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). ##STR00001##
Inventor(s):	Luo; Guanglin (Madison, CT), Dubowchik; Gene M. (Middlefield, CT), Macor; John E. (Gullford, CT)
Assignee:	Bristol-Myers Squibb Company (Princeton, NJ)
Application Number:	12/902,714
Patent Claims:	1. A compound of Formula I ##STR00080## where: R.sup.1 is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl; R.sup.2 is piperidinyl substituted with 1 substituent selected from the group consisting of ##STR00081## ##STR00082## R.sup.3 is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy; R.sup.4 is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy; R.sup.5 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R.sup.6 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R.sup.7 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R.sup.8 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R.sup.9 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R.sup.10 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R.sup.11 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, dialkylamino, alkoxycarbonyl, or benzyloxycarbonyl; or R.sup.10 and R.sup.11 taken together is O or N--OH; provided that at least one of R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, or R.sup.11 is not hydrogen; Ar.sup.1 is phenyl substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkylSO.sub.2; X is O, CH.sub.2, or NH; and Y is a bond, O, CH.sub.2, or NH; or a pharmaceutically acceptable salt thereof. 2. A compound of claim 1 where: R.sup.1 is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl; R.sup.2 is piperidinyl substituted with 1 substituent selected from the group consisting of ##STR00083## ##STR00084## R.sup.3 is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy; R.sup.4 is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy; R.sup.5 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R.sup.6 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R.sup.7 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R.sup.8 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R.sup.9 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R.sup.10 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R.sup.11 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; or R.sup.10 and R.sup.11 taken together is oxo; provided that at least one of R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, or R.sup.11 is not hydrogen; Ar.sup.1 is phenyl substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkylSO.sub.2; X is O, CH.sub.2, or NH; and Y is a bond, O, CH.sub.2, or NH; or a pharmaceutically acceptable salt thereof. 3. A compound of claim 1 with the designated stereochemistry. ##STR00085## 4. A compound of claim 3 where R.sup.1 is hydrogen, halo, cyano, amino, alkylamino, or dialkylamino; R.sup.2 is piperidinyl substituted with 1 substituent selected from the group consisting of ##STR00086## R.sup.3 is hydrogen or halo; R.sup.4 is hydrogen or halo; R.sup.5 is hydrogen or hydroxy; R.sup.6 is hydrogen; R.sup.7 is hydrogen; R.sup.8 is hydrogen; R.sup.9 is hydrogen or hydroxy; R.sup.10 is hydrogen, hydroxy, azido, amino, alkylamino, or dialkylamino; R.sup.11 is hydrogen; or R.sup.10 and R.sup.11 taken together is oxo; provided that at least one of R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, or R.sup.11 is not hydrogen; Ar.sup.1 is phenyl substituted with 0-2 halo substituents; X is O, CH.sub.2, or NH; and Y is O; or a pharmaceutically acceptable salt thereof. 5. A compound of claim 4 where R.sup.1 is hydrogen; R.sup.2 is piperidinyl substituted with 1 substituent selected from the group consisting of ##STR00087## R.sup.5 is hydrogen or hydroxy; R.sup.6 is hydrogen; R.sup.7 is hydrogen; R.sup.8 is hydrogen; R.sup.9 is hydrogen or hydroxy; R.sup.10 is hydroxy, azido, or amino; R.sup.11 is hydrogen; or R.sup.10 and R.sup.11 taken together is oxo; provided that at least one of R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, or R.sup.11 is not hydrogen; Ar.sup.1 is phenyl or difluorophenyl; X is O, CH.sub.2, or NH; and Y is O; or a pharmaceutically acceptable salt thereof. 6. A compound of claim 1 where R.sup.1 is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl. 7. A compound of claim 1 where R.sup.2 is N-piperidinyl and is 4-substituted. 8. A compound of claim 7 where the substituent is ##STR00088## 9. A compound of claim 1 where R.sup.5 is hydrogen, R.sup.6 is hydrogen, R.sup.7 is hydrogen, R.sup.8 is hydrogen, R.sup.9 is hydrogen, R.sup.10 is hydroxy, azido, or amino, and R.sup.11 is hydrogen; or where R.sup.5 is hydrogen, R.sup.6 is hydrogen, R.sup.7 is hydrogen, R.sup.8 is hydrogen, R.sup.9 is hydrogen or hydroxy, and R.sup.10 and R.sup.11 taken together is oxo; or where R.sup.5 is hydrogen, R.sup.6 is hydrogen, R.sup.7 is hydrogen, R.sup.8 is hydrogen, R.sup.9 is hydroxy, R.sup.10 is hydrogen or hydroxy, and R.sup.11 is hydrogen; or where R.sup.5 is hydroxy, R.sup.6 is hydrogen, R.sup.7 is hydrogen, R.sup.8 is hydrogen, R.sup.9 is hydrogen, R.sup.10 is hydrogen, and R.sup.11 is hydrogen. 10. A compound of claim 1 where Ar.sup.1 is phenyl substituted with 2 halo substituents. 11. A compound of claim 10 where Ar.sup.1 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-cycl- ohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxyla- te; (9R)-6-(2,3-difluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-cyclohepta[b]p- yridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxyla- te; (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-carboxyla- te; (5S,6S,9R)-6-(2,3-difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cycl- ohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxyla- te; (5S,6S,9R)-6-(2,3-difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cycl- ohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxyla- te; (5S,6R,9R)-6-(2,3-difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cycl- ohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxyla- te; (5S,6S,9R)-5-azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloh- epta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxyla- te; (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloh- epta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxyla- te; (6S,9R)-6-(2,3-difluorophenyl)-6-hydroxy-6,7,8,9-tetrahydro-5H-cyclohe- pta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxyla- te; (5S,6S,9R)-5-amino-6-(3,5-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloh- epta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxyla- te; (5S,6S,9R)-6-(3,5-difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cycl- ohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxyla- te; (6S,8R,9S)-6-(2,3-difluorophenyl)-8-hydroxy-6,7,8,9-tetrahydro-5H-cycl- ohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxyla- te; (5S,6S,9R)-6-(2,3-difluorophenyl)-5-(methylamino)-6,7,8,9-tetrahydro-5- H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxyla- te; (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-carboxyla- te; (5S,9R,Z)-6-(2,3-difluorophenyl)-5-(hydroxyimino)-6,7,8,9-tetrahydro-5- H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxyla- te; (6S,9R,E)-6-(2,3-difluorophenyl)-5-(hydroxyimino)-6,7,8,9-tetrahydro-5- H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxyla- te; (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloh- epta[b]pyridin-9-yl 2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridine]-5-yl- carbamate; tert-butyl(5S,6S,9R)-9-amino-6-(2,3-difluorophenyl)-6,7,8,9-tet- rahydro-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-imi- dazo[4,5-b]pyridin-1-yl)piperidin-1-yl)ethyl)-6,7,8,9-tetrahydro-5H-cycloh- epta[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-imi- dazo[4,5-b]pyridin-1-yl)piperidin-1-yl)ethyl)-6,7,8,9-tetrahydro-5H-cycloh- epta[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-cyclohept- a[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxyla- te; ##STR00089## 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-cyclohept- a[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxyla- te. 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-cyclohept- a[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxyla- te.