13 C NMR (100 MHz, CDCl 3) δ 179.0, 168.2, 156.8, 141.1, 134.3, 127.9, 126.1, 125.1, 124.6, 50.7, 44.7, 40.6, 39.9, 30.4, 29.1, 28.9, 28.8, 28.4, 27.9, 22.7 , 22.4, 14.1, 14.0; IR (KBr) ν 3289, 3070, 2956, 2929, 2870, 2370, 1700, 1651, 1633, 1551, 1446, 1401, 1361, 1329, 1231, 1097, 902, 747 cm -1 ; HRMS (orbitrap, ESI) calcd for C 25 H 40 N 3 O 3 [M + H] + 430.3064, found 430.3066.

8-16. N-Pentyl-1-pivaloylindoline-7-carboxamide (4ca)의 생성 및 구조분석8-16. Synthesis and structural analysis of N-Pentyl-1-pivaloylindoline-7-carboxamide (4ca)

[화학식 4ca][Chemical Formula 4ca]

Figure 112017037435453-pat00033
Figure 112017037435453-pat00033

6.5 mg (10%); white solid; mp = 186.0-188.3 oC; 1H NMR (500 MHz, CDCl3) δ 7.26 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 5.86 (br s, 1H), 4.20 (t, J = 8.0 Hz, 2H), 3.33 (q, J = 7.0 Hz, 2H), 3.05 (t, J = 8.0 Hz, 2H), 1.64-1.58 (m, 2H), 1.35 (br s, 11H), 1.25 (s, 2H), 0.90 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 178.1, 168.7, 141.3, 134.4, 128.3, 125.8, 125.7, 124.0, 50.3, 39.9, 39.7, 30.4, 29.3, 29.2, 27.9, 22.4, 13.9; IR (KBr) υ 3239, 3075, 2953, 2927, 2857, 2360, 2341, 1657, 1588, 1557, 1431, 1396, 1355, 1326, 1266, 1233, 1209, 1163, 1100, 1013, 899, 861, 799, 737 cm-1; HRMS (quadrupole, EI) calcd for C19H28N2O2 [M]+ 316.2151, found 316.2148.6.5 mg (10%); white solid; mp = 186.0-188.3 o C; 1 H NMR (500 MHz, CDCl 3) δ 7.26 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 5.86 (br J = 8.0 Hz, 2H), 3.64 (q, J = 7.0 Hz, 2H), 3.05 (t, 1.35 (br s, 1H), 1.25 (s, 2H), 0.90 (t, J = 7.0 Hz, 3H); 13 C NMR (125 MHz, CDCl 3) δ 178.1, 168.7, 141.3, 134.4, 128.3, 125.8, 125.7, 124.0, 50.3, 39.9, 39.7, 30.4, 29.3, 29.2, 27.9, 22.4, 13.9; IR (KBr) ν 3239, 3075, 2953, 2927, 2857, 2360, 2341, 1657, 1588, 1557, 1431, 1396, 1355, 1326, 1266, 1233, 1209, 1163, 1100, 1013, 899, 861, 799 , 737 cm &lt; -1 & gt ;; HRMS (quadrupole, EI) calcd for C 19 H 28 N 2 O 2 [M] + 316.2151, found 316.2148.

8-17. N-Hexyl-N-(hexylcarbamoyl)-1-pivaloylindoline-7-carboxamide (4d)의 생성 및 구조분석8-17. N-Hexyl-N- (hexylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4d)

[화학식 4d][Chemical formula 4d]

Figure 112017037435453-pat00034
Figure 112017037435453-pat00034

74.1 mg (81%); brown sticky solid; 1H NMR (400 MHz, CDCl3) δ 7.84 (br s, 1H), 7.23 (d, J = 7.3 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 4.38 (br s, 1H), 4.10-4.04 (m, 1H), 3.75 (br s, 2H), 3.25-3.16 (m, 1H), 3.01-2.95 (m, 3H), 1.68-1.59 (m, 2H), 1.33-1.27 (m, 15H), 1.14-1.02 (m, 6H), 0.85-0.78 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 179.1, 168.2, 156.8, 141.2, 134.4, 127.9, 126.1, 125.1, 124.6, 50.7, 44.8, 40.7, 39.9, 31.9, 31.6, 30.5, 28.7, 27.9, 26.6, 26.5, 22.7, 14.3, 14.2; IR (KBr) υ 3296, 3069, 2955, 2928, 2857, 2346, 1702, 1651, 1633, 1590, 1550, 1446, 1401, 1361, 1328, 1248, 1228, 1162, 1098, 1029, 901, 749 cm-1; HRMS (quadrupole, EI) calcd for C27H43N3O3 [M]+ 457.3304, found 457.3302.74.1 mg (81%); brown sticky solid; 1 H NMR (400 MHz, CDCl 3) δ 7.84 (br s, 1H), 7.23 (d, J = 7.3 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.99 (t, J = 7.5 1H), 4.38 (br s, 1H), 4.10-4.04 (m, 1H), 3.75 (br s, 2H), 3.25-3.16 1.59 (m, 2H), 1.33-1.27 (m, 15H), 1.14-1.02 (m, 6H), 0.85-0.78 (m, 8H); 13 C NMR (100 MHz, CDCl 3) δ 179.1, 168.2, 156.8, 141.2, 134.4, 127.9, 126.1, 125.1, 124.6, 50.7, 44.8, 40.7, 39.9, 31.9, 31.6, 30.5, 28.7, 27.9, 26.6, 26.5 , 22.7, 14.3, 14.2; IR (KBr) υ 3296, 3069 , 2955, 2928, 2857, 2346, 1702, 1651, 1633, 1590, 1550, 1446, 1401, 1361, 1328, 1248, 1228, 1162, 1098, 1029, 901, 749 cm - 1 ; HRMS (quadrupole, EI) calcd for C 27 H 43 N 3 O 3 [M] + 457.3304, found 457.3302.

8-18. N-Octyl-N-(octylcarbamoyl)-1-pivaloylindoline-7-carboxamide (4e)의 생성 및 구조분석8-18. N-Octyl-N- (octylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4e)

[화학식 4e][Chemical Formula 4e]

Figure 112017037435453-pat00035
Figure 112017037435453-pat00035

84.2 mg (82%); brown sticky solid; 1H NMR (400 MHz, CDCl3) δ 7.84 (br s, 1H), 7.21 (d, J = 7.3 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 4.37 (br s, 1H), 4.09-4.02 (m, 1H), 3.74 (br s, 2H), 3.20-3.15 (m, 1H), 2.99-2.93 (m, 3H), 1.67-1.59 (m, 2H), 1.32 (s, 9H), 1.23-1.03 (m, 22H), 0.84 (t, J = 6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 179.1, 168.2, 156.8, 141.2, 134.3, 127.9, 126.0, 125.1, 124.5, 50.7, 44.8, 40.7, 40.0, 32.0, 31.9, 30.5, 29.9, 29.6, 29.4, 29.3, 28.9, 28.7, 28.6, 27.9, 26.9, 26.8, 22.8, 14.3, 14.2; IR (KBr) υ 3294, 3073, 2954, 2923, 2854, 2361, 1703, 1651, 1634, 1590, 1550, 1446, 1401, 1360, 1325, 1236, 1162, 1099, 901, 749 cm-1; HRMS (quadrupole, EI) calcd for C31H51N3O3 [M]+ 513.3930, found 513.3931.84.2 mg (82%); brown sticky solid; 1 H NMR (400 MHz, CDCl 3) δ 7.84 (br s, 1H), 7.21 (d, J = 7.3 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.98 (t, J = 7.5 (M, 3H), 1.67 (m, IH), 4.37 (br s, IH), 4.09-4.02 1.59 (m, 2H), 1.32 (s, 9H), 1.23-1.03 (m, 22H), 0.84 (t, J = 6.9 Hz, 6H); 13 C NMR (100 MHz, CDCl 3) δ 179.1, 168.2, 156.8, 141.2, 134.3, 127.9, 126.0, 125.1, 124.5, 50.7, 44.8, 40.7, 40.0, 32.0, 31.9, 30.5, 29.9, 29.6, 29.4, 29.3 , 28.9, 28.7, 28.6, 27.9, 26.9, 26.8, 22.8, 14.3, 14.2; IR (KBr) ν 3294, 3073, 2954, 2923, 2854, 2361, 1703, 1651, 1634, 1590, 1550, 1446, 1401, 1360, 1325, 1236, 1162, 1099, 901, 749 cm -1 ; HRMS (quadrupole, EI) calcd for C 31 H 51 N 3 O 3 [M] + 513.3930, found 513.3931.

8-19. N-8-19. N- PhenethylPhenethyl -N-(-N- ( phenethylcarbamoyl폴리ethylcarbamoyl )-1-)-One- pivaloylindoline피발oylindoline -7--7- carboxamidecarboxamide (4f)의 생성 및 구조분석 (4f) and analysis of structure

[화학식 4f][Formula 4f]

Figure 112017037435453-pat00036
Figure 112017037435453-pat00036

67.6 mg (68%); yellow sticky solid; 1H NMR (400 MHz, CDCl3) δ 7.78 (br s, 1H), 7.33-6.93 (m, 13H), 4.34 (br s, 1H), 4.08-3.99 (m, 3H), 3.22 (br s, 2H), 3.05-2.89 (m, 4H), 2.40 (br s, 1H), 2.15 (br s, 1H), 1.34 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 178.9, 168.1, 156.6, 139.3, 138.9, 134.3, 129.4, 129.0, 128.8, 128.6, 128.5, 128.4, 128.3, 126.3, 126.2, 125.0, 124.4, 50.5, 46.1, 41.6, 40.0, 35.1, 30.4, 29.9, 27.9; IR (KBr) υ 3295, 3059, 2955, 2923, 2853, 2364, 1698, 1650, 1633, 1590, 1538, 1447, 1400, 1359, 1328, 1261, 1225, 1194, 1163, 1132, 1100, 1028, 902, 782, 734 cm-1; HRMS (quadrupole, EI) calcd for C31H35N3O3 [M]+ 497.2678, found 497.2676.67.6 mg (68%); yellow sticky solid; 1 H NMR (400 MHz, CDCl 3) δ 7.78 (br s, 1H), 7.33-6.93 (m, 13H), 4.34 (br s, 1H), 4.08-3.99 (m, 3H), 3.22 (br s, 2H), 3.05-2.89 (m, 4H), 2.40 (br s, 1H), 2.15 (br s, 1H), 1.34 (s, 9H); 13 C NMR (100 MHz, CDCl 3) δ 178.9, 168.1, 156.6, 139.3, 138.9, 134.3, 129.4, 129.0, 128.8, 128.6, 128.5, 128.4, 128.3, 126.3, 126.2, 125.0, 124.4, 50.5, 46.1, 41.6 , 40.0, 35.1, 30.4, 29.9, 27.9; IR (KBr) v 3295, 3059, 2955, 2923, 2853, 2364, 1698, 1650, 1633, 1590, 1538, 1447, 1400, 1359, 1328, 1261, 1225, 1194, 1163, 1132, 1100, 1028, 902 , 782, 734 cm &lt; -1 & gt ;; HRMS (quadrupole, EI) calcd for C 31 H 35 N 3 O 3 [M] + 497.2678, found 497.2676.

8-20. N-Benzyl-N-(benzylcarbamoyl)-1-pivaloylindoline-7-carboxamide (4g)의 생성 및 구조분석8-20. N-Benzyl-N- (benzylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4g)

[화학식 4g][Chemical Formula 4g]

Figure 112017037435453-pat00037
Figure 112017037435453-pat00037

68.5 mg (73%); white solid; mp = 138.2-139.8 oC; 1H NMR (400 MHz, CDCl3) δ 8.21 (br s, 1H), 7.55 (br s, 1H), 7.31-7.04 (m, 10H), 6.95 (t, J = 7.2 Hz, 1H), 6.59 (br s, 1H), 5.19-4.87 (m, 2H), 4.33 (d, J = 5.8 Hz, 2H), 4.12-4.03 (m, 2H), 3.14-2.96 (m, 2H), 1.32 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 178.8, 168.9, 156.2, 141.0, 139.5, 137.9, 134.5, 128.9, 128.4, 128.3, 127.6, 127.4, 127.1, 126.9, 126.3, 125.2, 124.9, 50.6, 44.9, 44.7, 39.9, 30.4, 27.9; IR (KBr) υ 3287, 2967, 2932, 2360, 2341, 1712, 1655, 1630, 1588, 1549, 1446, 1433, 1402, 1362, 1223, 1145, 1100, 1028, 905, 794, 745 cm-1; HRMS (quadrupole, EI) calcd for C29H31N3O3 [M]+ 469.2365, found 469.2368.68.5 mg (73%); white solid; mp = 138.2-139.8 o C; 1 H NMR (400 MHz, CDCl 3) δ 8.21 (br s, 1H), 7.55 (br s, 1H), 7.31-7.04 (m, 10H), 6.95 (t, J = 7.2 Hz, 1H), 6.59 ( (m, 2H), 1.32 (s, 9H), 4.32 (d, J = 5.8 Hz, 2H), 4.19-4.87 ); 13 C NMR (100 MHz, CDCl 3) δ 178.8, 168.9, 156.2, 141.0, 139.5, 137.9, 134.5, 128.9, 128.4, 128.3, 127.6, 127.4, 127.1, 126.9, 126.3, 125.2, 124.9, 50.6, 44.9, 44.7 , 39.9, 30.4, 27.9; IR (KBr) ν 3287, 2967, 2932, 2360, 2341, 1712, 1655, 1630, 1588, 1549, 1446, 1433, 1402, 1362, 1223, 1145, 1100, 1028, 905, 794, 745 cm -1 ; HRMS (quadrupole, EI) calcd for C 29 H 31 N 3 O 3 [M] + 469.2365, found 469.2368.

8-21. N-8-21. N- CyclopentylCyclopentyl -N-(-N- ( cyclopentylcarbamoylcyclopentylcarbamoyl )-1-)-One- pivaloylindoline피발oylindoline -7--7- carboxamidecarboxamide (4h)의 생성 및 구조분석 (4h) and analysis of structure

[화학식 4h][Chemical Formula 4h]

Figure 112017037435453-pat00038
Figure 112017037435453-pat00038

17.1 mg (20%); brown solid; mp = 124.9-125.3 oC; 1H NMR (400 MHz, CDCl3) δ 8.12 (br s, 1H), 7.23-7.18 (m, 2H), 7.01 (t, J = 7.5 Hz, 1H), 4.70-4.62 (m, 1H), 4.37 (t, J = 9.4 Hz, 1H), 4.04 (q, J = 9.9 Hz, 1H), 3.84 (br s, 1H), 3.24-3.15 (m, 1H), 2.99-2.93 (m, 1H), 2.20-2.13 (m, 1H), 1.97-1.67 (m, 9H), 1.39-1.24 (m, 15H); 13C NMR (100 MHz, CDCl3) δ 178.9, 167.8, 155.7, 141.0, 134.2, 128.4, 125.9, 125.2, 124.6, 52.4, 50.8, 40.1, 32.6, 31.3, 30.8, 30.5, 29.8, 28.8, 28.0, 24.8, 24.6, 23.4, 23.0; IR (KBr) υ 3272, 2959, 2870, 2360, 2341, 1715, 1653, 1634, 1557, 1446, 1362, 1222, 1158, 1095, 899, 759 cm-1; HRMS (quadrupole, EI) calcd for C25H35N3O3 [M]+ 425.2678, found 425.2675.17.1 mg (20%); brown solid; mp = 124.9-125.3 o C; 1 H NMR (400 MHz, CDCl 3) δ 8.12 (br s, 1H), 7.23-7.18 (m, 2H), 7.01 (t, J = 7.5 Hz, 1H), 4.70-4.62 (m, 1H), 4.37 (t, J = 9.4 Hz, IH), 4.04 (q, J = 9.9 Hz, IH), 3.84 (br s, IH), 3.24-3.15 (m, IH), 2.99-2.93 -2.13 (m, 1H), 1.97-1.67 (m, 9H), 1.39-1.24 (m, 15H); 13 C NMR (100 MHz, CDCl 3) δ 178.9, 167.8, 155.7, 141.0, 134.2, 128.4, 125.9, 125.2, 124.6, 52.4, 50.8, 40.1, 32.6, 31.3, 30.8, 30.5, 29.8, 28.8, 28.0, 24.8 , 24.6, 23.4, 23.0; IR (KBr) ν 3272, 2959, 2870, 2360, 2341, 1715, 1653, 1634, 1557, 1446, 1362, 1222, 1158, 1095, 899, 759 cm -1 ; HRMS (quadrupole, EI) calcd for C 25 H 35 N 3 O 3 [M] + 425.2678, found 425.2675.

8-22. N-Cyclopentyl-1-pivaloylindoline-7-carboxamide (4ha)의 생성 및 구조분석8-22. Production and structural analysis of N-Cyclopentyl-1-pivaloylindoline-7-carboxamide (4ha)

[화학식 4ha][Chemical Formula 4 ha]

Figure 112017037435453-pat00039
Figure 112017037435453-pat00039

32.1 mg (51%); white solid; mp = 186.2-189.8 oC; 1H NMR (400 MHz, CDCl3) δ 7.27-7.22 (m, 2H), 7.02 (t, J = 7.6 Hz, 1H), 5.75 (d, J = 7.2 Hz, 1H), 4.32-4.28 (m, 1H), 4.23 (t, J = 7.6 Hz, 2H), 3.06 (t, J = 7.6 Hz, 2H), 2.07-2.01 (m, 2H), 1.73-1.62 (m, 2H), 1.60-1.54 (m, 4H), 1.35 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 178.0, 168.4, 141.2, 134.2, 128.3, 125.8, 124.1 (two carbon overlap), 51.5, 50.4, 39.6, 33.0, 30.4, 27.9, 23.8; IR (KBr) υ 3225, 3055, 2991, 2953, 2923, 2867, 2362, 2341, 1658, 1619, 1586, 1549, 1473, 1450, 1432, 1394, 1351, 1324, 1305, 1267, 1237, 1207, 1162, 1102, 1029, 975, 954, 935, 907, 892, 871, 853, 777 cm-1; HRMS (quadrupole, EI) calcd for C19H26N2O2 [M]+ 314.1994, found 314.1992.32.1 mg (51%); white solid; mp = 186.2-189.8 o C; 1H NMR (400 MHz, CDCl 3 ) δ 7.27-7.22 (m, 2H), 7.02 (t, J = 7.6 Hz, 1H), 5.75 (d, J = 7.2 Hz, 1H), 4.32-4.28 (m, 1H 2H), 1.73-1.62 (m, 2H), 1.60-1.54 (m, 2H), 4.23 (t, J = 7.6 Hz, 2H) 4H), 1.35 (s, 9H); 13 C NMR (100 MHz, CDCl 3) δ 178.0, 168.4, 141.2, 134.2, 128.3, 125.8, 124.1 (two carbon overlap), 51.5, 50.4, 39.6, 33.0, 30.4, 27.9, 23.8; IR (KBr) υ 3225, 3055, 2991, 2953, 2923, 2867, 2362, 2341, 1658, 1619, 1586, 1549, 1473, 1450, 1432, 1394, 1351, 1324, 1305, 1267, 1237, 1207, 1162 , 1102, 1029, 975, 954, 935, 907, 892, 871, 853, 777 cm &lt; -1 & gt ;; HRMS (quadrupole, EI) calcd for C 19 H 26 N 2 O 2 [M] + 314.1994, found 314.1992.

8-23. N-Phenyl-N-(phenylcarbamoyl)-1-pivaloylindoline-7-carboxamide (4i)의 생성 및 구조분석8-23. N-Phenyl-N- (phenylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4i)

[화학식 4i][Formula 4i]

Figure 112017037435453-pat00040
Figure 112017037435453-pat00040

62.7 mg (71%); brown solid; mp = 126.9-128.0 oC; 1H NMR (400 MHz, CDCl3) δ 10.90 (br s, 1H), 7.41 (d, J = 7.1 Hz, 2H), 7.33-7.23 (m, 8H), 7.15 (d, J = 7.4 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 4.05 (br s, 2H), 3.02-2.98 (m, 2H), 1.39 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 178.0, 170.5, 152.9, 140.3, 138.4, 138.2, 133.8, 129.5, 128.9, 128.6, 127.9, 126.9, 126.4, 126.3, 124.5, 124.1, 119.9, 50.4, 40.0, 30.1, 28.1; IR (KBr) υ 3205, 3065, 2967, 2925, 2358, 2339, 1716, 1672, 1623, 1597, 1542, 1490, 1445, 1361, 1222, 1140, 1101, 1028, 901, 753 cm-1; HRMS (quadrupole, EI) calcd for C27H27N3O3 [M]+ 441.2052, found 441.2051.62.7 mg (71%); brown solid; mp = 126.9-128.0 o C; 1 H NMR (400 MHz, CDCl 3) δ 10.90 (br s, 1H), 7.41 (d, J = 7.1 Hz, 2H), 7.33-7.23 (m, 8H), 7.15 (d, J = 7.4 Hz, 1H ), 7.05 (t, J = 7.4 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 4.05 (br s, 2H), 3.02-2.98 (m, 2H), 1.39 (s, 9H); 13 C NMR (100 MHz, CDCl3 ) δ 178.0, 170.5, 152.9, 140.3, 138.4, 138.2, 133.8, 129.5, 128.9, 128.6, 127.9, 126.9, 126.4, 126.3, 124.5, 124.1, 119.9, 50.4, 40.0, 30.1, 28.1; IR (KBr) υ 3205, 3065, 2967, 2925, 2358, 2339, 1716, 1672, 1623, 1597, 1542, 1490, 1445, 1361, 1222, 1140, 1101, 1028, 901, 753 cm -1 ; HRMS (quadrupole, EI) calcd for C 27 H 27 N 3 O 3 [M] + 441.2052, found 441.2051.

8-24. 1-8-24. One- PivaloylPivaloyl -N-(p--N- (p- tolyltolyl )-N-(p-) -N- (p- tolylcarbamoyltolylcarbamoyl )) indolineindoline -7--7- carboxamidecarboxamide (4j)의 생성 및 구조분석 (4j) and analysis of structure

[화학식 4j][Chemical formula 4j]

Figure 112017037435453-pat00041
Figure 112017037435453-pat00041

44.1 mg (47%); brown solid; mp = 146.0-147.9 oC; 1H NMR (400 MHz, CDCl3) δ 10.81 (br s, 1H), 7.28-7.26 (m, 3H), 7.21 (d, J = 7.1Hz, 2H), 7.15 (d, J = 7.3 Hz, 1H), 7.09 (d, J = 7.4 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H), 6.96 (t, J = 7.6 Hz, 1H), 4.06 (br s, 2H), 3.01 (br s, 2H), 2.30 (s, 3H), 2.27 (s, 3H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 178.1, 166.7, 152.9, 140.3, 137.7, 135.7, 135.6, 133.8, 133.6, 129.4, 129.3, 129.1, 127.0, 126.3, 126.1, 124.5, 119.9, 50.4, 39.9, 30.1, 28.0, 21.3, 21.0; IR (KBr) υ 3258, 3029, 2966, 2920, 2360, 1713, 1670, 1626, 1588, 1538, 1500, 1474, 1444, 1402, 1359, 1313, 1268, 1238, 1205, 1169, 1140, 1101, 1064, 901, 813, 754 cm-1; HRMS (quadrupole, EI) calcd for C29H31N3O3 [M]+ 469.2365, found 469.2363.44.1 mg (47%); brown solid; mp = 146.0-147.9 o C; 1 H NMR (400 MHz, CDCl 3) δ 10.81 (br s, 1H), 7.28-7.26 (m, 3H), 7.21 (d, J = 7.1Hz, 2H), 7.15 (d, J = 7.3 Hz, 1H ), 7.09 (d, J = 7.4 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H), 6.96 (t, J = 7.6 Hz, 1H) , 2H), 2.30 (s, 3H), 2.27 (s, 3H), 1.38 (s, 9H); 13 C NMR (100 MHz, CDCl 3) δ 178.1, 166.7, 152.9, 140.3, 137.7, 135.7, 135.6, 133.8, 133.6, 129.4, 129.3, 129.1, 127.0, 126.3, 126.1, 124.5, 119.9, 50.4, 39.9, 30.1 , 28.0, 21.3, 21.0; IR (KBr) υ 3258, 3029, 2966, 2920, 2360, 1713, 1670, 1626, 1588, 1538, 1500, 1474, 1444, 1402, 1359, 1313, 1268, 1238, 1205, 1169, 1140, 1101, 1064 , 901, 813, 754 cm &lt; -1 & gt ;; HRMS (quadrupole, EI) calcd for C 29 H 31 N 3 O 3 [M] + 469.2365, found 469.2363.

8-25. N-(4-8-25. N- (4- FluorophenylFluorophenyl )-N-((4-) -N - ((4- fluorophenylfluorophenyl )) carbamoylcarbamoyl )-1-)-One- pivaloylindoline피발oylindoline -7--7- carboxamidecarboxamide (4k)의 생성 및 구조분석 (4k) generation and structural analysis

[화학식 4k][Chemical Formula 4k]

Figure 112017037435453-pat00042
Figure 112017037435453-pat00042

66.8 mg (70%); brown sticky solid; 1H NMR (400 MHz, CDCl3) δ 10.91 (br s, 1H), 7.36-7.27 (m, 4H), 7.20-7.19 (m, 2H), 7.07-6.90 (m, 5H), 4.13 (br s, 2H), 3.07 (br s, 2H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 178.4, 169.7, 162.0 (d, JCF = 246.0 Hz), 159.5 (d, JCF = 241.5 Hz), 140.5, 134.2 (d, JCF = 31.5 Hz), 134.0 (d, JCF = 25.2 Hz), 131.4 (d, JCF = 79.1 Hz), 131.3, 126.6, 126.5, 126.1, 124.5, 121.7 (d, JCF = 76.7 Hz), 115.7 (d, JCF = 37.8 Hz), 115.5 (d, JCF = 42.4 Hz), 50.5, 40.1, 30.2, 28.1; IR (KBr) υ 3221, 3072, 2965, 2923, 2379, 1714, 1672, 1611, 1549, 1505, 1475, 1402, 1505, 1475, 1402, 1360, 1334, 1271, 1216, 1153, 1140, 1101, 1064, 902, 833 cm-1; HRMS (orbitrap, ESI) calcd for C27H26F2N3O3 [M+H]+ 478.1937, found 478.1941.66.8 mg (70%); brown sticky solid; 1 H NMR (400 MHz, CDCl 3) δ 10.91 (br s, 1H), 7.36-7.27 (m, 4H), 7.20-7.19 (m, 2H), 7.07-6.90 (m, 5H), 4.13 (br s , 2H), 3.07 (br s, 2H), 1.40 (s, 9H); 13 C NMR (100 MHz, CDCl 3) δ 178.4, 169.7, 162.0 (d, J CF = 246.0 Hz), 159.5 (d, J CF = 241.5 Hz), 140.5, 134.2 (d, J CF = 31.5 Hz), 134.0 (d, J CF = 25.2 Hz), 131.4 (d, J CF = 79.1 Hz), 131.3, 126.6, 126.5, 126.1, 124.5, 121.7 (d, J CF = 76.7 Hz), 115.7 (d, J CF = 37.8 Hz), 115.5 (d, J CF = 42.4 Hz), 50.5, 40.1, 30.2, 28.1; IR (KBr) v 3221, 3072, 2965, 2923, 2379, 1714, 1672, 1611, 1549, 1505, 1475, 1402, 1505, 1475, 1402, 1360, 1334, 1271, 1216, 1153, 1140, 1101, 1064 , 902, 833 cm &lt; -1 & gt ;; HRMS (orbitrap, ESI) calcd for C 27 H 26 F 2 N 3 O 3 [M + H] + 478.1937, found 478.1941.

8-26. N-(4-8-26. N- (4- ChlorophenylChlorophenyl )-N-((4-) -N - ((4- chlorophenylklorophenyl )) carbamoylcarbamoyl )-1-)-One- pivaloylindoline피발oylindoline -7--7- carboxamidecarboxamide (4l)의 생성 및 구조분석 (4l) &lt; / RTI &gt;

[화학식 4l](4l)

Figure 112017037435453-pat00043
Figure 112017037435453-pat00043

71.3 mg (70%); light yellow solid; mp = 158.7-159.6 oC; 1H NMR (400 MHz, CDCl3) δ 10.96 (br s, 1H), 7.34-7.28 (m, 6H), 7.22-7.16 (m, 4H), 6.95 (t, J = 7.6 Hz, 1H), 4.12 (br s, 2H), 3.05 (t, J = 7.5 Hz, 2H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 178.3, 165.4, 152.7, 140.5, 136.8, 136.7, 134.0, 133.9, 130.9, 129.2, 129.0, 128.9, 126.7, 126.3, 126.0, 124.6, 121.1, 50.5, 40.1, 30.2, 28.1; IR (KBr) υ 3246, 3057, 2964, 2924, 2853, 2358, 2341, 1715, 1676, 1645, 1588, 1538, 1489, 1432, 1401, 1360, 1334, 1304, 1267, 1207, 1172, 1140, 1089, 1012, 827, 754 cm-1; HRMS (orbitrap, ESI) calcd for C27H26Cl2N3O3 [M+H]+ 510.1346, found 510.1351.71.3 mg (70%); light yellow solid; mp = 158.7-159.6 o C; 1 H NMR (400 MHz, CDCl 3 )? 10.96 (br s, 1 H), 7.34-7.28 (m, 6H), 7.22-7.16 (br s, 2H), 3.05 (t, J = 7.5 Hz, 2H), 1.38 (s, 9H); 13 C NMR (100 MHz, CDCl 3) δ 178.3, 165.4, 152.7, 140.5, 136.8, 136.7, 134.0, 133.9, 130.9, 129.2, 129.0, 128.9, 126.7, 126.3, 126.0, 124.6, 121.1, 50.5, 40.1, 30.2 , 28.1; IR (KBr) ν 3246, 3057, 2964, 2924, 2853, 2358, 2341, 1715, 1676, 1645, 1588, 1538, 1489, 1432, 1401, 1360, 1334, 1304, 1267, 1207, 1172, 1140, 1089 , 1012, 827, 754 cm &lt; -1 & gt ;; HRMS (orbitrap, ESI) calcd for C 27 H 26 C l2 N 3 O 3 [M + H] + 510.1346, found 510.1351.

실시예 9. N-아로일우레아 유도체의 항암 활성 평가Example 9. Evaluation of antitumor activity of N-aroylurea derivatives

상기 실시예 1 내지 8에서 제조 및 분석한 N-아로일우레아 유도체의 항암 활성을 평가하고자, MTT assay를 수행하여, 암 세포에 대한 성장 억제 효과를 확인하였다. 보다 구체적으로, 인간 전립선 선암 세포주 (DU145), 인간 유방암 세포주 (MCF-7) 및 삼중 음성 인간 유방암 세포주 (MDA-MB-231)는 1 %의 페니실린/스트렙토마이신 및 10 % 태아 소 혈청(모두 Life Technologies, Grand Island, NY로부터)이 첨가된 DMEM 배지에서 배양하였다. 세포를 24 시간 동안 100 μL의 성장 배지를 함유한 96-웰 플레이트(3x103 cells/well)에 분주(seeding)하였다. 배지를 제거한 후, 각 농도별로 각기 다른 아날로그 화합물(DMSO에 0.025 % 이하로 용해) 100 μL를 각 웰에 넣고 37 ℃에서 48시간 동안 배양하였다. 배양 48시간 후, MTT 시약 100μL를 각 웰에 첨가하였다. 37℃에서 4시간 배양한 후, 상등액을 흡인하고, 포르마잔 결정을 DMSO 100 μL에 37℃에서 10분 동안 완만하게 교반하면서 용해시켰다. 웰 당 흡광도는 VERSA max 마이크로 플레이트 판독기 (Molecular Devices Corp.)를 사용하여 540 nm에서 측정하였다. IC50 값은 최대량의 DMSO(0.025 %)로 처리된 세포와 비교하여 세포 증식을 50% 저해하는 화합물 농도로 정의하였고 100% 생존력으로 간주하였다.In order to evaluate the anticancer activity of the N-aroyl urea derivatives prepared and analyzed in Examples 1 to 8, MTT assay was performed to confirm the growth inhibitory effect on cancer cells. More specifically, human prostate adenocarcinoma cell line (DU145), human breast cancer cell line (MCF-7) and triple negative human breast cancer cell line (MDA-MB-231) were cultured in the presence of 1% penicillin / streptomycin and 10% fetal bovine serum Technologies, Grand Island, NY). Cells were seeded in 96-well plates (3 x 10 3 cells / well) containing 100 μL of growth medium for 24 hours. After removing the medium, 100 .mu.L of each analogue compound (dissolved in DMSO in an amount of 0.025% or less) was added to each well and cultured at 37.degree. C. for 48 hours. After 48 hours of incubation, 100 占 퐇 of MTT reagent was added to each well. After incubation at 37 ° C for 4 hours, the supernatant was aspirated and the formazan crystals were dissolved in 100 μL of DMSO at 37 ° C for 10 minutes with gentle stirring. Absorbance per well was measured at 540 nm using a VERSA max microplate reader (Molecular Devices Corp.). IC 50 values were defined as concentrations of compounds that inhibited cell proliferation by 50% compared to cells treated with the highest amount of DMSO (0.025%) and were considered to be 100% viability.

그 결과, 하기 표 2에 나타낸 바와 같이, 선형 알킬 측쇄를 가진 N-아로일유도체 유도체가 DU145 및 MCF-7 세포주에 대한 유망한 저해 활성을 보였다. 특히, 화합물 4d 및 4e는 DU145 암 세포주의 처리에서 가장 강력한 활성을 나타내었다(4d: IC50=10.9μM, 4e: IC50=9.8μM). 4d와 4e의 세포 독성은 양성 대조군으로 알려진 항암제인 시스플라틴 (IC50=30.1μM)보다 약3배 강한 것이 나타났다.As a result, N-aroyl derivative derivatives having linear alkyl side chains showed promising inhibitory activity on DU145 and MCF-7 cell lines, as shown in Table 2 below. In particular, and it showed the compound 4d and 4e have the strongest activity in the treatment of DU145 cancer cell lines (4d: IC 50 = 10.9μM, 4e: IC 50 = 9.8μM). Cytotoxicity of 4d and 4e was about 3 times stronger than that of cisplatin (IC 50 = 30.1 μM), a chemotherapeutic agent known as a positive control.

이러한 결과는 본 발명의 제조방법에 의해 제조된 N-아로일우레아 유도체가 전립선암, 또는 유방암 세포에 대한 새로운 억제제로서 활용될 수 있음을 암시하는 것이다.These results imply that the N-arylaurea derivatives prepared by the method of the present invention can be used as a novel inhibitor for prostate cancer or breast cancer cells.

compoundscompounds DU145 (μM)DU145 ([mu] M) MCF-7 (μM)MCF-7 ([mu] M) MDA-MB-231 (μM)MDA-MB-231 ([mu] M) 3a3a > 50> 50 > 50> 50 > 50> 50 3aa3aa > 50> 50 > 50> 50 > 50> 50 3c3c > 50> 50 > 50> 50 > 50> 50 3e3e > 50> 50 > 50> 50 > 50> 50 3f3f > 50> 50 > 50> 50 > 50> 50 3g3g > 50> 50 > 50> 50 > 50> 50 3h3h > 50> 50 > 50> 50 > 50> 50 3i3i > 50> 50 > 50> 50 > 50> 50 3j3j > 50> 50 > 50> 50 > 50> 50 3k3k > 50> 50 > 50> 50 > 50> 50 3ka3ka > 50> 50 > 50> 50 > 50> 50 3l3l > 50> 50 > 50> 50 > 50> 50 3m3m > 50> 50 > 50> 50 > 50> 50 3n3n > 50> 50 > 50> 50 > 50> 50 4b4b > 50> 50 > 50> 50 > 50> 50 4c4c 28.628.6 34.434.4 > 50> 50 4ca4ca > 50> 50 > 50> 50 > 50> 50 4d4d 10.910.9 15.715.7 25.525.5 4e4e 9.89.8 13.613.6 15.115.1 4f4f 11.911.9 16.216.2 17.417.4 4g4g 30.430.4 35.835.8 > 50> 50 4h4h > 50> 50 > 50> 50 > 50> 50 4ha4ha > 50> 50 > 50> 50 > 50> 50 4i4i > 50> 50 > 50> 50 > 50> 50 4j4j > 50> 50 > 50> 50 > 50> 50 4k4k > 50> 50 > 50> 50 > 50> 50 4l4l > 50> 50 > 50> 50 > 50> 50 doxorubicindoxorubicin 3.33.3 5.65.6 9.29.2 cisplatincisplatin 30.130.1 35.235.2 > 50> 50

전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.

Claims (10)

화학식 1로 표시되는 N-아로일우레아 유도체, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염:
[화학식 1]
Figure 112017037435453-pat00044

상기 화학식 1에 있어서,
상기 R1 은 수소, 할로겐, C1-C6 알킬, 또는 CO2Me이고;
상기 R2 는 수소 또는 C1-C6 알킬이며;
상기 R3 는 C1-C6 알킬 또는 C6-C20 아릴이고;
상기 R4 는 부틸, 펜틸, 헥실, 옥틸, 벤질, 페네틸, 사이클로펜틸, 페닐, 4-메틸페닐, 4-플루오로페닐, 또는 4-클로로페닐일 수 있다.
A N-aroylurea derivative represented by the formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
Figure 112017037435453-pat00044

In Formula 1,
Wherein R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or CO 2 Me;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is C 1 -C 6 alkyl or C 6 -C 20 aryl;
R 4 may be butyl, pentyl, hexyl, octyl, benzyl, phenethyl, cyclopentyl, phenyl, 4-methylphenyl, 4-fluorophenyl, or 4-chlorophenyl.
제 1항에 있어서,
상기 N-아로일우레아 유도체는 하기 화합물들로 이루어진 군으로부터 선택되는 어느 하나인 것을 특징으로 하는, N-아로일우레아 유도체, 이의 이성질체 또는 이의 약학적 허용 가능한 염:
N-에틸-N-에틸카르바모일-1-피발로일인돌린-7-카르복사마이드 (3a); 1-벤조일-N-에틸-N-(에틸카르바모일)인돌린-7-카르복사마이드 (3c); N-에틸-N-(에틸카르바모일)-4-메틸-1-피발로일인돌린-7-카르복사마이드 (3e); N-에틸-N-(에틸카르바모일)-5-메틸-1-피발로일인돌린-7-카르복사마이드 (3f); 5-클로로-N-에틸-N-(에틸카르바모일)-1-피발로일인돌린-7-카르복사마이드 (3g); 5-브로모-N-에틸-N-(에틸카르바모일)-1-피발로일인돌린-7-카르복사마이드 (3h); 메틸-7-(에틸(에틸카르바모일)카르바모일)-1-피발로일인돌린-5-카르복실레이트 (3i); N-에틸-N-(에틸카르바모일)-6-메틸-1-피발로일인돌린-7-카르복사마이드 (3j); 6-클로로-N-에틸-N-(에틸카르바모일)-1-피발로일인돌린-7-카르복사마이드 (3k); N-에틸-N-(에틸카르바모일)-2-메틸-1-피발로일인돌린-7-카르복사마이드 (3l); 5-클로로-N-에틸-N-(에틸카르바모일)-2-메틸-1-피발로일인돌린-7-카르복사마이드 (3m); N-에틸-N-(에틸카르바모일)-3-메틸-1-피발로일인돌린-7-카르복사마이드 (3n); N-부틸-N-(부틸카르바모일)-1-피발로일인돌린-7-카르복사마이드 (4b); N-펜틸-N-(펜틸카르바모일)-1-피발로일인돌린-7-카르복사마이드 (4c); N-헥실-N-(헥실카르바모일)-1-피발로일인돌린-7-카르복사마이드 (4d); N-옥틸-N-(옥틸카르바모일)-1-피발로일인돌린-7-카르복사마이드 (4e); N-페네틸-N-(패내틸카바모일)-1-피발로일인돌린-7-카르복사마이드 (4f); N-벤질-N-(벤질카바모일)-1-피발로일인돌린-7-카르복사마이드 (4g); N-사이클로펜틸-N-(사이클로펜틸카르바모일)-1-피발로일인돌린-7-카르복사마이드 (4h); N-페닐-N-(페닐카바모일)-1-피발로일인돌린-7-카르복사마이드 (4i); 1-피발로일-N-(피-톨일)-N-(피-톨일카바모일)인돌린-7-카르복사마이드 (4j); N-(4-플루오로페닐)-N-((4-플루오로페닐)카바모일)-1-피발로일인돌린-7-카르복사마이드 (4k); 및 N-(4-클로로페닐)-N-((4-클로로페닐)카바모일)-1-피발로일인돌린-7-카르복사마이드 (4l).
The method according to claim 1,
Wherein said N-arylaurea derivative is any one selected from the group consisting of the following compounds: an N-aroylurea derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof;
N-ethyl-N-ethylcarbamoyl-1-pivaloylindoline-7-carboxamide (3a); 1-Benzoyl-N-ethyl-N- (ethylcarbamoyl) indolin-7-carboxamide (3c); N-ethyl-N- (ethylcarbamoyl) -4-methyl-1-pivaloylindoline-7-carboxamide (3e); N-ethyl-N- (ethylcarbamoyl) -5-methyl-1-pivaloylindoline-7-carboxamide (3f); 5-Chloro-N-ethyl-N- (ethylcarbamoyl) -1-pivaloylindoline-7-carboxamide (3g); 5-Bromo-N-ethyl-N- (ethylcarbamoyl) -1-pivaloylindoline-7-carboxamide (3h); Methyl-7- (ethyl (ethylcarbamoyl) carbamoyl) -1-pivaloylindoline-5-carboxylate (3i); N-ethyl-N- (ethylcarbamoyl) -6-methyl-1-pivaloylindene-7-carboxamide (3j); 6-Chloro-N-ethyl-N- (ethylcarbamoyl) -1-pivaloylindoline-7-carboxamide (3k); N-ethyl-N- (ethylcarbamoyl) -2-methyl-1-pivaloylindoline-7-carboxamide (3l); 5-Chloro-N-ethyl-N- (ethylcarbamoyl) -2-methyl-1-pivaloylindoline-7-carboxamide (3m); N-ethyl-N- (ethylcarbamoyl) -3-methyl-1-pivaloylindoline-7-carboxamide (3n); N-butyl-N- (butylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4b); N-pentyl-N- (pentylcarbamoyl) -1-pivaloylindene-7-carboxamide (4c); N-hexyl-N- (hexylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4d); N-octyl-N- (octylcarbamoyl) -1-pivaloylindene-7-carboxamide (4e); N-phenethyl-N- (paratinylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4f); N-Benzyl-N- (benzylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4 g); N-cyclopentyl-N- (cyclopentylcarbamoyl) -1-pivaloylindene-7-carboxamide (4h); N-phenyl-N- (phenylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4i); 1-pivaloyl-N- (p-tolyl) -N- (p-tolylcarbamoyl) indolin-7-carboxamide (4j); N- (4-fluorophenyl) -N - ((4-fluorophenyl) carbamoyl) -1-pivaloylindoline-7-carboxamide (4k); And N- (4-chlorophenyl) -N - ((4-chlorophenyl) carbamoyl) -1-pivaloylindoline-7-carboxamide (4l).
로듐 촉매 존재 하에서, 하기 화학식 2로 표시되는 화합물을 화학식 3으로 표시되는 이소시아네이트와 반응시키는 단계를 포함하는, 하기 화학식 1로 표시되는 N-아로일우레아 유도체의 제조방법:
[화학식 1]
Figure 112017037435453-pat00045

[화학식 2]
Figure 112017037435453-pat00046

[화학식 3]
Figure 112017037435453-pat00047

상기 화학식 1 내지 화학식 3 중 어느 하나의 화학식에 있어서,
상기 R1 은 수소, 할로겐, C1-C6 알킬, 또는 CO2Me이고;
상기 R2 는 수소 또는 C1-C6 알킬이며;
상기 R3 는 C1-C6 알킬 또는 C6-C20 아릴이고; 및
상기 R4 는 부틸, 펜틸, 헥실, 옥틸, 벤질, 페네틸, 사이클로펜틸, 페닐, 4-메틸페닐, 4-플루오로페닐, 또는 4-클로로페닐일 수 있다.
A method for producing N-aroyl urea derivatives represented by the following formula (1), comprising reacting a compound represented by the following formula (2) with an isocyanate represented by the formula (3) in the presence of a rhodium catalyst:
[Chemical Formula 1]
Figure 112017037435453-pat00045

(2)
Figure 112017037435453-pat00046

(3)
Figure 112017037435453-pat00047

In the formulas of any one of formulas (1) to (3)
Wherein R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or CO 2 Me;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is C 1 -C 6 alkyl or C 6 -C 20 aryl; And
R 4 may be butyl, pentyl, hexyl, octyl, benzyl, phenethyl, cyclopentyl, phenyl, 4-methylphenyl, 4-fluorophenyl, or 4-chlorophenyl.
제 3항에 있어서,
상기 로듐 촉매는 C1-C5 알킬로 치환되거나, 또는 비치환된 사이클로펜타다이엔일(cyclopentadienyl) 로듐 (Ⅲ) 복합체 촉매인 것을 특징으로 하는, N-아로일우레아 유도체의 제조방법.
The method of claim 3,
Wherein the rhodium catalyst is cyclopentadienyl rhodium (III) complex catalyst substituted with C 1 -C 5 alkyl or unsubstituted cyclopentadienyl rhodium (III) complex catalyst.
제 4항에 있어서,
상기 로듐 촉매는 펜타메틸사이클로펜타다이엔일로듐(Ⅲ) 클로라이드 이량체 (Pentamethylcyclopentadienylrhodium(Ⅲ) chloride dimer; [RhCp*Cl2]2) 촉매인 것을 특징으로 하는, N-아로일우레아 유도체의 제조방법.
5. The method of claim 4,
Wherein the rhodium catalyst is a pentamethylcyclopentadienylrhodium (III) chloride dimer; [RhCp * Cl 2 ] 2 ) catalyst. The method for producing a N-aroylurea derivative .
제 3항에 있어서,
상기 반응은 첨가제를 더 포함하여 수행되는 것을 특징으로 하는, N-아로일우레아 유도체의 제조방법.
The method of claim 3,
Wherein the reaction is carried out further comprising an additive.
제 6항에 있어서,
상기 첨가제는 실버트리플루오로메틸설포닐이미드(silver tri(fluoromethylsulfonyl)imide, AgNTf2), 구리아세트산(Copper(Ⅱ) acetate; Cu(OAc)2), 또는 이들의 혼합물인 것을 특징으로 하는, N-아로일우레아 유도체의 제조방법.
The method according to claim 6,
Wherein the additive is silver tri (fluoromethylsulfonyl) imide, AgNTf 2 , copper (II) acetate, Cu (OAc) 2 ) A method for producing an N-aroylurea derivative.
제 3항에 있어서,
상기 제조방법은 다이클로로에테인(Dichloroethene; DCE), 또는 톨루엔(toluene) 용매에서 이루어지는 것을 특징으로 하는, N-아로일우레아 유도체의 제조방법.
The method of claim 3,
Wherein the production method is carried out in a solvent of dichloroethane (DCE) or toluene.
제 1 항 또는 제 2 항의 N-아로일우레아 유도체, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 암 예방 또는 치료용 약학적 조성물.
A pharmaceutical composition for preventing or treating cancer, which comprises the N-aroyl urea derivative of claim 1 or 2, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
제 9항에 있어서, 상기 암은 전립선암 또는 유방암인 것을 특징으로 하는, 암 예방 또는 치료용 약학적 조성물.
The pharmaceutical composition according to claim 9, wherein the cancer is prostate cancer or breast cancer.
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