KR20180088318A - Fused pyrimidine derivative as multi-kinase inhibitor - Google Patents
Fused pyrimidine derivative as multi-kinase inhibitor Download PDFInfo
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Abstract
Description
본 발명은 다중 표적 키나아제 저해제로서 유용한 융합피리미딘 유도체, 이의 약제학적으로 허용 가능한 염 또는 입체이성질체, 및 이를 약리학적 유효량으로 포함하는 암 또는 면역 관련 질환의 예방 또는 치료용 약제학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for the prevention or treatment of fungal pyrimidine derivatives useful as multiple target kinase inhibitors, pharmaceutically acceptable salts or stereoisomers thereof, and cancer or immune related diseases comprising the same in a pharmacologically effective amount.
키나아제는 ATP(adenosine triphosphate)의 감마 위치 인산기를 특정 기질에 전달하는 인산화 반응을 촉매하는 효소이다. 키나아제는 세포증식, 생존, 세포사멸, 대사, 전사 등의 생체신호전달에 폭넓게 관여한다. 지금까지 저분자 키나아제 저해제를 이용하여 암, 자가면역질환, 대사성 질환 등을 치료할 수 있는 것으로 알려져 있으며, 일부 키나아제 저해제들이 치료제로 승인되었거나 개발 중이다. (Trends of Pharmacological Sciences 2014, 35, 604-620. Advances in kinase targeting: current clinical use and clinical trials)Kinase is an enzyme that catalyzes the phosphorylation of ATP (adenosine triphosphate), which transfers the gamma position phosphate group to a specific substrate. Kinase is widely involved in cell signaling, cell survival, cell death, metabolism, and transcription. So far, it has been known that low-molecular kinase inhibitors can treat cancer, autoimmune diseases, metabolic diseases, etc., and some kinase inhibitors have been approved or under development. (Trends of Pharmacological Sciences 2014, 35, 604-620. Advances in kinase targeting: current clinical use and clinical trials)
TEC family에 속하는 BTK, BMX 키나아제는 비-수용체 타이로신 키나아제에 속하며, 이들 키나아제는 면역세포 신호전달에 중요한 역할을 한다. 따라서, 이들 키나아제를 효과적으로 억제함으로써 자가면역질환 및 암의 치료에 적용할 수 있다. (Nature Reviews Immunology, 2005, 5, 284-295. TEC-FAMILY KINASES: REGULATORS OF T-HELPER-CELL DIFFERENTIATION)BTK and BMX kinases belonging to the TEC family belong to non-receptor tyrosine kinases, and these kinases play important roles in immune cell signaling. Thus, by effectively inhibiting these kinases, they can be applied to the treatment of autoimmune diseases and cancer. (Nature Reviews Immunology, 2005, 5, 284-295. TEC-FAMILY KINASES: REGULATORS OF T-HELPER-CELL DIFFERENTIATION)
JAK3 키나아제는 비-수용체 타이로신 키나아제에 속하며 면역반응에 관여하는 싸이토카인을 분비한다. 따라서, JAK3 키나아제를 저해함으로써 자가면역질환 치료에 적용할 수 있다. (Current Opinion in Investigational Drugs 2003, 4(11), 1297-1303. JAK3 inhibition as a new concept for immune suppression)JAK3 kinase belongs to the non-receptor tyrosine kinase and secretes cytokines involved in the immune response. Therefore, it can be applied to the treatment of autoimmune diseases by inhibiting JAK3 kinase. (Current Opinion in Investigational Drugs 2003, 4 (11), 1297-1303. JAK3 inhibition as a new concept for immune suppression)
면역 세포 신호전달은 서로가 상호 네트워크를 통해 이루어지기 때문에 특정 신호전달에 관여하는 키나아제만 억제할 경우 다른 경로를 통해 면역 세포 신호전달이 활성화될 수 있다. 따라서 면역 세포 신호 전달에 관여하는 여러 개의 키나아제를 동시에 억제할 경우 자가 면역 질환이나 암치료에 보다 효과적일 수 있다.Since immune cell signaling is made through mutual networks, immune cell signaling can be activated through other pathways if only kinases involved in specific signal transduction are inhibited. Therefore, simultaneous inhibition of several kinases involved in immune cell signaling may be more effective in treating autoimmune diseases and cancer.
이에 본 발명의 목적은 암 및 면역 관련 질환의 치료에 적용할 수 있는 다중 표적 키나아제 저해제로서 융합 피리미딘 유도체, 이의 약제학적으로 허용 가능한 염 또는 입체이성질체를 제공하는 것이다.It is an object of the present invention to provide a fused pyrimidine derivative, a pharmaceutically acceptable salt or a stereoisomer thereof as a multi-target kinase inhibitor applicable to the treatment of cancer and immune-related diseases.
또한, 본 발명의 다른 목적은 상기 융합 피리미딘 유도체, 이의 약제학적으로 허용 가능한 염 또는 입체이성질체를 유효성분으로 포함하는 암 또는 면역 관련 질환의 예방 또는 치료용 약제학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating a cancer or immune-related disease comprising the fused pyrimidine derivative, a pharmaceutically acceptable salt or a stereoisomer thereof as an active ingredient.
본 발명자들은 상기 기술된 BTK, BMX 및 JAK3 키나아제를 동시에 억제할 수 있는 다중 표적 키나아제 저해제인 융합 피리미딘 유도체를 합성하였고, 이를 질환 모델 동물시험을 통해 확인함으로써 본 발명을 완성하였다.The present inventors synthesized fused pyrimidine derivatives, which are multi-target kinase inhibitors capable of simultaneously inhibiting the above-described BTK, BMX and JAK3 kinases, and confirmed the disease model animal test to complete the present invention.
이하에서 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 하기 화학식 1의 화합물 및 이의 약제학적으로 허용 가능한 염 또는 입체이성질체를 제공한다:The present invention provides a compound of formula 1 < EMI ID = 2.1 > and pharmaceutically acceptable salts or stereoisomers thereof:
[화학식 1][Chemical Formula 1]
상기 식에서,In this formula,
X는 직접결합, O, NH, C(=O) 또는 헤테로사이클로알킬이고; X is a direct bond, O, NH, C (= O) or heterocycloalkyl;
Y는 알콕시알킬, 헤테로사이클로알킬 또는 헤테로사이클로알킬알킬이며;Y is alkoxyalkyl, heterocycloalkyl or heterocycloalkylalkyl;
W는 O 또는 NH이고;W is O or NH;
Z는
또는 이며;Z is or ;R1은 수소, 알콕시 또는 할로겐이고;R < 1 > is hydrogen, alkoxy or halogen;
R2는 수소 또는 다이알킬아미노알킬이다.R < 2 > is hydrogen or dialkylaminoalkyl.
본원에서 용어 "알킬"은 단독으로 사용되는 경우 또는 그 밖에 추가적인 용어와의 조합으로 사용되는 경우(예를 들면, 알콕시) 직쇄형 또는 측쇄형의 바람직하게는 1개 내지 6개의 탄소 원자를 갖는 포화된 지방족 탄화수소 군의 라디칼을 의미한다.The term "alkyl" as used herein, when used alone or in combination with any other term (e. G., Alkoxy) means a straight or branched saturated, preferably saturated, Quot; means a radical of a group of aliphatic hydrocarbons.
본원에서 용어 "할로겐"은 F, Cl, Br 또는 I인 라디칼을 의미한다.The term "halogen" as used herein means a radical of F, Cl, Br or I.
본원에서 용어 "헤테로사이클로알킬"은 바람직하게는 N, O, S, Si 및 P로 이루어진 그룹으로부터 선택되는 1 내지 4개의 헤테로원자를 갖는 5 내지 10원의 포화 모노사이클릭 또는 바이사이클릭 환을 의미하고, 구체적인 예로는 피롤리딘(pyrrolidine), 피페리딘(piperidine), 테트라하이드로퓨란(tetrahydrofuran), 1,4-아자실란(1,4-azasilinane), 테트라하이드로피란 (tetrahydropyran), 몰포린(morpholine), 피페라진(piperazine), 1,4-아자포스피난(1,4-azaphosphinane) 및 2,7-다이아자스파이로[3.5]노네인(2,7-diazaspiro[3.5]nonane)을 포함하나 이에 제한되는 것은 아니다.The term "heterocycloalkyl" as used herein refers to a saturated 5- or 10-membered monocyclic or bicyclic ring having 1 to 4 heteroatoms, preferably selected from the group consisting of N, O, S, Si and P And specific examples thereof include pyrrolidine, piperidine, tetrahydrofuran, 1,4-azasilinane, tetrahydropyran, morpholine, piperazine, 1,4-azaphosphinane, and 2,7-diazaspiro [3.5] nonane, as well as 2,7-diazaspiro [3.5] But is not limited thereto.
본 발명에 따른 화합물들은 비대칭 탄소중심과 비대칭축 또는 비대칭평면을 가질 수 있으므로 E 또는 Z 이성질체, R 또는 S 이성질체, 라세미체 등의 입체이성질체로서 존재할 수 있으며, 이들 모든 이성질체 및 혼합물은 본 발명의 범위에 포함된다.The compounds according to the present invention may have asymmetric centers or asymmetric planes with an asymmetric carbon center and thus may exist as stereoisomers such as E or Z isomers, R or S isomers, racemates, and the like, ≪ / RTI >
본 발명의 일 측면에 따르면, 상기 화학식 1에서 X가 직접결합, O, NH, C(=O), 또는 N, O 및 S로부터 선택되는 1 내지 3개의 헤테로원자를 갖는 5 내지 10원 헤테로사이클로알킬이다.According to one aspect of the present invention there is provided a compound of formula I wherein X is a direct bond, O, NH, C (= O), or 5-10 membered heterocycle having 1 to 3 heteroatoms selected from N, Alkyl.
본 발명의 다른 측면에 따르면, 상기 화학식 1에서 X가 직접결합, O, NH, C(=O), 또는 1 또는 2개의 N 원자를 갖는 5 또는 6원 헤테로사이클로알킬이다.According to another aspect of the present invention, in Formula 1, X is a direct bond, O, NH, C (= O), or 5 or 6 membered heterocycloalkyl having 1 or 2 N atoms.
본 발명의 다른 측면에 따르면, 상기 화학식 1에서 Y가 C1-C6-알콕시-C1-C6-알킬, 5 내지 10원 헤테로사이클로알킬 또는 5 내지 10원 헤테로사이클로알킬-C1-C6-알킬이고, 여기에서 헤테로사이클로알킬은 N, O, S, Si 및 P로부터 선택되는 1 내지 4개의 헤테로원자를 갖고, 비치환되거나 C1-C6-알킬, 옥소, C1-C6-알킬카보닐, 아미노카보닐, 할로겐, C1-C6-알콕시-C1-C6-알킬 및 다이(C1-C6-알킬)아미노-C1-C6-알킬카보닐로 이루어지는 그룹으로부터 선택되는 하나 이상의 치환기로 치환되는 모노사이클릭 또는 바이사이클릭 화합물이다.According to another aspect of the present invention there is provided a compound of formula I wherein Y is C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, 5- to 10-membered heterocycloalkyl or 5- to 10-membered heterocycloalkyl-C 1 -C 6 -alkyl, wherein heterocycloalkyl has 1 to 4 heteroatoms selected from N, O, S, Si and P and is unsubstituted or substituted by C 1 -C 6 -alkyl, oxo, C 1 -C 6 (C 1 -C 6 -alkyl) amino-C 1 -C 6 -alkylcarbonyl which is optionally substituted by one or more substituents selected from the group consisting of halogen, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl and di Lt; / RTI > is a monocyclic or bicyclic compound substituted with one or more substituents selected from the group consisting of < RTI ID = 0.0 >
본 발명의 다른 측면에 따르면, 상기 화학식 1에서 Y가 C1-C6-알콕시-C1-C6-알킬, 5 내지 10원 헤테로사이클로알킬, 또는 5 또는 6원 헤테로사이클로알킬-C1-C6-알킬이고, 여기에서 헤테로사이클로알킬은 N, O, S, Si 및 P로부터 선택되는 1 내지 3개의 헤테로원자를 갖고, 비치환되거나 C1-C6-알킬, 옥소, C1-C6-알킬카보닐, 아미노카보닐, 할로겐, C1-C6-알콕시-C1-C6-알킬 및 다이(C1-C6-알킬)아미노-C1-C6-알킬카보닐로 이루어지는 그룹으로부터 선택되는 1 내지 3개의 치환기로 치환되는 모노사이클릭 또는 바이사이클릭 화합물이다.According to another aspect of the invention, Y is In Formula 1 C 1 -C 6 - alkoxy -C 1 -C 6 - alkyl, 5 to 10 membered heterocycloalkyl, or 5 or 6-membered heterocycloalkyl -C 1 - an alkyl, heterocycloalkyl here are N, O, S, Si, and has from 1 to 3 heteroatoms selected from P, unsubstituted or C 1 -C 6 - - C 6 alkyl, oxo, C 1 -C 6 - alkylcarbonyl-alkyl-carbonyl, aminocarbonyl, halogen, C 1 -C 6 - alkoxy -C 1 -C 6 -alkyl and di (C 1 -C 6 - alkyl) amino -C 1 -C 6 Or a monocyclic or bicyclic compound substituted with 1 to 3 substituents selected from the group consisting of
본 발명의 다른 측면에 따르면, 상기 화학식 1에서 R1은 수소, C1-C6-알콕시 또는 할로겐이고; R2는 수소 또는 다이(C1-C6-알킬)아미노-C1-C6-알킬이다.According to another aspect of the present invention, R 1 in the general formula ( 1) is hydrogen, C 1 -C 6 -alkoxy or halogen; R 2 is hydrogen or di (C 1 -C 6 -alkyl) amino-C 1 -C 6 -alkyl.
본 발명에 따른 화학식 1의 화합물의 대표적인 것에는 다음의 것이 포함된다:Representative compounds of formula (1) according to the present invention include:
N-(3-((2-((4-(4-(피롤리딘-1-일)피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((4- (4- ( pyrrolidin-1-yl) piperidin-1-yl) phenyl) amino) -6,7-dihydro-furnace to thieno [3, D ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-((테트라하이드로퓨란-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((4 - ((tetrahydrofuran-3-yl) oxy) phenyl) amino) -6,7- dihydrosothieno [3,2- d ] pyrimidin- Yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(1-메틸피페리딘-4-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((4- (1- methylpiperidin-4-yl) phenyl) amino) -6,7-dihydro-furnace to Im [3,2- d] pyrimidin -4 Yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(1-에틸피페리딘-4-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((4- (1- ethyl-4-yl) phenyl) amino) -6,7-dihydro-Im in the furnace [3,2- d] pyrimidin -4 Yl) oxy) phenyl) acrylamide;
(R)-N-(3-((2-((4-((1-메틸피롤리딘-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; (R) - N - (3 - ((2 - ((4 - ((1- methyl-pyrrolidin-3-yl) oxy) phenyl) amino) -6,7-dihydro-to Im [3,2 - d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
(S)-N-(3-((2-((4-((1-메틸피롤리딘-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; (S) - N - (3 - ((2 - ((4 - ((1- methyl-pyrrolidin-3-yl) oxy) phenyl) amino) -6,7-dihydro-to Im [3,2 - d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-((1-메틸피페리딘-4-일)아미노)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((4 - ((1- methylpiperidin-4-yl) amino) phenyl) amino) -6,7-dihydro-furnace to Im [3,2- d] pyrimidin 4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(2-(4,4-다이메틸-1,4-아자실란-1-일)에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((4- (2- (4,4-Dimethyl-1, 4-azacsilan-1-yl) ethoxy) phenyl) amino) -6, 7-dihydrothiazole Ethano [3,2- d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((3-플루오로-4-몰포리노페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((3- to 4-Dimorpholino Reno) amino) -6,7-dihydro-Im in no-fluoro [3,2- d] pyrimidin-4-yl) oxy) Phenyl) acrylamide;
N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((4- (4- methylpiperazin-1-yl) phenyl) amino) -6,7-dihydro-furnace to Im [3,2- d] pyrimidin-4 Yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)에탄설폰아마이드; N - (3 - ((2 - ((4- (4- methylpiperazin-1-yl) phenyl) amino) -6,7-dihydro-furnace to Im [3,2- d] pyrimidin-4 Yl) oxy) phenyl) ethanesulfonamide;
N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)아크릴아마이드; N - (3 - ((2 - ((4- (4- methylpiperazin-1-yl) phenyl) amino) -6,7-dihydro-furnace to Im [3,2- d] pyrimidin-4 Yl) amino) phenyl) acrylamide;
N-(3-((2-((4-(4-메틸-4-옥시도-1,4-아자포스피난-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2- ((4- (4-methyl-4-oxido-1,4-azaphosphinan-1-yl) phenyl) amino) -6,7- dihydrosothieno [ D ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((2-메톡시-4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((2- methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7-dihydro-Im in the furnace [3,2- d] Pyrimidin-4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-((1-메틸피페리딘-4-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((4 - ((1- methylpiperidin-4-yl) oxy) phenyl) amino) -6,7-dihydro-Im in the furnace [3,2- d] pyrimidin 4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(2-메톡시에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((4- (2- methoxyethoxy) phenyl) amino) -6,7-dihydro furnace to Im [3,2- d] pyrimidin-4-yl) oxy ) Phenyl) acrylamide;
N-(3-((2-((4-(4-에틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((4- (4- ethyl-piperazin-1-yl) phenyl) amino) -6,7-dihydro-furnace to Im [3,2- d] pyrimidin-4 Yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(4-아이소프로필피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((4- (4- isopropyl-piperazin-1-yl) phenyl) amino) -6,7-dihydro-furnace to Im [3,2- d] pyrimidin -4 Yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(4-아세틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((4- (4- acetyl-piperazin-1-yl) phenyl) amino) -6,7-dihydro-furnace to Im [3,2- d] pyrimidin-4 Yl) oxy) phenyl) acrylamide;
(S)-1-(4-((4-(3-아크릴아미도페녹시)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-2-일)아미노)페닐)피롤리딘-2-카르복사마이드; (S) -1- (4 - ((4- (3-acrylamidophenoxy) -6,7-dihydrothieno [3,2- d ] pyrimidin- Pyrrolidine-2-carboxamide;
N-(3-((2-((4-(2-아세틸-2,7-다이아자스파이로[3.5]노네인-7-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((4- (2- acetyl-2,7-diaza-Spy to [3.5] nonane-7-yl) phenyl) amino) -6,7-dihydro-Im in the furnace [3,2- d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-몰폴리노페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((4- morpholinophenyl) amino) -6,7-dihydro-furnace to Im [3,2- d] pyrimidin-4-yl) oxy) phenyl) acrylamide ;
N-(3-((2-((4-(피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((4- ( piperidin-1-yl) phenyl) amino) -6,7-dihydro-Im in the furnace [3,2- d] pyrimidin-4-yl) Oxy) phenyl) acrylamide;
N-(3-((2-((4-(4,4-다이플루오로피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((4- ( piperidin-1-yl) 4,4-difluorophenyl) amino) -6,7-dihydro-Im in the furnace [3,2- d] Pyrimidin-4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(1-아세틸피페리딘-4-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((4- (1-acetylpiperidin-4- yl) oxy) phenyl) amino) -6,7- dihydrosothieno [3,2- d ] pyrimidine Yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(4-(2-메톡시에틸)피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((4- (4- (2- methoxyethyl) piperazin-1-yl) phenyl) amino) -6,7-dihydro-Im in the furnace [3,2- d ] Pyrimidin-4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(2-몰포리노에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((4- (2- Dimorpholino Reno ethoxy) phenyl) amino) -6,7-dihydro furnace to Im [3,2- d] pyrimidin-4-yl) oxy ) Phenyl) acrylamide;
N-(3-((2-((4-(4-(2-(다이메틸아미노)아세틸)피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2 - ((4- (4- (2- ( dimethylamino) acetyl) piperazin-1-yl) phenyl) amino) -6,7-dihydro-furnace to thieno [3, D ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
N-(3-((2-((4-(4-메틸피페라진-1-카보닐)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]미리미딘-4-일)옥시)페닐)아크릴아마이드; N - (3 - ((2- ((4- (4-methylpiperazine-1-carbonyl) phenyl) amino) -6,7-dihydrosothieno [3,2- d ] Yl) oxy) phenyl) acrylamide;
(E)-4-(다이메틸아미노)-N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-5,6-다이하이드로싸이에노[2,3-d]피리미딘-4-일)옥시)페닐)뷰트-2-엔아마이드; 및 (E) -4- (dimethylamino) - N - (3 - ( (2 - ((4- (4- methylpiperazin-1-yl) phenyl) amino) 5,6-dihydro-Im in the furnace [2,3- d ] pyrimidin-4-yl) oxy) phenyl) but-2-enamide; And
(E)-4-(다이메틸아미노)-N-(3-((2-((4-몰폴리노페닐)아미노)-5,6-다이하이드로싸이에노[2,3-d]피리미딘-4-일)옥시)페닐)뷰트-2-엔아마이드. (E) -4- (dimethylamino) - N - (3 - ( (2 - ((4- morpholinophenyl) amino) -5,6-dihydro furnace to Im [2,3- d] pyrimidin Yl) oxy) phenyl) but-2-enamide.
본 발명에 따른 상기 화학식 1의 화합물은 하기 반응식 1의 대표적으로 도시된 방법에 의해 제조될 수 있다:The compounds of formula (I) according to the present invention can be prepared by the process illustrated by the following scheme:
[반응식 1][Reaction Scheme 1]
상기 반응식에서,In the above reaction formula,
X, Y, W, R1 및 R2는 상기 화학식 1에서 정의된 바와 같고, Z는 OH 또는 Cl이다.X, Y, W, R 1 and R 2 are as defined in Formula 1, and Z is OH or Cl.
상기 반응식 1에서, 화합물 8을 탄산칼륨 존재하에 N,N-다이메틸폼아마이드/아세톤 용매에서 화합물 7과 반응하여 중간체 6을 얻는다. 이어서, 팔라듐 촉매를 이용한 수소반응을 통하여 중간체 5를 얻는다. 그 다음으로, 중간체 5와 화합물 4의 축합반응을 통하여 중간체 3을 얻는다. 이어서, 트라이플루오로아세트산 존재하에 2-부탄올 용매에서 화합물 2와 반응하여 화학식 1의 화합물을 얻을 수 있다.In Scheme 1 above, Compound 8 is reacted with Compound 7 in a N , N -dimethylformamide / acetone solvent in the presence of potassium carbonate to afford Intermediate 6. Subsequently, intermediate 5 is obtained through a hydrogen reaction using a palladium catalyst. Next, the intermediate 3 is obtained through the condensation reaction of the intermediate 5 and the compound 4. The compound of formula 1 may then be reacted with compound 2 in a 2-butanol solvent in the presence of trifluoroacetic acid.
본 발명에 따른 화학식 1의 화합물은 무기산 또는 유기산으로 유도된 약제학적으로 허용 가능한 염 형태로 사용될 수 있으며, 이 경우 바람직한 염으로는 염산, 브롬화수소산, 황산, 인산, 질산, 아세트산, 글리콜산, 락트산, 피루브산, 말론산, 석신산, 글루타르산, 푸마르산, 말산, 만델산, 타르타르산, 시트르산, 아스코르브산, 팔미트산, 말레산, 벤조산, 하이드록시벤조산, 페닐아세트산, 신남산, 살리실산, 메탄설폰산, 에탄설폰산, 벤젠설폰산 또는 톨루엔설폰산 등으로부터 유도된 염을 들 수 있으나 이에 제한되는 것은 아니다.The compound of formula (I) according to the present invention may be used in the form of a pharmaceutically acceptable salt derived from an inorganic or organic acid. Preferred salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid , Pyruvic acid, malonic acid, succinic acid, glutaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, But are not limited to, salts derived from sulfonic acid, sulfonic acid, sulfonic acid, benzenesulfonic acid, or toluenesulfonic acid.
본 발명에 따른 화학식 1의 화합물, 이의 약제학적으로 허용 가능한 염 또는 입체이성질체는 BTK, BMX 및 JAK3 키나아제를 효과적으로 억제한다.The compounds of formula I according to the invention, their pharmaceutically acceptable salts or stereoisomers effectively inhibit BTK, BMX and JAK3 kinase.
이에, 본 발명은 유효성분으로서 화학식 1의 화합물, 이의 약제학적으로 허용 가능한 염 또는 입체이성질체를 포함하는, 암 또는 면역 관련 질환의 예방 또는 치료용 약제학적 조성물을 제공한다. 상기 암은 예를 들면, B-세포 림프종, 췌장암, 전립선암, 대장암, 위암 등이 있으나 이에 제한되지는 않는다. 상기 면역 관련 질환은 예를 들면, 류마티스 관절염, 쇼그렌 증후군, 건선, 전신 홍반 루푸스, 아토피, 천식, 다발성 경화증 등이 있으나 이에 제한되지는 않는다.Accordingly, the present invention provides a pharmaceutical composition for preventing or treating a cancer or an immune-related disease, comprising the compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof as an active ingredient. Such cancer includes, but is not limited to, for example, B-cell lymphoma, pancreatic cancer, prostate cancer, colon cancer, stomach cancer and the like. Such immune related diseases include, but are not limited to, rheumatoid arthritis, Sjogren's syndrome, psoriasis, systemic lupus erythematosus, atopy, asthma, multiple sclerosis and the like.
구체적으로 본 발명의 약제학적 조성물은 통상적인 방법에 따라 제제화 될 수 있으며, 정제, 환제, 산제, 캅셀제, 시럽, 에멀젼, 마이크로에멀젼 등의 다양한 경구 투여 형태로, 또는 근육내, 정맥내 또는 피하투여와 같은 비경구 투여 형태로 제조될 수 있다.Specifically, the pharmaceutical composition of the present invention may be formulated according to a conventional method, and may be formulated into various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions and microemulsions, or intramuscularly, intravenously or subcutaneously , ≪ / RTI > and the like.
본 발명의 약제학적 조성물이 경구 제형의 형태로 제조되는 경우, 사용되는 담체의 예로는 셀룰로오스, 규산칼슘, 락토스, 덱스트로스, 옥수수전분, 수크로스, 인산칼슘, 스테아르산, 스테아르산 마그네슘, 스테아르산 칼슘, 젤라틴, 탈크, 계면활성제, 유화제, 현탁제, 희석제 등을 들 수 있다. 본 발명의 약제학적 조성물이 주사제의 형태로 제조되는 경우, 상기 담체로는, 예를 들면 물, 식염수, 포도당 수용액, 유사 당 수용액, 알코올, 글리콜, 에테르(예: 폴리에틸렌글리콜 400), 오일, 지방산, 지방산에스테르, 글리세라이드, 계면활성제, 현탁제, 유화제 등을 사용할 수 있다.When the pharmaceutical composition of the present invention is prepared in the form of an oral dosage form, examples of the carrier to be used include cellulose, calcium silicate, lactose, dextrose, corn starch, sucrose, calcium phosphate, stearic acid, magnesium stearate, stearic acid Calcium, gelatin, talc, surfactants, emulsifiers, suspending agents, diluents and the like. When the pharmaceutical composition of the present invention is prepared in the form of an injection, examples of the carrier include water, saline solution, glucose aqueous solution, pseudosaccharide solution, alcohol, glycol, ether (e.g., polyethylene glycol 400) , Fatty acid esters, glycerides, surfactants, suspending agents, and emulsifiers.
본 발명에 따르면 BTK, BMX 및 JAK3 키나아제를 효과적으로 억제할 수 있는 신규한 융합 피리미딘 유도체가 제공될 수 있다. 따라서, 본 발명에 따른 융합 피리미딘 유도체, 이의 약제학적으로 허용 가능한 염 또는 입체이성질체는 상기 키나아제의 활성화에 의해 유발되는 암 또는 면역 관련 질환의 예방 또는 치료에 효과적으로 이용할 수 있다.According to the present invention, novel fused pyrimidine derivatives capable of effectively inhibiting BTK, BMX and JAK3 kinase can be provided. Accordingly, the fused pyrimidine derivatives, pharmaceutically acceptable salts or stereoisomers thereof according to the present invention can be effectively used for the prevention or treatment of cancer or immune-related diseases caused by activation of the kinase.
도 1은 콜라겐으로 유도한 마우스 관절염(CIA, collagen-induced arthritis) 모델에서 실시예 3의 화합물의 경구투여에 따른 관절염 스코어의 변화를 나타낸 그래프이다.FIG. 1 is a graph showing changes in arthritis score according to oral administration of the compound of Example 3 in a collagen-induced CIA (collagen-induced arthritis) model. FIG.
이하에서 본 발명을 실시예에 의해 상세히 설명한다. 다만 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.
제조예: Preparation Example: NN -(3-((2-클로로-6,7-다이하이드로싸이에노[3,2-- (3 - ((2-chloro-6,7-dihydrosothieno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
단계 1: 2-클로로-4-(3-나이트로페녹시)-6,7-다이하이드로싸이에노[3,2-Step 1: 2-Chloro-4- (3-nitrophenoxy) -6,7-dihydrosothieno [3,2- dd ]피리미딘의 제조] Pyrimidine
2,4-다이클로로-6,7-다이하이드로싸이에노[3,2-d]피리미딘(100 g, 0.48 mol)과 3-나이트로페놀(67.2 g, 0.48 mol)을 아세톤/N,N-다이메틸폼아마이드 혼합 용매(3:1, 2L)에 용해시킨 후, 탄산칼륨 (133.5 g, 0.96 mol)을 가하고 상온에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물에 증류수를 가하여 고체를 생성시킨 후, 여과하고 증류수로 세척하였다. 얻어진 고체를 n-헥산/다이클로로메탄 혼합 용매(1:10, 2L)에 트리튜레이션(trituration)하여 여과하고 건조하여 표제화합물 (146 g, 98%)을 얻었다.2,4-dichloro-6,7-dihydro-Im in the furnace [3,2- d] pyrimidine (100 g, 0.48 mol) and 3-nitro phenol (67.2 g, 0.48 mol) in acetone / N, N -dimethylformamide (3: 1, 2 L), potassium carbonate (133.5 g, 0.96 mol) was added, and the mixture was stirred at room temperature for 12 hours. When the reaction was completed, distilled water was added to the reaction mixture to form a solid, which was then filtered and washed with distilled water. The resulting solid was triturated with a mixed solvent of n -hexane / dichloromethane (1:10, 2 L), filtered and dried to give the title compound (146 g, 98%).
1H NMR (400 MHz, DMSO-d 6 ) 8.20 - 8.18 (m, 2H), 7.79 - 7.78 (m, 2H), 3.57 - 3.52 (m, 2H), 3.44 - 3.39 (m, 2H) 1 H NMR (400 MHz, DMSO- d 6) 8.20 - 8.18 (m, 2H), 7.79 - 7.78 (m, 2H), 3.57 - 3.52 (m, 2H), 3.44 - 3.39 (m, 2H)
단계 2: 3-((2-클로로-6,7-다이하이드로싸이에노 [3,2-Step 2: 3 - ((2-Chloro-6,7-dihydrosothieno [3,2- dd ]피리미딘-4-일)옥시)아닐린의 제조] Pyrimidin-4-yl) oxy) aniline
상기 단계 1에서 제조된 화합물(146 g, 0.47 mol)을 메탄올(4L)에 묽힌 후 염화제일주석(445.6 g, 2.35 mol)을 가하고 2시간 동안 가열 환류하였다. 반응이 종결되면 감압 증류로 용매를 제거한 후, 결과로 얻어진 잔사에 에틸 아세테이트(2L)와 증류수(2L)을 가하고 교반하면서 탄산 나트륨을 넣어 중화시켰다. 생성된 침전물을 셀라이트가 충진된 필터로 여과시켜 제거하고, 여액을 층분리를 이용하여 물과 유기층으로 분리시킨 후, 분리된 유기층을 무수황산마그네슘으로 건조, 여과 및 감압 증류하여 표제화합물(121 g, 92%)을 얻었다.The compound (146 g, 0.47 mol) prepared in the above step 1 was diluted with methanol (4 L), added with tin chloride (445.6 g, 2.35 mol) and refluxed for 2 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure. Ethyl acetate (2 L) and distilled water (2 L) were added to the resulting residue, and sodium carbonate was added thereto with stirring to neutralize it. The resulting precipitate was filtered off through a filter packed with celite, and the filtrate was separated into water and an organic layer using layer separation. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to give the title compound 121 g, 92%).
1H NMR (400 MHz, DMSO-d 6 ) δ 7.06 (t, 1H) 6.49 - 6.47 (m, 1H), 6.33 - 6.28 (m, 2H), 5.36 (s, 2H), 3.52 - 3.47 (m, 2H), 3.39 - 3.34 (m, 2H) 1 H NMR (400 MHz, DMSO- d 6) δ 7.06 (t, 1H) 6.49 - 6.47 (m, 1H), 6.33 - 6.28 (m, 2H), 5.36 (s, 2H), 3.52 - 3.47 (m, 2H), 3.39-3.34 (m, 2H)
단계 3: Step 3: NN -(3-((2-클로로-6,7-다이하이드로싸이에노[3,2-- (3 - ((2-chloro-6,7-dihydrosothieno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
상기 단계 2에서 제조된 화합물(120 g, 0.43 mol)과 N,N-다이아이소프로필에틸아민(150 mL, 0.86 mol)을 테트라하이드로퓨란(2.4 L)에 용해시킨 후, 아크릴로일 클로라이드(52 mL, 0.65 mol)를 적가하고 상온에서 1시간 동안 교반하였다. 반응이 종결되면 감압 증류로 용매를 제거하고 결과로 얻어진 고체에 물/메탄올 혼합용매(4:1, 1.2 L)를 가하고 상온에서 1시간 동안 교반시킨 후, 여과하고 증류수로 세척하였다. 결과로 얻어진 고체를 에틸 아세테이트에 트리튜레이션(trituration)하여 여과하고 건조하여 표제화합물(136 g, 95%)을 얻었다.After dissolving the compound prepared in Step 2 (120 g, 0.43 mol) and N, N -diisopropylethylamine (150 mL, 0.86 mol) in tetrahydrofuran (2.4 L), acryloyl chloride 52 mL, 0.65 mol) was added dropwise thereto, and the mixture was stirred at room temperature for 1 hour. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and a water / methanol mixed solvent (4: 1, 1.2 L) was added to the resultant solid. The resulting mixture was stirred at room temperature for 1 hour, filtered and washed with distilled water. The resulting solid was triturated with ethyl acetate, filtered and dried to give the title compound (136 g, 95%).
1H NMR (400 MHz, DMSO-d 6 ) δ 10.38 (s, 1H), 7.68 (d, 1H), 7.58 (d, 1H), 7.42 (t, 1H) 6.96 (d, 1H), 6.35 (dd, 1H), 6.29 (d, 1H), 5.80 - 5.77 (m, 1H), 3.52 (t, 2H), 3.39 (t, 2H) 1 H NMR (400 MHz, DMSO- d 6) δ 10.38 (s, 1H), 7.68 (d, 1H), 7.58 (d, 1H), 7.42 (t, 1H) 6.96 (d, 1H), 6.35 (dd 2H), 3.39 (t, 2H), 3.40 (d, IH)
실시예 1: Example 1: NN -(3-((2-((4-(4-(피롤리딘-1-일)피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-Yl) phenyl) amino) -6,7-dihydrosothieno [3,2 < RTI ID = 0.0 > - dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 1-1: 1-(4-나이트로페닐)-4-(피롤리딘-1-일)피페리딘의 제조Example 1-1: Preparation of 1- (4-nitrophenyl) -4- (pyrrolidin-1-yl) piperidine
4-플루오로나이트로 벤젠(2 g, 14.17 mmol)과 4-(피롤리딘-1-일)피페리딘(2.4 g, 15.59 mmol)을 아세토나이트릴(20 mL)에 용해시킨 후, 트라이에틸아민(2.37 mL, 17.01 mmol)을 가하고 12시간 동안 가열 환류하였다. 반응이 종결되면 실온으로 냉각한 후, 생성된 고체를 여과하고 물로 세척하여 표제화합물(3.6 g, 92%)을 얻었다.After dissolving 4-fluoronitrobenzene (2 g, 14.17 mmol) and 4- (pyrrolidin-1-yl) piperidine (2.4 g, 15.59 mmol) in acetonitrile (20 mL) Ethylamine (2.37 mL, 17.01 mmol) was added and the mixture was refluxed for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and the resulting solid was filtered and washed with water to obtain the title compound (3.6 g, 92%).
실시예 1-2: 4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린의 제조Example 1-2: Preparation of 4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline
상기 실시예 1-1에서 제조된 화합물(3 g, 10.9 mmol)을 메탄올(30 mL)에 용해시킨 후, 팔라듐 촉매 (10% Pd/C, 0.3 g, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(2.3 g, 87%)을 얻었다.The compound (3 g, 10.9 mmol) prepared in Example 1-1 was dissolved in methanol (30 mL), palladium catalyst (10% Pd / C, 0.3 g, 10 wt%) was added, Lt; / RTI > for 12 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (2.3 g, 87%).
실시예 1-3: Examples 1-3: NN -(3-((2-((4-(4-(피롤리딘-1-일)피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-Yl) phenyl) amino) -6,7-dihydrosothieno [3,2 < RTI ID = 0.0 > - dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
상기 실시예 1-2에서 제조된 화합물(290 mg, 1.2 mmol)과 N-(3-((2-클로로-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드(500 mg, 1.5 mmol)을 2-부탄올(15 mL)에 현탁시킨 후, 트라이플루오로아세트산(180 μL, 2 mmol)을 가하고 24시간 동안 가열 환류하였다. 반응혼합물을 다이클로로메탄에 묽힌 후, 염화 암모늄 수용액으로 2회 세척하고 무수황산마그네슘으로 건조, 여과 및 감압 증류하고 컬럼 크로마토그래피(다이클로로메탄 : 메탄올 = 9 : 1 (부피비))로 분리하여 표제화합물(23 mg, 3.5%)을 얻었다.The mixture of the compound prepared in Example 1-2 (290 mg, 1.2 mmol) and N - (3 - ((2-chloro-6,7-dihydrosothieno [3,2- d ] pyrimidin- (500 mg, 1.5 mmol) was suspended in 2-butanol (15 mL), trifluoroacetic acid (180 L, 2 mmol) was added, and the mixture was refluxed for 24 hours. The reaction mixture was diluted with dichloromethane, washed twice with an aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure, and separated by column chromatography (dichloromethane: methanol = 9: 1 (volume ratio) (23 mg, 3.5%).
1H NMR (400 MHz, CD3OD) δ 7.71 (d, 1H), 7.48 - 7.47 (m, 1H), 7.41 (t, 1H), 7.24 (d, 2H), 6.93 (dd, 1H), 6.72 (d, 2H), 6.43 - 6.38 (m, 2H), 5.78 (dd, 1H), 4.91 (s, 1H), 3.60 (d, 2H), 3.40 (t, 2H), 3.35 - 3.27 (m, 4H) 3.12 - 3.06 (m, 1H), 2.65 (t, 2H), 2.18 (d, 2H), 2.06 (s, 4H), 1.82 - 1.73 (m, 2H) 1 H NMR (400 MHz, CD 3 OD) ? 7.71 (d, 1H), 7.48-7.47 (m, 1H), 7.41 (d, 2H), 6.43-6.38 (m, 2H), 5.78 (dd, IH), 4.91 (s, IH) 2H), 2.18 (d, 2H), 2.06 (s, 4H), 1.82-1.73 (m, 2H)
실시예 2: Example 2: NN -(3-((2-((4-((테트라하이드로퓨란-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2 - ((4 - ((tetrahydrofuran-3-yl) oxy) phenyl) amino) -6,7- dihydrothi eno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 2-1: 3-(4-나이트로페녹시)테트라하이드로퓨란의 제조Example 2-1: Preparation of 3- (4-nitrophenoxy) tetrahydrofuran
소듐 하이드라이드(60%, 0.65 g, 14.88 mmol)를 N,N-다이메틸폼아마이드(14 mL)에 넣고 0℃로 냉각한 후, 질소가스하에 3-하이드록시테트라하이드로퓨란(1.18 mL, 14.88 mmol)을 적가하고 30분간 교반시켰다. 4-플루오로나이트로 벤젠(2 g, 14.17 mmol)을 한번에 집어넣은 후, 상온으로 서서히 상승하여 4시간 동안 교반시킨 후, 반응혼합물에 물을 첨가하여 반응을 종결하고 에틸 아세테이트로 추출한 후, 분리된 유기층을 무수황산마그네슘으로 건조, 여과 및 감압 증류하였다. 얻어진 잔사(2.96 g)를 정제하지 않고 다음 단계에 사용하였다. Sodium hydride (60%, 0.65 g, 14.88 mmol) was added to N, N -dimethylformamide (14 mL) and the mixture was cooled to 0 캜. Then, under nitrogen gas, 3-hydroxytetrahydrofuran (1.18 mL, mmol) was added dropwise and the mixture was stirred for 30 minutes. 4-Fluoronitrobenzene (2 g, 14.17 mmol) was added in one portion, and the mixture was gradually raised to room temperature. After stirring for 4 hours, water was added to the reaction mixture to terminate the reaction, and the mixture was extracted with ethyl acetate The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The resulting residue (2.96 g) was used in the next step without purification.
실시예 2-2: 4-((테트라하이드로퓨란-3-일)옥시)아닐린의 제조Example 2-2: Preparation of 4 - ((tetrahydrofuran-3-yl) oxy) aniline
상기 실시예 2-1에서 제조된 화합물(2.96 g, 14.17 mmol)을 메탄올(30 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 0.3 g, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(2.54 g, 100%)을 얻었다.The compound (2.96 g, 14.17 mmol) prepared in Example 2-1 was dissolved in methanol (30 mL), palladium catalyst (10% Pd / C, 0.3 g, 10 wt%) was added, Lt; / RTI > for 12 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (2.54 g, 100%).
실시예 2-3: Example 2-3: NN -(3-((2-((4-((테트라하이드로퓨란-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2 - ((4 - ((tetrahydrofuran-3-yl) oxy) phenyl) amino) -6,7- dihydrothi eno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-((테트라하이드로퓨란-3-일)옥시)아닐린(1.2 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(0.25 g, 45%)을 얻었다.Except that 4 - ((tetrahydrofuran-3-yl) oxy) aniline (1.2 mmol) was used instead of 4- (4- (pyrrolidin- 1 -yl) piperidin- The same procedures as in Example 1-3 were followed to give the title compound (0.25 g, 45%).
1H NMR (400 MHz, DMSO-d 6 ) δ 10.34 (s, 1H), 9.37 (s, 1H), 7.64 (t, 1H), 7.56 (d, 1H), 7.42 (t, 1H), 7.29 (d, 2H), 6.93 (dd, 1H), 6.58 (d, 2H), 6.43 (dd, 1H), 6.25 (dd, 1H), 5.79 - 5.76 (m, 1H), 4.83 (d, 1H), 3.85 - 3.68 (m, 4H), 3.40 (t, 2H), 3.23 (t, 2H), 2.17 - 2.10 (m, 1H), 1.91 - 1.84 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6) δ 10.34 (s, 1H), 9.37 (s, 1H), 7.64 (t, 1H), 7.56 (d, 1H), 7.42 (t, 1H), 7.29 ( (d, 2H), 6.93 (dd, 1H), 6.58 (d, 2H), 6.43 1H), 1.91-1.84 (m, 1H), 3.68 (m, 2H)
실시예 3: Example 3: NN -(3-((2-((4-(1-메틸피페리딘-4-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (1-methylpiperidin-4-yl) phenyl) amino) -6,7- dihydrothi eno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 3-1: 4-(4-나이트로페닐)피리딘의 제조Example 3-1: Preparation of 4- (4-nitrophenyl) pyridine
1-브로모-4-나이트로벤젠(3.94 g, 19.52 mmol)과 4-피리딘보로닉에시드(3 g, 24.41 mmol), 테트라키스(트라이페닐포스핀)팔라듐(0)(1.13 g, 0.98 mmol) 및 탄산칼륨(5.4 g, 39.04 mmol)을 1,4-다이옥세인/물 혼합용매(40 mL, 3:1)에 넣고, 질소가스로 15분 동안 용매에 통과시킨 후 12시간 동안 가열 환류하였다. 반응이 종결되면 반응 혼합물을 물에 녹인 후 에틸 아세테이트로 추출하였다. 분리된 유기층을 소금 수용액으로 씻어준 후, 무수 황산 마그네슘으로 건조시키고 감압 증류하여 용매를 제거하였다. 얻어진 고체를 n-헥산/다이클로로메탄 혼합 용매(1:10, 2L)에 트리튜레이션(trituration)하고 여과, 건조하여 표제화합물 (3.63 g, 93%)을 얻었다.(3.94 g, 19.52 mmol), 4-pyridineboronic acid (3 g, 24.41 mmol), tetrakis (triphenylphosphine) palladium (0) (1.13 g, 0.98 (5.4 g, 39.04 mmol) was added to a 1,4-dioxane / water mixed solvent (40 mL, 3: 1), passed through a solvent for 15 minutes with nitrogen gas, Respectively. When the reaction was completed, the reaction mixture was dissolved in water and extracted with ethyl acetate. The separated organic layer was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The resulting solid was triturated with a mixed solvent of n -hexane / dichloromethane (1:10, 2 L), filtered and dried to give the title compound (3.63 g, 93%).
실시예 3-2: 1-메틸-4-(4-나이트로페닐)피리딘-1-윰 아이오다이드의 제조Example 3-2: Preparation of 1-methyl-4- (4-nitrophenyl) pyridin-1-yl iodide
상기 실시예 3-1에서 제조된 화합물(2 g, 10 mmol)을 아세톤(20 mL)에 용해시킨 후, 아이오도메테인(3.1 mL, 50 mmol)을 가하고 상온에서 24시간 동안 교반시켰다. 반응이 종결되면, 생성된 고체를 여과하고 에틸 아세테이트로 세척하여 표제화합물(3.04 g, 89%)을 얻었다.The compound (2 g, 10 mmol) prepared in Example 3-1 was dissolved in acetone (20 mL), iodomethane (3.1 mL, 50 mmol) was added, and the mixture was stirred at room temperature for 24 hours. When the reaction was complete, the resulting solid was filtered and washed with ethyl acetate to give the title compound (3.04 g, 89%).
실시예 3-3: 1-메틸-4-(4-나이트로페닐)-1,2,3,6-테트라하이드로피리딘의 제조Example 3-3: Preparation of 1-methyl-4- (4-nitrophenyl) -1,2,3,6-tetrahydropyridine
상기 실시예 3-2에서 제조된 화합물(2 g, 5.85 mmol)을 메탄올(30 mL)에 용해시킨 후, 0℃로 냉각하고 소듐 보로하이드라이드(0.66 g, 17.54 mmol)를 소분하여 투입하였다. 반응혼합물을 상온으로 상승한 후 12시간 동안 교반하였다. 반응이 종결되면, 반응혼합물을 농축한 후, 물에 녹이고 에틸 아세테이트로 추출하였다. 분리된 유기층을 무수황산마그네슘으로 건조, 여과 및 감압 증류하였다. 얻어진 잔사(1.2 g)를 정제하지 않고 다음 단계에 사용하였다. The compound (2 g, 5.85 mmol) prepared in Example 3-2 was dissolved in methanol (30 mL), cooled to 0 占 폚, and sodium borohydride (0.66 g, 17.54 mmol) was subdivided. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. Upon completion of the reaction, the reaction mixture was concentrated, dissolved in water and extracted with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The resulting residue (1.2 g) was used in the next step without purification.
실시예 3-4: 4-(1-메틸피페리딘-4-일)아닐린의 제조Example 3-4: Preparation of 4- (1-methylpiperidin-4-yl) aniline
상기 실시예 3-3에서 제조된 화합물(630 mg, 2.89 mmol)을 메탄올(10 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 63 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(490 mg, 90%)을 얻었다.The compound (630 mg, 2.89 mmol) prepared in Example 3-3 was dissolved in methanol (10 mL), palladium catalyst (10% Pd / C, 63 mg, 10 wt%) was added, Lt; / RTI > for 12 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (490 mg, 90%).
실시예 3-5: Example 3-5: NN -(3-((2-((4-(1-메틸피페리딘-4-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (1-methylpiperidin-4-yl) phenyl) amino) -6,7- dihydrothi eno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(1-메틸피페리딘-4-일)아닐린 (1.2 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(135 mg, 23%)을 얻었다. Except that 4- (1-methylpiperidin-4-yl) aniline (1.2 mmol) was used instead of 4- (4- (pyrrolidin- 1 -yl) piperidin- The procedure of Example 1-3 was repeated to obtain the title compound (135 mg, 23%).
1H NMR (400 MHz, DMSO-d 6 ) δ 10.55 (s, 1H), 10.31 (s, 1H), 9.50 (s, 1H), 7.68 (t, 1H), 7.62 (d, 1H), 7.42 (t, 1H), 7.34 (d, 1H), 6.96 - 6.93 (m, 1H), 6.90 (d, 2H), 6.54 (dd, 1H), 6.26 (dd, 1H), 5.76 (dd, 1H), 3.46 - 3.40 (m, 4H), 3.25 (t, 2H), 3.06 - 2.97 (m, 2H), 2.75 (d, 3H), 2.65 - 2.60 (m, 1H), 1.94 - 1.88 (m, 4H) 1 H NMR (400 MHz, DMSO- d 6 ) ? 10.55 (s, IH), 10.31 (s, IH), 9.50 (s, IH), 7.68 (dd, 1H), 7.36 (d, 1H), 7.36 (d, 1H) 2H), 2.75 (d, 3H), 2.65-2.60 (m, 1H), 1.94-1.88 (m, 4H)
실시예 4: Example 4: NN -(3-((2-((4-(1-에틸피페리딘-4-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (1-ethylpiperidin-4-yl) phenyl) amino) -6,7- dihydrosothieno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 4-1: 1-에틸-4-(4-나이트로페닐)피리딘-1-윰 아이오다이드의 제조Example 4-1: Preparation of 1-ethyl-4- (4-nitrophenyl) pyridin-1-yl iodide
실시예 3-1에서 제조된 화합물(0.7 g, 3.5 mmol)을 아세톤(7 mL)에 용해시킨 후, 아이오도에테인(2.8 mL, 35 mmol)을 가하고 상온에서 24시간 동안 교반시켰다. 반응이 종결되면, 생성된 고체를 여과하고 에틸 아세테이트로 세척하여 표제화합물(0.86 g, 69%)을 얻었다.The compound (0.7 g, 3.5 mmol) prepared in Example 3-1 was dissolved in acetone (7 mL), followed by the addition of iodoethane (2.8 mL, 35 mmol) and stirring at room temperature for 24 hours. When the reaction was complete, the resulting solid was filtered and washed with ethyl acetate to give the title compound (0.86 g, 69%).
실시예 4-2: 1-에틸-4-(4-나이트로페닐)-1,2,3,6-테트라하이드로피리딘의 제조Example 4-2: Preparation of 1-ethyl-4- (4-nitrophenyl) -1,2,3,6-tetrahydropyridine
상기 실시예 4-1에서 제조된 화합물(0.8 g, 2.25 mmol)을 메탄올(20 mL)에 용해시킨 후, 0℃로 냉각하고 소듐 보로하이드라이드(0.26 g, 6.74 mmol)를 소분하여 투입하였다. 반응혼합물을 상온으로 상승한 후 12시간 동안 교반하였다. 반응이 종결되면, 반응혼합물을 농축한 후, 물에 녹이고 에틸 아세테이트로 추출하였다. 분리된 유기층을 무수황산마그네슘으로 건조, 여과 및 감압 증류하고 컬럼 크로마토그래피(다이클로로메탄 : 메탄올 = 10 : 1 (부피비))로 분리하여 표제화합물(0.44 g, 84%)을 얻었다.The compound (0.8 g, 2.25 mmol) prepared in Example 4-1 was dissolved in methanol (20 mL), cooled to 0 ° C, and sodium borohydride (0.26 g, 6.74 mmol) was subdivided. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. Upon completion of the reaction, the reaction mixture was concentrated, dissolved in water and extracted with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure, and then separated by column chromatography (dichloromethane: methanol = 10: 1 (by volume)) to obtain the title compound (0.44 g, 84%).
실시예 4-3: 4-(1-에틸피페리딘-4-일)아닐린의 제조Example 4-3: Preparation of 4- (1-ethylpiperidin-4-yl) aniline
상기 실시예 4-2에서 제조된 화합물(0.44 g, 1.9 mmol)을 메탄올(10 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 44 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(0.38 g, 98%)을 얻었다.The compound (0.44 g, 1.9 mmol) prepared in Example 4-2 was dissolved in methanol (10 mL), palladium catalyst (10% Pd / C, 44 mg, 10 wt%) was added, Lt; / RTI > for 12 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (0.38 g, 98%).
실시예 4-4: Example 4-4: NN -(3-((2-((4-(1-에틸피페리딘-4-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (1-ethylpiperidin-4-yl) phenyl) amino) -6,7- dihydrosothieno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(1-에틸피페리딘-4-일)아닐린 (1.2 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(205 mg, 34%)을 얻었다.Except that 4- (1-ethylpiperidin-4-yl) aniline (1.2 mmol) was used instead of 4- (4- (pyrrolidin- 1 -yl) piperidin- The same procedures as in Example 1-3 were followed to give the title compound (205 mg, 34%).
1H NMR (400 MHz, DMSO-d 6 ) δ 10.53 (s, 1H), 10.06 (s, 1H), 9.50 (s, 1H), 7.68 (t, 1H), 7.61 (d, 1H), 7.42 (t, 1H), 7.34 (d, 2H), 6.96 - 6.89 (m, 3H), 6.53 (dd, 1H), 6.26 (dd, 1H), 5.80 - 5.75 (m, 1H), 3.42 (t, 2H), 3.25 (t, 2H), 3.14 - 3.08 (m, 2H), 2.99 - 2.91 (m, 2H), 2.69 - 2.63 (m, 1H), 1.97 - 1.85 (m, 4H), 2.76 (t, 3H) 1 H NMR (400 MHz, DMSO- d 6) δ 10.53 (s, 1H), 10.06 (s, 1H), 9.50 (s, 1H), 7.68 (t, 1H), 7.61 (d, 1H), 7.42 ( 1H), 7.34 (d, 2H), 6.96-6. 89 (m, 3H), 6.53 (dd, 2H), 2.97-2.83 (m, 2H), 2.69-2.63 (m, 1H), 1.97-1.85 (m, 4H)
실시예 5: Example 5: (R)(R) -- NN -(3-((2-((4-((1-메틸피롤리딘-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2 - ((4 - ((1 -methylpyrrolidin-3- yl) oxy) phenyl) amino) -6,7- dihydrosothieno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 5-1: Example 5-1: (R)(R) -1-메틸-3-(4-나이트로페녹시)피롤리딘의 제조-1-methyl-3- (4-nitrophenoxy) pyrrolidine
소듐 하이드라이드(60%, 0.4 g, 9.89 mmol)를 무수 테트라하이드로퓨란(10 mL)에 넣고 0℃로 냉각한 후, 질소가스 하에 (R)-1-메틸-3-피롤리딘올(0.5 g, 4.94 mmol)을 적가하고 60분간 교반시켰다. 반응 혼합물에 4-플루오로나이트로 벤젠(0.73 mL, 6.92 mmol)을 적가하고 상온으로 서서히 상승하여 12시간 동안 교반시킨 후, 반응혼합물에 물을 첨가하여 반응을 종결하고 에틸 아세테이트로 추출한 후, 분리된 유기층을 무수황산마그네슘으로 건조, 여과 및 감압 증류하고 컬럼 크로마토그래피(다이클로로메탄 : 메탄올 = 95 : 5 (부피비))로 분리하여 표제화합물(1 g, 91%)을 얻었다.Sodium hydride (60%, 0.4 g, 9.89 mmol) was added to anhydrous tetrahydrofuran (10 mL), and the mixture was cooled to 0 캜. To the mixture was added dropwise a solution of ( R ) -1-methyl-3-pyrrolidinol , 4.94 mmol) was added dropwise and the mixture was stirred for 60 minutes. 4-Fluoronitrobenzene (0.73 mL, 6.92 mmol) was added dropwise to the reaction mixture, and the mixture was slowly stirred at room temperature for 12 hours. Water was added to the reaction mixture to terminate the reaction, extracted with ethyl acetate, The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The residue was subjected to column chromatography (dichloromethane: methanol = 95: 5 (by volume)) to obtain the title compound (1 g, 91%).
실시예 5-2: Example 5-2: (R)(R) -4-((1-메틸피롤리딘-3-일)옥시)아닐린의 제조-4 - ((1-methylpyrrolidin-3-yl) oxy) aniline
상기 실시예 5-1에서 제조된 화합물(1 g, 4.5 mmol)을 메탄올(10 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 100 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(0.87 g, 100%)을 얻었다.The compound (1 g, 4.5 mmol) prepared in Example 5-1 was dissolved in methanol (10 mL), palladium catalyst (10% Pd / C, 100 mg, 10 wt%) was added, Lt; / RTI > for 12 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (0.87 g, 100%).
실시예 5-3: Example 5-3: (R)(R) -- NN -(3-((2-((4-((1-메틸피롤리딘-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2 - ((4 - ((1 -methylpyrrolidin-3- yl) oxy) phenyl) amino) -6,7- dihydrosothieno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 (R)-4-((1-메틸피롤리딘 -3-일)옥시)아닐린(1.09 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(214 mg, 34%)을 얻었다.(1.09 mmol) of (R) -4 - ((1-methylpyrrolidin-3-yl) oxy) aniline in place of 4- (4- (pyrrolidin- 1 -yl) piperidin- , The title compound (214 mg, 34%) was obtained by carrying out the same processes as in Example 1-3.
1H NMR (400 MHz, DMSO-d 6 ) δ 10.45 (s, 1H), 9.34 (s, 1H), 7.63 - 7.58 (m, 2H), 7.45 (t, 1H), 7.32 (d, 2H), 6.96 (dd, 1H), 6.65 (d, 2H), 6.45 (dd, 1H), 6.28 (dd, 1H), 5.81 (d, 1H), 5.00 (s, 1H), 3.85 - 3.70 (m, 7H), 3.41 (t, 2H), 3.24 (t, 2H), 2.88 (s, 3H) 1 H NMR (400 MHz, DMSO- d 6) δ 10.45 (s, 1H), 9.34 (s, 1H), 7.63 - 7.58 (m, 2H), 7.45 (t, 1H), 7.32 (d, 2H), 1H), 6.85 (d, 1H), 6.65 (d, 2H), 6.45 (dd, , 3.41 (t, 2H), 3.24 (t, 2H), 2.88 (s, 3H)
실시예 6: Example 6: (S)(S) -- NN -(3-((2-((4-((1-메틸피롤리딘-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2 - ((4 - ((1 -methylpyrrolidin-3- yl) oxy) phenyl) amino) -6,7- dihydrosothieno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 6-1: Example 6-1: (S)(S) -1-메틸-3-(4-나이트로페녹시)피롤리딘의 제조-1-methyl-3- (4-nitrophenoxy) pyrrolidine
소듐 하이드라이드(60%, 0.4 g, 9.89 mmol)를 무수 테트라하이드로퓨란(10 mL)에 넣고 0℃로 냉각한 후, 질소가스 하에 (S)-(+)-1-메틸-3-피롤리딘올(0.5 g, 4.94 mmol)을 적가하고 60분간 교반시켰다. 반응 혼합물에 4-플루오로나이트로 벤젠(0.73 mL, 6.92 mmol)을 적가하고 상온으로 서서히 상승하여 12시간 동안 교반시킨 후, 반응혼합물에 물을 첨가하여 반응을 종결하고 에틸 아세테이트로 추출한 후, 분리된 유기층을 무수황산마그네슘으로 건조, 여과 및 감압 증류하고 컬럼 크로마토그래피(다이클로로메탄 : 메탄올 = 95 : 5 (부피비))로 분리하여 표제화합물(1 g, 91%)을 얻었다.Sodium hydride (60%, 0.4 g, 9.89 mmol) was added to anhydrous tetrahydrofuran (10 mL), and the mixture was cooled to 0 캜. To the solution was added (S) - (0.5 g, 4.94 mmol) was added dropwise and the mixture was stirred for 60 minutes. 4-Fluoronitrobenzene (0.73 mL, 6.92 mmol) was added dropwise to the reaction mixture, and the mixture was slowly stirred at room temperature for 12 hours. Water was added to the reaction mixture to terminate the reaction, extracted with ethyl acetate, The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The residue was subjected to column chromatography (dichloromethane: methanol = 95: 5 (by volume)) to obtain the title compound (1 g, 91%).
실시예 6-2: Example 6-2: (S)(S) -4-((1-메틸피롤리딘-3-일)옥시)아닐린의 제조-4 - ((1-methylpyrrolidin-3-yl) oxy) aniline
상기 실시예 6-1에서 제조된 화합물(1 g, 4.5 mmol)을 메탄올(10 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 100 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(0.87 g, 100%)을 얻었다.The compound (1 g, 4.5 mmol) prepared in Example 6-1 was dissolved in methanol (10 mL), palladium catalyst (10% Pd / C, 100 mg, 10 wt%) was added, Lt; / RTI > for 12 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (0.87 g, 100%).
실시예 6-3: Example 6-3: (S)(S) -- NN -(3-((2-((4-((1-메틸피롤리딘-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2 - ((4 - ((1 -methylpyrrolidin-3- yl) oxy) phenyl) amino) -6,7- dihydrosothieno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 (S)-4-((1-메틸피롤리딘-3-일)옥시)아닐린(1.04 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(0.17 g, 28%)을 얻었다. (S) -4 - ((1-Methylpyrrolidin-3-yl) oxy) aniline (1.04 mmol) instead of 4- (4- (pyrrolidin- 1 -yl) piperidin- , The title compound (0.17 g, 28%) was obtained by carrying out the same processes as in Example 1-3.
1H NMR (400 MHz, DMSO-d 6 ) δ 10.47 (s, 1H), 9.36 (s, 1H), 7.62 - 7.58 (m, 2H), 7.46 - 7.43 (m, 1H), 7.32 (d, 2H), 6.96 (d, 1H), 6.64 (d, 2H), 6.45 (dd, 1H), 6.28 (d, 1H), 5.80 (d, 1H), 4.98 (s, 1H), 3.86 - 3.64 (m, 6H), 3.52 (s, 1H), 3.41 (t, 2H), 3.23 (t, 2H), 2.85 (s, 3H) 1 H NMR (400 MHz, DMSO- d 6) δ 10.47 (s, 1H), 9.36 (s, 1H), 7.62 - 7.58 (m, 2H), 7.46 - 7.43 (m, 1H), 7.32 (d, 2H ), 6.96 (d, 1H), 6.64 (d, 2H), 6.45 (dd, 2H), 2.85 (s, 3H), 3.23 (t, 2H)
실시예 7: Example 7: NN -(3-((2-((4-((1-메틸피페리딘-4-일)아미노)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2 - ((4 - ((1-methylpiperidin-4-yl) amino) phenyl) amino) -6,7- dihydrosothieno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 7-1: 1-메틸-Example 7-1: 1-Methyl- NN -(4-나이트로페닐)피페리딘-4-아민의 제조- (4-nitrophenyl) piperidin-4-amine
1-메틸피페리딘-4-아민(5.7 g, 49.49 mmol)과 4-플루오로 나이트로벤젠(5 mL, 47.13 mmol)을 다이메틸 설폭사이드(47 mL)에 용해시킨 후 탄산칼륨(1.98 g, 49.49 mmol)을 가하고 상온에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물에 증류수를 가하여 고체를 생성시킨 후, 여과하고 증류수로 세척한 뒤 감압건조하여 표제화합물(9.0 g, 81%)을 얻었다.After dissolving 1-methylpiperidin-4-amine (5.7 g, 49.49 mmol) and 4-fluoronitrobenzene (5 mL, 47.13 mmol) in dimethylsulfoxide (47 mL), potassium carbonate , 49.49 mmol), and the mixture was stirred at room temperature for 12 hours. When the reaction was completed, distilled water was added to the reaction mixture to form a solid, which was then filtered, washed with distilled water and dried under reduced pressure to obtain the title compound (9.0 g, 81%).
실시예 7-2: Example 7-2: NN 1One -(1-메틸피페리딘-4-일)벤젠-1,4-다이아민의 제조- (1-methylpiperidin-4-yl) benzene-l, 4-diamine
상기 실시예 7-1에서 제조된 화합물(9.0 g, 38.09 mmol)을 메탄올(200 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 0.9 g, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(6.6 g, 84%)을 얻었다.The compound (9.0 g, 38.09 mmol) prepared in Example 7-1 was dissolved in methanol (200 mL), palladium catalyst (10% Pd / C, 0.9 g, 10 wt%) was added, Lt; / RTI > for 12 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (6.6 g, 84%).
실시예 7-3: Example 7-3: NN -(3-((2-((4-((1-메틸피페리딘-4-일)아미노)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2 - ((4 - ((1-methylpiperidin-4-yl) amino) phenyl) amino) -6,7- dihydrosothieno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 N 1-(1-메틸피페리딘-4-일)벤젠-1,4-다이아민(0.81 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(13 mg, 3.2%)을 얻었다.4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline instead of N 1 - (1- methylpiperidin-4-yl) benzene-1,4-diamine (0.81 mmol ), The same procedure as in Example 1-3 was performed to give the title compound (13 mg, 3.2%).
1H NMR (400 MHz, CDCl3) δ 7.64 (d, 1H), 7.38 (t, 2H), 7.29 (s, 1H), 7.10 (d, 2H), 6.97 (d, 1H), 6.68 (s, 1H), 6.46 - 6.40 (m, 3H), 6.23 (dd, 1H), 5.78 (dd, 1H), 3.39 - 3.35 (m, 2H), 3.26 - 3.18 (m, 3H), 2.81 (d, 2H), 2.31 (s, 3H), 2.16 - 2.10 (m, 2H), 2.01 (d, 2H), 1.49 - 1.44 (m, 2H) 1 H NMR (400 MHz, CDCl 3) δ 7.64 (d, 1H), 7.38 (t, 2H), 7.29 (s, 1H), 7.10 (d, 2H), 6.97 (d, 1H), 6.68 (s, 2H), 3.26-3.18 (m, 3H), 2.81 (d, 2H), 3.40-3.85 (m, , 2.31 (s, 3H), 2.16-2.10 (m, 2H), 2.01 (d, 2H), 1.49-1.44
실시예 8: Example 8: NN -(3-((2-((4-(2-(4,4-다이메틸-1,4-아자실란-1-일)에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2 - ((4- (2- (4,4-Dimethyl-1, 4-azacsilan-1-yl) ethoxy) phenyl) amino) -6, 7-dihydrothiazole 3, < RTI ID = dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 8-1: 4,4-다이메틸-1-(2-(4-나이트로페녹시)에틸)-1,4-아자실란의 제조Example 8-1: Preparation of 4,4-dimethyl-1- (2- (4-nitrophenoxy) ethyl) -1,4-aza-
1-(2-브로모에톡시)-4-나이트로벤젠(0.5, 2.03 mmol)과 4,4-다이메틸-1,4-아자실란 염산염(0.37 g, 2.24 mmol)을 아세토나이트릴(5 mL)에 용해시킨 후, N,N-다이아이소프로필에틸아민(0.78 mL, 4.48 mmol)을 가하고 50℃에서 12시간 동안 교반하였다. 반응이 종결되면 실온으로 냉각한 후, 반응혼합물을 물에 녹이고 에틸 아세테이트로 추출하였다. 분리된 유기층을 염화나트륨 수용액으로 3회 세척하고 무수황산마그네슘으로 건조, 여과 및 감압 증류하고 컬럼 크로마토그래피(다이클로로메탄 : 메탄올 = 10 : 1 (부피비))로 분리하여 표제화합물(424 mg, 71%)을 얻었다.4-Azamyl chloride hydrochloride (0.37 g, 2.24 mmol) and acetonitrile (5 mL) were added to a solution of 1- (2-bromoethoxy) ), N, N -diisopropylethylamine (0.78 mL, 4.48 mmol) was added, and the mixture was stirred at 50 占 폚 for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and then the reaction mixture was dissolved in water and extracted with ethyl acetate. The separated organic layer was washed three times with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The residue was separated by column chromatography (dichloromethane: methanol = 10: 1 (by volume) ).
실시예 8-2: 4-(2-(4,4-다이메틸-1,4-아자실란-1-일)에톡시)아닐린의 제조Example 8-2: Preparation of 4- (2- (4,4-dimethyl-1,4-azacyl-1-yl) ethoxy) aniline
상기 실시예 8-1에서 제조된 화합물(0.42 g, 1.43 mmol)을 메탄올(5 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 42 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(0.37 g, 97%)을 얻었다.The compound (0.42 g, 1.43 mmol) prepared in Example 8-1 was dissolved in methanol (5 mL), palladium catalyst (10% Pd / C, 42 mg, 10 wt%) was added, Lt; / RTI > for 12 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (0.37 g, 97%).
실시예 8-3: Example 8-3: NN -(3-((2-((4-(2-(4,4-다이메틸-1,4-아자실란-1-일)에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2 - ((4- (2- (4,4-Dimethyl-1, 4-azacsilan-1-yl) ethoxy) phenyl) amino) -6, 7-dihydrothiazole 3, < RTI ID = dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(2-(4,4-다이메틸-1,4-아자실란-1-일)에톡시)아닐린(0.33 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(65 mg, 35%)을 얻었다.A solution of 4- (2- (4,4-dimethyl-1,4-azacyl-1-yl) ethoxy) -pyrrolidine was used in the place of 4- (4- (pyrrolidin- ) Aniline (0.33 mmol) was used in place of diethyl azodicarboxylate, the title compound (65 mg, 35%) was obtained.
1H NMR (400 MHz, DMSO-d 6 ) δ 10.33 (s, 1H), 9.36 (s, 1H), 7.62 (s, 1H), 7.56 (d, 1H), 7.42 (t, 1H), 7.28 (d, 2H), 6.93 (dd, 1H), 6.60 (d, 2H), 6.43 (dd, 1H), 6.26 (dd, 1H), 5.78 - 5.75 (m 1H), 3.90 (s, 2H), 3.40 (t, 2H), 3.22 (t, 2H), 2.73 (s, 4H), 2.67 (s, 2H), 0.70 (s, 4H), 0.04 (s, 6H) 1 H NMR (400 MHz, DMSO- d 6) δ 10.33 (s, 1H), 9.36 (s, 1H), 7.62 (s, 1H), 7.56 (d, 1H), 7.42 (t, 1H), 7.28 ( (dd, 2H), 6.93 (dd, 1H), 6.60 (d, 2H), 6.43 2H), 3.70 (s, 4H), 0.04 (s, 6H)
실시예 9: Example 9: NN -(3-((2-((3-플루오로-4-몰포리노페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((3-fluoro-4-morpholinophenyl) amino) -6,7- dihydrosothieno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 3-플루오로-4-몰포리노아닐린(1 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(0.1 g, 20%)을 얻었다. Example 1 was repeated except that 3-fluoro-4-morpholinoaniline (1 mmol) was used instead of 4- (4- (pyrrolidin-1-yl) piperidin- , The title compound (0.1 g, 20%) was obtained.
1H NMR (400 MHz, DMSO-d 6 ) δ 10.33 (s, 1H), 9.58 (s, 1H), 7.67 (s, 1H), 7.53 (d, 1H), 7.42 (t, 1H), 7.29 (d, 1H), 7.08 (d, 1H), 6.95 (dd, 1H), 6.74 (t, 1H), 6.42 (dd, 1H), 6.24 (dd, 1H), 5.76 (dd, 1H), 3.69 (t, 4H), 3.41 (t, 2H), 3.25 (t, 2H), 2.83 (t, 4H) 1 H NMR (400 MHz, DMSO- d 6) δ 10.33 (s, 1H), 9.58 (s, 1H), 7.67 (s, 1H), 7.53 (d, 1H), 7.42 (t, 1H), 7.29 ( (dd, 1H), 7.08 (d, 1H), 6.95 (dd, 1H), 6.74 , 4H), 3.41 (t, 2H), 3.25 (t, 2H), 2.83 (t, 4H)
실시예 10: Example 10: NN -(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7- dihydrothi eno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 10-1: 1-메틸-4-(4-나이트로페닐)피페라진의 제조Example 10-1: Preparation of 1-methyl-4- (4-nitrophenyl) piperazine
1-메틸피페라진(7.3 g, 72.68 mmol)과 4-플루오로 나이트로벤젠(10 g, 70.87 mmol)을 다이메틸 설폭사이드(15 mL)에 용해시킨 후 탄산칼륨(10.8 g, 77.85 mmol)을 가하고 상온에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물에 증류수를 가하여 고체를 생성시킨 후, 여과하고 증류수로 세척한 뒤 감압건조하여 표제화합물(15.2 g, 97%)을 얻었다.After dissolving 1-methylpiperazine (7.3 g, 72.68 mmol) and 4-fluoronitrobenzene (10 g, 70.87 mmol) in dimethylsulfoxide (15 mL), potassium carbonate (10.8 g, 77.85 mmol) And the mixture was stirred at room temperature for 12 hours. After the reaction was completed, distilled water was added to the reaction mixture to form a solid, which was then filtered, washed with distilled water and dried under reduced pressure to obtain the title compound (15.2 g, 97%).
실시예 10-2: 4-(4-메틸피페라진-1-일)아닐린의 제조Example 10-2: Preparation of 4- (4-methylpiperazin-1-yl) aniline
상기 실시예 10-1에서 제조된 화합물(15.0 g, 67.79 mmol)을 메탄올(450 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 1.5 g, 10 wt%)를 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(11.0 g, 85%)을 얻었다.The compound (15.0 g, 67.79 mmol) prepared in Example 10-1 was dissolved in methanol (450 mL), palladium catalyst (10% Pd / C, 1.5 g, 10 wt%) was added, Lt; / RTI > for 12 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (11.0 g, 85%).
실시예 10-3:Example 10-3: NN -(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7- dihydrothi eno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(4-메틸피페라진-1-일)아닐린(0.78 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(80 mg, 21%)을 얻었다.Was used instead of 4- (4-methylpiperazin-1-yl) aniline (0.78 mmol) instead of 4- (4- (pyrrolidin- 1 -yl) piperidin- The title compound (80 mg, 21%) was obtained by carrying out the same processes as in Example 1-3.
1H NMR (400MHz, DMSO-d 6) δ 10.34 (s, 1H), 9.28 (s, 1H), 7.61 - 7.57 (m, 2H), 7.41 (t, 1H), 7.23 (d, 2H), 6.92 (m, 1H), 6.61 (d, 2H), 6.42 (m, 1H), 6.25 (m, 1H), 5.77 (m, 1H), 3.39 (t, 2H), 3.21 (t, 2H), 2.97 - 2.90 (m, 4H), 2.43 - 2.37 (m, 4H), 2.20 (s, 3H) 1 H NMR (400MHz, DMSO- d 6) δ 10.34 (s, 1H), 9.28 (s, 1H), 7.61 - 7.57 (m, 2H), 7.41 (t, 1H), 7.23 (d, 2H), 6.92 2H), 6.42 (m, IH), 6.25 (m, IH), 5.77 (m, 2.90 (m, 4H), 2.43-2.37 (m, 4H), 2.20 (s, 3H)
실시예 11: Example 11: NN -(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7- dihydrothi eno [ dd ]피리미딘-4-일)옥시)페닐)에탄설폰아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) ethanesulfonamide
2-클로로에탄설포닐 클로라이드(500 mg, 3.07 mmol)를 다이클로로메탄(5 mL)에 용해시킨 후, -78℃로 냉각하였다. 질소가스 하에 피리딘(1 mL, 12.28 mmol)을 적가한 후, 0℃로 서서히 상승시켜 1시간 동안 교반시켰다. 테트라하이드로퓨란(500 μL)에 용해시킨 4-(3-아미노페녹시)-N-(4-(4-메틸피페라진-1-일)페닐)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-2-아민(50 mg, 0.15 mmol)을 반응 혼합물에 적가한 후, 실온으로 서서히 상승시켜 1시간 동안 교반하였다. 반응이 종결되면 반응혼합물을 물에 넣고 다이클로로메탄으로 추출하였다. 분리된 유기층을, 염화 암모늄 수용액으로 3회 세척한 후, 무수황산마그네슘으로 건조, 여과 및 감압 증류하고 컬럼 크로마토그래피(에틸 아세테이트 : 헥산 = 2 : 1 (부피비))로 분리하여 표제화합물(20 mg, 25%)을 얻었다.2-Chloroethanesulfonyl chloride (500 mg, 3.07 mmol) was dissolved in dichloromethane (5 mL) and then cooled to -78 < 0 > C. Pyridine (1 mL, 12.28 mmol) was added dropwise under a nitrogen gas, then the temperature was gradually raised to 0 占 폚 and stirred for 1 hour. In tetrahydrofuran (3-aminophenoxy) was dissolved in 4 (500 μL) - N - (4- (4-methylpiperazin-1-yl) phenyl) -6,7-dihydro-furnace to thieno [3 , 2- d ] pyrimidin-2-amine (50 mg, 0.15 mmol) was added dropwise to the reaction mixture, then slowly raised to room temperature and stirred for 1 hour. When the reaction was complete, the reaction mixture was poured into water and extracted with dichloromethane. The separated organic layer was washed with an aqueous ammonium chloride solution three times, dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The residue was separated by column chromatography (ethyl acetate: hexane = 2: 1 (volume ratio) , 25%).
1H NMR (400 MHz, CDCl3) δ 7.27 (d, 2H), 7.19 (t, 1H), 6.98 (s, 2H), 6.78 (d, 2H), 6.60 - 6.57 (m, 2H), 6.53 - 6.52 (m, 1H), 5.01 (s, 1H), 3.75 (s, 1H), 3.37 (t, 2H), 3.25 (t, 2H), 3.13 (s, 4H), 2.63 (s, 4H), 2.27 (s, 3H) 1 H NMR (400 MHz, CDCl 3) δ 7.27 (d, 2H), 7.19 (t, 1H), 6.98 (s, 2H), 6.78 (d, 2H), 6.60 - 6.57 (m, 2H), 6.53 - 2H), 3.13 (s, 4H), 2.63 (s, 4H), 2.27 (s, 2H) (s, 3 H)
실시예 12: Example 12: NN -(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7- dihydrothi eno [ dd ]피리미딘-4-일)아미노)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) amino) phenyl) acrylamide
실시예 12-1: Example 12-1: NN -(3-((2-클로로-6,7-다이하이드로싸이에노[3,2-- (3 - ((2-chloro-6,7-dihydrosothieno [3,2- dd ]피리미딘-4-일)아미노)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) amino) phenyl) acrylamide
2,4-다이클로로싸이에노[3,2-d]피리미딘(500 mg, 3.7 mmol)을 다이메틸 폼아마이드(5 mL)에 용해시킨 후, N-(3-아미노페닐)아크릴아마이드(766 mg, 3.08 mmol)와 다이아이소프로필에틸아민(0.54 mL, 3.08 mmol)을 가하고 60℃에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물을 다이클로로메탄에 묽힌 후, 염화 암모늄 수용액으로 2회 세척하고 무수황산마그네슘으로 건조, 여과 및 감압 증류하고 컬럼 크로마토그래피(다이클로로메탄 : 에틸 아세테이트 = 5 : 1 (부피비))로 분리하여 표제화합물(542 mg, 53%)을 얻었다.Was dissolved in 2,4-furnace chloropropyltriethoxysilane Im [3,2- d] pyrimidine (500 mg, 3.7 mmol) to dimethylformamide (5 mL), N - ( 3- amino-phenyl) acrylamide ( 766 mg, 3.08 mmol) and diisopropylethylamine (0.54 mL, 3.08 mmol) were added, and the mixture was stirred at 60 ° C for 12 hours. After the reaction was completed, the reaction mixture was diluted with dichloromethane, washed twice with an aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure, and subjected to column chromatography (dichloromethane: ethyl acetate = 5: 1 ) To obtain the title compound (542 mg, 53%).
실시예 12-2:Example 12-2: NN -(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7- dihydrothi eno [ dd ]피리미딘-4-일)아미노)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) amino) phenyl) acrylamide
N-(3-((2-클로로-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드 대신 N-(3-((2-클로로-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)아크릴아마이드(1.37 mmol)를, 4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(4-메틸피페라진-1-일)아닐린(1.5 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(130 mg, 20%)을 얻었다. N - (3 - ((2- chloro-6,7-dihydro furnace to Im [3,2- d] pyrimidin-4-yl) oxy) phenyl) acrylamide instead of N - (3 - ((2- chloro-6,7-dihydro-Im in the furnace [3,2- d] pyrimidin-4-yl) amino) phenyl) acrylamide (1.37 mmol), 4- (4- ( pyrrolidin-1-yl (4-methylpiperazin-1-yl) piperidin-1-yl) aniline was used in place of 4- 130 mg, 20%).
1H NMR (400MHz, DMSO-d 6) δ 10.12 (s, 1H), 8.86 (s, 1H), 8.56 (s, 1H), 7.83 (s, 1H), 7.48 (d, 2H), 7.42 (d, 1H), 7.30 - 7.20 (m, 2H), 6.71 (d, 2H), 6.45 (m, 1H), 6.25 (m, 1H), 5.74 (m, 1H), 3.30 (t, 2H), 3.10 (t, 2H), 3.00 - 2.93 (m, 4H), 2.46 - 2.39 (m, 4H), 2.20 (s, 3H) 1 H NMR (400MHz, DMSO- d 6) δ 10.12 (s, 1H), 8.86 (s, 1H), 8.56 (s, 1H), 7.83 (s, 1H), 7.48 (d, 2H), 7.42 (d (M, 1H), 7.30 (m, 2H), 6.71 (d, 2H), 6.45 t, 2H), 3.00-2.93 (m, 4H), 2.46-2.39 (m, 4H)
실시예 13: Example 13: NN -(3-((2-((4-(4-메틸-4-옥시도-1,4-아자포스피난-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-Phenyl) amino) -6,7-dihydrosothieno [3 - ((4- ,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 13-1: 4-메틸-1-(4-나이트로페닐)-1,4-아자포스피네인 4-옥사이드의 제조Example 13-1: Preparation of 4-methyl-1- (4-nitrophenyl) -1,4-azaphosphine 4-oxide
4-메틸-1,4-아자포스피네인-4-옥사이드(3.5 g, 25.98 mmol)와 4-플루오로 나이트로벤젠(3.7 g, 25.98 mmol)을 다이메틸 설폭사이드(6 mL)에 용해시킨 후 탄산칼륨(4.0 g, 28.58 mmol)을 가하고 상온에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물에 증류수를 가하여 고체를 생성시킨 후, 여과하고 증류수로 세척한 뒤 감압건조하여 표제화합물(5.5 g, 84%)을 얻었다.(3.5 g, 25.98 mmol) and 4-fluoronitrobenzene (3.7 g, 25.98 mmol) were dissolved in dimethylsulfoxide (6 mL) Potassium furoate (4.0 g, 28.58 mmol) was added and stirred at room temperature for 12 hours. After the reaction was completed, distilled water was added to the reaction mixture to form a solid, which was then filtered, washed with distilled water and dried under reduced pressure to obtain the title compound (5.5 g, 84%).
실시예 13-2: 1-(4-아미노페닐)-4-메틸-1,4-아자포스피네인 4-옥사이드의 제조Example 13-2: Preparation of 1- (4-aminophenyl) -4-methyl-1,4-azaphosphine 4-oxide
상기 실시예 13-1에서 제조된 화합물(1 g, 3.93 mmol)을 메탄올(20 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 100 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(0.85 g, 96%)을 얻었다.The compound (1 g, 3.93 mmol) prepared in Example 13-1 was dissolved in methanol (20 mL), palladium catalyst (10% Pd / C, 100 mg, 10 wt%) was added, Lt; / RTI > for 12 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (0.85 g, 96%).
실시예 13-3: Example 13-3: NN -(3-((2-((4-(4-메틸-4-옥시도-1,4-아자포스피난-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-Phenyl) amino) -6,7-dihydrosothieno [3 - ((4- ,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 1-(4-아미노페닐)-4-메틸-1,4-아자포스피네인 4-옥사이드(0.67 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물 (160 mg, 47%)을 얻었다. (4-aminophenyl) -4-methyl-l, 4-azaphosphine 4-oxide (0.67 mmol) instead of 4- (4- (pyrrolidin- 1 -yl) piperidin- mmol), the same procedures as in Example 1-3 were performed to give the title compound (160 mg, 47%).
1H NMR (400MHz, DMSO-d 6) δ 10.36 (s, 1H), 9.26 (s, 1H), 7.62 - 7.55 (m, 2H), 7.40 (t, 1H), 7.24 (d, 2H), 6.91 (m, 1H), 6.63 (d, 2H), 6.43 (m, 1H), 6.26 (m, 1H), 5.76 (m, 1H), 3.77 - 3.60 (m, 2H), 3.40 (t, 2H), 3.38 - 3.26 (m, 2H), 3.21 (t, 2H), 1.80 - 1.61 (m, 4H), 1.48 (d, 3H) 1 H NMR (400MHz, DMSO- d 6) δ 10.36 (s, 1H), 9.26 (s, 1H), 7.62 - 7.55 (m, 2H), 7.40 (t, 1H), 7.24 (d, 2H), 6.91 2H), 6.63 (m, 1H), 6.76 (m, 1H), 6.76 (m, 2H), 1.80-1.61 (m, 4H), 1.48 (d, 3H)
실시예 14: Example 14: NN -(3-((2-((2-메톡시-4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-Phenyl) amino) -6,7-dihydrosothieno [3,2-c] pyridin-2-yl) dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 14-1: 1-(3-메톡시-4-나이트로페닐)-4-메틸피페라진의 제조Example 14-1: Preparation of 1- (3-methoxy-4-nitrophenyl) -4-methylpiperazine
1-메틸피페라진(2 mL, 18.17 mmol)과 4-플루오로-2-메톡시-1-나이트로벤젠(3.1 g, 18.17 mmol)을 다이메틸 설폭사이드(4 mL)에 용해시킨 후 탄산칼륨(2.8 g, 19.99 mmol)을 가하고 상온에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물에 증류수를 가하여 고체를 생성시킨 후, 여과하고 증류수로 세척한 뒤 감압건조하여 표제화합물(3.9 g, 85%)을 얻었다.1-Methylpiperazine (2 mL, 18.17 mmol) and 4-fluoro-2-methoxy-1-nitrobenzene (3.1 g, 18.17 mmol) were dissolved in dimethylsulfoxide (4 mL) (2.8 g, 19.99 mmol), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, distilled water was added to the reaction mixture to form a solid, which was then filtered, washed with distilled water and dried under reduced pressure to obtain the title compound (3.9 g, 85%).
실시예 14-2: 2-메톡시-4-(4-메틸피페라진-1-일)아닐린의 제조Example 14-2: Preparation of 2-methoxy-4- (4-methylpiperazin-1-yl) aniline
상기 실시예 14-1에서 제조된 화합물(3.0 g, 11.94 mmol)을 메탄올(150 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 300 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(2.5 g, 96%)을 얻었다.The compound (3.0 g, 11.94 mmol) prepared in Example 14-1 was dissolved in methanol (150 mL), palladium catalyst (10% Pd / C, 300 mg, 10 wt%) was added, Lt; / RTI > for 12 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (2.5 g, 96%).
실시예 14-3: Example 14-3: NN -(3-((2-((2-메톡시-4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-Phenyl) amino) -6,7-dihydrosothieno [3,2-c] pyridin-2-yl) dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 2-메톡시-4-(4-메틸피페라진-1-일)아닐린(0.9 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(158 mg, 34%)을 얻었다. Methoxy-4- (4-methylpiperazin-1-yl) aniline (0.9 mmol) instead of 4- (4- (pyrrolidin- 1 -yl) piperidin- , The title compound (158 mg, 34%) was obtained by carrying out the same processes as in Example 1-3.
1H NMR (400MHz, DMSO-d 6) δ 10.33 (s, 1H), 7.69 (s, 1H), 7.61 - 7.54 (m, 2H), 7.42 - 7.35 (m, 2H), 6.91 (m, 1H), 6.53 (m, 1H), 6.45 (m, 1H), 6.25 (m, 1H), 6.14 (m, 1H), 5.78 (m, 1H), 3.75 (s, 3H), 3.38 (t, 2H), 3.19 (t, 2H), 3.04 - 2.98 (m, 4H), 2.47 - 2.39 (m, 4H), 2.21 (s, 3H) 1 H NMR (400MHz, DMSO- d 6) δ 10.33 (s, 1H), 7.69 (s, 1H), 7.61 - 7.54 (m, 2H), 7.42 - 7.35 (m, 2H), 6.91 (m, 1H) , 6.53 (m, IH), 6.45 (m, IH), 6.25 (m, IH), 6.14 2H), 3.04-2.98 (m, 4H), 2.47-2.39 (m, 4H), 2.21 (s,
실시예 15: Example 15: NN -(3-((2-((4-((1-메틸피페리딘-4-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-Phenyl) amino) -6,7-dihydrosothieno [3,2-c] pyridin-2-yl) dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 15-1: 1-메틸-4-(4-나이트로페녹시)피페리딘의 제조Example 15-1: Preparation of 1-methyl-4- (4-nitrophenoxy) piperidine
소듐 하이드라이드(60%, 1.98 g, 49.49 mmol)를 N,N-다이메틸폼아마이드(47 mL)에 넣고 0℃로 냉각한 후, 질소가스 하에 1-메틸피페리딘-4-올(5.82 mL, 49.49 mmol)을 적가하고 60분간 교반시켰다. 반응 혼합물에 4-플루오로 나이트로벤젠(5 mL, 47.13 mmol)을 적가하고 상온으로 서서히 상승하여 12시간 동안 교반하였다. 반응혼합물에 물을 첨가하여 반응을 종결하고 에틸 아세테이트로 추출한 후, 분리된 유기층을 무수황산마그네슘으로 건조, 여과 및 감압 증류하고 컬럼 크로마토그래피(다이클로로메탄 : 메탄올 = 95 : 5 (부피비))로 분리하여 표제화합물(9 g, 81%)을 얻었다.Sodium hydride (60%, 1.98 g, 49.49 mmol) was added to N, N -dimethylformamide (47 mL), cooled to 0 ° C, and then 1- methylpiperidin- mL, 49.49 mmol) was added dropwise and the mixture was stirred for 60 minutes. 4-Fluoronitrobenzene (5 mL, 47.13 mmol) was added dropwise to the reaction mixture, the temperature was gradually raised to room temperature, and the mixture was stirred for 12 hours. Water was added to the reaction mixture to terminate the reaction, and the mixture was extracted with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 95: 5 To obtain the title compound (9 g, 81%).
실시예 15-2: 4-((1-메틸피페리딘-4-일)옥시)아닐린의 제조Example 15-2: Preparation of 4 - ((1-methylpiperidin-4-yl) oxy) aniline
상기 실시예 15-1에서 제조된 화합물(9.0 g, 38.09 mmol)을 메탄올(200 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 0.9 g, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(6.6 g, 84%)을 얻었다.The compound (9.0 g, 38.09 mmol) prepared in Example 15-1 was dissolved in methanol (200 mL), palladium catalyst (10% Pd / C, 0.9 g, 10 wt%) was added, Lt; / RTI > for 12 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (6.6 g, 84%).
실시예 15-3:Example 15-3: NN -(3-((2-((4-((1-메틸피페리딘-4-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-Phenyl) amino) -6,7-dihydrosothieno [3,2-c] pyridin-2-yl) dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-((1-메틸피페리딘-4-일)옥시)아닐린(1 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(126 mg, 25%)을 얻었다.Except that 4 - ((1-methylpiperidin-4-yl) oxy) aniline (1 mmol) was used instead of 4- (4- (pyrrolidin- 1 -yl) piperidin- , The title compound (126 mg, 25%) was obtained by carrying out the same processes as in Example 1-3.
1H NMR (400MHz, DMSO-d 6) δ 10.35 (s, 1H), 9.36 (s, 1H), 7.63 (m, 1H), 7.58 (m, 1H), 7.42 (t, 1H), 7.27 (d, 2H), 6.94 (m, 1H), 6.60 (d, 2H), 6.45 (m, 1H), 6.26 (m, 1H), 5.77 (m, 1H), 4.14 (m, 1H), 3.40 (t, 2H), 3.22 (t, 2H), 2.65 - 2.55 (m, 2H), 2.22 - 2.12 (m, 5H), 1.88 - 1.79 (m, 2H), 1.62 - 1.50 (m, 2H) 1 H NMR (400 MHz, DMSO- d 6 )? 10.35 (s, 1H), 9.36 (s, IH), 7.63 (m, IH), 7.58 (M, 2H), 6.94 (m, 1H), 6.60 (d, 2H), 6.45 2H), 1.62-1.50 (m, 2H), 3.22 (t, 2H), 2.65-2.55 (m, 2H), 2.22-2.12
실시예 16: Example 16: NN -(3-((2-((4-(2-메톡시에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (2-methoxyethoxy) phenyl) amino) -6,7- dihydrothi eno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 16-1: 1-(2-메톡시에톡시)-4-나이트로벤젠의 제조Example 16-1: Preparation of 1- (2-methoxyethoxy) -4-nitrobenzene
2-메톡시에탄올(2 mL, 25.49 mmol)과 4-플루오로 나이트로벤젠(2.7 mL, 25.49 mmol)을 다이메틸 설폭사이드(4 mL)에 용해시킨 후 탄산칼륨(3.9 g, 28.04 mmol)을 가하고 상온에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물에 증류수를 가하여 고체를 생성시킨 후, 여과하고 증류수로 세척한 뒤 감압건조하여 표제화합물(2.7 g, 53%)을 얻었다.After dissolving 2-methoxyethanol (2 mL, 25.49 mmol) and 4-fluoronitrobenzene (2.7 mL, 25.49 mmol) in dimethylsulfoxide (4 mL), potassium carbonate (3.9 g, 28.04 mmol) And the mixture was stirred at room temperature for 12 hours. When the reaction was completed, distilled water was added to the reaction mixture to form a solid, which was then filtered, washed with distilled water and dried under reduced pressure to obtain the title compound (2.7 g, 53%).
실시예 16-2: 4-(2-메톡시에톡시)아닐린의 제조Example 16-2: Preparation of 4- (2-methoxyethoxy) aniline
상기 실시예 16-1에서 제조된 화합물(1g, 5.07 mmol)을 메탄올(40 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 100 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(720 mg, 85%)을 얻었다.The compound (1 g, 5.07 mmol) prepared in Example 16-1 was dissolved in methanol (40 mL), palladium catalyst (10% Pd / C, 100 mg, 10 wt%) was added, Stir for 12 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (720 mg, 85%).
실시예 16-3:Example 16-3: NN -(3-((2-((4-(2-메톡시에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (2-methoxyethoxy) phenyl) amino) -6,7- dihydrothi eno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(2-메톡시에톡시)아닐린(1.2 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(167 mg, 30%)을 얻었다. Example 1 was repeated except for using 4- (2-methoxyethoxy) aniline (1.2 mmol) instead of 4- (4- (pyrrolidin-1-yl) piperidin- 3, the title compound (167 mg, 30%) was obtained.
1H NMR (400MHz, DMSO-d 6) δ 10.33 (s, 1H), 9.36 (s, 1H), 7.64 (m, 1H), 7.53 (m, 1H), 7.42 (t, 1H), 7.28 (d, 2H), 6.93 (m, 1H), 6.61 (d, 2H), 6.45 (m, 1H), 6.26 (m, 1H), 5.77 (m, 1H), 3.96 - 3.91 (m, 2H), 3.62 - 3.58 (m, 2H), 3.40 (t, 2H), 3.23 (t, 2H) 1 H NMR (400MHz, DMSO- d 6) δ 10.33 (s, 1H), 9.36 (s, 1H), 7.64 (m, 1H), 7.53 (m, 1H), 7.42 (t, 1H), 7.28 (d 2H), 6.93 (m, 2H), 6.93 (m, IH) 3.58 (m, 2H), 3.40 (t, 2H), 3.23 (t, 2H)
실시예 17: Example 17: NN -(3-((2-((4-(4-에틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (4-ethylpiperazin-1-yl) phenyl) amino) -6,7- dihydrosothieno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 17-1: 1-에틸-4-(4-나이트로페닐)피페라진의 제조Example 17-1: Preparation of 1-ethyl-4- (4-nitrophenyl) piperazine
1-에틸피페라진(5.0 mL, 31.17 mmol)과 4-플루오로 나이트로벤젠(3.3 mL, 31.17 mmol)을 다이메틸 설폭사이드(10 mL)에 용해시킨 후 탄산칼륨(4.7 g, 34.29 mmol)을 가하고 상온에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물에 증류수를 가하여 고체를 생성시킨 후, 여과하고 증류수로 세척한 뒤 감압건조하여 표제화합물(6.9 g, 94%)을 얻었다.After dissolving 1-ethylpiperazine (5.0 mL, 31.17 mmol) and 4-fluoronitrobenzene (3.3 mL, 31.17 mmol) in dimethylsulfoxide (10 mL), potassium carbonate (4.7 g, 34.29 mmol) And the mixture was stirred at room temperature for 12 hours. After completion of the reaction, distilled water was added to the reaction mixture to form a solid, which was then filtered, washed with distilled water and dried under reduced pressure to obtain the title compound (6.9 g, 94%).
실시예 17-2: 4-(4-에틸피페라진-1-일)아닐린의 제조Example 17-2: Preparation of 4- (4-ethylpiperazin-1-yl) aniline
상기 실시예 17-1에서 제조된 화합물(2.0 g, 8.5 mmol)을 메탄올(60 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 200 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(1.2 g, 69%)을 얻었다.The compound (2.0 g, 8.5 mmol) prepared in Example 17-1 was dissolved in methanol (60 mL), palladium catalyst (10% Pd / C, 200 mg, 10 wt%) was added, Lt; / RTI > for 12 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (1.2 g, 69%).
실시예 17-3:Example 17-3: NN -(3-((2-((4-(4-에틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (4-ethylpiperazin-1-yl) phenyl) amino) -6,7- dihydrosothieno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(4-에틸피페라진-1-일)아닐린(1.25 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(20 mg, 3%)을 얻었다.Was used instead of 4- (4-ethylpiperazin-1-yl) aniline (1.25 mmol) instead of 4- (4- (pyrrolidin- 1 -yl) piperidin- The title compound (20 mg, 3%) was obtained by carrying out the same processes as in Example 1-3.
1H NMR (400MHz, DMSO-d 6) δ 10.33 (s, 1H), 9.28 (s, 1H), 7.61 - 7.57 (m, 2H), 7.41 (t, 1H), 7.24 (d, 2H), 6.93 (m, 1H), 6.62 (d, 2H), 6.42 (m, 1H), 6.27 (m, 1H), 5.77 (m, 1H), 3.39 (t, 2H), 3.21 (t, 2H), 3.00 - 2.88 (m, 4H), 2.60 - 2.31 (m, 6H), 1.03 (t, 3H) 1 H NMR (400MHz, DMSO- d 6) δ 10.33 (s, 1H), 9.28 (s, 1H), 7.61 - 7.57 (m, 2H), 7.41 (t, 1H), 7.24 (d, 2H), 6.93 2H), 6.42 (m, 1H), 6.27 (m, 1H), 5.77 (m, 2.88 (m, 4H), 2.60-2.31 (m, 6H), 1.03 (t, 3H)
실시예 18: Example 18: NN -(3-((2-((4-(4-아이소프로필피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2 - ((4- (4-isopropylpiperazin-1-yl) phenyl) amino) -6,7- dihydrosothieno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 18-1: 1-아이소프로필-4-(4-나이트로페닐)피페라진의 제조Example 18-1: Preparation of 1-isopropyl-4- (4-nitrophenyl) piperazine
1-아이소프로필피페라진(5.0 g, 39 mmol)과 4-플루오로 나이트로벤젠(4.1 mL, 38.61 mmol)을 다이메틸 설폭사이드(12 mL)에 용해시킨 후 탄산칼륨(5.9 g, 42.9 mmol)을 가하고 상온에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물에 증류수를 가하여 고체를 생성시킨 후, 여과하고 증류수로 세척한 뒤 감압건조하여 표제화합물(9.3 g, 95%)을 얻었다.After dissolving 1-isopropylpiperazine (5.0 g, 39 mmol) and 4-fluoronitrobenzene (4.1 mL, 38.61 mmol) in dimethylsulfoxide (12 mL), potassium carbonate (5.9 g, 42.9 mmol) And the mixture was stirred at room temperature for 12 hours. After the reaction was completed, distilled water was added to the reaction mixture to form a solid, which was then filtered, washed with distilled water and dried under reduced pressure to obtain the title compound (9.3 g, 95%).
실시예 18-2: 4-(4-아이소프로필피페라진-1-일)아닐린의 제조Example 18-2: Preparation of 4- (4-isopropylpiperazin-1-yl) aniline
상기 실시예 18-1에서 제조된 화합물(2g, 8.02 mmol)을 메탄올(60 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 200 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(400 mg, 23%)을 얻었다.The compound (2 g, 8.02 mmol) prepared in Example 18-1 was dissolved in methanol (60 mL), palladium catalyst (10% Pd / C, 200 mg, 10 wt%) was added, Stir for 12 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (400 mg, 23%).
실시예 18-3:Example 18-3: NN -(3-((2-((4-(4-아이소프로필피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2 - ((4- (4-isopropylpiperazin-1-yl) phenyl) amino) -6,7- dihydrosothieno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(4-아이소프로필피페라진-1-일)아닐린(1.25 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(20 mg, 3%)을 얻었다.(4-isopropylpiperazin-1-yl) aniline (1.25 mmol) instead of 4- (4- (pyrrolidin- The procedure of Example 1-3 was repeated to give the title compound (20 mg, 3%).
1H NMR (400MHz, DMSO-d 6) δ 10.35 (s, 1H), 9.27 (s, 1H), 7.62 - 7.59 (m, 2H), 7.42 (t, 1H), 7.24 (d, 2H), 6.92 (m, 1H), 6.61 (d, 2H), 6.44 (m, 1H), 6.28 (m, 1H), 5.78 (m, 1H), 3.39 (t, 2H), 3.21 (t, 2H), 2.98 - 2.88 (m, 4H), 2.65 (m, 1H), 2.60 - 2.52 (m, 4H), 1.00 (d, 6H) 1 H NMR (400MHz, DMSO- d 6) δ 10.35 (s, 1H), 9.27 (s, 1H), 7.62 - 7.59 (m, 2H), 7.42 (t, 1H), 7.24 (d, 2H), 6.92 (t, 2H), 6.98 (m, 1H), 6.98 (m, 1H) (M, 4H), 2.65 (m, 1H), 2.60-2.52 (m, 4H)
실시예 19: Example 19: NN -(3-((2-((4-(4-아세틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (4-acetylpiperazin-1-yl) phenyl) amino) -6,7- dihydrosothieno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조 ] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 19-1: 1-아세틸-4-(4-나이트로페닐)피페라진의 제조Example 19-1: Preparation of 1-acetyl-4- (4-nitrophenyl) piperazine
1-아세틸피페라진(5.0 g, 39.01 mmol)과 4-플루오로 나이트로벤젠(4.1 mL, 39.01 mmol)을 다이메틸 설폭사이드(10 mL)에 용해시킨 후 탄산칼륨(5.9 g, 42.91 mmol)을 가하고 상온에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물에 증류수를 가하여 고체를 생성시킨 후, 여과하고 증류수로 세척한 뒤 감압건조하여 표제화합물 (8.7 g, 89%)을 얻었다.After dissolving 1-acetylpiperazine (5.0 g, 39.01 mmol) and 4-fluoronitrobenzene (4.1 mL, 39.01 mmol) in dimethylsulfoxide (10 mL), potassium carbonate (5.9 g, 42.91 mmol) And the mixture was stirred at room temperature for 12 hours. When the reaction was completed, distilled water was added to the reaction mixture to form a solid, which was then filtered, washed with distilled water and dried under reduced pressure to obtain the title compound (8.7 g, 89%).
실시예 19-2: 4-(4-아세틸피페라진-1-일)아닐린의 제조Example 19-2: Preparation of 4- (4-acetylpiperazin-1-yl) aniline
상기 실시예 19-1에서 제조된 화합물(2 g, 8.02 mmol)을 메탄올(60 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 200 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(1.2 g, 67%)을 얻었다.The compound (2 g, 8.02 mmol) prepared in Example 19-1 was dissolved in methanol (60 mL), palladium catalyst (10% Pd / C, 200 mg, 10 wt%) was added, Lt; / RTI > for 12 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (1.2 g, 67%).
실시예 19-3:Example 19-3: NN -(3-((2-((4-(4-아세틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (4-acetylpiperazin-1-yl) phenyl) amino) -6,7- dihydrosothieno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(4-아세틸피페라진-1-일)아닐린(1.25 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(110 mg, 17%)을 얻었다.Was used instead of 4- (4-acetylpiperazin-1-yl) aniline (1.25 mmol) instead of 4- (4- (pyrrolidin- 1 -yl) piperidin- The title compound (110 mg, 17%) was obtained by carrying out the same processes as in Example 1-3.
1H NMR (400MHz, DMSO-d 6) δ 10.34 (s, 1H), 9.32 (s, 1H), 7.60 (m, 2H), 7.43 (t, 1H), 7.26 (d, 2H), 6.94 (m, 1H), 6.65 (d, 2H), 6.43 (m, 1H), 6.26 (m, 1H), 5.77 (m, 1H), 3.57 - 3.49 (m, 4H), 3.39 (t, 2H), 3.21 (t, 2H), 3.00 - 2.88 (m, 4H), 2.00 (s, 3H) 1 H NMR (400MHz, DMSO- d 6) δ 10.34 (s, 1H), 9.32 (s, 1H), 7.60 (m, 2H), 7.43 (t, 1H), 7.26 (d, 2H), 6.94 (m (M, 1H), 6.65 (m, 4H), 3.39 (t, 2H), 3.21 t, 2H), 3.00-2.88 (m, 4H), 2.00 (s, 3H)
실시예 20: Example 20: (S)(S) -1-(4-((4-(3-아크릴아미도페녹시)-6,7-다이하이드로싸이에노[3,2--1- (4 - ((4- (3-acrylamidophenoxy) -6,7-dihydrosothieno [3,2- dd ]피리미딘-2-일)아미노)페닐)피롤리딘-2-카르복사마이드의 제조] Pyrimidin-2-yl) amino) phenyl) pyrrolidine-2-carboxamide
실시예 20-1: Example 20-1: (S)(S) -1-(4-나이트로페닐)피롤리딘-2-카르복사마이드의 제조-1- (4-nitrophenyl) pyrrolidine-2-carboxamide
(S)-피롤리딘-2-카르복사마이드(4 g, 35.04 mmol)와 4-플루오로 나이트로벤젠(3.7 mL, 34.7 mmol)을 다이메틸 설폭사이드(10 mL)에 용해시킨 후 탄산칼륨(5.3 g, 38.17 mmol)을 가하고 상온에서 12시간 동안 교반하였다. 반응이 종결되면 반응혼합물에 증류수를 가하여 고체를 생성시킨 후, 여과하고 증류수로 세척한 뒤 감압건조하여 표제화합물 (4.1 g, 50%)을 얻었다. ( 4 g, 35.04 mmol) and 4-fluoronitrobenzene (3.7 mL, 34.7 mmol) were dissolved in dimethylsulfoxide (10 mL) and potassium carbonate (5.3 g, 38.17 mmol), and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, distilled water was added to the reaction mixture to form a solid, which was filtered, washed with distilled water and dried under reduced pressure to obtain the title compound (4.1 g, 50%).
실시예 20-2: Example 20-2: (S)(S) -1-(4-아미노페닐)피롤리딘-2-카르복사마이드의 제조-1- (4-aminophenyl) pyrrolidine-2-carboxamide
상기 실시예 20-1에서 제조된 화합물(2g, 8.5 mmol)를 메탄올(60 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 200 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(1.1 g, 61%)을 얻었다.The compound (2 g, 8.5 mmol) prepared in Example 20-1 was dissolved in methanol (60 mL), palladium catalyst (10% Pd / C, 200 mg, 10 wt%) was added, Stir for 12 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (1.1 g, 61%).
실시예 20-3: Example 20-3: (S)(S) -1-(4-((4-(3-아크릴아미도페녹시)-6,7-다이하이드로싸이에노[3,2--1- (4 - ((4- (3-acrylamidophenoxy) -6,7-dihydrosothieno [3,2- dd ]피리미딘-2-일)아미노)페닐)피롤리딘-2-카르복사마이드의 제조] Pyrimidin-2-yl) amino) phenyl) pyrrolidine-2-carboxamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 (S)-1-(4-아미노페닐)피롤리딘-2-카르복사마이드(1.25 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(20 mg, 3%)을 얻었다. (S) -1- (4-aminophenyl) pyrrolidine-2-carboxamide (1.25 mmol) instead of 4- (4- (pyrrolidin- 1 -yl) piperidin- (20 mg, 3%) was obtained by carrying out the same processes as in Example 1-3.
1H NMR (400MHz, DMSO-d 6) δ 10.31 (s, 1H), 9.11 (s, 1H), 7.63 (s, 1H), 7.52 (m, 1H), 7.39 (t, 1H), 7.29 - 7.19 (m, 3H), 7.00 - 6.90 (m, 2H), 6.44 (m, 1H), 6.30 - 6.18 (m, 3H), 5.77 (m, 1H), 3.72 (m, 1H), 3.47 (m, 1H), 3.38 (t, 2H), 3.20 (t, 2H), 3.06 (m, 1H), 2.15 (m, 1H), 2.00 - 1.86 (m, 3H) 1 H NMR (400 MHz, DMSO- d 6 )? 10.31 (s, IH), 9.11 (s, IH), 7.63 (s, IH), 7.52 (m, 3H), 3.72 (m, 1H), 3.47 (m, 2H) ), 3.38 (t, 2H), 3.20 (t, 2H), 3.06 (m,
실시예 21: Example 21: NN -(3-((2-((4-(2-아세틸-2,7-다이아자스파이로[3.5]노네인-7-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-Phenyl) amino) -6,7-dihydrosothieno [3, 5-dihydro- 3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 21-1: 1-(7-(4-아미노페닐)-2,7-다이아자스파이로[3.5]노네인-2-일)에탄온의 제조 Example 21-1: Preparation of 1- (7- (4-aminophenyl) -2,7-diazaspiro [3.5] nonane-2-yl) ethanone
1-(7-(4-나이트로페닐)-2,7-다이아자스파이로[3.5]노네인-2-일)에탄온(150 mg, 0.52 mmol), 아연(170 mg, 2.59 mmol) 및 염화 암모늄 (140 mg, 2.59 mmol)을 테트라하이드로퓨란(10 mL)과 메탄올(10 mL)에 현탁시킨 후 상온에서 24 시간 동안 교반하였다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 아연 및 염화 암모늄을 제거하고, 여액을 감압 증류하여 표제화합물(48 mg, 36%)을 얻었다.Diazaspiro [3.5] nonane-2-yl) ethanone (150 mg, 0.52 mmol), zinc (170 mg, 2.59 mmol) and Ammonium chloride (140 mg, 2.59 mmol) was suspended in tetrahydrofuran (10 mL) and methanol (10 mL) and stirred at room temperature for 24 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove zinc and ammonium chloride, and the filtrate was distilled under reduced pressure to obtain the title compound (48 mg, 36%).
실시예 21-2: Example 21-2: NN -(3-((2-((4-(2-아세틸-2,7-다이아자스파이로[3.5]노네인-7-일l)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2 - ((4- (2-Acetyl-2,7-diazaspiro [3.5] nonane-7-yl) phenyl) amino) -6,7-dihydrothieno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 1-(7-(4-아미노페닐)-2,7-다이아자스파이로[3.5]노네인-2-일)에탄온(36 mg, 0.14 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(11 mg, 14%)을 얻었다.(7- (4-aminophenyl) -2,7-diazaspiro [3.5] nonane-2-carboxamide was used instead of 4- (4- (pyrrolidin- 1 -yl) piperidin- The title compound (11 mg, 14%) was obtained by following the same procedure as in Example 1-3, except that 2-yl) ethanone (36 mg, 0.14 mmol) was used.
1H-NMR (400 MHz, CDCl3) δ 7.66 (m, 1H), 7.40 (t, 1H), 7.20 (d, 2H), 6.99 (dd, 1H), 6.78 (s, 1H), 6.73 (d, 2H), 6.44 (dd, 1H), 6.23 (dd, 1H), 5.79 (dd, 1H), 3.83 (s, 2H), 3.73 (s, 2H), 3.38 (t, 2H), 3.26 (t, 2H), 2.99 (t, 3H), 1.89 (s, 3H) 1 H-NMR (400 MHz, CDCl 3) δ 7.66 (m, 1H), 7.40 (t, 1H), 7.20 (d, 2H), 6.99 (dd, 1H), 6.78 (s, 1H), 6.73 (d 2H), 3.43 (s, 2H), 3.44 (d, 2H), 3.44 (d, 2H), 2.99 (t, 3H), 1.89 (s, 3H)
실시예 22: Example 22: NN -(3-((2-((4-몰폴리노페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2 - ((4 -morpholinophenyl) amino) -6,7-dihydrosothieno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 22-1: 4-몰폴리노아닐린의 제조Example 22-1: Preparation of 4-mololyphenoaniline
1-(7-(4-나이트로페닐)-2,7-다이아자스파이로[3.5]노네인-2-일)에탄온 대신 4-(4-나이트로페닐)몰폴린(1.8 g, 8.65 mmol)을 사용한 것을 제외하고는, 실시예 21-1과 동일한 공정을 수행하여 표제화합물(0.8 g, 51%)을 얻었다.(4-nitrophenyl) morpholine (1.8 g, 8.65 mmol) instead of 1- (7- (4-nitrophenyl) -2,7- diazaspiro [3.5] mmol) was used in place of acetic anhydride, the title compound (0.8 g, 51%) was obtained.
실시예 22-2: Example 22-2: NN -(3-((2-((4-몰폴리노페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2 - ((4 -morpholinophenyl) amino) -6,7-dihydrosothieno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-몰폴리노아닐린(320 mg, 1.8 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(300 mg, 35%)을 얻었다.The procedure of Example 1-3 was repeated except that 4-morpholinoaniline (320 mg, 1.8 mmol) was used instead of 4- (4- (pyrrolidin-1-yl) piperidin- The same procedure was followed to give the title compound (300 mg, 35%).
1H-NMR (400 MHz, DMSO-d 6 ) δ 10.34 (s, 1H), 9.31 (s, 1H), 7.62 - 7.57 (m, 2H), 7.42 (t, 1H), 7.26 (d, 2H), 6.93 (ddd, 1H), 6.63 (d, 2H), 6.43 (dd, 1H), 6.26 (dd, 1H), 5.80 - 5.75 (m, 2H), 3.73 - 3.67 (m, 4H), 3.44 - 3.36 (m, 2H), 3.22 (t, 2H), 2.95 - 2.88 (m, 4H) 1 H-NMR (400 MHz, DMSO- d 6) δ 10.34 (s, 1H), 9.31 (s, 1H), 7.62 - 7.57 (m, 2H), 7.42 (t, 1H), 7.26 (d, 2H) , 6.93 (dd, 1H), 6.63 (d, 2H), 6.43 (dd, (m, 2H), 3.22 (t, 2H), 2.95-2.88 (m, 4H)
실시예 23: Example 23: NN -(3-((2-((4-(피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (piperidin-1-yl) phenyl) amino) -6,7- dihydrothi eno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 23-1: 4-(피페리딘-1-일)아닐린의 제조Example 23-1: Preparation of 4- (piperidin-1-yl) aniline
1-(7-(4-나이트로페닐)-2,7-다이아자스파이로[3.5]노네인-2-일)에탄온 대신 1-(4-나이트로페닐)피페리딘(2.8 g, 13.58 mmol)을 사용한 것을 제외하고는, 실시예 21-1과 동일한 공정을 수행하여 표제화합물(2.1 g, 86%)을 얻었다.L- (4-nitrophenyl) piperidine (2.8 g, 3.9 mmol) instead of l- (7- (4-nitrophenyl) 13.58 mmol), the title compound (2.1 g, 86%) was obtained.
실시예 23-2: Example 23-2: NN -(3-((2-((4-(피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (piperidin-1-yl) phenyl) amino) -6,7- dihydrothi eno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(피페리딘-1-일)아닐린(317 mg, 1.8 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(380 mg, 45%)을 얻었다.(317 mg, 1.8 mmol) instead of 4- (piperidin-1-yl) aniline instead of 4- (4- The procedure of Example 1-3 was repeated to obtain the title compound (380 mg, 45%).
1H-NMR (400 MHz, DMSO-d 6 ) δ 10.34 (s, 1H), 9.27 (s, 1H), 7.61 (m, 2H), 7.42 (t, 1H), 7.23 (d, 2H), 6.92 (ddd, 1H), 6.61 (d, 2H), 6.43 (dd, 1H), 6.26 (dd, 1H), 5.80 - 5.75 (m, 2H), 3.44 - 3.36 (m, 2H), 3.21 (t, 2H), 2.96 - 2.89 (m, 4H), 1.62 - 1.54 (m, 4H), 1.51 - 1.43 (m, 2H) 1 H-NMR (400 MHz, DMSO- d 6) δ 10.34 (s, 1H), 9.27 (s, 1H), 7.61 (m, 2H), 7.42 (t, 1H), 7.23 (d, 2H), 6.92 (dd, 1H), 6.61 (d, 2H), 6.43 (dd, 1H), 6.26 (dd, 1H), 5.80-5.75 (m, 2H), 3.44-3.36 ), 2.96-2.89 (m, 4H), 1.62-1.54 (m, 4H), 1.51-1.43 (m, 2H)
실시예 24: Example 24: NN -(3-((2-((4-(4,4-다이플루오로피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2 - ((4- (4,4-difluoropiperidin- 1 -yl) phenyl) amino) -6,7- dihydrothi eno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 24-1: 4-(4,4-다이플루오로피페리딘-1-일)아닐린의 제조Example 24-1: Preparation of 4- (4,4-difluoropiperidin-1-yl) aniline
1-(7-(4-나이트로페닐)-2,7-다이아자스파이로[3.5]노네인-2-일)에탄온 대신 4,4-다이플루오로-1-(4-나이트로페닐)피페리딘 (600 mg, 2.48 mmol)을 사용한 것을 제외하고, 실시예 21-1과 동일한 공정을 수행하여 표제화합물 (347 mg, 66%)을 얻었다.A solution of 4,4-difluoro-1- (4-nitrophenyl) -2,7-diaza-spiro [3.5] nonane- ) The title compound (347 mg, 66%) was obtained by following the same procedure as in Example 21-1, except using piperidine (600 mg, 2.48 mmol).
실시예 24-2: Example 24-2: NN -(3-((2-((4-(4,4-다이플루오로피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2 - ((4- (4,4-difluoropiperidin- 1 -yl) phenyl) amino) -6,7- dihydrothi eno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(4,4-다이플루오로피페리딘-1-일)아닐린(347 mg, 1.63 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(97 mg, 11%)을 얻었다.(347 mg, 1.63 mmol) instead of 4- (4,4-difluoropiperidin-1-yl) aniline in place of 4- (4- (pyrrolidin- 1 -yl) piperidin- , The title compound (97 mg, 11%) was obtained by carrying out the same step as in Example 1-3.
1H-NMR (400 MHz, DMSO-d 6 ) δ 10.34 (s, 1H), 9.33 (s, 1H), 7.60 (m, 2H), 7.42 (t, 1H), 7.27 (d, 2H), 6.93 (dd, 1H), 6.68 (d, 2H), 6.43 (dd, 1H), 6.26 (dd, 1H), 5.80 - 5.75 (m, 1H), 3.44 - 3.36 (m, 2H), 3.22 (t, 2H), 3.16 - 3.10 (m, 4H), 2.08 - 1.95 (m, 4H) 1 H-NMR (400 MHz, DMSO- d 6) δ 10.34 (s, 1H), 9.33 (s, 1H), 7.60 (m, 2H), 7.42 (t, 1H), 7.27 (d, 2H), 6.93 (m, 2H), 3.22 (t, 2H), 6.68 (d, 2H) ), 3.16-3.10 (m, 4H), 2.08-1.95 (m, 4H)
실시예 25: Example 25: NN -(3-((2-((4-(1-아세틸피페리딘-4-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2 - ((4- (1-acetylpiperidin-4-yl) oxy) phenyl) amino) -6,7- dihydrothi eno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 25-1: 1-(4-(4-아미노페녹시)피페리딘-1-일)에탄온의 제조Example 25-1: Preparation of 1- (4- (4-aminophenoxy) piperidin-1-yl) ethanone
1-(7-(4-나이트로페닐)-2,7-다이아자스파이로[3.5]노네인-2-일)에탄온 대신 1-(4-(4-나이트로페녹시)피페리딘-1-일)에탄온(1.5 g, 5.8 mmol)을 사용한 것을 제외하고, 실시예 21-1과 동일한 공정을 수행하여 표제화합물(0.8 g, 59%)을 얻었다.(4- (4-nitrophenoxy) piperidine was used instead of 1- (7- (4-nitrophenyl) -2,7- diazaspiro [3.5] -1-yl) ethanone (1.5 g, 5.8 mmol), the title compound (0.8 g, 59%) was obtained.
실시예 25-2: Example 25-2: NN -(3-((2-((4-(1-아세틸피페리딘-4-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2 - ((4- (1-acetylpiperidin-4-yl) oxy) phenyl) amino) -6,7- dihydrothi eno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 1-(4-(4-아미노페녹시)피페리딘-1-일)에탄온(600 mg, 2.56 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(330 mg, 24%)을 얻었다.(600 mg, 0.20 mmol) instead of 4- (4- (pyrrolidin-1-yl) piperidin- 2.56 mmol), the title compound (330 mg, 24%) was obtained.
1H-NMR (400 MHz, DMSO-d 6 ) δ 10.34 (s, 1H), 9.36 (s, 1H), 7.62 (t, 1H), 7.57 (d, 1H), 7.42 (t, 1H), 7.29 (d, 2H), 6.94 (dd, 1H), 6.65 (d, 2H), 6.43 (dd, 1H), 6.26 (dd, 1H), 5.80 - 5.75 (m, 2H), 4.38 (m, 1H), 3.79 (m, 1H), 3.63 (m, 1H), 3.44 - 3.29 (m, 4H), 3.23 (t, 2H), 1.91 - 1.75 (m, 2H), 1.59 - 1.36 (m, 2H) 1 H-NMR (400 MHz, DMSO- d 6) δ 10.34 (s, 1H), 9.36 (s, 1H), 7.62 (t, 1H), 7.57 (d, 1H), 7.42 (t, 1H), 7.29 (d, 2H), 6.94 (d, 2H), 6.94 (d, 2H) 2H), 1.91-1.75 (m, 2H), 1.59-1.36 (m, 2H), 3.79 (m,
실시예26: Example 26: NN -(3-((2-((4-(4-(2-메톡시에틸)피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-Yl) phenyl) amino) -6,7-dihydrosothieno [3,2-c] pyridin- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 26-1: 4-(4-(2-메톡시에틸)피페라진-1-일)아닐린의 제조Example 26-1: Preparation of 4- (4- (2-methoxyethyl) piperazin-1-yl) aniline
1-(2-메톡시에틸)-4-(4-나이트로페닐)피페라진(4.3g, 16.02 mmol)를 메탄올(120 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 430 mg, 10 wt%)를 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(3.7 g, 97%)을 얻었다.After dissolving 1- (2-methoxyethyl) -4- (4-nitrophenyl) piperazine (4.3 g, 16.02 mmol) in methanol (120 mL), palladium catalyst (10% Pd / C, 430 mg , 10 wt%) were added and stirred under hydrogen gas at room temperature for 12 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (3.7 g, 97%).
실시예 26-2: Example 26-2: NN -(3-((2-((4-(4-(2-메톡시에틸)피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-Yl) phenyl) amino) -6,7-dihydrosothieno [3,2-c] pyridin- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(4-(2-메톡시에틸)피페라진-1-일)아닐린(2.13 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물 (130 mg, 11%)을 얻었다. (2.13 mmol) of 4- (4- (2-methoxyethyl) piperazin-1-yl) aniline instead of 4- (4- (pyrrolidin- 1 -yl) piperidin- , The title compound (130 mg, 11%) was obtained by carrying out the same processes as in Example 1-3.
1H NMR (400MHz, DMSO-d 6) δ 10.34 (s, 1H), 9.28 (s, 1H), 7.63 - 7.55 (m, 2H), 7.42 (t, 1H), 7.24 (d, 2H), 6.93 (m, 1H), 6.61 (d, 2H), 6.43 (m, 1H), 6.26 (m, 1H), 5.77 (m, 1H), 3.46 (t, 2H), 3.39 (t, 2H), 3.25 (s, 3H), 3.21 (t, 2H), 2.97 - 2.90 (m, 4H), 2.54 - 2.48 (m, 6H) 1 H NMR (400MHz, DMSO- d 6) δ 10.34 (s, 1H), 9.28 (s, 1H), 7.63 - 7.55 (m, 2H), 7.42 (t, 1H), 7.24 (d, 2H), 6.93 (t, 2H), 3.39 (t, 2H), 3.25 (m, IH) (s, 3H), 3.21 (t, 2H), 2.97-2.90 (m, 4H), 2.54-2.48
실시예 27: Example 27: NN -(3-((2-((4-(2-몰포리노에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (2-morpholinoethoxy) phenyl) amino) -6,7- dihydrosothieno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 27-1: 4-(2-몰포리노에톡시)아닐린의 제조Example 27-1: Preparation of 4- (2-morpholinoethoxy) aniline
4-(2-(4-나이트로페녹시)에틸)몰폴린(3 g, 11.89 mmol)를 메탄올 (80 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 300 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물 (2.24 g, 85%)을 얻었다.Pd / C (300 mg, 10 wt%) was added to the solution after dissolving 4- (2- (4-nitrophenoxy) ethyl) morpholine (3 g, 11.89 mmol) ) Was added, and the mixture was stirred under a hydrogen gas atmosphere at room temperature for 12 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (2.24 g, 85%).
실시예 27-2: Example 27-2: NN -(3-((2-((4-(2-몰포리노에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (2-morpholinoethoxy) phenyl) amino) -6,7- dihydrosothieno [3,2- dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 4-(2-몰포리노에톡시)아닐린(1.35 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(50 mg, 7%)을 얻었다Example 1 was repeated except that 4- (2-morpholinoethoxy) aniline (1.35 mmol) was used instead of 4- (4- (pyrrolidin-1-yl) piperidin- 3, the title compound (50 mg, 7%) was obtained
1H NMR (400MHz, CDCl3) δ 8.08 (s, 1H), 7.55- 7 .39 (m, 2H), 7.30 (t, 1H), 7.17 (d, 2H), 7.11 (s, 1H), 6.92 (d, 1H), 6.65 (d, 2H), 6.39 (m, 1H), 6.23 (m, 1H), 5.70 (d, 1H), 3.39 (t, 2H), 3.21 (t, 2H), 2.97 - 2.90 (m, 4H), 2.43 - 2.37 (m, 4H), 2.20 (s, 3H) 1 H NMR (400MHz, CDCl 3 ) δ 8.08 (s, 1H), 7.55- 7 .39 (m, 2H), 7.30 (t, 1H), 7.17 (d, 2H), 7.11 (s, 1H), 6.92 (t, 2H), 2.97 (d, IH), 3.65 (d, IH) 2.90 (m, 4H), 2.43-2.37 (m, 4H), 2.20 (s, 3H)
실시예 28: Example 28: NN -(3-((2-((4-(4-(2-(다이메틸아미노)아세틸)피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-Yl) phenyl) amino) -6,7-dihydrosothieno [3,2 < RTI ID = 0.0 > - dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 28-1: 1-(4-(4-아미노페닐)피페라진-1-일)-2-(다이메틸아미노)에타논의 제조Example 28-1: Preparation of 1- (4- (4-aminophenyl) piperazin-1-yl) -2- (dimethylamino) ethanone
2-(다이메틸아미노)-1-(4-(4-나이트로페닐)피페라진-1-일)에타논(2 g, 6.84 mmol)을 메탄올(60 mL)에 용해시킨 후, 팔라듐 촉매(10% Pd/C, 200 mg, 10 wt%)을 가하고 수소가스 하에 상온에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 팔라듐 촉매를 제거하고, 여액을 감압 증류하여 표제화합물(1.6 g, 89%)을 얻었다.After dissolving 2- (dimethylamino) -1- (4- (4-nitrophenyl) piperazin-1-yl) ethanone (2 g, 6.84 mmol) in methanol (60 mL) 10% Pd / C, 200 mg, 10 wt%) was added and stirred under hydrogen gas at room temperature for 12 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove the palladium catalyst, and the filtrate was distilled under reduced pressure to obtain the title compound (1.6 g, 89%).
실시예 28-2: Example 28-2: NN -(3-((2-((4-(4-(2-(다이메틸아미노)아세틸)피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-Yl) phenyl) amino) -6,7-dihydrosothieno [3,2 < RTI ID = 0.0 > - dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 1-(4-(4-아미노페닐)피페라진-1-일)-2-(다이메틸아미노)에타논(1.91 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(150 mg, 14%)을 얻었다.(4-aminophenyl) piperazin-1-yl) -2- (dimethylamino) piperidine was used in the place of 4- (4- (pyrrolidin- 1 -yl) piperidin- The title compound (150 mg, 14%) was obtained by carrying out the same processes as in Example 1-3 except that ethanone (1.91 mmol) was used.
1H NMR (400MHz, DMSO-d 6) δ 10.38 (s, 1H), 9.33 (s, 1H), 7.64 - 7.57 (m, 2H), 7.42 (t, 1H), 7.26 (d, 2H), 6.93 (m, 1H), 6.65 (d, 2H), 6.44 (m, 1H), 6.26 (m, 1H), 5.77 (m, 1H), 3.67 - 3.60 (m, 2H), 3.59 - 3.52 (m, 2H), 3.40 (t, 2H), 3.22 (t, 2H), 3.16 (s, 2H), 2.99 - 2.86 (m, 4H), 2.22 (s, 6H) 1 H NMR (400MHz, DMSO- d 6) δ 10.38 (s, 1H), 9.33 (s, 1H), 7.64 - 7.57 (m, 2H), 7.42 (t, 1H), 7.26 (d, 2H), 6.93 (m, 2H), 6.65 (m, 1H), 6.65 (m, 1H), 6.65 ), 3.40 (t, 2H), 3.22 (t, 2H), 3.16 (s, 2H), 2.99-2.86
실시예 29: Example 29: NN -(3-((2-((4-(4-메틸피페라진-1-카보닐)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (4-methylpiperazine-1-carbonyl) phenyl) amino) -6,7- dihydrosothieno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
실시예 29-1: (4-아미노페닐)(4-메틸피페라진-1-일)메타논의 제조Example 29-1: Preparation of (4-aminophenyl) (4-methylpiperazin-1-yl) methanone
(4-메틸피페라진-1-일)(4-나이트로페닐)메타논(5.3 g, 21.14 mmol), 아연(7.1 g, 108.67 mmol) 및 염화 암모늄(5.8 g, 108.67 mmol)을 테트라하이드로퓨란(100 mL)과 메탄올(60 mL)에 현탁시킨 후 상온에서 24 시간 동안 교반하였다. 반응이 종결되면 반응 혼합물을 셀라이트가 충진된 필터로 여과시켜 아연 및 염화 암모늄을 제거하고, 여액을 감압 증류하여 표제화합물(4.6 g, 99%)을 얻었다.(5.3 g, 21.14 mmol), zinc (7.1 g, 108.67 mmol) and ammonium chloride (5.8 g, 108.67 mmol) in tetrahydrofuran (100 mL) and methanol (60 mL), and the mixture was stirred at room temperature for 24 hours. When the reaction was completed, the reaction mixture was filtered through a filter packed with celite to remove zinc and ammonium chloride, and the filtrate was distilled under reduced pressure to obtain the title compound (4.6 g, 99%).
실시예 29-2: Example 29-2: NN -(3-((2-((4-(4-메틸피페라진-1-카보닐)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-- (3 - ((2- ((4- (4-methylpiperazine-1-carbonyl) phenyl) amino) -6,7- dihydrosothieno [ dd ]피리미딘-4-일)옥시)페닐)아크릴아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) acrylamide
4-(4-(피롤리딘-1-일)피페리딘-1-일)아닐린 대신 (4-아미노페닐)(4-메틸피페라진-1-일)메타논(1.2 mmol)을 사용한 것을 제외하고는, 실시예 1-3과 동일한 공정을 수행하여 표제화합물(77 mg, 12%)을 얻었다.(1.2 mmol) of (4-aminophenyl) (4-methylpiperazin-1-yl) methanone was used instead of 4- (4- (pyrrolidin- 1 -yl) piperidin- , The procedure of Example 1-3 was repeated to obtain the title compound (77 mg, 12%).
1H NMR (400MHz, DMSO-d 6) δ 10.34 (s, 1H), 9.78 (s, 1H), 7.68 (t, 1H), 7.56 (m, 1H), 7.47 -7.39 (m, 3H), 7.05 (d, 2H), 6.96 (m, 1H), 6.42 (m, 1H), 6.24 (m, 1H), 5.76 (m, 1H), 3.51 - 3.33 (br, 4H), 3.43 (t, 2H), 3.28 (t, 2H), 2.97 - 2.90 (m, 4H), 2.31 - 2.22 (br, 4H), 2.19 (s, 3H) 1 H NMR (400MHz, DMSO- d 6) δ 10.34 (s, 1H), 9.78 (s, 1H), 7.68 (t, 1H), 7.56 (m, 1H), 7.47 -7.39 (m, 3H), 7.05 2H), 6.96 (m, 1H), 6.42 (m, 1H), 6.24 (m, 2H), 2.97-2.90 (m, 4H), 2.31-2.22 (br, 4H), 2.19 (s, 3H)
실시예 30: Example 30: (E)(E) -4-(다이메틸아미노)--4- (dimethylamino) - NN -(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-5,6-다이하이드로싸이에노[2,3-- (3 - ((2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) -5,6-dihydrothi eno [2,3- dd ]피리미딘-4-일)옥시)페닐)뷰트-2-엔아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) but-2-enamide
4-(3-아미노페녹시)-N-(4-(4-메틸피페라진-1-일)페닐)-5,6-다이하이드로싸이에노[2,3-d]피리미딘-2-아민(400 mg, 0.92 mmol)을 N,N-다이메틸폼아마이드(3 mL)에 용해시키고 (E)-4-(다이메틸아미노)뷰트-2-엔산 염산염(244 mg, 1.47 mmol), N-(3-다이메틸아미노프로필)-N'-에틸카보다이이미드 염산염(282 mg, 1.47 mmol)과 피리딘(0.3 mL, 3.68 mmol)을 가하여 상온에서 3 시간 동안 교반하였다. 반응이 완결되면 반응혼합물을 에틸 아세테이트로 묽히고 포화염수로 세척하였다. 유기층을 무수황산나트륨으로 건조한 후, 감압 여과 및 감압 증류하였다. 얻어진 잔사를 컬럼 크로마토그래피(다이클로로메탄 : 에틸 아세테이트 : 메탄올 = 3 : 3 : 1 (부피비))로 분리하여 표제화합물(226 mg, 45%)을 얻었다.4- (3-aminophenoxy) - N - (4- (4-methylpiperazin-1-yl) phenyl) -5,6-dihydro furnace to Im [2,3- d] pyrimidin-2 amine (400 mg, 0.92 mmol) of N, N - dimethyl was dissolved in dimethylformamide (3 mL) (E) -4- ( dimethylamino) -but-2-enoic acid hydrochloride (244 mg, 1.47 mmol), N -stirred-ethylcarbodiimide hydrochloride (282 mg, 1.47 mmol) and 3 h at room temperature was added pyridine (0.3 mL, 3.68 mmol) - (3- dimethylaminopropyl) - N '. When the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The obtained residue was separated by column chromatography (dichloromethane: ethyl acetate: methanol = 3: 3: 1 (volume ratio)) to obtain the title compound (226 mg, 45%).
1H NMR (400MHz, δ 10.20 (s, 1H), 9.24 (s, 1H), 7.58 - 7.49 (m, 2H), 7.36 (t, 1H), 7.19 (d, 2H), 6.86 (ddd, 1H), 6.69 (dt, 1H), 6.57 (d, 2H), 6.22 (dt, 1H), 3.35 (t, 2H), 3.17 (t, 2H), 3.00 (dd, 2H), 2.94 - 2.86 (m, 4H), 2.39 - 2.34 (m, 4H), 2.16 (s, 3H). 1 H NMR (400MHz, δ 10.20 (s, 1H), 9.24 (s, 1H), 7.58 - 7.49 (m, 2H), 7.36 (t, 1H), 7.19 (d, 2H), 6.86 (ddd, 1H) 2H), 3.69 (dd, 2H), 3.69 (d, 2H), 3.60 (d, ), 2.39-2.34 (m, 4H), 2.16 (s, 3H).
실시예 31: Example 31: (E)(E) -4-(다이메틸아미노)--4- (dimethylamino) - NN -(3-((2-((4-몰폴리노페닐)아미노)-5,6-다이하이드로싸이에노[2,3-- (3 - ((2- ((4 -morpholinophenyl) amino) -5,6-dihydrosothieno [2,3- dd ]피리미딘-4-일)옥시)페닐)뷰트-2-엔아마이드의 제조] Pyrimidin-4-yl) oxy) phenyl) but-2-enamide
4-(3-아미노페녹시)-N-(4-(4-메틸피페라진-1-일)페닐)-5,6-다이하이드로싸이에노[2,3-d]피리미딘-2-아민 대신 4-(3-아미노페녹시)-N-(4-몰폴리노페닐)-5,6-다이하이드로싸이에노[2,3-d]피리미딘-2-아민(150 mg, 0.36 mmol)을 사용한 것을 제외하고, 실시예 30과 동일한 공정을 수행하여 표제화합물(70 mg, 37%)을 얻었다.4- (3-aminophenoxy) - N - (4- (4-methylpiperazin-1-yl) phenyl) -5,6-dihydro furnace to Im [2,3- d] pyrimidin-2 amine instead of 4- (3-aminophenoxy) - N - (4-morpholinophenyl) -5,6-dihydro furnace to Im [2,3- d] pyrimidin-2-amine (150 mg, 0.36 mmol), the title compound (70 mg, 37%) was obtained by carrying out the same processes as in Example 30.
1H NMR (400MHz, δ 10.34 (s, 1H), 9.31 (s, 1H), 7.62 - 7.57 (m, 2H), 7.42 (t, 1H), 7.26 (d, 2H), 6.93 (ddd, 1H), 6.63 (d, 2H), 6.43 (dd, 1H), 6.26 (dd, 1H), 5.80 - 5.75 (m, 2H), 3.73 - 3.67 (m, 4H), 3.44 - 3.36 (m, 2H), 3.22 (t, 2H), 2.95 - 2.88 (m, 4H). 1 H NMR (400MHz, δ 10.34 (s, 1H), 9.31 (s, 1H), 7.62 - 7.57 (m, 2H), 7.42 (t, 1H), 7.26 (d, 2H), 6.93 (ddd, 1H) , 6.63 (d, 2H), 6.43 (dd, IH), 6.26 (dd, IH), 5.80-5.75 (m, 2H), 3.73-3.67 (t, 2H), 2.95-2.88 (m, 4H).
실험예 1: 키나아제 활성 시험Experimental Example 1: Kinase activity test
화합물의 BTK, BMX, JAK3 키나아제에 대한 활성억제율은 FRET을 이용한 기질(substrate)의 인산화작용 억제율을 측정함으로서 결정하였고, Thermo Fisher Scientific사에 의뢰하여 Z'-LYTE assay 시험법에 따라 진행되었다.The inhibition rate of the compounds against BTK, BMX, and JAK3 kinase was determined by measuring the inhibition rate of substrate phosphorylation using FRET, and was conducted according to the Z'-LYTE assay method, commissioned by Thermo Fisher Scientific.
측정하고자 하는 화합물은 각 키나아제를 반응하여 기질인 FRET-peptide 인산화 반응이 조절되고, 인산화 유무에 따라 FRET-peptide가 분열되거나 분열되지 않는다. 분열된 FRET-peptide(445 nm)와 분열되지 않은 FRET-peptide(520 nm)의 각각의 emission을 측정하고, emission ratio(445 nm/520 nm)를 계산하여 활성을 50% 억제하는 IC50 values를 확인하였다. IC50 값 범위는 표 1에 다음과 같이 표기하였다: A (IC50<100 nM), B (100 nM<IC50<1,000 nM), C (IC50>1,000 nM).The compound to be measured reacts with each kinase to control the substrate, the FRET-peptide phosphorylation, and the FRET-peptide is not cleaved or disrupted depending on phosphorylation status. By measuring each emission that is not split and the split FRET-peptide (445 nm) FRET -peptide (520 nm) , and calculating the emission ratio (445 nm / 520 nm ) of the active IC 50 values of 50% inhibition Respectively. The IC 50 value ranges are indicated in Table 1 as follows: A (IC 50 <100 nM), B (100 nM <IC 50 <1,000 nM), C (IC 50 > 1,000 nM).
[표 1] BTK, BMX 및 JAK3 키나아제 저해 활성 (IC50)[Table 1] BTK, BMX and JAK3 kinase inhibitory activity (IC 50 )
상기 표 1에서 볼 수 있듯이, 본 발명의 화합물들이 BTK, BMX 및 JAK3 키나아제를 매우 우수한 활성으로 억제함을 확인할 수 있었다.As can be seen from Table 1, it was confirmed that the compounds of the present invention inhibit BTK, BMX and JAK3 kinase with very excellent activity.
실험예 2: CIA(collagen-induced arthritis) 마우스 모델 시험Experimental Example 2: CIA (collagen-induced arthritis) mouse model test
콜라겐 주입을 통한 류마티스 관절염모델을 이용하여 시험물질의 관절염 개선효능을 탐색하고자 콜라겐-유도 관절염(collagen-induced arthritis, CIA) 모델을 제작하였다. 2 mg/ml의 소의 2형 콜라겐(collagen)과 4 mg/ml의 CFA(Freund's complete adjuvant)를 혼합하여 에멀젼화(emulsion)한 후, 이 용액을 6주령 수컷 DBA/1J 마우스의 꼬리 기저에서 2 cm 가량 되는 부위에 피내 주사하여 1차 면역을 유도하였다. 1차 면역 후 21일째에 소의 2형 콜라겐을 IFA(Freund's incomplete adjuvant)와 혼합하여 상기와 동일한 방법으로 에멀젼화 한 후, 꼬리 부위에 피내 주사하여 2차 면역(boosting) 반응을 유도하였으며, 2차 면역 반응 유도 10일 후 clinical score의 평균값(score index)을 기준으로 6 마리씩 5 그룹으로 군분리 하였다. 각 군은 (1) 질환 유도군 (2) 실시예 3 (10 mg/kg, QD), (3) 실시예 3 (30 mg/kg, QD), (4) 덱사메타손(dexamethasone) (0.05mg/kg, QD), (5) 실시예 3 (30 mg/kg, BID)의 조건으로 2주간 매일 경구 투여하였고, 투여기간 동안 매일 일반증상을 관찰하였으며, 주 2회씩 index score를 측정하여 그 결과를 도 1에 나타내었다. A collagen-induced arthritis (CIA) model was developed to investigate the efficacy of arthritis-improving agents in rheumatoid arthritis model through collagen injection. 2 mg / ml bovine type 2 collagen and 4 mg / ml CFA (Freund's complete adjuvant) were mixed and emulsified. The solution was applied to the tail base of 6-week-old male DBA / cm < / RTI > to induce primary immunity. On day 21 after the first immunization, bovine type 2 collagen was mixed with IFA (Freund ' s incomplete adjuvant), emulsified in the same manner as described above, and intracutaneously injected into the tail region to induce a secondary boosting reaction. After 10 days of induction of immune response, group was divided into 5 groups according to the average score of clinical score (score index). Each group was divided into three groups: (1) disease induction group (2), Example 3 (10 mg / kg, QD), (3) Example 3 (30 mg / kg, QD), (4) dexamethasone kg, QD), (5) Example 3 (30 mg / kg, BID) for 2 weeks, and the general symptoms were observed daily during the administration period. Index scores were measured twice a week, 1.
Claims (10)
[화학식 1]
상기 식에서,
X는 직접결합, O, NH, C(=O) 또는 헤테로사이클로알킬이고;
Y는 알콕시알킬, 헤테로사이클로알킬 또는 헤테로사이클로알킬알킬이며;
W는 O 또는 NH이고;
Z는 또는 이며;
R1은 수소, 알콕시 또는 할로겐이고;
R2는 수소 또는 다이알킬아미노알킬이다.Claims 1. A compound of the formula 1: < RTI ID = 0.0 > pharmaceutically < / RTI > acceptable salt or stereoisomer thereof:
[Chemical Formula 1]
In this formula,
X is a direct bond, O, NH, C (= O) or heterocycloalkyl;
Y is alkoxyalkyl, heterocycloalkyl or heterocycloalkylalkyl;
W is O or NH;
Z is or ;
R < 1 > is hydrogen, alkoxy or halogen;
R < 2 > is hydrogen or dialkylaminoalkyl.
N-(3-((2-((4-(4-(피롤리딘-1-일)피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((4-((테트라하이드로퓨란-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((4-(1-메틸피페리딘-4-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((4-(1-에틸피페리딘-4-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
(R)-N-(3-((2-((4-((1-메틸피롤리딘-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
(S)-N-(3-((2-((4-((1-메틸피롤리딘-3-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((4-((1-메틸피페리딘-4-일)아미노)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((4-(2-(4,4-다이메틸-1,4-아자실란-1-일)에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((3-플루오로-4-몰포리노페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)에탄설폰아마이드;
N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)아크릴아마이드;
N-(3-((2-((4-(4-메틸-4-옥시도-1,4-아자포스피난-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((2-메톡시-4-(4-메틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((4-((1-메틸피페리딘-4-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((4-(2-메톡시에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((4-(4-에틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((4-(4-아이소프로필피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((4-(4-아세틸피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
(S)-1-(4-((4-(3-아크릴아미도페녹시)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-2-일)아미노)페닐)피롤리딘-2-카르복사마이드;
N-(3-((2-((4-(2-아세틸-2,7-다이아자스파이로[3.5]노네인-7-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((4-몰폴리노페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((4-(피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((4-(4,4-다이플루오로피페리딘-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((4-(1-아세틸피페리딘-4-일)옥시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((4-(4-(2-메톡시에틸)피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((4-(2-몰포리노에톡시)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((4-(4-(2-(다이메틸아미노)아세틸)피페라진-1-일)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]피리미딘-4-일)옥시)페닐)아크릴아마이드;
N-(3-((2-((4-(4-메틸피페라진-1-카보닐)페닐)아미노)-6,7-다이하이드로싸이에노[3,2-d]미리미딘-4-일)옥시)페닐)아크릴아마이드;
(E)-4-(다이메틸아미노)-N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-5,6-다이하이드로싸이에노[2,3-d]피리미딘-4-일)옥시)페닐)뷰트-2-엔아마이드; 및
(E)-4-(다이메틸아미노)-N-(3-((2-((4-몰폴리노페닐)아미노)-5,6-다이하이드로싸이에노[2,3-d]피리미딘-4-일)옥시)페닐)뷰트-2-엔아마이드.2. A compound according to claim 1, wherein the compound is selected from the group consisting of the following compounds: < RTI ID = 0.0 > pharmaceutically < / RTI > acceptable salts or stereoisomers thereof:
N - (3 - ((2 - ((4- (4- ( pyrrolidin-1-yl) piperidin-1-yl) phenyl) amino) -6,7-dihydro-furnace to thieno [3, D ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
N - (3 - ((2 - ((4 - ((tetrahydrofuran-3-yl) oxy) phenyl) amino) -6,7- dihydrosothieno [3,2- d ] pyrimidin- Yl) oxy) phenyl) acrylamide;
N - (3 - ((2 - ((4- (1- methylpiperidin-4-yl) phenyl) amino) -6,7-dihydro-furnace to Im [3,2- d] pyrimidin -4 Yl) oxy) phenyl) acrylamide;
N - (3 - ((2 - ((4- (1- ethyl-4-yl) phenyl) amino) -6,7-dihydro-Im in the furnace [3,2- d] pyrimidin -4 Yl) oxy) phenyl) acrylamide;
(R) - N - (3 - ((2 - ((4 - ((1- methyl-pyrrolidin-3-yl) oxy) phenyl) amino) -6,7-dihydro-to Im [3,2 - d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
(S) - N - (3 - ((2 - ((4 - ((1- methyl-pyrrolidin-3-yl) oxy) phenyl) amino) -6,7-dihydro-to Im [3,2 - d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
N - (3 - ((2 - ((4 - ((1- methylpiperidin-4-yl) amino) phenyl) amino) -6,7-dihydro-furnace to Im [3,2- d] pyrimidin 4-yl) oxy) phenyl) acrylamide;
N - (3 - ((2 - ((4- (2- (4,4-Dimethyl-1, 4-azacsilan-1-yl) ethoxy) phenyl) amino) -6, 7-dihydrothiazole Ethano [3,2- d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
N - (3 - ((2 - ((3- to 4-Dimorpholino Reno) amino) -6,7-dihydro-Im in no-fluoro [3,2- d] pyrimidin-4-yl) oxy) Phenyl) acrylamide;
N - (3 - ((2 - ((4- (4- methylpiperazin-1-yl) phenyl) amino) -6,7-dihydro-furnace to Im [3,2- d] pyrimidin-4 Yl) oxy) phenyl) acrylamide;
N - (3 - ((2 - ((4- (4- methylpiperazin-1-yl) phenyl) amino) -6,7-dihydro-furnace to Im [3,2- d] pyrimidin-4 Yl) oxy) phenyl) ethanesulfonamide;
N - (3 - ((2 - ((4- (4- methylpiperazin-1-yl) phenyl) amino) -6,7-dihydro-furnace to Im [3,2- d] pyrimidin-4 Yl) amino) phenyl) acrylamide;
N - (3 - ((2- ((4- (4-methyl-4-oxido-1,4-azaphosphinan-1-yl) phenyl) amino) -6,7- dihydrosothieno [ D ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
N - (3 - ((2 - ((2- methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -6,7-dihydro-Im in the furnace [3,2- d] Pyrimidin-4-yl) oxy) phenyl) acrylamide;
N - (3 - ((2 - ((4 - ((1- methylpiperidin-4-yl) oxy) phenyl) amino) -6,7-dihydro-Im in the furnace [3,2- d] pyrimidin 4-yl) oxy) phenyl) acrylamide;
N - (3 - ((2 - ((4- (2- methoxyethoxy) phenyl) amino) -6,7-dihydro furnace to Im [3,2- d] pyrimidin-4-yl) oxy ) Phenyl) acrylamide;
N - (3 - ((2 - ((4- (4- ethyl-piperazin-1-yl) phenyl) amino) -6,7-dihydro-furnace to Im [3,2- d] pyrimidin-4 Yl) oxy) phenyl) acrylamide;
N - (3 - ((2 - ((4- (4- isopropyl-piperazin-1-yl) phenyl) amino) -6,7-dihydro-furnace to Im [3,2- d] pyrimidin -4 Yl) oxy) phenyl) acrylamide;
N - (3 - ((2 - ((4- (4- acetyl-piperazin-1-yl) phenyl) amino) -6,7-dihydro-furnace to Im [3,2- d] pyrimidin-4 Yl) oxy) phenyl) acrylamide;
(S) -1- (4 - ((4- (3-acrylamidophenoxy) -6,7-dihydrothieno [3,2- d ] pyrimidin- Pyrrolidine-2-carboxamide;
N - (3 - ((2 - ((4- (2- acetyl-2,7-diaza-Spy to [3.5] nonane-7-yl) phenyl) amino) -6,7-dihydro-Im in the furnace [3,2- d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
N - (3 - ((2 - ((4- morpholinophenyl) amino) -6,7-dihydro-furnace to Im [3,2- d] pyrimidin-4-yl) oxy) phenyl) acrylamide ;
N - (3 - ((2 - ((4- ( piperidin-1-yl) phenyl) amino) -6,7-dihydro-Im in the furnace [3,2- d] pyrimidin-4-yl) Oxy) phenyl) acrylamide;
N - (3 - ((2 - ((4- ( piperidin-1-yl) 4,4-difluorophenyl) amino) -6,7-dihydro-Im in the furnace [3,2- d] Pyrimidin-4-yl) oxy) phenyl) acrylamide;
N - (3 - ((2 - ((4- (1-acetylpiperidin-4- yl) oxy) phenyl) amino) -6,7- dihydrosothieno [3,2- d ] pyrimidine Yl) oxy) phenyl) acrylamide;
N - (3 - ((2 - ((4- (4- (2- methoxyethyl) piperazin-1-yl) phenyl) amino) -6,7-dihydro-Im in the furnace [3,2- d ] Pyrimidin-4-yl) oxy) phenyl) acrylamide;
N - (3 - ((2 - ((4- (2- Dimorpholino Reno ethoxy) phenyl) amino) -6,7-dihydro furnace to Im [3,2- d] pyrimidin-4-yl) oxy ) Phenyl) acrylamide;
N - (3 - ((2 - ((4- (4- (2- ( dimethylamino) acetyl) piperazin-1-yl) phenyl) amino) -6,7-dihydro-furnace to thieno [3, D ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
N - (3 - ((2- ((4- (4-methylpiperazine-1-carbonyl) phenyl) amino) -6,7-dihydrosothieno [3,2- d ] Yl) oxy) phenyl) acrylamide;
(E) -4- (dimethylamino) - N - (3 - ( (2 - ((4- (4- methylpiperazin-1-yl) phenyl) amino) 5,6-dihydro-Im in the furnace [2,3- d ] pyrimidin-4-yl) oxy) phenyl) but-2-enamide; And
(E) -4- (dimethylamino) - N - (3 - ( (2 - ((4- morpholinophenyl) amino) -5,6-dihydro furnace to Im [2,3- d] pyrimidin Yl) oxy) phenyl) but-2-enamide.
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WO2011079231A1 (en) * | 2009-12-23 | 2011-06-30 | Gatekeeper Pharmaceutical, Inc. | Compounds that modulate egfr activity and methods for treating or preventing conditions therewith |
SG186378A1 (en) * | 2010-06-23 | 2013-01-30 | Hanmi Science Co Ltd | Novel fused pyrimidine derivatives for inhibition of tyrosine kinase activity |
RU2015137298A (en) * | 2013-03-05 | 2017-04-10 | Ф. Хоффманн-Ля Рош Аг | BRUTON TYROSINKINASE INHIBITORS |
KR101704386B1 (en) * | 2013-06-28 | 2017-02-08 | 한국과학기술연구원 | Inhibitory activity of thieno[3,2-d]pyrimidine derivatives on T315I-Bcr-Abl point mutation |
WO2015006754A2 (en) * | 2013-07-11 | 2015-01-15 | Acea Biosciences Inc. | Heterocyclic compounds and uses thereof |
-
2018
- 2018-01-25 WO PCT/KR2018/001139 patent/WO2018139883A1/en active Application Filing
- 2018-01-26 KR KR1020180010271A patent/KR20180088318A/en unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022149856A1 (en) * | 2021-01-07 | 2022-07-14 | 주식회사 온코빅스 | Compound for inhibiting bruton's tyrosine kinase, and pharmaceutical use thereof |
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