KR20080002632A - Quinazoline derivatives for inhibiting the growth of cancer cell - Google Patents

Quinazoline derivatives for inhibiting the growth of cancer cell Download PDF

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KR20080002632A
KR20080002632A KR1020070047460A KR20070047460A KR20080002632A KR 20080002632 A KR20080002632 A KR 20080002632A KR 1020070047460 A KR1020070047460 A KR 1020070047460A KR 20070047460 A KR20070047460 A KR 20070047460A KR 20080002632 A KR20080002632 A KR 20080002632A
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chloro
acryloyl
carboxyamide
quinazolin
pyrrolidine
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KR1020070047460A
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KR100929146B1 (en
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이광옥
공지현
차미영
이창곤
김영훈
이규항
송태헌
송지연
박영진
김은영
이은영
이경익
김맹섭
이관순
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한미약품 주식회사
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/4025—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 not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine

Abstract

A novel quinazoline derivative is provided to inhibit cancer cell growth caused by epithelial growth factor and its mutants without any side effect selectively and efficiently. And a pharmaceutical composition for inhibiting cancer cell growth comprising the same is provided. A quinazoline derivative is represented by the formula(1). In the formula(1), R1 is C1-6 alkoxy substituted with a C1-6 alkoxy or heterocyclic group, wherein the heterocyclic group is a 5 or 6-membered heteroaromatic or non-aromatic group containing one to four of the elements selected from the group consisting of N, O and S; R2 is H or phenyl substituted with halogen; and A is -C(=O)- or -CH2-. A pharmaceutical composition for inhibiting the growth of cancer cells comprises the quinazoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient. The composition further comprises an anticancer agent selected from the group consisting of cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, antimetabolites, antibiotics, growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, biological reaction modifiers, antihormonal agents and antiandrogen.

Description

암세포 성장 억제 효과를 갖는 퀴나졸린 유도체 {QUINAZOLINE DERIVATIVES FOR INHIBITING THE GROWTH OF CANCER CELL}QUINAZOLINE DERIVATIVES FOR INHIBITING THE GROWTH OF CANCER CELL}

본 발명은 상피세포 성장인자 및 이의 변이체에 의해 유발되는 암세포의 성장을 선택적이고 효과적으로 억제하는, 신규한 퀴나졸린 유도체 및 이의 약학적으로 허용가능한 염, 및 이를 활성성분으로 함유하는 약학 조성물에 관한 것이다.The present invention relates to novel quinazoline derivatives and pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them as active ingredients, which selectively and effectively inhibit the growth of cancer cells caused by epidermal growth factors and variants thereof. .

세포 내에는 수많은 신호 전달 체계가 존재하고 이들 각 신호 전달 체계는 서로 유기적으로 연결되어 복잡한 메카니즘을 형성함으로써 세포의 증식, 성장, 사멸 등을 조절한다. 유전적, 환경적 영향에 의하여 세포 내의 조절 기능이 파괴되어 비정상적인 신호 전달의 증폭 또는 소멸이 나타날 경우 종양이 발생할 가능성이 높아진다.Numerous signal transduction systems exist within the cell, and each of these signal transduction systems is organically linked to each other to form complex mechanisms that regulate cell proliferation, growth, and death. Tumors are more likely to occur when genetic and environmental influences disrupt the regulatory functions in cells, resulting in amplification or disappearance of abnormal signal transduction.

단백질 티로신 키나제는 이러한 세포 내의 조절기능에 중요한 역할을 담당하며 암세포 내에서 이의 비정상적인 발현 및 변이가 많이 관찰된다. 단백질 티로신 키나제는 ATP로부터 단백질 기질 상에 위치하는 티로신으로 포스페이트기를 전달하는 것을 촉매하는 효소 부류이며, 수많은 성장 인자 수용체 단백질은 티로신 키나제로서 작용하며 이 과정에서 세포 신호 전달을 수행한다. 성장인자와 이들 수용 체간의 상호작용은 세포 성장의 정상적인 조절에 있어서 필수적이지만, 특정 조건 하에서 수용체의 돌연변이 또는 과발현으로 인해 이들 수용체에 의한 신호를 조절할 수 없게 되면 종양 세포 또는 궁극적으로 암이 유발된다.Protein tyrosine kinases play an important role in the regulatory function in these cells and many abnormal expressions and variations thereof are observed in cancer cells. Protein tyrosine kinases are a class of enzymes that catalyze the transfer of phosphate groups from ATP to tyrosine located on protein substrates, and a number of growth factor receptor proteins act as tyrosine kinases and perform cell signal transduction in the process. Interactions between growth factors and these receptors are essential for the normal regulation of cell growth, but under certain conditions, the inability to modulate signals by these receptors due to mutation or overexpression of the receptors results in tumor cells or ultimately cancer.

단백질 티로신 키나제는 성장인자와 관련하여 여러 패밀리로 분류되며, 이중 상피세포 성장인자 (EGF)와 관련된 상피세포 성장인자 수용체 (EGFR) 티로신 키나제에 관한 연구가 현재 활발하게 진행되고 있다. EGFR 티로신 키나제는 수용체 부분과 티로신 키나제 부분이 있으며 세포막을 통과하여 위치함으로써 세포 외부의 신호를 세포 내부로 전달하는 역할을 한다. EGFR 티로신 키나제 패밀리는 구조적 차이에 따라 EGFR (Erb-B1), Erb-B2, Erb-B3 및 Erb-B4의 4종으로 하위 분류되며, 구성원 모두는 동형2량체 또는 패밀리의 다른 구성원과 함께 이형2량체 신호 전달 복합체를 형성할 수 있고, 1종이 넘는 패밀리의 구성원이 악성 질병에서 과발현되는 경우 상승적 변형을 초래할 수 있다. 1종이 넘는 패밀리 구성원의 과잉발현은 인간의 악성 종양에서 비교적 흔하게 나타나고 있으며 EGFR과 Erb-B2는 이형2량체 신호 전달 복합체 형성에 있어 중요한 역할을 하는 것으로 알려져 있다.Protein tyrosine kinases are classified into several families in relation to growth factors, and studies on epidermal growth factor receptor (EGFR) tyrosine kinases related to dual epidermal growth factor (EGF) are currently being actively conducted. EGFR tyrosine kinase has a receptor moiety and a tyrosine kinase moiety, which is located through the cell membrane to transmit signals outside the cell into the cell. The EGFR tyrosine kinase family is subdivided into four types, EGFR (Erb-B1), Erb-B2, Erb-B3, and Erb-B4, depending on the structural differences, all of which are heterozygous with other members of the homodimer or family It may form a multimeric signal transduction complex and result in synergistic modifications when members of more than one family are overexpressed in malignant disease. Overexpression of more than one family member is relatively common in human malignancies, and EGFR and Erb-B2 are known to play an important role in the formation of heterodimer signal transduction complexes.

현재 개발되었거나 개발중인 EGFR 티로신 키나제 억제제로는 게피티닙 (Gefitinib), 엘로티닙 (Erlotinib), 라파티닙 (Lapatinib) 등을 들 수 있고, 이들 중 게피티닙 및 엘로티닙은 선택적으로 EGFR을 저해하며, 라파티닙은 EGFR과 Erb-B2를 동시에 저해하여 종양의 성장을 억제함으로서 환자의 수명을 연장시키거나 치료의 편의를 제공하고 있다.Currently developed or developing EGFR tyrosine kinase inhibitors include Gefitinib, Erlotinib, Lapatinib, among which Gefitinib and Erlotinib selectively inhibit EGFR, Lapatinib inhibits tumor growth by simultaneously inhibiting EGFR and Erb-B2, prolonging patient life and providing convenience for treatment.

한편, 최근, 폐암환자에 대한 EGFR 선택적 억제제인 게피티닙의 경우, EGFR 키나제의 엑손(exon) 20 영역에서 790 위치의 아미노산인 트레오닌(threonine)이 메티오닌(methionine)으로 변이된 T790M에 대해서는 효과가 없는 것으로 밝혀졌고 (문헌[Plos Medicine 2005, 2(3), 225-235] 참조), T790M 변이 환자들에 대해서도 실제 임상효과가 없는 것으로 밝혀졌다.On the other hand, gefitinib, an EGFR selective inhibitor for lung cancer patients, has an effect on T790M, in which threonine, an amino acid at position 790 in the exon 20 region of EGFR kinase, is mutated to methionine. It has been found to be absent (see Plos Medicine 2005 , 2 (3) , 225-235), and has been found to have no actual clinical effect in patients with T790M mutations.

따라서, EGFR 변종인 T790M에 우수한 활성을 나타내면서 기존 EGFR 억제제들이 갖고 있는 설사, 피부발진 등의 부작용을 줄일 수 있는 새로운 약물의 개발이 절실히 요구되고 있는 상황이다.Therefore, there is an urgent need for the development of a new drug that can reduce the side effects such as diarrhea and skin rashes of existing EGFR inhibitors while showing excellent activity against the EGFR strain T790M.

따라서, 본 발명의 목적은 부작용이 적고 상피세포 성장인자 및 이의 변이체에 의해 유발되는 암세포의 성장을 선택적이고 효과적으로 저해할 수 있는 신규한 퀴나졸린 유도체를 제공하는 것이다.Accordingly, it is an object of the present invention to provide novel quinazoline derivatives which have fewer side effects and which can selectively and effectively inhibit the growth of cancer cells caused by epidermal growth factor and variants thereof.

본 발명의 다른 목적은 상기 퀴나졸린 유도체를 활성성분으로 함유하는 암세포 성장 억제용 약학 조성물을 제공하는 것이다.Another object of the present invention to provide a pharmaceutical composition for inhibiting cancer cell growth containing the quinazoline derivative as an active ingredient.

상기 목적에 따라 본 발명은, 하기 화학식 1의 퀴나졸린 유도체 또는 이의 약학적으로 허용가능한 염을 제공한다:In accordance with the above object, the present invention provides a quinazoline derivative of formula 1 or a pharmaceutically acceptable salt thereof:

Figure 112007035977473-PAT00001
Figure 112007035977473-PAT00001

상기 식에서,Where

R1은 치환체 X를 갖는 C1-6알콕시이고;R 1 is C 1-6 alkoxy with substituent X;

R2는 수소 또는 할로겐으로 치환된 벤젠이고;R 2 is benzene substituted with hydrogen or halogen;

A는 -C(=O)- 또는 -CH2-이고;A is -C (= 0)-or -CH 2- ;

상기 치환체 X는 C1-6알콕시 또는 헤테로사이클이고;The substituent X is C 1-6 alkoxy or heterocycle;

상기 헤테로사이클은 N, O 및 S로 이루어진 군으로부터 선택된 1 내지 4개의 구성원을 포함하는, 5 또는 6원의 헤테로방향족 또는 비방향족 화합물이다.The heterocycle is a 5 or 6 membered heteroaromatic or nonaromatic compound comprising 1 to 4 members selected from the group consisting of N, O and S.

이하 본 발명을 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail.

본 발명에 따른 상기 화학식 1의 퀴나졸린 유도체에 있어서, 바람직하게는, R1은 2-메톡시에톡시, (테트라하이드로퓨란-2-일)메톡시, 2-모폴리노에톡시, (4-메틸티아졸-5-일)에톡시 또는 2-(1H-1,2,4-트리아졸-1-일)에톡시이고;In the quinazoline derivative of formula 1 according to the present invention, preferably, R 1 is 2-methoxyethoxy, (tetrahydrofuran-2-yl) methoxy, 2-morpholinoethoxy, (4 -Methylthiazol-5-yl) ethoxy or 2- (1 H -1,2,4-triazol-1-yl) ethoxy;

R2는 3-클로로-4-플루오로페닐, 3-클로로-2-플루오로페닐, 4-브로모-3-클로로-2-플루오로페닐, 2,3,4-트리플루오로페닐, 3,4-다이클로로페닐, 3,4-다이클로로 -2-플루오로페닐 또는 3-클로로-2,4-플루오로페닐이다.R 2 is 3-chloro-4-fluorophenyl, 3-chloro-2-fluorophenyl, 4-bromo-3-chloro-2-fluorophenyl, 2,3,4-trifluorophenyl, 3 , 4-dichlorophenyl, 3,4-dichloro-2-fluorophenyl or 3-chloro-2,4-fluorophenyl.

본 명세서에 사용된 용어 '할로겐'은 다른 언급이 없으면, 플루오로, 클로로, 브로모 또는 요오도를 의미한다.As used herein, the term "halogen" means fluoro, chloro, bromo or iodo, unless stated otherwise.

상기 화합물 중 더욱 바람직한 화합물의 구체적인 예는 다음과 같다.Specific examples of more preferable compounds among the above compounds are as follows.

1) (2S)-1-아크릴로일-N-[4-[3-클로로-2-플루오로페닐아미노]-7-(2-메톡시에톡시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드;1) ( 2S ) -1-acryloyl- N- [4- [3-chloro-2-fluorophenylamino] -7- (2-methoxyethoxy) quinazolin-6-yl] pyrroli Din-2-carboxyamide;

2) (2S)-1-아크릴로일-N-[4-[3-클로로-4-플루오로페닐아미노]-7-메톡시퀴나졸린-6-일]피롤리딘-2-카르복시아미드;2) (2S) -1-acryloyl- N- [4- [3-chloro-4-fluorophenylamino] -7-methoxyquinazolin-6-yl] pyrrolidine-2-carboxyamide;

3) (2S)-1-아크릴로일-N-[4-[4-브르모-3-클로로-2-플루오로페닐아미노]-7- (2-메톡시에톡시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드;3) (2 S) -1-yl acrylate - N - [4- [4- bracket reumo-3-chloro-2-fluoro-phenyl-amino] -7- (2-methoxyethoxy) quinazolin -6 -Yl] pyrrolidine-2-carboxyamide;

4) (2S)-1-아크릴로일-N-[4-[2,3,4-트리플루오로페닐아미노]-7-(2-메톡시에톡시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드;4) ( 2S ) -1-acryloyl- N- [4- [2,3,4-trifluorophenylamino] -7- (2-methoxyethoxy) quinazolin-6-yl] py Rollidine-2-carboxyamide;

5) (2S)-1-아크릴로일-N-[4-[3,4-다이클로로페닐아미노]-7-(2-메톡시에톡시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드;5) ( 2S ) -1-Acryloyl- N- [4- [3,4-dichlorophenylamino] -7- (2-methoxyethoxy) quinazolin-6-yl] pyrrolidine- 2-carboxyamide;

6) (2S)-1-아크릴로일-N-[4-[3-클로로-2,4-다이플루오로페닐아미노]-7-(2-메톡시에톡시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드;6) ( 2S ) -1-acryloyl- N- [4- [3-chloro-2,4-difluorophenylamino] -7- (2-methoxyethoxy) quinazolin-6-yl ] Pyrrolidine-2-carboxyamide;

7) (2S)-1-아크릴로일-N-[4-[3,4-다이클로로-2-플루오로페닐아미노]-7-(2-메톡시에톡시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드;7) ( 2S ) -1-acryloyl- N- [4- [3,4-dichloro-2-fluorophenylamino] -7- (2-methoxyethoxy) quinazolin-6-yl ] Pyrrolidine-2-carboxyamide;

8) (2S)-1-아크릴로일-N-{4-[3-클로로-4-플루오로페닐아미노]-7-[(테트라하 이드로퓨란-2-일)메톡시]퀴나졸린-6-일}피롤리딘-2-카르복시아미드;8) ( 2S ) -1-Acryloyl- N- {4- [3-chloro-4-fluorophenylamino] -7-[(tetrahydrofuran-2-yl) methoxy] quinazoline- 6-yl} pyrrolidine-2-carboxyamide;

9) (2S)-1-아크릴로일-N-{4-[4-브로모-3-클로로-4-플루오로페닐아미노]-7- [(테트라하이드로퓨란-2-일)메톡시]퀴나졸린-6-일}피롤리딘-2-카르복시아미드;9) ( 2S ) -1-acryloyl- N- {4- [4-bromo-3-chloro-4-fluorophenylamino] -7-[(tetrahydrofuran-2-yl) methoxy ] Quinazolin-6-yl} pyrrolidine-2-carboxyamide;

10) (2S)-1-아크릴로일-N-[4-[4-브로모-3-클로로-2-플루오로페닐아미노]-7- (2-모폴리노에톡시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드;10) ( 2S ) -1-acryloyl- N- [4- [4-bromo-3-chloro-2-fluorophenylamino] -7- (2-morpholinoethoxy) quinazoline- 6-yl] pyrrolidine-2-carboxyamide;

11) (2S)-1-아크릴로일-N-{4-[3-클로로-2-플루오로페닐아미노]-7-[2-(4-메틸티아졸-5-일)에톡시]퀴나졸린-6-일}피롤리딘-2-카르복시아미드;11) ( 2S ) -1-Acryloyl- N- {4- [3-chloro-2-fluorophenylamino] -7- [2- (4-methylthiazol-5-yl) ethoxy] Quinazolin-6-yl} pyrrolidine-2-carboxyamide;

12) (2S)-1-아크릴로일-N-{4-[3-클로로-2-플루오로페닐아미노]-7-[2-(1H- 1,2,4-트리아졸-1-일)에톡시]퀴나졸린-6-일}피롤리딘-2-카르복시아미드; 또는12) ( 2S ) -1-acryloyl- N- {4- [3-chloro-2-fluorophenylamino] -7- [2- ( 1H -1,2,4-triazole-1 -Yl) ethoxy] quinazolin-6-yl} pyrrolidine-2-carboxyamide; or

13) (2S)-1-(2-{[4-(4-브로모-3-클로로-2-플루오로페닐아미노)-7-(2-메톡시에톡시)퀴나졸린-6-일아미노]메틸}피롤리딘-1-일)프로-2-펜-1-온.13) ( 2S ) -1- (2-{[4- (4-bromo-3-chloro-2-fluorophenylamino) -7- (2-methoxyethoxy) quinazolin-6-yl Amino] methyl} pyrrolidin-1-yl) pro-2-phen-1-one.

본 발명에 따른 화학식 1의 화합물은 예를 들면 하기 반응식 1 (화학식 1a의 화합물, A = -C(=O)-) 또는 반응식 2 (화학식 1b의 화합물, A = -CH2-)에 의해 제조할 수 있다 (문헌[J. Med. Chem., 1996; 39: 918] 참조).The compound of formula 1 according to the present invention is prepared by, for example, the following reaction scheme 1 (compound 1a, A = -C (= O)-) or scheme 2 (compound 1b, A = -CH 2- ) (See J. Med. Chem ., 1996; 39: 918).

Figure 112007035977473-PAT00002
Figure 112007035977473-PAT00002

Figure 112007035977473-PAT00003
Figure 112007035977473-PAT00003

상기 식에서,Where

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

상기 반응식 1에서, 화학식 2의 화합물은, 유기 용매(예: 피리딘, 테트라하이드로퓨란, 메틸렌클로라이드, 클로로포름) 중에서 화학식 3의 화합물을 N-(tert-Boc)-프롤린과 축합반응시켜 얻을 수 있다. 축합반응에 사용되는 축합제로는 1-(3-다이메틸아미노프로필)-3-에틸카르보다이이미드(EDCI) 및 이의 산 부가염이 적합하다.In Scheme 1, the compound of Formula 2 may be obtained by condensation of the compound of Formula 3 with N- ( tert -Boc) -proline in an organic solvent (eg, pyridine, tetrahydrofuran, methylene chloride, chloroform). As the condensing agent used in the condensation reaction, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) and acid addition salts thereof are suitable.

이어, 화학식 2의 화합물을 CHCl3와 같은 유기 용매 중에서 트라이플루오로아세트산과 같은 유기산 또는 진한 염산과 같은 무기산을 사용하여 t-부톡시카르보닐기를 탈 보호한 후, 테트라하이드로퓨란과 물의 혼합용매와 같은 유기 용매 중에서 중탄산나트륨과 같은 염기의 존재 하에 아크릴로일 클로라이드를 이용하여 아크릴화 반응시킴으로써 화학식 1a (A = -C(=O)-)의 화합물을 얻을 수 있다.Subsequently, after deprotecting the t -butoxycarbonyl group using an organic acid such as trifluoroacetic acid or an inorganic acid such as concentrated hydrochloric acid in an organic solvent such as CHCl 3 , a compound of tetrahydrofuran and water The compound of formula 1a (A = -C (= O)-) can be obtained by acrylate reaction with acryloyl chloride in the presence of a base such as sodium bicarbonate in an organic solvent.

상기 반응식 2에서, 화학식 4의 화합물은, 에탄올 같은 유기 용매 중에서 아세트산과 소디움시아노보로하이드라이드 존재 하에 화학식 3의 화합물을 화학식 5의 화합물과 반응시켜 얻을 수 있다.In Scheme 2, the compound of Formula 4 may be obtained by reacting the compound of Formula 3 with the compound of Formula 5 in the presence of acetic acid and sodium cyanoborohydride in an organic solvent such as ethanol.

이어, CHCl3와 같은 유기 용매 중에서 트라이플루오로아세트산과 같은 유기산 또는 진한 염산과 같은 무기산을 사용하여 화학식 4의 화합물의 t-부톡시카르보닐기를 탈 보호한 후, 테트라하이드로퓨란과 물의 혼합용매와 같은 유기 용매 중에서 중탄산나트륨과 같은 염기의 존재하에 아크릴로일 클로라이드를 이용하여 아크릴화시킴으로써 화학식 1b (A = -CH2-)의 화합물을 얻을 수 있다.Subsequently, after deprotecting the t -butoxycarbonyl group of the compound of formula 4 using an organic acid such as trifluoroacetic acid or an inorganic acid such as concentrated hydrochloric acid in an organic solvent such as CHCl 3 , a mixed solvent of tetrahydrofuran and water Compounds of formula 1b (A = -CH 2- ) can be obtained by acrylatening with acryloyl chloride in the presence of a base such as sodium bicarbonate in an organic solvent.

본 발명에 따른 화학식 1의 화합물은 무기산 또는 유기산으로부터 유도된 약학적으로 허용가능한 염 형태로 사용될 수 있으며, 바람직한 염으로는 염산, 브롬화수소산, 황산, 인산, 질산, 아세트산, 글리콜산, 락트산, 피루브산, 말론산, 석신산, 글루타르산, 푸마르산, 말산, 만델산, 타르타르산, 시트르산, 아스코르브산, 팔미트산, 말레산, 하이드록시말레산, 벤조산, 하이드록시벤조산, 페닐아세트산, 신남산, 살리실산, 메탄설폰산, 벤젠설폰산, 톨루엔설폰산 등을 들 수 있다.The compound of formula 1 according to the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids, with preferred salts being hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid , Malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid And methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

본 발명에 따른 화합물 또는 이의 약학적으로 허용가능한 염은 상피세포 성장인자에 의해 유발되는 암세포 및 상피세포 성장인자 변이체에 의해 유발되는 암세포의 성장을 선택적이고 효과적으로 억제하며, 다른 항암제와 함께 병용 투여함으로써 항암제의 치료효과를 강화시킬 수 있다. 즉, 본 발명에 따른 화합물 또는 이의 약학적으로 허용가능한 염은 세포 신호 전달 억제제, 유사분열 억제제, 알킬화제, 항-대사제, 삽입 항생제, 성장 인자 억제제, 세포 주기 억제제, 토포아이소머라제 억제제, 생물 반응 개질제, 항-호르몬제, 및 항-안드로젠으로 이루어진 군 에서 선택된, 암 또는 기타 질환의 치료에 사용되는 항암제의 효과를 상승시키는데 유용하다.The compound according to the present invention or a pharmaceutically acceptable salt thereof selectively and effectively inhibits the growth of cancer cells induced by epidermal growth factor and cancer cells caused by epidermal growth factor variants, and is administered in combination with other anticancer agents. It can enhance the therapeutic effect of anticancer drugs. That is, the compound according to the present invention or a pharmaceutically acceptable salt thereof may be a cell signal transduction inhibitor, mitosis inhibitor, alkylating agent, anti-metabolic agent, insertion antibiotic, growth factor inhibitor, cell cycle inhibitor, topoisomerase inhibitor, biological response Useful for enhancing the effectiveness of anticancer agents used in the treatment of cancer or other diseases, selected from the group consisting of modifiers, anti-hormonal agents, and anti-androgens.

따라서, 본 발명에서는 활성성분으로서 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는, 암세포 성장 억제용 약학 조성물을 제공한다.Accordingly, the present invention provides a pharmaceutical composition for inhibiting cancer cell growth, comprising the compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

본 발명의 화합물 또는 이의 약학적으로 허용가능한 염 등의 활성성분의 투여량은 처리되는 대상, 질병 또는 상태의 심각도, 투여의 속도 및 처방 의사의 판단에 따른다. 유효 성분으로서 화학식 1의 화합물은 사람을 포함하는 포유동물에 대해 하루에 0.01 내지 100 ㎎/㎏ (체중), 바람직하게는 0.2 내지 50 ㎎/㎏ (체중)의 양으로 1일 1회 또는 분할하여 경구 또는 비경구적 경로를 통해 투여할 수 있다. 일부의 경우에 있어서, 상기 언급된 범위 보다 적은 투여량 수치가 보다 적합할 수 있고, 해로운 부작용을 일으키지 않으면서도 보다 많은 투여량이 사용될 수도 있으며, 보다 많은 투여량의 경우는 하루에 걸쳐 수회의 적은 투여량으로 분배된다.The dosage of active ingredient, such as a compound of the present invention or a pharmaceutically acceptable salt thereof, depends on the subject being treated, the severity of the disease or condition, the rate of administration and the judgment of the prescribing physician. As an active ingredient, the compound of formula 1 may be divided or divided once a day in an amount of 0.01 to 100 mg / kg body weight, preferably 0.2 to 50 mg / kg body weight, per day for mammals including humans. Administration can be via oral or parenteral routes. In some cases, lower dosage values than the above-mentioned ranges may be more suitable, more dosages may be used without causing harmful side effects, and for higher dosages several smaller dosages throughout the day Amount is distributed.

본 발명의 약학 조성물은 통상적인 방법에 따라 약학적으로 허용가능한 담체와 함께 제제화 할 수 있으며, 정제, 환제, 산제, 캅셀제, 시럽, 에멀젼, 마이크로에멀젼 등의 다양한 경구 투여 형태 또는 근육내, 정맥내 또는 피하투여와 같은 비경구 투여 형태로 제조될 수 있다.The pharmaceutical compositions of the present invention may be formulated with pharmaceutically acceptable carriers according to conventional methods and may be used in various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions or intramuscular, intravenous Or parenteral dosage forms such as subcutaneous administration.

본 발명의 약학 조성물이 경구제형의 형태로 제조되는 경우 사용되는 담체의 예로는 셀룰로오스, 규산칼슘, 옥수수전분, 락토오스, 수크로스, 덱스트로스, 인산칼슘, 스테아르산, 스테아르산 마그네슘, 스테아르산 칼슘, 젤라틴, 탈크, 계면활 성제, 현탁제, 유화제, 희석제 등을 들 수 있다. 본 발명의 약학 조성물이 주사제의 형태로 제조되는 경우 사용되는 담체의 예로는 물, 식염수, 포도당 수용액, 유사 당수용액, 알콜, 글리콜, 에테르 (예: 폴리에틸렌글리콜 200), 오일, 지방산, 지방산에스테르, 글리세라이드, 계면활성제, 현탁제, 유화제 등을 들 수 있다.Examples of the carrier used when the pharmaceutical composition of the present invention is prepared in oral dosage form include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, Gelatin, talc, surfactant, suspending agent, emulsifier, diluent and the like. Examples of carriers used when the pharmaceutical composition of the present invention is prepared in the form of injectables include water, saline, aqueous glucose solution, pseudoglucose solution, alcohol, glycol, ether (e.g. polyethylene glycol 200), oils, fatty acids, fatty acid esters, Glycerides, surfactants, suspending agents, emulsifiers and the like.

이하, 본 발명을 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited by the following examples.

실시예 1: (2Example 1: (2 SS )-1-아크릴로일-) -1-acryloyl- NN -{4-[3-클로로-2-플루오로페닐아미노]-7-(2-메톡시에톡시)퀴나졸린-6-일}피롤리딘-2-카르복시아미드-{4- [3-chloro-2-fluorophenylamino] -7- (2-methoxyethoxy) quinazolin-6-yl} pyrrolidine-2-carboxyamide

1-1. 1-1. NN -(3-클로로-2-플루오로페닐)-7-플루오로-6-니트로퀴나졸린-4-아민 염산염-(3-Chloro-2-fluorophenyl) -7-fluoro-6-nitroquinazolin-4-amine hydrochloride

4-클로로-7-플루오로-6-니트로 퀴나졸린 염산염 1 ｇ을 이소프로판올 10 ㎖에 녹인 다음, 3-클로로-2-플루오로 아닐린 550 ㎎을 첨가하고, 반응 온도를 80℃로 올려 3 시간 동안 교반시켰다. 반응이 완결되면 반응 용액을 실온으로 냉각시킨 다음 감압 여과하였다. 얻어진 고체를 이소프로판올로 세척한 후 훈풍 건조하여 상기 목적화합물 1.3 ｇ (97%)을 얻었다.1 g of 4-chloro-7-fluoro-6-nitroquinazoline hydrochloride was dissolved in 10 ml of isopropanol, and then 550 mg of 3-chloro-2-fluoro aniline was added and the reaction temperature was raised to 80 ° C. for 3 hours. Stirred. After the reaction was completed, the reaction solution was cooled to room temperature and filtered under reduced pressure. The obtained solid was washed with isopropanol and warmed to obtain 1.3 g (97%) of the target compound.

1H-NMR (DMSO-d6, 300MHz) δ : 9.45 (d, 1H), 8.60 (s, 1H), 7.80 (d, 1H), 7.50 (m, 2H), 7.25 (t, 1H). 1 H-NMR (DMSO-d 6, 300 MHz) δ: 9.45 (d, 1H), 8.60 (s, 1H), 7.80 (d, 1H), 7.50 (m, 2H), 7.25 (t, 1H).

1-2. 1-2. NN -(3-클로로-4-플루오로페닐)-7-(2-메톡시에톡시)-6-니트로퀴나졸린-4-아민-(3-chloro-4-fluorophenyl) -7- (2-methoxyethoxy) -6-nitroquinazolin-4-amine

N-(3-클로로-4-플루오로페닐)-7-플루오로-6-니트로퀴나졸린-4-아민 염산염 1 ｇ을 다이메틸설폭사이드(DMSO) 10 ㎖에 녹이고, 여기에 2-메톡시에탄올 0.42 ㎖와 포타시움 실란올레이트 1.5 ｇ을 첨가하여 상온에서 4 시간 동안 교반하였다. 반응이 완결되면 반응 용액에 얼음을 첨가하여 결정화시킨 후, 생성된 고체를 물 150 ㎖로 세척하여 감압 여과하였다. 얻어진 고체를 훈풍 건조하여 상기 목적화합물 830㎎ (79%)을 얻었다.1 g of N- (3-chloro-4-fluorophenyl) -7-fluoro-6-nitroquinazolin-4-amine hydrochloride is dissolved in 10 ml of dimethylsulfoxide (DMSO), and 2-methoxy 0.42 ml of ethanol and 1.5 g of potassium silanolate were added thereto, followed by stirring at room temperature for 4 hours. Upon completion of the reaction, ice was added to the reaction solution to crystallize, and the resulting solid was washed with 150 ml of water and filtered under reduced pressure. The obtained solid was warmed and dried to obtain 830 mg (79%) of the target compound.

1H-NMR (DMSO-d6, 300MHz) δ : 10.30 (br s, 1H), 9.08 (s, 1H), 8.40 (s, 1H), 7.45 (m, 3H), 7.20 (t, 1H), 4.38 (m, 2H), 3.69 (m, 2H), 3.28 (s, 3H). 1 H-NMR (DMSO-d 6, 300 MHz) δ: 10.30 (br s, 1H), 9.08 (s, 1H), 8.40 (s, 1H), 7.45 (m, 3H), 7.20 (t, 1H), 4.38 (m, 2 H), 3.69 (m, 2 H), 3.28 (s, 3 H).

1-3. 1-3. NN 44 -(3-클로로-2-플루오로페닐)-7-(2-메톡시에톡시)퀴나졸린-4,6-다이아민 (화학식 3의 화합물)-(3-chloro-2-fluorophenyl) -7- (2-methoxyethoxy) quinazolin-4,6-diamine (compound of formula 3)

철 590 ㎎을 50% 에탄올 수용액 10 ㎖에 용해시키고 진한 염산 0.07 ㎖를 첨가한 후 반응 온도를 100℃로 올려서 활성화시켰다. 여기에 N-(3-클로로-2-플루오로페닐)-7-메톡시-6-니트로퀴나졸린-4-아민 830 ㎎을 첨가하고 환류시켰다. 반응이 완결되면 뜨거운 반응 용액을 셀라이트 패드에 감압여과하고, 패드를 클로로포름과 메탄올로 세척한 후 얻어진 여과액을 포화 중탄산나트륨 수용액으로 세척하였다. 유기층을 황산나트륨으로 건조한 다음, 감압 여과 및 감압 증류하여 상기 목적화합물 727 ㎎ (95%)을 얻었다.590 mg of iron was dissolved in 10 ml of 50% ethanol aqueous solution, 0.07 ml of concentrated hydrochloric acid was added, and the reaction temperature was raised to 100 ° C. to activate. To this was added 830 mg of N- (3-chloro-2-fluorophenyl) -7-methoxy-6-nitroquinazolin-4-amine and refluxed. After the reaction was completed, the hot reaction solution was filtered under reduced pressure through a pad of celite, the pad was washed with chloroform and methanol, and then the filtrate was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered under reduced pressure and distilled under reduced pressure to obtain 727 mg (95%) of the target compound.

1H-NMR(CDCl3+CD3OD 1 drop, 300MHz) δ : 8.50 (s, 1H), 8.30 (m, 1H), 7.32 (s, 2H), 7.15 (m, 3H), 4.30 (m, 2H), 3.90 (m, 2H), 3.49 (s, 3H). 1 H-NMR (CDCl 3 + CD 3 OD 1 drop, 300 MHz) δ: 8.50 (s, 1H), 8.30 (m, 1H), 7.32 (s, 2H), 7.15 (m, 3H), 4.30 (m, 2H), 3.90 (m, 2H), 3.49 (s, 3H).

1-4. (21-4. (2 SS )-)- terttert -부틸 2-(4-(3-클로로-2-플루오로페닐아미노)-7-(2-메톡시에톡시)퀴나졸린-6-일카바모일)피롤리딘-1-카르복실레이트 (화학식 2의 화합물)-Butyl 2- (4- (3-chloro-2-fluorophenylamino) -7- (2-methoxyethoxy) quinazolin-6-ylcarbamoyl) pyrrolidine-1-carboxylate 2, compound)

상기 단계 (1-3)에서 제조된 출발물질 300 ㎎을 피리딘 7 ㎖에 용해시킨 다음, (2S)-1-(tert-부톡시카르보닐)피롤리딘-2-카르복실산 356 ㎎과 1-(3-다이메틸아미노프로필)-3-에틸카르보다이이미드 염산염 477 ㎎을 첨가하여 14 시간 동안 교반하였다. 반응이 완결되면 피리딘을 감압 증류하고 포화 중탄산나트륨 수용액으로 세척하였다. 유기층을 황산마그네슘으로 건조한 뒤 감압 여과 및 감압 증류하여 불순한 잔사를 얻고 이를 컬럼 크로마토그래피 (클로로포름 : 메탄올 = 15 : 1) 로 분리하여 목적화합물 470 ㎎을 정량적으로 얻었다.Dissolving the starting material 300 ㎎ prepared in Step (1-3) in pyridine 7 ㎖ then, (2 S) -1- (tert - butoxycarbonyl) pyrrolidine-2-carboxylic acid and 356 ㎎ 477 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added and stirred for 14 hours. Upon completion of the reaction, pyridine was distilled under reduced pressure and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered under reduced pressure and distilled under reduced pressure to obtain an impure residue, which was separated by column chromatography (chloroform: methanol = 15: 1) to obtain 470 mg of the target compound.

1H-NMR(CDCl3, 300MHz) δ : 9.10 (s, 1H), 8.95 (m, 1H), 8.69 (s, 1H), 8.40 (m, 1H), 7.28 (s, 1H), 7.15 (d, 2H), 4.35 (m, 3H), 3.90 (m, 2H), 3.50 (m, 2H), 3.48 (s, 3H), 1.99 (m, 4H), 1.47 (m, 9H). 1 H-NMR (CDCl 3, 300 MHz) δ: 9.10 (s, 1H), 8.95 (m, 1H), 8.69 (s, 1H), 8.40 (m, 1H), 7.28 (s, 1H), 7.15 (d , 2H), 4.35 (m, 3H), 3.90 (m, 2H), 3.50 (m, 2H), 3.48 (s, 3H), 1.99 (m, 4H), 1.47 (m, 9H).

1-5. (21-5. (2 SS )-)- NN -(4-(3-클로로-2-플루오로페닐아미노)-7-(2-메톡시에톡시)퀴나졸린-6-일)피롤리딘-2-카르복시아미드-(4- (3-chloro-2-fluorophenylamino) -7- (2-methoxyethoxy) quinazolin-6-yl) pyrrolidine-2-carboxyamide

상기 단계 (1-4)에서 제조된 화합물 476 ㎎을 메틸렌클로라이드 10 ㎖에 녹이고, 트라이플루오로아세트산 10 ㎖를 첨가하여 5 시간 동안 교반하였다. 반응이 완결되면 감압 증류하여 용매를 제거하고 잔사를 포화 중탄산나트륨 수용액으로 염기화한 다음, 클로로포름으로 추출하였다. 유기층을 무수 황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 목적화합물 320 ㎎ (82%)을 얻었다.476 mg of the compound prepared in step (1-4) was dissolved in 10 ml of methylene chloride, and 10 ml of trifluoroacetic acid was added and stirred for 5 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was basified with saturated aqueous sodium bicarbonate solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure to obtain 320 mg (82%) of the title compound.

1H-NMR(CDCl3, 300MHz) δ : 9.12 (s, 1H), 8.68 (s, 1H), 8.35 (m, 1H), 7.55 (br s, 1H), 7.15 (m, 2H), 4.35 (m, 2H), 3.93 (m, 1H), 3.89 (m, 2H), 3.51 (s, 3H), 3.10 (m, 2H), 2.20 (m, 2H), 2.13 (m, 2H). 1 H-NMR (CDCl 3, 300 MHz) δ: 9.12 (s, 1H), 8.68 (s, 1H), 8.35 (m, 1H), 7.55 (br s, 1H), 7.15 (m, 2H), 4.35 ( m, 2H), 3.93 (m, 1H), 3.89 (m, 2H), 3.51 (s, 3H), 3.10 (m, 2H), 2.20 (m, 2H), 2.13 (m, 2H).

1-6. (21-6. (2 SS )-1-아크릴로일-) -1-acryloyl- NN -[4-[3-클로로-2-플루오로페닐아미노]-7-(2-메톡시에톡시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드 (화학식 1a의 화합물; A = -C(=O)-)-[4- [3-chloro-2-fluorophenylamino] -7- (2-methoxyethoxy) quinazolin-6-yl] pyrrolidine-2-carboxyamide (compound of Formula 1a; A = -C (= O)-)

상기 단계 (1-5)에서 제조된 화합물 300 ㎎을 테트라하이드로퓨란 7 ㎖에 녹인 다음, 반응 온도를 0℃로 낮추고 아크릴산 70 ㎕를 천천히 적가하였다. 피리딘 0.12 ㎖와 1-(3-다이메틸아미노프로필)-3-에틸카르보다이이미드 염산염 249 ㎎을 첨가한 다음, 반응 온도를 서서히 상온으로 올리면서 4시간 동안 교반하였다. 반응이 완결되면 포화 중탄산나트륨 수용액을 첨가하고 클로로포름으로 추출한 다음, 유기층을 황산나트륨으로 건조한 뒤, 감압 여과 및 감압 증류하여 얻어진 잔사를 컬럼 크로마토그래피 (에틸아세테이트 : 메탄올 = 10 : 1)로 분리하여 목적화합물 35 ㎎ (10%)을 얻었다.300 mg of the compound prepared in step (1-5) was dissolved in 7 ml of tetrahydrofuran, and the reaction temperature was lowered to 0 ° C. and 70 μl of acrylic acid was slowly added dropwise. 0.12 mL of pyridine and 249 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added, followed by stirring for 4 hours while gradually raising the reaction temperature to room temperature. After completion of the reaction, saturated aqueous sodium bicarbonate solution was added, extracted with chloroform, the organic layer was dried over sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue was separated by column chromatography (ethyl acetate: methanol = 10: 1) to obtain a target compound. 35 mg (10%) were obtained.

1H-NMR(CDCl3, 300MHz) δ : 9.99 (s, 1H), 9.07 (s, 1H), 8.68 (s, 1H), 8.39 (dd, 1H), 7.53 (s, 1H), 7.14 (d, 2H), 6.55 (d, 1H), 6.53 (s, 1H), 5.82 (dd, 1H), 4.94 (d, 1H), 4.34 (m, 2H), 3.96 (m, 2H), 3.77 (td, 1H), 3.62 (m, 1H), 3.50 (s, 3H), 2.64 (m, 1H), 2.14 (m, 2H), 1.95 (m, 1H). 1 H-NMR (CDCl 3, 300 MHz) δ: 9.99 (s, 1H), 9.07 (s, 1H), 8.68 (s, 1H), 8.39 (dd, 1H), 7.53 (s, 1H), 7.14 (d , 2H), 6.55 (d, 1H), 6.53 (s, 1H), 5.82 (dd, 1H), 4.94 (d, 1H), 4.34 (m, 2H), 3.96 (m, 2H), 3.77 (td, 1H), 3.62 (m, 1H), 3.50 (s, 3H), 2.64 (m, 1H), 2.14 (m, 2H), 1.95 (m, 1H).

실시예 2: (2Example 2: (2 SS )-1-아크릴로일-) -1-acryloyl- NN -[4-[3-클로로-4-플루오로페닐아미노]-7-(2-메톡시에톡시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드-[4- [3-chloro-4-fluorophenylamino] -7- (2-methoxyethoxy) quinazolin-6-yl] pyrrolidine-2-carboxyamide

실시예 (1-1)에서 3-클로로-2-플루오로아닐린 대신 3-클로로-4-플루오로아닐린을 이용한 것을 제외하고는 실시예 1과 동일한 방법으로 목적화합물 600㎎ (28%)을 얻었다.600 mg (28%) of the title compound was obtained in the same manner as in Example 1, except that 3-chloro-4-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in Example (1-1). .

1H-NMR(DMSO-d6, 300MHz) δ : 9.83 (s, 1H), 9.52 (s, 1H), 8.81 (s, 1H), 8.06 (m, 1H), 7.73 (m, 1H), 7.38 (m, 1H), 7.27 (s, 1H), 6.67 (m, 1H), 6.20 (m, 1H), 5.74 (m, 1H), 4.73 (m, 1H), 4.30 (m, 2H), 3.63 (m, 2H), 3.61 (m, 2H), 3.32 (s, 3H), 2.09 (m, 2H), 1.95 (m, 2H). 1 H-NMR (DMSO-d 6, 300 MHz) δ: 9.83 (s, 1H), 9.52 (s, 1H), 8.81 (s, 1H), 8.06 (m, 1H), 7.73 (m, 1H), 7.38 (m, 1H), 7.27 (s, 1H), 6.67 (m, 1H), 6.20 (m, 1H), 5.74 (m, 1H), 4.73 (m, 1H), 4.30 (m, 2H), 3.63 ( m, 2H), 3.61 (m, 2H), 3.32 (s, 3H), 2.09 (m, 2H), 1.95 (m, 2H).

실시예 3: (2Example 3: (2 SS )-1-아크릴로일-) -1-acryloyl- NN -[4-[4-브로모-3-클로로-2-플루오로페닐아미노]-7-(2-메톡시에톡시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드-[4- [4-bromo-3-chloro-2-fluorophenylamino] -7- (2-methoxyethoxy) quinazolin-6-yl] pyrrolidine-2-carboxyamide

실시예 (1-1)에서 3-클로로-2-플루오로아닐린 대신 4-브로모-3-클로로-2-플 루오로아닐린을 이용한 것을 제외하고는 실시예 1과 동일한 방법으로 목적화합물 800㎎ (31%)을 얻었다.800 mg of the target compound in the same manner as in Example 1, except that 4-bromo-3-chloro-2-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in Example (1-1) (31%) was obtained.

1H-NMR (CDCl3, 300MHz) δ : 9.99 (s, 1H), 9.05 (s, 1H), 8.65 (s, 1H), 8.20 (t, 1H), 7.70 (bs, 1H), 7.43 (dd, 1H), 7.25 (s, 1H), 6.55 (m, 2H), 5.83 (m, 1H), 4.94 (m, 1H), 4.32 (m, 2H), 3.94 (m, 2H), 3.78 (m, 1H), 3.60 (m, 1H), 3.50 (s, 3H), 2.61 (m, 1H), 2.10 (m, 3H). 1 H-NMR (CDCl 3, 300 MHz) δ: 9.99 (s, 1H), 9.05 (s, 1H), 8.65 (s, 1H), 8.20 (t, 1H), 7.70 (bs, 1H), 7.43 (dd , 1H), 7.25 (s, 1H), 6.55 (m, 2H), 5.83 (m, 1H), 4.94 (m, 1H), 4.32 (m, 2H), 3.94 (m, 2H), 3.78 (m, 1H), 3.60 (m, 1H), 3.50 (s, 3H), 2.61 (m, 1H), 2.10 (m, 3H).

실시예 4: (2Example 4: (2 SS )-1-아크릴로일-) -1-acryloyl- NN -[4-[2,3,4-트리플루오로페닐아미노]-7-(2-메톡시에톡시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드-[4- [2,3,4-trifluorophenylamino] -7- (2-methoxyethoxy) quinazolin-6-yl] pyrrolidine-2-carboxyamide

실시예 (1-1)에서 3-클로로-2-플루오로아닐린 대신 2,3,4-트리플루오로아닐린을 이용한 것을 제외하고는 실시예 1과 동일한 방법으로 목적화합물 130 ㎎ (15%)을 얻었다.130 mg (15%) of the target compound were obtained in the same manner as in Example 1, except that 2,3,4-trifluoroaniline was used instead of 3-chloro-2-fluoroaniline in Example (1-1). Got it.

1H-NMR (CDCl3, 300MHz) δ : 9.87 (s, 1H), 8.97 (s, 1H), 8.55 (s, 1H), 7.80 - 7.74 (m, 2H), 7.16 (s, 1H), 6.95 - 6.92 (m, 1H), 6.52~6.48 (m, 2H), 5.81 - 5.76 (m, 1H), 4.91 - 4.89 (m, 1H), 4.22 - 4.27 (m, 2H), 3.91 - 3.86 (m, 2H), 3.76 - 3.73 (m, 1H), 3.60 - 3.58 (m, 1H), 3.45 (s, 3H), 2.80 (br s, 1H), 2.55 (br s, 1H), 2.09 - 1.94 (m, 2H). 1 H-NMR (CDCl 3 , 300 MHz) δ: 9.87 (s, 1H), 8.97 (s, 1H), 8.55 (s, 1H), 7.80-7.74 (m, 2H), 7.16 (s, 1H), 6.95 -6.92 (m, 1H), 6.52-6.68 (m, 2H), 5.81-5.76 (m, 1H), 4.91-4.89 (m, 1H), 4.22-4.27 (m, 2H), 3.91-3.86 (m, 2H), 3.76-3.73 (m, 1H), 3.60-3.58 (m, 1H), 3.45 (s, 3H), 2.80 (br s, 1H), 2.55 (br s, 1H), 2.09-1.94 (m, 2H).

실시예 5: (2Example 5: (2 SS )-1-아크릴로일-) -1-acryloyl- NN -[4-[3,4-다이클로로페닐아미노]-7-(2-메톡시에톡시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드-[4- [3,4-dichlorophenylamino] -7- (2-methoxyethoxy) quinazolin-6-yl] pyrrolidine-2-carboxyamide

실시예 (1-1)에서 3-클로로-2-플루오로아닐린 대신 3,4-다이클로로아닐린을 이용한 것을 제외하고는 실시예 1과 동일한 방법으로 목적화합물 140 ㎎ (12%)을 얻었다.140 mg (12%) of the title compound was obtained in the same manner as in Example 1, except that 3,4-dichloroaniline was used instead of 3-chloro-2-fluoroaniline in Example (1-1).

1H-NMR (CDCl3, 300MHz) δ : 9.92 (s, 1H), 9.58 (s, 1H), 8.87 (s, 1H), 8.55 (s, 1H), 8.20 (d, 1H), 7.84 (dd, 1H), 7.60 (d, 1H), 7.30 (s, 1H), 6.67 (m, 1H), 6.21 (m, 1H), 5.74 (m, 1H), 4.76 (m, 1H), 4.34 (t, 2H), 3.76 (m, 2H), 3.60 (m, 2H), 3.32 (s, 3H), 2.10 (m, 4H). 1 H-NMR (CDCl 3 , 300 MHz) δ: 9.92 (s, 1H), 9.58 (s, 1H), 8.87 (s, 1H), 8.55 (s, 1H), 8.20 (d, 1H), 7.84 (dd , 1H), 7.60 (d, 1H), 7.30 (s, 1H), 6.67 (m, 1H), 6.21 (m, 1H), 5.74 (m, 1H), 4.76 (m, 1H), 4.34 (t, 2H), 3.76 (m, 2H), 3.60 (m, 2H), 3.32 (s, 3H), 2.10 (m, 4H).

실시예 6: (2Example 6: (2 SS )-1-아크릴로일-) -1-acryloyl- NN -[4-[3-클로로-2,4-다이플루오로페닐아미노]-7-(2-메톡시에톡시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드-[4- [3-chloro-2,4-difluorophenylamino] -7- (2-methoxyethoxy) quinazolin-6-yl] pyrrolidine-2-carboxyamide

실시예 (1-1)에서 3-클로로-2-플루오로아닐린 대신 3-클로로-2,4-다이플루오로아닐린을 이용한 것을 제외하고는 실시예 1과 동일한 방법으로 목적화합물 135 ㎎ (14%)을 얻었다.135 mg (14%) of the target compound in the same manner as in Example 1, except that 3-chloro-2,4-difluoroaniline was used instead of 3-chloro-2-fluoroaniline in Example (1-1) )

1H-NMR (CDCl3, 300MHz) δ : 9.95 (s, 1H), 9.03 (s, 1H), 8.60 (s, 1H), 8.06 (m, 1H), 7.62 (bs, 1H), 7.21 (s, 1H), 7.01 (m, 1H), 6.53 (m, 2H), 5.82 (m, 1H), 4.94 (m, 1H), 4.30 (m, 2H), 3.94 (m, 2H), 3.76 (m, 1H), 3.62 (m, 1H), 3.49 (s, 3H), 2.58 (m, 1H), 2.33 (m, 1H), 2.13 (m, 2H), 1.95 (m, 1H). 1 H-NMR (CDCl 3 , 300 MHz) δ: 9.95 (s, 1H), 9.03 (s, 1H), 8.60 (s, 1H), 8.06 (m, 1H), 7.62 (bs, 1H), 7.21 (s , 1H), 7.01 (m, 1H), 6.53 (m, 2H), 5.82 (m, 1H), 4.94 (m, 1H), 4.30 (m, 2H), 3.94 (m, 2H), 3.76 (m, 1H), 3.62 (m, 1H), 3.49 (s, 3H), 2.58 (m, 1H), 2.33 (m, 1H), 2.13 (m, 2H), 1.95 (m, 1H).

실시예 7: (2Example 7: (2 SS )-1-아크릴로일-) -1-acryloyl- NN -[4-[3,4-다이클로로-2-플루오로페닐아미노]-7-(2-메톡시에톡시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드-[4- [3,4-dichloro-2-fluorophenylamino] -7- (2-methoxyethoxy) quinazolin-6-yl] pyrrolidine-2-carboxyamide

실시예 (1-1)에서 3-클로로-2-플루오로아닐린 대신 3,4-다이클로로-2-플루오로아닐린을 이용한 것을 제외하고는 실시예 1과 동일한 방법으로 목적화합물 120 ㎎ (10%)을 얻었다.120 mg (10%) of the target compound in the same manner as in Example 1, except that 3,4-dichloro-2-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in Example (1-1) )

1H-NMR (CDCl3, 300MHz) δ : 10.03 (s, 1H), 9.06 (s, 1H), 8.67 (s, 1H), 8.36 (t, 1H), 7.52 (s, 1H), 7.30 (dd, 1H), 7.24 (s, 1H), 6.55 (m, 2H), 5.83 (m, 1H), 4.95 (m, 1H), 4.33 (m, 2H), 3.95 (m, 2H), 3.76 (m, 1H), 3.62 (m, 1H), 3.51 (s, 3H), 2.61 (m, 1H), 2.13 (m, 2H), 1.97 (m, 1H). 1 H-NMR (CDCl 3 , 300 MHz) δ: 10.03 (s, 1H), 9.06 (s, 1H), 8.67 (s, 1H), 8.36 (t, 1H), 7.52 (s, 1H), 7.30 (dd , 1H), 7.24 (s, 1H), 6.55 (m, 2H), 5.83 (m, 1H), 4.95 (m, 1H), 4.33 (m, 2H), 3.95 (m, 2H), 3.76 (m, 1H), 3.62 (m, 1H), 3.51 (s, 3H), 2.61 (m, 1H), 2.13 (m, 2H), 1.97 (m, 1H).

실시예 8: (2Example 8: (2 SS )-1-아크릴로일-) -1-acryloyl- NN -{4-[3-클로로-4-플루오로페닐아미노]-7-[(테트라하이드로퓨란-2-일)메톡시]퀴나졸린-6-일}피롤리딘-2-카르복시아미드-{4- [3-chloro-4-fluorophenylamino] -7-[(tetrahydrofuran-2-yl) methoxy] quinazolin-6-yl} pyrrolidine-2-carboxyamide

실시예 (1-1)에서 3-클로로-2-플루오로아닐린 대신 3-클로로-4-플루오로아닐린을 이용하고, 실시예 (1-2)에서 2-메톡시에탄올 대신 테트라하이드로퓨란-2-일메틸알콜을 이용한 것을 제외하고는 실시예 1과 동일한 방법으로 목적화합물 50㎎ (11%)을 얻었다.3-chloro-4-fluoroaniline is used instead of 3-chloro-2-fluoroaniline in Example (1-1), and tetrahydrofuran-2 instead of 2-methoxyethanol in Example (1-2) 50 mg (11%) of the title compound was obtained in the same manner as in Example 1, except that ylmethyl alcohol was used.

1H-NMR (CDCl3, 300MHz) δ : 9.93 (s, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 7.86 (dd, 1H), 7.65 (m, 1H), 7.11 (t, 1H), 6.99 (s, 1H), 6.55 (dd, 1H), 6.45 (dd, 1H), 5.75 (dd, 1H), 5.00 (d, 1H), 4.30 (m, 1H), 3.86 (m, 4H), 3.65 (m, 2H), 2.50 (m, 1H), 2.13 (m, 4H), 1.97 (m, 2H), 1.65 (m, 1H). 1 H-NMR (CDCl 3 , 300 MHz) δ: 9.93 (s, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 7.86 (dd, 1H), 7.65 (m, 1H), 7.11 (t , 1H), 6.99 (s, 1H), 6.55 (dd, 1H), 6.45 (dd, 1H), 5.75 (dd, 1H), 5.00 (d, 1H), 4.30 (m, 1H), 3.86 (m, 4H), 3.65 (m, 2H), 2.50 (m, 1H), 2.13 (m, 4H), 1.97 (m, 2H), 1.65 (m, 1H).

실시예 9:　(2Example 9 SS )-1-아크릴로일-) -1-acryloyl- NN -{4-[4-브로모-3-클로로-4-플루오로페닐아미노]-7-[(테트라하이드로퓨란-2-일)메톡시]퀴나졸린-6-일}피롤리딘-2-카르복시아미드-{4- [4-bromo-3-chloro-4-fluorophenylamino] -7-[(tetrahydrofuran-2-yl) methoxy] quinazolin-6-yl} pyrrolidine-2- Carboxamide

실시예 (1-1)에서 3-클로로-2-플루오로아닐린 대신 4-브로모-3-클로로-4-플루오로아닐린을 이용하고, 실시예 (1-2)에서 2-메톡시에탄올 대신 테트라하이드로퓨란-2-일메틸알콜을 이용한 것을 제외하고는 실시예 1과 동일한 방법으로 목적화합물 65㎎ (10%)을 얻었다.4-bromo-3-chloro-4-fluoroaniline is used instead of 3-chloro-2-fluoroaniline in Example (1-1), and 2-methoxyethanol is used instead of 2-methoxyethanol in Example (1-2) 65 mg (10%) of the title compound was obtained in the same manner as in Example 1 except for using tetrahydrofuran-2-ylmethyl alcohol.

1H-NMR (CDCl3, 300MHz) δ : 9.92 (m, 1H), 9.03 (m, 1H), 8.63 (m, 1H), 8.20 (m, 1H), 7.74 (bs, 1H), 7.43 (m, 1H), 7.22 (m, 1H), 6.51 (m, 2H), 5.79 (m, 1H), 4.93 (m, 1H), 4.47 (m, 1H), 4.14 (m, 3H), 3.92 (m, 2H), 3.81 (m, 1H), 3.63 (m, 1H), 2.61 (m, 1H), 2.18 (m, 4H), 1.88 (m, 2H). 1 H-NMR (CDCl 3 , 300 MHz) δ: 9.92 (m, 1H), 9.03 (m, 1H), 8.63 (m, 1H), 8.20 (m, 1H), 7.74 (bs, 1H), 7.43 (m , 1H), 7.22 (m, 1H), 6.51 (m, 2H), 5.79 (m, 1H), 4.93 (m, 1H), 4.47 (m, 1H), 4.14 (m, 3H), 3.92 (m, 2H), 3.81 (m, 1H), 3.63 (m, 1H), 2.61 (m, 1H), 2.18 (m, 4H), 1.88 (m, 2H).

실시예 10: (2Example 10: (2 SS )-1-아크릴로일-) -1-acryloyl- NN -{4-[4-브로모-3-클로로-2-플루오로페닐아미노]-7-(2-모폴리노에톡시)퀴나졸린-6-일}피롤리딘-2-카르복시아미드-{4- [4-bromo-3-chloro-2-fluorophenylamino] -7- (2-morpholinoethoxy) quinazolin-6-yl} pyrrolidine-2-carboxyamide

실시예 (1-1)에서 3-클로로-2-플루오로아닐린 대신 4-브로모-3-클로로-4-플루오로아닐린을 이용하고, 실시예 (1-2)에서 2-메톡시에탄올 대신 2-모폴리노에탄올을 이용한 것을 제외하고는 실시예 1과 동일한 방법으로 목적화합물 70㎎ (11%)을 얻었다.4-bromo-3-chloro-4-fluoroaniline is used instead of 3-chloro-2-fluoroaniline in Example (1-1), and 2-methoxyethanol is used instead of 2-methoxyethanol in Example (1-2) 70 mg (11%) of the title compound was obtained in the same manner as in Example 1 except for using 2-morpholinoethanol.

1H-NMR (CDCl3, 300MHz) δ : 10.08 (s, 1H), 9.05 (s, 1H), 8.64 (s, 1H), 8.17 (m, 1H), 7.71 (bs, 1H), 7.40 (dd, 1H), 7.19 (s, 1H), 6.52 (m, 2H), 5.82 (m, 1H), 4.94 (m, 1H), 4.29 (m, 2H), 3.76 (m, 5H), 3.62 (m, 1H), 3.08 (m, 1H), 2.97 (m, 1H), 2.63 (m, 6H), 2.21 (m, 1H), 1.97 (m, 1H). 1 H-NMR (CDCl 3 , 300 MHz) δ: 10.08 (s, 1H), 9.05 (s, 1H), 8.64 (s, 1H), 8.17 (m, 1H), 7.71 (bs, 1H), 7.40 (dd , 1H), 7.19 (s, 1H), 6.52 (m, 2H), 5.82 (m, 1H), 4.94 (m, 1H), 4.29 (m, 2H), 3.76 (m, 5H), 3.62 (m, 1H), 3.08 (m, 1H), 2.97 (m, 1H), 2.63 (m, 6H), 2.21 (m, 1H), 1.97 (m, 1H).

실시예 11: (2Example 11: (2 SS )-1-아크릴로일-) -1-acryloyl- NN -(4-(3-클로로-2-플루오로페닐아미노)-7-(2-(4-메틸티아졸-5-일)에톡시)퀴나졸린-6-일)피롤리딘-2-카르복시아미드-(4- (3-chloro-2-fluorophenylamino) -7- (2- (4-methylthiazol-5-yl) ethoxy) quinazolin-6-yl) pyrrolidine-2-carboxy amides

실시예 (1-2)에서 2-메톡시에탄올 대신에 2-(4-메틸티아졸-5-일)에탄올을 이용한 것을 제외하고는 실시예 1과 동일한 방법으로 목적화합물 65 ㎎ (34%)을 얻었다.65 mg (34%) of the target compound in the same manner as in Example 1, except that 2- (4-methylthiazol-5-yl) ethanol was used instead of 2-methoxyethanol in Example (1-2) Got.

1H-NMR (CDCl3, 300MHz) δ : 10.07 (s, 1H), 9.06 (s, 1H), 8.66 (s, 1H), 8.61 (s, 1H), 8.31 (m, 1H), 7.70 (br s, 1H), 7.23 (s, 1H), 7.16 (m, 2H), 6.48 (dd, 1H), 6.45 (dd, 1H), 5.76 (dd, 1H), 4.93 (d, 1H), 4.37 (t, 2H), 3.71 (m, 1H), 3.63-3.44 (m, 3H), 2.55 (m, 1H), 2.48 (s, 3H), 2.16 (m, 2H), 1.95 (m, 1H). 1 H-NMR (CDCl 3 , 300 MHz) δ: 10.07 (s, 1H), 9.06 (s, 1H), 8.66 (s, 1H), 8.61 (s, 1H), 8.31 (m, 1H), 7.70 (br s, 1H), 7.23 (s, 1H), 7.16 (m, 2H), 6.48 (dd, 1H), 6.45 (dd, 1H), 5.76 (dd, 1H), 4.93 (d, 1H), 4.37 (t , 2H), 3.71 (m, 1H), 3.63-3.44 (m, 3H), 2.55 (m, 1H), 2.48 (s, 3H), 2.16 (m, 2H), 1.95 (m, 1H).

실시예 12: (2Example 12: (2 SS )-1-아크릴로일-) -1-acryloyl- NN -{4-[3-클로로-2-플루오로페닐아미노]-7-[2-(1-{4- [3-chloro-2-fluorophenylamino] -7- [2- (1 HH -1,2,4-트리아졸-1-일)에톡시]퀴나졸린-6-일}피롤리딘-2-카르복시아미드-1,2,4-triazol-1-yl) ethoxy] quinazolin-6-yl} pyrrolidine-2-carboxyamide

실시예 (1-2)에서 2-메톡시에탄올 대신에 2-(1H-1,2,4-트리아졸-1-일)에탄올 이용한 것을 제외하고는 실시예 1과 동일한 방법으로 목적화합물 50 ㎎ (12%)을 얻었다.Target compound 50 in the same manner as in Example 1, except that 2- ( 1H -1,2,4-triazol-1-yl) ethanol was used instead of 2-methoxyethanol in Example (1-2) Mg (12%) was obtained.

1H-NMR (CDCl3, 300MHz) δ : 10.37 (s, 1H), 8.99 (s, 2H), 8.59 (t, 1H), 8.10 (t, 1H), 7.98 (s, 1H), 7.13 (s, 1H), 7.08 (m, 2H), 6.54 (dd, 1H), 6.48 (dd, 1H), 5.84 (dd, 1H), 4.94 (m, 2H), 4.70 (d, 1H), 4.55 (t, 1H), 4.40 (m, 1H), 3.70 (m, 1H), 3.55 (m, 1H), 2.60 (m, 1H), 2.15 (m, 2H), 1.85 (m, 1H). 1 H-NMR (CDCl 3 , 300 MHz) δ: 10.37 (s, 1H), 8.99 (s, 2H), 8.59 (t, 1H), 8.10 (t, 1H), 7.98 (s, 1H), 7.13 (s , 1H), 7.08 (m, 2H), 6.54 (dd, 1H), 6.48 (dd, 1H), 5.84 (dd, 1H), 4.94 (m, 2H), 4.70 (d, 1H), 4.55 (t, 1H), 4.40 (m, 1H), 3.70 (m, 1H), 3.55 (m, 1H), 2.60 (m, 1H), 2.15 (m, 2H), 1.85 (m, 1H).

실시예 13: (2Example 13: (2 SS )-1-(2-{[4-(4-브로모-3-클로로-2-플루오로페닐아미노)-7-(2-메톡시에톡시)퀴나졸린-6-일아미노]메틸}피롤리딘-1-일)프로-2-펜-1-온) -1- (2-{[4- (4-bromo-3-chloro-2-fluorophenylamino) -7- (2-methoxyethoxy) quinazolin-6-ylamino] methyl} pi Ralidin-1-yl) pro-2-phen-1-one

13-1. 13-1. NN 44 -(4-브로모-3-클로로-2-플루오로페닐)-7-(2-메톡시에톡시)퀴나졸린-4,6-다이아민 (화학식 3의 화합물)-(4-bromo-3-chloro-2-fluorophenyl) -7- (2-methoxyethoxy) quinazolin-4,6-diamine (compound of formula 3)

실시예 (1-1)에서 3-클로로-2-플루오로아닐린 대신 4-브로모-3-클로로-4-플루오로아닐린을 이용한 것을 제외하고는, 실시예 (1-1) 내지 (1-3)과 동일한 방법에 따라 실시하여 목적화합물 0.78 g (3단계 82%)을 얻었다.Examples (1-1) to (1-), except that 4-bromo-3-chloro-4-fluoroaniline was used instead of 3-chloro-2-fluoroaniline in Example (1-1) The same procedure as in 3) was carried out to obtain 0.78 g of the target compound (82% in 3 steps).

13-2. (213-2. (2 SS )-)- terttert -부틸 2-{[(4-(4-브로모-3-클로로-2-플루오로페닐아미노)-7- (2-메톡시에톡시)퀴나졸린-6-일아미노]메틸}피롤리딘-1-카복실레이트 (화학식 4의 화합물)-Butyl 2-{[(4- (4-bromo-3-chloro-2-fluorophenylamino) -7- (2-methoxyethoxy) quinazolin-6-ylamino] methyl} pyrrolidine -1-carboxylate (compound of formula 4)

상기 단계 (13-1)에서 제조된 출발물질 600㎎과 (S)-tert-부틸-2-포밀피롤리딘-1-카르복실레이트 0.47 g을 아세트산 8㎖와 에탄올 8㎖에 묽힌 다음, 소디움시아노보로하이드라이드 270㎎을 첨가하여 상온에서 3시간 동안 교반하였다. 반응이 완결되면 반응용매를 감압 증류하고 포화 중탄산나트륨 수용액으로 염기화하였다. 그리고 메틸렌클로라이드로 추출해 낸 후 유기층을 황산마그네슘으로 건조한 뒤 감압 여과 및 감압 증류하여 얻어진 잔사를 컬럼 크로마토그래피 (에틸 아세테이트 : 메틸렌클로라이드 : 메탄올 = 7 : 7 : 1)로 분리하여 목적화합물 0.56 g (66 %)을 얻었다.600 mg of the starting material prepared in the step (13-1) and 0.47 g of (S) -tert-butyl-2-formylpyrrolidine-1-carboxylate were diluted in 8 ml of acetic acid and 8 ml of ethanol, and sodium 270 mg of cyanoborohydride was added and stirred at room temperature for 3 hours. Upon completion of the reaction, the reaction solvent was distilled under reduced pressure and basified with saturated aqueous sodium bicarbonate solution. After extraction with methylene chloride, the organic layer was dried over magnesium sulfate, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (ethyl acetate: methylene chloride: methanol = 7: 7: 1) to obtain 0.56 g (66) of the target compound. %) Was obtained.

1H-NMR (CDCl3, 300MHz) δ : 8.51 (s, 1H), 8.19 (s, 1H), 7.96 (s, 1H), 7.92 (t,1H), 7.45 (m, 1H), 7.12 (s, 1H), 5.12 (bt, 1H), 4.32 (t, 2H), 4.29 (m, 1H), 3.85 (m, 2H), 3.61 (m, 1H), 3.47 (s, 3H), 3.46 (m, 1H), 3.25 (m, 1H), 3.05 (m, 1H), 1.80 (m, 4H), 1.42 (s, 9H). 1 H-NMR (CDCl 3 , 300 MHz) δ: 8.51 (s, 1H), 8.19 (s, 1H), 7.96 (s, 1H), 7.92 (t, 1H), 7.45 (m, 1H), 7.12 (s , 1H), 5.12 (bt, 1H), 4.32 (t, 2H), 4.29 (m, 1H), 3.85 (m, 2H), 3.61 (m, 1H), 3.47 (s, 3H), 3.46 (m, 1H), 3.25 (m, 1H), 3.05 (m, 1H), 1.80 (m, 4H), 1.42 (s, 9H).

13-3. (213-3. (2 SS )-)- NN 44 -(4-브로모-3-클로로-2-플루오로페닐)-7-(2-메톡시에톡시)--(4-bromo-3-chloro-2-fluorophenyl) -7- (2-methoxyethoxy)- NN 66 -(피롤리딘-2-일메틸)퀴나졸린-4,6-디아민-(Pyrrolidin-2-ylmethyl) quinazolin-4,6-diamine

상기 단계 (13-2)에서 제조된 화합물 0.56 g을 메틸렌클로라이드 10 ㎖에 녹이고, 트라이플루오로아세트산 10 ㎖를 첨가하여 1시간 동안 교반하였다. 반응이 완결되면 감압 증류하여 용매를 제거하고 잔사를 포화 중탄산나트륨 수용액으로 염기화한 다음, 클로로포름으로 추출하였다. 유기층을 무수 황산나트륨으로 건조한 뒤, 감압 여과 및 감압 증류하여 목적화합물 404 ㎎ (86 %)을 얻었다.0.56 g of the compound prepared in step (13-2) was dissolved in 10 ml of methylene chloride, and 10 ml of trifluoroacetic acid was added thereto, followed by stirring for 1 hour. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was basified with saturated aqueous sodium bicarbonate solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure to obtain 404 mg (86%) of the title compound.

1H-NMR (CDCl3, 300MHz) δ : 8.50 (s, 1H), 8.25(t, 1H), 7.40 (m, 1H), 7.04 (s, 1H), 6.73 (s, 1H), 5.21 (bs, 1H), 4.28 (m, 3H), 3.82 (m, 2H), 3.57 (m, 1H), 3.45 (s, 3H), 3.32 (m, 1H), 3.05 (m, 2H), 2.03 (m, 1H), 1.87 (m, 2H), 1.62 (m, 1H). 1 H-NMR (CDCl 3, 300 MHz) δ: 8.50 (s, 1H), 8.25 (t, 1H), 7.40 (m, 1H), 7.04 (s, 1H), 6.73 (s, 1H), 5.21 (bs, 1H), 4.28 (m, 3H), 3.82 (m, 2H), 3.57 (m, 1H), 3.45 (s, 3H), 3.32 (m, 1H), 3.05 (m, 2H), 2.03 (m, 1H ), 1.87 (m, 2 H), 1.62 (m, 1 H).

13-4. (213-4. (2 SS )-1-(2-{[4-(4-브로모-3-클로로-2-플루오로페닐아미노)-7-(2-메톡시에톡시)퀴나졸린-6-일아미노]메틸}피롤리딘-1-일)프로-2-펜-1-온 (화학식 1b의 화합물)) -1- (2-{[4- (4-bromo-3-chloro-2-fluorophenylamino) -7- (2-methoxyethoxy) quinazolin-6-ylamino] methyl} pi Ralidin-1-yl) pro-2-phen-1-one (compound of Formula 1b)

상기 단계 (13-3)에서 제조된 화합물 383 ㎎을 테트라히드로퓨란 5 ㎖와 증류수 1㎖에 녹인 다음, 중탄산나트륨 184㎎을 가하고 아크릴로일 클로라이드 0.06 ㎖를 적가 하였다. 상온에서 2시간 동안 교반한 후, 반응이 완결되면 포화 중탄산나트륨 수용액을 첨가하고 클로로포름으로 추출한 다음, 유기층을 무수 황산나트륨으로 건조한 뒤, 감압 여과 및 감압 증류하여 얻어진 잔사를 컬럼 크로마토그래피 (에틸아세테이트 : 메틸렌클로라이드 : 메탄올 = 5 : 5 : 1)로 분리하여 목적화합물 177 ㎎ (42 %)을 얻었다.383 mg of the compound prepared in step (13-3) was dissolved in 5 ml of tetrahydrofuran and 1 ml of distilled water, and then 184 mg of sodium bicarbonate was added dropwise with 0.06 ml of acryloyl chloride. After stirring at room temperature for 2 hours, when the reaction was completed, saturated aqueous sodium bicarbonate solution was added, extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue was purified by column chromatography (ethyl acetate: methylene). Chloride: Methanol = 5: 5: 1) afforded 177 mg (42%) of the title compound.

1H-NMR (CDCl3, 300MHz) δ : 8.67 (s, 1H), 8.54 (s, 1H), 8.33 (s, 1H), 8.10 (t, 1H), 7.44 (dd, 1H), 7.14 (s, 1H), 6.47 (m, 2H), 5.75 (m, 1H), 5.13 (bt, 1H), 4.64 (m, 1H), 4.32 (t, 2H), 3.85 (m, 2H), 3.71 (m, 2H), 3.52 (m, 1H), 3.48 (s, 3H), 3.10 (m, 1H), 2.05 (m, 2H), 1.97 (m, 2H). 1 H-NMR (CDCl 3 , 300 MHz) δ: 8.67 (s, 1H), 8.54 (s, 1H), 8.33 (s, 1H), 8.10 (t, 1H), 7.44 (dd, 1H), 7.14 (s , 1H), 6.47 (m, 2H), 5.75 (m, 1H), 5.13 (bt, 1H), 4.64 (m, 1H), 4.32 (t, 2H), 3.85 (m, 2H), 3.71 (m, 2H), 3.52 (m, 1H), 3.48 (s, 3H), 3.10 (m, 1H), 2.05 (m, 2H), 1.97 (m, 2H).

상기 실시예에서 제조된 본 발명의 화합물들을 다음과 같이 제제화하였다:The compounds of the present invention prepared in the above examples were formulated as follows:

제제예 1Formulation Example 1

하기 표 1의 성분을 이용하여 통상적인 방법에 따라 상기 실시예 1 내지 13에서 제조된 화학식 1의 활성 화합물 각각을 함유하는 경구 투여용 단일 정제를 제조하였다.A single tablet for oral administration containing each of the active compounds of Formula 1 prepared in Examples 1 to 13 was prepared according to conventional methods using the components of Table 1 below.

Figure 112007035977473-PAT00004
Figure 112007035977473-PAT00004

제제예 2Formulation Example 2

하기 표 2의 성분을 이용하여 통상적인 방법에 따라 상기 실시예 1 내지 13에서 제조된 화학식 1의 활성 화합물 각각을 함유하는 경구 투여용 경질 젤라틴 캡슐을 제조하였다.Hard gelatine capsules for oral administration containing each of the active compounds of Formula 1 prepared in Examples 1 to 13 were prepared according to conventional methods using the components shown in Table 2 below.

Figure 112007035977473-PAT00005
Figure 112007035977473-PAT00005

제제예 3Formulation Example 3

하기 표 3의 성분을 이용하여 통상적인 방법에 따라 상기 실시예 1 내지 13에서 제조된 화학식 1의 활성 화합물 각각을 함유하는 주사용 제제를 제조하였다. 단, 화학식 1 화합물의 염을 사용하는 경우에는 pH를 조절하지 않았다.Injectable formulations containing each of the active compounds of Formula 1 prepared in Examples 1 to 13 were prepared according to conventional methods using the components shown in Table 3 below. However, when using the salt of the compound of formula (1) did not adjust the pH.

Figure 112007035977473-PAT00006
Figure 112007035977473-PAT00006

제제예 4Formulation Example 4

하기 표 4의 성분을 이용하여 통상적인 방법에 따라 상기 실시예 1 내지 13에서 제조된 화학식 1의 활성 화합물 각각을 함유하는 주사용 제제를 제조하였다.Injectable formulations containing each of the active compounds of Formula 1 prepared in Examples 1 to 13 were prepared according to conventional methods using the components shown in Table 4 below.

Figure 112007035977473-PAT00007
Figure 112007035977473-PAT00007

시험예Test Example 1:  One: EGFREGFR 효소 저해 Enzyme inhibition

96-웰 (well) 미세판의 각 웰에 10 ㎕의 EGF 수용체 (EGFR type 1 키나제)를 넣어준 후, EGFR 저해제로서 상기 실시예 1 내지 13에서 제조된 화합물들, 및 공지된 EGFR 저해제로서 이레사 (Iressa, 아스트라제네카사) 및 라파티닙 (Lapatinib, 글락소스미스클라인사) 각각을 정해진 농도로 단계적으로 희석하여 각 웰당 10 ㎕씩 첨가한 후 10분 동안 상온에서 배양하였다. 배양 후, 기질로 사용되는 폴리 (Glu, Tyr) 4:1 (시그마사)을 10 ㎕씩 각 웰에 첨가한 후 10 ㎕의 ATP를 첨가하여 키나제 반응을 개시하였다. 상온에서 1시간 배양 후에 100 mM EDTA를 10 ㎕씩 각 웰에 첨가하여 키나제 반응을 종결시킨 다음 5분 동안 교반기에서 서서히 혼합해 주었다. 각 웰에 10 ㎕의 10 X 항-포스포티로신 (anti-phosphotyrosine) 항체 (판베라사), 10 ㎕의 10 X PTK (프로테인 티로신 키나제, protein tyrosine kinase) 그린 트레이서 (판베라사) 및 30 ㎕의 FP (편광, fluorescence polarization) 희석 완충용액을 첨가한 후 30분 동안 상온에서 어두운 상태로 배양하였다. 배양 후에 VICTORⅢ 형광량계 (fluorescence meter, 퍼킨엘머사)를 이용하여 각 웰의 편광 (FP) 값을 측정하고 (이때, 여기필터: 488 nm 및 방출필터: 488 nm), EGFR 저해제를 처리하지 않은 웰에서 측정된 편광값 (mP)을 최대값으로 하고 100% 저해한 값을 최소값 (0%)으로 할 때, 50% 저해된 농도를 산출하여 IC50 값으로 정하였다. IC50 산출 및 결과 분석은 마이크로소프트 엑셀을 이용하였으며, 그 결과를 하기 표 5에 나타내었다.10 μl of EGF receptor (EGFR type 1 kinase) was added to each well of a 96-well microplate, and the compounds prepared in Examples 1 to 13 above as EGFR inhibitors, and Iresa as known EGFR inhibitors. (Iressa, AstraZeneca Co.) and Lapatinib (Lapatinib, GlaxoSmithKline Inc.) were each diluted stepwise to add 10 μl per well and incubated at room temperature for 10 minutes. After incubation, 10 μl of poly (Glu, Tyr) 4: 1 (Sigma) used as a substrate was added to each well, and then 10 μl of ATP was added to initiate the kinase reaction. After 1 hour of incubation at room temperature, 10 μl of 100 mM EDTA was added to each well to terminate the kinase reaction, and then slowly mixed in a stirrer for 5 minutes. Each well contains 10 μl of 10 × anti-phosphotyrosine antibody (panverasa), 10 μl of 10 × PTK (protein tyrosine kinase) protein green tracer (panverasa) and 30 μl FP (fluorescence polarization) dilution buffer was added and incubated in dark at room temperature for 30 minutes. After incubation, the polarization (FP) value of each well was measured using a VICTORIII fluorescence meter (Perkin Elmer), and the excitation filter (488 nm and the emission filter: 488 nm) was treated without EGFR inhibitor. When the polarization value (mP) measured in the well was the maximum value and the 100% inhibition value was the minimum value (0%), 50% inhibition concentration was calculated and determined as the IC 50 value. IC 50 calculation and analysis of results using Microsoft Excel, the results are shown in Table 5 below.

시험예 2: EGFR 변이 효소 (T790M) 저해Test Example 2: Inhibition of EGFR Mutant Enzyme (T790M)

96-웰 (well) 미세판의 각 웰에 10 ㎕의 EGF 변이수용체 (EGFR T790M 키나제, 업스테이트사)를 넣어준 후, EGFR 저해제로서 상기 실시예 1 내지 13에서 제조된 화합물들, 및 공지된 EGFR 저해제로서 이레사 (Iressa, 아스트라제네카사) 및 라파티닙 (Lapatinib, 글락소스미스클라인사) 각각을 정해진 농도로 단계적으로 희석하여 각 웰당 10 ㎕씩 첨가한 후 10분 동안 상온에서 배양하였다. 이후 반응은 상기 시험예 1과 동일한 조건에서 실험하였다. 그 결과를 하기 표 5에 나타내었다.10 μl of EGF variant receptor (EGFR T790M Kinase, Upstate) was added to each well of a 96-well microplate, and the compounds prepared in Examples 1 to 13 above as EGFR inhibitors, and known As EGFR inhibitors, each of Iressa (Iressa, AstraZeneca) and Lapatinib (Lapatinib, GlaxoSmithKline) was diluted stepwise to 10 μl per well and incubated at room temperature for 10 minutes. After the reaction was carried out under the same conditions as in Test Example 1. The results are shown in Table 5 below.

시험예 3: 암세포 성장 억제 시험Test Example 3: Cancer Cell Growth Inhibition Test

암세포 성장 억제 시험을 위해 피부암 세포주인 A431 (ATCC: CRL-1555), 유방암 세포주인 SK-Br3 (ATCC: HTB-30), 및 결장직장암 세포주인 SW-620 (ATCC: CCL-227)을 사용하였으며, 배양 배지로는 4.5 g/ℓ 글루코스 (glucose) 및 1.5 g/ℓ 수소화탄산나트륨을 포함하고 10% FBS (fetal bovine serum)가 첨가된 DMEM (Dulbecco's Modified Eagle's Medium) 배지를 사용하였다.Skin cancer cell line A431 (ATCC: CRL-1555), breast cancer cell line SK-Br3 (ATCC: HTB-30), and colorectal cancer cell line SW-620 (ATCC: CCL-227) were used for cancer cell growth inhibition test. As culture medium, DMEM (Dulbecco's Modified Eagle's Medium) medium containing 4.5 g / L glucose and 1.5 g / L sodium carbonate and 10% FBS (fetal bovine serum) was used.

액체 질소 탱크에 보관되어 있던 암세포주를 꺼내어 37℃에서 빠르게 녹인 후 원심분리하여 냉동보관 배지를 제거하였다. 원심분리하여 얻은 세포 펠렛 (pellet)을 배양 배지에 잘 섞어서 배양 플라스크에 넣어 37℃, 5% 이산화탄소 조건으로 배양하였다. 2 내지 3 일 후 세포가 안정적으로 배양되면 플라스크의 배지를 제거하고, DPBS (Dulbecco's Phosphate Buffered Saline)로 세척한 뒤, 트립신 (Tripsin)-EDTA 용액을 사용하여 세포를 플라스크에서 떼어낸 다음, A431의 경우 100,000 세포/㎖가 되도록, SK-Br3의 경우 200,000 세포/㎖가 되도록 배양 배지로 희석하여 준비하였다. 96-웰 미세판에 준비된 세포를 100 ㎕씩 분주하고 37℃, 5% 이산화탄소 조건으로 1 일간 배양하였다.The cancer cell line stored in the liquid nitrogen tank was taken out and rapidly dissolved at 37 ° C., and then centrifuged to remove the cryopreservation medium. Cell pellets obtained by centrifugation were mixed well in the culture medium, and placed in a culture flask, and cultured at 37 ° C. and 5% carbon dioxide conditions. After 2 to 3 days, the cells were stably cultured, the flask medium was removed, washed with DPBS (Dulbecco's Phosphate Buffered Saline), and the cells were removed from the flask using Trypsin-EDTA solution, followed by A431 In case of 100,000 cells / ml, SK-Br3 was prepared by diluting with culture medium to 200,000 cells / ml. 100 μl of cells prepared in 96-well microplate were dispensed and incubated for 1 day at 37 ° C. and 5% carbon dioxide.

시험물질로서 상기 실시예 1 내지 13에서 제조된 화합물들 및 공지된 EGFR 저해제로서 이레사 및 라파티닙을 각각 세포 배양급의 99.5% DMSO에 25 mM이 되도록 용해시켰다. 시험물질이 DMSO에 잘 용해되지 않는 경우에는 1% 염산 용액을 소량 첨가하여 용해시켰으며, 시험물질의 완전한 용해를 위해 약 40℃의 물 수조에 중탕으로 30 분 정도 보관하였다. 시험물질의 용액을 배양 배지로 희석하여 최종 100 μM의 농도로 만든 후 10 배씩 희석하여 10-6 μM까지 희석한 용액을 준비하였다 (최종 DMSO의 농도는 1% 이하가 되도록 한다).The compounds prepared in Examples 1 to 13 above as test substances and iresa and lapatinib as known EGFR inhibitors were dissolved to 25 mM in 99.5% DMSO of the cell culture grade, respectively. When the test material was not dissolved in DMSO, a small amount of 1% hydrochloric acid solution was added to dissolve it. The test material was stored in a water bath at about 40 ° C. for 30 minutes in a water bath for complete dissolution of the test material. A solution of the test substance was diluted with culture medium to a final concentration of 100 μM, and then diluted 10-fold to prepare a solution diluted to 10 −6 μM (final DMSO concentration was 1% or less).

배양된 세포가 들어 있는 96-웰 미세판의 배양액을 제거한 뒤 이미 희석하여 둔 시험물질의 용액을 100 ㎕씩 넣어주었다. 시험물질을 넣은 96-웰 미세판을 37℃, 5% 이산화탄소 조건으로 72 시간 배양하였다. 96-웰 미세판 내의 배지를 제거한 뒤 10% 삼염화아세트산을 50 ㎕ 넣고 37℃에서 1 시간 동안 반응시켜 세포를 플레이트 바닥에 고정시켰다. 10% 삼염화아세트산 용액을 제거하고 잘 건조한 뒤 SRB (Sulforhodamine-B) 염료 용액을 100 ㎕씩 넣어주고 10 분 동안 반응시켰다. SRB 염료 용액은 SRB를 1% 아세트산으로 용해시켜 0.4%의 농도로 제조하였다. 염료 용액을 제거하고 물을 이용하여 플레이트에 묻은 염료를 깨끗이 제거한 뒤 잘 건조시켰다. 물로 완전히 제거되지 않을 경우 1% 아세트산을 이용하였다. 10 mM 트라이스마 베이스 (trisma base) 150 ㎕를 각 웰에 분주하여 충분하게 섞어준 뒤 미세판 판독기 (microplate reader)로 570 nm 파장에서 흡광도를 측정하였다. 세포 성장 정도를 통해 분석되는 IC50 값은 시험물질을 처리하지 않은 웰에서 배양된 세포의 최종 농도값에서 처음 세포 농도값을 빼서 그 값을 100%으로 하였을 때 세포 성장을 50% 억제한 시험물질의 농도로 산출하였다. IC50 산출 및 결과 분석은 마이크로소프트 엑셀을 이용하였으며, 그 결과를 하기 표 5에 나타내었다.After removing the culture medium of the 96-well microplate containing the cultured cells, 100 μl of the diluted solution of test substance was added. 96-well microplates containing test material were incubated at 37 ° C. and 5% carbon dioxide for 72 hours. After removing the medium in the 96-well microplate, 50 μl of 10% trichloroacetic acid was added and reacted at 37 ° C. for 1 hour to fix the cells on the plate bottom. After removing the 10% trichloroacetic acid solution and drying well, 100 μl of SRB (Sulforhodamine-B) dye solution was added and reacted for 10 minutes. SRB dye solutions were prepared at a concentration of 0.4% by dissolving SRB with 1% acetic acid. The dye solution was removed, and the dye on the plate was completely removed using water and then dried well. If not completely removed with water, 1% acetic acid was used. 150 μl of 10 mM trisma base was aliquoted into each well, followed by sufficient mixing, and the absorbance was measured at 570 nm with a microplate reader. The IC 50 value analyzed by the degree of cell growth is the test substance that inhibited the cell growth by 50% when the initial cell concentration value was subtracted from the final concentration value of the cells cultured in the wells not treated with the test substance. It was calculated by the concentration of. IC 50 calculation and analysis of results using Microsoft Excel, the results are shown in Table 5 below.

Figure 112007035977473-PAT00008
Figure 112007035977473-PAT00008

상기 표 5로부터 알 수 있듯이, 본 발명의 화학식 1의 화합물들은 EGFR 키나제, EGFR T790M 돌연변이 키나제, EGFR이 과발현된 A431 세포주 및 Erb-B2가 과발현된 SK-Br3 세포주의 성장을 낮은 약물농도에서 효과적으로 억제하여 우수한 항암활성을 나타낸 반면, EGFR 및 Erb-B2가 과발현되지 않은 SW-620 세포주의 성장 억제에는 거의 영향을 미치지 않았으며, 특히 대조약물인 이레사 및 라파티닙과 비교시 전반적으로 우수한 활성을 나타내었다. 따라서, 본 발명의 화합물은 상피세포 성장인자 수용체가 과발현된 암세포 및 EGFR 변이 암세포의 성장을 효과적으로 억제할 수 있다.As can be seen from Table 5, the compounds of Formula 1 of the present invention effectively inhibit the growth of EGFR kinase, EGFR T790M mutant kinase, A431 cell line overexpressing EGFR and SK-Br3 cell line overexpressing Erb-B2 at low drug concentrations In contrast, EGFR and Erb-B2 did not significantly affect the growth inhibition of SW-620 cell line that was not overexpressed, especially in comparison with the control drugs iresa and lapatinib. Therefore, the compounds of the present invention can effectively inhibit the growth of cancer cells overexpressed epidermal growth factor receptor and EGFR variant cancer cells.

본 발명의 신규 퀴나졸린 유도체는 상피세포 성장인자 및 이의 변이체에 의해 유발되는 암세포의 성장을 선택적이고 효과적으로 억제할 수 있다.The novel quinazoline derivatives of the present invention can selectively and effectively inhibit the growth of cancer cells caused by epidermal growth factor and variants thereof.

Claims (6)

하기 화학식 1의 퀴나졸린 유도체 또는 이의 약학적으로 허용가능한 염:A quinazoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof: 화학식 1Formula 1
Figure 112007035977473-PAT00009
Figure 112007035977473-PAT00009
 상기 식에서,Where R1은 치환체 X를 갖는 C1-6알콕시이고;R 1 is C 1-6 alkoxy with substituent X; R2는 수소 또는 할로겐으로 치환된 벤젠이고;R 2 is benzene substituted with hydrogen or halogen; A는 -C(=O)- 또는 -CH2-이고;A is -C (= 0)-or -CH 2- ; 상기 치환체 X는 C1-6알콕시 또는 헤테로사이클이고;The substituent X is C 1-6 alkoxy or heterocycle; 상기 헤테로사이클은 N, O 및 S로 이루어진 군으로부터 선택된 1 내지 4개의 구성원을 포함하는, 5 또는 6원의 헤테로방향족 또는 비방향족 화합물이다.The heterocycle is a 5 or 6 membered heteroaromatic or nonaromatic compound comprising 1 to 4 members selected from the group consisting of N, O and S. 제 1 항에 있어서,The method of claim 1, R1이 2-메톡시에톡시, (테트라하이드로퓨란-2-일)메톡시, 2-모폴리노에톡시, (4-메틸티아졸-5-일)에톡시 또는 2-(1H-1,2,4-트리아졸-1-일)에톡시이고;R 1 is 2-methoxyethoxy, (tetrahydrofuran-2-yl) methoxy, 2-morpholinoethoxy, (4-methylthiazol-5-yl) ethoxy or 2- ( 1H − 1,2,4-triazol-1-yl) ethoxy; R2가 3-클로로-4-플루오로페닐, 3-클로로-2-플루오로페닐, 4-브로모-3-클로로-2-플루오로페닐, 2,3,4-트리플루오로페닐, 3,4-다이클로로페닐, 3,4-다이클로로-2-플루오로페닐 또는 3-클로로-2,4-플루오로페닐인 것을 특징으로 하는,R 2 is 3-chloro-4-fluorophenyl, 3-chloro-2-fluorophenyl, 4-bromo-3-chloro-2-fluorophenyl, 2,3,4-trifluorophenyl, 3 , 4-dichlorophenyl, 3,4-dichloro-2-fluorophenyl or 3-chloro-2,4-fluorophenyl, 퀴나졸린 유도체 또는 이의 약학적으로 허용가능한 염.Quinazoline derivatives or pharmaceutically acceptable salts thereof. 제 1 항에 있어서,The method of claim 1, 하기 화합물들로 이루어진 군으로부터 선택되는 퀴나졸린 유도체 또는 이의 약학적으로 허용가능한 염:Quinazolin derivatives or pharmaceutically acceptable salts thereof selected from the group consisting of: (2S)-1-아크릴로일-N-[4-[3-클로로-2-플루오로페닐아미노]-7-(2-메톡시에톡시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드;( 2S ) -1-acryloyl- N- [4- [3-chloro-2-fluorophenylamino] -7- (2-methoxyethoxy) quinazolin-6-yl] pyrrolidine- 2-carboxyamide; (2S)-1-아크릴로일-N-[4-[3-클로로-4-플루오로페닐아미노]-7-메톡시퀴나졸린-6-일]피롤리딘-2-카르복시아미드;(2S) -1-acryloyl- N- [4- [3-chloro-4-fluorophenylamino] -7-methoxyquinazolin-6-yl] pyrrolidine-2-carboxyamide; (2S)-1-아크릴로일-N-[4-[4-브르모-3-클로로-2-플루오로페닐아미노]-7-(2-메톡시에톡시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드;(2 S) -1-acryloyl - N - [4- [4- bracket reumo-3-chloro-2-fluoro-phenyl-amino] -7- (2-methoxyethoxy) quinazolin-6-yl ] Pyrrolidine-2-carboxyamide; (2S)-1-아크릴로일-N-[4-[2,3,4-트리플루오로페닐아미노]-7-(2-메톡시에톡시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드;( 2S ) -1-acryloyl- N- [4- [2,3,4-trifluorophenylamino] -7- (2-methoxyethoxy) quinazolin-6-yl] pyrrolidine -2-carboxyamide; (2S)-1-아크릴로일-N-[4-[3,4-다이클로로페닐아미노]-7-(2-메톡시에톡시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드;( 2S ) -1-acryloyl- N- [4- [3,4-dichlorophenylamino] -7- (2-methoxyethoxy) quinazolin-6-yl] pyrrolidine-2- Carboxyamide; (2S)-1-아크릴로일-N-[4-[3-클로로-2,4-다이플루오로페닐아미노]-7-(2-메톡시에톡 시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드;( 2S ) -1-acryloyl- N- [4- [3-chloro-2,4-difluorophenylamino] -7- (2-methoxyethoxy) quinazolin-6-yl] Pyrrolidine-2-carboxyamide; (2S)-1-아크릴로일-N-[4-[3,4-다이클로로-2-플루오로페닐아미노]-7-(2-메톡시에톡시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드;( 2S ) -1-acryloyl- N- [4- [3,4-dichloro-2-fluorophenylamino] -7- (2-methoxyethoxy) quinazolin-6-yl] py Rollidine-2-carboxyamide; (2S)-1-아크릴로일-N-{4-[3-클로로-4-플루오로페닐아미노]-7-[(테트라하이드로퓨란-2-일)메톡시]퀴나졸린-6-일}피롤리딘-2-카르복시아미드;( 2S ) -1-acryloyl- N- {4- [3-chloro-4-fluorophenylamino] -7-[(tetrahydrofuran-2-yl) methoxy] quinazolin-6-yl } Pyrrolidine-2-carboxyamide; (2S)-1-아크릴로일-N-{4-[4-브로모-3-클로로-4-플루오로페닐아미노]-7-[(테트라하이드로퓨란-2-일)메톡시]퀴나졸린-6-일}피롤리딘-2-카르복시아미드;( 2S ) -1-acryloyl- N- {4- [4-bromo-3-chloro-4-fluorophenylamino] -7-[(tetrahydrofuran-2-yl) methoxy] quina Zolin-6-yl} pyrrolidine-2-carboxyamide; (2S)-1-아크릴로일-N-[4-[4-브로모-3-클로로-2-플루오로페닐아미노]-7-(2-모폴리노에톡시)퀴나졸린-6-일]피롤리딘-2-카르복시아미드;( 2S ) -1-Acryloyl- N- [4- [4-bromo-3-chloro-2-fluorophenylamino] -7- (2-morpholinoethoxy) quinazolin-6- General] pyrrolidine-2-carboxyamide; (2S)-1-아크릴로일-N-{4-[3-클로로-2-플루오로페닐아미노]-7-[2-(4-메틸티아졸-5-일)에톡시]퀴나졸린-6-일}피롤리딘-2-카르복시아미드;( 2S ) -1-acryloyl- N- {4- [3-chloro-2-fluorophenylamino] -7- [2- (4-methylthiazol-5-yl) ethoxy] quinazoline -6-yl} pyrrolidine-2-carboxyamide; (2S)-1-아크릴로일-N-{4-[3-클로로-2-플루오로페닐아미노]-7-[2-(1H-1,2,4-트리아졸-1-일)에톡시]퀴나졸린-6-일}피롤리딘-2-카르복시아미드; 및( 2S ) -1-acryloyl- N- {4- [3-chloro-2-fluorophenylamino] -7- [2- ( 1H -1,2,4-triazol-1-yl ) Ethoxy] quinazolin-6-yl} pyrrolidine-2-carboxyamide; And (2S)-1-(2-{[4-(4-브로모-3-클로로-2-플루오로페닐아미노)-7-(2-메톡시에톡시)퀴나졸린-6-일아미노]메틸}피롤리딘-1-일)프로-2-펜-1-온.( 2S ) -1- (2-{[4- (4-bromo-3-chloro-2-fluorophenylamino) -7- (2-methoxyethoxy) quinazolin-6-ylamino] Methyl} pyrrolidin-1-yl) pro-2-phen-1-one. 활성성분으로서 제 1 항의 화학식 1의 퀴나졸린 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는, 암세포 성장 억제용 약학 조성물.A pharmaceutical composition for inhibiting cancer cell growth comprising the quinazoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 제 4 항에 있어서,The method of claim 4, wherein 상기 조성물이 세포 신호 전달 억제제, 유사 분열 억제제, 알킬화제, 항-대사제, 삽입 항생제, 성장 인자 억제제, 세포 주기 억제제, 토포아이소머라제 억제제, 생물 반응 개질제, 항-호르몬제, 항-안드로젠 및 이들의 혼합물로 이루어진 군으로부터 선택된 항암제를 추가로 포함하는 것을 특징으로 하는, 암세포 성장 억제용 약학 조성물.The composition may comprise cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, anti-metabolic agents, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, bioreaction modifiers, anti-hormonal agents, anti-androgens and their A pharmaceutical composition for inhibiting cancer cell growth, further comprising an anticancer agent selected from the group consisting of a mixture. 제 4 항에 있어서,The method of claim 4, wherein 상기 암세포가 상피세포 성장인자 및 이의 변이체에 의해 유발되는 것임을 특징으로 하는, 암세포 성장 억제용 약학 조성물.Characterized in that the cancer cells are induced by epidermal growth factor and its variants, cancer cell growth inhibition pharmaceutical composition.
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WO2008002039A1 (en) 2006-06-28 2008-01-03 Hanmi Pharm. Co., Ltd. Quinazoline derivatives for inhibiting the growth of cancer cell

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