CALCITONIN GENE RELATED PEPTIDE RECEPTOR ANTAGONISTSThe present invention relates to compounds of Formula (I) as antagonists of calcitonin gene-related peptide receptors ("CGRP-receptor"), pharmaceutical compositions comprising them, methods for identifying them, methods of treatment using them and their use in therapy for treatment of neurogenic vasodilation, neurogenic inflammation, migraine and other headaches, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), and other conditions the treatment of which can be effected by the antagonism of CGRP-receptors.A compound selected from the group consisting of(±)-3-(3-Cyano-lH-indol-5-yl)-2-{[4-(2-oxo-l,4-dihydro-2H-quinazolin-3-yl)- piperidine-l-carbonyl]-amino}-propionic acid methyl ester; (±)-4-(2-Oxo-l,4-dihydro-2H-quinazolin-3-yl)-piperidine-l -carboxylic acid [2-[l,4']bipiperidinyl-r-yl-l-(3-cyano-lH-indol-5-yl-methyl)-2-oxo-ethyl]-amide;(±)-4-(2-Oxo- 1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1 -carboxylic acid [2-[l,4']bipiperidinyl-r-yl-l(3-cyano-7-methyl-lH-indol-5-yl-methyl)-2-oxo-ethyl]- amide; (±)-3-(7-Isoρropyl- 1 H-indazol-5-yl)-2- { [4-(2-oxo- 1 ,4-dihydro-2H-quinazolin-3-yl)- piperidine-l-carbonyl]-amino}-propionic acid methyl ester;(±)-4-(2-Oxo-l ,4-dihydro-2H-quinazolin-3-yl)-piperidine-l -carboxylic acid [2-[l,4']bipiperidinyl-r-yl-l(7-isopropyl-lH-indazol-5-yl-methyl)-2-oxo-ethyl]-amide;(±)-4-(2-Oxo-l,4-dihydro-2H-quinazolin-3-yl)-piperidine-l -carboxylic acid [2- [l,4']bipiperidinyl-l '-yl-l(7-ethyl-lH-indazol-5-yl-methyl)-2-oxo-ethyl]-amide;(±)-4-(2,2-Dioxo-l,4-dihydro-2H-2λ6-benzo[l,2,6]thiadiazin-3-yl)-piperidine-l- carboxylic acid [2-[l,4']bipiperidinyl-r-yl-l(7-methyl-lH-indazol-5-yl-methyl)-2- oxo-ethyl] -amide;(±)-4-(2,2-Dioxo- 1 ,4-dihydro-2H-2λ6-benzo[ 1 ,2,6]thiadiazin-3-yl)-piperidine- 1 - carboxylic acid [2-[l,4']bipiperidinyl-l '-yl-l(7-ethyl-3-methyl-lH-indazol-5-yl- methyl)-2-oxo-ethyl] -amide;(±)-2-[4-(6-Cyano-2-oxo-l,4-dihydro-2H-qinazolin-3-yl)-piperidine-l-carbonyl]- amino]-3-(7-methyl-lH-indazol-5-yl)-propionic acid methyl ester;(±)-4-(6-Cyano-2-oxo-l,4-dihydro-2H-qinazolin-3-yl)-piperidine-l -carboxylic acid {2-[l,4']bipiperidinyl-l '-yl-l-(7-methyl-lH-indazol-5-yl methyl)-2-oxo-ethyl}- amide;(±)-4-(2-Oxo-l,2,4,5-tetrahydro-benzo[d][l,3]diazepin-3-yl-l -carboxylic acid {2-[ 1 ,4']bipiperidinyl- 1 '-yl- 1 -(7-methyl- 1 H-indazol-5-yl methyl)-2-oxo-ethyl} -amide;(±)-4-(6-Hydroxy-2-oxo-l,4-dihydro-2H-qinazolin-3-yl)-piperidine-l -carboxylic acid {2-[l,4']bipiperidinyl-l '-yl-l-(7-methyl-lH-indazol-5-yl methyl)-2-oxo-ethyl}- amide; (±)-4-(8-Methoxy-2-oxo- 1 ,4-dihydro-2H-qinazolin-3-yl)-piperidine- 1 -carboxylic acid {2-[l,4']bipiperidinyl-l '-yl-l-(7-methyl-lH-indazol-5-yl methyl)-2-oxo-ethyl}- amide;(±)-4-(8-Chloro-2-oxo- 1 ,4-dihydro-2H-qinazolin-3-yl)-piperidine- 1 -carboxylic acid {2-[l,4']biρiperidinyl-l '-yl-1 -(7-methyl- 1 H-indazol-5 -yl methyl)-2-oxo-ethyl}- amide;(±)-N-(3-(7-Ethyl-3-methyl- 1 H-indazol-5-yl)- 1 -oxo- 1 -(4-(piperidin- 1 -yl)piperidin- 1 - yl)propan-2-yl)-2 ' ,3 ' -dihydro-2 ' -oxospiro-(piperidine-4,4 ' -quinazoline)- 1 - carboxamide; (±)-N-(3-(7-Ethyl-3-methyll H-indazol-5-yl)- 1 -oxo- 1 -(4-(piperidin- 1 -yl)piperidin- 1 - yl)propan-2-yl)-2,4-dihydro-2'-oxospiro-(piperidine-4,4'-lH-benzo[d][l,3]oxazine)-1 -carboxamide;(±)-N-(3-(7-Ethyl-lH-indazol-5-yl)-l-(6,7-dihydro-lH-pyrazolo[4,3-c]pyridin-5(4H)- yl)- 1 -oxopropan-2-yl)-4-( 1 ,2-dihydro-2-oxoquinazolin-3 (4H)-yl)piperidine- 1 - carboxamide;(±)-N-(3-(7-Ethyl-lH-indazol-5-yl)-l-(6,7-dihydro-7,7-dimethyl-lH-pyrazolo[4,3- c]pyridin-5(4H)-yl)-l-oxopropan-2-yl)-4-(l,2-dihydro-2-oxoquinazolin-3(4H)- yl)piperidine- 1 -carboxamide;(±)-Methyl 2-(4-(8-fluoro-l ,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-l - carboxamido)-3-(7-methyl- 1 H-indazol-5-yl)propanoate;(±)-4-(8-Fluoro-l,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3-(7-methyl-lH-indazol-5-yl)- 1 -oxo- 1 -(4-(piperidin- 1 -yl)piperidin- 1 -yl)propan-2-yl)piperidine- 1 - carboxamide;(±)-4-(8-Fluoro- 1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3-(7-methyl- 1 H-indazol- 5-yl)- 1 -oxo- 1 -(4-phenylpiperazin-l -yl)propan-2-yl)piperidine-l -carboxamide;(±)-4-(8-Fluoro-l,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(l-(4-(4- fluorophenyl)piperazin- 1 -yl)-3-(7-methyl- 1 H-indazol-5-yl)- 1 -oxopropan-2- yl)piperidine- 1 -carboxamide;(±)-4-(8-Fluoro-l,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(l-(4-(2- fluorophenyl)piperazin-l-yl)-3-(7-methyl-lH-indazol-5-yl)-l-oxopropan-2- yl)piperidine- 1 -carboxamide;(±)-4-(8-Fluoro-l,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3-(7-methyl-lH-indazol-5 -yl)- 1 -oxo- 1 -(4-o-tolylpiperazin- 1 -yl)propan-2-yl)piperidine- 1 -carboxamide; (±)-Methyl 2-(4-(8-fluoro- 1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine- 1 - carboxamido)-3-(7-ethyl-3-methyl- 1 H-indazol-5-yl)propanoate;(±)-N-(3-(7-Ethyl-3-methyl- 1 H-indazol-5-yl)- 1 -oxo- 1 -(4-(piperidin- 1 -yl)piperidin- 1 - yl)propan-2-yl)-4-(8-fluoro- 1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine- 1 - carboxamide;(R)-N-((R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)- 1 -oxo- 1 -(4-(piperidin- 1 - yl)piperidin- 1 -yl)propan-2-yl)-4-(8-fluoro- 1 ,2-dihydro-2-oxoquinazolin-3(4H)- yl)piperidine- 1 -carboxamide;(±)-N-(3 -(7-Methyl- 1 H-indazol-5-yl)- 1 -oxo- 1 -(4-(piperidin- 1 -yl)piperidin- 1 - yl)propan-2-yl)-8 ' -fluoro-2 ' ,3 ' -dihydro-2 ' -oxospiro-(piperidine-4,4 ' -quinazoline)- 1 - carboxamide;(±)-4-(8-Fluoro-l,2-dihydro-2,4-dioxoquinazolin-3(4H)-yl)-N-(3-(7-methyl-lH- indazol-5 -yl)- 1 -oxo- 1 -(4-(piperidin- 1 -yl)piperidin- 1 -yl)propan-2-yl)piperidine- 1 - carboxamide; N-((R)-3-(2-(tr...
칼시토닌 유전자 관련 펩티드 수용체 길항제 본 발명은 칼시토닌 유전자-관련 펩티드 수용체 ("CGRP-수용체")로서의 화학식 (I)의 화합물, 이를 포함하는 제약 조성물, 이를 확인하는 방법, 이를 사용하는 치료 방법, 및 신경성 혈관확장, 신경성 염증, 편두통 및 다른 두통, 열성 손상, 순환성 쇼크, 폐경기 관련 홍조, 천식 및 만성 폐쇄성 폐질환 (COPD)과 같은 기도 염증성 질환, CGRP 수용체의 길항작용에 의해 효과를 볼 수 있는 다른 상태의 치료요법에서 이들의 용도에 관한 것이다. (±)-3-(3-시아노-1H-인돌-5-일)-2-{[4-(2-옥소-1,4-디히드로-2H-퀴나졸린-3-일)-피페리딘-1-카르보닐]-아미노}-프로피온산 메틸 에스테르; (±)-4-(2-옥소-1,4-디히드로-2H-퀴나졸린-3-일)-피페리딘-1-카르복실산 [2-[1,4']비피페리디닐-1'-일-1-(3-시아노-1H-인돌-5-일-메틸)-2-옥소-에틸]-아미드; (±)-4-(2-옥소-1,4-디히드로-2H-퀴나졸린-3-일)-피페리딘-1-카르복실산 [2-[1,4']비피페리디닐-1'-일-1(3-시아노-7-메틸-1H-인돌-5-일-메틸)-2-옥소-에틸]-아미드; (±)-3-(7-이소프로필-1H-인다졸-5-일)-2-{[4-(2-옥소-1,4-디히드로-2H-퀴나졸린-3-일)-피페리딘-1-카르보닐]-아미노}-프로피온산 메틸 에스테르; (±)-4-(2-옥소-1,4-디히드로-2H-퀴나졸린-3-일)-피페리딘-1-카르복실산 [2-[1,4']비피페리디닐-1'-일-1(7-이소프로필-1H-인다졸-5-일-메틸)-2-옥소-에틸]-아미드; (±)-4-(2-옥소-1,4-디히드로-2H-퀴나졸린-3-일)-피페리딘-1-카르복실산 [2-[1,4']비피페리디닐-1'-일-1(7-에틸-1H-인다졸-5-일-메틸)-2-옥소-에틸]-아미드; (±)-4-(2,2-디옥소-1,4-디히드로-2H-2λ6-벤조[1,2,6]티아디아진-3-일)-피페리딘-1-카르복실산 [2-[1,4']비피페리디닐-1'-일-1(7-메틸-1H-인다졸-5-일-메틸)-2-옥소-에틸]-아미드; (±)-4-(2,2-디옥소-1,4-디히드로-2H-2λ6-벤조[1,2,6]티아디아진-3-일)-피페리딘-1-카르복실산 [2-[1,4']비피페리디닐-1'-일-1(7-에틸-3-메틸-1H-인다졸-5-일-메틸)-2-옥소-에틸]-아미드; (±)-2-[4-(6-시아노-2-옥소-1,4-디히드로-2H-퀴나졸린-3-일)-피페리딘-1-카르보닐]-아미노]-3-(7-메틸-1H-인다졸-5-일)-프로피온산 메틸 에스테르; (±)-4-(6-시아노-2-옥소-1,4-디히드로-2H-퀴나졸린-3-일)-피페리딘-1-카르복실산 {2-[1,4']비피페리디닐-1'-일-1-(7-메틸-1H-인다졸-5-일 메틸)-2-옥소-에틸}-아미드; (±)-4-(2-옥소-1,2,4,5-테트라히드로-벤조[d][1,3]디아제핀-3-일-1-카르복실산 {2-[1,4']비피페리디닐-1'-일-1-(7-메틸-1H-인다졸-5-일 메틸)-2-옥소-에틸}-아미드; (±)-4-(6-히드록시-2-옥소-1,4-디히드로-2H-퀴나졸린-3-일)-피페리딘-1-카르복실산 {2-[1,4']비피페리디닐-1'-일-1-(7-메틸-1H-인다졸-5-일 메틸)-2-옥소-에틸}-아미드; (±)-4-(8-메톡시-2-옥소-1,4-디히드로-2H-퀴나졸린-3-일)-피페리딘-1-카르복실산 {2-[1,4']비피페리디닐-1'-일-1-(7-메틸-1H-인다졸-5-일 메틸)-2-옥소-에틸}-아미드; (±)-4-(8-클로로-2-옥소-1,4-디히드로-2H-퀴나졸린-3-일)-피페리딘-1-카르복실산 {2-[1,4']비피페리디닐-1'-일-1-(7-메틸-1H-인다졸-5-일 메틸)-2-옥소-에틸}-아미드; (±)-N-(3-(7-에틸-3-메틸-1H-인다졸-5-일)-1-옥소-1-(4-(피페리딘-1-일)피페리딘-1-일)프로판-2-일)-2',3'-디히드로-2'-옥소스피로-(피페리딘-4,4'-퀴나졸린)-1-카르복스아미드; (±)-N-(3-(7-에틸-3-메틸-1H-인다졸-5-일)-1-옥소-1-(4-(피페리딘-1-일)피페리딘-1-일)프로판-2-일)-2,4-디히드로-2'-옥소스피로-(피페리딘-4,4'-1H-벤조[d][1,3]옥사진)-1-카르복스아미드; (±)-N-(3-(7-에틸-1H-인다졸-5-일)-1-(6,7-디히드로-1H-피라졸로[4,3-c]피리딘-5(4H)-일)-1-옥소프로판-2-일)-4-(1,2-디히드로-2-옥소퀴나졸린-3(4H)-일)피페리딘-1-카르복스아미드; (±)-N-(3-(7-에틸-1H-인다졸-5-일)-1-(6,7-디히드로-7,7-디메틸-1H-피라졸로[4,3-c]피리딘-5(4H)-일)-1-옥소프로판-2-일)-4-(1,2-디히드로-2-옥소퀴나졸린-3(4H)-일)피페리딘-1-카르복스아미드; (±)-메틸 2-(4-(8-플루오로-1,2-디히드로-2-옥소퀴나졸린-3(4H)-일)피페리딘-1-카르복스아미도)-3-(7-메틸-1H-인다졸-5-일)프로파노에이트; (±)-4-(8-플루오로-1,2-디히드로-2-옥소퀴나졸린-3(4H)-일)-N-(3-(7-메틸-1H-인다졸-5-일)-1-옥소-1-(4-(피페리딘-1-일)피페리딘-1-일)프로판-2-일)피페리딘-1-카르복스아미드; (±)-4-(8-플루오로-1,2-디히드로-2-옥소퀴나졸린-3(4H)-일)-N-(3-(7-메틸-1H-인다졸-5-일)-1-옥소-1-(4-페닐피페라진-1-일)프로판-2-일)피페리딘-1-카르복스아미드; (±)-4-(8-플루오로-1,2-디히드로-2-옥소퀴나졸린-3(4H)-일)-N-(1-(4-(4-플루오로페닐)피페라진-1-일)-3-(7-메틸-1H-인다졸-5-일)-1-옥소프로판-2-일)피페리딘-1-카르복스아미드; (±)-4-(8-플루오로-1,2-디히드로-2-옥소퀴나졸린-3(4H)-일)-N-(1-(4-(2-플루오로페닐)피페라진-1-일)-3-(7-메틸-1H-인다졸-5-일)-1-옥소프로판-2-일)피페리딘-1-카르복스아미드; (±)-4-(8-플루오로-1,2-디히드로-2-옥소퀴나졸린-3(4H)-일)-N-(3-(7-메틸-1H-인다졸-5-일)-1-옥소-1-(4-o-톨릴피페라진-1-일)프로판-2-일)피페리딘-1-카르복스아미드; (±)-메틸 2-(4-(8-플루오로-1,2-디히드로-2-옥소퀴나졸린-3(4H)-일)피페리딘-1-카르복스아미도)-3-(7-에틸-3-메틸-1H-인다졸-5-일)프로파노에이트; (±)-N-(3-(7-에틸-3-메틸-1H-인다졸-5-일)-1-옥소-1-(4-(피페리딘-1-일)피페리딘-1-일)프로판-2-일)-4-(8-플루오로-1,2-디히드로-2-옥소퀴나졸린-3(4H)-일)피페리딘-1-카르복스아미드; (R)-N-((R)-3-(2-옥소-2,3-디히드로-벤조옥사졸-6-일)-1-옥소-1-(4-피페리딘-1-일)피페리딘-1-일)프로판-2-일)-4-(8-플루오로-1,2-디히드로-2-옥소퀴나졸린-3(4H)-일)피페리딘-1-카르복스아미드; (±)-N-(3-(7-메틸-1H-인다졸-5-일)-1-옥소-1-(4-(피페리딘-1-일)피페리딘-1-일)프로판-2-일)-8'-플루오로-2',3'-디히드로-2'-옥소스피로-(피페리딘-4,4'-퀴나졸린)-1-카르복스아미드; (±)-4-(8-플루오로-1,2-디히드로-2,4-디옥소퀴나졸린-3(4H)-일)-N-(3-(7-메틸-1H-인다졸-5-일)-1-옥소-1-(4-(피페리딘-1-일)피페리딘-1-일)프로판-2-일)피페리딘-1-카르복스아미드; N-((R)-3-(2-(트리플루오로메틸)-1H-벤조[d]이미다졸-5-일)-1-옥소-1-(4-(피페리딘-1-일)피페리딘-1-일)프로판-2-일)-4-(1,2-디히드로-2-옥소퀴나졸린-3(4H)-일)피페리딘-1-카르복스아미드; N-((R)-1-(디메틸카르바모일)-2-(2-(트리플루오로메틸)-1H-벤조[d]이미다졸-5-일)에틸)-4-(1,2-디히드로-2-옥소퀴나졸린-3(4H)-일)피페리딘-1-카르복스아미드; (R)-메틸 2-(4-(1,2-디히드로-2-옥소퀴나졸린-3(4H)-일)피페리딘-1-카르복스아미도)-3-(2,3-디히드로-2-옥소-1H-벤조[d]이미다졸-6-일)프로파노에이트; N-((R)-3-(2,3-디히드로-2-옥소-1H-벤조[d]이미다졸-6-일)-1-옥소-1(4-피페리딘-1-일)피페리딘-1-일)프로판-2-일)-4-(1,2-디히드로-2-옥소퀴나졸린-3(4H)-일)피페리딘-1-카르복스아미드; N-((R)-1-(디메틸카르바모일)-2-(2,3-디히드로-2-옥소-1H-벤조[d]이미다졸-6-일)에틸)-4-(1,2-디히드로-2-옥소퀴나졸린-3(4H)-일)피페리딘-1-카르복스아미드; N-((R)-3-(2,3-디히드로-2-옥소-1H-벤조[d]이미다졸-6-일)-1-옥소-1(4-피페리딘-1-일)피페리딘-1-일)프로판-2-일)-4-(2',3'-디히드로-2'-옥소스피로(피페리딘-4,4'-(1H)-퀴나졸린)카르복스아미드; 4-(1,2-디히드로-2,4-디옥소퀴나졸린-3(4H)-일)-N-((R)-3-(7-메틸-1H-벤조[d][1,2,3]트리아졸-5-일)-1-옥소-1-(4-(피페리딘-1-일)피페리딘-1-일)프로판-2-일)피페리딘-1-카르복스아미드; (R)-4-(2-옥소-1,4-디히드로-2H-퀴나졸린-3-일)-피페리딘-1-카르복실산 [2-(4-시클로헥실-피페라진-1-일)-2-옥소-1-(2-옥소-2,3-디히드로-벤조옥사졸-6-일메틸)-에틸]-아미드; (R)-4-(2-옥소-1,4-디히드로-2H-퀴나졸린-3-일)-피페리딘-1-카르복실산 [2-(4-이소프로필-피페라진-1-일)-2-옥소-1-(2-옥소-2,3-디히드로-벤조옥사졸-6-일메틸)-에틸]-아미드; (R)-N-((R)-3-(2-옥소-2,3-디히드로-벤조옥사졸-6-일)-1-옥소-1-(4-(피페리딘-1-일)피페리딘-1-일)프로판-2-일)-2,4-디히드로-2'-옥소스피로-(피페리딘-4,4'-1H-벤조[d][1,3]옥사진)-1-카르복스아미드; (R)-N-((R)-3-(2-옥소-2,3-디히드로-벤조옥사졸-6-일)-1-옥소-1-(4-(시클로헥스-1-일)피페라진-1-일)프로판-2-일)-2,4-디히드로-2'-옥소스피로-(피페리딘-4,4'-1H-벤조[d][1,3]옥사진)-1-카르복스아미드; (R)-N-((R)-3-(2-옥소-2,3-디히드로-벤조옥사졸-6-일)-1-옥소-1-(4-(프로프-2-일)피페라진-1-일)프로판-2-일)-2,4-디히드로-2'-옥소스피로-(피페리딘-4,4'-1H-벤조[d][1,3]옥사진)-1-카르복스아미드; (R)-N-((R)-3-(2-옥소-2,3-디히드로-벤조옥사졸-6-일)-1-옥소-1-(4-(피페리딘-1-일)피페리딘-1-일)프로판-2-일)-2,4-디히드로-2'-옥소스피로-(피페리딘-4,4'-1H-퀴나졸린)-1-카르복스아미드; (R)-N-((R)-3-(2-옥소-2,3-디히드로-벤조옥사졸-6-일)-1-옥소-1-(4-(시클로헥스-1-일)피페라진-1-일)프로판-2-일)-2,4-디히드로-2'-옥소스피로-(피페리딘-4,4'-1H-퀴나졸린)-1-카르복스아미드; (R)-N-((R)-3-(2-옥소-2,3-디히드로-벤조옥사졸-6-일)-1-옥소-1-(4-(프...