KR102397359B1 - 4-amino-quinazoline derivatives and antiviral composition comprising the same - Google Patents

4-amino-quinazoline derivatives and antiviral composition comprising the same Download PDF

Info

Publication number
KR102397359B1
KR102397359B1 KR1020190120648A KR20190120648A KR102397359B1 KR 102397359 B1 KR102397359 B1 KR 102397359B1 KR 1020190120648 A KR1020190120648 A KR 1020190120648A KR 20190120648 A KR20190120648 A KR 20190120648A KR 102397359 B1 KR102397359 B1 KR 102397359B1
Authority
KR
South Korea
Prior art keywords
group
quinazoline
diamine
amino
fluorophenyl
Prior art date
Application number
KR1020190120648A
Other languages
Korean (ko)
Other versions
KR20210038042A (en
Inventor
김형래
박철민
송종환
신영섭
이준영
장민성
권선오
김동언
민정선
진영희
김승택
이지혜
고미현
전상은
Original Assignee
한국화학연구원
한국 한의학 연구원
재단법인 한국파스퇴르연구소
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 한국화학연구원, 한국 한의학 연구원, 재단법인 한국파스퇴르연구소 filed Critical 한국화학연구원
Priority to KR1020190120648A priority Critical patent/KR102397359B1/en
Publication of KR20210038042A publication Critical patent/KR20210038042A/en
Application granted granted Critical
Publication of KR102397359B1 publication Critical patent/KR102397359B1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

본 발명은 4-아미노-퀴나졸린(4-amino-quinazoline) 유도체 또는 이의 약제학적으로 허용가능한 염과 이의 제조방법 및 이를 유효활성 성분으로 함유하는 바이러스 치료제에 관한 것이다. The present invention relates to a 4-amino-quinazoline derivative or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a therapeutic agent for viruses containing the same as an active ingredient.

Description

4-아미노-퀴나졸린 유도체 및 이를 포함하는 항바이러스용 조성물 {4-amino-quinazoline derivatives and antiviral composition comprising the same}4-amino-quinazoline derivative and antiviral composition comprising same {4-amino-quinazoline derivatives and antiviral composition comprising the same}

본 발명은 4-아미노-퀴나졸린(4-amino-quinazoline) 유도체 또는 이의 약제학적으로 허용가능한 염과 이의 제조방법 및 이를 유효활성 성분으로 함유하는 항바이러스 치료제에 관한 것이다. The present invention relates to a 4-amino-quinazoline derivative or a pharmaceutically acceptable salt thereof, a method for preparing the same, and an antiviral therapeutic agent containing the same as an active ingredient.

메르스바이러스는 베타 코로나바이러스에 속하며, 11개의 ORF를 가진 양성의 단일가닥 RNA 바이러스이다. 유전적으로 2003년 전 세계적으로 총 8,098명 확진자와 774명의 사망자를 냈던 중증호흡기증후군 (severe acute respiratory syndrome, SARS) 병원체인 SARS 코로나바이러스와 매우 밀접한 관계를 갖고 있다. 메르스바이러스는 S 단백질을 이용해 사람의 DPP4 (Dipeptidyl peptidase 4) 수용체에 결합하여 세포내 침투가 이루어지는 것으로 알려져 있다[Wang N, Shi X, Jiang LJ, Zhang S, Wang D, Tong P, Guo D, et al. Structure of MERS-CoV spike receptor-binding domain complexed with human receptor DPP4. Cell Research. 2013:23:986]. 중동과 국내 메르스 발생 (outbreak)을 기초로 동물 (낙타)과 사람간의 인수 감염, 사람 간 감염 경로, 병원내 감염 등이 규명되고 있다 [www.cdc.gov/sars/about/fs-SARS.html; H Y Park, E J Lee, Y W Ryu, et al. Epidemiological investigation of MERS-CoV spread in a single hospital in South Korea, May to June 2015, EuroSurveill. 2015;20 (25): pii=21169]. 현재까지 국내외적으로 허가된 메르스 백신과 치료제는 전무한 상황이다.MERS virus belongs to the beta-coronavirus family and is a positive single-stranded RNA virus with 11 ORFs. Genetically, it is closely related to the SARS coronavirus, a pathogen of severe acute respiratory syndrome (SARS) that caused a total of 8,098 confirmed cases and 774 deaths worldwide in 2003. It is known that MERS virus uses the S protein to bind to human DPP4 (Dipeptidyl peptidase 4) receptor and to penetrate into cells [Wang N, Shi X, Jiang LJ, Zhang S, Wang D, Tong P, Guo D, et al. Structure of MERS-CoV spike receptor-binding domain complexed with human receptor DPP4. Cell Research. 2013:23:986]. Based on the outbreak of MERS in the Middle East and Korea, animal-to-human transmission, human-to-human transmission routes, and nosocomial infections are being investigated [www.cdc.gov/sars/about/fs-SARS. html; H Y Park, E J Lee, Y W Ryu, et al. Epidemiological investigation of MERS-CoV spread in a single hospital in South Korea, May to June 2015, EuroSurveill. 2015;20 (25): pii=21169]. So far, there is no MERS vaccine or treatment approved domestically and internationally.

메르스바이러스에 대한 치료는 면역조절 인자인 인터페론과 항바이러스제인 리바비린(Ribarvirin) 혹은 로피나비어(lopinavir)와 같은 약물을 사용하는 것이 일반적인 권고사항이다. 그러나 인터페론과 리바비린의 경우, 골수 기능 저하, 빈혈, 바이러스 돌연변이 등 부작용을 일으켜 안전성을 우려하는 보고가 있다. 또한 원숭이 모델에서는 인터페론과 리바비린의 병용투여가 메르스 치료 효과를 보였지만, 실제 임상에서는 메르스 환자들에게 큰 효과를 보이지 못하여 보다 안전하면서 효과적인 메르스 치료제 개발이 요구되고 있다. For the treatment of MERS virus, it is generally recommended to use drugs such as interferon, an immunomodulatory factor, and ribavirin or lopinavir, an antiviral agent. However, in the case of interferon and ribavirin, there are reports of safety concerns due to adverse effects such as decreased bone marrow function, anemia, and viral mutations. Also, in the monkey model, the combined administration of interferon and ribavirin showed a MERS treatment effect, but in actual clinical practice, it did not show a great effect on MERS patients, so the development of a safer and more effective MERS treatment is required.

본 발명자는 4-아미노-퀴나졸린(4-amino-quinazoline) 유도체로서 6번 위치에 다양한 치환기가 도입된 유도체들이 메르스에 대한 억제효과를 가지는 화합물임을 밝혀 본 발명을 완성하였다.The present inventors have completed the present invention by finding that, as a 4-amino-quinazoline derivative, derivatives having various substituents introduced at the 6th position are compounds having an inhibitory effect on MERS.

KRUS 10201701354271020170135427 AA

본 발명의 목적은 4-아미노-퀴나졸린(4-amino-quinazoline) 유도체 또는 이의 약제학적으로 허용되는 염을 제공하는 것이다.An object of the present invention is to provide a 4-amino-quinazoline derivative or a pharmaceutically acceptable salt thereof.

본 발명의 또 다른 목적은 4-아미노-퀴나졸린(4-amino-quinazoline) 유도체 또는 이의 약제학적으로 허용되는 염의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing a 4-amino-quinazoline derivative or a pharmaceutically acceptable salt thereof.

본 발명의 또 다른 목적은 4-아미노-퀴나졸린(4-amino-quinazoline) 유도체 또는 이의 약제학적으로 허용되는 염을 포함하는 바이러스 치료제 조성물을 제공하는 것이다.Another object of the present invention is to provide a composition for treating viruses comprising a 4-amino-quinazoline derivative or a pharmaceutically acceptable salt thereof.

본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용되는 염을 제공한다.The present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

<화학식 1><Formula 1>

Figure 112019099775854-pat00001
Figure 112019099775854-pat00001

{상기 화학식 1에서, {In Formula 1,

R1 및 R2는 각각 독립적으로 수소; C1-C6 알킬기; C1-C6 알케닐기; C1-C6 알키닐기; C6-C10의 아릴기; -(X)n-C6-C10의 아릴기; C3-C6의 사이클로알킬기; 또는 아세틸기; 이고, R 1 and R 2 are each independently hydrogen; C 1 -C 6 alkyl group; C 1 -C 6 alkenyl group; C 1 -C 6 alkynyl group; C 6 -C 10 aryl group; -(X) an aryl group of n -C 6 -C 10 ; C 3 -C 6 cycloalkyl group; or an acetyl group; ego,

X는 -CH2; 카보닐(C=O); 또는 -C(=O)-CH=CH-;이며, n은 0 또는 1이고,X is -CH 2 ; carbonyl (C=O); or -C(=O)-CH=CH-; and n is 0 or 1,

상기 알킬기 및 아릴기는 중수소; 할로겐; OH; 시아노기; 니트로기; -C(=O)-(C1-C6 알킬)기; C(=O)NH2; C1-C6 알콕시기; 및 O, N, S 중 적어도 하나 이상의 헤테로원자를 포함하는 C2-C10의 헤테로고리기; 로 이루어진 군에서 선택된 하나 이상의 치환기로 더욱 치환될 수 있으며, 이들 치환기들은 서로 결합하여 고리를 형성할 수도 있고, 여기서 '고리'란 탄소수 3 내지 20의 지방족고리 또는 탄소수 6 내지 20의 방향족고리 또는 탄소수 2 내지 20의 헤테로고리 또는 이들의 조합으로 이루어진 융합 고리를 말하며, 포화 또는 불포화 고리를 포함한다.}The alkyl group and the aryl group are deuterium; halogen; OH; cyano group; nitro group; -C(=O)-(C 1 -C 6 alkyl) group; C(=O)NH 2 ; C 1 -C 6 alkoxy group; And O, N, S containing at least one heteroatom C 2 -C 10 A heterocyclic group; may be further substituted with one or more substituents selected from the group consisting of Refers to a fused ring consisting of 2 to 20 heterocycles or a combination thereof, including saturated or unsaturated rings.}

또한 본 발명은 상기 화학식 1로 표시되는 화합물이 하기 화학식 2로 표시되는 화합물을 포함한다.In addition, the present invention includes the compound represented by the formula (1) is represented by the formula (2).

<화학식 2><Formula 2>

Figure 112019099775854-pat00002
Figure 112019099775854-pat00002

{상기 화학식 2에서, R3은 수소; 할로겐; OH; CN; NO2; C1-C6의 알콕시기; -NH2C(=O); C1-C6의 알킬기; 및 불소가 치환된 C1-C6의 알킬기;로 이루어진 군에서 선택되고, {In Formula 2, R 3 is hydrogen; halogen; OH; CN; NO 2 ; C 1 -C 6 Alkoxy group; -NH 2 C(=O); C 1 -C 6 Alkyl group; and a fluorine-substituted C 1 -C 6 alkyl group; selected from the group consisting of,

a는 0 내지 5 중 어느 하나의 정수이고, a is an integer from 0 to 5,

a가 1 이상일 때 복수의 R3는 서로 동일하거나 상이하고, When a is 1 or more, a plurality of R 3 are the same as or different from each other,

R2는 상기에서 정의한 바와 동일하다.}R 2 is the same as defined above.}

또한 본 발명은 상기 화학식 1로 표시되는 화합물이 하기 화학식 3으로 표시되는 화합물을 포함한다.In addition, the present invention includes the compound represented by the formula (1) is represented by the following formula (3).

<화학식 3><Formula 3>

Figure 112019099775854-pat00003
Figure 112019099775854-pat00003

{상기 화학식 3에서,{In Formula 3,

R1은 상기에서 정의한 바와 동일하고,R 1 is the same as defined above,

b는 0 내지 5 중 어느 하나의 정수이며,b is an integer of any one of 0 to 5,

R4는 수소; 할로겐; OH; CN; NO2; C1-C6의 알콕시기; 아세틸기; 및 불소가 치환된 C1-C6의 알킬기;로 이루어진 군에서 선택되고, R 4 is hydrogen; halogen; OH; CN; NO 2 ; C 1 -C 6 Alkoxy group; acetyl group; and a fluorine-substituted C 1 -C 6 alkyl group; selected from the group consisting of,

b가 1 이상일 때 복수의 R4는 서로 동일하거나 상이하다.} When b is 1 or more, a plurality of R 4 are the same as or different from each other.}

또 다른 측면에서, 본 발명은 하기 화학식 4로 표시되는 화합물을 제공한다.In another aspect, the present invention provides a compound represented by the following formula (4).

<화학식 4><Formula 4>

Figure 112019099775854-pat00004
Figure 112019099775854-pat00004

{상기 화학식 4에서, a, b, R3 및 R4는 상기에서 정의한 바와 같고,{In Formula 4, a, b, R 3 and R 4 are as defined above,

a 또는 b가 1 이상일 때 복수의 R3 또는 R4는 서로 동일하거나 상이하다.}When a or b is 1 or more, a plurality of R 3 or R 4 are the same as or different from each other.}

본 발명에서 상기 화학식 1로 표시되는 화합물은 하기 화합물을 포함한다.In the present invention, the compound represented by Formula 1 includes the following compounds.

Figure 112019099775854-pat00005
Figure 112019099775854-pat00006
Figure 112019099775854-pat00005
Figure 112019099775854-pat00006

Figure 112019099775854-pat00007
Figure 112019099775854-pat00008
Figure 112019099775854-pat00007
Figure 112019099775854-pat00008

Figure 112019099775854-pat00009
Figure 112019099775854-pat00010
Figure 112019099775854-pat00009
Figure 112019099775854-pat00010

Figure 112019099775854-pat00011
Figure 112019099775854-pat00012
Figure 112019099775854-pat00011
Figure 112019099775854-pat00012

Figure 112019099775854-pat00013
Figure 112019099775854-pat00014
Figure 112019099775854-pat00013
Figure 112019099775854-pat00014

Figure 112019099775854-pat00015
Figure 112019099775854-pat00016
Figure 112019099775854-pat00015
Figure 112019099775854-pat00016

Figure 112019099775854-pat00017
Figure 112019099775854-pat00018
Figure 112019099775854-pat00017
Figure 112019099775854-pat00018

Figure 112019099775854-pat00019
Figure 112019099775854-pat00020
Figure 112019099775854-pat00019
Figure 112019099775854-pat00020

Figure 112019099775854-pat00021
Figure 112019099775854-pat00022
Figure 112019099775854-pat00021
Figure 112019099775854-pat00022

Figure 112019099775854-pat00023
Figure 112019099775854-pat00024
Figure 112019099775854-pat00023
Figure 112019099775854-pat00024

Figure 112019099775854-pat00025
Figure 112019099775854-pat00026
Figure 112019099775854-pat00027
Figure 112019099775854-pat00028
Figure 112019099775854-pat00025
Figure 112019099775854-pat00026
Figure 112019099775854-pat00027
Figure 112019099775854-pat00028

Figure 112019099775854-pat00029
Figure 112019099775854-pat00030
Figure 112019099775854-pat00029
Figure 112019099775854-pat00030

Figure 112019099775854-pat00031
Figure 112019099775854-pat00032
Figure 112019099775854-pat00031
Figure 112019099775854-pat00032

Figure 112019099775854-pat00033
Figure 112019099775854-pat00034
Figure 112019099775854-pat00033
Figure 112019099775854-pat00034

Figure 112019099775854-pat00035
Figure 112019099775854-pat00036
Figure 112019099775854-pat00035
Figure 112019099775854-pat00036

Figure 112019099775854-pat00037
Figure 112019099775854-pat00038
Figure 112019099775854-pat00037
Figure 112019099775854-pat00038

또한 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용되는 염을 유효성분으로 포함하는 바이러스 예방 및 치료용 약학조성물을 제공한다. The present invention also provides a pharmaceutical composition for preventing and treating viruses comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

또 다른 예로, 본 발명은 중동호흡기증후군(메르스(MERS)) 코로나 바이러스 예방 및 치료용 약학조성물을 제공한다. As another example, the present invention provides a pharmaceutical composition for preventing and treating the Middle East Respiratory Syndrome (MERS) corona virus.

또한 본 발명의 약학 조성물은 약학적으로 허용가능한 담체 하나 이상을 더 포함할 수 있으며, 공지의 항바이러스제 하나 이상을 더 포함할 수 있다.In addition, the pharmaceutical composition of the present invention may further include one or more pharmaceutically acceptable carriers, and may further include one or more known antiviral agents.

또 다른 예로, 본 발명은 상기 화학식 1에 따른 화합물 또는 이의 식품학적으로 허용되는 염을 유효성분으로 포함하는 바이러스 감염증 예방 및 개선용 건강식품조성물을 제공한다.As another example, the present invention provides a health food composition for preventing and improving viral infection comprising the compound according to Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

본 발명에 따른 화학식 1의 4-아미노-퀴나졸린(4-amino-quinazoline) 유도체 및 이의 약제학적으로 허용 가능한 염이 함유된 화합물은 Vero 세포주에 감염시킨 MERS CoV에 대한 증식 억제작용이 우수하며 Vero 세포주에 대한 독성이 적어 바이러스 치료제, 특히 메르스(MERS) 치료제로서 사용될 수 있다.The compound containing the 4-amino-quinazoline derivative of Formula 1 and a pharmaceutically acceptable salt thereof according to the present invention has excellent proliferation inhibitory effect on MERS CoV infected with Vero cell line, and Due to its low toxicity to cell lines, it can be used as a treatment for viruses, especially MERS.

본 명세서에서, 용어 '알킬'은 지방족 탄화수소 라디칼을 의미하며, 직쇄 또는 분지쇄 상의 탄화수소 라디칼을 모두 포함한다. 예를 들어 C1-C6 알킬은 1 내지 6개의 탄소원자를 갖는 지방족 탄화수소로서, 메틸, 에틸, 프로필, n-부틸, n-펜틸, n-헥실, 아이소프로필, 아이소부틸, sec-부틸, tert-부틸, 네오펜틸, 아이소펜틸 등을 모두 포함한다.As used herein, the term 'alkyl' refers to an aliphatic hydrocarbon radical, and includes both straight-chain or branched hydrocarbon radicals. For example, C1-C6 alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl , neopentyl, isopentyl, and the like.

또한, 용어 '알콕시'는 별도로 정의되지 않는 한 하이드록시 기의 수소 원자가 알킬로 치환된 라디칼을 의미하며, 예를 들어 C1-C6 알콕시는 메톡시, 에톡시, 프로폭시, n-부톡시, n-펜틸옥시, 아이소프로폭시, sec-부톡시, tert-부톡시, 네오펜틸옥시, 아이소펜틸옥시 등을 모두 포함한다.In addition, unless otherwise defined, the term 'alkoxy' refers to a radical in which a hydrogen atom of a hydroxy group is substituted with alkyl, for example, C1-C6 alkoxy is methoxy, ethoxy, propoxy, n-butoxy, n -pentyloxy, isopropoxy, sec-butoxy, tert-butoxy, neopentyloxy, includes all of isopentyloxy.

또한, 용어 '아릴'은 공유 파이 전자계를 가지는 하나 이상의 탄화수소 환을 의미하며, 페닐, 나프틸, 바이페닐등의 탄소수 6 내지 12의 탄화수소환을 포함한다.In addition, the term 'aryl' refers to one or more hydrocarbon rings having a shared pi electron system, and includes hydrocarbon rings having 6 to 12 carbon atoms, such as phenyl, naphthyl, and biphenyl.

본 발명은 화학식 1의 화합물 또는 그의 약학적으로 허용가능한 염을 제공한다.The present invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

화학식 1의 화합물 또는 그의 약학적으로 허용가능한 염은 비대칭 원자를 포함하는 치환기를 가질 수 있으며, 이 경우 화학식 1의 화합물 또는 그의 염은 (R), (S), 또는 라세믹체(RS) 등의 광학 이성질체로 존재할 수 있다. 따라서, 달리 표기하지 않는 한, 상기 화학식 1의 화합물 또는 그의 약학적으로 허용가능한 염은 (R), (S), 또는 라세믹체(RS) 등의 광학 이성질체를 모두 포함한다.The compound of Formula 1 or a pharmaceutically acceptable salt thereof may have a substituent including an asymmetric atom, and in this case, the compound of Formula 1 or a salt thereof is (R), (S), or a racemic form (RS). It may exist as optical isomers. Accordingly, unless otherwise indicated, the compound of Formula 1 or a pharmaceutically acceptable salt thereof includes all optical isomers such as (R), (S), or racemic (RS).

본 발명의 화학식 1의 화합물은 약학적으로 허용가능한 염의 형태일 수 있다. 상기 염은 통상의 산부가염, 예를 들어 염산, 브롬화수소산, 황산, 설팜산, 인산, 또는 질산과 같은 무기산으로부터 유도된 염 및 아세트산, 프로피온산, 숙신산, 글리콜산, 스테아르산, 말레산, 히드록시말레산, 페닐아세트산, 글루탐산, 벤조산, 살리실산, 설파닐산, 2-아세톡시-벤조산, 푸마르산, 톨루엔술폰산, 메탄술폰산, 에탄술폰산, 옥살산, 트라이플루오로아세트산, 시트르산, 락트산, 타르타르산, 쿠마릭산, 알긴산, 캄포설폰산, 카프릭산, 미리스틱산, 히프릭산 또는 오로트산과 같은 유기산으로부터 유도된 염을 포함한다. 또한, 상기 염은 수산화나트륨, 수산화리튬, 수산화칼륨, 수산화 칼슘, 탄산칼륨, 탄산칼슘, 포타슘 t-부톡사이드, 소듐 에톡사이드, 트라이에틸아민, 암모니아, 구아니딘, 에틸렌다이아민, 에탄올아민, 다이에탄올아민, 트라이에탄올아민, 페페라진, 몰포린, 또는 다이사이클로헥실아민으로부터 유도된 염을 포함한다.The compound of Formula 1 of the present invention may be in the form of a pharmaceutically acceptable salt. The salts include conventional acid addition salts, for example salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, or nitric acid and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, maleic acid, hydroxy acid Maleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, oxalic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, coumaric acid, alginic acid , salts derived from organic acids such as camphorsulfonic acid, capric acid, myristic acid, hyporic acid or orotic acid. In addition, the salt is sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, calcium carbonate, potassium t-butoxide, sodium ethoxide, triethylamine, ammonia, guanidine, ethylenediamine, ethanolamine, diethanol salts derived from amines, triethanolamine, peperazine, morpholine, or dicyclohexylamine.

상기 화학식 1의 화합물의 약학적으로 허용가능한 염은 화학식 1의 화합물로부터 통상적인 방법으로 제조할 수 있다. 일반적으로, 상기 염은 유리 산/염기 형태의 화학식 1의 화합물을 화학량론적 양 또는 과량의 목적하는 염-형성 무기산, 무기염, 유기산 또는 유기염과 적합한 용매 또는 용매들의 다양한 배합물 중에서 반응시켜 제조할 수 있다.A pharmaceutically acceptable salt of the compound of Formula 1 may be prepared from the compound of Formula 1 by a conventional method. Generally, the salts are prepared by reacting a compound of formula 1 in its free acid/base form with a stoichiometric amount or excess of the desired salt-forming inorganic acid, inorganic salt, organic acid or organic salt in a suitable solvent or various combinations of solvents. can

본 발명은 치료학적 유효량의 상기 화학식 1의 화합물 또는 그의 약학적으로 허용가능한 염을 유효성분으로 포함하는 코로나 바이러스의 예방 또는 치료용 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating coronavirus comprising a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

상기 약학 조성물은 통상적으로 사용되는 부형제, 붕해제, 감미제, 활택제 또는 향미제 등의 약학적으로 허용가능한 담체를 포함할 수 있으며, 통상의 방법에 따라 정제, 캅셀제, 산제, 과립제 및 현탁제, 유제 또는 시럽제와 같은 경구용 제제; 또는 주사제 등의 비경구 투여용 제제로 제제화될 수 있다. 상기 제제는 다양한 형태, 예를 들어 단회 투여형 또는 수회 투여형 투여 형태(dosage form)로 제제화될 수 있다. The pharmaceutical composition may include pharmaceutically acceptable carriers such as excipients, disintegrants, sweeteners, lubricants or flavoring agents commonly used, and tablets, capsules, powders, granules and suspensions according to conventional methods; oral preparations such as emulsions or syrups; Or it may be formulated as a preparation for parenteral administration, such as injection. The formulations may be formulated in a variety of forms, for example, single-dose or multiple-dose dosage forms.

본 발명의 조성물은 경구 투여하거나, 정맥내, 근육내, 복강내, 피하, 직장 및 국소 투여를 포함한 비경구로 투여될 수 있다. 본 발명의 조성물은 바람직하게는 경구 투여될 수 있다. 따라서, 본 발명의 조성물은 정제, 캅셀제, 수성액제 또는 현탁제 등의 다양한 형태로 제제화될 수 있다. 경구용 정제의 경우 락토즈, 옥수수 전분 등의 담체 및 마그네슘 스테아레이트와 같은 활택제가 통상 가해질 수 있다. 경구투여용 캅셀제의 경우, 락토즈 및/또는 건조 옥수수 전분이 희석제로서 사용될 수 있다. 경구용 수성 현탁제가 필요할 경우, 활성성분을 유화제 및/또는 현탁화제와 결합시킬 수 있다. 필요할 경우, 특정 감미제 및/또는 향미제를 가할 수 있다. 근육내, 복강내, 피하 및 정맥내 투여의 경우, 활성성분의 멸균 용액이 통상 제조되며, 용액의 pH를 적합하게 조절하고 완충시켜야 한다. 정맥내 투여의 경우, 용질의 총 농도는 제제에 등장성이 부여되도록 조절되어야 한다. 본 발명에 따른 조성물은 pH가 7.4인 염수와 같은 약제학적으로 허용되는 담체를 포함하는 수용액제의 형태일 수 있다. 상기 용액은 국소 주사(local bolus injection)로 환자의 근육내 혈류에 도입될 수 있다.The composition of the present invention may be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical administration. The composition of the present invention may preferably be administered orally. Accordingly, the composition of the present invention may be formulated in various forms such as tablets, capsules, aqueous solutions or suspensions. In the case of tablets for oral use, carriers such as lactose and corn starch and lubricants such as magnesium stearate may be usually added. In the case of capsules for oral administration, lactose and/or dry corn starch may be used as diluents. If an aqueous suspension for oral use is required, the active ingredient may be combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, a sterile solution of the active ingredient is usually prepared, and the pH of the solution must be appropriately adjusted and buffered. For intravenous administration, the total concentration of solutes should be adjusted to render the formulation isotonic. The composition according to the present invention may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier, such as saline having a pH of 7.4. The solution may be introduced into the patient's intramuscular bloodstream by local bolus injection.

본 발명에 따른 약학 조성물은 치료학적 유효량으로 투여될 수 있다. 따라서, 상기 약학 조성물에 함유되는 화학식 1의 화합물 또는 그의 약학적으로 허용가능한 염은 환자에게 약 10 mg/kg 내지 약 500 mg/kg per day의 유효량으로 투여될 수 있다. 물론, 상기 용량은 환자의 나이, 체중, 감수성, 증상 또는 화합물의 약효에 따라 변경될 수 있다.The pharmaceutical composition according to the present invention may be administered in a therapeutically effective amount. Accordingly, the compound of Formula 1 or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition may be administered to a patient in an effective amount of about 10 mg/kg to about 500 mg/kg per day. Of course, the dose may be changed according to the patient's age, weight, susceptibility, symptoms, or drug efficacy of the compound.

본 발명은 또한, 치료학적 유효량의 상기 화학식 1의 화합물 또는 그의 약학적으로 허용가능한 염을 인간을 포함한 포유동물에게 투여하는 것을 포함하는, 바이러스, 바람직하게는 코로나바이러스, 보다 바람직하게는 메르스의 예방 또는 치료방법을 제공한다.The present invention also provides a method of treating a virus, preferably a coronavirus, more preferably a MERS, comprising administering a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof to a mammal, including a human. A method of preventing or treating is provided.

본 발명은 또한, 바이러스의 예방 또는 치료용 약제의 제조를 위한, 상기 화학식 1의 화합물 또는 그의 약학적으로 허용가능한 염의 용도를 제공한다.The present invention also provides the use of the compound of Formula 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prophylaxis or treatment of viruses.

본 발명의 또 다른 양태로서, 본 발명은 화학식 1의 4-아미노-퀴나졸린(4-amino-quinazoline) 유도체 또는 이의 약제학적으로 허용되는 염을 유효성분으로 포함하는 메르스(MERS) 치료제에 관한 것이다. As another aspect of the present invention, the present invention relates to a treatment for MERS (MERS) comprising a 4-amino-quinazoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. will be.

화학식 1의 4-아미노-퀴나졸린(4-amino-quinazoline) 유도체는 메르스 바이러스를 감염시킨 Vero cell을 활용한 약효시험에서 메르스 바이러스를 효과적으로 저해하며 세포독성이 적어 메르스 치료효과를 기대할 수 있음을 확인하였다.The 4-amino-quinazoline derivative of Formula 1 effectively inhibits the MERS virus in a drug efficacy test using Vero cells infected with the MERS virus and has low cytotoxicity, so MERS treatment effect can be expected. confirmed that there is.

따라서, 본 발명에 따른 화학식 1의 화합물을 유효성분으로 하는 메르스 치료제 또는 약제 조성물은 화학식 1의 화합물에 통상의 무독성 약제학적으로 허용 가능한 담체, 보강제 또는 부형제 등을 첨가하여 약제학적 분야에서 통상적인 제제, 예를 들면 정제, 캅셀제, 트로키제, 액제, 현탁제 등의 경구투여용 제제로 제제화 할 수 있다. Therefore, the MERS therapeutic agent or pharmaceutical composition comprising the compound of Formula 1 according to the present invention as an active ingredient is conventional in the pharmaceutical field by adding a conventional non-toxic pharmaceutically acceptable carrier, adjuvant or excipient, etc. to the compound of Formula 1 It can be formulated as a preparation for oral administration, for example, tablets, capsules, troches, solutions, suspensions, and the like.

또한, 화학식 1의 화합물의 인체에 대한 투여용량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환정도에 따라 달라질 수 있으며, 몸무게가 70 ㎏인 성인 환자를 기준으로 할 때 일반적으로 10 내지 4,000 ㎎/일이며, 의사 또는 약사의 판단에 따라 일정 시간 간격으로 1일 1회 내지 수회로 분할 투여할 수 있다.In addition, the administration dose of the compound of Formula 1 to the human body may vary depending on the patient's age, weight, sex, dosage form, health status and disease level, and is generally 10 based on an adult patient weighing 70 kg. to 4,000 mg/day, and may be administered in divided doses once or several times a day at regular time intervals according to the judgment of a doctor or pharmacist.

이하, 본 발명을 하기 실시예를 참조하여 더욱 구체적으로 설명하기로 한다. 다만, 하기 실시예는 본 발명의 이해를 돕기 위한 것일 뿐, 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for helping understanding of the present invention, and the scope of the present invention is not limited to the following examples.

<실시예><Example>

<합성 반응식 예><Example of synthesis scheme>

Figure 112019099775854-pat00039
Figure 112019099775854-pat00039

<실시예> 1<Example> 1

NN 44 -(3-클로로-4-플루오로페닐)--(3-chloro-4-fluorophenyl)- NN 66 -(3-메톡시벤질)퀴나졸린-4,6-다이아민 의 합성법- Synthesis method of (3-methoxybenzyl) quinazoline-4,6-diamine

( E )- N ‘-(2-사이아노-4-니트로페닐)- N , N ’-다이메틸포름이미다미드 : 2-아미노-5-니트로벤조니트릴 (2 g, 12 mmol)을 톨루엔 (25 mL)에 녹이고, 디메틸포르아미드-다이메틸아세탈 (4 mL, 30 mmol)을 상온에서 천천히 첨가하고, 120oC에서 5시간 동안 가열하였다. 반응이 완결된 후, 상온으로 식히면 결정이 생성된다. 결정을 다이에틸에테르로 씻어서 (E)-N‘-(2-사이아노-4-니트로페닐)-N,N’-다이메틸포름이미다미드 (2.4 g, 90%)를 얻었다. ( E ) -N '-(2-cyano-4-nitrophenyl) -N , N' -dimethylformimidamide : 2-amino-5-nitrobenzonitrile (2 g, 12 mmol) in toluene ( 25 mL), dimethylformamide-dimethylacetal (4 mL, 30 mmol) was slowly added at room temperature, and heated at 120 o C for 5 hours. After the reaction is completed, when cooled to room temperature, crystals are formed. The crystals were washed with diethyl ether to obtain ( E ) -N '-(2-cyano-4-nitrophenyl) -N , N' -dimethylformimidamide (2.4 g, 90%).

1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, J = 2.7 Hz, 1H), 8.39 - 8.15 (m, 2H), 7.38 (d, J = 9.3 Hz, 1H), 3.12 (d, J = 24.6 Hz, 7H). 1 H NMR (300 MHz, DMSO-d6) δ 8.49 (d, J = 2.7 Hz, 1H), 8.39 - 8.15 (m, 2H), 7.38 (d, J = 9.3 Hz, 1H), 3.12 (d, J ) = 24.6 Hz, 7H).

N -(3-클로로-4-플로로페닐)-6-니트로퀴나졸린-4-아민 : (E)-N‘-(2-사이아노-4-니트로페닐)-N,N’-다이메틸포름이미다미드 (2.4 g, 11 mmol)을 아세트산에 녹이고, 3-클로로-4-플로로아닐린 (2 g, 13.2 mmol)을 첨가하고 120oC에서 7시간 동안 가열했다. 반응이 완결된 후, 상온으로 식히면 결정이 생성된다. 결정을 다이에틸에테르로 씻어서 N-(3-클로로-4-플로로페닐)-6-니트로퀴나졸린-4-아민 (2.9 g, 83%)를 얻었다. N- (3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine: ( E ) -N '-(2-cyano-4-nitrophenyl) -N , N' -dimethyl Formimidamide (2.4 g, 11 mmol) was dissolved in acetic acid, 3-chloro-4-fluoroaniline (2 g, 13.2 mmol) was added and heated at 120 o C for 7 hours. After the reaction is completed, when cooled to room temperature, crystals are formed. The crystals were washed with diethyl ether to obtain N -(3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine (2.9 g, 83%).

1H NMR (300 MHz, DMSO-d6) δ 9.63 (d, J = 2.4 Hz, 1H), 8.77 (s, 1H), 8.58 (dd, J = 9.2, 2.2 Hz, 1H), 8.18 (dd, J = 6.9, 2.4 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.91 - 7.75 (m, 1H), 7.50 (t, J = 9.1 Hz, 1H). 1 H NMR (300 MHz, DMSO-d6) δ 9.63 (d, J = 2.4 Hz, 1H), 8.77 (s, 1H), 8.58 (dd, J = 9.2, 2.2 Hz, 1H), 8.18 (dd, J ) = 6.9, 2.4 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.91 - 7.75 (m, 1H), 7.50 (t, J = 9.1 Hz, 1H).

N 4 -(3-클로로-4-플로로페닐)-퀴나졸린-4,6-다이아민 : 철 (2.3 g, 42 mmol)과 염화암모늄 (250 mg, 4.6 mmol)을 아이소프로파놀 40 mL와 물 4mL 혼합용매에 첨가한 후, 교반하면서 N-(3-클로로-4-플로로페닐)-6-니트로퀴나졸린-4-아민 (2.7 g, 8.3 mmol)을 넣었다. 반응물을 100oC에서 3시간 교반한 후, 상온으로 온도를 낮추고 고체를 셀라이트로 걸러서 제거하였다. 잔유물을 물과 에틸아세테이트로 추출한 유기층을 농축하여 실리카겔 크로마토그래피 (전개액 메탄올 : 디클로로메탄 = 1 : 13)하여 녹색 고체의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린- 4,6-다이아민 (2.0 g, 83%)를 얻었다. N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine: iron (2.3 g, 42 mmol) and ammonium chloride (250 mg, 4.6 mmol) were mixed with 40 mL of isopropanol After addition to 4 mL of water mixed solvent, N -(3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine (2.7 g, 8.3 mmol) was added while stirring. After the reaction was stirred at 100 o C for 3 hours, the temperature was lowered to room temperature, and the solid was removed by filtering through Celite. The organic layer obtained by extracting the residue with water and ethyl acetate was concentrated and subjected to silica gel chromatography (eluent methanol: dichloromethane = 1: 13) to form a green solid N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4 ,6-diamine (2.0 g, 83%) was obtained.

1H NMR (300 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.54 (s, 1H), 8.12 (dd, J = 6.9, 2.6 Hz, 1H), 7.77 (ddd, J = 9.0, 4.4, 2.7 Hz, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.58 - 7.40 (m, 2H), 7.35 (dd, J = 8.9, 2.2 Hz, 1H). 1 H NMR (300 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.54 (s, 1H), 8.12 (dd, J = 6.9, 2.6 Hz, 1H), 7.77 (ddd, J = 9.0, 4.4, 2.7 Hz, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.58 - 7.40 (m, 2H), 7.35 (dd, J = 8.9, 2.2 Hz, 1H).

N 4 -(3-클로로-4-플루오로페닐)- N 6 -(3-메톡시벤질)퀴나졸린-4,6-다이아민 : m-아니스알데히드 (52 mg, 0.38 mmol), 소듐 트라이아세톡시보로하이드라이드 (90 mg, 0.42 mmol), 트라이플루오로 아세트산 (54 μL, 0.7 mmol)을 아이소프로필 아세테이트 2 mL에 첨가한 후, 교반하면서 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린- 4,6-다이아민 (100 mg, 0.35 mmol)을 넣었다. 반응물을 100oC에서 2시간 교반한 후, 상온으로 온도를 낮추고, 1N 수산화나트륨 용액 (10 mL)을 넣고 에틸아세테이트로 추출하였다. 유기층을 농축하고 prep HPLC으로 정제하여 밝은 노란색고체의 N 4 -(3-클로로-4-플루오로페닐)-N 6 -(3-메톡시벤질)퀴나졸린-4,6-다이아민 (62 mg, 44%)를 얻었다. N 4 -(3-chloro-4-fluorophenyl)- N 6 -(3-methoxybenzyl)quinazoline-4,6-diamine: m-anisaldehyde (52 mg, 0.38 mmol), sodium triacetoxyborohydride (90 mg, 0.42 mmol), trifluoroacetic acid (54 μL, 0.7 mmol) were added to 2 mL of isopropyl acetate, followed by N 4 with stirring -(3-Chloro-4-fluorophenyl)-quinazoline- 4,6-diamine (100 mg, 0.35 mmol) was added. After the reaction was stirred at 100 o C for 2 hours, the temperature was lowered to room temperature, 1N sodium hydroxide solution (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and purified by prep HPLC as a light yellow solid N 4 -(3-chloro-4-fluorophenyl) -N 6 -(3-methoxybenzyl)quinazoline-4,6-diamine (62 mg , 44%) was obtained.

1H NMR (300 MHz, Chloroform-d) δ 8.57 (s, 1H), 7.88 (dd, J = 6.5, 2.7 Hz, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.52 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.24 - 7.09 (m, 2H), 7.06 - 6.94 (m, 2H), 6.92 - 6.82 (m, 1H), 6.61 (d, J = 2.4 Hz, 1H), 4.42 (s, 2H), 3.82 (s, 3H). LC/MS (ESI) m/z 409.0 [M+H]+. 1 H NMR (300 MHz, Chloroform-d) δ 8.57 (s, 1H), 7.88 (dd, J = 6.5, 2.7 Hz, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.52 (ddd, J ) = 8.9, 4.0, 2.8 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.24 - 7.09 (m, 2H), 7.06 - 6.94 (m, 2H), 6.92 - 6.82 (m, 1H), 6.61 (d, J = 2.4 Hz, 1H), 4.42 (s, 2H), 3.82 (s, 3H). LC/MS (ESI) m/z 409.0 [M+H] + .

<실시예> 2<Example> 2

NN 44 -(3-클로로-4-플루오로페닐)--(3-chloro-4-fluorophenyl)- NN 66 -(2-메톡시벤질)퀴나졸린-4,6-다이아민의 합성법- Synthesis method of (2-methoxybenzyl) quinazoline-4,6-diamine

실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린-4,6-다이아민과 2-메톡시벤즈알데히드로부터 44%의 수득율로 노란색 고체의 실시예 2의 화합물을 얻었다.The compound of Example 2 was obtained as a yellow solid in a yield of 44% from N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine and 2-methoxybenzaldehyde of Example 1 .

1H NMR (300 MHz, Chloroform-d) δ 8.58 (s, 1H), 7.89 (dd, J = 6.5, 2.7 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.52 (ddd, J = 8.9, 4.1, 2.7 Hz, 1H), 7.39 - 7.27 (m, 2H), 7.24 - 7.11 (m, 2H), 7.10 (s, 1H), 6.96 (t, J = 7.1 Hz, 2H), 6.68 (d, J = 2.4 Hz, 1H), 4.44 (s, 2H), 3.91 (s, 3H). LC/MS (ESI) m/z 409.54 [M+H]+. 1 H NMR (300 MHz, Chloroform-d) δ 8.58 (s, 1H), 7.89 (dd, J = 6.5, 2.7 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.52 (ddd, J ) = 8.9, 4.1, 2.7 Hz, 1H), 7.39 - 7.27 (m, 2H), 7.24 - 7.11 (m, 2H), 7.10 (s, 1H), 6.96 (t, J = 7.1 Hz, 2H), 6.68 ( d, J = 2.4 Hz, 1H), 4.44 (s, 2H), 3.91 (s, 3H). LC/MS (ESI) m/z 409.54 [M+H] + .

<실시예> 3<Example> 3

3-(((4-((3-클로로-4-플루오로페닐)아미노)퀴나졸린-6-일)아미노)메틸)페놀 의 합성법Synthesis of 3-(((4-((3-chloro-4-fluorophenyl)amino)quinazolin-6-yl)amino)methyl)phenol

실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린-4,6-다이아민과 2-하이드록시벤즈알데히드로부터 68%의 수득율로 노란색 고체의 실시예 3의 화합물을 얻었다.The compound of Example 3 was obtained as a yellow solid in a yield of 68% from N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine and 2-hydroxybenzaldehyde of Example 1 .

1H NMR (300 MHz, Methanol-d4) δ 8.56 (s, 1H), 7.93 (dd, J = 6.6, 2.6 Hz, 1H), 7.68 - 7.59 (m, 2H), 7.53 (dd, J = 9.2, 2.4 Hz, 1H), 7.42 - 7.28 (m, 2H), 7.16 (t, J = 7.8 Hz, 1H), 6.94 - 6.80 (m, 2H), 6.69 (ddd, J = 8.1, 2.6, 1.0 Hz, 1H), 4.46 (s, 2H). LC/MS (ESI) m/z 395.0 [M+H]+. 1 H NMR (300 MHz, Methanol-d4) δ 8.56 (s, 1H), 7.93 (dd, J = 6.6, 2.6 Hz, 1H), 7.68 - 7.59 (m, 2H), 7.53 (dd, J = 9.2, 2.4 Hz, 1H), 7.42 - 7.28 (m, 2H), 7.16 (t, J = 7.8 Hz, 1H), 6.94 - 6.80 (m, 2H), 6.69 (ddd, J = 8.1, 2.6, 1.0 Hz, 1H) ), 4.46 (s, 2H). LC/MS (ESI) m/z 395.0 [M+H] + .

<실시예> 4<Example> 4

NN 44 -(3-클로로-4-플루오로페닐)--(3-chloro-4-fluorophenyl)- NN 66 -(3,4-다이플루오로벤질)퀴나졸린-4,6-다이아민의 합성법- Synthesis method of (3,4-difluorobenzyl) quinazoline-4,6-diamine

실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린-4,6-다이아민과 3,4-다이플루오로벤즈알데히드로부터 56%의 수득율로 노란색 오일의 실시예 4의 화합물을 얻었다. N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine and 3,4-difluorobenzaldehyde of Example 1 of Example 4 in a yield of 56% The compound was obtained.

1H NMR (300 MHz, Chloroform-d) δ 8.55 (s, 1H), 7.86 (dd, J = 6.5, 2.6 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.48 (dt, J = 9.1, 3.4 Hz, 1H), 7.22 - 7.03 (m, 5H), 6.64 (d, J = 2.4 Hz, 1H), 4.39 (s, 2H). LC/MS (ESI) m/z 415.1 [M+H]+. 1 H NMR (300 MHz, Chloroform-d) δ 8.55 (s, 1H), 7.86 (dd, J = 6.5, 2.6 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.48 (dt, J ) = 9.1, 3.4 Hz, 1H), 7.22 - 7.03 (m, 5H), 6.64 (d, J = 2.4 Hz, 1H), 4.39 (s, 2H). LC/MS (ESI) m/z 415.1 [M+H] + .

<실시예> 5<Example> 5

NN 44 -(3-클로로-4-플루오로페닐)--(3-chloro-4-fluorophenyl)- NN 66 -(4-플루오로벤질)퀴나졸린-4,6-다이아민의 합성법- Synthesis method of (4-fluorobenzyl) quinazoline-4,6-diamine

실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린-4,6-다이아민과 4-플루오로벤즈알데히드로부터 36%의 수득율로 노란색 오일의 실시예 5의 화합물을 얻었다.The compound of Example 5 as a yellow oil was obtained in a yield of 36% from N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine and 4-fluorobenzaldehyde of Example 1 .

1H NMR (500 MHz, Chloroform-d) δ 8.58 (s, 1H), 7.89 (dd, J = 6.4, 2.7 Hz, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.54 - 7.43 (m, 1H), 7.41 - 7.33 (m, 2H), 7.23 - 7.12 (m, 3H), 7.12 - 6.99 (m, 2H), 6.63 (d, J = 2.3 Hz, 1H), 4.41 (s, 2H). LC/MS (ESI) m/z 397.0 [M+H]+. 1 H NMR (500 MHz, Chloroform-d) δ 8.58 (s, 1H), 7.89 (dd, J = 6.4, 2.7 Hz, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.54 - 7.43 (m , 1H), 7.41 - 7.33 (m, 2H), 7.23 - 7.12 (m, 3H), 7.12 - 6.99 (m, 2H), 6.63 (d, J = 2.3 Hz, 1H), 4.41 (s, 2H). LC/MS (ESI) m/z 397.0 [M+H] + .

<실시예> 6<Example> 6

NN 44 -(3-클로로-4-플루오로페닐)--(3-chloro-4-fluorophenyl)- NN 66 -(2-니트로벤질)퀴나졸린-4,6-다이아민-(2-nitrobenzyl)quinazoline-4,6-diamine

한국화합물은행으로부터 실시예 6 화합물을 입수하였다.The compound of Example 6 was obtained from the Korea Compound Bank.

(ChemBank#: 108434)(ChemBank#: 108434)

<실시예> 7<Example> 7

NN 44 -(3-클로로-4-플루오로페닐)--(3-chloro-4-fluorophenyl)- NN 66 -(3-니트로벤질)퀴나졸린-4,6-다이아민의 합성법- Synthesis method of (3-nitrobenzyl) quinazoline-4,6-diamine

실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린-4,6-다이아민과 3-니트로벤즈알데히드로부터 7%의 수득율로 노란색 고체의 실시예 7의 화합물을 얻었다.The compound of Example 7 was obtained as a yellow solid in a yield of 7% from N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine of Example 1 and 3-nitrobenzaldehyde.

1H NMR (300 MHz, Methanol-d4) δ 8.53 (s, 1H), 8.31 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.91 (dd, J = 6.7, 2.6 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.70 - 7.51 (m, 4H), 7.38 - 7.27 (m, 2H), 4.68 (s, 2H). LC/MS (ESI) 424.0 m/z [M+H]+. 1 H NMR (300 MHz, Methanol-d4) δ 8.53 (s, 1H), 8.31 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.91 (dd, J = 6.7, 2.6 Hz, 1H) ), 7.84 (d, J = 7.8 Hz, 1H), 7.70 - 7.51 (m, 4H), 7.38 - 7.27 (m, 2H), 4.68 (s, 2H). LC/MS (ESI) 424.0 m/z [M+H] + .

<실시예> 8<Example> 8

NN 44 -(3-클로로-4-플루오로페닐)--(3-chloro-4-fluorophenyl)- NN 66 -(4-니트로벤질)퀴나졸린-4,6-다이아민의 합성법- Synthesis method of (4-nitrobenzyl) quinazoline-4,6-diamine

실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린-4,6-다이아민과 4-니트로벤즈알데히드로부터 68%의 수득율로 노란색 고체의 실시예 8의 화합물을 얻었다.The compound of Example 8 was obtained as a yellow solid in a yield of 68% from N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine of Example 1 and 4-nitrobenzaldehyde.

1H NMR (300 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.38 (s, 1H), 8.31-8.20 (m, 2H), 8.12 (dd, J = 6.9, 2.6 Hz, 1H), 7.84 - 7.66 (m, 3H), 7.59 (d, J = 9.0 Hz, 1H), 7.50 - 7.32 (m, 2H), 7.28 (d, J = 2.4 Hz, 1H), 6.98 (t, J = 6.3 Hz, 1H), 4.63 (d, J = 6.1 Hz, 2H). LC/MS (ESI) m/z 424.0 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.38 (s, 1H), 8.31-8.20 (m, 2H), 8.12 (dd, J = 6.9, 2.6 Hz, 1H), 7.84 - 7.66 (m, 3H), 7.59 (d, J = 9.0 Hz, 1H), 7.50 - 7.32 (m, 2H), 7.28 (d, J = 2.4 Hz, 1H), 6.98 (t, J = 6.3 Hz, 1H), 4.63 (d, J = 6.1 Hz, 2H). LC/MS (ESI) m/z 424.0 [M+H] + .

<실시예> 9<Example> 9

NN 66 -(5-브로모-2-니트로벤질)--(5-Bromo-2-nitrobenzyl)- NN 44 -(3-클로로-4-플루오로페닐)퀴나졸린-4,6-다이아민의 합성법-(3-chloro-4-fluorophenyl) quinazoline-4,6-diamine synthesis method

실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린-4,6-다이아민과 5-브로모-2-니트로벤즈알데히드로부터 4%의 수득율로 노란색 고체의 실시예 9의 화합물을 얻었다.Example 9 of a yellow solid in a yield of 4% from N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine and 5-bromo-2-nitrobenzaldehyde of Example 1 of the compound was obtained.

<실시예> 10<Example> 10

2-(((4-((3-클로로-4-플루오로페닐)아미노)퀴나졸린-6-일)아미노)메틸)벤조니트릴의 합성법Synthesis of 2-(((4-((3-chloro-4-fluorophenyl)amino)quinazolin-6-yl)amino)methyl)benzonitrile

실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린-4,6-다이아민과 2-시아노벤즈알데히드로부터 21%의 수득율로 노란색 고체의 실시예 10의 화합물을 얻었다.The compound of Example 10 was obtained as a yellow solid in a yield of 21% from N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine and 2-cyanobenzaldehyde of Example 1 .

1H NMR (300 MHz, Methanol-d4) δ 8.88-8.79 (m, 2H), 8.33-8.19 (m, 2H), 8.07 (dd, J = 10.5, 7.8 Hz, 2H), 8.01 - 7.84 (m, 2H), 7.84 - 7.69 (m, 3H), 7.36 (t, J = 8.9 Hz, 1H), 5.43 (s, 2H). LC/MS (ESI) 404.0 m/z [M+H]+. 1 H NMR (300 MHz, Methanol-d4) δ 8.88-8.79 (m, 2H), 8.33-8.19 (m, 2H), 8.07 (dd, J = 10.5, 7.8 Hz, 2H), 8.01 - 7.84 (m, 2H), 7.84 - 7.69 (m, 3H), 7.36 (t, J = 8.9 Hz, 1H), 5.43 (s, 2H). LC/MS (ESI) 404.0 m/z [M+H] + .

<실시예> 11<Example> 11

3-(((4-((3-클로로-4-플루오로페닐)아미노)퀴나졸린-6-일)아미노)메틸)벤조니트릴의 합성법Synthesis of 3-(((4-((3-chloro-4-fluorophenyl)amino)quinazolin-6-yl)amino)methyl)benzonitrile

실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린-4,6-다이아민과 3-시아노벤즈알데히드로부터 39%의 수득율로 노란색 고체의 실시예 11의 화합물을 얻었다.The compound of Example 11 was obtained as a yellow solid in a yield of 39% from N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine and 3-cyanobenzaldehyde of Example 1 .

1H NMR (300 MHz, Methanol-d4) δ 8.60 (s, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 8.3 Hz, 4H), 7.67 (t, J = 9.1 Hz, 2H), 7.62 - 7.50 (m, 2H), 7.42 (d, J = 2.4 Hz, 1H), 4.63 (s, 2H). 1 H NMR (300 MHz, Methanol-d4) δ 8.60 (s, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 8.3 Hz, 4H), 7.67 (t, J = 9.1) Hz, 2H), 7.62 - 7.50 (m, 2H), 7.42 (d, J = 2.4 Hz, 1H), 4.63 (s, 2H).

<실시예> 12<Example> 12

4-(((4-((3-클로로-4-플루오로페닐)아미노)퀴나졸린-6-일)아미노)메틸)벤조니트릴의 합성법Synthesis of 4-(((4-((3-chloro-4-fluorophenyl)amino)quinazolin-6-yl)amino)methyl)benzonitrile

실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린-4,6-다이아민과 4-시아노벤즈알데히드로부터 34%의 수득율로 노란색 고체의 실시예 12의 화합물을 얻었다.The compound of Example 12 was obtained as a yellow solid in a yield of 34% from N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine and 4-cyanobenzaldehyde of Example 1 .

1H NMR (300 MHz, Methanol-d4) δ 8.60 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.84 - 7.64 (m, 5H), 7.59 (dd, J = 10.6, 8.5 Hz, 3H), 7.41 (d, J = 2.4 Hz, 1H), 4.66 (s, 2H). 1 H NMR (300 MHz, Methanol-d4) δ 8.60 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.84 - 7.64 (m, 5H), 7.59 (dd, J = 10.6, 8.5 Hz) , 3H), 7.41 (d, J = 2.4 Hz, 1H), 4.66 (s, 2H).

<실시예> 13<Example> 13

3-(((4-((3-클로로-4-플루오로페닐)아미노)퀴나졸린-6-일)아미노)메틸)벤즈아미드의 합성법Synthesis of 3-(((4-((3-chloro-4-fluorophenyl)amino)quinazolin-6-yl)amino)methyl)benzamide

실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린-4,6-다이아민과 3-포밀벤즈아미드로부터 32%의 수득율로 노란색 고체의 실시예 13의 화합물을 얻었다.The compound of Example 13 was obtained as a yellow solid in a yield of 32% from N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine and 3-formylbenzamide of Example 1 .

1H NMR (300 MHz, Methanol-d4) δ 8.57 (s, 1H), 7.96 (s, 1H), 7.92 (dd, J = 6.6, 2.6 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.69 - 7.51 (m, 4H), 7.46 (t, J = 7.7 Hz, 1H), 7.42 - 7.27 (m, 2H), 4.60 (s, 2H). LC/MS (ESI) 422.0 m/z [M+H]+. 1 H NMR (300 MHz, Methanol-d4) δ 8.57 (s, 1H), 7.96 (s, 1H), 7.92 (dd, J = 6.6, 2.6 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H) ), 7.69 - 7.51 (m, 4H), 7.46 (t, J = 7.7 Hz, 1H), 7.42 - 7.27 (m, 2H), 4.60 (s, 2H). LC/MS (ESI) 422.0 m/z [M+H] + .

<실시예> 14<Example> 14

NN 44 -(3-클로로-4-플루오로페닐)--(3-chloro-4-fluorophenyl)- NN 66 -(3-(트리플루오로메틸)벤질)퀴나졸린-4,6-다이아민의 합성법Synthesis of -(3-(trifluoromethyl)benzyl)quinazoline-4,6-diamine

실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린-4,6-다이아민과 3-트리플루오로메틸-벤즈알데히드로부터 41%의 수득율로 흰색 고체의 실시예 14의 화합물을 얻었다. N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine and 3-trifluoromethyl-benzaldehyde of Example 1 in a yield of 41% as a white solid of Example 14 The compound was obtained.

1H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.71 (s, 1H), 7.99 (dd, J = 6.9, 2.7 Hz, 1H), 7.84 (s, 1H), 7.74 (d, J = 7.3 Hz, 1H), 7.71 - 7.62 (m, 4H), 7.62 - 7.50 (m, 2H), 7.50 - 7.34 (m, 1H), 4.57 (s, 2H). LC/MS (ESI) m/z 447.4 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.71 (s, 1H), 7.99 (dd, J = 6.9, 2.7 Hz, 1H), 7.84 (s, 1H), 7.74 (d , J = 7.3 Hz, 1H), 7.71 - 7.62 (m, 4H), 7.62 - 7.50 (m, 2H), 7.50 - 7.34 (m, 1H), 4.57 (s, 2H). LC/MS (ESI) m/z 447.4 [M+H] + .

<실시예> 15<Example> 15

NN 66 ,N,N 66 -다이부틸--dibutyl- NN 44 -(3클로로-4-플루오로페닐)퀴나졸린-4,6-다이아민의 합성법- Synthesis method of (3chloro-4-fluorophenyl) quinazoline-4,6-diamine

부틸알데히드 (50 μL, 0.6 mmol), 소듐 트라이아세톡시보로하이드라이드 (44 mg, 0.21 mmol), 트라이플루오로 아세트산 (27 μL, 0.35 mmol)을 아이소프로필 아세테이트 1 mL에 첨가한 후, 교반하면서 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린- 4,6-다이아민(50 mg, 0.17 mmol)을 넣었다. 반응물을 100oC에서 2시간 교반한 후, 상온으로 온도를 낮추고, 1N 수산화나트륨 용액 (10 mL)을 넣고 에틸아세테이트로 추출하였다. 유기층을 농축하고 prep HPLC으로 정제하여 갈색 오일의 N 6 ,N 6 -다이부틸-N 4 -(3-클로로-4-플로로페닐)퀴나졸린-4,6-다이아민(16 mg, 23%)를 얻었다.Butylaldehyde (50 μL, 0.6 mmol), sodium triacetoxyborohydride (44 mg, 0.21 mmol), and trifluoroacetic acid (27 μL, 0.35 mmol) were added to 1 mL of isopropyl acetate, followed by stirring with stirring N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine (50 mg, 0.17 mmol) was added. After the reaction was stirred at 100 o C for 2 hours, the temperature was lowered to room temperature, 1N sodium hydroxide solution (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and purified by prep HPLC as a brown oil of N 6 , N 6 -dibutyl- N 4 -(3-chloro-4-fluorophenyl)quinazoline-4,6-diamine (16 mg, 23%) ) was obtained.

1H NMR (300 MHz, Methanol-d4) δ 8.53 (s, 1H), 7.90 (dd, J = 6.6, 2.5 Hz, 1H), 7.70 (d, J = 9.4 Hz, 1H), 7.66 - 7.57 (m, 2H), 7.46 - 7.31 (m, 2H), 3.58 - 3.50 (m, 4H), 1.65 (q, J = 7.8 Hz, 4H), 1.50 - 1.38 (m, 4H), 1.00 (t, J = 7.3 Hz, 6H). 1 H NMR (300 MHz, Methanol-d4) δ 8.53 (s, 1H), 7.90 (dd, J = 6.6, 2.5 Hz, 1H), 7.70 (d, J = 9.4 Hz, 1H), 7.66 - 7.57 (m) , 2H), 7.46 - 7.31 (m, 2H), 3.58 - 3.50 (m, 4H), 1.65 (q, J = 7.8 Hz, 4H), 1.50 - 1.38 (m, 4H), 1.00 (t, J = 7.3) Hz, 6H).

<실시예> 16<Example> 16

NN 44 -(3-클로로-4-플루오로페닐)--(3-chloro-4-fluorophenyl)- NN 66 -싸이클로헥실퀴나졸린-4,6-다이아민의 합성법-Synthesis of cyclohexylquinazoline-4,6-diamine

실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린-4,6-다이아민과 싸이클로헥사논으부터 69%의 수득율로 흰색 고체의 실시예 16의 화합물을 얻었다.The compound of Example 16 was obtained as a white solid in a yield of 69% from N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine and cyclohexanone of Example 1.

1H NMR (300 MHz, Methanol-d4) δ 8.53 (s, 1H), 7.92 (dd, J = 6.6, 2.6 Hz, 1H), 7.70 - 7.54 (m, 2H), 7.52 - 7.26 (m, 3H), 3.51 (ddt, J = 10.3, 7.6, 3.8 Hz, 1H), 2.11 (d, J = 12.1 Hz, 2H), 1.92 - 1.78 (m, 2H), 1.78 - 1.66 (m, 1H), 1.51 (q, J = 12.3 Hz, 2H), 1.40 - 1.20 (m, 3H). LC/MS (ESI) 371.1 m/z [M+H]+. 1 H NMR (300 MHz, Methanol-d4) δ 8.53 (s, 1H), 7.92 (dd, J = 6.6, 2.6 Hz, 1H), 7.70 - 7.54 (m, 2H), 7.52 - 7.26 (m, 3H) , 3.51 (ddt, J = 10.3, 7.6, 3.8 Hz, 1H), 2.11 (d, J = 12.1 Hz, 2H), 1.92 - 1.78 (m, 2H), 1.78 - 1.66 (m, 1H), 1.51 (q , J = 12.3 Hz, 2H), 1.40 - 1.20 (m, 3H). LC/MS (ESI) 371.1 m/z [M+H] + .

<실시예> 17<Example> 17

NN -(4-((3-클로로-4-플루오로페닐)아미노)퀴나졸린-6-일)아세트아미드의 합성법Synthesis of -(4-((3-chloro-4-fluorophenyl)amino)quinazolin-6-yl)acetamide

디클로로메탄 (1 mL)에 녹아있는 무수아세트산 (0.19 mmol)과 트리에틸 아민 (0.35 mmol) 용액에 실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린-4,6-다이아민 (0.17 mmol)을 첨가하였다. 상온에서 교반하였고, 반응이 완결된 후, 1N 염산 수용액을 넣었고, 디클로로메탄으로 추출하였다. 유기층을 농축하고 prep HPLC으로 정제하여 흰색 고체의 실시예 17 (60 mg, 99%)를 얻었다. N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6 of Example 1 in a solution of acetic anhydride (0.19 mmol) and triethyl amine (0.35 mmol) in dichloromethane (1 mL) -diamine (0.17 mmol) was added. The mixture was stirred at room temperature, and after the reaction was completed, 1N aqueous hydrochloric acid solution was added, and the mixture was extracted with dichloromethane. The organic layer was concentrated and purified by prep HPLC to give Example 17 (60 mg, 99%) as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 11.05 (s, 1H), 10.49 (s, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.80 (s, 1H), 8.02 (dd, J = 6.8, 2.6 Hz, 1H), 7.99 - 7.79 (m, 2H), 7.70 (ddd, J = 9.0, 4.4, 2.6 Hz, 1H), 7.53 (t, J = 9.1 Hz, 1H), 2.15 (s, 3H). LC/MS (ESI) 331.0 m/z [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 11.05 (s, 1H), 10.49 (s, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.80 (s, 1H), 8.02 (dd, J ) = 6.8, 2.6 Hz, 1H), 7.99 - 7.79 (m, 2H), 7.70 (ddd, J = 9.0, 4.4, 2.6 Hz, 1H), 7.53 (t, J = 9.1 Hz, 1H), 2.15 (s, 3H). LC/MS (ESI) 331.0 m/z [M+H] + .

<실시예> 18<Example> 18

NN -(4-((3-클로로-4-플루오로페닐)아미노)퀴나졸린-6-일)-3-싸이아노벤즈아미드의 합성법-(4-((3-chloro-4-fluorophenyl)amino)quinazolin-6-yl)-3-cyanobenzamide

3-싸이아노벤조산 (0.26 mmol), EDCI (0.19 mmol), DIPEA (0.52 mmol)을 DMF (1 mL)에 녹이고 실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린-4,6-다이아민 (0.17 mmol)을 첨가하였다. 상온에서 교반하였고, 반응이 완결된 후, prep HPLC으로 정제하여 흰색 고체의 실시예 18 (14 mg, 20%)를 얻었다.3-Cyanobenzoic acid (0.26 mmol), EDCI (0.19 mmol), and DIPEA (0.52 mmol) were dissolved in DMF (1 mL) and N 4 -(3-chloro-4-fluorophenyl)-quinazoline of Example 1 -4,6-diamine (0.17 mmol) was added. It was stirred at room temperature, and after the reaction was completed, it was purified by prep HPLC to obtain Example 18 (14 mg, 20%) as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 10.82 (s, 1H), 10.03 (s, 1H), 8.91 (d, J = 2.2 Hz, 1H), 8.61 (s, 1H), 8.49 (d, J = 1.8 Hz, 1H), 8.34 (dt, J = 8.0, 1.5 Hz, 1H), 8.24 - 8.07 (m, 2H), 8.02 (dd, J = 9.0, 2.1 Hz, 1H), 7.83 (q, J = 8.6, 7.8 Hz, 3H), 7.45 (t, J = 9.1 Hz, 1H). LC/MS (ESI) 418.0 m/z [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 10.82 (s, 1H), 10.03 (s, 1H), 8.91 (d, J = 2.2 Hz, 1H), 8.61 (s, 1H), 8.49 (d, J ) = 1.8 Hz, 1H), 8.34 (dt, J = 8.0, 1.5 Hz, 1H), 8.24 - 8.07 (m, 2H), 8.02 (dd, J = 9.0, 2.1 Hz, 1H), 7.83 (q, J = 8.6, 7.8 Hz, 3H), 7.45 (t, J = 9.1 Hz, 1H). LC/MS (ESI) 418.0 m/z [M+H] + .

<실시예> 19<Example> 19

(( EE )-)- NN -(4-((3-클로로-4-플루오로페닐)아미노)퀴나졸린-6-일)-3-(3-싸이아노페닐)아크릴아미드의 합성법-(4-((3-chloro-4-fluorophenyl)amino)quinazolin-6-yl)-3-(3-cyanophenyl)acrylamide

실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린-4,6-다이아민과 (E)-3-(3-싸이아노페닐)아크릴오일 클로라이드로부터 20%의 수득율로 흰색 고체의 실시예 19의 화합물을 얻었다.A yield of 20% from N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine and ( E )-3-(3-cyanophenyl)acryloyl chloride of Example 1 to obtain the compound of Example 19 as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.99 (d, J = 2.1 Hz, 1H), 8.74 (s, 1H), 8.16 (d, J = 1.7 Hz, 1H), 8.08 (dd, J = 6.8, 2.6 Hz, 1H), 8.05 - 7.97 (m, 2H), 7.95 - 7.82 (m, 2H), 7.81 - 7.62 (m, 3H), 7.61 - 7.39 (m, 1H), 7.03 (d, J = 15.8 Hz, 1H). LC/MS (ESI) 444.0 m/z [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.99 (d, J = 2.1 Hz, 1H), 8.74 (s, 1H), 8.16 (d, J = 1.7 Hz, 1H), 8.08 (dd, J = 6.8, 2.6 Hz, 1H), 8.05 - 7.97 (m, 2H), 7.95 - 7.82 (m, 2H), 7.81 - 7.62 (m, 3H), 7.61 - 7.39 (m, 1H), 7.03 (d, J = 15.8 Hz, 1H). LC/MS (ESI) 444.0 m/z [M+H] + .

<실시예> 20<Example> 20

NN 44 -(4-브로모페닐)--(4-bromophenyl)- NN 66 -(3-메톡시벤질)퀴나졸린-4,6-다이아민의 합성법- Synthesis method of (3-methoxybenzyl) quinazoline-4,6-diamine

N -(4-브로모페닐)-6-니트로퀴나졸린-4-아민 : 실시예 1의 N-(3-클로로-4- 플로로페닐)-6-니트로퀴나졸린-4-아민를 만드는 방법으로 갈색고체의 N-(4-브로모페닐)-6- 니트로퀴나졸린-4-아민을 98%의 수득율로 얻었다. N- (4-bromophenyl)-6-nitroquinazolin-4-amine: as a method for preparing N- (3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine of Example 1 N- (4-bromophenyl)-6-nitroquinazolin-4-amine as a brown solid was obtained in a yield of 98%.

1H NMR (300 MHz, DMSO-d6) δ 9.67 (d, J = 2.5 Hz, 1H), 8.74 (s, 1H), 8.58 (dd, J = 9.2, 2.4 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.93 - 7.79 (m, 2H), 7.73 - 7.55 (m, 2H), 2.36 (s, 1H). 1 H NMR (300 MHz, DMSO-d6) δ 9.67 (d, J = 2.5 Hz, 1H), 8.74 (s, 1H), 8.58 (dd, J = 9.2, 2.4 Hz, 1H), 7.96 (d, J ) = 9.2 Hz, 1H), 7.93 - 7.79 (m, 2H), 7.73 - 7.55 (m, 2H), 2.36 (s, 1H).

N 4 -(4-브로모페닐)-퀴나졸린-4,6-다이아민: 실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린- 4,6-다이아민을 만드는 방법으로 갈색 고체의 N 4 -(4- 브로모페닐)-퀴나졸린-4,6-다이아민을 84%의 수득률로 얻었다. N 4 -(4-bromophenyl)-quinazoline-4,6-diamine: N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine of Example 1 By the preparation method, N 4 -(4-bromophenyl)-quinazoline-4,6-diamine as a brown solid was obtained in a yield of 84%.

1H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.35 (s, 1H), 7.95-7.82 (m, 2H), 7.58-7.48 (m,3H), 7.34 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 8.9, 2.3 Hz, 1H), 5.69 (d, J = 37.7 Hz, 2H). 1 H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.35 (s, 1H), 7.95-7.82 (m, 2H), 7.58-7.48 (m,3H), 7.34 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 8.9, 2.3 Hz, 1H), 5.69 (d, J = 37.7 Hz, 2H).

N 4 -(4-브로모페닐)- N 6 -(3-메톡시벤질)퀴나졸린-4,6-다이아민 : 실시예 1의 방법으로 m-아니스알데히드 (52 mg, 0.38 mmol)와 N 4 -(4-브로모페닐)-퀴나졸린-4,6-다이아민으로부터 N 4 -(4-브로모페닐)-N 6 -(3-메톡시벤질)퀴나졸린-4,6-다이아민을 4% 수득률로 얻었다. N 4 -(4-bromophenyl) -N 6 -(3-methoxybenzyl)quinazoline-4,6-diamine: as in Example 1 m-Anisaldehyde (52 mg, 0.38 mmol) with N 4 -(4-bromophenyl)-quinazoline-4,6-diamine from N 4 -(4-bromophenyl) -N 6 -(3-methoxybenzyl) Quinazoline-4,6-diamine was obtained in 4% yield.

1H NMR (300 MHz, Chloroform-d) δ 8.59 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.32 (t, J = 7.9 Hz, 1H), 7.21 (dd, J = 9.0, 2.4 Hz, 1H), 7.06 - 6.94 (m, 2H), 6.92 - 6.80 (m, 1H), 6.62 (s, 1H), 4.44 (s, 2H), 3.81 (s, 3H). LC/MS (ESI) m/z 435.0 [M+H]+. 1 H NMR (300 MHz, Chloroform-d) δ 8.59 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.8) Hz, 2H), 7.32 (t, J = 7.9 Hz, 1H), 7.21 (dd, J = 9.0, 2.4 Hz, 1H), 7.06 - 6.94 (m, 2H), 6.92 - 6.80 (m, 1H), 6.62 (s, 1H), 4.44 (s, 2H), 3.81 (s, 3H). LC/MS (ESI) m/z 435.0 [M+H] + .

<실시예> 21<Example> 21

NN 44 -(4-플루오로페닐)--(4-fluorophenyl)- NN 66 -(3-메톡시벤질)퀴나졸린-4,6-다이아민의 합성법- Synthesis method of (3-methoxybenzyl) quinazoline-4,6-diamine

N -(4-플루오로페닐)-6-니트로퀴나졸린-4-아민 : 실시예 1의 N-(3-클로로-4- 플로로페닐)-6-니트로퀴나졸린-4-아민을 만드는 방법으로 갈색고체의 N-(4-플루오로페닐)-6- 니트로퀴나졸린-4-아민을 70%의 수득율로 얻었다. N- (4-fluorophenyl)-6-nitroquinazolin-4-amine: Method for preparing N- (3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine of Example 1 to obtain N- (4-fluorophenyl)-6-nitroquinazolin-4-amine as a brown solid in a yield of 70%.

1H NMR (300 MHz, DMSO-d6) δ 9.64 (d, J = 2.5 Hz, 1H), 8.69 (s, 1H), 8.56 (dd, J = 9.2, 2.4 Hz, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.89 - 7.71 (m, 2H), 7.27 (m, 2H). 1 H NMR (300 MHz, DMSO-d6) δ 9.64 (d, J = 2.5 Hz, 1H), 8.69 (s, 1H), 8.56 (dd, J = 9.2, 2.4 Hz, 1H), 7.93 (d, J ) = 9.2 Hz, 1H), 7.89 - 7.71 (m, 2H), 7.27 (m, 2H).

N 4 -(4-플루오로페닐)-퀴나졸린-4,6-다이아민 : 실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린- 4,6-다이아민을 만드는 방법으로 노란색 고체의 N 4 -(4- 플루오로페닐)-퀴나졸린-4,6-다이아민을 97%의 수득률로 얻었다. N 4 -(4-fluorophenyl)-quinazoline-4,6-diamine: Example 1 N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine as a yellow solid N 4 -(4-fluorophenyl)-quinazoline-4,6-dia Min was obtained in a yield of 97%.

1H NMR (300 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.31 (s, 1H), 7.94-7.73 (m, 2H), 7.53 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 2.3 Hz, 1H), 7.31 - 7.08 (m, 3H), 5.63 (s, 2H). LC/MS (ESI) m/z 255.01 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.31 (s, 1H), 7.94-7.73 (m, 2H), 7.53 (d, J = 8.8 Hz, 1H), 7.35 (d , J = 2.3 Hz, 1H), 7.31 - 7.08 (m, 3H), 5.63 (s, 2H). LC/MS (ESI) m/z 255.01 [M+H] + .

N 4 -(4-플루오로페닐)- N 6 -(3-메톡시벤질)퀴나졸린-4,6-다이아민 : 실시예 1의 방법으로 m-아니스알데히드 (52 mg, 0.38 mmol)와 N 4 -(4-플루오로페닐)-퀴나졸린-4,6-다이아민으로부터 N 4 -(4-플루오로페닐)-N 6 -(3-메톡시벤질)퀴나졸린-4,6-다이아민을 16% 수득률로 얻었다. N 4 -(4-fluorophenyl) -N 6 -(3-methoxybenzyl)quinazoline-4,6-diamine: as in Example 1 m-Anisaldehyde (52 mg, 0.38 mmol) with N 4 -(4-fluorophenyl)-quinazoline-4,6-diamine from N 4 -(4-fluorophenyl) -N 6 -(3-methoxybenzyl) Quinazoline-4,6-diamine was obtained in 16% yield.

1H NMR (300 MHz, Chloroform-d) δ 8.56 (s, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.68 - 7.56 (m, 2H), 7.31 (t, J = 7.9 Hz, 1H), 7.19 (dd, J = 9.0, 2.4 Hz, 1H), 7.16 - 7.04 (m, 3H), 7.03 - 6.92 (m, 2H), 6.86 (dd, J = 8.3, 2.6 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 4.40 (d, J = 4.4 Hz, 2H), 3.81 (s, 3H). LC/MS (ESI) m/z 375.1 [M+H]+. 1 H NMR (300 MHz, Chloroform-d) δ 8.56 (s, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.68 - 7.56 (m, 2H), 7.31 (t, J = 7.9 Hz, 1H) ), 7.19 (dd, J = 9.0, 2.4 Hz, 1H), 7.16 - 7.04 (m, 3H), 7.03 - 6.92 (m, 2H), 6.86 (dd, J = 8.3, 2.6 Hz, 1H), 6.66 ( d, J = 2.4 Hz, 1H), 4.40 (d, J = 4.4 Hz, 2H), 3.81 (s, 3H). LC/MS (ESI) m/z 375.1 [M+H] + .

<실시예> 22<Example> 22

NN 44 -(3-클로로페닐)--(3-chlorophenyl)- NN 66 -(3-메톡시벤질)퀴나졸린-4,6-다이아민의 합성법- Synthesis method of (3-methoxybenzyl) quinazoline-4,6-diamine

N -(3-클로로페닐)-6-니트로퀴나졸린-4-아민 : 실시예 1의 N-(3-클로로-4- 플로로페닐)-6-니트로퀴나졸린-4-아민을 만드는 방법으로 노란색고체의 N-(3-클로로페닐)-6- 니트로퀴나졸린-4-아민을 81%의 수득율로 얻었다. N- (3-chlorophenyl)-6-nitroquinazolin-4-amine: as a method for preparing N- (3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine of Example 1 N- (3-chlorophenyl)-6-nitroquinazolin-4-amine as a yellow solid was obtained in a yield of 81%.

1H NMR (300 MHz, DMSO-d6) δ 10.54 (s, 1H), 9.66 (d, J = 2.5 Hz, 1H), 8.78 (s, 1H), 8.57 (dd, J = 9.2, 2.4 Hz, 1H), 8.07 (t, J = 2.1 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.84 (dd, J = 7.7, 1.9 Hz, 1H), 7.46 (t, J = 8.1 Hz, 1H), 7.24 (dd, J = 8.1, 2.3 Hz, 1H). 1 H NMR (300 MHz, DMSO-d6) δ 10.54 (s, 1H), 9.66 (d, J = 2.5 Hz, 1H), 8.78 (s, 1H), 8.57 (dd, J = 9.2, 2.4 Hz, 1H) ), 8.07 (t, J = 2.1 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.84 (dd, J = 7.7, 1.9 Hz, 1H), 7.46 (t, J = 8.1 Hz, 1H) ), 7.24 (dd, J = 8.1, 2.3 Hz, 1H).

N 4 -(3-클로로페닐)-퀴나졸린-4,6-다이아민 : 실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린- 4,6-다이아민을 만드는 방법으로 노란색 고체의 N 4 -(3- 클로로페닐)-퀴나졸린-4,6-다이아민을 92%의 수득률로 얻었다. N 4 -(3-chlorophenyl)-quinazoline-4,6-diamine: preparing N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine of Example 1 N 4 -(3-chlorophenyl)-quinazoline-4,6-diamine as a yellow solid by the method was obtained in a yield of 92%.

1H NMR (300 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.39 (s, 1H), 8.13 (t, J = 2.1 Hz, 1H), 7.91 - 7.78 (m, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.46 - 7.32 (m, 2H), 7.27 (dd, J = 8.9, 2.3 Hz, 1H), 7.11 (ddd, J = 8.0, 2.1, 1.0 Hz, 1H), 5.64 (s, 2H). LC/MS (ESI) m/z 270.99 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.39 (s, 1H), 8.13 (t, J = 2.1 Hz, 1H), 7.91 - 7.78 (m, 1H), 7.56 (d , J = 8.9 Hz, 1H), 7.46 - 7.32 (m, 2H), 7.27 (dd, J = 8.9, 2.3 Hz, 1H), 7.11 (ddd, J = 8.0, 2.1, 1.0 Hz, 1H), 5.64 ( s, 2H). LC/MS (ESI) m/z 270.99 [M+H] + .

N 4 -(4-클로로페닐)- N 6 -(3-메톡시벤질)퀴나졸린-4,6-다이아민 : 실시예 1의 방법으로 m-아니스알데히드 (52 mg, 0.38 mmol)와 N 4 -(4-클로로페닐)-퀴나졸린-4,6-다이아민으로부터 N 4 -(4-클로로페닐)-N 6 -(3-메톡시벤질)퀴나졸린-4,6-다이아민을 35% 수득률로 얻었다. N 4 -(4-chlorophenyl) -N 6 -(3-methoxybenzyl)quinazoline-4,6-diamine: as in Example 1 m-Anisaldehyde (52 mg, 0.38 mmol) and N 4 -(4-chlorophenyl)-quinazoline-4,6-diamine from N 4 -(4-chlorophenyl) -N 6 -(3-methoxybenzyl)quinazoline -4,6-diamine was obtained in 35% yield.

1H NMR (500 MHz, Chloroform-d) δ 8.60 (s, 1H), 7.85 (t, J = 2.1 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.61 - 7.49 (m, 1H), 7.34 - 7.26 (m, 3H), 7.18 (dd, J = 9.0, 2.4 Hz, 1H), 7.09 (ddd, J = 8.0, 2.0, 0.9 Hz, 1H), 7.02 - 6.91 (m, 2H), 6.89 - 6.82 (m, 1H), 6.64 (d, J = 2.4 Hz, 1H), 4.38 (s, 2H), 3.81 (s, 3H). LC/MS (ESI) m/z 391.5 [M+H]+. 1 H NMR (500 MHz, Chloroform-d) δ 8.60 (s, 1H), 7.85 (t, J = 2.1 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.61 - 7.49 (m, 1H) ), 7.34 - 7.26 (m, 3H), 7.18 (dd, J = 9.0, 2.4 Hz, 1H), 7.09 (ddd, J = 8.0, 2.0, 0.9 Hz, 1H), 7.02 - 6.91 (m, 2H), 6.89 - 6.82 (m, 1H), 6.64 (d, J = 2.4 Hz, 1H), 4.38 (s, 2H), 3.81 (s, 3H). LC/MS (ESI) m/z 391.5 [M+H] + .

<실시예> 23<Example> 23

4-((6-((3-메톡시벤질)아미노)퀴나졸린-4-일)아미노)벤조니트릴의 합성법Synthesis of 4-((6-((3-methoxybenzyl)amino)quinazolin-4-yl)amino)benzonitrile

4-((6-니트로퀴나졸린-4-일)아미노)벤조니트릴 : 실시예 1의 N-(3-클로로-4- 플로로페닐)-6-니트로퀴나졸린-4-아민을 만드는 방법으로 노란색고체의 4-((6-니트로퀴나졸린-4-일)아미노)벤조니트릴을 92%의 수득율로 얻었다. 4-((6-nitroquinazolin-4-yl)amino)benzonitrile: by a method for preparing N- (3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine of Example 1 4-((6-nitroquinazolin-4-yl)amino)benzonitrile as a yellow solid was obtained in a yield of 92%.

1H NMR (300 MHz, DMSO-d6) δ 9.65 (d, J = 2.5 Hz, 1H), 8.79 (s, 1H), 8.57 (dd, J = 9.2, 2.4 Hz, 1H), 8.25 - 8.03 (m, 2H), 7.96 (d, J = 9.2 Hz, 1H), 7.93 - 7.81 (m, 2H), 2.41 (s, 1H). 1 H NMR (300 MHz, DMSO-d6) δ 9.65 (d, J = 2.5 Hz, 1H), 8.79 (s, 1H), 8.57 (dd, J = 9.2, 2.4 Hz, 1H), 8.25 - 8.03 (m) , 2H), 7.96 (d, J = 9.2 Hz, 1H), 7.93 - 7.81 (m, 2H), 2.41 (s, 1H).

4-((6-아미노퀴나졸린-4-일)아미노)벤조니트릴 : 실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린- 4,6-다이아민을 만드는 방법으로 노란색 고체의 4-((6-아미노퀴나졸린-4-일)아미노)벤조니트릴을 37%의 수득률로 얻었다. 4-((6-aminoquinazolin-4-yl)amino)benzonitrile: Method for preparing N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine of Example 1 4-((6-aminoquinazolin-4-yl)amino)benzonitrile as a yellow solid was obtained in a yield of 37%.

1H NMR (300 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.44 (s, 1H), 8.22-8.05 (m, 2H), 7.87-7.72 (m, 2H), 7.59 (d, J = 8.8 Hz, 1H), 7.42 - 7.19 (m, 2H), 5.71 (s, 2H). 1 H NMR (300 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.44 (s, 1H), 8.22-8.05 (m, 2H), 7.87-7.72 (m, 2H), 7.59 (d, J = 8.8 Hz, 1H), 7.42 - 7.19 (m, 2H), 5.71 (s, 2H).

4-((6-((3-메톡시벤질)아미노)퀴나졸린-4-일)아미노)벤조니트릴 (5Ea) : 실시예 1의 방법으로 m-아니스알데히드 (52 mg, 0.38 mmol)와 4-((6-아미노퀴나졸린-4-일)아미노)벤조니트릴로부터 4-((6-((3-메톡시벤질)아미노)퀴나졸린-4-일)아미노)벤조니트릴을 63% 수득률로 얻었다. 4-((6-((3-methoxybenzyl)amino)quinazolin-4-yl)amino)benzonitrile (5Ea): m-anisaldehyde (52 mg, 0.38 mmol) and 4 by the method of Example 1 -((6-aminoquinazolin-4-yl)amino)benzonitrile to 4-((6-((3-methoxybenzyl)amino)quinazolin-4-yl)amino)benzonitrile in 63% yield got it

1H NMR (300 MHz, Methanol-d4) δ 8.63 (s, 1H), 8.04-7.96 (m, 2H), 7.83 (d, J = 8.7 Hz, 2H), 7.74 - 7.63 (m, 1H), 7.63 - 7.49 (m, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.26 (q, J = 7.1, 6.2 Hz, 1H), 7.00 (d, J = 8.3 Hz, 3H), 6.84 (d, J = 8.9 Hz, 1H), 4.52 (s, 2H), 3.77 (s, 3H). LC/MS (ESI) m/z 382.1 [M+H]+. 1 H NMR (300 MHz, Methanol-d4) δ 8.63 (s, 1H), 8.04-7.96 (m, 2H), 7.83 (d, J = 8.7 Hz, 2H), 7.74 - 7.63 (m, 1H), 7.63 - 7.49 (m, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.26 (q, J = 7.1, 6.2 Hz, 1H), 7.00 (d, J = 8.3 Hz, 3H), 6.84 (d, J = 8.9 Hz, 1H), 4.52 (s, 2H), 3.77 (s, 3H). LC/MS (ESI) m/z 382.1 [M+H] + .

<실시예> 24<Example> 24

1-(3-((6-((3-메톡시벤질)아미노)퀴나졸린-4-일)아미노)페닐)에타논 (5Fa)의 합성법Synthesis of 1-(3-((6-((3-methoxybenzyl)amino)quinazolin-4-yl)amino)phenyl)ethanone (5Fa)

1-(3-((6-니트로퀴나졸린-4-일)아미노)페닐)에탄-1-온 : 실시예 1의 N-(3-클로로-4- 플로로페닐)-6-니트로퀴나졸린-4-아민을 만드는 방법으로 노란색고체의 1-(3-((6-니트로퀴나졸린-4-일)아미노)페닐)에탄-1-온을 73%의 수득율로 얻었다. 1-(3-((6-nitroquinazolin-4-yl)amino)phenyl)ethan-1-one: N- (3-chloro-4-fluorophenyl)-6-nitroquinazoline of Example 1 By the method for preparing -4-amine, 1-(3-((6-nitroquinazolin-4-yl)amino)phenyl)ethan-1-one as a yellow solid was obtained in a yield of 73%.

1H NMR (300 MHz, Chloroform-d) δ 9.04 (d, J = 2.4 Hz, 1H), 8.89 (s, 1H), 8.60 (dd, J = 9.2, 2.3 Hz, 1H), 8.36 (s, 1H), 8.18 (d, J = 8.3 Hz, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 2.68 (s, 3H). 1 H NMR (300 MHz, Chloroform-d) δ 9.04 (d, J = 2.4 Hz, 1H), 8.89 (s, 1H), 8.60 (dd, J = 9.2, 2.3 Hz, 1H), 8.36 (s, 1H) ), 8.18 (d, J = 8.3 Hz, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 2.68 (s, 3H).

1-(3-((6-아미노니트로퀴나졸린-4-일)아미노)페닐)에탄-1-온 : 실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린- 4,6-다이아민을 만드는 방법으로 노란색 고체의 1-(3-((6-아미노니트로퀴나졸린-4-일)아미노)페닐)에탄-1-온을 74%의 수득률로 얻었다. 1-(3-((6-aminonitroquinazolin-4-yl)amino)phenyl)ethan-1-one: N 4 of Example 1 -(3-chloro-4-fluorophenyl)-quinazoline- 1-(3-((6-aminonitroquinazolin-4-yl)amino)phenyl)ethan-1-one as a yellow solid was obtained in a yield of 74% by the method for preparing 4,6-diamine.

1H NMR (300 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.41 (t, J = 1.9 Hz, 1H), 8.35 (s, 1H), 8.22 (ddd, J = 8.1, 2.3, 1.1 Hz, 1H), 7.67 (dt, J = 7.8, 1.3 Hz, 1H), 7.62 - 7.45 (m, 2H), 7.38 (d, J = 2.4 Hz, 1H), 7.26 (dd, J = 8.8, 2.3 Hz, 1H), 5.61 (s, 2H), 2.60 (s, 3H). LC/MS (ESI) m/z 279.09 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.41 (t, J = 1.9 Hz, 1H), 8.35 (s, 1H), 8.22 (ddd, J = 8.1, 2.3, 1.1 Hz) , 1H), 7.67 (dt, J = 7.8, 1.3 Hz, 1H), 7.62 - 7.45 (m, 2H), 7.38 (d, J = 2.4 Hz, 1H), 7.26 (dd, J = 8.8, 2.3 Hz, 1H), 5.61 (s, 2H), 2.60 (s, 3H). LC/MS (ESI) m/z 279.09 [M+H] + .

1-(3-((6-((3-메톡시벤질)아미노)퀴나졸린-4-일)아미노)페닐)에탄-1-온 : 실시예1의 방법으로 m-아니스알데히드 (52 mg, 0.38 mmol)와 1-(3-((6-아미노니트로퀴나졸린-4-일)아미노)페닐)에탄-1-온으로부터 1-(3-((6-((3-메톡시벤질)아미노)퀴나졸린-4-일)아미노)페닐)에탄-1-온을 72% 수득률로 얻었다. 1-(3-((6-((3-methoxybenzyl)amino)quinazolin-4-yl)amino)phenyl)ethan-1-one: m-anisaldehyde (52 mg, 0.38 mmol) and 1-(3-((6-aminonitroquinazolin-4-yl)amino)phenyl)ethan-1-one from 1-(3-((6-((3-methoxybenzyl)amino )quinazolin-4-yl)amino)phenyl)ethan-1-one was obtained in 72% yield.

1H NMR (300 MHz, Methanol-d4) δ 8.55 (s, 1H), 8.31 (t, J = 1.9 Hz, 1H), 8.05 - 7.87 (m, 2H), 7.75 - 7.49 (m, 4H), 7.43 (d, J = 2.4 Hz, 1H), 7.38 - 7.18 (m, 1H), 7.01 (d, J = 7.5 Hz, 2H), 6.84 (d, J = 9.3 Hz, 1H), 4.51 (d, J = 3.1 Hz, 2H), 3.78 (s, 3H), 2.65 (s, 3H). LC/MS (ESI) m/z 399.1 [M+H]+. 1 H NMR (300 MHz, Methanol-d4) δ 8.55 (s, 1H), 8.31 (t, J = 1.9 Hz, 1H), 8.05 - 7.87 (m, 2H), 7.75 - 7.49 (m, 4H), 7.43 (d, J = 2.4 Hz, 1H), 7.38 - 7.18 (m, 1H), 7.01 (d, J = 7.5 Hz, 2H), 6.84 (d, J = 9.3 Hz, 1H), 4.51 (d, J = 3.1 Hz, 2H), 3.78 (s, 3H), 2.65 (s, 3H). LC/MS (ESI) m/z 399.1 [M+H] + .

<실시예> 25<Example> 25

NN 66 -(3-메톡시벤질)--(3-methoxybenzyl)- NN 44 -(4-(트리플루오로메틸)페닐)퀴나졸린-4,6-다이아민의 합성법Synthesis of -(4-(trifluoromethyl)phenyl)quinazoline-4,6-diamine

6-니트로- N -(4-(트리플루오로메틸)페닐)퀴나졸린-4-아민 : 실시예 1의 N-(3-클로로-4-플로로페닐)-6-니트로퀴나졸린-4-아민을 만드는 방법으로 노란색고체의 6-니트로-N-(4-(트리플루오로메틸)페닐)퀴나졸린-4-아민을 97%의 수득율로 얻었다. 6-Nitro- N- (4-(trifluoromethyl)phenyl)quinazolin-4-amine: N- (3-chloro-4-fluorophenyl)-6-nitroquinazoline-4- of Example 1 6-nitro- N- (4-(trifluoromethyl)phenyl)quinazolin-4-amine as a yellow solid was obtained in a yield of 97% by the method of preparing an amine.

1H NMR (300 MHz, Chloroform-d) δ 9.06 - 8.87 (m, 2H), 8.62 (dd, J = 9.2, 2.3 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 8.6 Hz, 2H). 1 H NMR (300 MHz, Chloroform-d) δ 9.06 - 8.87 (m, 2H), 8.62 (dd, J = 9.2, 2.3 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.99 (d) , J = 8.5 Hz, 2H), 7.73 (d, J = 8.6 Hz, 2H).

N 4 -(4-(트리플루오로메틸)페닐)퀴나졸린-4,6-다이아민 : 실시예 1의 N 4 -(3-클로로-4-플로로페닐)-퀴나졸린- 4,6-다이아민을 만드는 방법으로 노란색 고체의 N 4 -(4-(트리플루오로메틸)페닐)퀴나졸린-4,6-다이아민 (4G)를 63%의 수득률로 얻었다. N 4 -(4-(trifluoromethyl)phenyl)quinazoline-4,6-diamine: N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6- of Example 1 N 4 -(4-(trifluoromethyl)phenyl)quinazoline-4,6-diamine (4G) as a yellow solid was obtained in a yield of 63% by a method for preparing diamine.

1H NMR (300 MHz, Methanol-d4) δ 8.39 (s, 1H), 8.16-7.87 (m, 2H), 7.78-7.52 (m, 3H), 7.45-7.23 (m, 2H). LC/MS (ESI) m/z 305.09 [M+H]+. 1 H NMR (300 MHz, Methanol-d4) δ 8.39 (s, 1H), 8.16-7.87 (m, 2H), 7.78-7.52 (m, 3H), 7.45-7.23 (m, 2H). LC/MS (ESI) m/z 305.09 [M+H] + .

N 6 -(3-메톡시벤질)- N 4 -(4-(트리플루오로메틸)페닐)퀴나졸린-4,6-다이아민: 실시예 1의 방법으로 m-아니스알데히드 (52 mg, 0.38 mmol)와 N 4 -(4-(트리플루오로메틸)페닐)퀴나졸린-4,6-다이아민 (4G)으로부터 노란색 폼형태의 N 6 -(3-메톡시벤질)-N 4 -(4-(트리플루오로메틸)페닐)퀴나졸린-4,6-다이아민을 46% 수득률로 얻었다. N 6 -(3-methoxybenzyl) -N 4 -(4-(trifluoromethyl)phenyl)quinazoline-4,6-diamine: m-anisaldehyde (52 mg, 0.38 mmol) and N 4 -(4-(trifluoromethyl)phenyl)quinazoline-4,6-diamine (4G) in the form of yellow form N 6 -(3-methoxybenzyl) -N 4 -(4) -(trifluoromethyl)phenyl)quinazoline-4,6-diamine was obtained in 46% yield.

1H NMR (300 MHz, Methanol-d4) δ 8.59 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.5 Hz, 2H), 7.73 - 7.50 (m, 2H), 7.45 (d, J = 2.3 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 7.08 - 6.95 (m, 2H), 6.92 - 6.76 (m, 1H), 4.52 (s, 2H), 3.77 (s, 3H). LC/MS (ESI) m/z 425.1 [M+H]+. 1 H NMR (300 MHz, Methanol-d4) δ 8.59 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.5 Hz, 2H), 7.73 - 7.50 (m, 2H) ), 7.45 (d, J = 2.3 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 7.08 - 6.95 (m, 2H), 6.92 - 6.76 (m, 1H), 4.52 (s, 2H) , 3.77 (s, 3H). LC/MS (ESI) m/z 425.1 [M+H] + .

<실시예> 26<Example> 26

2-(((4-((4-(트리플루오로메틸)페닐)아미노)퀴나졸린-6-일)아미노)메틸)벤조니트릴의 합성법Synthesis of 2-(((4-((4-(trifluoromethyl)phenyl)amino)quinazolin-6-yl)amino)methyl)benzonitrile

실시예 1의 방법으로 2-싸이아노벤즈알데히드와 N 4 -(4-(트리플루오로메틸)페닐)퀴나졸린- 4,6-다이아민 (4G)으로부터 노란색 고체의 2-(((4-((4-(트리플루오로메틸)페닐)아미노)퀴나졸린- 4-일)아미노)메틸)벤조니트릴을 87% 수득률로 얻었다.2-(( ( 4 -((4-() (4-(trifluoromethyl)phenyl)amino)quinazolin-4-yl)amino)methyl)benzonitrile was obtained in 87% yield.

1H NMR (300 MHz, Methanol-d4) δ 8.99-8.70 (m, 2H), 8.30-8.15 (m, 2H), 8.10 (dd, J = 8.8, 3.2 Hz, 3H), 8.04 - 7.84 (m, 2H), 7.78 (dd, J = 12.7, 8.0 Hz, 3H), 5.44 (s, 2H). LC/MS (ESI) 420.1 m/z [M+H]+. 1 H NMR (300 MHz, Methanol-d4) δ 8.99-8.70 (m, 2H), 8.30-8.15 (m, 2H), 8.10 (dd, J = 8.8, 3.2 Hz, 3H), 8.04 - 7.84 (m, 2H), 7.78 (dd, J = 12.7, 8.0 Hz, 3H), 5.44 (s, 2H). LC/MS (ESI) 420.1 m/z [M+H] + .

<실시예> 27<Example> 27

3-(((4-((4-(트리플루오로메틸)페닐)아미노)퀴나졸린-6-일)아미노)메틸)벤조니트릴의 합성법Synthesis of 3-(((4-((4-(trifluoromethyl)phenyl)amino)quinazolin-6-yl)amino)methyl)benzonitrile

실시예 1의 방법으로 3-싸이아노벤즈알데히드와 N 4 -(4-(트리플루오로메틸)페닐)퀴나졸린- 4,6-다이아민으로부터 노란색 고체의 3-(((4-((4-(트리플루오로메틸)페닐)아미노)퀴나졸린- 4-일)아미노)메틸)벤조니트릴을 39% 수득률로 얻었다.In the method of Example 1 , 3-(( 4 -((4-) (trifluoromethyl)phenyl)amino)quinazolin-4-yl)amino)methyl)benzonitrile was obtained in 39% yield.

1H NMR (300 MHz, Methanol-d4) δ 8.60 (s, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 8.3 Hz, 4H), 7.67 (t, J = 9.1 Hz, 2H), 7.62 - 7.50 (m, 2H), 7.42 (d, J = 2.4 Hz, 1H), 4.63 (s, 2H). LC/MS (ESI) 420.1 m/z [M+H]+. 1 H NMR (300 MHz, Methanol-d4) δ 8.60 (s, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 8.3 Hz, 4H), 7.67 (t, J = 9.1) Hz, 2H), 7.62 - 7.50 (m, 2H), 7.42 (d, J = 2.4 Hz, 1H), 4.63 (s, 2H). LC/MS (ESI) 420.1 m/z [M+H] + .

<실시예> 28<Example> 28

4-(((4-((4-(트리플루오로메틸)페닐)아미노)퀴나졸린-6-일)아미노)메틸)벤조니트릴의 합성법Synthesis of 4-(((4-((4-(trifluoromethyl)phenyl)amino)quinazolin-6-yl)amino)methyl)benzonitrile

실시예 1의 방법으로 4-싸이아노벤즈알데히드와 N 4 -(4-(트리플루오로메틸)페닐)퀴나졸린- 4,6-다이아민으로부터 노란색 고체의 4-(((4-((4-(트리플루오로메틸)페닐)아미노)퀴나졸린- 4-일)아미노)메틸)벤조니트릴을 34% 수득률로 얻었다.4-( ( 4 -((4-(4-) (trifluoromethyl)phenyl)amino)quinazolin-4-yl)amino)methyl)benzonitrile was obtained in 34% yield.

1H NMR (300 MHz, Methanol-d4) δ 8.60 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.84 - 7.64 (m, 5H), 7.59 (dd, J = 10.6, 8.5 Hz, 3H), 7.41 (d, J = 2.4 Hz, 1H), 4.66 (s, 2H). LC/MS (ESI) 420.0 m/z [M+H]+. 1 H NMR (300 MHz, Methanol-d4) δ 8.60 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.84 - 7.64 (m, 5H), 7.59 (dd, J = 10.6, 8.5 Hz) , 3H), 7.41 (d, J = 2.4 Hz, 1H), 4.66 (s, 2H). LC/MS (ESI) 420.0 m/z [M+H] + .

<실시예> 29<Example> 29

NN 66 -(3-니트로벤질)--(3-nitrobenzyl)- NN 44 -(4-(트리플루오로메틸)페닐)퀴나졸린-4,6-다이아민의 합성법Synthesis of -(4-(trifluoromethyl)phenyl)quinazoline-4,6-diamine

실시예 1의 방법으로 3-니트로벤즈알데히드와 N 4 -(4-(트리플루오로메틸)페닐)퀴나졸린- 4,6-다이아민으로부터 노란색 고체의 N 6 -(3-니트로벤질)-N 4 -(4-(트리플루오로메틸)페닐)퀴나졸린-4,6-다이아민을 60% 수득률로 얻었다.From the method of Example 1, 3-nitrobenzaldehyde and N 4 -(4-(trifluoromethyl)phenyl)quinazoline-4,6-diamine as a yellow solid N 6 -(3-nitrobenzyl) -N 4 -(4-(trifluoromethyl)phenyl)quinazoline-4,6-diamine was obtained in 60% yield.

1H NMR (300 MHz, Methanol-d4) δ 8.59 (d, J = 6.8 Hz, 1H), 8.31 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.97 - 7.73 (m, 4H), 7.74 - 7.64 (m, 1H), 7.64 - 7.55 (m, 2H), 7.56 - 7.40 (m, 1H), 4.71 (s, 2H). LC/MS (ESI) 440.0 m/z [M+H]+. 1 H NMR (300 MHz, Methanol-d4) δ 8.59 (d, J = 6.8 Hz, 1H), 8.31 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.97 - 7.73 (m, 4H) ), 7.74 - 7.64 (m, 1H), 7.64 - 7.55 (m, 2H), 7.56 - 7.40 (m, 1H), 4.71 (s, 2H). LC/MS (ESI) 440.0 m/z [M+H] + .

<실시예> 30<Example> 30

NN 66 -(4-니트로벤질)--(4-nitrobenzyl)- NN 44 -(4-(트리플루오로메틸)페닐)퀴나졸린-4,6-다이아민의 합성법Synthesis of -(4-(trifluoromethyl)phenyl)quinazoline-4,6-diamine

실시예 1의 방법으로 4-니트로벤즈알데히드와 N 4 -(4-(트리플루오로메틸)페닐)퀴나졸린- 4,6-다이아민 (4G)으로부터 노란색 고체의 N 6 -(4-니트로벤질)-N 4 -(4-(트리플루오로메틸)페닐)퀴나졸린-4,6-다이아민을 40% 수득률로 얻었다.Yellow solid N 6 -(4-nitrobenzyl) from 4-nitrobenzaldehyde and N 4 -(4-(trifluoromethyl)phenyl)quinazoline-4,6-diamine (4G) by the method of Example 1 -N 4 -(4-(trifluoromethyl)phenyl)quinazoline-4,6-diamine was obtained in 40% yield.

1H NMR (300 MHz, Methanol-d4) δ 8.60 (s, 1H), 8.29-8.20 (m, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.6 Hz, 2H), 7.74 - 7.51 (m, 4H), 7.42 (d, J = 2.4 Hz, 1H), 4.71 (s, 2H). LC/MS (ESI) 440.0 m/z [M+H]+. 1 H NMR (300 MHz, Methanol-d4) δ 8.60 (s, 1H), 8.29-8.20 (m, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.6 Hz, 2H) ), 7.74 - 7.51 (m, 4H), 7.42 (d, J = 2.4 Hz, 1H), 4.71 (s, 2H). LC/MS (ESI) 440.0 m/z [M+H] + .

<실시예> 31<Example> 31

NN 44 -(3-브로모페닐)--(3-bromophenyl)- NN 66 -(2-메톡시벤질)퀴나졸린-4,6-다이아민-(2-Methoxybenzyl)quinazoline-4,6-diamine

한국화합물은행으로부터 실시예 31 화합물을 입수하였다. (ChemBank# : 108309)The compound of Example 31 was obtained from the Korea Compound Bank. (ChemBank#: 108309)

<실시예> 32<Example> 32

NN 44 -(3-브로모페닐)--(3-bromophenyl)- NN 66 -(4-메톡시벤질)퀴나졸린-4,6-다이아민-(4-Methoxybenzyl)quinazoline-4,6-diamine

한국화합물은행으로부터 실시예 32 화합물을 입수하였다. (ChemBank# : 108308)The compound of Example 32 was obtained from the Korea Compound Bank. (ChemBank#: 108308)

<실시예>33<Example> 33

NN 44 -(3-브로모페닐)--(3-bromophenyl)- NN 66 -((3-플루오로페닐)메틸)퀴나졸린-4,6-다이아민-((3-fluorophenyl)methyl)quinazoline-4,6-diamine

한국화합물은행으로부터 실시예 33 화합물을 입수하였다. (ChemBank# : 108322)The compound of Example 33 was obtained from the Korea Compound Bank. (ChemBank#: 108322)

<실시예> 34<Example> 34

NN 44 -(3-브로모페닐)--(3-bromophenyl)- NN 66 -((퍼플루오로페닐)메틸)퀴나졸린-4,6-다이아민 -((perfluorophenyl)methyl)quinazoline-4,6-diamine

한국화합물은행으로부터 실시예 34 화합물을 입수하였다. (ChemBank# : 108324)The compound of Example 34 was obtained from the Korea Compound Bank. (ChemBank#: 108324)

<실시예> 35<Example> 35

NN 44 -(3-브로모페닐)--(3-bromophenyl)- NN 66 -(4-메틸펜틸)퀴나졸린-4,6-다이아민-(4-methylpentyl)quinazoline-4,6-diamine

한국화합물은행으로부터 실시예 35 화합물을 입수하였다. (ChemBank# : 108336)The compound of Example 35 was obtained from the Korea Compound Bank. (ChemBank#: 108336)

<실험예 1> 항바이러스 활성평가<Experimental Example 1> Antiviral activity evaluation

<1-1> 세포주 및 바이러스 준비<1-1> Preparation of cell lines and viruses

본 발명에 사용한 베로 세포(vero cell)는 American Type Culture Collection (ATCC, CCL-81; Manassas, VA)로부터 구매하여 사용하였으며, 10% 열 불활성화 소 태아 혈청 및 1x 항생제-항진균제(Antibiotic-Antimycotic, Gibco/Thermo Fisher Scientific, Waltham, MA)가 포함된 Dulbecco's modified Eagle's medium (DMEM; Welgene, Gyeongsan, Korea)에 담아 37℃에서 5% 이산화탄소 하에서 배양하였다.Vero cells used in the present invention were purchased from American Type Culture Collection (ATCC, CCL-81; Manassas, VA) and used, 10% heat-inactivated fetal bovine serum and 1x antibiotic-antimycotic (Antibiotic-Antimycotic, Gibco/Thermo Fisher Scientific, Waltham, MA) was placed in Dulbecco's modified Eagle's medium (DMEM; Welgene, Gyeongsan, Korea) and cultured at 37°C under 5% carbon dioxide.

MERS-CoV 한국 분리주 (MERS-CoV/KOR/KNIH/002_05_2015, Genbank accession no. KT029139.1 [Kim et al., 2015 doi:10.1128/genomeA.00787-15])를 한국 질병관리본부 국립보건원으로부터 제공받아, Kim et al., 2016 doi:10.1093/cid/ciw239에 제시된 방법에 따라 베로 세포에서 증식하였다. MERS-CoV를 사용한 모든 실험은 한국질병관리본부부터 승인받은 국립보건원의 강화된 생물 안전 등급 3단계 (Biosafety Level 3, BL-3) 봉쇄 절차를 준수한 한국 파스퇴르 연구소에서 수행하였다.MERS-CoV Korean isolate (MERS-CoV/KOR/KNIH/002_05_2015, Genbank accession no. KT029139.1 [Kim et al., 2015 doi:10.1128/genomeA.00787-15]) was provided by the National Institutes of Health, Korea Centers for Disease Control and Prevention and proliferated in Vero cells according to the method presented in Kim et al., 2016 doi:10.1093/cid/ciw239. All experiments using MERS-CoV were performed at the Pasteur Institute in Korea in compliance with the National Institutes of Health's enhanced Biosafety Level 3 (BL-3) containment procedures approved by the Korea Centers for Disease Control and Prevention.

<1-2> 시약 준비<1-2> Preparation of reagents

클로로퀸 이인산염(Chloroquine diphosphate (CQ; C6628))과 로피나비르(lopinavir (LPV; GP6351))를 각각 SelleckChem (Houston, TX)과 Glentham Life Science (UK)에서 구매하였다. 일차 항체로 사용된 항-MERS-CoV spike 항체는 Sino Biological Inc. (Beijing, China)로부터 구매하였다. 이차항체인 Alexa Fluor 488 goat anti-rabbit IgG 및 세포핵 염색체인 Hoechst 33342는 MolecularProbes/ Thermo Fisher Scientific (Waltham, MA)에서 구매하였다. 32% Paraformaldehyde (PFA) 수용액과 정상염소 혈청은 각각 Electron Microscopy Sciences (Hatfield, PA) 및 Vector Laboratories, Inc. (Burlingame, CA)에서 구매하였다.Chloroquine diphosphate (CQ; C6628) and lopinavir (LPV; GP6351)) were purchased from SelleckChem (Houston, TX) and Glentham Life Science (UK), respectively. The anti-MERS-CoV spike antibody used as the primary antibody was obtained from Sino Biological Inc. (Beijing, China). Alexa Fluor 488 goat anti-rabbit IgG, a secondary antibody, and Hoechst 33342, a nuclear chromosome, were purchased from MolecularProbes/Thermo Fisher Scientific (Waltham, MA). 32% Paraformaldehyde (PFA) aqueous solution and normal goat serum were obtained from Electron Microscopy Sciences (Hatfield, PA) and Vector Laboratories, Inc., respectively. (Burlingame, CA).

<1-3> 면역형광어세이를 이용한 이미지 기반 어세이<1-3> Image-based assay using immunofluorescence assay

MERS-CoV에 감염된 세포는 바이러스 단백질을 발현하기 때문에 바이러스 단백질에 특이적으로 결합하는 항체를 사용하여 측정할 수 있다. 본 발명에서는 MERS-CoV의 스파이크(spike) 단백질에 결합하는 항체를 이용하여 세포를 염색하였고 현미경을 통해 감염된 세포를 이미지화하였다. 감염률 (MERS-CoV spike 단백질을 발현하는 세포의 수/총 세포수)은 내부에서 개발된 Image Mining 3.0 (IM 3.0) 플러그인으로 측정되었다. 저분자 화합물의 항바이러스 효과를 비교하기 위해 음성대조군으로 디메틸설폭사이드(DMSO)가 처리된 감염세포를 사용하였고, MERS-CoV에 대한 항바이러스 활성이 알려진 2개의 화합물(CQ 및 LPV)을 양성대조군으로 사용하여 이미지 기반 어세이를 최적화하였다.Since MERS-CoV-infected cells express viral proteins, they can be measured using antibodies that specifically bind to viral proteins. In the present invention, cells were stained using an antibody that binds to the MERS-CoV spike protein, and the infected cells were imaged through a microscope. The infection rate (the number of cells expressing the MERS-CoV spike protein/total number of cells) was measured with the internally developed Image Mining 3.0 (IM 3.0) plugin. In order to compare the antiviral effects of small molecule compounds, dimethyl sulfoxide (DMSO)-treated infected cells were used as negative controls, and two compounds (CQ and LPV) with known antiviral activity against MERS-CoV were used as positive controls. was used to optimize image-based assays.

<1-4> 저분자 화합물 라이브러리<1-4> Small molecule compound library

약 20만 개의 저분자 화합물들은 DMSO에 녹였으며 분석 전까지 -80℃에서 보관하였다.About 200,000 low molecular weight compounds were dissolved in DMSO and stored at -80°C until analysis.

<1-5> 이미지기반 저분자 화합물 스크리닝<1-5> Image-based low-molecular compound screening

베로 세포를 각 웰당 1.2ⅹ104세포로 4 mM L-Glutamine 및 1ⅹ Antibiotic-Antimycotic 가 포함된 Opti-PRO™ SFM 에 담아 블랙, 384-웰, 마이크로클리어 플레이트(Clear plates, Greiner bio-one, Kremsmunster, Austria)에 분주하였다. 24시간 후, 저분자 화합물을 바이러스 감염 전에 자동화 액체 처리 시스템(automated liquid handling system (Apricot Designs, Covina, CA))을 사용하여 각 웰에 첨가하였다. 실험 화합물의 최종 농도는 2.5 내지 28.2 μM 이었고, DMSO의 농도는 0.5 %로 유지하였다. 화합물이 처리된 군은 BL-3 봉쇄실로 옮긴 후, 0.0625 MOI의 MERS-CoV에 감염되었다.Vero cells at 1.2×10 4 cells per well in Opti-PRO™ SFM containing 4 mM L-Glutamine and 1× Antibiotic-Antimycotic were placed in black, 384-well, microclear plates (Clear plates, Greiner bio-one, Kremsmunster, Austria). After 24 hours, small molecule compounds were added to each well prior to viral infection using an automated liquid handling system (Apricot Designs, Covina, CA). The final concentration of the test compound was 2.5 to 28.2 μM, and the concentration of DMSO was maintained at 0.5%. The compound-treated group was transferred to a BL-3 containment chamber and then infected with MERS-CoV at an MOI of 0.0625.

감염 후 24시간에 PFA를 사용 (최종 PAF 농도= 4%) 하여 감염을 고정하였다. 항-MERS-CoV spike 항체를 고정된 세포에 처리한 후 Alexa Fluor 488 goat anti-rabbit IgG 및 Hoechst 33342를 사용하여 염색하였다. 감염된 세포의 고정 및 염색 후 20x 배율의 형광 이미징 시스템 (Perkin Elmer Operetta, 20x,Waltham, MA) 상에서 이미지화하였다. 저분자 화합물이 처리된 세포의 MERS-CoV에 대한 감염률은 각 플레이트 상에 있는 음성대조군 (0% 감염억제율) 및 양성대조군 (100% 감염억제율)로 하여 환산되었고, 90% 이상의 억제효과를 야기하는 저분자 화합물이 동정되었다.The infection was fixed by using PFA (final PAF concentration = 4%) 24 hours after infection. After treatment with anti-MERS-CoV spike antibody, fixed cells were stained with Alexa Fluor 488 goat anti-rabbit IgG and Hoechst 33342. After fixation and staining of infected cells, they were imaged on a fluorescence imaging system (Perkin Elmer Operetta, 20x, Waltham, Mass.) at 20x magnification. The infection rate for MERS-CoV of cells treated with the small molecule compound was converted into a negative control group (0% infection inhibition rate) and a positive control group (100% infection inhibition rate) on each plate. The compound was identified.

<1-6> 유효 화합물의 농도-반응곡선 실험<1-6> Concentration-response curve experiment of active compound

화합물의 농도에 따른 바이러스 감염의 억제효과를 농도-반응곡선 실험을 통해 알 수 있다. 실험화합물의 최고농도를 5 mM로 하여 DMSO를 사용하여 2배 희석하여 10단계까지 연속적으로 희석한다. 이를 상기 <1-5> 와 같은 방법으로 준비된 세포에 처리한다. 실험화합물의 최종농도의 최고농도는 25 μM가 되었고, DMSO의 농도는 0.5%로 유지하였다. 화합물 처리군은 BL-3 봉쇄실로 옮긴 후, 0.0625 MOI의 MERS-CoV에 감염되었다. 감염 24시간 후 상기 <1-5> 와 동일한 방법으로 감염률을 이미지화하고 환산하였다. 농도반응곡선 실험으로 화합물의 50% 바이러스 억제농도 (Inhibitory concentration 50 ;IC50)와 50% 세포독성농도 (Cytotoxicity concentration; CC50)를 산출하였다.The inhibitory effect of virus infection according to the concentration of the compound can be known through the concentration-response curve experiment. With the highest concentration of the test compound at 5 mM, dilute two-fold with DMSO and serially dilute up to 10 steps. This is treated with the cells prepared in the same way as in <1-5> above. The maximum concentration of the final concentration of the test compound was 25 μM, and the concentration of DMSO was maintained at 0.5%. The compound-treated group was transferred to the BL-3 containment chamber and then infected with MERS-CoV at an MOI of 0.0625. 24 hours after infection, the infection rate was imaged and converted in the same manner as in <1-5>. 50% virus inhibitory concentration (Inhibitory concentration 50 ;IC 50 ) and 50% cytotoxicity concentration (CC 50 ) of the compound were calculated by concentration-response curve experiment.

바이러스의 감염률을 50%로 억제하는 화합물의 농도인 IC50값을 하기 표 1에 나타내었다.The IC 50 value, which is the concentration of the compound that inhibits the viral infection rate by 50%, is shown in Table 1 below.

Figure 112019099775854-pat00040
Figure 112019099775854-pat00040

Figure 112019099775854-pat00041
Figure 112019099775854-pat00041

Figure 112019099775854-pat00042
Figure 112019099775854-pat00042

상기 표 1에 나타난 바와 같이,As shown in Table 1 above,

본 발명의 일 측면에 따른 화합물은 MERS-CoV에 대한 항바이러스 억제활성이 우수하므로, 메르스 치료제로 사용될 수 있음을 알 수 있다.Since the compound according to one aspect of the present invention has excellent antiviral inhibitory activity against MERS-CoV, it can be seen that it can be used as a treatment for MERS.

이상의 설명은 본 발명을 예시적으로 설명한 것에 불과한 것으로, 본 발명이 속하는 기술분야에서 통상의 지식을 가지는 자라면 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 다양한 변형이 가능할 것이다. 따라서, 본 명세서에 개시된 실시 예들은 본 발명을 한정하기 위한 것이 아니라 설명하기 위한 것이고, 이러한 실시 예에 의하여 본 발명의 사상과 범위가 한정되는 것은 아니다.The above description is merely illustrative of the present invention, and various modifications will be possible without departing from the essential characteristics of the present invention by those skilled in the art to which the present invention pertains. Accordingly, the embodiments disclosed in the present specification are intended to illustrate, not to limit the present invention, and the spirit and scope of the present invention are not limited by these embodiments.

본 발명의 보호범위는 아래의 청구범위에 의하여 해석되어야 하며, 그와 동등한 범위 내에 있는 모든 기술은 본 발명의 권리범위에 포함하는 것으로 해석되어야 할 것이다.The protection scope of the present invention should be construed by the following claims, and all technologies within the scope equivalent thereto should be construed as being included in the scope of the present invention.

Claims (11)

삭제delete 삭제delete 삭제delete 삭제delete 하기 화학식 중 어느 하나로 표시되는 화합물
Figure 112021129667356-pat00048

Figure 112021129667356-pat00049
Figure 112021129667356-pat00050

Figure 112021129667356-pat00051
Figure 112021129667356-pat00052

Figure 112021129667356-pat00053
Figure 112021129667356-pat00054

Figure 112021129667356-pat00055
Figure 112021129667356-pat00056

Figure 112021129667356-pat00057

Figure 112021129667356-pat00059
Figure 112021129667356-pat00060

Figure 112021129667356-pat00061
Figure 112021129667356-pat00062

Figure 112021129667356-pat00063
Figure 112021129667356-pat00064

Figure 112021129667356-pat00065
Figure 112021129667356-pat00066

Figure 112021129667356-pat00067
Figure 112021129667356-pat00068
Figure 112021129667356-pat00069
Figure 112021129667356-pat00070

Figure 112021129667356-pat00071
Figure 112021129667356-pat00072

Figure 112021129667356-pat00073
Figure 112021129667356-pat00074

Figure 112021129667356-pat00075
Figure 112021129667356-pat00076

Figure 112021129667356-pat00077
Figure 112021129667356-pat00078

Figure 112021129667356-pat00079
Figure 112021129667356-pat00080

A compound represented by any one of the following formulas
Figure 112021129667356-pat00048

Figure 112021129667356-pat00049
Figure 112021129667356-pat00050

Figure 112021129667356-pat00051
Figure 112021129667356-pat00052

Figure 112021129667356-pat00053
Figure 112021129667356-pat00054

Figure 112021129667356-pat00055
Figure 112021129667356-pat00056

Figure 112021129667356-pat00057

Figure 112021129667356-pat00059
Figure 112021129667356-pat00060

Figure 112021129667356-pat00061
Figure 112021129667356-pat00062

Figure 112021129667356-pat00063
Figure 112021129667356-pat00064

Figure 112021129667356-pat00065
Figure 112021129667356-pat00066

Figure 112021129667356-pat00067
Figure 112021129667356-pat00068
Figure 112021129667356-pat00069
Figure 112021129667356-pat00070

Figure 112021129667356-pat00071
Figure 112021129667356-pat00072

Figure 112021129667356-pat00073
Figure 112021129667356-pat00074

Figure 112021129667356-pat00075
Figure 112021129667356-pat00076

Figure 112021129667356-pat00077
Figure 112021129667356-pat00078

Figure 112021129667356-pat00079
Figure 112021129667356-pat00080

 하기 화학식 3으로 표시되는 화합물 또는 이의 약제학적으로 허용되는 염을 유효성분으로 포함하는 항바이러스용 약학조성물
<화학식 3>
Figure 112021129667356-pat00081

{상기 화학식 3에서,
R1 는 C1-C6 알킬기; C6-C10의 아릴기; -(X)n-C6-C10의 아릴기; C3-C6의 사이클로알킬기; 또는 아세틸기; 로 이루어진 군에서 선택되고,
R4는 할로겐; OH; CN; NO2; C1-C6의 알콕시기; 아세틸기; 및 불소가 치환된 C1-C6의 알킬기;로 이루어진 군에서 선택되고,
b는 0 내지 5 중 어느 하나의 정수이며,
X는 -CH2; 카보닐(C=O); 또는 -C(=O)-CH=CH-;이며, n은 0 또는 1이고,
상기 알킬기 및 아릴기는 중수소; 할로겐; OH; 시아노기; 니트로기; -C(=O)-(C1-C6 알킬)기; C(=O)NH2; 및 C1-C6 알콕시기;로 이루어진 군에서 선택된 하나 이상의 치환기로 더욱 치환될 수 있다.}
Antiviral pharmaceutical composition comprising a compound represented by the following formula (3) or a pharmaceutically acceptable salt thereof as an active ingredient
<Formula 3>
Figure 112021129667356-pat00081

{In Formula 3,
R 1 is a C 1 -C 6 alkyl group; C 6 -C 10 aryl group; -(X) an aryl group of n -C 6 -C 10 ; C 3 -C 6 cycloalkyl group; or an acetyl group; is selected from the group consisting of
R 4 is halogen; OH; CN; NO 2 ; C 1 -C 6 Alkoxy group; acetyl group; and a fluorine-substituted C 1 -C 6 alkyl group; selected from the group consisting of,
b is an integer of any one of 0 to 5,
X is -CH 2 ; carbonyl (C=O); or -C(=O)-CH=CH-; n is 0 or 1,
The alkyl group and the aryl group are deuterium; halogen; OH; cyano group; nitro group; -C(=O)-(C 1 -C 6 alkyl) group; C(=O)NH 2 ; And C 1 -C 6 alkoxy group; may be further substituted with one or more substituents selected from the group consisting of.}
 제6항에 있어서, 상기 바이러스는 코로나 바이러스인 것을 특징으로 하는 약학조성물
7. The pharmaceutical composition according to claim 6, wherein the virus is a corona virus.
 제 7항에 있어서, 상기 코로나 바이러스는 중동호흡기증후군(메르스(MERS)) 인 것을 특징으로 하는 약학조성물
The pharmaceutical composition according to claim 7, wherein the coronavirus is Middle East Respiratory Syndrome (MERS).
 제6항에 있어서, 약학적으로 허용가능한 담체 하나 이상을 더 포함하는 것을 특징으로 하는 약학 조성물.
7. The pharmaceutical composition according to claim 6, further comprising at least one pharmaceutically acceptable carrier.
 제6항에 있어서, 항바이러스제 하나 이상을 더 포함하는 것을 특징으로 하는 약학적 조성물.
The pharmaceutical composition according to claim 6, further comprising at least one antiviral agent.
 제6항에 따른 화합물 또는 이의 식품학적으로 허용되는 염을 유효성분으로 포함하는 바이러스 감염증 예방 및 개선용 건강식품조성물

A health food composition for preventing and improving viral infection comprising the compound according to claim 6 or a pharmaceutically acceptable salt thereof as an active ingredient
KR1020190120648A 2019-09-30 2019-09-30 4-amino-quinazoline derivatives and antiviral composition comprising the same KR102397359B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1020190120648A KR102397359B1 (en) 2019-09-30 2019-09-30 4-amino-quinazoline derivatives and antiviral composition comprising the same

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
KR1020190120648A KR102397359B1 (en) 2019-09-30 2019-09-30 4-amino-quinazoline derivatives and antiviral composition comprising the same

Publications (2)

Publication Number Publication Date
KR20210038042A KR20210038042A (en) 2021-04-07
KR102397359B1 true KR102397359B1 (en) 2022-05-11

Family

ID=75469325

Family Applications (1)

Application Number Title Priority Date Filing Date
KR1020190120648A KR102397359B1 (en) 2019-09-30 2019-09-30 4-amino-quinazoline derivatives and antiviral composition comprising the same

Country Status (1)

Country Link
KR (1) KR102397359B1 (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006039718A2 (en) 2004-10-01 2006-04-13 Amgen Inc Aryl nitrogen-containing bicyclic compounds and their use as kinase inhibitors

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1956966B (en) * 2004-02-19 2012-04-18 雷克斯安公司 Quinazoline derivatives and therapeutic use thereof
KR101990669B1 (en) 2016-05-31 2019-06-19 전남대학교산학협력단 Quinazoline derivatives, preparation method thereof and pharmaceutical composition for treating influenza virus containing the same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006039718A2 (en) 2004-10-01 2006-04-13 Amgen Inc Aryl nitrogen-containing bicyclic compounds and their use as kinase inhibitors

Also Published As

Publication number Publication date
KR20210038042A (en) 2021-04-07

Similar Documents

Publication Publication Date Title
US8466290B2 (en) STAT3 inhibitor containing quinolinecarboxamide derivative as active ingredient
TWI473792B (en) New quinoline compounds and their use
US20050288307A1 (en) Anti-viral compounds
JP4294960B2 (en) Cyclin-dependent kinase inhibitors as anticancer agents
RU2712196C2 (en) Pyrazolo[1,5-a]triazin-4-amine derivatives applicable in therapy
RU2744168C1 (en) New pyrimidine derivative with an effect of inhibiting growth of cancer cells and pharmaceutical composition containing it
WO2014040549A1 (en) Alkynyl heteroaromatic ring compound and application thereof
RU2689788C2 (en) Pyrazolo[1,5-a]pyrimidines as antiviral compounds
AU2002249389A1 (en) Inhibitors of cyclin dependent kinases as anti-cancer agent
JP6795518B2 (en) Compositions and Methods of Inhibiting Kinases
WO2014082578A1 (en) Heteroaryl alkyne compound and application thereof
CN114555588A (en) Quinazolines as AXL inhibitors
WO2020135507A1 (en) Polysubstituted anilinopyrimidine derivative and preparation method and application thereof
WO2008086730A1 (en) Tetrahydroquinazoline compounds and their use in preparing medicaments for treating and preventing virosis
WO2020221006A1 (en) Bet inhibitor, and preparation method and use thereof
CN107459496B (en) Use of thiazole derivatives for treating viral infections
KR20210143131A (en) 2-Aminoquinazoline derivatives and antiviral composition comrising the same
CN113880772A (en) CDK kinase inhibitor and application thereof
WO2022005961A1 (en) Prpk inhibitors
KR102397359B1 (en) 4-amino-quinazoline derivatives and antiviral composition comprising the same
CN111875583B (en) Triazole derivative and preparation method and application thereof
JP3354258B2 (en) New indoles or their salts
KR102456293B1 (en) Cyclic sulfonamide derivatives and antiviral composition comprising the same
KR102188708B1 (en) 2-phenylchroman-4-one derivatives and antiviral composition comprising the same
KR20230174613A (en) Quinolone derivatives, pharmaceutically acceptable salt thereof, and antibiral composition containing the same as an active ingredient

Legal Events

Date Code Title Description
E902 Notification of reason for refusal
E701 Decision to grant or registration of patent right
GRNT Written decision to grant