KR101191277B1

KR101191277B1 - 2-Azacyclicamino-4-phenylpyrimidine derivatives as IKK-ß inhibitors

Info

Publication number: KR101191277B1
Application number: KR20100073077A
Authority: KR
Inventors: 추현아; 배애님; 신계정; 남길수; 노은주; 조용서; 김소라; 정진교; 정혜진
Original assignee: 한국과학기술연구원
Priority date: 2010-07-28
Filing date: 2010-07-28
Publication date: 2012-10-16
Also published as: KR20120021370A

Abstract

본 발명은 IKK-β에 대하여 약학적 활성을 보이는 2-아자사이클릭아미노-4-페닐피리미딘 화합물 및 이의 약제학적으로 허용 가능한 염, 이들 화합물의 제조방법, 그리고 이들 화합물이 유효성분으로 함유된 약제조성물에 관한 것이다. The present invention relates to 2-azacyclic amino-4-phenylpyrimidine compounds and pharmaceutically acceptable salts thereof, to the preparation of these compounds, and to those compounds containing an active ingredient that exhibits pharmacological activity against IKK-β. It relates to a pharmaceutical composition.

Description

2-Azacyclicamino-4-phenylpyrimidine derivatives as IKK-β inhibitors}

NF-κB의 활성화는 류마티스 관절염을 비롯한 다양한 염증 반응에 관여한다. NF-κB의 신호전달 경로로는 고전적 경로와 대체 경로가 각각 알려져 있다. Activation of NF-κB is involved in various inflammatory reactions, including rheumatoid arthritis. As the signaling pathway of NF-κB, the classical pathway and the alternative pathway are known, respectively.

고전적 경로는 전염증성 시토킨인 TNF-α와 IL-1을 포함하는 다양한 염증성 자극들에 대한 반응과 T 세포 수용체의 접촉유지 혹은 리포다당류(lipopolysaccharide, LPS)와 같은 세균성 생성물들에 노출됨에 의해 유도된다. 이 경로는 Ser32와 Ser36 위치에 IκBα의 빠른 인산화와 26S 프로티좀(proteasome)에 의한 일련의 유비퀴틴 (ubiquitin)에 의해 유도되는 분해로 규정된다. 고전적 경로에서 IκB 인산화는 IKK 복합체의 활성화에 기인한다. IKK 복합체중 IKK-β가 가장 많은 IκB 카이네즈로 나타났다. 고전적 경로는 내재면역과 염증의 활성, 그리고 세포사멸 억제에 중요한 역할을 한다. The classical pathway is induced by response to various inflammatory stimuli, including the proinflammatory cytokines TNF-α and IL-1, and by exposure to bacterial products such as lipopolysaccharide (LPS) or contact maintenance of T cell receptors. do. This pathway is defined by the rapid phosphorylation of IκBα at the Ser32 and Ser36 positions and the degradation induced by a series of ubiquitins by the 26S proteasome. In the classical pathway, IκB phosphorylation is due to the activation of the IKK complex. Among the IKK complexes, IKK-β was the most IKB kinase. Classical pathways play an important role in intrinsic immunity, inflammation and inhibition of apoptosis.

대체 경로는 항종양괴사인자 종의 B 세포 활성인자 (BAFF)나 림포톡신 (LTβ)과 같은 NF-κB 활성 유도체 등에 의해서 활성화 된다. IKK-α가 활성화 되어 p100을 인산화 시켜 p52로 만드는 과정이다. 인산화 된 IκB는 유비퀴틴 리가제 과정을 거쳐 폴리유비퀴틴화 되어 파괴되거나 p100은 단백분해효소에 의해 처리된다. 자유롭게 된 NF-κB는 핵으로 이동하며 목표 유전자의 프로모터 (promoter)나 인핸서 (enhancer) 부위에 결합한다. 활성화된 NF-κB는 새롭게 합성된 IκB-α와 결합함으로써 세포질로 나오게 된다. 대체 경로의 경우, 이차 면역기관 발달, B 셀 성숙, 그리고 적응성 체액성 면역에 중요한 역할을 한다고 알려져 있다 (Nature Reviews, 2004, 3, 17-26).The alternative pathway is activated by NF-κB active derivatives such as B cell activator (BAFF) or lymphotoxin (LTβ) of antitumor necrosis factor species. IKK-α is activated to phosphorylate p100 to p52. Phosphorylated IκB is ubiquitin ligase and then polyubiquitinated and destroyed or p100 is processed by protease. Freed NF-κB migrates to the nucleus and binds to a promoter or enhancer region of the target gene. Activated NF-κB is released into the cytoplasm by binding to the newly synthesized IκB-α. Alternative pathways are known to play an important role in secondary immune system development, B cell maturation, and adaptive humoral immunity ( Nature Reviews , 2004 , 3 , 17-26).

IKK-β는 756 아미노산으로 구성된 세린-쓰레오닌 키나제이고, IKK-α와는 55% 동일성을 보이고, 호모 다이머나 IKK-α와 헤테로 다이머를 형성하여 IκB-α나 IκB-β를 인산화시킨다 (J. Biol. Chem. 1998, 273, 30736-30741). IKK-β는 지속적인 키나제 활성을 보이고, 이 효소가 과발현이 되면 NF-κB 활성에 의해 전사되는 전염증성 사이토킨이 많이 발현되는 것을 발견하였다. 또한 류마토이드 관절염이나 퇴행성 관절염을 앓고 있는 환자들에게서 IKK-β이 활성화되어 있는 것을 관찰하였다 (Cell, 1997, 91, 243-252; J. Immunol. 1999, 162, 3176-3187). IKK-β is a serine-threonine kinase consisting of 756 amino acids, shows 55% identity to IKK-α, and forms a heterodimer with homo dimers or IKK-α to phosphorylate IκB-α or IκB-β ( J Biol.Chem . 1998 , 273 , 30736-30741). IKK-β showed sustained kinase activity, and overexpression of this enzyme resulted in the expression of a large number of proinflammatory cytokines transcribed by NF-κB activity. In addition, the activation of IKK-β was observed in patients with rheumatoid arthritis or degenerative arthritis ( Cell , 1997 , 91 , 243-252; J. Immunol. 1999 , 162 , 3176-3187).

최근에 보고된 자료에 의하면, 염증질환과 암은 관련성이 깊은 것으로 알려져 있다. 미국 텍사스대학 앤더슨 암센터에서는 IKK-β가 TSC1 (tuberous sclerosis 1)을 억제하고 mTOR (mammalian target of rapamycine) 경로를 활성화시켜 혈관신생을 증가시키고 암을 발생시키는 과정을 규명하였다 (Cell, Vol 130, 440-455, 10 August 2007). 즉, TNFα에 의해 활성화된 IKK-β가 TSC1의 Ser487 및 Ser511을 인산화하여 TSC1/TSC2 복합체의 작용을 차단함으로써 mTOR 경로를 활성화하고, 활성화된 mTOR는 VEGF를 생성하여 혈관을 새로 만들고 암세포에 영양을 공급하는 진행경로를 밝혔다. 또한, 마우스 실험결과 IKK-β가 활성화된 마우스는 IKK-β가 불활성화되거나 mTOR가 억제된 마우스에 비교하여 상대적으로 종양크기가 컸음을 확인하였다. 또한, 유방암 환자들을 대상으로 한 임상실험에서 인산화에 의하여 종양세포의 TSC1/TSC2 복합체가 차단된 환자들은 TSC1/TSC2 복합체가 활성화된 환자에 비교하여 수명이 짧은 것을 확인하였다.Recently reported data suggest that inflammatory diseases and cancer are closely related. The Anderson Cancer Center, University of Texas, USA, identified the process by which IKK-β inhibits TSC1 (tuberous sclerosis 1) and activates the mTOR (mammalian target of rapamycine) pathway to increase angiogenesis and cancer (Cell, Vol 130, 440-455, 10 August 2007). In other words, IKK-β activated by TNFα phosphorylates Ser487 and Ser511 of TSC1 to block the action of the TSC1 / TSC2 complex, which activates the mTOR pathway. The route of supply is revealed. In addition, mouse experiments confirmed that the IKK-β-activated mice had a relatively large tumor size compared to mice in which IKK-β was inactivated or mTOR was inhibited. In the clinical trials of breast cancer patients, the patients whose TSC1 / TSC2 complexes of tumor cells were blocked by phosphorylation were found to have a shorter lifespan compared to patients with activated TSC1 / TSC2 complexes.

이상에서 살펴본 바와 같이, IKK-β는 각종 염증질환 및 발암을 조절하는 인자로서 선택적인 IKK-β 저해제의 개발이 요구되나, 현재까지 개발된 IKK-β 저해제는 극히 드물다. IKK-β 저해 물질로서 대한민국특허등록 제822,681호 및 제796,965호 등에는 티에노피리다진을 기본 골격구조로 갖는 화합물이 개시되어 있고, 대한민국특허등록 제738,165호에는 헤테로방향족 카르복사미드를 기본 골격구조로 갖는 화합물이 개시되어 있다. As described above, IKK-β is required to develop selective IKK-β inhibitors as a factor for controlling various inflammatory diseases and carcinogenesis, but the IKK-β inhibitors developed to date are extremely rare. As the IKK-β inhibitor, Korean Patent Registration Nos. 822,681 and 796,965, etc., disclose compounds having thienopyridazine as a basic skeleton structure, and Korean Patent Registration No. 738,165 contains a heteroaromatic carboxamide as a basic skeleton structure. The compound which has the is disclosed.

따라서 IKK-β 저해에 선택적이고 약물동력학 프로파일이 좋고, ADME(흡수, 분배, 대사, 배출)이 좋으면서도 류마티스 관절염, 퇴행성 관절염, 천식, 만성 폐쇄성 폐질환 등과 같은 염증질환과 암의 치료에 유효한 새로운 IKK-β 저해제의 개발이 절실히 요구되고 있다.
Therefore, it is selective for IKK-β inhibition and has good pharmacokinetic profile, good ADME (absorption, distribution, metabolism, excretion) and effective for the treatment of inflammatory diseases and cancers such as rheumatoid arthritis, degenerative arthritis, asthma and chronic obstructive pulmonary disease. There is an urgent need for the development of IKK-β inhibitors.

본 발명은 하기와 같은 발명의 목적을 갖고 있다.This invention has the objective of the following invention.

즉, 본 발명은 신규 구조의 2-아자사이클릭아미노-4-페닐피리미딘 화합물 및 이의 약제학적으로 허용 가능한 염을 제공하는데 그 목적이 있다.That is, an object of the present invention is to provide a 2-azacyclic amino-4-phenylpyrimidine compound having a novel structure and a pharmaceutically acceptable salt thereof.

또한, 본 발명은 2-아미노-4-페닐피리미딘 화합물과 아자사이클릭케톤 화합물간의 환원성 아민화 반응을 수행하거나, 3-디메틸아미노-1-아릴-프로페논과 구아니디늄과의 고리화반응을 수행하여, 상기한 2-아자사이클릭아미노-4-페닐피리미딘 화합물을 제조하는 방법을 제공하는데 다른 목적이 있다.In addition, the present invention performs a reductive amination reaction between a 2-amino-4-phenylpyrimidine compound and an azacyclic ketone compound, or a cyclization reaction of 3-dimethylamino-1-aryl-propenone with guanidinium. It is another object to provide a method for preparing the 2-azacyclicamino-4-phenylpyrimidine compound by performing the above.

또한, 본 발명은 상기한 2-아자사이클릭아미노-4-페닐피리미딘 화합물 및 이의 약제학적으로 허용 가능한 염이 유효성분으로 포함되어 있는 IKK-β 저해작용을 갖는 약제조성물을 제공하는데 또 다른 목적이 있다.Another object of the present invention is to provide a pharmaceutical composition having an IKK-β inhibitory activity in which the 2-azacyclicamino-4-phenylpyrimidine compound and a pharmaceutically acceptable salt thereof are included as an active ingredient. There is this.

또한, 본 발명은 상기한 2-아자사이클릭아미노-4-페닐피리미딘 화합물 및 이의 약제학적으로 허용 가능한 염이 유효성분으로 포함되어 있는 염증질환 또는 암의 예방 및 치료용 약제를 제공하는데 또 다른 목적이 있다.
In another aspect, the present invention provides a medicament for the prevention and treatment of inflammatory diseases or cancer, wherein the 2-azacyclicamino-4-phenylpyrimidine compound and a pharmaceutically acceptable salt thereof are included as an active ingredient. There is a purpose.

상기의 목적을 실현하기 위하여, 본 발명은 IKK-β 저해제로서 유효한 하기 화학식 1로 표시되는 2-아자사이클릭아미노-4-페닐피리미딘 화합물, 이 화합물의 제조방법, 이 화합물을 포함하는 약제조성물을 그 특징으로 한다.In order to realize the above object, the present invention provides a 2-azacyclic amino-4-phenylpyrimidine compound represented by the following general formula (1), which is effective as an IKK-β inhibitor, a method for preparing the compound, and a pharmaceutical composition comprising the compound. It is characterized by.

상기 화학식 1에서,In Formula 1,

R¹은 수소원자; 할로겐원자; 몰폴리노설포닐기; 또는 C₁-C₆알킬, 벤질옥시카보닐 및 tert-부틸카보닐로부터 선택된 치환체로 치환 또는 비치환된 피페라지노설포닐기를 나타내고, R²는 수소원자; C₁-C₆알킬기; C₁-C₆알킬아미노카보닐기; 아미노설포닐기; C₁-C₆알킬설포닐기; 할로, C₁-C₆알킬, C₁-C₆알콕시, 및 C₁-C₆할로알킬로 이루어진 1 내지 3개의 치환체로 치환 또는 비치환된 페닐설포닐기; 또는 할로, C₁-C₆알킬, C₁-C₆알콕시, 및 C₁-C₆할로알킬로 이루어진 1 내지 3개의 치환체로 치환 또는 비치환된 벤조일기를 나타내고, ℓ은 1 내지 3의 정수를 나타내고, m은 0 내지 6의 정수를 나타내고, n은 0 내지 2의 정수를 나타낸다.
R ¹ is a hydrogen atom; Halogen atom; Morpholinosulfonyl group; Or a piperazinosulfonyl group unsubstituted or substituted with a substituent selected from C ₁ -C ₆ alkyl, benzyloxycarbonyl and tert -butylcarbonyl, R ² is a hydrogen atom; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkylaminocarbonyl group; Aminosulfonyl group; C ₁ -C ₆ alkylsulfonyl group; Phenylsulfonyl group unsubstituted or substituted with 1 to 3 substituents consisting of halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ haloalkyl; Or a benzoyl group unsubstituted or substituted with 1 to 3 substituents consisting of halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ haloalkyl, where l represents an integer of 1 to 3. M represents the integer of 0-6, n represents the integer of 0-2.

본 발명에 따른 상기 화학식 1로 표시되는 2-아자사이클릭아미노-4-페닐피리미딘 화합물은 IKK-β 저해에 대한 선택성이 우수하고, 약물동력학 프로파일이 좋아서 류마티스 관절염, 퇴행성 관절염, 천식, 만성 폐쇄성 폐질환 등과 같은 염증질환과 암의 치료 및 예방에 유효한 효과를 가지고 있다.
2-azacyclic amino-4-phenylpyrimidine compound represented by the formula (1) according to the present invention is excellent in selectivity for IKK-β inhibition, good pharmacokinetic profile, rheumatoid arthritis, degenerative arthritis, asthma, chronic obstructive It is effective in the treatment and prevention of inflammatory diseases such as lung disease and cancer.

본 발명에 따른 상기 화학식 1로 표시되는 2-아자사이클릭아미노-4-페닐피리미딘 화합물은 하나 또는 그 이상의 비대칭 탄소를 가질 수 있고, 이러한 화합물의 경우 거울상 이성체 또는 부분입체이성체가 존재할 수 있다. 따라서, 본 발명의 화합물은 각각의 분리된 이성체 화합물 또는 이들 이성체 혼합물을 포함한다.The 2-azacyclicamino-4-phenylpyrimidine compound represented by Formula 1 according to the present invention may have one or more asymmetric carbons, and in the case of such compounds, enantiomers or diastereomers may be present. Accordingly, the compounds of the present invention include each isolated isomeric compound or mixture of these isomers.

또한, 본 발명에 따른 상기 화학식 1로 표시되는 2-아자사이클릭아미노-4-페닐피리미딘 화합물은 당해 기술 분야에서 통상적인 방법에 의해 약제학적으로 허용 가능한 염을 형성할 수 있다. 예를 들면, 염산, 브롬산, 술폰산, 아미도황산, 인산, 질산과 같은 무독성의 무기산, 또는 아세트산, 프로피온산, 숙신산, 글리콜산, 스테아르산, 젖산, 타르타르산, 시트르산, 파라톨루엔설폰산, 메탄설폰산과 같은 무독성의 유기산과 함께 약제학적으로 허용 가능한 이들의 산이 부가된 염을 형성할 수도 있다.In addition, the 2-azacyclicamino-4-phenylpyrimidine compound represented by Formula 1 according to the present invention may form a pharmaceutically acceptable salt by a conventional method in the art. Non-toxic inorganic acids such as hydrochloric acid, bromic acid, sulfonic acid, amido sulfuric acid, phosphoric acid, nitric acid, or acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, paratoluenesulfonic acid, methanesulfone In addition to nontoxic organic acids such as acids, pharmaceutically acceptable salts of these acids may be added.

본 발명에 따른 상기 화학식 1로 표시되는 2-아자사이클릭아미노-4-페닐피리미딘 화합물을 정의하기 위해 사용된 치환기를 좀 더 자세히 설명하면 다음과 같다. The substituents used to define the 2-azacyclicamino-4-phenylpyrimidine compound represented by Formula 1 according to the present invention will be described in more detail as follows.

"알킬기"는 1 내지 6개의 탄소원자를 가진 직쇄상, 분쇄상 및 고리상의 탄소사슬을 모두 포함하며, 선호하는 알킬기는 메틸, 에틸기, 노말프로필기, 아이소프로필기, 노말부틸기, 아이소부틸기, tert-부틸기, 시클로펜틸기, 시클로헥실기 등이 있다. "할로알킬기"는 플루오로, 클로로, 브로모, 아이오도와 같은 할로겐원자가 1 내지 13개 포함되고, 1 내지 6개의 탄소원자를 가진 직쇄상, 분쇄상 및 고리상의 탄소사슬을 모두 포함하며, 선호하는 할로알킬기는 플루오로메틸, 트리플루오로메틸, 1,2-디클로로에틸기, 1,1-디클로로에틸기, 펜타플루오로에틸기 등이 있다. "알콕시기"는 산소에 연결된 탄소의 알킬기를 의미하는 것으로, 이때 알킬은 상기에서 정의한 바와 같다."Alkyl group" includes all linear, pulverized and cyclic carbon chains having 1 to 6 carbon atoms, and preferred alkyl groups are methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, tert- butyl group, cyclopentyl group, cyclohexyl group, and the like. A "haloalkyl group" includes one to thirteen halogen atoms such as fluoro, chloro, bromo and iodo, and includes all linear, pulverized and cyclic carbon chains having one to six carbon atoms, and the preferred halo. The alkyl group includes a fluoromethyl, trifluoromethyl, 1,2-dichloroethyl group, 1,1-dichloroethyl group, pentafluoroethyl group and the like. "Alkoxy group" means an alkyl group of carbon linked to oxygen, wherein alkyl is as defined above.

상기 화학식 1로 표시되는 2-아자사이클릭아미노-4-페닐피리미딘 화합물에 있어서, 바람직하기로는 상기 R¹은 수소원자, 클로로원자, 몰폴리노설포닐기, 피페라지노설포닐기, 또는 메틸피페라지노설포닐기를 나타내고; 상기 R²는 수소원자, 메틸기, 메틸설포닐기, 트리플루오로메틸설포닐기, 아미노설포닐기, 페닐설포닐기, o-, m- 및 p-트리플루오로메틸페닐설포닐기, o-, m- 및 p-플루오로페닐설포닐기, 2,4-디플루오로페닐설포닐기, m- 및 p-메톡시페닐설포닐기, 2,5-디메톡시페닐설포닐기, n-부틸아미노카보닐기, m- 및 p-플루오로벤조일기, m- 및 p-메톡시벤조일기, p-트리플루오로메틸벤조일기를 나타내고; 상기 m은 0, 1, 또는 2의 정수를 나타내고; 상기 n은 0 또는 1의 정수를 나타내고; 상기 ℓ은 1 또는 2의 정수를 나타내는 화합물의 경우이다.In the 2-azacyclic amino-4-phenylpyrimidine compound represented by Formula 1, preferably, R ¹ is a hydrogen atom, a chloro atom, a morpholinosulfonyl group, a piperazinosulfonyl group, or methylpi A ferrazinosulfonyl group; R ² is a hydrogen atom, a methyl group, a methylsulfonyl group, a trifluoromethylsulfonyl group, an aminosulfonyl group, a phenylsulfonyl group, o- , m -and p -trifluoromethylphenylsulfonyl group, o- , m -and p -Fluorophenylsulfonyl group, 2,4-difluorophenylsulfonyl group, m -and p -methoxyphenylsulfonyl group, 2,5-dimethoxyphenylsulfonyl group, n -butylaminocarbonyl group, m -and p -Fluorobenzoyl group, m- and p -methoxybenzoyl group, and p -trifluoromethylbenzoyl group; M represents an integer of 0, 1, or 2; N represents an integer of 0 or 1; L is the case of the compound which shows the integer of 1 or 2.

특히 바람직한 상기 화학식 1로 표시되는 2-아자사이클릭아미노-4-페닐피리미딘 화합물을 예시하면 하기와 같다:Particularly preferred examples of the 2-azacyclicamino-4-phenylpyrimidine compound represented by Formula 1 are as follows:

화합물 1 : N-(1-(메틸설포닐)피페리딘-4-일)-4-페닐피리미딘-2-아민Compound 1: N- (1- (methylsulfonyl) piperidin-4-yl) -4-phenylpyrimidin-2-amine

화합물 2 : 4-페닐-N-(1-(페닐설포닐)피페리딘-4-일)피리미딘-2-아민Compound 2: 4-phenyl- N- (1- (phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine

화합물 3 : 4-페닐-N-(1-(4-(트리플루오로메틸)페닐설포닐)피페리딘-4-일)피리미딘-2-아민Compound 3: 4-phenyl- N- (1- (4- (trifluoromethyl) phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine

화합물 4 : 4-페닐-N-(1-(3-(트리플루오로메틸)페닐설포닐)피페리딘-4-일)피리미딘-2-아민Compound 4: 4-phenyl- N- (1- (3- (trifluoromethyl) phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine

화합물 5 : 4-페닐-N-(1-(2-(트리플루오로메틸)페닐설포닐)피페리딘-4-일)피리미딘-2-아민Compound 5: 4-phenyl- N- (1- (2- (trifluoromethyl) phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine

화합물 6 : N-(1-(4-플루오로페닐설포닐)피페리딘-4-일)-4-페닐피리미딘-2-아민Compound 6: N- (1- (4-fluorophenylsulfonyl) piperidin-4-yl) -4-phenylpyrimidin-2-amine

화합물 7 : N-(1-(3-플루오로페닐설포닐)피페리딘-4-일)-4-페닐피리미딘-2-아민Compound 7: N- (1- (3-fluorophenylsulfonyl) piperidin-4-yl) -4-phenylpyrimidin-2-amine

화합물 8 : N-(1-(2-플루오로페닐설포닐)피페리딘-4-일)-4-페닐피리미딘-2-아민Compound 8: N- (1- (2-fluorophenylsulfonyl) piperidin-4-yl) -4-phenylpyrimidin-2-amine

화합물 9 : N-(1-(2,4-디플루오로페닐설포닐)피페리딘-4-일)-4-페닐피리미딘-2-아민Compound 9: N- (1- (2,4-difluorophenylsulfonyl) piperidin-4-yl) -4-phenylpyrimidin-2-amine

화합물 10 : N-(1-(4-메톡시페닐설포닐)피페리딘-4-일)-4-페닐피리미딘-2-아민Compound 10: N- (1- (4-methoxyphenylsulfonyl) piperidin-4-yl) -4-phenylpyrimidin-2-amine

화합물 11 : N-(1-(3-메톡시페닐설포닐)피페리딘-4-일)-4-페닐피리미딘-2-아민Compound 11: N- (1- (3-methoxyphenylsulfonyl) piperidin-4-yl) -4-phenylpyrimidin-2-amine

화합물 12 : N-(1-(2,5-디메톡시페닐설포닐)피페리딘-4-일)-4-페닐피리미딘-2-아민Compound 12: N- (1- (2,5-dimethoxyphenylsulfonyl) piperidin-4-yl) -4-phenylpyrimidin-2-amine

화합물 13 : N-부틸-4-(4-페닐피리미딘-2-일아미노)피페리딘-1-카복사마이드Compound 13: N -butyl-4- (4-phenylpyrimidin-2-ylamino) piperidine-1-carboxamide

화합물 14 : (4-플루오로페닐)(4-(4-페닐피리미딘-2-일아미노)피페리딘-1-일)메타논Compound 14: (4-fluorophenyl) (4- (4-phenylpyrimidin-2-ylamino) piperidin-1-yl) methanone

화합물 15 : (3-플루오로페닐)(4-(4-페닐피리미딘-2-일아미노)피페리딘-1-일)메타논Compound 15: (3-fluorophenyl) (4- (4-phenylpyrimidin-2-ylamino) piperidin-1-yl) methanone

화합물 16 : (4-메톡시페닐)(4-(4-페닐피리미딘-2-일아미노)피페리딘-1-일)메타논Compound 16: (4-methoxyphenyl) (4- (4-phenylpyrimidin-2-ylamino) piperidin-1-yl) methanone

화합물 17 : (3-메톡시페닐)(4-(4-페닐피리미딘-2-일아미노)피페리딘-1-일)메타논Compound 17: (3-methoxyphenyl) (4- (4-phenylpyrimidin-2-ylamino) piperidin-1-yl) methanone

화합물 18 : (2,4-디메톡시페닐)(4-(4-페닐피리미딘-2-일아미노)피페리딘-1-일)메타논Compound 18: (2,4-dimethoxyphenyl) (4- (4-phenylpyrimidin-2-ylamino) piperidin-1-yl) methanone

화합물 19 : (4-(4-페닐피리미딘-2-일아미노)피페리딘-1-일)(4-(트리플루오로메틸)페닐)메타논 Compound 19: (4- (4-phenylpyrimidin-2-ylamino) piperidin-1-yl) (4- (trifluoromethyl) phenyl) methanone

화합물 20 : 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민Compound 20: 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine

화합물 21 : 4-(4-클로로페닐)-N-(1-메틸피페리딘-4-일)피리미딘-2-아민Compound 21: 4- (4-chlorophenyl) - N - (1- methylpiperidin-4-yl) pyrimidin-2-amine

화합물 22 : 4-(4-클로로페닐)-N-(1-(메틸설포닐)피페리딘-4-일)피리미딘-2-아민Compound 22: 4- (4-chlorophenyl) - N - (1- (methylsulfonyl) piperidin-4-yl) pyrimidin-2-amine

화합물 23 : 4-(4-클로로페닐)-N-(1-(트리플루오로메틸설포닐)피페리딘-4-일)피리미딘-2-아민Compound 23: 4- (4-chlorophenyl) - N - (1- (trifluoromethyl-sulfonyl) -piperidin-4-yl) pyrimidin-2-amine

화합물 24 : 4-(4-(4-클로로페닐)피리미딘-2-일아미노)피페리딘-1-설폰아마이드Compound 24: 4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidine-1-sulfonamide

화합물 25 : 4-(4-클로로페닐)-N-(1-(페닐설포닐)피페리딘-4-일)피리미딘-2-아민Compound 25: 4- (4-chlorophenyl) - N - (1- (phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine

화합물 26 : 4-(4-클로로페닐)-N-(1-(4-(트리플루오로메틸)페닐설포닐)피페리딘-4-일)피리미딘-2-아민Compound 26: 4- (4-chlorophenyl) - N - (1- (4- (trifluoromethyl) phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine

화합물 27 : 4-(4-클로로페닐)-N-(1-(3-(트리플루오로메틸)페닐설포닐)피페리딘-4-일)피리미딘-2-아민Compound 27: 4- (4-chlorophenyl) - N - (1- (3- (trifluoromethyl) phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine

화합물 28 : 4-(4-클로로페닐)-N-(1-(2-(트리플루오로메틸)페닐설포닐)피페리딘-4-일)피리미딘-2-아민Compound 28: 4- (4-chlorophenyl) - N - (1- (2- (trifluoromethyl) phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine

화합물 29 : 4-(4-클로로페닐)-N-(1-(4-플루오로페닐설포닐)피페리딘-4-일)피리미딘-2-아민Compound 29: 4- (4-chlorophenyl) - N - (1- (4-fluoro phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine

화합물 30 : 4-(4-클로로페닐)-N-(1-(3-플루오로페닐설포닐)피페리딘-4-일)피리미딘-2-아민Compound 30: 4- (4-chlorophenyl) - N - (1- (phenylsulfonyl-fluorobenzyl) piperidin-4-yl) pyrimidin-2-amine

화합물 31 : 4-(4-클로로페닐)-N-(1-(2-플루오로페닐설포닐)피페리딘-4-일)피리미딘-2-아민Compound 31: 4- (4-chlorophenyl) - N - (1- (phenylsulfonyl 2-fluorobenzyl) piperidin-4-yl) pyrimidin-2-amine

화합물 32 : 4-(4-클로로페닐)-N-(1-(2,4-디플루오로페닐설포닐)피페리딘-4-일)피리미딘-2-아민Compound 32: 4- (4-chlorophenyl) - N - (1- (2,4- difluorophenyl sulfonyl) piperidin-4-yl) pyrimidin-2-amine

화합물 33 : 4-(4-클로로페닐)-N-(1-(4-메톡시페닐설포닐)피페리딘-4-일)피리미딘-2-아민Compound 33: 4- (4-chlorophenyl) - N - (1- (4-methoxy-phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine

화합물 34 : 4-(4-클로로페닐)-N-(1-(3-메톡시페닐설포닐)피페리딘-4-일)피리미딘-2-아민Compound 34: 4- (4-chlorophenyl) - N - (1- (3- methoxy-phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine

화합물 35 : 4-(4-클로로페닐)-N-(1-(2,5-디메톡시페닐설포닐)피페리딘-4-일)피리미딘-2-아민Compound 35: 4- (4-chlorophenyl) - N - (1- (2,5- dimethoxy-phenyl-sulfonyl) -piperidin-4-yl) pyrimidin-2-amine

화합물 36 : N-부틸-4-(4-(4-클로로페닐)피리미딘-2-일아미노)피페리딘-1-카복사마이드Compound 36: N -butyl-4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidine-1-carboxamide

화합물 37 : (4-(4-(4-클로로페닐)피리미딘-2-일아미노)피페리딘-1-일)(4-플루오로페닐)메타논Compound 37: (4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidin-1-yl) (4-fluorophenyl) methanone

화합물 38 : (4-(4-(4-클로로페닐)피리미딘-2-일아미노)피페리딘-1-일)(3-플루오로페닐)메타논Compound 38: (4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidin-1-yl) (3-fluorophenyl) methanone

화합물 39 : (4-(4-(4-클로로페닐)피리미딘-2-일아미노)피페리딘-1-일)(4-메톡시페닐)메타논Compound 39: (4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidin-1-yl) (4-methoxyphenyl) methanone

화합물 40 : (4-(4-(4-클로로페닐)피리미딘-2-일아미노)피페리딘-1-일)(3-메톡시페닐)메타논Compound 40: (4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidin-1-yl) (3-methoxyphenyl) methanone

화합물 41 : (4-(4-(4-클로로페닐)피리미딘-2-일아미노)피페리딘-1-일)(2,4-디메톡시페닐)메타논Compound 41: (4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidin-1-yl) (2,4-dimethoxyphenyl) methanone

화합물 42 : (4-(4-(4-클로로페닐)피리미딘-2-일아미노)피페리딘-1-일)(4-(트리플루오로메틸)페닐)메타논Compound 42: (4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidin-1-yl) (4- (trifluoromethyl) phenyl) methanone

화합물 43 : 4-(4-(몰폴리노설포닐)페닐)-N-(피페리딘-4-일)피리미딘-2-아민Compound 43: 4- (4- (morpholino noseol) phenyl) - N - (piperidin-4-yl) pyrimidin-2-amine

화합물 44 : N-(1-메틸피페리딘-4-일)-4-(4-(몰폴리노설포닐)페닐)피리미딘-2-아민Compound 44: N- (1-methylpiperidin-4-yl) -4- (4- (morpholinosulfonyl) phenyl) pyrimidin-2-amine

화합물 45 : N-(1-(메틸설포닐)피페리딘-4-일)-4-(4-(몰폴리노설포닐)페닐)피리미딘-2-아민Compound 45: N- (1- (methylsulfonyl) piperidin-4-yl) -4- (4- (morpholinosulfonyl) phenyl) pyrimidin-2-amine

화합물 46 : 4-(4-(4-(몰폴리노설포닐)페닐)피리미딘-2-일아미노)피페리딘-1-설폰아마이드Compound 46: 4- (4- (4- (morpholinosulfonyl) phenyl) pyrimidin-2-ylamino) piperidine-1-sulfonamide

화합물 47 : 4-(4-(4-메틸피페라진-1-일설포닐)페닐)-N-(피페리딘-4-일)피리미딘-2-아민Compound 47: 4- (4- (4-methylpiperazin-1-ylsulphonyl) phenyl) - N - (piperidin-4-yl) pyrimidin-2-amine

화합물 48 : 4-(4-(4-메틸피페라진-1-일설포닐)페닐)-N-(1-(메틸설포닐)피페리딘-4-일)피리미딘-2-아민Compound 48: 4- (4- (4-methylpiperazin-1-ylsulphonyl) phenyl) - N - (1- (methylsulfonyl) piperidin-4-yl) pyrimidin-2-amine

화합물 49 : 4-(4-(4-(4-메틸피페라진-1-일설포닐)페닐)피리미딘-2-일아미노)피페리딘-1-설폰아마이드Compound 49: 4- (4- (4- (4-methylpiperazin-1-ylsulfonyl) phenyl) pyrimidin-2-ylamino) piperidine-1-sulfonamide

화합물 50 : 4-(4-(피페라진-1-일설포닐)페닐)-N-(피페리딘-4-일)피리미딘-2-아민Compound 50: 4- (4- (1-ylsulphonyl) phenyl) - N - (piperidin-4-yl) pyrimidin-2-amine

화합물 51 : N-(1-(메틸설포닐)피페리딘-4-일)-4-(4-(피페라진-1-일설포닐)페닐)피리미딘-2-아민Compound 51: N- (1- (methylsulfonyl) piperidin-4-yl) -4- (4- (piperazin-1-ylsulfonyl) phenyl) pyrimidin-2-amine

화합물 52 : 4-(4-(4-(피페라진-1-일설포닐)페닐)피리미딘-2-일아미노)피페리딘-1-설폰아마이드Compound 52: 4- (4- (4- (piperazin-1-ylsulfonyl) phenyl) pyrimidin-2-ylamino) piperidine-1-sulfonamide

화합물 53 : 4-(4-(피페라진-1-일설포닐)페닐)-N-(피페리딘-4-일메틸)피리미딘-2-아민Compound 53: 4- (4- (1-ylsulphonyl) phenyl) - N - (piperidin-4-ylmethyl) pyrimidin-2-amine

화합물 54 : 4-(4-(피페라진-1-일설포닐)페닐)-N-(피페리딘-3-일메틸)피리미딘-2-아민Compound 54: 4- (4- (1-ylsulphonyl) phenyl) - N - (piperidin-3-ylmethyl) pyrimidin-2-amine

화합물 55 : (S)-4-(4-(피페라진-1-일설포닐)페닐)-N-(피롤리딘-3-일)피리미딘-2-아민Compound 55: (S) -4- (4- ( 1-ylsulphonyl) phenyl) - N - (pyrrolidin-3-yl) pyrimidin-2-amine

화합물 56 : (R)-4-(4-(피페라진-1-일설포닐)페닐)-N-(피롤리딘-3-일)피리미딘-2-아민Compound 56: (R) -4- (4- ( 1-ylsulphonyl) phenyl) - N - (pyrrolidin-3-yl) pyrimidin-2-amine

화합물 57 : (R)-4-(4-(피페라진-1-일설포닐)페닐)-N-(피롤리딘-3-일메틸)피리미딘-2-아민Compound 57: (R) -4- (4- ( 1-ylsulphonyl) phenyl) - N - (pyrrolidin-3-ylmethyl) pyrimidin-2-amine

화합물 58 : (S)-4-(4-(피페라진-1-일설포닐)페닐)-N-(피롤리딘-3-일메틸)피리미딘-2-아민
Compound 58: (S) -4- (4- ( 1-ylsulphonyl) phenyl) - N - (pyrrolidin-3-ylmethyl) pyrimidin-2-amine

한편, 본 발명은 상기 화학식 1로 표시되는 2-아자사이클릭아미노-4-페닐피리미딘 화합물의 제조방법을 포함하는 바, 본 발명에 따른 제조방법은 하기 반응식 1로 표시할 수 있다.On the other hand, the present invention includes a method for preparing the 2-azacyclic amino-4-phenylpyrimidine compound represented by the formula (1), the production method according to the present invention can be represented by the following scheme 1.

[반응식 1][Reaction Scheme 1]

상기 반응식 1에서, R¹,R², ℓ, m, 및 n은 각각 상기 화학식 1에서 정의한 바와 같고, R⁴는 아민 보호기로서 벤질옥시카보닐기, tert-부틸카보닐기를 나타낸다. In Scheme 1, R ¹ , R ² , L, m, and n are as defined in Chemical Formula 1, respectively, and R ⁴ represents a benzyloxycarbonyl group and tert- butylcarbonyl group as an amine protecting group.

상기 반응식 1에서 나타낸 첫 번째 제조방법은 다음과 같다.The first production method shown in Scheme 1 is as follows.

ⅰ)상기 화학식 2로 표시되는 아세토페논을 N,N-디메틸포름아마이드디메틸아세탈과 반응시켜, 상기 화학식 3으로 표시되는 3-디메틸아미노-1-페닐프로프-2-엔-1-온 화합물을 얻는 과정; ⅱ)상기 화학식 3으로 표시되는 화합물을 구아니딘 또는 구아니딘 염산염과 반응시켜, 상기 화학식 4로 표시되는 2-아미노-4-페닐피리미딘 화합물을 얻는 과정; ⅲ)상기 화학식 4로 표시되는 화합물을 상기 화학식 6으로 표시되는 아민보호기가 치환된 아자사이클릭 케톤 화합물과 환원적 아민화 반응시켜, 상기 화학식 7로 표시되는 화합물을 얻는 과정; 및 ⅳ)상기 화학식 7로 표시되는 화합물을 아민 탈보호 반응 또는 R²치환기 도입반응시켜, 상기 화학식 1로 표시되는 2-아자사이클릭아미노-4-페닐피리미딘 화합물을 얻는 과정을 포함한다.Iii) reacting the acetophenone represented by Formula 2 with N, N- dimethylformamide dimethylacetal to obtain 3-dimethylamino-1-phenylprop-2-en-1-one compound represented by Formula 3 Process of obtaining; Ii) reacting the compound represented by Chemical Formula 3 with guanidine or guanidine hydrochloride to obtain a 2-amino-4-phenylpyrimidine compound represented by Chemical Formula 4; Iii) reductive amination of the compound represented by Formula 4 with an azacyclic ketone compound substituted with an amine protecting group represented by Formula 6 to obtain a compound represented by Formula 7; And iii) obtaining a 2-azacyclicamino-4-phenylpyrimidine compound represented by Chemical Formula 1 by subjecting the compound represented by Chemical Formula 7 to an amine deprotection reaction or introducing an R ² substituent.

또한, 상기 반응식 1에서 나타낸 두 번째 제조방법은 다음과 같다.In addition, the second manufacturing method shown in Scheme 1 is as follows.

a)상기 화학식 2로 표시되는 아세토페논을 N,N-디메틸포름아마이드디메틸아세탈과 반응시켜, 상기 화학식 3으로 표시되는 3-디메틸아미노-1-페닐프로프-2-엔-1-온 화합물을 얻는 과정; b)상기 화학식 3으로 표시되는 화합물을 상기 화학식 5로 표시되는 아민보호기가 치환된 아자사이클릭 구아니디늄 화합물과 반응시켜, 상기 화학식 7로 표시되는 화합물을 얻는 과정; 및 c)상기 화학식 7로 표시되는 화합물을 아민 탈보호 반응 또는 R²치환기 도입반응시켜, 상기 화학식 1로 표시되는 2-아자사이클릭아미노-4-페닐피리미딘 화합물을 얻는 과정을 포함한다.a) reacting the acetophenone represented by the formula (2) with N, N- dimethylformamide dimethyl acetal to obtain the 3-dimethylamino-1-phenylprop-2-en-1-one compound represented by the formula (3) Process of obtaining; b) reacting the compound represented by Chemical Formula 3 with an azacyclic guanidinium compound substituted with the amine protecting group represented by Chemical Formula 5 to obtain a compound represented by Chemical Formula 7; And c) obtaining a 2-azacyclic amino-4-phenylpyrimidine compound represented by Chemical Formula 1 by subjecting the compound represented by Chemical Formula 7 to an amine deprotection reaction or an R ² substituent introduction reaction.

상기 반응식 1에 따른 제조방법을 좀 더 구체적으로 설명하면 다음과 같다.The preparation method according to Scheme 1 will be described in more detail as follows.

ⅰ) 또는 a)에 나타낸 상기 화학식 3으로 표시되는 화합물의 제조반응은 용매 존재 하에서 또는 별도의 용매 사용 없이 반응을 진행시킬 수도 있으며, 반응 온도는 100℃ 내지 200℃ 온도 범위를 유지하며, 바람직하기로는 150℃ 내외의 온도 범위를 유지한다. 반응이 완결되면 반응물을 실온으로 냉각한 후 헥산, 이서, 에틸아세테이트, 페트롤륨 이서 등을 이용하여 고체화하여 상기 화학식 3으로 표시되는 화합물을 얻는다.The reaction of preparing the compound represented by Chemical Formula 3 shown in iii) or a) may be carried out in the presence of a solvent or without using a separate solvent, and the reaction temperature is maintained at a temperature of 100 ° C. to 200 ° C., preferably Maintains a temperature range of about 150 ℃. When the reaction is complete, the reaction is cooled to room temperature and then solidified using hexane, ether, ethyl acetate, petroleum ether, etc. to obtain a compound represented by Chemical Formula 3.

ⅱ)에 나타낸 상기 화학식 4로 표시되는 화합물의 제조반응은 구아니딘 또는 구아니디늄 염산염을 사용하여 수행한다. 이때 반응용매로는 메탄올, 에탄올, 이소프로판올, 부탄올, 벤젠, 톨루엔 등과 같은 용매를 사용할 수 있다. 반응온도는 사용된 용매의 환류온도를 유지하는 것이며, 구체적으로는 60℃ 내지 120℃ 온도로 가열한다. 반응이 완결되면 반응물을 실온으로 냉각하여, 상기 화학식 4로 표시되는 화합물을 고체로 얻는다.The reaction for preparing the compound represented by Chemical Formula 4 shown in ii) is carried out using guanidine or guanidinium hydrochloride. In this case, a solvent such as methanol, ethanol, isopropanol, butanol, benzene, toluene, or the like may be used as the reaction solvent. The reaction temperature is to maintain the reflux temperature of the solvent used, specifically heated to a temperature of 60 ℃ to 120 ℃. When the reaction is completed, the reaction is cooled to room temperature to obtain a compound represented by the formula (4) as a solid.

ⅲ) 또는 b)에 나타낸 상기 화학식 7로 표시되는 화합물의 제조반응은 환원적 아민화 반응에 의해 수행한다. 상기 환원적 아민화 반응은 TiCl₄, TiCl(OiPr)₃, Ti(OiPr)₄와 같은 루이스산, NaBH₃CN, NaBH(OAc)₃등과 같은 환원제, 그리고 아세트산과 같은 산 존재하에서 수행한다. 반응용매로는 에탄올, 메탄올, 이소프로판올, 부탄올, 벤젠, 톨루엔 등과 같은 용매를 사용할 수 있다. 반응온도는 사용된 용매의 환류온도를 유지하는 것이며, 구체적으로는 60℃ 내지 120℃ 온도로 가열한다. 반응이 완결되면 반응물을 실온으로 냉각하여, 상기 화학식 7로 표시되는 화합물을 얻는다.Preparation of the compound represented by the formula (7) shown in (iii) or b) is carried out by a reductive amination reaction. The reductive amination reaction is carried out in the presence of a Lewis acid such as TiCl ₄ , TiCl (OiPr) ₃ , Ti (OiPr) ₄ , a reducing agent such as NaBH ₃ CN, NaBH (OAc) ₃ , and an acid such as acetic acid. As the reaction solvent, solvents such as ethanol, methanol, isopropanol, butanol, benzene, toluene and the like can be used. The reaction temperature is to maintain the reflux temperature of the solvent used, specifically heated to a temperature of 60 ℃ to 120 ℃. When the reaction is complete, the reaction is cooled to room temperature to obtain a compound represented by the formula (7).

ⅳ) 또는 c)에 나타낸 상기 화학식 1로 표시되는 화합물의 제조반응은 본 발명의 목적 화합물을 수득하는 과정이다. 따라서, 필요에 따라 아민 탈보호 반응, 설폰화 반응, 유레아화 반응, 아실화 반응 등의 통상의 유기합성법을 수행하여 다양한 R²치환기를 도입할 수 있다.Preparation reaction of the compound represented by the formula (1) shown in (iii) or c) is a process for obtaining the target compound of the present invention. Accordingly, various R ² substituents may be introduced by performing conventional organic synthesis methods such as amine deprotection reaction, sulfonation reaction, ureaization reaction, and acylation reaction, as necessary.

상기에서 설명한 각 제조반응에서 합성된 화합물은 일반적인 분리 정제과정 예를 들면 유기 용매로 희석 및 세척한 후 유기층을 감압 농축할 수 있으며, 필요시 관 크로마토그래피로 정제할 수 있다.Compounds synthesized in each of the above-described preparation reactions may be diluted and washed with a general separation and purification process, for example, with an organic solvent, and the organic layer may be concentrated under reduced pressure, and, if necessary, purified by column chromatography.

또한, 본 발명은 상기 화학식 1로 표시되는 화합물의 약제학적으로 허용 가능한 염을 권리범위로 포함하는 바, 약제학적으로 허용 가능한 염의 제조방법은 공지된 문헌에 따른 통상적인 합성방법에 의하여 쉽게 제조될 수 있으며, 별다른 정제과정 없이도 순수하게 분리해 낼 수 있다. 다음에서는 염산염의 제조과정을 중심으로 상기 화학식 1로 표시되는 화합물의 약제학적으로 허용 가능한 염의 제조방법을 설명하고자 한다. 즉, 상기한 추출용매를 건조하고 증발시킨 다음, 잔여물을 에테르 소량에 녹이고, 여기에 염화수소의 에테르 용액을 약 1 내지 10 당량 정도 가하면 원하는 목표화합물의 염산염이 고체 형태로 생성된다. 염화수소 용액을 제조하는데 사용 할 수 있는 유기용매는 클로로포름, 메틸렌클로라이드, 에테르, 메탄올, 에틸아세테이트 또는 이들의 혼합용매를 사용할 수 있는데, 바람직하게는 에테르가 유용하다. 이때, 고체 형태로 얻어진 생성물은 원심 분리기나 간단한 솜을 사용한 용매 제거 장치를 사용하여 분리할 수 있다. 고체를 2 내지 3회에 걸쳐 1 내지 2 mL의 에테르로 씻어 준 다음 잘 건조시키면 높은 순도의 염산염이 얻어지게 된다.In addition, the present invention includes a pharmaceutically acceptable salt of the compound represented by the formula (1) as a right range, the method for preparing a pharmaceutically acceptable salt can be easily prepared by conventional synthetic methods according to known literature It can be separated purely without any purification process. Next, a method for preparing a pharmaceutically acceptable salt of a compound represented by Chemical Formula 1 will be described based on the preparation of hydrochloride. That is, the extractant is dried and evaporated, and then the residue is dissolved in a small amount of ether, and about 1 to 10 equivalents of an ether solution of hydrogen chloride is added to form a hydrochloride of a desired target compound in solid form. The organic solvent that can be used to prepare the hydrogen chloride solution may be used chloroform, methylene chloride, ether, methanol, ethyl acetate or a mixed solvent thereof, preferably ether. At this time, the product obtained in the solid form can be separated using a centrifuge or a solvent removal device using a simple cotton. The solids are washed 2-3 times with 1 to 2 mL of ether and then well dried to obtain high purity hydrochloride.

한편, 본 발명은 상기 화학식 1로 표시되는 2-아자사이클릭아미노-4-페닐피리미딘 화합물 또는 이의 약제학적 허용 가능한 염을 질환의 예방 및 치료를 목적으로 유효성분으로 포함하는 약제조성물을 포함한다.On the other hand, the present invention includes a pharmaceutical composition comprising a 2-azacyclic amino-4-phenylpyrimidine compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient for the purpose of preventing and treating diseases. .

본 발명의 약제조성물은 상기 화학식 1로 표시되는 2-아자사이클릭아미노-4-페닐피리미딘 화합물 또는 이의 약제학적 허용 가능한 염과 함께 기타 통상적인 담체, 보조제 또는 희석제 등을 포함시켜 통상의 제제화 방법으로 제형화하여 경구투여 또는 비경구투여에 적합한 형태로 제조될 수 있다. 경구투여의 경우에는 정제, 캡슐제, 용액, 시럽제, 현탁제 등의 형태로 제조될 수 있고, 비경구투여의 경우에는 복강, 피하, 근육, 경피에 대한 주사제의 형태로 제조될 수 있다.The pharmaceutical composition of the present invention is a conventional formulation method comprising the other 2-carrier, adjuvant or diluent, etc. together with the 2-azacyclic amino-4-phenylpyrimidine compound represented by the formula (1) or a pharmaceutically acceptable salt thereof It can be formulated into a form suitable for oral or parenteral administration. In the case of oral administration, it may be prepared in the form of tablets, capsules, solutions, syrups, suspensions, etc., and in the case of parenteral administration, it may be prepared in the form of injections for intraperitoneal, subcutaneous, muscle, and transdermal.

본 발명의 약제조성물의 IKK-β 저해제로서 1일 유효투여량은 성인을 기준으로 0.01 내지 1000 mg/day이나, 투여용량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 의사 또는 약사의 판단에 따라 일정 시간간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다. The effective daily dose of IKK-β inhibitor of the pharmaceutical composition of the present invention is 0.01 to 1000 mg / day based on an adult, but the dosage is depending on the age, weight, sex, dosage form, health condition and the degree of disease of the patient. It may vary, and may be divided once or several times a day at regular intervals according to the judgment of a doctor or pharmacist.

따라서, 본 발명은 상기 화학식 1로 표시되는 2-아자사이클릭아미노-4-페닐피리미딘 화합물 또는 약제학적으로 허용 가능한 이들의 염 또는 이를 함유하는 약제학적 조성물을 질환의 예방 및 치료를 목적으로 사용하는 의약적 용도를 제공한다.Accordingly, the present invention uses the 2-azacyclic amino-4-phenylpyrimidine compound represented by the formula (1) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same for the purpose of preventing and treating diseases. It provides a medicinal use.

즉, 본 발명은 IKK-β에 대한 활성을 가지므로, 류마티스 관절염, 퇴행성 관절염, 천식, 만성 폐쇄성 폐질환등과 같은 염증성 질환과 암의 예방 및 치료목적으로 사용되는 의약적 용도를 포함한다.That is, the present invention has an activity against IKK-β, and thus includes medicinal uses used for the prevention and treatment of inflammatory diseases such as rheumatoid arthritis, degenerative arthritis, asthma, chronic obstructive pulmonary disease and cancer.

상기한 바와 같은 본 발명은 다음의 실시예 및 실험예를 통하여 보다 상세히 설명하겠는 바, 본 발명이 이들 실시예 및 실험예에 의해 한정되는 것은 아니다.
The present invention as described above will be described in more detail through the following Examples and Experimental Examples, but the present invention is not limited to these Examples and Experimental Examples.

[실시예]
[Example]

참고예 1. 3-(디메틸아미노)-1-페닐프로프-2-엔-1-온Reference Example 1. 3- (dimethylamino) -1-phenylprop-2-en-1-one

반응용기에 아세토페논 (1 g, 8.3 mmol)과 N,N-디메틸포름아마이드디메틸아세탈 (7 mL)를 넣고 150℃에서 15시간 동안 환류한 후, 반응 진행과 결과를 TLC로 확인하였다. 반응 완결 후 반응 혼합물을 0℃로 냉각하고 헥산으로 재결정하여 생긴 화합물을 여과 세척하여 목적화합물 1.3 g (7.4 mmol, 90.6%)를 얻었다.Acetophenone (1 g, 8.3 mmol) and N, N- dimethylformamide dimethylacetal (7 mL) were added to the reaction vessel and refluxed at 150 ° C. for 15 hours, and the reaction progress and results were confirmed by TLC. After completion of the reaction, the reaction mixture was cooled to 0 ° C. and recrystallized with hexane, and the resulting compound was filtered and washed to obtain 1.3 g (7.4 mmol, 90.6%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 7.94-7.91 (m, 2H), 7.82 (d, J = 12.6 Hz, 1H), 7.50-7.41 (m, 3H), 5.74 (d, J = 12.6 Hz, 1H), 3.04 (d, J = 60.6 Hz, 6H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.94-7.91 (m, 2H), 7.82 (d, J = 12.6 Hz, 1H), 7.50-7.41 (m, 3H), 5.74 (d, J = 12.6 Hz, 1H), 3.04 (d, J = 60.6 Hz, 6H)

참고예 2. 4-페닐피리미딘-2-아민Reference Example 2. 4-phenylpyrimidin-2-amine

반응용기에 3-(디메틸아미노)-1-페닐프로프-2-엔-1-온 (1.18 g, 6.7 mmol)과 탄산칼륨 (1.86 g, 13.5 mmol)를 넣고 에탄올 15 mL에 녹인 후, 구아니딘 (1.29 g, 13.5 mmol)을 첨가하였다. 80℃에서 하루 동안 환류한 후, 반응 진행과 결과를 TLC로 확인하였다. 반응 완결 후 반응 혼합물을 0℃로 냉각하고 헥산으로 재결정하여 생긴 화합물을 여과 세척하여 목적화합물 700.4 mg (4.09 mmol, 60.9%)를 얻었다.Into the reaction vessel, 3- (dimethylamino) -1-phenylprop-2-en-1-one (1.18 g, 6.7 mmol) and potassium carbonate (1.86 g, 13.5 mmol) were dissolved in 15 mL of ethanol, followed by guanidine. (1.29 g, 13.5 mmol) was added. After refluxing for one day at 80 ℃, the reaction progress and results were confirmed by TLC. After completion of the reaction, the reaction mixture was cooled to 0 ° C. and recrystallized with hexane, and the resulting compound was filtered and washed to obtain 700.4 mg (4.09 mmol, 60.9%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.35 (d, J = 5.4 Hz, 1H), 8.02-7.98 (m, 2H), 7.50-7.45 (m, 3H), 7.05 (d, J = 5.1 Hz, 1H), 5.09 (s, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.35 (d, J = 5.4 Hz, 1H), 8.02-7.98 (m, 2H), 7.50-7.45 (m, 3H), 7.05 (d, J = 5.1 Hz, 1H), 5.09 (s, 2H)

참고예 3. tert-부틸 4-(4-페닐피리미딘-2-일아미노)피페리딘-1-카복실레이트Reference Example 3. tert- Butyl 4- (4-phenylpyrimidin-2-ylamino) piperidine-1-carboxylate

질소 하에 4-페닐피리미딘-2-아민 (200 mg, 1.17 mmol)와 tert-부틸 4-옥소피페리딘-1-카복실레이트 (233.12 mg, 1.17 mmol)를 디클로로메탄 15 mL에 녹인 후, 루이스 산인 TiCl(OiPr)₃ (610 ㎕, 2.56 mmol)를 넣고 상온에서 1시간 동안 교반하였다. 아세트산 3방울 넣고, NaBH(OAc)₃ (1.2 g, 5.85 mmol)를 천천히 첨가하고 3시간 동안 교반 후, 반응 진행과 결과를 TLC로 확인하였다. 반응 완결 후 반응 혼합물을 디클로로메탄으로 묽힌 후, 포화 NaHCO₃용액을 넣고 수층을 디클로로메탄으로 추출하고 유기층을 무수 MgSO₄로 건조시킨 후, 여과하였다. 여과액을 감암 농축시켜 농축액을 관 크로마토그래피 (CHCl:MeOH=50:1)로 분리 정제하여 목적화합물 228 mg (0.64 mmol, 55%)를 얻었다.Dissolve 4-phenylpyrimidin-2-amine (200 mg, 1.17 mmol) and tert- butyl 4-oxopiperidine-1-carboxylate (233.12 mg, 1.17 mmol) in 15 mL of dichloromethane under nitrogen, then TiCl (OiPr) ₃ (610 μl, 2.56 mmol) was added thereto and stirred at room temperature for 1 hour. Three drops of acetic acid were added, NaBH (OAc) ₃ (1.2 g, 5.85 mmol) was added slowly and stirred for 3 hours, and the reaction progress and results were confirmed by TLC. After completion of the reaction, the reaction mixture was diluted with dichloromethane, saturated NaHCO ₃ solution was added, the aqueous layer was extracted with dichloromethane, the organic layer was dried over anhydrous MgSO ₄ , and filtered. The filtrate was concentrated in dark and the concentrate was separated and purified by column chromatography (CHCl: MeOH = 50: 1) to give 228 mg (0.64 mmol, 55%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.38 (d, J = 5.4 Hz, 1H), 8.07-8.03 (m, 2H), 7.53-7.51 (m, 3H), 7.03 (d, J = 5.4 Hz, 1H), 5.19 (d, J = 7.5 Hz, 1H), 4.21-4.02 (m, 4H), 3.04 (t, J = 12 Hz, 2H), 2.20-2.12 (m, 2H), 1.52 (s, 9H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.38 (d, J = 5.4 Hz, 1H), 8.07-8.03 (m, 2H), 7.53-7.51 (m, 3H), 7.03 (d, J = 5.4 Hz, 1H), 5.19 (d, J = 7.5 Hz, 1H), 4.21-4.02 (m, 4H), 3.04 (t, J = 12 Hz, 2H), 2.20-2.12 (m, 2H), 1.52 (s, 9H )

참고예 4. 4-페닐-N-(피페리딘-4-일)피리미딘-2-아민Reference Example 4. 4-phenyl- N- (piperidin-4-yl) pyrimidin-2-amine

반응용기에 tert-부틸 4-(4-페닐피리미딘-2-일아미노)피페리딘-1-카복실레이트 (214 mg, 0.60 mmol)을 디클로로메탄 7.13 mL에 녹인 후, 트리플루오로아세트산 (TFA; 2.14 mL)을 천천히 첨가하였다. 2시간 동안 교반 후 반응 진행과 결과를 TLC로 확인하였다. 반응 완결 후 반응 혼합물을 디클로로메탄으로 묽힌 후, 포화 NaHCO₃용액을 넣고 수층을 디클로로메탄으로 추출하고 유기층을 무수 MgSO₄로 건조시킨 후, 여과하였다. 여과액을 감암 농축시켜 농축액을 관 크로마토그래피 (CHCl₃:MeOH:NH₃:H₂O=80:20:1:1)를 통하여 목적화합물 102.5 mg (0.40 mmol, 66.7%)을 얻었다.Dissolve tert- butyl 4- (4-phenylpyrimidin-2-ylamino) piperidine-1-carboxylate (214 mg, 0.60 mmol) in 7.13 mL of dichloromethane in a reaction vessel, followed by trifluoroacetic acid (TFA). ; 2.14 mL) was added slowly. After stirring for 2 hours, the reaction progress and results were confirmed by TLC. After completion of the reaction, the reaction mixture was diluted with dichloromethane, saturated NaHCO ₃ solution was added, the aqueous layer was extracted with dichloromethane, the organic layer was dried over anhydrous MgSO ₄ , and filtered. The filtrate was concentrated under reduced pressure to give 102.5 mg (0.40 mmol, 66.7%) of the title compound by column chromatography (CHCl ₃ : MeOH: NH ₃ : H ₂ O = 80: 20: 1: 1).

¹H NMR (300 MHz, CDCl₃) δ 8.38 (d, J = 5.1 Hz, 1H), 8.06-8.03 (m, 2H), 7.54-7.50 (m, 3H), 7.03 (d, J = 5.1 Hz, 1H), 5.24 (d, J = 7.8 Hz, 1H), 4.21-4.11 (m, 1H), 3.34-3.27 (m, 2H), 2.95 (td, J = 12.6 Hz, J = 2.7 Hz, 2H), 1.52-1.39 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.38 (d, J = 5.1 Hz, 1H), 8.06-8.03 (m, 2H), 7.54-7.50 (m, 3H), 7.03 (d, J = 5.1 Hz, 1H), 5.24 (d, J = 7.8 Hz, 1H), 4.21-4.11 (m, 1H), 3.34-3.27 (m, 2H), 2.95 (td, J = 12.6 Hz, J = 2.7 Hz, 2H), 1.52-1.39 (m, 2H)

참고예 5. 1-(4-클로로페닐)-3-(디메틸아미노)프로프-2-엔-1-온Reference Example 5. 1- (4-Chlorophenyl) -3- (dimethylamino) prop-2-en-1-one

반응용기에 4-클로로아세토페논 (0.84 mL, 6.47 mmol)와 N,N-디메틸포름아마이드디메틸아세탈 (7 mL)를 넣고 150℃에서 15시간 동안 환류한 후, 반응 진행과 결과를 TLC로 확인하였다. 반응 완결 후 반응 혼합물을 0℃로 냉각하고 헥산으로 재결정하여 생긴 화합물을 여과 세척하여 목적화합물 1.2 g (5.72 mmol, 90.6%)를 얻었다. 4-chloroacetophenone (0.84 mL, 6.47 mmol) and N, N- dimethylformamide dimethylacetal (7 mL) were added to the reaction vessel, and the mixture was refluxed at 150 ° C. for 15 hours. The reaction progress and results were confirmed by TLC. . After completion of the reaction, the reaction mixture was cooled to 0 ° C. and recrystallized with hexane, and the resulting compound was filtered and washed to obtain 1.2 g (5.72 mmol, 90.6%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 7.88-7.81 (m, 3H), 7.40 (d, J = 6.3 Hz, 2H), 6.69 (d, J = 14.1 Hz, 1H), 3.06 (d, J = 55.2 Hz, 6H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.88-7.81 (m, 3H), 7.40 (d, J = 6.3 Hz, 2H), 6.69 (d, J = 14.1 Hz, 1H), 3.06 (d, J = 55.2 Hz, 6H)

참고예 6. 4-(4-클로로페닐)피리미딘-2-아민Reference Example 6. 4- (4-chlorophenyl) pyrimidin-2-amine

반응용기에 1-(4-클로로페닐)-3-(디메틸아미노)프로프-2-엔-1-온 (1.2 g, 5.72 mmol)과 탄산칼륨 (869.3 mg, 6.29 mmol)를 넣고 에탄올 12 mL에 녹인 후, 구아니딘 (929 mg, 9.72 mmol)을 첨가하였다. 80℃에서 하루 동안 환류한 후, 반응 진행과 결과를 TLC로 확인하였다. 반응 완결 후 반응 혼합물을 0℃로 냉각하고 헥산으로 재결정하여 생긴 화합물을 여과 세척하여 목적화합물 497 mg (2.42 mmol, 42.1%)를 얻었다.1- (4-chlorophenyl) -3- (dimethylamino) prop-2-en-1-one (1.2 g, 5.72 mmol) and potassium carbonate (869.3 mg, 6.29 mmol) were added to the reaction vessel. After dissolving in, guanidine (929 mg, 9.72 mmol) was added. After refluxing for one day at 80 ℃, the reaction progress and results were confirmed by TLC. After completion of the reaction, the reaction mixture was cooled to 0 ° C. and recrystallized with hexane, and the resulting compound was filtered and washed to obtain 497 mg (2.42 mmol, 42.1%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.35 (d, J = 5.1 Hz, 1H), 7.96 (d, J = 11.1 Hz, 2H), 7.45 (d, J = 11.1 Hz, 2H), 7.02 (d, J = 5.4 Hz, 1H), 5.17 (s, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.35 (d, J = 5.1 Hz, 1H), 7.96 (d, J = 11.1 Hz, 2H), 7.45 (d, J = 11.1 Hz, 2H), 7.02 (d , J = 5.4 Hz, 1H), 5.17 (s, 2H)

참고예 7. tert-부틸 4-(4-(4-클로로페닐)피리미딘-2-일아미노)피페리딘-1-카복실레이트Reference Example 7. tert- Butyl 4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidine-1-carboxylate

질소 하에 4-(4-클로로페닐)피리미딘-2-아민 (200 mg, 1.17 mmol)와 tert-부틸 4-옥소피페리딘-1-카복실레이트 (193.78 mg, 1.17 mmol)를 디클로로메탄 15 mL에 녹인 후, 루이스 산인 TiCl(OiPr)₃ (510 ㎕, 2.13 mmol)를 넣고 상온에서 1시간 동안 교반하였다. 아세트산 3방울 넣고, NaBH(OAc)₃ (1.02 g, 4.85 mmol)를 천천히 첨가하고 3시간 동안 교반 후, 반응 진행과 결과를 TLC로 확인하였다. 반응 완결 후 반응 혼합물을 디클로로메탄으로 묽힌 후, 포화 NaHCO₃용액을 넣고 수층을 디클로로메탄으로 추출하고 유기층을 무수 MgSO₄로 건조시킨 후, 여과하였다. 여과액을 감암 농축시켜 농축액을 관 크로마토그래피 (CH₂Cl₂:MeOH=50:1)로 분리 정제하여 목적화합물 200 mg (0.51 mmol, 51%)를 얻었다.15 mL of 4- (4-chlorophenyl) pyrimidin-2-amine (200 mg, 1.17 mmol) and tert- butyl 4-oxopiperidine-1-carboxylate (193.78 mg, 1.17 mmol) under nitrogen After dissolving in, TiCl (OiPr) ₃ (510 μl, 2.13 mmol), which is a Lewis acid, was added thereto and stirred at room temperature for 1 hour. Three drops of acetic acid were added, NaBH (OAc) ₃ (1.02 g, 4.85 mmol) was added slowly and stirred for 3 hours, and the reaction progress and results were confirmed by TLC. After completion of the reaction, the reaction mixture was diluted with dichloromethane, saturated NaHCO ₃ solution was added, the aqueous layer was extracted with dichloromethane, the organic layer was dried over anhydrous MgSO ₄ , and filtered. The filtrate was concentrated in dark and the concentrate was separated and purified by column chromatography (CH ₂ Cl ₂ : MeOH = 50: 1) to obtain 200 mg (0.51 mmol, 51%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.38 (d, J = 5.7 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 9 Hz, 2H), 6.98 (d, J = 5.4 Hz, 1H), 5.15 (d, J = 7.5 Hz, 1H), 4.20-4.12 (m, 4H), 3.03 (t, J = 11.7 Hz, 2H), 2.14-2.08 (m, 2H), 1.51 (s, 9H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.38 (d, J = 5.7 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 9 Hz, 2H), 6.98 (d , J = 5.4 Hz, 1H), 5.15 (d, J = 7.5 Hz, 1H), 4.20-4.12 (m, 4H), 3.03 (t, J = 11.7 Hz, 2H), 2.14-2.08 (m, 2H) , 1.51 (s, 9H)

참고예 8. 1-(4-(몰폴리노설포닐)페닐)에타논Reference Example 8. 1- (4- (morpholinosulfonyl) phenyl) ethanone

반응용기에 4-아세틸벤젠-1-설포닐 클로라이드 (1 g, 4.57 mmol)를 디클로로메탄 13 mL에 녹인 뒤, 0℃에서 TEA (1.24 mL, 9.14 mmol)와 몰폴린 (0.59 mL, 6.86 mmol)를 적가한 취 상온에서 30분 동안 교반하고, 디클로로메탄으로 묽힌 뒤 5% HCl 용액, 물, 브라인으로 유기용액을 씻어 준 뒤 유기 용액을 무수 MgSO₄로 건조시킨 후, 여과하였다. 여과액을 감암 농축시켜 목적화합물 873 mg (71%)를 얻었다.Dissolve 4-acetylbenzene-1-sulfonyl chloride (1 g, 4.57 mmol) in 13 mL of dichloromethane in a reaction vessel, and then TEA (1.24 mL, 9.14 mmol) and morpholine (0.59 mL, 6.86 mmol) at 0 ° C. Was added dropwise at room temperature for 30 minutes, diluted with dichloromethane, washed with 5% HCl solution, water and brine, the organic solution was dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure to give 873 mg (71%) of the target compound.

¹H NMR (300 MHz, CDCl₃) δ 8.11-8.15 (m, 2H), 7.85-7.89 (m, 2H), 3.77 (t, J = 4.40 Hz, 4H), 3.04 (t, J = 4.8 Hz, 4H), 2.69 (s, 3H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.11-8.15 (m, 2H), 7.85-7.89 (m, 2H), 3.77 (t, J = 4.40 Hz, 4H), 3.04 (t, J = 4.8 Hz, 4H), 2.69 (s, 3H)

참고예 9. 3-(디메틸아미노)-1-(4-(몰폴리노설포닐)페닐)프로프-2-엔-1-온Reference Example 9. 3- (dimethylamino) -1- (4- (morpholinosulfonyl) phenyl) prop-2-en-1-one

반응용기에 1-(4-(몰폴리노설포닐)페닐)에타논 (873 mg, 3.24 mmol)와 N,N-디메틸포름아마이드디메틸아세탈 (9.2 mL, 26.2 mmol)를 넣고 150℃에서 15시간 동안 환류한 후, 반응 진행과 결과를 TLC로 확인하였다. 반응 완결 후 반응 혼합물을 0℃로 냉각하고 헥산으로 재결정하여 생긴 화합물을 여과 세척하여 목적화합물 977 mg (93%)를 얻었다. 1- (4- (morpholinosulfonyl) phenyl) ethanone (873 mg, 3.24 mmol) and N, N- dimethylformamide dimethylacetal (9.2 mL, 26.2 mmol) were added to the reaction vessel for 15 hours at 150 ° C. After reflux, the reaction progress and results were confirmed by TLC. After completion of the reaction, the reaction mixture was cooled to 0 ° C. and recrystallized with hexane, and the resulting compound was filtered and washed to obtain 977 mg (93%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.03 (d, J = 8.22 Hz, 2H), 7.86 (d, J = 12.24 Hz, 1H), 7.80 (d, J = 8.27 Hz, 2H), 5.68 (d, J = 12.26 Hz, 1H), 3.75 (t, J = 4.50 Hz, 4H), 3.21 (s, 3H), 3.03 (t, J = 4.71 Hz, 4H), 2.98 (s, 3H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.03 (d, J = 8.22 Hz, 2H), 7.86 (d, J = 12.24 Hz, 1H), 7.80 (d, J = 8.27 Hz, 2H), 5.68 (d , J = 12.26 Hz, 1H), 3.75 (t, J = 4.50 Hz, 4H), 3.21 (s, 3H), 3.03 (t, J = 4.71 Hz, 4H), 2.98 (s, 3H)

참고예 10. 1-(1-(tert-부톡시카보닐)피페리딘-4-일)구아니디늄 클로라이드Reference Example 10 1- (1- ( tert -butoxycarbonyl) piperidin-4-yl) guanidinium chloride

반응용기에 tert-부틸 4-아미노피페리딘-1-카복실레이트 (500 mg, 2.5 mmol)와 1-아미노피라졸구아니딘 염산염 (366.5 mg, 2.5 mmol)을 N,N-디메틸포름아마이드 (DMF) 7.5 mL에 녹인 후 디이소프로필에틸아민 (DIPEA; 0.45 mL, 2.5 mmol)를 적가한 뒤 80℃로 온도를 높여 주고 다음날 반응용액을 감압하에서 농축하고 에테르를 사용하여 고체화하여 목적화합물 680 mg (98%)를 얻었다. Tert- Butyl 4-aminopiperidine-1-carboxylate (500 mg, 2.5 mmol) and 1-aminopyrazoleguanidine hydrochloride (366.5 mg, 2.5 mmol) were added to the reaction vessel in N, N- dimethylformamide (DMF). After dissolving in 7.5 mL, diisopropylethylamine (DIPEA; 0.45 mL, 2.5 mmol) was added dropwise, the temperature was increased to 80 ° C. and the next day the reaction solution was concentrated under reduced pressure and solidified with ether to give 680 mg (98). %) Was obtained.

¹H NMR (300 MHz, DMSO-d ₆) δ 8.04 (d, J = 8.25 Hz, 1H), 7.15-7.39 (m, 3H), 3.82 (d, J = 13.4 Hz, 2H), 3.60 (t, J = 4.19 Hz, 1H), 2.88-2.94 (m, 2H), 1.76-1.85 (m, 2H), 1.38 (s, 9H), 1.17-1.32 (m, 2H)
¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.04 (d, J = 8.25 Hz, 1H), 7.15-7.39 (m, 3H), 3.82 (d, J = 13.4 Hz, 2H), 3.60 (t, J = 4.19 Hz, 1H), 2.88-2.94 (m, 2H), 1.76-1.85 (m, 2H), 1.38 (s, 9H), 1.17-1.32 (m, 2H)

참고예 11. tert-부틸 4-(4-(4-(몰폴리노설포닐)페닐)피리미딘-2-일아미노)피페리딘-1-카복실레이트Reference Example 11. tert- Butyl 4- (4- (4- (morpholinosulfonyl) phenyl) pyrimidin-2-ylamino) piperidine-1-carboxylate

반응용기에 3-(디메틸아미노)-1-(4-(몰폴리노설포닐)페닐)프로프-2-엔-1-온 (330 mg, 1.02 mmol), 1-(1-(tert-부톡시카보닐)피페리딘-4-일)구아니디늄 클로라이드 (482.26 mg, 1.73 mmol) 그리고 탄산칼륨 (168.6 mg, 1.22 mmol)을 무수 n-프로판올 (12 mL)에 녹인 후 100℃에서 환류하고, 반응이 종결되면, 상온으로 식혀 농축시킨 후 디클로로메탄으로 추출하고 무수 MgSO₄로 건조시킨 후, 여과하였다. 여과액을 감암 농축시켜 농축액을 관 크로마토그래피(SiO₂, EtOAc:Hex=2:1)로 분리 정제하여 목적화합물 379 mg (74%)를 얻었다. 3- (dimethylamino) -1- (4- (morpholinosulfonyl) phenyl) prop-2-en-1-one (330 mg, 1.02 mmol), 1- (1- ( tert- part) in the reaction vessel Toxylcarbonyl) piperidin-4-yl) guanidinium chloride (482.26 mg, 1.73 mmol) and potassium carbonate (168.6 mg, 1.22 mmol) were dissolved in anhydrous n-propanol (12 mL) and refluxed at 100 ° C. After the reaction was completed, the mixture was cooled to room temperature, concentrated, extracted with dichloromethane, dried over anhydrous MgSO ₄ , and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (SiO ₂ , EtOAc: Hex = 2: 1) to obtain 379 mg (74%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.42 (d, J = 5.04 Hz, 1H), 8.18 (d, J = 8.27 Hz, 2H), 7.86 (d, J = 8.30 Hz, 2H), 7.02 (d, J = 5.12 Hz, 1H), 5.16 (d, J = 7.81 Hz, 1H), 4.09-4.11 (m, 3H), 3.77 (t, J = 4.31 Hz, 4H), 2.90-3.07 (m, 6H), 2.11 (d, J = 12.7 Hz, 2H), 1.49 (s, 11H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.42 (d, J = 5.04 Hz, 1H), 8.18 (d, J = 8.27 Hz, 2H), 7.86 (d, J = 8.30 Hz, 2H), 7.02 (d , J = 5.12 Hz, 1H), 5.16 (d, J = 7.81 Hz, 1H), 4.09-4.11 (m, 3H), 3.77 (t, J = 4.31 Hz, 4H), 2.90-3.07 (m, 6H) , 2.11 (d, J = 12.7 Hz, 2H), 1.49 (s, 11H)

실시예 1. N-(1-(메틸설포닐)피페리딘-4-일)-4-페닐피리미딘-2-아민 (화합물 1)Example 1. N - (1- (methylsulfonyl) piperidin-4-yl) -4-phenyl-pyrimidin-2-amine (Compound 1)

반응용기에 4-페닐-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.079 mmol)을 디클로로메탄 2 mL에 녹이고 메탄설포닐 클로라이드 (5.5 ㎕, 0.071 mmol)를 천천히 첨가한 후 디이소프로필에틸아민 (DIPEA; 24 ㎕, 0.142 mmol)을 첨가하고 실온에서 1시간 동안 교반하였다. 반응이 완결된 수 반응 용액을 디클로로메탄으로 묽힌 후 포화 NaHCO₃용액을 넣고 추출하여 유기층을 무수 MgSO₄로 건조시킨 후 여과하고, 여과액을 농축시켜 농축액을 관 크로마토그래피 (CH₂Cl₂:MeOH=30:1)로 분리 정제하여 목적화합물 25 mg (0.075 mmol, 95%)을 얻었다.Dissolve 4-phenyl- N- (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.079 mmol) in 2 mL of dichloromethane and add methanesulfonyl chloride (5.5 μL, 0.071 mmol) to the reaction vessel. After slow addition diisopropylethylamine (DIPEA; 24 μl, 0.142 mmol) was added and stirred at room temperature for 1 hour. After completion of the reaction, the aqueous reaction solution was diluted with dichloromethane and extracted with saturated NaHCO ₃ solution. The organic layer was dried over anhydrous MgSO ₄ , filtered, and the filtrate was concentrated to give a concentrated solution by column chromatography (CH ₂ Cl ₂ : MeOH). = 30: 1) was purified by separation to give 25 mg (0.075 mmol, 95%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.38 (d, J = 5.4 Hz, 1H), 8.01-8.02 (m, 2H), 7.55-7.51 (m, 3H), 7.05 (d, J = 5.1 Hz, 1H), 5.20 (d, J = 7.8 Hz, 1H), 4.20-4.07 (m, 1H), 3.86-3.78 (m, 2H), 3.06-2.97 (m, 2H), 2.79 (s, 3H), 2.27 (dd, J = 12.9 Hz, J = 3.6 Hz, 2H), 1.73 (qd, J = 10.5 Hz, J = 3.9 Hz, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.38 (d, J = 5.4 Hz, 1H), 8.01-8.02 (m, 2H), 7.55-7.51 (m, 3H), 7.05 (d, J = 5.1 Hz, 1H), 5.20 (d, J = 7.8 Hz, 1H), 4.20-4.07 (m, 1H), 3.86-3.78 (m, 2H), 3.06-2.97 (m, 2H), 2.79 (s, 3H), 2.27 (dd, J = 12.9 Hz, J = 3.6 Hz, 2H), 1.73 (qd, J = 10.5 Hz, J = 3.9 Hz, 2H)

실시예 2. 4-페닐-N-(1-(페닐설포닐)피페리딘-4-일)피리미딘-2-아민 (화합물 2)Example 2. 4-phenyl- N- (1- (phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine (Compound 2)

상기 실시예 1의 합성 방법으로 4-페닐-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.079 mmol), 벤젠설포닐 클로라이드 (9.06 ㎕, 0.071 mmol), DIPEA (24 ㎕, 0.142 mmol)를 사용하여 목적화합물 25 mg (0.063 mmol, 80%)을 얻었다.Synthesis method of Example 1 4-phenyl- N- (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.079 mmol), benzenesulfonyl chloride (9.06 μl, 0.071 mmol), DIPEA (24 μl, 0.142 mmol) was used to obtain 25 mg (0.063 mmol, 80%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.33 (d, J = 5.1 Hz, 1H), 8.03-7.98 (m, 2H), 7.85-7.82 (m, 3H), 7.70-7.57 (m, 3H), 7.52-7.47 (m, 3H), 7.01 (d, J = 5.1 Hz, 1H), 5.22 (d, J = 7.5 Hz, 1H), 4.02-3.88 (m, 1H), 3.77-3.71 (m, 2H), 2.71-2.62 (m, 2H), 2.20 (dd, J = 13.2 Hz, J = 3.6 Hz, 2H), 1.69 (qd, J = 3.6 Hz, J = 10.8 Hz, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.33 (d, J = 5.1 Hz, 1H), 8.03-7.98 (m, 2H), 7.85-7.82 (m, 3H), 7.70-7.57 (m, 3H), 7.52-7.47 (m, 3H), 7.01 (d, J = 5.1 Hz, 1H), 5.22 (d, J = 7.5 Hz, 1H), 4.02-3.88 (m, 1H), 3.77-3.71 (m, 2H) , 2.71-2.62 (m, 2H), 2.20 (dd, J = 13.2 Hz, J = 3.6 Hz, 2H), 1.69 (qd, J = 3.6 Hz, J = 10.8 Hz, 2H)

실시예 3. 4-페닐-N-(1-(4-(트리플루오로메틸)페닐설포닐)피페리딘-4-일)피리미딘-2-아민 (화합물 3)Example 3. 4-phenyl- N- (1- (4- (trifluoromethyl) phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine (Compound 3)

상기 실시예 1의 합성 방법으로 4-페닐-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.079 mmol), 4-(트리플루오로메틸)벤젠설포닐 클로라이드 (17.4 mg, 0.071 mmol), DIPEA (24 ㎕, 0.142 mmol)를 사용하여 목적화합물 27 mg (0.058 mmol, 74%)을 얻었다.Synthesis method of Example 1 above 4-phenyl- N- (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.079 mmol), 4- (trifluoromethyl) benzenesulfonyl chloride ( 17.4 mg, 0.071 mmol) and DIPEA (24 μl, 0.142 mmol) gave 27 mg (0.058 mmol, 74%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.33 (d, J = 5.1 Hz, 1H), 8.01-7.95 (m, 4H), 7.87 (d, J = 8.1 Hz, 2H), 7.51-7.49 (m, 3H), 7.02 (d, J = 5.1 Hz, 1H), 5.13 (d, J = 7.5 Hz, 1H), 4.07-3.9 (m, 1H), 3.76 (d, J = 11.4 Hz, 1H), 2.72 (t, J = 10.2 Hz, 2H), 2.26-2.21 (m, 2H), 1.8-1.67 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.33 (d, J = 5.1 Hz, 1H), 8.01-7.95 (m, 4H), 7.87 (d, J = 8.1 Hz, 2H), 7.51-7.49 (m, 3H), 7.02 (d, J = 5.1 Hz, 1H), 5.13 (d, J = 7.5 Hz, 1H), 4.07-3.9 (m, 1H), 3.76 (d, J = 11.4 Hz, 1H), 2.72 ( t, J = 10.2 Hz, 2H), 2.26-2.21 (m, 2H), 1.8-1.67 (m, 2H)

실시예 4. 4-페닐-N-(1-(3-(트리플루오로메틸)페닐설포닐)피페리딘-4-일)피리미딘-2-아민 (화합물 4)Example 4. 4-phenyl- N- (1- (3- (trifluoromethyl) phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine (Compound 4)

상기 실시예 1의 합성 방법으로 4-페닐-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.079 mmol), 3-(트리플루오로메틸)벤젠설포닐 클로라이드 (11.3 ㎕, 0.071 mmol), DIPEA (24 ㎕, 0.142 mmol)를 사용하여 목적화합물 28.7 mg (0.062 mmol, 78%)을 얻었다. Synthesis method of Example 1 above 4-phenyl- N- (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.079 mmol), 3- (trifluoromethyl) benzenesulfonyl chloride ( 11.3 μl, 0.071 mmol) and DIPEA (24 μl, 0.142 mmol) gave 28.7 mg (0.062 mmol, 78%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.34 (d, J = 5.4 Hz, 1H), 8.09 (s, 1H), 8.04-7.97 (m, 3H), 7.95-7.92 (m, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.52-7.48 (m, 3H), 7.02 (d, J = 5.4 Hz, 1H), 5.16 (d, J = 7.5 Hz, 1H), 4.06-3.92 (m, 1H), 3.80-3.74 (m, 2H), 2.71 (td, J = 12 Hz, J = 2.7 Hz, 2H), 2.26-2.20 (m, 2H), 1.78-1.66 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.34 (d, J = 5.4 Hz, 1H), 8.09 (s, 1H), 8.04-7.97 (m, 3H), 7.95-7.92 (m, 1H), 7.76 ( t, J = 7.8 Hz, 1H), 7.52-7.48 (m, 3H), 7.02 (d, J = 5.4 Hz, 1H), 5.16 (d, J = 7.5 Hz, 1H), 4.06-3.92 (m, 1H ), 3.80-3.74 (m, 2H), 2.71 (td, J = 12 Hz, J = 2.7 Hz, 2H), 2.26-2.20 (m, 2H), 1.78-1.66 (m, 2H)

실시예 5. 4-페닐-N-(1-(2-(트리플루오로메틸)페닐설포닐)피페리딘-4-일)피리미딘-2-아민 (화합물 5)Example 5. 4-phenyl- N- (1- (2- (trifluoromethyl) phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine (Compound 5)

상기 실시예 1의 합성 방법으로 4-페닐-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.079 mmol), 2-(트리플루오로메틸)벤젠설포닐 클로라이드 (11 ㎕, 0.071 mmol), DIPEA (24 ㎕, 0.142 mmol)를 사용하여 목적화합물 21 mg (0.045 mmol, 57.5%)을 얻었다.Synthesis method of Example 1 above 4-phenyl- N- (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.079 mmol), 2- (trifluoromethyl) benzenesulfonyl chloride ( 11 μl, 0.071 mmol) and DIPEA (24 μl, 0.142 mmol) gave 21 mg (0.045 mmol, 57.5%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.26 (d, J = 5.1 Hz, 1H), 8.21-8.18 (m, 1H), 8.04-8.01 (m, 2H), 7.97-7.94 (m, 1H), 7.77-7.74 (m, 2H), 7.52-7.49 (m, 3H), 7.03 (d, J = 5.4 Hz, 1H), 5.17 (d, J = 8.1 Hz, 1H), 4.19-4.06 (m, 1H), 3.84 (d, J = 12.9 Hz, 2H), 3.10-3.01 (m, 2H), 2.24-2.19 (m, 2H), 1.75-1.62 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.26 (d, J = 5.1 Hz, 1H), 8.21-8.18 (m, 1H), 8.04-8.01 (m, 2H), 7.97-7.94 (m, 1H), 7.77-7.74 (m, 2H), 7.52-7.49 (m, 3H), 7.03 (d, J = 5.4 Hz, 1H), 5.17 (d, J = 8.1 Hz, 1H), 4.19-4.06 (m, 1H) , 3.84 (d, J = 12.9 Hz, 2H), 3.10-3.01 (m, 2H), 2.24-2.19 (m, 2H), 1.75-1.62 (m, 2H)

실시예 6. N-(1-(4-플루오로페닐설포닐)피페리딘-4-일)-4-페닐피리미딘-2-아민 (화합물 6)Example 6. N - (1- (phenylsulfonyl-fluorobenzyl) piperidin-4-yl) -4-phenyl-pyrimidin-2-amine (compound 6)

상기 실시예 1의 합성 방법으로 4-페닐-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.079 mmol), 4-플루오로벤젠설포닐 클로라이드 (11 ㎕, 0.071 mmol), DIPEA (24 ㎕, 0.142 mmol)를 사용하여 목적화합물 28 mg (0.068 mmol, 85.9%)을 얻었다.Synthesis method of Example 1 above 4-phenyl- N- (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.079 mmol), 4-fluorobenzenesulfonyl chloride (11 μl, 0.071 mmol) and DIPEA (24 μl, 0.142 mmol) gave 28 mg (0.068 mmol, 85.9%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.33 (d, J = 5.1 Hz, 1H), 8.03-7.97 (m, 2H), 7.88-7.812 (m, 2H), 7.52-7.46 (m, 3H), 7.31-7.24 (m, 2H), 7.02 (d, J = 5.4 Hz, 1H), 5.2 (d, J = 7.5 Hz, 1H), 4.03-3.90 (m, 1H), 3.78-3.69 (m, 2H), 2.67 (td, J = 11.7 Hz, J = 2.7 Hz, 2H), 2.24-2.18 (m, 2H), 1.77-1.64 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.33 (d, J = 5.1 Hz, 1H), 8.03-7.97 (m, 2H), 7.88-7.812 (m, 2H), 7.52-7.46 (m, 3H), 7.31-7.24 (m, 2H), 7.02 (d, J = 5.4 Hz, 1H), 5.2 (d, J = 7.5 Hz, 1H), 4.03-3.90 (m, 1H), 3.78-3.69 (m, 2H) , 2.67 (td, J = 11.7 Hz, J = 2.7 Hz, 2H), 2.24-2.18 (m, 2H), 1.77-1.64 (m, 2H)

실시예 7. N-(1-(3-플루오로페닐설포닐)피페리딘-4-일)-4-페닐피리미딘-2-아민 (화합물 7)Example 7. N - (1- (phenylsulfonyl-fluorobenzyl) piperidin-4-yl) -4-phenyl-pyrimidin-2-amine (compound 7)

상기 실시예 1의 합성 방법으로 4-페닐-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.079 mmol), 3-플루오로벤젠설포닐 클로라이드 (9.4 ㎕, 0.071 mmol), DIPEA (24 ㎕, 0.142 mmol)를 사용하여 목적화합물 20 mg (0.048 mmol, 61.4%)을 얻었다.Synthesis method of Example 1 4-phenyl- N- (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.079 mmol), 3-fluorobenzenesulfonyl chloride (9.4 μl, 0.071 mmol) and DIPEA (24 μl, 0.142 mmol) gave 20 mg (0.048 mmol, 61.4%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.34 (d, J = 5.4 Hz, 1H), 8.05-7.96 (m, 2H), 7.66-7.55 (m, 3H), 7.54-7.46 (m, 3H), 7.42-7.34 (m, 1H), 7.02 (d, J = 5.4 Hz, 1H), 5.17 (d, J = 7.5 Hz, 1H), 4.05-3.90 (m, 1H), 3.81-3.70 (m, 2H), 2.72 (t, J = 9 Hz, 2H), 2.28-2.19 (m, 2H), 1.79-1.65 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.34 (d, J = 5.4 Hz, 1H), 8.05-7.96 (m, 2H), 7.66-7.55 (m, 3H), 7.54-7.46 (m, 3H), 7.42-7.34 (m, 1H), 7.02 (d, J = 5.4 Hz, 1H), 5.17 (d, J = 7.5 Hz, 1H), 4.05-3.90 (m, 1H), 3.81-3.70 (m, 2H) , 2.72 (t, J = 9 Hz, 2H), 2.28-2.19 (m, 2H), 1.79-1.65 (m, 2H)

실시예 8. N-(1-(2-플루오로페닐설포닐)피페리딘-4-일)-4-페닐피리미딘-2-아민 (화합물 8)Example 8. N - (1- (phenylsulfonyl 2-fluorobenzyl) piperidin-4-yl) -4-phenyl-pyrimidin-2-amine (Compound 8)

상기 실시예 1의 합성 방법으로 4-페닐-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.079 mmol), 2-플루오로벤젠설포닐 클로라이드 (9.4 ㎕, 0.071 mmol), DIPEA (24 ㎕, 0.142 mmol)를 사용하여 목적화합물 18.6 mg (0.045 mmol, 57.6%)을 얻었다Synthesis method of Example 1 above 4-phenyl- N- (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.079 mmol), 2-fluorobenzenesulfonyl chloride (9.4 μl, 0.071 mmol) and DIPEA (24 μl, 0.142 mmol) gave 18.6 mg (0.045 mmol, 57.6%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.35 (d, J = 5.4 Hz, 1H), 8.03-7.98 (m, 2H), 7.94-7.89 (m, 1H), 7.68-7.60 (m, 1H), 7.55-7.48 (m, 3H), 7.37-7.25 (m, 3H), 7.02 (d, J = 5.1 Hz, 1H), 5.19 (d, J = 7.8 Hz, 1H), 4.11-3.98 (m, 1H), 3.88-3.80 (m, 2H), 2.93 (t, J = 12 Hz, 2H), 2.28-2.18 (m, 2H), 1.70 (qd, J = 10.8 Hz, J = 3.9Hz, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.35 (d, J = 5.4 Hz, 1H), 8.03-7.98 (m, 2H), 7.94-7.89 (m, 1H), 7.68-7.60 (m, 1H), 7.55-7.48 (m, 3H), 7.37-7.25 (m, 3H), 7.02 (d, J = 5.1 Hz, 1H), 5.19 (d, J = 7.8 Hz, 1H), 4.11-3.98 (m, 1H) , 3.88-3.80 (m, 2H), 2.93 (t, J = 12 Hz, 2H), 2.28-2.18 (m, 2H), 1.70 (qd, J = 10.8 Hz, J = 3.9 Hz, 2H)

실시예 9. N-(1-(2,4-디플루오로페닐설포닐)피페리딘-4-일)-4-페닐피리미딘-2-아민 (화합물 9)Example 9. N - (1- (2,4- difluorophenyl sulfonyl) -piperidin-4-yl) -4-phenyl-pyrimidin-2-amine (Compound 9)

상기 실시예 1의 합성방법으로4-페닐-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.079 mmol), 2,4-디플루오로벤젠설포닐 클로라이드 (9.5 ㎕, 0.071 mmol), DIPEA (24 ㎕, 0.142 mmol)를 사용하여 목적화합물 22.7 mg (0.053 mmol, 67%)을 얻었다.Synthesis method of Example 1 according to the synthesis method of 4-phenyl- N- (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.079 mmol), 2,4-difluorobenzenesulfonyl chloride (9.5 ΜL, 0.071 mmol) and DIPEA (24 μL, 0.142 mmol) gave 22.7 mg (0.053 mmol, 67%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.37 (s, 1H), 8.07 (s, 2H), 8.0-7.90 (m, 1H), 7.53 (s, 3H), 7.14-7.0 (m, 3H), 5.21-5.14 (m, 1H), 4.16-4.02 (m, 1H), 3.85 (d, J = 10.5 Hz, 2H), 2.96 (t, J = 11.1 Hz, 2H), 2.25 (d, J = 11.7 Hz, 2H), 1.80-1.65 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 8.07 (s, 2H), 8.0-7.90 (m, 1H), 7.53 (s, 3H), 7.14-7.0 (m, 3H), 5.21-5.14 (m, 1H), 4.16-4.02 (m, 1H), 3.85 (d, J = 10.5 Hz, 2H), 2.96 (t, J = 11.1 Hz, 2H), 2.25 (d, J = 11.7 Hz , 2H), 1.80-1.65 (m, 2H)

실시예 10. N-(1-(4-메톡시페닐설포닐)피페리딘-4-일)-4-페닐피리미딘-2-아민 (화합물 10)Example 10. N - (1- (4- methoxy-phenylsulfonyl) piperidin-4-yl) -4-phenyl-pyrimidin-2-amine (compound 10)

상기 실시예 1의 합성방법으로 4-페닐-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.079 mmol), 4-메톡시벤젠설포닐 클로라이드 (14.67 mg, 0.071 mmol), DIPEA (24 ㎕, 0.142 mmol)를 사용하여 목적화합물 20.9 mg (0.049 mmol, 62%)을 얻었다.Synthesis method of Example 1 4-phenyl- N- (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.079 mmol), 4-methoxybenzenesulfonyl chloride (14.67 mg, 0.071 mmol) and DIPEA (24 μl, 0.142 mmol) gave 20.9 mg (0.049 mmol, 62%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.33 (d, J = 5.1 Hz, 1H), 8.02-7.98 (m, 2H), 7.80-7.74 (m, 2H), 7.54-7.48 (m, 3H), 7.08-7.04 (m, 3H), 7.01 (d, J = 5.1 Hz, 1H), 5.19 (d, J = 7.8 Hz, 1H), 4.03-3.97 (m, 1H), 3.96 (s, 3H), 3.73-3.64 (m, 2H), 2.65 (t, J = 10.8 Hz, 2H), 2.25-2.14 (m, 2H), 1.70 (qd, J = 10.5 Hz, J = 3.6 Hz, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.33 (d, J = 5.1 Hz, 1H), 8.02-7.98 (m, 2H), 7.80-7.74 (m, 2H), 7.54-7.48 (m, 3H), 7.08-7.04 (m, 3H), 7.01 (d, J = 5.1 Hz, 1H), 5.19 (d, J = 7.8 Hz, 1H), 4.03-3.97 (m, 1H), 3.96 (s, 3H), 3.73 -3.64 (m, 2H), 2.65 (t, J = 10.8 Hz, 2H), 2.25-2.14 (m, 2H), 1.70 (qd, J = 10.5 Hz, J = 3.6 Hz, 2H)

실시예 11. N-(1-(3-메톡시페닐설포닐)피페리딘-4-일)-4-페닐피리미딘-2-아민 (화합물 11)Example 11. N - (1- (3- methoxy-phenylsulfonyl) piperidin-4-yl) -4-phenyl-pyrimidin-2-amine (compound 11)

상기 실시예 1의 합성방법으로 4-페닐-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.079 mmol), 3-메톡시벤젠설포닐 클로라이드 (10 ㎕, 0.071 mmol), DIPEA (24 ㎕, 0.142 mmol)를 사용하여 목적화합물 23 mg (0.054 mmol, 68.6%)을 얻었다.Synthesis method of Example 1 4-phenyl- N- (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.079 mmol), 3-methoxybenzenesulfonyl chloride (10 μl, 0.071 mmol) and DIPEA (24 μl, 0.142 mmol) gave 23 mg (0.054 mmol, 68.6%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.32 (d, J = 5.4 Hz, 1H), 8.04-7.88 (m, 2H), 7.54-7.48 (m, 4H), 7.42-7.38 (m, 1H), 7.33 (t, J = 2.4 Hz, 1H), 7.20-7.16 (m, 1H), 7.02 (d, 5.4 Hz, 1H), 5.32-5.21 (m, 1H), 4.03-3.93 (m, 1H), 3.92 (s, 3H), 3.75-3.67 (m, 2H), 2.77-2.66 (m, 2H), 2.26-2.15 (m, 2H), 1.71 (qd, J = 10.5 Hz, J = 3.9 Hz, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.32 (d, J = 5.4 Hz, 1H), 8.04-7.88 (m, 2H), 7.54-7.48 (m, 4H), 7.42-7.38 (m, 1H), 7.33 (t, J = 2.4 Hz, 1H), 7.20-7.16 (m, 1H), 7.02 (d, 5.4 Hz, 1H), 5.32-5.21 (m, 1H), 4.03-3.93 (m, 1H), 3.92 (s, 3H), 3.75-3.67 (m, 2H), 2.77-2.66 (m, 2H), 2.26-2.15 (m, 2H), 1.71 (qd, J = 10.5 Hz, J = 3.9 Hz, 2H)

실시예 12. N-(1-(2,5-디메톡시페닐설포닐)피페리딘-4-일)-4-페닐피리미딘-2-아민 (화합물 12)Example 12. N - (1- (2,5- dimethoxy-phenyl-sulfonyl) -piperidin-4-yl) -4-phenyl-pyrimidin-2-amine (compound 12)

상기 실시예 1의 합성방법으로 4-페닐-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.079 mmol), 2,5-디메톡시벤젠설포닐 클로라이드 (16.8 mg, 0.071 mmol), DIPEA (24 ㎕, 0.142 mmol)를 사용하여 목적화합물 30.9 mg (0.068 mmol, 86%)을 얻었다.Synthesis method of Example 1 4-phenyl- N- (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.079 mmol), 2,5-dimethoxybenzenesulfonyl chloride (16.8 mg , 0.071 mmol) and DIPEA (24 μl, 0.142 mmol) gave 30.9 mg (0.068 mmol, 86%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.35 (d, J = 5.4 Hz, 1H), 8.06-7.98 (m, 2H), 7.54-7.46 (m, 5H), 7.13-7.08 (m, 1H), 7.02 (d, J = 1.8 Hz, 1H), 7.00 (d, J = 5.7 Hz, 1H), 5.31 (d, J = 7.2 Hz, 1H), 4.14-4.00 (m, 1H), 3.96 (s, 3H), 3.88-3.81 (m, 2H), 3.83 (s, 3H), 3.03-2.94 (m, 2H), 2.22-2.13 (m, 2H), 1.65 (qd, J = 10.8 Hz, J = 3.9 Hz, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.35 (d, J = 5.4 Hz, 1H), 8.06-7.98 (m, 2H), 7.54-7.46 (m, 5H), 7.13-7.08 (m, 1H), 7.02 (d, J = 1.8 Hz, 1H), 7.00 (d, J = 5.7 Hz, 1H), 5.31 (d, J = 7.2 Hz, 1H), 4.14-4.00 (m, 1H), 3.96 (s, 3H ), 3.88-3.81 (m, 2H), 3.83 (s, 3H), 3.03-2.94 (m, 2H), 2.22-2.13 (m, 2H), 1.65 (qd, J = 10.8 Hz, J = 3.9 Hz, 2H)

실시예 13. N-부틸-4-(4-페닐피리미딘-2-일아미노)피페리딘-1-카복사마이드 (화합물 13)Example 13. N -butyl-4- (4-phenylpyrimidin-2-ylamino) piperidine-1-carboxamide (Compound 13)

반응 용기에 4-페닐-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.079 mmol)과 N-부틸 이소시아네이트 (7.92 ㎕, 0.071 mmol)를 넣고 정제된 피리딘 1 mL에 녹여 120℃에서 6시간 동안 환류하였다. 진행과 결과를 TLC로 확인하였다. 반응 완결 후 반응 혼합물을 디클로로메탄으로 묽힌 후 H₂O를 넣고 수층을 디클로로메탄으로 추출하고 유기층을 무수 MgSO₄로 건조시킨 후, 여과하였다. 여과액을 감암 농축시켜 농축액을 관 크로마토그래피(CH₂Cl₂:MeOH=40:1)로 분리 정제하여 목적화합물 21 mg (0.059 mmol, 75%)을 얻었다Into the reaction vessel, 4-phenyl- N- (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.079 mmol) and N -butyl isocyanate (7.92 μl, 0.071 mmol) were added and 1 mL of purified pyridine was added. It was dissolved in and refluxed at 120 ℃ for 6 hours. Progress and results were confirmed by TLC. After completion of the reaction, the reaction mixture was diluted with dichloromethane, H ₂ O was added, the aqueous layer was extracted with dichloromethane, the organic layer was dried over anhydrous MgSO ₄ , and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (CH ₂ Cl ₂ : MeOH = 40: 1) to obtain 21 mg (0.059 mmol, 75%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.36 (s, 1H), 8.06-8.00 (m, 2H), 7.60-7.47 (m, 3H), 7.05 (s, 1H), 4.57-4.56 (m, 1H), 4.22-4.08 (m, 1H), 3.96 (d, J = 13.5 Hz, 2H), 3.50 (s, 1H), 3.27 (q, J = 6.6 Hz, 2H), 3.06 (t, J = 11.7 Hz, 2H), 2.14 (d, J = 10.8 Hz, 2H), 1.62-1.47 (m, 4H), 1.42-1.30 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.36 (s, 1H), 8.06-8.00 (m, 2H), 7.60-7.47 (m, 3H), 7.05 (s, 1H), 4.57-4.56 (m, 1H ), 4.22-4.08 (m, 1H), 3.96 (d, J = 13.5 Hz, 2H), 3.50 (s, 1H), 3.27 (q, J = 6.6 Hz, 2H), 3.06 (t, J = 11.7 Hz , 2H), 2.14 (d, J = 10.8 Hz, 2H), 1.62-1.47 (m, 4H), 1.42-1.30 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H)

실시예 14. (4-플루오로페닐)(4-(4-페닐피리미딘-2-일아미노)피페리딘-1-일)메타논 (화합물 14)Example 14 (4-fluorophenyl) (4- (4-phenylpyrimidin-2-ylamino) piperidin-1-yl) methanone (Compound 14)

반응용기에 4-페닐-N-(피페리딘-4-일)피리미딘-2-아민 (30 mg, 0.12 mmol)와 디메틸아미노피리딘 (DMAP; 1.47 mg, 0.012 mmol)을 디클로로메탄 2 mL에 녹인 후, 피리딘 (17.5 ㎕, 0.22 mmol)를 첨가하였다. -78℃에서 4-플루오로벤조일 클로라이드 (12.8 ㎕, 1.07 mmol)를 천천히 첨가한 후 30분 동안 교반하였다. 반응 완결 후 반응용액을 디클로로메탄으로 묽히고 물을 넣고 추출한 뒤 유기층은 무수 MgSO₄로 건조시키고 여과하여 농축하여 농축액을 관 크로마토그래피(CH₂Cl₂:MeOH=40:1)로 분리 정제하여 목적화합물 28.5 mg (0.076 mmol, 70%)을 얻었다.To the reaction vessel, 4-phenyl- N- (piperidin-4-yl) pyrimidin-2-amine (30 mg, 0.12 mmol) and dimethylaminopyridine (DMAP; 1.47 mg, 0.012 mmol) were added to 2 mL of dichloromethane. After thawing, pyridine (17.5 μl, 0.22 mmol) was added. 4-fluorobenzoyl chloride (12.8 μl, 1.07 mmol) was added slowly at −78 ° C. and stirred for 30 minutes. After completion of the reaction, the reaction solution was diluted with dichloromethane, added with water, extracted, and the organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated. The concentrated solution was separated and purified by column chromatography (CH ₂ Cl ₂ : MeOH = 40: 1). 28.5 mg (0.076 mmol, 70%) were obtained.

¹H NMR (300 MHz, CDCl₃) δ 8.35 (d, J = 5.1 Hz, 1H), 8.05-7.98 (m, 2H), 7.52-7.46 (m, 3H), 7.45-7.40 (m, 2H), 7.15-7.05 (m, 2H), 7.01 (d, J = 5.1 Hz, 1H), 5.32 (d, J = 7.5 Hz, 1H), 4.59 (br s, 1H), 4.30-4.15 (m, 1H), 3.80 (br s, 1H), 3.19 (br s, 2H), 2.18 (br s, 2H), 1.53 (br s, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.35 (d, J = 5.1 Hz, 1H), 8.05-7.98 (m, 2H), 7.52-7.46 (m, 3H), 7.45-7.40 (m, 2H), 7.15-7.05 (m, 2H), 7.01 (d, J = 5.1 Hz, 1H), 5.32 (d, J = 7.5 Hz, 1H), 4.59 (br s, 1H), 4.30-4.15 (m, 1H), 3.80 (br s, 1H), 3.19 (br s, 2H), 2.18 (br s, 2H), 1.53 (br s, 2H)

실시예 15. (3-플루오로페닐)(4-(4-페닐피리미딘-2-일아미노)피페리딘-1-일)메타논 (화합물 15)Example 15. (3-fluorophenyl) (4- (4-phenylpyrimidin-2-ylamino) piperidin-1-yl) methanone (Compound 15)

상기 실시예 14의 합성방법으로 4-페닐-N-(피페리딘-4-일)피리미딘-2-아민 (30 mg, 0.12 mmol), 3-플루오로벤조일 클로라이드 (12.8 ㎕, 1.07 mmol), DMAP (1.47 mg, 0.012 mmol), 피리딘 (17.5 ㎕, 0.22 mmol)를 사용하여 목적화합물 21.9 mg (0.058 mmol, 54.5%)을 얻었다.Synthesis method of Example 14 4-phenyl- N- (piperidin-4-yl) pyrimidin-2-amine (30 mg, 0.12 mmol), 3-fluorobenzoyl chloride (12.8 μl, 1.07 mmol) , 21.9 mg (0.058 mmol, 54.5%) of the title compound was obtained using DMAP (1.47 mg, 0.012 mmol) and pyridine (17.5 μl, 0.22 mmol).

¹H NMR (300 MHz, CDCl₃) δ 8.35 (d, J = 5.1 Hz, 1H), 8.05-7.98 (m, 2H), 7.52-7.46 (m, 3H), 7.45-7.37 (m, 1H), 7.23-7.08 (m, 3H), 7.02 (d, J = 5.4 Hz, 1H), 5.32 (d, J = 7.5 Hz, 1H), 4.61 (br s, 1H), 4.30-4.17 (m, 1H), 3.76 (br s, 1H), 3.19 (br s, 2H), 2.181 (br s, 2H), 1.69-1.38 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.35 (d, J = 5.1 Hz, 1H), 8.05-7.98 (m, 2H), 7.52-7.46 (m, 3H), 7.45-7.37 (m, 1H), 7.23-7.08 (m, 3H), 7.02 (d, J = 5.4 Hz, 1H), 5.32 (d, J = 7.5 Hz, 1H), 4.61 (br s, 1H), 4.30-4.17 (m, 1H), 3.76 (br s, 1H), 3.19 (br s, 2H), 2.181 (br s, 2H), 1.69-1.38 (m, 2H)

실시예 16. (4-메톡시페닐)(4-(4-페닐피리미딘-2-일아미노)피페리딘-1-일)메타논 (화합물 16)Example 16. (4-methoxyphenyl) (4- (4-phenylpyrimidin-2-ylamino) piperidin-1-yl) methanone (Compound 16)

상기 실시예 14의 합성방법으로 4-페닐-N-(피페리딘-4-일)피리미딘-2-아민 (26 mg, 0.103 mmol), 4-메톡시벤조일 클로라이드 (12.7 ㎕, 0.092 mmol), DMAP (1.3 mg, 0.013 mmol), 피리딘 (15 ㎕, 0.19 mmol)를 사용하여 목적화합물 16 mg (0.041 mmol, 46%)을 얻었다.Synthesis method of Example 14 4-phenyl- N- (piperidin-4-yl) pyrimidin-2-amine (26 mg, 0.103 mmol), 4-methoxybenzoyl chloride (12.7 μl, 0.092 mmol) , DMAP (1.3 mg, 0.013 mmol) and pyridine (15 μl, 0.19 mmol) were used to obtain 16 mg (0.041 mmol, 46%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.34 (d, J = 5.4 Hz, 1H), 8.04-7.98 (m, 2H), 7.50-7.45 (m, 3H), 7.45-7.38 (m, 2H), 7.01-6.99 (m, 1H), 6.98-6.90 (m, 1H), 5.34 (d, J = 7.2 Hz, 1H), 4.29-4.16 (m, 1H), 3.77 (s, 3H), 3.28-3.12 (m, 2H), 2.22-2.10 (m, 2H), 1.62-1.47 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.34 (d, J = 5.4 Hz, 1H), 8.04-7.98 (m, 2H), 7.50-7.45 (m, 3H), 7.45-7.38 (m, 2H), 7.01-6.99 (m, 1H), 6.98-6.90 (m, 1H), 5.34 (d, J = 7.2 Hz, 1H), 4.29-4.16 (m, 1H), 3.77 (s, 3H), 3.28-3.12 ( m, 2H), 2.22-2.10 (m, 2H), 1.62-1.47 (m, 2H)

실시예 17. (3-메톡시페닐)(4-(4-페닐피리미딘-2-일아미노)피페리딘-1-일)메타논 (화합물 17)Example 17. (3-methoxyphenyl) (4- (4-phenylpyrimidin-2-ylamino) piperidin-1-yl) methanone (Compound 17)

상기 실시예 14의 합성방법으로 4-페닐-N-(피페리딘-4-일)피리미딘-2-아민 (30 mg, 0.12 mmol), 3-메톡시벤조일 클로라이드 (14.6 ㎕, 1.07 mmol), DMAP (1.47 mg, 0.012 mmol), 피리딘 (17.5 ㎕, 0.22 mmol)를 사용하여 목적화합물 21.9 mg (0.056 mmol, 53%)을 얻었다.Synthesis method of Example 14 4-phenyl- N- (piperidin-4-yl) pyrimidin-2-amine (30 mg, 0.12 mmol), 3-methoxybenzoyl chloride (14.6 μl, 1.07 mmol) , 21.9 mg (0.056 mmol, 53%) of the title compound were obtained using DMAP (1.47 mg, 0.012 mmol) and pyridine (17.5 μl, 0.22 mmol).

¹H NMR (300 MHz, CDCl₃) δ 8.34 (d, J = 5.1 Hz, 1H), 8.05-7.98 (m, 2H), 7.52-7.47 (m, 2H), 7.38-7.27 (m, 1H), 7.02-6.92 (m, 4H), 5.59 (br s, 1H), 4.60 (br s, 1H), 4.30-4.17 (m, 1H), 3.83 (s, 3H), 3.90-3.76 (br s, 1H), 3.20 (br s, 2H), 2.31-2.03 (m, 2H), 1.70-1.40 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.34 (d, J = 5.1 Hz, 1H), 8.05-7.98 (m, 2H), 7.52-7.47 (m, 2H), 7.38-7.27 (m, 1H), 7.02-6.92 (m, 4H), 5.59 (br s, 1H), 4.60 (br s, 1H), 4.30-4.17 (m, 1H), 3.83 (s, 3H), 3.90-3.76 (br s, 1H) , 3.20 (br s, 2H), 2.31-2.03 (m, 2H), 1.70-1.40 (m, 2H)

실시예 18. (2,4-디메톡시페닐)(4-(4-페닐피리미딘-2-일아미노)피페리딘-1-일)메타논 (화합물 18)Example 18. (2,4-dimethoxyphenyl) (4- (4-phenylpyrimidin-2-ylamino) piperidin-1-yl) methanone (Compound 18)

상기 실시예 14의 합성방법으로 4-페닐-N-(피페리딘-4-일)피리미딘-2-아민 (30 mg, 0.12 mmol), 2,4-디메톡시벤조일클로라이드 (21.5 mg, 1.07 mmol), DMAP (1 mg, 0.008 mmol), 피리딘 (17.5 ㎕, 0.22 mmol)를 사용하여 목적화합물 33.5 mg (0.080 mmol, 75%)을 얻었다.Synthesis method of Example 14 4-phenyl- N- (piperidin-4-yl) pyrimidin-2-amine (30 mg, 0.12 mmol), 2,4-dimethoxybenzoylchloride (21.5 mg, 1.07 mmol), DMAP (1 mg, 0.008 mmol), pyridine (17.5 μl, 0.22 mmol) to give 33.5 mg (0.080 mmol, 75%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.34 (d, J = 5.1 Hz, 1H), 8.04-7.98 (m, 2H), 7.50-7.45 (m, 3H), 7.04-6.98 (m, 3H), 6.87 (d, J = 8.4 Hz, 1H), 5.45-5.39 (m, 1H), 4.30-4.18 (m, 1H), 3.91 (s, 6H), 3.28-3.12 (m, 2H), 2.23-2.10 (m, 2H), 1.62-1.46 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.34 (d, J = 5.1 Hz, 1H), 8.04-7.98 (m, 2H), 7.50-7.45 (m, 3H), 7.04-6.98 (m, 3H), 6.87 (d, J = 8.4 Hz, 1H), 5.45-5.39 (m, 1H), 4.30-4.18 (m, 1H), 3.91 (s, 6H), 3.28-3.12 (m, 2H), 2.23-2.10 ( m, 2H), 1.62-1.46 (m, 2H)

실시예 19. (4-(4-페닐피리미딘-2-일아미노)피페리딘-1-일)(4-(트리플루오로메틸)페닐)메타논 (화합물 19)Example 19. (4- (4-phenylpyrimidin-2-ylamino) piperidin-1-yl) (4- (trifluoromethyl) phenyl) methanone (Compound 19)

상기 실시예 14의 합성방법으로 4-페닐-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.079 mmol), 4-(트리플루오로메틸)벤조일클로라이드 (10.5 ㎕, 0.071 mmol), DMAP (1.47 mg, 0.012 mmol), 피리딘(20.6 ㎕, 0.12 mmol)를 사용하여 목적화합물 8.6 mg (0.020 mmol, 25%)을 얻었다.Synthesis method of Example 14 4-phenyl- N- (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.079 mmol), 4- (trifluoromethyl) benzoylchloride (10.5 μl , 0.071 mmol), DMAP (1.47 mg, 0.012 mmol) and pyridine (20.6 μl, 0.12 mmol) gave 8.6 mg (0.020 mmol, 25%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.35 (d, J = 4.8 Hz, 1H), 8.02-7.98 (m, 2H), 7.7 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.52-7.46 (m, 3H), 5.18 (d, J = 7.8 Hz, 1H), 4.70-4.59 (m, 1H), 4.630-4.18 (m, 1H), 3.77-3.65 (m, 1H), 3.32-3.10 (m, 2H), 2.32-2.09 (m, H), 1.57-1.40 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.35 (d, J = 4.8 Hz, 1H), 8.02-7.98 (m, 2H), 7.7 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.52-7.46 (m, 3H), 5.18 (d, J = 7.8 Hz, 1H), 4.70-4.59 (m, 1H), 4.630-4.18 (m, 1H), 3.77-3.65 (m , 1H), 3.32-3.10 (m, 2H), 2.32-2.09 (m, H), 1.57-1.40 (m, 2H)

실시예 20. 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (화합물 20)Example 20 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (compound 20)

반응용기에 tert-부틸 4-(4-(4-클로로페닐)피리미딘-2-일아미노)피페리딘-1-카복실레이트 (238 mg, 0.61 mmol)을 디클로로메탄 11.9 mL에 녹인 후, 트리플루오로아세트산 (TFA; 2.38 mL)를 천천히 첨가하였다. 2시간 동안 교반 후 반응 진행과 결과를 TLC로 확인하였다. 반응 완결 후 반응 혼합물을 디클로로메탄으로 묽힌 후, 포화 NaHCO₃용액을 넣고 수층을 디클로로메탄으로 추출하고 유기층을 무수 MgSO₄로 건조시킨 후, 여과하였다. 여과액을 감암 농축시켜 농축액을 관 크로마토그래피 (CHCl₃:MeOH:NH₃:H₂O=80:20:1:1)로 분리 정제하여 목적화합물 117 mg (0.41 mmol, 66%)을 얻었다.After dissolving tert- butyl 4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidine-1-carboxylate (238 mg, 0.61 mmol) in 11.9 mL of dichloromethane, Fluoroacetic acid (TFA; 2.38 mL) was added slowly. After stirring for 2 hours, the reaction progress and results were confirmed by TLC. After completion of the reaction, the reaction mixture was diluted with dichloromethane, saturated NaHCO ₃ solution was added, the aqueous layer was extracted with dichloromethane, the organic layer was dried over anhydrous MgSO ₄ , and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (CHCl ₃ : MeOH: NH ₃ : H ₂ O = 80: 20: 1: 1) to obtain 117 mg (0.41 mmol, 66%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.36 (d, J = 5.4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 5.1 Hz, 1H), 5.30 (d, J = 7.8 Hz, 1H), 3.19-3.12 (m, 2H), 2.81 (td, J = 12.3 Hz, J = 2.4 Hz, 2H), 2.16-2.11 (m, 2H), 1.45 (qd, J = 11.1 Hz, J = 3.9 Hz, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.36 (d, J = 5.4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 6.94 (d , J = 5.1 Hz, 1H), 5.30 (d, J = 7.8 Hz, 1H), 3.19-3.12 (m, 2H), 2.81 (td, J = 12.3 Hz, J = 2.4 Hz, 2H), 2.16-2.11 (m, 2H), 1.45 (qd, J = 11.1 Hz, J = 3.9 Hz, 2H)

실시예 21. 4-(4-클로로페닐)-N-(1-메틸피페리딘-4-일)피리미딘-2-아민 (화합물 21)Example 21. 4- (4-chlorophenyl) - N - (1- methylpiperidin-4-yl) pyrimidin-2-amine (compound 21)

반응용기에 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (50 mg, 0.17 mmol)를 메탄올 3 mL에 녹인 후, 37% HCHO 용액(0.23 mL, 2.84 mmol)을 가하였다. 반응용액을 2시간동안 교반 후 NaBH(OAc)₃ (178.5 mg, 0.85 mmol)를 가하고 상온에서 교반하였다. 다음날 반응 용액을 디클로로메탄으로 추출하고 유기층을 무수 MgSO₄로 건조시킨 후, 여과하였다. 여과액을 감암 농축시켜 농축액을 관 크로마토그래피 (SiO₂, CHCl₃:MeOH:H₂O:NH₄OH=80:20:1:1)로 분리 정제하여 목적화합물 24.6 mg (47%)을 얻었다.To the reaction vessel of 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (50 mg, 0.17 mmol) was dissolved in methanol to a 3 mL, 37% HCHO solution (0.23 mL, 2.84 mmol) was added. The reaction solution was stirred for 2 hours, then NaBH (OAc) ₃ (178.5 mg, 0.85 mmol) was added and stirred at room temperature. The next day the reaction solution was extracted with dichloromethane and the organic layer was dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (SiO ₂ , CHCl ₃ : MeOH: H ₂ O: NH ₄ OH = 80: 20: 1: 1) to obtain 24.6 mg (47%) of the title compound. .

¹H NMR (300 MHz, CDCl₃) δ 8.35 (d, J = 5.06 Hz, 1H), 7.97 (d, J = 8.00 Hz, 2H), 7.43-7.46 (m, 2H), 6.92-6.94 (m, 1H), 5.11 (d, J = 7.94 Hz, 1H), 3.94-3.96 (m, 1H), 2.84 (d, J= 11.55 Hz, 2H), 2.33 (s, 3H), 2.11-2.25 (m, 4H), 1.57-1.68 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.35 (d, J = 5.06 Hz, 1H), 7.97 (d, J = 8.00 Hz, 2H), 7.43-7.46 (m, 2H), 6.92-6.94 (m, 1H), 5.11 (d, J = 7.94 Hz, 1H), 3.94-3.96 (m, 1H), 2.84 (d, J = 11.55 Hz, 2H), 2.33 (s, 3H), 2.11-2.25 (m, 4H ), 1.57-1.68 (m, 2H)

실시예 22. 4-(4-클로로페닐)-N-(1-(메틸설포닐)피페리딘-4-일)피리미딘-2-아민 (화합물 22)Example 22. 4- (4-chlorophenyl) - N - (1- (methylsulfonyl) piperidin-4-yl) pyrimidin-2-amine (Compound 22)

상기 실시예 1의 합성방법으로 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.069 mmol), 메탄설포닐 클로라이드(4.8 ㎕, 0.062 mmol), DIPEA (21.6 ㎕, 0.124 mmol)를 사용하여 목적화합물 21.5 mg (0.059 mmol, 86%)을 얻었다.A method for the synthesis of Example 1 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.069 mmol), methanesulfonyl chloride (4.8 ㎕, 0.062 mmol) and DIPEA (21.6 μl, 0.124 mmol) gave 21.5 mg (0.059 mmol, 86%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.39 (d, J = 5.4 Hz, 1H), 8.03-7.97 (m, 2H), 7.51-7.46 (m, 2H), 7.01 (d, J = 5.1 Hz, 1H), 5.21 (d, J = 7.5 Hz, 1H), 4.19-4.06 (m, 1H), 3.87-3.78 (m, 2H), 3.06-2.97 (m, 2H), 2.86 (s, 3H), 2.30-2.22 (m, 2H), 1.73 (qd, J = 10.5 Hz, J = 3.9 Hz, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.39 (d, J = 5.4 Hz, 1H), 8.03-7.97 (m, 2H), 7.51-7.46 (m, 2H), 7.01 (d, J = 5.1 Hz, 1H), 5.21 (d, J = 7.5 Hz, 1H), 4.19-4.06 (m, 1H), 3.87-3.78 (m, 2H), 3.06-2.97 (m, 2H), 2.86 (s, 3H), 2.30 -2.22 (m, 2H), 1.73 (qd, J = 10.5 Hz, J = 3.9 Hz, 2H)

실시예 23. 4-(4-클로로페닐)-N-(1-(트리플루오로메틸설포닐)피페리딘-4-일)피리미딘-2-아민 (화합물 23)Example 23. 4- (4-chlorophenyl) - N - (1- (trifluoromethyl-sulfonyl) -piperidin-4-yl) pyrimidin-2-amine (compound 23)

상기 실시예 1의 합성방법으로 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (27 mg, 0.093 mmol), 트리플루오로메탄설포닐 클로라이드 (36 ㎕, 0.34 mmol), DIPEA (29.6 ㎕, 0.17 mmol)를 사용하여 목적화합물 11.1 mg (28%)을 얻었다. N - - (piperidin-4-yl) pyrimidin-2-amine (27 mg, 0.093 mmol), methanesulfonyl chloride, trifluoromethanesulfonyl (4- (4-chlorophenyl) the synthesis method of Example 1 36 μl, 0.34 mmol) and DIPEA (29.6 μl, 0.17 mmol) gave 11.1 mg (28%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.36 (d, J = 4.97 Hz, 1H), 7.96 (d, J = 8.59 Hz, 2H), 7.45-7.47 (m, 2H), 6.98-7.01 (m, 1H), 5.15 (d, J= 7.29 Hz, 1H), 4.12-4.21 (m, 1H), 3.98 (d, J = 13.32 Hz, 2H), 3.32 (t, J = 12.21 Hz, 2H), 2.25 (dd, J = 13.43 Hz, 2H), 1.67 (dq, J = 11.02 Hz, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.36 (d, J = 4.97 Hz, 1H), 7.96 (d, J = 8.59 Hz, 2H), 7.45-7.47 (m, 2H), 6.98-7.01 (m, 1H), 5.15 (d, J = 7.29 Hz, 1H), 4.12-4.21 (m, 1H), 3.98 (d, J = 13.32 Hz, 2H), 3.32 (t, J = 12.21 Hz, 2H), 2.25 ( dd, J = 13.43 Hz, 2H), 1.67 (dq, J = 11.02 Hz, 2H)

실시예 24. 4-(4-(4-클로로페닐)피리미딘-2-일아미노)피페리딘-1-설폰아마이드 (화합물 24)Example 24. 4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidine-1-sulfonamide (Compound 24)

상기 실시예 1의 합성방법으로 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (30 mg, 0.1 mmol), 설파모일 클로라이드 (0.39 mL, 0.2 mmol), TEA (0.04 mL, 0.3 mmol)를 사용하여 목적화합물 17.4 mg (47%)을 얻었다. A method for the synthesis of Example 1 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (30 mg, 0.1 mmol), sulfamoyl chloride (0.39 mL, 0.2 mmol) and TEA (0.04 mL, 0.3 mmol) gave 17.4 mg (47%) of the title compound.

¹H NMR (300 MHz, DMSO-d ₆) δ 8.36 (d, J = 5.12 Hz, 1H), 8.12 (d, J = 8.43 Hz, 2H), 7.58 (d, J = 8.56 Hz, 2H), 7.19 (d, J = 7.71 Hz, 1H), 7.14 (d, J = 5.27 Hz, 1H), 5.19 (s, 2H), 3.79 (s, 1H), 3.39-3.46 (m, 2H), 2.64 (t, J = 12.20 Hz, 2H), 1.90 (d, J = 11.50 Hz, 2H), 1.45-1.57 (m, 2H)
¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.36 (d, J = 5.12 Hz, 1H), 8.12 (d, J = 8.43 Hz, 2H), 7.58 (d, J = 8.56 Hz, 2H), 7.19 (d, J = 7.71 Hz, 1H), 7.14 (d, J = 5.27 Hz, 1H), 5.19 (s, 2H), 3.79 (s, 1H), 3.39-3.46 (m, 2H), 2.64 (t, J = 12.20 Hz, 2H), 1.90 (d, J = 11.50 Hz, 2H), 1.45-1.57 (m, 2H)

실시예 25. 4-(4-클로로페닐)-N-(1-(페닐설포닐)피페리딘-4-일)피리미딘-2-아민 (화합물 25)Example 25. 4- (4-chlorophenyl) - N - (1- (phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine (compound 25)

상기 실시예 1의 합성방법으로 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (17 mg, 0.059 mmol), 벤젠설포닐 클로라이드 (6.7 ㎕, 0.053 mmol), DIPEA (18.5 ㎕, 0.106 mmol)를 사용하여 목적화합물 16.5 mg (0.038 mmol, 65%)를 얻었다.A method for the synthesis of Example 1 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (17 mg, 0.059 mmol), benzenesulfonyl chloride (6.7 ㎕, 0.053 mmol) and DIPEA (18.5 μl, 0.106 mmol) gave 16.5 mg (0.038 mmol, 65%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.33 (d, J = 5.4 Hz, 2H), 7.97-7.92 (m, 2H), 7.85-7.82 (m, 2H), 7.70-7.58 (m, 3H), 7.49-7.44 (m, 2H), 6.97 (d, J = 5.1 Hz, 2H), 5.14 (d, J = 7.5 Hz, 1H), 4.0-3.88 (m, 1H), 3.80-3.71 (m, 2H), 2.66 (t, J = 10.5 Hz, 2H), 2.24-2.16 (m, 2H), 1.70 (qd, J = 10.8 Hz, J = 3.9 Hz, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.33 (d, J = 5.4 Hz, 2H), 7.97-7.92 (m, 2H), 7.85-7.82 (m, 2H), 7.70-7.58 (m, 3H), 7.49-7.44 (m, 2H), 6.97 (d, J = 5.1 Hz, 2H), 5.14 (d, J = 7.5 Hz, 1H), 4.0-3.88 (m, 1H), 3.80-3.71 (m, 2H) , 2.66 (t, J = 10.5 Hz, 2H), 2.24-2.16 (m, 2H), 1.70 (qd, J = 10.8 Hz, J = 3.9 Hz, 2H)

실시예 26. 4-(4-클로로페닐)-N-(1-(4-(트리플루오로메틸)페닐설포닐)피페리딘-4-일)피리미딘-2-아민 (화합물 26)Example 26. 4- (4-chlorophenyl) - N - (1- (4- (trifluoromethyl) phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine (Compound 26)

상기 실시예 1의 합성방법으로 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.069 mmol), 4-(트리플루오로메틸)벤젠설포닐 클로라이드 (15.2 mg, 0.062 mmol), DIPEA (21.6 ㎕, 0.124 mmol)를 사용하여 목적화합물 16.5 mg (0.033 mmol, 48%)를 얻었다.A method for the synthesis of Example 1 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.069 mmol), ( trifluoromethyl) 4- Benzenesulfonyl chloride (15.2 mg, 0.062 mmol) and DIPEA (21.6 μl, 0.124 mmol) gave 16.5 mg (0.033 mmol, 48%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.34 (d, J = 5.4 Hz, 1H), 7.97-7.93 (m, 2H), 7.88-7.82 (m, 2H), 7.49-7.44 (m, 2H), 7.32-7.24 (m, 3H), 6.98 (d, J = 5.4 Hz, 1H), 5.14 (d, J = 7.8 Hz, 1H), 4.01-3.89 (m, 1H), 3.80-3.69 (m, 2H), 2.67 (t, J = 11.1 Hz, 2H), 2.26-2.17 (m, 2H), 1.71 (qd, J = 10.8 Hz, J = 3.9 Hz, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.34 (d, J = 5.4 Hz, 1H), 7.97-7.93 (m, 2H), 7.88-7.82 (m, 2H), 7.49-7.44 (m, 2H), 7.32-7.24 (m, 3H), 6.98 (d, J = 5.4 Hz, 1H), 5.14 (d, J = 7.8 Hz, 1H), 4.01-3.89 (m, 1H), 3.80-3.69 (m, 2H) , 2.67 (t, J = 11.1 Hz, 2H), 2.26-2.17 (m, 2H), 1.71 (qd, J = 10.8 Hz, J = 3.9 Hz, 2H)

실시예 27. 4-(4-클로로페닐)-N-(1-(3-(트리플루오로메틸)페닐설포닐)피페리딘-4-일)피리미딘-2-아민 (화합물 27)Example 27. 4- (4-chlorophenyl) - N - (1- (3- ( trifluoromethyl) phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine (compound 27)

상기 실시예 1의 합성방법으로 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.069 mmol), 3-(트리플루오로메틸)벤젠설포닐 클로라이드 (10 mg, 0.062 mmol), DIPEA (21.6 ㎕, 0.124 mmol)를 사용하여 목적화합물 23.7 mg (0.048 mmol, 69%)을 얻었다.A method for the synthesis of Example 1 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.069 mmol), ( trifluoromethyl) 3- Benzenesulfonyl chloride (10 mg, 0.062 mmol) and DIPEA (21.6 μl, 0.124 mmol) gave 23.7 mg (0.048 mmol, 69%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.34 (d, J = 5.1 Hz, 1H), 8.09 (s, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.99-7.91 (m, 3H), 7.77 (t, J = 7.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 5.1 Hz, 1H), 5.11 (d, J = 7.5 Hz, 1H), 4.02-3.90 (m, 1H), 3.81-3.73 (m, 2H), 2.70 (t, J = 11.4 Hz, 2H), 2.29-2.18 (m, 2H), 1.80-1.63 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.34 (d, J = 5.1 Hz, 1H), 8.09 (s, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.99-7.91 (m, 3H) , 7.77 (t, J = 7.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 5.1 Hz, 1H), 5.11 (d, J = 7.5 Hz, 1H), 4.02 -3.90 (m, 1H), 3.81-3.73 (m, 2H), 2.70 (t, J = 11.4 Hz, 2H), 2.29-2.18 (m, 2H), 1.80-1.63 (m, 2H)

실시예 28. 4-(4-클로로페닐)-N-(1-(2-(트리플루오로메틸)페닐설포닐)피페리딘-4-일)피리미딘-2-아민 (화합물 28)Example 28. 4- (4-chlorophenyl) - N - (1- (2- ( trifluoromethyl) phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine (compound 28)

상기 실시예 1의 합성방법으로 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.069 mmol), 2-(트리플루오로메틸)벤젠설포닐 클로라이드 (9.6 ㎕, 0.062 mmol), DIPEA (21.6 ㎕, 0.124 mmol)를 사용하여 목적화합물 21 mg (0.042 mmol, 57.5%)을 얻었다.A method for the synthesis of Example 1 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.069 mmol), ( trifluoromethyl) 2- Benzenesulfonyl chloride (9.6 μl, 0.062 mmol) and DIPEA (21.6 μl, 0.124 mmol) were used to obtain 21 mg (0.042 mmol, 57.5%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.36 (d, J = 5.1 Hz, 1H), 8.21-8.18 (m, 1H), 7.98-7.93 (m, 3H), 7.79-7.73 (m, 2H), 7.50-7.45 (m, 2H), 6.99 (d, J = 5.4 Hz, 1H), 5.34-5.28 (m, 1H), 4.48-4.02 (m, 1H), 3.89-3.79 (m, 2H), 3.07-2.99 (m, 2H), 2.25-2.14 (m, 2H), 1.76-1.61 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.36 (d, J = 5.1 Hz, 1H), 8.21-8.18 (m, 1H), 7.98-7.93 (m, 3H), 7.79-7.73 (m, 2H), 7.50-7.45 (m, 2H), 6.99 (d, J = 5.4 Hz, 1H), 5.34-5.28 (m, 1H), 4.48-4.02 (m, 1H), 3.89-3.79 (m, 2H), 3.07- 2.99 (m, 2H), 2.25-2.14 (m, 2H), 1.76-1.61 (m, 2H)

실시예 29. 4-(4-클로로페닐)-N-(1-(4-플루오로페닐설포닐)피페리딘-4-일)피리미딘-2-아민 (화합물 29)Example 29. 4- (4-chlorophenyl) - N - (1- (4-fluoro phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine (compound 29)

상기 실시예 1의 합성방법으로 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.069 mmol), 4-플루오로벤젠설포닐 클로라이드 (9.6 ㎕, 0.062 mmol), DIPEA (21.6 ㎕, 0.124 mmol)를 사용하여 목적화합물 26 mg (0.056 mmol, 84.4%)을 얻었다.A method for the synthesis of Example 1 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.069 mmol), benzenesulfonyl chloride there was obtained: 4-Fluoro (9.6 μl, 0.062 mmol) and DIPEA (21.6 μl, 0.124 mmol) gave 26 mg (0.056 mmol, 84.4%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.33 (d, J = 5.1 Hz, 1H), 7.98-7.91 (m, 2H), 7.87-7.82 (m, 2H), 7.49-7.44 (m, 2H), 7.31-7.23 (m, 2H), 6.97 (d, J = 5.4 Hz, 1H), 5.34 (d, J = 9 Hz, 1H), 4.0-3.87 (m, 1H), 3.78-3.69 (m, 2H), 2.65 (t, J = 11.4 Hz, 2H), 2.26-2.15 (m, 2H), 1.70 (qd, J = 12.9 Hz, J = 3.6 Hz, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.33 (d, J = 5.1 Hz, 1H), 7.98-7.91 (m, 2H), 7.87-7.82 (m, 2H), 7.49-7.44 (m, 2H), 7.31-7.23 (m, 2H), 6.97 (d, J = 5.4 Hz, 1H), 5.34 (d, J = 9 Hz, 1H), 4.0-3.87 (m, 1H), 3.78-3.69 (m, 2H) , 2.65 (t, J = 11.4 Hz, 2H), 2.26-2.15 (m, 2H), 1.70 (qd, J = 12.9 Hz, J = 3.6 Hz, 2H)

실시예 30. 4-(4-클로로페닐)-N-(1-(3-플루오로페닐설포닐)피페리딘-4-일)피리미딘-2-아민 (화합물 30)Example 30. 4- (4-chlorophenyl) - N - (1- (3-fluoro-phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine (compound 30)

상기 실시예 1의 합성방법으로 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (22 mg, 0.076 mmol), 3-플루오로벤젠설포닐 클로라이드 (8.3 ㎕, 0.062 mmol), DIPEA (21.6 ㎕, 0.124 mmol)를 사용하여 목적화합물 31 mg (0.066 mmol, 91%)을 얻었다.A method for the synthesis of Example 1 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (22 mg, 0.076 mmol), benzenesulfonyl chloride there was obtained: 3-Fluoro (8.3 μl, 0.062 mmol) and DIPEA (21.6 μl, 0.124 mmol) gave 31 mg (0.066 mmol, 91%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.34 (d, J = 5.1 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.64-7.58 (m, 2H), 7.56-7.52 (m, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.41-7.34 (m, 1H), 6.98 (d, J = 5.1 Hz, 1H), 5.20 (d, J = 7.8 Hz, 1H), 4.02-3.89 (m, 1H), 3.80-3.71 (m, 2H), 2.70 (t, J = 10.8 Hz, 2H), 2.21 (dd, J = 13.2 Hz, J = 3.6 Hz, 2H), 1.77-1.64 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.34 (d, J = 5.1 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.64-7.58 (m, 2H), 7.56-7.52 (m, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.41-7.34 (m, 1H), 6.98 (d, J = 5.1 Hz, 1H), 5.20 (d, J = 7.8 Hz, 1H), 4.02- 3.89 (m, 1H), 3.80-3.71 (m, 2H), 2.70 (t, J = 10.8 Hz, 2H), 2.21 (dd, J = 13.2 Hz, J = 3.6 Hz, 2H), 1.77-1.64 (m , 2H)

실시예 31. 4-(4-클로로페닐)-N-(1-(2-플루오로페닐설포닐)피페리딘-4-일)피리미딘-2-아민 (화합물 31)Example 31. 4- (4-chlorophenyl) - N - (1- (2- fluoro-phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine (compound 31)

상기 실시예 1의 합성방법으로 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.069 mmol), 2-플루오로벤젠설포닐 클로라이드 (8.2 ㎕, 0.062 mmol), DIPEA (21.6 ㎕, 0.124 mmol)를 사용하여 목적화합물 29 mg (0.065 mmol, 95%)을 얻었다.A method for the synthesis of Example 1 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.069 mmol), 2-fluoro-benzenesulfonyl chloride there was obtained: (8.2 μl, 0.062 mmol) and DIPEA (21.6 μl, 0.124 mmol) gave 29 mg (0.065 mmol, 95%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.35 (d, J = 5.4 Hz, 1H), 8.00-7.93 (m, 2H), 7.92-7.88 (m, 1H), 7.68-7.60 (m, 1H), 7.50-7.44 (m, 2H), 7.47-7.25 (m, 2H), 6.98 (d, J = 5.4 Hz, 1H), 5.30 (d, J = 7.2 Hz, 1H), 4.10-3.96 (m, 1H), 3.90-3.91 (m, 2H), 2.92 (t, J = 11.1 Hz, 2H), 2.27-2.17 (m, 2H), 1.68 (qd, J = 10.8 Hz, J = 3.9 Hz, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.35 (d, J = 5.4 Hz, 1H), 8.00-7.93 (m, 2H), 7.92-7.88 (m, 1H), 7.68-7.60 (m, 1H), 7.50-7.44 (m, 2H), 7.47-7.25 (m, 2H), 6.98 (d, J = 5.4 Hz, 1H), 5.30 (d, J = 7.2 Hz, 1H), 4.10-3.96 (m, 1H) , 3.90-3.91 (m, 2H), 2.92 (t, J = 11.1 Hz, 2H), 2.27-2.17 (m, 2H), 1.68 (qd, J = 10.8 Hz, J = 3.9 Hz, 2H)

실시예 32. 4-(4-클로로페닐)-N-(1-(2,4-디플루오로페닐설포닐)피페리딘-4-일)피리미딘-2-아민 (화합물 32)Example 32. 4- (4-chlorophenyl) - N - (1- (2,4- difluorophenyl sulfonyl) piperidin-4-yl) pyrimidin-2-amine (compound 32)

상기 실시예 1의 합성방법으로 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.069 mmol), 2,4-디플루오로벤젠설포닐 클로라이드 (8.3 ㎕, 0.062 mmol), DIPEA (21.6 ㎕, 0.124 mmol)를 사용하여 목적화합물 27.9 mg (0.060 mmol, 87%)을 얻었다.A method for the synthesis of Example 1 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.069 mmol), benzene 2,4 Sulfonyl chloride (8.3 μl, 0.062 mmol) and DIPEA (21.6 μl, 0.124 mmol) were used to give 27.9 mg (0.060 mmol, 87%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.38-8.31 (m, 1H), 7.96-7.86 (m, 3H), 7.47-7.42 (m, 2H), 7.09-7.00 (m, 2H), 6.99-6.94 (m, 1H), 5.18 (d, J = 6.3 Hz, 1H), 4.10-3.96 (m, 1H), 3.82 (d, J = 11.7 Hz, 2H), 2.90 (t, J = 11.1 Hz, 2H), 2.20 (d, J = 12.6 Hz, 2H), 1.78-1.60 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.38-8.31 (m, 1H), 7.96-7.86 (m, 3H), 7.47-7.42 (m, 2H), 7.09-7.00 (m, 2H), 6.99-6.94 (m, 1H), 5.18 (d, J = 6.3 Hz, 1H), 4.10-3.96 (m, 1H), 3.82 (d, J = 11.7 Hz, 2H), 2.90 (t, J = 11.1 Hz, 2H) , 2.20 (d, J = 12.6 Hz, 2H), 1.78-1.60 (m, 2H)

실시예 33. 4-(4-클로로페닐)-N-(1-(4-메톡시페닐설포닐)피페리딘-4-일)피리미딘-2-아민 (화합물 33)Example 33. 4- (4-chlorophenyl) - N - (1- (4-methoxy-phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine (compound 33)

상기 실시예 1의 합성방법으로 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.069 mmol), 4-메톡시벤젠설포닐 클로라이드 (12.8 mg, 0.062 mmol), DIPEA (21.6 ㎕, 0.124 mmol)를 사용하여 목적화합물 30 mg (0.065 mmol, 95%)을 얻었다.A method for the synthesis of Example 1 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.069 mmol), 4-methoxybenzenesulfonyl chloride (12.8 mg, 0.062 mmol) and DIPEA (21.6 μl, 0.124 mmol) gave 30 mg (0.065 mmol, 95%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.33 (d, J = 5.1 Hz, 1H), 7.95 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 5.1 Hz, 1H), 5.13 (d, J = 7.5 Hz, 1H), 3.94 (s, 4H), 3.77-3.67 (m, 2H), 2.65 (t, J = 11.1 Hz, 2H), 2.25-2.14 (m, 2H), 1.63-1.78 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.33 (d, J = 5.1 Hz, 1H), 7.95 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.7 Hz, 2H), 7.46 (d , J = 8.1 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 5.1 Hz, 1H), 5.13 (d, J = 7.5 Hz, 1H), 3.94 (s, 4H ), 3.77-3.67 (m, 2H), 2.65 (t, J = 11.1 Hz, 2H), 2.25-2.14 (m, 2H), 1.63-1.78 (m, 2H)

실시예 34. 4-(4-클로로페닐)-N-(1-(3-메톡시페닐설포닐)피페리딘-4-일)피리미딘-2-아민 (화합물 34)Example 34. 4- (4-chlorophenyl) - N - (1- (3- methoxy-phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine (Compound 34)

상기 실시예 1의 합성방법으로 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.069 mmol), 3-메톡시벤젠설포닐 클로라이드 (8.8 ㎕, 0.062 mmol), DIPEA (21.6 ㎕, 0.124 mmol)를 사용하여 목적화합물 23 mg (0.050 mmol, 73%)을 얻었다.A method for the synthesis of Example 1 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.069 mmol), 3- methoxybenzene sulfonyl chloride (8.8 μl, 0.062 mmol) and DIPEA (21.6 μl, 0.124 mmol) gave 23 mg (0.050 mmol, 73%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.33 (d, J = 5.4 Hz, 1H), 7.98-7.92 (m, 2H), 7.53-7.50 (m, 1H), 7.50-7.44 (m, 2H), 7.42-7.38 (m, 1H), 7.21-7.17 (m, 1H), 6.97 (d, J = 5.1 Hz, 1H), 5.18 (d, J = 7.8 Hz, 1H), 3.92 (s, 4H), 3.79-3.69 (m, 2H), 2.68 (t, J = 11.4 Hz, 2H), 2.25-2.14 (m, 2H), 1.70 (qd, J = 10.8 Hz, J = 3.9 Hz, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.33 (d, J = 5.4 Hz, 1H), 7.98-7.92 (m, 2H), 7.53-7.50 (m, 1H), 7.50-7.44 (m, 2H), 7.42-7.38 (m, 1H), 7.21-7.17 (m, 1H), 6.97 (d, J = 5.1 Hz, 1H), 5.18 (d, J = 7.8 Hz, 1H), 3.92 (s, 4H), 3.79 -3.69 (m, 2H), 2.68 (t, J = 11.4 Hz, 2H), 2.25-2.14 (m, 2H), 1.70 (qd, J = 10.8 Hz, J = 3.9 Hz, 2H)

실시예 35. 4-(4-클로로페닐)-N-(1-(2,5-디메톡시페닐설포닐)피페리딘-4-일)피리미딘-2-아민 (화합물 35)Example 35. 4- (4-chlorophenyl) - N - (1- (2,5- dimethoxy-phenyl-sulfonyl) -piperidin-4-yl) pyrimidin-2-amine (compound 35)

상기 실시예 1의 합성방법으로4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (20 mg, 0.069 mmol), 2,5-디메톡시벤젠설포닐 클로라이드 (8.8 ㎕, 0.062 mmol), DIPEA (21.6 ㎕, 0.124 mmol)를 사용하여 목적화합물 30.9 mg (0.063 mmol, 86%)을 얻었다.A method for the synthesis of Example 1 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.069 mmol), 2,5- Dimethoxy-benzenesulfonyl Ponyl chloride (8.8 μl, 0.062 mmol) and DIPEA (21.6 μl, 0.124 mmol) gave 30.9 mg (0.063 mmol, 86%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.35 (d, J = 5.1 Hz, 1H), 7.99-7.93 (m, 2H), 7.50-7.48 (m, 1H), 7.47-7.43 (m, 2H), 7.12-7.08 (m, 1H), 7.02 (s, 1H), 7.00-6.95 (m, 1H), 5.35-5.27 (m, 1H), 4.10-3.95 (m, 1H), 3.92 (s, 3H), 3.90-3.85 (m, 2H), 3.84 (s, 3H), 3.12-2.91 (m, 2H), 2.22-2.11 (m, 2H), 1.64 (qd, J = 10.8 Hz, J = 3.9 Hz, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.35 (d, J = 5.1 Hz, 1H), 7.99-7.93 (m, 2H), 7.50-7.48 (m, 1H), 7.47-7.43 (m, 2H), 7.12-7.08 (m, 1H), 7.02 (s, 1H), 7.00-6.95 (m, 1H), 5.35-5.27 (m, 1H), 4.10-3.95 (m, 1H), 3.92 (s, 3H), 3.90-3.85 (m, 2H), 3.84 (s, 3H), 3.12-2.91 (m, 2H), 2.22-2.11 (m, 2H), 1.64 (qd, J = 10.8 Hz, J = 3.9 Hz, 2H)

실시예 36. N-부틸-4-(4-(4-클로로페닐)피리미딘-2-일아미노)피페리딘-1-카복사마이드 (화합물 36)Example 36. N -butyl-4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidine-1-carboxamide (Compound 36)

반응 용기에 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민(20 mg, 0.079 mmol)과 N-부틸 이소시아네이트 (7 ㎕, 0.071 mmol)를 넣고 정제된 피리딘 1 mL에 녹여 120℃에서 6시간 동안 환류하였다. 진행과 결과를 TLC로 확인하였다. 반응 완결 후 반응 혼합물을 반응 완결 후 반응 혼합물을 디클로로메탄으로 묽힌 후 H₂O를 넣고 수층을 디클로로메탄으로 추출하고 유기층을 무수 MgSO₄로 건조시킨 후, 여과하였다. 여과액을 감암 농축시켜 농축액을 관 크로마토그래피(CH₂Cl₂:MeOH=40:1)로 분리 정제하여 목적화합물 11 mg (0.028 mmol, 35%)을 얻었다.To the reaction vessel of 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (20 mg, 0.079 mmol) and N - butyl isocyanate into the (7 ㎕, 0.071 mmol) It was dissolved in 1 mL of purified pyridine and refluxed at 120 ° C. for 6 hours. Progress and results were confirmed by TLC. After completion of the reaction, the reaction mixture was diluted with dichloromethane after completion of the reaction, H ₂ O was added, the aqueous layer was extracted with dichloromethane, and the organic layer was dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (CH ₂ Cl ₂ : MeOH = 40: 1) to obtain 11 mg (0.028 mmol, 35%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.37 (d, J = 5.1 Hz, 1H), 8.01-7.97 (m, 2H), 7.50-7.46 (m, 2H), 6.98 (d, J = 5.1 Hz, 1H), 5.20 (d, J = 7.8 Hz, 1H), 4.53 (t, J = 5.1 Hz, 1H), 4.20-4.08 (m, 1H), 3.95 (d, J = 13.5 Hz, 2H), 3.28 (q, J = 6.9 Hz, 2H), 3.12-3.00 (m, 2H), 2.20-2.10 (m, 2H), 1.58-1.49 (m, 4H), 1.47-1.33 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.37 (d, J = 5.1 Hz, 1H), 8.01-7.97 (m, 2H), 7.50-7.46 (m, 2H), 6.98 (d, J = 5.1 Hz, 1H), 5.20 (d, J = 7.8 Hz, 1H), 4.53 (t, J = 5.1 Hz, 1H), 4.20-4.08 (m, 1H), 3.95 (d, J = 13.5 Hz, 2H), 3.28 ( q, J = 6.9 Hz, 2H), 3.12-3.00 (m, 2H), 2.20-2.10 (m, 2H), 1.58-1.49 (m, 4H), 1.47-1.33 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H)

실시예 37. (4-(4-(4-클로로페닐)피리미딘-2-일아미노)피페리딘-1-일)(4-플루오로페닐)메타논 (화합물 37)Example 37. (4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidin-1-yl) (4-fluorophenyl) methanone (Compound 37)

상기 실시예 14의 합성방법으로 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (30 mg, 0.104 mmol), 4-플루오로벤조일 클로라이드 (11.2 ㎕, 0.094 mmol), DMAP (1.2 mg, 0.010 mmol), 피리딘 (10 ㎕, 0.125 mmol)를 사용하여 목적화합물 27 mg (0.066 mmol, 63%)을 얻었다.A method for the synthesis of Example 14 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (30 mg, 0.104 mmol), benzoyl chloride (11.2-fluoro 27 μl, 0.094 mmol), DMAP (1.2 mg, 0.010 mmol) and pyridine (10 μl, 0.125 mmol) were used to obtain 27 mg (0.066 mmol, 63%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.34 (d, J = 5.1 Hz, 1H), 7.97-7.91 (m, 2H), 7.50-7.42 (m, 4H), 7.16-7.07 (m, 2H), 6.97 (d, J = 5.4 Hz, 1H), 5.38 (br s, 1H), 4.60 (br s, 1H), 4.28-4.14 (m, 1H), 3.78 (br s, 1H), 3.20 (br s, 2H), 2.16 (br s, 2H), 1.53 (br s, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.34 (d, J = 5.1 Hz, 1H), 7.97-7.91 (m, 2H), 7.50-7.42 (m, 4H), 7.16-7.07 (m, 2H), 6.97 (d, J = 5.4 Hz, 1H), 5.38 (br s, 1H), 4.60 (br s, 1H), 4.28-4.14 (m, 1H), 3.78 (br s, 1H), 3.20 (br s, 2H), 2.16 (br s, 2H), 1.53 (br s, 2H)

실시예 38. (4-(4-(4-클로로페닐)피리미딘-2-일아미노)피페리딘-1-일)(3-플루오로페닐)메타논 (화합물 38)Example 38. (4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidin-1-yl) (3-fluorophenyl) methanone (Compound 38)

상기 실시예 14의 합성방법으로 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (30 mg, 0.104 mmol), 3-플루오로벤조일 클로라이드 (11.2 ㎕, 0.094 mmol), DMAP (1.2 mg, 0.010 mmol), 피리딘 (10 ㎕, 0.125 mmol)를 사용하여 목적화합물 18.7 mg (0.046 mmol, 44%)을 얻었다.A method for the synthesis of Example 14 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (30 mg, 0.104 mmol), benzoyl chloride (11.2 3-fluoro ΜL, 0.094 mmol), DMAP (1.2 mg, 0.010 mmol) and pyridine (10 μL, 0.125 mmol) were used to obtain 18.7 mg (0.046 mmol, 44%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.53 (d, J = 5.4 Hz, 1H), 7.99-7.93 (m, 2H), 7.47-7.45 (m, 2H), 7.44-7.37 (m, 1H), 7.22-7.18 (m, 1H), 7.17-7.09 (m, 2H), 6.97 (d, J = 5.1 Hz, 1H), 5.25 (d, J = 7.8 Hz, 1H), 4.62 (br s, 1H), 4.29-4.16 (m, 1H), 3.76 (br s, 1H), 3.20 (br s, 2H), 2.19 (br s, 2H), 1.70-1.37 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.53 (d, J = 5.4 Hz, 1H), 7.99-7.93 (m, 2H), 7.47-7.45 (m, 2H), 7.44-7.37 (m, 1H), 7.22-7.18 (m, 1H), 7.17-7.09 (m, 2H), 6.97 (d, J = 5.1 Hz, 1H), 5.25 (d, J = 7.8 Hz, 1H), 4.62 (br s, 1H), 4.29-4.16 (m, 1H), 3.76 (br s, 1H), 3.20 (br s, 2H), 2.19 (br s, 2H), 1.70-1.37 (m, 2H)

실시예 39. (4-(4-(4-클로로페닐)피리미딘-2-일아미노)피페리딘-1-일)(4-메톡시페닐)메타논 (화합물 39)Example 39. (4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidin-1-yl) (4-methoxyphenyl) methanone (Compound 39)

상기 실시예 14의 합성방법으로 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (30 mg, 0.104 mmol), 4-메톡시벤조일 클로라이드 (15.9 mg, 0.094 mmol), DMAP (1.2 mg, 0.010 mmol), 피리딘 (10 ㎕, 0.125 mmol)를 사용하여 목적화합물 25 mg (0.059 mmol, 56.7%)을 얻었다.A method for the synthesis of Example 14 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (30 mg, 0.104 mmol), 4-methoxybenzoyl chloride (15.9 mg, 0.094 mmol), DMAP (1.2 mg, 0.010 mmol) and pyridine (10 μl, 0.125 mmol) gave 25 mg (0.059 mmol, 56.7%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.31 (d, J = 5.1 Hz, 1H), 7.97-7.93 (m, 2H), 7.46-7.38 (m, 4H), 6.98-6.96 (m, 1H), 6.93-6.89 (m, 2H), 5.80 (br s, 1H), 4.20 (br s, 1H), 3.83 (s, 4H), 3.36 (br s, 1H), 3.28-3.10 (m, 2H), 2.21-2.08 (m, 2H), 1.64-1.48 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.31 (d, J = 5.1 Hz, 1H), 7.97-7.93 (m, 2H), 7.46-7.38 (m, 4H), 6.98-6.96 (m, 1H), 6.93-6.89 (m, 2H), 5.80 (br s, 1H), 4.20 (br s, 1H), 3.83 (s, 4H), 3.36 (br s, 1H), 3.28-3.10 (m, 2H), 2.21 -2.08 (m, 2H), 1.64-1.48 (m, 2H)

실시예 40. (4-(4-(4-클로로페닐)피리미딘-2-일아미노)피페리딘-1-일)(3-메톡시페닐)메타논 (화합물 40)Example 40. (4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidin-1-yl) (3-methoxyphenyl) methanone (Compound 40)

상기 실시예 14의 합성방법으로 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (30 mg, 0.104 mmol), 3-메톡시벤조일 클로라이드 (12.8 ㎕, 0.094 mmol), DMAP (1.2 mg, 0.010 mmol), 피리딘 (10 ㎕, 0.125 mmol)를 사용하여 목적화합물 26 mg (0.061 mmol, 59%)을 얻었다.A method for the synthesis of Example 14 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (30 mg, 0.104 mmol), 3- methoxy-benzoyl chloride (12.8 ΜL, 0.094 mmol), DMAP (1.2 mg, 0.010 mmol) and pyridine (10 μL, 0.125 mmol) were used to obtain 26 mg (0.061 mmol, 59%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.38 (d, J = 5.1 Hz, 1H), 8.01-7.96 (m, 2H), 7.38-7.31 (m, 1H), 7.02-6.97 (m, 4H), 5.32 (d, J = 8.1 Hz, 1H), 4.65 (br s, 1H), 4.30-4.18 (m, 1H), 8.36 (s, 4H), 3.2 1 (br s, 2H), 2.21 (br s, 2H), 1.51 (br s, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.38 (d, J = 5.1 Hz, 1H), 8.01-7.96 (m, 2H), 7.38-7.31 (m, 1H), 7.02-6.97 (m, 4H), 5.32 (d, J = 8.1 Hz, 1H), 4.65 (br s, 1H), 4.30-4.18 (m, 1H), 8.36 (s, 4H), 3.2 1 (br s, 2H), 2.21 (br s, 2H), 1.51 (br s, 2H)

실시예 41. (4-(4-(4-클로로페닐)피리미딘-2-일아미노)피페리딘-1-일)(2,4-디메톡시페닐)메타논 (화합물 41)Example 41. (4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidin-1-yl) (2,4-dimethoxyphenyl) methanone (Compound 41)

상기 실시예 14의 합성방법으로 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (30 mg, 0.104 mmol), 2,4-디메톡시벤조일 클로라이드 (18.8 mg, 0.094 mmol), DMAP (1.2 mg, 0.010 mmol), 피리딘 (10 ㎕, 0.125 mmol)를 사용하여 목적화합물 24.3 mg (0.054 mmol, 52%)을 얻었다.A method for the synthesis of Example 14 4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (30 mg, 0.104 mmol), 2,4- dimethoxybenzoyl chloride (18.8 mg, 0.094 mmol), DMAP (1.2 mg, 0.010 mmol) and pyridine (10 μl, 0.125 mmol) gave 24.3 mg (0.054 mmol, 52%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.34 (d, J = 5.1 Hz, 1H), 7.95 (d, J = 8.7 Hz, 2H), 7.46-7.42 (m, 2H), 7.03 (s, 1H), 7.02-6.99 (m, 1H), 6.92 (d, J = 8.7 Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H), 5.38 (br s, 1H), 4.28-4.15 (m, 1H), 3.91 (s, 7H), 3.27-3.48 (m, 2H), 2.23-2.12 (m, 2H), 1.64-1.48 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.34 (d, J = 5.1 Hz, 1H), 7.95 (d, J = 8.7 Hz, 2H), 7.46-7.42 (m, 2H), 7.03 (s, 1H) , 7.02-6.99 (m, 1H), 6.92 (d, J = 8.7 Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H), 5.38 (br s, 1H), 4.28-4.15 (m, 1H) , 3.91 (s, 7H), 3.27-3.48 (m, 2H), 2.23-2.12 (m, 2H), 1.64-1.48 (m, 2H)

실시예 42. (4-(4-(4-클로로페닐)피리미딘-2-일아미노)피페리딘-1-일)(4-(트리플루오로메틸)페닐)메타논 (화합물 42)Example 42. (4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidin-1-yl) (4- (trifluoromethyl) phenyl) methanone (Compound 42)

상기 실시예 14의 합성방법으로 4-(4-클로로페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (26 mg, 0.09 mmol), 4-(트리플루오로메틸)벤조일 클로라이드 (12 ㎕, 0.081 mmol), DMAP (1.0 mg, 0.009 mmol), 피리딘 (10.9 ㎕, 0.135 mmol)를 사용하여 목적화합물 21.3 mg (0.046 mmol, 51%)을 얻었다. N - - (piperidin-4-yl) pyrimidin-2-amine (26 mg, 0.09 mmol), ( trifluoromethyl) 4-4- (4-chlorophenyl) the synthesis method in Example 14 Benzoyl chloride (12 μl, 0.081 mmol), DMAP (1.0 mg, 0.009 mmol), pyridine (10.9 μl, 0.135 mmol) was used to give 21.3 mg (0.046 mmol, 51%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.36 (d, J = 5.4 Hz, 1H), 7.98-7.93 (m, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 7.47-7.43 (m, 2H), 6.98 (d, J = 5.1 HZ, 1H), 5.24 (d, J = 7.5 Hz, 1H), 4.71-4.58 (m, 1H), 4.30-4.17 (m, 1H), 3.78-3.66 (m, 1H), 3.31-3.10 (m, 2H), 2.31-2.08 (m, 2H), 1.72-1.39 (m, H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.36 (d, J = 5.4 Hz, 1H), 7.98-7.93 (m, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 7.47-7.43 (m, 2H), 6.98 (d, J = 5.1 HZ, 1H), 5.24 (d, J = 7.5 Hz, 1H), 4.71-4.58 (m, 1H), 4.30- 4.17 (m, 1H), 3.78-3.66 (m, 1H), 3.31-3.10 (m, 2H), 2.31-2.08 (m, 2H), 1.72-1.39 (m, H)

실시예 43. 4-(4-(몰폴리노설포닐)페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (화합물 43)Example 43. 4- (4- (morpholino noseol) phenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (Compound 43)

반응용기에 tert-부틸 4-(4-(4-(몰폴리노설포닐)페닐)피리미딘-2-일아미노)피페리딘-1-카복실레이트 (123 mg, 0.32 mmol)을 디클로로메탄 5.12 mL에 녹인 후, TFA (1.6 mL)를 천천히 첨가하였다. 3시간 동안 교반 후 반응 진행과 결과를 TLC로 확인하였다. 반응 완결 후 반응용액을 농축시킨 뒤 디클로로메탄으로 묽힌 후, 포화 NaHCO₃용액을 넣고 수층을 디클로로메탄으로 추출하고 유기층을 무수 MgSO₄로 건조시킨 후, 여과하였다. 여과액을 감암 농축시켜 농축액을 관 크로마토그래피 (CHCl₃:MeOH:NH₃:H₂O=80:20:1:1)를 통하여 목적화합물 151 mg (93%)을 얻었다. Tert- butyl 4- (4- (4- (4- (morpholinosulfonyl) phenyl) pyrimidin-2-ylamino) piperidine-1-carboxylate (123 mg, 0.32 mmol) in a reaction vessel, 5.12 mL After dissolving in, TFA (1.6 mL) was added slowly. After stirring for 3 hours, the reaction progress and results were confirmed by TLC. After completion of the reaction, the reaction solution was concentrated and diluted with dichloromethane, saturated NaHCO ₃ solution was added, the aqueous layer was extracted with dichloromethane, and the organic layer was dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure to give 151 mg (93%) of the target compound by column chromatography (CHCl ₃ : MeOH: NH ₃ : H ₂ O = 80: 20: 1: 1).

¹H NMR (300 MHz, CDCl₃) δ 8.43 (d, J = 4.94 Hz, 1H), 8.18 (d, J = 8.27 Hz, 2H), 7.87 (d, J = 8.19 Hz, 2H), 7.03 (d, J = 5.21 Hz, 1H), 5.20 (d, J = 7.86 Hz, 1H), 4.07-4.13 (m, 1H), 3.77 (t, J = 4.31 Hz, 4H), 3.29 (d, J = 12.89 Hz, 2H), 2.89-3.07 (m, 6H), 2.23 (d, J = 10.22 Hz, 2H), 1.58-1.70 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.43 (d, J = 4.94 Hz, 1H), 8.18 (d, J = 8.27 Hz, 2H), 7.87 (d, J = 8.19 Hz, 2H), 7.03 (d , J = 5.21 Hz, 1H), 5.20 (d, J = 7.86 Hz, 1H), 4.07-4.13 (m, 1H), 3.77 (t, J = 4.31 Hz, 4H), 3.29 (d, J = 12.89 Hz , 2H), 2.89-3.07 (m, 6H), 2.23 (d, J = 10.22 Hz, 2H), 1.58-1.70 (m, 2H)

실시예 44. N-(1-메틸피페리딘-4-일)-4-(4-(몰폴리노설포닐)페닐)피리미딘-2-아민 (화합물 44)Example 44. N - (1- methylpiperidin-4-yl) -4- (4- (morpholino noseol) phenyl) pyrimidin-2-amine (compound 44)

상기 실시예 21의 합성과 같은 방법으로 4-(4-(몰폴리노설포닐)페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (50 mg, 0.12 mmol), 37% HCHO 용액 (0.17 mL, 16.7 mmol), NaBH(OAc)₃ (127 mg, 0.6 mmol)를 사용하여 목적화합물 30.3 mg (60%)을 얻었다. In the same method as in Example 21, 4- (4- (morpholino noseol) phenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (50 mg, 0.12 mmol), 37 30.3 mg (60%) of the title compound were obtained using% HCHO solution (0.17 mL, 16.7 mmol) and NaBH (OAc) ₃ (127 mg, 0.6 mmol).

¹H NMR (300 MHz, CDCl₃) δ 8.41 (d, J = 5.03 Hz, 1H), 8.18 (d, J = 8.25 Hz, 2H), 7.85 (d, J = 8.43 Hz, 2H), 6.99 (d, J = 4.23 Hz, 1H), 5.24 (d, J = 7.41 Hz, 1H), 3.95-3.96 (m, 1H), 3.76 (t, J = 4.30 Hz, 4H), 3.04 (t, J = 4.56 Hz, 4H), 2.84 (d, J = 10.88 Hz, 2H), 2.33 (s, 3H), 2.23 (d, J = 10.66 Hz, 2H), 2.13 (d, J = 13.03 Hz, 2H), 1.57-1.69 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.41 (d, J = 5.03 Hz, 1H), 8.18 (d, J = 8.25 Hz, 2H), 7.85 (d, J = 8.43 Hz, 2H), 6.99 (d , J = 4.23 Hz, 1H), 5.24 (d, J = 7.41 Hz, 1H), 3.95-3.96 (m, 1H), 3.76 (t, J = 4.30 Hz, 4H), 3.04 (t, J = 4.56 Hz , 4H), 2.84 (d, J = 10.88 Hz, 2H), 2.33 (s, 3H), 2.23 (d, J = 10.66 Hz, 2H), 2.13 (d, J = 13.03 Hz, 2H), 1.57-1.69 (m, 2H)

실시예 45. N-(1-(메틸설포닐)피페리딘-4-일)-4-(4-(몰폴리노설포닐)페닐)피리미딘-2-아민 (화합물 45)Example 45. N - (1- (methylsulfonyl) piperidin-4-yl) -4- (4- (morpholino noseol) phenyl) pyrimidin-2-amine (compound 45)

상기 실시예 1의 합성방법으로 4-(4-(몰폴리노설포닐)페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (89.9 mg, 0.22 mmol), 메탄설포닐 클로라이드 (15.2 ㎕, 0.2 mmol) 그리고 DIPEA (69.6 ㎕, 0.4 mmol)를 사용하여 목적화합물 34.3 mg (32%)을 얻었다. Example 1 a method of synthesizing 4- (4- (morpholino noseol) phenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (89.9 mg, 0.22 mmol), methanesulfonyl Chloride (15.2 μl, 0.2 mmol) and DIPEA (69.6 μl, 0.4 mmol) gave 34.3 mg (32%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.43 (d, J = 5.12 Hz, 1H), 8.18 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 8.36 Hz, 2H), 7.05 (d, J = 5.18 Hz, 1H), 5.18 (d, J = 7.65 Hz, 1H), 4.07-4.11 (m, 1H), 3.76-3.83 (m, 6H), 3.05 (t, J = 4.81 Hz, 4H), 2.96 (d, J = 13.49 Hz, 2H), 2.84 (s, 3H), 2.25 (d, J = 10.46 Hz, 2H), 1.65-1.78 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.43 (d, J = 5.12 Hz, 1H), 8.18 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 8.36 Hz, 2H), 7.05 (d , J = 5.18 Hz, 1H), 5.18 (d, J = 7.65 Hz, 1H), 4.07-4.11 (m, 1H), 3.76-3.83 (m, 6H), 3.05 (t, J = 4.81 Hz, 4H) , 2.96 (d, J = 13.49 Hz, 2H), 2.84 (s, 3H), 2.25 (d, J = 10.46 Hz, 2H), 1.65-1.78 (m, 2H)

실시예 46. 4-(4-(4-(몰폴리노설포닐)페닐)피리미딘-2-일아미노)피페리딘-1-설폰아마이드 (화합물 46)Example 46. 4- (4- (4- (morpholinosulfonyl) phenyl) pyrimidin-2-ylamino) piperidine-1-sulfonamide (Compound 46)

상기 실시예 1의 합성방법으로 4-(4-(몰폴리노설포닐)페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (100 mg, 0.25 mmol), tert-부틸 클로로설포닐카바메이트 (0.25 mmol) 그리고 TEA (37 ㎕, 0.25 mmol)를 사용하여 tert-부틸 4-(4-(4-(몰폴리노설포닐)페닐)피리미딘-2-일아미노)피페리딘-1-일설포닐카바메이트 90 mg (60%)을 얻었다. 그런 다음, 상기 실시예 20과 같은 방법으로 Boc 그룹을 탈보호하여 목적화합물 40 mg (53%)을 얻었다. Example 1 Synthesis of 4- (4- (morpholino noseol) phenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (100 mg, 0.25 mmol), tert- butyl Tert- butyl 4- (4- (4- (morpholinosulfonyl) phenyl) pyrimidin-2-ylamino) piperi using chlorosulfonylcarbamate (0.25 mmol) and TEA (37 μl, 0.25 mmol) 90 mg (60%) of din-1-ylsulfonylcarbamate was obtained. Thereafter, the Boc group was deprotected in the same manner as in Example 20 to obtain 40 mg (53%) of the title compound.

¹H NMR (300 MHz, DMSO-d ₆) δ 8.45 (d, J = 5.00 Hz, 1H), 8.34 (d, J = 8.26 Hz, 2H), 7.86 (d, J = 8.41 Hz, 2H), 7.36 (d, J = 7.43 Hz, 1H), 7.24 (d, J = 5.15 Hz, 1H), 6.74 (s, 2H), 3.65 (t, J = 4.26 Hz, 4H), 3.47 (d, J = 11.02 Hz, 2H), 2.92 (t, J = 4.51 Hz, 4H), 2.70 (t, J = 10.52 Hz, 2H), 2.00 (d, J = 11.24 Hz, 2H), 1.61 (q, J = 9.14 Hz, 2H)
¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.45 (d, J = 5.00 Hz, 1H), 8.34 (d, J = 8.26 Hz, 2H), 7.86 (d, J = 8.41 Hz, 2H), 7.36 (d, J = 7.43 Hz, 1H), 7.24 (d, J = 5.15 Hz, 1H), 6.74 (s, 2H), 3.65 (t, J = 4.26 Hz, 4H), 3.47 (d, J = 11.02 Hz , 2H), 2.92 (t, J = 4.51 Hz, 4H), 2.70 (t, J = 10.52 Hz, 2H), 2.00 (d, J = 11.24 Hz, 2H), 1.61 (q, J = 9.14 Hz, 2H )

실시예 47. 4-(4-(4-메틸피페라진-1-일설포닐)페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (화합물 47)Example 47. 4- (4- (4-methylpiperazin-1-ylsulphonyl) phenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (compound 47)

상기 실시예 43의 탈보호 방법으로 tert-부틸 4-(4-(4-메틸피페라진-1-일설포닐)페닐)-N-(피페리딘-4-일)피리미딘-2-아민을 사용하여, 목적화합물 402 mg을 얻었다. A (piperidin-4-yl) pyrimidin-2-amine - N - tert- butyl 4- (4- (4-methylpiperazin-1-ylsulphonyl) phenyl) a deprotection method in Example 43 It used, and 402 mg of target compound were obtained.

¹H NMR (300 MHz, CDCl₃) δ 8.40 (d, J = 5.12 Hz, 1H), 8.15 (d, J = 8.47 Hz, 2H), 7.85 (d, J = 8.56 Hz, 2H), 6.98 (d, J = 5.14 Hz, 1H), 5.19 (d, J = 7.9 Hz, 1H), 4.00-4.06 (m, 3H), 3.09-3.19 (m, 6H), 2.81 (t, J = 13.64 Hz, 2H), 2.49 (t, J = 4.91 Hz, 4H), 2.28 (s, 3H), 2.14 (d, J = 10.08 Hz, 2H), 1.45-1.50 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.40 (d, J = 5.12 Hz, 1H), 8.15 (d, J = 8.47 Hz, 2H), 7.85 (d, J = 8.56 Hz, 2H), 6.98 (d , J = 5.14 Hz, 1H), 5.19 (d, J = 7.9 Hz, 1H), 4.00-4.06 (m, 3H), 3.09-3.19 (m, 6H), 2.81 (t, J = 13.64 Hz, 2H) , 2.49 (t, J = 4.91 Hz, 4H), 2.28 (s, 3H), 2.14 (d, J = 10.08 Hz, 2H), 1.45-1.50 (m, 2H)

실시예 48. 4-(4-(4-메틸피페라진-1-일설포닐)페닐)-N-(1-(메틸설포닐)피페리딘-4-일)피리미딘-2-아민 (화합물 48)Example 48. 4- (4- (4-methylpiperazin-1-ylsulphonyl) phenyl) - N - (1- (methylsulfonyl) piperidin-4-yl) pyrimidin-2-amine (compound 48)

상기 실시예 1의 합성방법으로 4-(4-(4-메틸피페라진-1-일설포닐)페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (115.3 mg, 0.28 mmol), 메탄설포닐 클로라이드 (19 ㎕, 0.25 mmol) 그리고 DIPEA (87 ㎕, 0.5mmol)를 사용하여 목적화합물 104 mg (75%)을 얻었다. A method for the synthesis of Example 1 4- (4- (4-methylpiperazin-1-ylsulphonyl) phenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (115.3 mg, 0.28 mmol), methanesulfonyl chloride (19 μl, 0.25 mmol) and DIPEA (87 μl, 0.5 mmol) were used to obtain 104 mg (75%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.42 (d, J = 5.14 Hz, 1H), 8.14 (d, J = 8.50 Hz, 2H), 7.86 (d, J = 8.49 Hz, 2H), 7.02 (d, J = 5.16 Hz, 1H), 5.18 (d, J = 7.72 Hz, 1H), 4.10-4.15 (m, 1H), 3.78-3.83 (m, 2H), 3.09 (s, 4H), 2.98 (t, J = 13.52 Hz, 2H), 2.84 (s, 3H), 2.50 (t, J = 4.91 Hz, 4H), 2.28 (s, 3H), 2.23 (d, J = 3.17 Hz, 2H), 1.66-1.74 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.42 (d, J = 5.14 Hz, 1H), 8.14 (d, J = 8.50 Hz, 2H), 7.86 (d, J = 8.49 Hz, 2H), 7.02 (d , J = 5.16 Hz, 1H), 5.18 (d, J = 7.72 Hz, 1H), 4.10-4.15 (m, 1H), 3.78-3.83 (m, 2H), 3.09 (s, 4H), 2.98 (t, J = 13.52 Hz, 2H), 2.84 (s, 3H), 2.50 (t, J = 4.91 Hz, 4H), 2.28 (s, 3H), 2.23 (d, J = 3.17 Hz, 2H), 1.66-1.74 ( m, 2H)

실시예 49. 4-(4-(4-(4-메틸피페라진-1-일설포닐)페닐)피리미딘-2-일아미노)피페리딘-1-설폰아마이드 (화합물 49)Example 49. 4- (4- (4- (4- (4-methylpiperazin-1-ylsulfonyl) phenyl) pyrimidin-2-ylamino) piperidine-1-sulfonamide (Compound 49)

상기 실시예 46의 합성방법으로 목적화합물 51 mg을 얻었다. 51 mg of the target compound was obtained by the synthesis method of Example 46.

¹H NMR (300 MHz, DMSO-d ₆) δ 8.44 (d, J = 5.11 Hz, 1H), 8.33 (d, J = 8.24Hz, 2H), 7.85 (d, J = 8.42 Hz, 2H), 7.36 (d, J = 7.61 Hz, 1H), 7.24 (d, J = 5.15 Hz, 1H), 6.74 (s, 2H), 3.88 (m, 1H), 3.47 (d, J = 11.84 Hz, 2H), 2.94 (s, 4H), 2.68 (t, J = 10.88 Hz, 2H), 2.40 (s, 4H), 2.16 (s, 3H), 2.00 (d, J = 10.77 Hz, 2H), 1.60-1.62 (m, 2H)
¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 5.11 Hz, 1H), 8.33 (d, J = 8.24 Hz, 2H), 7.85 (d, J = 8.42 Hz, 2H), 7.36 (d, J = 7.61 Hz, 1H), 7.24 (d, J = 5.15 Hz, 1H), 6.74 (s, 2H), 3.88 (m, 1H), 3.47 (d, J = 11.84 Hz, 2H), 2.94 (s, 4H), 2.68 (t, J = 10.88 Hz, 2H), 2.40 (s, 4H), 2.16 (s, 3H), 2.00 (d, J = 10.77 Hz, 2H), 1.60-1.62 (m, 2H)

실시예 50. 4-(4-(피페라진-1-일설포닐)페닐)-N-(피페리딘-4-일)피리미딘-2-아민 (화합물 50)Example 50. 4- (4- (1-ylsulphonyl) phenyl) - N - (piperidin-4-yl) pyrimidin-2-amine (compound 50)

벤질 4-(4-(2-(피페리딘-4-일아미노)피리미딘-4-일)페닐설포닐)피페라진-1-카복실레이트 (95 mg, 0.17 mmol)를 메탄올 25 mL에 녹이고, Pd(OH)₂/C (36mg), 수소 가스로 충진된 고무풍선을 이용하여 반응을 종결시킨 후, 셀라이트 필터 후 농축시켜 농축액을 관 크로마토그래피 (SiO₂, CH₂Cl₂:MeOH:H₂O:NH₄OH=70:30:3:3)를 이용하여 목적화합물 36 mg (52%)을 얻었다. Benzyl 4- (4- (2- (piperidin-4-ylamino) pyrimidin-4-yl) phenylsulfonyl) piperazin-1-carboxylate (95 mg, 0.17 mmol) was dissolved in 25 mL methanol. The reaction was terminated using a rubber balloon filled with Pd (OH) ₂ / C (36 mg) and hydrogen gas, and then concentrated after celite filter (SiO ₂ , CH ₂ Cl ₂ : MeOH: 36 mg (52%) of the title compound were obtained using H ₂ O: NH ₄ OH = 70: 30: 3: 3).

¹H NMR (300 MHz, MeOD-d ₄) δ 8.40 (d, J = 5.27 Hz, 1H), 8.34 (d, J = 8.43 Hz, 2H), 7.89 (d, J = 8.30 Hz, 2H), 7.22 (d, J = 5.18 Hz, 1H), 4.15 (m, 1H), 3.02 (s, 6H), 2.89 (d, J = 4.76 Hz, 4H), 2.22 (d, J = 13.97 Hz, 2H), 1.67-1.77 (m, 2H)
¹ H NMR (300 MHz, MeOD- d ₄ ) δ 8.40 (d, J = 5.27 Hz, 1H), 8.34 (d, J = 8.43 Hz, 2H), 7.89 (d, J = 8.30 Hz, 2H), 7.22 (d, J = 5.18 Hz, 1H), 4.15 (m, 1H), 3.02 (s, 6H), 2.89 (d, J = 4.76 Hz, 4H), 2.22 (d, J = 13.97 Hz, 2H), 1.67 -1.77 (m, 2H)

실시예 51. N-(1-(메틸설포닐)피페리딘-4-일)-4-(4-(피페라진-1-일설포닐)페닐)피리미딘-2-아민 (화합물 51)Example 51. N - (1- (methylsulfonyl) piperidin-4-yl) -4- (4- (1-ylsulphonyl) phenyl) pyrimidin-2-amine (compound 51)

상기 실시예 1의 합성방법으로 벤질 4-(4-(2-(피페리딘-4-일아미노)피리미딘-4-일)페닐설포닐)피페라진-1-카복실레이트 (30 mg, 0.056 mmol), 메탄설포닐 클로라이드 (3.8 ㎕, 0.05 mmol) 그리고 DIPEA (17.4 ㎕, 0.1mmol)을 사용하여 벤질 4-(4-(2-(1-(메틸설포닐)피페리딘-4-일아미노)피리미딘-4-일)페닐설포닐)피페라진-1-카복실레이트 25 mg (73%)을 얻었다.Benzyl 4- (4- (2- (piperidin-4-ylamino) pyrimidin-4-yl) phenylsulfonyl) piperazine-1-carboxylate (30 mg, 0.056) mmol), methanesulfonyl chloride (3.8 μl, 0.05 mmol) and DIPEA (17.4 μl, 0.1 mmol) using benzyl 4- (4- (2- (1- (methylsulfonyl) piperidin-4-yl 25 mg (73%) of amino) pyrimidin-4-yl) phenylsulfonyl) piperazine-1-carboxylate were obtained.

벤질 4-(4-(2-(1-(메틸설포닐)피페리딘-4-일아미노)피리미딘-4-일)페닐설포닐)피페라진-1-카복실레이트 (20 mg, 0.033 mmol)을 EA (20 mL), MeOH (4 mL), H₂O (0.4 mL), 아세트산(1 drop)의 혼합용액에 녹인 뒤 Pd(OH)₂/C (36 mg), 수소 가스로 충진된 고무풍선을 이용하여 반응을 종결시킨 후, 셀라이트 필터 후 농축시켜 농축액을 관 크로마토그래피(SiO₂, CH₂Cl₂:MeOH:H₂O:NH₄OH=70:30:3:3)를 이용하여 목적화합물 6.6 mg (42%)을 얻었다. Benzyl 4- (4- (2- (1- (methylsulfonyl) piperidin-4-ylamino) pyrimidin-4-yl) phenylsulfonyl) piperazin-1-carboxylate (20 mg, 0.033 mmol ) Was dissolved in a mixture of EA (20 mL), MeOH (4 mL), H ₂ O (0.4 mL), acetic acid (1 drop), and charged with Pd (OH) ₂ / C (36 mg), hydrogen gas. The reaction was terminated using a hot air balloon, and then concentrated after celite filter. The concentrate was subjected to column chromatography (SiO ₂ , CH ₂ Cl ₂ : MeOH: H ₂ O: NH ₄ OH = 70: 30: 3: 3). 6.6 mg (42%) of the title compound were obtained.

¹H NMR (300 MHz, CDCl₃) δ 8.42 (d, J = 5.21 Hz, 1H), 8.14 (d, J = 8.45 Hz, 2H),7.86 (d, J = 8.44 Hz, 2H), 7.02 (d, J = 5.15 Hz, 1H), 5.19 (d, J = 7.55 Hz, 1H), 4.08-4.11 (m, 1H), 3.78-3.83 (m, 2H), 2.94-3.08 (m, 6H), 2.84 (s, 3H), 2.50 (t, J = 4.85 Hz, 4H), 2.23 (d, J = 2.63 Hz, 2H), 1.68-1.74 (m, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.42 (d, J = 5.21 Hz, 1H), 8.14 (d, J = 8.45 Hz, 2H), 7.86 (d, J = 8.44 Hz, 2H), 7.02 (d , J = 5.15 Hz, 1H), 5.19 (d, J = 7.55 Hz, 1H), 4.08-4.11 (m, 1H), 3.78-3.83 (m, 2H), 2.94-3.08 (m, 6H), 2.84 ( s, 3H), 2.50 (t, J = 4.85 Hz, 4H), 2.23 (d, J = 2.63 Hz, 2H), 1.68-1.74 (m, 2H)

실시예 52. 4-(4-(4-(피페라진-1-일설포닐)페닐)피리미딘-2-일아미노)피페리딘-1-설폰아마이드 (화합물 52)Example 52. 4- (4- (4- (piperazin-1-ylsulfonyl) phenyl) pyrimidin-2-ylamino) piperidine-1-sulfonamide (Compound 52)

상기 실시예 46의 합성 방법으로 목적화합물 43 mg을 얻었다.43 mg of the target compound was obtained by the synthesis method of Example 46.

¹H NMR (300 MHz, DMSO-d ₆) δ 8.44 (d, J = 4.80 Hz, 1H), 8.33 (d, J = 7.79 Hz, 2H), 7.83 (d, J = 8.30 Hz, 2H), 7.37 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 5.10 Hz, 1H), 6.76 (s, 2H), 3.87-3.88 (m, 1H), 3.45-3.57 (m, 2H), 2.81 (m, 4H), 2.71 (m, 6H), 2.00 (d, J = 12.17 Hz, 2H), 1.54-1.65 (m, 2H)
¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.44 (d, J = 4.80 Hz, 1H), 8.33 (d, J = 7.79 Hz, 2H), 7.83 (d, J = 8.30 Hz, 2H), 7.37 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 5.10 Hz, 1H), 6.76 (s, 2H), 3.87-3.88 (m, 1H), 3.45-3.57 (m, 2H), 2.81 ( m, 4H), 2.71 (m, 6H), 2.00 (d, J = 12.17 Hz, 2H), 1.54-1.65 (m, 2H)

실시예 53. 4-(4-(피페라진-1-일설포닐)페닐)-N-(피페리딘-4-일메틸)피리미딘-2-아민 (화합물 53)Example 53. 4- (4- (1-ylsulphonyl) phenyl) - N - (piperidin-4-ylmethyl) pyrimidin-2-amine (compound 53)

상기 실시예 50의 합성 방법으로 tert-부틸 4-(아미노메틸)피페리딘-1-카복실레이트를 이용하여 목적화합물 9 mg을 얻었다.9 mg of the target compound was obtained using tert- butyl 4- (aminomethyl) piperidine-1-carboxylate in the synthesis method of Example 50.

¹H NMR (300 MHz, CDCl₃) δ 8.40 (d, J = 5.07 Hz, 1H), 8.18 (d, J = 8.22 Hz, 2H), 7.85 (d, J = 8.27 Hz, 2H), 6.99 (d, J = 5.08 Hz, 1H), 5.31-5.38 (m, 1H), 3.59 (t, J = 4.79 Hz, 4H), 3.45 (t, J= 6.04 Hz, 2H), 3.03-3.23 (m, 8H), 2.68 (t, 3H), 1.84-1.88 (m, 3H), 1.38 (q, 2H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.40 (d, J = 5.07 Hz, 1H), 8.18 (d, J = 8.22 Hz, 2H), 7.85 (d, J = 8.27 Hz, 2H), 6.99 (d , J = 5.08 Hz, 1H), 5.31-5.38 (m, 1H), 3.59 (t, J = 4.79 Hz, 4H), 3.45 (t, J = 6.04 Hz, 2H), 3.03-3.23 (m, 8H) , 2.68 (t, 3H), 1.84-1.88 (m, 3H), 1.38 (q, 2H)

실시예 54. 4-(4-(피페라진-1-일설포닐)페닐)-N-(피페리딘-3-일메틸)피리미딘-2-아민 (화합물 54)Example 54. 4- (4- (1-ylsulphonyl) phenyl) - N - (piperidin-3-ylmethyl) pyrimidin-2-amine (compound 54)

상기 실시예 50의 합성 방법으로 tert-부틸 3-(아미노메틸)피페리딘-1-카복실레이트를 이용하여 목적화합물 50 mg을 얻었다.50 mg of the target compound was obtained by using tert- butyl 3- (aminomethyl) piperidine-1-carboxylate in the synthesis method of Example 50.

¹H NMR (300 MHz, MeOD-d ₄) δ 8.31-8.37 (m, 3H), 7.88 (d, J = 8.39 Hz, 2H), 7.15 (d, J = 5.21 Hz, 1H), 3.32-3.38 (m, 3H), 3.18 (d, J = 11.76 Hz, 1H), 2.99-3.04 (m, 6H), 2.85-2.88 (m, 4H), 2.60-2.61 (m, 1H), 2.43 (t, J = 10.98 Hz, 1H), 1.92-1.95 (m, 2H), 1.73 (s, 1H), 1.24-1.28 (m, 1H)
¹ H NMR (300 MHz, MeOD- d ₄ ) δ 8.31-8.37 (m, 3H), 7.88 (d, J = 8.39 Hz, 2H), 7.15 (d, J = 5.21 Hz, 1H), 3.32-3.38 ( m, 3H), 3.18 (d, J = 11.76 Hz, 1H), 2.99-3.04 (m, 6H), 2.85-2.88 (m, 4H), 2.60-2.61 (m, 1H), 2.43 (t, J = 10.98 Hz, 1H), 1.92-1.95 (m, 2H), 1.73 (s, 1H), 1.24-1.28 (m, 1H)

실시예 55. (S)-4-(4-(피페라진-1-일설포닐)페닐)-N-(피롤리딘-3-일)피리미딘-2-아민 (화합물 55)Example 55. (S) -4- (4- (1-ylsulphonyl) phenyl) - N - (pyrrolidin-3-yl) pyrimidin-2-amine (compound 55)

상기 실시예 50의 합성 방법으로 (S)-tert-부틸 3-아미노피롤리딘-1-카복실레이트 이용하여 목적화합물 100 mg을 얻었다. 100 mg of the target compound was obtained by using (S) -tert- butyl 3-aminopyrrolidine-1-carboxylate in the synthesis method of Example 50.

¹H NMR (300 MHz, MeOD-d ₄) δ 8.40 (d, J = 5.21 Hz, 1H), 8.31 (d, J = 8.43 Hz, 2H), 7.86 (d, J = 8.46 Hz, 2H), 7.20 (d, J= 5.24 Hz, 1H), 4.57 (s, 1H), 3.37-3.39 (m, 1H), 3.28-3.33 (m, 1H), 3.07-3.17 (m, 2H), 2.98 (d, J = 4.81 Hz, 4H), 2.86 (t, J = 4.87 Hz, 4H), 2.28-2.30 (m, 1H), 1.97-1.99 (m, 1H)
¹ H NMR (300 MHz, MeOD- d ₄ ) δ 8.40 (d, J = 5.21 Hz, 1H), 8.31 (d, J = 8.43 Hz, 2H), 7.86 (d, J = 8.46 Hz, 2H), 7.20 (d, J = 5.24 Hz, 1H), 4.57 (s, 1H), 3.37-3.39 (m, 1H), 3.28-3.33 (m, 1H), 3.07-3.17 (m, 2H), 2.98 (d, J = 4.81 Hz, 4H), 2.86 (t, J = 4.87 Hz, 4H), 2.28-2.30 (m, 1H), 1.97-1.99 (m, 1H)

실시예 56. (R)-4-(4-(피페라진-1-일설포닐)페닐)-N-(피롤리딘-3-일)피리미딘-2-아민 (화합물 56)Example 56. (R) -4- (4- (1-ylsulphonyl) phenyl) - N - (pyrrolidin-3-yl) pyrimidin-2-amine (compound 56)

상기 실시예 50의 합성 방법으로 (R)-tert-부틸 3-아미노피롤리딘-1-카복실레이트를 사용하여 목적화합물 116 mg을 얻었다. 116 mg of the target compound was obtained using (R) -tert- butyl 3-aminopyrrolidine-1-carboxylate in the synthesis method of Example 50.

¹H NMR (300 MHz, MeOD-d ₄) δ 8.37 (d, J = 5.18 Hz, 1H), 8.30 (d, J = 8.36 Hz, 2H), 7.86 (d, J = 8.40 Hz, 2H), 7.15 (d, J= 5.21 Hz, 1H), 4.50 (s, 1H), 3.20-3.24 (m, 1H), 3.09-3.11 (m, 1H), 2.97-3.00 (m, 5H), 2.85-2.94 (m, 5H), 2.21-2.23 (m, 1H), 1.79-1.83 (m, 1H)
¹ H NMR (300 MHz, MeOD- d ₄ ) δ 8.37 (d, J = 5.18 Hz, 1H), 8.30 (d, J = 8.36 Hz, 2H), 7.86 (d, J = 8.40 Hz, 2H), 7.15 (d, J = 5.21 Hz, 1H), 4.50 (s, 1H), 3.20-3.24 (m, 1H), 3.09-3.11 (m, 1H), 2.97-3.00 (m, 5H), 2.85-2.94 (m , 5H), 2.21-2.23 (m, 1H), 1.79-1.83 (m, 1H)

실시예 57. (R)-4-(4-(피페라진-1-일설포닐)페닐)-N-(피롤리딘-3-일메틸)피리미딘-2-아민 (화합물 57)Example 57. (R) -4- (4- (1-ylsulphonyl) phenyl) - N - (pyrrolidin-3-ylmethyl) pyrimidin-2-amine (compound 57)

상기 실시예 50의 합성 방법으로 (R)-tert-부틸 3-(아미노메틸)피롤리딘-1-카복실레이트를 사용하여 목적화합물 54 mg을 얻었다. 54 mg of the target compound was obtained using (R) -tert- butyl 3- (aminomethyl) pyrrolidine-1-carboxylate in the synthesis method of Example 50.

¹H NMR (300 MHz, CDCl₃) δ 8.42 (d, J = 5.22Hz, 1H), 8.18 (d, J= 8.19 Hz, 2H), 7.85 (d, J = 8.49 Hz, 2H), 7.31-7.37 (m, 5H), 7.03 (d, J = 5.10 Hz, 1H), 5.55 (s, 1H), 5.08 (s, 2H), 3.57-3.62 (m, 7H), 3.19-3.27 (m, 2H), 3.10-3.17 (m, 1H), 2.97-3.03 (m, 5H), 2.66-2.73 (m, 1H), 2.05-2.18 (m, 1H), 1.68-1.83 (m, 1H)
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.42 (d, J = 5.22 Hz, 1H), 8.18 (d, J = 8.19 Hz, 2H), 7.85 (d, J = 8.49 Hz, 2H), 7.31-7.37 (m, 5H), 7.03 (d, J = 5.10 Hz, 1H), 5.55 (s, 1H), 5.08 (s, 2H), 3.57-3.62 (m, 7H), 3.19-3.27 (m, 2H), 3.10-3.17 (m, 1H), 2.97-3.03 (m, 5H), 2.66-2.73 (m, 1H), 2.05-2.18 (m, 1H), 1.68-1.83 (m, 1H)

실시예 58. (S)-4-(4-(피페라진-1-일설포닐)페닐)-N-(피롤리딘-3-일메틸)피리미딘-2-아민 (화합물 58)Example 58. (S) -4- (4- (1-ylsulphonyl) phenyl) - N - (pyrrolidin-3-ylmethyl) pyrimidin-2-amine (compound 58)

상기 실시예 50의 합성 방법으로 (S)-tert-부틸 3-(아미노메틸)피롤리딘-1-카복실레이트를 사용하여 목적실시예 9.7 mg을 얻었다. 9.7 mg of the target example was obtained using (S) -tert- butyl 3- (aminomethyl) pyrrolidine-1-carboxylate in the synthesis method of Example 50.

¹H NMR (300 MHz, MeOD-d ₄) δ 8.41 (d, J = 5.21 Hz, 1H), 8.36 (d, J = 8.52 Hz, 2H), 7.91 (d, J = 8.52 Hz, 2H), 7.23 (d, J = 5.23 Hz, 1H), 3.42-3.69 (m, 7H), 3.31-3.33 (m, 2H), 3.10-3.15 (m, 5H), 3.01-3.08 (m, 4H), 2.78-2.83 (m, 1H), 2.19-2.23 (m, 1H), 2.00-2.05 (m, 4H)
¹ H NMR (300 MHz, MeOD- d ₄ ) δ 8.41 (d, J = 5.21 Hz, 1H), 8.36 (d, J = 8.52 Hz, 2H), 7.91 (d, J = 8.52 Hz, 2H), 7.23 (d, J = 5.23 Hz, 1H), 3.42-3.69 (m, 7H), 3.31-3.33 (m, 2H), 3.10-3.15 (m, 5H), 3.01-3.08 (m, 4H), 2.78-2.83 (m, 1H), 2.19-2.23 (m, 1H), 2.00-2.05 (m, 4H)

[제제예] [Example]

한편, 본 발명에 따른 상기 화학식 1로 표시되는 신규 화합물은 목적에 따라 여러 형태로 제제화가 가능하다. 다음은 본 발명에 따른 상기 화학식 1로 표시되는 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.
On the other hand, the novel compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following is a description of some formulations containing the compound of Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

제제 1. 정제(직접 가압)Formulation 1.Tablet (Direct Press)

활성성분 5.0 ㎎을 체로 친 후, 락토스 14.1 ㎎, 크로스포비돈 USNF 0.8 ㎎ 및 마그네슘 스테아레이트 0.1 ㎎을 혼합하고 가압하여 정제로 만들었다.
After 5.0 mg of the active ingredient was sieved, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressurized to make tablets.

제제 2. 정제(습식 조립)Formulation 2. Tablet (Wet Granulation)

활성성분 5.0 ㎎을 체로 친 후, 락토스 16.0 ㎎과 녹말 4.0 ㎎을 섞었다. 폴리솔베이트 80 0.3 ㎎을 순수한 물에 녹인 후 이 용액의 적당량을 첨가한 다음, 미립화하였다. 건조 후에 미립을 체질한 후 콜로이달 실리콘 디옥사이드 2.7 ㎎ 및 마그네슘 스테아레이트 2.0 ㎎과 섞었다. 미립을 가압하여 정제로 만들었다.
After 5.0 mg of the active ingredient was sieved, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.

제제 3. 분말과 캡슐제Formulation 3. Powders and Capsules

활성성분 5.0 ㎎을 체로 친 후에, 락토스 14.8 ㎎, 폴리비닐 피롤리돈 10.0 ㎎, 마그네슘 스테아레이트 0.2 ㎎와 함께 섞었다. 혼합물을 적당한 장치를 사용하여 단단한 No. 5 젤라틴 캡슐에 채웠다.
5.0 mg of the active ingredient was sieved, followed by mixing with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. Filled in 5 gelatin capsules.

제제 4. 주사제Formulation 4. Injection

활성성분으로서 100 mg을 함유시키고, 그 밖에도 만니톨 180 mg, Na₂HPO₄?12H₂O 26 mg 및 증류수 2974 mg를 함유시켜 주사제를 제조하였다.
Injectables were prepared by containing 100 mg as the active ingredient, as well as 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ -12H ₂ O and 2974 mg of distilled water.

한편, 본 발명에 따른 상기 화학식 1로 표시되는 신규 화합물에 대해서는 하기 실험예에 나타낸 바와 같은 방법으로 IKK-β에 대한 저해작용에 대해 테스트를 하였다. 실험결과로서 TR-FRET를 이용하여 IKK-β에 대한 %억제율을 구하였고, 우수한 활성을 보이는 몇몇 화합물을 중심으로 IC₅₀를 구하였다.
On the other hand, for the novel compound represented by the formula (1) according to the present invention was tested for the inhibitory effect on IKK-β by the method as shown in the following experimental example. As a result of the experiment, TR-FRET was used to determine the% inhibition of IKK-β, and IC ₅₀ was determined based on a few compounds showing excellent activity.

본 발명에 따른 신규 화합물의 IKK-β에 대한 %억제율 및 IC₅₀를 일반적으로 알려진 TR-FRET 방법을 사용해서 구하였고, %억제율 및 IC₅₀는 하기 표 1에 나타내었다. The% inhibition and IC ₅₀ of IKK-β of the novel compounds according to the present invention were obtained using the commonly known TR-FRET method, and the% inhibition and IC ₅₀ are shown in Table 1 below.

실험화합물Experimental compound %억제율, (10 μM)% Inhibition rate, (10 μM) IC₅₀ in μM)IC ₅₀ in μM) 화합물 20Compound 20 75.0375.03 3.203.20 화합물 21Compound 21 38.6838.68 19.7019.70 화합물 22Compound 22 73.5873.58 3.673.67 화합물 24Compound 24 70.8670.86 3.803.80 화합물 43Compound 43 82.5182.51 2.092.09 화합물 44Compound 44 67.0667.06 5.605.60 화합물 45Compound 45 61.5161.51 2.202.20 화합물 46Compound 46 89.5589.55 0.920.92 화합물 47Compound 47 59.3559.35 7.027.02 화합물 49Compound 49 67.1167.11 4.254.25 화합물 50Compound 50 84.0884.08 1.301.30 화합물 56Compound 56 86.3886.38 2.102.10

이상에서 설명한 바와 같이, 본 발명에 따른 상기 화학식 1로 표시되는 2-아자사이클릭아미노-4-페닐피리미딘 화합물 또는 이의 약제학적으로 허용 가능한 염은 IKK-β 저해제로서 우수한 활성을 나타내므로, IKK-β 저해제로서 각종 염증질환 예를 들면 류마티스 관절염, 퇴행성 관절염, 천식, 만성 폐쇄성 폐질환은 물론이고, 암의 치료 및 예방제로 유용하다.As described above, the 2-azacyclicamino-4-phenylpyrimidine compound represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention exhibits excellent activity as an IKK-β inhibitor, and therefore, IKK As a -β inhibitor, it is useful as an agent for treating and preventing various inflammatory diseases such as rheumatoid arthritis, degenerative arthritis, asthma, chronic obstructive pulmonary disease, as well as cancer.

Claims

Compounds characterized in that selected from 2-azacyclicamino-4-phenylpyrimidine compounds represented by the following formula (1), and pharmaceutically acceptable salts thereof:
[Formula 1]

In Chemical Formula 1,
R ¹ is a hydrogen atom; Halogen atom; Morpholinosulfonyl group; Or a piperazinosulfonyl group unsubstituted or substituted with a substituent selected from C ₁ -C ₆ alkyl, benzyloxycarbonyl and tert -butylcarbonyl,
R ² is a hydrogen atom; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkylaminocarbonyl group; Aminosulfonyl group; C ₁ -C ₆ alkylsulfonyl group; Phenylsulfonyl group unsubstituted or substituted with 1 to 3 substituents consisting of halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ haloalkyl; Or a benzoyl group unsubstituted or substituted with 1 to 3 substituents consisting of halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ haloalkyl,
L represents an integer of 1 to 3,
m represents an integer of 0 to 6,
n represents the integer of 0-2.

The method according to claim 1,
R ¹ represents a hydrogen atom, a chloro atom, a morpholinosulfonyl group, a piperazinosulfonyl group, or a methyl piperazinosulfonyl group;
R ² is a hydrogen atom, a methyl group, a methylsulfonyl group, a trifluoromethylsulfonyl group, an aminosulfonyl group, a phenylsulfonyl group, o- , m -and p -trifluoromethylphenylsulfonyl group, o- , m -and p -Fluorophenylsulfonyl group, 2,4-difluorophenylsulfonyl group, m -and p -methoxyphenylsulfonyl group, 2,5-dimethoxyphenylsulfonyl group, n -butylaminocarbonyl group, m -and p -Fluorobenzoyl group, m- and p -methoxybenzoyl group, and p -trifluoromethylbenzoyl group;
M represents an integer of 0, 1, or 2;
N represents an integer of 0 or 1;
L represents an integer of 1 or 2.

The method according to claim 1,
N- (1- (methylsulfonyl) piperidin-4-yl) -4-phenylpyrimidin-2-amine;
4-phenyl- N- (1- (phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine;
4-phenyl- N- (1- (4- (trifluoromethyl) phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine;
4-phenyl- N- (1- (3- (trifluoromethyl) phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine;
4-phenyl- N- (1- (2- (trifluoromethyl) phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine;
N- (1- (4-fluorophenylsulfonyl) piperidin-4-yl) -4-phenylpyrimidin-2-amine;
N- (1- (3-fluorophenylsulfonyl) piperidin-4-yl) -4-phenylpyrimidin-2-amine;
N- (1- (2-fluorophenylsulfonyl) piperidin-4-yl) -4-phenylpyrimidin-2-amine;
N- (1- (2,4-difluorophenylsulfonyl) piperidin-4-yl) -4-phenylpyrimidin-2-amine;
N- (1- (4-methoxyphenylsulfonyl) piperidin-4-yl) -4-phenylpyrimidin-2-amine;
N- (1- (3-methoxyphenylsulfonyl) piperidin-4-yl) -4-phenylpyrimidin-2-amine;
N- (1- (2,5-dimethoxyphenylsulfonyl) piperidin-4-yl) -4-phenylpyrimidin-2-amine;
N -butyl-4- (4-phenylpyrimidin-2-ylamino) piperidine-1-carboxamide;
(4-fluorophenyl) (4- (4-phenylpyrimidin-2-ylamino) piperidin-1-yl) methanone;
(3-fluorophenyl) (4- (4-phenylpyrimidin-2-ylamino) piperidin-1-yl) methanone;
(4-methoxyphenyl) (4- (4-phenylpyrimidin-2-ylamino) piperidin-1-yl) methanone;
(3-methoxyphenyl) (4- (4-phenylpyrimidin-2-ylamino) piperidin-1-yl) methanone;
(2,4-dimethoxyphenyl) (4- (4-phenylpyrimidin-2-ylamino) piperidin-1-yl) methanone;
(4- (4-phenylpyrimidin-2-ylamino) piperidin-1-yl) (4- (trifluoromethyl) phenyl) methanone;
4- (4-chlorophenyl) - N - (piperidin-4-yl) pyrimidin-2-amine;
4- (4-chlorophenyl) - N - (1- methylpiperidin-4-yl) pyrimidin-2-amine;
4- (4-chlorophenyl) - N - (1- (methylsulfonyl) piperidin-4-yl) pyrimidin-2-amine;
4- (4-chlorophenyl) - N - (1- (trifluoromethyl-sulfonyl) -piperidin-4-yl) pyrimidin-2-amine;
4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidine-1-sulfonamide;
4- (4-chlorophenyl) - N - (1- (phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine;
4- (4-chlorophenyl) - N - (1- (4- (trifluoromethyl) phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine;
4- (4-chlorophenyl) - N - (1- (3- (trifluoromethyl) phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine;
4- (4-chlorophenyl) - N - (1- (2- (trifluoromethyl) phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine;
4- (4-chlorophenyl) - N - (1- (phenylsulfonyl) piperidin-4-yl 4-fluorophenyl) pyrimidin-2-amine;
4- (4-chlorophenyl) - N - (1- (phenylsulfonyl) piperidin-4-yl 3-fluorophenyl) pyrimidin-2-amine;
4- (4-chlorophenyl) - N - (1- (phenylsulfonyl) piperidin-4-yl 2-fluorophenyl) pyrimidin-2-amine;
4- (4-chlorophenyl) - N - (1- (2,4- difluorophenyl sulfonyl) piperidin-4-yl) pyrimidin-2-amine;
4- (4-chlorophenyl) - N - (1- (4-methoxy-phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine;
4- (4-chlorophenyl) - N - (1- (3- methoxy-phenylsulfonyl) piperidin-4-yl) pyrimidin-2-amine;
4- (4-chlorophenyl) - N - (1- (2,5- dimethoxy-phenyl-sulfonyl) -piperidin-4-yl) pyrimidin-2-amine;
N -butyl-4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidine-1-carboxamide;
(4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidin-1-yl) (4-fluorophenyl) methanone;
(4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidin-1-yl) (3-fluorophenyl) methanone;
(4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidin-1-yl) (4-methoxyphenyl) methanone;
(4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidin-1-yl) (3-methoxyphenyl) methanone;
(4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidin-1-yl) (2,4-dimethoxyphenyl) methanone;
(4- (4- (4-chlorophenyl) pyrimidin-2-ylamino) piperidin-1-yl) (4- (trifluoromethyl) phenyl) methanone;
4- (4- (morpholino noseol) phenyl) - N - (piperidin-4-yl) pyrimidin-2-amine;
N- (1-methylpiperidin-4-yl) -4- (4- (morpholinosulfonyl) phenyl) pyrimidin-2-amine;
N- (1- (methylsulfonyl) piperidin-4-yl) -4- (4- (morpholinosulfonyl) phenyl) pyrimidin-2-amine;
4- (4- (4- (morpholinosulfonyl) phenyl) pyrimidin-2-ylamino) piperidine-1-sulfonamide;
4- (4- (4-methylpiperazin-1-ylsulphonyl) phenyl) - N - (piperidin-4-yl) pyrimidin-2-amine;
4- (4- (4-methylpiperazin-1-ylsulphonyl) phenyl) - N - (1- (methylsulfonyl) piperidin-4-yl) pyrimidin-2-amine;
4- (4- (4- (4-methylpiperazin-1-ylsulfonyl) phenyl) pyrimidin-2-ylamino) piperidine-1-sulfonamide;
4- (4- (1-ylsulphonyl) phenyl) - N - (piperidin-4-yl) pyrimidin-2-amine;
N- (1- (methylsulfonyl) piperidin-4-yl) -4- (4- (piperazin-1-ylsulfonyl) phenyl) pyrimidin-2-amine;
4- (4- (4- (piperazin-1-ylsulfonyl) phenyl) pyrimidin-2-ylamino) piperidine-1-sulfonamide;
4- (4- (1-ylsulphonyl) phenyl) - N - (piperidin-4-ylmethyl) pyrimidin-2-amine;
4- (4- (1-ylsulphonyl) phenyl) - N - (piperidin-3-ylmethyl) pyrimidin-2-amine;
(S) -4- (4- (1-ylsulphonyl) phenyl) - N - (pyrrolidin-3-yl) pyrimidin-2-amine;
(R) -4- (4- (1-ylsulphonyl) phenyl) - N - (pyrrolidin-3-yl) pyrimidin-2-amine;
(R) -4- (4- (1-ylsulphonyl) phenyl) - N - (pyrrolidin-3-ylmethyl) pyrimidin-2-amine;
(S) -4- (4- (1-ylsulphonyl) phenyl) - N - (pyrrolidin-3-ylmethyl) pyrimidin-2-amine; And
And a pharmaceutically acceptable salt thereof.

The pharmaceutical composition for the treatment of inflammatory diseases or cancer diseases, characterized in that the compound of any one of the claims 1 to 3 as an active ingredient.

The method of claim 4,
The inflammatory disease is a pharmaceutical composition, characterized in that selected from the group consisting of rheumatoid arthritis, degenerative arthritis, asthma, and chronic obstructive pulmonary disease.

Iii) reacting the acetophenone represented by the following formula (2) with N, N- dimethylformamide dimethylacetal to obtain the 3-dimethylamino-1-phenylprop-2-en-1-one compound represented by the following formula (3). Process of obtaining;

(Wherein R ¹ is as defined in claim 1 above)
Ii) reacting the compound represented by Formula 3 with guanidine or guanidine hydrochloride to obtain a 2-amino-4-phenylpyrimidine compound represented by Formula 4;

(Wherein R ¹ is as defined in claim 1 above)
Iii) subjecting the compound represented by the following formula (4) to reduction amination reaction with the azacyclic ketone compound substituted with the amine protecting group represented by the following formula (6) to obtain a compound represented by the following formula (7); And

(In the above scheme, R ¹ , l, m, and n are as defined in claim 1, respectively, and R ⁴ represents a benzyloxycarbonyl group, tert- butylcarbonyl group as amine protecting group)
Iii) amine deprotection reaction of the compound represented by the following formula (7), or by introducing an R ² substituent to obtain a 2-azacyclicamino-4-phenylpyrimidine compound represented by the following formula (1);

(In the above scheme, R ¹ , R ² , l, m, and n are as defined in claim 1, respectively)
Method for producing a compound represented by the following formula (1) comprising a.

a) Reacting the acetophenone represented by the following formula (2) with N, N- dimethylformamide dimethyl acetal to obtain a 3-dimethylamino-1-phenylprop-2-en-1-one compound represented by the following formula (3) Process of obtaining;

(Wherein R ¹ is as defined in claim 1 above)
b) reacting the compound represented by Chemical Formula 3 with an azacyclic guanidinium compound substituted with an amine protecting group represented by Chemical Formula 5 to obtain a compound represented by Chemical Formula 7; And

(In the above scheme, R ¹ , l, m, and n are as defined in claim 1, respectively, and R ⁴ represents a benzyloxycarbonyl group, tert- butylcarbonyl group as amine protecting group)
c) amine deprotection reaction of the compound represented by the following formula (7), or R ² substituent is introduced to obtain a 2-azacyclic amino-4-phenylpyrimidine compound represented by the formula (1);