KR20120011357A - Substituted pyridinone derivatives and methods for manufacturing the same - Google Patents

Substituted pyridinone derivatives and methods for manufacturing the same Download PDF

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KR20120011357A
KR20120011357A KR1020100071674A KR20100071674A KR20120011357A KR 20120011357 A KR20120011357 A KR 20120011357A KR 1020100071674 A KR1020100071674 A KR 1020100071674A KR 20100071674 A KR20100071674 A KR 20100071674A KR 20120011357 A KR20120011357 A KR 20120011357A
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cycloalkyl
aryl
alkyl
heterocyclyl
pyridin
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KR1020100071674A
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Korean (ko)
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박용규
방성훈
김진웅
이한규
김재현
손창모
이준희
신창용
이종찬
이재걸
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현대약품 주식회사
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Priority to KR1020100071674A priority Critical patent/KR20120011357A/en
Priority to PCT/KR2011/005268 priority patent/WO2012011707A2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

PURPOSE: A pharmaceutical composition containing a novel compound or pharmaceutically acceptable salt thereof for treaitng metabolism-associated disorders is provided. CONSTITUTION: A substituted pyridinone derivative is denoted by chemical formula 1. A pharmaceutical composition for treating metabolism-associated disorders contains the compound of chemical formula 1 or pharmaceutically acceptable salt thereof as an active ingredient. The metabolism-associated disorder is obesity type I, diabetes type II or I, insulin resistance, hyperglycemia, or hyperlipidemia. The compound of chemical formula 1 is prepared by reacting compounds of chemical formulas 4 and 5.

Description

치환된 피리디논 유도체 및 이의 제조방법{Substituted pyridinone derivatives and methods for manufacturing the same}Substituted pyridinone derivatives and methods for manufacturing the same

본 발명은 신규 화합물 또는 이의 약제학적으로 허용되는 염, 이의 제조방법 및 이를 포함하는 대사 관련 장애 치료용 약학 조성물에 관한 것이다.
The present invention relates to a novel compound or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for treating metabolic related disorders including the same.

당뇨병은 전세계적으로 1억 명이 넘는 사람들이 앓고 있는 심각한 질환으로, 사람의 건강을 계속적으로 위협하고 있다. 당뇨병은 2개의 임상 증후군, I형 및 II형 당뇨병으로 분류할 수 있다. 인슐린 의존성 당뇨병 (IDDM)으로도 공지된 제 I형 당뇨병은 인슐린을 생산하는 췌장 베타세포의 자가면역적인 파괴에 의해 비롯되며 외인성 인슐린의 정기적 투여를 필요로 한다. 비인슐린 의존성 당뇨병(NIDDM)으로도 공지된 제 II형 당뇨병은 혈당 수치를 적절하게 조절되는 능력이 상실됨으로 나타난다. 제 II형 당뇨병은 인슐린 분비에서의 결함 또는 인슐린 저항 (insulin resistance), 즉 인슐린이 거의 없거나 인슐린을 효과적으로 사용할 수 없는 제 II형 당뇨병을 앓는 사람들에 의해 특징될 수 있다.
Diabetes is a serious disease that affects more than 100 million people worldwide and continues to threaten human health. Diabetes can be classified into two clinical syndromes, type I and type II diabetes. Type I diabetes, also known as insulin dependent diabetes (IDDM), is caused by the autoimmune destruction of insulin producing pancreatic beta cells and requires regular administration of exogenous insulin. Type II diabetes, also known as non-insulin dependent diabetes mellitus (NIDDM), appears to lack the ability to properly regulate blood glucose levels. Type II diabetes can be characterized by a deficiency in insulin secretion or by insulin resistance, ie, people with type II diabetes who have little insulin or are unable to use insulin effectively.

당뇨병 환자에서, 글루코스 수치 (glucose level)가 혈액 및 소변 내에 축적되고, 이는 과도한 배뇨, 갈증, 배고픔, 지방 및 단백질 대사와 관련한 문제를 일으킨다. 이러한 당뇨병은 삶을 위협하는 합병증, 예컨대 시력상실, 신장 부전 및 심장 질환을 일으킬 수 있으며, 안구 후면의 망막에 손상을 유발하는 원인이며, 백내장 및 녹내장의 위험성을 증가시킨다. 당뇨병은 또한 다리 및 발의 신경 손상과 관련되며, 이는 통증을 느끼는 능력을 방해하고, 심각한 감염의 원인이 된다.
In diabetics, glucose levels accumulate in the blood and urine, which causes problems with excessive urination, thirst, hunger, fat and protein metabolism. Such diabetes can lead to life-threatening complications such as blindness, kidney failure and heart disease, cause damage to the retina of the back of the eye, and increase the risk of cataracts and glaucoma. Diabetes is also associated with nerve damage to the legs and feet, which interferes with the ability to feel pain and causes serious infections.

당뇨병에 대한 현재의 치료에는 인슐린, 인슐린 분비촉진제, 글루코스 저하 이펙터(effector), 퍼옥시좀 증식자-활성화된 수용체 (PPAR)의 활성화제 등이 있다. 그러나, 저혈당, 체중 증가, 시간 경과에 따른 치료에 대한 반응성 감소, 위장관 문제 및 부종을 포함하여, 현재 이용 가능한 치료법과 관련된 문제들이 있다.
Current treatments for diabetes include insulin, insulin secretagogues, glucose lowering effectors, activators of peroxysome proliferator-activated receptors (PPARs), and the like. However, there are problems associated with currently available therapies, including hypoglycemia, weight gain, decreased responsiveness to treatment over time, gastrointestinal problems and edema.

새로운 더욱 효과적인 치료법을 시장에 도입하기 위해 여러 영역을 목표로 연구가 이루어 지고 있으며, 하나의 구체적인 표적이 GPR119이다. GPR119는 췌장, 소장, 결장 및 지방 조직에서 주로 발현되는 G-단백질 커플링된 수용체 (GPCR)이다. GPR119 발현 프로파일은 비만 및 당뇨병의 치료를 위한 목표로서 이의 잠재적 유용성을 나타낸다. GPR119 활성화는 cAMP를 자극하여 글루코스 의존적인 GLP-1 및 인슐린 분비를 유도하는 것으로 입증되었다 (T. Soga et al., Biochemical 및 Biophysical Research Communication 326 (2005) 744-751). 혈장 글루코스 수준에 대한 효과 이외에도, GPR119 활성화제는 또한 만성 투여 이후에 래트에서의 급성 음식 섭취의 감소를 일으키고, 체중을 감소시키는 것으로 입증되었다 (문헌 [Overton, H.A. et al., "Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agent" Cell metabolism,3:167-175 (2006)], 및 특허 출원 WO 05/007647 및 WO 05/007658).
In order to introduce new more effective therapies to the market, research is being conducted in various areas, and one specific target is GPR119. GPR119 is a G-protein coupled receptor (GPCR) expressed primarily in the pancreas, small intestine, colon and adipose tissue. The GPR119 expression profile shows its potential utility as a target for the treatment of obesity and diabetes. GPR119 activation has been demonstrated to stimulate cAMP to induce glucose dependent GLP-1 and insulin secretion (T. Soga et al., Biochemical and Biophysical Research Communication 326 (2005) 744-751). In addition to effects on plasma glucose levels, GPR119 activators have also been demonstrated to cause acute food intake reduction and weight loss in rats after chronic administration (Overton, HA et al., "Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agent "Cell metabolism, 3: 167-175 (2006), and patent applications WO 05/007647 and WO 05/007658).

GPR119에 대한 활성화제는 당뇨병 및 관련 질병, 당뇨병과 관련된 미세혈관 합병증, 당뇨병과 관련된 거대혈관 합병증, 심혈관 이상, 대사성 증후군 및 그의 구성 질병, 비만 및 다른 병의 치료에 사용될 수 있다.
Activators for GPR119 can be used for the treatment of diabetes and related diseases, microvascular complications associated with diabetes, macrovascular complications associated with diabetes, cardiovascular abnormalities, metabolic syndrome and its component diseases, obesity and other diseases.

본 발명은 신규 화합물 또는 이의 약제학적으로 허용되는 염, 이의 제조방법 및 이를 포함하는 대사 관련 장애 치료용 약학 조성물을 제공한다.
The present invention provides a novel compound or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for treating metabolic related disorders including the same.

본 발명은 하기 화학식 1의 화합물 또는 이의 약제학적으로 허용되는 염을 제공한다.The present invention provides a compound of formula 1 or a pharmaceutically acceptable salt thereof.

[화학식 1][Formula 1]

Figure pat00001
Figure pat00001

상기 화학식 1에서,In Chemical Formula 1,

X는

Figure pat00002
, 아릴 또는 헤테로아릴이고, 여기서 상기 아릴 또는 헤테로아릴은 R1a, R1b, R1c, R1d 및 R1e로부터 선택된 하나 이상의 구성원으로 치환되거나 비치환될 수 있고;X is
Figure pat00002
, Aryl or heteroaryl, wherein the aryl or heteroaryl can be unsubstituted or substituted with one or more members selected from R 1a , R 1b , R 1c , R 1d and R 1e ;

R1a, R1b, R1c, R1d 및 R1e는 각각 수소, 알킬, 알케닐, 알키닐, 시클로알킬, 아릴, 헤테로시클릴, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)OR10, -OCF3, -OR11, -OH, -SH, -SR11, -S(O)3H, -P(O)3H2, -C(=O)NR9R9, -NR12R12, -S(O)2NR9R9, -NR9S(O)2CF3, -C(=O)NR9S(O)2R9, -S(O)2NR9C(=O)OR9, -S(O)2NR9C(=O)NR9R9, -C(=O)NR9S(O)2CF3, -C(=O)R11, -NR9C(=O)H, -NR9C(=O)R10, -OC(=O)R10, -OC(=O)NR9R9, -C(=NR14)NR9R9, -NHC(=NR14)NR14R14, -S(=O)R11, -S(O)2R11, -NR9C(=O)OR8 및 -NR9S(O2)R8로 이루어진 군으로부터 독립적으로 선택되고, 여기서: (a) 알케닐, 알키닐, 시클로알킬, 아릴 및 헤테로시클릴은 각각 하나 이상의 R6으로 치환되거나 비치환될 수 있고; (b) 알킬은 하나 이상의 R7로 치환되거나 비치환될 수 있고;
R 1a , R 1b , R 1c , R 1d and R 1e are each hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, halo, -NH 2 , -CN, -NO 2 , -C (= O) OH, -C (= O) OR 10 , -OCF 3 , -OR 11 , -OH, -SH, -SR 11 , -S (O) 3 H, -P (O) 3 H 2 , -C (= 0) NR 9 R 9 , -NR 12 R 12 , -S (O) 2 NR 9 R 9 , -NR 9 S (O) 2 CF 3 , -C (= O) NR 9 S (O ) 2 R 9 , -S (O) 2 NR 9 C (= O) OR 9 , -S (O) 2 NR 9 C (= O) NR 9 R 9 , -C (= O) NR 9 S (O ) 2 CF 3 , -C (= O) R 11 , -NR 9 C (= O) H, -NR 9 C (= O) R 10 , -OC (= O) R 10 , -OC (= O) NR 9 R 9 , -C (= NR 14 ) NR 9 R 9 , -NHC (= NR 14 ) NR 14 R 14 , -S (= O) R 11 , -S (O) 2 R 11 , -NR 9 C (= 0) OR 8 and -NR 9 S (O 2 ) R 8 are independently selected from the group consisting of: (a) alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl, each May be substituted or unsubstituted with R 6 ; (b) alkyl may be unsubstituted or substituted with one or more R 7 ;

Y는 S 또는 O이고;Y is S or O;

K는 CH 또는 N이고;K is CH or N;

Z1은 C 또는 N이고;Z 1 is C or N;

Z2는 C 또는 N이며, 단 Z1 및 Z2가 모두 N은 아니고;Z 2 is C or N, provided that both Z 1 and Z 2 are not N;

L1은 CH2, N(R3), C(=O), O, OCR9R9, S, S(=O) 또는 S(O)2이고;L 1 is CH 2 , N (R 3 ), C (═O), O, OCR 9 R 9 , S, S (═O) or S (O) 2 ;

n1은 0 내지 2이고;n 1 is 0 to 2;

n2는 0 내지 2이고;n 2 is 0 to 2;

n3은 0 내지 2이고;n 3 is 0 to 2;

P1은 아릴, 헤테로아릴, 시클로알킬 또는 헤테로시클로알킬이고, 이들 각각은 R1a, R1b, R1c, R1d 및 R1e로부터 선택된 하나 이상의 구성원으로 치환되거나 비치환될 수 있고;P 1 is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of which may be unsubstituted or substituted with one or more members selected from R 1a , R 1b , R 1c , R 1d and R 1e ;

R1a, R1b, R1c, R1d 및 R1e는 각각 수소, 알킬, 알케닐, 알키닐, 시클로알킬, 아릴, 헤테로시클릴, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)OR10, -OCF3, -OR11, -OH, -SH, -SR11, -S(O)3H, -P(O)3H2, -C(=O)NR9R9, -NR12R12, -S(O)2NR9R9, -NR9S(O)2CF3, -C(=O)NR9S(O)2R9, -S(O)2NR9C(=O)OR9, -S(O)2NR9C(=O)NR9R9, -C(=O)NR9S(O)2CF3, -C(=O)R11, -NR9C(=O)H, -NR9C(=O)R10, -OC(=O)R10, -OC(=O)NR9R9, -C(=NR14)NR9R9, -NHC(=NR14)NR14R14, -S(=O)R11, -S(O)2R11, -NR9C(=O)OR8 및 -NR9S(O2)R8로 이루어진 군으로부터 독립적으로 선택되고, 여기서: (a) 알케닐, 알키닐, 시클로알킬, 아릴 및 헤테로시클릴은 각각 하나 이상의 R6으로 치환되거나 비치환될 수 있고; (b) 알킬은 하나 이상의 R7로 치환되거나 비치환될 수 있고;R 1a , R 1b , R 1c , R 1d and R 1e are each hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, halo, -NH 2 , -CN, -NO 2 , -C (= O) OH, -C (= O) OR 10 , -OCF 3 , -OR 11 , -OH, -SH, -SR 11 , -S (O) 3 H, -P (O) 3 H 2 , -C (= 0) NR 9 R 9 , -NR 12 R 12 , -S (O) 2 NR 9 R 9 , -NR 9 S (O) 2 CF 3 , -C (= O) NR 9 S (O ) 2 R 9 , -S (O) 2 NR 9 C (= O) OR 9 , -S (O) 2 NR 9 C (= O) NR 9 R 9 , -C (= O) NR 9 S (O ) 2 CF 3 , -C (= O) R 11 , -NR 9 C (= O) H, -NR 9 C (= O) R 10 , -OC (= O) R 10 , -OC (= O) NR 9 R 9 , -C (= NR 14 ) NR 9 R 9 , -NHC (= NR 14 ) NR 14 R 14 , -S (= O) R 11 , -S (O) 2 R 11 , -NR 9 C (= 0) OR 8 and -NR 9 S (O 2 ) R 8 are independently selected from the group consisting of: (a) alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl, each May be substituted or unsubstituted with R 6 ; (b) alkyl may be unsubstituted or substituted with one or more R 7 ;

R2는 알킬, 시클로알킬, 아릴, 헤테로아릴, 헤테로시클릴, -S(O)2R5, -C(=O)NR3R5, -C(=O)R5 또는 -C(=O)OR5이고, 여기서 알킬, 시클로알킬, 아릴, 헤테로아릴 및 헤테로시클릴은 각각 하나 이상의 R6으로 치환되거나 비치환될 수 있고;R 2 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -S (O) 2 R 5 , -C (= 0) NR 3 R 5 , -C (= 0) R 5 or -C (= O) OR 5 , wherein alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may each be substituted or unsubstituted with one or more R 6 ;

R3는 수소, 알킬, 알콕시, 시클로알킬, 아릴, 아릴알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴 또는 헤테로시클릴알킬이고;R 3 is hydrogen, alkyl, alkoxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl;

R4는 치환되거나 비치환된 C1 -3 알킬렌이고, n4는 0 내지 2의 정수이고, 여기서 치환된 C1 -3 알킬렌은 C1 -6 알킬 또는 할로겐으로 치환될 수 있고, 단, Y가 O이고 n4가 0인 경우, P1은 시클로알킬 또는 헤테로시클로알킬이고;R 4 is a substituted or unsubstituted C 1 -3 alkylene, n 4 is an integer from 0 to 2, wherein the substituted C 1 -3 alkylene can be optionally substituted with C 1 -6 alkyl or halogen, with the proviso that When Y is O and n 4 is 0, P 1 is cycloalkyl or heterocycloalkyl;

R5는 알킬, 알케닐, 아릴, 시클로알킬, 헤테로아릴 또는 헤테로시클릴이고, 이들 각각은 하나 이상의 R6으로 치환되거나 비치환될 수 있고;R 5 is alkyl, alkenyl, aryl, cycloalkyl, heteroaryl or heterocyclyl, each of which may be unsubstituted or substituted with one or more R 6 ;

R6은, 각각의 경우에 알킬, 할로알킬, 아릴, 알케닐, 알키닐, 시클로알킬, 시클로알킬알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴, 헤테로시클릴알킬, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)OR10, -OCF3, -OR10, -OH, -SH, -SR10, -S(O)3H, -P(O)3H2, -C(=O)NR9R9, -NR9R9, -S(O)2NR9R9, -NR9S(O)2CF3, -C(=O)NR9S(O)2R9, -S(O)2NR9C(=O)OR9, -S(O)2NR9C(=O)NR9R9, -C(=O)NR9S(O)2CF3, -C(=O)R10, -NR9C(=O)H, -NR9C(=O)R10, -OC(=O)R10, -C(=NR14)NR9R9, -NHC(=NR14)NR14R14, -S(=O)R10, -S(O)2R10, =O, -NR9C(=O)OR8 및 -NR9S(O2)R8로부터 독립적으로 선택되고, 여기서 알킬, 알케닐, 알키닐, 아릴, 시클로알킬, 시클로알킬알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴 및 헤테로시클릴알킬은 각각 0 내지 5개의 R9a로 치환되거나 비치환될 수 있고;R 6 in each occurrence is alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , -CN, -NO 2 , -C (= O) OH, -C (= O) OR 10 , -OCF 3 , -OR 10 , -OH, -SH, -SR 10 , -S (O) 3 H, -P (O) 3 H 2 , -C (= 0) NR 9 R 9 , -NR 9 R 9 , -S (O) 2 NR 9 R 9 , -NR 9 S (O) 2 CF 3 , -C (= O) NR 9 S (O) 2 R 9 , -S (O) 2 NR 9 C (= O) OR 9 , -S (O) 2 NR 9 C (= O) NR 9 R 9 , -C (= O) NR 9 S (O) 2 CF 3 , -C (= O) R 10 , -NR 9 C (= O) H, -NR 9 C (= O) R 10 , -OC (= O) R 10 , -C (= NR 14 ) NR 9 R 9 , -NHC (= NR 14 ) NR 14 R 14 , -S (= O) R 10 , -S (O) 2 R 10 , = O, -NR Independently selected from 9 C (= 0) OR 8 and -NR 9 S (O 2 ) R 8 wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclyl and heterocyclylalkyl may each be unsubstituted or substituted with 0 to 5 R 9a ;

R7은, 각각의 경우에 알킬, 할로알킬, 아릴, 알케닐, 알키닐, 시클로알킬, 시클로알킬알킬, 헤테로시클릴, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)OR10, -OCF3, -OR10, -OH, -SH, -SR10, -S(O)3H, -P(O)3H2, -C(=O)NR9R9, -NR9R9, -S(O)2NR9R9, -NR9S(O)2CF3, -C(=O)NR9S(O)2R9, -S(O)2NR9C(=O)OR9, -S(O)2NR9C(=O)NR9R9, -C(=O)NR9S(O)2CF3, -C(=O)R10, -NR9C(=O)H, -NR9C(=O)R10, -OC(=O)R10, -C(=NR14)NR9R9, -NHC(=NR14)NR14R14, -S(=O)R10, -S(O)2R10, =O, -NR9C(=O)OR8 및 -NR9S(O2)R8로 이루어진 군으로부터 독립적으로 선택되고, 여기서 알킬, 알케닐, 알키닐, 아릴, 시클로알킬, 시클로알킬알킬 및 헤테로시클릴은 각각 0 내지 5개의 R9a로 치환되거나 비치환될 수 있고;R 7 is in each case alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, halo, -NH 2 , -CN, -NO 2 , -C (= 0 ) OH, -C (= O) OR 10 , -OCF 3 , -OR 10 , -OH, -SH, -SR 10 , -S (O) 3 H, -P (O) 3 H 2 , -C ( = O) NR 9 R 9 , -NR 9 R 9 , -S (O) 2 NR 9 R 9 , -NR 9 S (O) 2 CF 3 , -C (= O) NR 9 S (O) 2 R 9 , -S (O) 2 NR 9 C (= O) OR 9 , -S (O) 2 NR 9 C (= O) NR 9 R 9 , -C (= O) NR 9 S (O) 2 CF 3 , -C (= O) R 10 , -NR 9 C (= O) H, -NR 9 C (= O) R 10 , -OC (= O) R 10 , -C (= NR 14 ) NR 9 R 9 , -NHC (= NR 14 ) NR 14 R 14 , -S (= O) R 10 , -S (O) 2 R 10 , = O, -NR 9 C (= O) OR 8 and -NR 9 Independently selected from the group consisting of S (O 2 ) R 8 , wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl and heterocyclyl are each substituted or unsubstituted with from 0 to 5 R 9 a May be ringed;

R8은, 각각의 경우에 알킬, 아릴, 시클로알킬, 헤테로아릴 및 헤테로시클릴로 이루어진 군으로부터 독립적으로 선택되고, 이들 각각은 하나 이상의 R8a로 치환되거나 비치환될 수 있고;R 8 in each occurrence is independently selected from the group consisting of alkyl, aryl, cycloalkyl, heteroaryl and heterocyclyl, each of which may be substituted or unsubstituted with one or more R 8 a;

R8a는, 각각의 경우에 알킬, 할로알킬, 아릴, 알케닐, 알키닐, 시클로알킬, 시클로알킬알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴, 헤테로시클릴알킬, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)OR14, -OCF3, -OR14, -OH, -SH, -SR14, -S(O)3H, -P(O)3H2, -C(=O)NR14R14, -NR14R14, -S(O)2NR14R14, -NR14S(O)2CF3, -C(=O)NR14S(O)2R14, -S(O)2NR14C(=O)OR14, -S(O)2NR14C(=O)NR14R14, -C(=O)NR14S(O)2CF3, -C(=O)R14, -NR14C(=O)H, -NR14C(=O)R14, -OC(=O)R14, -C(=NR14)NR14R14, -NHC(=NR14)NR14R14, -S(=O)R14, -S(O)2R14, =O, -NR14C(=O)OR14 및 -NR14S(O2)R14로부터 독립적으로 선택되고;R 8a in each occurrence is alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , -CN, -NO 2 , -C (= O) OH, -C (= O) OR 14 , -OCF 3 , -OR 14 , -OH, -SH, -SR 14 , -S (O) 3 H, -P (O) 3 H 2 , -C (= 0) NR 14 R 14 , -NR 14 R 14 , -S (O) 2 NR 14 R 14 , -NR 14 S (O) 2 CF 3 , -C (= O) NR 14 S (O) 2 R 14 , -S (O) 2 NR 14 C (= O) OR 14 , -S (O) 2 NR 14 C (= O) NR 14 R 14 , -C (= O) NR 14 S (O) 2 CF 3 , -C (= 0) R 14 , -NR 14 C (= 0) H, -NR 14 C (= 0) R 14 , -OC (= 0) R 14 , -C (= NR 14 ) NR 14 R 14 , -NHC (= NR 14 ) NR 14 R 14 , -S (= O) R 14 , -S (O) 2 R 14 , = O, -NR Independently from 14 C (= 0) OR 14 and -NR 14 S (O 2 ) R 14 ;

R9는, 각각의 경우에 수소, 알킬, 알콕시, 시클로알킬, 아릴, 아릴알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴 및 헤테로시클릴알킬로부터 독립적으로 선택되고, 여기서 알킬, 시클로알킬, 아릴, 아릴알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴 및 헤테로시클릴알킬은 각각 0 내지 5개의 R9a로 치환되거나 비치환될 수 있고;R 9 in each occurrence is independently selected from hydrogen, alkyl, alkoxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein alkyl, cycloalkyl, aryl , Arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may each be unsubstituted or substituted with 0 to 5 R 9 a;

R9a는, 각각의 경우에 알킬, 할로알킬, 아릴, 알케닐, 알키닐, 시클로알킬, 시클로알킬알킬, 헤테로아릴, 헤테로 아릴알킬, 헤테로시클릴, 헤테로시클릴알킬, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)OR14, -OCF3, -OR14, -OH, -SH, -SR14, -S(O)3H, -P(O)3H2, -C(=O)NR14R14, -NR14R14, -S(O)2NR14R14, -NR14S(O)2CF3, -C(=O)NR14S(O)2R10, -S(O)2NR14C(=O)OR10, -S(O)2NR14C(=O)NR14R14, -C(=O)NR14S(O)2CF3, -C(=O)R14, -NR14C(=O)H, -NR14C(=O)R14, -OC(=O)R14, -C(=NR14)NR14R14, -NHC(=NR14)NR14R14, -S(=O)R14, -S(O)2R14, -NR14C(=O)OR8, -NR14S(O2)R8, =O 및 아릴알킬로부터 독립적으로 선택되고;R 9a in each occurrence is alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, hetero arylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , -CN, -NO 2 , -C (= O) OH, -C (= O) OR 14 , -OCF 3 , -OR 14 , -OH, -SH, -SR 14 , -S (O) 3 H, -P (O) 3 H 2 , -C (= 0) NR 14 R 14 , -NR 14 R 14 , -S (O) 2 NR 14 R 14 , -NR 14 S (O) 2 CF 3 , -C (= O) NR 14 S (O) 2 R 10 , -S (O) 2 NR 14 C (= O) OR 10 , -S (O) 2 NR 14 C (= O) NR 14 R 14 , -C (= O) NR 14 S (O) 2 CF 3 , -C (= 0) R 14 , -NR 14 C (= 0) H, -NR 14 C (= 0) R 14 , -OC (= 0) R 14 , -C (= NR 14 ) NR 14 R 14 , -NHC (= NR 14 ) NR 14 R 14 , -S (= O) R 14 , -S (O) 2 R 14 , -NR 14 C ( Independently selected from ═O) OR 8 , —NR 14 S (O 2 ) R 8 , ═O and arylalkyl;

R10은, 각각의 경우에 알킬, 알케닐, 알키닐, 시클로알킬, 아릴, 아릴알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴 및 헤테로시클릴알킬로부터 독립적으로 선택되고, 여기서 시클로알킬, 아릴, 아릴알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴 및 헤테로시클릴알킬은 각각 0 내지 3개의 R10a로 치환되거나 비치환될 수 있고;R 10 in each occurrence is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein cycloalkyl, aryl , Arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may each be substituted or unsubstituted with 0 to 3 R 10 a;

R10a는, 각각의 경우에 알킬, 할로알킬, 아릴, 알케닐, 알키닐, 시클로알킬, 시클로알킬알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴, 헤테로시클릴알킬, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)OR14, -OCF3, -OR14, -OH, -SH, -SR14, -S(O)3H, -P(O)3H2, -C(=O)NR14R14, -NR14R14, -S(O)2NR14R14, -NR14S(O)2CF3, -C(=O)NR14S(O)2R9, -S(O)2NR14C(=O)OR9, -S(O)2NR14C(=O)NR14R14, -C(=O)NR14S(O)2CF3, -C(=O)R14, -NR14C(=O)H, -NR14C(=O)R14, -OC(=O)R14, -C(=NR14)NR14R14, -NHC(=NR14)NR14R14, -S(=O)R14, -S(O)2R14, -NR14C(=O)OR8, -NR14S(O2)R8 및 아릴알킬로부터 독립적으로 선택되고;R 10a in each case is alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , -CN, -NO 2 , -C (= O) OH, -C (= O) OR 14 , -OCF 3 , -OR 14 , -OH, -SH, -SR 14 , -S (O) 3 H, -P (O) 3 H 2 , -C (= 0) NR 14 R 14 , -NR 14 R 14 , -S (O) 2 NR 14 R 14 , -NR 14 S (O) 2 CF 3 , -C (= O) NR 14 S (O) 2 R 9 , -S (O) 2 NR 14 C (= O) OR 9 , -S (O) 2 NR 14 C (= O) NR 14 R 14 , -C (= O) NR 14 S (O) 2 CF 3 , -C (= 0) R 14 , -NR 14 C (= 0) H, -NR 14 C (= 0) R 14 , -OC (= 0) R 14 , -C (= NR 14 ) NR 14 R 14 , -NHC (= NR 14 ) NR 14 R 14 , -S (= O) R 14 , -S (O) 2 R 14 , -NR 14 C ( = O) OR 8 , -NR 14 S (O 2 ) R 8 and arylalkyl;

R11은, 각각의 경우에 알킬, 알케닐, 알키닐, 시클로알킬, 아릴, 아릴알킬, 헤테로시클릴 및 헤테로시클릴알킬로부터 독립적으로 선택되고, 여기서 시클로알킬, 아릴, 아릴알킬, 헤테로시클릴 및 헤테로시클릴알킬은 각각 0 내지 3개의 R11a로 치환되거나 비치환될 수 있고;R 11 in each occurrence is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl and heterocyclylalkyl, wherein cycloalkyl, aryl, arylalkyl, heterocyclyl And heterocyclylalkyl may each be unsubstituted or substituted with 0 to 3 R 11a ;

R11a는, 각각의 경우에 알킬, 할로알킬, 아릴, 알케닐, 알키닐, 시클로알킬, 시클로알킬알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴, 헤테로시클릴알킬, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)OR14, -OCF3, -OR14, -OH, -SH, -SR14, -S(O)3H, -P(O)3H2, -C(=O)NR14R14, -NR14R14, -S(O)2NR14R14, -NR14S(O)2CF3, -C(=O)NR14S(O)2R9, -S(O)2NR14C(=O)OR9, -S(O)2NR14C(=O)NR14R14, -C(=O)NR14S(O)2CF3, -C(=O)R14, -NR14C(=O)H, -NR14C(=O)R14, -OC(=O)R14, -C(=NR14)NR14R14, -NHC(=NR14)NR14R14, -S(=O)R14, -S(O)2R14, -NR14C(=O)OR8, -NR14S(O2)R8 및 아릴알킬로부터 독립적으로 선택되고;R 11a in each occurrence is alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , -CN, -NO 2 , -C (= O) OH, -C (= O) OR 14 , -OCF 3 , -OR 14 , -OH, -SH, -SR 14 , -S (O) 3 H, -P (O) 3 H 2 , -C (= 0) NR 14 R 14 , -NR 14 R 14 , -S (O) 2 NR 14 R 14 , -NR 14 S (O) 2 CF 3 , -C (= O) NR 14 S (O) 2 R 9 , -S (O) 2 NR 14 C (= O) OR 9 , -S (O) 2 NR 14 C (= O) NR 14 R 14 , -C (= O) NR 14 S (O) 2 CF 3 , -C (= 0) R 14 , -NR 14 C (= 0) H, -NR 14 C (= 0) R 14 , -OC (= 0) R 14 , -C (= NR 14 ) NR 14 R 14 , -NHC (= NR 14 ) NR 14 R 14 , -S (= O) R 14 , -S (O) 2 R 14 , -NR 14 C ( = O) OR 8 , -NR 14 S (O 2 ) R 8 and arylalkyl;

R12는, 각각의 경우에 수소, 알킬, 알케닐, 알키닐, 시클로알킬, 아릴, 아릴알킬, 헤테로시클릴 및 헤테로시클릴알킬로부터 독립적으로 선택되고, 여기서 시클로알킬, 아릴, 아릴알킬, 헤테로시클릴 및 헤테로시클릴알킬은 각각 0 내지 3개의 R10a로 치환되거나 비치환될 수 있고;R 12 in each occurrence is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl and heterocyclylalkyl, wherein cycloalkyl, aryl, arylalkyl, hetero Cyclyl and heterocyclylalkyl may each be unsubstituted or substituted with 0 to 3 R 10a ;

R14는, 각각의 경우에 수소, 알킬, 시클로알킬 및 아릴로부터 독립적으로 선택되고;R 14 in each occurrence is independently selected from hydrogen, alkyl, cycloalkyl and aryl;

P2, P3 및 P4는 각각 수소, 알킬, 할로알킬, 시클로알킬, 할로, -CN, -C(=O)OH, -C(=O)OR10, -OCF3, -OR10, -OH, -C(=O)NR9R9, -C(=O)R10 및 -OC(=O)R10으로 이루어진 군으로부터 독립적으로 선택된다.
P 2 , P 3 and P 4 are each hydrogen, alkyl, haloalkyl, cycloalkyl, halo, -CN, -C (= 0) OH, -C (= 0) OR 10 , -OCF 3 , -OR 10 , -OH, -C (= 0) NR 9 R 9 , -C (= 0) R 10 and -OC (= 0) R 10 are independently selected.

또한 본 발명은 화학식 1의 화합물이 하기 화학식 2의 화합물 또는 하기 화학식 3의 화합물인 것을 특징으로 하는, 화합물 및 이의 약제학적으로 허용되는 염을 제공한다.The present invention also provides a compound and a pharmaceutically acceptable salt thereof, characterized in that the compound of Formula 1 is a compound of Formula 2 or a compound of Formula 3.

[화학식 2][Formula 2]

Figure pat00003
Figure pat00003

[화학식 3](3)

Figure pat00004
Figure pat00004

상기 화학식 2 및 화학식 3에서, In Chemical Formulas 2 and 3,

D는 NR3, S 또는 O이고;D is NR 3 , S or O;

G는 S 또는 O이고;G is S or O;

R`은 알킬, 시클로알킬, 아릴, 헤테로아릴, 헤테로시클릴, -S(O)2R5, -C(=O)NR3R5, -C(=O)R5 또는 -C(=O)OR5이고, 여기서 알킬, 시클로알킬, 아릴, 헤테로아릴 및 헤테로시클릴은 각각 하나 이상의 R6으로 치환되거나 비치환될 수 있고;R` is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -S (O) 2 R 5 , -C (= 0) NR 3 R 5 , -C (= 0) R 5 or -C (= O) OR 5 , wherein alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may each be substituted or unsubstituted with one or more R 6 ;

R``은 수소, 알킬, 알케닐, 알키닐, 시클로알킬, 아릴, 헤테로시클릴, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)OR10, -OCF3, -OR11, -OH, -SH, -SR11, -S(O)3H, -P(O)3H2, -C(=O)NR9R9, -NR12R12, -S(O)2NR9R9, -NR9S(O)2CF3, -C(=O)NR9S(O)2R9, -S(O)2NR9C(=O)OR9, -S(O)2NR9C(=O)NR9R9, -C(=O)NR9S(O)2CF3, -C(=O)R11, -NR9C(=O)H, -NR9C(=O)R10, -OC(=O)R10, -OC(=O)NR9R9, -C(=NR14)NR9R9, -NHC(=NR14)NR14R14, -S(=O)R11,R`` is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, halo, -NH 2 , -CN, -NO 2 , -C (= 0) OH, -C (= 0) OR 10 , -OCF 3 , -OR 11 , -OH, -SH, -SR 11 , -S (O) 3 H, -P (O) 3 H 2 , -C (= O) NR 9 R 9 ,- NR 12 R 12 , -S (O) 2 NR 9 R 9 , -NR 9 S (O) 2 CF 3 , -C (= O) NR 9 S (O) 2 R 9 , -S (O) 2 NR 9 C (= 0) OR 9 , -S (O) 2 NR 9 C (= 0) NR 9 R 9 , -C (= 0) NR 9 S (O) 2 CF 3 , -C (= 0) R 11 , -NR 9 C (= 0) H, -NR 9 C (= 0) R 10 , -OC (= 0) R 10 , -OC (= 0) NR 9 R 9 , -C (= NR 14 ) NR 9 R 9 , -NHC (= NR 14 ) NR 14 R 14 , -S (= O) R 11 ,

-S(O)2R11, -NR9C(=O)OR8 및 -NR9S(O2)R8로 이루어진 군으로부터 독립적으로 선택되고, 여기서: (a) 알케닐, 알키닐, 시클로알킬, 아릴 및 헤테로시클릴은 각각 하나 이상의 R6으로 치환되거나 비치환될 수 있고; (b) 알킬은 하나 이상의 R7로 치환되거나 비치환될 수 있고;-S (O) 2 R 11 , -NR 9 C (= 0) OR 8 and -NR 9 S (O 2 ) R 8 , independently selected from the group consisting of: (a) alkenyl, alkynyl, Cycloalkyl, aryl and heterocyclyl may each be substituted or unsubstituted with one or more R 6 ; (b) alkyl may be unsubstituted or substituted with one or more R 7 ;

R```은 수소, 알킬 또는 할로겐이고;R` '' is hydrogen, alkyl or halogen;

상기 R3 , R6, R7 및 P3는 앞에서 정의한 바와 같다.
R 3 , R 6 , R 7 and P 3 are as defined above.

나아가 본 발명은 화학식 1의 화합물이 아래 화합물로 구성된 군으로부터 선택된 어느 하나인 것을 특징으로 하는 화합물 또는 이의 입체이성질체 또는 이들의 약제학적으로 허용되는 염을 제공한다:The present invention further provides a compound or stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of Formula 1 is any one selected from the group consisting of the following compounds:

4-{5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-티옥소-2H-피리딘-1-일}-2-플루오로-벤조니트릴;4- {5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-thioxo-2H-pyridin-1-yl} -2 -Fluoro-benzonitrile;

4-[5-클로로-1-(4-시아노-3-플루오로-페닐)-2-티옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [5-Chloro-1- (4-cyano-3-fluoro-phenyl) -2-thioxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxyl Ric acid tert-butyl ester;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-메탄설포닐-페닐)-1H-피리딘-2-티온;5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-methanesulfonyl-phenyl) -1H-pyridine-2- Thion;

4-[5-클로로-1-(4-메탄설포닐-페닐)-2-티옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [5-Chloro-1- (4-methanesulfonyl-phenyl) -2-thioxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert- Butyl esters;

4-(1-tert-부톡시카보닐-피페리딘-4-일옥시)-5-클로로-2-티옥소-3',4',5',6'-테트라히드로-2H,2'H-[1,4']바이피리디닐-1'-카복실릭 에시드 tert-부틸 에스테르;4- (1-tert-butoxycarbonyl-piperidin-4-yloxy) -5-chloro-2-thioxo-3 ', 4', 5 ', 6'-tetrahydro-2H, 2' H- [1,4 '] bipyridinyl-1'-carboxylic acid tert-butyl ester;

4-[1-(4-메탄설포닐-페닐)-2-티옥소-1,2-디히드로-피리미딘-4-일아미노]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [1- (4-Methanesulfonyl-phenyl) -2-thioxo-1,2-dihydro-pyrimidin-4-ylamino] -piperidine-1-carboxylic acid tert-butyl ester;

3-브로모-5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-메탄설포닐-페닐)-1H-피리딘-2-티온;3-Bromo-5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-methanesulfonyl-phenyl) -1H -Pyridine-2-thione;

5-클로로-5'-클로로메틸-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-[1,2']바이피리디닐-2-티온;5-Chloro-5'-chloromethyl-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy]-[1,2 '] bipyridinyl-2- Thion;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1'-메탄설포닐-1',2',3',4',5',6'-헥사히드로-[1,4']바이피리디닐-2-티온;5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1'-methanesulfonyl-1 ', 2', 3 ', 4' , 5 ', 6'-hexahydro- [1,4'] bipyridinyl-2-thione;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-티옥소-2H-[1,2']바이피리디닐-5'-카보니트릴;5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-thioxo-2H- [1,2 '] bipyridinyl-5 '-Carbonitrile;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-5'-메탄설포닐-[1,2']바이피리디닐-2-티온;5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -5'-methanesulfonyl- [1,2 '] bipyridinyl-2 -Thione;

3-{4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-벤조니트릴;3- {4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -benzonitrile;

3-{4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-티옥소-2H-피리딘-1-일메틸}-벤조니트릴;3- {4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-thioxo-2H-pyridin-1-ylmethyl} -benzonitrile;

4-[1-(3-시아노-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [1- (3-Cyano-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester;

4-[1-(3-시아노-벤질)-2-티옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [1- (3-Cyano-benzyl) -2-thioxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester;

4-[1-(3-시아노-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시메틸]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [1- (3-Cyano-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxymethyl] -piperidine-1-carboxylic acid tert-butyl ester;

4-[1-(3-시아노-벤질)-2-티옥소-1,2-디히드로-피리딘-4-일옥시메틸]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [1- (3-Cyano-benzyl) -2-thioxo-1,2-dihydro-pyridin-4-yloxymethyl] -piperidine-1-carboxylic acid tert-butyl ester;

4-{4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-티옥소-2H-피리딘-1-일}-2-플루오로-벤조니트릴;4- {4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-thioxo-2H-pyridin-1-yl} -2-fluoro- Benzonitrile;

4-[1-(4-플루오로-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [1- (4-Fluoro-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester;

4-[1-(3-메톡시-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [1- (3-methoxy-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester;

4-(4-{4-[1-(tert-뷰톡시카보닐)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-티아졸-2-일)-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- (4- {4- [1- (tert-Butoxycarbonyl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -thiazol-2-yl ) -Piperidine-1-carboxylic acid tert-butyl ester;

4-[1-(1-메탄설포닐-피페리딘-4-일메틸)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [1- (1-Methanesulfonyl-piperidin-4-ylmethyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester;

4-[1-(4-플루오로-벤질)-2-티옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [1- (4-Fluoro-benzyl) -2-thioxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester;

4-[1-(3-메톡시-벤질)-2-티옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [1- (3-methoxy-benzyl) -2-thioxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester;

4-[1-(4-메톡시카보닐-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [1- (4-methoxycarbonyl-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester;

4-[1-(4-시아노-2-플루오로-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [1- (4-Cyano-2-fluoro-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester;

4-{5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-3-플루오로-벤조니트릴;4- {5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -3 -Fluoro-benzonitrile;

5-클로로-1-(6-클로로-피리딘-3-일메틸)-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1H-피리딘-2-온;5-Chloro-1- (6-chloro-pyridin-3-ylmethyl) -4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1 H-pyridine 2-one;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(3-트리플루오로메틸-벤질)-1H-피리딘-2-온;5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (3-trifluoromethyl-benzyl) -1H-pyridine-2 -On;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-트리플루오로메틸-벤질)-1H-피리딘-2-온;5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-trifluoromethyl-benzyl) -1H-pyridine-2 -On;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-메톡시-벤질)-1H-피리딘-2-온;5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-methoxy-benzyl) -1H-pyridin-2-one ;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(3-메톡시-벤질)-1H-피리딘-2-온;5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (3-methoxy-benzyl) -1H-pyridin-2-one ;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(3-트리플루오로메톡시-벤질)-1H-피리딘-2-온;5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (3-trifluoromethoxy-benzyl) -1H-pyridine-2 -On;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-플루오로-벤질)-1H-피리딘-2-온;5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-fluoro-benzyl) -1H-pyridin-2-one ;

4-{5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-벤조니트릴;4- {5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -benzo Nitrile;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-이소프로필-벤질)-1H-피리딘-2-온;5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-isopropyl-benzyl) -1H-pyridin-2-one ;

5-클로로-1-(3,4-디플루오로-벤질)-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1H-피리딘-2-온;5-Chloro-1- (3,4-difluoro-benzyl) -4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1 H-pyridine- 2-one;

4-[5-클로로-1-(3,4-디플루오로-벤조일)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드tert-부틸 에스테르;4- [5-Chloro-1- (3,4-difluoro-benzoyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert Butyl ester;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(3-플루오로-벤질)-1H-피리딘-2-온;5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (3-fluoro-benzyl) -1H-pyridin-2-one ;

3-{5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-벤조니트릴;3- {5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -benzo Nitrile;

4-[5-클로로-1-(3-시아노-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [5-Chloro-1- (3-cyano-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester ;

4-[5-클로로-1-(3-시아노-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리디움 클로라이드;4- [5-Chloro-1- (3-cyano-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidium chloride;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-메틸설파닐-벤질)-1H-피리딘-2-온;5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-methylsulfanyl-benzyl) -1H-pyridine-2- On;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-메탄설피닐-벤질)-1H-피리딘-2-온;5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-methanesulfinyl-benzyl) -1H-pyridine-2- On;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-메탄설포닐-벤질)-1H-피리딘-2-온;5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-methanesulfonyl-benzyl) -1H-pyridine-2- On;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(2-플루오로-벤질)-1H-피리딘-2-온;5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (2-fluoro-benzyl) -1H-pyridin-2-one ;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(3-플루오로-4-메틸설파닐-벤질)-1H-피리딘-2-온;5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (3-fluoro-4-methylsulfanyl-benzyl) -1H -Pyridin-2-one;

3-{5-클로로-4-[1-(4-메틸설파닐-벤조일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-벤조니트릴;3- {5-Chloro-4- [1- (4-methylsulfanyl-benzoyl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -benzonitrile;

3-[4-(1-벤조옥사졸-2-일-피페리딘-4-일옥시)-5-클로로-2-옥소-2H-피리딘-1-일메틸]-벤조니트릴;3- [4- (1-benzooxazol-2-yl-piperidin-4-yloxy) -5-chloro-2-oxo-2H-pyridin-1-ylmethyl] -benzonitrile;

4-[5-클로로-1-(3-플루오로-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [5-Chloro-1- (3-fluoro-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester ;

3-[5-클로로-4-(1-이소부티릴-피페리딘-4-일옥시)-2-옥소-2H-피리딘-1-일메틸]-벤조니트릴;3- [5-chloro-4- (1-isobutyryl-piperidin-4-yloxy) -2-oxo-2H-pyridin-1-ylmethyl] -benzonitrile;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-[2-(4-플루오로-페닐)-에틸]-1H-피리딘-2-온;5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- [2- (4-fluoro-phenyl) -ethyl] -1 H -Pyridin-2-one;

3-{4-[1-(5-브로모-피리미딘-2-일)-피페리딘-4-일옥시]-5-클로로-2-옥소-2H-피리딘-1-일메틸}-벤조니트릴; 및3- {4- [1- (5-Bromo-pyrimidin-2-yl) -piperidin-4-yloxy] -5-chloro-2-oxo-2H-pyridin-1-ylmethyl}- Benzonitrile; And

4-(1-{4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일}-에틸)-벤조니트릴.
4- (1- {4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-yl} -ethyl)- Benzonitrile.

여기서, 화학식 1의 화합물은 아래 화합물로 구성된 군으로부터 선택된 어느 하나인 것이 바람직하다: Herein, the compound of Formula 1 is preferably any one selected from the group consisting of the following compounds:

4-{5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-티옥소-2H-피리딘-1-일}-2-플루오로-벤조니트릴;4- {5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-thioxo-2H-pyridin-1-yl} -2 -Fluoro-benzonitrile;

4-[5-클로로-1-(4-시아노-3-플루오로-페닐)-2-티옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [5-Chloro-1- (4-cyano-3-fluoro-phenyl) -2-thioxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxyl Ric acid tert-butyl ester;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-메탄설포닐-페닐)-1H-피리딘-2-티온;5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-methanesulfonyl-phenyl) -1H-pyridine-2- Thion;

4-[5-클로로-1-(4-메탄설포닐-페닐)-2-티옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [5-Chloro-1- (4-methanesulfonyl-phenyl) -2-thioxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert- Butyl esters;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-5'-메탄설포닐-[1,2']바이피리디닐-2-티온;5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -5'-methanesulfonyl- [1,2 '] bipyridinyl-2 -Thione;

3-{4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-벤조니트릴;3- {4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -benzonitrile;

4-[1-(3-시아노-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [1- (3-Cyano-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester;

4-{4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-티옥소-2H-피리딘-1-일}-2-플루오로-벤조니트릴;4- {4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-thioxo-2H-pyridin-1-yl} -2-fluoro- Benzonitrile;

4-[1-(4-시아노-2-플루오로-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [1- (4-Cyano-2-fluoro-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester;

4-{5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-3-플루오로-벤조니트릴;4- {5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -3 -Fluoro-benzonitrile;

4-{5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-벤조니트릴;4- {5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -benzo Nitrile;

3-{5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-벤조니트릴;3- {5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -benzo Nitrile;

4-[5-클로로-1-(3-시아노-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르;4- [5-Chloro-1- (3-cyano-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester ;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-메틸설파닐-벤질)-1H-피리딘-2-온;5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-methylsulfanyl-benzyl) -1H-pyridine-2- On;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-메탄설피닐-벤질)-1H-피리딘-2-온;5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-methanesulfinyl-benzyl) -1H-pyridine-2- On;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-메탄설포닐-벤질)-1H-피리딘-2-온;5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-methanesulfonyl-benzyl) -1H-pyridine-2- On;

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(3-플루오로-4-메틸설파닐-벤질)-1H-피리딘-2-온;5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (3-fluoro-4-methylsulfanyl-benzyl) -1H -Pyridin-2-one;

3-[5-클로로-4-(1-이소부티릴-피페리딘-4-일옥시)-2-옥소-2H-피리딘-1-일메틸]-벤조니트릴; 및3- [5-chloro-4- (1-isobutyryl-piperidin-4-yloxy) -2-oxo-2H-pyridin-1-ylmethyl] -benzonitrile; And

3-{4-[1-(5-브로모-피리미딘-2-일)-피페리딘-4-일옥시]-5-클로로-2-옥소-2H-피리딘-1-일메틸}-벤조니트릴.
3- {4- [1- (5-Bromo-pyrimidin-2-yl) -piperidin-4-yloxy] -5-chloro-2-oxo-2H-pyridin-1-ylmethyl}- Benzonitrile.

또한 본 발명은 본 발명의 화합물 또는 이의 약제학적으로 허용되는 염을 유효성분으로 포함하는, 대사 관련 장애 치료용 약학 조성물을 제공한다.
The present invention also provides a pharmaceutical composition for treating metabolic related disorders, comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

여기서 상기 대사 관련 장애는 예를 들면 비만, I형 당뇨병, II형 당뇨병, 부적합한 내당력, 인슐린 내성, 고혈당증, 고지질혈증, 고중성지방혈증, 고콜레스테롤혈증, 이상지질혈증 및 X 증후군 등을 포함한다
Wherein the metabolic related disorders include, for example, obesity, type I diabetes, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, X syndrome, etc. do

또한 본 발명은 하기 화학식 4의 화합물과 하기 화학식 5의 화합물을 반응시켜 제1항의 화합물을 제조하는 방법을 제공한다:
The present invention also provides a method for preparing the compound of claim 1 by reacting a compound of formula 4 with a compound of formula 5 below:

[화학식 4][Formula 4]

Figure pat00005
Figure pat00005

[화학식 5][Chemical Formula 5]

Figure pat00006
Figure pat00006

상기 화학식에서,In the above formula,

A 및 B는 할로겐이고,A and B are halogen,

X, Y, L1, R4, n4, Z1, Z2, P1, P2 및 P3는 앞에서 정의한 바와 같다.
X, Y, L 1 , R 4 , n 4 , Z 1 , Z 2 , P 1 , P 2 and P 3 are as defined above.

도 1은 화합물의 농도에 따른 효력, 효능 비교 그래프이다.1 is a graph comparing the potency and potency according to the concentration of the compound.

이하, 본 발명을 하기의 제조예 및 실시예에 의해 상세히 설명한다. 단, 하기 제조예 및 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 이에 의해 한정되는 것은 아니다.
Hereinafter, the present invention will be described in detail by the following Preparation Examples and Examples. However, the following Preparation Examples and Examples are merely to illustrate the present invention, but the content of the present invention is not limited thereto.

모든 시약은 시그마알드리치, 플루카(Fluka), TCI 사의 제조된 시약을 구매 사용하였고, 1H NMR Spectra는 테트라메틸실란(tetramethyl silane)을 내부 표준물질로 사용하여 Bruker Biospin AVANCE II 400 기기를 활용 기록하였다.
All reagents were purchased from Sigma Aldrich, Fluka and TCI, and 1 H NMR Spectra was recorded using a Bruker Biospin AVANCE II 400 instrument using tetramethylsilane as an internal standard. It was.

제조예 1. 1-(5-메틸-피리미딘-2-일)-피페리딘-4-올의 합성Preparation Example 1 Synthesis of 1- (5-methyl-pyrimidin-2-yl) -piperidin-4-ol

Figure pat00007
Figure pat00007

질소대기하의 500mL 플라스크에 4-히드록시피페리딘 9.6 g 과 아세토니트릴/증류수 2/1 용액 250 mL 를 넣고 교반하여 용해 시키고 디이소프로필에틸아민 19.5 mL 와 2-클로로-5-에틸피리미딘 11.2 g 을 넣은 후 2.5일 이상 가열환류한다. 온도를 상온으로 낮춘 후 1N HCl 수용액 200 mL에 녹이고 에틸 아세테이트 200 mL로 씻어 준다. 수층을 1N NaOH 수용액을 이용하여 pH를 7까지 맞추고 에틸 아세테이트 200 mL로 추출한다. 유기층을 무수황산마그네슘으로 건조하고 감압건조 하여 목적화합물을 얻었다.
Into a 500 mL flask under nitrogen atmosphere, 9.6 g of 4-hydroxypiperidine and 250 mL of acetonitrile / distilled water 2/1 were added thereto, stirred, and dissolved. After putting g, it is heated to reflux for 2.5 days or more. Lower the temperature to room temperature, dissolve in 200 mL of 1N HCl aqueous solution and wash with 200 mL of ethyl acetate. The aqueous layer was adjusted to pH 7 with 1N NaOH aqueous solution and extracted with 200 mL of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and dried under reduced pressure to obtain the target compound.

1H NMR (400MHz, CDCl3) : 8.18(2H, s), 4.37-4,48(2H, m), 3.91-4.01(1H, m), 3.22-3.31(2H, m), 2.42-2.51(2H, m), 1.49-1.99(4H, m), 1.17-1.21(3H, m).
 1 H NMR (400 MHz, CDCl 3 ): 8.18 (2H, s), 4.37-4,48 (2H, m), 3.91-4.01 (1H, m), 3.22-3.31 (2H, m), 2.42-2.51 ( 2H, m), 1.49-1.99 (4H, m), 1.17-1.21 (3H, m).

제조예 2. 5-클로로-4-히드록시-1H-피리딘-2-티온의 합성Preparation Example 2 Synthesis of 5-Chloro-4-hydroxy-1H-pyridine-2-thione

Figure pat00008
Figure pat00008

질소대기하의 500mL 플라스크에 5-클로로-4-히드록시-1H-피리딘-2-온 16 g과 N,N-디메틸포름아미드 200mL를 넣고 교반하여 용해 시키고 Lawesson`s reagent 8.9g을 넣은 후 12시간 이상 가열환류한다. 이후 반응 종결 혼합물에 증류수 200 mL와 초산에칠 200 ml을 넣고 추출하여 분리된 유기층을 brine 200 ml로 씻어 준 후 무수황산마그네슘으로 건조하고 농축 후 실리카 컬럼 크로마토그래피로 분리하여 목적 화합물을 얻었다.
16 g of 5-chloro-4-hydroxy-1H-pyridin-2-one and 200 mL of N, N-dimethylformamide were added to a 500 mL flask under nitrogen atmosphere, and then dissolved by stirring. After adding 8.9 g of Lawesson`s reagent, 12 hours It is heated under reflux. Then, 200 mL of distilled water and 200 ml of ethyl acetate were added to the reaction mixture, and the separated organic layer was washed with brine 200 ml, dried over anhydrous magnesium sulfate, concentrated, and separated by silica column chromatography to obtain a target compound.

1H NMR (400MHz, DMSO-d6) : 7.61-7.82(1H, m), 7.01-7.03(1H, m).
 1 H NMR (400 MHz, DMSO-d 6 ): 7.61-7.82 (1 H, m), 7.01-7.03 (1 H, m).

제조예 3. 4-(5-클로로-2-티옥소-1,2-디히드로-피리딘-4-일옥시)-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르의 합성Preparation Example 3 Synthesis of 4- (5-Chloro-2-thioxo-1,2-dihydro-pyridin-4-yloxy) -piperidine-1-carboxylic acid tert-butyl ester

Figure pat00009
Figure pat00009

질소대기하의 500mL 플라스크에 5-클로로-4-히드록시-1H-피리딘-2-티온 15 g과 N,N-디메틸포름아미드 300 mL를 넣고 교반하여 용해시키고 트리페닐포스핀 40 g과 4-히드록시-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르 22.5 g을 넣은 후, 0oC에서 디이소프로필 아자디카복실레이트 30.5 mL를 dropping funnel을 이용하여 천천히 적가하여 상온에서 12시간 이상 교반한다. 이후 반응 종결 화합물에 초산에칠 300 mL에 녹인 후, 증류수 300 mL로 washing 하고 1N HCl 수용액으로 2회 추출한 다음 수층을 초산에칠 300 mL로 2회 washing한다. 분리된 수층을 포화 소디움 바이카보네이트 수용액을 이용하여 pH 10으로 맞춘 다음 초산에칠 300 mL를 이용하여 유기층으로 두 번 추출하여 무수황산마그네슘으로 건조하고 감압건조 하여 목적 화합물을 얻었다.
15 g of 5-chloro-4-hydroxy-1H-pyridine-2-thione and 300 mL of N, N-dimethylformamide were added to a 500 mL flask under nitrogen atmosphere, and stirred to dissolve. 40 g of triphenylphosphine and 4-hydride were dissolved. Add 22.5 g of oxy-piperidine-1-carboxylic acid tert-butyl ester, and slowly add dropwise 30.5 mL of diisopropyl azadicarboxylate at 0 o C using a dropping funnel and stir at room temperature for at least 12 hours. . After dissolving in 300 mL of ethyl acetate in the reaction terminating compound, it was washed with distilled water 300 mL and extracted twice with 1N HCl aqueous solution and the aqueous layer was washed twice with 300 mL of ethyl acetate. The separated aqueous layer was adjusted to pH 10 using saturated sodium bicarbonate aqueous solution, extracted twice with an organic layer using 300 mL of ethyl acetate, dried over anhydrous magnesium sulfate, and dried under reduced pressure to obtain the target compound.

1H NMR (400MHz, CDCl3) : 7.35(1H, s), 7.24(1H, s), 4.58-4.61(1H, m), 3.47-3.66 (4H, m), 1.84-1.95(4H, m), 1.61(9H, s).
 1 H NMR (400 MHz, CDCl 3 ): 7.35 (1 H, s), 7.24 (1 H, s), 4.58-4.61 (1 H, m), 3.47-3.66 (4 H, m), 1.84-1.95 (4 H, m) , 1.61 (9H, s).

제조예 4. 5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1H-피리딘-2-티온의 합성Preparation Example 4 Synthesis of 5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1H-pyridine-2-thione

Figure pat00010
Figure pat00010

4-히드록시-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르를 대신하여 1-(5-에틸-피리미딘-2-일)-피페리딘-4-올을 이용하여 제조예 3과 같은 방법으로 목적화합물을 얻었다.
Preparation Example 3 using 1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-ol in place of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester In the same manner to obtain the target compound.

1H NMR (400MHz, CDCl3) : 8.21(2H, s), 7.46(1H, s), 7.27(1H, s), 4.57-4.65(1H, m), 3.69-4.04(4H, m), 2.36-2.48(2H, m), 1.87-1.95(4H, m), 1.18-1.23(3H, m).
 1 H NMR (400 MHz, CDCl 3 ): 8.21 (2H, s), 7.46 (1H, s), 7.27 (1H, s), 4.57-4.65 (1H, m), 3.69-4.04 (4H, m), 2.36 -2.48 (2H, m), 1.87-1.95 (4H, m), 1.18-1.23 (3H, m).

제조예 5. 4-아미노-1H-피리미딘-2-티온의 합성Preparation Example 5 Synthesis of 4-amino-1H-pyrimidine-2-thione

Figure pat00011
Figure pat00011

5-클로로-4-히드록시-1H-피리딘-2-온을 대신하여 4-아미노-1H-피리미딘-2-온4-amino-1H-pyrimidin-2-one in place of 5-chloro-4-hydroxy-1H-pyridin-2-one

을 이용하여 제조예 2와 같은 방법으로 목적 화합물을 얻었다.
Using the same method as in Preparation Example 2 to obtain the target compound.

1H NMR (400MHz, DMSO-d6) : 8.29(1H, m), 7.21-7.23(1H, m).
 1 H NMR (400 MHz, DMSO-d 6 ): 8.29 (1 H, m), 7.21-7.23 (1 H, m).

제조예 6. 4-(2-티옥소-1,2-디히드로-피리미딘-4-일아미노)-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르의 합성Preparation Example 6 Synthesis of 4- (2-Tioxo-1,2-dihydro-pyrimidin-4-ylamino) -piperidine-1-carboxylic acid tert-butyl ester

Figure pat00012
Figure pat00012

5-클로로-4-히드록시-1H-피리딘-2-티온을 대신하여 4-아미노-1H-피리미딘-2-티온을 이용하여 제조예 3과 같은 방법으로 목적 화합물을 얻었다.
The desired compound was obtained in the same manner as in Preparation Example 3 using 4-amino-1H-pyrimidine-2-thione in place of 5-chloro-4-hydroxy-1H-pyridine-2-thione.

1H NMR (400MHz, CDCl3) : 8.05(1H, d), 7.22(1H, d), 4.72-4.81(1H, m), 3.69-3.84 (4H, m), 1.83-2.08(4H, m), 1.59(9H, s).
 1 H NMR (400 MHz, CDCl 3 ): 8.05 (1H, d), 7.22 (1H, d), 4.72-4.81 (1H, m), 3.69-3.84 (4H, m), 1.83-2.08 (4H, m) , 1.59 (9H, s).

제조예 7. 메탄설포닉 에시드 1-메탄설포닐-피페리딘-4-일 에스테르의 합성Preparation Example 7 Synthesis of Methanesulphonic Acid 1-methanesulfonyl-piperidin-4-yl Ester

Figure pat00013
Figure pat00013

질소대기하의 250mL 플라스크에 4-히드록시피페리딘 5g 과 MC 100 mL 를 넣고 교반하여 용해 시키고 트리에틸아민 17.5 mL 와 메탄설포닐 클로라이드 12.5 mL을 넣은 후 상온에서 6시간 반응한다. 이후 반응 종결 화합물에 증류수 100 mL를 천천히 가하고 초산에칠 100 mL로 추출한 다음 brine 100ml로 씻어 준 후 무수황산마그네슘으로 건조하고 농축 후 실리카 컬럼 크로마토그래피로 분리하여 목적 화합물을 얻었다.
In a 250 mL flask under nitrogen atmosphere, 5 g of 4-hydroxypiperidine and 100 mL of MC were added thereto, stirred, and dissolved. After adding 17.5 mL of triethylamine and 12.5 mL of methanesulfonyl chloride, the mixture was reacted at room temperature for 6 hours. Then, 100 mL of distilled water was slowly added to the reaction terminating compound, extracted with 100 mL of ethyl acetate, washed with 100 mL of brine, dried over anhydrous magnesium sulfate, concentrated, and separated by silica column chromatography to obtain a target compound.

1H NMR (400MHz, CDCl3) : 4.11-4.13(2H, d), 3.87-3.91(2H, m), 3.05(3H, s), 2.81(3H, s), 2.66-2.73(2H, m), 1.91-1.93(3H, m), 1.41-1.50(2H, m).
 1 H NMR (400 MHz, CDCl 3 ): 4.11-4.13 (2H, d), 3.87-3.91 (2H, m), 3.05 (3H, s), 2.81 (3H, s), 2.66-2.73 (2H, m) , 1.91-1.93 (3H, m), 1.41-1.50 (2H, m).

제조예 8. 2-브로모-5-메틸설파닐-피리딘의 합성Preparation Example 8 Synthesis of 2-bromo-5-methylsulfanyl-pyridine

Figure pat00014
Figure pat00014

질소대기하의 500mL 플라스크에 2,5-디브로모-피리딘 12 g과 에테르 250 mL 을 넣고 -78oC에서 n-부틸 리튬(1.52M in n-hexane) 34 mL를 넣은 뒤 한 시간 후에 디메틸디설피드 4.9 mL를 적가한다. 상온에서 12시간 교반 후 0oC에서 증류수를 천천히 적가하고 초산에칠200 mL로 추출 한 다음 1N-HCl 200mL로 washing 하여 유기층을 무수황산마그네슘으로 건조하고 감압건조 하여 목적화합물을 얻었다.
12 g of 2,5-dibromo-pyridine and 250 mL of ether were added to a 500 mL flask under nitrogen atmosphere, and 34 mL of n-butyl lithium (1.52 M in n-hexane) was added at -78 o C. 4.9 mL of feed is added dropwise. After stirring for 12 hours at room temperature, distilled water was slowly added dropwise at 0 o C, extracted with 200 mL of ethyl acetate, washed with 200 mL of 1N-HCl, and the organic layer was dried over anhydrous magnesium sulfate and dried under reduced pressure to obtain a target compound.

1H NMR (400MHz, CDCl3) : 8.25(1H, s), 7.38-7.44(2H, m), 2.51(3H, s).
 1 H NMR (400 MHz, CDCl 3 ): 8.25 (1H, s), 7.38-7.44 (2H, m), 2.51 (3H, s).

제조예 9. 2-브로모-5-메탄설포닐-피리딘의 합성Preparation Example 9 Synthesis of 2-bromo-5-methanesulfonyl-pyridine

Figure pat00015
Figure pat00015

질소대기하의 500mL 플라스크에 5-메틸티오-2-브로모피리딘 5 g 을 THF 200 mL/증류수 40 mL에 넣고 교반한 다음 0oC에서 옥손(Oxone) 40 g을 넣고 상온에서 3시간 교반한다. 이후 반응물을 filter한 후 filtlate를 증류수 200mL와 초산에칠 200mL를 이용하여 추출한 후 유기층을 무수황산마그네슘으로 건조하고 감압건조 하여 목적화합물을 얻었다.
In a 500 mL flask under nitrogen atmosphere, 5 g of 5-methylthio-2-bromopyridine was added to 200 mL of THF / 40 mL of distilled water, followed by stirring. 40 g of Oxone was added at 0 ° C. and stirred at room temperature for 3 hours. After filtering the reaction product, the filtlate was extracted using distilled water 200mL and ethyl acetate 200mL, the organic layer was dried over anhydrous magnesium sulfate and dried under reduced pressure to obtain the target compound.

1H NMR (400MHz, CDCl3) : 8.93(1H, s), 8.06-8.09(1H, d), 7.73-7.75(1H, d), 3.14(3H, s).
 1 H NMR (400 MHz, CDCl 3 ): 8.93 (1H, s), 8.06-8.09 (1H, d), 7.73-7.75 (1H, d), 3.14 (3H, s).

제조예 10. 4-히드록시-1H-피리딘-2-티온의 합성Preparation Example 10 Synthesis of 4-hydroxy-1H-pyridine-2-thione

Figure pat00016
Figure pat00016

5-클로로-4-히드록시-1H-피리딘-2-온을 대신하여 4-히드록시-1H-피리딘-2-온을 이용하여 제조예 2와 같은 방법으로 목적 화합물을 얻었다.
The target compound was obtained in the same manner as in Preparation Example 2 using 4-hydroxy-1H-pyridin-2-one instead of 5-chloro-4-hydroxy-1H-pyridin-2-one.

1H NMR (400MHz, DMSO-d6) : 7.53(1H, d), 7.22(1H, s), 5.97(1H, d),
 1 H NMR (400 MHz, DMSO-d 6 ): 7.53 (1 H, d), 7.22 (1 H, s), 5.97 (1 H, d),

제조예 11. 4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1H-피리딘-2-티온의 합성Preparation Example 11 Synthesis of 4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1H-pyridine-2-thione

Figure pat00017
Figure pat00017

5-클로로-4-히드록시-1H-피리딘-2-티온을 대신하여 4-히드록시-1H-피리딘-2-티온을 이용하여 제조예 4와 같은 방법으로 목적 화합물을 얻었다.
The target compound was obtained in the same manner as in Preparation Example 4, using 4-hydroxy-1H-pyridine-2-thione instead of 5-chloro-4-hydroxy-1H-pyridine-2-thione.

1H NMR (400MHz, CDCl3) : 8.19(2H, s), 7.42(1H, d), 7.23(1H, s), 6.05(1H, d), 4.55-4.56(1H, m), 3.61-4.56 (4H, m), 2.46-2.49(2H, m), 1.81-2.08(4H, m), 1.22-1.28(3H, m).
 1 H NMR (400 MHz, CDCl 3 ): 8.19 (2H, s), 7.42 (1H, d), 7.23 (1H, s), 6.05 (1H, d), 4.55-4.56 (1H, m), 3.61-4.56 (4H, m), 2.46-2.49 (2H, m), 1.81-2.08 (4H, m), 1.22-1.28 (3H, m).

제조예 12. 3-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴의 합성Preparation Example 12 Synthesis of 3- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile

Figure pat00018
Figure pat00018

질소대기하의 50 mL 플라스크에 4-히드록시-2(1H)-피리돈 300 mg 과 N,N-디메틸포름아미드 20ml를 넣고 교반하여 용해 시키고 소디움 하이드라이드 108 mg 과 3-브로모메틸벤조니트릴 530 mg 을 넣고 상온에서 5시간 이상 교반한다. 반응 혼합물을 에틸 아세테이트 100 mL에 녹이고 증류수 100 mL로 2회 씻어준 후 유기층을 무수황산마그네슘으로 건조하고 감압건조 하고 감압건조 한 후 얻어진 잔사를 실리카 컬럼으로 정제, 분리하여 목적화합물을 얻었다.
Into a 50 mL flask under nitrogen atmosphere, 300 mg of 4-hydroxy-2 (1H) -pyridone and 20 ml of N, N-dimethylformamide were added and dissolved by stirring. Sodium hydride 108 mg and 3-bromomethylbenzonitrile 530 were dissolved. Add mg and stir at room temperature for at least 5 hours. The reaction mixture was dissolved in 100 mL of ethyl acetate, washed twice with 100 mL of distilled water, and then the organic layer was dried over anhydrous magnesium sulfate, dried under reduced pressure, and dried under reduced pressure, and the obtained residue was purified by silica column and separated to obtain a target compound.

1H NMR (400MHz, DMSO-d6) 7.78(1H,d), 7.76-7.65(2H,m), 7.63-7.52(2H,m), 5.92(1H,d), 5.61(1H,s) 5.10(2H,s)
 1 H NMR (400 MHz, DMSO-d 6 ) 7.78 (1H, d), 7.76-7.65 (2H, m), 7.63-7.52 (2H, m), 5.92 (1H, d), 5.61 (1H, s) 5.10 (2H, s)

제조예 13. Preparation Example 13.

1-(4-플루오로-벤질)-4-히드록시-1H-피리딘-2-온의 합성Synthesis of 1- (4-fluoro-benzyl) -4-hydroxy-1H-pyridin-2-one

Figure pat00019
Figure pat00019

3-브로모메틸벤조니트릴을 대신하여 4-플루오로벤질 브로마이드를 이용하여 제조예 12 와 같은 방법으로 목적화합물을 얻었다.
The target compound was obtained in the same manner as in Preparation Example 12, using 4-fluorobenzyl bromide instead of 3-bromomethylbenzonitrile.

1H NMR (400MHz, CDCl3) : 7.31(2H,d) 7.15(1H.d), 7.06(2H,t) 5.7(1H,d), 5.5(1H,d), 4.9(2H,S)
 1 H NMR (400 MHz, CDCl 3 ): 7.31 (2H, d) 7.15 (1H.d), 7.06 (2H, t) 5.7 (1H, d), 5.5 (1H, d), 4.9 (2H, S)

제조예 14. 4-히드록시-1-(3-메톡시-벤질)-1H-피리딘-2-온의 합성Preparation Example 14 Synthesis of 4-hydroxy-1- (3-methoxy-benzyl) -1H-pyridin-2-one

Figure pat00020
Figure pat00020

3-브로모메틸벤조니트릴을 대신하여 3-메톡시벤질 브로마이드를 이용하여 제조예 12 와 같은 방법으로 목적화합물을 얻었다.
The target compound was obtained in the same manner as in Preparation Example 12 using 3-methoxybenzyl bromide instead of 3-bromomethylbenzonitrile.

1H NMR (400MHz, CDCl3) : 7.28(1H,m), 7.14(1H,d), 6.88-6.82(3H,m), 5.78(1H,d), 5.64(1H,s),4.92(2H,s)
 1 H NMR (400 MHz, CDCl 3 ): 7.28 (1H, m), 7.14 (1H, d), 6.88-6.82 (3H, m), 5.78 (1H, d), 5.64 (1H, s), 4.92 (2H , s)

제조예 15. 4-[4-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-티아졸-2-일]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르의 합성Preparation Example 15 4- [4- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -thiazol-2-yl] -piperidine-1-carboxylic acid tert-butyl ester Synthesis of

Figure pat00021
Figure pat00021

3-브로모메틸벤조니트릴을 대신하여 4-(4-클로로메틸-티아졸e-2-일)-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르를 이용하여 제조예 12 와 같은 방법으로 목적화합물을 얻었다.
In the same manner as in Preparation Example 12 using 4- (4-chloromethyl-thiazole-2-yl) -piperidine-1-carboxylic acid tert-butyl ester instead of 3-bromomethylbenzonitrile The desired compound was obtained.

1H(400MHz, CDCl3) 7.41(1H,d), 7.15(1H,s),5.81(1H,d), 5.61(1H,s), 5.2(2H.s), 4.30-4.10(1H,s)3.20-3.10(1H,m), 3.0-2.8(2H,m), 2.15-2.07(2H,m), 1.80-1.56(2H,m), 1.52(9H,s)
 1 H (400 MHz, CDCl 3 ) 7.41 (1 H, d), 7.15 (1 H, s), 5.81 (1 H, d), 5.61 (1 H, s), 5.2 (2 H.s), 4.30-4.10 (1 H, s 3.20-3.10 (1H, m), 3.0-2.8 (2H, m), 2.15-2.07 (2H, m), 1.80-1.56 (2H, m), 1.52 (9H, s)

제조예 16. 메탄설포닉 에시드 1-메탄설포닐-피페리딘-4-일메틸 에스테르의 합성Preparation Example 16 Synthesis of Methanesulphonic Acid 1-Methanesulfonyl-piperidin-4-ylmethyl Ester

Figure pat00022
Figure pat00022

질소대기하의 50 mL 플라스크에 4-피페리딘메탄올 500 mg 과 테트라히드로퓨란 30ml를 넣고 교반하여 용해 시키고 트리에틸아민 0.91 mL 와 메탄설포닐 클로라이드 0.17 mL 를 넣고 상온에서 10시간 이상 교반한다. 증류수 30 mL 를 넣고 테트라히드로퓨란 감압증류로 제거한 후 고체를 여과하고 증류수 50ml로 씻어 준 후 건조하여 목적화합물을 얻었다.
In a 50 mL flask under nitrogen atmosphere, 500 mg of 4-piperidinemethanol and 30 ml of tetrahydrofuran were added to the mixture, followed by stirring. 30 mL of distilled water was added thereto, followed by tetrahydrofuran distillation under reduced pressure, and then the solid was filtered, washed with 50 ml of distilled water, and dried to obtain the target compound.

1H(400MHz, CDCl3) 4.11(2H,d), 3.89(2H,d), 3.05(3H,s), 2.81(3H,s), 2.69(2H,t), 1.92(3H,d), 1.47-1.40(2H,m)
 1 H (400 MHz, CDCl 3 ) 4.11 (2H, d), 3.89 (2H, d), 3.05 (3H, s), 2.81 (3H, s), 2.69 (2H, t), 1.92 (3H, d), 1.47-1.40 (2H, m)

제조예 17. 4-히드록시-1-(1-메탄설포닐-피페리딘-4-일메틸)-1H-피리딘-2-온의 합성Preparation Example 17 Synthesis of 4-hydroxy-1- (1-methanesulfonyl-piperidin-4-ylmethyl) -1H-pyridin-2-one

Figure pat00023
Figure pat00023

3-브로모메틸벤조니트릴을 대신하여 메탄설포닉 에시드 1-메탄설포닐-피페리딘-4-일메틸 에스테르 이용하여 제조예 12 와 같은 방법으로 목적화합물을 얻었다.
The target compound was obtained in the same manner as in Preparation Example 12, using methanesulphonic acid 1-methanesulfonyl-piperidin-4-ylmethyl ester in place of 3-bromomethylbenzonitrile.

1H(400MHz, CDCl3) 7.06(1H,d), 5.7(1H,d), 5.52(1H,s), 4.82(2H,d), 3.67(2H,d), 2.78(3H,s), 2.62(2H,t), 2.14-2.04(1H,m), 1.65(2H,m), 1.42-1.37(2H,m)
 1 H (400 MHz, CDCl 3 ) 7.06 (1H, d), 5.7 (1H, d), 5.52 (1H, s), 4.82 (2H, d), 3.67 (2H, d), 2.78 (3H, s), 2.62 (2H, t), 2.14-2.04 (1H, m), 1.65 (2H, m), 1.42-1.37 (2H, m)

제조예 18. 4-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조익 에시드 메틸 에스테르의 합성Preparation Example 18 Synthesis of 4- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzoic acid methyl ester

Figure pat00024
Figure pat00024

3-브로모메틸벤조니트릴을 대신하여 메틸 4-(브로모메틸)벤조에이트를 이용하여 제조예 12 와 같은 방법으로 목적화합물을 얻었다.
The target compound was obtained in the same manner as in Preparation Example 12 using methyl 4- (bromomethyl) benzoate instead of 3-bromomethylbenzonitrile.

1H(400MHz, CDCl3) 7.82(2H,d), 7.24(2H,d), 7.15(1H,d), 5.7(1H,d), 5.52(1H,s), 5.05(2H,s), 3.62(3H,s)
 1 H (400 MHz, CDCl 3 ) 7.82 (2H, d), 7.24 (2H, d), 7.15 (1H, d), 5.7 (1H, d), 5.52 (1H, s), 5.05 (2H, s), 3.62 (3H, s)

제조예 19. 3-플루오로-4-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴의 합성Preparation Example 19 Synthesis of 3-fluoro-4- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile

Figure pat00025
Figure pat00025

3-브로모메틸벤조니트릴을 대신하여 4-(브로모메틸)-3-플루오로벤조니트릴을 이용하여 제조예 12 와 같은 방법으로 목적화합물을 얻었다.
The target compound was obtained in the same manner as in Preparation Example 12 using 4- (bromomethyl) -3-fluorobenzonitrile instead of 3-bromomethylbenzonitrile.

1H(400MHz, CDCl3) 7.46(1H,t), 7.35-7.30(2H,m), 7.18(1H,d), 5.7(1H,d), 5.52(1H,s), 4.98(2H,s)
 1 H (400 MHz, CDCl 3 ) 7.46 (1 H, t), 7.35-7.30 (2 H, m), 7.18 (1 H, d), 5.7 (1 H, d), 5.52 (1 H, s), 4.98 (2 H, s )

제조예 20. 4-(5-클로로-4-히드록시-2-옥소-2H-피리딘-1-일메틸)-3-플루오로-벤조니트릴의 합성Preparation Example 20 Synthesis of 4- (5-chloro-4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -3-fluoro-benzonitrile

Figure pat00026
Figure pat00026

질소대기하의 50 mL 플라스크에 5-클로로-4-히드록시-2(1H)-피리디논 300 mg 과 N,N-디메틸포름아미드 20ml를 넣고 교반하여 용해 시키고 소디움 하이드라이드 82 mg 과 4-(브로모메틸)-3-플루오로벤조니트릴 441 mg 을 넣고 상온에서 5시간 이상 교반한다. 반응 혼합물을 에틸 아세테이트 100 mL에 녹이고 증류수 100 mL로 2회 씻어준 후 유기층을 무수황산마그네슘으로 건조하고 감압건조 하고 감압건조 한 후 얻어진 잔사를 실리카 컬럼으로 정제, 분리하여 목적화합물을 얻었다.
In a 50 mL flask under nitrogen atmosphere, 300 mg of 5-chloro-4-hydroxy-2 (1H) -pyridinone and 20 ml of N, N-dimethylformamide were added and dissolved by stirring. Sodium hydride 82 mg and 4- (bro 441 mg of mother methyl) -3-fluorobenzonitrile was added thereto and stirred at room temperature for at least 5 hours. The reaction mixture was dissolved in 100 mL of ethyl acetate, washed twice with 100 mL of distilled water, and then the organic layer was dried over anhydrous magnesium sulfate, dried under reduced pressure, and dried under reduced pressure, and the obtained residue was purified by silica column and separated to obtain a target compound.

1H(400MHz, CDCl3) 7.46(1H,t), 7.35-7.30(2H,m), 7.18(1H,d), 5.52(1H,s), 4.98(2H,s)
 1 H (400 MHz, CDCl 3 ) 7.46 (1 H, t), 7.35-7.30 (2 H, m), 7.18 (1 H, d), 5.52 (1 H, s), 4.98 (2 H, s)

제조예 21. 5-클로로-1-(6-클로로-피리딘-3-일메틸)-4-히드록시-1H-피리딘-2-온의 합성Preparation Example 21 Synthesis of 5-chloro-1- (6-chloro-pyridin-3-ylmethyl) -4-hydroxy-1H-pyridin-2-one

Figure pat00027
Figure pat00027

4-(브로모메틸)-3-플루오로벤조니트릴을 대신하여 2-클로로-5-(클로로메틸)피리딘 를 이용하여 제조예 20 과 같은 방법으로 목적화합물을 얻었다.
The target compound was obtained in the same manner as in Preparation Example 20 using 2-chloro-5- (chloromethyl) pyridine in place of 4- (bromomethyl) -3-fluorobenzonitrile.

1H(400MHz, CDCl3) 8.21(1H,s), 7.62(1H,d), 7.28-7.23(2H,m), 5.72(1H,s), 4.84(2H,s)
 1 H (400 MHz, CDCl 3 ) 8.21 (1H, s), 7.62 (1H, d), 7.28-7.23 (2H, m), 5.72 (1H, s), 4.84 (2H, s)

제조예 22. 5-클로로-4-히드록시-1-(3-트리플루오로메틸-벤질)-1H-피리딘-2-온의 합성Preparation Example 22 Synthesis of 5-chloro-4-hydroxy-1- (3-trifluoromethyl-benzyl) -1H-pyridin-2-one

Figure pat00028
Figure pat00028

4-(브로모메틸)-3-플루오로벤조니트릴을 대신하여 3-(트리플루오로메틸)벤질 브로마이드를 이용하여 제조예 20 과 같은 방법으로 목적화합물을 얻었다.
Using the 3- (trifluoromethyl) benzyl bromide in place of 4- (bromomethyl) -3-fluorobenzonitrile, the target compound was obtained in the same manner as in Preparation Example 20.

1H(400MHz, CDCl3) 7.41-7.28(4H,m), 7.12(1H,s), 5.48(1H,s), 4,91(2H,s)
 1 H (400 MHz, CDCl 3 ) 7.41-7.28 (4H, m), 7.12 (1H, s), 5.48 (1H, s), 4,91 (2H, s)

제조예 23. 5-클로로-4-히드록시-1-(4-트리플루오로메틸-벤질)-1H-피리딘-2-온의 합성Preparation Example 23 Synthesis of 5-chloro-4-hydroxy-1- (4-trifluoromethyl-benzyl) -1H-pyridin-2-one

Figure pat00029
Figure pat00029

4-(브로모메틸)-3-플루오로벤조니트릴을 대신하여 4-(트리플루오로메틸)벤질 브로마이드 를 이용하여 제조예 20 과 같은 방법으로 목적화합물을 얻었다.
The target compound was obtained in the same manner as in Preparation Example 20 using 4- (trifluoromethyl) benzyl bromide instead of 4- (bromomethyl) -3-fluorobenzonitrile.

1H(400MHz, CDCl3) 7.44(2H,d), 7.22(2H,d), 6.98(1H,s), 5.87(1H,s), 4.98(2H,s)
 1 H (400 MHz, CDCl 3 ) 7.44 (2H, d), 7.22 (2H, d), 6.98 (1H, s), 5.87 (1H, s), 4.98 (2H, s)

제조예 24. 5-클로로-4-히드록시-1-(4-메톡시-벤질)-1H-피리딘-2-온의 합성Preparation Example 24 Synthesis of 5-chloro-4-hydroxy-1- (4-methoxy-benzyl) -1H-pyridin-2-one

Figure pat00030
Figure pat00030

4-(브로모메틸)-3-플루오로벤조니트릴을 대신하여 4-메톡시벤질 브로마이드를 이용하여 제조예 20 과 같은 방법으로 목적화합물을 얻었다.
The target compound was obtained in the same manner as in Preparation Example 20 using 4-methoxybenzyl bromide in place of 4- (bromomethyl) -3-fluorobenzonitrile.

1H(400MHz, CDCl3) 7.18(2H,d), 7.11(1H,s), 6.73(2H,d), 5.87(1H,s), 4.98(2H,s), 3.67(3H,s)
 1 H (400 MHz, CDCl 3 ) 7.18 (2H, d), 7.11 (1H, s), 6.73 (2H, d), 5.87 (1H, s), 4.98 (2H, s), 3.67 (3H, s)

제조예 25. 5-클로로-4-히드록시-1-(3-메톡시-벤질)-1H-피리딘-2-온의 합성Preparation Example 25 Synthesis of 5-Chloro-4-hydroxy-1- (3-methoxy-benzyl) -1H-pyridin-2-one

Figure pat00031
Figure pat00031

4-(브로모메틸)-3-플루오로벤조니트릴을 대신하여 3-메톡시벤질 브로마이드를 이용하여 제조예 20 과 같은 방법으로 목적화합물을 얻었다.
Using the 3-methoxybenzyl bromide in place of 4- (bromomethyl) -3-fluorobenzonitrile to obtain the target compound in the same manner as in Preparation Example 20.

1H(400MHz, CDCl3) 7.28(1H,s), 7.16(1H,s), 6.98-6.87(3H,m), 4.78(2H,s), 3,84(3H,s)
 1 H (400 MHz, CDCl 3 ) 7.28 (1H, s), 7.16 (1H, s), 6.98-6.87 (3H, m), 4.78 (2H, s), 3,84 (3H, s)

제조예 26. 5-클로로-4-히드록시-1-(3-트리플루오로메톡시-벤질)-1H-피리딘-2-온의 합성Preparation Example 26 Synthesis of 5-chloro-4-hydroxy-1- (3-trifluoromethoxy-benzyl) -1H-pyridin-2-one

Figure pat00032
Figure pat00032

4-(브로모메틸)-3-플루오로벤조니트릴을 대신하여 3-(트리플루오로메톡시)벤질 브로마이드를 이용하여 제조예 20 과 같은 방법으로 목적화합물을 얻었다.
Using the 3- (trifluoromethoxy) benzyl bromide in place of 4- (bromomethyl) -3-fluorobenzonitrile, the target compound was obtained in the same manner as in Preparation Example 20.

1H(400MHz, CDCl3) 7.42-7.40(1H,m), 7.28-7.18(3H,m), 6.92(1H,s), 5.88(1H,s), 4.78(2H,s)
 1 H (400 MHz, CDCl 3 ) 7.42-7.40 (1 H, m), 7.28-7.18 (3 H, m), 6.92 (1 H, s), 5.88 (1 H, s), 4.78 (2 H, s)

제조예 27. 5-클로로-1-(4-플루오로-벤질)-4-히드록시-1H-피리딘-2-온의 합성Preparation Example 27 Synthesis of 5-Chloro-1- (4-fluoro-benzyl) -4-hydroxy-1H-pyridin-2-one

Figure pat00033
Figure pat00033

4-(브로모메틸)-3-플루오로벤조니트릴을 대신하여 4-플루오로벤질 브로마이드를 이용하여 제조예 20 과 같은 방법으로 목적화합물을 얻었다.
The target compound was obtained in the same manner as in Preparation Example 20 using 4-fluorobenzyl bromide instead of 4- (bromomethyl) -3-fluorobenzonitrile.

1H(400MHz, CDCl3) 7.9(1H,s), 7.20-7.28(2H,m), 7.18-7.05(2H,m), 5.99(1H,s), 4.98(2H,s)
 1 H (400 MHz, CDCl 3 ) 7.9 (1H, s), 7.20-7.28 (2H, m), 7.18-7.05 (2H, m), 5.99 (1H, s), 4.98 (2H, s)

제조예 28. 4-(5-클로로-4-히드록시-2-옥소-2H-피리딘-1-일m에틸)-벤조니트릴의 합성Preparation Example 28 Synthesis of 4- (5-chloro-4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile

Figure pat00034
Figure pat00034

4-(브로모메틸)-3-플루오로벤조니트릴을 대신하여 4-(브로모메틸)벤조니트릴을 이용하여 제조예 20 과 같은 방법으로 목적화합물을 얻었다.
The target compound was obtained in the same manner as in Preparation Example 20 using 4- (bromomethyl) benzonitrile instead of 4- (bromomethyl) -3-fluorobenzonitrile.

1H(400MHz, CDCl3) 7.42(2H,d), 7.22(2h,d), 7.02(1H,s), 5.97(1H,s), 4.87(2H,s)
 1 H (400 MHz, CDCl 3 ) 7.42 (2H, d), 7.22 (2h, d), 7.02 (1H, s), 5.97 (1H, s), 4.87 (2H, s)

제조예 29. 5-클로로-4-히드록시-1-(4-이소프로필-벤질)-1H-피리딘-2-온의 합성Preparation 29. Synthesis of 5-chloro-4-hydroxy-1- (4-isopropyl-benzyl) -1H-pyridin-2-one

Figure pat00035
Figure pat00035

4-(브로모메틸)-3-플루오로벤조니트릴을 대신하여 4-이소프로필 벤질 브로마이드를 이용하여 제조예 20 과 같은 방법으로 목적화합물을 얻었다.
The desired compound was obtained in the same manner as in Preparation Example 20 using 4-isopropyl benzyl bromide in place of 4- (bromomethyl) -3-fluorobenzonitrile.

1H(400MHz, CDCl3) 7.12(2H,d), 7.02(1H,s), 6.00(1H,s), 4.78(2H,s), 2.87-2.82(1H,m), 1.21-1.19(6H,d)
 1 H (400 MHz, CDCl 3 ) 7.12 (2H, d), 7.02 (1H, s), 6.00 (1H, s), 4.78 (2H, s), 2.87-2.82 (1H, m), 1.21-1.19 (6H , d)

제조예 30. 5-클로로-1-(3,4-디플루오로-벤질)-4-히드록시-1H-피리딘-2-온의 합성Preparation Example 30 Synthesis of 5-chloro-1- (3,4-difluoro-benzyl) -4-hydroxy-1H-pyridin-2-one

Figure pat00036
Figure pat00036

4-(브로모메틸)-3-플루오로벤조니트릴을 대신하여 3,4-디플루오로벤질 브로마이드를 이용하여 제조예 20 과 같은 방법으로 목적화합물을 얻었다.
Using the 3,4-difluorobenzyl bromide in place of 4- (bromomethyl) -3-fluorobenzonitrile to obtain the target compound in the same manner as in Preparation Example 20.

1H(400MHz, CDCl3) 7.23-7.11(4H,m), 5.98(1H,s), 4.85(2H,s)
 1 H (400 MHz, CDCl 3 ) 7.23-7.11 (4H, m), 5.98 (1H, s), 4.85 (2H, s)

제조예 31. 5-클로로-1-(3,4-디플루오로-벤조일)-4-히드록시-1H-피리딘-2-온의 합성Preparation 31.Synthesis of 5-chloro-1- (3,4-difluoro-benzoyl) -4-hydroxy-1H-pyridin-2-one

Figure pat00037
Figure pat00037

4-(브로모메틸)-3-플루오로벤조니트릴을 대신하여 3,4-디플루오로벤조일 클로라이드를 이용하여 제조예 20 과 같은 방법으로 목적화합물을 얻었다.
Using the 3,4-difluorobenzoyl chloride instead of 4- (bromomethyl) -3-fluorobenzonitrile to obtain the target compound in the same manner as in Preparation Example 20.

1H(400MHz, CDCl3) 7.88-7.84(2h,m), 7.33-7.31(1H,m), 6.34(1H,s)
 1 H (400 MHz, CDCl 3 ) 7.88-7.84 (2 h, m), 7.33-7.31 (1 H, m), 6.34 (1 H, s)

제조예 32. 5-클로로-1-(3-플루오로-벤질)-4-히드록시-1H-피리딘-2-온의 합성Preparation Example 32 Synthesis of 5-chloro-1- (3-fluoro-benzyl) -4-hydroxy-1H-pyridin-2-one

Figure pat00038
Figure pat00038

4-(브로모메틸)-3-플루오로벤조니트릴을 대신하여 3-플루오로벤질 브로마이드를 이용하여 제조예 20 과 같은 방법으로 목적화합물을 얻었다.
Using the 3-fluorobenzyl bromide instead of 4- (bromomethyl) -3-fluorobenzonitrile to obtain the target compound in the same manner as in Preparation Example 20.

1H(400MHz, CDCl3) 7.34-7.28(1H,m), 7.10-7.01(4H,m), 5.88(1H,s), 4.96(2H,s)
 1 H (400 MHz, CDCl 3 ) 7.34-7.28 (1 H, m), 7.10-7.01 (4 H, m), 5.88 (1 H, s), 4.96 (2H, s)

제조예 33. 3-(5-클로로-4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴의 합성Preparation Example 33 Synthesis of 3- (5-chloro-4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile

Figure pat00039
Figure pat00039

4-(브로모메틸)-3-플루오로벤조니트릴을 대신하여 3-(브로모메틸)벤조니트릴을 이용하여 제조예 20 과 같은 방법으로 목적화합물을 얻었다.
The target compound was obtained in the same manner as in Preparation Example 20, using 3- (bromomethyl) benzonitrile instead of 4- (bromomethyl) -3-fluorobenzonitrile.

1H(400MHz, CDCl3) 7.34-7.28(1H,m), 7.10-7.01(4H,m), 5.92(1H,s), 4.96(2H,s) 1 H (400 MHz, CDCl 3 ) 7.34-7.28 (1H, m), 7.10-7.01 (4H, m), 5.92 (1H, s), 4.96 (2H, s)

제조예 34. 5-클로로-4-히드록시-1-(4-메틸설파닐-벤질)-1H-피리딘-2-온의 합성Preparation 34. Synthesis of 5-chloro-4-hydroxy-1- (4-methylsulfanyl-benzyl) -1H-pyridin-2-one

Figure pat00040
Figure pat00040

4-(브로모메틸)-3-플루오로벤조니트릴을 대신하여 4-(메틸티오)벤질 브로마이드를 이용하여 제조예 20 과 같은 방법으로 목적화합물을 얻었다.
Using the 4- (methylthio) benzyl bromide in place of 4- (bromomethyl) -3-fluorobenzonitrile, the target compound was obtained in the same manner as in Preparation Example 20.

1H(400MHz, CDCl3) 7.9(1H,s), 7.20-7.28(2H,m), 7.18-7.05(2H,m), 5.99(1H,s), 4.98(2H,s)
 1 H (400 MHz, CDCl 3 ) 7.9 (1H, s), 7.20-7.28 (2H, m), 7.18-7.05 (2H, m), 5.99 (1H, s), 4.98 (2H, s)

제조예 35. 5-클로로-1-(2-플루오로-벤질)-4-히드록시-1H-피리딘-2-온의 합성Preparation 35. Synthesis of 5-chloro-1- (2-fluoro-benzyl) -4-hydroxy-1H-pyridin-2-one

Figure pat00041
Figure pat00041

4-(브로모메틸)-3-플루오로벤조니트릴을 대신하여 2-플루오로벤질 브로마이드를 이용하여 제조예 20 과 같은 방법으로 목적화합물을 얻었다.
The target compound was obtained in the same manner as in Preparation Example 20 using 2-fluorobenzyl bromide instead of 4- (bromomethyl) -3-fluorobenzonitrile.

1H(400MHz, CDCl3) 7.28-7.26(3H,m), 7.17-7.08(2H,m), 5.98(1H,s), 5.01(2H,s)
 1 H (400 MHz, CDCl 3 ) 7.28-7.26 (3H, m), 7.17-7.08 (2H, m), 5.98 (1H, s), 5.01 (2H, s)

제조예 36. 5-클로로-1-[2-(4-플루오로-페닐)-에틸]-4-히드록시-1H-피리딘-2-온의 합성Preparation 36. Synthesis of 5-chloro-1- [2- (4-fluoro-phenyl) -ethyl] -4-hydroxy-1H-pyridin-2-one

Figure pat00042
Figure pat00042

4-(브로모메틸)-3-플루오로벤조니트릴을 대신하여 4-플루오로펜에틸 브로마이드를 이용하여 제조예 20 과 같은 방법으로 목적화합물을 얻었다.
The target compound was obtained in the same manner as in Preparation Example 20 using 4-fluorophenethyl bromide instead of 4- (bromomethyl) -3-fluorobenzonitrile.

1H(400MHz, CDCl3) 7.18-7.13(2H,m), 7.04-7.01(2H,m), 6.98(1H,s), 5.98(1H,s), 3.99-3.78(2H,m), 3.03-3..00(2H,m)
 1 H (400 MHz, CDCl 3 ) 7.18-7.13 (2H, m), 7.04-7.01 (2H, m), 6.98 (1H, s), 5.98 (1H, s), 3.99-3.78 (2H, m), 3.03 -3..00 (2H, m)

제조예 37. 4-(1-브로모-에틸)-벤조니트릴의 합성Preparation Example 37 Synthesis of 4- (1-bromo-ethyl) -benzonitrile

Figure pat00043
Figure pat00043

대기하의 500ml 플라스크에 2-아세틸벤조니트릴을 넣고 메탄올에 용해 후 교반하여 용해시킨 후 0℃ 에서 소디움 보로하이드라이드 2.6g 을 넣고 상온에서 24시간 교반 후 트리페닐 포스핀 10g 과 카보테트라브로마이드 11g 을 넣고 상온에서 24시간 교반한다.2-acetylbenzonitrile was added to a 500 ml flask under air, dissolved in methanol, and dissolved. Stir at room temperature for 24 hours.

반응 혼합물에 에틸 아세테이트 500ml을 넣고 추출하여 유기층을 취한 후 1N-HCl 수용액 20ml 로 씻어 준 뒤 1N-NaOH 수용액 20ml 로 씻은 후 무수황산마그네슘으로 건조하고 감압건조 한 후 얻어진 잔사를 실리카 컬럼으로 정제, 분리하여 목적화합물을 얻었다.
500 ml of ethyl acetate was added to the reaction mixture, followed by extraction. The organic layer was washed with 20 ml of 1N-HCl aqueous solution, and then with 20 ml of 1N-NaOH aqueous solution. To obtain the target compound.

1H NMR (400MHz, CDCl3) : 7.67 (2H, d), 7.54 (2H, d), 5.18 (1H, q), 2.06 (3H, d) 1 H NMR (400 MHz, CDCl 3 ): 7.67 (2H, d), 7.54 (2H, d), 5.18 (1H, q), 2.06 (3H, d)

제조예 38. Preparation Example 38.

Figure pat00044
Figure pat00044

4-(브로모메틸)-3-플루오로벤조니트릴을 대신하여 4-(1-브로모-에틸)-벤조니트릴을 이용하여 제조예 20 과 같은 방법으로 목적화합물을 얻었다.
The target compound was obtained in the same manner as in Preparation Example 20 using 4- (1-bromo-ethyl) -benzonitrile in place of 4- (bromomethyl) -3-fluorobenzonitrile.

1H NMR (400MHz, CDCl3) : 7.73 (2H, d), 7.45 (2H, d), 7.21 (1H, s), 6.37 (1H, m), 6.07 (1H, s), 1.83 (3H, d)
 1 H NMR (400 MHz, CDCl 3 ): 7.73 (2H, d), 7.45 (2H, d), 7.21 (1H, s), 6.37 (1H, m), 6.07 (1H, s), 1.83 (3H, d )

실시예 1 Example 1

4-{5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-티옥소-2H-피리딘-1-일}-2-플루오로-벤조니트릴의 합성.
4- {5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-thioxo-2H-pyridin-1-yl} -2 Synthesis of -fluoro-benzonitrile.

질소대기하의 100ml 플라스크에 5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1H-피리딘-2-티온 1 g과 N,N-디메틸포름아미드 50 ml를 넣고 교반하여 용해 시키고 0℃에서 소디움 하이드라이드 240 mg을 천천히 적가하여 1시간 이상 교반한 후 2,4-디플루오로벤조니트릴 465 mg을 넣고 12시간 이상 가열환류한다. 이후 0℃에서 반응 종결 화합물에 증류수 100 mL를 천천히 가하고 초산에칠 100 mL로 추출한 다음 brine 100 ml로 씻어 준 후 무수황산마그네슘으로 건조하고 농축 후 실리카 컬럼 크로마토그래피로 분리하여 목적 화합물을 얻었다.
1 g of 5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1H-pyridine-2-thione and N, in a 100 ml flask under nitrogen atmosphere, Add 50 ml of N-dimethylformamide, dissolve it, dissolve it, slowly add dropwise sodium hydride 240 mg at 0 ° C, stir for 1 hour or more, add 465 mg of 2,4-difluorobenzonitrile and heat reflux for 12 hours or more. . Thereafter, 100 mL of distilled water was slowly added to the reaction terminating compound at 0 ° C, extracted with ethyl acetate, 100 mL, washed with 100 mL of brine, dried over anhydrous magnesium sulfate, concentrated, and separated by silica column chromatography to obtain a target compound.

1H NMR (400MHz, CDCl3) : 8.22(2H, s), 7.81-7.86(1H, m), 7.59(1H, s), 7.44-7.47(1H, m), 7.31-7.34(1H, m), 7.25(1H, s), 4.71-4.81(1H, m), 3.81-4.15(4H, m), 2.48-2.53(2H, m), 1.94-2.09(4H, m), 1.21-1.25(3H, m).
 1 H NMR (400 MHz, CDCl 3 ): 8.22 (2H, s), 7.81-7.86 (1H, m), 7.59 (1H, s), 7.44-7.47 (1H, m), 7.31-7.34 (1H, m) , 7.25 (1H, s), 4.71-4.81 (1H, m), 3.81-4.15 (4H, m), 2.48-2.53 (2H, m), 1.94-2.09 (4H, m), 1.21-1.25 (3H, m).

실시예 2Example 2

4-[5-클로로-1-(4-시아노-3-플루오로-페닐)-2-티옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르의 합성.
4- [5-Chloro-1- (4-cyano-3-fluoro-phenyl) -2-thioxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxyl Synthesis of Lic Acid tert-Butyl Ester.

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1H-피리딘-2-티온을 대신하여 4-(5-클로로-2-티옥소-1,2-디히드로-피리딘-4-일옥시)-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르를 이용하여 실시예 1과 같은 방법으로 목적화합물을 얻었다.
5- (5-chloro-2 on behalf of 5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1H-pyridine-2-thione The target compound was obtained in the same manner as in Example 1 using -thioxo-1,2-dihydro-pyridin-4-yloxy) -piperidine-1-carboxylic acid tert-butyl ester.

1H NMR (400MHz, CDCl3) : 7.81-7.86(1H, m), 7.59(1H, s), 7.35-7.41(1H, m), 7.31-7.34(1H, m), 7.25(1H, s), 4.71-4.81(1H, m), 3.51-3.64 (4H, m), 1.94-2.09(4H, m), 1.66(9H, s).
 1 H NMR (400 MHz, CDCl 3 ): 7.81-7.86 (1H, m), 7.59 (1H, s), 7.35-7.41 (1H, m), 7.31-7.34 (1H, m), 7.25 (1H, s) , 4.71-4.81 (1H, m), 3.51-3.64 (4H, m), 1.94-2.09 (4H, m), 1.66 (9H, s).

실시예 3Example 3

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-메탄설포닐-페닐)-1H-피리딘-2-티온의 합성.
5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-methanesulfonyl-phenyl) -1H-pyridine-2- Synthesis of thion.

2,4-디플루오로벤조니트릴을 대신하여 1-플루오로-4-(메틸설포닐)벤젠을 이용하여 실시예 1과 같은 방법으로 목적화합물을 얻었다.
The target compound was obtained in the same manner as in Example 1 using 1-fluoro-4- (methylsulfonyl) benzene in place of 2,4-difluorobenzonitrile.

1H NMR (400MHz, CDCl3) : 8.22(2H, s), 8.15(2H, d), 7.63(1H, s), 7.61(2H, d), 7.29(1H, s), 4.71-4.81(1H, m), 3.81-4.15(4H, m), 2.48-2.53(2H, m), 1.94-2.09(4H, m), 1.21-1.25(3H, m).
 1 H NMR (400 MHz, CDCl 3 ): 8.22 (2H, s), 8.15 (2H, d), 7.63 (1H, s), 7.61 (2H, d), 7.29 (1H, s), 4.71-4.81 (1H m), 3.81-4.15 (4H, m), 2.48-2.53 (2H, m), 1.94-2.09 (4H, m), 1.21-1.25 (3H, m).

실시예 4Example 4

4-[5-클로로-1-(4-메탄설포닐-페닐)-2-티옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르의 합성.
4- [5-Chloro-1- (4-methanesulfonyl-phenyl) -2-thioxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert- Synthesis of Butyl Ester.

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1H-피리딘-2-티온을 대신하여 4-(5-클로로-2-티옥소-1,2-디히드로-피리딘-4-일옥시)-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르를 이용하여 실시예 3과 같은 방법으로 목적화합물을 얻었다.
5- (5-chloro-2 on behalf of 5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1H-pyridine-2-thione The target compound was obtained in the same manner as in Example 3 using -thioxo-1,2-dihydro-pyridin-4-yloxy) -piperidine-1-carboxylic acid tert-butyl ester.

1H NMR (400MHz, CDCl3) : 8.13(2H, d), 7.61(1H, s), 7.59(2H, d), 7.25(1H, s), 4.71-4.81(1H, m), 3.51-3.64 (4H, m), 3.15(3H, s), 1.94-2.09(4H, m), 1.66(9H, s).
 1 H NMR (400 MHz, CDCl 3 ): 8.13 (2H, d), 7.61 (1H, s), 7.59 (2H, d), 7.25 (1H, s), 4.71-4.81 (1H, m), 3.51-3.64 (4H, m), 3.15 (3H, s), 1.94-2.09 (4H, m), 1.66 (9H, s).

실시예 5Example 5

4-(1-tert-부톡시카보닐-피페리딘-4-일옥시)-5-클로로-2-티옥소-3',4',5',6'-테트라히드로-2H,2'H-[1,4']바이피리디닐-1'-카복실릭 에시드 tert-부틸 에스테르의 합성.
4- (1-tert-butoxycarbonyl-piperidin-4-yloxy) -5-chloro-2-thioxo-3 ', 4', 5 ', 6'-tetrahydro-2H, 2' Synthesis of H- [1,4 '] bipyridinyl-1'-carboxylic acid tert-butyl ester.

질소대기하의 100ml 플라스크에 4-(5-클로로-2-티옥소-1,2-디히드로-피리딘-4-일옥시)-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르 1 g과 N,N-디메틸포름아미드 50 mL를 넣고 교반하여 용해 시키고 0℃에서 소디움 하이드라이드 240 mg을 천천히 적가하여 1시간 이상 교반한 후 t-부틸-4-히드록시-1-피페리딘카복실레이트 650 mg을 넣고 12시간 이상 가열환류한다. 이후 0℃에서 반응 종결 화합물에 증류수 100 mL를 천천히 가하고 초산에칠 100 mL로 추출한 다음 brine 100 ml로 씻어 준 후 무수황산마그네슘으로 건조하고 농축 후 실리카 컬럼 크로마토그래피로 분리하여 목적 화합물을 얻었다.
1 g of 4- (5-chloro-2-thioxo-1,2-dihydro-pyridin-4-yloxy) -piperidine-1-carboxylic acid tert-butyl ester in a 100 ml flask under nitrogen atmosphere and N 50 mL of N-dimethylformamide was added to the mixture to dissolve it, and 240 mg of sodium hydride was slowly added dropwise at 0 ° C., followed by stirring for at least 1 hour, followed by 650 mg of t-butyl-4-hydroxy-1-piperidinecarboxylate. Add and reflux at least 12 hours. Thereafter, 100 mL of distilled water was slowly added to the reaction terminating compound at 0 ° C, extracted with ethyl acetate, 100 mL, washed with 100 mL of brine, dried over anhydrous magnesium sulfate, concentrated, and separated by silica column chromatography to obtain a target compound.

1H NMR (400MHz, CDCl3) : 8.99(1H, m), 7.24(1H, s), 5.15-5.23(1H, m), 4.59-4.67(1H, m), 3.21-3.89 (8H, m), 1.65-2.11(8H, m), 1.49(18H, s).
 1 H NMR (400 MHz, CDCl 3 ): 8.99 (1 H, m), 7.24 (1 H, s), 5.15-5.23 (1 H, m), 4.59-4.67 (1 H, m), 3.21-3.89 (8 H, m) , 1.65-2.11 (8H, m), 1.49 (18H, s).

실시예 6Example 6

4-[1-(4-메탄설포닐-페닐)-2-티옥소-1,2-디히드로-피리미딘-4-일아미노]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르의 합성.
4- [1- (4-Methanesulfonyl-phenyl) -2-thioxo-1,2-dihydro-pyrimidin-4-ylamino] -piperidine-1-carboxylic acid tert-butyl ester of synthesis.

4-(5-클로로-2-티옥소-1,2-디히드로-피리딘-4-일옥시)-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르를 대신하여 4-(2-티옥소-1,2-디히드로-피리미딘-4-일아미노)-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르를 이용하여 실시예 4와 같은 방법으로 목적 화합물을 얻었다.
4- (2-Tioxo on behalf of 4- (5-chloro-2-thioxo-1,2-dihydro-pyridin-4-yloxy) -piperidine-1-carboxylic acid tert-butyl ester The target compound was obtained in the same manner as in Example 4 using -1,2-dihydro-pyrimidin-4-ylamino) -piperidine-1-carboxylic acid tert-butyl ester.

1H NMR (400MHz, CDCl3) : 8.18(1H, d), 7.87-7.93(4H, m), 7.24(1H, d), 5.01-5.08(1H, m), 3.53-3.78 (4H, m), 3.16(3H, s), 1.92-2.05(4H, m), 1.63(9H, s).
 1 H NMR (400 MHz, CDCl 3 ): 8.18 (1H, d), 7.87-7.93 (4H, m), 7.24 (1H, d), 5.01-5.08 (1H, m), 3.53-3.78 (4H, m) , 3.16 (3H, s), 1.92-2.05 (4H, m), 1.63 (9H, s).

실시예 7Example 7

3-브로모-5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-메탄설포닐-페닐)-1H-피리딘-2-티온의 합성.
3-Bromo-5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-methanesulfonyl-phenyl) -1H Synthesis of pyridine-2-thione.

질소대기하의 50ml 플라스크에 5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-메탄설포닐-페닐)-1H-피리딘-2-티온 100 mg과 MC 20 ml를 교반하여 용해 시키고 상온에서 N-브로모숙신이미드 0.03 mL를 넣고 가열환류한다. 이후 반응 종결 화합물에 증류수 20 mL를 가하고 초산에칠 20 mL로 추출한 다음 포화 소디움 바이카보네이트 수용액을 이용하여 초산에칠 20 mL로 유기층으로 추출하여 무수황산마그네슘으로 건조하고 농축 후 실리카 컬럼 크로마토그래피로 분리하여 목적 화합물을 얻었다.
In a 50 ml flask under nitrogen atmosphere, 5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-methanesulfonyl-phenyl)- Dissolve by stirring 100 mg of 1H-pyridine-2-thione and 20 ml of MC, add 0.03 mL of N-bromosuccinimide at room temperature, and reflux it. Then, 20 mL of distilled water was added to the reaction terminating compound, extracted with 20 mL of ethyl acetate, extracted with 20 mL of ethyl acetate using an aqueous saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, concentrated, and separated by silica column chromatography. To obtain the target compound.

1H NMR (400MHz, CDCl3) : 8.22(2H, s), 8.81-8.13(2H, d), 7.64-7.69(2H, d), 7.51(1H, s), 4.91-4.99(1H, m), 3.48-4.49(4H, m), 3.15(3H, s), 2.48-2.53(2H, m), 1.94-2.19(4H, m), 1.21-1.25(3H, m).
 1 H NMR (400 MHz, CDCl 3 ): 8.22 (2H, s), 8.81-8.13 (2H, d), 7.64-7.69 (2H, d), 7.51 (1H, s), 4.91-4.99 (1H, m) , 3.48-4.49 (4H, m), 3.15 (3H, s), 2.48-2.53 (2H, m), 1.94-2.19 (4H, m), 1.21-1.25 (3H, m).

실시예 8Example 8

5-클로로-5'-클로로메틸-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-[1,2']바이피리디닐-2-티온의 합성.
5-Chloro-5'-chloromethyl-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy]-[1,2 '] bipyridinyl-2- Synthesis of thion.

2,4-디플루오로벤조니트릴을 대신하여 2-클로로-5-(클로로메틸)피리딘을 이용하여 실시예 1과 같은 방법으로 목적화합물을 얻었다.
The target compound was obtained in the same manner as in Example 1 using 2-chloro-5- (chloromethyl) pyridine instead of 2,4-difluorobenzonitrile.

1H NMR (400MHz, CDCl3) : 8.51(1H, s), 8.21(2H, s), 8.02(1H, s), 7.75-7.78(1H, d), 7.31-7.34(1H, d), 7.25(1H, s), 5.36(2H, s), 4.71-4.81(1H, m), 3.81-4.15(4H, m), 2.48-2.53(2H, m), 1.94-2.09(4H, m), 1.21-1.25(3H, m).
 1 H NMR (400 MHz, CDCl 3 ): 8.51 (1H, s), 8.21 (2H, s), 8.02 (1H, s), 7.75-7.78 (1H, d), 7.31-7.34 (1H, d), 7.25 (1H, s), 5.36 (2H, s), 4.71-4.81 (1H, m), 3.81-4.15 (4H, m), 2.48-2.53 (2H, m), 1.94-2.09 (4H, m), 1.21 -1.25 (3H, m).

실시예 9Example 9

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1'-메탄설포닐-1',2',3',4',5',6'-헥사히드로-[1,4']바이피리디닐-2-티온의 합성.
5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1'-methanesulfonyl-1 ', 2', 3 ', 4' Synthesis of, 5 ', 6'-hexahydro- [1,4'] bipyridinyl-2-thione.

2,4-디플루오로벤조니트릴을 대신하여 메탄설포닉 에시드 1-메탄설포닐-피페리딘-4-일 에스테르를 이용하여 실시예 1과 같은 방법으로 목적화합물을 얻었다.
The target compound was obtained in the same manner as in Example 1 using methanesulphonic acid 1-methanesulfonyl-piperidin-4-yl ester in place of 2,4-difluorobenzonitrile.

1H NMR (400MHz, CDCl3) : 8.22(2H, s), 7.99(1H, s), 7.26(1H, s), 5.17-5.24(1H, m), 4.71-4.81(1H, m), 3.81-4.15(4H, m), 3.21-3.59(4H, m), 2.83(3H, s), 2.48-2.53(2H, m), 1.94-2.18(4H, m), 1.86-1.98(4H, m), 1.21-1.25(3H, m).
 1 H NMR (400 MHz, CDCl 3 ): 8.22 (2H, s), 7.99 (1H, s), 7.26 (1H, s), 5.17-5.24 (1H, m), 4.71-4.81 (1H, m), 3.81 -4.15 (4H, m), 3.21-3.59 (4H, m), 2.83 (3H, s), 2.48-2.53 (2H, m), 1.94-2.18 (4H, m), 1.86-1.98 (4H, m) , 1.21-1.25 (3H, m).

실시예 10Example 10

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-티옥소-2H-[1,2']바이피리디닐-5'-카보니트릴의 합성.
5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-thioxo-2H- [1,2 '] bipyridinyl-5 Synthesis of '-carbonitrile.

2,4-디플루오로벤조니트릴을 대신하여 6-클로로니코티노니트릴을 이용하여 실시예 1과 같은 방법으로 목적화합물을 얻었다.
6-chloronicotinonitrile was used in place of 2,4-difluorobenzonitrile to obtain the target compound in the same manner as in Example 1.

1H NMR (400MHz, CDCl3) : 8.82(1H, s), 8.37-8.39(1H, d), 8.27(1H, s), 8.22(2H, s), 8.08-8.11(1H, d), 7.26(1H, s), 4.71-4.81(1H, m), 3.81-4.15(4H, m), 2.48-2.53(2H, m), 1.94-2.09(4H, m), 1.21-1.25(3H, m).
 1 H NMR (400 MHz, CDCl 3 ): 8.82 (1H, s), 8.37-8.39 (1H, d), 8.27 (1H, s), 8.22 (2H, s), 8.08-8.11 (1H, d), 7.26 (1H, s), 4.71-4.81 (1H, m), 3.81-4.15 (4H, m), 2.48-2.53 (2H, m), 1.94-2.09 (4H, m), 1.21-1.25 (3H, m) .

실시예 11Example 11

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-5'-메탄설포닐-[1,2']바이피리디닐-2-티온의 합성.
5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -5'-methanesulfonyl- [1,2 '] bipyridinyl-2 -Synthesis of thions.

2,4-디플루오로벤조니트릴을 대신하여 2-브로모-5-메탄설포닐-피리딘을 이용하여 실시예 1과 같은 방법으로 목적화합물을 얻었다.
The desired compound was obtained in the same manner as in Example 1 using 2-bromo-5-methanesulfonyl-pyridine instead of 2,4-difluorobenzonitrile.

1H NMR (400MHz, CDCl3) : 9.07(1H, s), 8.33-8.41(2H, m), 8.26(1H, s), 8.21(2H, s), 7.26(1H, s), 4.71-4.81(1H, m), 3.81-4.15(4H, m), 2.48-2.53(2H, m), 1.94-2.09(4H, m), 1.21-1.25(3H, m).
 1 H NMR (400 MHz, CDCl 3 ): 9.07 (1H, s), 8.33-8.41 (2H, m), 8.26 (1H, s), 8.21 (2H, s), 7.26 (1H, s), 4.71-4.81 (1H, m), 3.81-4.15 (4H, m), 2.48-2.53 (2H, m), 1.94-2.09 (4H, m), 1.21-1.25 (3H, m).

실시예 12Example 12

3-{4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-벤조니트릴의 합성
Synthesis of 3- {4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -benzonitrile

질소 대기하의 50 mL 플라스크에 3-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴473 mg 과 N,N-디메틸포름아미드 30ml를 넣고 교반하여 용해 시키고 1-(5-에틸-피리미딘-2-일)-피페리딘-4-올 290 mg 과 트리페닐포스핀 550 mg 과 디이소프로필 아조디카복실레이트 0.4 mL 를 넣고 상온에서 10시간 이상 교반한다. 반응 혼합물을 에틸 아세테이트 100 mL에 녹이고 증류수 100 mL로 2회 씻어준 후 유기층을 무수황산마그네슘으로 건조하고 감압건조 하고 감압건조 한 후 얻어진 잔사를 실리카 컬럼으로 정제, 분리하여 목적화합물을 얻었다.
Into a 50 mL flask under a nitrogen atmosphere, 473 mg of 3- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile and 30 ml of N, N-dimethylformamide were dissolved by stirring and dissolved. 290 mg of (5-ethyl-pyrimidin-2-yl) -piperidin-4-ol, 550 mg of triphenylphosphine and 0.4 mL of diisopropyl azodicarboxylate are added and stirred at room temperature for at least 10 hours. The reaction mixture was dissolved in 100 mL of ethyl acetate, washed twice with 100 mL of distilled water, and then the organic layer was dried over anhydrous magnesium sulfate, dried under reduced pressure, and dried under reduced pressure, and the obtained residue was purified by silica column and separated to obtain a target compound.

1H(400MHz, CDCl3) 8.20(2H,s), 7.62-7.56(3H,m), 7.49-7.45(1H,m), 7.17-7.15(1H,d), 6.06-5.95(2H,m), 6.00-5.95(2H,m), 5.10(2H,s), 4.57-4.51(1H,m), 4.22-4.16(2H,m), 3.66-3.60(2H,m),2.50-2.46(2H,m), 2.10-2.03(2H,m), 1.86-1.78(2H,m), 1.23-1.19(3H,m)
 1 H (400 MHz, CDCl 3 ) 8.20 (2H, s), 7.62-7.56 (3H, m), 7.49-7.45 (1H, m), 7.17-7.15 (1H, d), 6.06-5.95 (2H, m) , 6.00-5.95 (2H, m), 5.10 (2H, s), 4.57-4.51 (1H, m), 4.22-4.16 (2H, m), 3.66-3.60 (2H, m), 2.50-2.46 (2H, m), 2.10-2.03 (2H, m), 1.86-1.78 (2H, m), 1.23-1.19 (3H, m)

실시예 13Example 13

3-{4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-티옥소-2H-피리딘-1-일메틸}-벤조니트릴의 합성
Synthesis of 3- {4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-thioxo-2H-pyridin-1-ylmethyl} -benzonitrile

질소대기하의 50mL 플라스크에 3-{4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-벤조니트릴 300 mg과 toluene 20 mL를 넣고 교반하여 용해 시키고 Lawesson`s reagent 160 mg을 넣은 후 12시간 이상 가열환류한다. 이후 반응 종결 혼합물에 증류수 100 mL와 초산에칠 100 ml을 넣고 추출하여 분리된 유기층을 brine 100 ml로 씻어 준 후 무수황산마그네슘으로 건조하고 농축 후 실리카 컬럼으로 정제, 분리하여 목적화합물을 얻었다.
In a 50 mL flask under nitrogen atmosphere, 3- {4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -Add 300 mg of benzonitrile and 20 mL of toluene, dissolve it, add 160 mg of Lawesson's reagent, and reflux it for at least 12 hours. Thereafter, 100 mL of distilled water and 100 ml of ethyl acetate were added to the reaction mixture, and the extracted organic layer was washed with 100 ml of brine, dried over anhydrous magnesium sulfate, concentrated, purified and separated by a silica column to obtain a target compound.

1H(400MHz, CDCl3) 8.20(2H,s), 7.63-7.61(2H,d), 7.57(1H,s), 7.51-7.49(2H,m), 7.28(1H,s), 6.38-6.35(1H,m), 5.83(2H,s), 4.66-4.65(1H,m), 4.24-4.19(2H,m), 3.63-3.58(2H,m), 2.52-2.46(2H,m), 2.07-2.06(2H,m), 1.84-1.78(2H,m), 1.28-1.19(3H,m)
 1 H (400 MHz, CDCl 3 ) 8.20 (2H, s), 7.63-7.61 (2H, d), 7.57 (1H, s), 7.51-7.49 (2H, m), 7.28 (1H, s), 6.38-6.35 (1H, m), 5.83 (2H, s), 4.66-4.65 (1H, m), 4.24-4.19 (2H, m), 3.63-3.58 (2H, m), 2.52-2.46 (2H, m), 2.07 -2.06 (2H, m), 1.84-1.78 (2H, m), 1.28-1.19 (3H, m)

실시예 14Example 14

4-[1-(3-시아노-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르의 합성
Synthesis of 4- [1- (3-cyano-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester

1-(5-에틸-피리미딘-2-일)-피페리딘-4-올을 대신하여 tert-부틸 4-히드록시-1-피페리딘카복실레이트를 이용하여 실시예 12 와 같은 방법으로 목적화합물을 얻었다.
In the same manner as in Example 12 using tert-butyl 4-hydroxy-1-piperidinecarboxylate in place of 1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-ol The desired compound was obtained.

1H(400MHz, CDCl3) 7.61-7.28(4H,m), 7.17-7.15(1H,m), 5.95-5.94(2H,m), 5.11(2H,s), 5.11(2H,s), 4.48-4.44(1H,m), 3.75-3.69(2H,m), 3.36-3.30(2H,m), 2.06-1.94(2H,m), 1.78-1.73(2H,m), 1.47(9H,s)
 1 H (400 MHz, CDCl 3 ) 7.61-7.28 (4H, m), 7.17-7.15 (1H, m), 5.95-5.94 (2H, m), 5.11 (2H, s), 5.11 (2H, s), 4.48 -4.44 (1H, m), 3.75-3.69 (2H, m), 3.36-3.30 (2H, m), 2.06-1.94 (2H, m), 1.78-1.73 (2H, m), 1.47 (9H, s)

실시예 15Example 15

4-[1-(3-시아노-벤질)-2-티옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르의 합성
Synthesis of 4- [1- (3-cyano-benzyl) -2-thioxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester

3-{4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-벤조니트릴을 대신하여 4-[1-(3-시아노-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르를 이용하여 실시예 13 과 같은 방법으로 목적화합물을 얻었다.
3- {4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -benzonitrile 4- [1- (3-cyano-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester In the same manner as in Example 13, the target compound was obtained.

1H(400MHz, CDCl3) 7.60-7.45(5H,m), 7.22-7.21(2H,d), 6.35-6.32(1H,m), 5.80(2H,s), 4.57-4.53(1H,m), 3.73-3.70(2H,m), 3.33-3.27(2H,m), 2.04-1.95(2H,m), 1.76-1.72(2H,m), 1.48(9H,m)
 1 H (400 MHz, CDCl 3 ) 7.60-7.45 (5H, m), 7.22-7.21 (2H, d), 6.35-6.32 (1H, m), 5.80 (2H, s), 4.57-4.53 (1H, m) , 3.73-3.70 (2H, m), 3.33-3.27 (2H, m), 2.04-1.95 (2H, m), 1.76-1.72 (2H, m), 1.48 (9H, m)

실시예 16Example 16

4-[1-(3-시아노-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시메틸]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르의 합성
Synthesis of 4- [1- (3-cyano-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxymethyl] -piperidine-1-carboxylic acid tert-butyl ester

1-(5-에틸-피리미딘-2-일)-피페리딘-4-올을 대신하여 tert-부틸 4-(히드록시메틸)-1-피페리딘카복실레이트를 이용하여 실시예 12 와 같은 방법으로 목적화합물을 얻었다.
Example 12 using tert-butyl 4- (hydroxymethyl) -1-piperidinecarboxylate in place of 1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-ol In the same manner to obtain the target compound.

1H(400MHz, CDCl3) 7.61-7.45(3H,m), 7.15-7.13(1H,d), 5.97-5.92(2H,m), 5.11(2H,s), 4.21-4.76(1H,m), 3.80-3.79(2H,d), 2.80-2.72(2H,m), 19.7-1.96(1H,m), 1.80-1.77(2H,m), 1.42(9H,s), 1.33-1.24(2H,m)
 1 H (400 MHz, CDCl 3 ) 7.61-7.45 (3H, m), 7.15-7.13 (1H, d), 5.97-5.92 (2H, m), 5.11 (2H, s), 4.21-4.76 (1H, m) , 3.80-3.79 (2H, d), 2.80-2.72 (2H, m), 19.7-1.96 (1H, m), 1.80-1.77 (2H, m), 1.42 (9H, s), 1.33-1.24 (2H, m)

실시예 17Example 17

4-[1-(3-시아노-벤질)-2-티옥소-1,2-디히드로-피리딘-4-일옥시메틸]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르의 합성
Synthesis of 4- [1- (3-cyano-benzyl) -2-thioxo-1,2-dihydro-pyridin-4-yloxymethyl] -piperidine-1-carboxylic acid tert-butyl ester

3-{4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-벤조니트릴을 대신하여 4-[1-(3-시아노-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시메틸]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르를 이용하여 실시예 13 과 같은 방법으로 목적화합물을 얻었다.
3- {4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -benzonitrile 4- [1- (3-Cyano-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxymethyl] -piperidine-1-carboxylic acid tert-butyl ester The target compound was obtained in the same manner as in Example 13.

1H(400MHz, CDCl3) 7.62-7.46(5H,m), 7.22(1H,d), 6.36-6.34(1H,m), 5.82(2H,s), 4.19-4.17(2H,m), 3.88(2H,d), 2.77-2.37(2H,m), 2.04-1.96(1H,m), 1.79-1.76(2H,m), 1.48(9H,s), 1.21-1.22(2H,m)
 1 H (400 MHz, CDCl 3 ) 7.62-7.46 (5H, m), 7.22 (1H, d), 6.36-6.34 (1H, m), 5.82 (2H, s), 4.19-4.17 (2H, m), 3.88 (2H, d), 2.77-2.37 (2H, m), 2.04-1.96 (1H, m), 1.79-1.76 (2H, m), 1.48 (9H, s), 1.21-1.22 (2H, m)

실시예 18Example 18

4-{4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-티옥소-2H-피리딘-1-일}-2-플루오로-벤조니트릴의 합성.
4- {4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-thioxo-2H-pyridin-1-yl} -2-fluoro- Synthesis of Benzonitrile.

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1H-피리딘-2-티온을 대신하여 4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1H-피리딘-2-티온을 이용하여 실시예 1과 같은 방법으로 목적화합물을 얻었다.
5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1H-pyridine-2-thione in place of 4- [1- (5- The target compound was obtained in the same manner as in Example 1 using ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1H-pyridine-2-thione.

1H NMR (400MHz, CDCl3) : 8.21(2H, s), 7.79-7.83(1H, m), 7.41-7.43(1H, d), 7.32-7.34(2H, m), 7.25(1H, s), 6.43-6.46(1H, d), 4.71-4.81(1H, m), 3.81-4.15(4H, m), 2.48-2.53(2H, m), 1.94-2.09(4H, m), 1.21-1.25(3H, m).
 1 H NMR (400 MHz, CDCl 3 ): 8.21 (2H, s), 7.79-7.83 (1H, m), 7.41-7.43 (1H, d), 7.32-7.34 (2H, m), 7.25 (1H, s) , 6.43-6.46 (1H, d), 4.71-4.81 (1H, m), 3.81-4.15 (4H, m), 2.48-2.53 (2H, m), 1.94-2.09 (4H, m), 1.21-1.25 ( 3H, m).

실시예 19Example 19

4-[1-(4-플루오로-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르의 합성
Synthesis of 4- [1- (4-fluoro-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester

질소 대기하의 50 mL 플라스크에 1-(4-플루오로-벤질)-4-히드록시-1H-피리딘-2-온 250 mg 과 N,N-디메틸포름아미드 30ml를 넣고 교반하여 용해 시키고 4-히드록시-1-피페리딘카복실레이트 230 mg 과 트리페닐포스핀 450 mg 과 디이소프로필 아조디카복실레이트 0.34 mL 를 넣고 상온에서 10시간 이상 교반한다. 반응 혼합물을 에틸 아세테이트 100 mL에 녹이고 증류수 100 mL로 2회 씻어준 후 유기층을 무수황산마그네슘으로 건조하고 감압건조 하고 감압건조 한 후 얻어진 잔사를 실리카 컬럼으로 정제, 분리하여 목적화합물을 얻었다.In a 50 mL flask under a nitrogen atmosphere, 250 mg of 1- (4-fluoro-benzyl) -4-hydroxy-1H-pyridin-2-one and 30 ml of N, N-dimethylformamide were added, stirred, and dissolved. 230 mg of oxy-1-piperidine carboxylate, 450 mg of triphenylphosphine and 0.34 mL of diisopropyl azodicarboxylate are added and stirred at room temperature for at least 10 hours. The reaction mixture was dissolved in 100 mL of ethyl acetate, washed twice with 100 mL of distilled water, and then the organic layer was dried over anhydrous magnesium sulfate, dried under reduced pressure, and dried under reduced pressure, and the obtained residue was purified by silica column and separated to obtain a target compound.

1H(400MHz, CDCl3) 7.31(2H,d) 7.15(1H,d), 7.06(2H,t), 5.94(1H,d) 5.90(1H,d), 5.06(2H,s), 4.46-4.42(1H,m), 3.72-3.69(2H,m), 3.35-3.28(2H,m), 1.97-1.93(2H,m), 1.93-1.75(2H,m), 1.32(9H,s)
 1 H (400 MHz, CDCl 3 ) 7.31 (2H, d) 7.15 (1H, d), 7.06 (2H, t), 5.94 (1H, d) 5.90 (1H, d), 5.06 (2H, s), 4.46- 4.42 (1H, m), 3.72-3.69 (2H, m), 3.35-3.28 (2H, m), 1.97-1.93 (2H, m), 1.93-1.75 (2H, m), 1.32 (9H, s)

실시예 20 Example 20

4-[1-(3-메톡시-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르의 합성
Synthesis of 4- [1- (3-methoxy-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester

1-(4-플루오로-벤질)-4-히드록시-1H-피리딘-2-온을 대신하여 4-히드록시-1-(3-메톡시-벤질)-1H-피리딘-2-온을 이용하여 실시예 19 와 같은 방법으로 목적화합물을 얻었다.
4-hydroxy-1- (3-methoxy-benzyl) -1H-pyridin-2-one is substituted for 1- (4-fluoro-benzyl) -4-hydroxy-1H-pyridin-2-one In the same manner as in Example 19, the target compound was obtained.

1H(400MHz, CDCl3) 7.28(1H,s), 7.14(1H,d), 6.87-6.83(3H,m), 5.94(1H,s), 5.88(1H,d), 5.07(2H,s), 4.46-4.42(1H,s), 3.80(3H,s), 3.75-3.65(2H,m), 3.35-3.29(2H,m), 1.98-1.94(2H,m), 1.95-1.94(2H,m), 1.50(9H,s)
 1 H (400 MHz, CDCl 3 ) 7.28 (1 H, s), 7.14 (1 H, d), 6.87-6.83 (3 H, m), 5.94 (1 H, s), 5.88 (1 H, d), 5.07 (2 H, s ), 4.46-4.42 (1H, s), 3.80 (3H, s), 3.75-3.65 (2H, m), 3.35-3.29 (2H, m), 1.98-1.94 (2H, m), 1.95-1.94 (2H , m), 1.50 (9H, s)

실시예 21Example 21

4-(4-{4-[1-(tert-뷰톡시카보닐)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-티아졸-2-일)-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르의 합성
4- (4- {4- [1- (tert-Butoxycarbonyl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -thiazol-2-yl Synthesis of) -piperidine-1-carboxylic acid tert-butyl ester

1-(4-플루오로-벤질)-4-히드록시-1H-피리딘-2-온을 대신하여 4-[4-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-티아졸-2-일]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르를 이용하여 실시예 19 와 같은 방법으로 목적화합물을 얻었다.
4- [4- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) instead of 1- (4-fluoro-benzyl) -4-hydroxy-1H-pyridin-2-one The target compound was obtained in the same manner as in Example 19 using -thiazol-2-yl] -piperidine-1-carboxylic acid tert-butyl ester.

1H(400MHz, CDCl3) 7.48(1Hd), 7.15(1H,s), 5.92-5.93(2H,m), 5.14(2H,s), 4.49-4.38(1H,m), 4.30-4.12(2H,m), 3.81-3.65(2H,m), 3.40-3.28(2H,m), 3.18-3.07(1H,m), 2.98-2.87(2H,m), 2.21-2.13(2H.m), 2.01-1.87(2H,m), 1.76-1.65(4H,m), 1.48(18H,s)
 1 H (400 MHz, CDCl 3 ) 7.48 (1 Hd), 7.15 (1 H, s), 5.92-5.93 (2H, m), 5.14 (2H, s), 4.49-4.38 (1H, m), 4.30-4.12 (2H , m), 3.81-3.65 (2H, m), 3.40-3.28 (2H, m), 3.18-3.07 (1H, m), 2.98-2.87 (2H, m), 2.21-2.13 (2H.m), 2.01 -1.87 (2H, m), 1.76-1.65 (4H, m), 1.48 (18H, s)

실시예 22Example 22

4-[1-(1-메탄설포닐-피페리딘-4-일메틸)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르의 합성
4- [1- (1-Methanesulfonyl-piperidin-4-ylmethyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid Synthesis of tert-butyl ester

1-(4-플루오로-벤질)-4-히드록시-1H-피리딘-2-온을 대신하여 4-히드록시-1-(1-메탄설포닐-피페리딘-4-일메틸)-1H-피리딘-2-온을 이용하여 실시예 19 와 같은 방법으로 목적화합물을 얻었다.
4-hydroxy-1- (1-methanesulfonyl-piperidin-4-ylmethyl)-in place of 1- (4-fluoro-benzyl) -4-hydroxy-1H-pyridin-2-one Using 1H-pyridin-2-one, the target compound was obtained in the same manner as in Example 19.

1H(400MHz, CDCl3) 7.28(1H,d), 5.88-5.87(2H,m), 4.44-4.42(1H,m), 3.84-3.87(2H,m) , 3.77-3.3.75(2H,d), 3.70-3.69(2H,m), 3.35-3.29(2H,m), 2.68(3H,s), 2.67-2.61(2H,m), 2.10-2.00(1H,m), 1.97-1.93(2H,m), 1.92-1.73(4H,m), 1.48(9H,s)
 1 H (400 MHz, CDCl 3 ) 7.28 (1H, d), 5.88-5.87 (2H, m), 4.44-4.42 (1H, m), 3.84-3.87 (2H, m), 3.77-3.3.75 (2H, d), 3.70-3.69 (2H, m), 3.35-3.29 (2H, m), 2.68 (3H, s), 2.67-2.61 (2H, m), 2.10-2.00 (1H, m), 1.97-1.93 ( 2H, m), 1.92-1.73 (4H, m), 1.48 (9H, s)

실시예 23Example 23

4-[1-(4-플루오로-벤질)-2-티옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르의 합성
Synthesis of 4- [1- (4-fluoro-benzyl) -2-thioxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester

3-{4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-벤조니트릴을 대신하여 4-[1-(4-플루오로-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르를 이용하여 실시예 13 과 같은 방법으로 목적화합물을 얻었다.
3- {4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -benzonitrile 4- [1- (4-Fluoro-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester In the same manner as in Example 13, the target compound was obtained.

1H(400MHz, CDCl3) 7.47-7.45(1H,d), 7.37-7.33(2H,m), 7.24-7.23(1H,d), 7.08-7.04(2H,m), 6.30-6.27(1H,m), 5.76(2H,,s), 4.57-4.51(1H,m), 3.72-3.71(2H,m), 3.32-3.26(2H,m), 1.99-1.94(2H,m), 1.75-1.71(2H,m), 1.46(9H,s)
 1 H (400 MHz, CDCl 3 ) 7.47-7.45 (1H, d), 7.37-7.33 (2H, m), 7.24-7.23 (1H, d), 7.08-7.04 (2H, m), 6.30-6.27 (1H, m), 5.76 (2H ,, s), 4.57-4.51 (1H, m), 3.72-3.71 (2H, m), 3.32-3.26 (2H, m), 1.99-1.94 (2H, m), 1.75-1.71 (2H, m), 1.46 (9H, s)

실시예 24Example 24

4-[1-(3-메톡시-벤질)-2-티옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르의 합성
Synthesis of 4- [1- (3-methoxy-benzyl) -2-thioxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester

3-{4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-벤조니트릴을 대신하여 4-[1-(3-메톡시-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르를 이용하여 실시예 13 과 같은 방법으로 목적화합물을 얻었다.
3- {4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -benzonitrile 4- [1- (3-methoxy-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester In the same manner as in Example 13, the target compound was obtained.

1H(400MHz, CDCl3) 7.45-7.44(1H,d), 7.31-7.27(1H,m), 7.24(1H,d), 6.90-6.86(3H,m), 6.28-6.25(1H,m), 5.75(2H,s), 4.57-4.52(1H,m), 3.81(3H,s), 3.74-3.71(2H,m), 3.32-3.26(2H,m), 1.99-1.94(2H,m), 1.75-1.72(2H,m), 1.47(9H,s)
 1 H (400 MHz, CDCl 3 ) 7.45-7.44 (1H, d), 7.31-7.27 (1H, m), 7.24 (1H, d), 6.90-6.86 (3H, m), 6.28-6.25 (1H, m) , 5.75 (2H, s), 4.57-4.52 (1H, m), 3.81 (3H, s), 3.74-3.71 (2H, m), 3.32-3.26 (2H, m), 1.99-1.94 (2H, m) , 1.75-1.72 (2H, m), 1.47 (9H, s)

실시예 25Example 25

4-[1-(4-메톡시카보닐-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르의 합성
Synthesis of 4- [1- (4-methoxycarbonyl-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester

1-(4-플루오로-벤질)-4-히드록시-1H-피리딘-2-온을 대신하여 4-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조익 에시드 메틸 에스테르를 이용하여 실시예 19 와 같은 방법으로 목적화합물을 얻었다.
4- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzoic instead of 1- (4-fluoro-benzyl) -4-hydroxy-1H-pyridin-2-one The target compound was obtained in the same manner as in Example 19 using an acid methyl ester.

1H(400MHz, CDCl3) 8.03(2H,d), 7.35(2H,d), 7.15(1H,d), 5,95(1H,s), 5.91(1H,d), 1.15, 2H,s), 4.5-4.4(1H,m), 3.92(3H,s), 3.76-3.66(2H,M), 3.38-3.26(2H,m), 2.23-1.92(2H,m), 1.81-1.69(2H,m), 1.48(9H,s)
 1 H (400 MHz, CDCl 3 ) 8.03 (2H, d), 7.35 (2H, d), 7.15 (1H, d), 5,95 (1H, s), 5.91 (1H, d), 1.15, 2H, s ), 4.5-4.4 (1H, m), 3.92 (3H, s), 3.76-3.66 (2H, M), 3.38-3.26 (2H, m), 2.23-1.92 (2H, m), 1.81-1.69 (2H) , m), 1.48 (9 H, s)

실시예 26Example 26

4-[1-(4-시아노-2-플루오로-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르의 합성
4- [1- (4-Cyano-2-fluoro-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl Synthesis of Ester

1-(4-플루오로-벤질)-4-히드록시-1H-피리딘-2-온을 대신하여 3-플루오로-4-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 이용하여 실시예 19 와 같은 방법으로 목적화합물을 얻었다.
3-fluoro-4- (4-hydroxy-2-oxo-2H-pyridin-1-yl in place of 1- (4-fluoro-benzyl) -4-hydroxy-1H-pyridin-2-one The desired compound was obtained in the same manner as in Example 19 using methyl) -benzonitrile.

1H(400MHz, CDCl3) 7.56(1H,t), 7.57-7.37(2H,m), 7.26-7.24(1H,d), 5.96-5.93(2H,m), 5.14(2H,s), 4.45-4.41(1H,m), 3.71-3.67(2H,m), 3.35-3.29(2H,m), 1.97-1.95(2H,m), 1.94-1.92(2H,m), 1.49(9H,s)
 1 H (400 MHz, CDCl 3 ) 7.56 (1H, t), 7.57-7.37 (2H, m), 7.26-7.24 (1H, d), 5.96-5.93 (2H, m), 5.14 (2H, s), 4.45 -4.41 (1H, m), 3.71-3.67 (2H, m), 3.35-3.29 (2H, m), 1.97-1.95 (2H, m), 1.94-1.92 (2H, m), 1.49 (9H, s)

실시예 27Example 27

4-{5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-3-플루오로-벤조니트릴의 합성
4- {5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -3 Synthesis of -fluoro-benzonitrile

3-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 대신하여 4-(5-클로로-4-히드록시-2-옥소-2H-피리딘-1-일메틸)-3-플루오로-벤조니트릴을 이용하여 실시예 12 와 같은 방법으로 목적화합물을 얻었다.
4- (5-chloro-4-hydroxy-2-oxo-2H-pyridin-1-yl in place of 3- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile The target compound was obtained in the same manner as in Example 12 using methyl) -3-fluoro-benzonitrile.

1H(400MHz, CDCl3) 8.32(2H,s), 7.61(1H,t), 7.49-7.41(3H,m), 6.00(1H,s), 5.14(2H,s), 4.70-4.68(1H,m), 4.-20-4.12(2H,m), 4.01-3.96(2H,m), 2.59-2.53(2H,m), 2.05-2.04(4H,m), 1.27-1.23(3H,m)
 1 H (400 MHz, CDCl 3 ) 8.32 (2H, s), 7.61 (1H, t), 7.49-7.41 (3H, m), 6.00 (1H, s), 5.14 (2H, s), 4.70-4.68 (1H , m), 4.-20-4.12 (2H, m), 4.01-3.96 (2H, m), 2.59-2.53 (2H, m), 2.05-2.04 (4H, m), 1.27-1.23 (3H, m) )

실시예 28Example 28

5-클로로-1-(6-클로로-피리딘-3-일메틸)-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1H-피리딘-2-온의 합성
5-Chloro-1- (6-chloro-pyridin-3-ylmethyl) -4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1 H-pyridine Synthesis of 2-one

3-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 대신하여 5-클로로-1-(6-클로로-피리딘-3-일메틸)-4-히드록시-1H-피리딘-2-온을 이용하여 실시예 12 와 같은 방법으로 목적화합물을 얻었다.
5-Chloro-1- (6-chloro-pyridin-3-ylmethyl) -4-hydroxy in place of 3- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile The target compound was obtained in the same manner as in Example 12 using -1H-pyridin-2-one.

1H(400MHz, CDCl3) 8.40-8.29(1H,d), 8.20(2H,s), 7.72-7-70(1H,m), 7.35(1H,s), 7.33(1H,s), 6.02(1H,s), 5.06(2H,s), 4.63-4.61(1H,m), 4.08-4.02(2H,m), 3.85-3.79(2H,m), 2.52-2.46(2H,m), 2.06-2.01(2H,m), 1.94-1.86(2H,m), 1.24-1.19(3H,m)
 1 H (400 MHz, CDCl 3 ) 8.40-8.29 (1 H, d), 8.20 (2 H, s), 7.72-7-70 (1 H, m), 7.35 (1 H, s), 7.33 (1 H, s), 6.02 (1H, s), 5.06 (2H, s), 4.63-4.61 (1H, m), 4.08-4.02 (2H, m), 3.85-3.79 (2H, m), 2.52-2.46 (2H, m), 2.06 -2.01 (2H, m), 1.94-1.86 (2H, m), 1.24-1.19 (3H, m)

실시예 29Example 29

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(3-트리플루오로메틸-벤질)-1H-피리딘-2-온의 합성
5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (3-trifluoromethyl-benzyl) -1H-pyridine-2 Synthesis of -one

3-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 대신하여 5-클로로-4-히드록시-1-(3-트리플루오로메틸-벤질)-1H-피리딘-2-온을 이용하여 실시예 12 와 같은 방법으로 목적화합물을 얻었다.
5-Chloro-4-hydroxy-1- (3-trifluoromethyl-benzyl) -1H in place of 3- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile Using pyridine-2-one, the target compound was obtained in the same manner as in Example 12.

1H(400MHz, CDCl3) 8.20(2H,s), 7.61-7.58(2H,m), 7.52-7.50(2H,m), 7.32(1H,s), 6.05(1H,s), 5.13(2H,s), 4.64-4.37(1H,m), 4.10-4.03(2H,m), 3.84-3.78(2H,m), 2.52-2.46(2H,m), 2.07-2.02(2H,m), 1.94-1.90(2H,m), 1.24-1.19(3H,m)
 1 H (400 MHz, CDCl 3 ) 8.20 (2H, s), 7.61-7.58 (2H, m), 7.52-7.50 (2H, m), 7.32 (1H, s), 6.05 (1H, s), 5.13 (2H , s), 4.64-4.37 (1H, m), 4.10-4.03 (2H, m), 3.84-3.78 (2H, m), 2.52-2.46 (2H, m), 2.07-2.02 (2H, m), 1.94 -1.90 (2H, m), 1.24-1.19 (3H, m)

실시예 30Example 30

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-트리플루오로메틸-벤질)-1H-피리딘-2-온의 합성
5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-trifluoromethyl-benzyl) -1H-pyridine-2 Synthesis of -one

3-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 대신하여 5-클로로-4-히드록시-1-(4-트리플루오로메틸-벤질)-1H-피리딘-2-온을 이용하여 실시예 12 와 같은 방법으로 목적화합물을 얻었다.
5-Chloro-4-hydroxy-1- (4-trifluoromethyl-benzyl) -1H in place of 3- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile Using pyridine-2-one, the target compound was obtained in the same manner as in Example 12.

1H(400MHz, CDCl3) 8.20(2H,s), 7.63(2H,d), 7.43(2H,d), 7.31(1H,s), 6.04(1H,s), 5.13(2H,s), 4.65-4.61(1H,m), 4.09-4.02(2H,m), 3.85-3.79(2H,m), 2.52-2.46(2H,m), 2.07-2.01(2H,m), 1.95-1.88(2H,m), 1.23-1.19(3H,m)
 1 H (400 MHz, CDCl 3 ) 8.20 (2H, s), 7.63 (2H, d), 7.43 (2H, d), 7.31 (1H, s), 6.04 (1H, s), 5.13 (2H, s), 4.65-4.61 (1H, m), 4.09-4.02 (2H, m), 3.85-3.79 (2H, m), 2.52-2.46 (2H, m), 2.07-2.01 (2H, m), 1.95-1.88 (2H , m), 1.23-1.19 (3H, m)

실시예 31Example 31

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-메톡시-벤질)-1H-피리딘-2-온의 합성
5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-methoxy-benzyl) -1H-pyridin-2-one Synthesis of

3-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 대신하여 5-클로로-4-히드록시-1-(4-메톡시-벤질)-1H-피리딘-2-온을 이용하여 실시예 12 와 같은 방법으로 목적화합물을 얻었다.
5-Chloro-4-hydroxy-1- (4-methoxy-benzyl) -1H-pyridine in place of 3- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile Using the 2-one, the target compound was obtained in the same manner as in Example 12.

1H(400MHz, CDCl3) 8.20(2H,s), 7.28-7.26(3H,m), 6.92(2H,d), 6.03(1H,s), 5.02(2H,s), 4.63-4.60(1H,m), 4.08-4.01(2H,m), 3.85-3.78(5H,m), 2.51-2.46(2H,m), 2.06-2.00(2H,m), 1.93-1.86(2H,m), 1.23-1.18(3H,m)
 1 H (400 MHz, CDCl 3 ) 8.20 (2H, s), 7.28-7.26 (3H, m), 6.92 (2H, d), 6.03 (1H, s), 5.02 (2H, s), 4.63-4.60 (1H , m), 4.08-4.01 (2H, m), 3.85-3.78 (5H, m), 2.51-2.46 (2H, m), 2.06-2.00 (2H, m), 1.93-1.86 (2H, m), 1.23 -1.18 (3H, m)

실시예 32Example 32

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(3-메톡시-벤질)-1H-피리딘-2-온의 합성
5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (3-methoxy-benzyl) -1H-pyridin-2-one Synthesis of

3-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 대신하여 5-클로로-4-히드록시-1-(3-메톡시-벤질)-1H-피리딘-2-온을 이용하여 실시예 12 와 같은 방법으로 목적화합물을 얻었다.
5-Chloro-4-hydroxy-1- (3-methoxy-benzyl) -1H-pyridine in place of 3- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile Using the 2-one, the target compound was obtained in the same manner as in Example 12.

1H(400MHz, CDCl3) 8.20(2H,s), 7.30-7.28(2H,m), 6.90-6.85(3H,m), 6.04(1H,s), 5.06(2H,s), 4.64-4.60(1H,m), 4.09-4.02(2H,m), 3.84-3.78(5H,m), 2.52-2.46(2H,m), 2.52-2.46(2H,m), 2.06-2.02(2H,m), 1.29-1.19(3H,m)
 1 H (400 MHz, CDCl 3 ) 8.20 (2H, s), 7.30-7.28 (2H, m), 6.90-6.85 (3H, m), 6.04 (1H, s), 5.06 (2H, s), 4.64-4.60 (1H, m), 4.09-4.02 (2H, m), 3.84-3.78 (5H, m), 2.52-2.46 (2H, m), 2.52-2.46 (2H, m), 2.06-2.02 (2H, m) , 1.29-1.19 (3H, m)

실시예 33Example 33

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(3-트리플루오로메톡시-벤질)-1H-피리딘-2-온의 합성
5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (3-trifluoromethoxy-benzyl) -1H-pyridine-2 Synthesis of -one

3-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 대신하여 5-클로로-4-히드록시-1-(3-트리플루오로메톡시-벤질)-1H-피리딘-2-온을 이용하여 실시예 12 와 같은 방법으로 목적화합물을 얻었다.
5-Chloro-4-hydroxy-1- (3-trifluoromethoxy-benzyl) -1H in place of 3- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile Using pyridine-2-one, the target compound was obtained in the same manner as in Example 12.

1H(400MHz, CDCl3) 8.20 (2H,s), 7.43-7.30(1H,m), 7.28(1H,s), 7.25-7.17(2H,m), 6.05(1H,s), 5.09(2H,s), 4.65-4.62(1H,m), 4.09-4.03(2H,m), 3.84-3.78(2H,m), 2.52-2.46(2H,m), 2.07-2.02(2H,m), 1.95-1.86(2H,m), 1.24-1.19(3H,m)
 1 H (400 MHz, CDCl 3 ) 8.20 (2H, s), 7.43-7.30 (1H, m), 7.28 (1H, s), 7.25-7.17 (2H, m), 6.05 (1H, s), 5.09 (2H , s), 4.65-4.62 (1H, m), 4.09-4.03 (2H, m), 3.84-3.78 (2H, m), 2.52-2.46 (2H, m), 2.07-2.02 (2H, m), 1.95 -1.86 (2H, m), 1.24-1.19 (3H, m)

실시예 34Example 34

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-플루오로-벤질)-1H-피리딘-2-온의 합성
5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-fluoro-benzyl) -1H-pyridin-2-one Synthesis of

3-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 대신하여 5-클로로-1-(4-플루오로-벤질)-4-히드록시-1H-피리딘-2-온을 이용하여 실시예 12 와 같은 방법으로 목적화합물을 얻었다.
5-Chloro-1- (4-fluoro-benzyl) -4-hydroxy-1H-pyridine in place of 3- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile Using the 2-one, the target compound was obtained in the same manner as in Example 12.

1H(400MHz, DMSO-d6) 8.26(2H,s), 8.14(1h,s), 7.40-7.36(2H,m), 7.20-7.15(2H,m), 6.14(1H,s), 5.00(2H,s), 4.82-4.80(1H,m), 4.06-4.01(2H,m), 3.63-3.57(2H,m), 2.46-2.40(2H,M), 1.96-1.93(2H,m), 1.64-1.59(2H,m), 1.15-1.11(3H,m)
 1 H (400 MHz, DMSO-d 6 ) 8.26 (2H, s), 8.14 (1h, s), 7.40-7.36 (2H, m), 7.20-7.15 (2H, m), 6.14 (1H, s), 5.00 (2H, s), 4.82-4.80 (1H, m), 4.06-4.01 (2H, m), 3.63-3.57 (2H, m), 2.46-2.40 (2H, M), 1.96-1.93 (2H, m) , 1.64-1.59 (2H, m), 1.15-1.11 (3H, m)

실시예 35Example 35

4-{5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-벤조니트릴의 합성
4- {5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -benzo Synthesis of Nitrile

3-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 대신하여 4-(5-클로로-4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 이용하여 실시예 12 와 같은 방법으로 목적화합물을 얻었다.
4- (5-chloro-4-hydroxy-2-oxo-2H-pyridin-1-yl in place of 3- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile The target compound was obtained in the same manner as in Example 12 using methyl) -benzonitrile.

1H(400MHz, CDCl3) 8.20(2H,s), 7.68(2H,d), 7.42(2H,d), 7.31(1H,s), 6.04(1H,s), 5.1392H,s), 4.65-4.6291H,m), 4.09-4.03(2H,m), 3.85-3.79(2H,m), 2.52-2.46(2H,m), 2.07-2.02(2H,m), 1.95-1.87(2H,m), 1.23-1.19(3H,m)
 1 H (400 MHz, CDCl 3 ) 8.20 (2H, s), 7.68 (2H, d), 7.42 (2H, d), 7.31 (1H, s), 6.04 (1H, s), 5.1392H, s), 4.65 -4.6291H, m), 4.09-4.03 (2H, m), 3.85-3.79 (2H, m), 2.52-2.46 (2H, m), 2.07-2.02 (2H, m), 1.95-1.87 (2H, m ), 1.23-1.19 (3H, m)

실시예 36Example 36

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-이소프로필-벤질)-1H-피리딘-2-온의 합성
5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-isopropyl-benzyl) -1H-pyridin-2-one Synthesis of

3-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 대신하여 5-클로로-4-히드록시-1-(4-이소프로필-벤질)-1H-피리딘-2-온을 이용하여 실시예 12 와 같은 방법으로 목적화합물을 얻었다.
5-Chloro-4-hydroxy-1- (4-isopropyl-benzyl) -1H-pyridine in place of 3- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile Using the 2-one, the target compound was obtained in the same manner as in Example 12.

1H(400MHz, CDCl3) 8.2(2H,s), 7.29-7.24(3H,m), 6.03(1H,s), 5.05(2H,s), 4.68-4.62(1H,m), 4.07-4.03(2H,m), 3.82-3.79(2H,m), 2.93-2.90(1H,m), 2.51-2.46(2H,m), 2.03-2.01(2H,m), 1.94-1.91(2H,m), 1.29-1.19(9H,m)
 1 H (400 MHz, CDCl 3 ) 8.2 (2H, s), 7.29-7.24 (3H, m), 6.03 (1H, s), 5.05 (2H, s), 4.68-4.62 (1H, m), 4.07-4.03 (2H, m), 3.82-3.79 (2H, m), 2.93-2.90 (1H, m), 2.51-2.46 (2H, m), 2.03-2.01 (2H, m), 1.94-1.91 (2H, m) , 1.29-1.19 (9H, m)

실시예 37Example 37

5-클로로-1-(3,4-디플루오로-벤질)-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1H-피리딘-2-온의 합성
5-Chloro-1- (3,4-difluoro-benzyl) -4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1 H-pyridine- 2-one synthesis

3-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 대신하여 5-클로로-1-(3,4-디플루오로-벤질)-4-히드록시-1H-피리딘-2-온을 이용하여 실시예 12 와 같은 방법으로 목적화합물을 얻었다.
5-Chloro-1- (3,4-difluoro-benzyl) -4-hydroxy- in place of 3- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile Using 1H-pyridin-2-one, the target compound was obtained in the same manner as in Example 12.

1H(400MHz, CDCl3) 8.02(2H,s0, 7.29(1H,s), 7.19-7.17(2H,m), 7.13-7.07(1H,m), 6.03(1H,s), 5.02(2H,s), 4.63-4.61(1H,m), 4.09-4.02(2H,m), 3.85-3.78(2H,m), 2.52-2.46(2H,m), 2.06-2.01(2H,m), 1.95-1.88(2H,m), 1.24-1.19(3H,m)
 1 H (400 MHz, CDCl 3 ) 8.02 (2H, s0, 7.29 (1H, s), 7.19-7.17 (2H, m), 7.13-7.07 (1H, m), 6.03 (1H, s), 5.02 (2H, s), 4.63-4.61 (1H, m), 4.09-4.02 (2H, m), 3.85-3.78 (2H, m), 2.52-2.46 (2H, m), 2.06-2.01 (2H, m), 1.95- 1.88 (2H, m), 1.24-1.19 (3H, m)

실시예 38Example 38

4-[5-클로로-1-(3,4-디플루오로-벤조일)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드tert-부틸 에스테르의 합성
4- [5-Chloro-1- (3,4-difluoro-benzoyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert Synthesis of -butyl Ester

1-(4-플루오로-벤질)-4-히드록시-1H-피리딘-2-온을 대신하여 5-클로로-1-(3,4-디플루오로-벤조일)-4-히드록시-1H-피리딘-2-온을 이용하여 실시예 19 와 같은 방법으로 목적화합물을 얻었다.
5-Chloro-1- (3,4-difluoro-benzoyl) -4-hydroxy-1H in place of 1- (4-fluoro-benzyl) -4-hydroxy-1H-pyridin-2-one Using pyridine-2-one, the target compound was obtained in the same manner as in Example 19.

1H(400MHz, CDCl3) 8.31(2H,s), 8.07-8.01(2H,m), 7.36-7.28(1H,m), 6.74(1H,s), 4.71-4.69(1H,m), 3.68-3.61(2H,m), 3.55-3.47(2H,m), 1.97-1.88(4H,m), 1.49(9H,s)
 1 H (400 MHz, CDCl 3 ) 8.31 (2H, s), 8.07-8.01 (2H, m), 7.36-7.28 (1H, m), 6.74 (1H, s), 4.71-4.69 (1H, m), 3.68 -3.61 (2H, m), 3.55-3.47 (2H, m), 1.97-1.88 (4H, m), 1.49 (9H, s)

실시예 39Example 39

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(3-플루오로-벤질)-1H-피리딘-2-온의 합성
5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (3-fluoro-benzyl) -1H-pyridin-2-one Synthesis of

3-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 대신하여 5-클로로-1-(3-플루오로-벤질)-4-히드록시-1H-피리딘-2-온을 이용하여 실시예 12 과 같은 방법으로 목적화합물을 얻었다.
5-Chloro-1- (3-fluoro-benzyl) -4-hydroxy-1H-pyridine in place of 3- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile Using the 2-one, the target compound was obtained in the same manner as in Example 12.

1H(400MHz, CDCl3) 8.20(2H,s), 7.37-7.29(2H,m), 7.10-7.01(3H,m), 6.04(1H,s), 5.08(2H,s), 4.65-4.61(1H,m), 4.09-40.3(2H,m), 3.85-3.79(2H,m), 2.52-2.46(2H,m), 2.07-2.02(2H,m), 1.95-1.87(2H.m), 1.24-1.19(3H,m)
 1 H (400 MHz, CDCl 3 ) 8.20 (2H, s), 7.37-7.29 (2H, m), 7.10-7.01 (3H, m), 6.04 (1H, s), 5.08 (2H, s), 4.65-4.61 (1H, m), 4.09-40.3 (2H, m), 3.85-3.79 (2H, m), 2.52-2.46 (2H, m), 2.07-2.02 (2H, m), 1.95-1.87 (2H.m) , 1.24-1.19 (3H, m)

실시예 40 Example 40

3-{5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-벤조니트릴의 합성
3- {5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -benzo Synthesis of Nitrile

3-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 대신하여 3-(5-클로로-4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 이용하여 실시예 12 과 같은 방법으로 목적화합물을 얻었다.
3- (5-chloro-4-hydroxy-2-oxo-2H-pyridin-1-yl in place of 3- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile The target compound was obtained in the same manner as in Example 12 using methyl) -benzonitrile.

1H(400MHz, CDCl3) 8.20(2H,s), 7.64~-7.48(4H,m), 7.35(1H,s), 6.05(1H,s), 5.10(1H,s), 4.65-4.64(1H,m), 4.63-4.04(2H,m), 3.84-3.79(2H,m), 2.52-2.46(2H,m), 2.08-2.03(2H,m), 2.02-1.91(2H,m), 1.23-1.19(3H,m)
 1 H (400 MHz, CDCl 3 ) 8.20 (2H, s), 7.64-7.48 (4H, m), 7.35 (1H, s), 6.05 (1H, s), 5.10 (1H, s), 4.65-4.64 ( 1H, m), 4.63-4.04 (2H, m), 3.84-3.79 (2H, m), 2.52-2.46 (2H, m), 2.08-2.03 (2H, m), 2.02-1.91 (2H, m), 1.23-1.19 (3H, m)

실시예 41Example 41

4-[5-클로로-1-(3-시아노-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르의 합성
4- [5-Chloro-1- (3-cyano-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester Synthesis of

1-(4-플루오로-벤질)-4-히드록시-1H-피리딘-2-온을 대신하여 3-(5-클로로-4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 이용하여 실시예 19 과 같은 방법으로 목적화합물을 얻었다.
3- (5-chloro-4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl instead of 1- (4-fluoro-benzyl) -4-hydroxy-1H-pyridin-2-one The target compound was obtained in the same manner as in Example 19 using) -benzonitrile.

1H(400MHz, CDCl3) (7.68-7.47(4H,m), 7.32(1H,s), 6.00(1H,s), 5.09(2H,s),4.57-4.55(1H,s), 3.65-3.59(2H,m), 3.50-3.47(2H,m), 1.94-1.84(2H,m), 1.48(9H,s)
 1 H (400 MHz, CDCl 3 ) (7.68-7.47 (4H, m), 7.32 (1H, s), 6.00 (1H, s), 5.09 (2H, s), 4.57-4.55 (1H, s), 3.65- 3.59 (2H, m), 3.50-3.47 (2H, m), 1.94-1.84 (2H, m), 1.48 (9H, s)

실시예 42Example 42

4-[5-클로로-1-(3-시아노-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리디움 클로라이드의 합성
Synthesis of 4- [5-chloro-1- (3-cyano-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidium chloride

질소 대기하의 50 mL 플라스크에 HD-G-504 1.0 g 과 디클로로메탄 /메탄올 (5/2)solution 21mL를 넣고 교반하여 용해 시키고 HCl in 1,4-디옥산 2.4 mL 을 넣고 상온에서 1시간 이상 교반한다. 반응 혼합물에 디에틸 에테르 20 mL 를 넣고 30분 교반 한 후 생성된 고체를 여과하고 디에틸 에테르 50 mL 로 씻어 준 후 건조하여 목적화합물을 얻었다.
1.0 g of HD-G-504 and 21 mL of dichloromethane / methanol (5/2) solution were added and dissolved in a 50 mL flask under nitrogen atmosphere. Then, 2.4 mL of HCl in 1,4-dioxane was added and stirred at room temperature for 1 hour or more. do. 20 mL of diethyl ether was added to the reaction mixture, which was stirred for 30 minutes. The resulting solid was filtered, washed with 50 mL of diethyl ether, and dried to obtain the target compound.

1H(400MHz, CDCl3) 9.03(2H,s), 8.22(1H,s), 7.78-7.76(2H,m), 7.66-7.55(2H,m), 6.18(1H,s), 5.06(2H,s), 4.79-4.77(1H,m), 3.16-3.08(4H,m), 2.13-2.10(2H,m), 1.91-1.85(2H,m)
 1 H (400 MHz, CDCl 3 ) 9.03 (2H, s), 8.22 (1H, s), 7.78-7.76 (2H, m), 7.66-7.55 (2H, m), 6.18 (1H, s), 5.06 (2H , s), 4.79-4.77 (1H, m), 3.16-3.08 (4H, m), 2.13-2.10 (2H, m), 1.91-1.85 (2H, m)

실시예 43Example 43

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-메틸설파닐-벤질)-1H-피리딘-2-온의 합성
5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-methylsulfanyl-benzyl) -1H-pyridine-2- Synthesis of On

3-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 대신하여 5-클로로-4-히드록시-1-(4-메틸설파닐-벤질)-1H-피리딘-2-온을 이용하여 실시예 12 과 같은 방법으로 목적화합물을 얻었다.
5-Chloro-4-hydroxy-1- (4-methylsulfanyl-benzyl) -1H- in place of 3- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile Using pyridine-2-one, the target compound was obtained in the same manner as in Example 12.

1H(400MHz, CDCl3) 8.20(2H,s), 7.28-7.25(5H,m), 6.03(1H,s), 5.03(2H,s), 4.62-4.60(1H,m), 4.08-4.02(2H,m), 3.84-3.78(2H,m), 2.52-2.46(5H,m), 2.06-2.01(2H,m), 1.94-1.87(2H,m), 1.23-1.19(3H,m)
 1 H (400 MHz, CDCl 3 ) 8.20 (2H, s), 7.28-7.25 (5H, m), 6.03 (1H, s), 5.03 (2H, s), 4.62-4.60 (1H, m), 4.08-4.02 (2H, m), 3.84-3.78 (2H, m), 2.52-2.46 (5H, m), 2.06-2.01 (2H, m), 1.94-1.87 (2H, m), 1.23-1.19 (3H, m)

실시예 44Example 44

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-메탄설피닐-벤질)-1H-피리딘-2-온의 합성
5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-methanesulfinyl-benzyl) -1H-pyridine-2- Synthesis of On

질소 대기하의 50 mL 플라스크에 5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-메틸설파닐-벤질)-1H-피리딘-2-온 250 mg 과 디클로로메탄 30ml를 넣고 교반하여 용해 시키고 3-클로로퍼벤조익 에시드 137 mg 을 넣고 상온에서 2시간 이상 교반한다. 반응 혼합물을 감압건조 한 후 잔사를 에틸 아세테이트 100 mL에 녹이고 증류수 100 mL로 2회 씻어준 후 유기층을 무수황산마그네슘으로 건조하고 감압건조 하고 감압건조 한 후 얻어진 잔사를 실리카 컬럼으로 정제, 분리하여 목적화합물을 얻었다.
In a 50 mL flask under nitrogen atmosphere, 5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-methylsulfanyl-benzyl) Add 250 mg of -1H-pyridin-2-one and 30 ml of dichloromethane to dissolve and dissolve. Add 137 mg of 3-chloroperbenzoic acid and stir at room temperature for 2 hours or more. After drying the reaction mixture under reduced pressure, the residue was dissolved in 100 mL of ethyl acetate and washed twice with 100 mL of distilled water. The organic layer was dried over anhydrous magnesium sulfate, dried under reduced pressure, dried under reduced pressure, and then purified and separated from the residue by silica column. The compound was obtained.

1H(400MHz, CDCl3) 8.20(2H,s), 7.67-7.65(2H,d), 7.49-7.47(2H,d), 7.33(1H,s), 6.05(1H,s), 5.14(2H,s), 4.64-4.61(1H,s), 4.09-4.03(2H,m), 3.84-3.78(2H,m), 2.73(3H,s), 2.52-2.46(2H,m), 2.07-2.02(2H,m), 1.94-1.87(2H,m), 1.27-1.19(3H,m)
 1 H (400 MHz, CDCl 3 ) 8.20 (2H, s), 7.67-7.65 (2H, d), 7.49-7.47 (2H, d), 7.33 (1H, s), 6.05 (1H, s), 5.14 (2H , s), 4.64-4.61 (1H, s), 4.09-4.03 (2H, m), 3.84-3.78 (2H, m), 2.73 (3H, s), 2.52-2.46 (2H, m), 2.07-2.02 (2H, m), 1.94-1.87 (2H, m), 1.27-1.19 (3H, m)

실시예 45Example 45

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-메탄설포닐-벤질)-1H-피리딘-2-온의 합성
5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-methanesulfonyl-benzyl) -1H-pyridine-2- Synthesis of On

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-메틸설파닐-벤질)-1H-피리딘-2-온을 대신하여 5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(4-메탄sulfinyl-벤질)-1H-피리딘-2-온을 이용하여 실시예 44 와 같은 방법으로 목적화합물을 얻었다.
5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-methylsulfanyl-benzyl) -1H-pyridine-2- 5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (4-methanesulfinyl-benzyl) -1H-pyridine in place of one Using the 2-one, the target compound was obtained in the same manner as in Example 44.

1H(400MHz, CDCl3) 8.20(2H,s), 7.96-7.94(2H,d), 7.52-7.50(2H,d), 7.34(1H,s), 6.05(1H,s), 5.16(2H,s), 4.65-4.62(1H,m), 4.15-4.03(2H,m), 3.85-3.79(2H,m), 3.06(3H,s), 2.52-2.46(2H,m), 2.07-2.02(2H,m), 1.95-1.89(2H,m), 1.26-1.19(3H,m)
 1 H (400 MHz, CDCl 3 ) 8.20 (2H, s), 7.96-7.94 (2H, d), 7.52-7.50 (2H, d), 7.34 (1H, s), 6.05 (1H, s), 5.16 (2H , s), 4.65-4.62 (1H, m), 4.15-4.03 (2H, m), 3.85-3.79 (2H, m), 3.06 (3H, s), 2.52-2.46 (2H, m), 2.07-2.02 (2H, m), 1.95-1.89 (2H, m), 1.26-1.19 (3H, m)

실시예 46Example 46

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(2-플루오로-벤질)-1H-피리딘-2-온의 합성
5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (2-fluoro-benzyl) -1H-pyridin-2-one Synthesis of

3-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 대신하여 5-클로로-1-(2-플루오로-벤질)-4-히드록시-1H-피리딘-2-온을 이용하여 실시예 12 과 같은 방법으로 목적화합물을 얻었다.
5-Chloro-1- (2-fluoro-benzyl) -4-hydroxy-1H-pyridine in place of 3- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile Using the 2-one, the target compound was obtained in the same manner as in Example 12.

1H(400MHz, CDCl3) 8.20(2H,s), 7.47-7.36(2H,m), 7.35-7.32(1H,m), 7.17-7.08(2H,m), 6.00(1H,s), 5.13(2H,s), 4.62-4.59(1H,m), 4.06-4.01(2H,m), 3.84-3.78(2H,m), 2.51-2.46(2H,m), 2.05-2.00(2H,m), 1.92-1.85(2H,m), 1.23-1.19(3H,m)
 1 H (400 MHz, CDCl 3 ) 8.20 (2H, s), 7.47-7.36 (2H, m), 7.35-7.32 (1H, m), 7.17-7.08 (2H, m), 6.00 (1H, s), 5.13 (2H, s), 4.62-4.59 (1H, m), 4.06-4.01 (2H, m), 3.84-3.78 (2H, m), 2.51-2.46 (2H, m), 2.05-2.00 (2H, m) , 1.92-1.85 (2H, m), 1.23-1.19 (3H, m)

실시예 47Example 47

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-(3-플루오로-4-메틸설파닐-벤질)-1H-피리딘-2-온의 합성
5-chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- (3-fluoro-4-methylsulfanyl-benzyl) -1H Synthesis of -pyridin-2-one

질소 대기하의 50 mL 플라스크에 5-클로로-1-(3,4-디플루오로-벤질)-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1H-피리딘-2-온 300 mg 과 디메틸 설폭사이드 20ml를 넣고 교반하여 용해 시키고 소디움 티오메톡사이드 92mg 과 세슘 카보네이트 425 mg 을 넣고 50℃에서 10시간 이상 교반한다. 반응 혼합물을 에틸 아세테이트 100 mL에 녹이고 증류수 100 mL로 2회 씻어준 후 유기층을 무수황산마그네슘으로 건조하고 감압건조 하고 감압건조 한 후 얻어진 잔사를 실리카 컬럼으로 정제, 분리하여 목적화합물을 얻었다.
5-chloro-1- (3,4-difluoro-benzyl) -4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yljade in a 50 mL flask under nitrogen atmosphere Put 300 mg of C] -1H-pyridin-2-one and 20 ml of dimethyl sulfoxide to dissolve it. Then, add 92 mg of sodium thiomethoxide and 425 mg of cesium carbonate, and stir at 50 ° C. for at least 10 hours. The reaction mixture was dissolved in 100 mL of ethyl acetate, washed twice with 100 mL of distilled water, and then the organic layer was dried over anhydrous magnesium sulfate, dried under reduced pressure, and dried under reduced pressure, and the obtained residue was purified by silica column and separated to obtain a target compound.

1H(400MHz, CDCl3) 8.20(2H,s), 7.28-7.19(2H,m), 7.10-7.00(2H,s), 6.03(1H,s), 5.03(2H,s), 4.67-4.60(1H,m), 4.07-4.02(2H,m), 3.83-3.78(2H,m), 2.52-2.46(5H,m), 2.06-2.01(2H,m), 1.92-1.88(2H,m), 1.23-1.19(3H,m)
 1 H (400 MHz, CDCl 3 ) 8.20 (2H, s), 7.28-7.19 (2H, m), 7.10-7.00 (2H, s), 6.03 (1H, s), 5.03 (2H, s), 4.67-4.60 (1H, m), 4.07-4.02 (2H, m), 3.83-3.78 (2H, m), 2.52-2.46 (5H, m), 2.06-2.01 (2H, m), 1.92-1.88 (2H, m) , 1.23-1.19 (3H, m)

실시예 48Example 48

3-{5-클로로-4-[1-(4-메틸설파닐-벤조일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일메틸}-벤조니트릴의 합성
Synthesis of 3- {5-chloro-4- [1- (4-methylsulfanyl-benzoyl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-ylmethyl} -benzonitrile

질소 대기하의 50 mL 플라스크에 4-[5-클로로-1-(3-시아노-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리디늄 클로라이드 110 mg 과 아세토니트릴 /H2O (5/3)solution 24mL를 넣고 교반하여 용해 시키고 트리에틸아민 0.1 mL 와 4-(메틸티오)벤조일 클로라이드 53 mg 을 넣고 상온에서 1시간 이상 교반한다. 반응 혼합물을 에틸 아세테이트 100 mL에 녹이고 증류수 100 mL로 2회 씻어준 후 유기층을 무수황산마그네슘으로 건조하고 감압건조 하고 감압건조 한 후 얻어진 잔사를 실리카 컬럼으로 정제, 분리하여 목적화합물을 얻었다.
110 mg 4- [5-chloro-l- (3-cyano-benzyl) -2-oxo-l, 2-dihydro-pyridin-4-yloxy] -piperidinium chloride in a 50 mL flask under nitrogen atmosphere Add 24 mL of acetonitrile / H 2 O (5/3) solution, dissolve, and dissolve. Add 0.1 mL of triethylamine and 53 mg of 4- (methylthio) benzoyl chloride, and stir at room temperature for at least 1 hour. The reaction mixture was dissolved in 100 mL of ethyl acetate, washed twice with 100 mL of distilled water, and then the organic layer was dried over anhydrous magnesium sulfate, dried under reduced pressure, and dried under reduced pressure, and the obtained residue was purified by silica column and separated to obtain a target compound.

1H(400MHz, CDCl3) 7.64-7.47(4H,m), 7.38-7.33(3H,m), 7.29-7.27(2H,m), 6.00(1H,s), 5.09(2H,s), 4.72-4.62(1H,m), 4.01-3.42(4H,m), 2.52(3H,s), 2.20-1.81(4H,m)
 1 H (400 MHz, CDCl 3 ) 7.64-7.47 (4H, m), 7.38-7.33 (3H, m), 7.29-7.27 (2H, m), 6.00 (1H, s), 5.09 (2H, s), 4.72 -4.62 (1H, m), 4.01-3.42 (4H, m), 2.52 (3H, s), 2.20-1.81 (4H, m)

실시예 49Example 49

3-[4-(1-벤조옥사졸-2-일-피페리딘-4-일옥시)-5-클로로-2-옥소-2H-피리딘-1-일메틸]-벤조니트릴의 합성
Synthesis of 3- [4- (1-benzooxazol-2-yl-piperidin-4-yloxy) -5-chloro-2-oxo-2H-pyridin-1-ylmethyl] -benzonitrile

4-(메틸티오)벤조일 클로라이드를 대신하여 2-클로로-1,3-벤즈옥사졸을 이용하여 실시예 48 과 같은 방법으로 목적화합물을 얻었다.
The target compound was obtained in the same manner as in Example 48 using 2-chloro-1,3-benzoxazole in place of 4- (methylthio) benzoyl chloride.

1H(400MHz, CDCl3) 7.65-7.48(4H,m), 7.39-7.29(3H,m), 7.21-7.17(1H,m), 7.08-7.03(1H,m), 6.04(1H,s), 5.10(2H,s), 4.70-4.69(1H,m), 3.88-3.85(4H,m), 2.12-2.03(4H,m)
 1 H (400 MHz, CDCl 3 ) 7.65-7.48 (4H, m), 7.39-7.29 (3H, m), 7.21-7.17 (1H, m), 7.08-7.03 (1H, m), 6.04 (1H, s) , 5.10 (2H, s), 4.70-4.69 (1H, m), 3.88-3.85 (4H, m), 2.12-2.03 (4H, m)

실시예 50Example 50

4-[5-클로로-1-(3-플루오로-벤질)-2-옥소-1,2-디히드로-피리딘-4-일옥시]-피페리딘-1-카복실릭 에시드 tert-부틸 에스테르의 합성
4- [5-Chloro-1- (3-fluoro-benzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxy] -piperidine-1-carboxylic acid tert-butyl ester Synthesis of

1-(4-플루오로-벤질)-4-히드록시-1H-피리딘-2-온을 대신하여 5-클로로-1-(3-플루오로-벤질)-4-히드록시-1H-피리딘-2-온을 이용하여 실시예 19 와 같은 방법으로 목적화합물을 얻었다.
5-Chloro-1- (3-fluoro-benzyl) -4-hydroxy-1H-pyridine- in place of 1- (4-fluoro-benzyl) -4-hydroxy-1H-pyridin-2-one Using the 2-one, the target compound was obtained in the same manner as in Example 19.

1H(400MHz, CDCl3) 7.37-7.31(1H,m), 7.29(1H.s), 7.09-6.99(3H,m), 5.99(1H,s), 5.07(2H,s), 4.57-4.54(1H,s), 3.65-3.58(2H,m), 3.52-3.47(2H,m), 1.94-1.83(4H,m), 1.48(9H,s)
 1 H (400 MHz, CDCl 3 ) 7.37-7.31 (1 H, m), 7.29 (1 H.s), 7.09-6.99 (3 H, m), 5.99 (1 H, s), 5.07 (2H, s), 4.57-4.54 (1H, s), 3.65-3.58 (2H, m), 3.52-3.47 (2H, m), 1.94-1.83 (4H, m), 1.48 (9H, s)

실시예 51Example 51

3-[5-클로로-4-(1-이소부티릴-피페리딘-4-일옥시)-2-옥소-2H-피리딘-1-일메틸]-벤조니트릴의 합성
Synthesis of 3- [5-chloro-4- (1-isobutyryl-piperidin-4-yloxy) -2-oxo-2H-pyridin-1-ylmethyl] -benzonitrile

4-(메틸티오)벤조일 클로라이드를 대신하여 이소부티릴 클로라이드를 이용하여 실시예 48 과 같은 방법으로 목적화합물을 얻었다.
The desired compound was obtained in the same manner as in Example 48 using isobutyryl chloride instead of 4- (methylthio) benzoyl chloride.

1H(400MHz, CDCl3) 7.64-7.62(1H,d), 7.58-7.56(2H,m), 7.51-7.47(1H,m), 7.33(1H,s), 6.01(1H,s), 5.31(2H,s), 5.15-5.04(2H,m), 4.64-4.62(1H,m), 3.85-3.54(4H,m), 2.04-1.87(4H,m), 1.21-1.08(6H,d)
 1 H (400 MHz, CDCl 3 ) 7.64-7.62 (1H, d), 7.58-7.56 (2H, m), 7.51-7.47 (1H, m), 7.33 (1H, s), 6.01 (1H, s), 5.31 (2H, s), 5.15-5.04 (2H, m), 4.64-4.62 (1H, m), 3.85-3.54 (4H, m), 2.04-1.87 (4H, m), 1.21-1.08 (6H, d)

실시예 52Example 52

5-클로로-4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-1-[2-(4-플루오로-페닐)-에틸]-1H-피리딘-2-온의 합성5-Chloro-4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -1- [2- (4-fluoro-phenyl) -ethyl] -1 H Synthesis of -pyridin-2-one

3-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 대신하여 5-클로로-1-[2-(4-플루오로-페닐)-에틸]-4-히드록시-1H-피리딘-2-온을 이용하여 실시예 12 와 같은 방법으로 목적화합물을 얻었다.
5-Chloro-1- [2- (4-fluoro-phenyl) -ethyl] -4- in place of 3- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile The target compound was obtained in the same manner as in Example 12 using hydroxy-1H-pyridin-2-one.

1H(400MHz, CDCl3) 8.20(2H,s), 7.17-7.13(2H,m), 7.04-7.00(3H,m), 6.01(1H,s), 4.62-4.60(1H,m), 4.10-4.04(4H,m), 3.83-3.77(2H,m), 3.03-3.00(2H,m), 2.52-2.46(2H,m), 2.07-2.02(2H,m), 1.94-1.86(2H,m), 1.24-1.19(3H,m)
 1 H (400 MHz, CDCl 3 ) 8.20 (2H, s), 7.17-7.13 (2H, m), 7.04-7.00 (3H, m), 6.01 (1H, s), 4.62-4.60 (1H, m), 4.10 -4.04 (4H, m), 3.83-3.77 (2H, m), 3.03-3.00 (2H, m), 2.52-2.46 (2H, m), 2.07-2.02 (2H, m), 1.94-1.86 (2H, m), 1.24-1.19 (3H, m)

실시예 53Example 53

3-{4-[1-(5-브로모-피리미딘-2-일)-피페리딘-4-일옥시]-5-클로로-2-옥소-2H-피리딘-1-일메틸}-벤조니트릴의 합성
3- {4- [1- (5-Bromo-pyrimidin-2-yl) -piperidin-4-yloxy] -5-chloro-2-oxo-2H-pyridin-1-ylmethyl}- Synthesis of Benzonitrile

4-(메틸티오)벤조일 클로라이드를 대신하여 5-브로모-2-클로로피리미딘을 이용하여 실시예 48 과 같은 방법으로 목적화합물을 얻었다.
The target compound was obtained in the same manner as in Example 48 using 5-bromo-2-chloropyrimidine in place of 4- (methylthio) benzoyl chloride.

1H(400MHz, CDCl3) 8.31(2H,s), 7.64-7.48(4H,m), 7.33(1H,s), 6.04(1H,s), 5.10(2H,s), 4.66-4.64(1H,s), 4.02-3.87(4H,m), 2.06-1.90(4H,4)
 1 H (400 MHz, CDCl 3 ) 8.31 (2H, s), 7.64-7.48 (4H, m), 7.33 (1H, s), 6.04 (1H, s), 5.10 (2H, s), 4.66-4.64 (1H , s), 4.02-3.87 (4H, m), 2.06-1.90 (4H, 4)

실시예 54Example 54

4-(1-{4-[1-(5-에틸-피리미딘-2-일)-피페리딘-4-일옥시]-2-옥소-2H-피리딘-1-일}-에틸)-벤조니트릴의 합성4- (1- {4- [1- (5-ethyl-pyrimidin-2-yl) -piperidin-4-yloxy] -2-oxo-2H-pyridin-1-yl} -ethyl)- Synthesis of Benzonitrile

Figure pat00045
Figure pat00045

3-(4-히드록시-2-옥소-2H-피리딘-1-일메틸)-벤조니트릴을 대신하여 4-[1-(4-히드록시-2-옥소-2H-피리딘-1-일)-에틸]-벤조니트릴을 이용하여 실시예 12 와 같은 방법으로 목적화합물을 얻었다.
4- [1- (4-hydroxy-2-oxo-2H-pyridin-1-yl) instead of 3- (4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile The target compound was obtained in the same manner as in Example 12 using -ethyl] -benzonitrile.

1H NMR (400MHz, CDCl3) : 8.21(2H, s), 7.68-7.71(2H, d), 7.41-7.43(2H, d), 7.13(1H, s), 6.34-6.36(1H, m), 6.03(1H, s), 4.63-4.64(1H, m), 3.79-4.07(4H, m), 2.46-2.52(2H, m), 1.87-2.09(4H, m), 1.76(2H, d), 1.21(3H, m).
 1 H NMR (400 MHz, CDCl 3 ): 8.21 (2H, s), 7.68-7.71 (2H, d), 7.41-7.43 (2H, d), 7.13 (1H, s), 6.34-6.36 (1H, m) , 6.03 (1H, s), 4.63-4.64 (1H, m), 3.79-4.07 (4H, m), 2.46-2.52 (2H, m), 1.87-2.09 (4H, m), 1.76 (2H, d) , 1.21 (3H, m).

상기 실시예 1-54 화합물들의 구조식은 다음 표 1과 같다.
The structural formulas of the compounds of Examples 1-54 are shown in Table 1 below.

[표 1][Table 1]

Figure pat00046
Figure pat00046

Figure pat00047

Figure pat00047

Figure pat00048
Figure pat00048

Figure pat00049

Figure pat00049

실시예 55. cAMP 자극에 대한 화합물 활성의 결정
Example 55. Determination of Compound Activity on cAMP Stimulation

GPR119 작용제에 대한 반응으로 세포내 cAMP 활성을 측정하기 위하여 햄스터에서 유래된 베타세포인 HIT-T15 세포 (한국세포주은행)를 사용하였다. 96 웰 플레이트에 웰 당 60,000 숫자로 HIT-T15 세포를 플레이팅하였다. 플레이팅 다음 날 세포를 1시간 동안 다양한 농도의 GPR119 작용제와 함께 37℃에서 인큐베이션하였다. 화합물은 0.0032 내지 10 마이크로몰 범위의 6 농도로 처리하였다. cAMP 활성은 Cis Bio (Bedford, MA)로부터의 cAMP 다이나믹 키트를 사용하여 제조자의 지시에 따라 측정하였다. 세포를 용해하고 D2 표지된 cAMP 및 크립테이트 표지된 항 cAMP 항체를 사용하여 경쟁적 면역분석법에 의해 cAMP 수준을 측정하였다. 형광은 Molecular Devices사의 Flex Station으로 판독하였다. D2와 크립테이트는 매우 근접했을 때 형광 공명 에너지 전이 (FRET)를 겪으며, 형광비 (665/620nm)로서 측정된다. 세포 용해물 내의 미표지된 cAMP는 크립테이트 표지된 항체에 대하여 D2 표지된 cAMP와 경쟁하였다. 얻어진 FRET 신호 감소는 세포내 cAMP 수준에 해당한다. 화합물의 활성은 DMSO 조절로부터 FRET 신호변화 정도로 계산하였다. 그 결과는 하기 표 2에 나타내었다. Hamster-derived beta cells, HIT-T15 cells (Korea Cell Line Bank), were used to measure intracellular cAMP activity in response to GPR119 agonists. HIT-T15 cells were plated at 60,000 numbers per well in 96 well plates. The day after plating the cells were incubated at 37 ° C. with various concentrations of GPR119 agonist for 1 hour. Compounds were treated at 6 concentrations ranging from 0.0032 to 10 micromolar. cAMP activity was measured using the cAMP dynamic kit from Cis Bio (Bedford, Mass.) according to the manufacturer's instructions. Cells were lysed and cAMP levels were measured by competitive immunoassay using D2 labeled cAMP and cryptate labeled anti cAMP antibodies. Fluorescence was read with a Flex Station from Molecular Devices. D2 and cryptate undergo fluorescence resonance energy transfer (FRET) when in close proximity and are measured as fluorescence ratio (665/620 nm). Unlabeled cAMP in cell lysates competed with D2 labeled cAMP for cryptate labeled antibodies. The resulting FRET signal reduction corresponds to intracellular cAMP levels. Compound activity was calculated to the extent of FRET signal change from DMSO regulation. The results are shown in Table 2 below.

실시예Example EC50 (nM)EC50 (nM) 1One 55 22 3030 33 1010 44 4545 1212 2121 1313 5151 1515 110110 2727 2727 2828 100100 3232 4040 3737 3.23.2 3939 3.23.2 4040 3.23.2 4141 3030 4444 3.23.2 4747 2323 4949 4040

실시예 56. 경구 당 부하 검사(Oral Glucose Tolerance Test; OGTT)
Example 56. Oral Glucose Tolerance Test (OGTT)

8~10 주령의 수컷 C57/6J 쥐를 이용하여 최소 7일간의 순화기간을 둔 후에 건강한 개체만을 이용하여 OGTT 시험을 실시하였다. 12~15시간 절식 후에 각 군당 10마리씩 공복 혈당을 기준으로 군분리한 후, Vehicle (80% PEG, 10% tween 80, 10% ethanol)이나 시험물질(실시예 1, 3, 12, 44, 45)을 각각 20 mg/kg 용량으로 투여하였다. Vehicle과 시험물질은 10 ml/kg으로 경구 투여하였다. Vehicle이나 시험 물질투여 30분 후 glucose (3g/kg)를 10 ml/kg의 용량으로 경구 투여하였다. 혈당은 아큐첵 고(Rosche diagnostic Co.)을 이용하여 측정하였으며, 측정시간은 glucose 투여 기준 -30, 0, 20, 40, 60 및 120 분에 미정맥을 천자하여 측정하였다. 시험결과 시험물질 5종(실시예 1, 3, 12, 44, 45)은 표3과 같이 각각 vehicle 대비 약 30~60 %의 AUC(area under curve) 강하 효과를 보였다. 그 결과는 하기 표 3에 나타내었다. After 8 to 10 weeks old male C57 / 6J rats were allowed to undergo at least 7 days of acclimatization, followed by OGTT test using only healthy subjects. After fasting for 12 to 15 hours, groups of 10 animals were fasted based on fasting blood glucose, followed by vehicle (80% PEG, 10% tween 80, 10% ethanol) or test substance (Examples 1, 3, 12, 44, 45). ) Was administered at a 20 mg / kg dose each. Vehicle and test substance were administered orally at 10 ml / kg. Thirty minutes after vehicle or test substance administration, glucose (3g / kg) was orally administered at a dose of 10 ml / kg. Blood glucose was measured using Accusture Co., Ltd. (Rosche diagnostic Co.), and the measurement time was measured by puncture of the microvenous veins at -30, 0, 20, 40, 60 and 120 minutes based on glucose administration. As a result of the test, five test materials (Examples 1, 3, 12, 44, and 45) showed an AUC (area under curve) drop effect of about 30 to 60%, respectively, as shown in Table 3. The results are shown in Table 3 below.

시험물질Test substance % AUC of vehicle% AUC of vehicle 실시예 1Example 1 54.9 %54.9% 실시예 3Example 3 62.7 %62.7% 실시예 12Example 12 31.3 %31.3% 실시예 44Example 44 33.3 %33.3% 실시예 45Example 45 31.3 %31.3%

실시예 57. Example 57.

활성화제의 평가는 효력 (potency)과 효능 (efficacy) 두 가지 측면에서 판단한다.Evaluation of activators is judged in two aspects: potency and efficacy.

최고효능 (intrinsic activity)은 용량과 상관없이 그 약물이 일으킬 수 있는 최대 효과를 말한다.Intrinsic activity is the maximum effect the drug can produce, regardless of dose.

실시예 12 내지 15의 경우 CYP3A4 억제율을 측정한 결과(10 uM) 95 내지 100%의 억제율을 나타내었다. In the case of Examples 12 to 15, the inhibition rate of CYP3A4 was measured (10 uM), and the inhibition rate was 95 to 100%.

한편, 도 1에 나타낸 바와 같이, 특징적으로 카르보닐 기를 가지는 O 화합물과 티오-카르보닐 기를 가지는 S 화합물의 농도에 따른 효력, 효능 및 최고 효능의 그래프를 단적으로 도시하였을 때, S 화합물은 효력과 효능에서 10nM 이하의 우수한 결과를 보여주고 있고, 더 나아가 약물이 나타낼 수 있는 최고 효능의 측면에서 O 화합물과 비교 하였을 때 더욱 더 확연히 높은 활성을 나타내었다. 따라서 S 화합물이 잠재적으로 더 많은 용량 범위에서 O 화합물에 대하여 보다 확실한 최대 효과를 나타내므로 유효 용량 범위의 폭을 증대시킬 수 있고 이는 치료 용량의 선정 및 안정성 확보에 큰 장점으로 작용함을 나타낼 수 있다.On the other hand, as shown in Figure 1, when showing a graph of the potency, potency and the highest efficacy according to the concentration of the O compound having a carbonyl group and S compound having a thio-carbonyl group characteristically, the S compound is potency and efficacy Shows excellent results of less than 10 nM, and even more significantly higher activity compared to the O compound in terms of the highest efficacy that the drug can exhibit. Therefore, the S compound can potentially increase the width of the effective dose range because it shows a more pronounced maximum effect on the O compound in potentially higher dose ranges, which may indicate a great advantage in the selection of therapeutic doses and ensuring stability. .

또한, S 화합물과 O 화합물의 CYP 억제율 (10 uM) 측정에서도 가장 major type인 3A4에 대한 측정 결과 O 화합물의 경우 82 %의 억제 값을 나타내었지만, S 화합물의 경우 100%의 억제 값을 나타내어 세포수준에서의 대사 활성 관계에서도 더 우수한 결과를 나타내었다.
In addition, in the measurement of CYP inhibition rate (10 uM) of S and O compounds, the measurement result of 3A4, which is the major type, showed 82% inhibition value for O compound, but 100% inhibition value for S compound. The metabolic activity at the level also showed better results.

Claims (7)

하기 화학식 1의 화합물 또는 이의 약제학적으로 허용되는 염.
[화학식 1]
Figure pat00050

상기 화학식 1에서,
X는
Figure pat00051
, 아릴 또는 헤테로아릴이고, 여기서 상기 아릴 또는 헤테로아릴은 R1a, R1b, R1c, R1d 및 R1e로부터 선택된 하나 이상의 구성원으로 치환되거나 비치환될 수 있고;
R1a, R1b, R1c, R1d 및 R1e는 각각 수소, 알킬, 알케닐, 알키닐, 시클로알킬, 아릴, 헤테로시클릴, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)OR10, -OCF3, -OR11, -OH, -SH, -SR11, -S(O)3H, -P(O)3H2, -C(=O)NR9R9, -NR12R12, -S(O)2NR9R9, -NR9S(O)2CF3, -C(=O)NR9S(O)2R9, -S(O)2NR9C(=O)OR9, -S(O)2NR9C(=O)NR9R9, -C(=O)NR9S(O)2CF3, -C(=O)R11, -NR9C(=O)H, -NR9C(=O)R10, -OC(=O)R10, -OC(=O)NR9R9, -C(=NR14)NR9R9, -NHC(=NR14)NR14R14, -S(=O)R11, -S(O)2R11, -NR9C(=O)OR8 및 -NR9S(O2)R8로 이루어진 군으로부터 독립적으로 선택되고, 여기서: (a) 알케닐, 알키닐, 시클로알킬, 아릴 및 헤테로시클릴은 각각 하나 이상의 R6으로 치환되거나 비치환될 수 있고; (b) 알킬은 하나 이상의 R7로 치환되거나 비치환될 수 있고;
Y는 S 또는 O이고;
K는 CH 또는 N이고;
Z1은 C 또는 N이고;
Z2는 C 또는 N이며, 단 Z1 및 Z2가 모두 N은 아니고;
L1은 CH2, N(R3), C(=O), O, OCR9R9, S, S(=O) 또는 S(O)2이고;
n1은 0 내지 2이고;
n2는 0 내지 2이고;
n3은 0 내지 2이고;
P1은 아릴, 헤테로아릴, 시클로알킬 또는 헤테로시클로알킬이고, 이들 각각은 R1a, R1b, R1c, R1d 및 R1e로부터 선택된 하나 이상의 구성원으로 치환되거나 비치환될 수 있고;
R1a, R1b, R1c, R1d 및 R1e는 각각 수소, 알킬, 알케닐, 알키닐, 시클로알킬, 아릴, 헤테로시클릴, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)OR10, -OCF3, -OR11, -OH, -SH, -SR11, -S(O)3H, -P(O)3H2, -C(=O)NR9R9, -NR12R12, -S(O)2NR9R9, -NR9S(O)2CF3, -C(=O)NR9S(O)2R9, -S(O)2NR9C(=O)OR9, -S(O)2NR9C(=O)NR9R9, -C(=O)NR9S(O)2CF3, -C(=O)R11, -NR9C(=O)H, -NR9C(=O)R10, -OC(=O)R10, -OC(=O)NR9R9, -C(=NR14)NR9R9, -NHC(=NR14)NR14R14, -S(=O)R11, -S(O)2R11, -NR9C(=O)OR8 및 -NR9S(O2)R8로 이루어진 군으로부터 독립적으로 선택되고, 여기서: (a) 알케닐, 알키닐, 시클로알킬, 아릴 및 헤테로시클릴은 각각 하나 이상의 R6으로 치환되거나 비치환될 수 있고; (b) 알킬은 하나 이상의 R7로 치환되거나 비치환될 수 있고;
R2는 알킬, 시클로알킬, 아릴, 헤테로아릴, 헤테로시클릴, -S(O)2R5, -C(=O)NR3R5, -C(=O)R5 또는 -C(=O)OR5이고, 여기서 알킬, 시클로알킬, 아릴, 헤테로아릴 및 헤테로시클릴은 각각 하나 이상의 R6으로 치환되거나 비치환될 수 있고;
R3는 수소, 알킬, 알콕시, 시클로알킬, 아릴, 아릴알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴 또는 헤테로시클릴알킬이고;
R4는 치환되거나 비치환된 C1 -3 알킬렌이고, n4는 0 내지 2의 정수이고, 여기서 치환된 C1 -3 알킬렌은 C1 -6 알킬 또는 할로겐으로 치환될 수 있고, 단, Y가 O이고 n4가 0인 경우, P1은 시클로알킬 또는 헤테로시클로알킬이고;
R5는 알킬, 알케닐, 아릴, 시클로알킬, 헤테로아릴 또는 헤테로시클릴이고, 이들 각각은 하나 이상의 R6으로 치환되거나 비치환될 수 있고;
R6은, 각각의 경우에 알킬, 할로알킬, 아릴, 알케닐, 알키닐, 시클로알킬, 시클로알킬알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴, 헤테로시클릴알킬, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)OR10, -OCF3, -OR10, -OH, -SH, -SR10, -S(O)3H, -P(O)3H2, -C(=O)NR9R9, -NR9R9, -S(O)2NR9R9, -NR9S(O)2CF3, -C(=O)NR9S(O)2R9, -S(O)2NR9C(=O)OR9, -S(O)2NR9C(=O)NR9R9, -C(=O)NR9S(O)2CF3, -C(=O)R10, -NR9C(=O)H, -NR9C(=O)R10, -OC(=O)R10, -C(=NR14)NR9R9, -NHC(=NR14)NR14R14, -S(=O)R10, -S(O)2R10, =O, -NR9C(=O)OR8 및 -NR9S(O2)R8로부터 독립적으로 선택되고, 여기서 알킬, 알케닐, 알키닐, 아릴, 시클로알킬, 시클로알킬알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴 및 헤테로시클릴알킬은 각각 0 내지 5개의 R9a로 치환되거나 비치환될 수 있고;
R7은, 각각의 경우에 알킬, 할로알킬, 아릴, 알케닐, 알키닐, 시클로알킬, 시클로알킬알킬, 헤테로시클릴, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)OR10, -OCF3, -OR10, -OH, -SH, -SR10, -S(O)3H, -P(O)3H2, -C(=O)NR9R9, -NR9R9, -S(O)2NR9R9, -NR9S(O)2CF3, -C(=O)NR9S(O)2R9, -S(O)2NR9C(=O)OR9, -S(O)2NR9C(=O)NR9R9, -C(=O)NR9S(O)2CF3, -C(=O)R10, -NR9C(=O)H, -NR9C(=O)R10, -OC(=O)R10, -C(=NR14)NR9R9, -NHC(=NR14)NR14R14, -S(=O)R10, -S(O)2R10, =O, -NR9C(=O)OR8 및 -NR9S(O2)R8로 이루어진 군으로부터 독립적으로 선택되고, 여기서 알킬, 알케닐, 알키닐, 아릴, 시클로알킬, 시클로알킬알킬 및 헤테로시클릴은 각각 0 내지 5개의 R9a로 치환되거나 비치환될 수 있고;
R8은, 각각의 경우에 알킬, 아릴, 시클로알킬, 헤테로아릴 및 헤테로시클릴로 이루어진 군으로부터 독립적으로 선택되고, 이들 각각은 하나 이상의 R8a로 치환되거나 비치환될 수 있고;
R8a는, 각각의 경우에 알킬, 할로알킬, 아릴, 알케닐, 알키닐, 시클로알킬, 시클로알킬알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴, 헤테로시클릴알킬, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)OR14, -OCF3, -OR14, -OH, -SH, -SR14, -S(O)3H, -P(O)3H2, -C(=O)NR14R14, -NR14R14, -S(O)2NR14R14, -NR14S(O)2CF3, -C(=O)NR14S(O)2R14, -S(O)2NR14C(=O)OR14, -S(O)2NR14C(=O)NR14R14, -C(=O)NR14S(O)2CF3, -C(=O)R14, -NR14C(=O)H, -NR14C(=O)R14, -OC(=O)R14, -C(=NR14)NR14R14, -NHC(=NR14)NR14R14, -S(=O)R14, -S(O)2R14, =O, -NR14C(=O)OR14 및 -NR14S(O2)R14로부터 독립적으로 선택되고;
R9는, 각각의 경우에 수소, 알킬, 알콕시, 시클로알킬, 아릴, 아릴알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴 및 헤테로시클릴알킬로부터 독립적으로 선택되고, 여기서 알킬, 시클로알킬, 아릴, 아릴알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴 및 헤테로시클릴알킬은 각각 0 내지 5개의 R9a로 치환되거나 비치환될 수 있고;
R9a는, 각각의 경우에 알킬, 할로알킬, 아릴, 알케닐, 알키닐, 시클로알킬, 시클로알킬알킬, 헤테로아릴, 헤테로 아릴알킬, 헤테로시클릴, 헤테로시클릴알킬, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)OR14, -OCF3, -OR14, -OH, -SH, -SR14, -S(O)3H, -P(O)3H2, -C(=O)NR14R14, -NR14R14, -S(O)2NR14R14, -NR14S(O)2CF3, -C(=O)NR14S(O)2R10, -S(O)2NR14C(=O)OR10, -S(O)2NR14C(=O)NR14R14, -C(=O)NR14S(O)2CF3, -C(=O)R14, -NR14C(=O)H, -NR14C(=O)R14, -OC(=O)R14, -C(=NR14)NR14R14, -NHC(=NR14)NR14R14, -S(=O)R14, -S(O)2R14, -NR14C(=O)OR8, -NR14S(O2)R8, =O 및 아릴알킬로부터 독립적으로 선택되고;
R10은, 각각의 경우에 알킬, 알케닐, 알키닐, 시클로알킬, 아릴, 아릴알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴 및 헤테로시클릴알킬로부터 독립적으로 선택되고, 여기서 시클로알킬, 아릴, 아릴알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴 및 헤테로시클릴알킬은 각각 0 내지 3개의 R10a로 치환되거나 비치환될 수 있고;
R10a는, 각각의 경우에 알킬, 할로알킬, 아릴, 알케닐, 알키닐, 시클로알킬, 시클로알킬알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴, 헤테로시클릴알킬, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)OR14, -OCF3, -OR14, -OH, -SH, -SR14, -S(O)3H, -P(O)3H2, -C(=O)NR14R14, -NR14R14, -S(O)2NR14R14, -NR14S(O)2CF3, -C(=O)NR14S(O)2R9, -S(O)2NR14C(=O)OR9, -S(O)2NR14C(=O)NR14R14, -C(=O)NR14S(O)2CF3, -C(=O)R14, -NR14C(=O)H, -NR14C(=O)R14, -OC(=O)R14, -C(=NR14)NR14R14, -NHC(=NR14)NR14R14, -S(=O)R14, -S(O)2R14, -NR14C(=O)OR8, -NR14S(O2)R8 및 아릴알킬로부터 독립적으로 선택되고;
R11은, 각각의 경우에 알킬, 알케닐, 알키닐, 시클로알킬, 아릴, 아릴알킬, 헤테로시클릴 및 헤테로시클릴알킬로부터 독립적으로 선택되고, 여기서 시클로알킬, 아릴, 아릴알킬, 헤테로시클릴 및 헤테로시클릴알킬은 각각 0 내지 3개의 R11a로 치환되거나 비치환될 수 있고;
R11a는, 각각의 경우에 알킬, 할로알킬, 아릴, 알케닐, 알키닐, 시클로알킬, 시클로알킬알킬, 헤테로아릴, 헤테로아릴알킬, 헤테로시클릴, 헤테로시클릴알킬, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)OR14, -OCF3, -OR14, -OH, -SH, -SR14, -S(O)3H, -P(O)3H2, -C(=O)NR14R14, -NR14R14, -S(O)2NR14R14, -NR14S(O)2CF3, -C(=O)NR14S(O)2R9, -S(O)2NR14C(=O)OR9, -S(O)2NR14C(=O)NR14R14, -C(=O)NR14S(O)2CF3, -C(=O)R14, -NR14C(=O)H, -NR14C(=O)R14, -OC(=O)R14, -C(=NR14)NR14R14, -NHC(=NR14)NR14R14, -S(=O)R14, -S(O)2R14, -NR14C(=O)OR8, -NR14S(O2)R8 및 아릴알킬로부터 독립적으로 선택되고;
R12는, 각각의 경우에 수소, 알킬, 알케닐, 알키닐, 시클로알킬, 아릴, 아릴알킬, 헤테로시클릴 및 헤테로시클릴알킬로부터 독립적으로 선택되고, 여기서 시클로알킬, 아릴, 아릴알킬, 헤테로시클릴 및 헤테로시클릴알킬은 각각 0 내지 3개의 R10a로 치환되거나 비치환될 수 있고;
R14는, 각각의 경우에 수소, 알킬, 시클로알킬 및 아릴로부터 독립적으로 선택되고;
P2, P3 및 P4는 각각 수소, 알킬, 할로알킬, 시클로알킬, 할로, -CN, -C(=O)OH, -C(=O)OR10, -OCF3, -OR10, -OH, -C(=O)NR9R9, -C(=O)R10 및 -OC(=O)R10으로 이루어진 군으로부터 독립적으로 선택된다.
A compound of Formula 1 or a pharmaceutically acceptable salt thereof.
[Formula 1]
Figure pat00050

In Chemical Formula 1,
X is
Figure pat00051
, Aryl or heteroaryl, wherein the aryl or heteroaryl can be unsubstituted or substituted with one or more members selected from R 1a , R 1b , R 1c , R 1d and R 1e ;
R 1a , R 1b , R 1c , R 1d and R 1e are each hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, halo, -NH 2 , -CN, -NO 2 , -C (= O) OH, -C (= O) OR 10 , -OCF 3 , -OR 11 , -OH, -SH, -SR 11 , -S (O) 3 H, -P (O) 3 H 2 , -C (= 0) NR 9 R 9 , -NR 12 R 12 , -S (O) 2 NR 9 R 9 , -NR 9 S (O) 2 CF 3 , -C (= O) NR 9 S (O ) 2 R 9 , -S (O) 2 NR 9 C (= O) OR 9 , -S (O) 2 NR 9 C (= O) NR 9 R 9 , -C (= O) NR 9 S (O ) 2 CF 3 , -C (= O) R 11 , -NR 9 C (= O) H, -NR 9 C (= O) R 10 , -OC (= O) R 10 , -OC (= O) NR 9 R 9 , -C (= NR 14 ) NR 9 R 9 , -NHC (= NR 14 ) NR 14 R 14 , -S (= O) R 11 , -S (O) 2 R 11 , -NR 9 C (= 0) OR 8 and -NR 9 S (O 2 ) R 8 are independently selected from the group consisting of: (a) alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl, each May be substituted or unsubstituted with R 6 ; (b) alkyl may be unsubstituted or substituted with one or more R 7 ;
Y is S or O;
K is CH or N;
Z 1 is C or N;
Z 2 is C or N, provided that both Z 1 and Z 2 are not N;
L 1 is CH 2 , N (R 3 ), C (═O), O, OCR 9 R 9 , S, S (═O) or S (O) 2 ;
n 1 is 0 to 2;
n 2 is 0 to 2;
n 3 is 0 to 2;
P 1 is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of which may be unsubstituted or substituted with one or more members selected from R 1a , R 1b , R 1c , R 1d and R 1e ;
R 1a , R 1b , R 1c , R 1d and R 1e are each hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, halo, -NH 2 , -CN, -NO 2 , -C (= O) OH, -C (= O) OR 10 , -OCF 3 , -OR 11 , -OH, -SH, -SR 11 , -S (O) 3 H, -P (O) 3 H 2 , -C (= 0) NR 9 R 9 , -NR 12 R 12 , -S (O) 2 NR 9 R 9 , -NR 9 S (O) 2 CF 3 , -C (= O) NR 9 S (O ) 2 R 9 , -S (O) 2 NR 9 C (= O) OR 9 , -S (O) 2 NR 9 C (= O) NR 9 R 9 , -C (= O) NR 9 S (O ) 2 CF 3 , -C (= O) R 11 , -NR 9 C (= O) H, -NR 9 C (= O) R 10 , -OC (= O) R 10 , -OC (= O) NR 9 R 9 , -C (= NR 14 ) NR 9 R 9 , -NHC (= NR 14 ) NR 14 R 14 , -S (= O) R 11 , -S (O) 2 R 11 , -NR 9 C (= 0) OR 8 and -NR 9 S (O 2 ) R 8 are independently selected from the group consisting of: (a) alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl, each May be substituted or unsubstituted with R 6 ; (b) alkyl may be unsubstituted or substituted with one or more R 7 ;
R 2 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -S (O) 2 R 5 , -C (= 0) NR 3 R 5 , -C (= 0) R 5 or -C (= O) OR 5 , wherein alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may each be substituted or unsubstituted with one or more R 6 ;
R 3 is hydrogen, alkyl, alkoxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl;
R 4 is a substituted or unsubstituted C 1 -3 alkylene, n 4 is an integer from 0 to 2, wherein the substituted C 1 -3 alkylene can be optionally substituted with C 1 -6 alkyl or halogen, with the proviso that When Y is O and n 4 is 0, P 1 is cycloalkyl or heterocycloalkyl;
R 5 is alkyl, alkenyl, aryl, cycloalkyl, heteroaryl or heterocyclyl, each of which may be unsubstituted or substituted with one or more R 6 ;
R 6 in each occurrence is alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , -CN, -NO 2 , -C (= O) OH, -C (= O) OR 10 , -OCF 3 , -OR 10 , -OH, -SH, -SR 10 , -S (O) 3 H, -P (O) 3 H 2 , -C (= 0) NR 9 R 9 , -NR 9 R 9 , -S (O) 2 NR 9 R 9 , -NR 9 S (O) 2 CF 3 , -C (= O) NR 9 S (O) 2 R 9 , -S (O) 2 NR 9 C (= O) OR 9 , -S (O) 2 NR 9 C (= O) NR 9 R 9 , -C (= O) NR 9 S (O) 2 CF 3 , -C (= O) R 10 , -NR 9 C (= O) H, -NR 9 C (= O) R 10 , -OC (= O) R 10 , -C (= NR 14 ) NR 9 R 9 , -NHC (= NR 14 ) NR 14 R 14 , -S (= O) R 10 , -S (O) 2 R 10 , = O, -NR Independently selected from 9 C (= 0) OR 8 and -NR 9 S (O 2 ) R 8 wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclyl and heterocyclylalkyl may each be unsubstituted or substituted with 0 to 5 R 9a ;
R 7 is in each case alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, halo, -NH 2 , -CN, -NO 2 , -C (= 0 ) OH, -C (= O) OR 10 , -OCF 3 , -OR 10 , -OH, -SH, -SR 10 , -S (O) 3 H, -P (O) 3 H 2 , -C ( = O) NR 9 R 9 , -NR 9 R 9 , -S (O) 2 NR 9 R 9 , -NR 9 S (O) 2 CF 3 , -C (= O) NR 9 S (O) 2 R 9 , -S (O) 2 NR 9 C (= O) OR 9 , -S (O) 2 NR 9 C (= O) NR 9 R 9 , -C (= O) NR 9 S (O) 2 CF 3 , -C (= O) R 10 , -NR 9 C (= O) H, -NR 9 C (= O) R 10 , -OC (= O) R 10 , -C (= NR 14 ) NR 9 R 9 , -NHC (= NR 14 ) NR 14 R 14 , -S (= O) R 10 , -S (O) 2 R 10 , = O, -NR 9 C (= O) OR 8 and -NR 9 Independently selected from the group consisting of S (O 2 ) R 8 , wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl and heterocyclyl are each substituted or unsubstituted with from 0 to 5 R 9 a May be ringed;
R 8 in each occurrence is independently selected from the group consisting of alkyl, aryl, cycloalkyl, heteroaryl and heterocyclyl, each of which may be substituted or unsubstituted with one or more R 8 a;
R 8a in each occurrence is alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , -CN, -NO 2 , -C (= O) OH, -C (= O) OR 14 , -OCF 3 , -OR 14 , -OH, -SH, -SR 14 , -S (O) 3 H, -P (O) 3 H 2 , -C (= 0) NR 14 R 14 , -NR 14 R 14 , -S (O) 2 NR 14 R 14 , -NR 14 S (O) 2 CF 3 , -C (= O) NR 14 S (O) 2 R 14 , -S (O) 2 NR 14 C (= O) OR 14 , -S (O) 2 NR 14 C (= O) NR 14 R 14 , -C (= O) NR 14 S (O) 2 CF 3 , -C (= 0) R 14 , -NR 14 C (= 0) H, -NR 14 C (= 0) R 14 , -OC (= 0) R 14 , -C (= NR 14 ) NR 14 R 14 , -NHC (= NR 14 ) NR 14 R 14 , -S (= O) R 14 , -S (O) 2 R 14 , = O, -NR Independently from 14 C (= 0) OR 14 and -NR 14 S (O 2 ) R 14 ;
R 9 in each occurrence is independently selected from hydrogen, alkyl, alkoxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein alkyl, cycloalkyl, aryl , Arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may each be unsubstituted or substituted with 0 to 5 R 9 a;
R 9a in each occurrence is alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, hetero arylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , -CN, -NO 2 , -C (= O) OH, -C (= O) OR 14 , -OCF 3 , -OR 14 , -OH, -SH, -SR 14 , -S (O) 3 H, -P (O) 3 H 2 , -C (= 0) NR 14 R 14 , -NR 14 R 14 , -S (O) 2 NR 14 R 14 , -NR 14 S (O) 2 CF 3 , -C (= O) NR 14 S (O) 2 R 10 , -S (O) 2 NR 14 C (= O) OR 10 , -S (O) 2 NR 14 C (= O) NR 14 R 14 , -C (= O) NR 14 S (O) 2 CF 3 , -C (= 0) R 14 , -NR 14 C (= 0) H, -NR 14 C (= 0) R 14 , -OC (= 0) R 14 , -C (= NR 14 ) NR 14 R 14 , -NHC (= NR 14 ) NR 14 R 14 , -S (= O) R 14 , -S (O) 2 R 14 , -NR 14 C ( Independently selected from ═O) OR 8 , —NR 14 S (O 2 ) R 8 , ═O and arylalkyl;
R 10 in each occurrence is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein cycloalkyl, aryl , Arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may each be substituted or unsubstituted with 0 to 3 R 10 a;
R 10a in each case is alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , -CN, -NO 2 , -C (= O) OH, -C (= O) OR 14 , -OCF 3 , -OR 14 , -OH, -SH, -SR 14 , -S (O) 3 H, -P (O) 3 H 2 , -C (= 0) NR 14 R 14 , -NR 14 R 14 , -S (O) 2 NR 14 R 14 , -NR 14 S (O) 2 CF 3 , -C (= O) NR 14 S (O) 2 R 9 , -S (O) 2 NR 14 C (= O) OR 9 , -S (O) 2 NR 14 C (= O) NR 14 R 14 , -C (= O) NR 14 S (O) 2 CF 3 , -C (= 0) R 14 , -NR 14 C (= 0) H, -NR 14 C (= 0) R 14 , -OC (= 0) R 14 , -C (= NR 14 ) NR 14 R 14 , -NHC (= NR 14 ) NR 14 R 14 , -S (= O) R 14 , -S (O) 2 R 14 , -NR 14 C ( = O) OR 8 , -NR 14 S (O 2 ) R 8 and arylalkyl;
R 11 in each occurrence is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl and heterocyclylalkyl, wherein cycloalkyl, aryl, arylalkyl, heterocyclyl And heterocyclylalkyl may each be unsubstituted or substituted with 0 to 3 R 11a ;
R 11a in each occurrence is alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , -CN, -NO 2 , -C (= O) OH, -C (= O) OR 14 , -OCF 3 , -OR 14 , -OH, -SH, -SR 14 , -S (O) 3 H, -P (O) 3 H 2 , -C (= 0) NR 14 R 14 , -NR 14 R 14 , -S (O) 2 NR 14 R 14 , -NR 14 S (O) 2 CF 3 , -C (= O) NR 14 S (O) 2 R 9 , -S (O) 2 NR 14 C (= O) OR 9 , -S (O) 2 NR 14 C (= O) NR 14 R 14 , -C (= O) NR 14 S (O) 2 CF 3 , -C (= 0) R 14 , -NR 14 C (= 0) H, -NR 14 C (= 0) R 14 , -OC (= 0) R 14 , -C (= NR 14 ) NR 14 R 14 , -NHC (= NR 14 ) NR 14 R 14 , -S (= O) R 14 , -S (O) 2 R 14 , -NR 14 C ( = O) OR 8 , -NR 14 S (O 2 ) R 8 and arylalkyl;
R 12 in each occurrence is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl and heterocyclylalkyl, wherein cycloalkyl, aryl, arylalkyl, hetero Cyclyl and heterocyclylalkyl may each be unsubstituted or substituted with 0 to 3 R 10a ;
R 14 in each occurrence is independently selected from hydrogen, alkyl, cycloalkyl and aryl;
P 2 , P 3 and P 4 are each hydrogen, alkyl, haloalkyl, cycloalkyl, halo, -CN, -C (= 0) OH, -C (= 0) OR 10 , -OCF 3 , -OR 10 , -OH, -C (= 0) NR 9 R 9 , -C (= 0) R 10 and -OC (= 0) R 10 are independently selected.
제1항에 있어서,
화학식 1의 화합물은 하기 화학식 2의 화합물 또는 하기 화학식 3의 화합물인 것을 특징으로 하는, 화합물 및 이의 약제학적으로 허용되는 염.
[화학식 2]

Figure pat00052

[화학식 3]
Figure pat00053

상기 화학식 2 및 화학식 3에서,
D는 NR3, S 또는 O이고;
G는 S 또는 O이고;
R`은 알킬, 시클로알킬, 아릴, 헤테로아릴, 헤테로시클릴, -S(O)2R5, -C(=O)NR3R5, -C(=O)R5 또는 -C(=O)OR5이고, 여기서 알킬, 시클로알킬, 아릴, 헤테로아릴 및 헤테로시클릴은 각각 하나 이상의 R6으로 치환되거나 비치환될 수 있고;
R``은 수소, 알킬, 알케닐, 알키닐, 시클로알킬, 아릴, 헤테로시클릴, 할로, -NH2, -CN, -NO2, -C(=O)OH, -C(=O)OR10, -OCF3, -OR11, -OH, -SH, -SR11, -S(O)3H, -P(O)3H2, -C(=O)NR9R9, -NR12R12, -S(O)2NR9R9, -NR9S(O)2CF3, -C(=O)NR9S(O)2R9, -S(O)2NR9C(=O)OR9, -S(O)2NR9C(=O)NR9R9, -C(=O)NR9S(O)2CF3, -C(=O)R11, -NR9C(=O)H, -NR9C(=O)R10, -OC(=O)R10, -OC(=O)NR9R9, -C(=NR14)NR9R9, -NHC(=NR14)NR14R14, -S(=O)R11,
-S(O)2R11, -NR9C(=O)OR8 및 -NR9S(O2)R8로 이루어진 군으로부터 독립적으로 선택되고, 여기서: (a) 알케닐, 알키닐, 시클로알킬, 아릴 및 헤테로시클릴은 각각 하나 이상의 R6으로 치환되거나 비치환될 수 있고; (b) 알킬은 하나 이상의 R7로 치환되거나 비치환될 수 있고;
R```은 수소, 알킬 또는 할로겐이고;
상기 R3 , R6, R7 및 P3는 제1항에서 정의한 바와 같다.
The method of claim 1,
The compound of formula 1 is a compound of formula (2) or a compound of formula (3), and a pharmaceutically acceptable salt thereof.
(2)

Figure pat00052

(3)
Figure pat00053

In Chemical Formulas 2 and 3,
D is NR 3 , S or O;
G is S or O;
R` is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -S (O) 2 R 5 , -C (= 0) NR 3 R 5 , -C (= 0) R 5 or -C (= O) OR 5 , wherein alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may each be substituted or unsubstituted with one or more R 6 ;
R`` is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, halo, -NH 2 , -CN, -NO 2 , -C (= 0) OH, -C (= 0) OR 10 , -OCF 3 , -OR 11 , -OH, -SH, -SR 11 , -S (O) 3 H, -P (O) 3 H 2 , -C (= O) NR 9 R 9 ,- NR 12 R 12 , -S (O) 2 NR 9 R 9 , -NR 9 S (O) 2 CF 3 , -C (= O) NR 9 S (O) 2 R 9 , -S (O) 2 NR 9 C (= 0) OR 9 , -S (O) 2 NR 9 C (= 0) NR 9 R 9 , -C (= 0) NR 9 S (O) 2 CF 3 , -C (= 0) R 11 , -NR 9 C (= 0) H, -NR 9 C (= 0) R 10 , -OC (= 0) R 10 , -OC (= 0) NR 9 R 9 , -C (= NR 14 ) NR 9 R 9 , -NHC (= NR 14 ) NR 14 R 14 , -S (= O) R 11 ,
-S (O) 2 R 11 , -NR 9 C (= 0) OR 8 and -NR 9 S (O 2 ) R 8 , independently selected from the group consisting of: (a) alkenyl, alkynyl, Cycloalkyl, aryl and heterocyclyl may each be substituted or unsubstituted with one or more R 6 ; (b) alkyl may be unsubstituted or substituted with one or more R 7 ;
R` '' is hydrogen, alkyl or halogen;
R 3 , R 6 , R 7 And P 3 is as defined in claim 1.
제1항에 있어서,
화학식 1의 화합물이 아래 화합물로 구성된 군으로부터 선택된 어느 하나인 것을 특징으로 하는 화합물 또는 이의 입체이성질체 또는 이들의 약제학적으로 허용되는 염:
Figure pat00054

Figure pat00055

Figure pat00056

Figure pat00057
The method of claim 1,
Compounds or stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein the compound of Formula 1 is any one selected from the group consisting of:
Figure pat00054

Figure pat00055

Figure pat00056

Figure pat00057
 제1항에 있어서,
화학식 1의 화합물이 아래 화합물로 구성된 군으로부터 선택된 어느 하나인 것을 특징으로 하는 화합물 또는 이의 입체이성질체 또는 이들의 약제학적으로 허용되는 염:
Figure pat00058

Figure pat00059
The method of claim 1,
Compounds or stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein the compound of Formula 1 is any one selected from the group consisting of:
Figure pat00058

Figure pat00059
 제1항 내지 제4항 중 어느 한 항의 화합물 또는 이의 약제학적으로 허용되는 염을 유효성분으로 포함하는, 대사 관련 장애 치료용 약학 조성물.
A pharmaceutical composition for treating metabolic related disorders comprising the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient.
제5항에 있어서,
상기 대사 관련 장애는 비만, I형 당뇨병, II형 당뇨병, 부적합한 내당력, 인슐린 내성, 고혈당증, 고지질혈증, 고중성지방혈증, 고콜레스테롤혈증, 이상지질혈증 및 X 증후군으로 구성된 군에서 선택된 어느 하나인 것을 특징으로 하는, 대사 관련 장애 치료용 약학 조성물.
The method of claim 5,
The metabolic related disorder is any one selected from the group consisting of obesity, type I diabetes, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and X syndrome A pharmaceutical composition for treating metabolic related disorders.
하기 화학식 4의 화합물과 하기 화학식 5의 화합물을 반응시켜 제1항의 화합물을 제조하는 방법:

[화학식 4]
Figure pat00060

[화학식 5]
Figure pat00061

상기 화학식에서,
A 및 B는 할로겐이고,
X, Y, L1, R4, n4, Z1, Z2, P1, P2 및 P3는 제1항에서 정의한 바와 같다. A method of preparing the compound of claim 1 by reacting a compound of Formula 4 with a compound of Formula 5

[Chemical Formula 4]
Figure pat00060

[Chemical Formula 5]
Figure pat00061

In the above formulas,
A and B are halogen,
X, Y, L 1 , R 4, n 4 , Z 1 , Z 2 , P 1 , P 2 and P 3 are as defined in claim 1.
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