KR20210039666A - Bicyclic compound and use thereof - Google Patents

Bicyclic compound and use thereof Download PDF

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KR20210039666A
KR20210039666A KR1020190122176A KR20190122176A KR20210039666A KR 20210039666 A KR20210039666 A KR 20210039666A KR 1020190122176 A KR1020190122176 A KR 1020190122176A KR 20190122176 A KR20190122176 A KR 20190122176A KR 20210039666 A KR20210039666 A KR 20210039666A
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dihydro
isoquinolin
propyl
hydroxy
methyl
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신용제
김진희
이준
최현석
김세혁
강은지
이호연
이호열
박숙경
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에스케이바이오팜 주식회사
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Abstract

The present invention relates to a compound derivative containing a 6-7 bicyclic ring and uses thereof, and the compound according to the present invention can be usefully used for the prevention or treatment of PRMT5 induced diseases by acting as a PRMT5 inhibitor. The present invention provides the compound of chemical formula 1, or an optical isomer, stereoisomer, or a pharmaceutically acceptable salt thereof.

Description

바이사이클릭 화합물 및 이의 용도{BICYCLIC COMPOUND AND USE THEREOF}Bicyclic compounds and uses thereof {BICYCLIC COMPOUND AND USE THEREOF}

본 발명은 6-7 바이사이클릭 고리를 포함하는 화합물 유도체 및 이의 용도에 관한 것으로, 본 발명에 따른 화합물은 PRMT5 억제제로 작동하여 PRMT5에 의해 유발되는 질환의 예방 또는 치료에 유용하게 사용될 수 있다.The present invention relates to a compound derivative comprising a 6-7 bicyclic ring and a use thereof, and the compound according to the present invention acts as a PRMT5 inhibitor and can be usefully used in the prevention or treatment of a disease caused by PRMT5.

PRMT(protein arginine methyltransferases)는 보조인자 SAM(S-아데노실 메티오닌)을 이용해서 표적 단백질에 있는 아르기닌에 메틸기를 전이시키는 효소이다. 현재까지 알려진 PRMT 이소형은 총 9가지 (PRMT1~9)이며, 이들은 크게 3가지 타입으로 나뉘어 진다. 타입 I PRMT에는 PRMT1, 2, 3, 4, 6, 8이 존재하여 아르기닌의 모노메틸화 및 비대칭형 디메틸화를 야기하며, 타입 II PRMT에 속하는 PRMT5와 PRMT9는 아르기닌의 모노메틸화 및 대칭형 디메틸화를 유도하는 것으로 알려져 있다. 한편 타입 III PRMT인 PRMT7은 아르기닌의 모노메틸화를 주로 야기한다. PRMT는 핵 및 세포질 내에 존재하는 다양한 기질들의 메틸화를 유도하고 있는데, 이를 통해서 세포 증식, 분화 및 스플라이싱 등과 같이 세포 내 중요한 생물학적 과정들을 조절하고 있다.PRMT (protein arginine methyltransferases) are enzymes that transfer methyl groups to arginine in target proteins using the cofactor SAM (S-adenosyl methionine). There are a total of 9 PRMT isoforms known to date (PRMT1~9), and these are largely divided into 3 types. PRMT1, 2, 3, 4, 6, 8 exist in type I PRMT, causing monomethylation and asymmetric dimethylation of arginine, and PRMT5 and PRMT9 belonging to type II PRMT induce monomethylation and symmetric dimethylation of arginine It is known to do. On the other hand, PRMT7, a type III PRMT, mainly causes monomethylation of arginine. PRMT induces methylation of various substrates present in the nucleus and cytoplasm, through which it regulates important biological processes in cells such as cell proliferation, differentiation and splicing.

PRMT5는 타입 II PRMT 가운데 주요 아르기닌 메틸기 전이 효소로서, 메틸로좀 (methylosome) 단백질 50 (MEP50)과 기능성 복합체를 형성하여 표적 단백질의 메틸화를 일으킨다. PRMT5는 핵 내의 히스톤 단백질과 비-히스톤 단백질의 일종인 p53, NFκB, PI3K/AKT, CRAF와 같은 표적 단백질들을 메틸화 시킴으로써 백혈병, 림프종, 교모세포종, 폐암, 유방암 등의 형성에 관련되어 있다. 특히, PRMT5에 의한 암 형성은 종양세포의 증식, 분화, 침투 (invasion), 이동 (migration)이 촉진되면서 발생하는 것으로 잘 알려져 있다. 또한, 몇몇 보고에 의하면 PRMT5 발현이 높을 수록 암 환자들의 예후가 좋지 않은 것으로 알려져 있으며, 반대로 PRMT5의 발현이 저해된 경우에는 종양세포의 증식이 억제될 수 있음이 관찰된 바 있다.PRMT5 is a major arginine methyl group transfer enzyme among type II PRMTs. It forms a functional complex with methylosome protein 50 (MEP50) to cause methylation of the target protein. PRMT5 is involved in the formation of leukemia, lymphoma, glioblastoma, lung cancer, and breast cancer by methylating target proteins such as p53, NFκB, PI3K/AKT, and CRAF, which are a kind of histone protein and non-histone protein in the nucleus. In particular, it is well known that cancer formation by PRMT5 occurs when the proliferation, differentiation, invasion, and migration of tumor cells are promoted. In addition, according to several reports, it is known that the higher the expression of PRMT5, the poorer the prognosis of cancer patients. Conversely, it has been observed that when the expression of PRMT5 is inhibited, the proliferation of tumor cells may be suppressed.

한편, 최근에는 암 이외의 다른 질환들 역시 PRMT5에 의해 매개될 수 있음이 보고되고 있다.Meanwhile, it has been recently reported that other diseases other than cancer can also be mediated by PRMT5.

본 발명은 우수한 PRMT5 억제 효과를 나타내는 6-7 바이사이클릭 고리 기반의 신규 화합물, 또는 이의 광학 이성질체, 입체 이성질체 또는 약제학적으로 허용되는 염을 제공하는 것을 목적으로 한다.An object of the present invention is to provide a novel compound based on a 6-7 bicyclic ring exhibiting excellent PRMT5 inhibitory effect, or an optical isomer, stereoisomer, or pharmaceutically acceptable salt thereof.

또한, 본 발명은 상기 6-7 바이사이클릭 고리 기반의 신규 화합물, 또는 이의 광학 이성질체, 입체 이성질체 또는 약제학적으로 허용되는 염을 유효성분으로 포함하는 약제학적 조성물을 제공하는 것을 다른 목적으로 한다.In addition, another object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, a novel compound based on the 6-7 bicyclic ring, or an optical isomer, stereoisomer or pharmaceutically acceptable salt thereof.

상기 목적을 달성하기 위하여, 본 발명에서는 하기 화학식 1의 화합물, 또는 이의 광학 이성질체, 입체 이성질체 또는 약제학적으로 허용되는 염을 제공한다:In order to achieve the above object, the present invention provides a compound represented by the following Formula 1, or an optical isomer, stereoisomer or pharmaceutically acceptable salt thereof:

[화학식 1][Formula 1]

Figure pat00001
Figure pat00001

상기 화학식 1에서,In Formula 1,

X1 및 X2는 각각 독립적으로 탄소 또는 질소를 나타내고;X 1 and X 2 each independently represent carbon or nitrogen;

Y는 탄소, 산소 또는 질소를 나타내며;Y represents carbon, oxygen or nitrogen;

Z는 탄소를 나타내고;Z represents carbon;

n은 0 또는 1의 정수를 나타내며;n represents an integer of 0 or 1;

m은 0 내지 2의 정수를 나타내고;m represents an integer of 0 to 2;

R1은

Figure pat00002
를 나타내며; 여기에서 R9 및 R10은 각각 독립적으로 수소, 알킬, 사이클로알킬, N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 갖는 4원 내지 10원의 헤테로사이클로알킬, 또는 N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 갖는 4원 내지 10원의 헤테로아릴-알킬을 나타내거나; R9 및 R10은 결합하는 N과 함께 N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 갖는 4원 내지 10원의 헤테로사이클로알킬을 형성할 수 있고; 상기 헤테로사이클로알킬 또는 헤테로아릴은 할로, 옥소, 포르밀(-CHO), 알킬, 알콕시, 알킬카르보닐, 알콕시카르보닐, 디알킬아미노, 및 N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 갖는 4원 내지 10원의 헤테로사이클로알킬로부터 선택되는 하나 이상의 치환기로 치환될 수 있고;R 1 is
Figure pat00002
Represents; Wherein R 9 and R 10 are each independently selected from hydrogen, alkyl, cycloalkyl, 4 to 10 membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, or N, O and S Or 4 to 10 membered heteroaryl-alkyl having one or more heteroatoms; R 9 and R 10 together with the N to which they are attached may form a 4-10 membered heterocycloalkyl having one or more heteroatoms selected from N, O and S; The heterocycloalkyl or heteroaryl has one or more heteroatoms selected from halo, oxo, formyl (-CHO), alkyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, dialkylamino, and N, O and S. May be substituted with one or more substituents selected from 4-10 membered heterocycloalkyl;

R2는 수소 또는 알킬을 나타내며;R 2 represents hydrogen or alkyl;

R3는 수소 또는 알킬을 나타내거나; m이 2일 경우 결합하는 C와 함께 사이클로알킬을 형성할 수 있고;R 3 represents hydrogen or alkyl; When m is 2, it may form a cycloalkyl with C to which it is bonded;

R4, R5, R6 및 R7은 각각 독립적으로 수소 또는 알킬을 나타내며;R 4 , R 5 , R 6 and R 7 each independently represent hydrogen or alkyl;

R8은 수소, 할로, 알킬, 알콕시 또는 아미노를 나타낸다.R 8 represents hydrogen, halo, alkyl, alkoxy or amino.

별도로 기술되지 않는 한, 본원에서 용어 “알킬”은 단독으로 사용되는 경우 또는 그 밖에 추가적인 용어와의 조합으로 사용되는 경우(예를 들면, 할로알킬) 직쇄형 또는 측쇄형의, 예를 들면 1개 내지 7개의 탄소 원자를 갖는 포화된 지방족 탄화수소 군의 라디칼을 의미한다. 전형적인 알킬 그룹의 예로는 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, 세크-부틸, 터트-부틸, n-펜틸, 이소펜틸, 네오펜틸, 터트-펜틸, 1-메틸부틸, 2-메틸부틸, 1-에틸프로필 및 1,2-디메틸프로필 등을 포함하나 이에 제한되는 것은 아니다.Unless otherwise stated, the term “alkyl” herein, when used alone or in combination with other additional terms (eg, haloalkyl), is straight or branched, for example one It means a radical of the group of saturated aliphatic hydrocarbons having from 7 to 7 carbon atoms. Examples of typical alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl , 2-methylbutyl, 1-ethylpropyl, and 1,2-dimethylpropyl, but are not limited thereto.

별도로 기술되지 않는 한, 본원에서 용어 “사이클로알킬”은 단독으로 사용되는 경우 또는 그 밖에 추가적인 용어와의 조합으로 사용되는 경우(예를 들면, 사이클로알킬-알킬) 고리형의, 예를 들면 3개 내지 7개의 탄소 원자를 갖는 포화된 지방족 탄화수소 군의 라디칼을 의미한다. 전형적인 사이클로알킬 그룹의 예로는 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실 등을 포함하나 이에 제한되는 것은 아니다.Unless otherwise stated, the term “cycloalkyl” herein when used alone or in combination with other additional terms (eg, cycloalkyl-alkyl) of a cyclic, for example three It means a radical of the group of saturated aliphatic hydrocarbons having from 7 to 7 carbon atoms. Examples of typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

별도로 기술되지 않는 한, 본원에서 용어 “알콕시”는 알킬옥시, 예를 들면 1개 내지 7개의 탄소 원자를 갖는 알킬옥시를 의미한다.Unless otherwise stated, the term “alkoxy” herein means alkyloxy, for example alkyloxy having 1 to 7 carbon atoms.

별도로 기술되지 않는 한, 본원에서 용어 “할로”는 단독으로 사용되는 경우 또는 그 밖에 추가적인 용어와의 조합으로 사용되는 경우 (예를 들면, 할로알킬) F, Cl, Br 또는 I인 라디칼을 의미한다.Unless otherwise stated, the term “halo” herein refers to a radical that is F, Cl, Br or I when used alone or in combination with other additional terms (eg haloalkyl). .

별도로 기술되지 않는 한, 본원에서 용어 “헤테로사이클로알킬”은 질소(N), 산소(O) 및 황(S)으로 구성된 군으로부터 선택되는 하나 이상의 헤테로원자를 갖는 4원 내지 10원의 포화 모노사이클릭 환을 의미하고, 바람직하게는 질소, 산소 및 황으로부터 선택되는 1 또는 3개의 헤테로원자를 갖는 4원 내지 8원의 포화 모노사이클릭 환을 의미하고, 구체적인 예로는 피롤리디닐(pyrrolidinyl), 피페리디닐(piperidinyl), 테트라하이드로퓨라닐(tetrahydrofuranyl), 테트라하이드로피라닐 (tetrahydropyranyl), 몰포리닐(morpholinyl)을 포함하나 이에 제한되는 것은 아니다.Unless otherwise stated, the term “heterocycloalkyl” herein refers to a 4-10 membered saturated monocyclic group having one or more heteroatoms selected from the group consisting of nitrogen (N), oxygen (O) and sulfur (S). It means a click ring, and preferably means a 4 to 8 membered saturated monocyclic ring having 1 or 3 heteroatoms selected from nitrogen, oxygen and sulfur, and specific examples are pyrrolidinyl, Piperidinyl (piperidinyl), tetrahydrofuranyl (tetrahydrofuranyl), tetrahydropyranyl (tetrahydropyranyl), including, but not limited to, morpholinyl (morpholinyl).

별도로 기술되지 않는 한, 본원에서 용어 “헤테로아릴”은 질소(N), 산소(O) 및 황(S)으로 구성된 군으로부터 선택되는 하나 이상의 헤테로원자를 갖는 4원 내지 10원의 방향족 탄화수소를 의미하고, 바람직하게는 질소, 산소 및 황으로부터 선택되는 1 또는 3개의 헤테로원자를 갖는 4원 내지 8원의 방향족 탄화수소를 의미하고, 구체적인 예로는 피리디닐, 피리미디닐, 피리다지닐, 피라지닐, 옥사디아졸릴, 이속사디아졸릴, 테트라졸릴, 트리아졸릴, 인돌릴, 인다졸릴, 이속사졸릴, 옥사졸릴, 티아졸릴, 아이소티아졸릴, 퓨라닐, 벤조퓨라닐, 이미다졸릴, 티오페닐 등을 포함하나 이에 제한되는 것은 아니다.Unless otherwise stated, the term “heteroaryl” herein refers to a 4- to 10-membered aromatic hydrocarbon having one or more heteroatoms selected from the group consisting of nitrogen (N), oxygen (O) and sulfur (S). And, preferably, it means a 4 to 8 membered aromatic hydrocarbon having 1 or 3 heteroatoms selected from nitrogen, oxygen and sulfur, and specific examples are pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, Oxadiazolyl, isoxadiazolyl, tetrazolyl, triazolyl, indolyl, indazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, furanyl, benzofuranyl, imidazolyl, thiophenyl, etc. Including, but not limited to.

본 발명의 일 측면에 따르면, 상기 화학식 1에서 According to an aspect of the present invention, in Formula 1

X1 및 X2는 각각 독립적으로 CH 또는 N을 나타내고;X 1 and X 2 each independently represent CH or N;

Y는 n이 0일 경우 CH2, O 또는 NH를 나타내며, n이 1일 경우 CH 또는 N을 나타내고; Y represents CH 2 , O or NH when n is 0, and CH or N when n is 1;

Z는 m이 0일 경우 CH2 또는 CH를 나타내며, m이 1일 경우 CH 또는 C를 나타내고, m이 2일 경우 C를 나타내며; Z represents CH 2 or CH when m is 0, CH or C when m is 1, and C when m is 2;

R1은

Figure pat00003
를 나타내고; 여기에서 R9 및 R10은 각각 독립적으로 수소, C1-C7 알킬, C3-C7 사이클로알킬, N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 갖는 4원 내지 8원의 헤테로사이클로알킬, 또는 N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 갖는 4원 내지 8원의 헤테로아릴-C1-C7 알킬을 나타내며; 상기 헤테로사이클로알킬 또는 헤테로아릴은 할로, 옥소, 포르밀(-CHO), C1-C7 알킬, C1-C7 알콕시, C1-C7 알킬카르보닐, C1-C7 알콕시카르보닐, 디(C1-C7 알킬)아미노, 및 N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 갖는 4원 내지 8원의 헤테로사이클로알킬로부터 선택되는 1개 내지 3개의 치환기로 치환될 수 있고;R 1 is
Figure pat00003
Represents; Wherein R 9 and R 10 are each independently a 4 to 8 membered heterocyclo having one or more heteroatoms selected from hydrogen, C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, N, O and S. Alkyl or 4 to 8 membered heteroaryl-C 1 -C 7 alkyl having one or more heteroatoms selected from N, O and S; The heterocycloalkyl or heteroaryl is halo, oxo, formyl (-CHO), C 1 -C 7 alkyl, C 1 -C 7 alkoxy, C 1 -C 7 alkylcarbonyl, C 1 -C 7 alkoxycarbonyl , Di(C 1 -C 7 alkyl) amino, and 4 to 8 membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, and may be substituted with 1 to 3 substituents, ;

R2는 수소 또는 C1-C7 알킬을 나타내며;R 2 represents hydrogen or C 1 -C 7 alkyl;

R3는 수소 또는 C1-C7 알킬을 나타내거나; m이 2일 경우 결합하는 C와 함께 C3-C7 사이클로알킬을 형성할 수 있고;R 3 represents hydrogen or C 1 -C 7 alkyl; When m is 2, C 3 -C 7 cycloalkyl may be formed with C to which it is bonded;

R4, R5, R6 및 R7은 각각 독립적으로 수소 또는 C1-C7 알킬을 나타내며;R 4 , R 5 , R 6 and R 7 each independently represent hydrogen or C 1 -C 7 alkyl;

R8은 수소, 할로, C1-C7 알킬, C1-C7 알콕시 또는 아미노를 나타낸다.R 8 represents hydrogen, halo, C 1 -C 7 alkyl, C 1 -C 7 alkoxy or amino.

본 발명의 다른 측면에 따르면, 상기 화학식 1에서According to another aspect of the present invention, in Formula 1

X1 및 X2는 각각 독립적으로 CH 또는 N을 나타내고;X 1 and X 2 each independently represent CH or N;

Y는 n이 0일 경우 CH2, O 또는 NH를 나타내며, n이 1일 경우 CH 또는 N을 나타내고; Y represents CH 2 , O or NH when n is 0, and CH or N when n is 1;

Z는 m이 0일 경우 CH2 또는 CH를 나타내며, m이 1일 경우 CH 또는 C를 나타내고, m이 2일 경우 C를 나타내며; Z represents CH 2 or CH when m is 0, CH or C when m is 1, and C when m is 2;

R1은

Figure pat00004
를 나타내고; 여기에서 R9 및 R10은 결합하는 N과 함께 N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 갖는 4원 내지 8원의 헤테로사이클로알킬을 형성하며; 상기 헤테로사이클로알킬은 할로, 옥소, 포르밀(-CHO), C1-C7 알킬, C1-C7 알콕시, C1-C7 알킬카르보닐, C1-C7 알콕시카르보닐, 디(C1-C7 알킬)아미노, 및 N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 갖는 4원 내지 8원의 헤테로사이클로알킬로부터 선택되는 1개 내지 3개의 치환기로 치환될 수 있고;R 1 is
Figure pat00004
Represents; Wherein R 9 and R 10 together with N to which they are attached form a 4 to 8 membered heterocycloalkyl having one or more heteroatoms selected from N, O and S; The heterocycloalkyl is halo, oxo, formyl (-CHO), C 1 -C 7 alkyl, C 1 -C 7 alkoxy, C 1 -C 7 alkylcarbonyl, C 1 -C 7 alkoxycarbonyl, di( C 1 -C 7 alkyl) amino, and 4 to 8 membered heterocycloalkyl having one or more heteroatoms selected from N, O and S;

R2는 수소 또는 C1-C7 알킬을 나타내며;R 2 represents hydrogen or C 1 -C 7 alkyl;

R3는 수소 또는 C1-C7 알킬을 나타내거나; m이 2일 경우 결합하는 C와 함께 C3-C7 사이클로알킬을 형성할 수 있고;R 3 represents hydrogen or C 1 -C 7 alkyl; When m is 2, C 3 -C 7 cycloalkyl may be formed with C to which it is bonded;

R4, R5, R6 및 R7은 각각 독립적으로 수소 또는 C1-C7 알킬을 나타내며;R 4 , R 5 , R 6 and R 7 each independently represent hydrogen or C 1 -C 7 alkyl;

R8은 수소, 할로, C1-C7 알킬, C1-C7 알콕시 또는 아미노를 나타낸다.R 8 represents hydrogen, halo, C 1 -C 7 alkyl, C 1 -C 7 alkoxy or amino.

본 발명에 따른 화학식 1의 화합물의 대표적인 것에는 다음의 표 1에 열거된 것이 포함되나 이에 제한되는 것은 아니다:Representative of the compounds of Formula 1 according to the present invention include, but are not limited to, those listed in Table 1 below:

[표 1][Table 1]

Figure pat00005
Figure pat00005

Figure pat00006
Figure pat00006

본 발명에 따른 화합물들은 비대칭 탄소중심과 비대칭축 또는 비대칭평면을 가질 수 있으므로 R 및 S 거울상체 (enantiomer)와 같이 실질적으로 순수한 거울상체뿐만 아니라 혼합 라세미체 (mixture racemate)를 포함한 모든 광학 및 입체 이성질체로서 존재할 수 있으며, 이들 모든 이성질체 및 혼합물은 본 발명의 범위에 포함된다. 순수 거울상체와 관련하여, 옥사다이아졸을 포함하는 화학식 1로 표현되는 이러한 거울상체 및 약학적으로 허용되는 이의 염의 광학적 순도는 바람직하게는 60%ee 이상, 더욱 바람직하게는 95%ee 이상, 그리고 가장 바람직하게는 98%ee 이상일 수 있다.Since the compounds according to the present invention may have an asymmetric carbon center and an asymmetric axis or asymmetric plane, not only substantially pure enantiomers such as R and S enantiomers, but also all optical and stereoscopic substances including mixture racemates. It may exist as isomers, and all of these isomers and mixtures are included within the scope of the present invention. With respect to the pure enantiomer, the optical purity of such an enantiomer represented by Formula 1 including oxadiazole and a pharmaceutically acceptable salt thereof is preferably 60%ee or more, more preferably 95%ee or more, and Most preferably, it may be 98%ee or more.

상기 용어 "ee"는 광학순도 (enantiomeric excess)를 의미한다. 예를 들어, 특정 화합물 내 하나의 거울상체는 다른 거울상체에 비해 많은 양으로 상기 화합물에 거울상체들의 혼합물로 존재한다. 거울상체가 풍부한 형태는 특정 화합물의 거울상체 혼합물 중 단일의 거울상체 농도가 상기 화합물의 다른 거울상체와 관련하여 50% 이상인, 보다 전형적으로는 60%, 70%, 80%, 또는 90% 이상이거나, 또는 그 이상인 (예컨대, >95%, >97%, >98%, >99%, >99.5%) 특정 화합물의 거울상체 혼합물을 포함할 수 있다.The term "ee" means optical purity (enantiomeric excess). For example, one enantiomer in a compound is present as a mixture of enantiomers in the compound in a larger amount than the other enantiomer. The enantio-enriched form is that the concentration of a single enantiomer in the enantiomeric mixture of a particular compound is at least 50% relative to the other enantiomers of the compound, more typically at least 60%, 70%, 80%, or 90% or , Or more (e.g., >95%, >97%, >98%, >99%, >99.5%).

본 명세서에서는 편의상 달리 명시되지 않는 한, 화학식 1의 화합물은 화학식 1의 화합물, 이의 광학 이성질체, 입체 이성질체 및 약제학적으로 허용되는 염을 모두 포함하는 의미로 사용된다.In the present specification, unless otherwise specified for convenience, the compound of Formula 1 is used to include all of the compound of Formula 1, its optical isomer, stereoisomer, and pharmaceutically acceptable salt.

본 발명에 따른 화학식 1의 화합물은 약제학적으로 허용되는 염을 형성할 수 있다. 상기 약제학적으로 허용 가능한 염으로는 산 또는 염기의 부가염 및 그의 입체화학적 이성질체 형태가 모두 포함된다. 상기 염에는 투여 대상인 객체에서 모 화합물 (parent compound)의 활성을 유지하며 바람직하지 못한 효과를 유발하지 않는 염이라면 어느 것이든 포함되는 것으로, 특별히 제한되는 것이 아니다. 그러한 염에는 무기염과 유기염이 포함되며, 예를 들어, 아세트산, 질산, 아스파트산, 술폰산, 설퓨릭산, 말레산, 글루탐산, 포름산, 숙신산, 인산, 프탈산, 탄닌산, 타르타르산, 히드로브롬산, 프로피온산, 벤젠술폰산, 벤조산, 스테아르산, 에실산, 락산, 비카르본산, 비설퓨릭산, 비타르타르산, 옥살산, 부틸산, 칼슘 이데트산, 캄실리산, 카르보닉산, 클로로벤조산, 시트르산, 이데트산, 톨루엔술폰산, 에디실린산, 에실린산, 퓨말산, 글루셉트산, 파모익산, 글루코닉산, 글리콜릴라르사닐산, 메틸니트릭산, 폴리갈라트록닉산, 헥실리소르시논산, 말론산, 히드라밤산, 히드로클로린산, 히드로요도익산, 하이드록시나프톨산, 이세티온산, 락토비오닉산, 만델산, 에스톨린산, 점액산, 나프실릭산, 뮤코닉산, p-니트로메탄설포닉산, 헥사믹산, 판토테닉산, 모노히드로겐인산, 디히드로겐인산, 살리실산, 술파민산, 술파닐린산, 메탄술폰산, 테오클릭산일 수 있다. 또한, 상기 염기성 염의 형태로는 예를 들어, 암모늄 염, 리튬 염, 소듐 염, 포타슘 염, 마그네슘 염 및 칼슘 염과 같은 알칼리 및 알칼리 토금속 염, 예를 들어, 벤자틴, N-메틸-D-글루카민, 하이드라바민 염과 같은 유기 염기를 갖는 염 및 예를 들어, 아르기닌, 리신과 같은 아미노산을 갖는 염을 포함한다. 또한, 상기 염 형태는 적당한 염기 또는 산으로 처리함으로써 유리 형태로 전환될 수도 있다. 용어, "부가염 (addtional salt)"은 화학식 1의 화합물 및 이의 염이 형성할 수 있는 용매 화합물을 포함한다. 그러한 용매 화합물은 예를 들어, 수화물, 알콜화물이다. The compound of formula 1 according to the present invention can form a pharmaceutically acceptable salt. The pharmaceutically acceptable salts include addition salts of acids or bases and stereochemically isomeric forms thereof. The salt includes any salt that maintains the activity of the parent compound in the object to be administered and does not cause undesirable effects, and is not particularly limited. Such salts include inorganic and organic salts, such as acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfonic acid, maleic acid, glutamic acid, formic acid, succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid, hydrobromic acid. , Propionic acid, benzenesulfonic acid, benzoic acid, stearic acid, ethyl acid, lactic acid, bicarboxylic acid, bisulfuric acid, bitartric acid, oxalic acid, butyric acid, calcium idetic acid, camsylic acid, carbonyl acid, chlorobenzoic acid, citric acid, ide Tic acid, toluenesulfonic acid, edicillic acid, esylic acid, fumaric acid, gluceptic acid, pamoic acid, gluconic acid, glycolyllarsanylic acid, methylnitric acid, polygalatroxanic acid, hexylysorbic acid, malonic acid , Hydrabamic acid, hydrochloric acid, hydroiodoic acid, hydroxynaphthoic acid, isethionic acid, lactobionic acid, mandelic acid, estolinic acid, mucous acid, napsylic acid, muconic acid, p-nitromethanesulphonic acid , Hexamic acid, pantothenic acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, salicylic acid, sulfamic acid, sulfanilic acid, methanesulfonic acid, and theocyclic acid. In addition, in the form of the basic salt, for example, alkali and alkaline earth metal salts such as ammonium salt, lithium salt, sodium salt, potassium salt, magnesium salt and calcium salt, for example, benzathine, N-methyl-D- And salts with organic bases such as glucamine and hydrabamine salts, and salts with amino acids such as arginine and lysine. In addition, the salt form can also be converted to the free form by treatment with a suitable base or acid. The term "addtional salt" includes a compound of formula 1 and a solvate which salts thereof may form. Such solvates are, for example, hydrates, alcoholates.

본 명세서에서 사용된 용어와 약어들은 달리 정의되지 않는 한 그 본래의 의미를 갖는다.Terms and abbreviations used herein have their original meanings unless defined otherwise.

본 발명은 또한 화학식 1의 화합물을 제조하는 방법을 제공한다. 이하에서는 본 발명에 대한 이해를 돕기 위해 화학식 1의 화합물의 제조방법을 예시적인 반응식에 기초하여 설명한다. 그러나, 본 발명이 속한 기술분야에서 통상의 지식을 가진 자라면 화학식 1의 구조를 바탕으로 공지의 화합물들 또는 이로부터 용이하게 제조할 수 있는 화합물들을 사용하여 다양한 방법에 의해 화학식 1의 화합물을 제조할 수 있으며, 이러한 방법들은 모두 본 발명의 범주에 포함되는 것으로 해석되어야 한다. 즉, 본 명세서에 기재되거나 선행기술에 개시된 여러 합성법들을 임의로 조합하여 화학식 1의 화합물을 제조할 수 있고, 따라서 상기 화학식 1의 화합물의 제조 방법과 관련된 하기의 설명은 예시적인 방법들을 제시하는 것에 지나지 않으며, 필요에 따라 단위 조작의 순서 등이 선택적으로 바뀔 수 있는 것으로서, 본 발명의 제조 방법의 범위가 이에 제한되는 것은 아니다.The invention also provides a method of preparing the compound of formula 1. Hereinafter, a method of preparing the compound of Formula 1 will be described based on an exemplary reaction scheme in order to aid understanding of the present invention. However, those of ordinary skill in the art to prepare the compound of Formula 1 by various methods using known compounds based on the structure of Formula 1 or compounds that can be easily prepared therefrom. All of these methods are to be construed as being included in the scope of the present invention. That is, the compound of Formula 1 may be prepared by arbitrarily combining various synthetic methods described in the present specification or disclosed in the prior art, and therefore, the following description related to the method of preparing the compound of Formula 1 is only to present exemplary methods. In addition, the order of unit operations and the like may be selectively changed as necessary, and the scope of the manufacturing method of the present invention is not limited thereto.

[반응식 1] [Scheme 1]

Figure pat00007
Figure pat00007

일반적인 합성 방법은 출발물질인 2로부터, 치환 반응을 통해 옥시란이 도입된 중간체 3을 얻고, 테트라하이드로아이소퀴놀린의 첨가반응을 통해 주요 중간체 4를 얻을 수 있다. 화합물 4를 출발물질로 하여 팔라듐 조건하에서 Buchwald-Hartwig amination 반응으로 아민 그룹이 치환된 최종화합물 1a를 얻을 수 있다. In a general synthesis method, intermediate 3 into which oxirane is introduced through a substitution reaction is obtained from 2, which is a starting material, and main intermediate 4 can be obtained through addition reaction of tetrahydroisoquinoline. Using compound 4 as a starting material, a final compound 1a in which an amine group is substituted can be obtained by a Buchwald-Hartwig amination reaction under palladium conditions.

본 발명의 다른 측면에 따르면, 유효성분으로서 치료학적 유효량의 화학식 1의 화합물, 또는 이의 광학 이성질체, 입체 이성질체 또는 약제학적으로 허용되는 염을 약제학적으로 허용되는 담체와 함께 포함하는, PRMT5 저해와 관련된 질병의 예방 또는 치료용 약제학적 조성물이 제공된다. 또한, 생체 내에서 목적한 바에 따라 화학식 1의 화합물로 전환되는 다양한 형태의 전구약물(prodrug)들도 본 발명의 범위에 포함된다. 상기 약제학적 조성물은 약제학적으로 허용 가능한 담체, 희석제 또는 보조제로 구성된 군으로부터 선택되는 1종 이상의 첨가제를 더 포함할 수 있다.According to another aspect of the present invention, as an active ingredient, a therapeutically effective amount of a compound of Formula 1, or an optical isomer, stereoisomer, or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, is associated with PRMT5 inhibition. A pharmaceutical composition for preventing or treating diseases is provided. In addition, various types of prodrugs that are converted to the compound of Formula 1 according to the purpose in vivo are also included in the scope of the present invention. The pharmaceutical composition may further include one or more additives selected from the group consisting of a pharmaceutically acceptable carrier, diluent, or adjuvant.

본 명세서에서 “치료”란 발병 증상을 보이는 객체에 사용될 때 질병의 진행을 중단, 지연 또는 완화시키는 것을 의미한다.In the present specification, “treatment” means stopping, delaying, or alleviating the progression of a disease when used in a subject showing onset symptoms.

본 명세서에서 “예방”이란 질병에 걸릴 가능성을 감소시키거나 가능성을 제거하는 것을 의미한다.In the present specification, “prevention” means reducing or eliminating the likelihood of getting a disease.

본 명세서에서 "약제학적 조성물(pharmaceutical composition)"은 본 발명에 따른 활성 화합물에 추가하여 담체, 희석제, 부형제 등과 같은 다른 화학 성분들을 포함할 수 있다. 따라서, 상기 약제학적 조성물에는 필요에 따라 약제학적으로 허용되는 담체, 희석제, 부형제, 또는 이들의 조합이 포함될 수 있다. 이러한 약제학적 조성물은 생물체 내로 활성 화합물의 투여를 용이하게 한다. 화합물을 포함하는 약제학적 조성물을 투여하는 다양한 기술이 알려져 있으며, 여기에는 경구, 주사, 에어로졸, 비경구, 및 국소 투여 등이 포함되지만, 이들만으로 한정되는 것은 아니다. 또한, 상기 약제학적 조성물은 멸균되거나, 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제를 더 포함할 수도 있고, 기타 치료적으로 유용한 물질을 더 포함할 수도 있으며, 혼합, 과립화 또는 코팅의 통상적인 방법에 따라 제제화될 수 있다.In the present specification, the "pharmaceutical composition" may include other chemical components such as carriers, diluents, excipients, etc. in addition to the active compound according to the present invention. Accordingly, the pharmaceutical composition may include a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof, if necessary. Such pharmaceutical compositions facilitate administration of the active compound into an organism. Various techniques for administering a pharmaceutical composition containing a compound are known, and include, but are not limited to, oral, injection, aerosol, parenteral, and topical administration. In addition, the pharmaceutical composition may be sterilized or further include adjuvants such as preservatives, stabilizers, hydrating agents or emulsification accelerators, salts and/or buffers for controlling osmotic pressure, or other therapeutically useful substances. And, it may be formulated according to a conventional method of mixing, granulating or coating.

본 명세서에서 “담체(carrier)”란 세포 또는 조직 내로 화합물의 투입을 용이하게 하는 화합물을 의미한다. 예를 들어, 디메틸설폭사이드(DMSO)는 생물체의 세포 또는 조직 내로 많은 유기 화합물의 투입을 용이하게 하는 통상의 담체이다.In the present specification, "carrier" refers to a compound that facilitates injection of the compound into cells or tissues. For example, dimethylsulfoxide (DMSO) is a common carrier that facilitates the introduction of many organic compounds into cells or tissues of an organism.

본 명세서에서 “희석제(diluent)”란 대상 화합물의 생물학적 활성 형태를 안정화시킬 뿐만 아니라, 화합물을 용해시키는 물에서 희석되는 화합물로 정의된다. 완충액에 용해되어 있는 염은 당해 분야에서 희석제로 사용된다. 통상 사용되는 완충액은 인체 용액의 염 형태를 모방하고 있는 포스페이트 완충 식염수이다. 완충제 염은 낮은 농도에서 용액의 pH를 제어할 수 있기 때문에, 완충 희석제가 화합물의 생물학적 활성을 변형시키는 일은 드물다.In the present specification, "diluent" is defined as a compound that is diluted in water to dissolve the compound as well as stabilize the biologically active form of the target compound. Salts dissolved in buffer are used as diluents in the art. A commonly used buffer solution is a phosphate buffered saline solution that mimics the salt form of a human solution. Because buffer salts can control the pH of a solution at low concentrations, buffering diluents rarely alter the biological activity of a compound.

본 명세서에서 “약제학적으로 허용되는(pharmaceutically acceptable)”이란, 화합물의 생물학적 활성과 물성들을 손상시키지 않는 성질을 의미한다.As used herein, "pharmaceutically acceptable" means a property that does not impair the biological activity and physical properties of the compound.

또한, 상기 약제학적 조성물은 PRMT5 저해와 관련된 질병의 예방 및/또는 치료용 조성물일 수 있다. 여기에서, 상기 PRMT5 저해와 관련된 질병은, 예를 들면 암, 혈액 질환, 자가면역질환, 염증성 질환 또는 신경퇴행성 질환일 수 있고, 기타 PRMT5와 관련된 것으로 알려진 임의의 질환을 포함할 수 있다.In addition, the pharmaceutical composition may be a composition for preventing and/or treating diseases associated with PRMT5 inhibition. Here, the disease associated with the PRMT5 inhibition may be, for example, cancer, blood disease, autoimmune disease, inflammatory disease or neurodegenerative disease, and may include any disease known to be related to other PRMT5.

상기 암은 청신경종, 선암종, 부신암, 항문암, 혈관 육종, 양성 단클론성 감마글로불린병증, 담관암, 방광암, 유방암, 뇌암, 기관지암, 자궁경부암, 두개인두종, 결장직장암, 상피 암종, 상의세포종, 내피 육종, 자궁 내막 암, 식도암, 바렛 선암종(Barrett's adenocarcinoma), 유잉 육종(Ewing's sarcoma), 눈의 암, 쓸개 암, 위암, 위장관 간질 종양 (GIST), 두경부암, 구강암(OSCC), 인후암, 조혈기계 암, 혈관 모세포종, 염증성 근섬유모세포 종양, 면역세포성 아밀로이드증, 신장암, 간암, 폐암, 골수이형성 증후군 (MDS), 중피종, 골수 증식성 장애 (MPD), 만성 특발성 골수섬유증, 만성 골수성 백혈병 (CML), 만성 호중구성 백혈병 (CNL), 신경 모세포종, 신경 섬유종, 신경내분비암, 골육종, 난소암, 유두 선암종, 췌장암, 음경암, 전립선암, 직장암, 횡문근 육종, 타액선 암, 피부암, 소장암, 연조직 육종, 갑상선암, 요도암, 질암 및 외음부 암을 포함하지만 이에 한정되지 않는다.　 상기 뇌암은 수막종, 신경교종, 수모세포종, 및 교모세포종을 포함하지만 이에 한정되지 않는다.The cancers are auditory neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma, benign monoclonal gammaglobulinopathy, bile duct cancer, bladder cancer, breast cancer, brain cancer, bronchial cancer, cervical cancer, craniocephaloma, colorectal cancer, epithelial carcinoma, epithelial cell tumor, Endothelial sarcoma, endometrial cancer, esophageal cancer, Barrett's adenocarcinoma, Ewing's sarcoma, eye cancer, gallbladder cancer, gastric cancer, gastrointestinal interstitial tumor (GIST), head and neck cancer, oral cancer (OSCC), throat cancer, hematopoietic Mechanical cancer, hemangioblastoma, inflammatory myofibroblast tumor, immune cell amyloidosis, kidney cancer, liver cancer, lung cancer, myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML) ), chronic neutrophilic leukemia (CNL), neuroblastoma, neurofibroma, neuroendocrine cancer, osteosarcoma, ovarian cancer, papillary adenocarcinoma, pancreatic cancer, penile cancer, prostate cancer, rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue Sarcoma, thyroid cancer, urethral cancer, vaginal cancer, and vulvar cancer. The brain cancer includes, but is not limited to, meningioma, glioma, medulloblastoma, and glioblastoma.

상기 혈액 질환은 혈색소병증, 겸상 적혈구성 빈혈일 수 있으나 이에 한정되지 않는다.The blood disease may be hemoglobinemia or sickle cell anemia, but is not limited thereto.

상기 자가면역질환은 류마티스 관절염, 척추관절병, 통풍성 관절염, 퇴행성 관절 질환, 골관절염, 전신성 홍반성 루푸스, 다발성 경화증, 건선성 관절염, 소아 관절염, 천식, 죽상동맥경화증, 골다공증, 기관지염, 건염, 건선, 습진, 화상, 피부염, 소양증, 야뇨증, 호산구성 질환, 소화성 궤양, 국한성 장염, 게실염, 위장 출혈, 호산구성 식도염, 호산구성 위염, 호산구성 위장염 및 호산구성 결장염을 포함하지만 이에 한정되지 않는다.The autoimmune diseases include rheumatoid arthritis, spinal arthritis, gouty arthritis, degenerative joint disease, osteoarthritis, systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, juvenile arthritis, asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, psoriasis, Eczema, burns, dermatitis, pruritus, nocturia, eosinophilic disease, peptic ulcer, localized enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis and eosinophilic colitis.

상기 염증성 질환은 여드름과 관련된 염증, 재생불량성 빈혈, 용혈성 자가면역 빈혈, 비염, 천식, 다발동맥염, 측두동맥염, 결절성 동맥주위염, 타카야스 동맥염(Takayasu's arteritis), 결정체 관절염, 골관절염, 건선성 관절염, 통풍성 관절염, 반응성 관절염, 류마티스 관절염, 근위축성 측삭 경화증, 자가 면역 질환, 알레르기 또는 알레르기 반응, 죽상동맥경화증, 기관지염, 활액낭염, 만성 전립선염, 결막염, 만성 폐쇄성 폐 질환, 피부근염, I형 당뇨병, 2형 당뇨병, 건선, 습진, 습진 과민 반응, 화상, 피부염, 소양증, 자궁내막증, 감염, 허혈성 심장 질환, 사구체신염, 치은염, 과민증, 편두통, 긴장성 두통, 수술후 장폐색, 패혈증 동안의 장폐색, 특발성 혈소판 감소성 자반증, 방광 통증 증후군, 소화성 궤양, 국한성 장염, 게실염, 위장 출혈, 호산구성 식도염, 호산구성 위염, 호산구성 위장염, 호산구성 결장염, 위염, 설사, 위식도 역류 질환, 크론 병, 궤양성 결장염, 콜라겐성 결장염, 림프구성 결장염, 허혈성 결장염, 우회 결장염, 베체트 증후군, 불확정 결장염, 염증성 장 증후군 (IBS), 루푸스, 반상경피증, 중증 근무력증 및 심근허혈을 포함하지만 이에 한정되지 않는다.The inflammatory diseases include acne-related inflammation, aplastic anemia, hemolytic autoimmune anemia, rhinitis, asthma, polyarteritis, temporal arteritis, nodular periarteritis, Takayasu's arteritis, crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty. Arthritis, reactive arthritis, rheumatoid arthritis, amyotrophic lateral sclerosis, autoimmune disease, allergic or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, chronic obstructive pulmonary disease, dermatitis, type I diabetes, type 2 Diabetes, psoriasis, eczema, eczema hypersensitivity reaction, burns, dermatitis, pruritus, endometriosis, infection, ischemic heart disease, glomerulonephritis, gingivitis, hypersensitivity, migraine, tension headache, postoperative intestinal obstruction, intestinal obstruction during sepsis, idiopathic thrombocytopenia purpura , Bladder pain syndrome, peptic ulcer, localized enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis, gastritis, diarrhea, gastroesophageal reflux disease, Crohn's disease, ulcerative colitis, collagenous Colitis, lymphocytic colitis, ischemic colitis, bypass colitis, Behcet's syndrome, indeterminate colitis, inflammatory bowel syndrome (IBS), lupus, ecchymosis, myasthenia gravis and myocardial ischemia.

상기 신경퇴행성 질환의 예는 운동 신경 질환, 픽 병(Pick's disease), 알츠하이머 병, AIDS-관련 치매, 파킨슨 병, 근위축성 측삭 경화증, 망막색소변성증, 척수성 근위축 및 소뇌 변성을 포함하지만 이에 한정되지 않는다.Examples of the neurodegenerative disease include, but are limited to, motor neuron disease, Pick's disease, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinal pigmentation, spinal muscular atrophy and cerebellar degeneration. It doesn't work.

상기 약학 조성물은 다양한 경구 투여 형태 또는 비경구 투여 형태로 제형화될 수 있다. 예를 들어, 정제, 환제, 경·연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭서제 (elixirs) 등의 임의의 경구 투여용 제형으로 될 수 있다. 이러한 경구 투여용 제형은 각 제형의 통상적인 구성에 따라 상기 유효 성분 외에, 예를 들어, 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신 등의 희석제나, 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌 글리콜 등의 활택제 등의 약제학적으로 허용 가능한 담체를 포함할 수 있다.The pharmaceutical composition may be formulated in various oral or parenteral dosage forms. For example, it may be a formulation for oral administration such as tablets, pills, hard/soft capsules, liquids, suspensions, emulsifiers, syrups, granules, elixirs, and the like. Such formulations for oral administration are, in addition to the active ingredients, depending on the usual composition of each formulation, for example, diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, silica, and talc. , Stearic acid and its magnesium or calcium salt, and/or a pharmaceutically acceptable carrier such as a lubricant such as polyethylene glycol.

또한, 상기 경구 투여용 제형이 정제인 경우, 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 트라가칸스, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘 등의 결합제를 포함할 수 있고, 경우에 따라, 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제나, 비등 혼합물 및/또는 흡수제, 착색제, 향미제 또는 감미제 등을 추가로 포함할 수 있다. In addition, when the dosage form for oral administration is a tablet, it may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and if Depending on, it may further include a disintegrant, such as starch, agar, alginic acid, or sodium salt thereof, a boiling mixture and/or an absorbent, a colorant, a flavoring agent, or a sweetening agent.

상기 약제학적 조성물은 비경구 투여 형태로 제형화될 수도 있는데, 이러한 경우 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사 등의 비경구 투여 방법에 의해 투여된다. 이 때, 상기 비경구 투여용 제형으로 제제화하기 위하여, 상기 약제학적 조성물은 유효 성분, 즉, 화학식 (1)의 화합물 또는 이의 약제학적으로 허용 가능한 염이 안정제 또는 완충제와 함께 물에서 혼합되어 용액 또는 현탁액으로 제조되고, 이러한 용액 또는 현탁액이 앰플 또는 바이알의 단위 투여형으로 제조될 수 있다.The pharmaceutical composition may be formulated in a parenteral dosage form, in which case it is administered by a parenteral administration method such as subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. At this time, in order to formulate the formulation for parenteral administration, the pharmaceutical composition includes an active ingredient, that is, a compound of formula (1) or a pharmaceutically acceptable salt thereof, mixed in water with a stabilizer or a buffering agent in water or It is prepared as a suspension, and such solutions or suspensions may be prepared in unit dosage form in ampoules or vials.

또한, 상기 약제학적 조성물은 멸균되거나, 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제를 더 포함할 수도 있고, 기타 치료적으로 유용한 물질을 더 포함할 수도 있으며, 혼합, 과립화 또는 코팅의 통상적인 방법에 따라 제제화될 수 있다.In addition, the pharmaceutical composition may be sterilized or further include adjuvants such as preservatives, stabilizers, hydrating agents or emulsification accelerators, salts and/or buffers for controlling osmotic pressure, or other therapeutically useful substances. And, it may be formulated according to a conventional method of mixing, granulating or coating.

상기 유효 성분, 즉 상기 화학식 1의 화합물, 또는 이의 광학 이성질체, 입체 이성질체 또는 약제학적으로 허용되는 염은 사람을 포함하는 포유류에 대하여, 하루에 0.1 내지 500 ㎎/㎏(체중), 바람직하게는 0.5 내지 100 ㎎/㎏(체중)의 유효량으로 상기 약제학적 조성물에 포함될 수 있고, 이러한 약제학적 조성물이 1 일 1 회 또는 2 회 이상 분할되어 경구 또는 비경구적 경로를 통해 투여될 수 있다.The active ingredient, that is, the compound of Formula 1, or an optical isomer, stereoisomer or pharmaceutically acceptable salt thereof, is 0.1 to 500 mg/kg (body weight) per day, preferably 0.5, for mammals including humans. It may be included in the pharmaceutical composition in an effective amount of to 100 mg/kg (body weight), and the pharmaceutical composition may be divided once or twice a day and administered through an oral or parenteral route.

본 발명에 따르면, 우수한 PRMT5 억제 효과를 나타내는 6-7 바이사이클릭 고리 기반의 화합물, 또는 이의 광학 이성질체, 입체 이성질체 또는 약제학적으로 허용되는 염이 제공될 수 있다. 따라서, 이러한 화합물, 또는 이의 광학 이성질체, 입체 이성질체 또는 약제학적으로 허용되는 염은 PRMT5 저해와 관련된 질병, 예를 들어 암, 혈액 질환, 자가면역질환, 염증성 질환 또는 신경퇴행성 질환의 예방 또는 치료를 위해 효과적으로 사용될 수 있다. According to the present invention, a 6-7 bicyclic ring-based compound exhibiting excellent PRMT5 inhibitory effect, or an optical isomer, stereoisomer, or pharmaceutically acceptable salt thereof may be provided. Accordingly, such compounds, or optical isomers, stereoisomers or pharmaceutically acceptable salts thereof, are used for the prevention or treatment of diseases associated with PRMT5 inhibition, such as cancer, blood diseases, autoimmune diseases, inflammatory diseases or neurodegenerative diseases. It can be used effectively.

또한, 본 발명에 따른 화합물, 또는 이의 광학 이성질체, 입체 이성질체 또는 약제학적으로 허용되는 염은 개선된 혈뇌장벽 투과능, 우월한 효능 또는 개선된 약동학적 특성을 가질 수 있다.In addition, the compounds according to the present invention, or optical isomers, stereoisomers or pharmaceutically acceptable salts thereof, may have improved blood-brain barrier permeability, superior efficacy or improved pharmacokinetic properties.

이하에서 본 발명을 실시예를 통하여 보다 상세하게 설명한다. 그러나, 실시예는 본원 발명을 예시적으로 설명하기 위한 것일 뿐 발명의 범위가 이에 의해서 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples. However, the examples are for illustrative purposes only, and the scope of the invention is not limited thereto.

실시예Example 1: 21: 2 -[(2R)-3-(3,4--[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아이소퀴놀린Isoquinoline -2-일)-2--2-yl)-2- 하이드록시Hydroxy -프로필]-7-모르폴리노-4,5-다이하이드로-3H-2-벤즈아제핀-1-온의 합성 Synthesis of -propyl]-7-morpholino-4,5-dihydro-3H-2-benzazepin-1-one

Figure pat00008
Figure pat00008

실시예Example 1- One- 1: 71: 7 -- 브로모Bromo -2-[[(2S)--2-[[(2S)- 옥시란Oxirane -2-일]-2 days] 메틸methyl ]-4,5-]-4,5- 다이하이드로Dihydro -3H-2-벤즈아제핀-1-온의 합성Synthesis of -3H-2-benzazepin-1-one

7-브로모-2,3,4,5-테트라하이드로-2-벤즈아제핀-1-온 (1.5 g, 6.25 mmol)을 디메틸포름아미드에 녹이고 얼음 중탕 하에 60% 소듐하이드라이드 (375 mg, 9.37 mmol)를 첨가하였다. 반응용액을 0oC에서 30 분 동안 교반한 뒤 (R)-(-)-글라이시딜 노실레이트 (2.11 g, 8.13 mmol)을 천천히 첨가하고, 2시간동안 실온에서 교반하였다. 반응혼합물에 메탄올을 넣어 반응을 종결하고 에틸아세테이트를 가한 다음, 포화 염화암모늄 수용액, 포화 염화나트륨 수용액으로 씻어 준 뒤, 유기층을 무수 마그네슘설페이트로 건조하였다. 용매를 감압증발로 제거하고, 추가적인 정제 없이 다음 반응에 사용하였다.7-Bromo-2,3,4,5-tetrahydro-2-benzazepin-1-one (1.5 g, 6.25 mmol) was dissolved in dimethylformamide and 60% sodium hydride (375 mg, 9.37 mmol) was added. The reaction solution was stirred at 0 o C for 30 minutes, then (R)-(-)-glycidyl nosylate (2.11 g, 8.13 mmol) was slowly added, followed by stirring at room temperature for 2 hours. Methanol was added to the reaction mixture to terminate the reaction, ethyl acetate was added, washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and used in the next reaction without further purification.

실시예Example 1- One- 2: 72: 7 -- 브로모Bromo -2-[(2R)-3-(3,4--2-[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아이소퀴놀린Isoquinoline -2-일)-2-하이드록시-프로필]-4,5-다이하이드로-3H-2-벤즈아제핀-1-온의 합성Synthesis of -2-yl)-2-hydroxy-propyl]-4,5-dihydro-3H-2-benzazepin-1-one

실시예 1-1에서 얻은 7-브로모-2-[[(2S)-옥시란-2-일]메틸]-4,5-다이하이드로-3H-2-벤즈아제핀-1-온 (453 mg, 1.54 mmol)이 녹아있는 이소프로판올 용액에 테트라하이드로아이소퀴놀린 (0.19 mL, 1.54 mmol)를 넣고 80oC에서 12 시간동안 교반하였다. 온도를 상온으로 내리고, 용매를 농축하여 얻은 기름상의 액체를 속성 크로마토그래피로 정제하여 투명한 끈적한 고체의 표제 화합물을 합성하였다.7-bromo-2-[[(2S)-oxiran-2-yl]methyl]-4,5-dihydro-3H-2-benzazepin-1-one obtained in Example 1-1 (453 mg, 1.54 mmol) was added tetrahydroisoquinoline (0.19 mL, 1.54 mmol) to the isopropanol solution and stirred at 80 o C for 12 hours. The temperature was lowered to room temperature, and the oily liquid obtained by concentrating the solvent was purified by flash chromatography to synthesize the title compound as a transparent sticky solid.

실시예Example 1- One- 3: 23: 2 -[(2R)-3-(3,4--[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아이소퀴놀린Isoquinoline -2-일)-2--2-yl)-2- 하이드록시Hydroxy -프로필]-7-모르폴리노-4,5-다이하이드로-3H-2-벤즈아제핀-1-온의 합성Synthesis of -propyl]-7-morpholino-4,5-dihydro-3H-2-benzazepin-1-one

7-브로모-2-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-4,5-다이하이드로-3H-2-벤즈아제핀-1-온 (86 mg, 0.2 mmol)과 모르폴린 (0.07 mL, 0.8 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), NaOtBu (29 mg, 0.3 mmol), BINAP (13 mg, 0.02 mmol)을 톨루엔 2 mL에 녹인 후 마이크로웨이브에서 120oC로 2시간동안 교반하였다. 반응혼합물을 에틸아세테이트로 희석하여 셀라이트에 여과하였다. 용매를 감압증발로 제거하여 얻은 기름상의 액체를 속성 크로마토그래피로 정제하여 끈적한 고체인 표제화합물을 합성하였다.7-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro-3H-2 -Benzazepin-1-one (86 mg, 0.2 mmol) and morpholine (0.07 mL, 0.8 mmol), Pd 2 (dba) 3 (9 mg, 0.01 mmol), NaO t Bu (29 mg, 0.3 mmol) , BINAP (13 mg, 0.02 mmol) was dissolved in 2 mL of toluene and stirred in a microwave at 120 o C for 2 hours. The reaction mixture was diluted with ethyl acetate and filtered through Celite. The oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to synthesize the title compound as a sticky solid.

1H NMR (400 MHz, methanol-d 4) δ 7.49 (d, J = 8.5 Hz, 1H), 7.14 - 7.02 (m, 4H), 6.91 (dd, J = 8.5, 2.2 Hz, 1H), 6.80 (d, J = 1.8 Hz, 1H), 4.28 - 4.18 (m, 1H), 3.91 (dd, J = 13.8, 3.8 Hz, 1H), 3.84 (t, J = 4.8 Hz, 4H), 3.77 (s, 2H), 3.45 - 3.32 (m, 3H), 3.25 (t, J = 4.8 Hz, 4H), 2.99 - 2.86 (m, 4H), 2.78 (t, J = 7.1 Hz, 2H), 2.71 - 2.59 (m, 2H), 2.13 (p, J = 6.8 Hz, 2H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.49 (d, J = 8.5 Hz, 1H), 7.14-7.02 (m, 4H), 6.91 (dd, J = 8.5, 2.2 Hz, 1H), 6.80 ( d, J = 1.8 Hz, 1H), 4.28-4.18 (m, 1H), 3.91 (dd, J = 13.8, 3.8 Hz, 1H), 3.84 (t, J = 4.8 Hz, 4H), 3.77 (s, 2H ), 3.45-3.32 (m, 3H), 3.25 (t, J = 4.8 Hz, 4H), 2.99-2.86 (m, 4H), 2.78 (t, J = 7.1 Hz, 2H), 2.71-2.59 (m, 2H), 2.13 (p, J = 6.8 Hz, 2H).

실시예Example 2: 72: 7 -(-( 사이클로헥실아미노Cyclohexylamino )-2-[(2R)-3-(3,4-)-2-[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아이소퀴놀린Isoquinoline -2-일)-2-하이드록시-프로필]-4,5-다이하이드로-3H-2-벤즈아제핀-1-온의 합성 Synthesis of -2-yl)-2-hydroxy-propyl]-4,5-dihydro-3H-2-benzazepin-1-one

Figure pat00009
Figure pat00009

실시예 1-3에서 모르폴린을 사이클로헥실아민으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다.After changing morpholine to cyclohexylamine in Example 1-3, the title compound was synthesized by the same method.

1H NMR (400 MHz, cloroform-d) δ 7.51 (d, J = 8.4 Hz, 1H), 7.13 (q, J = 5.4, 4.8 Hz, 3H), 7.02 (d, J = 6.1 Hz, 1H), 6.52 - 6.44 (m, 1H), 6.29 (s, 1H), 4.08 (d, J = 7.0 Hz, 1H), 3.89 - 3.74 (m, 2H), 3.65 (d, J = 14.9 Hz, 1H), 3.57 - 3.22 (m, 4H), 2.90 (s, 3H), 2.78 (dt, J = 12.5, 6.6 Hz, 1H), 2.67 (dt, J = 18.0, 6.1 Hz, 2H), 2.56 (dd, J = 12.5, 8.8 Hz, 1H), 2.05 (q, J = 6.2, 5.7 Hz, 3H), 1.76 (dd, J = 10.8, 6.8 Hz, 2H), 1.71 - 1.51 (m, 4H), 1.38 (q, J = 12.5 Hz, 2H), 1.29 - 1.10 (m, 3H). 1 H NMR (400 MHz, cloroform- d ) δ 7.51 (d, J = 8.4 Hz, 1H), 7.13 (q, J = 5.4, 4.8 Hz, 3H), 7.02 (d, J = 6.1 Hz, 1H), 6.52-6.44 (m, 1H), 6.29 (s, 1H), 4.08 (d, J = 7.0 Hz, 1H), 3.89-3.74 (m, 2H), 3.65 (d, J = 14.9 Hz, 1H), 3.57 -3.22 (m, 4H), 2.90 (s, 3H), 2.78 (dt, J = 12.5, 6.6 Hz, 1H), 2.67 (dt, J = 18.0, 6.1 Hz, 2H), 2.56 (dd, J = 12.5 , 8.8 Hz, 1H), 2.05 (q, J = 6.2, 5.7 Hz, 3H), 1.76 (dd, J = 10.8, 6.8 Hz, 2H), 1.71-1.51 (m, 4H), 1.38 (q, J = 12.5 Hz, 2H), 1.29-1.10 (m, 3H).

실시예Example 3: 43: 4 -[(2R)-3-(3,4--[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아이소퀴놀린Isoquinoline -2-일)-2--2-yl)-2- 하이드록시Hydroxy -프로필]-8-모르폴리노-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성 Synthesis of -propyl]-8-morpholino-2,3-dihydro-1,4-benzoxazepin-5-one

Figure pat00010
Figure pat00010

실시예Example 3- 3- 1: 81: 8 -- 브로모Bromo -4-[(2R)-3-(3,4--4-[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아이소퀴놀린Isoquinoline -2-일)-2-하이드록시-프로필]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성Synthesis of -2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

출발물질로 8-브로모-3,4-다이하이드로-2H-1,4-벤즈옥사제핀-5-온을 사용하고 실시예 1-1, 1-2와 동일한 방법에 의해 표제화합물을 합성하였다.The title compound was synthesized in the same manner as in Examples 1-1 and 1-2 using 8-bromo-3,4-dihydro-2H-1,4-benzoxazepin-5-one as a starting material. .

실시예Example 3- 3- 2:2: 44 -[(2R)-3-(3,4--[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아이소퀴놀린Isoquinoline -2-일)-2--2-yl)-2- 하이드록시Hydroxy -프로필]-8-모르폴리노-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성Synthesis of -propyl]-8-morpholino-2,3-dihydro-1,4-benzoxazepin-5-one

8-브로모-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온 (86 mg, 0.2 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), BINAP (13 mg, 0.02 mmol), NaOtBu (29 mg, 0.3 mmol)을 2 mL의 톨루엔에 녹이고 반응용기를 질소로 치환하였다. 반응 용액을 마이크로웨이브를 사용하여 120oC에서 2 시간동안 교반하였다. 반응 혼합물을 에틸아세테이트로 희석하고 셀라이트를 통하여 필터하고 감압하여 농축하였다. 얻어진 반응 농축액을 속성 컬럼크로그래피로 정제하여 표제화합물 60 mg을 합성하였다.8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4 -Benzoxazepin-5-one (86 mg, 0.2 mmol), Pd 2 (dba) 3 (9 mg, 0.01 mmol), BINAP (13 mg, 0.02 mmol), NaO t Bu (29 mg, 0.3 mmol) It was dissolved in 2 mL of toluene and the reaction vessel was replaced with nitrogen. The reaction solution was stirred at 120 o C for 2 hours using a microwave. The reaction mixture was diluted with ethyl acetate, filtered through celite, and concentrated under reduced pressure. The obtained reaction concentrate was purified by rapid column chromatography to synthesize 60 mg of the title compound.

1H NMR (400 MHz, methanol-d 4) δ 7.64 (d, J = 8.8 Hz, 1H), 7.17 - 7.00 (m, 4H), 6.74 (d, J = 9.0 Hz, 1H), 6.51 (d, J = 1.8 Hz, 1H), 4.43 (t, J = 5.0 Hz, 2H), 4.27 - 4.16 (m, 1H), 3.96 (dd, J = 13.9, 3.6 Hz, 1H), 3.81 (t, J = 4.9 Hz, 4H), 3.74 (s, 2H), 3.70 (t, J = 5.1 Hz, 2H), 3.39 (dd, J = 13.9, 7.7 Hz, 1H), 3.22 (t, J = 4.9 Hz, 4H), 2.99 - 2.81 (m, 4H), 2.63 (d, J = 6.6 Hz, 2H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.64 (d, J = 8.8 Hz, 1H), 7.17-7.00 (m, 4H), 6.74 (d, J = 9.0 Hz, 1H), 6.51 (d, J = 1.8 Hz, 1H), 4.43 (t, J = 5.0 Hz, 2H), 4.27-4.16 (m, 1H), 3.96 (dd, J = 13.9, 3.6 Hz, 1H), 3.81 (t, J = 4.9 Hz, 4H), 3.74 (s, 2H), 3.70 (t, J = 5.1 Hz, 2H), 3.39 (dd, J = 13.9, 7.7 Hz, 1H), 3.22 (t, J = 4.9 Hz, 4H), 2.99-2.81 (m, 4H), 2.63 (d, J = 6.6 Hz, 2H).

실시예Example 4: 84: 8 -(-( 아제티딘Azetidine -1-일)-4-[(2R)-3-(3,4--1-yl)-4-[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아이소퀴놀린Isoquinoline -2-일)-2-하이드록시-프로필]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성 Synthesis of -2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

Figure pat00011
Figure pat00011

실시예 3-2에서 모르폴린을 아제티딘으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다.After changing morpholine to azetidine in Example 3-2, the title compound was synthesized by the same method.

1H NMR (400 MHz, methanol-d 4) δ 7.52 (d, J = 8.6 Hz, 1H), 7.13 - 6.97 (m, 4H), 6.18 (d, J = 8.6 Hz, 1H), 5.95 (d, J = 1.9 Hz, 1H), 4.37 (t, J = 5.1 Hz, 2H), 4.22 - 4.13 (m, 1H), 3.95 - 3.83 (m, 5H), 3.71 (s, 2H), 3.65 (t, J = 5.1 Hz, 2H), 3.36 (dd, J = 13.9, 7.5 Hz, 1H), 2.94 - 2.85 (m, 2H), 2.86 - 2.78 (m, 2H), 2.63 - 2.54 (m, 2H), 2.36 (p, J = 7.3 Hz, 2H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.52 (d, J = 8.6 Hz, 1H), 7.13-6.97 (m, 4H), 6.18 (d, J = 8.6 Hz, 1H), 5.95 (d, J = 1.9 Hz, 1H), 4.37 (t, J = 5.1 Hz, 2H), 4.22-4.13 (m, 1H), 3.95-3.83 (m, 5H), 3.71 (s, 2H), 3.65 (t, J = 5.1 Hz, 2H), 3.36 (dd, J = 13.9, 7.5 Hz, 1H), 2.94-2.85 (m, 2H), 2.86-2.78 (m, 2H), 2.63-2.54 (m, 2H), 2.36 ( p, J = 7.3 Hz, 2H).

실시예Example 5: 45: 4 -[(2R)-3-(3,4--[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아이소퀴놀린Isoquinoline -2-일)-2--2-yl)-2- 하이드록시Hydroxy -프로필]-8-(3-메톡시아제티딘-1-일)-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성 Synthesis of -propyl]-8-(3-methoxyazetidin-1-yl)-2,3-dihydro-1,4-benzoxazepin-5-one

Figure pat00012
Figure pat00012

실시예 3-2에서 모르폴린을 3-메톡시아제티딘으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다.After changing morpholine to 3-methoxyazetidine in Example 3-2, the title compound was synthesized by the same method.

1H NMR (400 MHz, methanol-d 4) δ 7.57 (d, J = 8.6 Hz, 1H), 7.17 - 7.02 (m, 4H), 6.27 (dd, J = 8.5, 2.2 Hz, 1H), 6.04 (d, J = 2.3 Hz, 1H), 4.43 (t, J = 5.0 Hz, 2H), 4.40 - 4.33 (m, 1H), 4.27 - 4.18 (m, 2H), 4.18 - 4.10 (m, 2H), 3.95 (dd, J = 14.0, 3.7 Hz, 1H), 3.84 - 3.67 (m, 6H), 3.42 (dd, J = 13.8, 7.5 Hz, 1H), 3.35 (s, 3H), 2.99 - 2.83 (m, 4H), 2.71 - 2.59 (m, 2H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.57 (d, J = 8.6 Hz, 1H), 7.17-7.02 (m, 4H), 6.27 (dd, J = 8.5, 2.2 Hz, 1H), 6.04 ( d, J = 2.3 Hz, 1H), 4.43 (t, J = 5.0 Hz, 2H), 4.40-4.33 (m, 1H), 4.27-4.18 (m, 2H), 4.18-4.10 (m, 2H), 3.95 (dd, J = 14.0, 3.7 Hz, 1H), 3.84-3.67 (m, 6H), 3.42 (dd, J = 13.8, 7.5 Hz, 1H), 3.35 (s, 3H), 2.99-2.83 (m, 4H) ), 2.71-2.59 (m, 2H).

실시예Example 6: 8-(4-아세틸피페라진-1-일)-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성 6: 8-(4-acetylpiperazin-1-yl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl] Synthesis of -2,3-dihydro-1,4-benzoxazepin-5-one

Figure pat00013
Figure pat00013

실시예 3-2에서 모르폴린을 1-피페라진-1-일에탄온으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다.In Example 3-2, after changing morpholine to 1-piperazin-1-ylethanone, the title compound was synthesized by the same method.

1H NMR (400 MHz, methanol-d 4) δ 7.64 (d, J = 8.9 Hz, 1H), 7.17 - 7.02 (m, 4H), 6.79 (d, J = 8.9 Hz, 1H), 6.55 (d, J = 2.2 Hz, 1H), 4.46 (t, J = 5.0 Hz, 2H), 4.28 - 4.18 (m, 1H), 3.97 (dd, J = 14.0, 3.6 Hz, 1H), 3.80 - 3.65 (m, 7H), 3.45 - 3.35 (m, 3H), 2.91 (dd, J = 19.7, 5.6 Hz, 4H), 2.69 - 2.60 (m, 2H), 2.17 (s, 3H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.64 (d, J = 8.9 Hz, 1H), 7.17-7.02 (m, 4H), 6.79 (d, J = 8.9 Hz, 1H), 6.55 (d, J = 2.2 Hz, 1H), 4.46 (t, J = 5.0 Hz, 2H), 4.28-4.18 (m, 1H), 3.97 (dd, J = 14.0, 3.6 Hz, 1H), 3.80-3.65 (m, 7H ), 3.45-3.35 (m, 3H), 2.91 (dd, J = 19.7, 5.6 Hz, 4H), 2.69-2.60 (m, 2H), 2.17 (s, 3H).

실시예Example 7: 4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-8-(4-메틸-3-옥소-피페라진-1-일)-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성 7: 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-methyl-3-oxo-piperazine Synthesis of -1-yl)-2,3-dihydro-1,4-benzoxazepin-5-one

Figure pat00014
Figure pat00014

실시예 3-2에서 모르폴린을 1-메틸피페라진-2-온으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다.After changing morpholine to 1-methylpiperazin-2-one in Example 3-2, the title compound was synthesized by the same method.

1H NMR (400 MHz, methanol-d 4) δ 7.66 (d, J = 8.8 Hz, 1H), 7.17 - 7.01 (m, 4H), 6.75 (d, J = 8.9 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 4.46 (t, J = 5.0 Hz, 2H), 4.27 - 4.17 (m, 1H), 4.01 - 3.90 (m, 3H), 3.79 - 3.68 (m, 4H), 3.63 (t, J = 5.3 Hz, 2H), 3.54 (t, J = 5.3 Hz, 2H), 3.41 (dd, J = 13.7, 7.4 Hz, 1H), 3.08 - 2.97 (m, 4H), 2.96 - 2.86 (m, 4H), 2.70 - 2.57 (m, 2H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.66 (d, J = 8.8 Hz, 1H), 7.17-7.01 (m, 4H), 6.75 (d, J = 8.9 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 4.46 (t, J = 5.0 Hz, 2H), 4.27-4.17 (m, 1H), 4.01-3.90 (m, 3H), 3.79-3.68 (m, 4H), 3.63 (t , J = 5.3 Hz, 2H), 3.54 (t, J = 5.3 Hz, 2H), 3.41 (dd, J = 13.7, 7.4 Hz, 1H), 3.08-2.97 (m, 4H), 2.96-2.86 (m, 4H), 2.70-2.57 (m, 2H).

실시예Example 8: 4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-8-[4-(옥세탄-3-일)피페라진-1-일]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성 8: 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[4-(oxetan-3-yl) Piperazin-1-yl]-2,3-dihydro-1,4-benzoxazepin-5-one synthesis

Figure pat00015
Figure pat00015

실시예 3-2에서 모르폴린을 1-(옥세탄-3-일)피페라진으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다.After changing morpholine to 1-(oxetan-3-yl)piperazine in Example 3-2, the title compound was synthesized by the same method.

1H NMR (400 MHz, methanol-d 4) δ 7.63 (d, J = 8.8 Hz, 1H), 7.24 - 7.00 (m, 4H), 6.77 (d, J = 9.0 Hz, 1H), 6.53 (s, 1H), 4.74 (t, J = 6.6 Hz, 2H), 4.65 (t, J = 6.2 Hz, 2H), 4.45 (t, J = 5.2 Hz, 2H), 4.24 (s, 1H), 3.96 (d, J = 14.9 Hz, 1H), 3.81 (s, 2H), 3.73 (t, J = 5.1 Hz, 2H), 3.64 - 3.49 (m, 1H), 3.43 (dd, J = 14.0, 7.5 Hz, 1H), 2.94 (d, J = 7.3 Hz, 4H), 2.69 (d, J = 7.2 Hz, 2H), 2.51 (t, J = 5.0 Hz, 4H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.63 (d, J = 8.8 Hz, 1H), 7.24-7.00 (m, 4H), 6.77 (d, J = 9.0 Hz, 1H), 6.53 (s, 1H), 4.74 (t, J = 6.6 Hz, 2H), 4.65 (t, J = 6.2 Hz, 2H), 4.45 (t, J = 5.2 Hz, 2H), 4.24 (s, 1H), 3.96 (d, J = 14.9 Hz, 1H), 3.81 (s, 2H), 3.73 (t, J = 5.1 Hz, 2H), 3.64-3.49 (m, 1H), 3.43 (dd, J = 14.0, 7.5 Hz, 1H), 2.94 (d, J = 7.3 Hz, 4H), 2.69 (d, J = 7.2 Hz, 2H), 2.51 (t, J = 5.0 Hz, 4H).

실시예Example 9: 4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-8-[4-(다이메틸아미노)-1-피페리딜]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성 9: 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[4-(dimethylamino)-1- Piperidyl]-2,3-dihydro-1,4-benzoxazepin-5-one synthesis

Figure pat00016
Figure pat00016

실시예 3-2에서 모르폴린을 N,N-다이메틸피페리딘-4-아민으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다.In Example 3-2, after changing morpholine to N,N-dimethylpiperidin-4-amine, the title compound was synthesized by the same method.

1H NMR (400 MHz, methanol-d 4) δ 7.61 (d, J = 8.9 Hz, 1H), 7.11 (d, J = 4.0 Hz, 3H), 7.06 (s, 1H), 6.76 (d, J = 9.0 Hz, 1H), 6.52 (s, 1H), 4.44 (t, J = 5.1 Hz, 2H), 4.22 (s, 1H), 3.96 (d, J = 14.4 Hz, 3H), 3.84 - 3.70 (m, 4H), 3.41 (dd, J = 14.0, 7.7 Hz, 1H), 2.93 (d, J = 5.8 Hz, 2H), 2.90 - 2.84 (m, 3H), 2.80 (d, J = 12.5 Hz, 1H), 2.64 (d, J = 6.3 Hz, 2H), 2.50 - 2.37 (m, 1H), 2.34 (s, 5H), 2.04 - 1.93 (m, 2H), 1.57 (dd, J = 13.9, 10.2 Hz, 2H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.61 (d, J = 8.9 Hz, 1H), 7.11 (d, J = 4.0 Hz, 3H), 7.06 (s, 1H), 6.76 (d, J = 9.0 Hz, 1H), 6.52 (s, 1H), 4.44 (t, J = 5.1 Hz, 2H), 4.22 (s, 1H), 3.96 (d, J = 14.4 Hz, 3H), 3.84-3.70 (m, 4H), 3.41 (dd, J = 14.0, 7.7 Hz, 1H), 2.93 (d, J = 5.8 Hz, 2H), 2.90-2.84 (m, 3H), 2.80 (d, J = 12.5 Hz, 1H), 2.64 (d, J = 6.3 Hz, 2H), 2.50-2.37 (m, 1H), 2.34 (s, 5H), 2.04-1.93 (m, 2H), 1.57 (dd, J = 13.9, 10.2 Hz, 2H) .

실시예Example 10: 8-(사이클로프로필아미노)-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성 10: 8-(cyclopropylamino)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-di Synthesis of hydro-1,4-benzoxazepin-5-one

Figure pat00017
Figure pat00017

실시예 3-2에서 모르폴린을 사이클로프로판아민으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다.After changing morpholine to cyclopropanamine in Example 3-2, the title compound was synthesized by the same method.

1H NMR (400 MHz, methanol-d 4) δ 7.50 (d, J = 8.6 Hz, 1H), 7.17 - 7.03 (m, 4H), 6.53 (dd, J = 8.7, 2.2 Hz, 1H), 6.38 (d, J = 2.1 Hz, 1H), 4.42 (t, J = 5.0 Hz, 2H), 4.23 (d, J = 8.1 Hz, 1H), 3.95 (dd, J = 13.9, 3.7 Hz, 1H), 3.82 - 3.66 (m, 4H), 3.46 - 3.37 (m, 1H), 2.94-2.88 (m, 4H), 2.72 - 2.57 (m, 2H), 2.45 - 2.36 (m, 1H), 0.76 (q, J = 5.9 Hz, 2H), 0.48 (q, J = 3.7, 3.1 Hz, 2H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.50 (d, J = 8.6 Hz, 1H), 7.17-7.03 (m, 4H), 6.53 (dd, J = 8.7, 2.2 Hz, 1H), 6.38 ( d, J = 2.1 Hz, 1H), 4.42 (t, J = 5.0 Hz, 2H), 4.23 (d, J = 8.1 Hz, 1H), 3.95 (dd, J = 13.9, 3.7 Hz, 1H), 3.82- 3.66 (m, 4H), 3.46-3.37 (m, 1H), 2.94-2.88 (m, 4H), 2.72-2.57 (m, 2H), 2.45-2.36 (m, 1H), 0.76 (q, J = 5.9 Hz, 2H), 0.48 (q, J = 3.7, 3.1 Hz, 2H).

실시예Example 11: 811: 8 -(-( 사이클로헥실아미노Cyclohexylamino )-4-[(2R)-3-(3,4-)-4-[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아이소퀴놀린Isoquinoline -2-일)-2-하이드록시-프로필]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성 Synthesis of -2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

Figure pat00018
Figure pat00018

실시예 3-2에서 모르폴린을 사이클로헥산아민으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다.After changing morpholine to cyclohexanamine in Example 3-2, the title compound was synthesized by the same method.

1H NMR (400 MHz, methanol-d 4) δ 7.48 (d, J = 9.3 Hz, 1H), 7.15 - 7.03 (m, 4H), 6.39 (d, J = 8.6 Hz, 1H), 6.16 (d, J = 2.0 Hz, 1H), 4.41 (t, J = 4.9 Hz, 2H), 4.21 (s, 1H), 3.95 (dd, J = 13.9, 3.5 Hz, 1H), 3.76 (s, 2H), 3.71 (t, J = 5.1 Hz, 2H), 3.40 (dd, J = 14.0, 7.4 Hz, 1H), 3.33-3.32 (m, 1H), 2.94-2.87 (m, 4H), 2.64 (d, J = 5.4 Hz, 2H), 2.02 (d, J = 12.4 Hz, 2H), 1.80 (d, J = 13.4 Hz, 2H), 1.69 (d, J = 13.1 Hz, 1H), 1.43 (q, J = 12.7 Hz, 2H), 1.33 - 1.15 (m, 3H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.48 (d, J = 9.3 Hz, 1H), 7.15-7.03 (m, 4H), 6.39 (d, J = 8.6 Hz, 1H), 6.16 (d, J = 2.0 Hz, 1H), 4.41 (t, J = 4.9 Hz, 2H), 4.21 (s, 1H), 3.95 (dd, J = 13.9, 3.5 Hz, 1H), 3.76 (s, 2H), 3.71 ( t, J = 5.1 Hz, 2H), 3.40 (dd, J = 14.0, 7.4 Hz, 1H), 3.33-3.32 (m, 1H), 2.94-2.87 (m, 4H), 2.64 (d, J = 5.4 Hz , 2H), 2.02 (d, J = 12.4 Hz, 2H), 1.80 (d, J = 13.4 Hz, 2H), 1.69 (d, J = 13.1 Hz, 1H), 1.43 (q, J = 12.7 Hz, 2H ), 1.33-1.15 (m, 3H).

실시예Example 12: 8-[사이클로헥실(메틸)아미노]-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성 12: 8-[cyclohexyl(methyl)amino]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2, Synthesis of 3-dihydro-1,4-benzoxazepin-5-one

Figure pat00019
Figure pat00019

실시예 3-2에서 모르폴린을 N-메틸사이클로헥산아민으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다.After changing morpholine to N-methylcyclohexanamine in Example 3-2, the title compound was synthesized by the same method.

1H NMR (400 MHz, methanol-d 4) δ 7.59 (d, J = 9.0 Hz, 1H), 7.18 - 7.02 (m, 4H), 6.64 - 6.56 (m, 1H), 6.32 (d, J = 2.5 Hz, 1H), 4.62 (s, 1H), 4.43 (t, J = 5.1 Hz, 2H), 4.30 - 4.18 (m, 1H), 3.95 (dd, J = 14.0, 3.7 Hz, 1H), 3.79 (s, 2H), 3.77 - 3.64 (m, 3H), 3.42 (dd, J = 13.9, 7.5 Hz, 1H), 3.00 - 2.88 (m, 4H), 2.84 (s, 3H), 2.74 - 2.60 (m, 2H), 2.03 (s, 1H), 1.88 (d, J = 12.8 Hz, 2H), 1.74 (t, J = 13.4 Hz, 3H), 1.66 - 1.39 (m, 1H), 1.38 - 1.15 (m, 3H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.59 (d, J = 9.0 Hz, 1H), 7.18-7.02 (m, 4H), 6.64-6.56 (m, 1H), 6.32 (d, J = 2.5 Hz, 1H), 4.62 (s, 1H), 4.43 (t, J = 5.1 Hz, 2H), 4.30-4.18 (m, 1H), 3.95 (dd, J = 14.0, 3.7 Hz, 1H), 3.79 (s , 2H), 3.77-3.64 (m, 3H), 3.42 (dd, J = 13.9, 7.5 Hz, 1H), 3.00-2.88 (m, 4H), 2.84 (s, 3H), 2.74-2.60 (m, 2H), 2.03 (s, 1H), 1.88 (d, J = 12.8 Hz, 2H), 1.74 (t, J = 13.4 Hz, 3H), 1.66-1.39 (m, 1H), 1.38 -1.15 (m, 3H).

실시예Example 13: 4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-8-[메틸(테트라하이드로피란-4-일)아미노]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성 13: 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[methyl(tetrahydropyran-4-yl) Synthesis of amino]-2,3-dihydro-1,4-benzoxazepin-5-one

Figure pat00020
Figure pat00020

실시예 3-2에서 모르폴린을 N-메틸테트라하이드로피란-4-아민으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다.In Example 3-2, after changing morpholine to N-methyltetrahydropyran-4-amine, the title compound was synthesized by the same method.

1H NMR (400 MHz, methanol-d 4) δ 7.61 (d, J = 8.9 Hz, 1H), 7.18 - 7.02 (m, 4H), 6.67 (dd, J = 9.0, 2.6 Hz, 1H), 6.40 (s, 1H), 4.44 (t, J = 5.0 Hz, 2H), 4.28 - 4.18 (m, 1H), 4.10 - 3.91 (m, 4H), 3.78 (s, 2H), 3.72 (t, J = 5.0 Hz, 2H), 3.57 (t, J = 11.7 Hz, 2H), 3.41 (dd, J = 13.9, 7.5 Hz, 1H), 2.99 - 2.86 (m, 4H), 2.86 (s, 3H), 2.71 - 2.60 (m, 2H), 1.90 (qd, J = 12.3, 4.9 Hz, 2H), 1.71 - 1.61 (m, 2H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.61 (d, J = 8.9 Hz, 1H), 7.18-7.02 (m, 4H), 6.67 (dd, J = 9.0, 2.6 Hz, 1H), 6.40 ( s, 1H), 4.44 (t, J = 5.0 Hz, 2H), 4.28-4.18 (m, 1H), 4.10-3.91 (m, 4H), 3.78 (s, 2H), 3.72 (t, J = 5.0 Hz , 2H), 3.57 (t, J = 11.7 Hz, 2H), 3.41 (dd, J = 13.9, 7.5 Hz, 1H), 2.99-2.86 (m, 4H), 2.86 (s, 3H), 2.71-2.60 ( m, 2H), 1.90 (qd, J = 12.3, 4.9 Hz, 2H), 1.71-1.61 (m, 2H).

실시예Example 14: 8-[(1-아세틸-4-피페리딜)아미노]-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성 14: 8-[(1-acetyl-4-piperidyl)amino]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy Synthesis of -propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

Figure pat00021
Figure pat00021

실시예 3-2에서 모르폴린을 1-(4-아미노-1-피페리딜)에탄온으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다.After changing morpholine to 1-(4-amino-1-piperidyl)ethanone in Example 3-2, the title compound was synthesized by the same method.

1H NMR (400 MHz, methanol-d 4) δ 7.51 (d, J = 8.7 Hz, 1H), 7.17 - 7.02 (m, 4H), 6.45 (d, J = 8.7 Hz, 1H), 6.24 (s, 1H), 4.48 - 4.33 (m, 3H), 4.27 - 4.17 (m, 1H), 3.94 (t, J = 12.6 Hz, 2H), 3.81 - 3.68 (m, 4H), 3.68 - 3.54 (m, 1H), 3.41 (dd, J = 14.0, 7.5 Hz, 1H), 3.01 - 2.82 (m, 5H), 2.69 - 2.58 (m, 2H), 2.13 (s, 3H), 2.13 - 1.98 (m, 2H), 1.50 - 1.28 (m, 3H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.51 (d, J = 8.7 Hz, 1H), 7.17-7.02 (m, 4H), 6.45 (d, J = 8.7 Hz, 1H), 6.24 (s, 1H), 4.48-4.33 (m, 3H), 4.27-4.17 (m, 1H), 3.94 (t, J = 12.6 Hz, 2H), 3.81-3.68 (m, 4H), 3.68-3.54 (m, 1H) , 3.41 (dd, J = 14.0, 7.5 Hz, 1H), 3.01-2.82 (m, 5H), 2.69-2.58 (m, 2H), 2.13 (s, 3H), 2.13-1.98 (m, 2H), 1.50 -1.28 (m, 3H).

실시예Example 15: 4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-8-[(3-플루오로-4-피리딜)메틸아미노]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성 15: 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-4-pyridyl )Methylamino]-2,3-dihydro-1,4-benzoxazepin-5-one synthesis

Figure pat00022
Figure pat00022

실시예 3-2에서 모르폴린을 (3-플루오로-4-피리딜)메탄아민으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다.After changing morpholine to (3-fluoro-4-pyridyl) methanamine in Example 3-2, the title compound was synthesized by the same method.

1H NMR (400 MHz, methanol-d 4) δ 8.43 (s, 1H), 8.32 (d, J = 5.0 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.44 (t, J = 5.4 Hz, 1H), 7.19 - 6.99 (m, 4H), 6.44 (d, J = 8.9 Hz, 1H), 6.15 (s, 1H), 4.53 (s, 2H), 4.39 (t, J = 4.7 Hz, 2H), 4.27 - 4.14 (m, 1H), 3.94 (dd, J = 13.5, 3.3 Hz, 1H), 3.75 (s, 2H), 3.70 (t, J = 4.6 Hz, 2H), 3.39 (dd, J = 13.9, 7.4 Hz, 1H), 2.98 - 2.82 (m, 4H), 2.67 - 2.58 (m, 2H). 1 H NMR (400 MHz, methanol- d 4 ) δ 8.43 (s, 1H), 8.32 (d, J = 5.0 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.44 (t, J = 5.4 Hz, 1H), 7.19-6.99 (m, 4H), 6.44 (d, J = 8.9 Hz, 1H), 6.15 (s, 1H), 4.53 (s, 2H), 4.39 (t, J = 4.7 Hz, 2H), 4.27-4.14 (m, 1H), 3.94 (dd, J = 13.5, 3.3 Hz, 1H), 3.75 (s, 2H), 3.70 (t, J = 4.6 Hz, 2H), 3.39 (dd, J = 13.9, 7.4 Hz, 1H), 2.98-2.82 (m, 4H), 2.67-2.58 (m, 2H).

실시예Example 16: 416: 4 -[(2R)-3-(3,4--[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아이소퀴놀린Isoquinoline -2-일)-2--2-yl)-2- 하이드록시Hydroxy -프로필]-2,2-다이메틸-8-모르폴리노-3H-1,4-벤즈옥사제핀-5-온의 합성 Synthesis of -propyl]-2,2-dimethyl-8-morpholino-3H-1,4-benzoxazepin-5-one

Figure pat00023
Figure pat00023

실시예Example 16- 16- 1: 71: 7 -- 브로모Bromo -2,2--2,2- 다이메틸Dimethyl -- 크로만Chroman -4-온의 합성Synthesis of -4-one

1-(4-브로모-2-하이드록시-페닐)에탄온 (5.0 g, 23.2 mmol)을 20 mL의 메탄올에 녹이고 얼음중탕 하에 피롤리딘 (5 mL, 60.9 mmol)을 넣고 30분간 교반하였다. 반응용액에 아세톤 (2.5 mL, 33.7 mmol)을 넣고 4 시간동안 가열환류하고 물을 넣고 반응을 종결하여 에틸아세테이트로 3번 추출하였다. 합친 유기층을 무수마그네슘설페이트로 건조하고 농축하여 다시 에틸아세테이트에 녹이고 소량의 실리카를 통하여 여과하였다. 용액을 감압하고 농축하여 추가적인 정제과정 없이 결정형 고체의 표제 화합물 4.7 g을 합성하였다.1-(4-bromo-2-hydroxy-phenyl)ethanone (5.0 g, 23.2 mmol) was dissolved in 20 mL of methanol, and pyrrolidine (5 mL, 60.9 mmol) was added in an ice bath, followed by stirring for 30 minutes. . Acetone (2.5 mL, 33.7 mmol) was added to the reaction solution, heated to reflux for 4 hours, water was added, and the reaction was terminated, followed by extraction with ethyl acetate three times. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated, dissolved in ethyl acetate, and filtered through a small amount of silica. The solution was reduced pressure and concentrated to synthesize 4.7 g of the title compound as a crystalline solid without further purification.

실시예Example 16- 16- 2: 82: 8 -- 브로모Bromo -2,2--2,2- 다이메틸Dimethyl -3,4--3,4- 다이하이드로Dihydro -1,4--1,4- 벤즈옥사제핀Benzoxazepine -5-온의 합성Synthesis of -5-one

실시예 16-1로부터 얻은 7-브로모-2,2-다이메틸-크로만-4-온(4.7 g, 18.6 mmol)을 25 mL의 메탄설폰 산에 녹이고 얼음 중탕 하에 소듐아자이드 (1.81 g, 27.9 mmol)을 천천히 첨가하였다. 반응용액을 실온에서 5시간동안 교반 하고 얼음 중탕 하에서 0 oC로 유지하면서 1 몰 농도의 수산화소듐 수용액을 천천히 가하였다. 반응용액의 pH가 10 이상 될 때까지 염기화한 뒤 에틸 아세테이트를 넣고 3번 추출하였다. 합친 유기 층을 무수 마그네슘설페이트로 건조하고 용매를 감압 증발로 제거한 후 디클로로메탄과 핵산으로 재결정하여 고체인 표제 화합물을 합성하였다.7-bromo-2,2-dimethyl-chroman-4-one (4.7 g, 18.6 mmol) obtained from Example 16-1 was dissolved in 25 mL of methanesulfonic acid, and sodium azide (1.81 g) in an ice bath , 27.9 mmol) was added slowly. The reaction solution was stirred at room temperature for 5 hours, and an aqueous sodium hydroxide solution of 1 molar concentration was slowly added while maintaining the temperature at 0 o C in an ice bath. After basifying the reaction solution until the pH was 10 or higher, ethyl acetate was added and extracted three times. The combined organic layer was dried over anhydrous magnesium sulfate, the solvent was removed by evaporation under reduced pressure, and then recrystallized from dichloromethane and nucleic acid to synthesize the solid title compound.

실시예Example 16- 16- 3: 83: 8 -- 브로모Bromo -4-[(2R)-3-(3,4--4-[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아이소퀴놀린Isoquinoline -2-일)-2-하이드록시-프로필]-2,2-다이메틸-3H-1,4-벤즈옥사제핀-5-온의 합성Synthesis of -2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one

실시예 16-2로부터 얻은 8-브로모-2,2-다이메틸-3,4-다이하이드로-1,4-벤즈옥사제핀-5-온을 출발물질로 사용하고 실시예 1-1, 1-2와 동일한 방법에 의해 표제화합물을 합성하였다.Using 8-bromo-2,2-dimethyl-3,4-dihydro-1,4-benzoxazepin-5-one obtained from Example 16-2 as a starting material, Examples 1-1, 1 The title compound was synthesized by the same method as -2.

실시예Example 16- 16- 4: 44: 4 -[(2R)-3-(3,4--[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아이소퀴놀린Isoquinoline -2-일)-2--2-yl)-2- 하이드록시Hydroxy -프로필]-2,2-다이메틸-8-모르폴리노-3H-1,4-벤즈옥사제핀-5-온의 합성Synthesis of -propyl]-2,2-dimethyl-8-morpholino-3H-1,4-benzoxazepin-5-one

실시예 16-3으로부터 얻은 8-브로모-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-2,2-다이메틸-3H-1,4-벤즈옥사제핀-5-온을 출발물질로 사용하고 실시예 3-2와 동일한 방법에 의해 표제 화합물을 합성하였다. 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2 obtained from Example 16-3 -Dimethyl-3H-1,4-benzoxazepin-5-one was used as a starting material and the title compound was synthesized in the same manner as in Example 3-2.

1H NMR (400 MHz, methanol-d 4) δ 7.53 (d, J = 8.7 Hz, 1H), 7.17 - 7.01 (m, 4H), 6.80 (d, J = 8.8 Hz, 1H), 6.47 (s, 1H), 4.33 - 4.22 (m, 1H), 4.03 (dd, J = 13.8, 2.9 Hz, 1H), 3.83 (t, J = 5.0 Hz, 4H), 3.76 (s, 2H), 3.54 - 3.46 (m, 2H), 3.43 - 3.37 (m, 1H), 3.25 (t, J = 5.0 Hz, 4H), 2.99 - 2.83 (m, 4H), 2.69 - 2.58 (m, 2H), 1.42 (s, 3H), 1.33 (s, 3H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.53 (d, J = 8.7 Hz, 1H), 7.17-7.01 (m, 4H), 6.80 (d, J = 8.8 Hz, 1H), 6.47 (s, 1H), 4.33-4.22 (m, 1H), 4.03 (dd, J = 13.8, 2.9 Hz, 1H), 3.83 (t, J = 5.0 Hz, 4H), 3.76 (s, 2H), 3.54-3.46 (m , 2H), 3.43-3.37 (m, 1H), 3.25 (t, J = 5.0 Hz, 4H), 2.99-2.83 (m, 4H), 2.69-2.58 (m, 2H), 1.42 (s, 3H), 1.33 (s, 3H).

실시예Example 17: 417: 4 -[(2R)-3-(3,4--[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아이소퀴놀린Isoquinoline -2-일)-2--2-yl)-2- 하이드록시Hydroxy -프로필]-2,2-다이메틸-8-피롤리딘-1-일-3H-1,4-벤즈옥사제핀-5-온의 합성 Synthesis of -propyl]-2,2-dimethyl-8-pyrrolidin-1-yl-3H-1,4-benzoxazepin-5-one

Figure pat00024
Figure pat00024

실시예 16-3으로부터 얻은 물질을 출발물질로 사용하고 실시예 3-2에서 모르폴린을 피롤리딘으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다. The material obtained from Example 16-3 was used as a starting material, and the title compound was synthesized by the same method after changing morpholine to pyrrolidine in Example 3-2.

1H NMR (400 MHz, methanol-d 4) δ 7.48 (d, J = 8.7 Hz, 1H), 7.16 - 6.99 (m, 4H), 6.41 (d, J = 8.8 Hz, 1H), 6.08 (s, 1H), 4.34 - 4.21 (m, 1H), 4.01 (d, J = 13.6 Hz, 1H), 3.75 (s, 2H), 3.55 - 3.46 (m, 3H), 3.42 - 3.38 (m, 1H), 2.99 - 2.82 (m, 4H), 2.70 - 2.57 (m, 2H), 2.05 (t, J = 4.5 Hz, 4H), 1.42 (s, 3H), 1.33 (s, 3H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.48 (d, J = 8.7 Hz, 1H), 7.16-6.99 (m, 4H), 6.41 (d, J = 8.8 Hz, 1H), 6.08 (s, 1H), 4.34-4.21 (m, 1H), 4.01 (d, J = 13.6 Hz, 1H), 3.75 (s, 2H), 3.55-3.46 (m, 3H), 3.42-3.38 (m, 1H), 2.99 -2.82 (m, 4H), 2.70-2.57 (m, 2H), 2.05 (t, J = 4.5 Hz, 4H), 1.42 (s, 3H), 1.33 (s, 3H).

실시예Example 18: 818: 8 -(-( 아제티딘Azetidine -1-일)-4-[(2R)-3-(3,4--1-yl)-4-[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아이소퀴놀린Isoquinoline -2-일)-2-하이드록시-프로필]-2,2-다이메틸-3H-1,4-벤즈옥사제핀-5-온의 합성 Synthesis of -2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one

Figure pat00025
Figure pat00025

실시예 16-3으로부터 얻은 물질을 출발물질로 사용하고 실시예 3-2에서 모르폴린을 아제티딘으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다. The material obtained from Example 16-3 was used as a starting material, and the title compound was synthesized by the same method after changing morpholine to azetidine in Example 3-2.

1H NMR (400 MHz, methanol-d 4) δ 7.47 (d, J = 8.5 Hz, 1H), 7.17 - 6.99 (m, 4H), 6.25 (d, J = 8.4 Hz, 1H), 5.93 (d, J = 2.7 Hz, 1H), 4.33 - 4.22 (m, 1H), 4.01 (dd, J = 13.7, 3.0 Hz, 1H), 3.94 (t, J = 7.2 Hz, 4H), 3.76 (s, 2H), 3.48 (d, J = 3.7 Hz, 2H), 3.42 - 3.37 (m, 1H), 2.99 - 2.82 (m, 4H), 2.69 - 2.56 (m, 2H), 2.42 (p, J = 7.0, 6.5 Hz, 2H), 1.41 (s, 3H), 1.32 (s, 3H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.47 (d, J = 8.5 Hz, 1H), 7.17-6.99 (m, 4H), 6.25 (d, J = 8.4 Hz, 1H), 5.93 (d, J = 2.7 Hz, 1H), 4.33-4.22 (m, 1H), 4.01 (dd, J = 13.7, 3.0 Hz, 1H), 3.94 (t, J = 7.2 Hz, 4H), 3.76 (s, 2H), 3.48 (d, J = 3.7 Hz, 2H), 3.42-3.37 (m, 1H), 2.99-2.82 (m, 4H), 2.69-2.56 (m, 2H), 2.42 (p, J = 7.0, 6.5 Hz, 2H), 1.41 (s, 3H), 1.32 (s, 3H).

실시예Example 19: 19: 4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-8-[(5-플루오로-2-피리딜)메틸아미노]-2,2-다이메틸-3H-1,4-벤즈옥사제핀-5-온의 합성 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(5-fluoro-2-pyridyl)methyl Synthesis of amino]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one

Figure pat00026
Figure pat00026

실시예 16-3으로부터 얻은 물질을 출발물질로 사용하고 실시예 3-2에서 모르폴린을 (5-플루오로-2-피리딜)메탄아민으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다. The material obtained from Example 16-3 was used as a starting material, and the title compound was synthesized by the same method after changing morpholine to (5-fluoro-2-pyridyl) methanamine in Example 3-2.

1H NMR (400 MHz, methanol-d 4) δ 8.44 (s, 1H), 7.59 (t, J = 8.9 Hz, 1H), 7.52 - 7.43 (m, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.17 - 7.01 (m, 4H), 6.45 (d, J = 8.7 Hz, 1H), 6.10 (s, 1H), 4.46 (s, 2H), 4.32 - 4.20 (m, 1H), 3.99 (d, J = 13.6 Hz, 1H), 3.76 (s, 2H), 3.53 - 3.42 (m, 2H), 3.40 - 3.34 (m, 1H), 2.99 - 2.82 (m, 4H), 2.69 - 2.55 (m, 2H), 1.36 (s, 3H), 1.26 (s, 3H). 1 H NMR (400 MHz, methanol- d 4 ) δ 8.44 (s, 1H), 7.59 (t, J = 8.9 Hz, 1H), 7.52-7.43 (m, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.17-7.01 (m, 4H), 6.45 (d, J = 8.7 Hz, 1H), 6.10 (s, 1H), 4.46 (s, 2H), 4.32-4.20 (m, 1H), 3.99 (d , J = 13.6 Hz, 1H), 3.76 (s, 2H), 3.53-3.42 (m, 2H), 3.40-3.34 (m, 1H), 2.99-2.82 (m, 4H), 2.69-2.55 (m, 2H) ), 1.36 (s, 3H), 1.26 (s, 3H).

실시예Example 20: 820: 8 -(4--(4- 아세틸피페라진Acetylpiperazine -1-일)-4-[(2R)-3-(3,4--1-yl)-4-[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아Ah 이소퀴놀린-2-일)-2-하이드록시-프로필]-2,2-다이메틸-3H-1,4-벤즈옥사제핀-5-온의 합성 Synthesis of isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one

Figure pat00027
Figure pat00027

실시예 16-3으로부터 얻은 물질을 출발물질로 사용하고 실시예 3-2에서 모르폴린을 1-피페라진-1-일에탄온으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다. The material obtained from Example 16-3 was used as a starting material, and the title compound was synthesized by the same method after changing morpholine to 1-piperazin-1-ylethanone in Example 3-2.

1H NMR (400 MHz, methanol-d 4) δ 7.57 - 7.50 (m, 1H), 7.16 - 7.02 (m, 4H), 6.82 (d, J = 8.8 Hz, 1H), 6.50 (s, 1H), 4.32 - 4.23 (m, 1H), 4.02 (d, J = 13.7 Hz, 1H), 3.81 - 3.66 (m, 6H), 3.50 (s, 2H), 3.44 - 3.34 (m, 4H), 2.98 - 2.84 (m, 4H), 2.69 - 2.57 (m, 2H), 2.16 (s, 3H), 1.42 (s, 3H), 1.34 (s, 3H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.57-7.50 (m, 1H), 7.16-7.02 (m, 4H), 6.82 (d, J = 8.8 Hz, 1H), 6.50 (s, 1H), 4.32-4.23 (m, 1H), 4.02 (d, J = 13.7 Hz, 1H), 3.81-3.66 (m, 6H), 3.50 (s, 2H), 3.44-3.34 (m, 4H), 2.98-2.84 ( m, 4H), 2.69-2.57 (m, 2H), 2.16 (s, 3H), 1.42 (s, 3H), 1.34 (s, 3H).

실시예Example 21: 4-[4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-2,2-다이메틸-5-옥소-3H-1,4-벤즈옥사제핀-8-일]피페라진-1-카브알데하이드의 합성 21: 4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo Synthesis of -3H-1,4-benzoxazepin-8-yl]piperazine-1-carbaldehyde

Figure pat00028
Figure pat00028

실시예 16-3으로부터 얻은 물질을 출발물질로 사용하고 실시예 3-2에서 모르폴린을 피페라진-1-카브알데하이드로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다. The material obtained from Example 16-3 was used as a starting material, and the title compound was synthesized by the same method after changing morpholine to piperazine-1-carbaldehyde in Example 3-2.

1H NMR (400 MHz, methanol-d 4) δ 8.12 (s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.17 - 7.01 (m, 4H), 6.84 (d, J = 8.8 Hz, 1H), 6.52 (s, 1H), 4.34 - 4.20 (m, 2H), 4.02 (d, J = 13.7 Hz, 1H), 3.76 (s, 2H), 3.68 (t, J = 5.2 Hz, 2H), 3.60 (t, J = 5.3 Hz, 2H), 3.50 (s, 2H), 3.45 - 3.34 (m, 7H), 2.99 - 2.81 (m, 4H), 2.70 - 2.56 (m, 2H), 1.42 (s, 3H), 1.34 (s, 3H). 1 H NMR (400 MHz, methanol- d 4 ) δ 8.12 (s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.17-7.01 (m, 4H), 6.84 (d, J = 8.8 Hz, 1H), 6.52 (s, 1H), 4.34-4.20 (m, 2H), 4.02 (d, J = 13.7 Hz, 1H), 3.76 (s, 2H), 3.68 (t, J = 5.2 Hz, 2H), 3.60 (t, J = 5.3 Hz, 2H), 3.50 (s, 2H), 3.45-3.34 (m, 7H), 2.99-2.81 (m, 4H), 2.70-2.56 (m, 2H), 1.42 (s, 3H), 1.34 (s, 3H).

실시예Example 22: 4-[4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-5-옥소-스파이로[3H-1,4-벤즈옥사제핀-2,1'-사이클로부탄]-8-일]피페라진-1-카브알데하이드의 합성 22: 4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-spiro[3H-1 Synthesis of ,4-benzoxazepine-2,1'-cyclobutane]-8-yl]piperazine-1-carbaldehyde

Figure pat00029
Figure pat00029

실시예 22-1: 7-브로모스파이로[크로만-2,1'-사이클로부탄]-4-온의 합성Example 22-1: Synthesis of 7-bromospiro[chroman-2,1'-cyclobutan]-4-one

실시예 16-1에서 아세톤을 사이클로부탄온으로 변경하고 동일한 방법에 의해 표제화합물을 합성하였다.In Example 16-1, acetone was changed to cyclobutanone, and the title compound was synthesized by the same method.

실시예Example 22- 22- 2: 82: 8 -- 브로모스파이로Bromo Spiro [3,4-[3,4- 다이하이드로Dihydro -1,4--1,4- 벤즈옥사제핀Benzoxazepine -2,1'-사이클로부탄]-5-온의 합성Synthesis of -2,1'-cyclobutan]-5-one

실시예 22-1로부터 얻은 물질을 출발물질로 하고 실시예 16-2와 동일한 방법에 의해 표제화합물을 합성하였다.Using the material obtained in Example 22-1 as a starting material, the title compound was synthesized in the same manner as in Example 16-2.

실시예Example 22-3: 8-브로모-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]스파이로[3H-1,4-벤즈옥사제핀-2,1'-사이클로부탄]-5-온의 합성 22-3: 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]spiro[3H-1, Synthesis of 4-benzoxazepine-2,1'-cyclobutan]-5-one

실시예 22-2로부터 얻은 물질을 출발물질로 하고 실시예 1-1, 1-2와 동일한 방법에 의해 표제화합물을 합성하였다.Using the material obtained in Example 22-2 as a starting material, the title compound was synthesized in the same manner as in Examples 1-1 and 1-2.

실시예Example 22-4: 4-[4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-5-옥소-스파이로[3H-1,4-벤즈옥사제핀-2,1'-사이클로부탄]-8-일]피페라진-1-카브알데하이드의 합성 22-4: 4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-spiro[3H Synthesis of -1,4-benzoxazepine-2,1'-cyclobutan]-8-yl]piperazine-1-carbaldehyde

실시예 22-3으로부터 얻은 물질을 출발물질로 하여 실시예 3-2에서 모르폴린을 피페라진-1-카브알데하이드로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다. Using the material obtained in Example 22-3 as a starting material, after changing morpholine to piperazine-1-carbaldehyde in Example 3-2, the title compound was synthesized by the same method.

1H NMR (400 MHz, methanol-d 4) δ 8.12 (s, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.11-7.04 (m, 4H), 6.81 (d, J = 8.8 Hz, 1H), 6.55 (s, 1H), 4.31 - 4.21 (m, 1H), 4.05 (d, J = 14.2 Hz, 1H), 3.83 - 3.66 (m, 4H), 3.66 (d, J = 5.6 Hz, 2H), 3.63 - 3.55 (m, 2H), 3.46 (dd, J = 13.9, 8.3 Hz, 1H), 3.39 - 3.34 (m, 3H), 2.99 - 2.84 (m, 4H), 2.69 - 2.59 (m, 2H), 2.44 - 2.31 (m, 2H), 2.31 - 2.20 (m, 1H), 2.20 - 2.09 (m, 1H), 1.97 - 1.87 (m, 1H), 1.75 - 1.64 (m, 1H). 1 H NMR (400 MHz, methanol- d 4 ) δ 8.12 (s, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.11-7.04 (m, 4H), 6.81 (d, J = 8.8 Hz, 1H), 6.55 (s, 1H), 4.31-4.21 (m, 1H), 4.05 (d, J = 14.2 Hz, 1H), 3.83-3.66 (m, 4H), 3.66 (d, J = 5.6 Hz, 2H ), 3.63-3.55 (m, 2H), 3.46 (dd, J = 13.9, 8.3 Hz, 1H), 3.39-3.34 (m, 3H), 2.99-2.84 (m, 4H), 2.69-2.59 (m, 2H ), 2.44-2.31 (m, 2H), 2.31-2.20 (m, 1H), 2.20-2.09 (m, 1H), 1.97-1.87 (m, 1H), 1.75-1.64 (m, 1H).

실시예Example 23: 23: terttert -부틸 4-[[4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-5-옥소-2,3-다이하이드로-1,4-벤조다이아제핀-8-일]아미노]피페리딘-1-카르복실레이트의 합성-Butyl 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-5-oxo-2 Synthesis of ,3-dihydro-1,4-benzodiazepin-8-yl]amino]piperidine-1-carboxylate

Figure pat00030
Figure pat00030

실시예Example 23- 23- 1: 81: 8 -- 브로모Bromo -4-[(2R)-3-(3,4--4-[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아이소퀴놀린Isoquinoline -2-일)-2-하이드록시-프로필]-1-메틸-2,3-다이하이드로-1,4-벤조다이아제핀-5-온의 합성Synthesis of -2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

출발물질로 8-브로모-1-메틸-3,4-다이하이드로-2H-1,4-벤조다이아제핀-5-온을 사용하고 실시예 1-1 및 1-2와 동일한 방법에 의해 표제화합물을 합성하였다.Using 8-bromo-1-methyl-3,4-dihydro-2H-1,4-benzodiazepin-5-one as a starting material, and using the same method as in Examples 1-1 and 1-2, the title The compound was synthesized.

실시예Example 23-2: 23-2: terttert -부틸 4-[[4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-5-옥소-2,3-다이하이드로-1,4-벤조다이아제핀-8-일]아미노]피페리딘-1-카르복실레이트의 합성-Butyl 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-5-oxo-2 Synthesis of ,3-dihydro-1,4-benzodiazepin-8-yl]amino]piperidine-1-carboxylate

8-브로모-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-2,3-다이하이드로-1,4-벤조다이아제핀-5-온을 출발물질로 사용하고 실시예 3-2에서 모르폴린을 tert-부틸 4-아미노피페리딘-1-카르복실레이트로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다. 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro -1,4-benzodiazepin-5-one was used as a starting material, and morpholine was changed to tert-butyl 4-aminopiperidine-1-carboxylate in Example 3-2, and then titled by the same method. The compound was synthesized.

1H NMR (400 MHz, chloroform-d) δ 7.51 (d, J = 8.4 Hz, 1H), 7.14 - 7.08 (m, 3H), 7.01 (d, J = 6.8 Hz, 1H), 6.21 (d, J = 8.5 Hz, 1H), 5.99 (s, 1H), 4.24 - 3.97 (m, 4H), 3.82 (dd, J = 22.9, 14.5 Hz, 2H), 3.71 - 3.51 (m, 4H), 3.45 (d, J = 10.9 Hz, 1H), 3.36 (dt, J = 11.7, 6.0 Hz, 1H), 3.33 - 3.19 (m, 1H), 2.92 (d, J = 10.2 Hz, 6H), 2.79 (s, 4H), 2.62 (t, J = 7.4 Hz, 2H), 2.03 (d, J = 10.5 Hz, 4H), 1.47 (s, 9H), 1.42 - 1.18 (m, 4H). 1 H NMR (400 MHz, chloroform- d ) δ 7.51 (d, J = 8.4 Hz, 1H), 7.14-7.08 (m, 3H), 7.01 (d, J = 6.8 Hz, 1H), 6.21 (d, J = 8.5 Hz, 1H), 5.99 (s, 1H), 4.24-3.97 (m, 4H), 3.82 (dd, J = 22.9, 14.5 Hz, 2H), 3.71-3.51 (m, 4H), 3.45 (d, J = 10.9 Hz, 1H), 3.36 (dt, J = 11.7, 6.0 Hz, 1H), 3.33-3.19 (m, 1H), 2.92 (d, J = 10.2 Hz, 6H), 2.79 (s, 4H), 2.62 (t, J = 7.4 Hz, 2H), 2.03 (d, J = 10.5 Hz, 4H), 1.47 (s, 9H), 1.42-1.18 (m, 4H).

실시예Example 24: 24: terttert -부틸 3-[[4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-5-옥소-2,3-다이하이드로-1,4-벤조다이아제핀-8-일]아미노]피페리딘-1-카르복실레이트의 합성-Butyl 3-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-5-oxo-2 Synthesis of ,3-dihydro-1,4-benzodiazepin-8-yl]amino]piperidine-1-carboxylate

Figure pat00031
Figure pat00031

8-브로모-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-2,3-다이하이드로-1,4-벤조다이아제핀-5-온을 출발물질로 사용하고 실시예 3-2에서 모르폴린을 tert-부틸 3-아미노피페리딘-1-카르복실레이트로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다. 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro -1,4-benzodiazepin-5-one was used as a starting material, and morpholine was changed to tert -butyl 3-aminopiperidine-1-carboxylate in Example 3-2 and then titled by the same method. The compound was synthesized.

1H NMR (400 MHz, chloroform-d) δ 7.52 (d, J = 8.4 Hz, 1H), 7.19 - 7.06 (m, 3H), 7.02 (d, J = 5.9 Hz, 1H), 6.25 (d, J = 8.4 Hz, 1H), 6.02 (s, 1H), 4.24 - 4.04 (m, 2H), 3.82 (dd, J = 23.7, 14.6 Hz, 2H), 3.71 - 3.47 (m, 5H), 3.51 - 3.30 (m, 3H), 2.27 (dt, J = 10.7, 5.3 Hz, 1H), 3.13 (d, J = 10.9 Hz, 1H), 2.91 (s, 3H), 2.80 (s, 4H), 2.63 (t, J = 7.0 Hz, 2H), 2.05 (s, 2H), 1.99 (t, J = 7.4 Hz, 1H), 1.82 - 1.64 (m, 1H), 1.45 (s, 11H), 1.26 (t, J = 7.1 Hz, 2H). 1 H NMR (400 MHz, chloroform- d ) δ 7.52 (d, J = 8.4 Hz, 1H), 7.19-7.06 (m, 3H), 7.02 (d, J = 5.9 Hz, 1H), 6.25 (d, J = 8.4 Hz, 1H), 6.02 (s, 1H), 4.24-4.04 (m, 2H), 3.82 (dd, J = 23.7, 14.6 Hz, 2H), 3.71-3.47 (m, 5H), 3.51-3.30 ( m, 3H), 2.27 (dt, J = 10.7, 5.3 Hz, 1H), 3.13 (d, J = 10.9 Hz, 1H), 2.91 (s, 3H), 2.80 (s, 4H), 2.63 (t, J = 7.0 Hz, 2H), 2.05 (s, 2H), 1.99 (t, J = 7.4 Hz, 1H), 1.82-1.64 (m, 1H), 1.45 (s, 11H), 1.26 (t, J = 7.1 Hz , 2H).

실시예Example 25: 4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-8-(3-피페리딜아미노)-2,3-다이하이드로-1,4-벤조다이아제핀-5-온의 합성 25: 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(3-piperidylamino ) Synthesis of -2,3-dihydro-1,4-benzodiazepin-5-one

Figure pat00032
Figure pat00032

실시예 24로부터 얻은 물질을 메탄올에 녹이고, 1,4-디옥산에 녹여진 4 N 염산 용액을 첨가하였다. 실온에서 반응이 종결될 때까지 교반하고, 에틸다이에틸 에터로 희석하고 여과하여 흰색 고체의 2 염산 염 형태의 표제화합물을 얻었다.The material obtained in Example 24 was dissolved in methanol, and a 4N hydrochloric acid solution dissolved in 1,4-dioxane was added. The mixture was stirred at room temperature until the reaction was completed, diluted with ethyldiethyl ether, and filtered to obtain the title compound in the form of a white solid dihydrochloric acid salt.

2 염산 염 형태의 표제화합에 물을 가하고 에틸아세테이트로 3번 씻어 주었다. 얻어진 물층을 수산화소듐 수용액으로 pH14가 될 때까지 염기화 하고 다시 에틸아세테이트를 가하여 3번 추출하였다. 합친 유기층을 무수 소듐설페이트로 건조하고 여과한 뒤 감압하여 농축하여 추가적인 정제 과정 없이 표제화합물을 합성하였다. 2 Water was added to the title compound in the form of hydrochloric acid, and washed 3 times with ethyl acetate. The obtained aqueous layer was basified with sodium hydroxide aqueous solution until the pH reached 14, and ethyl acetate was added again, followed by extraction three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to synthesize the title compound without further purification.

1H NMR (400 MHz, methanol-d 4) δ 7.35 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 3.9 Hz, 3H), 7.06 (s, 1H), 6.29 (d, J = 8.5 Hz, 1H), 6.19 (s, 1H), 5.51 (s, 1H), 4.23 (s, 1H), 4.02 - 3.84 (m, 1H), 3.76 (s, 2H), 3.61 (s, 2H), 3.57 - 3.39 (m, 2H), 3.04 (d, J = 13.2 Hz, 2H), 2.98 - 2.77 (m, 2H), 2.66 (d, J = 9.8 Hz, 3H), 2.58 - 2.40 (m, 1H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.35 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 3.9 Hz, 3H), 7.06 (s, 1H), 6.29 (d, J = 8.5 Hz, 1H), 6.19 (s, 1H), 5.51 (s, 1H), 4.23 (s, 1H), 4.02-3.84 (m, 1H), 3.76 (s, 2H), 3.61 (s, 2H), 3.57-3.39 (m, 2H), 3.04 (d, J = 13.2 Hz, 2H), 2.98-2.77 (m, 2H), 2.66 (d, J = 9.8 Hz, 3H), 2.58-2.40 (m, 1H) .

실시예Example 26: 4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-8-(4-메틸-3-옥소-피페라진-1-일)-2,3-다이하이드로-1,4-벤조다이아제핀-5-온의 합성 26: 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(4-methyl-3- Synthesis of oxo-piperazin-1-yl)-2,3-dihydro-1,4-benzodiazepin-5-one

Figure pat00033
Figure pat00033

8-브로모-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-2,3-다이하이드로-1,4-벤조다이아제핀-5-온을 출발물질로 사용하고 실시예 3-2에서 모르폴린을 피페라진-2-온으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다. 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro After -1,4-benzodiazepin-5-one was used as a starting material and morpholine was changed to piperazin-2-one in Example 3-2, the title compound was synthesized by the same method.

1H NMR (400 MHz, chloroform-d) δ 7.60 (d, J = 8.7 Hz, 1H), 7.19 - 7.08 (m, 3H), 7.02 (d, J = 6.6 Hz, 1H), 6.47 (dd, J = 8.8, 2.2 Hz, 1H), 6.22 (d, J = 2.2 Hz, 1H), 4.12 (q, J = 7.6 Hz, 1H), 3.95 (s, 2H), 3.92 - 3.76 (m, 2H), 3.68 - 3.46 (m, 9H), 3.41 (dt, J = 11.5, 5.9 Hz, 1H), 3.31 (q, J = 5.3 Hz, 1H), 3.05 (s, 3H), 2.93 (q, J = 10.3, 9.1 Hz, 4H), 2.83 (s, 3H), 2.78 - 2.71 (m, 1H), 2.70 - 2.55 (m, 2H), 2.05 (s, 1H), 1.42 - 1.21 (m, 2H). 1 H NMR (400 MHz, chloroform- d ) δ 7.60 (d, J = 8.7 Hz, 1H), 7.19-7.08 (m, 3H), 7.02 (d, J = 6.6 Hz, 1H), 6.47 (dd, J = 8.8, 2.2 Hz, 1H), 6.22 (d, J = 2.2 Hz, 1H), 4.12 (q, J = 7.6 Hz, 1H), 3.95 (s, 2H), 3.92-3.76 (m, 2H), 3.68 -3.46 (m, 9H), 3.41 (dt, J = 11.5, 5.9 Hz, 1H), 3.31 (q, J = 5.3 Hz, 1H), 3.05 (s, 3H), 2.93 (q, J = 10.3, 9.1 Hz, 4H), 2.83 (s, 3H), 2.78-2.71 (m, 1H), 2.70-2.55 (m, 2H), 2.05 (s, 1H), 1.42-1.21 (m, 2H).

실시예Example 27: 27: terttert -부틸 4-[4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-5-옥소-2,3-다이하이드로-1,4-벤조다이아제핀-8-일]피페라진-1-카르복실레이트의 합성 -Butyl 4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-5-oxo-2, Synthesis of 3-dihydro-1,4-benzodiazepin-8-yl]piperazine-1-carboxylate

Figure pat00034
Figure pat00034

8-브로모-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-2,3-다이하이드로-1,4-벤조다이아제핀-5-온을 출발물질로 사용하고 실시예 3-2에서 모르폴린을 tert-부틸 피페라진-1-카르복실레이트로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다. 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro -1,4-benzodiazepin-5-one was used as a starting material, and morpholine was changed to tert -butyl piperazine-1-carboxylate in Example 3-2, and the title compound was synthesized by the same method. .

1H NMR (400 MHz, chloroform-d) δ 7.57 (d, J = 8.6 Hz, 1H), 7.13 (d, J = 8.4 Hz, 4H), 7.03 (s, 1H), 6.51 (d, J = 8.4 Hz, 1H), 6.31 (s, 1H), 4.11 (s, 1H), 3.87 (d, J = 14.5 Hz, 1H), 3.58 (s, 5H), 3.38 (d, J = 6.2 Hz, 2H), 3.26 (d, J = 31.5 Hz, 4H), 2.90 (d, J = 13.7 Hz, 2H), 2.83 (s, 2H), 1.49 (s, 9H), 1.25 (s, 4H). 1 H NMR (400 MHz, chloroform- d ) δ 7.57 (d, J = 8.6 Hz, 1H), 7.13 (d, J = 8.4 Hz, 4H), 7.03 (s, 1H), 6.51 (d, J = 8.4 Hz, 1H), 6.31 (s, 1H), 4.11 (s, 1H), 3.87 (d, J = 14.5 Hz, 1H), 3.58 (s, 5H), 3.38 (d, J = 6.2 Hz, 2H), 3.26 (d, J = 31.5 Hz, 4H), 2.90 (d, J = 13.7 Hz, 2H), 2.83 (s, 2H), 1.49 (s, 9H), 1.25 (s, 4H).

실시예Example 28: 4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-8-피페라진-1-일-2,3-다이하이드로-1,4-벤조다이아제핀-5-온의 합성 28: 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-piperazin-1-yl- Synthesis of 2,3-dihydro-1,4-benzodiazepin-5-one

Figure pat00035
Figure pat00035

실시예 27으로부터 얻은 물질을 출발물질로 사용하고 실시예 25와 동일한 방법에 의해 표제 화합물을 합성하였다. The material obtained from Example 27 was used as a starting material, and the title compound was synthesized in the same manner as in Example 25.

1H NMR (400 MHz, chloroform-d) δ 7.57 (d, J = 8.6 Hz, 1H), 7.13 (d, J = 8.4 Hz, 3H), 7.02 (s, 1H), 6.52 (d, J = 8.5 Hz, 1H), 6.32 (d, J = 2.3 Hz, 1H), 4.11 (t, J = 7.4 Hz, 1H), 3.84 (dd, J = 22.4, 14.4 Hz, 2H), 3.60 (dd, J = 13.6, 6.9 Hz, 3H), 3.49 - 3.33 (m, 1H), 3.29 (q, J = 5.2 Hz, 1H), 3.22 (t, J = 4.9 Hz, 4H), 3.03 (t, J = 4.9 Hz, 4H), 2.91 (s, 5H), 2.83 (s, 3H), 2.74 (d, J = 10.4 Hz, 1H), 2.63 (dd, J = 12.4, 4.9 Hz, 2H), 2.05 (s, 1H), 1.25 (s, 3H). 1 H NMR (400 MHz, chloroform- d ) δ 7.57 (d, J = 8.6 Hz, 1H), 7.13 (d, J = 8.4 Hz, 3H), 7.02 (s, 1H), 6.52 (d, J = 8.5 Hz, 1H), 6.32 (d, J = 2.3 Hz, 1H), 4.11 (t, J = 7.4 Hz, 1H), 3.84 (dd, J = 22.4, 14.4 Hz, 2H), 3.60 (dd, J = 13.6 , 6.9 Hz, 3H), 3.49-3.33 (m, 1H), 3.29 (q, J = 5.2 Hz, 1H), 3.22 (t, J = 4.9 Hz, 4H), 3.03 (t, J = 4.9 Hz, 4H ), 2.91 (s, 5H), 2.83 (s, 3H), 2.74 (d, J = 10.4 Hz, 1H), 2.63 (dd, J = 12.4, 4.9 Hz, 2H), 2.05 (s, 1H), 1.25 (s, 3H).

실시예Example 29: 8-(4-아세틸피페라진-1-일)-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-2,3-다이하이드로-1,4-벤조다이아제핀-5-온의 합성 29: 8-(4-acetylpiperazin-1-yl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl] Synthesis of -1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

Figure pat00036
Figure pat00036

8-브로모-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-2,3-다이하이드로-1,4-벤조다이아제핀-5-온을 출발물질로 사용하고 실시예 3-2에서 모르폴린을 1-피페라진-1-일에탄온으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다. 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro -1,4-benzodiazepin-5-one was used as a starting material, and morpholine was changed to 1-piperazin-1-ylethanone in Example 3-2, and the title compound was synthesized by the same method.

1H NMR (400 MHz, chloroform-d) δ 7.58 (d, J = 8.5 Hz, 1H), 7.14 (q, J = 5.9, 5.4 Hz, 3H), 7.02 (d, J = 6.7 Hz, 1H), 6.58 - 6.48 (m, 1H), 6.30 (s, 1H), 4.11 (t, J = 7.2 Hz, 1H), 3.95 - 3.81 (m, 2H), 3.81 - 3.74 (m, 2H), 3.70 - 3.54 (m, 5H), 3.40 (dt, J = 11.7, 5.9 Hz, 1H), 3.27 (ddd, J = 18.5, 10.8, 7.3 Hz, 4H), 2.91 (d, J = 8.1 Hz, 3H), 2.83 (s, 3H), 2.76 (d, J = 8.9 Hz, 1H), 2.71 - 2.55 (m, 2H), 2.15 (s, 3H), 2.05 (s, 1H), 1.26 (t, J = 7.2 Hz, 1H). 1 H NMR (400 MHz, chloroform- d ) δ 7.58 (d, J = 8.5 Hz, 1H), 7.14 (q, J = 5.9, 5.4 Hz, 3H), 7.02 (d, J = 6.7 Hz, 1H), 6.58-6.48 (m, 1H), 6.30 (s, 1H), 4.11 (t, J = 7.2 Hz, 1H), 3.95-3.81 (m, 2H), 3.81-3.74 (m, 2H), 3.70-3.54 ( m, 5H), 3.40 (dt, J = 11.7, 5.9 Hz, 1H), 3.27 (ddd, J = 18.5, 10.8, 7.3 Hz, 4H), 2.91 (d, J = 8.1 Hz, 3H), 2.83 (s , 3H), 2.76 (d, J = 8.9 Hz, 1H), 2.71-2.55 (m, 2H), 2.15 (s, 3H), 2.05 (s, 1H), 1.26 (t, J = 7.2 Hz, 1H) .

실시예Example 30: 8-[(1-아세틸-4-피페리딜)아미노]-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-2,3-다이하이드로-1,4-벤조다이아제핀-5-온의 합성 30: 8-[(1-acetyl-4-piperidyl)amino]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy Synthesis of -propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

Figure pat00037
Figure pat00037

8-브로모-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-2,3-다이하이드로-1,4-벤조다이아제핀-5-온을 출발물질로 사용하고 실시예 3-2에서 모르폴린을 1-(4-아미노-1-피페리딜)에탄온으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다. 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro -1,4-benzodiazepin-5-one was used as a starting material, and morpholine was changed to 1-(4-amino-1-piperidyl)ethanone in Example 3-2, and then titled by the same method. The compound was synthesized.

1H NMR (400 MHz, chloroform-d) δ 7.52 (d, J = 8.4 Hz, 1H), 7.14 (dd, J = 9.2, 5.5 Hz, 3H), 7.02 (d, J = 6.8 Hz, 1H), 6.22 (d, J = 8.4 Hz, 1H), 5.99 (s, 1H), 4.50 (d, J = 14.1 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.84 (t, J = 14.2 Hz, 3H), 3.75 - 3.43 (m, 6H), 3.45 - 3.17 (m, 4H), 2.91 (d, J = 7.0 Hz, 4H), 2.79 (s, 4H), 2.64 (t, J = 7.6 Hz, 2H), 2.33 - 1.94 (m, 6H), 1.37 (q, J = 10.6, 9.5 Hz, 2H), 1.28 - 1.19 (m, 3H). 1 H NMR (400 MHz, chloroform- d ) δ 7.52 (d, J = 8.4 Hz, 1H), 7.14 (dd, J = 9.2, 5.5 Hz, 3H), 7.02 (d, J = 6.8 Hz, 1H), 6.22 (d, J = 8.4 Hz, 1H), 5.99 (s, 1H), 4.50 (d, J = 14.1 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.84 (t, J = 14.2 Hz, 3H), 3.75-3.43 (m, 6H), 3.45-3.17 (m, 4H), 2.91 (d, J = 7.0 Hz, 4H), 2.79 (s, 4H), 2.64 (t, J = 7.6 Hz , 2H), 2.33-1.94 (m, 6H), 1.37 (q, J = 10.6, 9.5 Hz, 2H), 1.28-1.19 (m, 3H).

실시예Example 31: 8-[(1-아세틸-3-피페리딜)아미노]-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-2,3-다이하이드로-1,4-벤조다이아제핀-5-온의 합성 31: 8-[(1-acetyl-3-piperidyl)amino]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy Synthesis of -propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

Figure pat00038
Figure pat00038

8-브로모-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-2,3-다이하이드로-1,4-벤조다이아제핀-5-온을 출발물질로 사용하고 실시예 3-2에서 모르폴린을 1-(3-아미노-1-피페리딜)에탄온으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다. 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro -1,4-benzodiazepin-5-one was used as a starting material, and morpholine was changed to 1-(3-amino-1-piperidyl)ethanone in Example 3-2, and then titled by the same method. The compound was synthesized.

1H NMR (400 MHz, chloroform-d) δ 7.52 (dd, J = 17.0, 8.4 Hz, 1H), 7.13 (s, 3H), 7.01 (s, 1H), 6.21 (d, J = 8.5 Hz, 1H), 6.10 (s, 1H), 4.45 (s, 1H), 4.12 (q, J = 7.4 Hz, 2H), 4.03 - 3.71 (m, 4H), 3.74 - 3.54 (m, 4H), 3.51 - 3.17 (m, 4H), 2.91 (s, 3H), 2.81 (d, J = 13.8 Hz, 3H), 2.63 (s, 2H), 2.14 (s, 1H), 2.04 (d, J = 5.1 Hz, 3H), 1.26 (t, J = 7.2 Hz, 2H). 1 H NMR (400 MHz, chloroform- d ) δ 7.52 (dd, J = 17.0, 8.4 Hz, 1H), 7.13 (s, 3H), 7.01 (s, 1H), 6.21 (d, J = 8.5 Hz, 1H ), 6.10 (s, 1H), 4.45 (s, 1H), 4.12 (q, J = 7.4 Hz, 2H), 4.03-3.71 (m, 4H), 3.74-3.54 (m, 4H), 3.51-3.17 ( m, 4H), 2.91 (s, 3H), 2.81 (d, J = 13.8 Hz, 3H), 2.63 (s, 2H), 2.14 (s, 1H), 2.04 (d, J = 5.1 Hz, 3H), 1.26 (t, J = 7.2 Hz, 2H).

실시예Example 32: 4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-8-[4-(다이메틸아미노)-1-피페리딜]-1-메틸-2,3-다이하이드로-1,4-벤조다이아제핀-5-온의 합성 32: 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[4-(dimethylamino)-1- Piperidyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one synthesis

Figure pat00039
Figure pat00039

8-브로모-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-2,3-다이하이드로-1,4-벤조다이아제핀-5-온을 출발물질로 사용하고 실시예 3-2에서 모르폴린을 N,N-다이메틸피페리딘-4-아민으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다. 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro -1,4-benzodiazepin-5-one was used as a starting material, and morpholine was changed to N,N-dimethylpiperidin-4-amine in Example 3-2, and the title compound was prepared by the same method. Synthesized.

1H NMR (400 MHz, methanol-d 4) δ 7.42 (d, J = 8.5 Hz, 1H), 7.11 (d, J = 3.4 Hz, 3H), 7.06 (s, 1H), 6.60 (d, J = 8.7 Hz, 1H), 6.44 (s, 1H), 4.23 (s, 1H), 3.92 (d, J = 13.0 Hz, 3H), 3.76 (s, 2H), 3.61 (d, J = 5.3 Hz, 2H), 3.43 (dt, J = 14.3, 7.0 Hz, 2H), 2.91 (dd, J = 20.1, 5.7 Hz, 2H), 2.84 (s, 4H), 2.79 (d, J = 12.5 Hz, 2H), 2.65 (d, J = 7.9 Hz, 2H), 2.35 (s, 6H), 2.02 (t, J = 14.5 Hz, 3H), 1.59 (q, J = 11.7 Hz, 2H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.42 (d, J = 8.5 Hz, 1H), 7.11 (d, J = 3.4 Hz, 3H), 7.06 (s, 1H), 6.60 (d, J = 8.7 Hz, 1H), 6.44 (s, 1H), 4.23 (s, 1H), 3.92 (d, J = 13.0 Hz, 3H), 3.76 (s, 2H), 3.61 (d, J = 5.3 Hz, 2H) , 3.43 (dt, J = 14.3, 7.0 Hz, 2H), 2.91 (dd, J = 20.1, 5.7 Hz, 2H), 2.84 (s, 4H), 2.79 (d, J = 12.5 Hz, 2H), 2.65 ( d, J = 7.9 Hz, 2H), 2.35 (s, 6H), 2.02 (t, J = 14.5 Hz, 3H), 1.59 (q, J = 11.7 Hz, 2H).

실시예Example 33: 4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-8-(2-옥소피롤리딘-1-일)-2,3-다이하이드로-1,4-벤조다이아제핀-5-온의 합성 33: 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(2-oxopyrrolidine Synthesis of -1-yl)-2,3-dihydro-1,4-benzodiazepin-5-one

Figure pat00040
Figure pat00040

8-브로모-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-2,3-다이하이드로-1,4-벤조다이아제핀-5-온을 출발물질로 사용하고 실시예 3-2에서 모르폴린을 피롤리딘-2-온으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다. 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro After -1,4-benzodiazepin-5-one was used as a starting material and morpholine was changed to pyrrolidin-2-one in Example 3-2, the title compound was synthesized by the same method.

1H NMR (400 MHz, methanol-d 4) δ 7.55 (d, J = 8.4 Hz, 1H), 7.48 (s, 1H), 7.13 (d, J = 3.3 Hz, 4H), 7.07 (s, 1H), 4.25 (s, 1H), 4.09 - 3.89 (m, 3H), 3.81 (s, 2H), 3.63 (s, 2H), 3.49 - 3.37 (m, 3H), 2.94 (d, J = 7.5 Hz, 5H), 2.86 (s, 3H), 2.70 (d, J = 7.9 Hz, 2H), 2.62 (d, J = 8.1 Hz, 2H), 2.36 - 2.15 (m, 2H), 1.31 (s, 1H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.55 (d, J = 8.4 Hz, 1H), 7.48 (s, 1H), 7.13 (d, J = 3.3 Hz, 4H), 7.07 (s, 1H) , 4.25 (s, 1H), 4.09-3.89 (m, 3H), 3.81 (s, 2H), 3.63 (s, 2H), 3.49-3.37 (m, 3H), 2.94 (d, J = 7.5 Hz, 5H ), 2.86 (s, 3H), 2.70 (d, J = 7.9 Hz, 2H), 2.62 (d, J = 8.1 Hz, 2H), 2.36-2.15 (m, 2H), 1.31 (s, 1H).

실시예Example 34: 4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-8-(2-메틸-5-옥소-피롤리딘-1-일)-2,3-다이하이드로-1,4-벤조다이아제핀-5-온의 합성 34: 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(2-methyl-5- Synthesis of oxo-pyrrolidin-1-yl)-2,3-dihydro-1,4-benzodiazepin-5-one

Figure pat00041
Figure pat00041

8-브로모-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-2,3-다이하이드로-1,4-벤조다이아제핀-5-온을 출발물질로 사용하고 실시예 3-2에서 모르폴린을 5-메틸피롤리딘-2-온으로 변경 후 동일한 방법에 의해 표제 화합물을 합성하였다. 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro -1,4-benzodiazepin-5-one was used as a starting material, and morpholine was changed to 5-methylpyrrolidin-2-one in Example 3-2, and the title compound was synthesized by the same method.

1H NMR (400 MHz, methanol-d 4) δ 7.58 (d, J = 8.3 Hz, 1H), 7.26 - 7.09 (m, 4H), 7.07 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.47 (q, J = 6.4 Hz, 1H), 4.25 (s, 1H), 3.94 (d, J = 13.9 Hz, 1H), 3.79 (s, 2H), 3.64 (s, 2H), 3.54 - 3.40 (m, 3H), 2.93 (dd, J = 12.1, 4.6 Hz, 4H), 2.85 (s, 3H), 2.69 (d, J = 7.7 Hz, 3H), 2.56 (dt, J = 16.9, 8.0 Hz, 1H), 2.43 (t, J = 10.6 Hz, 1H), 1.88 - 1.72 (m, 1H), 1.30 - 1.13 (m, 4H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.58 (d, J = 8.3 Hz, 1H), 7.26-7.09 (m, 4H), 7.07 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.47 (q, J = 6.4 Hz, 1H), 4.25 (s, 1H), 3.94 (d, J = 13.9 Hz, 1H), 3.79 (s, 2H), 3.64 (s, 2H), 3.54- 3.40 (m, 3H), 2.93 (dd, J = 12.1, 4.6 Hz, 4H), 2.85 (s, 3H), 2.69 (d, J = 7.7 Hz, 3H), 2.56 (dt, J = 16.9, 8.0 Hz , 1H), 2.43 (t, J = 10.6 Hz, 1H), 1.88-1.72 (m, 1H), 1.30-1.13 (m, 4H).

실시예Example 35: 435: 4 -[(2R)-3-(3,4--[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아이소퀴놀린Isoquinoline -2-일)-2--2-yl)-2- 하이드록시프로필Hydroxypropyl ]-2-메틸-8-모르폴리노-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성 ]-2-Methyl-8-morpholino-2,3-dihydro-1,4-benzoxazepin-5-one synthesis

Figure pat00042
Figure pat00042

실시예Example 35-1: 35-1: 메틸methyl 4- 4- 브로모Bromo -2-[2-(-2-[2-( terttert -- 부톡시카보닐아미노Butoxycarbonylamino )) 프로폭시Propoxy ]] 벤조에이트의Benzoate 합성 synthesis

메틸 4-브로모-2-하이드록시-벤조에이트 (3 g, 12.98 mmol), Cs2CO3 (12.7 g, 51.9 mmol), [2-(tert-부톡시카보닐아미노)-1-메틸-에틸] 메탄설포네이트 (7 mL, 25.98 mmol)을 아세토나이트릴에 녹이고 하루동안 교반하면서 가열 환류 하였다. 반응용액을 실온으로 식히고 증류수를 첨가하고 에틸아세테이트로 추출하였다. 합친 유기층을 무수 마그네슘 설페이트로 건조하고 농축하여 속성 크로마토그래피로 정제하여 표제화합물을 얻었다.Methyl 4-bromo-2-hydroxy-benzoate (3 g, 12.98 mmol), Cs 2 CO 3 (12.7 g, 51.9 mmol), [2-(tert-butoxycarbonylamino)-1-methyl- Ethyl] methanesulfonate (7 mL, 25.98 mmol) was dissolved in acetonitrile and heated to reflux while stirring for a day. The reaction solution was cooled to room temperature, distilled water was added, and extraction was performed with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated, and purified by flash chromatography to obtain the title compound.

실시예Example 35-2: 35-2: 메틸methyl 2-(2- 2-(2- 아미노프로폭시Aminopropoxy )-4-)-4- 브로모Bromo -- 벤조에이트;하이드로클로라이드의Benzoate; of hydrochloride 합성 synthesis

실시예 35-1로부터 얻은 물질을 출발물질로 사용하고 메탄올에 녹인 후 1,4-디옥산에 녹여진 4 N HCl을 첨가한 후 실온에서 교반하였다. 반응용액을 감압하여 농축하고 추가적인 정제과정없이 표제화합물을 얻었다.The material obtained from Example 35-1 was used as a starting material, dissolved in methanol, and then 4N HCl dissolved in 1,4-dioxane was added, followed by stirring at room temperature. The reaction solution was concentrated under reduced pressure to obtain the title compound without further purification.

실시예Example 35- 35- 3: 83: 8 -- 브로모Bromo -2--2- 메틸methyl -3,4--3,4- 다이하이드로Dihydro -2H-1,4--2H-1,4- 벤즈옥사제핀Benzoxazepine -5-온의 합성Synthesis of -5-one

실시예 35-2로부터 얻은 물질 (2.3 g, 8.01 mmol)을 톨루엔에 녹이고 트라이에틸아민 (4.5 mL, 32 mmol)을 첨가하였다. 반응용액을 교반하면서 가열환류하고, 반응이 종결된 것을 확인한 후 실온으로 식히고 감압하여 용매를 제거하였다. 농축액을 속성 크로마토그래피로 정제하여 표제화합물을 얻었다.The material obtained from Example 35-2 (2.3 g, 8.01 mmol) was dissolved in toluene, and triethylamine (4.5 mL, 32 mmol) was added. The reaction solution was heated to reflux while stirring, and after confirming that the reaction was complete, it was cooled to room temperature and reduced pressure to remove the solvent. The concentrate was purified by flash chromatography to obtain the title compound.

실시예Example 35- 35- 4: 84: 8 -- 브로모Bromo -4-[(2R)-3-(3,4--4-[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아이소퀴놀린Isoquinoline -2-일)-2-하이드록시프로필]-2-메틸-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성Synthesis of -2-yl)-2-hydroxypropyl]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

실시예 35-3으로부터 얻은 물질을 출발물질로하여 실시예 1-1, 1-2와 동일한 방법에의해 표제화합물을 합성하였다.Using the material obtained in Example 35-3 as a starting material, the title compound was synthesized in the same manner as in Examples 1-1 and 1-2.

실시예Example 35- 35- 5: 45: 4 -[(2R)-3-(3,4--[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아이소퀴놀린Isoquinoline -2-일)-2--2-yl)-2- 하이드록시프로필Hydroxypropyl ]-2-메틸-8-모르폴리노-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성]-2-Methyl-8-morpholino-2,3-dihydro-1,4-benzoxazepin-5-one synthesis

실시예 35-4로부터 얻은 8-브로모-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시프로필]-2-메틸-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온을 출발물질로 사용하고 실시예 3-2와 동일한 방법에 의해 표제물질을 합성하였다.8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl- obtained from Example 35-4 Using 2,3-dihydro-1,4-benzoxazepin-5-one as a starting material, the title material was synthesized in the same manner as in Example 3-2.

1H NMR (400 MHz, Methanol-d 4) δ 7.58 (dd, J = 8.5, 3.3 Hz, 1H), 7.16 - 7.02 (m, 4H), 6.78 (d, J = 8.5 Hz, 1H), 6.50 (s, 1H), 4.83 - 4.70 (m, 1H), 4.24 (s, 1H), 3.87 - 3.74 (m, 6H), 3.68 - 3.55 (m, 2H), 3.47 (dd, J = 15.5, 8.9 Hz, 1H), 3.24 (d, J = 5.6 Hz, 4H), 2.98 - 2.84 (m, 4H), 2.70 - 2.57 (m, 2H), 1.30 (dd, J = 15.6, 6.4 Hz, 3H). 1 H NMR (400 MHz, Methanol- d 4 ) δ 7.58 (dd, J = 8.5, 3.3 Hz, 1H), 7.16-7.02 (m, 4H), 6.78 (d, J = 8.5 Hz, 1H), 6.50 ( s, 1H), 4.83-4.70 (m, 1H), 4.24 (s, 1H), 3.87-3.74 (m, 6H), 3.68-3.55 (m, 2H), 3.47 (dd, J = 15.5, 8.9 Hz, 1H), 3.24 (d, J = 5.6 Hz, 4H), 2.98-2.84 (m, 4H), 2.70-2.57 (m, 2H), 1.30 (dd, J = 15.6, 6.4 Hz, 3H).

실시예Example 36: 8-(4-아세틸피페라진-1-일)-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-2-메틸-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성 36: 8-(4-acetylpiperazin-1-yl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl] Synthesis of -2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

Figure pat00043
Figure pat00043

8-브로모-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시프로필]-2-메틸-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온을 출발물질로 사용하고 실시예 6과 동일한 방법에 의해 표제물질을 합성하였다.8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-2,3-dihydro- Using 1,4-benzoxazepin-5-one as a starting material, the title material was synthesized in the same manner as in Example 6.

1H NMR (400 MHz, Methanol-d 4) δ 7.59 (dd, J = 9.0, 3.0 Hz, 1H), 7.20 - 7.03 (m, 4H), 6.84 - 6.76 (m, 1H), 6.52 (s, 1H), 4.78 (t, J = 8.8 Hz, 1H), 4.29 - 4.20 (m, 1H), 4.17 - 4.06 (m, 1H), 3.85 (d, J = 7.7 Hz, 2H), 3.76 - 3.66 (m, 4H), 3.66 - 3.56 (m, 1H), 3.53 - 3.42 (m, 1H), 3.37 (d, J = 5.2 Hz, 6H), 3.10 (d, J = 1.9 Hz, 1H), 2.97 (d, J = 5.1 Hz, 4H), 2.73 (dd, J = 13.0, 6.0 Hz, 2H), 2.16 (d, J = 1.8 Hz, 3H), 2.03 (s, 1H), 1.50 (d, J = 1.9 Hz, 2H), 1.35 - 1.24 (m, 4H). 1 H NMR (400 MHz, Methanol- d 4 ) δ 7.59 (dd, J = 9.0, 3.0 Hz, 1H), 7.20-7.03 (m, 4H), 6.84-6.76 (m, 1H), 6.52 (s, 1H) ), 4.78 (t, J = 8.8 Hz, 1H), 4.29-4.20 (m, 1H), 4.17-4.06 (m, 1H), 3.85 (d, J = 7.7 Hz, 2H), 3.76-3.66 (m, 4H), 3.66-3.56 (m, 1H), 3.53-3.42 (m, 1H), 3.37 (d, J = 5.2 Hz, 6H), 3.10 (d, J = 1.9 Hz, 1H), 2.97 (d, J = 5.1 Hz, 4H), 2.73 (dd, J = 13.0, 6.0 Hz, 2H), 2.16 (d, J = 1.8 Hz, 3H), 2.03 (s, 1H), 1.50 (d, J = 1.9 Hz, 2H ), 1.35-1.24 (m, 4H).

실시예Example 37: (2R)-4-[(2R)-3-(3,4- 37: (2R)-4-[(2R)-3-(3,4- 다이하이드로Dihydro -1H--1H- 아이소퀴놀린Isoquinoline -2-일)-2--2-yl)-2- 하이드록시프로필Hydroxypropyl ]-2-메틸-8-모르폴리노-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성]-2-Methyl-8-morpholino-2,3-dihydro-1,4-benzoxazepin-5-one synthesis

Figure pat00044
Figure pat00044

실시예 35-1에서 [2-(tert-부톡시카보닐아미노)-1-메틸-에틸] 메탄설포네이트를 [(1S)-2-(tert-부톡시카보닐아미노)-1-메틸-에틸] 메탄설포네이트로 변경하고 실시예 35와 동일한 방법에 의해 표제물질을 합성하였다.In Example 35-1, [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate was added to [(1S)-2-( tert -butoxycarbonylamino)-1-methyl- Ethyl] was changed to methanesulfonate and the title material was synthesized in the same manner as in Example 35.

1H NMR (400 MHz, Methanol-d 4) δ 7.58 (d, J = 8.6 Hz, 1H), 7.27 (s, 1H), 7.18 - 7.04 (m, 3H), 6.78 (d, J = 8.9 Hz, 1H), 6.50 (d, J = 3.1 Hz, 1H), 4.76 (s, 2H), 4.26 (s, 1H), 4.12 (d, J = 12.2 Hz, 1H), 3.84 (d, J = 4.9 Hz, 5H), 3.63 (d, J = 15.2 Hz, 2H), 3.50 (dd, J = 15.0, 7.5 Hz, 2H), 3.25 (s, 4H), 2.97 (s, 3H), 2.78 - 2.62 (m, 2H), 1.33 (d, J = 6.5 Hz, 3H). 1 H NMR (400 MHz, Methanol- d 4 ) δ 7.58 (d, J = 8.6 Hz, 1H), 7.27 (s, 1H), 7.18-7.04 (m, 3H), 6.78 (d, J = 8.9 Hz, 1H), 6.50 (d, J = 3.1 Hz, 1H), 4.76 (s, 2H), 4.26 (s, 1H), 4.12 (d, J = 12.2 Hz, 1H), 3.84 (d, J = 4.9 Hz, 5H), 3.63 (d, J = 15.2 Hz, 2H), 3.50 (dd, J = 15.0, 7.5 Hz, 2H), 3.25 (s, 4H), 2.97 (s, 3H), 2.78-2.62 (m, 2H ), 1.33 (d, J = 6.5 Hz, 3H).

실시예Example 38: (2S)-8-(4-아세틸피페라진-1-일)-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-2-메틸-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온의 합성 38: (2S)-8-(4-acetylpiperazin-1-yl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hyde Synthesis of Roxy-propyl]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

Figure pat00045
Figure pat00045

실시예 35-1에서 [2-(tert-부톡시카보닐아미노)-1-메틸-에틸] 메탄설포네이트를 [(1R)-2-(tert-부톡시카보닐아미노)-1-메틸-에틸] 메탄설포네이트로 변경하여 합성한 출발물질로부터 실시예 36과 동일한 방법에 의해 표제물질을 합성하였다.In Example 35-1, [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate was added to [(1R)-2-(tert-butoxycarbonylamino)-1-methyl- Ethyl] from the starting material synthesized by changing to methanesulfonate, the title material was synthesized in the same manner as in Example 36.

1H NMR (400 MHz, Methanol-d 4) δ 7.58 (d, J = 9.1 Hz, 1H), 7.16 - 7.05 (m, 3H), 6.81 (d, J = 8.8 Hz, 1H), 6.53 (s, 1H), 4.80 (s, 1H), 4.25 (s, 1H), 3.82 (s, 2H), 3.72 (d, J = 13.9 Hz, 4H), 3.68 - 3.57 (m, 2H), 3.48 (dd, J = 15.6, 9.0 Hz, 2H), 3.37 (d, J = 4.6 Hz, 2H), 2.95 (s, 3H), 2.71 (d, J = 6.2 Hz, 2H), 2.17 (d, J = 1.9 Hz, 3H), 1.29 (d, J = 6.5 Hz, 3H). 1 H NMR (400 MHz, Methanol- d 4 ) δ 7.58 (d, J = 9.1 Hz, 1H), 7.16-7.05 (m, 3H), 6.81 (d, J = 8.8 Hz, 1H), 6.53 (s, 1H), 4.80 (s, 1H), 4.25 (s, 1H), 3.82 (s, 2H), 3.72 (d, J = 13.9 Hz, 4H), 3.68-3.57 (m, 2H), 3.48 (dd, J = 15.6, 9.0 Hz, 2H), 3.37 (d, J = 4.6 Hz, 2H), 2.95 (s, 3H), 2.71 (d, J = 6.2 Hz, 2H), 2.17 (d, J = 1.9 Hz, 3H ), 1.29 (d, J = 6.5 Hz, 3H).

실험예Experimental example

Enzyme activity 측정 방법Enzyme activity measurement method

시험관내 분석법: PRMT5-MEP50 효소 복합체와 보조인자 S-아데노실메티오닌 (SAM) 그리고 히스톤 H4 펩티드를 시험관내에서 반응시켜 히스톤 H4의 3번째 아미노산인 아르기닌 (H4R3)의 메틸화를 측정하여 PRMT5의 효소활성도를 측정하였다. In vitro assay: PRMT5-MEP50 enzyme complex, cofactor S-adenosylmethionine (SAM) and histone H4 peptide were reacted in vitro to measure methylation of arginine (H4R3), the third amino acid of histone H4, to measure the enzyme activity of PRMT5. Was measured.

시약: PRMT5-MEP50 효소 복합체 (카달로그번호 51045), 블로킹 완충액 (52100-B), 히스톤 메틸전이효소 반응 완충액 2 (4x HMT assay buffer 2, 카달로그번호 52170), 1차 항체 (primary antibody 4-3, 카달로그번호 52150)는 BPS 바이오사이언스(BPS Bioscience, 미국)로부터 구매하였다. 히스톤 H4 펩티드 (1~20 아미노산)는 고마바이오텍 (Komabiotech, 한국)에서 주문 제작하여 사용하였다. S-아데노실메티오닌은 NEB (New England Biolabs, 미국, 카달로그번호 B9003S)로부터 구매하였다. 히스톤 H4 펩티드를 코팅 하기위한 플레이트, 세척용 완충액 및 발색용 시약은 아래의 구매처로부터 각각 구매하였다. 플레이트 (ImmobilizerTM-Amino Plate, NUNC, 덴마크, 카달로그번호 436023), 카보네이트-바이카보네이트 완충액 (Carbonate-Bicarbonate Buffer, Sigma-Aldrich, 미국, 카달로그번호 C3041), 세척용 완충액 (10X TBST, Biosesang, 한국, 카달로그번호 T2005), TMB 기질 (TMB ELISA substrate, Abcam, 영국, 카달로그번호 ab210902), 호스래디시퍼옥시다아제 결합 항체 (HRP-conjugated antibody, Abcam, 영국, 카달로그번호 ab6721).Reagents: PRMT5-MEP50 enzyme complex (catalog number 51045), blocking buffer (52100-B), histone methyltransferase reaction buffer 2 (4x HMT assay buffer 2, catalog number 52170), primary antibody (primary antibody 4-3, Catalog No. 52150) was purchased from BPS Bioscience (USA). The histone H4 peptide (1-20 amino acids) was custom made and used by Komabiotech (Korea). S-adenosylmethionine was purchased from NEB (New England Biolabs, USA, catalog number B9003S). Plates for coating histone H4 peptide, washing buffer, and color development reagent were each purchased from the following vendors. Plate (Immobilizer TM -Amino Plate, NUNC, Denmark, catalog number 436023), Carbonate-Bicarbonate Buffer (Sigma-Aldrich, USA, catalog number C3041), washing buffer (10X TBST, Biosesang, Korea, Catalog number T2005), TMB substrate (TMB ELISA substrate, Abcam, UK, catalog number ab210902), horseradish peroxidase binding antibody (HRP-conjugated antibody, Abcam, UK, catalog number ab6721).

실험절차: 히스톤 H4 펩티드를 카보네이트-바이카보네이트 완충액으로 희석하여 100 μg/mL로 조제 후 플레이트에 100 μL씩 분주하여 37℃에서 1시간 동안 반응시켰다. PRMT5-MEP50 효소 복합체와 S-아데노실메티오닌을 히스톤 메틸전이효소 반응 완충액으로 희석하여 각각 5 μg/mL, 2 μM로 조제 한 후, 앞서 준비한 플레이트에 PRMT5-MEP50 효소복합체와 S-아데노실메티오닌을 각각 20 μL, 25 μL씩 분주하였다. 10% 디메틸 술폭시드 용액에 희석한 화합물 5 uL를 첨가하여 실온에서 2 시간동안 반응 시켰다 (최종 부피 = 50 μL). 화합물의 농도는 10 μM에서 1:5로 희석하여 최저 농도 0.128 nM까지 8개 지점을 시험에 사용하였다. 1차 항체를 블로킹 완충액으로 1:2000으로 희석하여 준비한 후, 100 μL를 넣고 실온에서 1시간 동안 반응 시켰다. 호스래디시퍼옥시다아제 결합 항체는 블로킹 완충액으로 1:10,000으로 희석하여 100 μL를 넣고 실온에서 1시간 동안 반응 시킨 후 TMB 기질 100 μL를 넣고 실온에서 3분 동안 반응 시켰고, 이후 1 N 황산 100 μL를 넣고 반응을 종료 시켰다. 그리고, 450 nM에서의 흡광도를 측정하여 화합물의 IC50 값을 계산하였다. (+++: 1 내지 100 nm, ++: 100 초과 내지 1,000 nm, +: 1,000 초과 내지 10,000 nm)Experimental procedure: The histone H4 peptide was diluted with carbonate-bicarbonate buffer and prepared to 100 μg/mL, and then 100 μL was dispensed onto the plate and reacted at 37°C for 1 hour. PRMT5-MEP50 enzyme complex and S-adenosylmethionine were diluted with histone methyltransferase reaction buffer to prepare 5 μg/mL and 2 μM, respectively, and PRMT5-MEP50 enzyme complex and S-adenosylmethionine were added to the prepared plate. Each of 20 μL and 25 μL was dispensed. 5 uL of the diluted compound was added to 10% dimethyl sulfoxide solution and reacted at room temperature for 2 hours (final volume = 50 μL). The concentration of the compound was diluted 1:5 in 10 μM, and 8 points were used for the test until the lowest concentration of 0.128 nM. After preparing the primary antibody by diluting 1:2000 with blocking buffer, 100 μL was added and reacted at room temperature for 1 hour. Horseradish peroxidase-binding antibody was diluted 1:10,000 with blocking buffer, added 100 μL, reacted for 1 hour at room temperature, and then added 100 μL of TMB substrate and reacted for 3 minutes at room temperature, and then 100 μL of 1 N sulfuric acid was added. The reaction was terminated. Then, the absorbance at 450 nM was measured to calculate the IC 50 value of the compound. (+++: 1 to 100 nm, ++: more than 100 to 1,000 nm, +: more than 1,000 to 10,000 nm)

[표 2][Table 2]

Figure pat00046
Figure pat00046

동물체내 타겟 억제능 확인시험Test to confirm target inhibitory ability in animals

종양세포를 누드마우스 피하에 이식한 후, PRMT5 억제제 투여에 의해 종양 내 SDMA 수준이 감소되는 정도를 측정하였다.After the tumor cells were implanted subcutaneously in nude mice, the degree to which the SDMA level in the tumor decreased by administration of a PRMT5 inhibitor was measured.

시약: 브래드포드 용액(카달로그번호 500-0006)은 바이오 라드(Bio-rad, 미국)로부터 구매하였다. SDMA 항체(카달로그번호 13222s)는 셀 시그널링 테그놀로지(Cell signaling Technology, 미국)에서 구매하였다. SmD3 항체(카달로그 번호 ap12451a)와 2차 항체(카달로그 번호 ab6721), TMB 기질(카달로그번호 ab210902)는 에이비캠(Abcam, 영국)에서 구매하였다.Reagent: Bradford solution (catalog number 500-0006) was purchased from Bio-rad (USA). The SDMA antibody (catalog number 13222s) was purchased from Cell signaling Technology (USA). SmD3 antibody (catalog number ap12451a), secondary antibody (catalog number ab6721), and TMB substrate (catalog number ab210902) were purchased from Abcam (UK).

실험절차: 마우스에 이식한 종양 조직을 적출 하여 세포를 용해 시킨 뒤, 브래드포드 용액으로 정량 하였다. 한 샘플당 10 μg의 단백질을 카보네이트-바이카보네이트 완충액으로 희석하여 96웰 플레이트에 분주하여 실온에서 2시간동안 반응 시켰다. 0.05% Tween-20이 함유된 인산완충식염수(PBST)로 3회 세척한 후, 5% 소 혈청 알부민(BSA)이 함유된 PBST(BSA-PBST) 200 μL를 넣고 실온에서 2시간 동안 반응 시켰다. PBST로 3회 세척한 후 SDMA 항체 및 SmD3 항체를 BSA-PBST에 희석하여 각각 100 μL씩 분주하여 4℃에서 하룻밤 동안 반응 시켰다. 다음날 PBST로 3회 세척한 후, BSA-PBST에 희석한 2차 항체 100 μL를 넣고 실온에서 1시간 동안 반응 시켰다. PBST로 3회 세척한 후, TMB 기질 100 μL를 넣고 실온에서 10~20분간 반응 시켰으며 1N 황산용액 100 μL를 추가하여 반응을 종료 시켰다. 그리고 450 nM에서의 흡광도를 측정하여 화합물에 의한 SDMA 저해 정도를 계산하였다. Experimental procedure: The tumor tissue transplanted into the mouse was excised, the cells were lysed, and then quantified with Bradford solution. 10 μg of protein per sample was diluted with carbonate-bicarbonate buffer and dispensed into a 96-well plate, followed by reaction at room temperature for 2 hours. After washing three times with phosphate buffered saline (PBST) containing 0.05% Tween-20, 200 μL of PBST (BSA-PBST) containing 5% bovine serum albumin (BSA) was added and reacted at room temperature for 2 hours. After washing three times with PBST, the SDMA antibody and the SmD3 antibody were diluted in BSA-PBST, and each 100 μL was dispensed and reacted at 4° C. overnight. After washing three times with PBST the next day, 100 μL of the secondary antibody diluted in BSA-PBST was added and reacted at room temperature for 1 hour. After washing three times with PBST, 100 μL of TMB substrate was added and reacted at room temperature for 10 to 20 minutes, and 100 μL of 1N sulfuric acid solution was added to terminate the reaction. And absorbance at 450 nM was measured to calculate the degree of SDMA inhibition by the compound.

Claims (7)

하기 화학식 1의 화합물, 또는 이의 광학 이성질체, 입체 이성질체 또는 약제학적으로 허용되는 염:
[화학식 1]
Figure pat00047


상기 화학식 1에서,
X1 및 X2는 각각 독립적으로 탄소 또는 질소를 나타내고;
Y는 탄소, 산소 또는 질소를 나타내며;
Z는 탄소를 나타내고;
n은 0 또는 1의 정수를 나타내며;
m은 0 내지 2의 정수를 나타내고;
R1은
Figure pat00048
를 나타내며; 여기에서 R9 및 R10은 각각 독립적으로 수소, 알킬, 사이클로알킬, N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 갖는 4원 내지 10원의 헤테로사이클로알킬, 또는 N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 갖는 4원 내지 10원의 헤테로아릴-알킬을 나타내거나; R9 및 R10은 결합하는 N과 함께 N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 갖는 4원 내지 10원의 헤테로사이클로알킬을 형성할 수 있고; 상기 헤테로사이클로알킬 또는 헤테로아릴은 할로, 옥소, 포르밀(-CHO), 알킬, 알콕시, 알킬카르보닐, 알콕시카르보닐, 디알킬아미노, 및 N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 갖는 4원 내지 10원의 헤테로사이클로알킬로부터 선택되는 하나 이상의 치환기로 치환될 수 있고;
R2는 수소 또는 알킬을 나타내며;
R3는 수소 또는 알킬을 나타내거나; m이 2일 경우 결합하는 C와 함께 사이클로알킬을 형성할 수 있고;
R4, R5, R6 및 R7은 각각 독립적으로 수소 또는 알킬을 나타내며;
R8은 수소, 할로, 알킬, 알콕시 또는 아미노를 나타낸다.
A compound of Formula 1, or an optical isomer, stereoisomer or pharmaceutically acceptable salt thereof:
[Formula 1]
Figure pat00047


In Formula 1,
X 1 and X 2 each independently represent carbon or nitrogen;
Y represents carbon, oxygen or nitrogen;
Z represents carbon;
n represents an integer of 0 or 1;
m represents an integer of 0 to 2;
R 1 is
Figure pat00048
Represents; Wherein R 9 and R 10 are each independently selected from hydrogen, alkyl, cycloalkyl, 4 to 10 membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, or N, O and S Or 4 to 10 membered heteroaryl-alkyl having one or more heteroatoms; R 9 and R 10 together with the N to which they are attached may form a 4-10 membered heterocycloalkyl having one or more heteroatoms selected from N, O and S; The heterocycloalkyl or heteroaryl has one or more heteroatoms selected from halo, oxo, formyl (-CHO), alkyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, dialkylamino, and N, O and S. May be substituted with one or more substituents selected from 4-10 membered heterocycloalkyl;
R 2 represents hydrogen or alkyl;
R 3 represents hydrogen or alkyl; When m is 2, it may form a cycloalkyl with C to which it is bonded;
R 4 , R 5 , R 6 and R 7 each independently represent hydrogen or alkyl;
R 8 represents hydrogen, halo, alkyl, alkoxy or amino.
 제1항에 있어서,
X1 및 X2는 각각 독립적으로 CH 또는 N을 나타내고;
Y는 n이 0일 경우 CH2, O 또는 NH를 나타내며, n이 1일 경우 CH 또는 N을 나타내고;
Z는 m이 0일 경우 CH2 또는 CH를 나타내며, m이 1일 경우 CH 또는 C를 나타내고, m이 2일 경우 C를 나타내며;
R1은
Figure pat00049
를 나타내고; 여기에서 R9 및 R10은 각각 독립적으로 수소, C1-C7 알킬, C3-C7 사이클로알킬, N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 갖는 4원 내지 8원의 헤테로사이클로알킬, 또는 N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 갖는 4원 내지 8원의 헤테로아릴-C1-C7 알킬을 나타내며; 상기 헤테로사이클로알킬 또는 헤테로아릴은 할로, 옥소, 포르밀(-CHO), C1-C7 알킬, C1-C7 알콕시, C1-C7 알킬카르보닐, C1-C7 알콕시카르보닐, 디(C1-C7 알킬)아미노, 및 N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 갖는 4원 내지 8원의 헤테로사이클로알킬로부터 선택되는 1개 내지 3개의 치환기로 치환될 수 있고;
R2는 수소 또는 C1-C7 알킬을 나타내며;
R3는 수소 또는 C1-C7 알킬을 나타내거나; m이 2일 경우 결합하는 C와 함께 C3-C7 사이클로알킬을 형성할 수 있고;
R4, R5, R6 및 R7은 각각 독립적으로 수소 또는 C1-C7 알킬을 나타내며;
R8은 수소, 할로, C1-C7 알킬, C1-C7 알콕시 또는 아미노를 나타내는,
화합물, 또는 이의 광학 이성질체, 입체 이성질체 또는 약제학적으로 허용되는 염.
The method of claim 1,
X 1 and X 2 each independently represent CH or N;
Y represents CH 2 , O or NH when n is 0, and CH or N when n is 1;
Z represents CH 2 or CH when m is 0, CH or C when m is 1, and C when m is 2;
R 1 is
Figure pat00049
Represents; Wherein R 9 and R 10 are each independently a 4 to 8 membered heterocyclo having one or more heteroatoms selected from hydrogen, C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, N, O and S. Alkyl or 4 to 8 membered heteroaryl-C 1 -C 7 alkyl having one or more heteroatoms selected from N, O and S; The heterocycloalkyl or heteroaryl is halo, oxo, formyl (-CHO), C 1 -C 7 alkyl, C 1 -C 7 alkoxy, C 1 -C 7 alkylcarbonyl, C 1 -C 7 alkoxycarbonyl , Di(C 1 -C 7 alkyl) amino, and 4 to 8 membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, and may be substituted with 1 to 3 substituents, ;
R 2 represents hydrogen or C 1 -C 7 alkyl;
R 3 represents hydrogen or C 1 -C 7 alkyl; When m is 2, C 3 -C 7 cycloalkyl may be formed with C to which it is bonded;
R 4 , R 5 , R 6 and R 7 each independently represent hydrogen or C 1 -C 7 alkyl;
R 8 represents hydrogen, halo, C 1 -C 7 alkyl, C 1 -C 7 alkoxy or amino,
A compound, or an optical isomer, stereoisomer or pharmaceutically acceptable salt thereof.
 제1항에 있어서,
X1 및 X2는 각각 독립적으로 CH 또는 N을 나타내고;
Y는 n이 0일 경우 CH2, O 또는 NH를 나타내며, n이 1일 경우 CH 또는 N을 나타내고;
Z는 m이 0일 경우 CH2 또는 CH를 나타내며, m이 1일 경우 CH 또는 C를 나타내고, m이 2일 경우 C를 나타내며;
R1은
Figure pat00050
를 나타내고; 여기에서 R9 및 R10은 결합하는 N과 함께 N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 갖는 4원 내지 8원의 헤테로사이클로알킬을 형성하며; 상기 헤테로사이클로알킬은 할로, 옥소, 포르밀(-CHO), C1-C7 알킬, C1-C7 알콕시, C1-C7 알킬카르보닐, C1-C7 알콕시카르보닐, 디(C1-C7 알킬)아미노, 및 N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 갖는 4원 내지 8원의 헤테로사이클로알킬로부터 선택되는 1개 내지 3개의 치환기로 치환될 수 있고;
R2는 수소 또는 C1-C7 알킬을 나타내며;
R3는 수소 또는 C1-C7 알킬을 나타내거나; m이 2일 경우 결합하는 C와 함께 C3-C7 사이클로알킬을 형성할 수 있고;
R4, R5, R6 및 R7은 각각 독립적으로 수소 또는 C1-C7 알킬을 나타내며;
R8은 수소, 할로, C1-C7 알킬, C1-C7 알콕시 또는 아미노를 나타내는,
화합물, 또는 이의 광학 이성질체, 입체 이성질체 또는 약제학적으로 허용되는 염.
The method of claim 1,
X 1 and X 2 each independently represent CH or N;
Y represents CH 2 , O or NH when n is 0, and CH or N when n is 1;
Z represents CH 2 or CH when m is 0, CH or C when m is 1, and C when m is 2;
R 1 is
Figure pat00050
Represents; Wherein R 9 and R 10 together with N to which they are attached form a 4 to 8 membered heterocycloalkyl having one or more heteroatoms selected from N, O and S; The heterocycloalkyl is halo, oxo, formyl (-CHO), C 1 -C 7 alkyl, C 1 -C 7 alkoxy, C 1 -C 7 alkylcarbonyl, C 1 -C 7 alkoxycarbonyl, di( C 1 -C 7 alkyl) amino, and 4 to 8 membered heterocycloalkyl having one or more heteroatoms selected from N, O and S;
R 2 represents hydrogen or C 1 -C 7 alkyl;
R 3 represents hydrogen or C 1 -C 7 alkyl; When m is 2, C 3 -C 7 cycloalkyl may be formed with C to which it is bonded;
R 4 , R 5 , R 6 and R 7 each independently represent hydrogen or C 1 -C 7 alkyl;
R 8 represents hydrogen, halo, C 1 -C 7 alkyl, C 1 -C 7 alkoxy or amino,
A compound, or an optical isomer, stereoisomer or pharmaceutically acceptable salt thereof.
 제2항에 있어서, 다음의 화합물로부터 선택되는 화합물, 또는 이의 광학 이성질체, 입체 이성질체 또는 약제학적으로 허용되는 염:
7-(사이클로헥실아미노)-2-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-4,5-다이하이드로-3H-2-벤즈아제핀-1-온;
8-(사이클로프로필아미노)-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온;
8-(사이클로헥실아미노)-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온;
8-[사이클로헥실(메틸)아미노]-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온;
4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-8-[메틸(테트라하이드로피란-4-일)아미노]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온;
8-[(1-아세틸-4-피페리딜)아미노]-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온;
4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-8-[(3-플루오로-4-피리딜)메틸아미노]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온;
4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-8-[(5-플루오로-2-피리딜)메틸아미노]-2,2-다이메틸-3H-1,4-벤즈옥사제핀-5-온;
tert-부틸 4-[[4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-5-옥소-2,3-다이하이드로-1,4-벤조디아제핀-8-일]아미노]피페리딘-1-카르복실레이트;
tert-부틸 3-[[4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-5-옥소-2,3-다이하이드로-1,4-벤조디아제핀-8-일]아미노]피페리딘-1-카르복실레이트;
4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-8-(3-피페리딜아미노)-2,3-다이하이드로-1,4-벤조디아제핀-5-온;
8-[(1-아세틸-4-피페리딜)아미노]-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-2,3-다이하이드로-1,4-벤조디아제핀-5-온; 및
8-[(1-아세틸-3-피페리딜)아미노]-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-2,3-다이하이드로-1,4-벤조디아제핀-5-온.
The compound according to claim 2, selected from the following compounds, or optical isomers, stereoisomers or pharmaceutically acceptable salts thereof:
7-(cyclohexylamino)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro- 3H-2-benzazepin-1-one;
8-(cyclopropylamino)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro- 1,4-benzoxazepin-5-one;
8-(cyclohexylamino)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro- 1,4-benzoxazepin-5-one;
8-[cyclohexyl(methyl)amino]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3- Dihydro-1,4-benzoxazepin-5-one;
4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[methyl(tetrahydropyran-4-yl)amino] -2,3-dihydro-1,4-benzoxazepin-5-one;
8-[(1-acetyl-4-piperidyl)amino]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl ]-2,3-dihydro-1,4-benzoxazepin-5-one;
4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-4-pyridyl)methyl Amino]-2,3-dihydro-1,4-benzoxazepin-5-one;
4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(5-fluoro-2-pyridyl)methyl Amino]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one;
tert-Butyl 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-5-oxo- 2,3-dihydro-1,4-benzodiazepin-8-yl]amino]piperidine-1-carboxylate;
tert-Butyl 3-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-5-oxo- 2,3-dihydro-1,4-benzodiazepin-8-yl]amino]piperidine-1-carboxylate;
4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(3-piperidylamino)- 2,3-dihydro-1,4-benzodiazepin-5-one;
8-[(1-acetyl-4-piperidyl)amino]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl ]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one; And
8-[(1-acetyl-3-piperidyl)amino]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl ]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one.
 제3항에 있어서, 다음의 화합물로부터 선택되는 화합물, 또는 이의 광학 이성질체, 입체 이성질체 또는 약제학적으로 허용되는 염:
2-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-7-모르폴리노-4,5-다이하이드로-3H-2-벤즈아제핀-1-온;
4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-8-모르폴리노-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온;
8-(아제티딘-1-일)-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온;
4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-8-(3-메톡시아제티딘-1-일)-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온;
8-(4-아세틸피페라진-1-일)-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온;
4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-8-(4-메틸-3-옥소-피페라진-1-일)-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온;
4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-8-[4-(옥세탄-3-일)피페라진-1-일]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온;
4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-8-[4-(다이메틸아미노)-1-피페리딜]-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온;
4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-2,2-다이메틸-8-모르폴리노-3H-1,4-벤즈옥사제핀-5-온;
4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-2,2-다이메틸-8-피롤리딘-1-일-3H-1,4-벤즈옥사제핀-5-온;
8-(아제티딘-1-일)-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-2,2-다이메틸-3H-1,4-벤즈옥사제핀-5-온;
8-(4-아세틸피페라진-1-일)-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-2,2-다이메틸-3H-1,4-벤즈옥사제핀-5-온;
4-[4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-2,2-다이메틸-5-옥소-3H-1,4-벤즈옥사제핀-8-일]피페라진-1-카브알데하이드;
4-[4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-5-옥소-스파이로[3H-1,4-벤즈옥사제핀e-2,1'-사이클로부탄]-8-일]피페라진e-1-카브알데하이드;
4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-8-(4-메틸-3-옥소-피페라진-1-일)-2,3-다이하이드로-1,4-벤조디아제핀-5-온;
tert-부틸 4-[4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-5-옥소-2,3-다이하이드로-1,4-벤조디아제핀-8-일]피페라진-1-카르복실레이트
4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-8-피페라진-1-일-2,3-다이하이드로-1,4-벤조디아제핀-5-온;
8-(4-아세틸피페라진-1-일)-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-2,3-다이하이드로-1,4-벤조디아제핀-5-온;
4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-8-[4-(다이메틸아미노)-1-피페리딜]-1-메틸-2,3-다이하이드로-1,4-벤조디아제핀-5-온;
4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-8-(2-옥소피롤리딘-1-일)-2,3-다이하이드로-1,4-벤조디아제핀-5-온;
4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시-프로필]-1-메틸-8-(2-메틸-5-옥소-피롤리딘-1-일)-2,3-다이하이드로-1,4-벤조디아제핀-5-온;
4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시프로필]-2-메틸-8-모르폴리노-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온;
8-(4-아세틸피페라진-1-일)-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시프로필]-2-메틸-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온;
(2R)-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시프로필]-2-메틸-8-모르폴리노-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온; 및
(2S)-8-(4-아세틸피페라진-1-일)-4-[(2R)-3-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-하이드록시프로필]-2-메틸-2,3-다이하이드로-1,4-벤즈옥사제핀-5-온.
The compound according to claim 3, selected from the following compounds, or optical isomers, stereoisomers or pharmaceutically acceptable salts thereof:
2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-morpholino-4,5-dihydro-3H- 2-benzazepin-1-one;
4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-morpholino-2,3-dihydro-1, 4-benzoxazepin-5-one;
8-(azetidin-1-yl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3- Dihydro-1,4-benzoxazepin-5-one;
4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-methoxyazetidin-1-yl)- 2,3-dihydro-1,4-benzoxazepin-5-one;
8-(4-acetylpiperazin-1-yl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2 ,3-dihydro-1,4-benzoxazepin-5-one;
4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-methyl-3-oxo-piperazine-1 -Yl)-2,3-dihydro-1,4-benzoxazepin-5-one;
4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[4-(oxetan-3-yl)piperazine -1-yl]-2,3-dihydro-1,4-benzoxazepin-5-one;
4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[4-(dimethylamino)-1-piperi Dill]-2,3-dihydro-1,4-benzoxazepin-5-one;
4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-morpholino-3H- 1,4-benzoxazepin-5-one;
4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-pyrrolidine-1- Yl-3H-1,4-benzoxazepin-5-one;
8-(azetidin-1-yl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2- Dimethyl-3H-1,4-benzoxazepin-5-one;
8-(4-acetylpiperazin-1-yl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2 ,2-dimethyl-3H-1,4-benzoxazepin-5-one;
4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H -1,4-benzoxazepin-8-yl]piperazine-1-carbaldehyde;
4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-spiro[3H-1,4 -Benzoxazepine e-2,1'-cyclobutane]-8-yl]piperazine e-1-carbaldehyde;
4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(4-methyl-3-oxo- Piperazin-1-yl)-2,3-dihydro-1,4-benzodiazepin-5-one;
tert-Butyl 4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-5-oxo-2 ,3-dihydro-1,4-benzodiazepin-8-yl]piperazine-1-carboxylate
4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-piperazin-1-yl-2, 3-dihydro-1,4-benzodiazepin-5-one;
8-(4-acetylpiperazin-1-yl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1 -Methyl-2,3-dihydro-1,4-benzodiazepin-5-one;
4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[4-(dimethylamino)-1-piperi Diyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one;
4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(2-oxopyrrolidine-1 -Yl)-2,3-dihydro-1,4-benzodiazepin-5-one;
4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(2-methyl-5-oxo- Pyrrolidin-1-yl)-2,3-dihydro-1,4-benzodiazepin-5-one;
4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-morpholino-2,3-dihydro -1,4-benzoxazepin-5-one;
8-(4-acetylpiperazin-1-yl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2- Methyl-2,3-dihydro-1,4-benzoxazepin-5-one;
(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-morpholino-2, 3-dihydro-1,4-benzoxazepin-5-one; And
(2S)-8-(4-acetylpiperazin-1-yl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl ]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one.
 유효성분으로서 치료학적 유효량의 제1항 내지 제5항 중 어느 한 항에 따른 화학식 1의 화합물, 또는 이의 광학 이성질체, 입체 이성질체 또는 약제학적으로 허용되는 염을 약제학적으로 허용되는 담체와 함께 포함하는, PRMT5 저해와 관련된 질병의 예방 또는 치료용 약제학적 조성물.
Comprising a therapeutically effective amount of a compound of Formula 1 according to any one of claims 1 to 5 as an active ingredient, or an optical isomer, stereoisomer, or pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. , A pharmaceutical composition for preventing or treating diseases associated with PRMT5 inhibition.
 제6항에 있어서, PRMT5 저해와 관련된 질병이 암, 혈액 질환, 자가면역질환, 염증성 질환및 신경퇴행성 질환으로부터 선택되는 것인 약제학적 조성물.
The pharmaceutical composition according to claim 6, wherein the disease associated with PRMT5 inhibition is selected from cancer, blood diseases, autoimmune diseases, inflammatory diseases and neurodegenerative diseases.
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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2022206964A1 (en) * 2021-04-02 2022-10-06 海思科医药集团股份有限公司 Prmt5 inhibitor and use thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022206964A1 (en) * 2021-04-02 2022-10-06 海思科医药集团股份有限公司 Prmt5 inhibitor and use thereof

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