CGRP receptor antagonists
The disclosures herein relate to novel compounds of formula wherein R 1 , R 2 , R 3 and R 4 are as defined herein, and their use in treating, preventing, ameliorating, controlling or reducing cerebrovascular or vascular disorders associated with CGRP receptor function.
1. A compound of formula (I)
or a salt thereof, wherein R 1 is H or Q-(C 1 -C 6 )alkyl; where Q is a bond, C(O) or C(O)O and where the (C 1 -C 6 )alkyl can be optionally substituted by N(C 1 -C 3 alkyl) 2 or CO 2 H;
R 2 is H or forms a spirocyclic heterocyclic ring with R 3 ;
R 3 forms a spirocyclic heterocyclic ring with R 2 or is a heterocyclic ring if R 2 is H; and
R 4 is an optionally substituted aryl group which is fused to a further ring.
2. The compound according to claim 1 , or a salt thereof, wherein R 4 is
3. The compound according to claim 1 , or a salt thereof, wherein R 2 is H and R 3 is:
4. The compound according to claim 1 , or a salt thereof, wherein R 2 forms a spirocyclic heterocyclic ring with R 3 to form:
5. The compound according to claim 1 , or a salt thereof, wherein R 2 is H or forms a spirocyclic heterocyclic ring with R 3 to form:
and wherein when R 2 is H, R 3 is:
and
R 4 is:
6. The compound according to claim 1 , or a salt thereof, wherein R 1 is H, CO 2 t Bu, CH 2 CH 3 , CH 2 CH 2 CH 3 , COCH 2 CH 2 CH 2 CH 3 , CH 2 CH 2 N(CH 3 ) 2 , COCH 2 CO 2 H.
7. The compound according to claim 1 , or a salt thereof, wherein R 1 is H.
8. The compound according to claim 1 , wherein the compound is selected from the group consisting of:
N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide;
tert-butyl 4-{(2S)-2-{[(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoyl]amino}-3-oxo-3-[4-(pyridin-4-yl)piperazin-1-yl]propyl}piperidine-1-carboxylate;
N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide;
N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(1-propylpiperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide;
N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(1-pentanoylpiperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide;
N-[(2R)-1-({(2S)-3-(1-ethylpiperidin-4-yl)-1-oxo-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide;
N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide;
N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-({(2S)-1-oxo-3-(piperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-2′-oxo-1′,2′-dihydro-1H-spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazine]-1-carboxamide;
N-[(2R)-1-({(2S)-3-{1-[2-(dimethylamino)ethyl]piperidin-4-yl}-1-oxo-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide; and
3-(4-{(2S)-2-{[(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b]pyridin-1-yl)piperidin-1-yl]carbonyl}amino)propanoyl]amino}-3-oxo-3-[4-(pyridin-4-yl)piperazin-1-yl]propyl}piperidin-1-yl)-3-oxopropanoic acid, ammonium salt;
or a salt thereof.
9. The compound according to claim 8 , wherein the compound is:
or a salt thereof.
10. A method of synthesis of the compound according to claim 1 comprising any one of the following procedures: