KR20050083563A - Substituted amides active at the cannabinoid-1 receptor - Google Patents

Substituted amides active at the cannabinoid-1 receptor Download PDF

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KR20050083563A
KR20050083563A KR1020047014299A KR20047014299A KR20050083563A KR 20050083563 A KR20050083563 A KR 20050083563A KR 1020047014299 A KR1020047014299 A KR 1020047014299A KR 20047014299 A KR20047014299 A KR 20047014299A KR 20050083563 A KR20050083563 A KR 20050083563A
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methylpropanamide
trifluoromethyl
chlorophenyl
pyridyloxy
methylpropyl
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KR100748380B1 (en
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윌리엄 케이 하그만
리누스 에스 린
쉬레니크 케이 샤
라빈드라 엔 구티콘다
훙보 치
린다 엘 창
핑 류
헬렌 엠 암스트롱
제임스 피 지울
토마스 제이 쥬니어 란자
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머크 앤드 캄파니 인코포레이티드
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Abstract

Novel compounds of the structural formula (I) are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson s disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, the treatment of obesity or eating disorders, as well as the treatment of asthma, constipation, chronic intestinal pseudo-obstruction, and cirrhosis of the liver.

Description

카나비노이드-1 수용체에서 활성인 치환된 아미드{Substituted amides active at the cannabinoid-1 receptor} Substituted amides active at the cannabinoid-1 receptor

관련 출원에 대한 상호참조Cross Reference to Related Application

해당되지 않음 Not applicable

발병의 배경Background of Onset

마리화나(대마(Cannabis Sativa L)) 및 이의 유도체는 수세기 동안 의약 및 기분전환의 목적으로 사용되어 왔다. 마리화나 및 허쉬쉬의 주된 활성 성분은 Δ9-테르하이드로카나비놀(Δ9-THC)인 것으로 측정되었다. 상세한 조사로 Δ9-THC 및 카나비노이드 부류의 다른 구성원의 생물학적 작용이 CB1 및 CB2로 명명되는 2개의 G-단백질 커플링된 수용체를 통해 일어난다는 것이 밝혀졌다. CB1 수용체는 주로 중추신경계 및 말초신경계에서 발견되며 일부 말초 기관에서는 보다 적은 정도로 발견된다. CB2 수용체는 주로 림프 조직 및 세포에서 발견된다. 아라키돈산으로부터 유도되는 카나비노이드 수용체에 대한 3가지 내인성 리간드가 확인되었다(아난다마이드, 2-아라키도노일 글리세롤 및 2-아라키도닐 글리세롤 에테르). 각각은 진정, 체온저하, 장 부동, 항통각, 진통, 강직, 항구토 및 식욕 촉진을 포함하는 Δ9-THC와 유사한 활성을 갖는 효능제이다.Marijuana (Cannabis Sativa L) and its derivatives have been used for centuries for medicinal and recreational purposes. The main active ingredient in marijuana and allowed hush is Δ 9 - was determined to be dihydro-Terminus Carnaby play (Δ 9 -THC). A detailed investigation revealed that the biological action of Δ 9 -THC and other members of the cannabinoid family occurs through two G-protein coupled receptors named CB1 and CB2. CB1 receptors are found primarily in the central and peripheral nervous systems and to a lesser extent in some peripheral organs. CB2 receptors are found primarily in lymphoid tissues and cells. Three endogenous ligands have been identified for cannabinoid receptors derived from arachidonic acid (anandamide, 2-arachidonoyl glycerol and 2-arachidonyl glycerol ether). Each is an agonist with similar activity to Δ 9 -THC including sedation, hypothermia, intestinal immobility, analgesic, analgesic, stiffness, antiemetic and palpitation.

각각의 카나비노이드 수용체에 대한 유전자는 각각 마우스에서 파괴되었다. CB1-/- 수용체 녹아웃(knockout) 마우스는 정상적이고 수정능력이 있는 것으로 나타났다. 이들은 Δ9-THC의 효과에 대해 내성이었으며 모르핀의 강화 특성 및 금단증후군의 중증도에 있어 강한 감소를 나타냈다. 이들은 또한 감소된 운동 활성 및 통각감퇴를 나타냈다. Δ9-THC에 대한 과도한 노출은 과식, 정신병, 체온저하, 기억력 손실 및 진정을 유도할 수 있다. 현재로서는 식이장애 치료를 위한 임상 시험에서 역 효능제 또는 길항제로서 확인된 하나 이상의 CB1 조절제, N-(1-피페리디닐)-5-(4-클로로페닐)-1-(2,4-디클로로페닐)-4-메틸피라졸-3-카복스아미드(SR141716A)가 있다. 사람 약제로서 사용하기에 적합한 약역학 및 약동학 특성을 갖는 효능적 저분자량 CB1 조절제가 여전히 요구되고 있다.The genes for each cannabinoid receptor were respectively destroyed in mice. CB1 − / − receptor knockout mice have been shown to be normal and fertile. They were resistant to the effects of Δ 9 -THC and showed a strong decrease in the stiffening properties of morphine and the severity of withdrawal syndrome. They also exhibited reduced motor activity and pain loss. Excessive exposure to Δ 9 -THC can lead to overeating, psychosis, hypothermia, memory loss and sedation. One or more CB1 modulators, N- (1-piperidinyl) -5- (4-chlorophenyl) -1- (2,4-dichloro, currently identified as inverse agonists or antagonists in clinical trials for the treatment of eating disorders Phenyl) -4-methylpyrazole-3-carboxamide (SR141716A). There is still a need for efficient low molecular weight CB1 modulators with pharmacodynamic and pharmacokinetic properties suitable for use as human pharmaceuticals.

천식을 CB1 수용체 조절제(예: CB1 역 효능제)로 치료하는 것은 전시냅스 카나비노이드 CB1 수용체가 (기니아 피그 폐에서) 노르아드레날린 방출의 억제를 매개한다는 사실로 뒷받침된다[참조: Europ. J. of Pharmacology, 2001, 431(2), 237-244].Treatment of asthma with CB1 receptor modulators (eg CB1 inverse agonists) is supported by the fact that the warp synapse cannabinoid CB1 receptor mediates the inhibition of noradrenaline release (in guinea pig lungs). Europ. J. of Pharmacology, 2001, 431 (2), 237-244].

간경화증을 CB1 수용체 조절제로 치료하는 것은 CB1 수용체 조절제가 사염화탄소-유도된 간경화증을 갖는 랫트에서 관찰되는 저혈압을 역전시킬 수 있으며 상승된 장간막 혈류 및 문맥압을 저하시킬 수 있다는 사실로 뒷받침된다[참조: Nature Medicine, 2001, 7(7), 827-832]. Treatment of cirrhosis with CB1 receptor modulators is supported by the fact that CB1 receptor modulators can reverse the hypotension observed in rats with carbon tetrachloride-induced hepatic cirrhosis and decrease elevated mesenteric blood flow and portal pressure. , 2001, 7 (7), 827-832.

미국 특허 제5,624,941호 및 제6,028,084호, PCT 출원 제W098/43636호 및 제W098/43635호 및 EPO 출원 제EP-658546호에는 카나비노이드 수용체에 대한 활성을 갖는 치환된 피라졸이 기재되어 있다.U.S. Patents 5,624,941 and 6,028,084, PCT Applications W098 / 43636 and W098 / 43635 and EPO Application EP-658546 describe substituted pyrazoles having activity on cannabinoid receptors.

PCT 출원 제W098/31227호 및 제W098/41519호에도 카나비노이드 수용체에 대한 활성을 갖는 치환된 피라졸이 기재되어 있다. PCT applications W098 / 31227 and W098 / 41519 also describe substituted pyrazoles having activity against cannabinoid receptors.

PCT 출원 제W098/37061호, 제WO00/10967호 및 제WO00/10968호에는 카나비노이드 수용체에 대한 활성을 갖는 디아릴 에테르 설폰아미드가 기재되어 있다.PCT applications WO098 / 37061, WO00 / 10967 and WO00 / 10968 describe diaryl ether sulfonamides having activity on cannabinoid receptors.

PCT 출원 제W097/29079호 및 제W099/02499호에는 알콕시-이소인돌론 및 알콕시-퀴놀론이 카나비노이드 수용체에 대한 활성을 갖는 것으로 기재되어 있다.PCT applications WO097 / 29079 and WO99 / 02499 describe alkoxy-isoindolones and alkoxy-quinolones having activity on cannabinoid receptors.

미국 특허 제US 5,532,237호에는 카나비노이드 수용체에 대한 활성을 갖는 N-벤조일-인돌 유도체가 기재되어 있다. US 5,532,237 describes N-benzoyl-indole derivatives having activity on cannabinoid receptors.

미국 특허 제US 4,973,587호, 제US 5,013,837호, 제US 5,081,122호 및 제US 5,112,820호, 제US 5,292,736호에는 아미노알킬인돌 유도체가 카나비노이드 수용체에 대한 활성을 갖는 것으로 기재되어 있다.US Pat. Nos. 4,973,587, US 5,013,837, US 5,081,122 and US 5,112,820, US 5,292,736 describe aminoalkylindole derivatives having activity against cannabinoid receptors.

PCT 공개공보 제WO 01/58869호에는 호흡기 및 비호흡기 백혈구 활성화 관련 질환을 치료하기 위한 피라졸, 피롤 및 이미다졸 카나비노이드 수용체가 기재되어 있다.PCT Publication No. WO 01/58869 describes pyrazole, pyrrole and imidazole cannabinoid receptors for treating diseases associated with respiratory and non-respiratory leukocyte activation.

아벤티스(Aventis)에게 양도된 PCT 공개공보 제WO 01/64632호, 제01/64633호 및 제01/64634호는 카나비노이드 길항제로서의 아제티딘 유도체에 관한 것이다. PCT Publications WO 01/64632, 01/64633 and 01/64634, assigned to Aventis, relate to azetidine derivatives as cannabinoid antagonists.

문헌[참조: Schultz, E.M, et al. J. Med Chem. 1967, 10, 717 and Pines, S.H. et al. J. Med. Chem. 1967, 10, 725]에는 혈장 콜레스테롤 및 페니실린 배출에 영향을 미치는 말레아미드산이 기재되어 있다.See Schultz, E.M, et al. J. Med Chem. 1967, 10, 717 and Pines, S.H. et al. J. Med. Chem. 1967, 10, 725 describe maleamic acids that affect plasma cholesterol and penicillin release.

본 발명의 화합물은 카나비노이드-1(CB1) 수용체의 조절제이며 카나비노이드-1(CB1) 수용체에 의해 매개되는 질병의 치료, 예방 및 억제시에 유용하다. 특히, 본 발명의 화합물은 CB1 수용체의 길항제 또는 역 효능제이다. 본 발명은 카나비노이드-1(CB1) 수용체를 조절하기 위한 상기 화합물의 용도에 관한 것이다. 이와 같이, 본 발명의 화합물은 정신병, 기억력 결핍, 인지 장애, 편두통, 신경병증, 다발성경화증 및 길리안-베르(Guillain-Barre) 증후군 및 바이러스성 뇌염, 뇌혈관장애 및 두부 손상의 염증 후유증을 포함하는 신경-염증 장애, 불안장애, 스트레스, 간질, 파킨슨 질환, 운동 장애 및 정신분열증의 치료시에 중추신경 작용 약물로서 유용하다. 당해 화합물은 특히 아편제, 알콜, 마리화나 및 니코틴의 물질 남용 장애의 치료용으로 또한 유용하다. 당해 화합물은 또한 과도한 음식 섭취 및 이로 인한 비만 및 이와 관련된 합병증을 억제함으로써 식이 장애를 치료하는데 유용하다. 당해 화합물은 변비 및 만성 가성 장폐쇄증의 치료뿐만 아니라 천식 및 간경화증의 치료용으로도 유용하다.The compounds of the present invention are modulators of cannabinoid-1 (CB1) receptors and are useful in the treatment, prevention and inhibition of diseases mediated by cannabinoid-1 (CB1) receptors. In particular, the compounds of the invention are antagonists or inverse agonists of the CB1 receptor. The present invention relates to the use of such compounds for modulating cannabinoid-1 (CB1) receptors. As such, compounds of the present invention include psychosis, memory deficiency, cognitive impairment, migraine, neuropathy, multiple sclerosis and Guillain-Barre syndrome and inflammatory sequelae of viral encephalitis, cerebrovascular disorders and head injury It is useful as a CNS drug in the treatment of neuro-inflammatory disorders, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders and schizophrenia. The compounds are also particularly useful for the treatment of substance abuse disorders of opiates, alcohols, marijuana and nicotine. The compounds are also useful for treating eating disorders by inhibiting excessive food intake and the resulting obesity and associated complications. The compounds are useful for the treatment of constipation and chronic pseudointestinal obstruction as well as for the treatment of asthma and liver cirrhosis.

발명의 요약Summary of the Invention

본 발명은 카나비노이드-1(CB1)의 길항제 및/또는 역 효능제이며 카나비노이드-1(CB1) 수용체에 의해 매개되는 질병의 치료, 예방 및 억제시에 유용한 하기 화학식 I의 신규한 치환된 아미드 및 약제학적으로 허용되는 이의 염에 관한 것이다. The present invention is a novel substituted amide and medicament of formula (I) wherein antagonists and / or inverse agonists of cannabinoid-1 (CB1) are useful in the treatment, prevention and inhibition of diseases mediated by cannabinoid-1 (CB1) receptors. It is about a salt thereof which is academically acceptable.

본 발명은 카나비노이드-1(CB1) 수용체를 선택적으로 길항시키는 이러한 신규 화합물의 용도에 관한 것이다. 이와 같이, 본 발명의 화합물은 정신병, 기억력 결핍, 인지 장애, 편두통, 신경병증, 다발성경화증 및 길리안-베르 증후군 및 바이러스성 뇌염, 뇌혈관장애 및 두부 손상의 염증 후유증을 포함하는 신경-염증 질환, 불안장애, 스트레스, 간질, 파킨슨 질환, 운동 장애 및 정신분열증의 치료시에 중추신경 작용 약물로서 유용하다. 당해 화합물은 흡연 중단을 포함한, 특히 아편제제, 알콜, 마리화나 및 니코틴의 물질 남용 장애의 치료용으로 또한 유용하다. 당해 화합물은 또한 비만 또는 과도한 음식 섭취와 관련된 식이 장애 및 이와 관련된 합병증을 치료하는데 유용하다. 당해 화합물은 또한 변비 및 만성 가성 장폐쇄증의 치료에 유용하다. 당해 화합물은 또한 간경화증의 치료에 유용하다. 당해 화합물은 천식의 치료에도 유용하다.The present invention relates to the use of such novel compounds to selectively antagonize cannabinoid-1 (CB1) receptors. As such, the compounds of the present invention are neuro-inflammatory diseases including psychosis, memory deficiency, cognitive impairment, migraine, neuropathy, multiple sclerosis and Gillian-Ber syndrome and inflammatory sequelae of viral encephalitis, cerebrovascular disorders and head injury, It is useful as a CNS drug in the treatment of anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, particularly of opiates, alcohols, marijuana and nicotine, including quitting smoking. The compounds are also useful for treating eating disorders and complications associated with obesity or excessive food intake. The compounds are also useful for the treatment of constipation and chronic pseudointestinal obstruction. The compounds are also useful for the treatment of cirrhosis of the liver. The compounds are also useful for the treatment of asthma.

본 발명은 상기한 상태의 치료 및 상기한 상태의 치료시에 유용한 의약의 제조를 위한 본 발명의 화합물의 용도에 관한 것이다. 또한, 본 발명은 화학식 I의 화합물과 현재 입수가능한 기타 약제와의 배합을 통한 상기한 상태의 치료에 관한 것이다.The present invention relates to the use of the compounds of the invention for the treatment of the above-mentioned conditions and for the preparation of a medicament useful in the treatment of the above-mentioned conditions. The present invention also relates to the treatment of the above-mentioned conditions through the combination of a compound of formula (I) with other agents currently available.

본 발명은 또한 화학식 I의 신규 화합물에 관한 것이다. The invention also relates to novel compounds of formula (I).

본 발명은 또한 활성 성분으로서 하나 이상의 당해 화합물을 포함하는 약제학적 제형에 관한 것이다.The present invention also relates to pharmaceutical formulations comprising one or more of the compounds as active ingredients.

본 발명은 추가로 본 발명의 화합물의 제조 방법에 관한 것이다.The invention further relates to a process for the preparation of the compounds of the invention.

발명의 상세한 설명Detailed description of the invention

본 발명의 방법에서 사용되는 화합물은 하기 화학식 I의 화합물 또는 약제학적으로 허용되는 이의 염으로 대표된다.The compounds used in the process of the invention are represented by a compound of formula (I) or a pharmaceutically acceptable salt thereof.

화학식 IFormula I

상기 화학식 I에서,In Formula I,

R1은 (1) 사이클로헤테로알킬, (2) 아릴, (3) 헤테로아릴 및 (4) -NRaRc[여기서, 아릴 및 헤테로아릴은 Rb로부터 독립적으로 선택되는 1 내지 3개의 치환체에 의해 임의로 치환된다]으로부터 선택되고,R 1 is selected from (1) cycloheteroalkyl, (2) aryl, (3) heteroaryl and (4) -NR a R c wherein aryl and heteroaryl are selected from 1 to 3 substituents independently selected from R b Optionally substituted by

R2는 (1) C1-10알킬, (2) C3-10사이클로알킬-C1-4알킬, (3) 아릴-C1-4알킬 및 (4) 헤테로아릴-C1-4알킬[여기서, 각각의 사이클로알킬, 아릴 및 헤테로아릴은 Rb로부터 독립적으로 선택되는 1 내지 3개의 치환체에 의해 임의로 치환된다]로부터 선택되며,R 2 is (1) C 1-10 alkyl, (2) C 3-10 cycloalkyl-C 1-4 alkyl, (3) aryl-C 1-4 alkyl and (4) heteroaryl-C 1-4 alkyl Wherein each cycloalkyl, aryl and heteroaryl is optionally substituted by 1 to 3 substituents independently selected from R b ;

각각의 Ra는 (1) 수소, (2) 메틸 및 (3) -CF3로부터 독립적으로 선택되고,Each R a is independently selected from (1) hydrogen, (2) methyl and (3) -CF 3 ,

각각의 Rb는 (1) 할로겐, (2) 시아노, (3) 트리플루오로메틸, (4) 트리플루오로메톡시, (5) C1-3알킬옥시 및 (6) C1-3알킬로부터 독립적으로 선택되며,Each R b is (1) halogen, (2) cyano, (3) trifluoromethyl, (4) trifluoromethoxy, (5) C 1-3 alkyloxy and (6) C 1-3 alkyl Are independently selected from

Rc는 (1) 수소, (2) C1-6알킬, (3) 아릴, (4) 헤테로아릴, (5) 아릴-메틸 및 (6) 헤테로아릴-메틸로부터 독립적으로 선택되고,R c is independently selected from (1) hydrogen, (2) C 1-6 alkyl, (3) aryl, (4) heteroaryl, (5) aryl-methyl and (6) heteroaryl-methyl,

각각의 Rc는 비치환되거나 Rh로부터 선택되는 1 내지 3개의 치환체에 의해 치환될 수 있으며,Each R c may be unsubstituted or substituted by 1 to 3 substituents selected from R h ,

Rd는 (1) 사이클로알킬, (2) 아릴 및 (3) 헤테로아릴로부터 독립적으로 선택되고,R d is independently selected from (1) cycloalkyl, (2) aryl and (3) heteroaryl,

각각의 Rd는 비치환되거나 Rh로부터 선택되는 1 내지 3개의 치환체에 의해 치환될 수 있으며.Each R d may be unsubstituted or substituted with 1 to 3 substituents selected from R h .

각각의 Rh는 (1) 할로겐, (2) C1-3알킬, (3) -CN 및 (4) -CF3로부터 독립적으로 선택되고, 여기서, 피리딜 그룹이 질소에서 비치환되는 경우 이들은 임의로 N-옥사이드로서 존재할 수 있다.Each R h is independently selected from (1) halogen, (2) C 1-3 alkyl, (3) -CN and (4) -CF 3 , wherein when the pyridyl group is unsubstituted in nitrogen Optionally as N-oxide.

본 발명의 하나의 양태에서, R1은 (1) 페닐, (2) 피리딜, (3) 인돌릴, (4) 7-아자-인돌릴, (5) 티오페닐 및 (6) 로부터 선택되고, 여기서, 각각의 아릴 및 헤테로아릴은 Rb로부터 독립적으로 선택되는 1 또는 2개의 치환체에 의해 임의로 치환되며, 각각의 피리딜은 임의로 N-옥사이드로서 존재할 수 있다.In one embodiment of the invention, R 1 is (1) phenyl, (2) pyridyl, (3) indolyl, (4) 7-aza-indolyl, (5) thiophenyl and (6) Wherein each aryl and heteroaryl are optionally substituted by one or two substituents independently selected from R b , and each pyridyl may optionally be present as an N-oxide.

본 발명의 이러한 양태의 한가지 부류에서, R1은 (1) 페닐, (2) 3-시아노페닐, (3) 3-메틸페닐, (4) 3,5-디플루오로페닐, (5) 3-피리딜, (6) 5-클로로-3-피리딜, (7) 5-메틸-3-피리딜, (8) 5-시아노-3-피리딜, (9) 1-옥시도-5-시아노-3-피리딜, (10) 1-인돌릴, (11) 7-아자-인돌-N-일, (12) 2-티오페닐 및 (13) 로부터 선택된다.In one class of this aspect of the invention, R 1 is (1) phenyl, (2) 3-cyanophenyl, (3) 3-methylphenyl, (4) 3,5-difluorophenyl, (5) 3 -Pyridyl, (6) 5-chloro-3-pyridyl, (7) 5-methyl-3-pyridyl, (8) 5-cyano-3-pyridyl, (9) 1-oxido-5 -Cyano-3-pyridyl, (10) 1-indolyl, (11) 7-aza-indol-N-yl, (12) 2-thiophenyl and (13) Is selected from.

본 발명의 이러한 부류의 하위부류에서, R1은 5-시아노-3-피리딜이다.In a subclass of this class of the invention, R 1 is 5-cyano-3-pyridyl.

본 발명의 또 다른 양태에서, R2는 (1) C1-6알킬, (2) C3-6사이클로알킬메틸, (3) 페닐메틸 및 (4) 헤테로아릴메틸로부터 선택되고, 여기서, 사이클로알킬, 페닐 및 헤테로아릴은 Rb로부터 독립적으로 선택되는 1 내지 3개의 치환체에 의해 임의로 치환된다.In another embodiment of the invention, R 2 is selected from (1) C 1-6 alkyl, (2) C 3-6 cycloalkylmethyl, (3) phenylmethyl and (4) heteroarylmethyl, wherein cyclo Alkyl, phenyl and heteroaryl are optionally substituted by 1 to 3 substituents independently selected from R b .

본 발명의 이러한 양태의 하나의 부류에서, R2는 (1) C1-6알킬, (2) C4-6사이클로알킬메틸, (3) 페닐메틸 및 (4) 피리딜로부터 선택되고, 여기서, 각각의 사이클로알킬, 페닐 및 헤테로아릴은 Rb로부터 독립적으로 선택되는 1 또는 2개의 치환체에 의해 임의로 치환된다.In one class of this aspect of the invention, R 2 is selected from (1) C 1-6 alkyl, (2) C 4-6 cycloalkylmethyl, (3) phenylmethyl and (4) pyridyl , Each cycloalkyl, phenyl and heteroaryl is optionally substituted by one or two substituents independently selected from R b .

본 발명의 이러한 부류의 하위부류에서, R2는 (1) 2-메틸프로필, (2) n-펜틸, (3) 사이클로부틸메틸, (4) 사이클로펜틸메틸, (5) 사이클로헥실메틸, (6) 벤질, (7) 4-클로로벤질, (8) 4-메틸벤질, (9) 4-플루오로벤질, (10) 4-메톡시벤질 및 (11) (5-클로로-2-피리딜) 메틸로부터 선택된다.In a subclass of this class of the invention, R 2 is (1) 2-methylpropyl, (2) n-pentyl, (3) cyclobutylmethyl, (4) cyclopentylmethyl, (5) cyclohexylmethyl, ( 6) benzyl, (7) 4-chlorobenzyl, (8) 4-methylbenzyl, (9) 4-fluorobenzyl, (10) 4-methoxybenzyl and (11) (5-chloro-2-pyridyl ) Is selected from methyl.

본 발명의 하나의 양태에서, 각각의 Ra는 (1) 수소, (2) 메틸 및 (3) -CF3로부터 독립적으로 선택된다.In one embodiment of the invention, each R a is independently selected from (1) hydrogen, (2) methyl and (3) -CF 3 .

본 발명의 이러한 양태의 하나의 부류에서, 각각의 Ra는 (1) 수소 및 (2) 메틸로부터 독립적으로 선택된다.In one class of this aspect of the invention, each R a is independently selected from (1) hydrogen and (2) methyl.

본 발명의 하나의 양태에서, 각각의 Rb는 (1) 할로겐, (2) 시아노, (3) C1-3알킬옥시 및 (4) C1-3알킬로부터 독립적으로 선택된다.In one embodiment of the invention, each R b is independently selected from (1) halogen, (2) cyano, (3) C 1-3 alkyloxy and (4) C 1-3 alkyl.

본 발명의 이러한 양태의 하나의 부류에서, 각각의 Rb는 (1) 플루오로, (2) 클로로, (3) 브로모, (4) 요오도, (5) 시아노, (6) 메톡시 및 (7) 메틸로부터 독립적으로 선택된다.In one class of this aspect of the invention, each R b is (1) fluoro, (2) chloro, (3) bromo, (4) iodo, (5) cyano, (6) methoxy And (7) methyl independently.

이러한 부류의 하나의 하위부류에서, 각각의 Rb는 (1) 플루오로, (2) 클로로, (3) 시아노, (4) 메톡시 및 (5) 메틸로부터 독립적으로 선택된다.In one subclass of this class, each R b is independently selected from (1) fluoro, (2) chloro, (3) cyano, (4) methoxy and (5) methyl.

본 발명의 하나의 양태에서, 각각의 Rc는 (1) 수소, (2) C1-6알킬, (3) 페닐, (4) 피리딜, (5) 벤질 및 (6) 피리딜-메틸로부터 독립적으로 선택되며, 각각의 Rc는 비치환되거나 Rh로부터 선택되는 치환체에 의해 치환될 수 있다.In one embodiment of the invention, each R c is (1) hydrogen, (2) C 1-6 alkyl, (3) phenyl, (4) pyridyl, (5) benzyl and (6) pyridyl-methyl Are independently selected from, and each R c may be unsubstituted or substituted by a substituent selected from R h .

하나의 부류에서, Rc는 페닐이다.In one class, R c is phenyl.

본 발명의 하나의 양태에서, Rd는 (1) C4-6사이클로알킬, (2) 아릴 및 (3) 헤테로아릴로부터 선택되며, 여기서 Rd는 비치환되거나 Rh로부터 선택되는 1 또는 2개의 치환체에 의해 치환될 수 있다.In one embodiment of the invention, R d is selected from (1) C 4-6 cycloalkyl, (2) aryl and (3) heteroaryl, wherein R d is 1 or 2 unsubstituted or selected from R h It may be substituted by four substituents.

본 발명의 하나의 부류에서, Rd는 (1) 페닐, (2) 피리딜 및 (3) 피리미디닐로부터 선택되며, 여기서 Rd는 비치환되거나 Rh로부터 선택되는 1 또는 2개의 치환체에 의해 치환될 수 있다.In one class of the invention, R d is selected from (1) phenyl, (2) pyridyl and (3) pyrimidinyl, wherein R d is unsubstituted or substituted with one or two substituents selected from R h It may be substituted by.

본 발명의 하나의 하위부류에서, Rd는 (1) 페닐, (2) 4-클로로페닐, (3) 3-클로로페닐, (4) 3,5-디플루오로페닐, (5) 3,5-디클로로페닐, (6) 2-피리딜, (7) 5-클로로-2-피리딜, (8) 6-메틸-2-피리딜, (9) 5-트리플루오로메틸-2-피리딜, (10) 4-트리플루오로메틸-2-피리딜, (11) 4-트리플루오로메틸-2-피리미디닐 및 (12) 6-트리플루오로메틸-4-피리미디닐로부터 선택된다.In one subclass of the invention, R d represents (1) phenyl, (2) 4-chlorophenyl, (3) 3-chlorophenyl, (4) 3,5-difluorophenyl, (5) 3, 5-dichlorophenyl, (6) 2-pyridyl, (7) 5-chloro-2-pyridyl, (8) 6-methyl-2-pyridyl, (9) 5-trifluoromethyl-2-pyri Dill, (10) 4-trifluoromethyl-2-pyridyl, (11) 4-trifluoromethyl-2-pyrimidinyl and (12) 6-trifluoromethyl-4-pyrimidinyl do.

본 발명의 또 다른 하위부류에서, Rd는 5-트리플루오로메틸-2-피리딜이다.In another subclass of the invention, R d is 5-trifluoromethyl-2-pyridyl.

본 발명의 하나의 양태에서, 각각의 Rh는 (1) 할로겐, (2) C1-3알킬, (3) -CN 및 (4) -CF3로부터 독립적으로 선택된다.In one embodiment of the invention, each R h is independently selected from (1) halogen, (2) C 1-3 alkyl, (3) -CN and (4) -CF 3 .

이러한 양태의 하나의 부류에서, 각각의 Rh는 (1) 플루오로, (2) 클로로, (3) 메틸, (4) -CN 및 (5) -CF3로부터 독립적으로 선택된다.In one class of this embodiment, each R h is independently selected from (1) fluoro, (2) chloro, (3) methyl, (4) -CN and (5) -CF 3 .

본 발명의 방법, 용도 및 조성물에서 사용될 수 있는 특정 신규 화합물로는 다음이 포함된다:Certain novel compounds that can be used in the methods, uses and compositions of the present invention include:

(1) N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(4-클로로페닐옥시)-2-메틸프로판아미드; (1) N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (4-chlorophenyloxy) -2-methylpropanamide;

(2) N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(2-피리딜옥시)-2-메틸프로판아미드; (2) N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (2-pyridyloxy) -2-methylpropanamide;

(3) N-[3-(4-클로로페닐)-1-메틸-2-(3-피리딜)프로필]-2-(4-클로로페닐옥시)-2-메틸프로판아미드; (3) N- [3- (4-chlorophenyl) -1-methyl-2- (3-pyridyl) propyl] -2- (4-chlorophenyloxy) -2-methylpropanamide;

(4) N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(3,5-디플루오로페닐옥시)-2-메틸프로판아미드; (4) N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (3,5-difluorophenyloxy) -2-methylpropanamide;

(5) N-[3-(4-클로로페닐)-2-페닐-1-메틸프로필]-2-(3,5-디클로로페닐옥시)-2-메틸프로판아미드; (5) N- [3- (4-chlorophenyl) -2-phenyl-1-methylpropyl] -2- (3,5-dichlorophenyloxy) -2-methylpropanamide;

(6) N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(3-클로로페닐옥시)-2-메틸프로판아미드; (6) N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (3-chlorophenyloxy) -2-methylpropanamide;

(7) N-[3-(4-클로로페닐)-2-(3,5-디플루오로페닐)-1-메틸프로필]-2-(2-피리딜옥시)-2-메틸프로판아미드; (7) N- [3- (4-chlorophenyl) -2- (3,5-difluorophenyl) -1-methylpropyl] -2- (2-pyridyloxy) -2-methylpropanamide;

(8) N-[3-(4-클로로페닐)-1-메틸-2-페닐-프로필]-2-(5-클로로-2-피리딜옥시)-2-메틸프로판아미드; (8) N- [3- (4-chlorophenyl) -1-methyl-2-phenyl-propyl] -2- (5-chloro-2-pyridyloxy) -2-methylpropanamide;

(9) N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(6-메틸-피리딜옥시)-2-메틸프로판아미드; (9) N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (6-methyl-pyridyloxy) -2-methylpropanamide;

(10) N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(페닐옥시)-2-메틸프로판아미드; (10) N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (phenyloxy) -2-methylpropanamide;

(11) N-[(3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(5-트리플루오로메틸피리딜옥시)-2-메틸프로판아미드; (11) N-[(3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (5-trifluoromethylpyridyloxy) -2-methylpropanamide;

(12) N-[3-(4-클로로페닐)-2-(3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드; (12) N- [3- (4-chlorophenyl) -2- (3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methyl Propanamide;

(13) N-[3-(4-클로로페닐)-2-(3-시아노페닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드; (13) N- [3- (4-chlorophenyl) -2- (3-cyanophenyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2- Methylpropanamide;

(14) N-[3-(4-클로로페닐)-2-(5-클로로-3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드; (14) N- [3- (4-chlorophenyl) -2- (5-chloro-3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide;

(15) N-[3-(4-클로로페닐)-2-(5-메틸-3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드; (15) N- [3- (4-chlorophenyl) -2- (5-methyl-3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide;

(16) N-[3-(4-클로로페닐)-2-(5-시아노-3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드; (16) N- [3- (4-chlorophenyl) -2- (5-cyano-3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy ) -2-methylpropanamide;

(17) N-[3-(4-클로로페닐)-2-(3-메틸페닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드; (17) N- [3- (4-chlorophenyl) -2- (3-methylphenyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropane amides;

(18) N-[3-(4-클로로페닐)-2-페닐-1-메틸프로필]-2-(4-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드; (18) N- [3- (4-chlorophenyl) -2-phenyl-1-methylpropyl] -2- (4-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide;

(19) N-[3-(4-클로로페닐)-2-페닐-1-메틸프로필]-2-(4-트리플루오로메틸-2-피리미딜옥시)-2-메틸프로판아미드; (19) N- [3- (4-chlorophenyl) -2-phenyl-1-methylpropyl] -2- (4-trifluoromethyl-2-pyrimidyloxy) -2-methylpropanamide;

(20) N-[3-(4-클로로페닐)-1-메틸-2-(티오펜-3-일)프로필]-2-(5-클로로-2-피리딜옥시)-2-메틸프로판아미드; (20) N- [3- (4-chlorophenyl) -1-methyl-2- (thiophen-3-yl) propyl] -2- (5-chloro-2-pyridyloxy) -2-methylpropane amides;

(21) N-[3-(5-클로로-2-피리딜)-2-페닐-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드; (21) N- [3- (5-chloro-2-pyridyl) -2-phenyl-1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropane amides;

(22) N-[3-(4-메틸-페닐)-1-메틸-2-페닐프로필]-2-(4-트리플루오로메틸-페닐옥시)-2-메틸프로판아미드; (22) N- [3- (4-methyl-phenyl) -1-methyl-2-phenylpropyl] -2- (4-trifluoromethyl-phenyloxy) -2-methylpropanamide;

(23) N-[3-(4-플루오로-페닐)-2-(3-시아노-페닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드; (23) N- [3- (4-fluoro-phenyl) -2- (3-cyano-phenyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide;

(24) N-[3-(4-클로로페닐)-2-(1-인돌릴)-1-메틸)프로필]-2-(5-트리플루오로메틸-2-옥시피리딘-2-일)-2-메틸프로판아미드; (24) N- [3- (4-chlorophenyl) -2- (1-indolyl) -1-methyl) propyl] -2- (5-trifluoromethyl-2-oxypyridin-2-yl) -2-methylpropanamide;

(25) N-[3-(4-클로로페닐)-2-(7-아자인돌-N-일)-1-메틸)프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드; (25) N- [3- (4-chlorophenyl) -2- (7-azaindol-N-yl) -1-methyl) propyl] -2- (5-trifluoromethyl-2-pyridyloxy ) -2-methylpropanamide;

(26) N-[3-(4-클로로-페닐)-2-(1-인돌리닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드; (26) N- [3- (4-chloro-phenyl) -2- (1-indolinyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2- Methylpropanamide;

(27) N-[3-(4-클로로-페닐)-2-(N-메틸-아닐리노)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드; (27) N- [3- (4-chloro-phenyl) -2- (N-methyl-anilino) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy)- 2-methylpropanamide;

(28) N-[3-(4-메톡시-페닐)-2-(3-시아노-페닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드; (28) N- [3- (4-methoxy-phenyl) -2- (3-cyano-phenyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide;

(29) N-[3-(4-클로로페닐)-2-(3-시아노페닐)-1-메틸프로필]-2-(6-트리플루오로메틸-4-피리미딜옥시)-2-메틸프로판아미드; (29) N- [3- (4-chlorophenyl) -2- (3-cyanophenyl) -1-methylpropyl] -2- (6-trifluoromethyl-4-pyrimidyloxy) -2- Methylpropanamide;

(30) N-[2-(3-시아노페닐)-1,4-디메틸펜틸]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드; (30) N- [2- (3-cyanophenyl) -1,4-dimethylpentyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide;

(31) N-[3-(4-클로로페닐)-2-(1-옥시도-5-시아노-3-피리딜]-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드; (31) N- [3- (4-chlorophenyl) -2- (1-oxido-5-cyano-3-pyridyl] -1-methylpropyl] -2- (5-trifluoromethyl- 2-pyridyloxy) -2-methylpropanamide;

(32) N-[2-(3-시아노페닐)-3-사이클로부틸-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드; (32) N- [2- (3-cyanophenyl) -3-cyclobutyl-1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide;

(33) N-[2-(3-시아노페닐)-1-메틸-헵틸]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드; (33) N- [2- (3-cyanophenyl) -1-methyl-heptyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide;

(34) N-[2-(3-시아노페닐)-3-사이클로펜틸-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드; (34) N- [2- (3-cyanophenyl) -3-cyclopentyl-1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide;

(35) N-[2-(3-시아노페닐)-3-사이클로헥실-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드; 및 약제학적으로 허용되는 이들의 염.(35) N- [2- (3-cyanophenyl) -3-cyclohexyl-1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide; And pharmaceutically acceptable salts thereof.

"알킬"뿐만 아니라 접두사 "알크"를 갖는 기타 그룹, 예를 들어, 알콕시, 알카노일은 직쇄 또는 측쇄 또는 이들의 조합을 갖는 탄소 쇄를 의미한다. 알킬 그룹의 예로는 메틸, 에틸, 프로필, 이소프로필, 부틸, 2급- 및 3급-부틸, 펜틸, 헥실, 헵틸, 옥틸, 노닐 등이 포함된다."Alkyl" as well as other groups having the prefix "alk", for example alkoxy, alkanoyl, mean carbon chains having straight or branched chains or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, secondary- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like.

"사이클로알킬"은 각각이 3 내지 10개의 탄소원자를 갖는 모노- 또는 비사이클릭 또는 브릿지된 포화 카보사이클릭 환을 의미한다. 카보알킬의 예로는 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸 등이 포함된다."Cycloalkyl" means a mono- or bicyclic or bridged saturated carbocyclic ring, each having 3 to 10 carbon atoms. Examples of carboalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

"아릴"은 탄소원자만을 함유하는 모노- 또는 비사이클릭 방향족 환을 의미한다. 아릴의 예로는 페닐, 나프틸 등이 포함된다."Aryl" means a mono- or bicyclic aromatic ring containing only carbon atoms. Examples of aryl include phenyl, naphthyl and the like.

"헤테로아릴"은 각각의 환이 5 내지 6개의 원자를 함유하는, N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 함유하는 모노- 또는 비사이클릭 방향족 환을 의미한다. 헤테로아릴의 예로는 피롤릴, 이속사졸릴, 이소티아졸릴, 피라졸릴, 피리딜, 옥사졸릴, 옥사디아졸릴, 티아디아졸릴, 티아졸릴, 이미다졸릴, 트리아졸릴, 테트라졸릴, 푸라닐, 트리아지닐, 티에닐, 피리미딜, 피리다지닐, 피라지닐, 벤족사졸릴, 벤조티아졸릴, 벤즈이미다졸릴, 벤조푸라닐, 벤조티오페닐, 푸로(2,3-b)피리딜, 퀴놀릴, 인돌릴, 이소퀴놀릴, 이미다조티아졸릴 등이 포함된다. 특히, "헤테로아릴"로는 피리딜, 피리미딜 및 티오페닐이 포함된다. 헤테로아릴 환은 하나 이상의 탄소 또는 질소 원자에서 치환될 수 있다. "Heteroaryl" means a mono- or bicyclic aromatic ring containing one or more heteroatoms selected from N, O and S, each ring containing 5-6 atoms. Examples of heteroaryls include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxdiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, tria Genyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo (2,3-b) pyridyl, quinolyl, Indolyl, isoquinolyl, imidazothiazolyl and the like. In particular, "heteroaryl" includes pyridyl, pyrimidyl and thiophenyl. Heteroaryl rings may be substituted at one or more carbon or nitrogen atoms.

"사이클로헤테로알킬"은 각각의 환이 부착점이 탄소 또는 질소일 수 있는 3 내지 10개의 원자를 함유하는, N, S 및 O로부터 선택되는 하나 이상의 헤테로원자를 함유하는 모노- 또는 비사이클릭 또는 브릿지된 포화 환을 의미한다. 상기 용어는 또한 부착점이 비방향족 부분에 위치하는 아릴 또는 헤테로아릴 그룹에 융합된 모노사이클릭 헤테로사이클을 포함한다. "사이클로헤테로알킬"의 예로는 인돌릴, 아자인돌릴 등이 포함된다. 사이클로헤테로알킬 환은 환 탄소 및/또는 환 질소에서 치환될 수 있다."Cycloheteroalkyl" is a mono- or bicyclic or bridged ring containing one or more heteroatoms selected from N, S and O, each ring containing 3 to 10 atoms where the point of attachment may be carbon or nitrogen It means a saturated ring. The term also encompasses monocyclic heterocycles fused to aryl or heteroaryl groups where the point of attachment is located in the nonaromatic moiety. Examples of "cycloheteroalkyl" include indolyl, azaindoleyl, and the like. Cycloheteroalkyl rings may be substituted at the ring carbon and / or ring nitrogen.

"할로겐"은 불소, 염소, 브롬 및 요오드를 포함한다."Halogen" includes fluorine, chlorine, bromine and iodine.

임의의 성분 또는 화학식 I에서 1회 이상 임의의 변수(예: R1, Rd 등)가 발생하는 경우, 각 경우에서의 이의 정의는 매번 다른 경우에서의 이의 정의와 독립적이다. 또한, 치환체 및/또는 변수의 조합은 이러한 조합이 적합한 화합물을 초래하는 경우에만 허용될 수 있다.If any component or any variable occurs more than one time in formula (eg R 1 , R d, etc.), its definition in each case is independent of its definition in each other case. In addition, combinations of substituents and / or variables may be acceptable only if such combinations result in suitable compounds.

본 명세서 전반에 걸쳐 사용되는 표준 명명법하에, 지정된 측쇄의 말단 부분이 가장 먼저 기재되며 이어서 부착점에 가까운 인접 작용기가 기재된다. 예를 들어, C1-5 알킬카보닐아미노 C1-6 알킬 치환체는 과 동등하다.Under standard nomenclature used throughout this specification, the terminal portion of the designated side chain is described first, followed by adjacent functional groups close to the point of attachment. For example, C 1-5 alkylcarbonylamino C 1-6 alkyl substituents Is equivalent to

본 발명의 화합물을 선택하는데 있어, 당해 분야의 숙련가는 다양한 치환체, 즉 R1, R2 등이 화학적 구조 연관성 및 안정성의 익히 공지된 원리와 부합되게 선택됨을 인지할 것이다.In selecting compounds of the present invention, one skilled in the art will recognize that various substituents, ie, R 1 , R 2, etc., are selected in accordance with well known principles of chemical structural association and stability.

"치환된"이란 용어는 명명된 치환체에 의한 치환의 다중 정도를 포함하는 것으로 간주될 것이다. 다수의 치환체 잔기가 기재되거나 청구되는 경우, 치환된 화합물은 기재되거나 청구된 하나 이상의 치환체 잔기에 의해 단독으로 또는 여러개가 독립적으로 치환될 수 있다. 독립적으로 치환된이란, (2개 이상의) 치환체가 동일하거나 상이할 수 있음을 의미한다.The term "substituted" will be considered to encompass multiple degrees of substitution by the named substituents. When multiple substituent residues are described or claimed, the substituted compounds may be substituted alone or several independently by one or more substituent residues described or claimed. Independently substituted means that two or more substituents may be the same or different.

화학식 I의 화합물은 하나 이상의 비대칭 중심을 함유할 수 있으며, 따라서 라세미체 또는 라세미 혼합물, 단일 에난티오머, 부분입체이성체 혼합물 및 개개의 부분입체이성체로서 발생할 수 있다. 본 발명은 이러한 화학식 I의 화합물의 이성체 형태를 모두 포함한다.Compounds of formula (I) may contain one or more asymmetric centers and may therefore arise as racemates or racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention includes all such isomeric forms of the compounds of formula (I).

본원에서 기술하는 화합물의 일부는 올레핀 이중 결합을 함유하며, 달리 언급하지 않는 한, E 및 Z 기하이성체 둘다를 포함한다.Some of the compounds described herein contain olefinic double bonds and include both E and Z geometric isomers, unless stated otherwise.

호변이성체는 화합물의 하나의 원자로부터 이 화합물의 다른 원자로 신속하게 양자가 이동되는 화합물로서 정의된다. 본원에서 기술하는 화합물의 일부는 상이한 수소 부착점을 갖는 호변이성체로서 존재할 수 있다. 이러한 예는 케토-엔올 호변이성체로서 공지된 케톤 및 이의 엔올 형태일 수 있다. 개개의 호변이성체뿐만 아니라 이의 혼합물도 화학식 I의 화합물에 포함된다.Tautomers are defined as compounds in which protons are rapidly transferred from one atom of a compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different hydrogen attachment points. Such examples may be in the form of ketones and their enols known as keto-enol tautomers. Individual tautomers as well as mixtures thereof are included in the compounds of formula (I).

화학식 I의 화합물은 예를 들어, 적합한 용매, 예를 들어, MeOH 또는 EtOAc 또는 이들의 혼합물로부터 분별 결정화시킴으로써 에난티오머의 부분입체이성체 쌍으로 분리시킬 수 있다. 이렇게 수득된 에난티오머 쌍은 통상의 수단, 예를 들어, 분해제로서 광학 활성 아민을 사용하거나 키랄 HPLC 컬럼을 사용함으로써 개개의 입체이성체로서 분리시킬 수 있다.Compounds of formula (I) can be separated into diastereomeric pairs of enantiomers, for example by fractional crystallization from a suitable solvent such as MeOH or EtOAc or mixtures thereof. The enantiomeric pairs thus obtained can be separated as individual stereoisomers by conventional means, for example, using optically active amines as disintegrating agents or by using chiral HPLC columns.

대안으로, 화학식 I의 화합물의 에난티오머는 광학적으로 순수한 출발 물질 또는 공지된 배위의 시약을 사용한 입체특이적 합성에 의해 수득할 수 있다.Alternatively, enantiomers of compounds of formula (I) can be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

본 발명의 화합물을 에난티오머적으로 순수한 제형으로 투여하는 것이 일반적으로 바람직하다. 라세미 혼합물은 다수의 통상의 방법중 어떠한 방법으로도 이의 개개의 에난티오머로 분리시킬 수 있다. 이러한 방법으로는 키랄 크로마토그래피, 키랄 보조제를 이용한 유도체화 후의 크로마토그래피 또는 결정화에 의한 분리 및 부분입체이성체 염의 분별 결정화가 포함된다.It is generally preferred to administer the compounds of the invention in enantiomerically pure formulations. The racemic mixture can be separated into its individual enantiomers by any of a number of conventional methods. Such methods include chiral chromatography, separation after derivatization with chiral auxiliaries or separation by crystallization and fractional crystallization of diastereomeric salts.

추가로, 본 발명의 화합물에 대한 결정 형태의 일부는 다형체로서 존재할 수 있으며 그 자체로 본 발명에 포함된다. 또한, 본 발명의 화합물의 일부는 물 또는 통상의 유기 용매와의 용매화물을 형성할 수 있다. 이러한 용매화물은 본 발명의 범주에 포함된다.In addition, some of the crystalline forms for the compounds of the present invention may exist as polymorphs and are themselves included in the present invention. In addition, some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates fall within the scope of the present invention.

"약제학적으로 허용되는 염"이란 용어는 무기 또는 유기 염기 및 무기 또는 유기 산을 포함하는 약제학적으로 허용되는 비독성 염기 또는 산으로부터 생성된 염을 의미한다. 무기 염기로부터 유도된 염으로는 알루미늄, 암모늄, 칼슘, 구리, 제2철, 제1철, 리튬, 마그네슘, 3가 망간 염, 2가 망간, 칼륨, 나트륨, 아연 등이 포함된다. 암모늄, 칼슘, 마그네슘, 칼륨 및 나트륨 염이 특히 바람직하다. 약제학적으로 허용되는 유기 비독성 염기로부터 유도된 염으로는 1급, 2급 및 3급 아민, 천연의 치환된 아민을 포함하는 치환된 아민, 사이클릭 아민 및 염기성 이온 교환 수지, 예를 들어, 아르기닌, 베타인, 카페인, 콜린, N,N'-디벤질에틸렌디아민, 디에틸아민, 2-디에틸아미노에탄올, 2-디메틸아미노에탄올, 에탄올아민, 에틸렌디아민, N-에틸-모르폴린, N-에틸피페리딘, 글루카민, 글루코사민, 히스티딘, 하이드라바민, 이소프로필아민, 라이신, 메틸글루카민, 모르폴린, 피페라진, 피페리딘, 폴리아민 수지, 프로카인, 푸린, 테오브로민, 트리에틸아민, 트리메틸아민, 트리프로필아민, 트로메타민 등이 포함된다. "약제학적으로 허용되는 염"이란 용어는 또한 용해도 또는 가수분해 특성을 개질시키기 위한 투여 형태로서 사용될 수 있거나 서방출 또는 프로드럭 제형에서 사용될 수 있는 아세테이트, 락토비오네이트, 벤젠설포네이트, 라우레이트, 벤조에이트, 말레이트, 비카보네이트, 말레에이트, 비설페이트, 만델레이트, 비타르트레이트, 메실레이트, 보레이트, 메틸브로마이드, 브로마이드, 메틸니트레이트, 칼슘 에데테이트, 메틸설페이트, 캄실레이트, 무케이트, 카보네이트, 나프실레이트, 클로라이드, 니트레이트, 클라불라네이트, N-메틸글루카민, 시트레이트, 암모늄 염, 디하이드로클로라이드, 올레이트, 에데테이트, 옥살레이트, 에디실레이트, 파모에이트(엠보네이트), 에스톨레이트, 팔미테이트, 에실레이트, 판토테네이트, 푸마레이트, 포스페이트/디포스페이트, 글루셉테이트, 폴리갈락투로네이트, 글루코네이트, 살리실레이트, 글루타메이트, 스테아레이트, 글리콜리아르사닐레이트, 설페이트, 헥실레소르시네이트, 수바케테이트, 하이드라바민, 석시네이트, 하이드로브로마이드, 탄네이트, 하이드로클로라이드, 타르트레이트, 하이드록시나프토에이트, 테오클레이트, 요오다이드, 토실레이트, 이소티오네이트, 트리에티오다이드, 락테이트, 파노에이트, 발레레이트 등과 같은 모든 허용되는 염을 포함한다.The term "pharmaceutically acceptable salts" means salts formed from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, trivalent manganese salts, divalent manganese, potassium, sodium, zinc and the like. Particular preference is given to ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins such as Arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N Ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine , Trimethylamine, tripropylamine, tromethamine, and the like. The term "pharmaceutically acceptable salts" may also be used as dosage forms to modify solubility or hydrolysis properties or used in slow release or prodrug formulations such as acetates, lactobionates, benzenesulfonates, laurates, Benzoate, Maleate, Bicarbonate, Maleate, Bisulfate, Mandelate, Bitartrate, Mesylate, Borate, Methylbromide, Bromide, Methylnitrate, Calcium Edetate, Methylsulfate, Camsylate, Mucate, Carbonate , Naphsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), Estolate, palmitate, ecylate, pantothenate, fumarate, phosphate / di Phosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycolarisananilate, sulfate, hexylsorbinate, subbakate, hydrabamine, succinate, All such as hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, theoclate, iodide, tosylate, isothionate, triethoxide, lactate, phanoate, valerate, etc. And acceptable salts.

본원에서 사용되는 바와 같이, 화학식 I의 화합물에 대한 인용은 약제학적으로 허용되는 염을 또한 포함하는 것으로 이해된다. As used herein, reference to a compound of Formula (I) is understood to also include pharmaceutically acceptable salts.

본 발명의 화합물은 CB1 수용체의 조절제이다. 특히, 화학식 I의 화합물은 CB1 수용체의 길항제 또는 역 효능제이다.Compounds of the invention are modulators of the CB1 receptor. In particular, the compounds of formula (I) are antagonists or inverse agonists of the CB1 receptor.

"효능제"는 수용체에 결합하여 수용체의 입체형태적 변화를 유도하고, 이어서 상기 수용체에 대한 생리학적으로 관련되는 효능제 리간드(들)에 의해 유도되는 것과 유사한 수축, 이완, 분비, 효소 활성의 변화와 같은 반응을 생성시키는 화합물(호르몬, 신경전달물질 또는 합성 화합물)이다. "길항제"는 효능제의 효과를 감쇠시키는 화합물이다. "역 효능제"는 수용체에서 작용하지만 특정 수용체의 효능제에 의해 생성되는 효과와 상반되는 효과를 생성시키는 화합물이다.An “agonist” binds to a receptor and induces a conformational change in the receptor, followed by a similar contraction, relaxation, secretion, enzymatic activity of that induced by the physiologically relevant agonist ligand (s) for that receptor. A compound (hormone, neurotransmitter or synthetic compound) that produces a response, such as a change. An “antagonist” is a compound that attenuates the effect of an agonist. A "reverse agonist" is a compound that acts on a receptor but produces an effect that is contrary to the effect produced by the agonist of a particular receptor.

본 발명의 화합물은 CB1 수용체의 조절제이며, 그 자체로 정신병, 기억력 결핍, 인지 장애, 편두통, 신경병증, 다발성 경화증 및 길리안-베르 증후군 및 바이러스성 뇌염, 뇌혈관장애 및 두부 손상의 염증 후유증을 포함하는 신경-염증 질환, 불안장애, 스트레스, 간질, 파킨슨 질환, 운동 장애 및 정신분열증의 치료시에 중추신경 작용 약물로서 유용하다. 당해 화합물은 특히 아편제, 알콜, 마리화나 및 니코틴에 대한 물질 남용 장애의 치료용으로 또한 유용하다. 당해 화합물은 또한 과도한 음식 섭취 및 이로 인한 비만 및 이와 관련된 합병증을 억제함으로써 식이 장애를 치료하기 위해 유용하다. 당해 화합물은 변비 및 만성 가성 장폐쇄증의 치료용으로 유용하다. 당해 화합물은 또한 간 경화증의 치료용으로 유용하다. 당해 화합물은 천식의 치료용으로도 유용하다.Compounds of the present invention are modulators of the CB1 receptor and in themselves include psychosis, memory deficiency, cognitive impairment, migraine, neuropathy, multiple sclerosis and Gillian-Ber syndrome and viral encephalitis, cerebrovascular disorders and inflammatory sequelae of head injury It is useful as a CNS drug in the treatment of neuro-inflammatory diseases, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders and schizophrenia. The compounds are also particularly useful for the treatment of substance abuse disorders against opiates, alcohols, marijuana and nicotine. The compounds are also useful for treating eating disorders by inhibiting excessive food intake and the resulting obesity and associated complications. The compounds are useful for the treatment of constipation and chronic pseudointestinal obstruction. The compounds are also useful for the treatment of cirrhosis of the liver. The compounds are also useful for the treatment of asthma.

화합물의 "투여" 및/또는 화합물을 "투여하다"란 용어는 본 발명의 화합물 또는 본 발명의 화합물의 프로드럭을 치료를 필요로 하는 개체에게 제공함을 의미하는 것으로 이해되어야 한다.The term "administering" a compound and / or "administering a compound" should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to an individual in need thereof.

본 발명의 치료방법을 실시하기 위한 화학식 I의 화합물의 투여는 유효량의 화학식 I의 화합물을 이러한 치료 또는 예방을 필요로 하는 환자에게 투여함으로써 수행한다. 본 발명의 방법에 따른 예방적 투여의 필요성은 익히 공지된 위험 요소의 사용을 통해 측정된다. 개개 화합물의 유효량은 최종 분석시에 담당 주치의에 의해 결정되지만, 치료하고자 하는 정확한 질환, 질환의 중증도 및 환자가 앓는 기타 질환이나 상태, 선택된 투여 경로, 환자가 동시에 필요로 할 수 있는 기타 약물과 치료 및 주치의의 판단에서의 기타 요인에 따라 좌우된다.Administration of a compound of formula (I) for practicing the method of treatment of the invention is carried out by administering an effective amount of a compound of formula (I) to a patient in need of such treatment or prevention. The need for prophylactic administration according to the method of the invention is measured through the use of well-known risk factors. The effective amount of an individual compound is determined by the attending physician at the time of the final analysis, but the exact disease to be treated, the severity of the disease and other diseases or conditions the patient suffers from, the route of administration chosen and other drugs and treatments that the patient may need simultaneously. And other factors in the judgment of the attending physician.

이러한 질환 또는 장애에서의 본 발명의 화합물의 용도는 문헌에 보고된 바 있는 동물 질환 모델에서 입증될 수 있다. 다음은 이러한 동물 질환 모델의 예이다: (a) 랫트에서 음식 섭취의 억제 및 이로 인한 체중 손실[참조; Life Sciences 1998, 63, 113-117]; b) 마모셋에서 단 음식 섭취의 감소[참조: Behavioural Pharm. 1998, 9, 179-181]; c) 마우스에서 슈크로즈와 에탄올 섭취의 감소[참조: Psychopharm. 1997, 132, 104-106]; d) 랫트에서 증가된 운동 활성 및 위치 조건화[참조: Psychopharm. 1998, 135, 324-332; Psychopharmacol 2000, 151:25-30]; e) 마우스에서 자발 운동 활성[참조: J. Pharm. Exp. Ther. 1996, 277, 586-594]; f) 마우스에서 아편제 자가 투여의 감소[참조: Sci. 1999, 283, 401-404]; g) 천식의 다양한 상태에 대한 모델로서 양과 기니아 피그에서의 기관지 과민반응[참조: W. M. Abraham et al., "α4-Integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep. "J. Clin. Invest. 93, 776(1993) and A. A. Y. Milne and P. P. Piper, "Role of VLA-4 integrin in leucocyte recruitment and bronchial hyperresponsiveness in the gunea-pig. "Eur. J. Pharmacol., 282,243(1995)]; h) 사염화탄소에 의해 유도된 진행성 간경변에서의 혈관확장된 상태의 매개[참조: Nature Medicine, 2001, 7(7), 827-832]; i) 완하제의 배출에 유리한 시아노몰구스 원숭이에서의 아미트리프틸린-유도된 변비[참조: Biol. Pharm. Bulletin(Japan), 2000,23(5), 657-9]; j) 소아의 만성 가성 장폐쇄증의 신경병증 및 소아의 만성 가성 장폐쇄증의 신경병증과 관련된 동물 모델[참조: Journal of Pathology(England), 2001,194(3), 277-88].The use of the compounds of the present invention in such diseases or disorders can be demonstrated in animal disease models as reported in the literature. The following are examples of such animal disease models: (a) suppressing food intake and resulting weight loss in rats [see; Life Sciences 1998, 63, 113-117; b) reduction of sweet food intake from marmosets [Behavioural Pharm. 1998, 9, 179-181; c) reduction of sucrose and ethanol intake in mice [Psychopharm. 1997, 132, 104-106; d) Increased motor activity and location conditioning in rats [Psychopharm. 1998, 135, 324-332; Psychopharmacol 2000, 151: 25-30; e) spontaneous motor activity in mice [J. Pharm. Exp. Ther. 1996, 277, 586-594; f) reduction of opiate self-administration in mice [Sci. 1999, 283, 401-404; g) Bronchial hypersensitivity in sheep and guinea pigs as a model for various conditions of asthma [WM Abraham et al., "α 4 -Integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep." Clin. Invest. 93, 776 (1993) and AAY Milne and PP Piper, "Role of VLA-4 integrin in leucocyte recruitment and bronchial hyperresponsiveness in the gunea-pig." Eur. J. Pharmacol., 282, 243 (1995); h) mediation of vasodilated conditions in progressive cirrhosis induced by carbon tetrachloride (Nature Medicine, 2001, 7 (7), 827-832); i) Amitriftylin-induced constipation in cyanomolgus monkeys favoring the release of laxatives [Biol. Pharm. Bulletin (Japan), 2000, 23 (5), 657-9; j) Animal models associated with neuropathy of chronic pseudointestinal obstruction in children and neuropathy of chronic pseudointestinal obstruction in children (Journal of Pathology (England), 2001,194 (3), 277-88).

물론, 화학식 I의 화합물의 예방학적 또는 치료학적 용량의 정도는 치료하고자 하는 상태의 중증도와 성질 및 화학식 I의 특정 화합물과 이의 투여 경로에 따라 달라질 수 있다. 이는 또한 개개 환자의 연령, 체중 및 반응성에 따라 달라질 수도 있다. 일반적으로, 1일 투여량 범위는 단일 또는 분할된 투여량으로서 포유동물의 체중 kg당 약 0.001mg 내지 약 100mg, 바람직하게는 kg당 0.01mg 내지 약 50mg이며, 가장 바람직하게는 kg당 0.1 내지 10mg의 범위이다. 반면에, 일부 경우에서는 상기한 범위 이외의 투여량을 사용하는 것이 필수적일 수 있다.Of course, the degree of prophylactic or therapeutic dose of a compound of formula (I) may vary depending on the severity and nature of the condition to be treated and the particular compound of formula (I) and its route of administration. It may also depend on the age, weight and responsiveness of the individual patient. In general, the daily dosage range is from about 0.001 mg to about 100 mg per kg body weight of the mammal, in single or divided doses, preferably from 0.01 mg to about 50 mg per kg, most preferably 0.1 to 10 mg per kg Range. On the other hand, in some cases it may be necessary to use doses other than those described above.

정맥내 투여용 조성물이 사용되는 용도의 경우, 적합한 투여량 범위는 1일마다 체중 kg당 화학식 I의 화합물 약 0.001mg 내지 약 25mg(바람직하게는 0.01mg 내지 약 1mg)이며, 예방적 용도의 경우에는 1일마다 체중 kg당 화학식 I의 화합물 약 0.1mg 내지 약 100mg(바람직하게는 약 1mg 내지 약 100mg 및 보다 바람직하게는 약 1mg 내지 약 10mg)이다.For uses in which the composition for intravenous administration is used, a suitable dosage range is from about 0.001 mg to about 25 mg (preferably 0.01 mg to about 1 mg) of the compound of formula I per kg body weight per day, for prophylactic use. And about 0.1 mg to about 100 mg (preferably about 1 mg to about 100 mg and more preferably about 1 mg to about 10 mg) of the compound of formula (I) per kg body weight per day.

경구 조성물이 사용되는 경우, 적합한 투여량 범위는 예를 들어, 1일마다 화학식 I의 화합물 약 0.01mg 내지 약 1000mg, 바람직하게는 1일마다 약 0.1mg 내지 약 10mg이다. 경구 투여의 경우, 조성물은 치료될 환자에게 증상 조정을 위한 활성 성분 0.01 내지 1,000mg, 바람직하게는 0.01, 0.05, 0.1, 0.5, 1, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 100, 250, 500, 750 또는 1000mg을 함유하는 정제로서 제공되는 것이 바람직하다.When an oral composition is used, a suitable dosage range is, for example, about 0.01 mg to about 1000 mg of the compound of formula I per day, preferably about 0.1 mg to about 10 mg per day. In the case of oral administration, the composition comprises 0.01 to 1,000 mg of active ingredient for controlling symptoms, preferably 0.01, 0.05, 0.1, 0.5, 1, 2.5, 5, 10, 15, 20, 25, 30, 40 to the patient to be treated. It is preferably provided as a tablet containing 50, 100, 250, 500, 750 or 1000 mg.

본 발명의 또 다른 양상은 화학식 I의 화합물과 약제학적으로 허용되는 담체를 포함하는 약제학적 조성물을 제공한다. 약제학적 조성물에서와 같이 "조성물"이란 용어는 활성 성분(들) 및 담체를 구성하는 불활성 성분(들)(약제학적으로 허용되는 부형제)를 포함하는 생성물뿐만 아니라 임의의 2개 이상의 성분들의 배합, 복합 또는 응집으로부터 또는 하나 이상의 성분의 해리로부터 또는 하나 이상의 성분의 다른 종류의 반응 또는 상호작용으로부터 초래되는 임의의 생성물을 포함한다. 따라서, 본 발명의 약제학적 조성물은 화학식 I의 화합물, 추가의 활성 성분(들)과 약제학적으로 허용되는 담체들을 혼합하여 제조되는 모든 조성물을 포함한다.Another aspect of the invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. As in pharmaceutical compositions, the term "composition" refers to a combination of any two or more components, as well as products comprising the active ingredient (s) and inert ingredient (s) (pharmaceutically acceptable excipients) that make up the carrier, Any product resulting from complex or aggregation or from dissociation of one or more components or from other kinds of reactions or interactions of one or more components. Accordingly, the pharmaceutical compositions of the present invention include all compositions prepared by admixing a compound of formula (I), additional active ingredient (s), and a pharmaceutically acceptable carrier.

포유동물, 특히 사람에게 유효량의 본 발명의 화합물을 제공하기 위해 어떠한 적합한 투여 경로라도 사용할 수 있다. 예를 들어, 경구, 직장, 국소, 비경구, 안구, 폐 및 비내 투여 등을 사용할 수 있다. 투여 형태로는 정제, 트로키제, 분산제, 현탁제, 용제, 캡슐제, 크림제, 연고제, 에어로졸 등이 포함된다. Any suitable route of administration may be used to provide an effective amount of a compound of the invention to a mammal, especially a human. For example, oral, rectal, topical, parenteral, ocular, pulmonary and intranasal administration can be used. Dosage forms include tablets, troches, dispersants, suspensions, solvents, capsules, creams, ointments, aerosols, and the like.

본 발명의 약제학적 조성물은 활성 성분으로서 화학식 I의 화합물 또는 약제학적으로 허용되는 이의 염을 포함하며 약제학적으로 허용되는 담체와 임의로 기타 치료학적 성분을 함유할 수도 있다. "약제학적으로 허용되는"이란, 담체, 희석제 또는 부형제가 제형의 기타 성분과 혼화성이어서 이의 수용자에게 해롭지않아야 함을 의미한다. 특히, "약제학적으로 허용되는 염"이란 용어는 무기 염기 또는 산 및 유기 염기 또는 산을 포함하는 약제학적 비독성 염기 또는 산으로부터 생성된 염을 의미한다.The pharmaceutical compositions of the present invention comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient and may contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. “Pharmaceutically acceptable” means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not be harmful to its recipient. In particular, the term “pharmaceutically acceptable salts” means salts formed from pharmaceutically nontoxic bases or acids, including inorganic bases or acids and organic bases or acids.

임의의 경우에서 가장 적합한 경로가 치료되는 상태의 성질과 중증도 및 활성 성분의 성질에 따라 좌우될 수 있다 해도, 조성물은 경구, 직장, 국소, 비경구(피하, 근육내 및 정맥내를 포함), 안구(눈), 폐(에어로졸 흡입) 또는 비내 투여에 적합한 조성물을 포함한다. 조성물은 편의상 단위 투여 형태로 존재하며 약학 분야에 익히 공지된 임의의 방법을 사용하여 제조한다.In any case, the composition may be oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), although the most suitable route may depend on the nature and severity of the condition being treated and the nature of the active ingredient, Compositions suitable for ocular (eye), pulmonary (aerosol inhalation) or intranasal administration. The composition is conveniently presented in unit dosage form and prepared using any method well known in the art of pharmacy.

흡입에 의한 투여의 경우, 본 발명의 조성물은 편의상 가압된 팩 또는 분무기로부터의 에어로졸 스프레이 형태로 전잘된다. 화합물은 제형화될수 있는 분말로서 전달될 수도 있으며 분말 조성물은 흡입 분말 흡입 장치를 보조로 하여 흡입될 수 있다. 흡입에 바람직한 전달 시스템은 탄화불소 또는 탄화수소와 같은 적합한 추진제 중의 화학식 I의 화합물의 현탁액 또는 용액으로서 제형화될 수 있는 무수 분말 계량된 용량 흡입(metered dose inhalation; MDI) 에어로졸 및 추가의 부형제와 함께 또는 추가의 부형제 없이 화학식 I의 화합물의 무수 분말로서 제형화될 수 있는 무수 분말 흡입(DPI) 에어로졸이다. For administration by inhalation, the compositions of the present invention are conveniently prepared in the form of aerosol sprays from pressurized packs or nebulizers for convenience. The compound may be delivered as a powder that can be formulated and the powder composition may be inhaled with the aid of an inhaled powder inhalation device. Preferred delivery systems for inhalation are anhydrous powder metered dose inhalation (MDI) aerosols and additional excipients which may be formulated as a suspension or solution of a compound of formula (I) in a suitable propellant such as fluorocarbon or hydrocarbons. Anhydrous powder inhalation (DPI) aerosol that can be formulated as anhydrous powder of the compound of formula (I) without additional excipients.

화학식 I의 화합물의 적합한 국소 제형으로는 경피 장치, 에어로졸, 크림제, 용제, 연고제, 겔제, 로션제, 산포용 산제 등이 포함된다. 본 발명의 화합물을 함유하는 국소 약제학적 조성물은 통상적으로 약제학적으로 허용되는 비히클과 혼합된 활성 화합물 약 0.005중량% 내지 5중량%를 포함한다. 본 발명의 화합물을 투여하기에 유용한 경피 패치로는 당해 분야의 숙련가에게 익히 공지된 패치들이 포함된다. 경피 전달 시스템의 형태로 투여하기 위해, 투여량 투여는 물론 투여량 섭생 전반에 걸쳐 간헐적이기 보다는 연속적일 것이다.Suitable topical formulations of compounds of formula (I) include transdermal devices, aerosols, creams, solvents, ointments, gels, lotions, dispersants, and the like. Topical pharmaceutical compositions containing a compound of the present invention typically comprise from about 0.005% to 5% by weight of the active compound in admixture with a pharmaceutically acceptable vehicle. Transdermal patches useful for administering a compound of the present invention include patches well known to those skilled in the art. For administration in the form of a transdermal delivery system, dosage administration will of course be continuous rather than intermittent throughout the dosage regimen.

실제 사용시, 화학식 I의 화합물은 통상의 약제학적 합성 기술에 따라 약제학적 담체와 친밀하게 혼합된 활성 성분으로서 배합할 수 있다. 담체는 투여에 바람직한 제제 형태, 예를 들어, 경구 또는 비경구(정맥내 포함) 형태에 따라 매우 다양한 형태를 취할 수 있다. 경구 투여 형태의 조성물의 제조시, 예를 들어, 현탁제, 엘릭서제 및 용제와 같은 경구 액체 제제의 경우에는 물, 글리콜, 오일, 알콜, 풍미제, 방부제, 착색제 등; 또는 예를 들어, 산제, 캡슐제 및 정제와 같은 경구 고체 제제의 경우에는 전분, 당, 미정질 셀룰로즈, 희석제, 과립화제, 윤활제, 결합제, 붕해제 등과 같은 임의의 통상적 약제학적 매질을 사용할 수 있으며, 고체 경구 제제가 액체 제제보다 바람직하다. 투여 용이성 때문에, 고체 약제학적 담체가 명백히 사용되는 경우에는 정제 및 캡슐제가 대표적인 가장 유리한 경구 투여 단위 형태가 된다. 경우에 따라, 정제는 표준 수성 또는 비수성 기술로 피복시킬 수 있다.In practical use, the compounds of formula (I) can be formulated as active ingredients intimately mixed with pharmaceutical carriers according to conventional pharmaceutical synthesis techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, eg, oral or parenteral (including intravenous). In the preparation of compositions in oral dosage form, for example, oral liquid preparations such as suspending agents, elixirs and solvents, water, glycols, oils, alcohols, flavors, preservatives, colorants and the like; Or any conventional pharmaceutical medium such as starch, sugar, microcrystalline cellulose, diluent, granulating agent, lubricant, binder, disintegrant, etc., for example, in the case of oral solid preparations such as powders, capsules and tablets. Solid oral formulations are preferred over liquid formulations. Because of their ease of administration, where solid pharmaceutical carriers are explicitly used, tablets and capsules are representative of the most advantageous oral dosage unit forms. If desired, tablets may be coated by standard aqueous or non-aqueous techniques.

경구 투여에 적합한 본 발명의 약제학적 조성물은 각각 예정된 양의 활성 성분을 함유하는 캡슐제(지효성 및 서방성 제형을 포함), 환제, 샤세제, 산제, 입제 또는 정제와 같은 분할된 단위로서, 분말 또는 과립으로서 또는 엘릭서제, 팅크제, 용제, 현탁제, 시럽제 및 유제를 포함하는 수성 액체, 비수성 액체, 수중유 에멀젼 또는 유중수 액체 에멀전 중의 용액 또는 현탁액으로서 존재할 수 있다. 이러한 조성물은 어떠한 약제학 방법으로도 제조할 수 있지만, 모든 방법은 활성 성분이 하나 이상의 필수 성분을 구성하는 담체와 혼합되도록 하는 단계를 포함한다. 일반적으로, 조성물은 활성성분을 액체 담체 또는 미분된 고체 담체 또는 이들 둘다와 균일하고 친밀하게 혼합한 다음, 필요에 따라 생성물을 목적하는 형태로 성형함으로써 제조한다. 예를 들어, 정제는 임의로 하나 이상의 보조 성분과 함께 압착 또는 성형함으로써 제조할 수 있다. 압착된 정제는 적합한 기계내에서, 임의로 결합제, 윤활제, 불활성 희석제, 표면활성제 또는 분산제와 혼합된 분말 또는 과립과 같은 자유 유동성 형태인 활성 성분를 압착시켜 제조할 수 있다. 성형된 정제는 적합한 기계내에서, 불활성 액체 희석제로 습윤화된 분말화된 화합물의 혼합물을 성형하여 제조할 수 있다. 바람직하게는, 각각의 정제는 투여량을 증상에 따라 치료하고자 하는 환자에 맞게 조절하기 위해 활성 성분 0.01 내지 1,000mg, 특히 0.01, 0.05, 0.1, 0.5, 1, 2.5, 3, 5, 6, 10, 15, 25, 50, 75, 100, 125, 150, 175, 180, 200, 225, 500, 750 및 1,000mg을 함유하며, 각각의 샤세제 또는 캡슐제는 투여량을 증상에 따라 치료하고자 하는 환자에 맞게 조절하기 위해 활성 성분 0.01 내지 1,000mg, 특히 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 3, 5, 6, 10, 15, 25, 50, 75, 100, 125, 150, 175, 180, 200, 225, 500, 750 및 1,000mg을 함유한다. Pharmaceutical compositions of the invention suitable for oral administration are divided units, such as capsules (including sustained release and sustained release formulations), pills, cachets, powders, granules or tablets, each containing a predetermined amount of the active ingredient, Or as a solution or suspension in an aqueous liquid, non-aqueous liquid, oil-in-water emulsion or water-in-oil liquid emulsion, including granules or elixirs, tinctures, solvents, suspensions, syrups and emulsions. Such compositions may be prepared by any pharmaceutical method, but all methods include the step of bringing the active ingredient into admixture with the carrier which constitutes one or more essential ingredients. Generally, the compositions are prepared by mixing the active ingredient uniformly and intimately with a liquid carrier or finely divided solid carrier or both, and then molding the product into the desired form, if desired. For example, tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in free flowing form, such as powders or granules, mixed with a binder, lubricant, inert diluent, surfactant or dispersant. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Preferably, each tablet contains 0.01 to 1,000 mg of active ingredient, in particular 0.01, 0.05, 0.1, 0.5, 1, 2.5, 3, 5, 6, 10, in order to adjust the dosage to the patient to be treated symptomatically. , 15, 25, 50, 75, 100, 125, 150, 175, 180, 200, 225, 500, 750 and 1,000 mg, each sachet or capsule is intended to treat the dosage depending on the condition 0.01 to 1,000 mg of active ingredient, in particular 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 3, 5, 6, 10, 15, 25, 50, 75, 100, 125, 150, 175, It contains 180, 200, 225, 500, 750 and 1,000 mg.

본 발명의 화합물의 추가의 적합한 투여 수단은 주사, 정맥내 거환 또는 주입, 복강내, 피하, 근육내 및 폐색을 동반하거나 동반하지 않는 국소 투여를 포함한다.Further suitable means of administration of the compounds of the invention include topical administration with or without injection, intravenous bolus or infusion, intraperitoneal, subcutaneous, intramuscular and obstructive.

본 발명은 상기한 임의의 화합물과 약제학적으로 허용되는 담체를 포함하는 조성물로 예시된다. 또한, 본 발명은 상기한 임의의 화합물과 약제학적으로 허용되는 담체를 배합함으로써 제조된 약제학적 조성물로 예시된다. 본 발명의 실례는 상기한 임의의 화합물과 약제학적으로 허용되는 담체를 배합함을 포함하는, 약제학적 조성물의 제조방법이다.The present invention is exemplified by a composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. The present invention is also exemplified by pharmaceutical compositions prepared by combining any of the compounds described above with a pharmaceutically acceptable carrier. An example of the present invention is a method of making a pharmaceutical composition comprising combining any of the compounds described above with a pharmaceutically acceptable carrier.

투여량을 단일 1일 투여량으로서 투여할 수 있거나 전체 1일 투여량을 1일 2회, 3회 또는 4회의 분할된 투여량으로서 투여할 수 있다. 또한, 투여용으로 선택된 개개 화합물의 특성에 기초하여, 투여량을 덜 빈번하게, 예를 들어, 주 1회, 주 2회, 매월 1회 등으로 투여할 수 있다. 단위 투여량은 물론 보다 덜 빈번한 투여에 맞게 보다 다량일 수 있다.The dosage may be administered as a single daily dose or the total daily dosage may be administered as divided doses twice, three or four times daily. In addition, based on the nature of the individual compound selected for administration, the dosage may be administered less frequently, for example, once a week, twice a week, once a month, or the like. The unit dose may of course be higher in order to accommodate less frequent administration.

비내 경로, 경피 경로를 통해, 직장 또는 질 좌제에 의해 또는 연속적 정맥내 용액을 통해 투여되는 경우, 투여량 투여는 간헌절이기 보다는 연속적일 것이다.When administered via the nasal route, transdermal route, by rectal or vaginal suppositories, or via continuous intravenous solution, the dosage administration will be continuous rather than hepatic dedication.

다음은 화학식 I의 화합물에 대한 대표적 약제학적 투여 형태의 예이다. The following is an example of a representative pharmaceutical dosage form for the compound of formula (I).

주사가능한 현탁액(I.M.) mg/mLInjectable Suspension (I.M.) mg / mL

화학식 I의 화합물 10 Compound 10 of Formula I

메틸셀룰로즈 5.0Methylcellulose 5.0

트윈 80 0.5 Twin 80 0.5

벤질 알콜 9.0 Benzyl Alcohol 9.0

벤잘코늄 클로라이드 1.0 Benzalkonium Chloride 1.0

전체 용적이 1mL이 되도록 하는 주사용수Water for injection to ensure a total volume of 1 mL

정제 mg/정제Tablets mg / tablet

화학식 I의 화합물 25Compound 25 Of Formula I

미정질 셀룰로즈 415Microcrystalline Cellulose 415

포비돈 14.0 Povidone 14.0

호화 전분 43.5 Luxury Starch 43.5

마그네슘 스테아레이트 2.5 Magnesium Stearate 2.5

500                              500

캡슐제 mg/캡슐제Capsule mg / capsules

화학식 I의 화합물 25Compound 25 Of Formula I

락토즈 분말 573.5Lactose Powder 573.5

마그네슘 스테아레이트 1.5Magnesium Stearate 1.5

600                               600

에어로졸 캐니스터당Per aerosol canister

화학식 I의 화합물 24mg 24 mg of compound of formula I

레시틴, NF 액체 농축액 1.2mgLecithin, NF Liquid Concentrate 1.2mg

트리클로로플루오로메탄, NF 4.025gTrichlorofluoromethane, NF 4.025g

디클로로플루오로메탄, NF 12.15g Dichlorofluoromethane, NF 12.15 g

화학식 I의 화합물은 화학식 I의 화합물이 유용한 질병 또는 상태의 치료/예방/억제 또는 경감시에 사용되는 기타 약물과 함께 사용할 수 있다. 이러한 기타 약물은 일반적으로 사용되는 경로 및 양으로, 화학식 I의 화합물과 동시에 또는 순차적으로 투여할 수 있다. 화학식 I의 화합물이 하나 이상의 기타 약물과 동시에 사용되는 경우, 화학식 I의 화합물 이외에 이러한 기타 약물을 함유하는 약제학적 조성물이 바람직하다. 따라서, 본 발명의 약제학적 조성물은 화학식 I의 화합물 이외에 하나 이상의 기타 활성 성분을 또한 함유하는 약제학적 조성물을 포함한다. 화학식 I의 화합물과 함께 배합될 수 있는 기타 활성 성분의 예로는 개별적으로 투여될 수 있거나 동일한 약제학적 조성물 중에서 투여될 수 있는 항정신병제, 인지 증강제, 항편두통제, 항천식제, 소염제, 항불안제, 항파킨슨병제, 항간질제, 식욕억제제 및 세로토닌 재흡수 억제제 및 기타 항비만제가 포함되나 이에 제한되지는 않는다.The compounds of formula (I) can be used in conjunction with other drugs in which the compounds of formula (I) are used in the treatment / prevention / inhibition or alleviation of diseases or conditions in which the compounds of formula (I) are useful. Such other drugs may be administered simultaneously or sequentially with the compound of formula (I) in the routes and amounts generally used. If the compound of formula (I) is used simultaneously with one or more other drugs, pharmaceutical compositions containing such other drugs in addition to the compound of formula (I) are preferred. Accordingly, the pharmaceutical compositions of the present invention include pharmaceutical compositions which also contain one or more other active ingredients in addition to the compound of formula (I). Examples of other active ingredients that may be combined with the compound of formula (I) include, but are not limited to, antipsychotics, cognitive enhancers, antimigraines, antiasthma agents, anti-inflammatory agents, anti-anxiety agents, which may be administered separately or in the same pharmaceutical composition, Anti-Parkinson's, antiepileptic, appetite suppressant and serotonin reuptake inhibitors and other anti-obesity agents.

비만, 폭식증 및 강박 식이 장애를 포함하는 식이 장애의 치료 또는 예방을 위해, 본 발명의 화합물을 기타 식욕억제제와 함께 사용할 수 있음이 인지될 것이다.It will be appreciated that the compounds of the present invention can be used with other appetite suppressants for the treatment or prevention of eating disorders, including obesity, bulimia and compulsive eating disorders.

본 발명은 또한 식이 장애의 치료가 필요한 환자에게 본 발명의 화합물과 식욕억제제를 함께 효과적 경감을 제공하는 양으로 투여함을 포함하는, 식이 장애의 치료 또는 예방 방법을 제공한다.The present invention also provides a method of treating or preventing a eating disorder, comprising administering to a patient in need thereof a compound of the invention and an appetite suppressant in an amount that provides effective relief.

"비만"은 체지방이 과도하게 있는 상태이다. 비만의 실질적 정의는 제곱 미터인 신장당 체중으로서 계산되는 체질량 지수(BMI)(kg/m2)에 기초한다. "비만"은 그 밖의 건강한 환자의 체질량 지수(BMI)가 30kg/m2 이상인 상태 또는 하나 이상의 합병증을 갖는 환자의 BMI가 27kg/m2 이상인 상태를 의미한다. "비만 환자"란 체질량 지수(BMI)가 30kg/m2인 그 밖의 건강한 환자 또는 BMI가 27kg/m2 이상인 하나 이상의 합병증을 갖는 환자를 의미한다. "비만의 위험에 처한 환자"는 BMI가 25kg/m2 내지 30kg/m2 미만인 건강한 환자 또는 BMI가 25kg/m2 내지 27kg/m2 미만인 하나 이상의 합병증을 갖는 환자를 의미한다."Obesity" is a state of excessive body fat. The substantial definition of obesity is based on the Body Mass Index (BMI) (kg / m 2 ), calculated as the body weight per square meter. By "obesity" is meant a condition in which the body mass index (BMI) of other healthy patients is at least 30 kg / m 2, or that the BMI of patients with one or more complications is at least 27 kg / m 2 . And "obese" is body mass index (BMI) is 30kg / m 2 of the other healthy patients or patients with a BMI of means having a 27kg / m 2 or more at least one complication. "Subject at risk for obesity" means a patient having a BMI of 25kg / m 2 to about 30kg / m 2 is less than a healthy patient or a BMI 25kg / m 2 to about 27kg / m 2 is less than one or more complications.

비만과 관련된 증가된 위험은 아시아에서 낮은 체질량 지수(BMI)에서 일어난다. 일본을 포함한 아시아 국가에서, "비만"은 체중 감소를 요하거나 체중 감소에 의해 개선될 수 있는, 하나 이상의 비만-유도된 또는 비만-관련 합병증을 갖는 환자가 25kg/m2 이상인 BMI를 갖는 상태를 의미한다. 일본을 포함한 아시아 국가에서, "비만 환자"는 체중 감소를 요하거나 체중 감소에 의해 개선될 수 있으며 25kg/m2 이상인 BMI를 갖는, 하나 이상의 비만-유도된 또는 비만-관련 합병증을 갖는 환자를 의미한다. 아시아 국가에서, "비만의 위험에 처한 환자"는 BMI가 23kg/m2 초과 내지 25kg/m2 미만인 환자를 의미한다.Increased risk associated with obesity occurs at lower body mass index (BMI) in Asia. In Asian countries, including Japan, "obesity" refers to a condition in which a patient with one or more obesity-induced or obesity-related complications has a BMI of 25 kg / m 2 or more, which may require or be ameliorated by weight loss. it means. In Asian countries, including Japan, "obesity patients" means patients with one or more obesity-induced or obesity-related complications, which may require weight loss or may be ameliorated by weight loss and have a BMI of 25 kg / m 2 or more do. In Asian countries, "subject at risk of obesity" refers to a patient's BMI 23kg / m 2 to greater than 25kg / m 2 below.

본원에서 사용되는 바와 같이, "비만"이란 용어는 상기한 비만의 모든 정의를 포함한다.As used herein, the term "obesity" includes all definitions of obesity described above.

비만-유도된 또는 비만-관련 합병증으로는 당뇨병, 인슐린 비의존적 진성 당뇨병 2형, 내당력 장애, 공복혈당 장애, 인슐린 내성 증후군, 이상지질혈증, 고혈압, 고요산혈증, 통풍, 관상 동맥 질환, 심근 경색, 협심증, 수면 무호흡 증후군, 비만저호흡(Pickwickian) 증후군, 지방간, 뇌경색, 뇌혈전증, 일과성 허혈 발작, 정형외과 질병, 변형 관절염, 요통, 월경이상 및 불임이 포함되나 이에 제한되지는 않는다. 특히, 합병증으로는 고혈압, 고지혈증, 이상지질혈증, 내당력, 심혈관 질환, 수면 무호흡, 진성 당뇨병 및 기타 비만 관련 상태가 포함된다.Obesity-induced or obesity-related complications include diabetes, insulin-independent diabetes mellitus type 2, impaired glucose tolerance, impaired fasting glucose, insulin resistance syndrome, dyslipidemia, hypertension, hyperuricemia, gout, coronary artery disease, myocardial infarction , Angina pectoris, sleep apnea syndrome, Pickwickian syndrome, fatty liver, cerebral infarction, thrombosis, transient ischemic attack, orthopedic disease, modified arthritis, back pain, dysmenorrhea and infertility. In particular, complications include hypertension, hyperlipidemia, dyslipidemia, glucose tolerance, cardiovascular disease, sleep apnea, diabetes mellitus and other obesity related conditions.

(비만 및 비만 관련 질병의) "치료"는 본 발명의 화합물 또는 조성물을 투여하여 비만 환자의 체중을 감소시키거나 유지시킴을 의미한다. 치료의 한가지 결과는 환자의 체중을 본 발명의 화합물 또는 조성물을 투여하기 직전의 환자의 체중에 비해 감소시킬 수 있다. 치료의 다른 결과는 다이어트, 운동 또는 약물요법의 결과로서 이미 감소된 체중의 복귀의 예방일 수 있다. 치료의 또 다른 결과는 비만 관련 질환의 발병 및/또는 중증도의 감소일 수 있다. 치료는 적합하게는 이를 필요로 하는 환자에서 전체 음식 섭취량의 감소 또는 탄수화물이나 지방과 같은 식품의 특정 성분의 섭취의 감소; 및/또는 영양 흡수의 억제; 및/또는 대사율 감소의 억제를 포함하는 환자에 의한 음식 또는 열량 섭취의 감소 및 체중 감소를 초래할 수 있다. 치료는 또한 대사율 감소의 억제보다는 또는 대사율 감소의 억제 이외에 대사율의 증가와 같은 대사율의 변화 및/또는 정상적으로 체중 손실로부터 초래되는 대사 내성의 감소를 초래할 수 있다."Treatment" (of obesity and obesity-related diseases) means administering a compound or composition of the present invention to reduce or maintain the weight of an obese patient. One result of the treatment may be to reduce the weight of the patient relative to the weight of the patient immediately prior to administering the compound or composition of the present invention. Another outcome of the treatment may be the prevention of the return of already lost weight as a result of diet, exercise or pharmacotherapy. Another consequence of treatment may be a reduction in the incidence and / or severity of obesity related diseases. Treatment suitably includes a reduction in overall food intake or a reduction in the intake of certain components of a food such as carbohydrates or fats in a patient in need thereof; And / or inhibition of nutrient absorption; And / or a reduction in food or calorie intake and weight loss by the patient, including inhibition of a decrease in metabolic rate. Treatment may also result in a change in metabolic rate such as an increase in metabolic rate and / or a decrease in metabolic resistance normally resulting from weight loss rather than an inhibition of metabolic rate reduction.

(비만 및 비만 관련 질병의) "예방"은 본 발명의 화합물 또는 조성물을 투여하여 비만의 위험에 처한 환자의 체중을 감소시키거나 유지시킴을 의미한다. 예방의 한가지 결과는 비만의 위험에 처한 환자의 체중을 본 발명의 화합물 또는 조성물을 투여하기 직전의 환자의 체중에 비해 감소시키는 것일 수 있다. 예방의 다른 결과는 다이어트, 운동 또는 약물요법의 결과로서 이미 감소된 체중의 복귀의 예방일 수 있다. 예방의 또 다른 결과는 비만의 위험에 처한 환자에서 비만이 발병하기 전에 치료가 시행된 경우에 비만이 발병하지 않도록 예방하는 것일 수 있다. 예방의 또 다른 결과는 비만의 위험에 처한 환자에서 비만이 발병하기 전에 치료가 시행된 경우에 비만 관련 질병의 발병 및/또는 중증도를 감소시키는 것일 수 있다. 또한, 치료가 이미 비만한 환자에서 시작된 경우, 이러한 치료는 동맥경화증, 2형 당뇨병, 다낭 난소 질환, 심혈관 질환, 골관절염, 피부과 질병, 고혈압, 인슐린 내성, 고콜레스테롤혈증, 고중성지방혈증 및 담석증을 포함하나 이에 제한되지 않는 비만 관련 질병의 발병, 진행 또는 중증도를 예방할 수 있다."Prevention" (of obesity and obesity-related diseases) means administering a compound or composition of the present invention to reduce or maintain the weight of a patient at risk of obesity. One consequence of prevention may be to reduce the weight of a patient at risk of obesity relative to the weight of the patient immediately prior to administering the compound or composition of the present invention. Another consequence of prevention may be the prevention of the return of already reduced body weight as a result of diet, exercise or pharmacotherapy. Another consequence of prevention may be to prevent the development of obesity in patients who are at risk of obesity, if treatment is performed before the onset of obesity. Another consequence of prevention may be the reduction in the incidence and / or severity of obesity-related diseases in patients at risk of obesity, if treatment is performed prior to the onset of obesity. In addition, if the treatment has already begun in an obese patient, the treatment may include atherosclerosis, type 2 diabetes, polycystic ovarian disease, cardiovascular disease, osteoarthritis, dermatology, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia and cholelithiasis It can prevent the onset, progression or severity of obesity-related diseases, including but not limited to.

비만 관련 질병은 비만과 관련되거나 비만에 의해 유발되거나 비만으로부터 초래된다. 비만 관련 질병의 예로는 과식 및 폭식증, 고혈압, 당뇨병, 상승된 혈장 인슐린 농도 및 인슐린 내성, 이상지질혈증, 고지혈증, 자궁내막, 유방, 전립선 및 결장 암, 골관절염, 폐쇄성 수면 무호흡증, 담석증, 담석, 심장 질환, 비정상적 심박동 및 부정맥, 심근 경색, 울혈성 심부전증, 관상 심장 질환, 급사, 뇌졸중, 다낭 난소 질환, 두개인두종, 프라더 윌리(Prader-Willi) 증후군, 프롤리히(Frohlich) 증후군, GH-결핍 환자, 저신장증의 정상적 변형, 터너(Turner) 증후군 및 감소된 대사 활성 또는 예를 들어, 급성 림프모구 백혈병을 앓는 아동에서와 같이 전체 제지방량의 백분율로서의 잉여 에너지 소비의 감소를 나타내는 기타 병리학적 상태가 포함된다. 비만 관련 질병의 추가 예로는 X 증후군으로서도 공지된 대사 증후군, 인슐린 내성 증후군, 성기능장애 및 생식기능장애(예: 불임), 남성의 생식선저하증 및 여성의 다모증, 위장관 운동 장애(예: 비만 관련 위식도 역류), 호흡기 질병(예: 비만-호흡저하 증후군(비만저호흡 증후군)), 심혈관 장애, 염증(예: 혈관의 전신성 염증), 동맥경화증, 고콜레스테롤혈증, 고요산혈증, 하부 요통, 담낭 질환, 통풍 및 신장 암이 있다. 본 발명의 조성물은 또한 좌심실 비대의 위험을 감소시키는 바와 같이 비만의 2차적 결과의 위험을 감소시키는데 유용하다.Obesity-related diseases are associated with, caused by, or result from obesity. Examples of obesity-related diseases include overeating and bulimia, hypertension, diabetes, elevated plasma insulin levels and insulin resistance, dyslipidemia, hyperlipidemia, endometrium, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, gallstones, gallstones, heart Diseases, abnormal heartbeats and arrhythmia, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovary disease, craniocytoma, Prader-Willi syndrome, Frohlich syndrome, GH-deficiency Patients, normal modification of nephropathy, Turner syndrome and other pathological conditions that indicate reduced metabolic activity or decrease in surplus energy consumption as a percentage of total lean body mass, eg, in children with acute lymphocytic leukemia. Included. Further examples of obesity-related diseases include metabolic syndrome, also known as X syndrome, insulin resistance syndrome, sexual and reproductive dysfunctions (e.g. infertility), hypogonadism in men and hirsutism in women, gastrointestinal motility disorders (e.g. obesity-related gastroesophageal) Reflux), respiratory diseases (e.g. obesity-low-breath syndrome), cardiovascular disorders, inflammation (e.g. systemic inflammation of blood vessels), arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, Gout and kidney cancer. The compositions of the present invention are also useful for reducing the risk of secondary consequences of obesity, such as reducing the risk of left ventricular hypertrophy.

본원에서 사용되는 바와 같이 "당뇨병"이란 용어는 인슐린 의존적 진성 당뇨병(즉, I형 당뇨병으로도 공지되어 있는 IDDM) 및 인슐린 비의존적 진성 당뇨병(즉, II형 당뇨병으로도 공지되어 있는 NIDDM) 둘다를 포함한다. I형 당뇨병 또는 인슐린 의존적 당뇨병은 글루코즈 소모를 조절하는 호르몬인 인슐린의 절대적 결핍의 결과이다. II형 당뇨병 또는 인슐린 독립적 당뇨병(즉, 인슐린 비의존적 진성 당뇨병)은 흔히 정상적 또는 심지어 상승된 수준의 인슐린인 경우에도 발생하며 인슐린에 적절하게 반응할 수 없는 조직의 불능의 결과인 것으로 보인다. II형 당뇨병의 대부분은 또한 비만이다. 본 발명의 화합물 및 조성물은 I형 및 II형 당뇨병 둘다를 치료하는데 유용하다. 당해 화합물 및 조성물은 특히 II형 당뇨병의 치료에 효과적이다. 본 발명의 화합물 및 조성물은 또한 임신성 진성 당뇨병의 치료 및/또는 예방에도 유용하다.As used herein, the term "diabetes" refers to both insulin dependent diabetes mellitus (ie, IDDM, also known as type I diabetes) and insulin independent diabetes mellitus (ie, NIDDM, also known as type II diabetes). Include. Type I diabetes or insulin dependent diabetes is the result of an absolute deficiency of insulin, a hormone that regulates glucose consumption. Type II diabetes or insulin independent diabetes (ie insulin independent diabetes mellitus) often occurs with normal or even elevated levels of insulin and appears to be the result of tissue inability to respond properly to insulin. Most of type II diabetes is also obese. The compounds and compositions of the present invention are useful for treating both type I and type II diabetes. The compounds and compositions are particularly effective for the treatment of type II diabetes. The compounds and compositions of the present invention are also useful for the treatment and / or prevention of gestational diabetes mellitus.

본원에서 사용되는 바와 같이, "물질 남용 장애"란 용어는 물질 의존성 또는 생리적 의존을 동반하거나 동반하지 않은 남용을 포함한다. 이러한 장애와 관련된 물질로는 알콜, 암페타민(또는 암페타민 유사 물질), 카페인, 카나비스, 코카인, 환각제, 흡입제, 마리화나, 니코틴, 아편제, 펜사이클리딘(또는 펜사이클리딘 유사 화합물), 진정-최면제 또는 벤조디아제핀 및 기타(또는 미공지된) 물질 및 상기 모든 물질의 배합물이 있다.As used herein, the term "substance abuse disorder" includes abuse with or without substance dependence or physiological dependence. Substances associated with this disorder include alcohol, amphetamines (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, marijuana, nicotine, opiates, phencyclidines (or phencycline-like compounds), sedatives Hypnotic or benzodiazepines and other (or unknown) materials and combinations of all of the above.

특히, "물질 남용 장애"란 용어는 지각장애를 동반하거나 동반하지 않은 알콜 금단; 섬망을 동반한 알콜 금단; 암페타민 금단; 코카인 금단; 니코틴 금단; 아편제 금단; 지각장애를 동반하거나 동반하지 않은 진정제, 최면제 또는 항불안제 금단; 진정제, 최면제 또는 항불안제 금단 섬망; 및 기타 물질로 인한 금단 증상과 같은 약물 금단 장애를 포함한다. 니코틴 금단의 치료에 대한 인용이 금연과 관련된 증상의 치료를 포함함이 이해될 것이다.In particular, the term "substance abuse disorder" includes alcohol withdrawal with or without perceptual impairment; Alcohol withdrawal with delirium; Amphetamine withdrawal; Cocaine withdrawal; Nicotine withdrawal; Opiate withdrawal; Withdrawal of sedatives, hypnosis or anti-anxiety with or without perceptual impairment; Sedative, hypnotic or anti-anxiety withdrawal delirium; And drug withdrawal disorders such as withdrawal symptoms caused by other substances. It will be appreciated that citation to the treatment of nicotine withdrawal includes treatment of symptoms associated with smoking cessation.

기타 "물질 남용 장애"로는 금단 동안 개시되는 물질-유도된 불안 장애; 금단 동안 개시되는 물질-유도된 정동 장애; 및 금단 동안 개시되는 물질-유도된 수면 장애가 포함된다.Other "substance abuse disorders" include substance-induced anxiety disorders initiated during withdrawal; Substance-induced affective disorders initiated during withdrawal; And substance-induced sleep disorders initiated during withdrawal.

통상의 항정신병제 약물과 CB1 수용체 조절제와의 배합물이 조증의 치료시에 증강된 효과를 제공할 수 있음이 이해될 것이다. 이러한 배합물은 신속한 작용 개시를 제공하여 조증 현상을 치료함으로써 "필요에 따른" 처방을 가능하게 하는 것으로 예상될 수 있다. 추가로, 이러한 배합물은 사용될 항정신병제의 효능을 감소시키지 않으면서 항정신병제의 용량을 저하시킴으로써 부작용의 위험을 최소화시킬 수 있다. 이러한 배합물의 추가의 잇점은 CB1 수용체 조절제의 작용으로 인해, 항정신병제에 의해 유발되는 부작용, 예를 들어, 급성 근육긴장이상, 운동이상증, 정좌불능 및 떨림을 감소시키거나 예방할 수 있다는 점이다.It will be appreciated that combinations of conventional antipsychotic drugs with CB1 receptor modulators may provide enhanced effects in the treatment of mania. Such a combination can be expected to provide a rapid onset of action to allow for "on demand" prescriptions by treating mania. In addition, such combinations can minimize the risk of side effects by lowering the dose of antipsychotics without reducing the efficacy of the antipsychotics to be used. A further advantage of this combination is that due to the action of CB1 receptor modulators, it can reduce or prevent side effects caused by antipsychotics, such as acute dystonia, dyskinesia, dyspnea and tremors.

본 발명은 또한 조증의 치료가 필요하거나 조증 발병의 위험에 처한 환자에게 CB1 수용체 조절제 및 항정신병제를 함께 효과적 경감을 제공하는 양으로 투여함을 포함하는, 조증의 치료 또는 예방 방법을 제공한다.The invention also provides a method of treating or preventing mania, comprising administering CB1 receptor modulators and antipsychotics together in an amount that provides effective alleviation to a patient in need of treatment or at risk of developing mania.

CB1 수용체 조절제 및 항정신병제가 조증의 치료 또는 예방을 위해 동시적, 개별적 또는 순차적 사용을 위한 배합된 제제로서 존재할 수 있음이 이해될 것이다.It will be appreciated that CB1 receptor modulators and antipsychotics may exist as formulated agents for simultaneous, separate or sequential use for the treatment or prevention of mania.

본 발명의 배합물을 사용하는 경우, CB1 수용체 조절제와 항정신병제가 동일한 약제학적으로 허용되는 담체중에 존재하여 동시에 투여될 수 있음이 이해될 것이다. CB1 수용체 조절제와 항정신병제는 동시에 섭취되는 통상의 경구 투여 형태와 같이 개별적 약제학적 담체 중에 존재할 수 있다. "배합물"이란 용어는 화합물이 별개의 투여 형태로 제공되어 순차적으로 투여되는 경우를 의미한다. 따라서, 예를 들어, 항정신병제를 정제로서 투여한 다음, 합리적 기간내에 CB1 수용체 조절제를 정제와 같은 경구 투여 형태 또는 속용성 경구 투여 형태로서 투여할 수 있다. "속용성 경구 제형"이란, 환자의 혀상에 위치하는 경우에 약 10초 이내에 용해되는 경구 전달 형태를 의미한다.When using the combinations of the present invention, it will be appreciated that the CB1 receptor modulator and antipsychotic may be present in the same pharmaceutically acceptable carrier and administered simultaneously. CB1 receptor modulators and antipsychotics may be present in separate pharmaceutical carriers, such as conventional oral dosage forms, which are taken simultaneously. The term “combination” means when the compounds are provided in separate dosage forms and administered sequentially. Thus, for example, an antipsychotic may be administered as a tablet, and then within a reasonable period of time, the CB1 receptor modulator may be administered as an oral dosage form, such as a tablet, or as a quick-release oral dosage form. By "rapid oral dosage form" is meant an oral delivery form that dissolves within about 10 seconds when placed on the patient's tongue.

통상의 항정신병 약물과 CB1 수용체 조절제의 배합물이 정신분열 질병의 치료시에 증강된 효과를 제공할 수 있음이 이해될 것이다. 이러한 배합물은 신속한 작용 개시를 제공하여 정신분열 증상을 치료함으로써 "필요에 따른" 처방을 가능하게 하는 것으로 예상될 수 있다. 추가로, 이러한 배합물은 사용될 항정신병제의 효능을 감소시키지 않으면서 CNS 제제의 용량을 저하시킴으로써 부작용의 위험을 최소화시킬 수 있다. 이러한 배합물의 추가의 잇점은 CB1 수용체 조절제의 작용으로 인해, 항정신병제에 의해 유발되는 부작용, 예를 들어, 급성 근육긴장이상, 운동이상증, 정좌불능 및 떨림을 감소시키거나 예방할 수 있다는 점이다.It will be appreciated that a combination of conventional antipsychotic drugs and CB1 receptor modulators may provide enhanced effects in the treatment of schizophrenic diseases. Such a combination can be expected to provide a rapid onset of action to allow for "on demand" prescriptions by treating schizophrenic symptoms. In addition, such combinations can minimize the risk of side effects by lowering the dose of the CNS agent without reducing the efficacy of the antipsychotic agent to be used. A further advantage of this combination is that due to the action of CB1 receptor modulators, it can reduce or prevent side effects caused by antipsychotics, such as acute dystonia, dyskinesia, dyspnea and tremors.

통상의 항천식 약물과 CB1 수용체 조절제의 배합물이 천식의 치료시에 증강된 효과를 제공할 수 있음이 이해될 것이다.It will be appreciated that combinations of conventional anti-asthmatic drugs with CB1 receptor modulators may provide enhanced effects in the treatment of asthma.

따라서, 본 발명의 추가의 양상에 따라서, 천식의 치료 또는 예방용 의약을 제조하기 위한 CB1 수용체 조절제 및 항천식제의 용도가 제공된다.Thus, according to a further aspect of the present invention there is provided the use of CB1 receptor modulators and anti-asthma agents for the manufacture of a medicament for the treatment or prevention of asthma.

본 발명은 또한 천식의 치료가 필요한 환자에게 본 발명의 화합물과 항천식제를 함께 효과적 경감을 제공하는 양으로 투여함을 포함하는, 천식의 치료 또는 예방 방법이 제공한다.The invention also provides a method of treating or preventing asthma, comprising administering to a patient in need thereof a compound of the invention and an anti-asthma agent in an amount that provides effective relief.

본 발명의 치료 방법은 기타 CB 또는 G-단백질 커플링된 수용체 보다는 CB1 수용체를 선택적으로 길항하는 본 발명의 화합물의 비독성 치료학적 유효량을 이러한 치료를 필요로 하는 환자에게 투여함으로써, CB1 수용체를 조절하고 CB1 수용체 매개된 질병을 치료하는 방법을 포함한다. The method of treatment of the invention modulates the CB1 receptor by administering to a patient in need of such treatment a nontoxic therapeutically effective amount of a compound of the invention that selectively antagonizes the CB1 receptor over other CB or G-protein coupled receptors. And methods of treating CB1 receptor mediated diseases.

본원에서 사용되는 바와 같이 "치료학적 유효량"이란 용어는 치료하는 질병의 증상의 경감을 포함하여, 조사자, 수의사, 의사 또는 기타 임상의가 조사하는 조직, 시스템, 동물 또는 사람에서 생물학적 또는 의학적 반응을 유도하는 활성 화합물 또는 약제학적 제제의 양을 의미한다. 본 발명의 신규한 치료 방법은 당해 분야의 숙련가에게 공지되어 있는 질병을 위한 것이다. "포유동물"이란 용어는 사람을 포함한다.As used herein, the term “therapeutically effective amount” refers to a biological or medical response in a tissue, system, animal or human being investigated by an investigator, veterinarian, doctor or other clinician, including alleviation of the symptoms of the disease being treated. The amount of the active compound or pharmaceutical agent that induces. The novel therapeutic methods of the invention are for diseases known to those skilled in the art. The term "mammal" includes humans.

다음 반응식 및 실시예에서 사용되는 약어는 다음과 같다: aq.: 수성; API-ES: 대기압 이온화-전자분무(질량 스펙트럼 용어); DMF: 디메틸포름아미드; DMSO: 디메틸설폭시드; EDC:1-에틸-3-(3-디메틸아미노프로필)-카보디이미드 하이드로클로라이드; EPA:에틸렌 폴리아크릴아미드(플라스틱); EtOAc:에틸 아세테이트; h: 시간; Hex: 헥산; HOBt: 1-하이드록시벤조트리아졸; HPLC: 고성능 액체 크로마토그래피; HPLC/MS: 고압 액체 크로마토그래피/질량 스펙트럼; in vacuo: 회전증발(rotoevaporation); IPAC: 이소프로필 아세테이트; KHMDS: 칼륨 헥사메틸디실라지드; LC: 액체 크로마토그래피; LC/MS, LC-MS: 액체 크로마토그래피-질량 스펙트럼; M: 몰농도; Me: 메틸; MeOH : 메탄올; mmol: 밀리몰; MS 또는 ms: 질량 스펙트럼; N: 노르말농도; NaHMDS : 나트륨 헥사메틸디실라지드; NMR : 핵 자기 공명; PyBOP:(벤조트리아졸-1-일옥시)트리피롤리디노포스포늄 헥사플루오로포스페이트; Rt: 체류 시간; rt 또는 RT: 실온; TFA: 트리플루오로아세트산; THF: 테트라하이드로푸란; TLC: 박층 크로마토그래피.Abbreviations used in the following schemes and examples are as follows: aq .: aqueous; API-ES: atmospheric ionization-electrospray (mass spectral terminology); DMF: dimethylformamide; DMSO: dimethyl sulfoxide; EDC: 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride; EPA: ethylene polyacrylamide (plastic); EtOAc: ethyl acetate; h: hour; Hex: hexane; HOBt: 1-hydroxybenzotriazole; HPLC: high performance liquid chromatography; HPLC / MS: high pressure liquid chromatography / mass spectra; in vacuo: rotoevaporation; IPAC: isopropyl acetate; KHMDS: Potassium hexamethyldisilazide; LC: liquid chromatography; LC / MS, LC-MS: liquid chromatography-mass spectrum; M: molarity; Me: methyl; MeOH: Methanol; mmol: mmol; MS or ms: mass spectrum; N: normal concentration; NaHMDS: sodium hexamethyldisilazide; NMR: nuclear magnetic resonance; PyBOP: (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate; R t : retention time; rt or RT: room temperature; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TLC: thin layer chromatography.

본 발명의 화합물은 첨부되는 반응식 및 실시예에서 설명되는 방법으로 제조할 수 있다.The compounds of the present invention can be prepared by the methods described in the accompanying schemes and examples.

반응식 1에서, 적절하게 치환된 아민(A)를 표준 아미드 결합 형성 조건하에 카복실산(B)와 반응시켜 아릴아미드(C)를 수득한다. 본 발명을 예시하기 위해, 다음 실시예가 포함된다. 이들 실시예는 본 발명을 제한하지 않는다. 이들 실시예는 단지 실시되는 본 발명을 감소시키는 방법을 제시하기 위함이다. 당해 분야의 숙련가라면 이들이 쉽게 인지할 수 있는 본 발명의 다른 실시 방법을 찾을 수 있을 것이다. 그러나, 이들 방법도 본 발명의 범주내에 포함된다.In Scheme 1, an appropriately substituted amine (A) is reacted with carboxylic acid (B) under standard amide bond formation conditions to yield arylamide (C). To illustrate the invention, the following examples are included. These examples do not limit the invention. These examples are only intended to present a method of reducing the invention to be practiced. Those skilled in the art will find other ways of practicing the invention that are readily recognizable. However, these methods are also included within the scope of the present invention.

일반적 공정. 4.5분에 걸쳐 10 내지 95% B에 이어서 95% 에서 0.5분 동안의 용매 구배로 2.5mL/분에서 용출시키는 YMC ODS-A 4.6 x 50 mm 컬럼을 사용한 AGILENT 1100 시리즈 HPLC에 커플링된 MICROMASS ZMD 질량 분광계를 사용하여 LC/MS 분석을 수행하였다 용매 A = 수중 0.06% TFA; 용매 B = 아세토니트릴중 0.05% TFA. 1H-NMR 스펙트럼을 명시한 바와 같은 CDCl3 또는 CD30D 중에서 500 MHz VARIAN 분광계로 수득하였고, 화학적 이동을 참조로서 용매 피크를 사용하여 δ로서 기재하고 커플링 상수를 헤르츠(Hz) 단위로 기재한다. General process. MICROMASS ZMD mass coupled to AGILENT 1100 series HPLC using a YMC ODS-A 4.6 x 50 mm column eluting at 2.5 mL / min with a solvent gradient from 10 to 95% B and then 95% to 0.5 minutes over 4.5 minutes LC / MS analysis was performed using a spectrometer Solvent A = 0.06% TFA in water; Solvent B = 0.05% TFA in acetonitrile. 1 H-NMR spectra were obtained with a 500 MHz VARIAN spectrometer in CDCl 3 or CD 3 0D as indicated, chemical shifts are described as δ using solvent peaks as reference and coupling constants are stated in Hertz (Hz). .

참조 실시예 1 Reference Example 1

N-[2,3-비스(4-클로로페닐)-1-메틸프로필]-아민 하이드로클로라이드N- [2,3-bis (4-chlorophenyl) -1-methylpropyl] -amine hydrochloride

N-[2,3-비스(4-클로로페닐)-1-메틸프로필]-아민 하이드로클로라이드 염의 2개의 부분입체이성체(알파 및 베타)의 제조는 기재되어 있다[참조: Schultz, E.M, et al. J. Med Chem. 1967, 10, 717]. 부분입체이성체 α: LC-MS: C16H17Cl2 N에 대한 계산치 293, 관측치 m/e 294(M + H)+(체류시간 : 2.5분). 부분입체이성체 β: LC-MS: C16H17Cl2N에 대한 계산치 293, 관측치 m/e 294(M + H)+(체류시간 : 2.2분)The preparation of two diastereomers (alpha and beta) of the N- [2,3-bis (4-chlorophenyl) -1-methylpropyl] -amine hydrochloride salt is described by Schultz, EM, et al. . J. Med Chem. 1967, 10, 717. Diastereomer α: LC-MS: calcd for C 16 H 17 Cl 2 N 293, found m / e 294 (M + H) + (ret. Time: 2.5 min). Diastereomer β: LC-MS: calcd for C 16 H 17 Cl 2 N 293, found m / e 294 (M + H) + (ret. Time: 2.2 min)

참조 실시예 2Reference Example 2

2-아미노-4-(4-클로로페닐)-3-페닐부탄 하이드로클로라이드 염2-amino-4- (4-chlorophenyl) -3-phenylbutane hydrochloride salt

표제 화합물은 참조 실시예 1에서 기술한 방법으로 제조하였다. The title compound was prepared by the method described in Reference Example 1.

부분입체이성체 α: LC-MS: C16H18ClN에 대한 계산치 259, 관측치 m/e 260(M + H)+(2.3분). 부분입체이성체 β: C16H18ClN에 대한 계산치 259, 관측치 m/e 260(M + H)+(2.2분)Diastereomer α: LC-MS: calcd for C 16 H 18 ClN 259, found m / e 260 (M + H) + (2.3 min). Diastereomer β: calcd for C 16 H 18 ClN 259, found m / e 260 (M + H) + (2.2 min)

참조 실시예 3Reference Example 3

N-[3-(4-클로로페닐)-2-페닐-1-메틸프로필]-아민 하이드로클로라이드(부분입체이성체 α) N- [3- (4-chlorophenyl) -2-phenyl-1-methylpropyl] -amine hydrochloride (diastereomer α)

단계 A 3-(4-클로로페닐)-2-페닐프로판산, 메틸 에스테르.Step A 3- (4-Chlorophenyl) -2-phenylpropanoic acid, methyl ester .

250mL 무수 THF 중의 메틸 페닐아세테이트(12g, 80mmol) 및 4-클로로벤질 브로마이드(16g, 80mmol)의 용액에 -78℃에서 헥사메틸디실라지드(THF 중의 1M, 80mL, 80mmol)(톨루엔중의 칼륨 헥사메틸디실라지드를 사용하여 유사한 결과를 수득할 수 있다)을 첨가하였다. 반응물을 실온으로 밤새 가온시켰다. 휘발성 물질을 회전 증발기에서 제거하고, 수득된 혼합물을 포화 염화암모늄(200mL)과 EtOAc(200mL) 사이에 분배시켰다. 유기 층을 분리시키고, 수성 층을 EtOAc(2 x 200mL)으로 추출하였다. 합한 유기 추출물을 무수 황산나트륨상에서 건조시키고 여과하고 농축 건조시켜 표제 화합물을 수득하였다. To a solution of methyl phenylacetate (12 g, 80 mmol) and 4-chlorobenzyl bromide (16 g, 80 mmol) in 250 mL anhydrous THF, hexamethyldisilazide (1M in THF, 80 mL, 80 mmol) (potassium hexa in toluene) at -78 ° C. Similar results can be obtained using methyldisilazide). The reaction was allowed to warm to room temperature overnight. The volatiles were removed on a rotary evaporator and the resulting mixture was partitioned between saturated ammonium chloride (200 mL) and EtOAc (200 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to dryness to afford the title compound.

1H NMR(500 MHz, CD3OD): δ7.36-7.10(m, 9H), 3.81(dd, 1H), 3.52(s, 3H), 3.36(dd, 1H), 3.02(dd, 1H). 1 H NMR (500 MHz, CD 3 OD): δ 7.36-7.10 (m, 9H), 3.81 (dd, 1H), 3.52 (s, 3H), 3.36 (dd, 1H), 3.02 (dd, 1H) .

단계 B 3-(4-클로로페닐)-2-페닐프로판산. Step B 3- (4-Chlorophenyl) -2-phenylpropanoic acid.

아세토니트릴(100mL) 중의 메틸 3-(4-클로로페닐)-2-페닐프로피오네이트(단계 A, 20g, 74mmol)과 물(100mL)의 혼합물에 수산화리튬 1수화물(8.8g, 0.21mol)으 첨가하였다. 실온에서 3일 동안 교반한 후, 휘발성 물질을 회전 증발기에서 농축시켜 제거하고 잔사를 물(300mL)과 헥산/에테르(1: 1,200mL) 사이에 분배시켰다. 물 층을 분리시키고, 2 내지 3의 pH로 산성화시키고 EtOAc(2 x 200mL)로 추출하였다. 합한 유기 추출물을 무수 황산나트륨상에서 건조시키고, 여과하고, 농축 건조시켜 표제 화합물을 수득하였다. 1H NMR(500 MHz, CD3OD): δ7.34-7.10(m, 9H), 3.82(dd, 1H), 3.36(dd, 1H), 2.98(dd, 1H).To a mixture of methyl 3- (4-chlorophenyl) -2-phenylpropionate (step A, 20 g, 74 mmol) and water (100 mL) in acetonitrile (100 mL) was added lithium hydroxide monohydrate (8.8 g, 0.21 mol). Added. After stirring for 3 days at room temperature, the volatiles were removed by concentration on a rotary evaporator and the residue was partitioned between water (300 mL) and hexane / ether (1: 1,200 mL). The water layer was separated, acidified to a pH of 2-3 and extracted with EtOAc (2 × 200 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to dryness to afford the title compound. 1 H NMR (500 MHz, CD 3 OD): δ 7.34-7.10 (m, 9H), 3.82 (dd, 1H), 3.36 (dd, 1H), 2.98 (dd, 1H).

단계 C N-메톡시-N-메틸-3-(4-클로로페닐)-2-페닐프로판아미드. Step C N-methoxy-N-methyl-3- (4-chlorophenyl) -2-phenylpropanamide.

CH2Cl2(125mL) 중의 3-(4-클로로페닐)-2-페닐프로피온산(단계 B, 14g, 55mmol)의 용액에 0℃에서 디메틸 포름아미드(50㎕) 및 옥살릴 클로라이드(14g, 0.11mol)을 적가하였다. 반응물을 실온으로 밤새 가온시키고 농축 건조시켜, 추가의 정제없이 사용되는 조 아실 클로라이드를 수득하여다. 이어서, CH2Cl2(250mL) 중의 아실 클로라이드의 용액에 0℃에서 N-메톡시-N-메틸아민 하이드로클로라이드(11g, 0.11mol) 및 트리에틸 아민(활성화된 분자체상에서 건조시킴, 30mL, 0.22mol)를 첨가하였다. 실온에서 4시간 동안 교반한 후, 반응 혼합물을 에테르(500mL)로 희석시키고 물, 묽은 수성 황산수소나트륨 및 염수로 연속적으로 세척하고, 무수 MgSO4상에서 건조시키고 여과시키고 농축 건조시켜, 추가의 정제없이 사용되는 표제 화합물을 수득하였다. 1H NMR(500 MHz, CD3OD): δ7.4-7.1(m, 9H), 4.38(br, 1H), 3.48(s, 3H), 3.35(dd, 1H), 3.10(s, 3H), 2.92(dd, 1H); LC-MS: m/e 304(3.6분).To a solution of 3- (4-chlorophenyl) -2-phenylpropionic acid (step B, 14 g, 55 mmol) in CH 2 Cl 2 (125 mL) at 0 ° C. dimethyl formamide (50 μl) and oxalyl chloride (14 g, 0.11 mol) was added dropwise. The reaction is warmed to rt overnight and concentrated to dryness to afford crude acyl chloride which is used without further purification. Then to a solution of acyl chloride in CH 2 Cl 2 (250 mL) N-methoxy-N-methylamine hydrochloride (11 g, 0.11 mol) and triethyl amine (dry on activated molecular sieve, 30 mL, at 0 ° C.). 0.22 mol) was added. After stirring for 4 hours at room temperature, the reaction mixture is diluted with ether (500 mL) and washed successively with water, diluted aqueous sodium hydrogen sulphate and brine, dried over anhydrous MgSO 4 , filtered and concentrated to dry, without further purification. The title compound used was obtained. 1 H NMR (500 MHz, CD 3 OD): δ 7.4-7.1 (m, 9H), 4.38 (br, 1H), 3.48 (s, 3H), 3.35 (dd, 1H), 3.10 (s, 3H) , 2.92 (dd, 1 H); LC-MS: m / e 304 (3.6 min).

단계 D 4-(4-클로로페닐)-3-페닐-2-부타논. Step D 4- (4-Chlorophenyl) -3-phenyl-2-butanone.

무수 THF(200mL) 중의 N-메톡시-N-메틸-3-(4-클로로페닐)-2-페닐프로판아미드(단계 C, 16g, 53mmol, 톨루엔과 공비혼합시켜 건조시킴)의 용액에 0℃에서 메틸마그네슘 브로마이드(에테르중의 3M, 35mL, 0.11mol)를 첨가하였다. 0℃에서 2시간 동안 교반한 후, 반응물을 MeOH(5mL) 및 2M 염산(50mL)으로 급냉시켰다. 휘발성 물질을 회전 증발기에서 농축시켜 제거하고 잔사를 포화 염화암모늄(200mL) 및 에테르(200mL) 사이에 분배시켰다. 유기 층을 분리시키고, 수성 층을 에테르(2 x 200mL)로 추출하였다. 합합 유기 추출물을 무수 MgSO4상에서 건조시키고 여과하고 농축 건조시켜, 추가의 정제없이 사용되는 표제 화합물을 수득하였다. 1H NMR(500 MHz, CD3OD): δ7.45-7.02(m, 9H), 4.08(dd, 1H), 3.34(dd, 1H), 2.90(dd, 1H), 2.03(s, 3H).0 ° C. to a solution of N-methoxy-N-methyl-3- (4-chlorophenyl) -2-phenylpropanamide (Step C, 16 g, 53 mmol, azeotropically mixed with toluene and dried) in dry THF (200 mL). Methylmagnesium bromide (3M in ether, 35 mL, 0.11 mol) was added. After stirring at 0 ° C. for 2 hours, the reaction was quenched with MeOH (5 mL) and 2M hydrochloric acid (50 mL). The volatiles were removed by concentration in a rotary evaporator and the residue was partitioned between saturated ammonium chloride (200 mL) and ether (200 mL). The organic layer was separated and the aqueous layer was extracted with ether (2 x 200 mL). The combined organic extracts were dried over anhydrous MgSO 4, filtered and concentrated to dryness to afford the title compound which was used without further purification. 1 H NMR (500 MHz, CD 3 OD): δ 7.45-7.02 (m, 9H), 4.08 (dd, 1H), 3.34 (dd, 1H), 2.90 (dd, 1H), 2.03 (s, 3H) .

단계 E 4-(4-클로로페닐)-3-페닐-2-부탄올. Step E 4- (4-Chlorophenyl) -3-phenyl-2-butanol.

MeOH(100mL) 중의 4-(4-클로로페닐)-3-페닐-2-부타논(단계 D, 13g, 50mmol)의 용액에 0℃에서 수소화붕소나트륨(3.8g, 100mmol)을 첨가하였다. 0℃에서 30분 동안 교반한 후, 반응물을 2M 염산(50mL)을 첨가하여 급냉시켰다. 휘발성 물질을 회전 증발기에서 농축시켜 제거하고 잔사를 물(100mL)과 EtOAc(200mL) 사이에 분배시켰다. 유기 층을 분리시키고, 수성 층을 EtOAc(2 x 200mL)로 추출하였다. 합한 유기 추출물을 염수로 세척하고, 무수 황산나트륨상에서 건조시키고, 여과하고, 농축 건조시켜 조 생성물을 수득하고, 이를 실리카 겔에서 헥산 중의 10% EtOAc로 용출시키면서 섬광 컬럼 크로마토그래피로 정제하여, 신속하게 용출되는 순수한 이성체 및 보다 신속하게 용출되는 이성체와 보다 서서히 용출되는 이성체 둘다를 함유하는 혼합물을 수득하였다. 보다 신속하게 용출되는 이성체: 1H NMR(500 MHz, CD3OD): δ7.25-7.00(m, 9H), 4.00(m, 1H), 3.15(m, 1H), 2.97(m, 1H), 2.85(m, 1H), 1.10(d, 3H).To a solution of 4- (4-chlorophenyl) -3-phenyl-2-butanone (step D, 13 g, 50 mmol) in MeOH (100 mL) was added sodium borohydride (3.8 g, 100 mmol) at 0 ° C. After stirring for 30 min at 0 ° C., the reaction was quenched by addition of 2M hydrochloric acid (50 mL). The volatiles were removed by concentration on a rotary evaporator and the residue was partitioned between water (100 mL) and EtOAc (200 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to afford the crude product which was purified by flash column chromatography on silica gel, eluting with 10% EtOAc in hexanes, quickly eluting. A mixture containing both pure isomers and more rapidly eluting isomers and more slowly eluting isomers was obtained. Isomers eluted more quickly: 1 H NMR (500 MHz, CD 3 OD): δ7.25-7.00 (m, 9H), 4.00 (m, 1H), 3.15 (m, 1H), 2.97 (m, 1H) , 2.85 (m, 1 H), 1.10 (d, 3 H).

단계 F 4-(4-클로로페닐)-2-메탄설포닐옥시-3-페닐부탄. Step F 4- (4-Chlorophenyl) -2-methanesulfonyloxy-3-phenylbutane.

EtOAc(100mL) 중의 4-(4-클로로페닐)-3-페닐-2-부탄올(단계 E, 보다 신속하게 용출되는 이성체, 9.0g, 34mmol)의 용액에 0℃에서 트리에틸 아민(활성화된 분자체상에서 건조시킴, 5.8mL. 42mmol) 및 메탄설포닐 클로라이드(3.0mL, 38mmol)을 첨가하였다. 0℃에서 30분 동안 교반한 후, 반응물을 포화 수성 수소화붕소나트륨(100mL)을 첨가하여 급냉시켰다. 실온에서 1시간 동안 교반한 후, 유기 층을 분리시키고, 무수 황산나트륨상에서 건조시키고 여과하고 농축 건조시켜, 추가의 정제없이 사용되는 표제 화합물을 수득하였다. 1H NMR(500 MHz, CD30D) : δ 7.3-7.0(m, 9H), 5.05(m, 1H), 3.2-3.0(m, 3H), 2.80(s, 3H), 1.40(d, 3H).Triethyl amine (activated minutes) at 0 ° C. in a solution of 4- (4-chlorophenyl) -3-phenyl-2-butanol (step E, more rapidly eluting isomer, 9.0 g, 34 mmol) in EtOAc (100 mL) Drying on itself, 5.8 mL. 42 mmol) and methanesulfonyl chloride (3.0 mL, 38 mmol) were added. After stirring at 0 ° C. for 30 minutes, the reaction was quenched by addition of saturated aqueous sodium borohydride (100 mL). After stirring for 1 hour at room temperature, the organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to afford the title compound which was used without further purification. 1 H NMR (500 MHz, CD 3 0D): δ 7.3-7.0 (m, 9H), 5.05 (m, 1H), 3.2-3.0 (m, 3H), 2.80 (s, 3H), 1.40 (d, 3H ).

단계 G 2-아지도-4-(4-클로로페닐)-3-페닐부탄. Step G 2-azido-4- (4-chlorophenyl) -3-phenylbutane.

DMF(50mL) 중의 4-(4-클로로페닐)-2-메탄설포닐옥시-3-페닐부탄(단계 F, 12g, 34mmol)의 용액에 나트륨 아지드(11g, 0.17mol)을 첨가하였다. 120℃에서 1시간 동안 교반한 후, 반응 혼합물을 물(200mL)에 붓고, 생성물을 에테르(2 x 100mL)로 추출하였다. 합한 유기 추출물을 물로 세척하고 MgSO4상에서 건조시키고 여과하고, 농축 건조시키고, 잔사를 실리카 겔 컬럼에서 헥산으로 용출시켜 정제하여 표제 화합물을 수득하였다.To a solution of 4- (4-chlorophenyl) -2-methanesulfonyloxy-3-phenylbutane (step F, 12 g, 34 mmol) in DMF (50 mL) was added sodium azide (11 g, 0.17 mol). After stirring for 1 h at 120 ° C., the reaction mixture was poured into water (200 mL) and the product was extracted with ether (2 × 100 mL). The combined organic extracts were washed with water, dried over MgSO 4 , filtered, concentrated to dryness and the residue was purified by eluting with hexanes on a silica gel column to afford the title compound.

단계 H 2-(N-3급-부톡시카보닐)아미노-4-(4-클로로페닐)-3-페닐부탄 Step H 2- (N-tert-butoxycarbonyl) amino-4- (4-chlorophenyl) -3-phenylbutane

EtOAc(150mL)중의 2-아지도-4-(4-클로로페닐)-3-페닐부탄(단계 G, 7.0g, 24mmol)의 용액에 디(3급-부틸)디카보네이트(8.0g, 37mmol) 및 이산화백금(0.50g, 2.2mmol)을 첨가하였다. 혼합물을 탈기시키고 풍선을 이용하여 수소로 충전시켰다. 1일 동안 교반한 후, 반응 혼합물을 CELITE 규조토를 통해 여과하고, 여액을 농축시켜, 미반응된 일부 디(3급-부틸)디카보네이트로 오염된 조 생성물을 수득하였다. 1H NMR(500 MHz, CD3OD): δ7.25-6.88(m, 9H), 3.89(m, 1H), 3.20(m, 1H), 2.86-2.77(m, 2H), 1.54(s, 9H), 0.92(d, 3H).Di (tert-butyl) dicarbonate (8.0 g, 37 mmol) in a solution of 2-azido-4- (4-chlorophenyl) -3-phenylbutane (step G, 7.0 g, 24 mmol) in EtOAc (150 mL). And platinum dioxide (0.50 g, 2.2 mmol) was added. The mixture was degassed and charged with hydrogen using a balloon. After stirring for 1 day, the reaction mixture was filtered through CELITE diatomaceous earth and the filtrate was concentrated to give the crude product contaminated with some unreacted di (tert-butyl) dicarbonate. 1 H NMR (500 MHz, CD 3 OD): δ 7.25-6.88 (m, 9H), 3.89 (m, 1H), 3.20 (m, 1H), 2.86-2.77 (m, 2H), 1.54 (s, 9H), 0.92 (d, 3H).

단계 I N-[3-(4-클로로페닐)-2-페닐-1-메틸프로필]-아민 하이드로클로라이드(부분입체이성체 α). Step I N- [3- (4-Chlorophenyl) -2-phenyl-1-methylpropyl] -amine hydrochloride (diastereomer α).

2-(N-3급-부톡시카보닐)아미노-4-(4-클로로페닐)-3-페닐부탄(단계 H, 7.0g, 24mmol)을 실온에서 30분 동안 EtOAc(100mL)중의 포화 염화수소 용액(디옥산중의 4M 염화수소를 사용하여 유사한 결과를 수득할 수 있다)으로 처리하였다. 혼합물을 농축 건조시켜 표제 화합물을 수득하였다. 1H NMR(500 MHz, CD3OD): δ7.35-6.98(m, 9H), 3.62(m, 1H), 3.20(dd, 1H), 3.05(m, 1H), 2.98(dd, 1H), 1.19(d, 3H). LC-MS: m/e 260(M + H)+(2.3분).2- (N-tert-butoxycarbonyl) amino-4- (4-chlorophenyl) -3-phenylbutane (step H, 7.0 g, 24 mmol) was saturated hydrogen chloride in EtOAc (100 mL) for 30 minutes at room temperature. It was treated with a solution (4M hydrogen chloride in dioxane can be used to obtain similar results). The mixture was concentrated to dryness to afford the title compound. 1 H NMR (500 MHz, CD 3 OD): δ 7.35-6.98 (m, 9H), 3.62 (m, 1H), 3.20 (dd, 1H), 3.05 (m, 1H), 2.98 (dd, 1H) , 1.19 (d, 3 H). LC-MS: m / e 260 (M + H) + (2.3 min).

참조 실시예 4Reference Example 4

N-[3-(4-클로로페닐)-2(S)-페닐-1(S)-메틸프로필]-아민 하이드로클로라이드N- [3- (4-Chlorophenyl) -2 (S) -phenyl-1 (S) -methylpropyl] -amine hydrochloride

단계 A 4-(4-클로로페닐)-3(S)-페닐-2(R)-부탄올. Step A 4- (4-Chlorophenyl) -3 (S) -phenyl-2 (R) -butanol.

마그네슘 샘플(20g, 0.82mol)을 12시간 동안 질소하에 교반하여 활성화시키고, 무수 에테르(100mL)를 첨가하여 고체 물질을 보호시켰다. 혼합물을 0℃로 냉각시키고 400mL 무수 에테르 중의 4-클로로벤질 클로라이드(40g, 0.25mmol)를 적가하였다. 실온에서 1시간 동안 교반한 후, 상기 용액 샘플(32mL)을 0℃에서 주사기를 통해 100mL 에테르중의 (1R,2R)-1-페닐프로필렌 옥사이드(1.0g, 7.5mmol)에 첨가하였다. 0℃에서 2시간 동안 교반한 후, 반응물을 포화 수성 염화암모늄(100mL)을 첨가하여 급냉시켰다. 유기 층을 분리시키고, 수성 층을 에테르(2 x 100mL)로 추출하였다. 합한 유기 추출물을 염수로 세척하고, 무수 MgSO4상에서 건조시키고, 여과하고, 농축 건조시키고, 잔사를 실리카 겔에서 헥산 내지 헥산 중의 15% EtOAc로 용출시키면서 섬광 컬럼 크로마토그래피로 정제하여 표제 화합물을 수득하였다. 1H NMR(500 MHz, CD3OD): δ7.28-7.02(m, 9H), 4.01(m, 1H), 3.14(dd, 1H), 2.97(dd, 1H), 2.85(m, 1H), 1.12(d, 3H).A magnesium sample (20 g, 0.82 mol) was activated by stirring under nitrogen for 12 hours and anhydrous ether (100 mL) was added to protect the solid material. The mixture was cooled to 0 ° C. and 4-chlorobenzyl chloride (40 g, 0.25 mmol) in 400 mL anhydrous ether was added dropwise. After stirring for 1 hour at room temperature, the solution sample (32 mL) was added via syringe at 0 ° C. to (1R, 2R) -1-phenylpropylene oxide (1.0 g, 7.5 mmol) in 100 mL ether. After stirring at 0 ° C. for 2 hours, the reaction was quenched by addition of saturated aqueous ammonium chloride (100 mL). The organic layer was separated and the aqueous layer was extracted with ether (2 x 100 mL). The combined organic extracts were washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated to dryness and the residue was purified by flash column chromatography eluting with silica gel from hexanes to 15% EtOAc in hexanes to afford the title compound. . 1 H NMR (500 MHz, CD 3 OD): δ 7.28-7.02 (m, 9H), 4.01 (m, 1H), 3.14 (dd, 1H), 2.97 (dd, 1H), 2.85 (m, 1H) , 1.12 (d, 3 H).

단계 B N-[3-(4-클로로페닐)-2(S)-페닐-1(S)-메틸프로필]-아민, 하이드로클로라이드 Step B N- [3- (4-Chlorophenyl) -2 (S) -phenyl-1 (S) -methylpropyl] -amine, hydrochloride

단계 A의 생성물(4-(4-클로로페닐)-3(S)-페닐-2(R)-부탄올, 1.8g, 7.0mmol)을, EtOAc중의 염화수소 대신에 디옥산(4M) 중의 염화수소가 사용된다는 것을 제외하고는 참조 실시예 3에서 기술한 단계, 단계 F 내지 I를 수행하여 표제 화합물로 전환시켰다. 1H NMR(500 MHz, CD3OD): δ7.35-6.98(m, 9H), 3.62(m, 1H), 3.20(dd, 1H), 3.05(m, 1H), 2.98(dd, 1H), 1.19(d, 3H). LC-MS: m/e 260(M + H)+(2.3분).The product of step A (4- (4-chlorophenyl) -3 (S) -phenyl-2 (R) -butanol, 1.8 g, 7.0 mmol) was used with hydrogen chloride in dioxane (4M) instead of hydrogen chloride in EtOAc. Except that, steps F to I described in Reference Example 3 were carried out to convert to the title compound. 1 H NMR (500 MHz, CD 3 OD): δ 7.35-6.98 (m, 9H), 3.62 (m, 1H), 3.20 (dd, 1H), 3.05 (m, 1H), 2.98 (dd, 1H) , 1.19 (d, 3 H). LC-MS: m / e 260 (M + H) + (2.3 min).

참조 실시예 5Reference Example 5

N-[3-(4-클로로페닐)-2-(3-피리딜)-1-메틸프로필]-아민, 하이드로클로라이드(부분입체이성체 α/β10: 1의 혼합물)N- [3- (4-chlorophenyl) -2- (3-pyridyl) -1-methylpropyl] -amine, hydrochloride (mixture of diastereomers α / β10: 1)

단계 A 4-(4-클로로페닐)-3-피리딜-2-부타논. Step A 4- (4-Chlorophenyl) -3-pyridyl-2-butanone.

100mL CH2Cl2 중의 3-피리딜아세톤 하이드로클로라이드[참조: Wibaud, van der V. Recl. Trav. Chim. Pays-Bas. 1952, 71, 798)(10g, 58mmol) 및 4-클로로벤질 클로라이드(9.1g, 58mmol)의 용액에 -78℃에서 수산화세슘 1수화물(39g, 0.23mol) 및 테트라부틸 암모늄 요오다이드(1g)을 첨가하였다. 반응물을 실온으로 밤새 가온시키고, 생성된 혼합물을 염수(100mL) 및 EtOAc(100mL) 사이에 분배시켰다. 유기 층을 분리시키고, 수성 층을 EtOAc(2 x 100mL)로 추출하였다. 합한 유기 추출물을 무수 MgSO4상에서 건조시키고, 여과하고 농축 건조시켜 표제 화합물을 수득하였다. 1H NMR(500 MHz, CD30D): δ 8.42(d, 1H), 8.34(d, 1H), 7.72(d, 1H), 7.40(dd, 1H), 7.18(d, 2H), 7.06(d, 1H), 4.23(dd, 1H), 3.38(dd, 1H), 2.95(dd, 1H), 2.10(s, 3H). LC-MS: m/e 260(M + H)+(1.9분).3-pyridylacetone hydrochloride in 100 mL CH 2 Cl 2 [Wbaud, van der V. Recl. Trav. Chim. Pays-Bas. In a solution of 1952, 71, 798 (10 g, 58 mmol) and 4-chlorobenzyl chloride (9.1 g, 58 mmol) cesium hydroxide monohydrate (39 g, 0.23 mol) and tetrabutyl ammonium iodide (1 g) at -78 ° C. Was added. The reaction was warmed to rt overnight and the resulting mixture was partitioned between brine (100 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous MgSO 4 , filtered and concentrated to dryness to afford the title compound. 1 H NMR (500 MHz, CD 3 0D): δ 8.42 (d, 1H), 8.34 (d, 1H), 7.72 (d, 1H), 7.40 (dd, 1H), 7.18 (d, 2H), 7.06 ( d, 1H), 4.23 (dd, 1H), 3.38 (dd, 1H), 2.95 (dd, 1H), 2.10 (s, 3H). LC-MS: m / e 260 (M + H) + (1.9 min).

단계 B N-[3-(4-클로로페닐)-2-(3-피리딜)-1-메틸프로필]-아민, 하이드로클로라이드(부분입체이성체 α/β 10:1의 혼합물). Step B N- [3- (4-Chlorophenyl) -2- (3-pyridyl) -1-methylpropyl] -amine, hydrochloride (mixture of diastereomers α / β 10: 1).

단계 A의 생성물(4-(4-클로로페닐)-3-피리딜-2-부타논)(14g, 57mmol)을 참조 실시예 3의 단계 E 내지 I에서 기술한 방법을 수행하여 표제 화하물로 전환시켰다. LC-MS: m/e 261(M + H)+(1.2분).The product of step A (4- (4-chlorophenyl) -3-pyridyl-2-butanone) (14 g, 57 mmol) was subjected to the method described in steps E to I of Example 3 as the title compound. Switched. LC-MS: m / e 261 (M + H) + (1.2 min).

참조 실시예 6Reference Example 6

2-(2-플루오로페닐옥시)-2-메틸프로피온산2- (2-fluorophenyloxy) -2-methylpropionic acid

단계 A 2-(2-플루오로페닐옥시)-2-메틸프로피온산 Step A 2- (2-Fluorophenyloxy) -2-methylpropionic acid

아세톤(100mL) 중의 2-플루오로페놀(2.0g, 18mmol) 및 1,1,1-트리클로로-2-메틸-2-프로판올(7.9g, 45mmol)의 용액에 수산화나트륨(7.1g, 0.18mol)을 첨가하고, 빙수 욕조를 주기적으로 적용시켜 온화한 환류를 유지시켰다. 환류가 소멸된 후, 반응물을 추가로 1시간 동안 교반하였다. 휘발성 물질을 회전 증발기에서 제거하고, 잔사를 에테르(100mL), 헥산(100mL) 및 물(200mL) 사이에 분배시켰다. 수성 층을 분리시키고 진한 황산(pH = 2)으로 산성화시키고 에테르(3 x 100mL)로 추출하였다. 합한 추출물을 무수 MgSO4상에서 건조시키고, 여과하고, 농축 건조시켜, 추가의 정제없이 사용되는 표제 화합물을 수득하였다. 1H NMR(500 MHz, CD3OD): δ7.15-7.05(m, 4H), 1.56(s, 6H). LC-MS: m/e 199(M + 1)+(2.3분).Sodium hydroxide (7.1 g, 0.18 mol) in a solution of 2-fluorophenol (2.0 g, 18 mmol) and 1,1,1-trichloro-2-methyl-2-propanol (7.9 g, 45 mmol) in acetone (100 mL) ) And an ice bath was applied periodically to maintain a gentle reflux. After reflux disappeared, the reaction was stirred for an additional hour. The volatiles were removed on a rotary evaporator and the residue was partitioned between ether (100 mL), hexane (100 mL) and water (200 mL). The aqueous layer was separated, acidified with concentrated sulfuric acid (pH = 2) and extracted with ether (3 x 100 mL). The combined extracts were dried over anhydrous MgSO 4 , filtered and concentrated to dryness to afford the title compound which was used without further purification. 1 H NMR (500 MHz, CD 3 OD): δ 7.15-7.05 (m, 4H), 1.56 (s, 6H). LC-MS: m / e 199 (M + 1) + (2.3 min).

참조 실시예 7 및 8의 산은 2-플루오로페놀을 적절하게 치환된 페놀로 대체시켜 참조 실시예 6에 대해 기술한 방법을 수행하여 제조하였다. The acids of Reference Examples 7 and 8 were prepared by performing the method described for Reference Example 6 by replacing 2-fluorophenol with an appropriately substituted phenol.

참조 실시예 7Reference Example 7

2-(3-클로로페닐옥시)-2-메틸프로피온산2- (3-Chlorophenyloxy) -2-methylpropionic acid

1H NMR(500 MHz, CD3OD): δ 7.23(t, 1H), 7.00(dd, 1H), 6.93(t, 1H), 6.84(dd, 1H), 1.59(s, 6H). 1 H NMR (500 MHz, CD 3 OD): δ 7.23 (t, 1H), 7.00 (dd, 1H), 6.93 (t, 1H), 6.84 (dd, 1H), 1.59 (s, 6H).

LC-MS: m/e 215(M + 1)+(2.7분).LC-MS: m / e 215 (M + 1) + (2.7 min).

참조 실시예 8Reference Example 8

2-(3,5-디클로로페닐옥시)-2-메틸프로피온산2- (3,5-Dichlorophenyloxy) -2-methylpropionic acid

1H NMR(500 MHz, CD30D): δ 7.05(t, 1H), 6.84(d, 2H), 1.60(s, 6H). 1 H NMR (500 MHz, CD 3 0D): δ 7.05 (t, 1H), 6.84 (d, 2H), 1.60 (s, 6H).

참조 실시예 9Reference Example 9

2-(2-피리딜옥시)-2-메틸부탄산2- (2-pyridyloxy) -2-methylbutanoic acid

단계 A 벤질 2-(2-피리딜옥시)프로피오네이트 Step A benzyl 2- (2-pyridyloxy) propionate

100mL CH2Cl2 중의 2-하이드록시피리딘(2.9g, 30mmol), 벤질 락테이트(5.0g, 21mmol) 및 트리페닐포스핀(12g, 47mmol)의 혼합물에 0℃에서 디에틸아조디카복실레이트(7.8mL, 45mmol)을 첨가하였다. 반응물을 4시간 동안 실온으로 가온시켰다. 수득된 혼합물을 헥산(100mL)으로 희석시키고 실리카 겔 20g로 농축시켰다. 물질을 실리카 겔 컬럼에 부하하고, 이를 헥산 중의 10% EtOAc로 용출시켜 표제 화합물을 수득하였다. 1H NMR(500 MHz, CD3OD): δ8.00(dd, 1H), 7.68(ddd, 1H), 7.36-7.28(m, 5 H), 6.94(dd, 1H), 6.84(dd, 1H), 5.30(q, 1H), 5.18(s, 2H), 1.59(d, 3H). LC-MS: m/e 258(M + H)+(3.3분).To a mixture of 2-hydroxypyridine (2.9 g, 30 mmol), benzyl lactate (5.0 g, 21 mmol) and triphenylphosphine (12 g, 47 mmol) in 100 mL CH 2 Cl 2 , diethylazodicarboxylate ( 7.8 mL, 45 mmol) was added. The reaction was allowed to warm to room temperature for 4 hours. The resulting mixture was diluted with hexane (100 mL) and concentrated to 20 g of silica gel. The material was loaded onto a silica gel column and eluted with 10% EtOAc in hexanes to afford the title compound. 1 H NMR (500 MHz, CD 3 OD): δ8.00 (dd, 1H), 7.68 (ddd, 1H), 7.36-7.28 (m, 5H), 6.94 (dd, 1H), 6.84 (dd, 1H ), 5.30 (q, 1 H), 5.18 (s, 2 H), 1.59 (d, 3 H). LC-MS: m / e 258 (M + H) + (3.3 min).

단계 B 벤질 2-(2-피리딜옥시)-2-메틸부타노에이트 Step B benzyl 2- (2-pyridyloxy) -2-methylbutanoate

무수 THF 10mL중의 벤질 2-(2-피리딜옥시)프로피오네이트(1.6g, 6.2mmol) 및 에틸 요오다이드(1.5mL, 25mmol)의 용액에 -78℃에서 나트륨 헥사메틸디실라지드(THF 중의 1M, 9.3mL, 9.3mmol)(톨루엔 중의 칼륨 헥사메틸디실라지드를 사용하여 유사한 결과를 수득할 수 있다)를 첨가하였다. 반응물을 2시간에 걸쳐 실온으로 가온시키고 포화 염화암모늄(100mL) 및 EtOAc(100mL) 사이에 분배시켰다. 유기 층을 분리시키고, 수성 층을 EtOAc(2 x 50mL)로 추출하였다. 합한 유기 추출물을 무수 황산나트륨상에서 건조시키고, 여과하고, 농축 건조시키고, 잔사를 실리카 겔에서 헥산 중의 10% EtOAc로 용출시키면서 섬광 컬럼 크로마토그래피로 정제하여 표제 화합물을 수득하였다. 1H NMR(500 MHz, CD30D): δ 7.87(dd, 1H), 7.63(ddd, 1H), 7.27(m, 3H), 7.18.(m, 2H), 6.85(dd, 1H), 6.74(dd, 1H), 5.08(ABq, 2H), 2.13(m, 1H), 1.94(m, 1H), 1.65(s, 3H), 0.95(t, 3H). LC-MS: m/e 286(M + H)+(3.8분).To a solution of benzyl 2- (2-pyridyloxy) propionate (1.6 g, 6.2 mmol) and ethyl iodide (1.5 mL, 25 mmol) in 10 mL of dry THF, sodium hexamethyldisilazide (THF) at -78 ° C. 1M in 9.3 mL, 9.3 mmol) (similar results can be obtained using potassium hexamethyldisilazide in toluene). The reaction was allowed to warm to room temperature over 2 hours and partitioned between saturated ammonium chloride (100 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, concentrated to dryness and the residue was purified by flash column chromatography eluting with silica gel in 10% EtOAc in hexanes to afford the title compound. 1 H NMR (500 MHz, CD 3 0D): δ 7.87 (dd, 1H), 7.63 (ddd, 1H), 7.27 (m, 3H), 7.18. (M, 2H), 6.85 (dd, 1H), 6.74 (dd, 1H), 5.08 (ABq, 2H), 2.13 (m, 1H), 1.94 (m, 1H), 1.65 (s, 3H), 0.95 (t, 3H). LC-MS: m / e 286 (M + H) + (3.8 min).

단계 C 2-(2-피리딜옥시)-2-메틸부탄산 Step C 2- (2-Pyridyloxy) -2-methylbutanoic acid

MeOH 50mL 중의 벤질 2-(2-피리딜옥시)-2-메틸부타노에이트(1.6g, 5.5mmol)과 10% 탄소상 팔라듐(50mg)의 혼합물을 탈기시키고 풍선을 이용하여 수소로 충전시켰다. 실온에서 밤새 교반한 후, 반응 혼합물을 CELITE 규조토를 통해 여과하고 MeOH(20mL)로 세척하고, 여액을 농축 건조시켜 표제 화합물을 수득하였다. 1H NMR(500 MHz, CD3OD): δ 8.03(dd, 1H), 7.64(ddd, 1H), 6.89(dd, 1H), 6.76(dd, 1H), 2.14(m, 1H), 1.94(m, 1H), 1.64(s, 3H), 0.99(t, 3H). LC-MS: m/e 196(M + H)+(1.8분).A mixture of benzyl 2- (2-pyridyloxy) -2-methylbutanoate (1.6 g, 5.5 mmol) and 10% palladium on carbon (50 mg) in 50 mL MeOH was degassed and charged with hydrogen using a balloon. After stirring at room temperature overnight, the reaction mixture was filtered through CELITE diatomaceous earth, washed with MeOH (20 mL) and the filtrate was concentrated to dryness to afford the title compound. 1 H NMR (500 MHz, CD 3 OD): δ 8.03 (dd, 1H), 7.64 (ddd, 1H), 6.89 (dd, 1H), 6.76 (dd, 1H), 2.14 (m, 1H), 1.94 ( m, 1H), 1.64 (s, 3H), 0.99 (t, 3H). LC-MS: m / e 196 (M + H) + (1.8 min).

참조 실시예 10Reference Example 10

2-(2-피리딜옥시)-2-메틸프로피온산2- (2-pyridyloxy) -2-methylpropionic acid

표제 화합물을, 단계 B에서 에틸 요오다이드 및 나트륨 헥사메틸디실라지드를 각각 메틸 요오다이드 및 칼륨 헥사메틸디실라지드로 대체시켜 참조 실시예 9에 대해 기술한 방법을 수행하여 제조하였다.The title compound was prepared by performing the method described for Reference Example 9 by replacing ethyl iodide and sodium hexamethyldisilazide with methyl iodide and potassium hexamethyldisilazide in step B, respectively.

1H NMR(500 MHz, CD3OD): δ 8.04(dd, 1H), 7.64(ddd, 1H), 6.89(dd, 1H), 6.76(dd, 1H), 1.66(s, 6H). LC-MS: m/e 182(M + H)+(1.5분). 1 H NMR (500 MHz, CD 3 OD): δ 8.04 (dd, 1H), 7.64 (ddd, 1H), 6.89 (dd, 1H), 6.76 (dd, 1H), 1.66 (s, 6H). LC-MS: m / e 182 (M + H) + (1.5 min).

참조 실시예 11 Reference Example 11

N-[3-(4-클로로페닐)-2-(3,5-디플루오로페닐)-1-메틸프로필]아민 하이드로클로라이드(부분입체이성체 α)N- [3- (4-chlorophenyl) -2- (3,5-difluorophenyl) -1-methylpropyl] amine hydrochloride (diastereomer α)

표제 화합물을, 단계 A에서 메틸 페닐아세테이트를 메틸 3,5-디플루오로페닐아세테이트(3,5-디플루오로페닐아세트산 및 트리메틸실릴디아조메탄으로부터 제조함)로 대체시키고 단계 E에서 MeOH 중의 수소화붕소나트륨을 THF 중의 리튬 트리(2급-부틸보로하이드라이드)로 대체시켜 참조 실시예 3에 대해 기술한 방법을 수행하여 제조하였다. LC-MS: m/e 296(M + H)+(2.39분).The title compound was replaced with methyl phenylacetate in step A with methyl 3,5-difluorophenylacetate (prepared from 3,5-difluorophenylacetic acid and trimethylsilyldiazomethane) and hydrogenated in MeOH in step E Sodium boron was prepared by performing the method described for Reference Example 3 by replacing lithium tri (secondary-butylborohydride) in THF. LC-MS: m / e 296 (M + H) + (2.39 min).

참조 실시예 12Reference Example 12

N-[3-(4-클로로페닐)-2-(3-시아노페닐)-1-메틸프로필]아민 하이드로클로라이드(부분입체이성체 α)N- [3- (4-chlorophenyl) -2- (3-cyanophenyl) -1-methylpropyl] amine hydrochloride (diastereomer α)

단계 A 2-(N-3급-부톡시카보닐)아미노-4-(4-클로로페닐)-3-(3-시아노페닐)부탄 Step A 2- (N-tert-butoxycarbonyl) amino-4- (4-chlorophenyl) -3- (3-cyanophenyl) butane

5mL DMF중의 2-(N-3급-부톡시카보닐)아미노-3-브로모페닐-4-(4-클로로페닐)부탄(참조 실시예 3의 단계 H에 따라 제조함, 1.0g, 2.3mmol)의 용액에 시안화아연(0.16g, 1.4mmol), 트리스(디벤질리덴-아세톤)디팔라듐 클로로포름 착물(3.0mg, 2.8μmol), 1,1'-비스(디페닐포스피노)페로센(5.0mg, 9.0μmol) 및 물(0.1mL)을 첨가하였다. 질소하에 120℃에서 6시간 동안 가열한 후, 시안화아연(0.16g, 1.4mmol), 트리스(디벤질리덴아세톤)디팔라듐 클로로포름 착물(5.0mg, 4.8μmol), 1,1'-비스(디페닐포스피노)페로센(5.0mg, 9.0μmol) 및 물(0.05mL)의 또 다른 뱃치를 첨가하고, 다시 18시간 동안 가열을 지속하였다. 실온으로 냉각시킨 후, 생성된 혼합물을 물(50mL)과 에테르(50mL) 사이에 분배시켰다. 유기 층을 분리시키고, 수성 층을 에테르(2 x 50mL)로 추출하였다. 합한 추출물을 무수 MgSO4상에서 건조시키고, 여과하고, 농축시키고, 잔사를 실리카 겔에서 헥산 중의 20% EtOAc로 용출시키면서 섬광 컬럼 크로마토그래피로 정제하여 표제 화합물을 수득하였다. 1H NMR(400 MHz, CD3OD): δ7.6-7.3(m, 4H), 7.10(d, 2H), 6.92(d, 2H), 3.88(m, 1H), 3.20(m, 1H), 2.97(m, 1H), 1.82(m, 1H), 1.45(s, 9H), 0.94(d, 3H). LC-MS: m/e 385(M + H)+(3.9분).2- (N-tert-butoxycarbonyl) amino-3-bromophenyl-4- (4-chlorophenyl) butane in 5 mL DMF (prepared according to step H of Reference Example 3, 1.0 g, 2.3 mmol) in a solution of zinc cyanide (0.16 g, 1.4 mmol), tris (dibenzylidene-acetone) dipalladium chloroform complex (3.0 mg, 2.8 μmol), 1,1'-bis (diphenylphosphino) ferrocene (5.0 mg, 9.0 μmol) and water (0.1 mL) were added. After heating for 6 hours at 120 ° C. under nitrogen, zinc cyanide (0.16 g, 1.4 mmol), tris (dibenzylideneacetone) dipalladium chloroform complex (5.0 mg, 4.8 μmol), 1,1′-bis (diphenyl Another batch of phosphino) ferrocene (5.0 mg, 9.0 μmol) and water (0.05 mL) was added and heating was continued for another 18 hours. After cooling to room temperature, the resulting mixture was partitioned between water (50 mL) and ether (50 mL). The organic layer was separated and the aqueous layer was extracted with ether (2 x 50 mL). The combined extracts were dried over anhydrous MgS0 4 , filtered, concentrated and the residue was purified by flash column chromatography eluting with silica gel in 20% EtOAc in hexanes to afford the title compound. 1 H NMR (400 MHz, CD 3 OD): δ 7.6-7.3 (m, 4H), 7.10 (d, 2H), 6.92 (d, 2H), 3.88 (m, 1H), 3.20 (m, 1H) , 2.97 (m, 1 H), 1.82 (m, 1 H), 1.45 (s, 9 H), 0.94 (d, 3H). LC-MS: m / e 385 (M + H) + (3.9 min).

단계 B N-[3-(4-클로로페닐)-2-(3-시아노페닐)-1-메틸프로필]아민 하이드로클로라이드(부분입체이성체 α) Step B N- [3- (4-Chlorophenyl) -2- (3-cyanophenyl) -1-methylpropyl] amine hydrochloride (diastereomer α)

표제 화합물을 참조 실시예 3의 단계 I에 대해 기술한 방법을 수행하여 제조하였다. LC-MS: m/e 285(M + H)+(2.2분).The title compound was prepared by following the method described for step I of Reference Example 3. LC-MS: m / e 285 (M + H) + (2.2 min).

참조 실시예 13Reference Example 13

2-메틸-2-(5-클로로-2-피리딜옥시)프로피온산 2-Methyl-2- (5-chloro-2-pyridyloxy) propionic acid

단계 A 에틸 2-메틸-2-(5-클로로-2-피리딜옥시)프로피오네이트 Step A ethyl 2-methyl-2- (5-chloro-2-pyridyloxy) propionate

50mL 아세토니트릴 중의 5-클로로-2-하이드록시피리딘(5.0g, 39mmol), 에틸 2-브로모이소부티레이트(5.7mL, 39mmol)과 탄산세슘(25g, 77mmol)의 혼합물을 50℃에서 밤새 가열하였다. 휘발성 물질을 회전 증발기에서 농축시켜 제거하고, 잔사를 물(100mL)과 EtOAc(100mL) 사이에 분배시켰다. 유기 층을 분리시키고, 수성 층을 EtOAc(2 x 100mL)로 추출하였다. 합한 유기 추출물을 무수 황산나트륨상에서 건조시키고, 여과하고, 농축 건조시키고, 잔사를 실리카 겔에서 헥산 중의 5% EtOAc로 용출시키면서 섬광 컬럼 크로마토그래피로 정제하여 표제 화합물을 수득하였다. 1H NMR(500 MHz, CD3OD): δ7.99(d, 1H), 7.67(dd, 1H), 6.68(d, 1H), 4.13(q, 2H), 1.64(s, 6H), 1.14(t, 3H). LC-MS: m/e 244(M + H)+(3.41분).A mixture of 5-chloro-2-hydroxypyridine (5.0 g, 39 mmol), ethyl 2-bromoisobutyrate (5.7 mL, 39 mmol) and cesium carbonate (25 g, 77 mmol) in 50 mL acetonitrile was heated at 50 ° C. overnight. . The volatiles were removed by concentration on a rotary evaporator and the residue was partitioned between water (100 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, concentrated to dryness and the residue was purified by flash column chromatography eluting with silica gel in 5% EtOAc in hexanes to afford the title compound. 1 H NMR (500 MHz, CD 3 OD): δ 7.99 (d, 1H), 7.67 (dd, 1H), 6.68 (d, 1H), 4.13 (q, 2H), 1.64 (s, 6H), 1.14 (t, 3H). LC-MS: m / e 244 (M + H) + (3.41 min).

단계 B 2-메틸-2-(5-클로로-2-피리딜옥시)프로피온산 Step B 2-Methyl-2- (5-chloro-2-pyridyloxy) propionic acid

아세토니트릴 15mL와 물 15mL중의 에틸 2-메틸-2-(5-클로로-2-피리딜옥시) 프로피오네이트와 수산화나트륨(0.85g, 21mmol)의 혼합물을 50℃에서 밤새 가열하였다. 휘발성 물질을 회전 증발기에서 농축시켜 제거하고, 잔사를 2M 염산(100mL)과 에테르(100mL) 사이에 분배시켰다. 유기 층을 분리시키고, 물(2 x 50mL)로 세척하고, 무수 MgSO4상에서 건조시키고, 여과하고, 농축 건조시켜 표제 화합물을 수득하였다. 1H NMR(500 MHz, CD30D): δ 8.02(d, 1H), 7.65(dd, 1H), 6.77(d, 1H), 1.62(s, 6H). LC-MS: m/e 216(M + H)+(2.33분).A mixture of ethyl 2-methyl-2- (5-chloro-2-pyridyloxy) propionate and sodium hydroxide (0.85 g, 21 mmol) in 15 mL acetonitrile and 15 mL water was heated at 50 ° C. overnight. The volatiles were removed by concentration in a rotary evaporator and the residue was partitioned between 2M hydrochloric acid (100 mL) and ether (100 mL). The organic layer was separated, washed with water (2 × 50 mL), dried over anhydrous MgSO 4 , filtered and concentrated to dryness to afford the title compound. 1 H NMR (500 MHz, CD 3 0D): δ 8.02 (d, 1H), 7.65 (dd, 1H), 6.77 (d, 1H), 1.62 (s, 6H). LC-MS: m / e 216 (M + H) + (2.33 min).

참조 실시예 14Reference Example 14

2-메틸-2-(5-트리플루오로메틸-2-피리딜옥시)프로피온산2-Methyl-2- (5-trifluoromethyl-2-pyridyloxy) propionic acid

표제 화합물을 단계 A에서 5-클로로-2-하이드록스피리딘을 5-트리플루오로메틸-2-하이드록스피리딘으로 대체시켜 참조 실시예 13에 대해 기술한 방법을 수행하여 제조하였다. 1H NMR(500 MHz, CD30D): δ 8.38(br s, 1H), 7.93(dd, 1H), 7.13(d, 1H), 1.70(s, 6H). LC-MS: m/e 250(M + H)+(2.6분).The title compound was prepared by following the method described for Reference Example 13 by replacing 5-chloro-2-hydroxypyridine with 5-trifluoromethyl-2-hydroxypyridine in Step A. 1 H NMR (500 MHz, CD 3 0D): δ 8.38 (br s, 1 H), 7.93 (dd, 1 H), 7.13 (d, 1 H), 1.70 (s, 6 H). LC-MS: m / e 250 (M + H) + (2.6 min).

참조 실시예 15Reference Example 15

2-메틸-2-(6-메틸-2-피리딜옥시)프로피온산2-Methyl-2- (6-methyl-2-pyridyloxy) propionic acid

표제 화합물을 5-클로로-2-하이드록스피리딘을 단계 A에서 6-메틸-2-하이드록스피리딘으로 대체시켜 참조 실시예 13에 대해 기술한 방법을 수행하여 제조하였다. 1H NMR(500 MHz, CD3OD): δ7.51(t, 1H), 6.74(d, 1H), 6.53(d, 1H), 2.34(s, 3H), 1.64(s, 6H). LC-MS: m/e 196(M + H)+(1.3분).The title compound was prepared by following the method described for Reference Example 13, replacing 5-chloro-2-hydroxypyridine with 6-methyl-2-hydroxypyridine in Step A. 1 H NMR (500 MHz, CD 3 OD): δ 7.51 (t, 1H), 6.74 (d, 1H), 6.53 (d, 1H), 2.34 (s, 3H), 1.64 (s, 6H). LC-MS: m / e 196 (M + H) + (1.3 min).

참조 실시예 16Reference Example 16

2-아미노-3-(1-(1,2,3-트리아졸릴))-4-(4-클로로페닐)부탄:2-amino-3- (1- (1,2,3-triazolyl))-4- (4-chlorophenyl) butane:

단계 A 벤질 2-(1-(1,2,3-트리아졸릴))아세테이트: Step A Benzyl 2- (1- (1,2,3-triazolyl)) acetate:

CH2Cl2 40mL 중의 1,2,3-트리아졸(2.07g, 30mmol), 페닐 브로모아세테이트(6.9g, 30mmol)과 디이소프로필에틸아민(5,1mL, 30mmol)의 혼합물을 실온에서 밤새 교반하였다. 이어서, 상기 혼합물을 추가의 침전물이 형서되지 않을 때까지 에테르로 희석시켰다. 고체를 여과하고 에테르로 세척하였다. 여액을 농축시키고 잔사를 실리카 겔에서 CH2C12중의 10% 헥산을 사용하여 표제 화합물의 이성체, 벤질 2-(2-(1,2,3-트리아졸릴) 아세테이트를 무정형 고체로서 수득하였다. 등량의 에테르와 CH2Cl2를 함유하는 용매 혼합물로 추가로 용출시켜 표제 화합물을 무정형 고체로서 수득하였다. 1H NMR(400 MHz, CDC13): δ 2.251(s, 2H0, 7.267-7.390(m, 5H), 7.723(s, 1H), 7.785(s, LH).A mixture of 1,2,3-triazole (2.07 g, 30 mmol), phenyl bromoacetate (6.9 g, 30 mmol) and diisopropylethylamine (5,1 mL, 30 mmol) in 40 mL CH 2 Cl 2 overnight at room temperature Stirred. The mixture was then diluted with ether until no further precipitate formed. The solid was filtered off and washed with ether. The filtrate was concentrated and the residue was obtained on silica gel using 10% hexane in CH 2 C1 2 to give the isomer of the title compound, benzyl 2- (2- (1,2,3-triazolyl) acetate as an amorphous solid. Further elution with a solvent mixture containing ether and CH 2 Cl 2 gave the title compound as an amorphous solid: 1 H NMR (400 MHz, CDC1 3 ): δ 2.251 (s, 2H0, 7.267-7.390 (m, 5H), 7.723 (s, 1 H), 7.785 (s, LH).

단계 B 2-(1-(1,2,3-트리아졸릴))아세트산: Step B 2- (1- (1,2,3-triazolyl)) acetic acid:

수산화팔라듐(탄소상 20%, 800mg)를 MeOH 150mL중의 벤질 2-(1-(1,2,3-트리아졸릴))아세테이트(단계 A, 8.68g, 39.9mmol)의 용액에 첨가하고, 혼합물을 실온 및 45psi에서 수소 대기하에 파르(Parr) 진탕기에서 밤새 수소화시켰다. 결정을 CELITE 규조토 베드를 통해 여과하고 MeOH로 세척하였다. 여액을 농축시켜 고체를 수득하고, 이를 진공하에 50℃에서 36시간 동안 건조시켜 표제 화합물을 수득하였다. 1H NMR(400 MHz, CD3OD): δ5.3(s, 2H), 7,75(s, 1HO, 8.016(s, 1H).Palladium hydroxide (20% on carbon, 800 mg) was added to a solution of benzyl 2- (1- (1,2,3-triazolyl)) acetate (step A, 8.68 g, 39.9 mmol) in 150 mL of MeOH and the mixture was Hydrogenation overnight on a Parr shaker under hydrogen atmosphere at room temperature and 45 psi. The crystals were filtered through a CELITE diatomaceous earth bed and washed with MeOH. The filtrate was concentrated to give a solid which was dried under vacuum at 50 ° C. for 36 hours to afford the title compound. 1 H NMR (400 MHz, CD 3 OD): δ 5.3 (s, 2H), 7,75 (s, 1HO, 8.016 (s, 1H).

단계 C N-메톡시-N-메틸-2-(1-(1,2,3-트리아졸릴))아세트아미드: Step C N-methoxy-N-methyl-2- (1- (1,2,3-triazolyl)) acetamide:

옥살릴 클로라이드(0.95mL, 11mmol)를 DMF 0.05mL를 함유하는 CH2Cl2 10mL 중의 2-(1-1,2,3-트리아졸릴))아세트산(단계 B, 1.27g, 10mmol)의 현탁액에 적가하였다. 활발한 발포작용이 관찰되었다. 상기 혼합물을 실온에서 4시간 동안 교반하고 -78℃로 냉각시켰다. CH2C12 10mL 중의 N,O-디메틸하이드록실아민 하이드로클로라이드(1.2g, 13mmol) 및 디이소프로필에틸 아민(6.0mL, 35mmol)을 3분에 걸쳐 천천히 첨가하였다. 이어서, 혼합물을 실온으로 가온시키고 밤새 교반하였다. 이어서, 반응 혼합물을 추가의 침전물이 보이지 않을 때까지 에테르로 희석시켰다. 고체를 여과하고 에테르로 세척하였다. 여액을 농축시키고, 잔사를 실리카 겔에서 용매로서 EtOAc를 사용하여 정제하여 표제 화합물을 무정형 고체로서 수득하였다. 1H NMR(400 MHz, CDCl3): δ 3.252(s, 3H0, 3.812(s, 3H), 5.379(s, 2H), 7.753 & 7.761(s's, 2H).Oxalyl chloride (0.95 mL, 11 mmol) was added to a suspension of 2- (1-1,2,3-triazolyl)) acetic acid (step B, 1.27 g, 10 mmol) in 10 mL of CH 2 Cl 2 containing 0.05 mL of DMF. Added dropwise. Active foaming was observed. The mixture was stirred at rt for 4 h and cooled to -78 ° C. N, O-dimethylhydroxylamine hydrochloride (1.2 g, 13 mmol) and diisopropylethyl amine (6.0 mL, 35 mmol) in 10 mL of CH 2 C1 2 were slowly added over 3 minutes. The mixture was then warmed to room temperature and stirred overnight. The reaction mixture was then diluted with ether until no further precipitate was seen. The solid was filtered off and washed with ether. The filtrate was concentrated and the residue was purified on silica gel using EtOAc as solvent to afford the title compound as an amorphous solid. 1 H NMR (400 MHz, CDCl 3 ): δ 3.252 (s, 3HO, 3.812 (s, 3H), 5.379 (s, 2H), 7.753 & 7.761 (s's, 2H).

단계 D N-메톡시-N-메틸-3-(4-클로로페닐)-2-(1-(1,2,3-트리아졸릴))프로피온아미드 Step D N-methoxy-N-methyl-3- (4-chlorophenyl) -2- (1- (1,2,3-triazolyl)) propionamide

리튬 헥사메틸디실라지드(THF 중의 1M, 8.4mL, 8.4mmol)를 -78℃에서 THF 15mL 중의 N-메톡시-N-메틸-2-(1-(1,2,3-트리아졸릴))아세트아미드(단계 C, 1.19g, 7mmol)의 용액에 적가하였다. 30분 동안 추가로 교반한 후, 5mL THF 중의 4-클로로벤질 브로마이드(1.65g, 8mmol)의 용액을 적가하였다. 혼합물을 실온으로 가온시키고 5.5시간 동안 교반하였다. 상기 혼합물을 실리카 겔에서 헥산 중의 40% EtOAc를 사용하여 정제하여 표제 화합물을 수득하였다. 1H NMR(400 MHz, CDC13): δ 3.186(s, 3H), 3.234-3.267(m, 1H), 3.453-3.506(m, 1H), 3.582(s, 3H), 6.145-6.188(m, 1H), 7.048-7.279(m, 4H), 7.726(s, 1H), 7.954(s, 1H).Lithium hexamethyldisilazide (1M in THF, 8.4 mL, 8.4 mmol) was added N-methoxy-N-methyl-2- (1- (1,2,3-triazolyl) in 15 mL of THF at −78 ° C.) To the solution of acetamide (step C, 1.19 g, 7 mmol) was added dropwise. After further stirring for 30 minutes, a solution of 4-chlorobenzyl bromide (1.65 g, 8 mmol) in 5 mL THF was added dropwise. The mixture was allowed to warm to rt and stirred for 5.5 h. The mixture was purified on silica gel using 40% EtOAc in hexanes to afford the title compound. 1 H NMR (400 MHz, CDC1 3 ): δ 3.186 (s, 3H), 3.234-3.267 (m, 1H), 3.453-3.506 (m, 1H), 3.582 (s, 3H), 6.145-6.188 (m, 1H), 7.048-7.279 (m, 4H), 7.726 (s, 1H), 7.954 (s, 1H).

단계 E 2-아지도-3-(1-(1,2,3-트리아졸릴))-4-(4-클로로페닐)부탄: Step E 2-azido-3- (1- (1,2,3-triazolyl))-4- (4-chlorophenyl) butane:

단계 D의 생성물 N-메톡시-N-메틸-3-(4-클로로페닐)-2-(1-(1,2,3-트리아졸릴)프로피온아미드를 참조 실시예 3의 단계 D 내지 G에 기재된 방법을 수행하여 표제 화합물로 전환시켰다. 1H NMR(400 MHz, CDC13): δ 1.219-1.246(d's 3H), 3.253-4.754(m, 4H0, 6.866-7.299(d's, 4H), 7.313, 7.618, 7.63, & 7.706(s's, 2H).The product of step D, N-methoxy-N-methyl-3- (4-chlorophenyl) -2- (1- (1,2,3-triazolyl) propionamide, is referred to in steps D to G of Reference Example 3. The method described was followed to convert to the title compound: 1 H NMR (400 MHz, CDC1 3 ): δ 1.219-1.246 (d's 3H), 3.253-4.754 (m, 4H0, 6.866-7.299 (d's, 4H), 7.313, 7.618, 7.63, & 7.706 (s's, 2H).

단계 F 2-아미노-3-(1-(1,2,3-트리아졸릴))-4-(4-클로로페닐)부탄: Step F 2-Amino-3- (1- (1,2,3-triazolyl))-4- (4-chlorophenyl) butane:

산화백금(14mg)을 4mL MeOH 중의 2-아지도-3-(1-(1,2,3-트리아졸릴))-4-(4-클로로페닐)부탄(단계 E, 138mg, 0.5mmol)의 용액에 첨가하였다. 상기 혼합물을 실온에서 3시간 동안 수소로 충전된 풍선을 이용하여 수소 대기하에 수소화시켰다. 촉매를 CELITE 규조토 베드를 통해 여과하고 MeOH로 세척하였다. 여액을 농축시켜 표제 화합물을 오일로서 수득하였다. 1H NMR(400 MHz, CDCl3): δ 1.085-1.174(d's 3H), 3.220-3.361(m, 2H), 3.517-3.563(m, 1H), 4.379-4.431(m, 1H), 6.679-7.179(d's, 4H), 7.297, 7.40, 7.592 & 7.607(s's, 2H).Platinum oxide (14 mg) of 2-azido-3- (1- (1,2,3-triazolyl))-4- (4-chlorophenyl) butane (step E, 138 mg, 0.5 mmol) in 4 mL MeOH To the solution. The mixture was hydrogenated under a hydrogen atmosphere using a balloon filled with hydrogen at room temperature for 3 hours. The catalyst was filtered through a CELITE diatomaceous earth bed and washed with MeOH. The filtrate was concentrated to give the title compound as an oil. 1 H NMR (400 MHz, CDCl 3 ): δ 1.085-1.174 (d's 3H), 3.220-3.361 (m, 2H), 3.517-3.563 (m, 1H), 4.379-4.431 (m, 1H), 6.679-7.179 (d's, 4H), 7.297, 7.40, 7.592 & 7.607 (s's, 2H).

참조 실시예 17Reference Example 17

N-[3-(4-클로로페닐)-2-(3-메틸페닐)-1-메틸프로필]아민 하이드로클로라이드(부분입체이성체 α) N- [3- (4-chlorophenyl) -2- (3-methylphenyl) -1-methylpropyl] amine hydrochloride (diastereomer α)

단계 A 2-(N-3급-부톡시카보닐)아미노-4-(4-클로로페닐)-3-(3-메틸페닐)부탄 Step A 2- (N-tert-butoxycarbonyl) amino-4- (4-chlorophenyl) -3- (3-methylphenyl) butane

20mL 무수 DMF 중의 2-(N-3급-부톡시카보닐)아미노-3-(3-브로모페닐)-4-(4-클로로페닐)부탄(참조 실시예 3, 단계 H, 0.50g, 1.1mmol), 테트라메틸주석(0.41g, 2.3mmol), 트리페닐포스핀(0.12g, 0.46mmol), 염화리튬(0.38g, 9.1mmol)과 디클로로비스(트리페닐포스핀)팔라듐(0.12g, 0.17mmol)의 혼합물을 질소하에 18시간 동안 가열하였다. 반응 혼합물을 실온으로 냉각시키고 물(100mL)과 에테르(100mL) 사이에 분배시켰다. 유기 층을 분리시키고, 수성 층을 에테르(100mL)로 추출하였다. 합한 추출물을 무수 MgSO4상에서 건조시키고 여과하고 농축 건조시키고 잔사를 실리카 겔에서 헥산 중의 10% EtOAc로 용출시키면서 섬광 컬럼 크로마토그래피로 정제하여 표제 화합물을 수득하였다. 1H NMR(400 MHz, CD3OD): δ 7.2-6.8(m, 8H), 3.84(m, 1H), 3.16(m, 1H), 2.80-2.68(m, 2H), 2.24(s, 3H), 1.45(s, 9H), 0.86(d, 3H). LC-MS: m/e 396(M + Na)+(4.4분).2- (N-tert-butoxycarbonyl) amino-3- (3-bromophenyl) -4- (4-chlorophenyl) butane in 20 mL anhydrous DMF (Reference Example 3, Step H, 0.50 g, 1.1 mmol), tetramethyltin (0.41 g, 2.3 mmol), triphenylphosphine (0.12 g, 0.46 mmol), lithium chloride (0.38 g, 9.1 mmol) and dichlorobis (triphenylphosphine) palladium (0.12 g, 0.17 mmol) was heated under nitrogen for 18 hours. The reaction mixture was cooled to room temperature and partitioned between water (100 mL) and ether (100 mL). The organic layer was separated and the aqueous layer was extracted with ether (100 mL). The combined extracts were dried over anhydrous MgSO 4, filtered and concentrated to dryness and the residue was purified by flash column chromatography eluting with silica gel in 10% EtOAc in hexanes to afford the title compound. 1 H NMR (400 MHz, CD 3 OD): δ 7.2-6.8 (m, 8H), 3.84 (m, 1H), 3.16 (m, 1H), 2.80-2.68 (m, 2H), 2.24 (s, 3H ), 1.45 (s, 9 H), 0.86 (d, 3 H). LC-MS: m / e 396 (M + Na) + (4.4 min).

단계 B N-[3-(4-클로로페닐)-2-(3-메틸페닐)-1-메틸프로필]아민 하이드로클로라이드(부분입체이성체 α) Step B N- [3- (4-Chlorophenyl) -2- (3-methylphenyl) -1-methylpropyl] amine hydrochloride (diastereomer α)

표제 화합물을 참조 실시예 3의 단계 I에 대해 기술한 방법을 수행하여 제조하였다. LC-MS: m/e 274(M + H)+(2.5분).The title compound was prepared by following the method described for step I of Reference Example 3. LC-MS: m / e 274 (M + H) + (2.5 min).

참조 실시예 18Reference Example 18

N-[3-(5-클로로-2-피리딜)-2(S)-페닐-1(S)-메틸프로필]아민 하이드로클로라이드(부분입체이성체 α)N- [3- (5-chloro-2-pyridyl) -2 (S) -phenyl-1 (S) -methylpropyl] amine hydrochloride (diastereomer α)

단계 A 5-클로로-2-메틸피리딘 Step A 5-Chloro-2-methylpyridine

200mL 무수 DMF 중의 2,5-디클로로피리딘(15g, 0.10mol), 테트라메틸주석(15mL, 0.11mol)과 디클로로비스(트리페닐포스핀)팔라듐(2.0g, 2.8mmol)의 혼합물을 질소하에 72시간 동안 110℃에서 가열하였다. 반응 혼합물을 실온으로 냉각시키고 불화칼륨 포화 용액(200mL)에 부었다. 생성된 혼합물을 물(500mL)과 에테르(500mL) 사이에 분배시켰다. 유기 층을 분리시키고, 수성 층을 에테르(200mL)로 추출하였다. 합한 추출물을 무수 MgSO4상에서 건조시키고, 여과하고, 농축 건조시키고, 잔사를 실리카 겔에서 헥산 중의 2% 내지 10% 에테르로 용출시키면서 섬광 컬럼 크로마토그래피로 정제하여 표제 화합물을 수득하였다. 1H NMR(500 MHz, CD3OD): δ 8.41(d, 1H), 7.75(dd, 1H), 7.30(d, 1H), 2.53(s, 3H).A mixture of 2,5-dichloropyridine (15 g, 0.10 mol), tetramethyltin (15 mL, 0.11 mol) and dichlorobis (triphenylphosphine) palladium (2.0 g, 2.8 mmol) in 200 mL anhydrous DMF under nitrogen for 72 hours Heated at 110 ° C. The reaction mixture was cooled to room temperature and poured into saturated potassium fluoride solution (200 mL). The resulting mixture was partitioned between water (500 mL) and ether (500 mL). The organic layer was separated and the aqueous layer was extracted with ether (200 mL). The combined extracts were dried over anhydrous MgSO 4 , filtered, concentrated to dryness and the residue was purified by flash column chromatography eluting with 2% to 10% ether in hexane on silica gel to afford the title compound. 1 H NMR (500 MHz, CD 3 OD): δ 8.41 (d, 1H), 7.75 (dd, 1H), 7.30 (d, 1H), 2.53 (s, 3H).

단계 B 4-(5-클로로-2-피리딜)-3(S)-페닐-2(R)-부탄올.Step B 4- (5-Chloro-2-pyridyl) -3 (S) -phenyl-2 (R) -butanol .

15mL 무수 에테르 중의 5-클로로-2-메틸피리딘(단계 A, 1.1g, 8.7mmol)의 용액에 0℃에서 페닐 리튬(사이클로헥산/에테르 중의 1.8M, 7.2mL, 13mmol)을 첨가하고, 반응물을 실온에서 30분 동안 교반하였다. 생성된 혼합물을 다시 0℃로 냉각시키고 (1R,2R)-1-페닐프로필렌 옥사이드(2.3g, 17mmol)를 첨가하고, 반응물을 실온으로 밤새 가온시켰다. 반응 혼합물을 EtOAc(100mL)과 물(100mL) 사이에 분배시켰다. 유기 층을 분리시키고, 수성 층을 EtOAc(2 x 100mL)로 추출하였다. 합한 유기 추출물을 무수 MgSO4상에서 건조시키고 여과하고 농축 건조시키고, 잔사를 실리카 겔에서 헥산 중의 10% 내지 40% EtOAc로 용출시키면서 섬광 컬럼 크로마토그래피로 정제하여 표제 화합물을 수득하였다. 1H NMR(500 MHz, CD3OD): δ 8.28(d, 1H), 7.59(dd, 1H), 7.25-7.12(m, 5H), 7.05(d, 1H), 4.03(m, 1H), 3.29(dd, 1H), 3.19(dd, 1H), 3.12(m, 1H), 1.12(d, 3H).To a solution of 5-chloro-2-methylpyridine (step A, 1.1 g, 8.7 mmol) in 15 mL anhydrous ether was added phenyl lithium (1.8 M in cyclohexane / ether, 7.2 mL, 13 mmol) at 0 ° C. and the reaction was Stir at room temperature for 30 minutes. The resulting mixture was cooled back to 0 ° C. and (1R, 2R) -1-phenylpropylene oxide (2.3 g, 17 mmol) was added and the reaction was allowed to warm to room temperature overnight. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous MgSO 4, filtered and concentrated to dryness, and the residue was purified by flash column chromatography eluting with silica gel in 10% to 40% EtOAc in hexanes to afford the title compound. 1 H NMR (500 MHz, CD 3 OD): δ 8.28 (d, 1H), 7.59 (dd, 1H), 7.25-7.12 (m, 5H), 7.05 (d, 1H), 4.03 (m, 1H), 3.29 (dd, 1H), 3.19 (dd, 1H), 3.12 (m, 1H), 1.12 (d, 3H).

단계 C 2(S)-아지도-4-(5-클로로-2-피리딜)-3(S)-페닐부탄 Step C 2 (S) -azido-4- (5-chloro-2-pyridyl) -3 (S) -phenylbutane

5mL 무수 THF 중의 4-(5-클로로-2-피리딜)-3-페닐-2-부탄올(단계 B, 0.24g, 0.92mmol), 트리페닐포스핀(1.5g, 1.4mmol)과 디페닐포스포릴 아지드(0.30mL, 1.4mmol)의 혼합물에 디에틸아조디카복실레이트(0.24mL, 1.4mmol)를 첨가하였다. 실온에서 밤새 교반한 후, 생성된 혼합물을 실리카 겔(10g)로 농축시키고, 잔사를 실리카 겔 컬럼에 부하하였다. 헥산 중의 5% 내지 15% EtOAc로 용출시켜 표제 화합물을 수득하였다. 1H NMR(500 MHz, CD30D): δ 8.35(d, 1H), 7.52(dd, 1H), 7.25-7.05(m, 5H), 6.95(d, 1H), 3.81(m, 1H), 3.48(m, 1H), 3.15-3.05(m, 2H), 1.14(d, 3H).4- (5-chloro-2-pyridyl) -3-phenyl-2-butanol (step B, 0.24 g, 0.92 mmol) in 5 mL anhydrous THF, triphenylphosphine (1.5 g, 1.4 mmol) and diphenylphosph To a mixture of foryl azide (0.30 mL, 1.4 mmol) was added diethylazodicarboxylate (0.24 mL, 1.4 mmol). After stirring at room temperature overnight, the resulting mixture was concentrated with silica gel (10 g) and the residue was loaded on a silica gel column. Elution with 5% to 15% EtOAc in hexanes gave the title compound. 1 H NMR (500 MHz, CD 3 0D): δ 8.35 (d, 1H), 7.52 (dd, 1H), 7.25-7.05 (m, 5H), 6.95 (d, 1H), 3.81 (m, 1H), 3.48 (m, 1 H), 3.15-3.05 (m, 2 H), 1.14 (d, 3 H).

단계 D N-[3-(5-클로로-2-피리딜)-2(S)-페닐-1(S)-메틸프로필]아민, 하이드로클로라이드 Step D N- [3- (5-Chloro-2-pyridyl) -2 (S) -phenyl-1 (S) -methylpropyl] amine, hydrochloride

단계 C의 생성물(0.20g, 0.70mmol)을 EtOAc 중의 염화수소 대신에 디옥산(4M) 중의 염화 수소를 사용한다는 것을 제외하고는 참조 실시예 3의 단계 H 및 I에 기재된 방법을 수행하여 표제 화합물로 전환시켰다.The product of step C (0.20 g, 0.70 mmol) was subjected to the method described in steps H and I of Reference Example 3, except that hydrogen chloride in dioxane (4M) was used instead of hydrogen chloride in EtOAc to obtain the title compound. Switched.

1H NMR(500 MHz, CD30D): δ 8.75(d, 1H), 8.19(dd, 1H), 7.55(d, 1H), 7.4-7.2(m, 5H), 3.78(m, 1H), 3.62(dd, 1H), 3.48(m, 1H), 3.43(dd, 1H), 1.22(d, 3H). LC-MS: m/e 261(M + H)+(2.2분). 1 H NMR (500 MHz, CD 3 0D): δ 8.75 (d, 1H), 8.19 (dd, 1H), 7.55 (d, 1H), 7.4-7.2 (m, 5H), 3.78 (m, 1H), 3.62 (dd, 1H), 3.48 (m, 1H), 3.43 (dd, 1H), 1.22 (d, 3H). LC-MS: m / e 261 (M + H) + (2.2 min).

참조 실시예 19Reference Example 19

N-[2-(3-브로모페닐)-3-(5-클로로-2-피리딜)-1-메틸프로필]아민 하이드로클로라이드(부분입체이성체 α) N- [2- (3-bromophenyl) -3- (5-chloro-2-pyridyl) -1-methylpropyl] amine hydrochloride (diastereomer α)

단계 A 3-브로모페닐아세톤 Step A 3-Bromophenylacetone

100mL 무수 에테르 중의 N-메톡시-N-메틸아세트아미드(10g, 100mmol)의 용액에 0℃에서 3-브로모벤질마그네슘 브로마이드(에테르중의 0.25M, 200mL, 50mmol)을 첨가하였다. 반응물을 실온으로 밤새 가온시키고 포화 염화암모늄(100mL)을 첨가하여 급냉시켰다. 유기 층을 분리시키고, 수성 층을 헥산(100mL)으로 추출하였다. 합한 추출물을 무수 MgSO4상에서 건조시키고, 여과하고, 농축 건조시켜 표제 화합물을 수득하였다. 1H NMR(500 MHz, CD3OD): δ 7.45-7.40(m, 2H), 7.26(t, 1H), 7.19(d, 1H), 2.20(s, 3H).To a solution of N-methoxy-N-methylacetamide (10 g, 100 mmol) in 100 mL anhydrous ether was added 3-bromobenzylmagnesium bromide (0.25 M in ether, 200 mL, 50 mmol) at 0 ° C. The reaction was warmed to room temperature overnight and quenched by addition of saturated ammonium chloride (100 mL). The organic layer was separated and the aqueous layer was extracted with hexane (100 mL). The combined extracts were dried over anhydrous MgSO 4 , filtered and concentrated to dryness to afford the title compound. 1 H NMR (500 MHz, CD 3 OD): δ 7.45-7.40 (m, 2H), 7.26 (t, 1H), 7.19 (d, 1H), 2.20 (s, 3H).

단계 B 3-(3-브로모페닐)-4-(5-클로로-2-피리딜)-2-부타논 Step B 3-(3-Bromophenyl) -4- (5-chloro-2-pyridyl) -2-butanone

5-클로로-2-메틸피리딘(참조 실시예 18, 단계 A, 6.4g, 50mmol)의 현탁액 및 100mL 사염화탄소중의 N-브로모석신이미드(12.5g, 70mmol)를 가열하여 온화하게 환류(둘다 온도 90℃)시키고, 2,2'-아조비스이소부티로니트릴(0.74g)을 30분에 걸쳐서 수개의 분획으로 첨가하였다. 상기 온도에서 5시간 동안 교반한 후, 반응 혼합물을 농축시켰다. 생성된 슬러리를 EtOAc(100mL)로 희석시키고 물(100mL), 포화 수성 중탄산나트륨/포화 수성 티오황산나트륨 및 염수로 세척하였다. 유기 용액을 무수 황산나트륨상에서 건조시키고 여과하고 농축 건조시키고, 잔사를 실리카 겔에서 헥산 중의 2 내지 15% 에테르/CH2Cl2(1:1)로 용출시키면서 섬광 컬럼 크로마토그래피로 정제하여 2-브로모메틸-5-클로로피리딘(6.0g, 60%)을 수득하고, 이를 후속적 반응을 위해 즉시 사용하였다. 이어서, 30mL CH2C12 중의 2-브로모메틸-5-클로로피리딘(6.0g, 29mmol) 및 3-브로모페닐 아세톤(단계 A, 6.0g, 28mmol) 및 테트라부틸암모늄 요오다이드(20mg)의 격렬하게 교반되는 용액에 -78℃에서 수산화세슘 1수화물(10g, 60mmol)을 첨가하고, 반응물을 실온으로 밤새 천천히 가온시켰다. 반응 혼합물을 EtOAc(100mL)와 물(100mL) 사이에 분배시켰다. 유기 층을 분리시키고, 수성 층을 EtOAc(2 x 100mL)로 추출하였다. 합한 유기 추출물을 무수 황산나트륨상에서 건조시키고 여과하고 농축 건조시키고, 잔사를 실리카 겔에서 헥산 중의 5 내지 40% EtOAc으로 용출시키면서 섬광 컬럼 크로마토그래피로 정제하여 표제 화합물을 수득하였다. 1H NMR(500 MHz, CD3OD): δ8.44(d, 1H), 7.66(dd, 1H), 7.46-7.41(m, 2H), 7.24(t, 1H), 7.22(d, 1H), 7.15(d, LH), 4.42(dd, 1H), 3.54(dd, 1H), 3.07(dd, 1H), 2.12(s, 3H). LC-MS: m/e 338(M + H)+(3.0분).A suspension of 5-chloro-2-methylpyridine (Reference Example 18, Step A, 6.4 g, 50 mmol) and N-bromosuccinimide (12.5 g, 70 mmol) in 100 mL carbon tetrachloride were heated to reflux gently. Temperature 90 ° C.) and 2,2′-azobisisobutyronitrile (0.74 g) was added in several fractions over 30 minutes. After stirring for 5 hours at this temperature, the reaction mixture was concentrated. The resulting slurry was diluted with EtOAc (100 mL) and washed with water (100 mL), saturated aqueous sodium bicarbonate / saturated aqueous sodium thiosulfate and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel, eluting with 2-15% ether / CH 2 Cl 2 (1: 1) in hexane, to 2-bromo. Methyl-5-chloropyridine (6.0 g, 60%) was obtained and used immediately for subsequent reaction. Then 2 -bromomethyl-5-chloropyridine (6.0 g, 29 mmol) and 3-bromophenyl acetone (step A, 6.0 g, 28 mmol) and tetrabutylammonium iodide (20 mg) in 30 mL CH 2 C1 2 . Cesium hydroxide monohydrate (10 g, 60 mmol) was added at -78 ° C to the vigorously stirred solution of and the reaction was allowed to slowly warm to room temperature overnight. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and the residue was purified by flash column chromatography eluting with silica gel with 5-40% EtOAc in hexanes to afford the title compound. 1 H NMR (500 MHz, CD 3 OD): δ 8.44 (d, 1H), 7.66 (dd, 1H), 7.46-7.41 (m, 2H), 7.24 (t, 1H), 7.22 (d, 1H) , 7.15 (d, LH), 4.42 (dd, 1H), 3.54 (dd, 1H), 3.07 (dd, 1H), 2.12 (s, 3H). LC-MS: m / e 338 (M + H) + (3.0 min).

단계 C 3-(3-브로모페닐)-4-(5-클로로-2-피리딜)-2-부탄올 Step C 3- (3-Bromophenyl) -4- (5-chloro-2-pyridyl) -2-butanol

50mL 무수 THF 중의 3-(3-브로모페닐)-4-(5-클로로-2-피리딜)-2-부타논(단계 B, 6.7g, 20mmol)의 용액에 리튬 트리(2급-부틸)보로하이드라이드(THF 중의 1.0M , 30mL, 30mmol)을 첨가하고, 반응물을 실온으로 밤새 가온시켰다. 반응물을 0℃로 냉각시키고 2M 염산(50mL)을 조심스럽게 첨가하고, 생성된 혼합물을 헥산(200mL)과 물(200mL) 사이에 분배시켰다. 수성 층을 분리시키고, 유기 층을 2M 염산(2 x 100mL)으로 추출하였다. 합한 수성 추출물을 5N 수성 수산화나트륨(pH > 12)으로 중화시키고, EtOAc(2×200mL)로 추출하였다. 합한 추출물을 무수 황산나트륨상에서 건조시키고, 여과하고 농축 건조시켜 표제 화합물을 수득하였다.Lithium tri (secondary-butyl) in a solution of 3- (3-bromophenyl) -4- (5-chloro-2-pyridyl) -2-butanone (step B, 6.7 g, 20 mmol) in 50 mL anhydrous THF ) Borohydride (1.0 M in THF, 30 mL, 30 mmol) was added and the reaction was allowed to warm to room temperature overnight. The reaction was cooled to 0 ° C. and 2M hydrochloric acid (50 mL) was carefully added and the resulting mixture was partitioned between hexane (200 mL) and water (200 mL). The aqueous layer was separated and the organic layer was extracted with 2M hydrochloric acid (2 × 100 mL). The combined aqueous extracts were neutralized with 5N aqueous sodium hydroxide (pH> 12) and extracted with EtOAc (2 × 200 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated to dryness to afford the title compound.

단계 D N-[2-(3-브로모페닐)-3-(5-클로로-2-피리딜)-1-메틸프로필]아민, 하이드로클로라이드 Step D N- [2- (3-Bromophenyl) -3- (5-chloro-2-pyridyl) -1-methylpropyl] amine, hydrochloride

단계 C의 생성물(5.9g, 17mmol)을 참조 실시예 18의 단계 C 내지 D에 기재된 방법을 수행하여 표제 화합물로 전환시켰다. LC-MS: m/e 338(M + H)+(2.3분).The product of Step C (5.9 g, 17 mmol) was converted to the title compound by following the method described in Steps C to D of Reference Example 18. LC-MS: m / e 338 (M + H) + (2.3 min).

참조 실시예 20Reference Example 20

N-[2-(5-브로모-2-피리딜)-3-(4-클로로페닐)-1-메틸프로필]아민 하이드로클로라이드(부분입체이성체 α)N- [2- (5-bromo-2-pyridyl) -3- (4-chlorophenyl) -1-methylpropyl] amine hydrochloride (diastereomer α)

단계 A 5-브로모-3-피리딜아세톤 Step A 5-Bromo-3-pyridylacetone

400mL 톨루엔 중의 3,5-디브로모피리딘(50g, 0.21mol), 이소프레닐 아세테이트(26mL, 0.23mmol), 트리스(디벤질리덴아세톤)디팔라듐(1.0g, 1.1mmol)과 2-(디페닐포스피노)-2'(N,N-디메틸아미노)비페닐(1.6g, 4.2mmol)의 혼합물을 100℃에서 질소하에 2시간 동안 가열하였다. 반응 혼합물을 실온으로 냉각시키고 약 100mL로 농축시켰다. 생성된 혼합물을 실리카 겔 컬럼에 부하하고, 이를 헥산 중의 0% 내지 60% EtOAc으로 용출시켜 표제 화합물을 수득하였다. 1H NMR(500 MHz, CD30D): δ 8.54(br s, 1H), 8.33(br s, 1H), 7.88(br s, 1H), 3.90(s, 2H), 2.25(s, 3H).3,5-dibromopyridine (50 g, 0.21 mol), isoprenyl acetate (26 mL, 0.23 mmol), tris (dibenzylideneacetone) dipalladium (1.0 g, 1.1 mmol) and 2- (di) in 400 mL toluene A mixture of phenylphosphino) -2 '(N, N-dimethylamino) biphenyl (1.6 g, 4.2 mmol) was heated at 100 ° C. under nitrogen for 2 hours. The reaction mixture was cooled to room temperature and concentrated to about 100 mL. The resulting mixture was loaded on a silica gel column and eluted with 0% to 60% EtOAc in hexanes to afford the title compound. 1 H NMR (500 MHz, CD 3 0D): δ 8.54 (br s, 1H), 8.33 (br s, 1H), 7.88 (br s, 1H), 3.90 (s, 2H), 2.25 (s, 3H) .

단계 B 3-(5-브로모-3-피리딜)-4-(4-클로로페닐)-2-부탄올 Step B 3- (5-Bromo-3-pyridyl) -4- (4-chlorophenyl) -2-butanol

표제 화합물을, 2-브로모메틸-5-클로로피리딘을 4-클로로벤질 클로라이드으로 대체시키고 3-브로모페닐아세톤을 5-브로모-3-피리딜아세톤으로 대체시켜(단계 A) 참조 실시예 19의 단계 B 내지 C에 기재된 방법을 수행하여 제조하였다. 1H NMR(500 MHz, CD3OD): δ 8.43(d, 1H), 8.24(d, 1H), 7.98(dd, 1H), 7.17(d, 2H), 7.07(d, 2H), 4.04(m, 1H), 3.16(dd, 1H), 3.0-2.9(m, 2H), 1.04(d, 3H).The title compound was replaced by replacing 2-bromomethyl-5-chloropyridine with 4-chlorobenzyl chloride and 3-bromophenylacetone with 5-bromo-3-pyridylacetone (step A). Prepared by carrying out the method described in steps B to C of 19. 1 H NMR (500 MHz, CD 3 OD): δ 8.43 (d, 1H), 8.24 (d, 1H), 7.98 (dd, 1H), 7.17 (d, 2H), 7.07 (d, 2H), 4.04 ( m, 1H), 3.16 (dd, 1H), 3.0-2.9 (m, 2H), 1.04 (d, 3H).

단계 C N-[2-(5-브로모-3-피리딜)-3-(4-클로로페닐)-1-메틸프로필]아민 하이드로클로라이드(부분입체이성체 α) Step C N- [2- (5-Bromo-3-pyridyl) -3- (4-chlorophenyl) -1-methylpropyl] amine hydrochloride (diastereomer α)

표제 화합물을 참조 실시예 4의 단계 B에 기재된 방법을 수행하여 제조하였다. LC-MS: m/e 339(M + H)+(2.5분).The title compound was prepared by following the method described in Step B of Reference Example 4. LC-MS: m / e 339 (M + H) + (2.5 min).

참조 실시예 21 Reference Example 21

N-[3-(4-클로로페닐)-2-(5-시아노-3-피리딜)-1-메틸프로필]아민 하이드로클로라이드(부분입체이성체 α)N- [3- (4-chlorophenyl) -2- (5-cyano-3-pyridyl) -1-methylpropyl] amine hydrochloride (diastereomer α)

단계 A 5-시아노-3-피리딜아세톤 Step A 5-cyano-3-pyridylacetone

표제 화합물을, 단계 A에서 3,5-디브로모피리딘을 5-브로모니코티노니트릴(5-브로모-3-시아노피리딘)로 치환시켜 참조 실시예 20에 대해 기재된 방법을 수행하여 제조하였다. 1H NMR(400 MHz, CD30D): δ 8.89(d, 1H), 8.60(d, 1H), 8.02(t, 1H), 3.98(s, 2H), 2.24(s, 3H).The title compound was prepared by performing the method described for Reference Example 20 by replacing 3,5-dibromopyridine with 5-bromonicotinonitrile (5-bromo-3-cyanopyridine) in Step A. It was. 1 H NMR (400 MHz, CD 3 0D): δ 8.89 (d, 1H), 8.60 (d, 1H), 8.02 (t, 1H), 3.98 (s, 2H), 2.24 (s, 3H).

단계 B N-[3-(4-클로로페닐)-2-(5-시아노-2-피리딜)-1-메틸프로필]아민 하이드로클로라이드(부분입체이성체 α/β 5:1) Step B N- [3- (4-Chlorophenyl) -2- (5-cyano-2-pyridyl) -1-methylpropyl] amine hydrochloride (diastereomer α / β 5: 1)

표제 화합물을 3-피리딜아세톤을 5-시아노-3-피리딜아세톤으로 치환시켜(단계 A). 참조 실시예 5에 대해 기재한 방법을 수행하여 제조하였다. LC-MS: m/e 286(M + H)+(1.9분).The title compound is substituted with 3-pyridylacetone with 5-cyano-3-pyridylacetone (step A). Prepared by carrying out the method described for Reference Example 5. LC-MS: m / e 286 (M + H) + (1.9 min).

참조 실시예 22 Reference Example 22

N-[3-(4-클로로페닐)-2-(5-클로로-3-피리딜)-1-메틸프로필]아민 하이드로클로라이드(부분입체이성체 α)N- [3- (4-chlorophenyl) -2- (5-chloro-3-pyridyl) -1-methylpropyl] amine hydrochloride (diastereomer α)

단계 A 5-클로로-3-피리딜아세톤 Step A 5-Chloro-3-pyridylacetone

표제 화합물을, 단계 A에서 3,5-디브로모피리딘을 3,5-디클로로피리딘으로 대체시키고 2-(디페닐포스피노)-2'(N,N-디메틸아미노)비페닐을 2-(디-t-부틸포스피노)비페닐로 대체시켜 참조 실시예 20에 대해 기재한 방법을 수행하여 제조하였다. 1H NMR(500 MHz, CD3OD): δ8.42(d, 1H), 8.27(d, 1H), 7.73(dd, 1H), 3.90(s, 2H), 2.25(s, 3H).The title compound was substituted for 3,5-dibromopyridine with 3,5-dichloropyridine in Step A and 2- (diphenylphosphino) -2 '(N, N-dimethylamino) biphenyl was substituted with 2- ( Prepared by following the method described for Reference Example 20, replacing di-t-butylphosphino) biphenyl. 1 H NMR (500 MHz, CD 3 OD): δ 8.42 (d, 1H), 8.27 (d, 1H), 7.73 (dd, 1H), 3.90 (s, 2H), 2.25 (s, 3H).

단계 B N-[3-(4-클로로페닐)-2-(5-클로로-3-피리딜)-1-메틸프로필]아민 하이드로클로라이드(부분입체이성체 α) Step B N- [3- (4-Chlorophenyl) -2- (5-chloro-3-pyridyl) -1-methylpropyl] amine hydrochloride (diastereomer α)

표제 화합물을, 단계 B에서 5-브로모-3-피리딜아세톤을 5-클로로-3-피리딜아세톤으로 대체시켜 참조 실시예 20의 단계 B 내지 C를 수행하여 제조하였다. LC-MS: m/e 295(M + H)+(1.9분).The title compound was prepared by following Steps B through C of Reference Example 20 by replacing 5-bromo-3-pyridylacetone in Step B with 5-chloro-3-pyridylacetone. LC-MS: m / e 295 (M + H) + (1.9 min).

참조 실시예 23 Reference Example 23

N-[3-(4-클로로페닐)-2-(5-메틸-3-피리딜)-1-메틸프로필]아민 하이드로클로라이드(부분입체이성체 α) N- [3- (4-chlorophenyl) -2- (5-methyl-3-pyridyl) -1-methylpropyl] amine hydrochloride (diastereomer α)

표제 화합물을 단계 A에서 2-(N-3급-부톡시카보닐)아미노-3-(3-브로모페닐)-4-(4-클로로페닐)부탄을 2-(N-3급-부톡시카보닐)아미노-3-(5-브로모-3-피리딜)-4-(4-클로로페닐)부탄(참조 실시예 20의 중간체, 단계 B)으로 대체시켜 참조 실시예 17에 대해 기재한 방법을 수행하여 제조하였다. LC-MS: m/e 275(M + H)+(1.3분).The title compound was prepared in step A with 2- (N-tert-butoxycarbonyl) amino-3- (3-bromophenyl) -4- (4-chlorophenyl) butane. Oxycarbonyl) amino-3- (5-bromo-3-pyridyl) -4- (4-chlorophenyl) butane (Intermediate of Reference Example 20, Step B), described for Reference Example 17 Prepared by one method. LC-MS: m / e 275 (M + H) + (1.3 min).

참조 실시예 24Reference Example 24

2-메틸-2-(2-피리미딜옥시)프로피온산 2-Methyl-2- (2-pyrimidyloxy) propionic acid

표제 화합물을, 단계 A에서 5-클로로-2-하이드록스피리딘을 2-하이드록스피리미딘으로 대체시켜 참조 실시예 13에 대해 기재한 방법을 수행하여 제조하였다. 1H NMR(500 MHz, CD30D): δ 8.53(d, 2H), 7.09(t, 1H), 1.74(s, 6H).The title compound was prepared by following the method described for Reference Example 13 by replacing 5-chloro-2-hydroxypyridine with 2-hydroxypyrimidine in Step A. 1 H NMR (500 MHz, CD 3 0D): δ 8.53 (d, 2H), 7.09 (t, 1H), 1.74 (s, 6H).

참조 실시예 25Reference Example 25

2-메틸-2-(4-트리플루오로메틸-2-피리딜옥시)프로피온산2-Methyl-2- (4-trifluoromethyl-2-pyridyloxy) propionic acid

표제 화합물을, 단계 A에서 5-클로로-2-하이드록스피리딘을 4-트리플루오로메틸-2-하이드록스피리딘으로 대체시켜 참조 실시예 13에 대해 기술한 방법을 수행하여 제조하였다. 1H NMR(500 MHz, CD3OD): δ 8.30(d, 1H), 7.18(d, 1H), 7.05(s, 1H), 1.71(s, 6H).The title compound was prepared by following the method described for Reference Example 13, replacing 5-chloro-2-hydroxypyridine with 4-trifluoromethyl-2-hydroxypyridine in Step A. 1 H NMR (500 MHz, CD 3 OD): δ 8.30 (d, 1H), 7.18 (d, 1H), 7.05 (s, 1H), 1.71 (s, 6H).

참조 실시예 26Reference Example 26

2-메틸-2-(6-트리플루오로메틸-4-피리미딜옥시)프로피온산2-Methyl-2- (6-trifluoromethyl-4-pyrimidyloxy) propionic acid

표제 화합물을 단계 A에서 5-클로로-2-하이드록스피리딘을 6-트리플루오로메틸-4-하이드록스피리미딘으로 대체시켜 참조 실시예 13에 대해 기재한 방법을 수행하여 제조하였다. 1H NMR(500 MHz, CD30D): δ 8.81(s, 1H), 7.28(s, 1H), 1.75(s, 6H). LC-MS: m/e 251(M + H)+(2.1분).The title compound was prepared by following the method described for Reference Example 13 by replacing 5-chloro-2-hydroxypyridine with 6-trifluoromethyl-4-hydroxypyrimidine in Step A. 1 H NMR (500 MHz, CD 3 0D): δ 8.81 (s, 1H), 7.28 (s, 1H), 1.75 (s, 6H). LC-MS: m / e 251 (M + H) + (2.1 min).

참조 실시예 27Reference Example 27

2-메틸-2-(5-트리플루오로메틸)-2-피리딜옥시)프로피온산2-Methyl-2- (5-trifluoromethyl) -2-pyridyloxy) propionic acid

질소로 2회 플러싱한, 각각 온도계 및 환류 콘덴서가 장착된 12L들이 3구 환저 플라스크에 THF(0.91M, 각각 3.52L, 3.205mol, 1.5당량) 중의 KHMDS를 충전시켰다. 용액을 -70℃로 냉각시키고 자기적으로 교반하였다. 반응 온도를 -62℃ 이하로 유지시키면서 에틸-2-하이드록시이소부티레이트(98%)(463mL, 447g, 3.38mol)를 30분에 걸쳐 각 플라스크에 첨가하였다. 10분 후, 2-클로로-5-트리플루오르메틸피리딘(388g, 2.14mol)을 1개의 분획으로서 각 플라스크게 첨가하였다. 냉각 조를 제거하고, 반응물을 20℃로 밤새 가온시켰다(약 16시간 동안). 반응물을 TLC(실리카, 90/10 Hex/EtOAc) 및 HPLC로 모니터링하였다. A 12 L three-necked round bottom flask equipped with a thermometer and a reflux condenser, flushed twice with nitrogen, was charged with KHMDS in THF (0.91 M, 3.52 L, 3.205 mol, 1.5 equiv), respectively. The solution was cooled to -70 ° C and stirred magnetically. Ethyl-2-hydroxyisobutyrate (98%) (463 mL, 447 g, 3.38 mol) was added to each flask over 30 minutes while maintaining the reaction temperature below -62 ° C. After 10 minutes, 2-chloro-5-trifluoromethylpyridine (388 g, 2.14 mol) was added to each flask as one fraction. The cold bath was removed and the reaction was warmed to 20 ° C. overnight (about 16 hours). The reaction was monitored by TLC (silica, 90/10 Hex / EtOAc) and HPLC.

수산화나트륨(1.36L, 5N)을 각각의 반응 플라스크에 첨가하고, 반응물을 밤새 환류시켰다(약 22시간 동안). 반응물을 회전 증발기에서 함께 농축시켜 THF를 제거하였다. 농축물에 물(4L)를 첨가하고 용액을 n-헵탄(2 x 4L)으로 추출하였다. 수성 층을 교반하면서 10분에 걸쳐 2N HCl(9L, 18mol)에 첨가하였다. 생성된 현탁액을 30분(온도 30℃) 동안 숙성시킨 다음, 여과하였다. 케이크를 물(3 x 2L)로 세척하고 습윤한 황갈색 고체로 공기-건조시켰다.Sodium hydroxide (1.36 L, 5N) was added to each reaction flask and the reaction was refluxed overnight (about 22 hours). The reactions were concentrated together in a rotary evaporator to remove THF. Water (4 L) was added to the concentrate and the solution was extracted with n-heptane (2 x 4 L). The aqueous layer was added to 2N HCl (9 L, 18 mol) over 10 minutes with stirring. The resulting suspension was aged for 30 minutes (temperature 30 ° C.) and then filtered. The cake was washed with water (3 × 2 L) and air-dried to a wet tan solid.

물질을 65℃에서 n-헵탄(4 L) 속에 용해시켰다. IPAc(1L) 및 DARCO KB(40g, 100 메쉬)를 첨가하였다. 혼합물을 15분 동안 교반하고, CELITE 규조토를 통해 여과하고, 케이크를 4:1 헵탄/IPAc(3 x 500mL)으로 세척하였다. 여액을 약 2L로 농축시켜 백색 현탁액을 수득하였다. 슬러리를 헵탄(2 x 3L)으로 플러싱하고 약 3L로 농축시켰다. 생성된 백색 현탁액을 0℃로 냉각시키고 1시간 동안 숙성시켰다. 생성물을 여과하고, 케이크를 차가운 헵탄(1L)으로 세척하여 표제 화합물을 백색 결정 물질로서 수득하였다. HPLC 컬럼: YMC Combiscreen Pro C18,50 x 4.6mm; 이동상: A H20 중의 0.1% TFA; B CH3CN. 구배 : 4분 동안 90/10 A/B 내지 10/90 A/B. 유속: 4mL/분. 검출: 254nm. RT 2-클로로-5-트리플루오로메틸피리딘 2.1분. RT 2-에톡시-5-트리플루오로메틸피리딘 2.9분. RT 생성물 에스테르 3.1분. RT 최종 산 2.05분.The material was dissolved in n-heptane (4 L) at 65 ° C. IPAc (1 L) and DARCO KB (40 g, 100 mesh) were added. The mixture was stirred for 15 minutes, filtered through CELITE diatomaceous earth, and the cake was washed with 4: 1 heptanes / IPAc (3 × 500 mL). The filtrate was concentrated to about 2 L to give a white suspension. The slurry was flushed with heptane (2 × 3L) and concentrated to about 3L. The resulting white suspension was cooled to 0 ° C. and aged for 1 hour. The product was filtered and the cake washed with cold heptane (1 L) to afford the title compound as white crystalline material. HPLC column: YMC Combiscreen Pro C18, 50 × 4.6 mm; Mobile phase: 0.1% TFA in AH 2 O; B CH 3 CN. Gradient: 90/10 A / B to 10/90 A / B for 4 minutes. Flow rate: 4 mL / min. Detection: 254 nm. RT 2-Chloro-5-trifluoromethylpyridine 2.1 min. RT 2-ethoxy-5-trifluoromethylpyridine 2.9 min. RT product ester 3.1 min. RT final acid 2.05 min.

참조 실시예 28Reference Example 28

2-아미노-3-인돌린-N-일-4(4-클로로)페닐부탄2-amino-3-indolin-N-yl-4 (4-chloro) phenylbutane

단계 A. 에틸 3-(4-클로로페닐)-2-인돌린-N-일프로파노에이트. Step A. Ethyl 3- (4-chlorophenyl) -2-indolin-N-ylpropanoate.

질소 대기하에 오븐 건조된 플라스크내에서, DMF(20mL)중의 LiOH-H20 1.1g(26.25mmol)를 4Å 분자체의 교반되는 현탁액에 첨가하였다. 실온에서 30분 동안 교반한 후, 인돌린 2.8mL(25mmol)을 적가하였다. 실온에서 1시간 후, 에틸 브로모아세테이트 2.9mL(26.25mmol)를 적가하였다. 1.5시간 후, 고체 물질을 여과하고, 잔사를 다량의 EtOAc로 세척하였다. 유기 물질을 물로 3회 세척하고, 이 유기 물질을 MgSO4상에서 건조시켰다. 용매를 감압하에 제거하였다. 이어서, 조 물질을 무수 THF 75mL 속에 용해시키고, 질소 대기하에 오븐 건조된 환저 플라스크내로 충전시키고 -78℃로 냉각시킨 다음, NaHMDS의 1M 용액 26.25mL으로 처리하였다. 용액을 -78℃에서 30분 동안 교반한 후, 에놀레이트를 파라클로로벤질 브로마이드(무수 THF 25mL중의 용액) 5.4g(26.25mmol)으로 알킬화시켰다. 반응물을 밤새 실온으로 가온시켰다. 다음날, 반응물을 물로 급냉시켰다. 수성층을 EtOAc의 3개의 큰 분획으로 추출하였다. 합한 유기 무질을 MgSO4상에서 건조시켰다. 용매를 감압하에 제거하고, 잔사를 섬광 크로마토그래피로 정제하여 표제 화합물을 황색 오일로서 수득하였다. LC/MS m/e=331(M+1). TLC Rf=0.22(20:1 헥산:EtOAc). 1H NMR(500 MHz, CDC13): δ 1.11(t, J=3.55 Hz, 3H), 2.96(m, 2H), 3.06(m, 1H), 3.25(m, 1H), 3.60(t, 2H), 4.07(m, 2H), 4.36(t, J=3.75 Hz, 1H).In an oven dried flask under a nitrogen atmosphere, 1.1 g (26.25 mmol) of LiOH-H 2 0 in DMF (20 mL) was added to a stirred suspension of 4 mm molecular sieve. After stirring for 30 minutes at room temperature, 2.8 mL (25 mmol) of indoline was added dropwise. After 1 hour at room temperature 2.9 mL (26.25 mmol) ethyl bromoacetate was added dropwise. After 1.5 h, the solid material was filtered off and the residue was washed with a large amount of EtOAc. The organic material was washed three times with water and the organic material was dried over MgSO 4 . The solvent was removed under reduced pressure. The crude material was then dissolved in 75 mL of anhydrous THF, charged into an oven dried round bottomed flask under nitrogen atmosphere, cooled to -78 ° C and treated with 26.25 mL of a 1M solution of NaHMDS. After the solution was stirred at −78 ° C. for 30 minutes, the enolate was alkylated with 5.4 g (26.25 mmol) of parachlorobenzyl bromide (solution in 25 mL of anhydrous THF). The reaction was allowed to warm to room temperature overnight. The next day, the reaction was quenched with water. The aqueous layer was extracted with three large fractions of EtOAc. The combined organic matters were dried over MgSO 4 . The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the title compound as a yellow oil. LC / MS m / e = 331 (M + l). TLC R f = 0.22 (20: 1 hexanes: EtOAc). 1 H NMR (500 MHz, CDC1 3 ): δ 1.11 (t, J = 3.55 Hz, 3H), 2.96 (m, 2H), 3.06 (m, 1H), 3.25 (m, 1H), 3.60 (t, 2H ), 4.07 (m, 2H), 4.36 (t, J = 3.75 Hz, 1H).

단계 B. N,O-디메틸-3-(4-클로로페닐)-2-인돌린-N-일프로판아미드. Step B. N, O-dimethyl-3- (4-chlorophenyl) -2-indolin-N-ylpropanamide.

질소 대기하에 오븐 건조된 플라스크내에, CH2C12 중의 (CH3)2AlCl의 1M 용액을 0℃에서 추가의 깔대기를 통해 N,O-디메틸하이드록실아민 하이드로클로라이드 1.15 g(11.75mmol)의 교반되는 현탁액에 첨가하였다. 실온으로 가온시킨 후, 10mL 중의 에틸 3-(4-클로로페닐)-2-인돌리닐프로파노에이트(단계 A로부터 수득됨) 970mg(2.94mmol)의 용액을 추가의 깔때기를 통해 첨가하였다. 실온에서 5시간 동안 교반한 후, pH 8의 포스페이트 완충 용액 35mL을 첨가하고, 생성된 혼합물을 30분 동안 격렬하게 교반하였다. 상을 분리시키고, 수성 층을 클로로포름으로 2회 추출하였다. 합한 유기 물질을 물로 세척한 다음, MgSO4상에서 건조시켰다. 갈색 오일을 수집하였다. 조 물질을 다음 단계에서 사용하였다. TLC Rf=0.12(10:1 헥산:EtOAc). 1H NMR(500 MHz, CDC13): δ 2.83(m, 1H), 2.97(m, 2H), 3.13(s, 3H), 3.34(m, 1H), 3.45(s, 3H), 3.61(m, 2H), 4.87(b, 1H), 6.54(D, 1H), 6.66(t, J=7.1 Hz, 1H), 7.07(t, J=7.1 Hz, 2H), 7.18(d, J=8.5 Hz, 2H), 7.24(d, J=8.5 Hz, 2H)In an oven dried flask under a nitrogen atmosphere, a 1M solution of (CH 3 ) 2 AlCl in CH 2 C1 2 was stirred at 15 ° C. with an additional funnel at 1.15 g (11.75 mmol) of N, O-dimethylhydroxylamine hydrochloride. To the suspension. After warming to room temperature, a solution of 970 mg (2.94 mmol) of ethyl 3- (4-chlorophenyl) -2-indolinylpropanoate (obtained from step A) in 10 mL was added via an additional funnel. After stirring for 5 hours at room temperature, 35 mL of a phosphate buffer solution of pH 8 was added and the resulting mixture was stirred vigorously for 30 minutes. The phases were separated and the aqueous layer was extracted twice with chloroform. The combined organics were washed with water and then dried over MgSO 4 . Brown oil was collected. The crude material was used in the next step. TLC R f = 0.12 (10: 1 hexanes: EtOAc). 1 H NMR (500 MHz, CDC1 3 ): δ 2.83 (m, 1H), 2.97 (m, 2H), 3.13 (s, 3H), 3.34 (m, 1H), 3.45 (s, 3H), 3.61 (m , 2H), 4.87 (b, 1H), 6.54 (D, 1H), 6.66 (t, J = 7.1 Hz, 1H), 7.07 (t, J = 7.1 Hz, 2H), 7.18 (d, J = 8.5 Hz , 2H), 7.24 (d, J = 8.5 Hz, 2H)

단계 C. 4-(4-클로로페닐)-3-인돌린-N-일부탄-2-온. Step C. 4- (4-Chlorophenyl) -3-indoline-N-ylbutan-2-one.

질소 대기하에 오븐 건조된 플라스크내에서, THF 중의 CH3MgBr의 1M 용액 2.8mL을 무수 THF 25mL 중의 N,O-디메틸-3-(4-클로로페닐)-2-인돌리닐프로판아미드(단계 B로부터 수득됨, 965mg)의 교반되는 용액에 적가하였다. 용액을 실온으로 가온시키면서 4시간 동안 교반하였다. 이어서, 물 약 20mL를 첨가하였다. 혼합물을 50mL 에테르로 3회 추출하였다. 합한 추출물을 MgSO4상에서 건조시켰다. 용매를 감압하에 제거하여 갈색 오일을 수득하고, 이를 추가의 정제없이 다음 단계에서 사용하였다. LC/MS m/e=301(M+1). TLC Rf=0.5(4:1 헥산: EtOAc). 1H NMR(500 MHz, CDC13): δ 2.14(s, 3H), 2.81(dd, J=14.6, 6.6 Hz, 1H), 2.97(t, J=8.5 Hz, 2H), 3.26(m, 2H), 3.5(m, 1H), 4.21(dd, J=6.6, 6.6 Hz), 6.39(d, J=8 Hz, 1H), 6.66(dd, J=7,7 Hz, 1H), 7.07(m, 2H), 7.13(d, J=8.5 Hz), 7.22(d, J=8.3 Hz).In an oven dried flask under nitrogen atmosphere, 2.8 mL of a 1M solution of CH 3 MgBr in THF was added with N, O-dimethyl-3- (4-chlorophenyl) -2-indolinylpropanamide (from step B) in 25 mL of anhydrous THF. Obtained, 965 mg) was added dropwise to the stirred solution. The solution was stirred for 4 hours while warming to room temperature. Then about 20 mL of water was added. The mixture was extracted three times with 50 mL ether. The combined extracts were dried over MgSO 4 . The solvent was removed under reduced pressure to give a brown oil which was used in the next step without further purification. LC / MS m / e = 301 (M + l). TLC R f = 0.5 (4: 1 hexanes: EtOAc). 1 H NMR (500 MHz, CDC1 3 ): δ 2.14 (s, 3H), 2.81 (dd, J = 14.6, 6.6 Hz, 1H), 2.97 (t, J = 8.5 Hz, 2H), 3.26 (m, 2H ), 3.5 (m, 1H), 4.21 (dd, J = 6.6, 6.6 Hz), 6.39 (d, J = 8 Hz, 1H), 6.66 (dd, J = 7,7 Hz, 1H), 7.07 (m) , 2H), 7.13 (d, J = 8.5 Hz), 7.22 (d, J = 8.3 Hz).

단계 D. 4-(4-클로로페닐)-3-인돌린-N-일부탄-2-온 메톡심 Step D. 4- (4-Chlorophenyl) -3-indolin-N-ylbutan-2-one methoxime

무수 에탄올 중의 단계 C의 생성물 472mg(1.573mmol)과 메톡실아민 하이드로클로라이드 263mg(3.147mmol)의 용액을 피리딘 255㎕(3.147mmol)으로 처리하였다. 용액을 실온에서 2시간 동안 교반하였다. 용매를 감압하에 제거하고, 잔사를 물과 에테르 사이에 분배시켰다. 물을 다시 에테르로 추출하였다. 이어서, 추출물을 합하고 MgSO4상에서 건조시키고 여과하고 농축시켜 조 물질을 수득하였다. E 이성체 및 Z 이성체 둘다를 다음 단계에서 사용하였다. LC/MS m/e=330(M+1) TLC Rf=0.77 및 0.65(4:1 헥산: EtOAc). 1H NMR(500 MHz, CDCl3): δ 1.78(2s, 1H), 2.88(dd, J=6.2, 13.8 Hz, 1H), 2.95(m, 2H), 3.30(m, 2H), 3.45(m, 1H), 3.75 및 3.89(2s, 3H), 4.21(dd, J=6.9, 7.8 Hz, 1H), 6.28 및 6.47(2d, J=8.1, 1H), 6.61(m, 1H), 7.02(m, 2H), 7.22(m, 4H).A solution of 472 mg (1.573 mmol) of the product of Step C and 263 mg (3.147 mmol) of methoxylamine hydrochloride in anhydrous ethanol was treated with 255 μl (3.147 mmol) of pyridine. The solution was stirred at rt for 2 h. The solvent was removed under reduced pressure and the residue was partitioned between water and ether. Water was extracted again with ether. The extracts were then combined, dried over MgSO 4, filtered and concentrated to give crude. Both E and Z isomers were used in the next step. LC / MS m / e = 330 (M + l) TLC R f = 0.77 and 0.65 (4: 1 hexanes: EtOAc). 1 H NMR (500 MHz, CDCl 3): δ 1.78 (2s, 1H), 2.88 (dd, J = 6.2, 13.8 Hz, 1H), 2.95 (m, 2H), 3.30 (m, 2H), 3.45 (m, 1H), 3.75 and 3.89 (2s, 3H), 4.21 (dd, J = 6.9, 7.8 Hz, 1H), 6.28 and 6.47 (2d, J = 8.1, 1H), 6.61 (m, 1H), 7.02 (m, 2H), 7.22 (m, 4H).

단계 E. 2-아미노-3-인돌린-N-일-4(4-클로로)페닐부탄 Step E. 2-Amino-3-indolin-N-yl-4 (4-chloro) phenylbutane

질소 대기하에 물 콘덴서가 장착된 오븐 건조된 플라스크내에서, 무수 THF 1.5mL 중의 4-(4-클로로페닐)-3-인돌리닐부탄-2-온 메톡심(단계 D로부터 수득함) 301mg(0.914mmol)을 실온에서 1M BH3·THF 3.7mL(3.7mmol)로 처리하였다. 이어서, 용액을 75℃에서 2일 동안 가열하였다. 이어서, 용액을 0℃로 냉각시키고 버블링이 소멸될 때까지 얼음 조각으로 처리하였다. 20% KOH 500㎕를 첨가하고 용액을 45℃에서 2시간 동안 가열하였다. 이어서, 용액을 실온으로 냉각시키고 에테르 3x로 추출하였다. 합한 추출물을 MgSO4상에서 건조시키고 여과하고 농축시켜 조 물질을 수득하고, 이를 추가의 정제없이 다음 실험에서 사용하였다. LC/MS m/e=302(M+1). 1H NMR(500 MHz, CDCl3): δ 1.13, 1.14(2d, J=6.5 Hz, 1H), 1.55-1.60(m, 2H), 2.80-3.10(m, 4H), 3.30-3.60(m, 2H), 6.348 및 6.38(2d, J=7.9 Hz, 1H), 6.50-6.78(m, 2H), 6.95-7.24(m, 5H).In an oven dried flask equipped with a water condenser under nitrogen atmosphere, 301 mg (0.914) of 4- (4-chlorophenyl) -3-indolinylbutan-2-one methoxime (obtained from step D) in 1.5 mL of dry THF. mmol) was treated with 3.7 mL (3.7 mmol) of 1M BH 3 .THF at room temperature. The solution was then heated at 75 ° C. for 2 days. The solution was then cooled to 0 ° C. and treated with ice cubes until bubbling disappeared. 500 μl 20% KOH was added and the solution was heated at 45 ° C. for 2 hours. The solution was then cooled to rt and extracted with ether 3x. The combined extracts were dried over MgSO 4, filtered and concentrated to give crude material which was used in the next experiment without further purification. LC / MS m / e = 302 (M + l). 1 H NMR (500 MHz, CDCl 3 ): δ 1.13, 1.14 (2d, J = 6.5 Hz, 1H), 1.55-1.60 (m, 2H), 2.80-3.10 (m, 4H), 3.30-3.60 (m, 2H), 6.348 and 6.38 (2d, J = 7.9 Hz, 1H), 6.50-6.78 (m, 2H), 6.95-7.24 (m, 5H).

참조 실시예 29Reference Example 29

2-아미노-3-인돌-N-일-4(4-클로로)페닐부탄2-amino-3-indol-N-yl-4 (4-chloro) phenylbutane

상기 화합물은 단계 A 동안 수산화리튬 1수화물/분자체 배합물 대신에 수산화 나트륨을 염기로서 사용한다는 것을 제외하고 참조 실시예 28과 유사한 방식으로 제조하였다. LC/MS: C18H19ClN2에 대한 계산치 299 관측치 m/e 300(M + H)+(2.4분).The compound was prepared in a similar manner to Reference Example 28 except that sodium hydroxide was used as the base instead of the lithium hydroxide monohydrate / molecular sieve formulation during step A. LC / MS: calcd for C 18 H 19 ClN 2 299 observation m / e 300 (M + H) + (2.4 min).

참조 실시예 30Reference Example 30

2-아미노-3-(N-메틸, N-페닐)아미노-4(4-클로로)페닐부탄2-amino-3- (N-methyl, N-phenyl) amino-4 (4-chloro) phenylbutane

상기 화합물을 참조 실시예 28과 유사한 방식으로 제조하였다. LC/MS: C17H21ClN2에 대한 계산치 289, 관측치 m/e 290(M + H)+(2.4분).The compound was prepared in a similar manner to Reference Example 28. LC / MS: calcd for C 17 H 21 ClN 2 289, found m / e 290 (M + H) + (2.4 min).

참조 실시예 31Reference Example 31

2-아미노-3-(7-아자인돌-N-일)-4(4-클로로)페닐부탄2-amino-3- (7-azaindol-N-yl) -4 (4-chloro) phenylbutane

상기 화합물을 참조 실시예 28과 유사한 방식으로 제조하였다. LC/MS: C17H18ClN3에 대한 계산치 300, 관측치 m/e 301(M + H)+(2.7분).The compound was prepared in a similar manner to Reference Example 28. LC / MS: calcd for C 17 H 18 ClN 3 300, obsd. M / e 301 (M + H) + (2.7 min).

참조 실시예 32Reference Example 32

4-(4-메틸페닐)-3-페닐부탄-2-아민(4개 이성체의 혼합물)4- (4-methylphenyl) -3-phenylbutan-2-amine (mixture of four isomers)

단계 A 1-페닐아세톤 Step A 1-phenylacetone

에테르(300mL) 중의 N-메틸-N-메톡시아세트아미드(9.9mL. 97mmol) 용액에 0℃에서 벤질마그네슘 클로라이드(97mL, 에테르 중의 1M 용액)를 첨가하였다. 혼탁한 백색 반응 혼합물을 2시간 동안 실온으로 가온시킨 다음, 1N 염산(100mL)을 조심스럽게 첨가하여 급냉시켰다. 유기 상을 분리시키고 염수로 세척하고 MgSO4상에서 건조시키고 농축시켰다. 조 물질을 실리카 겔에서 0 내지 10% EtOAc/헥산으로 용출시키면서 컬럼 크로마토그래피로 정제하여 표제 화합물을 수득하였다. 1H NMR(500 MHz, CDC13): δ 7.36(t, J =7.1Hz, 2H), 7.30(t, J = 7.3Hz, 1H), 7.24(d, J = 7.3Hz, 2H), 3.72(s, 2H), 2.18(s, 3H). LC-MS: m/e 135(M + H)+(1.95분).To a solution of N-methyl-N-methoxyacetamide (9.9 mL. 97 mmol) in ether (300 mL) was added benzylmagnesium chloride (97 mL, 1M solution in ether) at 0 ° C. The cloudy white reaction mixture was allowed to warm to room temperature for 2 hours and then quenched by the careful addition of 1N hydrochloric acid (100 mL). The organic phase was separated, washed with brine, dried over MgSO 4 and concentrated. The crude material was purified by column chromatography eluting with silica gel with 0-10% EtOAc / hexanes to afford the title compound. 1 H NMR (500 MHz, CDC1 3 ): δ 7.36 (t, J = 7.1 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 7.24 (d, J = 7.3 Hz, 2H), 3.72 ( s, 2H), 2.18 (s, 3H). LC-MS: m / e 135 (M + H) + (1.95 min).

단계 B 4-(4-메틸페닐)-3-페닐부탄-2-온 Step B 4- (4-methylphenyl) -3-phenylbutan-2-one

1-페닐아세톤(200mg, 1.49mmol)을 용매를 함유하지 않는 플라스크내에서 분말화된 수산화칼륨(167mg, 2.98mmol) 및 테트라-n-부틸암모늄 브로마이드(lmol%, 5mg)과 혼합하였다. 상기 혼합물을 1-(클로로메틸)-4-메틸벤젠(198㎕, 1.49mmol)을 첨가하기 전에 실온에서 90분 동안 교반하였다. 이어서, 반응 혼합물을 물 및 CH2Cl2로 희석시키기 전에 밤새 교반하였다. 수성 층을 분리시키고 2N 염산으로 중화시키고 다시 CH2C12로 추출하였다. 합한 유기 추출물을 MgSO4로 건조시키고 농축시켰다. 조 물질을 실리카 겔에서 0 내지 10% EtOAc/헥산으로 용출시키면서 컬럼 크로마토그래피로 정제하여 표제 화합물을 수득하였다. 1H NMR(500 MHz, CDC13): δ 7.35(t, J = 7.0 Hz, 2H), 7.29(t, J = 7.4 Hz, 1H), 7.23(d, J = 7.1 Hz, 2H), 7.05(d, 7.8 Hz, 2H), 6.98(d, J = 7.8 Hz, 2H), 3.94(t, J = 7.3 Hz, 1H), 3.43(dd, J = 13.9, 7.5 Hz, 1H), 2.91(dd, J = 14, 7.1 Hz, 1H), 2.32(s, 3H), 2.08(s, 3H). LC-MS: m/e 239(M + H)+(3.61분).1-phenylacetone (200 mg, 1.49 mmol) was mixed with powdered potassium hydroxide (167 mg, 2.98 mmol) and tetra-n-butylammonium bromide (lmol%, 5 mg) in a flask containing no solvent. The mixture was stirred at room temperature for 90 minutes before adding 1- (chloromethyl) -4-methylbenzene (198 μl, 1.49 mmol). The reaction mixture was then stirred overnight before diluting with water and CH 2 Cl 2 . The aqueous layer was separated, neutralized with 2N hydrochloric acid and extracted again with CH 2 C1 2 . The combined organic extracts were dried over MgSO 4 and concentrated. The crude material was purified by column chromatography eluting with silica gel with 0-10% EtOAc / hexanes to afford the title compound. 1 H NMR (500 MHz, CDC1 3 ): δ 7.35 (t, J = 7.0 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 7.1 Hz, 2H), 7.05 ( d, 7.8 Hz, 2H), 6.98 (d, J = 7.8 Hz, 2H), 3.94 (t, J = 7.3 Hz, 1H), 3.43 (dd, J = 13.9, 7.5 Hz, 1H), 2.91 (dd, J = 14, 7.1 Hz, 1H), 2.32 (s, 3H), 2.08 (s, 3H). LC-MS: m / e 239 (M + H) + (3.61 min).

단계 C 4-(4-메틸페닐)-3-페닐부탄-2-아민 Step C 4- (4-Methylphenyl) -3-phenylbutan-2-amine

MeOH (5mL) 및 아세트산(3mL)중의 7M 암모니아 중의 4-(4-메틸페닐)-3-페닐부탄-2-온(308mg, 1.29mmol)의 용액에 시아노수소화붕소나트륨(130mg, 2.06mmol)을 첨가하고, 반응물을 실온에서 밤새 교반하였다. 반응물을 2M 탄산나트륨 용액에 부어서 급냉시키고 EtOAc로 추출하였다. 수성 층을 가염하고 재추출하였다. 합한 유기 추출물을 MgSO4상에서 건조시키고 농축시켜 표제 화합물을 추가의 정제없이 사용되는 4개 이성체의 혼합물로서 수득하였다. LC-MS: m/e 240(M + H)+(2.22분).To a solution of 4- (4-methylphenyl) -3-phenylbutan-2-one (308 mg, 1.29 mmol) in 7M ammonia in MeOH (5 mL) and acetic acid (3 mL) was added sodium cyanoborohydride (130 mg, 2.06 mmol). Was added and the reaction stirred overnight at room temperature. The reaction was poured into 2M sodium carbonate solution, quenched and extracted with EtOAc. The aqueous layer was salted and reextracted. The combined organic extracts were dried over MgSO 4 and concentrated to afford the title compound as a mixture of four isomers used without further purification. LC-MS: m / e 240 (M + H) + (2.22 min).

참조 실시예 33 Reference Example 33

3-[2-아미노-1-(4-플루오로벤질)프로필]벤조니트릴3- [2-amino-1- (4-fluorobenzyl) propyl] benzonitrile

상기 화합물은 3-(2-옥소프로필)벤조니트릴 및 1-(클로로메틸)-4-플루오로벤젠을 단계 B에서 반응물로서 사용하여 실시예 5의 단계 B 및 C에 기재된 방법을 사용함으로써 제조하였다. LC-MS: m/e 269(M + H)+(2.87분).The compound was prepared by using the methods described in steps B and C of Example 5 using 3- (2-oxopropyl) benzonitrile and 1- (chloromethyl) -4-fluorobenzene as reactants in Step B. . LC-MS: m / e 269 (M + H) + (2.87 min).

참조 실시예 34Reference Example 34

2-(1H-1,2,3-벤조트리아졸-1-일)-3-(4-클로로페닐)-1-메틸프로필아민2- (1H-1,2,3-benzotriazol-1-yl) -3- (4-chlorophenyl) -1-methylpropylamine

단계 A 2-(1H-1,2,3-벤조트리아졸-1-일)-N-메톡시-N-메틸아세트아미드Step A 2- (1H-1,2,3-benzotriazol-1-yl) -N-methoxy-N-methylacetamide

CH2Cl2 50mL 중의 2-(1H-1,2,3-벤조트리아졸-1-일)아세트산 1.77g(10mmol), N,O-디메틸하이드록실아민 하이드로클로라이드 1.07g(11mmoles), PyBOP 5.8g(11mmol)과 디이소프로필에틸아민 3.4mL(24.2mmol)의 혼합물을 RT에서 밤새 교반하였다. 상기 혼합물을 EtOAc과 물 사이에 분배시켰다. 유기 층을 염수로 세척하고 무수 MgSO4상에서 건조시켰다. 용매를 제거하여 조 생성물을 수득하고, 이를 실리카 겔에서 용매로서 헥산 중의 60% EtOAc를 사용하여 정제하여 목적하는 아미드를 고체로서 수득하였다. 1H NMR:(CDC13): δ 3.26(s, 3H), 3.84(s, 3H), 5.63(s, 2H), 7.35-8.2(M, 4H).1.77 g (10 mmol) of 2- (1H-1,2,3-benzotriazol-1-yl) acetic acid in 50 mL of CH 2 Cl 2 , 1.07 g (11 mmoles) of N, O-dimethylhydroxylamine hydrochloride, PyBOP 5.8 A mixture of g (11 mmol) and 3.4 mL (24.2 mmol) of diisopropylethylamine was stirred at RT overnight. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous MgSO 4 . Removal of solvent gave crude product which was purified on silica gel using 60% EtOAc in hexane as solvent to afford the desired amide as a solid. 1 H NMR: (CDC1 3 ): δ 3.26 (s, 3H), 3.84 (s, 3H), 5.63 (s, 2H), 7.35-8.2 (M, 4H).

단계 B 2-(1H-1,2,3-벤조트리아졸-1-일)-3-(4-클로로페닐)-N-메톡시-N-메틸-프로판아미드. Step B 2- (1H-1,2,3-Benzotriazol-1-yl) -3- (4-chlorophenyl) -N-methoxy-N-methyl-propanamide.

무수 THF 15mL 중의 2-(1H-1,2,3-벤조트리아졸-1-일)-N-메톡시-N-메틸아세트아미드 2.0g(9mmol)의 용액에 -78℃에서 1M 리튬 비스(트리메틸실릴)아미드 10mL(10mmol)를 적가하였다. 25분 동안 교반한 후, 무수 THF 2mL 중의 4-클로로벤질 브로마이드 2.06g(10mmol)의 용액을 첨가하였다. 생성된 반응 혼합물을 RT로 가온시키고 6시간 동안 교반하였다. 상기 반응물을 급냉시키고 EtOAc 75mL로 희석시키고 염수 각각 10mL로 3회 세척하였다. 유기 상을 건조시킨 후, 용매를 제거하여 조 생성물을 수득하고 이를 실리카 겔에서 용매로서 헥산 중의 40% EtOAc를 사용하여 정제하여 목적하는 생성물을 고체로서 수득하였다. 1H NMR:(CDCl3): δ 3.2(s, 3H), 3.34(s, 3H), 3.52(M, 1H), 3.7(M, 1H), 6.32(t, 1H), 6.9-8.2(M, 8H).To a solution of 2.0 g (9 mmol) of 2- (1H-1,2,3-benzotriazol-1-yl) -N-methoxy-N-methylacetamide in 15 mL of dry THF, 1M lithium bis ( 10 mL (10 mmol) of trimethylsilyl) amide was added dropwise. After stirring for 25 minutes, a solution of 2.06 g (10 mmol) of 4-chlorobenzyl bromide in 2 mL of dry THF was added. The resulting reaction mixture was warmed to RT and stirred for 6 h. The reaction was quenched, diluted with 75 mL EtOAc and washed three times with 10 mL each brine. After drying the organic phase, the solvent was removed to give the crude product which was purified on silica gel using 40% EtOAc in hexane as solvent to afford the desired product as a solid. 1 H NMR: (CDCl 3 ): δ 3.2 (s, 3H), 3.34 (s, 3H), 3.52 (M, 1H), 3.7 (M, 1H), 6.32 (t, 1H), 6.9-8.2 (M , 8H).

단계 C 2-(1H-1,2,3-벤조트리아졸-1-일)-3-(4-클로로페닐)-부탄-2-온. Step C 2- (1H-1,2,3-Benzotriazol-1-yl) -3- (4-chlorophenyl) -butan-2-one.

무수 THF 10mL 중의 2-(1H-1,2,3-벤조트리아졸-1-일)-3-(4-클로로페닐)-N-메톡시-N-메틸-프로판아미드 1.73g(5mmol)의 용액에 0℃에서 에테르 중의 2.5M 메틸 마그네슘 브로마이드 4mL(10mmol)를 첨가하였다. 반응 혼합물을 RT로 가온시키면서 4시간 동안 교반하였다. 반응물을 1N HCl 10mL을 첨가하여 급냉시키고, 생성된 혼합물을 EtOAc과 물 사이에 분배시켰다. 유기 상을 염수로 세척하고, 무수 MgSO4상에서 건조시켰다. 용매를 제거하여 조 케톤을 수득하고, 이를 실리카 겔에서 헥산 중의 40% EtOAc를 사용하여 정제하여 목적하는 케톤을 수득하였다.1.73 g (5 mmol) of 2- (1H-1,2,3-benzotriazol-1-yl) -3- (4-chlorophenyl) -N-methoxy-N-methyl-propanamide in 10 mL of dry THF To the solution was added 4 mL (10 mmol) of 2.5M methyl magnesium bromide in ether at 0 ° C. The reaction mixture was stirred for 4 h while warming to RT. The reaction was quenched by addition of 10 mL of 1N HCl and the resulting mixture was partitioned between EtOAc and water. The organic phase was washed with brine and dried over anhydrous MgSO 4 . Removal of solvent gave crude ketone, which was purified on silica gel with 40% EtOAc in hexane to afford the desired ketone.

단계 D 2-(1H-1,2,3-벤조트리아졸-1-일)-3-(4-클로로페닐)-1-메틸 프로필아민 Step D 2- (1H-1,2,3-benzotriazol-1-yl) -3- (4-chlorophenyl) -1-methyl propylamine

MeOH 중의 7N 암모니아 8.5mL(60mmol) 중의 2-(1H-1,2,3-벤조트리아졸-1-일)-3-(4-클로로페닐)-부탄-2-온 1.18g(4mmol)의 용액에 0℃에서 빙초산 4mL(964mmol)을 첨가한 다음, 시아노수소화붕소나트륨 410mg(6.5mmol)을 첨가하였다. 반응 혼합물을 RT로 가온시키고 밤새 교반하였다. 반응물을 EtOAc과 포화 NaHC03 용액 사이에 분배시켰다. 유기 상을 무수 MgSO4상에서 건조시켰다. 용매를 진공하에 제거하고, 잔사를 실리카 겔에서 5% 2N 메탄올성 암모니아 용액과 95% CH2Cl2의 혼합물을 사용하여 정제하여 목적하는 아민을 부분입체이성체의 혼합물로서 수득하였다. LC-MS, RT = 2.0분, m/e = 301.1.18 g (4 mmol) of 2- (1H-1,2,3-benzotriazol-1-yl) -3- (4-chlorophenyl) -butan-2-one in 8.5 mL (60 mmol) of 7N ammonia in MeOH To the solution was added 4 mL (964 mmol) of glacial acetic acid at 0 ° C., followed by 410 mg (6.5 mmol) of sodium cyanoborohydride. The reaction mixture was warmed to RT and stirred overnight. The reaction was partitioned between EtOAc and saturated NaHCO 3 solution. The organic phase was dried over anhydrous MgSO 4 . The solvent was removed in vacuo and the residue was purified on silica gel using a mixture of 5% 2N methanolic ammonia solution and 95% CH 2 Cl 2 to afford the desired amine as a mixture of diastereomers. LC-MS, RT = 2.0 min, m / e = 301.

참조 실시예 35Reference Example 35

3-(4-클로로페닐)-2-(티오펜-3-일)-1-메틸프로필아민3- (4-chlorophenyl) -2- (thiophen-3-yl) -1-methylpropylamine

표제 아민을, 단계 A에서 2-(1H-1,2,3-벤조트리아졸-1-일)아세트산을 티오펜-3-아세트산으로 대체시켜 참조 실시예 34에서 기술한 방법으로 제조하였다. LC-MS, RT = 2.19분, m/e = 266. The title amine was prepared by the method described in Reference Example 34 by replacing 2- (1H-1,2,3-benzotriazol-1-yl) acetic acid with thiophen-3-acetic acid in Step A. LC-MS, RT = 2.19 min, m / e = 266.

참조 실시예 36Reference Example 36

2-(3-시아노페닐)-3-사이클로부틸-1-메틸프로필아민2- (3-cyanophenyl) -3-cyclobutyl-1-methylpropylamine

단계 A 1-(3-시아노페닐)아세톤 Step A 1- (3-cyanophenyl) acetone

표제 화합물을, 참조 실시예 20의 단계 A의 방법을 사용하여 3-브로모벤조니트릴 및 이소프로페닐 아세테이트로부터 제조하였다.The title compound was prepared from 3-bromobenzonitrile and isopropenyl acetate using the method of step A of Reference Example 20.

단계 B 3-(3-시아노페닐)-4-사이클로부틸-부탄-2-온 Step B 3- (3-cyanophenyl) -4-cyclobutyl-butan-2-one

아세토니트릴 18mL 중의 1-(3-시아노페닐)아세톤 1.45g(9.07mmol)의 용액에 사이클로부틸 브로마이드 1.1mL(9.5mmol) 및 탄산세슘 5.91g(18.1mmol)를 첨가하였다. 용액을 60℃ 욕조에서 밤새 가열한 후, 냉각시키고 여과하였다. 여액을 물과 EtOAc 사이에 분배시키고, 수성 층을 EtOAc로 추출하였다. 합한 유기 상을 염수로 세척하고 건조시키고 농축시켰다. 잔사를 섬광 컬럼에서 5 내지 10% EtOAc/헥산의 구배를 사용하여 표제 화합물을 분리시켰다. 1H NMR:(500 MHz, CDC13): δ 1.5-2.2(m, 9H), 2.13(s, 3H), 3.64(m, 1H), 7.4-7.7(m, 4H).To a solution of 1.45 g (9.07 mmol) of 1- (3-cyanophenyl) acetone in 18 mL of acetonitrile were added 1.1 mL (9.5 mmol) of cyclobutyl bromide and 5.91 g (18.1 mmol) of cesium carbonate. The solution was heated overnight in a 60 ° C. bath, then cooled and filtered. The filtrate was partitioned between water and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with brine, dried and concentrated. The residue was separated on a flash column using a gradient of 5-10% EtOAc / hexanes to separate the title compound. 1 H NMR: (500 MHz, CDC1 3 ): δ 1.5-2.2 (m, 9H), 2.13 (s, 3H), 3.64 (m, 1H), 7.4-7.7 (m, 4H).

단계 C 2-(3-시아노페닐)-3-사이클로부틸-1-메틸프로필아민 Step C 2- (3-Cyanophenyl) -3-cyclobutyl-1-methylpropylamine

상기 아민을 참조 실시예 3의 단계 E 내지 I의 방법을 수행하여 제조하였다. LC-MS, RT = 2.48분, M/E = 229. The amine was prepared by following the method of Steps E to I of Reference Example 3. LC-MS, RT = 2.48 min, M / E = 229.

참조 실시예 37 및 38의 화합물은 참조 실시예 36에 기술된 방법으로 수득하였다. The compounds of Reference Examples 37 and 38 were obtained by the method described in Reference Example 36.

참조 실시예 37Reference Example 37

2-(3-시아노페닐)-3-사이클로펜틸-1-메틸프로필아민2- (3-cyanophenyl) -3-cyclopentyl-1-methylpropylamine

LC-MS, RT = 2.7분, m/e = 243. LC-MS, RT = 2.7 min, m / e = 243.

참조 실시예 38Reference Example 38

2-(3-시아노페닐)-3-사이클로헥실-1-메틸프로필아민2- (3-cyanophenyl) -3-cyclohexyl-1-methylpropylamine

LC-MS, RT = 2.8분, m/e = 257. LC-MS, RT = 2.8 min, m / e = 257.

실시예 1Example 1

1차원 아미드 라이브러리의 자동화 합성Automated Synthesis of One-dimensional Amide Libraries

다음과 같은 1차원의 순수한 단일 화합물 라이브러리의 합성을 MYRIAD CORE 시스템에서 수행하였다. 모든 반응 용기를 사용전에 질소 스트림하에 120℃에서 12시간 동안 건조시켰다. 모든 용매를 사용전에 12시간 이상 체상에서 건조시켰다. N-[2,3-비스(4-클로로페닐)-1-메틸프로필]-아민 하이드로클로라이드(α이성체)의 적절한 스톡 용액을 사용 직전에 0.05당량(N-[2,3-비스(4-클로로페닐)-1-메틸프로필]-아민 하이드로클로라이드(α이성체)에 대해)의 디메틸아미노피리딘이 첨가된 피리딘 속에서 제조하였다; 시판원으로부터 입수가능한 다양한 카복실산은 사용 직전에 DMSO 속에 용해시켰다. 반응물과 커플링 시약의 상대량은 하기 표 1에 기재한다. Synthesis of the following one-dimensional pure single compound library was performed in the MYRIAD CORE system. All reaction vessels were dried for 12 h at 120 ° C. under a stream of nitrogen prior to use. All solvents were dried on sieves for at least 12 hours before use. 0.05 equivalents of N- [2,3-bis (4-chlorophenyl) -1-methylpropyl] -amine hydrochloride (α isomer) immediately prior to use are 0.05 equivalents (N- [2,3-bis (4- Dimethylaminopyridine of chlorophenyl) -1-methylpropyl] -amine hydrochloride (a isomer)) was prepared in pyridine added; Various carboxylic acids available from commercial sources were dissolved in DMSO just prior to use. Relative amounts of reactants and coupling reagents are listed in Table 1 below.

물질matter 반응 용기당 양Amount Per Reaction Vessel MWMW 농도density mmolsmmols 당량equivalent weight DMSO 중의 산Acid in DMSO 1mL1 mL N/AN / A 0.2M0.2M 0.20.2 1.671.67 중수소화 클로로포름 중의 EDC/HOBt 칵테일EDC / HOBt Cocktail in Deuterated Chloroform 0.8mL0.8 mL EDC:191.71HOBt:135.13EDC: 191.71HOBt: 135.13 각각 0.25M0.25M each 각각 0.20.2 each 각각 1.671.67 each 촉매 디메틸아미노피리딘(약 0.05당량)을 함유한 피리딘 중의 아민Amines in pyridine containing catalytic dimethylaminopyridine (about 0.05 equivalents) 0.6mL0.6 mL 294.227294.227 0.2M0.2M 0.120.12 1.01.0

방법: 전체 192개의 건조된 10mL들이 소결 MYRIAD 반응 용기 중 하나의 용기에 적절한 다양한 산 서브유닛(1.0mL, 0.2mmoles, DMSO 중의 0.2M)을 첨가하였다; 다양한 산이 모든 192개의 반응 용기로 각각 첨가될 때까지 이를 나머지 191개의 반응 용기에 대해서 반복한다. 이어서, 질소하에 각각의 192개의 반응 용기에 EDC/HOBt 칵테일(0.8mL, 0.2mmoles, 중수소화 클로로포름 중의 각각 0.25M)을 첨가하였다. 마지막으로, 각각의 192개의 반응 용기에 N-[2,3-비스(4-클로로페닐)-1-메틸프로필]-아민 하이드로클로라이드(알파 이성체)(0.6mL, 0.12mmoles, 피리딘 중의 0.2M)을 첨가하였다. 이어서, 반응물을 실온(20 내지 25℃)에서 4시간 동안 숙성시킨 다음, 공기주입 교반(매 30분마다 질소 1초 펄스)을 이용하여 65℃에서 16시간 동안 숙성시켰다. 조 반응물을 HPLC-MS 방법 1에 의해 분석하였다.Method: A total of 192 dried 10 mL sintered MYRIAD reaction vessels were added with various acid subunits (1.0 mL, 0.2 mmoles, 0.2 M in DMSO) as appropriate; This is repeated for the remaining 191 reaction vessels until various acids are added to all 192 reaction vessels, respectively. EDC / HOBt cocktails (0.8 mL, 0.2 mmoles, 0.25 M each in deuterated chloroform) were then added to each of the 192 reaction vessels under nitrogen. Finally, N- [2,3-bis (4-chlorophenyl) -1-methylpropyl] -amine hydrochloride (alpha isomer) (0.6 mL, 0.12 mmoles, 0.2 M in pyridine) was added to each of the 192 reaction vessels. Was added. The reaction was then aged at room temperature (20-25 [deg.] C.) for 4 hours and then aged at 65 [deg.] C. for 16 hours using air injection agitation (1 second pulse of nitrogen every 30 minutes). The crude reaction was analyzed by HPLC-MS Method 1.

분석적 LC 방법 1:Analytical LC Method 1:

컬럼: MetaChem Polaris C-18A, 30mm X 4.6mm, 5.0㎛Column: MetaChem Polaris C-18A, 30 mm x 4.6 mm, 5.0 μm

용리제 A: 수중 0.1% TFA Eluent A: 0.1% TFA in water

용리제 B: 아세토니트릴 중 0.1% TFA Eluent B: 0.1% TFA in acetonitrile

구배: 3.3분 동안 5% B 내지 95 % B, 이어서 다시 0.3분 동안 5% BGradient: 5% B to 95% B for 3.3 minutes, then again 5% B for 0.3 minutes

유속: 2.5mL/분. Flow rate: 2.5 mL / min.

컬럼 온도: 50℃ Column temperature: 50 ℃

주입량: 희석되지 않은 조 반응 혼합물 5㎕Injection volume: 5 μL undiluted crude reaction mixture

검출: 220 및 254nm에서 UV Detection: UV at 220 and 254 nm

MS: API-ES 이온화 모드, 질량 스캔 범위(100 내지 700) MS: API-ES ionization mode, mass scan range (100 to 700)

ELSD: 광 산란 검출기ELSD: Light Scattering Detector

조 반응물을 UV 기반 검출을 이용하여 분취용 HPLC로 정제하였다(분취 방법 2). 이어서, 수집된 분획을 LC-MS에 의해 순도에 대해 분석하였다(분석적 방법 3); 90% 순도를 초과하는 것으로 밝혀진 분획을 자체중량이 측정된 40mL EPA 바이알내로 수집하고 동결건조시켰다.The crude reaction was purified by preparative HPLC using UV based detection (preparative method 2). The collected fractions were then analyzed for purity by LC-MS (analytical method 3); Fractions found to be above 90% purity were collected into self weighed 40 mL EPA vials and lyophilized.

분취용 LC 방법 2:Preparative LC Method 2:

컬럼: MetaChem Polaris C-18A, 100mm X 21.2mm, 10㎛ Column: MetaChem Polaris C-18A, 100 mm x 21.2 mm, 10 μm

용리제 A: 수중 0.1% TFA Eluent A: 0.1% TFA in water

용리제 B: 아세토니트릴 중 0.1% TFAEluent B: 0.1% TFA in acetonitrile

주입전 평형: 1.0분 Equilibrium before injection: 1.0 min

주입후 유지: 0.0분 Retention after injection: 0.0 min

구배: 6.0분 동안 10% B 내지 100% B, 100% B에서 추가로 2.0분 동안 유지시키고 이어서 다시 1.5분 동안 100% B 내지 10% B. Gradient: hold for an additional 2.0 minutes at 10% B to 100% B, 100% B for 6.0 minutes and then again 100% B to 10% B for 1.5 minutes.

유속: 25mL/분. Flow rate: 25 mL / min.

컬럼 온도: 주위 온도Column temperature: ambient temperature

주입량: 1.5mL 희석되지 않은 조 반응 혼합물Injection volume: 1.5 mL undiluted crude reaction mixture

검출:220 및 254nm에서 UV Detection: UV at 220 and 254 nm

분석적 LC 방법 3:Analytical LC Method 3:

컬럼: MetaChem Polaris C-18A, 30mm X 2.0mm, 3.0㎛ Column: MetaChem Polaris C-18A, 30 mm x 2.0 mm, 3.0 μm

용리제 A: 수중 0.1% TFAEluent A: 0.1% TFA in water

용리제 B: 아세토니트릴 중 0.1% TFAEluent B: 0.1% TFA in acetonitrile

구배: 2.0분 동안 5% B 내지 95% B 이어서 다시 0.1분 동안 5% BGradient: 5% B to 95% B for 2.0 min, then 5% B for 0.1 min

유속: 1.75mL/분. Flow rate: 1.75 mL / min.

컬럼 온도: 60℃ Column temperature: 60 ℃

주입량: 희석되지 않은 분획 5㎕Injection volume: 5 µL undiluted fraction

검출:220 및 254nm에서 UV Detection: UV at 220 and 254 nm

MS: API-ES 이온화 모드, 질량 스캔 범위(100 내지 700) MS: API-ES ionization mode, mass scan range (100 to 700)

ELSD: 광 산란 검출기 ELSD: Light Scattering Detector

이온화 매개변수Ionization parameters

초기 동결 세트포인트: -70℃에서 1시간Initial freeze set point: 1 hour at -70 ° C

건조 상 콘덴서 세트포인트:-50℃ Dry Phase Condenser Set Point: -50 ℃

건조 상 표:Dry Trade Table:

자체 온도(C)Self temperature (C) 기간(분)Duration (minutes) 진공 세트포인트(mTorr)Vacuum set point (mTorr) -60°-60 ° 240240 2525 -40°-40 ° 240240 2525 5°5 ° 480480 2525 20°20 ° 10001000 2525

실시예 2 및 3Examples 2 and 3

N-[2,3-비스(4-클로로페닐)-1-메틸프로필]-2-(4-클로로페닐옥시)-2-메틸프로판아미드(부분입체이성체 α 및 β). N- [2,3-bis (4-chlorophenyl) -1-methylpropyl] -2- (4-chlorophenyloxy) -2-methylpropanamide (diastereomers α and β).

CH2Cl2(2mL) 중의 2-(4-클로로페닐옥시)-2-메틸프로피온산(제조원: Aldrich, 0.22g, 1.0mmol)의 용액에 0℃에서 한 방울의 DMF 및 옥살릴 클로라이드(0.27mL, 3.0mmol)을 첨가하였다. 실온에서 1시간 동안 교반한 후, 반응 혼합물을 회전 증발기에서 농축시키고 진공하에 건조시키고, 생성된 조 아실 클로라이드를 추가의 정제없이 사용하였다. 따라서, 조 아실 클로라이드를 1mL CH2Cl2 속에 용해시키고, 4mL CH2C12중의 2-아미노-3,4-비스(4-클로로페닐)부탄 하이드로클로라이드 염(참조 실시예 1)(일부 부분입체이성체 β로 오염된 부분입체이성체 α, 0.20g, 0.60mmol) 및 N-메틸모르폴린(0.27mL, 2.4mmol)의 현탁액에 첨가하였다. 실온에서 6시간 동안 교반한 후, 반응 혼합물을 실리카 겔 컬럼에 부하하고, 이를 10% EtOAc로 용출시켜 보다 신속하게 용출되는 순수한 이성체(부분입체이성체 α) 및 보다 서서히 용출되는 이성체(부분입체이성체 β)를 수득하였다.To a solution of 2- (4-chlorophenyloxy) -2-methylpropionic acid (Aldrich, 0.22 g, 1.0 mmol) in CH 2 Cl 2 (2 mL) at 0 ° C. one drop of DMF and oxalyl chloride (0.27 mL , 3.0 mmol) was added. After stirring for 1 hour at room temperature, the reaction mixture was concentrated on a rotary evaporator and dried under vacuum and the resulting crude acyl chloride was used without further purification. Thus, the crude acyl chloride was dissolved in 1 mL CH 2 Cl 2 and the 2 -amino-3,4-bis (4-chlorophenyl) butane hydrochloride salt in 4 mL CH 2 C1 2 (Reference Example 1) (some diastereomers) To a suspension of diastereomers α, 0.20 g, 0.60 mmol) and N-methylmorpholine (0.27 mL, 2.4 mmol) contaminated with isomer β. After stirring for 6 hours at room temperature, the reaction mixture is loaded onto a silica gel column, which is eluted with 10% EtOAc to more quickly elute the pure isomers (diastereomer α) and the more slowly eluted isomers (diastereomer β ) Was obtained.

부분입체이성체 α: 1H NMR(500 MHz, CD30D): δ 7.24(d, 2H), 7.20(d, 2H), 7.05(d, 2H), 7.01(d, 2H), 6.94(d, 2H), 6.76(d, 2H), 4.25(m, 1H), 3.03(dd, 1H), 2.88(ddd, 1H), 2.67(dd, 1H), 1.59(s, 3H), 1.53(s, 3H), 0.88(d, 3H). LC-MS: m/e 490(M + H)+(4.7분).Diastereomer α: 1 H NMR (500 MHz, CD 3 0D): δ 7.24 (d, 2H), 7.20 (d, 2H), 7.05 (d, 2H), 7.01 (d, 2H), 6.94 (d, 2H), 6.76 (d, 2H), 4.25 (m, 1H), 3.03 (dd, 1H), 2.88 (ddd, 1H), 2.67 (dd, 1H), 1.59 (s, 3H), 1.53 (s, 3H) ), 0.88 (d, 3 H). LC-MS: m / e 490 (M + H) + (4.7 min).

부분입체이성체 β: 1H NMR(500 MHz, CD3OD): δ7.16(d, 2H), 7.14(d, 2H), 7.09(d, 2H), 6.99(d, 2H), 6.88(d, 2H), 6.64(d, 2H), 4.33(m, 1H), 3.12(dd, 1H), 3.03(ddd, 1H), 2.74(dd, 1H), 1.36(s, 3H), 1.30(d, 3H), 1.30(s, 3H). LC-MS: m/e 490(M + H)+(4.7분).Diastereomer β: 1 H NMR (500 MHz, CD 3 OD): δ 7.16 (d, 2H), 7.14 (d, 2H), 7.09 (d, 2H), 6.99 (d, 2H), 6.88 (d , 2H), 6.64 (d, 2H), 4.33 (m, 1H), 3.12 (dd, 1H), 3.03 (ddd, 1H), 2.74 (dd, 1H), 1.36 (s, 3H), 1.30 (d, 3H), 1.30 (s, 3H). LC-MS: m / e 490 (M + H) + (4.7 min).

실시예 4 내지 7(표 2)를, 2-아미노-3,4-비스(4-클로로페닐)부탄 하이드로클로라이드 염을 참조 실시예의 적절한 아민으로 대체시키고 2-(4-클로로페닐옥시)-2-메틸프로피온산을 참조 실시예의 적절한 산으로 대체시켜 실시예 2 및 3에서 기술한 방법을 수행하여 제조하였다. 일부 경우에는, 시판되는 산 또는 아실 클로라이드를 사용하였고, N-디이소프로필-에틸아민을 N-메틸모르폴린 대신에 사용하여 유사한 결과를 수득하였다. 부분입체이성체 명칭(α 또는 β)은 출발 아민의 명칭에 상응하다. Examples 4-7 (Table 2) were replaced with the 2-amino-3,4-bis (4-chlorophenyl) butane hydrochloride salt with the appropriate amines of the Reference Example and 2- (4-chlorophenyloxy) -2 Prepared by carrying out the process described in Examples 2 and 3 by replacing methylpropionic acid with the appropriate acid of the Reference Example. In some cases, commercially available acids or acyl chlorides were used and N-diisopropyl-ethylamine was used in place of N-methylmorpholine to obtain similar results. The diastereomeric name (α or β) corresponds to the name of the starting amine.

실시예 2 및 3에서 기술한 방법에 따라 제조한 화합물Compounds prepared according to the methods described in Examples 2 and 3 실시예 번호Example number 명칭designation 구조rescue 체류 시간(분)Retention time (minutes) HPLC-질량 스펙트럼 m/eHPLC-mass spectrum m / e 부분입체이성체 α및/또는 βDiastereomers α and / or β 44 N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(3-클로로페닐옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (3-chlorophenyloxy) -2-methylpropanamide 4.54.5 456456 αα 55 N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(3,5-디플루오로페닐옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (3,5-difluorophenyloxy) -2-methylpropanamide 4.44.4 458458 αα 66 N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (2-pyridyloxy) -2-methylpropanamide 3.93.9 423423 αα 77 N-[3-(4-클로로페닐)-1-메틸-2-(3-피리딜)프로필]-2-(4-클로로페닐옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -1-methyl-2- (3-pyridyl) propyl] -2- (4-chlorophenyloxy) -2-methylpropanamide 3.03.0 457457 αα

실시예 8 및 9  Examples 8 and 9

N-[2,3-비스(4-클로로페닐)-1-메틸프로필]-2-(4-클로로페닐옥시)-2-메틸프로판아미드(부분입체이성체 α, 에난티오머 A 및 B).N- [2,3-bis (4-chlorophenyl) -1-methylpropyl] -2- (4-chlorophenyloxy) -2-methylpropanamide (diastereomer α, enantiomer A and B).

에난티오머를 분리하기 위해 분취 HPLC를 Gilson HPLC 시스템에서 수행하였다. 따라서, 헥산(3mL)/에탄올(7mL) 중의 N-[2,3-비스(4-클로로페닐)-1-메틸프로필]-2-(4-클로로페닐옥시)-2-메틸프로판아미드(부분입체이성체 α)(실시예 60, 1.0g)의 용액을 Chiralpak AD 컬럼(2 cm x 25 cm)에 부하하고, 이를 헥산 중의 5% 에탄올(유속 9mL/분, 주입당 500㎕)로 용출시켜 2개의 순수한 에난티오머를 수득하여다.Preparative HPLC was performed on a Gilson HPLC system to separate enantiomers. Thus, N- [2,3-bis (4-chlorophenyl) -1-methylpropyl] -2- (4-chlorophenyloxy) -2-methylpropanamide (partially in hexane (3 mL) / ethanol (7 mL) A solution of stereoisomer α) (Example 60, 1.0 g) was loaded onto a Chiralpak AD column (2 cm × 25 cm), eluted with 5% ethanol (flow rate 9 mL / min, 500 μl per injection) in hexanes to give 2 Four pure enantiomers were obtained.

보다 신속히 용출되는 에난티오머(에난티오머 A): 분석적 HPLC: 체류 시간 = 7.8분(Chiralpak AD 컬럼, 유속 = 0.75mL/분, 5% 에탄올/헥산). LC-MS: m/e 490(M + H)+(4.7분).Enantiomer eluting more quickly (Enantiomer A): Analytical HPLC: Retention time = 7.8 min (Chiralpak AD column, flow rate = 0.75 mL / min, 5% ethanol / hexane). LC-MS: m / e 490 (M + H) + (4.7 min).

보다 서서히 용출되는 에난티오머(에난티오머 B): 분석적 HPLC: 체류 시간 = 9.6분(Chiralpak AD 컬럼, 유속 = 0.75mL/분, 5% 에탄올/헥산). LC-MS: m/e 490(M + H)+(4.7분).Slower eluting enantiomer (Enantiomer B): Analytical HPLC: Retention time = 9.6 min (Chiralpak AD column, flow rate = 0.75 mL / min, 5% ethanol / hexane). LC-MS: m / e 490 (M + H) + (4.7 min).

실시예 10 내지 17(표 3)을, (1) 용리제 조성(4 내지 15% 에탄올/헥산), (2) 유속(6 내지 9mL/분) 및 (3) 주입 용적(200 내지 2000㎕)을 적절히 변형시켜 실시예 8 및 9에 기술된 방법을 수행하여 상응하는 라세미 물질(표 2)로부터 단일 에난티오머로서 분리시켰다. Examples 10-17 (Table 3) were prepared by (1) eluent composition (4-15% ethanol / hexane), (2) flow rate (6-9 mL / min) and (3) injection volume (200-2000 μl) Was appropriately modified to carry out the method described in Examples 8 and 9 to separate from the corresponding racemic material (Table 2) as a single enantiomer.

실시예 8 및 9에 기술한 방법에 따라 분리된 에난티오머 화합물Enantiomeric compounds isolated according to the methods described in Examples 8 and 9 실시예 번호Example number 명칭designation 구조rescue 체류 시간(분)Retention time (minutes) HPLC-질량 스펙트럼 m/eHPLC-mass spectrum m / e 부분입체이성체 α및/또는 βDiastereomers α and / or β 1010 N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(3-클로로페닐옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (3-chlorophenyloxy) -2-methylpropanamide 4.54.5 456456 AA 1111 N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(3-클로로페닐옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (3-chlorophenyloxy) -2-methylpropanamide 4.54.5 456456 BB 1212 N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(3,5-디플루오로페닐옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (3,5-difluorophenyloxy) -2-methylpropanamide 4.34.3 458458 AA 1313 N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(3,5-디플루오로페닐옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (3,5-difluorophenyloxy) -2-methylpropanamide 4.34.3 458458 BB 1414 N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (2-pyridyloxy) -2-methylpropanamide 3.93.9 423423 AA 1515 N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (2-pyridyloxy) -2-methylpropanamide 3.93.9 423423 BB 1616 N-[3-(4-클로로페닐)-1-메틸-2-(3-피리딜)프로필]-2-(4-클로로페닐옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -1-methyl-2- (3-pyridyl) propyl] -2- (4-chlorophenyloxy) -2-methylpropanamide 3.03.0 457457 AA 1717 N-[3-(4-클로로페닐)-1-메틸-2-(3-피리딜)프로필]-2-(4-클로로페닐옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -1-methyl-2- (3-pyridyl) propyl] -2- (4-chlorophenyloxy) -2-methylpropanamide 3.03.0 457457 BB

실시예 18(표 4)를 적절한 카복실산에 커플링된 참조 실시예 4로부터의 N-[3-(4-클로로페닐)-2(S)-페닐-1(S)-메틸프로필]-아민, 하이드로클로라이드를 사용하여 실시예 2 및 3에 기술된 방법을 수행하여 제조하였다.Example 18 (Table 4), N- [3- (4-chlorophenyl) -2 (S) -phenyl-1 (S) -methylpropyl] -amine from Reference Example 4 coupled to a suitable carboxylic acid, Prepared by carrying out the method described in Examples 2 and 3 using hydrochloride.

참조 실시예 4로부터의 N-[3-(4-클로로페닐)-2(S)-페닐-1(S)-메틸프로필]-아민, 하이드로클로라이드로 제조한 단일 에난티오머 화합물Single Enantiomeric Compound Prepared from N- [3- (4-chlorophenyl) -2 (S) -phenyl-1 (S) -methylpropyl] -amine, hydrochloride from Reference Example 4 실시예 번호Example number 명칭designation 구조rescue 체류 시간(분)Retention time (minutes) HPLC-질량 스펙트럼 m/eHPLC-mass spectrum m / e 1818 N-[3-(4-클로로페닐)-2(S)-페닐-1(S)-메틸프로필]-2-(3,5-디클로로페닐옥시)-2-메틸프로판아미드N- [3- (4-Chlorophenyl) -2 (S) -phenyl-1 (S) -methylpropyl] -2- (3,5-dichlorophenyloxy) -2-methylpropanamide 4.74.7 490490

실시예 19Example 19

N-[2,3-비스(4-클로로페닐)-1-메틸프로필]-2-(4-클로로페닐아미노)-2-메틸프로판아미드N- [2,3-bis (4-chlorophenyl) -1-methylpropyl] -2- (4-chlorophenylamino) -2-methylpropanamide

CH2Cl2 5mL 중의 2-아미노-3,4-비스(4-클로로페닐)부탄 하이드로클로라이드 염(부분입체이성체 α, 단락 I, 참조 실시예 1, 0.31g, 0.94mmol)과 2-(4-클로로페닐아미노)-2-메틸프로피온산(0.20g, 0.94mmol)의 혼합물에 N-메틸모르폴린(0.41mL, 3.5mmol) 및 트리스(피롤린디닐)포스포늄 헥사플루오로포스페이트(0.73g, 1.4mmol)을 첨가하였다. 실온에서 밤새 교반한 후, 반응 혼합물을 실리카 겔 컬럼에 부하하고, 이를 헥산 중의 30% EtOAc로 용출시켜 표제 화합물을 수득하였다. 1H NMR(400 MHz, CD3OD): δ 7.18(d, 2H), 7.04(d, 2H), 7.02(d, 2H), 6.97(d, 2H), 6.70(d, 2H), 6.56(d, 2H), 4.20(m, 1H), 3.02(dd, 1H), 2.78(ddd, 1H), 2.64(dd, 1H), 1.52(s, 3H), 1.45(s, 3H), 0.82(d, 3H). LC-MS: m/e 489(M + H)+(4.3분). 2 -amino-3,4-bis (4-chlorophenyl) butane hydrochloride salt in 5 mL of CH 2 Cl 2 (diastereomer α, paragraph I, reference example 1, 0.31 g, 0.94 mmol) and 2- (4 N-methylmorpholine (0.41 mL, 3.5 mmol) and tris (pyrrolidinyl) phosphonium hexafluorophosphate (0.73 g, 1.4 in a mixture of -chlorophenylamino) -2-methylpropionic acid (0.20 g, 0.94 mmol) mmol) was added. After stirring at room temperature overnight, the reaction mixture was loaded onto a silica gel column and eluted with 30% EtOAc in hexanes to afford the title compound. 1 H NMR (400 MHz, CD 3 OD): δ 7.18 (d, 2H), 7.04 (d, 2H), 7.02 (d, 2H), 6.97 (d, 2H), 6.70 (d, 2H), 6.56 ( d, 2H), 4.20 (m, 1H), 3.02 (dd, 1H), 2.78 (ddd, 1H), 2.64 (dd, 1H), 1.52 (s, 3H), 1.45 (s, 3H), 0.82 (d , 3H). LC-MS: m / e 489 (M + H) + (4.3 min).

실시예 20Example 20

N-(2,3-디페닐-1-메틸프로필)-2-(4-클로로페녹시)-2-메틸프로판아미드(부분입체이성체 β)N- (2,3-diphenyl-1-methylpropyl) -2- (4-chlorophenoxy) -2-methylpropanamide (diastereomer β)

CH2C12(1mL) 및 DMF(10㎕) 중의 2-(4-클로로페녹시)-2-메틸프로피온산(20mg, 0.095mmol)의 용액을 옥살릴 클로라이드(11㎕)로 처리하였다. 30분 후, 반응물을 농축시키고, 잔사를 CH2C12 1mL 속에 용해시켰다. 상기 용액을 N-(2,3-디페닐-1-메틸프로필아민(참조 실시예 2로부터의 β이성체 참조 실시예 2) 16mg과 포화 NaHCO3 1mL의 혼합물에 첨가하였다. 반응물을 밤새 교반하고 유기 층을 피펫으로 제거하였다. 상기 용액을 30% EtOAc/헥산으로 용출시키면서 분취 TLC로 정제하여 표제 화합물을 수득하였다. 1H NMR: (500 MHz, CDC13): δ 1.17(d, 3H), 1.36(s, 3H), 1.46(s, 3H), 2.85-3.05(m, 3H), 4.44(m, 1H), 6.37(d, 1H), 6.75-7.4(m, 14H). LC-MS: Rt = 4.4분. m/e = 422.2(M+1).A solution of 2- (4-chlorophenoxy) -2-methylpropionic acid (20 mg, 0.095 mmol) in CH 2 C1 2 (1 mL) and DMF (10 μl) was treated with oxalyl chloride (11 μl). After 30 minutes, the reaction was concentrated and the residue was dissolved in 1 mL of CH 2 C1 2 . The solution was added to a mixture of 16 mg N- (2,3-diphenyl-1-methylpropylamine (β isomer reference Example 2 from Reference Example 2) and 1 mL of saturated NaHCO 3. The reaction was stirred overnight and organic The layer was removed by pipette The solution was purified by preparative TLC eluting with 30% EtOAc / hexanes to give the title compound: 1 H NMR: (500 MHz, CDC1 3 ): δ 1.17 (d, 3H), 1.36 (s, 3H), 1.46 (s, 3H), 2.85-3.05 (m, 3H), 4.44 (m, 1H), 6.37 (d, 1H), 6.75-7.4 (m, 14H) .LC-MS: R t = 4.4 min. m / e = 422.2 (M + 1).

표 5의 다음 화합물들은 N-(2,3-디페닐-1-메틸프로필아민)을 적절한 아민으로 대체시키고 2-(4-클로로페녹시)-2-메틸-프로피온산을 적절한 카복실산으로 대체시켜 실시예 20의 방법을 수행하여 제조하였다. The following compounds in Table 5 were carried out by replacing N- (2,3-diphenyl-1-methylpropylamine) with the appropriate amine and replacing 2- (4-chlorophenoxy) -2-methyl-propionic acid with the appropriate carboxylic acid. Prepared by the method of Example 20.

실시예 번호Example number 명칭designation 구조rescue 체류 시간(분)Retention time (minutes) HPLC-질량 스펙트럼 m/eHPLC-mass spectrum m / e 2121 N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(4-클로로페닐옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (4-chlorophenyloxy) -2-methylpropanamide 4.54.5 456.0456.0 2222 N-[3-(4-클로로페닐)-2-페닐-1-메틸프로필)-2-메틸-2-페녹시-프로판아미드N- [3- (4-chlorophenyl) -2-phenyl-1-methylpropyl) -2-methyl-2-phenoxy-propanamide 4.34.3 422.2422.2

표 6의 다음 화합물들은 N-(2,3-디페닐-1-메틸프로필아민)을 적절한 아민으로 대체시키고 2-(4-클로로페녹시)-2-메틸-프로피온산을 적절한 카복실산으로 대체시켜 실시예 2 및 3의 방법을 수행하여 제조하였다. The following compounds in Table 6 were carried out by replacing N- (2,3-diphenyl-1-methylpropylamine) with the appropriate amine and replacing 2- (4-chlorophenoxy) -2-methyl-propionic acid with the appropriate carboxylic acid. Prepared by the method of Examples 2 and 3.

실시예 2 및 3에 기술된 방법에 따라 제조된 화합물Compounds Prepared According to the Methods Described in Examples 2 and 3 실시예 번호Example number 명칭designation 구조rescue 체류 시간(분)Retention time (minutes) HPLC-질량 스펙트럼 m/eHPLC-mass spectrum m / e 부분입체이성체 α 및/또는 βDiastereomers α and / or β 2323 N-[3-(4-클로로페닐)-2-(3,5-디플루오로페닐)-1-메틸프로필]-2-메틸-2-(2-피리딜옥시)프로판아미드N- [3- (4-chlorophenyl) -2- (3,5-difluorophenyl) -1-methylpropyl] -2-methyl-2- (2-pyridyloxy) propanamide 3.93.9 459459 αα

표 7의 다음 화합물들을 실시예 8 및 9에 기술된 에닌티오머로부터 분리시키는 방법에 따라 분리시켰다.The following compounds of Table 7 were isolated according to the method of separation from the eninomers described in Examples 8 and 9.

실시예 8 및 9에 기술된 방법에 따라 분리된 에난티오머 화합물Enantiomeric compounds isolated according to the methods described in Examples 8 and 9 실시예 번호Example number 명칭designation 구조rescue 체류 시간(분)Retention time (minutes) HPLC-질량 스펙트럼 m/eHPLC-mass spectrum m / e 에난티오머 A 또는 BEnantiomer A or B 2424 N-[3-(4-클로로페닐)-2-(3,5-디플루오로페닐)-1-메틸프로필]-2-메틸-2-(2-피리딜옥시)프로판아미드N- [3- (4-chlorophenyl) -2- (3,5-difluorophenyl) -1-methylpropyl] -2-methyl-2- (2-pyridyloxy) propanamide 3.93.9 459459 AA 2525 N-[3-(4-클로로페닐)-2-(3,5-디플루오로페닐)-1-메틸프로필]-2-메틸-2-(2-피리딜옥시)프로판아미드N- [3- (4-chlorophenyl) -2- (3,5-difluorophenyl) -1-methylpropyl] -2-methyl-2- (2-pyridyloxy) propanamide 3.93.9 459459 BB

표 8의 다음 화합물들을 참조 실시예 4로부터의 N-[3-(4-클로로페닐)-2(S)-페닐-1(S)-메틸프로필]-아민, 하이드로클로라이드 및 적절한 산으로부터 제조하여 단일 에난티오머를 수득하였다.The following compounds of Table 8 were prepared from N- [3- (4-chlorophenyl) -2 (S) -phenyl-1 (S) -methylpropyl] -amine, hydrochloride and the appropriate acid from Reference Example 4 Single enantiomers were obtained.

N-[3-(4-클로로페닐)-2(S)-페닐-1(S)-메틸프로필]-아민, 하이드로클로라이드로 제조한 단일 에난티오머 화합물N- [3- (4-chlorophenyl) -2 (S) -phenyl-1 (S) -methylpropyl] -amine, single enantiomer compound prepared from hydrochloride 실시예 번호Example number 명칭designation 구조rescue 체류 시간(분)Retention time (minutes) HPLC-질량 스펙트럼 m/eHPLC-mass spectrum m / e 2626 N-[(2S,3S)-3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(5-클로로피리딜옥시)-2-메틸프로판아미드N-[(2S, 3S) -3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (5-chloropyridyloxy) -2-methylpropanamide 4.24.2 457457 2727 N-[(2S,3S)-3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(6-메틸피리딜옥시)-2-메틸프로판아미드N-[(2S, 3S) -3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (6-methylpyridyloxy) -2-methylpropanamide 3.83.8 437437 2828 N-[(2S,3S)-3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(4-트리플루오로메틸페닐옥시)-2-메틸프로판아미드N-[(2S, 3S) -3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (4-trifluoromethylphenyloxy) -2-methylpropanamide 4.54.5 490490 2929 N-[(2S,3S)-3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(5-트리플루오로메틸피리딜옥시)-2-메틸프로판아미드N-[(2S, 3S) -3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (5-trifluoromethylpyridyloxy) -2-methylpropanamide 4.34.3 491491

실시예 30 내지 33(표 9)은 실시예 2 및 3(아실 클로라이드 중간체를 통해) 또는 실시예 19(커플링 시약 사용)에 기술된 방법을 수행하여 N-[3-(4-클로로페닐)-2(S)-페닐-1(S)-메틸프로필]아민, 하이드로클로라이드(참조 실시예 4) 또는 N-[3-(5-클로로-2-피리딜)-2(S)-페닐-1(S)-메틸프로필]아민, 하이드로클로라이드(참조 실시예 18) 및 적절한 카복실산으로부터 제조하였다. Examples 30-33 (Table 9) were subjected to the process described in Examples 2 and 3 (via acyl chloride intermediate) or Example 19 (using coupling reagent) to give N- [3- (4-chlorophenyl) -2 (S) -phenyl-1 (S) -methylpropyl] amine, hydrochloride (see Example 4) or N- [3- (5-chloro-2-pyridyl) -2 (S) -phenyl- Prepared from 1 (S) -methylpropyl] amine, hydrochloride (see Example 18) and the appropriate carboxylic acid.

실시예 번호Example number 명칭designation 구조rescue 체류 시간(분)Retention time (minutes) HPLC-질량 스펙트럼 m/eHPLC-mass spectrum m / e 3030 N-[3-(5-클로로-2-피리딜)-2(S)-페닐-1(S)-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드N- [3- (5-chloro-2-pyridyl) -2 (S) -phenyl-1 (S) -methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2 Methylpropanamide 3.73.7 492492 3131 N-[3-(4-클로로페닐)-2(S)-페닐-1(S)-메틸프로필]-2-(4-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-Chlorophenyl) -2 (S) -phenyl-1 (S) -methylpropyl] -2- (4-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide 4.34.3 491491 3232 N-[3-(4-클로로페닐)-2(S)-페닐-1(S)-메틸프로필]-2-(4-트리플루오로메틸-2-피리미딜옥시)-2-메틸프로판아미드N- [3- (4-Chlorophenyl) -2 (S) -phenyl-1 (S) -methylpropyl] -2- (4-trifluoromethyl-2-pyrimidyloxy) -2-methylpropanamide 3.93.9 492492 3333 N-[3-(4-클로로페닐)-2(S)-페닐-1(S)-메틸프로필]-2-(4-트리플루오로메틸-4-피리미딜옥시)-2-메틸프로판아미드N- [3- (4-Chlorophenyl) -2 (S) -phenyl-1 (S) -methylpropyl] -2- (4-trifluoromethyl-4-pyrimidyloxy) -2-methylpropanamide 4.14.1 492492

실시예 34 내지 39(표 10)을 실시예 2 및 3(아실 클로라이드 중간체를 통해) 또는 실시예 19(커플링 시약을 사용)에 기술된 방법을 수행하여 참조 실시예의 적절한 아민과 산으로부터 제조하였다. Examples 34-39 (Table 10) were prepared from the appropriate amines and acids of the reference examples by following the method described in Examples 2 and 3 (via acyl chloride intermediates) or Example 19 (using coupling reagents). .

실시예 번호Example number 명칭designation 구조rescue 체류 시간(분)Retention time (minutes) HPLC-질량 스펙트럼 m/eHPLC-mass spectrum m / e 부분입체이성체 α 및/또는 βDiastereomers α and / or β 3434 N-[3-(4-클로로페닐)-2-(3-메틸페닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (3-methylphenyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide 4.44.4 505505 αα 3535 N-[3-(4-클로로페닐)-2-(3-시아노페닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (3-cyanophenyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide 4.14.1 516516 αα 3636 N-[3-(4-클로로페닐)-2-(3-시아노페닐)-1-메틸프로필]-2-(6-트리플루오로메틸-4-피리미딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (3-cyanophenyl) -1-methylpropyl] -2- (6-trifluoromethyl-4-pyrimidyloxy) -2-methylpropanamide 4.04.0 517517 αα 3737 N-[3-(4-클로로페닐)-2-(3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide 2.72.7 492492 αα 3838 N-[3-(4-클로로페닐)-2-(5-클로로-3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (5-chloro-3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2- Methylpropanamide 3.93.9 526526 αα 3939 N-[3-(4-클로로페닐)-2-(5-시아노-3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (5-cyano-3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2 Methylpropanamide 3.73.7 517517 αα 4040 N-[3-(4-클로로페닐)-2-(5-메틸-3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (5-methyl-3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2- Methylpropanamide 2.82.8 506506 αα

실시예 41 내지 52(표 11)을 (1) 용리제 조성(4 내지 15% 에탄올/헥산), (2) 유속(6 내지 9mL/분) 및 (3) 주입 용적(200 내지 2000㎕)을 적절히 변형시켜 실시예 8 및 9에 기술된 방법을 수행하여 상응하는 라세미 물질(표 10)로부터 단일 에난티오머로서 분리시켰다. Examples 41-52 (Table 11) were prepared using (1) eluent composition (4-15% ethanol / hexane), (2) flow rate (6-9 mL / min) and (3) injection volume (200-2000 μl). Appropriate modifications were made to perform the methods described in Examples 8 and 9 to separate as single enantiomers from the corresponding racemic materials (Table 10).

실시예 8 및 9에 기술된 방법에 따라 분리된 에난티오머 화합물Enantiomeric compounds isolated according to the methods described in Examples 8 and 9 실시예 번호Example number 명칭designation 구조rescue 체류 시간(분)Retention time (minutes) HPLC-질량 스펙트럼 m/eHPLC-mass spectrum m / e 에난티오머 A 또는 BEnantiomer A or B 4141 N-[3-(4-클로로페닐)-2-(3-메틸페닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (3-methylphenyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide 4.44.4 505505 AA 4242 N-[3-(4-클로로페닐)-2-(3-메틸페닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (3-methylphenyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide 4.44.4 505505 BB 4343 N-[3-(4-클로로페닐)-2-(3-시아노페닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (3-cyanophenyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide 3.93.9 516516 AA 4444 N-[3-(4-클로로페닐)-2-(3-시아노페닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (3-cyanophenyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide 3.93.9 516516 BB 4545 N-[3-(4-클로로페닐)-2-(3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide 2.72.7 492492 AA

실시예번호Example Number 명칭designation 구조rescue 체류 시간(분)Retention time (minutes) HPLC-질량스펙트럼 m/eHPLC-mass spectrum m / e 에난티오머 A 또는 BEnantiomer A or B 4646 N-[3-(4-클로로페닐)-2-(3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide 2.72.7 492492 BB 4747 N-[3-(4-클로로페닐)-2-(5-클로로-3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (5-chloro-3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2- Methylpropanamide 3.83.8 526526 AA 4848 N-[3-(4-클로로페닐)-2-(5-클로로-3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (5-chloro-3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2- Methylpropanamide 3.83.8 526526 BB 4949 N-[3-(4-클로로페닐)-2-(5-시아노-3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (5-cyano-3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2 Methylpropanamide 3.73.7 517517 AA 5050 N-[3-(4-클로로페닐)-2-(5-클로로-3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (5-chloro-3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2- Methylpropanamide 3.73.7 517517 BB 5151 N-[3-(4-클로로페닐)-2-(5-메틸-3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (5-methyl-3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2- Methylpropanamide 2.82.8 506506 AA 5252 N-[3-(4-클로로페닐)-2-(5-메틸-3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (5-methyl-3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2- Methylpropanamide 2.82.8 506506 BB

실시예 53 내지 56(표 12)을 실리카 겔 크로마토그래피 컬럼에서 명시한 바와 같은 부분입체이성체(이성체 A 또는 B)로서 분리시켰다. 주지된 단일 에난티오머를 상기 주지된 키랄 AD 컬럼에서 분리시켰다.Examples 53-56 (Table 12) were separated as diastereomers (isomer A or B) as specified in the silica gel chromatography column. The well known single enantiomers were separated on the chiral AD columns noted above.

실시예 번호Example number 명칭designation 구조rescue 체류 시간(분)Retention time (minutes) HPLC-질량 스펙트럼 m/eHPLC-mass spectrum m / e 에난티오머 A 또는 BEnantiomer A or B 5353 N-[3-(4-클로로페닐)-2-(7-아자인돌-N-일)-1-메틸)프로필-2-(5-트리플루오로메틸-2-옥시피리딘-2-일)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (7-azaindol-N-yl) -1-methyl) propyl-2- (5-trifluoromethyl-2-oxypyridin-2-yl) 2-methylpropanamide 3.893.89 532.1532.1 BB 5454 N-[3-(4-클로로페닐)-2-(N-메틸-N-페닐)아미노-1-메틸)프로필-2-(5-트리플루오로메틸-2-옥시피리딘-2-일)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (N-methyl-N-phenyl) amino-1-methyl) propyl-2- (5-trifluoromethyl-2-oxypyridin-2-yl) 2-methylpropanamide 4.404.40 521521 이성체 B로부터 유도된 단일 에난티오머Single Enantiomer Derived from Isomer B 5555 N-[3-(4-클로로페닐)-2-(인돌-N-일)-1-메틸)프로필-2-(5-트리플루오로메틸-2-옥시피리딘-2-일)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -2- (indol-N-yl) -1-methyl) propyl-2- (5-trifluoromethyl-2-oxypyridin-2-yl) -2- Methylpropanamide 4.32b,c 4.32 b, c 531531 이성체 B로부터 유오된 단일 에난티오머Single Enantiomer Derived from Isomer B 5656 N-(3-클로로페닐)-2-(인돌린-N-일)-1-메틸)프로필-2-(5-트리플루오로메틸-2-옥시피리딘-2-일)-2-메틸프로판아미드N- (3-chlorophenyl) -2- (indolin-N-yl) -1-methyl) propyl-2- (5-trifluoromethyl-2-oxypyridin-2-yl) -2-methylpropane amides 4.404.40 533533 BB

실시예 57Example 57

2-메틸-N-[1-메틸-3-(4-메틸페닐)-2-페닐프로필]-2-{[5-(트리플루오로메틸) 피리딘-2-일1옥시}프로판아미드2-methyl-N- [1-methyl-3- (4-methylphenyl) -2-phenylpropyl] -2-{[5- (trifluoromethyl) pyridin-2-yl1oxy} propanamide

CH2Cl2(5.5mL) 중의 2-메틸-2-{[5-(트리플루오로메틸)피리딘-2-일]옥시}프로판산(참조 실시예 14,250mg, 1.04mmol) 및 4-(4-메틸페닐)-3-페닐부탄-2-아민(참조 실시예 102, 260mg, 1.04mmol, 4개 이성체의 혼합물)의 용액에 RT에서 디이소프로필에틸아민(272㎕, 1.56mmol)에 이어서 PyBOP(649mg, 1.25mmol)을 첨가하고, 반응 혼합물을 밤새 교반하였다. 반응 혼합물을 실리카 겔 컬럼에 직접 부하하고 0 내지 30% EtOAc/헥산으로 용출시켜 반응물을 정제함으로써 표제 화합물을 4개 이성체의 혼합물로서 수득하였다. 부분입체이성체를 ZORBAX RxSi 컬럼에서 20mL/분에서 97% 헥산: 3% 에탄올을 다음과 같은 체류 시간으로 용출시키면서 HPLC로 분리하였다: 저극성 부분입체이성체는 4.73분에서 용출되었으며 보다 극성인 부분입체이성체는 5.87분에서 용출되었다. 보다 극성인 부분입체이성체는 ChiralPak AD 컬럼에서 8mL/분에서 95% 헥산: 5% 에탄올을 다음과 같은 체류 시간으로 용출시키면서 추가로 분리시켰다: 저극성 에난티오머는 6.84분에서 용출되었으며 보다 극성인 부분입체이성체는 8.36분에서 용출되었다. 2 -methyl-2-{[5- (trifluoromethyl) pyridin-2-yl] oxy} propanoic acid (Reference Example 14,250 mg, 1.04 mmol) and 4- (4 in CH 2 Cl 2 (5.5 mL). In a solution of -methylphenyl) -3-phenylbutan-2-amine (Reference Example 102, 260 mg, 1.04 mmol, a mixture of four isomers) at RT followed by diisopropylethylamine (272 μL, 1.56 mmol) followed by PyBOP ( 649 mg, 1.25 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was loaded directly onto a silica gel column and eluted with 0-30% EtOAc / hexanes to purify the reaction to afford the title compound as a mixture of four isomers. Diastereomers were separated by HPLC on a ZORBAX RxSi column at 20 mL / min with 97% hexanes: 3% ethanol eluting with the following residence time: The low polar diastereomer eluted at 4.73 minutes and the more polar diastereomers Eluted at 5.87 min. The more polar diastereomers were further separated on a ChiralPak AD column with 95% hexanes: 5% ethanol at 8 mL / min eluting with the following residence time: the low polar enantiomer eluted at 6.84 minutes and the more polar moiety. Stereoisomer eluted at 8.36 minutes.

저극성 부분입체이성체: 1H NMR(500 MHz, CDCl3): δ 8.44(s, 1H), 7.86(dd, J = 8.6, 2.5 Hz, 1H), 7.19(t, J = 3.2 Hz, 3H), 7.00(dd, J = 21.3, 8.0 Hz, 4H), 6.91(m, 2H), 6.83(d, J = 8.7 Hz, 1H), 5.70(d, J = 9.4 Hz, 1H), 4.43(m, 1H), 3.02(dd, J = 13.3, 6.7 Hz, 1H), 2.84(dt, J = 7.3, 4.3 Hz, 1H), 2.84(dd, J = 13.2, 7.7 Hz, 1H), 2.29(s, 3H), 1.69(s, 3H), 1.66(s, 3H), 1.03(d, J = 6.8 Hz, 3H). LC-MS: m/e 471(M + H)+(4.22분).Low polar diastereomers: 1 H NMR (500 MHz, CDCl 3 ): δ 8.44 (s, 1H), 7.86 (dd, J = 8.6, 2.5 Hz, 1H), 7.19 (t, J = 3.2 Hz, 3H) , 7.00 (dd, J = 21.3, 8.0 Hz, 4H), 6.91 (m, 2H), 6.83 (d, J = 8.7 Hz, 1H), 5.70 (d, J = 9.4 Hz, 1H), 4.43 (m, 1H), 3.02 (dd, J = 13.3, 6.7 Hz, 1H), 2.84 (dt, J = 7.3, 4.3 Hz, 1H), 2.84 (dd, J = 13.2, 7.7 Hz, 1H), 2.29 (s, 3H ), 1.69 (s, 3H), 1.66 (s, 3H), 1.03 (d, J = 6.8 Hz, 3H). LC-MS: m / e 471 (M + H) + (4.22 min).

보다 극성인 부분입체이성체: 1H NMR(500 MHz, CDC13): δ 8.40(s, 1H), 7.83(dd, J = 8.7, 2.6 Hz, 1H), 7.21(m, 3H), 7.00(dd, J = 30.4, 6.2 Hz, 4H), 6.82(t, J = 9.2 Hz, 3H), 5.84(d, J = 9.2 Hz, 1H), 4.36(ddt, J = 9.1, 6.7, 6.6 Hz, 1H), 3.06(dd, J=12.8, 4.1 Hz, 1H), 2.88(m, 1H), 2.26(s, 3H), 1.78(s, 3H), 1.73(s, 3H), 0.92(d, J = 6.6 H : 3H). LC-MS: m/e 471(M + H)+(4.17분).More polar diastereomers: 1 H NMR (500 MHz, CDC1 3 ): δ 8.40 (s, 1H), 7.83 (dd, J = 8.7, 2.6 Hz, 1H), 7.21 (m, 3H), 7.00 (dd , J = 30.4, 6.2 Hz, 4H), 6.82 (t, J = 9.2 Hz, 3H), 5.84 (d, J = 9.2 Hz, 1H), 4.36 (ddt, J = 9.1, 6.7, 6.6 Hz, 1H) , 3.06 (dd, J = 12.8, 4.1 Hz, 1H), 2.88 (m, 1H), 2.26 (s, 3H), 1.78 (s, 3H), 1.73 (s, 3H), 0.92 (d, J = 6.6 H: 3H). LC-MS: m / e 471 (M + H) + (4.17 min).

실시예 58Example 58

N-[2-(3-시아노페닐)-3-(4-플루오로페닐)-1-메틸프로필]-2-메틸-2-{[5-(트리플루오로메틸)피리딘-2-일]옥시}프로판아미드N- [2- (3-cyanophenyl) -3- (4-fluorophenyl) -1-methylpropyl] -2-methyl-2-{[5- (trifluoromethyl) pyridin-2-yl ] Oxy} propanamide

아민 성분으로서 3-[2-아미노-1-(4-플루오로벤질)프로필]벤조니트릴(참조 실시예 33)만을 사용하여 실시예 5에서와 같이 제조하여 표제 화합물을 4개 이성체의 혼합물로서 수득하였다. 부분입체이성체를 Zorbax RxSi 컬럼에서 20mL/분에서 96% 헥산:4% 에탄올을 다음과 같은 체류 시간으로 용출시키면서 분리시켰다: 저극성 부분입체이성체는 11.75분에서 용출되었으며 보다 극성인 부분입체이성체는 15.17분에서 용출되었다. 보다 극성인 부분입체이성체를 ChiralPak AD 컬럼에서 92% 헥산: 8% 에탄올을 9.65분에서 용출시켜 에난티오머로서 추가로 분리시켰으며, 이때 체류 시간은 다음과 같았다: 저극성 에난티오머는 9.65분에서 용출되었으며 보다 극성인 부분입체이성체는 11.78분에서 용출되었다. Prepared as in Example 5 using only 3- [2-amino-1- (4-fluorobenzyl) propyl] benzonitrile (reference Example 33) as the amine component to give the title compound as a mixture of four isomers It was. Diastereomers were separated on a Zorbax RxSi column at 20 mL / min with 96% hexanes: 4% ethanol eluting with the following residence time: the low polar diastereomer eluted at 11.75 minutes and the more polar diastereomer 15.17 Eluted in minutes. The more polar diastereomers were further separated as enantiomers by eluting 92% hexanes: 8% ethanol at 9.65 min on a ChiralPak AD column, where the residence time was as follows: Low polar enantiomer at 9.65 min Eluted and more polar diastereomer eluted at 11.78 min.

저극성 부부입체이성체: 1H NMR(500 MHz, CD30D): δ 8.29(s, 1H), 7.93(dd, J = 8.7, 2.5 Hz, 1H), 7.50(m, 1H), 7.42(m, 1H), 7.27(m, 2H), 6.96-6.78(m, 5H 5.70(d, J = 9.6 Hz, 1H), 4.33(m, 1H), 3.18-3.04(m, 2H), 2.7(dd, J = 13.5, 6.6 Hz, 1H), 1.52(s, 3H), 1.35(s, 3H), 1.17(d, J = 6.6 Hz, 3H). LC-MS: m/e 500(M + H)+(4.33분).Low polar diastereomers: 1 H NMR (500 MHz, CD 3 0D): δ 8.29 (s, 1H), 7.93 (dd, J = 8.7, 2.5 Hz, 1H), 7.50 (m, 1H), 7.42 (m , 1H), 7.27 (m, 2H), 6.96-6.78 (m, 5H 5.70 (d, J = 9.6 Hz, 1H), 4.33 (m, 1H), 3.18-3.04 (m, 2H), 2.7 (dd, J = 13.5, 6.6 Hz, 1H), 1.52 (s, 3H), 1.35 (s, 3H), 1.17 (d, J = 6.6 Hz, 3H) LC-MS: m / e 500 (M + H) + (4.33 minutes).

보다 극성인 부분입체이성체: 1H NMR(500 MHz, CD3OD): δ 8.28(s, 1H), 7.95(dd, J = 8.7, 2.5 Hz, 1H), 7.50(d, J = 7.5 Hz, 1H), 7.36(m, 3H), 7.05(d, J = 8.9 Hz, 3H), 6.78(m, 2H), 6.72(m, 2H) 4.26(dq, J = 10, 6.6 Hz, 1H), 3.04(dd, J = 13.7, 3.4 Hz, 1H), 2.85(ddt J = 11.2, 3.7 Hz, 1H), 2.63(dd, J = 13.7, 11.4 Hz, 1H), 1.77(s, 3H), 1.74(s, 3H), 0.81(d, J = 6.8 Hz, 3H). LC-MS: m/e 500(M + H)+(4.25분).More polar diastereomers: 1 H NMR (500 MHz, CD 3 OD): δ 8.28 (s, 1H), 7.95 (dd, J = 8.7, 2.5 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.36 (m, 3H), 7.05 (d, J = 8.9 Hz, 3H), 6.78 (m, 2H), 6.72 (m, 2H) 4.26 (dq, J = 10, 6.6 Hz, 1H), 3.04 (dd, J = 13.7, 3.4 Hz, 1H), 2.85 (ddt J = 11.2, 3.7 Hz, 1H), 2.63 (dd, J = 13.7, 11.4 Hz, 1H), 1.77 (s, 3H), 1.74 (s , 3H), 0.81 (d, J = 6.8 Hz, 3H). LC-MS: m / e 500 (M + H) + (4.25 min).

표 13의 화합물은 실시예 2 및 3(아실 클로라이드 중간체를 통해) 또는 실시예 19(커플링 시약 사용)에 기술된 방법을 수행하여 참조 실시예의 적절한 아민과 산으로부터 제조하였다. The compounds in Table 13 were prepared from the appropriate amines and acids of the Reference Examples by following the method described in Examples 2 and 3 (via acyl chloride intermediate) or Example 19 (using coupling reagent).

실시예 번호Example number 명칭designation 구조rescue 체류 시간(분)Retention time (minutes) HPLC-질량 스펙트럼 m/eHPLC-mass spectrum m / e 2121 N-[3-(4-클로로페닐)-1-메틸-2-(티오펜-3-일)프로필)-2-메틸-2-(5-클로로피리딘-2-일)옥시)-2-메틸프로판아미드N- [3- (4-chlorophenyl) -1-methyl-2- (thiophen-3-yl) propyl) -2-methyl-2- (5-chloropyridin-2-yl) oxy) -2- Methylpropanamide 4.214.21 463463

표 14의 화합물은 실시예 8 및 9에 기술된 에난티오머를 분리시키는 방법에 따라서 분리시켰다. The compounds in Table 14 were isolated following the method for separating enantiomers described in Examples 8 and 9.

실시예 8 및 9에 기술된 방법에 따라 분리된 에난티오머 화합물Enantiomeric compounds isolated according to the methods described in Examples 8 and 9 실시예 번호Example number 명칭designation 구조rescue 체류 시간(분)Retention time (minutes) HPLC-질량 스펙트럼 m/eHPLC-mass spectrum m / e 에난티오머 A 또는 BEnantiomer A or B 6060 N-(2-(3-시아노페닐)-1,4-디메틸펜틸)-2-메틸-2-((5-(트리플루오로메틸)피리딘-2-일)옥시)-프로판아미드N- (2- (3-cyanophenyl) -1,4-dimethylpentyl) -2-methyl-2-((5- (trifluoromethyl) pyridin-2-yl) oxy) -propanamide 4.04.0 448448 BB 6161 N-(2-(3-시아노페닐)-3-사이클로부틸-1-메틸프로필)-2-메틸-2-((5-(트리플루오로메틸)피리딘-2-일)옥시)-프로판아미드N- (2- (3-cyanophenyl) -3-cyclobutyl-1-methylpropyl) -2-methyl-2-((5- (trifluoromethyl) pyridin-2-yl) oxy) -propane amides 4.14.1 460460 BB 6262 N-(2-(3-시아노페닐)-3-사이클로펜틸-1-메틸프로필)-2-메틸-2-((5-(트리플루오로메틸)피리딘-2-일)옥시)-프로판아미드N- (2- (3-cyanophenyl) -3-cyclopentyl-1-methylpropyl) -2-methyl-2-((5- (trifluoromethyl) pyridin-2-yl) oxy) -propane amides 4.184.18 474474 BB 6363 N-(2-(3-시아노페닐)-3-사이클로헥실-1-메틸프로필)-2-메틸-2-((5-(트리플루오로메틸)피리딘-2-일)옥시)-프로판아미드N- (2- (3-cyanophenyl) -3-cyclohexyl-1-methylpropyl) -2-methyl-2-((5- (trifluoromethyl) pyridin-2-yl) oxy) -propane amides 4.294.29 488488 BB

실시예 64Example 64

N-[3-(4-클로로페닐)-2-(5-시아노-3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드(에난티오머 B)의 피리딘 N-옥사이드N- [3- (4-chlorophenyl) -2- (5-cyano-3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2 -Pyridine N-oxides of -methylpropanamide (enantiomer B)

메틸렌 클로라이드 2mL 중의 N-[3-(4-클로로페닐)-2-(5-시아노-3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드(에난티오머 B, 실시예 50, 0.10g, 0.19mmol) 및 m-클로로퍼벤조산(77%, 0.15g, 0.67mmol)을 실온에서 14시간 동안 교반하였다. 반응 혼합물을 농축시키고, 잔사를 역상 C18 컬럼에서 수중 30 내지 100% 아세토니트릴(0.1% 트리플루오로아세트산 함유)로 용출시키면서 HPLC로 정제하여 표제 화합물을 수득하였다. 1H NMR(500 MHz, CD3OD): δ 8.58(s, 1H), 8.32(br s, 1H), 8.17(s, 1H), 7.99(br d, 1H), 7.97(dd, 1H), 7.81(s, 1H), 7.16(d, 2H), 7.06(d, 1H), 6.87(d, 2H), 4.28(m, 1H), 3.11(dd, 1H), 3.01(m, 1H), 2.71(dd, 1H), 1.75(s, 3H), 1.74(s, 3H), 0.94(d, 3H). LC-MS: m/e 533(M + H)+(4.1분).N- [3- (4-chlorophenyl) -2- (5-cyano-3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyl in 2 mL methylene chloride Oxy) -2-methylpropanamide (Enantiomer B, Example 50, 0.10 g, 0.19 mmol) and m-chloroperbenzoic acid (77%, 0.15 g, 0.67 mmol) were stirred at room temperature for 14 hours. The reaction mixture was concentrated and the residue was purified by HPLC eluting with 30-100% acetonitrile (containing 0.1% trifluoroacetic acid) in water on a reverse phase C18 column to afford the title compound. 1 H NMR (500 MHz, CD 3 OD): δ 8.58 (s, 1 H), 8.32 (br s, 1 H), 8.17 (s, 1 H), 7.99 (br d, 1 H), 7.97 (dd, 1 H), 7.81 (s, 1H), 7.16 (d, 2H), 7.06 (d, 1H), 6.87 (d, 2H), 4.28 (m, 1H), 3.11 (dd, 1H), 3.01 (m, 1H), 2.71 (dd, 1H), 1.75 (s, 3H), 1.74 (s, 3H), 0.94 (d, 3H). LC-MS: m / e 533 (M + H) + (4.1 min).

실시예 65Example 65

카나비노이드 수용체-1(CB1) 결합 검정Cannabinoid Receptor-1 (CB1) Binding Assay

결합 친화도 측정은 중국 햄스터 난소(CHO) 세포[참조: Felder et al, Mol. Pharmacol. 48: 443-450, 1995]에서 발현되는 재조합 사람 CB1수용체에 기초한다. 전체 검정 용적은 250㎕(240㎕ CB1 수용체 막 용액 + 5㎕ 시험 화합물 용액 + 5㎕ [3H]CP-55940 용액)이다. [3H]CP-55940의 최종 농도는 0.6nM이다. 결합 완충액은 50mM Tris-HCl, pH 7.4, 2.5mM EDTA, 5mM MgCl2, 0.5mg/mL 지방산 비함유 소 혈청 알부민 및 프로테아제 억제제(카탈로그 번호 P8340, 제조원: Sigma)을 함유한다. 결합 반응을 개시하기 위해, 방사성리간드 용액 5㎕를 첨가하고, 혼합물을 30℃에서 1.5시간 동안 진탕기에서 온화하게 진탕시키면서 항온처리하였다. 결합을 96웰 수거기를 사용하고 0.05% 폴리에틸렌이민 속에 미리 침지된 GF/C 필터를 통해 여과하여 종결시킨다. 결합된 방사선표지를 신틸레이션 계수기를 사용하여 정량화한다. 각종 화합물에 대한 외견적 결합 친화도를 IC50 값으로부터 계산한다[참조: DeBlasi et al., Trends Pharmacol Sci 10: 227-229, 1989].Binding affinity measurements were determined by Chinese hamster ovary (CHO) cells [Felder et al, Mol. Pharmacol. 48: 443-450, 1995, which is based on the recombinant human CB1 receptor. The total assay volume is 250 μl (240 μl CB1 receptor membrane solution + 5 μl test compound solution + 5 μl [3 H] CP-55940 solution). The final concentration of [3 H] CP-55940 is 0.6 nM. Binding buffer contains 50 mM Tris-HCl, pH 7.4, 2.5 mM EDTA, 5 mM MgCl 2 , 0.5 mg / mL fatty acid free bovine serum albumin and protease inhibitor (Catalog No. P8340, Sigma). To initiate the binding reaction, 5 μl of radioligand solution was added and the mixture was incubated with gentle shaking on a shaker at 30 ° C. for 1.5 h. The binding is terminated using a 96 well collector and filtered through a GF / C filter pre-soaked in 0.05% polyethyleneimine. Bound radiolabels are quantified using a scintillation counter. Apparent binding affinity for various compounds is calculated from IC 50 values (DeBlasi et al., Trends Pharmacol Sci 10: 227-229, 1989).

CB2 수용체에 대한 결합 검정을 CHO 세포에서 발현되는 재조합 사람 CB2 수용체와 유사하게 수행한다. Binding assays for CB2 receptors are performed similar to recombinant human CB2 receptors expressed in CHO cells.

실시예 66 Example 66

카나비노이드 수용체-1(CB1) 기능적 활성 검정Cannabinoid Receptor-1 (CB1) Functional Activity Assay

CB1 수용체의 기능적 활성화는 CHO 세포[참조: Felder et al, Mol. Pharmacol. 48: 443-450, 1995]에서 발현되는 재조합 사람 CB1수용체에 기초한다. 임의의 시험 화합물의 효능제 활성 또는 역 효능제 활성을 측정하기 위해, CB1-CHO 세포 현탁액 50㎕를 96웰 플레이트에서 시험 화합물, 및 0.34mM 3-이소부틸-1-메틸크산틴 및 5.1μM의 포르스콜린을 함유하는 검정 완충액 70㎕와 혼합하였다. 상기 검정 완충액은 5mM MgCl2, 1mM 글루타민, 10mM HEPES 및 1mg/mL 소 혈청 알부민이 보충된 얼스 밸런스 염 용액(Earle's Balanced Salt Solution)으로 구성된다. 혼합물을 실온에서 30분 동안 항온처리하고, 30㎕/웰의 0.5M HCl을 첨가하여 종결시킨다. 전체 세포내 cAMP 수준을 뉴잉글랜드 뉴클리어 플래스플레이트(New England Nuclear Flashplate) 및 cAMP 방사성면역검정 키트를 사용하여 정량화한다.Functional activation of the CB1 receptor has been described in CHO cells [Felder et al, Mol. Pharmacol. 48: 443-450, 1995, which is based on the recombinant human CB1 receptor. To determine agonist activity or reverse agonist activity of any test compound, 50 μl of CB1-CHO cell suspension was added in a 96 well plate of test compound, and 0.34 mM 3-isobutyl-1-methylxanthine and 5.1 μM. Mix with 70 μl of assay buffer containing forskolin. The assay buffer consists of Earle's Balanced Salt Solution supplemented with 5 mM MgCl 2 , 1 mM glutamine, 10 mM HEPES and 1 mg / mL bovine serum albumin. The mixture is incubated for 30 minutes at room temperature and terminated by addition of 30 μl / well of 0.5 M HCl. Total intracellular cAMP levels are quantified using the New England Nuclear Flashplate and the cAMP Radioimmunoassay Kit.

시험 화합물의 길항제 활성을 측정하기 위해, 반응 혼합물은 또한 0.05nM의 효능제 CP55940을 함유하며, CP55940 효과의 반전을 정량화한다. 대안으로, CP55940에 대한 일련의 용량 반응 곡선을 각각의 용량 반응 곡선에서 시험 화합물의 농도를 증가시키면서 작성한다.To determine the antagonist activity of the test compound, the reaction mixture also contains 0.05 nM of agonist CP55940 and quantifies the reversal of the CP55940 effect. Alternatively, a series of dose response curves for CP55940 are prepared with increasing concentrations of test compound in each dose response curve.

CB2 수용체의 기능적 검정을 CHO 세포에서 발현되는 재조합 사람 CB2 수용체와 유사하게 수행한다.Functional assays of CB2 receptors are performed similar to recombinant human CB2 receptors expressed in CHO cells.

본 발명을 이의 특정한 양태를 참조로 하여 기술하고 설명하였지만, 당해 분야의 숙련가라면 본 발명의 취지 및 범주에서 벗어남이 없이 각종 변화, 변형 및 치환이 이루어질 수 있음을 인지할 것이다. 따라서, 본 발명은 하기의 청구의 범위로 한정되고 이러한 청구의 범위는 합당한 수준에서 광범위하게 해석된다.While the invention has been described and described with reference to specific embodiments thereof, those skilled in the art will recognize that various changes, modifications and substitutions may be made without departing from the spirit and scope of the invention. Accordingly, the invention is limited to the following claims, which are to be construed broadly at the reasonable level.

Claims (17)

화학식 I의 화합물 또는 약제학적으로 허용되는 이의 염.A compound of formula (I) or a pharmaceutically acceptable salt thereof. 화학식 IFormula I 상기 화학식 I에서,In Formula I, R1은 (1) 사이클로헤테로알킬, (2) 아릴, (3) 헤테로아릴 및 (4) -NRaRc[여기서, 아릴 및 헤테로아릴은 Rb로부터 독립적으로 선택되는 1 내지 3개의 치환체에 의해 임의로 치환된다]으로부터 선택되고,R 1 is selected from (1) cycloheteroalkyl, (2) aryl, (3) heteroaryl and (4) -NR a R c wherein aryl and heteroaryl are selected from 1 to 3 substituents independently selected from R b Optionally substituted by R2는 (1) C1-10알킬, (2) C3-10사이클로알킬-C1-4알킬, (3) 아릴-C1-4알킬 및 (4) 헤테로아릴-C1-4알킬[여기서, 각각의 사이클로알킬, 아릴 및 헤테로아릴은 Rb로부터 독립적으로 선택되는 1 내지 3개의 치환체에 의해 임의로 치환된다]로부터 선택되며,R 2 is (1) C 1-10 alkyl, (2) C 3-10 cycloalkyl-C 1-4 alkyl, (3) aryl-C 1-4 alkyl and (4) heteroaryl-C 1-4 alkyl Wherein each cycloalkyl, aryl and heteroaryl is optionally substituted by 1 to 3 substituents independently selected from R b ; 각각의 Ra는 (1) 수소, (2) 메틸 및 (3) -CF3로부터 독립적으로 선택되고,Each R a is independently selected from (1) hydrogen, (2) methyl and (3) -CF 3 , 각각의 Rb는 (1) 할로겐, (2) 시아노, (3) 트리플루오로메틸, (4) 트리플루오로메톡시, (5) C1-3알킬옥시 및 (6) C1-3알킬로부터 독립적으로 선택되며,Each R b is (1) halogen, (2) cyano, (3) trifluoromethyl, (4) trifluoromethoxy, (5) C 1-3 alkyloxy and (6) C 1-3 alkyl Are independently selected from Rc는 (1) 수소, (2) C1-6알킬, (3) 아릴, (4) 헤테로아릴, (5) 아릴-메틸 및 (6) 헤테로아릴-메틸로부터 독립적으로 선택되고,R c is independently selected from (1) hydrogen, (2) C 1-6 alkyl, (3) aryl, (4) heteroaryl, (5) aryl-methyl and (6) heteroaryl-methyl, 각각의 Rc는 비치환되거나 Rh로부터 선택되는 1 내지 3개의 치환체에 의해 치환될 수 있으며,Each R c may be unsubstituted or substituted by 1 to 3 substituents selected from R h , Rd는 (1) 사이클로알킬, (2) 아릴 및 (3) 헤테로아릴로부터 독립적으로 선택되고,R d is independently selected from (1) cycloalkyl, (2) aryl and (3) heteroaryl, 각각의 Rd는 비치환되거나 Rh로부터 선택되는 1 내지 3개의 치환체에 의해 치환될 수 있으며.Each R d may be unsubstituted or substituted with 1 to 3 substituents selected from R h . 각각의 Rh는 (1) 할로겐, (2) C1-3알킬, (3) -CN 및 (4) -CF3로부터 독립적으로 선택되고, 여기서, 피리딜 그룹이 질소에서 비치환되는 경우 이들은 임의로 N-옥사이드로서 존재할 수 있다.Each R h is independently selected from (1) halogen, (2) C 1-3 alkyl, (3) -CN and (4) -CF 3 , wherein when the pyridyl group is unsubstituted in nitrogen Optionally as N-oxide. 제1항에 있어서, R1이 (1) 페닐, (2) 피리딜, (3) 인돌릴, (4) 7-아자-인돌릴, (5) 티오페닐 및 (6) 로부터 독립적으로 선택되고, 여기서, 각각의 아릴 및 헤테로아릴은 Rb로부터 독립적으로 선택되는 1 또는 2개의 치환체에 의해 임의로 치환되며, 각각의 피리딜은 임의로 N-옥사이드로서 존재할 수 있는 화합물 또는 약제학적으로 허용되는 이의 염.A compound according to claim 1, wherein R 1 is (1) phenyl, (2) pyridyl, (3) indolyl, (4) 7-aza-indolyl, (5) thiophenyl and (6) Are independently selected from wherein each aryl and heteroaryl is optionally substituted by one or two substituents independently selected from R b , each pyridyl may optionally be present as an N-oxide or a pharmaceutical Acceptable salts thereof. 제2항에 있어서, R1이 (1) 페닐, (2) 3-시아노페닐, (3) 3-메틸페닐, (4) 3,5-디플루오로페닐, (5) 3-피리딜, (6) 5-클로로-3-피리딜, (7) 5-메틸-3-피리딜, (8) 5-시아노-3-피리딜, (9) 1-옥시도-5-시아노-3-피리딜, (10) 1-인돌릴, (11) 7-아자인돌-N-일, (12) 2-티오페닐 및 (13) 로부터 선택되는 화합물 및 약제학적으로 허용되는 이의 염.The compound of claim 2, wherein R 1 is (1) phenyl, (2) 3-cyanophenyl, (3) 3-methylphenyl, (4) 3,5-difluorophenyl, (5) 3-pyridyl, (6) 5-chloro-3-pyridyl, (7) 5-methyl-3-pyridyl, (8) 5-cyano-3-pyridyl, (9) 1-oxido-5-cyano- 3-pyridyl, (10) 1-indolyl, (11) 7-azaindol-N-yl, (12) 2-thiophenyl and (13) Compounds selected from pharmaceutically acceptable salts thereof. 제3항에 있어서, R1이 5-시아노-3-피리딜인 화합물 및 약제학적으로 허용되는 이의 염.4. A compound according to claim 3, wherein R 1 is 5-cyano-3-pyridyl and a pharmaceutically acceptable salt thereof. 제2항에 있어서, R2가 (1) C1-6알킬, (2) C3-6사이클로알킬메틸, (3) 페닐메틸 및 (4) 헤테로아릴메틸로부터 선택되고, 여기서, 각각의 사이클로알킬, 아릴 및 헤테로아릴은 Rb로부터 독립적으로 선택되는 1 내지 3개의 치환체에 의해 임의로 치환되는 화합물 및 약제학적으로 허용되는 이의 염.The compound of claim 2, wherein R 2 is selected from (1) C 1-6 alkyl, (2) C 3-6 cycloalkylmethyl, (3) phenylmethyl and (4) heteroarylmethyl, wherein each cyclo Alkyl, aryl and heteroaryl are compounds optionally substituted by one to three substituents independently selected from R b and pharmaceutically acceptable salts thereof. 제5항에 있어서, R2가 (1) 2-메틸프로필, (2) n-펜틸, (3) 사이클로부틸메틸, (4) 사이클로펜틸메틸, (5) 사이클로헥실메틸, (6) 벤질, (7) 4-클로로벤질, (8) 4-메틸벤질, (9) 4-플루오로벤질, (10) 4-메톡시벤질 및 (11) (5-클로로-2-피리딜)메틸로부터 선택되는 화합물 및 약제학적으로 허용되는 이의 염.The compound of claim 5, wherein R 2 is (1) 2-methylpropyl, (2) n-pentyl, (3) cyclobutylmethyl, (4) cyclopentylmethyl, (5) cyclohexylmethyl, (6) benzyl, (7) 4-chlorobenzyl, (8) 4-methylbenzyl, (9) 4-fluorobenzyl, (10) 4-methoxybenzyl and (11) (5-chloro-2-pyridyl) methyl Compounds and pharmaceutically acceptable salts thereof. 제2항에 있어서, Rd가 (1) C4-6사이클로알킬, (2) 아릴 및 (3) 헤테로아릴로부터 선택되고, 여기서, Rd는 비치환되거나 Rh로부터 선택되는 1 또는 2개의 치환체에 의해 치환될 수 있는 화합물 및 약제학적으로 허용되는 이의 염.The compound of claim 2, wherein R d is selected from (1) C 4-6 cycloalkyl, (2) aryl and (3) heteroaryl, wherein R d is unsubstituted or selected from R h Compounds which can be substituted by substituents and pharmaceutically acceptable salts thereof. 제7항에 있어서, Rd가 (1) 페닐, (2) 피리딜 및 (3) 피리미디닐로부터 선택되고, 여기서, Rd는 비치환되거나 Rh로부터 선택되는 1 또는 2개의 치환체에 의해 치환될 수 있는 화합물 및 약제학적으로 허용되는 이의 염.8. The compound of claim 7 wherein R d is selected from (1) phenyl, (2) pyridyl and (3) pyrimidinyl, wherein R d is unsubstituted or substituted with one or two substituents selected from R h . Compounds which may be substituted and pharmaceutically acceptable salts thereof. 제8항에 있어서, Rd가 (1) 페닐, (2) 4-클로로페닐, (3) 3-클로로페닐, (4) 3,5-디플루오로페닐, (5) 3,5-디클로로페닐, (6) 2-피리딜, (7) 5-클로로-2-피리딜, (8) 6-메틸-2-피리딜, (9) 5-트리플루오로메틸-2-피리딜, (10) 4-트리플루오로메틸-2-피리딜, (11) 4-트리플루오로메틸-2-피리미딜 및 (12) 6-트리플루오로메틸-4-피리미딜로부터 선택되는 화합물 및 약제학적으로 허용되는 이의 염.The compound of claim 8, wherein R d is (1) phenyl, (2) 4-chlorophenyl, (3) 3-chlorophenyl, (4) 3,5-difluorophenyl, (5) 3,5-dichloro Phenyl, (6) 2-pyridyl, (7) 5-chloro-2-pyridyl, (8) 6-methyl-2-pyridyl, (9) 5-trifluoromethyl-2-pyridyl, ( 10) 4-trifluoromethyl-2-pyridyl, (11) 4-trifluoromethyl-2-pyrimidyl and (12) 6-trifluoromethyl-4-pyrimidyl and pharmaceuticals Acceptable salts thereof. 제1항에 있어서, The method of claim 1, (1) N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(4-클로로페닐옥시)-2-메틸프로판아미드;(1) N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (4-chlorophenyloxy) -2-methylpropanamide; (2) N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(2-피리딜옥시)-2-메틸프로판아미드;(2) N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (2-pyridyloxy) -2-methylpropanamide; (3) N-[3-(4-클로로페닐)-1-메틸-2-(3-피리딜)프로필]-2-(4-클로로페닐옥시)-2-메틸프로판아미드;(3) N- [3- (4-chlorophenyl) -1-methyl-2- (3-pyridyl) propyl] -2- (4-chlorophenyloxy) -2-methylpropanamide; (4) N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(3,5-디플루오로페닐옥시)-2-메틸프로판아미드;(4) N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (3,5-difluorophenyloxy) -2-methylpropanamide; (5) N-[3-(4-클로로페닐)-2-페닐-1-메틸프로필]-2-(3,5-디클로로페닐옥시)-2-메틸프로판아미드;(5) N- [3- (4-chlorophenyl) -2-phenyl-1-methylpropyl] -2- (3,5-dichlorophenyloxy) -2-methylpropanamide; (6) N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(3-클로로페닐옥시)-2-메틸프로판아미드;(6) N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (3-chlorophenyloxy) -2-methylpropanamide; (7) N-[3-(4-클로로페닐)-2-(3,5-디플루오로페닐)-1-메틸프로필]-2-(2-피리딜옥시)-2-메틸프로판아미드;(7) N- [3- (4-chlorophenyl) -2- (3,5-difluorophenyl) -1-methylpropyl] -2- (2-pyridyloxy) -2-methylpropanamide; (8) N-[3-(4-클로로페닐)-1-메틸-2-페닐-프로필]-2-(5-클로로-2-피리딜옥시)-2-메틸프로판아미드;(8) N- [3- (4-chlorophenyl) -1-methyl-2-phenyl-propyl] -2- (5-chloro-2-pyridyloxy) -2-methylpropanamide; (9) N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(6-메틸-피리딜옥시)-2-메틸프로판아미드;(9) N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (6-methyl-pyridyloxy) -2-methylpropanamide; (10) N-[3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(페닐옥시)-2-메틸프로판아미드;(10) N- [3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (phenyloxy) -2-methylpropanamide; (11) N-[(3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(5-트리플루오로메틸피리딜옥시)-2-메틸프로판아미드;(11) N-[(3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (5-trifluoromethylpyridyloxy) -2-methylpropanamide; (12) N-[3-(4-클로로페닐)-2-(3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(12) N- [3- (4-chlorophenyl) -2- (3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methyl Propanamide; (13) N-[3-(4-클로로페닐)-2-(3-시아노페닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(13) N- [3- (4-chlorophenyl) -2- (3-cyanophenyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2- Methylpropanamide; (14) N-[3-(4-클로로페닐)-2-(5-클로로-3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드; (14) N- [3- (4-chlorophenyl) -2- (5-chloro-3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide; (15) N-[3-(4-클로로페닐)-2-(5-메틸-3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(15) N- [3- (4-chlorophenyl) -2- (5-methyl-3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide; (16) N-[3-(4-클로로페닐)-2-(5-시아노-3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(16) N- [3- (4-chlorophenyl) -2- (5-cyano-3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy ) -2-methylpropanamide; (17) N-[3-(4-클로로페닐)-2-(3-메틸페닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(17) N- [3- (4-chlorophenyl) -2- (3-methylphenyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropane amides; (18) N-[3-(4-클로로페닐)-2-페닐-1-메틸프로필]-2-(4-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(18) N- [3- (4-chlorophenyl) -2-phenyl-1-methylpropyl] -2- (4-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide; (19) N-[3-(4-클로로페닐)-2-페닐-1-메틸프로필]-2-(4-트리플루오로메틸-2-피리미딜옥시)-2-메틸프로판아미드;(19) N- [3- (4-chlorophenyl) -2-phenyl-1-methylpropyl] -2- (4-trifluoromethyl-2-pyrimidyloxy) -2-methylpropanamide; (20) N-[3-(4-클로로페닐)-1-메틸-2-(티오펜-3-일)프로필]-2-(5-클로로-2-피리딜옥시)-2-메틸프로판아미드;(20) N- [3- (4-chlorophenyl) -1-methyl-2- (thiophen-3-yl) propyl] -2- (5-chloro-2-pyridyloxy) -2-methylpropane amides; (21) N-[3-(5-클로로-2-피리딜)-2-페닐-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(21) N- [3- (5-chloro-2-pyridyl) -2-phenyl-1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropane amides; (22) N-[3-(4-메틸-페닐)-1-메틸-2-페닐프로필]-2-(4-트리플루오로메틸-페닐옥시)-2-메틸프로판아미드;(22) N- [3- (4-methyl-phenyl) -1-methyl-2-phenylpropyl] -2- (4-trifluoromethyl-phenyloxy) -2-methylpropanamide; (23) N-[3-(4-플루오로-페닐)-2-(3-시아노-페닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(23) N- [3- (4-fluoro-phenyl) -2- (3-cyano-phenyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide; (24) N-[3-(4-클로로페닐)-2-(1-인돌릴)-1-메틸)프로필]-2-(5-트리플루오로메틸-2-옥시피리딘-2-일)-2-메틸프로판아미드;(24) N- [3- (4-chlorophenyl) -2- (1-indolyl) -1-methyl) propyl] -2- (5-trifluoromethyl-2-oxypyridin-2-yl) -2-methylpropanamide; (25) N-[3-(4-클로로페닐)-2-(7-아자인돌-N-일)-1-메틸)프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(25) N- [3- (4-chlorophenyl) -2- (7-azaindol-N-yl) -1-methyl) propyl] -2- (5-trifluoromethyl-2-pyridyloxy ) -2-methylpropanamide; (26) N-[3-(4-클로로-페닐)-2-(1-인돌리닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(26) N- [3- (4-chloro-phenyl) -2- (1-indolinyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2- Methylpropanamide; (27) N-[3-(4-클로로-페닐)-2-(N-메틸-아닐리노)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(27) N- [3- (4-chloro-phenyl) -2- (N-methyl-anilino) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy)- 2-methylpropanamide; (28) N-[3-(4-메톡시-페닐)-2-(3-시아노-페닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(28) N- [3- (4-methoxy-phenyl) -2- (3-cyano-phenyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide; (29) N-[3-(4-클로로페닐)-2-(3-시아노페닐)-1-메틸프로필]-2-(6-트리플루오로메틸-4-피리미딜옥시)-2-메틸프로판아미드;(29) N- [3- (4-chlorophenyl) -2- (3-cyanophenyl) -1-methylpropyl] -2- (6-trifluoromethyl-4-pyrimidyloxy) -2- Methylpropanamide; (30) N-[2-(3-시아노페닐)-1,4-디메틸펜틸]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(30) N- [2- (3-cyanophenyl) -1,4-dimethylpentyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide; (31) N-[3-(4-클로로페닐)-2-(1-옥시도-5-시아노-3-피리딜]-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(31) N- [3- (4-chlorophenyl) -2- (1-oxido-5-cyano-3-pyridyl] -1-methylpropyl] -2- (5-trifluoromethyl- 2-pyridyloxy) -2-methylpropanamide; (32) N-[2-(3-시아노페닐)-3-사이클로부틸-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(32) N- [2- (3-cyanophenyl) -3-cyclobutyl-1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide; (33) N-[2-(3-시아노페닐)-1-메틸-헵틸]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(33) N- [2- (3-cyanophenyl) -1-methyl-heptyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide; (34) N-[2-(3-시아노페닐)-3-사이클로펜틸-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드 및(34) N- [2- (3-cyanophenyl) -3-cyclopentyl-1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide and (35) N-[2-(3-시아노페닐)-3-사이클로헥실-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드로부터 선택되는 화합물 및 약제학적으로 허용되는 이의 염. (35) from N- [2- (3-cyanophenyl) -3-cyclohexyl-1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide Selected compounds and pharmaceutically acceptable salts thereof. 제9항에 있어서, Rd가 5-트리플루오로메틸-2-피리딜인 화합물 및 약제학적으로 허용되는 이의 염.The compound and pharmaceutically acceptable salt thereof according to claim 9, wherein R d is 5-trifluoromethyl-2-pyridyl. 제11항에 있어서, The method of claim 11, (1) N-[(3-(4-클로로페닐)-1-메틸-2-페닐프로필]-2-(5-트리플루오로메틸피리딜옥시)-2-메틸프로판아미드;(1) N-[(3- (4-chlorophenyl) -1-methyl-2-phenylpropyl] -2- (5-trifluoromethylpyridyloxy) -2-methylpropanamide; (2) N-[3-(4-클로로페닐)-2-(3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(2) N- [3- (4-chlorophenyl) -2- (3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methyl Propanamide; (3) N-[3-(4-클로로페닐)-2-(3-시아노페닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(3) N- [3- (4-chlorophenyl) -2- (3-cyanophenyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2- Methylpropanamide; (4) N-[3-(4-클로로페닐)-2-(5-클로로-3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(4) N- [3- (4-chlorophenyl) -2- (5-chloro-3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide; (5) N-[3-(4-클로로페닐)-2-(5-메틸-3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(5) N- [3- (4-chlorophenyl) -2- (5-methyl-3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide; (6) N-[3-(4-클로로페닐)-2-(5-시아노-3-피리딜)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(6) N- [3- (4-chlorophenyl) -2- (5-cyano-3-pyridyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy ) -2-methylpropanamide; (7) N-[3-(4-클로로페닐)-2-(3-메틸페닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(7) N- [3- (4-chlorophenyl) -2- (3-methylphenyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropane amides; (8) N-[3-(5-클로로-2-피리딜)-2-페닐-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(8) N- [3- (5-chloro-2-pyridyl) -2-phenyl-1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropane amides; (9) N-[3-(4-플루오로-페닐)-2-(3-시아노-페닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(9) N- [3- (4-fluoro-phenyl) -2- (3-cyano-phenyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide; (10) N-[3-(4-클로로페닐)-2-(1-인돌릴)-1-메틸)프로필]-2-(5-트리플루오로메틸-2-옥시피리딘-2-일)-2-메틸프로판아미드;(10) N- [3- (4-chlorophenyl) -2- (1-indolyl) -1-methyl) propyl] -2- (5-trifluoromethyl-2-oxypyridin-2-yl) -2-methylpropanamide; (11) N-[3-(4-클로로페닐)-2-(7-아자인돌-N-일)-1-메틸)프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(11) N- [3- (4-chlorophenyl) -2- (7-azaindol-N-yl) -1-methyl) propyl] -2- (5-trifluoromethyl-2-pyridyloxy ) -2-methylpropanamide; (12) N-[3-(4-클로로-페닐)-2-(1-인돌리닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(12) N- [3- (4-chloro-phenyl) -2- (1-indolinyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2- Methylpropanamide; (13) N-[3-(4-클로로-페닐)-2-(N-메틸-아닐리노)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(13) N- [3- (4-chloro-phenyl) -2- (N-methyl-anilino) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy)- 2-methylpropanamide; (14) N-[3-(4-메톡시-페닐)-2-(3-시아노-페닐)-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(14) N- [3- (4-methoxy-phenyl) -2- (3-cyano-phenyl) -1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide; (15) N-[2-(3-시아노페닐)-1,4-디메틸펜틸]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(15) N- [2- (3-cyanophenyl) -1,4-dimethylpentyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide; (16) N-[3-(4-클로로페닐)-2-(1-옥시도-5-시아노-3-피리딜]-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(16) N- [3- (4-chlorophenyl) -2- (1-oxido-5-cyano-3-pyridyl] -1-methylpropyl] -2- (5-trifluoromethyl- 2-pyridyloxy) -2-methylpropanamide; (17) N-[2-(3-시아노페닐)-3-사이클로부틸-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(17) N- [2- (3-cyanophenyl) -3-cyclobutyl-1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide; (18) N-[2-(3-시아노페닐)-1-메틸-헵틸]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드;(18) N- [2- (3-cyanophenyl) -1-methyl-heptyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide; (19) N-[2-(3-시아노페닐)-3-사이클로펜틸-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드 및(19) N- [2- (3-cyanophenyl) -3-cyclopentyl-1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide and (20) N-[2-(3-시아노페닐)-3-사이클로헥실-1-메틸프로필]-2-(5-트리플루오로메틸-2-피리딜옥시)-2-메틸프로판아미드로부터 선택되는 화합물 및 약제학적으로 허용되는 이의 염. (20) from N- [2- (3-cyanophenyl) -3-cyclohexyl-1-methylpropyl] -2- (5-trifluoromethyl-2-pyridyloxy) -2-methylpropanamide Selected compounds and pharmaceutically acceptable salts thereof. 제1항에 따른 화합물과 약제학적으로 허용되는 담체를 포함하는 조성물.A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. 카나비노이드-1 수용체에 의해 매개되는 질병의 치료가 필요한 사람 환자에 있어 카나비노이드-1 수용체에 의해 매개되는 질병의 치료에 유용한 의약을 제조하기 위한 제1항에 따른 화합물의 용도.Use of a compound according to claim 1 for the manufacture of a medicament useful for the treatment of diseases mediated by cannabinoid-1 receptors in human patients in need of the treatment of diseases mediated by cannabinoid-1 receptors. 제14항에 있어서, 카나비노이드-1 수용체에 의해 매개되는 질병이 과도한 음식 섭취와 관련된 식이 장애인 용도.The use of claim 14, wherein the disease mediated by the cannabinoid-1 receptor is associated with excessive food intake. 제15항에 있어서, 과도한 음식 섭취와 관련된 식이 장애가 비만인 용도.Use according to claim 15, wherein the eating disorder associated with excessive food intake is obese. 비만의 위험에 처한 사람에 있어 비만 예방용 의약을 제조하기 위한 제1항에 따른 화합물의 용도.Use of a compound according to claim 1 for the manufacture of a medicament for preventing obesity in a person at risk of obesity.
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