Claims for Patent: 8,314,117

Summary for Patent: 8,314,117

Title:	CGRP receptor antagonists
Abstract:	The disclosure generally relates to the novel compounds of formula I, including pharmaceutically acceptable salts, which are CGRP receptor antagonists. The disclosure also relates to pharmaceutical compositions and methods for using the compounds in the treatment of CGRP related disorders including migraine and other headaches, neurogenic vasodilation, neurogenic inflammation, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases such as asthma, and chronic obstructive pulmonary disease (COPD).
Inventor(s):	Guanglin Luo, Gene M. Dubowchik, John E. Macor
Assignee:	Bristol Myers Squibb Co
Application Number:	US12/902,714
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,314,117
Patent Claims:	1. A compound of Formula I where: R1 is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl; R2 is piperidinyl substituted with 1 substituent selected from the group consisting of R3 is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy; R4 is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy; R5 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R6 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R7 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R8 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R9 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R10 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R11 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, dialkylamino, alkoxycarbonyl, or benzyloxycarbonyl; or R10 and R11 taken together is O or N—OH; provided that at least one of R5, R6, R7, R8, R9, R10, or R11 is not hydrogen; Ar1 is phenyl substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkylSO2; X is O, CH2, or NH; and Y is a bond, O, CH2, or NH; or a pharmaceutically acceptable salt thereof. 2. A compound of claim 1 where: R1 is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl; R2 is piperidinyl substituted with 1 substituent selected from the group consisting of R3 is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy; R4 is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy; R5 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R6 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R7 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R8 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R9 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R10 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R11 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; or R10 and R11 taken together is oxo; provided that at least one of R5, R6, R7, R8, R9, R10, or R11 is not hydrogen; Ar1 is phenyl substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkylSO2; X is O, CH2, or NH; and Y is a bond, O, CH2, or NH; or a pharmaceutically acceptable salt thereof. 3. A compound of claim 1 with the designated stereochemistry. 4. A compound of claim 3 where R1 is hydrogen, halo, cyano, amino, alkylamino, or dialkylamino; R2 is piperidinyl substituted with 1 substituent selected from the group consisting of R3 is hydrogen or halo; R4 is hydrogen or halo; R5 is hydrogen or hydroxy; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen or hydroxy; R10 is hydrogen, hydroxy, azido, amino, alkylamino, or dialkylamino; R11 is hydrogen; or R10 and R11 taken together is oxo; provided that at least one of R5, R6, R7, R8, R9, R10, or R11 is not hydrogen; Ar1 is phenyl substituted with 0-2 halo substituents; X is O, CH2, or NH; and Y is O; or a pharmaceutically acceptable salt thereof. 5. A compound of claim 4 where R1 is hydrogen; R2 is piperidinyl substituted with 1 substituent selected from the group consisting of R5 is hydrogen or hydroxy; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen or hydroxy; R10 is hydroxy, azido, or amino; R11 is hydrogen; or R10 and R11 taken together is oxo; provided that at least one of R5, R6, R7, R8, R9, R10, or R11 is not hydrogen; Ar1 is phenyl or difluorophenyl; X is O, CH2, or NH; and Y is O; or a pharmaceutically acceptable salt thereof. 6. A compound of claim 1 where R1 is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl. 7. A compound of claim 1 where R2 is N-piperidinyl and is 4-substituted. 8. A compound of claim 7 where the substituent is 9. A compound of claim 1 where R5 is hydrogen, R6 is hydrogen, R7 is hydrogen, R8 is hydrogen, R9 is hydrogen, R10 is hydroxy, azido, or amino, and R11 is hydrogen; or where R5 is hydrogen, R6 is hydrogen, R7 is hydrogen, R8 is hydrogen, R9 is hydrogen or hydroxy, and R10 and R11 taken together is oxo; or where R5 is hydrogen, R6 is hydrogen, R7 is hydrogen, R8 is hydrogen, R9 is hydroxy, R10 is hydrogen or hydroxy, and R11 is hydrogen; or where R5 is hydroxy, R6 is hydrogen, R7 is hydrogen, R8 is hydrogen, R9 is hydrogen, R10 is hydrogen, and R11 is hydrogen. 10. A compound of claim 1 where Ar1 is phenyl substituted with 2 halo substituents. 11. A compound of claim 10 where Ar1 is 2,3-difluorophenyl. 12. A compound of claim 1 where X is O. 13. A compound of claim 1 selected from the group consisting of (6R,9R)-6-(2,3-Difluorophenyl)-6-hydroxy-5-oxo-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; (9R)-6-(2,3-difluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; (5S,6R,9R)-6-(2,3-difluorophenyl)-5,6-dihydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; (5S,6S,9R)-6-(2,3-difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; (5S,6S,9R)-6-(2,3-difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; (5S,6R,9R)-6-(2,3-difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; (5S,6S,9R)-5-azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; (6S,9R)-6-(2,3-difluorophenyl)-6-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; (5S,6S,9R)-5-amino-6-(3,5-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; (5S,6S,9R)-6-(3,5-difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; (6S,8R,9S)-6-(2,3-difluorophenyl)-8-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; (5S,6S,9R)-6-(2,3-difluorophenyl)-5-(methylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; (5S,6S,9R)-6-(2,3-difluorophenyl)-5-(dimethylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; (5S,9R,Z)-6-(2,3-difluorophenyl)-5-(hydroxyimino)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; (6S,9R,E)-6-(2,3-difluorophenyl)-5-(hydroxyimino)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-ylcarbamate; tert-butyl(5S,6S,9R)-9-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ylcarbamate; tert-butyl (5S,6S,9S)-6-(2,3-difluorophenyl)-9-(2-oxo-2-(4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl)ethyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-yl carbamate; tert-butyl (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(2-oxo-2-(4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl)ethyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ylcarbamate; and 1-(1-(2-((5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one; or a pharmaceutically acceptable salt thereof. 14. The compound of claim 1 (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; or a pharmaceutically acceptable salt thereof. 15. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 16. The pharmaceutical composition of claim 15 where the compound of claim 1 is (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate. 17. A method of treating migraine comprising the administration of a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, to a patient. 18. The method of claim 17 where the compound of claim 1 is (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate.