KR20220052435A - Aminopyridine derivatives pharmaceutical composition having Bruton's Tyrosine kinase inhibitory activity - Google Patents
Aminopyridine derivatives pharmaceutical composition having Bruton's Tyrosine kinase inhibitory activity Download PDFInfo
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- KR20220052435A KR20220052435A KR1020200136302A KR20200136302A KR20220052435A KR 20220052435 A KR20220052435 A KR 20220052435A KR 1020200136302 A KR1020200136302 A KR 1020200136302A KR 20200136302 A KR20200136302 A KR 20200136302A KR 20220052435 A KR20220052435 A KR 20220052435A
- Authority
- KR
- South Korea
- Prior art keywords
- amino
- acrylic acid
- yloxy
- pyridin
- btk
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 17
- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 title claims description 74
- 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 title claims 11
- 150000003927 aminopyridines Chemical class 0.000 title abstract description 9
- 230000002401 inhibitory effect Effects 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
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- 150000003839 salts Chemical class 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
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Abstract
Description
아미노피리딘 계열의 브루톤티로신인산화효소 저해 활성을 갖는 약학적 조성물에 관한 것이다.It relates to a pharmaceutical composition having an aminopyridine-based Bruton's tyrosine kinase inhibitory activity.
타이로신 단백질 키나아제 Tec(Tyrosine protein kinase Tec, TEC) 중 하나인 BTK(Bruton's tyrosine kinase)은 B 세포, 골수세포(myeloid cells), 비만세포(mast cells), 대식세포(macrophages)에서 발현된다. BTK는 B 세포 성장 및 기능 조절에 중요한 역할을 하며, B 세포 수용체(B cell receptor, BCR)의 다운스트림(downstream)에서 활성화된다. BTK의 비정상적 기능은 B 세포 증식, 성장, 분화 및 세포 사멸의 여러 단계에서 중요한 역할을 하며, 이는 과민성 염증 및 혈액암(hematologic malignancy)을 유발한다(Buggy, J. J. et al., International reviews of immunology 2012, 31(2), 119-32).One of tyrosine protein kinase Tec (Tyrosine protein kinase Tec, TEC), Bruton's tyrosine kinase (BTK), is expressed in B cells, myeloid cells, mast cells, and macrophages. BTK plays an important role in the regulation of B cell growth and function, and is activated downstream of the B cell receptor (BCR). Abnormal function of BTK plays an important role in multiple stages of B cell proliferation, growth, differentiation and apoptosis, leading to hypersensitivity inflammation and hematologic malignancy (Buggy, J. J. et al., International reviews of immunology 2012). , 31(2), 119-32).
이브루티닙(Ibrutinib)은 최초로 FDA 승인된 BTK 억제제로서, ATP 결합 부위의 인접한 잔기인 Cys481을 표적으로 하는 비가역적 공유결합 억제제이다. 이브루티닙은 만성 림프구성 백혈병(chronic lymphocytic leukemia), 발덴스트룀 거대글로불린혈증(Waldenstrom macroglobulinemia), 외투세포림프종(mantle cell lymphoma) 및 만성 이식편대숙주병(chronic graft versus host disease)의 치료를 위해 승인되었다. 또 다른 비가역적 BTK 억제제인 아칼라브루티닙(acalabrutinib)은 외투세포림프종의 치료에 대해 FDA 승인을 받았으며, 다른 여러 공유결합 억제제가 임상 시험 중에 있다 (에보브루티닙(Evobrutinib), RN-486, CHMFL-BTK-01). 이브루티닙의 대부분의 부작용은 TEC, JAK3 및 EGFR 억제로 인한 오프 타겟(off-target) 효과와 관련이 있을 것으로 예상된다. 이들은 ATP 결합 부위 근처의 Cys 잔기의 위치에 따라 그룹 3F(Group 3F)로 분류될 수 있다. 이러한 부작용 문제를 극복하기 위해서는 선택성이 매우 높은 BTK 억제제의 발견이 필요하다.Ibrutinib is the first FDA-approved BTK inhibitor, an irreversible covalent inhibitor that targets Cys481, a residue adjacent to the ATP binding site. Ibrutinib is indicated for the treatment of chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, mantle cell lymphoma and chronic graft versus host disease. Approved. Another irreversible BTK inhibitor, acalabrutinib, has received FDA approval for the treatment of mantle cell lymphoma, and several other covalent inhibitors are in clinical trials (Evobrutinib, RN-486, CHMFL). -BTK-01). Most side effects of ibrutinib are expected to be related to off-target effects due to TEC, JAK3 and EGFR inhibition. They can be classified into Group 3F according to the location of the Cys residue near the ATP binding site. In order to overcome these side effects, it is necessary to discover highly selective BTK inhibitors.
이브루티닙은 Met449, Ile472, Leu542 및 Phe540에 의해 형성된 선택성 포켓(selectivity pocket)과 소수성 상호작용을 형성하는 페녹시페닐기를 포함한다. 선택성 포켓은 Thr474 게이트 키퍼(gatekeeper) 잔기 뒤에 있으며 αC-helix out conformation에 의해 유도된다. 아칼라브루티닙은 이런 친유성 치환체로 페녹시 그룹 대신 피리딜아마이드 그룹을 갖는다. 이러한 특정 구조적 변화는 키나아제 선택성 프로파일을 크게 향상시키는 결과를 가져오며, 이는 친유성 그룹을 변화시키는 것이 BTK 선택성을 위해 좋은 접근법임을 보여준다. 이를 통해 본 발명자들은 친유성 링커를 확장하면 αC-helix out conformation 뿐만 아니라 화합물의 친화성과 선택성을 높일 수 있는 DFG-out conformation까지 유도할 수 있을 것으로 예상하였다. 현재 유효한 type Ⅱ BTK 억제제가 없으므로 type Ⅱ BTK 억제제의 설계는 신규한 선택적 BTK 억제제를 개발하는데 좋은 출발점이 될 것이다.Ibrutinib contains a phenoxyphenyl group that forms a hydrophobic interaction with the selectivity pocket formed by Met449, Ile472, Leu542 and Phe540. The selectivity pocket lies behind the Thr474 gatekeeper residue and is driven by the αC-helix out conformation. Acalabrutinib has a pyridylamide group instead of a phenoxy group as this lipophilic substituent. This specific conformational change results in a greatly improved kinase selectivity profile, indicating that changing the lipophilic group is a good approach for BTK selectivity. Through this, the present inventors predicted that by extending the lipophilic linker, not only the αC-helix out conformation but also the DFG-out conformation, which can increase the affinity and selectivity of the compound, could be induced. Since there are currently no effective type II BTK inhibitors, the design of type II BTK inhibitors will be a good starting point for the development of novel selective BTK inhibitors.
상기한 배경 하에, 본 발명자들은 선택성이 높은 공유결합성 BTK 억제제를 개발하기 위해 노력하던 중, 아미노피리딘 유도체가 BTK 활성 부위에 높은 선택성을 나타내는 것을 확인하여 본 발명을 완성하였다.Under the above background, the present inventors have completed the present invention by confirming that aminopyridine derivatives exhibit high selectivity to the BTK active site while trying to develop a covalent BTK inhibitor with high selectivity.
본 발명의 일 목적은 BTK 활성 부위에 우수하게 결합할 수 있고, 동시에 BTK에 대한 특이도와 선택도가 높은 BTK 억제제를 제공하는 것으로서, 이로부터 부작용의 우려를 낮추고, 개선된 약효를 달성할 수 있는 BTK 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.One object of the present invention is to provide a BTK inhibitor capable of excellent binding to the BTK active site and at the same time having high specificity and selectivity for BTK, thereby reducing the risk of side effects and achieving improved drug efficacy. To provide a pharmaceutical composition for preventing or treating BTK-related diseases.
상기 목적을 달성하기 위하여,In order to achieve the above object,
하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 제공한다:Provided are a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
상기 X1은 또는 이고;wherein X 1 is or ego;
상기 R2는 수소 또는 -OR3이고;wherein R 2 is hydrogen or —OR 3 ;
상기 R1 및 R3은 각각 독립적으로 수소, 치환 또는 비치환된 직쇄 또는 분지쇄의 C1- 10알킬, 또는 치환 또는 비치환된 C1- 10알콕시카보닐이고,Wherein R 1 and R 3 are each independently hydrogen, a substituted or unsubstituted straight - chain or branched C 1-10 alkyl , or a substituted or unsubstituted C 1-10 alkoxycarbonyl,
상기 치환된 직쇄 또는 분지쇄의 C1- 10알킬, 및 C1- 10알콕시는 각각 할로젠, 하나 이상의 C1- 5알콕시 또는 할로젠으로 치환되거나 비치환된 페닐, 및 C3- 8사이클로알킬로 이루어진 군으로부터 선택되는 1종 이상의 치환기로 치환되고; 및wherein said substituted straight - chain or branched C 1-10 alkyl , and C 1-10 alkoxy are each halogen, phenyl unsubstituted or substituted with one or more C 1-5 alkoxy or halogen, and C 3-8 cycloalkyl substituted with one or more substituents selected from the group consisting of; and
상기 X2는 이다.wherein X 2 is am.
본 발명의 다른 일 측면은 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 BTK(Bruton's tyrosine kinase) 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.Another aspect of the present invention provides a pharmaceutical composition for preventing or treating a BTK (Bruton's tyrosine kinase)-related disease comprising the compound represented by Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient do.
본 발명의 또 다른 일 측면은 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 BTK(Bruton's tyrosine kinase) 관련 질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.Another aspect of the present invention is a health functional food composition for preventing or improving BTK (Bruton's tyrosine kinase)-related disease containing the compound represented by Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient provides
본 발명의 다른 일 측면은 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 이를 필요로 하는 대상(subject)에게 투여하는 단계를 포함하는 BTK(Bruton's tyrosine kinase) 관련 질환의 치료방법을 제공한다.Another aspect of the present invention is a BTK (Bruton's tyrosine kinase)-related disease comprising administering to a subject in need thereof a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof treatment methods are provided.
본 발명의 또 다른 일 측면은 BTK(Bruton's tyrosine kinase) 관련 질환의 예방 또는 치료에 사용하기 위한 약물의 제조에 있어서, 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염의 용도를 제공한다.In another aspect of the present invention, in the manufacture of a drug for use in the prevention or treatment of BTK (Bruton's tyrosine kinase)-related diseases, the use of the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof provides
본 발명의 아미노피리딘 계열 화합물은 BTK 활성 부위에 우수한 결합력을 나타낼 뿐 아니라, BTK에 대한 특이도와 선택도가 높아, 이로부터 부작용의 우려를 낮추고, BTK 관련 질환의 예방 또는 치료에 개선된 약효를 달성할 수 있는 약학적 조성물이 제공되는 유용한 효과가 있다.The aminopyridine-based compound of the present invention not only exhibits excellent binding to the BTK active site, but also has high specificity and selectivity for BTK, thereby lowering concerns about side effects and achieving improved efficacy in preventing or treating BTK-related diseases. There is a useful effect provided that a pharmaceutical composition capable of doing so.
도 1은 실시예 16 화합물의 도킹 분석 결과, 실시예 16 화합물이 BTK의 키나아제 도메인에 결합하는 모드를 예측하여 나타낸 도면이다 (초록색 선은 수소결합 상호작용을 나타냄).
도 2는 실시예 16 화합물의 도킹 분석 결과, 활성 부위의 소수성 지도(hydrophobicity map)을 나타낸 도면이다 (보라색 선은 알킬-알킬 상호작용을 나타냄).
도 3은 실시예 9 및 실시예 16 화합물의 In vivo 이종이식(xenograft) 모델 분석 결과, 체중 변화를 그래프로 나타낸 도면이다.
도 4는 실시예 9 및 실시예 16 화합물의 In vivo 이종이식(xenograft) 모델 분석 결과, 종양의 부피 변화를 그래프로 나타낸 도면이다.1 is a diagram showing the prediction of the binding mode of the compound of Example 16 to the kinase domain of BTK as a result of docking analysis of the compound of Example 16 (green line indicates hydrogen bonding interaction).
2 is a diagram showing a hydrophobicity map of the active site as a result of docking analysis of the compound of Example 16 (purple line indicates alkyl-alkyl interaction).
3 shows the compounds of Example 9 and Example 16. It is a diagram showing the change in body weight as a result of the analysis of the in vivo xenograft model.
4 shows the compounds of Example 9 and Example 16. As a result of the analysis of the in vivo xenograft model, it is a diagram showing the change in the volume of the tumor as a graph.
이하, 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 일 측면은 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 제공한다:One aspect of the present invention provides a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
상기 X1은 또는 이고;wherein X 1 is or ego;
상기 R2는 수소 또는 -OR3이고;wherein R 2 is hydrogen or —OR 3 ;
상기 R1 및 R3은 각각 독립적으로 수소, 치환 또는 비치환된 직쇄 또는 분지쇄의 C1- 10알킬, 또는 치환 또는 비치환된 C1- 10알콕시카보닐이고,Wherein R 1 and R 3 are each independently hydrogen, a substituted or unsubstituted straight - chain or branched C 1-10 alkyl , or a substituted or unsubstituted C 1-10 alkoxycarbonyl,
상기 치환된 직쇄 또는 분지쇄의 C1- 10알킬, 및 C1- 10알콕시는 각각 할로젠, 하나 이상의 C1- 5알콕시 또는 할로젠으로 치환되거나 비치환된 페닐, 및 C3- 8사이클로알킬로 이루어진 군으로부터 선택되는 1종 이상의 치환기로 치환되고; 및wherein said substituted straight - chain or branched C 1-10 alkyl , and C 1-10 alkoxy are each halogen, phenyl unsubstituted or substituted with one or more C 1-5 alkoxy or halogen, and C 3-8 cycloalkyl substituted with one or more substituents selected from the group consisting of; and
상기 X2는 이다.wherein X 2 is am.
일 구체예에서, 상기 R1 및 R3은 각각 독립적으로 수소, 치환 또는 비치환된 직쇄 또는 분지쇄의 C1- 6알킬, 또는 치환 또는 비치환된 C1- 6알콕시카보닐이고,In one embodiment, R 1 and R 3 are each independently hydrogen, a substituted or unsubstituted straight - chain or branched C 1-6 alkyl , or a substituted or unsubstituted C 1-6 alkoxycarbonyl,
상기 치환된 직쇄 또는 분지쇄의 C1- 6알킬, 및 C1- 6알콕시는 각각 할로젠, 하나 이상의 C1- 3알콕시 또는 할로젠으로 치환되거나 비치환된 페닐, 및 C3- 6사이클로알킬로 이루어진 군으로부터 선택되는 1종 이상의 치환기로 치환된다.wherein said substituted straight - chain or branched C 1-6 alkyl , and C 1-6 alkoxy are each halogen, phenyl unsubstituted or substituted with one or more C 1-3 alkoxy or halogen, and C 3-6 cycloalkyl It is substituted with one or more substituents selected from the group consisting of.
다른 일 구체예에서, 상기 R1 및 R3은 각각 독립적으로 수소, 치환 또는 비치환된 직쇄 또는 분지쇄의 C1-3알킬, 또는 치환 또는 비치환된 C1-3알콕시카보닐이고,In another embodiment, R 1 and R 3 are each independently hydrogen, a substituted or unsubstituted straight-chain or branched C 1-3 alkyl, or a substituted or unsubstituted C 1-3 alkoxycarbonyl,
상기 치환된 직쇄 또는 분지쇄의 C1- 3알킬, 및 C1- 3알콕시는 각각 할로젠, 하나 이상의 C1- 2알콕시 또는 할로젠으로 치환되거나 비치환된 페닐, 및 C3- 5사이클로알킬로 이루어진 군으로부터 선택되는 1종 이상의 치환기로 치환된다.wherein said substituted straight - chain or branched C 1-3 alkyl , and C 1-3 alkoxy are each halogen, phenyl unsubstituted or substituted with one or more C 1-2 alkoxy or halogen, and C 3-5 cycloalkyl It is substituted with one or more substituents selected from the group consisting of.
일 구체예에서, 상기 R2는 자리에 치환된다.In one embodiment, R 2 is replaced in place
일 구체예에서, 상기 X2는 오쏘(ortho) 또는 메타(meta) 자리에 치환된다.In one embodiment, the X 2 is substituted at an ortho or meta site.
일 구체예에서, 상기 R1 및 R3은 각각 독립적으로 수소, , , , , , , , , 또는 이다.In one embodiment, the R 1 and R 3 are each independently hydrogen, , , , , , , , , or am.
다른 일 구체예에서, 상기 화학식 1로 표시되는 화합물은, 하기 화합물 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 화합물이다.In another embodiment, the compound represented by Formula 1 is a compound, characterized in that any one selected from the following compound group.
(1) 아크릴산 3-(6-아미노-5-피페라진일피리딘-3-일옥시)페닐 에스터;(1) acrylic acid 3-(6-amino-5-piperazinylpyridin-3-yloxy)phenyl ester;
(2) 아크릴산 3-[6-아미노-5-(4-벤질피페라진일)피리딘-3-일옥시]페닐 에스터;(2) acrylic acid 3-[6-amino-5-(4-benzylpiperazinyl)pyridin-3-yloxy]phenyl ester;
(3) 아크릴산 3-{6-아미노-5-[4-(4-플루오로벤질)피페라진일]피리딘-3-일옥시}페닐 에스터;(3) acrylic acid 3-{6-amino-5-[4-(4-fluorobenzyl)piperazinyl]pyridin-3-yloxy}phenyl ester;
(4) 아크릴산 3-{6-아미노-5-[4-(4-클로로벤질)피페라진일]피리딘-3-일옥시}페닐 에스터;(4) acrylic acid 3-{6-amino-5-[4-(4-chlorobenzyl)piperazinyl]pyridin-3-yloxy}phenyl ester;
(5) 아크릴산 3-[6-아미노-5-(4-페네틸피페라진일)피리딘-3-일옥시]페닐 에스터;(5) acrylic acid 3-[6-amino-5-(4-phenethylpiperazinyl)pyridin-3-yloxy]phenyl ester;
(6) 아크릴산 3-(6-아미노-5-{4-[2-(4-클로로페닐)에틸]피페라진일}피리딘-3-일옥시)페닐 에스터;(6) acrylic acid 3-(6-amino-5-{4-[2-(4-chlorophenyl)ethyl]piperazinyl}pyridin-3-yloxy)phenyl ester;
(7) 4-[5-(3-아크릴로일옥시페녹시)-2-아미노피리딘-3-일]피페라진 카복실산 벤질에스터;(7) 4-[5-(3-acryloyloxyphenoxy)-2-aminopyridin-3-yl]piperazine carboxylic acid benzylester;
(8) 아크릴산 2-[6-아미노-5-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)피리딘-3-일옥시]페닐 에스터;(8) acrylic acid 2-[6-amino-5-(3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester;
(9) 아크릴산 2-[6-아미노-5-(6-벤질옥시-3,4-다이하이드로-1H-아이소퀴놀린-2-일)피리딘-3-일옥시]페닐 에스터;(9) acrylic acid 2-[6-amino-5-(6-benzyloxy-3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester;
(10) 아크릴산 3-[6-아미노-5-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)피리딘-3-일옥시]페닐에스터;(10) acrylic acid 3-[6-amino-5-(3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxy]phenylester;
(11) 아크릴산 3-[6-아미노-5-(6-프로포옥시-3,4-다이하이드로-1H-아이소퀴놀린-2-일)피리딘-3-일옥시페닐 에스터;(11) acrylic acid 3-[6-amino-5-(6-propooxy-3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxyphenyl ester;
(12) 아크릴산 3-[6-아미노-5-(6-사이클로프로필메톡시-3,4-다이하이드로-1H-아이소퀴놀린-2-일)피리딘-3-일옥시]페닐 에스터;(12) acrylic acid 3-[6-amino-5-(6-cyclopropylmethoxy-3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester;
(13) 아크릴산 3-[6-아미노-5-(6-벤질옥시-3,4-다이하이드로-1H-아이소퀴놀린-2-일)피리딘-3-일옥시]페닐에스터;(13) acrylic acid 3-[6-amino-5-(6-benzyloxy-3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxy]phenylester;
(14) 아크릴산 3-{6-아미노-5-[6-(4-플루오로벤질옥시)-3,4-다이하이드로-1H-아이소퀴놀린-2-일]피리딘-3-일옥시}페닐 에스터;(14) acrylic acid 3-{6-amino-5-[6-(4-fluorobenzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]pyridin-3-yloxy}phenyl ester ;
(15) 아크릴산 3-{6-아미노-5-[6-(4-클로로벤질옥시)-3,4-다이하이드로-1H-아이소퀴놀린-2-일]피리딘-3-일옥시}페닐 에스터; 및(15) acrylic acid 3-{6-amino-5-[6-(4-chlorobenzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]pyridin-3-yloxy}phenyl ester; and
(16) 아크릴산 3-{6-아미노-5-[6-(4-메톡시벤질옥시)-3,4-다이하이드로-1H-아이소퀴놀린-2-일]피리딘-3-일옥시}페닐 에스터.(16) acrylic acid 3-{6-amino-5-[6-(4-methoxybenzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]pyridin-3-yloxy}phenyl ester .
본 발명의 상기 화학식 1로 표시되는 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산, 아인산 등과 같은 무기산류, 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류 등과 같은 무독성 유기산, 트리플루오로아세트산, 아세테이트, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산 등과 같은 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염의 종류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트 등을 포함한다.The compound represented by Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc., organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. get it from Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Late, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, βhydroxybutyrate, glycol late, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.
본 발명에 따른 산 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 유도체를 메탄올, 에탄올, 아세톤, 메틸렌클로라이드, 아세토니트릴 등과 같은 유기용매에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조시켜 제조하거나, 용매와 과량의 산을 감압 증류한 후 건조시켜 유기용매 하에서 결정화시켜서 제조할 수 있다. The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid It can be prepared by filtration and drying, or by distilling the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염(예, 질산은)과 반응시켜 얻는다.In addition, a pharmaceutically acceptable metal salt can be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. The corresponding salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).
나아가, 본 발명은 상기 화학식 1로 표시되는 화합물 및 이의 약학적으로 허용 가능한 염뿐만 아니라, 이로부터 제조될 수 있는 용매화물, 광학 이성질체, 수화물 등을 모두 포함한다.Furthermore, the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, optical isomers, hydrates, and the like, which may be prepared therefrom.
본 발명의 다른 일 측면은 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 BTK(Bruton's tyrosine kinase) 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.Another aspect of the present invention provides a pharmaceutical composition for preventing or treating a BTK (Bruton's tyrosine kinase)-related disease comprising the compound represented by Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient do.
상기 BTK 관련 질환은 BTK 이상 활성 또는 발현, 예를 들어 BTK 과발현에 의해 유발되거나 발병되는 질환으로 이해될 수 있고, 또는 현재까지 BTK와 관련되는 것으로 보고 된 질환을 포함하는 것으로 이해될 수 있고, 예를 들어 상기 BTK 관련 질환은 자가면역 질환 또는 암일 수 있다.The BTK-related disease may be understood as a disease caused or caused by aberrant activity or expression of BTK, for example, overexpression of BTK, or may be understood to include diseases reported to be related to BTK to date, e.g. For example, the BTK-related disease may be an autoimmune disease or cancer.
일 구체예에서, 상기 BTK 관련 질환은 혈액학적 악성종양(hematological malignancy), 혈액암, B-세포 만성림프성백혈병, 급성림프성백혈병, 비호지킨림프종, 호지킨림프종, 급성골수성백혈병, 미만성거대B-세포림프종, 다발성골수종, 재킷세포림프종, 소림프구성림프종, 맨틀세포림프종(MCL) 또는 림프구성 백혈병(CLL)일 수 있다.In one embodiment, the BTK-related disease is hematological malignancy, hematologic cancer, B-cell chronic lymphocytic leukemia, acute lymphoblastic leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute myeloid leukemia, diffuse giant B -Can be cell lymphoma, multiple myeloma, jacket cell lymphoma, small lymphocytic lymphoma, mantle cell lymphoma (MCL) or lymphocytic leukemia (CLL).
다른 일 구체예에서, 상기 BTK 관련 질환은 류마티스 관절염, 골관절염, 연소성관절염, 만성폐쇄성 폐질환, 다발성경화증, 천식, 전신성홍반성루푸스, 건선, 건선성관절염, 크론병, 궤양성대장염 또는 과민성대장증후군일 수 있다.In another embodiment, the BTK-related disease is rheumatoid arthritis, osteoarthritis, juvenile arthritis, chronic obstructive pulmonary disease, multiple sclerosis, asthma, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis or irritable bowel syndrome can be
본 발명 화학식 1 화합물은 BTK 활성 부위에 결합하는 소분자 화합물로서, BTK 활성 부위와 비가역적 공유결합을 형성할 수 있다. 이에, 특정 이론에 본 발명이 한정되는 것은 아니나, 예를 들어 본 발명 화학식 1 화합물은 BTK 비가역적 억제제로서 BTK 활성을 저해시켜 BTK 관련 질환의 예방 또는 치료하는 것이다. 또한, 본 발명 화학식 1 화합물은 BTK에 대한 특이도와 선택도가 높은 화합물로서, 부작용에 대한 우려가 적어, 보다 고용량으로 약물을 사용할 수 있고 질환 치료에 충분한 약효를 달성할 수 있다.The compound of formula 1 of the present invention is a small molecule compound that binds to the BTK active site, and can form an irreversible covalent bond with the BTK active site. Accordingly, although the present invention is not limited to a particular theory, for example, the compound of Formula 1 of the present invention is an irreversible inhibitor of BTK, which inhibits BTK activity to prevent or treat BTK-related diseases. In addition, the compound of formula 1 of the present invention is a compound with high specificity and selectivity for BTK, and there is little concern about side effects, so that the drug can be used at a higher dose and sufficient drug efficacy can be achieved for disease treatment.
본 발명 화학식 1 화합물은 수소결합, 반데르발스 결합을 통해 BTK 활성 부위에 결합하여 BTK에 대한 특이도와 선택도가 높도록 한다(도 1 및 도 2 참조). 본 발명의 일 구체예에서는 본 발명 화학식 1의 아미노피리딘 계열 화합물이 BTK에 대한 특이도와 선택도가 높아, In vivo 이종이식(xenograft) 모델에서 체중 감소 없이 종양 크기를 상당히 감소시킴을 확인하였다(도 3 및 도 4 참조).The compound of formula 1 of the present invention binds to the BTK active site through hydrogen bonding and van der Waals bonding, thereby increasing specificity and selectivity for BTK (see FIGS. 1 and 2 ). In one embodiment of the present invention, it was confirmed that the aminopyridine-based compound of Formula 1 of the present invention had high specificity and selectivity for BTK, and significantly reduced tumor size without weight loss in an in vivo xenograft model (Fig. 3 and 4).
본 발명의 약학적 조성물은 단일제로도 사용할 수 있으며, 공인된 BTK 억제제 또는 BTK 관련 질환 예방 또는 치료 효과를 가진다고 알려진 약학적 조성물을 추가로 포함하여 복합제제로 제조하여 사용할 수 있다. 약학적으로 허용 가능한 담체, 부형제, 또는 희석제를 추가하여 약제학적 단위 투여형으로 제형화할 수 있다.The pharmaceutical composition of the present invention may be used as a single agent, and may be prepared and used as a combination formulation by additionally including a recognized BTK inhibitor or a pharmaceutical composition known to have a preventive or therapeutic effect on BTK-related diseases. A pharmaceutical unit dosage form may be formulated by adding a pharmaceutically acceptable carrier, excipient, or diluent.
본 발명에 있어서, "치료"는 본 발명에 따른 조성물의 투여로 BTK 관련 질환의 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.In the present invention, "treatment" refers to any action in which the symptoms of BTK-related diseases are improved or beneficially changed by administration of the composition according to the present invention.
본 발명에 있어서, "예방"은 본 발명에 따른 조성물의 투여로 BTK 관련 질환의 발병을 억제 또는 지연시키는 모든 행위를 의미한다.In the present invention, "prevention" refers to any action that inhibits or delays the onset of BTK-related diseases by administration of the composition according to the present invention.
본 발명에 있어서, "약학적으로 허용 가능한"이란 생물체를 상당히 자극하지 않고 투여 활성 물질의 생물학적 활성 및 특성을 저해하지 않는 것을 의미한다.In the present invention, "pharmaceutically acceptable" means that it does not significantly stimulate the organism and does not impair the biological activity and properties of the administered active substance.
본 발명에서 약학적으로 허용 가능한 담체를 포함하는 상기 약학적 조성물은 정제, 환제, 산제, 과립제, 캡슐제, 현탁제, 내용액제, 유제, 시럽제, 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제 및 좌제로 이루어진 군으로부터 선택되는 어느 하나의 제형을 가질 수 있다. 상기 약학적 조성물은 경구 또는 비경구의 여러 가지 제형일 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. In the present invention, the pharmaceutical composition comprising a pharmaceutically acceptable carrier is a tablet, pill, powder, granule, capsule, suspension, internal solution, emulsion, syrup, sterile aqueous solution, non-aqueous solvent, suspension, emulsion, It may have any one formulation selected from the group consisting of freeze-dried formulations and suppositories. The pharmaceutical composition may be in various oral or parenteral formulations. In the case of formulation, it can be prepared using a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, surfactant, etc. commonly used.
경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용될 수 있다. 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in one or more compounds, for example, starch, calcium carbonate, sucrose or lactose ( lactose), gelatin, etc. can be mixed to prepare it. In addition to simple excipients, lubricants such as magnesium stearate, talc and the like may also be used. Liquid preparations for oral administration include suspensions, internal solutions, emulsions, syrups, etc. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is.
비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함될 수 있다. 비수성용제, 현탁용제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있으나, 이에 제한되지 않는다.Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, etc. may be used, but is not limited thereto.
본 발명의 조성물에서 화학식 1 화합물은 약학적으로 유효한 양으로 포함될 수 있다. "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효용량 수준은 환자의 건강상태, 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.In the composition of the present invention, the compound of Formula 1 may be included in a pharmaceutically effective amount. "Pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level is determined by the patient's health condition, type of disease, The severity, activity of the drug, sensitivity to the drug, administration method, administration time, administration route and excretion rate, duration of treatment, factors including drugs used in combination or concomitantly, and other factors well known in the medical field can be determined according to factors. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.
본 발명의 또 다른 일 측면은 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 BTK(Bruton's tyrosine kinase) 관련 질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.Another aspect of the present invention is a health functional food composition for preventing or improving BTK (Bruton's tyrosine kinase)-related disease containing the compound represented by Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient provides
본 발명에 있어서, "개선"은 상기 조성물의 섭취로 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 감소시키는 모든 행위를 의미한다.In the present invention, "improvement" refers to any action that reduces a parameter related to a condition to be treated by ingestion of the composition, for example, the severity of symptoms.
상기 건강식품이란 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 정제, 캡슐, 분말, 과립, 액상 및 환 등의 형태로 제조 및 가공한 식품을 의미한다. 본 발명의 건강기능식품은 당업계에서 통상적으로 사용되는 방법에 의하여 제조 가능하며, 상기 제조시에는 당업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 상기 건강기능식품의 제형 또한 건강기능식품으로 인정되는 제형이면 제한 없이 제조될 수 있다.The health food refers to food manufactured and processed in the form of tablets, capsules, powders, granules, liquids and pills using raw materials or ingredients useful for the human body. The health functional food of the present invention can be prepared by a method commonly used in the art, and during the manufacture, it can be prepared by adding raw materials and components commonly added in the art. In addition, the dosage form of the health functional food may be manufactured without limitation as long as it is a dosage form recognized as a health functional food.
본 발명의 다른 일 측면은 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 이를 필요로 하는 대상(subject)에게 투여하는 단계를 포함하는 BTK(Bruton's tyrosine kinase) 관련 질환의 치료방법을 제공한다.Another aspect of the present invention is a BTK (Bruton's tyrosine kinase)-related disease comprising administering to a subject in need thereof a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof treatment methods are provided.
본 발명에 있어서, "대상"란 상기 BTK 관련 질환이 발병하였거나 발병할 가능성이 있는 포유류와 비포유류를 모두 포함하며, 예를 들어 인간이다.In the present invention, the term "subject" includes both mammals and non-mammals that have or are likely to develop the BTK-related disease, for example, humans.
본 발명에 있어서, "투여"란 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미하며, 본 발명의 조성물의 투여 경로는 목적 조직에 도 달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다.In the present invention, "administration" means providing a predetermined substance to a patient by any suitable method, and the administration route of the composition of the present invention may be administered through any general route as long as it can reach the target tissue. there is.
본 발명의 또 다른 일 측면은 BTK(Bruton's tyrosine kinase) 관련 질환의 예방 또는 치료에 사용하기 위한 약물의 제조에 있어서, 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염의 용도를 제공한다.In another aspect of the present invention, in the manufacture of a drug for use in the prevention or treatment of BTK (Bruton's tyrosine kinase)-related diseases, the use of the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof provides
이하, 본 발명의 실시예 및 실험예를 하기에 구체적으로 예시하여 설명한다. 다만, 후술하는 실시예 및 실험예는 본 발명의 일부를 예시하는 것일 뿐, 본 발명에 이에 한정되는 것은 아니다.Hereinafter, Examples and Experimental Examples of the present invention will be specifically illustrated and described below. However, the Examples and Experimental Examples to be described below are only illustrative of a part of the present invention, and are not limited thereto.
<< 실시예Example 1> 아크릴산 3-(6-아미노-5- 1> Acrylic acid 3-(6-amino-5- 피페라진일피리딘piperazinylpyridine -3--3- 일옥시Iloxy )페닐 에스터의 제조) Preparation of phenyl esters
[반응식 1][Scheme 1]
상기 반응식 1에서와 같이, 2-아미노-3,5-다이클로로피리딘의 아민 그룹을 K2S208, H2SO4, 90 ℃ 조건에서 24시간 동안 반응하여 나이트로 그룹으로 전환한 후, 1-Boc-피페라진, K2CO3, 톨루엔, 50 ℃ 조건에서 15시간 동안 반응하여 피리딘의 C3 위치를 Boc-피페라진(Boc-piperazine)으로 치환한 뒤, Boc 그룹을 TFA으로 탈보호하여 3-피페라진일피리딘을 제조하였다. 그 다음 DMF 용매 하에서 Cs2CO3를 70 ℃ 조건에서 24시간 반응하여 친핵성 치환을 통해 레조르시놀(resorcinol)기를 도입한 후 마이클 어셉터(Michael acceptor)로 아실레이션하고, SnCl2ㆍ2H2O, EtOH를 이용하여 0 ℃에서 1시간 동안 반응시켜 나이트로그룹을 아민으로 전환하여 아크릴산 3-(6-아미노-5-피페라진일피리딘-3-일옥시)페닐 에스터(Acrylic acid 3-(6-amino-5-piperazinylpyridin-3-yloxy)phenyl ester)를 제조하였다.As in Reaction Scheme 1, the amine group of 2-amino-3,5-dichloropyridine was converted to a nitro group by reacting under the conditions of K 2 S 2 0 8 , H 2 SO 4 and 90 ° C. for 24 hours. , 1-Boc-piperazine, K 2 CO 3 , toluene, and at 50 ° C. for 15 hours to replace the C3 position of pyridine with Boc-piperazine, and then deprotect the Boc group with TFA. Thus, 3-piperazinylpyridine was prepared. Then, Cs 2 CO 3 in a DMF solvent was reacted at 70 ° C. for 24 hours to introduce a resorcinol group through nucleophilic substitution, followed by acylation with a Michael acceptor, and SnCl 2 ㆍ2H 2 Acrylic acid 3-(6-amino-5-piperazinylpyridin-3-yloxy)phenyl ester (Acrylic acid 3-( 6-amino-5-piperazinylpyridin-3-yloxy)phenyl ester) was prepared.
갈색 고체 (수율 4%); IR (neat, cm-1) 3340.09, 2923.62, 2852.31, 1735.98, 1640.23, 1595.58, 1466.46, 1367.40, 1335.50, 1272.67, 1244.25, 1176.36, 1137.91, 1043.36, 993.22, 967.52; 1H NMR (500 MHz, CDCl3) δ 7.63 (1H, br s), 7.14 (1H, t, J = 8.0 Hz), 6.96 (1H, d, J = 2.5 Hz), 6.58 (1H, dd, J = 10.5, 17.0 Hz), 6.55 (1H, dd, J = 2.0, 8.0 Hz), 6.49 (1H, dd, J = 2.0, 8.0 Hz), 6.38 (1H, t, J = 2.0 Hz), 6.33 (1H, dd, J = 1.5, 17.0 Hz), 5.75 (1H, dd, J = 1.5, 10.5 Hz), 4.90 (2H, br s), 3.81 (2H, br s), 3.71 (2H, br s), 2.90 (4H, br s); 13C NMR (500 MHz, CDCl3) δ 165.8, 159.7, 157.8, 151.0, 150.2, 134.5, 133.7, 130.7, 128.9, 127.2, 121.1, 110.3, 109.2, 104.4, 51.0, 50.5, 46.3, 42.5; LCMS (ESI) m/z calcd for C18H20N4O3, 340.15; Found 341.5 [M + H]+. brown solid (yield 4%); IR (neat, cm -1 ) 3340.09, 2923.62, 2852.31, 1735.98, 1640.23, 1595.58, 1466.46, 1367.40, 1335.50, 1272.67, 1244.25, 1176.36, 1137.91, 1043.36, 993.22, 967.52; 1 H NMR (500 MHz, CDCl 3 ) δ 7.63 (1H, br s), 7.14 (1H, t, J = 8.0 Hz), 6.96 (1H, d, J = 2.5 Hz), 6.58 (1H, dd, J = 10.5, 17.0 Hz), 6.55 (1H, dd, J = 2.0, 8.0 Hz), 6.49 (1H, dd, J = 2.0, 8.0 Hz), 6.38 (1H, t, J = 2.0 Hz), 6.33 (1H) , dd, J = 1.5, 17.0 Hz), 5.75 (1H, dd, J = 1.5, 10.5 Hz), 4.90 (2H, br s), 3.81 (2H, br s), 3.71 (2H, br s), 2.90 (4H, br s); 13 C NMR (500 MHz, CDCl 3 ) δ 165.8, 159.7, 157.8, 151.0, 150.2, 134.5, 133.7, 130.7, 128.9, 127.2, 121.1, 110.3, 109.2, 104.4, 51.0, 50.5, 46.3, 42.5; LCMS (ESI) m/z calcd for C 18 H 20 N 4 O 3 , 340.15; Found 341.5 [M + H] + .
<< 실시예Example 2> 아크릴산 3-[6-아미노-5-(4- 2> Acrylic acid 3-[6-amino-5-(4- 벤질피페라진일benzylpiperazinyl )피리딘-3-)pyridine-3- 일옥시Iloxy ]페닐 에스터의 제조]Production of phenyl esters
상기 실시예 1의 제조방법과 동일하게 수행하되, 3-피페라진일피리딘을 제조후, 피페라진 그룹의 N-알킬화(N-alkylation)을 위해 상온에서 5시간 동안 (할로메틸)벤젠, K2CO3, DMF와 반응시키는 단계를 더 포함하여 아크릴산 3-[6-아미노-5-(4-벤질피페라진일)피리딘-3-일옥시]페닐 에스터(Acrylic acid 3-[6-amino-5-(4-benzylpiperazinyl)pyridin-3-yloxy]phenyl ester)를 제조하였다.It was carried out in the same manner as in Example 1, except that after preparing 3-piperazinylpyridine, (halomethyl)benzene, K 2 at room temperature for N-alkylation of the piperazine group for 5 hours CO 3 , further comprising the step of reacting with DMF, acrylic acid 3-[6-amino-5-(4-benzylpiperazinyl)pyridin-3-yloxy]phenyl ester (Acrylic acid 3-[6-amino-5 -(4-benzylpiperazinyl)pyridin-3-yloxy]phenyl ester) was prepared.
갈색 고체 (수율 15%); IR (neat, cm-1) 3058.17, 2942.12, 2820.72, 1664.56, 1594.22, 1462.81, 1369.10, 1336.85, 1265.54, 1214.68, 1178.91, 1134.30, 996.06, 737.15, 700.62; 1H NMR (500 MHz, CDCl3) δ 7.69 (1H, d, J = 2.5 Hz), 7.34-7.26 (6H, m), 6.98 (1H, d, J = 2.5 Hz), 6.83-6.80 (2H, m), 6.70 (1H, t, J = 2.0 Hz), 6.58 (1H, dd, J = 1.0, 17.5 Hz), 6.28 (1H, dd, J = 10.5, 17.5 Hz), 6.00 (1H, dd, J = 1.0, 10.5 Hz), 4.63 (2H, br s), 3.58 (2H, s), 2.93 (4H, br s), 2.60 (4H, br s); 13C NMR (500 MHz, CDCl3) δ 164.3, 159.7, 151.6, 151.4, 145.1, 138.0, 135.2, 134.3, 132.8, 130.1, 129.3, 128.4, 127.9, 127.3, 120.1, 115.6, 114.2, 110.4, 63.1, 53.5, 50.6; LCMS (ESI) m/z calcd for C25H26N4O3, 430.20; Found 431.7 [M + H]+.brown solid (yield 15%); IR (neat, cm -1 ) 3058.17, 2942.12, 2820.72, 1664.56, 1594.22, 1462.81, 1369.10, 1336.85, 1265.54, 1214.68, 1178.91, 1134.30, 996.06, 737.15, 700.62; 1 H NMR (500 MHz, CDCl 3 ) δ 7.69 (1H, d, J = 2.5 Hz), 7.34-7.26 (6H, m), 6.98 (1H, d, J = 2.5 Hz), 6.83-6.80 (2H, m), 6.70 (1H, t, J = 2.0 Hz), 6.58 (1H, dd, J = 1.0, 17.5 Hz), 6.28 (1H, dd, J = 10.5, 17.5 Hz), 6.00 (1H, dd, J ) = 1.0, 10.5 Hz), 4.63 (2H, br s), 3.58 (2H, s), 2.93 (4H, br s), 2.60 (4H, br s); 13 C NMR (500 MHz, CDCl 3 ) δ 164.3, 159.7, 151.6, 151.4, 145.1, 138.0, 135.2, 134.3, 132.8, 130.1, 129.3, 128.4, 127.9, 127.3, 120.1, 115.6, 114.2, 110.4, 63.1, 53.5 , 50.6; LCMS (ESI) m/z calcd for C 25 H 26 N 4 O 3 , 430.20; Found 431.7 [M + H] + .
<< 실시예Example 3> 아크릴산 3-{6-아미노-5-[4-(4- 3> Acrylic acid 3-{6-amino-5-[4-(4-) 플루오로벤질Fluorobenzyl )피페라진일]피리딘-3-일옥시}페닐 에스터의 제조) Preparation of piperazinyl]pyridin-3-yloxy}phenyl ester
상기 실시예 2의 제조방법과 동일하게 수행하되, (할로메틸)벤젠 대신 1-(할로메틸)-4-플루오로벤젠을 사용하여 아크릴산 3-{6-아미노-5-[4-(4-플루오로벤질)피페라진일]피리딘-3-일옥시}페닐 에스터(Acrylic acid 3-{6-amino-5-[4-(4-fluorobenzyl)piperazinyl]pyridin-3-yloxy}phenyl ester)를 제조하였다.Acrylic acid 3-{6-amino-5-[4-(4-) was carried out in the same manner as in Example 2, but using 1-(halomethyl)-4-fluorobenzene instead of (halomethyl)benzene Preparation of fluorobenzyl)piperazinyl]pyridin-3-yloxy}phenyl ester (Acrylic acid 3-{6-amino-5-[4-(4-fluorobenzyl)piperazinyl]pyridin-3-yloxy}phenyl ester) did
갈색 고체 (수율 12%); IR (neat, cm-1) 2939.63, 2821.27, 1740.60, 1602.75, 1507.57, 1479.89, 1402.43, 1366.12, 1312.43, 1243.62, 1220.03, 1157.24, 1025.69, 1002.28, 841.48, 796.97, 736.57, 700.72; 1H NMR (500 MHz, CDCl3) δ 7.68 (1H, d, J = 2.5 Hz), 7.31-7.27 (3H, m), 7.01 (2H, t, J = 8.5 Hz), 6.98 (1H, d, J = 2.5 Hz), 6.81 (2H, t, J = 8.5 Hz), 6.70 (1H, t, J = 2.5 Hz), 6.58 (1H, dd, J = 1.0, 17.5 Hz), 6.28 (1H, dd, J = 10.5, 17.5 Hz), 6.00 (1H, dd, J = 1.0, 10.5 Hz), 4.71 (2H, br s), 3.53 (2H, s), 2.93 (4H, br s), 2.58 (4H, br s); 13C NMR (500 MHz, CDCl3) δ 164.3, 162.2 (d, J C -F = 243.9 Hz), 159.7, 151.7, 151.5, 145.1, 135.3, 134.2, 133.7 (d, J C -F = 3.1 Hz), 132.9, 130.7 (d, J C -F = 7.9 Hz), 130.2, 127.9, 120.3, 115.6, 115.2 (d, J C -F = 21.1 Hz), 114.2, 110.4, 62.3, 53.5, 50.6; LCMS (ESI) m/z calcd for C25H25FN4O3, 448.19; Found 449.6 [M + H]+.brown solid (yield 12%); IR (neat, cm -1 ) 2939.63, 2821.27, 1740.60, 1602.75, 1507.57, 1479.89, 1402.43, 1366.12, 1312.43, 1243.62, 1220.03, 1157.24, 1025.69, 1002.28, 841.48, 796.97, 736.57, 700.72; 1 H NMR (500 MHz, CDCl 3 ) δ 7.68 (1H, d, J = 2.5 Hz), 7.31-7.27 (3H, m), 7.01 (2H, t, J = 8.5 Hz), 6.98 (1H, d, J = 2.5 Hz), 6.81 (2H, t, J = 8.5 Hz), 6.70 (1H, t, J = 2.5 Hz), 6.58 (1H, dd, J = 1.0, 17.5 Hz), 6.28 (1H, dd, J = 10.5, 17.5 Hz), 6.00 (1H, dd, J = 1.0, 10.5 Hz), 4.71 (2H, br s), 3.53 (2H, s), 2.93 (4H, br s), 2.58 (4H, br) s); 13 C NMR (500 MHz, CDCl 3 ) δ 164.3, 162.2 (d, J C -F = 243.9 Hz), 159.7, 151.7, 151.5, 145.1, 135.3, 134.2, 133.7 (d, J C -F = 3.1 Hz), 132.9, 130.7 (d, J C -F = 7.9 Hz), 130.2, 127.9, 120.3, 115.6, 115.2 (d, J C -F = 21.1 Hz), 114.2, 110.4, 62.3, 53.5, 50.6; LCMS (ESI) m/z calcd for C 25 H 25 FN 4 O 3 , 448.19; Found 449.6 [M + H] + .
<< 실시예Example 4> 아크릴산 3-{6-아미노-5-[4-(4- 4> Acrylic acid 3-{6-amino-5-[4-(4- 클로로벤질chlorobenzyl )피페라진일]피리딘-3-일옥시}페닐 에스터의 제조) Preparation of piperazinyl]pyridin-3-yloxy}phenyl ester
상기 실시예 2의 제조방법과 동일하게 수행하되, (할로메틸)벤젠 대신 1-(할로메틸)-4-클로로벤젠을 사용하여 아크릴산 3-{6-아미노-5-[4-(4-클로로벤질)피페라진일]피리딘-3-일옥시}페닐 에스터(Acrylic acid 3-{6-amino-5-[4-(4-chlorobenzyl)piperazinyl]pyridin-3-yloxy}phenyl ester)를 제조하였다.It was carried out in the same manner as in Example 2, except that 1-(halomethyl)-4-chlorobenzene was used instead of (halomethyl)benzene, and acrylic acid 3-{6-amino-5-[4-(4-chlorobenzene) was used. Benzyl)piperazinyl]pyridin-3-yloxy}phenyl ester (Acrylic acid 3-{6-amino-5-[4-(4-chlorobenzyl)piperazinyl]pyridin-3-yloxy}phenyl ester) was prepared.
갈색 고체 (수율 10%); IR (neat, cm-1) 3048.82, 2940.26, 2821.49, 1742.76, 1594.96, 1488.78, 1402.63, 1367.11, 1311.85, 1293.49, 1247.75, 1212.80, 1157.75, 1086.29, 1002.35, 795.38, 736.3; 1H NMR (500 MHz, CDCl3) δ 7.69 (1H, d, J = 2.5 Hz), 7.32-7.26 (5H, m), 6.98 (1H, d, J = 2.5 Hz), 6.83-6.80 (2H, m), 6.70 (1H, t, J = 2.5 Hz), 6.58 (1H, dd, J = 1.0, 17.5 Hz), 6.28 (1H, dd, J = 10.5, 17.5 Hz), 6.00 (1H, dd, J = 1.0, 10.5 Hz), 4.63 (2H, br s), 3.53 (2H, s), 2.93 (4H, br s), 2.58 (4H, br s); 13C NMR (500 MHz, CDCl3) δ 164.4, 159.8, 151.7, 151.5, 145.1, 136.6, 135.2, 134.5, 133.0, 132.9, 130.5, 130.2, 128.6, 127.9, 120.2, 115.6, 114.2, 110.4, 62.3, 53.5, 50.6; LCMS (ESI) m/z calcd for C25H25ClN4O3, 464.16; Found 465.6 [M + H]+.brown solid (10% yield); IR (neat, cm -1 ) 3048.82, 2940.26, 2821.49, 1742.76, 1594.96, 1488.78, 1402.63, 1367.11, 1311.85, 1293.49, 1247.75, 1212.80, 1157.75, 1086.29, 1002.35, 795.38, 736.3; 1 H NMR (500 MHz, CDCl 3 ) δ 7.69 (1H, d, J = 2.5 Hz), 7.32-7.26 (5H, m), 6.98 (1H, d, J = 2.5 Hz), 6.83-6.80 (2H, m), 6.70 (1H, t, J = 2.5 Hz), 6.58 (1H, dd, J = 1.0, 17.5 Hz), 6.28 (1H, dd, J = 10.5, 17.5 Hz), 6.00 (1H, dd, J ) = 1.0, 10.5 Hz), 4.63 (2H, br s), 3.53 (2H, s), 2.93 (4H, br s), 2.58 (4H, br s); 13 C NMR (500 MHz, CDCl 3 ) δ 164.4, 159.8, 151.7, 151.5, 145.1, 136.6, 135.2, 134.5, 133.0, 132.9, 130.5, 130.2, 128.6, 127.9, 120.2, 115.6, 114.2, 110.4, 62.3, 53.5 , 50.6; LCMS (ESI) m/z calcd for C 25 H 25 ClN 4 O 3 , 464.16; Found 465.6 [M + H] + .
<< 실시예Example 5> 아크릴산 3-[6-아미노-5-(4- 5> Acrylic acid 3-[6-amino-5-(4- 페네틸피페라진일phenethylpiperazinyl )피리딘-3-)pyridine-3- 일옥시Iloxy ]페닐 에스터의 제조]Production of phenyl esters
상기 실시예 2의 제조방법과 동일하게 수행하되, (할로메틸)벤젠 대신 (2-할로에틸)벤젠을 사용하여 아크릴산 3-[6-아미노-5-(4-페네틸피페라진일)피리딘-3-일옥시]페닐 에스터(Acrylic acid 3-[6-amino-5-(4-phenethylpiperazinyl)pyridin-3-yloxy]phenyl ester)를 제조하였다.It was carried out in the same manner as in Example 2, except that (2-haloethyl)benzene was used instead of (halomethyl)benzene, and acrylic acid 3-[6-amino-5-(4-phenethylpiperazinyl)pyridine- 3-yloxy] phenyl ester (Acrylic acid 3- [6-amino-5- (4-phenethylpiperazinyl) pyridin-3-yloxy] phenyl ester) was prepared.
갈색 고체 (수율 19%); IR (neat, cm-1) 3025.91, 2942.72, 2819.03, 1743.57, 1608.10, 1464.13, 1402.22, 1372.06, 1336.13, 1247.66, 1152.02, 1023.95, 1001.77, 775.70, 735.23, 700.10; 1H NMR (500 MHz, CDCl3) δ 7.70 (1H, d, J = 2.5 Hz), 7.31-7.28 (3H, m), 7.23-7.21 (3H, m), 7.00 (1H, d, J = 2.5 Hz), 6.83-6.81 (2H, m), 6.71 (1H, t, J = 2.5 Hz), 6.59 (1H, dd, J = 1.0, 17.5 Hz), 6.29 (1H, dd, J = 10.5, 17.5 Hz), 6.01 (1H, dd, J = 1.0, 10.5 Hz), 4.65 (2H, br s), 2.97 (4H, br s), 2.85-2.82 (2H, m), 2.69-2.66 (6H, m); 13C NMR (500 MHz, CDCl3) δ 164.4, 159.7, 151.7, 151.4, 145.1, 140.3, 135.2, 134.4, 132.9, 130.2, 128.8, 128.6, 127.9, 126.3, 120.2, 115.6, 114.2, 110.4, 60.6, 53.7, 50.6, 33.8; LCMS (ESI) m/z calcd for C26H28N4O3, 444.22; Found 445.6 [M + H]+.brown solid (yield 19%); IR (neat, cm -1 ) 3025.91, 2942.72, 2819.03, 1743.57, 1608.10, 1464.13, 1402.22, 1372.06, 1336.13, 1247.66, 1152.02, 1023.95, 1001.77, 775.70, 735.23, 700.10; 1 H NMR (500 MHz, CDCl 3 ) δ 7.70 (1H, d, J = 2.5 Hz), 7.31-7.28 (3H, m), 7.23-7.21 (3H, m), 7.00 (1H, d, J = 2.5) Hz), 6.83-6.81 (2H, m), 6.71 (1H, t, J = 2.5 Hz), 6.59 (1H, dd, J = 1.0, 17.5 Hz), 6.29 (1H, dd, J = 10.5, 17.5 Hz) ), 6.01 (1H, dd, J = 1.0, 10.5 Hz), 4.65 (2H, br s), 2.97 (4H, br s), 2.85-2.82 (2H, m), 2.69-2.66 (6H, m); 13 C NMR (500 MHz, CDCl 3 ) δ 164.4, 159.7, 151.7, 151.4, 145.1, 140.3, 135.2, 134.4, 132.9, 130.2, 128.8, 128.6, 127.9, 126.3, 120.2, 115.6, 114.2, 110.4, 60.6, 53.7 , 50.6, 33.8; LCMS (ESI) m/z calcd for C 26 H 28 N 4 O 3 , 444.22; Found 445.6 [M + H] + .
<< 실시예Example 6> 아크릴산 3-(6-아미노-5-{4-[2-(4- 6> Acrylic acid 3-(6-amino-5-{4-[2-(4- 클로로페닐chlorophenyl )에틸]피페라진일}피리딘-3-일옥시)페닐 에스터의 제조Preparation of )ethyl]piperazinyl}pyridin-3-yloxy)phenyl ester
상기 실시예 2의 제조방법과 동일하게 수행하되, (할로메틸)벤젠 대신 1-클로로-4-(2-할로에틸)벤젠을 사용하여 아크릴산 3-(6-아미노-5-{4-[2-(4-클로로페닐)에틸]피페라진일}피리딘-3-일옥시)페닐 에스터(Acrylic acid 3-(6-amino-5-{4-[2-(4-chlorophenyl)ethyl]piperazinyl}pyridin-3-yloxy)phenyl ester)를 제조하였다.Acrylic acid 3-(6-amino-5-{4-[2] was carried out in the same manner as in Example 2, except that 1-chloro-4-(2-haloethyl)benzene was used instead of (halomethyl)benzene. -(4-chlorophenyl)ethyl]piperazinyl}pyridin-3-yloxy)phenyl ester (Acrylic acid 3-(6-amino-5-{4-[2-(4-chlorophenyl)ethyl]piperazinyl}pyridin) -3-yloxy)phenyl ester) was prepared.
갈색 고체 (수율 4%); IR (neat, cm-1) 3355.04, 2938.20, 2821.01, 1742.91, 1608.93, 1464.96, 1402.98, 1336.85, 1247.88, 1154.36, 1002.08, 776.31; 1H NMR (500 MHz, CDCl3) δ 7.69 (1H, d, J = 2.5 Hz), 7.29 (1H, t, J = 8.5 Hz), 7.25 (2H, d, J = 8.5 Hz), 7.14 (2H, d, J = 8.5 Hz), 6.99 (2H, d, J = 2.5 Hz), 6.83-6.80 (2H, m), 6.71 (1H, t, J = 2.5 Hz), 6.58 (1H, dd, J = 1.0, 17.5 Hz), 6.29 (1H, dd, J = 10.5, 17.5 Hz), 6.01 (1H, dd, J = 1.0, 10.5 Hz), 4.68 (2H, br s), 2.96 (4H, br s), 2.81-2.78 (2H, m), 2.65-2.62 (6H, m); LCMS (ESI) m/z calcd for C26H27ClN4, 478.18; Found 479.7 [M + H]+.brown solid (yield 4%); IR (neat, cm -1 ) 3355.04, 2938.20, 2821.01, 1742.91, 1608.93, 1464.96, 1402.98, 1336.85, 1247.88, 1154.36, 1002.08, 776.31; 1 H NMR (500 MHz, CDCl 3 ) δ 7.69 (1H, d, J = 2.5 Hz), 7.29 (1H, t, J = 8.5 Hz), 7.25 (2H, d, J = 8.5 Hz), 7.14 (2H) , d, J = 8.5 Hz), 6.99 (2H, d, J = 2.5 Hz), 6.83-6.80 (2H, m), 6.71 (1H, t, J = 2.5 Hz), 6.58 (1H, dd, J = 2.5 Hz) 1.0, 17.5 Hz), 6.29 (1H, dd, J = 10.5, 17.5 Hz), 6.01 (1H, dd, J = 1.0, 10.5 Hz), 4.68 (2H, br s), 2.96 (4H, br s), 2.81-2.78 (2H, m), 2.65-2.62 (6H, m); LCMS (ESI) m/z calcd for C 26 H 27 ClN 4 , 478.18; Found 479.7 [M + H] + .
<< 실시예Example 7> 4-[5-(3- 7> 4-[5-(3- 아크릴로일옥시페녹시acryloyloxyphenoxy )-2-)-2- 아미노피리딘aminopyridine -3-일]피페라진 카복실산 -3-yl]piperazine carboxylic acid 벤질에스터의of benzyl ester 제조 Produce
상기 실시예 2의 제조방법과 동일하게 수행하되, (할로메틸)벤젠 대신 벤질 카보노할로리데이트를 사용하여 4-[5-(3-아크릴로일옥시페녹시)-2-아미노피리딘-3-일]피페라진 카복실산 벤질에스터(4-[5-(3-Acryloyloxyphenoxy)-2-aminopyridin-3-yl]piperazine carboxylic acid benzyl ester)를 제조하였다.It was carried out in the same manner as in Example 2, but using benzyl carbonohaloridate instead of (halomethyl)benzene, 4-[5-(3-acryloyloxyphenoxy)-2-aminopyridine-3 -yl]piperazine carboxylic acid benzyl ester (4-[5-(3-Acryloyloxyphenoxy)-2-aminopyridin-3-yl]piperazine carboxylic acid benzyl ester) was prepared.
갈색 고체 (수율 23%); IR (neat, cm-1) 3351.96, 3062.09, 2827.34, 1742.87, 1688.0, 1608.87, 1466.27, 1403.28, 1361.16, 1333.67, 1284.80, 1245.40, 1152.18, 1087.69. 1044.80, 992.50, 908.43, 735.68, 699.05; 1H NMR (500 MHz, CDCl3) δ 7.72 (1H, d, J = 2.5 Hz), 7.39-7.32 (5H, m), 7.29 (1H, t, J = 8.0 Hz), 6.95 (1H, d, J = 2.5 Hz), 6.82 (2H, td, J = 2.0, 8.0 Hz), 6.70 (1H, t, J = 2.5 Hz), 6.58 (1H, dd, J = 1.0, 17.5 Hz), 6.28 (1H, dd, J = 10.5, 17.5 Hz), 6.01 (1H, dd, J = 1.0, 10.5 Hz), 5.16 (2H, s), 4.65 (2H, br s), 3.65 (4H, br s), 2.88 (4H, br s); 13C NMR (500 MHz, CDCl3) δ 164.3, 159.6, 155.4, 151.7, 151.3, 145.2, 136.7, 135.1, 134.6, 133.0, 130.3, 128.7, 128.3, 128.1, 127.9, 120.4, 115.7, 114.3, 110.5, 67.5, 50.5, 44.4; LCMS (ESI) m/z calcd for C26H26N4O5, 474.19; Found 475.7 [M + H]+.brown solid (23% yield); IR (neat, cm -1 ) 3351.96, 3062.09, 2827.34, 1742.87, 1688.0, 1608.87, 1466.27, 1403.28, 1361.16, 1333.67, 1284.80, 1245.40, 1152.18, 1087.69. 1044.80, 992.50, 908.43, 735.68, 699.05; 1 H NMR (500 MHz, CDCl 3 ) δ 7.72 (1H, d, J = 2.5 Hz), 7.39-7.32 (5H, m), 7.29 (1H, t, J = 8.0 Hz), 6.95 (1H, d, J = 2.5 Hz), 6.82 (2H, td, J = 2.0, 8.0 Hz), 6.70 (1H, t, J = 2.5 Hz), 6.58 (1H, dd, J = 1.0, 17.5 Hz), 6.28 (1H, dd, J = 10.5, 17.5 Hz), 6.01 (1H, dd, J = 1.0, 10.5 Hz), 5.16 (2H, s), 4.65 (2H, br s), 3.65 (4H, br s), 2.88 (4H) , br s); 13 C NMR (500 MHz, CDCl 3 ) δ 164.3, 159.6, 155.4, 151.7, 151.3, 145.2, 136.7, 135.1, 134.6, 133.0, 130.3, 128.7, 128.3, 128.1, 127.9, 120.4, 115.7, 114.3, 110.5, 67.5 , 50.5, 44.4; LCMS (ESI) m/z calcd for C 26 H 26 N 4 O 5 , 474.19; Found 475.7 [M + H] + .
<< 실시예Example 8> 아크릴산 2-[6-아미노-5-(3,4- 8> Acrylic acid 2- [6-amino-5- (3,4- 다이하이드로dihydro -1H--1H- 아이소퀴놀린isoquinoline -2-일)피리딘-3-일옥시]페닐 에스터의 제조Preparation of -2-yl) pyridin-3-yloxy] phenyl ester
[반응식 2][Scheme 2]
상기 반응식 2에서와 같이, 3,5-다이클로로-2-나이트로피리딘을 K2CO3, 톨루엔, 60 ℃ 조건에서 10시간 동안 테트라하이드로아이소퀴놀린과 반응한 후, K2CO3, DMSO, 18-crown-6, 100 ℃ 조건에서 10시간 동안 카테콜과 반응하고, 상온에서 TEA, DCM 조건 하에 1시간 동안 아크릴로일클로라이드와 반응하였다. 그 다음 SnCl2ㆍ2H2O, EtOH를 이용하여 상온에서 1시간 동안 반응시켜 나이트로그룹을 아민으로 전환하여 아크릴산 2-[6-아미노-5-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)피리딘-3-일옥시]페닐 에스터(Acrylic acid 2-[6-amino-5-(3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester)를 제조하였다.As in
노란색 고체 (수율 31%); IR (neat, cm-1) 2980.52, 2888.53, 1596.48, 1460.26, 1380.12, 1315.59, 1230.72, 1315.59, 1238.76, 1150.52, 1023.45, 971.17; 1H NMR (500 MHz, CDCl3) δ 7.69 (1H, d, J = 2.5 Hz), 7.21-7.14 (5H, m), 7.10-7.06 (2H, m), 7.03 (1H, d, J = 2.5 Hz), 6.89 (1H, dd, J = 1.5, 8.5 Hz), 6.59 (1H, dd, J = 1.0, 17.5 Hz), 6.32 (1H, dd, J = 10.5, 17.5 Hz), 6.00 (1H, dd, J = 1.0, 10.5 Hz), 4.66 (2H, br s), 4.06 (2H, s), 3.22 (2H, t, J = 6.0 Hz), 3.01 (2H, t, J = 6.0 Hz); 13C NMR (500 MHz, CDCl3) δ 164.1, 151.4, 150.2, 145.8, 140.8, 135.1, 134.5, 133.9, 132.9, 129.1, 127.6, 127.1, 126.6, 123.7, 123.3, 119.9, 118.0, 53.2, 48.9, 29.8; LCMS (ESI) m/z calcd for C23H21N3O3, 387.16; Found 388.16 [M + H]+. yellow solid (yield 31%); IR (neat, cm -1 ) 2980.52, 2888.53, 1596.48, 1460.26, 1380.12, 1315.59, 1230.72, 1315.59, 1238.76, 1150.52, 1023.45, 971.17; 1 H NMR (500 MHz, CDCl 3 ) δ 7.69 (1H, d, J = 2.5 Hz), 7.21-7.14 (5H, m), 7.10-7.06 (2H, m), 7.03 (1H, d, J = 2.5) Hz), 6.89 (1H, dd, J = 1.5, 8.5 Hz), 6.59 (1H, dd, J = 1.0, 17.5 Hz), 6.32 (1H, dd, J = 10.5, 17.5 Hz), 6.00 (1H, dd) , J = 1.0, 10.5 Hz), 4.66 (2H, br s), 4.06 (2H, s), 3.22 (2H, t, J = 6.0 Hz), 3.01 (2H, t, J = 6.0 Hz); 13 C NMR (500 MHz, CDCl 3 ) δ 164.1, 151.4, 150.2, 145.8, 140.8, 135.1, 134.5, 133.9, 132.9, 129.1, 127.6, 127.1, 126.6, 123.7, 123.3, 119.9, 118.0, 53.2, 48.9, 29.8 ; LCMS (ESI) m/z calcd for C 23 H 21 N 3 O 3 , 387.16; Found 388.16 [M + H] + .
<< 실시예Example 9> 아크릴산 2-[6-아미노-5-(6- 9> Acrylic acid 2- [6-amino-5- (6- 벤질옥시benzyloxy -3,4--3,4- 다이하이드로dihydro -1H--1H- 아이소퀴놀린isoquinoline -2-일)피리딘-3-일옥시]페닐 에스터의 제조Preparation of -2-yl) pyridin-3-yloxy] phenyl ester
상기 실시예 8의 제조방법과 동일하게 수행하되, 테트라하이드로아이소퀴놀린 대신 6-(벤질옥시)-1,2,3,4-테트라하이드로아이소퀴놀린을 사용하여 아크릴산 2-[6-아미노-5-(6-벤질옥시-3,4-다이하이드로-1H-아이소퀴놀린-2-일)피리딘-3-일옥시]페닐 에스터(Acrylic acid 2-[6-amino-5-(6-benzyloxy-3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester)를 제조하였다.Acrylic acid 2-[6-amino-5-] was carried out in the same manner as in Example 8, except that 6-(benzyloxy)-1,2,3,4-tetrahydroisoquinoline was used instead of tetrahydroisoquinoline. (6-Benzyloxy-3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester (Acrylic acid 2-[6-amino-5-(6-benzyloxy-3, 4-dihydro- 1H -isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester) was prepared.
아이보리색 고체 (수율 23%); IR (neat, cm-1) 2980.65, 2888.60, 1735.13, 1610.91, 1461.97, 1380.75, 1239.82, 1150.48, 1015.44, 969.35; 1H NMR (500 MHz, CDCl3) δ 7.68 (1H, d, J = 2.5 Hz), 7.42 (2H, d, J = 7.5 Hz), 7.38 (2H, t, J = 7.5 Hz), 7.31 (1H, t, J = 7.5 Hz), 7.15 (2H, t, J = 7.5Hz), 7.07 (1H, t, J = 7.5 Hz), 7.01 (1H, d, J = 2.5 Hz), 6.97 (1H, d, J = 8.5 Hz), 6.88 (1H, d, J = 8.0 Hz), 6.81-6.77 (2H, m), 6.57 (1H, dd, J = 1.0, 17.0 Hz), 6.31 (1H, dd, J = 10.5, 17.0 Hz), 5.98 (1H, dd, J = 1.0, 10.5 Hz), 5.04 (2H, s), 4.72 (2H, br s), 3.98 (2H, s), 3.17 (2H, t, J = 5.5 Hz), 2.95 (2H, t, J = 5.5 Hz); 13C NMR (500 MHz, CDCl3) δ 164.1, 159.8, 157.6, 154.5, 151.4, 150.2, 145.7, 140.7, 137.2, 135.1, 135.1, 133.7, 132.9, 130.2, 128.7, 128.1, 127.5, 127.5, 127.1, 126.9, 123.6, 123.2, 119.8, 117.9, 114.7, 113.2, 70.2, 52.7, 48.7, 30.0; LCMS (ESI) m/z calcd for C30H27N3O4, 493.20; Found 494.20 [M + H]+. ivory solid (23% yield); IR (neat, cm -1 ) 2980.65, 2888.60, 1735.13, 1610.91, 1461.97, 1380.75, 1239.82, 1150.48, 1015.44, 969.35; 1 H NMR (500 MHz, CDCl 3 ) δ 7.68 (1H, d, J = 2.5 Hz), 7.42 (2H, d, J = 7.5 Hz), 7.38 (2H, t, J = 7.5 Hz), 7.31 (1H) , t, J = 7.5 Hz), 7.15 (2H, t, J = 7.5 Hz), 7.07 (1H, t, J = 7.5 Hz), 7.01 (1H, d, J = 2.5 Hz), 6.97 (1H, d) , J = 8.5 Hz), 6.88 (1H, d, J = 8.0 Hz), 6.81-6.77 (2H, m), 6.57 (1H, dd, J = 1.0, 17.0 Hz), 6.31 (1H, dd, J = 10.5, 17.0 Hz), 5.98 (1H, dd, J = 1.0, 10.5 Hz), 5.04 (2H, s), 4.72 (2H, br s), 3.98 (2H, s), 3.17 (2H, t, J = 5.5 Hz), 2.95 (2H, t, J = 5.5 Hz); 13 C NMR (500 MHz, CDCl 3 ) δ 164.1, 159.8, 157.6, 154.5, 151.4, 150.2, 145.7, 140.7, 137.2, 135.1, 135.1, 133.7, 132.9, 130.2, 128.7, 128.1, 127.5, 127.5, 127.1, 126.9 , 123.6, 123.2, 119.8, 117.9, 114.7, 113.2, 70.2, 52.7, 48.7, 30.0; LCMS (ESI) m/z calcd for C 30 H 27 N 3 O 4 , 493.20; Found 494.20 [M + H] + .
<< 실시예Example 10> 아크릴산 3-[6-아미노-5-(3,4- 10> Acrylic acid 3- [6-amino-5- (3,4- 다이하이드로dihydro -1H--1H- 아이소퀴놀린isoquinoline -2-일)피리딘-3-일옥시]페닐에스터의 제조Preparation of -2-yl) pyridin-3-yloxy] phenyl ester
상기 실시예 8의 제조방법과 동일하게 수행하되, 카테콜 대신 레조르시놀을 사용하여 아크릴산 3-[6-아미노-5-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)피리딘-3-일옥시]페닐에스터(Acrylic acid 3-[6-amino-5-(3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester)를 제조하였다.It was carried out in the same manner as in Example 8, except that resorcinol was used instead of catechol and acrylic acid 3-[6-amino-5-(3,4-dihydro-1H-isoquinolin-2-yl)pyridine was used. -3-yloxy]phenyl ester (Acrylic acid 3-[6-amino-5-(3,4-dihydro- 1H -isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester) was prepared.
노란색 고체 (수율 30%); IR (neat, cm-1) 2980.40, 2888.74, 1461.83, 1382.18, 1239.58, 1151.98, 966.99; 1H NMR (500 MHz, CDCl3) δ 7.73 (1H, d, J = 2.5 Hz), 7.30 (1H, t, J = 8.0 Hz), 7.21-7.15 (3H, m), 7.07 (1H, d, J = 7.0 Hz), 7.06 (1H, d, J = 2.5 Hz), 6.83 (1H, dd, J = 2.5, 8.5 Hz), 6.82 (1H, dd, J = 2.0, 8.5 Hz), 6.73 (1H, dd, J = 2.0, 2.5 Hz), 6.59 (1H, d, J = 1.5, 17.5 Hz), 6.29 (1H, dd, J =10.5, 17.5 Hz), 6.01 (1H, d, J = 1.5, 10.5 Hz), 4.73 (2H, br s), 4.09 (2H, s), 3.24 (2H, t, J = 6.0 Hz), 3.02 (2H, t, J = 6.0 Hz); 13C NMR (500 MHz, CDCl3) δ 164.4, 159.7, 151.8, 151.6, 144.9, 135.4, 134.3, 133.8, 133.8, 132.9, 130.2, 129.1, 127.9, 126.7, 126.5, 126.1, 120.9, 115.7, 114.2, 110.4, 53.3, 48.9, 29.6; LCMS (ESI) m/z calcd for C23H21N3O3, 387.16; Found 388.16 [M + H]+.yellow solid (yield 30%); IR (neat, cm -1 ) 2980.40, 2888.74, 1461.83, 1382.18, 1239.58, 1151.98, 966.99; 1 H NMR (500 MHz, CDCl 3 ) δ 7.73 (1H, d, J = 2.5 Hz), 7.30 (1H, t, J = 8.0 Hz), 7.21-7.15 (3H, m), 7.07 (1H, d, J = 7.0 Hz), 7.06 (1H, d, J = 2.5 Hz), 6.83 (1H, dd, J = 2.5, 8.5 Hz), 6.82 (1H, dd, J = 2.0, 8.5 Hz), 6.73 (1H, dd, J = 2.0, 2.5 Hz), 6.59 (1H, d, J = 1.5, 17.5 Hz), 6.29 (1H, dd, J =10.5, 17.5 Hz), 6.01 (1H, d, J = 1.5, 10.5 Hz) ), 4.73 (2H, br s), 4.09 (2H, s), 3.24 (2H, t, J = 6.0 Hz), 3.02 (2H, t, J = 6.0 Hz); 13 C NMR (500 MHz, CDCl 3 ) δ 164.4, 159.7, 151.8, 151.6, 144.9, 135.4, 134.3, 133.8, 133.8, 132.9, 130.2, 129.1, 127.9, 126.7, 126.5, 126.1, 120.9, 115.7, 114.2, 110.4 , 53.3, 48.9, 29.6; LCMS (ESI) m/z calcd for C 23 H 21 N 3 O 3 , 387.16; Found 388.16 [M + H] + .
<< 실시예Example 11> 아크릴산 3-[6-아미노-5-(6- 11> Acrylic acid 3-[6-amino-5-(6- 프로포옥시propoxy -3,4--3,4- 다이하이드로dihydro -1H-아이소퀴놀린-2-일)피리딘-3-일옥시페닐 에스터의 제조Preparation of -1H-isoquinolin-2-yl)pyridin-3-yloxyphenyl ester
상기 실시예 10의 제조방법과 동일하게 수행하되, 테트라하이드로아이소퀴놀린 대신 6-프로폭시-1,2,3,4-테트라하이드로아이소퀴놀린을 사용하여 아크릴산 3-[6-아미노-5-(6-프로포옥시-3,4-다이하이드로-1H-아이소퀴놀린-2-일)피리딘-3-일옥시페닐 에스터(Acrylic acid 3-[6-amino-5-(6-propoxy-3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester)를 제조하였다.Acrylic acid 3-[6-amino-5-(6) was carried out in the same manner as in Example 10, except that 6-propoxy-1,2,3,4-tetrahydroisoquinoline was used instead of tetrahydroisoquinoline. -Propoxy-3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxyphenyl ester (Acrylic acid 3-[6-amino-5-(6-propoxy-3,4-) dihydro- 1H -isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester) was prepared.
노란색 고체 (수율 23%); IR (neat, cm-1) 2980.97, 2883.67, 1595.77, 1459.04, 1399.69, 1381.50, 1314.25, 1237.69, 1151.35, 1023.03, 981.04; 1H NMR (500 MHz, CDCl3) δ 7.72 (1H, d, J = 2.5 Hz), 7.30 (1H, t, J = 8.5 Hz), 7.05 (1H, d, J = 2.5 Hz), 6.98 (1H, d, J = 8.5 Hz), 6.83-6.81 (2H, m), 6.75-6.70 (3H, m), 6.58 (1H, dd, J = 1.0, 17.5 Hz), 6.29 (1H, dd, J = 10.5, 17.5 Hz), 6.00 (1H, dd, J = 1.0, 10.5 Hz), 4.73 (2H, br s), 4.02 (2H, s), 3.91 (2H, t, J = 7.0 Hz), 3.21 (2H, t, J = 6.0 Hz), 2.97 (2H, t, J = 6.0 Hz), 1.80 (2H, sext., J = 7.0 Hz), 1.03 (3H, t, J = 7.0 Hz); 13C NMR (500 MHz, CDCl3) δ 164.3, 159.6, 157.8, 151.6, 151.5, 144.9, 135.3, 134.9, 133.8, 133.2, 132.8, 130.2, 127.8, 127.3, 126.2, 125.4, 120.9, 115.5, 114.3, 114.1, 110.2, 52.7, 52.0, 51.5, 48.7, 29.2; LCMS (ESI) m/z calcd for C26H27N3O4, 445.20; Found 446.21 [M + H]+. yellow solid (23% yield); IR (neat, cm −1 ) 2980.97, 2883.67, 1595.77, 1459.04, 1399.69, 1381.50, 1314.25, 1237.69, 1151.35, 1023.03, 981.04; 1 H NMR (500 MHz, CDCl 3 ) δ 7.72 (1H, d, J = 2.5 Hz), 7.30 (1H, t, J = 8.5 Hz), 7.05 (1H, d, J = 2.5 Hz), 6.98 (1H) , d, J = 8.5 Hz), 6.83-6.81 (2H, m), 6.75-6.70 (3H, m), 6.58 (1H, dd, J = 1.0, 17.5 Hz), 6.29 (1H, dd, J = 10.5) , 17.5 Hz), 6.00 (1H, dd, J = 1.0, 10.5 Hz), 4.73 (2H, br s), 4.02 (2H, s), 3.91 (2H, t, J = 7.0 Hz), 3.21 (2H, t, J = 6.0 Hz), 2.97 (2H, t, J = 6.0 Hz), 1.80 (2H, sext., J = 7.0 Hz), 1.03 (3H, t, J = 7.0 Hz); 13 C NMR (500 MHz, CDCl 3 ) δ 164.3, 159.6, 157.8, 151.6, 151.5, 144.9, 135.3, 134.9, 133.8, 133.2, 132.8, 130.2, 127.8, 127.3, 126.2, 125.4, 120.9, 115.5, 114.3, 114.1 , 110.2, 52.7, 52.0, 51.5, 48.7, 29.2; LCMS (ESI) m/z calcd for C 26 H 27 N 3 O 4 , 445.20; Found 444.21 [M + H] + .
<< 실시예Example 12> 아크릴산 3-[6-아미노-5-(6- 12> Acrylic acid 3-[6-amino-5-(6- 사이클로프로필메톡시cyclopropylmethoxy -3,4--3,4- 다이하이드로dihydro -1H-아이소퀴놀린-2-일)피리딘-3-일옥시]페닐 에스터의 제조Preparation of -1H-isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester
상기 실시예 10의 제조방법과 동일하게 수행하되, 테트라하이드로아이소퀴놀린 대신 6-(사이클로프로필메톡시)-1,2,3,4-테트라하이드로아이소퀴놀린을 사용하여 아크릴산 3-[6-아미노-5-(6-사이클로프로필메톡시-3,4-다이하이드로-1H-아이소퀴놀린-2-일)피리딘-3-일옥시]페닐 에스터(Acrylic acid 3-[6-amino-5-(6-cyclopropylmethoxy-3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester)를 제조하였다.Acrylic acid 3- [6-amino- 5- (6-cyclopropylmethoxy-3,4-dihydro-1H-isoquinolin-2-yl) pyridin-3-yloxy] phenyl ester (Acrylic acid 3- [6-amino-5- (6- cyclopropylmethoxy-3,4-dihydro- 1H -isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester) was prepared.
노란색 고체 (수율 67%); IR (neat, cm-1) 2981.10, 2884.01, 1595.97, 1459.23, 1399.20, 1369.08, 1311.93, 1276.07, 1237.12, 1153.63, 1129.55, 1021.23; 1H NMR (500 MHz, CDCl3) δ 7.70 (1H, d, J = 2.5 Hz), 7.30 (1H, t, J = 8.0 Hz), 7.05 (1H, d, J = 2.5 Hz), 6.98 (1H, d, J = 8.5 Hz), 6.82 (2H, dd, J = 2.5, 8.5 Hz), 6.76-6.70 (3H, m), 6.59 (1H, dd, J = 1.5, 17.5 Hz), 6.29 (1H, dd, J = 10.5, 17.5 Hz), 6.01 (1H, dd, J = 1.5, 10.5 Hz), 4.79 (2H, br s), 4.02 (2H, s), 3.79 (2H, d, J = 7.0 Hz), 3.21 (2H, t, J = 6.0 Hz), 2.97 (2H, t, J = 6.0 Hz), 1.30-1.23 (1H, m), 0.64 (2H, dd, J = 5.0, 12.5 Hz), 0.34 (2H, dd, J = 5.0, 10.0 Hz); 13C NMR (500 MHz, CDCl3) δ 164.3, 159.6, 157.7, 151.6, 151.5, 144.9, 135.3, 134.9, 133.9, 132.8, 130.1, 127.8, 127.7, 127.4, 126.4, 120.9, 120.6, 115.5, 114.3, 114.1, 113.0, 110.3, 52.7, 50.7, 48.6, 40.6, 29.8; LCMS (ESI) m/z calcd for C27H27N3O4, 457.20; Found 458.22 [M + H]+. yellow solid (yield 67%); IR (neat, cm -1 ) 2981.10, 2884.01, 1595.97, 1459.23, 1399.20, 1369.08, 1311.93, 1276.07, 1237.12, 1153.63, 1129.55, 1021.23; 1 H NMR (500 MHz, CDCl 3 ) δ 7.70 (1H, d, J = 2.5 Hz), 7.30 (1H, t, J = 8.0 Hz), 7.05 (1H, d, J = 2.5 Hz), 6.98 (1H) , d, J = 8.5 Hz), 6.82 (2H, dd, J = 2.5, 8.5 Hz), 6.76-6.70 (3H, m), 6.59 (1H, dd, J = 1.5, 17.5 Hz), 6.29 (1H, dd, J = 10.5, 17.5 Hz), 6.01 (1H, dd, J = 1.5, 10.5 Hz), 4.79 (2H, br s), 4.02 (2H, s), 3.79 (2H, d, J = 7.0 Hz) , 3.21 (2H, t, J = 6.0 Hz), 2.97 (2H, t, J = 6.0 Hz), 1.30-1.23 (1H, m), 0.64 (2H, dd, J = 5.0, 12.5 Hz), 0.34 ( 2H, dd, J = 5.0, 10.0 Hz); 13 C NMR (500 MHz, CDCl 3 ) δ 164.3, 159.6, 157.7, 151.6, 151.5, 144.9, 135.3, 134.9, 133.9, 132.8, 130.1, 127.8, 127.7, 127.4, 126.4, 120.9, 120.6, 115.5, 114.3, 114.1 , 113.0, 110.3, 52.7, 50.7, 48.6, 40.6, 29.8; LCMS (ESI) m/z calcd for C 27 H 27 N 3 O 4 , 457.20; Found 458.22 [M + H] + .
<< 실시예Example 13> 아크릴산 3-[6-아미노-5-(6- 13> Acrylic acid 3-[6-amino-5-(6- 벤질옥시benzyloxy -3,4--3,4- 다이하이드로dihydro -1H--1H- 아이소퀴놀린isoquinoline -2-일)피리딘-3-일옥시]페닐에스터의 제조Preparation of -2-yl) pyridin-3-yloxy] phenyl ester
상기 실시예 10의 제조방법과 동일하게 수행하되, 테트라하이드로아이소퀴놀린 대신 6-(벤질옥시)-1,2,3,4-테트라하이드로아이소퀴놀린을 사용하여 아크릴산 3-[6-아미노-5-(6-벤질옥시-3,4-다이하이드로-1H-아이소퀴놀린-2-일)피리딘-3-일옥시]페닐에스터(Acrylic acid 3-[6-amino-5-(6-benzyloxy-3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester)를 제조하였다.Acrylic acid 3-[6-amino-5-] was carried out in the same manner as in Example 10, except that 6-(benzyloxy)-1,2,3,4-tetrahydroisoquinoline was used instead of tetrahydroisoquinoline. (6-benzyloxy-3,4-dihydro-1H-isoquinolin-2-yl) pyridin-3-yloxy] phenyl ester (Acrylic acid 3- [6-amino-5- (6-benzyloxy-3, 4-dihydro- 1H -isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester) was prepared.
노란색 고체 (수율 63%); IR (neat, cm-1) 2980.57, 1739.16, 1607.15, 1462.79, 1401.07, 1378.91, 1313.43, 1237.60, 1151.77, 1023.59, 1001.65; 1H NMR (500 MHz, CDCl3) δ 7.72 (1H, d, J = 2.5 Hz), 7.43 (2H, d, J = 7.0 Hz), 7.38 (2H, t, J = 7.5 Hz), 7.33-7.28 (2H, m), 7.04 (1H, d, J = 2.5 Hz), 6.99 (1H, d, J = 8.0 Hz), 6.83-6.78 (4H, m), 6.72 (1H, t, J = 2.5Hz), 6.58 (1H, dd, J = 1.0, 17.5 Hz), 6.29 (1H, dd, J = 10.5, 17.5 Hz), 6.00 (1H, dd, J = 1.5, 10.5 Hz), 5.05 (2H, s), 4.72 (2H, br s), 4.02 (2H, s), 3.21 (2H, t, J = 6.0 Hz), 2.97 (2H, t, J = 6.0 Hz); 13C NMR (500 MHz, CDCl3) δ 164.4, 159.8, 157.6, 154.5, 151.7, 151.6, 145.0, 137.2, 135.2, 135.1, 134.5, 132.9, 130.2, 128.7, 128.1, 127.9, 127.6, 127.5, 126.9, 120.5, 115.6, 114.8, 114.2, 113.3, 110.4, 70.2, 52.8, 48.7, 29.9; LCMS (ESI) m/z calcd for C30H27N3O4, 493.20; Found 494.21 [M + H]+.yellow solid (yield 63%); IR (neat, cm -1 ) 2980.57, 1739.16, 1607.15, 1462.79, 1401.07, 1378.91, 1313.43, 1237.60, 1151.77, 1023.59, 1001.65; 1 H NMR (500 MHz, CDCl 3 ) δ 7.72 (1H, d, J = 2.5 Hz), 7.43 (2H, d, J = 7.0 Hz), 7.38 (2H, t, J = 7.5 Hz), 7.33-7.28 (2H, m), 7.04 (1H, d, J = 2.5 Hz), 6.99 (1H, d, J = 8.0 Hz), 6.83-6.78 (4H, m), 6.72 (1H, t, J = 2.5 Hz) , 6.58 (1H, dd, J = 1.0, 17.5 Hz), 6.29 (1H, dd, J = 10.5, 17.5 Hz), 6.00 (1H, dd, J = 1.5, 10.5 Hz), 5.05 (2H, s), 4.72 (2H, br s), 4.02 (2H, s), 3.21 (2H, t, J = 6.0 Hz), 2.97 (2H, t, J = 6.0 Hz); 13 C NMR (500 MHz, CDCl 3 ) δ 164.4, 159.8, 157.6, 154.5, 151.7, 151.6, 145.0, 137.2, 135.2, 135.1, 134.5, 132.9, 130.2, 128.7, 128.1, 127.9, 127.6, 127.5, 126.9, 120.5 , 115.6, 114.8, 114.2, 113.3, 110.4, 70.2, 52.8, 48.7, 29.9; LCMS (ESI) m/z calcd for C 30 H 27 N 3 O 4 , 493.20; Found 494.21 [M + H] + .
<< 실시예Example 14> 아크릴산 3-{6-아미노-5-[6-(4- 14> Acrylic acid 3-{6-amino-5-[6-(4- 플루오로벤질옥시Fluorobenzyloxy )-3,4-)-3,4- 다이하이드로dihydro -1H-아이소퀴놀린-2-일]피리딘-3-일옥시}페닐 에스터의 제조Preparation of -1H-isoquinolin-2-yl]pyridin-3-yloxy}phenyl ester
상기 실시예 10의 제조방법과 동일하게 수행하되, 테트라하이드로아이소퀴놀린 대신 6-((4-플루오로벤질)옥시)-1,2,3,4-테트라하이드로아이소퀴놀린을 사용하여 아크릴산 3-{6-아미노-5-[6-(4-플루오로벤질옥시)-3,4-다이하이드로-1H-아이소퀴놀린-2-일]피리딘-3-일옥시}페닐 에스터(Acrylic acid 3-{6-amino-5-[6-(4-fluorobenzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]pyridin-3-yloxy}phenyl ester)를 제조하였다.Acrylic acid 3-{ 6-amino-5-[6-(4-fluorobenzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]pyridin-3-yloxy}phenyl ester (Acrylic acid 3-{6 -amino-5-[6-(4-fluorobenzyloxy)-3,4-dihydro- 1H -isoquinolin-2-yl]pyridin-3-yloxy}phenyl ester) was prepared.
노란색 고체 (수율 4%); IR (neat, cm-1) 3321.71, 2922.44, 2850.45, 1735.63, 1603.52, 1508.71, 1460.41, 1400.57, 1379.29, 1235.92, 1151.94, 1022.79; 1H NMR (500 MHz, CDCl3) δ 7.71 (1H, d, J = 2.0 Hz), 7.42 (2H, m), 7.32 (1H, t, J = 8.0 Hz), 7.09 (3H, m), 7.00 (1H, d, J = 8.5 Hz), 6.84 (2H, m), 6.81 (1H, dd, J = 2.0, 8.5 Hz), 6.77 (1H, d, J = 2.0 Hz), 6.73 (1H, d, J = 2.0 Hz), 6.57 (1H, d, J = 17.0 Hz), 6.32 (1H, dd, J = 10.5, 17.0 Hz), 6.02 (1H, d, J = 10.5 Hz), 5.01 (2H, s), 4.82 (2H, br s), 4.03 (2H, s), 3.23 (2H, t, J = 6.0 Hz), 2.99 (2H, t, J = 6.0 Hz); 13C NMR (500 MHz, CDCl3) δ 164.4, 159.7, 157.4, 151.8, 151.7, 145.0, 135.4, 132.9, 130.2, 129.4, 129.4, 127.9, 127.6, 127.0, 120.8, 115.9, 115.7, 115.7, 115.5, 115.3, 114.8, 114.2, 113.3, 110.4, 69.5, 53.6, 52.8, 48.7, 29.9; LCMS (ESI) m/z calcd for C30H25FN3O4, 511.19; Found 512.19 [M + H]+.yellow solid (yield 4%); IR (neat, cm -1 ) 3321.71, 2922.44, 2850.45, 1735.63, 1603.52, 1508.71, 1460.41, 1400.57, 1379.29, 1235.92, 1151.94, 1022.79; 1 H NMR (500 MHz, CDCl 3 ) δ 7.71 (1H, d, J = 2.0 Hz), 7.42 (2H, m), 7.32 (1H, t, J = 8.0 Hz), 7.09 (3H, m), 7.00 (1H, d, J = 8.5 Hz), 6.84 (2H, m), 6.81 (1H, dd, J = 2.0, 8.5 Hz), 6.77 (1H, d, J = 2.0 Hz), 6.73 (1H, d, J = 2.0 Hz), 6.57 (1H, d, J = 17.0 Hz), 6.32 (1H, dd, J = 10.5, 17.0 Hz), 6.02 (1H, d, J = 10.5 Hz), 5.01 (2H, s) , 4.82 (2H, br s), 4.03 (2H, s), 3.23 (2H, t, J = 6.0 Hz), 2.99 (2H, t, J = 6.0 Hz); 13 C NMR (500 MHz, CDCl 3 ) δ 164.4, 159.7, 157.4, 151.8, 151.7, 145.0, 135.4, 132.9, 130.2, 129.4, 129.4, 127.9, 127.6, 127.0, 120.8, 115.9, 115.7, 115.7, 115.5, 115.3 , 114.8, 114.2, 113.3, 110.4, 69.5, 53.6, 52.8, 48.7, 29.9; LCMS (ESI) m/z calcd for C 30 H 25 FN 3 O 4 , 511.19; Found 512.19 [M + H] + .
<< 실시예Example 15> 아크릴산 3-{6-아미노-5-[6-(4- 15> Acrylic acid 3-{6-amino-5-[6-(4- 클로로벤질옥시chlorobenzyloxy )-3,4-)-3,4- 다이하이드로dihydro -1H-아이소퀴놀린-2-일]피리딘-3-일옥시}페닐 에스터의 제조Preparation of -1H-isoquinolin-2-yl]pyridin-3-yloxy}phenyl ester
상기 실시예 10의 제조방법과 동일하게 수행하되, 테트라하이드로아이소퀴놀린 대신 6-((4-클로로벤질)옥시)-1,2,3,4-테트라하이드로아이소퀴놀린을 사용하여 아크릴산 3-{6-아미노-5-[6-(4-클로로벤질옥시)-3,4-다이하이드로-1H-아이소퀴놀린-2-일]피리딘-3-일옥시}페닐 에스터(Acrylic acid 3-{6-amino-5-[6-(4-chlorobenzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]pyridin-3-yloxy}phenyl ester)를 제조하였다.Acrylic acid 3-{6 was carried out in the same manner as in Example 10, except that 6-((4-chlorobenzyl)oxy)-1,2,3,4-tetrahydroisoquinoline was used instead of tetrahydroisoquinoline. -Amino-5-[6-(4-chlorobenzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]pyridin-3-yloxy}phenyl ester (Acrylic acid 3-{6-amino -5-[6-(4-chlorobenzyloxy)-3,4-dihydro- 1H -isoquinolin-2-yl]pyridin-3-yloxy}phenyl ester) was prepared.
노란색 고체 (yield 55%); IR (neat, cm-1) 2980.88, 2952.96, 2888.90, 1458.99, 1443.76, 1234.19, 1148.64, 1015.34; 1H NMR (500 MHz, CDCl3) δ 7.72 (1H, d, J = 2.5 Hz), 7.36 (4H, s), 7.30 (1H, t, J = 8.5 Hz), 7.05 (1H, d, J = 2.5 Hz), 7.00 (1H, d, J = 8.5 Hz), 6.83 (1H, d, J = 8.0 Hz), 6.82 (1H, d, J = 8.0 Hz), 6.79 (1H, dd, J = 2.5, 8.0 Hz), 6.76 (1H, d, J = 2.5 Hz), 6.72 (1H, t, J = 2.5 Hz), 6.59 (1H, dd, J = 1.0, 17.0 Hz), 6.29 (1H, dd, J = 10.0, 17.0 Hz), 6.01 (1H, dd, J = 1.0, 10.0 Hz), 5.02 (2H, s), 4.72 (2H, br s), 4.03 (2H, s), 3.22 (2H, t, J = 5.5 Hz), 2.98 (2H, t, J = 5.5 Hz); 13C NMR (500 MHz, CDCl3) δ 164.4, 159.8, 157.3, 151.7, 151.6, 145.0, 135.7, 135.2, 134.4, 133.9, 132.9, 130.2, 128.9, 128.8, 128.7, 127.9, 127.6, 126.9, 120.6, 115.6, 114.8, 114.2, 113.2, 110.4, 69.4, 52.8, 48.7, 29.9; LCMS (ESI) m/z calcd for C30H25C1N3O4, 527.16; Found 528.16 [M + H]+.yellow solid (yield 55%); IR (neat, cm -1 ) 2980.88, 2952.96, 2888.90, 1458.99, 1443.76, 1234.19, 1148.64, 1015.34; 1 H NMR (500 MHz, CDCl 3 ) δ 7.72 (1H, d, J = 2.5 Hz), 7.36 (4H, s), 7.30 (1H, t, J = 8.5 Hz), 7.05 (1H, d, J = 2.5 Hz) 2.5 Hz), 7.00 (1H, d, J = 8.5 Hz), 6.83 (1H, d, J = 8.0 Hz), 6.82 (1H, d, J = 8.0 Hz), 6.79 (1H, dd, J = 2.5, 8.0 Hz), 6.76 (1H, d, J = 2.5 Hz), 6.72 (1H, t, J = 2.5 Hz), 6.59 (1H, dd, J = 1.0, 17.0 Hz), 6.29 (1H, dd, J = 10.0, 17.0 Hz), 6.01 (1H, dd, J = 1.0, 10.0 Hz), 5.02 (2H, s), 4.72 (2H, br s), 4.03 (2H, s), 3.22 (2H, t, J = 5.5 Hz), 2.98 (2H, t, J = 5.5 Hz); 13 C NMR (500 MHz, CDCl 3 ) δ 164.4, 159.8, 157.3, 151.7, 151.6, 145.0, 135.7, 135.2, 134.4, 133.9, 132.9, 130.2, 128.9, 128.8, 128.7, 127.9, 127.6, 126.9, 120.6, 115.6 , 114.8, 114.2, 113.2, 110.4, 69.4, 52.8, 48.7, 29.9; LCMS (ESI) m/z calcd for C 30 H 25 C 1 N 3 O 4 , 527.16; Found 528.16 [M + H] + .
<< 실시예Example 16> 아크릴산 3-{6-아미노-5-[6-(4- 16> Acrylic acid 3-{6-amino-5-[6-(4- 메톡시벤질옥시methoxybenzyloxy )-3,4-)-3,4- 다이하이드로dihydro -1H-아이소퀴놀린-2-일]피리딘-3-일옥시}페닐 에스터의 제조Preparation of -1H-isoquinolin-2-yl]pyridin-3-yloxy}phenyl ester
상기 실시예 10의 제조방법과 동일하게 수행하되, 테트라하이드로아이소퀴놀린 대신 6-((4-메톡시벤질)옥시)-1,2,3,4-테트라하이드로아이소퀴놀린을 사용하여 아크릴산 3-{6-아미노-5-[6-(4-메톡시벤질옥시)-3,4-다이하이드로-1H-아이소퀴놀린-2-일]피리딘-3-일옥시}페닐 에스터(Acrylic acid 3-{6-amino-5-[6-(4-methoxybenzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]pyridin-3-yloxy}phenyl ester)를 제조하였다.Acrylic acid 3-{ 6-amino-5-[6-(4-methoxybenzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]pyridin-3-yloxy}phenyl ester (Acrylic acid 3-{6 -amino-5-[6-(4-methoxybenzyloxy)-3,4-dihydro- 1H -isoquinolin-2-yl]pyridin-3-yloxy}phenyl ester) was prepared.
노란색 고체 (수율 42%); IR (neat, cm-1) 3345.48, 2980.40, 2970.51, 2930.34, 1740.92, 1609.63, 1513.79, 1462.81, 1400.63, 1379.59, 1304.07, 1241.82, 1153.82, 1025.10, 1001.88; 1H NMR (500 MHz, CDCl3) δ 7.70 (1H, d, J = 2.5 Hz), 7.33 (2H, d, J = 8.5 Hz), 7.28 (1H, t, J = 8.0 Hz), 7.03 (1H, d, J = 2.5 Hz), 6.96 (1H, d, J = 8.5 Hz), 6.90 (2H, d, J = 8.5 Hz), 6.82-6.77 (3H, m), 6.76 (1H, d, J = 2.0 Hz), 6.73 (1H, t, J = 2.5 Hz), 6.57 (1H, dd, J = 1.0, 17.5 Hz), 6.27 (1H, dd, J = 10.5, 17.5 Hz), 5.98 (1H, dd, J = 1.0, 10.5 Hz), 4.95 (2H, s), 4.82 (2H, br s), 4.00 (2H, s), 3.78 (3H, s), 3.18 (2H, t, J = 6.0 Hz), 2.95 (2H, t, J = 6.0 Hz); 13C NMR (500 MHz, CDCl3) δ 164.4, 159.8, 159.6, 157.7, 151.7, 151.7, 145.0, 135.3, 135.1, 134.4, 132.9, 130.2, 129.3, 129.2, 127.9, 127.5, 126.8, 120.6, 115.6, 114.8, 114.2, 114.2, 113.3, 110.4, 70.0, 55.5, 52.8, 48.8, 29.9; LCMS (ESI) m/z calcd for C31H29N3O5, 523.21; Found 524.22 [M + H]+.yellow solid (yield 42%); IR (neat, cm -1 ) 3345.48, 2980.40, 2970.51, 2930.34, 1740.92, 1609.63, 1513.79, 1462.81, 1400.63, 1379.59, 1304.07, 1241.82, 1153.82, 1025.10, 1001.88; 1 H NMR (500 MHz, CDCl 3 ) δ 7.70 (1H, d, J = 2.5 Hz), 7.33 (2H, d, J = 8.5 Hz), 7.28 (1H, t, J = 8.0 Hz), 7.03 (1H) , d, J = 2.5 Hz), 6.96 (1H, d, J = 8.5 Hz), 6.90 (2H, d, J = 8.5 Hz), 6.82-6.77 (3H, m), 6.76 (1H, d, J = 8.5 Hz) 2.0 Hz), 6.73 (1H, t, J = 2.5 Hz), 6.57 (1H, dd, J = 1.0, 17.5 Hz), 6.27 (1H, dd, J = 10.5, 17.5 Hz), 5.98 (1H, dd, J = 1.0, 10.5 Hz), 4.95 (2H, s), 4.82 (2H, br s), 4.00 (2H, s), 3.78 (3H, s), 3.18 (2H, t, J = 6.0 Hz), 2.95 (2H, t, J = 6.0 Hz); 13 C NMR (500 MHz, CDCl 3 ) δ 164.4, 159.8, 159.6, 157.7, 151.7, 151.7, 145.0, 135.3, 135.1, 134.4, 132.9, 130.2, 129.3, 129.2, 127.9, 127.5, 126.8, 120.6, 115.6, 114.8 , 114.2, 114.2, 113.3, 110.4, 70.0, 55.5, 52.8, 48.8, 29.9; LCMS (ESI) m/z calcd for C 31 H 29 N 3 O 5 , 523.21; Found 524.22 [M + H] + .
상기 실시예 1 내지 실시예 16에서 제조한 화합물의 화학 구조를 하기 표 1에 도시하였다.Chemical structures of the compounds prepared in Examples 1 to 16 are shown in Table 1 below.
<< 실험예Experimental example 1> 분자 도킹 분석(Molecular docking analysis) 1> Molecular docking analysis
실시예 16에 따른 화합물의 분자 도킹 분석(Molecular docking analysis)을 위하여 DFG-out conformation에 의해 유도된 알로스테릭 포켓(allosteric pocket)이 있는 인간 BTK 구조 (PDB ID: 3PJ3)을 기반으로 분석하였다. 그 결과를 도 1 및 도 2에 나타내었다. 그 결과, 실시예 16 화합물의 테트라하이드로아이소퀴놀린 링커는 타입 Ⅱ 방법(type Ⅱ method)으로 BTK 키나아제 도메인의 알로스테릭 포켓에 위치한 친유성 모이어티를 생성함을 확인할 수 있었다. 아미노피리딘 힌지 바인더(hinge binder)는 힌지 Glu475 및 게이트키퍼 Thr474와 함께 두 개의 수소 결합을 형성하며, 파라-메톡시벤질 그룹은 Met449, Leu452, Leu512 및 Phe517으로 둘러싸인 알로스테릭 친수성 포켓으로 향한다. 친유성 치환체는 테트라하이드로아이소퀴놀린 고리에 의해 안정화되며, 이는 Lys430과 반데르발스 상호작용(van der Waals interactions)을 하게 한다. 또한, Michael 수용체 링커 페닐 고리는 Leu408 및 Gly480 사이의 틈에 존재하며 이를 통해 아크릴 그룹의 카보닐과 Cys481의 백본 사이의 수소결합이 형성된다.For molecular docking analysis of the compound according to Example 16, it was analyzed based on the human BTK structure (PDB ID: 3PJ3) with an allosteric pocket induced by DFG-out conformation. The results are shown in FIGS. 1 and 2 . As a result, it was confirmed that the tetrahydroisoquinoline linker of the compound of Example 16 generates a lipophilic moiety located in the allosteric pocket of the BTK kinase domain by the type II method. The aminopyridine hinge binder forms two hydrogen bonds with hinge Glu475 and gatekeeper Thr474, and the para-methoxybenzyl group is directed into an allosteric hydrophilic pocket surrounded by Met449, Leu452, Leu512 and Phe517. The lipophilic substituent is stabilized by a tetrahydroisoquinoline ring, which allows for van der Waals interactions with Lys430. In addition, a Michael acceptor linker phenyl ring exists in the gap between Leu408 and Gly480, through which a hydrogen bond is formed between the carbonyl of the acrylic group and the backbone of Cys481.
<< 실험예Experimental example 2> 2> BTKBTK 활서bow letter 억제 평가 Inhibition Assessment
실시예 1 내지 실시예 16의 BTK 억제 활성을 평가하기 위하여, 단일 농도(20μM)에서의 BTK 저해활성 및 IC50를 ADP-Glo assay (Promega, USA) 및 HotSpot Kinase assay (Reaction Biology Corporation, USA)를 ATP 농도 10 μM에서 분석하였다. 그 결과를 하기 표 2에 나타내었다.In order to evaluate the BTK inhibitory activity of Examples 1 to 16, BTK inhibitory activity and IC 50 at a single concentration (20 μM) were measured by ADP-Glo assay (Promega, USA) and HotSpot Kinase assay (Reaction Biology Corporation, USA) was analyzed at an ATP concentration of 10 μM. The results are shown in Table 2 below.
표 2에서 확인되는 바와 같이, 본 발명에 따른 아미노피리딘 계열의 화합물은 BTK 억제에 우수한 활성이 있는 것으로 나타났다.As can be seen in Table 2, the aminopyridine-based compound according to the present invention was found to have excellent activity in inhibiting BTK.
<< 실험예Experimental example 3> 3> BTKBTK 특이도 및 선택도 평가 Evaluation of specificity and selectivity
BTK에 대한 선택도 및 다른 TEC 및 SRC 계열의 키나아제에 대한 선택도를 분석하기 위하여, 실시예 9, 실시예 13 및 실시예 16 화합물을 이용하여 상기 실험예 2와 동일한 방법으로 실험하였다. 그 결과를 하기 표 3에 나타내었다.In order to analyze the selectivity to BTK and the selectivity to other TEC and SRC family kinases, Example 9, Example 13, and Example 16 were tested in the same manner as in Experimental Example 2 using the compounds. The results are shown in Table 3 below.
표 3의 결과와 같이, 본 발명 화합물은 BTK에 대한 특이도와 선택도가 높은 것으로 확인되었다. 상기한 결과로부터 본 발명 화합물은 기존의 BTK 억제제 화합물과 다른 스캐폴드를 가지는 것으로, BTK 활성 부위에 적절하게 위치하여 우수한 결합력을 나타낼 뿐 아니라, BTK에 대한 특이도와 선택도가 높아, 이로부터 부작용의 우려를 낮추고, BTK 관련 질환의 예방 또는 치료에 보다 개선 된 약효를 달성하는 약물이 제공될 수 있음을 확인하였다.As shown in Table 3, the compound of the present invention was confirmed to have high specificity and selectivity to BTK. From the above results, the compound of the present invention has a scaffold different from that of the existing BTK inhibitor compound, and is appropriately located at the BTK active site to exhibit excellent binding force, and has high specificity and selectivity for BTK, thereby reducing side effects. It has been confirmed that a drug that lowers concerns and achieves more improved efficacy in the prevention or treatment of BTK-related diseases can be provided.
<< 실험예Experimental example 4> 혈액학적 악성종양(hematological malignancy)에 대한 효과 분석 4> Effect analysis on hematological malignancy
4-1. In vitro 성장 억제 실험4-1. In vitro growth inhibition experiment
본 발명 화합물의 혈액학적 악성종양(hematological malignancy)에 대한 효과를 분석하기 위하여 먼저, 실시예 9 및 실시예 16 화합물의 세포 독성을 CellTiter-Glo 발광 세포 생존력을 분석하였다. Raji (ATCC CCL-86) 및 Ramos (ATCC CRL-1596) 세포를 opaque-walled 96-well plate (1 × 104 cells/well)에 접종하고, 다양한 농도의 실시예 9 및 실시예 16 화합물로 처리하였다. 48시간 후, 100 μL의 CellTiter-Glo Reagent (Promega, USA)를 각 웰에 첨가하고, 플레이트를 실온에서 10분 동안 인큐베이션하였다. 발광 신호는 GloMax-Multi Detection System (Promega, USA)를 사용하여 측정하였으며, GI50 값은 GraphPad Prism (GraphPad, USA)을 사용하여 계산하였다. 그 결과를 하기 표 4에 나타내었다.In order to analyze the effect of the compound of the present invention on hematological malignancy, first, the cell viability of Example 9 and Example 16 was analyzed for cytotoxicity and CellTiter-Glo luminescent cell viability. Raji (ATCC CCL-86) and Ramos (ATCC CRL-1596) cells were inoculated into opaque-walled 96-well plates (1 × 104 cells/well) and treated with various concentrations of Example 9 and Example 16 compounds. . After 48 hours, 100 μL of CellTiter-Glo Reagent (Promega, USA) was added to each well and the plate was incubated for 10 minutes at room temperature. The luminescence signal was measured using the GloMax-Multi Detection System (Promega, USA), and the GI 50 value was calculated using GraphPad Prism (GraphPad, USA). The results are shown in Table 4 below.
그 결과 두 화합물 모두 Raji 및 Ramos 세포주에서 유사한 GI50 값을 나타내었다.As a result, both compounds showed similar GI 50 values in Raji and Ramos cell lines.
4-2. In 4-2. In vivoin vivo 이종이식( xenotransplantation ( xenograftxenograft ) 모델 분석) model analysis
본 발명 실시예 9 및 실시예 16 화합물의 In vivo 활성 평가를 위해 다음과 같이 실험하였다. 구체적으로, 실험은 한국 생명 공학 연구원(Korea Research Institute of Bioscience and Biotechnology)의 IACUC (Institutional Animal Care and Use Committee) 승인을 받아 진행되었고, 6주령 암컷 BALB/c nu/nu 마우스 (Orient Bio, Korea)의 오른쪽 옆구리에 Raji 세포 (9x106 cells/head)에 피하 접종하였다. 1주 후, 마우스를 무작위 배분하고, 비히클(5% DMSO and 5% Tween 80 in corn oil), 2 mg/kg 독소루비신 하이드로클로라이드(doxorubicin hydrochloride), 50 mg/kg 실시예 9 및 실시예 16 화합물을 매주 5회 처리하였다. 종양의 부피는 버니어캘리퍼스(vernier calipers)로 측정하고, 길이 (mm) × 너비 (mm) × 높이 (mm) / 2 공식으로 추정하였으며, 체중은 일주일에 세번 모니터링하였다. 14일째에 마우스를 희생시키고 종양 무게를 측정하였다. 통계 분석은 GraphPad Prism (GraphPad, USA)을 사용하여 수행하였다. 체중 및 종양 부피의 변화는 양방향 ANOVA 및 Bonferroni 다중 비교 테스트를 사용하여 분석되었으며, <0.05의 p 값은 통계적으로 유의 한 것으로 간주하였다. 그 결과를 도 3 및 도 4에 나타내었다.In order to evaluate the in vivo activity of the compounds of Examples 9 and 16 of the present invention, an experiment was performed as follows. Specifically, the experiment was conducted with IACUC (Institutional Animal Care and Use Committee) approval of the Korea Research Institute of Bioscience and Biotechnology, and 6-week-old female BALB/c nu/nu mice (Orient Bio, Korea) Raji cells (9x10 6 cells/head) were subcutaneously inoculated into the right flank of After 1 week, mice were randomized and administered vehicle (5% DMSO and 5
그 결과, 두 화합물 모두 임상 및 부검 결과에 근거한 독성 증상은 없었다. 대조군은 약간의 체중 감소를 보인 반면, 실시예 9 및 실시예 16 화합물 그룹에서는 체중 감소가 보이지 않았다. 또한, 실시예 16은 비히클과 비교하여 46.8%의 억제효과로 종양 크기를 상당히 감소시키는 것으로 나타났다. 따라서 본 발명 화합물은 혈액학적 악성종양 치료 및 개선에 우수한 효과가 있음을 알 수 있다.As a result, there were no toxic symptoms based on clinical and autopsy results for both compounds. The control group showed a slight weight loss, whereas the Example 9 and Example 16 compound groups showed no weight loss. In addition, Example 16 was shown to significantly reduce tumor size with an inhibitory effect of 46.8% compared to vehicle. Therefore, it can be seen that the compound of the present invention has an excellent effect in the treatment and improvement of hematologic malignancies.
이상, 본 발명을 바람직한 제조예, 실시예 및 실험예를 통해 상세히 설명하였으나, 본 발명의 범위는 특성 실시예에 한정되는 것은 아니며, 첨부된 특허청구범위에 의하여 해석되어야 할 것이다. 또한, 이 기술분야에서 통상의 지식을 습득한 자라면, 본 발명의 범위에서 벗어나지 않으면서도 많은 수정과 변형이 가능함을 이해하여야 할 것이다.As mentioned above, although the present invention has been described in detail through preferred preparation examples, examples and experimental examples, the scope of the present invention is not limited to the characteristic examples, and should be interpreted by the appended claims. In addition, those skilled in the art will understand that many modifications and variations are possible without departing from the scope of the present invention.
Claims (13)
[화학식 1]
상기 화학식 1에서,
상기 X1은 또는 이고;
상기 R2는 수소 또는 -OR3이고;
상기 R1 및 R3은 각각 독립적으로 수소, 치환 또는 비치환된 직쇄 또는 분지쇄의 C1-10알킬, 또는 치환 또는 비치환된 C1- 10알콕시카보닐이고,
상기 치환된 직쇄 또는 분지쇄의 C1- 10알킬, 및 C1- 10알콕시는 각각 할로젠, 하나 이상의 C1- 5알콕시 또는 할로젠으로 치환되거나 비치환된 페닐, 및 C3- 8사이클로알킬로 이루어진 군으로부터 선택되는 1종 이상의 치환기로 치환되고; 및
상기 X2는 이다.
A compound represented by the following formula (1), a stereoisomer or a pharmaceutically acceptable salt thereof:
[Formula 1]
In Formula 1,
wherein X 1 is or ego;
wherein R 2 is hydrogen or —OR 3 ;
Wherein R 1 and R 3 are each independently hydrogen, a substituted or unsubstituted straight-chain or branched C 1-10 alkyl , or a substituted or unsubstituted C 1-10 alkoxycarbonyl,
wherein said substituted straight - chain or branched C 1-10 alkyl , and C 1-10 alkoxy are each halogen, phenyl unsubstituted or substituted with one or more C 1-5 alkoxy or halogen, and C 3-8 cycloalkyl substituted with one or more substituents selected from the group consisting of; and
wherein X 2 is am.
상기 R1 및 R3은 각각 독립적으로 수소, 치환 또는 비치환된 직쇄 또는 분지쇄의 C1-6알킬, 또는 치환 또는 비치환된 C1-6알콕시카보닐이고,
상기 치환된 직쇄 또는 분지쇄의 C1- 6알킬, 및 C1- 6알콕시는 각각 할로젠, 하나 이상의 C1- 3알콕시 또는 할로젠으로 치환되거나 비치환된 페닐, 및 C3- 6사이클로알킬로 이루어진 군으로부터 선택되는 1종 이상의 치환기로 치환되는 것을 특징으로 하는, 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염.
According to claim 1,
Wherein R 1 and R 3 are each independently hydrogen, a substituted or unsubstituted straight-chain or branched C 1-6 alkyl, or a substituted or unsubstituted C 1-6 alkoxycarbonyl,
wherein said substituted straight - chain or branched C 1-6 alkyl , and C 1-6 alkoxy are each halogen, phenyl unsubstituted or substituted with one or more C 1-3 alkoxy or halogen, and C 3-6 cycloalkyl A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is substituted with one or more substituents selected from the group consisting of.
상기 X2는 오쏘(ortho) 또는 메타(meta) 자리에 치환되는 것을 특징으로 하는, 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염.
According to claim 1,
Wherein X 2 Is ortho (ortho) or meta (meta), characterized in that substituted at the site, a compound, a stereoisomer or a pharmaceutically acceptable salt thereof.
상기 R1 및 R3은 각각 독립적으로 수소, , , , , , , , , 또는 인 것을 특징으로 하는, 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염.
According to claim 1,
The R 1 and R 3 are each independently hydrogen, , , , , , , , , or Characterized in that, a compound, a stereoisomer or a pharmaceutically acceptable salt thereof.
상기 화학식 1로 표시되는 화합물은,
하기 화합물 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염:
(1) 아크릴산 3-(6-아미노-5-피페라진일피리딘-3-일옥시)페닐 에스터;
(2) 아크릴산 3-[6-아미노-5-(4-벤질피페라진일)피리딘-3-일옥시]페닐 에스터;
(3) 아크릴산 3-{6-아미노-5-[4-(4-플루오로벤질)피페라진일]피리딘-3-일옥시}페닐 에스터;
(4) 아크릴산 3-{6-아미노-5-[4-(4-클로로벤질)피페라진일]피리딘-3-일옥시}페닐 에스터;
(5) 아크릴산 3-[6-아미노-5-(4-페네틸피페라진일)피리딘-3-일옥시]페닐 에스터;
(6) 아크릴산 3-(6-아미노-5-{4-[2-(4-클로로페닐)에틸]피페라진일}피리딘-3-일옥시)페닐 에스터;
(7) 4-[5-(3-아크릴로일옥시페녹시)-2-아미노피리딘-3-일]피페라진 카복실산 벤질에스터;
(8) 아크릴산 2-[6-아미노-5-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)피리딘-3-일옥시]페닐 에스터;
(9) 아크릴산 2-[6-아미노-5-(6-벤질옥시-3,4-다이하이드로-1H-아이소퀴놀린-2-일)피리딘-3-일옥시]페닐 에스터;
(10) 아크릴산 3-[6-아미노-5-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)피리딘-3-일옥시]페닐에스터;
(11) 아크릴산 3-[6-아미노-5-(6-프로포옥시-3,4-다이하이드로-1H-아이소퀴놀린-2-일)피리딘-3-일옥시페닐 에스터;
(12) 아크릴산 3-[6-아미노-5-(6-사이클로프로필메톡시-3,4-다이하이드로-1H-아이소퀴놀린-2-일)피리딘-3-일옥시]페닐 에스터;
(13) 아크릴산 3-[6-아미노-5-(6-벤질옥시-3,4-다이하이드로-1H-아이소퀴놀린-2-일)피리딘-3-일옥시]페닐에스터;
(14) 아크릴산 3-{6-아미노-5-[6-(4-플루오로벤질옥시)-3,4-다이하이드로-1H-아이소퀴놀린-2-일]피리딘-3-일옥시}페닐 에스터;
(15) 아크릴산 3-{6-아미노-5-[6-(4-클로로벤질옥시)-3,4-다이하이드로-1H-아이소퀴놀린-2-일]피리딘-3-일옥시}페닐 에스터; 및
(16) 아크릴산 3-{6-아미노-5-[6-(4-메톡시벤질옥시)-3,4-다이하이드로-1H-아이소퀴놀린-2-일]피리딘-3-일옥시}페닐 에스터.
According to claim 1,
The compound represented by Formula 1 is,
A compound, characterized in that it is any one selected from the group of compounds, a stereoisomer or a pharmaceutically acceptable salt thereof:
(1) acrylic acid 3-(6-amino-5-piperazinylpyridin-3-yloxy)phenyl ester;
(2) acrylic acid 3-[6-amino-5-(4-benzylpiperazinyl)pyridin-3-yloxy]phenyl ester;
(3) acrylic acid 3-{6-amino-5-[4-(4-fluorobenzyl)piperazinyl]pyridin-3-yloxy}phenyl ester;
(4) acrylic acid 3-{6-amino-5-[4-(4-chlorobenzyl)piperazinyl]pyridin-3-yloxy}phenyl ester;
(5) acrylic acid 3-[6-amino-5-(4-phenethylpiperazinyl)pyridin-3-yloxy]phenyl ester;
(6) acrylic acid 3-(6-amino-5-{4-[2-(4-chlorophenyl)ethyl]piperazinyl}pyridin-3-yloxy)phenyl ester;
(7) 4-[5-(3-acryloyloxyphenoxy)-2-aminopyridin-3-yl]piperazine carboxylic acid benzylester;
(8) acrylic acid 2-[6-amino-5-(3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester;
(9) acrylic acid 2-[6-amino-5-(6-benzyloxy-3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester;
(10) acrylic acid 3-[6-amino-5-(3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxy]phenylester;
(11) acrylic acid 3-[6-amino-5-(6-propooxy-3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxyphenyl ester;
(12) acrylic acid 3-[6-amino-5-(6-cyclopropylmethoxy-3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester;
(13) acrylic acid 3-[6-amino-5-(6-benzyloxy-3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxy]phenylester;
(14) acrylic acid 3-{6-amino-5-[6-(4-fluorobenzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]pyridin-3-yloxy}phenyl ester ;
(15) acrylic acid 3-{6-amino-5-[6-(4-chlorobenzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]pyridin-3-yloxy}phenyl ester; and
(16) Acrylic acid 3-{6-amino-5-[6-(4-methoxybenzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]pyridin-3-yloxy}phenyl ester .
[화학식 1]
상기 화학식 1에서,
X1 및 X2는 제1항의 화학식 1에서 정의한 바와 같다.
A pharmaceutical composition for preventing or treating a BTK (Bruton's tyrosine kinase)-related disease comprising a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]
In Formula 1,
X 1 and X 2 are as defined in Formula 1 of claim 1.
상기 BTK 관련 질환은 자가면역 질환 또는 암인 것을 특징으로 하는 약학적 조성물.
7. The method of claim 6,
The BTK-related disease is an autoimmune disease or a pharmaceutical composition, characterized in that cancer.
상기 BTK 관련 질환은 혈액학적 악성종양(hematological malignancy), 혈액암, B-세포 만성림프성백혈병, 급성림프성백혈병, 비호지킨림프종, 호지킨림프종, 급성골수성백혈병, 미만성거대B-세포림프종, 다발성골수종, 재킷세포림프종, 소림프구성림프종, 맨틀세포림프종(MCL) 및 림프구성 백혈병(CLL)으로 이루어진 군에서 선택되는 것을 특징으로 하는 약학적 조성물.
7. The method of claim 6,
The BTK-related disease is hematological malignancy, hematologic cancer, B-cell chronic lymphocytic leukemia, acute lymphoblastic leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute myeloid leukemia, diffuse giant B-cell lymphoma, multiple A pharmaceutical composition selected from the group consisting of myeloma, jacket cell lymphoma, small lymphocytic lymphoma, mantle cell lymphoma (MCL) and lymphocytic leukemia (CLL).
상기 BTK 관련 질환은 류마티스 관절염, 골관절염, 연소성관절염, 만성폐쇄성 폐질환, 다발성경화증, 천식, 전신성홍반성루푸스, 건선, 건선성관절염, 크론병, 궤양성대장염 및 과민성대장증후군으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 약학적 조성물.
7. The method of claim 6,
The BTK-related disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, juvenile arthritis, chronic obstructive pulmonary disease, multiple sclerosis, asthma, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis and irritable bowel syndrome. Characterized in that, the pharmaceutical composition.
상기 BTK 관련 질환은 혈액학적 악성종양(hematological malignancy)인 것을 특징으로 하는, 약학적 조성물.
7. The method of claim 6,
The BTK-related disease is characterized in that the hematological malignancy (hematological malignancy), the pharmaceutical composition.
[화학식 1]
상기 화학식 1에서,
X1 및 X2는 제1항의 화학식 1에서 정의한 바와 같다.
A health functional food composition for preventing or improving BTK (Bruton's tyrosine kinase)-related disease containing a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]
In Formula 1,
X 1 and X 2 are as defined in Formula 1 of claim 1.
상기 BTK 관련 질환은 자가면역 질환 또는 암인 것을 특징으로 하는 건강기능식품 조성물.
12. The method of claim 11,
The BTK-related disease is an autoimmune disease or a health functional food composition, characterized in that cancer.
상기 BTK 관련 질환은 혈액학적 악성종양(hematological malignancy)인 것을 특징으로 하는, 건강기능식품 조성물.12. The method of claim 11,
The BTK-related disease is characterized in that the hematological malignancy (hematological malignancy), health functional food composition.
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Non-Patent Citations (2)
Title |
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Caldwell, R. D. et al, Journal of Medicinal Chemistry, 2019, Volume 62, pages 7643-7655 * |
Lee, E. et al., International Journal of Molecular Sciences, 2020, Volume 21, Page 8006 * |
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WO2022255806A1 (en) * | 2021-06-01 | 2022-12-08 | 연세대학교 산학협력단 | Composition for preventing or treating brain cancer |
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