Octahydro-pyrrolo[3,4-b]pyrrole derivatives
View Patent ↗Octahydro-pyrrolo[3,4-b]pyrrole derivatives are useful in treating conditions or disorders prevented by or ameliorated by histamine-3 receptor ligands, Octahydro-pyrrolo[3,4-b]pyrrole compounds, methods for using such compounds, compositions for making them, and processes for preparing such compounds are disclosed herein.
1. A compound of the formula:
or a pharmaceutically acceptable salt, ester, amide, or radiolabelled form thereof, wherein:
R 1 is alkyl, C 3 -C 5 cycloalkyl, or (C 3 -C 5 cycloalkyl)methyl;
R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f each are independently hydrogen, methyl, or fluoromethyl;
R 3a , R 3b , R 3c , and R 3d are each independently hydrogen, alkyl, fluoroalkyl, fluoroalkoxy, alkoxy, thioalkoxy, halogen, or nitrile, with the proviso that when one or more of R 3a , R 3b , R 3c , and R 3d are alkyl, then at least one of R 3a , R 3b , R 3c , and R 3d is fluoroalkyl, fluoroalkoxy, alkoxy, thioalkoxy, halogen, or nitrile;
L 1 is a bond, oxygen, sulfur, carbonyl, alkylene, alkylcarbonyl, alkylamino, —C(═N—Oalkyl)-, or NR 4 ,
L 2 is a bond, oxygen, sulfur, carbonyl, alkylene, alkylcarbonyl, alkylamino, —C(═N—Oalkyl)-, NR 5 , —C(═O)NR 5 —, or —NR 5 C(═O)—,
Cy 1 is aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocycle;
Cy 2 is aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocycle, wherein the heteroaryl or heterocycle moiety has 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur, provided that at least one heteroatom is nitrogen; and
R 4 and R 5 at each occurrence is hydrogen or alkyl;
provided that Cy 2 is not
2. The compound of claim 1 , wherein L 1 is a bond.
3. The compound of claim 1 , wherein L 2 is a bond.
4. The compound of claim 1 , wherein L 1 and L 2 each are a bond.
5. The compound of claim 1 , wherein R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f all are hydrogen.
6. The compound of claim 1 , wherein at least two of R 3a , R 3b , R 3c , or R 3d are a substituent other than hydrogen.
7. The compound of claim 1 , wherein R 3a , R 3b , R 3c , and R 3d are all hydrogen.
8. The compound of claim 1 , wherein L 1 is a bond; L 2 is a bond; R 3a , R 3b , R 3c , and R 3d are all hydrogen; Cy 1 is phenyl, and Cy 2 is aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocycle, wherein the heteroaryl or heterocycle moiety has 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur, provided that at least one heteroatom is nitrogen.
9. The compound of claim 8 , wherein Cy 2 is pyridazinone.
10. The compound of claim 1 , wherein R 1 is alkyl; L 1 is a bond; L 2 is a bond; R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f each is hydrogen; R 3a , R 3b , R 3c , and R 3d are all hydrogen; Cy 1 is phenyl, and Cy 2 pyridazinone.
11. The compound of claim 10 , wherein R 1 is methyl.
12. The compound of claim 1 , wherein L 1 is a bond; L 2 is a bond; R 3a , R 3b , R 3c , and R 3d are all hydrogen; Cy 1 is piperazine, and Cy 2 is aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocycle, wherein the heteroaryl or heterocycle moiety has 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur, provided that at least one heteroatom is nitrogen.
13. The compound of claim 12 , wherein Cy 2 is pyridine optionally substituted with cyano.
14. The compound of claim 1 , selected from the group consisting of:
2-{4′-[(3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]-1,1′-biphenyl-4-yl}pyridazin-3(2H)-one;
(3aR,6aR)-5-methyl-1-(4′-pyrimidin-5-yl-1,1′-biphenyl-4-yl)octahydropyrrolo[3,4-b]pyrrole;
4″-[(3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]-1,1′:4′,1″-terphenyl-3-carbonitrile;
(3aR,6aR)-1-[4′-(6-fluoropyridin-3-yl)-1,1′-biphenyl-4-yl]-5-methyloctahydropyrrolo[3,4-b]pyrrole;
(3aR,6aR)-1-[4′-(2,6-dimethylpyridin-3-yl)-1,1′-biphenyl-4-yl]-5-methyloctahydropyrrolo[3,4-b]pyrrole;
(3aR,6aR)-1-[4′-(6-chloropyridin-3-yl)-1,1-biphenyl-4-yl]-5-methyloctahydropyrrolo[3,4-b]pyrrole;
4″-[(3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]-1,1′:4′,1″-terphenyl-4-carbonitrile;
6-(4-{4-[(3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]phenyl}piperazin-1-yl)nicotinonitrile;
(3aR,6aR)-1-{4-[4-(6-chloropyridazin-3-yl)piperazin-1-yl]phenyl}-5-methyloctahydropyrrolo[3,4-b]pyrrole;
(3aR,6aR)-5-methyl-1-{4-[4-(1,3-thiazol-2-yl)piperazin-1-yl]phenyl}octahydropyrrolo[3,4-b]pyrrole;
(3aR,6aR)-5-methyl-1-[4-(4-pyridin-2-ylpiperazin-1-yl)phenyl]octahydropyrrolo[3,4-b]pyrrole;
(3aR,6aR)-5-methyl-1-{4-[4-(4-nitrophenyl)piperazin-1-yl]phenyl}octahydropyrrolo[3,4-b]pyrrole;
2-(4-{4-[(3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]phenyl}piperazin-1-yl)benzonitrile;
(3aR,6aR)-5-methyl-1-[4-(4-pyridin-4-ylpiperazin-1-yl)phenyl]octahydropyrrolo[3,4-b]pyrrole;
(3aR,6aR)-5-methyl-1-{4-[4-(6-methylpyridazin-3-yl)piperazin-1-yl]phenyl}octahydropyrrolo[3,4-b]pyrrole;
(3aR,6aR)-5-methyl-1-[4-(4-pyrazin-2-ylpiperazin-1-yl)phenyl]octahydropyrrolo[3,4-b]pyrrole;
(3aR,6aR)-5-methyl-1-[4-(4-pyrimidin-2-ylpiperazin-1-yl)phenyl]octahydropyrrolo[3,4-b]pyrrole;
4-(4-{4-[(3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]phenyl}piperazin-1-yl)benzonitrile;
(3aR,6aR)-1-{4-[4-(5-ethylpyrimidin-2-yl)piperazin-1-yl]phenyl}-5-methyloctahydropyrrolo[3,4-b]pyrrole;
(3aR,6aR)-5-methyl-1-[4-(4-pyrimidin-5-ylpiperazin-1-yl)phenyl]octahydropyrrolo[3,4-b]pyrrole;
(3aR,6aR)-2-{4-[4-(5-methyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-phenyl]-piperazin-1-yl}-nicotinonitrile;
4′-{4-[(3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]phenoxy}-1,1′-biphenyl-4-carbonitrile;
2-(5-{4-[(3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]phenyl}pyridin-2-yl)pyridazin-3(2H)-one;
2-(6-{4-[(3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]phenyl}pyridin-3-yl)pyridazin-3(2H)-one;
2-(5-{4-[(3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]phenyl}-1,3-thiazol-2-yl)pyridazin-3(2H)-one;
5-(4-{4-[(3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]phenyl}piperazin-1-yl)pyridine-2-carbonitrile;
(3aR,6aR)-1-[4′-(2-methoxypyrimidin-5-yl)-1,1′-biphenyl-4-yl]-5-methyloctahydropyrrolo[3,4-b]pyrrole;
5-{4′-[(3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]-1,1′-biphenyl-4-yl}pyridine-2-carbonitrile;
6-methyl-2-{4′-[(3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]-1,1′-biphenyl-4-yl}pyridazin-3(2H)-one;
(3aR,6aR)-5-methyl-1-[4′-(1-methyl-1H-pyrazol-4-yl)-1,1′-biphenyl-4-yl]octahydropyrrolo[3,4-b]pyrrole;
(3aR,6aR)-1-[4′-(3,5-dimethyl-1H-pyrazol-4-yl)-1,1′-biphenyl-4-yl]-5-methyloctahydropyrrolo[3,4-b]pyrrole;
(3aR,6aR)-5-methyl-1-[4′-(1H-pyrazol-4-yl)-1,1′-biphenyl-4-yl]octahydropyrrolo[3,4-b]pyrrole;
3-methyl-1-{4′-[(3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]-1,1′-biphenyl-4-yl}pyridin-2(1H)-one;
5-methyl-1-{4′-[(3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]-1,1′-biphenyl-4-yl}pyridin-2(1H)-one;
6-methyl-1-{4′-[(3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]-1,1′-biphenyl-4-yl}pyridin-2(1H)-one;
2-{4′-[(3aR,6aR)-5-ethylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]-1,1′-biphenyl-4-yl}pyridazin-3(2H)-one;
2-{4′-[(3aR,6aR)-5-cyclobutylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]-1,1′-biphenyl-4-yl}pyridazin-3(2H)-one; and
2-{4′-[(3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]biphenyl-4-yl}-4,5-dihydropyridazin-3(2H)-one.
15. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
16. A compound that is 2-{4′[(3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]-1,1′-biphenyl-4-yl}pyridazin-3(2H)-one or a pharmaceutically acceptable salt thereof.
17. A compound that is 2-(5-{4-[(3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]phenyl}pyridin-2-yl)pyridazin-3(2H)-one or a pharmaceutically acceptable salt thereof.
18. A compound that is 2-(6-{4-[(3aR6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]phenyl}pyridin-3-yl)pyridazin-3(2H)-one or a pharmaceutically acceptable salt thereof.