Provided are D 2 or D 3 antagonist compounds and pharmaceutical compositions of formula I and pharmaceutically acceptable salts thereof, or isomers thereof, wherein R 1 , R 2 and R 3 are as defined herein. The invention further comprises methods for making the compounds of the invention and methods for the treatment of conditions mediated by the dopamine D 2 or D 3 receptor from the compounds of the invention.
1. A compound of formula I
or a pharmaceutically acceptable salt thereof, or isomer thereof, wherein
R 1 is chosen from the group consisting of
(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)(C 2 -C 4 alkyl) optionally substituted at the 3 position with cyclopropyl or at the 6 position with chlorine,
(2-oxobenzo[d]oxazol-3(2H)-yl)(C 2 -C 4 alkyl),
(2-oxobenzo[d]thiazol-3(2H)-yl)(C 2 -C 4 alkyl),
(1H-benzo[d][1,2,3]triazol-1-yl)(C 2 -C 4 alkyl),
2,3-dihydrobenzo[b][1,4]dioxine-2-(C 2 -C 4 alkyl),
3-oxo-2H-benzo[b][1,4]oxazin-4-yl))(C 2 -C 4 alkyl),
(2-(cycloalkyl)-1H-benzo[d]imidazol-1-yl)(C 2 -C 4 alkyl),
((3-((C 1 -C 6 alkyl)carbonyloxy(methyl))-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl))(C 2 -C 4 alkyl),
((3-(methoxycarbonylethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl))(C 2 -C 4 alkyl),
((2-(t-butoxycarbonyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl))(C 2 -C 4 alkyl), or
1H-indazol-3-yl(C 2 -C 4 alkyl),
R 2 is phenyl optionally para-substituted with chloro, fluoro or methoxy, or R 2 is cycloalkyl of three to seven carbon atoms optionally substituted with one to six halogens;
R 3 is
wherein n is 3-5,
and
R 10 is H or alkyl of one to six carbons.
2. The compound of claim 1 , wherein R 3 is represented by formula A, C, D, or F and R 10 is H.
3. The compound of claim 2 , wherein R 3 is represented by formula A or D.
4. The compound of claim 1 , wherein R 2 is phenyl or cyclohexyl.
5. The compound of claim 4 , wherein R 2 is cyclohexyl.
6. The compound of claim 4 , wherein R 2 is phenyl.
7. The compound of claim 1 , wherein
R 2 is phenyl or cyclohexyl; and
R 3 is represented by formula A, C, D, or F and R 10 is H.
8. The compound of claim 7 , wherein R 2 is cyclohexyl.
9. The compound of claim 8 , wherein R 3 is represented by formula A.
10. A compound chosen from the group consisting of
3((4-Oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid
(R)-2-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetic acid
(S)-2-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetic acid
3-((1-(4-Fluorophenyl)-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid
3-((l-cyclohexyl-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid, formate
3-((4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid, hydrochloride
3-((4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid, hydrochloride salt
3-((1-(4-Fluorophenyl)-4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid
3-((1-(4-Fluorophenyl)-4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid
2((4-Oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid
2((4-Oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid
2-((1-(4-Fluorophenyl)-4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid
2-((1-(4-Fluorophenyl)-4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid
2-((8-(3-(3-Fluoro-3-methyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid
11. A composition comprising a compound of claim 1 and at least one pharmaceutically acceptable excipient.
12. The compound of claim 1 , wherein the pharmaceutically acceptable salt is a maleic acid salt.
13. A composition comprising a compound of claim 10 and at least one pharmaceutically acceptable excipient.