KR101122376B1

KR101122376B1 - Novel 5,6-dimethylpyrimidine derivatives and processes for the preparation thereof

Info

Publication number: KR101122376B1
Application number: KR1020050019502A
Authority: KR
Inventors: 박찬선; 윤영애; 김재규; 윤석원; 이혁우; 안병락; 최현호; 강희일
Original assignee: 주식회사유한양행
Priority date: 2005-03-09
Filing date: 2005-03-09
Publication date: 2012-03-26
Also published as: KR20060098908A

Abstract

본 발명은 위산분비 억제효과가 우수한 하기 화학식 1의 5,6-다이메틸피리미딘 유도체 또는 이의 약제학적으로 허용되는 염, 및 이의 제조방법 및 이를 함유하는 약제학적 조성물에 관한 것이다.The present invention relates to a 5,6-dimethylpyrimidine derivative of Formula 1 having excellent gastric acid secretion inhibitory effect or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition containing the same.

화학식 1Formula 1

상기 식에서, Where

R₁, R₂, R₃, R₄, R₅ 및 R₆는 각각 상세한 설명에 정의된 바와 같다.R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are each as defined in the detailed description.

피리미딘, 항궤양제, 프로톤 펌프, 위산분비 Pyrimidine, antiulcer, proton pump, gastric acid secretion

Description

신규의 5,6-다이메틸피리미딘 유도체 및 그의 제조방법 {Novel 5,6-dimethylpyrimidine derivatives and processes for the preparation thereof}Novel 5,6-dimethylpyrimidine derivatives and processes for the preparation thereof

본 발명은 위산분비 억제효과가 우수한 신규의 5,6-다이메틸피리미딘 유도체 또는 이의 약제학적으로 허용되는 염, 및 이의 제조방법 및 이를 함유하는 약제학적 조성물에 관한 것이다.The present invention relates to a novel 5,6-dimethylpyrimidine derivative or a pharmaceutically acceptable salt thereof having excellent gastric acid secretion inhibitory effect, a preparation method thereof, and a pharmaceutical composition containing the same.

소화성 궤양은 위산의 분비와 관련된 공격인자가 강하거나 위장 점막의 방어인자가 약할 때 발생한다. 소화성 궤양의 치료를 위해서 사용되고 있는 종래의 약물로는 제산제, 항콜린성 약물, 위벽세포 보호약물, H₂-수용체 길항제의 개발을 거쳐 프로톤 펌프 저해제가 있다. 프로톤 펌프 저해제의 약물로 오메프라졸(Omeprazole)이 개발되어 위산 생성의 최종단계를 차단하는 독특한 작용기전을 바탕으로 현재 소화성 궤양 환자의 치료에 가장 널리 사용되고 있다. Peptic ulcers occur when the attackers associated with the secretion of gastric acid are strong or when the gastrointestinal mucosa is weak. Conventional drugs used for the treatment of peptic ulcers include proton pump inhibitors through the development of antacids, anticholinergic drugs, gastric cell protective drugs, and H ₂ -receptor antagonists. Omeprazole has been developed as a drug for proton pump inhibitors and is currently widely used in the treatment of peptic ulcer patients based on its unique mechanism of action that blocks the final stage of gastric acid production.

그러나, 오메프라졸은 프로톤 펌프 저해작용이 비가역적인 작용기전이므로 장기간 위내의 위산분비 억제상태를 초래하여 부작용 유발 가능성에 대한 문제점이 제기되고 있어, 이를 극복하는 가역적인 프로톤 펌프 저해제를 개발하려는 시도가 활발히 행해지고 있다. 예를 들면, 가역적인 프로톤 펌프 억제제로서 이미다조피리딘 유도체가 WO 제98/37080호(AstraZeneca AB), WO 제00/17200호(Byk Gulden Lomberg Chem.) 및 미국특허 제4,450,164호(Schering Corporation)에 공지된 바 있다. 이외에 피리미딘 유도체가 유럽특허 제0,775,120호(Yuhan Corp.)에 공지된 바 있다. However, since omeprazole is an irreversible mechanism of action of proton pump, there is a problem about the possibility of causing side effects by causing gastric acid secretion inhibition in the stomach for a long time, and attempts to develop a reversible proton pump inhibitor to overcome this are actively made. have. For example, imidazopyridine derivatives as reversible proton pump inhibitors are disclosed in WO 98/37080 (AstraZeneca AB), WO 00/17200 (Byk Gulden Lomberg Chem.) And US Pat. No. 4,450,164 (Schering Corporation). It is known. In addition, pyrimidine derivatives are known from European Patent No. 0,775,120 (Yuhan Corp.).

본 발명자들은 가역적인 프로톤 펌프 저해제를 개발하고자 많은 연구를 거듭한 결과, 신규의 5,6-다이메틸피리미딘 유도체가 프로톤 펌프 억제효과가 뛰어나고 위산분비 억제력이 우수할 뿐만 아니라 가역적인 프로톤 펌프 억제 효과의 작용기전을 갖는다는 것을 발견하여 본 발명을 완성하게 되었다. The present inventors have conducted a lot of research to develop a reversible proton pump inhibitor, the new 5,6-dimethylpyrimidine derivative is not only excellent proton pump inhibitory effect, gastric acid secretion inhibitory effect, but also reversible proton pump inhibitory effect The present invention has been found to have a mechanism of action.

본 발명의 목적은 우수한 위산분비 억제효과를 가지는 신규의 5,6-다이메틸피리미딘 유도체 또는 이의 약제학적으로 허용되는 염을 제공하는 것이다.An object of the present invention is to provide a novel 5,6-dimethylpyrimidine derivative or a pharmaceutically acceptable salt thereof having excellent gastric acid secretion inhibitory effect.

또한, 본 발명의 목적은 신규의 5,6-다이메틸피리미딘 유도체 또는 이의 약제학적으로 허용되는 염의 제조방법을 제공하는 것이다.It is also an object of the present invention to provide a method for preparing a novel 5,6-dimethylpyrimidine derivative or a pharmaceutically acceptable salt thereof.

또한, 본 발명의 목적은 신규의 5,6-다이메틸피리미딘 유도체 또는 이들의 약제학적으로 허용되는 염을 유효성분으로 함유하는 위산분비 억제 조성물을 제공하는 것이다.It is also an object of the present invention to provide a gastric acid secretion inhibiting composition containing a novel 5,6-dimethylpyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

상기 목적에 따라, 본 발명에서는 하기 화학식 1로 표시되는 5,6-다이메틸피리미딘 유도체 또는 이의 약제학적으로 허용되는 염을 제공한다:In accordance with the above object, the present invention provides a 5,6-dimethylpyrimidine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

상기에서From above

R₁은 수소 또는 C_1-5 알킬이고;R ₁ is hydrogen or C _1-5 alkyl;

R₂는 수소 또는 C_1-5 알킬이고;R ₂ is hydrogen or C _1-5 alkyl;

R₃는 수소, 할로겐, C_1-5 알킬 또는 C_1-5 알콕시이고; R ₃ is hydrogen, halogen, C _1-5 alkyl or C _1-5 alkoxy;

R₄ 및 R₅는 서로 독립적으로 수소, 할로겐, C_1-5 알킬, 하이드록시, C_1-5 알콕시 또는 아미노이거나, 임의적으로 서로 융합하여 (CH₂)n 고리를 형성하거나(여기서 n은 2 내지 5의 정수이다), 또는 임의적으로 서로 융합하여 이중결합을 이루어

또는

(여기서 R´은 수소 또는 C_1-5 알킬이다)를 형성할 수 있고; 및R ₄ and R ₅ are independently of each other hydrogen, halogen, C _1-5 alkyl, hydroxy, C _1-5 alkoxy or amino, or optionally fuse with each other to form a (CH ₂ ) n ring, wherein n is 2 To an integer of 5), or optionally fused with each other to form a double bond.

or

Wherein R 'is hydrogen or C _1-5 alkyl; And

R₆는 단일 또는 이치환기로서 수소, 할로겐, C_1-5 알킬 또는 C_1-5 알콕시이고,R ₆ is hydrogen, halogen, C _1-5 alkyl or C _1-5 alkoxy as a single or disubstituted group,

상기에서 R₁, R₂, R₃, R₄, R₅ 및 R₆ 로서의 알킬 및 알콕시는 임의적으로 하 나 이상의 할로겐으로 치환될 수 있다. Alkyl and alkoxy as R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R _{6 in the} above may optionally be substituted with one or more halogens.

화학식 1로 표시되는 본 발명에 따른 화합물은 광학 이성질체 즉, (R)형, (S)형, 또는 이들의 혼합물의 형태로 존재할 수 있으며, 이들은 각각 우수한 위산분비억제효과를 가진다. 따라서, 본 발명은 이러한 광학 이성질체를 포함한다.The compounds according to the present invention represented by the formula (1) may exist in the form of optical isomers, namely (R), (S), or mixtures thereof, each having an excellent gastric acid secretion inhibitory effect. Thus, the present invention includes such optical isomers.

본 발명에 따른 화학식 1의 화합물은 바람직하게 하기 화합물들을 포함한다:The compound of formula 1 according to the invention preferably comprises the following compounds:

2-(4-플루오로벤질)-4-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(1-메틸-3,4-다이하이드로-6-플루오로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (1-methyl-3,4-dihydro-6-fluoro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(1(R)-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (1 (R) -methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(1(S)-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (1 (S) -methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(1,4-다이메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (1,4-dimethyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(1-트라이플루오로메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (1-trifluoromethyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(7-클로로-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (7-chloro-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(5-클로로-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (5-chloro-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(7-메톡시-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (7-methoxy-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(1,8-다이메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (1,8-dimethyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(1,6-다이메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (1,6-dimethyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(6-메톡시-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (6-methoxy-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(1,7-다이메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (1,7-dimethyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(7-플루오로-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (7-fluoro-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(3-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (3-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(6-클로로-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (6-chloro-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(1-에틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (1-ethyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(7-플루오로-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (7-fluoro-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(7-클로로-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (7-chloro-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(2-플루오로벤질)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (2-fluorobenzyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(3-클로로벤질)-4-(6-플루오로-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (3-chlorobenzyl) -4- (6-fluoro-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-클로로벤질)-4-(1(R)-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-chlorobenzyl) -4- (1 (R) -methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-클로로벤질)-4-(1(S)-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-chlorobenzyl) -4- (1 (S) -methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

5,6-다이메틸-2-(1-페닐에틸)-4-(1(R)-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘 염산염;5,6-dimethyl-2- (1-phenylethyl) -4- (1 (R) -methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -pyrimidine hydrochloride;

5,6-다이메틸-2-(1-페닐에틸)-4-(1,6-다이메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘 염산염;5,6-dimethyl-2- (1-phenylethyl) -4- (1,6-dimethyl-3,4-dihydro-1 H -isoquinolin-2-yl) -pyrimidine hydrochloride;

5,6-다이메틸-2-(1-페닐에틸)-4-(1,7-다이메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘 염산염;5,6-dimethyl-2- (1-phenylethyl) -4- (1,7-dimethyl-3,4-dihydro-1 H -isoquinolin-2-yl) -pyrimidine hydrochloride;

[1-(4-플루오로페닐)-1-메틸-에틸]-5,6-다이메틸-4-(1,6-다이메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘 염산염;[1- (4-Fluorophenyl) -1-methyl-ethyl] -5,6-dimethyl-4- (1,6-dimethyl-3,4-dihydro-1 H -isoquinoline-2- Yl) -pyrimidine hydrochloride;

2-[1-(4-플루오로페닐)-사이클로프로필]-5,6-다이메틸-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘 염산염;2- [1- (4-Fluorophenyl) -cyclopropyl] -5,6-dimethyl-4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -pyri Midine hydrochloride;

2-[1-(4-플루오로페닐)-사이클로프로필]-5,6-다이메틸-4-(1,6-다이메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘 염산염;2- [1- (4-fluorophenyl) -cyclopropyl] -5,6-dimethyl-4- (1,6-dimethyl-3,4-dihydro-1 H -isoquinolin-2-yl ) -Pyrimidine hydrochloride;

5,6-다이메틸-2-(1-페닐프로필)-4-(1(S)-메틸-1,2,3,4-테트라하이드로아이소퀴놀린-2-일)-피리미딘 염산염;5,6-dimethyl-2- (1-phenylpropyl) -4- (1 (S) -methyl-1,2,3,4-tetrahydroisoquinolin-2-yl) -pyrimidine hydrochloride;

2-(2-플루오로벤질)-4-(6-클로로-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (2-fluorobenzyl) -4- (6-chloro-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(3-플루오로벤질)-4-(6-클로로-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (3-fluorobenzyl) -4- (6-chloro-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-메틸벤질)-4-(6-클로로-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-methylbenzyl) -4- (6-chloro-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-트라이플루오로메틸벤질)-4-(6-클로로-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-trifluoromethylbenzyl) -4- (6-chloro-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride ;

2-(4-트라이플루오로메톡시벤질)-4-(6-클로로-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-trifluoromethoxybenzyl) -4- (6-chloro-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride ;

2-(2-클로로벤질)-4-(6-클로로-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (2-chlorobenzyl) -4- (6-chloro-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-페닐메틸-5,6-다이메틸피리미딘 염산염;4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -2-phenylmethyl-5,6-dimethylpyrimidine hydrochloride;

2-(4-트라이플루오로메틸벤조일)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-trifluoromethylbenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤조일)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-벤조일-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2-benzoyl-4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(2-메틸벤조일)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (2-methylbenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-클로로벤조일)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-chlorobenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(2,4-다이플루오로벤조일)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (2,4-difluorobenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(2-플루오로벤조일)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (2-fluorobenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(2-클로로벤조일)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (2-chlorobenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-메틸벤조일)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-methylbenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로페닐-하이드록시이미노)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘;2- (4-fluorophenyl-hydroxyimino) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine;

2-(4-플루오로페닐-메톡시이미노)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorophenyl-methoxyimino) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-[4-플루오로페닐-(2-하이드록시에틸)]-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- [4-fluorophenyl- (2-hydroxyethyl)]-4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyri Midine hydrochloride;

2-[1-(4-플루오로페닐)-1-메톡시-에틸]-5,6-다이메틸-2-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘 염산염;2- [1- (4-fluorophenyl) -1-methoxy-ethyl] -5,6-dimethyl-2- (1-methyl-3,4-dihydro-1 H -isoquinoline-2- Yl) -pyrimidine hydrochloride;

2-[4-플루오로페닐-하이드록시메틸]-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- [4-fluorophenyl-hydroxymethyl] -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-[(4-플루오로페닐)-메톡시-메틸]-5,6-다이메틸-2-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘 염산염;2-[(4-Fluorophenyl) -methoxy-methyl] -5,6-dimethyl-2- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -pyri Midine hydrochloride;

2-[다이플루오로-(4-플루오로페닐)-메틸]-5,6-다이메틸-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘 염산염;2- [difluoro- (4-fluorophenyl) -methyl] -5,6-dimethyl-4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl)- Pyrimidine hydrochloride;

1-[5,6-다이메틸-6-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘-2-일]-1-(4-플루오로페닐)-에틸아민 염산염;1- [5,6-dimethyl-6- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -pyrimidin-2-yl] -1- (4-fluoro Phenyl) -ethylamine hydrochloride;

2-[4-플루오로페닐-아미노메틸]-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- [4-fluorophenyl-aminomethyl] -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤조일)-4-(1,6-다이메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzoyl) -4- (1,6-dimethyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-[4-플루오로페닐-하이드록시메틸]-4-(1,6-다이메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- [4-fluorophenyl-hydroxymethyl] -4- (1,6-dimethyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine Hydrochloride;

2-[플루오로-(4-플루오로페닐)-메틸]-4-(1,6-다이메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- [fluoro- (4-fluorophenyl) -methyl] -4- (1,6-dimethyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-di Methylpyrimidine hydrochloride;

화학식 1로 표시되는 본 발명에 따른 신규의 5,6-다이메틸피리미딘 유도체는 약제학적으로 허용되는 염의 형태일 수 있으며, 그 염으로는 항궤양제 분야에서 통상적으로 사용가능한 무독성 염, 예를 들면, 비독성 무기산 또는 유기산으로부터 생성된 염의 형태일 수 있다. 이러한 통상적인 무독성 염에는 염산, 브롬화수소산, 황산, 설폰산, 설팜산, 인산 또는 질산과 같은 무기산으로부터 유도된 염 및 아세트산, 프로피온산, 석신산, 글라이콜산, 스테아르산, 시트르산, 말레산, 말론산, 메테인설폰산, 타타르산, 하이드록시말레산, 페닐아세트산, 글루탐산, 벤조산, 살리실산, 2-아세톡시-벤조산, 퓨마르산, 톨루엔설폰산, 옥살산 또는 트라이플루오로아세트산과 같은 유기산으로부터 제조된 염 등을 포함한다. 일반적으로, 염은 유기 염기를 화학양론적 양 또는 과량의 목적하는 염-형성 무기산 또는 유기산과 적합한 용매 또는 용매들의 다양한 배합물 중에서 반응시켜 제조할 수 있다.The novel 5,6-dimethylpyrimidine derivatives according to the invention represented by formula (1) may be in the form of pharmaceutically acceptable salts, which include non-toxic salts commonly used in the field of anti-ulcers, for example For example, it may be in the form of salts generated from non-toxic inorganic or organic acids. Such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acid, sulfamic acid, phosphoric acid or nitric acid and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, citric acid, maleic acid, mal Salts prepared from organic acids such as lonic acid, methanesulfonic acid, tartaric acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, oxalic acid or trifluoroacetic acid And the like. In general, salts may be prepared by reacting an organic base in a stoichiometric amount or in excess of the desired salt-forming inorganic or organic acid with a suitable solvent or various combinations of solvents.

본 발명의 화학식 1의 화합물은 하기 반응식 1에 나타낸 바와 같이, 화학식 2의 화합물과 화학식 3의 화합물을 치환 반응시켜 제조할 수 있다:Compounds of formula 1 of the present invention can be prepared by substitution reaction of the compound of formula 2 with the compound of formula 3, as shown in Scheme 1 below:

상기 식에서In the above formula

R₁, R₂, R₃, R₄, R₅ 및 R₆은 상기에서 정의한 것과 동일하고, X는 할로겐을 나타낸다. R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are the same as defined above, and X represents halogen.

상기 반응식 1에서, 화학식 2의 화합물을 화학식 3의 화합물과 친핵성 방향족 치환반응을 시켜 화학식 1의 화합물을 제조할 수 있다. 이때 사용가능한 염기로는 트라이에틸아민, 소듐하이드라이드, tert-뷰톡시화칼륨, 탄산나트륨, 수산화칼륨 등이 바람직하며, 용매로는 무수테트라하이드로퓨란, N,N-다이메틸포름아마이드 등이 바람직하다. 반응온도는 실온 또는 가온의 조건 (50℃ ~ 150℃)에서 반응시키는 것이 바람직하다. In Scheme 1, the compound of Formula 2 may be prepared by nucleophilic aromatic substitution reaction of the compound of Formula 2 with the compound of Formula 3. The base usable here is preferably triethylamine, sodium hydride, tert-butoxylated potassium, sodium carbonate, potassium hydroxide, and the like, and the solvent is preferably anhydrous tetrahydrofuran, N, N-dimethylformamide, or the like. It is preferable to make reaction temperature react on the condition of room temperature or heating (50 degreeC-150 degreeC).

상기 반응식 1에서, 화학식 3의 화합물은 공지의 방법을 응용하여 용이하게 제조할 수 있으며(EP 230871, J. Org. Chem., 1991, 56, 6034, WO 제97/042186호, WO 제98/018784호), 화학식 2의 화합물은 화학식 4의 화합물을 출발물질로 아미딘 합성 반응을 수행하여 화학식 5의 화합물을 제조한 후, 화학식 5의 화합물을 화학식 6의 화합물과 고리화 반응시켜 화학식 7의 화합물을 제조한 후, 화학식 7의 화합물을 할로겐화 반응시켜 제조할 수 있으며, 이를 반응식으로 나타내면 하기 반응식 2와 같다:In Scheme 1, the compound of Formula 3 may be easily prepared by applying a known method (EP 230871, J. Org. Chem., 1991, 56, 6034, WO 97/042186, WO 98 / 018784), the compound of Formula 2 is prepared by the amidine synthesis reaction of the compound of Formula 4 as a starting material to prepare a compound of Formula 5, and then the compound of Formula 5 is cyclized with the compound of Formula 6 After preparing the compound, the compound of Chemical Formula 7 may be prepared by halogenation reaction, which is represented by the following Scheme 2:

상기 식에서In the above formula

R₄, R₅ 및 R₆은 상기에서 정의한 것과 동일하고, X는 할로겐을 나타낸다. R ₄ , R ₅ and R ₆ are the same as defined above and X represents halogen.

상기 반응식 2에서, 화학식 4의 화합물 및 화학식 6의 화합물은 상업적으로 구입이 가능하다. 화학식 4의 화합물을 트라이메틸알루미늄 및 암모늄클로라이드를 저온조건 (-20℃ ~ 0℃)에서 가하고 가열반응(80℃)시켜 화학식 5의 화합물을 제조할 수 있다(Tetrahedron Lett., 1991, 36, 8761). 또 다른 방법으로서 아미딘화 반응시약으로 염화수소 및 암모니아를 사용할 수 있으며, 반응온도는 -20℃ ~ 0℃ 또는 실온에서 반응시키는 것이 바람직하고, 용매로는 무수 톨루엔이 바람직하다. 제조된 화학식 5의 화합물과 화학식 6의 화합물을 환류 반응시켜 화학식 7의 화합물을 제조할 수 있다(J. Chem. Soc., 1946, 5). 이때 사용가능한 염기로는 소듐알콕사이드가 바람직하며, 용매로는 알코올, N,N-다이메틸포름아마이드 등이 바람직하다. 제조된 화학식 7의 화합물을 할로겐화 반응시켜 화학식 2의 화합물을 제조할 수 있다(J. Heterocyclic Chem., 1991, 28, 231). 이때 바람직한 할로겐화 반응시약으로는 포스포러스 옥시트리할라이드 또는 싸이오닐클로라이드를 사용할 수 있으며, 촉매로는 N,N-다이메틸아닐린, N,N-다이메틸포름아마이드등의 3급 아민이 바람직하며, 반응온도는 50℃ ~ 100℃ 또는 실온에서 반응시키는 것이 바람직하다. In Scheme 2, the compound of Formula 4 and the compound of Formula 6 are commercially available. Trimethylaluminum and ammonium chloride may be added to the compound of Formula 4 at low temperature (-20 ° C. to 0 ° C.) and heated to a temperature of 80 ° C. to prepare the compound of Formula 5 ( Tetrahedron Lett. , 1991, 36, 8761). ). As another method, hydrogen chloride and ammonia may be used as the amidation reagent, the reaction temperature is preferably -20 ° C to 0 ° C or room temperature, and toluene is preferably used as the solvent. The compound of Formula 7 may be prepared by refluxing the compound of Formula 5 with the compound of Formula 6 ( J. Chem. Soc. , 1946, 5). At this time, sodium alkoxide is preferable as the base which can be used, and alcohol, N, N-dimethylformamide, etc. are preferable as the solvent. The compound of formula 7 may be prepared by halogenation of the compound of formula 7 ( J. Heterocyclic Chem. , 1991, 28, 231). In this case the preferred halogenating reagent may be a phosphorus oxy trihalide or a thionyl chloride, the catalyst include N, N - dimethyl aniline, N, N - dimethyl and a tertiary amine, such as dimethylformamide Preferably, the reaction It is preferable to make temperature react at 50 degreeC-100 degreeC, or room temperature.

또한, 본 발명의 화학식 1의 화합물은 화학식 8의 화합물의 할로겐('X')을 유기 주석화합물('Y')로 치환한 화학식 9의 화합물을 화학식 10의 화합물과 스틸(Stille) 반응시켜 제조할 수 있으며, 이를 반응식으로 나타내면 하기 반응식 3과 같다:In addition, the compound of formula 1 of the present invention is prepared by the reaction of the compound of formula (9) in which the halogen ('X') of the compound of formula (8) with organic tin compound ('Y') It can be represented by the reaction scheme shown in Scheme 3:

상기 식에서In the above formula

R₁, R₂, R₃, R₄, R₅ 및 R₆는 상기에서 정의한 것과 동일하고, X는 할로겐을 나타내고, Y는 트라이알킬주석을 나타낸다. R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are the same as defined above, X represents halogen and Y represents trialkyltin.

상기 반응식 3에서, 화학식 8의 화합물은 공지의 방법에 따라 제조될 수 있으며(WO96/005177), 화학식 10의 화합물은 상업적으로 구입이 가능하다. 화학식 8의 화합물을 리튬트라이알킬틴하이드라이드와 반응시켜 화학식 9의 화합물을 제조할 수 있다. 이때 사용가능한 용매로는 무수 테트라하이드로퓨란이 바람직하며, 반응온도는 -78℃ ~ 0℃ 에서 반응시키는 것이 바람직하다. 제조된 화학식 9의 화합물을 화학식 10의 화합물과 스틸(Stille) 반응시켜 화학식 1의 화합물을 제조할 수 있다(Tetrahedron, 1994, 50, 275). 이 때 촉매로 다양한 유기 팔라듐 화합물이 사 용될 수 있으며, 그 중 비스(트라이페닐포스핀)다이클로로팔라듐(II)이 바람직하다. 사용가능한 용매로는 무수 테트라하이드로퓨란, N,N-다이메틸포름아마이드, 헥사메틸포스포릭트라이아마이드, 1,2-다이클로로에테인이 바람직하며, 반응온도는 80℃ ~ 160℃ 에서 반응시키는 것이 바람직하다.In Scheme 3, the compound of Formula 8 may be prepared according to a known method (WO96 / 005177), and the compound of Formula 10 is commercially available. The compound of formula 8 may be reacted with lithium trialkyltin hydride to prepare the compound of formula 9. At this time, as the solvent usable, anhydrous tetrahydrofuran is preferable, and the reaction temperature is preferably reacted at -78 ° C to 0 ° C. The compound of Formula 9 may be prepared by sterilizing the compound of Formula 9 with the compound of Formula 10 ( Tetrahedron , 1994, 50, 275). In this case, various organic palladium compounds may be used as a catalyst, and bis (triphenylphosphine) dichloropalladium (II) is preferable. Preferable solvents include anhydrous tetrahydrofuran, N , N -dimethylformamide, hexamethylphosphoric triamide and 1,2-dichloroethane, and the reaction temperature is preferably reacted at 80 ° C to 160 ° C. Do.

또한, 본 발명의 화학식 1a로 표시되는 화합물은 화학식 9의 화합물과 화학식 11의 화합물을 스틸(Stille) 반응시켜 제조할 수 있다. 상기에서 제조된 화학식 1a의 화합물을 다양한 친핵성 첨가 반응시켜 화학식 1의 화합물을 제조할 수 있다. 이를 반응식으로 나타내면 하기 반응식 4과 같다:In addition, the compound represented by the formula (1a) of the present invention can be prepared by the still (Stille) reaction of the compound of formula 9 and the compound of formula (11). The compound of Formula 1a prepared above may be prepared by various nucleophilic addition reactions. This is shown in Scheme 4:

상기 식에서In the above formula

R₁, R₂, R₃, R₄, R₅, R₆, X 및 Y는 상기에서 정의한 것과 동일하다. R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , X and Y are the same as defined above.

상기 반응식 4에서, 화학식 11의 화합물은 상업적으로 구입이 가능하다. 화학식 9의 화합물과 화학식 11의 화합물을 스틸(Stille) 반응시켜 화학식 1a의 화합물을 제조할 수 있으며, 이 때 용매는 무수 테트라하이드로퓨란이 바람직하게 사용될 수 있으며, 반응온도는 -78℃ ~ 0℃ 에서 반응시키는 것이 바람직하다. In Scheme 4, the compound of Formula 11 is commercially available. The compound of formula (9) and the compound of formula (11) can be prepared by the still (Stille) reaction, the compound of formula (1a) can be prepared, wherein the solvent is preferably anhydrous tetrahydrofuran, the reaction temperature is -78 ℃ ~ 0 ℃ It is preferable to react at.

상기에서 제조된 화학식 1a의 화합물을 다양한 친핵체를 사용하여 친핵성 첨가 반응시켜 화학식 1의 화합물을 제조할 수 있으며, 이 때 용매로는 알코올, 테트라하이드로퓨란, 다이클로로메테인이 바람직하게 사용될 수 있으며, 반응온도는 저온 또는 -78℃ ~ 120 ℃ 에서 반응시키는 것이 바람직하다.The compound of Formula 1a prepared above may be prepared by nucleophilic addition using various nucleophiles to prepare a compound of Formula 1, wherein a solvent may be preferably alcohol, tetrahydrofuran, dichloromethane. It is preferable to make reaction temperature react at low temperature or -78 degreeC-120 degreeC.

본 발명은 화학식 1로 표시되는 신규의 5,6-다이메틸피리미딘 유도체 또는 이의 약제학적으로 허용되는 염을 유효성분으로 함유하고 약제학적으로 허용되는 담체를 포함하는 위산분비 억제 조성물을 포함한다. 본 발명에 따른 조성물은 락토 즈, 옥수수전분 등의 부형제, 마그네슘 스테아레이트 등의 윤활제, 공지되어 사용가능한 유화제, 현탁제, 완충제, 등장화제 등을 포함할 수 있으며, 경우에 따라 감미제 및/또는 향미제를 포함할 수 있다. The present invention includes a gastric acid secretion inhibiting composition containing a novel 5,6-dimethylpyrimidine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier. The composition according to the present invention may include excipients such as lactose, corn starch, lubricants such as magnesium stearate, emulsifiers, suspending agents, buffers, isotonic agents and the like which are well known and can be used. It may include the agent.

본 발명에 따른 조성물은 경구 투여하거나, 정맥내, 복강내, 피하, 직장 및 국소 투여를 포함한 비경구 투여를 실시할 수 있다. 즉, 본 발명에 따른 조성물은 정제 또는 캡슐제 형태로, 또는 수성용제 또는 현탁제로서 투여할 수 있다. 경구용 정제의 경우 통상 사용되는 담체에는 락토즈 및 옥수수 전분이 포함되고, 마그네슘 스테아레이트와 같은 윤활제를 통상 가할 수 있다. 캡슐제 형태의 경우 유용한 희석제로서 락토즈 및 건조 옥수수 분말을 포함할 수 있다. 경구용으로 수성 현탁제가 필요할 경우 활성성분에 유화제 및 현탁제를 포함할 수 있다. 경우에 따라 특정 감미제 및/또는 향미제를 가할 수 있다. 근육내, 복강내, 피하 및 정맥내 투여의 경우, 통상 활성성분의 멸균 용액을 제조하고, 용액의 pH를 적합하게 조절할 수 있는 완충제를 포함할 수 있으며, 정맥내 투여의 경우 용질의 총 농도는 제제에 등장성이 부여되도록 조절할 수 있는 등장화제를 포함할 수 있다. 또한, 본 발명에 따른 조성물은 pH가 7.4인 염수와 같은 약제학적으로 허용되는 담체를 포함하는 수용액제의 형태가 될 수 있으며, 용액제의 형태로 국소적으로 환자의 근육내 혈류에 도입할 수 있다. The compositions according to the invention can be administered orally or parenterally, including intravenous, intraperitoneal, subcutaneous, rectal and topical administration. That is, the composition according to the present invention may be administered in the form of a tablet or capsule, or as an aqueous solvent or suspension. In the case of oral tablets, carriers commonly used include lactose and corn starch, and lubricants such as magnesium stearate can usually be added. Useful diluents for capsule form may include lactose and dry corn powder. If an aqueous suspension is required for oral use, the active ingredient may include emulsifiers and suspensions. If desired, certain sweetening and / or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, a sterile solution of the active ingredient is usually prepared and may contain a buffer that can suitably adjust the pH of the solution. For intravenous administration, the total concentration of the solute is It may include isotonic agents that can be adjusted to impart isotonicity to the formulation. In addition, the composition according to the present invention may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier such as saline having a pH of 7.4, and may be locally introduced into the patient's intramuscular blood flow in the form of a solution. have.

이하, 본 발명을 실시예를 통하여 더욱 상세히 설명하였다. 그러나, 이것이 본 발명의 범위를 제한하는 것은 아니다.Hereinafter, the present invention has been described in more detail with reference to Examples. However, this does not limit the scope of the invention.

참조예 1. 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘Reference Example 1. 4-Chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine

단계 1: 2-(4-플루오로페닐)-아세트아미딘 염산염Step 1: 2- (4-fluorophenyl) -acetamide hydrochloride

암모늄클로라이드(3.96 g, 74.0 mmol)와 무수 톨루엔(68 ml) 혼합액에 트라이메틸알루미늄(37 ml, 2.0 M 톨루엔용액)를 0℃ 에서 서서히 적가하고, 반응혼합물을 실온에서 30분간 교반하였다. 2-(4-플루오로페닐)아세토나이트릴(5.0 g, 40.0 mmol)을 가하고 80℃ 에서 22시간 동안 교반하였다. 반응혼합물을 실온으로 냉각하고 실리카겔(30 g)과 클로로폼(100 ml) 현탁액을 가하고 10분 동안 교반하여 여과한 후, 실리카겔층을 메탄올/클로로폼(1:1, v/v)용액(200 ml)으로 세척하고 여과액을 감압농축하였다.Trimethylaluminum (37 ml, 2.0 M toluene solution) was slowly added dropwise at 0 ° C to a mixture of ammonium chloride (3.96 g, 74.0 mmol) and anhydrous toluene (68 ml), and the reaction mixture was stirred at room temperature for 30 minutes. 2- (4-fluorophenyl) acetonitrile (5.0 g, 40.0 mmol) was added and stirred at 80 ° C. for 22 hours. The reaction mixture was cooled to room temperature, a suspension of silica gel (30 g) and chloroform (100 ml) were added thereto, stirred for 10 minutes, and filtered. The silica gel layer was diluted with methanol / chloroform (1: 1, v / v) solution (200). ml) and the filtrate was concentrated under reduced pressure.

농축한 잔사를 메탄올/아세톤(1:1, v/v)혼합액(50 ml)에 녹이고, 불용물을 여과하여 제거한 후, 여과액을 감압농축하여 백색 고체상의 표제화합물(4.8 g)을 제조하였다. 더 이상의 정제과정없이 다음 단계에 사용하였다.The concentrated residue was dissolved in a methanol / acetone (1: 1, v / v) mixture (50 ml), the insolubles were filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (4.8 g) as a white solid. . Used for the next step without further purification.

단계 2: 2-(4-플루오로벤질)-5,6-다이메틸피리미딘-4-올 Step 2: 2- (4-fluorobenzyl) -5,6-dimethylpyrimidin-4-ol

단계 1에서 제조한 2-(4-플루오로페닐)-아세트아미딘 염산염(3.35 g, 17.78 mmol)을 무수 메탄올(178 ml)에 용해하고, 소듐메톡사이드(2.88 g, 53.32 mmol)와 에틸 2-메틸아세토아세테이트(2.82 mg, 19.55 mmol)를 가하고 10시간 동안 환류교반 하였다. 반응혼합물을 실온으로 냉각하고 진한 염산수용액으로 산성화한 후, 다 이클로로메테인(300 ml)으로 추출하였다. 유기층을 무수 황산마그네슘으로 건조하고 여과 감압농축하여 백색 고체상의 표제화합물(2.1 g, 51.0%)을 제조하였다.2- (4-fluorophenyl) -acetamidine hydrochloride (3.35 g, 17.78 mmol) prepared in step 1 was dissolved in anhydrous methanol (178 ml), sodium methoxide (2.88 g, 53.32 mmol) and ethyl 2 -Methyl acetoacetate (2.82 mg, 19.55 mmol) was added and stirred under reflux for 10 hours. The reaction mixture was cooled to room temperature, acidified with concentrated aqueous hydrochloric acid solution, and extracted with dichloromethane (300 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (2.1 g, 51.0%) as a white solid.

Rf = 0.92 (다이클로로메테인/메탄올 = 5/1, v/v)Rf = 0.92 (dichloromethane / methanol = 5/1, v / v)

¹H-NMR (400MHz, DMSO-d₆) δ 7.37-7.40 (m, 2H), 6.97-7.02 (m, 2H), 3.93 (s, 2H), 2.32 (s, 3H), 2.05 (s, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.37-7.40 (m, 2H), 6.97-7.02 (m, 2H), 3.93 (s, 2H), 2.32 (s, 3H), 2.05 (s, 3H )

단계 3: 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘 Step 3: 4-chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine

단계 2 에서 제조한 2-(4-플루오로벤질)-5,6-다이메틸피리미딘-4-올(2.1 g, 9.04 mmol)을 포스포러스옥시클로라이드(42 ml)에 가하고 2시간 동안 환류교반하였다. 반응혼합물을 실온으로 냉각하고 얼음물(300 ml)에 가한 후, 0℃ 에서 1시간 동안 교반하고 다이클로로메테인(300 ml)으로 추출하였다. 유기층을 무수 황산마그네슘으로 건조하고 여과 감압농축한 잔사를 다이에틸에테르(100 ml)에 가하여 교반한 후, 여과하여 백색 고체상의 표제화합물(1.4 g, 62.0%)을 제조하였다.2- (4-fluorobenzyl) -5,6-dimethylpyrimidin-4-ol (2.1 g, 9.04 mmol) prepared in step 2 was added to phosphorus oxychloride (42 ml) and stirred under reflux for 2 hours. It was. The reaction mixture was cooled to room temperature, added to ice water (300 ml), stirred at 0 ° C. for 1 hour, and extracted with dichloromethane (300 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and the concentrated under reduced pressure was added to diethyl ether (100 ml) and stirred, followed by filtration to give the title compound (1.4 g, 62.0%) as a white solid.

Rf = 0.44 (에틸아세테이트/n-헥세인 = 3/7, v/v)Rf = 0.44 (ethyl acetate / n-hexane = 3/7, v / v)

¹H-NMR (400MHz, CDCl₃) δ 7.62-7.65 (m, 2H), 7.00-7.04 (m, 2H), 4.65 (s, 2H), 3.01 (s, 3H), 2.46 (s, 3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.62-7.65 (m, 2H), 7.00-7.04 (m, 2H), 4.65 (s, 2H), 3.01 (s, 3H), 2.46 (s, 3H)

참조예 2. 5,6-다이메틸-4-(6-클로로-1-메틸-3,4-다이하이드로-1Reference Example 2. 5,6-Dimethyl-4- (6-chloro-l-methyl-3,4-dihydro-1 HH -아이소퀴 놀린-2-일)-2-트라이뷰틸스텐일피리미딘-Isoquinolin-2-yl) -2-tributylstenylpyrimidine

무수테트라하이드로퓨란(180 ml)에 리튬다이아이소프로필아마이드(35.1 ml, 2.0 M n-헥세인/테트라하이드로퓨란 용액)를 가한 용액에 트라이(n-뷰틸)틴하이드라이드(18.9 ml, 70.20 mmol)를 0℃ 에서 적가한 후, 2시간 동안 교반하였다. 반응혼합물을 -78℃ 로 냉각하고 2-클로로-5,6-다이메틸-4-(6-클로로-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘(17.4 g, 54.0 mmol)을 가하고 동일온도에서 3시간 동안 교반하였다. 실온에서 포화 암모늄클로라이드(10 ml)를 가하고 다이클로로메테인(300 ml)으로 추출한 유기층을 무수 황산마그네슘으로 건조 여과하여 감압농축하였다. 감압농축한 잔사를 실리카겔 관 크로마토그래피(에틸아세테이트/n-헥세인/트라이에틸아민 = 10/85/5, v/v/v)로 분리하여 무색 유체상의 표제화합물(12.43 g)을 제조하였다. Lithium diisopropylamide (35.1 ml, 2.0 M n-hexane / tetrahydrofuran solution) was added to anhydrous tetrahydrofuran (180 ml) to tri (n-butyl) tinhydride (18.9 ml, 70.20 mmol). Was added dropwise at 0 ° C. and stirred for 2 hours. The reaction mixture was cooled to -78 ° C and 2-chloro-5,6-dimethyl-4- (6-chloro-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -pyri Midine (17.4 g, 54.0 mmol) was added and stirred at the same temperature for 3 hours. Saturated ammonium chloride (10 ml) was added at room temperature, and the organic layer extracted with dichloromethane (300 ml) was concentrated under reduced pressure by dry filtration over anhydrous magnesium sulfate. The concentrated residue under reduced pressure was separated by silica gel column chromatography (ethyl acetate / n-hexane / triethylamine = 10/85/5, v / v / v) to give the title compound (12.43 g) as a colorless fluid.

Rf = 0.41 (에틸아세테이트 /n-헥세인 = 3/7, v/v)Rf = 0.41 (ethyl acetate / n-hexane = 3/7, v / v)

¹H-NMR (400MHz, CDCl₃) δ 7.09-7.12 (m, 2H), 7.01 (d, 1H), 4.99 (q, 1H), 3.85 (dd, 1H), 3.40-3.47 (m, 1H), 3.16 (m, 1H), 2.70 (dd, 1H), 2.37 (s, 3H), 2.15 (s, 3H), 1.49-1.65 (m, 6H), 1.49 (d, 3H), 1.34 (m, 6H), 0.99-1.16 (m, 6H), 0.87 (t, 9H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.09-7.12 (m, 2H), 7.01 (d, 1H), 4.99 (q, 1H), 3.85 (dd, 1H), 3.40-3.47 (m, 1H), 3.16 (m, 1H), 2.70 (dd, 1H), 2.37 (s, 3H), 2.15 (s, 3H), 1.49-1.65 (m, 6H), 1.49 (d, 3H), 1.34 (m, 6H) , 0.99-1.16 (m, 6H), 0.87 (t, 9H)

참조예 3. 7-메톡시-1-메틸-1,2,3,4-테트라하이드로아이소퀴놀린Reference Example 3. 7-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline

단계 1: N-[2-(4-메톡시페닐)-에틸]-아세트아마이드Step 1: N- [2- (4-methoxyphenyl) -ethyl] -acetamide

다이클로로메테인(50 ml)에 4-메톡시-펜에틸아민(50 g, 330 mmol)을 첨가하고 이 용액에 2N 수산화 나트륨 수용액(25 ml)를 첨가한 후 0℃ 에서 아세틸 클로라이드(26 ml, 364 mmol)를 서서히 적가 한 후, 반응 혼합물을 철야 교반하였다. 다이클로로메테인으로 희석하고 물과 포화 염화 나트륨 수용액으로 세척후 유기층을 무수 황산 마그네슘으로 건조하고 감압, 농축하여 백색 고체상의 표제 화합물 (68 g)을 제조하였다. 이 화합물을 추가의 정제없이 다음 반응에 사용하였다.4-methoxy-phenethylamine (50 g, 330 mmol) was added to dichloromethane (50 ml), and 2N aqueous sodium hydroxide solution (25 ml) was added to this solution, followed by acetyl chloride (26 ml) at 0 ° C. , 364 mmol) was added dropwise slowly, and the reaction mixture was stirred overnight. Diluted with dichloromethane, washed with water and saturated aqueous sodium chloride solution, the organic layer was dried over anhydrous magnesium sulfate, reduced pressure and concentrated to give the title compound (68 g) as a white solid. This compound was used in the next reaction without further purification.

단계 2: 7-메톡시-1-메틸-3,4-다이하이드로-아이소퀴놀린Step 2: 7-methoxy-1-methyl-3,4-dihydro-isoquinoline

단계 1에서 제조한 N-[2-(4-메톡시페닐)-에틸]-아세트아마이드(50 g, 258.73 mmol)과 포스포러스옥시트라이클로라이드(48 ml, 517.46 mmol) 혼합물에 오산화인(22 g, 155.24 mmol)을 첨가하고 반응 혼합물을 3시간 동안 환류 교반하였다. 반응 혼합물을 실온으로 냉각하여 얼음물에 붓고 2N 수산화 칼륨 수용액으로 염기화하고 에틸아세테이트(500 ml)로 추출한 후, 유기층을 포화 염화 나트륨 수용액으로 세척하여 무수 황산 마그네슘으로 건조하였다. 여과후 감압, 농축한 갈색 유체상의 표제 화합물(14.72 g, 32%)을 제조하였다. 이 화합물을 추가의 정제없이 다음 반응에 사용하였다.Phosphorous pentoxide (22 g) in a mixture of N- [2- (4-methoxyphenyl) -ethyl] -acetamide (50 g, 258.73 mmol) and phosphorus oxytrichloride (48 ml, 517.46 mmol) prepared in step 1 155.24 mmol) was added and the reaction mixture was stirred at reflux for 3 hours. The reaction mixture was cooled to room temperature, poured into iced water, basified with 2N aqueous potassium hydroxide solution, extracted with ethyl acetate (500 ml), and the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The title compound (14.72 g, 32%) was prepared after filtration under reduced pressure and concentrated to a brown fluid. This compound was used in the next reaction without further purification.

단계 3: 7-메톡시-1-메틸-1,2,3,4-테트라하이드로아이소퀴놀린Step 3: 7-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline

단계 2에서 제조한 7-메톡시-1-메틸-3,4-다이하이드로-아이소퀴놀린(14.72 g, 84 mmol)을 메탄올(100 ml)에 용해하고 소듐보로하이드라이드(3.81 g, 100.8 mmol)를 0℃에서 서서히 첨가하고 실온에서 철야 교반하였다. 반응 혼합물에 1N 염산을 첨가하고 감압, 농축하여 수산화 칼륨으로 염기화하여 다이클로로메테인(500 ml)으로 추출하였다. 포화 염화 나트륨 수용액으로 세척하고 무수 황산 마그네슘으로 건조한 후 감압 농축하여 갈색 유체상의 표제 화합물(11.01 g, 74%)을 제조하였다. 이 화합물을 추가의 정제없이 다음 반응에 사용하였다.7-methoxy-1-methyl-3,4-dihydro-isoquinoline (14.72 g, 84 mmol) prepared in step 2 was dissolved in methanol (100 ml) and sodium borohydride (3.81 g, 100.8 mmol) ) Was added slowly at 0 ° C. and stirred overnight at room temperature. 1N hydrochloric acid was added to the reaction mixture, and the residue was concentrated under reduced pressure, basified with potassium hydroxide, and extracted with dichloromethane (500 ml). Washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (11.01 g, 74%) as a brown fluid. This compound was used in the next reaction without further purification.

실시예 1. 2-(4-플루오로벤질)-4-(3,4-다이하이드로-1Example 1. 2- (4-fluorobenzyl) -4- (3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 1에서 제조한 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘(300 mg, 1.20 mmol) 을 6 ml의 N,N-다이메틸포름아마이드에 녹이고 트라이에틸아민(0.50 ml, 3.59 mmol)과 1,2,3,4-테트라하이드로아이소퀴놀린(191 mg, 0.634 mmol)을 가한 반응혼합액을 7시간 동안 환류교반하였다. 반응물을 실온으로 냉각하고 다이클로로메테인(10 ml)으로 희석하고 물(10 ml)로 3회 세척하였다. 분리한 유기층을 무수 황산마그네슘으로 건조 여과하여 감압농축하였다. 4-chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine (300 mg, 1.20 mmol) prepared in Reference Example 1 was dissolved in 6 ml of N , N -dimethylformamide and Ethylamine (0.50 ml, 3.59 mmol) and 1,2,3,4-tetrahydroisoquinoline (191 mg, 0.634 mmol) were added and the reaction mixture was stirred under reflux for 7 hours. The reaction was cooled to rt, diluted with dichloromethane (10 ml) and washed three times with water (10 ml). The separated organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.

감압농축한 잔사를 실리카겔 관 크로마토그래피(에틸아세테이트/n-헥세인 = 15/85, v/v)를 사용하여 분리정제하여 백색 고체상의 2-(4-플루오로벤질)-4-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘(277 mg, 67.0%)을 제조 하였다. 2-(4-플루오로벤질)-4-(3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘(177 mg, 0.509 mmol)의 에틸 아세테이트 용액(2 ml)에 HCl 기체를 0℃에서 가한 후 1시간 동안 교반하여 형성된 백색의 고체를 여과, 진공 건조하여 표제화합물(193 mg, 99%)을 제조하였다.The concentrated residue under reduced pressure was purified by silica gel column chromatography (ethyl acetate / n-hexane = 15/85, v / v) to give 2- (4-fluorobenzyl) -4- (3, 4-Dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine (277 mg, 67.0%) was prepared. Ethyl acetate solution of 2- (4-fluorobenzyl) -4- (3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine (177 mg, 0.509 mmol) HCl gas was added to (2 ml) at 0 ° C., followed by stirring for 1 hour to form a white solid that was filtered and dried in vacuo to give the title compound (193 mg, 99%).

¹H-NMR (400MHz, DMSO-d₆) δ 7.47-7.51 (m, 2H), 7.16-7.21 (m, 6H), 4.87 (s, 2H), 4.20 (s, 2H), 3.92 (t, 2H), 2.93 (t, 2H), 2.48 (s, 3H), 2.34 (s, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.47-7.51 (m, 2H), 7.16-7.21 (m, 6H), 4.87 (s, 2H), 4.20 (s, 2H), 3.92 (t, 2H ), 2.93 (t, 2H), 2.48 (s, 3H), 2.34 (s, 3H)

실시예 2. 2-(4-플루오로벤질)-4-(1-메틸-3,4-다이하이드로-1Example 2. 2- (4-fluorobenzyl) -4- (1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 1에서 제조한 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘(600 mg, 2.39 mmol)과 참조예 3과 동일한 방법으로 제조한 1-메틸-1,2,3,4-테트라하이드로아이소퀴놀린(422 mg, 2.87 mmol) 을 사용하여 실시예 1과 동일한 방법으로 표제화합물(65.2%)을 제조하였다.4-Chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine (600 mg, 2.39 mmol) prepared in Reference Example 1 and 1-methyl-1 prepared in the same manner as in Reference Example 3 The title compound (65.2%) was prepared in the same manner as in Example 1 using, 2,3,4-tetrahydroisoquinoline (422 mg, 2.87 mmol).

실시예 3. 2-(4-플루오로벤질)-4-(1-메틸-3,4-다이하이드로-6-플루오로-1Example 3. 2- (4-fluorobenzyl) -4- (1-methyl-3,4-dihydro-6-fluoro-1 HH - 아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 1에서 제조한 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘(300 mg, 1.20 mmol)과 참조예 3과 동일한 방법으로 제조한 6-플루오로-1-메틸-1,2,3,4-테트라하이드로아이소퀴놀린(237 mg, 1.44 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(49.8%)을 제조하였다.4-Chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine (300 mg, 1.20 mmol) prepared in Reference Example 1 and 6-fluoro- prepared in the same manner as in Reference Example 3 The title compound (49.8%) was prepared in the same manner as in Example 1 using 1-methyl-1,2,3,4-tetrahydroisoquinoline (237 mg, 1.44 mmol).

실시예 4. 2-(4-플루오로벤질)-4-(1(R)-메틸-3,4-다이하이드로-1Example 4. 2- (4-fluorobenzyl) -4- (1 (R) -methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 1에서 제조한 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘(300 mg, 1.20 mmol)과 공지의 방법(KR1998-0030034)으로 제조한 1(R)-메틸-1,2,3,4-테트라하이드로아이소퀴놀린(528 mg, 3.59 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(65.1%)을 제조하였다.4-Chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine (300 mg, 1.20 mmol) prepared in Reference Example 1 and 1 (R) prepared by a known method (KR1998-0030034) ) The title compound (65.1%) was prepared in the same manner as in Example 1 using) -methyl-1,2,3,4-tetrahydroisoquinoline (528 mg, 3.59 mmol).

¹H-NMR (400MHz, DMSO-d₆) δ 7.45-7.48 (m, 2H), 7.16-7.21 (m, 6H), 5.48 (s, 1H), 4.29 (d, 1H), 4.18 (dd, 3H), 3.62 (m, 1H), 3.09-3.11 (m, 1H), 2.88 (m, 1H), 2.47 (s, 3H), 2.29 (s, 3H), 1.54 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.45-7.48 (m, 2H), 7.16-7.21 (m, 6H), 5.48 (s, 1H), 4.29 (d, 1H), 4.18 (dd, 3H ), 3.62 (m, 1H), 3.09-3.11 (m, 1H), 2.88 (m, 1H), 2.47 (s, 3H), 2.29 (s, 3H), 1.54 (d, 3H)

실시예 5. 2-(4-플루오로벤질)-4-(1(S)-메틸-3,4-다이하이드로-1Example 5. 2- (4-fluorobenzyl) -4- (1 (S) -methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 1에서 제조한 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘(300 mg, 1.20 mmol)과 공지의 방법(KR1998-0030033)으로 제조한 1(S)-메틸-1,2,3,4-테트라하이드로아이소퀴놀린(528 mg, 3.59 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(61.9%)을 제조하였다.4-Chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine (300 mg, 1.20 mmol) prepared in Reference Example 1 and 1 (S prepared by a known method (KR1998-0030033)) ) The title compound (61.9%) was prepared in the same manner as in Example 1 using) -methyl-1,2,3,4-tetrahydroisoquinoline (528 mg, 3.59 mmol).

¹H-NMR (400MHz, MeOD) δ 7.41-7.44 (m, 2H), 7.08-7.19 (m, 6H), 5.55 (s, 1H), 4.34 (m, 1H), 4.17 (dd, 2H), 3.67 (m, 1H), 3.11 (m, 1H), 2.89-2.93 (m, 1H), 2.51 (s, 3H), 2.35 (s, 3H), 1.57 (d, 3H) ¹ H-NMR (400 MHz, MeOD) δ 7.41-7.44 (m, 2H), 7.08-7.19 (m, 6H), 5.55 (s, 1H), 4.34 (m, 1H), 4.17 (dd, 2H), 3.67 (m, 1H), 3.11 (m, 1H), 2.89-2.93 (m, 1H), 2.51 (s, 3H), 2.35 (s, 3H), 1.57 (d, 3H)

실시예 6. 2-(4-플루오로벤질)-4-(1,4-다이메틸-3,4-다이하이드로-1Example 6. 2- (4-fluorobenzyl) -4- (1,4-dimethyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 1에서 제조한 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘(200 mg, 0.798 mmol)과 참조예 3과 동일한 방법으로 제조한 1,4-다이메틸-1,2,3,4-테트라하이드로아이소퀴놀린(643 mg, 3.99 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(34.8%)을 제조하였다.4-chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine (200 mg, 0.798 mmol) prepared in Reference Example 1 and 1,4-di prepared in the same manner as in Reference Example 3 The title compound (34.8%) was prepared in the same manner as in Example 1 using methyl-1,2,3,4-tetrahydroisoquinoline (643 mg, 3.99 mmol).

¹H-NMR (400MHz, DMSO-d₆) δ 7.41-7.44 (m, 2H), 7.16-7.22 (m, 6H), 5.71 (m, 1H), 4.34 (m, 1H), 4.15 (dd, 2H), 3.78 (m, 1H), 3.12 (m, 1H), 2.46 (s, 3H), 2.32 (s, 3H), 1.28 (d, 3H), 1.03 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.41-7.44 (m, 2H), 7.16-7.22 (m, 6H), 5.71 (m, 1H), 4.34 (m, 1H), 4.15 (dd, 2H ), 3.78 (m, 1H), 3.12 (m, 1H), 2.46 (s, 3H), 2.32 (s, 3H), 1.28 (d, 3H), 1.03 (d, 3H)

실시예 7. 2-(4-플루오로벤질)-4-(1-트라이플루오로메틸-3,4-다이하이드로-1Example 7. 2- (4-fluorobenzyl) -4- (1-trifluoromethyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 1에서 제조한 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘(200 mg, 0.798 mmol)과 참조예 3과 동일한 방법으로 제조한 1-트라이플루오로메틸-1,2,3,4-테트라하이드로아이소퀴놀린(803 mg, 3.99 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(56.3%)을 제조하였다.4-chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine (200 mg, 0.798 mmol) prepared in Reference Example 1 and 1-trifluoro prepared in the same manner as in Reference Example 3. The title compound (56.3%) was prepared in the same manner as in Example 1 using methyl-1,2,3,4-tetrahydroisoquinoline (803 mg, 3.99 mmol).

¹H-NMR (400MHz, DMSO-d₆) δ 7.29-7.44 (m, 6H), 7.16 (t, 2H), 6.48 (q, 1H), 4.19-4.28 (m, 3H), 3.75-3.82 (m, 1H), 3.00-3.04 (m, 2H), 2.56 (s, 3H), 2.31 (s, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.29-7.44 (m, 6H), 7.16 (t, 2H), 6.48 (q, 1H), 4.19-4.28 (m, 3H), 3.75-3.82 (m , 1H), 3.00-3.04 (m, 2H), 2.56 (s, 3H), 2.31 (s, 3H)

실시예 8. 2-(4-플루오로벤질)-4-(7-클로로-1-메틸-3,4-다이하이드로-1Example 8. 2- (4-fluorobenzyl) -4- (7-chloro-1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 1에서 제조한 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘(200 mg, 0.798 mmol)과 참조예 3과 동일한 방법으로 제조한 7-클로로-1-메틸-1,2,3,4-테트라하이드로아이소퀴놀린(725 mg, 3.99 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(54.6%)을 제조하였다.4-Chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine (200 mg, 0.798 mmol) prepared in Reference Example 1 and 7-chloro-1 prepared in the same manner as in Reference Example 3. The title compound (54.6%) was prepared in the same manner as in Example 1 using -methyl-1,2,3,4-tetrahydroisoquinoline (725 mg, 3.99 mmol).

¹H-NMR (400MHz, DMSO-d₆) δ 7.47 (dd, 2H), 7.37 (s, 1H), 7.18-7.26 (m, 4H), 5.48 (q, 1H), 4.27 (dd, 1H), 4.17 (dd, 2H), 3.58 (m, 1H), 2.98-3.04 (m, 1H), 2.86 (dd, 1H), 2.47 (s, 3H), 2.26 (s, 3H), 1.55 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.47 (dd, 2H), 7.37 (s, 1H), 7.18-7.26 (m, 4H), 5.48 (q, 1H), 4.27 (dd, 1H), 4.17 (dd, 2H), 3.58 (m, 1H), 2.98-3.04 (m, 1H), 2.86 (dd, 1H), 2.47 (s, 3H), 2.26 (s, 3H), 1.55 (d, 3H)

실시예 9. 2-(4-플루오로벤질)-4-(5-클로로-1-메틸-3,4-다이하이드로-1Example 9. 2- (4-fluorobenzyl) -4- (5-chloro-1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 1에서 제조한 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘(200 mg, 0.798 mmol)과 참조예 3과 동일한 방법으로 제조한 5-클로로-1-메틸-1,2,3,4-테트라하이드로아이소퀴놀린(725 mg, 3.99 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(48.5%)을 제조하였다.4-Chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine (200 mg, 0.798 mmol) prepared in Reference Example 1 and 5-chloro-1 prepared in the same manner as in Reference Example 3 The title compound (48.5%) was prepared in the same manner as in Example 1 using -methyl-1,2,3,4-tetrahydroisoquinoline (725 mg, 3.99 mmol).

¹H-NMR (400MHz, DMSO-d₆) δ 7.46 (dd, 2H), 7.35 (d, 1H), 7.17-7.28 (m, 4H), 5.43 (q, 1H), 4.33 (dd, 1H), 4.18 (dd, 2H), 3.61 (m, 1H), 2.90 (m, 2H), 2.47 (s, 3H), 2.27 (s, 3H), 1.57 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.46 (dd, 2H), 7.35 (d, 1H), 7.17-7.28 (m, 4H), 5.43 (q, 1H), 4.33 (dd, 1H), 4.18 (dd, 2H), 3.61 (m, 1H), 2.90 (m, 2H), 2.47 (s, 3H), 2.27 (s, 3H), 1.57 (d, 3H)

실시예 10. 2-(4-플루오로벤질)-4-(7-메톡시-1-메틸-3,4-다이하이드로-1Example 10. 2- (4-fluorobenzyl) -4- (7-methoxy-1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 1에서 제조한 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘(200 mg, 0.798 mmol)과 참조예 3에서 제조한 7-메톡시-1-메틸-1,2,3,4-테트라하이드로아이소퀴놀린(707 mg, 3.99 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(62.4%)을 제조하였다.4-chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine (200 mg, 0.798 mmol) prepared in Reference Example 1 and 7-methoxy-1-methyl prepared in Reference Example 3 The title compound (62.4%) was prepared in the same manner as in Example 1 using -1,2,3,4-tetrahydroisoquinoline (707 mg, 3.99 mmol).

¹H-NMR (400MHz, DMSO-d₆) δ 7.47-7.51 (m, 2H), 7.19 (t, 2H), 7.08 (d, 1H), 6.79-6.90 (m, 2H), 5.44 (q, 1H), 4.28 (m, 1H), 4.19 (dd, 2H), 3.75 (s, 3H), 3.57 (m, 1H), 2.95-3.00 (m, 1H), 2.79 (dd, 1H), 2.48 (s, 3H), 2.26 (s, 3H), 1.54 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.47-7.51 (m, 2H), 7.19 (t, 2H), 7.08 (d, 1H), 6.79-6.90 (m, 2H), 5.44 (q, 1H ), 4.28 (m, 1H), 4.19 (dd, 2H), 3.75 (s, 3H), 3.57 (m, 1H), 2.95-3.00 (m, 1H), 2.79 (dd, 1H), 2.48 (s, 3H), 2.26 (s, 3H), 1.54 (d, 3H)

실시예 11. 2-(4-플루오로벤질)-4-(1,8-다이메틸-3,4-다이하이드로-1Example 11. 2- (4-fluorobenzyl) -4- (1,8-dimethyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 1에서 제조한 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘(150 mg, 0.598 mmol)과 참조예 3과 동일한 방법으로 제조한 1,8-다이메틸- 1,2,3,4-테트라하이드로아이소퀴놀린(482 mg, 2.99 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(63.8%)을 제조하였다.4-Chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine (150 mg, 0.598 mmol) prepared in Reference Example 1 and 1,8-di prepared in the same manner as Reference Example 3 The title compound (63.8%) was prepared in the same manner as in Example 1 using methyl-1,2,3,4-tetrahydroisoquinoline (482 mg, 2.99 mmol).

(Free base) ¹H-NMR (400MHz, CDCl₃) d 7.27 (dd, 2H), 7.05-7.09 (m, 1H), 6.90-7.00 (m, 4H), 5.11 (q, 1H), 4.00 (dd, 2H), 3.85 (dd, 1H), 3.53-3.61 (m, 1H), 3.10 (m, 1H), 2.75 (dd, 1H), 2.37 (s, 3H), 2.29 (s, 3H), 2.15 (s, 3H), 1.42 (d, 3H)(Free base) ¹ H-NMR (400 MHz, CDCl ₃ ) d 7.27 (dd, 2H), 7.05-7.09 (m, 1H), 6.90-7.00 (m, 4H), 5.11 (q, 1H), 4.00 (dd , 2H), 3.85 (dd, 1H), 3.53-3.61 (m, 1H), 3.10 (m, 1H), 2.75 (dd, 1H), 2.37 (s, 3H), 2.29 (s, 3H), 2.15 ( s, 3H), 1.42 (d, 3H)

실시예 12. 2-(4-플루오로벤질)-4-(1,6-다이메틸-3,4-다이하이드로-1Example 12. 2- (4-fluorobenzyl) -4- (1,6-dimethyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 1에서 제조한 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘(150 mg, 0.598 mmol)과 참조예 3과 동일한 방법으로 제조한 1,6-다이메틸-1,2,3,4-테트라하이드로아이소퀴놀린(482 mg, 2.99 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(42.2%)을 제조하였다.4-chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine (150 mg, 0.598 mmol) prepared in Reference Example 1 and 1,6-di prepared in the same manner as in Reference Example 3 The title compound (42.2%) was prepared in the same manner as in Example 1 using methyl-1,2,3,4-tetrahydroisoquinoline (482 mg, 2.99 mmol).

¹H-NMR (400MHz, DMSO-d₆) δ 7.41 (dd, 2H), 7.15 (t, 2H), 6.92-7.04 (m, 3H), 5.35 (q, 1H), 4.28 (dd, 1H), 4.16 (dd, 2H), 3.52 (m, 1H), 2.99 (m, 1H), 2.76 (dd, 1H), 2.42 (s, 3H), 2.21 (s, 6H), 1.45 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.41 (dd, 2H), 7.15 (t, 2H), 6.92-7.04 (m, 3H), 5.35 (q, 1H), 4.28 (dd, 1H), 4.16 (dd, 2H), 3.52 (m, 1H), 2.99 (m, 1H), 2.76 (dd, 1H), 2.42 (s, 3H), 2.21 (s, 6H), 1.45 (d, 3H)

실시예 13. 2-(4-플루오로벤질)-4-(6-메톡시-1-메틸-3,4-다이하이드로-1Example 13. 2- (4-fluorobenzyl) -4- (6-methoxy-1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 1에서 제조한 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘(150 mg, 0.598 mmol)과 참조예 3과 동일한 방법으로 제조한 6-메톡시-1-메틸-1,2,3,4-테트라하이드로아이소퀴놀린(530 mg, 2.99 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(71.2%)을 제조하였다.4-Chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine (150 mg, 0.598 mmol) prepared in Reference Example 1 and 6-methoxy- prepared in the same manner as in Reference Example 3. The title compound (71.2%) was prepared in the same manner as in Example 1 using 1-methyl-1,2,3,4-tetrahydroisoquinoline (530 mg, 2.99 mmol).

(Free base) ¹H-NMR (400MHz, CDCl₃) δ 7.29 (dd, 2H), 6.91-6.99 (m, 3H), 6.74 (dd, 1H), 6.62 (d, 1H), 4.94 (q, 1H), 4.12 (dd, 2H), 3.87 (dd, 1H), 3.78 (s, 3H), 3.38-3.45 (m, 1H), 3.10 (m, 1H), 2.66 (dd, 1H), 2.36 (s, 3H), 2.15 (s, 3H), 1.45 (d, 3H)(Free base) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.29 (dd, 2H), 6.91-6.99 (m, 3H), 6.74 (dd, 1H), 6.62 (d, 1H), 4.94 (q, 1H ), 4.12 (dd, 2H), 3.87 (dd, 1H), 3.78 (s, 3H), 3.38-3.45 (m, 1H), 3.10 (m, 1H), 2.66 (dd, 1H), 2.36 (s, 3H), 2.15 (s, 3H), 1.45 (d, 3H)

실시예 14. 2-(4-플루오로벤질)-4-(1,7-다이메틸-3,4-다이하이드로-1Example 14. 2- (4-fluorobenzyl) -4- (1,7-dimethyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 1에서 제조한 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘(200 mg, 0.798 mmol)과 참조예 3과 동일한 방법으로 제조한 1,7-다이메틸-1,2,3,4-테트라하이드로아이소퀴놀린(643 mg, 3.99 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(56.4%)을 제조하였다.4-chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine (200 mg, 0.798 mmol) prepared in Reference Example 1 and 1,7-di prepared in the same manner as in Reference Example 3. The title compound (56.4%) was prepared in the same manner as in Example 1 using methyl-1,2,3,4-tetrahydroisoquinoline (643 mg, 3.99 mmol).

¹H-NMR (400MHz, DMSO-d₆ with TFA) δ 7.46 (dd, 2H), 7.20 (t, 2H), 7.00-7.06 (m, 3H), 5.41 (q, 1H), 4.24 (m, 1H), 4.17 (dd, 2H), 3.58 (m, 1H), 3.00 (m, 1H), 2.82 (dd, 1H), 2.46 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 1.52 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ with TFA) δ 7.46 (dd, 2H), 7.20 (t, 2H), 7.00-7.06 (m, 3H), 5.41 (q, 1H), 4.24 (m, 1H ), 4.17 (dd, 2H), 3.58 (m, 1H), 3.00 (m, 1H), 2.82 (dd, 1H), 2.46 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H) , 1.52 (d, 3H)

실시예 15. 2-(4-플루오로벤질)-4-(7-플루오로-1-메틸-3,4-다이하이드로-1Example 15. 2- (4-fluorobenzyl) -4- (7-fluoro-1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 1에서 제조한 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘(150 mg, 0.598 mmol)과 참조예 3과 동일한 방법으로 제조한 7-플루오로-1-메틸-1,2,3,4-테트라하이드로아이소퀴놀린(494 mg, 2.99 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(52.9%)을 제조하였다.4-Chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine (150 mg, 0.598 mmol) prepared in Reference Example 1 and 7-fluoro- prepared in the same manner as in Reference Example 3 The title compound (52.9%) was prepared in the same manner as in Example 1 using 1-methyl-1,2,3,4-tetrahydroisoquinoline (494 mg, 2.99 mmol).

¹H-NMR (400MHz, DMSO-d₆) δ 7.44 (dd, 2H), 7.15-7.21 (m, 3H), 7.10 (d, 1H), 7.01 (dd, 1H), 5.45 (q, 1H), 4.24 (dd, 1H), 4.15 (dd, 2H), 3.55 (m, 1H), 2.98 (m, 1H), 2.83 (dd, 1H), 2.45 (s, 3H), 2.24 (s, 3H), 1.52 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.44 (dd, 2H), 7.15-7.21 (m, 3H), 7.10 (d, 1H), 7.01 (dd, 1H), 5.45 (q, 1H), 4.24 (dd, 1H), 4.15 (dd, 2H), 3.55 (m, 1H), 2.98 (m, 1H), 2.83 (dd, 1H), 2.45 (s, 3H), 2.24 (s, 3H), 1.52 (d, 3H)

실시예 16. 2-(4-플루오로벤질)-4-(3-메틸-3,4-다이하이드로-1Example 16. 2- (4-fluorobenzyl) -4- (3-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 1에서 제조한 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘(200 mg, 0.798 mmol)과 참조예 3과 동일한 방법으로 제조한 3-메틸-1,2,3,4-테트라하이드로아이소퀴놀린(587 mg, 3.99 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(61.0%)을 제조하였다.4-Chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine (200 mg, 0.798 mmol) prepared in Reference Example 1 and 3-methyl-1 prepared in the same manner as in Reference Example 3 The title compound (61.0%) was prepared in the same manner as in Example 1 using, 2,3,4-tetrahydroisoquinoline (587 mg, 3.99 mmol).

¹H-NMR (400MHz, DMSO-d₆) δ 7.42-7.45 (dd, 2H), 7.16-7.24 (m, 6H), 4.91 (d, 1H), 4.89 (m, 1H), 4.74 (d, 1H), 4.16 (s, 2H), 3.11 (dd, 1H), 2.73 (dd, 1H), 2.47 (s, 3H), 2.28 (s, 3H), 1.17 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.42-7.45 (dd, 2H), 7.16-7.24 (m, 6H), 4.91 (d, 1H), 4.89 (m, 1H), 4.74 (d, 1H ), 4.16 (s, 2H), 3.11 (dd, 1H), 2.73 (dd, 1H), 2.47 (s, 3H), 2.28 (s, 3H), 1.17 (d, 3H)

실시예 17. 2-(4-플루오로벤질)-4-(6-클로로-1-메틸-3,4-다이하이드로-1Example 17. 2- (4-fluorobenzyl) -4- (6-chloro-1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 1에서 제조한 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘(200 mg, 0.798 mmol)과 참조예 3과 동일한 방법으로 제조한 6-클로로-1-메틸-1,2,3,4-테트라하이드로아이소퀴놀린(725 mg, 3.99 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(64.2%)을 제조하였다.4-Chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine (200 mg, 0.798 mmol) prepared in Reference Example 1 and 6-chloro-1 prepared in the same manner as in Reference Example 3. The title compound (64.2%) was prepared in the same manner as in Example 1 using -methyl-1,2,3,4-tetrahydroisoquinoline (725 mg, 3.99 mmol).

¹H-NMR (400MHz, DMSO-d₆) δ 7.43-7.46 (dd, 2H), 7.23 (m, 3H), 7.16 (t, 2H), 5.43 (q, 1H), 4.24 (dd, 1H), 4.16 (dd, 2H), 3.54 (m, 1H), 3.02 (m, 1H), 2.86 (dd, 1H), 2.45 (s, 3H), 2.23 (s, 3H), 1.48 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.43-7.46 (dd, 2H), 7.23 (m, 3H), 7.16 (t, 2H), 5.43 (q, 1H), 4.24 (dd, 1H), 4.16 (dd, 2H), 3.54 (m, 1H), 3.02 (m, 1H), 2.86 (dd, 1H), 2.45 (s, 3H), 2.23 (s, 3H), 1.48 (d, 3H)

실시예 18. 2-(4-플루오로벤질)-4-(1-에틸-3,4-다이하이드로-1Example 18. 2- (4-fluorobenzyl) -4- (1-ethyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 1에서 제조한 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘(200 mg, 0.798 mmol)과 참조예 3과 동일한 방법으로 제조한 1-에틸-1,2,3,4-테트라하이드로아이소퀴놀린(643 mg, 3.99 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(58.9%)을 제조하였다.4-Chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine (200 mg, 0.798 mmol) prepared in Reference Example 1 and 1-ethyl-1 prepared in the same manner as in Reference Example 3. The title compound (58.9%) was prepared in the same manner as in Example 1 using, 2,3,4-tetrahydroisoquinoline (643 mg, 3.99 mmol).

¹H-NMR (400MHz, DMSO-d₆) δ 7.40 (dd, 2H), 7.14-7.21 (m, 6H), 5.50 (q, 1H), 4.22 (dd, 1H), 4.13 (dd, 2H), 3.74 (m, 1H), 2.89-2.97 (m, 2H), 2.44 (s, 3H), 2.24 (s, 3H), 1.74-1.91 (m, 2H), 0.76 (t, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.40 (dd, 2H), 7.14-7.21 (m, 6H), 5.50 (q, 1H), 4.22 (dd, 1H), 4.13 (dd, 2H), 3.74 (m, 1H), 2.89-2.97 (m, 2H), 2.44 (s, 3H), 2.24 (s, 3H), 1.74-1.91 (m, 2H), 0.76 (t, 3H)

실시예 19. 2-(4-플루오로벤질)-4-(7-플루오로-3,4-다이하이드로-1Example 19. 2- (4-fluorobenzyl) -4- (7-fluoro-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 1에서 제조한 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘(사용량 200 mg, 0.798 mmol)과 참조예 3과 동일한 방법으로 제조한 7-플루오로-1,2,3,4-테트라하이드로아이소퀴놀린(643 mg, 3.99 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(63.0%)을 제조하였다.4-Chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine (use amount 200 mg, 0.798 mmol) prepared in Reference Example 1 and 7-fluoro prepared in the same manner as in Reference Example 3. The title compound (63.0%) was prepared in the same manner as in Example 1 using -1,2,3,4-tetrahydroisoquinoline (643 mg, 3.99 mmol).

¹H-NMR (400MHz, DMSO-d₆) δ 7.54 (dd, 2H), 7.15-7.45 (m, 5H), 4.99 (dd, 2H), 4.25 (m, 1H), 4.04 (dt, 2H), 2.98 (m, 2H), 2.54 (s, 3H), 2.35 (s, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.54 (dd, 2H), 7.15-7.45 (m, 5H), 4.99 (dd, 2H), 4.25 (m, 1H), 4.04 (dt, 2H), 2.98 (m, 2H), 2.54 (s, 3H), 2.35 (s, 3H)

실시예 20. 2-(4-플루오로벤질)-4-(7-클로로-3,4-다이하이드로-1Example 20. 2- (4-fluorobenzyl) -4- (7-chloro-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 1에서 제조한 4-클로로-2-(4-플루오로벤질)-5,6-다이메틸피리미딘(200 mg, 0.798 mmol)과 참조예 3과 동일한 방법으로 제조한 7-클로로-1,2,3,4-테트라하이드로아이소퀴놀린(669 mg, 3.99 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(57.1%)을 제조하였다.4-Chloro-2- (4-fluorobenzyl) -5,6-dimethylpyrimidine (200 mg, 0.798 mmol) prepared in Reference Example 1 and 7-chloro-1 prepared in the same manner as in Reference Example 3. The title compound (57.1%) was prepared in the same manner as in Example 1 using, 2,3,4-tetrahydroisoquinoline (669 mg, 3.99 mmol).

¹H-NMR (400MHz, DMSO-d₆) δ 7.59 (m, 2H), 7.30-7.35 (m, 6H), 5.03 (m, 2H), 4.30 (s, 2H), 4.08 (t, 2H), 3.07 (t, 2H), 2.59 (s, 3H), 2.41 (s, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.59 (m, 2H), 7.30-7.35 (m, 6H), 5.03 (m, 2H), 4.30 (s, 2H), 4.08 (t, 2H), 3.07 (t, 2H), 2.59 (s, 3H), 2.41 (s, 3H)

실시예 21. 2-(2-플루오로벤질)-4-(1-메틸-3,4-다이하이드로-1Example 21. 2- (2-fluorobenzyl) -4- (1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

단계 1: 2-(2-플루오로페닐)-아세트아미딘 염산염Step 1: 2- (2-fluorophenyl) -acetamidine hydrochloride

2-(2-플루오로페닐)아세토나이트릴(1.2 g, 78.36 mmol)을 사용하여, 참조예 1의 단계 1과 동일한 방법으로 표제화합물(9.0 g)을 제조하여, 추가의 정제 과정 없이 다음 단계에서 사용하였다.Using the 2- (2-fluorophenyl) acetonitrile (1.2 g, 78.36 mmol) to prepare the title compound (9.0 g) in the same manner as in Step 1 of Reference Example 1, the following step was carried out without further purification. Used in

단계 2: 2-(2-플루오로벤질)-5,6-다이메틸피리미딘-4-올 Step 2: 2- (2-fluorobenzyl) -5,6-dimethylpyrimidin-4-ol

단계 1에서 제조한 2-(2-플루오로페닐)-아세트아미딘 염산염(9.0 g, 59.14 mmol)을 사용하여 참조예 1의 단계 2와 동일한 방법으로 표제화합물(60%)을 제조하였다.The title compound (60%) was prepared in the same manner as Step 2 of Reference Example 1 using 2- (2-fluorophenyl) -acetamidine hydrochloride (9.0 g, 59.14 mmol) prepared in Step 1.

Rf = 0.1 (n-헥세인 /에틸아세테이트 = 2/1, v/v)Rf = 0.1 (n-hexane / ethyl acetate = 2/1, v / v)

¹H-NMR (400MHz, CDCl₃) δ d 11.1(brs,1H), 7.4(m,1H), 7.3(m,1H), 7.1(m,2H), 4.0(s,2H), 2.3(s,3H), 2.0(s,3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ d 11.1 (brs, 1H), 7.4 (m, 1H), 7.3 (m, 1H), 7.1 (m, 2H), 4.0 (s, 2H), 2.3 (s , 3H), 2.0 (s, 3H)

단계 3: 2-(2-플루오로벤질)-4-클로로-5,6-다이메틸피리미딘 Step 3: 2- (2-fluorobenzyl) -4-chloro-5,6-dimethylpyrimidine

단계 2 에서 제조한 2-(2-플루오로벤질)-5,6-다이메틸피리미딘-4-올(4.0 g, 17.22 mmol)을 사용하여 참조예 1의 단계 3과 동일한 방법으로 표제화합물(82.3%)을 제조하였다.Using 2- (2-fluorobenzyl) -5,6-dimethylpyrimidin-4-ol (4.0 g, 17.22 mmol) prepared in Step 2, the title compound ( 82.3%) was prepared.

Rf = 0.6 (n-헥세인 /에틸아세테이트 = 2/1, v/v)Rf = 0.6 (n-hexane / ethyl acetate = 2/1, v / v)

¹H-NMR (400MHz, CDCl₃) δ 7.3(m,1H), 7.1(m,1H), 7.0(m,2H), 4.2(s,2H), 2.5(s,3H), 2.3(s,3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.3 (m, 1H), 7.1 (m, 1H), 7.0 (m, 2H), 4.2 (s, 2H), 2.5 (s, 3H), 2.3 (s, 3H)

단계 4: 2-(2-플루오로벤질)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Step 4: 2- (2-fluorobenzyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

단계 3에서 제조한 2-(2-플루오로벤질)-4-클로로-5,6-다이메틸피리미딘(1.0 g, 3.99 mmol)과 참조예 3과 동일한 방법으로 제조한 1-메틸-1,2,3,4-테트라하이드로아이소퀴놀린(0.6 g, 3.99 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(46.0%)을 제조하였다.2- (2-fluorobenzyl) -4-chloro-5,6-dimethylpyrimidine (1.0 g, 3.99 mmol) prepared in step 3 and 1-methyl-1 prepared in the same manner as in Reference Example 3; The title compound (46.0%) was prepared in the same manner as in Example 1 using 2,3,4-tetrahydroisoquinoline (0.6 g, 3.99 mmol).

Rf = 0.4(n-헥세인 /에틸아세테이트 = 2/1, v/v) Rf = 0.4 (n-hexane / ethyl acetate = 2/1, v / v)

¹H-NMR (400MHz, CDCl₃) δ 7.5(t,1H), 7.3(m,1H), 7.2(m,2H), 7.1(m,3H), 7.0(m,1H), 5.3(m,1H), 4.6(dd,2H), 4.3(m,1H), 3.6(m,1H), 3.0(m,1H), 2.9(m,1H), 2.7(s,3H), 2.3(s,3H), 1.5(s,3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.5 (t, 1H), 7.3 (m, 1H), 7.2 (m, 2H), 7.1 (m, 3H), 7.0 (m, 1H), 5.3 (m, 1H), 4.6 (dd, 2H), 4.3 (m, 1H), 3.6 (m, 1H), 3.0 (m, 1H), 2.9 (m, 1H), 2.7 (s, 3H), 2.3 (s, 3H ), 1.5 (s, 3H)

실시예 22. 2-(3-클로로벤질)-4-(6-플루오로-1-메틸-3,4-다이하이드로-1Example 22. 2- (3-chlorobenzyl) -4- (6-fluoro-1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

단계 1: 2-(3-클로로페닐)-아세트아미딘 염산염Step 1: 2- (3-chlorophenyl) -acetamide hydrochloride

2-(3-클로로페닐)아세토나이트릴을 사용하여, 참조예 1의 단계 1과 동일한 방법으로 표제화합물을 제조하여, 추가의 정제 과정 없이 다음 단계에서 사용하였다.The title compound was prepared in the same manner as in Step 1 of Reference Example 1 using 2- (3-chlorophenyl) acetonitrile, and used in the next step without further purification.

단계 2: 2-(3-클로로벤질)-5,6-다이메틸피리미딘-4-올Step 2: 2- (3-chlorobenzyl) -5,6-dimethylpyrimidin-4-ol

단계 1에서 제조한 2-(3-클로로페닐)-아세트아미딘 염산염을 사용하여 참조예 1의 단계 2와 동일한 방법으로 표제화합물(85%)을 제조하였다.The title compound (85%) was prepared in the same manner as Step 2 of Reference Example 1 using 2- (3-chlorophenyl) -acetamidine hydrochloride prepared in Step 1.

Rf = 0.47 (다이클로로메테인/메탄올 = 10/1, v/v)Rf = 0.47 (dichloromethane / methanol = 10/1, v / v)

¹H-NMR (400MHz, CDCl₃) δ 7.46 (s, 1H), 7.13-7.32 (m, 3H), 3.91 (s, 2H), 2.33 (s, 3H), 2.07 (s, 3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.46 (s, 1H), 7.13-7.32 (m, 3H), 3.91 (s, 2H), 2.33 (s, 3H), 2.07 (s, 3H)

단계 3: 2-(3-클로로벤질)-4-클로로-5,6-다이메틸피리미딘 Step 3: 2- (3-chlorobenzyl) -4-chloro-5,6-dimethylpyrimidine

단계 2 에서 제조한 2-(3-클로로벤질)-5,6-다이메틸피리미딘-4-올을 사용하여 참조예 1의 단계 3과 동일한 방법으로 표제화합물(95%)을 제조하였다.The title compound (95%) was prepared in the same manner as Step 3 of Reference Example 1 using 2- (3-chlorobenzyl) -5,6-dimethylpyrimidin-4-ol prepared in Step 2.

Rf = 0.54 (에틸아세테이트/n-헥세인 = 3/7, v/v)Rf = 0.54 (ethyl acetate / n-hexane = 3/7, v / v)

¹H-NMR (400MHz, CDCl₃) δ 7.41 (s, 1H), 7.34-7.36 (m, 1H), 7.18-7.25 (m, 2H), 4.29 (s, 2H), 2.66 (s, 3H), 2.35 (s, 3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.41 (s, 1H), 7.34-7.36 (m, 1H), 7.18-7.25 (m, 2H), 4.29 (s, 2H), 2.66 (s, 3H), 2.35 (s, 3 H)

단계 4: 2-(3-클로로벤질)-4-(6-플루오로-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Step 4: 2- (3-chlorobenzyl) -4- (6-fluoro-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine Hydrochloride

단계 3에서 제조한 2-(3-클로로벤질)-4-클로로-5,6-다이메틸피리미딘(500 mg, 1.87 mmol)과 참조예 3과 동일한 방법으로 제조한 6-플루오로-1-메틸-1,2,3,4-테트라하이드로아이소퀴놀린(464 mg, 2.81 mmol)을 사용하여 실시예 1과 동일한 방법으로 백색 고체상의 표제화합물(72%)을 제조하였다.2- (3-chlorobenzyl) -4-chloro-5,6-dimethylpyrimidine (500 mg, 1.87 mmol) prepared in step 3 and 6-fluoro-1- prepared in the same manner as in Reference Example 3 The title compound (72%) was prepared in the same manner as in Example 1 using methyl-1,2,3,4-tetrahydroisoquinoline (464 mg, 2.81 mmol).

¹H-NMR (400MHz, DMSO) δ 7.53 (s, 1H), 7.36-7.41 (m, 3H), 7.22-7.26 (m, 1H), 7.00-7.06(m, 2H), 5.46 (br, 1H), 4.28 (br, 1H), 4.19 (dd, 2H), 3.60 (m, 1H), 3.04-3.07 (m, 1H), 2.88-2.91 (m, 1H), 2.46 (s, 3H), 2.28 (s, 3H), 1.51 (d, 3H) ¹ H-NMR (400 MHz, DMSO) δ 7.53 (s, 1H), 7.36-7.41 (m, 3H), 7.22-7.26 (m, 1H), 7.00-7.06 (m, 2H), 5.46 (br, 1H) , 4.28 (br, 1H), 4.19 (dd, 2H), 3.60 (m, 1H), 3.04-3.07 (m, 1H), 2.88-2.91 (m, 1H), 2.46 (s, 3H), 2.28 (s , 3H), 1.51 (d, 3H)

실시예 23. 2-(4-클로로벤질)-4-(1(R)-메틸-3,4-다이하이드로-1Example 23. 2- (4-Chlorobenzyl) -4- (1 (R) -methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

단계 1: 2-(4-클로로페닐)-아세트아미딘 염산염Step 1: 2- (4-chlorophenyl) -acetamidine hydrochloride

2-(4-클로로페닐)아세토나이트릴을 사용하여, 참조예 1의 단계 1과 동일한 방법으로 표제화합물을 제조하여, 추가의 정제 과정 없이 다음 단계에서 사용하였다.The title compound was prepared in the same manner as Step 1 of Reference Example 1 using 2- (4-chlorophenyl) acetonitrile, and used in the next step without further purification.

단계 2: 2-(4-클로로벤질)-5,6-다이메틸피리미딘-4-올 Step 2: 2- (4-chlorobenzyl) -5,6-dimethylpyrimidin-4-ol

단계 1에서 제조한 2-(4-클로로페닐)-아세트아미딘 염산염을 사용하여 참조예 1의 단계 2와 동일한 방법으로 표제화합물(55%)을 제조하였다.The title compound (55%) was prepared in the same manner as Step 2 of Reference Example 1 using 2- (4-chlorophenyl) -acetamidine hydrochloride prepared in Step 1.

Rf = 0.54 (메탄올/다이클로로메테인 = 1/10, v/v)Rf = 0.54 (methanol / dichloromethane = 1/10, v / v)

¹H-NMR (400MHz, CDCl₃) δ 7.36-7.38 (m, 2H), 7.24-7.26 (m, 2H), 3.90 (s, 2H), 2.32 (s, 3H), 2.05 (s, 3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.36-7.38 (m, 2H), 7.24-7.26 (m, 2H), 3.90 (s, 2H), 2.32 (s, 3H), 2.05 (s, 3H)

단계 3: 4-클로로-2-(4-클로로벤질)-5,6-다이메틸피리미딘Step 3: 4-chloro-2- (4-chlorobenzyl) -5,6-dimethylpyrimidine

단계 2 에서 제조한 2-(4-클로로벤질)-5,6-다이메틸피리미딘-4-올을 사용하여 참조예 1의 단계 3과 동일한 방법으로 표제화합물(99%)을 제조하였다.The title compound (99%) was prepared in the same manner as in Step 3 of Reference Example 1, using 2- (4-chlorobenzyl) -5,6-dimethylpyrimidin-4-ol prepared in Step 2.

Rf = 0.47 (에틸아세테이트/n-헥세인 = 3/7, v/v)Rf = 0.47 (ethyl acetate / n-hexane = 3/7, v / v)

¹H-NMR (400MHz, CDCl₃) δ 7.36-7.37 (m, 2H), 7.24-7.26 (m, 2H), 4.26 (s, 2H), 2.64 (s, 3H), 2.36 (s, 3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.36-7.37 (m, 2H), 7.24-7.26 (m, 2H), 4.26 (s, 2H), 2.64 (s, 3H), 2.36 (s, 3H)

단계 4: 2-(4-클로로벤질)-4-(1(R)-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Step 4: 2- (4-chlorobenzyl) -4- (1 (R) -methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

단계 3에서 제조한 4-클로로-2-(4-클로로벤질)-5,6-다이메틸피리미딘(300 mg, 1.12 mmol)과 공지의 방법(KR1998-0030034)으로 제조한 1(R)-메틸-1,2,3,4-테 트라하이드로아이소퀴놀린(496 mg, 3.37 mmol)을 사용하여 실시예 1과 동일한 방법으로 백색 고체상의 표제화합물(38.5%)을 제조하였다.4-chloro-2- (4-chlorobenzyl) -5,6-dimethylpyrimidine (300 mg, 1.12 mmol) prepared in step 3 and 1 (R)-prepared by the known method (KR1998-0030034). The title compound (38.5%) in white solid phase was prepared in the same manner as in Example 1 using methyl-1,2,3,4-tetrahydroisoquinoline (496 mg, 3.37 mmol).

¹H-NMR (400MHz, DMSO-d₆) δ d 7.44 (mr, 4H), 7.17-7.20 (m, 4H), 5.45 (br, 1H), 4.27 (dd, 1H), 4.19 (dd, 2H), 3.57-3.65 (m, 1H), 3.03-3.09 (m, 1H), 2.87 (dd, 1H), 2.47 (s, 3H), 2.27 (s, 3H), 1.52 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ d 7.44 (mr, 4H), 7.17-7.20 (m, 4H), 5.45 (br, 1H), 4.27 (dd, 1H), 4.19 (dd, 2H) , 3.57-3.65 (m, 1H), 3.03-3.09 (m, 1H), 2.87 (dd, 1H), 2.47 (s, 3H), 2.27 (s, 3H), 1.52 (d, 3H)

실시예 24. 2-(4-클로로벤질)-4-(1(S)-메틸-3,4-다이하이드로-1Example 24. 2- (4-Chlorobenzyl) -4- (1 (S) -methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

실시예 23의 단계 3에서 제조한 2-(4-클로로벤질)-4-클로로-5,6-다이메틸피리미딘(300 mg, 1.12 mmol)과 공지의 방법(KR1998-0030033)으로 제조한 1(S)-메틸-1,2,3,4-테트라하이드로아이소퀴놀린(496 mg, 3.37 mmol)을 사용하여 실시예 1과 동일한 방법으로 백색 고체상의 표제화합물(33.5%)을 제조하였다.2- (4-chlorobenzyl) -4-chloro-5,6-dimethylpyrimidine (300 mg, 1.12 mmol) prepared in step 3 of Example 23 and 1 prepared by a known method (KR1998-0030033). Using (S) -methyl-1,2,3,4-tetrahydroisoquinoline (496 mg, 3.37 mmol), the title compound (33.5%) was prepared in the same manner as in Example 1.

¹H-NMR (400MHz, DMSO-d₆) δ 7.44 (m, 4H), 7.16-7.21 (m, 4H), 5.45 (br, 1H), 4.28 (dd, 1H), 4.19 (dd, 2H), 3.59-3.65 (m, 1H), 3.04-3.11 (m, 1H), 2.88 (dd, 1H), 2.47 (s, 3H), 2.28 (s, 3H), 1.53 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.44 (m, 4H), 7.16-7.21 (m, 4H), 5.45 (br, 1H), 4.28 (dd, 1H), 4.19 (dd, 2H), 3.59-3.65 (m, 1H), 3.04-3.11 (m, 1H), 2.88 (dd, 1H), 2.47 (s, 3H), 2.28 (s, 3H), 1.53 (d, 3H)

실시예 25. 5,6-다이메틸-2-(1-페닐에틸)-4-(1(R)-메틸-3,4-다이하이드로- 1Example 25. 5,6-dimethyl-2- (1-phenylethyl) -4- (1 (R) -methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-피리미딘 염산염Isoquinolin-2-yl) -pyrimidine hydrochloride

단계 1: 2-페닐프로피온아미딘 염산염Step 1: 2-phenylpropionamidine hydrochloride

2-페닐프로피오나이트릴을 사용하여, 참조예 1의 단계 1과 동일한 방법으로 표제화합물을 제조하여, 추가의 정제 과정 없이 다음 단계에서 사용하였다.Using 2-phenylpropionitrile, the title compound was prepared in the same manner as in Step 1 of Reference Example 1, and used in the next step without further purification.

단계 2: 5,6-다이메틸-2-(1-페닐에틸)-피리미딘-4-올Step 2: 5,6-dimethyl-2- (1-phenylethyl) -pyrimidin-4-ol

단계 1에서 제조한 2-페닐프로피온아미딘 염산염을 사용하여 참조예 1의 단계 2와 동일한 방법으로 표제화합물(74%)을 제조하였다.The title compound (74%) was prepared in the same manner as in Step 2 of Reference Example 1, using 2-phenylpropionamidine hydrochloride prepared in Step 1.

Rf = 0.30 (에틸아세테이트/n-헥세인 = 3/7, v/v)Rf = 0.30 (ethyl acetate / n-hexane = 3/7, v / v)

¹H-NMR (400MHz, CDCl₃) δ 7.38-7.40 (m, 2H), 7.21-7.31 (m, 3H), 4.04 (q, 1H), 2.33 (s, 3H), 2.04 (s, 3H), 1.66 (d, 3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.38-7.40 (m, 2H), 7.21-7.31 (m, 3H), 4.04 (q, 1H), 2.33 (s, 3H), 2.04 (s, 3H), 1.66 (d, 3 H)

단계 3: 4-클로로-5,6-다이메틸-2-(1-페닐에틸)-피리미딘Step 3: 4-chloro-5,6-dimethyl-2- (1-phenylethyl) -pyrimidine

단계 2 에서 제조한 5,6-다이메틸-2-(1-페닐에틸)-피리미딘-4-올을 사용하여 참조예 1의 단계 3과 동일한 방법으로 표제화합물(99%)을 수율로 제조하였다.Using the 5,6-dimethyl-2- (1-phenylethyl) -pyrimidin-4-ol prepared in step 2, the title compound (99%) was prepared in the same manner as in step 3 of Reference Example 1. It was.

Rf = 0.59 (에틸아세테이트/n-헥세인 = 3/7, v/v)Rf = 0.59 (ethyl acetate / n-hexane = 3/7, v / v)

1H-NMR (400MHz, CDCl3) d 7.44-7.46 (m, 2H), 7.26-7.30 (m, 2H), 7.18-7.22 (m, 1H). 4.45 (q, 1H), 2.57 (s, 3H), 2.31 (s, 3H), 1.72 (d, 3H)1 H-NMR (400 MHz, CDCl 3) d 7.44-7.46 (m, 2H), 7.26-7.30 (m, 2H), 7.18-7.22 (m, 1H). 4.45 (q, 1H), 2.57 (s, 3H), 2.31 (s, 3H), 1.72 (d, 3H)

단계 4: 5,6-다이메틸-2-(1-페닐에틸)-4-(1(R)-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘 염산염Step 4: 5,6-dimethyl-2- (1-phenylethyl) -4- (1 (R) -methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -pyrimidine hydrochloride

단계 3에서 제조한 4-클로로-5,6-다이메틸-2-(1-페닐에틸)-피리미딘(600 mg, 2.43 mmol)과 공지의 방법(KR1998-0030034)으로 제조한 1(R)-메틸-1,2,3,4-테트라하이드로아이소퀴놀린(1790 mg, 12.16 mmol)을 사용하여 실시예 1과 동일한 방법으로 백색 고체상의 표제화합물(46.5%)을 제조하였다.4-Chloro-5,6-dimethyl-2- (1-phenylethyl) -pyrimidine (600 mg, 2.43 mmol) prepared in step 3 and 1 (R) prepared by a known method (KR1998-0030034) The title compound (46.5%) in white solid phase was prepared in the same manner as in Example 1 using -methyl-1,2,3,4-tetrahydroisoquinoline (1790 mg, 12.16 mmol).

¹H-NMR (400MHz, DMSO-d₆) δ 7.52 (s, 2H), 7.43 (s, 2H), 7.18-7.36 (m, 14H), 5.56 (br, 2H), 4.51 (br, 2H), 4.34 (br, 2H), 3.56-3.67 (m, 2H), 3.03-3.19 (m, 2H), 2.87-2.94 (m, 2H), 2.45 (s, 6H), 2.24 (s, 3H), 2.22 (s, 3H), 1.63-1.70 (m, 9H), 1.54 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.52 (s, 2H), 7.43 (s, 2H), 7.18-7.36 (m, 14H), 5.56 (br, 2H), 4.51 (br, 2H), 4.34 (br, 2H), 3.56-3.67 (m, 2H), 3.03-3.19 (m, 2H), 2.87-2.94 (m, 2H), 2.45 (s, 6H), 2.24 (s, 3H), 2.22 ( s, 3H), 1.63-1.70 (m, 9H), 1.54 (d, 3H)

실시예 26. 5,6-다이메틸-2-(1-페닐에틸)-4-(1,6-다이메틸-3,4-다이하이드로-1Example 26. 5,6-Dimethyl-2- (1-phenylethyl) -4- (1,6-dimethyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-피리미딘 염산염Isoquinolin-2-yl) -pyrimidine hydrochloride

실시예 25의 단계 3에서 제조한 4-클로로-5,6-다이메틸-2-(1-페닐에틸)-피리미딘(200 mg, 0.811 mmol)과 참조예 3과 동일한 방법으로 제조한 1,6-다이메틸-1,2,3,4-테트라하이드로아이소퀴놀린(431 mg, 2.43 mmol)을 사용하여 실시예 1과 동일한 방법으로 백색 고체상의 표제화합물(34.5%)을 제조하였다.4-Chloro-5,6-dimethyl-2- (1-phenylethyl) -pyrimidine (200 mg, 0.811 mmol) prepared in Step 3 of Example 25, and 1, prepared in the same manner as in Reference Example 3, Using the 6-dimethyl-1,2,3,4-tetrahydroisoquinoline (431 mg, 2.43 mmol), the title compound (34.5%) was prepared in the same manner as in Example 1.

¹H-NMR (400MHz, DMSO-d₆ with TFA) δ 7.40-7.42 (m, 4H), 7.22-7.32 (m, 6H), 6.92-7.10 (m, 6H), 5.48 (br, 2H), 4.30-4.40 (m, 4H), 3.51-3.57 (m, 2H), 2.96 (m, 2H), 2.78-2.81 (m, 2H), 2.37 (s, 6H), 2.19 (s, 12H), 1.64 (d, 3H), 1.58 (d, 3H), 1.53 (d, 3H), 1.47 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ with TFA) δ 7.40-7.42 (m, 4H), 7.22-7.32 (m, 6H), 6.92-7.10 (m, 6H), 5.48 (br, 2H), 4.30 -4.40 (m, 4H), 3.51-3.57 (m, 2H), 2.96 (m, 2H), 2.78-2.81 (m, 2H), 2.37 (s, 6H), 2.19 (s, 12H), 1.64 (d , 3H), 1.58 (d, 3H), 1.53 (d, 3H), 1.47 (d, 3H)

실시예 27. 5,6-다이메틸-2-(1-페닐에틸)-4-(1,7-다이메틸-3,4-다이하이드로-1Example 27. 5,6-dimethyl-2- (1-phenylethyl) -4- (1,7-dimethyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-피리미딘 염산염Isoquinolin-2-yl) -pyrimidine hydrochloride

실시예 25의 단계 3에서 제조한 4-클로로-5,6-다이메틸-2-(1-페닐에틸)-피리미딘(200 mg, 0.811 mmol)과 참조예 3과 동일한 방법으로 제조한 1,7-다이메틸-1,2,3,4-테트라하이드로아이소퀴놀린(653 mg, 4.05 mmol)을 사용하여 실시예 1과 동일한 방법으로 백색 고체상의 표제화합물(63.8%)을 제조하였다.4-Chloro-5,6-dimethyl-2- (1-phenylethyl) -pyrimidine (200 mg, 0.811 mmol) prepared in Step 3 of Example 25, and 1, prepared in the same manner as in Reference Example 3, Using the 7-dimethyl-1,2,3,4-tetrahydroisoquinoline (653 mg, 4.05 mmol), the title compound (63.8%) in white solid was prepared in the same manner as in Example 1.

¹H-NMR (400MHz, DMSO-d₆with TFA) δ 7.48 (d, 4H), 7.27-7.40 (m, 6H), 7.00-7.10 (m, 6H), 5.57 (br, 2H), 4.37-4.41 (m, 4H), 3.61 (m, 2H), 3.03 (m, 2H), 2.89 (m, 2H), 2.43 (s, 6H), 2.28 (s, 6H), 2.26 (s, 6H), 1.66 (d, 6H), 1.56 (d, 6H) ¹ H-NMR (400 MHz, DMSO-d ₆ with TFA) δ 7.48 (d, 4H), 7.27-7.40 (m, 6H), 7.00-7.10 (m, 6H), 5.57 (br, 2H), 4.37-4.41 (m, 4H), 3.61 (m, 2H), 3.03 (m, 2H), 2.89 (m, 2H), 2.43 (s, 6H), 2.28 (s, 6H), 2.26 (s, 6H), 1.66 ( d, 6H), 1.56 (d, 6H)

실시예 28. [1-(4-플루오로페닐)-1-메틸-에틸]-5,6-다이메틸-4-(1,6-다이메 틸-3,4-다이하이드로-1Example 28. [1- (4-Fluorophenyl) -1-methyl-ethyl] -5,6-dimethyl-4- (1,6-dimethyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-피리미딘 염산염Isoquinolin-2-yl) -pyrimidine hydrochloride

단계 1: 2-(4-플루오로페닐)-2-메틸프로피오나이트릴Step 1: 2- (4-fluorophenyl) -2-methylpropionitrile

(4-플루오로페닐)아세토나이트릴(5 g, 37 mmol)의 무수 테트라하이드로퓨란(555 ml) 용액에 메틸 아이오다이드(5.1 ml, 81.40 mmol), 18-크라운-6(2.45 g, 9.25 mmol)을 상온에서 가하였다. 혼합물을 -78℃로 냉각한 후, tert-뷰톡시화칼륨(9.13 mg, 81.40 mmol)을 가하고 -78℃에서 2시간, 상온에서 2시간씩 교반하였다. 염화암모늄 포화수용액(100 ml)를 -78℃에서 가한 후, 상온에서 다이클로로메테인(15 ml x 5)으로 추출하였다. 추출액을 무수 황산마그네슘으로 건조하고 여과, 감압 농축한 잔사를 실리카겔 관 크로마토그래피(에틸아세테이트/n-헥세인 = 5/95, v/v)로 분리하여 무색 유체상의 표제화합물(5.58 g, 92%)을 제조하였다.To a solution of (4-fluorophenyl) acetonitrile (5 g, 37 mmol) in anhydrous tetrahydrofuran (555 ml) methyl iodide (5.1 ml, 81.40 mmol), 18-crown-6 (2.45 g, 9.25 mmol) was added at room temperature. After the mixture was cooled to -78 ° C, tert -butoxylated potassium potassium (9.13 mg, 81.40 mmol) was added thereto, and stirred at -78 ° C for 2 hours and at room temperature for 2 hours. A saturated aqueous ammonium chloride solution (100 ml) was added at -78 ° C, and extracted with dichloromethane (15 ml x 5) at room temperature. The extract was dried over anhydrous magnesium sulfate, filtered and the residue concentrated under reduced pressure was separated by silica gel column chromatography (ethyl acetate / n-hexane = 5/95, v / v) to give the title compound as a colorless fluid (5.58 g, 92%). ) Was prepared.

Rf = 0.58 (에틸아세테이트/n-헥세인 = 3/7, v/v)Rf = 0.58 (ethyl acetate / n-hexane = 3/7, v / v)

¹H-NMR (400MHz, CDCl₃) δ 7.46-7.48 (m, 2H), 7.05-7.10 (m, 2H), 1.72 (s, 6H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.46-7.48 (m, 2H), 7.05-7.10 (m, 2H), 1.72 (s, 6H)

단계 2: 2-(4-플루오로페닐)-2-메틸프로피온아미딘 염산염Step 2: 2- (4-fluorophenyl) -2-methylpropionamidine hydrochloride

단계 1에서 제조한 2-(4-플루오로페닐)-2-메틸프로피오나이트릴을 사용하여 참조예 1의 단계 1과 같은 방법으로 표제화합물을 제조하여 추가 정제 없이 다음 단계에서 사용하였다.The title compound was prepared in the same manner as Step 1 of Reference Example 1 using 2- (4-fluorophenyl) -2-methylpropionitrile prepared in Step 1, and used in the next step without further purification.

단계 3: 2-[1-(4-플루오로페닐)-1-메틸-에틸]-5,6-다이메틸피리미딘-4-올Step 3: 2- [1- (4-fluorophenyl) -1-methyl-ethyl] -5,6-dimethylpyrimidin-4-ol

단계 2에서 제조한 2-(4-플루오로페닐)-2-메틸프로피온아미딘 염산염을 사용하여 참조예 1의 단계 2와 동일한 방법으로 표제화합물(66%)을 제조하였다.The title compound (66%) was prepared in the same manner as in Step 2 of Reference Example 1, using 2- (4-fluorophenyl) -2-methylpropionamidine hydrochloride prepared in Step 2.

Rf = 0.53 (다이클로로메테인/메탄올 = 1/10, v/v)Rf = 0.53 (dichloromethane / methanol = 1/10, v / v)

¹H-NMR (400MHz, CDCl₃) δ 7.23-7.26 (m, 2H), 5.96-7.01 (m, 3H), 2.33 (s, 3H), 2.00 (s, 3H), 1.67 (d, 6H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.23-7.26 (m, 2H), 5.96-7.01 (m, 3H), 2.33 (s, 3H), 2.00 (s, 3H), 1.67 (d, 6H)

단계4: 4-클로로-2-[1-(4-플루오로페닐)-1-메틸-에틸]-5,6-다이메틸피리미딘Step 4: 4-chloro-2- [1- (4-fluorophenyl) -1-methyl-ethyl] -5,6-dimethylpyrimidine

단계 3 에서 제조한 2-[1-(4-플루오로페닐)-1-메틸-에틸]-5,6-다이메틸피리미딘-4-올을 사용하여 참조예 1의 단계 3과 동일한 방법으로 표제화합물(97%)을 제조하였다.In the same manner as in Step 3 of Reference Example 1, using 2- [1- (4-fluorophenyl) -1-methyl-ethyl] -5,6-dimethylpyrimidin-4-ol prepared in Step 3 The title compound (97%) was prepared.

Rf = 0.91 (에틸아세테이트/n-헥세인 = 3/7, v/v)Rf = 0.91 (ethyl acetate / n-hexane = 3/7, v / v)

¹H-NMR (400MHz, CDCl₃) δ 7.25-7.29 (m, 2H), 6.91-6.95 (m, 3H), 2.47 (s, 3H), 2.29 (s, 3H), 1.76 (d, 6H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.25-7.29 (m, 2H), 6.91-6.95 (m, 3H), 2.47 (s, 3H), 2.29 (s, 3H), 1.76 (d, 6H)

단계 5: [1-(4-플루오로페닐)-1-메틸-에틸]-5,6-다이메틸-4-(1,6-다이메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘 염산염Step 5: [1- (4-Fluorophenyl) -1-methyl-ethyl] -5,6-dimethyl-4- (1,6-dimethyl-3,4-dihydro-1 H -isoquinoline 2-yl) -pyrimidine hydrochloride

단계 4에서 제조한 4-클로로-2-[1-(4-플루오로페닐)-1-메틸-에틸]-5,6-다이메틸피리미딘(200 mg, 0.717 mmol)과 참조예 3과 동일한 방법으로 제조한 1,6-다이메틸-1,2,3,4-테트라하이드로아이소퀴놀린(347 mg, 2.15 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(46%)을 제조하였다.4-Chloro-2- [1- (4-fluorophenyl) -1-methyl-ethyl] -5,6-dimethylpyrimidine (200 mg, 0.717 mmol) prepared in Step 4 was the same as in Reference Example 3. The title compound (46%) was prepared in the same manner as in Example 1 using 1,6-dimethyl-1,2,3,4-tetrahydroisoquinoline (347 mg, 2.15 mmol) prepared by the method.

¹H-NMR (400MHz, DMSO-d₆ with TFA) δ 7.32-7.46 (m, 2H), 7.24-7.29 (m, 3H), 7.13-7.16 (m, 2H), 5.65 (br, 1H), 4.46 (br, 1H), 3.76 (t, 1H), 3.23 (t, 1H), 3.00 (dd, 1H), 2.54 (s, 3H), 2.39 (s, 3H), 2.38 (s, 3H), 1.88 (s, 3H), 1.87 (s, 3H), 1.72 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ with TFA) δ 7.32-7.46 (m, 2H), 7.24-7.29 (m, 3H), 7.13-7.16 (m, 2H), 5.65 (br, 1H), 4.46 (br, 1H), 3.76 (t, 1H), 3.23 (t, 1H), 3.00 (dd, 1H), 2.54 (s, 3H), 2.39 (s, 3H), 2.38 (s, 3H), 1.88 ( s, 3H), 1.87 (s, 3H), 1.72 (d, 3H)

실시예 29. 2-[1-(4-플루오로페닐)-사이클로프로필]-5,6-다이메틸-4-(1-메틸-3,4-다이하이드로-1Example 29. 2- [1- (4-fluorophenyl) -cyclopropyl] -5,6-dimethyl-4- (1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-피리미딘 염산염Isoquinolin-2-yl) -pyrimidine hydrochloride

단계 1: 1-(4-플루오로페닐)-사이클로프로페인카보나이트릴Step 1: 1- (4-fluorophenyl) -cyclopropanecarbonitrile

(4-플루오로페닐)아세토나이트릴(5.0 g, 40.0 mmol), N,N,N-트라이메틸벤질암모늄클로라이드(138 mg, 0.70 mmol) 및 1-브로모-2-클로로에테인(6.16 ml, 74.0 mmol)의 반응혼합물에 50% 수산화나트륨 수용액(20.72 g, 74.0 mmol)을 45℃에서 천천히 적가하였다. 반응혼합물을 동일온도에서 6시간 동안 교반하고 실온으로 냉각 한 후, 물(50 ml)로 희석하고 다이클로로메테인(15 ml)으로 5회 추출하였다. 분리한 유기층을 무수 황산마그네슘으로 건조 여과하여 감압농축하였다. 감압농축한 잔사를 실리카겔 관 크로마토그래피(에틸아세테이트/n-헥세인 = 3/7, v/v)로 분리정제하여 무색 유체상의 표제화합물(2.5 g, 42%)을 제조하였다.(4-fluorophenyl) acetonitrile (5.0 g, 40.0 mmol), N , N , N -trimethylbenzylammonium chloride (138 mg, 0.70 mmol) and 1-bromo-2-chloroethane (6.16 ml, 74.0 mmol) of the reaction mixture was slowly added dropwise at 50 ° C to 50% aqueous sodium hydroxide solution (20.72 g, 74.0 mmol). The reaction mixture was stirred at the same temperature for 6 hours, cooled to room temperature, diluted with water (50 ml) and extracted five times with dichloromethane (15 ml). The separated organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated residue under reduced pressure was purified by silica gel column chromatography (ethyl acetate / n-hexane = 3/7, v / v) to obtain the title compound (2.5 g, 42%) as a colorless fluid.

¹H-NMR (400MHz, CDCl₃) δ 7.26-7.30 (m, 2H), 7.02-7.06 (m, 2H), 1.71 (dd, 2H), 1.36 (dd, 2H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.26-7.30 (m, 2H), 7.02-7.06 (m, 2H), 1.71 (dd, 2H), 1.36 (dd, 2H)

단계 2: 1-(4-플루오로페닐)-사이클로프로페인카복스아미딘 염산염Step 2: 1- (4-fluorophenyl) -cyclopropanecarboxamidine hydrochloride

단계 1에서 제조한 1-(4-플루오로페닐)-사이클로프로페인카보나이트릴을 사용하여 참조예 1의 단계 1과 같은 방법으로 표제화합물을 제조하여 추가 정제 없이 다음 단계에서 사용하였다.Using the 1- (4-fluorophenyl) -cyclopropanecarbonitrile prepared in step 1 in the same manner as in step 1 of Reference Example 1, the title compound was prepared and used in the next step without further purification.

단계 3: 2-[1-(4-플루오로페닐)-사이클로프로필]-5,6-다이메틸피리미딘-4-올Step 3: 2- [1- (4-fluorophenyl) -cyclopropyl] -5,6-dimethylpyrimidin-4-ol

단계 2에서 제조한 1-(4-플루오로페닐)-사이클로프로페인카복스아미딘 염산염을 사용하여 참조예 1의 단계 2와 동일한 방법으로 표제화합물(65%)을 제조하였다.The title compound (65%) was prepared in the same manner as in Step 2 of Reference Example 1, using 1- (4-fluorophenyl) -cyclopropanecarboxamidine hydrochloride prepared in Step 2.

Rf = 0.63 (다이클로로메테인/메탄올 = 1/10, v/v)Rf = 0.63 (dichloromethane / methanol = 1/10, v / v)

¹H-NMR (400MHz, CDCl₃) δ 8.74 (br, 1H), 7.37-7.40 (m, 2H), 7.07-7.11 (m, 2H), 2.25 (s, 3H), 1.99 (s, 3H), 1.75 (dd, 2H), 1.28 (dd, 2H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.74 (br, 1H), 7.37-7.40 (m, 2H), 7.07-7.11 (m, 2H), 2.25 (s, 3H), 1.99 (s, 3H), 1.75 (dd, 2H), 1.28 (dd, 2H)

단계 4: 4-클로로-2-[1-(4-플루오로페닐)-사이클로프로필]-5,6-다이메틸피리미딘Step 4: 4-chloro-2- [1- (4-fluorophenyl) -cyclopropyl] -5,6-dimethylpyrimidine

단계 3에서 제조한 2-[1-(4-플루오로페닐)-사이클로프로필]-5,6-다이메틸피리미딘-4-올을 사용하여 참조예 1의 단계 3과 동일한 방법으로 표제화합물(91%)을 제조하였다.Using the 2- [1- (4-fluorophenyl) -cyclopropyl] -5,6-dimethylpyrimidin-4-ol prepared in step 3 in the same manner as in step 3 of Reference Example 1 91%) was prepared.

Rf = 0.62 (에틸아세테이트/n-헥세인 = 3/7, v/v)Rf = 0.62 (ethyl acetate / n-hexane = 3/7, v / v)

¹H-NMR (400MHz, CDCl₃) δ 7.32-7.36 (m, 2H), 5.97-7.01 (m, 2H), 2.39 (s, 3H), 2.26 (s, 3H), 1.67 (dd, 2H), 1.31 (dd, 2H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.32-7.36 (m, 2H), 5.97-7.01 (m, 2H), 2.39 (s, 3H), 2.26 (s, 3H), 1.67 (dd, 2H), 1.31 (dd, 2H)

단계 5: 2-[1-(4-플루오로페닐)-사이클로프로필]-5,6-다이메틸-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘 염산염Step 5: 2- [1- (4-Fluorophenyl) -cyclopropyl] -5,6-dimethyl-4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl ) -Pyrimidine hydrochloride

단계 4에서 제조한 4-클로로-2-[1-(4-플루오로페닐)-사이클로프로필]-5,6-다이메틸피리미딘(600 mg, 2.17 mmol)과 참조예 3과 동일한 방법으로 제조한 1-메틸-1,2,3,4-테트라하이드로아이소퀴놀린(1.596 g, 10.84 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(85%)을 제조하였다.4-Chloro-2- [1- (4-fluorophenyl) -cyclopropyl] -5,6-dimethylpyrimidine (600 mg, 2.17 mmol) prepared in Step 4 was prepared in the same manner as in Reference Example 3. Using the 1-methyl-1,2,3,4-tetrahydroisoquinoline (1.596 g, 10.84 mmol) in the same manner as in Example 1 to prepare the title compound (85%).

¹H-NMR (400MHz, DMSO-d₆) δ 7.47 (m, 2H), 7.21 (m, 6H), 5.47 (q, 1H), 4.30 (m, 1H), 3.64 (m, 1H), 3.11 (m, 1H), 2.91 (dd, 1H), 2.45 (s, 3H), 2.28 (s, 3H), 1.89 (dd, 1H), 1.72 (dd, 1H), 1.57 (m, 4H), 1.26 (dd, 1H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.47 (m, 2H), 7.21 (m, 6H), 5.47 (q, 1H), 4.30 (m, 1H), 3.64 (m, 1H), 3.11 ( m, 1H), 2.91 (dd, 1H), 2.45 (s, 3H), 2.28 (s, 3H), 1.89 (dd, 1H), 1.72 (dd, 1H), 1.57 (m, 4H), 1.26 (dd , 1H)

실시예 30. 2-[1-(4-플루오로페닐)-사이클로프로필]-5,6-다이메틸-4-(1,6-다이메틸-3,4-다이하이드로-1Example 30. 2- [1- (4-fluorophenyl) -cyclopropyl] -5,6-dimethyl-4- (1,6-dimethyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-피리미딘 염산염Isoquinolin-2-yl) -pyrimidine hydrochloride

실시예 29의 단계 4에서 제조한 4-클로로-2-[1-(4-플루오로페닐)-사이클로프로필]-5,6-다이메틸피리미딘(200 mg, 0.723 mmol)과 참조예 3과 동일한 방법으로 제조한 1-메틸-1,2,3,4-테트라하이드로아이소퀴놀린(350 mg, 2.17 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(85%)을 제조하였다.4-chloro-2- [1- (4-fluorophenyl) -cyclopropyl] -5,6-dimethylpyrimidine (200 mg, 0.723 mmol) prepared in Step 4 of Example 29, and Reference Example 3 The title compound (85%) was prepared in the same manner as in Example 1 using 1-methyl-1,2,3,4-tetrahydroisoquinoline (350 mg, 2.17 mmol) prepared in the same manner.

¹H-NMR (DMSO-d₆ with TFA) δ 7.18 (dd, 2H), 6.94 (t, 2H), 6.74-6.85 (m, 3H), 5.14 (brs, 1H), 4.00 (m, 1H), 3.33 (m, 1H), 2.78 (m, 1H), 2.58 (dd, 1H), 2.17 (s, 3H), 2.00 (s, 6H), 1.57-1.60 (m, 1H), 1.39-1.44 (m, 1H), 1.27-1.31 (m, 1H), 1.27 (d, 3H), 1.15-1.18 (m, 1H) ¹ H-NMR (DMSO-d ₆ with TFA) δ 7.18 (dd, 2H), 6.94 (t, 2H), 6.74-6.85 (m, 3H), 5.14 (brs, 1H), 4.00 (m, 1H), 3.33 (m, 1H), 2.78 (m, 1H), 2.58 (dd, 1H), 2.17 (s, 3H), 2.00 (s, 6H), 1.57-1.60 (m, 1H), 1.39-1.44 (m, 1H), 1.27-1.31 (m, 1H), 1.27 (d, 3H), 1.15-1.18 (m, 1H)

실시예 31. 5,6-다이메틸-2-(1-페닐프로필)-4-(1(S)-메틸-1,2,3,4-테트라하이드로아이소퀴놀린-2-일)-피리미딘 염산염Example 31. 5,6-dimethyl-2- (1-phenylpropyl) -4- (1 (S) -methyl-1,2,3,4-tetrahydroisoquinolin-2-yl) -pyrimidine Hydrochloride

단계 1: 2-페닐뷰틸아미딘 염산염Step 1: 2-phenylbutylamidine hydrochloride

2-페닐뷰타이로나이트릴을 사용하여 참조예 1의 단계 1과 동일한 방법으로 표제화합물을 제조하여 추가의 정제없이 다음 단계에서 사용하였다.The title compound was prepared in the same manner as in Step 1 of Reference Example 1 using 2-phenylbutyronitrile, and used in the next step without further purification.

단계 2: 5,6-다이메틸-2-(1-페닐프로필)-피리미딘-4-올Step 2: 5,6-dimethyl-2- (1-phenylpropyl) -pyrimidin-4-ol

단계 1에서 제조한 2-페닐뷰틸아미딘 염산염을 사용하여 참조예 1의 단계 2와 동일한 방법으로 표제화합물(85%)을 제조하였다.The title compound (85%) was prepared in the same manner as in Step 2 of Reference Example 1, using 2-phenylbutylamidine hydrochloride prepared in Step 1.

Rf = 0.70 (메탄올/ 다이클로로메테인 = 1/10, v/v)Rf = 0.70 (methanol / dichloromethane = 1/10, v / v)

¹H-NMR (400MHz, CDCl₃) δ 7.40-7.42 (m, 2H), 7.20-7.30 (m, 3H), 3.72 (t, 1H), 2.33 (s, 3H), 2.22-2.31 (m, 1H), 1.97-2.08 (m, 1H), 2.05 (s, 3H), 0.89 (d, 3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.40-7.42 (m, 2H), 7.20-7.30 (m, 3H), 3.72 (t, 1H), 2.33 (s, 3H), 2.22-2.31 (m, 1H ), 1.97-2.08 (m, 1H), 2.05 (s, 3H), 0.89 (d, 3H)

단계 3: 4-클로로-5,6-다이메틸-2-(1-페닐프로필)-피리미딘Step 3: 4-chloro-5,6-dimethyl-2- (1-phenylpropyl) -pyrimidine

단계 2에서 제조한 5,6-다이메틸-2-(1-페닐프로필)-피리미딘-4-올(721 mg, 29.38 mmol)을 사용하여 참조예 1의 단계 3과 동일한 방법으로 표제화합물(98%)을 제조하였다.Using 5,6-dimethyl-2- (1-phenylpropyl) -pyrimidin-4-ol (721 mg, 29.38 mmol) prepared in step 2, the title compound ( 98%) was prepared.

Rf = 0.72 (에틸아세테이트/n-헥세인 = 3/7, v/v)Rf = 0.72 (ethyl acetate / n-hexane = 3/7, v / v)

¹H-NMR (400MHz, CDCl₃) δ 7.57-7.59 (m, 2H), 7.24-7.35 (m, 3H), 4.69 (t, 1H), 2.88 (s, 3H), 2.45 (s, 3H), 2.27-2.37 (m, 1H), 2.18-2.25 (m, 1H), 0.94 (d, 3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.57-7.59 (m, 2H), 7.24-7.35 (m, 3H), 4.69 (t, 1H), 2.88 (s, 3H), 2.45 (s, 3H), 2.27-2.37 (m, 1H), 2.18-2.25 (m, 1H), 0.94 (d, 3H)

단계 4: 5,6-다이메틸-2-(1-페닐프로필)-4-(1(S)-메틸-1,2,3,4-테트라하이드로아이소퀴놀린-2-일)-피리미딘 염산염Step 4: 5,6-dimethyl-2- (1-phenylpropyl) -4- (1 (S) -methyl-1,2,3,4-tetrahydroisoquinolin-2-yl) -pyrimidine hydrochloride

단계 3에서 제조한 4-클로로-5,6-다이메틸-2-(1-페닐프로필)-피리미딘(500 mg, 1.92 mmol)과 공지의 방법(KR1998-0030033)으로 제조한 1(S)-메틸-1,2,3,4-테트라하이드로아이소퀴놀린(847 mg, 5.75 mmol)을 사용하여 실시예 1과 동일한 방법으로 표제화합물(35%)을 제조하였다.4-Chloro-5,6-dimethyl-2- (1-phenylpropyl) -pyrimidine (500 mg, 1.92 mmol) prepared in step 3 and 1 (S) prepared by the known method (KR1998-0030033) The title compound (35%) was prepared in the same manner as in Example 1 using -methyl-1,2,3,4-tetrahydroisoquinoline (847 mg, 5.75 mmol).

¹H-NMR (400MHz, DMSO-d₆) δ 7.52-7.54 (m, 2H), 7.44-7.46 (m, 2H), 7.22-7.40 (m, 14H), 5.74 (br, 2H), 4.39 (br, 2H), 4.12-4.18 (m, 2H), 3.58-3.72 (m, 2H), 3.08-3.22 (m, 2H), 2.92-2.99 (m, 2H), 2.46 (s, 3H), 2.44 (s, 3H), 2.21-2.38 (m, 2H), 2.27 (s, 3H), 2.26 (s, 3H), 2.09 (m, 2H), 1.70 (d, 3H), 1.60 (d, 3H), 0.90 (t, 3H), 0.84 (t, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.52-7.54 (m, 2H), 7.44-7.46 (m, 2H), 7.22-7.40 (m, 14H), 5.74 (br, 2H), 4.39 (br , 2H), 4.12-4.18 (m, 2H), 3.58-3.72 (m, 2H), 3.08-3.22 (m, 2H), 2.92-2.99 (m, 2H), 2.46 (s, 3H), 2.44 (s , 3H), 2.21-2.38 (m, 2H), 2.27 (s, 3H), 2.26 (s, 3H), 2.09 (m, 2H), 1.70 (d, 3H), 1.60 (d, 3H), 0.90 ( t, 3H), 0.84 (t, 3H)

실시예 32. 2-(2-플루오로벤질)-4-(6-클로로-1-메틸-3,4-다이하이드로-1Example 32. 2- (2-fluorobenzyl) -4- (6-chloro-1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 2에서 제조한 5,6-다이메틸-4-(6-클로로-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-트라이뷰틸스텐일피리미딘(100 mg, 0.173 mmol)을 1,2-다이클로로에테인(3.2 ml)에 녹이고 비스(트라이페닐포스핀)다이클로로팔라듐(II)(6 mg, 5mol%, 0.009 mmol)과 2-플루오로벤질클로라이드(0.031 ml, 0.260 mmol)을 가 하고 10시간 동안 환류교반하였다. 반응혼합물을 감압농축하고 잔사를 실리카겔 관 크로마토그래피(에틸아세테이트/n-헥세인 = 3/7, v/v)를 사용하여 정제하여 무색 유체상의 2-(2-플루오로벤질)-4-(6-클로로-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘(15.0 mg, 22%)을 제조하고, 에틸아세테이트(2 ml)에 녹인 후 염산기체를 포화시켜 생성된 침전물을 여과, 분리하여 백색 고체상의 표제화합물(10 mg, 63%)을 제조하였다.5,6-dimethyl-4- (6-chloro-1-methyl-3,4-dihydro- 1H -isoquinolin-2-yl) -2-tributylstenylpyrimidine prepared in Reference Example 2 (100 mg, 0.173 mmol) is dissolved in 1,2-dichloroethane (3.2 ml) and bis (triphenylphosphine) dichloropalladium (II) (6 mg, 5mol%, 0.009 mmol) and 2-fluorobenzyl Chloride (0.031 ml, 0.260 mmol) was added and stirred under reflux for 10 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 3/7, v / v) to give 2- (2-fluorobenzyl) -4- ( Prepare 6-Chloro-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine (15.0 mg, 22%), and ethyl acetate (2 ml). ), And then, the resulting precipitate was filtered and separated by saturation of hydrochloric acid gas to obtain the title compound (10 mg, 63%) as a white solid.

¹H-NMR (400MHz, CDCl₃) δ 7.00-7.24 (m, 6H), 6.93 (d, 1H), 4.88 (q, 1H), 4.10 (dd, 2H), 3.80 (dd, 1H), 3.31-3.38 (m, 1H), 3.01 (m, 1H), 2.59 (dd, 1H), 2.39 (s, 3H), 2.15 (s, 3H), 1.40 (d, 3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.00-7.24 (m, 6H), 6.93 (d, 1H), 4.88 (q, 1H), 4.10 (dd, 2H), 3.80 (dd, 1H), 3.31- 3.38 (m, 1H), 3.01 (m, 1H), 2.59 (dd, 1H), 2.39 (s, 3H), 2.15 (s, 3H), 1.40 (d, 3H)

실시예 33. 2-(3-플루오로벤질)-4-(6-클로로-1-메틸-3,4-다이하이드로-1Example 33. 2- (3-fluorobenzyl) -4- (6-chloro-1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 2에서 제조한 5,6-다이메틸-4-(6-클로로-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-트라이뷰틸스텐일피리미딘(100 mg, 0.173 mmol)과 3-플루오로벤질클로라이드(0.032 ml, 0.260 mmol)를 사용하여 실시예 32와 동일한 방법으로 백색 고체상의 표제화합물(43%)을 제조하였다.5,6-dimethyl-4- (6-chloro-1-methyl-3,4-dihydro- 1H -isoquinolin-2-yl) -2-tributylstenylpyrimidine prepared in Reference Example 2 (100 mg, 0.173 mmol) and 3-fluorobenzylchloride (0.032 ml, 0.260 mmol) were prepared in the same manner as in Example 32, to obtain the title compound (43%) as a white solid.

¹H-NMR (400MHz, CDCl₃) δ 5.99-7.21 (m, 6H), 6.88 (t, 1H), 4.97 (q, 1H), 4.03 (dd, 2H), 3.85 (dd, 1H), 3.38-3.45 (m, 1H), 3.07 (m, 1H), 2.67 (dd, 1H), 2.38 (s, 3H), 2.15 (s, 3H), 1.46 (d, 3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 5.99-7.21 (m, 6H), 6.88 (t, 1H), 4.97 (q, 1H), 4.03 (dd, 2H), 3.85 (dd, 1H), 3.38- 3.45 (m, 1H), 3.07 (m, 1H), 2.67 (dd, 1H), 2.38 (s, 3H), 2.15 (s, 3H), 1.46 (d, 3H)

실시예 34. 2-(4-메틸벤질)-4-(6-클로로-1-메틸-3,4-다이하이드로-1Example 34. 2- (4-Methylbenzyl) -4- (6-chloro-1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 2에서 제조한 5,6-다이메틸-4-(6-클로로-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-트라이뷰틸스텐일피리미딘(100 mg, 0.173 mmol)과 4-메틸벤질클로라이드(0.034 ml, 0.26 mmol)를 사용하여 실시예 32와 동일한 방법으로 백색 고체상의 표제화합물(28.5%)을 제조하였다.5,6-dimethyl-4- (6-chloro-1-methyl-3,4-dihydro- 1H -isoquinolin-2-yl) -2-tributylstenylpyrimidine prepared in Reference Example 2 (100 mg, 0.173 mmol) and 4-methylbenzylchloride (0.034 ml, 0.26 mmol) were prepared in the same manner as in Example 32, to obtain the title compound (28.5%) as a white solid.

(Free base) ¹H-NMR (400MHz, CDCl₃) δ 7.22 (d, 2H), 7.00-7.13 (m, 5H), 4.97 (q, 1H), 3.99 (dd, 2H), 3.84 (dd, 1H), 3.37-3.45 (m, 1H), 3.08 (m, 1H), 2.67 (dd, 1H), 2.36 (s, 3H), 2.30 (s, 3H), 2.13 (s, 3H), 1.46 (d, 3H)(Free base) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.22 (d, 2H), 7.00-7.13 (m, 5H), 4.97 (q, 1H), 3.99 (dd, 2H), 3.84 (dd, 1H ), 3.37-3.45 (m, 1H), 3.08 (m, 1H), 2.67 (dd, 1H), 2.36 (s, 3H), 2.30 (s, 3H), 2.13 (s, 3H), 1.46 (d, 3H)

실시예 35. 2-(4-트라이플루오로메틸벤질)-4-(6-클로로-1-메틸-3,4-다이하이드로-1Example 35. 2- (4-Trifluoromethylbenzyl) -4- (6-chloro-1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 2에서 제조한 5,6-다이메틸-4-(6-클로로-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-트라이뷰틸스텐일피리미딘(100 mg, 0.173 mmol)과 4-트라 이플루오로메틸벤질클로라이드(62 mg, 0.26 mmol)를 사용하여 실시예 32와 동일한 방법으로 백색 고체상의 표제화합물(19.6%)을 제조하였다.5,6-dimethyl-4- (6-chloro-1-methyl-3,4-dihydro- 1H -isoquinolin-2-yl) -2-tributylstenylpyrimidine prepared in Reference Example 2 (100 mg, 0.173 mmol) and 4-trifluoromethylbenzylchloride (62 mg, 0.26 mmol) were prepared in the same manner as in Example 32, to obtain the title compound (19.6%) as a white solid.

(Free base) ¹H-NMR (400MHz, CDCl₃) δ 7.50 (d, 2H), 7.42 (d, 2H), 7.13 (dd, 1H), 7.07 (s, 1H), 6.98 (d, 1H), 4.93 (q, 1H), 4.08 (dd, 2H), 3.82 (dd, 1H), 3.37-3.44 (m, 1H), 3.01 (m, 1H), 2.64 (dd, 1H), 2.38 (s, 3H), 2.15 (s, 3H), 1.45 (d, 3H)(Free base) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.50 (d, 2H), 7.42 (d, 2H), 7.13 (dd, 1H), 7.07 (s, 1H), 6.98 (d, 1H), 4.93 (q, 1H), 4.08 (dd, 2H), 3.82 (dd, 1H), 3.37-3.44 (m, 1H), 3.01 (m, 1H), 2.64 (dd, 1H), 2.38 (s, 3H) , 2.15 (s, 3H), 1.45 (d, 3H)

실시예 36. 2-(4-트라이플루오로메톡시벤질)-4-(6-클로로-1-메틸-3,4-다이하이드로-1Example 36. 2- (4-Trifluoromethoxybenzyl) -4- (6-chloro-1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 2에서 제조한 5,6-다이메틸-4-(6-클로로-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-트라이뷰틸스텐일피리미딘(100 mg, 0.173 mmol)과 4-트라이플루오로메톡시벤질클로라이드(0.042 ml, 0.26 mmol)를 사용하여 실시예 32와 동일한 방법으로 백색 고체상의 표제화합물(22.4%)을 제조하였다.5,6-dimethyl-4- (6-chloro-1-methyl-3,4-dihydro- 1H -isoquinolin-2-yl) -2-tributylstenylpyrimidine prepared in Reference Example 2 (100 mg, 0.173 mmol) and 4-trifluoromethoxybenzylchloride (0.042 ml, 0.26 mmol) were prepared in the same manner as in Example 32, to obtain the title compound (22.4%) as a white solid.

(Free base) ¹H-NMR (400MHz, CDCl₃) δ 7.32 (d, 2H), 7.07-7.14 (m, 4H), 6.99 (d, 1H), 4.95 (q, 1H), 4.03 (dd, 2H), 3.83 (dd, 1H), 3.37-3.44 (m, 1H), 3.02 (m, 1H), 2.64 (dd, 1H), 2.38 (s, 3H), 2.15 (s, 3H), 1.45 (d, 3H)(Free base) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.32 (d, 2H), 7.07-7.14 (m, 4H), 6.99 (d, 1H), 4.95 (q, 1H), 4.03 (dd, 2H ), 3.83 (dd, 1H), 3.37-3.44 (m, 1H), 3.02 (m, 1H), 2.64 (dd, 1H), 2.38 (s, 3H), 2.15 (s, 3H), 1.45 (d, 3H)

실시예 37. 2-(2-클로로벤질)-4-(6-클로로-1-메틸-3,4-다이하이드로-1Example 37. 2- (2-chlorobenzyl) -4- (6-chloro-1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

참조예 2에서 제조한 5,6-다이메틸-4-(6-클로로-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-트라이뷰틸스텐일피리미딘(100 mg, 0.173 mmol)과 2-클로로벤질클로라이드(0.033 ml, 0.26 mmol)를 사용하여 실시예 32와 동일한 방법으로 백색 고체상의 표제화합물(25.8%)을 제조하였다.5,6-dimethyl-4- (6-chloro-1-methyl-3,4-dihydro- 1H -isoquinolin-2-yl) -2-tributylstenylpyrimidine prepared in Reference Example 2 (100 mg, 0.173 mmol) and 2-chlorobenzylchloride (0.033 ml, 0.26 mmol) were prepared in the same manner as in Example 32, to obtain the title compound (25.8%) as a white solid.

¹H-NMR (400MHz, CDCl₃) δ 7.36 (dd, 1H), 7.15-7.21 (m, 3H), 7.03-7.09 (m, 2H), 6.91 (d, 1H), 4.84 (q, 1H), 4.21 (dd, 2H), 3.77 (dd, 1H), 3.29-3.36 (m, 1H), 2.97 (m, 1H), 2.56 (dd, 1H), 2.39 (s, 3H), 2.16 (s, 3H), 1.36 (d, 3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.36 (dd, 1H), 7.15-7.21 (m, 3H), 7.03-7.09 (m, 2H), 6.91 (d, 1H), 4.84 (q, 1H), 4.21 (dd, 2H), 3.77 (dd, 1H), 3.29-3.36 (m, 1H), 2.97 (m, 1H), 2.56 (dd, 1H), 2.39 (s, 3H), 2.16 (s, 3H) , 1.36 (d, 3H)

실시예 38. 4-(1-메틸-3,4-다이하이드로-1Example 38. 4- (1-Methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-2-페닐메틸-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -2-phenylmethyl-5,6-dimethylpyrimidine hydrochloride

질소기류하에서 무수테트라하이드로퓨란(10 ml)에 벤질마그네슘클로라이드(1 ml, 2 mmol, 2.0 M 테트라하이드로퓨란용액)를 가하고 염화아연(II)(782 mg, 5.74 mmol)을 실온에서 천천히 적가하였다. 반응혼합물에 2-클로로-5,6-다이메틸-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘(500 mg, 1.74 mmol)과 촉 매량의 테트라키스(트라이페닐포스핀)팔라듐(0)(40 mg, 0.035 mmol)을 가하고 철야환류 교반하였다. 반응혼합물을 실온으로 냉각하고 pH 8의 에틸렌다이아민테트라아세트산 수용액에 가하였다. 수층을 에틸아세테이트(50 ml)로 추출하고 감압농축한 잔사를 실리카겔 관 크로마토그래피(에틸아세테이트/n-헥세인 = 15/85, v/v)를 사용하여 분리정제하여 백색고체상의 4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-페닐메틸-5,6-다이메틸피리미딘(320 mg)을 제조하였다. 4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-페닐메틸-5,6-다이메틸피리미딘(300 mg)을 에틸아세테이트(2 ml)에 녹인 후 염산기체를 포화시켜 생성된 침전물을 여과, 분리하여 백색 고체상의 표제화합물(320 mg)을 제조하였다.Benzyl magnesium chloride (1 ml, 2 mmol, 2.0 M tetrahydrofuran solution) was added to anhydrous tetrahydrofuran (10 ml) under nitrogen stream, and zinc (II) chloride (782 mg, 5.74 mmol) was slowly added dropwise at room temperature. The reaction mixture was reacted with 2-chloro-5,6-dimethyl-4- (1-methyl-3,4-dihydro- 1H -isoquinolin-2-yl) -pyrimidine (500 mg, 1.74 mmol). A quantity of tetrakis (triphenylphosphine) palladium (0) (40 mg, 0.035 mmol) was added and stirred at reflux overnight. The reaction mixture was cooled to room temperature and added to an aqueous solution of ethylenediaminetetraacetic acid at pH 8. The aqueous layer was extracted with ethyl acetate (50 ml), and the residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 15/85, v / v) to give a white solid of 4- (1). -Methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -2-phenylmethyl-5,6-dimethylpyrimidine (320 mg) was prepared. 4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -2-phenylmethyl-5,6-dimethylpyrimidine (300 mg) in ethyl acetate (2 ml) After melting, the hydrochloric acid gas was saturated, and the resulting precipitate was filtered and separated to obtain the title compound (320 mg) as a white solid.

¹H-NMR (400MHz, CDCl₃) δ 7.58 (d, 2H), 7.32 (m, 2H), 7.22 (m, 3H), 7.14 (d, 1H), 7.10 (d, 1H), 5.45 (brs, 1H), 4.53 (d, 1H), 4.36 (d, 1H), 4.30 (m, 1H), 3.57 (t, 1H), 3.13 (t, 1H), 2.89 (d, 1H), 2.71 (s, 3H), 2.24 (s, 3H), 1.57 (d, 3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.58 (d, 2H), 7.32 (m, 2H), 7.22 (m, 3H), 7.14 (d, 1H), 7.10 (d, 1H), 5.45 (brs, 1H), 4.53 (d, 1H), 4.36 (d, 1H), 4.30 (m, 1H), 3.57 (t, 1H), 3.13 (t, 1H), 2.89 (d, 1H), 2.71 (s, 3H ), 2.24 (s, 3H), 1.57 (d, 3H)

실시예 39. 2-(4-플루오로벤조일)-4-(1-메틸-3,4-다이하이드로-1Example 39. 2- (4-fluorobenzoyl) -4- (1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

단계 1: 5,6-다이메틸-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-트라이뷰틸스텐일피리미딘Step 1: 5,6-dimethyl-4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -2-tributylstenylpyrimidine

2-클로로-5,6-다이메틸-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘을 사용하여 참조예 2와 동일한 방법으로 무색 유체상의 표제화합물(15%)을 제조하였다.Colorless fluid in the same manner as in Reference Example 2 using 2-chloro-5,6-dimethyl-4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -pyrimidine The title compound (15%) of the phase was prepared.

Rf = 0.25 (에틸아세테이트/n-헥세인 = 3/7, v/v)Rf = 0.25 (ethyl acetate / n-hexane = 3/7, v / v)

¹H-NMR (400MHz, CDCl₃) δ 7.07-7.17 (m, 4H), 5.03 (q, 1H), 3.90 (dd, 1H), 3.47 (m, 1H), 3.23 (m, 1H), 2.75 (m, 1H), 2.37 (s, 3H), 2.16 (s, 3H), 1.51-1.68 (m, 6H), 1.49 (d, 3H), 1.28-1.37 (m, 6H), 1.00-1.17 (m, 6H), 0.87 (t, 9H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.07-7.17 (m, 4H), 5.03 (q, 1H), 3.90 (dd, 1H), 3.47 (m, 1H), 3.23 (m, 1H), 2.75 ( m, 1H), 2.37 (s, 3H), 2.16 (s, 3H), 1.51-1.68 (m, 6H), 1.49 (d, 3H), 1.28-1.37 (m, 6H), 1.00-1.17 (m, 6H), 0.87 (t, 9H)

단계 2: 2-(4-플루오로벤조일)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Step 2: 2- (4-fluorobenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

단계 1에서 제조한 5,6-다이메틸-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-트라이뷰틸스텐일피리미딘(180 mg, 0.332 mmol)을 10 ml의 테트라하이드로퓨란에 녹이고 -78℃에서 4-플루오로벤조일클로라이드(0.063 ml, 0.498 mmol)을 천천히 적가하고 동일온도에서 3시간 동안 교반하였다. 반응혼합물을 실온으로 유지하고 5 ml의 포화 탄산수소나트륨을 가하고 다이클로로메테인(20 ml)으로 추출하였다. 분리한 유기층을 감압농축하고, 잔사를 실리카겔 관 크로마토그래피(에틸아세테이트/n-헥세인 = 25/75, v/v)를 사용하여 분리정제하고, 에틸아세테이트(2 ml)에 녹인 후 염산기체를 포화시켜 생성된 침전물을 여과, 분리하여 백색 고체상 의 표제화합물(38 mg, 28%)을 제조하였다.5,6-dimethyl-4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -2-tributylstenylpyrimidine (180 mg, 0.332 prepared in step 1) mmol) was dissolved in 10 ml of tetrahydrofuran, and 4-fluorobenzoylchloride (0.063 ml, 0.498 mmol) was slowly added dropwise at -78 ° C, and stirred for 3 hours at the same temperature. The reaction mixture was kept at room temperature and 5 ml of saturated sodium bicarbonate was added and extracted with dichloromethane (20 ml). The separated organic layer was concentrated under reduced pressure, and the residue was separated and purified using silica gel column chromatography (ethyl acetate / n-hexane = 25/75, v / v), dissolved in ethyl acetate (2 ml), and hydrochloric acid gas. The precipitate produced by saturation was filtered and separated to give the title compound (38 mg, 28%) as a white solid.

¹H-NMR (400MHz, DMSO-d₆) δ 8.30 (t, 2H), 7.49 (t, 2H), 7.20-7.28 (m, 4H), 5.49 (q, 1H), 4.33 (dd, 1H), 3.70-3.76 (m, 1H), 3.09-3.18 (m, 1H), 2.59 (s, 3H), 2.40 (s, 3H), 1.64 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (t, 2H), 7.49 (t, 2H), 7.20-7.28 (m, 4H), 5.49 (q, 1H), 4.33 (dd, 1H), 3.70-3.76 (m, 1H), 3.09-3.18 (m, 1H), 2.59 (s, 3H), 2.40 (s, 3H), 1.64 (d, 3H)

실시예 40. 2-벤조일-4-(1-메틸-3,4-다이하이드로-1Example 40. 2-benzoyl-4- (1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

실시예 39의 단계 1에서 제조한 5,6-다이메틸-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-트라이뷰틸스텐일피리미딘(100 mg, 0.184 mmol)과 벤조일클로라이드(0.05 ml, 0.369 mmol)를 사용하여, 실시예 39의 단계 2와 동일한 방법으로 백색 고체상의 표제화합물(24.5%)을 제조하였다.5,6-dimethyl-4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -2-tributylstenylpyrimidine prepared in Step 1 of Example 39 ( 100 mg, 0.184 mmol) and benzoyl chloride (0.05 ml, 0.369 mmol) were used to prepare the title compound (24.5%) as a white solid in the same manner as in Step 2 of Example 39.

¹H-NMR (400MHz, DMSO-d₆) δ 8.23 (d, 2H), 7.82 (t, 1H), 7.66 (t, 2H), 7.21 (m, 4H), 5.55 (q ,1H), 4.38 (dd, 1H), 3.73 (m, 1H), 3.21 (m, 1H), 2.94 (dd, 1H), 2.61 (s, 3H), 2.42 (s, 3H), 1.64 ( d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.23 (d, 2H), 7.82 (t, 1H), 7.66 (t, 2H), 7.21 (m, 4H), 5.55 (q, 1H), 4.38 ( dd, 1H), 3.73 (m, 1H), 3.21 (m, 1H), 2.94 (dd, 1H), 2.61 (s, 3H), 2.42 (s, 3H), 1.64 (d, 3H)

실시예 41. 2-(2-메틸벤조일)-4-(1-메틸-3,4-다이하이드로-1Example 41. 2- (2-methylbenzoyl) -4- (1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

실시예 39의 단계 1에서 제조한 5,6-다이메틸-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-트라이뷰틸스텐일피리미딘(100 mg, 0.184 mmol)과 2-메틸벤조일클로라이드(0.05 ml, 0.369 mmol)를 사용하여, 실시예 39의 단계 2와 동일한 방법으로 백색 고체상의 표제화합물(18.8%)을 제조하였다.5,6-dimethyl-4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -2-tributylstenylpyrimidine prepared in Step 1 of Example 39 ( 100 mg, 0.184 mmol) and 2-methylbenzoylchloride (0.05 ml, 0.369 mmol) were used to prepare the title compound (18.8%) as a white solid in the same manner as in Step 2 of Example 39.

¹H-NMR (400MHz, DMSO-d₆) δ 7.69 (d, 1H), 7.53 (dd, 1H), 7.39 (d, 1H), 7.34 (t, 1H), 7.15 (m, 3H), 7.03 (m, 1H), 5.34 (q, 1H), 4.23 (dd, 1H), 3.63-3.70 (m, 1H), 3.11 (m, 1H), 2.84 (dd, 1H), 2.58 (s, 3H), 2.44 (s, 3H), 2.41 (s, 3H), 1.63 (s, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.69 (d, 1H), 7.53 (dd, 1H), 7.39 (d, 1H), 7.34 (t, 1H), 7.15 (m, 3H), 7.03 ( m, 1H), 5.34 (q, 1H), 4.23 (dd, 1H), 3.63-3.70 (m, 1H), 3.11 (m, 1H), 2.84 (dd, 1H), 2.58 (s, 3H), 2.44 (s, 3H), 2.41 (s, 3H), 1.63 (s, 3H)

실시예 42. 2-(4-클로로벤조일)-4-(1-메틸-3,4-다이하이드로-1Example 42. 2- (4-Chlorobenzoyl) -4- (1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

실시예 39의 단계 1에서 제조한 5,6-다이메틸-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-트라이뷰틸스텐일피리미딘(500 mg, 0.922 mmol)과 4-클로로벤조일클로라이드(0.18 ml, 1.38 mmol)를 사용하여, 실시예 39의 단계 2와 동일한 방법으로 백색 고체상의 표제화합물(25.8%)을 제조하였다.5,6-dimethyl-4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -2-tributylstenylpyrimidine prepared in Step 1 of Example 39 ( 500 mg, 0.922 mmol) and 4-chlorobenzoylchloride (0.18 ml, 1.38 mmol) gave the title compound (25.8%) as a white solid in the same manner as in Step 2 of Example 39.

¹H-NMR (400MHz, DMSO-d₆) δ 8.25 (d, 2H), 7.73 (d, 2H), 7.21-7.26 (m, 4H), 5.54(q, 1H), 4.38 (dd, 1H), 3.72-3.79 (m, 1H), 3.12-3.19 (m, 1H), 2.95 (dd, 1H), 2.62(s, 3H), 2.42 (s, 3H), 1.65 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.25 (d, 2H), 7.73 (d, 2H), 7.21-7.26 (m, 4H), 5.54 (q, 1H), 4.38 (dd, 1H), 3.72-3.79 (m, 1H), 3.12-3.19 (m, 1H), 2.95 (dd, 1H), 2.62 (s, 3H), 2.42 (s, 3H), 1.65 (d, 3H)

실시예 43. 2-(2,4-다이플루오로벤조일)-4-(1-메틸-3,4-다이하이드로-1Example 43. 2- (2,4-difluorobenzoyl) -4- (1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

실시예 39의 단계 1에서 제조한 5,6-다이메틸-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-트라이뷰틸스텐일피리미딘(300 mg, 0.553 mmol)과 2,4-다이플루오로벤조일클로라이드(0.34 ml, 2.77 mmol)를 사용하여, 실시예 39의 단계 2와 동일한 방법으로 백색 고체상의 표제화합물(35.8%)을 제조하였다.5,6-dimethyl-4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -2-tributylstenylpyrimidine prepared in Step 1 of Example 39 ( 300 mg, 0.553 mmol) and 2,4-difluorobenzoylchloride (0.34 ml, 2.77 mmol) gave the title compound (35.8%) as a white solid in the same manner as in Step 2 of Example 39.

¹H-NMR (400MHz, DMSO-d₆ with TFA) δ 8.12 (dd, 1H), 7.44 (t, 1H), 7.34 (t, 1H), 7.18-7.20 (m, 4H), 5.43 (q, 1H), 4.40 (dd, 1H), 3.71 (m, 1H), 3.11 (m, 1H), 2.90 (dd, 1H), 2.62 (s, 3H), 2.41 (s, 3H), 1.58 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ with TFA) δ 8.12 (dd, 1H), 7.44 (t, 1H), 7.34 (t, 1H), 7.18-7.20 (m, 4H), 5.43 (q, 1H ), 4.40 (dd, 1H), 3.71 (m, 1H), 3.11 (m, 1H), 2.90 (dd, 1H), 2.62 (s, 3H), 2.41 (s, 3H), 1.58 (d, 3H)

실시예 44. 2-(2-플루오로벤조일)-4-(1-메틸-3,4-다이하이드로-1Example 44. 2- (2-fluorobenzoyl) -4- (1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

실시예 39의 단계 1에서 제조한 5,6-다이메틸-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-트라이뷰틸스텐일피리미딘(300 mg, 0.553 mmol)과 2-플루 오로벤조일클로라이드(0.33 ml, 2.77 mmol)를 사용하여, 실시예 39의 단계 2와 동일한 방법으로 백색 고체상의 표제화합물(33.2%)을 제조하였다.5,6-dimethyl-4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -2-tributylstenylpyrimidine prepared in Step 1 of Example 39 ( 300 mg, 0.553 mmol) and 2-fluorobenzoyl chloride (0.33 ml, 2.77 mmol) were used to prepare the title compound (33.2%) as a white solid in the same manner as in Step 2 of Example 39.

¹H-NMR (400MHz, DMSO-d₆ with TFA) δ 7.96 (m, 1H), 7.83 (m, 1H), 7.45 (m, 2H), 7.13-7.18 (m, 4H), 5.37 (q, 1H), 4.25 (dd, 1H), 3.80 (m, 1H), 3.08 (m, 1H), 2.87 (dd, 1H), 2.60 (s, 3H), 2.39 (s, 3H), 1.54 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ with TFA) δ 7.96 (m, 1H), 7.83 (m, 1H), 7.45 (m, 2H), 7.13-7.18 (m, 4H), 5.37 (q, 1H ), 4.25 (dd, 1H), 3.80 (m, 1H), 3.08 (m, 1H), 2.87 (dd, 1H), 2.60 (s, 3H), 2.39 (s, 3H), 1.54 (d, 3H)

실시예 45. 2-(2-클로로벤조일)-4-(1-메틸-3,4-다이하이드로-1Example 45. 2- (2-Chlorobenzoyl) -4- (1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

실시예 39의 단계 1에서 제조한 5,6-다이메틸-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-트라이뷰틸스텐일피리미딘(300 mg, 0.553 mmol)과 2-클로로벤조일클로라이드(0.33 ml, 2.77 mmol)를 사용하여, 실시예 39의 단계 2와 동일한 방법으로 백색 고체상의 표제화합물(25.1%)을 제조하였다.5,6-dimethyl-4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -2-tributylstenylpyrimidine prepared in Step 1 of Example 39 ( 300 mg, 0.553 mmol) and 2-chlorobenzoylchloride (0.33 ml, 2.77 mmol) gave the title compound (25.1%) as a white solid in the same manner as in Step 2 of Example 39.

¹H-NMR (400MHz, DMSO-d₆ with TFA) δ 7.61-7.84 (m, 4H), 7.06-7.18 (m, 4H), 5.23 (q, 1H), 4.15 (dd, 1H), 3.63 (m, 1H), 3.03 (m, 1H), 2.82 (dd, 1H), 2.61 (s, 3H), 2.38 (s, 3H), 1.48 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ with TFA) δ 7.61-7.84 (m, 4H), 7.06-7.18 (m, 4H), 5.23 (q, 1H), 4.15 (dd, 1H), 3.63 (m , 1H), 3.03 (m, 1H), 2.82 (dd, 1H), 2.61 (s, 3H), 2.38 (s, 3H), 1.48 (d, 3H)

실시예 46. 2-(4-메틸벤조일)-4-(1-메틸-3,4-다이하이드로-1Example 46. 2- (4-Methylbenzoyl) -4- (1-methyl-3,4-dihydro-1 HH -아이소퀴놀린- 2-일)-5,6-다이메틸피리미딘 염산염-Isoquinolin-2 -yl) -5,6-dimethylpyrimidine hydrochloride

실시예 39의 단계 1에서 제조한 5,6-다이메틸-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-트라이뷰틸스텐일피리미딘(300 mg, 0.553 mmol)과 4-메틸벤조일클로라이드(0.37 ml, 2.77 mmol)를 사용하여, 실시예 39의 단계 2와 동일한 방법으로 백색 고체상의 표제화합물(33.0%)을 제조하였다.5,6-dimethyl-4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -2-tributylstenylpyrimidine prepared in Step 1 of Example 39 ( 300 mg, 0.553 mmol) and 4-methylbenzoylchloride (0.37 ml, 2.77 mmol) gave the title compound (33.0%) as a white solid in the same manner as in Step 2 of Example 39.

¹H-NMR (400MHz, CDCl₃) δ 7.94 (d, 2H), 7.22 (dd, 2H), 7.11-7.16 (m, 3H), 7.05-7.07 (m, 1H), 5.10 (q, 1H), 4.01 (dd, 1H), 3.48-3.55 (m, 1H), 3.21 (m, 1H), 2.75 (dd, 1H), 2.50 (s, 3H), 2.42 (s, 3H), 2.29 (s, 3H), 1.54 (d, 3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.94 (d, 2H), 7.22 (dd, 2H), 7.11-7.16 (m, 3H), 7.05-7.07 (m, 1H), 5.10 (q, 1H), 4.01 (dd, 1H), 3.48-3.55 (m, 1H), 3.21 (m, 1H), 2.75 (dd, 1H), 2.50 (s, 3H), 2.42 (s, 3H), 2.29 (s, 3H) , 1.54 (d, 3H)

실시예 47. 2-(4-플루오로벤조일)-4-(7-메톡시-1-메틸-3,4-다이하이드로-1Example 47. 2- (4-fluorobenzoyl) -4- (7-methoxy-1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

단계 1: 5,6-다이메틸-4-(7-메톡시-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-트라이뷰틸스텐일피리미딘Step 1: 5,6-dimethyl-4- (7-methoxy-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -2-tributylstenylpyrimidine

2-클로로-5,6-다이메틸-4-(7-메톡시-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘(28.35 g, 89.21 mmol)을 사용하여 참조예 2와 동일한 방법으로 무색 유체상의 표제화합물(15%)을 제조하였다.2-Chloro-5,6-dimethyl-4- (7-methoxy-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -pyrimidine (28.35 g, 89.21 mmol) To give the title compound (15%) as a colorless fluid in the same manner as in Reference Example 2.

Rf = 0.42 (에틸아세테이트/n-헥세인 = 3/7, v/v)Rf = 0.42 (ethyl acetate / n-hexane = 3/7, v / v)

¹H-NMR (CDCl₃) δ 6.99 (d, 1H), 6.72 (d, 1H), 6.64 (s, 1H), 4.96 (q, 1H), 3.90 (dd, 1H), 3.77 (s, 3H), 3.40-3.48 (m, 1H), 3.23 (m, 1H), 2.71 (dd, 1H), 2.36 (s, 3H), 2.15 (s, 3H), 1.46-1.71 (m, 6H), 1.49 (d, 3H), 1.30-1.36 (m, 6H), 1.06-1.11(m, 6H), 0.87 (t, 9H) ¹ H-NMR (CDCl ₃ ) δ 6.99 (d, 1H), 6.72 (d, 1H), 6.64 (s, 1H), 4.96 (q, 1H), 3.90 (dd, 1H), 3.77 (s, 3H) , 3.40-3.48 (m, 1H), 3.23 (m, 1H), 2.71 (dd, 1H), 2.36 (s, 3H), 2.15 (s, 3H), 1.46-1.71 (m, 6H), 1.49 (d , 3H), 1.30-1.36 (m, 6H), 1.06-1.11 (m, 6H), 0.87 (t, 9H)

단계 2: 2-(4-플루오로벤조일)-4-(7-메톡시-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Step 2: 2- (4-fluorobenzoyl) -4- (7-methoxy-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyri Midine hydrochloride

단계 1에서 제조한 5,6-다이메틸-4-(7-메톡시-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-트라이뷰틸스텐일피리미딘(648 mg, 1.13 mmol)과 4-플루오로벤조일클로라이드(0.72 ml, 6.12 mmol)를 사용하여 실시예 39의 단계 2와 동일한 방법으로 백색 고체상의 표제화합물(43.7%)을 제조하였다.5,6-dimethyl-4- (7-methoxy-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -2-tributylstenylpyrimidine prepared in step 1 (648 mg, 1.13 mmol) and 4-fluorobenzoylchloride (0.72 ml, 6.12 mmol) were used to prepare the title compound (43.7%) as a white solid in the same manner as in Step 2 of Example 39.

¹H-NMR (CDCl₃) δ 8.09 (dd, 2H), 7.09 (t, 2H), 6.98 (d, 1H), 6.73 (dd, 1H), 6.64 (d, 1H), 5.04 (q, 1H), 3.95 (dd, 1H), 3.78 (s, 3H), 3.47-3.54 (m, 1H), 3.17 (m, 1H), 2.71 (dd, 1H), 2.50 (s, 3H), 2.29 (s, 3H), 1.51 (d, 3H) ¹ H-NMR (CDCl ₃ ) δ 8.09 (dd, 2H), 7.09 (t, 2H), 6.98 (d, 1H), 6.73 (dd, 1H), 6.64 (d, 1H), 5.04 (q, 1H) , 3.95 (dd, 1H), 3.78 (s, 3H), 3.47-3.54 (m, 1H), 3.17 (m, 1H), 2.71 (dd, 1H), 2.50 (s, 3H), 2.29 (s, 3H ), 1.51 (d, 3H)

실시예 48. 2-(4-플루오로페닐-하이드록시이미노)-4-(1-메틸-3,4-다이하이드로-1Example 48. 2- (4-Fluorophenyl-hydroxyimino) -4- (1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘Isoquinolin-2-yl) -5,6-dimethylpyrimidine

실시예 39에서 제조한 2-(4-플루오로벤조일)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염(240 mg, 0.639 mmol)을 3.2 ml의 에탄올/피리딘(1:1, v/v)에 녹이고 하이드록시아민 염산염(133 mg, 0.639 mmol)을 가하고 24시간 동안 환류교반하였다. 반응혼합물을 냉각하고 감압농축한 잔사를 물(20 ml)로 세척하고 다이클로로메테인(30 ml)으로 추출한 후, 분리한 유기층을 감압농축하였다. 잔사를 다이클로로메테인/에틸세테이트(1/10, v/v)(5 ml)로 재결정하여 백색 고체상의 표제화합물(110 mg, 44%)을 제조하였다.2- (4-fluorobenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride prepared in Example 39 (240 mg, 0.639 mmol) was dissolved in 3.2 ml of ethanol / pyridine (1: 1, v / v) and hydroxyamine hydrochloride (133 mg, 0.639 mmol) was added and stirred under reflux for 24 hours. The reaction mixture was cooled, the residue concentrated under reduced pressure was washed with water (20 ml), extracted with dichloromethane (30 ml), and the separated organic layer was concentrated under reduced pressure. The residue was recrystallized from dichloromethane / ethyl acetate (1/10, v / v) (5 ml) to give the title compound (110 mg, 44%) as a white solid.

Rf = 0.30 (다이클로로메테인/메탄올 = 15/1, v/v)Rf = 0.30 (dichloromethane / methanol = 15/1, v / v)

¹H-NMR (400MHz, CDCl₃) δ 7.49 (dd, 2H), 7.06-7.14 (m, 5H), 6.95 (dd, 1H), 4.89 (q, 1H), 3.79 (dd, 1H), 3.35-3.42 (m, 1H), 2.99 (m, 1H), 2.61 (dd, 1H), 2.46 (s, 3H), 2.22 (s, 3H), 1.41 (d, 3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.49 (dd, 2H), 7.06-7.14 (m, 5H), 6.95 (dd, 1H), 4.89 (q, 1H), 3.79 (dd, 1H), 3.35- 3.42 (m, 1H), 2.99 (m, 1H), 2.61 (dd, 1H), 2.46 (s, 3H), 2.22 (s, 3H), 1.41 (d, 3H)

실시예 49. 2-(4-플루오로페닐-메톡시이미노)-4-(1-메틸-3,4-다이하이드로-1Example 49. 2- (4-Fluorophenyl-methoxyimino) -4- (1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

실시예 39에서 제조한 2-(4-플루오로벤조일)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염(200 mg, 0.533 mmol)과 메톡시아민염산염(89 mg, 1.07 mmol)을 사용하여 실시예 48과 동일한 방법으로 무색 유 체상의 2-(4-플루오로페닐-메톡시이미노)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘(71%)을 제조하였다. 2-(4-플루오로페닐-메톡시이미노)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘(153 mg, 0.378 mmol)을 에틸아세테이트(2 ml)에 녹인 후 염산기체를 포화시켜 생성된 침전물을 여과, 분리하여 백색 고체상의 표제화합물(99%)을 제조하였다.2- (4-fluorobenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride prepared in Example 39 (200 mg, 0.533 mmol) and methoxyamine hydrochloride (89 mg, 1.07 mmol) in the same manner as in Example 48 using 2- (4-fluorophenyl-methoxyimino) -4- ( 1-Methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine (71%) was prepared. 2- (4-fluorophenyl-methoxyimino) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine (153 mg , 0.378 mmol) was dissolved in ethyl acetate (2 ml), and the resulting precipitate was filtered and separated by saturation of hydrochloric acid gas to obtain the title compound (99%) as a white solid.

¹H-NMR (400MHz, DMSO-d₆ with TFA) δ 7.70 (dd, 2H), 7.18-7.29 (m, 6H), 5.58 (q, 1H), 4.38 (dd, 1H), 4.02 (s, 3H), 3.73 (m, 1H), 3.15-3.21 (m, 1H), 2.52 (s, 3H), 2.40 (s, 3H), 1.62 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ with TFA) δ 7.70 (dd, 2H), 7.18-7.29 (m, 6H), 5.58 (q, 1H), 4.38 (dd, 1H), 4.02 (s, 3H ), 3.73 (m, 1H), 3.15-3.21 (m, 1H), 2.52 (s, 3H), 2.40 (s, 3H), 1.62 (d, 3H)

실시예 50. 2-[4-플루오로페닐-(2-하이드록시에틸)]-4-(1-메틸-3,4-다이하이드로-1Example 50. 2- [4-fluorophenyl- (2-hydroxyethyl)]-4- (1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

실시예 39에서 제조한 2-(4-플루오로벤조일)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염을 포화 탄산수소나트륨으로 처리한 2-(4-플루오로벤조일)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘(200 mg, 0.533 mmol)을 다이에틸에테르(2.7 ml)에 녹이고 메틸마그네슘브로마이드(0.89 ml, 1.332 mmol, 3.0 M 테트라하이드로퓨란용액)를 -78℃에서 가하고, 반응혼합물을 0℃에서 5시간 동안 교반하였다. 포화 염화암모늄수용액(1 ml)을 가하고 다이클로로메테인(15 ml)으로 추출한 유기층을 실리카겔 관 크로마토그래피(메틸렌클로라이드/메탄올 = 10/1, v/v)를 사용하여 분리정제하여 무색 유체상의 2-[4-플루오로페닐-(2-하이드록시에틸)]-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘(145 mg, 69.0%)을 제조하였다. 2-[4-플루오로페닐-(2-하이드록시에틸)]-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘(134 mg)을 에틸아세테이트(3 ml)에 녹이고 염산기체를 포화시켜 생성된 침전물을 여과, 분리하여 백색 고체상의 표제화합물(159 mg, 99%)을 제조하였다.2- (4-fluorobenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride prepared in Example 39 2- (4-fluorobenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyri treated with saturated sodium bicarbonate Midine (200 mg, 0.533 mmol) was dissolved in diethyl ether (2.7 ml) and methylmagnesium bromide (0.89 ml, 1.332 mmol, 3.0 M tetrahydrofuran solution) was added at -78 ° C, and the reaction mixture was stirred at 0 ° C for 5 hours. Was stirred. Saturated ammonium chloride solution (1 ml) was added, and the organic layer extracted with dichloromethane (15 ml) was separated and purified using silica gel column chromatography (methylene chloride / methanol = 10/1, v / v) to obtain a colorless liquid. -[4-fluorophenyl- (2-hydroxyethyl)]-4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine (145 mg, 69.0%) was prepared. 2- [4-fluorophenyl- (2-hydroxyethyl)]-4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyri Midine (134 mg) was dissolved in ethyl acetate (3 ml), and the resulting precipitate was filtered and separated by saturation of hydrochloric acid gas to obtain the title compound (159 mg, 99%) as a white solid.

¹H-NMR (400MHz, CDCl₃) δ 7.63-7.75 (m, 2H), 7.14-7.28 (m, 6H), 5.57 (m, 1H), 4.32 (m, 1H), 3.59-3.66 (m, 1H), 2.98-3.02 (m, 1H), 2.89-2.92 (m, 1H), 2.53 (s, 3H), 2.28 (s, 3H), 1.98 (s, 3H), 1.51 (d, 3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.63-7.75 (m, 2H), 7.14-7.28 (m, 6H), 5.57 (m, 1H), 4.32 (m, 1H), 3.59-3.66 (m, 1H ), 2.98-3.02 (m, 1H), 2.89-2.92 (m, 1H), 2.53 (s, 3H), 2.28 (s, 3H), 1.98 (s, 3H), 1.51 (d, 3H)

실시예 51. 2-[1-(4-플루오로페닐)-1-메톡시-에틸]-5,6-다이메틸-2-(1-메틸-3,4-다이하이드로-1Example 51. 2- [1- (4-fluorophenyl) -1-methoxy-ethyl] -5,6-dimethyl-2- (1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-피리미딘 염산염Isoquinolin-2-yl) -pyrimidine hydrochloride

실시예 50에서 제조한 2-[4-플루오로페닐-(2-하이드록시에틸)]-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염(64 mg, 0.163 mmol)의 무수 테트라하이드로퓨란(1.0 ml)용액에 소듐하이드라이드(60 wt%, 14 mg, 0.360 mmol)을 0℃에서 가하고 30분간 교반한 뒤, 아이오도메테인(24.13 ㎕, 0.17 mmol)을 0℃에서 가하고 상온에서 12시간 동안 교반하였다. 물로 반응을 종 료하고, 다이클로로메테인(10 ml)으로 추출한 유기층을 무수 황산마그네슘으로 건조, 여과하였다. 여과액을 진공 건조한 잔사를 실리카겔 크로마토그래피(에틸아세테이트/n-헥세인 = 15/85, v/v)로 정제하여 무색 유체상의 2-[1-(4-플루오로페닐)-1-메톡시-에틸]-5,6-다이메틸-2-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘(43 mg, 65%)를 제조하였다. 2-[1-(4-플루오로페닐)-1-메톡시-에틸]-5,6-다이메틸-2-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘(43 mg, 0.106 mmol)을 에틸아세테이트(2 ml)에 녹이고 0℃에서 염산기체에 포화시킨 후, 생성된 침전물을 여과, 진공 건조하여 백색 고체인 표제화합물(65%)을 제조하였다.2- [4-fluorophenyl- (2-hydroxyethyl)]-4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5 prepared in Example 50 To anhydrous tetrahydrofuran (1.0 ml) solution of 6-dimethylpyrimidine hydrochloride (64 mg, 0.163 mmol) was added sodium hydride (60 wt%, 14 mg, 0.360 mmol) at 0 ° C. and stirred for 30 minutes. Iodomethane (24.13 μl, 0.17 mmol) was added at 0 ° C. and stirred at room temperature for 12 hours. The reaction was terminated with water, and the organic layer extracted with dichloromethane (10 ml) was dried over anhydrous magnesium sulfate and filtered. The filtrate was dried in vacuo, and the residue was purified by silica gel chromatography (ethyl acetate / n-hexane = 15/85, v / v) to give 2- [1- (4-fluorophenyl) -1-methoxy as a colorless fluid. -Ethyl] -5,6-dimethyl-2- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -pyrimidine (43 mg, 65%) was prepared. 2- [1- (4-fluorophenyl) -1-methoxy-ethyl] -5,6-dimethyl-2- (1-methyl-3,4-dihydro-1 H -isoquinoline-2- Il) -pyrimidine (43 mg, 0.106 mmol) was dissolved in ethyl acetate (2 ml), saturated with hydrochloric acid at 0 ° C., and the resulting precipitate was filtered and dried in vacuo to yield the title compound (65%) as a white solid. Prepared.

(Free base) ¹H-NMR (400MHz, CDCl₃) δ 7.42 (dd, 2H), 7.35 (dd, 2H), 7.13-7.15 (m, 4H), 7.07- 7.09 (m, 4H), 6.89-6.95 (m, 4H), 4.94-5.01 (m, 2H), 3.81-3.88 (m, 2H), 3.40-3.50 (m, 2H), 3.27 (s, 3H), 3.25 (s, 3H), 3.01-3.12 (m, 2H), 2.69 (m, 2H), 2.41 (s, 3H), 2.40 (s, 3H), 2.17 (s, 6H), 1.92 (s, 3H), 1.90 (s, 3H), 1.51 (d, 3H), 1.47 (d, 3H) (Free base) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.42 (dd, 2H), 7.35 (dd, 2H), 7.13-7.15 (m, 4H), 7.07-7.09 (m, 4H), 6.89-6.95 (m, 4H), 4.94-5.01 (m, 2H), 3.81-3.88 (m, 2H), 3.40-3.50 (m, 2H), 3.27 (s, 3H), 3.25 (s, 3H), 3.01-3.12 (m, 2H), 2.69 (m, 2H), 2.41 (s, 3H), 2.40 (s, 3H), 2.17 (s, 6H), 1.92 (s, 3H), 1.90 (s, 3H), 1.51 ( d, 3H), 1.47 (d, 3H)

실시예 52. 2-[4-플루오로페닐-하이드록시메틸]-4-(1-메틸-3,4-다이하이드로-1Example 52. 2- [4-fluorophenyl-hydroxymethyl] -4- (1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

실시예 39에서 제조한 2-(4-플루오로벤조일)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염을 포화 탄산수소나트륨으로 처리한 2-(4-플루오로벤조일)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘(83 mg, 0.221 mmol)을 1.2 ml의 아이소프로필알코올에 녹이고 소듐보로하이드라이드(42 mg, 1.105 mmol)을 가하고 14시간 동안 환류교반하였다. 반응혼합물을 실온으로 냉각하고 물을 가하고 다이클로로메테인(10 ml)으로 추출한 유기층을 실리카겔 관 크로마토그래피(에틸아세테이트/n-헥산 = 3/7, v/v)를 사용하여 분리정제하여 무색 유체상의 2-[4-플루오로페닐-하이드록시메틸]-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 (78 mg, 94%)을 제조하였다. 2-[4-플루오로페닐-하이드록시메틸]-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘(78 mg, 0.207 mmol)을 에틸아세테이트(3 ml)에 녹이고 염산기체를 포화시켜 생성된 침전물을 여과, 분리하여 백색 고체상의 표제화합물(85 mg, 99%)을 제조하였다.2- (4-fluorobenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride prepared in Example 39 2- (4-fluorobenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyri treated with saturated sodium bicarbonate Midine (83 mg, 0.221 mmol) was dissolved in 1.2 ml of isopropyl alcohol, sodium borohydride (42 mg, 1.105 mmol) was added and the mixture was stirred under reflux for 14 hours. The reaction mixture was cooled to room temperature, water was added, and the organic layer extracted with dichloromethane (10 ml) was separated and purified using silica gel column chromatography (ethyl acetate / n-hexane = 3/7, v / v) to give a colorless fluid. [4-Fluorophenyl-hydroxymethyl] -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine on (78 mg, 94%) was prepared. 2- [4-fluorophenyl-hydroxymethyl] -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine (78 mg , 0.207 mmol) was dissolved in ethyl acetate (3 ml), and the resulting precipitate was filtered and separated by saturation of hydrochloric acid gas to obtain the title compound (85 mg, 99%) as a white solid.

¹H-NMR (400MHz, DMSO-d₆) δ 7.59-7.66 (m, 2H), 7.19-7.22 (m, 6H), 5.82 (s, 1H), 5.49 (m, 1H), 4.29 (m, 1H), 3.62 (m, 1H), 3.11-3.14 (m, 1H), 2.89-2.93 (m, 1H), 2.54 (s, 3H), 2.28 (s, 3H), 1.62 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.59-7.66 (m, 2H), 7.19-7.22 (m, 6H), 5.82 (s, 1H), 5.49 (m, 1H), 4.29 (m, 1H ), 3.62 (m, 1H), 3.11-3.14 (m, 1H), 2.89-2.93 (m, 1H), 2.54 (s, 3H), 2.28 (s, 3H), 1.62 (d, 3H)

실시예 53. 2-[(4-플루오로페닐)-메톡시-메틸]-5,6-다이메틸-2-(1-메틸-3,4-다이하이드로-1Example 53. 2-[(4-fluorophenyl) -methoxy-methyl] -5,6-dimethyl-2- (1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-피리미딘 염산염Isoquinolin-2-yl) -pyrimidine hydrochloride

실시예 52에서 제조한 2-[4-플루오로페닐-하이드록시메틸]-4-(1-메틸-3,4-다 이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염(70 mg, 0.185 mmol)과 아이오도 메테인을 사용하여 실시예 51과 동일한 방법으로 표제화합물(75%)을 제조하였다.2- [4-fluorophenyl-hydroxymethyl] -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6- prepared in Example 52 The title compound (75%) was prepared in the same manner as in Example 51 using dimethylpyrimidine hydrochloride (70 mg, 0.185 mmol) and iodo methane.

¹H-NMR (400MHz, DMSO-d₆ with TFA) δ 7.44-7.50 (m, 4H), 7.07-7.18 (m, 12H), 5.44 (s, 2H), 5.47 (m, 2H), 4.15 (m, 2H), 3.50 (m, 2H), 3.34 (s, 6H), 2.91-2.94 (m, 2H), 2.78 (m, 2H), 2.41 (s, 6H), 2.17 (s, 6H), 1.38-1.48 (m, 6H) ¹ H-NMR (400 MHz, DMSO-d ₆ with TFA) δ 7.44-7.50 (m, 4H), 7.07-7.18 (m, 12H), 5.44 (s, 2H), 5.47 (m, 2H), 4.15 (m , 2H), 3.50 (m, 2H), 3.34 (s, 6H), 2.91-2.94 (m, 2H), 2.78 (m, 2H), 2.41 (s, 6H), 2.17 (s, 6H), 1.38- 1.48 (m, 6H)

실시예 54. 2-[다이플루오로-(4-플루오로페닐)-메틸]-5,6-다이메틸-4-(1-메틸-3,4-다이하이드로-1Example 54. 2- [difluoro- (4-fluorophenyl) -methyl] -5,6-dimethyl-4- (1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-피리미딘 염산염Isoquinolin-2-yl) -pyrimidine hydrochloride

실시예 39에서 제조한 2-(4-플루오로벤조일)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염을 포화 탄산수소나트륨으로 처리한 2-(4-플루오로벤조일)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘(100 mg, 0.266 mmol)의 다이클로로메테인(1.5 ml)용액에 (다이에틸아미노)설퍼 트라이플로라이드(0.44 ml, 2.661 mmol)을 0℃에서 가하고 5시간 동안 교반하였다. 상온에서 탄산수소나트륨 포화 수용액(5 ml)로 반응을 종료하고 다이클로로메테인(15 ml)으로 추출한 유기층을 무수 황산마그네슘으로 건조, 여과하였다. 여과액을 진공 건조한 잔사를 실리카겔 크로마토그래피(에틸아세테이트 /n-헥세인 = 1/9, v/v)로 정제하여 황색 유체상의 2-[다이플루오로-(4-플루오로페닐)-메틸]-5,6-다이메틸-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘(60 mg, 57%)을 제조하였다. 2-[다이플루오로-(4-플루오로페닐)-메틸]-5,6-다이메틸-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘(60 mg, 0.264 mmol)을 에틸아세테이트(3 ml)에 녹인 용액을 염산 기체로 포화시켜 얻은 백색 고체를 여과, 진공 건조하여 표제화합물(47%)을 제조하였다.2- (4-fluorobenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride prepared in Example 39 2- (4-fluorobenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyri treated with saturated sodium bicarbonate To a solution of midine (100 mg, 0.266 mmol) in dichloromethane (1.5 ml) was added (diethylamino) sulfur trifluoride (0.44 ml, 2.661 mmol) at 0 ° C. and stirred for 5 hours. The reaction was terminated with saturated aqueous sodium hydrogen carbonate solution (5 ml) at room temperature, and the organic layer extracted with dichloromethane (15 ml) was dried over anhydrous magnesium sulfate and filtered. The filtrate was dried in vacuo and the residue was purified by silica gel chromatography (ethyl acetate / n-hexane = 1/9, v / v) to give 2- [difluoro- (4-fluorophenyl) -methyl] as a yellow fluid. -5,6-Dimethyl-4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -pyrimidine (60 mg, 57%) was prepared. 2- [difluoro- (4-fluorophenyl) -methyl] -5,6-dimethyl-4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl)- A white solid obtained by saturating a solution of pyrimidine (60 mg, 0.264 mmol) in ethyl acetate (3 ml) with hydrochloric acid gas was filtered and dried in vacuo to give the title compound (47%).

¹H-NMR (400MHz, CDCl₃) δ 7.61-7.65 (m, 2H), 7.03-7.17 (m, 6H), 5.02 (q, 1H), 3.91 (dd, 1H), 3.43-3.50 (m, 1H), 3.12 (m, 1H), 2.71 (dd, 1H), 2.45 (s, 3H), 2.21 (s, 3H), 1.52 (d, 3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.61-7.65 (m, 2H), 7.03-7.17 (m, 6H), 5.02 (q, 1H), 3.91 (dd, 1H), 3.43-3.50 (m, 1H ), 3.12 (m, 1H), 2.71 (dd, 1H), 2.45 (s, 3H), 2.21 (s, 3H), 1.52 (d, 3H)

실시예 55. 1-[5,6-다이메틸-6-(1-메틸-3,4-다이하이드로-1Example 55. 1- [5,6-dimethyl-6- (1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-피리미딘-2-일]-1-(4-플루오로페닐)-에틸아민 염산염Isoquinolin-2-yl) -pyrimidin-2-yl] -1- (4-fluorophenyl) -ethylamine hydrochloride

실시예 39에서 제조한 2-(4-플루오로벤조일)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염을 포화 탄산수소나트륨으로 처리한 2-(4-플루오로벤조일)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘(200 mg, 0.553 mmol)의 에테르(2.7 ml) 용액에 리튬 비스(트라이메틸실릴)아마이드(0.64 ml, 0.639 mmol, 1.0 M 테트라하이드로퓨란 용액)을 -78℃에서 가하였다. 반응혼합물에 메틸마그네슘 브로마이드(0.36 ml, 1.065 mmol, 3.0 M 에테르 용액 )을 0℃에서 가하고 2시간 동안 교반하였다. 반응 용액을 포화 암모늄클로라이드 수용액으로 종료하고 다이클로로메테인(20 ml)으로 추출하였다. 유기층을 무수 황산마그네슘으로 건조하고 여과, 진공건조한 잔사를 실리카겔 관 크로마토그래피(다이클로로메테인/메탄올 = 20/1, v/v)로 정제하여 무색 유체상의 1-[5,6-다이메틸-6-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘-2-일]-1-(4-플루오로페닐)-에틸아민(75 mg, 36%)을 제조하였다. 1-[5,6-다이메틸-6-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘-2-일]-1-(4-플루오로페닐)-에틸아민(75 mg, 0.192 mmol)의 에틸아세테이트(2 ml) 용액을 염산 기체로 포화시켜 생성된 백색 고체를 여과, 진공 건조하여 표제화합물(83 mg, 99%)을 제조하였다.2- (4-fluorobenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride prepared in Example 39 2- (4-fluorobenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyri treated with saturated sodium bicarbonate To a solution of midine (200 mg, 0.553 mmol) ether (2.7 ml) was added lithium bis (trimethylsilyl) amide (0.64 ml, 0.639 mmol, 1.0 M tetrahydrofuran solution) at -78 ° C. Methyl magnesium bromide (0.36 ml, 1.065 mmol, 3.0 M ether solution) was added to the reaction mixture at 0 ° C. and stirred for 2 hours. The reaction solution was terminated with saturated aqueous ammonium chloride solution and extracted with dichloromethane (20 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and the vacuum dried residue was purified by silica gel column chromatography (dichloromethane / methanol = 20/1, v / v) to give 1- [5,6-dimethyl- as a colorless fluid. 6- (1-Methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -pyrimidin-2-yl] -1- (4-fluorophenyl) -ethylamine (75 mg, 36 %) Was prepared. 1- [5,6-dimethyl-6- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -pyrimidin-2-yl] -1- (4-fluoro A white solid produced by saturation of ethyl acetate (2 ml) solution of phenyl) -ethylamine (75 mg, 0.192 mmol) with hydrochloric acid gas was filtered and dried in vacuo to give the title compound (83 mg, 99%).

¹H-NMR (400MHz, DMSO-d₆) δ 7.67-7.80 (m, 2H), 7.63-7.66 (m, 2H), 7.23-7.41 (m, 12H), 5.87-5.95 (m, 2H), 4.53-4.64 (m, 2H), 3.70-3.83 (m, 2H), 3.12-3.27 (m, 2H), 2.97-3.01 (m, 2H), 2.70 (s, 3H), 2.62 (s, 3H), 2.44 (s, 3H), 2.41 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H), 1.70 (d, 3H), 1.68 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.67-7.80 (m, 2H), 7.63-7.66 (m, 2H), 7.23-7.41 (m, 12H), 5.87-5.95 (m, 2H), 4.53 -4.64 (m, 2H), 3.70-3.83 (m, 2H), 3.12-3.27 (m, 2H), 2.97-3.01 (m, 2H), 2.70 (s, 3H), 2.62 (s, 3H), 2.44 (s, 3H), 2.41 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H), 1.70 (d, 3H), 1.68 (d, 3H)

실시예 56. 2-[4-플루오로페닐-아미노메틸]-4-(1-메틸-3,4-다이하이드로-1Example 56. 2- [4-fluorophenyl-aminomethyl] -4- (1-methyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

실시예 39에서 제조한 2-(4-플루오로벤조일)-4-(1-메틸-3,4-다이하이드로- 1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염을 포화 탄산수소나트륨으로 처리한 2-(4-플루오로벤조일)-4-(1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘(200 mg, 0.553 mmol)을 다이에틸에테르(2.7 ml)에 녹이고 리튬비스(트라이메틸실릴)아마이드(0.64 ml, 0.639 mmol, 1.0 M 테트라하이드로퓨란용액)을 -78℃에서 가하고 동일온도에서 30분간 교반하고 0℃로 가온하였다. 반응혼합물에 소듐사이아노보로하이드라이드(1.1 ml, 1.065 mmol)을 가하고 -78℃에서 2시간 동안 교반하였다. 포화 염화암모늄(1 ml) 수용액을 가하고 다이클로로메테인(30 ml)으로 추출한 유기층을 실리카겔 관 크로마토그래피(다이클로로메테인/메탄올 = 1/9, v/v)를 사용하여 분리정제하여 에틸아세테이트(3 ml)에 녹이고 염산기체를 포화시켜 생성된 침전물을 여과, 분리하여 백색 고체상의 표제화합물(81 mg, 36%)을 제조하였다.2- (4-fluorobenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride prepared in Example 39 2- (4-fluorobenzoyl) -4- (1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyri treated with saturated sodium bicarbonate Midine (200 mg, 0.553 mmol) was dissolved in diethyl ether (2.7 ml), and lithium bis (trimethylsilyl) amide (0.64 ml, 0.639 mmol, 1.0 M tetrahydrofuran solution) was added at -78 ° C and 30 at the same temperature. Stir for minutes and warm to 0 ° C. Sodium cyanoborohydride (1.1 ml, 1.065 mmol) was added to the reaction mixture, which was then stirred at -78 ° C for 2 hours. Saturated ammonium chloride (1 ml) aqueous solution was added, and the organic layer extracted with dichloromethane (30 ml) was separated and purified using silica gel column chromatography (dichloromethane / methanol = 1/9, v / v) to ethyl acetate. Dissolve in (3 ml) and saturate the hydrochloric acid gas, the resulting precipitate was filtered and separated to give the title compound (81 mg, 36%) as a white solid.

¹H-NMR (400MHz, DMSO-d₆) δ 7.69-7.73 (m, 2H), 7.58-7.61 (m, 2H), 7.17-7.32 (m, 12H), 5.94 (m, 1H), 5.82 (m, 1H), 5.77 (s, 1H), 5.64 (s, 1H), 4.51-4.57 (m, 2H), 3.68 (m, 2H), 3.08-3.26 (m, 2H), 2.90-2.93 (m, 2H), 2.40 (s, 3H), 2.36 (s, 3H), 2.28 (s, 3H), 2.26 (s, 3H), 1.67 (d, 3H), 1.61 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.69-7.73 (m, 2H), 7.58-7.61 (m, 2H), 7.17-7.32 (m, 12H), 5.94 (m, 1H), 5.82 (m , 1H), 5.77 (s, 1H), 5.64 (s, 1H), 4.51-4.57 (m, 2H), 3.68 (m, 2H), 3.08-3.26 (m, 2H), 2.90-2.93 (m, 2H ), 2.40 (s, 3H), 2.36 (s, 3H), 2.28 (s, 3H), 2.26 (s, 3H), 1.67 (d, 3H), 1.61 (d, 3H)

실시예 57. 2-(4-플루오로벤조일)-4-(1,6-다이메틸-3,4-다이하이드로-1Example 57. 2- (4-fluorobenzoyl) -4- (1,6-dimethyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

단계 1: 5,6-다이메틸-4-(1,6-다이메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-트라이뷰틸스텐일피리미딘Step 1: 5,6-dimethyl-4- (1,6-dimethyl-3,4-dihydro-1 H -isoquinolin-2-yl) -2-tributylstenylpyrimidine

2-클로로-5,6-다이메틸-4-(1,6-다이메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-피리미딘(28.35 g, 89.21 mmol)을 사용하여 참조예 2와 동일한 방법으로 무색 유체상의 표제화합물(42%)을 제조하였다.2-chloro-5,6-dimethyl-4- (1,6-dimethyl-3,4-dihydro-1 H -isoquinolin-2-yl) -pyrimidine (28.35 g, 89.21 mmol) was used In the same manner as in Reference Example 2, the title compound (42%) was obtained as a colorless fluid.

¹H-NMR (400MHz, CDCl₃) δ 5.96-7.01 (m, 3H), 5.07 (q, 1H), 4.00 (dd, 1H), 3.45-3.52 (m, 1H), 3.21 (m, 1H), 2.75 (dd, 1H), 2.37 (s, 3H), 2.30 (s, 3H), 2.17 (s, 3H), 1.54 (d, 3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 5.96-7.01 (m, 3H), 5.07 (q, 1H), 4.00 (dd, 1H), 3.45-3.52 (m, 1H), 3.21 (m, 1H), 2.75 (dd, 1H), 2.37 (s, 3H), 2.30 (s, 3H), 2.17 (s, 3H), 1.54 (d, 3H)

단계 2: 2-(4-플루오로벤조일)-4-(1,6-다이메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Step 2: 2- (4-fluorobenzoyl) -4- (1,6-dimethyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

단계 1에서 제조한 5,6-다이메틸-4-(1,6-다이메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-2-트라이뷰틸스텐일피리미딘(850 mg, 1.53 mmol)과 4-플루오로벤조일클로라이드(0.54 ml, 4.58 mmol)를 사용하여 실시예 39의 단계 2와 동일한 방법으로 백색 고체상의 표제화합물(92%)을 제조하였다.5,6-dimethyl-4- (1,6-dimethyl-3,4-dihydro-1 H -isoquinolin-2-yl) -2-tributylstenylpyrimidine (850 prepared in step 1 mg, 1.53 mmol) and 4-fluorobenzoylchloride (0.54 ml, 4.58 mmol) gave the title compound (92%) as a white solid in the same manner as in Step 2 of Example 39.

¹H-NMR (400MHz, DMSO-d₆ with TFA) δ 8.29 (m, 2H), 7.49 (m, 2H), 7.01-7.13 (m, 3H), 5.45 (br, 1H), 4.31 (m, 1H), 3.70 (t, 1H), 3.09 (t, 1H), 2.88 (dd, 1H), 2.59 (s, 3H), 2.39 (s, 3H), 2.26 (s, 3H), 1.59 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ with TFA) δ 8.29 (m, 2H), 7.49 (m, 2H), 7.01-7.13 (m, 3H), 5.45 (br, 1H), 4.31 (m, 1H ), 3.70 (t, 1H), 3.09 (t, 1H), 2.88 (dd, 1H), 2.59 (s, 3H), 2.39 (s, 3H), 2.26 (s, 3H), 1.59 (d, 3H)

실시예 58. 2-[4-플루오로페닐-하이드록시메틸]-4-(1,6-다이메틸-3,4-다이하이드로-1Example 58. 2- [4-fluorophenyl-hydroxymethyl] -4- (1,6-dimethyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

실시예 57에서 제조한 2-(4-플루오로벤조일)- 4-(1,6-다이메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘(110 mg, 0.282 mmol)을 사용하여 실시예 52와 동일한 방법으로 표제화합물(88%)을 제조하였다.2- (4-fluorobenzoyl) -4- (1,6-dimethyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethyl prepared in Example 57 The title compound (88%) was prepared in the same manner as in Example 52 using pyrimidine (110 mg, 0.282 mmol).

(Free base) ¹H-NMR (400MHz, CDCl₃) δ 7.44-7.48 (m, 4H), 6.92-6.99 (m, 10H), 5.62 (s, 1H), 5.59 (s, 1H), 5.02 (m, 2H), 3.93 (dd, 2H), 3.43-3.52 (m, 2H), 2.99-3.15 (m, 2H), 2.69-2.73 (m, 2H), 2.39 (s, 6H), 2.31 (s, 3H), 2.30 (s, 3H), 2.17 (s, 6H), 1.54 (d, 3H), 1.49 (d, 3H) (Free base) ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.44-7.48 (m, 4H), 6.92-6.99 (m, 10H), 5.62 (s, 1H), 5.59 (s, 1H), 5.02 (m , 2H), 3.93 (dd, 2H), 3.43-3.52 (m, 2H), 2.99-3.15 (m, 2H), 2.69-2.73 (m, 2H), 2.39 (s, 6H), 2.31 (s, 3H ), 2.30 (s, 3H), 2.17 (s, 6H), 1.54 (d, 3H), 1.49 (d, 3H)

실시예 59. 2-[플루오로-(4-플루오로페닐)-메틸]-4-(1,6-다이메틸-3,4-다이하이드로-1Example 59. 2- [Fluoro- (4-fluorophenyl) -methyl] -4- (1,6-dimethyl-3,4-dihydro-1 HH -아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염Isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride

실시예 58에서 제조한 2-[4-플루오로페닐-하이드록시메틸]]-4-(1,6-다이메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염을 포화 탄산수소나트륨으로 처리한 2-[4-플루오로페닐-하이드록시메틸]]-4-(1,6-다이메틸- 3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘을 (103 mg, 0.263 mmol)을 다이클로로메테인(1.3 ml)에 녹이고 -78℃에서 (다이에틸아미노)설퍼 트라이플로라이드(0.07 ml, 0.526 mmol)를 가한 후, 동일온도에서 1시간 동안 교반하였다. 포화 탄산수소나트륨수용액(0.5 ml)을 가하고 실온으로 가온하였다. 다이클로로메테인(5 ml)으로 추출하고 실리카겔 관 크로마토그래피(에틸아세테이트/n-헥산 = 3/7, v/v)를 사용하여 분리정제하고 에틸아세테이트(1 ml)에 녹이고 염산기체를 포화시켜 생성된 침전물을 여과, 분리하여 백색 고체상의 표제화합물(81 mg, 73%)을 제조하였다.2- [4-fluorophenyl-hydroxymethyl]]-4- (1,6-dimethyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5 prepared in Example 58 2- [4-fluorophenyl-hydroxymethyl]]-4- (1,6-dimethyl-3,4-dihydro- 1H treated with, 6-dimethylpyrimidine hydrochloride with saturated sodium bicarbonate -Isoquinolin-2-yl) -5,6-dimethylpyrimidine (103 mg, 0.263 mmol) was dissolved in dichloromethane (1.3 ml) and (diethylamino) sulfur trifluoride at -78 ° C. 0.07 ml, 0.526 mmol) was added and stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution (0.5 ml) was added and allowed to warm to room temperature. Extracted with dichloromethane (5 ml), separated and purified using silica gel column chromatography (ethyl acetate / n-hexane = 3/7, v / v), dissolved in ethyl acetate (1 ml), and saturated with hydrochloric acid. The resulting precipitate was filtered and separated to give the title compound (81 mg, 73%) as a white solid.

¹H-NMR (400MHz, DMSO-d₆ with TFA) δ 7.59 (m, 4H), 7.23 (m, 4H), 6.91-7.03 (m, 6H) 6.77 (d, 1H), 6.66 (d, 1H), 5.34 (m, 2H), 4.20 (dd, 2H), 3.48-3.56 (m, 2H), 2.86-3.15 (m, 2H), 2.78 (dd, 2H), 2.45 (s, 6H), 2.23 (s, 6H), 2.19 (s, 6H), 1.49 (d, 3H), 1.38 (d, 3H) ¹ H-NMR (400 MHz, DMSO-d ₆ with TFA) δ 7.59 (m, 4H), 7.23 (m, 4H), 6.91-7.03 (m, 6H) 6.77 (d, 1H), 6.66 (d, 1H) , 5.34 (m, 2H), 4.20 (dd, 2H), 3.48-3.56 (m, 2H), 2.86-3.15 (m, 2H), 2.78 (dd, 2H), 2.45 (s, 6H), 2.23 (s , 6H), 2.19 (s, 6H), 1.49 (d, 3H), 1.38 (d, 3H)

시험예 1. 프로톤펌프(HTest Example 1. Proton Pump (H ⁺⁺ /K/ K ⁺⁺ - ATPase) 활성 억제 효과-ATPase) inhibitory effect

1-1. 프로톤 펌프 효소원의 제조1-1. Preparation of Proton Pump Enzyme Sources

돼지(Hog)를 치사시킨 뒤 위를 적출하여 위 내벽세포를 유리판을 이용하여 취한 다음, 0.25M 슈크로스 완충액 상에서 호모게나이저로 세포를 균질화하였다. 이 균질액을 8,000 rpm 속도로 35분간 원심분리하고 상층액을 다시 25,000 rpm에서 1시간 15분 동안 초고속 원심 분리하여 얻어진 침전물(pellet)을 다시 슈크로스 완 충액에서 균질화한 후 농도구배가 형성된 완충액과 9% 피콜 용액 튜브위로 위치시킨 후 다시 초고속 원심분리를 3시간 15분 동안 수행하였다. 원심분리 후 프로톤 펌프를 포함하는 중간층만을 취하여 40분 동안 초고속 원심분리를 수행하여 침전물을 얻은 후 pH 6.1의 5 mM 히피스-트리스 완충용액에 현탁시킨 후 1 ml 씩 튜브에 분주하여 동결 건조시켜 냉동(-70℃)보관 하였다. 이 마이크로좀을 프로톤 펌프의 시험관내 효소반응(in vitro enzyme reaction assay)을 수행하는 효소원으로 사용하였다. After killing pigs, the stomachs were extracted, gastric lining cells were taken using a glass plate, and the cells were homogenized with a homogenizer on 0.25M sucrose buffer. The homogenate was centrifuged at 8,000 rpm for 35 minutes, and the supernatant was again centrifuged at 25,000 rpm for 1 hour and 15 minutes at high speed, and the pellet obtained was homogenized again in sucrose buffer. After placing on a 9% Picol solution tube, ultrafast centrifugation was again performed for 3 hours and 15 minutes. After centrifugation, only the intermediate layer containing the proton pump was taken and ultrafast centrifugation was carried out for 40 minutes to obtain a precipitate, which was suspended in 5 mM hippies-tris buffer solution at pH 6.1, and then aliquoted into tubes by 1 ml and freeze-dried. (-70 ° C) was stored. This microsome was used as an enzyme source for performing an in vitro enzyme reaction assay of a proton pump.

1-2. 프로톤 펌프에 대한 억제력 측정1-2. Determination of Proton Pump

본 발명의 화합물들에 대한 프로톤 펌프 활성 억제 효과는 96웰 플레이트 상에서 효소반응시험으로 측정하였다. 즉 마그네슘이온(Mg⁺⁺)으로 자극된 활성도를 음성 대조군의 활성도로, 마그네슘(Mg⁺⁺)과 칼륨이온(K⁺)으로 자극된 활성도를 양성 대조군의 활성도로 하여 이들간의 차이값을 프로톤 펌프의 활성도로 사용하였다. 96웰 플레이트 상에서, 음성 대조군(제1군)과 양성 대조군(제2군)에는 화합물을 용해하는 다이메틸설폭사이드를 1% 첨가하고 시험물질 투여군(제3군)에는 5개의 농도로 제조된 화합물을 처리하여 활성도 억제력을 측정하였다.The inhibitory effect of proton pump activity on the compounds of the present invention was determined by enzymatic reaction on 96 well plates. That is the magnesium ion-stimulated activity as (Mg ⁺⁺⁾ in the activity of the negative control group, magnesium (Mg ⁺⁺⁾ and proton pump with the difference between them to the activity of the positive stimulating activity as a potassium ion (K ⁺⁾ control group It was used as the activity of. On 96-well plates, 1% dimethyl sulfoxide soluble compound was added to the negative control group (Group 1) and positive control group (Group 2), and the compound prepared at 5 concentrations in the test substance administration group (Group 3). Was treated to measure the activity inhibitory power.

효소반응은 최종 부피 100 ㎕에서 모든 농도를 산출하여 실험하며, 효소는 사용 전까지 얼음에 보관하고 상온에서 반응을 실시하였다. 제3군은 5개의 농도에서 최종 다이메틸설폭사이드의 농도가 최종 1%가 되도록 하여 10 ㎕씩 처리하였고, 제1군과 제2군에는 10% 다이메틸설폭사이드를 포함하는 완충액 10 ㎕씩 처리하였다. 얼음에 보관중인 효소를 모든 웰에 30 ㎕ 부피로 각 반응당 5 ㎍씩 들어가도록 처리 후 플레이트 쉐이커를 이용하여 1분간 1000 rpm에서 섞은 후 상온에서 5분 동안 반응시켰다. 그 후 96웰 상의 음성 대조군 내로 제1군 완충액을 30 ㎕ 부피로 처리하고 이를 제외한 모든 웰에 제2군 완충액을 30 ㎕씩 처리하였다. 기질로서 ATP의 처리는 최종 농도가 0.5 mM이 되도록 30 ㎕를 처리하여 쉐이커를 이용하여 혼합한 후 37℃ 에서 30분 동안 반응을 수행하였다. 반응 종료 후 모든 웰에 발색시약을 100 ㎕씩 처리 후 쉐이커를 이용하여 섞어준 후 620 nm의 파장에서 흡광도를 측정함으로서 각 시험 군에서의 프로톤 펌프 활성을 측정하였다. Enzyme reaction was conducted by calculating all concentrations in the final volume of 100 μl. The enzyme was stored on ice until use and the reaction was performed at room temperature. The third group was treated with 10 [mu] l each so that the final concentration of dimethyl sulfoxide was at 1% at 5 concentrations. It was. Enzyme stored on ice was treated to enter 5 μg of each reaction in a volume of 30 μl in all wells, followed by mixing at 1000 rpm for 1 minute using a plate shaker, and then reacting at room temperature for 5 minutes. The group 1 buffer was then treated with 30 μl volume into the negative control on 96 wells and all wells were treated with 30 μl of group 2 buffer. Treatment of ATP as a substrate was treated with 30 μl so that the final concentration was 0.5 mM, mixed using a shaker, and the reaction was performed at 37 ° C. for 30 minutes. After completion of the reaction, all wells were treated with 100 μl of the coloring reagent, and then mixed using a shaker, and then absorbance was measured at a wavelength of 620 nm to measure proton pump activity in each test group.

제1군과 제2군의 측정치 차이를 K⁺ 특이적 프로톤 펌프의 활성도로 하고, 이 값을 기준으로 제3군의 각각의 화합물 농도에서 나타나는 프로톤펌프 활성도에 대한 억제도를 %값으로 계산하였다. 제3군의 각 5개 농도가 활성도에 대하여 갖는 억제도 %값을 리치필드-윌콕슨(Litchfield-Wilcoxon) 분석식(J. Pharmacol. Exp. Ther. (1949) 96, 99)을 이용하여 시험물질의 IC₅₀ 값을 계산하였다. 그 결과를 표 1에 나타내었다.The difference between the measured values of the first group and the second group was taken as the activity of the K ⁺ specific proton pump, and based on this value, the inhibition of the proton pump activity at each compound concentration of the third group was calculated as a% value. . The percent inhibition value of each of the five concentrations in Group 3 with respect to activity was tested using the Litchfield-Wilcoxon assay ( J. Pharmacol. Exp. Ther . (1949) 96, 99). The IC ₅₀ value of the material was calculated. The results are shown in Table 1.

실시예Example IC₅₀(uM)IC ₅₀ (uM) 실시예Example IC₅₀(uM)IC ₅₀ (uM) 44 0.280.28 3535 0.970.97 55 0.980.98 3838 0.510.51 66 0.610.61 3939 0.610.61 1010 0.050.05 4040 0.680.68 1111 0.70.7 4141 0.410.41 1212 0.210.21 4343 0.990.99 1313 0.170.17 4444 0.720.72 1414 0.30.3 4545 0.320.32 1717 0.940.94 4848 0.40.4 1818 0.410.41 4949 0.320.32 1919 0.210.21 5050 0.940.94 2525 0.610.61 5252 0.310.31 2626 0.370.37 5454 0.940.94 3232 0.630.63 5656 0.560.56 3333 0.750.75

상기 표 1의 결과로부터 본 발명에 따른 화학식 1의 화합물은 프로톤펌프에 대한 억제효과가 우수함을 확인할 수 있었다.From the results of Table 1, the compound of Chemical Formula 1 according to the present invention was confirmed to have an excellent inhibitory effect on the proton pump.

시험예 2. 기초 위산분비 억제효과Test Example 2 Inhibition Effect of Basic Gastric Acid Secretion

기초위산분비 억제효과는 Shay′s rat 모델(Shay, H., et al., (1945) Gastroenterology 5, 43-61)에 따라 시험하였다. 200±10 g의 스프래그-돌리 (Sprague-Dawley)계 웅성랫트를 3개 군으로 나누어(n=5) 24시간 동안 물만 공급하면서 절식시킨 후, 제1군에는 대조군으로써 0.5% 메틸셀룰로오스 수용액을 1.0 ㎖/200 g으로 경구로 투여하였다. 제2군에는 본 발명의 화학식 1의 화합물을 0.5% 메틸셀룰로오스 수용액에 10 mg/kg 농도로 현탁시킨 후 3 mg/kg, 1 mg/kg 농도가 되도록 0.5% 메틸셀룰로오스 수용액으로 희석한 후 랫트에 경구 투여하였다.The inhibitory effect of basal gastric acid secretion was tested according to Shay's rat model (Shay, H., et al., (1945) Gastroenterology 5, 43-61). 200 ± 10 g of Sprague-Dawley male rats were divided into three groups (n = 5) and fasted with water for 24 hours.The first group was treated with 0.5% aqueous methylcellulose solution as a control. It was administered orally at 1.0 mL / 200 g. In the second group, the compound of Chemical Formula 1 of the present invention was suspended in 0.5% aqueous solution of methyl cellulose at a concentration of 10 mg / kg, and then diluted with 0.5% aqueous solution of methyl cellulose to a concentration of 3 mg / kg and 1 mg / kg. Oral administration.

화합물 투여 1시간 후에 랫트를 에테르로 마취한 다음 복강을 절개하여 유문부를 결찰하였다. 결찰 직후에 복강을 다시 봉합하고 5시간 경과 후에 경추 탈골법으로 치사시켜 위를 적출하여 위액을 받았다. 얻어진 위액을 1,000×g로 10분간 원심분리하여 침전물을 제거한 후, 위액의 양(ml)과 위액을 pH 7.0까지 적정에 필요한 0.01N-NaOH의 부피(ueq/ml)를 측정하였으며, 이렇게 하여 얻어진 결과로부터 5시간 동안 분비된 총위산량(ueq/5hr, 위액의 부피 × 적정에 소요된 0.01N-NaOH의 부피)을 구하였다. 시험물질은 각각 세 용량에 대해 다음 식에 의해 위산분비억제력(%)을 산출하였으며, 각 투여 용량별로 구해진 억제율로 리치필드-윌콕슨 방법을 이용하여 ED₅₀(mg/kg)를 산출하여 그 결과를 표 2에 나타내었다.One hour after compound administration, rats were anesthetized with ether and the abdominal cavity was dissected to ligation the pyloric region. Immediately after the ligation, the abdominal cavity was sutured again, and after 5 hours, it was lethal by cervical dislocation and the stomach was extracted to receive gastric juice. The obtained gastric juice was centrifuged at 1,000 × g for 10 minutes to remove the precipitate, and then the amount of gastric juice (ml) and the volume of 0.01N-NaOH (ueq / ml) required for titration of the gastric juice to pH 7.0 were measured. From the results, the total amount of gastric acid secreted for 5 hours (ueq / 5hr, volume of gastric juice x volume of 0.01N-NaOH spent for titration) was calculated. For each test substance, gastric acid secretion inhibition rate (%) was calculated by the following equation for each of the three doses, and ED ₅₀ (mg / kg) was calculated using the Richfield-Wilcoxon method with the inhibition rate obtained for each dose. Is shown in Table 2.

[식][expression]

시험화합물의 위산분비억제력 Gastric acid secretion inhibitory power of test compound

= (제1군 총위산량-제2군 총위산량) / (제1군 총위산량) × 100= (Total Gastric Acid of Group 1-Total Gastric Acid of Group 2) / (Total Gastric Acid of Group 1) × 100

실시예Example ED₅₀(mg/kg)ED ₅₀ (mg / kg) 1010 2.442.44 3838 6.266.26

상기 표 2의 결과로부터 본 발명에 따른 화학식 1의 화합물은 기초위산분비 억제효과가 우수함을 확인할 수 있었다.From the results of Table 2, the compound of Chemical Formula 1 according to the present invention was confirmed that the basal acid secretion effect is excellent.

시험예 3. 가역성 시험 Test Example 3 Reversibility Test

3-1. 위장관 소포(gastric vesicle)의 제조3-1. Preparation of gastric vesicles

위장관 소포(gastric vesicle)는 사코마니(Saccomani) 등의 방법(Saccomani G, Stewart HB, Shqw D, Lewin M and Sachs G, Characterization of gastric mucosal membranes. IX. Fraction and purification of K-ATPase-containing vesicles by zonal centrifugation and free-flow electrophoresis technique. Biochem. Biophy. Acta.(BBA) - Biomembranes 465, 311-330, 1977.)에 따라 돼지의 위에서 분리 제조하였다. 제조한 위장관 소포는 동결건조 소포(Lyophilized vesicle) 상태로 -70℃에서 보관하였다. 제조한 소포단백질은 소혈청알부민(Bovine Serum Albumin)을 비교기준물질로 사용하여 브래드포드법에 따라 정량하였다(Bradford MM, A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 72, 248-254, 1976)Gastrointestinal vesicles can be obtained by Saccomani et al. (Saccomani G, Stewart HB, Shqw D, Lewin M and Sachs G, Characterization of gastric mucosal membranes.IX. .... zonal centrifugation and free -flow electrophoresis technique Biochem Biophy Acta (BBA) - separated from the top of a pig was prepared in accordance with the Biomembranes 465, 311-330, 1977.). The prepared gastrointestinal vesicles were stored at −70 ° C. in lyophilized vesicles. The prepared vesicle protein was quantified according to the Bradford method using bovine serum albumin as a comparative reference (Bradford MM, A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein- dye binding.Anal Biochem . 72, 248-254, 1976)

3-2. 가역적 억제 시험 3-2. Reversible Suppression Test

프로톤 펌프에 50% 억제력을 갖는 화합물의 농도를 상기에서 제조 분리한 동결건조 소포들을 이용하여 유리된 무기 인산량을 측정할 수 있는 찬(Chan) 등의 발색검색법(Chan KM, Delfert D, and Junger KD, A direct colorimetric assay for Ca²⁺-stimulated ATPase activity. Anal Biochem, 157, 375-380, 1986)에 따라 산출하였다. 본 발명의 화학식 1의 화합물의 프로톤 펌프에 대한 억제 작용기전은 베일(Beil) 등의 워시아웃(Washout) 방법(Beil W, Staar U, and Sewing KF, Substituted thieno[3,4-d]imidazoles, a novel group of H+/K(+)-ATPase inhibitors. Differentiation of their inhibition characteristics from those of omeprazole. Eur. J. Pharmacol., 187, 455-67, 1990)에 따라 실험하였다. 약 50% 프로톤 펌프 억제 농도의 화합물 처리군과 화합물 미처리군으로 분리하여 모두 5 mM Pipes/Tris 완충용액에서 상온에서 5분 동안 전반응시킨 후, 2 mM MgCl₂, 50 mM KCl, 2.5 uM Valinomycin 및 0.5 mM ATP를 처리하여 37℃ 에서 30분 동안 반응을 수행하였다. 발색검색법에 따라 프로톤 펌프의 활성을 측정하고 100,000×g에서 초고속 원심분리를 수행하였다. 1시간 후에 잔사(pellet)된 소포의 상등액을 화합물이 첨가되지 않은 새로운 완충용액으로 교체하여(washout) 상온에서 5분간 전반응시키고 동일한 조건으로 37℃에서 30분간 반응시킨 후, 발색검색법에 따라 프로톤 펌프의 활성을 평가하였다. 그 결과 프로톤 펌프는 Washout 전에는 시험물질에 의해 약 50%의 활성을 나타내었으나 Washout 후에는 화합물 미처리군 수준으로 활성을 회복하였으므로 본 발명의 화학식 1의 화합물이 가역적 억제기전을 나타낸다는 것을 확인할 수 있다. Chan et al. (Chan KM, Delfert D, and and Chan), which can measure the amount of free inorganic phosphoric acid using lyophilized vesicles prepared and separated in the concentration of a compound having a 50% inhibitory power in a proton pump. Junger KD, A direct colorimetric assay for Ca ²⁺ -stimulated ATPase activity.Anal Biochem , 157, 375-380, 1986). The inhibitory mechanism for the proton pump of the compound of Formula 1 of the present invention is washout method such as Beil (Beil W, Staar U, and Sewing KF, Substituted thieno [3,4-d] imidazoles, a novel group of H + / K (+)-ATPase inhibitors.Differentiation of their inhibition characteristics from those of omeprazole.Eur . J. Pharmacol., 187, 455-67, 1990). After separating the compound treated group and the compound untreated group at about 50% proton pump inhibition concentration, both were prereacted for 5 minutes at room temperature in 5 mM Pipes / Tris buffer, followed by 2 mM MgCl ₂ , 50 mM KCl, 2.5 uM Valinomycin and The reaction was carried out at 37 ° C. for 30 minutes with 0.5 mM ATP. The activity of the proton pump was measured according to the color search method, and ultrafast centrifugation was performed at 100,000 × g. After 1 hour, the supernatant of the pelleted vesicles was washed with new compound without addition of the compound (washout), pre-reacted for 5 minutes at room temperature, and reacted for 30 minutes at 37 ° C under the same conditions. The activity of the proton pump was evaluated. As a result, the proton pump showed about 50% of the activity by the test substance before the washout, but after the washout, the compound was restored to the untreated group level, and thus, the compound of formula 1 of the present invention showed a reversible inhibitory mechanism.

본 발명의 화학식 1의 5,6-다이메틸피리미딘 유도체는 프로톤 펌프 억제효과가 뛰어나고 위산분비 억제력이 우수할 뿐만 아니라 가역적인 프로톤 펌프 억제 효과를 가진다.The 5,6-dimethylpyrimidine derivatives of the general formula (1) of the present invention have excellent proton pump inhibitory effect, excellent gastric acid secretion inhibitory effect, and reversible proton pump inhibitory effect.

Claims

하기 화학식 1로 표시되는 피리미딘 유도체 또는 이의 약제학적으로 허용되는 염: A pyrimidine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof:

상기 식에서In the above formula

R₁은 수소 또는 C_1-5 알킬이고;R ₁ is hydrogen or C _1-5 alkyl;

R₂는 수소 또는 C_1-5 알킬이고;R ₂ is hydrogen or C _1-5 alkyl;

또는

or

Wherein R 'is hydrogen or C _1-5 alkyl; And

R₆는 단일 또는 이치환기로서 수소, 할로겐, C_1-5 알킬 또는 C_1-5 알콕시이다R ₆ is hydrogen, halogen, C _1-5 alkyl or C _1-5 alkoxy as a single or disubstituted group

(상기에서 R₁, R₂, R₃, R₄, R₅ 및 R₆ 로서의 알킬 및 알콕시는 임의적으로 하나 이상의 할로겐으로 치환될 수 있다). (In the above, alkyl and alkoxy as R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ may be optionally substituted with one or more halogens).

제1항에 있어서, The method of claim 1,

R₁은 수소 또는 C_1-3 알킬이고;R ₁ is hydrogen or C _1-3 alkyl;

R₂는 수소 또는 C_1-3 알킬이고;R ₂ is hydrogen or C _1-3 alkyl;

R₃는 수소, 할로겐, C_1-3 알킬 또는 C_1-3 알콕시이고; R ₃ is hydrogen, halogen, C _1-3 alkyl or C _1-3 alkoxy;

R₄ 및 R₅는 서로 독립적으로 수소, 할로겐, C_1-3 알킬, 하이드록시, C_1-3 알콕시 또는 아미노이거나, 임의적으로 서로 융합하여 (CH₂)n 고리를 형성하거나(여기서 n은 2 내지 5의 정수이다), 또는 임의적으로 서로 융합하여 이중결합을 이루어

또는

(여기서 R´은 수소 또는 C_1-3 알킬이다)를 형성할 수 있고; 및R ₄ and R ₅ are independently of each other hydrogen, halogen, C _1-3 alkyl, hydroxy, C _1-3 alkoxy or amino, or optionally fuse with each other to form a (CH ₂ ) n ring, wherein n is 2 To an integer of 5), or optionally fused with each other to form a double bond.

or

Wherein R 'is hydrogen or C _1-3 alkyl; And

R₆는 단일 또는 이치환기로서 수소, 할로겐, C_1-3 알킬 또는 C_1-3 알콕시R ₆ is hydrogen or halogen, C _1-3 alkyl or C _1-3 alkoxy

(여기서 R₁, R₂, R₃, R₄, R₅ 및 R₆ 로서의 알킬 및 알콕시는 임의적으로 하나 이상의 할로겐으로 치환될 수 있다)Wherein alkyl and alkoxy as R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ may be optionally substituted with one or more halogens.

인 화학식 1로 표시되는 피리미딘 유도체 또는 이의 약제학적으로 허용되는 염. A pyrimidine derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof.

제1항에 있어서, The method of claim 1,

R₁은 수소 또는 C_1-2 알킬이고(여기서 R₁ 으로서의 알킬은 임의적으로 하나 이상의 할로겐으로 치환될 수 있다); R₂는 수소 또는 메틸이고; R₃는 수소, 할로겐, 메틸 또는 메톡시이고; R₄ 및 R₅는 서로 독립적으로 수소, 할로겐, 메틸, 하이드록시 또는 아미노이거나, 임의적으로 서로 융합하여 (CH₂)n 고리를 형성하거나 (여기서 n은 2 이다), 또는 임의적으로 서로 융합하여 이중결합을 이루어

또는

(여기서 R´은 수소 또는 C_1-3 알킬이다)를 형성할 수 있고; 및 R₆는 단일 또는 이치환기로서 수소, 할로겐, 메틸, 트라이플루오로메틸 또는 트라이플루오로메톡시인 화학식 1로 표시되는 피리미딘 유도체 또는 이의 약제학적으로 허용되는 염. R ₁ is hydrogen or C _1-2 alkyl, wherein alkyl as R ₁ may be optionally substituted with one or more halogens; R ₂ is hydrogen or methyl; R ₃ is hydrogen, halogen, methyl or methoxy; R ₄ and R ₅ are independently of each other hydrogen, halogen, methyl, hydroxy or amino, or optionally fused to each other to form a (CH ₂ ) n ring (where n is 2), or optionally fused to each other In combination

or

Wherein R 'is hydrogen or C _1-3 alkyl; And R ₆ is hydrogen, halogen, methyl, trifluoromethyl or trifluoromethoxy as a single or disubstituted pyrimidine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof.

제1항에 있어서, The method of claim 1,

2-(4-플루오로벤질)-4-(8-메틸-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (8-methyl-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(6-메틸-1-메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (6-methyl-1-methyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-(4-플루오로벤질)-4-(7-플루오로3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염;2- (4-fluorobenzyl) -4- (7-fluoro3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-dimethylpyrimidine hydrochloride;

2-[플루오로-(4-플루오로페닐)-메틸]-4-(1,6-다이메틸-3,4-다이하이드로-1H-아이소퀴놀린-2-일)-5,6-다이메틸피리미딘 염산염2- [fluoro- (4-fluorophenyl) -methyl] -4- (1,6-dimethyl-3,4-dihydro-1 H -isoquinolin-2-yl) -5,6-di Methylpyrimidine Hydrochloride

으로 이루어진 군으로부터 선택되는 화학식 1로 표시되는 피리미딘 유도체 또는 이의 약제학적으로 허용되는 염.A pyrimidine derivative represented by formula (1) selected from the group consisting of or a pharmaceutically acceptable salt thereof.

화학식 2의 화합물과 화학식 3의 화합물을 치환반응시켜 화학식 1의 화합물 또는 이의 약제학적으로 허용되는 염을 제조하는 방법: Method of preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof by substitution reaction of a compound of formula 2 with a compound of formula 3

상기에서From above

R₁, R₂, R₃, R₄, R₅ 및 R₆는 제1항에서 정의한 것과 동일하고, X는 할로겐을 나타낸다.R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are the same as defined in claim 1, and X represents halogen.

화학식 8의 화합물을 유기 주석화합물로 치환하여 화학식 9의 화합물을 제조한 후 화학식 10의 화합물과 스틸(Stille) 반응시켜 화학식 1의 화합물을 제조하는 방법: Method of preparing a compound of formula 1 by replacing the compound of formula 8 with an organic tin compound to prepare a compound of formula 9, and then reacting the compound of formula 10 with Stille

상기에서From above

R₁, R₂, R₃, R₄, R₅ 및 R₆는 제1항에서 정의한 것과 동일하고, X는 할로겐을, Y는 트라이알킬주석을 나타낸다.R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are the same as defined in claim 1, X represents halogen and Y represents trialkyltin.

화학식 9의 화합물과 화학식 11의 화합물을 스틸(Stille) 반응을 시켜 화학식 1a의 화합물을 제조하는 방법: To prepare a compound of Formula 1a by carrying out a Stille reaction between a compound of Formula 9 and a compound of Formula 11:

상기에서From above

R₁, R₂, R₃ 및 R₆는 상기 제1항에서 정의한 것과 동일하고, Y는 트라이알킬주석을 나타낸다.R ₁ , R ₂ , R ₃ and R ₆ are the same as defined in claim 1 above, and Y represents trialkyltin.

하기 화학식 1로 표시되는 피리미딘 유도체 또는 이의 약제학적으로 허용되는 염을 유효성분으로 함유하는 위산분비 억제용 약학 조성물: A pharmaceutical composition for inhibiting gastric acid secretion containing a pyrimidine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

상기에서 From above

R₁, R₂, R₃, R₄, R₅ 및 R₆는 상기 제1항에서 정의한 것과 동일하다.R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are the same as defined in claim 1 above.